Int. J. Radiation Oncology Biol. Phys., Vol. 62, No. 1, pp.

138 –147, 2005

Copyright © 2005 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/05/$–see front matter

doi:10.1016/j.ijrobp.2004.09.032

CLINICAL INVESTIGATION Vagina

DEFINITIVE RADIATION THERAPY FOR SQUAMOUS CELL CARCINOMA

OF THE VAGINA

STEVEN J. FRANK, M.D.,* ANUJA JHINGRAN, M.D.,* CHARLES LEVENBACK, M.D.,† AND
PATRICIA J. EIFEL, M.D.*
*Division of Radiation Oncology and †Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer
Center, Houston, TX

Purpose: To evaluate outcome and describe clinical treatment guidelines for patients with primary squamous cell
carcinoma of the vagina treated with definitive radiation therapy.
Methods and Materials: Between 1970 and 2000, a total of 193 patients were treated with definitive radiation
therapy for squamous cell carcinoma of the vagina at The University of Texas M. D. Anderson Cancer Center.
The patients’ medical records were reviewed to obtain information about patient, tumor, and treatment
characteristics, as well as outcome and patterns of recurrence. Surviving patients were followed for a median of
137 months. Survival rates were calculated using the Kaplan–Meier method, with differences assessed using
log–rank tests.
Results: Disease-specific survival (DSS) and pelvic disease control rates correlated with International Federation
of Gynecology and Obstetrics (FIGO) stage and tumor size. At 5 years, DSS rates were 85% for the 50 patients
with Stage I, 78% for the 97 patients with Stage II, and 58% for the 46 patients with Stage III–IVA disease (p
ⴝ 0.0013). Five-year DSS rates were 82% and 60% for patients with tumors <4 cm or >4 cm, respectively (p
ⴝ 0.0001). At 5 years, pelvic disease control rates were 86% for Stage I, 84% for Stage II, and 71% for Stage
III–IVA (p ⴝ 0.027). The predominant mode of relapse after definitive radiation therapy was local-regional (68%
and 83%, respectively, for patients with stages I–II or III–IVA disease). The incidence of major complications
was correlated with FIGO stage; at 5 years, the rates of major complications were 4% for Stage I, 9% for Stage
II, and 21% for Stage III–IVA (p < 0.01).
Conclusions: Excellent outcomes can be achieved with definitive radiation therapy for invasive squamous cell
carcinoma of the vagina. However, to achieve these results, treatment must be individualized according to the site
and size of the tumor at presentation and the response to initial external-beam radiation therapy. Brachytherapy
plays an important role in the treatment of many vaginal cancers but should be carefully selected and applied
to obtain optimal coverage of the target volume. © 2005 Elsevier Inc.

Vaginal cancer, Radiation therapy, Brachytherapy.

INTRODUCTION for study. To our knowledge, there have been no prospec-

Vaginal carcinomas are rare, comprising only 2% of gyne-
cologic malignancies. Treatment of vaginal carcinomas
poses special challenges to the multidisciplinary team, be-
cause the techniques used to treat them are highly special-
ized and because the distribution of disease in the vagina
and paravaginal tissues has an important influence on the
type of treatment needed to obtain the best results. Because
of the vagina’s close proximity to critical structures, cancers
arising in this area are rarely amenable to curative organ-
sparing surgery; fortunately, radiation therapy is an effec-
tive treatment and is currently used to treat most patients
with invasive vaginal cancers.
The rarity of vaginal cancer makes it a difficult subject
tive randomized trials of vaginal cancer treatment. Most
retrospective studies have been small or have included
patients who had rare, nonsquamous cancers or a previous
history of treatment for cervical or other gynecologic ma-
lignancies. During the last 50 years, there have been several
retrospective reviews of the experience with vaginal cancer
at The University of Texas M. D. Anderson Cancer Center
(1–5). Most recently, Chyle et al. (3) reported results of
radical radiation therapy in patients treated between 1953
and 1991. Although that series was relatively large, it in-
cluded patients treated before high-energy accelerators were
available and patients who had in situ disease or adenocar-
cinoma or presented with a previous history of invasive

Reprint requests to: Patricia J. Eifel, M.D., Division of Radia-
tion Oncology, Box 97, The University of Texas M. D. Anderson
Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
Tel: (713) 563-2343; Fax: (713) 792-3642; E-mail: peifel@
mdanderson.org
Presented at the 45th Annual Meeting of the American Society
of Therapeutic Radiology and Oncology, Salt Lake City, UT,
October 18 –23, 2003.
Received Jun 17, 2004, and in revised form Sep 1, 2004.
Accepted for publication Sep 10, 2004.

