Browsing by Author "Lenz, Heinz-Josef"
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Item Age and comorbidity association with survival outcomes in metastatic colorectal cancer: CALGB 80405 analysis(Elsevier, 2022) McCleary, Nadine J.; Zhang, Sui; Ma, Chao; Ou, Fang-Shu; Bainter, Tiffany M.; Venook, Alan P.; Niedzwiecki, Donna; Lenz, Heinz-Josef; Innocenti, Federico; O'Neil, Bert H.; Polite, Blase N.; Hochster, Howard S.; Atkins, James N.; Goldberg, Richard M.; Ng, Kimmie; Mayer, Robert J.; Blanke, Charles D.; O'Reilly, Eileen M.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineBackground: Little is known about the interaction of comorbidities and age on survival outcomes in colorectal cancer (mCRC), nor how comorbidities impact treatment tolerance. Methods: We utilized a cohort of 1345 mCRC patients enrolled in CALGB/SWOG 80405, a multicenter phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) plus bevacizumab, cetuximab or both. Endpoints were overall survival (OS), progression-free survival (PFS), and grade ≥ 3 toxicities assessed using NCI CTCAE v.3.0. Participants completed a questionnaire, including a modified Charlson Comorbidity Index. Adjusted Cox and logistic regression models tested associations of comorbidities and age on the endpoints. Results: In CALGB/SWOG 80405, 1095 (81%) subjects were < 70 years and >70 250 (19%). Presence of ≥1 comorbidity was not significantly associated with either OS (HR 1.10, 95% CI 0.96-1.25) or PFS (HR 1.03, 95% CI 0.91-1.16). Compared to subjects <70 with no comorbidities, OS was non-significantly inferior for ≥70 with no comorbidities (HR 1.21, 95% CI 0.98-1.49) and significantly inferior for ≥70 with at least one comorbidity (HR 1.51, 95% CI 1.22-1.86). There were no significant associations or interactions between age or comorbidity with PFS. Comorbidities were not associated with treatment-related toxicities. Age ≥ 70 was associated with greater risk of grade ≥ 3 toxicities (OR 2.15, 95% CI 1.50-3.09, p < 0.001). Conclusions: Among participants in a clinical trial of combination chemotherapy for mCRC, presence of older age with comorbidities was associated with worse OS but not PFS. The association of age with toxicity suggests additional factors of care should be measured in clinical trials.Item Association of Coffee Intake With Survival in Patients With Advanced or Metastatic Colorectal Cancer(American Medical Association, 2020-11-01) Mackintosh, Christopher; Yuan, Chen; Ou, Fang-Shu; Zhang, Sui; Niedzwiecki, Donna; Chang, I-Wen; O’Neil, Bert H.; Mullen, Brian C.; Lenz, Heinz-Josef; Blanke, Charles D.; Venook, Alan P.; Mayer, Robert J.; Fuchs, Charles S.; Innocenti, Federico; Nixon, Andrew B.; Goldberg, Richard M.; O’Reilly, Eileen M.; Meyerhardt, Jeffrey A.; Ng, Kimmie; Medicine, School of MedicineImportance: Several compounds found in coffee possess antioxidant, anti-inflammatory, and insulin-sensitizing effects, which may contribute to anticancer activity. Epidemiological studies have identified associations between increased coffee consumption and decreased recurrence and mortality of colorectal cancer. The association between coffee consumption and survival in patients with advanced or metastatic colorectal cancer is unknown. Objective: To evaluate the association of coffee consumption with disease progression and death in patients with advanced or metastatic colorectal cancer. Design, setting, and participants: This prospective observational cohort study included 1171 patients with previously untreated locally advanced or metastatic colorectal cancer who were enrolled in Cancer and Leukemia Group B (Alliance)/SWOG 80405, a completed phase 3 clinical trial comparing the addition of cetuximab and/or bevacizumab to standard chemotherapy. Patients reported dietary intake using a semiquantitative food frequency questionnaire at the time of enrollment. Data were collected from October 27, 2005, to January 18, 2018, and analyzed from May 1 to August 31, 2018. Exposures: Consumption of total, decaffeinated, and caffeinated coffee measured in cups per day. Main outcomes and measures: Overall survival (OS) and progression-free survival (PFS). Results: Among the 1171 patients included in the analysis (694 men [59%]; median age, 59 [interquartile range, 51-67] years). The median follow-up time among living patients was 5.4 years (10th percentile, 1.3 years; IQR, 3.2-6.3 years). A total of 1092 patients (93%) had died or had disease progression. Increased consumption of coffee was associated