Morikazu Miyamoto

Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers.

OBJECTIVES Currently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC. METHODS Thirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m(2) of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. RESULTS Overall response rate was 33%, and clinical benefit rate (CR+PD+SD) was 73%. Median progression-free survival was 6 months (range: 2-20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed non-hematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death. CONCLUSION The present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies.

Clear cell histology as a poor prognostic factor for advanced epithelial ovarian cancer: a single institutional case series through central pathologic review

Objective Compared with serous adenocarcinoma (SAC), clear cell carcinoma (CCC) often shows chemo-resistance, which would potentially lead to a poor prognosis. On the other hand, there have been arguments over prognoses of CCC and SAC disease. In the present study, multivariate analysis to compare prognosis of CCC patients with that of SAC was aimed for the patients selected from central pathologic review. Methods Between 1984 and 2009, a total of 500 ovarian cancer patients were treated at our university hospital. Among them, 111 patients with CCC and 199 patients with SAC were identified through central pathological review. Overall survival and progression-free survival were compared using Kaplan-Meier method, and prognostic factors were investigated by multiple regression analyses. Results Median age was 52 years for CCC and 55 years for SAC (p=0.03). The ratio of stage I patients were significantly higher in CCC compared with SAC (55% vs. 13%, p<0.01). Among evaluable cases, response rate was significantly lower in CCC than that in SAC (32% vs. 78%, p<0.01). No significant differences of progression-free survival and overall survival were observed in stage I patients; however, prognoses of CCC were significantly poorer than those of SAC in advanced-stage disease. In stage II-IV patients, not only residual tumors and clinical stages, but also clear cell histology were identified as predictors for poor prognosis. Conclusion Clear cell histology was identified as a prognostic factor for advanced-stage ovarian cancers. Histologic subtypes should be considered in further clinical studies, especially for advanced epithelial ovarian cancers.

DNA mismatch repair-related protein loss as a prognostic factor in endometrial cancers

Objective Recent investigations have revealed DNA mismatch repair (MMR) gene mutations are closely related with carcinogenesis of endometrial cancer; however the impact of MMR protein expression on prognosis is not determined. Correlations between MMR-related protein expression and clinicopathological factors of endometrial cancers are analyzed in the present study. Methods A total of 191 endometrial cancer tissues treated between 1990 and 2007 in our hospital were enrolled. Immunoreactions for MSH2, MLH1, MSH6, and PMS2 on tissue microarray specimens and clinicopathological features were analyzed retrospectively. Results Seventy-six cases (40%) had at least one immunohistochemical alteration in MMR proteins (MMR-deficient group). There were statistically significant differences of histology, International Federation of Gynecology and Obstetrics (FIGO) stage, and histological grade between MMR-deficient group and the other cases (MMR-retained group). Response rate of first-line chemotherapy in evaluable cases was slightly higher in MMR-deficient cases (67% vs. 44%, p=0.34). MMR-deficient cases had significantly better progression-free and overall survival (OS) compared with MMR-retained cases. Multivariate analysis revealed MMR status was an independent prognostic factor for OS in endometrial cancers. Conclusion MMR-related proteins expression was identified as an independent prognostic factor for OS, suggesting that MMR was a key biomarker for further investigations of endometrial cancers.

Complete Remission of Metastatic and Relapsed Uterine Cervical Cancers Using Weekly Administration of Bevacizumab and Paclitaxel/Carboplatin

Background: Palliative therapy is usually employed for the treatment of metastatic or relapsed cervical cancer. Many agents including cisplatin have been used for fighting the tumor; however, the gold standard therapy has not yet been confirmed. Case Report: Two cases of recurrent metastatic or refractory cervical cancer successfully treated with weekly administration of bevacizumab (2 mg/kg), paclitaxel (80 mg/m2), and carboplatin (area under the curve (AUC) = 2.0) are presented. 1 course of the therapy consisted of weekly paclitaxel/carboplatin on days 1, 8, and 15 and weekly bevacizumab on days 1, 8, 15, and 21, q28 days. Complete remission was observed after 3–4 courses of the therapy. Hematologic and non-hematologic toxicities higher than grade 3 were not observed during the chemotherapy. In both cases, there was no evidence of disease more than 10 months after the therapy. Conclusions: Weekly administration of bevacizumab and paclitaxel/carboplatin has potential activity in recurrent, metastatic, and refractory cervical carcinomas. These findings warrant further trials in such clinical settings.

X-chromosome-linked inhibitor of apoptosis as a key factor for chemoresistance in clear cell carcinoma of the ovary.