138
 RT for vaginal carcinoma ● S. J. FRANK et al. 139

cervical cancer. The purpose of this report is to update our Table 1. FIGO/AJCC/UICC stage definitions for carcinoma of
institutional experience, focusing on patients with primary the vagina and patient distribution by disease stage (n ⫽ 193)
invasive squamous cell carcinoma of the vagina who had Number of
not previously been treated for gynecologic malignancies, Stage Definition patients (%)
and to suggest guidelines for treatment of these rare cancers.
I Tumor confined to vagina 50 (26)
II Tumor invades paravaginal tissue, 97 (50)
METHODS AND MATERIALS but not to pelvic wall
III Tumor extends to the pelvic wall 39 (20)
Patients ⫹/⫺ pelvic or inguinal lymph
The medical records, including clinical notes and tumor diagrams, node metastasis
of all patients treated with definitive radiation therapy for primary IVA Tumor invades mucosa of bladder or 7 (4)
invasive squamous cell carcinoma of the vagina at M. D. Anderson rectum and/or extends beyond the
Cancer Center between January 1970 and December 2000 were true pelvis
reviewed retrospectively. Patients whose tumors involved the vulva or Abbreviations: FIGO ⫽ International Federation of Gynecology
extended to the external os of the cervix were excluded (6). Patients and Obstetrics; AJCC ⫽ American Joint Committee on Cancer;
who had noninvasive carcinoma of the vagina (i.e., in situ disease) or UICC ⫽ Union Internationale Contre le Cancer.
nonsquamous histologic subtypes also were excluded, as were 5
patients treated with external-beam neutron therapy and 3 patients
treated palliatively for metastatic disease. Patients who had a previous preference) why the remaining 10 patients who had all their
history of invasive gynecologic malignancy (i.e., carcinoma of the treatment at M. D. Anderson Cancer Center had excisions before
cervix, endometrium, vulva, or vagina) were excluded from this radiation therapy. The remaining 175 patients (91%) were treated
study. One hundred ninety-three consecutive patients with primary with definitive radiation therapy alone.
invasive squamous cell carcinoma of the vagina who did not meet any One hundred nineteen patients (62%) were treated with exter-
of the aforementioned exclusion criteria were the subjects of this nal-beam radiation therapy (EBRT) followed by brachytherapy.
analysis. Sixty-three patients (32%) were treated with EBRT alone. Most
Data regarding patient, tumor, and treatment characteristics patients were treated with initial regional EBRT followed by
were abstracted from the hospital and radiation oncology records focused central treatment, which was individually tailored to the
of each patient. Selected charts were coded independently by two tumor characteristics and initial response of the disease. Table 2
authors to verify that data abstraction methods were consistent. summarizes the methods of treatment according to the combined
Follow-up was obtained from the patients’ records or from com- FIGO/UICC/AJCC stage. The techniques of radiation therapy have
munications with patients or their physicians. Patients who were been described previously (1, 3, 4). Through the 1980s, EBRT was
no longer being followed at M. D. Anderson clinics were contacted delivered using anteroposterior parallel-opposed fields that cov-
annually by the institution’s Department of Medical Informatics to ered the true pelvis (L5–S1 to approximately 3 cm below the
obtain information about tumor status and general medical prob- lowest extent of disease with 1–1.5 cm lateral to the pelvic brim).
lems. This information was recorded in each patient’s medical The medial inguinal nodes were treated electively when the tumor
record. involved the distal third of the vagina. In the 1970s, 11 patients,
most of whom were elderly or frail women with small Stage I
Pretreatment evaluation tumors, were treated with narrow EBRT fields that covered only
Both a gynecologic oncologist and a radiation oncologist exam-
ined all patients in a multidisciplinary clinic. The clinical findings,
including sites of involvement and tumor size, and the treatment Table 2. Methods of treatment according to FIGO stage
plan were recorded in a clinic note and tumor diagram. Examina-
tion under anesthesia was not routinely performed. Number of patients by FIGO stage
During the years of this study, clinical evaluation varied but
usually included chest radiography, intravenous pyelography, bar- Treatment I II III IVA Total
ium enema or proctoscopy, cystoscopy, and routine blood work
workup. Pretreatment evaluation also included staging lymphade- Type of RT
nectomy in 11 patients (6%), lymphangiography in 84 (43%), and TV only 1 0 0 0 1
IC only 4 0 0 0 4
computed tomography in 58 (30%). The stage definitions accord-
Interstitial only 5 2 0 0 7
ing to the combined International Federation of Gynecology and EB ⫹ IC 22 34 2 0 58
Obstetrics (FIGO), American Joint Committee on Cancer (AJCC) EB ⫹ interstitial 11 37 12 1 61
(6), and Union Internationale Contre le Cancer (UICC) systems are EB only 7 24 25 6 62
presented in Table 1 (6). RT volume
Central only 21 3 6 0 30
Treatment methods for patients overall Whole pelvis 29 93 34 7 163
Eighteen patients underwent a gross excision of their primary
Abbreviations: FIGO ⫽ International Federation of Gynecology
vaginal tumors before radiation therapy. Of these, 10 had Stage I and Obstetrics; RT ⫽ radiotherapy; TV ⫽ transvaginal cone; IC ⫽
tumors, and 8 had larger tumors that were excised at the discretion intracavitary; EB ⫽ external beam; Central ⫽ vagina ⫹/⫺ imme-
of the attending physician. Eight of the excisions were performed diate paravaginal area; Whole pelvis ⫽ regional lymph nodes
before the patients were referred to M. D. Anderson Cancer (including medial inguinal nodes for patients with distal vaginal
Center. We were unable to find any reason (other than attending involvement).
140 I. J. Radiation Oncology ● Biology ● Physics
the vagina and paravaginal regions (4). During the 30 years of this
study, 11 patients with early-stage disease were treated with
brachytherapy alone. However, in more recent years, there has
been a greater tendency to include the regional lymph nodes even
in the treatment of Stage I disease.
After initial regional treatment, central disease was treated with
additional radiation therapy using reduced external-beam fields, in-
