Treatment of stage II endometrial carcinoma

GYNECOLOGIC

33, 204-208

ONCOLOGY

(1989)

Treatment of Stage II Endometrial Carcinoma RICHARD A. BOOTHBY, M.D.,

CRNP,

MARK

JOHN A. CARLSON, M.D., WADE NEIMAN, M.D., MARY M. RUBIN, R.N.C., A. MORGAN, M.D., DELRAY SCHULTZ, M.A., AND JOHN J. MIKUTA, M.D.

M.S.N.,

Divisions of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, and Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 Received November 2. 1987

The optimal managementof stageII carcinomaof the endometrium remainsto be established.We reviewed our experience in treating 42 patientswith stageII endometrialcancerby surgery, radiation, or combinedradiation and surgery at the Hospital of the University of Pennsylvania. The overall S-year survival was 47.6%. The 5-year survivals of patients treated by surgery only, radiation only, or combinationradiation and surgery were 68.5, 36.5, and46.1%,respectively,which werenot significantlydifferent. Histologic grade was found a significant prognostic factor but type of cervical involvement was not. Major complication rates were similar in each treatment group. We conclude that the majority of patientswith stageII endometrialcarcinomaare best treated by combination radiation and surgery, but in a select subsetof patients, radical hysterectomy and lymphadenectomy constitute a reasonabletreatment option. D 1989 Academic PIW, IIS INTRODUCTION

Carcinoma of the endometrium affected approximately 36,000 women in 1986 [I]. Stage II carcinoma of the endometrium is defined by the International Federation of Gynecology and Obstetrics (FIGO) as extension of tumor from the corpus uteri to the cervix [2]. Most series report the incidence of stage II endometrial cancer as 7-15% [3, 41. The overall 5-year survival for stage I endometrial cancer is 76%, whereas only 49% of patients with stage II disease survive [5]. One reason for this significant decrease is the higher incidence of lymph node metastasis in stage II (29.4%) than stage I (8.2%) [6]. Adequate treatment of stage II endometrial carcinoma then should include the parametria, upper vagina, and pelvic lymph nodes in addition to the corpus and cervix. The optimal management of patients with stage II carcinoma of the endometrium remains to be established. Various combinations of surgery and/or radiation have been utilized including radical hysterectomy and pelvic lymphadenectomy [3,7], radiation therapy [8,91, or a 204

00904X258/89$1.50 Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.

combination of radiation and surgery [IO,1 1,131. While there are no prospective randomized trials comparing these regimens, some retrospective reviews have indicated that either radical hysterectomy or hysterectomy and radiation are superior to radiation alone [3,11]. When radical surgery and combined surgery-radiation are compared, little difference is identified, although there tends to be a slight survival advantage to patients treated with combined-modality therapy [ 10,111. At the Hospital of the University of Pennsylvania (HUP), patients with stage II endometrial cancer have been treated with radical hysterectomy and lymphadenectomy, combined surgery and radiation, and radiation alone. We report our analysis of this experience with emphasis on prognostic variables, recurrence patterns, and complications. MATERIALS

AND METHODS

A retrospective review of patients with endometrial carcinoma treated at HUP from January 1, 1970, to December 31, 1981, was performed. These patients were identified by review of our hospital tumor registry and office records. This was a nonrandomized series of patients. Patient admittance to the study was stopped in 1981 to allow for a minimum 5-year follow-up on all patients. During the study period, a total f 473 patients were diagnosed with endometrial carcinoma. Of these, 42 (9.1%) patients had stage II carcinoma identified by definite histologic evidence of cervical stromal or mucosal invasion established by cervical biopsy, cone biopsy, or fractional curettage. Patients were selected for therapy by several criteria. Patients were considered possible candidates for radical hysterectomy and lymphadenectomy only if they had occult involvement of the cervix proven by cone or cervical biopsies. If patients had macroscopic involvement of the

