Elsevier

Gynecologic Oncology

Volume 112, Issue 3, March 2009, Pages 543-552
Gynecologic Oncology

A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study,☆☆

https://doi.org/10.1016/j.ygyno.2008.11.014Get rights and content

Abstract

Objectives

After surgical debulking and volume-directed irradiation of the pelvis/para-aortic lymph nodes, treatment was randomized to compare recurrence-free survival (RFS) and toxicity between two chemotherapy regimens for the treatment of women with advanced stage endometrial carcinoma.

Methods

Treatment was randomized between 6 cycles of cisplatin [C] (50 mg/m2) and doxorubicin [D] (45 mg/m2) with or without paclitaxel [P] (160 mg/m2). Initially in paclitaxel treated patients and, after May 2002, all patients received granulocyte growth factor with each cycle.

Results

Of 659 patients enrolled following surgery, 552 eligible patients were randomized to chemotherapy after irradiation. Accrual closed to Stage IV patients in June, 2003. Approximately 80% completed six cycles of chemotherapy. Three deaths resulted from bowel complications and one death was due to renal failure. Hematologic adverse events, sensory neuropathy and myalgia, were more frequent and severe in the paclitaxel arm (p < 0.01) which was confirmed by Quality of Life assessments. Percentage of patients alive and recurrence-free at 36 months was 62% for CD vs. 64% for CDP. The hazard of recurrence or death relative to the CD arm stratified by stage is 0.90 (95% CI is 0.69 to 1.17, p = 0.21, one-tail). However, in subgroup analysis, CDP was associated with a 50% reduction in the risk of recurrence or death among patients with gross residual disease (95% CI: 0.26 to 0.92). Stage, residual disease, histology/grade, positive para-aortic node and cytology, pelvic metastases and age were significantly associated with RFS.

Conclusion

The addition of paclitaxel to cisplatin and doxorubicin following surgery and radiation was not associated with a significant improvement in RFS but was associated with increased toxicity.

Introduction

The optimal adjuvant therapy following surgical staging and maximum cytoreduction in stage III and IV endometrial carcinoma is yet to be established. Postoperative abdomino-pelvic irradiation has been found to be efficacious for advanced endometrial cancer. [1], [2], [3], [4], [5]. Gynecologic Oncology Group (GOG) Protocol 94, a single arm phase II trial, established WAI to be tolerable with reasonable efficacy [6].

Chemotherapeutic options were explored in GOG Protocol 107, which compared single-agent doxorubicin with the combination of doxorubicin and cisplatin [7]. Although no differences in survival were seen, the response rate was significantly higher with the two-drug regimen and the data suggested an increase in progression-free survival.

The results of GOG Protocols 94 and 107 led to the design of GOG 122, which compared WAI to the combination of cisplatin and doxorubicin [8] in patients with advanced, optimally debulked (≤ 2 cm residual disease) endometrial cancer. In that study, WAI was prescribed as 30 Gy in 20 fractions to the abdomen followed by 15 Gy in 8 fractions to the pelvis. The chemotherapy regimen consisted of seven cycles of doxorubicin 60 mg/m2 and cisplatin 50 mg/m2 every 3 weeks followed by one additional cycle of cisplatin.

Paclitaxel appears to elicit good response in endometrial cancer based upon both phase II and phase III data. In GOG 129-C, as a second line single agent for persistent or advanced endometrial carcinoma, paclitaxel achieved a 28% response rate with a 6.5% compete response rate [9].

It was thought that further advantages may be realized by combining both adjuvant chemotherapy and radiation given prior results suggesting activity and/or feasibility of combining irradiation with chemotherapeutic in the treatment of advanced endometrial cancer. [10], [11], [12]. Considering the higher objective response rates reported in GOG 107 for the combination of doxorubicin and cisplatin in advanced endometrial carcinoma combined with the favorable irradiation results of GOG 94 and the positive findings of GOG 129-C with respect to paclitaxel, it seemed appropriate to combine tumor volume-directed pelvic irradiation with chemotherapy arms containing all active chemotherapeutic agents.

