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.

Effect of Adapted Physical Activity in Patients With Advanced Pancreatic Cancer: The APACaP GERCOR Randomized Trial.

BACKGROUND: The impact of adapted physical activity (APA) on health-related quality of life (HRQoL) in patients with advanced pancreatic ductal adenocarcinoma (aPDAC) is unknown. This study evaluated whether APA in addition to standard care improved HRQoL in patients who have aPDAC who are receiving first-line chemotherapy. PATIENTS AND METHODS: Patients with locally advanced/metastatic PDAC and an ECOG performance status of 0 to 2 were randomized (1:1) to receive standard care (standard arm) or standard care plus a home-based 16-week APA program (APA arm). The primary objective was the effect of the APA program on 3 dimensions of the EORTC QLQ-C30: global health status, physical function, and fatigue at week 16 (W16), with a one-sided type I error of 0.017 for each dimension. The primary HRQoL analysis was performed in patients with available baseline and W16 scores for the dimensions (ie, the modified intention-to-treat population 1 [mITT1]), and secondary longitudinal HRQoL analyses using the mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD) methods were performed in the mITT1 population and in patients with baseline and at least one follow-up questionnaire (mITT2 population). A difference of ≥5 points was considered to be clinically relevant. RESULTS: Of 326 included patients, 313 were randomized to the standard (n=157) or APA (n=156) arms. In the mITT1 population (n=172), the mean differences in global health status, physical function, and fatigue at W16 adjusted from baseline were -0.98 (SD, 23.9; P=.39), -2.08 (SD, 21.3; P=.26), and 4.16 (SD, 29.2; P=.17), respectively, showing a non-statistically significant benefit with APA. In the mITT2 population (n=259), APA was associated with statistically significant and clinically relevant improvement in 5 and 8 dimensions of the HRQoL in the longitudinal MMRM and TUDD analyses, respectively. CONCLUSIONS: APA improved several dimensions of HRQoL in patients with aPDAC receiving first-line chemotherapy and standard care.

Performance of a blood-based RNA signature for gemcitabine-based treatment in metastatic pancreatic adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, and chemotherapy is a key treatment for advanced PDAC. Gemcitabine chemotherapy is still an important component of treatment; however, there is no routine biomarker to predict its efficacy. Predictive tests may help clinicians to decide on the best first-line chemotherapy. Methods: This study is a confirmatory study of a blood-based RNA signature, called the GemciTest. This test measures the expression levels of nine genes using real-time polymerase chain reaction (PCR) processes. Clinical validation was carried out, through a discovery and a validation phases, on 336 patients (mean 68.7 years; range, 37-88 years) for whom blood was collected from two prospective cohorts and two tumor biobanks. These cohorts included previously untreated advanced PDAC patients who received either a gemcitabine- or fluoropyrimidine-based regimen. Results: Gemcitabine-based treated patients with a positive GemciTest (22.9%) had a significantly longer progression-free survival (PFS) {5.3 vs. 2.8 months; hazard ratio (HR) =0.53 [95% confidence interval (CI): 0.31-0.92]; P=0.023} and overall survival (OS) [10.4 vs. 4.8 months; HR =0.49 (95% CI: 0.29-0.85); P=0.0091]. On the contrary, fluoropyrimidine-based treated patients showed no significant difference in PFS and OS using this blood signature. Conclusions: The GemciTest demonstrated that a blood-based RNA signature has the potential to aid in personalized therapy for PDAC, leading to better survival rates for patients receiving a gemcitabine-based first-line treatment.

Desmoid tumors located in the abdomen or associated with adenomatous polyposis: French intergroup clinical practice guidelines for diagnosis, treatment, and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, SFR).

INTRODUCTION: Desmoid tumor (DT) of the abdomen is a challenging and rare disease. The level of evidence available to document their treatment is relatively low, however, recent publications of prospective studies have allowed to precise their management. METHODS: This document is a summary of the French intergroup guidelines realized by all French medical and surgical societies involved in the management of DT located in the abdomen or associated with adenomatous polyposis. Recommendations are graded in four categories (A, B, C and D), according to the level of evidence found in the literature until January 2021. RESULTS: When the diagnosis of DT is suspected a percutaneous biopsy should be performed when possible. A molecular analysis looking for pathogenic mutations of the CTNNB1 and APC genes should be systematically performed. When a somatic pathogenic variant of the APC gene is present, an intestinal polyposis should be searched. Due to a high rate of spontaneous regression, non-complicated DT should first benefit from an active surveillance with MRI within 2 months after diagnosis to assess the dynamic of tumor growth. The treatment decision must be discussed in an expert center, favoring the less toxic treatments which can include broad spectrum tyrosine kinase inhibitor or conventional chemotherapy (methotrexate-vinblastine). Surgery, outside the context of emergency, should only be considered for favorable location in an expert center. CONCLUSION: French guidelines for DT management were elaborated to help offering the best personalized therapeutic strategy in daily clinical practice as the DT therapeutic landscape is complexifying. Each individual case must be discussed within a multidisciplinary expert team.

