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1934
Radiation Alone for Carcinoma of the Vagina
Variation in Response Related to the Location of the Primary Tumor
Moinuddin M. Ali, M.D.'
David T. Huang, M.D., Ph.D.'
Dean R. Goplerud, M.D?
Robert Howells, M.s.c.'
Jian dong Lu, Ph.0.'
'
Department of Radiation Oncology, Medical
College of Virginia Hospitals, Virginia Commonwealth University, Richmond, Virginia.
Department of Obstetrics and Gynecology, Division of Gynecology/Oncology, Medical College
of Virginia Hospitals, Virginia Commonwealth
University, Richmond, Virginia.
BACKGROUND. A retrospective study of 40 patients with histologically confirmed
carcinoma of the vagina is reported. The patients were treated by radiation alone
(a combination of external beam therapy and implants) between October 1969
and September 1991 at the Medical College of Virginia Hospital in Richmond.
METHODS. Thirty-three patients (82%) had squamous cell carcinoma, 2 patients
(7%) had adenocarcinoma, and 2 patients (5%) had poorly differentiated cancers
(1 melanoma and 1 leiomyosarcoma). The patients were staged according to the
International Federation of Gynecology and Obstetrics (FIGO) staging system; there
were 13 patients (33%) in Stage 1, 21 (52%) in Stage I I , 4 (10%) in Stage 111, and 2
(5%) in Stage IV. Thirty-six patients (90%)were treated with external beam therapy
and some combination of implant: cylinder, ovoid, or interstitial implants with
iodine-125 or iridium-192 (afterloading). Only 4 patients (10%) received treatment
by implant only.
RESULTS. Based on their response, two groups of patients were identified. Group
I had 23 patients with tumors predominantly located in the proximal half of the
vagina; there were 8 patients in Stage I, 11 in Stage 11, 3 in Stage 111, and 1 in Stage
IV. Of these, three patients failed: one each in Stages I11 and IV and one Stage I1
patient was salvaged by surgery. Three patients died due to unrelated causes but
with local control. The 5-year actuarial survival in this group was 81%. Group I1
had 17 patients with tumors located in the mid to distal half of the vagina; there
were 5 patients in Stage I, 10 in Stage 11, and 2 in Stage IV. Ten patients failed.
Eight patients in Stage I1 had persistent disease, were lost to follow-up, and are
presumed dead. Two patients with Stage IV disease also had inadequate local
control. The overall actuarid survival in the distal group was 41%, which was
significantly worse than the proximal group (81%),at a Pvalue of 0.05.
CONCLUSIONS. This study discusses the curability of carcinoma of the vagina based
on its anatomic location when predominantly similar treatment techniques and radiation doses were applied to either the proximal or the distal part of the vagina, those
with cancer in the proximal half had better survival (81%) than those whose cancer
was in the distal half (41%). Cancer 1996; 721934-9. 0 1996American Cancer Society.
KEYWORDS: vaginal carcinoma, proximal and distal radiation doses, treatment outcome, external beam therapy, implants.
Presented at the 77th Annual Meeting of the
American Radium Society, Paris, April 29-May
3, 1995.
Address for reprints: Moinuddin M. Ali, M.D.,
Radiation Oncology, Medical College of Virginia
Hospitals, P. 0. Box 980058, Richmond, VA
23298-0058.
Received August 3, 1995; revision received November 22,1995; accepted December 20,1995.
0 1996 American Cancer Society
P
rimary carcinoma of the vagina accounts for I-2% of gynecologic
rnalignancie~.'-~
Although extension to the vagina from tumors of the
cervix or vulva is observed frequently, tumors that involve both the vagina
and the cervix are classified as cervical cancers and those that involve
the vagina and vulva are considered neoplasms of the vulva?v6
Local surgical excision and partial or complete vaginectomy, which
used to be the mainstay of treatment, have given way to a more individualized approach that takes into consideration the patient's age and
Radiation for Carcinoma of the VaginaIAli et al.
