Elsevier

Gynecologic Oncology

Volume 133, Issue 3, June 2014, Pages 537-541
Gynecologic Oncology

A phase II evaluation of pazopanib in the treatment of recurrent or persistent carcinosarcoma of the uterus: A Gynecologic Oncology Group study

https://doi.org/10.1016/j.ygyno.2014.02.036Get rights and content

Highlights

  • Clinical evidence suggests that angiogenesis plays a role in endometrial cancer.

  • Pazopanib, a small molecule inhibitor of VEGFR, has limited activity in the management of carcinosarcoma of the uterus.

  • Mutational profiles and chromosomal amplifications may profile potential driver of disease.

Abstract

Objective

Carcinosarcomas of the female genital tract, also called malignant mixed müllerian tumors, are aggressive biphasic tumors. Second-line treatment options in the recurrent/persistent setting have yielded marginal responses. Given the potential role of angiogenesis in the gynecological carcinomas, pazopanib, a VEGFR inhibitor, was investigated in the management of patients with recurrent carcinosarcoma of the uterus.

Methods

Eligible patients had histologically confirmed carcinosarcoma of the uterus, a maximum of two prior lines of therapy, adequate renal, hepatic and hematologic function and a performance status of 0–2. Pazopanib was administered orally at 800 mg. Two dose reductions were allowed. The primary objective was to ascertain the activity of pazopanib as measured by the proportion of patients who survive progression-free for at least six months and the proportion of patients that have objective tumor responses. Secondary objectives included the frequency and severity of adverse events as assessed by CTCAE v4.0.

Results

Of the 22 enrolled patients, 19 were eligible and evaluable for toxicity and survival. No patients had a partial or complete response (90% confidence interval [CI]: 0%, 14.6%). Three patients (15.8%) had PFS ≥ 6 months (90% CI: 4.4%, 35.9%). The median PFS was 2.0 months (first and third quartiles were 1.6 and 4.0 months, respectively). The median overall survival was 8.7 months (first and third quartiles were 2.6 and 14.0 months, respectively).

Conclusion

Pazopanib demonstrated minimal activity as a second or third line treatment for advanced uterine carcinosarcoma. Potential clinical trial participation should be discussed with the patients.

Introduction

Malignant uterine neoplasms that contain both carcinomatous and sarcomatous elements are designated carcinosarcomas. These neoplasms arise most commonly in the uterus, and with a lesser frequency in the ovary, fallopian tube, cervix or peritoneum. They are regarded as rare aggressive malignancies with a high potential to develop distant metastases and are associated with an overall poor survival.

The histogenesis of this neoplasm has been debated. A number of studies have accumulated evidence suggesting that most of these neoplasms, but not all, are monoclonal in origin rather than true collision tumors [1], [2], [3], [4], [5], [6], [7], [8]. Schipf et al. investigated the molecular genetic aberrations of both ovarian and uterine carcinosarcomas using comparative genomic hybridization and fluorescence in situ hybridization. In the 30 cases studied, the molecular cytogenetic analysis revealed a high level of homology of chromosomal aberrations between the different tumor components suggesting a monoclonal origin of these tumors [9].

Evidence suggests that the carcinomatous component of carcinosarcomas is the more aggressive element of the cancer. Proliferation indices in both carcinomatous and sarcomatous tumor components (immunohistochemical Ki-67 staining) revealed a significantly higher proliferation index in the carcinomatous tumor element (mean 70%) compared to that in the sarcomatous tumor element (mean 28%; p < 0.001) [9]. The data highlight that the carcinomatous component may be the driving force and that the sarcomatous component is derived from the carcinoma or from a stem cell that undergoes divergent differentiation.

Five-year survival figures for patients with carcinosarcoma are poor [10]. First line treatment of patients with advanced uterine carcinosarcoma with paclitaxel plus carboplatin achieved an objective response rate of 54% of patients. Progression-free survival (PFS) and overall survival (OS) for the entire cohort were 7.6 months and 14.7 months, respectively [11]. Response rates to second line therapy have been limited [12], [13], [14], [15], [16], [17]. Despite several studies suggesting the activity of various cytotoxic agents, enthusiasm for cytotoxic chemotherapy has been tempered by the rapid emergence of resistance [10], [12], [13], [14], [15], [16]. The aggressive nature of this malignancy coupled with a high relapse rate defines a poor clinical course for most patients. As such, a focus on alternative targeted therapeutics has emerged. Huh et al. initiated a multi-institutional phase II trial to assess the activity and toxicity of imatinib mesylate in recurrent or persistent uterine carcinosarcoma [18]. Imatinib mesylate had minimal activity as a single agent in unscreened patients.

