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Int. J. Radiation Oncology Biol. Phys., Vol. 44, No. 1, pp.

37– 45, 1999


Copyright © 1999 Elsevier Science Inc.
Printed in the USA. All rights reserved
0360-3016/99/$–see front matter

PII S0360-3016(98)00530-6

CLINICAL INVESTIGATION Female Genitalia

FACTORS AFFECTING LONG-TERM OUTCOME OF IRRADIATION IN


CARCINOMA OF THE VAGINA

CARLOS A. PEREZ, M.D.,* PERRY W. GRIGSBY, M.D.,* MELAHAT GARIPAGAOGLU, M.D.,‡


DAVID G. MUTCH, M.D.,† AND MARY ANN LOCKETT, M.B.A.*
*Radiation Oncology Center, Mallinckrodt Institute of Radiology, and †Division of Gynecologic Oncology, Department of Obstetrics
and Gynecology, Washington University Medical Center, St. Louis, MO; and ‡Radiation Oncology Department, Ankara University
Medical School, Dikimevi, Ankara, Turkey

Objective: This report evaluates prognostic and technical factors affecting outcome of patients with primary
carcinoma of the vagina treated with definitive radiation therapy.
Methods and Materials: A retrospective analysis was performed on records of 212 patients with histologically
confirmed carcinoma of the vagina treated with irradiation.
Results: Tumor stage was the most significant prognostic factor; actuarial 10-year disease-free survival was 94%
for Stage 0 (20 patients), 80% for Stage I (59 patients), 55% for Stage IIA (63 patients), 35% for Stage IIB (34
patients), 38% for Stage III (20 patients), and 0% for Stage IV (15 patients). All in situ lesions except one were
controlled with intracavitary therapy. Of the patients with Stage I disease, 86% showed no evidence of vaginal
or pelvic recurrence; most of them received interstitial or intracavitary therapy or both, and the addition of
external-beam irradiation did not significantly increase survival or tumor control. In Stage IIA (paravaginal
extension) and IIB (parametrial involvement) 66% and 56% of the tumors, respectively, were controlled with a
combination of brachytherapy and external-beam irradiation; 13 of 20 (65%) Stage III tumors were controlled
in the pelvis. Four patients with Stage IV disease (27%) had no recurrence in the pelvis. The total incidence of
distant metastases was 13% in Stage I, 30% in Stage IIA, 52% in Stage IIB, 50% in Stage III, and 47% in Stage
IV. The dose of irradiation delivered to the primary tumor or the parametrial extension was of relative
importance in achieving successful results. In patients with Stage I disease, brachytherapy alone achieved the
same local tumor control (80 –100%) as in patients receiving external pelvic irradiation (78 –100%) as well. In
Stage II and III there was a trend toward better tumor control (57– 80%) with combined external irradiation and
brachytherapy than with the latter alone (33–50%) (p 5 0.42). The incidence of grade 2–3 complications (12%)
correlated with the stage of the tumor and type of treatment given.
Conclusion: Radiation therapy is an effective treatment for patients with vaginal carcinoma, particularly Stage
I. More effective irradiation techniques, including optimization of dose distribution combining external irradi-
ation and interstitial brachytherapy in tumors beyond Stage I, are necessary to enhance locoregional tumor
control. The high incidence of distant metastases emphasizes the need for earlier diagnosis and effective systemic
cytotoxic agents to improve survival in these patients. © 1999 Elsevier Science Inc.

Vagina, Radiation therapy, Brachytherapy, Tumor control.

INTRODUCTION analyzes factors affecting tumor control and survival in a


larger patient population. Careful dosimetric assessment of
Primary carcinoma of the vagina is rare; it accounts for doses of radiation delivered to the primary lesion or the
about 2% of all gynecologic malignancies at Washington parametria was correlated with tumor control.
University Medical Center. Radiation therapy is the treat-
ment of choice in the majority of patients with primary
carcinoma of the vagina, with wide local excision or vagi- METHODS AND MATERIALS
nectomy sometimes being used for in situ or early invasive The records of 192 patients with primary invasive carci-
tumors (1). We previously reported that higher doses of noma and 20 patients with in situ carcinoma of the vagina
irradiation are required to control more advanced stages (2); treated at the Radiation Oncology Center, Mallinckrodt
judicious use of brachytherapy techniques will yield optimal Institute of Radiology, Washington University Medical
tumor control in patients with smaller lesions at the same Center, between January 1953 and December 1991, were
time that optimal functional results are achieved. reviewed. Over 60% of the patients were over 60 years of
The present report updates a previous publication (2) and age; 171 patients had invasive epidermoid carcinoma, 14

Reprint requests to: Carlos A. Perez, M.D., Radiation Oncology 63108. E-mail: perez@roc.wustl.edu
Center, 4511 Forest Park Boulevard, Suite 200, St. Louis, MO Accepted for publication 4 December 1998.

