FOLFIRI Plus Durvalumab With or Without Tremelimumab in Second-Line Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: The PRODIGE 59-FFCD 1707-DURIGAST Randomized Clinical Trial.

Importance: Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited. Ojectives: To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma. Design, Setting, and Participants: The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy. Intervention: Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023. Main outcome and Measures: The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators. Results: Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%). Conclusions and Relevance: Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03959293.

Prognostic score for synchronous metastatic rectal cancer: A real-world study.

BACKGROUND: Prognostic factors of metastatic rectal cancer are not well known. AIM: The objective of this study was to identify prognostic factors of overall survival (OS) in a cohort of patients with non-resectable synchronous metastatic rectal cancer. METHODS: Patients were retrospectively enrolled from 18 French centres. Univariate and multivariate analyses were performed to identify prognostic factors for OS. A simple score was derived from this a development cohort RESULTS: A total of 243 patients with metastatic rectal cancer were included in the study. Median OS was 24.4 months, 95% CI [19.4-27.2]. Among patients with non-resected metastases (n=141), six independent prognostic factors associated with better OS were identified in multivariate analysis: primary tumour surgery, WHO score 0-1, middle or upper rectal tumour, lung metastases only, systemic chemotherapy and targeted agent in first line. A prognostic score individualized three groups, each factor counting for one point in the score (<3, = 3 et > 3). Their median OS were respectively 27.9 months, 95% CI [21.7-35.1], 17.1 months [11.9-19.7] (HR2/1=2.08, 95%, CI [1.31-3.30], p2/1=0.002) and 9.1 months [4.9-11.7] (HR3/2=2.32, 95% CI [1.38-3.92], p3/2=0.001). CONCLUSION: A prognostic score for non-resectable synchronous metastatic rectal cancer can be proposed to classify patients in three prognostic groups.

Anal ulcerations in Crohn's disease: Natural history in the era of biological therapy.

BACKGROUND: The natural history of anal ulcerations in Crohn's disease remains unknown. AIMS: To assess the long-term outcomes of anorectal ulcerations. METHODS: Data from consecutive patients with perineal Crohn's disease were prospectively recorded. The data of patients with anal ulceration were extracted. RESULTS: Anal ulcerations were observed in 154 of 282 patients (54.6%), and 77 cases involved cavitating ulcerations. The cumulative healing rates were 47%, 70% and 82% at 1, 2 and 3 years, respectively. Patients with a primary fistula phenotype had a shorter median time to healing of their anal ulceration (28 [13-83] weeks) than those with a stricture (81 [28-135] weeks) or those with isolated ulceration (74 [31-181] weeks) (p=0.004). Among patients with ulcerations but no fistula at referral (n=67), only 4 (6%) developed de novo abscesses and/or fistula during follow-up. There was no benefit associated with introducing or optimising biologics, nor with combining immunosuppressants and biologics. CONCLUSION: Anal ulceration in Crohn's disease usually requires a long time to achieve sustained healing. Determining the impact of biologics on healing rates will require dedicated randomised trials although it does not show a significant healing benefit in the present study.

Gemcitabine as second-line chemotherapy after Folfirinox failure in advanced pancreatic adenocarcinoma: A retrospective study.

BACKGROUND: Pancreatic adenocarcinoma (PA) is diagnosed in most cases at an advanced stage requiring chemotherapy. Folfirinox is the standard first-line treatment. After Folfirinox failure, gemcitabine alone is routinely used as second-line therapy without data supporting this attitude. AIM: Determine the response rate and outcome of patients with advanced PA treated with gemcitabine after Folfirinox failure. METHODS: We retrospectively analyzed all consecutive patients treated with gemcitabine after Folfirinox failure for a locally advanced or metastatic PA between 2009 and 2015. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Response rate, control rate and tolerability were assessed. RESULTS: 96 patients were included (male, 51%; median age, 62; performance status (PS) 0-1, 47%). Median duration on gemcitabine was 2.1 months. The overall disease control rate was 40%. Median OS was 3.7 months (95%CI: 2.5-5.2) and median PFS was 2.1 months (95%CI: 2.0-2.6). Reasons for treatment discontinuation were mostly progression (51%). Age at diagnosis and PS were independently associated with OS in multivariate analysis (HR of 1.86; p=0.0055 and 2.42; p<0.0001 respectively). 34 patients experienced a grade 3 adverse event. CONCLUSIONS: This study suggests that gemcitabine is not beneficial to all patients failing on Folfirinox first-line therapy and should be restricted to young patients with good PS.

