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Background: The QUATTRO-II trial examined the efficacy and safety of capecitabine+oxaliplatin+irinotecan (CAPOXIRI)+bevacizumab (BEV) vs. 5-fluorouracil+folinic acid+oxaliplatin+irinotecan (FOLFOXIRI)+BEV in metastatic colorectal cancer (mCRC)., Methods: In this phase II study (ClinicalTrials.gov: NCT04097444; jRCTs041190072), patients were randomized (1:1) to FOLFOXIRI+BEV or CAPOXIRI+BEV. The induction treatment in the FOLFOXIRI+BEV/CAPOXIRI+BEV arms was continued for 8/6 cycles (maximum 12/8 cycles if feasible), and the maintenance treatment was 5-fluorouracil/leucovorin+BEV or capecitabine+BEV at the investigators' discretion. The primary endpoint was progression-free survival (PFS), with the two arms deemed equivalent if the hazard ratio (HR) of the point estimate was 0.80 < HR < 1.25. Secondary endpoints were overall response rate (ORR), overall survival (OS), incidence of adverse events (AEs), and patient-reported outcomes., Findings: Overall, 51 and 52 patients were randomized to FOLFOXIRI+BEV and CAPOXIRI+BEV, respectively. The study met its primary endpoint; PFS at median follow-up of 23.7 months was 10.6 months (95% confidence interval [CI], 7.7-13.3) in the FOLFOXIRI+BEV arm vs. 10.9 months (95% CI, 9.3-14.3) in the CAPOXIRI+BEV arm (HR 1.114 [0.80 < HR < 1.25], p = 0.654). In the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms, the 2-year OS rate (95% CI) was 65.5% (49.5%-77.6%) vs. 74.3% (59.8%-84.2%), and the ORR (95% CI) was 76.5% (62.5%-87.2%) vs. 84.6% (71.9%-93.1%). Major (grade ≥3) AEs in the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms were neutropenia (68.6% vs. 40.4%), febrile neutropenia (9.8% vs. 11.5%), diarrhea (7.8% vs. 17.3%), and appetite loss (7.8% vs. 17.3%)., Conclusion: CAPOXIRI+BEV was well tolerated with reduced hematological toxicity and efficacy comparable to those of FOLFOXIRI+BEV, providing a potentially convenient first-line treatment alternative to FOLFOXIRI+BEV in patients with mCRC., Funding: Chugai Pharmaceutical Co., Ltd., Competing Interests: Declaration of interests H.B. received grants from Ono Pharmaceutical. H.B. also reports honoraria for lectures from Ono Pharmaceutical, Eli Lilly Japan, and Taiho Pharmaceutical. D.K. reports honoraria from Takeda Pharmaceutical, Chugai Pharmaceutical, Novartis, Eli Lilly, Seagen, MSD, Ono Pharmaceutical, Eisai, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi-Sankyo, Pfizer, Merck Biopharma, and Sysmex and research funding from Ono Pharmaceutical, MSD, Novartis, Servier, Janssen, IQVIA, Syneoshealth, CIMIC, and Cimic Shift Zero. H.S. received grants from Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, and Sanofi and reports honoraria from Bayer, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Bio Pharma, MSD, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha. T.H. reports honoraria for lectures from Chugai Pharmaceutical. M.S. is on the speakers’ bureau at Johnson & Johnson, Kaken Pharmaceutical, Eli Lilly Japan, Merck Serono, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha. M.K. reports honoraria for lectures from Chugai Pharmaceutical, Takeda Pharmaceutical, Eli Lilly, Yakult Honsha, and Taiho Pharmaceutical. T. Masuishi reports honoraria from Bayer Yakuhin, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Serono, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha and reports research funding from Amgen (Inst), Boehringer Ingelheim (Inst), CMIC (Inst), Daiichi Sankyo (Inst), Eli Lilly Japan (Inst), MSD (Inst), Novartis (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), and Syneos Health (Inst). H.Y. reports honoraria from Chugai Pharmaceutical and Yakult Honsha. Y. Kagawa reports honoraria from Chugai Pharmaceutical and Yakult Honsha. Y. Komatsu received grants from Ono Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Shionogi, Nippon Zoki Pharmaceutical, Asahi Kasei Pharma Corporation, Nippon Kayaku, Daichi Sankyo, IQVIA Services Japan, MSD, Astellas Pharma, Incyte Corporation, Eisai, National Cancer Center Japan, Syneos Health Clinical, Shift Zero, PARAXEL International, Japan Clinical Cancer Research Organization, EPS Holdings, SYSMEX Corporation, Public Health Research Foundation, Aichi Cancer Center, and the Kyushu Study group of Clinical Cancer and reports honoraria for lectures from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly and Company, Alfresa Pharma Corporation, Astellas Pharma, EA Pharma, Nippon Kayaku, Pfizer, Nippon Zoki Pharmaceutical, Sanofi, NIPRO, MOROO, Boehringer lngelheim, Hakodate National Hospital, Asahi Kasei Pharma Corporation, MSD, Zeria Pharmaceutical, Bayer Yakuhin, Yakult Honsha, Sumitomo Dainippon Pharma, Incyte Corporation, Merck Biopharma, The Japanese Gastroenterological Association, Sapporo Minami Tokushukai Hospital, and Pancan Japan. E.O. is on the speakers’ bureau at Bristol-Myers Squibb Japan, Chugai Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical and received research funding from Guardant Health. Y.Y. reports honoraria for lectures from Ono Pharmaceutical, Bristol Myers Squibb, Yakult, Chugai Pharmaceutical, Eli Lily, Bayer, Taiho Pharmaceutical, Servier, Takeda Pharmaceutical, Daiichi Sankyo, Teijin, and Insight. H.K. received grants or contracts from Chugai Pharmaceutical, Taiho Pharmaceutical, and Eisai and received consulting fees from BMS, Eli Lilly Japan, Ono Pharmaceutical, Daiichi Sankyo, and Taiho Pharmaceutical; and has received honoraria from BMS, Bayer Yakuhin, Eli Lilly Japan, MSD, Ono Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical, and Taiho Pharmaceutical. T. Misumi reports honoraria from Chugai Pharmaceutical, AstraZeneca, and Miyarisan. H.T. received lecture fees from Takeda Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Merck Biopharma, and Chugai Pharmaceutical and received research funds from Takeda Pharmaceutical, Daiichi Sankyo, and Ono Pharmaceutical. K.Y. reports honoraria for lectures from Chugai Pharmaceutical, Yakult, Daiichi Sankyo, Merk Serono, Sanofi, MSD, Takeda Pharmaceutical, Taiho Pharmaceutical, Bayer, Eli Lily, Ono Pharmaceutical, and Bristol-Myers Squibb. K.M. reports honoraria from Bristol-Myers Squibb, Daiichi Sankyo, MSD, Eli Lilly, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical; reports a consulting or advisory role at Amgen, Astellas Pharma, AstraZeneca, Chugai Pharmaceutical, and Ono Pharmaceutical; and received research funding from Amgen (Inst), Astellas Pharma (Inst), Chugai Pharmaceutical (Inst), Eisai (Inst), MSD (Inst), Novartis (Inst), Ono Pharmaceutical (Inst), Sanofi (Inst), and Taiho Pharmaceutical (Inst). T.Y. received consulting fees Sumitomo Corporation; received grants from Amgen, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, FALCO biosystems, Genomedia, Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, and Taiho Pharmaceutical; and reports honoraria for presentations from Bayer Yakuhin, Chugai Pharmaceutical, Merck Biopharma, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical. T.K. reports honoraria for lectures from Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Eli Lilly and Company. A.T. is on the speakers' bureau at Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Merck Serono, Sanofi, Taiho Pharmaceutical, and Takeda Pharmaceutical and reports research funding from Ono Pharmaceutical (Inst), Sanofi (Inst), and Taiho Pharmaceutical (Inst)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy., Methods: This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m 2 ) with intravenous leucovorin (20 mg/m 2 ) and 5-fluorouracil (400 mg/m 2 ). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS)., Results: Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached)., Conclusions: Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy., (Copyright © 2024 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