37
38 I. J. Radiation Oncology ● Biology ● Physics Volume 44, Number 1, 1999

had adenocarcinoma, 2 had clear cell carcinoma not related between curves were made using the statistical method of
to diethylstilbestrol, and 5 had undifferentiated carcinoma; Mantel (5). All other comparisons used the Yates-corrected
20 patients had carcinoma in situ. In all cases, the bona fide Chi-square test. All analyses were performed on a VAX
primary nature of the vaginal tumor was documented, and computer using BMDP statistical software (6).
patients with other primary tumors in the uterus or the
cervix or other sites that may metastasize to the vagina were
excluded. However, patients with prior history of carcinoma Methods of irradiation
of the cervix or endometrium previously treated, who had The techniques of radiation therapy have been previously
been disease-free for more than 5 years after initial treat- described (2). Briefly, all but two patients with carcinoma in
ment, were included in the analysis, because over 95% of situ were treated with intracavitary insertions to deliver
the failures from these primary lesions develop within 5 60 –70 Gy mucosal dose. In most instances, only a cylinder
years from treatment; the survival of this selected group of was used to cover the entire vagina. In one patient, the
patients has been reported to be equivalent to that of patients vaginal vault was treated with an ovoid containing a 20-mg
with primary vaginal carcinoma and is certainly superior to source, and tumor recurrence was noted distal to this area;
that of recurrent lesions of the cervix or endometrium. the patient was salvaged by an anterior exenteration.
Patients were jointly evaluated and staged by the staff of In 32 patients with Stage I tumors, either intracavitary or
Radiation Oncology and Gynecologic Oncology. A routine interstitial brachytherapy (single or double-plane implant)
physical and pelvic examination, chest X-ray, and intrave- or both, combined with external irradiation, were used. In
nous pyelogram were performed. Patients with tumors be- 25 patients, only brachytherapy without external-beam irra-
yond Stage IIA frequently had cystoscopy and barium en- diation was used. One patient who had a vaginectomy
ema. Based on the clinical description and anatomic received postoperative external-beam irradiation. Doses in
drawings in the radiation oncology records, all tumors were the range of 60 –70 Gy were administered in the majority of
staged following the classification adopted by the Interna- patients (calculated at 0.5 cm beyond the plane of the
tional Federation of Gynecology and Obstetrics (3) with a implant or vaginal mucosa). The vaginal mucosa received
minor modification for Stage II (2), which consisted of doses in the range of 80 –120 Gy. In patients receiving
dividing these tumors into IIA when there was paravaginal external irradiation, 10 or 20 Gy to the whole pelvis was
tumor extension or IIB when there was parametrial involve- delivered, and additional parametrial dose with a midline
ment. block was administered to give a total of 40 –50 Gy to the
Follow-up information was updated in all patients within lateral pelvic wall using high-energy photon beams (6 –25
the 3 months before the current review either by examina- MV from linear accelerators or betatron). The treatment
tion at the Medical Center or from information received portals measured 15 cm in width, to cover the entire true
from the referring physician or, in a few instances, by direct pelvis; the upper margin extended to the upper sacral area
correspondence with the patients or relatives. The minimum (L5–S1), and distally, the entire vagina was treated, usually
follow-up was 3 years, and the mean follow-up at last visit including the inguinal/femoral lymph nodes in the irradia-
for surviving patients was 12 years. Patients lost to fol- tion portal.
low-up were considered dead of tumor if there was any Patients with Stage II tumors were treated with similar
suspicion of recurrence. Patients dying of intercurrent dis- combinations of external irradiation and brachytherapy. The
ease are included in the overall analysis of survival. When whole-pelvis dose was 20 – 40 Gy, with additional parame-
the site of recurrence was known, it was classified as local, trial irradiation given using midline block to deliver a total
pelvic, distant metastases (including paraaortic nodes), or of 50 – 60 Gy to the lateral pelvic wall using 18 –25 MV or
combinations thereof. 4 – 6 MV X-rays as indicated. In eight patients, only brachy-
In patients on whom isodose distributions were available, therapy was used, and in two patients external-beam irradi-
or in a group of 65 patients treated after 1964 on whom ation alone was delivered. Patients with Stage IIB, III, and
there was adequate description of the implants in the chart, IV disease received 40 Gy to the whole pelvis and addi-
the dose of irradiation delivered by intracavitary or intersti- tional parametrial dose with midline shielding to complete
tial techniques was calculated. The external-beam doses minimum tumor doses of 65–75 Gy and 55– 60 Gy to the
were recalculated in patients treated before 1971 because of lateral pelvic wall, in combination with interstitial or intra-
minor dosimetric variations in calibration procedures. Ex- cavitary insertions, in most instances; a few of these patients
ternal-beam and brachytherapy doses were added without received brachytherapy or external-beam irradiation only
regard for possible differences for biologic effect because of because of poor clinical condition. Intracavitary brachyther-
dose rate. Total minimum doses, at the greatest estimated apy was administered with vaginal cylinders or Fletcher-
tumor depth (clinical examination) and to the lateral pelvic Suit ovoids, or both, and in some patients, with the
wall, were calculated. Mallinckrodt Institute of Radiology afterloading vaginal
Disease-free survival and overall survival curves were applicator (MIRALVA) (7).
calculated by the actuarial life table as applied by Cutler and Dose to the tumor was calculated at the clinically per-
Ederer (4). Times for survival or failure were calculated ceived depth of the vaginal lesion. Medial parametrial dose
from the onset of definitive therapy. Tests of differences was calculated 2 cm lateral to the vaginal intracavitary
Carcinoma of the vagina ● C. A. PEREZ et al. 39

