Haematological toxicity of pemetrexed in patients with metastatic non-squamous non-small cell carcinoma of lung with third-space fluid

Our plain-English summary of Haematological toxicity of pemetrexed in patients with metastatic non-squamous non-small cell carcinoma of lung with third-space fluid, by W.C. Kwok, T.F. Cheong, K.Y. Chiang, et al (Lung Cancer, 2021).

The study

• Authors: W.C. Kwok, T.F. Cheong, K.Y. Chiang, J.C.M. Ho, D.C.L. Lam, M.S.M. Ip, T.C.C. Tam
• Journal: Lung Cancer
• Published: 2021;152:15-20
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Pemetrexed was approved by United States Food and Drug Administration (US FDA) in combination with platinum for the treatment of advanced non-squamous non-small cell lung carcinoma (NSCLC) and malignant mesothelioma. Due to the structural similarity with methotrexate, there has been concern about the accumulation of pemetrexed in third space fluid that may result in increased toxicity. Previous small-scale studies have yet to conclusively prove this association.

Methods: This was a retrospective single-center cohort study conducted in Queen Mary Hospital in Hong Kong. The study included 329 patients with advanced stage non-squamous NSCLC that received first line pemetrexed and platinum. Patients who had non-evacuated third-space fluid, evacuated third-space fluid and without third-space fluid were compared. The primary endpoint was the occurrence of hematological toxicity.

Results: The presence of non-evacuated third-space fluid was shown to be associated with significantly more hematological toxicities, namely grade 3 or above hematological toxicities [Odd ratio (OR) = 2.450, p = 0.002], postponement of chemotherapy (OR = 3.837, p = 0.000) and need for dose adjustment (OR = 2.436, p = 0.022) when compared with those without third-space fluid. For patients with evacuated third-space fluid, these adverse effects were nullified.

Conclusions: Presence of non-evacuated third-space fluid in patients with advanced non-squamous NSCLC predispose patients to significant hematological toxicity when pemetrexed and platinum chemotherapy is used. Evacuation of third-space fluid should be considered before starting pemetrexed and platinum doublet.

Copyright © 2020 Elsevier B.V. All rights reserved.

In plain English

This retrospective study at Queen Mary Hospital in Hong Kong looked at 329 patients with advanced non-squamous non-small cell lung cancer treated between 2014 and 2018. All received first-line chemotherapy with pemetrexed plus platinum (cisplatin or carboplatin). It compared blood-related (haematological) side effects in three groups. 184 patients had no third-space fluid, meaning fluid collecting in spaces such as around the lungs or heart. 78 had their fluid drained, and 67 did not. Grade 3 or worse haematological toxicity occurred in 40 of 67 patients with undrained fluid and 65 of 184 without fluid. Compared with patients without fluid, those with undrained fluid had higher odds of grade 3 or worse toxicity (odds ratio 2.450, 95% confidence interval 1.373 to 4.372), dose adjustment (2.436, 1.135 to 5.229) and postponed chemotherapy (3.837, 2.050 to 7.182). These remained significant after adjusting for factors including age and smoking. Patients whose fluid was drained showed no significant differences. The authors concluded that draining fluid should be considered before this chemotherapy. They noted it was a single-center study and that they could not be certain which drug caused the effect.

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: retrospective single-center cohort study
• Who was studied: 329 patients with advanced stage non-squamous non-small cell lung cancer on first-line pemetrexed and platinum at Queen Mary Hospital, Hong Kong, 1 January 2014 to 31 December 2018. Groups: no third-space fluid (n = 184), drained third-space fluid (n = 78), non-evacuated third-space fluid (n = 67).
• Exposure: Presence of third-space fluid (pleural effusion, pericardial effusion, ascites), drained or not, in patients receiving pemetrexed 500 mg/m2 with cisplatin or carboplatin. No asbestos exposure was studied.
• Main results:
  • Grade 3 or above haematological toxicity occurred in 40 (59.7 %) of the non-evacuated fluid group, 29 (37.1 %) of the drained group and 65 (printed as 33.7 %) of the no-fluid group.
  • Non-evacuated fluid vs no fluid: grade 3 or above haematological toxicity OR 2.450 (95 % CI 1.373 to 4.372), p 0.002.
  • Non-evacuated fluid vs no fluid: dose adjustment for cytopenia OR 2.436 (95 % CI 1.135 to 5.229), p 0.022.
  • Non-evacuated fluid vs no fluid: postponement of chemotherapy due to cytopenia OR 3.837 (95 % CI 2.050 to 7.182), p printed as 0.000.
  • These findings remained statistically significant after adjustment for age, gender, smoking status, mutation profile, performance status, platinum choice, prior brain or bone radiotherapy and baseline creatinine clearance.
  • Drained fluid vs no fluid: no significant difference in grade 3 or above toxicity (OR 1.053, 95 % CI 0.583 to 1.900), dose adjustment (OR 1.356, 95 % CI 0.596 to 3.088) or postponement (OR 1.603, 95 % CI 0.829 to 3.100).
  • No statistically significant difference among the three groups in neutropenic fever (p = 0.776) or need for blood transfusion (p = 0.279).
  • In the pleural effusion subgroup, non-evacuated effusion vs no effusion: grade 3 or above toxicity OR 2.501 (95 % CI 1.361 to 4.598), p 0.003. The difference was not significant after evacuation.
• The authors' conclusion: The authors concluded that non-evacuated third-space fluid can predispose patients receiving pemetrexed and platinum to significant haematological toxicity, and that evacuation of the fluid should be considered.
• Limitations the authors state:
  • Single-center study.
  • All patients received pemetrexed with platinum, so the authors could not be certain which drug caused the observed effect.
  • Pemetrexed levels in plasma and third-space fluid were not measured; the authors say this would have been more definitive.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Carcinoma, Malignant Mesothelioma, Cohort Study, Chemotherapy.

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• Predictive markers for haematological toxicity of pemetrexed — S.C. Kao, V.H. Phan, et al. (2010)
• Pemetrexed-induced scleroderma-like conditions in the lower legs of a patient with non-small cell lung carcinoma — K. Ishikawa, T. Sakai, et al. (2016)
• Cytomorphological features of metastatic squamous cell carcinoma in serous effusions — C.C. Huang, C.W. Michael (2014)
• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)

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