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After immune checkpoint inhibitor (ICI) comes into third-line treatment of advanced gastric cancer, the therapeutic strategy has been dramatically changed. Recent first-line regimen, which consists of ICI and chemotherapeutic agents, prolonged progression-free survival, and subsequent treatment options enabled continuous treatment beyond second-line therapy. Moreover, the advent of vascular endothelial growth factor (VEGF)-targeted agents including angiogenesis inhibitors and TKIs provides an opportunity of considering the interaction between ICI and anti-VEGF agents, and facilitating novel treatment proposal. Although clinical benefit of prolonged VEGF blockade after disease progression has not been confirmed in gastric cancer, combination therapy of cytotoxic agents and anti-VEGF agent, such as irinotecan plus ramucirumab demonstrated favorable objective response rate and progression-free survival in third- or later-line setting. In this review, we discuss recent progress and future directions of later-line treatments of HER2-negative advancer gastric cancer., (© 2024. The Author(s).)

Background: First-line pembrolizumab plus chemotherapy (pembrolizumab-chemotherapy) demonstrated improved efficacy and a manageable safety profile versus placebo plus chemotherapy (placebo-chemotherapy) in the subgroup analysis of Japanese patients with advanced/metastatic esophageal cancer in KEYNOTE-590 at a median follow-up of 24.4 months. Longer-term data from the Japanese subgroup analysis of KEYNOTE-590 are reported., Methods: Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for ≤ 35 cycles plus chemotherapy (cisplatin 80 mg/m 2 and 5-fluorouracil 800 mg/m 2 /day). Endpoints included overall survival (OS) and progression-free survival (PFS; investigator-assessed per RECIST v1.1; dual primary) and safety (secondary). Early tumor shrinkage (ETS) and depth of response (DpR) were assessed post hoc., Results: Overall, 141 patients were enrolled in Japan. As of July 9, 2021, median follow-up was 36.6 months (range, 29.8-45.7). Pembrolizumab-chemotherapy showed a trend toward favorable OS (hazard ratio [HR], 0.70; 95% confidence interval [CI] 0.47-1.03) and PFS (0.57; 0.39-0.83) versus placebo-chemotherapy. In the pembrolizumab-chemotherapy group, patients with ETS ≥ 20% (55/74; 74.3%) versus < 20% (19/74; 25.7%) had favorable OS (HR, 0.23; 95% CI 0.12-0.42) and PFS (0.24; 0.13-0.43). Patients with DpR ≥ 60% (31/74; 41.9%) versus < 60% (43/74; 58.1%) had favorable OS (HR, 0.37; 95% CI 0.20-0.68) and PFS (0.24; 0.13-0.43). Grade 3-5 treatment-related adverse events occurred in 55/74 patients (74.3%) with pembrolizumab-chemotherapy and 41/67 patients (61.2%) with placebo-chemotherapy., Conclusions: With longer-term follow-up of Japanese patients with advanced/metastatic esophageal cancer, efficacy continued to favor pembrolizumab-chemotherapy compared with placebo-chemotherapy, with no new safety signals observed., Clinical Trial Registration: ClinicalTrials.gov, NCT03189719., (© 2024. The Author(s).)

Background: The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished., Patients and Methods: In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included. Interactions between pretreatment and treatment groups for progression-free survival (PFS), overall survival (OS), and response rate (RR) were assessed using the propensity-score weighted Cox proportional hazards model., Results: From February 2018 to September 2020, 283 patients were analyzed in the 2L cohort. A strong interaction was observed for PFS between BEV and RAM with HGF, sNeuropilin-1, sVEGFR-1, and sVEGFR-3. Interactions for RR between the BEV and RAM groups were observed for sNeuropilin-1 and sVEGFR-1. Contrarily, OS, PlGF, sVEGFR-1, and sVEGFR-3 differentiated the treatment effect between BEV and AFL. Plasma samples were evaluable for dynamic analysis in 203 patients. At progression, VEGF-A levels significantly decreased in the BEV group and increased in the RAM and AFL groups., Conclusion: The pretreatment plasma sVEGFR-1 and sVEGFR-3 levels could be predictive biomarkers for distinguishing BEV and RAM when combined with chemotherapy in 2L mCRC treatment. Based on the VEGF-A dynamics at progression, selecting RAM or AFL for patients with significantly elevated VEGF-A levels may be a 2L treatment strategy, with BEV considered for the third-line treatment., Clinical Trial Number: UMIN000028616., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAF V600E -mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAF V600E -mutant mCRC., Materials and Methods: The EAP was an open-label, single-arm study including Japanese patients with BRAF V600E -mutant mCRC whose disease progressed after 1 to 2 prior regimens. The patients received the BEACON triplet regimen with 28-day cycles. The subsequent follow-up study assessed the survival outcomes following EAP completion. Safety was assessed only during the EAP., Results: Among the 86 enrolled patients, 81 received the BEACON triplet regimen. The objective response rate and median progression-free survival were 27.6% (95% confidence interval [CI], 18.0%-39.1%) and 5.26 (95% CI, 4.14-5.52) months, respectively. Grade 3 to 4 adverse events and treatment-related adverse events occurred in 43.2% and 28.4% of patients, respectively. No new safety signals were observed during the EAP. Among 58 patients with confirmed survival at EAP completion, 57 were included in the follow-up study. With a median observation period of 9.17 months through the EAP and follow-up study, the median overall survival was 10.38 (95% CI, 9.00-16.16) months., Conclusion: The efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAF V600E -mutant mCRC were consistent with those reported in the BEACON CRC trial, supporting its use as a standard treatment for pretreated patients with BRAF V600E -mutant mCRC., Competing Interests: Disclosure DK reports honoraria from Takeda, Chugai, Lilly, Merck Sharp and Dome (MSD), Ono, Taiho, Bristol-Myers Squibb (BMS), Daiichi Sankyo, Pfizer, Novartis, Eisai, Seagen, Merck Biopharma, and Sysmex; and research funding from Ono, MSD, Novartis, Servier, Janssen, IQVIA, Syneos Health, Cmic, and Cmic ShiftZero. AT reports grants from MSD, Amgen, BMS, AstraZeneca, Eisai, and Ono; and honoraria from Lilly, Taiho, Takeda, Ono, Chugai, and Merck Serono. TK reports honoraria from Chugai, Takeda, Eli Lilly, and Ono. TS reports grants from Ono, Chugai, and Yakult Honsha; and honoraria from Eli Lilly, Ono, BMS, and Daiichi Sankyo. TM reports grants from MSD, Daiichi Sankyo, Ono, Novartis, Amgen, Syneos Health Clinical, Boehringer Ingelheim, Pfizer, Cmic ShiftZero, and Eli Lilly; and honoraria from Takeda, Chugai, Merck Bio Pharma, Taiho, Bayer, Lilly Japan, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, BMS, and Nippon Kayaku. YK reports grants and scholarships funding from Ono, Taiho, Daiichi Sankyo, and Chugai; funding from IQVIA Services Japan, MSD, Astellas Pharma, Incyte Bioscience Japan, Eisai, National Cancer Center Hospital East, Syneos Health, Cmic Holdings, Parexel International, and National Cancer Center Japan; scholarships from Shionogi, Nippon Zoki, Nippon Kayaku, and Asahi Kasei; and honoraria from Ono, Chugai, Bayer Yakuhin, Astellas, Daiichi Sankyo, Taiho, Eli Lilly, MSD, Yakult, and Incyte Bioscience Japan. TE reports grants from MSD, Daiichi Sankyo, Pfizer, Astellas, Quintiles, Syneos Health, Chugai, Amgen, Ono, Novartis, Astellas Amgen Biopharma, Asahi Kasei, and IQVIA; and honoraria from Chugai, Daiichi Sankyo, Taiho, Eli Lilly, BMS, and MSD. NI reports a grant from Ono. ST reports honoraria from Chugai and Eli Lilly. HB reports honoraria from Ono, Eli Lilly Japan, and Taiho. SI reports grants from Ono and BMS; honoraria from Ono and BMS; and employment by Chugai. HT reports grants from Takeda, Ono, and Daiichi Sankyo; and honoraria from Ono, Merck Biopharma, Eli Lilly, Chugai, and Takeda. TYo reported grants from Amgen K.K., Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia, Molecular Health GmbH, MSD K.K., Nippon Boehringer Ingelheim, Ono, Pfizer Japan, Roche Diagnostics K.K., Sanofi K.K., Sysmex, and Taiho; and consulting fees from Sumitomo Corporation; honoraria from Bayer Yakuhin, Chugai, Merck Biopharma, MSD K.K., Ono, and Takeda. YU, TO, and CI are employees of Ono. Other authors have declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Three patients aged 79, 75, and 81 years with unresectable hepatocellular carcinoma (HCC) and undergoing maintenance hemodialysis were treated with a combination of atezolizumab and bevacizumab. The patients, respectively, received their 22nd, 2nd, and 4th treatment cycles, and one achieved long-term stable disease. No serious adverse events, including immune-related adverse events, were observed in any patient. Remarkable progress has been made in chemotherapy for cancer; however, the efficacy and safety of chemotherapy in patients undergoing hemodialysis have not been adequately elucidated. This report provides novel insights into the feasibility and outcomes of atezolizumab and bevacizumab combination therapy in patients with HCC undergoing hemodialysis, highlighting its potential as a viable treatment option with manageable side effects., (© 2024. Japanese Society of Gastroenterology.)

