PII S0360-3016(98)00173-4

● Clinical Investigation

IS THERE A ROLE FOR A BRACHYTHERAPY VAGINAL CUFF BOOST INTHE ADJUVANT MANAGEMENT OF PATIENTS WITH UTERINE-CONFINED

ENDOMETRIAL CANCER?

KATHRYN M. GREVEN, M.D.,* RALPH B. D’A GOSTINO, JR., PH.D.,§ RACHELLE M. LANCIANO, M.D.,†

BENJAMIN W. CORN, M.D.#

*Wake Forest University School of Medicine, Department of Radiation Oncology, Winston-Salem, NC;§Wake Forest UniversitySchool of Medicine, Department of Public Health Sciences, Winston-Salem, NC;†Delaware County Regional Cancer Center, Drexel

Hill, PA; #Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA

Purpose/Objective: Many patients who have uterine-confined endometrial cancer with prognostic factors pre-dictive of recurrence are treated with adjuvant pelvic radiation. The addition of a brachytherapy vaginal cuffboost is controversial.Materials and Methods: Between 1983 and 1993, 270 patients received adjuvant postoperative pelvic irradiationfollowing hysterectomy for Stage I or II endometrial cancer. Group A includes 173 patients who received externalbeam irradiation alone (EBRT), while group B includes 97 patients who received EBRT with a vaginalbrachytherapy application. The median dose of EBRT was 45 Gy. Vaginal brachytherapy consisted of a low doserate ovoid or cylinder in 41 patients, a high dose rate cylinder in 54 patients, and a radioactive gold seed implantin two patients. The median follow-up time was 64 months. The two groups were compared in terms of age,histologic grade, favorable versus unfavorable histology, capillary space invasion, depth of myometrial invasion,and pathologic stage.Results: Chi-square analysis revealed that the only difference between the two groups was the presence of moreStage II patients in group B (38% versus 14%). No difference was detected for 5 year pelvic control anddisease-free survival rates between groups A and B.Conclusion: There is no suggestion that the addition of a vaginal cuff brachytherapy boost to pelvic radiation isbeneficial for pelvic control or disease-free survival for patients with Stage I or II endometrial cancer. Prospectiverandomized trials designed to study external irradiation alone versus external beam treatment plus vaginalbrachytherapy are unlikely to show a positive result. Because EBRT provides excellent pelvic control, protocoldevelopment for uterine-confined corpus cancer should focus on identifying patients at risk for recurrence as wellas other means of augmenting EBRT (e.g. addition of chemotherapy) in order to improve disease free survivalin those subgroups. © 1998 Elsevier Science Inc.

Endometrial cancer, brachytherapy, adjuvant radiation

INTRODUCTION

Many patients who have uterine-confined endometrial can-cer with prognostic factors predictive of recurrence aretreated with adjuvant pelvic radiation. The addition of abrachytherapy vaginal cuff boost for these women is con-troversial.

MATERIALS AND METHODS

Between 1983 and 1993, 294 patients received adjuvantpostoperative irradiation from one of three academic radia-tion practices for pathologic Stage 1 and 2 endometrialcarcinoma. Patients were staged using the current 1988FIGO staging system.(1) Fifty-one patients were treated atThomas Jefferson University from 1986 to 1993, 147 pa-

tients received treatment at Wake Forest University MedicalCenter from 1983 to 1993. Ninety-six patients receivedtreatment at Fox Chase Cancer Center from 1986 to 1993.The median follow-up time was 64 months (range, 3–151months). The patients ranged in age from 28–89 years(median, 66 years).

All patients underwent total abdominal hysterectomy andbilateral salpingo-oophorectomy. Forty-nine percent of pa-tients had pathologic lymph node evaluations and forty-eight percent of patients had pathologic assessment of peri-toneal cytology.

After surgery, all patients received adjuvant RT. Twenty-four patients who received treatment with vaginal brachy-therapy alone are excluded from this report. Group A com-prises 173 patients who received external beam irradiationalone, while group B includes 97 patients who received

Reprint requests to: Kathryn M. Greven, M.D., Wake ForestUniversity School of Medicine, Medical Center Boulevard, Win-

ston-Salem, NC 27157. Phone: 336-716-4981. Fax: 336-716-5972.E-mail: Kgreven@wfubmc.edu

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0360-3016/98 $19.001 .00

101

EBRT with a vaginal brachytherapy application. Table 1demonstrates the distribution of the following patient char-acteristics by group: age, histologic grade, favorable versusunfavorable histology, capillary space invasion, depth ofmyometrial invasion, and pathologic stage.