Fig. 1. Disease-free survival for all patients with primary carcinoma of the vagina (Stages 0 through IVA). From: Perez
CA, Garipagaoglu M: Vagina. In Perez CA, Brady LW, editors: Principles and Practice of Radiation Oncology, ed 3,
pp 1891–1914. Philadelphia, Lippincott-Raven, 1998.

sources (similar to point A for cervical carcinoma). The because of inadequate coverage of the entire vagina with the
lateral parametrial dose was calculated 6 cm from the mid- intracavitary therapy. In Stage I, 8 of 59 patients (14%)
line, at a site where the pelvic lymph nodes are generally failed in the pelvis, 3 of them combined with distant me-
visualized on the lymphangiogram. tastases.
In Stage IIA, 22 patients had local or parametrial failures
(34%), 11 of them with distant metastases. In Stage IIB, 15
RESULTS
of 34 patients (44%) had local/parametrial failures, 10 of
Disease-free and overall survival them in combination with distant metastases. Seven of 20
Patients who died of intercurrent disease were excluded patients (35%) with Stage III and 11 of 15 (73%) with Stage
as censored observations. The 10-year disease-free survival IVA had local/pelvic failures.
was 94% for Stage 0, 80% for Stage I, 55% for Stage IIA, The total incidence of distant metastases was 13% in
35% for Stage IIB, and 38% for Stage III (Fig. 1). The Stage I, 30% in Stage IIA, 52% in Stage IIB, 50% in Stage
overall actuarial survival was significantly lower because a III, and 47% in Stage IV. This pattern of failure points
number of patients died of intercurrent disease (Table 1), toward a slightly more aggressive clinical behavior in Stage
and there was less impact of the clinical stage of the tumor II than in epidermoid carcinoma of the uterine cervix (Fig. 2).
on probability of overall survival.

Anatomic sites of failure Tumor control and technique of irradiation


Data are shown in Table 1. Only 1 of 20 patients with There was only 1 local failure distal to the vaginal vault
carcinoma in situ failed locally, as described previously, in the 20 patients with carcinoma in situ treated with intra-

Table 1. Carcinoma of the vagina: Anatomic sites of failure

No. of Local/Parametrial Local/Parametrial Distant metastases Dead of


Stage Patients only and distant metastases only intercurrent disease

0 20 1 (5) 0 0 8 (40)
I 59 5 (8) 3 (5) 5 (8) 23 (39)
} }}}}

(14)
IIA 64 11 (17) 11 (17) 8 (13) 17 (27)
(34)
IIB 34 5 (15) 10 (29) 9 (26) 7 (21)
(44)
III 20 1 (5) 6 (30) 4 (20) 5 (25)
(35)
IVA 15 4 (27) 7 (47) 0 3 (20)
(73)

() Percent.
40 I. J. Radiation Oncology ● Biology ● Physics Volume 44, Number 1, 1999

Fig. 2. Patterns of failure (pelvic recurrence, alone or combined with distant metastasis, or distant metastasis only) in
patients reported with primary carcinoma of the vagina compared with 1499 patients with invasive carcinoma of the
cervix treated at Washington University during the same period of time. A slightly higher incidence of pelvic failures
is noted in Stage IIA and IIB vaginal carcinoma. Also, in these stages, the overall incidence of failure is somewhat
higher in vaginal cancer than in primary cervix carcinoma. From: Perez CA, Garipagaoglu M: Vagina. In Perez CA,
Brady LW, editors: Principles and Practice of Radiation Oncology, ed 3, pp 1891–1914. Philadelphia, Lippincott-Raven,
1998.

