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Abstract Purpose Although early tumor shrinkage (ETS) is a predictor of improved overall survival (OS), the association between ETS and health-related quality of life (HRQOL) remains unclear for patients with metastatic colorectal cancer (mCRC) treated with first-line cetuximab plus chemotherapy. Methods The data were collected from a prospective trial that assessed HRQOL using the EORTC QLQ-C30. The impact of ETS on HRQOL was estimated using a linear mixed-effects model for repeated measures. Results ETS was achieved in 82 (64.1%) of 128 mCRC patients treated with first-line cetuximab plus chemotherapy, and these patients had a significantly longer OS than those without ETS (HR, 0.38; 95% CI, 0.20–0.72; P = .002). Asymptomatic patients with ETS had a favorable OS, while symptomatic patients without ETS had a worse OS (2-year OS rates, 77.8% vs. 42.5%). Symptomatic patients with ETS had similar outcomes as asymptomatic patients without ETS (2-year OS rates, 64.1% vs. 67.0%). For symptomatic patients, ETS was associated with improved HRQOL scores between baseline and 8 weeks: the mean changes for patients with and without ETS were 5.86 and -4.94 for global health status (GHS)/QOL, 26.73 and 3.79 for physical functioning, and 13.58 and -3.10 for social functioning, respectively. The improved HRQOL was comparable to that of asymptomatic patients without ETS. For asymptomatic patients, ETS showed a decreased deterioration in HRQOL. Conclusion Our findings highlight the importance of ETS for HRQOL and prognostic estimates, and assessing ETS may provide clinically useful information for physicians and patients to make more informed decisions.

Abstract Purpose Effective second‐line chemotherapy options are limited in treating advanced biliary tract cancers (BTCs). Resminostat is an oral histone deacetylase inhibitor. Such inhibitors increase sensitivity to fluorouracil, the active form of S‐1. In the phase I study, addition of resminostat to S‐1 was suggested to have promising efficacy for pre‐treated BTCs. This study investigated the efficacy and safety of resminostat plus S‐1 in second‐line therapy for BTCs. Methods Patients were randomly assigned to receive resminostat or placebo (200 mg orally per day; days 1–5 and 8–12) and S‐1 group (80–120 mg orally per day by body surface area; days 1–14) over a 21‐day cycle. The primary endpoint was progression‐free survival (PFS). Secondary endpoints comprised overall survival (OS), response rate (RR), disease control rate (DCR), and safety. Results Among 101 patients enrolled, 50 received resminostat+S‐1 and 51 received placebo+S‐1. Median PFS was 2.9 months for resminostat+S‐1 vs. 3.0 months for placebo+S‐1 (HR: 1.154, 95% CI: 0.759–1.757, p = 0.502); median OS was 7.8 months vs. 7.5 months, respectively (HR: 1.049, 95% CI: 0.653–1.684, p = 0.834); the RR and DCR were 6.0% vs. 9.8% and 70.0% vs. 78.4%, respectively. Treatment‐related adverse events (TrAEs) of grade ≥ 3 occurring more frequently (≥10% difference) in the resminostat+S‐1 than in the placebo+S‐1 comprised platelet count decreased (18.0% vs. 2.0%) and decreased appetite (16.0% vs. 2.0%). Conclusions Resminostat plus S‐1 therapy improved neither PFS nor OS for patients with pre‐treated BTCs. Addition of resminostat to S‐1 was associated with higher incidence of TrAEs, but these were manageable (JapicCTI‐183883).

