Steroid Dose and Taxanes

This podcast discusses the study, steroid dose reduction, practice experience, and guidance changes.   TRANSCRIPT [MUSIC PLAYING] ROBIN ZON: This JCO podcast provides observations and commentary on the JCO article-- "Do Steroids Matter: A Retrospective Review of Pre-Medication for Taxane Chemotherapy and Hypersensitivity Reactions," by Lansinger et al. My name is Dr. Robin Zon. And I am the quality oncology practice initiative lead physician for Michiana Hematology Oncology, an independent community oncology practice located in Mishawaka, Indiana. My oncologic specialty is general medical oncology. And I have a strong interest in breast cancer. This article is based on the premise that there exists significant variation regarding the prescribing practices of steroids for pre-medication to minimize the known hypersensitivity reactions associated with the taxanes paclitaxel and docetaxel. In fact, the authors remind the reader that initial clinical development of paclitaxel was delayed due to the notable hypersensitivity rate of 25% to 30%, as patients did not receive pre-medication. Subsequent trials used a pre-medication strategy of dexamethasone, diphenhydramine, and H2 antagonist, with a reduction of the reaction occurrence to 2% to 3%. As a result of the improved reaction rates in clinical trials with the use of a pre-medication regimen, both paclitaxel and docetaxel, FDA approved package inserts recommend oral corticosteroid pre-medication, 20 milligrams, 12 and 6 hours prior to the taxane administration. However, there has been no dose optimization to date. In fact, the authors note that lower dose regimens are routinely used in daily practice and may lead to increased risk of hypersensitivity reactions. Furthermore, steroids can cause multiple adverse effects if taken for extended periods of time, which can range from mild to moderate in their severity. This study reviewed steroid prescribing patterns in patients receiving the first dose of paclitaxel or docetaxel at Stanford Cancer Institute between 2010 and 2020. A total of 3,181 patients met criteria for analysis, with an 8.3% rate of hypersensitivity reactions. And the adjusted multivariate analysis, the authors found no correlation between the hypersensitivity reaction rate or the severity among the variables evaluated, except for the gynecology/oncology clinic patients who had an increased risk for hypersensitivity reactions overall with a hazard ratio of 1.34 and high grade hypersensitivity reactions with a hazard ratio of 2.34, and female patients who had a higher rate of hypersensitivity reactions overall with a hazard ratio of 1.26, but not high grade hypersensitivity reactions. The conclusion of the article is that neither dexamethasone dose nor route, IV or oral, correlated with subsequent hypersensitivity reactions. And that the recommended 40 milligrams dose of dexamethasone prior to taxane administration is no better than the 10 milligrams dose for protecting against hypersensitivity reactions. Therefore, the lower doses used in clinical practice is acceptable and even preferable to higher doses. Although the study authors point out that the strength of the study is the large data set reviewed, they also point out that this study was a retrospective analysis completed on first dose dexamethasone use and not on subsequent taxane exposures Additionally, the authors also point out that since there was no external validity, the results may not be generalizable to other patient populations treated at other institutions. For the remainder of this podcast, the commentary represents my opinion only and may not represent the opinion of this journal or its editors. First, I would like to commend the authors on this analysis, which addresses a very practical question-- do steroids matter. And is it possible to safely vary from the package insert? The work dedicated to collecting this data set does not go unnoticed. As the authors acknowledge, the prescribing practice patterns for steroid pre-medication does vary considerably across and within practices. Furthermore, the common references that practices use for treatment guidance, including NCCN and UpToDate, describe differing options. For example, the NCCN order template for weekly paclitaxel refers to using pre-medication of H2 blocker plus diphenhydramine and dexamethasone 10 milligrams IV with weekly doses, one to three, then may consider dose reduction of dexamethasone to 4 milligrams with weekly dose 4, and does not elaborate on further dose reduction. For Q2 or three-week paclitaxel dosing, the NCCN template follows the package insert. UpToDate also recommends 20 milligrams of dexamethasone orally 12 and 6 hours prior to drug administration with H1 and H2 receptor antagonists as a pre-medication regimen for Q2 or three-week treatment. However, for weekly paclitaxel, UpToDate offers consideration of a dexamethasone dose of 10 milligrams IV with H1 and H2 blockers, then tapering the glucocorticoid by 2 milligrams decrements after weekly dose 3 or 4, and can even discontinue the dexamethasone in patients without infusion reactions. For docetaxel, UpToDate suggests dexamethasone 8 milligrams orally BID for three days. To further confirm the practical world of dexamethasone pre-medication variability, in a straw poll within our practice and outside our practice, many providers do utilize the 10 milligrams dexamethasone dose for the first dose of Q2 or three-week taxanes, and reduce and then eliminate dexamethasone for weekly taxanes when feasible and have done so for many years, while other providers strictly follow FDA labeling. Importantly the reason providers are willing to de-escalate the pre-treatment medications for taxanes is that patients have less side effects and are grateful to have this drug reduced or even eliminated from their treatment. So the question asked and the knowledge generated by the study becomes extremely relevant as providers consider ways to de-escalate interventions, especially if patient outcomes are not placed at risk and quality of life can be improved. The next question relates to the authors' concern of lacking external validity and generalizability to other patient populations. In my opinion, it would not be feasible to conduct this labor-intensive data set collection and analysis at a multitude of independent community and academic sites. However, this could be an opportunity to query real world data platforms, such as ASCO's CancerLinQ, to look for steroid complications such as grade 3 and grade 4 events related to change in pre-medication strategies. But even real world databases may have limits based on the specificity of the query and the inadequate capture of adverse events, especially less severe toxicities, as this structure data may not be recorded in the electronic medical record. Finally, the most relevant question is whether practice and guidelines should change as a result of this data. As I have discussed, many practices have already made this initial dose modification, and even safely dose reduced beyond the scope of this data set inquiry. Therefore, I do think that initial dosing as suggested by this study should be more widely guideline adopted and that consideration for further reduction with additional taxane doses be based on practice-specific experience and guidelines. This concludes this JCO podcast. Thank you for listening. [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.