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0 Original Contribution

HYSTERECTOMY AND ADJUVANT IRRADIATION FOR PATHOLOGIC STAGE III ADENOCARCINOMA OF THE ENDOMETRIUM

STEVEN STOKES, M.D.,’ JOHN BEDWINEK, M.D.,* CARLOS A. PEREZ, M.D.,3 H. MARVIN CAMEL, M.D.4 AND MING-SHIAN KAO, M.D.4

‘Jackson Hospital Radiation Center, Montgomery, AL; 2Department of Radiation Oncology, East Tennessee Baptist Hospital, Knoxville. TN; 3Division of Radiation Oncology, Mallinckrodt Institute of Radiology, 4Department of Obstetrics and Gynecology,

Washington University School of Medicine, St. Louis, MO

Three hundred and four evaluable patients with FIG0 clinical Stage I adenocarcinoma of the endometrium were treated with hysterectomy and adjuvant irradiation. At surgery, 15 patients (5%) were found to have disease outside the uterus, but within the pelvis Pathologic Stage III (PSIII). A higher grade of tumor was not associated with an increase in the frequency of PSIII, being 7/158 (4%), 5/89 (6%), and 3/57 (5%) for Grades 1, 2, and 3 respectively. Depth of myometrial invasion correlated with PSI11 disease in 5/69 (7%) for less than l/3 myometrial invasion versus 7/33 (21%) for greater than l/3 invasion (p = .05). One patient died of intercurrent disease at 4 months with 6/14 (43%) of the remaining patients developing recurrent disease. The site of initial failure was pelvis l/15 (7%), pelvis and distant metastasis 3/15 (20%), and distant metastasis alone 2/15 (13%). Of seven patients who received external pelvic irradiation, there was one local failure (14%), which is not statistically significant from the 3/8 (38%) local failure rate among patients not receiving external pelvic irradiation (p = .569). None of the seven patients experienced a treatment related complication as a result of adjuvant irradiation.

Endometrial Ca, Pathologic Stage III; Sites of failure; Survival.

INTRODUCTION

Classification and staging of adenocarcinoma of the uterus, according to the definition of the International Federation of Gynecology and Obstetrics (FIGO), is based on clinical examination. In patients with clinical Stage I disease, 2 to 13%1,2,4,5,6,8 are found, at surgery, to have extrauterine extension confined to the pelvis (pathologic Stage III). This retrospective study attempts to clarify fac- tors associated with extrauterine disease, survival in the presence of extrauterine extension, sites of failure, and possible efficacy of external pelvic irradiation.

METHODS AND MATERIALS

Patient material We reviewed the charts of all patients with FIG0 clin-

ical Stage I adenocarcinoma of the endometrium treated with surgery and adjuvant irradiation at Washington University School of Medicine between January 1964 and December 1978. Three hundred thirty-one patients were identified; of these, 26 had a second primary malignancy (prior to, simultaneous with, or subsequent to therapy) and were excluded. One patient was lost to follow-up.

The remaining 304 patients have a minimum, maximum, and median follow-up of 3, 14, and 6.4 years, respectively. One hundred fifty-eight (52%) had well-differentiated tu- mors, 89 (29%) had moderately differentiated tumors, and 5 7 ( 19%) had poorly differentiated tumors. Fifteen patients were found to have extrauterine disease confined to the pelvis at the time of surgery (pathologic Stage III) and constitute the basis of this study.

Treatment methods All patients in this study were treated with surgery and

adjuvant irradiation. The surgery consisted of an extra- fascial total abdominal hysterectomy and bilateral sal- pingo-oophorectomy. The type of adjuvant irradiation varied considerably during the period of study, depending on the treatment philosophies of individual physicians. In most cases, it was given preoperatively, but many pa- tients received postoperative irradiation instead. The ra- diation, whether pre- or postoperative, usually consisted of an intracavitary insertion, with some patients receiving additional external pelvic irradiation, eight patients re- ceived external pelvic irradiation alone. Table 1 lists the various types of adjuvant irradiation administered. The

Reprint requests to: Carlos A. Perez, M.D., Division of Ra- diation Oncology, 45 11 Forest Park Blvd., St. Louis, MO 63 108.

