H2 blockers in the prevention of paclitaxel-related hypersensitivity reaction

SUMMARY

Dexamethasone and histaminic (H1 and H2) blockers are routinely used as pre-medication drugs for the paclitaxel-related hypersensitivity reaction (HSR). The inclusion of this strategy was more empirical than evidence-based following the initial experience with life-threatening HSR during phase 1 studies done in early 1981.¹ The inclusion was to reciprocate the prevention strategy similar to contrast-induced HSR.² People worldwide continued to use the same preventive measures over the past 40 years. Of the three components of a preventive strategy, the most argued one is the role of H2 receptor antagonists.³ We congratulate Cox et al. for raising and successfully testing the research question. However, they selected a pre–post interventional study. A randomized study design is a preferred scheme to get a value close to the true one. In this study, steroids and clemastine (H1 blockers) were given with or without ranitidine (H2 blockers) during October 2018 to April 2019 and April to December 2019. The study design was an open-labelled, non-randomized, non-inferiority trial. The trial enrolled adult patients (18 years or above) who were to receive the first cycle of conventional paclitaxel (weekly or three-weekly, with or without partner drug) for a maximum of six cycles. The primary end-point was the incidence of grade 3 or more HSR. The sample size was 366 with a 6% non-inferiority margin, 90% power and a one-sided alpha error of 0.05. The common tumour type was oesophagus (42%), breast (32%), lung (9%) and gynaecological (14%). In both the arms, an equal proportion of patients received corticosteroids (9.8%) and antihistamines (4.95) for other associated comorbid conditions. In the two study arms with and without ranitidine, the rate of all grades HSR was (20% v. 12%), grade 3 or higher HSR (4.4% v. 1.6%) and grade 1–2 HSR (16% v. 10%).⁴ The difference between the two arms was –2.7% (90% CI –6.2% to 0.1%). The present study concluded that ranitidine (H2 blocker) can be safely omitted from the standard paclitaxel pre-medication strategy.

COMMENT

It is good to see a real-life, simple question being addressed, which has remained neglected for the past four decades. Although ranitidine is a cheap drug, its routine use with paclitaxel (one of the most commonly used chemotherapy drugs) adds cost to cancer care. Interestingly, the rate of severe (4.4% v. 1.6%) and all grade HSR rates (20% v. 12%) were numerically lower in the arm without ranitidine. The data presented provide reassurance to safely omit H2 blockers. Ranitidine is associated with a HSR, hepatotoxicity, nephrotoxicity and thus omission of unnecessary use is welcome.^5–7 Lately, ranitidine has been associated with cancer risk due to contamination with a chemical called NNitrosodimethylamine (NDMA). The discovery of ranitidine containing a high level of NDMA led to the US Food and Drug Administration announcing holding its sales across the USA.⁸ Similar regulations were implemented in Canada and France. It is not clear whether it is related to contamination or part of drug decomposition. However, in India, the drug is not banned and is commonly used for the prevention of paclitaxel-induced HSRs. Avoiding the unnecessary use of ranitidine carries the potential to reduce both the cost and the side-effects. However, we believe that several issues require clarification before a change in practice.

The study design has a few limitations. A randomized, blinded, placebo-controlled trial would have been the best to provide evidence to change the present practice. However, this study was a single-centre, non-randomized, open-label study. The study design thus has a potential for various forms of bias. The rate of all and severe grade HSRs vary markedly in the published literature (2%–45%).^2,9,10 In the study, the rate of all grade HSR rate was almost half in the ranitidine arm, which cannot be explained. There is no well-defined prospectively evaluated identifiable risk factor for paclitaxel HSR. Thus, a non-randomized study has a high potential for unbalanced allocation of unknown confounding factors between the two arms. The study did not provide details of the HSR in the weekly and three-weekly arms. There was a higher proportion of gynaecological cancer in the ranitidine arm (19.1% v. 8.1%). Gynaecological cancer was associated with the severe form of HSR on the univariate analysis. Although no comparative randomized data exist, retrospective studies suggest a higher rate of paclitaxel-related HSR with the three-weekly regimen.¹¹

Hence, we consider the study as hypothesis-generating given the above-mentioned limitations and suggest caution against the omission of H2 receptor blocker (ranitidine) as part of the paclitaxel pre-medication strategy. Similar studies with a large sample size will generate confidence among clinicians.

This study has encouraged us, and we have planned a phase 3, randomized, blinded, placebo-controlled, parallel assigned, with non-inferiority study design at our centre to answer the study question in a more rational and well-controlled setting and to gain experience at the same time.