Abstract Background FOLFOXIRI plus bevacizumab is used as a first-line therapy for patients with unresectable or metastatic colorectal cancer. However, there are no clear recommendations for second-line therapy after FOLFOXIRI plus bevacizumab combination. Here, we describe our planning for the EFFORT study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Methods EFFORT is an open-label, multicenter, single arm phase II study to evaluate whether a FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for mCRC. Patients with unresectable or metastatic colorectal cancer who received FOLFOXIRI plus bevacizumab as a first-line therapy will receive aflibercept and FOLFIRI (aflibercept 4 mg/kg, irinotecan 150 mg/m2 IV over 90 min, with levofolinate 200 mg/m2 IV over 2 h, followed by fluorouracil 400 mg/m2 bolus and fluorouracil 2400 mg/m2 continuous infusion over 46 h) every 2 weeks on day 1 of each cycle. The primary endpoint is progression-free survival (PFS). To achieve 80% power to show a significant response benefit with a one-sided alpha level of 0.10, assuming a threshold progression-free survival of 3 months and an expected value of at least 5.4 months, we estimated that 32 patients are necessary. Secondary endpoints include overall survival, overall response rate, safety, and exploratory biomarker analysis for differentiating anti-VEGF drug in 2nd-line chemotherapy for unresectable or metastatic colorectal cancer. Discussion This is the first study to investigate whether FOLFIRI plus aflibercept has efficacy following FOLFOXIRI plus bevacizumab for unresectable or metastatic colorectal cancer. Switching to a different type of anti-VEGF drug in second-line therapy after FOLFOXIRI plus bevacizumab appears to be an attractive treatment strategy when considering survival benefit. It is expected that this phase II study will prove the efficacy of this strategy and that a biomarker for drug selection will be discovered. Trial registration Japan Registry of Clinical Trials jRCTs071190003 . Registered April 18, 2019.

Abstract Background First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPIRI+BEV [capecitabine (CAP: 1600 mg/m2), irinotecan (IRI: 200 mg/m2), and BEV (7.5 mg/m2)] was non-inferior to FOLFIRI+BEV as a second-line therapy for mCRC patients and was associated with a lower incidence of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods QUATTRO-II is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses of OX and IRI will be investigated as a safety lead-in. In Step 2, patients will be randomized to the recommended dose of either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV treatments will be administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The primary endpoint is progression-free survival (PFS). The similarity in PFS between the two arms will be evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and 1.25. Ensuring a 70% probability that the observed HR will be “0.8

Abstract Background It remains unclear whether patients’ self‐perceptions of symptoms at baseline clinically impact the prognostic relevance, treatment efficacy, or toxicity profiles in metastatic colorectal cancer (mCRC) patients treated with the first‐line cetuximab and standard chemotherapy. Methods The data were collected from a prospective trial that assessed the relationships between quality of life (QOL), treatment efficacy, and adverse events (AEs). Results The analysis of 137 mCRC patients revealed a significant association between the presence of baseline tumor‐related symptoms and a lower overall survival (OS) compared to the absence of symptoms (HR, 2.49; 95% CI, 1.37‐4.62; P = .003). The asymptomatic responders had favorable outcomes compared to the symptomatic nonresponders (2‐year OS rates: 83.6% and 35.9%, respectively), while the symptomatic responders had similar outcomes to the asymptomatic nonresponders. The median postprogression survival differed significantly: 10.2 months for the symptomatic patients and 15.9 months for the asymptomatic patients (HR, 2.29; 95% CI, 1.25‐4.29, P = .008). The objective response rates and patient toxicity profiles were similar irrespective of the severity of baseline symptoms. Conclusion Baseline symptoms were associated with worse OS but not with impaired treatment efficacy or more frequent AEs in mCRC patients treated with cetuximab in addition to chemotherapy.