The activation of tumor cell immunogenicity through oxaliplatin (OXP)-induced immunogenic cell death (ICD) has significant implications in cancer treatment. However, the anti-tumor effect of OXP monotherapy still has many shortcomings, and the systemic administration of OXP leads to low drug concentration at the tumor site, which is susceptible to systemic toxic side effects. In this study, a combined therapeutic strategy using folate-modified nanoliposomes co-delivered with rapamycin (Rapa) and OXP (abbreviated as FA@R/O Lps) is proposed for the treatment of colorectal cancer (CRC). Rapa and OXP can directly inhibit tumor cell proliferation and induce apoptosis. OXP induces ICD by triggering the release of danger signals, such as HMGB1, ATP, and calreticulin. FA@R/O Lps with a particle size of about 134.1±1.8 nm and a small dispersion were successfully prepared. This novel liposomal system can be used to target and increase drug accumulation in tumors. In-vivo experiments showed that FA@R/O Lps successfully inhibit CRC growth and liver metastasis, and simultaneously reduce off-target toxicity. In particular, FA@R/O Lps showed greater therapeutic effects than free Rapa/OXP and R/O Lps. Taken together, this study provides a novel combination of Rapa and OXP, and a nano-delivery system for enhanced anti-CRC efficacy. The results suggest that FA@R/O Lps could be a promising strategy for the treatment of CRC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pengke Yan reports financial support was provided by he Natural Science Foundation of Guangdong Province (No. 2022A1515010199). Wengting Zhu reports financial support was provided by Plan on Enhancing Scientific Research in GMU (2024SRP104). Wengting Zhu reports financial support was provided by Lin He’s New Medicine and Clinical Translation Academician Workstation Research Fund (2021HLKY07). Hanhui Huang reports financial support was provided by Medical Scientific Research Foundation of Guangdong Province(B2023154). Pengke Yan, and Wengting Zhureport financial support was provided by Guangzhou Basic and Applied Basic Research Foundation (2024A03J0189, 2024A03J0188). Hang Yu reports financial support was provided by Medical Scientific Research Foundation of Guangdong Province (A2024212). Pengke Yan reports financial support was provided by Guangzhou Municipal Bureau of Science and Technology Key Research and Development Program (2024B03J0056). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Treatment recommendations for metastatic colorectal cancer (mCRC) do not differ by age group; nevertheless, aggressive multiagent chemotherapy comprising FOLFOXIRI+bevacizumab (triplet+bev) is routinely administered in younger patients. This study analyzed real-world data on index triplet+bev use and subsequent systemic therapies., Materials and Methods: This retrospective, observational cohort study was conducted in patients aged ≥ 18 years with mCRC, who were initiated on triplet+bev. Data were derived from the Optum de-identified electronic health record dataset., Results: Of 36,056 patients, 14%, 36%, and 50% were aged 18-49, 50-64, and ≥ 65 years, respectively. During the study period (2010-2021), triplet+bev use increased in patients aged 18-49 years (1%-4%) but remained at approximately 3% and 1% in patients aged 50-64 and ≥ 65 years, respectively. Patient demographics and clinical characteristics varied slightly; of patients receiving triplet+bev (n = 921) versus nontriplet+bev (n = 35,132) most were male (57% vs. 52%), resided in the Midwest (54% vs. 49%) and Northeast (18% vs. 14%) US regions, and had secondary malignancies (86% vs. 73%). Following triplet+bev, most patients received subsequent therapies (including continued triplet component therapies; 97%) or subsequent "new" therapies (therapies that did not include any agents comprising triplet+bev; 57%), most frequently EGFR inhibitors (28%) and regorafenib (21%), with a similar trend among all age groups., Conclusions: Overall, this study shows that younger patients with mCRC are more likely to receive first-line triplet+bev. These results also reveal that nonchemotherapy options are often used beyond first-line triplet chemotherapy for patients with mCRC., Competing Interests: Disclosure The data that support the findings of this study are available from Optum, which were used under license for the current study, and so are not publicly available. Interested researchers should contact Optum (https://www.optum.com). AB has received payments from Bayer for educational activities. HO, ZPV, and JX are employees of Bayer. ZPV reports stock ownership with Bayer. XF was an employee of Bayer at the time of the study. XF reports stock ownership with Jazz Pharmaceuticals., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) with peritoneal metastases is a complex disease and its management presents significant clinical challenges. In well-selected patients at experienced centers, CRS/hyperthermic intraperitoneal chemotherapy (HIPEC) can be performed with acceptable morbidity and is associated with prolonged survival. Based on the results of recent randomized controlled trials, HIPEC using oxaliplatin after CRS with shortened perfusion periods (30 minutes) is no longer recommended. There is a movement toward utilizing mitomycin C as a first-line intraperitoneal agent with extended perfusion times (90-120 minutes); however, there is currently little prospective evidence to support its widespread use., Competing Interests: Disclosure None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Platinum(II)-based drugs (Pt II ), which hinder DNA replication, are the most widely used chemotherapeutics. However, current Pt II drugs often miss their DNA targets, leading to severe side effects and drug resistance. To overcome this challenge, we developed a oxaliplatin-based platinum(IV) (Pt IV ) prodrug amphiphile (C 16 -OPt IV -R 8 K), integrating a long-chain hydrophobic lipid and a nucleus-targeting hydrophilic peptide (R 8 K). This design allows the prodrug to self-assemble into highly uniform lipid nanoparticles (NTPt IV ) for enhanced targeting chemotherapy and immunotherapy. Subsequently, NTPt IV 's bioactivity and effects were examined at diverse levels, encompassing cancer cells, 3D tumor spheres, and in vivo. Our in vitro studies show a 74% cancer cell nucleus localization of platinum drugs-3.6 times higher than that of oxaliplatin, achieving more than a ten-fold increase in eliminating drug-resistant cancer cells. In vivo, NTPt IV shows efficient tumor accumulation, leading to suppressed tumor growth of murine breast cancer. Moreover, NTPt IV recruited more CD4 + and CD8 + T cells and reduced CD4 + Foxp3 + Tregs to synergistically enhance targeted chemotherapy and immunotherapy. Overall, this strategy presents a promising advancement in nucleus-targeted cancer therapy, synergistically boosting the efficacy of chemotherapy and immunotherapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: In the FIGHT study (NCT03694522) bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 showed clinically meaningful efficacy in patients with FGFR2b-positive (2+/3+ membranous staining by immunohistochemistry) locally advanced unresectable/metastatic gastric/gastroesophageal cancer (G/GEJC). A meaningful proportion of patients in FIGHT were enrolled in East Asia, reflecting global epidemiology of G/GEJC., Methods: This subgroup analysis of the global, phase 2, double-blind FIGHT study included all patients enrolled in East Asian sites. Patients were randomized 1:1 to bemarituzumab-mFOLFOX6 (15 mg/kg and one 7.5 mg/kg dose on cycle 1, day 8) or matching placebo-mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months., Results: The East Asian subgroup comprised 89 patients (57% of overall study population); 45 were randomized to bemarituzumab-mFOLFOX6 and 44 to placebo-mFOLFOX6. Median PFS (95% confidence interval [CI]) was 12.9 months (8.8-17.9) with bemarituzumab-mFOLFOX6 and 8.2 months (5.6-10.3) with placebo-mFOLFOX6 (HR 0.50, 95% CI 0.29-0.87); median OS (95% CI) was 24.7 months (13.8-33.1) vs 12.9 months (9.3-21.4), respectively (HR 0.56, 95% CI 0.32-0.96). Treatment benefit was more pronounced in patients with FGFR2b-positive G/GEJC in ≥ 10% of tumor cells. No new safety signals were reported., Conclusion: In East Asian patients with FGFR2b-positive advanced/metastatic G/GEJC enrolled in the global FIGHT study, bemarituzumab-mFOLFOX6 showed clinically meaningful outcomes over placebo-mFOLFOX6., (© 2024. The Author(s).)