High-grade anal intraepithelial neoplasia: Progression to invasive cancer is not a certainty.

BACKGROUND: The incidences of high-grade anal intraepithelial neoplasia (HSIL) and superficially invasive squamous cell carcinomas (SISCCA) related to human papillomavirus (HPV) have increased. These lesions can progress to invasive anal cancer. The aim of the study was to assess the clinical outcome with a special focus on the healing rate. METHODS: Forty-six consecutive patients (M/F: 35/11; HIV+: 30) with histologically proven HSIL lesions (N=41) or SISCCA (N=5) were enrolled in a follow-up survey. RESULTS: Of the 46 patients, 40 were treated by excision (n=9), electrocoagulation (n=13), topical treatment (n=2) or combined strategies (n=16). After a mean follow-up of 35 (27-43) months, only one patient progressed to an invasive cancer. Regression and healing were observed in 14 (30%) and 15 (33%) patients. The cumulative probabilities of healing were 14%, 49% and 74% after 1, 3 and 5 years. None of the current smokers healed. Heterosexual patients, sexual abstinence, patients older than 44 years old, non-smokers, patients without any past history of condyloma and those with less than 2 high-risk HPVs at baseline were more likely to heal. CONCLUSION: Progression to invasive cancer is a rare event. Large, prospective cohort studies are needed to plan coherent strategies for both follow-up and treatment.

Risk factors for Raynaud's phenomenon in the workforce.

OBJECTIVE: To assess the prevalence of and risk factors for Raynaud's phenomenon (RP) in a French working population characterized by various levels of exposure to work-related constraints. METHODS: The study population comprised 3,710 workers (2,161 men and 1,549 women) who were followed up by 83 occupational physicians and were representative of the region's workforce. RP, as diagnosed by a questionnaire and a standardized interview, was defined as the occurrence of at least occasional attacks of finger blanching triggered by exposure to environmental cold during the previous 12 months. Personal factors and work exposure were assessed by self-administered questionnaires. The associations between RP and personal and occupational factors were analyzed using logistic regression modeling. RESULTS: A total of 87 cases of RP (56 women and 31 men) were diagnosed. The population-based annual prevalence rates of RP were 3.6% (95% confidence interval [95% CI] 2.7-4.5%) for women and 1.4% (95% CI 0.9-1.9%) for men. Women had a higher risk of RP (odds ratio [OR] 2.1 [95% CI 1.3-3.4]) and the risk decreased continuously with body mass index (OR for 1-kg/m(2) increment 0.87 [95% CI 0.81-0.94]). The risk of RP increased consistently but moderately with age after 35 years (ORs ranging from 2.0 [95% CI 1.1-3.8] to 2.9 [95% CI 1.6-5.2]). Among the work-related factors studied, RP was associated with an exposure to a cold environment or objects (OR 2.2 [95% CI 1.0-4.6]), a high repetitiveness of a task (OR 1.7 [95% CI 1.0-2.7]), a high psychological demand at work (OR 1.7 [95% CI 1.0-2.7]), and low support from supervisors (OR 2.4 [95% CI 1.5-3.8]). CONCLUSION: Personal and work-related factors were associated with RP, with a clear difference between the sexes. Work-related psychosocial stressors played a significant role independently of biomechanical and environmental exposure.