Individual Fluorouracil Dose Adjustment in FOLFOX Based on Pharmacokinetic Follow-Up Compared With Conventional Body-Area-Surface Dosing: A Phase II, Proof-of-Concept Study

BackgroundTo compare the efficacy and safety of pharmacokinetically (PK) guided fluorouracil (5-FU) dose adjustment vs. standard body-surface-area (BSA) dosing in a FOLFOX (folinic acid, fluorouracil, oxaliplatin) regimen in metastatic colorectal cancer (mCRC). Patients And Methods A total of 118 patients with mCRC were administered individually determined PK-adjusted 5-FU in first-line FOLFOX chemotherapy. The comparison arm consisted of 39 patients, and these patients were also treated with FOLFOX with 5-FU by BSA. For the PK-adjusted arm 5-FU was monitored during infusion, and the dose for the next cycle was based on a dose-adjustment chart to achieve a therapeutic area under curve range (5-FUODPM Protocol). Results The objective response rate was 69.7% in the PK-adjusted arm, and median overall survival and median progression-free survival were 28 and 16 months, respectively. In the traditional patients who received BSA dosage, objective response rate was 46%, and overall survival and progression-free survival were 22 and 10 months, respectively. Grade 3/4 toxicity was 1.7% for diarrhea, 0.8% for mucositis, and 18% for neutropenia in the dose-monitored group; they were 12%, 15%, and 25%, respectively, in the BSA group. Conclusions Efficacy and tolerability of PK-adjusted FOLFOX dosing was much higher than traditional BSA dosing in agreement with previous reports for 5-FU monotherapy PK-adjusted dosing. Analysis of these results suggests that PK-guided 5-FU therapy offers added value to combination therapy for mCRC

Évolution des cancers de l’œsophage : impact de la stratégie thérapeutique

PURPOSE: To assess the outcome of esophageal cancer according to therapeutic strategy. PATIENTS AND METHODS: One-hundred and twenty patients with esophageal cancer treated by an association of radiotherapy and chemotherapy and possibly surgery, between 2004 and 2010, were retrospectively studied. The first site of relapse was classified as follows: local (tumour), locoregional (tumour and/or nodal: celiac, mediastinal, sus-clavicular) or metastatic. RESULTS: With a 15.7-months (1.4-62) median follow-up, there were 89 deaths and 79 recurrences. Three types of treatments were performed: 50Gy exclusive chemoradiotherapy (47 patients) or 50 to 65Gy exclusive chemoradiotherapy (44 patients) or chemoradiotherapy followed by surgery (27 patients). The local first relapse was as much frequent as distant relapse (50 patients). With a-5cm margin up and down to the tumour, there was only one nodal relapse. Two-year survival was 39.5% (95% confidence interval [IC]: 30.5-40.8) and relapse-free survival was 26.5% (CI: 18.6-35). Multivariate analysis revealed that treatment type and disease stage had a significant impact on survival, relapse-free survival and locoregional control. Compared to exclusive chemoradiotherapy, surgery improved locoregional control (40.2 versus 8.7 months, P=0.0004) but in a younger population. Despite postoperative mortality, the gain was maintained for distance relapse-free survival (40.2 versus 10 months, P=0.0147) and overall survival (29.3 versus 14.2 months, P=0.0088). Compared to 50Gy chemoradiotherapy, local control was improved if high dose chemoradiotherapy was performed (13.8 versus 7.5 months, P=0.05) but not overall survival (14.0 versus 15.4 months, P=0.24). CONCLUSION: More than one-third relapse is local. Locoregional control is better with high dose chemoradiotherapy. In this study, surgery performed in selected patients only, improved locoregional control, relapse-free disease and overall survival

Apport de la TEP-FDG dans le staging initial des cancers du sein localement avancés traités par chimiothérapie néo-adjuvante

L’atteinte ganglionnaire axillaire et la présence de métastases à distance sont des facteurs pronostiques majeurs dans la prise en charge du cancer du sein. L’objectif de notre travail a été d’évaluer les performances de la TEP-FDG dans le bilan initial de cancers du sein localement avancés (CSLA) traités par chimiothérapie néo-adjuvante (CNA) et chirurgie, et de comparer les données de la TEP préthérapeutique à celles de l’histologie du curage réalisé après CNA (classification de Sataloff). Cette étude rétrospective a concerné 89 patientes porteuses d’un CSLA, explorées avant mise en route de la CNA par une TEP en complément du bilan d’extension standard (BS). Toutes les patientes ont bénéficié après CNA d’une tumorectomie/mastectomie et d’un curage axillaire. Une atteinte axillaire a été retrouvée chez 58 patientes (65 %) par la TEP et 39 patientes (44 %) par le BS. Comparées à l’histologie du curage axillaire post-CNA, les sensibilité et spécificité de la TEP ont été calculées à 80 % et 63 %. La TEP a révélé une atteinte ganglionnaire extra-axillaire, non suspectée par le BS, chez 25 patientes (28 %). Des lésions métastatiques méconnues par le BS ont été découvertes au niveau osseux chez deux patientes et pulmonaire chez une patiente. Un cas de faux-positif TEP hépatique a été observé (adénomatose). Cette étude confirme l’intérêt de la TEP dans le staging initial des CSLA, notamment au niveau ganglionnaire extra-axillaire. Au niveau axillaire, une TEP positive suggère fortement une atteinte métastatique ; les cas d’interprétation douteuse incitant à réaliser en complément une cytoponction échoguidée