tracavitary implants, or interstitial brachytherapy; these treatments
were individualized according to the response to the initial EBRT and
the site of disease. External-beam techniques included anteroposteri-
or-posteroanterior fields in the early years and have progressed to
conformal therapy with controlled bladder volume in the last decade.
Intracavitary radiation therapy boosts were used only for patients who
had minimal residual disease (usually in the vaginal apex). Such
boosts were prescribed to the vaginal surface and were delivered
using vaginal cylinders or Fletcher-Suit-Delclos colpostats (3, 7–9).
Freehand interstitial implants of 192Ir were used to treat localized
lesions that involved the distal two-thirds of the vagina if there was
not extensive involvement of the rectovaginal septum; in selected
cases involving the vaginal apex, interstitial implants were inserted
under laparoscopic guidance using Syed templates (10). The median
duration of radiotherapy was 45 days (range, 2–115 days; interquartile
range, 41–51 days).
Treatment of early-stage (Stage I or II) disease
Most early-stage lesions (71%) were treated using a combina-
tion of EBRT and brachytherapy. The mean and median total doses
of EBRT and brachytherapy delivered to the vaginal surface (for
superficial tumors) or tumor volume (for deeper lesions) were 85
Gy and 81 Gy, respectively. Patients with apical tumors who were
treated with intracavitary brachytherapy after 40 – 45 Gy of exter-
nal beam irradiation usually received 50 – 60 Gy to the vaginal
surface in approximately 72 hours. Patients with early-stage dis-
ease were more likely to receive EBRT alone if they had tumor
that encompassed the entire vagina or if they had significant
comorbid disease. The mean and median doses for the 62 patients
treated with EBRT alone were both 66 Gy. The mean and median
doses for the 11 patients treated with brachytherapy alone were
both 65 Gy.
Treatment of advanced-stage (Stage III or IVA) disease
Most advanced lesions (66%) were treated with EBRT alone,
although a combination of EBRT followed by brachytherapy has
recently been used with greater frequency. A shrinking-field tech-
nique was usually used during treatment with EBRT alone, with
mean and median doses of 64 Gy and 66 Gy, respectively (range,
40 –70 Gy). Patients treated with a combination of EBRT and
brachytherapy were prescribed doses between 65 and 90 Gy, with
mean and median doses of 76 Gy and 77 Gy, respectively.
During the last two decades, there has been a general trend
toward more frequent combined-modality therapy for Stage III and
IVA lesions (used in 0% of patients before 1980 and 33% after
1980): Overall, 5% of patients with Stage III or IVA disease
received neoadjuvant chemotherapy with regimens consisting of
bleomycin, cisplatin, mitomycin-C, floxuridine, and vincristine
before local radiation therapy, and 17% of patients received con-
current chemoradiotherapy with cisplatin-based regimens.
Analysis of sites of disease recurrence
Treatment failures were classified as local, pelvic, or distant.
Local failures were defined as recurrences located in the vagina or
Volume 62, Number 1, 2005
paravaginal area. Pelvic failures were defined as recurrences in the
vagina, paravagina, pelvic (iliac) lymph nodes, or inguinal lymph
nodes; recurrences that involved the para-aortic nodes were con-
sidered distant failures. Marginal recurrences were defined as
recurrences that occurred within 2 cm of the treatment fields; all
simulation and port films were reviewed to determine whether
recurrences were within or marginal to the treatment fields.
Follow-up
Patients who were followed at M. D. Anderson Cancer Center
were usually seen in follow-up at 3-month intervals for 2–3 years,
at 6-month intervals for an additional 2 years, and then yearly. One
hundred twenty-two patients were followed until death. For 72
surviving patients, the median follow-up time from the date of
initial local treatment was 137 months (interquartile range, 68 –209
months).
Statistical methods
The probabilities of vaginal disease control, pelvic disease control,
and disease-specific survival were calculated using Berkson and Gage
life table methods with all time intervals measured from the date of
initial treatment. Comparisons between actuarial curves were made
using the Wilcoxon (Gehan) statistic. For calculations of disease-
specific survival, the following were scored as events: deaths due to
disease, deaths resulting directly or indirectly from treatment-related
complications, and deaths due to unknown causes that occurred less
than 5 years after treatment.
The Cox proportional hazards model was used for multivariate
analysis to assess the effect of patient characteristics and other
prognostic factors of significance on the end points (11). All
variables with a p value of 0.25 or less on univariate analysis were
entered into the model, and backwards elimination was carried out.
The final model consisted of variables with p values of 0.05 or less.
The Wald test was used to assess the role of covariates in the
model. The significance of differences between proportions was
tested with the Chi-square statistic (12).
RESULTS
Patient and tumor characteristics
The pretreatment characteristics of the 193 patients in-
cluded in this analysis are summarized in Table 3. The
median age was 61 years (range, 31–92 years). The most
common presenting symptom was vaginal bleeding, which
was present in 104 patients (54%); 39 patients (20%) pre-
sented with vaginal discharge, and 30 patients (16%) pre-
sented with vaginal pain or dyspareunia. One hundred twen-
ty-one patients (63%) had had a previous hysterectomy for
benign or preinvasive disease (20%); the most common
reasons for hysterectomy were uterine bleeding, uterine
fibroids, and cervical intraepithelial neoplasia. Forty-six pa-
tients (24%) had a history of smoking.
Most patients (76%) had Stage I or II disease. The pattern
of tumor involvement within the vagina varied widely.
Although most tumors were located in the upper two-thirds
of the vagina, 22% were confined to the distal third. Forty
patients presented with Stage III disease. Three of the 40
were classified as having Stage III disease, because they had
inguinal lymph node metastases (without any pelvic side-
 RT for vaginal carcinoma ● S. J. FRANK et al. 141

