Elsevier

Gynecologic Oncology

Volume 96, Issue 1, January 2005, Pages 103-107
Gynecologic Oncology

Evaluation of gemcitabine in previously treated patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group

https://doi.org/10.1016/j.ygyno.2004.09.027Get rights and content

Abstract

Purpose

A multicenter study was conducted to evaluate the activity and toxicity of gemcitabine in patients with previously treated non-squamous cell carcinoma of the uterine cervix.

Patients and methods

Eligible patients were required to have measurable disease with a GOG performance status of 0–2 and adequate bone marrow, renal, and hepatic function. Histologic confirmation of the primary diagnosis was mandatory. Patients were required to have received one prior chemotherapy regimen for metastatic, persistent or recurrent disease. The initial dosage of gemcitabine was 800 mg/m2 weekly times three with 1 week off until progressive disease or adverse side effects prohibited further therapy. Doses were escalated or reduced based on the disease toxicity experiences during the previous cycle.

Results

Twenty-two women were entered into the trial. Three patients did not complete follow-up assessment for tumor response leaving 19 evaluable patients for response. All 22 patients were evaluable for toxicity. A median of two cycles was administered to each patient (range: 1–8). The overall response rate (1 partial response) was 4.5% with 36.4% of patients having stable disease. The median progression-free interval was 2.1 months (range: 0.5–12.7) and the overall survival was 6.5 months (range: 0.6–21.9). One patient had a grade 4 gastrointestinal adverse event (rectovaginal fistula formation attributed to the underlying cancer and not the study agent) complicated by grade 4 metabolic derangement. There were no grade 4 hematologic toxicities or treatment-related deaths.

Conclusions

Gemcitabine as a single agent had minimal activity in previously treated patients with non-squamous cell carcinoma of the uterine cervix.

Introduction

In 2003, an estimated 12,200 women will be diagnosed with cervical cancer [1]. Approximately 4100 patients will die of this disease. Worldwide, cervical carcinoma remains a major cause of cancer death. Most cases are successfully managed with local treatment modalities, that is, surgery and/or radiation therapy, as the mainstays of treatment. Less than 20% of cases are of non-squamous cell histology [2]. However, recent Surveillance, Epidemiologic, and End Results (SEER) data indicate that the incidence of non-squamous cell cervical cancer has increased 29.1% over the last 20 years [3].

Evaluation of new therapies for non-squamous cell carcinoma of the cervix is hampered by its low incidence. Previous trials conducted by the Gynecologic Oncology Group (GOG) constitute virtually all of the available data on the use of chemotherapy in this disease. Only cisplatin, ifosfamide, paclitaxel, and piperazinedione have been demonstrated to have activity against this form of cervical cancer [4], [5]. Responses were usually only partial in nature and of short duration. Recently, oral etoposide has been shown to have modest activity in patients with advanced non-squamous cell carcinoma of the cervix who were treatment-naive [6]. Prior radiation therapy significantly limited the ability to deliver effective doses. Active new agents are needed for the treatment of this disease, particularly drugs that ultimately can be combined with cisplatin and/or radiotherapy to improve front-line treatment.

Gemcitabine is a drug which has these desirable properties. It is a deoxycytidine analogue antimetabolite originally developed as an antiviral agent [7]. When diflurodeoxycytidine triphosphate (dFdCTP) accumulates, apoptosis is triggered through DNA polymerase inhibition and premature chain termination [8]. Gemcitabine is active in multiple preclinical systems against cell lines of various tumor types, including cervical carcinoma [9]. Gemcitabine has been shown to be a potent radiosensitizer as well [10].

Gemcitabine has clinical activity in a variety of solid tumors. It has superior 1 year and overall survival compared with 5-fluorouracil in advanced pancreatic carcinoma [11]. It is active when combined with cisplatin in non-small lung [12] and bladder cancers [13]. There is known single agent activity in ovarian cancer [14] and it seems to act synergistically with cisplatin in this disease [15]. Single agent activity has also been documented in breast cancer [16]. Thus, there is sufficient activity in various non-squamous cell carcinoma cell types to evaluate gemcitabine in patients with non-squamous cell carcinoma of the cervix. Accordingly, a phase II trial was conducted evaluating gemcitabine in this population.

Section snippets

Materials and methods

Patients were enrolled onto the trial with persistent or recurrent non-squamous cell carcinoma of the cervix with documented disease progression. Histologic confirmation of the original primary tumor was required. Eligible cell types included adenocarcinoma, adenosquamous carcinoma, and undifferentiated carcinoma. Patients were required to have measurable disease as defined as lesions which can be measured in at least two dimensions by physical examination or by means of medical imaging

Results

Twenty-two patients were entered onto this trial. Patient characteristics are listed in Table 1. All patients had received prior cisplatin. In two cases, cisplatin was administered only as a radiation sensitizer. Twenty-one of 22 patients had prior radiation therapy.

A median of two cycles (range, 1–8) was administered per patient. There were no treatment related deaths. One patient died before cycle 2 due to progressive disease. Five patients received dose escalation according to protocol

Discussion

It remains controversial whether non-squamous cell carcinoma of the cervix has a worse prognosis compared with squamous cell cancer of the same site [19]. The FIGO Annual Report from 1998 revealed no difference in survival in stage I cervical cancers independent of histologies. However, other studies involving patients with stage IB or stage II disease showed a worse survival for the patients with non-squamous cell cancer [20]. Historically, the GOG conducted separate trials for the two types

Acknowledgments

This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517). The following Gynecologic Oncology Group member institutions participated in this study:

University of Mississippi Medical Center (CA 13633), University of California Medical Center at Los Angeles (CA 13630), Hospital of the University of Pennsylvania (CA 15977), University of Cincinnati College

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