BACKGROUND:Cetuximab improves progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild type (wt) metastatic colorectal cancer (mCRC). Few data are available on factors impacting both efficacy and compliance to cetuximab treatment, which is, in combination with chemotherapy, a standard-of-care first-line treatment regimen for patients with KRAS wt mCRC. PATIENTS AND METHODS:PREMIUM is a prospective, French multicenter, observational study that recruited patients with KRAS wt mCRC scheduled to receive cetuximab, with or without first-line chemotherapy, as part of routine clinical practice, between October 28, 2009 and April 5, 2012 (ClinicalTrials.gov Identifier: NCT01756625). The main endpoints were the factors impacting on efficacy and compliance to cetuximab treatment. Predefined efficacy endpoints were PFS and safety. RESULTS:A total of 493 patients were recruited by 94 physicians. Median follow-up was 12.9 months. Median progression-free survival was 11 months [9.6-12]. In univariate analyses, ECOG performance status (PS), smoking status, primary tumor location, number of metastatic organs, metastasis resectability, surgery, folliculitis, xerosis and paronychia maximum grade, and acne preventive treatment were statistically significant. In multivariate analysis (Hazard Ratios of multivariate stepwise Cox models), ECOG PS, surgery, xerosis and folliculitis were positive prognostics factors for longer PFS. Among all patients, 69 (14%) were non-compliant. In multivariate analysis, no variables were statistically significant. The safety profile of cetuximab was consistent with previous studies. CONCLUSIONS:ECOG PS <2, surgical treatment performed, and maximum grade xerosis or folliculitis developed were predictive factors of cetuximab efficacy on KRAS wt mCRC patients. Unfortunately, we failed in identifying predictive factors for compliance in these patients.

Background MMR Deficiency (dMMR) and edPOLE mutations (mt) are responsible for hypermutated tumoral phenotype. Immunotherapy have shown efficacy in dMMR/high mutation burden patients (pts). One of the French AcSe Nivolumab trial cohorts aims to assess Nivolumab in advanced edPOLE mt tumors. These mt occur in 1-2% of Colorectal Cancer (CRC). We aimed to define the most relevant criterias in CRC to facilitate the screening for inclusion in the AcSe Nivolumab edPOLE cohort. Methods edPOLE mutational status was evaluated in a cohort of locally advanced/metastatic (LA/M) CRC cancers enriched for BRAF mt, RAS mt, and unusual BRAF/RAS mt using High Resolution Melting PCR on the three hotspots described in the literature (codons 286, 411 and 459). Patients harboring edPOLE mt were then analyzed using FoundationOne genomic testing including tumor mutational burden (TMB). Results 386 CRC pts were analysed between 2012 and 2018 (208 with atypical RAS or BRAF mutation, 119 with classical RAS or BRAF mutation, 59 RAS/BRAF wild type): 11 edPOLE mutated tumors were identified, most frequently in young male pts (Sex ratio 4,5, mean age: 54 years), pMMR (91%, 10/11), with left-sided tumors (73%, 8/11). The prevalence of edPOLE mt in atypical KRAS/BRAF mutated tumor was 5.3% (11/208) vs 0% (0/178) in other cases (p = 0.02). Among the 11 edPOLE mt cases, 2 had a low TMB ( Conclusions A screening strategy based on clinicopathological (male gender, young age, left-sided tumors), and molecular criterias (pMMR, unusual BRAF/KRAS mutations) may help to identify pathogenic edPOLE mt (codons 286, 411, 459 and 461) associated with a high TMB in LA/M CRC. The use of these criterias could help to select patients for POLE mt screening and facilitate their access to immunotherapy. Clinical trial identification NCT03012581. Legal entity responsible for the study The authors. Funding Roche. Disclosure B.J. Rousseau: Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Novartis. All other authors have declared no conflicts of interest.

