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Objectives: We conducted a phase II study to investigate the efficacy and toxicities of irinotecan plus oral S-1 in patients with advanced or recurrent uterine cervical cancer. Methods: Patients with advanced or recurrent cervical cancer previously treated with platinum based chemotherapy were enrolled. Irinotecan (150 mg/m2) was administered intravenously over the course of 90 min on day 1, and S-1 (80 mg/m2) was given orally in two divided doses from days 1 to 14 of a 21 day cycle. The primary endpoint of this phase II study was response rate. Secondary endpoints included safety, progression free survival, and overall survival. Results: A total of 19 patients were enrolled and treated. The response rate was 29.4%. Grade 3–4 hematologic toxicities were observed in three patients (15.7%). The only grade 3–4 non-hematologic toxicity observed was grade 3 diarrhea. The median progression free survival and overall survival were 3 months and 9 months, respectively. Conclusion: S-1 plus irinotecan in a 3 weekly setting is safe and active in women with advanced or recurrent cervical cancer previously treated with platinum based chemotherapy. Future corroborative clinical studies are warranted. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to determine the maximum tolerated dose and acute dose-limiting toxicities (DLTs) of intravenous irinotecan plus oral S-1 in patients with advanced or recurrent uterine cervical cancer. Methods: Irinotecan was administered intravenously over the course of 90 minutes on day 1, and S-1 was given orally in 2 divided doses from days 1 to 14 of a 21-day cycle. The dose of S-1 was escalated in a stepwise fashion from 40 (level 1) to 60 mg/m2 (level 2) and then 80 mg/m2 (level 3), whereas the dosage of irinotecan remained the same (150 mg/m2). The primary end point for the escalation study was acute DLT that occurred within 2 cycles of chemotherapy. Results: Twelve patients were enrolled and treated over 3 dose levels. Their median age was 47 years (range, 28–48 years). At level 1, one episode of grade 3 anemia and a grade 3 fatigue were observed, but no DLT developed. At level 2, the first patient experienced febrile neutropenia, which was considered to be a DLT. To evaluate the toxicity of this dose level, 5 more patients were evaluated. However, no DLT developed in these patients. At level 3, although grade 1 to 2 hematological and nonhematological toxicities developed, no DLT occurred. Conclusions: In women with advanced or recurrent cervical cancer previously treated with platinum-based chemotherapy, S-1 plus irinotecan in a triweekly setting is a reasonable treatment regimen with an acceptable toxicity profile. The recommended doses of S-1 and irinotecan for this regimen are 80 and 150 mg/m2, respectively. [ABSTRACT FROM AUTHOR]

Clear cell carcinoma of the ovary (CCC) is a histologic subtype of epithelial ovarian cancer with a distinct clinical behavior. There are marked geographic differences in the prevalence of CCC. The CCC is more likely to be detected at an early stage than high-grade serous cancers, and when confined within the ovary, the prognosis is good. However, advanced disease is associated with a very poor prognosis and resistance to standard treatment. Cytoreductive surgery should be performed for patients with stage II, III, or IV disease. An international phase III study to compare irinotecan/cisplatin and paclitaxel/carboplatin as adjuvant chemotherapy for stage IIV CCC has completed enrollment (GCIG/JGOG3017). Considering the frequent PIK3CA mutation in CCC, dual inhibitors targeting PI3K, AKT in the mTOR pathway, are promising. Performing these trials and generating the evidence will require considerable international collaboration. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the chemotherapeutic agents that produce the strongest synergistic effects when combined with trabectedin against ovarian clear cell carcinoma (CCC), which is regarded as an aggressive chemoresistant histological subtype.Using 4 human CCC cell lines (RMG1, RMG2, KOC7C, and HAC2), the cytotoxicities of trabectedin, SN-38, topotecan, doxorubicin, cisplatin, and paclitaxel as single agents were first assessed using the MTS assay. Then, the cytotoxicities of combination treatments involving trabectedin and 1 of the other 4 agents were evaluated by isobologram analysis to examine whether these combinations displayed synergistic, additive, or antagonistic effects. The antitumor activities of the combination treatments were also examined using cisplatin-resistant and