A prospective observational study of on-treatment plasma homocysteine levels as a biomarker of toxicity, depression and vitamin supplementation lead-in time pre pemetrexed, in patients with non-small cell lung cancer and malignant mesothelioma

Abstract

ObjectivesVitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity.Material and methodsPrimary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3–4 toxicities.ResultsEighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%–55.3%) and in USS group was 18.8% (95% CI 4.0%–45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6–16.5) in the SS group and 8.8 months (95% CI 6.6–16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3–4 toxicities.ConclusionOn-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short.

Energy metabolism as the hub of advanced non-small cell lung cancer management: a comprehensive view in the framework of predictive, preventive, and personalized medicine

“…High plasma homocysteine (Hcy) and low folate levels have been associated with lung cancer development and progression [ 24 ], among other maliganancies which Hcy detection was suggested to be phenotypically relevant for [ 25 ]. Contextually, vitamin 6, 9, and 12 supplements seem to be protective against lung carcinogenesis [ 26 ] and supportive for the mental health intervention in treated NSCLC [ 27 ]. On the other hand, there are several clearly defined phenotypes in the population which suffer from enhanced Hcy levels in blood and therefore considered a target group to protect against lung cancer predisposition such as individuals with imbalanced diet and insufficient vitamin B 6, 9, and 12 intake diagnosed with disordered one-carbon metabolism diagnosed with obstructive sleep apnea associated with increased Hcy in blood [ 28 ], amongst others.…”