Accepted for publication 30 October 1985.

335

336 1. J. Radiation Oncology 0 Biology 0 Physics

Table 1. Adjuvant irradiation Depth mvometrial invasion

Irradiation

Pre-op Implant Implant + external External

No. patients

199 43

8

250

Post-op Implant Implant + External

26 18

44

Pre-op implant + post-op external 10

Patients available for evaluation 304

In a separate report” we determined that delaying the hysterectomy 4 to 6 weeks following adjuvant irradiation results in a substantial reduction in the patients with deep myometrial invasion. In patients having delayed hyster- ectomies, the depth of myometrial invasion was no longer a valid prognostic factor. Therefore, we concluded that only in 102 patients undergoing an initial hysterectomy without prior irradiation or a hysterectomy immediately following an implant, could depth of myometrial invasion be adequately evaluated. The patients with deep myo- metrial involvement (defined as greater than l/3 myo- metrial invasion) have a higher incidence of PSI11 disease 7/33 (21%) versus 5/69 (7%) p = .05 (Table 3).

specific doses and details of irradiation are described in an associated report.’

In Table 2, the patients are listed by grade of tumor, adjuvant irradiation, site of extrauterine disease, site of initial failure, and current status.

RESULTS

Grade There was no association of increasing grade of tumor

with PSI11 disease, being 4% (7/158), 6% (5/89). and 5% (3/57) for grades 1, 2, and 3, respectively.

March 1986, Volume 12, Number 3

Site of’extrauterine involvement and initial recurrence Table 4 lists the sites of extrauterine disease and initial

recurrence of the patients by grade. The fallopian tubes and ovaries were the most frequent sites of extrauterine disease, occurring in 12 of 15 patients. Three patients had parametrial extension of whom two had microscopic dis- ease identified in the hysterectomy specimen. Patient #5 had extensive pelvic disease extending to the side wall, which was incompletely excised, and in addition, random biopsies of her periaortic nodes were positive for metas- tasis. As periaortic node biopsies were infrequently per- formed, we felt it appropriate to include this patient in the current evaluation.

Six of 15 patients experienced recurrent disease (Table 4). For the sake of simplicity, distal vagina is considered

Table 2. Clinical data on patient with surgical Stage III carcinoma of the endometrium

Patient Tumor No. grade

Adjuvant XRT

Implant External

Site of extrauterine

disease Site of initial failure Status

I 2 3

4 5

6 7

8 9

10 11

12

13

14 15

1 Pre-op Ovary NED@72 mos. 1 Pre-op Post-op Ovary NED@48 mos. I Post-op Ovary Lung, bone, distal

vagina DOD@26 mos. I Pre-op Post-op Tube NED@48 mos. 1 Pre-op Parametria Pelvis, abdominal DOD@22 mos.

Ovary carcinomatosis Periaortic node

1 Post-op Post-op Ovary NED@84 mos. 1 Post-op Ovary NED@96 mos.

2 Pre-op Post-op Tube Died ICD@4 mos. 2 Pre-op Post-op Parametria NED@60 mos. 2 Pre-op Ovary NED@60 mos. 2 Pre-op Ovary Liver, mesenteric AWD@39 mos. post recurrence

nodes 2 Pre-op Post-op Ovary Lung AWD@66 mos. post recurrence

3 Pre-op Post-op Parametria Distal vagina DOD@ 1 Smos. Endocervix

3 Pre-op Ovary NED@65 mos. 3 Pre-op Ovary Pelvis inguinal nodes DOD@2 1 mos.

NED = No evidence of disease; DOD = Died of disease; AWD = Alive with disease; ICD = Intercurrent disease.

