[Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists]. / Intérêts et limites de la recherche du déficit en dihydropyrimidine déshydrogénase dans le suivi des patients traités par fluoropyrimidines : résultats de deux enquêtes nationales de pratiques réalisées auprès des médecins et des biologistes.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy.

Quality of life and cost of strategies of two chemotherapy lines in metastatic colorectal cancer: results of the FFCD 2000-05 trial.

Objectives: This study compared the cost and quality of life (QoL) of 407 advanced colorectal cancer patients, randomly assigned to receive LV5FU2 followed by FOLFOX6 (sequential strategy) or FOLFOX6 followed by FOLFIRI (combination strategy). Methods: Costs were compared from the French health insurance perspective, until the end of the second line of treatment. Consumed resources, collected during the trial, included medicines, hospitalizations, examinations, and transportation. Valuations were made using 2009 and 2016 tariffs. QoL was assessed using the QLQ-C30 questionnaire and clinically significant variations were searched. Results: In 2009, the mean cost per patient was significantly lower for the sequential strategy compared to the combination strategy (18,061€ and 23,119€, p = 0.001). In 2016, the difference was no longer significant (16,876€ and 18,090€, p = 0.41) because oxaliplatin and irinotecan became generics. The QoL analysis (292 patients) showed that there was significantly less improvement of global health status in the sequential strategy than in the combination strategy (29% and 42%; p = 0.02) during first-line therapy. No significant differences were observed for emotional functioning (p = 0.45) and physical functioning (p = 0.07) or during second-line therapy. Conclusion: The choice to treat patients with advanced colorectal cancer using one or the other strategy cannot be based on costs or QoL.

Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: Prognostic value and early assessment of therapeutic effects.

BACKGROUND: The identification of dynamic biomarkers in advanced gastric and oesogastric junction adenocarcinoma (GOA) could help to tailor strategies for each patient. Enumeration of circulating tumour cells (CTCs) is approved by the US Food and Drug Administration in breast, colon and prostate cancer but is not in advanced GOA. Our study aims to establish the optimal threshold and the clinical significance of CTC count in advanced GOA before and during treatment. METHODS: One hundred six patients with untreated advanced GOA were included in the ancillary study of the PRODIGE 17-ACCORD 20 trial. CTCs were detected in the peripheral blood using the CellSearch system on day 0 (D0) and day 28 (D28). The prognostic value of CTCs at D0 and D28 was analysed by testing several thresholds. RESULTS: At baseline, median CTC count was 1 (range, 0-415). While CTCs ≥1, 2 or 3 at D0 were all significantly associated with worse overall survival (OS) and progression-free survival (PFS), CTCs ≥2 were the optimal threshold, on D0 or D28. CTCs ≥2 at D28 were also predictive of disease control. Taking into account both D0 and D28 CTC count defined 3 groups (low/low, high/low and low-high/high) with significantly different PFS (p = 0.0002) and OS (p = 0.003). CONCLUSION: Quantification of CTCs at baseline and during treatment may be a useful prognostic tool in advanced GOA, as it is associated with worse PFS and OS. A threshold ≥2 CTCs seems to have the best discriminant value. Change in CTC count between baseline and D28 could help to tailor treatment to each individual patient.

The added value of quality of life (QoL) for prognosis of overall survival in patients with palliative hepatocellular carcinoma.

BACKGROUND & AIMS: Several prognostic classifications (PCs) have been developed for use in palliative care in patients with hepatocellular carcinoma (HCC). We have recently suggested that CLIP combined with WHO PS has the greatest discriminative power. We evaluated the prognostic value of quality of life (QoL) data and whether the latter could improve classification of palliative HCC patients. METHODS: This was a reanalysis from the CHOC trial with an evaluation of the discriminative power for overall survival (OS) of the established CLIP/GRETCH/BCLC/BoBar prognostic systems alone and then in association with each of the following groups of parameters: selected clinical factors, QoL as continuous variables, dichotomized QoL, selected clinical factors and continuous QoL, selected clinical factors and dichotomized QoL. Baseline QoL was assessed using the EORTC QLQ-C30. Discriminative power was evaluated with the Harrell's C-index and net reclassification improvement. RESULTS: Quality of life was available in 79% of the patients (n=271). Univariate analysis revealed that better role functioning (HR=0.991 [0.987-0.995]) and better physical functioning (0.991 [0.984-0.997]) scores were associated with longer survival. In contrast, poorer score for fatigue (1.011 [1.006-1.015]) and diarrhoea (1.008 [1.002-1.013]) were associated with shorter survival. After adjustment for clinical and sociodemographic variables, only better role functioning score (0.993 [0.988-0.998]) was associated with longer survival. Adding oedema, hepatomegaly, fatigue and diarrhoea QoL scales to CLIP resulted in the best performance. CONCLUSIONS: Our results confirm that QoL scales are independent prognostic factors of OS in palliative HCC patients. Incorporation of QoL data improved all the studied PCs.