Background: The optimal number of neoadjuvant chemotherapy (NAC) cycles remains to be established for treating oesophageal squamous cell carcinoma (ESCC). We compared two versus three courses of NAC for treating locally advanced ESCC in a multi-institutional, randomised, Phase II trial., Methods: We randomly assigned 180 patients with locally advanced ESCC at 6 institutions to either two (N = 91) or three (N = 89) courses of DCF (docetaxel 70 mg/m 2 , cisplatin 70 mg/m 2 i.v. on day 1, fluorouracil 700 mg/m 2 continuous infusion for 5 days) every 3 weeks, prior to surgery. The primary endpoint was 2-year progression-free survival (PFS) with an intention-to-treat analysis., Results: Patient background parameters were well-balanced. The R0 resection rates were 98.9 and 96.5% in the two- and three-course groups, respectively (P = 0.830). In resected cases, the two- and three-course groups had comparable pN0 rates (P = 0.225) and histological responses (P = 0.898). The 2-year PFS rate was also comparable between the two groups (71.4 vs. 71.1%, P = 0.669). Among subgroups based on baseline characteristics, only patients aged under 65 years old showed a tendency for better survival with the three-course treatment (hazard ratio = 2.612, 95% confidence interval: 1.012-7.517)., Conclusions: Two courses of a DCF regimen showed potential as an optional NAC treatment for locally advanced ESCC., Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN 000015788)., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Among patients with colorectal cancer (CRC) treated with oxaliplatin (L-OHP)-based chemotherapy, delayed chemotherapy-induced nausea and vomiting (CINV) have not been well controlled., Methods: We pooled data from two prospective observational studies in Japan and one phase III clinical trial to assess whether delayed CINV could be controlled with a combination of three antiemetics adding a neurokinin-1 receptor antagonist and identified individual risk factors, using an inverse probability treatment-weighted analysis., Results: A total of 661 patients were evaluable in this study (median age: 64 years; 391 male, and 270 female). 3 antiemetics controlled delayed nausea (33.18% vs. 42.25%; p = 0.0510) and vomiting (4.15% vs. 16.08%; p < 0.0001) better than with 2 antiemetics. Female and 2 antiemetics were risk factors for both delayed nausea (female-odds ratio [OR]: 1.918; 95% confidence interval [CI]: 1.292-2.848; p = 0.0012; 2 antiemetics-OR: 1.485; 95% CI: 1.000-2.204; p = 0.0498) and delayed vomiting (female-OR: 2.735; 95% CI: 1.410-5.304; p = 0.0029; 2 antiemetics-OR: 4.551; 95% CI: 2.116-9.785; p = 0.0001)., Conclusions: Identifying individual risk factors can facilitate personalized treatments for delayed CINV. We recommend a 3-antiemetic combination prophylaxis for CRC patients treated with L-OHP-based chemotherapy, especially for female patients., (© 2021. The Author(s).)

Objective: To compare short-term outcomes between two- vs. three courses of neoadjuvant chemotherapy (NAC) to clarify the optimal treatment for esophageal squamous cell cancer (ESCC) in a multicenter, randomized, phase II trial., Background: An optimal number of NAC cycles remains to be established for locally advanced ESCC., Methods: Patients with locally advanced ESCC were randomly assigned to either two (N = 91) or three (N = 89) courses of DCF (70 mg/m 2 intravenous docetaxel and 70 mg/m 2 intravenous cisplatin on day 1, and a continuous 700 mg/m 2 fluorouracil infusion for 5 days) every 3 weeks followed by surgery. We compared the two groups for perioperative parameters, adverse events, and the response to NAC., Results: The two- and three-course groups showed similar completion rates and overall NAC dose reductions. Although the two-course group showed significantly lower overall grades 3-4 leukopenia and anemia compared to the three-course group, the two groups had similar overall toxicity rates. Postoperative complications were not significantly different between the two groups, except arrhythmia (13 vs. 0%, P = 0.0007). Only two postoperative in-hospital deaths occurred in the three-course group, due to sepsis following severe pneumonia. Compared to the two-course group, the three-course group was associated with a significantly better clinical response (42.9 vs. 65.2%, P = 0.0027) and a relatively higher rate of pathological complete response (9.1 vs. 15.3%, P = 0.212)., Conclusion: Both two- and three-course DCF regimens in the NAC setting seemed to be equally feasible in locally advanced ESCC patients. Additional DCF courses led to a better NAC response without increasing the incidence of adverse events or postoperative morbidity., Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry of Japan (Identification Number UMIN 000015788)., (© 2021. The Japan Esophageal Society.)

Background: There is no standard chemotherapy for esophageal squamous cell carcinoma (ESCC) refractory to first-line fluoropyrimidine- and platinum-based chemotherapy. We therefore performed a randomized, selection-design phase II trial to compare docetaxel (DTX) and paclitaxel (PTX) in this setting., Patients and Methods: Eligible patients were randomly assigned to receive either DTX (70 mg/m 2 on day 1 of each 21-day cycle) or PTX (100 mg/m 2 on days 1, 8, 15, 22, 29 and 36 of each 49-day cycle). The primary end-point was overall survival (OS), and secondary end-points included progression-free survival (PFS), time to treatment failure (TTF), response rate (RR) and safety., Results: Seventy-eight eligible patients (N = 39 in each group) were included for efficacy analysis. OS was significantly longer in the PTX group than in the DTX group (median, 8.8 versus 7.3 months; hazard ratio [HR], 0.62; P = 0.047). A significant benefit of PTX over DTX was also apparent in PFS (median, 4.4 versus 2.1 months; HR, 0.49; P = 0.002) and TTF (median, 3.8 versus 2.1 months; HR, 0.45; P < 0.001). RR (25.6% versus 7.7%, P = 0.065) were higher in the PTX group than in the DTX group. Compared to the PTX group, neutropenia (28% versus 80%) and leukopenia (28% versus 76%) of grade ≥3 as well as febrile neutropenia (0% vs. 46%, P < 0.0001) occurred more frequently in the DTX group., Conclusion: PTX showed a significantly better efficacy as well as a more manageable toxicity compared with DTX., Clinical Trial Registration: UMIN000007940., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: HK has received consulting fees and research funding from Bristol-Myers Squibb Co. Ltd. as well as honoraria and lecture fees from Bristol-Myers Squibb Co. Ltd. and Takeda Pharmaceutical Co. Ltd. HH has received honoraria from Bristol-Myers Squibb Co. Ltd., Yakult Honsha Co. Ltd., Sanofi K. K., and Takeda Pharmaceutical Co. Ltd., as well as research funding from Bristol-Myers Squibb Co. Ltd., Yakult Honsha Co. Ltd., Sanofi K. K., Takeda Pharmaceutical Co. Ltd., and Pfizer Japan Inc. Y Kurokawa has received lecture fees from Bristol-Myers Squibb Co. Ltd., Yakult Honsha Co. Ltd., Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., and Pfizer Japan Inc. T Satoh has received grants and other funding from Yakult Honsha Co. Ltd. and Bristol-Myers Squibb Co. Ltd. All remaining authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS., Methods: This randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled., Results: Overall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively)., Conclusions: The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen., Trial Registration: UMIN Clinical Trials Registry ( UMIN000006706 ). Date of registration: NOV/11/2011. URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000007920., (© 2021. The Author(s).)

Aim: The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy., Methods: Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (<4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon's minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed., Results: For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55-86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4-84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%-69.3%), median prostate-specific antigen-progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%)., Conclusions: Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen-progression-free survival was shorter than that reported in previous studies. Considering the benefit-risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Cisplatin plus S-1 (CS) is the standard first-line chemotherapy for advanced gastric cancer (AGC) in Japan. A previous phase III trial showed that docetaxel plus S-1 (DS) was effective for AGC without measurable lesions, but no studies have compared these two regimens., Methods: Eligible patients had unresectable or recurrent HER2-negative AGC without measurable lesions. Patients were randomized to DS (docetaxel 40 mg/m 2 on day 1, S-1 80-120 mg on days 1-14, every 3 weeks) or CS (cisplatin 60 mg/m 2 on day 8, S-1 80-120 mg on days 1-21, every 5 weeks). The primary endpoint was overall survival (OS)., Results: All patients had unresectable primary disease. Sixty-one patients were randomly assigned to DS (n = 30) or CS (n = 31). One CS patient was ineligible due to HER2 positivity. The median number of cycles was 9.5 (range 2-49) with DS and 5.5 (range 1-10) with CS. There were no treatment-related deaths. The most common grade 3-4 non-hematological toxicity was fatigue (7% with DS, 13% with CS), followed by anorexia (3% with DS, 10% with CS) and diarrhea (3% with DS, 10% with CS). The 2-year OS rates were 43.3% with DS and 30.0% with CS (log-rank P = 0.113), with a hazard ratio of 0.617 (95% confidence interval 0.337-1.128), indicating non-inferiority of DS to CS with respect to OS (P < 0.001)., Conclusions: DS showed slightly but nonsignificantly less toxicity and higher efficacy than CS for AGC without measurable lesions. DS should be further investigated in phase III trials.

Treatment options for patients with HER2-positive advanced gastric cancer are limited, and the prognosis for these patients is poor. Pembrolizumab has demonstrated promising antitumor activity in patients with advanced gastric or gastroesophageal junction adenocarcinoma as monotherapy, in combination with chemotherapy and in combination with trastuzumab. Combining pembrolizumab with trastuzumab and chemotherapy may therefore provide a benefit for patients with advanced HER2-positive gastric cancer. Here we aimed to describe the design of and rationale for the randomized, double-blind, placebo-controlled Phase III KEYNOTE-811 study, which will evaluate the efficacy and safety of pembrolizumab or placebo in combination with trastuzumab and chemotherapy as first-line treatment for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma. Clinical trial registration: NCT03615326 (ClinicalTrials.gov).

