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Originally published as JCO Early Release 10.1200/JCO.2004.00.7617 on December 5 2005 © 2006 American Society of Clinical Oncology. Randomized Phase III Trial of Whole-Abdominal Irradiation Versus Doxorubicin and Cisplatin Chemotherapy in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group StudyFrom Leo W. Jenkins Cancer Center, Brody School of Medicine at East Carolina University, Greenville, NC; Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; Department of Medicine, University of Vermont-Fletcher Allen Health Care, Burlington, VT; Women's Cancer Center at Community Hospital, Los Gatos, CA; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK; Division of Gynecologic Oncology, James Cancer Hospital and Solove Research Institute, Ohio State University, Columbus, OH; Division of Oncology, Department of Medicine, University of Mississippi Medical Center, Jackson, MS; and Departments of Pathology and Obstetrics and Gynecology, University of Iowa Hospitals, IA City, IA Address reprint requests to Denise Mackey, Gynecologic Oncology Group Administrative Office, Four Penn Center, 1600 JFK Blvd, Ste 1020, Philadelphia, PA 19103; e-mail: dmackey{at}gog.org
PURPOSE: To compare whole-abdominal irradiation (WAI) and doxorubicin-cisplatin (AP) chemotherapy in women with stage III or IV endometrial carcinoma having a maximum of 2 cm of postoperative residual disease. PATIENTS AND METHODS: Four hundred twenty-two patients were entered onto this trial. Of 396 assessable patients, 202 were randomly allocated to receive WAI, and 194 were allocated to receive AP. Irradiation dosage was 30 Gy in 20 fractions, with a 15-Gy boost. Chemotherapy consisted of doxorubicin 60 mg/m2 and cisplatin 50 mg/m2 every 3 weeks for seven cycles, followed by one cycle of cisplatin. RESULTS: Most patient and tumor characteristics were well balanced. The median patient age was 63 years; 50% had endometrioid tumors. Median follow-up time was 74 months. The hazard ratio for progression adjusted for stage was 0.71 favoring AP (95% CI, 0.55 to 0.91; P < .01). At 60 months, 50% of patients receiving AP were predicted to be alive and disease free when adjusting for stage compared with 38% of patients receiving WAI. The stage-adjusted death hazard ratio was 0.68 (95% CI, 0.52 to 0.89; P < .01) favoring AP. Moreover, at 60 months and adjusting for stage, 55% of AP patients were predicted to be alive compared with 42% of WAI patients. Greater acute toxicity was seen with AP. Treatment probably contributed to the deaths of eight patients (4%) on the AP arm and five patients (2%) on the WAI arm. CONCLUSION: Chemotherapy with AP significantly improved progression-free and overall survival compared with WAI. Nevertheless, further advances in efficacy and reduction in toxicity are clearly needed.
Endometrial carcinoma is the most common gynecologic malignancy in the United States, with approximately 7,100 deaths in 2004, usually from metastatic disease.1 Surgical staging (including lymph node assessment and/or dissection) has better defined this disease.2 Nevertheless, stage III and IV endometrial carcinoma is a heterogeneous group of tumors with variable prognoses.3,4 A significant rate of relapse within the abdomen has given impetus to the use of whole-abdominal irradiation (WAI),5-9 whereas, for extra-abdominal sites, cytotoxic chemotherapy10-17 or combinations of chemotherapy and radiation have been used.18-21 Using WAI, Smith et al7 reported 3-year estimated progression-free survival (PFS) and overall survival (OS) rates of 79% and 89%, respectively, in stage III and IV patients with adenocarcinoma (not papillary serous or clear cell) and PFS and OS rates of 32% and 61%, respectively, in patients with stage III and IV clear-cell or serous papillary carcinoma. In that study, WAI was well tolerated, with a 7% actuarial risk of major complications at 3 years. Gibbons et al5 reviewed 56 patients at high risk for abdominal recurrences who were treated with WAI. Seven-year PFS rates were 58% and 25% for stage III and IV patients, respectively. Potish8 reported a 5-year PFS rate of 63% in stage III and IV patients after WAI. Cytotoxic chemotherapy has been used primarily as palliative therapy for patients with advanced endometrial carcinoma. In previous trials by the Gynecologic Oncology Group (GOG) and others, doxorubicin, cisplatin, and other single agents have shown complete and partial response rates of 20% to 45%.22-25 In two randomized trials, the response rate for the combination of doxorubicin and cisplatin (AP) was superior to doxorubicin alone.11,12 Response rates up to 71% with multiagent regimens have been reported in phase II trials.15 These results indicated the need for a direct comparison of WAI and chemotherapy, which is the subject of this report.
