The rates and severity of paclitaxel hypersensitivity reactions remained similar despite the use of a modified Markman’s protocol as primary prophylaxis compared to a standard 3-h infusion regimen. The rate of paclitaxel hypersensitivity reactions in our study was consistent with the literature, with reported rates ranging from 5 to 15% with the use of pre-medications [1, 3, 6, 8, 9, 12,13,14,15,16,17]. Although the incidence of hypersensitivity reactions was similar with modified Markman’s protocol to our standard 3-h infusion protocol, there were no grade 3 hypersensitivity reactions, and all patients who experienced reactions were able to be successfully rechallenged using a modified Markman’s protocol. Nonetheless, given the additional cost and similar rate of hypersensitivity reactions, Markman’s protocol should be reserved as a rechallenge strategy for patients who have previously had a paclitaxel hypersensitivity reaction, using the higher doses of dexamethasone and antihistamines originally reported.

Paclitaxel is a key chemotherapy agent used in the treatment of many cancers, especially gynaecological cancers. Therefore, any effort toward minimising the rates of paclitaxel hypersensitivity reactions has major clinical implications for the treatment of these patients. Pre-medications with dexamethasone and H1 and H2 antagonists have been highly successful in preventing severe or life-threatening paclitaxel hypersensitivity reactions [1]. However, there is much variation in clinical practice regarding the use of paclitaxel pre-medications. In our study, the same pre-medications were used in the pre-implementation and post-implementation groups. Multiple studies have analysed different pre-medications in both weekly paclitaxel and paclitaxel every 21 days with mixed results [6, 12,13,14,15,16, 19]. A meta-analysis which included 28 studies assessing the use of pre-medications in both weekly and 21-day paclitaxel regimens found that a tapering dexamethasone regimen in patients without hypersensitivity reactions after the first weekly dose of paclitaxel is safe. It also found that a single dose of 20 mg IV dexamethasone instead of the standard oral 20 mg dexamethasone regimen prior to the administration of 21-day paclitaxel is likely to be associated with a higher rate of hypersensitivity reactions, suggesting that multiple doses of dexamethasone pre-medication may have a role in reducing the rate of paclitaxel hypersensitivity reactions [12]. A double-blind randomised controlled trial compared the efficacy and side effects of intravenous 20 mg versus oral 20 mg dexamethasone pre-medication for 281 patients receiving paclitaxel for gynaecological cancers, with no significant difference in rates of reactions [18]. Another retrospective study included women receiving paclitaxel 175 mg/m2, 93 of whom received oral 20 mg dexamethasone and 55 of whom received IV 20 mg dexamethasone [13]. The rate of hypersensitivity reactions was 5.4% in the oral dexamethasone group compared to 14.5% in the IV dexamethasone group.