Background:X-chromosome-linked inhibitor of apoptosis (XIAP) is one of the anti-apoptotic proteins leading to chemoresistance in several cancers. The aim of this study is to evaluate the impact of XIAP expression upon ovarian clear cell carcinoma (CCC) that has a platinum-resistant phenotype.Methods:Tissue microarrays made from 90 CCC patients were analysed for immunohistochemical expression levels of XIAP, c-Met, p-Akt and Bcl-XL. In addition, CCC cell lines were evaluated whether XIAP silencing could modulate sensitivity to platinum agent in vitro.Results:High XIAP expression was observed in 30 (33%) of 90 CCC cases, and was associated with c-Met (<0.01) and Bcl-XL (<0.01) expression. Cases with high XIAP expression had lower response rate to primary platinum-based chemotherapy (10% vs 65%, P=0.02). In stages II–IV tumours, high XIAP expression was related with worse progression-free survival (PFS, P=0.02). Furthermore, high XIAP expression was identified as an independent worse prognostic factor for PFS and overall survival. Finally, downregulation of XIAP using XIAP-specific small interfering RNA increased sensitivity to cisplatin in human cancer cells derived from CCC.Conclusions:X-chromosome-linked inhibitor of apoptosis expression was correlated with chemoresistance of primary chemotherapy, and identified as a prognostic marker for CCC. X-chromosome-linked inhibitor of apoptosis could be a candidate for new therapeutic target in CCC.

Short response duration even in responders to chemotherapy using conventional cytotoxic agents in recurrent or refractory clear cell carcinomas of the ovary

We would like to congratulate Yoshino and colleagues [1] for their excellent article investigating the efficacy of salvage chemotherapy for recurrent or persistent clear cell cancers of the ovary (CCC). In their article, they suggested that gemcitabine showed modest activity in the regimens they had tested. As most gynecologic oncologists are aware, recurrent or persistent CCCs have a chemo-resistant phenotype. Articles in English describing objective response to chemotherapy or radiotherapy when used against recurrent CCC over the last 20 years were searched through Pubmed and are listed in Table 1. Single agent gemcitabine could be a candidate for salvage therapy for CCC, as the authors suggested. Other regimens that showed objective response included irinotecan/platinum, etoposide/ platinum, and paclitaxel/carboplatin; however, the efficacy was limited with a progression-free interval of approximately 6 months. Despite the importance of response, it is just as important to monitor whether the adverse effects of chemotherapy worsen the patients’ quality of life. On the other hand, radiotherapy yielded a complete response in two cases of refractory CCC, and the progression-free interval was over 1 year in both cases [2, 3]. It is necessary to be very careful about the possibility of publication bias, because radiotherapy is usually used for patients with confined tumors without peritonitis carcinomatosa. Nevertheless, another report clearly demonstrated that radiotherapy with or without chemotherapy had a higher benefit-to-failure ratio than salvage chemotherapy [4]. If radiotherapy were indicated, we would be confident to recommend this therapy for patients with recurrent or refractory CCCs. Among systemic therapies for recurrent or refractory CCC, a regimen using temsirolimus yielded a 14-month progression-free interval in one case with no toxicity higher than Grade 2. Surprisingly, the response duration was longer than that obtained using any cytotoxic agents so far. There are two international collaborating studies led by the Gynecologic Oncology Group (GOG) to evaluate efficacy of molecular targeting agents for CCC of the ovary [5, 6]. It is true that, among patients with CCC, some are super-responders to molecular targeting agents. Consequently, further studies to evaluate these new drugs should include biomarker analysis to predict response and adverse effects during clinical application. A review of response reports on recurrent or refractory CCC would encourage the rethinking of fundamental considerations concerning salvage chemotherapy for CCC, searching for more effective systemic therapy and tailormade therapy.

Potential survival benefit of secondary cytoreductive surgery for recurrent epithelial ovarian, tubal, and peritoneal cancers.

Objective: Although treatment for recurrent epithelial ovarian, tubal, and peritoneal cancers is usually not curative and intends to be palliative, a certain significance of secondary cytoreductive surgery (SCS) for recurrent tumor has been reported; still, there are limitations in this strategy including difficulty in predicting successful complete resection and selecting good candidates. The purpose of this study was to explore the potential survival benefit of SCS in patients with recurrent epithelial ovarian, tubal, and peritoneal cancers. Methods: Among all patients who underwent primary therapy for epithelial ovarian, tubal, and peritoneal cancers between 1994 and 2006 at our institute, medical records of patients who were submitted to SCS for recurrence following complete remission after primary therapy were retrospectively investigated. Kaplan-Meier method and log-rank test were used for survival analysis, and Cox proportional hazard regression model was used for quantifying the relations between survival and covariates. Results: Thirty-four patients met the inclusion criteria. Complete resection of all visible tumors at SCS was achieved in 24 of patients (75%). Median postrecurrence survival was 60 months. On univariate analysis, solitary recurrence, disease-free interval, CA125 value at recurrence, and complete resection were significant prognostic factors on postrecurrence survival; whereas on multivariate analysis, CA125 value at recurrence and complete resection were independent prognostic factors. In addition, a comparison according to the initial method that detected recurrence revealed that patients whose recurrence was detected with CA125 elevations had significantly worse postrecurrence survival than those detected with routine examinations including image scans (P = 0.021). Conclusions: In the present study, the impact of SCS on the significant survival benefit was identified for patients with low CA125 value at recurrence as well as with complete resection. Although further analyses are needed, patients whose recurrence was diagnosed by routine examinations without CA125 elevation might be better candidates for SCS.

