Elsevier

Gynecologic Oncology

Volume 97, Issue 3, June 2005, Pages 893-897
Gynecologic Oncology

Irinotecan hydrochloride (CPT-11) and mitomycin C as the first line chemotherapy for ovarian clear cell adenocarcinoma

https://doi.org/10.1016/j.ygyno.2005.03.009Get rights and content

Abstract

Objective.

The purpose of this study was to report the results of adjuvant CPT-11 and MMC combination chemotherapy (CPT-M) for ovarian clear cell adenocarcinoma (OCCA).

Methods.

Between 1996 and 2002, 20 patients with OCCA underwent primary debulking surgery and received 6 treatments of CPT-11 (140 mg/m2) in combination with MMC (7 mg/m2), 2 weeks apart with a space of 3–4 weeks between the 3rd and 4th treatment in adjuvant setting. Overall survival was compared with our historical control treated between 1983 and 1995, in which 14 patients with OCCA were treated with an initial optimal standard surgery and postoperative adjuvant cyclophosphamide, doxorubicin, and cisplatin (CAP) combination chemotherapy.

Results.

Median age was 51 years old (range, 29–74). Twelve patients were in stage Ic, 1 in stage IIa, 5 in stage IIc, 1 in stage IIIc, and 1 in stage IV. Optimal cytoreduction with standard surgery was obtained in all 20 patients. The major toxicity with this regimen was neutropenia, which was reversible. The incidences of grade 3 and 4 neutropenia were 25% and 15%, respectively. The non-hematological toxicities were generally mild and well tolerated. One patient with stage Ic refused chemotherapy after the first cycle of CPT-M, and died of her disease 8 months after initial surgery. Five-year survival rate was 95.0% for CPT-M group, and 63.5% for CAP group (P = 0.042). Survival was significantly better for patients treated with CPT-M.

Conclusion.

This preliminary study shows that the combination of CPT-M appears to be safe and useful in patients with OCCA. Prospective randomized trials should be conducted to assess this regimen appropriate for women with OCCA.

Introduction

Ovarian clear cell carcinoma (OCCA) was originally termed mesonephroid by Schiller in 1939 as it was thought to originate from mesonephric structures and seemed to resemble renal cell carcinoma [1]. However, in 1967, Scully and Barlow noted the frequent association of clear cell carcinomas with endometriosis and endometrioid carcinoma of the ovary, suggesting a mullerian origin [2]. In 1973, the World Health Organization recognized clear cell carcinoma as a distinct type of epithelial ovarian neoplasm [3]. Many gynecologic oncologists seem to feel that OCCA is somehow different from other subtypes of epithelial ovarian cancer, and they sometimes express disappointment with the treatment results in OCCA patients.

The introduction of cisplatin-based chemotherapy in the late 1970s markedly changed the postoperative management of ovarian cancer patients. Nonetheless, the results and value of these efforts and therapies applied to OCCA are as yet undetermined [4], [5], [6], [7]. Crozier et al. [8] found no differences in progression-free interval or survival of OCCA patients among 17 patients not treated with chemotherapy, 19 treated with platinum-containing regimen, 18 treated with single agents, and 5 treated with nonplatinum-containing combinations. In the study by Goff et al. [6], overall, 70% of the 23 evaluable patients with stage III OCCA showed progression of disease while on platinum-based chemotherapy, which is significantly different from 29% rate of progressive disease observed in patients with papillary serous carcinoma. Other reports also indicate that OCCA has very low sensitivity to platinum-based chemotherapy [9], [10]. Recently, Sugiyama et al. examined the clinical response to platinum-based chemotherapy in patients with measurable residual OCCA. Patients with OCCA showed a very low response rate of 11.1% (3 of 27), but a high incidence rate of progressive disease (PD) (22 of 27; 81.5%), whereas patients with serous subtype had a high response rate of 72.5% (79 of 109) and a low incidence rate of PD (20 of 109; 18.3%), a difference that was apparently significant [11]. Similarly, the only previous study to date on the subject by Goff et al. reported a higher rate of incidence of PD with platinum-based chemotherapy in OCCA patients with measurable or nonmeasurable disease (16 of 23; 70%) compared with serous subtype patients (10 of 34; 29%) [6]. Another group of authors demonstrated that platinum-based chemotherapy did not appear to improve the survival of patients with OCCA compared with the survival from nonplatinum-based chemotherapy [12]. There are no reports indicating that any patient with pure OCCA shows an appreciable response to platinum-combination chemotherapy.

Several reports demonstrated to establish the treatment for OCCA using irinotecan hydrochloride (CPT-11). In vitro study, SN-38 (the active metabolite of CPT-11) was reported to be the most effective agent, followed by MMC, while there was considerable resistance to cisplatin [13]. The efficacy of CPT-11 and mitomycin C (MMC) combination chemotherapy (CPT-M) had been reported to demonstrate significant activity in patients with platinum-refractory OCCA or mucinous adenocarcinoma [14], [15]. The purpose of this study was to report the results of adjuvant CPT-M for OCCA.

Section snippets

Patients and methods

This was a nonrandomized trial. Women with OCCA who underwent primary debulking surgery between 1996 and 2002 at Niigata University hospital were entered into this trial. Eligibility criteria for this trial included the following. All patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≦2, adequate hematologic (WBC count, 4000/μl to 10,000/μl; absolute neutrophil count, ≧2000/μl; hemoglobin, ≧9.0 g/dl, and platelet count, ≧100,000/μl), hepatic

Patient characteristics and treatment summary

Between April 1996 and December 2002, twenty patients were enrolled into this trial at Niigata University Hospital (CPT-M group). All patents were evaluable for toxicity. Pretreatment characteristics are shown in Table 1. The median age was 51 years (range, 29–74 years). Twelve patients were in stage Ic, 1 in stage IIa, 5 in stage IIc, 1 in stage IIIc, and 1 in stage IV. Optimal cytoreduction (residual disease less than 1 cm) with their initial surgery was obtained in all 20 patients. In our

Discussion

Currently, no anticancer agents are definitively effective for OCCA based on large-scale clinical studies, and the mechanism of resistance to chemotherapy in OCCA is not well understood. Several reports demonstrated to establish the treatment for OCCA using CPT-11. Shimizu et al. performed sensitivity tests of anticancer agents using OCCA cell lines, demonstrating that SN-38 (the active metabolite of CPT-11) was the most effective agent, followed by MMC, while there was considerable resistance

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