Background: We previously reported the HERBIS-4A phase II trial comparing S-1 plus cisplatin (SP) with capecitabine plus cisplatin (XP) in chemotherapy-naïve patients with HER2-negative advanced gastric cancer (GC). We performed a pooled analysis of HERBIS-4A and HERBIS-2, the phase II trial comparing SP with XP in HER2-negative recurrent GC patients with a recurrence-free interval after S-1 adjuvant therapy of ≥ 6 months., Patients and Methods: Patients were randomly assigned to receive either SP [S-1 (40-60 mg twice daily for 21 days) plus cisplatin (60 mg/m 2  on day 8), every 5 weeks] or XP [capecitabine (1000 mg/m 2  twice daily for 14 days) plus cisplatin (80 mg/m 2 on day 1), every 3 weeks]., Results: In the pooled analysis, SP (n = 44-50) showed a longer progression-free survival [6.4 versus 5.1 months; hazard ratio (HR), 0.666; P = 0.062], overall survival (14.8 versus 10.6 months; HR, 0.695; P = 0.099), and time to treatment failure (4.6 versus 3.6 months; HR, 0.668; P = 0.045) as well as a higher disease control rate (86.4% versus 68.1%, P = 0.149) compared with XP (n = 47-51). A significant survival advantage for SP over XP was apparent in patients with a performance status of 0, a differentiated-type tumor histology, or a primary tumor localization to the upper portion of the stomach., Conclusion: Our pooled analysis supports the use of SP in the first-line setting for patients with HER2-negative advanced or recurrent GC with a recurrence-free interval of ≥ 6 months., Clinical Trial Registration: The HERBIS-2 trial was registered with UMIN-CTR as UMIN000006105.

Background: Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study., Patients and Methods: Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety., Results: From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%)., Conclusion: Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC., Competing Interests: Conflict of interest statement DS reports grants from Yakult Honsha, Chugai, Ono, Eli Lilly, Daiichi Sankyo, Incyte and Taiho, and personal fee from Chugai, outside the submitted work. T.T. reports receiving personal fees from Merck Serono Co., Ltd, and Takeda Pharmaceutical Co., Ltd., during the conduct of the study, and receiving grants from Ono Pharmaceutical, Bristol-Myers Squibb and Japan AMED, outside the submitted work. N.S. reports receiving personal fees from Merck-Biopharm and Takeda Pharmaceutical Co.Ltd. , and ONO Pharmaceutical Co.,Ltd., MSD, Sanofi, Daiichi Sankyo, Parexel International, Sumitomo Dainippon Pharma, Bristol-Myers Squibb, Solasia Pharma, Chugai Parmaceutical, Taiho Pharmaceutical and Eli Lilly, outside the submitted work. T.N. reports grants and personal fees from Taiho pharma, grants and personal fees from Chugai pharma, grants from Daiichi sankyo pharma, grants from MSD, grants and personal fees from Ono pharma, grants and personal fees from Bristol myers squibb, grants and personal fees from Lilly pharma, grants from Dainippon sumitomo pharma, outside the submitted work. H.H. reports paid consulting or advisory roles for MSD and Ono; honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono, Sanofi, Taiho, Takeda and Yakult; and research funding from Astellas, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Incyte, LSK BioPharma, Merck Biopharma, MSD, Ono, Pfizer, and Taiho, outside the submitted work. T.E. reports research funding from Taiho, MSD, Eli Lilly, Daiichi Sankyo, Ono, Bayer, Novartis, Astellas, Astellas Amgen Biopharma, BeiGene, Pierre Fabre Medicament, Ignyta, Array BioPharma, Dainippon Sumitomo, and honoraria from Taiho, MSD, Eli Lilly, Daiichi Sankyo, Ono, Bayer, Chugai, Nihon Kayaku, Sanofi, Takeda, Merck Serono, Bristol, Eisai. T.D. reports personal fees from SAWAI Pharmaceutical Co, personal fees from Sysmex, grants from MSD, grants from ONO Pharmaceutical, outside the submitted work. T.S. reports receiving personal fees from Merck-BioPharm and Takeda Pharmaceutical and grants and personal fees from Yakult Honsha and Daiichi-Sankyo, outside the submitted work. A.M. reports receiving personal fees from Lily, Chugai and Takeda, outside the submitted work. A.H. reports receiving personal fees from Taiho Pharmaceutical, Takeda Pharmaceutical, Ono Pharmaceutical, Novartis, Eisai, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, Teijin Pharma, Sanofi and Merck Biopharma and grants from Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, Eisai and Yakult Honsha, outside the submitted work.T.M. reports receiving grants and personal fees from Taiho Pharmaceutical, Yakult Honsha and Takeda Pharmaceutical; receiving personal fees from Chugai Pharmaceutical, Novelpharma, Merck Serono and Sanofi and receiving grants from Boehringer Ingelheim and Eisai, outside the submitted work. H.Y. reports research funding from MSD, Daiichi Sankyo, and Ono Pharmaceutical, personal fees from Taiho Pharmaceutical, honoraria from Chugai Pharma, Bristol-Myers Squibb Japan, Daiichi Sankyo, TERUMO, Eli Lilly Japan, Merk Biopharma, and Yakult Honsha, outside the submitted work. A.T. reports receiving personal fees from Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Merck Serono Co., Ltd. E.B. reports receiving grants and personal fees from Ono, Merck-Serono, Taiho, Chugai and Daiichi-Sankyo and personal fees from BMS, Takeda, Eli lilly, Tsumura, Kyowa-Kirin and Yakult, outside the submitted work. K.S. reports personal fees from SHIONOGI & CO., LTD., personal fees from Takeda Pharmaceutical Company Limited, personal fees from Taiho Pharmaceutical Co Ltd, personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Merck Biopharma Co., Ltd, personal fees from NIPPON KAYAKU Co., Ltd., personal fees from Asahi Kasei Pharma, from Eisai Co., Ltd., personal fees from Bayer Yakuhin, Ltd., personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from CHUGAI PHARMACEUTICAL CO., LTD., personal fees from MOCHIDA PHARMACEUTICAL CO.,LTD., personal fees from Eli Lilly Japan K.K., personal fees from DAIICHI SANKYO COMPANY, LIMITED, outside the submitted work. M.G. reports receiving grants, personal fees and non-financial support from Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Chugai Pharmaceutical Co., Ltd., during the conduct of the study and personal fees and non-financial support from Takeda Pharmaceutical Co., Ltd., Novartis Pharmaceuticals and Bayer Yakuhin, Ltd., outside the submitted work. S.K. reports receiving grants and personal fees from Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical and Bristol-Myers Squibb and personal fees from Chugai Pharma, Merck Serono, Bayer, Eisai and Yakult Honsha, outside the submitted work. Y.K. reports receiving research grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim Japan, Ono Pharmaceutical, Bristol-Myers Squibb, and Tosoh Corp., research grants from MSD, Toppan Printing, Terumo and On-chip Biotechnologies, and personal fees from Thermo Fisher, and Lilly outside the submitted work. K.Y. reports receiving personal fees and other fees from Chugai, Bayer and MSD; personal fees from Takeda, Taiho, Yakult, Daiichi Sankyo, Merck Serono, Sanofi, Lily and other fees from Boehringer Ingelheim, outside the submitted work. S.H. reports receiving personal fees from Ono Pharm, Bristol-Myers Squibb, Taiho Pharm, Yakult Honsha, Daiichi Sankyo, Lilly, Chugai Pharm, Nihonkayaku and Tsumura & Co., outside the submitted work. N.B. reports receiving research grant from Ono, Bristol-Myers Squibb and Taiho and honorarium from Ono, Bristol-Myers Squibb, Taiho, Eli-Lilly and Chugai. I.H. reports receiving grants and personal fees from Chugai, Taiho, Takeda, Ono, Daiichi-Sankyo and Yakult-Honsha and personal fees from Merck-Serono, outside the submitted work. K.M. reports receiving grants and personal fees from ONO Pharmaceutical CO.,LTD. and Sanofi, and grants from Daiichi Sankyo, Parexel International, Shionogi Pharmaceutical, Sumitomo Dainippon Pharma, MSD, Pfizer, Mediscience Planning, Solasia Pharma, and Merck Serono. He also reports receiving personal fees from Eli Lilly, Chugai Pharmaceutical, Takeda Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, and Bayer; outside the submitted work. The other authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Chemotherapy in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of reintroducing modified FOLFOX6 (mFOLFOX6) or CAPOX with or without bevacizumab in recurrent colorectal cancer patients after oxaliplatin adjuvant chemotherapy., Methods: Patients that participated in this trial had a medical history of adjuvant chemotherapy, including oxaliplatin with a cumulative dose greater than 400 mg/m 2 , and recurrence that was diagnosed more six months post adjuvant chemotherapy. Primary endpoints were response rate (RR) and disease control rate (DCR), while key secondary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety., Results: A total of 31 patients were enrolled between October 2012 and October 2016. Of the 29 eligible patients, 7 received mFOLFOX6 and 22 received CAPOX. The RR was 62.1% (95% confidence interval 42.3-79.3) and the DCR was 82.8% (95% confidence interval 64.2-94.2). The RR for oxaliplatin-free interval was 100.0% in months 6-12 and 56.0% after 12 months. Median TTF, PFS, and OS were 6.3, 10.8, and 28.7 months, respectively. Grade 3 or worse peripheral sensory neuropathy developed in 6.5%. Allergic reactions occurred in 12.9% of the patients, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events., Conclusion: Reintroduction of oxaliplatin was feasible and achieved high RR or DCR in patients after more than 6 months post oxaliplatin adjuvant chemotherapy.

