Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment

Item does not contain fulltextPemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m(2) would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment

The prognostic value of early onset, CT derived loss of muscle and adipose tissue during chemotherapy in metastatic non-small cell lung cancer

Objectives: To evaluate the relationship between early changes in muscle and adipose tissue during chemotherapy and overall survival (OS) in stage IV non-small cell lung cancer (NSCLC). Materials and methods: In this post-hoc analysis of the first line NVALT12 trial (NCT01171170) in stage IV NSCLC, skeletal muscle (SM), radiation attenuation (RA), subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were assessed at the third lumbar level on CT-images obtained before initiation of chemotherapy and shortly after administration of the second cycle. The contribution of changes in different body compartments to overall survival was assessed. Results: CT scans of 111 patients were included. Analysis of body composition changes between the baseline and the follow-up scan, revealed that overall SM cross sectional area (CSA), radiation attenuation and SAT CSA decreased respectively by −1.2 ± 2.9 cm2 /m2 (p < 0.001), −0.7 ± 3.3 HU (p = 0.026) and −1.9 ± 8.7 cm2 /m2 (p = 0.026), while no significant changes in VAT tissue were observed. Longitudinally, median OS was significantly shorter among patients losing SM compared to patients with preserved SM (9.4 versus 14.2 months; HR 1.9, 95% CI: 1.23, 2.79, p = 0.003). Multivariate analyses showed that proportional loss of muscle mass was associated with poor OS (HR 0.949, 95% CI: 0.915, 0.985, p = 0.006) independent from important clinical prognostic factors including WHO-PS, gender, age and Charlson comorbidity index. Conclusion: Early loss of SM during first line chemotherapy is a poor prognostic factor in stage IV NSCLC patients. Future studies have to reveal whether early supportive intervention guided by initial CT muscle response to chemotherapy can influence the wasting process and related mortality ris

Chemotherapy for pulmonary large cell neuroendocrine carcinomas: Does the regimen matter?

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COVID-19 vaccination: the VOICE for patients with cancer

Pathogenesis and treatment of chronic pulmonary disease