treatment of stage i adenocarcinoma of the endometriuim by hysterectomy and adjuvant irradiation: a...

la. J. Radrarion Oncology Biol Phys Vol. 12. PP. 339-344 Printed in the U.S.A. All rights reserved.

0360-3016/86 $3.00 + .OO Copyright 0 1986 Pergamon Press Ltd.

??Original Contribution

TREATMENT OF STAGE I ADENOCARCINOMA OF THE ENDOMETRIUM BY HYSTERECTOMY AND ADJUVANT IRRADIATION:

A RETROSPECTIVE ANALYSIS OF 304 PATIENTS

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

Washington University School of Medicine, St. Louis, MO

Three hundred and four evaluahle patients with FIG0 Stage I adenocarcinoma of the endometrium were treated with hysterectomy and irradiation. Irradiation was preoperative in 250 and postoperative in 44 patients. Ten patients had a preoperative implant and postoperative external irradiation. The 5 year actuarial survival was 94%, 80% and 76% for grades 1, 2 and 3, respectively. Within each grade and for all patients there was no difference in survival for Stage IA versus IB. The initial failure rate was 26/304 (9%) with 2% of patients having only a pelvic failure, 2% pelvic and distal failure and 4% a distal failure only. There were four distal vaginal failures and no isolated cuff recurrences. The upper abdomen was the most frequent site of extra-pelvic failure for grade 3, while the periaortic nodes and lung constituted the most common sites of distal failure for grades 1 and 2 tumors. Timing of the hysterectomy following the irradiation was of importance when evaluating the prognostic significance of residual disease or depth of myometrial invasion. The presence of residual disease or greater than l/3 myometrial invasion had a significantly worse prognosis only among patients who received no preoperative irradiation or who underwent their hysterectomy immediately following a preoperative implant. There was no difference in survival among patients with an initial local failure only as compared to those with an initial distal metastases, as the majority of patients with an initial local failure subsequently developed distant metastases.

Endometrial cancer, Prognostic factors, Sites of failure, Survival following recurrence.

INTRODUCTION

The management of endometrial carcinoma has tradi- tionally involved a combination of surgery and irradiation. Although the value of adjuvant irradiation has not been conclusively proven in randomized prospective trials, it has been widely used in the past,3*24,30 and continues to be popular primarily for high-grade tumors. This report retrospectively analyzes prognostic factors, survival and sites of failure in a group of 304 patients treated over a 14-year period with a combination of surgery and irradiation.

METHODS AND MATERIALS

Patient material We reviewed the charts of all patients with FIG0 Stage

I adenocarcinoma of the endometrium treated with surgery and adjuvant irradiation at Washington University

School of Medicine between January 1964 and December 1978. Of 33 1 patients identified, 26 of these 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 constitute the basis of this study and have a minimum, maximum, and median followup of 3, 14, and 6.4 years, respectively. Fifteen patients (5%) were found to have extrauterine disease confined to the pelvis (pathologic Stage III) at the time of hysterectomy. These patients are included in this material and are the subject of a separate more detailed analysis.*’ A total of 158 patients (52%) had well-differentiated, 89 (29%) moderately-differentiated, and 57 (19%) poorly differentiated tumors.

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

adjuvant irradiation. The operation consisted of an ex-

* Division of Radiation Oncology, Mallinckrodt Institute of Radiology.

t Division of Gynecologic Oncology, Department of Obstet- rics and Gynecology.

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

339

Acknowledgements-The authors acknowledge the valuable contribution of Barbara Fineberg and Sherry Breaux in the col- lection and analysis of data, Alice Becker in the preparation of the manuscript and Leslie MacConnell-Clubbs for art work.

