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

Our plain-English summary of 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, by A. Minchom, D. Mak, R. Gunapala, et al (PloS One, 2019).

The study

• Authors: A. Minchom, D. Mak, R. Gunapala, D. Walder, R. Kumar, N. Yousaf, A. Hodgkiss, J. Bhosle, S. Popat, M.E.R. O'Brien
• Journal: PloS One
• Published: 2019;14(11):e0225509
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: 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.

Results: 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.

Conclusion: 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.

In plain English

This prospective observational study at the Royal Marsden NHS Foundation Trust followed patients with advanced non-small cell lung cancer or malignant pleural mesothelioma receiving pemetrexed-based chemotherapy with vitamin B12 and folic acid. It did not study asbestos exposure. The authors measured blood homocysteine at the second chemotherapy cycle to test whether a high level, a sign that supplementation had not worked, predicted more side effects. Of 100 patients analysed, 84% had a normal level. A treatment delay, dose reduction, drug change or hospitalisation in the first six weeks occurred in 44.0% (37/84; 95% CI 33.2%–55.3%) of the normal-level group and 18.8% (3/16; 95% CI 4.0%–45.6%) of the high-level group (p = 0.09, not statistically significant). The trial was stopped at a planned interim analysis. Of 44 patients who completed an anxiety and depression questionnaire, 66% scored above 7. A post-hoc analysis compared starting vitamins less than 7 days before pemetrexed with 7 days or more. It found no significant difference in that combined outcome or in grade 3–4 toxicities. The authors concluded that on-treatment homocysteine levels were not a biomarker of toxicity or depression. They noted that the small high-level group confounded the results.

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: Prospective, observational, single-arm study with a planned interim analysis; the analyses of vitamin lead-in time were post-hoc
• Who was studied: Adults with advanced (stage IIIB/IV) adeno-non-small cell lung cancer or malignant pleural mesothelioma receiving palliative pemetrexed-based chemotherapy. They were recruited at Royal Marsden NHS Foundation Trust outpatient clinics (United Kingdom) from 25 February 2014 to 25 September 2015. Of 115 recruited, 3 were ineligible and 100 were analysed. 17.9% had malignant pleural mesothelioma; the rest had adeno-NSCLC.
• Exposure: Not asbestos. Patients took oral folic acid 400 mcg daily and received intramuscular vitamin B12 1000 mcg alongside pemetrexed, given alone or with cisplatin or carboplatin. Plasma homocysteine was measured on cycle 2 day 1, after at least 3 weeks of supplementation. A level below 10 micromol/L counted as successfully supplemented; 10 micromol/L or above counted as unsuccessfully supplemented. The study also looked at the gap between starting vitamins and the first pemetrexed dose (less than 7 days vs 7 days or more).
• Main results:
  • 84% of the 100 analysed patients had a normal homocysteine level (the successfully supplemented group).
  • Primary endpoint (treatment delay, dose reduction, drug change or hospitalisation in the first six weeks): 44.0% (37/84 patients; 95% CI 33.2%–55.3%) in the successfully supplemented group vs 18.8% (3/16 patients; 95% CI 4.0%–45.6%) in the unsuccessfully supplemented group, p = 0.09.
  • Grade 3–4 toxicity: 14.5% (12/83 patients; 95% CI 7.7%–23.9%) in the successfully supplemented group vs 18.8% (3/16 patients; 95% CI 4.0%–45.6%) in the unsuccessfully supplemented group, p = 0.70.
  • Median overall survival: 11.8 months (95% CI 8.6–16.5) in the successfully supplemented group vs 8.8 months (95% CI 6.6–16.2) in the unsuccessfully supplemented group, p = 0.5.
  • 44 patients had a Hospital Anxiety and Depression score recorded, and 66% of them (29/44) scored above 7. The rate was 63.9% (23/36) in the successfully supplemented group and 75% (6/8) in the unsuccessfully supplemented group, p = 0.70.
  • Post-hoc analysis: starting vitamins less than 7 days before pemetrexed (53 patients) was compared with 7 days or more (47 patients). There was no significant difference in the primary endpoint (39.6% vs 40.4%, p = 0.94) or in grade 3–4 toxicities (15.4% vs 14.9%, p = 0.95).
• The authors' conclusion: The authors concluded that on-treatment homocysteine levels were not a biomarker of toxicity or depression. They also concluded that standard vitamin supplementation is probably adequate in most patients and that the vitamin lead-in time can be shortened. In their view, the questionnaire scores suggest a high rate of subclinical or undiagnosed depression, offering an opportunity for mental health intervention.
• Limitations the authors state:
  • Most patients were successfully supplemented, so the unsuccessfully supplemented group was small. The authors say this confounded the results.
  • The study was not powered to assess overall survival.
  • The depression questionnaire was added midway through the trial, and the numbers for the homocysteine–depression comparison were small.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pemetrexed (Alimta), Non-Small Cell Lung Cancer, Mesothelioma, Chemotherapy, confidence interval, Median Overall Survival.

Related studies

• 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 — A.R. Minchom, K. Saksornchai, et al. (2014)
• Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non-Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis — Z. Schlei, W. Tan, et al. (2018)
• Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study — Y. Takeda, G. Naka, et al. (2023)
• The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication — C.E. Hooper, I.D. Lyburn, et al. (2015)
• Plasma vitamin concentrations and incidence of mesothelioma and lung cancer in individuals exposed to crocidolite at Wittenoom, Western Australia — H.S. Alfonso, L. Fritschi, et al. (2006)
• Correlation of prechemotherapy urinary megalin ectodomain (A-megalin) levels with the development of cisplatin-induced nephrotoxicity: a prospective observational study — S. Shoji, M. Hosojima, et al. (2019)

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