Effect of renal function on pemetrexed-induced haematotoxicity

Our plain-English summary of Effect of renal function on pemetrexed-induced haematotoxicity, by Y. Ando, T. Hayashi, M. Ujita, et al (Cancer Chemotherapy and Pharmacology, 2016).

The study

• Authors: Y. Ando, T. Hayashi, M. Ujita, S. Murai, H. Ohta, K. Ito, T. Yamaguchi, M. Funatsu, Y. Ikeda, K. Imaizumi, K. Kawada, K. Yasuda, S. Yamada
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2016;78(1):183-9
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Pemetrexed (PEM) is an anticancer agent used for the treatment of non-small cell lung cancer, malignant pleural mesothelioma and thymoma. Reportedly, PEM has higher efficacy and safety when used in combination with platinum-based agents. However, there are only few reports on the safety of PEM in patients with an eGFR of ≤45 mL/min. We examined the effect of renal function on the safety of regimens containing PEM.

Methods: We retrospectively reviewed 221 patients with lung cancer, malignant pleural mesothelioma or thymoma who received treatment with a PEM-containing regimen between 2009 and 2014. Subgroup analyses were performed on the basis of pre-treatment renal function: group A [creatinine clearance (CLcr), <45 mL/min]; group B (CLcr, 45-80 mL/min); and group C (CLcr, ≥80 mL/min). For the purpose of this analysis, the lowest documented blood cell counts and haemoglobin levels, the highest levels of serum creatinine, aspartate aminotransferase, alanine aminotransferase and CLcr from the time of initial administration up to prior to the start of second administration were considered.

Results: Groups A, B and C had 8, 123 and 90 patients, respectively. The incidence of grade 2 thrombocytopaenia was significantly higher in group A as compared to that in groups B (P < 0.01) and C (P < 0.05). On multivariate analysis, only a CLcr of <45 mL/min was an independent risk factor for thrombocytopaenia of ≥grade 2.

Conclusion: When administering a PEM-containing regimen, thrombocytopaenia of ≥grade 2 is more likely to develop in patients with a CLcr of <45 mL/min.

In plain English

This retrospective study at a Japanese university hospital reviewed 221 patients treated with pemetrexed-containing chemotherapy for lung cancer, malignant pleural mesothelioma or thymoma between September 2009 and August 2014. It is about a cancer drug, not asbestos exposure, and it does not say how many patients had mesothelioma. Patients were grouped by kidney function (creatinine clearance) before treatment: under 45 mL/min (group A, 8 patients), 45 to 80 (group B, 123) and 80 or more (group C, 90). Grade 2 low platelet counts (thrombocytopaenia) occurred in 4 of 8 patients in group A (50.0%), 6 of 123 in group B (4.9%) and 7 of 90 in group C (7.8%). In the multivariate analysis, creatinine clearance under 45 mL/min was the only independent risk factor for thrombocytopaenia of grade 2 or higher (odds ratio 6.40, 95% CI 1.41 to 29.10). Severe effects on other blood counts and on liver tests did not differ significantly between groups. The authors concluded this thrombocytopaenia is more likely with creatinine clearance under 45 mL/min. They named the retrospective design and the small group A as limitations.

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 review of hospital medical records
• Who was studied: 221 patients with lung cancer, malignant pleural mesothelioma or thymoma treated with a pemetrexed-containing regimen at Fujita Health University Hospital, Japan, 1 September 2009 to 31 August 2014. Group A had 8 patients (creatinine clearance under 45 mL/min), group B had 123 (45 to 80 mL/min) and group C had 90 (80 mL/min or more). The number with mesothelioma is not reported separately.
• Exposure: Pemetrexed-containing chemotherapy: pemetrexed alone or combined with cisplatin, carboplatin and/or bevacizumab. Patients were compared by pre-treatment kidney function (creatinine clearance). This is a drug study and involves no asbestos exposure. Group A received a lower average pemetrexed dose (432.7 mg/m2) than groups B (488.3) and C (485.1).
• Main results:
  • Grade 2 thrombocytopaenia occurred in 4 of 8 patients (50.0%) in group A, 6 of 123 (4.9%) in group B and 7 of 90 (7.8%) in group C. Group A's rate was significantly higher than group B's (P < 0.01) and group C's (P < 0.05).
  • In multivariate analysis, creatinine clearance under 45 mL/min was the only independent risk factor for thrombocytopaenia of grade 2 or higher: odds ratio 6.40 (95% CI 1.41 to 29.10), P = 0.016. In univariate analysis the odds ratio was 10.17 (95% CI 2.31 to 44.77).
  • Carboplatin use was not an independent risk factor in the multivariate analysis: odds ratio 2.47 (95% CI 0.86 to 7.09), P = 0.093. Neither was cisplatin: odds ratio 0.56 (95% CI 0.15 to 2.08), P = 0.39.
  • The three groups showed no significant differences in severe (grade 3 or higher) effects on leucocyte, neutrophil and red blood cell counts, haemoglobin levels, or raised AST and ALT liver enzymes.
  • In group A, 7 of the 8 patients received pemetrexed plus carboplatin. Neutropaenia of grade 3 or higher occurred in 37.5% and thrombocytopaenia of grade 3 or higher in 12.5%. The authors judged these rates to be within the permissible range.
• The authors' conclusion: The authors concluded that thrombocytopaenia of grade 2 or higher is more likely to develop in patients with creatinine clearance under 45 mL/min who receive a pemetrexed-containing regimen. They suggested close monitoring of platelet counts in these patients.
• Limitations the authors state:
  • The study was retrospective.
  • Group A contained only eight patients, because pemetrexed is not currently recommended in Japan for patients with creatinine clearance under 45 mL/min.
  • The small group A is likely to have biased patient characteristics.
  • Side effects that cannot be seen in laboratory results were not assessed.

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Non-Small Cell Lung Cancer, Pleural Mesothelioma, EGFR, Lung Cancer, Multivariate Analysis.

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• Influence of co-morbidity on renal function assessment by Cockcroft-Gault calculation in lung cancer and mesothelioma patients receiving platinum-based chemotherapy — R.A. Hubner, R. Goldstein, et al. (2011)
• Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis — N. de Rouw, S. Croes, et al. (2019)
• Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis — N. de Rouw, R.J. Boosman, et al. (2021)
• Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients — T. Shukuya, T. Takahashi, et al. (2014)
• Dexamethasone alleviates pemetrexed-induced senescence in Non-Small-Cell Lung Cancer — H. Ge, J. Ke, et al. (2018)

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