Is there any predictor for hypersensitivity reactions in gynecologic cancer patients treated with paclitaxel-based therapy?

PurposeRecently, generic drugs of paclitaxel have been commonly used mainly by economic reasons; however, predictive factors for toxicities are not fully determined. Hypersensitivity reaction (HSR) is one of the most important adverse events in the paclitaxel-based therapy, and sometimes leads to lethal condition. The aim of the study was to identify predictors for HSR in patients treated with paclitaxel-based regimens.MethodsAll the patients treated with chemotherapy including paclitaxel at our hospital between 1998 and 2013 were retrospectively evaluated. Clinicopathological factors of the patients that developed HSR and those without HSR were compared, and predictive factors for HSR were identified.ResultsAmong 414 patients enrolled in the study, 26 patients (6.3%) developed HSR. Multivariate analyses showed that younger age (odds ratio 6.31), a history of allergy (odds ratio 3.79), and short-course premedication (odds ratio 14.1) were identified as predictive factors for HSR. There was no significant difference in the incidence of HSR between original paclitaxel and generic drug. The incidence of HSR was higher as the number of these predictors was accumulated.ConclusionsThree factors were identified as predictive factors for HSR: younger age, a history of allergy, and short-course premedication. Accumulation of these factors increased the incidence of HSR; however, the use of generic drug was not associated HSR in gynecologic cancer patients.

Evaluation of Endometrial Cytology: Cytohistological Correlations in 1,441 Cancer Patients

Background: Endometrial cytology by direct intrauterine sampling is the most common test for an initial evaluation of the endometrium in Japan. However, its diagnostic value for endometrial cancer remains unknown. Here, we assess the correlation between cytopathology and histopathology to evaluate the diagnostic value of cytology for endometrial cancer. Methods: Patients with histologically confirmed endometrial cancer and controls with a normal endometrium confirmed by hysterectomy had all undergone preoperative endometrial cytology between 2001 and 2010 at our eight institutions and were retrospectively analyzed. The cytological results were compared by clinical stage, histological type, differentiation, and sampling instrument. Results: We analyzed 1,441 endometrial cancer and 1,361 control cases. Endometrial cytology detected cancer in 1,279 (916 positive and 363 suspicious) cases with a sensitivity (positive plus suspicious cases) of 88.8% and a specificity of 98.5%. The positive rate was high in advanced-stage, nonendometrioid, and undifferentiated cases, but there was no significant difference in sensitivity between these clinical conditions. Conclusion: Endometrial cytology shows a relatively high sensitivity and specificity for endometrial cancer, and neither statistical measure is significantly affected by clinical stage, histological type, differentiation, sample numbers, or sampling instrument. These findings form a superior dataset for evaluating the efficacy of endometrial cytology.

JAK2/STAT3 pathway as a therapeutic target in ovarian cancers

The activation of JAK2/STAT3 pathway has been reported to have critical roles in several solid tumors. The present study aimed to evaluate the correlation between JAK2/STAT3 activation and clinicopathological parameters in ovarian cancer types. Tissue microarrays made from the patients treated at the National Defense Medical College Hospital between 1984 and 2008 were evaluated using immunohistochemical (IHC) stainings. Medical charts of these patients including IHC results were retrospectively analyzed, and prognostic factors for progression-free survival and overall survival were evaluated. Among 341 enrolled patients, positive expression of p-STAT3 was observed in 95 cases (28%). Positive p-STAT3 was an independent worse prognostic factor for overall survival in all the cases. Additionally, p-STAT3 expression was related with overall survival in patients with clear-cell histology, but not in serous histology. The effect of an inhibitor of STAT3, niclosamide, was evaluated in ovarian clear-cell cancer cells, and niclosamide treatment decreased expression of p-STAT3, leading to increased apoptosis in a dose-dependent manner in vitro. The activation of JAK2/STAT3 pathway had significant impact on survival of ovarian cancers, especially for the cases with clear-cell histology. Although further analyses are needed, suppression of this pathway could be a candidate for the treatment of ovarian cancers.