1236 seccin III Oncologa de Radiacin clnica parte G Gastrointestinal

Factores de tratamiento Estos ensayos se describen aqu y en la Tabla 62.4. 41,71-78 Las referencias originales
se deben consultar para ms detalles de la elegibilidad del paciente, los regmenes
La respuesta temprana, y el grado de respuesta, a la quimiorradioterapia se correlacionaron
de tratamiento, los resultados y anlisis estadsticos. Tambin se han producido ms
con la supervivencia en varios anlisis multivariantes. 54,69,70 Una asociacin con la dosis total
de 100 estudios no aleatorios, muchas de las cuales proporcionados posteriormente
de radiacin o con la duracin del tratamiento, mientras que se esperaba, no se ha
hiptesis ensayada en los estudios aleatorios, o la informacin que ha guiado el
demostrado de forma consistente, ya sea para control locorregional o la supervivencia. Un
desarrollo de los aspectos tcnicos del tratamiento de radiacin. 79
tamao de la fraccin diaria de 2,5 Gy parece estar asociado con aumento de la toxicidad
aguda y tarda, en comparacin con 2-Gy fracciones. 39

Es de sealar que la combinacin de RT y la quimioterapia ha suplantado a la

TRATAMIENTO DE CNCER ANAL
Aunque el cncer de clulas escamosas del conducto anal es una neoplasia
relativamente poco comn, varios ensayos multicntricos aleatorizados han
completado con xito. Estos han establecido RT, 5-FU, y MMC, reservando la ciruga
para el fracaso, como el estndar contra el cual deben compararse a otros
tratamientos.
ciruga como el tratamiento preferido para el canal anal cncer de clulas escamosas
y sin comparacin formal en un ensayo aleatorio. comparaciones no aleatorizadas de
reseccin radical con esta combinacin de RT, 5-FU, y MMC 32 o con radioterapia sola 80
han demostrado la capacidad de los regmenes basados en radiacin para producir
tasas de supervivencia al menos iguales a las de series quirrgicas, mientras que
permite la conservacin de la funcin anorrectal en la mayora de los pacientes.

TABLA 62.4 Los resultados seleccionados de la fase III ENSAYOS

Local (LF) o Colostoma Rate (CR) o

locorregional (FLR) colostoma supervivencia libre Supervivencia libre

Ensayo (Referencia) norte Tratamiento fallo (%) (CSA) (%) de enfermedad (%) Sobrevivencia promedio (%)

3-yr LRF 3-yr CR 3 aos 3 aos

UKCCCR (ACT I) (41) 292 RT, 5-FU, MMC 39 24 notario pblico sesenta y cinco

285 RT 61 40 notario pblico 58

RR 0.54 notario pblico notario pblico 0.86
PAG <. 0001 notario pblico notario pblico . 25

De 10 aos LRF De 10 aos SFC 10 aos 10 aos

Actualizacin (71) 292 RT, 5-FU, MMC 34 36 36 42

285 RT 59 26 24 36
HORA 0.46 notario pblico 0.70 0.86
PAG <. 001 sig <. 001 . 12

5 aos LRF 5 aos SFC 5 aos 5 aos

EORTC (72) 51 RT, 5-FU, MMC 32 un 72 un notario pblico 58 un

52 RT 48 un 40 un notario pblico 53 un

PAG . 02 . 002 notario pblico . 17

LF 4 aos 4 aos CR 4 aos 4 aos

RTOG 8704 / ECOG 1289 (73) 146 RT, 5-FU, MMC diecisis 9 73 76
145 RT, 5-FU 34 22 51 67
PAG . 0008 . 002 . 0003 . 31

5 aos LRF 3-yr CR 3 aos 3 aos

RTOG 9811 (74) 324 RT, 5-FU, MMC 25 10 60 75

320 RT, 5-FU, CDDP 33 19 54 70
HORA 1.32 1.68 1.20 1.28
PAG . 07 . 02 . 17 . 10

5 aos LRF 5 aos CR 5 aos 5 aos

Actualizacin (75) 325 RT, 5-FU, MMC 20 12 68 78

324 RT, 5-FU, CDDP 27 17 58 71
PAG . 089 . 075 . 004 . 021

3 aos 3-yr CR 3 aos segundo 3 aos segundo

UKCR (ACT II) (76) 471 RT, 5-FU, MMC notario pblico 14 notario pblico notario pblico

469 RT, 5-FU, CDDP notario pblico 11 notario pblico notario pblico

446 No la quimioterapia de mantenimiento notario pblico notario pblico 75 85

448 quimioterapia de mantenimiento notario pblico notario pblico 75 84
HORA notario pblico 11 0.89 0.79
PAG . 26 . 42 . 19

De 3 aos libre de eventos

LF de 3 aos 3-yr CFS Supervivencia 3 aos

ACCORD-03 (77,78) 307 totales Std RT, 5-FU, CDDP 10 86 67 notario pblico

HD RT, 5-FU, CDDP 13 80 68 notario pblico

Ind CT + Std RTQT 20 83 70 notario pblico

Ind CT + HD RTQT 4 85 78 notario pblico

Ind brazos CT notario pblico 84 vs 83

brazos HD RTQT notario pblico 84 vs 83
PAG no sig no sig no sig no sig

UKCCCR, Reino Unido Comit de Coordinacin para la Investigacin del Cncer; EORTC, Organizacin Europea para la Investigacin sobre el Tratamiento del Cncer; RTOG, Radiation Therapy Oncology Group; ECOG,
Eastern Cooperative Oncology Group; np, no publicado; sig, significativa; No sig, no significativo; RT, la terapia de radiacin; 5-FU, 5-fluorouracilo; MMC, mitomicina C; CDDP, cisplatino; Std, estndar; HD RT, radiacin de alta
dosis; Ind CT, la quimioterapia de induccin; RTQT, quimiorradioterapia.
un Nmeros derivados de curvas. segundo En los pacientes que recibieron quimioterapia de mantenimiento.

booksmedicos.org

Radiacin combinada y la
quimioterapia
Radiacin, 5-fluorouracilo, y mitomicina-C Versus
radiacin sola
Tanto en el Reino Unido y Europa en la dcada de 1970, ms que en Amrica del
Norte, ya exista cierta aceptacin de la RT como el tratamiento primario para el
cncer anal 81; Esto facilit el desarrollo de los primeros ensayos aleatorios
multi-institucionales en los que la RT sola se compar con RT ms quimioterapia. Los
ensayos aleatorios realizados por el Comit de Coordinacin del Reino Unido para la
Investigacin del Cncer (UKCCCR) 41 y la Organizacin Europea para la Investigacin
sobre el Tratamiento del Cncer (EORTC) 72
tanto demostrado una mejora significativa en el control del cncer primario y los
ganglios regionales y en la tasa de colostoma o la supervivencia libre de colostoma en
los pacientes que recibieron RT, 5-FU, y
MMC. tasas de supervivencia global no se mejoraron significativamente en los informes
iniciales. Sin embargo, en un informe posterior del juicio UKCCCR despus de una mediana de
13 aos de seguimiento, el control locorregional, la supervivencia libre de colostoma, la
supervivencia libre de enfermedad y muertes debidas a cncer anal toda signi fi cativamente
favoreci la quimiorradioterapia. 71 La diferencia absoluta en el riesgo de muerte por todas las
causas fue del 5,1% menor en el grupo de quimiorradioterapia a los 5 aos y un 5,6% inferior a
los 12 aos a partir de la aleatorizacin. Esta diferencia se acerc significacin estadstica (HR
0,86; 95% intervalo de confianza [IC],
0,70-1,04; P = . 12). 71
El ensayo UKCCCR incluy 577 pacientes con todas las etapas (sistema de
estadificacin UICC, 1987 edicin) de cncer de clulas escamosas del conducto anal
(75% de los pacientes) o el margen anal (23%). 41 La dosis de radiacin fue de 45 Gy en
20 a 25 fracciones en 4 a 5 semanas. Aquellos asignados al azar a quimioterapia
recibieron 5-FU (1000 mg / m 2 / da durante 4 das o 750 mg / m 2 / da durante 5 das) por
infusin continua intravenosa perifrica en la primera y la semana fi nales de tratamiento
de radiacin, adems de MMC (12 mg / m 2) por inyeccin intravenosa de bolo en el da 1
del curso primera de la quimioterapia. Si el tumor primario no se haba retrocedido por al
menos 50% en 6 semanas despus del tratamiento (como ocurri en 10% en cada
grupo), se recomienda la ciruga; de lo contrario, los pacientes recibieron un 15 Gy
adicional en 6 fracciones por un campo perineal o 25 Gy durante 2 a 3 das por implante
de iridio-192. Las tasas de recurrencia locorregional a los 3 aos eran 61% despus de
RT y 39% despus de RT, 5-FU, y MMC ( P <. 0001). Las tasas de supervivencia global
a los 3 aos fueron del 58% y el 65% ( P = . 25), respectivamente. Haba seis (2%)
muertes debido a tratamiento en el brazo de modalidad combinada y dos (0,7%) en el
brazo de irradiacin sola. Toxicidad aguda, que no sea hematolgica, se consider
comparable en cada grupo. En la primera pocos aos despus del tratamiento, la
ciruga que incluye colostoma era necesaria para la gestin de la toxicidad en 10
pacientes (3,5%) en cada grupo. 41 eventos toxicidad tarda (gravedad no se clasific)
despus de una mediana de 13 aos de seguimiento fueron similares en cada grupo de
tratamiento. 71
En el estudio EORTC, 103 pacientes con cnceres avanzados del canal anal se
asignaron al azar en un ensayo de diseo similar. 72
La dosis de radiacin fue de 45 Gy en 25 fracciones durante 5 semanas. La
quimioterapia incluye 5-FU (750 mg / m 2 / da durante 5 das) en las semanas 1 y 5 de la
radiacin, y una dosis nica de MMC (15 mg / m 2) por inyeccin intravenosa de bolo en el
da 1 del primer curso fi de slo el 5-FU. Despus de 6 semanas, aumentar la irradiacin
de 15 Gy (si se haba producido la respuesta clnica completa al tratamiento anterior) o
20 Gy (despus de la respuesta parcial) fue dada por haz externo o irradiacin
intersticial. La tasa de recurrencia locorregional 5 aos fue del 48% despus de RT y
32% despus de RT, 5-FU, y MMC ( P = . 02). La diferencia entre las tasas de
supervivencia global (53% y 58%, respectivamente) no fue significativa. Uno de 51
pacientes que recibieron tratamiento de modalidad combinada murieron de toxicidad. De
lo contrario, las tasas de toxicidad aguda y tarda no difirieron notablemente. Estos dos
ensayos establecieron RT, 5-FU, y MMC como el tratamiento de primera lnea estndar.
booksmedicos.org
captulo 62 El cncer anal 1237
Radiacin, 5-fluorouracilo y mitomicina-CVersus
radiacin y 5-fluorouracilo
El Cooperative Oncology Group RTOG y Este (ECOG) establecida en un ensayo
aleatorio que la combinacin de MMC con 5-FU y RT es ms eficaz que el 5-FU solo
con RT. 73
Este estudio se realiz para determinar si MMC era un componente necesario del
protocolo y si la toxicidad hematolgica de esa droga podra evitarse. Doscientos
noventa y un pacientes con cnceres del canal anal de cualquier categora T y N
(sistema de estadificacin RTOG) que no tiene evidencia de metstasis extraplvicos
recibi 45 Gy a 50,4 Gy en 25 a 28 fracciones durante 5 semanas, ms 2 cursos de
5-FU (1000 mg / m 2 / da por infusin intravenosa perifrica continua) ms de 4 das,
con o sin MMC (10 mg / m 2 por inyeccin intravenosa en bolo) en el primer da de
cada ciclo de quimioterapia. La quimioterapia se administra en las semanas 1 y 5 de
la terapia de radiacin. Todos los pacientes fueron sometidos a biopsia del sitio del
tumor primario 6 semanas despus del tratamiento. Las biopsias fueron positivas en
el 15% de los que recibieron 5-FU y en el 8% de los que recibieron la MMC y con
5-FU ( = P. 14). Los pacientes con biopsias positivas tenan la opcin de recibir un 9
Gy adicional en 5 tratamientos simultneamente con una infusin de 4-da de 5-FU
Clinical Radiation Oncology
(1000 mg / m 2 /
da) y una nica inyeccin de cisplatino (CDDP) (100 mg / m 2) Si se pensaba que la
funcin anal todava puede ser salvado. A los 4 aos, las tasas de fracaso local (16%
vs. 34%; P = . 0008) y de colostoma (9% vs. 22%; P = . 002), de forma significativa
favoreci el tratamiento con radiacin, 5-FU, y MMC. No hubo diferencia significativa
en las tasas de supervivencia global (76% con RT, 5-FU, y MMC vs. 67%); sin
embargo, la tasa de supervivencia libre de enfermedad (73% vs. 51%; P = . 0003) se
mejor por la combinacin de tres agente. toxicidad hematolgica aguda fue ms
comn en los pacientes que recibieron MMC, pero las tasas de otros efectos txicos
agudos y tardos fueron similares en cada grupo de tratamiento. Cuatro de 146
(2,7%) pacientes que recibieron tanto 5-FU y MMC sufrieron toxicidad fatal como lo
hizo 1 de 145 tratados con RT y 5-FU solo. En la prueba de este ensayo, MMC se
retuvo en combinacin con RT y 5-FU.
Radiacin, 5-fluorouracilo y mitomicina-C Versus
radiacin, 5-fluorouracilo y cisplatino
Varios estudios piloto sugieren tasas de respuesta alta tumorales a concurrente, de
induccin, o la induccin ms concurrente 5-FU y CDDP con RT. 82-88 El cisplatino se
sabe que es eficaz contra los cnceres de clulas escamosas en varios otros sitios y
que se asocia con evidencia de laboratorio ms fuerte como un radiosensibilizador de
MMC.
El RTOG elegido para evaluar una estrategia de quimioterapia de induccin a
base de CDDP la intencin de reducir el tamao del tumor primario y la metstasis
nodales antes de quimiorradiacin concurrente. Este ensayo incluy una mayor dosis
de radiacin total que el ensayo aleatorizado RTOG anterior, 73 basado en el anlisis de
los estudios no aleatorizados que sugeran una relacin de control de dosis de
radiacin, 89,90 y en estudios piloto que se haba demostrado que una proporcin de
pacientes poda tolerar horarios de radiacin ininterrumpidos de hasta 59,4 Gy ms de
6,5 semanas, ya sea con MMC concurrente con 5-FU 91,92 o CDDP con 5-FU. 83
En RTOG-9811, 74 un grupo de pacientes recibi 59 Gy en 6,5 semanas (45 Gy en
1,8-Gy fracciones, seguido sin interrupcin por 14 Gy en 2-Gy fracciones), junto con
concurrente 5-FU (1000 mg / m 2 / da) por infusin continua en los das 1 a 4 y 29 a 32,
ms MMC 10 mg / m 2 bolo intravenoso en los das 1 y 29; el otro grupo recibi 5-FU
(1000 mg / m 2 / da) los das 1 a
4, 29 a 32, 57 a 60, y 85 a 88, ms CDDP (75 mg / m 2 inyeccin de bolo en los das 1,
29, 57, y 85) con el mismo programa de radiacin 59 Gy (iniciar da 57). aguda grado
3 o 4 nonhema tasas de toxicidad tologic eran 75% en cada brazo, pero la toxicidad
hematolgica fue mayor en el grupo de MMC (67% vs. 47%). No se reportaron
muertes treatmentrelated. La tasa de severa a largo plazo
1238 seccin III Oncologa de Radiacin clnica parte G Gastrointestinal
toxicidad fue similar en cada grupo (11% vs. 10% MMC CDDP). El primer informe de este ensayo
(despus de la mediana seguimiento de los pacientes de
2.5 aos) describieron una significativamente mayor tasa de colostoma a los 3 aos
en los que recibieron CDDP en lugar de MMC plus 5-FU y TA. No hubo diferencias
significativas en libre de enfermedad o tasas de supervivencia global.
Despus de seguimiento ms largo, las tasas de colostoma de 5 aos y las tasas de
fracaso locorregional mostraron tendencias a favor de 5-FU, MMC-y RT, pero no fueron
significativos. Sin embargo, la libre de enfermedad (68% vs. 58% a los 5 aos; P = . 004) y en
general las tasas de supervivencia (78% frente a 71%; P = . 021) de manera significativa a favor
de RT, 5-FU, y
MMC. 75 Los investigadores concluyeron que la RT, 5-FU, y MMC deben seguir siendo
el enfoque estndar.
El segundo UK cncer anal de prueba (ACT II) tambin tiene no identi fi c un papel
para CDDP, adems de o en lugar de MMC. Este ensayo ha sido descrito hasta ahora
slo en abstracto. 76 El ensayo incorpora un doble asignacin al azar, ya sea para 5-FU y
MMC o para 5-FU y CDDP simultneamente con RT; y a 2 ciclos de adyuvante (o
mantenimiento) 5-FU y CDDP o a ninguna quimioterapia adicional despus de
quimiorradiacin concurrente. Los puntos finales primarios fueron mejoras en las tasas
de respuesta completa del tumor y las tasas de supervivencia libre de enfermedad. las
tasas de respuesta completa del tumor a los 6 meses fueron similares: 94% (brazo MMC)
y 95% (brazo CDDP). las tasas de supervivencia de tres aos libre de enfermedad y no
se mejoraron en aquellos que recibieron adyuvante con 5-FU y CDDP. pacientes MMC
tratados tuvieron toxicidad hematolgica ms grave, pero las tasas de sepsis
neutropnica fueron similares (aproximadamente 3%).
A intergrupo francs realiz un ensayo fourarm factorial diseado (ACCORD 03)
que evalu la adicin de induccin 5-FU y CDDP y de una dosis mayor de impulso
RT (20 Gy a 25 Gy vs. estndar de 15 Gy). El horario RT estndar basal fue de 45 Gy
en 25 fracciones en 5 semanas. El resultado ha sido reportado slo en abstracto. 77 , 78 La
tasa de supervivencia colostomyfree 3-aos actuarial (el estudio principal punto final)
vari de 80% a 85% en los cuatro brazos, con no hay ventajas significativas, ya sea
para el tratamiento experimental. El control local, la supervivencia libre de eventos, y
las tasas de supervivencia global fue similar en cada brazo.
Otras Drogas radiacin Combinaciones
En un esfuerzo para desarrollar un calendario simplificada, el Reino Unido Instituto
Nacional de Investigacin del Cncer Anal Subgrupo llev a cabo un ensayo de fase II
de RT (50,4 Gy en 28 fracciones en 5,5 semanas), de una sola inyeccin intravenosa de
MMC (12 mg / m 2 en el da 1) y capecitabina oral (825 mg / m 2 dos veces al da en cada
da de tratamiento RT). 93 El calendario fue descrito como bien tolerada con cumplimiento
aceptable (aunque slo el 58% recibi las dosis planificadas completas). La tasa global
de respuesta del tumor despus del tratamiento fue del 90% (completa en 24 de 31 y
parcial en 4 de 31). Aunque este uso de capecitabina oral es prometedor y elimina la
necesidad de infusiones intravenosas continuas de 5-FU, en este momento, la entrega
de tanto 5-FU y MMC va intravenosa sigue siendo estndar.
La EORTC llev a cabo un ensayo aleatorizado de fase II en la que RT (36 Gy +
espacio de 2 semanas + 23,4 Gy) se combin con cualquiera de MMC y 5-FU o MMC
y CDDP. Las tasas globales de respuesta a las 8 semanas fueron del 92% (34 de 37)
a RT, MMC, y CDDP frente a 80% (31 de 39) a RT, 5-FU, y MMC, aunque un mayor
cumplimiento con el rgimen completo fue visto con RT, 5-FU, y MMC. 94 No se sabe si
este grupo ha procedido a un ensayo de fase III planificada. 95
Debido a que el receptor del factor de crecimiento epidrmico (EGFR) es conocido
que se sobreexpresa en muchos cnceres epiteliales, incluyendo el cncer de clulas
escamosas del conducto anal, 96 Se estn evaluando bloqueadores EGFR. El ECOG
est llevando a cabo un estudio de fase II de RT, 5-FU, CDDP, y cetuximab en
pacientes VIH negativos. 95 El Clinical Trials Consortium SIDA Malignidad est
realizando un estudio similar en pacientes VIH positivos. 95 Otros agentes anti-EGFR en
estudio incluyen Nimotuzumab y panitumumab. 95
Los estudios iniciales de laboratorio sugieren que el EGFR y K-RAS anlisis de la mutacin no es
probable que sea til como una prueba de deteccin para la sensibilidad a la terapia anti-EGFR
en cncer del canal anal. 96
booksmedicos.org
En Suecia, la bleomicina se le dio forma concurrente con RT en estudios no
aleatorios, pero no beneficio era evidente. 97-98, 99 Un estudio piloto en el Reino Unido en
el que los tres de los principales frmacos investigados, 5FU, MMC, y CDDP, se
combinaron con RT que no se prosigui debido a la toxicidad excesiva. 100
Conclusin
Queda mucho por aprender acerca de los mecanismos de interaccin entre la radiacin y
la quimioterapia en el tratamiento del cncer. Las interacciones sinrgicas de varias
combinaciones de RT, 5-FU, MMC-y CDDP observado en algunos estudios de laboratorio
son difciles de evaluar clnicamente, y no se han realizado ensayos diseados para
estudiar dichas interacciones. Adems, no ha habido comparaciones formales de ms
prolongada, pero intensa de dosis menos diarias, infusiones de 5-FU con las de 96 horas
a 120 horas infusiones generalmente favorecidas, ni de inyecciones en bolo con
infusiones continuas de 5-FU o CDDP . En la mayora de serie, el momento de
administracin de quimioterapia cada da con respecto a la irradiacin no estaba
estrechamente controlada, y la importancia de la programacin no se conoce.
La combinacin quimiorradiacin estndar actual es RT con dos 96 horas o 120
horas infusiones intravenosas continuas concurrentes de 5-FU y una o dos
inyecciones de bolo MMC. No se han establecido las dosis ms eficaces. Cuando los
pacientes deben ser manejados fuera de un ensayo clnico, se sugiere que un horario
utilizado en uno de los ensayos aleatorios, para los que existen datos sobre la e fi
cacia y la toxicidad, se adoptar.
TERAPIA DE RADIACIN
El uso de RT sola, ya sea braquiterapia o haz externo, se ha reducido en gran medida ya
que la confirmacin de la mejora de resultados de la terapia de modalidad combinada.
La radioterapia sola ahora se recomienda principalmente a pacientes que no pueden
someterse a RT ms quimioterapia, o para el tratamiento de los cnceres ms pequeos
hasta alrededor de 3 a 4 cm de tamao, donde el mdico no desea aadir la
quimioterapia. Al igual que con combinada RT y la quimioterapia, el control del tumor
primario es mejor con tumores pequeos. Los resultados seleccionados, principalmente
del perodo anterior a la adopcin de quimiorradiacin, se muestran en la Tabla 62.5.
CIRUGA
Para residual y el cncer recurrente
biopsias aleatorias desde el sitio del tumor primario o ganglios anormales, poco despus
de la quimiorradioterapia han sido defendida por algunos, pero no son necesarios.
biopsias electivos en momentos predeterminados no parecen conducir a mejores
resultados que se puede lograr mediante biopsias dirigidas nicamente a las zonas
sospechosas de albergar clnicamente cncer residual o recurrente. Una biopsia negativa
no excluye la posibilidad de que el nuevo crecimiento del cncer. 105106
masas residuales en el sitio del cncer anal originales pueden tardar varios meses en
resolverse por completo despus de la quimiorradioterapia o RT sola. 39 , 106 La mayora de los
autores recomiendan ahora biopsia slo cuando existe sospecha clnica de cncer persistente.
Sospecha de cncer residual o recurrente en el sitio primario o en nodos regionales deben
ser confirmada histolgicamente si es posible. Se recomienda imgenes nueva puesta en
escena completa. exploraciones PET-FDG pueden revelar cncer fi ed de lo contrario no
identificado. 107 por lo general se requiere la reseccin abdominoperineal o reseccin plvica
multivisceral. Las tasas de supervivencia son pobres cuando no se puede lograr una reseccin
R0. 108, 109 recurrencia locorregional es comn, a pesar de manifiesto la reseccin R0. 108, 110 Las
tasas de supervivencia a cinco aos siguientes gama ciruga de rescate del 30% al 50%, lo
que refleja la diversidad de criterios aplicados cuando la seleccin de pacientes para la ciruga. 108,
109-110, 111
Salvage para metstasis en los ganglios inguinales es por lo general por linfadenectoma
inguinofemoral radical o selectiva. Plvicos metstasis en los ganglios de la pared lateral pueden
no ser resecable debido a la invasin de msculo o hueso o estructuras neurovasculares.

TABLA 62.5 Los resultados seleccionados DE radioterapia sola
Control de Tumor primario T1
Autor (Referencia) Radiacin
Newman et al. (101) 50 Gy / 20/4 sem 8/9
( 2 cm) ( 5 cm)
Cummings et al. (102) 50 Gy / 20/4 sem 6/6
(Algunos EB-I / I) ( 2 cm) ( 5 cm)
Martenson y 45-50 Gy / 25-28 / 5-6 sem Plus 9/9 ( 2 17/17 (100%) ( 5 -
Gunderson (103) impulso a 55-67 Gy cm)
Otim-Oyet et al. (104) 60-65 Gy / 30-33 / 6-7 sem 2/2
(Algunos con impulso) ( 2 cm) ( 4 cm)
Papillon y 42 Gy / 10 / 2,5 sem Plus NS
Montbarbon (80) I 20 Gy en 8 sem
EB, haz externo; I, braquiterapia intersticial; NS: no se ha establecido; temporal, temporal.
Para el cncer de Primaria
La ciruga es el principal tratamiento para la neoplasia intraepitelial anal 112 pero
conserva slo un lugar limitado en el tratamiento inicial de cncer anal invasivo
primario. Unos pocos pacientes (<5% en la mayor parte de la serie) son incontinentes
para heces slidas en la presentacin. Esto es generalmente debido a tumores
extensos que han destruido la competencia de los esfnteres anales o fi stulized en la
vagina. Erradicacin del cncer por RT, con o sin quimioterapia, no restaura la
continencia en tales pacientes, probablemente porque el cncer se sustituye por
tejido fibroso en lugar de msculo especializado de los esfnteres anales. Un enfoque
consiste en realizar colostoma antes de RT preoperatoria y quimioterapia utilizando
dosis de 45 a 50 Gy de ms de 5 semanas, seguido de la reseccin inmediata o
retardada. Una alternativa es la reseccin abdominoperineal inicial con postoperatorio
RT y la quimioterapia. Existen datos insu fi ciente para comparar los resultados de
estos enfoques.
escisin local, la preservacin de la funcin anorrectal, es posible en algunos
pacientes, aunque esto est normalmente restringida a pequeos cnceres de clulas
escamosas bien diferenciados que no han invadido los msculos del esfnter y estn
situados distal a la lnea dentada. 113-115
Este enfoque se basa en el hallazgo en serie quirrgico que pararrectales o metstasis
de ganglios linfticos sistema hemorroidal superior se asociaron con <5% de los cnceres
de clulas escamosas bien diferenciadas <2 cm de tamao. 31 , 34 La escisin local de
pequeos cnceres del canal o perianal piel distal es generalmente ms conveniente y
asociado con una menor morbilidad que los tratamientos basados en la radiacin. Sin
embargo, si los mrgenes de reseccin son positivos escisin local o se considera
inadecuada y, adems, no es posible, el paciente debe recibir quimiorradioterapia o RT
sola. No hay evidencia de que la administracin electiva por escisin del tumor limitado y
protocolos basados en radiacin postoperatoria mejora el control local. 116
El papel de la ciruga en el tratamiento de metstasis en los ganglios inguinales
detectadas en el diagnstico inicial no ha sido bien definida. Aunque las metstasis
nodales son generalmente tratados con xito por las mismas dosis de RT y la
quimioterapia eficaz contra el cncer primario, no hay consenso acerca de si el control
de la regin nodal involucrados se mejora mediante diseccin de los ganglios limitado
antes de la RT y la quimioterapia y de cmo este enfoque afecta a la morbilidad, tales
como fines de edema de las extremidades. 36,38-39 , 40
Despus de la escisin local de metstasis en los ganglios brutos, la dosis a la ingle por lo
general puede ser limitada a 50 a 54 Gy durante 5 a 6 semanas, con la condicin de
formacin de imgenes no muestra metstasis residuales. La combinacin de ciruga local y
RT y la quimioterapia ha resultado en tasas de control regionales en la ingle de 80% o
mejor. 38,39
Sin embargo, las tasas de supervivencia a 5 aos son por lo general - 20% menos que en los que no se
presentan con metstasis en los ganglios inguinales.
extraplvicos metstasis
Las muertes por metstasis extraplvicos solos son relativamente poco frecuentes. metstasis
extraplvico son identi fi ed en aproximadamente 10% a
booksmedicos.org
captulo 62 El cncer anal 1239
Seria
complicaciones-
T2 T3T4 colostoma Supervivencia a 5 aos
42/52 (81%) 13/20 (65%) 2 66%
(> 5 cm o T4)
19/29 (66%) 13/28 (46%) 6 61%
(> 5 cm o T4)
2 temp 94%, actuarial
cm)
16/22 (73%) 8/17 (47%) 1 56%
(> 4 cm) causas especficas
29/39 (74%) ( 4 27/64 (42%) (> 6 60%
cm) 4 cm)
Clinical Radiation Oncology
20% de los pacientes. Entre 77 pacientes en el ensayo UKCCCR ACT I, que muri de
cncer anal despus del tratamiento con RT, 5-FU, y
MMC, 38 de los 77 (49% de las muertes por cncer) tenido cncer en slo la pelvis, y
21 de 77 (27%) tenan slo metstasis extraplvicos. En ese ensayo, la tasa bruta
global de metstasis en los que recibieron RT y quimioterapia fue del 10%, en
comparacin con el 17% de los tratados con RT sola. 41 En el ensayo EORTC, el 17%
de los tratados con RT y quimioterapia desarroll metstasis, al igual que el 21% de los
pacientes tratados slo RT. 72 En RTOG-9811, las tasas de metstasis a distancia a los
5 aos fueron del 13% en aquellos que recibieron RT, 5-FU, y MMC y 18% despus de
la RT, 5-FU, y CDDP. 75 En el
Reino Unido ACT II de prueba, no haba indicacin alguna en el libre de enfermedad a 3
aos y las tasas de supervivencia global de beneficiarse de la adicin de 2 cursos de
adyuvante con 5-FU y CDDP. 76 Las tasas de metstasis en pacientes tratados por
quimiorradiacin son similares a los reportados siguiente gestin del cncer primario y
linfticos regionales por la ciruga o RT solamente. Todava hay considerable
incertidumbre con respecto a los efectos sobre las metstasis subclnicas fuera de la
pelvis de la quimioterapia administrada conjuntamente con RT y tratamiento de induccin
o adyuvante como a corto plazo.
El tiempo medio de supervivencia despus del diagnstico de metstasis
extraplvicos vara de 8 a aproximadamente 24 meses. 55 , 56, 117 Estas metstasis han sido
relativamente resistente hasta el momento para todos quimioterapia, RT, o protocolos
de modalidad combinada. 117 La combinacin ms activo es 5-FU y CDDP, aunque las
respuestas completas duraderas o son poco comunes. Muchos frmacos recientemente
desarrollados y agentes moleculares dirigidas an no han sido evaluadas, pero la
posibilidad de nuevos enfoques se ilustra con los informes preliminares de las
respuestas a cetuximab e irinotecn. 118 La radioterapia sola puede proporcionar
paliacin til, especialmente para las metstasis dolorosas. radioterapia corporal
estereotctica o metastasectoma se pueden ofrecer a los pacientes seleccionados,
pero las metstasis son comnmente mltiple.
TRATAMIENTO DE CNCER PERIANAL
El tipo histolgico ms comn de cncer invasivo de la piel perianal es el carcinoma de
clulas escamosas, por lo general queratinizante. Tambin se pueden producir cnceres de
clulas basales y adenocarcinomas.
Se recomienda la escisin local amplia con un margen de 1-cm para todos los tipos
histolgicos, proporcionado continencia anal puede ser preservada. 115 solo o en
combinacin con quimioterapia La radiacin tambin es eficaz contra los cnceres de
clulas escamosas. 40, 69119 , 120-121, 122-123
protocolos basados en radiacin idnticos a aquellos para el cncer del canal anal se prefieren
cuando la continencia anal se vera afectada por la ciruga. En el ensayo UKCCCR ACT I, uno
de los cuatro pacientes tenan un cncer que surge en la piel perianal (margen anal).
Resultados por sitio de origen del cncer no se informaron, pero el control local y causar
espec tasas de supervivencia fi c favorecidos terapia de modalidad combinada. 41,71 Los
investigadores del Reino Unido tambin incluyen cnceres en perianales
1240 seccin III Oncologa de Radiacin clnica parte G Gastrointestinal
su juicio posterior. 76 En serie a base de institucin, las tasas de control locorregionales
vari de 60% a 90%, las tasas de preservacin del esfnter de 65% a 85%, y la
supervivencia global a los 5 aos del 55% al 80%. 40, 69119 , 120-121, 122-123 La necrosis local fue
visto como una complicacin ms frecuentemente cuando se utiliza la braquiterapia,
aunque en general las tasas de complicaciones graves fueron <5%.
Los nodos regionales para la piel perianal son los ganglios inguinales ipsilaterales.
metstasis en los ganglios perirrectal y plvicos son comunes a menos que el cncer
implica el canal anal ampliamente. El riesgo de metstasis en los ganglios inguinales es
aproximadamente 10%, principalmente, a la categora T3 o T4 tumores o cnceres
pobremente diferenciados. irradiacin nodal inguinal bilateral electiva puede ser
considerada cuando estos tumores ms grandes son tratados, aunque algunos defensor
inguinal electiva RT para todos los cnceres perianales. 123
Los ganglios plvicos inferiores deben ser incluidos si es invadido el canal anal. La
gestin de los ganglios inguinales anormales es similar a la de cncer del canal anal.
Los principios de gestin de la clula basal poco comn y adenocarcinomas de la
piel perianal son similares a los de estos tipos histolgicos en otras partes de la piel.
Pacientes con Human
VIRUS DE LA INMUNODEFICIENCIA / sndrome de
inmunodeficiencia adquirida
El nmero de pacientes infectados por VIH con cncer de clulas escamosas anal estn
aumentando. 23 La edad media al diagnstico es en la cuarta dcada, unos 20 aos antes
que en pacientes no infectados por el VIH. Hay una preponderancia significativa de
pacientes masculinos. 23
pacientes infectados por el VIH no eran elegibles para cualquiera de los ensayos
aleatorios descritos anteriormente. cnceres anal en pacientes infectados por VIH han
sido tratados por terapia de modalidad combinada o RT sola. 62-63, 64 , 124, 125 , 126, 127-128 pacientes
infectados por VIH estn en mayor riesgo de toxicidad, en particular en la piel perineal,
mucosa anorectal, y el sistema hematolgico cuando son tratados con RT con o sin nodos pararrectales y ilaca interna en hasta el 30%, y en los ganglios inguinales en
quimioterapia. No se conocen los mecanismos de este aumento de la toxicidad. 129 informeshasta un 20%, ha alentado la mayora de onclogos de radiacin para irradiar estos
ms recientes indican que no es necesario modificar de forma electiva protocolos
estndar de RT (con respecto a la dosis, fraccionamiento, o volumen) y quimioterapia
(ya sea 5-FU y MMC, o 5-FU y CDDP), pero modificaciones deben basarse de la
gravedad de los efectos secundarios en cada paciente individual. 62.124 Dos factores
pueden predecir la toxicidad aguda elevada tejido normal o pobre control del cncer:
un recuento de CD4
< 200 / L al inicio del tratamiento, o la presencia de SIDA. 63130
Sin embargo, estos hallazgos no estn asociados inevitablemente con escasa tolerancia.
terapia antirretroviral concomitante no reduce de forma fiable la gravedad o la incidencia de la
toxicidad de la RT y la quimioterapia. 30
las tasas de control locorregional de alrededor de 65% o mejor se describieron en
algunas series, similares a los de los pacientes VIH negativos. Sin embargo, algunos
investigadores informaron menores tasas de control local y la preservacin del
esfnter en pacientes VIH positivos, a pesar de la enfermedad anterior etapa y buena
respuesta inicial tumor. 64.128 En un estudio de 40 pacientes VIH-positivos, la tasa de
supervivencia global a los 5 aos fue similar a la de 81 pacientes VIH-negativos, pero
la principal causa de muerte en los pacientes VIH-positivos fue del cncer anal, a
diferencia del VIH-negativas pacientes en los que causas distintas al cncer
predominaba. 64
Los adenocarcinomas
La mayora de los adenocarcinomas que implican el canal anal surgen de tipo rectal mucosa que
se extiende por debajo del lmite musculoso superior del canal. Ellos son generalmente tratados
de manera similar a los que surgen en el recto. Los adenocarcinomas poco comunes que se
desarrollan a partir de las glndulas anales o en fstulas son ms agresivos que los cnceres
escamosos y con frecuencia producen metstasis temprana. 131 Por lo general, se han logrado
mediante la reseccin abdominoperineal. las tasas de supervivencia de cinco aos despus de la
ciruga por s solos son generalmente por debajo del 50%, con tasas de recurrencia local de
alrededor del 25%. 32 , 115131, 132 , 133, 134
booksmedicos.org
Cualquier ventaja de la radiacin y la quimioterapia adyuvante es desconocida, aunque, por
analoga, los protocolos utilizados para los cnceres rectales primarios se aplican a veces.
Unos pocos centros han tratado algunos adenocarcinomas anales por protocolos de
quimiorradiacin desarrollados para los cnceres de clulas escamosas o
adenocarcinomas rectales y han diferido ciruga. La experiencia es limitada, pero la funcin
anorrectal se ha mantenido, y se ha informado de curaciones aparentes, particularmente en
pacientes con cnceres de menor tamao, despus del tratamiento con RT solo o con RT y
la quimioterapia. 131, 132 , 133, 134-135 , 136-137
Carcinomas de clulas SMALL
Los carcinomas de clulas pequeas son cnceres poco frecuentes que se caracterizan por
metstasis temprana y tienen un mal pronstico. 31 El tumor primario puede ser administrado por
ciruga o radiacin. La quimioterapia sistmica similar a la utilizada para los pequeos cnceres de
clulas que surgen en otros lugares puede ser combinado con la radiacin para el tumor primario y
usarse para tratar las metstasis, pero las respuestas son generalmente limitados.
Terapia de Radiacin: TCNICAS Y
DOSIS
El cncer del canal anal
las estrategias de tratamiento de radiacin actuales se han desarrollado mediante una
mejor comprensin de la historia natural del cncer anal y correlacin de los sitios de
fracaso del tratamiento con el plan de tratamiento. 138-140 La mayora de los fracasos fueron
en el sitio del tumor primario, seguido por los grupos de ganglios plvicos regionales y
otras.
Los volmenes de tratamiento de inters son tambin influido por la filosofa
adoptada con respecto a la que grupos de ganglios linfticos deben ser tratados de forma
electiva. Slo bien diferenciado cnceres de clulas escamosas 2 cm de tamao
situados en el canal distal parecen tener un riesgo de metstasis nodales <5%. 31 , 34 El
hallazgo en serie quirrgica de las metstasis fi ed de veri histopatolgicamente en los
grupos de nodos de forma electiva. Estudios retrospectivos y prospectivos han
demostrado las ventajas de la irradiacin ganglionar electiva (ENI). 38 , 39 Siguiendo ENI a
una dosis total de 40 a 50 Gy (1,8 a fracciones de 2 Gy), los investigadores de Francia
inform de 5 aos las tasas acumuladas de recurrencia inguinal de 2% en aquellos que
recibieron ENI (n = 75) versus 16% en los que no lo hizo (n =
106). En el grupo de no-ENI, las tasas de recidiva fueron del 12% de T1 a T2 y 30% a
partir de T3 a los tumores T4. 38 En un estudio prospectivo en Australasia en la que los
pacientes con T1 o T2 tumores de hasta 4 cm de dimetro no recibi inguinal ENI,
fallo de nodo inguinal ocurri en 9 de 40 (23%), en 5 como primer sitio de fallo. 141
El tratamiento de los cnceres ms grandes por braquiterapia intersticial solo result en
fracaso en linfticos plvicos por encima del volumen tratado en el 16% (14 de 88). 142 El
control de la mayora de las metstasis en los ganglios plvicos subclnicas por plvica ENI y
la quimioterapia se puede inferir de las tasas de fracaso bajos reportados en sitios de
ganglios plvicos. 138-140 La dosis mnima eficaz para ENI no se conoce. Dosis tan bajas como
24 Gy en 12 fracciones en 2,5 semanas apareci eficaz en una serie, 39
pero la mayora de los centros de dan de 30,6 Gy en 17 fracciones en 3,5 semanas a 50 Gy en 25
fracciones en 5 semanas. 38,73,74
Los ensayos aleatorios descritos anteriormente todos los planes de radiacin
utilizadas generados por dos o tres dimensiones (2D o 3D) tcnicas de planificacin, y,
en su mayor parte, empleadas tcnicas de campo opuestas predominantemente
anterior-posterior para una parte sustancial de la programacin. La mayora de
onclogos de radiacin prefieren para tratar el tumor primario, la ilaca interna regional,
y los nodos perirrectales y linfticos inguinales y otros grupos de ganglios plvicos,
como la ilaca externa y nodos presacros en continuidad. Si el paciente es propenso, el
ano puede ser visualizado fcilmente y bolo coloca selectivamente sobre cualquier
extensin del tumor perianal. Sin embargo, es difcil de aumentar el rea inguinal
cuando el paciente es propenso si se utiliza una tcnica de 2D o tratamiento 3D.
Alternativamente, el paciente puede ser tratado supina. esto facilita