Patient Eligibility Patients with International Federation of Gynecology and Obstetrics (FIGO) stage III or IV endometrial carcinoma of any histology were eligible for this trial. Eligibility required total abdominal hysterectomy and bilateral salpingo-oophorectomy, surgical staging, tumor resection, and no single site of residual tumor more than 2 cm. Nodal sampling was optional for patients with stage III or IV disease by clinical or surgical criteria. Patients with positive para-aortic lymph nodes (PALNs) were required to have negative scalene node biopsies and chest computed tomography scans. Adequate hematologic (WBC  3,000/µL, platelets 100,000/µL, and granulocytes 1,500/µL), renal (creatinine  2 mg %), and hepatic (bilirubin 1.5x the institutional normal value and AST 3x the institutional normal value) function was required, as was a normal cardiac ejection fraction and Zubrod (GOG) performance status of 0 to 3. Ineligible patients included patients with recurrent disease; parenchymal liver, lung, or other hematogenous metastasis; inguinal lymph node involvement; or a history of pelvic or abdominal radiation therapy or chemotherapy. Protocol treatment was to be started within 8 weeks of surgery. The institutional review board at each participating institution approved the protocol, and all patients provided written informed consent consistent with all institutional, state, and federal regulations before study randomization.
Radiation Therapy Pelvic (± para-aortic) boosts were accomplished using a four-field box technique with custom blocking to minimize the treated small-bowel volume. The boost dose was 15 Gy in 8 fractions. All fields were treated once daily, 5 days per week. If more than a 2-week treatment interruption was required, resumption of treatment was at the physician's discretion, and follow-up continued regardless of treatment.
Chemotherapy A normal cardiac ejection fraction based on institutional values was required. A decline in the ejection fraction of 20% of the baseline value or development of congestive heart failure or other life-threatening cardiac problems required discontinuation of doxorubicin; however, cisplatin treatment continued. Only cisplatin was withheld for serum creatinine more than 2.0 mg. Treatment interruptions as a result of neurotoxicity, including hearing loss, were left to the discretion of the patient and physician.
Patient Follow-Up After protocol treatment, patients were evaluated every 3 months for 2 years and then every 6 months. A chest radiograph was required every 6 months for the first 2 years and then annually. Patients were observed for progression and survival. PFS was defined as the length of time a patient survived from study entry without reappearance or progression of tumor. Patients alive without tumor recurrence or progression were censored at the date of last contact. OS was defined as the observed length of life from study entry to death from any cause or, for living patients, the date of last contact.
Quality Assurance
Statistical Considerations The primary end point for comparison of the treatment regimens was PFS; OS was a secondary end point. The original accrual goal was 240 patients, with follow-up to continue until 192 treatment failures (tumor recurrence, progression, or death) were reported. This sample size was increased when a review of the original statistical assumptions revealed that the hazard decreased over time, as in a Gompertz survival distribution, in contrast to the assumed constant hazard of an exponential distribution. The original assumption overestimated the number of treatment failures at the planned time of analysis. Simply extending follow-up was not considered a sufficient remedy. The plan to increase accrual was approved by the GOG Data Monitoring Committee without knowledge of treatment results. One hundred ninety-two treatment failures would provide statistical power of 80% to detect a proportional decrease of 33% in the hazard rate when testing at the level of 0.05 with a two-tailed test.25 This report includes 246 treatment failures and 222 deaths, with a median follow-up of 74 months among living patients. An interim analysis of PFS was completed, with 109 reported disease recurrences using an O'Brien and Fleming type spending function,26 and was reported to the Data Monitoring Committee in July of 1998. The intent-to-treat principle was applied in treatment group comparisons of PFS and OS after excluding ineligible patients. A log-rank test27 stratified by FIGO stage (III v IV) was used to test the independence of treatment with PFS and OS. The product-limit method28 was used to obtain PFS and OS estimates. The treatment effect on PFS and survival, adjusted for FIGO stage, was estimated using a Cox proportional hazards model.29 Analyses using proportional hazards regression models of clinical, pathologic, and host characteristics were carried out to identify putative prognostic factors. Exploratory analyses of OS and PFS were performed within subgroups to crudely assess the heterogeneity of treatment effects. Treatment hazard ratios with 95% CIs are reported. Additionally, toxicity analyses included only patients who received assigned treatment.
