Oxaliplatin Dose Reduction Research Articles

Pharmacokinetics of oxaliplatin in patients with severe hepatic dysfunction

Data are lacking on the pharmacokinetics of oxaliplatin in patients with severe hepatic dysfunction. The aim of this study was to determine the pharmacokinetic parameters of platinum after administration of oxaliplatin in cancer patients with severe hepatic impairment due to extended metastases into the liver. Two female breast cancer patients and one male colon cancer patient were treated with oxaliplatin monotherapy at 130 mg/m(2) given as a 3-h intravenous infusion. The patients exhibited bilirubin concentrations of 9.6, 22.5 and 41.1 mg/dl indicating severe hepatic dysfunction. Serial blood samples were collected immediately before treatment, and at fixed intervals up to 27 h after start of therapy. Platinum concentrations in plasma, ultrafilterable plasma, and whole blood were determined using a validated flameless atomic absorption spectrometry (FAAS) method. Pharmacokinetic data analysis was performed assuming a two-compartment model. Individual pharmacokinetic parameters were compared with a reference population with normal hepatic function. The area under the curve (AUC from 0 to infinity) as well as the elimination half-life of platinum in ultrafilterable plasma were substantially increased and clearance accordingly decreased in the three patients with severe hepatic dysfunction. In plasma and whole blood, the deviations from the reference population were less pronounced. However, partial AUC from 0 up to 2 h after end of infusion reflecting better the exposure with cytotoxic platinum species was not different or only slightly altered. Moreover, no acute oxaliplatin-associated neurotoxicity was observed. The comparable platinum exposure early after administration in conjunction with the lack of acute toxicity do not support a dose reduction of oxaliplatin in patients with markedly elevated bilirubin concentrations. However, a larger number of patients must be examined before valid dose recommendations can be derived.

Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer

BackgroundNew chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity.MethodsA detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity.ResultsEighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients.ConclusionOxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity.

Addition of gabapentin (G) to a modified FOLFOX regimen does not reduce neurotoxicity in patients (pts) with advanced colorectal cancer (CRC)

3581 Background: In order to determine the neuroprotectant effect of G against oxaliplatin-induced neurotoxicity, we sequentially recruited pt cohorts in a non-randomised phase II trial to FOLFOX then FOLFOX+G. Inclusion criteria were: advanced CRC; chemonaive except adjuvant completed ≥ 6 mths; measurable disease; PS 0–2. Pts received on D1 oxaliplatin 100mg/m2 IV over 2 hrs, LV 20mg/m2 bolus, 5-FU 400mg/m2 bolus then 5FU 2.4g/m2 46-hour infusion. Cycles were 2-wkly until PD or unacceptable toxicity. In addition, G cohort pts received G 300mg/d po, increased as required by 300mg/d increments (max 1800mg). Over 2 yrs, 40 pts were recruited to FOLFOX then 41 to FOLFOX+G. Minimum f/up was 18 mths. All but one pt received at least one dose of oxaliplatin and were evaluable for toxicity and treatment delivery. Pt characteristics were well balanced between cohorts. Maximum doses of G were 300mg/d in 10 pts, 600mg/d in 15, 900mg/d in 4, 1200mg/d in 9, and 1800mg/d in 3 pts. Treatment delivery for FOLFOX and FOLFOX+G cohorts respectively: median cycles 10 (1–13) vs 9 (1–12); oxaliplatin dose reduction >10% in 55% vs 50% of pts; cycles delayed >2days 19% vs 14%; treatment cessation due to toxicity 36% vs 37% (NS). RDI for FOLFOX and FOLFOX+G was oxaliplatin 82% vs 87%; 5FU bolus 52% vs 69%; 5FU infusion 82% vs 87% (NS). Responses (CR+PR) were seen in 48% of pts in each cohort. There were no significant difference in non-neurological toxicity.There was no significant difference in severity of neurotoxicity. For pts with grade 2/3 neurotoxicity, median time to recovery to grade 0/1 was 3.3mths for FOLFOX and 0.5mths for FOLFOX+G, however persistence of grade 2/3 neurotoxicity at 1 yr was 0% vs 17% respectively (NS). Conclusions: Addition of G to FOLFOX does not improve ability to deliver protocol-specified treatment and does not significantly reduce either severity or duration of neurotoxicity. This trial was sponsored by Sanofi-Synthelabo. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi Sanofi Sanofi Sanofi