impulsa a las reas inguinal y reduce algunos de los inhomogeneidades producidos
por las curvaturas naturales de los tejidos blandos de la pelvis. En esa posicin, es
difcil de asegurar que bolo se coloca sobre la zona anal permanece en su lugar.
En la discusin que sigue, las dosis de radiacin descritas son tpicas de las
prescritas cuando RT se combina con 5-FU y MMC. Cuando se utiliza un par opuesto
anterior-posterior de campos, el borde superior de los campos se coloca en la unin
lumbosacra si la intencin es incluir la ilaca comn, presacro superior, e inferior nodos
rectosigmoides, adems de los nodos regionales. Esta frontera se mueve comnmente
abajo durante el tratamiento para el extremo inferior de las articulaciones sacroilacas
(tpicamente despus de 30,6 Gy en 17 fracciones a 36 Gy en 20 fracciones),
abarcando as en la reduccin del volumen slo el perirrectal, inferior presacro, y los
nodos ilacas internas ( y, si los campos estn su fi cientemente amplia, los ganglios
iliacos externos ms bajos), con el fin de reducir el riesgo de enteritis por radiacin
(Fig. 62.3). Una reduccin adicional de campo se realiza en 45 Gy, despus de lo cual
una fase final de tratamiento de 9 Gy en 5 fracciones o 14,4 Gy en 8 fracciones se
entrega al tumor primario. Es aconsejable aadir un margen de CTV de 2 a 3 cm
alrededor del tumor primario para esta fase de impulso. Si el tumor primario no puede
ser identificado fi en la CT de planificacin, el complejo del esfnter anal se utiliza a
menudo como un objetivo sustituto, ajustado por cualquier extensin tumoral conocido
ms all del canal anal. La dosis total general para el tumor primario es de 54 Gy en 30
fracciones en 6 semanas a 59,4 Gy en 33 fracciones en 6,5 semanas cuando todo RT
se entrega por la radiacin de haz externo. Si hay linfticos metastsicos, stos son
tratados por los campos apropiados a la misma dosis total que el tumor primario.
Puede que no sea posible entregar ms de alrededor de 45 a 50,4 Gy a los nodos
anormales en la pelvis si stos se encuentran adyacentes a intestino delgado; en
muchos casos, estas dosis son suficientes para lograr el control. En ausencia de nodos
anormales en la pelvis inferior, algunos consideran tratamiento electivo de nodos
normales radiolgicamente por encima del borde inferior de las articulaciones
sacroilacas innecesarios. 39 , 102143
La frontera de campo inferior se coloca 3 cm distales a la inferior ms extensin
del tumor primario, que debe ser indicada por un marcador radio-opaco durante la
simulacin.
La posicin de los bordes laterales depende de la filosofa adoptada con respecto
a la conveniencia de tratar a un volumen homogneo continuo, sin mltiples campos
y uniones de campo, y la minimizacin de la irradiacin de la cabeza femoral y el
cuello. Las opciones incluyen campos posteriores de igual tamao que abarca los
ganglios inguinales anterior y; campos posteriores de igual tamao anterior y, pero
restringen a incluir los bordes mediales de la pelvis solamente, los ganglios inguinales
siendo tratados por haces de electrones anterior emparejados a los campos de
fotones fi; campos de fotones fi asimtricos, con un mayor campo anterior fi para
cubrir el tumor primario y los ganglios plvicos e inguinales en continuidad; y una viga
posterior restringido al tumor primario y linfticos de la pelvis. En esta ltima
disposicin,
TABLA 62.6 Estudios seleccionados DE radiacin de conformacin tridimensional y de intensidad modulada
TERAPIA DE RADIACIN
Estudio (Referencia) RTOG 9811 brazo MMC (74)
N de pacientes 324
tcnica de radiacin conformacional 3D
aguda grado 3 o 4 toxicidad
Hematolgicas (%) 61
Piel (%) 48
GI (%) 36
GU (%) 4 5
interrupciones en el tratamiento 61
resultados de 2 aos
control locorregional (%) 77
supervivencia libre de colostoma (%) 84
Supervivencia libre de enfermedad (%) 71
RTOG, Radiation Therapy Oncology Group; MMC, mitomicina-C; 3D, tridimensional; IMRT, la radioterapia de intensidad modulada; NP, no publicado; GI,
gastrointestinal; GU, genitourinario.
booksmedicos.org
captulo 62 El cncer anal 1241
La ubicacin y la profundidad de los ganglios inguinales deben obtenerse mediante
formacin de imgenes axial. 144 Otra alternativa popular, si
30,6 a 36 Gy en 3,5 a 4 semanas se percibe como bastar dosis fi ciente para ENI
para los nodos normales radiolgicamente, es tratar a los nodos primario y plvicos e
inguinales con la AP: campos PA, y luego utilizar una disposicin de campo de tres fi
(posterior y dos campos laterales) para abarcar el tumor primario a 45 a 59.4 dosis
total Gy, de acuerdo con el tamao del cncer primario y la prctica local. Otros
arreglos de campo, tales como campos oblicua fi 145 y una fi perineal directo ELD
acopla con un haz de arco parcial posterior 142 se han descrito. Cuando se utilizan
campos asimtricos o coincidentes, hay potencial para tanto sobre y infradosificacin. 146
La fase final del tratamiento, ms all de que incluye tanto los ganglios linfticos
y cncer primario, tpicamente entrega del 9 al 20 Gy a un volumen reducido que
abarca slo el tumor primario. Esta fase puede ser entregado por braquiterapia. La
braquiterapia se utiliza ms comnmente en Europa que en Amrica del Norte, donde
se favorece el tratamiento de haz externo. Hay una serie de informes de braquiterapia
eficaz, incluyendo tasa de dosis baja (LDR), 69147 , 161 Tasa de dosis pulsadas (PDR), 148 ,
149-150 y la alta tasa de dosis (HDR) tcnicas. 151152 La braquiterapia generalmente se ha
Clinical Radiation Oncology
dado 2 a 8 semanas despus de la terapia de haz externo, aunque un horario
introdujo HDR en el intervalo durante la terapia de haz externo de ciclo dividido. 151 No
hay acuerdo sobre si el volumen de tratamiento debe incluir toda la extensin del
cncer primario inicial 69142 , 149151 o slo el tumor restante en el momento de implante. 153 La
dosis de braquiterapia depende de la dosis de material compuesto de la prescripcin
de radiacin total. De vez en cuando, la toxicidad signi fi cativo ha sido encontrado.
La introduccin de la radioterapia de intensidad modulada (IMRT) ofrece la posibilidad
de reducir an ms la dosis para tejidos normales ms all de la que puede conseguirse
con las tcnicas de conformacin en 3D. Varios estudios iniciales de IMRT y tcnicas
altamente conformal similares describen mejoras en la distribucin de dosis de radiacin. 139
, 154-157, 158-159 Sin embargo, es evidente de los resultados seleccionados de la Tabla 62.6 que
se observ una amplia gama de toxicidades agudas graves, y que cerca de la mitad de los
pacientes tratados por IMRT tenido interrupciones en el tratamiento. Las comparaciones
de las diferentes series de casos y la interpretacin son difciles porque la mayora de los
estudios utilizaron diferentes tcnicas y dosis RT y prcticas para el registro de las
toxicidades. No existen datos todava sobre la toxicidad a largo plazo siguientes IMRT para
el cncer anal.
IMRT muy conformes y tcnicas relacionadas requieren una atencin considerable a la
identificacin de los volmenes brutos objetivo (GTV) y los volmenes correspondientes
electivos clnicos objetivo (CTV). En un ensayo realizado por RTOG para probar la
reproducibilidad de IMRT en mltiples centros, 79% de los 51 casos se encontraron en
opinin pretratamiento para no cumplir con los volmenes de tratamiento de protocolo, en
particular los de las regiones nodales a ser irradiada de forma electiva. 158
El RTOG public posteriormente un atlas de plantillas CTV electivos desarrollados por un
panel de consenso para su uso en la planificacin de IMRT para los cnceres anales y
rectales. 160 Cuando las tcnicas de IMRT
Boston (159) RTOG 0529 (158) Toronto (139)
43 51 58
IMRT IMRT IMRT
49 notario pblico 38
7 20 46
7 22 (GI / GU) 9
22 (GI / GU) 0
40 49 55
95 (local) 80 85
94 86 87
notario pblico 77 75
1242 seccin III Oncologa de Radiacin clnica parte G Gastrointestinal
se van a utilizar, una atencin particular a la posicin del paciente y la inmovilizacin es
necesario. Si es posible, la exactitud de la configuracin debe ser verificable ed con
frecuencia, por ejemplo, por tratamiento de radiacin guiado por imgenes.
A pesar de que los resultados observados en la IMRT parecen similares a los
conseguidos con conformacional 3D RT, este ltimo todava se considera el estndar, hasta
ahora no se ha informado de los resultados clnicos a largo plazo con la IMRT.
Ha habido una creciente atencin a los factores de radiacin en tiempo de la dosis.
protocolos recientes han tratado de mejorar las tasas de control local, en particular para los
tumores ms grandes, mediante la intensificacin de RT o quimioterapia o ambas. las tasas de
control del tumor primario (excluyendo tratamiento de rescate) en la mayora de los estudios de
RT, 5-FU, y MMC son alrededor de 90% a 100% para los tumores de hasta 2 cm (T1), 65% a
75% para los tumores de 2 a 5 cm (T2), y 40% a 55% para aquellos> 5 cm y para los cnceres
ms profundamente invasivos (T3 o T4); la tasa de control del tumor primario es de
aproximadamente 60% del total. 39 , 57106161162 - 165
El aumento de la dosis de radiacin total se han defendido. Cuando se combina con
5-FU y MMC, dosis de radiacin de tan poco como 30 Gy en 15 fracciones se han mostrado
ms de 3 semanas para erradicar hasta aproximadamente 90% de los cnceres 3 cm de
tamao. Las dosis ms altas, a partir de 45 Gy en 25 fracciones en 5 semanas a 54 Gy en
30 fracciones en 6 semanas, a veces complementados con radiacin adicional despus de
un intervalo de 6 a 8 semanas para un total de 60 a 65 Gy durante un tiempo total de
aproximadamente 12 semanas, han controlado de 65% a 75% de primario tumores> 4 cm. 39
, 57,106,162,163-165 Los ensayos recientes en Amrica del Norte utilizados hasta 59 Gy en 32
fracciones durante 6,5 semanas para los cnceres grande o ganglios positivos 74 , 83,91,92; la
eficacia y la tolerabilidad a largo plazo de estas dosis ms elevadas todava no ha sido
reportado en detalle. Un anlisis reciente del ensayo UKCCCR ACT I sugiri que la entrega
de radiacin impulso de 15 a 25 Gy 6 semanas despus de la inicial de 45 Gy en 4 a 5
semanas no mejor el control local pero se asoci con un mayor riesgo de necrosis (8% vs
. 0% si no se le dio impulso). 166 Muchos centros estn desarrollando programas de dosis
graduadas de acuerdo con el tamao de las metstasis tumorales y de ganglios linfticos
primarios. 74138 , 155, 159
Una ventaja potencial propuesto con frecuencia para IMRT es la capacidad de
aumentar selectivamente la dosis de radiacin al cncer. No se sabe si esto ser
posible como estrategia para aumentar las tasas de control para los tumores anales
ms grandes debido a las tolerancias limitadas del recto distal, canal anal y la piel
perianal. 167168 La introduccin de planes de IMRT monofsicos ha llevado al uso de
fraccionamiento de la dosis no estndar, en particular para regiones de ganglios
linfticos tratados de forma electiva. Por ejemplo, si todos los volmenes de destino
deben ser tratados a 30 fracciones y el tumor primario es recibir 54 Gy a 1,8 Gy por
fraccin, tratamiento electivo de nodos no involucrados a 36 Gy sera entregado a 1,2
Gy por fraccin y a 45 Gy en 1,5 Gy por fraccin. Algunos autores tambin han
introducido correcciones dosis biolgicamente eficaces para permitir diferentes dosis
fraccionadas o alteraciones en tiempo sobre el cual se entregan las dosis ms bajas. 155,
159 La eficacia a largo plazo de estas dosis no estndar no se ha determinado.
En la era de la planificacin del tratamiento 2D, y ms tarde con la planificacin
conformal 3D, las interrupciones en el tratamiento de haz externo, generalmente de no
ms de 2 semanas, pero de hasta 4 semanas en algunas series, se introdujeron en
muchos protocolos de modalidad combinada, ya sea como electiva descansos despus
del tratamiento de 3 semanas o de lo requerido por los pacientes individuales, para
reducir la gravedad de anoproctitis aguda y dermatitis perineal. Intervalos ms largos
de 6 a 8 semanas eran parte de algunos horarios para dar tiempo a la regresin del
tumor, en particular cuando ms RT deba ser prescrito sobre la base de la magnitud
de la respuesta clnica o histopatolgico a la primera fase del tratamiento. 41,72,73,142 Los
posibles efectos adversos de la irradiacin de ciclo dividido en el control del cncer anal
no se han estudiado formalmente, pero los limitados datos disponibles sobre el tumor
tiempo potencial de cncer anal duplicar sugerir que es relativamente rpida y del
orden de 4 das (rango 1 a 30 das; n = 26), 169 por lo que algunos efectos adversos se
puede esperar de un tratamiento prolongado innecesariamente. Recientes anlisis de
la duracin del tratamiento indican que el trata- general
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tiempo ment (OTT), incluyendo el tiempo para la quimioterapia de induccin si se les da y
para intervalos prolongados antes de aumentar la temperatura ambiente, puede tener
ms influencia sobre el resultado de la duracin de la radiacin (RTT). Revisin del
proceso UKCCCR ACT I no identific una asociacin entre OTT y el fracaso
locorregional. 166 El anlisis de dos ensayos RTOG 73,74 mostr una tendencia hacia una
asociacin entre ya fracaso OTT y colostoma y una asociacin estadsticamente
significativa con el fracaso local. RTT y OTT no se correlacionaron con los ndices
generales o libre de colostoma de supervivencia. 170
Hay muchos factores de confusin potenciales en estas comparaciones
retrospectivas, y la duracin ptima del tratamiento global o la radioterapia no se
conoce. La introduccin de tcnicas de IMRT no parece haber conducido a una
reduccin constante en las interrupciones de TA. El principio general recomendado
es evitar, o reducir al mnimo la longitud de, todas las interrupciones en la entrega de
radiacin.
La radioterapia sola
Si se da la irradiacin de haz externo sin quimioterapia concurrente, es usual, como en
otros tipos de cncer, para prescribir dosis cercanas a la tolerancia de los tejidos
normales. No se han realizado estudios para establecer los factores ptimos en tiempo de
la dosis. Una dosis al tumor primario de 60 a 65 Gy durante 6 a 7 semanas, en 1.8to
fracciones 2-Gy, se prescribe comnmente, con dosis a los ganglios linfticos a ser
tratados de forma electiva en el intervalo de 36 Gy en 4 semanas a 50,4 Gy en 5,5
semanas. La braquiterapia puede ser usada para parte del tratamiento. Al igual que con
quimiorradioterapia, interrupciones en el tratamiento deben ser minimizados.
cncer perianal
Si pequeos (<4 cm) cnceres perianales con bajo riesgo de metstasis en los ganglios
regionales son tratados por radiacin, una dosis de 60 a 66 Gy en fracciones de 2-Gy de
ms de 6 semanas puede ser utilizado. Se prefiere un campo perineal directo ya que
esto reduce al mnimo el rea de la piel irradiada. equipo ortovoltaje puede bastar,
aunque electrones o fotones de baja energa megavoltage (con bolo) son ms
comnmente utilizados. Se debe tener cuidado para aplanar el perineo tanto como sea
posible para evitar zonas de sobre o infradosificacin. cnceres perianales ms grandes,
o los cnceres que invaden el canal anal, generalmente se tratan por las tcnicas y los
horarios de la radiacin y la quimioterapia se usa para cnceres del canal anal, en base
a los resultados del ensayo UKCCCR ACT I. 41 irradiacin ganglionar electiva se da a los
ganglios iliacos inguinales e inferior externos y a los nodos ilacas perirrectales e internos
inferiores si el tumor se extiende en el canal anal. El borde superior de los campos se
coloca generalmente en el extremo inferior de las articulaciones sacroilacas. La fase
final de la radiacin puede ser dada por fotn perineal directa o terapia de electrones.
Aunque la braquiterapia se puede utilizar para la fase final, el tratamiento completo de
los cnceres perianales por braquiterapia se asoci con altas tasas de necrosis en
algunas series.
Secuelas de THERAPY
Las encuestas de los estudios publicados sugieren que la administracin de
quimioterapia concurrente con RT se asocia ms con el aumento de aguda en lugar de
la toxicidad tejido normal tarde, ms all de la que se espera con la RT sola. Algunas
series no aleatorizado han descrito tasas de toxicidad superior agudas y tardas de la
terapia de modalidad combinada que los reportados en los ensayos multicntricos
aleatorios. Esto probablemente es el resultado del uso de diferentes criterios para el
registro y notificacin de toxicidad.
En los programas que combinaban la terapia de radiacin, de 96 horas a las
infusiones de 120 horas de 5-FU (750 a 1000 mg / m 2 / 24 horas) y inyecciones en
bolo de MMC (10 a 15 mg / m 2), leucopenia moderada, trombocitopenia, anoproctitis, y
dermatitis perineal se registraron en aproximadamente 30% de los pacientes despus
de dosis de 25 a 30 Gy en 2,5 a 3 semanas. 39 , 171 Ms profunda proctitis y dermatitis
ocurrieron en hasta un 55% de los que recibieron 50 Gy en 4 a 5 semanas 39 , 106 a 59,4
Gy en 6,5 semanas. 91 Cuando

CDDP sustituido por MMC, toxicidad sea fue menor, pero a dosis de radiacin de 59,4 Gy
en 6,5 semanas, las tasas de toxicidad de los tejidos blandos agudos fueron similares. 74 , 83 La
mayora de los estudios grandes de RT, 5-FU, y MMC o CDDP informado de algunos
mortalidad (<2% en total) asociado con toxicidad aguda, por lo general como resultado de
la neutropenia con sepsis. Este riesgo puede reducirse con antibiticos profilcticos 41 y la
atencin de apoyo agresivo.
Serious toxicidad tarda no se ha informado despus de dosis de 30 Gy en 3
semanas con 5-FU y MMC, pero las complicaciones significativas, requiriendo a menudo
la ciruga, se registraron en aproximadamente 5% a 10% de los que recibieron las dosis
ms altas de radiacin. Una revisin de la gestin del cncer anal en Dinamarca
1995-2003 encontr 5 aos incidencias acumuladas de y colostoma de 26% (IC del
95%, 21% a 32%) y 8% treatmentrelated relacionada con el tumor (95%
CI, 5% a 12%), respectivamente. 172 En el ensayo aleatorizado RTOG-9811, en los que
recibieron RT, 5-FU, y MMC, slo 10 de los 30 procedimientos de colostoma realizadas por
cerca de 3 aos fueron por problemas relacionados con el tratamiento, la tasa bruta de
aproximadamente 3%. 59 Es probable que algunos informes, muchos de los cuales eran
retrospectivos, tambin daba cierta toxicidad relacionada con el tratamiento. Por ejemplo,
un estudio de cohorte de 556 mujeres con edades 65 que desarrollaron cncer anal
mostraron un mayor riesgo de fractura de la pelvis, principalmente de la cadera, en los que
recibieron radiacin (n = 399) en comparacin con los no irradiados (n = 157). La tasa de
fractura acumulativa 5 aos fue del 14% frente a 7,5% ( P <. 01). 173 Uno de los objetivos de
las tcnicas de conformacin en 3D y de IMRT actuales es para reducir la dosis RT a los
fmures proximales.
Hay dos reas adicionales de la posible toxicidad que necesitan ms estudios. RT
plvica aumenta el riesgo de neoplasias secundarias, 174 y algunos de los agentes de
quimioterapia para tratar el cncer anal tambin se asocian con un riesgo elevado;
estos riesgos no han sido ed fi cuanti en detalle para los pacientes tratados de cncer
anal. En segundo lugar, en el nico informe en lo que va de largo plazo de seguimiento
de los pacientes en un ensayo aleatorio, se encontr que haba ms muertes debido a
causas distintas al cncer, especialmente cardiovascular relacionada, en la primera 10
aos despus del tratamiento con RT , 5-FU, y MMC. 71 Esta diferencia alcanz + 9% a
los 5 aos, pero el efecto desapareci casi por 10 aos. La magnitud de esta diferencia
fue menor que la reduccin de las muertes por cncer del ano. Se necesita informacin
de otros ensayos aleatorios para determinar si esta observacin era un fenmeno
oportunidad o un riesgo que debe ser abordado por la investigacin adicional.
A pesar de que la preservacin de la anatoma anorrectal es una ventaja del
tratamiento con quimiorradioterapia, a finales de la funcin anorrectal es a menudo
anormal. Los efectos secundarios del tratamiento son muy comunes y pueden causar a
los pacientes una considerable malestar y discapacidad social, aunque a menudo se
clasifican como nico nivel 1 o 2 toxicidad. 175-176, 177-178 Estos efectos incluyen cambios en
la funcin anorrectal tales como urgencia y frecuencia de la defecacin, sangrado de
telangiectasia anorrectal, dermatitis perineal, fibrosis plvica, dispareunia, y la
impotencia. Por lo general son tratados mdicamente con xito variable. Las
evaluaciones sistemticas y potenciales de la funcin de la regin anorrectal y de otros
rganos que puedan verse afectados por el tratamiento ahora se estn reportando, al
igual que los estudios formales de calidad de vida. 139 , 179 A menudo hay disociacin entre
un paciente y su o de la evaluacin de su mdico de la funcin y la continencia anal y
rectal y mediciones fisiolgicas de la funcin anorrectal. Los pocos estudios en esta
rea han sido concluyentes. 177 , 180 se puede esperar que los estudios prospectivos de la
funcin del rgano plvico para ayudar al desarrollo de protocolos de tratamiento de
radiacin, facilitando la correlacin de la funcin con las interacciones radiacin de
quimioterapia, tcnicas de radiacin y distribuciones de dosis, y los factores de dosis
tiempo.
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129. Formenti SC, Chak L, Gill P, et al. Aumento de la radiosensibilidad de fibroblastos de tejido normal en
pacientes con inmunodeficiencia adquirida sndrome de deficiencia (SIDA) y con el sarcoma de Kaposi. Int J
Radiat Biol 1995; 68: 411-412.
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132. Belkacemi Y, Berger C, Poortmans P, et al. Tratamiento del adenocarcinoma del canal anal: un gran estudio
retrospectivo de la Red Rare cncer. Int J Radiat Oncol Biol Phys 2003; 56: 1274-1283.
134. Chang GJ, Gonzlez RJ, Skibbar JM, et al. Una experiencia de veinte aos con adenocarcinoma del canal
anal. Dis Colon Recto 2009; 52: 1375-80.
135. Joon DL, Chao MW, Ngan SY, et al. El adenocarcinoma primario del ano: un anlisis retrospectivo. Int J
Radiat Oncol Biol Phys 1999; 45: 1199-1205.
138. Wright JL, Patil SM, templo LK, et al. carcinoma de clulas escamosas del conducto anal: patrones y
predictores de fallo y las implicaciones para el tratamiento de radiacin de intensidad modulada y la
planificacin. Int J Radiat Oncol Biol Phys 2010; 78: 1064-72.
139. Han K, Craig T, Skliarenko J, et al. Evaluacin prospectiva de la IMRT para el cncer anal y perianal:
primeros patrones de fracaso. Int J Radiat Oncol Biol Phys 2011; 81 (2 Suppl): S125-S126.
140. Das P, Bhatia S, Eng C, et al. Las predicciones y los patrones de recurrencia despus de la quimiorradioterapia
definitivo para el cncer anal. Int J Radiat Oncol Biol Phys 2007; 68: 794-
800.
142. Papillon J. cnceres rectales y anales: el tratamiento conservador por irradiacin. un
alternativa a la ciruga radical. Berln: Springer-Verlag, 1982.
144. Koh WJ, Chiu M, Stelzer KJ, et al. profundidad vaso femoral y las implicaciones para la radiacin nodo ingle. Int
J Radiat Oncol Biol Phys 1993; 27: 969-974.
147. Papillon J, Montbarbon JF, Gerard JP, et al. curieterapia intersticial en el tratamiento conservador de los
cnceres anales y rectales. Int J Radiat Oncol Biol Phys
1989; 17: 1161-1169.
148. Gerard JP, Mauro F, Thomas L, et al. El tratamiento de clulas de carcinoma del canal anal escamosas con
braquiterapia de tasa de dosis de pulso. Estudio de viabilidad de un Grupo de Cooperacin Francs. radioter
Oncol 1999; 51: 129-131.
158. Kachnic L, Winter K, Myerson R, et al. RTOG 0529: Una evaluacin de fase II de dosepainted IMRT en
combinacin con uorouracilo 5-fl y mitomicina-C para reduccin de la morbilidad aguda en el carcinoma
del canal anal. Int J Radiat Oncol Biol Phys
2009; 75 (Suppl): S5.
159. Kachnic LA, Tsai HK, Coen JJ, et al. Dosis-pintado radioterapia de intensidad modulada para el cncer anal;
un informe multi-institucional de la toxicidad aguda y respuesta al tratamiento. Int J Radiat Oncol Biol Phys 2010;
78 (Suppl 3): S55.
160. Myerson RJ, Garofolo MC, El Naqa I, et al. volmenes electivos objetivo clnicos para la terapia conformal en
el cncer anorrectal: un panel de consenso Terapia de Radiacin Oncology Group contorneado atlas. Int J
Radiat Oncol Biol Phys 2009; 74: 824-830.
166. Glynne-Jones R, Sebag-Monte mineral fi D, Adams R, et al. Cuidado con la brecha, el impacto de las variaciones en
la duracin de la brecha de tratamiento y el tiempo total de tratamiento en el primer ensayo UK cncer anal (ACT
I). Int J Radiat Oncol Biol Phys 2011; 81: 1488-
1494.
167. Cummings BJ. Hay un lmite a la escalada de dosis para el cncer rectal? Clin Oncol
2007; 19: 730-737.
168. Heemsbergen WD, Hoogeman MS, Hart GA, et al. La toxicidad gastrointestinal y su relacin con la dosis
distribuciones en la regin anorrectal de pacientes con cncer de prstata tratados con radioterapia. Int J
Radiat Oncol Biol Phys 2005; 61: 1001-18.
169. Wong CS, Tsang RW, Cummings BJ, et al. parmetros de la proliferacin en carcinomas epidermoides de
canal anal. radioter Oncol 2000; 56: 349-353.
170. Ben-Josef E, Moughan J, Ajani JA, et al. Impacto del tiempo total de tratamiento sobre la supervivencia y el
control local en pacientes con cncer anal; un anlisis de datos agrupados de los ensayos Radiation
Therapy Oncology Group 87-04 y 98-11. J Clin Oncol
2010; 28: 5061 a 5.066.
172. Sunesen KG, Norgaard M, Lundby L, et al. las tasas por causas espec fi cas de colostoma despus de la radioterapia para
el cncer anal: un estudio de cohortes multicntrico dans. J Clin Oncol
2011; 29: 3.535 a 3.540.
173. Baxter NN, Habermann EB, Tepper JE, et al. Riesgo de fracturas plvicas en las mujeres de edad despus de
la irradiacin plvica. JAMA 2005; 294: 2587-2593.
174. Wright JD, St Clair CM, Deutsch I, et al. radioterapia plvica y el riesgo de leucemia secundaria y mieloma
mltiple. Cncer 2010; 116: 2486-2492.
177. Vordermark D, Sailer M, Flentje M, et al. La terapia de radiacin intencin curativa en el carcinoma anal:
calidad de vida y la funcin del esfnter. radioter Oncol 1999; 52: 239-
243.
178. Das P, Cantor SB, Parker CL, et al. calidad a largo plazo de la vida despus de la radioterapia para el tratamiento del
cncer de ano. Cncer 2010; 116: 822-829.
 Parte H Tracto urinario
captulo 63
El cncer de rin, pelvis renal, urter y
Hiram A. Gay y Jeff M. Michalski
ANATOMA
Los riones son estructuras retroperitoneales situados en el nivel entre la nervadura
11 y la apfisis transversa de la tercera cuerpo vertebral lumbar. Por lo general, el
rin derecho es inferior al lbulo heptico derecho y un poco ms inferior que el
rin izquierdo. El eje renal corre paralela a la margen lateral del msculo psoas.
Cada rin es de aproximadamente 11 a 12 cm de longitud. El rin est encerrado
por una cpsula fibrosa y rodeado de grasa perirrenal, que est envuelto por la fascia
de Gerota. En el hilio renal son la pelvis, el urter, la arteria renal y la vena. Los
rganos adyacentes al rin derecho incluyen el hgado superiormente, el duodeno y
los cuerpos vertebrales medialmente, y el colon transverso y el intestino delgado
anterior. A la izquierda, el rin se apoya en el bazo lateralmente; el estmago, el
pncreas y los cuerpos vertebrales medialmente;
El rin se compone de la corteza (glomrulos, tbulos contorneados) y la
mdula (bucles de Henle, conductos colectores, y pirmides de tbulos
convergentes). Cada papila se abre en los clices menores, que se unen en los
grandes clices y desembocan en la pelvis renal. Los sistemas de recogida de
caliciales se encuentran en la superficie anteromedial de cada rin. La unin
pieloureteral es variable en la posicin, sino que sirve como punto de referencia para
separar la pelvis renal y el urter. Los urteres curso posterior e inferior, en paralelo
con el borde lateral del msculo psoas hasta que la curva de la parte anterior a unirse
a la vejiga en el trgono. Las superficies mucosas del renal tbulos colectores, los
clices, pelvis renal, urter, la vejiga y la uretra todos tienen el mismo origen
embriolgico. La pelvis renal y el urter tienen las siguientes capas: epitelio,
Los linfticos del rin y pelvis renal drenan a lo largo de los vasos renales. El
rin derecho desages predominantemente en los ganglios linfticos paracavos y
interaortocavas, y los drenajes de rin izquierdo exclusivamente a los ganglios
paraarticos. 1 El drenaje linftico del urter est segmentado y difusa y puede implicar
cualquiera de los hiliar renal, abdominal para-artico, paracava, ilaca comn, iliaca
interna, o ganglios linfticos ilacos externos.
EPIDEMIOLOGA Y FACTORES DE RIESGO
Las lesiones tratadas en este captulo se limitan a carcinoma renal de clulas adulto
(RCC, por ejemplo, hipernefroma, tumor de Grawitz) y carcinoma urotelial de la pelvis
renal y el urter. Linfomas, sarcomas retroperitoneales primarios, y de Wilms
booksmedicos.org
tumores se discuten en los captulos 78, 83, y 85, respectivamente. Aproximadamente el
88% de las masas renales slidas son malignos, y la probabilidad de malignidad es
proporcional al tamao de la lesin. 2 RCC comprenden 80% a 85% de los tumores de
rin primarias, mientras que uroteliales (telfonos de transicin) carcinomas de la pelvis
renal representan el 7% de los tumores renales.
Carcinoma de clulas renales
A nivel mundial en el ao 2008, la incidencia del cncer de rin y la mortalidad tasa
estandarizada por edad por 100.000 hombres (ASR) fue de 11,8 y
4,1 en las zonas ms desarrollados, y 2,5 y 1,3 en zonas menos desarrolladas,
respectivamente. Los nuevos casos de cncer de rin en los hombres estimados en los
pases desarrollados fueron 111.100, con 43.000 muertes. En contraste, la hembra la
incidencia de cncer renal y la mortalidad ASR fue de 5,8 y 1,7 en las zonas ms
desarrolladas, y
1.4 y 0.8 en las reas menos desarrolladas, respectivamente. 3
En los Estados Unidos en 2011, el nmero estimado de nuevos casos de rin y
pelvis renal cncer era 60.920, con
13.120 muertes. 4 Estas cifras representan aproximadamente el 4% de todos los nuevos casos
de cncer y 2% de las muertes relacionadas con el cncer. La incidencia de CCR ha ido en
aumento en los Estados Unidos, mientras que el tamao de los RCC primarias ha ido
disminuyendo gradualmente. 5 Esto es en parte debido a que el incremento en el uso de la
tomografa abdominal computarizada (TC) y ultrasonidos de enfermedades mdicas no
malignas ha aumentado el nmero de los CCR incidentales.
La edad media de diagnstico de CCR es de 65 aos, y los machos se ven
afectadas con mayor frecuencia que las mujeres, con una proporcin de 1,5: 1.
Empleos asociados con un mayor riesgo de RCC son el empleo en la industria de alto
horno, horno de coque, o de hierro y acero, as como la exposicin al amianto, cadmio,
disolventes de limpieza en seco, la gasolina y otros productos del petrleo. 6 Adems,
varios otros ambiental (por ejemplo, la exposicin a dixido de torio), hormonales (por
ejemplo, dietilestilbestrol), en la dieta (por ejemplo, alta ingesta de energa total y
carnes fritas aumentan el riesgo, mientras que verduras, frutas, y el alcohol son de
proteccin), celular, y los factores genticos se han asociado con el desarrollo de CCR. 7-9
el hbito de fumar a largo plazo se asocia con un mayor riesgo de desarrollar
CCR. La obesidad, diabetes, hepatitis C, y la hipertensin tambin se asocian con un
mayor riesgo relativo para el desarrollo de estos tumores. 10-12 La quimioterapia
citotxica puede predisponer sobrevivientes de cncer infantil para RCC
translocacin, teniendo TFE3 o gen TFEB fusiones. 13
enfermedad renal qustica adquirida (ERCA), que se produce en hasta el 50% de
los pacientes en dilisis por> 3 aos, est asociada con un 50 veces mayor riesgo de
desarrollar CCR. 14,15 RCC asociado-ERCA se ve sobre todo en los hombres, se
produce aproximadamente 20 aos antes que en la poblacin general, y es
frecuentemente bilateral (9%) y multicntrico (50%). 15
1245
1246 seccin III Oncologa de Radiacin clnica Parte H Tracto urinario
Varios sndromes de cncer hereditarios afectan el rin: von Hippel-Lindau
(VHL), cncer hereditario papilar renal (HPRC), leiomiomatosis hereditaria y
carcinoma de clulas renales (HLRCC), Birt-Hogg-Dub (BHD), y constitucional
cromosoma 3 translocacin. VHL es autosmica dominante y est causada por
mutaciones de la lnea germinal del gen supresor de tumor VHL, localizados en el
cromosoma 3p25-26. La protena VHL est implicado en la regulacin del ciclo celular
y la angiognesis. En pacientes con la enfermedad de VHL, la prdida de la suela
alelo funcionamiento BVS en tejidos somticos provoca una situacin similar a la
hipoxia, con niveles elevados de HIF-1 alfa, a pesar de la presencia de la tensin de
oxgeno normal. diecisis
Las manifestaciones renales de VHL son quistes renales y RCC de clulas claras. La edad
media de inicio de la BVS asociado de clulas claras RCC es de 37 aos, y una revisin
peridica con imgenes de resonancia magntica (MRI) debe comenzar despus de la edad
de 10 aos. 17
HPRC es autosmica dominante con alta penetrancia y se caracteriza por
mltiples, RCC papilares, bilaterales de aparicin tarda. HLRCC es autosmica
dominante con una predisposicin a papilar tipo 2 RCC. BHD es autosmica
dominante con penetrancia incompleta y se asocia con mltiples y cromfobo RCC
de clulas claras, RCC papilares, y oncocitomas. Constitucional cromosoma 3
translocacin se asocia con mltiples RCC de clulas claras bilaterales,. 18 enfermedad
renal poliqustica autosmica dominante no parece aumentar la incidencia de CCR;
sin embargo, los tumores son ms a menudo multicntrica (28% vs. 6%), bilateral
(12% vs. 1% a 5%), y sarcomatoide en el tipo (33% vs. 1% a 5%) que en la poblacin
general . 19
Pelvis renal y el urter Carcinoma
El carcinoma urotelial de las cuentas del tracto urinario superior para 7% de todos los
tumores de rin y 5% de todos los tumores malignos uroteliales. 20 La incidencia de
tumores del tracto urinario superior bilateral es
1,5% a 2% para sincrnica y 6% a 8% para presentaciones asncronas. 21 Renal pelvis
tumors are found two to three times more commonly in men than in women, and the
peak incidence is in the fth and sixth decades of life. Because the mucosal surfaces
of the renal pelvis, ureter, and bladder have the same embryologic origin, many of the
etiologic factors in renal pelvis and ureter tumors also apply to tumors of the urinary
bladder. Urothelial carcinomas of the upper urinary tract tend to be multifocal owing to
eld cancerization, which may be caused by exposure of the urothelium to potential
carcinogens. Urothelial tumors can also spread to urothelial structures that are either
distal or proximal to the primary tumor and are referred to as drop metastases. About
40% to 50% of patients with upper urinary tract tumors will have a synchronous or
metachronous bladder cancer. 22,23
Cigarette smoking is the most important factor contributing to the overall
incidence of urothelial cancer in Western countries. Patients with Lynch syndrome, an
autosomal dominant genetic condition attributable to inherited mutations that impair
DNA mismatch repair, have an increased risk of developing urinary tract cancer. 24
Exposure to aristolochic acid has been associated with acute, near end-stage
renal disease. Aristolochic acid is commonly found in the Aristolochiaceae family of
plants commonly used in Chinese herbal medicine. A high incidence of cellular atypia
and urothelial carcinoma of the renal pelvis, ureter, and bladder has been associated
with aristolochic acid nephropathy. 25 Arsenic-contaminated water has been associated
with a high incidence of upper urinary tract urothelial carcinoma in Taiwan. 26 Prolonged
heavy phenacetin-containing analgesic use can lead to urothelial carcinomas of the
renal pelvis, ureter, and bladder (which may be multiple and bilateral). 27
Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease of
unknown etiology most commonly reported in southeastern Europe. A high frequency
of urothelial atypia, occasionally progressing to tumors of the renal pelvis and urethra,
but also involving the bladder, is associated with BEN. 27
booksmedicos.org
NATURAL HISTORY
Renal Cell Carcinoma
Primary renal cell tumors may spread by local inltration through the renal capsule to
involve the perinephric fat and Gerotas fascia. The tumor may grow directly along the
venous channels to the renal vein or vena cava. Lymph node metastases occur with
an incidence of 9% to 27%, and most often involve the renal hilar, para-aortic, and
paracaval lymph nodes. 28,29
La vena renal es invadido por tumor en el 21% de los casos, y la vena cava inferior es
invadido en tanto como 4% de los casos. 30
Aproximadamente el 45% de los pacientes con RCC tienen enfermedad localizada, 25% tenan
enfermedad regional, y alrededor del 30% tienen evidencia de metstasis a distancia en el momento
del diagnstico. 29,31 De los pacientes con metstasis, aproximadamente 1% a 3% tienen lesiones
solitarias. 32 Aproximadamente la mitad de los pacientes con CCR eventualmente desarrollan la
enfermedad metastsica. 33
Entre los pacientes que se presentan con RCC metastsico, los sitios de metstasis incluyen
pulmn, hueso, cerebro, hgado y la glndula adrenal. Los pacientes con enfermedad metastsica
en el momento del diagnstico, tienen un muy mal pronstico, con una supervivencia esperada <5
aos, independientemente del sitio de la metstasis. 29,31
Pelvis renal y el urter Carcinoma
Upper urinary tract carcinoma is frequently a multifocal process. Patients with cancer
at one site in the upper urinary tract are at signicant risk for the development of
tumors elsewhere along the urothelium. The probability of multifocal occurrence is
greatest in patients with large tumors and those with carcinoma in situ. Ureteral
tumors tend to occur in the distal third of the ureter.
El carcinoma urotelial del tracto urotelial superior puede propagarse por extensin
directa, y por hematgena y metstasis linfticas. La implantacin de clulas tumorales
en la vejiga se ha demostrado, especialmente en reas previamente traumatizados. La
incidencia de metstasis en los ganglios linfticos depende en gran medida del grado del
tumor primario. Los tumores de bajo grado tienen una propensin muy baja metastsico.
En una serie de 94 pacientes, ninguno de los 43 tumores de bajo grado de metstasis en
ndulos linfticos, en comparacin con 3 de 22 grado 3 o 4 tumores. 34 metstasis en los
ganglios linfticos fueron reportados en 9 de 26 pacientes seleccionados para recibir
radioterapia adyuvante. 35
PRESENTACIN CLNICA
Carcinoma de clulas renales
Los pacientes con RCC pueden presentar con un tumor primario oculto, o con signos
y sntomas atribuibles a una masa local o sndromes paraneoplsicos sistmicos.
hematuria, masa palpable flanco y dolor describen una trada clsica que se produce
slo en un 5% a un 10% de los pacientes. 36 , 37 De hecho, un hallazgo de la triada
clsica sugiere a menudo la enfermedad avanzada con un mal pronstico. El sntoma
ms frecuente asociado con RCC es la hematuria, ya sea macroscpica o
microscpica, cuando hay invasin del sistema colector. 38 varicoceles escrotales,
sobre todo del lado izquierdo, se observan hasta en el 11% de los hombres con CCR. 39
Otros sntomas incluyen anemia, disfuncin heptica en ausencia de metstasis
hepticas (llamada sndrome de Stauffer y atribuible a una elevacin paraneoplsico
de la fosfatasa alcalina), la amiloidosis AA secundaria, fiebre, hipercalcemia,
caquexia, eritrocitosis, trombocitosis, y un sndrome que se asemeja rhumatica
polimialgia. 39, 40 , 41-44, 45 RCC se presenta como una masa incidental en un estudio de
diagnstico por imagen ordenada para otros fines representa el 61% de todos los
diagnsticos. 46
Una amplia gama de sndromes paraneoplsicos se ha asociado con RCC.
Parathyroidlike hormonas, eritropoyetina, la renina, gonadotropinas, lactgeno de la
placenta, prolactina, enteroglucagn, hormonas a la insulina, la hormona
adrenocorticotrpica, y prostaglandinas han sido identificados en pacientes con CCR. 47,48

