Utility and limitations of abdominal radiotherapy in the management of endometrial carcinomas

Gynecologic Oncology 96 (2005) 635 – 642 www.elsevier.com/locate/ygyno

Utility and limitations of abdominal radiotherapy in the management of endometrial carcinomas Kathryn E. Dusenberya,*, Roger A. Potisha,b, Douglas G. Golda, Matthew P. Boenteb a

Department of Therapeutic Radiology-Radiation Oncology, 420 Delaware St. SE, Mayo Mail Code 494, Minneapolis, MN 55455, USA b Department of Obstetrics and Gynecology, University of Minnesota, Minneapolis, MN 55455, USA Received 5 May 2004 Available online 28 January 2005

Abstract Objective. The present review analyzes long-term survival, recurrence sites, and toxicity in women with peritoneal spread of endometrial treated with abdominal radiotherapy, in order to provide therapeutic options as a function of disease spread and histology. Methods. Retrospective medical record review was performed of 86 patients receiving abdominal radiotherapy for endometrial carcinomas from 1975 to 1995 at the University of Minnesota. Results. FIGO stage distribution was 54 stage IIIA, 2 stage IIIB, 11 stage IIIC, and 19 stage IVB. Disease-free survivals were 55% at 5 years, 46% at 10 years, and 36% at 20 years. Recurrence rates were 16% for stage IIIA with one peritoneal site, 48% for stage IIIA with multiple peritoneal sites or stage IIIB or stage IIIC, and 72% for stage IVB. With univariate analysis, statistical significance was found for stage, gross peritoneal disease, nodal metastases, histology, concurrent chemotherapy, isolated adnexal spread, grade, angiolymphatic invasion, myometrial invasion, and age. Multivariate analysis found only stage, histology, and age to be significant. Most recurrences were pulmonary or peritoneal. Acute toxicity was acceptable. Six percent of patients required surgical intervention for small bowel obstructions. Conclusions. Abdominal radiotherapy confers an excellent prognosis for women with stage IIIA cancers with one site of peritoneal involvement. Lack of randomized trials makes definitive treatment recommendations difficult to provide. Results are less optimal with multiple peritoneal sites of involvement, gross peritoneal spread, or papillary serous/clear cell pathology but a substantial number of such women can be cured as well. D 2004 Elsevier Inc. All rights reserved. Keywords: Endometrial carcinoma; Peritoneal metastases; Whole abdominal radiotherapy; Retrospective study

Introduction Endometrial cancer remains the most common gynecologic malignancy in the United States with an estimated 40,100 new cases and 6800 deaths in 2003, with an 84% 5-year relative-survival rate for all stages as high as it is primarily due to the high proportion of cases diagnosed and treated in early stages [1]. Contemporary 5-year overall survivals approximate 90% for stage I (confined to the uterine corpus) and 75% for stage II (confined to the

* Corresponding author. Fax: +1 612 624 5445. E-mail address: [email protected] (K.E. Dusenbery). 0090-8258/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2004.11.048

corpus and cervix) endometrial cancers [2]. With spread beyond the corpus and cervix, that is, stages III and IV, 5year survivals fall below 60% and 20%, respectively [2]. Although certain subsets of stage IIIA (isolated malignant cells in the peritoneal fluid or isolated adnexal spread) have 5-year disease-free survivals in excess of 80%, other subsets of stage IIIA and all of stage IV patients fare substantially poorer, even when the disease is confined to the peritoneal cavity and/or to the regional lymph nodes [3–8]. Within stages III and IV, 5-year survival rates are as low as 25% for papillary serous and 0% for clear cell carcinomas [9–11]. The basic treatment modalities for women with peritoneal spread of endometrial carcinoma are platinum-

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doxorubicin chemotherapy [12,13] and whole abdominal radiotherapy [14–21]. The only randomized comparison between these options found a 13% predicted difference at 2 years in favor of chemotherapy [22]. The current study updates the 35-year experience of whole abdominal radiotherapy in women with stages III and IV endometrial cancers at the University of Minnesota in order to analyze long-term survival, recurrence sites, and toxicity to demonstrate the importance of peritoneal prognostic factors and to offer treatment options as a function of disease spread and histology [17].

Materials and methods From 1975 through 1995, 86 patients with FIGO stages III and IV endometrial cancers received abdominal radiotherapy after surgical documentation of peritoneal metastases and/or papillary serous histology (Table 1). Pretreatment evaluation included pelvic and general physical examination, dilatation and curettage, chest Xray, intravenous pyelogram or abdominal CT scan, cystoscopy, proctoscopy, and standard laboratory studies. Ages ranged from 36 to 89 years (median 63 years). According to 1988 FIGO surgical staging system criteria, there were 54 stage IIIA, 2 stage IIIB, 11 stage IIIC, and 19 stage IVB patients (Table 1) [23]. There were 69 endometrioid, 12 papillary serous, 4 clear cell, and 1 mixed clear cell, and endometrioid carcinoma. FIGO grading distribution was 10 grade I, 48 grade II, and 26 grade III, with grade unknown for two patients. Of the 84 patients with known depth of myometrial invasion, 49 had

