Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions

Elsoueidi, Raymond; Lander, Michael J; Richa, Elie; Adane, Eyob D.

doi:10.1177/1078155215583523

Cited by 9 publications

(7 citation statements)

References 17 publications

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“…6 A retrospective study found that the Another retrospective study reported that in 14 cases of metastatic NSCLC patients pretreated with a single dose of dexamethasone 20 mg prior to pemetrexed, there were no patient reports of grade 3 or higher cutaneous reactions throughout the course of their treatments. 7 Results from this study were similar to the results of prior studies looking at incidence of cutaneous reactions with dexamethasone use in patients receiving pemetrexed. The cutaneous reactions that occurred in this study included rash, cellulitis, pruritus without rash, and pigmentation.…”

Section: Discussionsupporting

confidence: 84%

Incidence of cutaneous reactions with pemetrexed: Comparison of patients who received three days of oral dexamethasone twice daily to patients who did not

Clark

Anselmo

2018

J Oncol Pharm Pract

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Pemetrexed is a multitargeted antifolate indicated for locally advanced or metastatic non-squamous non-small-cell lung cancer and malignant pleural mesothelioma. Cutaneous reactions are associated with pemetrexed use. Pemetrexed prescribing information recommends oral dexamethasone 4 mg twice daily for three days starting the day before pemetrexed infusion to prevent cutaneous reactions. Patients receive intravenous dexamethasone before pemetrexed infusion at the University of New Mexico Comprehensive Cancer Center, but the oral dexamethasone recommendation is not always followed. The objective of this study was to determine if there is a difference between patients who received three days of oral dexamethasone starting the day before pemetrexed infusion and patients who did not by determining incidence of cutaneous reactions, delay in therapy, and therapy change due to adverse reactions. Eighty-five patients received at least one dose of pemetrexed between August 1, 2012 and August 31, 2017. Twenty-nine patients did not receive three days of oral dexamethasone 4 mg twice daily and 56 patients did (34.1% vs. 65.9%). There was no statistically significant difference in the incidence of cutaneous reactions between the intervention group and the control group (13.8% vs. 25.0%; p = 0.384), delay in pemetrexed therapy between groups (44.8% vs. 32.1%; p = 0.2), or therapy change due to adverse events (34.5% vs. 23.2%; p = 0.654). Results suggest three days of oral dexamethasone 4 mg twice daily did not significantly affect incidence rates of cutaneous reactions, delay in therapy, or therapy change in patients who received intravenous dexamethasone before pemetrexed infusion at University of New Mexico Comprehensive Cancer Center.

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Section: Discussionsupporting

confidence: 84%

Incidence of cutaneous reactions with pemetrexed: Comparison of patients who received three days of oral dexamethasone twice daily to patients who did not

Clark

Anselmo

2018

J Oncol Pharm Pract

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“…1 For other chemotherapeutics, such as pemetrexed, dexamethasone needs to be coadministered to prevent hypersensitivity drug reactions. 16 Dexamethasone is a common synthetic glucocorticoid agonist that is largely successful in limiting these side effects. However, due to its wide ranging immunosuppressive properties, 3 we wanted to test whether dexamethasone might inhibit the positive immunostimulatory effects of checkpoint blocking antibodies.…”

Section: Discussionmentioning

confidence: 99%

Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment

et al. 2019

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Dexamethasone is a synthetic glucocorticoid commonly used for the prevention and management of side effects in cancer patients undergoing chemotherapy. While it is effective as an anti-emetic and in preventing hypersensitivity reactions, dexamethasone depletes peripheral blood lymphocytes and impacts immune responses. The effect of dexamethasone on the number and quality of tumourinfiltrating leukocytes has not been reported. To address this, we calibrated the dose in two different strains of mice to achieve the same extent of peripheral blood lymphocyte depletion observed in patients with cancer. Doses that caused analogous depletion of T and B lymphocytes and NK cells from the peripheral blood, elicited no change in these populations within the tumour. The expression of immune checkpoint molecules PD-1, OX40, GITR and TIM3 on tumour-infiltrating lymphocytes was not altered. We found that dexamethasone had a small but significant deleterious impact on weakly efficacious chemoimmunotherapy but had no effect when the protocol was highly efficacious. Based on these results, we predict that dexamethasone will have a modest negative influence on the overall effectiveness of chemoimmunotherapy treatment.