Pelvis renal y el urter Carcinoma
hematuria macroscpica o microscpica se produce en 70% a 95% de los pacientes
con tumores de la pelvis renal o del urter. 20 Los otros sntomas menos comunes
incluyen dolor (8% a 40%), irritacin de la vejiga (5% a 10%), u otros sntomas
constitucionales (5%). Alrededor del 10% al 20% de los pacientes puede presentar con
un flanco masa secundaria a tumor o hidronefrosis.
estudio diagnstico
Carcinoma de clulas renales
Las masas renales no son poco comunes, y la mayora de ellos son benignos. Una masa
renal central puede sugerir carcinoma urotelial; si es as, la citologa de orina o ureteroscopia
deben ser considerados. masas renales son frecuentemente diagnosticados como un
hallazgo incidental durante la exploracin abdominal para la evaluacin metastsico de un
tumor maligno no relacionado o otra enfermedad.
Se ha propuesto un algoritmo para el estudio diagnstico de las masas renales. 49 If
CT or ultrasound clearly identify the mass as a cyst, no further workup is necessary. If
a solid lesion is identied, then tumor removal by nephrectomy should be considered.
In the case of small lesions, a follow-up CT scan to evaluate potential growth of the
mass may raise the suspicion of malignancy. The diagnostic and staging workup for
RCC is given in Table
63.1. The diagnosis of RCC is established clinically and radiographically in most
cases. Pathologic conrmation often is made at the time of nephrectomy.
Once a radiographic diagnosis is made, a staging evaluation should be
undertaken, which should include: a complete history and physical examination,
complete blood count, and liver and kidney function tests. A metastatic workup should
include a chest CT and an abdominal/pelvic CT (preferred) or abdominal MRI scan.
Patients with symptoms suggestive of bone metastases and those with an elevated
alkaline phosphatase level should undergo a bone scan. If metastatic lesions are
detected, histologic conrmation should be made by biopsy of either the metastatic
focus or the primary tumor. MRI can be valuable when evaluating the extent of
involvement of the collecting system or inferior vena cava, or radiographic contrast
cannot be administered. Renal arteriography is sometimes helpful in planning surgery.
Renal Pelvis and Ureter Carcinoma
El estudio diagnstico para pelvis renal y carcinoma urter se enumeran en la Tabla
63.2. Puesta en escena incluye una historia completa y un examen fsico,
hemograma completo, y el hgado y
TABLE 63.1 DIAGNOSTIC WORKUP FOR RENAL CELL CARCINOMA
General
History and physical examination
Los estudios radiogrficos
CT MRI plvico / abdominal (preferido) o abdominal con o sin contraste dependiendo de la funcin renal.
La RM es superior a la TC en la evaluacin de la vena cava inferior y la aurcula derecha de la
afectacin tumoral
Considere urografa CT, lo que permite obtener imgenes de ambos el parnquima renal y el sistema
colector
TC de trax o radiografa de trax
La gammagrafa sea, si el paciente tiene dolor de huesos o tiene una fosfatasa alcalina elevada
RM cerebral, si sospecha de metstasis cerebrales
Evitar la biopsia si se est considerando la reseccin. Considere la biopsia con aguja, si est indicado
clnicamente, para lesiones pequeas para confirmar el diagnstico o gua de vigilancia, criociruga, o
estrategias de ablacin por radiofrecuencia
Los estudios de laboratorio
hemograma completo
Panel metablico Integral (incluyendo lactato deshidrogenasa, el calcio srico, pruebas de
funcin heptica, nitrgeno ureico en sangre y creatinina en suero)
Anlisis de orina
CT, tomografa computarizada; MRI, imgenes por resonancia magntica.
booksmedicos.org
captulo 63 El cncer de rin, pelvis renal, urter y 1247
TABLA 63.2 Estudio diagnstico PARA pelvis renal y el urter
CARCINOMA
General
Historia y examen fsico
Los estudios radiogrficos
TC del abdomen y la pelvis o urografa RM
urografa TC multidetector
TC de trax o radiografa de trax
La gammagrafa sea, si el paciente tiene dolor de huesos o tiene una fosfatasa alcalina elevada
RM cerebral, si sospecha de metstasis cerebrales
pruebas especiales
La cistoscopia-todo el tracto urinario tiene que ser evaluada debido a la alta incidencia de tumores
mltiples
visualizacin Uteroscopic del tumor es deseable, y biopsia de tejido a travs de un uteroscopio
puede llevarse a cabo si es factible
citologa de orina puede ayudar a determinar el grado del tumor si el tejido no est disponible. tasa de
falsos negativos puede ser alta en la parte alta del tracto y tumores de bajo grado
Los estudios de laboratorio
recuento sanguneo completo
Clinical Radiation Oncology
Panel metablico Integral (incluyendo pruebas de funcin heptica, nitrgeno ureico en sangre y
creatinina srica)
Anlisis de orina
CT, tomografa computarizada; MRI, imgenes por resonancia magntica.
pruebas de la funcin renal. Uro-TAC ahora se utiliza para evaluar a los pacientes con
carcinoma de pelvis renal. CT o MRI del abdomen y la pelvis antes y despus de la
administracin de contraste proporciona informacin til con respecto a la posible
extensin del tumor fuera del sistema colector. visualizacin Uteroscopic del tumor es
deseable, y biopsia de tejido a travs de un uteroscopio debe realizarse si es factible.
La cistoscopia es muy importante debido a la alta incidencia de tumores mltiples.
citologa de orina puede ayudar a determinar el grado del tumor si el tejido no est
disponible; sin embargo, las tasas de falsos negativos pueden ser altos para los
tumores del tracto superior y de bajo grado.
PUESTA EN ESCENA
Carcinoma de clulas renales
El Comit Estadounidense Conjunto sobre el sistema de Cncer (AJCC) se utiliza para
organizar los pacientes con CCR 50 ( Tabla 63.3). cnceres T1 y T2 estn limitados al rin.
tumores T3 se extienden a las venas principales o tejidos perirrenales, aunque no en la
glndula adrenal ipsilateral, y no ms all de la fascia de Gerota. tumores T4 invaden
ms all de la fascia de Gerota (incluyendo extensin contigua en la glndula suprarrenal
ipsilateral). metstasis de ganglios linfticos regionales pueden implican extendido a la
hiliar renal, paracava, artica, o sitios de drenaje retroperitoneales. Metstasis en los
ganglios linfticos regionales (s) es clasificado como N1. Este sistema de estadificacin
se someti a fi caciones signi fi cativo caciones en el AJCC 7 edicin 2010 de su
Cancer Staging Manual: lesiones T2 se dividieron en T2a (> 7 cm pero 10 cm) and
T2b (>10 cm); ipsilateral adrenal involvement was reclassied as T4 if contiguous
invasion and M1 if not contiguous; renal vein involvement was reclassied as T3a;
and nodal involvement was simplied to N0 versus N1.
Renal Pelvis and Ureter Carcinoma
Tumors of the renal pelvis and ureter have a natural history that is not too dissimilar
from that of other urothelial malignancies originating in the bladder. Their prognoses
depend on tumor invasiveness and pathologic grade. The 2010 AJCC 7th edition
staging classication for renal pelvis and ureter carcinoma is shown in Table 63.4. 51
PATHOLOGIC CLASSIFICATION
Renal Cell Carcinoma
RCC is a group of malignancies arising from the epithelium of the renal tubules and
comprises 90% of all malignancies in the
1248 seccin III Oncologa de Radiacin clnica Parte H Tracto urinario

TABLA 63.3 AMERICAN COMIT MIXTO DE CNCER 2010 ESTADIFICACIN TABLA 63.4 AMERICAN COMIT MIXTO DE CNCER 2010 ESTADIFICACIN

CLASIFICACIN PARA tumores renales CLASIFICACIN PARA pelvis renal y tumores del urter

Tumor primario (T) Tumor primario (T)

TX El tumor primario no se puede evaluar TX El tumor primario no se puede evaluar

T0 No hay evidencia de tumor primario T0 No hay evidencia de tumor primario
T1 Tumor de 7 cm en su mayor dimensin, limitado al rin Ejrcito de reserva El carcinoma papilar no invasivo
T1a Tumor 4 cm en su mayor dimensin, limitado al rin tis Carcinoma in situ
T1b Tumor> 4 cm pero 7 cm en su mayor dimensin, limitado al rin T1 El tumor invade el tejido conectivo subepitelial
T2 Tumor> 7 cm en su mayor dimensin, limitado al rin T2 El tumor invade la muscularis
T2a Tumor> 7 cm pero 10 cm en su mayor dimensin, limitado al rin T3 (Para pelvis renal solamente) El tumor invade ms all de la muscularis

T2b Tumor> 10 cm, limitado al rin en grasa periplvica o la T3 parnquima renal (Slo para urter) El tumor

T3 El tumor se extiende a las venas principales o tejidos perirrenales pero no en la glndula invade ms all de la capa muscular en la grasa periureteral

suprarrenal ipsilateral y no ms all de la fascia de Gerota

T3a El tumor se extiende macroscpicamente a la vena renal o (que contiene msculo) su T4 El tumor invade rganos adyacentes, o a travs del rin en

segmental ramas, o tumor invade la grasa del seno perirrenal y / o renal, pero no la grasa perirrenal

ms all de la fascia de Gerota

Ganglios linfticos regionales (N) un
T3b El tumor se extiende macroscpicamente a la vena cava por debajo del diafragma
NX Los ganglios linfticos regionales no se pueden evaluar
t3c El tumor se extiende macroscpicamente a la vena cava por encima del diafragma o
N0 No metstasis en los ganglios linfticos regionales
invade la pared de la vena cava
N1 Metstasis en un solo ganglio linftico, 2 cm en su mayor
T4 El tumor invade ms all de la fascia de Gerota (incluyendo extensin contigua
dimensin
en la glndula suprarrenal ipsilateral)
N2 Metstasis en un solo ganglio linftico,> 2 cm pero 5 cm de
Ganglios linfticos regionales (N) un dimensin mayor; o mltiples ganglios linfticos, ninguno

NX Los ganglios linfticos regionales no se pueden evaluar > 5 cm en su mayor dimensin

N0 No metstasis en los ganglios linfticos regionales N3 Metstasis en un ganglio linftico,> 5 cm en su mayor dimensin
N1 Metstasis en los ganglios linfticos regionales (s)
Metstasis a distancia (M)
Metstasis a distancia (M) MX metstasis a distancia no puede evaluarse
MX La presencia de metstasis a distancia no puede evaluarse M0 No hay metstasis a distancia
M0 No hay metstasis a distancia M1 metstasis a distancia
M1 metstasis a distancia
Agrupacin de las etapas
Agrupacin de las etapas
El estadio 0a Ejrcito de reserva N0 M0
La etapa I T1 N0 M0
0is etapa tis N0 M0
etapa II T2 N0 M0
La etapa I T1 N0 M0
etapa III T1 o T2 N1 M0
etapa II T2 N0 M0
T3 N0 o N1 M0
etapa III T3 N0 M0
etapa IV T4 cualquier N M0
etapa IV T4 N0 M0
cualquier T cualquier N M1
cualquier T N1, N2 o N3 M0
Grado histopatolgico cualquier T cualquier N M1
GX Grado no puede evaluarse
Grado histopatolgico
G1 Bien diferenciado OMS / ISUP de clasificacin recomendado para histologas urotelial: LG
G2 moderadamente diferenciado
Grado bajo
G3 pobremente diferenciado
HG de alto grado
G4 indiferenciada Si el sistema de clasificacin no se especifica, por lo general se utiliza el siguiente sistema: GX
un Los ganglios linfticos regionales son los siguientes: hiliar renal, la vena cava (paracava, precava, y Grado no puede evaluarse

retrocava), interaortocava, y artica (para-artico, preartica, y retroartica). G1 Bien diferenciado

G2 moderadamente diferenciado
Nota: La estadificacin se aplica slo a carcinoma de clulas renales (RCC) y adenomas estn excluidos de esta
G3 pobremente diferenciado
clasificacin.
G4 indiferenciada
Usado con el permiso del Comit Americano Conjunto sobre el Cncer (AJCC), Chicago, Illinois. La
fuente original para este material es el AJCC Cancer Staging Manual, 7 ed. (2010), publicado por OMS, Organizacin Mundial de la Salud; ISUP, Sociedad Internacional de Patologa Urolgica.
un Laterality does not affect the N classification. The regional lymph nodes for the renal pelvis are as follows:
Springer Science and Business Media LLC, www.springer.com.
renal, hilar, paracaval, aortic, and retroperitoneal, not otherwise specified (NOS). The regional lymph nodes
for the ureter are as follows: renal hilar, iliac (common, internal [hypogastric], external), paracaval,
periureteral, and pelvic, NOS.

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The
rin. 18 The World Health Organization (WHO) classies renal cell tumors as clear cell
original source for this material is the AJCC Cancer Staging Manual, 7th ed. (2010) published by
RCC, multilocular clear cell RCC, papillary RCC, chromophobe RCC, carcinoma of
Springer Science and Business Media LLC, www.springer.com.
the collecting ducts of Bellini, renal medullary carcinoma, Xp11 translocation
carcinomas, carcinoma associated with neuroblastoma, mucinous tubular and spindle
cell carcinoma, papillary adenoma, oncocytoma, and RCC unclassied. 18

carcinomas. La OMS clasi fi es tumores uroteliales como en fi carcinoma ltrating

Clear cell RCC is the most common (80% to 90% of tumors), followed by papillary
RCC (10% to 15%) and chromophobe RCC (4% to 5%). Papillary RCC can be
subdivided into type 1, which tends to be low grade and have a better prognosis, and
type 2, which is the opposite. Renal medullary carcinoma is a very aggressive
malignancy mostly associated with young black patients with sickle cell trait and, less
commonly, sickle cell disease. 52
Renal Pelvis and Ureter Carcinoma
Ms del 90% de los tumores malignos que surgen de la pelvis renal y el urter son
urotelial (tambin llamado de clulas de transicin)
urotelial (con diferenciacin escamosa, la diferenciacin glandular, diferenciacin
trofoblstica, variante anidada, variante microctica, variante micropapilar,
lymphoepitheliomalike carcinoma, lymphomalike variante, variante plasmocitoide,
variante sarcomatoide, con clulas gigantes, y carcinoma no diferenciado). 18 La
variante histolgico ms comn es diferenciacin escamosa seguido por glandular. 18 carcinomas
de clulas escamosas representan slo el 7% a 8% de la pelvis y el urter
carcinomas renales, y a menudo se asocian con la enfermedad de clculo crnica y
la infeccin. cnceres escamosos de la pelvis renal y el urter son a menudo
localmente avanzado y se asocian con una alta tasa de recidiva local. 53

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PROGNOSTIC FACTORS
Renal Cell Carcinoma
The 5-year survival rate of patients with kidney cancer has doubled over the past 50
years, from 34% in 1954 to 70.9% in 2007. 54, 55 The stage at initial presentation
remains the most important prognostic factor for RCC survival. Using the current 7th
edition AJCC staging, the 5-year kidney cancer survival for stage I is 80.9%, 73.7%
for stage II, 53.3% for stage III, and 8.2% for stage IV. Prognostic features for RCC
are tumor, patient, and laboratory related. Tumor-related prognostic factors include
stage, tumor size, tumor grade, histologic type, tumor necrosis, sarcomatoid
transformation, and more than two sites of organ metastases. Patient-related factors
include asymptomatic versus local symptoms versus systemic symptoms, weight loss,
paraneoplastic syndromes, and an interval
< 1 year from original diagnosis to start of systemic therapy. Laboratory prognostic
factors include thrombocytosis as well as elevated erythrocyte sedimentation rate
(ESR) or C-reactive protein (CRP). 50,56
For patients with metastatic RCC, the following factors were predictive of survival
in a retrospective study of 670 patients: low Karnofsky performance status (KPS;
<80), high lactate dehydrogenase (LDH; >1.5 times upper limit of normal), low
hemoglobin (less than the lower limit of normal), high corrected serum calcium (>10
mg/dL or 2.5 mmol/L), and absence of prior nephrectomy. 57
Lymph node metastases are associated with increased rates of local recurrence
and distant metastasis. 36 ,5859, 60 Nuclear grade, sarcomatoid component, tumor size,
stage, and the presence of tumor necrosis increase the likelihood of lymph node
involvement. 61 The overall risk of lymph node metastases is 20%. 62 , 63 Patients with
lymph node metastases in radical nephrectomy specimens have a local failure rate of
21%, compared with only 4% in patients without lymph node metastases ( p = . 0002). 60 A
select group of patients with solitary metastases may have a 5-year survival rate of
25% to 35%. 64, 65
Nuclear grade, after stage, is the most important prognostic feature of clear cell
carcinoma. Fuhrman et al. 66 developed a four-tier grading system that is based on
nuclear and nucleolar size, shape, and content. Fuhrmans grade is the most widely
used grading system. Grade is also an independent prognostic factor for papillary
RCC and chromophobe RCC especially when using standardized criteria. 67 Worsening
pathologic grade is associated with a poor 5-year disease-free survival. 31, 36
Papillary RCC has a 5-year survival rate that approaches 90% and metastasizes
less frequently than clear cell RCC. The spindle cell or sarcomatoid variants of RCC
are associated with statistically signicant inferior 5-year survival rates, compared with
pure clear, or clear and granular, histologic variants. 31, 36
Nuclear morphology is a strong predictor of tumor stage and prognosis. 66 High
nuclear grade is associated with an increased incidence of advanced tumor stage,
lymph node involvement, distant metastases, renal vein involvement, tumor size, and
perirenal fat involvement. In a series of 190 patients reported by Bretheau et al., 68 the
5-year actuarial survival rates of patients with grade I, II, III, and IV tumors were 76%,
72%, 51%, and 35%, respectively. Sarcomatoid differentiation carries a signicantly
poorer prognosis than the clear cell or granular cell subtypes. Almost half of patients
with sarcomatoid RCC have bone metastases at presentation. The median survival
time of patients with sarcomatoid renal cell cancer is only 6.6 months, compared with
19 months for other histologic types. 69
Nomograms and algorithms have been described to facilitate the determination of
cancer-free survival in patients with RCC. Based on 601 patients treated at Memorial
Sloan-Kettering Cancer Center with radical nephrectomy, Kattan et al. 70 used variables
including patient symptoms (incidental, local, or
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Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1249
systemic), histology (chromophobe, papillary, or conventional), tumor size, and
pathologic stage to predict risk of recurrence after surgery. ( Note: Kattan et al. 70 uses
the older 1997 staging and is available at the Memorial Sloan-Kettering Cancer
Center website, http://nomograms.mskcc.org/Renal/PostSurgery.aspx.) Frank et al. 71 from
the Mayo Clinic developed a predictive algorithm based on 1,801 patients treated with
radical nephrectomy. This system combines stage, size, grade, and necrosis (SSIGN)
to predict patient survival. Finally, Zisman et al. 72 from the University of CaliforniaLos
Angeles (UCLA) have developed an algorithm that utilizes the AJCC TNM stage,
Fuhrmans grade, and Eastern Cooperative Oncology Group (ECOG) performance
status to divide patients into low-, intermediate-, and high-risk groups. This model is
also known as the UISS, or the UCLA integrated staging system.
Several molecular markers are being explored for their prognostic signicance,
including lack of B7H1 expression, 73
immunohistochemical detection of carbonic anhydrase IX (CAIX), 74 the proliferative
marker Ki67, 74 immunohistochemical expression of IMP3, 75 and others.
Clinical Radiation Oncology
Renal Pelvis and Ureter Carcinoma
The major prognostic factors in patients with renal pelvis or ureter carcinoma are initial
stage and grade of the tumor. There is no signicant difference in prognosis between
urothelial carcinomas originating in the ureter compared to those arising in the renal
pelvis. 76 Using the current 7th edition AJCC staging, the 5-year renal pelvis and ureter
cancer survival is as follows: stage 0a, 72.3%; stage 0is, 70.0%; stage I, 63.9%; stage
II, 56.7%; stage III, 36.5%; and stage IV, 10.2%. High-grade tumors are associated
with a higher incidence of metastases and worse survival. Corrado et al. 77 reported
5-year survival rates of 83%, 75%, 52%, and 0% for grades 1 through
4, respectively. These results are comparable to those described by Heney et al., 78 who
reported 100% survival for grade 1, 81% for grade 2, and 0% for grade 3. Local
recurrence was identied in 3 of 24 patients with grade 3 tumors. No survival
differences were seen for patients with papillary versus solid tumors. In the series of
Charbit et al., 23 lymph node metastases were seen exclusively in patients with
high-grade tumors. Of tumor-related deaths, 90% were in patients with high-grade
tumors. Hall et al. 79 reported a retrospective series of 252 patients treated surgically for
upper urinary tract urothelial cancers. Signicant factors for recurrence included high
tumor grade and advanced clinical stage. Older patients and patients treated with
parenchymal-sparing surgical procedures had higher rates of recurrence. In their
series of 77 patients, Akdogan et al. 80
reported from a multivariate analysis that higher recurrence rates were associated
with tumor location, higher grade, and advanced T-stage. Tumors in the ureters were
more likely to recur than tumors involving the renal pelvis. In a series of 86 patients,
Park et al. 81 also reported a higher rate of recurrence in ureteral tumors, compared to
those arising in the renal pelvis.
A prior history of bladder cancer has been reported to worsen the prognosis of
patients with second urothelial cancers involving the upper tracts. 80,82 From the
Memorial SloanKettering Cancer Center series of 129 patients, a multivariate analysis
demonstrated that patients with advanced primary tumors and a prior history of
bladder cancer were associated with worse disease-free survival. 82
Flow cytometry may aid in estimating long-term prognosis. In a multivariate
analysis, Corrado et al. 77 demonstrated that although stage and grade were the most
important prognostic indices, DNA pattern (diploid vs. nondiploid) and the number of
lesions (unifocal vs. multifocal) identied at initial diagnosis also determined
prognosis. Patients with diploid tumors had a 79% survival rate, compared with only
46% in patients with nondiploid tumors ( p = . 0003). Recent data suggest that
1250 Section III Clinical Radiation Oncology Part H Urinary Tract
hypermethylation of the promoter region of patients with urothelial cancers is
associated with a worse prognosis. Tumors of the renal pelvis and ureters
demonstrate hypermethylation in 94% of cases compared to 76% of similar-appearing
tumors in the bladder ( p < 0.0001). Hypermethylation was also associated with higher
tumor stage, tumor progression, and mortality. 83
GENERAL MANAGEMENT
Renal Cell Carcinoma
Surgery is the therapeutic foundation for the management of kidney cancer.
Radiotherapy has an important and growing role in the palliative management of
RCC. Although RCC is traditionally considered to be radioresistant, it has a clear dose
response to radiation. 84,85 As long as sufcient radiation dose is delivered to the tumor
while respecting normal tissue dose constraints, RCC radioresistance can be
overcome with modern techniques. At present, no effective, clinically proven, adjuvant
therapy exists for RCC. The kidney cancer National Comprehensive Cancer Network
(NCCN) guidelines (version 1.2013) offers the following surgical options depending on
the stage 86 :
Stage IA: Partial (preferred) or radical nephrectomy, active surveillance in
selected patients, or ablative techniques for nonsurgical candidates
Stage IB: Partial or radical nephrectomy
Stage II and III: Radical nephrectomy
Stage IV: Nephrectomy and surgical metastasectomy for a solitary metastasis if
feasible, followed by systemic rst-line therapy; cytoreductive nephrectomy if
feasible when multiple metastatic sites, followed by systemic rst-line therapy; or
systemic rst-line therapy if surgery is not feasible.
Active surveillance should be considered for patients with localized disease and
short life expectancy, or signicant comorbidities placing them at a surgical risk.
Surgery
A radical nephrectomy includes a perifascial resection of the kidney, perirenal fat,
regional lymph nodes, and ipsilateral adrenal gland. It is the preferred treatment if the
tumor extends into the inferior vena cava and usually requires the assistance of a
cardiovascular surgeon if there is a caval or atrial thrombus. An experienced team
should be involved in the context of a thrombus, as treatment-related mortality can
reach 10%. 86 This operation is undertaken by a thoracoabdominal or transabdominal
approach. Improved preoperative assessment with CT can identify patients who have
no signicant risk of adrenal gland involvement. 87 In 76% of cases, the adrenal gland
can be spared at the time of surgery. The European Organisation for Research and
Treatment of Cancer 88 ( EORTC) conducted a randomized trial of radical nephrectomy
with or without an elective lymph node dissection, and there was no survival
advantage between the two study groups. The incidence of unsuspected lymph node
metastases was low (4%). 88
Nevertheless, lymph node dissection does provide valuable prognostic information.
Radical nephrectomies should be avoided if nephron-sparing surgery is feasible
for T1a and T1b renal tumors. In this setting, nephron-sparing surgery has shown
equivalent outcomes to radical nephrectomy. 89,90 Radical nephrectomyinduced
chronic renal insufciency is associated with an increased risk of cardiovascular death
and death from any cause. 91 For this reason, nephron-sparing surgery is preferred in
T1a and T1b tumors. Nephron-sparing surgery is also preferred in patients with
hereditary RCC to preserve renal function and decrease the risk of cardiovascular
events. 92 In a matched pair analysis of 164 patients undergoing nephron-sparing
surgery at the Mayo Clinic, the disease-free survival was 79%, which compared
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favorably to 77% in patients undergoing radical nephrectomy. 93
In 117 patients with renal tumors 4 cm undergoing partial nephrectomy at the
Memorial Sloan-Kettering Cancer Center, the 5-year freedom from recurrence was
98.6% compared to
96.4% in a similar group of 173 patients undergoing radical nephrectomy. Compared
to patients undergoing partial nephrectomy, those undergoing radical nephrectomy
were at a higher risk of chronic renal insufciency. 94 There is some risk that sparing of
the renal parenchyma may leave microscopic residual tumor or inadequately treat
multifocal cancers. 9596, 97 Bilateral RCC occurs in 2% to 3% of patients. In these
patients, nephronsparing surgery is an attractive option because bilateral radical
nephrectomy sentences the patient to a lifetime of renal dialysis or the need for a
renal transplant.
Following surgery, 20% to 30% of patients with localized tumors relapse, with a
median time to relapse of 1 to 2 years, and most occurring within 3 years. 86 Although
at present there is no role for adjuvant therapy after surgery, several recent trials are
exploring the role of targeted therapy.
Patients who have local symptoms, such as hematuria, pain, hypertension, or
other paraneoplastic syndromes, may benet from palliative nephrectomy.
Spontaneous regression of metastatic renal cell cancer after nephrectomy has been
reported. In an extensive literature review, the incidence of regression of metastatic
foci induced by nephrectomy was
0.8% (4 of 474 patients). 33 Cytoreductive surgery performed to prolong or increase the
response of metastatic disease in response to systemic therapy may be benecial. 98 ,99100,
101
Thermal Ablation
Recently, the minimally invasive ablative technologies of cryoablation and
radiofrequency ablation (RFA) have emerged as potential treatment options for
clinically localized RCC, especially in the elderly or in patients with a solitary kidney or
comorbidities impeding surgery. Long-term oncologic efcacy for these modalities
remains to be established. The most favorable lesions for this approach are <4 cm
and in the periphery of the kidney. Relative contraindications for RFA and cryoablation
include distant metastases, tumors >5 cm, tumors in the hilum or central collecting
system, and life expectancy <1 year. A meta-analysis comparing cryoablation and
RFA suggested that cryoablation results in fewer re-treatments and improved local
tumor control, and that cryoablation may be associated with a lower risk of metastatic
progression compared with RFA. 101
Renal Stereotactic Body Radiotherapy
Renal stereotactic body radiotherapy (SBRT) as an alternative to thermal ablation is in
its infancy. Beitler et al. 102 identied nine RCC patients with primary kidney tumors who
received SBRT to 8 Gy ve fractions. The tumors ranged from 1.5 to 10 cm in
diameter. With a median follow up of 26.7 months, four of the nine patients were alive.
One of the nine patients failed in the ipsilateral kidney, away from the initial radiation
treatment volume, while the other eight patients had durable local control. One patient
had a radiation injury to the stomach resulting in a 30 lb weight loss in 1 month. 102 Wersall
et al. 103 reported eight patients treated with stereotactic radiotherapy to medically
inoperable primary tumors using a radiation treatment schedule of 8 Gy ve
fractions. Seven of the eight patients were locally controlled, and the median survival
exceeded 58 months. 103 Ponsky et al. 104 also reported their initial experience on three
patients treated with 4 Gy four fractions. Two of three patients had evidence of
residual disease at these low doses at the time of partial nephrectomy 8 weeks later. 104
Svedman et al. 105 reported their SBRT experience with seven patients who were
treated for metastases from a malignant kidney to its contralateral counterpart.
Dose/fractionation schedules varied between 10 Gy three fractions and 10 Gy
four fractions depending on target location and size. Local control was obtained in six
of seven patients and regained after
 Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1251

TABLE 63.5 SURVIVAL AFTER NEPHRECTOMY OR NEOADJUVANT RADIOTHERAPY AND NEPHRECTOMY FOR RENAL

CELL CARCINOMA, PROSPECTIVE RANDOMIZED TRIALS

Radiation Dose/ 5-Year Survival Rate

Study (Reference) Number of Patients Fraction Size (Gy) Treatment (%) Comments

Van der Werf-Messing 85 N 50 No significant survival

et al. (106,107) difference
89 3040/2 N + NART
Juusela et al. (108) 50 N 63 No significant survival
difference
38 33/2.2 N + NART 47

N, nephrectomy; NART, neoadjuvant radiotherapy.

retreatment in the one patient whose lesion progressed. Side effects were generally
mild, and in ve of the seven patients kidney function remained unaffected after
treatment. In two patients, the creatinine levels remained moderately elevated but
dialysis was not required. 105
after radiotherapy to a right-sided nephrectomy bed. Patients in this study received 55
Gy in 2.04 Gy daily fractions. 7 A second randomized study conducted by the
Copenhagen Renal Cancer Study Group compared patients with stage II or III renal
cell cancer treated with nephrectomy alone with patients who received nephrectomy
and adjuvant 50 Gy in 20 fractions to the kidney bed and regional ipsilateral and

Clinical Radiation Oncology

Neoadjuvant (Preoperative) Radiotherapy
Neoadjuvant radiotherapy is not recommended in patients with resectable RCC. Two
European studies were undertaken to test the efcacy of neoadjuvant/preoperative
radiotherapy in renal cell cancer (Table 63.5). A prospective randomized study of
neoadjuvant radiotherapy and nephrectomy versus nephrectomy alone was
conducted in Rotterdam. No advantage was demonstrated in patients receiving
radiotherapy with respect to overall survival or survival free from distant metastases.
In this trial, patients received a 30-Gy midplane dose to the involved kidney and
regional lymph nodes, with 2 Gy daily fractions administered over a period of 3 weeks.
Nephrectomy immediately followed the completion of radiotherapy. Neoadjuvant
radiotherapy did appear to increase the rate of complete resectability in patients with
locally advanced tumors. 106 This study was continued after the preliminary 1973
analysis. Subsequent patients received 40-Gy neoadjuvant radiotherapy. No benet
was demonstrated at the higher radiation dose. 107 In Sweden, a second prospective
randomized clinical trial was also unable to demonstrate an advantage for
neoadjuvant radiotherapy. In this trial, patients were randomly assigned to receive
neoadjuvant radiotherapy to 33 Gy in 15 fractions administered to the ank with a
betatron unit followed by nephrectomy or nephrectomy alone. Patients receiving
neoadjuvant radiotherapy had a 5-year survival rate of 47%, compared with 63% for
patients undergoing surgery alone. 108
contralateral lymph nodes. No difference in the relapse rate was found between the
two study groups. There were signicant complications involving the stomach,
duodenum, and liver in 44% of patients receiving adjuvant radiotherapy. In fact, 19%
of deaths in the radiotherapy group were attributed to radiation-induced complications. 110
Aref et al. 111 analyzed at the patterns of failure in 116 patients undergoing
nephrectomy for RCC. They observed that locoregional failure is rare following
nephrectomy and that distant metastases is the main pattern of failure. Consequently,
their data did not support the role of adjuvant radiation in RCC. 111 Moreover, a
retrospective study of 1,344 patients who underwent 1,390 partial nephrectomies for
kidney cancer found that positive surgical margins were not associated with an
increased risk of local recurrence or metastatic disease. 112
This further supports avoiding adjuvant radiotherapy for RCC.
In contrast, a meta-analysis including the two prospective randomized trials
previously mentioned and ve retrospective trials with a total of 735 patients observed
a signicant reduction in locoregional failure with adjuvant radiotherapy ( p < 0.0001).
The patient accrual for all studies combined spanned from 1968 to 1999. There was
no difference in overall survival or disease-free survival. The authors proposed a
prospective randomized trial using modern radiotherapy techniques for high-risk
patients with tumor size >5 cm, positive margins or gross residual disease, perinephric
fat invasion, capsule invasion, renal vein/inferior vena cava invasion, positive lymph
nodes, or high-grade histology. 113

Adjuvant (Postoperative) Radiotherapy

Adjuvant radiotherapy is not recommended in RCC after complete resection. Two
prospective randomized studies testing the value of adjuvant radiotherapy did not
demonstrate an advantage to patients receiving radiotherapy after surgery (Table
63.6). The rst study from New Castle, United Kingdom, demonstrated an inferior
survival for patients receiving adjuvant radiotherapy compared with those treated by
surgery alone. 109 Local recurrence rates were not affected by adjuvant radiotherapy.
No stratication of patients by tumor stage or grade was made. Four patients died of
fatal hepatotoxicity
Systemic Therapy in the Treatment for Relapsed, Metastatic,
or Unresectable Renal Cell Carcinoma
Until recently, systemic treatment for RCC was mostly limited to cytokine therapy.
High-dose interleukin-2 (IL-2; category 2)based immunotherapy can achieve
long-lasting complete or partial remissions in a small subset of patients with
predominantly clear cell carcinoma. Cytoreductive nephrectomy is recommended for
patients with metastatic RCC prior to

TABLE 63.6 SURVIVAL AFTER NEPHRECTOMY OR NEPHRECTOMY AND ADJUVANT RADIOTHERAPY FOR RENAL CELL CARCINOMA, PROSPECTIVE RANDOMIZED TRIALS

Study Number of Radiation Dose/ 5-Year Survival Local Recurrence RT-Related

(Reference) Stage Patients Fraction Size (Gy) Treatment Rate (%) (%) Mortality (%) RT Complications (%)

Fugitt (109) NS 48 55/2.04 N N + ART 47 (17/35) 36 7 18 > 20

52 (14/39) 7

Kjaer (64) II, III 33 55/2.5 N N + ART 63 a 1 19 44

32 38 a 0

RT, radiotherapy; NS, not stated; N, nephrectomy; ART, adjuvant radiotherapy.

a Interpolated from graph; number at risk not known.