340 I. J. Radiation Oncology 0 Biology 0 Physics March 1986. Volume 12. Number 3

trafascial total abdominal hysterectomy and bilateral sal- pingo-oophorectomy. The type of adjuvant radiation var- ied considerably during the period of study depending on the treatment philosophies of individual physicians. In most cases, it was given preoperatively, but a number of patients received postoperative irradiation instead. The irradiation, whether pre- or postoperative, usually consisted of an intracavitary insertion along or in combination with external pelvic irradiation; in eight patients it was external pelvic irradiation alone. Table 1 lists the various types of adjuvant irradiation administered.

Until 1976, when the adjuvant irradiation consisted of a preoperative insertion only, the hysterectomy was usually performed 4 to 6 weeks following the implant. In the last 2 years of the study, some patients had the hysterectomy 2 to 3 days following the implant. Postoperative external irradiation was added in these “immediate hysterectomy” cases if deep myometrial invasion was found in the operative specimen; there were 10 such cases (Table 1). When the adjuvant irradiation consisted of both a preoperative implant and preoperative external irradiation, the operation was always performed 4 to 6 weeks following completion of the external pelvic irradiation.

The preoperative insertion was accomplished by packing the uterus with a tandem and Heyman capsules (Si- mon-Heyman afterloading capsules were used after 1976) along with colpostats in the vaginal fornices (usually Fletcher-Suit afterloading colpostats). The uterine cavity received an average of 3 100 milligram-hours (mgh) from the Heyman capsules and tandem, and the vaginal apex received an additional average of 1900 mgh from the colpostats. The dose in rad to the mucosa ofthe vaginal apex from the colpostats was calculated using the technique described by Sharma et ~l.,~~ with most patients receiving about 6000 cGy.

When the implant was given postoperatively, it consisted of colpostats placed in the vaginal cuff and held in place by packing. The dose delivered with postoperative vaginal vault insertions averaged 2500 mgh (mucosal dose of approximately 7000 cGy).

Table I. Adjuvant irradiation

Irradiation No.

Patients

Preoperative Intracavitary Intracavitary + External External

Postoperative Intracavitary Intracavitary + External

Preoperative implant + postoperative external RT

Patients available for evaluation

199

43 8

250

26 18 44

10

304

External pelvic irradiation, when given, was delivered through 15 X 15 cm anterior and posterior opposing fields using 22 MV photons from a Betatron or 25 MV photons from a 35 MeV linear accelerator. These fields encom- passed the entire true pelvis (so called “whole pelvis” technique) for a dose ranging from 2000-4000 cGy. A few of these patients, however, received only 2000-3000 cGy with whole pelvis technique and an additional 2000- 3000 cGy to the pelvic sidewalls and parametrial tissues with a “split field” technique (5 half value layer midline block) to shield out the central volume treated with the intracavitary implant. Daily fraction size was usually 180 cGy. Twelve patients (4%) experienced a serious compli- cation as a result of their adjuvant irradiation. A detailed analysis of treatment technique associated with complications is the subject of a separate report.26

Patients who developed recurrent disease were treated by a variety of local and systemic modalities depending upon the clinical situation. In general, patients with an isolated recurrence received curative doses of external beam irradiation alone or in combination with intracavitary therapy. In addition, most patients received systemic progestational agents alone with a few patients receiving chemotherapy. Patients who presented with extensive generalized disease and poor performance status tended to receive supportive care only.

RESULTS

Survivul by grade Figure 1 shows the disease free survival (NED) for the

304 evaluable patients. The 5-year NED survival for grades 1, 2 and 3 is 93%, 90% and 84%, respectively. Pa- tients with poorly differentiated tumors have a significantly worse survival than grade 1, while patients with grade 2 tumors have an intermediate NED survival.

Survival by size of uterine cavity (IA vs II?) There was no significant difference in the NED survival

according to the size of the uterine cavity for all patients. Figure 2 shows that there is no difference in survival for Stages IA and IB for the various grades of tumor differentiation.

