Yasushi Tsuji

Background/Objectives: BRAF mutations occur in 5–10% of metastatic colorectal cancer (mCRC) cases, but their implications for prognosis and optimal treatment remain unclear. Methods: This multicenter, prospective observational study analyzed 377 RAS wild-type cases from 511 patients across 32 centers, using PCR-based methods. Results: BRAF mutations were identified in 21% (79/377) of cases, predominantly V600E (89.9%) with a minority of non-V600E (10.1%). Microsatellite instability (MSI) testing revealed MSI-high in 11.3%, exclusively among V600E cases. V600E mutations were linked to right-sided tumors, poor differentiation, and elevated CA19-9 levels. Median survival was significantly lower in V600E cases compared to BRAF wild-type (12.4 vs. 37.5 months, HR 3.25, p < 0.001) and marginally lower non-V600E cases (12.4 vs. 34.7 months, HR 0.61, p = 0.057). Chemotherapy regimens (doublet vs. triplet) and targeted treatments (bevacizumab vs. anti-EGFR) showed no significant survival differences in V600E patients. Similarly, RAS/BRAF wild-type patients had comparable survival with bevacizumab versus anti-EGFR, even for left-sided tumors. Conclusions: These findings highlight distinct clinical and prognostic profiles for BRAF V600E and non-V600E mutations, while treatment choice appears to have limited impact on survival in these subgroups or RAS/BRAF wild-type cases.

Surgical resection is currently the best curative approach for gastric cancer (GC); however, the prognosis of patients with advanced GC remains poor even with curative resection. For this reason, perioperative chemotherapy has been combined with surgery to reduce the risk of postoperative recurrence. Standard perioperative chemotherapy for resectable advanced GC varies from region to region. Postoperative S-1 therapy was standardized via the ACTS-GC study in East Asia, perioperative ECF (Epirubicin + Cisplatin + Fluorouracil) was standardized via the MAGIC study in Europe, and postoperative chemoradiotherapy was standardized via the US intergroup study in North America. Since then, more intensive regimens have been developed. In recent years, perioperative therapy using novel agents, such as molecular-targeted drugs and immune checkpoint inhibitors (ICIs), has also been tested and evaluated in the three major regions (East Asia, Europe, and North America) with promising results. Perioperative chemotherapy has become an integral part of many treatment strategies and requires continued research and evaluation.

The prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combined chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled.

Objectives: Chemotherapy is an indispensable therapeutic approach for colorectal cancer both in the adjuvant and metastatic setting. Although chemotherapy-induced nausea and vomiting (CINV) is one of the most crucial adverse events, many aspects of CINV in patients with colorectal cancer remain unclear. Methods: This multicenter, prospective, observational study analyzed the data of 190 colorectal cancer patients scheduled for moderately emetogenic chemotherapy (MEC). The patients recorded the incidence of CINV and severity of nausea by visual analogue scales daily for 7 days after receiving chemotherapy. Results: All 190 patients received MEC and 99% of patients received antiemetic therapy in compliance with guidelines. Acute CINV was well controlled. 13 (6.8%) patients suffered from acute nausea and 4 (2.1%) experienced acute vomiting, whereas the prevalence of delayed CINV was relatively high. Delayed nausea occurred in 71 (37.4%) patients and delayed vomiting in 24 (12.6%). History of motion sickness was a significant independent risk factor for delayed nausea (Odd ratio 3.89, 95% confidence interval 1.49–10.19, p = 0.0056). Conclusions: The compliance with CINV guidelines in colorectal cancer chemotherapy was quite high and led to good control of chemotherapy-induced vomiting in Japan. However, the incidence of delayed nausea remained high in patients receiving MEC.

TPS222 Background: Systemic chemotherapy with oral fluoropyrimidine and platinum is recommended for the first-line treatment for unresectable or recurrent gastric cancer in Japan. However, some patients with severe peritoneal metastasis cannot take oral medications because of obstruction or dysfunction of the gastrointestinal tract. FOLFOX is regarded as one of the candidates for the standard of care for gastric cancer, and is now being evaluated in clinical trials. Intraperitoneal (IP) paclitaxel (PTX) provides sustained high local concentrations, and its efficacy has been shown in ovarian and gastric cancer. We developed a regimen combining IP PTX with S-1/PTX, and the phase III trial comparing with S-1/cisplatin suggested efficacy of this regimen. Therefore, we designed a regimen combining IP PTX with mFOLFOX6, and started an exploratory study in gastric cancer patients with peritoneal metastasis and inadequate oral intake. Methods: This is a prospective, multicenter, single-arm phase I/II study. Eligibility criteria include: pathologically proven unresectable or recurrent gastric adenocarcinoma; peritoneal metastasis; inadequate oral intake; adequate bone marrow function; acceptable liver and renal function; ECOG performance status of 0-2 and age between 20-80 years. Patients undergo diagnostic laparoscopy and are implanted with an IP port in the subcutaneous space of the lower abdomen, with a catheter placed in the pelvic cavity. mFOLFOX6 is administered bi-weekly, and IP PTX 20 mg/m² is administered through an IP port on days 1, 8 and 15. The treatment course is repeated every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint is the 1-year overall survival rate. Secondary endpoints are progression free survival, time to treatment failure, response rate, negative conversion rate on peritoneal cytology and safety. Twenty medical institutions from all over Japan participate in this study, and 34 patients are to be enrolled in two years. Toxicity will be evaluated in the early stage, and the protocol will be reconsidered and revised if all of the first 3 or more than 2 of the first 6 patients develop dose-limiting toxicities. Clinical trial information: UMIN000019206.