Table 1 FIGO stage, sites of intraperitoneal metastases and number of recurrences Stage/sites IIIA Positive peritoneal cytology onlya Uterine serosa onlya Adnexa onlya Positive cytology + adnexab Uterine serosa + adnexab Total Stage IIIA IIIB Uterine serosa or positive cytology + adnexab IIIC Pelvic/periaortic nodes onlyb Pelvic/periaortic nodes + positive cytologyb Pelvic/periaortic nodes + uterine serosab Pelvic/periaortic nodes + adnexab Pelvic/periaortic nodes + adnexa + positive cytologyb Total Stage IIIC IVB Gross peritoneal spread Total of IIIA, IIIB, IIIC, IVB a b

IIIA with single factor 7/45 (16%). IIIA with multiple factors, IIIB and IIIC 11/23 (48%).

Recurrences/ patients 4/24 1/4 2/17 4/8 1/1 12/54 (22%) 1/2 (50%) 2/2 1/3 0/1 1/3 1/3 5/12 (42%) 13/18 (72%) 31/86 (36%)

greater than 50% invasion, 30 had some but less than 50% invasion, and 5 had disease limited to the endometrium. All patients received abdominal radiotherapy because of the presence of intraperitoneal metastases or papillary serous histology (Table 1). Two stage IIIC patients had no peritoneal spread but did have papillary serous histology, and the remaining patients all had evidence of peritoneal spread. Peritoneal fluid cytology washings were positive in 50 out of 73 sampled patients, and positive cytology was the only evidence of peritoneal metastases in 24 of those patients. In 17 patients, adnexal spread was the sole indicator of peritoneal spread. In the 64 patients with lymph node sampling, 11 had positive pelvic nodes only, 1 had positive periaortic nodes only, and 5 patients had both positive pelvic and periaortic nodes. It was not possible to establish the extent of gross residual tumor in the 18 patients with Stage IVB disease, 5 of whom also had pathologic documentation of nodal metastases. Thirteen women received concurrent chemotherapy, generally consisting of cisplatinum in patients with more advanced disease at the discretion of the gynecologic oncologist. Radiation volumes and doses were administered uniformly throughout the two decades of the study. Cobalt-60 was replaced by linear accelerators with 4-, 6-, or 10-MV photons for the abdominal radiation later in the study, with lower energies to assure dose buildup within the peritoneal cavity. Anterior and posterior whole abdominal portals delivered 20 Gy in 20 fractions without hepatic or renal shielding. Two patients received 13 Gy and one received 18 Gy because of poor tolerance but proceeded to pelvic boosts and brachytherapy. All patients received 10 or 18 MV external beam pelvic boosts ranging from 7 to 43 Gy (median 22 Gy), with pelvic fraction sizes of 1.75 to 1.80 Gy. Patients with isolated pelvic node metastases received boosts extending to the 2nd lumbar vertebral body level, and fields were further extended to the 10th thoracic vertebral body level in women with periaortic nodal metastases [16]. Total periaortic doses ranged 44–50 Gy. Areas of positive pelvic nodes were boosted with pelvic portals to a total dose of 51 to 60 Gy. Radium or cesium was employed for intracavitary therapy with Fletcher afterloading colpostats applied to the upper vagina. Four patients received preoperative brachytherapy with uterine tandems and vaginal colpostats at the discretion of the gynecologic oncologist, while the remainder received postoperative vaginal brachytherapy following completion of external beam therapy. Cumulative vaginal surface doses ranged from 68 to 107 Gy (median 91 Gy). Tolerance dosages of 80 Gy and 70 cGy were assumed for the bladder and rectum, respectively, but these were never exceeded. Disease-free survival and overall survival estimates were calculated by Kaplan–Meier actuarial methods [24]. In the calculation of disease-free survival, the three patients, determined to have persistent disease after completion of therapy, were assigned a disease-free survival of zero

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months. The significance of survival differences was assessed by the log-rank test [25] and the Wilcoxon test of Gehan [26]. The following prognostic factors were initially analyzed univariately with both of these tests for disease-free survival: age (analyzed as a continuous variable), stage, histology (endometrioid versus papillary serous/clear cell), pelvic/periaortic nodal involvement (yes or no), grade (1, 2, or 3), presence of angiolymphatic invasion (yes or no), depth of myometrial invasion (none, inner half, outer half), presence of gross peritoneal disease (yes or no), presence of positive peritoneal cytology as the only evidence of peritoneal metastases (yes or no), presence of adnexal involvement as the only evidence of peritoneal spread (yes or no), and number of extrauterine sites of disease. All risk factors in the univariate analysis, starting with the most statistically significant and proceeding to less significant, were sequentially added to a stepwise multivariate Cox regression model [27]. Toxicity criteria utilized the Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events [28].