STAGE II ENDOMETRIAL

cervix, they were not considered for radical surgery and were then candidates for one of the other treatments. If, on the basis of cervical involvement, the patient was an acceptable candidate for radical surgery, then their overall medical condition, age, and body habitus became selection factors for treatment. Treatment characteristics are reviewed in Table 1. Twenty-one patients underwent external-beam radiation therapy using supervoltage radiation delivering 34 to 60 Gy (1 Gy = 100 rad) via opposed anterior-posterior portals or four-field box technique. Intracavitary radiation was given additionally to 17 patients. Thirteen patients had placement of Fletcher-Suit tandem and ovoids and received from 18 to 45 Gy to point A. Three patients had placement of Heyman capsules and received from 39 to 48 Gy to a depth of 1.5 cm from the endometrial lining. One patient had placement of an Ernst applicator and received 60 Gy to point A. Total dose to point A delivered through external and intracavitary radiation ranged from 73 to 108 Gy. Nine patients were treated with surgery only. Of these, eight underwent radical hysterectomy and bilateral pelvic and paraaortic lymphadenectomy, and one patient was treated with an extrafascial hysterectomy only. There were 12 patients who were treated with a combination of radiation and surgery. Of these, 4 had preoperative radiation consisting of 40 to 50 Gy externalbeam radiation via four-field technique and Fletcher-Suit tandem and ovoids which delivered an additional 25 to 34 Gy to point A. All cases subsequently had an extrafascial hysterectomy and, in some, selected lymphadenectomy. Six patients underwent an extrafascial hysterectomy. All were followed by external-beam radiation with 45 to 50 Gy by four-field technique and Fletchersuit ovoids with 24 to 45 Gy to the vaginal surface. Two patients who underwent radical hysterectomy and bilateral pelvic lymphadenectomy had postoperative external radiation with 50 Gy by four-field technique. One additionally received a 45-Gy surface dose to the vaginal apex by Fletcher-suit ovoids. TABLE 1 Treatment Characteristics of 41 Patients with Stage II Endometrial Carcinoma Treatment Radiation only External beam only External beam and intracavitary Surgery only: radical hysterectomy with lymphadenectomy Combined surgery and radiation Preoperative radiation Postoperative radiation

Number of patients 4 17 8 4 8

205

CARCINOMA

The BMDP statistical package was used to estimate the survival distributions (Kaplan-Meier product-limit method) and compute test statistics. The analysis was run on the University of Pennsylvania Medical School Vax 8600 computer. RESULTS For purposes of analysis, we divided our patient population into three groups: radiation only, surgery (radical hysterectomy and lymphadenectomy) only, and combination radiation and surgery. Table 2 shows the patients divided by treatment group and the distribution by histology, tumor grade, and type of cervical involvement. Excluded from analysis in the surgery-only group was an 8 1-year-old patient treated palliatively by extrafascial hysterectomy and bilateral salpingo-oophorectomy who died 2 months after surgery from progressive disease. Survival distributions as estimated by the Kaplan-Meier method are seen in Fig. 1. When the Mantel-Cox and Breslow statistical tests were applied, the survival distribution among the three groups was not statistically significant (P = 0.22 and 0.15, respectively). There does, however, seem to be a slightly better survival in the surgery-only group, among which seven of eight (87.5%) were alive and well at 36 months. However, at 5 years, two of these patients were lost to follow-up and one had recurrent disease. A total of 21 patients were treated with supervoltage radiation only. They ranged in age from 50 to 90 years, median age 70. Their corrected 5-year survival was 36.5%. Three patients in this group died of intercurrent disease. TABLE 2 Characteristics of Patients in Study Separated by Treatment Group

Radiation only Number of patients Median age Histology Adenocarcinoma Adenosquamous Clear cell Grade 1 2 3 Unknown Type of cervical involvement Microscopic Gross

Radical hysterectomy with lymphadenectomy

Combination radiation and surgery

21 73

8 60

13 56

16 4 1

6 2 0

11 1 0

4 5 5 7

3 1 4 0

2 3 7 1

18 3

8 0

11 2

206

BOOTHBY

ET AL.

TABLE 4 Characteristicsof Patients Treated with Radical Hysterectomy and Pelvic, Paraaortic Lymphadenectomy

Patient 1 .2

_

.1

_

mm-

hDlWki’ERECD3W

... . .. .

SJRGERY

8 Rnol~Tttrr

-

RADIATION

CNLY

12

24

36

48

3 2 3 3

2 3 4 5 6 7 8

t 60

Depth of myometrial invasion

Histologic grade

l/3 113 113

Superhcial

1

l/3 l/3

3

1 1

Superficial 113

Status”

Site of failure

NED DOD NED NED NED AWD NED NED

Pelvic and distant Distant -

FIG. 1. Corrected survival for 42 patients with stage II endometrial carcinoma by treatment group.

a NED, no evidence of disease; DOD, dead of disease; AWD, alive with disease.

