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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.

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.

Purpose: Early-onset (EO) colorectal cancer (CRC, age < 50 years) incidence is increasing. Decisions on optimal adjuvant therapy should consider treatment adherence, adverse events, and expected outcomes in a population with life expectancy longer than later-onset (LO) CRC (age ≥ 50 years)., Materials and Methods: Individual patient data from six trials in the International Duration Evaluation of Adjuvant Chemotherapy database were analyzed. Characteristics, treatment adherence, and adverse events in stage II or III EO-CRC and LO-CRC were compared. To reduce confounders of non-cancer-related deaths because of age or comorbidities, time to recurrence (3-year relapse-free rate) and cancer-specific survival (5-year cancer-specific mortality rate) were considered., Results: Out of 16,349 patients, 1,564 (9.6%) had EO-CRC. Compared with LO-CRC, EO-CRC had better performance status (86% v 80%, P < .01), similar T stage (% T1-3/T4: 76/24 v 77/23, P = .97), higher N2 disease rate (24% v 22%, P < .01), more likely to complete the planned treatment duration (83.2% v 78.2%, P < .01), and received a higher treatment dose intensity, especially with 6-month regimens. Gastrointestinal toxicity was more common in EO-CRC; hematologic toxicity was more frequent in LO-CRC. Compared with LO-CRC, significantly worse cancer-specific outcomes were demonstrated especially in high-risk stage III EO-CRC: lower 3-year relapse-free rate (54% v 65%; hazard ratio [HR] 1.33; 95% CI, 1.14 to 1.55; P value < .001) and higher 5-year cancer-specific mortality rate (24% v 20%; HR 1.21; 95% CI, 1.00 to 1.47; P value < .06). In this subgroup, no difference was observed with 3 or 6 months of therapy, with equally poor disease-free survival rates (57% v 56%; HR 0.97; 95% CI, 0.73 to 1.29; P value = .85)., Conclusion: Young age is negatively prognostic in high-risk stage III CRC and associated with significantly higher relapse rate; this is despite better treatment adherence and higher administered treatment intensity, suggesting more aggressive disease biology., Competing Interests: Elisa FontanaEmployment: HCA/Sarah CannonConsulting or Advisory Role: Astellas Pharma (I), Celgene (I), Servier (I), Bristol Myers Squibb (I)Patents, Royalties, Other Intellectual Property: Patent No: 1716712.3 pending (I)Travel, Accommodations, Expenses: Bristol Myers Squibb (I), Servier (I) Alberto SobreroStock and Other Ownership Interests: BayerConsulting or Advisory Role: Merck Serono, Servier, Sanofi, Celgene, Amgen, Bayer, MenariniSpeakers' Bureau: Sanofi, Merck Serono, Takeda, Roche, Bayer, Amgen, Celgene, Lilly, AstraZeneca, Bristol Myers SquibbTravel, Accommodations, Expenses: Bayer, Merck Serono, Roche, Takeda Timothy IvesonHonoraria: ServierConsulting or Advisory Role: Servier, Bristol Myers Squibb, Pierre Fabre, MSD Oncology Anthony F. ShieldsConsulting or Advisory Role: ImaginAb, Caris Life SciencesSpeakers' Bureau: Caris Life SciencesResearch Funding: Taiho Pharmaceutical, Bayer, Boehringer Ingelheim, Plexxikon, Eisai, Inovio Pharmaceuticals, H3 Biomedicine, Caris Life Sciences, ImaginAb, Exelixis, Xencor, Lexicon, Daiichi Sankyo, Halozyme, Incyte, LSK BioPharma, Esperas Pharma, Nouscom, Boston Biomedical, Astellas Pharma, AstraZeneca, Five Prime Therapeutics, MSK Pharma, Esperas Pharma, Alkermes, Repertoire Immune Medicines, Telix Pharmaceuticals, Hutchison China Meditech, Seattle Genetics, Jiangsu Alphamab Biopharmaceuticals, Shanghai HaiHe Pharmaceutical, TopAlliance BioSciences Inc (Inst)Travel, Accommodations, Expenses: GE Healthcare, Caris Life Sciences, TransTarget, ImaginAb, Inovio Pharmaceuticals Julien TaiebConsulting or Advisory Role: Roche, Merck KGaA, Amgen, Servier, MSD, Pierre Fabre, NovartisSpeakers' Bureau: Servier, Amgen, Roche/Genentech, Sanofi, Merck, Lilly, MSD, Pierre Fabre Takayuki YoshinoHonoraria: Chugai Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical, Lilly, Taiho PharmaceuticalResearch Funding: Chugai