Results For the entire cohort, overall and disease-free survivals were 57% and 55% at 5 years, 48% and 46% at 10 years, 41% and 38% at 20 years, respectively, with endometrioid faring better than papillary serous/clear cell ( P b 0.004) (Fig. 1). No recurrences occurred after 13 years. No woman who recurred was salvaged by any form of additional therapy. Median follow-up for the surviving patients was 10 years. Only 5 patients had less than 5 years of follow-up. For patients overall and for all subsets, disease-free and overall survivals were virtually identical, and subsequent figures depict only disease-free survivals.

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From 5 to 10 years, disease-free survival decreased from 65% to 58% for endometrioid and from 24% to 19% for papillary serous/clear cell, demonstrating a persistent 40% disease-free survival advantage for endometrioid histology in the total group ( P b 0.05) (Fig. 1). Statistically different disease-free survivals were found between stage III endometrioid and stage IV endometrioid and between stage III papillary serous/clear cell and stage IV papillary serous/clear cell ( P b 0.05) (Fig. 2). There was a statistically significant survival difference between stage III endometrioid and stage III papillary serous/clear cell ( P b 0.01) but not between stage IV endometrioid and stage IV papillary serous/clear cell ( P N 0.095) (Fig. 2). From 5 to 10 years, disease-free survival in stage III decreased from 84% to 74% for endometrioid and from 37% to 28% for stage III papillary serous/clear cell. In stage IV, diseasefree survival was constant at 29% at 5 and 10 years for endometrioid, but fell to zero by 3 years for papillary serous/clear cell. Recurrence rates were 16% for stage IIIA with one peritoneal site, 48% for stage IIIA with multiple peritoneal sites or stage IIIB or stage IIIC, and 72% for stage IVB ( P b 0.003) (Table 1). All recurrences in women with gross peritoneal spread (stage IVB) occurred within 3 years. The latest recurrences were 13 years in a woman with isolated adnexal spread and 12 years in a woman with only malignant cells in the peritoneal fluid. The peritoneal cavity was the most frequent site of initial failure, with 18 recurrences, 12 of which were solitary (Fig. 3). Distant metastases were next in frequency with 13, 7 of which were solitary. These distant sites consisted of six lung only, one lung and liver, one lung and brain, one brain only, two liver only, one bone only, and one supraclavicular lymph node only. There were only six initial pelvic failures, three of which were solitary.

Fig. 1. Overall and disease-free survival for all stages III and IV endometrial cancer patients and disease-free survival as a function of histology.

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Fig. 2. Disease-free survival as a function of stage and histology.

Univariate proportional hazards regression analysis of the effect of prognostic variables on disease-free survival found all but two factors (positive cytology only and number of extrauterine sites of disease) to reach statistical significance (Table 2). Stepwise multivariate Cox regression analysis found histology, stage, and age to be the only significant factors for disease-free survival (Table 2). Acute toxicity was acceptable, as only three patients (3.4%) failed to receive the prescribed abdominal dose because of gastrointestinal or hematologic intolerance. Another measure of acute toxicity was weight change, with a median of 2.5 kg (range +1 to 8.6). Although difficult to quantitate, virtually all patients developed some degree of nausea, diarrhea, anorexia, and malaise. Ten (11.6%) patients experienced mild bladder irritation. The only Grade 4 chronic complications occurred in six women (7%) who developed small bowel obstructions, five (6%) of which required surgical intervention [28]. No fistulas developed, and no bladder, ureteric, renal, hepatic, or spinal cord damage occurred.

Fig 3. Initial sites of recurrence.

Discussion For any set of patients, it is logical to assert that survival is a function of the interaction between prognostic and therapeutic factors. However, this may not be the case for adjuvant treatment, as some patients do well without aggressive abdominopelvic radiotherapy or multiagent chemotherapy. Given the consistency of treatment in the present study, the effects prognostic factors for whole abdominal radiotherapy are clear (Tables 1, 2, Figs. 1–3). Despite the relatively small sample size, univariate analysis identified 10 significant prognostic factors for disease-free survival (Table 2). Multivariate analysis further reduced

Table 2 Univariate and multivariate effect of prognostic factors on disease-free survival Prognostic factors

Univariate P valuea

Multivariate P valueb

Hazard ratio (CI)b

Stage

b0.0001

b0.0001

6.3 (3.1, 13.1)

Gross peritoneal disease Lymph node involvement Histology

b0.0001 b0.0001 0.0005

ns ns 0.0007

Concurrent chemotherapy Adnexal spread only Grade Angiolymphatic invasion Depth of myometrial invasion Agec

0.002 0.004 0.005 0.03 0.03

ns ns ns ns ns

0.02

0.008

Positive cytology only Extrauterine sitesc

ns ns

ns ns

Note. CI, 95% confidence interval; ns, not significant. a Log-rank test. b Multivariate stepwise Cox regression. c Analyzed as continuous variable.