After failure of first-line chemotherapy with fluoropyrimidines and platinum compounds for advanced gastric cancer, second-line chemotherapy with ramucirumab plus paclitaxel, which elicits a durable response, and third-line or later chemotherapy with nivolumab have been shown to lead to a more favorable prognosis in advanced gastric cancer patients. As new and more effective drugs are now available, sequential chemotherapy would contribute to prolonged survival. From this point of view, the patient's disease course should be frequently monitored in order to adapt treatment regimens. This review summarizes the points to note in regard to radiological assessment, and discusses the integration of prognostic factors, tumor markers, and clinical symptoms that need to be taken into account to change treatment at an appropriate timing.

Background: Older or frail patients are often underrepresented in clinical trials for metastatic colorectal cancer (mCRC). We here assessed the efficacy and safety of 5-fluorouracil (5-FU)-leucovorin plus bevacizumab in such patients., Methods: The study (OGSG 0802) was designed as a single-arm, open-label, multicenter phase II trial. Eligible patients had mCRC and at least one of the following: an age of ≥ 65 years, an Eastern Cooperative Oncology Group performance status of 1 or 2, a serum albumin level of ≤ 3.5 g/dL, incompatibility with oxaliplatin or irinotecan, and a history of abdominal or pelvic radiotherapy. Patients received 5-FU (600 mg/m 2 ) and l-leucovorin (200 mg/m 2 ) on days 1, 8, and 15 together with bevacizumab (5 mg/kg) on days 1 and 15 every 4 weeks. The primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety., Results: Forty-one patients were enrolled and eligible. Median age was 76 years (range 56-90 years), and 51% of patients had a performance status of 0. The ORR was 36.6% [95% confidence interval (CI) 22.1-53.1%], median PFS was 9.4 months (95% CI 7.4-17.7 months), and median OS was 24.0 months (95% CI 19.9 months-not reached). The most common treatment-related adverse events of grade ≥ 3 were neutropenia (24%), anorexia (10%), leukopenia (7%), and mucositis/stomatitis (7%). There were no treatment-related deaths., Conclusion: Weekly 5-FU-leucovorin with biweekly bevacizumab may be a tolerable and effective treatment option for older or frail patients with mCRC.

Background: Adjuvant S-1 monotherapy is standard of care for stage II and III gastric cancer (GC), but there is still a need to improve the efficacy of treatment for stage III disease. We conducted phase II study of eight cycles of S-1 plus docetaxel (DS) followed by S-1 monotherapy for up to 1 year after D2 gastrectomy for stage III GC., Patients and Methods: Sixty-two patients with stage III GC were enrolled. They received oral S-1 (80 mg/m 2 /day) for 2 consecutive weeks and intravenous docetaxel (40 mg/m 2 ) on day 1, repeated every 3 weeks for 8 cycles, followed by S-1 until 1 year postgastrectomy. Treatment safety, tolerability, and survival were evaluated., Results: The completion rate for eight cycles of DS therapy was 77.4% [95% confidence interval (CI) 65.0-87.1%]. Subsequent S-1 monotherapy for 1 year was feasible in 71.0% (95% CI 58.1-81.8%) of patients. The incidence of neutropenia, leukopenia, anorexia, and fatigue of grade 3 or higher was 10% or higher. There were no treatment-related deaths. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 72.4% (95% CI 62.1-84.5%) and 60.0% (95% CI 48.8-73.9%), respectively. Subgroup analyses by disease stage showed 5-year OS and DFS rates of 74.5% (95% CI 60.7-91.5%) and 59.3% (95% CI 43.8-80.2%) for stage IIIA and 70.0% (95% CI 55.4-88.5%) and 60.0% (95% CI 44.8-80.4%) for stage IIIB, respectively., Conclusions: Adjuvant eight cycles of DS therapy might be safe and manageable and has promising OS and DFS for stage III GC.

Background: Despite recent findings that epithelial cell adhesion molecule (EPCAM) deletions can cause Lynch syndrome (LS), its clinical characteristics are still unknown. We present the first case of ileum cancer in a patient with germline EPCAM gene deletion, which was discovered during ovarian tumor surgery., Case Presentation: A 59-year-old woman presented with a history of colon cancer occurring at 38 and 55 years old. Five of her siblings had a history of colon cancer, and an elder sister had confirmed LS. As imaging examination revealed an ovarian tumor, and we performed hysterectomy and bilateral salpingo-oophorectomy. Careful observation during surgery revealed a cherry-sized tumor in the ileum, prompting partial ileal resection. Pathological examination showed the ovarian tumor to be a metastasis of ileum cancer. Genetic testing with blood-relative information using multiplex ligation-dependent probe amplification showed EPCAM exons 8 and 9 deletions, confirming LS. The patient received adjuvant chemotherapy with CAPOX (capecitabine and oxaliplatin) and has remained disease-free for 24 months., Conclusions: We were fortunate to identify ileum cancer that would have been difficult to find preoperatively through careful observation during ovarian tumor surgery and successfully treated the patient by using surgical resection and CAPOX chemotherapy. When treating patients with hereditary cancer syndromes including LS, we should keep all associated cancers in mind.

Background: Dysphagia is a major symptom of esophageal cancer (EC) that significantly affects patient quality of life; however, little is known regarding its clinical impact on the treatment course in patients with EC., Methods: This retrospective study included 434 consecutive patients with EC who received docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy as an initial treatment. We evaluated the relationships between the dysphagia score at diagnosis and clinicopathological factors, including DCF therapy-related adverse events, tumor response, and survival., Results: The dysphagia scores were 0 in 208 patients (47.9%), 1 in 82 patients (18.9%), 2 in 52 patients (12.0%), 3 in 59 patients (13.6%), and 4 in 33 patients (7.6%). High (≥ 3) dysphagia scores were significantly associated with high incidences of grade 3/4 febrile neutropenia (FN) (79.3 vs. 35.7%, P < 0.001) and diarrhea (63.0 vs. 28.1%, P < 0.001) compared with low (≤ 2) scores. Logistic regression analysis further identified the dysphagia scores as an independent predictor of both FN and severe diarrhea during DCF chemotherapy. Furthermore, compared with low scores, high dysphagia scores were associated with a worse clinical response to chemotherapy (response rate 65.2 vs. 78.7%, P = 0.008) and worse 5-year overall survival (35.4 vs. 56.4%, P = 0.001)., Conclusions: The dysphagia score at diagnosis was an independent predictor of FN and severe diarrhea. Furthermore, this score might be useful in predicting chemotherapy response and long-term survival in patients treated with DCF.