Pharma (Inst), MSD (Inst), Daiichi Sankyo Company, Limited (Inst), PAREXEL International Inc (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Amgen (Inst), Sanofi (Inst) Ioannis SouglakosConsulting or Advisory Role: Roche (Inst), Servier (Inst), Ipsen (Inst), Pierre Fabre, MSD, Bristol Myers Squibb-Ono PharmaceuticalSpeakers' Bureau: Sanofi, Merck KGaA (Inst), Roche (Inst), MSDResearch Funding: Amgen (Inst), Sanofi (Inst)Travel, Accommodations, Expenses: Merck Serono, Amgen, Sanofi, Roche, Servier Elizabeth C. SmythEmployment: HCA International (I)Honoraria: Servier, Novartis, Bristol Meyer Squibb, PfizerConsulting or Advisory Role: Servier, Amal Therapeutics, BeiGene, Zymeworks, Novartis, Bristol Myers Squibb, Merck Serono, Roche, AstraZeneca, AmgenResearch Funding: Bristol Myers Squibb (Inst) Florian LordickHonoraria: Lilly, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Elsevier, BioNTech AG, Servier, Merck KGaA, Roche, Medscape, Incyte, Art Tempi, Medupdate, Streamedup!Consulting or Advisory Role: Lilly, Merck Sharp & Dohme, Bristol Myers Squibb, Astellas Pharma, Servier, Zymeworks, AmgenResearch Funding: Bristol Myers Squibb (Inst), MSD (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Lilly Markus MoehlerHonoraria: Amgen, Roche/Genentech, Merck Serono, MSD Oncology, Bristol Myers Squibb, AstraZeneca/MedImmune, Servier, Pierre Fabre, SanofiConsulting or Advisory Role: Bayer, MSD, Merck Serono, Amgen, Taiho Pharmaceutical, Pfizer, Roche, Lilly, Servier, BeiGene, BMSResearch Funding: Amgen (Inst), Leap Therapeutics (Inst), Merck Serono (Inst), AstraZeneca (Inst), MSD (Inst)Travel, Accommodations, Expenses: Amgen, Merck Serono, Roche, Bayer, ASCO, German Cancer Society, MSD, ESMO Roberto LabiancaConsulting or Advisory Role: Roche, Lilly, Sanofi, Merck SeronoTravel, Accommodations, Expenses: Roche, Merck Serono, Servier Jeffrey MeyerhardtHonoraria: Cota Healthcare, Taiho PharmaceuticalResearch Funding: Boston Biomedical (Inst) Thierry AndréHonoraria: Roche/Genentech, Bristol Myers Squibb, Servier, Bayer, Sanofi, Amgen, Pierre Fabre, Ventana Medical Systems, GlaxoSmithKlineConsulting or Advisory Role: Amgen, Bristol Myers Squibb, HalioDX, MSD Oncology, Servier, Bayer, AstraZeneca/MedImmune, Tesaro, Clovis Oncology, Gastrointestinal Cancers Advice, Pierre Fabre, GamaMabs Pharma, Astellas Pharma, Kaleido Biosciences, Gritstone Oncology, GlaxoSmithKline, Seagen, TransgeneTravel, Accommodations, Expenses: Roche/Genentech, Amgen, Bristol Myers Squibb, MSD Oncology, Roche, Ventana Medical Systems Ioannis BoukovinasEmployment: Pierre Fabre (I)Honoraria: Roche, MSD, Bristol Myers Squibb, Pfizer, Novartis, Merck, AstraZeneca, LEO Pharma, ServierConsulting or Advisory Role: Roche, Sanofi, AstraZeneca, Bristol Myers Squibb, LEO Pharma, MSD, Novartis, Ipsen, Genesis PharmaResearch Funding: Roche, Novartis, Bristol Myers Squibb, MSD, Regeneron, Boehringer Ingelheim, Lilly, PfizerTravel, Accommodations, Expenses: MSD, Roche, Pfizer, Bristol Myers Squibb, Servier, Ipsen Sara LonardiConsulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, MSDSpeakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, AmgenResearch Funding: Amgen, Merck Serono, Bayer (Inst), Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst) Mark SaundersHonoraria: Servier, Merck SeronoTravel, Accommodations, Expenses: Servier Dewi VernereyConsulting or Advisory Role: OSE Immunotherapeutics, Janssen-Cilag, HalioDx, Pfizer, CellProthera, GERCOR, Incyte, Fondazione Smith Kline, Invectys, AC BiotechTravel, Accommodations, Expenses: MSD Eiji OkiSpeakers' Bureau: Chugai Pharma, Lilly Japan, Takeda, Ono Pharmaceutical, Bayer Yakuhin, Bristol Myers Squibb Japan Vassilis GeorgouliasConsulting or Advisory Role: Novartis, Pfizer, AstraZeneca Qian ShiStock and Other Ownership Interests: Amgen, Johnson & Johnson, MerckHonoraria: Chugai PharmaConsulting or Advisory Role: Yiviva, Boehringer Ingelheim, Regeneron, Hoosier Cancer Research NetworkResearch Funding: Celgene (Inst), Roche/Genentech (Inst), Janssen (Inst), BMS (Inst), Novartis (Inst)No other potential conflicts of interest were reported.

