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

Autoři: Anna Minchom aff001;  Daisy Mak aff001;  Ranga Gunapala aff001;  David Walder aff001;  Rajiv Kumar aff001;  Nadia Yousaf aff002;  Andrew Hodgkiss aff003;  Jaishree Bhosle aff001;  Sanjay Popat aff002;  Mary E. R. O’Brien aff001
Působiště autorů: Lung Cancer Unit, Royal Marsden NHS Foundation Trust, Sutton, United Kingdom aff001;  Lung Cancer Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom aff002;  Adult Psychological Support Service, Royal Marsden NHS Foundation Trust, Sutton, United Kingdom aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225509



Vitamin 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 methods

Primary 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.


Eighty-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.


On-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.

Klíčová slova:

Cancer treatment – Cobalamins – Depression – Drug therapy – Folic acid – Chemotherapy – Toxicity – Vitamins


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