Background: The liver is affected by two groups of malignant tumours: primary liver cancers and liver metastases. Liver metastases are significantly more common than primary liver cancer, and five-year survival after radical surgical treatment of liver metastases ranges from 28% to 50%, depending on primary cancer site. However, R0 resection (resection for cure) is not feasible in most people; therefore, other treatments have to be considered in the case of non-resectability. One possible option is based on the concept that the blood supply to hepatic tumours originates predominantly from the hepatic artery. Transarterial chemoembolisation (TACE) of the peripheral branches of the hepatic artery can be achieved by administering a chemotherapeutic drug followed by vascular occlusive agents and can lead to selective necrosis of the cancer tissue while leaving normal liver parenchyma virtually unaffected. The entire procedure can be performed without infusion of chemotherapy and is then called bland transarterial embolisation (TAE). These procedures are usually applied over a few sessions. Another possible treatment option is systemic chemotherapy which, in the case of colorectal cancer metastases, is most commonly performed using FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) regimens applied in multiple sessions over a long period of time. These therapies disrupt the cell cycle, leading to death of rapidly dividing malignant cells. Current guidelines determine the role of TAE and TACE as non-curative treatment options applicable in people with liver-only or liver-dominant metastatic disease that is unresectable or non-ablatable, and in people who have failed systemic chemotherapy. Regarding the treatment modalities in people with colorectal cancer liver metastases, we found no systematic reviews comparing the efficacy of TAE or TACE versus systemic chemotherapy., Objectives: To evaluate the beneficial and harmful effects of transarterial embolisation (TAE) or transarterial chemoembolisation (TACE) compared with systemic chemotherapy in people with liver-dominant unresectable colorectal cancer liver metastases., Search Methods: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and three additional databases up to 4 April 2024. We also searched two trials registers and the European Medicines Agency database and checked reference lists of retrieved publications., Selection Criteria: We included randomised clinical trials assessing beneficial and harmful effects of TAE or TACE versus systemic chemotherapy in adults (aged 18 years or older) with colorectal cancer liver metastases., Data Collection and Analysis: We used standard Cochrane methods. Our primary outcomes were all-cause mortality; overall survival (time to mortality); and any adverse events or complications. Our secondary outcomes were cancer mortality; health-related quality of life; progression-free survival; proportion of participants dying or surviving with progression of the disease; time to progression of liver metastases; recurrence of liver metastases; and tumour response measures (complete response, partial response, stable disease, and progressive disease). For the purpose of the review and to perform necessary analyses, whenever possible, we converted survival rates to mortality rates, as this was our primary outcome. For the analysis of dichotomous outcomes, we used the risk ratio (RR); for continuous outcomes, we used the mean difference; and for time to event outcomes, we calculated hazard ratios (HRs), all with 95% confidence intervals (CI). We used the standardised mean difference with 95% CIs when the trials used different instruments. We used GRADE to assess the certainty of evidence for each outcome. We based our conclusions on outcomes analysed at the longest follow-up., Main Results: We included three trials with 118 participants randomised to TACE versus 120 participants to systemic chemotherapy. Four participants were excluded; one due to disease progression prior to treatment and three due to decline in health. The trials reported data on one or more outcomes. Two trials were performed in China and one in Italy. The trials differed in terms of embolisation techniques and chemotherapeutic agents. Follow-up ranged from 12 months to 50 months. TACE may reduce mortality at longest follow-up (RR 0.86, 95% CI 0.79 to 0.94; 3 trials, 234 participants; very low-certainty evidence), but the evidence is very uncertain. TACE may have little to no effect on overall survival (time to mortality) (HR 0.61, 95% CI 0.37 to 1.01; 1 trial, 70 participants; very low-certainty evidence), any adverse events or complications (3 trials, 234 participants; very low-certainty evidence), health-related quality of life (2 trials, 154 participants; very low-certainty evidence), progression-free survival (1 trial, 70 participants; very low-certainty evidence), and tumour response measures (presented as the overall response rate) (RR 1.81, 95% CI 1.11 to 2.96; 3 trials, 234 participants; very low-certainty evidence), but the evidence is very uncertain. No trials reported cancer mortality, proportion of participants dying or surviving with progression of the disease, and recurrence of liver metastases. We found no trials comparing the effects of TAE versus systemic chemotherapy in people with colorectal cancer liver metastases., Authors' Conclusions: The evidence regarding effectiveness of TACE versus systemic chemotherapy in people with colorectal cancer liver metastases is of very low certainty and is based on three trials. Our confidence in the results is limited due to the risk of bias, inconsistency, indirectness, and imprecision. It is very uncertain whether TACE confers benefits with regard to reduction in mortality, overall survival (time to mortality), reduction in adverse events or complications, improvement in health-related quality of life, improvement in progression-free survival, and tumour response measures (presented as the overall response rate). Data on cancer mortality, proportion of participants dying or surviving with progression of the disease, and recurrence of liver metastases are lacking. We found no trials assessing TAE versus systemic chemotherapy. More randomised clinical trials are needed to strengthen the body of evidence and provide insight into the benefits and harms of TACE or TAE in comparison with systemic chemotherapy in people with liver metastases from colorectal cancer., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: In this study, we retrospectively analysed the efficacy and safety of three treatment models, namely, short-course radiotherapy sequential XELOX chemotherapy, neoadjuvant mFOLFOX6 concurrent radiotherapy and long-course concurrent radiotherapy with total mesorectal excision (TME) after treatment of locally advanced rectal cancer with high-risk factors., Methods: We collected clinical data on 177 patients with locally advanced rectal cancer (cT3-4 and/or cN+) who were treated at the Department of Abdominal Oncology of the Affiliated Cancer Hospital of Guizhou Medical University from December 2017 to December 2022. All patients were associated with 2-3 risk factors [T4b, N2, Extramural Vascular Invasion (EMVI), Mesorectal Fascia (MRF) positivity], positive lateral lymph nodes. Among them, there were 45 cases in the short course radiotherapy sequential XELOX chemotherapy group (RT + XELOX group); 64 cases in the neoadjuvant mFOLFOX6 concurrent radiotherapy group (mFOLFOX6 + CRT group); and 68 cases in the long course concurrent radiotherapy group (CRT group). The RT + XELOX group and mFOLFOX6 + CRT group completed radiotherapy and 4 cycles of neoadjuvant chemotherapy, respectively, and then rested for 1-2 weeks before TME surgery; the CRT group completed concurrent radiotherapy and then rested for 6-8 weeks before TME surgery.Adjuvant chemotherapy was conducted after surgery in each of the three groups: 2 cycles of adjuvant chemotherapy with XELOX regimen in the RT + XELOX group, 4-6 cycles of adjuvant chemotherapy with mFOLFOX6 in the mFOLFOX6 + CRT group, and 8-12 cycles of adjuvant chemotherapy with mFOLFOX6 in the CRT group.The pathological complete response rate (pCR rate), tumour downstage rate, tumour complete resection rate (R0 resection rate), local recurrence rate, distant metastasis rate, overall survival rate, incidence of adverse reactions, surgical complications and completion rate of perioperative systemic chemotherapy were compared among patients in the three groups of cases after TME., Results: The pCR rate (21.95% vs 17.24% vs 5.00%, p = 0.034) and and tumour downstage rate (78.05% vs 68.97% vs 53.33%, p = 0.029) were higher in the RT + XELOX group and mFOLFOX6 + CRT group compared to the CRT group. The RT + XELOX group had a lower 3-year distant metastasis rate (14.63% vs 36.67%, p = 0.048) and improved 3-year overall survival (76.57% vs 48.56%, p < 0.001) compared to the CRT group. There was no significant reduction in the 3-year distant metastasis rate in the mFOLFOX6 + CRT group versus the CRT group (27.59% vs 36.67%, p = 0.719), and the 3-year overall survival was similar (51.23% vs 48.56%, p = 0.35). Multi-logistic regression analysis and stratified analysis showed that patients in the RT + XELOX group and mFOLFOX6 + CRT group were more likely to achieve pCR than the CRT group (RT + XELOX group: OR 7.3, 95% CI [2.6-20.8], p < 0.001; mFOLFOX6 + CRT group OR 2.9, 95% CI [1.1-7.9], p = 0.036). The completion rates of perioperative systemic chemotherapy in the RT + XELOX, mFOLFOX6 + CRT, and CRT groups were 82.93% vs. 84.48% vs. 61.67% (χ 2 =9.95, p = 0.007), respectively. And there were significant differences in grade 3-4 leukopenia and thrombocytopenia (incidence of leukopenia: 15.50% vs. 7.81% vs. 1.47%, p = 0.045; incidence of thrombocytopenia: 13.33% vs 7.81% vs 1.47%, p = 0.027). There was no significant difference in the incidence of intraoperative and postoperative complications among the three groups (p > 0.05)., Conclusions: RT + XELOX group and mFOLFOX6 + CRT group significantly improved the near-term outcome (e.g., pCR rate) in patients with locally advanced rectal cancer with high-risk factors compared with CRT group. The RT + XELOX group also reduced the 3-year distant metastasis rate, increased the 3-year overall survival rate, and did not increase the incidence of perioperative surgical complications. It provides an effective means for the comprehensive treatment of locally advanced rectal cancer and has important clinical guidance and application value.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report 4-year results of the phase II randomized AtezoTRIBE study. Eligible patients with metastatic colorectal cancer (mCRC) received first-line fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (control group, n = 73) or FOLFOXIRI/bevacizumab plus atezolizumab (experimental group, n = 145). We present overall survival (OS) and updated outcomes according to tumor immune-related biomarkers, both in the intention-to-treat (ITT) population and the cohort of patients with proficient mismatch repair (pMMR) tumors. Median follow-up was 45.2 months (IQR, 42.6-49.2). In the ITT population, median OS was 33.0 and 27.2 months for experimental and control groups, respectively (hazard ratio [HR], 0.78 [80% CI, 0.61 to 0.98]; P = .084). An interaction effect between Immunoscore Immune-Checkpoint (IC) and treatment arm was observed ( P int , .089), with higher benefit from atezolizumab in the Immunoscore IC-high group. In the pMMR cohort (N = 202), median OS was 30.8 and 29.2 months for experimental and control groups, respectively (HR, 0.80 [80% CI, 0.63 to 1.02]; P = .117). Interactions between treatment group and tumor mutational burden (TMB) and Immunoscore IC were reported ( P int , .043 and .092, respectively), with patients bearing TMB-high and Immunoscore IC-high tumors deriving higher benefit from the addition of atezolizumab. First-line FOLFOXIRI/bevacizumab plus atezolizumab improves OS in patients with mCRC. In the pMMR group, patients with Immunoscore IC-high and/or TMB-high tumors are identified as a subgroup of interest to further develop this treatment.