Background: BRAF V600E mutations are associated with aggressive biology and limited response to standard chemotherapy, especially during second-line and beyond therapies. BRAF V600E mutant and wild-type colorectal cancers (CRCs) differ in their expression profiles, and preclinical evidence suggests that microtubule inhibitors have an antitumour effect on xenograft models of BRAF V600E mutant CRCs. Eribulin has the best growth inhibitory activity in vitro of the microtubule inhibitors. Also, we have evidenced a hint of activity for patients with BRAF V600E mutant metastatic CRC (mCRC) with tumour shrinkage following eribulin treatment., Trial Design: The BRAVERY study is a multicentre phase II study to evaluate the efficacy and safety of eribulin in patients with BRAF V600E mutant mCRC detected in either tumour tissues (primary analysis part) or circulating tumour DNA assays (liquid biopsy part). Key eligibility criteria are refractoriness and intolerance to at least one regimen (including irinotecan or oxaliplatin) containing fluoropyrimidine and Eastern Cooperative Oncology Group performance status of 0-1. Eribulin is to be administered intravenously at a dose of 1.4 mg/m 2 on days 1 and 8 and repeated every 21 days. The primary endpoint is the confirmed objective response rate (ORR) by investigator's assessment. We calculated the sample size of the primary analysis part at 27 patients using a two-stage design with 25% ORR deemed promising and 5% unacceptable (one-sided α, 0.05; β, 0.1). Secondary endpoints include disease control rate, progression-free survival, overall survival and adverse events. Moreover, we will collect pretreated tissue and serial blood samples for biomarker analyses, focusing on gene expression associated with BRAF mutant-like CRC to find predictive markers and acquired gene alterations to detect resistance mechanisms to eribulin. We initiated patient enrolment in March 2018, completed the primary analysis on May 2019, and are currently continuing with the liquid biopsy part., Trial Registration Number: UMIN000031221 and 000031552., Competing Interests: Competing interests: TM has received honoraria from Takeda, Chugai, Merck Serono, Taiho, Bayer, Lilly Japan, Yakult Honsha, and Sanofi and has received research funding from Yakult Honsha, MSD, Daiichi Sankyo, and Ono; HT has received honoraria from Takeda, Chugai, Merck Serono, Taiho, Bayer, Lilly Japan, and Yakult Honsha, Sanofi; DK has received honoraria from Takeda, Chugai, Lilly and Merck Serono; HB has received honoraria from Taiho and Eli Lilly Japan and has received research funding from Taiho, Astrazeneca and Sysmex; YK has received honoraria Takeda, Chugai, Bristol-Myers Squibb, Ono, Merck Biopharma, Taiho, Bayer, Lilly, Yakult Honsha, Sanofi, Nipro, Moroo, Asahi Kasei, Mitsubishi Tanabe, Otsuka, Medical Review, and Shiseido and has received research funding from MSD, Daiichi Sankyo, NanoCarrier, Eisai, Sysmex, Shionogi, IQVIA, Parexel International, Astellas, Mediscience, Sumitomo Dainippon, A2 Healthcare, Ono, Taiho, Bayer, Yakult Honsha, and Sanofi, ES has received honoraria from Taiho, Yakult, Chugai, Lilly, Sanofi, Merck bioparm, and Takeda; TEN has received honoraria from Takeda, Chugai, Merck Serono, Taiho, Bayer, Lilly Japan, Sanofi, Kyowa Hakko Kirin, Sawai, Bristol-Myers Squibb Japan, Ono, Dainippon Sumitomo Pharma, MSD, Nippon Kayaku, Celltrion Healthcare Japan, and Teijin and has received research funding from Takeda, Chugai, Merck Serono, Taiho, Lilly Japan, Sanofi, Ono, Dainippon Sumitomo Pharma, MSD, Nippon Kayaku, Eisai, Daiichi Sankyo, A2 Healthcare and Solasia Pharma; TS has received honoraria from Chugai, Merck Serono, Bristol-Myers Squibb, Takeda, Yakult Honsha, Lilly, Bayer Yakuhin, Ono, Merck, Astellas Pharma, Taiho and Nihonkayaku, has received consulting or advisory role from Bayer, Lilly, Ono, Takara Bio, Merck Serono, and Nihonkayaku, and has received research funding from Yakult Honsha, Chugai, Ono, Sanofi, Lilly, Daiichi Sankyo, Merck Serono, Gilead Sciences, and Dainippon Sumitomo; TE has received honoraria from Lilly, Taiho, Bristol-Myers Squibb Japan, Eisai, Daiichi Sankyo, Merck Serono, Chugai, Ono, Takeda, Bayer, and Sanofi and has received research funding from Daiichi Sankyo, Merck Serono, MSD, Novartis, Dainippon Sumitomo, Ono, Astellas Pharma, Lilly, Bayer, Nihonkayaku, Pfizer, and Bristol-Myers Squibb Japan; MW has received honoraria from Chugai and Johnson and Johnson; SN has received honoraria from Taiho and Astrazeneca, AS has received research funding from MSD, Eisai, Ono, Taiho, Takeda, and Bayer, Atsushi Ohtsu has received honoraria from Ono, BMS, Chugai, Taiho, Eisai, and Amgen and has received research funding from Bristol-Myers Squibb and immediate family member of Atsushi Ohtsu have been employed by Celgene, and Takayuki Yoshino has received research funding from Novartis, MSD, Sumitomo Dainippon, Chugai, Sanofi, Daiichi Sankyo, Parexel, Ono, GlaxoSmithKline and Boehringer Ingelheim., (© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background/aim: In this study, we assessed the safety and efficacy of combination therapy with S-1, oxaliplatin and leucovorin (SOL) in advanced esophageal squamous cell carcinoma (ESCC) patients., Patients and Methods: Ten unresectable or recurrence ESCC patients, who had been previously treated with more than two regimens were included in this study. The treatment schedule comprised S-1 40-60 mg and fixed dose of leucovorin 25 mg together orally twice a day for one week, followed by one-week of rest. Oxaliplatin 85 mg/m 2 was given as an intravenous infusion on day one, repeated every two weeks., Results: Of the eight patients with measurable lesions, two patients with partial response (25%) and two with stable disease (25%) were observed. Disease control rate was 50%. Median progression-free survival and overall survival were 5.0 and 9.3 months, respectively. The main common adverse events were malaise (60%), decreased appetite (50%), peripheral sensory neuropathy (40%)., Conclusion: SOL therapy showed promising antitumor activity with acceptable toxicity even for heavily pretreated ESCC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma, and initial or predominant presentation in the lungs is uncommon. The synchronous occurrence of IVLBCL and malignant tumors is less frequent, and no such reports have described pulmonary presentations. We report a rare case of pulmonary IVLBCL accompanying lung cancer and interstitial lesions. A 73-year-old man with a history of pneumonia underwent a follow-up examination. Computed tomography revealed diffuse, bilateral ground-glass opacities (GGO) with a partial solid mass. Histologically, the mass consisted of adenocarcinoma. However, two other types of interstitial lesions were scattered throughout the resected lung: 1) peribronchovascular thickening with the aggregation of macrophages and anthracosis, and 2) alveolar septal thickening in the centrilobular area with atypical CD20-positive large cells in the capillaries. These two types of lesions were not mixed. Computed tomography and positron emission tomography demonstrated no other organ involvement. The patient was considered to have the synchronous occurrence of pulmonary IVLBCL and lung cancer (adenocarcinoma). After R-CHOP therapy, GGO on CT disappeared. Lung cancer often accompanies benign background lesions, and the combination of these lesions with lung cancer may make it difficult to detect the presence of pulmonary IVLBCL. However, the histological distribution pattern of IVLBCL may be a clue to the correct diagnosis.

Background: Preoperative 5-FU-based chemoradiation is currently a standard treatment for advanced rectal cancer, particularly in Western countries. Although it reduced the local recurrence, it could not necessarily improve overall survival. Furthermore, it can also produce adverse effects and long-term sphincter function deficiency. Adjuvant oxaliplatin plus capecitabine (XELOX) is a recommended regimen for patients with curatively resected colon cancer. However, the efficacy of postoperative adjuvant therapy for rectal cancer patients who have not undergone preoperative chemoradiation remains unknown. We aimed to evaluate the efficacy of surgery and postoperative XELOX without preoperative chemoradiation for treating rectal cancer., Methods: We performed a prospective, multicenter, open-label, single arm phase II study. Patients with curatively resected high-risk stage II and stage III rectal cancer who had not undergone preoperative therapy were treated with a 120 min intravenous infusion of oxaliplatin (130 mg/m 2 ) on day 1 and capecitabine (2000 mg/m 2 /day) in 2 divided doses for 14 days of a 3-week cycle, for a total of 8 cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS)., Results: Between August 2012 and June 2015, 60 men and 47 women with a median age was 63 years (range: 29-77 years) were enrolled. Ninety-three patients had Eastern Cooperative Oncology Group performance status scores of '0' and 14 had scores of '1'. Tumors were located in the upper and lower rectums in 54 and 48 patients, respectively; 8 patients had stage II disease and 99 had stage III. The 3-year DFS was 70.1% (95% confidence interval, 60.8-78.0%) and 33 patients (31%) experienced recurrence, most commonly in the lung (16 patients) followed by local recurrence (9) and hepatic recurrence (7)., Conclusions: Postoperative XELOX without preoperative chemoradiation is effective for rectal cancer and provides adequate 3-year DFS prospects., Trial Registration: This clinical trial was registered in the University Hospital Medical Information Network registry system as UMIN000008634 at Aug 06, 2012.

Objectives: The aim of this study was to determine the recommended dose (RD) of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as a neoadjuvant chemotherapy in patients with locally advanced rectal cancer., Method: Patients received irinotecan and oxaliplatin (85 mg/m2) on day 1, and capecitabine (1,000 mg/m2 orally twice daily) on days 1-7 of a biweekly schedule. Three dose levels, ranging from 100 to 150 mg/m2, were explored for irinotecan in sequential cohorts of 6 patients. Dose-limiting toxicities (DLTs) were assessed in the first cycle to determine the RD., Results: Six patients were enrolled. The DLT was grade 3 febrile neutropenia, which was observed in 2 of the 6 patients at dose level 1. The RD of irinotecan was defined as 150 mg/m2. Toxicity was manageable: the most common grade ≥3 toxicities were neutropenia (2 patients), anemia (1 patient), and anorexia (1 patient). Nodal downstaging (cN+ to ypN0) was detected in 2 patients and the T stage was downstaged in 3 patients., Conclusions: XELOXIRI is a feasible and active regimen for patients with locally advanced rectal cancer. Febrile neutropenia was the DLT, and the RD of irinotecan is 150 mg/m2., (© 2019 S. Karger AG, Basel.)

Lessons Learned: Evidence has suggested that capecitabine-cisplatin is similar or possibly superior to S-1-cisplatin in terms of safety and efficacy for Japanese patients with advanced gastric cancer (AGC).As far as we are aware, our study is the first randomized trial of two regimens consisting of an oral fluoropyrimidine plus cisplatin in human epidermal growth receptor 2-negative AGC patients with measurable lesions., Background: We performed a phase II study to evaluate the safety and efficacy of capecitabine plus cisplatin in comparison with S-1 plus cisplatin for first-line treatment of human epidermal growth receptor 2 (HER2)-negative advanced gastric cancer in Japan., Methods: Eligible patients were randomly assigned to receive either capecitabine at 1,000 mg/m 2 twice daily for 14 days plus cisplatin at 80 mg/m 2 on day 1 every 3 weeks ( n = 43) or S-1 at 40-60 mg twice daily for 21 days plus cisplatin at 60 mg/m 2 on day 8 every 5 weeks ( n = 41). The primary endpoint of the study was response rate., Results: Response rate did not differ significantly between the capecitabine-cisplatin and S-1-cisplatin groups (53.5% vs. 51.2%, respectively, p  > .999). S-1-cisplatin tended to confer a better progression-free survival (PFS; median of 5.9 vs. 4.1 months, p = .284), overall survival (OS; median of 13.5 vs. 10.0 months, p = .290), and time to treatment failure (TTF; median of 4.5 vs. 3.1 months, p = .052) compared with capecitabine-cisplatin. Common hematologic toxicities of grade 3 or 4 included anemia and neutropenia in both groups. However, anorexia, fatigue, and hyponatremia of grade 3 or 4 occurred more frequently in the capecitabine-cisplatin group., Conclusion: Capecitabine-cisplatin failed to demonstrate superior efficacy compared with S-1-cisplatin. The higher incidence of severe adverse events with capecitabine-cisplatin suggests that S-1-cisplatin should remain the standard first-line chemotherapy for HER2-negative advanced gastric cancer in Japan., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press; the data published online to support this summary is the property of the authors.)