Table 3. Patient, tumor, and treatment characteristics and correlation with outcome for 193 patients with squamous cell carcinoma of
the vagina

Number of
Characteristic patients (%) PDC rate p DSS rate p

Age, years 0.18 0.32

ⱕ60 89 (46) 78 72
⬎60 104 (54) 85 77
Race/ethnicity 0.76 0.43
White 127 (66) 81 76
Hispanic 29 (15) 82 79
Black 36 (19) 80 63
Asian 1 (1) 100 100
Previous hysterectomy 0.70 0.75
Yes 121 (63) 83 74
No 72 (39) 79 75
Vaginal bleeding at diagnosis 0.54 0.83
Present 104 (54) 81 73
Absent 89 (46) 79 76
Stage 0.027 0.0013*
I 50 (26) 86 85
II 97 (50) 84 78
III or IVA 46 (24) 71 58
III 39 (20) (69)
IVA 7 (4) (86)
Tumor size 0.015 0.0001*
ⱕ4 cm 129 (67) 85 82
⬎4 cm 64 (33) 75 60
Tumor site 0.71 0.13
Apex 28 (14) 87 82
Upper 2/3 94 (49) 81 77
Lower 1/3 42 (22) 77 73
Whole vagina 29 (15) 83 58
Circumferential location 0.81 0.49
Anterior 33 (17) 87 84
Posterior 48 (25) 74 67
Lateral 41 (22) 84 77
Circumferential 43 (22) 79 68
Surgical excision before RT 0.80 0.26
Yes 18 (9) 87 87
No 175 (91) 81 73
Radiation therapy 0.20 0.17
Brachytherapy alone 11 (6) 80 91
EB ⫹ intracavitary implant 58 (30) 90 82
EB ⫹ interstitial implant 61 (32) 79 72
EB alone 63 (32) 76 67
Total dose 0.85 0.67
⬍75 Gy 94 (49) 81 73
ⱖ75 Gy 99 (51) 82 76

Abbreviations: PDC ⫽ pelvic disease control rate at 5 years; DSS ⫽ disease-specific survival rate at 5 years; RT ⫽ radiation therapy;
EB ⫽ external-beam radiation therapy.
* Significant in multivariate analysis (p ⬍ 0.01).