Background: Trifluridine/tipiracil (FTD/TPI) is approved in third-line treatment of patients with advanced/metastatic gastric and gastroesophageal junction adenocarcinomas (aGA/GEJA). The association of oxaliplatin with FTD/TPI is promising and the combination of FTD/TPI + oxaliplatin + nivolumab has shown a predictable and manageable safety profile., Aims: The aim is to evaluate the efficacy and safety of FTD/TPI plus oxaliplatin with or without nivolumab in patients, with HER2 negative aGA/GEJA, unfit for triplet chemotherapy (TFOX/mFLOT regimen), in the first-line metastatic setting in comparison with the standard of care FOLFOX with or without nivolumab., Methods: This study is a prospective randomised, open label, comparative, multicentre, phase II trial designed to include 118 patients. The primary objective is to evaluate the superiority of FTD/TPI plus oxaliplatin with or without nivolumab over FOLFOX regimen with or without nivolumab in terms of PFS in a population of patients non candidate for triplet chemotherapy. Nivolumab will be used for patients whose tumour express PD-L1 with a CPS score ≥5., Discussion: PRODIGE73-UCGI40-LOGICAN study will provide efficacy and safety data on the association of FTD/TPI plus oxaliplatin with or without nivolumab versus FOLFOX regimen with or without nivolumab in first-line palliative setting, in patients with aGA/GEJA (NCT05476796)., Competing Interests: Conflict of interest D.B. reports personal fees as a speaker and/or in an advisory role from Accord Healthcare, Amgen, Sanofi, Servier, and Pierre Fabre, outside the submitted work. O.B. reports personal fees as a speaker and/or in an advisory role from Merck, Bayer, Apmonia Therapeutics, Deciphera, Takeda, MSD, Amgen, Servier, and Pierre Fabre, outside the submitted work. C.C. reports personal fees as speaker and/or in an advisory role from Amgen, Astra-Zeneca, Pierre Fabre, Daiichy Sankyo, BMS, MSD, Merck Serono, Servier, outside the submitted work. O.D. reports personal fees as speaker and/or in an advisory role from Astra-Zeneca, BMS, MSD, Merck Serono, Sanofi, Servier outside the submitted work. DT: Honoraria: Amgen, Roche, Sanofi, Bristol Myers Squibb, Merck Serono, MSD, Bristol Myers Squibb, Servier, Ipsen, Pierre Fabre, AstraZeneca, Takeda, BeiGene, Astra Zeneca. Consulting or Advisory Role: Sanofi, MSD, Pierre Fabre, AstraZeneca, Novartis, Takeda. Research Funding: AstraZeneca (Inst), Servier (Inst), Roche (Inst), MSD (Inst), BTG (Inst). Travel, Accommodations, Expenses: Roche, Amgen, Bristol Myers Squibb, MSD, Pierre Fabre. CDLF: Honoraria: Amgen, AstraZeneca,Bayer, BeiGene, Bristol Myers Squibb, Ipsen, Merck, MSD, Pierre Fabre, Servier, Roche, Sanofi, Takeda. Consulting or Advisory Role: MSD, Pierre Fabre, AstraZeneca, Takeda. Research Funding: Servier (Inst), Roche (Inst), MSD (Inst). Travel, Accommodations, Expenses: Roche, Amgen, MSD, Pierre Fabre, Servier., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rational: Patients with gastric cancer show a relatively low incidence of developing secondary myelodysplastic syndrome (MDS)., Patient Concerns: A 60-year-old man was admitted because of pain and discomfort in the upper abdomen and intermittent abdominal pain., Diagnoses: Ulcerative moderately poorly differentiated adenocarcinoma (pT2N2M0G3, stage IIB) and MDS., Interventions: The patient underwent chemotherapy with oxaliplatin (OXP, intravenously guttae on day 1) plus capecitabine (CAP, bis in die orally on day 1-14). The patient developed degree III myelosuppression after OXP plus CAP chemotherapy and MDS was subsequently confirmed by diagnosis of the bone marrow biopsy. Temporary but significant hematological improvements were observed after the patient received corresponding treatment, which helped achieve remission and improve pancytopenia., Outcomes: The patient presented partial remission after corresponding treatment and no other complications have been recorded., Lessons: Acute MDS is an unusual adverse effect induced by OXP plus CAP chemotherapy. It is urgent to suggest implementing a supplementary assessment or examination for patients receiving these therapies in future cases., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis., Methods: The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens., Results: A total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs., Conclusion: In summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs., (© 2024. The Author(s).)

Background: Endoscopic submucosal dissection (ESD) is a potentially efficient therapeutic intervention for superficial esophageal cancer. Additional treatment such as chemoradiotherapy (CRT) or esophagectomy is recommended in cases of muscularis mucosa invasion with positive resection margins or lymphovascular invasion or submucosal layer invasion, which are considered noncurative ESD, due to an increased risk of lymph node metastasis. However, the adequacy of additional CRT after near-circumferential or full-circumferential noncurative ESD has not been fully discussed. In this study, we retrospectively evaluated the efficacy and toxicity of additional CRT for superficial esophageal squamous cell carcinoma (SCC) after near-circumferential or full-circumferential noncurative ESD, which was defined as a mucosal defect measuring ≥ 3/4 of the esophageal circumference., Methods: We retrospectively evaluated 24 patients who received additional CRT for superficial esophageal SCC after near-circumferential or full-circumferential noncurative ESD between 2012 and 2018. Elective nodal irradiation (ENI) was performed in all patients and boost irradiation (BI) was performed after ENI in 4 patients with positive resection margins. The prescription doses of ENI and BI were 41.4 Gy in 23 fractions and 9 Gy in 5 fractions, respectively. Concurrent chemotherapy (a combination of cisplatin or nedaplatin and 5-fluorouracil) was administered to all patients., Results: The 3-year and 5-year overall survival rates were 92% and 78%, respectively, while the 3-year and 5-year progression-free survival rates were 83% and 70%, respectively. Grade 2 esophageal stenosis occurred in 8 (33%) patients. There was no case of Grade 3 or worse esophageal stenosis. Among them, 4 (17%) patients developed stenosis before additional CRT, which persisted after the completion of additional CRT. The remaining 4 (17%) patients developed de novo stenosis within 5 months following the completion of additional CRT. One patient (4%) still requires regular bougie dilation. Grade 3 and Grade 4 acute toxicity, including anemia, neutropenia, thrombocytopenia, and esophagitis occurred in 1 (4%) and 0 (0%), 6 (25%) and 1 (4%), 1 (4%) and 0 (0%), and 1 (4%) and 0 (0%) patients, respectively. One (4%) patient who underwent salvage CRT for the out-of-field lymph node recurrence died with acute myeloid leukemia., Conclusions: Additional CRT is a viable treatment option even in patients who have undergone near-circumferential or full-circumferential noncurative ESD. Esophageal stenosis after additional CRT following near-circumferential or full-circumferential noncurative ESD is manageable and acceptable., (© 2024. The Author(s).)

Background: Colorectal cancer (CRC) is a significant malignancy with widespread implications. Despite progress in surgical interventions for rectal cancer, improvements in overall prognosis remain disproportionate. Standard preoperative chemoradiation, while established as the standard treatment for the majority of rectal cancers, exhibits limited effectiveness in enhancing disease-free survival (DFS) and mitigating distant metastases, particularly in cases of locally advanced rectal cancer (LARC)., Methods: This randomised clinical trial assessed 286 patients with LARC in two paralleled groups. Group A underwent six courses of neoadjuvant MFOLFOX chemotherapy, chemoradiation, surgery, and six adjuvant chemotherapy cycles. Group B received concurrent chemoradiation, surgery, and twelve adjuvant chemotherapy cycles. Patient evaluations were achieved at multiple stages of treatment and follow-up., Results: Group A had significantly lower local recurrence (11.64%) than Group B (21.74%, P = 0.025). The distant metastasis rate in Group A (8.90%) was lower than in Group B (20.29%) but was not significant (p = 0.143). More patients in Group A experienced downstaging (80.82% vs. 60.87%, p < 0.001). Specifically, 72.60% demonstrated downstaging of tumour invasion and 54.79% downstaging of lymph node involvement, compared to 57.25% and 41.30% in Group B (p = 0.009 and p = 0.025, respectively) as well as higher pCR rate (26.03% vs. 15.25%, p = 0.030) and three-year DFS rate (82.19% vs. 71.01%, p = 0.035) in group A compare to group B., Conclusion: This innovative strategy for LARC showed promising results with lower local recurrence and higher rates of downstaging and pCR. Treatment side effects were similar in both groups but less frequent in Group A. Anaemia was the most common haematological side effect (A: 58%, B: 68%), and peripheral sensory neuropathy was the most common non-haematological complication (A: 63%, B: 64%). These findings suggest this regimen could be a valuable therapeutic approach for LARC., Trial Registration: This trial was registered on 2023-12-08 within the IRCT.IR database under the number IRCT20210308050628N1., (© 2024. The Author(s).)

Metastatic colorectal neuroendocrine carcinoma (NEC) is often treated using a chemotherapy protocol for small-cell lung cancer; however, the prognosis is extremely poor. A 55-year-old woman with BRAF V600E-mutated transverse colon NEC and liver metastases underwent colectomy followed by FOLFOXIRI plus bevacizumab. Consequently, the liver metastases markedly shrank. Owing to later worsening of the liver metastases, she received encorafenib and binimetinib plus cetuximab. Despite discontinuing binimetinib due to myalgia, she had a long-term response with a progression-free survival of 14 months and an overall survival of more than 27 months. A chemotherapy protocol for BRAF-mutated metastatic colorectal cancer may be a treatment option for BRAF V600E-mutated colorectal NEC.

A 64-year-old man complained of lower abdominal pain and vomiting. The CT scan showed adhesional ileus; therefore, small bowel resection procedure was performed. Histological findings showed signet-ring cell carcinoma and poorly differentiated adenocarcinoma. We performed ileocecal resection as an additional surgery. The operative findings revealed peritoneal nodules. The histological findings suggested goblet cell carcinoid with peritoneal dissemination. mFOLFOX+bevacizumab was administered, and no progression was observed for 30 months after the surgery. Appendiceal goblet cell carcinoid is rare and its prognosis is poor. Here, we report a case of appendiceal GCC that achieved a relatively long-term survival despite peritoneal dissemination.