paclitaxel-resistant CCC sublines, which were derived from the parental CCC cells by continuously exposing them to cisplatin or paclitaxel. Finally, we determined the effect of everolimus on the antitumor efficacy of trabectedin-based combination chemotherapy.Concurrent exposure to trabectedin and SN-38 or topotecan resulted in synergistic interactions in all 4 CCC cell lines. Among the tested combinations, trabectedin plus SN-38 was the most effective cytotoxic regimen. The combination of trabectedin plus SN-38 also had strong synergistic effects on both the cisplatin-resistant and paclitaxel-resistant CCC cell lines. Treatment with everolimus significantly enhanced the antitumor activity of trabectedin plus SN-38 or topotecan.Combination treatment with trabectedin and SN-38 displays the greatest cytotoxic effect against ovarian CCC. Our in vitro study provides the rationale for future clinical trials of trabectedin plus irinotecan with or without everolimus in patients with ovarian CCC in both the front-line chemotherapy setting and as a second-line treatment of recurrent CCC that had previously been treated with cisplatin or paclitaxel. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effectiveness and feasibility of reirradiation using high-dose-rate interstitial brachytherapy (HDR-ISBT) in patients with recurrent cervical cancer.The records of 52 consecutive women with central pelvic recurrence who were salvaged with HDR-ISBT-based reirradiation were retrospectively reviewed. Data regarding the primary disease, follow-up findings, recurrence, the treatment outcome, and toxicities were collected. Multivariate analysis was performed using the Cox proportional hazards regression model to identify predictors of the response to HDR-ISBT. Survival rate was calculated using the Kaplan-Meier method and compared using the log-rank test.A total of 52 patients who had been treated with HDR-ISBT-based reirradiation were included in our database. The local control rate was 76.9% (40/52), and the median postrecurrence survival period was 32 months. Grade 3 or 4 late toxicities were observed in 13 patients (25%). Multivariate analysis revealed that tumor size and the treatment-free interval were significant poor prognostic factors of postrecurrence survival. In a comparison between the patients who were salvaged with HDR-ISBT-based reirradiation (ISBT group) and those who were treated with palliative therapy alone (palliative group), we found that among the patients who displayed 0 or 1 poor prognostic factors, the patients in the ISBT group survived significantly longer than those in the palliative group. In contrast, similar survival rates were seen in both groups among the patients with 2 or more poor prognostic factors.Reirradiation using HDR-ISBT is effective and feasible in patients with recurrent cervical cancer. Our 2-clinical variable prognostic model might enable physicians to identify patients who would not derive clinical benefit from HDR-ISBT and offer them the opportunity to receive other types of treatment. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLTs) of intravenous carboplatin plus paclitaxel combined with intensity-modulated pelvic radiotherapy (pelvic IMRT) as an adjuvant treatment for early-stage cervical cancer patients with positive pelvic lymph nodes.Women with uterine cervical cancer who were treated with radical hysterectomy and pelvic lymphadenectomy and displayed positive pelvic lymph nodes were eligible for this study. The patients were postoperatively treated with pelvic IMRT (50.4 Gy). The concurrent weekly chemotherapy consisted of carboplatin (area under the curve [AUC], 2) and paclitaxel (starting at 35 mg/m2 and escalating by 5 mg/m2 in 3 patient cohorts). The primary end point of the escalation study was acute DLT that occurred within 30 days of the completion of radiation therapy.Nine patients were enrolled and treated at 2 dose levels until DLT occurred. The median age of the patients was 47 years (range, 28-66 years). The median radiotherapy treatment time was 39.5 days (range, 38-64 days). At dose level I (35 mg/m2 paclitaxel), 2 grade 3 leukopenia and a neutropenia were observed, but no DLT occurred. At dose level II (40 mg/m2 paclitaxel), the first patient experienced a grade 2 hypersensitive reaction, which resulted in discontinuation of planned treatment. Thus, 2 more patients were evaluated at this dose level. Of these, 1 patient experienced febrile neutropenia, which was considered to be a DLT, and the other patient experienced long-lasting grade 3 leukopenia and grade 3 neutropenia, which resulted in the discontinuation of chemotherapy for 2 weeks (a DLT). We then evaluated 3 more patients at dose level 1, but no DLT occurred. The MTD of paclitaxel and carboplatin was thus defined as 35 mg/m2 and an AUC of 2.0, respectively.Weekly paclitaxel/carboplatin and pelvic IMRT is a reasonable adjuvant treatment regimen for cervical cancer patients after radical hysterectomy. The MTD of paclitaxel and carboplatin for future phase II trials of this regimen is 35 mg/m2 and an AUC of 2.0, respectively. [ABSTRACT FROM AUTHOR]