1935
TABLE 1A
Patient Characteristics
Variable
Statistics
Proximal group
Distal group
Group difference
Race
No. (%) White
No. (%) Black
Mean (SD)
Median
Median
6 (50)
6 (50)
63.2 (10.7)
64
31
17 (60.7)
11 (39.3)
65.4 (15)
70
NSa
37
pisb
Age
Follow-up time (rno.)
NSb
SD, standard deviation; NS: not significant.
'Chi-square test at level 0.05.
bKmskal-Wallis test at level 0.05.
TABLE 1B
Patient Characteristics (cont'd)
Stagea
Proximal group
Distal group
Histology"
I
I1
I11
N
Total
I
I1
111
Iv
Total
SCC
Adeno
Others
8
0
0
8
2
1
19
2
2
2
0
0
0
14
1
0
5
0
0
1
1
2
1
0
0
8
I
0
2
Total
8
11
3
1
23
5
10
0
2
17
0
SCC smallcell carcinoma; adeno: adenocarcinoma.
'No significant difference between groups at level 0.05 by chi-square test.
the extent of the lesion (whether it is localized or multicentric). There is not enough data in the literature regarding the curability of primary carcinoma of the vagina based on location (proximal versus distal).
In young patients with early stage disease, treatment
also depends on the desire to preserve a functional vagina. In most patients, the major treatment modality is
Intracavitary and interstitial radiation is used
in small superficial Stage I disease, a combination of external beam therapy and interstitial implants is used in
extensive Stage I and Stage I1 disease, and a combination
of internal and external radiation is used in Stages I11
and IV disease. Survival rates with this malignancy are
approximately 65-90% for Stage I, 40-66% for Stage 11,
and 20-50% for Stages 111 and IV.'
This study discusses the curability or failure pattern
of carcinoma of the vagina. Based on our study, there
appears to be a difference in the local control of the tumor
at different locations (proximal versus distal vagina) when
similar treatment modalities and radiation doses are applied.
MATERIALS AND METHODS
This is a retrospective review of the charts of 40 patients
with primary carcinoma of the vagina treated at the Department of Radiation Oncology at the Medical College of
Virginia Hospital in Richmond during the period October
1969 through September 1991. The mean follow-up time
was 45.6 months (median, 33.2 months; range, 13-155.2
months). Although these patients had confirmed invasive
carcinoma of the vagina, four patients who were treated
for adenocarcinoma of the endometrium more than 5
years earlier and had a different histology were included
in this series. The patients were staged according to the
International Federation of Gynecology and Obstetrics
(FIGO) classification." Management was individualized
based on the tumor size, location, and stage as well as
the patient's age and general health. All patients were
treated with radiotherapy. Table 2 summarizes the various radiation treatment modalities utilized. Different
treatment techniques were used in the management of
these patients because of the various time periods involved in this study. Histologically, 93-95% of these ma-
1936
CANCER May 1,1996 / Volume 77 / Number 9
~ _ _ _ _ _ _ _ _23_ _ . _ _ _ _ _ _ . _
04
0.5
02
01
LI
t
1
II
p=.o19
01
0
35
72
108
144
180
Time (months)
FIGURE 2. Overall survival of patients by group.
FIGURE 1. Age distribution of patients by group
lignancies were classified as squamous cell carcinoma.
Other types included adenocarcinoma, papillary and
clear cell variety of adenocarcinoma, melanoma, and undifferentiated carcinoma. There were 12 patients in the
proximal group with an equal racial division. There were
17 whites and 11 African-Americans in the distal tumor
group, which was not statistically significant (Table 1).
The age distribution is approximately the same for all the
stages and also for Groups I & 11. Greater than 70% of the
patients were older than 60 years of age. (Fig. 1) There
was no statistical significance between the age and the
survival of patients in the proximal versus the distal tumor groups (Table 1).
The exact etiology of carcinoma of the vagina remains unknown. However, it is observed frequently during the sixth and the seventh decades of life and women
who have had hysterectomies are believed to be at a
higher risk."