Background: Total neoadjuvant therapy (TNT) before surgical intervention represents a unique therapeutic approach for the management of locally advanced rectal cancer (LARC) and has witnessed a notable rise in utilization within recent years. However, the efficacy and safety of this treatment remain subjects of ongoing debate and investigation. This randomized controlled trial aimed to evaluate the potential impact of administering induction chemotherapy (IC) before the conventional neoadjuvant concomitant chemoradiotherapy (nCRT) in LARC patients., Materials & Methods: patients with resectable stage II-III LARC were randomly allocated to receive either biweekly 6 cycles of FOLFOX4 regimen as IC followed by CRT and total mesorectal excision (TME) (experimental group) or nCRT followed by TME (control group). The primary endpoint was the rate of pathological complete response (pCR). The secondary endpoints encompassed the evaluation of treatment-related adverse events as well as the assessment of survival outcomes., Results: 67 patients were enrolled in this study (32 in the experimental group and 35 in the control group). The median age of the patients was 45 years. Stage IIIB was observed in 46.3% of the patients. The patients who underwent induction chemotherapy demonstrated a notably higher rate of achieving pCR in comparison to the control group (28.1% vs 8.6%; P=0.001). There were no statistically significant differences observed in terms of their toxicity profile and survival outcomes., Conclusions: Implementation of induction chemotherapy utilizing the FOLFOX4 regimen has demonstrated a notable enhancement in the rate of pathological complete response. However, this improvement does not appear to translate into significant advancements in overall survival outcomes.

Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ)., Methods: This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue., Results: Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations., Conclusion: FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944)., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration., Methods: We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors., Results: Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%)., Conclusions: FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin., (© 2024. The Author(s).)

Background: This study evaluated the safety and efficiency of intraperitoneal irrigation chemotherapy with lobaplatin for the treatment of advanced gastric cancer (GC)., Methods: A total of 56 locally advanced GC patients (experimental group) who received intraoperative intraperitoneal irrigation chemotherapy in addition to undergoing radical D2 surgery were matched 1:1 based on 8 covariates to 56 patients without drug treatment (control group). Clinical data were collected and analyzed., Result: The two groups were well balanced in basic characteristics and had comparable clinical indices. All patients had similar time to first flatus (2.8 ± 0.3 vs. 2.9 ± 0.3 d, P = 0.076), time to first oral intake (3.5 ± 3.4 vs. 4.1 ± 4.6 d, P = 0.439), and duration of postoperative hospitalization (9.1 ± 3.2 vs. 9.6 ± 4.0 d, P = 0.446). There were no significant differences in postoperative complications including anastomotic and duodenal stump leakage, abdominal and anastomotic bleeding, seroperitoneum, and incision infection between the experimental and control groups (P > 0.05). The rates of chemotherapy-related side effects including allergic reaction, neurotoxicity, diarrhea, and nausea/vomiting were also similar between the two groups, and there were no abnormalities in leukocyte and platelet levels and liver and renal function during the first 5 days after surgery., Conclusion: Intraperitoneal irrigation chemotherapy with lobaplatin is safe for patients with advanced gastric cancer.

Purpose: Patient outcomes may differ from randomized trial averages. We aimed to predict benefit from FOLFOXIRI versus infusional fluorouracil, leucovorin, and oxaliplatin/fluorouracil, leucovorin, and irinotecan (FOLFOX/FOLFIRI), both plus bevacizumab, in patients with metastatic colorectal cancer (mCRC)., Methods: A Cox model with prespecified clinical, molecular, and laboratory variables was developed in 639 patients from the TRIBE2 trial for predicting 2-year mortality. Data from the CHARTA (n = 232), TRIBE1 (n = 504), and CAIRO5 (liver-only mCRC, n = 287) trials were used for external validation and heterogeneity of treatment effects (HTE) analysis. This involves categorizing patients into risk groups and assessing treatment effects across these groups. Performance was assessed by the C-index and calibration plots. The C-for-benefit was calculated to assess evidence for HTE. The c-for-benefit is specifically designed for HTE analysis. Like the commonly known c-statistic, it summarizes the discrimination of a model. Values over 0.5 indicate evidence for HTE., Results: In TRIBE2, the overoptimism-corrected C-index was 0.66 (95% CI, 0.63 to 0.69). At external validation, the C-index was 0.69 (95% CI, 0.64 to 0.75), 0.68 (95% CI, 0.64 to 0.72), and 0.65 (95% CI, 0.65 to 0.66), in CHARTA, TRIBE1, and CAIRO5, respectively. Calibration plots indicated slight underestimation of mortality. The c-for-benefit indicated evidence for HTE in CHARTA (0.56, 95% CI, 0.48 to 0.65), but not in TRIBE1 (0.49, 95% CI, 0.44 to 0.55) and CAIRO5 (0.40, 95% CI, 0.32 to 0.48)., Conclusion: Although 2-year mortality could be reasonably estimated, the HTE analysis showed that clinically available variables did not reliably identify which patients with mCRC benefit from FOLFOXIRI versus FOLFOX/FOLFIRI, both plus bevacizumab, across the three studies.

Purpose: A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC)., Materials and Methods: We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment., Results: A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years., Conclusion: In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Objective: The present study aims to compare the efficacy and side effects of a platinum-containing combination regimen and platinum single-drug concurrent chemoradiotherapy (CCRT) in patients with advanced cervical cancer (CC) and to understand the prognostic factors in patients with CC., Methods: A total of 108 cases of CC treated in Wenzhou Central Hospital were retrospectively selected. Patients in the monotherapy (single-drug) group received external pelvic radiotherapy (RT) and platinum-based single-drug chemotherapy (CT). Patients in the combined group received external pelvic RT and platinum-containing CT. The efficacy, CCRT time, 3-year survival rate after treatment and side effects were compared between the two groups, and the prognostic factors were analysed., Results: The total effective rate was 74.07% in the monotherapy group and 72.22% in the combined group ( p  = .828). The incidences of myelosuppression, gastrointestinal reaction and abnormal liver function in the grades III-IV combined group were significantly higher than those in the monotherapy group ( p  < .001; p  = .236; p  = .022). Furthermore, the CCRT time was significantly longer in the combined group than in the monotherapy group, and the 3-year overall survival (OS) was 81.48% in the monotherapy group and 79.63% in the combined group ( p  = .643; p  = .808). The older the age was, the higher the serum squamous cell carcinoma antigen (SCC-Ag) value before treatment and the shorter the progression-free survival time. In addition, the older the adenocarcinoma (AC) was, the shorter the OS., Conclusion: The efficacy of the two regimens in the treatment of advanced CC was similar. However, the side effects increased significantly during combined treatment., Prognostic Factors: A higher patient age, having an AC and stage of IIIa and a high SCC-Ag value before treatment resulted in a relatively low survival rate.

Background: The therapeutic benefit of concurrent chemoradiotherapy (CCRT) in elderly nasopharyngeal carcinoma (NPC) patients remains controversial. This study aimed to investigate the efficacy and toxicity of lobaplatin-based CCRT in elderly patients with NPC., Methods: We included stage II-IVA NPC patients aged ≥65 years who received lobaplatin concomitant with intensity-modulated radiation therapy (IMRT) between March 2019 and January 2023. Objective response rates and treatment-related toxicity were assessed. Kaplan-Meier's analysis was performed to calculate survival rates., Results: A total of 29 patients were included with a median age of 67 years. There were 19 patients (65.5%) who had comorbidities. All patients had serum EBV-DNA detective before treatment; the median EBV-DNA load was 236 IU/mL. There were 25 (86.2%) patients treated with induction chemotherapy, and the overall response rate was 92.0%. All patients received IMRT and concurrent chemotherapy with lobaplatin. During the CCRT, the most common adverse effect was haematological toxicity. Three patients (10.3%) had grade 3 leucopenia, three patients (10.3%) had grade 3 neutropenia, and eight patients (27.6%) had grade 3-4 thrombocytopenia. The rate of grade 3 mucositis was 34.5%. No patients had liver and kidney dysfunction. The median weight loss was 4 kg during CCRT. After three months of CCRT, the total response rate was 100%. EBV-DNA was not detected in any patients. The median follow-up was 32.1 months. The 3-year locoregional recurrence-free survival, distant metastasis-free survival, progression-free survival and overall survival were 95.8%, 85.7%, 82.5% and 100%, respectively., Conclusions: Lobaplatin-based CCRT is safe and feasible for elderly NPC patients, with satisfactory short-term survival outcomes and acceptable toxicities. A phase 2 trial is ongoing to investigate the role of lobaplatin-based CCRT on long-term survival and treatment toxicities for this population.