Complications of the radiation treatment are listed in Table 3. There were no deaths due to complications of treatment. The 5-year survival for the eight patients treated with radical hysterectomy and bilateral pelvic and paraaortic lymphadenectomy was 68.5%. They ranged in age from 50 to 67 years, median age 59. Lymphadenectomies performed in this group yielded an average of 31 nodes per patient, all of which were negative for tumor. There were four patients with grade 3 tumors, and three of these were without disease at 5 years although one had a recurrence. All surgical specimens showed definite evidence of cervical involvement although this was microscopic in all cases. This was the only group in which depth of myometrial invasion could be accurately assessed. Five had penetration of greater than one-third myometrial invasion, and two were felt to have superficial involvement. The outcome in this group can be seen in Table 4. Surgical complications were evaluated and are summarized in Table 3. Length of hospital stay ranged from 11 to 33 days, mean 18.2 days. There were no intraoperative or postoperative deaths.

The ages of the 12 patients treated with combination therapy ranged from 36 to 73 years, median age 56. One patient in this group was lost to follow-up 3 years after treatment and, at that time, was free of disease. Eight of the twelve patients had evaluation of pelvic and/or paraaortic lymph nodes. The two patients with positive nodes were dead of disease within 2 years. As seen in Fig. 1, corrected 5-year survival for this group overall was 46.1%. There was no difference in 5-year survival between the histological types adenocarcinoma and adenosquamous, 41.9 and 40%, respectively. Grade of tumor adversely affected survival as seen in Fig. 2. When the survival distributions of patients with grade 1 and 2 tumors are compared with those with grade 3, there is a significant difference (Z’ < 0.01). The 5-year survival was 25.0% versus 48.7%, respectively. Table 5 shows the characteristics of those patients who recurred. The overall recurrence rate in the study group was 45.2%. Among recurrences, 56% had grade 3 tumors. In both the surgery-only group and the combination surgery-radiation group, there were no local recurrences without an associated distant recurrence. The radiation

TABLE 3 ComplicationsSeenin Each Treatment Group

1.0 .9

Treatment group (%) Complication Rectovaginal tistula Vaginal vault necrosis Small bowel obstruction Ureteral flstula Wound infection Pelvic hematoma Pelvic abscess Proctitis Radiation enteritis

.a

Radiation only

Radical hysterectomy

Surgery and radiation

9.5 4.7 4.7

0 0 0

0

0 0 0 0

37.5 25.0 25.0

0

4.7 4.7

0 0 0

8.3 8.3

4

:d

^

I

16.7

0 8.3

0 0

FIG. 2. Corrected survival for 34 patients with stage II endometrial carcinoma by grade.