with decreased risk of cancer progression (hazard ratio [HR] for 1-cup/d increment, 0.95; 95% CI, 0.91-1.00; P = .04 for trend) and death (HR for 1-cup/d increment, 0.93; 95% CI, 0.89-0.98; P = .004 for trend). Participants who consumed 2 to 3 cups of coffee per day had a multivariable HR for OS of 0.82 (95% CI, 0.67-1.00) and for PFS of 0.82 (95% CI, 0.68-0.99), compared with those who did not drink coffee. Participants who consumed at least 4 cups of coffee per day had a multivariable HR for OS of 0.64 (95% CI, 0.46-0.87) and for PFS of 0.78 (95% CI, 0.59-1.05). Significant associations were noted for both caffeinated and decaffeinated coffee. Conclusions and relevance: Coffee consumption may be associated with reduced risk of disease progression and death in patients with advanced or metastatic colorectal cancer. Further research is warranted to elucidate underlying biological mechanisms.Item Association of Diet Quality With Survival Among People With Metastatic Colorectal Cancer in the Cancer and Leukemia B and Southwest Oncology Group 80405 Trial(AMA, 2020-10-30) Van Blarigan, Erin L.; Zhang, Sui; Ou, Fang-Shu; Venlo, Alan; Ng, Kimmie; Atreya, Chloe; Van Loon, Katherine; Niedzwiecki, Donna; Giovannucci, Edward; Wolfe, Eric G.; Lenz, Heinz-Josef; Innocenti, Federico; O'Neil, Bert H.; Shaw, James E.; Polite, Blase N.; Hochster, Howard S.; Atkins, James N.; Goldberg, Richard M.; Mayer, Robert J.; Blanke, Charles D.; O'Reilly, Eileen M.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineImportance: Diet has been associated with survival in patients with stage I to III colorectal cancer, but data on patients with metastatic colorectal cancer are limited. Objective: To examine the association between diet quality and overall survival among individuals with metastatic colorectal cancer. Design, Setting, and Participants: This was a prospective cohort study of patients with metastatic colorectal cancer who were enrolled in the Cancer and Leukemia Group B (Alliance) and Southwest Oncology Group 80405 trial between October 27, 2005, and February 29, 2012, and followed up through January 2018. Exposures: Participants completed a validated food frequency questionnaire within 4 weeks after initiation of first-line treatment for metastatic colorectal cancer. Diets were categorized according to the Alternative Healthy Eating Index (AHEI), Alternate Mediterranean Diet (AMED) score, Dietary Approaches to Stop Hypertension (DASH) score, and Western and prudent dietary patterns derived using principal component analysis. Participants were categorized into sex-specific quintiles. Main Outcomes and Measures: Multivariable hazard ratios (HRs) and 95% CIs for overall survival. Results: In this cohort study of 1284 individuals with metastatic colorectal cancer, the median age was 59 (interquartile range [IQR]: 51-68) years, median body mass index was 27.2 (IQR, 24.1-31.4), 521 (41%) were female, and 1102 (86%) were White. There were 1100 deaths during a median follow-up of 73 months (IQR, 64-87 months). We observed an inverse association between the AMED score and risk of death (HR quintile 5 vs quintile 1, 0.83; 95% CI, 0.67-1.04; P = .04 for trend), but the point estimates were not statistically significant. None of the other diet scores or patterns were associated with overall survival. Conclusions and Relevance: In this prospective analysis of patients with metastatic colorectal cancer, diet quality assessed at initiation of first-line treatment for metastatic disease was not associated with overall survival.Item Body Mass Index and Weight Loss in Metastatic Colorectal Cancer in CALGB (Alliance)/SWOG 80405(Oxford University Press, 2020-03-31) Guercio, Brendan J.; Zhang, Sui; Venook, Alan P.; Ou, Fang-Shu; Niedzwiecki, Donna; Lenz, Heinz-Josef; Innocenti, Federico; Mullen, Brian C.; O’Neil, Bert H.; Shaw, James E.; Polite, Blase N.; Hochster, Howard S.; Atkins, James N.; Goldberg, Richard M.; Brown, Justin C.; O’Reilly, Eileen M.; Mayer, Robert J.; Blanke, Charles D.