PURPOSE: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m² for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m² once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

Mabuchi S, et al. J Gynecol Oncol. 2015 Dec;27(3):e31. http://dx.doi.org/10.3802/jgo.2016.27.e31

Several clinical trials to establish standard treatment modality for ovarian cancers included a high abundance of patients with serous histologic tumors, which were quite sensitive to platinum-based chemotherapy. On the other hand, ovarian tumor with rare histologic subtypes such as clear cell or mucinous tumors have been recognized to show chemo-resistant phenotype, leading to poorer prognosis. Especially, clear cell carcinoma of the ovary (CCC) is a distinctive tumor, deriving from endometriosis or clear cell adenofibroma, and response rate to platinum-based therapy is extremely low. It was implied that complete surgical staging enabled us to distinguish a high risk group of recurrence in CCC patients whose disease was confined to the ovary (pT1M0); however, complete surgical staging procedures could not lead to improved survival. Moreover, the status of peritoneal cytology was recognized as an independent prognostic factor in early-staged CCC patients, even after complete surgical staging. In advanced cases with CCC, the patients with no residual tumor had significantly better survival than those with the tumor less than 1 cm or those with tumor diameter more than 1 cm. Therefore, the importance of achieving no macroscopic residual disease at primary surgery is so important compared with other histologic subtypes. On the other hand, many studies have shown that conventional platinum-based chemotherapy regimens yielded a poorer prognosis in patients with CCC than in patients with serous subtypes. The response rate by paclitaxel plus carboplatin (TC) was slightly higher, ranging from 22% to 56%, which was not satisfactory enough. Another regimen for CCC tumors is now being explored: irinotecan plus cisplatin, and molecular targeting agents. In this review article, we discuss the surgical issues for early-staged and advanced CCC including possibility of fertility-sparing surgery, and the chemotherapy for CCC disease.

Matsuo K, et al. J Gynecol Oncol. 2017 Sep;29(1):e11. https://doi.org/10.3802/jgo.2018.29.e11

Aberrant expression of class III beta-tubulin, TUBB3, has been reported to be one of the important mechanisms responsible for taxane resistance in diverse human malignancies. We investigated aberrant TUBB3 expression and its epigenetic modification in 66 primary tumors and 3 cell lines (OVCAR-3, JHOC-5 and JHOC-8) of ovarian cancers. Overexpression of TUBB3 protein was observed in 56 (85%) of the 66 ovarian cancers, and was significantly associated with aggressive tumor behavior (advanced stage, presence of ascites, suboptimal cytoreduction at surgery and presence of lymph node metastasis) (P<0.05). Responses to treatment with a demethylating agent (5-aza-2'-deoxycytidine, 5-Aza-CdR) and a histone deacetylase inhibitor (4-phenylbutyric acid, PBA) differed among the ovarian cancer cell lines. In 2 cell lines with weak expression of TUBB3 protein (OVCAR-3 and JHOC-8), TUBB3 induction was independently induced by treatment with 5-Aza-CdR (JHOC-8) or PBA (OVCAR-3), while neither agent markedly altered TUBB3 mRNA/protein expression in a strongly TUBB3-expressing cell line (JHOC-5). A CpG island within intron 1 was hypermethylated in 1 cell line (JHOC-8) that expressed TUBB3 weakly and required 5-Aza-CdR treatment for gene expression. A CpG island of another cell line showing faint expression of TUBB3 protein (OVCAR-3), in which a significant gain of TUBB3 expression was induced by treatment with PBA but not with 5-Aza-CdR, was hypomethylated, similarly to a cell line (JHOC-5) showing constitutive expression of TUBB3. We evaluated methylation status in this region in 14 primary tumors using methylation-specific PCR, but there was no significant relationship with TUBB3 immunoreactivity. These findings suggest that aberrant expression of TUBB3 protein might be associated with aggressive behavior of ovarian cancers, and that epigenetic modulation (DNA methylation and chromatin acetylation) might be partly involved in TUBB3 expression.

Adding bevacizumab to chemotherapy for recurrent, persistent or metastatic cervical cancer significantly improved overall survival (primary endpoint), progression-free survival and overall response rate in the randomized Phase III GOG-0240 trial. However, data for bevacizumab-containing therapy are scarce in Japanese patients with advanced cervical cancer. The primary objective of the single-arm multicenter Phase II JO29569 study was to evaluate the tolerability of paclitaxel (135 mg/m² over 24 h or 175 mg/m² over 3 h), cisplatin (50 mg/m²) and bevacizumab (15 mg/kg), administered every 3 weeks until disease progression or unacceptable toxicity in Japanese patients with stage IVB, persistent or recurrent cervical cancer. The seven treated patients received a median of nine (range 7–12) bevacizumab cycles and six (range 4–12) chemotherapy cycles. None of the predefined adverse events occurred during the tolerability evaluation period. The most common all-grade adverse events were alopecia, hypertension, decreased appetite, nausea and peripheral sensory neuropathy. There were no cases of fistula. The most common grade ≥3 adverse events were hypertension, neutrophil count decreased and neutropenia. Only one patient experienced febrile neutropenia. The overall response rate was 86% (95% confidence interval, 42–100%), including a complete response in one patient. At data cutoff, disease had progressed in one patient; bevacizumab therapy was ongoing in the remaining six. According to the specified primary objective, a regimen of cisplatin, paclitaxel and bevacizumab was tolerable in Japanese patients and demonstrated encouraging activity in this small single-arm study. Further study is warranted to confirm the safety and effectiveness of bevacizumab in Japanese patients with cervical cancer.