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Circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA), which can be obtained from serial liquid biopsies to enable tumor genome analysis throughout the course of treatment. We investigated cfDNA and mutant ctDNA as potential biomarkers to predict the best outcomes of regorafenib-treated metastatic colorectal cancer (mCRC) patients. We analyzed longitudinally collected plasma cfDNA of 43 mCRC patients prospectively enrolled in the phase II TEXCAN trial by IntPlex qPCR. Qualitative (KRAS, NRAS, BRAF V600E mutations) and quantitative (total cfDNA concentration, mutant ctDNA concentration, mutant ctDNA fraction) parameters were correlated with overall survival (OS) and progression-free survival (PFS). When examined as classes or continuous variables, the concentrations of total cfDNA, mutant ctDNA, and, partly, mutant ctDNA fraction prior to regorafenib treatment correlated with OS. Patients with baseline cfDNA > 26 ng·mL -1 had shorter OS than those with cfDNA value below this threshold (4.0 vs 6.9 months; log-rank P = 0.0366). Patients with baseline mutant ctDNA > 2 ng·mL -1 had shorter OS than those with mutant ctDNA below this threshold (log-rank P = 0.0154). We show that pretreatment cfDNA and mutant ctDNA levels may identify mCRC patients that may benefit from regorafenib treatment., (© 2021 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Background: Adjuvant treatment for stage II colon cancer (CC) can be proposed to patients with high-risk disease. Recently, 2.35 ng/mL carcinoembryonic antigen (CEA) was identified as the best cut-off value. This post hoc analysis of the MOSAIC trial assessed post-operative CEA prognostic value for survival outcomes and predictive value for the addition of oxaliplatin to adjuvant treatment., Methods: Prognostic and predictive values of post-operative CEA in patients with stage II CC were evaluated with Kaplan-Meier survival curves and Cox model with interaction terms. Disease-free survival (DFS) and overall survival (OS) were estimated., Results: Among 899 stage II CC patients, post-operative CEA was available in 867 (96.4%); and 434 (48.65%) had a high-risk stage II disease. The 3-year DFS rate was 88.5% and 78.7% in the ≤ 2.35 ng/mL and > 2.35 ng/mL group, respectively (P = 0.006). Use of oxaliplatin showed survival benefit only in patients with high-risk stage II CC and post-operative CEA > 2.35 ng/ml (interaction term P = 0.09 and 0.03 for DFS and OS)., Conclusion: CEA is a strong prognostic factor for DFS and OS in stage II CC. In the MOSAIC trial, only high-risk stage II CC patients with post-operative CEA > 2.35 ng/mL benefited from the addition of oxaliplatin to LV5FU2., Trial Registration: NCT00275210 (January 11, 2006).

Background: Sunitinib is a tyrosine kinase inhibitor approved in the first-line metastatic renal cell carcinoma (MRCC) setting at the dose of 50 mg daily for 4 weeks followed by a pause of 2 weeks. Due to toxicity, this standard schedule (50 mg daily 4/2) can induce up to 50% of sunitinib dose modification (reduction and/or interruption). The current recommendation in such case is to reduce the dose to 37.5 mg per day (standard schedule 4/2). Recent data highlight an alternative schedule: 2 weeks of treatment followed by 1 week of pause (experimental schedule 2/1). The SURF trial is set up to evaluate prospectively experimental schedule 2/1 when toxicity occurs. This article displays the key elements of the study protocol., Methods/design: SURF [NCT02689167] is a prospective, randomized, open-label phase IIb study. Patients are included at sunitinib initiation while receiving standard schedule 4/2 (50 mg daily) according to the marketing authorization indication. When a dose adjustment of sunitinib is required, patients are randomized between standard schedule 4/2 (37.5 mg daily) and experimental schedule 2/1 (50 mg daily). Key eligibility criteria are the following: patients with locally advanced inoperable or MRCC who are starting first-line treatment with sunitinib, with histologically or cytologically confirmed renal cancer clear cell variant or with a clear cell component, and with Karnofsky performance status ≥70%. The primary objective is to assess the median duration of sunitinib treatment (DOT) in each group. The key secondary objectives are progression-free survival, overall survival, time to randomization, objective response rate, safety, sunitinib dose intensity, health-related quality of life, and the description of main drivers triggering randomization. We hypothesized that experimental schedule 2/1 would result in an improvement in median DOT from 6 to 8.5 months. It was estimated that 112 patients would be needed in each arm during 24 months. In order to take into account the possibility of treatment discontinuation before randomization, 248 patients are necessary., Discussion: The SURF trial is asking a pragmatic question adapted to the current practice on what is the best way to adapt sunitinib when treatment-related adverse events occur. The results of the SURF trial will bring high-value data to support the use of an alternative schedule in sunitinib treatment., Trial Registration: ClinicalTrials.gov, NCT02689167 . Registered on 26 February 2016.