STAGE II ENDOMETRIAL

CARCINOMA

207

Berman et al. reported a 5-year survival of 66.1% in a surgically treated group including 7 patients treated by extrafascial hysterectomy, 10 patients treated by radical Depth of hysterectomy, and 8 patients treated by radical hysterHistologic myometrial Site of failure ectomy and node dissection [4]. In their report, 62% of invasion Treatment” Stat& grade the patients had grade 2 to 3 tumors. Only 25% of patients Distant Rad-Surg DOD 3 l/3 treated surgically had lymph node evaluation. Of those Rad-Surg DOD Distant 3 Superficial patients sampled, 47% had malignant involvement of posDOD Distant 3 Rad-Surg l/3 itive pelvic and/or paraaortic nodes, and 25% survived Rad-Surg DOD Distant 3 l/3 DOD Pelvic/distant 3 Rad-Surg 5 years. The percentage of patients in Berman’s series l/3 DOD Pelvic/distant 2 Surg l/3 with malignant nodal involvement may be artificially elAWD Distant 3 Surg l/3 evated because lymph nodes were evaluated more fre3 N.E.’ Rad DOD Pelvic quently in patients with clinically suspicious nodes. Also, Rad DOD Pelvic/distant Unknown N.E. deep myometrial invasion (penetration >33% of uterine Rad DOD Distant 3 N.E. DOD Pelvic Unknown N.E. Rad wall) was seen in 80% of patients and was associated Pelvic 2 N.E. Rad DOD with a 58% 5-year survival [4]. DOD Distant 1 N.E. Rad Five-year survival in our eight patients treated by radical Pelvic/distant Unknown N.E. Rad DOD hysterectomy and lymph node dissection was 68.6%. In 1 N.E. Rad DOD Distant our patient population, 50% had grade 3 tumors and 62% DOD Distant 3 N.E. Rad had deep myometrial invasion. Of note was the fact that a Rad-Surg, combination radiation and surgery; Surg, surgery only; despite extensive node sampling, none of our patients Rad, radiation only. had positive pelvic or paraaortic nodes, which certainly b DOD, dead of disease; AWD, alive with disease. contributed to the overall survival in this group. With ’ Not examined. an expected frequency of 20-30% positive nodes in stage II patients, in our group of eight we should have seen only-group had a higher number of only local recurrences two patients with positive nodes. The fact that we did (19.0%). not can easily be explained statistically. Bruckman et al. feel that combined surgery and radiation DISCUSSION provide optimal treatment for stage II endometrial carWhile the optimal treatment of stage II endometrial cinoma [lo]. They reported a 5-year actuarial survival carcinoma has not been established, many have reported of 80% in 40 patients, 23 treated by preoperative extemala higher failure rate in patients treated with radiation beam 40-Gy whole-pelvis and intracavitary therapy with therapy alone. Bickenbach et al. reported a 5-year survival Fletcher-Suite applicator at a dose of 4000 mg/hr. This of 49% in 31 patients treated with radiation only [9]. No was followed by a total abdominal hysterectomy and details of radiation dose or method of administration bilateral salpingo-oophorectomy. The remaining patients were given. Of reports in which details of radiotherapy received varying combinations of pre- and postoperative could be obtained, Madoc-Jones reported a 5-year survival radiation therapy and total abdominal hysterectomy with of 58% in 20 patients treated with 40-50 Gy whole-pelvis bilateral salpingo-oophorectomy. Kinsella et al. [1 11 and external therapy and 3500-4500 mg/hr by brachytherapy Berman et al. [4] reported 5-year survival rates of 75 [13]. Surwit et al. reported a 3-year survival of 29% in and 58.5%, respectively, in a total of 96 patients treated 34 patients treated similarly [7]. Kottmeier treated 105 similarly, which are better than the 46% 5-year survival patients with external therapy (55 Gy) and intracavitary observed in the 13 HUP patients. However, 61% of the Heyman packing and reported a 53.3% 5-year survival HUP series had grade 3 tumors, which may have con[8]. In this group, 39% had grade 3 tumors. In our report, tributed to the lower survival compared to the only 34% 45% of the radiation-only group had grade 2 to 3 tumors. with grade 3 tumors in the Kinsella et al. report. It is difficult to compare patient survival among several In our patients, five had recurrences only outside the reports as selection criteria for patients to receive only surgical or radiation fields while one failed with both radiation differ. Our 5-year survival of 36.5% is within distant and pelvic disease. Surwit et al. reported distant the range of other reports (29-77%) [4,7-10,141. and/or combined pelvic and distant metastases in 13% Radical surgery with node dissection was shown by of his patients treated with combination therapy and 12% Homesley et al. to provide a 78% 5-year survival in 26 with only pelvic recurrence, a phenomenon that we did patients [3]. In his group of patients, 19% had malignant not encounter [7]. involvement of pelvic or paraaortic nodes of which there There was no definite influence of the type of cervical were only two 5-year survivors. Approximately 50% of involvement on survival in our patients. While Homesley their patients with positive nodes had grade 3 tumors. saw a trend toward better survival in patients with miTABLE 5 Characteristicsof 16 Patientswith Recurrence

208

BOOTHBY

croscopic versus gross cervical involvement (61% vs 48%) the difference did not reach statistical significance [3]. Also, in a study involving 58 patients who received combination radiation and surgery, Larson et al. were unable to show any difference in survival rates among patients with microscopic or gross cervical involvement (65% vs 70%) [151. Conflicting reports exist, however. Berman et al. [4] and Kinsella et al. [ 111 have reported significant differences (74% vs 31% and 95% vs 56%, respectively) in a total of 152 patients, both with P values less than 0.001. Morbidity occurred in all patient groups. In our combination therapy group, there was a 23% incidence of major complications including vaginal vault necrosis and small bowel obstruction requiring surgical correction. Others have reported major complication rates in patients treated by combination radiation and surgery of 5 to 14.6% [12,13,18]. These complications include rectovaginal fistulas, rectal stenosis, and small bowel obstruction. In those patients treated with radical hysterectomy we observed mobridity mainly as a result of ureteral injury. Others have reported morbidity rates up to 25% with radical hysterectomy and operative mortality from 0 to 7% [16]. Nahhas et al. reported no significant complications in 16 patients treated by external pelvic radiation followed by radical hysterectomy [17]. In our radiation only group, we saw a major complication rate of 19%; rectovaginal fistulas and vaginal vault necrosis were the most common complications. In our study there was no significant difference in survival among patients treated by radiation alone, radical hysterectomy and lymphadenectomy, or combination radiation and surgery. Homesley et al. also was unable to prove one particular method superior in comparing 84 patients treated with surgery alone, radiation alone, or combination radiation and surgery [3]. Also, when Berman et al. compared 97 patients treated by either surgery alone or combination radiation and surgery, they found no statistical difference in survival between the two groups [4]. Others, however, have reported a difference between radiation alone and combination radiation and surgery. Madoc-Jones reported that the S-year survival in patients treated with radiation alone was 58% compared to 90% in patients treated by combined-modality therapy (P = 0.01) [ 131. Bickenbach et al. reported differences in survival between surgery (70%) and radiation alone (49%), but also stated that some of the “surgery-only” patients received postoperative radiation [9]. The majority of patients with stage II endometrial cancer appear to be well treated by combination radiation and surgery. However, a certain subset of patients with stage II endometrial carcinoma (grade 1 to 2, microscopic cervical involvement, and negative nodes) may be candidates for radical hvsterectomv and lvmnhadenectomy. In par-