Twenty-two of 23 patients (96%) in the proximal
group (Group I) and 14 of 17 patients (82%) in the distal
tumor group (Group 11) were treated with external beam
therapy with some combination of implants. Only a small
percentage of patients (1 of 23 [Group I] and 3 of 17
[Group 111) were treated with implants alone without the
use of external beam therapy. (Table 2)
In patients with proximal lesions and surgically absent uteri, ovoid or cylinder implants were used unless
the lesions were extensive or thick, in which case an interstitial implant with iridium- 192 (afterloading technique)
was utilized.
In the majority of patients, external pelvic irradiation
was delivered using megavoltage radiation (cobalt-60,6
or 10 megavolt linear accelerator). The isotopes used were
iridium-192 for temporary implants and iodine-125 for
permanent implantation. Computerized dosimetry was
obtained for all interstitial and intracavitary applications
using the standard commercial treatment planning systems. Pelvic fields were treated either with anterior and
posterior portals or with a four-field technique encompassing the entire vagina and the pelvic lymph nodes."
In tumors involving the distal half or distal third of
the vagina with clinically negative groins, the portal treatment included the groins. The dose of external beam therapy ranged between 40 to 50 Gray (Gy) for 4.5 weeks to
5.5 weeks, depending on the stage and extent of the disease. In the case of advanced lesions, additional parametrial boost treatments were added. In patients undergoing
interstitial implants with centrally located lesions, the
rectum and bladder were shielded at a dose level of 40
to 45 Gy. For temporary implants, a Syed-Neblett template was used' and the doses were prescribed at 0.5-cm
depth from the plane of the implant. The implant doses
ranged from about 25 Gy to 30 Gy for 3 to 4 days. Based
on local control, two groups of patients were identified.
To analyze the treatment results, certain statistical methods were used.
Statistical Methods
The outcome chosen was overall survival. Survival time
was measured from the end of radiotherapy to the date
of death or last follow-up, which was treated as censored
observation. The differences in patient characteristics
and treatment parameters between the two groups were
tested by chi-square tests, if categoric data was involved,
or the Kruskal-Wallis test if continuous data was given.
Estimation of survival curves were obtained by the
Kaplan-Meier method and comparisons of survival
curves were made by log rank tests. In addition, we stratified the patients based on stage information and then
tested the significance of the risk factors including tumor
site (proximal tumor group vs. distal tumor group), histology, race, age, and total dose.
RESULTS
Group I had 23 patients with lesions predominantly located in the proximal half of the vagina. Eight patients
were Stage I, 11 patients were Stage 11, and 4 patients had
Stage I11 and J
Y disease. Among the five patients who
Radiation for Carcinoma of the Vagina/Ali et al.
1937
TABLE 2
Treatment Information
Variable
Statistics
Proximal group
Distal group
Group difference
External Beam
EBT Dose (Gy)
No. (%)
Mean (SD)
Median
No. (%) None
No. (%) Brachy
No. (W)Cylin.
No. (W)Ovoids
Mean (SD)
Median
Mean (SD)
Median
22 (95.7)
48.3 (7.3)
50
1 (4.4)
12 (52.1)
9 (39.1)
1 (4.4)
83.0 (18.3)
78
2.8 (1.8)
2.9
14 (82.4)
45.2 (10.8)
47
2 (11.8)
3 (17.6)
10 (58.8)
2 (11.8)
79.0 (35.4)
70
1.9 (1)
1.9
NS"
NSb
Implant methodology
Total dose (Cy)
Total treatment time
(mo)
NS"
NSb
NSbP = 0.079
EBT external beam therapy; S D standard deviation; NS: not significant; Brachy: brachytherapy; Cylin: cylinder.
'Chi-square test at level 0.05.
bKruska-Wallis test at level 0.05.
TABLE 3
Outcome Summary
Stage
Proximal
Distal
Local control status
I
I1
IIIlN
Total
I
I1
IIllN
Total
NED
Failure
Total
8
0
8
10
2
2
4
20
3
23
5
2
8
10
0
2
2
7
10
1
11
0
5
17
N E D no evidence of disease.
died, three died of intercurrent disease and two died of
recurrent disease. There were only three local failures and
one Stage I1 patient was salvaged by surgery. The two
patients who died of disease progression were Stage 111
and Stage IV,respectively. The overall 5-year survival in
this group was 81%.