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“…Dexamethasone is administered primarily to mitigate untoward side effects often experienced with this chemotherapeutic combination including hypersensitivity reactions and fluid retention reactions[ 17 ]. Typically dexamethasone is administered with a 3 day regimen, dosed the day before, day of and day after the administration of pemetrexed and cisplatin or carboplatin, although some oncologists choose to only give dexamethasone on the day of therapy[ 17 , 18 ]. Since dexamethasone has been demonstrated to suppress TK1 expression[ 14 ], and TK1 activity and expression is central to the pemetrexed-induced “flare” in thymidine salvage pathway activity, we asked the question whether co-administration of dexamethasone with pemetrexed could impair the use of the pemetrexed-induced “flare” as a predictive imaging tool in this setting.…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone pretreatment impairs the thymidylate synthase inhibition mediated flare in thymidine salvage pathway activity in non-small cell lung cancer

2018

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IntroductionSuccessful inhibition of thymidylate synthase (TS) by pemetrexed, a TS inhibitor, results in a reproducible transient burst or “flare” in thymidine salvage pathway activity at 2 hrs. of therapy which can be measurable with FLT-PET ([18F]fluorothymidine-positron emission tomography) in non-small cell lung cancer (NSCLC). Routine administration of dexamethasone with pemetrexed-based therapy could potentially confound this imaging approach since dexamethasone is known to inhibit expression of thymidine kinase 1, a key enzyme in the thymidine salvage pathway. Here we examine the potential impact of dexamethasone on the TS inhibition-mediated thymidine salvage pathway “flare” in NSCLC.Materials and methodsIn order to determine NSCLC cell line sensitivity to dexamethasone and pemetrexed, IC50 studies were performed on NSCLC cell lines H23, H1975, H460, H1299. TS inhibition-mediated “flare” in thymidine salvage pathway activity was then measured at 2hrs. of exposure to pemetrexed and cisplatin in NSCLC cells lines following using 3H-thymidine incorporation assays under the following conditions: control (no chemotherapy or dexamethasone), or treated with pemetrexed and cisplatin without dexamethasone, with 24 hrs. pre-treatment of dexamethasone or with dexamethasone administered together with chemotherapy. These conditions were chosen to model the delivery of pemetrexed-based therapy in the clinic.ResultsThe IC50 of H23, H1975, H460, H1299 for dexamethasone and pemetrexed were 40, 5.9, 718, 362 μM and 0.22, 0.73, 0.14 and 0.66 μM respectively. Significant blunting of the thymidine salvage pathway “flare” is observed at 2hrs. of pemetrexed-based therapy when dexamethasone sensitive cell lines H23 and H1975 were pretreated with dexamethasone but not when dexamethasone was given together with pemetrexed therapy or in the setting of dexamethasone resistance (H460 and H1299).Conclusion24 hr. pretreatment with dexamethasone, but not same day co-administration of dexamethasone with therapy, impairs the TS inhibition-mediated “flare” in thymidine salvage pathway activity in NSCLC.

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Single-dose dexamethasone for the prevention of pemetrexed associated cutaneous adverse reactions

Cited by 9 publications

References 17 publications

Incidence of cutaneous reactions with pemetrexed: Comparison of patients who received three days of oral dexamethasone twice daily to patients who did not

Incidence of cutaneous reactions with pemetrexed: Comparison of patients who received three days of oral dexamethasone twice daily to patients who did not

Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment

Dexamethasone pretreatment impairs the thymidylate synthase inhibition mediated flare in thymidine salvage pathway activity in non-small cell lung cancer

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