Prevention of Pemetrexed-Induced Rash Using Low-Dose Corticosteroids: A Phase II Study

Our plain-English summary of Prevention of Pemetrexed-Induced Rash Using Low-Dose Corticosteroids: A Phase II Study, by T. Sakurada, H. Nokihara, T. Koga, et al (The Oncologist, 2022).

The study

• Authors: T. Sakurada, H. Nokihara, T. Koga, Y. Zamami, M. Goda, K. Yagi, H. Hamano, F. Aizawa, H. Ogino, S. Sato, Y. Kirino, H. Goto, Y. Nishioka, K. Ishizawa
• Journal: The Oncologist
• Published: 2022;27(7):e554-e560
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Rash eruptions are a common side-effect of pemetrexed, for which the administration of 8 mg/day of dexamethasone for 3 days from the day preceding pemetrexed administration is recommended. This study aimed to prospectively assess the effectiveness of prophylactic administration of low-dose dexamethasone for pemetrexed-induced rashes.

Methods: This single-arm, phase II study recruited patients with non-squamous non-small cell lung cancer and malignant pleural mesothelioma scheduled to receive chemotherapy including pemetrexed. Patients received 2 mg of dexamethasone daily from days 2 to 6 after chemotherapy with pemetrexed. The primary endpoint was the 3-week incidence of rash eruptions.

Results: Twenty-five patients were enrolled between September 2017 and May 2019. The incidence of rash after 3 weeks was 16.7%. Rashes erupted mainly on the upper half of the body, such as the chest and neck, and were of grades 1 and 2 in 2 patients each. No rashes of grade 3 or higher were observed, and there were no adverse events associated with additional corticosteroids.

Conclusion: Prophylactic administration of low-dose dexamethasone for 5 days from the day after pemetrexed administration resulted in a milder incidence and severity of rash. These findings may provide a standard preventative strategy for pemetrexed-induced rashes. (Trial identifier: UMIN000025666).

© The Author(s) 2022. Published by Oxford University Press.

In plain English

This single-arm phase II trial in Japan tested whether low-dose dexamethasone, a steroid, could prevent skin rash from the chemotherapy drug pemetrexed. Twenty-five patients receiving pemetrexed for the first time were enrolled between September 2017 and May 2019. Twenty-four were analyzed: 21 with non-squamous non-small cell lung cancer and 3 with malignant pleural mesothelioma. Results were not reported separately for the mesothelioma patients. Besides day-1 dexamethasone against nausea, patients took 2 mg of dexamethasone by mouth daily on days 2 to 6. Rash within 3 weeks occurred in 4 of 24 patients (16.7%, 95% confidence interval, or CI, 4.7 to 37.4). Two rashes were grade 1 and two grade 2; none was grade 3 or higher, and all resolved. For comparison, the authors used earlier trials: rash occurred in 77 of 114 patients (67.5%, 95% CI 58.1 to 76.0) given no steroids, and in 14.0% (95% CI 10.0 to 18.7) of 265 patients given higher-dose dexamethasone. The authors concluded that the low dose worked comparably to the high dose. They noted that the study was small and had no control group of its own.

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 single-arm phase II clinical trial, compared with historical controls from earlier trials
• Who was studied: 25 patients receiving pemetrexed for the first time, enrolled September 2017 to May 2019 at Tokushima University Hospital, Japan. Eligible patients had non-squamous non-small cell lung cancer or malignant pleural mesothelioma. One patient was excluded, leaving 24 analyzed: 21 with non-small cell lung cancer and 3 with malignant pleural mesothelioma.
• Exposure: Not an asbestos exposure study. The intervention was oral dexamethasone 2 mg/day on days 2 to 6 after pemetrexed (500 mg/m2 on day 1). Intravenous dexamethasone was also given on day 1 to prevent nausea: 9.9 mg with carboplatin or 6.6 mg without.
• Main results:
  • Rash within 3 weeks occurred in 4 of 24 analyzed patients (16.7%, 95% CI 4.7-37.4).
  • Rashes were mainly on the upper body, such as the chest and neck. Two were grade 1 and two were grade 2.
  • Compared with historical controls, rash incidence was lower than the 67.5% (95% CI 58.1-76.0) reported without corticosteroids. It was not higher than the 14.0% (95% CI 10.0-18.7) reported with higher-dose corticosteroids.
  • In the historical phase II trial without corticosteroids, 77 of 114 patients (67.5%) developed rash. Figure 1 gives the historical phase III trial with oral dexamethasone (4 mg twice daily the day before, the day of, and the day after pemetrexed) as n = 265.
  • None of the rashes affected continuation of pemetrexed chemotherapy, and all four were recorded as cured.
  • More previous lines of chemotherapy was a statistically significant factor for rash. The odds ratio is printed differently in different places; Table 1 gives 3.21 (95% CI 1.14-12.85).
  • Adverse events of grade 3 or higher occurred in 2 of 13 patients (15.4%) not given carboplatin and 5 of 11 patients (45.5%) given carboplatin. No serious non-blood adverse events were reported.
• The authors' conclusion: The authors concluded that low-dose dexamethasone (2 mg/day) suppressed pemetrexed-induced rash with efficacy comparable to high-dose corticosteroids, and that the findings may provide a standard preventive strategy.
• Limitations the authors state:
  • The study had no control group of its own and relied on indirect historical controls.
  • Single-arm study findings may not generalize to other populations.
  • Patient characteristics, such as other medications and prior chemotherapy, differed from the historical controls and may have influenced rash.
  • The number of cases was small.
  • Patients needing other systemic corticosteroids or antihistamines were excluded, which the authors say may have biased findings on the causes of rash.

Topics

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

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

Related studies

• Pemetrexed-Induced Rash May Be Prevented by Supplementary Corticosteroids — T. Sakurada, S. Kakiuchi, et al. (2015)
• Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions — R. Elsoueidi, M.J. Lander, et al. (2016)
• Dexamethasone alleviates pemetrexed-induced senescence in Non-Small-Cell Lung Cancer — H. Ge, J. Ke, et al. (2018)
• Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers — E. Beddowes, J. Spicer, et al. (2017)
• 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)
• A phase 2, multicenter, open-label study of anti-LAG-3 ieramilimab in combination with anti-PD-1 spartalizumab in patients with advanced solid malignancies — C.C. Lin, E. Garralda, et al. (2024)

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