Abstract Background A previous phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab for patients with heavily pretreated metastatic colorectal cancer (mCRC) showed promising activity with an acceptable toxicity profile. This retrospective study aimed to investigate the safety and efficacy of trifluridine/tipiracil plus bevacizumab compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC in clinical settings. Methods Records of patients with mCRC refractory to standard therapies who initiated trifluridine/tipiracil plus bevacizumab from January 2016 to March 2018 or trifluridine/tipiracil monotherapy from June 2014 to December 2015 were retrospectively reviewed at our institution. Results Totally, 60 patients received trifluridine/tipiracil plus bevacizumab and 66 received trifluridine/tipiracil monotherapy. All patients had previously received standard chemotherapy. Median progression-free survival (PFS) was 3.7 months [95% confidence interval (CI), 2.3–5.1] in the trifluridine/tipiracil plus bevacizumab group and 2.2 months (95% CI, 1.8–2.6) in the trifluridine/tipiracil monotherapy group [hazards ratio (HR) 0.69; 95% CI 0.48–0.99]. PFS rate at 16 weeks was 46.6% for the trifluridine/tipiracil plus bevacizumab group and 33.9% for the trifluridine/tipiracil monotherapy group. Although a relatively higher incidence of grade ≥ 3 neutropenia was observed in the trifluridine/tipiracil plus bevacizumab group than that in the other group (50.0% vs. 40.9%, p = 0.371), the incidence of febrile neutropenia was not high (3.3% vs. 7.8%, p = 0.444). Conclusions In real-world settings, trifluridine/tipiracil plus bevacizumab prolonged PFS and helped achieve higher 16-week PFS rate compared with trifluridine/tipiracil monotherapy in patients with heavily pretreated mCRC with manageable toxicities. Trial registration Retrospectively registered.

Abstract Background Clinicopathological and molecular features of responders to nivolumab for advanced gastric cancer (AGC) are not well understood. Methods Patients (pts) with AGC who were treated with nivolumab after two or more chemotherapy regimens in a single institution from September 2017 to May 2018 were enrolled in this study. PD-L1 expression in tumor cells (TC) and mismatch repair (MMR) were analyzed by immunohistochemistry. Epstein-Barr virus (EBV) was detected by in situ hybridization. Cancer genome alterations were evaluated by a next-generation sequencing-based panel. High tumor mutation burden (TMB) was defined as more than 10 mutations/megabase. Results A total of 80 pts were analyzed in this study. Tumor response was evaluated in 72 pts with measurable lesions and 14 pts (19%) had an objective response. Overall response rate (ORR) was significantly higher in pts with ECOGPS 0 in those with PS 1 or 2, MMR-deficient (MMR-D) in those with MMR-proficient (MMR-P), PD-L1+ in TC in those with PD-L1- in TC and PIK3CA mutation in those with PIK3CA wild-type. ORR was 31% in pts with at least one of the following factors; MMR-D, high TMB, EBV+ and PD-L1+ in TC vs. 0% in those without these factors. Progression-free survival was significantly longer in pts with PS 0 than in those with PS 1 or 2, MMR-D than in those with MMR-P, and PD-L1+ in TC than in those with PD-L1- in TC. Conclusions Some features were associated with favorable response to nivolumab for AGC. Combining these features might be useful to predict efficacy.

Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) showed survival benefits in metastatic colorectal cancer patients previously treated with standard chemotherapies; therefore, we compared the efficacy and safety of these two treatments. Patients with metastatic colorectal cancer treated with REG or FTD/TPI as a salvage-line therapy from May 2014 to December 2017 were included. We retrospectively analyzed long-term survival, safety, and clinical outcomes. Among 134 patients, 57 and 77 received REG and FTD/TPI, respectively. The REG group received more prior systemic chemotherapies and significantly more frequent additional chemotherapies than the FTD/TPI group did. The median follow-up was 6.2 months, whereas the median overall survival was 9.9 and 11.4 months in the REG and FTD/TPI groups, respectively (hazard ratio = 0.954, p = 0.837). The median progression-free survival was 2.0 and 3.3 months in the REG and FTD/TPI groups, respectively (hazard ratio = 0.52, p = 0.00047), indicating significant differences, whereas the objective response and disease control rates did not differ. The median overall survival of patients with additional subsequent chemotherapies after disease progression was longer than that of patients without additional chemotherapy. The most frequent grade ≥3 adverse events were hypertension and neutropenia in the REG and FTD/TPI groups, respectively. Our study suggested that sequential use of both drugs may prolong survival.