Background: Monitoring adverse effects (AEs) induced by antitumor therapies remain a clinical challenge for outpatients with cancer. Their delayed management might impair patient quality of life and lead to dose-lowering or discontinuation of treatment. The use of e-health may improve the communication between caregivers and patients, as well as the continuity of care. We assessed if Onco'nect®, a new digital follow-up tool, could be used easily by cancer outpatients undergoing active antitumor treatment in a routine clinical practice setting. Methods: Outpatients diagnosed with any type of cancer and undergoing intravenous or oral anticancer in the department of Medical Oncology of Creteil Teaching Hospital were eligible. No informatics knowledge was required for patients to be included in the study. At different times of each chemotherapy cycle, patients were sent a standardized 12-question survey assessing AEs. A chat was available for patients and caregivers to improve their communication. Grade ≥2 AEs, and deliberate requests of patients raised an alert system. Caregivers were notified of such events by emails and "red alerts" on the web-based interface. Results: Our study enrolled 51 patients, with distinct types of anticancer treatment (chemotherapy, oral therapy, immunotherapy and clinical trial therapy): 5 (9.8%) patients were over 75-year-old. Four patients could not use a computer or a smartphone but had a relative able to help. We called 21 (41.2%) patients at least once because they reported ≥ grade 2 AEs. We modified symptomatic treatments, or diet and lifestyle in 11 (21.6%) cases. Four patients deliberately raised the alert system, resulting in one hospitalization. The chat was used to: manage daily AEs, answer patients' questions, send prescriptions, receive medical imaging and blood test results. After a 2-month use, all the patients asked reported that Onco'nect® was easy to use and clinically-efficient. Conclusions: Onco'nect® is a user-friendly web-based tool to monitor outpatients undergoing anticancer treatment. It can be integrated in a current practice in oncology, even with elderly patients. Onco'nect® might help to anticipate chemotherapy prescriptions and reduce the admission in emergency rooms. Legal entity responsible for the study: Service d'Oncologie Médicale, Hôpital Henri Mondor, AP-HP, Créteil. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background: [F-18] 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)FDG-PET/CT) has high sensitivity for detecting recurrences of colorectal cancer (CRC). Our objective was to determine whether adding routine 6-monthly (18)FDG-PET/CT to our usual monitoring strategy improved patient outcomes and to assess the effect on costs. Patients and methods: In this open-label multicentre trial, patients in remission of CRC (stage II perforated, stage III, or stage IV) after curative surgery were randomly assigned (1:1) to usual monitoring alone (3-monthly physical and tumour marker assays, 6-monthly liver ultrasound and chest radiograph, and 6-monthly whole-body computed tomography) or with 6-monthly (18)FDG-PET/CT, for 3 years. A multidisciplinary committee reviewed each patient's data every 3 months and classified the recurrence status as yes/no/doubtful. Recurrences were treated with curative surgery alone if feasible and with chemotherapy otherwise. The primary end point was treatment failure defined as unresectable recurrence or death. Relative risks were estimated, and survival was analysed using the Kaplan-Meier method, log-rank test, and Cox models. Direct costs were compared. Results: Of the 239 enrolled patients, 120 were in the intervention arm and 119 in the control arm. The failure rate was 29.2% (31 unresectable recurrences and 4 deaths) in the intervention group and 23.7% (27 unresectable recurrences and 1 death) in the control group (relative risk = 1.23; 95% confidence interval, 0.80-1.88; P = 0.34). The multivariate analysis also showed no significant difference (hazards ratio, 1.33; 95% confidence interval, 0.8-2.19; P = 0.27). Median time to diagnosis of unresectable recurrence (months) was significantly shorter in the intervention group [7 (3-20) versus 14.3 (7.3-27), P = 0.016]. Mean cost/patient was higher in the intervention group (18 192 +/- 27 679 (sic) versus 11 131 +/- 13 (sic), P<0.033). Conclusion: (18)FDG-PET/CT, when added every 6 months, increased costs without decreasing treatment failure rates in patients in remission of CRC. The control group had very close follow-up, and any additional improvement (if present) would be small and hard to detect.

BackgroundRAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort.Patients and methodsPlasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precision ± 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary.ResultsFrom July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers.ConclusionThis prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients.Clinical Trial registrationClinicaltrials.gov, NCT02502656.