Olaratumab, a monoclonal antibody targeting human platelet-derived growth factor receptor α, plus doxorubicin significantly improved overall survival in patients with advanced soft-tissue sarcoma (STS) in a prior phase 1b/2 randomized trial. Subsequent exposure-response analysis suggested that higher olaratumab exposures earlier might improve outcomes in patients at risk of early disease progression. This phase 1 study (3 treatment cohorts; minimum 6 patients each) investigated the safety, pharmacokinetics and antitumor activity of olaratumab plus doxorubicin in Japanese patients with STS. Patients received olaratumab 15 mg/kg on Days 1 and 8 during each 21-day cycle until disease progression. Patients in Cohort 3 received a 20 mg/kg loading dose of olaratumab in Cycle 1. Doxorubicin was administered for up to 6 cycles. Patients in Cohort 1 received doxorubicin 25 mg/m 2 on Days 1, 2 and 3. Patients in Cohorts 2 and 3 received doxorubicin 75 mg/m 2 on Day 1. One patient in Cohort 2 experienced a dose-limiting toxicity of Grade 3 febrile neutropenia. Most treatment-emergent adverse events were of mild and moderate severity, and were known doxorubicin toxicities. Olaratumab serum concentrations in Cohort 3 reached a steady-state exceeding the target level in Cycle 1. Partial response was confirmed in 4 patients (2 each in Cohorts 2 and 3). Olaratumab plus doxorubicin had an acceptable safety profile in patients with STS. A loading dose of olaratumab 20 mg/kg was effective for achieving minimum serum concentrations above the target trough level in Cycle 1., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: AVAGAST was an international, randomized, placebo-controlled phase III study of chemotherapy with or without bevacizumab as first-line therapy for patients with advanced gastric cancer. We performed exploratory analyses to evaluate regional differences observed in the trial., Methods: Analyses were performed in the placebo plus chemotherapy arm (intention-to-treat population). Chemotherapy was cisplatin 80 mg/m 2 for six cycles plus capecitabine (1000 mg/m 2 orally bid days 1-14) or 5-fluorouracil (800 mg/m 2 /day continuous IV infusion days 1-5) every 3 weeks until disease progression or unacceptable toxicity., Results: Overall, 387 patients were assigned to placebo plus chemotherapy (eastern Europe/South America, n = 118; USA/western Europe, n = 81; Korea/other Asia, n = 94; Japan, n = 94). At baseline, poor performance status, liver metastases, and larger tumors were most frequent in eastern Europe/South America and least frequent in Japan. Patients received subsequent chemotherapy after disease progression as follows: eastern Europe/South America (14%); USA/western Europe (37%); Korea/other Asia (61%); and Japan (77%). Hazard ratios for overall survival versus USA/western Europe were 1.47 (95% CI, 1.09-1.99) for eastern Europe/South America, 0.91 (95% CI, 0.67-1.25) for Korea/other Asia, and 0.87 (95% CI, 0.64-1.19) for Japan., Conclusions: Regional differences in the healthcare environment may have contributed to the differences in overall survival observed in the AVAGAST study.

Background: An important clinical question of great interest to clinicians is how to best sequence androgen receptor targeted agents (ARTAs) and chemotherapy for metastatic castration-resistant prostate cancer (mCRPC), but the answer is still unclear., Materials and Methods: To evaluate and compare the clinical outcomes of ARTA and docetaxel (DTX) as second-line treatment in the post first-line ARTA, we conducted a retrospective analysis of chemotherapy-naive mCRPC patients who had received sequential treatment with ARTA followed by another ARTA (ARTA-ARTA) or ARTA followed by DTX (ARTA-DTX)., Results: A total of 97 patients were treated with the ARTA-ARTA sequence and 42 with the ARTA-DTX sequence. A prostate-specific antigen (PSA) response to the second-line treatment was observed in 18.6% in the ARTA-ARTA and in 33.3% in the ARTA-DTX sequence, but the difference in PSA response was not statistically significant (P = .057). The median progression-free survival (PFS) was significantly different between ARTA and DTX in the second-line treatment (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.24-0.59; P < .001). The favorable outcome in the ARTA-DTX sequence compared with the ARTA-ARTA sequence remained (HR, 0.51, 95% CI, 0.33-0.80; P = .004) in the combined PFS (first-line PFS + second-line PFS). However, no statistically significant difference in overall survival (OS) between the 2 groups was observed (HR, 0.60; 95% CI, 0.34-1.09; P = .095). In multivariate analysis, the ARTA-DTX sequence was identified as an independent prognostic factor for combined PFS, but not OS., Conclusion: ARTA-DTX might improve clinical outcomes in terms of second-line PFS and combined PFS, compared with the ARTA-ARTA sequence. However, this significance was not observed for OS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The patient was a 52-year-old man who had a positive fecal occult-blood test on a medical check-upi n April 2015 and was referred to our hospital in June. Detailed preoperative examinations resulted in a diagnosis of cancer of the lower rectum, multiple liver metastases, and clinical Stage IV . A biopsy showed moderately differentiated tubular adenocarcinoma. All-RAS was wild type, and the patient was asymptomatic. Unresectable advanced rectal cancer was diagnosed, and the patient was scheduled to receive systemic chemotherapy. The patient received a total of 16 courses of combination chemotherapy with 5- fluorouracil, Leucovorin, and oxaliplatin(FOLFOX)plus panitumumab, starting in October 2015. In July 2016, Colonoscopy showed scar findings at the site of the primary rectal cancer lesion. A biopsy revealed no cancer cells. It was difficult to identify the primary lesion on computed tomography, and there was no evidence of clinically significant lymphadenopathy. Positronemission tomography and computed tomography showed shrinkage of the liver metastases, with no accumulation of tracer in the primary lesion or lymph nodes. The primary lesion had a clinical complete response(CR), and the metastatic lesions had a clinical partial response(PR). In October 2016, laparoscopic partial hepatectomy was performed to treat the liver metastases. Histologic examination showed that the liver metastases were from rectal cancer. It is currently under observation.

Purpose: This study aimed at evaluating the applicability of the concept of platinum sensitivity to recurrent cervical cancer., Methods: The clinical information of patients with recurrent cervical cancer, who were initially treated with platinum-based chemotherapy and received second-line platinum-based chemotherapy at the time of recurrence between January 2008 and December 2012, was retrospectively reviewed., Results: A total of 677 patients from 71 medical centers were analyzed. The median overall survival (OS) for patients with platinum-free interval (PFI) of <6, 6-11, 12-17, and ≥18 months was 12.1 (95% CI 11.0-14.1) months, 17.4 (15.5-20.4) months, 20.2 (17.9-27.6) months, and 29.9 (26.7-36.0) months, respectively (P < 0.0001, log-rank). The best cut-off value of PFI that affected OS was 7 months, analyzed by the minimum P value method. The median progression-free survival (PFS) for patients with less than and more than PFI of 7 months was 6.2 months (95% CI 4.8-9.3) and 21.0 months (18.9-24.8) (P < 0.0001, log-rank), respectively, and the median OS for patients with less than and more than PFI of 7 months was 12.3 months (11.2-14.1) and 24.2 months (20.8-25.8) (P < 0.0001, log-rank). Multivariate analysis revealed that PFI (P < 0.0001, HR 0.449, 95% CI 0.369-0.548) alone had a statistically significant association with OS., Conclusions: This study showed that the concept of platinum sensitivity could be applied to recurrent cervical cancer and PFI could be one of the independent prognostic factors for patients with recurrent cervical cancer who have previously been treated with platinum-based chemotherapy.

Purpose: The GEST study showed non-inferiority of S-1 but not superiority of gemcitabine plus S-1 (GS) to gemcitabine alone for overall survival with the data by the cut-off date of 31st July in 2010 for chemo-naïve patients with advanced pancreatic cancer. We considered it important to determine whether S-1 maintains non-inferiority after a long-term follow-up in the GEST study and to obtain a firm positive conclusion. In addition, it may be an interesting challenge to explore the efficacious profile of GS in the long-term follow-up study. Using the data from the follow-up period, background and efficacy in patients from Taiwan and Japan, as well as the rates of tumor shrinkage in locally advanced and metastatic patients (Waterfall plot) were also analyzed., Methods: The results of the primary analysis were reconfirmed, and subset analysis of overall survival and progression-free survival was performed based on the overall survival data updated by the cut-off date of 31st July in 2011., Results: The median follow-up period was 29.8 months, and 795 deaths occurred (95.6%). The median overall survival was 8.8 months for gemcitabine, 9.7 months for S-1 (hazard ratio [HR], 0.96; 97.5% confidence interval [CI], 0.79-1.17), and 9.9 months for GS (HR 0.91; 97.5% CI 0.75-1.11). In patients with performance status (PS) 0, the median overall survival was 9.8 months for gemcitabine, 10.9 months for S-1, and 10.5 months for GS. In patients with PS 1, the median overall survival was 6.2 months for gemcitabine, 6.3 months for S-1, and 9.6 months for GS., Conclusion: Our survey reconfirmed the non-inferiority of S-1 to gemcitabine and showed S-1 can be used as one of the standard treatment options for advanced pancreatic cancer., Trial Registration: ClinicalTrials.gov: NCT00498225.

Background: We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer., Methods: Patients were treated with oral S-1 (80-120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m -2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80-120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS)., Results: Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S-1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53-1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51-1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group., Conclusions: There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer.