3.7 (1.7, 7.9)

1.04 (1.01, 1.08)

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these to three-stage, histology, and age. Although all three achieved statistical significance, hazard ratios for stage and histology were substantially greater than for age (Table 2). These same three factors have achieved significance elsewhere [14]. The 13 patients receiving chemotherapy complicated interpretation of the data. Statistical significance of its effect could not be shown in view of its sporadic and selected use, with chemotherapy more likely to be administered in patients with worse prognoses and in patients treated in the later years of the study. In addition, single agents were generally used, unlike more contemporary multiagent chemotherapy [22,29]. As the study was not randomized and as some of the women were probably cured by surgery, the benefits of abdominal radiotherapy remain unproven. It is clear, however, that some prognostic categories require therapy beyond that given in this study. The importance of stage, the first of the three independent prognostic factors, is well documented and emphasizes the necessity of meticulous surgical staging, both because of the limitations of preoperative clinical staging and because radiotherapy and chemotherapy can potentially cure women with peritoneal and lymphatic metastases [2,14,22,30,31]. Surgical staging adds little morbidity to the primary surgical procedure of total abdominal hysterectomy and bilateral salpingo-oophorectomy [32–34]. Finally, surgical staging distinguishes women requiring adjuvant therapy for peritoneal and lymphatic metastases and allows a substantial fraction of women with early disease to be treated with surgery alone [16,33]. Three prognostic categories emerge as a function of surgical stage following whole abdominal radiotherapy for women with stages III and IV endometrial carcinomas. Recurrence rates are 16% for stage IIIA with one peritoneal site of involvement, 48% for stage IIIA with multiple peritoneal sites of involvement or stages IIIB or IIIC, and 72% for stage IVB (Table 2). The role of histology, the second independent prognostic factor, in the management of advanced endometrial carcinoma cannot be overemphasized, with patients with endometrioid clearly faring better than papillary serous/ clear cell (Table 2) [3,9]. For stage III and stage IV together, 5-year disease-free survivals are 65% for endometrioid and 24% for papillary serous/clear cell (Fig. 1). Similar results with whole abdominal radiotherapy have been reported elsewhere for combined stages III and IV, with 9-year disease-free survivals of 79% for endometrioid and 32% for papillary serous/clear cell [14]. This 47% difference at 9 years mirrors the 39% difference at 10 years in the present study (Fig. 1). Moreover, the difference in disease-free survivals between the histologies increases with time out to at least seven years; the last relapses of papillary serous/ clear cell and endometrioid carcinoma occurred at 7 and 13 years, respectively. The dismal outlook for women with stage IVB papillary serous carcinomas has been confirmed elsewhere [9,14,35,36]. Not all studies have been able to demonstrate such dramatic differences, but this may be a function of sample size, prognostic factor distribution and

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therapeutic interventions [20]. It is possible that clear cell carcinomas recur even more often than do papillary serous carcinomas, especially in advanced stages [10,37]. Although stage and histology are independently significant, they are even more predictive in combination, with stage IV papillary serous/clear cell disease having the most dismal outlook (Fig. 2). Survivals within a particular stage for papillary serous/clear cell histology trend lower than their endometrioid counterparts, but a statistically significant different disease-free survival between histologies within each stage can only be shown only for stage III disease in view of the limited sample size of only five women with stage IVB papillary serous/clear cell carcinomas, all of whom recurred. Age, the third independent prognostic factor, demonstrates the risk of recurrence to increase by a factor of 1.04 with each added year of age at diagnosis. Thus, 10 years of age adds a 1.48 risk of dying from recurrent cancer (1.0410). Although its mechanism remains unknown, the effect of advancing age has been widely noted in the literature [7,14,18,20,21]. It appears to represent more than poor tolerance to therapy, as noted by the high completion rate noted in the present study. Recurrence after abdominal radiotherapy most commonly occurs in the upper abdomen, but distant metastases, especially to the lung, are common as well (Fig. 3). Other authors have noted a high propensity for abdominal and pulmonary metastases in conjunction with less frequent recurrences in the vagina, pelvis, periaortic lymph nodes, brain, spine, supraclavicular nodes, liver, and bone marrow [14,15,18,20,21,23]. Failure patterns are influenced by the treatment modality and pathologic subtype as well. One study of clear cell carcinomas, none of which received upper abdominal radiotherapy, found no pelvic recurrences in women who had received pelvic radiotherapy but had a 50% pelvic failure rate if pelvic radiotherapy was not administered; only 2% of patients developed an isolated abdominal recurrence [37]. A study of patients with primarily stages III and IV in combination with unfavorable histology treated with chemotherapy but without radiotherapy had a 40% pelvic failure rate at 3 years [38]. In addition, although exact numbers were not given, recurrences were bfrequent, predominantly in the pelvis and abdomen in both armsQ of Gynecologic Oncology Group (GOG) Protocol #122, which randomized between platinum-doxorubicin chemotherapy and abdominopelvic radiation [22]. Genitourinary, gastrointestinal, and hematopoietic toxicity are acceptable with the doses and volumes of the present study. Only three women (3.5%) did not achieve the prescribed 20 Gy of whole abdominal radiation. Median weight loss was 2.5 kg. The only Grade 4 toxicity was the eventual development of small bowel obstruction in six patients, five of whom required surgery [28]. This level of enteric morbidity is among the lowest reported in the literature [14,15,18,20,23]. If indicated, lymph nodes can be boosted without excessive morbidity with anterior and

