Low-grade serous ovarian cancer (LGSOC) accounts for 10% of serous ovarian cancers and is characterized by an early age of onset (median age, 46 years), indolent growth rate, and resistance to cytotoxic chemotherapy.1–4 Low-grade serous (LGS) ovarian or primary peritoneal cancers can arise de novo or from serous borderline disease (also called serous tumors of low malignant potential).5–13 It is histologically, molecularly, and clinically distinct from high-grade serous ovarian cancer.1,3,4,9,14–19 Response rates to cytotoxic chemotherapy in both the neoadjuvant and recurrent settings are typically less than or equal to 4%.20–22 Despite these low response rates, systemic chemotherapy is still the standard of care for unresectable LGSOC, primarily due to the lack of alternative effective therapeutic agents for this disease.
Patients with recurrent disease are generally treated with operative resection when feasible, whereas systemic chemotherapy or hormonal therapies are utilized in the unresectable setting. Hormonal therapies including tamoxifen, anastrozole, and letrozole have modest antitumor activity with an observed response rate of 9% in patients with recurrent LGS carcinoma of the ovary or peritoneum.7
Angiogenesis is a hallmark of neoplastic transformation and is critical for tumor growth and invasion.23 Tumor angiogenesis is regulated by a number of cytokines and growth factors, including fibroblast growth factors, platelet-derived growth factor, tumor necrosis factor α, interleukins 6 and 8, and vascular endothelial growth factor (VEGF). Vascular endothelial growth factor A and its receptors, VEGF receptors 1 and 2, comprise a central signaling pathway in developmental and tumor angiogenesis.24
Bevacizumab is a humanized anti–VEGF-A monoclonal antibody that is approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer, nonsquamous non–small cell lung cancer, glioblastoma, and renal cell carcinoma. Bevacizumab has shown promising results for the treatment of recurrent ovarian cancer, either alone25,26 or in combination with chemotherapy27–29; however, most patients treated on those studies carried a diagnosis of high-grade serous ovarian cancer.
Because of the rarity of the disease, prospective trials investigating the treatment of LGSOC are lacking. Indeed, only 1 prospective therapeutic trial in patients with LGSOC has been completed to date, a trial in which the mitogen-activated protein kinase (MEK1/2) inhibitor selumetinib was administered to patients with recurrent LGSOC. This study reported a 15% response rate in patients treated with single-agent selumetinib.30 Several case reports have shown responses to treatment with bevacizumab in heavily pretreated patients with LGS ovarian or primary peritoneal cancer.31,32 In the largest series reported, 17 patients with recurrent LGSOC were treated at the MD Anderson Cancer Center with bevacizumab in combination with various chemotherapies. Five partial responses (PRs) were observed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST) out of 13 evaluable patients, yielding a surprisingly high response rate of 39%.33
Encouraged by these results, in an attempt to help remedy the dearth of effective therapies for this disease, we chose to conduct the current study. We examined patients with serous borderline or LGS ovarian or primary peritoneal cancer who were treated with bevacizumab for recurrent disease at the Memorial Sloan Kettering Cancer Center (MSK) to determine the response rate to antiangiogenic therapy.
MATERIALS AND METHODS
After the institutional review board approval, clinical data were collected on all patients with a diagnosis of serous borderline or LGS ovarian or primary peritoneal cancer who were treated with bevacizumab for recurrent disease at the MSK. The dates of treatment were between July 2005 (the date that bevacizumab was first administered off-label at the MSK for this indication) and June 2012.
Tumor histology was reviewed and confirmed by a gynecologic pathologist. Original pathology reports were reviewed to determine the stage at the time of diagnosis based on the 2010 American Joint Committee on Cancer staging system (seventh edition) for ovarian and primary peritoneal cancer. All included patients were required to have had computed tomography imaging performed at the MSK. Computed tomography scans were reviewed by a reference radiologist for the determination of best overall response with the use of RECIST 1.1. Stable disease (SD) was reported for those patients who achieved SD lasting 3 months or more. Descriptive statistics were used to summarize the data. Overall survival (OS) was calculated from the diagnosis date to the date of last follow-up or death. The median OS was obtained using the Kaplan-Meier method.