Background: Deficient mismatch repair (dMMR) colon cancer (CC) is reportedly resistant to 5-fluorouracil (5FU) adjuvant chemotherapy while preliminary data suggest chemosensitivity to oxaliplatin. We assessed the efficacy of fluoropyrimidine with and without oxaliplatin in a large cohort of dMMR CC patients., Methods: This retrospective multicenter study included all consecutive patients who underwent curative surgical resection for stage II or III dMMR CC between 2000 and 2011. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided., Results: A total of 433 dMMR CC patients were included (56.8% stage II, 43.2% stage III). Mean follow-up was 47.0 months. The patients received surgery alone (n = 263) or surgery plus adjuvant chemotherapy consisting of fluoropyrimidine with (n = 119) or without (n = 51) oxaliplatin. Adjuvant chemotherapy was administered to 16.7% of stage II and 69.0% of stage III CC patients. As compared with surgery alone, adjuvant oxaliplatin-based chemotherapy improved disease-free survival (DFS) in multivariable analysis (HR = 0.35, 95% CI = 0.19 to 0.65, P < .001), contrary to adjuvant fluoropyrimidine alone (HR = 0.73, 95% CI = 0.36 to 1.49, P = .38). In the subgroup analysis, the DFS benefit of oxaliplatin-based chemotherapy was statistically significant in multivariable analysis only in stage III (HR = 0.41, 95% CI = 0.19 to 0.87, P = .02)., Conclusion: This study supports the use of adjuvant chemotherapy with fluoropyrimidine plus oxaliplatin in stage III dMMR CC., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer., Methods: This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824., Findings: Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%])., Interpretation: Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy., Funding: GERCOR and F Hoffmann-La Roche., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Our study describes the feasibility and efficacy of a first‐line FOLFIRINOX (5‐fluorouracil [5FU], folinic acid, irinotecan, and oxaliplatin) induction chemotherapy (CT) followed by de‐escalation as a maintenance strategy for advanced pancreatic cancer. Materials and Methods: This multicenter retrospective study was conducted from January 2011 to December 2018. FOLFIRINOX de‐escalation was defined as stopping oxaliplatin and/or irinotecan after at least four cycles of FOLFIRINOX, without evidence of disease progression. Maintenance schedules were fluoropyrimidine monotherapy (intravenous or oral [capecitabine]), FOLFOX (5FU, oxaliplatin), or FOLFIRI (5FU, irinotecan). Primary endpoint was overall survival (OS). Secondary endpoints were first progression‐free survival (PFS1), second progression‐free survival (PFS2), and toxicity. Results: Among 321 patients treated with FOLFIRINOX, 147 (45.8%) were included. Median OS was 16.1 months (95% confidence interval [CI], 13.7–20.3) and median PFS1 was 9.4 months (95% CI, 8.5–10.4). The preferred maintenance regimen was FOLFIRI in 66 (45%) patients versus 5FU monotherapy in 52 (35%) and FOLFOX in 25 (17%) patients. Among 118 patients who received maintenance CT with FOLFIRI or 5FU, there was no difference in PFS1 (median, 9.0 vs. 10.1 months, respectively; p =.33) or OS (median, 16.6 vs. 18.7 months; p =.86) between the two maintenance regimens. Reintroduction of FOLFIRINOX was performed in 20.2% of patients, with a median PFS2 of 2.8 months (95% CI, 2.0–22.3). The rates of grade 3–4 toxicity were significantly higher with FOLFIRI maintenance CT than with 5FU (41% vs. 22%; p =.03), especially for neuropathy (73% vs. 9%). Conclusion: 5FU monotherapy maintenance appeared to be as effective as FOLFIRI, in a FOLFIRINOX de‐escalation strategy, which is largely used in France. Implications for Practice: FOLFIRINOX de‐escalation and maintenance is a feasible strategy in advanced pancreatic cancer that decreases chemotherapy toxicity to improve both survival and quality of life. Survivals in patients with maintenance therapy are clinically meaningful. Fluoropyrimidine monotherapy maintenance seems to be as efficient as FOLFIRI and should be a reference arm in future pancreatic cancer maintenance trials. This article provides a descriptive overview of the feasibility and efficacy results of therapeutic de‐escalation of FOLFIRINOX in patients with metastatic pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: At time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC.Methods: PANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence.Discussion: The "ideal" cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC.Trial Registration: ClinicalTrials.gov , NCT02959879 . Trial registration date: November 9, 2016. [ABSTRACT FROM AUTHOR]