Independent studies have reported an increase in microvessel density with the progression of a benign to a malignant endometrium [19], [20], [21], [22]. These studies have also reported the association of microvessel density with PFS and OS. Wright et al. reported a retrospective analysis of patients (n = 11) with recurrent uterine neoplasms treated with bevacizumab [23]. Two partial responses were noted in this heavily pretreated cohort and their median progression free intervals were 5.4 months and 8.7 months. Aghajanian et al. investigated the role of bevacizumab in the treatment of patients with recurrent/persistent endometrial carcinoma [24]. The median PFS was 4.2 months while the median OS was 10.5 months. Twenty one patients (40.4%) survived progression free for at least 6 months. Nimeiri studied the role of sorafenib, a multi-targeted kinase inhibitor with anti-angiogenic activity, in advanced recurrent endometrial carcinomas and carcinosarcomas. In a group of 39 patients, 5% were reported as having a partial response while 50% had stable disease after two months [25].

Angiogenesis in uterine carcinosarcomas is less well characterized than that in endometrial carcinomas. Emoto et al. described the localization of the vascular endothelial growth factor (VEGF) and angiopoietin genes in uterine carcinosarcoma [26]. The microvessel density in the epithelial element was found to be higher than that in the mesenchymal element. Ang-2 mRNA was also seen in the vasculature adjacent to the periphery of carcinoma cells. Giatromanolaki et al. explored the expression of phosphorylated kinase domain receptor (KDR/VEGFR-2) in endometrial cells utilizing a novel monoclonal antibody that recognized the activated (phosphorylated) form of the KDR (VEGFR-2) receptor [27]. Approximately one-third of patients with endometrial cancer exhibited intense cytoplasmic and nuclear pKDR expression in both cancer cells and peritumoral vessels. This reactivity in the cancer cells was related directly to VEGF and VEGF/KDR complexes. In addition, pKDR expression was associated with poor prognosis. A phase II GOG study of thalidomide in this patient cohort reported an association between high pre-treatment VEGF-serum levels and poor prognosis in this population [28].

Pazopanib is a potent competitive, small molecule inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor (PDGFR)-α-, -β- and -c-kit. In preclinical models pazopanib inhibited VEGF-induced VEGFR-2 phosphorylation and was 3- to 400-fold selective for VEGFRs. Pazopanib is approved by the Food and Drug Administration (FDA) for the treatment of soft tissue sarcomas and renal cell carcinoma, and has been evaluated in the management of gynecological cancers [29], [30], [31], [32]. Based on the following rationale: (1) the lack of standard second line therapy in patients with advanced carcinosarcoma; (2) the expression of VEGF-mRNA in carcinosarcomas; (3) evidence that angiogenesis plays a role in endometrial carcinomas; and (4) the expression of phosphorylated KDR (VEGFR-2) in endometrial cells, the GOG initiated a phase II study of pazopanib, as second or third-line treatment for patients with recurrent uterine carcinosarcomas.

Section snippets

Eligibility

Eligible patients had histologically confirmed recurrent or persistent uterine carcinosarcoma and measurable disease defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) [33]. All patients must have received one prior chemotherapeutic regimen administered after surgical or non-surgical assessments. Patients were allowed to have received one additional cytotoxic regimen for management of recurrent or persistent disease. Patients were not allowed to have received

Patients and eligibility

Twenty-two patients were enrolled over the period of 12 months. Of these 19 were evaluable and eligible (two patients were ineligible due to the wrong cell type; one patient was enrolled but never treated).

Patient characteristics are listed in Table 1. The median age was 69 years (range, 50–79). Fourteen patients (74%) had a performance status of 0 while two (11%) and three (16%) had a performance status of 1 and 2, respectively. Ten patients (53%) had received one prior line of therapy and nine

Discussion

Pazopanib is a potent and selective, orally bioavailable, adenosine triphosphate competitive, small molecule inhibitor of VEGFR-1, -2, and -3, platelet-derived growth factor receptor (PDGFR)-α-, -β-, and c-kit. The rationale for evaluating this drug in recurrent carcinosarcomas was based on the strong association of VEGF–mRNA in carcinosarcomas, evidence that angiogenesis plays a role in endometrial cancer, the expression of phosphorylated KDR (VEGFR-2) in endometrial cells, a recent report of

Conflict of interest

The co-authors have no conflicts of interest to declare.

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