Background: We previously reported in the SENRI trial on the usefulness of aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in colorectal cancer patients receiving an oxaliplatin-based regimen which is classified as moderately emetogenic cancer chemotherapy. In the present subgroup analysis of the SENRI trial, we assessed the risk factors for CINV in colorectal cancer patients who received oxaliplatin-based chemotherapy., Methods: Multivariate logistic regression models were used to assess the impact of aprepitant use and patient characteristics on vomiting and nausea. We also assessed the proportion of CINV in patients by gender., Results: Female gender and aprepitant use were associated with the incidence of vomiting and no significant nausea. Significantly more men achieved no vomiting than women (92.9 vs 84.5 % in men and women, respectively; P = 0.0001). The rate of no nausea, complete response, complete protection, and total control was also higher in men. The rate rescue therapy use was significantly higher in women than men. We compared the rate of CINV between aprepitant and control groups and found a significant difference in male patients who achieved no vomiting and complete protection in the overall phase. In women, the rate of no nausea, no vomiting, and total control was higher in the aprepitant group than in the control group., Conclusions: Gender and aprepitant use were risk factors for CINV in colorectal patients who received oxaliplatin-based chemotherapy. Aprepitant therapy was more effective for women than for men in the prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen.

Objective: To examine the antitumor activity of zoledronic acid (ZA) combined with androgen deprivation therapy (ADT) for men with treatment-naive prostate cancer and bone metastasis., Methods: We enrolled 227 men with treatment-naive prostate cancer and bone metastasis. Participants were randomly assigned (1:1 ratio) to receive combined androgen blockade alone (CAB group) or ZA with combined androgen blockade (CZ group). Time to treatment failure (TTTF), time to the first skeletal-related event (TTfSRE), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. Median follow-up duration was 41.5 months., Results: Median TTTFs were 12.4 and 9.7 months for the CZ and CAB groups, respectively (HR 0.75; 95 % CI 0.57-1.00; p = 0.051). For men with baseline prostate-specific antigen levels <200 ng/mL, median TTTFs were 23.7 and 9.8 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.35-0.93; p = 0.023). Median TTfSREs were 64.7 and 45.9 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.38-0.88; p = 0.009). OS was similar between the groups., Conclusions: This study failed to demonstrate that combined use of ZA and ADT significantly prolonged TTTF in men with treatment-naive prostate cancer and bone metastasis. However, it generates a new hypothesis that the combined therapy could delay the development of castration resistance in a subgroup of patients with low baseline prostate-specific antigen values <200 ng/mL. The treatment also significantly prolonged TTfSRE but did not affect OS.

Background: This phase II trial evaluated the efficacy of cisplatin and fluorouracil (CF)-based combination neoadjuvant chemotherapy on the outcome of patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC). We compared the recurrence-free survival (RFS) associated with CF plus Adriamycin (ACF) with that associated with CF plus docetaxel (DCF) to select an alternative regimen in a new phase III trial investigating the optimal neoadjuvant treatment of patients with ESCC., Patients and Methods: Patients with resectable advanced ESCC were randomly assigned to either ACF (Adriamycin 35 mg/m2, cisplatin 70 mg/m2 i.v. on day 1, fluorouracil 700 mg/m2 continuous infusion for 7 days) every 4 weeks or DCF (docetaxel 70 mg/m2, cisplatin 70 mg/m2 i.v. on day 1, fluorouracil 700 mg/m2 continuous infusion for 5 days) every 3 weeks. Surgery was scheduled after completion of two cycles of chemotherapy. The primary end point was RFS, analyzed by the intention-to-treat., Results: Between October 2011 and October 2013, 162 patients at 10 institutions were enrolled in the study, all of whom were eligible and randomly assigned to the two groups (81 to the ACF group and 81 to the DCF group). The R0 resection rates for the ACF and DCF groups were equivalent (95.9% versus 96.2%, P = 0.93). The 2-year RFS and overall survival rates for DCF versus ACF were 64.1% versus 42.9% (hazard ratio 0.53, 95% confidence interval 0.33-0.83, P = 0.0057) and 78.6% versus 65.4% (P = 0.08), respectively., Conclusion: Compared with ACF, DCF chemotherapy was associated with prolonged RFS for patients with resectable advanced ESCC. Thus, DCF chemotherapy has potential as a standard neoadjuvant therapy for resectable ESCC., Clinical Trial Registration: University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN000004555/000004616)., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Capecitabine and irinotecan combination therapy (XELIRI) has been examined at various dose levels to treat metastatic colorectal cancer (mCRC). Recently, in the Association of Medical Oncology of the German Cancer Society (AIO) 0604 trial, tri-weekly XELIRI plus bevacizumab, with reduced doses of irinotecan (200 mg/m 2 on day 1) and capecitabine (1600 mg/m 2 on days 1-14), repeated every 3 weeks, has shown favorable tolerability and efficacy which were comparable to those of capecitabine and oxaliplatin (XELOX) plus bevacizumab. The doses of capecitabine and irinotecan in the AIO trial are considered optimal. In a phase I/II study, XELIRI plus bevacizumab (BIX) as second-line chemotherapy was well tolerated and had promising efficacy in Japanese patients., Methods: The Asian XELIRI ProjecT (AXEPT) is an East Asian collaborative, open-labelled, randomized, phase III clinical trial which was designed to demonstrate the non-inferiority of XELIRI with or without bevacizumab versus standard FOLFIRI (5-fluorouracil, leucovorin, and irinotecan combination) with or without bevacizumab as second-line chemotherapy for patients with mCRC. Patients with 20 years of age or older, histologically confirmed mCRC, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and disease progression or intolerance of the first-line regimen will be eligible. Patients will be randomized (1:1) to receive standard FOLFIRI with or without bevacizumab (5 mg/kg on day 1), repeated every 2 weeks (FOLIRI arm) or XELIRI with or without bevacizumab (7.5 mg/kg on day 1), repeated every 3 weeks (XELIRI arm). A total of 464 events were estimated as necessary to show non-inferiority with a power of 80% at a one-sided α of 0.025, requiring a target sample size of 600 patients. The 95% confidence interval (CI) upper limit of the hazard ratio was pre-specified as less than 1.3., Conclusion: The Asian XELIRI ProjecT is a multinational phase III trial being conducted to provide evidence for XELIRI with or without bevacizumab as a second-line treatment option of mCRC. Trial registration ClinicalTrials.gov NCT01996306. UMIN000012263.

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.)

Background: This multicenter, randomized phase II trial was conducted to compare the efficacy and safety of nimotuzumab plus irinotecan (N-IRI) versus irinotecan alone (IRI) in patients with advanced gastric cancer (AGC) showing disease progression after previous 5-fluorouracil-based therapy., Methods: Irinotecan-naive patients (n = 82) received N-IRI (nimotuzumab 400 mg weekly plus irinotecan 150 mg/m(2) biweekly) or IRI (irinotecan 150 mg/m(2) biweekly) until disease progression. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), response rate (RR), safety, tolerability, and the correlation between efficacy and tumor epidermal growth factor receptor (EGFR) expression., Results: Of 83 patients, 40 and 43 patients were randomly assigned to the N-IRI and IRI groups, respectively. In the N-IRI/IRI treatment group, median PFS was 73.0/85.0 days (P = 0.5668), and median OS and RR at 18 months were 250.5/232.0 days (P = 0.9778) and 18.4/10.3 %, respectively. Median PFS and OS in the EGFR 2+/3+ subgroups were 118.5/59.0 and 358.5/229.5 days, respectively. The RR was 33.3/0.0 % in the N-IRI/IRI treatment group. The incidence of grade 3 or higher adverse events was 77.5/64.3 %. No adverse events of grade 3 or higher skin rash or grade 3 or higher infusion-related reaction were reported., Conclusions: There was no superiority of N-IRI over IRI alone in terms of PFS in 5-fluorouracil-refractory AGC patients. However, N-IRI showed potential improvement in the EGFR 2+/3+ subgroup based on improved RR, PFS, and OS.

Standardized treatments for indolent B cell lymphoma primarily consisting of follicular lymphoma (FL) and for mantle cell lymphoma (MCL) have yet to be established. Here the Hokuriku Hematology Oncology Study Group conducted a multicenter prospective study to investigate the efficacy and safety of a combination regimen of rituximab, cladribine, mitoxantrone, and dexamethasone (R-CMD) in indolent B cell lymphoma and MCL. A total of 33 CD20-positive patients who received care between January 2008 and August 2011 were investigated. These patients' illnesses were FL (n = 21), nodal marginal zone B cell lymphoma (NMZB, n = 3), MCL (n = 3), splenic marginal zone B cell lymphoma (n = 2), hairy cell leukemia (n = 1), Waldenstrom macroglobulinemia (WM, n = 1), and lymphoplasmacytic lymphoma (LPL, n = 2). Patients received four 21-day cycles of rituximab 375 mg/m(2) (day 1), cladribine 0.10 mg/kg (days 1-3), mitoxantrone 8 mg/m(2) (day 1), and dexamethasone 8 mg/body (days 1-3), with four additional rituximab doses at 4-week intervals. Of the 33 patients, 26 achieved complete response/unconfirmed complete response, and six achieved a partial response (4 with FL, 1 with NMZB, 1 with WM). One had progressive disease (FL), and four relapsed after remission (1 with FL, 2 with MCL, 1 with LPL). R-CMD therapy was relatively convenient and effective in indolent B cell lymphoma and MCL. Nonetheless, to suppress the number and function of both B cells and T cells, comprehensive infection prevention and follow-up are necessary in the future.