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posterior fields as long as spinal cord and small bowel tolerances are respected [16]. Whole abdominal radiotherapy can be administered in two basic ways, 20 Gy without kidney shielding as in the present study or 30 Gy with kidney shielding as in GOG Protocol #122 [22]. Since renal tolerance is only 20 Gy, techniques delivering 30 Gy to the abdomen must have renal blocks to protect the kidneys [39]. These in turn will in turn shield a substantial part of the peritoneal cavity and its tumor spread from the radiation beam. The potential advantage of these more complicated shielding techniques is the provision of somewhat higher dosage to the part of the diaphragm and upper abdomen not shielded by the kidney blocks [14,20]. Although no randomized trial of abdominal dose levels for endometrial cancer has been published, a randomized clinical trial of abdominopelvic radiotherapy for Stages I, II, and optimally debulked III ovarian cancer found no difference in survival, tumor control, or toxicity between 22.5 and 27.5 Gy in 27 to the abdomen (with kidney shielding to keep renal dosage below 20 Gy) followed by a pelvic boost [40]. Given the lack of a randomized trial concerning abdominal higher doses, the most optimal technique remains unclear. Intensity modulated radiotherapy and tomotherapy may allow higher and more uniform doses to be given but are limited by respiratory motion of the diaphragm and of the kidneys [41–43]. Intensity-modulated pelvic radiotherapy can spare the bone marrow to some extent and reduce bowel dosage [44,45]. These newer radiation modalities are unable to protect the small bowel while treating the entire abdominal cavity. With liver and kidney shielding, the small bowel becomes the dose-limiting organ. Any greater dosage to the small bowel may well increase the already substantial rate of severe chronic enteric morbidity. The limitations of surgery and radiotherapy have led to the use of chemotherapy for advanced endometrial carcinomas. Recently published in abstract form, GOG Study #122 compared outcomes of stage III/IV endometrial cancer patients randomized between abdominal radiotherapy and platinum-doxorubicin chemotherapy; with statistically significant 2-year disease-free survivals of 46% for radiation and 59% for chemotherapy [22]. In that study, advanced endometrial carcinoma was defined as surgical stage III or IV, with maximal debulking to 2 cm or less, and positive periaortic node patients to have negative chest-computed tomography and negative scalene node biopsy. Although these preliminary results are encouraging, a substantial number of pelvic and upper abdominal recurrences have occurred within the two years of follow-up and more will do so later (Figs. 2, 3). Radiotherapy may be shown to be equivalent or superior with further follow-up and subset analysis. The substantial pelvic recurrence rate following chemotherapy alone suggests the potential utility of its combination with radiotherapy [22,37,38]. Ongoing GOG Protocol #184 may give further information in this regard [29]. This

study defines advanced endometrial carcinoma as surgical stage III, with maximal debulking to 2 cm or less, and positive periaortic node patients to have negative chest computed tomography. Both GOG #122 and GOG #184 include stage IIIA patients and their relatively favorable prognosis but GOG #122 also includes stage IVB while GOG #184 includes only stage III [22]. GOG #122 prescribes 30 Gy to the upper abdomen and 45 Gy to the pelvis (with or without periaortic boost), while GOG #184 prescribes 50 Gy to the pelvis, and both protocols treat nodal metastases with periaortic fields [22,29]. Thus, GOG Protocol #184 relies on subsequent chemotherapy (cisplatinum and doxorubicin F paclitaxel) to control any peritoneal spread of disease. Survival and recurrence data suggest a variety of therapeutic interventions for advanced endometrial carcinomas. When stage IIIA is manifest by malignant cells in the peritoneal cavity as the sole spread of abdominal metastases, several approaches are justifiable. The excellent results of whole abdominal radiotherapy (Table 1) have been well documented elsewhere [14]. Pelvic external beam boost, with or without vaginal brachytherapy, can be considered in women with risk factors for pelvic recurrence (i.e., high grade, deep myometrial invasion, or cervical involvement) [33]. Another option for isolated malignant peritoneal cytology is observation: some data suggest no adverse effect of positive cytology unless associated with other risk factors [3,4,31,46,47]. Immunocytodiagnostic or other morphologic means may clarify the independent prognostic effect of cytology and clarify which patients might benefit from adjuvant therapy [48,49]. Intraperitoneal isotopes are only rarely utilized, in view of concerns about isotopic distribution and severe toxicity, especially associated with the addition of pelvic boost therapy [50,51]. Isolated adnexal spread has an excellent outcome with whole abdominal radiotherapy with a pelvic boost (Table 1). Favorable outcomes have been reported for patients with isolated adnexal spread undergoing a variety of treatments, although the papillary serous/clear cell histology is more ominous [14,52–54]. There may well be two patterns of ovarian metastases, one via the fallopian tube to the ovarian surface (without nodal spread but with a 100% positive cytology rate) and the other within the ovary itself (with 36% nodal spread and 10% positive cytology rates) [55]. In one series, women with isolated ovarian metastases had a 72% 5-year disease-free survival with surgery alone [55]. The difficulty of distinguishing an ovarian metastasis from a synchronous ovarian primary further clouds choice of therapy although either abdominopelvic radiotherapy or chemotherapy furnishes acceptable treatment for early stages of both diseases. Nevertheless, the necessity of abdominopelvic radiotherapy has not been proven by randomized trials, and survivals have been reported for adnexal spread treated by surgery, with or without adjuvant pelvic radiation [52,55].