cavitary brachytherapy; the tumor was inadequately treated beam irradiation and brachytherapy, in contrast to that in a
initially with an ovoid containing a 20-mg radium source. few patients who were treated with intracavitary or intersti-
In Stage I, there was no significant correlation between tial irradiation alone, usually because of medical reasons.
the technique of irradiation used and the incidence of re- Local tumor control was achieved in only 4 of 15 patients
currence locally or in the pelvis. The addition of external with Stage IVA disease. Results are summarized in Table 2.
irradiation did not increase tumor control (78 –92%) in
comparison with the patients treated with brachytherapy Pelvic tumor control (including local) correlated with
only (80 –100%). However, in Stage IIA the local tumor dose of irradiation
control rate was 70% (37 of 53) in patients receiving Analysis of irradiation doses or even techniques and
brachytherapy combined with external-beam irradiation in impact on local or pelvic tumor control is fraught with
comparison with 40% (4 of 10) in patients treated with possible bias, as this is a retrospective, not a prospective,
either brachytherapy or external-beam irradiation alone dose-escalation study; from clinical experience we know
( p 5 0.42). In Stage IIB and III there was also slightly that radiation oncologists prescribe higher doses of irra-
higher local tumor control with combinations of external- diation for tumors with increased risk of local failure or

Table 2. Carcinoma of the vagina: Tumor control correlated with type of therapy

Stage

Therapy 0 I IIA IIB III IVA

Intracavitary 13/14 (93) 12/15 (80) 1/2 (50) 0/1 0 0


Interstitial 6
intracavitary 1/1 (100) 10/10 (100) 2/6 (33) 1/2 (50) 1/3 (33) 0
Intracavitary 6
interstitial and
external
irradiation 1/1 (100) 14/18 (78) 17/22 (77) 11/15 (73) 4/7 (57) 1/2 (50)
Intracavitary and
interstitial and
external
irradiation 0 12/13 (92) 20/31 (65) 6/13 (46) 8/10 (80) 3/11 (27)
External
irradiation 0 1/1 (100) 1/2 (50) 1/3 (33) 0 0/2

() Percent.
Carcinoma of the vagina ● C. A. PEREZ et al. 41

Table 3. Carcinoma of the vagina: Pelvic tumor control Table 5. Carcinoma of the vagina: Pelvic tumor control
correlated with minimum dose to vaginal tumor correlated with lateral parametrial dose

Stage Dose to
Dose Stage
lateral
(Gy) I IIA IIB III IVA parametrium
(Gy) I IIA IIB III IVA
#55 4/4 (100) 2/6 (33) 2/4 (50) 1/5 (20) 0/1
55.01–65 10/12 (83) 8/11 (73) 2/5 (40) 3/4 (75) 0/1 #40 28/32 (88) 19/30 (63) 2/7 (29) 2/4 (50) 2/3 (67)
65.01–75 10/11 (91) 12/17 (71) 2/5 (40) 6/7 (86) 0/1 40.01–50 4/5 (80) 9/12 (75) 1/5 (20) 2/7 (29) 0/1
75.01–85 7/9 (78) 7/10 (70) 4/5 (80) 1/1 (100) 3/3 (100) 50.01–60 3/4 (75) 8/11 (73) 6/9 (67) 3/3 (100) 1/1 (100)
85.01–95 6/7 (86) 5/6 (83) 4/6 (67) 1/1 (100) — .60 1/1 (100) 2/4 (50) 5/5 (100) 5/5 (100) 0/1
.95 11/12 (92) 7/10 (70) 3/4 (75) 0/1 —
() Percent.
() Percent. Table includes only patients with complete dosimetry data.
Table includes only patients with complete dosimetry data.

