Elsevier

Gynecologic Oncology

Volume 88, Issue 3, March 2003, Pages 266-269
Gynecologic Oncology

Regular article
Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer

https://doi.org/10.1016/S0090-8258(03)00011-8Get rights and content

Abstract

Objective

To determine the activity and tolerability of gemcitabine in the palliative treatment of ovarian cancer.

Methods

Patients affected by ovarian cancer, and with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, were enrolled into this phase II study. Gemcitabine, 1000 mg/m2, was administered on days 1, 8, and 15, by 30-min intravenous infusion. Cycles were repeated every 28 days.

Results

Fifty patients were enrolled. All the patients were platinum and/or paclitaxel resistant (median number of previous regimens, 2; range, 1–5). Median platinum-free interval was 3 (range, 1–11) months and median paclitaxel-free interval was 6 (range, 1–36) months. A total of 210 courses were evaluable for toxicity, with a median number of four cycles administered per patient (range, 1–10). A grade 3 or 4 hematological toxicity was observed in 27 patients (54%) (anemia grade 3, 16%; grade 4, 2%; neutropenia grade 3, 24%; grade 4, 18%; thrombocytopenia grade 3, 8%; grade 4, 0%). A 20–50% dose reduction was required for 36 patients (72%, 55% of cycles). Blood transfusions were necessary for 15 patients (30%), while 2 (4%) were treated with erythropoetin. Granulocyte colony-stimulating factor was necessary in 4 patients (8%). Nonhematological toxicity was mild and manageable. Only 4 patients (8%) experienced a grade 3 hepatic toxicity (elevated liver enzymes). Forty-one patients (82%) are, so far, evaluable for response. Among them, 7 partial responses (17%; 95% confidence interval [CI], 6–29), 15 disease stabilizations (>16 weeks) (36.6%; 95% CI, 21.9–51.3), and 19 progressions (46.3%; 95% CI, 31.0–61.6) have been registered. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks.

Conclusions

This study confirms the activity and safety of gemcitabine in heavily pretreated patients with recurrent ovarian cancer.

Introduction

Ovarian cancer is the gynecological malignancy with the highest mortality [1]. Cytoreductive surgery and the introduction of platinum/taxane based-chemotherapy in the past decade have improved progression-free and overall survival. However, the majority of ovarian cancer patients still relapse within 2 years of the end of primary treatment and die of disease within 5 years from their initial diagnosis [2]. The management of tumor recurrence remains a clinical challenge, since the chance of response to a secondary treatment is currently less than 20% [3], especially if the disease is platinum resistant [4]. To improve this outcome, several clinical trials are now exploring the possibility of incorporating new drugs into the first-line chemotherapy regimen [5]. Furthermore, new biological agents and molecularly targeted therapies aimed to overcome drug resistance with less toxic effects are under investigation [6].

Pharmaceutical research has also been focusing on the synthesis of new antineoplastic compounds whose profiles match ease of administration and low toxicity, to warrant the probability of cure with a minor impact on patient quality of life. Gemcitabine, a novel nucleoside analogue that replaces natural deoxycytidine into the DNA strand and blocks DNA synthesis, seems to respond to these requirements, since it combines an effective antiproliferative property with safety and tolerability [7]. This drug proved to be highly active in a variety of solid tumors [8], and several studies have been performed using gemcitabine in ovarian cancer patients, with response rates of approximately 20% even in platinum-resistant cases, with low and well-tolerated hematological and nonhematological toxicity [9], [10], [11], [12].

In this phase II study gemcitabine has been given to a subset of ovarian cancer patients with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, and who, in most cases, had already failed a further salvage treatment.

Section snippets

Patients and methods

Patients with a documented primary or secondary platinum/paclitaxel resistance were evaluated. Resistance to cytotoxic agents was defined as progression during or relapse within 6 months after stopping first-line therapy. Patients who had previously experienced a clinical remission under platinum or paclitaxel, and relapsed after a treatment-free interval of more than 6 months, had been retreated with platinum and/or paclitaxel before entering the study. Many patients were also treated with

Results

From September 1996 to March 2002, 50 patients were enrolled at the Department of Gynecologic Oncology of the University Hospitals, in Leuven, Belgium. Patient characteristics, including the number of prior chemotherapeutic regimens, are detailed in Table 1. The median age was 57 (range, 24–83) years. Six patients had also received whole abdomen radiotherapy. In the majority of cases, further previous treatments consisted of drugs such as topotecan, doxorubicin, hexamethylmelamine, oxaliplatin,

Discussion

Recurrence of disease is the major clinical problem in the management of ovarian cancer. During the last decade, progress made in clinical research has led to the introduction in clinical practice of such a quantity of new active drugs that physicians now have many options when disease relapses. Disappointingly, when the tumor is platinum resistant, the reported response rates are lower than 20%, regardless of therapy [16].

In this study gemcitabine proved to be well tolerated in heavily

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