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The third means of inclusion into stage IIIA is uterine serosal involvement. Only one of four women with isolated serosal involvement recurred (Table 1). As is the case for isolated adnexal spread, cures in women with isolated uterine serosal involvement treated with only pelvic radiotherapy have been reported. Women with solitary uterine serosal involvement not treated with whole abdominal radiotherapy had a 5-year disease-free survival of 42% [56]. Recurrence rates approach 50% for women with multiple stage IIIA risk factors, and either abdominal radiotherapy or chemotherapy can be considered. Stages IIIB and IIIC must be individualized on the basis of histopathology and of vaginal, nodal, and peritoneal metastases. Unless papillary serous carcinoma and/or peritoneal spread are present, the upper abdomen is not treated [20]. Most patients with vaginal involvement will have had preoperative pelvic external beam therapy and brachytherapy, and it is extremely difficult if not impossible to treat the abdomen following prior pelvic. As nodal involvement is unlikely to be detected preoperatively and as preoperative radiation is seldom used except in women with vaginal involvement, the difficult situation of matching preoperative pelvic fields with postoperative periaortic fields will not often occur [16]. Chemotherapy is becoming an important part of the management of these women [22,29]. The gross peritoneal spread of Stage IVB is difficult to manage with abdominal radiotherapy but long-term recurrence-free survivals do occur, especially with endometrioid histology (Table 1, Fig. 2). Whether treated with adjuvant radiotherapy or chemotherapy, there may be an advantage to initial surgical debulking [21,57,58]. Although the optimal level of debulking is uncertain, it is desirable to be a minimum of less than 1 cm of residual disease and preferably down to microscopic residuum [21,22,57,58]. In summary, with whole abdominal radiotherapy, the prognosis of women with peritoneal spread manifest by positive peritoneal fluid only, isolated adnexal involvement, or isolated uterine serosal involvement is excellent. Although it is logical that peritoneal spread would require abdominal radiotherapy, it has not been proven by randomized clinical trials. Survival approaches 50% for women with either multiple stage IIIA risk factors or stage IIB/IIIC with peritoneal spread and/or papillary serous histology (Table 1) [16]. Stage III papillary serous/clear cell histology can be successfully managed with whole abdominal radiotherapy [20]. For stage IVB, particularly in conjunction with papillary serous/clear cell histology, whole abdominal radiotherapy is clearly less effective, but even in stage IVB, long-term survival occurs (Figs. 2, 3). The sporadic use of chemotherapy in the present series precludes analysis of its effect and may have clouded the results of the overall series. As chemotherapy assumes a greater role in the management of advanced endometrial cancer, radiation retains its curative potential, and technologic advances may well enhance its utility. Intensity modulated abdominal

