A phase II study of gemcitabine (gemzar, LY188011) in the treatment of recurrent or persistent endometrial carcinoma: A gynecologic oncology group study

doi:10.1016/j.ygyno.2010.11.027

Gynecologic Oncology

Volume 121, Issue 1, April 2011, Pages 118-121

https://doi.org/10.1016/j.ygyno.2010.11.027 Get rights and content

Abstract

Objective

The study aims to evaluate the anti-tumor activity and toxicity of gemcitabine in patients with persistent or recurrent endometrial carcinoma.

Methods

Patients with advanced or recurrent carcinoma of the endometrium previously treated with one chemotherapy regimen were treated on a phase II trial conducted by the Gynecologic Oncology Group (GOG). Gemcitabine was administered as an intravenous infusion at a dose of 800 mg/m² over 30 min on days 1 and 8 every 21 days.

Results

Twenty-four patients were entered by 11 GOG member institutions. One patient was ineligible due to wrong primary tumor. A total of ninety 21-day cycles of therapy were administered with 35% of patients receiving four or more cycles. All patients had been previously treated with a platinum-based regimen. One patient had a partial response (4%), nine had stable disease (39%), and twelve had increasing disease (52%). The median progression-free survival was 1.7 months. Treatment was generally well tolerated with only 22% of patients experiencing grade 3 or grade 4 hematologic toxicity. There was one treated-related death due to pulmonary toxicity.

Conclusion

Gemcitabine has minimal activity in the treatment of recurrent or persistent endometrial carcinoma at the dose and schedule tested.

Research Highlights

► Gemcitabine was minimally active in the treatment of advanced endometrial carcinoma. ► The partial response rate was 4% and the stable disease rate was 39%. ► Grade 3 or grade 4 toxicity occurred in 22% of patience.

Introduction

Carcinoma of the endometrium is the most common gynecologic malignancy in the United States and typically presents as an early stage amenable to curative local therapy. Unfortunately, patients with metastatic disease have poor outcomes. Cytotoxic agents have shown only temporary effectiveness in the treatment of advanced or recurrent endometrial carcinoma. To date, only three drugs with definite activity against endometrial carcinoma have been identified: doxorubicin, cisplatin, and paclitaxel [1], [2], [3], [4], [5], [6], [7]. Other less active agents against endometrial carcinoma have been reported and include 5-fluorouracil, vincristine, Ifosfamide, and ixabepilone [8], [9], [10], [11]. The Gynecologic Oncology Group (GOG) has evaluated many additional cytotoxic agents in phase II trials treating metastatic endometrial carcinoma and none of these have demonstrated significant activity [12].

Gemcitabine (Gemzar, LY188011, Eli Lilly and Company, Indianapolis, Indiana) interferes with malignant cells undergoing DNA synthesis (S-phase) and blocks G1/S progression through the formation of active diphosphate and triphosphate metabolites. The cytotoxic effect of gemcitabine is through actions of both diphosphate and triphosphate metabolites. Gemcitabine diphosphate inhibits ribonucleotide reductase blocking the production of deoxynucleoside triphosphates for DNA synthesis. Gemcitabine triphosphate competes with dCTP incorporation into DNA. After incorporation of the gemcitabine nucleotide into the DNA, only one additional nucleotide can be added to the growing DNA strand, halting DNA synthesis. A “masked chain termination” occurs when DNA polymerase epsilon is unable to remove the gemcitabine nucleotide [13].

Gemcitabine has activity in multiple malignancies including pancreas, non-small cell lung carcinoma, biliary, breast, ovarian, cervical, and leiomyosarcoma of the uterus [14], [15], [16], [17], [18], [19], [20]. Gemcitabine is the single most active cytotoxic agent in the treatment of pancreatic carcinoma, characterized as an aggressive, chemotherapy-resistant malignancy. The GOG has evaluated gemcitabine in multiple tumor types and was included in phase III trials of ovarian and cervical cancer treatment as well as phase II studies in leiomyosarcoma of the uterus. No clinical trials of gemcitabine treatment of endometrial carcinoma have been reported. The diverse activity of gemcitabine against multiple tumor types makes gemcitabine an appropriate agent to evaluate in patients with advanced or recurrent carcinoma of the endometrium. The purpose of this study (GOG 129-Q) is to determine the anti-neoplastic activity of gemcitabine in patients with advanced or recurrent endometrial carcinoma who failed treatment with other cytotoxic agents and to determine the nature and degree of toxicity in this cohort of patients.

