Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study☆,☆☆
Research highlights
► The GOG evaluated the efficacy and tolerability of cetuximab in cervical cancer. ► Cetuximab is well tolerated but has limited activity in persistent/recurrent disease. ► Cetuximab activity may be limited to cervical cancer with squamous cell histology.
Introduction
Cervical cancer remains the second leading cause of cancer death among women worldwide and remains an important health problem for women especially in underserved and minority groups in the Unites States [1]. Although cervical cancer can be cured by radical surgery or radiotherapy with equal effectiveness, pelvic chemo-radiation represents the standard therapy for the treatment of locally advanced disease [2]. Despite technological advances, however, up to 35% of patients overall will develop persistent/recurrent/metastatic disease. Platinum-based chemotherapy represents the gold standard therapy for the treatment of cervical cancer patients who have not responded to primary therapy or have recurrent disease no longer amenable to control with surgery and/or radiation therapy. Unfortunately, most responses to chemotherapy are partial and of short duration, and the most effective treatment of patients with progressive disease on platinum-based chemotherapy has yet to be defined.
The epidermal growth factor receptor (EGFR; HER1/erbB-1) has recently been identified as a target for cancer therapy in multiple human tumors [3], [4], [5], [6], [7], [8]. On endogenous ligand binding, EGFR activation occurs, with receptor homo- or heterodimerization and autophosphorylation of the intracellular tyrosine kinase domain [9], [10]. Subsequently, a complex network of signal transduction pathways is induced, which plays a key role in regulating cell proliferation, differentiation, motility, invasion, and angiogenesis [9], [10], [11], [12], [13]. EGFR is expressed in a variety of human malignancies and its high level of expression has been previously correlated with poor patient prognosis and resistance to treatment in many tumor entities including cervical carcinoma [13], [14], [15], [16], [17], [18].
Cetuximab (C225) is a human/murine chimeric monoclonal antibody formed by cloning the heavy and light chains of the murine antibody (M225) and adapting them for expression with the constant regions of the human immunoglobulin kappa light chain and gamma 1 heavy chain [4], [6], [19]. Preclinical studies have demonstrated that cetuximab binds to the EGFR with high affinity and is able to compete with EGF and TGFα binding, thereby inhibiting subsequent receptor activation and signaling [20], [21]. In addition, binding of cetuximab to EGFR induces receptor dimerization, internalization and receptor down regulation [22], [23]. These processes may consequently lead to several effects such as cell-cycle arrest via upregulation of cyclin-dependent kinase inhibitor p27KIP1, and potentiation of apoptosis [24], [25]. Other effects include inhibition of tumor production of VEGF leading to reduced tumor microvessel density and inhibition of invasion and metastases by inhibiting matrix metalloproteinases [26], [27].
Clinical studies of cetuximab either alone or in combination with cytotoxic agents have demonstrated efficacy in patients with chemotherapy-refractory head and neck or colorectal cancer [28], [29], [30], [31], [32]. In patients with irinotecan-refractory advanced colorectal cancer, treatment with cetuximab either as a single agent or in combination with irinotecan resulted in overall remission rates of 10.8% (95% CI, 5.7% to 18.1%) and 22.9% (95% CI, 17.5% to 29.1%), respectively [30], [31]. Similar results have been reported for patients with platinum-refractory head and neck cancer or non-small-cell lung cancer with cetuximab in combination with chemotherapy [32].
Cervical cancer patients with metastatic/recurrent disease not amenable to radical local excision or regional radiation and who have progressed on platinum-based chemotherapy have limited therapeutic options. The GOG conducted a phase II trial of single-agent cetuximab in patients with persistent or recurrent squamous or non-squamous cervical carcinoma. The primary endpoints of this study were the frequency of patients with tumor responses or who survived progression-free for at least 6 months (PFS at 6 months). The secondary objectives were to estimate the distribution of overall survival (OS), the distribution of PFS, the duration of objective response, and the frequency and severity of adverse events.
Section snippets
Eligibility
Eligibility criteria included patients with persistent or recurrent squamous and non-squamous cell carcinoma of the cervix that was measurable by Response Evaluation Criteria in Solid Tumors (RECIST); one or two prior cytotoxic regimens, not including prior cisplatin-based chemotherapy concomitantly administered with primary pelvic radiation; GOG performance status (PS) of 0 or 1, with PS level 2 allowed in patients having received only one prior cytotoxic regimen; and adequate hematologic
Patient characteristics
From June 2007 through July 2009, 38 patients were enrolled, of whom 3 were excluded (1 for inappropriate prior therapy, 1 because required tests were not performed, and 1 for no documentation of treatment with cetuximab). Thus, the study sample consisted of 35 patients; 26 patients (74.3%) were Caucasian, 5 patients (14.3%) were African-American, 2 patients (5.7%) were Asian and 2 (5.7%) were Hispanic. Patient characteristics of the study group are listed in Table 1.
A total of 103 cycles of
Discussion
The management of cervical cancer no longer amenable to control with surgery or radiation therapy has only minimally improved with the advent of modern chemotherapy. The median survival rate for these patients when treated with current systemic cisplatin combination regimens is only 9 to 10 months [35], [36]. Thus, the development of innovative, effective therapies against advanced/recurrent/metastatic cervical cancer refractory to standard salvage treatment remains a high priority.
One class of
Conflict of interest statement
Dr. Cecelia H. Boardman is on the Speaker's Bureau for Glaso-Smith-Kline and Merck. All other co-authors have no conflict of interest to declare.
Acknowledgment
We thank Sandra Dascomb, Gynecologic Oncology Group (GOG) Statistical and Data Center (SDC), Buffalo NY, for her support in data abstraction and Kim Blaser for publications management. We also wish to thank BMS/ImClone for their industry support.
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This study was presented at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer, March 6–9, 2011, Orlando, Fl.
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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 Office (CA 37517) and R01 CA122728-01A2 CA Grant to AS from the National Institutes of Health. The following Gynecologic Oncology Group member institutions participated in the primary treatment studies: Roswell Park Cancer Institute, Abington Memorial Hospital, University of Mississippi Medical Center, University of Cincinnati, University of North Carolina School of Medicine, University of California Medical Center at Irvine, Rush-Presbyterian-St. Luke's Medical Center, The Cleveland Clinic Foundation, State University of New York at Stony Brook, Washington University School of Medicine, Memorial Sloan-Kettering Cancer Center, Columbus Cancer Council, MD Anderson Cancer Center, University of Oklahoma, University of Wisconsin Hospital and Community Clinical Oncology Program.