Survival as a $mtion of residual disease There was no difference in survival among the patients

with or without residual tumor within the hysterectomy specimen. Figure 3 shows the NED survival of patients who did not receive preoperative irradiation or who underwent a hysterectomy 2 to 3 days following an implant. Among these patients one would not expect the status of tumor within the uterus to have been distorted by the irradiation as may have occurred in patients undergoing a delayed hysterectomy. Unlike the patients receiving a delayed hysterectomy, the presence of residual tumor in the uterus did adversely affect the NED survival among this group of patients.

Hysterectomy and irradiation for Stage I adenocarcinoma of the endometrium 0 S. STOKES ef a/. 341

NED Survival by Grade

G-l (n=l58)

L G-2 (n=89)

G-3 (n=57)

I I I I 2 3 4 5

YEARS

Error Bars: 90% Confidence Limits

Fig. 1. Disease-free survival for 304 patients with adenocarcinoma of the endometrium treated at the Mallinckrodt Institute of Radiology between 1964 and 1978.

Survival as a function of myometrial invasion For patients treated with an immediate hysterectomy

following a preoperative implant or who received postoperative irradiation, greater than l/3 myometrial invasion was noted in 29%, 41% and 33% for grades 1,2, and 3, respectively. However, for patients undergoing hysterectomy 4 to 6 weeks after irradiation myometrial invasion greater than l/3 was noted in I%, 5%, and 6% for grades 1, 2, and 3, respectively.

There was no difference in survival for patients with greater than l/3 myometrial invasion as compared to those with no tumor within the specimen, tumor but no invasion, or invasion less than l/3 of the myometrial thickness.

However, among patients who did not receive preoperative irradiation or who underwent a hysterectomy 2 to 3 days following a preoperative implant, greater than l/ 3 myometrial invasion was associated with a significantly reduced NED survival (Figure 4).

Irradiation 4 to 6 weeks prior to the hysterectomy results in substantial distortion of the tumor status within the uterus. In this instance the presence of residual disease and depth of myometrial invasion are no longer valid prognostic factors.

Sites offailure Table 2 shows the sites of tumor recurrence by grade

of tumor differentiation. There were four distal vaginal failures, which are included as pelvic (local) failures. The

overall failure rate for all grades was pelvic-2%, simultaneous pelvis and distant metastasis-2% and distant metastases-4%. There was a significant trend of increasing failure rate with higher tumor grade (Chi Square = .004).

As seen in Table 3 patients with grade 3 tumors have a significantly greater risk of a pelvic failure than patients with grades 1 or 2 (p = .05). In addition there is a significantly increasing trend of distal failure alone with or without a component of pelvic failure with higher histologic grade (Chi Square = .02).

Table 4 shows the sites of initial distal failure by grade. The most frequent site of initial distal failure varies according to grade of the tumor: for grade 1 tumors distal failure is infrequent 5/l 58 (3%) but when present most frequently involves the periaortic nodes. For patients with grade 2 tumors distal failure generally occurred in the lung (5/7). However, patients with grade 3 tumors relapsed most frequently in the upper abdomen (5/7).

In view of the small number of patients with grade 1 and 2 tumors who experienced a recurrence, a correlation of failure rate with irradiation technique was limited to patients with grade 3 tumor only. This analysis is the subject of a separate report4

NED Survival by Grade and Stage

0 I-A (n=94) G-l A I-B (n=52)

.80

.70

I G-2 ??I-A (n=60)

1.0 A I-B (n=29)

.90 -

.80 -

.70 1

I G-3 ??I-A (n=24)

A I-B (n=31) -5

I. II)

.70 -

I I I I 1 2 3 4 5

YEARS Fig. 2. Survival for Stages IA and IB according to histological grade of tumor differentiation.

342 I. J. Radiation Oncology 0 Biology 0 Physics March 1986, Volume 12, Number 3

NED Survival by Depth of Myometrial Invasion (Quick or Post-op Radiotherapy)

_L 0.6

0.5

0.4

0.3

::I , ( , , ,

I 2 3 4 5 YEARS

??No tumor, no lnvaslon or lnvaslon <l/3 (69) A Invasion >I/3 (33)

Error Bars: 90% Confidence Limits

Fig. 3. NED survival correlated with depth of myometrial invasion in patients who did not receive preoperative irradiation or who underwent hysterectomy within 3 days of implant.