Purpose: Immunoscore (IS) is prognostic in stage III colorectal cancer (CRC) and may predict benefit of duration (6 v 3 months) of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. We sought to determine IS prognostic and predictive value in stage-III CRC treated with adjuvant FOLFOX or oral capecitabine and infusional oxaliplatin (CAPOX) in the SCOT and IDEA-HORG trials., Methods: Three thousand sixty-one cases had tumor samples, of which 2,643 (1,792 CAPOX) were eligible for IS testing. Predefined cutoffs (IS-Low and IS-High) were used to classify cases into two groups for analysis of disease-free survival (3-year DFS) and multivariable-adjusted hazard ratios (mvHRs) by Cox regression., Results: IS was determined in 2,608 (99.5%) eligible cases, with 877 (33.7%) samples classified as IS-Low. IS-Low tumors were more commonly high-risk (T4 and/or N2; 52.9% IS-Low v 42.2% IS-High; P < .001) and in younger patients ( P = .024). Patients with IS-Low tumors had significantly shorter DFS in the CAPOX, FOLFOX, and combined cohorts (mvHR, 1.52 [95% CI, 1.28 to 1.82]; mvHR, 1.58 [95% CI, 1.22 to 2.04]; and mvHR, 1.55 [95% CI, 1.34 to 1.79], respectively; P < .001 all comparisons), regardless of sex, BMI, clinical risk group, tumor location, treatment duration, or chemotherapy regimen. IS prognostic value was greater in younger (≤65 years) than older (>65 years) patients in the CAPOX cohort (mvHR, 1.92 [95% CI, 1.50 to 2.46] v 1.28 [95% CI, 1.01 to 1.63], P INTERACTION = .026), and in DNA mismatch repair proficient than deficient mismatch repair disease (mvHR, 1.68 [95% CI, 1.41 to 2.00] v 0.67 [95% CI, 0.30 to 1.49], P INTERACTION = .03), although these exploratory analyses were uncorrected for multiple testing. Adding IS to a model containing all clinical variables significantly improved prediction of DFS (likelihood ratio test, P < .001) regardless of MMR status., Conclusion: IS is prognostic in stage III CRC treated with FOLFOX or CAPOX, including within clinically relevant tumor subgroups. Possible variation in IS prognostic value by age and MMR status, and prediction of benefit from extended adjuvant therapy merit validation.

Background: Previous studies have shown that the addition of platinum to neoadjuvant chemotherapy (NAC) improved outcomes for patients with triple-negative breast cancer (TNBC). However, no studies have assessed the efficacy and safety of the combination of taxane and lobaplatin. In this study, we conducted a randomized controlled phase II clinical study to compare the efficacy and safety of taxane combined with lobaplatin or anthracycline., Methods: We randomly allocated patients with stage I-III TNBC into Arm A and Arm B. Arm A received six cycles of taxane combined with lobaplatin (TL). Arm B received six cycles of taxane combined with anthracycline and cyclophosphamide (TEC) or eight cycles of anthracycline combined with cyclophosphamide and sequential use of taxane (EC-T). Both Arms underwent surgery after NAC. The primary endpoint was the pathologic complete response (pCR). Secondary endpoints were event-free survival (EFS), overall survival (OS), and safety., Results: A total of 103 patients (51 in Arm A and 52 in Arm B) were assessed. The pCR rate of Arm A was significantly higher than that of Arm B (41.2% vs. 21.2%, P = 0.028). Patients with positive lymph nodes and low neutrophil-to-lymphocyte ratio (NLR) benefited significantly more from Arm A than those with negative lymph nodes and high NLR (P interaction  = 0.001, P interaction  = 0.012, respectively). There was no significant difference in EFS (P = 0.895) or OS (P = 0.633) between the two arms. The prevalence of grade-3/4 anemia was higher in Arm A (P = 0.015), and the prevalence of grade-3/4 neutropenia was higher in Arm B (P = 0.044)., Conclusions: Neoadjuvant taxane plus lobaplatin has shown better efficacy than taxane plus anthracycline, and both regimens have similar toxicity profiles. This trial may provide a reference for a better combination strategy of immunotherapy in NAC for TNBC in the future., (© 2024. The Author(s).)

Background: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab., Patients and Methods: 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM)., Results: Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity., Conclusions: We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress., Competing Interests: “•Thomas Seufferlein reports research funding to the institution from Sanofi during the conduct of the study; honoraria from Lilly, Pierre Fabre, BMS, MSD; advisory/consultancy roles with Amgen, Lilly, BMS, MSD, Pierre Fabre, Servier, Immodulon, Biontech, Mirati, Boehringer; Travel expenses from Takeda • Stefan Kasper discloses honoraria (self) from Merck, Amgen, Roche, Sanofi-Aventis, Servier, and Lilly; honoraria (institution) from Merck, Amgen, Roche, and Lilly; advisory/consultancy roles with Merck, BMS, Amgen, Roche, MSD, Sanofi-Aventis, Servier, and Lilly; research grants/funding (self) from Merck, Roche, BMS and Lilly; research grants/funding (institution) from Merck, Roche, BMS and Lilly; travel/accommodation expenses from Merck, Amgen, BMS, Roche, Sanofi, Aventis, Servier, and Lilly. • Thomas J. Ettrich reports honoraria from Roche, Sanofi; advisory/consultancy roles with Roche, Sanofi; research funding from Servier. • All other authors declare to have no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials”., (Copyright: © 2024 Seufferlein et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer., Patients and Methods: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory., Results: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed., Conclusion: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration., Gov Identifier: ClinicalTrials.gov; NCT03374254., Competing Interests: Disclosure R. Kim reports honoraria from Taiho; advisory/consultancy roles with Bayer Servier, Ipsen, and Roche; and speakers bureau for Eisai, Pfizer, and Incyte. M. Tehfe reports advisory/consultancy roles with Merck & Co., Inc., Rahway, NJ, USA, BMS, Taiho, and Pfizer; and speakers bureau for BMS and Taiho. P. Kavan reports advisory/consultancy role with Merck; expert testimony for Merck & Co., Inc., Rahway, NJ, USA; and an institutional educational grant to their institution. J. S. Kortmansky reports research funding to their institution from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Genentech. E. X. Chen reports advisory/consultancy roles from AstraZeneca, Eisai, and GSK and research funding to their institution from AstraZeneca, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, BMS, Novartis, Roche, Zymeworks, and 1Globe. C. H. Lieu reports advisory/consultancy roles with Natera; and research funding to their institution from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. M. Fakih reports advisory/consultancy roles with AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Mirati, Nouscom, PsiOxus, Roche/Genentech, and Taiho. K. Spencer reports advisory/consultancy roles with QED Therapeutics, Helsinn, Lynx Group, and Caris. Q. Zhao reports stock ownership at Merck & Co., Inc., Rahway, NJ, USA. R. Predoiu, C. Li, P. Leconte, and D. Adelberg report employment with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. P. Leconte and D. Adelberg report stock ownership at Merck & Co., Inc., Rahway, NJ, USA. E. G. Chiorean reports advisory/consultancy roles with Astellas, Bayer, Cardiff, Foundation, G1 Therapeutics, Ipsen, Noxxon, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, and Stemline; research funding to their institution from Aadi, Biosplice, BioMed Valley, Boehringer Ingelheim, Clovis, Corcept, Erasca, Fibrogen, Lona, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Rafael, and Stemline; and travel/accommodations from G1 Therapeutics. J. Chaves and L. Wong report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although patients with stage IV gastric cancer who respond well to systemic chemotherapy can be treated with gastrectomy, the prognosis of patients with multiple liver metastases is poor. We herein describe a patient with stage IV gastric cancer with multiple liver metastases who underwent conversion surgery after systemic treatment with S-1 plus oxaliplatin. The patient was a 62-year-old man. Upper gastrointestinal endoscopy revealed a 30-mm type 2 tumor in the greater curvature of the stomach at the anterior wall, and biopsy revealed a poorly differentiated adenocarcinoma. Imaging showed three suspected liver metastases in liver segment S8. The patient was judged to have gastric cancer, cStage IV (cT3N1M1(H)), and systemic chemotherapy was administered. He was treated with a total of six courses of chemotherapy. After re-evaluation, the primary tumor had shrunk significantly, and liver metastases could not be detected. Confirming no signs of seeding by laparoscopy, robot-assisted pylorus-preserving gastrectomy with D2 dissection and laparoscopic partial hepatic (S8) resection were performed. The patient was diagnosed with a complete pathological response. Conversion surgery is an option for stage IV gastric cancer when distant metastases are controlled with chemotherapy and when R0 resection is possible., (© 2024. Japanese Society of Gastroenterology.)

Introduction: The incidence of primary liver cancer (PLC) has experienced a significant global increase, primarily attributed to the rise in hepatocellular carcinoma (HCC). Unfortunately, HCC is often diagnosed in advanced stages, leaving patients with limited treatment options. Therefore, transformation therapy is a crucial approach for long-term survival and radical resection in patients with advanced HCC. Conversion therapy has demonstrated promise in the treatment of advanced HCC. When integrated with the FOLFOX regimen, hepatic artery infusion chemotherapy (HAIC) can significantly improve tumor response efficiency, leading to high conversion and resection rates., Areas Covered: We reviewed landmark trials of HAIC in combination with different drugs or means for the treatment of HCC to determine the clinical value of HAIC-centric translational therapies in HCC treatment. Furthermore, we specifically emphasize the advantages associated with employing FOLFOX-HAIC in the treatment of advanced HCC., Expert Opinion: The combination of HAIC with the FOLFOX regimen can help prevent the low intratumoral accumulation and high adverse reaction rate caused by the FOLFOX alone, holding significant potential in the comprehensive treatment of future HCC patients.

