Background
Folate and vitamin B12 supplementation with chemotherapy
Up to half of lung patients with cancer with advanced disease can be malnourished, on the basis of body mass index.1 There a number of potential reasons for this including poor diet, cancer-induced nausea, paraneoplastic processes and as a result of chronic smoking. Palliative chemotherapy is associated with grade 3/4 rates of neutropenia between 20% and 40%. There appears to be little difference in rates between the different carboplatin and cisplatin regimens commonly used in non-small cell lung cancer (NSCLC).2 ,3 The incidence of toxicity is similar when the same regimens are used in malignant mesothelioma (MM).4 The incidence is higher in regimens used in small cell lung cancer (SCLC) and in second-line NSCLC.5 ,6
Some preclinical trials have highlighted the impact of folate supplements on chemotherapy-induced toxicity and clinical response. Branda et al7 found that survival was significantly better in folate-supplemented rats receiving cyclophosphamide and 5-FU and this group developed less host toxicity compared to their folate deficient counterparts. The authors of the study hypothesised that the mechanism behind the interaction between folate metabolism and chemotherapy may be secondary to the relationship between folate status and glutathione level, which has been shown to correlate with chemotherapy toxicity.8 ,9
Pemetrexed containing regimes have been established as the standard of care for the treatment of MM and non-small cell lung cancer (NSCLC). The use of vitamin B12 and folic acid has been shown to decrease toxicity.4 This is logical given the inhibitory actions of pemetrexed in the folate pathway. In Vogelzang et al's trial of pemetrexed and ciplatin versus cisplatin alone in mesothelioma the incidence of grade 3 and 4 neutropenia in the cisplatin/pemetrexed arm was reduced from 41.4% to 23.2% (p=0.011) with vitamin supplementation. Febrile neutropenia was reduced from 5.2% to 0.6% (p=0.53).4 Interestingly however vitamin supplementation also appeared to benefit patients receiving cisplatin alone. There has been little further investigation of the role of folate and vitamin B12 supplementation in non-pemetrexed containing regimes despite this clinical and preclinical data.
Homocysteine levels as a marker of folate and vitamin B12 supplementation
Niyikiza et al carried out an analysis of pemetrexed-treated patients to identify predictive factors for severe toxicity. The results showed that pretreatment total plasma homocysteine (HC) levels significantly predicted severe thrombocytopenia and neutropenia and subsequent supplementation with vitamin B12 and folate reduced the incidence and severity of such toxicities without affecting efficacy. The normal range in this study was 7.5–11.5 μM/L in line with reports from cardiovascular study populations.10 High baseline homocysteine levels are associated with folate and vitamin B12 deficiency.11 Patients with high baseline HC level were found in other studies to have a high risk of severe haematological toxicity and vitamin-supplemented patients tended to improve or lower their concentrations of HC.10–12 Since total plasma HC level is affected by a series of genetic, physiological, lifestyle and clinical factors, Refsum et al13 have proposed that, in routine clinical setting, significant change in total plasma HC should be defined as a change of greater than 25% to 30% between samples collected on two occasions.
In this single centre, unblinded phase II randomised study, the aim was to assess the impact of vitamin B12 and folic acid supplementation on non-pemetrexed-based chemotherapy-related neutropenic events and to determine the potential role of using total plasma HC level before and after vitamin B12 and folic acid supplementation (using 30% reduction of HC level as a cut-off for successful supplementation) as a predictive biomarker of toxicity.