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radiotherapy and tomotherapy offer kidney and liver sparing with a greater dosage to the upper abdomen but with the possibility of increased small bowel injury [41,42]. At the other end of the spectrum, it is possible that some stage IIIA patients require neither whole abdominal radiotherapy nor chemotherapy but this remains unproven. References [1] Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5 – 26. [2] Creasman W, Odicino F, Maissonneuve P, et al. Carcinoma of the corpus uteri. FIGO annual report. J Epidemiol Biostat 2001;6:45 – 86. [3] Mariani A, Webb MJ, Keeney GL, et al. Assessment of prognostic factors in stage IIIA endometrial cancer. Gynecol Oncol 2002;86: 38 – 44. [4] Kasamatsu T, Onda T, Katsumata N, et al. Prognostic significance of positive peritoneal cytology in endometrial carcinoma confined to the uterus. Br J Cancer 2003;88:245 – 50. [5] Nelson G, Randall M, Sutton G, et al. FIGO stage IIIC endometrial carcinoma with metastases confined to pelvic lymph nodes: analysis of treatment outcomes, prognostic variables, and failure patterns following adjuvant radiation therapy. Gynecol Oncol 1999;75:211 – 4. [6] Gerszten K, Faul C, Huang Q. Pathologic stage III endometrial cancer treated with adjuvant radiation therapy. Int J Gynecol Cancer 1999;9:243 – 6. [7] McMeekin DS, Lashbrook D, Gold M, et al. Analysis of FIGO stage IIIC endometrial cancer patients. Gynecol Oncol 2001;81:273 – 8. [8] Mariani A, Webb MJ, Keeney GL, et al. Stage IIIC endometrioid corpus cancer includes distinct subgroups. Gynecol Oncol 2002;87: 112 – 7. [9] Kato DT, Ferry JA, Goodman A, et al. Uterine papillary serous carcinoma (UPSC): a clinicopathologic study of 30 cases. Gynecol Oncol 1995;59:384 – 9. [10] Abeler VM, Vergote IB, Kjorsted KE, et al. Clear cell carcinoma of the endometrium: prognosis and metastatic pattern. Cancer 1996;78: 1740 – 7. [11] Eifel PJ, Ross J, Hendrickson M, et al. Adenocarcinoma of the endometrium. Analysis of 256 cases with disease limited to the uterine corpus: treatment comparison. Cancer 1983;52:1026 – 31. [12] Burke TW, Stringer CA, Morris M, et al. Prospective treatment of advanced or recurrent endometrial carcinoma with cisplatin, doxorubicin, and cyclophosphamide. Gynecol Oncol 1991;40:264 – 7. [13] Dunton CJ, Pfeifer SM, Braitman LE, et al. Treatment of advanced and recurrent endometrial cancer with cisplatin, doxorubicin, and cyclophosphamide. Gynecol Oncol 1991;41:113 – 6. [14] Smith RS, Kapp DS, Chen Q, et al. Treatment of high-risk uterine cancer with whole abdominopelvic radiation therapy. Int J Radiat Oncol Biol Phys 2000;48:767 – 78. [15] Small WS, Mahadevan A, Roland P, et al. Whole-abdominal radiation in endometrial carcinoma: an analysis of toxicity, patterns of recurrence, and survival. Cancer J 2000;6:394 – 400. [16] Potish RA, Twiggs LB, Savage JE, et al. Paraaortic radiotherapy in cancer of the uterine corpus. Obstet Gynecol 1985;65:251 – 6. [17] Potish RA. Abdominal radiotherapy for cancer of the uterine cervix and endometrium. Int J Radiat Oncol Biol Phys 1989;16:1453 – 8. [18] Gibbons S, Martinez A, Schray M, et al. Adjuvant whole abdominopelvic irradiation for high risk endometrial carcinoma. Int J Radiat Oncol Biol Phys 1991;21:1019 – 25. [19] Martinez A, Schray M, Podratz K, et al. Postoperative whole abdomino-pelvic irradiation for patients with high risk endometrial cancer. Int J Radiat Oncol Biol Phys 1989;17:371 – 7. [20] Martinez AA, Weiner S, Podratz K, et al. Improved outcome at 10 years for serous-papillary/clear cell or high-risk endometrial cancer

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[21]

[22]

[23] [24] [25]

[26] [27] [28]

[29]

[30] [31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

K.E. Dusenbery et al. / Gynecologic Oncology 96 (2005) 635–642 patients treated by adjuvant high-dose whole abdomino-pelvic irradiation. Gynecol Oncol 2003;90:537 – 46. Greer BE, Hamberger AD. Treatment of intraperitoneal metastatic adenocarcinoma of the endometrium by the whole-abdomen movingstrip technique and pelvic boost irradiation. Gynecol Oncol 1983;16:365 – 73. Randall ME, Brunetto G, Muss RS, et al. Whole abdominal radiotherapy versus combination doxorubicin-cisplatin chemotherapy in advanced endometrial carcinoma: a randomized phase III trial of the Gynecologic Oncology Group [abstract]. Proc Am Soc Clin Oncol 2003;22:2. FIGO. Corpus cancer staging. Int J Gynecol Obstet 1989;28:16. Kaplan EL, Meier P. Nonparametric estimation for incomplete observations. J Am Stat Assoc 1958;53:457 – 81. Mantel N. Evaluation of survival data and two new rank-order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163 – 70. Gehan EA. A generalized Wilcoxon test for comparing arbitrarily singly censored samples. Biometrika 1965;52:203 – 23. Cox DR, Oakes D. Analysis of survival data. New York7 Chapman & Hall; p. 91 – 109. Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS. 2003. (http://ctep.cancer.gov). Thigpen JT, Brady MF, Homesley HD, et al. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a gynecologic oncology group study. J Clin Oncol 2004;22(19):3902 – 8. Connor JP, Andrews JI, Anderson B, et al. Computed tomography in endometrial carcinoma. Obstet Gynecol 2000;95:692 – 6. Zerbe MJ, Bristow R, Grumbin FC, et al. Inability of preoperative computed tomography scans to accurately predict the extent of myometrial invasion and extracorporal spread in endometrial cancer. Gynecol Oncol 2000;78:67 – 70. Moore DH, Fowler Jr WC, Walton LA, et al. Morbidity of lymph node sampling in cancers of the uterine corpus and cervix. Obstet Gynecol 1989;74:180 – 4. Morrow P, Bundy BN, Kurman RJ, et al. Relationship between surgical–pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a gynecologic oncology group study. Gynecol Oncol 1991;40:55 – 65. Marino BD, Burke TW, Tornos C, et al. Staging laparotomy for endometrial carcinoma: assessment of peritoneal spread. Gynecol Oncol 1995;56:34 – 8. Cirisano Jr FD, Robboy SJ, Dodge RK, et al. Epidemiologic and surgicopathologic findings of papillary serous and clear cell cancers when compared to endometrioid carcinoma. Gynecol Oncol 1999;74:385 – 94. Sakuragi N, Hareyama H, Todo Y, et al. Prognostic significance of serous and clear cell adenocarcinoma in surgically staged endometrial carcinoma. Acta Obstet Gynecol Scand 2000;79:311 – 6. Murphy KT, Rotmensch J, Yamada SD, et al. Outcome and patterns of failure in pathologic stages I–IV clear-cell carcinoma of the endometrium: implications for adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 2003;55:1272 – 6. Mundt AJ, McBride R, Rotmensch J, et al. Significant pelvic recurrence in high-risk stage I–IV endometrial carcinoma patients after adjuvant chemotherapy alone: implications for adjuvant radiation therapy. Int J Radiat Oncol Biol Phys 2001;50:1145 – 53. Kost S, Dorr W, Keinert K, et al. Effect of dose and dosedistribution in damage to the kidney following abdominal radiotherapy. Int J Radiat Biol 2002;78:695 – 702.

