Tadaaki Nishikawa

Intravenous/intraperitoneal paclitaxel and intraperitoneal carboplatin in patients with epithelial ovarian, fallopian tube, or peritoneal carcinoma: a feasibility study.

Objective This study aimed to evaluate intravenous (IV)/intraperitoneal (IP) paclitaxel and IP carboplatin (TCipTip therapy) feasibility in epithelial ovarian (EOC), fallopian tube (FTC), or peritoneal carcinoma (PC) patients. Methods From December 2007 to August 2010, 20 women with histologically confirmed stage IC to IV EOC, FTC, or PC received 6 TCipTip cycles after the primary cytoreductive surgery. Intravenous paclitaxel was administered at 135 mg/m2 followed by IP carboplatin based on the area under the curve = 6 on day 1; IP paclitaxel at 60 mg/m2 was administered on day 8. The toxicity grade was determined by CTCAE version 3.0. The institutional review board requested we reduce the IP paclitaxel dose in the first cycle to ensure safety. Results Twenty women, including 18 with EOC, 1 with stage IIC FTC, and 1 with stage IV primary PC, received TCipTip therapy. There were 12 serous, 5 endometrioid, 1 mucinous, 1 clear cell adenocarcinoma, and 1 mixed carcinoma (clear cell and endometrioid) cases. Eleven women achieved optimal status at primary surgery. Grade 3/4 hematologic toxicity incidence was 73% (neutrocytopenia), 9% (thrombocytopenia), and 24% (anemia). Grade 3/4 nonhematologic toxicities were observed in 5 patients (4 with grade 3 allergy and 1 with grade 3 ileus). Twelve patients (60%) completed more than 6 chemotherapy cycles. Reasons for interruption included paclitaxel allergy, grade 2 abdominal pain, carboplatin allergy during the seventh cycle, disease progression, pleural embolism, ileus, and address change. Conclusions Toxicities for TCipTip therapy were acceptable; this therapy is feasible for EOC, FTC, or PC patients. Further TCipTip therapy evaluation is warranted.

Clear-cell carcinoma of the ovary

Clear-cell carcinoma of the ovary (CCCO) is a distinct entity of epithelial ovarian cancer in terms of clinical, histopathological, or genetic features. The incidence of CCCO is different by ethnicity but the reason is not clear yet. Overall prognosis of CCCO is good because most CCCO is found in stage I. However, advanced disease is associated with a very poor prognosis and resistance to standard treatment. The same is true for recurrent disease. Therefore, genetic analysis of CCCO is important to find the right target(s) and better therapeutic approaches. Because of its rarity, international collaboration is necessary to conduct randomized clinical trials for CCCO.

Optimal cytoreductive surgery in patients with advanced uterine carcinosarcoma: A multi-institutional retrospective study from the Japanese gynecologic oncology group

BACKGROUND The benefits of cytoreductive surgery for uterine carcinosarcoma (UCS) are unknown. The objective of this study was to determine the impact of optimal surgery on advanced UCS patient survival. METHODS We performed a multi-institutional, retrospective study of women diagnosed with stage IIIIV UCS between 2007 and 2012. Data were obtained retrospectively from medical records, including demographic, clinicopathologic, treatment, and outcome information. Optimal cytoreductive surgery was defined as surgery resulting in a maximum residual tumor of ≤1cm. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS), and the Cox regression model was used to examine the impact of selected factors on survival. RESULTS A total of 225 UCS patients (median age, 63years) were identified, including 136 (60%) with stage III and 89 (40%) with stage IV disease. Among these patients, 170 (76%) received optimal cytoreductive surgery. The median follow-up time was 19months. The median PFS was 11.5months (95% confidence interval [CI], 10.6-13.4) and 8.1months (95% CI, 5.1-9.5) for patients who received optimal and suboptimal cytoreductive surgery, respectively (P<0.0001). The median OS was 37.9months (95% CI, 28.3-not reached) and 18months (95% CI, 9.6-21) for patients who received optimal and suboptimal cytoreductive surgery, respectively (P<0.0001). Residual tumor >1cm was associated with worse OS while pelvic lymph node dissection was associated with improved OS. CONCLUSION Optimal cytoreductive surgery and pelvic lymph node dissection are associated with improved OS in advanced UCS patients.

A single-arm study evaluating bevacizumab, cisplatin, and paclitaxel followed by single-agent bevacizumab in Japanese patients with advanced cervical cancer

Background 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. Methods 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. Results 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. Conclusions 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.