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1252 Section III Clinical Radiation Oncology Part H Urinary Tract
immunotherapy based on results from phase III trials from the Southwest Oncology
Group (SWOG) and the EORTC. A combined analysis of these trials showed that
median survival favored the surgery plus interferon (IFN)- group (13.6 vs.
7.8 months for IFN- alone). 99,100, 114,115 Treatment with IL-2 is associated with
considerable toxicity and is limited to patients with excellent performance status and
normal organ function. Currently, newer targeted agents are often favored over
cytokine therapy as rst-line therapy owing to their efcacy and more favorable toxicity
prole.
At present, seven targeted agents are U.S. Food and Drug Administration (FDA)
approved in the treatment for advanced RCC: sunitinib, sorafenib, pazopanib,
temsirolimus, everolimus, axitinib, and bevacizumab in combination with IFN. As
rst-line therapy for relapsed or medically unresectable predominantly clear cell
carcinoma, the options are sunitinib (category 1), bevacizumab with IFN (category 1),
pazopanib (category 1), temsirolimus (category 1 for poor-prognosis patients),
sorafenib and high dose IL-2 for selected patients. Subsequent category 1 therapy
following a tyrosine kinase inhibitor for predominant clear cell carcinoma includes
everolimus or axitinib. Subsequent category 1 therapy following cytokine therapy for
predominant clear cell carcinoma includes sorafenib, sunitinib, pazopanib, and
axitinib. For nonclear cell RCC, temsirolimus is a category 1 agent. 86
Sunitinib, an oral small-molecule multityrosine kinase inhibitor, was studied in a
large multinational phase III trial of 750 patients with largely good- or
intermediate-prognosis metastatic clear cell RCC who had not received prior systemic
therapy. Patients were randomly assigned to 6-week cycles of sunitinib (50 mg daily
for 4 weeks, followed by 1 week off ) or IFN-
(9 million units three times per week). The objective response rate was signicantly
increased with sunitinib (47% vs. 12% with IFN- ). Median progression-free survival
was signicantly prolonged with sunitinib (11 months vs. 5 months, hazard ratio [HR]
0.54). As well, overall survival was prolonged with sunitinib (median 26.4 months vs.
21.8 months, HR 0.82, 95% condence interval [CI] 0.673 to 1.001, p = . 051). 116
Pazopanib, a multitargeted receptor tyrosine kinase inhibitor, was evaluated in a
phase III trial of 435 patients who were previously untreated or had received only
cytokine therapy and were randomly assigned to pazopanib or placebo. There was a
signicant increase in progression-free survival with pazopanib compared with
placebo (median 9.2 months vs. 4.2 months, HR 0.46, 95% CI 0.34 to 0.62). 117
Temsirolimus, a parenterally administered mTOR inhibitor, was evaluated in a
phase III trial in which 626 previously untreated poor-prognosis patients with
metastatic or recurrent RCC were randomly assigned to temsirolimus (25 mg
intravenously per week), temsirolimus (15 mg intravenously per week) plus IFN- ( escalated
up to 6 million units three times per week as tolerated), or IFN- monotherapy
(escalated up to 18 million units three times per week as tolerated). Temsirolimus as a
single agent signicantly prolonged the median overall survival compared to IFN- as
a single agent (10.9 months vs. 7.3 months; HR for mortality 0.73, 95% CI 0.58 to
0.92). Both overall and progression-free survival rates for the combination of
temsirolimus plus IFN- were not signicantly better than with IFN- alone. 56
Bevacizumab, a recombinant monoclonal antibody against vascular endothelial
growth factor (VEGF), was evaluated in the phase III AVOREN trial, where 649
previously untreated patients were randomly assigned to IFN- ( 9 million units three
times per week for 1 year) plus either bevacizumab (10 mg/kg every 2 weeks) or
placebo. There was a signicant prolongation of progression-free survival (10.2
months vs.
5.5 months, HR 0.63, 95% CI 0.45 to 0.72) and a signicantly increased objective
response rate (31% vs. 13%). 118
Sorafenib, a small-molecule multityrosine kinase and Raf inhibitor, was studied
in the phase III TARGET trial, in which 903 patients with advanced RCC who had
failed prior standard therapy were randomly assigned to sorafenib (400 mg orally
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twice daily) or placebo. The median progression-free survival was signicantly longer
in those receiving sorafenib compared with placebo (5.5 months vs. 2.8 months, HR
0.44, 95% CI 0.35 to 0.55). Overall survival with sorafenib was not signicantly
prolonged compared to placebo. 119,120
Everolimus, an orally administered mTOR inhibitor, was studied in 410 patients
with metastatic clear cell RCC whose disease had progressed on VEGF
receptortyrosine kinase inhibitors (sunitinib, sorafenib). The median progression-free
survival with everolimus was signicantly prolonged compared to placebo (4.9 months
vs. 1.9 months, HR 0.30, 95% CI 0.22 to
0.40). There was no statistically signicant difference in overall survival. 121 Other
targeted agents in development are cediranib, tivozanib, and regorafenib.
Chemotherapy has limited use in RCC because it is one of the most
chemotherapy-resistant solid tumors. For patients with relapsed or medically
unresectable stage IV disease with nonclear cell histology, gemcitabine in
combination with doxorubicin or capecitabine has shown moderate activity in patients
with sarcomatoid tumors and may be considered as rst-line therapy. 86
Metastasectomy
Patients with a solitary metastatic lesion have a 5-year survival rate of 24%
(compared with 4% for those with more than one metastatic focus), and they may
benet from aggressive therapy. 122 The resection of one or a limited number of
metastases in combination with nephrectomy or at relapse has been associated with a
13% to 50% 5-year survival in small series of selected patients. 123, 124125 Selected lung,
bone, brain, liver, and even pancreatic metastases, among other sites, have been
treated using this approach.
Whole-Brain Radiotherapy for Brain Metastases
A retrospective study of 60 patients receiving whole-brain radiotherapy (WBRT) for
RCC brain metastases showed that local control at 6 months was 21% after 3 Gy 10
fractions and 57% after higher doses of 2 Gy 20 fractions or 3 Gy 15 fractions ( p = . 013).
The local control at 12 months was 7% and 35%, respectively. The overall survival at
6 months was 29% after 3 Gy 10 fractions and 52% after higher doses ( p = . 003).
The overall survival at 12 months was 13% and 47%, respectively. The authors 126 concluded
that escalating the WBRT dose beyond 3 Gy 10 fractions could improve the
outcomes in RCC patients with brain metastases and proposed a randomized trial.
Stereotactic Radiosurgery for Brain Metastases
A retrospective study of 280 consecutive patients with metastatic brain tumors (of
which 80 were RCC) treated with Gamma Knife radiosurgery (GKS) observed that to
control symptomatic peritumoral edema, a higher marginal dose 25 Gy was
necessary. The authors 127 developed an algorithm for the management of RCC
metastases where lesions 3 cm undergo resection; lesions >2 cm with symptomatic
peritumoral edema undergo resection (because 25 Gy was not considered safe for
tumors >2 cm) and those without it GKS; and lesions 2 cm receive GKS. Another
retrospective study of 46 patients and 99 RCC brain lesions treated with radiosurgery
observed that the good-response group (as assessed by MRI) survived signicantly
longer than the poor-response group (median survival times of 18 and 9 months,
respectively; p = . 025). 128
Kano et al. 129 reported 158 consecutive RCC patients (531 lesions) who
underwent stereotactic radiosurgery (SRS). The overall survival after SRS was 60%,
38%, and 19% at 6, 12, and 24 months, respectively, with a median survival of 8.2
months. Median survival for patients with <2 brain metastases, higher KPS (>90), and
no prior WBRT was 12 months after SRS. Sustained local tumor control was achieved
in 92% of patients. Symptomatic adverse radiation effects occurred in 7%. Overall,
70% of patients improved or remained neurologically stable. 129

A B
FIGURE 63.1. Patient with renal cell carcinoma (RCC) who received 375 cGy 13 fractions over 5 weeks to a painful, fixed, and pulsatile cutaneous RCC metastasis. Appearance
after 3 fractions ( A) and complete response 6 months after the completion of treatment ( B). The patient had durable pain palliation without local recurrence until death. (From Gay HA,
et al. Complete response in a cutaneous facial metastatic nodule from renal cell carcinoma after hypofractionated radiotherapy. Dermatol Online J 2007;13:6; 2007 Dermatology
Online Journal.)
Conventional Radiotherapy for Extracranial Metastases
Palliative radiotherapy is effective in relieving symptoms from metastatic RCC. 130131, 132,
133 A patient with a solitary bone metastasis may have a long survival time, and a
sufcient radiation dose should be administered to allow durable pain relief. If surgery
is used to remove a metastatic lesion, postoperative radiotherapy is indicated to
prevent its recurrence. In a prospective phase II study using validated quality-of-life
questionnaires, Lee et al. 132 from the Princess Margaret Hospital demonstrated that
83% of patients treated for pain had experienced signicant pain relief with 30-Gy
delivered in 10 fractions. DiBiase et al. 84
observed a dose response in the palliative treatment of 107 patients with RCC. A
biologically effective dose (BED) >50 Gy 10
( / ratio of 10) was associated with a statistically signicant increased rate of
response: 59% versus 39% ( p = 0.001). Figure 63.1 illustrates a painful RCC
cutaneous metastasis that had a complete response after 375 cGy 13 fractions
(BED = 67 Gy 10) over 5 weeks. The lesion was treated with electrons, a custom bolus,
and a 2-cm peripheral margin. 134
Stereotactic Body Radiation Therapy for
Extracranial Metastases
In a series of 50 patients with metastatic RCC, Wersall et al. 103
reported that stereotactically delivered radiation to sites including the lung, liver, and
adrenal resulted in complete regression in 30% of cases and either partial regression
or stabilization of the lesions in 60%. Of 162 treated tumors, only 3 tumors recurred.
Dose and fractionation ranged from 8 Gy four fractions, 10 Gy
four fractions, and 15 Gy three fractions all delivered in 1 week.
A retrospective study of 17 patients with metastatic melanoma (28 lesions) and 13
patients with RCC (25 lesions) to the lung, liver, and bone concluded that to achieve
high rates of durable control, SBRT of at least 16 Gy three fractions were necessary. 135
Another retrospective study of 126 extracranial metastases in 103 patients treated
with single fractions observed that RCC displayed a profound dose-response effect,
with an 80% local relapse-free survival at the high-dose level (23 to 24 Gy) versus
37% at low doses ( 22 Gy) ( p = . 04). 136
Further analysis of RCC patients revealed that a single 24-Gy dose had a 3-year local
progression-free survival of 88%. 85
In study of 48 patients (55 lesions) with metastatic RCC to the spine, patients
received 24 Gy one fraction, 9 Gy three
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Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1253
Clinical Radiation Oncology
fractions, or 6 Gy ve fractions. The actuarial 1-year spine tumor progression-free
survival was 82.1%. At pretreatment baseline, 23% of patients were pain free; at 1
month and 12 months post-SBRT, 44% and 52% of patients were pain free,
respectively. No grade 3 or 4 neurologic toxicity was observed. 137
A unique case report showed how a large 7-cm RCC metastasis in the
parieto-occipital vertex of the skull was treated with SBRT to 7 Gy ve fractions. No
signicant bleeding was observed 5 weeks later at the time of tumor resection.
Histologically, the tumor was largely avascular and necrotic, and the authors 138 proposed
SBRT as a potential alternative to preoperative embolization.
A potential added benet of extracranial stereotactic radiotherapy is what is called
the abscopal effect, in which there is tumor response at a distance from the irradiated
volume. Wersall et al. 139 observed an abscopal effect in 4 out of 28 RCC patients with
treated and untreated metastatic lesions. In these 4 patients, nonirradiated
metastases regressed either temporarily or seemingly permanently after treatment
with SBRT of either the primary tumor or other metastatic lesions. The authors 139 ndings
argued for a more active and liberal use of SBRT in metastatic RCC. They suggested
that further studies were necessary to dene the underlying mechanisms behind such
responses or to combine SBRT with immunomodulating agents.
Ongoing Phase III Clinical Trials
There are numerous clinical trials taking place in advanced RCC. Many of these trials
are employing antiangiogenesis agents, thymidine kinase inhibitors, mTOR inhibitors,
and immunological therapies, alone or in combination.
Renal Pelvis and Ureter Carcinoma
Surgery is the therapeutic foundation for the management of renal pelvis and ureter
carcinoma. The bladder cancer NCCN guidelines (version 1.2013) recommend the
following treatment options for renal pelvis low-grade tumors: nephroureterectomy
with a cuff of bladder, a nephron-sparing procedure, or endoscopic resection with or
without postsurgical intrapelvic chemotherapy or bacille Calmette-Guerin (BCG). 140 High-grade
renal pelvis tumors or large tumors that invade the renal parenchyma have the
following management options: nephroureterectomy with a cuff of bladder and
regional lymphadenectomy,
1254 Section III Clinical Radiation Oncology Part H Urinary Tract
with neoadjuvant chemotherapy in selected patients, extrapolating from bladder
cancer series.
The management of ureter tumors depends on the location of the tumorupper,
mid, or distaland on disease extent. Neoadjuvant chemotherapy may be considered
in selected patients. 141 Tumors in the upper ureter are more commonly treated with
nephroureterectomy with a cuff of bladder and regional lymphadenectomy for
high-grade tumors. Low-grade tumors may be managed endoscopically.
Tumors in the mid portion of the ureter can be managed according to grade and
size. Small, low-grade tumors can be treated with ureteroureterostomy, endoscopic
resection, or nephroureterectomy with a cuff of bladder with or without regional
lymphadenectomy. High-grade lesions are managed with nephroureterectomy with a
cuff of bladder and regional lymphadenectomy with consideration of neoadjuvant
chemotherapy in selected patients.
Finally, distal ureteral tumors may be managed with a distal ureterectomy and
reimplantation of the ureter (ideal if feasible), endoscopic resection, or
nephroureterectomy with a cuff of bladder and regional lymphadenectomy for
high-grade tumors. Neoadjuvant chemotherapy may be considered in select patients.
For both renal pelvis and ureter tumors, once the pathologic staging is obtained,
patients with pathologic stage pT2, pT3, pT4, or N+ should be considered for adjuvant
chemotherapy with or without radiotherapy.
Surgery
Radical nephroureterectomy is the only potentially curative treatment for most patients
with urothelial carcinoma of the renal pelvis or ureter. This operation includes removal
of the contents of Gerotas fascia, including the ipsilateral ureter with a cuff of bladder
at its distal extent. Less radical surgeries have been plagued by high local or regional
recurrence rates, sometimes approaching 30%. 142 Hall et al. 79 reported an increase rate
of recurrence when parenchymal-sparing procedures were performed. Conservative
surgical excision should be considered only in patients with low-grade, low-stage,
solitary tumors in whom radical nephrectomy is not indicated because of poor kidney
function or an absent contralateral kidney.
Adjuvant Radiotherapy
There are no randomized trials on the role of postoperative radiotherapy in patients
who have had a complete resection of an upper urinary tract cancer. Tumors of the
renal pelvis and ureter have a signicantly high local recurrence rate after
nephroureterectomy, particularly in patients with high-grade tumors or deep invasion. 53
Retrospective studies suggest that adjuvant radiotherapy may diminish the likelihood
of local recurrence, although it does not appear to have an impact on overall survival
or reduction of future distant metastases. 34,143
Cozad et al. 143 reported a retrospective study of 94 patients with urothelial
carcinoma of the renal pelvis, of which 77 patients had resections without residual. On
multivariate analysis, adjuvant radiotherapy had a signicant effect on local control ( p
= . 02). In terms of survival, the use of adjuvant radiotherapy was of borderline
signicance ( p = . 07). Of the 27 patients who were excluded from local failure and
survival analysis, 19 patients had unresectable local disease, and of these, 11
patients received radiotherapy. Two long-term disease-free survivors in this group
received 45 and 50.4 Gy, respectively.The authors 34 recommended consideration of
adjuvant radiotherapy in patients with high grade or stage, close surgical margins, or
positive lymph nodes to improve local control.
In another retrospective study of 133 patients with urothelial carcinoma of the
renal pelvis, 67 patients received externalbeam radiotherapy following surgery
(radiotherapy group), and 66 patients received intravesical chemotherapy
(nonradiotherapy group). The clinical target volume included the renal fossa,
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the course of the ureter to the entire bladder, and the paracaval and para-aortic lymph
nodes (Fig. 63.2). The tumor bed or residual tumor was targeted in 14 patients. The
median radiation dose administered was 50 Gy. There was a signicant difference
between the survival rates for these groups based on patients with stage T3 and T4
cancer. A signicant difference was observed in the bladder tumor relapse rate
between the irradiated and nonirradiated bladder groups ( p = . 004). The authors 144 concluded
that radiotherapy may improve the overall survival for patients with T3 and T4 cancer
of the renal pelvis or ureter and may delay bladder tumor recurrences.
The patterns of failure were described in 252 patients undergoing surgery at the
University of Texas Southwest Medical Center for urothelial carcinoma of the upper
urinary tract. 79
Local recurrence occurred only 9% of the time, whereas new invasive urothelial
tumors or distant metastases occurred in 69% and 22% of cases, respectively.
Isolated local recurrences were rare. Another series from the Princess Margaret
Hospital conrms the high rate of distant metastases. Although local failure occurred
in 35% of patients with locally advanced disease, most patients also experienced
distant metastases as well. 145
Systemic Chemotherapy
The pathologic similarity of urothelial carcinoma of the renal pelvis and ureter to
bladder cancer has encouraged medical oncologists to use similar chemotherapeutic
regimens in the management of upper-tract urothelial carcinomas. The MVAC
regimen (methotrexate, vinblastine, doxorubicin, and cisplatin) has objective response
rates of almost 70% in patients with metastatic urothelial carcinoma of the bladder,
ureter, and kidney. 146,147 Gemcitabine plus cisplatin is also effective in urothelial
carcinoma. Palliative chemotherapy may be considered in patients with metastatic
disease.
A series of 31 patients treated with adjuvant radiotherapy for nonmetastatic
urothelial cancer of the upper urinary tract was reported by Czito et al. 148 Nine patients
also received chemotherapy consisting of methotrexate, cisplatin, and vinblastine
prior to receiving radiation concurrent with cisplatin. The 5-year locoregional control
rate was 67%. The 5-year overall and diseasespecic survival appeared to be
improved with the administration of concurrent chemotherapy. The overall survival for
patients receiving concurrent chemotherapy and radiotherapy was 67% compared to
27% receiving postoperative radiation alone ( p = . 01). The disease-free survival for
patients receiving concurrent chemotherapy and radiotherapy was 76% compared to
41% receiving postoperative radiation alone ( p = . 06). In circumstances in which
conservative resection is performed, postoperative radiotherapy should be
considered. Conservative surgical options in selected cases include laparoscopic
nephroureterectomy, nephrectomy and partial ureterectomy, endoscopic resection,
and fulguration. The role of lymph node dissection in this disease is unclear. Patients
who have the highest risk of lymph node metastases also have a high risk of systemic
disease.
Ongoing Phase III Clinical Trials
Phase III Randomized Study of Gemcitabine Hydrochloride and Cisplatin with Versus
without Bevacizumab in Patients with Advanced Transitional Cell Carcinoma of the
Urinary Tract (NCT00942331).
RADIOTHERAPY TECHNIQUES
Normal Tissue Dose Constraints
Several organs at risk have to be taken into consideration when palliating an
unresected kidney tumor or a kidney tumor bed recurrence. These organs include the
spinal cord, liver, spleen, stomach, duodenum, small bowel, any normal contralateral
or ipsilateral kidney, and normal adrenal gland(s).
 Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1255

A B

Clinical Radiation Oncology

C D

E F

FIGURE 63.2. Dose distribution of a patient with renal pelvis cancer and beam arrangements of 0-degree, 129-degree, and 229-degree gantry.
A: Renal fossa. B,C: Course of ureter. D: Bladder. Digitally reconstructed radiograph for views of 0-degree gantry ( E) and 90-degree gantry ( F).
Internal pink and yellow lines represent the clinical tumor volume (CTV) 50 and CTV 40, respectively. (From Chen B, et al. Radiotherapy may improve overall survival of patients with T3
and T4 transitional cell carcinoma of the renal pelvis or ureter and delay bladder tumour relapse. BMC Cancer
2011;11:297; 2011 Chen et al; licensee BioMed Central Ltd.)

There are no established dose constraints for sparing the remaining kidney after
nephrectomy or in the palliative setting when both kidneys are present. In the context
of two normal kidneys, the Qualitative Analyses of Normal Tissue Effects in the Clinic
(QUANTEC) Kidney Cancer Panel recommended a
mean bilateral kidney dose <15 to 18 Gy and a bilateral kidney dose-volume
histogram (DVH) with a V 12 < 55%, V 20 < 32%, V 23
< 30%, and V 28 < 20%. 149 The dose to the stomach should be kept at <45 Gy, and the
small bowel V 45 < 195 cc when it is contoured as a bowel bag 150 ( Fig. 63.3). The male
and female

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1256 Section III Clinical Radiation Oncology Part H Urinary Tract
Norm.
volume
A B
FIGURE 63.3. Patient with metastatic clear cell renal cell carcinoma (RCC) who developed a painful, destructive, 55-cc metastasis in the left 12th rib. Treatment plan ( A) and
dose-volume histogram ( B) showing the normalized volume versus dose (cGy). The metastasis was treated with 10 Gy five fractions using a six-field step and shoot, 6-MV IMRT
technique. The isodose-based methodology was used to evaluate the plan. 158 The skin was limited to the 40% isodose (400 cGy five fractions), the spinal cord to the 30% isodose
(300 cGy five fractions), and the spleen to the 10% isodose (100 cGy five fractions) or less as feasible. The cyan-filled contour is the gross tumor volume (GTV). Doses to the
bowel, liver, remaining kidney, and duodenum were well below tolerance. Patient was pain free one month later.
Radiation Therapy Oncology Group (RTOG) normal pelvis atlases illustrate how to
contour the bowel bag (accessible at
http://www.rtog.org/CoreLab/ContouringAtlases.aspx). The mean liver dose should be
kept at <30 to 32 Gy, excluding patients with pre-existing liver disease or
hepatocellular carcinoma who have a lower tolerance. Sparing at least 700 cc of liver
from radiation is another potential strategy to avoid complications. 151 There are no
recognized splenic or adrenal dose constraints. Nevertheless, based on the spleens
exquisite radiosensitivity and experience with palliative radiotherapy for
myeloproliferative disorders, 152 it seems prudent to limit the spleen to a total of 5 to 10
Gy. The spinal dose should be limited to an absolute maximum of 45 Gy.
Renal Cell Carcinoma
Neoadjuvant or adjuvant radiotherapy is not routinely recommended for patients with
RCC. However, there may be special cases where the clinician may consider
neoadjuvant radiotherapy to improve respectability or adjuvant radiotherapy if there
are clinical tumor features suggestive of a high risk of local recurrence. Careful
planning is paramount because ignoring any of the critical structures surrounding the
kidney or nephrectomy bed could result in serious, even fatal, patient toxicity.
Patients receiving radiotherapy to the kidney may be simulated supine, arms up,
using a wing board or alpha cradle, a wire on the surgical scar, and a planning CT
scan. The kidneys are mobile organs and move vertically within the retroperitoneum
an average of 0.9 to 1.3 cm, and as much as 4 cm during normal respiration. 153154, 155 In
going from the supine to upright position, the kidneys can shift inferiorly between 0.5
cm and
7.5 cm with an average of 3.6 cm. 156 This nding, although critical for total body
irradiation treatments, further highlights the mobility of the kidneys.
The high complication rates reported in the prospective trials of postoperative
radiotherapy have taught radiation oncologists an important lesson regarding radiation
therapy planning, patient selection, and the tolerance of the upper abdominal viscera.
Intensity-modulated radiotherapy (IMRT) may be a reasonable consideration owing to
the sensitivity of adjacent surrounding structures. If IMRT is considered, a plan to
manage the uncertainties in target localization such as fourdimensional (4D) CT
treatment planning, image-guided radiotherapy (IGRT), abdominal immobilization
devices, gating, or breathing control needs to be considered. Renal function scans
may assist in the treatment planning or patient selection process, although this has
not been formally studied.
In unresectable lesions, 40 to 50 Gy neoadjuvant radiotherapy (1.8 to 2 Gy per
fraction) directed to the kidney tumor and
Dose volume histogram
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Spleen
Cord
0.0 0
1,000 2,000 3,000 4,000 5,000 6,000
Dose (cGy)
regional lymphatics may improve resectability. 107 Multiple-eld techniques, similar to
those described for adjuvant radiotherapy, should be considered in patients receiving
preoperative treatment.
CT-based treatment planning contributes to good local control with minimal
morbidity. Careful denition of the target volume to encompass the nephrectomy bed,
lymph node drainage sites, and surgical clips on the planning CT scan is important.
Exclusive use of anterior- and posterior-eld arrangements, particularly on the right
side, is likely to result in irradiation of large volumes of bowel and liver beyond
tolerance. The use of multiple beams is paramount for protecting the surrounding
normal structures. Total radiation doses of 45 to 50 Gy (1.8 to 2 Gy per fraction) to the
nephrectomy bed and regional lymph nodes with a boost to small volumes of
microscopic or gross residual disease of 10 to 15 Gy (total dose 50 to 60 Gy) are
appropriate. Stein et al. 157 reported two scar recurrences and recommended that the
incision site be included in the target volume. If the scar cannot be covered without
increasing the amount of normal tissue irradiated, an additional electronbeam eld to
treat the scar may be considered.
Figure 63.3 illustrates a patient with metastatic clear cell RCC, with sarcomatoid
and rhabdoid differentiation, status post left radical nephrectomy, pT3aN1M1. The
kidney tumor was Fuhrman nuclear grade IV and 15.5 cm in diameter. The patient
was treated with temsirolimus, pazopanib, bevacizumab, and nally Adriamycin plus
gemcitabine with some objective response. The patient developed a painful,
destructive, 55-cc metastasis in the left 12th rib. The metastasis was treated with 10
Gy ve fractions using a six-eld (RPO 210, LAO 60, LT LAT 90, LPO 120, LPO 150,
PA) step and shoot, 6-MV IMRT technique. The isodose-based methodology was
used to evaluate the plan and is explained in detail in Gay et al. 158 The skin was limited
to the 40% isodose (400 cGy ve fractions), the spinal cord to the 30% isodose (300
cGy ve fractions), and the spleen to the 10% isodose (100 cGy ve fractions) or
less as feasible. Doses to the bowel, liver, remaining kidney, and duodenum were well
below tolerance (Fig.
63.3A). Daily imaging with two-dimensional (2D):2D match and cone-beam CT was
used prior to the delivery of the ve fractions over 3 weeks.
Because of the possibility of long survival even in the presence of distant
metastases, aggressive treatment for palliation should be considered in patients who
have limited metastatic disease with good performance status. Treatment elds
should encompass metastatic foci with adequate (2- to 3-cm) margins. (See the
following previous sections: Conventional Radiotherapy for Extracranial Metastases,
Whole-Brain Radiotherapy for
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Brain Metastases, and Stereotactic Radiosurgery for Brain Metastases.)
Renal Pelvis and Ureter Carcinoma
Adjuvant radiotherapy has been used in the management of renal pelvis and ureter
cancers. For elective radiotherapy, the clinical target volume should include the renal
fossa, the course of the ureter to the bladder, the entire bladder, and the paracaval
and para-aortic lymph nodes 144 ( Fig. 63.2). As in RCC, CT-based planning may
facilitate dosimetric coverage of the regions at risk while minimizing dose to normal
tissues. Radiation doses of 45 to 50 Gy at 1.8 to 2 Gy per day are appropriate to treat
subclinical and microscopic disease. For more extensive disease (e.g., multiple
positive nodes), R1 (microscopic positive margins) or R2 (macroscopic residual
margins) resections, a boost of 5 to 10 Gy should be considered. For unresectable or
gross residual disease, higher doses may be necessary. In this case, multiple-eld
arrangements including oblique and lateral elds with eld reductions are important to
minimize toxicity to surrounding normal structures (Fig. 63.2). CT-based simulation,
three-dimensional (3D) treatment planning, and contrast-enhanced radiographs are
helpful in dening the radiotherapy target volume. IMRT can be considered if organ
motion is managed to avoid underdosing the planning target volume. Chemotherapy
may allow a lower radiation dose for gross disease. Cozad et al. 143 reported two
patients with gross residual disease who achieved local tumor control with radiation
doses of 45 and 50.4 Gy. One of these patients had a pathologically proven complete
response at reoperation after receiving radiotherapy and concomitant MVAC.
FOLLOW-UP
Renal Cell Carcinoma
The NCCN Kidney Cancer Panel recommends that patients be seen every 6 months
for the rst 2 years after surgery, then annually thereafter. Each visit should include a
history and physical examination and comprehensive metabolic panel (blood urea
nitrogen, serum creatinine, calcium, LDH, and liver function tests). The NCCN
recommends abdominal and chest imaging 2 to 6 months after surgery and as
clinically indicated thereafter. 86 The UCLA UISS (described in the Prognostic Factors
section) uses the older 1997 TNM staging and also provides surveillance
recommendations according to risk category. 159 The greatest risk of recurrence
following surgery for RCC is in the rst 3 to 5 years; however, recurrences can occur
more than a decade later. Early diagnosis of metastatic disease could identify patients
who may be candidates for metastasectomy and potentially result in long-term
survival.
Renal Pelvis and Ureter Carcinoma
Patients with urothelial carcinoma of the upper urinary tract are at a high risk of
urothelial tumors of the bladder, thus monitoring with cystoscopy at periodic intervals
is necessary. For patients who have undergone a renal-sparing procedure, imaging
with CT or MRI and/or ureteroscopy may be necessary. The NCCN Bladder Cancer
Panel recommends a cystoscopy every 3 months for 1 year, then at increasing
intervals. For endoscopic procedures, imaging (intravenous pyelogram [IVP], CT
urography, retrograde pyelogram, ureteroscopy, or MRI urogram) of the upper tract
collecting system at 3- to 12-month intervals is recommended. Imaging to exclude
metastatic disease such as a chest radiograph, or CT scan or MRI, should be
considered.
SEQUELAE OF RADIOTHERAPY
The side effects and complications from radiotherapy for cancer of the kidney, renal
pelvis, and ureters are similar to those
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Chapter 63 Cancer of the Kidney, Renal Pelvis, and Ureter 1257
expected from irradiation of the upper abdomen and pelvis. These side effects include
nausea, vomiting, diarrhea, and abdominal cramping. Patients with right-sided tumors
may have signicant portions of the liver irradiated, and radiation-induced liver
damage is possible. The Copenhagen Renal Cancer Study Group reported that 12
(44%) of 27 patients developed signicant complications: 3 patients had biochemical
changes indicating radiation hepatitis, 3 patients had duodenum and small bowel
stenosis, and 6 patients had duodenum and small bowel bleeding. 110 Surgery was
performed on 4 of 9 patients with bowel-related radiotherapy complications, and 5
patients died of treatment-related complications. The total radiation dose in this study
was 50 Gy given in 2.5-Gy fractions per daya fractionation schedule that may
account for the high rate of complications. Fugitt et al. 109 also reported four cases of
liver failure among 52 patients who received postoperative radiotherapy.
The complication rate after radiotherapy for tumors of the kidney and upper
urinary tract is related to the total dose, fraction size, and technique of irradiation.
Clinical Radiation Oncology
CT-based simulation and 3D treatment planning may decrease the risk of
complications after elective radiotherapy in patients with upper urinary tract
malignancies. In a series of 56 patients receiving 46 Gy postoperatively reported by
Stein et al., 157 signicant toxicity was seen in only 3 patients (5%). These 3 patients
were treated before the routine use of CT-based treatment planning. In 12 patients
receiving a median dose of 45 Gy reported by Kao et al., 160 no long-term
treatment-related morbidity was identied.
ACKNOWLEDGMENTS
Thanks to Michael Watts, MS, CMD, for masterfully planning the case in Figure 63.3
and obtaining screen captures of the plan.
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62. Pantuck AJ, et al. Renal cell carcinoma with retroperitoneal lymph nodes. Impact on survival and benets of
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63. Vasselli JR, et al. Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal
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66. Fuhrman SA, Lasky LC, Limas C. Prognostic signicance of morphologic parameters in renal cell
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67. Lohse CM, et al. Comparison of standardized and nonstandardized nuclear grade of renal cell carcinoma to
predict outcome among 2,042 patients. Am J Clin Pathol 2002;118(6):877886.
68. Bretheau D, et al. Prognostic value of nuclear grade of renal cell carcinoma.
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70. Kattan MW, et al. A postoperative prognostic nomogram for renal cell carcinoma.
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71. Frank I, et al. An outcome prediction model for patients with clear cell renal cell carcinoma treated with
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72. Zisman A, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin
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73. Thompson RH, Kwon ED. Signicance of B7-H1 overexpression in kidney cancer.
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74. Bui MH, et al. Prognostic value of carbonic anhydrase IX and KI67 as predictors of survival for renal clear
cell carcinoma. J Urol 2004;171(6 Pt 1):24612466.
75. Jiang Z, et al. Analysis of RNA-binding protein IMP3 to predict metastasis and prognosis of renal-cell
carcinoma: a retrospective study. Lancet Oncol 2006; 7(7):556564.
76. Raman JD, et al. Impact of tumor location on prognosis for patients with upper tract urothelial carcinoma
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77. Corrado F, et al. Transitional cell carcinoma of the upper urinary tract: evaluation of prognostic factors by
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79. Hall MC, et al. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary
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80. Akdogan B, et al. Prognostic signicance of bladder tumor history and tumor location in upper tract
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81. Park S, et al. The impact of tumor location on prognosis of transitional cell carcinoma of the upper urinary
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82. Mullerad M, et al. Bladder cancer as a prognostic factor for upper tract transitional cell carcinoma. J Urol 2004;172(6
Pt 1):21772181.
83. Catto JW, et al. Promoter hypermethylation is associated with tumor location, stage, and subsequent
progression in transitional cell carcinoma. J Clin Oncol 2005; 23(13):29032910. Epub 2005 Mar 7.
84. DiBiase SJ, et al. Palliative irradiation for focally symptomatic metastatic renal cell carcinoma: support for
dose escalation based on a biological model. J Urol
1997;158(3 Pt 1):746749.
85. Zelefsky MJ, et al. Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided
intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma. Int J Radiat Oncol
Biol Phys 2012;82(5):17441748.
86. National Comprehensive Cancer Network. Kidney cancer. In: NCCN clinical prac-
tice guidelines in oncology 2012, Version 1.2013. Available at: http://www.nccn.
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87. Gill IS, et al. Adrenal involvement from renal cell carcinoma: predictive value of computerized tomography. J
Urol 1994;152(4):10821085.
88. Blom JH, et al. Radical nephrectomy with and without lymph-node dissection: nal results of European
Organization for Research and Treatment of Cancer (EORTC) randomized phase 3 trial 30881. Eur Urol 2009;55(1):2834.
89. Hollingsworth JM, et al. Surgical management of low-stage renal cell carcinoma: technology does not
supersede biology. Urology 2006;67(6):11751180.
90. Leibovich BC, et al. Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and
7 cm results in outcome similar to radical nephrectomy. J Urol 2004;171(3):10661070.
91. Weight CJ, et al. Nephrectomy induced chronic renal insufciency is associated with increased risk of
cardiovascular death and death from any cause in patients with localized cT1b renal masses. J Urol 2010;183(4):13171323. nccn.org/professionals/physician_gls/pdf/bladder.pdf.
92. Weight CJ, et al. Partial nephrectomy is associated with improved overall survival compared to radical
nephrectomy in patients with unanticipated benign renal tumours. Eur Urol 2010;58(2):293298.
93. Lau WK, et al. Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with
unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc 2000;75(12):12361242.
94. McKiernan J, et al. Natural history of chronic renal insufciency after partial and radical nephrectomy. Urology 2002;59(6):816820.
97. Whang M, et al. The incidence of multifocal renal cell carcinoma in patients who are candidates for partial
nephrectomy. J Urol 1995;154(3):968970; discussion 970971.
98. Bennett RT, et al. Cytoreductive surgery for stage IV renal cell carcinoma. J Urol
1995;154(1):3234.
101. Kunkle DA, Uzzo RG. Cryoablation or radiofrequency ablation of the small renal mass: a meta-analysis. Cancer
2008;113(10):26712680.
102. Beitler JJ, et al. Denitive, high-dose-per-fraction, conformal, stereotactic external radiation for renal cell
carcinoma. Am J Clin Oncol 2004;27(6):646648.
103. Wersall PJ, et al. Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma. Radiother
Oncol 2005;77(1):8895. Epub 2005 Jun 20.
104. Ponsky LE, et al. Renal radiosurgery: initial clinical experience with histological evaluation. Surg Innov 2007;14(4):265269.
105. Svedman C, et al. Stereotactic body radiotherapy of primary and metastatic renal lesions for patients with
only one functioning kidney. Acta Oncol 2008;47(8):15781583.
106. Van der Werf-Messing B. Proceedings: carcinoma of the kidney. Cancer 1973;32(5):
10561061.
107. Van der Werf-Messing B, van der Heul RO, Ledeboer RC. Renal cell carcinoma trial. Strahlentherapie
[Sonderb] 1981;76:169715.
108. Juusela H, et al. Preoperative irradiation in the treatment of renal adenocarcinoma. Scand J Urol Nephrol 1977;11(3):277281.
109. Fugitt RB, Wu GS, Martinelli LC. An evaluation of postoperative radiotherapy in hypernephroma
treatment-a clinical trial. Cancer 1973;32(6):13321340.
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110. Kjaer M, Frederiksen PL, Engelholm SA. Postoperative radiotherapy in stage II and III renal adenocarcinoma.
A randomized trial by the Copenhagen Renal Cancer Study Group. Int J Radiat Oncol Biol Phys 1987;13(5):665672.
111. Aref I, Bociek RG, Salhani D. Is post-operative radiation for renal cell carcinoma justied? Radiother Oncol 1997;43(2):155157.
112. Yossepowitch O, et al. Positive surgical margins at partial nephrectomy: predictors and oncological
outcomes. J Urol 2008;179(6):21582163.
113. Tunio MA, Hashmi A, Ra M. Need for a new trial to evaluate postoperative radiotherapy in renal cell
carcinoma: a meta-analysis of randomized controlled trials. Ann Oncol 2010;21(9):18391845.
114. Flanigan RC, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J
Urol 2004;171(3):10711076.
115. Polcari AJ, et al. The role of cytoreductive nephrectomy in the era of molecular targeted therapy. Int J Urol 2009;16(3):227233.
116. Motzer RJ, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients
with metastatic renal cell carcinoma. J Clin Oncol 2009; 27(22):35843590.
randomized phase III trial. J Clin Oncol 2010;28(6):10611068.
118. Escudier B, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a
randomised, double-blind phase III trial. Lancet
2007;370(9605):21032111.
119. Escudier B, et al. Sorafenib for treatment of renal cell carcinoma: nal efcacy and safety results of the phase
III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009;27(20):33123318.
120. Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J
Med 2007;356(2):125134.
121. Motzer RJ, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: nal results and analysis of
prognostic factors. Cancer 2010;116(18):42564265.
124. Piltz S, et al. Long-term results after pulmonary resection of renal cell carcinoma metastases. Ann Thorac Surg 2002;73(4):10821087.
125. Zerbi A, et al. Pancreatic metastasis from renal cell carcinoma: which patients benet from surgical
resection? Ann Surg Oncol 2008;15(4):11611168.
126. Rades D, Heisterkamp C, Schild SE. Do patients receiving whole-brain radiotherapy for brain metastases
from renal cell carcinoma benet from escalation of the radiation dose? Int J Radiat Oncol Biol Phys 2010;78(2):398403.
127. Shuto T, et al. Treatment strategy for metastatic brain tumors from renal cell carcinoma: selection of gamma
knife surgery or craniotomy for control of growth and peritumoral edema. J Neurooncol 2010;98(2):169175.
128. Kim WH, et al. Early signicant tumor volume reduction after radiosurgery in brain metastases from renal cell
carcinoma results in long-term survival. Int J Radiat Oncol Biol Phys 2012;82(5):17491755.
129. Kano H, et al. Outcome predictors of gamma knife radiosurgery for renal cell carcinoma metastases. Neurosurgery
2011;69(6):12321239.
132. Lee J, et al. A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma. Cancer 2005;104(9):18941900.
134. Gay HA, et al. Complete response in a cutaneous facial metastatic nodule from renal cell carcinoma after
hypofractionated radiotherapy. Dermatol Online J 2007;13(4):6.
135. Stinauer MA, et al. Stereotactic body radiation therapy for melanoma and renal cell carcinoma: impact of
single fraction equivalent dose on local control. Radiat Oncol 2011;6(1):34.
136. Greco C, et al. Predictors of local control after single-dose stereotactic imageguided intensity-modulated
radiotherapy for extracranial metastases. Int J Radiat Oncol Biol Phys 2011;79(4):11511157.
137. Nguyen Q-N, et al. Management of spinal metastases from renal cell carcinoma using stereotactic body
radiotherapy. Int J Radiat Oncol Biol Phys 2010; 76(4):11851192.
138. Mitera G, et al. Preoperative stereotactic body radiotherapy to a skull renal cell metastasis: an alternative to
preoperative embolization? J Palliat Med 2011;14(2): 157160.
139. Wersall PJ, et al. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in
metastatic renal cell carcinoma. Acta Oncol 2006; 45(4):493497.
140. National Comprehensive Cancer Network. Bladder cancer. In: NCCN clinical
practice guidelines in oncology 2012, Version 1.2013 Available at: http://www.
141. Audenet F, et al. The role of chemotherapy in the treatment of urothelial cell carcinoma of the upper urinary
tract (UUT-UCC). Urol Oncol 2010 Sep 28. [Epub ahead of print].
143. Cozad SC, et al. Adjuvant radiotherapy in high stage transitional cell carcinoma of the renal pelvis and ureter.
Int J Radiat Oncol Biol Phys 1992;24(4):743
745.
144. Chen B, et al. Radiotherapy may improve overall survival of patients with T3/T4 transitional cell carcinoma of
the renal pelvis or ureter and delay bladder tumour relapse. BMC Cancer 2011;11(1):297.
145. Catton CN, et al. Transitional cell carcinoma of the renal pelvis and ureter; outcome and patterns of relapse in
patients treated with postoperative radiation.
Urol Oncol 1996;2:171176.
148. Czito B, et al. Adjuvant radiotherapy with and without concurrent chemotherapy for locally advanced
transitional cell carcinoma of the renal pelvis and ureter.
J Urol 2004;172(4 Pt 1):12711275.
149. Dawson LA, et al. Radiation-associated kidney injury. Int J Radiat Oncol Biol
Phys 2010;76(3 Suppl):S108S115.
150. Kavanagh BD, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol
Phys 2010;76(3 Suppl):S101S107.
151. Pan CC, et al. Radiation-associated liver injury. Int J Radiat Oncol Biol Phys
2010;76(3 Suppl):S94S100.
155. Van Sornsen de Koste JR, et al. Renal mobility during uncoached quiet respiration: an analysis of 4DCT
scans. Int J Radiat Oncol Biol Phys 2006;64(3):799803.
157. Stein M, et al. The value of postoperative irradiation in renal cell cancer.
Radiother Oncol 1992;24(1):4144.
158. Gay HA, et al. Isodose-based methodology for minimizing the morbidity and mortality of thoracic
hypofractionated radiotherapy. Radiother Oncol 2009; 91(3):369378.
159. Lam JS, et al. Postoperative surveillance protocol for patients with localized and locally advanced renal cell
carcinoma based on a validated prognostic nomogram and risk group stratication system. J Urol 2005;174(2):466472;
discussion 472; quiz 801.
 Chapter 64 Bladder Cancer 1259