To our knowledge, no studies have utilised Markman’s desensitisation protocol as a primary prophylaxis measure with the aim of reducing the rate of paclitaxel hypersensitivity reactions. However, a prospective study of 222 first- and second-lifetime exposure to paclitaxel and docetaxel infusions comparing a three-step titration method compared to a non-titration method did show a significant reduction in hypersensitivity reactions (19% in the non-titrated group compared to 7% in the titrated group) [20]. This study was also a small (n = 222 infusions) single-centre study that used a titrated infusion method, which differed from the three-bag titration method used in our study. While our study did not show a significant difference in the rate of paclitaxel hypersensitivity reactions, this study did. Further studies assessing titration methods with the aim of reducing the rate of paclitaxel hypersensitivity reactions are required. Multiple other studies have been conducted to assess the effectiveness of other interventions in reducing the rate of paclitaxel hypersensitivity reactions, with varying results. A study that assessed the effectiveness of a test dose program with taxanes on hypersensitivity reactions and cost included 206 patients receiving either paclitaxel or docetaxel from 1998 to 2000 [4]. They found that the rate of hypersensitivity reactions was comparable between the two groups. Another study also assessed the cost-effectiveness of a test dose program for paclitaxel to reduce drug wastage related to infusion reactions and included 162 patients who received paclitaxel prior to the implementation of the test dose, from January 1997 until February 2003, 10 of whom developed a hypersensitivity reaction [16]. The test dose was then implemented (a single 12 mg dose of paclitaxel given at a rate of 2 mg/min), and 130 patients who received 244 test doses from June 2003 to March 2005 were included in the study. They found a 63% reduction in paclitaxel hypersensitivity reactions but a 29% increase in the cost. A study assessing the impact of infusion time on hypersensitivity reactions compared two cohorts of patients: one group that received a titrated dose of paclitaxel (N = 143) and one group that did not (N = 46) [21]. They found that a slow or titrated infusion rate did not mitigate hypersensitivity reactions and that it was associated with an increased likelihood of infusion reactions during the first two dose administrations. A limitation was that there were relatively few patients in the standard rate cohort. A retrospective, single-centre review compared the use of rescue medications in two cohorts of patients: one receiving infusion rate escalation (N = 77) and the other cohort receiving a standard infusion (N = 22) rate [22]. The use of rescue medications was 23% in the rate escalation infusion cohort and 5% in the standard infusion cohort [22].

For patients who have had a previous paclitaxel hypersensitivity reaction, paclitaxel desensitisation is an option and commonly used except in patients who experienced a severe life-threatening immunocytotoxic reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or drug-induced eosinophilia and systemic symptoms (DRESS) [3]. Skin testing has also been studied but is not validated for taxanes as the mechanism of hypersensitivity reactions is not thought to be primarily IgE mediated [17]. In patients who have had a significant hypersensitivity reaction to paclitaxel, there are alternative options such as docetaxel, although some studies have reported a cross-reactivity rate of up to 90% [1, 5]. Another alternative is the use of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as the formulation with albumin allows reconstitution of nab-paclitaxel with a saline solution instead of solvents, has lower rates of hypersensitivity and therefore does not require pre-medication with corticosteroids, although there are no studies showing that nab-paclitaxel is safe in patients who have previously had a grade 3 or 4 paclitaxel hypersensitivity reaction [23].

In our audit, for the data collected retrospectively from the pre-implementation period, there was unavoidably missing data for infusion time and assessment of paclitaxel hypersensitivity reactions. However, the variations in assessment appeared to be minimal and did not affect the quality of the data collected overall. The implementation of modified Markman’s infusion was then protocolized, and the data for the post-implementation group was prospectively collected to ensure a quality assessment of hypersensitivity reactions during this period. Since our analysis only focused on the female population with gynaecological cancers, the results may not be generalisable to the male population and other types of cancers. It is also important to acknowledge the inherent limitations of conducting a single-centre retrospective study. Firstly, although our results provide valuable insights into the outcomes within our centre, caution should be exercised when extrapolating these findings to different settings or populations. The unique characteristics of our patient population and the specific treatment protocols utilised here may not be directly applicable to other contexts. Secondly, we acknowledge that the sample size of our study may limit the ability to detect small effect sizes. This limitation underscores the need for cautious interpretation of our findings and highlights the need for additional studies to validate and expand upon our results.

We did not observe a significant difference in the rate of paclitaxel hypersensitivity reactions using a modified Marman’s desensitisation protocol as a primary prophylaxis measure. The management and prevention of hypersensitivity reactions remain an important issue in the management of multiple malignancies, particularly gynaecological malignancies where paclitaxel is frequently used. Furthermore, studies on variations to pre-medications have not consistently yielded an improvement in the rates of paclitaxel hypersensitivity reactions. Given the time and cost for the administration, Markman’s desensitisation protocol with higher dose steroids should be reserved for those with paclitaxel hypersensitivity reactions who are not successfully rechallenged and for whom paclitaxel is considered essential.