The general underlying hypothesis was that, following surgical cytoreduction and radiotherapy, combination chemotherapy may reduce both locoregional and systemic recurrence rates. Sequential rather than concurrent delivery of the two modalities was proposed in an attempt to limit the overall toxicity and allow a maximum therapeutic dosing of both modalities. Therefore, the primary objective of this trial was to test the hypothesis of no increase in recurrence-free survival associated with the addition of paclitaxel to cisplatin and doxorubicin in patients with Stage III or IV endometrial carcinoma (≤ 2 cm residual disease) following initial surgery and tumor volume directed irradiation. Both acute and long term adverse events were to be assessed including patient-reported peripheral neuropathy.

Section snippets

Methods

Patients diagnosed with Stage III or IV endometrial carcinoma of any histology, including clear cell and serous papillary carcinomas, with disease limited to the pelvis and abdomen, were initially eligible. When the results of GOG 122 were reported demonstrating chemotherapy to be superior to radiation, patients with disease outside of the pelvis were no longer permitted to enroll in this study except patients with positive para-aortic nodes. As of June 2003, eligible patients had to have

Results

From July 3, 2000 to September 13, 2004, 659 patients were enrolled onto this trial following surgery and informed consent. Of the 659 registered patients, 552 were subsequently deemed eligible and, following irradiation, received a random treatment assignment. (Fig. 1). Following irradiation, there were 30 patients who refused further treatment or randomization, 29 patients with intervening progression of cancer and 14 patients with various other reasons for not participating in the randomized

Discussion

In this trial, when added to cisplatin and doxorubicin following completion of surgery and radiation therapy, paclitaxel added toxicity including patient-reported peripheral neuropathy; however, it did not contribute to a significant improvement in recurrence-free survival. An exception may be noted in patients with macroscopic residual endometrial cancer.

Approximately 80% of patients completed six cycles of chemotherapy using either drug regimen, reflecting acceptable tolerance of chemotherapy

Conflict of interest statement

The authors declare that there are no conflicts of interest with the exception of Dr. Susan K. Gibbons who reports EntreMed Millennium Stock purchase 2003 < $1500 and Dr. Harry J. Long III who reports stock ownership of < $10,000 per company: AstraZeneca, Amgen, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Novartis, Sanofi-Aventis, Pfizer.

Acknowledgments

The authors would like to acknowledge Helen Huang, MS, Biostatistician, Gynecologic Oncology Group Statistical and Data Center, for the expert analysis and reporting of the patient-reported neurotoxicity data in this manuscript and Patty Brehm for her careful coordination of the clinical data.

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    This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469) and the GOG Statistical and Data Center (CA 37517).

    ☆☆

    The following GOG institutions participated in the related treatment study: Roswell Park Cancer Institute, 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 PC, University of Washington/Puget Sound Oncology Consortium, University of Pennsylvania Cancer Center, Milton S. Hershey Medical Center, University of Cincinnati Medical Center, University of North Carolina School of Medicine, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical Center at Dallas, Indiana University School of Medicine, Wake Forest University School of Medicine, University of California-Irvine, Tufts-New England Medical Center, Rush-Presbyterian-St. Luke's Medical Center, Magee Women’s Hospital, State University of New York-Downstate, University of Kentucky, University of New Mexico Health Sciences Center, Cleveland Clinic Foundation, State University of New York-Stony Brook, Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Cooper Hospital/University Medical Center, Columbus Cancer Council, University of Massachusetts Medical School, Fox Chase Cancer Center, Women's Cancer Center, University of Oklahoma, University of Virginia, University of Chicago, Tacoma General Hospital, ECOG Statistical Center, Mayo Clinic, Case Western Reserve University, Tampa Bay/H. Lee Moffitt Cancer Center, Gynecologic Oncology Network, Ellis Fischel Cancer Center, Fletcher Allen Health Care, Yale University, University of Texas – Galveston, and Ozarks Regional CCOP.

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