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Objective: This study was to analyze patterns and risk factors of relapse after postoperative adjuvant chemotherapy for endometrial cancer., Methods: Among patients enrolled in a randomized phase III trial (JGOG2043) investigating the efficacy of adjuvant chemotherapy for endometrial cancer at a high risk of progression, the recurrent patients were studied. Clinical information were collected, and correlation between relapse-related factors and clinicopathological factors were analyzed., Results: Among 193 patients analyzed, 50% had local relapse and 63% had distant relapse. Local relapse involved regional lymph nodes in 30%, while distant relapse involved the abdominal cavity in 42%. Imaging was used to confirm relapse in 83%, and the median disease-free interval (DFI) was 11.5 months. Factors showing a significant correlation with DFI ≤12 months were residual tumor at surgery (p < 0.01), Grade 3 histology (p < 0.01), and lymph node metastasis (p = 0.03). In contrast, treatment with paclitaxel and carboplatin showed a significant correlation with DFI >12 months (p = 0.04). The median post-relapse overall survival (RS) was 23.9 months. In multivariate analysis, CA125 ≥ 100 U/mL prior to relapse (p < 0.01), distant metastasis (p < 0.01), DFI ≤ 12 months (p = 0.02), and not performing para-aortic lymphadenectomy (p = 0.01) were independently related to poor RS., Conclusions: Relapse of endometrial cancer following adjuvant chemotherapy often occurs by 1 year after treatment, with common relapse sites of the abdominal cavity and regional lymph nodes. Among treatment-related factors, RS was correlated with DFI and para-aortic lymphadenectomy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: The efficacy of taxane plus platinum regimens has been demonstrated for advanced or recurrent endometrial cancer; however, it has not been assessed in postoperative adjuvant chemotherapy for endometrial cancer., Objective: To evaluate the clinical benefit of taxane plus platinum compared with standard doxorubicin plus cisplatin as postoperative adjuvant chemotherapy in endometrial cancer., Design, Setting, and Participants: In this multicenter, open-label, phase 3 randomized clinical trial, patients with endometrial cancer at high-risk stage I or II or stage III or IV that did not extend beyond the abdominal cavity and had 2 cm or greater residual tumor were included from 118 institutions in Japan from November 24, 2006, to January 7, 2011. Data was analyzed from March 15, 2017, to June 30, 2017., Interventions: Eligible patients were randomly assigned (1:1:1) to receive 6 cycles of doxorubicin, 60 mg/m2, plus cisplatin, 50 mg/m2, on day 1; docetaxel, 70 mg/m2, plus cisplatin, 60 mg/m2, on day 1; or paclitaxel, 180 mg/m2, plus carboplatin (area under the curve, 6.0 mg/mL × min) on day 1 every 3 weeks., Main Outcomes and Measures: The primary end point was progression-free survival. Secondary end points were overall survival, occurrence of adverse events, tolerability, and status of lymph node dissection., Results: Among 788 eligible patients, the median (SD) age was 59 (22-74) years; 263 patients were assigned to doxorubicin plus cisplatin treatment, 263 patients to docetaxel plus cisplatin treatment, and 262 patients to paclitaxel plus carboplatin treatment. The number of patients who did not complete 6 cycles was 53 (20.1%) for the doxorubicin plus cisplatin group, 45 (17.1%) for the docetaxel plus cisplatin group, and 63 (24.0%) for the paclitaxel plus carboplatin group. Tolerability of these regimens were not statistically different. After a median follow-up period of 7 years, there was no statistical difference of progression-free survival (doxorubicin plus cisplatin, 191; docetaxel plus cisplatin, 208; paclitaxel plus carboplatin, 187; P = .12) or overall survival (doxorubicin plus cisplatin, 217; docetaxel plus cisplatin, 223; paclitaxel plus carboplatin, 215; P = .67) among the 3 groups. The 5-year progression-free survival rate was 73.3% for the doxorubicin plus cisplatin group, 79.0% for the docetaxel plus cisplatin group, and 73.9% for the paclitaxel plus carboplatin group, while the 5-year overall survival rates were 82.7%, 88.1%, and 86.1%, respectively., Conclusions and Relevance: There was no significant difference of survival among patients receiving doxorubicin plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin as postoperative adjuvant chemotherapy for endometrial cancer. Because each regimen showed adequate tolerability but different toxic effects, taxane plus platinum regimens may be a reasonable alternative to treatment with doxorubicin plus cisplatin., Trial Registration: UMIN-CTR identifier: UMIN000000522.