Background: Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies., Methods: In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics., Results: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10 -8 ). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively)., Conclusions: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To investigate the sensitivity of tumor organoids derived from samples of colorectal cancer to lobaplatin and oxaliplatin hyperthermic perfusion in vitro and to assist clinical development of hyperthermic intraperitoneal chemotherapy. Method: Tumor samples and relevant clinical data were collected from patients with pathologically confirmed colorectal cancer in the Sixth Affiliated Hospital of Sun Yat-sen University from July 2021 to December 2022. Organoids were cultured and tumor tissue were passaged. In vitro hyperthermic perfusion experiments were performed on organoids with good viability. Firstly, 10 organoids were treated with oxaliplatin and lobaplatin at the following six concentrations: 1 000, 250, 62.5, 15.6, 3.9, and 0.98 μmol/L. The organoids were exposed to oxaliplatin at 42℃ for 30 minutes and to lobaplatin at 42℃ for 60 minutes. Dose-response curves of responses to in vitro hyperthermic perfusion with these two drugs were constructed and evaluated. Clinical doses of oxaliplatin and lobaplatin were further tested on 30 organoids. This testing revealed oxaliplatin was effective at 579 µmol/L at a hyperthermic perfusion temperature of 42℃ for 30 min and lobaplatin was effective at 240 µmol/L at a hyperthermic perfusion temperature of 42℃ for 60 minutes. Result: Thirty-two tumor organoids were cultured from samples of colorectal cancer. The median concentration required for oxaliplatin to eliminate 50% of tumor cells (IC50) was 577.45 µmol/L (IQR: 1846.09 µmol/L). The median IC50 for lobaplatin was 85.04 µmol/L (IQR: 305.01 µmol/L).The difference between the two groups was not statistically significant ( Z =1.784, P =0.084). In seven of 10 organoids, lobaplatin showed a greater IC50 after in vitro hyperthermic perfusion than did oxaliplatin. Testing of 30 organoids with clinical doses of oxaliplatin and lobaplatin revealed that oxaliplatin achieved an average inhibition rate of 39.6% (95%CI: 32.1%‒47.0%), whereas the average rate of inhibition for lobaplatin was 89.7% (95%CI: 87.0%‒92.3%): this difference is statistically significant ( t =‒15.282, P <0.001). Conclusion: The rate of inhibition achieved by hyperthermic perfusion of lobaplatin in vitro is better than that achieved by hyperthermic perfusion with oxaliplatin. Lobaplatin is more effective than oxaliplatin when administered by hyperthermic intraperitoneal perfusion and therefore has the potential to replace oxaliplatin in this setting.

Background: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM., Methods and Findings: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection., Conclusions: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity., Trial Registration: ClinicalTrials.gov Identifier: NCT03493048., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC., Materials and Methods: Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs)., Results: A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7-30.1) and the median PFS was 11.9 months (95% CI, 6.7-17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs., Conclusion: Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Zhou, Miao, Xiong, Wei, Li and Guo.)

Background: The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated., Aim: To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC., Methods: We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen., Results: The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs)., Conclusion: The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background and Aims: The prognosis of hepatocellular carcinoma (HCC) with macrovascular invasion(MaVI)is poor, and the treatment is limited. This study aims to explore the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC), combined with lenvatinib and programmed cell death-1(PD-1) inhibitor in the first-line treatment of HCC with MaVI., Methods: From July 2020 to February 2022, we retrospectively analyzed consecutive patients with HCC with MaVI who received hepatic arterial infusion FOLFOX(oxaliplatin, 5-fluorouracil, and leucovorin)combined with lenvatinib and PD-1 inhibitor. The efficacy was evaluated by RECIST 1.1. Kaplan-Meier was used to explore the overall survival and progression-free survival (PFS), and the COX regression model was used to analyze the risk factors of PFS. Adverse events (AEs) were evaluated according to CTCAE5.0., Results: Thirty-two patients with HCC complicated with MaVI were recruited from the Second Affiliated Hospital of Nanchang University. Among the patients treated with HAIC combined with lenvatinib and PD-1 inhibitor, ten patients (31.25%) got partial response, eighteen patients (56.25%) maintained stable disease and four patients (12.50%) suffered progressive disease during follow-up; and objective response rate was 31.25%, and disease control rate was 87.5%. The median PFS was 179 days. Univariate and multivariate Cox analysis showed that the extrahepatic metastases and Child-Pugh score were independent prognostic factors of PFS. Twenty-two (68.75%) patients suffered adverse reactions. The main AEs were elevated transaminase (46.87%), thrombocytopenia (40.63%), hypoalbuminemia (28.13%), nausea and vomiting (21.88%), leukopenia (18.76%), abdominal pain (15.63%), hypertension (15.63%) and fever (15.63%). There were seven cases (21.88%) that had grade 3 or above AEs; Among them, two cases with elevated transaminase (6.25%), leukopenia, thrombocytopenia, nausea and vomiting, abdominal pain, and diarrhea occurred in one case respectively. Moreover, no treatment-related death was observed., Conclusions: Hepatic arterial infusion of FOLFOX combined with lenvatinib and PD-1 inhibitor as the first-line treatment for HCC complicated with MaVI is effective, and adverse reactions are tolerable., (© 2024. The Author(s).)

A 74-year-old man underwent laparoscopic-assisted high anterior resection with D3 lymph node dissection for rectal cancer, which was simultaneously accompanied by multiple liver metastases. The patient received mFOLFOX6 therapy for liver metastases 1 month after the surgery. Anorexia, nausea, and vomiting appeared on the second day of treatment. On the third day of treatment, impaired consciousness(JCS Ⅱ-20)and flapping tremors appeared. Blood tests revealed hyperammonemia, and the patient was diagnosed with impaired consciousness due to hyperammonemia, which was inferred to be caused by 5-fluorouracil(5-FU). Intravenous infusion and branched-chain amino acids were administered, and the patient recovered. The underlying disease of renal dysfunction, constipation, and dehydration due to chemotherapy might have induced the hyperammonemia. It is important to note that hyperammonemia can lead to a disturbance of consciousness during chemotherapy including 5-FU.

Introduction: This article is a summary of the French intergroup guidelines regarding the management of non-metastatic colon cancer (CC), revised in November 2022., Methods: These guidelines represent collaborative work of all French medical and surgical societies involved in the management of CC. Recommendations were graded in three categories (A, B, and C) according to the level of evidence found in the literature published up to November 2022., Results: Initial evaluation of CC is based on clinical examination, colonoscopy, chest-abdomen-pelvis computed tomography (CT) scan, and carcinoembryonic antigen (CEA) assay. CC is usually managed by surgery and adjuvant treatment depending on the pathological findings. The use of adjuvant therapy remains a challenging question in stage II disease. For high-risk stage II CC, adjuvant chemotherapy must be discussed and fluoropyrimidine monotherapy or oxaliplatin-based chemotherapy proposed according to the type and number of poor prognostic features. Oxaliplatin-based chemotherapy (FOLFOX or CAPOX) is the current standard for adjuvant therapy of patients with stage III CC. However, these regimens are associated with significant oxaliplatin-induced neurotoxicity. The results of the recent IDEA study provide evidence that 3 months of treatment with CAPOX is as effective as 6 months of oxaliplatin-based therapy in patients with low-risk stage III CC (T1-3 and N1). A 6-month oxaliplatin-based therapy remains the standard of care for high-risk stage III CC (T4 and/or N2). For patients unfit for oxaliplatin, fluoropyrimidine monotherapy is recommended., Conclusion: French guidelines for non-metastatic CC management help to offer the best personalized therapeutic strategy in daily clinical practice. Each individual case must be discussed within a multidisciplinary tumor board and then the treatment option decided with the patient., Competing Interests: Conflict of interest T. Lecomte: Amgen, Merck Serono, Pierre Fabre, and Servier. D. Tougeron: Amgen, Merck Serono, Pierre Fabre, Servier, MSD, BMS, Astra Zeneca, Sanofi, and Roche. F. Bibeau: Astellas, Astra-Zeneca, BMS, Incyte, MSD, Pierre Fabre, and Sanofi. R. Cohen: MSD Oncology, Pierre Fabre, Bristol-Myers Squibb, Mylan Medical, Servier, Exeliom Biosciences, and Enterome Bioscience. T. Aparicio: MSD, Pierre Fabre, BMS, Servier, and Amgen. O. Bouché: Amgen, Apmomia Therapeutics Bayer, Grunenthal, Merck KGaA, MSD, Pierre Fabre, and Servier. The other authors have reported no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A major advance has been made in the management of rectal cancer, with the emergence in 2021 of total neoadjuvant treatment. The main publications from the RAPIDO and PRODIGE-23 trials reported a significant improvement in progression-free survival and the pathological complete response rate. The aim of this review is to synthesize recent data on neoadjuvant treatment of rectal cancer, to explain the long-term results of the RAPIDO and PRODIGE-23 trials, and to put them into perspective, considering current advances in de-escalation strategies. The update of the 5-year survival data from the RAPIDO trial highlights an increased risk of loco-regional relapse, with 11.7% of relapses in the experimental group and 8.1% in the control group, while the update of the PRODIGE-23 trial confirms the benefits of this treatment regimen, with a significant improvement in overall survival. In addition, the results of the OPRA and PROPSPECT trials confirm the benefit of total neoadjuvant treatment with induction chemotherapy, as well as the possibility of surgical de-escalation in the OPRA trial and radiotherapy in the PROSPECT trial. The challenge for the future is to identify patients who require total neoadjuvant treatment with the aim of curative surgery to obtain a cure without local or distant relapse, and those for whom therapeutic de-escalation can be envisaged., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: A combination of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is the standard for adjuvant therapy of resected early-stage colon cancer (CC). Oxaliplatin leads to lasting and disabling neurotoxicity. Reserving the regimen for patients who benefit from oxaliplatin would maximize efficacy and minimize unnecessary adverse side effects., Methods: We trained a new machine learning model, referred to as the colon oxaliplatin signature (COLOXIS) model, for predicting response to oxaliplatin-containing regimens. We examined whether COLOXIS was predictive of oxaliplatin benefits in the CC adjuvant setting among 1,065 patients treated with 5-fluorouracil plus leucovorin (FULV; n = 421) or FULV + oxaliplatin (FOLFOX; n = 644) from NSABP C-07 and C-08 phase III trials. The COLOXIS model dichotomizes patients into COLOXIS+ (oxaliplatin responder) and COLOXIS- (nonresponder) groups. Eight-year recurrence-free survival was used to evaluate oxaliplatin benefits within each of the groups, and the predictive value of the COLOXIS model was assessed using the P value associated with the interaction term (int P ) between the model prediction and the treatment effect., Results: Among 1,065 patients, 526 were predicted as COLOXIS+ and 539 as COLOXIS-. The COLOXIS+ prediction was associated with prognosis for FULV-treated patients (hazard ratio [HR], 1.52 [95% CI, 1.07 to 2.15]; P = .017). The model was predictive of oxaliplatin benefits: COLOXIS+ patients benefited from oxaliplatin (HR, 0.65 [95% CI, 0.48 to 0.89]; P = .0065; int P = .03), but COLOXIS- patients did not (COLOXIS- HR, 1.08 [95% CI, 0.77 to 1.52]; P = .65)., Conclusion: The COLOXIS model is predictive of oxaliplatin benefits in the CC adjuvant setting. The results provide evidence supporting a change in CC adjuvant therapy: reserve oxaliplatin only for COLOXIS+ patients, but further investigation is warranted.