Background: A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results., Methods: In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025., Findings: With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded., Interpretation: Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration., Funding: US National Cancer Institute., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Survival of patients with stage III colon cancer varies widely according to T-N sub-stages. Estimating the benefit of each therapeutic option in each T-N subgroup may provide more accurate information helping doctors and patients in the complex shared decision-making process surrounding adjuvant therapy., Methods: The outcomes data of 12,834 patients with stage III colon cancer enrolled in the IDEA trial served as our database. Patients were categorised in 16 sub-stages, based on T-N categories. We created a meta-regression model to predict the expected 5-year DFS within each T-N sub-stage. We then evaluated the efficacy of each therapeutic option in every sub-stage, working backward by subtraction, using an average of the HRs reported in pertinent trial publications as a conversion factor., Results: Large differences in 5-year DFS rate were observed among the subgroups, ranging from 89% (T1N1a) to 31% (T4N2b) in the overall population. The contribution to the outcome of each therapeutic option in this setting varied widely across sub-stages. According to our model, patients with T1N1a cancers have a projected 5-year DFS of 79.6% with surgery alone. Adjuvant fluoropyrimidine alone results in 5.6% absolute DFS gain; an additional 2.3% and 0.8% gain is seen with oxaliplatin for 3 and 6 months, respectively. Patients with T4N2b cancers show a 13.9% 5-year DFS with surgery alone, and an 11.2%, 6.4%, 2.5% increase with the aforementioned adjuvant options, respectively., Conclusion: The resulting overlay bar graph gives patients and doctors the projected relative benefit of each treatment option and may substantially help the shared decision-making process, although caution must be exercised in using this model due to the significant variance of the estimates., Competing Interests: Conflict of interest statement None to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The efficacy and safety of the FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) regimen combined with aflibercept has not been studied in the first-line management of patients with metastatic colorectal cancer (mCRC)., Patients and Methods: In the context of a prospective single-arm trial (NCT02129257), patients with mCRC received standard doses of a maximum of 12 cycles of FOLFIRI combined with aflibercept (4 mg/kg body weight delivered intravenously) every 2 weeks, followed by aflibercept maintenance. Endpoints were 12-month progression-free survival rate, efficacy, and toxicity., Results: Seventy-three fit patients were enrolled onto the study between 2014 and 2016. Median relative dose intensities administered were 0.80 for irinotecan and 1.0 for aflibercept. The most common grade 3/4 adverse events were neutropenia (13 patients, 18%), febrile neutropenia (3 patients, 4%), diarrhea (11 patients, 15%), hypertension (19 patients, 26%), proteinuria (8 patients, 11%), infections (8 patients, 11%), and mucositis (6 patients, 8%), with no toxic deaths. The objective response rate was 46.6%, significantly associated with the presence of right-sided primary, synchronous metastases, and a relapse-free interval of < 12 months (odds ratio = 3.00, 2.92, and 3.75 respectively, P ≤ .05). Intermediate infiltration by stromal core lymphocytes correlated with progression-free survival (hazard ratio = 0.40, [95% confidence interval (CI), 0.19-0.83], P = .014). At a median follow-up of 24.5 months, 12-month progression-free survival rate was 21.9% (median overall survival 20.9 months [95% CI, 16.6-29], median progression-free survival 8.4 months [95% CI, 7.4-9.3])., Conclusion: The FOLFIRI + aflibercept regimen is active and tolerable; however, it failed to improve historical benchmarks of efficacy in chemonaive patients with mCRC. Preliminary data hint that this regimen has cytoreductive activity in disease with adverse biology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Six months of adjuvant oxaliplatin-based chemotherapy is standard for patients with stage III colon cancer following surgery. However, oxaliplatin is associated with peripheral neurotoxicity which worsens over treatment duration. Consequently, a shorter treatment duration, if equally effective, would be extremely beneficial. A pooled analysis of data for 12 834 stage III colon cancer patients, from six randomised phase III trials of adjuvant therapy, the International Duration Evaluation of Adjuvant chemotherapy study, was carried out and the results presented at the ASCO Annual Meeting 2017. To clarify the potential impact of these results on clinical practice, ESMO decided to sponsor a special session at their 2017 Annual Meeting dedicated to achieving a more meaningful interpretation of the results., Methods: Medical oncologists from Europe, the United States and Asia selected for their involvement in the trials, together with an independent statistician and an independent clinician, were invited to provide their independent interpretations of the results and contribute to a moderated panel discussion. The pooled analysis evaluated the non-inferiority of 3 versus 6 months of adjuvant FOLFOX/CAPOX therapy but not the non-inferiority of 3 months CAPOX versus 6 months FOLFOX therapy., Results: There was strong evidence of an interaction between the choice of regimen (CAPOX or FOLFOX) and duration of treatment. Patients were classified as either 'fighters' or 'fatalists', and 3-month CAPOX was considered standard for patients classified as fatalists even if they had high-risk disease. However, patients classified as 'fighters' would only receive 3 months of CAPOX if they had low-risk disease but would always receive 6 months of CAPOX/FOLFOX if they had T4 disease. The panel was split on whether they would advocate 3 or 6 months CAPOX therapy based on high-risk N2 disease., Conclusions: The main drivers of the duration of treatment were choice of regimen and patient attitude, with risk, based mainly on T4 stage, having less influence.