SOCRATE-PRODIGE 55 trial: A randomized phase II study to evaluate second-line ramucirumab alone or with paclitaxel in older patients with advanced gastric cancer.

INTRODUCTION: Patients ≥ 70 years old constitute 40% of patients with advanced gastric cancer (GC). Ramucirumab plus Paclitaxel is a therapeutic option validated in the second-line treatment of advanced GC, but as older patients are at higher risk of severe toxicity, due to comorbidities and/or frailty, we aimed to evaluate second-line Ramucirumab alone or combined with Paclitaxel in terms of overall survival (OS) and quality of life (QoL) in patients ≥ 70 years-old with advanced GC. METHODS: In this multicenter, randomized, open-label, non-comparative, prospective phase II clinical trial, the main inclusion criteria are: patients ≥ 70 years old, with advanced GC having progressed after first-line chemotherapy or in the six months following the last administration of adjuvant chemotherapy, with WHO performance status <2. They are randomized to receive either ramucirumab alone (arm A) or ramucirumab plus Paclitaxel (arm B). The primary endpoint is 6-month OS and QoL evaluated with the EORTC QLQ-ELD14 questionnaire. The secondary endpoints include other parameters of QoL, time to definitive deterioration (TTDD) in QoL and TTDD in autonomy, treatment toxicities, other parameters of survival and disease control, identification of geriatric and nutritional prognostic scores and predictive factors of treatment safety and efficacy. OS of 60% is expected at 6 months (H0:40%). Using a Simon-minimax design, with one-sided α risk of 2% and 80% power for OS, and considering 5% lost to follow-up, it is necessary to randomize 56 patients in each arm. PERSPECTIVES: As older patients are at higher risk of chemotherapy toxicity, ramucirumab alone could be an interesting alternative to Paclitaxel plus ramucirumab, as a second-line therapy for patients ≥ 70 years old with advanced GC, and needs to be evaluated.

[Familial adenomatous polyposis, desmoid tumors and Gardner syndrome]. / Polypose adénomateuse familiale, tumeurs desmoïdes et syndrome de Gardner.

About 15 % of patients with familial adenomatous polyposis "PAF" develop one or more desmoid tumors in their lifetime. These are benign mesenchymal tumors with local aggressivity but with no potential for metastases. Most of the desmoids tumors result from a sporadic genetic anomaly in the ß catenin gene. When related to familial adenomatous polyposis or "PAF", this mutation is not present, and the patients must be sent in genetic counselling. The PAF is a dominant autosomic illness related to a germinal mutation in the APC gene. Sometimes, these tumors can be the first manifestation of the illness. The diagnosis in a context of PAF can be easily done by imaging, but a pathological confirmation is needed. These tumors raise a therapeutic problem because of their heterogeneity and the absence of predictive biomarkers along illness evolution. The identification of prognostic biological and clinical factors would make easier the selection of patients requiring first-line treatment, as spontaneous remissions have also been observed in patients with FAP whom which an active surveillance could also be a valid therapeutic option. The particularity of desmoids tumors associated to PAF lies in their predominantly intra-abdominal location and the risk of complication. In the last ten years, surgery has largely given way to conservative treatments such as chemotherapy and more recently to tyrosine kinase inhibitors that have shown their efficacy with a significant improvement in progression-free survival of patients.

Inclusion of Older Patients with Cancer in Clinical Trials: The SAGE Prospective Multicenter Cohort Survey.

