An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of severe neutropenic toxicity

Our plain-English summary of An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12 and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of severe neutropenic toxicity, by A.R. Minchom, K. Saksornchai, J. Bhosle, et al (BMJ Open Respiratory Research, 2014).

The study

• Authors: A.R. Minchom, K. Saksornchai, J. Bhosle, R. Gunapala, M. Puglisi, S.K. Lu, K. Nimako, J. Coward, K.C. Yu, P. Bordi, S. Popat, M.E. O'Brien
• Journal: BMJ Open Respiratory Research
• Published: 2014;1(1):e000061
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Vitamin B12 and folic acid (referred to as vitamin supplementation) improves the toxicity profile of pemetrexed containing regimens. Low baseline vitamin B12 and folate levels are reflected in a raised total homocysteine level (HC). Studies have suggested that pretreatment HC levels predict neutropenia toxicity. We have tested supplementation with vitamin B12 and folate in non-pemetrexed platinum-based regimens to decrease treatment-related toxicity and looked for a correlation between toxicity and change in homocysteine levels.

Patient And Method: Eighty-three patients with advanced lung cancer and malignant mesothelioma were randomly assigned to receive platinum-based chemotherapy with (arm A) or without (arm B) vitamin B12 and folic acid supplementation. The primary end point was grade 3/4 neutropenia and death within 30 days of treatment. Secondary end points included quality of life, overall survival (OS) and the relationship between baseline and post supplementation HC levels and toxicity.

Results: In the intention-to-treat population, no significant difference was seen between the two groups with respect to chemotherapy-induced grade 3/4 neutropenia and death within 30 days of chemotherapy (36% vs 37%; p=0.966, emesis (2% vs 6%; p=0.9) or OS (12.3 months vs 7 months; p=0.41). There was no significant difference in survival rates by baseline HC level (p=0.9). Decrease in HC with vitamin supplementation was less frequent than expected. High baseline HC levels decreased with vitamin supplementation in only 9/36 (25%) patients (successful supplementation). Post hoc analysis showed that patients in arm A who were successfully supplemented (9/36=25%) had less neutropenic toxicity (0% vs 69%; p=0.02) compared to unsupplemented patients.

Conclusions: The addition of vitamin B12 and folic acid to platinum-containing regimens did not overall improve the toxicity, quality of life or OS. Rates of grade 3/4 neutropenia at 36/37% was as predicted. Further studies to increase the rate of successful supplementation and to further test the biomarker potential of post supplementation HC levels in predicting chemotherapy-induced neutropenia in platinum-based chemotherapy are warranted.

Trial Registration Number: EudracCT 2005-002736-10 ISRCTN8734355.

In plain English

This single-centre, unblinded, randomised phase II trial took place at the Royal Marsden Hospital, UK. It analysed 83 patients with advanced lung cancer or malignant mesothelioma (4 with mesothelioma). All received platinum-based chemotherapy; arm A also received daily folic acid tablets and vitamin B12 injections. Severe (grade 3/4) neutropenia (very low infection-fighting white blood cells) or death within 30 days of treatment affected 13 of 36 arm A patients analysed for toxicity (36%, 95% CI 26 to 48%) and 15 of 41 arm B patients (37%, 95% CI 22 to 53%; p=0.966). Median survival was 12.3 months with vitamins and 7.0 months without, not a statistically significant difference (p=0.41). Quality of life did not differ significantly between groups. In arm A, a raised blood homocysteine fell by at least 30% in only 9 of 36 patients (25%). In a post hoc (after-the-fact) analysis, none of these nine had neutropenia, versus 69% of unsupplemented patients (p=0.02). The authors concluded they had failed to show vitamins improved chemotherapy toxicity in unselected patients. They called for research on vitamin dose and schedule.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-centre, unblinded, randomised phase II trial (1:1 randomisation, not placebo controlled)
• Who was studied: 84 patients were recruited at the Royal Marsden Hospital, Sutton, UK, between September 2006 and February 2011: 41 to arm A and 43 to arm B. One patient had myeloma and was excluded, leaving 83 (Table 1: arm A N=40, arm B N=43). By diagnosis there were 73 with non-small cell lung cancer, 6 with small cell lung cancer and 4 with mesothelioma (3 in arm A, 1 in arm B). 77 were analysed for toxicity and 78 for quality of life, survival and homocysteine.
• Exposure: No asbestos exposure was studied. The intervention was oral folic acid 400 μg daily, starting at least 1 week before chemotherapy, plus vitamin B12 1 mg by intramuscular injection before treatment and every 9 weeks. This was added to platinum-based chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC5 with a second drug) and compared with chemotherapy alone.
• Main results:
  • Primary end point (grade 3/4 neutropenia or death within 30 days of treatment), among the 77 patients analysed for toxicity: 13 of 36 (36%, 95% CI 26 to 48%) in arm A (vitamins) versus 15 of 41 (37%, 95% CI 22 to 53%) in arm B (chemotherapy alone). The difference was not significant (p=0.966).
  • There were 3 deaths within 30 days of treatment in arm A and 1 in arm B.
  • Median overall survival was 12.3 months in the vitamin arm and 7.0 months in the chemotherapy-alone arm. The difference was not statistically significant (p=0.41).
  • Baseline homocysteine levels did not predict neutrophil-related myelosuppression (p=0.75).
  • Successful supplementation, defined as at least a 30% decrease from a raised baseline homocysteine, occurred in 9 of 36 patients (25%) in arm A and in 2 patients (5%) in arm B.
  • In a post hoc analysis, none of the nine successfully supplemented arm A patients had neutropenia, compared with 69% of unsupplemented patients (0% vs 69%; p=0.02).
  • Quality of life (mean change from baseline at 6 weeks and 3 months) did not differ significantly between the treatment groups.
• The authors' conclusion: The authors concluded that they failed to demonstrate that vitamin supplementation in unselected patients improves the toxicity of platinum-based chemotherapy. They said future research is needed on the dose and schedule of vitamin B12 and folate needed to lower homocysteine in more patients. They described the post hoc finding in the small successfully supplemented group as interesting.
• Limitations the authors state:
  • The authors described it as a small, single-centre phase II study.
  • The study was unblinded and not placebo controlled.
  • The study was powered to detect only a large difference in neutropenia (40% down to 10%).
  • Unexpectedly few patients were successfully supplemented, which limited a true comparison of the intervention.
  • Trends toward better quality of life with vitamins were not statistically significant and, the authors said, need to be interpreted with caution.

Topics

Medical terms in this study, explained in our Lexicon: Chemotherapy, Lung Cancer, Biomarker, Pemetrexed (Alimta), Neutropenia, Mesothelioma, Quality of Life, Overall Survival.

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