Purpose: The purpose of this study was to evaluate renal function in lung cancer patients who were administered cisplatin with continuous higher-volume hydration (CH) or a short hydration (SH) regimen., Methods: We retrospectively evaluated patients with lung cancer who were treated with chemotherapy regimens including >50 mg/m 2 of cisplatin between August 2007 and March 2015. Between August 2007 and December 2012, patients received a continuous higher-volume hydration regimen without magnesium (Mg) supplementation (CH group), and after May 2013, patients received a short hydration regimen with Mg supplementation (SH group). To evaluate the factors influencing serum creatinine (SCr) increase during the first course of cisplatin chemotherapy, univariate and multivariate logistic regression analyses were conducted., Results: A total of 122 patients were evaluated, 62 patients in the CH group and 60 patients in the SH group. Grade 1 (National Cancer Institute Common Toxicity Criteria for Adverse Events; version 4.0) or higher SCr increases were more frequently observed in the CH group than in the SH group after the first cycle (P = 0.01, Fisher's exact test) and for all cycles (P = 0.03). Multivariate analysis revealed that short hydration (odds ratio (OR), 0.30; 95% confidence internal (CI) (0.11-0.75), P = 0.01) and estimated creatinine clearance (eCcr) of ≥70 mL/min (OR, 0.25; 95% CI (0.088-0.69), P = 0.008) were associated with a significantly reduced risk for cisplatin-induced grade 1 or higher SCr increase., Conclusion: Our study suggested that a short hydration method with Mg supplementation and eCcr of ≥70 mL/min reduced the risk of cisplatin-induced nephrotoxicity.

Background: We conducted a phase III, non-inferiority trial comparing upfront primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy (NAC) for stage III/IV ovarian, tubal, and peritoneal cancers (JCOG0602). Two earlier studies, EORTC55971 and CHORUS, demonstrated non-inferior survival of patients treated with NAC. However, they could not evaluate true treatment invasiveness because of adding diagnostic laparotomy or laparoscopy before treatment in over 30% of both arms of EORTC55971 and in 16% of NAC arm of CHORUS., Methods: Patients were randomised into the standard arm (PDS followed by eight cycles of paclitaxel and carboplatin [TC]) and NAC arm (four cycles of TC, IDS, and four cycles of TC). In the standard arm, IDS was optional for patients who had undergone suboptimal or incomplete PDS. Treatment invasiveness was compared between arms (UMIN000000523)., Results: Between November 2006 and October 2011, 301 patients were randomised. In the standard arm, 147/149 underwent PDS and 49 underwent IDS. In the NAC arm, 130/152 underwent IDS. The NAC arm required fewer surgeries (mean 0.86 versus 1.32, p < 0.001) and shorter total operation time (median 273 min versus 341 min, p < 0.001) than the standard arm and required a lower frequency of abdominal organ resection (23.7% versus 37.6%, p = 0.012) or distant metastases resection (3.9% versus 10.7%, p = 0.027). In the NAC arm IDS, blood/ascites loss was smaller (median 787 ml versus 3235 ml, p < 0.001) and albumin transfusion and G3/4 adverse events after surgery in total were less frequent (26.2% versus 58.5%, p < 0.001; 4.6% versus 15.0%, p = 0.005, respectively)., Conclusion: Our findings demonstrated that NAC treatment is less invasive than standard treatment. NAC treatment may become the new standard treatment for advanced ovarian cancer when non-inferior survival is confirmed in the planned primary analysis in 2017., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: In metastatic or recurrent cervical cancer, cisplatin-based chemotherapy is standard. The JCOG0505 randomized phase III trial evaluated the clinical benefits of carboplatin-based regimen., Patients and Methods: Eligible patients had metastatic or recurrent cervical cancer and had ≤ one platinum-containing treatment and no prior taxane. Patients were randomly assigned either to conventional paclitaxel plus cisplatin (TP; paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 50 mg/m(2) on day 2, repeated every 3 weeks) or paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m(2) over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeated every 3 weeks). Primary end point was overall survival (OS). Planned sample size was 250 patients to confirm the noninferiority of TC versus TP with the threshold hazard ratio (HR) of 1.29., Results: Between February 2006 and November 2009, 253 patients were enrolled. The HR of OS was 0.994 (90% CI, 0.79 to 1.25; noninferiority P = .032 by stratified Cox regression). Median OS was 18.3 months with TP versus 17.5 months with TC. Among patients who had not received prior cisplatin, OS was shorter with TC (13.0 v 23.2 months; HR, 1.571; 95% CI, 1.06 to 2.32). One treatment-related death occurred with TC. Proportion of nonhospitalization periods was significantly longer with TC (P < .001)., Conclusion: TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents., (© 2015 by American Society of Clinical Oncology.)