Patient Characteristics Four hundred twenty-two women were entered between May 1992 and February 2000, of whom 388 were initially eligible (198 were randomly assigned to receive WAI and 190 were assigned to receive AP). Reasons for the exclusion of 34 patients (15 on the WAI arm and 19 on the AP arm) included wrong stage (n = 3), double primary (n = 8), wrong cell type (n = 4), prior malignancy (n = 1), residual disease more than 2 cm (n = 1), incomplete lymph node sampling or laparoscopic surgery (n = 8), registration error (n = 1), and inadequate documentation of pathology (n = 8). The eight patients (four on each arm) deemed ineligible because of unilateral lymph node sampling or use of laparoscopic surgery are included in the analyses. Since this study was initiated, acceptance and use of laparoscopic surgery has widened, and these patients are otherwise eligible. Their inclusion does not change the study results. The treatment arms were balanced in terms of patient characteristics. There are slight imbalances with respect to mixed cell type and FIGO stage (Table 1). More notable imbalances between treatment arms are apparent in nodal involvement and individual sites of disease (Table 2). Most imbalances are skewed toward poor prognosis in the AP arm.
Treatment Approximately 84% of patients completed radiation therapy, and 63% of patients completed eight cycles of chemotherapy (Table 2). Patients discontinued therapy early most often as a result of toxicity (17% in the AP arm v 3% in the WAI arm; Table 2). Five patients died before completing therapy; four were on the AP arm. The median radiation dose (WAI + boost) was 45 Gy; the median number of fractions (WAI + boost) was 28. The median radiation boost (to the true pelvis or extended field) was 15 Gy; the median number of fractions was 8 (range, 1 to 28 fractions). The median dose delivered to the PALN area was 15 Gy (range, 0 to 45 Gy); the median number of fractions was 8 (range, 1 to 25 fractions). The median duration of radiation treatment was 1.3 months (range, 2 days to 2 months). In 94% of patients, the timing of chemotherapy administration was consistent with protocol requirements, and 84% of patients received their calculated drug dose. Chemotherapy dose reductions without justification constituted protocol violations in 11% of patients based on dose and time parameters up to the time point that chemotherapy was completed (eight cycles) or discontinued. The median cumulative dose of doxorubicin for all patients was 405 mg/m2 (range, 0 to 487 mg/m2), and the median dose of cisplatin was 392 mg/m2 (range, 0 to 461 mg/m2). The median duration of chemotherapy was 5.1 months (range, 1 day to 8.3 months). Any exposure to protocol chemotherapy up to the maximum of eight cycles constitutes assessability for toxicity. Twelve patients on the WAI arm did not receive abdominal irradiation; four of these patients received radiotherapy (RT) to the pelvis with or without extended-field RT to the para-aortic chain. None of these patients received chemotherapy before progression. Three patients on the AP arm received no protocol chemotherapy. One of these patients received WAI, one received alternate chemotherapy (carboplatin and paclitaxel), and one died of sepsis within 1 month of surgery and received no adjuvant therapy. These 15 patients are not included in the toxicity analysis but are included in PFS and OS calculations.
Adverse Effects of Treatment
Treatment probably contributed to eight deaths on the AP arm (two patients had sepsis, two patients had congestive heart failure, and one patient each had sepsis plus left ventricular/aortic thrombus, hypoglycemic shock with myelosuppression, stroke secondary to congestive heart failure, and renal failure with severe thrombocytopenia) and five deaths on the WAI arm (one patient each had veno-occlusive liver disease, disease progression with hepatomegaly, aspiration and liver necrosis, renal and liver failure secondary to sepsis with severe ascites, and sepsis and liver failure; Table 5). The age range of patients suffering treatment-related deaths was 48 to 68 years (median, 62 years) and 50 to 76 years (median, 68.5 years) in the WAI and AP arms, respectively. Initial performance status was 0 to 1 in all patients experiencing treatment-related deaths, except for one patient on the AP arm who had a performance status of 2.