ET AL.

titular, younger patients in good medical health without extensive cervical involvement may be suitable. REFERENCES 1. Silverberg, E., and Lubera, J. Cancer statistics, 1986, CA 36, 925 (1986). 2. Report presented by the Cancer Committee to the General Assembly of FIGO. Classification and staging of malignant tumor in the female pelvis, Znt. J. Gynecol. Obstet. 9, 172-179 (1971). 3. Homesley, H. D., Boronow, R. C., and Lewis, J. L. Stage II endometrial carcinoma-Memorial Hospital for Cancer, 1949-1965, Obstet. Gynecol. 49, 604-608 (1977). 4. Berman, M. L., Muhammed, A. A., Kanbor, A. I., and Ball, H. G. Risk factors and prognosis in stage II endometrial cancer, Gynecol. Oncol. 14, 49-61 (1982). 5. Berman, M. L., Bullon, S. C., Lagasse, L. D., and Watering, W. G. Prognosis and treatment of endometrial cancer, Amer. J. Obstet. Gynecol. 136(5), 679-688 (1980). 6. Morrow, C. P., DiSaia, P. J., and Townsend, D. E. Current management of endometrial carcinoma, Obstet. Gynecol. 42, 399-406 (1973). 7. Surwit, E. A., Fowler, W. C., Rogoff, E. E., Jelovsek, F., Parker, R. T., and Creasman, W. T. Stage II carcinoma of the endometrium, Znt. J. Radiat. Oncol. Biol. Phys. 5, 323-327 (1979). 8. Kottmeier, H. L. Corpus et colli. What is the disease? What is the treatment? Clin. Obstet. Gynecol. 16, 276-285 (1973). 9. Bickenbach, H., Lochmuller, G., Dirhch, G., Ruland, G., and Thurmayer, R. Factor analysis of endometrial carcinoma in relation to treatment, Obstet. Gynecol. 29, 632-636 (1967). 10. Bruckman, J. E., Goodman, R. L., Murthy, A., and Marck, A. Combined irradiation and surgery in the treatment of stage II carcinoma of the endometrium, Cancer 42, 1146-l 151 (1978). 11. Kinsella, T. J., Bloomer, W. D., Lavin, P. T., and Knapp, R. C. Stage II endometrial carcinoma: IO-Year follow-up of combined radiation and surgical treatment, Gynecol. Oncol. 10, 290-297 (1980). 12. DePalo, G., Kenda, R., Andreola, S., Bandieramonte, G., Luciani, L., and Stefawon, B. A retrospective analysis of 53 patients with pathologic stage II and III endometrial carcinoma, Tumori 68,341347 (1982). 13. Madoc-Jones, H. Adenocarcinoma of the endometrium, stage II: Problems in definition and management, Znt. J. Radiat. Oncol. Biol. Phys. 6, 887-890 (1980). 14. Landgren, R. C., Fletcher, G. H., Delclos, L., and Wharton, J. T. Irradiation of endometrial cancer in patients with medical contraindication to surgery or with unresectable lesions, Amer. J. Roentgenol. 126, 148-154 (1976). 15. Larson, D. M., Copeland, L. J., Gallager, H. S., Gershenson, D. M., Freedman, R. S., Wharton, J. T., and Kline, R. C. Nature of cervical involvement in endometrial carcinoma, Cancer 59, 959%2 (1987). 16. Jones, H. W. Treatment of adenocarcinoma of the endometrium, Obstet. Gynecol. Surv. 30, 147-169 (1975). 17. Nahhas, W. A., Whitney, C. W., Stryker, J. A., Curry, S. L., Chung, C. K., and Mortel, R. Stage II endometrial carcinoma, Gynecol. Oncol. 10, 303-311 (1980). 18. Onsrod, M., Aalders, J., Abeler, V., and Taylor, P. Endometrial carcinoma with cervical involvement (stage II): Prognostic factors and value of combined radiological-surgical treatment, Gynecol. Oncol. 13, 76-86 (1982).