tumor control in comparison with 21 of 25 (84%) treated in


when the tumor does not respond to “standard doses.” a longer period of time. In Stage III, the corresponding
The correlation with doses delivered to the vaginal tumor figures are 6 of 10 (60%) and 6 of 9 (75%), respectively.
suggests that, in Stages II and III, doses in the range of
70 –75 Gy to the primary tumor or the medial parame- Pelvic tumor control and location, size, or morphology of
trium are necessary to achieve better tumor control. Table primary tumor
3 shows that patients with Stage IIA tumors receiving Other authors such as Whelton and Kottmeier (8) re-
doses higher than 55 Gy exhibited better local and pelvic ported decreased tumor control in patients with lesions
tumor control. As noted in Table 4, in patients with Stage located in the posterior wall. Our analysis showed no sig-
IIB and III disease, it appears that a dose to the medial nificant correlation with this parameter, although Stage II
parametrium higher than 65 Gy results in significantly lesions with more extensive involvement of the upper/mid-
higher tumor control than with lower doses, although the dle/lower vagina may have lower tumor control (20 – 60%)
differences are not statistically significant because of the compared with those in other locations (50 – 80%). This is
small number of patients. Likewise, in Stages IIB and III most likely related to the extent of the disease (bulk of
doses to the lateral parametrium (pelvic lymph nodes) tumor) rather than anatomic location.
higher than 50 Gy are associated with marked improve- As noted in Table 6, whereas tumor stage was an impor-
ment in pelvic tumor control compared with lower doses tant predictor of pelvic tumor control and 5-year disease-
(Table 5). free survival, the size of the tumor in Stage I patients was
A more definite statement cannot be made concerning not a significant prognostic indicator. However, in Stage IIA
dose and tumor control correlation because of the small disease, lower pelvic tumor control and survival were noted
number of patients in the various stages. with tumors larger than 4 cm. In Stages IIB and III, tumor
size was not a significant prognostic factor.
Pelvic tumor control correlated with elapsed treatment Analysis of tumor recurrence and survival according to
time gross appearance of the lesion showed that 39 patients with
Prolongation of treatment time did not have a significant Stage I superficially ulcerated exophytic tumors had fewer
impact on pelvic tumor control in these patients. In Stage I, local recurrences (8%) and distant metastases (8%) than
23 of 27 patients (85%) treated in 49 days or less had pelvic those with infiltrating or necrotic lesions (20% local recur-
tumor control in comparison with 6 of 8 (75%) treated in a rence and 20% distant metastases) ( p 5 0.14). The differ-
longer time period (up to 63 days). In Stage II, 34 of 60 ence, however, is statistically significant only for disease-
patients (57%) treated in fewer than 49 days had pelvic free survival (84% vs. 58%, respectively, p 5 0.05). In
patients with Stage II disease, pelvic failure rates were
Table 4. Carcinoma of the vagina: Pelvic tumor control
similar (21% and 18%, respectively), as was 5-year disease-
correlated with medial parametrial dose free survival (53% and 50%, respectively).

Dose to Control of tumor in inguinal lymph nodes


Stage
medial Of 7 patients who received elective irradiation to clini-
parametrium
(Gy) I IIA IIB III IVA cally negative inguinal lymph nodes, only 1 with a large
lesion involving the entire vagina developed an inguinal
#65 24/28 (86) 22/33 (67) 2/10 (20) 3/9 (33) 2/3 (67) lymph node recurrence after 50 Gy. Of 100 patients with
65.01–85 11/13 (85) 15/21 (71) 7/11 (64) 5/6 (83) 1/3 (33) primary tumors in the upper and middle third of the vagina
.85.01 2/2 (100) 2/4 (50) 7/7 (100) 4/4 (100) —
who received no elective irradiation, none developed met-
() Percent. astatic inguinal lymph nodes, in contrast to 3 of 29 (10%)
Table includes only patients with complete dosimetry data. with lower-third primary tumors and one of 20 with tumor
42 I. J. Radiation Oncology ● Biology ● Physics Volume 44, Number 1, 1999

Table 6. Carcinoma of the vagina: Pelvic tumor control and 5-year disease-free survival correlated with stage and tumor size

Stage

Tumor size (cm) I IIA IIB III IVA

Tumor control
#2 16/17 (94) 8/8 (100) 0/2 — 1/1 (100)
2.1–4 12/15 (80) 20/29 (69) 6/12 (50) 2/2 (100) 3/5 (60)
.4 16/18 (89) 12/24 (50) 11/18 (61) 10/16 (62) 0/9
5-Year disease-free survival
#2 87% 74% 0% — 100%
2.1–4 73% 71% 31% 50% 80%
.4 83% 41% 39% 49% 0%

() Percent.