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineBackground: In nonmetastatic colorectal cancer, overweight and mild-to-moderately obese patients experience improved outcomes compared with other patients. Obesity's influence on advanced or metastatic colorectal cancer (mCRC) is relatively unexplored. Methods: We conducted a prospective body mass index (BMI) companion study in Cancer and Leukemia Group B (now Alliance)/SWOG 80405, a phase III metastatic colorectal cancer (mCRC) treatment trial. BMI was measured at trial registration. Primary and secondary endpoints were overall and progression-free survival, respectively. To minimize confounding by poor and rapidly declining health, we used Cox proportional hazards regression to adjust for known prognostic factors, comorbidities, physical activity, and weight loss during the 6 months prior to study entry. We also examined weight loss prior to enrollment as an independent predictor of patient outcome. All statistical tests were two-sided. Results: Among 2323 patients with mCRC, there were no statistically significant associations between BMI and overall or progression-free survival (adjusted P trend = .12 and .40, respectively). Weight loss during the 6 months prior to study entry was associated with shorter overall and progression-free survival; compared with individuals with stable weight ±4.9%, individuals with weight loss greater than 15% experienced an adjusted hazard ratio of 1.52 for all-cause mortality (95% confidence interval [CI] = 1.26 to 1.84; P trend < .001) and of 1.23 for disease progression or death (95% CI = 1.02 to 1.47; P trend = .006). Conclusions: In this prospective study of patients with mCRC, BMI at time of first-line chemotherapy initiation was not associated with patient outcome. Weight loss prior to study entry was associated with increased risk of patient mortality and disease progression.Item ESMO / ASCO Recommendations for a Global Curriculum in Medical Oncology Edition 2016(BMJ Publishing Group, 2016) Dittrich, Christian; Kosty, Michael; Jezdic, Svetlana; Pyle, Doug; Berardi, Rossana; Bergh, Jonas; El-Saghir, Nagi; Lotz, Jean-Pierre; Österlund, Pia; Pavlidis, Nicholas; Purkalne, Gunta; Awada, Ahmad; Banerjee, Susana; Bhatia, Smita; Bogaerts, Jan; Buckner, Jan; Cardoso, Fatima; Casali, Paolo; Chu, Edward; Close, Julia Lee; Coiffier, Bertrand; Connolly, Roisin; Coupland, Sarah; De Petris, Luigi; De Santis, Maria; de Vries, Elisabeth G. E.; Dizon, Don S.; Duff, Jennifer; Duska, Linda R.; Eniu, Alexandru; Ernstoff, Marc; Felip, Enriqueta; Fey, Martin F.; Gilbert, Jill; Girard, Nicolas; Glaudemans, Andor W. J. M.; Gopalan, Priya K.; Grothey, Axel; Hahn, Stephen M.; Hanna, Diana; Herold, Christian; Herrstedt, Jørn; Homicsko, Krisztian; Jones, Dennie V.; Jost, Lorenz; Keilholz, Ulrich; Khan, Saad; Kiss, Alexander; Köhne, Claus-Henning; Kunstfeld, Rainer; Lenz, Heinz-Josef; Lichtman, Stuart; Licitra, Lisa; Lion, Thomas; Litière, Saskia; Liu, Lifang; Loehrer, Patrick J.; Markham, Merry Jennifer; Markman, Ben; Mayerhoefer, Marius; Meran, Johannes G.; Michielin, Olivier; Moser, Elizabeth Charlotte; Mountzios, Giannis; Moynihan, Timothy; Nielsen, Torsten; Ohe, Yuichiro; Öberg, Kjell; Palumbo, Antonio; Peccatori, Fedro Alessandro; Pfeilstöcker, Michael; Raut, Chandrajit; Remick, Scot C.; Robson, Mark; Rutkowski, Piotr; Salgado, Roberto; Schapira, Lidia; Schernhammer, Eva; Schlumberger, Martin; Schmoll, Hans-Joachim; Schnipper, Lowell; Sessa, Cristiana; Shapiro, Charles L.; Steele, Julie; Sternberg, Cora N.; Stiefel, Friedrich; Strasser, Florian; Stupp, Roger; Sullivan, Richard; Tabernero, Josep; Travado, Luzia; Verheij, Marcel; Voest, Emile; Vokes, Everett; Von Roenn, Jamie; Weber, Jeffrey S.; Wildiers, Hans; Yarden, Yosef; Department of Medicine, School of MedicineThe European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.Item Identification of a Genomic Region Between SLC29A1 and HSP90AB1 Associated With Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance)(American Association for Cancer Research, 2019-10-01) Li, Megan; Mulkey, Flora; Jiang, Chen; O’Neil, Bert H.; Schneider, Bryan P.; Shen, Fei; Friedman, Paula N.; Momozawa, Yukihide; Kubo, Michiaki; Niedzwiecki, Donna; Hochster, Howard S.; Lenz, Heinz-Josef; Atkins, James N.; Rugo, Hope S.; Halabi, Susan; Kelly, William Kevin; McLeod, Howard L.; Innocenti, Federico; Ratain, Mark J.; Venook, Alan P.; Owzar, Kouros; Kroetz, Deanna L.; Medicine, School of MedicinePurpose: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.Experimental Design: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes.Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension.Item IGF-Binding Proteins, Adiponectin, and Survival in Metastatic Colorectal Cancer: Results From CALGB (Alliance)/SWOG 80405(Oxford University Press, 2020-08-27) Guercio, Brendan J.; Zhang, Sui; Ou, Fang-Shu; Venook, Alan P.; Niedzwiecki, Donna; Lenz, Heinz-Josef; Innocenti, Federico; Pollak, Michael N.; Nixon, Andrew B.; Mullen, Brian C.; O'Neil, Bert H.; Shaw, James E.; Polite, Blase N.; Benson, Al Bowen, III.; Atkins, James N.; Goldberg, Richard M.; Brown, Justin C.; O'Reilly, Eileen M.; Mayer, Robert J.; Blanke, Charles D.