Chapter 64
Bladder Cancer

Nicholas James, Richard T. Bryan, Richard Viney, Prashant Patel, and Syed A. Hussain

The basic management of bladder tumors has remained essentially unchanged for
over 50 years, and in spite of its importance in terms of incidence, prognosis, and
cost, bladder cancer research remains signicantly underfunded. 1
Every aspect of the perceptions and management of this disease requires change;
bladder, with the vas deferens entering the middle of the V. The ureters enter into
departing from the use of the term supercial bladder cancer is just the rst step, 2 because
the term is both inaccurate and implies an inappropriate lack of importance. In
particular, given the very high costs to health care systems from long-term
surveillance and treatment of the disease, 3 it is particularly surprising that there has not
superiorly to the bladder, which is potentially a critical site to consider when planning
radiotherapy, particularly in men. In women it is associated with the uterus and ileum.
The base of the bladder is posterior and is separated from the rectum by the vas
deferens, seminal vesicles, and ureters in the male, and by the uterus and vagina in
the female. The seminal vesicles form a V-shaped structure at the base of the
the bladder slightly superior and lateral to the seminal vesicles, with the vas deferens
coursing above and in a caudal direction to the ureters. Again these relations are
critical as enlarging tumors either at the base or in the prostate can involve the ureters

Clinical Radiation Oncology

been more emphasis on the disease from health policymakers and pharmaceutical
companies.
In addition, a rethinking of the view that cystectomy is the gold standard for
invasive bladder cancer is long overdue. Comparisons of large surgical 4 and
radiotherapy 5 series suggest very similar long-term survival rates, and
population-based studies do not appear to show any survival differences linked to the
mode of treatment. 6 Furthermore, most large surgical series have median ages in the
mid-60s, 4 ,7 well below the (rising) disease population median, suggesting the results
may not be applicable to many or even most patients with invasive bladder cancer.
Use of bladder preservation varies worldwide from around 10% in the United States 8 to
25% in Scandinavia 9 to around 50% in the United Kingdom. 10 Moreover, there is good
evidence that older or less t patients in low-volume centers are less likely to be
referred for surgery, despite the likelihood of them being t for radiotherapy. 8 ,9
In contrast, recent large randomized radiotherapy series from the United Kingdom
suggest that radical radiotherapy with sensitization, either with low-dose
chemotherapy 11 or with hypoxia-targeting agents, 12 is effective and well tolerated by
elderly patients (median age in both studies was 72 to 73 years). Long-term functional
outcomes with radiotherapy are excellent, 1113 making it particularly suitable for less-t
patients who may struggle with major surgery or a urinary diversion.
This chapter outlines the evidence base for the current therapeutic approaches to
bladder cancer and in particular will examine the proposition that bladder preservation
for muscleinvasive disease is an approach that merits re-examination.
ANATOMY OF THE BLADDER
The bladder is a hollow, muscular organ situated in the pelvis when empty but able to
extend up into the abdomen when full, particularly in situations where bladder
emptying is impeded. At birth, the pelvis is relatively small in comparison to the
abdomen, and thus the bladder has a larger abdominal component at birth and
becomes more pelvic as growth and maturity proceed. By puberty, the bladder has
migrated to the connes of the deepened true pelvis.
with consequent hydronephrosis. Inferiorly and laterally to the bladder lie the various
pelvic bones and muscles: pubis, the levator ani, and obturator internus muscles.
Within the pelvis, the lateral parts of the bladder are surrounded by loose connective
tissue. Anteriorly the bladder is separated from the pubic bone by the retropubic
space. The inferior part of the bladder is described as the neck and is in continuity
with the urethra and, very importantly, the prostate gland in males. The neck of the
bladder is anchored in the pelvis, and the superior portions distend and expand
upward as the bladder lls.
The mucosal lining of the bladder comprises a transitional epithelium that extends
from the renal pelvis to the urethra. The most common tumors arising in the urinary
system are transition cell (or urothelial) carcinomas (TCC or UC). These tumors can
arise from anywhere within the urothelium, so diagnosis, treatment, and surveillance
protocols must take account of this important biological feature. As a distensible
organ, the macroscopic appearance of the urothelium varies with distension from
smooth and at to folded when empty. A ridge called the interureteral fold lies
between the ureteric orices.
EPIDEMIOLOGY
Bladder cancer, with over 385,000 new cases reported worldwide in 2008, 14 is a major
cause of cancer morbidity and mortality (Table 64.1). Median age at diagnosis is
above 70 years and, as the tumor is often smoking related, many patients have
signicant comorbidity, posing risks for radical surgical approaches. Survival rates are
poor, with around 45% of muscle-invasive cancer patients surviving 5 years
irrespective of treatment modality. 4,5 ,7 Demographically, the industrializing nations will
contribute to a signicant rise in the global incidence of bladder UC, 15 with particularly
large numbers likely in China given the rapid improvement in standards of living and
the high prevalence of smoking. However, despite the decreasing incidence in
developed nations, there remain

TABLE 64.1 2008 UROLOGICAL CANCER INCIDENCE AND MORTALITY

The bladder is described as having an apex, a superior surface, two inferolateral WORLDWIDE

surfaces, a base or posterior surface, a trigone, and a neck. The apex reaches a short Cancer Site Cases All Cases (%) Deaths All Deaths (%)
distance cephalad above the pubic bone and ends as a brous cord, the remnant of
Prostate 899,102 7.1 258,133 3.4
the fetal urachus, which connects the bladder to the allantois. The urachus lies
Bladder 382,660 3.0 150,282 2.0
anterior to the peritoneal cavity and is important as tumors can arise in the urachal
Kidney 273,518 2.2 116,368 1.5
remnant. The superior surface is covered by the peritoneum, again an important
Testis 52,323 0.4 9,874 0.1
anatomical feature as it means that there is bowel lying
All cancers 12,662,554 7,564,802

Data from GLOBOCAN http://globocan.iarc.fr.

booksmedicos.org
1260 Section III Clinical Radiation Oncology Part H Urinary Tract
specic challenges, mainly due to the aging population and increased life-expectancy.
Within two large cohorts separated by 15 years (1991 to 1992 and 2005 to 2010),
researchers have recently demonstrated an increase in the median age at
presentation of 4 years, with an increase from 13% to 24% in the proportion of
patients over 80 years old. 16 Overall around 75% to 80% of patients with bladder
cancer are male, mostly reecting historic trends in cigarette smoking.
There are well-known associations of squamous cell bladder carcinomas with
bilharzia caused by Schistosoma haematobium infection in Africa, particularly in Egypt. 17
Aromatic amines, polycyclic aromatic and chlorinated hydrocarbons, arsenic-laced
drinking water, aristolochic acid, cyclophosphamide exposure, and a range of
industrial chemicals have been implicated in urothelial carcinogenesis. Importantly, as
with most carcinogens, there are variations in individual susceptibility, and the basis of
some of these polymorphisms regulating varied detoxication mechanisms has been
identied. 18 With increasing awareness of these industrial associations, regulation of
these processes means that these cases are becoming increasingly rare in the
developed world. Their principal importance now is that those with industrially linked
tumors may be entitled to compensation payments. In Egypt there have been
successful public health approaches to the control of S. haematobium infections,
leading to a substantial decline in incidence and mortality from squamous carcinomas
of the bladder. 19
Within the developed world, the overwhelming majority of bladder tumors are now
TCCs, and the main known causative factor is tobacco (particularly cigarette)
smoking, 20, 2122 ,2325
explaining approximately half of the cases in men and onethird of the cases in women
in Europe (discussed in detail below). The relation between smoking and other
prognostic factors is interesting, as it could give insight into biological mechanisms of
disease and, perhaps more importantly, have clinical implications by increasing our
ability to identify patients at risk of more malignant disease.
NATURAL HISTORY
Non-muscle-Invasive Bladder Cancer
Most cases (70% to 80%) present with non-muscle-invasive bladder cancer (NMIBC,
stage Ta, T1, and carcinoma in situ
[Tis]), which is rarely lethal, but shows a high recurrence rate of 50% to 70% after
treatment by transurethral resection of the bladder tumor (TURBT). 26 In about 10% to
20% of patients with NMIBC, the disease progresses to muscle invasion ( T2
lesions), which can lead to metastasis and death. 26 However, the majority of patients
with NMIBC will die of other causes, given the typically advanced age at presentation
and the strong association with cigarette smoking, 20, 2122 ,2325 although it is worth noting
that up to 21% of patients with Ta tumors and 49% of patients with T1 tumors will die
from bladder cancer. 27 For patients with NMIBC, it has been observed that tumor grade
and stage, and also tumor number, size, presence of carcinoma in situ ( CIS),
recurrence rate, and age at diagnosis are risk factors of progression. 2829, 30 The risk of
both recurrence and progression necessitates lifelong follow-up for patients with
bladder tumors. However, there are factors that predict a higher risk of progression (to
invasion) as opposed to recurrence in lower risk tumors, and the European
Organisation for Research and Treatment of Cancer (EORTC) bladder cancer
calculator quanties the risk depending on the tumor characteristics imputed. 30
Invasive Disease
Muscle-invasive bladder cancer has a poor prognosis due to a very high rate of occult
metastatic disease at the time of diagnosis. Evidence for this comes from the high rate
of death from metastasis after apparently successful surgery. Furthermore, reported
5-year survival rates with radiotherapy or surgery
booksmedicos.org
are remarkably similar at around 45% to 50%, 4,5 despite a higher rate of pelvic
recurrence after radiotherapy versus surgery, suggesting that prognosis is driven by
the presence or otherwise of metastases at the time of diagnosis, driven by
tumor-related factors such as stage and grade. 6
Metastatic Disease
A minority of patients (probably <10%) present with metastatic disease; most patients
with metastatic disease have had prior treatment for apparently localized disease.
Metastatic disease carries a poor prognosis. Overall survival from diagnosis of
metastasis is difcult to ascertain as many patients receive only palliative treatment. A
minority of patients are t for systemic chemotherapy, and there are good data on
outcomes with chemotherapy. In essence, extensive randomized studies, mostly
carried out in the 1980s and 1990s, have demonstrated the superiority of
cisplatinum-based combinations over those containing other drugs or cisplatinum
alone. 31 Of the platinumbased combinations, methotrexate/vinblastine/doxorubicin
(Adriamycin)/cisplatinum (MVAC) 32 and gemcitabine/cisplatinum (GC) 33 have proven to
be superior to other combinations and broadly similar in efcacy to each other 34 ,35 ( as
reviewed by Hussain and James 36). Median survival is 12 to 18 months, depending on
the extent of disease and tness of the patient. Intriguingly, however, a small minority
of patients do appear to survive long term after chemotherapy for metastatic disease,
but this percentage has sadly proved very hard to increase from that originally
observed in the MVAC trials.
ETIOLOGY
The link between occupational exposure and an increased risk of urothelial cancer of
the bladder was established more than a century ago when Rehn 37 reported on three
cases of bladder cancer in a German chemical dye works in 1895. 38 During the
following 40 years, similar reports appeared from around the world. 39 In 1938, Hueper
et al. 39 demonstrated that when naphthylamine, an industrial arylamine used in the
synthetic dye industry, was fed to dogs, it caused bladder carcinomas identical to the
human disease. The link between industrial arylamines and bladder cancer was thus
established and later conrmed by Case et al. 40 in 1954. These authors also identied
an excess of bladder cancer in the tire industry, attributable to the use of
2-naphthylamine in the manufacture of rubber. 38,40
Around this time the o-aminophenol hypothesis of arylamineinduced human bladder
cancer was proposed, suggesting that conjugation of aromatic amines by the liver and
excretion in the urine with subsequent urinary reactions would liberate the carcinogen
o-aminophenol. 41 Other workers later added to this hypothesis: arylamines are
hydroxylated in the liver and conjugated with glucuronic acid, followed by excretion
into urine and reliberalization of the active carcinogenic metabolite into the bladder
lumen by urinary glucuronidases. 38,42 ,43 Slow acetylation by N- acetyltransferase, an
enzyme involved in the metabolism of arylamines, has been shown to be a
contributory risk factor for bladder carcinogenesis. 20, 44 ,45
Due to the widespread use of arylamines in textile dyes, hair dyes, and paint
pigments, a number of high-risk occupations have been identied, including chemical,
dye, textile, and rubber workers and painters and hairstylists. 21 ,4648 In addition, the
presence of various arylamines in tobacco smoke means that a signicant proportion
of bladder cancer cases can be attributed to cigarette smoking. 20, 2122 ,2325 In fact,
abandonment of the manufacture of many of these arylamines in the latter half of the
20th century means that smoking is currently the single most important cause of
urothelial cancer. 24,25,4951
Tobacco (particularly cigarette) smoking now explains approximately half of bladder
cancer cases in men and one-third of cases in women in Europe. It has been
demonstrated that an

increased smoking frequency and duration and a lower age at initiation are associated
with an increased risk of bladder cancer, while cessation seems to reduce the risk. 49 The
relation between smoking and other prognostic factors is interesting, as it could give
insight into biological mechanisms of disease and, perhaps more importantly, have
clinical implications by increasing the ability to identify patients at risk of more
malignant disease. Cigarette smoking also appears to be a risk factor for disease
recurrence following a diagnosis of bladder UC, 49,52 although due to a lack of
conclusive evidence, there is currently a low rate of physicians providing smoking
cessation assistance. 49
Studies also demonstrate a relation between N- acetyltransferase-2 slow
acetylators and cigarette smoking, resulting in a further increase in the risk of bladder
cancer, especially in those individuals with a high smoking intensity. 5355 A similar
relation has also been demonstrated with arylamine exposure. 56,57 A number of other
susceptibility loci have also been identied, although such markers do not yet have
sufcient discriminatory ability to be utilized for risk prediction in the general
population or for prediction or prognostication in patients diagnosed with bladder
cancer. 54,58,59
CHRONIC INFLAMMATION AND
BLADDER CANCER
Squamous metaplasia is considered a precursor of squamous cell carcinoma of the
bladder and is a relatively common occurrence, especially on the trigone of the female
bladder where a prevalence of up to 50% is reported. 60, 61 Experimental evidence
suggests that this does not occur by direct transformation of the supercial apical
umbrella cells of the urothelium or by their dedifferentiation and redifferentiation; it is
postulated that basal cells (probable stem cells) are selectively activated. 60
The normal urothelium is slowly proliferating, but urothelium undergoing squamous
metaplasia becomes hyperplastic, and it may be that the hyperplasia component of
urothelial squamous metaplasia is a major contributor to an enhanced risk of cancer
formation. 60, 61
Squamous cell carcinoma and adenocarcinoma of the bladder often occur in the
presence of chronic inammation. In Africa and the Middle East, where these tumors
are much more prevalent, the chronic inammation occurs as a result of infestation
with the parasite S. haematobium ( bilharziasis), with a bladder carcinoma incidence of
2 to 4 per 100,000 in S. haematobium endemic areas. 62 ,6367 This infestation can lead to
malignancy through local tissue damage, mechanical irritation, bilharzial toxins,
secondary bacterial infection, and the production of nitrosamines. 62 ,68,69 With liver
involvement and subsequent liver dysfunction, tryptophan metabolism may be
disturbed, resulting in excretion of carcinogenic metabolites. 62 In
S. haematobium infected individuals, the prevalence of squamous metaplasia rises
signicantly during the rst 10 to 15 years of life, with a plateau at roughly constant
levels thereafter (30% to 40% in males and 40% to 50% in females) when the active
infection may have subsided. 61 It is suggested that proliferative changes in the bladder
urothelium may become independent of ongoing infection after long periods of chronic
S. haematobium induced inammation. 68,69 Severe metaplasia of the bladder may
represent a precancerous transformation in some individuals, but in others it may only
represent a marker for the prolonged inammation that is associated with a high
cancer risk. 68,69 This sort of proliferative growth combined with the increased excretion
or local formation of mutagens in the
S. haematobium- inamed bladder may signicantly contribute to the onset of cancer
formation, possibly involving mutations of the p53 and CDKN2 tumor-suppressor
genes. 68
In Europe and North America, the stimulus of chronic bladder inammation is
usually chronic bacterial infection, bladder
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Chapter 64 Bladder Cancer 1261
calculi, or long-term indwelling catheters. 7073 A number of metaplastic conditions
(squamous metaplasia, von Brunns nests, cystitis cystica, and cystitis glandularis)
may occur prior to frank malignant change, although the premalignant nature of some
of these lesions is still unclear. 7079
Field Cancerization and Clonality
A fundamental characteristic of neoplasia is monoclonality, in which one transformed
cell gives rise to daughter cells that all exhibit the same genetic changes that provided
the initial growth advantages to the originally transformed parent cell. 80 Further genetic
changes accumulate in subsequent daughter cells and provide additional growth
advantages. 80 However, TCC behaves as a multifocal disease, often with multiple
primary tumors and frequent recurrences that can occur anywhere in the urinary tract
from the renal pelvis to the urethra. These observations gave rise to the idea of a
eld defect or eld cancerization, suggesting that the whole urothelium is exposed
to the same urinary carcinogens, leading to the transformation of many independent
separate urothelial cells and resulting in multiple tumors developing independently in
multiple sites. Such tumors are thus genetically unrelated. An alternative explanation
Clinical Radiation Oncology
is that the multifocality of TCC arises as a result of a single carcinogenic insult to a
single cell or group of cells. The progeny or clones of these cells spread throughout
the bladder, either through intraepithelial migration or through cell shedding and
reimplantation, leading to multiple synchronous and metachronous tumors. 80 These
tumors are thus topographically distinct but are genetically related. This is the
hypothesis of clonality.
Utilizing the relatively rudimentary technique of
X-inactivation, 80 ,8182 the early studies in this eld appeared to show that the urothelium
is derived from a small number of cells (200 to 300), which subsequently develop into
larger patches; each patch is clonally related and possesses different predispositions
to tumorigenesis. 83 Such stem cellderived clonal units actively replenish the
urothelium during aging. 84
Multiple synchronous and metachronous TCCs in the same patient appear to be
clonally related when studied by X-inactivation. 80 ,82,8588 However, these studies only
provide a 50% probability that one particular TCC is related to the primary TCC,
although that probability improves when multiple TCCs are analyzed. Clonal patch
size also needs to be taken into consideration, and because of the large patch size of
the urothelium (120 mm 2), X-inactivation studies are heavily biased toward
demonstrating monoclonality. 81 Ideally, these studies should have taken into account
the relation of the tumors to patch boundaries. 81 In addition, DNA methylation patterns
change as a natural consequence of aging. 89 Therefore, although X-inactivation
studies provided an early insight into the relative importance of the processes of
clonality and eld cancerization, they cannot be considered as entirely accurate and
reliable. Similarly, using immunohistochemistry to study specic p53
and pRb mutations cannot be considered to be wholly reliable for demonstrating
monoclonality.
The accuracy of these investigations has been improved by utilizing newer and
more sensitive techniques such as comparative genomic hybridization, uorescence in
situ hybridization, and loss of heterozygosity studies. These experiments revealed both
monoclonality and oligoclonality in synchronous and metachronous TCCs. More
recently, research has suggested that a genetic expression prole is established early
in bladder tumor development, and that this prole is stable and maintained in
recurring tumors. 9091, 92 Majewski et al. 91 matched the clonal allelic losses in distinct
chromosomal regions to specic phases of bladder neoplasia: these genetic changes
mapped to six regions or forerunner genes involved in the early phases of bladder
cancer development, representing critical hits driving bladder carcinogenesis. It is
suggested that the clonal expansion, over vast expanses of the bladder mucosa, of
urothelial cell
1262 Section III Clinical Radiation Oncology Part H Urinary Tract

populations containing losses of forerunner genes may represent the earliest Normal urothelium
molecular change in bladder carcinogenesis. A further wave of genetic hits within
subregions of these clonally expanded cells leads to the rst microscopically
recognizable features of dysplasia, and a third and nal wave is associated with the Chromosome 9 LOH

fully transformed phenotype of severe dysplasia or CIS. 91,93 The genetic changes map
to six chromosomal regions that are suggested to represent the critical hits driving the
development of bladder cancer. 91,93 In addition, Knowles et al. 94 have demonstrated
FGFR3 or hRAS P53 mutation or RB1
that deletions of chromosome 9 occur in over half of bladder tumors of all grades and
activating mutation loss
stages (9p, 51%; 9q, 57%). Loss of heterozygosity also occurs on 17p (32%), 11p
(32%), 8p (23%), 4p (22%), and 13q (15%), and loss of heterozygosity of 5p, 8p, and
21q are signicantly associated with worse grade and stage. 94 Genomic copy number Low-grade, non-muscle- Carcinoma in situ
alterations are also frequent in bladder TCC, with the most frequent changes involving invasive tumor
complete or partial loss of 4q (83%) and gain of 20q (78%). 95 Other frequent losses are
of 18q (65%), 8p (65%), 2q (61%), 6q (61%), 3p (56%), 13q (56%), 4p (52%), 6p
(52%), 10p (52%), 10q (52%), and 5p (43%). 94 High-grade, non-muscle- RB1 mutation
invasive tumor

P53 mutation or RB1 Muscle-invasive

loss/FGFR3 mutation tumor

Taken together, the studies described above show that multifocal TCCs are FIGURE 64.1. Pathways to development of bladder cancer. (Data from Pollard C, Smith SC, Theodorescu D.
Molecular genesis of non-muscle-invasive urothelial carcinoma (NMIUC).
frequently monoclonal, whereas others show oligoclonality. The evidence for both
Expert Rev Mol Med 2010;12:e10.)
theories is compelling (as reviewed by Duggan et al. 96), with evidence supporting both
the clonality and eld cancerization theories. In reality, these theories are equally
to work in this eld have been made by Knowles et al. 110 ,113119
valid, with both processes seemingly often occurring simultaneously in the same
(Leeds, UK); in their 2010 review, Goebell and Knowles 113 propose a third
patient. 86,87 In addition, many of these studies have demonstrated that deletions on
hypothetical pathway for the development of highgrade papillary tumors.
chromosome 9p occur most frequently and early in transitional cell carcinogenesis
with 17p13 losses ( p53 gene mutations) occurring in more advanced TCCs, shedding
A detailed examination of these pathways and related biomarkers is beyond the
some light on the molecular pathology of bladder TCC.
scope of this chapter. In addition, this is a rapidly changing eld and new
developments appear frequently with the advent of high-throughput experimental
platforms, including deep sequencing, 120 proteomics, 121,122

and metabolomics, 123 so readers are directed to the reviews cited above or to the

Pathways to Muscle-Invasive and latest work in this eld.

Nonmuscle-Invasive Bladder Cancer

A number of different approaches can be taken to describe the molecular alterations SYMPTOMS AND SIGNS
involved in bladder tumorigenesis (TCC). Some authors 97,98 have previously described
The typical presenting symptoms of bladder cancer include painless, visible
such pathways in detail based on the six original hallmarks of cancer described by
hematuria, infection, and storage symptoms. As the rst of these is typically transient
Hanahan and Weinberg 99 in 2000. In 2011, Hanahan and Weinberg 100 updated their
and the latter two are also attributable to prostate problems, patients often go
original landmark review, describing genome instability and inammation as
undiagnosed for considerable periods. 27 Given the intermittent nature of the hematuria
underlying these hallmark changes and proposed reprogramming of energy
associated with bladder cancer, patients presenting with a convincing episode of
metabolism and evading immune destruction as two emerging hallmarks with
hematuria require urgent assessment. Similar considerations apply to male patients
potential for generality. In addition, they reported that tumors exhibit another
with a urinary tract infection. Female patients present a more difcult problem due to
dimension of complexity by containing a repertoire of recruited, ostensibly normal cells
the higher incidence of urinary infection and the lower risk of bladder cancer.
that contribute to the acquisition of hallmark traits by creating the tumor
Hematuria is also more likely to be misinterpreted in women of childbearing age.
microenvironment. 100 The particular timing and sequence of hallmark events can vary
widely between tumors of the same type and within the same tumor, but ultimately
these hallmark capabilities of cancer will be reached. 99 In their 2011 update, Hanahan
and Weinberg 100 also introduce the concept of cancer stem cells, a concept that has
existed for quite some time for hematopoietic malignancies. 101 ,102 Cancer stem cells
are a subset of tumor cells that have the ability to self-renew and to generate all of the INVESTIGATION OF PATIENTS WITH
heterogeneous cells that comprise a tumor (properties that are analogous to a stem
BLADDER CANCER
cell, the original cell of an organ, and responsible for organogenesis and organ
maintenance). 101 ,103106 It is proposed that these cells are responsible for This section is divided into the investigation of patients with suspected bladder cancer
tumorigenesis, tumor differentiation, tumor maintenance, tumor spread, and tumor and the subsequent staging of those with an established diagnosis.
relapse. 101 ,103106 In the setting of bladder cancer, cancer stem cells appear to play a
role in a subset of tumors, but their true signicance has yet to be claried. 104
Suspected Bladder Cancer
In developed countries, most patients will be referred to some sort of rapid access
hematuria or suspected bladder cancer clinic. A minority may present via other routes
(e.g., gynecological clinics) or with metastatic symptoms (<10%). Hematuria clinics
will generally include a clinical assessment, full blood count and biochemical prole,
prostate-specic antigen (if indicated), urine cytological examination, exible
cystoscopy, and some sort of imaging of the urothelium (e.g., ultrasound, intravenous
A number of other authors have also reviewed this eld in detail, 107112 and there is urogram, or computed tomography [CT] urogram), which will vary with local practice
general consensus on a divergent pathway for the development of Ta/T1 disease and and facilities. 124,125 Patients
Tcis/T2+ disease, as illustrated in Figure 64.1. Signicant contributions

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 Chapter 64 Bladder Cancer 1263

identied as having a bladder tumor on exible cystoscopy will then require further TABLE 64.2 TNM CLASSIFICATION OF TUMORS (2009)
investigations to stage the disease.
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Staging Bladder Cancer Ta No invasive papillary carcinoma
The next stage for most patients will be an examination under anesthetic coupled with Tis Carcinoma in situ: Flat tumor
TURBT. The presence or absence of a mass after TURBT is also an important T1 Tumor invades subepithelial connective tissue
prognostic factor as it potentially indicates either unsuccessful clearance of tumor, T2 Tumor invades muscle T2a Superficial

extravesical extension, or both. This serves as both denitive staging of the bladder muscle (inner half) T2b Deep muscle (outer

lesion as well as a substantial proportion of the initial treatment. Pathological review of half)
T3 Tumor invades perivesical tissue: T3a
the resected specimen will ascertain whether muscle invasion is present or not and
microscopically T3b macroscopically (extravesical
whether there is CIS; these are the key determinants of further investigation and
mass)
treatment. Patients with NMIBC, including CIS, do not usually require detailed further
T4 Tumor invades any of the following: prostate stroma, seminal vesicles, uterus,
imaging, and treatment and surveillance are primarily by intravesical means. The main vagina, pelvic wall, abdominal wall T4a Tumor invades prostate, stroma,
exception to this is patients with either extensive CIS or grade 3 lesions for whom seminal vesicles, uterus, or
additional cross- sectional imaging may be warranted. Patients with muscle-invasive vagina T4b Tumor invades pelvis or abdominal wall
bladder cancer (MIBC) will require detailed cross- sectional staging with CT or
magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis. If there are any N0 Regional Defined as nodes of the true pelvis below the bifurcation of the common

features suggestive of bone metastasis (e.g., raised alkaline phosphatase, bone pain), lymph nodes iliac arteries. Laterality does not affect the N classification.

an isotope bone scan will be indicated in addition.

Clinical Radiation Oncology

Nx Nodes cannot be assessed
N0 No lymph node metastasis
N1 Metastasis in a single lymph node in the true pelvis (hypogastric,
obturator, external iliac, or presacral)
N2 Metastasis in multiple lymph nodes in the true pelvis (hypogas-
tric, obturator, external iliac, or presacral)
A major confounding factor with imaging in bladder cancer is the effect of TURBT N3 Metastasis in a common iliac lymph node(s)
on the interpretation of the extent of the primary bladder tumor. Recent TURBT will MDistant Metastasis
cause perivesical changes that may be interpreted as extravesical spread. For similar Mx Cannot be assessed
reasons, enlarged pelvic nodes may be related to reactive rather than metastatic M0 No distant metastasis

effects. On the other hand, changes such as inltration of adjacent organs or M1 Distant metastasis present

hydronephrosis are likely to be reliable indicators of tumor stage and poor prognosis. Stage Grouping
Stage 0a Ta N0 M0
Stage 0is Tis N0 M0
Stage I T1 N0 M0
Stage II T2a,b N0 M0
Stage III T3a,b N0 M0
STAGING SYSTEM T4a N0 M0
Stage IV T4b N0 M0
The 2010 version of the UICC International Union Against Cancers TNM system is
Any T N1, 2, 3 M0
the current, internationally used staging system, 126 and it is based on the size and Any T Any N M1
extent of the primary tumor (T stage), presence or absence of nodal (N), and
From UICC International Union Against Cancer. TNM classication of malignant tumours, 7th ed.
metastatic (M) spread (Table 64.2). The TNM stage must be used in conjunction with
Hoboken, NJ: Wiley-Blackwell, 2009, with permission.
the pathological assessment of tumor removed at TURBT to decide on optimal
therapy. Disappointingly, despite a substantial volume of research, no biomarkers
have yet established themselves in clinical practice as either prognostic or predictive
markers as has happened, for example, with estrogen-receptor or HER2 status in TREATMENT OF BLADDER CANCER
breast cancer. It is hoped that the wider availability of high throughput systems such
as proteomics, in-depth sequencing, and others to be developed will allow the Non-muscle-Invasive Bladder Cancer
development of such markers in the future. Around 80% of patients with bladder cancer present with nonmuscle-invasive disease.
These are classied as Tis, Ta, and T1 by the TMN classication system. The gold
standard for diagnosis is the resection of the lesion with adequate sampling of the
detrusor muscle deep to the lesion (TURBT). This will give tissue for accurate staging
of the bladder lesion as well as denitive treatment for the lesion. Recurrences after
TURBT are found in up to 70% of patients undergoing surveillance, and, more
PATHOLOGY importantly, up to 15% of patients on surveillance will progress to muscle-invasive
In excess of 90% of bladder cancers are transitional cell carcinomas. Of the bladder cancer. At the time of diagnosis, the upper urinary tract also needs
remainder, around 5% are squamous, although it should be noted that squamous assessment. This can be done with intravenous urography, CT urography or
differentiation is often present in poorly differentiated TCCs, so the extent to which ultrasound. The incidence of upper tract tumors at the time of presentation with
these are genuinely distinct is open to question. As already noted, infestation with S. hematuria is only 1.8%, calling into question the use of contrast imaging for the group
haematobium can lead to squamous cell carcinoma, but this is rapidly decreasing due as a whole. 128
to eradication programs. Small cell carcinoma is rare but important as it is generally
very chemosensitive and treatment tends to follow schedules adapted from treating
small cell lung cancer. Other tumor types include melanoma, carcinosarcoma, and
adenocarcinoma (particularly in the urachal remnant). Typically bladder TCCs will be Ultrasound is now being used more frequently, with contrast imaging modalities being
graded using the standard TNM system of Gx (cannot be assessed) then G1 through used for the higher risk disease.
to G3 (well through to poorly differentiated). 127 CIS will frequently be found in addition Prognostication and management strategy are based on accurate initial staging
to a tumor mass and critically affects treatment choices. and grading of the disease. There can be variation in the interpretation of pathological
specimens, so review of pathology is recommended (European Association of Urology
[EAU] guidelines 129). If there is uncertainty over the pathology, a further early
re-resection is indicated. The risk of