Seventeen patients were included in this analysis, 15 of whom were evaluable for the primary end point of best overall response (10 patients with LGSOC, 3 patients with LGS peritoneal cancer, and 4 patients with serous borderline disease). The mean number of prior cytotoxic therapies was 3.4 (range, 1–9; median, 2). Five patients received hormonal therapy (2 letrozole, 1 leuprolide, 1 exemestane, and 1 anastrozole) before the treatment with bevacizumab. Patient characteristics are summarized in Table 1. Two patients, one with LGSOC and one with LGS primary peritoneal cancer, experienced toxicity during treatment with bevacizumab, necessitating discontinuation of treatment before their first radiographic evaluation (one due to poorly healing leg ulcer, the other due to small bowel fistula formation). These 2 patients were not evaluable for the primary end point of best overall response.
Two patients were treated with single-agent bevacizumab. The remainder (n = 15) received bevacizumab in combination with weekly paclitaxel (n = 7), topotecan (n = 1), oral cyclophosphamide (n = 3), gemcitabine (n = 2), or gemcitabine and carboplatin (n = 2) (Fig. 1). The dose of bevacizumab administered was 10 mg/kg (n = 7), 15 mg/kg (n = 7), or 7.5 mg/kg (n = 3). The median duration of treatment for evaluable subjects, measured from the date of the first bevacizumab administration to the date of the last bevacizumab administration, was 23 weeks (mean, 32.2 weeks; range, 6–79.4 weeks).
Fifteen patients were evaluable for best overall response with the use of RECIST 1.1. There were no complete responses (CRs). A PR was observed in 6 patients (5 patients received concurrent paclitaxel, and 1 patient received concurrent gemcitabine). Stable disease lasting 3 months or more was observed in 5 patients, yielding a response rate (CR + PR) of 40% and a clinical benefit rate (CR + PR + SD) of 73.3% (Table 2). The best overall response for each patient is described in Table 3. The 5-year OS rate was found to be 61.8% (95% confidence interval, 33.6%–80.8%). The median OS was found to be 102.5 months (95% confidence interval, 39.3-not evaluable). This is comparable to historical survival rates for LGS carcinomas, where 5-year and 10-year survival rates have been reported as 70% and 50%, respectively.34
In this single-institution retrospective study, we show that bevacizumab in combination with chemotherapy may offer a promising treatment strategy for patients with LGSOC. Our data validate those results previously reported by Schmeler et al,33 with comparable response rates to bevacizumab-based treatment.
Patients with serous borderline disease are generally unresponsive to treatment with cytotoxic chemotherapy.34–36 It is therefore not surprising that no complete responses or PRs were observed in the 4 patients with serous borderline disease treated here. Six of the 11 patients with LGS ovarian or primary peritoneal cancer who were evaluable for objective response were found to have a PR, yielding a response rate of 55% within this group. The finding of SD in 33% of the patients is of limited clinical significance, given the relatively slow growth pattern of LGSOC.
This study is limited by the small number of subjects and the heterogeneous treatment schedules with regards to bevacizumab dosing and concomitant therapies. Bevacizumab was administered at doses of 15 mg/kg, 10 mg/kg, or 7.5 mg/kg; notably, responses were seen in patients treated with each of these doses. Weekly paclitaxel was the most common chemotherapy administered in conjunction with bevacizumab and accounted for 5 of the 6 responses seen. The most commonly administered dose of weekly paclitaxel was 60 mg/m2 (n = 3), followed by 80 mg/m2 (n = 2), and 70 mg/m2 (n = 2). No responses were seen in the 2 patients treated with bevacizumab as a single agent.
Prior prospective studies of bevacizumab in combination with chemotherapy for the treatment of recurrent epithelial ovarian cancer have shown response rates of 24% to 78.5%27–29; however, the majority of patients enrolled on those trials were treated for high-grade serous ovarian cancer, and prospective data regarding treatment of patients with LGSOC are lacking.
The observed 40% response rate overall, and 55% response rate among patients with LGS histology, is substantially higher than the anticipated 4% response rate to chemotherapy alone and is remarkably similar to the data reported in abstract form by Schmeler et al.33 The results presented here indicate that bevacizumab in combination with chemotherapy is an active treatment for recurrent LGSOC. A prospective trial of bevacizumab in combination with weekly paclitaxel for the treatment of recurrent LGSOC is recommended.
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Keywords:© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.
Low-grade serous; Ovarian cancer; Serous borderline; Low malignant potential; Bevacizumab