Folliculitis induced by EGFR inhibitors, preventive and curative efficacy of tetracyclines in the management and incidence rates according to the type of EGFR inhibitor administered: a systematic literature review.

INTRODUCTION: Folliculitis is the most common side effect of epidermal growth factor receptor (EGFR) inhibitors (EGFRIs). It is often apparent, altering patients' quality of life and possibly impacting compliance. Variations in terms of the treatment-related incidence and intensity have not been fully elucidated. Tetracyclines have been recommended for the prophylaxis and treatment of folliculitis but their efficacy is yet to be established. MATERIALS AND METHODS: We carried out two systematic literature reviews. The first assessed the preventive and curative efficacy of tetracyclines. The second assessed the incidence of grade 3-4 folliculitis in the main clinical studies published. RESULTS: In four randomized studies, preventive tetracycline treatment was associated with a significantly lower incidence of grade 2-3 folliculitis and a better quality of life in three of the four studies. In curative terms, tetracycline efficacy was not evaluated in any randomized study, but an improvement in grade ≥2 folliculitis was reported in case series. The frequency and severity of folliculitis seem to be greater with the antibodies than with the tyrosine kinase inhibitors. Analysis restricted to lung cancer studies showed a statistically greater incidence in terms of grade 3-4 folliculitis with cetuximab (9%) and erlotinib (8%) than with gefitinib (2%) (p < .0001). CONCLUSION: Unless contraindicated, a tetracycline should be routinely prescribed prophylactically for patients treated with an EGFRI (level of evidence, B2). In curative therapy, the level of evidence for tetracycline efficacy is low (level of evidence, D). The incidence of grade 3-4 folliculitis induced by EGFRIs appears to be lower with gefitinib.

Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05.

PURPOSE: The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. RESULTS: The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5'UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5'UTR genotypes, respectively. Conversely, patients with the TS-5'UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). CONCLUSION: A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.

Assessment of baseline clinical predictive factors of response to cetuximab-irinotecan in patients with irinotecan-refractory metastatic colorectal cancer.

OBJECTIVE: To identify easily available predictive factors of response to cetuximab-irinotecan in patients with irinotecan-refractory metastatic colorectal cancer. METHODS: Retrospective analysis of patients treated with cetuximab (400 mg/m(2) in week 1, 250 mg/m(2) in subsequent weeks) plus irinotecan (180 mg/m(2) every 2 weeks). We assessed demographic data, prior response to chemotherapy, number of metastatic sites, disease and metastatic disease durations, irinotecan-free interval and tumoral immunohistochemical epidermal growth factor receptor status. RESULTS: We analyzed 311 patients. Objective response rate under cetuximab-irinotecan was 26%. In univariate analysis, prior response to irinotecan, presence of only 1 metastatic site, disease duration, metastatic disease duration and irinotecan-free interval equal or above median (24, 18 and 1.8 months, respectively) were predictive of response to cetuximab-irinotecan. Multivariate analysis confirmed independent predictive value of prior response to irinotecan, number of metastatic sites and disease duration. CONCLUSION: Prior response to irinotecan, number of metastatic sites and disease duration may contribute to better select patients suitable for cetuximab-irinotecan therapy.

Cost-effectiveness analysis of first-line chemotherapies in metastatic colorectal cancer. Results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 randomized trial.

BACKGROUND: The De Gramont regimen (or high-dose LV5FU2, HD-LV5FU2) is considered a standard treatment for metastatic colorectal cancer. The aim of the study was to evaluate the efficacy and the costs of three regimens as compared to HD-LV5FU2: raltitrexed (R), LV5FU2 with a lower dose of folinic acid (LD-LV5FU2), and weekly infusional 5FU (WI-FU). METHODS: An economic analysis was performed prospectively as part of a randomized trial comparing first-line chemotherapy regimens in 294 patients with unresectable metastatic colorectal cancer. The primary endpoint was event-free survival (EFS). Direct medical costs were computed from the health system viewpoint using 2001 unit costs. RESULTS: None of the three regimens improved EFS as compared to HD-LV5FU2. R was less effective and more toxic. The mean total cost per patient was euro 15,970 for HD-LV5FU2. The cost of R (10,687 euro) was lower than that of HD-LV5FU2 (p = 0.008). The cost of LD-LV5FU2 (14,888 euro) and of WI-FU (13,760 euro) was not significantly different from that of HD-LV5FU2. CONCLUSION: The lower efficacy and increased toxicity of R made it a clinically inferior regimen despite its easy administration and lower cost. The HD-LV5FU2 protocol remains a better treatment. LD-LV5FU2 appeared a good alternative regimen because it reduced costs without jeopardizing its efficacy. The WI-FU regimen did not show a significant difference in terms of efficacy, but suggested toxicity to be slightly increased.