Abstract A prospective trial has not been performed to investigate associations between quality of life (QOL), adverse events (AEs), and overall survival (OS) in the first‐line treatment with cetuximab plus standard chemotherapy for advanced/metastatic colorectal cancer (mCRC). Associations between patient outcome and health‐related QOL (HRQOL) together with skin toxicity‐related QOL were prospectively evaluated using EORTC QLQ‐C30 and DLQI questionnaires. One hundred and forty mCRC patients were analyzed in this study, and 87.8% received pre‐emptive skin treatment. Skin toxicity had no clinical impact on HRQOL or skin‐related QOL during the first 8 weeks and throughout the study period. An early skin reaction with a grade ≥2 at 8 weeks was significantly associated with a favorable OS compared with a grade of ≤1 (HR, 0.50; 95% CI, 0.24‐0.95; P = .035) and was confirmed to be an independent predictor of OS (HR, 0.48; 95% CI, 0.21‐0.97; P = .040). Patients symptomatic at baseline who responded to treatment had improved HRQOL compared to nonresponding patients. Severe mucositis/stomatitis had a statistically significant and clinically meaningful negative impact on HRQOL (mean changes from baseline throughout the study period in global health status were −12.64 for a grade of ≥2 vs −0.35 for a grade of 0 or 1 (P = .005)). In conclusion, severe early skin reactions predict favorable OS for patients treated with cetuximab plus chemotherapy without impairing QOL. In addition, mucositis/stomatitis was the most substantial AE compromising both QOL and treatment compliance.

Abstract Background Recent studies demonstrated the efficacy of S-1-based adjuvant chemotherapy administered for six months after curative surgery for stage III gastric cancer; however, it is unproven whether this type of combination chemotherapy is more effective than the standard adjuvant chemotherapy of S-1 for one year. Methods This multicenter phase II study evaluate the efficacy and safety of adjuvant chemotherapy using S-1 plus oxaliplatin followed by S-1 for up to one year for curatively resected stage III gastric cancer in patients aged over 20 years. Treatment initially comprises oral fluoropyrimidine S-1 (80 mg/m2) administered twice daily for the first 2 weeks of a 3-week cycle. On day 1 of a second 3-week cycle, patients will receive 100 mg/m2 of intravenous oxaliplatin followed by 80 mg/m2 of S-1 (maximum 8 cycles). Then, the patients will receive 80 mg/m2 of S-1 daily for 4 weeks, followed by 2 weeks of no chemotherapy. This 6-week cycle will be repeated during the first year after surgery. The primary endpoint is relapse-free survival for 3 years and secondary endpoints are safety, including the incidence of adverse events, and grading of neuropathy with each treatment cycle. The planned sample size of 75 patients is appropriate for this trial. The data will be analyzed on an intention-to-treat basis, assuming a two-sided test with a 5% level of significance. Discussion In contrast to previous trials, the current study involves administration of S-1 until one year after surgery in addition to prior S-1 plus oxaliplatin, and is the first study to evaluate the safety and efficacy of S-1 plus oxaliplatin followed by S-1 for up to one year in patients with curatively resected stage III gastric cancer. Trial registration This trial is registered in the University Hospital Medical Information Network’s Clinical Trials Registry (UMIN-CTR) registration number, R000029656 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000029656). Registered January 24, 2017.

Japanese mortality due to colorectal cancer is on the rise, surpassing 49,000 in 2015. Many new treatment methods have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2016 for the treatment of colorectal cancer (JSCCR Guidelines 2016) were prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines were prepared by consensus reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches, and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2016. [ABSTRACT FROM AUTHOR]

