Elsevier

Gynecologic Oncology

Volume 103, Issue 2, November 2006, Pages 523-526
Gynecologic Oncology

Phase II study of oxaliplatin as second-line chemotherapy in endometrial carcinoma: A Gynecologic Oncology Group study

https://doi.org/10.1016/j.ygyno.2006.03.043Get rights and content

Abstract

Objective.

A phase II study was conducted to determine the efficacy of oxaliplatin therapy in patients with advanced or recurrent endometrial cancer who had received one prior platinum therapy.

Methods.

Eligible patients were to have measurable disease and one prior chemotherapy regimen which could include cisplatin or carboplatin. Oxaliplatin 130 mg/m2 was administered intravenously over 2 h. This treatment was repeated every 21 days until progression of disease or adverse effects prohibited further therapy.

Results.

Fifty-four patients were entered on study, of which 52 were eligible and 50 had had prior platinum therapy. The overall response rate was 13.5%, with three patients (5.8%) achieving a complete response and four patients (7.7%) achieving a partial response. Median duration of response was 10.9+ (range: 4.1–50.3+) months. Stable disease was reported in 15 (28.8%) patients, with an associated median duration of 5.4 (range: 2.2–19.6) months. Drug-related toxicities consisted of anemia, nausea and vomiting, and neurotoxicity.

Conclusions.

Oxaliplatin at the dose and schedule employed has limited activity in patients with advanced or recurrent endometrial carcinoma who have had previous platinum therapy.

Introduction

Endometrial carcinoma is the fourth most frequent cause of cancer in American women accounting for 40,880 new diagnoses and 7310 deaths in 2005 [1]. Although many women present with early disease and are cured with surgery or surgery combined with radiation therapy, a minority of women will recur with locally advanced or metastatic disease. Treatment for these women consists of palliation with hormonal therapy and, in hormonally unresponsive disease, with chemotherapy [2], [3], [4], [5].

The platinum analogs cis-diamminedichloroplatinum (cisplatin) and carboplatin are active agents in endometrial cancer and are used in combination with other drugs for the treatment of recurrent or advanced disease [5]. The Gynecologic Oncology Group (GOG) reported activity using cisplatin as a single agent in previously treated and untreated patients, with response rates of 4% and 20%, respectively [6], [7]. In smaller trials, higher response rates of up to 42% have been reported with this agent [5]. In addition, carboplatin has been shown to have response rates in the range of 30% in untreated patients [5] and, in two randomized trials, response rates improved when cisplatin was used in combination with doxorubicin [8], [9]. These trials have demonstrated the importance of platinum in the treatment of advanced disease. Therefore, a platinum analogue with improved activity would be of interest in endometrial cancer.

Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatin, Eloxatine) is a novel diaminocyclo-hexane platinum derivative with a wide range of activity against human and murine tumor cell lines, including cisplatin-resistant lines (reviewed in [10], [11], [12]). The mechanism of action of oxaliplatin is thought to be similar to that of other platinum derivatives that exert their cytotoxic effects through the formation of DNA adducts with subsequent impairment of DNA replication and transcription and resultant cell death. Preclinical data suggest that the platinum–DNA adducts formed by oxaliplatin may be responsible for its unique cytotoxic activity as compared to cisplatin. In particular, the 1,2-diaminocyclohexane-platinum (dach-PT) adducts formed from oxaliplatin may be more effective in DNA synthesis inhibition than the cis-diamine-PT adducts formed from cisplatin, and DNA mismatch–repair complexes do not recognize dach-PT adducts (reviewed in [10], [11], [12]).

Early studies with oxaliplatin have demonstrated a favorable safety profile [10], [13], [14]. The dose-limiting toxicity was a cumulative, peripheral sensory neuropathy often exacerbated by cold. Nausea and vomiting were noted but, unlike cisplatin or carboplatin, renal, hematologic, and ototoxicity were absent. The recommended phase II dose was 125 to 130 mg/m2 given every 3 weeks or 85 mg/m2 every 2 weeks. In phase II/III studies in advanced colon cancer, efficacy was noted when oxaliplatin was used as a single agent and in combination with 5-fluorouracil and leucovorin. As a result, the combination of oxaliplatin, 5-fluorouracil and leucovorin has been approved for this purpose in the United States in 2003.

Given that single-agent oxaliplatin has been shown to have activity in cisplatin-resistant cell lines in preclinical studies and has little renal, hematologic or ototoxicity in clinical studies, this phase II study was designed to investigate the activity and toxicity of oxaliplatin in women with advanced endometrial carcinoma.

Section snippets

Materials and methods

Member institutions of the Gynecologic Oncology Group (GOG) entered 54 patients with recurrent or persistent endometrial carcinoma on GOG Protocol 129-K to evaluate the efficacy of oxaliplatin. Patients were required to have measurable disease. Patients who received one previous chemotherapy treatment were eligible, but those with a history of allergy to platinum compounds or who had received prior therapy with oxaliplatin were ineligible.

Patients must have been at least 18 years old and have

Results

Between November 1999 and July 2004, fifty-four patients were entered onto this trial. Two patients did not receive treatment, and, of the remaining 52, all were evaluable for toxicity and response. Patient characteristics are presented in Table 1. The median age was 67 years, and the median performance status was 0. Forty-nine (94.2%) had received chemotherapy with a platinum-containing regimen.

A total of 209 treatment cycles were given, with a median of three (range: 1–10) cycles per patient.

Discussion

The most active single agents in advanced or recurrent endometrial carcinoma are doxorubicin, cisplatin, carboplatin, paclitaxel, epirubicin, and ifosfamide, with response rates from 4% to 40% [5]. Combination regimens produce higher response rates than single agents, with an overall median survival of 7–10 months [5]. Given response rate of 42%, progression-free survival of 5.7 months, and the potential toxicity with doxorubicin and cisplatin, there is a need for more effective and less toxic

Acknowledgments

The authors wish to thank the following individuals for their contributions: S. Percy Ivy, M.D., Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, for her assistance in the development and execution of this study; Teresa J. Vietti, M.D. and Sherry A. Goodner, R.N., M.A., for their editorial assistance; Suzanne Baskerville of the GOG Statistical and Data Center, for her expertise in data collection and analyses; and Kia Neff and Meg Colahan of the GOG

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This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical Office (CA 37517) and a Clinical Oncology Career Development Award from the American Cancer Society to PMF. The following member institutions participated in this study: Abington Memorial Hospital; University of Alabama at Birmingham; University of California Medical Center at Irvine; Case Western Reserve University; University of Chicago; University of Cincinnati; The Cleveland Clinic Foundation; Community Clinical Oncology Program; Colorado Gynecologic Oncology Group P.C.; Columbus Cancer Council; Cooper Hospital/University Medical Center; Fox Chase Cancer Center; Milton S. Hershey Medical Center; University of Iowa Hospitals and Clinics; University of Minnesota Medical School; University of Mississippi Medical Center; University of North Carolina School of Medicine; University of Oklahoma; Rush-Presbyterian—St. Luke's Medical Center; State University of New York at Stony Brook; SUNY Downstate Medical Center; Thomas Jefferson University Hospital; Tampa Bay Cancer Consortium; Tufts-New England Medical Center; Wake Forest University School of Medicine.

1

Current address: Rocky Mountain Cancer Center, Denver, CO 80218, USA.

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