involving the entire length of the vagina. Of 7 patients with Multivariate analysis
initially palpable inguinal lymph nodes treated with doses in On multivariate analysis, stage of the primary tumor and
the range of 60 Gy, only 1 developed a nodal recurrence. medial parametrial dose were significant prognostic factors
As before, we recommend that elective irradiation of the for local failure. Clinical stage of the disease and histologic
inguinal lymph nodes be carried out only in patients with grade were significant factors for predicting the develop-
primary tumors in the lower third of the vagina or those ment of distant metastases. Both the stage of the primary
involving the entire organ. tumor and the dose to the medial parametrium were signif-
icant prognostic factors for disease-free survival ( p values
Results in patients with history of previously treated all ,0.05). Analysis is summarized in Table 8.
uterine tumors Analysis of our patients failed to demonstrate any definite
There were 49 patients with carcinoma of the vagina who relationship between the location of the primary tumor in
had a history of previously treated primary carcinoma of the the various thirds or walls of the vagina and the incidence of
cervix or the endometrium (irradiation, hysterectomy, or complications (data not shown).
combination of both); they had received treatment over 5
years before the diagnosis of vaginal carcinoma, and none
had evidence of tumor activity at any other site. The pos- Complications of therapy
sibility of the vaginal lesion being a local recurrence or The incidence of complications has been relatively low
metastasis was considered unlikely, because 95% of the (Table 9) and are comparable to those observed in carci-
recurrences after treatment of primary carcinoma of the noma of the uterine cervix at our institution. In 73 patients
cervix or endometrium occur within 5 years after therapy. with Stage 0 and I disease, 5 Grade 2–3 complications were
Table 7 shows sites of failure and the survival in these noted that could be ascribed to radiation therapy (7%). In
patients, which are equivalent to those in patients with bona the Stage II patients, 4 rectovaginal and 2 vesicovaginal
fide primary carcinoma of the vagina. As before (2), we fistulae were noted (7%), as well as 2 cases of proctitis, 1
conclude that these lesions are most likely second primary rectal stricture, and 1 rectal ulcer. An enterocutaneous fis-
tumors and should be treated with definitive radiation ther- tula was noted in a patient who underwent pelvic exenter-
apy. ation for local/pelvic recurrence. In the patients with Stage

Table 7. Carcinoma of the vagina: Patients with previous cervix or endometrial primary carcinoma (over 5 years): Site of
post-treatment failure

5-Year
Local/Parametrial disease-free
No. of Local/Parametrial and distant Distant survival
Stage patients only metastasis metastasis only (%)

0 8 1 (13) — — 88
I 15 2 (13) 2 (13) — 76
IIA 13 2 (15) 4 (31) 2 (15) 49
IIB 7 2 (29) 2 (29) 2 (29) 14
III 3 — 1 (33) 1 (33) 33
IVA 3 1 (33) 1 (33) — 33

() Percent.
Carcinoma of the vagina ● C. A. PEREZ et al. 43

Table 8. Carcinoma of the vagina: Multivariate analysis ported for patients with carcinoma of the cervix, which
( p values) range from 20% to 80% at 5 years, depending on stage of
Local Distant Disease-free disease (9).
Variable failure metastasis survival Brown et al. (10) and Perez et al. (2) reported excellent
tumor control and survival rates in patients with carcinoma
Stage 0.031 0.053 0.045 in situ and Stage I invasive carcinoma. These authors cau-
Medial parametrial dose 0.009 0.620 0.050
Histologic grade 0.282 0.044 0.071 tioned against overly aggressive therapy in these early le-
Treatment technique* 0.592 0.517 0.533 sions because of the possibility of producing mucosal injury
Age 0.625 0.669 0.665 and interference with sexual function. In patients with le-
Lateral parametrial dose 0.265 0.541 0.751 sions thicker than 0.5 cm in diameter, it is advisable to
Elapsed days of irradiation 0.219 0.898 0.821
combine intracavitary therapy with interstitial irradiation
Primary tumor irradiation dose 0.998 0.652 0.822
Primary tumor site† 0.715 0.626 0.922 (single-plane implant) because this enhances the probability
of tumor control without exposing the entire mucosa of the
* Brachytherapy (intracavitary, interstitial, or both) alone or vagina to high doses of irradiation. Hintz et al. (11), after
combined with external beam irradiation.
† analysis of 16 patients with carcinoma of the vagina who
Upper or lower vagina.
had local tumor control for a minimum of 18 months,
indicated that doses of irradiation greater than 140 Gy to the
III and IV tumors, the most significant morbidity was 2 upper vaginal mucosa and 98 Gy to the lower vaginal
rectovaginal and 1 vesicovaginal fistulae (about 10%). mucosa (both external-beam and brachytherapy contribu-
tions) result in a higher incidence of complications with
dose rates less than 0.8 Gy/h. In Stage I disease, external-
DISCUSSION beam irradiation, in addition to brachytherapy, is advocated
Radiation therapy is the treatment of choice for carci- only for infiltrating or poorly differentiated tumors that may
noma of the vagina, since it provides good tumor control, have a higher probability of lymph node metastases.
particularly in the small superficial tumors, and satisfactory The high incidence of pelvic failures in Stages II and III
functional results. Tumor control in Stage 0 and I is ade- is of major concern and suggests that a more radical ap-
quate with brachytherapy alone, and the addition of external proach is necessary in these advanced tumors. Either the
irradiation does not improve probability of local tumor external-beam dose should be increased or there should be
control. With adequate therapy, the survival rates of patients wider use of parametrial interstitial implants. Templates
with carcinoma of the vagina are comparable to those re- such as the Martinez multiple-site perineal template