Combination chemotherapy with capecitabine and oxaliplatin for gastric cancer (G-XELOX) is considered as a potentially promising regimen. However, the use of the G-XELOX regimen in Japanese patients has not been investigated to date, and recommended doses of G-XELOX for Japanese patients with metastatic gastric cancer have not been established. The aim of the present study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) for systemic chemotherapy with G-XELOX for metastatic gastric cancer. The enrolled patients received systemic chemotherapy with oxaliplatin 130 mg/m2 on day 1 and capecitabine 2,000 mg/m2/day, b.i.d. for 14 days, repeated every 3 weeks. A decrease in oxaliplatin dose was planned from start level 1 (130 mg/m2). A total of 6 patients were enrolled between January and July 2015. MTD was not reached at level 1. Oxaliplatin 130 mg/m2 in combination with capecitabine 2,000 mg/m2/day b.i.d. could be administered with acceptable toxicity, and all patients were treated at these doses. One case of grade 3 stomatitis was considered as a dose-limiting toxicity at level 1; however, excluding this case, no grade 3 or 4 non-hematological toxicity was observed. There were no treatment-related deaths. The median relative dose intensity was 71.3% for capecitabine and 92.1% for oxaliplatin. Of the 6 patients, 3 had measurable lesions according to the Response Evaluation Criteria In Solid Tumors; the response rate and disease control rate were both 67%. Therefore, systemic chemotherapy with G-XELOX was well-tolerated by patients with advanced gastric cancer. The RD was defined as oxaliplatin 130 mg/m2 in combination with capecitabine 2,000 mg/m2/day b.i.d. [ABSTRACT FROM AUTHOR]

We herein report the case of a patient with mucinous gastric carcinoma with peritoneal dissemination that disappeared after neoadjuvant chemotherapy with S-1 alone. The patient has survived for over 23 months after surgery, without recurrence. A 60-year old man was referred to our hospital because of an advanced gastric cancer, detected by upper gastrointestinal endoscopy at another hospital. Staging laparoscopy was performed on October 25, 2002, and revealed massive peritoneal dissemination. Two courses of neoadjuvant chemotherapy with S-1 were administered, at 120?mg/day for 28 days, as one course. Total gastrectomy, with D2 lymph node dissection, was performed on January 24, 2003. The peritoneal dissemination had macroscopically disappeared and the cytology of the peritoneal lavage fluid was class III. His final diagnosis was gastric carcinoma, MLU, type 3, T2(SS), P0, H0, M0, N3, CY0, stage IV. [ABSTRACT FROM AUTHOR]

Purpose: In Asian countries, paclitaxel once per week is used as second-line treatment in advanced gastric cancer, including human epidermal growth factor receptor 2 (HER2) -positive tumors. The role of anti-HER2 agents, including lapatinib, in this setting and population is unclear., Patients and Methods: TyTAN was a two-part, parallel-group, phase III study in Asian patients. An open-label, dose-optimization phase (n = 12) was followed by a randomized phase (n = 261), in which patients who were HER2 positive by fluorescence in situ hybridization (FISH) received lapatinib 1,500 mg once per day plus once-per-week paclitaxel 80 mg/m(2) or paclitaxel alone. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), time to progression (TTP), overall response rate (ORR), time to response, response duration, and safety. Analyses were based on immunohistochemistry (IHC) and gastrectomy status, prior trastuzumab therapy, and regional subpopulations., Results: Median OS was 11.0 months with lapatinib plus paclitaxel versus 8.9 months with paclitaxel alone (P = .1044), with no significant difference in median PFS (5.4 v 4.4 months) or TTP (5.5 v 4.4 months). ORR was higher with lapatinib plus paclitaxel versus paclitaxel alone (odds ratio, 3.85; P < .001). Better efficacy with lapatinib plus paclitaxel was demonstrated in IHC3+ compared with IHC0/1+ and 2+ patients and in Chinese compared with Japanese patients. A similar proportion of patients experienced adverse events with each treatment (lapatinib plus paclitaxel, 100% v paclitaxel alone, 98%)., Conclusion: Lapatinib plus paclitaxel demonstrated activity in the second-line treatment of patients with HER2 FISH-positive IHC3+ advanced gastric cancer but did not significantly improve OS in the intent-to-treat population., (© 2014 by American Society of Clinical Oncology.)