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