Table 9. Carcinoma of the vagina: Morbidity of therapy

Stages 0 and I Stage II Stages III and IV

BT EB 6 BT BT EB 6 BT BT EB 6 BT
6 (n 5 40) (n 5 33) (n 5 11) (n 5 86) (n 5 3) (n 5 32)

Rectovaginal fistula 1 3 2
Vesicovaginal fistula 2 1
Rectal stricture 1* 1
Proctitis 2†
Rectal ulcer 1
Diverticulitis 1
Small bowel obstruction 1‡
Enterocutaneous fistula 1§
Bladder neck contracture 1¶
Urethral stricture 2 1
Cardiac arrest 1
Neuritis 1
Cystitis 1
Vaginal necrosis 1
Leg edema 1
Vaginal stenosis 1

BT 5 brachytherapy; EB6 5 external-beam irradiation with or without brachytherapy.


* Patient required partial colectomy.

One patient required colostomy.

Colostomy required.
§
After pelvic exenteration (complication of surgery).

Patient required transurethral resection.
44 I. J. Radiation Oncology ● Biology ● Physics Volume 44, Number 1, 1999

(MUPIT) (12) are frequently used in an effort to improve Stage II patients, 35% in 55 Stage III patients, and 60% in
the dose distribution; they help to achieve better placement 16 patients with Stage IVA disease. As in our patients, the
of the radioactive sources in the pelvis. Integrated preoper- 10-year local recurrence rate was 22% in 80 patients with a
ative irradiation and surgical resection when feasible should history of previous gynecologic malignancy and 22% in 191
be judiciously used (13). However, an aggressive approach without such a history. Ten-year survival rates were 78% in
must be weighed against an expected greater incidence of Stage 0, 55% in Stage I, 51% in Stage II, 37% in Stage III,
complications, and caution should be exercised because and 40% in Stage IVA disease. As in our patients, the
many of these patients are of advanced age and may have 10-year survival rate was 59% in patients with a history of
had previous pelvic surgery or may have medical conditions previous gynecologic malignancy and 49% in those without
that preclude overly aggressive therapy that will jeopardize such a history ( p 5 0.15).
the patient’s welfare. Also, a greater frequency of compli- Likewise, Urbanski et al. (19) reported on 125 patients
cations has been observed with combined high doses of with vaginal carcinoma treated with a combination of ex-
irradiation and radical surgery in the treatment of pelvic ternal-beam and intracavitary irradiation. Five-year survival
tumors (14). The high incidence of distant metastases was the same in 16 patients who had previous hysterectomy
strongly emphasizes the need for effective chemotherapeu- (43.8%) and 109 without such a previous history (42.2%).
tic agents to improve survival in these patients. Efforts to Kucera and Vavra (20) reported on 434 patients treated
enhance the biologic effects of irradiation with chemical with irradiation for invasive vaginal carcinoma, with more
sensitizers, chemotherapeutic agents such as cisplatin or details for 110 treated in more recent years. Intracavitary
5-fluorouracil, which are being used in patients with ad- radium was the standard primary treatment, to deliver
vanced cervical and endometrial carcinoma, or hyperther- 60 –90 Gy to the tumor and 30 Gy to the surrounding
mia, which is used in the management of patients with vagina. For more advanced lesions, external irradiation (56
advanced carcinoma of the uterine cervix, may be helpful. Gy to the lateral pelvic wall) was delivered. Contrary to our
We noted that, in carcinoma in situ and Stage I vaginal experience, 5-year survival was higher in patients with
carcinoma, tumor control in the pelvis was approximately tumors in the upper third (21 of 35, 60%) compared with
the same with brachytherapy alone or when combined with those in the middle or lower third (19 of 51, 37.5%) or those
external-beam irradiation. However, although not statisti- involving the whole vagina (5 of 24, 20.8%).
cally significant, better tumor control (65%) was observed Kirkbride et al. (21) described results in 153 patients with
in Stage II and III disease with the addition of external vaginal carcinoma, 15 of whom had carcinoma in situ; 128
irradiation in comparison with brachytherapy only (40%) were treated with radiation therapy (10 received irradiation
( p 5 0.11). These observations are similar to those of postoperatively and 26 concomitant chemotherapy). The
MacNaught et al. (15), who in an analysis of 78 cases of 5-year cause-specific survival rates were 100% for Stage 0
primary vaginal carcinoma (61 squamous cell carcinoma), (CIS), 77% for Stages I and II, and 56% for Stages III and
reported better tumor control and survival with combined IV, results similar to ours. Late complications from treat-
external-beam and interstitial treatment compared with ment were infrequent and were classified as severe in only
brachytherapy alone, despite the staging distribution being 12 patients (10%). Univariate analysis indicated that size
in favor of the patients treated with brachytherapy only. and stage of tumor, histologic grade, patient age, and irra-
Similar observations were described by Leung and Sexton diation dose greater than 70 Gy were significant factors in
(16) in a review of 103 patients. predicting survival, although in a multivariate analysis only
Prempree and Amornmarn (9) and Puthawala et al. (17) size and stage retained significance.
described tumor control rates in the pelvis ranging from Fine et al. (22), in 55 patients with various stages of
65% to 80% with a combination of external irradiation, and vaginal carcinoma treated with radiation therapy, noted
when appropriate, paravaginal or parametrial interstitial im- fewer recurrences in patients who received doses higher
plant, in addition to intracavitary brachytherapy. than 75 Gy. Eight patients developed complications.
Chyle et al. (18) of the M.D. Anderson Cancer Center Lee et al. (23) reported on the importance of overall
updated the results in 301 patients with primary vaginal treatment time in 65 patients with primary carcinoma of the
carcinoma (271 squamous cell and 30 adenocarcinoma) vagina treated with radiation therapy. Five-year cause-spe-
treated with radiation therapy. Brachytherapy alone was cific survival was 100% in 6 patients with Stage 0, 94% in
used in 25 Stage I patients, external beam and brachyther- 17 with Stage I, 80% in 6 with Stage IIA, 39% in 10 with
apy in 38, and transvaginal orthovoltage X-rays in 2 pa- Stage IIB, 29% in 10 with Stage III, and 62% in 6 patients
tients. In Stage II patients, brachytherapy alone was used in with Stage IVA disease. If the entire course of irradiation
20, external beam and brachytherapy in 66, and external was completed within 9 weeks, pelvic tumor control was
irradiation alone in 36 patients. In patients with Stage III 97%, in contrast to only 54% when treatment time extended
disease, external-beam irradiation and brachytherapy were beyond 9 weeks ( p 5 0.0003). The incidence of major
used in 15, and external-beam irradiation alone was used in treatment morbidity was 12%; in patients receiving less than
45 patients. Mean dose was 74.7 Gy, and median dose was 80 Gy, severe complications were noted in 9% (5 of 53),
70 Gy. The 10-year local recurrence rate was 17% in 37 whereas in those receiving doses higher than 80 Gy, mor-
Stage 0 patients, 15% in 59 Stage I patients, 18% in 104 bidity incidence was 25% (3 of 12).
Carcinoma of the vagina ● C. A. PEREZ et al. 45

