No Need For H - Antagonists in Premedication Regimens For Paclitaxel Infusions: Less Is More

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EDITORIAL
No need for H2-antagonists in premedication regimens for
paclitaxel infusions: less is more
The theoretical basis for use of histamine 2 (H2)-receptor inhibitors to prevent hypersensitivity reactions for paclitaxel infusions is
weak. This Editorial discusses a clinical study showing that ranitidine is not indicated any more in this setting and puts this in the
context of other valuable efforts leaving non-evidence-based interventions behind us.
British Journal of Cancer (2021) 124:1613–1614; https://doi.org/10.1038/s41416-021-01316-x
MAIN Although the study by Cox et al.3 was, for practical and financial
Even in this era of evidence-based medicine many interventions reasons, not randomised, the study was prospective, well
are still based on scarce or even contradictory evidence. A good balanced and adequately powered, and the results were in line
example is the use of a histamine 2 (H2)-receptor antagonist such with the preclinical rationale. Therefore, the data are convincing us
as ranitidine in premedication schedules for paclitaxel infusions. to refrain from ranitidine, and thus H2-receptor antagonist
Hypersensitivity reactions (HSR) to paclitaxel, thought to be mainly premedication in all future patients receiving paclitaxel.
due, but not limited to, its solvent Cremophor EL are an important Omitting the unproven intervention not only is cost-efficient, but
side effect that can be severe or even life-threatening.1 This side- also reduces risks due to the measures and these studies should
effect was significantly reduced by premedication consisting of therefore be stimulated. In the example of ranitidine and paclitaxel
ranitidine in combination with dexamethasone and a histamine-1 cost-effectiveness has not yet formally been calculated but the
(H1) receptor antagonist. It is however unsure which components authors rightly explain that lower hospital and drug resource use for
of the 3-drug premedication regimen, consisting of dexametha- this frequently used drug will inevitably reduce time and costs. Not
sone and an H1 and H2 receptor antagonist, are necessary to only the current ranitidine shortage related to uncertainty about its
prevent these allergic reactions. The theoretical basis for use of carcinogenic effects, but also the COVID-19 overall hospital resource
ranitidine is the weakest of the 3 medications used while it is shortage adds to the fact that the results of this study are
known that ranitidine itself may result in hypersensitivity reactions welcomed and ready to be implemented as of now.
in 0.7% of infusions.2 Since the added value of an H2-receptor The question now is: what is next? It is well known that more than
antagonist has thus far not been systematically studied in the 90% of all paclitaxel related HSRs occur in the first 2 cycles and
clinic, Cox and colleagues3 performed a pre-post interventional, therefore multiple studies were performed to omit dexamethasone
non-inferiority study assessing ranitidine prophylaxis for paclitaxel e.g. from cycle 3 onwards in patients who had no prior HSR.6,7 Given
infusions. The results of this practice changing study are presented the results of these kind of studies and the broad range of short-
in this issue of the British Journal of Cancer.3 and long-term side effects of dexamethasone, discontinuation of
All consecutive patients receiving their first cycle of paclitaxel dexamethasone beyond cycle 3, especially when used in a weekly
from a single centre were enrolled in this study. All 183 patients in schedule, could be considered especially for those with a high risk
the pre-intervention group received the standard premedication for steroid-induced side effects, such as patients with diabetes. Also,
consisting of dexamethasone (10 mg IV), clemastine (2 mg IV) and it remains to be studied what optimal lowest dose of dexametha-
ranitidine (50 mg IV) and all 183 patients in the sequential post- sone should be used: 10-20 mg seems quite a high dose, especially
interventional group received the experimental premedication when given for multiple cycles. The role of H1-receptor antagonist
regimen without ranitidine. HSR of any grade during paclitaxel beyond cycle 3 also needs to be studied in the future as drowsiness
infusion occurred in 37 (20%) in the pre-interventional group with is a common side effect of these drugs and for the same reasons of
ranitidine and 22 (12%) in the post-interventional group without cost-effectiveness as discussed earlier.
ranitidine. Regarding the comparison of—any grade—HSRs, a The novel taxanes, not formulated in Cremophor EL such as
regimen without ranitidine showed to be non-inferior to the pre- docetaxel and more recently cabazitaxel (both formulated in
intervention regimen with ranitidine (difference −8.2%, 95% CI polysorbate 80) have a much lower risk of HSRs: the optimal
−15.0%; −1.4%, p = 0.046). The severity of HSRs, the number of premedication regimen should be re-evaluated for these taxanes
paclitaxel dosages and time to first HSR occurrence did not differ as well. A very high dose of dexamethasone is advised for
between the groups. docetaxel, up to 8 mg twice daily for 3 days. Therefore, we are
The authors should be applauded for their work and this study currently performing a dexamethasone dose de-escalation study
adds to several others that were done to omit non-evidence based (NCT02776436) which should lead to a confirmatory larger trial.
interventions e.g. withholding pre-hydration in patients with stage Ultimately newer taxanes with minimal chance of HSRs, such as
3 chronic kidney disease undergoing contrast-enhanced com- albumin bound nab-paclitaxel, should pave the way to a safe and
puted tomography4 and omitting calcium/magnesium infusions HSR-free future for this important class chemotherapeutics in
to protect against oxaliplatin induced neuropathy.5 In these oncology. Meanwhile, as long as paclitaxel is still one of the most
examples rigorous prospective Phase 3 studies were used to frequently used taxanes, the study by Cox et al.3 has shown us
convince the medical community to stop doing the intervention. how to improve its use in clinical practice: less is more.
Received: 17 January 2021 Revised: 26 January 2021 Accepted: 9 February 2021

