Oxaliplatin in Tumors Other Than Colorectal Cancer

Introduction

In preclinical studies, oxaliplatin(Drug information on oxaliplatin) (Eloxatin) has demonstrated in vivo activity that is comparable or superior to cisplatin(Drug information on cisplatin) (Platinol) at equitoxic doses in a variety of murine tumors. It is active in several tumor models, including colon adenocarcinomas #26 and #38, L1210 leukemia, P388 leukemia, Lewis lung carcinoma, B16 melanoma, M5076 reticulum cell sarcoma, and mammary 16/C models (see Table 1 and Table 2). Xenograft studies have shown the superior activity of oxaliplatin compared with other platinum compounds in mammary and non-small-cell lung cancer, as well as in colorectal tumors.[1]

Additivity or synergistic activity in various tumors has also been reported for oxaliplatin in combination with a number of agents. These include fluorouracil(Drug information on fluorouracil) (5-FU) in GR mammary and human HT-29 colorectal cancer cell lines, cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) and carboplatin(Drug information on carboplatin) (Paraplatin) in L1210 leukemia, paclitaxel(Drug information on paclitaxel) (Taxol) in MV-522 human lung carcinomas, and irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) in GR mammary tumors.[1]

Data have been reported from clinical trials of oxaliplatin for a number of cancers other than colorectal cancer. The greatest amount of accumulated data in this regard has been in ovarian cancer, although smaller studies have been conducted in a variety of disease settings, including breast, pancreatic, and non-small-cell lung cancer, and in patients with lymphoma and germ-cell tumors. These data indicate that oxaliplatin may play an important role in the treatment of many of these settings.

Ovarian Cancer

Oxaliplatin has been evaluated as monotherapy in pretreated patients with advanced ovarian cancer in a number of studies.[2-4] In the initial 1996 phase II study by Chollet and colleagues,[2] treatment of oxaliplatin in 34 patients (31 evaluable) with epithelial ovarian cancer was associated with an overall response rate of 29% and a median survival of 12 months. All study patients received platinum therapy previously, and 16% had prior treatment with a taxane; patients had a median of three prior courses of chemotherapy. This compassionate-use trial accrued patients who were otherwise ineligible for phase II studies.

A response was observed in 6 of 13 patients (46%) with platinum-sensitive disease (ie, relapse at > 6 months after prior platinum treatment) and in 3 of 18 (17%) with platinum-resistant disease. The investigators concluded that the data justified further confirmatory phase II and combination chemotherapy studies.

In a recent report by Bougnoux and coworkers,[3] the overall response rate in a group of 48 patients (42 evaluable) with advanced ovarian cancer who had been treated with single-agent oxaliplatin was 26.1%, with a median overall survival of 15 months. All study patients had received prior platinum treatment, and 44% had prior treatment with a taxane; patients had a median of one prior course of chemotherapy. Response rates were 41.7% (10 of 24) in those with platinum-sensitive disease and 5.5% (1 of 18) in those with platinum-resistant disease. These data confirmed previous reports on the single-agent activity of oxaliplatin in pretreated patients with advanced ovarian cancer, and demonstrated a good tolerance profile.

Phase II Study

The European Organization for Research and Treatment of Cancer (EORTC) gynecologic cancer cooperative group recently performed an open-label, randomized, phase II study comparing oxaliplatin at 130 mg/m² every 3 weeks (2-hour infusion) and paclitaxel at 175 mg/m² every 3 weeks (3-hour infusion) in patients with pretreated advanced ovarian cancer.[4] Eligibility criteria included metastatic epithelial ovarian carcinoma, measurable disease, one or two prior courses of a platinum-containing chemotherapy, and a platinum-free interval of ≤ 12 months.

The characteristics of the 41 patients who were randomized to paclitaxel and the 45 who were randomized to oxaliplatin were comparable with regard to median age (62 vs 59 years), World Health Organization (WHO) performance status (PS) 0/1 (85% vs 84%), serous histologic subtype (73% vs 73%), one to two prior chemotherapy courses (73%/27% vs 64%/36%), and platinum-free intervals of < 6 months/6 to 12 months (76%/24% vs 71%/29%) (see Table 3). Patients were treated until disease progression or discontinuation due to excessive toxicity.