3557 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Primary results of the J003-10040030 randomized phase 2 trial demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) favoring TAS-102 vs placebo (pbo) in patients (pts) with metastatic colorectal cancer refractory/intolerant to standard therapies (Yoshino T, et al. Lancet Oncology 2012). Neutropenia is the most common TAS-102-associated adverse event and it has been hypothesized to reflect a relatively high FTD concentration in pts. Methods: Study J003 data were analyzed post hoc for correlations between initial onset of Grade 3/4 neutropenia and OS benefit. Results: Of 112 pts given TAS-102, 31 (28%) developed Grade 3/4 neutropenia in treatment cycle 1, 19 (17%) in cycle 2, and 8 (7%) in ≥ cycle 3. Onset of Grade 3/4 neutropenia at cycle 1 and 2 was associated with longer median OS compared to pts without neutropenia as summarized by the hazard ratio (against cycle-matched placebo control groups) and the corresponding median OS differences (see Table). Conclusions: Pts experienced Grade 3/4 neutropenia in cycle 1 and 2 showed a greater OS benefit over pbo. In contrast, pts who did not experience Grade 3/4 neutropenia appear to show no OS benefit. The occurrence of Grade 3/4 neutropenia might become an on-treatment predictive biomarker of TAS-102 and TAS-102 treatment should not be discontinued permanently due to the onset of Grade 3/4 neutropenia. The correlation between efficacy of TAS-102 and onset of neutropenia warrants further analyses. Clinical trial information: 090880.

SUMMARY. Chemotherapy is an indispensable therapeutic approach for esophageal cancer. Although chemotherapy-induced nausea and vomiting (CINV) is one of the mos

Introduction: Colorectal cancer (CRC) is the third most common cancer in the western world and also in Japan. The key factors in curing CRC are early detection, surgery and adequate adjuvant chemotherapy if needed. Areas covered: Based on the results of following pivotal adjuvant trials, FOLFOX or XELOX are considered standard adjuvant chemotherapy for patients with stage III colon cancer in the western countries. On the other hand, 5-FU based monotherapies showed favorable results as adjuvant chemotherapy in Japan providing comparable results to doublet strategies in the western countries. There are two key factors that could provide better outcome: D3 lymph node dissection (LND) and thorough pathological examinations. Expert opinion: I believe that oxaliplatin based adjuvant chemotherapy may not be suitable for at least substage IIIA patients who underwent D3 surgery and were diagnosed by thorough pathological examinations for the following two reasons: toxicities and strongly stage-dependent added benefit of oxaliplatin in overall survival. We are awaiting the final results of three Japanese ongoing trials focusing on oxaliplatin based adjuvant chemotherapy. These results will hopefully help us create and implement global guidelines for truly standardizing the management of colon cancer prevalent all over the world, and help physicians recommend the treatment strategy available to each patient.

Purpose: This study is performed to investigate the incidence of cemotherapy-induced nausea and vomiting (CINV) for patients (pts) with colorectal cancer received moderately emetogenic chemotherapy. We also assessed whether the medical staff accurately recognized the incidence of CINV in practices. Methods: A prospective observational study of patients receiving the first cycle of oxaliplatin or irinotecan-based chemotherapy was performed. A 7-day diary for CINV was provided to the patients, and the incidence of CINV was recorded daily by themselves. The observed incidence rates of CINV in acute (day1) and delayed (days2-7) were compared with the medical staff's predictions. Results: A total of 191 pts were registered between April 2011 and December 2012. All pts were treated with oxaliplatin-based (n = 175) or irinotecan-based chemotherapy (n = 16). Acute vomiting episode was observed in 4 pts (2.1%), while delayed vomiting was observed in 19 pts (10%). Acute nausea occurred in 14 pts (7.3%), while delayed nausea occurred in 63 pts (33%). Irinotecan significantly induced acute nausea more frequently than oxaliplatin (P = 0.019). The presence of motion sickness was significantly associated with the incidence of acute nausea (P < 0.001) and vomiting (P = 0.003). Antiemetic agents were given according to the guideline to all pts. 58 pts were given a neurokinin-1 (NK-1) receptor antagonist. Pts with NK-1 receptor antagonist showed significantly less incidence of delayed vomiting than pts without one (3% vs 13%, P = 0.048). 30 pts (15.7%) needed rescue antiemetics. Staffs had estimated the incidence of acute CINV in 91 pts (47.6%). However, acute CINV really occurred in 14 pts (7.3%). Conclusions: CINV seems to be controllable with appropriate management, but delayed CINV remains an important problem. The presence of motion sickness should be affected by efficient antiemetic management. The extent of CINV in this patient group seems to be overestimated.