PSI11 adenocarcinoma of endometrium 0 S. STOKES et al. 331

Table 3. Incidence of PSI11 disease by grade according to depth of myometrial invasion

Grade Myometrial invasion

<l/3 >1/3

: 2147 4119 2116 l/l 1

3 l/6 213

5/69* (7%) 7/33* (21%)

Two-tailed Fisher’s Exact Test, p* = .05.

a pelvic failure. The sites of initial failure were pelvis alone 7%, simultaneous pelvis and distal 20%, and distal me- tastases alone, 13%. One patient who initially had a distal vaginal failure alone, subsequently developed distal me- tastases 6 months later. Therefore, all patients who re- curred ultimately had a component of distant metastasis.

Of seven patients receiving external pelvic irradia- tion, one patient ( 14%) developed a distal vaginal recur- rence. This patient experienced an additional recurrence in the hysterectomy incision site and inguinal nodes. Of eight patients not receiving external pelvic irradiation, three (38%) developed a pelvic recurrence, one of which was located in the distal vagina. This difference was not statistically significantly (p = S69).

Survival The disease free survival (NED) for PSI11 patients is

substantially less than that of PSI patients (Fig. 1). How- ever, as noted in Table 2, there were two patients with G- 2 tumors who had prolonged survival following the ap- pearance of distant metastases. Patient # 11 developed bi- opsy proven hepatic and mesenteric metastases 65 months following therapy. She remains alive with disease, 39 months after commencing Megace and combination che- motherapy. Patient # 12 developed multiple pulmonary nodules consistent with metastases 60 months following therapy. The patient’s pulmonary lesions disappeared after commencing Megace and she remains disease free at 66 months. The remaining 4 patients died of their recurrent disease.

NED Survival by Surgical Stage

100

- Pathologic Stage I (289 patients) o-o Pathologic Stage III (15 patients)

I I I I I I I 1 2 4 6 8

YEARS Fig. 1. NED survival of patients with carcinoma of the endo- metrium PSI and PSIII.

DISCUSSION

The overall incidence of subclinical extrauterine pelvic extension in FIG0 Stage I is unusual, varying from 2 to 1 3%.‘,2,4,5*6,8 This report also confirms the efficacy of the FIG0 system in detecting extrauterine disease as only 5% of clinically staged patients in this series were found to have pelvic extension at hysterectomy.

Aalders et al.’ previously noted that grade of tumor and depth of myometrial invasion were of prognostic sig- nificance in the survival of PSI11 patients. However, this report failed to determine the association of these factors with extrauterine extension. In the current series, there was no association of increasing grade with greater inci- dence of PSI11 disease. However, deep myometrial inva-

Table 4. Site of extrauterine involvement and subsequent initial recurrence

Grade

Site of involvement

Tube/ovary Parametria Pelvis

Site of initial recurrence

Pelvis + distal Distal

: 6 4 1* 1 - - 3 2 1t l$

Total 12/15 (80%) 3/15 (20%) l/15 (7%)

* Patient had extensive pelvic disease incompletely resected. t Patient had microscopic disease involving both parametria and endocervix. $ Patient initially failed in distal vagina, subsequent distal metastases.

- 2 - 2 1 -

3/ 15 (20%) 2/15 (13%)

338 1. J. Radiation Oncology 0 Biology 0 Physics March 1986, Volume 12, Number 3

sion did correlate with extrauterine extension: 2 1% of the patients with deep myometrial invasion had PSI11 disease, which was significantly higher than the 7% encountered among patients with less extensive myometrial invasion (a = .05).

as compared to those who did not (38%) this difference was not significant.

As this was a retrospective review covering 14 years, a certain degree of patient selection by the referring phy- sicians was possible. During the latter part of the study, there was a trend toward patients with G-l tumors un- dergoing an initial hysterectomy. Only in the event of poor prognostic factors such as deep myometrial invasion or extrauterine disease were the patients referred for post- operative irradiation. This practice would tend to over- estimate the true incidence of PSI11 disease among patients with G-l tumors.