BACKGROUND: The primary objective was to evaluate the rates of older patients with colorectal cancer (CRC) who were eligible for a clinical trial, invited to participate, and, ultimately, included. The secondary objective was to assess the reasons for ineligibility, noninvitation, and noninclusion and factors associated. MATERIALS AND METHODS: The Sujets AGés dans les Essais Cliniques (SAGE; Older Subjects in Clinical Trials) multicenter prospective cohort was established in seven centers (10 departments of medical oncology, digestive oncology, and digestive surgery) between 2012 and 2016. All patients with CRC aged 65 or older were studied. The endpoints were clinical trial availability, patient's eligibility, invitation, and enrollment in a trial. RESULTS: We included 577 older patients (mean age ± SD: 75.6 ± 7 years; males: 56%; metastasis: 41%). Thirty-seven trials were ongoing (one trial for older patients). Of the 474 patients with at least one available trial for their cancer stage and site, 127 (27%) were eligible; 84 of these 127 (66%) were invited to participate, and 70 of these 84 (83%) were included. In a multivariate analysis, noninvitation was found to be associated with older age (p = .016): adjusted relative risk (95% confidence interval), 0.14 (0.02-0.60) for ≥80 vs. 65-69; 0.54 (0.18-1.04) for 75-79 vs. 65-69; 0.47 (0.17-0.93) for 70-74 vs. 65-69. CONCLUSION: Three-quarters of older patients with CRC were ineligible for a clinical trial. One-third of the eligible patients were not invited to participate in a trial, and 17% of invited patients were not included. Few trials are reserved for older patients. Patients aged 80 or older were significantly less likely to be eligible for a trial and invited to participate. Clinical trial identification number: NCT01754636. IMPLICATIONS FOR PRACTICE: The results of this study suggest that barriers to participation of older patients in clinical trials are particularly marked at age 80 years or older. Secondly, the results emphasize the need for trials for older patients. Thirdly, there is also a need for more pragmatic "real-world" trials, rather than solely randomized trials performed in idealized settings with strictly selected patients. Large prospective observational cohorts with a precise follow-up of toxicity, functional decline, and quality of life may constitute one way of generating more data on the risk-benefit ratio for cancer treatments in older patients.

[Cardiac and vascular toxicity of chemotherapies]. / Toxicité cardiaque et vasculaire des chimiothérapies.

Cardiac and vascular toxicity of chemotherapies. Cardiovascular complications due to oncologic management are multiple including left ventricular systolic dysfunction, acute myocarditis, hypertension, and QT interval prolongation. Their frequencies are variable depending on the drugs administered. Anthracycline, molecular targeted agents and immune check points inhibitors could lead to left ventricular systolic dysfunction. Anthracyclines could provoke left ventricular systolic dysfunction, which is considered in most of cases as dose-dependent, cumulative and generally irreversible (type 1 toxicity). Targeted molecular agents could lead to left ventricular systolic dysfunction and/or congestive heart failure, which does not appear to be dose dependent, usually reversible at the cessation of treatment and/or the introduction of a cardio-protective treatment (type 2 toxicity).

Toxicité cardiaque et vasculaire des chimiothérapies. Les complications cardiovasculaires secondaires aux prises en charge oncologiques sont multiples, comprenant les dysfonctions systoliques du ventricule gauche et/ou l'insuffisance cardiaque, les myocardites aiguës, l'hypertension artérielle, et l'allongement de l'intervalle QT. Les fréquences et de mécanismes de ces toxicités sont variables, dépendant de la chimiothérapie administrée. Les anthracyclines peuvent entraîner une dysfonction systolique du ventricule gauche et/ou une insuffisance cardiaque ; cette toxicité est considérée comme dépendant de la dose, cumulative et en général irréversible - toxicité de type 1. Les thérapies moléculaires ciblées peuvent entraîner une dysfonction systolique du ventricule gauche, qui ne semble pas être dépendante de la dose administrée, le plus souvent réversible à l'arrêt du traitement et/ou à l'instauration d'un traitement cardioprotecteur adapté - toxicité de type2.

[Nab-paclitaxel]. / Le nab-paclitaxel.

Paclitaxel is conventionally used in a wide range of oncology indications. Nab-paclitaxel is synthesized by a process of high pressure homogenization of paclitaxel in the presence of human albumin and it was originally developed to reduce the toxicity usually associated with cremophor in soluble paclitaxel and to increase its penetration in tumor tissues. After the trials that led to its approval in first-line treatment of metastatic pancreatic carcinomas and in second line therapy for metastatic breast cancer, nab-paclitaxel is being tested for many other situations in oncology due to its profile of security and its good tolerance. Different lines of research are being developed about the possible biomarkers that could predict the effect of nab-paclitaxel. This review summarizes the results of trials that led to the approval of the nab-paclitaxel in advanced breast cancer and pancreatic cancer, and also resumes the lines of research to the future development of the drug.