Survival following recurrence As previously noted, an isolated pelvic (local) recur-

rence (a potentially curable situation) was unusual, oc- curring in only 71304 (2%) of patients. With definitive salvage irradiation only one patient died of uncontrolled local tumor; however, five of the patients died at 4 to 13 months after developing distant metastases. Only one pa-

NED Survival, Residual vs. No Residual Disease (Quick or Post-op Radiotherapy)

I 0 No Reslduol (n=l7)

I T Residual (n=91)

OE- d 107-

h 106-- U-J

Q05- z +04- 6 go3-

fo2-

Ol-

I I I I I I 2 3 4 5

YEARS

Fig. 4. NED survival correlated with presence of residual tumor for patients who did not receive preoperative irradiation or who were treated with a hysterectomy within 3 days of preoperative implant.

Table 2. Site of initial failure by grade

Pelvis No. Pelvis + distant Distant Total*

Grade oatients (%l (%) (%) (%)

I 158 2 (1) 4 (3) l(l) 7 (4) 2 89 2 (2) l(l) 6 (7) 9 (10) 3 57 3 (5) 2 (4) 5 (9) 10 (18)

Total 304 7 (2) 7 (2) 12 (4) 26 (9)

* Chi Square = .004.

tient with a distal vaginal recurrence is alive and disease- free at 10 years; she experienced a rectovaginal fistula following salvage irradiation.

Nineteen patients (6%) had a distal failure with or without a simultaneous pelvic failure. Only three of these patients ( 16%) had a survival in excess of five years with the remainder dying of their distant metastases. Figure 5 demonstrates there is no significant difference in survival amont patients experiencing an initial local failure alone as compared to patients having distant metastases with or without a local failure.

The survival of patients following a recurrence appears to be more dependent upon the grade of tumor than site of recurrence. No patient with a grade 3 tumor who re- curred survived longer than 2 years. However, 29% and 20% of patients with grade 1 and 2 tumors respectively, have had prolonged survival following recurrence treated with local irradiation and systemic progestational agents.

DISCUSSION

Although there is no consensus as to the best treatment of endometrial adenocarcinoma,‘* adjuvant irradiation continues to be widely used3~24~30 especially to prevent pelvic and vaginal cuff recurrence.

Adjuvant vaginal irradiation has been shown to be of ‘benefit in reducing cuff recurrences.g,20 In addition, both randomized and retrospective studies demonstrate that the pelvic failure rate with surgery alone (8% to 27%) can be significantly reduced with adjuvant external irradiation (3-8%).2,‘7,23 In the current series all patients received surgery and adjuvant irradiation, in line with these prior reports, local failure was unusual: 14/304 (5%).

Table 3. Site of initial failure by grade (local vs distant)

Grade

1 2 3

No. patients

158 89 57

Pelvis Distant f distant + pelvis*

(%) (%)

6 (4) 5 (3) 3 (3) 7 (8) 5 (9) 7 (12)

P* - Two-tailed Fisher Exact (.05). * Chi Square = .02.

Hysterectomy and irradiation for Stage I adenocarcinoma of the endometrium 0 S. STOKES rt a/. 343

Table 4. Site of initial distal failure by grade

Grade Lung Upper abdomen Periaortic Mist Total

1 - - 3 2 5 2 4 2* - 1 7 3 2 5 - 7

Total 6/19 (32%) 7/19 (37%) 3/19 (16%) 3/19 (16%) 19

* One patient had simultaneous lung and upper abdominal failure. Mist: 2 bone metastases, 1 surgical incision.