Section snippets

Methods

Patients had to have recurrent or persistent endometrial adenocarcinoma that was refractory to curative therapy or established treatments to be eligible for this protocol. Histologic confirmation through a central review by the GOG pathology committee was required. All patients must have had measurable disease, defined as at last one lesion that can be accurately measured in at least one dimension. Each lesion had to be ≥ 20 mm when measured by conventional techniques, including palpation, plain

Results

From February 2, 2009 to July 27, 2009, 24 patients were entered by 11 member institutions of the GOG. Pathology review deemed one patient ineligible for incorrect tumor type. Table 1 represents the characteristics of the 23 eligible and evaluable patients. The median age was 64 years (range 48–79). Endometrioid carcinoma was the most common histology occurring in 52% of patients. All 23 patients had received previous treatment with a platinum-based chemotherapy regimen with 16 patients

Discussion

The search for effective treatment of metastatic endometrial cancer untreatable by surgery or radiation has been disappointing. Choices for treatment of these patients are limited to chemotherapy or endocrine therapy. To date, only doxorubicin, cisplatin, and paclitaxel have demonstrated definitive cytotoxic activity against carcinoma of the endometrium [2], [4], [5], [7]. Other data has suggested possible activity of ifosfamide, 5-fluorouracil, vincristine, and ixabepilone [8], [9], [10], [11]

Conflict of interest statement

Dr. David Tait is a speaker with Merck. All other co-authors have no conflicts of interest to declare.

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Endometrial cancer incidence and mortality are rising among all ethnic groups. Carboplatin plus paclitaxel is the established frontline treatment for advanced/recurrent disease; however, subsequent treatment with traditional cytotoxic chemotherapy is challenging. The molecular characterization of endometrial cancer has provided important insights into the biological drivers of carcinogenesis, which has allowed for the development of newer precision immunotherapies and targeted therapies, including pembrolizumab, dostarlimab, and lenvatinib. Until recently, platinum rechallenge was often considered at the time of recurrence, given the lack of other available therapeutic options; however, “platinum sensitivity” in endometrial cancer is subjective and largely based on expert opinion and/or practitioner experience. Small retrospective studies have tried to provide guidance on the utility of platinum rechallenge, but they are limited by variable patient characteristics and small sample sizes. The applicability of these retrospective studies to contemporary clinical practice is difficult in the setting of changing patient demographics, a better understanding of endometrial cancer drivers, and the recent approvals of immune checkpoint inhibitors and the combination of lenvatinib plus pembrolizumab in the second-line setting. The primary focus of this review is to distill the available data regarding platinum-doublet chemotherapy rechallenge and highlight recent pivotal developments in endometrial cancer treatment, as well as future directions.
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^☆: 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, University of North Carolina School of Medicine, Rush-Presbyterian St. Luke's Medical Center, Washington University School of Medicine, Women's Cancer Center, University of Oklahoma, Case Western Reserve University, University of Wisconsin, Women and Infants Hospital, The Hospital of Central Connecticut and Community Clinical Oncology Program.

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A phase II study of gemcitabine (gemzar, LY188011) in the treatment of recurrent or persistent endometrial carcinoma: A gynecologic oncology group study☆

Abstract

Objective

Methods

Results

Conclusion

Research Highlights

Introduction

Section snippets

Methods

Results

Discussion

Conflict of interest statement

Gynecol. Oncol.

Gynecol. Oncol.

Gynecol. Oncol.

Gynecol. Oncol.

Gynecol. Oncol.

Gynecol. Oncol.

Comparison of adriamycin with cyclophosphamide in patients with advanced endometrial cancer

Cancer Treat. Rep.

Phase II Trial of Adriamycin in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study

Cancer Treat. Rep.

A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study

J. Clin. Oncol.

A phase II trial of cisplatin as second-line chemotherapy in patients with advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group Study

Am. J. Clin. Oncol.

Circadian-timed combination doxorubicin-cisplatin chemotherapy for advanced endometrial carcinoma. A phase II Study of the Gynecologic Oncology Group

Am. J. Clin. Oncol.

Chemotherapy in management of advanced or recurrent cervical and endometrial carcinoma

Cancer

A phase II trial of vincristine in advanced or recurrent endometrial carcinoma. A Gynecologic Oncology Group Study

Am. J. Clin. Oncol.