wall involvement); the fourth patient had inguinal metasta-
ses and locally advanced tumor extending to the pelvic wall.
Pelvic disease control
The 5-year and 10-year rates of pelvic disease control for
FIGO Stages I–IVA were 81% and 78%, respectively. Most
pelvic relapses occurred within 5 years of radiation therapy,
as illustrated in Fig. 1. The 5-year pelvic disease control
rates were 86% for Stage I, 84% for Stage II, and 71% for
combined Stage III and IVA (p ⫽ 0.027, Table 3). The
pelvic disease control rate was significantly poorer for pa-
tients with tumors larger than 4 cm (85% vs. 75%, p ⫽
0.015). No other patient, tumor, or treatment factors were
found to correlate with a significant improvement in pelvic
control.
The 5-year and 10-year vaginal disease control rates for
all 193 patients were both 89%. The 5-year vaginal disease
control rates for early-stage disease (Stage I or II) and
locally advanced disease (Stage III or IVA) were 91% and
83%, respectively (Fig. 2, p ⫽ 0.05). The vaginal disease
142 I. J. Radiation Oncology ● Biology ● Physics
Fig. 1. Pelvic disease control for all 193 patients with squamous
cell carcinoma of the vagina. Numbers in parentheses indicate the
number of patients at risk 5 or 10 years after treatment.
control rate was 88% for the 11 patients treated with brachy-
therapy alone (10 of 11).
Overall and disease-specific survival
The 5-year overall survival and disease-specific survival
rates for all 193 patients were 58%and 75%, respectively;
the 10-year overall survival and disease-specific survival
rates were 48% and 72%, respectively. The relationships
between patient, tumor, and treatment factors and outcomes
are summarized in Table 3. The 5-year disease-specific
survival rates by stage were 85% for Stage I, 78% for Stage
II, and 58% for Stage III or IVA (Fig. 3, p ⬍ 0.01);
disease-specific survival was also correlated with the size of
the tumor at presentation (ⱕ4 cm vs. ⬎4 cm) (Table 3, Fig.
4, p ⬍ 0.001). In multivariate analysis, only stage and tumor
size independently correlated with survival (p ⬍ 0.01).
Outcomes after chemoradiation therapy
Four patients (2 with Stage II disease and 2 with Stage III
disease) received neoadjuvant chemotherapy; all 4 experi-
enced relapse (at 7, 13, 17, and 66 months, respectively) and
died of their disease. Nine patients (2 with Stage II disease,
3 with Stage III disease, and 4 with Stage IVA disease)
received concurrent chemoradiation at a mean follow-up
duration of 129 months; 44% (4 of 9) of the patients with
locally advanced disease treated with definitive chemora-
diation therapy were without evidence of disease. Of the 6
patients who received varying doses of concurrent cisplatin
and 5-fluorouracil, 3 patients, including 2 with Stage III
disease, had no evidence of disease at follow-up durations
of 103, 137, and 138 months; 1 patient was lost to follow-up
at 3 months, and 2 died after developing pelvic recurrences.
Volume 62, Number 1, 2005
Patterns of failure
Of the 193 patients in the study, 49 developed a recur-
rence. Figure 5 shows the sites of relapse in patients with
early-stage (Stage I or II) and locally advanced (Stage III or
IVA) disease. The Venn diagrams illustrate that for both
early-stage disease and locally advanced disease, the pre-
dominant mode of relapse after definitive radiation therapy
was local-regional (68% and 83%, respectively). Of the 4
patients whose recurrences involved the vagina as well as
regional sites, 2 had synchronous detection of lateral pelvic
and vaginal recurrence, and 2 had evidence of regional
recurrence 3 and 9 months, respectively, after vaginal re-
lapse. The only patient who experienced a groin failure
recurred in unirradiated inguinal lymph nodes 3 months
after an extensive recurrence in the vagina.
Twenty-one patients with Stage I disease (42%) were
treated with local radiation therapy only (i.e., without re-
gional node coverage); 9 of these 21 were treated with
brachytherapy alone, 11 were treated with EBRT with or
without brachytherapy, and 1 was treated with local EBRT
using a transvaginal orthovoltage cone. Of the 9 patients
treated with brachytherapy alone, 3 developed recurrent
disease in the pelvis, for a 10-year actuarial pelvic disease
control rate of 67%. There were no pelvic recurrences in the
11 patients who received local EBRT with or without
brachytherapy.
For 21 of 22 patients who had extravaginal pelvic recur-
rences, the sites of recurrence were described with sufficient
detail to assess their relationship to the region of radiation
treatment. Of these 21, 13 appeared to have been well
within the treated fields. Seven recurrences occurred at the
margins of the treated area: 2 in the lateral pelvis after
treatment with brachytherapy alone, 1 superior and lateral to
small (12 ⫻ 12 cm) central pelvic fields, and 4 in common
iliac lymph nodes at the superior margins of the treatment
fields. In addition, 1 patient had a recurrence in para-aortic
lymph nodes superior to L4/5 at the border of her pelvic
radiation fields.
Complications