Patterns of Initial Treatment Failure Of the 202 patients whose random treatment assignment was WAI, 109 (54%) had documented tumor recurrence. The initial site of recurrence was limited to the pelvis in 27 patients (13%), within the abdomen in 33 patients (16%), and extra-abdominal or liver metastases in 45 patients (22%). In four patients on the WAI arm and in two patients on the AP arm, sites of initial recurrence were unknown. Of the 194 patients whose random treatment assignment was to AP, 97 (50%) had documented tumor recurrence. The initial site of recurrence was limited to the pelvis in 34 patients (18%); 27 patients (14%) experienced disease recurrence within the abdomen, and, in 34 patients (18%), the first recurrence included extra-abdominal or liver metastases.
Treatment Outcomes There is a statistically significant difference in PFS between the two regimens (Fig 1). The progression hazard ratio relative to the WAI arm, adjusted for stage, was 0.71 (95% CI, 0.55 to 0.91; P = .007). This adjusted relative hazard ratio was associated with a predicted increase in PFS at 60 months of 12% (50% for AP v 38% for WAI). There was also a statistically significant difference in OS between the two arms (Fig 2).
The hazard ratio of death relative to the WAI arm, adjusted for stage, was 0.68 (95% CI, 0.52 to 0.89; P = .004). This adjusted relative hazard estimate was associated with a predicted increase in survival at 60 months of 13% for patients on the AP arm versus WAI patients (55% v 42%, respectively). Unadjusted Kaplan-Meier estimates of 5-year PFS and OS were 42% and 53%, respectively, in the AP arm compared with 38% and 42%, respectively, in the WAI arm.
Subsequent Treatment
Prognostic Factors
Subgroup Analyses The treatment effects given by the AP death hazard ratio relative to that of WAI within subgroups of stage were as follows: IIIA, 0.47; IIIB, 0.54; IIIC, 0.75; and IV, 0.68. For combined subcategories of stage III, the relative hazard ratio was 0.68 (Fig 5). All 95% CIs for these estimates included the overall adjusted hazard ratio. Similar results for age, cell type, and residual disease status subgroups are also illustrated in Figure 5.
For the first time, this trial has demonstrated that chemotherapy of advanced endometrial carcinoma significantly improves both PFS and OS when compared with WAI. Adverse effects of treatment tended to be more frequent and more severe on the AP arm, but the majority of acute toxicities were expected and manageable. Standardized surgical staging and analysis of treatment failure in endometrial carcinoma have provided clinicians with a better understanding of prognostic groups, risk factors, and limitations of previously used therapies.2,31,32 Randall and Reisinger3 suggested that patients with surgical stage III and IV disease can be separated into favorable or unfavorable categories. Characteristics of favorable patients include FIGO stage IIIA with positive peritoneal cytology in the absence of other extrauterine disease or isolated adnexal or serosal involvement, a concept supported by data from Mariani et al33 and others.34,35 Subsequently, studies suggested that isolated PLN involvement with surgically confirmed negative PALN potentially constitutes an additional favorable subset of patients who may be candidates for less intensive therapies,4,36 although other investigators disagree.37-39 Unfavorable patients include those with positive PALN (and possibly PLN), gross residual tumor after surgery, multiple sites of extrauterine cancer spread, high histologic grade, lymphovascular space invasion, peritoneal dissemination, and papillary serous or clear-cell histologies.2,3,40-43 Patients with advanced endometrial carcinoma often have a combination of these high-risk features, with a significant risk of locoregional recurrence (including the peritoneal cavity), as well as a substantial risk of developing extra-abdominal spread. The data reported herein suggest that AP chemotherapy decreased the distant failure rate, reducing the crude percentage of initial extra-abdominal failure from 19% to 10%. However, this analysis only provides the initial reported sites of failure. Furthermore, the protocol did not require a complete evaluation of all potential sites of recurrence. Thus, this report does not account for competing risks of ever developing a distant metastasis and may not completely identify all sites of failure for each patient. Grade 3 and 4 adverse effects (particularly hematologic, GI, cardiac, and neurologic) were significantly more common in the AP arm, and treatment may have contributed to the death of five patients on the WAI arm and eight patients on the AP arm. The use of hematopoietic growth factors to minimize complications associated with neutropenia should be