External treatment technique included whole pelvis irra-diation (259 patients), small pelvic field irradiation (5 pa-tients), and whole abdominal irradiation (2 patients). PelvicRT doses ranged from 40–55 Gy (median, 47 Gy). Patientstreated with external RT alone (Group A) were treated withdoses ranging from 40–55 Gy with a median of 48.5 Gy.Fourteen patients in group A received pelvic doses of 45–50.4 Gy with a median of 46.1 Gy followed by an externalboost of 0.5 to 35.3 Gy with a mean of 1.1 Gy. Patients whoreceived a brachytherapy boost (Group B) received pel-vic doses ranging from 40 Gy to 50.4 Gy with a median of45.8 Gy.

Of the patients who received a vaginal brachytherapyapplication in addition to an external beam dose, treatmentconsisted of Manchester ovoids (25–40 Gy) in 14 patients,colpostats (17.5–50 Gy) in 25 patients, low dose rate cyl-inder (25–36 Gy) in 2 patients, radioactive seed implant(30–75 Gy) in 2 patients, and high dose-rate cylinder (40–120 Gy at 0.5 cm) in 54 patients.

The time to relapse was calculated from the date of thehysterectomy. Patterns of disease recurrence were identifiedas pelvic if they occurred in the standard pelvic RT field.The Kaplan-Meier product limit method was employed toobtain actuarial estimates of outcome. Log rank tests wereused to compare the outcomes between the two groups.

RESULTS

OutcomeChi-square analysis of the characteristics in table 1 re-

vealed that the only difference between Group A and GroupB was the presence of more Stage II patients in group B. Ofthe patients who received a brachytherapy boost, 38% wereStage II in Group B as compared to 14% for Group A. Themajority of Stage II patients in Group B were noted to havestromal involvement.

The 5 year pelvic control rates for Group A and Group B

were 96% and 94%, respectively. When stage II patients areconsidered separately, the 5 year pelvic control rates forGroup A and Group B were 93% and 90%, respectively.Similarly, there was no difference in the disease-free sur-vival rates between group A and group B. These results canbe seen in Table 2.

When Stage II patients were subdivided into stages IIAand IIB, no difference could be shown in pelvic failure ratesbetween Groups A and B. Pelvic control at 5 years for IIAwas 100% and 81% for Groups A and B, respectively (p5.15). Pelvic control at 5 years for IIB was 83% and 95%, forGroups A and B, respectively (p5 .43). Interpretation ofthis information is limited because of the small samplesizes.

ComplicationsBowel, bladder and rectal complications were assessed

and graded according to RTOG scoring criteria. Seriouscomplications included grade 3 sequelae which requiredhospitalization and grade 4 sequelae which required sur-gery. One grade 3 rectal complication occurred in Group Aand Group B. Small bowel complications were documentedmore often in patients treated with a vaginal brachytherapyapplication although this was not statistically significant.Three grade 3 or 4 complications resulted for Group A(1.7%) compared with 4 grade 3 or 4 (4.1%) complicationsfor Group B. No patient had a significant bladder compli-cation. More vaginal complications consisting of atrophy,stenosis, and adhesions were documented in the patientstreated with a brachytherapy application. However, becausethese were not documented with a uniform scoring systemin all patients, it is not possible to reach firm conclusions.

DISCUSSION

Adjuvant external beam irradiation has been associatedwith decreased pelvic failure rates compared with surgeryalone. A recently completed Gynecologic Oncology Groupstudy has demonstrated a statistically improved pelvic con-trol rate with EBRT compared to surgery alone (2). Pub-lished retrospective reports (Table 3) have reported pelvicfailure rates for patients with uterine confined disease afterEBRT with or without a brachytherapy boost to range from

Table 1. Patient and tumor characteristics of Group A (externalalone) compared with Group B (external with brachytherapy)

CharacteristicNo. ofpatients

GroupA

GroupB

pValue

Age (median) 64.7 years 63.3 years 0.294Grade 3 76 27% 31% 0.464Unfavorable histology* 27 12% 6% 0.114Capillary space invasion 44 22% 15% 0.181Myometrial depth.2/3 128 45% 54% 0.150Cervix Invasion 61 14% 38% 0.001

IIA 30 9% 14%IIB 31 5% 24%

* Includes papillary serous or clear cell carcinoma.