Objective: Abiraterone acetate and docetaxel are promising treatment options for metastatic castration-resistant prostate cancer patients. However, the optimal sequencing of these agents is unclear, and no previous reports discuss Japanese metastatic castration-resistant prostate cancer patients. The purpose of this analysis is to reveal the outcomes of Japanese metastatic castration-resistant prostate cancer patients treated with abiraterone acetate followed by docetaxel., Methods: We retrospectively reviewed Japanese Phase 1 and Phase 2 trials of metastatic castration-resistant prostate cancer patients treated with abiraterone acetate until disease progression and subsequently treated with docetaxel. The primary outcome measure was the rates of prostate-specific antigen declines ≧30 and ≧50%, respectively, with docetaxel. Secondary outcome measures included progression-free survival with docetaxel, and overall survival after initiation of abiraterone acetate and docetaxel. We performed correlation analysis between previous prostate-specific antigen response to abiraterone acetate and subsequent prostate-specific antigen response to docetaxel., Results: We identified 15 patients had experienced disease progression with abiraterone acetate and subsequently were treated with docetaxel. Prostate-specific antigen declines ≧30 and ≧50% with docetaxel were observed in five patients (33%) and two patients (13%), respectively. The median progression-free survival with docetaxel was 3.7 months (95% confidence interval: 2.9-4.6). The median overall survival from initiation of docetaxel and abiraterone acetate were 14.4 months (95% confidence interval: 6.3-22.4), and 25.7 months (95% confidence interval: 20.1-30.7), respectively. No significant correlation was observed between these prostate-specific antigen responses (Pearson r = 0.206, P = 0.46)., Conclusion: The efficacy of docetaxel in Japanese mCRPC patients that was resistant to abiraterone acetate was modest. The prostate-specific antigen response to previous abiraterone acetate could not predict the efficacy of subsequent docetaxel. Larger prospective trials are needed to validate these findings., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.)

Introduction: The oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin., Methods: In this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT3-receptor antagonist+dexamethasone) or aprepitant group (5-HT3-receptor antagonist+dexamethasone+aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis., Results: A total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups., Conclusion: The aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Objectives: We carried out a phase II trial to evaluate the feasibility, efficacy, and tolerability of perioperative chemotherapy including single intraperitoneal(IP) administration of paclitaxel(PTX) followed by intravenous(IV) administrations of PTX with S-1 in a neoadjuvant setting for serosa-positive gastric cancer., Methods: Patients with cT4a gastric cancer were enrolled. A laparoscopic survey was performed before study inclusion for the confirmation of serosal invasion, negative lavage cytology, and negative peritoneal metastasis. IP PTX (80 mg/m(2)) was administered, followed by systemic chemotherapy. Surgery was performed after the completion of chemotherapy. The primary endpoint was the treatment completion rate., Results: 37 patients were recruited. The treatment completion rate was 67.6% (25/37; 90% CI, 52.8-80.1%), which was significantly higher than 50%; we set this as a threshold value (P = 2.4% [one-sided]). 14 patients had target lesions; of these, 10 showed a partial response (71.4%), three had stable disease (21.4%), and one had progressive disease(7.2%). The response rate was 71.4% (10/14). All patients underwent gastrectomy with D2 lymph node dissection. The 3- and 5-year OS rates were 78.0 and 74.9%, respectively., Conclusions: Perioperative chemotherapy including neoadjuvant IP PTX followed by sequential IV PTX with S-1 for serosa-positive gastric cancer is feasible, safe, and efficient., (© 2015 Wiley Periodicals, Inc.)

Fertility-sparing treatment has been accepted as a standard treatment for epithelial ovarian cancer in stage IA non-clear cell histology grade 1/grade 2. In order to expand an indication of fertility-sparing treatment, we have started a non-randomized confirmatory trial for stage IA clear cell histology and stage IC unilateral non-clear cell histology grade 1/grade 2. The protocol-defined fertility-sparing surgery is optimal staging laparotomy including unilateral salpingo-oophorectomy, omentectomy, peritoneal cytology and pelvic and para-aortic lymph node dissection or biopsy. After fertility-sparing surgery, four to six cycles of adjuvant chemotherapy with paclitaxel and carboplatin are administered. We plan to enroll 250 patients with an indication of fertility-sparing surgery, and then the primary analysis is to be conducted for 63 operated patients with pathologically confirmed stage IA clear cell histology and stage IC unilateral non-clear cell histology grade 1/grade 2. The primary endpoint is 5-year overall survival. Secondary endpoints are other survival endpoints and factors related to reproduction. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000013380., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To assess the safety and efficacy of the combination of oral etoposide and intravenous irinotecan in patients with platinum-resistant and taxane-pretreated ovarian cancer., Methods: Eligible patients (age, 20-75years; platinum-free interval, ≤28weeks) with an adequate organ function received oral etoposide (50mg/m(2) once a day) from day 1 to day 21 and intravenous irinotecan (70mg/m(2)) on days 1 and 15. The regimen was repeated every 28days up to 6cycles. The primary endpoint was the response rate (RR) with a threshold of 20%. The response was evaluated according to RECIST 1.0 and Gynecologic Cancer Intergroup CA-125 Response Definition, and toxicities were evaluated according to CTCAE version 3.0. This trial was registered at UMIN-CTR as UMIN000001837., Results: Between April 1, 2009 and January 20, 2012, 61 patients were enrolled. Sixty patients were eligible. 1 CR and 12 PRs were confirmed; RR was 21.7% (p=0.42, the exact binomial test). PFS and OS were 4.1 and 11.9months, respectively. Major toxicities of ≥grade 3 were neutropenia (60%), anemia (36.7%), thrombocytopenia (11.7%), febrile neutropenia (18.3%), fatigue (13.3%), anorexia (11.7%), and nausea (11.7%). Three patients died from treatment related death (interstitial pneumonia, a pulmonary embolism, and DIC due to infection). Two of these patients were aged ≥65years., Conclusions: Oral etoposide and intravenous irinotecan had a moderate RR but did not meet the primary endpoint. Because of toxicity, we do not recommend this regimen outside of clinical trials. In particular, when considering this regimen for elderly patients, extreme caution is advised., (Copyright © 2014. Published by Elsevier Inc.)

Aim: The aim of this study was to investigate prognostic factors, including postoperative chemotherapy regimen, for the treatment of ovarian yolk sac tumour (YST), and resulting fertility outcome., Methods: A multi-institutional retrospective investigation was undertaken to identify patients with ovarian pure or mixed YST who were treated between 1980 and 2007. Postoperative chemotherapy regimen and other variables were assessed in univariate and multivariate analyses. Additionally, the reproductive safety of the BEP (bleomycin, etoposide and cisplatin) regimen was evaluated., Results: There were 211 patients enrolled from 43 institutions. The BEP regimen and a non-BEP regimen were administered to 112 and 99 patients as postoperative chemotherapy, respectively. In univariate and multivariate analyses, age⩾22, alpha-fetoprotein⩾33,000 ng/ml, residual tumours after surgery and non-BEP regimen were independently and significantly associated with poor overall survival (OS). BEP was significantly superior to non-BEP in 5-year OS (93.6% versus 74.6%, P=0.0004). Reduced-dose BEP (<75% standard-dose bleomycin and<50% etoposide dose) was significantly associated with poorer 5-year OS compared with standard-dose BEP (89.4% versus 100%, P=0.02 and 62.5% versus 96.9%, P=0.0002). All patients who underwent fertility-sparing surgery recovered their menstrual cycles. Sixteen of 23 patients receiving BEP (70.0%) and 13 of 17 patients receiving non-BEP (76.5%) who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 21 and 19 healthy children, respectively., Conclusions: The results of the present study suggest that standard-dose BEP should be administered for ovarian YST. BEP is as safe as non-BEP for preserving reproductive function., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) plus bevacizumab has been widely used for the first-line chemotherapy of metastatic colorectal cancer (mCRC). S-1 is an oral fluoropyrimidine preparation that combines tegafur, a prodrug of 5-fluorouracil, with two modulators. Several studies of combination chemotherapy with oxaliplatin plus S-1 (SOX) conducted in Asia have reported promising efficacy and safety in patients with mCRC, suggesting the potential to replace mFOLFOX6. The SOFT trial (JapicCTI-090699) was a randomized Phase III trial designed to evaluate the noninferiority of SOX plus bevacizumab to mFOLFOX6 plus bevacizumab in patients with mCRC. This review summarizes the drug concept of S-1 and the results of clinical trials of S-1 and SOX in CRC and presents an overview of the SOFT trial.

Purpose: The FIRIS study previously demonstrated non-inferiority of IRIS (irinotecan plus S-1) to FOLFIRI (5-fluorouracil/leucovorin with irinotecan) for progression-free survival as the second-line chemotherapy for metastatic colorectal cancer (mCRC) as the primary endpoint. The overall survival (OS) data were immature at the time of the primary analysis., Methods: Between 30 January 2006 and 29 January 2008, 426 patients with mCRC who failed in first-line chemotherapy were randomly assigned to receive either FOLFIRI or IRIS. After the primary analysis, the follow-up survey was cut off on 29 July 2010, and the final OS data were analysed., Results: With a median follow-up of 39.2 months, the median OS was 17.4 months in the FOLFIRI group and 17.8 months in the IRIS group [hazard ratio (HR) 0.900; 95% confidence interval (CI) 0.728-1.112]. In the pre-planned subgroup of patients who received prior chemotherapy containing oxaliplatin, the median OS was 12.7 months in the FOLFIRI group and 15.3 months in the IRIS group (HR 0.755; 95% CI 0.580-0.983)., Conclusions: IRIS is non-inferior to FOLFIRI for OS as second-line chemotherapy for mCRC. IRIS can be an option for second-line chemotherapy of mCRC. (ClinicalTrials.gov Number: NCT00284258).