considered in selected high-risk patients. In addition, patients receiving more than 300 mg/m2 of doxorubicin should be closely monitored for left ventricular function. Of note, less than two thirds of patients in this study completed all eight cycles of chemotherapy as prescribed. Unfortunately, the data do not permit definitive subset analyses assessing heterogeneity of the treatment effect within smaller groups of patients. However, there is no evidence to suggest that the study conclusions apply only to a subset of patients. For example, the treatment effects within stage subcategories are all in the direction favoring the AP arm. Furthermore, each 95% CI of the treatment effect within subgroups contained the estimated overall treatment effect value. WAI may not be the most effective RT approach. For example, there is literature suggesting that WAI has, at best, a limited therapeutic role in patients with stage III disease4,40,44,45 either because good outcomes have been demonstrated using less aggressive therapies with lower complication risks or because of the high rates of distant failure in these patients.37,39,44,46 As noted previously, patients with endometrial adenocarcinoma and extrauterine spread limited to the peritoneal fluid and/or adnexae (stage IIIA) have favorable outcomes compared with patients with aortic nodal or intra-abdominal metastasis.2,31 Many clinicians recommend no adjuvant therapy for stage IIIA (grade 1 or 2) patients who have positive cytology as the only component of extrauterine disease. Patients with isolated adnexal involvement and even positive lymph nodes confined to the pelvis may have a favorable prognosis.3,4,47 Even in patients with involved PALNs, published series have consistently reported a long-term no evidence of disease survival of approximately 50% with extended-field RT.46,48-51 More tailored (pelvic or pelvic and para-aortic) radiation fields when treated with higher doses of conventional fractionation may produce a higher therapeutic ratio. Adjuvant chemoradiotherapy might further improve results, which is a concept supported by Onda.52 In addition, the use of RT after chemotherapy has yielded median survival times in excess of 2 years in 42 patients with unresectable stage III or IV endometrial carcinoma.53 Regarding chemotherapy, paclitaxel has displayed antitumor activity in patients with metastatic endometrial cancer; regimens including this agent are being evaluated in the adjuvant setting. In summary, patients with surgical stage III or IV endometrial carcinoma treated with AP experienced a statistically significant improvement in survival when compared with patients who received WAI, but they also experienced more frequent and more severe acute toxicity. Clearly, greater efficacy and less toxicity are needed. Avenues for further progress remain to be explored.
The following Gynecologic Oncology Group member institutions participated in this study: University of Alabama at Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center, Wayne State University, University of Minnesota Medical School, University of Mississippi Medical Center, Colorado Gynecologic Oncology Group, University of California Los Angeles, University of Washington, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University Medical Center, Wake Forest University School of Medicine, Albany Medical College, University of California Medical Center at Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St Luke's Medical Center, State University of New York Downstate Medical Center, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical Center, Fox Chase Cancer Center, Medical University of South Carolina, Women's Cancer Center, University of Oklahoma, University of Virginia, University of Chicago, Tacoma General Hospital, Thomas Jefferson University Hospital, Mayo Clinic, Case Western Reserve University, Tampa Bay Cancer Consortium, Brookview Research Inc, and Ellis Fischel Cancer Center.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
The Radiological Physics Center (RPC), through its comprehensive quality assurance program, ensured that the radiation doses delivered to all patients in this study were clinically comparable. The RPC reviewed all technical aspects of the treatment and verified the reported doses of all patients. In addition, the RPC monitored the calibration of the therapy units using mailed dosimeters at all participating institutions and conducted on-site evaluations of selected institutions as needed.
Supported by National Cancer Institute Grants No. CA 27469 to the Gynecologic Oncology Group (GOG) Administrative Office and CA 37517 to the GOG Statistical and Data Center. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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