The activity of taxanes compared with bleomycin, etoposide, and cisplatin in the treatment of sex cord-stromal ovarian tumors

Abstract

Objective

We compared the efficacy and side effects of taxanes, with or without platinum, to bleomycin, etoposide, and cisplatin (BEP) in treating sex cord-stromal ovarian tumors.

Methods

We conducted a retrospective review of all patients with sex cord-stromal ovarian tumors seen at our institution from 1985 to 2002. Eligible patients were those who underwent pathologic confirmation, clinical evaluation, and treatment with a taxane or BEP for initial or recurrent disease.

Results

Of 222 patients identified, 21 received BEP for new (n = 11) or recurrent disease (n = 10); 44 received a taxane during 48 treatment episodes (four patients on two occasions each) for new (n = 11) or recurrent disease (n = 37). Newly diagnosed patients treated with BEP vs. taxanes had no significant difference in response rate (Fisher's exact test, P = 1), progression-free survival (PFS) (log-rank test, P = 0.213), or overall survival (log-rank test, P = 0.994). Among patients treated for recurrent measurable disease, the response rate was higher for BEP-treated (71%) than for taxane-treated patients (37%), but this was not statistically significant. In all patients treated for recurrent disease, there was no significant difference in failure to progress at chemotherapy completion between BEP- (70%) and taxane-treated patients (62%) or in median PFS (11.2 vs. 7.2 months). The presence of platinum in taxane-containing regimens correlated with response. Taxane-related side effects included neutropenia (n = 6), anemia (n = 1), thrombocytopenia (n = 1), myelodysplasia (n = 1), and hypersensitivity (n = 1). BEP-related side effects included pulmonary fibrosis (n = 3) and neutropenia (n = 2).

Conclusions

Taxanes demonstrated activity against sex cord-stromal tumors of the ovary and may be less toxic than BEP. Taxane and platinum combination chemotherapy warrants further investigation in this disease.

Introduction

Sex cord-stromal tumors (SCSTs) of the ovary are rare neoplasms that account for only 7% of all ovarian malignancies [1]. Because SCSTs are uncommon, determining the optimal treatment has been difficult. Most published studies have combined several histologic subtypes of SCSTs, so the recommendations for treating specific tumors have been based on limited data. Most data have been gathered from patients with adult granulosa cell tumors, but treatment has often been generalized to other tumor types. Additionally, many of these tumors are clinically indolent, so long-term follow-up is required to accurately interpret outcomes data.

Surgery remains the cornerstone of initial treatment for SCSTs, but this is followed in many cases by cytotoxic chemotherapy. Over the past three decades, the recommended chemotherapy regimen has changed from vincristine, doxorubicin, and cyclophosphamide (VAC) to bleomycin, etoposide, and cisplatin (BEP), and since the 1980s, platinum-based chemotherapy has been the most widely used postoperative treatment [2], [3], [4], [5]. Studies in 1986 and 1990 investigated combinations of cisplatin, vinblastine, and bleomycin for treating advanced stage and metastatic granulosa cell tumors of the ovary [6], [7]. In 1996, Gershenson et al. reported a high rate of response to BEP in patients with poor-prognosis SCSTs of the ovary [8]. The use of etoposide instead of vinblastine was based on an earlier study in which patients with testicular germ cell tumors demonstrated reduced toxicity and equivalent efficacy with this substitution [9]. The Gynecologic Oncology Group (GOG) subsequently evaluated BEP in the treatment of incompletely resected stages II–IV or recurrent SCSTs of the ovary [10]. The investigators found that 14 of the 38 patients who underwent a second-look laparotomy had negative findings and that the 6 complete responders had a 24.4-month median duration of response. Based on the results of this trial, surgery followed by BEP has become a commonly utilized treatment option for patients with advanced SCSTs of the ovary.

Unfortunately, this treatment approach is not optimal. The 1999 GOG trial also showed that only one of seven patients with advanced disease experienced a durable remission and that nearly half of the patients with recurrent disease experienced progression. Gershenson et al. noted similar limitations in durable remission [8]. Both trials also revealed significant bleomycin-related toxicity, including two cases of pulmonary toxicity and two additional deaths from bleomycin-related pulmonary fibrosis [8], [10]. Toxicity has also resulted from the use of etoposide, which is associated with the subsequent development of secondary malignancies [11].

In view of the limited activity and significant toxicity associated with BEP, we have sought to identify other regimens with equivalent or improved activity and decreased toxicity. Attempts to eliminate bleomycin from the BEP treatment regimen and administer only etoposide and cisplatin have previously been unsuccessful in patients with nonseminomatous testicular germ cell tumors, resulting in decreased toxicity but loss of therapeutic activity [12], [13]. For this reason, etoposide and cisplatin alone have been thought to constitute inadequate therapy in this group of malignancies, and etoposide and cisplatin have not been pursued as a potential treatment regimen for SCSTs of the ovary.

Over the past decade or so, we have treated patients with newly diagnosed or recurrent SCSTs with taxanes, alone or in combination with platinum and other agents, as well as with the standard BEP regimen. Prior to this, the use of taxanes to treat SCSTs had been reported in only two patients with granulosa cell tumors [14], [15]. Our initial experience with taxanes suggested antitumor activity in patients with initial and recurrent SCSTs of the ovary [16]. The purpose of this study was to retrospectively compare our taxane chemotherapy experience with our BEP experience during the same period to determine whether taxanes, alone or in combination with platinum agents, warrant further study as a treatment option for patients with SCSTs of the ovary.