Background: Deficient mismatch repair (dMMR) colon cancer (CC) is reportedly resistant to 5-fluorouracil (5FU) adjuvant chemotherapy while preliminary data suggest chemosensitivity to oxaliplatin. We assessed the efficacy of fluoropyrimidine with and without oxaliplatin in a large cohort of dMMR CC patients.Methods: This retrospective multicenter study included all consecutive patients who underwent curative surgical resection for stage II or III dMMR CC between 2000 and 2011. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided.Results: A total of 433 dMMR CC patients were included (56.8% stage II, 43.2% stage III). Mean follow-up was 47.0 months. The patients received surgery alone (n = 263) or surgery plus adjuvant chemotherapy consisting of fluoropyrimidine with (n = 119) or without (n = 51) oxaliplatin. Adjuvant chemotherapy was administered to 16.7% of stage II and 69.0% of stage III CC patients. As compared with surgery alone, adjuvant oxaliplatin-based chemotherapy improved disease-free survival (DFS) in multivariable analysis (HR = 0.35, 95% CI = 0.19 to 0.65, P < .001), contrary to adjuvant fluoropyrimidine alone (HR = 0.73, 95% CI = 0.36 to 1.49, P = .38). In the subgroup analysis, the DFS benefit of oxaliplatin-based chemotherapy was statistically significant in multivariable analysis only in stage III (HR = 0.41, 95% CI = 0.19 to 0.87, P = .02).Conclusion: This study supports the use of adjuvant chemotherapy with fluoropyrimidine plus oxaliplatin in stage III dMMR CC. [ABSTRACT FROM AUTHOR]

Background: In advanced pancreatic ductal adenocarcinoma (aPDAC), there is no consensual strategy for second-line chemotherapy (L2). Better discrimination of overall survival (OS) may help clinical decision-making. We aimed to predict OS from the beginning of L2 and to assess the benefit from chemotherapy among the identified risk groups.Methods: Analyses were derived from all consecutive aPDAC patients treated at Besancon University Hospital, Besancon, France, between January 2003 and December 2013 (n = 462). The association of 50 parameters with OS was evaluated using univariate and multivariable Cox analyses. Based on the final model, a prognostic nomogram and score were developed and externally validated. Patients in the external validation cohort who received L2 (n = 163) were treated at three French institutions between January 2010 and April 2016. All statistical tests were two-sided.Results: In the development cohort, 395 patients (85.5%) were eligible for L2, of which 261 (66.1%) were treated. Age, smoking status, liver metastases, performance status, pain, jaundice, ascites, duration of first-line, and type of L2 regimen were identified as independent prognostic factors for OS in L2. The score determined three groups with median OS of 11.3 months (95% confidence interval [CI] = 9.1 to 12.9 months), 3.6 months (95% CI = 2.6 to 4.7 months), and 1.4 months (95% CI = 1.2 to 1.7 months), for low-, intermediate-, and high-risk groups, respectively ( P < .001). By applying the score in the population eligible for L2 but untreated, the chemotherapy benefit was statistically significant across all groups, but with a magnitude of the effect decreased statistically significantly from low- to high-risk groups ( P = .001 for treatment and risk groups interaction term). The ability of the score to discriminate OS was confirmed in the external validation cohort.Conclusions: This prognostic nomogram and score in patients with aPDAC can accurately predict OS before administration of L2 and may help clinicians in their therapeutic decisions. [ABSTRACT FROM AUTHOR]

The IMMUNOBIL PRODIGE 57 trial is a non-comparative randomized phase II study assessing the efficacy and safety of the durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) combination with or without weekly paclitaxel in patients with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy. Taxanes have already been safely combined with immune checkpoint inhibitors in other tumors. We report results of the 20-patient safety run-in. Patients received durvalumab (1500 mg at day 1 [D1] of each cycle)/tremelimumab (75 mg at D1 for 4 cycles; Arm A) or durvalumab/tremelimumab with paclitaxel (80 mg/m2 at D1, D8, D15; Arm B) every 28 days. Twenty patients were enrolled (Arm A/B: 10/10). There were no dose-limiting toxicities (DLTs) in Arm A. Six DLTs were observed in five patients (50%) in Arm B, meeting a stopping rule for the trial inclusions. DLTs included three serious anaphylactic reactions (with one cardiac arrest), two enterocolitis, and one infectious pneumopathy with septic shock. There were no patients with history of personal or familial auto-immune disease. The safety run-in part of IMMUNOBIL PRODIGE 57 raised concerns regarding co-administration of paclitaxel with durvalumab and tremelimumab in BTC, with an unexpected increase in anaphylactic adverse events. Phase II of the study will only evaluate the durvalumab and tremelimumab combination arm. NCT03704480. • IMMUNOBIL phase II trial enrolls patients with advanced biliary tract cancers (BTC). • Patients received durvalumab and tremelimumab with or without paclitaxel. • With six dose-limiting toxicities in Arm B, a stopping rule was met. • An unexpected increase in anaphylactic adverse events was observed. • It raised concerns for durvalumab/tremelimumab combined with paclitaxel in BTC. [ABSTRACT FROM AUTHOR]