Group I1 had 17 patients who had tumors located in
the distal half of the vagina. Five patients had Stage I
disease, 10 Stage I1 disease, and 2 Stage IV disease. Ten
patients had local failure; among these ten patients, four
were lost to follow-up and were believed to have died
because of the disease progression in this analysis. The
remaining six patients died of recurrent disease. The 5year overall survival rate in this group was 41%. N o apparent differences in patient characteristics between the
groups were identified.
The 5-year survival by stage for the 40 patients was
100%for Stage I, 53% for Stage 11, and 22% for Stages 111
and IV (Fig. 3). Table 4 shows the 5-year overall survival
for each group of patients and their corresponding stages.
The differences in overall survival was statistically significant between Group I and Group I1 ( P = 0.004), after
adjusting for stage.
Local Control
All patients who died of disease had local failure. In Group
I, one patient failure (Stage 11) of the three was salvaged by
surgery. Ten patients in Group I1 had local failure. Four of
these patients were lost to follow-up but had persistent
disease at the time of their last follow-up and so were believed to have died. There is not enough follow-up data to
reach a statistical conclusion with respect to local control.
Dose Response
The median dose in Group I was 78 Gy. For Group 11, the
median dose was 70 Gy (Table 2). There is no significant
difference in doses received between patients in Group I
and Group 11.
1938
CANCER May 1,1996 I Volume 77 I Number 9
11
Stage I
Stage ll
-Stage
IllllV
01
-.
10
00
36
72
FIGURE 4. Overall survival of
FIGURE 3. Overall survival of patients by stage.
The ratio of brachytherapy dose to the external beam
dose was also compared without significant difference
between the two groups. The median of the ratio was
0.72 for the proximal tumor group (Group I) and 0.65 for
the distal tumor group (Group 11).There was no statistical
significant difference between the groups ( P = 0.8).
108
144
180
Time (months)
Time (months)
09
i
. ....... . _
_.
08
0.7 ~0 6 ~0 5
0 4 --
03
02
Stage II patients by group.
~ A
~
:
: 4
~~
01
0,
COMPLICATIONS
The Radiation Therapy Oncology Group system was utilized to grade the toxicity or complications of treatment.
There was one recurrence and four severe complications.
In Group I, one Stage I1 patient had parametrial recurrence and required total pelvic exenteration. Four patients in Group 11 developed Grade 3 and Grade 4 complications. Two patients developed a rectovaginal fistula
(Stage I11 and Tv), and two additional patients developed
small bowel obstruction, (Grade 4) without any tumor
recurrence.
DISCUSSION
Radiation therapy is the treatment of choice for carcinoma
of the vagina regardless of the anatomic location of the
tumor either in the proximal or the distal part of the vag i ~ ~ a . Radiation
~-’
therapy provides excellent local tumor
control in early and superficial lesions with satisfactory
functional results.13 It is also important to note overly aggressive treatment may result in damage to the normal tiss u e ~ . It’ ~is clear from a review of the literature that the
outcome for carcinoma of the vagina has improved over
the past 50-60 years partly because of our ability to understand the natural history of the disease and partly due to
the radio responsiveness of this diseasels along with improvements in treatment techniques. External pelvic irradiation, especially in patients with bulky vaginal lesions, helps
to shrink the tumor and optimize the use of brachytherapy,
thereby reducing the volume of irradiation,and contributes
to the success of treatment.
Patients with Stage I1 and IiI tumors often require a
combination of external beam and interstitial therapy. In
our experience (Table 3), and that of others, local tumor
control has been better when both modalities were uti-
FIGURE 5. Overall survival of Stage III/IV patients by group.
lized.” In our series, there has been a significantlyhigher
number of local failures in the distal tumor group (Table
3): 8 of 10 patients (80%)as compared with the proximal
tumor group (Table 3). Although optimum radiation
doses (Table 2) were delivered utilizing both external
beam and implants in 82-96% of patients, the local failure rate was extremely high in the Group I1 patients.