Feasibility Study of Combination Chemotherapy with Paclitaxel, Doxorubicin and Cisplatin without Prophylactic Granulocyte Colony-stimulating Factor Injection for Intermediate-to-high Risk or Recurrent Endometrial Cancer

OBJECTIVE We evaluated the feasibility of combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection for intermediate-to-high-risk or recurrent endometrial cancer. METHODS Women with histologically confirmed FIGO Stages I-II with >1/2 myometrial invasion, Stage III/IV or recurrent endometrial cancer were enrolled. Patients received intravenous doxorubicin (45 mg/m(2)), followed by cisplatin (50 mg/m(2)) on Day 1 and intravenous paclitaxel (160 mg/m(2)) on Day 2. Granisetron (75 µg) was administered depending on neutrophil counts on Days 3 and 8. Treatment was repeated every 21 days for six cycles or until disease progression or unacceptable toxicity. The primary endpoint was the completion rate of the scheduled chemotherapy; secondary endpoints were Grade 3/4 toxicity and response rate in patients with measurable lesions. RESULTS From September 2010 to December 2012, 35 women, including 7 with FIGO Stage I, 4 with Stage II, 13 with Stage III, 10 with Stage IV and 1 with recurrent endometrial cancer, were enrolled. There were 26 endometrial carcinomas (Grade 1, 16; Grade 2, 6; Grade 3, 4), 4 carcinosarcomas, 2 serous adenocarcinomas, 1 neuroendocrine carcinoma, 1 poorly differentiated carcinoma and 1 mixed carcinoma. Twenty-five patients (71%) completed six chemotherapy cycles. Grade 3/4 hematological toxicities included neutrocytopenia (97%), thrombocytopenia (6%) and anemia (34%). Three patients (9%) experienced neutropenic fever. Grade 3/4 non-hematological toxicities were observed in 13 patients. In 15 patients with evaluable lesions, the response rate was 80%. CONCLUSIONS Combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection is feasible.

The Risk of Ovarian Malignancy Algorithm (ROMA) as a Predictive Marker of Peritoneal Dissemination in Epithelial Ovarian Cancer Patients

Background: This study aimed to determine the efficacy of the risk of ovarian malignancy algorithm (ROMA), calculated using the carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) levels and the menopausal status, as a predictor of peritoneal dissemination in ovarian cancer. Methods: The CA125 and HE4 levels and the ROMA were compared between ovarian cancer patients (n = 122) with or without peritoneal dissemination. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and the results were compared with those of computed tomography (CT). Results: The CA125, HE4, and ROMA values differed significantly depending on the presence of peritoneal dissemination (p < 0.0001). The cut-off values were 181 U/ml for CA125, 161 pmol/ml for HE4, 44% for the ROMA (premenopausal), and 86% for the ROMA (postmenopausal). Among these markers, the ROMA (premenopausal) was the strongest predictor of peritoneal dissemination, with a specificity of 85.0% and a positive predictive value of 81.3%. In addition, the detection rates of small disseminations with less than 2 cm in diameter for the ROMA (93%) and HE4 (60%) were superior to that of CT (53%). Conclusions: The ROMA was a significant predictor of peritoneal dissemination and may be superior to CT for the detection of patients with small disseminations.

Pazopanib as a second line treatment for uterine and ovarian carcinosarcoma: a single institutional study

Uterine carcinosarcoma (UCS) is a relatively rare tumor in gynecologic malignancy that comprises less than 5% of uterine cancers, but it often shows an aggressive phenotype that has contributed to 30% of uterine cancer deaths [1]. Ovarian carcinosarcoma (OCS) is a very rare ovarian tumor that accounts for only 1% of ovarian cancer, and is composed of both malignant epithelial and mesenchymal elements, as well as UCS [1,2]. Prognosis of UCS and OCS is poor because up to 2/3 of patients present with advanced stage [2,3]. Currently, prognostic factors of carcinosarcoma (CS) are not well defined, but published reports have suggested pathological features and age as prognostic factors [4,5,6]. Previously, gynecological CS had been considered and treated as a sarcoma subtype [7]. However, CS is now recognized as a metaplastic carcinoma with the sarcoma component resulting from dedifferentiation of the carcinoma component [8], and therefore it is recommended that CS is treated similar to high-risk endometrial or ovarian carcinoma [9]. While combination chemotherapy of ifosfamide and paclitaxel is currently considered as a standard chemotherapy for UCS [10], an alternative combination is carboplatin and paclitaxel. The efficacy of combination carboplatin and paclitaxel has been reported in several phase II trials, and this combination appears to be better tolerated [11,12]. Based on these results, the combination of carboplatin plus paclitaxel is often used as a standard first line treatment for UCS or OCS, but second line treatment options are limited.

The Efficacy of Low-Dose Paclitaxel Added to Combination Chemotherapy of Carboplatin and Gemcitabine or Pegylated Liposomal Doxorubicin.

