Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study.

BACKGROUND: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus. METHODS: In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants. FINDINGS: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths. INTERPRETATION: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies. FUNDING: GERCOR, Roche.

Efficacy of aflibercept with FOLFOX and maintenance with fluoropyrimidine as first­line therapy for metastatic colorectal cancer: GERCOR VELVET phase II study.

Aflibercept in combination with 5­fluorouracil (5­FU)/irinotecan improves overall survival in the second­line therapy of patients with metastatic colorectal cancer (mCRC). In this study, we evaluated the effects of aflibercept in first­line therapy with FOLFOX followed by maintenance with fluoropyrimidine. VELVET was a prospective, single­arm multicenter phase II study (completed). Patients with previously untreated, unresectable, evaluable or measurable mCRC, with an age ≥18 years, and an ECOG performance status of 0­2 received 6 cycles of modified FOLFOX7 (5­FU/folinic acid and oxaliplatin) with aflibercept at 4 mg/kg every 2 weeks followed by maintenance therapy with fluoropyrimidine with aflibercept until disease progression or limiting toxicity. The reintroduction of oxaliplatin was performed at first progression. The primary endpoint was progression­free survival (PFS) at 6 months. From May, 2013 to May, 2014, 49 patients were included and 48 were evaluable for response. In total, 33 patients (67.4%) were alive without progression at 6 months. The Kaplan­Meier survival 6­month and 1­year PFS rates were 79.1 and 36.1%, respectively, and the median PFS was 9.3 months (95% CI, 8.3­12.5). The objective response rate was 59.2% (N=29/49). The most common (≥10%) grade 3­4 adverse events were hypertension (23%), fatigue (15%), neutropenia (12%), neuropathy (12%) and stomatitis (10%). Three (6%) treatment­related deaths occurred: One from stroke, one from pulmonary embolism and one from neutropenic sepsis. On the whole, this study demonstrates the efficacy of aflibercept in combination with an oxaliplatin­based regimen in the first­line therapy of patients with mCRC. A strict monitoring of blood pressure and immediate management of hypertension during therapy is mandatory.

Feasibility of Capecitabine and Oxaliplatin Combination Chemotherapy Without Central Venous Access Device in Patients With Stage III Colorectal Cancer.

BACKGROUND: 5-Fluorouracil and leucovorin plus oxaliplatin (FOLFOX) or capecitabine plus oxaliplatin (XELOX) is a standard adjuvant treatment for patients with stage III colon cancer (CC). Capecitabine is an oral fluoropyrimidine, and administration of oxaliplatin does not necessarily require the insertion of a central venous access device (CVAD). We evaluated the feasibility of XELOX without a CVAD as adjuvant treatment in patients with stage III CC. PATIENTS AND METHODS: We retrospectively studied prospectively collected data from patients with stage III CC treated with XELOX in the International Duration Evaluation of Adjuvant Chemotherapy French trial. Patients were divided into 2 groups: those with a CVAD and those with peripheral venous access (PVA), including patients who had and had not had a CVAD at the first cycle of chemotherapy. Chemotherapy without a CVAD was considered feasible if the patient received all cycles of adjuvant therapy without it. RESULTS: A total of 203 patients were included: 86 (43%) in the PVA group and 116 (57%) in the CVAD group. Of the 85 patients in the PVA group (1 patient was not treated), 69 (81.2%) did not require the insertion of a CVAD. However, 16 (18.8%) required CVAD insertion owing to systematic delay of the initially planned CVAD before the second cycle of chemotherapy in 7, complications related to PVA usage in 5, a switch to the modified FOLFOX6 regimen in 2, and other reasons in 2. The oxaliplatin dose was similar in both groups regardless of the chemotherapy duration. XELOX without a CVAD was feasible for 81.2% of the patients for whom a CVAD had not been planned before chemotherapy and for 88.4% of patients for whom chemotherapy was planned without the use of a CVAD. CONCLUSION: XELOX chemotherapy without a CVAD is a feasible approach for treating patients with stage III CC in the adjuvant setting.

PEPCOL: a GERCOR randomized phase II study of nanoliposomal irinotecan PEP02 (MM-398) or irinotecan with leucovorin/5-fluorouracil as second-line therapy in metastatic colorectal cancer.

A multicenter, open-label, noncomparative, randomized phase II study (PEPCOL) was conducted to evaluate the efficacy and safety of the irinotecan or PEP02 (MM-398, nanoliposomal irinotecan) with leucovorin (LV)/5-fluorouracil (5-FU) combination as second-line treatment in patients with metastatic colorectal cancer (mCRC). Patients with unresectable mCRC who had failed one prior oxaliplatin-based first-line therapy were randomized toirinotecan with LV/5-FU (FOLFIRI) or PEP02 with LV/5-FU (FUPEP; PEP02 80 mg/m(2) with LV 400 mg/m(2) on day 1 and 5-FU 2400 mg/m(2) on days 1-2). Bevacizumab (5 mg/kg, biweekly) was allowed in both arms. The primary endpoint was 2-month response rate (RR). Fifty-five patients were randomized (FOLFIRI, n = 27; FUPEP, n = 28). In the intent-to-treat population (n = 55), 2-month RR response rate was observed in two (7.4%) and three (10.7%) patients in the FOLFIRI and FUPEP arms, respectively. The most common grade 3-4 adverse events reported in the respective FOLFIRI and FUPEP arms were diarrhea (33% vs. 21%), neutropenia (30% vs. 11%), mucositis (11% vs. 11%), and grade 2 alopecia (26% vs. 25%). FUPEP has activity and acceptable safety profile in oxaliplatin-pretreated mCRC patients.

[The benefit of self-assessment in rehabilitation]. / Intérêt de l'auto-évaluation en réhabilitation.

The clinical stabilisation of the patient is a phase which is favourable for carrying out self-assessment to help them determine their resources. Adapted assessment scales are useful tools. On the basis of these, an initial care project is put in place which takes shape as and when the assessments are carried out. Ensuring the patient follows a therapeutic education programme aims particularly at improving their knowledge of their health.

[DNA mismatch repair and BRAF status in colorectal cancer: Interest for the therapeutic management?]. / Statuts MMR et BRAF dans les cancers colorectaux: intérêts pour la prise en charge thérapeutique?

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in France. Recently, colorectal cancer subtyping consortium (CRCSC) identified 4 consensus molecular subtypes (CMS). CMS1 is enriched for CRC with deficient DNA mismatch repair system (dMMR) and tumors with mutated BRAF. Intriguingly, CMS1 is characterized by better relapse-free survival but worse survival after relapse, compared with the other subtypes. In this review, we provide a comprehensive overview of prognostic and predictive impacts of MMR and BRAF status. We highlight immune checkpoints inhibitors as potentially future therapeutics for CRC with deficient MMR. We also focus on the management of BRAF mutant metastatic CRC, with a particular interest on targeted therapies.