The reported overall response rates were 17% in the paclitaxel arm and 16% in the oxaliplatin arm, with a median time to progression of 14 and 12 weeks, respectively, and median overall survival durations of 8.5 and 9.6 months, respectively (see Table 4).[4] In general, grade 3/4 toxicities were more common in the paclitaxel arm than in oxaliplatin recipients, with neutropenia occurring in 22% vs 0%, arthralgia/myalgia in 12% vs 0%, alopecia in 54% vs 0%, sensory neurotoxicity in 7% vs 9%, motor neurotoxicity in 7% vs 0%, and nausea/vomiting in 5% vs 11%.[4]

Oxaliplatin in Combination Regimens

A number of investigators have assessed the utility of oxaliplatin in combination chemotherapy for ovarian cancer. There is considerable rationale for combination platinum ("biplatin") regimens, including synergistic activity, absence of cross-resistance, and the ability to increase platinum dose intensity. Soulie and collaborators[5] treated 25 heavily pretreated patients (13 with cisplatin-refractory disease) with oxaliplatin at 130 mg/m2 (2-hour infusion) plus cisplatin at 100 mg/m2; any dose reductions maintained the 1.3 to 1 dose ratio.

Dose-limiting toxicities consisted of grade 3 cumulative peripheral sensory neuropathy, which resolved within a few months after discontinuation of treatment, and grade 3/4 neutropenia and/or thrombocytopenia, which occurred in 35% to 40% of patients. The overall response rate in 22 measurable/evaluable patients was 40% (95% confidence interval [CI]: 21%-61%), with complete responses reported in 8% and partial responses in 32%. The median duration of response was 4 months. Objective responses were observed in 58% of patients (7/12; 95% CI: 28%-85%) with potentially platinum-sensitive disease and in 23% (3/13; 95% CI: 5%-54%) with platinum-resistant disease. Soulie et al concluded that these encouraging results provided the basis for new first-line and second-line combination regimens in ovarian carcinoma.[5]

Compassionate-Use Study

In a compassionate-use study of oxaliplatin and paclitaxel, Kalla and coworkers[6] assessed a combination of oxaliplatin and paclitaxel in 37 pretreated patients with recurrent ovarian cancer. Twenty patients were refractory to platinum compounds, 16 were sensitive, and one was unclassified. All patients had received one prior treatment regimen, and 12 had received both cisplatin and carboplatin therapy. Oxaliplatin (100-135 mg/m²) and paclitaxel (135-175 mg/m²) were administered sequentially on the same day, with the cycle repeated every 3 to 4 weeks.

The main grade 3/4 toxicity was neutropenia (16%/13%). Peripheral neurotoxicity, the most common side effect, occurred in 94% of patients (grade 2/3 in 12 and 6 patients). The overall response rate was 41%, with patients in the evaluable cohort achieving a response rate of 48% and platinum-resistant patients, a response rate of 33%. The median progression-free survival was 9.4 months and the median overall survival was 25 months. This combination is very promising after platinum failure.

Phase II/III Trial

Misset and colleagues[7] have reported the final results of a phase II/III trial comparing oxaliplatin vs cisplatin in 177 previously untreated patients with stage IIc, III, and IV advanced ovarian cancer. Both arms included cyclophosphamide at 1,000 mg/m² with either oxaliplatin at 130 mg/m² (n = 85) or cisplatin at 100 mg/m² (n = 92). A total of 453 cycles in 85 patients were evaluable for toxicity in the oxaliplatin arm vs 455 cycles in 92 patients in the cisplatin arm. Significant differences in toxicities included grade 3/4 anemia, 5 patients in the oxaliplatin arm vs 31 patients in the cisplatin arm (P < .0001); grade 3/4 vomiting, 22 vs 51 patients, respectively (P < .0001); and grade 3/4 leukopenia, 32 vs 51 patients, respectively (P < .042). Peripheral neuropathy was mild (grade 1-2), with one grade 3 neuropathy in the cisplatin arm. Creatinine clearance at the end of treatment favored the oxaliplatin arm, confirming its lack of nephrotoxicity.

Response was reviewed according to both surgical assessment and objective response criteria. A surgical response was noted in 32 of 50 patients (64%) in the oxaliplatin arm, and in 33 of 49 patients (67%) in the cisplatin arm. A clinical response was noted in 23 of 69 patients (33%) and in 29 of 69 patients (42%) in the two groups, respectively. This recent update shows survival favoring the oxaliplatin arm, with median survival of 36 months vs 25 months in the cisplatin arm. Progression-free survival was 13 months in both arms. The authors concluded that the safety and efficacy of the oxaliplatin combination confirm the interest of oxaliplatin combined with new agents active in advanced ovarian cancer.