Objective Paclitaxel is known to produce the “platelet-sparing effect” that prevents the carboplatin-induced decrease in platelet count. We conducted a pilot study to assess whether the addition of low-dose paclitaxel to carboplatin-based combination chemotherapy prevents thrombocytopenia. Methods Patients with platinum-sensitive recurrent ovarian cancer received intravenous (IV) paclitaxel at 60 mg/m2 followed by IV carboplatin at an area under the curve of 6 and IV pegylated liposomal doxorubicin at 30 mg/m2 on day 1 in a 28-day cycle (DC-LOP) or IV gemcitabine at 1000 mg/m2 on days 1 and 8 in a 21-day cycle (GC-LOP). Results During May 2011 to December 2011, 7 patients received 29 cycles of DC-LOP; during January 2012 to May 2013, 15 patients received 88 cycles of GC-LOP. Grade 3/4 thrombocytopenia occurred in 2 (33%) of 6 and 9 (56%) of 16 patients in the DC-LOP and GC-LOP groups, respectively. No grade 3/4 nonhematological toxicity was observed. Only one patient who received GC-LOP had grade 2 sensory and motor peripheral neuropathy. Paclitaxel-related toxicities, including muscle pain, arthralgia, and peripheral neuropathy, were consistently rare and mild. The response rates of DC-LOP and GC-LOP were 33% (0, complete response; 2, partial response; 3, stable disease; 1, progression disease) and 50% (2, complete response; 6, partial response; 7, stable disease; 1, progression disease), respectively. Conclusions Although low-dose paclitaxel addition did not alleviate thrombocytopenia in the setting of this pilot study, the results do not deny the existence of the “platelet-sparing effect” by low-dose paclitaxel. Further investigation of the carboplatin-based combination chemotherapy including a drug with mild hematological toxicity is warranted.

Utility of Bayesian Single-Arm Design in New Drug Application for Rare Cancers in Japan: A Case Study of Phase 2 Trial for Sarcoma

Investigational drugs for rare cancers are often approved based solely on a single-arm phase II trial that primarily evaluates response rate in Japan. Such trials typically use a fixed sample size determined on the basis of the frequentist manner. However, since predicting the speed of patient enrollment is challenging because of the disease rarity, the time needed to complete the enrollment of the fixed number of patients is prolonged in some cases. A Bayesian design without fixing the sample size is useful for single-arm phase II trials of rare cancers. However, the arbitrariness of prior distribution specifications and the frequentist operating characteristics are regulatory issues. We recently started a Bayesian single-arm phase II trial of nivolumab in patients with sarcoma for new drug application in Japan and examined the statistical rationale and design consideration. In the Bayesian design, we specify the minimum and maximum numbers of enrolled patients during the enrollment period and the prior distributions of response rates. Considering these parameters, we obtain the minimum number of responders needed for the positive conclusion of the efficacy of nivolumab for each sample size. Simulation studies demonstrated that the operating characteristics of this design would be acceptable from the frequentist view. The Bayesian design provided an adaptive decision rule for efficacy conclusion for the drug without fixing the sample size. We hope our trial’s success will provide a new drug development option for rare cancers in Japan.

PIK3CA mutation profiling in patients with breast cancer, using a highly sensitive detection system

PIK3CA mutations are common activating mutations associated with breast cancer (occurring in 20–30% of all cases) and are potent predictive markers for responses to PI3K inhibitors. Thus, it is important to develop sensitive methods to detect these mutations. We established a novel detection method using a quenching probe (QP) system to identify PIK3CA mutations, using DNA from 309 breast cancer tissues. In a developmental cohort, we determined the optimal detection threshold of the QP system with human tumor DNA from 119 freshly frozen tumor samples. We found a 96% concordance rate with the QP system between DNA from 26 matching fresh‐frozen specimens and formalin‐fixed paraffin‐embedded (FFPE) specimens from the same patients, and known PIK3CA mutation status in the developmental cohort. In a validation cohort, we evaluated whether the threshold for judging mutations using the QP system with frozen specimen‐derived DNA was applicable with FFPE‐derived DNA. In the validation cohort, 30 DNA samples from 190 FFPE‐derived DNA samples with known PIK3CA mutation status were analyzed by direct sequencing (DS) and droplet digital PCR, in a blinded manner. The sensitivity and specificity of the droplet digital PCR results were 100% and 100% (QP system), and 60% and 100% (DS), respectively. We also analyzed the relationship between clinical outcomes and the PIK3CA mutational status of 309 breast cancer samples, including the developmental cohort and validation cohort samples. Multivariate analysis suggested that PIK3CA mutations, especially H1047R, were prognostic factors of relapse‐free survival. Our novel detection system could be more useful than DS for detecting clinical PIK3CA mutations.