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineBackground: Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study. Methods: Baseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute-sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided. Results: Median follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; P nonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; P trend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; P trend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; P trend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (P nonlinearity = .03). Conclusions: Among patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.Item Plasma 25-Hydroxyvitamin D Levels and Survival in Patients with Advanced or Metastatic Colorectal Cancer: Findings from CALGB/SWOG 80405 (Alliance)(American Association for Cancer Research, 2019-12-15) Yuan, Chen; Sato, Kaori; Hollis, Bruce W.; Zhang, Sui; Niedzwiecki, Donna; Ou, Fang-Shu; Chang, I.-Wen; O'Neil, Bert H.; Innocenti, Federico; Lenz, Heinz-Josef; Blanke, Charles D.; Goldberg, Richard M.; Venook, Alan P.; Mayer, Robert J.; Fuchs, Charles S.; MeyerhardtMeyerhardt, Jeffrey A.; Ng, Kimmie; Medicine, School of MedicinePurpose: Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer (CRC) risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic CRC. Experimental design: We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic CRC participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders. Results: At study entry, 63% of patients were vitamin D deficient (<20 ng/mL) and 31% were vitamin D insufficient (20 to <30 ng/mL). Higher 25(OH)D levels were associated with an improvement in OS and PFS (Ptrend=0.0009 and 0.03, respectively). Compared to patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53 to 0.83) for OS and 0.81 (95% CI, 0.66 to 1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics. Conclusions: In this large cohort of patients with advanced or metastatic CRC, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in CRC patients are warranted.Item Plasma Protein Biomarkers in Advanced or Metastatic Colorectal Cancer Patients Receiving Chemotherapy With Bevacizumab or Cetuximab: Results from CALGB 80405 (Alliance)(American Association for Cancer Research, 2022) Nixon, Andrew B.; Sibley, Alexander B.; Liu, Yingmiao; Hatch, Ace J.; Jiang, Chen; Mulkey, Flora; Starr, Mark D.; Brady, John C.; Niedzwiecki, Donna; Venook, Alan P.; Baez-Diaz, Luis; Lenz, Heinz-Josef; O’Neil, Bert H.; Innocenti, Federico; Meyerhardt, Jeffrey A.; O’Reilly, Eileen M.; Owzar, Kouros; Hurwitz, Herbert I.; Medicine, School of MedicinePurpose: CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent. Patients and methods: In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment. Results: In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10-2.06; cetuximab HR, 0.94; 95% CI, 0.71-1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19-2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68-1.24; Pinteraction = 0.0097). Conclusions: In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner.Item The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer(Elsevier, 2017-12-01) Cutsem, Eric Van; Mayer, Robert J.; Laurent, Stéphanie; Winkler, Robert; Grávalos, Cristina; Benavides, Manuel; Longo-Munoz, Federico; Portales, Fabienne; Ciardiello, Fortunato; Siena, Salvatore; Yamaguchi, Kensei; Muro, Kei; Denda, Tadamichi; Tsuji, Yasushi; Makris, Lukas; Loehrer, Patrick; Lenz, Heinz-Josef; Ohtsu, Atsushi; Medicine, School of MedicineBackground: In the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups. Methods: Primary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ≥65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics. Results: Eight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59–0.81; P = 0.0001). Median OS in the three regions was 6.5–7.8 months in the trifluridine/tipiracil arm and 4.3–6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34–0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48–0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57–1.00; P = 0.0470). Median PFS was 2.0–2.8 months for trifluridine/tipiracil and 1.7–1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability. Conclusions: Trifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status.