Table 2. Five-year pelvic control and disease-free survival ratesfor patients treated with external beam alone (Group A) and

external beam with brachytherapy (Group B)

5-year rates

p ValueGroup A Group B

All patientsPelvic control 96% 93% 0.32Disease-free survival 88% 83% 0.41

Stage II onlyPelvic control 94% 90% 0.61Disease-free survival 76% 74% 0.90

102 I. J. Radiation Oncology● Biology ● Physics Volume 42, Number 1, 1998

0–6.5% (3, 4–7, 8–10). This report could find no sugges-tion that the addition of a vaginal cuff brachytherapy boostto pelvic radiation is beneficial for pelvic control or disease-free survival for patients with surgical Stage I or II endo-metrial cancer. Similarly, Randall et al found no differencein pelvic failure rates for patients with clinical stage Idisease treated with external beam RT alone comparedexternal beam RT with a brachytherapy boost (8).

This report has many of the inherent problems associatedwith retrospective reviews. It must be recognized that thesepatients were not uniformly staged and comprehensive re-view of the pathology slides was not performed. Histologicgrade, depth of myometrial penetration, and presence ofcapillary space invasion sometimes vary when separate pa-thologists are interpreting these factors. Approximately halfthe patients had node dissections or examination of perito-neal cytology. However, no difference could be determinedfor recurrence free survival for those patients that were“completely staged” compared with those that were not (4).It is uncommon for patients to have isolated nodal or cyto-logic involvement in the absence of other extrauterine dis-ease. Unfortunately, it was not possible to determine theexact site of pelvic recurrence in the few patients who didrecur, and so determination of vaginal recurrences versusother pelvic sites could not be made. In spite of these flaws,it is reassuring that pelvic recurrence is minimal after EBRTwith or without a brachytherapy boost.

Are there subsets of patients who might benefit from theaddition of a brachytherapy boost? It is possible that pa-tients with a potentially higher residual tumor burden i.e.close/positive margins of resection, cervical stromal in-volvement, and lymphovascular space invasion may benefitfrom the addition of a higher dose of radiation to the vaginalcuff. It could be argued that more of the patients treated witha vaginal brachytherapy boost had cervical stromal involve-

ment and they did equally as well as the patients withcervical glandular involvement treated with external beamalone. However, several reports have failed to demonstratea difference in prognosis between the subcategories of IIaand IIb (11–13).

Perhaps a more intriguing question concerns which pa-tients may be appropriate to treat with a vaginal brachyther-apy insertion alone. Vaginal brachytherapy is usually lesscostly and results in fewer sequelae than external beamradiation. Greven et al reported no serious sequelae in 32patients treated with brachytherapy alone compared withmorbidity rates of 3.6%-8.4% for patients treated with ex-ternal beam irradiation (14). Morrow et al (7) and Elliott etal (15) demonstrated a very low rate of vaginal or pelvicrecurrences in patients treated in this manner. Fanning et alhas suggested that patients staged with pelvic and periaorticlymphadenectomy may be adequately treated with a vaginalcylinder alone if lymph node metastasis are not found (16).Of twenty-two patients with deep invasion, grade 3 histol-ogy, or cervical involvement treated in this way only onehas recurred with a median follow-up of 3 years. Eltabbakhet al reported excellent pelvic control and no vaginal recur-rences for 303 patients with grade 1 or 2 histology and lessthan 50% myometrial invasion who did not undergo staginglymph node sampling (17). Greven et al reported a group ofpathological stage I patients treated with vaginal brachy-therapy alone who had a 100% pelvic control rate at fiveyears (14). A randomized trial from the Norwegian RadiumHospital suggested that a vaginal cylinder alone was ade-quate treatment for patients who did not have deep myome-trial penetration with grade 3 histology (18). There is onlyanecdotal information for the treatment of Stage II patientswith vaginal brachytherapy alone.

Prospective randomized trials designed to study externalirradiation alone versus external beam treatment plus vagi-nal brachytherapy are unlikely to show a positive resultbecause of the large numbers of patients that would berequired for such a study. Because EBRT provides excellentpelvic control, protocol development for uterine-confinedcorpus cancer should focus on identifying patients at risk fordistant recurrence following EBRT as well as other meansof augmenting EBRT (e.g. addition of chemotherapy) inorder to improve disease-free survival in those subgroups.Identification of subgroups of patients who may benefitfrom treatment with vaginal brachytherapy alone may resultin decreased cost and morbidity to these patients.