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1264 Section III Clinical Radiation Oncology Part H Urinary Tract
residual tumor can be as high as 53% in T1 tumors. 130 If the disease is dened as
NMIBC, it can be characterized as low, intermediate, or high risk, and this will dictate
how the disease is managed (see below). The EORTC bladder cancer calculator
provides a valuable online tool for doing this and determining follow-up frequency. 131
Following resection of the tumor, there is good evidence that a single dose of
mitomycin-C administrated into the bladder for 1 hour within 24 hours of surgery will
reduce the relative risk of recurrence by 24.2% but will not impact disease progression
and disease survival. 132 Recurrences after TURBT are found in up to 70% of patients
undergoing surveillance, and up to 15% of patients on surveillance will progress to
muscle-invasive bladder cancer. Emerging endoscopic techniques employing
photodynamic therapy aimed at improving diagnostic yield and thereby ultimately
reducing the rates of recurrence and progression have demonstrated promising
results. 133
Low-risk tumors are single tumors that are <3 cm in diameter are graded as G1
disease and staged as Ta with no evidence of CIS. These tumors have a 15%
probability of recurrence and a 0.2% risk of progression at 1 year. 30 These patients
should undergo a exible cystoscopy 3 months after the initial resection, and if this is
negative, a exible cystoscopy should be undertaken 9 months later and then
annually thereafter.
Intermediate- and high-risk tumors are dened using a scoring system based on a
number of clinical and pathological factors:
a. Number of tumors
b. Tumor size
c. Prior recurrence rate
d. T category
e. Presence of concurrent CIS
f. Tumor grade 131
The high-risk tumors should be followed up with 3 monthly exible cystoscopy for
2 years and 6 monthly for a further 5 years and then annually thereafter. Intermediate
risk tumors should be followed up using a surveillance regime somewhere between
that used for low- and high-risk disease, which is adapted according to personal and
subjective factors. The intermediate-risk tumors have up to a 38% probability of
recurrence and a 5% risk of progression at 1 year. The high-risk tumors have a 61%
probability of recurrence and a 17% risk of progression at 1 year. 30
The use of exible cystoscopy with urine cytology is the standard of bladder
surveillance. There is ongoing research into improving the sensitivity and specicity of
exible cystoscopy using variations in the wavelength of the light source used (e.g.,
narrow band imaging). There are a wide number of urinary biomarkers available such
as NMP22, UroVysion (Abbott Laboratories, Abbott Park, Illinois), and ImmunoCyt
(Scimedx, Denville, New Jersey). These agents suffer from high falsepositive rates
and variable sensitivity and are costly (as reviewed by Vrooman and Witjes 134).
The presence of CIS in the bladder carries a 54% risk of disease progression
without treatment. 135 Patients with high-risk tumors or CIS should be offered
intravesical immunotherapy using bacille Calmette-Gurin (BCG) (EAU and American
Urology Association guidelines). 129,136 There are a variety of treatment schedules in the
literature, but the authors recommend an intravesical treatment once a week for 6
weeks followed by a subsequent 3 weeks as an induction treatment. If there is no
cystoscopic evidence of recurrence, the patient should then be offered ongoing
maintenance BCG with 6-week courses of BCG every 3 to 6 months with regular
cystoscopic surveillance. In a recent meta-analysis of trials with BCG maintenance, a
32% reduction in the risk of recurrence was seen for BCG compared with mitomycin-C
( P <. 0001), whereas there was a 28% increase in the risk of recurrence ( P = . 006) for
patients treated with BCG in the trials without BCG mainte-
booksmedicos.org
nance. 137 BCG is a very effective treatment, but not all patients with NMIBC should be
treated with BCG due to the risk of toxicity. In a phase III study for NMIBC tumors
using maintenance BCG therapy, 20.3% patients stopped BCG due to side effects,
mostly local side effects; 68% who stopped due to side effects did so during the rst 6
months. 138 The choice of treatment depends on the patients risk of recurrence and
progression based on EORTC subgroups. The use of BCG does not alter the natural
course of tumors in the low risk of recurrence subgroup and is therefore considered to
be overtreatment. In patients with tumors at high risk of progression, for whom
cystectomy is not carried out, BCG including at least 1-year maintenance, is indicated.
In patients at intermediate or high risk of recurrence and intermediate risk of
progression, BCG with 1-year maintenance is more effective than chemotherapy for
prevention of recurrence; however, it has more side effects than chemotherapy. For
this reason both BCG with maintenance and intravesical chemotherapy remain
options. The nal choice should reect the individual patients risk of recurrence and
progression and the efcacy and side effects of each treatment modality (EAU
guidelines). In treatment refractory disease, the patient should be offered radical
treatment for the bladder.
Muscle-Invasive, Nonmetastatic Disease
Relative Roles of Cystectomy and Bladder Preservation
Radiotherapy has been used as the primary treatment for muscle-invasive bladder
cancer for many years, but utilization rates vary around the world from around 10% in
the United States 8 to 25% in Scandinavia 139 to in excess of 50% in the United Kingdom. 10
There are no prospective randomized trials comparing surgery with radiotherapy, so
the data on comparative efcacy can only be inferred indirectly. U.S. authors in
particular tend to refer to surgery as the gold standard of care, with bladder
preservation with radiotherapy (with or without chemotherapy) being viewed as
experimental. However, this opinion seems to be based on custom and practice and
not on any hard comparative data. It is thus worth examining in some detail the data
that exist on this topic. There is a solitary attempt using modern techniques to
compare surgery with bladder preservation combining chemotherapy and
radiotherapy. The UK SPARE trial (randomized trial of Selective Bladder Preservation
against Radical Excision [cystectomy] in muscleinvasive T2/T3 transitional cell
carcinoma of the bladder) was a feasibility study that has now closed due to poor
recruitment. 140
This phase II and III trial attempted to investigate the potential of using the response
to neoadjuvant chemotherapy as a predictive tool for selecting patients for
radiotherapy compared with the surgical standard. In the authors experience, one of
the problems with the trial was that the study used response to neoadjuvant
chemotherapy to decide on suitability for bladder preservation. However, once this
was explained to the patients in the information sheet, there were patients who had a
good response but were reluctant to undergo surgery, particularly if the bladder was
free of tumor at the interim cystoscopy.
Large population-based studies suggest that the main determinants of survival
after diagnosis of bladder cancer are stage, grade, age, and to some extent social
class. For example, Hayter et al. 6 studied patterns of care and outcomes in over
20,000 patients with bladder cancer in Ontario. They found signicant variations in the
use of cystectomy and radiotherapy between different districts but no evidence that
these variations led to any differences in long-term outcomes. They concluded that
bladder-sparing approaches were equivalent to surgery for invasive bladder cancer.
Another way to compare outcomes between surgery and radiotherapy is to look at
large published series. In the United Kingdom, where both of these approaches are
routinely employed, it is possible to compare the outcomes in Cancer Registry data. A
recent paper from Munro et al. 10 examined

outcomes in 458 patients with invasive bladder cancer treated in Yorkshire between
1993 and 1996. The ratio of cystectomy to radiotherapy was 1 to 3, reecting UK
practice at the time. Overall 10-year survival was similar between those who
underwent radiotherapy (22%) versus radical cystectomy (24%). Prognostic factors for
inferior outcome at 10 years were: female versus male, poor performance status,
hydronephrosis and increasing T stage; treatment modality was not a factor in the
prognosis.
One of the most widely quoted surgical series comes from the University of
Southern California and reports the results of
1,054 patients undergoing cystectomy with overall 5- and 10 year survival rates of
60% and 43%, respectively. This series is discussed in detail below. However, this
series included patients undergoing surgery for noninvasive tumors and excluded
from the denominator 112 patients referred but deemed incurable at operation. If we
look at the 5-year survival of those with invasive tumors, the rate drops to around 47%
from the quoted 60%. A contemporary series of radiotherapy cases from Rdel et al. 5 reports
5- and 10-year survivals of 51% and 31% but included patients deemed inoperable.
Furthermore, if we look at the outcomes in the surgical control arm in the US
Intergroup Neoadjuvant MVAC trial, the median survival was 38 months and the
5-year survival was 42%. Other relatively contemporary series quote similar 5-year
survivals: for example, Dalbagni et al. 141 cite 45% overall and 65% disease-specic
survival rates in a series of 300 patients. Furthermore, the only signicant prognostic
factors in this series were age, T stage, and use or nonuse of neoadjuvant
chemotherapy (see the Role of Systemic Therapy section). Data also exist from single
institution series with widespread use of both modalities. For example, Kotwal et al. 142 report
results on 169 patients treated between March 1996 and December 2000 in Leeds,
UK. There were no differences in overall, cause-specic, and distant recurrence-free
survival at 5 years between the two groups, despite the radiotherapy group being
older (median age, 75.3 vs. 68.2 years). There were 31 local bladder recurrences in
the radiotherapy group (24 of which were solitary and hence potentially suitable for
salvage surgery), but no signicant difference in distant recurrence-free survival. In
another more recent (2002 to 2006) cohort, the median age of radiotherapy patients
but not the cystectomy patients had increased to 78.4 from 75.3 years, respectively,
while the age of those undergoing surgery remained similar at 67.9 and 68.2 years for
surgery, consistent with the aging trend in new bladder cancer cases. These authors
concluded that although the patients undergoing radical cystectomy were signicantly
younger than the radiotherapy patients, treatment modality did not inuence survival.
They went on to state that radical radiotherapy is a viable treatment option for these
patients, with the advantage of organ preservation. The data thus suggest that
bladder preservation gives equivalent long-term survival to surgery when factors such
as case selection are accounted for.
A proportion of patients undergoing radiotherapy will relapse within the bladder
and go on to salvage cystectomy. An important consideration, therefore, is whether
cystectomy after radiotherapy can be carried out safely and whether the delay
compromises survival. Again, there are no randomized data on this topic. However,
UK surgeons in particular have good practical experience on this topic and have
commented that neither prior chemotherapy nor radiotherapy compromises surgical
salvage and that long-term results appear similar to primary cystectomy series. 143,144
Particularly intriguing in this regard is a comparison of survival rates following
primary surgery or salvage surgery following failed radiotherapy from the Christie
Hospital in Manchester, UK. The group examined the outcomes in 552 patients who
underwent radical cystectomy between 1970 and
2005. Of these, 313 patients underwent primary radical cystectomy and 239
underwent salvage radical cystectomy following
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Chapter 64 Bladder Cancer 1265
radiation failure. The median age was 62.5 years (range, 32.2 to 87.2) for the primary
surgical group compared with 65.5 years for the salvage group. Overall 5-year
survivals reported were 45.5% for the primary group and 42% for the salvage group,
with cause-specic survivals of 51% and 50%, respectively. These differences
persisted after stratication for stage, and the authors concluded that a policy of
primary radiotherapy with surgical salvage did not compromise the long-term survival
chances of patients. 143
Clearly there are surgical series with much higher survival rates than this in the
literature. However, there are two factors accounting for this. One is case selection,
the other is that these series are, to a degree, personal, so to publish results that
appear inferior to other major centers is potentially a threat to a centers (or surgeons)
reputation and will tend to have a ratchet effect on published results. These data
also suggest that the predominant prognosis driver in bladder cancer is the presence
or absence of distant micrometastasis at diagnosis of invasive disease. The (relatively
modest) effect of neoadjuvant chemotherapy tends to bear this out, particularly as the
biggest effect in the Medical Research Council (MRC)/EORTC trial was on
metastasis-free survival rather than pelvic control rates. 145
Clinical Radiation Oncology
There is little in the way of randomized data on the efcacy of radiotherapy in
either nonmuscle-invasive disease or CIS. The only randomized trial on this topic
comes from the United Kingdom and compared radiotherapy with surveillance for
patients with a new diagnosis of pT1G3 NXM0 transitional cell carcinoma with unifocal
disease and no CIS. Patients with multifocal disease or CIS were randomized
between intravesical therapy and radiotherapy. There was no evidence of benet from
radiotherapy in terms of progression-free interval (hazard ratio [HR] 1.07; 95%
condence interval [CI], 0.65 to 1.74;
P = . 785), progression-free survival (HR 1.35; 95% CI, 0.92 to
1.98; P = . 133), or overall survival (HR 1.32; 95% CI, 0.86 to
2.04; P = . 193). 146 There is thus no indication for radiotherapy in these groups of
patients.
In truth, surgery and radiotherapy are not competing, but are complementary
approaches to invasive bladder cancer. There are particular groups who appear to do
poorly with primary radiotherapy, for example, those with poorly functioning bladders
or extensive CIS in addition to their invasive disease. In the former case, radiotherapy
is unlikely to improve bladder function; in the latter, the lack of effect of radiotherapy
on CIS means that the patient remains at risk of further bladder intervention and
ultimately cystectomy. 146 Similar considerations apply to patients with pT1G3 disease. 146
North American authors will also cite features such as hydronephrosis as a
contraindication to radiotherapy. 147 However, hydronephrosis is also a poor prognostic
factor for surgery and does not help in selecting patients one way or another. 6 On the
other hand, there are many patients who may benet from radical therapy but are
poor surgical candidates, such as older patients, the obese, diabetics, poor anesthetic
risk patients, or those who may struggle with whatever form of neobladder is
fashioned. Although large surgical series will include patients over age 80, these will
typically comprise only a few percentage of the total, whereas, with a median age at
diagnosis of bladder cancer in the middle to late 70s, there are probably many more
who do not make it to surgery.
Surgery
Management of Invasive Bladder Cancer
Although the majority of patients present with NMIBC, 20% to 40% will either present
with or ultimately develop muscleinvasive disease. Invasive bladder cancer is a lethal
malignancy; if untreated over 85% of patients will die of the disease within 2 years of
diagnosis. 148 Furthermore, a certain percentage of patients with high-grade bladder
tumors without involvement of the lamina propria will recur or progress or fail
intravesical management, and they may be best treated with an earlier
1266 Section III Clinical Radiation Oncology Part H Urinary Tract
cystectomy when survival outcomes are optimal. 149 In these groups of patients, the
5-year survival rates after cystectomy exceed 80%. 150,151
The rationale for an aggressive treatment approach employing radical cystectomy
for high-grade, invasive bladder cancer is based on several important observations.
First, the good long-term survival rates, coupled with the lowest local recurrences, are
seen following a denitive surgical approach removing the primary bladder tumor and
regional lymph nodes. 4,152,153
Although there are no randomized trials comparing radical cystectomy with bladder
preserving approaches, surgery remains the preferred treatment option for many
clinicians for advanced, localized invasive bladder cancer. 154 Second, the morbidity
and mortality of radical cystectomy has substantially improved over the past several
decades. 152,155 Third, advocates say that radical cystectomy provides accurate
pathologic staging of the primary bladder tumor (p stage) and regional lymph nodes,
thus, selectively determining the need for adjuvant therapy based on precise
pathologic evaluation. However, it should be noted that the evidence base for
adjuvant (as opposed to neoadjuvant) therapy is rather weak (see on the Role of
Systemic Therapy section). For the above-mentioned reasons, radical cystectomy has
become a standard form of therapy for high-grade, invasive bladder cancer.
Nonetheless, many articles on cystectomy emphasize the need for careful patient
selection to achieve optimal results. Although this is undoubtedly true, it begs the
question of what should be done with patients who do not meet these stringent
selection standards but still need to be treated. This issue is rarely, if ever, addressed
in cystectomy series publications.
The evolution and improvements in lower urinary tract reconstruction, particularly
orthotopic diversion, have been major components in enhancing the quality of life of
patients requiring cystectomy. Currently, most men and women can safely undergo
orthotopic lower urinary tract reconstruction to the native, intact urethra following
cystectomy, 156 although availability varies worldwide. Orthotopic reconstruction aims to
mimic the native bladder in location and function, provides a continent means to store
urine, and allows volitional voiding per urethra, although patients need to do this by
coordinating opening the sphincter with a Valsalva maneuver, which does require
training. The orthotopic neobladder eliminates the need for a cutaneous stoma,
urostomy appliance, and the need for intermittent catheterization in most cases.
These efforts have improved the quality of life of patients who require removal of their
bladders and have also stimulated patients and physicians to consider radical
cystectomy at an earlier more curable stage for high-grade, invasive bladder cancer. 157,158
A dedicated effort has been made to improve the surgical technique of radical
cystectomy and to provide an acceptable form of urinary diversion, without
compromise of a sound cancer operation. 158, 159 Timing of cystectomy after the TURBT
is important, and it has been demonstrated that a delay of more than 3 months
undermines patient survival. This evidence forms the basis to negotiating resource
needs with health care providers. 160,161 Certain technical issues regarding radical
cystectomy and an appropriate lymph node dissection are critical to mini-
TABLE 64.3 CYSTECTOMY OUTCOMES IN SELECTED SINGLE INSTITUTION SERIES
Number of Median Median
Period Patients Age Follow-Up
Author (Reference) (Year) (Male/Female) (Year) (Year)
Stein et al./USC (4) 19711997 1,054 66 10.2
(843/211)
Madersbacher et al./ 19852000 507 66 3.75
Bern (153) (400/107)
Hautmann et al./Ulm 19862003 788 64 2.9 yrs
(155) (652/136)
booksmedicos.org
mize local recurrence and positive surgical margins and to maximize cancer-specic
survival. 162 Attention to surgical detail is important in optimizing the successful
functional outcomes of orthotopic diversion by preserving the urinary sphincter
mechanism and therefore continence. Finally, the observed associations between
hospital volume and operative mortality are largely mediated by surgeon volume.
Patients can often improve their chances of survival substantially, even at
high-volume hospitals, by selecting surgeons who perform the operations frequently,
as those centers that have adopted this strategy have demonstrated declining
mortality in the past decade. 163, 164
Radical cystectomy by denition implies the en bloc removal of the pelviciliac
lymph nodes along with the pelvic organs anterior to the rectum: the bladder, urachus,
prostate, seminal vesicles, and visceral peritoneum in men; the bladder, urachus,
ovaries, fallopian tubes, uterus, cervix, vaginal cuff, and the anterior pelvic peritoneum
in women. An appropriate lymphadenectomy is an important component of radical
cystectomy and is related to the clinical outcomes of patients with highgrade, invasive
bladder cancer. Evidence suggests that a more extended lymphadenectomy is
benecial in both lymph node positive and lymph nodenegative patients with
bladder cancer, 165, 166 ,167 although this could be a surrogate for either case selection or
surgical skill. Although the exact limits of the lymphadenectomy for patients with
bladder cancer undergoing cystectomy are currently debated, the boundaries include
initiation at the level of the inferior mesenteric artery (superior limits of dissection),
extending laterally over the inferior vena cava or aorta to the genitofemoral nerve
(lateral limits of dissection), and distally to the lymph node of Cloquet medially (on
Coopers ligament) and the circumex iliac vein laterally. This dissection includes
bilaterally all obturator, hypogastric, presciatic, and presacral lymph nodes. 168170 Removal
of more than 15 lymph nodes has been postulated to be both sufcient for the
evaluation of the lymph node status as well as benecial for overall survival in
retrospective studies. 166,171174 However, potential interindividual differences in the
number of pelvic and retroperitoneal lymph nodes and difculties in processing of the
removed tissue by pathologists are issues. Furthermore, the reality is that even in
todays practice the number of lymph nodes retrieved are low (<10) in a majority of
patients (75%) and the chance are even lower if the patients are older, Hispanic (in
the United States), and managed at low-volume, nonurban centers. 170 The true
curative value of lymph node dissection and the optimal extent of dissection are both
still unknown.
Technical variations from the standard cystectomy have been performed to
improve patients quality of life, including prostate-sparing cystectomy in order to
preserve continence and potency. However, it carries a higher risk of missing
unsuspected adenocarcinoma of the prostate. Coexistent prostate cancer and
prostatic urothelial cancer are reported in 23% to 54% cases, of which 29% were
clinically signicant, leading to local recurrence and even metastasis. 175,176
Radical cystectomy is an appropriate standard treatment for patients with
high-grade, invasive bladder cancer. The clinical outcomes are presented in Table
64.3. These results should
Pathologic Subgroup (%)
30-Day Organ Confined Extravesical Lymph Node
Histology Mortality (%) Positive
TCC 3 56 20 24
(94% high-grade)
TCC (95% high-grade) 7 43 33 24
TCC 5 63 19 18
(82% high-grade)
 Chapter 64 Bladder Cancer 1267

provide a benchmark for outcomes to which other therapies can be compared.
Both laparoscopic and robot-assisted cystectomy have been shown to be feasible
and safe, but with a relatively shorter follow-up. 177 ,178179 Despite an increased
materials cost for a robotic-assisted cystectomy, it has been demonstrated to be
cost-effective in a subgroup of patients undergoing ileal conduit when the impact of
complications are considered in a single institution series. 179,180
Morbidity and Mortality of Radical Cystectomy and
Lymphadenectomy
The early clinical results and outcomes with regard to the morbidity and mortality of
radical cystectomy were disappointing. Lack of universal acceptance of this procedure
was attributed to the considerable complication rate and the need for improvements in
urinary diversion. Prior to 1970, perioperative complication rates of radical cystectomy
were approximately 35%, with a mortality rate of nearly 20%. However, with
contemporary medical, surgical, and anaesthetic techniques, along with better patient
selection, the mortality and morbidity from radical cystectomy have dramatically
included all events related to the cystectomy, perioperative care, and urinary
diversion. The administration of preoperative therapy (radiation or chemotherapy) and
the form of urinary diversion did not signicantly increase the early complication rate
in these cystectomy patients. Most early complications following radical cystectomy
are unrelated to the urinary diversion (85% diversion unrelated) and can be managed
conservatively without the need for reoperation in approximately 90% of cases. 181 The
most common early diversion-unrelated complication is dehydration, while the most
common early diversionrelated complication following radical cystectomy is prolonged
urinary leakage. Overall, the most surgical complications after cystectomy are
associated with urinary diversion in relation to the intestinal segments. 152 ,182
Neoadjuvant chemotherapy is discussed in a later section, but it does not seem to
increase the perioperative morbidity or mortality. 7, 183 Preoperative radiation therapy is
discussed below.
Radical cystectomy may appropriately be performed in carefully selected elderly
patients, 184 however, this emphasis in the surgical literature on careful selection

Clinical Radiation Oncology

decreased (Table 64.3). Importantly, in high-volume centers, the administration of
preoperative therapy (radiation or chemotherapy) and the form of urinary diversion
performed (continent or incontinent) did not obviously increase the mortality rate of
patients undergoing radical cystectomy. 150 The issue of the need to select patients for
surgery complicates the comparison of bladder-sparing techniques, because
frequently those not suitable for surgery will be the ones who appear in the
radiotherapy-based series.
highlights as much the deciencies as the efcacy of cystectomy as it emphasizes
that the published results are not applicable to the entire population. It is emphasized
that physiologic age may be more important than chronologic age when determining
appropriate candidacy for radical cystectomy. Proper patient selection, strict attention
to perioperative details, along with a dedicated and meticulous team-oriented surgical
approach are critical components to minimize the morbidity and mortality of surgery
and to ensure the best clinical outcomes in all patients following radical cystectomy. 185187
A recommended approach from the authors center previously pioneered by the
Danish is adoption of an enhanced recovery pathway protocol (Fig. 64.2). 188

The early complication rate following radical cystectomy should not be

underestimated in this elderly group of patients. The median age of patients
undergoing cystectomy in a University of Southern California series was 66 years. 4 Of
the
1,054 patients treated, 28% developed an early complication within the rst 3 months
of surgery. Early complications
Pathologic Stage and Subgroups
The pathologic stage of the primary bladder tumor and the presence of regional lymph
node metastases are the most important survival determinants in patients undergoing
cystectomy for

Optimising preoperative
Planned mobilisation
Referral from haemoglobin levels Admission on day
Rapid hydration &
Managing preexisting Optimised fluid nourishment
primary care hydration
comorbidities e.g. diabetes
Appropriate IV therapy
CHO loading
No wound drains
Reduced starvation
No NG (bowel surgery)
No/reduced oral bowel
Preoperative preparation (bowel Catheters removed early
surgery)

Regular oral analgesia

Paracetamol and
NSAIDS
Admission Avoidance of systemic
opiate-based analgesia where
Optimised health/ possible or administered
medical condition topically
Informed decision
making Intraoperative
Minimally invasive surgery
Preoperative health & risk
Use of transverse incisions
assessment
(abdominal)
PT information and
No NG tube (bowel
expectation managed
surgery) Postoperative
DX planning (EDD)
Use of regional / LA with
Preoperative therapy
sedation
instruction as appropriate
Epidural management (inc.
DX when criteria met Follow
thoracic)
Therapy support up
Optimised fluid (stoma, physio)
management individualised
goal directed fluid therapy 24hr telephone follow up

FIGURE 64.2. Schematic representation of the enhanced recovery program in patients undergoing a radical cystectomy.

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1268 Section III Clinical Radiation Oncology Part H Urinary Tract

TABLE 64.4 SELECTED DATA FROM THE UNIVERSITY OF SOUTHERN CALIFORNIA

taken in delaying denitive therapy in patients with high-risk, nonmuscle-invasive
BLADDER CANCER STUDY OF RADICAL CYSTECTOMY
bladder tumors or those with nonmuscleinvasive tumors that have not appropriately
responded to conservative forms of therapy. 149
Probability Overall Survival (%)
Number of
Pathologic Stage a Patients 5 Years 10 Years

T2a N0 94 77 57
Extravesical, Lymph NodeNegative Tumors
T2b N0 98 64 44
Nonorgan conned (extravesical), lymph nodenegative tumors were found in 20% of
T3 N0 135 49 29 University of Southern California series patients undergoing cystectomy (Table 64.4).
T4a N0 79 44 23 No obvious survival differences between extravesical P3 and P4 (node-negative)
Extravesical N0 214 47 27 tumors were observed. The 5- and 10-year recurrence-free survival for this pathologic
All node negative pooled 808 69 49 subgroup was 58% and 55%, respectively. Similar outcomes were reported by
All node positive pooled 246 31 23 Madersbacher et al. 153 and Dhar et al., 171 who demonstrated a 56% 5-year
a From ref. 192. recurrence-free survival for the same pathologic subgroup. Patients with locally
advanced tumors have higher recurrence rates and decreased survival compared with
those with organ-conned, lymph node negative tumors. 191 The 1997 AJCC TNM
bladder cancer. 4,153,155 These pathologic determinants may also be categorized into staging system 192 used for these studies straties extravesical tumor involvement
pathologic subgroups that provide risk stratication and direct the need for adjuvant (previously dened as pT3b) into microscopic (pT3a) and gross (pT3b) extravesical
therapy in the appropriately selected individual. Pathologic subgroups are dened as tumor extension. No signicant difference was observed in the recurrence-free and
organ-conned, lymph nodenegative tumors (P0, Pa, Pis, P1, P2a, P2b), nonorgan overall survival in patients when evaluating for pT3a and pT3b extravesical extension. 191
conned (extravesical) lymph node negative tumors (P3, P4), and lymph node
positive disease (N+); representing 56%, 20%, and 24% of patients, respectively. 155 The
5- and 10-year recurrence-free survival for the entire group of

1,054 patients in the University of Southern California series was 68% and 66%,
respectively (Table 64.3). Most deaths occurred within the rst 3 years following
radical cystectomy and were attributed to cancer recurrence. However, with longer
follow-up (>3 years), most deaths in this elderly group of patients were primarily
related to comorbid diseases unrelated to bladder cancer. This underscores the
effective and durable outcomes of radical cystectomy.
Organ-Confined, Lymph NodeNegative Tumors
In the University of Southern California series, 56% of patients demonstrated
pathologically organ-conned, lymph node negative tumor. 4 The outcomes in this
pathologic subgroup were excellent (Table 64.4), with a 5- and 10-year recurrencefree
survival of 85% and 82%, respectively. No signicant survival differences were
observed when comparing supercially noninvasive (Pis, Pa), lamina propria invasive
(P1), and muscle-invasive (P2a, P2b) tumors as long as the tumor was conned to the
bladder without evidence of lymph node involvement. Similar outcomes for patients
with pathologic nonmuscle- invasive bladder tumors following cystectomy have been
previously reported. 4,155 ,189, 190 Collectively, these data support the treatment of patients
with surgery when a tumor is conned to the bladder, without evidence of extravesical
extension or lymph node metastasis. Treatment delays in patients with invasive
bladder cancer should be avoided. Evidence suggests that prolonged delays may lead
to more advanced pathologic stage and decreased survival in patients with
muscle-invasive bladder cancer. 160 Furthermore, caution should be
The incidence of lymph node involvement was similar (approximately 45%); however,
the presence of lymph node involvement was associated with a higher risk of
recurrence and worse survival compared with node-negative patients.
Lymph NodePositive Disease
Perhaps one-fourth of patients in large cystectomy series will have positive lymph
nodes (Tables 64.3 and 64.5). Although patients with lymph node tumor involvement
are a high-risk group of patients, nearly one-third of these patients were alive at 5
years in the series by Stein et al. 4 It is possible that the surgical approach employing
an extended lymph node dissection provides some survival advantage in selected
individuals with node-positive disease. 171 The role of adjuvant therapy in these patients
is difcult to assess due to the absence of adequately powered trial data (see on the
Role of Systemic Therapy section). In an analysis of lymph nodepositive patients
carried out by the University of Southern California group, the administration of
adjuvant chemotherapy was a signicant and independent predictor for recurrence
and overall survival in this group, 193 however, case-mix effects will be prominent in this
type of retrospective analysis as patients need to survive long enough and be t
enough to even start chemotherapy to gure in the analysis. Inevitably this will bias
results in favor of adjuvant chemotherapy by excluding those who died early or who
never became t enough postoperatively to receive chemotherapy. The authors own
experience with attempting to recruit to adjuvant chemotherapy trials suggests that
only the most t patients are able to recover quickly enough postoperatively to
undergo systemic chemotherapy, so these data are highly likely

TABLE 64.5 INCIDENCE OF LYMPH NODE METASTASIS FOLLOWING RADICAL CYSTECTOMY, CORRELATION TO PRIMARY TUMOR

Bladder Tumor Stage a (%)

Lymph Node
Study (Reference) Period (Year) Number of Patients Metastasis (%) P0, Pis, Pa, P1 P2a P2b P3 P4

Poulsen et al. (292) 19901997 191 50 (26) 2 (4) 4 (18) 7 (25) 33 (51) 4 (43)
Vieweg et al. (195) 19801990 686 193 (28) 10 (10) 12 (9) 22 (23) 97 (42) 52 (41)
Leissner et al. (166) 19992002 290 81 (28) 1 (3) 5 (13) 12 (22) 53 (43) 10 (50)
Stein et al. (4) 19711997 1,054 246 (24) 19 (5) 21 (18) 35 (27) 113 (44) 58 (42)
Vazina et al. (293) 19922002 176 43 (24) 1 (215) 10 (16) 20 (236) 12 (50)
Abdel-Latif et al. (294) 19971999 418 110 (26) 3 (215) 4 (7) 29 (25) 59 (48) 15 (65)
Madersbacher et al. (153) 19852000 507 124 (24) 2 (3) 26 (17) 64 (34) 32 (41)
Hautmann et al. (155) 19862003 788 142 (18) 2 (2) 31 (10) 73 (41) 36 (43)

Total 4,110 989 (24)

a From ref. 192.

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to be biased by underlying patient tness. A further interesting feature of the BC2001
trial, 194 discussed in detail below, was that although no attempt was made to include
pelvic nodes in the treatment eld, the rate of nodal relapse was low at around 6%
with radiotherapy alone, falling to 4% with chemoradiation. One possible interpretation
of these data is that successful treatment of the primary, with either surgery or
radiotherapy, may affect the subsequent behavior of low-volume nodal disease.
The prognosis in patients with lymph nodepositive disease can be stratied by
the number of lymph nodes involved (tumor burden), the stage of the primary tumor,
and the presence of lymph node capsule perforation. 4,173 Patients with fewer than ve
positive lymph nodes among those with lymph nodepositive organ-conned bladder
tumors had a signicantly improved recurrence-free survival rate. 4,166,195
The number of lymph nodes involved with tumor and the extent of the lymph node
dissection are both important variables for patients undergoing cystectomy for bladder
cancer. Stein et al. 193 examined 246 patients with lymph node tumor involvement
following radical cystectomy to evaluate other prognostic factors in this high-risk
group. They used lymph node density to account for the extent of the lymph node
dissection (number of lymph nodes removed) and the tumor burden (number of
positive lymph nodes) following cystectomy for patients with lymph nodepositive
disease. Lymph node density as dened in this study was a signicant and
independent prognostic variable in patients with lymph node metastases. Future
staging systems and the application of adjuvant therapy in clinical trials may consider
applying these concepts to better stratify this high-risk group of patients.
Recurrence Following Radical Cystectomy
Recurrence following radical cystectomy for bladder cancer correlates well with the
pathologic stage and subgroup. 4,153
With long-term follow-up (median, >10 years) recurrences in the University of
Southern California series were classied as local (pelvic), distant, and urethral. Local
recurrences were dened as those occurring within the soft tissue eld of
exenteration. Distant recurrences were dened as those occurring outside the pelvis,
while urethral tumors were classied as a new primary tumor occurring in the retained
urethra. Overall, 30% of all patients in the University of Southern California series
experienced tumor recurrence. 4 The median time to any recurrence was 12 months,
with 86% of all patients developing their recurrences within the rst 3 years of
cystectomy. Of the 311 patients who developed a recurrence, the median time to
distant recurrence was 12 months, while the median time to local recurrence was 18
months. Late tumor recurrences, dened as 5 years or more after surgery, do occur
and underscore the need for lifelong follow-up.
Pelvic (Local) Recurrence
Pelvic recurrence rates of 6% to 9% are reported in large series, 153,155,190 with higher
rates in tumors with extravesical spread or node-positive disease at cystectomy. 4
Metastatic (Distant) Recurrence
Recurrences following radical cystectomy are most commonly found at distant sites.
This is consistent with the ben-
TABLE 64.6 RECURRENCE-FREE SURVIVAL AND THE INCIDENCE OF RECURRENCE IN SELECTED STUDIES OF
RADICAL CYSTECTOMY
Recurrence-Free Survival (%)
Number of Median Follow-Up
Study (Reference) Patients (Month) 5 Year
Stein et al./USC (4) 1,054 122 68
Madersbacher et al./Bern (153) 507 45 62
Hautmann et al./Ulm (154) 788 53 65
Yafi et al./Canada (190) 2,287 29 48
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Chapter 64 Bladder Cancer 1269
ets observed in the neoadjuvant chemotherapy trials, where the maximum effect
would be expected on low-volume, occult metastases rather than large-volume
primary disease (discussed below). Distant recurrence rates of 20% to 35% are
reported in large series (Table 64.6). However, overall death rates from bladder
cancer are higher than this, so there would appear to be either underreporting of
deaths in these series or the cases selected were not representative of wider
experience.
Urethral Recurrence
Urethral tumor recurrence in patients with a history of bladder cancer following radical
cystectomy represents a second manifestation of the multicentric defect of the primary
transitional cell mucosa that led to the original bladder tumor. The term urethral
recurrence is therefore somewhat misleading, suggesting a failure of denitive
treatment of the bladder cancer. Most urethral tumors probably represent simply
another occurrence of the transitional cell carcinoma in the remaining urothelium.
Because radical cystectomy with orthotopic diversion has increasingly been
performed, the fate of the retained urethra has become an increasingly important
oncologic issue.
Clinical Radiation Oncology
The advent of orthotopic lower urinary tract reconstruction has provided a more
natural voiding pattern in patients following radical cystectomy. Approximately 85% of
all patients undergoing cystectomy for TCC of the bladder at the University of
Southern California research center receive an orthotopic neobladder substitute. From
an oncologic perspective, only those with a positive surgical margin at the proximal
urethra (distal to the apex of the prostate in men and just distal to the bladder neck in
women) on intraoperative frozen section are absolutely excluded from orthotopic
reconstruction. This enthusiasm to preserve the native urethra following radical
cystectomy and allow for orthotopic reconstruction has rightfully increased concerns
for a urethral recurrence in these patients.
Prior to the orthotopic era in women, urethral tumor recurrence was not an
important oncologic issue because the entire urethra was removed at the time of
cystectomy. With a better understanding of female pelvic anatomy and the innervation
of the urinary sphincter and continence mechanism in women, 196
along with the identication of various pathologic risk factors for urethral tumor
involvement in these patients, orthotopic diversion has now become a commonly
performed form of urinary diversion in women following cystectomy. 197 Tumor involving
the bladder neck is the most important risk factor for urethral tumor involvement in
women. 198,199 Although bladder neck involvement is a signicant risk factor for urethral
tumors, not all women with tumor involving the bladder neck will have urethral tumors.
Approximately 50% of female patients with tumor at the bladder neck will have an
uninvolved urethra free of tumor. In this situation, the patient may potentially be
considered an appropriate candidate for orthotopic diversion. Furthermore,
intraoperative frozen-section analysis of the distal surgical margin is an accurate and
reliable means to pathologically evaluate the proximal urethra. 199
A growing population of male patients reconstructed to the urethra following
cystectomy exists today. With longer followup, could this expose them to a greater risk
for a urethral recurrence? The historical incidence of urethral recurrence in the
retained urethra following cystectomy
for bladder
cancer ranges from 6% to 10%. 200,201 Specic
clinical and pathologic risk factors
Recurrence (%) that have been identied to provided
risk assessment for urethral
10 Year Local Distant
66 7.3 22.2 recurrence
50 7.9 35.3 include multifocal tumors, CIS, tumor
59 9.3 17.8
involvement of the prostate
6.0 27.0
(particularly
1270 Section III Clinical Radiation Oncology Part H Urinary Tract
invasion of the prostatic stroma), and the form of urinary diversion (orthotopic or
cutaneous) performed. 198,200,202204
Stein et al. 205 have evaluated urethral recurrence in a large group of male patients
undergoing radical cystectomy and urinary diversion for TCC of the bladder. In this
study, the clinical and pathological results of 768 consecutive male patients
undergoing radical cystectomy with a median follow-up of 13 years were analyzed. Of
these 768 patients, 397 men (51%) underwent an orthotopic diversion (median
follow-up 10 years) and 371 men (49%) underwent a cutaneous diversion (median
follow-up 19 years). Overall, 45 patients (7%) developed a urethral recurrence. The
median time to a urethral recurrence was 2 years (range, 0.2 to 13.6 years). Of these
45 patients, 16 men (5%) had an orthotopic and 29 (9%) had a cutaneous form of
urinary diversion. In this cohort of male patients, multiple risk factors were analyzed
with regard to urethral recurrence. In a multivariate analysis, two important variables
were identied that signicantly increased the risk of a urethral tumor recurrence
following cystectomy,
including any prostate
involvement and the form of urinary diversion. The estimated 5-year probability of a
urethral recurrence was 5% without prostate involvement, which increased to 12%
and 18% with supercial (prostatic urethra and ducts) and invasive (stroma) prostate
involvement, respectively. Patients undergoing an orthotopic diversion demonstrated
a statistically signicantly lower risk of urethral recurrence compared with those
undergoing a cutaneous form of urinary diversion.
The follow-up and management of the urethra in male patients treated for
high-grade invasive bladder cancer is of importance. The indications and timing of a
prophylactic urethrectomy in those undergoing cystectomy and a cutaneous diversion
is debatable. It may include urethrectomy at the time of cystectomy based on
preoperative clinical parameters, based on the intraoperative frozen-section analysis
of the urethral margin, or a delayed urethrectomy based on nal pathologic evaluation
of the cystectomy specimen. These issues are best detailed with the patient
preoperatively ensuring proper informed consent.
Management of the Retained Urethra Following
Cystectomy
Intraoperative frozen-section analysis of the proximal urethra by an experienced
pathologist is a reliable and accurate means to determine indications for orthotopic
diversion in all patients. It is good practice to proceed with an orthotopic neobladder in
men and women whose intraoperative frozen section of the proximal urethra is free of
tumor. This approach does not appear to increase the risk of a urethral recurrence in
these patients. 197,206 Male patients with known prostatic tumor involvement should not
necessarily be excluded from an orthotopic substitute if the intraoperative biopsy is
normal. Similarly, female patients with bladder neck involvement should not
necessarily be excluded from an orthotopic neobladder if the intraoperative biopsy is
also normal. All patients should be carefully counseled regarding the need for
follow-up, the long-term risks of a urethral recurrence, and the possible need for
urethrectomy following cystectomy.
Salvage Cystectomy
Salvage cystectomy after prior radiotherapy was discussed above in the section
comparing surgical with bladder-sparing approaches.
Summary of Surgical Therapy
Surgery is an important mode of therapy for invasive bladder cancer and undoubtedly
can provide durable disease control for many patients with the disease. In addition, an
integrated approach with other treatment modalities such as neoadjuvant
chemotherapy and radiotherapy is essential if the best results are to be achieved in
the entire patient population, especially
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those who are borderline t for major surgery. Radical cystectomy probably provides
the best local pelvic control of the disease and provides accurate evaluation of the
primary bladder tumor along with the regional lymph nodes yielding important
prognostic information. This, coupled with the evolution and successful application of
orthotopic lower urinary tract reconstruction in both men and women, has provided
patients a more physiological and acceptable means to store and eliminate urine.
However, most deaths from bladder cancer still occur due to distant metastases,
presumably present at the time of original surgery, so further improvements in
outcome will depend on the development of both better systemic therapies and also
predictive (as opposed to prognostic) markers that will allow better selection of
therapies.
Radiotherapy
External-Beam Radiotherapy
Whatever the merits or otherwise of radiotherapy as a treatment for bladder cancer,
its use in the United States has declined markedly since the 1980s, and the treatment
is now used mainly in certain centers such as Boston in carefully selected patients
rather than as a mainstream alternative to surgery. As discussed above, patterns vary
worldwide with the U.S. pattern of care predominating. Potential indications for
radiotherapy are summarized in Table 64.7. Patients with radiological node-positive or
metastatic disease should be managed predominantly with either chemotherapy or
palliative approaches such as local radiotherapy to bulk disease (see below). Patients
with radiological node-negative, muscle-invasive disease may be considered for
radical radiotherapy. In North America, radiotherapy is administered as part of a
package of care comprising maximal TURBT, chemotherapy, and radiotherapy, the
so-called trimodality therapy (Fig. 64.3). 207,208
The schedules used are complex but can be summarized as initial maximal
TURBT followed by initial radiotherapy combined with synchronous chemotherapy,
usually with cisplatinum followed by interim check cystoscopy. Patients experiencing a
good response to treatment continue to consolidation chemoradiotherapy and then
adjuvant polychemotherapy, usually with a cisplatinum base. Patients remain on
long-term cystoscopic surveillance. Noninvasive recurrence can be managed by
further TURBT and intravesical therapy. Those with isolated muscle-invasive
recurrence or failure to respond (but with no systemic relapse) can undergo salvage
cystectomy with or without further chemotherapy.
The optimal radiotherapy schedule has yet to be established. In North America,
split schedules often used are 39 or 40 Gy in
1.8- or 2-Gy fractions with an interval cystoscopy; patients with responding disease
proceed to a total dose of 64 to 66 Gy. Generally, these schedules achieve long-term
survival comparable to surgical series. 209,210 A signicant risk of cystectomy remains,
however, with 22% undergoing immediate cystectomy, 13% delayed cystectomy for
local recurrence, and 65% retaining a functioning bladder. 211
In some countries, particularly the United Kingdom and Australia, an alternative
schema is used (Fig. 64.4). As in the
TABLE 64.7 INDICATIONS FOR RADIOTHERAPY IN BLADDER CANCER
Stage Recommendation
CIS, Ta, T1 No role for radiotherapy
T2-T4aN0M0 Potential role for radiotherapy, combined with synchronous chemotherapy
if patient sufficiently fit
TanyN13M0 or No role for radical radiotherapy as sole treatment for stage IV disease. It may
TanyNanyM1 be worth considering, however, as part of a package of radical palliation in
concert with systemic chemotherapy. No randomized data on the use of
radiotherapy in this setting beyond studies of fractionation.
 Chapter 64 Bladder Cancer 1271

