No abstract

No abstract

No abstract

Purpose: Oxaliplatin displays a frequent dose-limiting neurotoxicity due to its interference with neuron voltage-gated sodium channels through one of its metabolites, oxalate, a calcium chelator. Different clinical approaches failed in neurotoxicity prevention, except calcium-magnesium infusions. We characterized oxalate outcome following oxaliplatin administration and its interference with cations and amino acids. We then looked for genetic predictive factors of oxaliplatininduced neurotoxicity.Experimental Design: We first tested patients for cations and oxalate levels and did amino acid chromatograms in urine following oxaliplatin infusion. In the second stage, before treatment with FOLFOX regimen, we prospectively looked for variants in genes coding for the enzymes involved (a) in the oxalate metabolism, especially glyoxylate aminotransferase (AGXT), and (b) in the detoxification glutathione cycle, glutathione S-transferase k, and for genes coding for membrane efflux proteins (ABCC2). Results: In the first 10 patients, urinary excretions of oxalate and cations increased significantly within hours following oxaliplatin infusion, accompanied by increased excretions of four amino acids (glycine, alanine, serine, and taurine) linked to oxalate metabolism. In a further 135 patients, a minor haplotype of AGXT was found significantly predictive of both acute and chronic neurotoxicity. Neither glutathione S-transferase k nor ABCC2 single nucleotide polymorphisms we looked for were linked to neurotoxicity. Conclusion: These data confirm the involvement of oxalate in oxaliplatin neurotoxicity and support the future use of AGXTgenotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity.Oxaliplatin, a platinum-based chemotherapeutic agent with a 1,2-diaminocyclohexane (DACH) carrier ligand, displays a characteristic pattern of neurotoxicity, which is the most frequent dose-limiting toxicity, with an acute onset of distal dysesthesia and/or paresthesia, induced or exacerbated by cold and prolonged muscular contraction after a voluntary contraction. Although these symptoms that occur during or short after infusion are transient and generally mild, when treatment is continued, a persistent sensory peripheral neuropathy can develop, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment (1). The mechanism of chronic neurotoxicity evoked by some authors is close to that of cisplatin-being the progressive accumulation of a heavy metal, the DACH platin, in neurons and the implication of the detoxication system of glutathione (2).However, clinical neurophysiologic examinations and nerve biopsy studies have shown that patients displaying sensory symptoms have no signs or very mild signs of axonal degeneration (1). Oxaliplatin has a direct ''pharmacologic'' effect on the excitability of sensory neurons and muscle cells that has not previously been described with other platinum agents (3). Furthermore, the acute symptoms induced by oxaliplati...

Background Low-level laser therapy (LLLT) also called Photobiomodulation therapy (PBMT) could reduce oral mucositis (OM) incidence and severity in head and neck cancer patients treated by chemoradiotherapy, however randomised data about efficacy and safety are missing with curative dose 4 J/cm 2 . Methods This phase III trial was conducted in patients with oral cavity, or oro/hypopharyngeal cancers (stage III or IV). Patients were treated by lasertherapy on OM lesions grade ≥ 2 (4 J/cm 2 or placebo), during chemoradiotherapy and until recovery. Severity of OM (incidence and duration of grades ≥3) was used as primary endpoint and blindly assessed. Results Among 97 randomised patients, 83 patients (85.6%) could be assessed finally (erroneous inclusions, chemoradiotherapy interruptions) and 32 patients had no lasertherapy because of unreachable OM lesions. Randomisation and population characteristics (sex ratio, age, chemoradiotherapy procedures, toxicities incidence) were still comparable between the two LLLT/PBMT groups. An acute OM (grade ≥ 3) was observed in 41 patients (49.4%): 23 patients (54.8%) of the active laser group versus 18 (43.9%) in the control group (modified intend to treat, p = 0.32). Median time before occurrence of OM ≥ grade 3 in half of the patients was 8 weeks in active laser group (vs. 9 weeks in control group). However, 95% of patients exhibited a very good tolerance of LLLT/PBMT. Conclusions This study assessed LLLT/PBMT according to the Multinational Association of Supportive care in Cancer recommendations but lacked power. LLLT/PBMT was well tolerated with a good safety profile, which promotes its use in clinical routine for severe OM treatment. Trial registration ClinicalTrials.gov Identifier: NCT01772706 . Title: Laser Mucite ORL: Effectiveness of Laser Therapy for Mucositis Induced by a Radio-chemotherapy in Head and Neck Cancer (LaserMucite). Study Start Date: October 2008. Primary Completion Date: October 2016. Responsible Party: Institut de Cancérologie de l’Ouest – Paul Papin. Principal Investigator: Eric Jadaud, M.D., Institut de Cancérologie de l’Ouest – Paul Papin. Funding: French Ministry of Health, French national funding scheme (PHRC 2008).

No abstract

The purpose of this study was to determine simple genetic factors helpful to tailor 5-FU administration and determine strategy in first-line chemotherapy of advanced colorectal cancer. In 76 patients initially treated by 5-FU, thymidylate synthase, dihydropyrimidine dehydrogenase and methylene tetrahydrofolate reductase germinal polymorphisms, dihydrouracil/uracil plasma ratio and 5-FU plasma clearance were investigated and correlated for tolerance (10.5% grade 3 and 4 toxicity) and efficacy (32.9% objective response rate and 20 months median overall survival time). Toxicity was linked to performance status 42 (P ¼ 0.004), low UH 2 /U ratio, 2846 A4T, IVS 14 þ 1G4A for DPD (P ¼ 0.031), and homozygoty C/C for MTHFR 1298 A4C (P ¼ 0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C4T or A/A for 1298 A4C was statistically shorter (log-rank test P ¼ 0.0065). Genetic factors permit the tailoring of 5-FU treatment. They should occupy center stage in future clinical trials for specifically designing treatment for patients with a given biologic feature.

The addition of sunitinib to capecitabine does not improve the clinical outcome of patients with MBC pretreated with anthracyclines and taxanes.