Elsevier

Gynecologic Oncology

Volume 94, Issue 2, August 2004, Pages 502-508
Gynecologic Oncology

Phase II trial of Oxaliplatin and 5-Fluorouracil/Leucovorin combination in epithelial ovarian carcinoma relapsing within 2 years of platinum-based therapy

https://doi.org/10.1016/j.ygyno.2004.04.020Get rights and content

Abstract

Objective. To evaluate the efficacy and toxicity of Oxaliplatin and 5-Fluorouracil (5-FU)/Leucovorin (LV) combination in ovarian cancer relapsing within 2 years of prior platinum-based chemotherapy in a phase II trial.

Methods. Eligible patients had at least one prior platinum-based chemotherapy regimen, elevated CA-125 ≥ 60 IU/l, radiological evidence of disease progression and adequate hepatic, renal and bone marrow function. Patients with raised CA-125 levels alone as marker of disease relapse were not eligible. Oxaliplatin (85 mg/m2) was given on day 1, and 5-Fluorouracil (370 mg/m2) and Leucovorin (30 mg) was given on days 1 and 8 of a 14-day cycle.

Results. Twenty-seven patients were enrolled. The median age was 57 years (range 42–74 years). The median platinum-free interval (PFI) was 5 months (range 0–17 months) with only 30% of patients being platinum sensitive (PFI > 6 months). Six patients (22%) had two prior regimens of chemotherapy. A total of 191 cycles were administered (median 7; range 2–12). All patients were evaluable for toxicity. The following grade 3/4 toxicities were noted: anemia 4%; neutropenia 15%; thrombocytopenia 11%; neurotoxicity 8%; lethargy 4%; diarrhea 4%; hypokalemia 11%; hypomagnesemia 11%. Among 27 enrolled patients, 20 patients were evaluable for response by WHO criteria and 25 patients were evaluable by Rustin's CA-125 criteria. The overall response rate (RR) by WHO criteria was 30% (95% CI: 15– 52) [three complete responses (CRs) and three partial responses (PRs)]. The CA-125 response rate was 56% (95% CI: 37–73). Significantly, a 25% (95% CI: 9–53) radiological and a 50% (95% CI: 28–72) CA-125 response rate were noted in platinum resistant patients (PFI < 6 months). The median response duration was 4 months (range 3–12) and the median overall survival was 10 months.

Conclusion. Oxaliplatin and 5-Fluorouracil/Leucovorin combination has a good safety profile and is active in platinum-pretreated advanced epithelial ovarian cancer.

Introduction

Epithelial ovarian cancer remains a major health problem for women in the United States and Europe with incidence rates exceeding 10 per 100,000 [1], [2]. Worldwide, the incidence of ovarian cancer is estimated to be approximately 190,000 cases per annum with 115,000 patients dying from the disease each year [2]. The survival of ovarian cancer patients' correlates most strongly with surgical stage but the disease is rarely detected at an early stage because of the relative lack of specific symptoms. As a result, 75% of patients have advanced disease at presentation [3].

The standard of care for advanced ovarian cancer patients is maximal surgical cytoreduction and chemotherapy [4]. Paclitaxel plus platinum-based chemotherapy has been established as a standard first-line chemotherapy by the GOG studies although the recent ICON3 trial results suggest that carboplatin monotherapy is also a valid treatment option [5], [6]. Most women (>75%) respond to primary chemotherapy but a majority will relapse and they are candidates for further systemic therapy with platinum and non-platinum-based agents [3], [7]. Second-line chemotherapy is palliative and most of the responses are of short duration. Hence, there is a need for non-cross-resistant regimes with better efficacy.

Oxaliplatin is a third-generation platinum derivative which exerts its cytotoxicity by formation of platinated inter- and intra-strand adducts and inhibition of DNA synthesis [8]. Oxaliplatin has in vitro activity against ovarian cell lines and is only minimally cross-resistant with cisplatin [9], [10]. Oxaliplatin has clinical activity in many solid tumors including ovarian cancer [8]. Compared with the other first- and second-generation platinum drugs such as cisplatin and carboplatin, Oxaliplatin is not nephrotoxic, cardiotoxic or mutagenic, and the hematological toxicity and neurotoxicity are usually mild to moderate [11], [12]. The good safety profile of Oxaliplatin makes it a drug suitable for combination therapy.

5-Fluorouracil (5-FU) has in vitro and clinical activity against ovarian cancer, and in the past, 5-FU has been used as part of combination therapy for the first-line treatment of the disease [13], [14], [15]. 5-FU also has modest activity in recurrent epithelial ovarian carcinoma [16], [17]. LV (folinic acid) has been extensively studied as a modulator of 5-Fluorouracil [18]. Oxaliplatin has a favorable pharmacokinetic and safety profile in combination with 5-FU and LV [19]. The combination of Oxaliplatin and 5-FU has synergistic activity and is active even in 5-FU-refractory colorectal cancer patients [19], [20]. Moreover, this synergistic activity is not associated with significantly increased toxicities [21]. The weekly 5-FU/LV bolus regimen was selected for this study because of the better toxicity profile compared with the Mayo regimen [22]. Moreover, preclinical data indicate that the Oxaliplatin and 5-FU/LV combination is more cytotoxic when 5-FU is given as a short exposure [23].

The primary objective of this open-label phase II study was to evaluate the efficacy (radiological and CA-125 response rates) and toxicity of Oxaliplatin and 5-FU/LV combination in patients with relapsed platinum-pretreated ovarian cancer.

Section snippets

Patients and methods

The local institutional ethics committee approved the protocol and written informed consent was obtained from all the patients.

Women ≥18 years with histologically confirmed ovarian cancer and recurrent disease documented by clinical, radiological and CA-125 findings were enrolled. Patients with raised CA-125 levels alone as marker of disease relapse were not eligible. Eligible patients had at least one prior platinum-based chemotherapy regimen, elevated CA-125 ≥60 IU/l, radiological evidence of

Patient characteristics

A total of 27 patients were enrolled between September 1999 and November 2001. Patients' characteristics are listed in Table 1. The median age of patients was 57 years (range 42–74 years). The performance status of 78% of patients was 0 or 1. A majority of patients had serous histology (67%) and advanced disease at presentation (stage III/IV: 59%/33%). All 27 patients had received at least one prior platinum-based chemotherapy regimen and 21 patients had received a prior taxane-based regime.

Discussion

Apart from platinum compounds, chemotherapeutic agents that are useful in the second-line setting include Paclitaxel, Topotecan, Etoposide, Pegylated Liposomal Doxorubicin, Gemcitabine, Vinorelbine and Ifosfamide. The response rates to these agents range from 6% to 44% [7], [30]. The response of relapsed ovarian cancer to second-line agents is heavily influenced by the disease-free interval or platinum-free interval (PFI) [7]. The response rates to second-line agents in platinum-sensitive

Acknowledgements

Sanofi-synthelabo provided a grant-in-aid for the conduct of this phase II trial. We thank Arlene Mitchell and Dr. Subhash Khanna for their help in conducting this trial.

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