Background: Predictive factors of the efficacy of chemotherapy for Japanese patients with recurrent cervical cancer who have been previously treated with concurrent chemoradiotherapy (CCRT) are currently unknown, and hence we aimed to investigate this., Methods: We retrospectively studied the prognostic outcomes of patients with recurrent cervical cancer treated with CCRT between 2002 and 2010 at four medical facilities., Results: A total of 64 patients were included in this study. Forty-two patients received definitive CCRT and 22 patients received postoperative adjuvant CCRT, with 55 receiving platinum-based combination chemotherapy and nine receiving single-agent chemotherapy. The overall response rate (ORR) was 12.5%, with one complete response. The median survival period was 12 months. The ORR and overall survival rate did not differ significantly according to recurrence site, post-CCRT interval, or chemotherapy regimen., Conclusion: None of the factors analyzed in this study were identified as positive predictive factors for the efficacy of chemotherapy in patients with recurrent cervical cancer after CCRT. Based on the results of previous studies, in order to improve long-term prognosis in recurrent cases, adjuvant chemotherapy should be considered as a potential treatment option for selected patients, especially as postoperative adjuvant therapy.

Objective: This single-arm Phase II trial was designed to assess the safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer., Methods: Patients with a histological diagnosis of epithelial ovarian, fallopian tube or primary peritoneal carcinoma, who were relapse-free at least 6 months after completion of first-line platinum-based chemotherapy, and who had measurable disease and gave consent to participate in this study received infusions of pegylated liposomal doxorubicin (30 mg/m(2)) at 1 mg/min, followed by carboplatin (AUC 5 mg min/ml) over 30 min every 28 days., Results: Thirty-three of 35 enrolled patients were eligible for efficacy analysis. One patient (3.0%) achieved a complete response, while 16 (48.5%) achieved a partial response, with an overall objective response rate of 51.5% (95% confidence interval, 34.5-68.6%). Among the 22 patients who had evaluable CA125 levels at entry, responses were observed in 18 patients, with a response rate of 81.8% (95% confidence interval, 65.3-98.3%). The median progression-free survival and overall survival rates for all 35 patients were 10.7 months (95% confidence interval, 8.1-13.2 months) and 38.8 months (95% confidence interval, 31.0-46.7 months), respectively. The most frequent Grade 3-4 toxicities, regardless of cause, were neutropenia (82.9%), thrombocytopenia (51.4%), leukopenia (45.7%) and anemia (17.1%)., Conclusions: The safety and efficacy of pegylated liposomal doxorubicin and carboplatin combination chemotherapy in patients with platinum-sensitive recurrent ovarian cancer were confirmed. Although there were concerns of severe hematological toxicity with this therapy, this potential complication was safely managed through adequate monitoring of bone marrow function., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Cisplatin plus pemetrexed is considered the standard of care for the first-line treatment of patients with advanced non-squamous non-small-cell lung cancer (NSCLC). However, little is known about the efficacy and safety of this regimen in Japanese patients in a daily clinical setting., Methods: We retrospectively analyzed 40 patients who received cisplatin (75 mg/m/(2)) and pemetrexed (500 mg/m(2)) as a first-line treatment for advanced non-squamous NSCLC., Results: Recorded Grade 3 or 4 hematological toxicities included neutropenia in 7 cases (17.5%), leukopenia in 5 cases (12.5%), anemia in 1 case (2.5%), thrombocytopenia in 1 case (2.5%), and febrile neutropenia in 1 case (2.5%). Grade 3 or 4 nonhematological toxicities included anorexia in 3 cases (7.5%), infection in 1 case (2.5%), rash in 1 case (2.5%), and increased transaminase expression in 1 case (2.5%). Therefore, the adverse events were mostly mild. There were no treatment related deaths. The overall response rate was 37.5%, median progression free survival was 5.6 months, and median overall survival (OS) was 18.8 months. In an epidermal growth factor receptor (EGFR) mutation status subgroup analysis, the median OS of patients with wild-type EGFR or unknown status (n=28)was 16.8 months., Conclusion: Cisplatin plus pemetrexed was well tolerated as a first-line treatment and effective in Japanese patients with advanced non-squamous NSCLC.