Hepatic toxicity of chemotherapy for colorectal cancer and its complications after hepatic metastasis surgery are unclear. Studies reporting hepatic lesions after chemotherapy for colorectal cancer and published before July 2009 have been identified by searching the Medline database. Data concerning these hepatic lesions and outcome after surgery are resumed in this review.Studies concerning the link between hepatic steatosis and chemotherapy have contradictory results but steatosis is clearly associated to an increase of postoperative morbidity. Steatohepatitis, especially due to irinotecan, is associated with increased postoperative mortality. Sinusoidal obstruction syndrome, a severe form of vascular hepatic lesion, associated to oxaliplatin, seems to be linked with an increase of postoperative morbidity, but not mortality. Bevacizumab would not increase, when used in combination with oxaliplatin, the rate of postoperative complications. Some studies suggest a decrease of vascular hepatic lesions when bevacizumab is administered with chemotherapy. The literature concerning hepatic toxicity of anti-EGF-R antibody is freak.The fact that irinotecan may be linked to an increased risk of hepatic failure and postoperative death, which is not the case of oxaliplatine, must be taken in consideration in the choice of the preoperative chemotherapy before resection of hepatic metastasis of colorectal cancer.

Aim. Hepatic toxicity of chemotherapy for colorectal cancer and its complications after hepatic metastasis surgery are unclear. Studies reporting hepatic lesions after chemotherapy for colorectal cancer and published before July 2009 have been identified by searching the Medline database. Data concerning these hepatic lesions and outcome after surgery are resumed in this review. Results. Studies concerning the link between hepatic steatosis and chemotherapy have contradictory results but steatosis is clearly associated to an increase of postoperative morbidity. Steatohepatitis, especially due to irinotecan, is associated with increased postoperative mortality. Sinusoidal obstruction syndrome, a severe form of vascular hepatic lesion, associated to oxaliplatin, seems to be linked with an increase of postoperative morbidity, but not mortality. Bevacizumab would not increase, when used in combination with oxaliplatin, the rate of postoperative complications. Some studies suggest a decrease of vascular hepatic lesions when bevacizumab is administered with chemotherapy. The literature concerning hepatic toxicity of anti-EGF-R antibody is freak. Conclusion. The fact that irinotecan may be linked to an increased risk of hepatic failure and postoperative death, which is not the case of oxaliplatine, must be took in consideration in the choice of the preoperative chemotherapy before resection of hepatic metastasis of colorectal cancer. triangle

e15004 In C96.1 study (André T et al; J Clin Oncol. 2007 20;25:3732–8), patients were randomized to either monthly 5FU-LV hd (dl LV 200 mg/m2 or l LV 100 mg/m2 15 min iv followed by 5FU 400 mg/m2 15 min iv, d1–5 q4 wk) or LV5FU2 (dl LV 200 mg/m2 or l LV 100 mg/m2 2-hour infusion followed by iv bolus 5FU 400 mg/m2 and 22 hours continuous infusion 600 mg/m2, d1 and d2 q 2 wk). Form l LV was administered to 60% (n=519) of patients and dl LV to 40% (n=357) of patients. It was unknown in 29 patients. No randomization was made between form l or dl (It was the choice of each center). The aim of this analysis was to compare the 2 LV forms in term of safety and efficacy. Important prognostic characteristics were well balanced between the 2 groups. The proportion of any grade III-IV toxicity was 20% in l form and 17% in dl form. There was no difference in term of toxicity between the two groups, except a trend for more diarrhea grade 3–4 in form l (8% in l form vs 4% in dl form, p=0.07). The median follow-up time was 6.2 years in l form and 6.0 years in dl form. There were no statistically significant differences between l and dl forms in term of disease free survival (33.3% vs 32.8% of patients with at least one event in l and dl forms respectively, hazard ratio=1.03, 95% CI=[0.82–1.31], p=0.78). In term of overall survival, there was a trend without statistical significance in favor of l form (21.8% vs 25.5% of patients who died, hazard ratio=1.28, 95% CI=[0.97–1.69], p=0.078). We conclude that the toxicity profile is similar between the two forms (excepted diarrhea). The difference in overall survival should not be attributed to folinic acid form as no difference was observed on DFS. No significant financial relationships to disclose.

Introduction: La pose d'une prothèse colique pour le traitement de l'occlusion par cancer est une alternative à la chirurgie. Elle constitue un traitement d'attente de la chirurgie curatrice pour les patients non métastatiques ou métastatiques résécables d'emblée. Le but de notre étude était de comparer les résultats des patients traités par prothèse puis chirurgie ou par chirurgie seule.