The Common Terminology Criteria for Adverse Events
were used to grade the side effects and complications of
treatment (13). The 5-year and 10-year cumulative rates of
major (i.e., Grade 3 or 4) complications were 10% and 17%,
respectively. Twenty patients had a total of 25 major com-
plications. Nineteen of the 25 (76%) major complications
were gastrointestinal. Major gastrointestinal complications
included proctitis requiring transfusion (7 patients), fistula
(5 patients), small-bowel obstruction (4 patients), large-
bowel obstruction (1 patient), rectal ulcer (1 patient), and
incontinence (1 patient). Eight of 11 patients (73%) with
major rectal complications had had tumors that involved the
posterior vaginal wall.
Major genitourinary complications included 1 urethral
and 5 bladder complications. One patient developed a ure-
thral stricture at 204 months. Grade 3– 4 bladder complica-
tions included 2 vesicovaginal fistulae, which occurred at 20
 RT for vaginal carcinoma
and 23 months, and 3 cases of hemorrhagic cystitis. All of
the 5 serious bladder complications occurred in patients
who were treated for cancers that involved the anterior
vaginal wall.
Two factors—FIGO stage and smoking history—were
significantly correlated with subsequent complications in
univariate analysis. The 5-year incidences of complica-
tions by stage were as follows: Stage I, 4%; Stage II, 9%;
and Stage III or IVA, 21% (p ⬍ 0.01). At 5 years, the risk
of major complications was 25% in current smokers and
18% in patients who claimed to have quit more than 6
months before radiation therapy, compared with only 5%
in patients who had no smoking history (p ⬍ 0.01).
Personal history of diabetes or hypertension, tumor size
or site, radiation treatment type or dose, and chemother-
apy did not correlate with the likelihood of complica-
tions.
DISCUSSION
This report describes the largest single-institution study
of definitive radiation therapy for patients with invasive
squamous cell carcinoma of the vagina without a prior
history of an invasive gynecologic malignancy. Although
other authors (1–5) have described results of radiation ther-
apy in patients treated with radiation for vaginal cancer, the
small size and heterogeneity of their study populations have
often made it difficult to generalize their conclusions to
current practice. Our study demonstrates that carefully tai-
lored radiation therapy can achieve high local-regional con-
trol rates; in addition, because isolated extrapelvic recur-
rences are uncommon, this treatment also yields excellent
survival rates.
Our results suggest also that radiation treatment for in-
vasive squamous cell carcinoma of the vagina should be
individualized, with the optimal treatment approach se-
lected according to the tumor size, tumor site, extent of
disease, and response to initial EBRT (Fig. 6). The benefit
of this approach is validated by the excellent pelvic disease
control and disease-specific survival rates achieved in pa-
tients treated at our facility during the past 30 years.
Initial EBRT fields and dose should be determined
after consideration of the distribution of gross disease
and possible sites of microscopic paravaginal or nodal
disease. In their classic description of the lymphatics of
the vagina, Plentl and Friedman (14) state that, “all
lymph nodes in the pelvis may at one time or other serve
as primary sites or regional drainage nodes for vaginal
lymph.” The external, internal, and common iliac nodes
are most frequently affected. However, vaginal cancers,
particularly those that involve the posterior wall, can
drain to the inferior gluteal, presacral, or perirectal nodes,
and lesions that involve the distal third of the vagina may
drain directly to the inguinofemoral chain. This diverse
nodal drainage must be carefully considered in the design
of treatment fields.
In our practice, we almost always begin treatment with a
● S. J. FRANK et al. 143
Fig. 2. Vaginal disease control for all 193 patients with squamous
cell carcinoma of the vagina. Numbers in parentheses indicate the
number of patients at risk 5 or 10 years after treatment.
course of EBRT. Some investigators have advocated treat-
ment with brachytherapy alone for small superficial Stage I
lesions (15–18). Perez et al. (19) observed 3 recurrences in
15 patients who were treated with intracavitary therapy
alone (20%) and a 10-year pelvic failure rate of 14% for all
Stage I lesions. They recommended the use of EBRT in
addition to brachytherapy only for tumors that were “infil-
trating” or poorly differentiated and that were believed to
have a higher probability of lymph node metastasis. How-
ever, we are concerned that underestimation of the extent of
submucosal disease and of the risk of microscopic paravag-
inal or nodal disease can lead to unexpected recurrences
when these early tumors are treated with intracavitary or
even interstitial therapy alone. In our series, the pelvic
relapse rate was 18% at 10 years for Stage I lesions, but all
3 pelvic failures occurred in patients who were treated with
brachytherapy alone. Although we still occasionally treat