To identify groups of patients who derive clinical benefit from postoperative adjuvant concurrent chemoradiotherapy (CCRT), we retrospectively investigated the survival outcomes of surgically treated early-stage cervical cancer patients.We reviewed the medical records of 316 patients with FIGO stage IB1-IIB cervical cancer who had been treated with adjuvant radiotherapy (RT) (n = 124, RT group) or adjuvant CCRT (n = 192, CCRT group) after radical hysterectomy between January 1996 and December 2009. Of these, 187 patients displayed high-risk prognostic factors (high-risk group), and 129 displayed intermediate-risk prognostic factors (intermediate-risk group). Sixty patients with 1 intermediate-risk prognostic factor who received no adjuvant therapy were also identified and used as controls (NFT group). Survival was calculated using the Kaplan-Meier method and compared using the log-rank test.In the high-risk group, adjuvant CCRT was significantly superior to RT alone with regard to recurrence rate, progression-free survival (PFS), and overall survival. In the intermediate-risk group, CCRT was superior to RT with regard to recurrence rate and PFS in patents with 2 or more risk factors. Among the patients with only 1 intermediate-risk factor, although no survival benefit of CCRT over RT was observed, addition of adjuvant treatment resulted in significantly improved PFS compared with the NFT group in patients with deep stromal invasion (log-rank, P = 0.012).Postoperative CCRT improved the prognosis of FIGO stage IB1-IIB cervical cancer patients in the high-risk group and patients who displayed 2 or more intermediate-risk factors. Patients who displayed deep stromal invasion alone also derived clinical benefit from adjuvant treatment. [ABSTRACT FROM AUTHOR]

To evaluate the significance of adenosquamous carcinoma (ASC) compared with adenocarcinoma (AC) in the survival of surgically treated early-stage cervical cancer.We retrospectively reviewed the medical records of 163 patients with International Federation of Gynecology and Obstetrics stage IA2 to stage IIB cervical cancer who had been treated with radical hysterectomy with or without adjuvant radiotherapy between January 1998 and December 2008. The patients were classified according to the following: (1) histological subtype (ASC group or AC group) and (2) pathological risk factors (low-risk or intermediate/high-risk group). Survival was evaluated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis of progression-free survival (PFS) was performed using the Cox proportional hazards regression model to investigate the prognostic significance of histological subtype.Clinicopathological characteristics were similar between the ASC and AC histology groups. Patients with the ASC histology displayed a PFS rate similar to that of the patients with the AC histology in both the low-risk and intermediate/high-risk groups. Neither the recurrence rate nor the pattern of recurrence differed between the ASC group and the AC group. Univariate analysis revealed that patients with pelvic lymph node metastasis and parametrial invasion achieved significantly shorter PFS than those without these risk factors.Characteristics of the patients and the tumors as well as survival outcomes of ASC were comparable to adenocarcinoma of early-stage uterine cervix treated with radical hysterectomy. Our results in part support that the management of ASC could be the same as the one of AC of the uterine cervix. [ABSTRACT FROM AUTHOR]