[40] Fyles AW, Thomas GM, Pintilie M, et al. A randomized study of two doses of abdominopelvic radiation therapy for patients with optimally debulked stage I, II, and III ovarian cancer. Int J Radiat Oncol Biol Phys 1998;41:543 – 9. [41] Hong L, Alektiar K, Chui C, et al. IMRT of large fields: wholeabdomen irradiation. Int J Radiat Oncol Biol Phys 2002;54:278 – 89. [42] Duthoy W, De Gersem W, Vergoete K, et al. Whole abdominopelvic radiotherapy (WAPRT) using intensity-modulated arc therapy (IMAT): first clinical experience. Int J Radiat Oncol Biol Phys 2003;57:1019 – 32. [43] Ahmad NR, Huq MS, Corn BW. Respiration-induced motion of the kidneys in whole abdominal radiotherapy: implications for treatment planning and late toxicity. Radiother Oncol 1997;42:87 – 90. [44] Lujan AE, Mundy AJ, Yamada SD, et al. Intensity-modulated radiotherapy as a means of reducing dose to bone marrow in gynecologic patients receiving whole pelvic radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:516 –21. [45] Adli M, Mayr NA, Kaiser HS, et al. Does prone positioning reduce small bowel dose in pelvic radiation with intensity-modulated radiotherapy for gynecologic cancer? Int J Radiat Oncol Biol Phys 2003;57:230 – 8. [46] Kadar N, Homesley HD, Malfetano JH. Positive peritoneal cytology is an adverse factor in endometrial carcinoma only of there is other evidence of extrauterine disease. Gynecol Oncol 1992;46:145 – 9. [47] Takeshima N, Nishida H, Tabata T, et al. Positive peritoneal cytology in endometrial cancer: enhancement of other prognostic factors. Gynecol Oncol 2001;82:470 – 3. [48] Benevelo M, Mariani L, Vocaturo G, et al. Independent prognostic value of peritoneal immunocytodiagnosis in endometrial carcinoma. Am J Surg Pathol 2000;24:241 – 7. [49] Yanoh K, Takeshima N, Hirai Y, et al. Identification of a high-risk subgroup in cytology-positive stage IIIA endometrial cancer. Acta Cytol 2001;45:691 – 6. [50] Soper JT, Creasman WT, Clarke-Pearson DL, et al. Intraperitoneal chromic phosphate P32 suspension therapy of malignant peritoneal cytology in endometrial carcinoma. Am J Obstet Gynecol 1985;153: 191 – 6. [51] Klaassen D, Starreveld A, Shelly W, et al. External beam pelvic radiotherapy plus intraperitoneal radioactive chromic phosphate in early stage ovarian cancer: a toxic combination. A national cancer institute of Canada clinical trials group report. Int J Radiat Oncol Biol Phys 1985;11:1801 – 4. [52] Greven KM, Curran WJ, Whittington R, et al. Analysis of failure patterns in stage III endometrial carcinoma and therapeutic implications. Int J Radiat Oncol Biol Phys 1989;17:35 – 9. [53] Bruckman JE, Bloomer WD, Marck A, et al. Stage III adenocarcinoma of the endometrium: two prognostic groups. Gynecol Oncol 1980;9:12 – 7. [54] Antoniades J, Brady LW, Lewis GC. The management of stage III carcinoma of the endometrium. Cancer 1976;38:1838 – 42. [55] Takeshima N, Hirai Y, Yano K, et al. Ovarian metastasis in endometrial carcinoma. Gynecol Oncol 1998;70:183 – 7. [56] Ashman JB, Connell PP, Yamada D, et al. Outcome of endometrial carcinoma patients with involvement of the uterine serosa. Gynecol Oncol 2001;82:338 – 43. [57] Bristow RE, Duska LR, Montz FJ. The role of cytoreductive surgery in the management of stage IV uterine papillary serous carcinoma. Gynecol Oncol 2001;81:92 – 9. [58] Ayhan A, Taskiran C, Celik C, et al. The influence of cytoreductive surgery on survival and morbidity in stage IVB endometrial cancer. Int J Gynecol Cancer 2002;12:448 – 53.