patients who have very small, very superficial lesions with
brachytherapy alone, our threshold for including EBRT in
the treatment plan has lowered over the years.
Therefore, in our practice, most patients receive an
initial course of pelvic irradiation to a dose of 40 – 45 Gy
in 20 –25 fractions with 15-MV or 18-MV photons. Op-
posed anterior-posterior and posterior-anterior fields are
often required because of the extensive anterior and
posterior nodal drainage of these cancers; when lateral
treatment fields are used, they must be carefully designed
to avoid shielding presacral, perirectal, or anterior exter-
nal iliac nodes that may be involved with cancer. The
inferior border of the fields is usually placed 4 cm below
the most caudad extent of disease, localized with the aid
of a small platinum marker seed inserted in the distal
edge of the tumor at the time of physical examination. If
144 I. J. Radiation Oncology ● Biology ● Physics
Fig. 3. Disease-specific survival by disease stage for all 193
patients with squamous cell carcinoma of the vagina. Patients with
Stage III and IVA disease were combined for the analysis because
of the small number of patients (n ⫽ 7) with Stage IVA disease
(p ⬍ 0.01). Numbers in parentheses indicate the number of pa-
tients at risk 5 or 10 years after treatment.
tumor involves the distal third of the vagina, the medial
inguinofemoral lymph nodes (i.e., medial to the femoral
vessels) are included in the target volume. In patients
with very distal lesions, it is often necessary to treat the
vulva to achieve adequate tumor coverage; in such cases,
we usually treat patients in an open-leg position to reduce
the vulvar skin reaction.
After the patient has received 40 – 45 Gy, she is reeval-
uated with pelvic examination to determine whether addi-
tional treatment to the primary tumor would be given most
effectively in the form of interstitial, intracavitary, or addi-
tional external-beam therapy. The extent, thickness, mor-
phology, and location of initial and residual disease, the
presence or absence of the uterus, the proximity of critical
structures, and the patient’s medical condition are all con-
sidered in making this determination. In general, we tend to
favor brachytherapy if the target is well defined, involves
less than 50 – 60% of the circumference of the vagina, and
does not extensively involve the rectovaginal septum; in
some cases, a small volume encompassing the central tumor
may be treated with an additional 5–10 Gy of EBRT (usu-
ally using lateral fields) before brachytherapy. Apical le-
sions that are 0.5 cm or less in thickness after EBRT are
usually treated with low-dose-rate intracavitary brachyther-
apy, using a Delclos dome cylinder (8), in 1 or 2 sessions to
deliver 50 – 60 Gy to the vaginal surface. If the uterus is
present, more extensive lesions may be treated with intra-
cavitary brachytherapy. However, apical vaginal cancers are
more often diagnosed in patients who have had a previous
hysterectomy. In these cases, if the tumor is discrete but too
thick for adequate coverage to be obtained with intracavi-
Volume 62, Number 1, 2005
Fig. 4. Disease-specific survival by tumor size for all 193 patients
with squamous cell carcinoma of the vagina. Tumor size indepen-
dently correlated with outcome in multivariate analysis (p ⬍
0.001). Numbers in parentheses indicate the number of patients at
risk 5 or 10 years after treatment.
tary therapy, additional treatment with interstitial brachy-
therapy may be delivered, using a perineal template with
needles inserted under laparoscopic guidance.
For patients who have more distal lesions, the proximity
of the rectum, bladder, and urethra can make it difficult to
deliver optimal doses of 70 – 80 Gy to residual tumor with-
out overdosing critical structures. In selected patients who
have very superficial lateral wall tumors, intracavitary ther-
apy may provide sufficient tumor coverage; for such cases,
we have used a customized cylinder that has a central
channel for cesium and peripheral channels for iridium
sources. However, we favor interstitial brachytherapy for
most tumors that involve the distal two-thirds of the lateral
and anterior walls, because it provides greater coverage of
deep tumors and more conformal coverage of the target
volume than can be achieved with intracavitary brachyther-
apy. We use a freehand interstitial technique (7) that allows
the brachytherapist to palpate the tumor and monitor the
rectum while placing individual needles; uninvolved tissues
are distanced from the implant by placing a Delclos cylinder
in the vagina. In most cases, sources are selected to deliver
treatment at 40 – 60 cGy per hour and are left in place to
deliver a total of 75– 80 Gy (including EBRT) to the tumor.
In some cases, to achieve additional coverage of possible
microscopic paravaginal disease, small conformal EBRT
fields are used to deliver an additional dose of 5–10 Gy after
initial pelvic irradiation and before brachytherapy. Because
it often permits delivery of a high dose (up to 85 Gy) to the