Molecular markers of response and toxicity to FOLFOX chemotherapy in metastatic colorectal cancer

BACKGROUND: To investigate three genetic alterations (TP53 mutation, Kras mutation and microsatellite instability (MSI)) and three polymorphisms (methylene tetrahydrofolate reductase (MTHFR) C677T, excision repair cross complementing group 1 (ERCC1)-118 and X-ray repair cross complementing group 1 (XRCC1)-399) for their ability to predict response, survival and toxicity to FOLFOX first line chemotherapy in the treatment of metastatic colorectal cancer (mCRC). METHODS: Tumour tissues from 118 mCRC patients who underwent FOLFOX treatment from three successive phase II trials were evaluated for mutations in TP53 (exons 5–8) and Kras (codons 12 and 13) and for MSI using PCR-based analysis. Genotyping for common single nucleotide polymorphisms in the MTHFR (codon 677), ERCC1 (codon 118) and XRCC1 (codon 399) genes was also carried out using PCR techniques. These genetic markers were correlated with clinical response, survival and toxicity to treatment. RESULTS: Patients with the T allele of ERCC1-118 showed significantly worse progression-free survival in univariate analysis (HR 2.62; 95 % CI 1.14–6.02; P 0.02). None of the genetic alterations or polymorphisms showed significant association with clinical response to FOLFOX. The MTHFR, ERCC1 and XRCC1 polymorphisms showed no associations with overall haematological, gastrointestinal or neurological toxicity to FOLFOX, although MTHFR 677 TT genotype patients showed a significantly higher incidence of grade 3 or 4 diarrhoea (26%) compared with CC or CT genotype patients (6%, P 0.02). CONCLUSIONS: The ERCC1-118 and MTHFR C677T polymorphisms were associated with progression and severe diarrhoea

Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5′UTR and 3′UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3–4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome

Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer

Background:There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study.Methods:The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed.Results:MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C–1298C) and diplotypes (CA–TA and TA–TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response.Conclusion:MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug

Edward Said on Popular Music

Although Edward Said, generally known as one of the founders of postcolonial studies, has written extensively on music, he almost completely ignores popular music. However, the few moments in which he does reflect on popular music are highly revealing. In this article I provide a comprehensive overview and a critical analysis of Said’s public statements on popular music, and argue that these strongly create dissonance with his interventions in postcolonial theory and politics. More specifically, I argue that in these reflections on popular music Said voices problematic elitist, orientalist, and universalist claims. Consequently, Said’s notion of popular music constitutes perhaps the most antagonistic aspect of his oeuvre

Facteurs influençant le retour au travail et le maintien en emploi après un cancer du sein

International audienceObjectifL’âge et le taux de guérison chez les femmes atteintes d’un cancer du sein font que la question du retour à l’emploi se pose fréquemment. L’objectif de l’étude était d’analyser les obstacles et les facteurs favorisant le retour au travail 2 ans après le traitement pour cancer du sein.MéthodeÉtude rétrospective, par auto-questionnaire postal chez les femmes âgées de 18 à 55 ans, traitées à l’Institut de cancérologie de l’ouest pour un cancer du sein entre 2009 et 2011, en rémission. Analyses statistiques des facteurs sociodémographiques, médicaux et professionnels influençant le retour au travail.RésultatsNous avons reçu 215 questionnaires exploitables (taux de réponse de 55,5 %). Deux ans après la fin du traitement, 91 % des femmes étaient au travail (médiane d’arrêt = 410 jours). Parmi les femmes ayant repris à temps partiel thérapeutique, 86 % avaient rencontré le médecin du travail alors que seulement 25 % des femmes ayant continué à travailler l’ont rencontré pendant le traitement. Les facteurs favorisant la reprise du travail étaient le sentiment de capacité de travailler (p = 2 × 10−8), la reprise à temps partiel thérapeutique (p < 0,001), le fait de vivre en couple (p < 0,05) et la peur de perte de revenu (p < 0,01). Les facteurs limitant étaient le licenciement (p = 2 × 10−8), l’appréhension à la reprise (p < 0,001), la précarité de l’emploi (p < 0,05), le curage ganglionnaire (p < 0,05) et l’âge inférieur à 50 ans (p < 0,01).DiscussionLa coordination de la prise en charge médicale et socioprofessionnelle doit impliquer le médecin du travail pour favoriser la transition entre les milieux du soin et du travail