Objectives: This study aimed to examine the effectiveness of the best response rate (BRR) as a surrogate for overall survival (OS), using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), in patients with unresectable hepatocellular carcinoma (HCC) undergoing hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) combined with molecular targeting and immunotherapy., Methods: This study enrolled 111 consecutive patients who had complete imaging data. The median age of patients was 58 years (IQR 50.5-65.0). Among the patients, those with Barcelona Clinic Liver Cancer (BCLC) stage A, BCLC stage B, and BCLC stage C comprised 6.4%, 19.1%, and 73.6%, respectively. The optimal threshold of BRR can be determined using restricted cubic splines (RCS) and the rank sum statistics of maximum selection. Survival curves of patients in the high rating and low rating groups were plotted. We then used the change-in-estimate (CIE) method to filter out confounders and the inverse probability of treatment weighting (IPTW) to balance confounders between the two groups to assess the robustness of the results., Results: The median frequency of the combination treatment regimens administered in the overall population was 3 times (IQR 2.0-3.0). The optimal BRR truncation value calculated was -0.2. Based on this value, 77 patients were categorized as the low rating group and 34 as the high rating group. The differences in the OS between the high and low rating groups were statistically significant (7 months [95%CI 6.0-14.0] vs. 30 months [95%CI 30.0-]; p< 0.001). Using the absolute 10% cut-off value, the CIE method was used to screen out the following confounding factors affecting prognosis: successful conversion surgery, baseline tumor size, BCLC stage, serum total bilirubin level, number of interventional treatments, alpha-fetoprotein level, presence of inferior vena cava tumor thrombus, and partial thrombin activation time. The survival curve was then plotted again using IPTW for confounding factors, and it was found that the low rating group continued to have better OS than the high rating group. Finally, the relationship between BRR and baseline factors was analyzed, and inferior vena cava tumor thrombus and baseline tumor size correlated significantly with BRR., Conclusions: BRR can be used as a surrogate endpoint for OS in unresectable HCC patients undergoing FOLFOX-HAIC in combination with molecular targeting and immunotherapy. Thus, by calculating the BRR, the prognosis of HCC patients after combination therapy can be predicted. Inferior vena cava tumor thrombus and baseline tumor size were closely associated with the BRR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Liao, Wang, Lv, Sun, Xu, Guo, Quan, Qin, Yu, Zhang, Xing and Yu.)

Purpose: Total neoadjuvant therapy (TNT) with pre-operative chemotherapy and chemoradiotherapy results in improved survival and is becoming the new standard of care in locally advanced rectal cancer (LARC). We describe our experience with TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin., Methods: Adults with biopsy-proven, newly diagnosed LARC with high-risk characteristics on pelvic MRI (T4a or T4b, extramural vascular invasion, N2, mesorectal fascia involvement, enlargement/tumor deposits on lateral lymph nodes) were included. The TNT protocol comprised of six biweekly courses of modified FOLFOX6 followed by pelvic RT with four concurrent cycles of biweekly 5-FU 2600 mg/m2 + LV 200 mg/m2 without oxaliplatin to complete 20 uninterrupted weeks of full dose 5FU. Surgery was planned 11-13 weeks after completing chemoradiotherapy., Results: Eighty-four LARC patients, including 26% with signet-ring cell carcinoma, with high-risk MRI characteristics were treated with the TNT protocol with a 96% completion rate. Significant (> grade 3) toxicities included neutropenia (23.8%), diarrhea (14.2%) anemia (10.7%), and two deaths. The median DFS at 2 years was 22.5 months with better survival noted for those who underwent surgery or had cCR (with NOM) compared to those who did not undergo surgery (due to progression, inadequate regression, or patient preference despite residual disease) -mDFS 27.7 months versus 11.4 months, p =  < 0.0001 and mOS 29.2 months versus 15 months p =  < 0.0001., Conclusion: The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment-related deaths. Ability to undergo surgery after TNT predicted for improved DFS and OS., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A 65-years-old man undergoing hemodialysis for chronic kidney disease was diagnosed with ascending colon cancer and 3 hepatic metastases. He was administered mFOLFOX6 (reducing the dose to 50%) plus bevacizumab (BEV) therapy. Hemodialysis was performed 4 h after administration of oxaliplatin on day1 and repeated three times a week. No serious adverse events were observed. After 4 courses of chemotherapy, a computer tomography scan showed that the hepatic metastases had reduced. 2 courses of mFOLFOX6 (increasing the dose to 75%) plus BEV therapy were added, he was operated by laparoscopic right hemicolectomy and laparoscopic patrial hepatectomy. He has been in remission for 2 years and 4 months since the surgery. Dose-adjusted chemotherapy with hemodialysis was effective and improve the prognosis of the patient.

Introduction: In patients with unresectable liver metastases from colorectal cancer (CRCLM), systemic doublet or triplet chemotherapy and targeted therapy is considered a standard first-line treatment. Hepatic arterial infusion of oxaliplatin (HAI-ox) generates a high response rate, but this still needs to be confirmed in a randomized trial. We incorporated HAI-ox in doublet or triplet + targeted therapy to validate its efficacy., Aim: The OSCAR study is an ongoing randomized phase III trial comparing FOLFOX + targeted therapy according to RAS status, or FOLFOXIRI + bevacizumab in patients eligible for triplet therapy, with the same regimen but with HAI-ox instead of IV-ox as the first-line treatment for CRCLM., Materials and Methods: Main eligibility criteria are colorectal cancer, unresectable liver metastasis, no extra-hepatic metastases except pulmonary nodules if ≤3 and <10 mm, ECOG performance status 0 or 1., Endpoint: The primary endpoint is progression-free survival (PFS). A difference of 4 months for the median PFS in favor of HAI-ox is expected (HR = 0.73). Secondary endpoints include overall survival, overall response rate, secondary liver resection, safety, and quality of life., Conclusion: This study is planned to include 348 patients to demonstrate the superiority of HAI-ox over systemic oxaliplatin in first-line CRCLM treatment (NCT02885753)., Competing Interests: Conflict of interest PRODIGE 49 – Oscar Trial is funded in part by Amen Simon Pernot has received honoraria as a speaker and/or in an advisory role from Merck KGaA, Sanofi, Astra Zeneca, Servier, Pierre Fabre, and Amgen David Tougeron has received honoraria as a speaker and/or in an advisory role from Merck KGaA, Sanofi, Roche Genentech, MSD, BMS, Astra Zeneca, Servier, Pierre Fabre, Sandoz and Amgen Claire Gallois has received honoraria as a speaker and/or in an advisory role from Sanofi, Servier Faiza Khemissa has received honoraria as a speaker and/or in an advisory role from Sanofi, Bayer Michel Ducreux has received honoraria as a speaker and/or in an advisory role from Merck KGaA, Sanofi, Roche Genentech, MSD, BMS, Astra Zeneca, Servier, Pierre Fabre, Sandoz and Amgen Julien Taieb has received honoraria as a speaker and/or in an advisory role from Merck KGaA, Sanofi, Roche Genentech, MSD, BMS, Astra Zeneca, Servier, Pierre Fabre, Sandoz and Amgen Other authors didn't declare any conflict of interest., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)