We investigated the prognostic significance of multiple pelvic node metastases in cervical cancer patients who were treated with radical hysterectomy plus adjuvant chemoradiotherapy.We retrospectively reviewed the medical records of 311 patients with International Federation of Gynecology and Obstetrics stage IB1-IIB cervical cancer who had been treated with radical hysterectomy plus adjuvant radiotherapy (RT) between January 1998 and December 2008. Of these, 119 received adjuvant RT and 192 received adjuvant concurrent chemoradiotherapy (CCRT) postoperatively. Multivariate analysis for progression-free survival (PFS) was performed using the Cox proportional hazards regression model to investigate the prognostic significance of pelvic node metastases in the 2 treatment groups. Survival was calculated using the Kaplan-Meier method and compared using the log-rank test.Multivariate analysis demonstrated pelvic node metastasis to be an independent prognostic factor for shorter PFS in both treatment groups. When the node-positive patients were analyzed according to the number of positive pelvic nodes, we found that the patients with multiple pelvic node metastases (≥3) displayed significantly shorter PFS than those with 1 or 2 pelvic node metastases in the RT group. In contrast, in the CCRT group, the PFS of the patients with multiple pelvic node metastases (≥3) was similar to that observed of the patients with 1 or 2 pelvic node metastases.The presence of multiple pelvic node metastases was not an independent predictor of shorter PFS in the CCRT group. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify the prognostic factors and to establish a model for the prediction of life expectancy in patients with recurrent cervical cancer that had previously been treated with radiotherapy.The records of consecutive women with recurrent cervical cancer after radiotherapy were retrospectively reviewed. Primary disease, follow-up, and recurrence data were collected. Univariate and multivariate analyses of prognostic factors of survival were performed.A total of 162 patients were included in our database. The median survival after recurrence was 15 months. Multivariate analysis revealed that symptom status, the site of relapse, prior chemoradiotherapy, and treatment modality were significant prognostic factors in terms of survival after recurrence. Patient survival was inversely correlated with the number of these prognostic factors. When the patients were divided into 3 prognostic groups, (low risk: patients with no poor prognostic factors; intermediate: patients with one poor prognostic factor; and high-risk: patients with more than 2 poor prognostic factors), the patients in the high-risk group had a significantly shorter survival (median, 10 months) than those with one risk factor (median, 20 months) or no risk factors (median, 36 months).Symptom status, the site of relapse, prior chemoradiotherapy, and treatment modality are significant prognostic factors in patients with recurrent cervical cancer that had previously been treated with radiotherapy. Our prognostic model, composed of 4 clinical variables, may enable physicians to predict survival more accurately.Abbreviations: CT - Computed tomography, PET-CT - Positron emission tomography in combination with computed tomography, ISBT - Interstitial brachytherapy, DFI - Disease-free interval [ABSTRACT FROM AUTHOR]

Ovarian cancer is known to be highly invasive. The poor prognosis of advanced ovarian cancer comes from increased invasiveness of human ovarian cancer cells. The lysophosphatidic acid (LPA)/Rho/Rho-associated kinase (ROCK) pathway is intimately involved in the course of ovarian cancer progression, and the inhibition of this pathway attenuates ovarian cancer invasiveness. Fasudil (1-[5-isoquinolinesulfonyl]-homopiperazine; HA-1077) is a drug that has been in clinical use in Japan for the prevention of vasospasm after subarachnoid hemorrhage and is known to be a potent ROCK-specific inhibitor. In this study, we examined the effect of fasudil on LPA-induced invasiveness of human ovarian cancer cells to explore the potential of fasudil as an anticancer agent against ovarian cancer. Fasudil induced changes in cell morphology but not in cell viability. Fasudil significantly inhibited LPA-induced invasion and motility of human ovarian cancer cells in a dose-dependent manner. Furthermore, fasudil caused the loss of intracellular cytoskeletal rearrangement, which is necessary for cell motility, such as stress fiber formation and focal adhesion assembly. Fasudil suppressed LPA-induced tyrosine phosphorylation of paxillin, a representative focal adhesion protein, and serine phosphorylation of myosin light chain, which are essential for the process for cell migration. These findings showed that fasudil attenuated the invasiveness of human ovarian cancer cells via inhibition of the LPA/Rho/ROCK pathway. In SKOV-3ip1 ovarian cancer xenografts, intraperitoneal treatment with fasudil significantly reduced tumor burden and ascites formation. Our findings suggest that fasudil might be useful to prevent the progression of ovarian cancer in clinical settings. [ABSTRACT FROM AUTHOR]