REFERENCES

1. FIGO Stages - 1988 Revision (Announcements). Gynecol.Oncol. 35:125–126; 1989.

2. Roberts, J. A.; Brunetto, V. L.; Keys, H. M.; Zaino R.; Spirtos,N. M.; Bloss, J. D.; Pearlman, A.; Maiman, M. A.; Bell, J. G.A phase III randomized study of surgery vs. surgery plusadjunctive radiation therapy in intermediate risk endometrialadenocarcinoma (GOG 99) (Abstr.) Society of GynecologicOncologists, 99th Annual Meeting, p. 70, 1998.

3. Carey, M. S.; O’Connell, G. J.; Johanson, C. R.; Goodyear,M. D.; Murphy, K. J.; Daya, D. M.; Schepansky, A.; Peloquin,A.; Lumsden, B. J. Good outcome associated with a standard-ized treatment protocol using selective postoperative radiationin patients with clinical stage I adenocarcinoma of the endo-metrium. Gynecol. Oncol. 57:138–144; 1995.

4. Greven, K. M.; Corn, B. W.; Case, D.; Purser, P.; Lanciano, R.Which prognostic factors influence the outcome of patients

Table 3. Five-year pelvic control rates after external beamradiation alone or with a brachytherapy boost

External beam RT aloneTorrisi et al. (10) 93.5%Rushet al. (9) 100%Current report 96%*

External beam RT1 brachytherapyAalderset al. (18) 98.1%Kuceraet al. (5) 97.8%Current report 93.0%*

* Actuarial estimates.

103Vaginal cuff boots for endometrial cancer● K. GREVEN

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8. Randall, M.; Wilder, J.; Greven, K.; Raben, M. Role of int-racavitary cuff boost after adjuvant external irradiation inearly endometrial carcinoma. Int. J. Radiat. Oncol. Biol. Phys.19:49–54; 1990.

9. Rush, S.; Gal, D.; Potters, L.; Bosworth, J.; Lovecchio, J.Pelvic control following external beam radiation for surgicalstage I endometrial adenocarcinoma. Int. J. Radiat. Oncol.Biol. Phys. 33:851–854; 1995.

10. Torrisi, J. R.; Barnes, W. A.; Popescu, G.; Whitfield, G.;Barter, J.; Lewandowski, G.; Delgado, G. Postoperative adju-vant external-beam radiotherapy in surgical stage I endome-trial carcinoma. Cancer 64:1414–1417; 1989.

11. Lanciano, R. M.; Curran, W. J. Jr.; Greven, K. M.; et al.

Influence of grade, histologic subtype, and timing of radio-therapy on outcome among patients with stage II carcinoma ofthe endometrium. Gynecol. Oncol. 39:368–373; 1990.

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13. Larson, D.; Copeland, L.; Gallager, H. S.; et al. Nature ofcervical involvement in endometrial carcinoma. Cancer 59:959–962; 1987.

14. Greven, K. M.; Lanciano, R. M.; Herbert, S. H.; Hogan, P. E.Analysis of complications in patients with endometrial carci-noma receiving adjuvant irradiation. Int. J. Radiat. Oncol.Biol. Phys. 21:919–923; 1991.

15. Elliott, P.; Green, D.; Coates, A.; Krieger, M.; Russell, P.;Coppleson, M.; Solomon, J.; Tattersall, M. The efficacy ofpostoperative vaginal irradiation in preventing vaginal recur-rence in endometrial cancer. Int. J. Gynecol. Cancer 4:84–93;1994.

16. Fanning, J.; Nanavati P. J.; Hilgers, R. D. Surgical staging andHigh Dose Rate Brachytherapy for endometrial cancer: Lim-iting external radiotherapy to node-positive tumors. ObstetGynecol. 87:1041–44; 1996.

17. Eltabbakh, G.; Piver, M.; Hempling, R.; Shin, K. Excellentlong-term survival and absence of vaginal recurrences in 332patients with low-risk stage I endometrial adenocarcinomatreated with hysterectomy and vaginal brachytherapy withoutformal staging lymph node sampling; report of a prospectivetrial. Int J Radiat Oncol Biol Phys. 38:373–80; 1997.

18. Aalders, J.; Abeler, V.; Kolst, P.; Onsrud, M. Postoperativeeternal irradiation and prognostic parameters in stage I endo-metrial carcinoma: Clinical and histologic study of 540 pa-tients. Obstet. Gynecol. 56:419–427; 1980.

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