Boronow et al. (24) advocated a combination of surgery Patients treated with radiation therapy for carcinoma of
and irradiation for treatment of patients with advanced vulvo- the vagina should be carefully followed, because early de-
vaginal cancer. Most of the 37 patients treated with this tech- tection of recurrences allows a surgical procedure for sal-
nique had advanced primary tumors of the vulva. The 5-year vage that may result in subsequent cure of a significant
survival rate for the primary cases was 75.6%. For patients proportion of patients with recurring lesions.
with recurrent disease, the 5-year survival rate was As noted by Gore et al. (27), high-dose-rate vaginal
62.6%. In most patients (94.8%), the bladder and rectum cylinders may provide dose distributions that have less
were preserved. variation than low-dose-rate applicators; experience with
Stock et al. (25) reported on 100 cases of vaginal carci- this modality is minimal.
noma; 50% of patients had hysterectomy before the diag- Although radiation therapy is an effective method of treat-
nosis of vaginal cancer. Treatment consisted of surgery in ment for patients with early-stage vaginal carcinoma, there is
40 patients, radiation therapy in 47, and surgery plus irra- still a significant recurrence rate in patients with Stage IIB and
diation in 13. With a median follow-up of 11.2 years, 5-year III tumors. More effective irradiation techniques, including
disease-free survival was 67% for Stage I (23 patients), 53% optimized dose distribution with external irradiation, and in-
for Stage II (58 patients), 0% for Stage III (9 patients), and terstitial as well as intercavitary brachytherapy or concurrent
15% for Stage IV disease (10 patients). The same authors (26), administration of cytotoxic agents with irradiation, may be
in an analysis of 49 patients, emphasized the role of brachy- necessary to improve the survival of these patients. Additional
therapy in the treatment of these patients. clinical trials are strongly encouraged.

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