Biopsy-proven muscle-invasive bladder cancer

Maximal transurethral resection of tumor

Induction chemoradiotherapy 3 weeks

Cystoscopy and biopsy week 7

T0 or noninvasive Residual disease or

disease only new T1+

Consolidation chemoradiotherapy weeks 89 Cystectomy

Cystoscopy and biopsy week 17

Clinical Radiation Oncology

T0 Ta or Tis disease T1+ disease

Adjuvant
chemotherapy in
Surveillance Intravesical therapy Salvage cystectomy selected cases
FIGURE 64.3. Trimodality therapy.

trimodality approach, patients will undergo maximal TURBT for diagnostic and staging
purposes. They can then be treated either with primary surgery (as elsewhere) or
alternatively with either neoadjuvant chemotherapy or primary radiotherapy. The role
of cystectomy was discussed above, and the evidence and use of neoadjuvant
therapy is discussed in the section Role of Systemic Therapy. In the United Kingdom,
the radiotherapy itself is given as a single radical course, usually to the whole bladder,
only with no attempt to treat the nodes (as discussed below). Typical dose schedules
would be 64 Gy in 32 fractions or hypofractionated schedules such as 55 Gy in 20
fractions. Following radiotherapy, patients undergo cystoscopic surveillance as in the
U.S. model, with salvage cystectomy for isolated local failure.
are more likely to get surgery and older or less t patients radiotherapy. 10,12,142 ,143,194 Interestingly,
the long-term bladder preservation rates in older series seem similar to the rates for
salvage cystectomy postradiotherapy occurring in approximately one-fourth of patients
managed with radiotherapy alone at 10 years median follow-up, 213 with around
two-thirds of surviving patients retaining their bladders. The authors own more recent
chemoradiotherapy series suggests a higher rate of bladder preservation with the use
of synchronous chemotherapy combined with full-dose radical radiotherapy. 11

There are key differences between these two approaches. The rst and most
obvious is that in most disease sites radical radiotherapy is not given as a split course
but as a single treatment as in the United Kingdom. To understand how this approach
has arisen, it has to be understood that trimodality therapy is offered as an alternative
to cystectomy in countries where the prevailing opinion is that surgery is the treatment
of choice. Patients undergoing this treatment are offered what is termed selective
bladder preservation, with the multiple checkpoints allowing early exit to surgery
aimed at providing reassurance to surgeons in particular that the opportunity for cure
is not being lost. The median ages (mid-60s) reported in studies using this approach
reect this patient selection 147,208,212
and are similar to large surgical series. 4,141 The UK approach is completely different in
this respect as there is a long tradition of using radical radiotherapy after TURBT, and
the much older patient groups compared with surgical series reect a different
decision-making process in which younger, more t patients
Treatment Results
It is difcult to compare results of older series to more contemporary ones for a
number of reasons. First, staging systems have changed over the years, as have
imaging techniques. Patients who may have been staged as organ conned in the
early or pre-CT era may now be more accurately staged as more advanced with
contemporary imaging. In contrast, surgical series will report accurate pathological
stage. It is well documented that more accurate staging will bring about a paradoxical
improvement in reported results by stage due to upstaging of apparently early disease
cases, the so-called Will Rogers phenomenon. 214 Treatment techniques in the past
were obviously less rened, with little or no ability for conformal beam shaping and
hence toxicity would have been higher. Nonetheless, it is clear from large series that
tumor control could be attained in signicant numbers of patients. For example, a
study from Western General Hospital, Edinburgh, conducted between 1971 and 1982,
reported treatment results from 963 patients. The reported stage mix was: T1, 20%,
T2, 32%, T3, 40%, and T4, 8%, with the administered dose of 55 Gy in 20
fractionsa widely used UK schedule. The overall

Neoadjuvant Radiotherapy Cystectomy

chemotherapy

Salvage Chemotherapy on Adjuvant

Cystectomy Radiotherapy
cystectomy relapse chemotherapy in FIGURE 64.4. Integration of neoadjuvant chemotherapy,
selected cases radiotherapy, and surgery in the United Kingdom.

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1272 Section III Clinical Radiation Oncology Part H Urinary Tract

55 Gy / week 20 64 Gy / week 32
100% 100%
90%
80% 80%
70%
% of non-missing

60% 60%
50%
40% 40%
30%
20% 20%
10%
0% 1 2 3 4 0%
1234 1234567 1234567
Week Week Week Week
CT No CT CT No CT

FIGURE 64.5. Acute toxicity of radiotherapy with and without synchronous chemotherapy. Graphs show worst grade of on-treatment toxicity by radiotherapy dose and week.
Darkest bars indicate National Cancer Institute common terminology class grade 4; white indicates grade 0. Proportions with a grade 3 or 4 at any time on treatment: 64/178
(36.0%) chemotherapy (CT) versus 50/182 (27.5%). No CT-stratified chi-square test ( P = . 07).

5- and 10-year survival rates were 30% and 18%, respectively. 215 This study reports
tumor control at cystoscopy in 46% of patients, and this seems to be a pretty typical
response rate with radiotherapy alone.
Similar control rates were reported in the radiotherapy alone arm of the National
Cancer Institute of Canada (NCIC) trial comparing radiotherapy with
chemoradiotherapy with cisplatinum 212 and also in the radiotherapy only arms at 2
years of the UK trials BCON 12 and BC2001 194 at 2 years. The latter two trials give an
accurate reection of the results of modern radiotherapy. They ran
contemporaneously between 2000 and 2009 and between them recruited more than
800 patients from around 70 UK sites, including all major UK radiotherapy centers.
Both trials had similar designs, including near identical entry criteria (essentially
T24aN0M0, with a small number of T1G3 patients entered the BCON trial), the same
control arms (radical radiotherapy to bladder only to either 55 Gy in 20 fractions or 64
Gy in 32 fractions), and the same outcome measures (locoregional disease-free and
overall survival). Both trials assessed both acute and late toxicity (Figs. 64.5 and
64.6). In addition, the BC2001 trial included
an optional second randomization comparing whole-bladder radiotherapy with a
reduced dose to uninvolved bladder of 80% of the isocenter dose. The BC2001
permitted neoadjuvant chemotherapy, which was a stratication factor. Around
one-third of the chemoradiotherapy patients also received neoadjuvant chemotherapy.
The trials give a comprehensive insight into UK radiotherapy practice and great
detail on outcomes. Median age in both trials was 73 to 74 years, with age range up to
90 years. Overall, around 40% of patients received 55 Gy in 20 fractions and 60% 64
Gy in 32 fractions. In both trials, over 95% of patients received at least 90% of the
target dose in both arms, with no reduction associated with the two radio-sensitizing
treatments. Although the protocol recommended complete debulking at TURBT, this
was only achieved in one-third to one-half of the cases, probably reecting technical
factors at surgery rather than deliberate intent.
The overall 5-year survival rate was 50% for radiotherapy plus carbogen and
nicotinamide compared with 39% for radiotherapy alone (48% and 35%, respectively,
if T1 tumors are excluded), with the greatest effect seen in T2 tumors. For

50% 50%

45% 45%
Standard Reduced high
CT No CT
40% RT dose volume RT 40%

35% 35%

30% 30%

25% 25%

20% 20%

15% 15%

10% 10%

5% 5%

0% 0%
6 9 12 24 36 48 60 6 9 12 24 36 48 60 6 9 12 24 36 48 60 6 9 12 24 36 48 60

Month

FIGURE 64.6. Late toxicity in the BC2001 trial. Darkest bars indicate Radiation Therapy Oncology Group (RTOG) grade 4; white indicates grade
0. Proportion of patients with grade 3 or 4 RTOG toxicity at any month during follow-up (6 months onward), up to 3 months before a recurrence: RT: 12.9% sRT vs. 17.9% RHDV; odds
ratio (95% confidence interval) 1.34 (0.55, 3.24); P = . 52; CT: 8.3% CT vs. 15.7% no CT; odds ratio 0.48 (0.21,
1.10); P = . 07. Patients with no available assessment were excluded from analysis. RT, radiotherapy; sRT, standard volume radiotherapy; RHDV, reduced high dose volume
radiotherapy; CT, chemotherapy with radiotherapy.

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BC2001, the estimated 5-year survival with radiotherapy alone was very similar at
34% (95% CI, 25% to 43%).
Toxicity
The toxicity of radical radiotherapy varies with the dose and schedule used. Within
BC2001 and BCON, there were two schedules: 55 Gy in 20 fractions and 64 Gy in 32
fractions. Acute toxicity is shown in Figure 64.5 for both schedules, with and without
chemotherapy with 5-uorouacil/mitomycin-C.
As can be seen, the majority of patients experience only grade 1 or 2 toxicity with
very low rates of grade 4 events. Synchronous chemotherapy increased toxicity but
was predominantly grade 1 or 2, with a nonstatistically signicant effect on grade 3 or
4 events (27.5 vs. 36%; P = . 07; boundary for signicance set at 0.01 to reect
multiplicity of testing). The reduced volume randomization failed to demonstrate a
reduction in overall toxicity. However, when the volume of bowel irradiated was
calculated, this did show a signicant reduction; in an exploratory analysis, volume of
bowel irradiated did correlate with the risk of grade 3 or 4 toxicity. There was no
increase in acute toxicity observed in BC2001 if patients had received prior
neoadjuvant chemotherapy.
Treatment completion rates in both trials were very high, with an excess of 95% of
patients receiving the prescribed dose. The majority of patients failing to complete did
so for tumorrelated reasons rather than toxicity. Late toxicity was of great interest in
both trials and was analyzed somewhat differently. In BCON, the cumulative rates of
grade 3 or 4 events were reported, which gives the worst-case scenario but does not
reect the overall toxicity at any given time point posttreatment. BC2001 reports the
toxicity rates at prespecied time points.
There are a number of points of note here. First, late toxicity was the same with
both randomizations in BC2001 (i.e., reduced-volume radiotherapy did not impact late
toxicity). More signicantly, the addition of synchronous chemotherapy also had no
effect on reported late side effects. In addition, at any given point, 75% to 80% of
patients report no late toxicity at all. This is supported by bladder capacity
measurements in BC2001, which show a mean change in bladder volume at 1 and 2
years of <5 mL. Of those reported side effects, fewer than 5% report grade 4 events
and fewer than 10% overall grade 3. Very similar ndings pertain to the BCON trial. 12 In
2009, Efstathiou et al. 216 reported late toxicity results in 285 patients who had
participated in four Radiation Therapy Oncology Group trimodality therapy trials.
Overall 5.7% reported persistent late genitourinary and 1.9% gastrointestinal toxicity
of grade 3 or above, consistent with the BCON and BC2001
ILRDFS
82% (95% CI: 75%, 88%)
Proportion invasive locoregional disease-free
68% (95% CI: 59%, 75%) 2-yr
HR = 0.53 (95% CI: 0.33, 0.84); p = 0.007
Months since randomisation
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Chapter 64 Bladder Cancer 1273
results. The good toxicity and functional results associated with radiotherapy are
borne out by surveys of quality of life and symptoms in cystectomy and radiotherapy
patients carried out by Henningsohn et al. 13 ,217220 Furthermore, radiotherapy and
cystectomy patients report different patterns of symptoms, with sexual dysfunction
being more prominent in surgical patients and bowel symptoms more prominent in
radiotherapy patients. The preservation of sexual function by radiotherapy is
particularly striking given that the patients were an average of around 10 years older.
Effect of Synchronous Chemotherapy
There are a large number of phase I or II trials from North America, 208 ,216,221222, 223 ,224230,
231 ,232237 mainland Europe, 5 ,238240
and the United Kingdom 241, 242 that have examined various chemotherapy agents in
combination with radiotherapy. There are, however, only a few trials reported in which
radiotherapy alone is compared with radiotherapy with synchronous chemotherapy.
The only randomized study using the trimodality therapy approach was carried out by
the NCIC and reported in 1996. 212 This study compared radiotherapy to 40 Gy in 20
Clinical Radiation Oncology
fractions with the same schedule combined with cisplatinum 100 mg/m 2 twice weekly 3.
Patients then underwent interim cystoscopy and either consolidation radiotherapy to
20 Gy in 10 fractions or cystectomy depending on response and tness for surgery.
Synchronous cisplatinum had no effect on the rate of distant metastasis, consistent
with a lack of effect in neoadjuvant trials. 243 The study, however, was relatively small
and could only have detected very large effects. Concurrent cisplatinum had a highly
signicant effect on pelvic recurrence, with 25 of 48 control patients having a pelvic
recurrence, compared with 15 of 51 cisplatinum-treated patients ( P = . 036; HR 0.50;
90% CI, 0.29 to 0.86). It should be noted that a similar platinum schedule given prior
to radiotherapy had no effect whatsoever on recurrences, either local or distant. 213, 243
There are two randomized trials of radio sensitization using UK schedules: the
BC2001 and BCON studies, as already discussed. These two large phase III
randomized control trials reported results in 2009 to 2010. These trials used
radiosensitization with either concurrent chemotherapy (BC2001) or carbogen and
nicotinamide (BCON). BC2001 has shown a signicant improvement in locoregional
disease-free survival with concurrent 5-uorouracil and mitomycin-C of 34% (HR 0.66;
95% CI, 0.46 to 0.95) driven by a reduction of 47% in invasive locoregional
recurrences (HR 0.53; P = . 007), which is very similar to that observed in the NCIC trial
with cisplatinum using the trimodality approach. 212 Figure 64.7 shows the Kaplan-Meier
CT = 28/182
No CT = 51/178
FIGURE 64.7. Invasive locoregional disease-free survival with or without chemotherapy.
1274 Section III Clinical Radiation Oncology Part H Urinary Tract
Loco-regional
recurrence
53
Non-muscle Muscle invasive
invasive 18
25
FIGURE 64.8. Patterns of failure after chemoradiotherapy in BC2001.
curves for invasive locoregional disease-free survival. Survival data show a trend
toward an improvement in overall survival (HR 0.81; P = . 16), although the data are
immature. 194 The BCON trial 12 with synchronous carbogen and nicotinamide narrowly
failed to meet its primary end point of an improvement in local relapse-free survival
(HR 0.87; 63% vs. 74%; P = . 1) but did report an improvement in overall survival at 3
years (46% vs. 59%; HR 0.86; 95% CI, 0.745 to 0.996; P = . 04). Taken together the
trial data with chemoradiotherapy suggests good tolerability even in relatively elderly
patients with excellent late toxicity proles in the majority of patients whether treated
with the North American trimodality approach 216 or the UK single treatment block. 194 The
similar hazard ratios observed with cisplatinum and 5-uorouacil/mitomycin-C
suggests that a range of chemotherapy approaches can probably be used with the
selection based on toxicity. It is noteworthy that comparisons of platinum and
5-uorouacil-based chemoradiotherapy combinations have been carried out in anal
cancer, with the two approaches being similarly effective. 244 The high rates of
locoregional control seen make radical chemoradiotherapy a viable treatment option
for many patients presenting with muscle-invasive bladder cancer.
Pattern of Failure
As already discussed above, a signicant proportion of patients will experience local
failure and undergo salvage surgery. The BC2001 study gives a good indication of
patterns of failure using the single block approach to radical radiotherapy. A summary
of relapse patterns in the chemoradiotherapy arm of the trial is shown in Figure 64.8.
There are a number of features of note here. First, the majority of locoregional
failures are in the bladder, and there are more noninvasive than invasive recurrences.
This underlines the need for regular surveillance postradiotherapy and the
requirement for good integration of radiotherapy and surgical services if patients are
to be managed by bladder conservation. In the authors experience, the majority of
noninvasive recurrences can be successfully managed conservatively without the
need for cystectomy. For those with invasive recurrence, cystectomy remains an
option if the patients are sufciently t. The low rate of nodal relapse in BC2001 is
also of interest, as no attempt was made to include pelvic nodes in the eld, although
lower pelvic nodes would have been included in the treated volume. For improvement
in the metastatic relapse rate, better systemic therapies must be found. However, the
rate of second cancer is also notable and probably relates to the age of the patients
and the historic high rate of tobacco consumption in the bladder cancer population.
Altered Fractionation Schedules
There are old data examining hyperfractionation in comparison to conventional
treatment to 64 Gy in 32 fractions, both
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Any recurrence
93/182 pts
Distant recurrence or
second primary
40
Pelvic nodes Metastasis Second primary
6 29 11
given as a split course. The data suggest an improvement with the hyperfractionated
regimen; however, given the suboptimal nature of the control arm, it is hard to draw
rm conclusions from this. 245,246 A study from the Royal Marsden Hospital compared 64
Gy in 32 fractions to 60.8 Gy in 32 fractions over 26 days in 228 patients. 247 Hypofractionated
schedules are widely used in the United Kingdom and elsewhere for radical treatment
and for palliation (as discussed below). There are no modern trials comparing these
schedules to 64 Gy in 32 fractions.
Palliative Radiotherapy
A prospective randomized trial was conducted in 500 patients to compare the
outcome in two treatment groups. Group 1 received 35 Gy in 10 fractions and group 2
received 21 Gy in 3 fractions. Five hundred patients were recruited, but data on
symptomatic improvement at 3 months were only available on 272 patients. Of these,
68% achieved symptomatic improvement (71% for 35 Gy, 64% for 21 Gy), with no
evidence of a difference in efcacy or toxicity between the two arms. On the basis of
these results, 21 Gy in 3 fractions is widely used in the United Kingdom as a palliative
schedule. 248 The data are congruent with other data on hypofractionation for palliation 249,250
as well as the growing trend for hypofractionation in other pelvic sites, in particular
the prostate.
Preoperative Irradiation
Preoperative radiotherapy has been investigated in the past, but interest in the
technique has waned, largely because none of the trials carried out showed any
evidence of worthwhile benet. In addition, the observed chemosensitivity of bladder
cancer lead to a wave of neoadjuvant chemotherapy trials carried out in the 1980s
and 1990s, effectively ending interest in the technique. Given the subsequent
improvements in both radiotherapy and surgical technique, it may be appropriate to
revisit the possibility of combining surgery with radiotherapy, particularly given the
apparent plateau in progress with systemic therapy since the licensing of gemcitabine
more than 10 years ago. Most of the studies in the literature are old, retrospective,
nonrandomized comparisons and little can be concluded from them. 251
There are few randomized trials in the literature, and those that are available are
also old, for the reasons outlined above. A study from the Royal Marsden Hospital
randomized patients to preoperative radiotherapy to 40 Gy in 4 weeks followed by
cystectomy, against denitive radiotherapy to 60 Gy in 6 weeks. The 5-year survival in
patients receiving the combined therapy was 38% versus 29% for those treated with
radiotherapy alone, the difference not reaching statistical signicance. 252 This trial of
course did not compare radiotherapy plus surgery versus surgery alone and thus does
not address the primary question in this section. However, it is noteworthy that no
tumor was found in 31% of the cystectomy specimens, a similar complete

response rate to that observed in the intergroup neoadjuvant MVAC study. 7 Similar
response rates have been reported in other series. 253
A second randomized study was carried out by the Memorial Sloan-Kettering
Cancer Center in New York comparing radiotherapy to 40 Gy in 4 weeks followed by
cystectomy 4 weeks later with a shorter 20 Gy in a 5-day course with immediate
cystectomy modeled on the Swedish preoperative rectal cancer trials. Again this study
is not informative on the primary issue of the utility of adding radiotherapy to surgery
but does demonstrate the feasibility and safety of such an approach. 254 A retrospective
review from the MD Anderson Cancer Center assessed the use of preoperative
irradiation (50 Gy in 5 weeks) in patients with T3b bladder tumors. 255 The 5-year local
control rate was 91% in the preoperative group (n = 92) compared with 72% for those
treated with radical cystectomy alone (n = 43; P = . 003). Parsons and Million 256 reviewed
the results of retrospective studies and six prospective randomized trials on the use of
preoperative irradiation. They concluded that the use of the technique may improve
outcomes by up to 15% to 20% at 5 years. In particular, they noted that many
preoperative radiotherapy series report pathological complete response rates of
around one-third, similar to that seen with neoadjuvant chemotherapy. There are no
modern trials of preoperative radiotherapy, and the topic seems to be ripe for
revisiting with modern techniques, particularly given the low long-term toxicity
associated with chemoradiotherapy schedules, as summarized above.
Postoperative Radiotherapy
As with many areas of bladder cancer practice, there are little in the way of
randomized data on the use of adjuvant radiotherapy following surgery. When used, it
is mostly based on the grounds of positive surgical margins or tumor spillage at
surgery, where a high local recurrence rate can be anticipated. With the use of
neoadjuvant chemotherapy worldwide being at low levels, chemo-naive patients at
high risk of recurrence can be offered adjuvant chemotherapy, although the evidence
base for this approach is also somewhat thin. What few data there are on
radiotherapy suggests that limited doses are well tolerated. 257 Given the more solid
evidence base for neoadjuvant chemotherapy and the failure of adjuvant
chemotherapy trials to accrue, the use of postoperative radiotherapy would also seem
to be a topic well-worth revisiting with modern treatment techniques. An approach
combining neoadjuvant chemotherapy, surgery, and adjuvant radiotherapy for patients
at high risk of local recurrence would combine all three of the major bladder cancer
treatment modalities in a novel fashion.
Electron Beam
Electron beams are really only of interest in the context of intraoperative radiotherapy.
The role of intraoperative radiotherapy for carcinoma of the bladder needs to be
assessed in a prospective trial and cannot at present be recommended outside of a
suitable study.
Neutron Beam
There are a small number of studies examining the use of neutrons beams for bladder
cancer therapy. A single randomized trial failed to show a survival advantage but did
show increased morbidity. 258 ,259 There are currently no reasons to recommend neutron
therapy for bladder cancer.
Treatment Techniques
Patient Position and Immobilization
The patient should be planned and treated in the same position; supine with arms
on their chest. Knee and ankle immobilization should be used to ensure patient
positioning is reproducible.
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Chapter 64 Bladder Cancer 1275
The rectum should be empty of atus and feces. The use of daily microenemas
may be considered.
Patients should be asked to empty the bladder 15 minutes prior to scan.
While breathing normally, the patient should have a CT scan performed with 3 to
5-mm slice spacing. Patients are scanned from bottom of ischial tuberosities to 3
cm above the dome of the bladder or bottom of L5 (whichever is higher). A at top
CT scanner should be used.
Neither intravenous nor oral contrast is thought to be of benet in this instance.
Reference tattoos should be made at the base of the abdomen and over each hip.
The location of the tattoos should be marked on the planning scan by the use of
radio-opaque markers to allow cross-referencing of planning scan and setup
instructions.
Volume or Field Localization
Clinical Radiation Oncology
The gross tumor volume can be difficult to define and should integrate information
from the staging CT or MRI as well as the TURBT. MRI-CT fusion may be helpful,
where available.
The use of ducial markers or contrast medium such as lipiodol at the time of
TURBT has been explored and may help identify tumor for image-guided adaptive
radiotherapy.
There are few data on the optimal radiotherapy volume. A standard approach is to
dene the planning target volume as the whole bladder, identied by its
noninvolved outer bladder wall with a 1.5-cm margin plus extravesical extent of
tumor with a 2-cm margin.
All planning and treatment should be carried out with the bladder empty to
minimize the risk of geographic miss and to keep the treated volumes as small as
possible. Patients with signicant residual volumes post voiding should be
considered for planning and treatment with a catheter
in situ, although this is likely to increase urinary toxicity.
There are no data to support the routine irradiation of radiologically negative
lymph nodes. The nodal relapse rate in the BC2001 trial, with planning target
volume and clinical target volume dened as above, was only 3% in the
chemoradiotherapy arm and 6% with radiotherapy only.
Brachytherapy
There is considerable historic literature on the use of brachytherapy, particularly from
the Netherlands. Reported results seem to be very good, for example, van der
Werf-Messing et al. 260 report the outcomes in 328 patients treated with 3
3.5 Gy external irradiation followed by a radium implant. Overall 5- and 10-year
survival was 56% for T2 tumors and 39% and 13%, respectively, for T3 disease.
Similar results have been obtained in more recent series with iridium-192 implants
and manual afterloading. 261,262 There are also descriptions in the literature of the use of
high-dose rate afterloading, although one paper suggests that this may be less
effective and more toxic than low-dose rate treatment. 263 The striking feature of most of
these series is the very low patient numbers and long time spans reported, suggesting
that these techniques are only rarely used, even in centers with the relevant expertise.
Hyperthermia
Details on hyperthermia in combination with external-beam radiation therapy or
chemotherapy are beyond the scope of this chapter.
Treatment of Patients with Uncommon Bladder
Tumors
Squamous cell carcinoma is uncommon in the developed world, and many reported
cases may in addition reect sampling of
1276 Section III Clinical Radiation Oncology Part H Urinary Tract
squamous elements within a transitional cell carcinoma. As these tumors are often
excluded from systemic therapy trials, there are few data on outcomes with treatment
as most papers are retrospective collections of unconnected observations. 264265 ,266 It
appears that local failure may be more prevalent than distant relapse, but even that
observation is based on very few cases. Urachal adenocarcinomas are extremely
rare. Surgical resection with a partial cystectomy and en bloc resection of the urachal
ligament with umbilicus is the treatment of choice in the setting of localized disease.
There is currently no denitive role for neoadjuvant or adjuvant chemotherapy in this
tumor. Unfortunately, there are many patients who present with metastatic disease,
which currently is not likely to be curable. There is no standard chemotherapy regimen
for these patients. Carcinosarcoma is even more rare and appears to have a poor
prognosis. 267269 Similar considerations apply to small cell carcinoma, although the
consensus seems to be that metastasis is more likely and initial response to
chemotherapy is usually good. These patients generally get treated along the same
lines as small cell lung carcinoma, but the benet of prophylactic cranial irradiation is
unclear. 270275
ROLE OF SYSTEMIC THERAPY
Up to 50% of patients will develop metastatic disease. Bladder cancer is a
chemosensitive disease, with responses reported to a range of agents. Systemic
combination chemotherapy can be effective and result in tumor responses and
symptom control. Overall response rates may be as high as 70%, 286 with a median
survival of approximately 12 to 14 months. 35 These agents were initially evaluated in
the metastatic setting and subsequently in the neoadjuvant and adjuvant settings.
However, despite over 30 years of research in the eld, there remain many
unanswered questions, including the role of adjuvant therapy and optimal second-line
chemotherapy.
Neoadjuvant Chemotherapy
There are two principal rationales for neoadjuvant chemotherapy: rst, to improve
survival in patients with micrometastatic disease, 277 and second, to preserve the
bladder by shrinking the primary tumor to facilitate radiotherapy as an alternative
denitive therapy to surgery. 278 The potential disadvantage of neoadjuvant
chemotherapy, and a frequent reason cited for its nonuse, is the delay in denitive
treatment (cystectomy or chemoradiotherapy), because this may lead to disease
progression in a proportion of nonresponding patients who may conceivably become
inoperable or unsuitable for radical organ preservation treatment. However, it is
equally plausible that by undergoing neoadjuvant chemotherapy these patients can be
identied as those with biologically aggressive disease and therefore spared the
morbidity of futile radical therapy. It should also be noted that a signicant proportion,
possibly up to two-thirds, of bladder cancer patients are elderly with multiple
comorbidities and poor renal function and, therefore, unsuitable for neoadjuvant
chemotherapy. However, in the authors experience, a patient who is considered t for
a radical cystectomy is likely to be t for chemotherapy as well.
There are two particularly key studies in the area of neoadjuvant chemotherapy.
The South Western Oncology Group (SWOG) neoadjuvant study comparing surgery
alone with 3 cycles of MVAC followed by surgery reported an estimated median
survival of 6.2 years versus 3.8 years in favor of patients having neoadjuvant
chemotherapy ( P = . 027). 7 Updated results from the UK MRC/EORTC neoadjuvant
chemotherapy trial, which used 3 cycles of cisplatinum, methotrexate, and vinblastine
(CMV) prior to surgery or radiotherapy, show a statistically signicant 16% reduction
in the risk of death (HR 0.84; 95% CI,
0.72 to 0.99; P = . 037), corresponding to an increase in 10-year survival from 30% to
36% after neoadjuvant chemotherapy. 279
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In total, 976 patients with high-grade T2 to T4a urothelial bladder cancer accrued over
5.5 years from 106 institutions were randomly assigned to 3 cycles of neoadjuvant
CMV chemotherapy (n = 491) or no chemotherapy (n = 485), followed by the
institutions choice of denitive therapy with either radical cystectomy or radiation
therapy. Of patients in the chemotherapy and no chemotherapy groups, 42% and
43%, respectively, received radiation therapy alone as denitive therapy. Pathologic
complete response with neoadjuvant chemotherapy was 33%. Overall survival at 3
years in the two groups was 55.5% versus 50%, respectively. The recent update, after
8 years of follow-up, showed an increase in 3-year survival from 50% to 56%, an
increase in 10-year survival from 30% to 36%, and an increase in median survival
time of 7 months (from 37 to 44 months) in CMV-treated patients compared with those
treated with local therapy only. The SWOG study showed that of the 82% patients
who underwent cystectomy, 38% had no evidence of disease pathologically. Patients
who achieved pT0 status had a better prognosis than those who did not, although this
difference may be accounted for by better disease biology rather than treatment
effect. By denition, the SWOG study did not address organ preservation, because
the mandated treatment plan was for surgery following neoadjuvant chemotherapy.
Meta-analyses show a 5% overall survival benet at 5 years with
cisplatin-containing regimens. 31 Thus, there have been two large randomized
neoadjuvant studies in muscle-invasive bladder cancer, both showing signicant
survival advantage. Although many disciplines in cancer care would consider these
data sufcient to change the standard of care, this does not seem to have taken place
for the management of invasive bladder cancer. 280 The lack of widespread adoption of
neoadjuvant chemotherapy may relate to the selected patients in clinical trials, not
reecting typical muscle-invasive bladder cancer patients who may be older or have
impaired renal functions, which may limit the applicability of some chemotherapy
regimens. GC, 33 standard, 7 or accelerated 281 MVAC are widely used with denitive
radical treatment (either surgery or radiotherapy/synchronous chemoradiotherapy) 4
to 6 weeks later. It is worth noting that these trials have been restricted to patients
with well-preserved renal function (typically glomerular ltration rate >60 mL/min), thus
excluding a signicant proportion of bladder cancer patients who are elderly or have
ureteric obstruction and therefore deemed unsuitable for neoadjuvant chemotherapy.
This regimen requires in-patient or prolonged hydration and therefore has a signicant
impact on patient quality of life and health service resources. Clinical trials
investigating chemotherapy regimens that may broaden the spectrum of patients
receiving cisplatin-based treatment have been conducted in palliative settings, for
example, a split-dose regimen of cisplatin in combination with gemcitabine on days 1
and 8 of a 21-day schedule allowed safe treatment of patients with calculated
glomerular ltration rate as low as 40 mL/min in the day-case setting. 282 This regimen
could be tested within a randomized clinical trial in the neoadjuvant setting and may
go far in increasing the uptake of neoadjuvant chemotherapy. It is the responsibility of
urology and oncology colleagues to work together to provide state-of-art care for our
patients with muscle-invasive bladder cancer, which should include neoadjuvant
chemotherapy prior to surgery or organ-preservation therapy in t patients.
Adjuvant Chemotherapy
Adjuvant chemotherapy has the potential advantage of enabling better patient
selection based on the ndings at surgical and pathological staging. The major
disadvantages, although, are the delay in systemic therapy and the inability to assess
the response to chemotherapy in the absence of measurable disease. Randomized
adjuvant chemotherapy studies