Distant metastasis occurred in 40% (6/15) of the pa- tients. This compares favorably with the 23 to 56% rates reported by Danoff et aL3 and Aalders et al. ’ The potential for distant metastases accounts for the poor (35-72%) dis- ease-free survival noted among these patients.‘,2V3 In the event of recurrent disease, progestational agents are of efficacy.7 Two of three patients who received progesta- tional agents are alive 39 and 66 months respectively, following the appearance of distant metastases.

The value of external irradiation in reducing pelvic re- currences is difficult to ascertain. Previous series, in which all patients received external beam irradiation, report a local failure rate of zero3 to 39’70.’ In the current series. all patients received an intracavitary insertion with ap- proximately half also undergoing external pelvic irradia- tion. Although patients receiving this additional external irradiation had a reduction in the local failure rate ( 14%)

In conclusion, the current analysis of patients with FIG0 Stage I, pathological Stage III endometrial adeno- carcinoma demonstrates a significant reduction in survival as compared to pathologic Stage I patients. Deep myo- metrial invasion was associated with an increased inci- dence of extrauterine disease while grade of tumor was not. Distant metastases remain a significant problem in this population, occurring in 40% of patients. In the event of recurrence, patients may experience prolonged remis- sion of their disease with progestational agents; however, a significant improvement in survival awaits the devel- opment of more successful systemic therapy.

REFERENCES

I. Aalders, J.G., Abeler, V., Kostad, P.: Clinical (Stage III) as compared to subclinical intrapelvic extrauterine tumor spread in endometrial carcinoma: a clinical and histopath- ological study of 175 patients. Gvn. Oncol. 17: 64-74, 1984.

2. Bergsjo, P., Nilsen, P.A.: Carcinoma of the endometrium. Am. J. Obstet. Gynecol. 95: 496-507, 1966.

3. Danoff, B.F., McDay, J., Louka, M., Lewis, G.C., Lee, J.. Kramer, S.: Stage III endometrial carcinoma: analysis of patterns of failure and therapeutic implications. Int. J. Ra- diat. Oncol. Biol. Phys. 6: 1491-1495, 1980.

4. Frick, H.C., Munnell, E.W., Richart, R.M., Berger, A.P., Lawry, M.F.: Carcinoma of the endometrium. Am. J. Obstet. Gynecol. 115: 663-672, 1973.

5. Keller, D., Kempson, R.L., Levine, G., McLennan, C.: Management of the patient with early endometrial carci- noma. Cancer 33: 1108- 1116, 1974.

6. Macasaet, M., Brigati, D., Boyce, J., Nicastri, A., Waxman. M., Nelson, J., Fruchter, R.: The significance of residual

disease after radiotherapy in endometrial carcinoma: Clin- icopathologic correlation. Am. J. O&et. Gynecol. 138: 557- 563. 1980.

7. Rozier, J.C., Underwood, P.B.: Use of progestational agents in endometrial adenocarcinoma. Obstet. Gynecol. 44: 60- 64, 1974.

8. Shah, G.A.. Gocen, T.H.: Evaluation of current manage- ment of endometrial carcinoma. Obstet. Gynceol. 39: 500- 508, 1972.

9. Stokes, S., Bedwinek, J., Breaux, S., Kao, M.S., Camel, M., Perez, C.A.: Treatment of Stage I adenocarcinoma of the endometrium by hysterectomy and irradiation: Analysis of complications. Obstet. Gynecol. 65: 86-92, 1985.

10. Stokes, S., Bedwinek. J., Fineberg, B., Kao, M.S., Camel, M., Perez, C.A.: Treatment of stage I adenocarcinoma of the endometrium by hysterectomy and irradiation: Prog- nostic factors and sites of failure. Int. J. Radiat. Oncol. Biol. Phys. (In press).