Irinotecan (CPT-11) combined with cisplatin in patients with refractory or recurrent ovarian cancer

Abstract

Irinotecan hydrochloride (CPT-11) is reportedly effective for the treatment of refractory or recurrent ovarian cancer. We investigated the antitumor efficacy and toxicity of combination therapy with CPT-11 and cisplatin in 25 patients (mean age 55 years, range 35–73 years) with refractory or recurrent ovarian cancer who had previously undergone platinum-based combination chemotherapy. Patients received two or more courses of treatment consisting of 50 or 60 mg/m² of CPT-11 on days 1, 8 and 15 and 50 or 60 mg/m² of cisplatin on day 1 administered intravenously. All patients were evaluable for the response and the toxicity profile. Complete responses were obtained in two (8.0%) patients and partial responses were obtained in eight (32.0%) patients, giving an overall response rate of 40% (10 of 25 patients) (95% CI 23.0–59.0%). The median duration of response was 5.5 months (range 2–27 months), the median time to tumor progression was 6 months (range 3–28 months) and the median overall survival was 12 months (range 3–39+ months). Grade 3 or 4 neutropenia, which was the most frequent and severe toxic effect, occurred in 36 (54.5%) of the 66 treatment courses and in 16 (64.0%) of 25 patients. The nadir of the leukocyte count occurred on days 18–19. Neutropenia was reversed by short-term administration of granulocyte colony-stimulating factor for 2–10 days. Less serious hematologic effects and non-hematologic effects, such as diarrhea, were also observed. This preliminary study showed that this regimen of CPT-11 and cisplatin was effective in patients with recurrent ovarian cancer.

Introduction

Although 70–80% of patients with ovarian cancer respond to initial treatment with combination chemotherapy, including platinum 1, 2, most of these cancers recur and the patients eventually die of disease that is resistant to the available cytotoxic agents. One current research approach focuses on identifying new agents without cross-resistance to currently available cytotoxic agents. Over the past few years, several drugs with novel mechanisms of action and good activity against ovarian cancer, such as paclitaxel, topotecan and irinotecan, have been identified. The concomitant use of paclitaxel and cisplatin has been introduced as first-line chemotherapy for the treatment of patients with advanced ovarian cancer [3]. However, the effect of topotecan or irinotecan, which are topoisomerase-I inhibitors, in combination with cisplatin has not been investigated.

Irinotecan hydrochloride (CPT-11) is a semisynthetic derivative of camptothecin, an alkaloid contained in such plants as Camptotheca acuminata which originated in China [4]. CPT-11 stabilizes the topoisomerase-I DNA complex, which is necessary for the replication of DNA. Topoisomerase-I mediates the relaxation of supercoiled DNA by cleaving a single strand of DNA and then reseals the cleavage site after uncoiling 5, 6. The camptothecins bind to this topoisomerase-I DNA complex and prevent the re-ligation of DNA. They also block DNA and RNA synthesis by inhibiting the polymerase action in dividing cells, which results in cell apoptosis 7, 8, 9.

Several phase II studies have shown that CPT-11 is active against colorectal cancer [10], small-cell lung cancer 11, 12, non-small-cell lung cancer 13, 14, 15, lymphoma [16], stomach cancer [17], breast cancer [18], cervical cancer and ovarian cancer 19, 20, 21, 22, 23, 24. Because cisplatin and CPT-11 are active against ovarian cancer as single agent therapy and because CPT-11 has additive and synergistic effects in combination with cisplatin [25], we conducted a preliminary study to evaluate the therapeutic activity and the toxicity profile of the combination of CPT-11 and cisplatin in patients with recurrent ovarian cancer.