target without excessive irradiation of critical structures, we
use brachytherapy whenever we feel that it can be used
safely to cover the target completely. However, we do
believe that some tumors are best treated with carefully
 RT for vaginal carcinoma
Fig. 5. Patterns of relapse for the 147 patients with early-stage (Stage I or II) disease and for the 46 patients with
advanced-stage (Stage III or IVA) disease. Sixty-eight percent of the relapses in patients with early-stage disease and
83% of the relapses in patients with advanced-stage disease had a local-regional component. One recurrence in the
inguinal lymph nodes was included in the pelvic recurrence group.
applied EBRT alone. In particular, extensive, very deeply
infiltrating tumors that have indistinct margins or that ex-
tensively involve the rectovaginal septum or bladder tend to
be poor candidates for intracavitary or interstitial brachy-
therapy; without a uterus in place, intracavitary therapy is
unable to achieve a sufficient dose to the deep margins of
these tumors, and indistinct margins or involvement of
critical structures may preclude effective tumor coverage
with interstitial needles. In such cases, we believe that
Fig. 6. Guidelines for tailoring definitive radiation therapy on the
basis of tumor location, tumor size, and the tumor response to
treatment. EBRT ⫽ external-beam radiation therapy; fx ⫽ frac-
tions; ICRT ⫽ intracavitary radiation therapy; VSD ⫽ vaginal
surface dose.
● S. J. FRANK et al. 145
treatment with EBRT alone may be a better compromise
than inadequate coverage with brachytherapy. Today, we
boost the primary tumor using conformal techniques, paying
careful attention to possible internal organ motion. To mini-
mize daily variation in the position of the target, for most
proximal lesions and some distal lesions, simulation and treat-
ment are carried out each day with a fixed volume of saline that
is instilled in the bladder using a Foley catheter. Depending on
the size, location, and response of the tumor, a total dose of
64 –70 Gy is usually delivered to the gross tumor volume when
conformal boost therapy is used.
Although some authors have argued that brachytherapy
should be used for nearly all patients (17, 20, 21), we
believe that our excellent results justify the use of tai-
lored EBRT to boost the primary site in selected cases. If
the tumor volume can be encompassed adequately with-
out excessive irradiation of critical structures, brachy-
therapy should be used, because it permits delivery of a
relatively high total dose to the target (usually more than
75 Gy) without unacceptable risk of normal tissue injury.
Brachytherapy is still the best tool available to deliver a
high dose to a defined volume in this difficult area; for
small tumors, skillfully applied brachytherapy combined
with EBRT should be able to achieve vaginal disease
control rates of 90 –100% and pelvic disease control rates
of 80 –90% for patients with early-stage disease. How-
ever, in some more advanced cases, the lower dose de-
liverable with EBRT alone may be balanced by the wider,
more homogeneous coverage achieved with external-
beam fields; in these cases, conformal EBRT may provide
the best compromise between tumor coverage and dose.
146 I. J. Radiation Oncology ● Biology ● Physics
Our high vaginal and pelvic disease control rates in
patients with bulky or advanced tumors, many of whom
were treated with EBRT alone, suggest that our approach
has been successful.
The efficacy of combined chemotherapy and radiation
therapy cannot be determined from our series, and the rarity
of vaginal cancer makes it unlikely that randomized trials
will ever be done to address this question. However, the
similarities in histology, epidemiology, and natural history
between cervical and vaginal cancers suggest that it may be
reasonable to extrapolate from the results of trials in patients
with cervical cancer to select rational treatments for patients
with high-risk vaginal lesions. We do not believe that neo-
adjuvant chemotherapy has a role in the routine manage-
ment of this disease; most trials of neoadjuvant chemother-
apy before radiation therapy for cervical cancers have been
negative, and in our series of patients with vaginal cancer,
all 4 of the patients treated with neoadjuvant chemotherapy
had a relapse and died of their disease. On the other hand,
randomized trials in patients treated with radiation for cer-
vical cancer have consistently revealed a benefit from con-
current cisplatin-based chemotherapy (22–24). On the basis
of these data, we currently consider concurrent chemoradia-
tion for most patients who have high-risk vaginal cancers
and good performance status. Patients who have Stage III or
IVA disease and those with tumors larger than 4 cm are
most likely to benefit from combined treatment. Our results
and those of other investigators (19, 21, 25) suggest that
patients with these more advanced lesions have pelvic dis-
ease recurrence rates of at least 25–30%, similar to the
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