Published online: 24 March 2021
© The Author(s), under exclusive licence to Cancer Research UK 2021

Editorial
1614
AUTHOR CONTRIBUTIONS REFERENCES
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ADDITIONAL INFORMATION 2. Demirkan, K., Bozkurt, B., Karakaya, G. & Kalyoncu, A. F. Anaphylactic
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(2006).
Data availability Not applicable. 3. Cox, J. M., van Doorn, L., Malmberg, R., Oomen-de Hoop, E., Bosch, T. M., van den
Bemt, P. M. L. A. et al. The added value of H2-antagonists in premedication regi-
Competing interests The authors declare no competing interests. mens during paclitaxel treatment. Br. J. Cancer (2021), https://doi.org/10.1038/
s41416-021-01313-0.
Funding information None. 4. Timal, R. J., Kooiman, J., Sijpkens, Y. W. J., de Vries, J. P. M., Verberk-Jonkers, I. J. A. M.,
Brulez, H. F. H. et al. Effect of no prehydration vs sodium bicarbonate prehydration
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims prior to contrast-enhanced computed tomography in the prevention of post-
in published maps and institutional affiliations. contrast acute kidney injury in adults with chronic kidney disease: the Kompas
randomized clinical trial. JAMA Intern. Med. 180, 533–541 (2020).
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Phase III randomized, placebo-controlled, double-blind study of intravenous cal-
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Department of Medical Oncology, Leiden University Medical Center, 6. Berger, M. J., Vargo, C., Vincent, M., Shaver, K., Phillips, G., Layman,R. et al. Stopping
Leiden, The Netherlands and 2Department of Clinical Pharmacy and paclitaxel premedication after 2 doses in patients not experiencing a previous
Toxicology, Leiden University Medical Center, Leiden, The Netherlands infusion hypersensitivity reaction. Support Care Cancer 23, 2019–2024 (2015).
Correspondence: Hans Gelderblom (a.j.gelderblom@lumc.nl) 7. de Castro Baccarin, A. L., Macilon Nonato, I., de Iracema Gomes Cubero, D., Ariana
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Cancer 27, 927–/931 (2019).

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British Journal of Cancer (2021) 124:1613–1614; https://doi.org/10.1038/s41416-021-01316-x

Received: 17 January 2021 Revised: 26 January 2021 Accepted: 9 February 2021

© The Author(s), under exclusive licence to Cancer Research UK 2021

Cancer 27, 927–/931 (2019).

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