As point out by Perez et al., the higher incidence of
pelvic failures in Stages Ii and 111 is of major concern and
they suggested that a more radical approach be adopted in
these advanced tumors?,’**In our series, the treatment results of the proximal and the distal vagina in Stage I1 patients were drastically different. (Figs. 2 and 4) The overall
survival was in excess of 85% in the proximal tumor group
but was very low (10%)in the distal group (Fig. 4). In our
series, although the numbers are small in these two groups,
it appears that the proximal tumor group has much better
results than the distal tumor group (Fig. 5).
There was 1 failure in a Stage I1 patient in the proximal tumor group (32 months after treatment); this patient
underwent radical surgery and remains alive with no evidence of disease thus far. The poor results in the distal
tumor group in Stage I1 patients may be due to factors
such as poor response to radiation, lack of vascularity,
inadequacy in the staging system, or the longer elapsed
time to deliver the definitive treatment.I6 (Table 4 and 5)
Alternatively, either a higher external beam dose or
wider use of interstitial implants may help to improve
the target volume dose distribution and might help to
Radiation for Carcinoma of the Vagina/Ali et al.
1939
TABLE 4
2- and 5-Year Survival Rate
Stage
Proxlmal
Distal
Survival rate (W)
1
II
Ill/Iv
Total
I
I1
lllllv
Total
2-year
5-year
100
100
90. I
90.1
7s
37.5
91.1
81
100
100
so
50
0
64.7
14.4
Stage and group (pmrimal 6 .distak 2 = O.OG4) are significan: factors for the ouicome at level 3.05 by the
25
log iank ies:.
TABLE 5
Patients Who Failed (by Group)
Stage
Histology
Implant methodology
Total treatment time
Total dose (Gy)
Proximal (3)
Distal (10)
1, !I; I , 111; I, !v
2, SCC; I, Sarcoma
3, Brachy
2, 3 mo; I, 6 mo
67.6- 105
8, 11; 2, !v
7, SCC; I, Adeno: 1, Melanoma; I, Pap Adeno
2, None; 2, Brachy; 6, Cylinder
Median; 2 months; Range; 0.6-3.4 nio
60-180
SCC: small cell carcinoma; Adeno: adenocarcinoma; Pap Adeno: papillary adenocarcinoma; Brachy: brachytherapy.
improve local control in tumors of the distal
New therapeutic strategies such as high LET radiation, as
well as the adjuvant use of radiosensitizers and radioprotectors should be considered for more advanced lesions
as suggested by Nori et al.,15 particularly in the middle
and lower third vaginal lesions. Chemotherapeutic regimens should be investigated as radiosensitizers in the
management of advanced tumors.
8.
9.
10.
1.
Cancer Facts and Figures - 1995. American Cancer Society,
1995.
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1955-1982. I n t ] Radiat Oncol Biol Phys 1988; 14:745-9.
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6 . Haskel CM. Cancer treatment. 2nd edition. Philadelphia:
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irradiation of carcinoma of the vagina. Int J Radial Oncol
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Perez CA, Di Saia PI, Knapp RD. Gynecologic tumors. In:
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Puthawala A, Syed AM, Nalick H , iMcNamara C, Di Saia PJ.
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MacNaught R, Symmonds RP, Hole D, Watson ER. Improved
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Deppe Q, Lawrence WD. Cancer of the vagina including
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Q, editors. Female genital cancer. New York: Churchill Livingstone, 1988253-74.
Plentl AA, Friedman FA. Lymphatic system of the female
genitalia: the morphologic basis of oncologic diagnosis and
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Kottmeir HII.. Annual report on the result of treatment in
gynecological cancer. Int Fed Gynecol Obstet Sweden
1979;13,18.
Brown GR, Fletcher GII, Rutledge FN. Irradiation of in situ
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Nori I>, Hilaris BS, Stanimir G, I.ewis JL. Radiation therapy
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