Pemetrexed-Induced Rash May Be Prevented by Supplementary Corticosteroids

Our plain-English summary of Pemetrexed-Induced Rash May Be Prevented by Supplementary Corticosteroids, by T. Sakurada, S. Kakiuchi, S. Tajima, et al (Biological & Pharmaceutical Bulletin, 2015).

The study

• Authors: T. Sakurada, S. Kakiuchi, S. Tajima, Y. Horinouchi, K. Konaka, N. Okada, H. Nishisako, T. Nakamura, K. Teraoka, K. Kawazoe, H. Yanagawa, Y. Nishioka, K. Ishizawa
• Journal: Biological & Pharmaceutical Bulletin
• Published: 2015;38(11):1752-6
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pemetrexed, a chemotherapeutic drug, is highly active in non-small cell lung cancer and malignant pleural mesothelioma. Unfortunately, rashes are more commonly associated with pemetrexed than other chemotherapies, and it is recommended that patients receive corticosteroids (8 mg/d of dexamethasone) for 3 d, including the day of pemetrexed administration (day 1). However, the efficacy of corticosteroids in this context has not been fully verified. In this retrospective study, we evaluated the medical records of 78 patients who received pemetrexed between April 2009 and March 2014, to confirm whether supplementary corticosteroids prevented rash development. The incidence of rash was lower in the 47 patients who received supplementary corticosteroids (after day 1) compared with the incidence among the 31 patients who did not receive supplementary corticosteroids (19.1% vs. 38.7%). The average cutoff dosage of supplementary corticosteroids on day 2 and day 3 was 1.5 mg/d of dexamethasone, as calculated using the receiver operating characteristic curve, and the odds ratio was 0.33 (95% confidence interval: 0.12-0.94). Administration of ≥1.5 mg of corticosteroids on day 2 and day 3 significantly reduced the severity of the rash compared to no supplementary treatment (grades 2/3, 13.3% vs. 33.3%, p<0.05). However, increasing the dose of corticosteroids had no additional effect on rash development. These results suggest that ≥1.5 mg of supplementary dexamethasone on day 2 and day 3 (in addition to day 1) may be necessary for preventing pemetrexed-induced rash, but high doses of dexamethasone (e.g., 8 mg/d) are unnecessary.

In plain English

This retrospective study reviewed the medical records of 78 patients at Tokushima University Hospital in Japan who received the chemotherapy drug pemetrexed for the first time between April 2009 and March 2014. Five had malignant pleural mesothelioma and 73 had non-small cell lung cancer. It asked whether extra corticosteroids, counted as dexamethasone and given on days 2 and 3 after the day 1 dose, were linked to fewer pemetrexed rashes. Rash occurred in 19.1% of patients who got supplementary corticosteroids and 38.7% of those who did not, a difference that was not statistically significant. Patients given 1.5 mg or more of dexamethasone on days 2 and 3 had rash less often than those given less than 1.5 mg or none (17.8% vs 39.4%; odds ratio 0.33, 95% CI 0.12 to 0.94). Higher doses added no further benefit. The authors noted that the 1.5 mg cutoff rested on a relatively weak statistical fit, and that other drugs could not be ruled out. They concluded that all pemetrexed patients should receive a small amount of supplementary corticosteroids to prevent rash.

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 (single hospital), with univariate analyses
• Who was studied: 78 patients treated with pemetrexed for the first time between April 2009 and March 2014 in the Department of Respiratory Medicine and Rheumatology, Tokushima University Hospital, Japan. 73 had non-small cell lung cancer (NSCLC) and 5 had malignant pleural mesothelioma (MPM). Patients who might have had antibiotic-related rash, or who received corticosteroids for more than 2 days after pemetrexed, were excluded.
• Exposure: Supplementary corticosteroids, with doses converted to dexamethasone equivalents, given on day 2 and day 3 after pemetrexed administration. All patients received corticosteroids on day 1. Asbestos exposure was not studied.
• Main results:
  • Overall, 21 of 78 patients (26.9%) developed pemetrexed-induced rash: grade 1 in 5.1%, grade 2 in 19.2% and grade 3 in 2.6%.
  • Rash occurred in 19.1% of the 47 patients who received supplementary corticosteroids after day 1 and in 38.7% of the 31 who did not. The difference was not statistically significant (p = 0.06 in Table 2).
  • The ROC-derived cutoff was 1.5 mg of dexamethasone (area under the curve 0.63). Rash of any grade occurred in 8 of 45 patients (17.8%) given 1.5 mg or more on days 2 and 3, versus 13 of 33 (39.4%) in the less-than-1.5 mg group, which included patients who received no supplementary corticosteroids (odds ratio 0.33, 95% CI 0.12 to 0.94, p = 0.04).
  • Grade 2 or 3 rash occurred in 6 of 45 patients (13.3%) given 1.5 mg or more, versus 11 of 33 (33.3%) in the less-than-1.5 mg group (odds ratio 0.31, 95% CI 0.10 to 0.95, p = 0.04).
  • Supplementary corticosteroids on days 2 and 3 showed no dose-dependent effect on rash.
  • Transient fever (6.5% with supplementary corticosteroids vs 22.6% without) and CRP elevation (25.6% vs 44.4%) were less frequent with supplementary corticosteroids. These differences were not statistically significant (p = 0.08 and p = 0.10).
  • Elevated liver enzymes were more frequent in patients given supplementary corticosteroids: AST 31.9% vs 22.6%, ALT 27.7% vs 19.4%, and gamma-GTP 19.1% vs 10.3%. None of these differences was statistically significant.
• The authors' conclusion: The authors concluded that 1.5 mg or more of corticosteroids on days 2 and 3 significantly suppressed rash, that high doses such as 8 mg/d appear unnecessary, and that, because high-risk patients cannot be predicted, all patients receiving pemetrexed should also receive a small amount of supplementary corticosteroids to prevent rash.
• Limitations the authors state:
  • The study was retrospective, and corticosteroids were shown to be effective only for a range of dexamethasone doses (1.5 mg or more), which the authors call a major limitation.
  • The dexamethasone cutoff was derived from an ROC curve with a relatively low area under the curve (0.63).
  • The possible influence of antiemetics or other drugs could not be completely excluded.

Topics

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

Related studies

• Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients — T. Takahashi, Y. Nakamura, et al. (2011)
• Dexamethasone alleviates pemetrexed-induced senescence in Non-Small-Cell Lung Cancer — H. Ge, J. Ke, et al. (2018)
• Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions — R. Elsoueidi, M.J. Lander, et al. (2016)
• Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage — G. Rombolà, F. Vaira, et al. (2015)
• 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)
• Pemetrexed-induced painful erythematous nodules in both legs in a patient with recurrent mesothelioma — M. Llamas-Velasco, E. Ovejero-Merino, et al. (2018)

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