Objective: The purpose of this study was to assess the outcome of alternating chemoradiotherapy in patients with high-risk cervical cancer., Methods: We performed definitive alternating chemoradiotherapy in cervical cancer patients with at least one high-risk factor such as International Federation of Gynecology and Obstetrics III or IVA disease, primary tumor diameter ≥50 mm, positive pelvic node, and positive para-aortic node. Our chemoradiotherapy protocol was as follows: (i) alternating chemoradiotherapy with 5-fluorouracil and nedaplatin; (ii) whole pelvic radiotherapy with the dynamic conformal technique combined with intracavitary brachytherapy; (iii) prophylactic irradiation to the para-aortic region for International Federation of Gynecology and Obstetrics III/IVA or positive pelvic node and full-dose radiotherapy for positive para-aortic node. Between 1998 and 2010, 121 patients were treated with this protocol., Results: The median follow-up period was 53.7 months (7.6-162.2). International Federation of Gynecology and Obstetrics stages were IB; (9.1%), IIA; 6 (5.0%), IIB; 53 (43.8%), IIIA; 7 (5.8%), IIIB; 37 (30.6%) and IVA; 7 (5.8%), respectively. Nodal involvement was reported in 77 patients (63.6%) at the pelvis and 25 (20.7%) at the para-aortic region. The 5-year overall survival and progression-free survival rates were 80.0 and 63.4%, respectively. Regarding Grade ≥3 late toxicities, three patients developed urinary and three developed intestinal toxicities. We encountered no treatment-related death., Conclusions: The clinical results of our alternating chemoradiotherapy protocol for high-risk cervical cancer are promising., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: It is controversial whether patients with stage I ovarian clear cell carcinoma (CCC) benefit from postoperative chemotherapy. This study was designed to evaluate the postoperative outcomes associated with the inclusion or exclusion of adjuvant therapy in these patients., Methods: A total of 185 patients who were treated for stage I CCC between 1991 and 2007 were retrospectively evaluated. All of the patients had received comprehensive surgical staging, and their condition had been diagnosed by a central pathological review system. Only one patient with stage IB was excluded from this study., Results: Median follow-up time was 62 months (range 7-191 months). Median age was 52 years (30-75 years). There were 41, 93, and 50 patients in stage IA, intraoperative capsule ruptured IC (rupture-IC), and all other-IC groups, respectively. The 5-year recurrence-free survival rates for the substage were 97.6%, 87.8%, and 70.4% (P < 0.001), respectively. Among 134 patients consisting of those in the stage IA and rupture-IC groups, 91 patients received adjuvant chemotherapy (AC) and 43 patients did not (non-AC). There was no significant survival difference in each substage group between the non-AC and AC groups in 5-year recurrence-free survival rate (stage IA, 100% vs 93.8%; rupture-IC, 94.1% vs 86.6%). Multivariate analysis demonstrated that there was no significant prognostic factor for both recurrence and survival among the IA and rupture-IC groups. Postoperative therapy, regimen, and chemotherapy cycles were not significantly affected., Conclusions: This study indicates that adjuvant chemotherapy does not contribute to the improving prognosis of stage IA ovarian CCC. Whereas the histological type is CCC, the routine adjuvant chemotherapy after comprehensive surgical staging may be unnecessary for patients with at least stage IA.

Objective: The aim of this prospective trial was to evaluate the efficacy and safety of the combination of paclitaxel and carboplatin (TC) in patients with metastatic or recurrent cervical cancer., Methods: This was a multicenter phase II trial of 3 weekly paclitaxel 175 mg/m(2) 3-hour iv day 1 followed by carboplatin AUC5 1-hour iv day 1 for maximum of 6 cycles until disease progression or prohibitive toxicity. Eligible patients had squamous or adenocarcinoma of the cervix with measurable stage IVB or recurrent, aged 20-75 years, Eastern Cooperative Oncology Group performance status 0-2, prior platinum-containing regimen 0-1, and no prior taxane. The primary endpoint was overall response rate (ORR) by RECIST., Results: 41 patients were enrolled, of which 39 were evaluable for analysis. 