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