TABLE 64.8 RANDOMIZED TRIALS OF ADJUVANT CHEMOTHERAPY
Author (Reference) N Standard Arm Adjuvant Arm
Skinner et al. (295) 91 Cystectomy Cystectomy + CAP
Stockle et al. (296) 49 Cystectomy Cystectomy + MVAC
Studer et al. (297) 77 Cystectomy Cystectomy + cisplatinum No benefit.
Freiha et al. (298) 55 Cystectomy Cystectomy + CMV
Bono et al. (284) 83 Cystectomy Cystectomy + CM
CAP, cyclophosphamide/Adriamycin (doxorubicin)/cisplatin; MVAC, methotrexate/vinblastine/doxorubicin (Adriamycin)/cisplatinum;
CMV, cisplatinum/methotrexate/vinblastine; CM, cisplatinum/methotrexate.
(Table 64.8) have been conducted with the methodological aws of inadequate
sample size, early closure, and suboptimal choice of chemotherapy, preventing a
clear interpretation of the results. A systematic review and meta-analysis of updated
individual patient data from all available randomized controlled trials in the adjuvant
setting has been performed. Updated data were collected, validated, and reanalyzed
for 491 patients from 6 randomized controlled trials, representing 90% of all patients
randomized in cisplatin-based combination chemotherapy trials and 66% of patients
from all eligible trials. In view of this, the power of this meta-analysis was limited. The
overall hazard ratio for survival of 0.75 (95% CI, 0.60 to 0.96;
P = . 019) suggests a 25% relative reduction in the risk of death favoring adjuvant
chemotherapy. However, the impact of trials that stopped early, of patients not
receiving allocated treatments, or not receiving salvage chemotherapy is less clear. 283
An Italian multicenter randomized phase III trial enrolled 194 patients (one-third of its
target) with muscle-invasive TCC and assigned them to 4 cycles of GC or observation
after cystectomy. The trial was stopped early due to poor accrual. After a median
follow-up of 32.5 months, relapses were similar in both groups (43% vs. 45%) with no
difference in disease-free survival. The 3-year overall survival was 67% for the
chemotherapy arm and 48% for the observation arm and the 3-year disease-free
survival was 47% and 35%, respectively, suggesting no statistically signicant
improvement in either survival rate with adjuvant GC in these patients. 284 A large
phase III trial by EORTC (protocol 30994) evaluating observation versus adjuvant
chemotherapy with one of the three chemotherapy regimens (GC, MVAC, or
high-dose MVAC) in high-risk bladder cancer (pT34 and/or node-positive disease)
was also prematurely closed due to poor accrual after enrollment of 278 of a planned
1,344 patients. This appropriately designed and sized study thus failed to conclusively
address the issue of adjuvant chemotherapy following cystectomy. A possible reason
for the failure of this trial was the tight window postsurgery for commencing
chemotherapy. In the authors experience, relatively few patients were able to enter
the trial sufciently soon due to slow postoperative recovery. This suggests that
adjuvant chemotherapy may be less suitable than neoadjuvant chemotherapy in this
patient population. The adjuvant chemotherapy question still requires international
collaboration with an appropriately sized pragmatic study for a conclusive answer. In
various disease sites neoadjuvant chemotherapy followed by adjuvant chemotherapy
is an acceptable norm with level I evidence. With an anticipated rise in uptake of
neoadjuvant chemotherapy, patients with bladder cancer should not be precluded
from this strategy where neoadjuvant chemotherapy is followed by radical treatment
followed by a trial of adjuvant chemotherapy versus no chemotherapy in an
appropriately sized phase III trial that meets its recruitment target, thus providing a
denite answer for or against this strategy. Previous failures in meeting recruitment
targets can be overcome by using better-tolerated regimens in common use now and
by extending the recruitment window from 12 to 16 weeks to allow full recovery
postsurgery and to allow more dose-intense adjuvant chemotherapy treatment.
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Chapter 64 Bladder Cancer 1277
Results
Benefit, but few patients received planned therapy.
Benefit, but limited trial size, premature closure, and no therapy
upon relapse.
Benefit limited to relapse-free survival.
No benefit.
Choice of Chemotherapy Regimen in
Metastatic Disease
Currently, systemic combination chemotherapy is the only treatment that may prolong
survival in patients with metastatic disease. The chemosensitivity of bladder cancer is
demonstrated by objective response rates of 12% to 73% and complete response
Clinical Radiation Oncology
rates of 0% to 35%. 285 Although antitumor activity has been demonstrated with several
single agents, the median survival associated with single-agent therapy is short (4 to 6
months). Prior to the development of gemcitabine, a range of trials were done with
doublet regimes, which typically showed median survival times of approximately 8
months. 285 The development of the four drug combination for MVAC chemotherapy
extended this to over 12 months and became the established standard of care. 286
The triplet combination CMV is also widely used but has not been compared with
MVAC directly. Experimental data suggested that a combination of gemcitabine and
cisplatin given using an appropriate schedule (simultaneous or close proximity
exposure) can act synergistically. Synergy may be mediated either by inhibition of
ribonucleotide reductase by gemcitabine, depleting the deoxynucleotide pool required
for DNA replication and thereby inhibiting excision repair of cisplatin-induced DNA
crosslinks, or by gemcitabine incorporation into DNA, facilitating cisplatin crosslink
formation. 287,288 The combination of the two drugs proved active and tolerable 33 and
was subsequently compared with MVAC in a phase III trial. Patients were randomized
to GC (gemcitabine 1,000 mg/m 2 days 1, 8, and 15; cisplatin 70 mg/m 2 day 2) or
standard MVAC every 28 days for a maximum of 6 cycles. Four hundred ve patients
were randomized (GC, n = 203; MVAC, n = 202). The groups were well balanced with
respect to prognostic factors. Overall survival was similar on both arms (HR 1.04; 95%
CI, 0.82 to 1.32;
P = . 75), as were time to progressive disease (HR 1.05; 95% CI,
0.85 to 1.30), time to treatment failure (HR 0.89; 95% CI, 0.72 to 1.10), and response
rate (GC, 49%; MVAC, 46%). More GC patients completed 6 cycles of therapy, with
fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the
MVAC arm. More GC than MVAC patients had grade 3 or 4 anaemia (27% vs. 18%,
respectively) and thrombocytopenia (57% vs. 21%, respectively). More MVAC
patients, had grade 3 or 4 neutropenia (82% vs. 71%), neutropenic fever (14% vs.
2%), neutropenic sepsis (12% vs. 1%), grade 3 or 4 mucositis (22% vs. 1%), and
alopecia (55% vs. 11%). Because of the higher incidence of neutropenic fever and
mucositis, more hospital admissions were required for the MVAC arm (49 admissions
for a total of 272 days) than for the GC group (9 admissions for a total of 33 days),
resulting in considerably greater hospital resource utilization. The quality of life was
maintained during treatment on both arms; however, patients on GC fared better
regarding weight, performance status, and fatigue. This study thus demonstrated that
GC provides a similar survival to MVAC with a better safety prole and tolerability. 34 ,35 Therefore,
although this trial was not designed to show equivalence of the two regimens, many
interpret the results as showing therapeutic noninferiority and have adopted GC as the
new standard in
1278 Section III Clinical Radiation Oncology Part H Urinary Tract
view of the better tolerability. With the upper boundary of the condence interval of the
adjusted hazard ratio for survival close to 1.2, noninferiority can reasonably be
assumed. Therefore, GC is a valuable alternative for the growing elderly patient
population with metastatic bladder cancer who may derive equal benet from this
regimen as compared with MVAC but with fewer side effects.
The addition of paclitaxel to GC was evaluated in a phase III clinical trial by
EORTC (protocol 30987), which enrolled 627 patients with advanced urothelial
carcinoma. The regimens were well tolerated. Results showed that the GCP arm
resulted in a higher rate of overall response rate (57% vs. 46%) CR (15% vs. 10%)
and survival (15.7 vs. 12.8 months) compared with GC arm, but these differences
were not statistically signicant. 289
Combination of docetaxel and cisplatin (DC) has been compared with MVAC in a
multicenter phase III clinical trial by the Hellenic Co-operative Oncology Group. 290 Patients
(n = 220) were randomly assigned to MVAC every 4 weeks versus docetaxel plus
cisplatin every 3 weeks. Treatment with MVAC resulted in signicantly superior
response rate (54.2% vs.
37.4%), median time to progression (9.4 vs. 6.1 months), and median survival (14.2
vs. 9.3 months), suggesting that MVAC was superior to DC. Toxicity of MVAC was
considerably lower than that previously reported for MVAC administered without
granulocyte colony-stimulating factor. Currently GC, MVAC, and high-dose MVAC
with granulocyte colony-stimulating factor support are the acceptable standard of care
as rst-line chemotherapy in advanced or metastatic bladder cancer setting.
Second-Line Chemotherapy Treatment
The role of salvage chemotherapy after relapse following rstline chemotherapy
remains an important subject of recent clinical trials. The enrollment in such trials is
challenging in view of patients poor performance status and deranged renal functions.
Although various phase I or II studies have been reported, to date there is only one
completed phase III trial comparing vinunine with best supportive care (BSC) alone.
Patients (n = 370) were randomly assigned in a 2 to 1 ratio to receive vinunine plus
BSC (n = 253) or BSC alone (n = 117). Both arms were well balanced. Grade 3
toxicities for the vinunine arm were neutropenia (50%), febrile neutropenia (6%),
anemia (19%), fatigue (19%), and constipation (16%). A median survival advantage of
2.3 months (6.9 months for vinunine plus BSC vs. 4.6 months for BSC) was achieved
but was not statistically signicant ( P = . 287). Cox multivariate analysis adjusting for
prognostic factors showed a statistically signicant effect of vinunine on overall
survival ( P = . 036), reducing the death risk by 23%. Objective response rate (8.6% vs.
0%), disease control (41.4% vs. 24.8%), and progression-free survival (3.0 vs. 1.5
months) were all statistically signicant, favoring vinunine. Because vinunine was
well tolerated, it is a reasonable second-line therapy option for patients with bladder
cancer who have relapsed following cisplatin-based therapy. 291
Future second-line chemotherapy studies should incorporate vinunine as the
standard of care arm when testing any experimental treatment in a randomized trial.
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247. Horwich A, Dearnaley D, Huddart R, et al. A randomised trial of accelerated radiotherapy for localised
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248. Duchesne GM, Bolger JJ, Grifths GO, et al. A randomized trial of hypofractionated schedules of palliative
radiotherapy in the management of bladder carcinoma: results of medical research council trial BA09. Int J
Radiat Oncol Biol Phys 2000;47(2):379388.
Clinical Radiation Oncology
252. Bloom HJ, Hendry WF, Wallace DM, et al. Treatment of T3 bladder cancer: controlled trial of pre-operative
radiotherapy and radical cystectomy versus radical radiotherapy. Br J Urol 1982;54(2):136151.
258. Duncan W, Williams JR, Kerr GR, et al. An analysis of the radiation related morbidity observed in a
randomized trial of neutron therapy for bladder cancer. Int J Radiat Oncol Biol Phys 1986;12(12):20852092.
260. van der Werf-Messing BH, Menon RS, Hop WC. Carcinoma of the urinary bladder category T2, T3, NX, MO
treated by interstitial radium implant. Prog Clin Biol Res 1988;260:511524.
264. Kassouf W, Spiess PE, Siefker-Radtke A, et al. Outcome and patterns of recurrence of nonbilharzial pure
squamous cell carcinoma of the bladder: a contemporary review of the University of Texas MD Anderson
Cancer Center experience.
Cancer 2007;110(4):764769.
265. Kastritis E, Dimopoulos MA, Antoniou N, et al. The outcome of patients with advanced pure squamous or
mixed squamous and transitional urothelial carcinomas following platinum-based chemotherapy. Anticancer
Res 2006;26(5B): 38653869.
276. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and
prognostic factors predicting outcome of therapy.
J Clin Oncol 1999;17(10):31733181.
279. Grifths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin,
methotrexate, and vinblastine chemotherapy for muscleinvasive bladder cancer: long-term results of the
BA06 30894 trial. J Clin Oncol
2011;29(16):21712177.
281. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity
methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human
granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European
Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001;19(10):26382646.
283. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Adjuvant chemotherapy in invasive bladder
cancer: a systematic review and meta-analysis of individual patient data Advanced Bladder Cancer (ABC)
Meta-analysis Collaboration. Eur Urol 2005;48(2):189199.
291. Bellmunt J, Theodore C, Demkov T, et al. Phase III trial of vinunine plus best supportive care compared with
best supportive care alone after a platinumcontaining regimen in patients with advanced transitional cell
carcinoma of the urothelial tract. J Clin Oncol 2009;27(27):44544461.
 Part I Male Genitourinary

Chapter 65
Low-Risk Prostate Cancer

Michael J. Zelefsky, Megan E. Daly, and Richard K. Valicenti

The prostate is contained within a thin, brous adherent capsule that is

ANATOMY
Gross Anatomy and External Architecture
The prostate gland is an ovoid-shaped structure composed of brous, glandular, and
muscular elements. It is located in the pelvis, adjacent to the rectum, bladder, dorsal,
and periprostatic venous complexes, pelvic sidewall musculature, the pelvic plexus,
and cavernous nerves. Because of its shape, the prostate and the rectum curve away
from each other as two convex surfaces. The prostate surrounds segments of the
urethra before it passes through the genitourinary diaphragm (GUD; Fig. 65.1). The
male urethra is composed of ve segments: the pre-prostatic urethra adjacent to the
pre-prostatic sphincter; the prostatic urethra, which is from the verumontanum to the
GUD; the membranous urethra as it courses through the GUD, which is surrounded
by the external sphincter; the bulbar urethra in the penile bulb; and the penile urethra
as it passes through the corpus spongiosum. The paired seminal vesicles are situated
posterosuperiorly to the prostate gland and secrete seminal uid into the bilateral
ductus deferens as they become the ejaculatory ducts. These ducts transverse the
prostate to join the urethra at the verumontanum (Fig. 65.1, right). At this point, the
urethra changes its angulation by bending 30 to 40 degrees anteriorly.
structurally continuous with the stroma of the gland. The apex of the gland rests
above the GUD. The GUD surrounds the membranous sphincter and may vary in
length and thickness. The puboprostatic ligaments extend anteriorly from the surface
of the gland to the pubic symphysis. The prostate is separated from the rectum
posteriorly by Denonvilliers fascia (retrovesical septum), which attaches above to the
peritoneum and below to the GUD. It is this portion of the prostatic fascia that restricts
posterior extension of prostatic carcinoma into the rectum. The lateral margins of the
prostate are usually delineated against the levator ani muscles, forming the lateral
prostatic sulci.
The anterior aspect of the prostate and the lateral pelvic oor are covered with the
periprostatic fascia (Fig. 65.2). The endopelvic fascia lateral to the prostate gland
contains neurovascular structures, including the venous plexus of Santorini, which is
the primary drainage for the penis. This venous network, also referred to as the dorsal
vein complex, covers the anterolateral surfaces of the prostate. The primary arterial
blood supply to the prostate is via branches of the internal pudendal, inferior vesical,
and middle hemorrhoidal arteries. The internal pudendal arteries also provide the
blood ow to the penis. The nerves originate from the pelvic plexus, containing both
sympathetic

Seminal
SV vesicle
Central zone
Pre-prostatic
(CZ)
sphincter Median lobe

CZ Periurethral
stroma

TZ

FIGURE 65.1. Zonal anatomy of the prostate. On the left, a young man with zone (PZ) AFS
minimal transition zone (TZ) hypertrophy. Note that the preprostatic sphincter and
periejaculatory duct zone (central zone of McLean) are clearly defined. On the Peripheral Transition
right, an older man with TZ hypertrophy, which effaces the preprostatic sphincter
PZ zone (TZ)
and compresses the periejaculatory duct zone. AFS, anterior fibromuscular stroma;
CZ, central zone; PZ, peripheral zone; SV, seminal vesicle. (From McLaughlin PW,
Troyer S, Berri S, et al. Functional anatomy of the prostate: implications for Verumontanum
Anterior
treatment planning. Int J Radiat Oncol Biol Phys 2005;63:479491; with permission External
fibromuscular
from Elsevier.) sphincter
stroma (AFS)

1280
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Ejaculatory duct
Prostate
Endopelvic fascia
Ilium
Obturator internus m.
Urethra
Sphincter urethrae m.
Pudendal canal:
int. pudendal a.
int. pudendal v.
pudendal n.
Perineal memb.
Fascia lata
Bulbospongiosus m.
Corpus spongiosum penis
FIGURE 65.2. Frontal section of male pelvis at right angles to perineal membrane. (From Oelrich TM. The urethral sphincter muscle in the male.
Am J Anat 1980;158:229246;reproduced with permission of John Wiley & Sons, Inc.)
and parasympathetic bers, and are distributed to the prostate, seminal vesicles, and
the corpora cavernosa of the penis and urethra.
The prostatic apex is denable on diagnostic imaging and is important
anatomically for radiation therapy treatment planning. Although the apex and the
GUD, which surrounds the membranous sphincter, are easily visualized on coronal
magnetic resonance imaging (MRI), it is important to recognize that the level of the
GUD from the apex to the penile bulb may vary because the absence of an apical
capsule contributes to the difculty in discrimination of the gland from the GUD during
computed tomography (CT)-based treatment planning. Delineation of the
neurovascular bundle is also limited on CT imaging.
Prostatic Zonal Anatomy
Zonal anatomy has essentially replaced lobar anatomy of the prostate. There are four
zones of the prostate (Fig. 65.1): the peripheral zone (PZ), transition zone (TZ),
central zone, and anterior bromuscular stroma zone. The central zone that surrounds
the ejaculatory ducts has marked histologic differences from the PZ. It is the PZ,
extending across the entire posterior surface of the gland that is palpated on rectal
examination and is the location of most prostate cancers. The TZ is the location of
benign prostatic hypertrophy. The anterior bromuscular zone consists of an anterior
band of bromuscular tissue contiguous with bladder muscle and external sphincter.
In young men, the PZ is the prominent zone, whereas the TZ becomes the dominant
zone with age. It is important to note that there is no median lobe zone in this
nomenclature, although such a lobe may be present in some prostate cancer
patients and may have important implications for treatment planning and treatment
selection. Histologically, the median lobe arises from the TZ or periurethral stroma,
with varying proportions of brous, glandular, and muscle tissue.
Prostate Physiology
Histologically, the prostate consists of compound tubuloalveolar glands lined by two
layers of cells. The glands are embedded
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Chapter 65 Low-Risk Prostate Cancer 1281
Amp. ductus deferens
Seminal vesicle
Puboprostatic lig.
Sheath of prostate
Pelvic diaphragm
Obturator memb.
Transversalis fascia
Clinical Radiation Oncology
ramus (ischiopubic)
Corpus cavernosum
wb penis Inf. pubic
Deep fascia
Ischiocavernosus m.
Superficial perineal fascia
in connective tissue comprising collagen and abundant smooth muscle that
constitutes the prostatic stroma. This bromuscular stroma functions both to control
micturition by acting as a sphincter of the urethra and to express acidic prostatic
secretions into the urethra by contracting during ejaculation.
The major function of the prostate is the production of seminal uid that protects
and nourishes the sperm after ejaculation. The prostate contributes approximately
30% to the seminal uid, and the seminal vesicles, testicles, and bulbourethral glands
provide the remaining 70%. Enzymes, including acid phosphatase and
prostate-specic antigen (PSA), are secreted into the seminal uid. PSA is a serine
protease that is involved in the liquefaction of the seminal coagulum. Because PSA is
produced primarily by benign and malignant prostatic epithelial cells and normally
found at low concentrations in the serum, it is useful for prostate cancer screening and
posttreatment monitoring of disease status.
The synthetic activity and growth of the prostate gland is regulated by androgens.
The primary circulating androgen is testosterone. In the prostatic stroma, testosterone
is converted to its active and more potent form, - dihydrotestosterone, by 5- - reductase.
Secretory epithelial cells and stromal cells have intracellular androgen receptors.
Dihydrotestosterone forms a complex with the dihydrotestosterone-binding domain of
the androgen receptor, altering the structure of the DNA-binding domain such that it
can reversibly bind DNA sequences known as androgen response elements in
promoter or enhancer regions of androgen-regulated genes. The response includes
stimulation of cell division, inhibition of apoptosis (programmed cell death), or cellular
differentiation. In secretory epithelial cells, testosterone stimulation may result in the
production and secretion of prostatic uid. These mechanisms are tightly regulated at
many levels, from the hypothalamus secreting luteinizing hormone releasing
hormone to maintain testosterone levels in the blood, to the local regulation of 5- - reductase
in the prostate stroma. All of these factors acting at the same time determine the
balance between cellular proliferation, cell death, and differentiation of a prostatic
epithelial cell.
1282 Section III Clinical Radiation Oncology Part I Male Genitourinary

EPIDEMIOLOGY AND RISK FACTORS TABLE 65.1 KNOWN OR SUSPECTED RISK FACTORS FOR PROSTATE CANCER

Factor Effect on Prostate Cancer Risk

Clinical Incidence
Adenocarcinoma of the prostate is the most frequently diagnosed visceral cancer of Age Increase

men in the United States, accounting for 33% of non-skin cancers. The lifetime risk for African American race Increase
Geography Scandinavia, high; Asia, low
American White and African American men is 18% and 21%, respectively. This
Family history Increase
corresponds to a respective lifetime risk of prostate-specic mortality of 3% and 5%. 1,2 After
Dietary fat Increase
large annual increases from 1988 to 1992, coinciding with the introduction of the PSA
Agent Orange May increase
screening test, prostate cancer incidence in the United States leveled off, then
Vasectomy No effect
showed modest decreases of approximately 1.9% per year between 2000 and 2008
Benign prostatic conditions No effect
(Fig. 65.3). Incidence rates between 2004 and 2008 were approximately 153 per Sexually transmitted diseases No effect
100,000 men. 2 Tobacco Inconclusive data
Androgens Inconclusive data

Perhaps because of widespread use of PSA screening and effective early

treatment for localized disease, the age-adjusted death rates have begun to decrease. races, there is considerable variability in the incidence of clinically evident disease
It was estimated that and mortality among different populations worldwide and in the United States. 6
241,740 new cases of prostate cancer would be diagnosed in
2012, but only approximately 28,170 patients would die of the disease. 2 This compares The highest rates of prostate cancer are in Scandinavia, where it is the leading
with 189,000 new cases and 30,200 estimated deaths in 2002. 1 Despite these
cause of male cancer death. The lowest recorded rates are in Asia. In the United
encouraging trends, in 2008 carcinoma of the prostate remained the second greatest
States, incidence and mortality are higher among African Americans. A 30- to 50-fold
cause of male cancer mortality behind cancer of the lung and bronchus. 3
difference in risk between African American men at the highest end of the spectrum
and native Japanese at its lowest end has been reported. The mortality rates of
prostate cancer in Japan dramatically increased from 1960 to 2000 in all age groups
Of the known or suspected risk factors for prostate cancer, the most important is before showing modest but sustained decreases from 2000 onward. 7
age (Table 65.1). 4 The median age at diagnosis is 68 years, and the disease incidence
escalates sharply with increasing age. The incidence among men age 40 to 59 years
is 1 in 38, increasing to 1 in 15 among men age 60 to 69 years and 1 in 8 among
those age 70 years and older. According to autopsy data, 70% of men older than 80
years of age and 40% of men older than 50 years of age have pathologic evidence of
cancer in the prostate. 5 Risk Factors
Hormonal Influences
It is relatively well established that androgenic inuences over time affect prostate
carcinogenesis and disease progression. 8
Although the risk for development of histologic evidence of cancer in the prostate
is fairly constant across countries and Generally, androgens are required for the development of

FIGURE 65.3. Surveillance, Epidemiology, and End Results (SEER) prostate cancer incidence and mortality rates by race, United States, 19752008. (SEER Cancer Statistics
Review, 19752008. Available at: http://seer.cancer.gov.)

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prostate cancer, and it has been noted that men decient in
2,5 reductase are rarely diagnosed with benign prostatic hypertrophy or prostate
cancer. In a study of 1,008 men, there was a positive correlation with plasma
androstenedione levels and the development of prostate cancer. 9 However, Gann et
al. 10 found no clear association between individual hormone levels, including
dihydrotestosterone, and the incidence of prostatic cancer. Yet, these investigators
noted that high levels of testosterone in combination with low levels of the serum
protein that binds testosterone, sex hormonebinding globulin, correlated with a
higher risk of prostate cancer. Meikle et al. 11
observed a higher sex hormonebinding globulin level and a higher rate of
testosterone synthesis in men with prostate cancer compared with control subjects.
The most conclusive evidence supporting the hormonal inuence in the
development of prostate cancer comes from two large, randomized trials evaluating
the use of 5 - reductase inhibitors in chemoprevention. The Prostate Cancer
Prevention Trial was the rst large-scale, population-based trial testing the hypothesis
that treatment with nasteride, which lowers intraprostatic dihydrotestosterone levels,
prevents prostate cancer. 12
In this trial, a total of 18,882 men 55 years old and with normal digital rectal
examination (DRE) and PSA level 3.0 ng/mL were randomized to 7 years of
nasteride (5 mg/day) or placebo. This study found that the prevalence of prostate
cancer was reduced by 25% in men taking nasteride compared to placebo, with the
prevalence of Gleason sum 7 to 10 tumors higher in the former group. The Reduction
by Dutasteride of Prostate Cancer Events (REDUCE) trial randomized 8,231 men at
high risk for prostate cancer (age 50 to 60 years with a PSA of 2.5 to
10.0 or age 60 years with a PSA of 2.5 to 10.0 and a negative prostate biopsy within
6 months of enrollment) to dutasteride (0.5 mg daily) or placebo. 13 At 4 years, a
relative risk reduction in the diagnosis or a subsequent prostate cancer of 22.8% was
noted in men taking dutasteride. However, a trend toward increased Gleason 8 to 10
tumors was noted among men taking dutasteride. For both trials, it remains
controversial whether this increased risk of high-Gleason tumors is real or artifactual.
However, the U.S. Food and Drug Administration has declined to add
chemoprevention of prostate cancer as an indication for nasteride and dutasteride. 14
Dietary Influences
The development of prostate cancer may be attributed to both familial and
environmental factors. Epidemiologic studies strongly suggest that a diet decient in
certain micronutrients is an important environmental risk factor. This has been
supported through migration studies that indicate higher rates of prostate cancer in
Asian men living in the United States compared with their counterparts in Japan or
China. 15,16 It has been postulated that nutritional factors play a role in stimulating the
progression of microscopic disease. Salient features of the Western diet that differ
from the traditional Asian diet are high fat intake and low soy consumption. A Western
diet has been associated with increased production of both androgens and estrogens
and a vegetarian diet with lower levels. 17
Numerous casecontrol and cohort studies demonstrated an association between
increased dietary fat intake and a higher risk of prostate cancer. 18 Diets high in fat
content may increase the relative risk of prostate cancer by a factor of 1.6 to 1.9. 19,20
In addition, several studies showed that men with diets high in ber and presumably
lower in fat have a decreased risk of prostate cancer. 21,22
One prospective study found that the type of fat intake was directly related to risk
of prostate cancer. 23 Red meat represented the food group with the strongest positive
association with advanced cancer, with a relative risk of 2.64. Fat from dairy products
(with the exception of butter) or sh was unrelated to risk. When analyzed by fatty acid
type, only - linolenic acid (an omega-3 fatty acid found in red meats and butter), and
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Chapter 65 Low-Risk Prostate Cancer 1283
not linoleic acid (omega-6 fatty acid found in sh oil), was implicated, with an increase
in risk for prostate cancer of more than threefold. Conversely, a subsequent Canadian
casecontrolled study suggested that saturated fat consumption, not
- linolenic acid consumption, may play a role in prostate cancer progression. 24 Finally,
a Swedish study of 406 men with prostate cancer and 1,208 without it (control
subjects) demonstrated that body mass index and total amount of food consumed
were independent risk factors. 25
Plant-based foods and their products, such as soy, tomatoes, cruciferous
vegetables, and certain nutrients, are favorably associated with prostate cancer. It is
believed that these dietary factors contribute to antioxidant effects against DNA and
cell damage.
Several vitamins and trace nutrients, including selenium, vitamin E, and vitamin
C, have garnered attention as potential protective agents. Selenium is an essential
trace nutrient that humans obtain through their diet of plants (related to soil
composition; highest in Brazil nuts) and animal products (highest in seafood) and is
present in nutritional supplements. Early experimental and epidemiologic data
Clinical Radiation Oncology
supported the anticarcinogenic effects of selenium through apoptotic, angiogenic, or
antioxidative pathways. 26 The Nutrition Prevention Trial identied a 50% reduction in
prostate cancer risk in men blindly and randomly assigned selenium supplements
compared with placebo. 27 Promising data for vitamin E as a protective agent was
reported in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer (ATBC) Prevention
Study, which evaluated supplementation with vitamin E and beta-carotene in male
smokers for chemoprevention of lung cancer. 28 Secondary analysis suggested a 32%
reduction in prostate cancer risk among men randomized to receive vitamin E.
However, a large, prospective, randomized trial failed to conrm these ndings for
selenium or vitamin E. The Selenium and Vitamin E Cancer Prevention (SELECT)
Trial randomized 35,533 men to four arms: selenium (200 g/day), vitamin E (400
IU/day rac- - tocopheryl acetate), both selenium and vitamin E, or placebo only. 29 With
a minimum follow-up of 7 years, the study identied no reduction in risk of prostate
cancer with either vitamin E or selenium supplementation but identied an increased
hazard ratio for development of prostate cancer among men randomized to vitamin E
alone of 1.17. Vitamin E was contemporaneously evaluated in the randomized
Physicians Health Study II, which failed to demonstrate a reduction in prostate cancer
incidence by supplementation with vitamin E or C. 30
The benecial effects of soy are attributed to isoavones, one of several plant
pigments found in soybeans. Isoavones are a type of phytoestrogencompounds
that have weak estrogenic, antiestrogenic, and antioxidant effects that may all be
protective against progression of prostate cancer in humans. These isoavones, most
signicantly genistein and daidzein, have been shown to inhibit the growth of prostate
cancer cell lines in nude mice. 18 In particular, genistein has been shown to be a potent
inhibitor of several steroid-metabolizing enzymes, such as aromatase, 5 - reductase,
and 17 - hydroxysteroid dehydrogenase, as well as enzymes that are crucial to
cellular proliferation, such as tyrosine kinase and topoisomerases I and II. Genistein is
also an inhibitor of angiogenesis. It is estimated that Japanese men consume
approximately 20 mg of isoavones per day, whereas for Western men the daily
consumption is <1 mg/day. This is reected in a mean plasma concentration of
genistein of 180 ng/mL in Japanese men, compared with a level of <10 ng/mL for
Western men. 31
Another protective nutrient is lycopene, prevalent in the Western diet, a
carotenoid that is present in tomatoes, processed tomato products, and other fruits. It
is one of the most potent antioxidants among dietary carotenoids. Although the
antioxidant properties of lycopene are believed to be primarily responsible for its
benecial effects, other mechanisms may
1284 Section III Clinical Radiation Oncology Part I Male Genitourinary

TABLE 65.2 NUTRITIONAL RISK FACTORS FOR PROSTATE CANCER

Despite the familial clustering of prostate cancer observed in these epidemiologic
INCIDENCE, RECURRENCE, AND MORTALITY studies, causation cannot be inferred, given the shared environmental factors among
family members. Segregation analyses of cancer in multiple family members have
Direction of Association Direction of Association with Overall
been used to examine the role of genetic factors and inheritance patterns in prostate
with Prostate Cancer Risk Prostate Cancer Recurrence Quality of
cancer. Segregation analysis is a statistical method used to determine the best-tting
Food or Nutrient or Mortality Evidence
model of inheritance for a particular disease in a study population. The largest
Selenium Inverse Strong segregation analysis of prostate cancer families suggested that the familial pattern
Tomato and Inverse Inverse a Good was best explained by Mendelian inheritance of a rare, autosomal dominant gene in a
lycopenes
subset of men with early-onset prostate cancer. 42 The allele is highly penetrant,
Other carotenoids Inverse Inverse a Good a
accounting for cancer by age 85 years in 88% of carriers compared with only 5% of
Vitamin E Inverse (seen in Inverse a Good
noncarriers. Although this gene appears to be responsible for many of the early-onset
smokers)
cases, only 9% of all prostate cancer cases are in patients with this genetic
Vitamin D Inverse Good
Calcium and dairy Null to positive Good
predisposition, a percentage similar to that seen in both hereditary breast and colon
Red meat Positive Good cancers. Twin studies have also been used in the analysis of prostate cancer
Fish/omega-3 Inverse Inverse a inheritance and have shown four to ve times higher concordance rates for
Soy/isoflavones Null to inverse Null for PSA recurrence Fair a monozygotic twins. 43
Tea/polyphenols Null to inverse Fair a
Zinc Positive Fair a
Heterocyclic amines Positive Fair a

a Limited data available.

Modied from Chan JM, Gann PH, Giovannucci, EL. Role of diet in prostate cancer development and
progression. J Clin Oncol 2005;23:81528160.

Genetic and Molecular Influences

Researchers are now focusing on the molecular level to identify genetic alterations
also be involved. In a review of 72 epidemiologic studies that investigated a link
that may be involved in the multistep process of carcinogenesis. Progress in
between cancer risk and consumption of tomato products, 57 linked tomato intake
cytogenetic studies using polymerase chain reaction (PCR)based polymorphism
with a reduced risk; in 35 of those studies, the association was considered statistically
analysis has facilitated the identication of regions of the genome associated with
signicant. 32 Two large, prospective studies reported a decrease in prostate cancer
various types of cancer. Linkage analysis is used to determine whether there is an
risk with higher tomato product consumption. 33,34 Tomatoes were one of only four
association between a particular genetic defect and clinical disease. There is ongoing
specic food items associated with signicantly reduced prostate cancer risk in a
investigation into the role of chromosomal deletions, oncogenes, and tumor
prospective study of 14,000 Seventh-Day Adventist men. 34 A prospective study
suppressor genes in the initiation and progression of prostate cancer. Emerging data
examined the relationship between the plasma concentration of several antioxidants
from analysis of DNA from high-risk families suggest that specic high-risk alleles
and the risk for prostate cancer, using plasma samples obtained in the Physicians
exist for prostate cancer, as they do for other tumors. A major susceptibility locus for
Health Study. Higher serum and tissue lycopene levels were found to be inversely
prostate cancer on the long arm of chromosome 1 (1q24-25) was identied through a
related to the incidence of prostate cancer development. 35 In a recent meta-analysis of
genome-wide scan. 44 The gene, HPC1 ( hereditary prostate cancer 1), has been linked
21 studies, high intake of tomatoes was associated with a 10% to 20% risk reduction
to families with multiple members affected with an early average age at diagnosis. 45 However,
in prostate cancer, with lower risk due to cooked versus raw tomatoes. 36 A summary of
this association has not been identied in all studies. Subsequent studies have sought
various epidemiologic studies indicating associations of various dietary factors to
to identify additional susceptibility loci and germline mutations implicated in familial
prostate cancer development and morality is shown in Table 65.2.
prostate cancer. A recent study by Ewing et al. 46 identied a recurrent mutation in
HOXB13, a homeobox transcription factor gene involved in prostate development on
the long arm of chromosome 17 (17q21-22) implicated in early-onset, familial prostate
cancer. A number of other candidate susceptibility genes have been studied, 47 several
of which are summarized in Table 65.3.

Familial Associations
A large cohort study of the Utah Mormon population demonstrated a positive family
history of prostate cancer in 6.6% of families of probands with prostate cancer and
only 2.2% of families of probands without prostate cancer. 37 A subsequent study using
data from the Utah State Cancer Registry reported a familial relative risk of prostate
cancer of 2.2. 38 Multiple studies have conrmed these ndings, including a large
casecontrol study from Johns Hopkins. 39 Extensive cancer pedigrees were obtained
from 691 prostate cancer cases and 640 spouse control subjects showing a twofold
increased risk in men with a family history of prostate cancer in a single rst-degree
relative. There was a vefold risk if there were two affected relatives, and the relative
risk rose to 11 for three rst-degree relatives with prostate cancer.
In a Canadian study, the frequency of prostate cancer detected in men who had a
rst-degree relative with a history of prostate cancer was 2.6 times greater than for
men without such a history. 40 Aprikian et al., 41 in a study of 2,968 patients, noted that
prostate cancer was detected in 40% (1,300 patients) of men with a family history of
prostate cancer, compared with 29% of 769 men without a family history ( p < . 0001). In
a review of the epidemiology of prostate cancer, Giovannucci 33
reported that approximately 9% of cases may be attributed directly to a family history,
although this may be as high as 43% among men younger than 55 years of age.
Research delving into the molecular physiology of the prostate gland has also
uncovered specic DNA sequences that may be related to the occurrence and
progression of prostate cancer. It is well known that prostate cancer cells, like their
normal counterparts, are usually sensitive to androgens, and their growth depends on
androgen-stimulated cell division. Prostate cell growth is controlled by the interaction
of circulating androgens, such as testosterone and dihydrotestosterone, with the
androgen receptor. The androgen receptor gene contains a polymorphic CAG repeat
sequence that encodes the portion of the receptor involved in DNA transcription. The
length of the CAG repeat sequence was found to be inversely proportional to the
activity of the androgen receptor; therefore, shorter CAG repeat sequences may be
related to prostate cancer growth. 48
Giovannucci et al., 49 in an analysis of the activity of the androgen receptor in men with
prostate cancer, found that a shorter CAG repeat sequence in the androgen receptor
gene predicts higher grade and more advanced stage of prostate cancer at diagnosis,
as well as metastasis and mortality from the disease. Other studies found that the
prevalence of short CAG repeats is higher

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 Chapter 65 Low-Risk Prostate Cancer 1285

TABLE 65.3 PARTIAL LIST OF PROSTATE CANCER SUSCEPTIBILITY GENES AND CANDIDATE GENES
5-hydroxy-3-methylglutaryl-coenzyme
A reductase inhibitors (statins). Data
Gene Location Alterations Proposed Phenotypic Consequences
for the effects of statin use on
RNASEL/HPC1 1q24-25 Base substitutions Encodes endoribonuclease Early subsequent risk of prostate cancer
Four-base deletion leading to premature age at diagnosis
are conicting, with some
truncation
observational cohort studies and
ELAC2/HPC2 17p11 Base insertion leading to premature Unknown
retrospective analyses
termination Base
substitutions
MSR1 8p22-23 Base substitutions Encodes subunit of class A macrophage-scavenger
suggesting a
receptor reduced risk of advanced prostate
AR Xq11-12 Polymorphic polyglutamine (CAG) and Encodes androgen receptor, and androgen dependent transcription cancer, 55 reduced risk of death from
polyglycine (GGC) repeats factor prostate cancer, 56 and lower rates of
CYP17 10q24.3 Base substitutions in transcriptional Encodes cytochrome P-450c17 , and enzymes that relapse following radiotherapy 57 or
promoter (T C transition leading to a new catalyzes key reactions in sex-steroid biosynthesis radical prostatectomy (RP). 58 However,
Sp1 recognition site) several large meta-analyses failed to
SRD5A2 2p23 Base substitutions Encodes the predominant 5- - reductase in the prostate, converts identify a relationship between statin
testosterone to dihydrotestosterone
use and prostate cancer risk, 59,60
AMACR 5p13.2 Missense mutations Unknown
BRCA2 13q12-13 Various Possible link to higher Gleason score and stage at
diagnosis

Clinical Radiation Oncology

CHEK2 22q12.1 Frameshift/missense mutations Unknown
HOXB13 17q21 Missense mutations in highly Early age at diagnosis and no prospective, randomized
conserved functional domain studies have conrmed these
KFL6 10p15 DNA polymorphism leads to alternative splicing in encoded tumor observations.
suppressor gene
Other risk factors for prostate
MMR genes Various Various Various
cancer have been implicated but not
(MLH1, MSH2,
corroborated. Several
HSH6, PMS2)
NBS1 8q21 Loss of heterozygosity in carriers Role in DNA repair
reports
HPCX Xq27-28 Unknown Unknown suggested an association between
CAPB 1p36 Unknown Early age at diagnosis; association with CNS malignancies vasectomy and prostate cancer. In a
prospective study of 10,055
Adapted from: (1) Nelson WG, De Marzo AM, Isaacs WB. Prostate cancer. N Engl J Med 2003;349:366381 (2) Langeberg WJ, Isaacs WB, Stanford JL. Genetic Etiology of
vasectomized men and
Hereditary Prostate Cancer. Front Biosci 2007 May 1;12:41014110 (3) www.cancer.gov. Genetics of Prostate Cancer. Accessed December 21, 2012.

37,800 nonvasectomized men,

Giovannucci et al. 61

found an increased risk of

among African Americans than Whites 50 and that these sequences are longest among
Chinese men. 8 These ndings may partly explain the higher risk for development of
prostate cancer among African Americans and the lower risk in Asian countries.
In addition to these genetic alterations identied in prostate cancer, epigenetic
changes such as abnormal DNA methylation have also been observed and may play
a role in upregulation or loss of expression of genes. 51 Millar et al. 52 observed that
abnormal methylation of specic sites throughout the genome of prostate cancer cells
leads to loss of glutathione S- transferase P1 (GSTP1) gene expression. The GSTP1
gene product is an enzyme that provides protection to mammalian cells against
electrophilic metabolites of carcinogens and reactive oxygen species. Loss of GSTP1
may lead to a transition between proliferative inammatory atrophy and prostatic
intraepithelial neoplasia or prostate cancer. 53
1.85 in the vasectomized men. In a retrospective study of 14,607 vasectomized or
nonvasectomized men, the increased risk was
1.56. 62 A recent population-based casecontrol study of 923 new cases of prostate
cancer among men aged 40 to 74 years from the New Zealand Cancer Registry
showed no association between prostate cancer and vasectomy. 63 Although there
appears to be no denite etiologic relationship, it is possible that men undergoing
vasectomy are more conscious of health care and more likely to be screened for
prostate cancer. 64 Circumcision has not been correlated with development of prostate
cancer. 65
Armenian et al., 66 in a study of 296 patients with benign prostatic hyperplasia
diagnosed either histologically or clinically and 299 age-matched control subjects
observed from 7 to 27 years, found the incidence of prostatic cancer to be 3.7 times
higher in the hyperplasia group than in the control group. This association was not
observed by others. 67

Other Risk Factors
Chronic or recurrent inammation may have a role in the development of prostate
cancer, as has been recognized in many other human cancers. Although various
microbial organisms have been identied to infect prostate tissue, the specic
offending pathogen causing prostatitis has not been isolated. However, the specic
cause may not be necessary, as it is the host inammatory response to an infection
rather than the infectious agent itself that may lead to prostate cancer. In one large
populationbased study, prostate cancer risk was increased in men with a history of
gonorrhea or syphilis (odds ratio, 1.6; 95% condence interval, 1.2 to 2.1). 54 A criticism
of such epidemiologic studies is the bias that men with symptomatic prostatitis
compared with men without it are more likely to seek out care with urologists, have an
increased serum PSA test, and have prostate biopsies. 53
Some studies correlated smoking with increased risk of prostate cancer, 68 whereas
another study did not nd a signicant correlation. 69 In one analysis of 359 patients, 70 a
greater tumor-specic mortality rate among smokers than nonsmokers with stage A
and D tumors was observed. No occupational factors have been conrmed as risks,
but some evidence suggests that occupational exposure to cadmium and some
aspects of farming may increase risks moderately, although these factors would
account for only a small proportion of the total cases. Japanese men exposed to
atomic bomb explosions in Hiroshima and Nagasaki have not had a signicantly
higher incidence of prostatic cancer. 71
NATURAL HISTORY

Local Growth Patterns

The studies of prostate morphology conducted by McNeal 72
Several commonly used medications have gained attention as potential showed that almost all prostatic carcinomas (>70%) develop in the PZ of the prostate,
chemopreventive agents, with particular interest in whereas benign prostatic hyperplasia

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