33 patients (84.6%) received prior radiotherapy. The confirmed ORR was 59% (95% CI, 43% to 75%); 5 patients (13%) achieved a complete response and median response duration was 5.2 months. The response rates for patients who had adenocarcinoma (n=10) and prior platinum-based chemotherapy<6 months (n=7) were 40.0% and 0%, respectively. The median progression-free survival and overall survival times were 5.3 and 9.6 months, respectively. The most frequent grade 3 or 4 adverse events were neutropenia (79%), anemia (46%), thrombocytopenia (15%), and fatigue (8%). No treatment-related death was seen., Conclusions: TC seemed to be feasible and effective similar to other cisplatin-based doublets for the treatment of metastatic or recurrent cervical cancer. Phase III trial is warranted to establish the clinical benefits of this combination., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate the efficacy and toxicities of cisplatin and daily oral etoposide in patients with recurrent cervical cancer., Patients and Methods: Treatment was initiated with oral etoposide 25 mg/day for 21 consecutive days, with intravenous cisplatin at 50 mg/m², on day 1, every 4 weeks, then the etoposide dose was increased to 50 mg/day., Results: Thirty patients were enrolled in this study. Twenty-seven (90.0%) patients had a history of prior treatment (cisplatin with concurrent chemoradiotherapy in 15, radiation therapy in 3, chemotherapy in 1, and both radiation therapy and chemotherapy in 9), and 22 (73.3%) patients had a treatment-free interval of less than 6 months. NCI-CTC grade 3/4 hematologic toxicities were leukopenia in 19 (63.3%), neutropenia in 17 (58.6%), anemia in 15 (50.0%) and thrombocytopenia in 6 (20.0%). Four patients developed febrile neutropenia. NCI-CTC grade 3 nonhematologic toxicities consisted of nausea/vomiting in 2 (6.7%), anorexia in 4 (13.3%) and fatigue in 2 (6.7%). The overall response rate was 16.7% including one complete response. The median progression-free survival period and overall survival period were 4.5 and 9.7 months, respectively., Conclusion: Combination chemotherapy consisting of oral etoposide and intravenous cisplatin is safe and effective for recurrent cervical cancer.

Background: To assess the safety and efficacy of neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) for müllerian carcinomas, such as ovarian, tubal, and peritoneal cancers, and to determine whether we can omit diagnostic laparoscopy before treatment initiation, a feasibility study was performed., Methods: Eligible patients had presumed stage III/IV müllerian carcinomas clinically diagnosed by imaging studies, cytology, and tumor markers. All patients underwent diagnostic laparoscopy to confirm the clinical diagnosis. Four cycles of paclitaxel and carboplatin were administered as NAC, followed by interval debulking surgery and an additional 4 cycles of chemotherapy. The primary end point was the proportion of patients achieving clinical complete remission (cCR) among all stage III/IV müllerian carcinomas confirmed by diagnostic laparoscopy. The major secondary end point was the positive predictive value (PPV) of clinical diagnosis., Results: Fifty-six patients were enrolled into the study. The PPV of overall clinical diagnosis for the tumor origin, histology, and stage was 95% (53/56). Fifty-three patients received the protocol treatment starting with NAC. IDS was performed in 89% (47/53) of patients. Complete resection without residual tumors was achieved in 55% (29/53) and residual tumors became <1 cm in 17% (9/53) of patients. Twenty-two patients (42%) achieved cCR after completion of the treatment. The median overall and progression-free survival was 45 and 14 months, respectively., Conclusion: NAC without diagnostic laparoscopy for advanced müllerian carcinomas holds sufficient promise to be compared with direct surgery in a phase III trial.

Purpose: To assess the efficacy of alternating chemoradiotherapy combined with extended-field conformal radiotherapy for patients with high-risk cervical cancer., Methods and Materials: Patients with previously untreated cervical cancer, with Stage III/IVA disease, or Stage IB/II with high-risk factor (primary tumor diameter >/=50 mm or positive lymph node) were entered into this study. Three cycles of chemotherapy with 3,500 mg/m(2) of 5-fluorouracil (5-FU) and nedaplatin (NDP) were accompanied with pelvic irradiation of 45.6-51.3 Gy in 24-27 fractions over 6 weeks. Prophylactic (36 Gy/20 fractions) or definitive (45-56 Gy) irradiation for para-aortic region was followed by pelvic irradiation., Results: Between 1998 and 2004, 40 patients were recruited for this protocol study. Eighteen patients from Phase I setting were registered. Twenty-two patients were treated with NDP of 140 mg/m(2) (the recommended dose) in the Phase II segment. Twenty-five patients had T3 disease, and 25 patients had nodal disease including para-aortic involvement (n = 5). Overall/progression-free survival rates at 5 years were 78.8 and 66.5%, respectively. The median follow-up time was 61.8 months (25.5-106.7). Hematologic and gastrointestinal Grade 3 or more toxicities were relatively high rate (27.5-45%); however, they were well manageable. Two for bladder toxicity of Grade 3 were noted. Comparing the data from historical control group evaluated by magnetic resonance imaging, alternating chemoradiotherapy revealed a significant favorable factor for survival and disease recurrence in multivariate analysis (p < 0.05)., Conclusion: Acquired results from our unique protocol for cervical cancer with high-risk factor were thought to be promising, considering that the majority of our cohort consisted of high-risk population.