However, in most series, this reduction in local failure rate has not resulted in an overall improvement in survival.‘7,23 Therefore, it is not surprising that recent reports recommend an initial hysterectomy with subsequent adjuvant pelvic or vaginal irradiation only in the event of poor prognostic factors.‘.’ “I3

Aalders et al., unlike Onsrud et al.” were able to demonstrate a survival benefit with external pelvic irradiation among patients with poorly differentiated tumors having deep myometrial invasion. Similarly, recent reports by Bedwinek et ~1.~ and Surwit et a1.28 have shown that a preoperative intracavitary insertion for anaplastic tumors is associated with a significant reduction of both pelvic and distant failures. Thus, we continue to recommend a preoperative intracavitary insertion for patients with moderately or poorly differentiated tumors. Postoperative external pelvic irradiation is reserved for those patients with deep myometrial invasion. For patients with well differentiated tumors adjuvant vaginal cuff brachytherapy and external pelvic irradiation are reserved for those with deep myometrial invasion.

Although FIG0 staging incorporates the depth of the uterine cavity, this parameter had no prognostic significance in the current series. The overall failure rate, or

Actuarial Survival Following Initial Recurrence

100

e--e Local Failure Only (7 patients) A--A Distal f Local Failure (19 patients)

ZSO

3 t\ \

01 ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ 0 12 24 36 46 60 72

TIME IN MONTHS

Fig. 5. Actuarial survival correlated with site of failure (local vs local and distal).

failure within each grade, was not significantly different for Stages IA and IB. This finding is consistent with other recent reports demonstrating that depth of the uterine cavity is of little prognostic significance especially when considered within each histologic grade.8”4,24129

In line with other studies we also noted a progressively worse NED survival among patients with more anaplastic tumors: 93%, 90%, and 84% for grades 1, 2, and 3, respectively.2,5.‘0.‘5

Depth of myometrial invasion has repeatedly been shown to be of prognostic significance.‘.8,‘4.‘6,29 However, previous reports 6,‘9.3’ have observed that the degree of myometrial invasion can be significantly distorted by preoperative irradiation. Wilson et ~1.~’ demonstrated that the proportion of patients with no residual tumor increases significantly as the interval from irradiation to surgery lengthens. Similarly, we noted that the incidence of deep myometrial invasion among patients who had received irradiation 4 to 6 weeks prior to surgery (l%, 5% and 6% for grades 1, 2, and 3, respectively) was substantially less than that for patients undergoing surgery prior to or immediately after irradiation (29%, 4 1% and 33% for grades 1,2, and 3, respectively). In examining survival as a function of myometrial invasion, greater than 4 invasion was associated with a significantly worse prognosis only among patients who received no preoperative irradiation or a hysterectomy 2 to 3 days following a preoperative implant. In those patients undergoing a preoperative intracavitary insertion, it is important that the hysterectomy be performed as soon as possible so the depth of myometrial invasion can be accurately determined.

In current series, for patients receiving adjuvant irradiation, vaginal recurrence was infrequent; there were no cuff failures and only 4/304 (1%) distal vaginal recurrences. Unlike Phillips et uI.,‘~ who reported a 44%, 5- year NED survival for patients following a lower vaginal recurrence, three out of the four patients in our series with vaginal recurrence subsequently died of distant metastasis. This is similar to the report by Price et ~1.~’ in which all four patients with middle or distal vaginal recurrences subsequently died of disease.

Of the seven patients with an initial local failure, only one died of uncontrolled local disease. However, since 5/ 7 subsequently developed distant metastasis, their survival was not substantially different from the 19 patients who presented initially with distal failures. Overall, 5/26 ( 19%)

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

of patients were alive 5 years following a recurrence, which for grades 1 and 2 as compared to 9% for grade 3. We compares favorably with the 20%-44% survival reported also noted that survival correlated with grade; 29% and by other authors.‘~‘8~20~2’~22 20% of grades 1 and 2 respectively were alive at 5 years

In a report by Aalders et al.’ survival following recur- while no patient with a grade 3 tumor survived in excess rence was a function of tumor grade with 20% survival of 2 years.

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treatment of stage i adenocarcinoma of the endometriuim by hysterectomy and adjuvant irradiation: a...

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