Paclitaxel Hypersensitivity Reactions Research Articles

Is a low dose of dexamethasone sufficient to prevent paclitaxel-related hypersensitivity reactions? A retrospective study in patients with gynecologic malignancy

ABSTRACT Background Paclitaxel hypersensitivity reactions (HSRs) are prevalent, especially in females. The common paclitaxel pretreatment, dexamethasone, may inhibit chemotherapy efficacy and accelerate tumor progression. We aimed to balance paclitaxel HSRs and the lowest dexamethasone dose for gynecologic malignancies. Methods We retrospectively examined 1,074 cycles of 3-weekly paclitaxel-containing treatment for 231 gynecologic malignancies at Xiangya Hospital. HSR incidence with different dexamethasone regimens was the primary outcome. Risk factors were examined in all cycles using univariate and multivariate models with generalized estimating equations. A subgroup analysis of initial exposure to paclitaxel was also conducted. Results HSR occurred in 33 patients (14.29%) and 49 cycles (4.56%), including 69.39% in cycles 1–2. There were no severe HSRs (grade ≥3). Different premedication regimens, including dexamethasone dosage and route, ranitidine presence or absence, didn’t affect HSR incidence in univariate and multivariate analyzes (p > 0.05). Premenopausal women exerted fewer HSRs (ORadj 0.22, 95%CI 0.08–0.58; p = 0.002). At the first exposure to paclitaxel, more than 10 mg of dexamethasone didn’t diminish HSRs (OR 0.83, 95%CI 0.27–2.59; p = 0.753). Conclusions In gynecologic malignancies, 10 mg dexamethasone along with 20 mg diphenhydramine may be adequate to prevent paclitaxel HSRs without ranitidine. It is necessary to reevaluate paclitaxel premedication regimens.

Rates of paclitaxel hypersensitivity reactions using a modified Markman’s infusion protocol as primary prophylaxis

PurposeMarkman’s desensitisation protocol allows successful retreatment of patients who have had significant paclitaxel hypersensitivity reactions. We aimed to reduce the risk and severity of paclitaxel hypersensitivity reactions by introducing this protocol as primary prophylaxis.MethodsWe evaluated all patients with a gynaecological malignancy receiving paclitaxel before (December 2018 to September 2019) and after (October 2019 to July 2020) the implementation of a modified Markman’s desensitisation protocol. The pre-implementation group received paclitaxel over a gradually up-titrated rate from 60 to 180 ml/h. The post-implementation group received paclitaxel via 3 fixed-dose infusion bags in the first 2 cycles. Rates and severity of paclitaxel hypersensitivity reactions were compared.ResultsA total of 426 paclitaxel infusions were administered to 78 patients. The median age was 64 years (range 34–81), and the most common diagnosis was ovarian, fallopian tube and primary peritoneal cancer (67%, n = 52/78). Paclitaxel hypersensitivity reaction rates were similar in the pre-implementation (8%, n = 16/195) and post-implementation groups (9%, n = 20/231; p = 0.87). Most paclitaxel hypersensitivity reactions occurred within 30 min (pre- vs. post-implementation, 88% [n = 14/16] vs. 75% [n = 15/20]; p = 0.45) and were grade 2 in severity (pre- vs. post-implementation, 81% [n = 13/16] vs. 75% [n = 15/20]; p = 0.37). There was one grade 3 paclitaxel hypersensitivity reaction in the pre-implementation group. All patients were successfully rechallenged in the post-implementation group compared to 81% (n = 13/16) in the pre-implementation group (p = 0.43).ConclusionThe modified Markman’s desensitisation protocol as primary prophylaxis did not reduce the rate or severity of paclitaxel hypersensitivity reactions, although all patients could be successfully rechallenged.

Hypersensitivity Reactions to Taxanes: A Multicenter Study for Outcomes and Safety of Rapid Drug Desensitization.

Taxanes can cause hypersensitivity reactions (HSRs), which pose a significant challenge in the treatment of malignancies. Patients who are eligible for rapid drug desensitization (RDD) can continue treatment; however, some patients experience breakthrough reactions (BTRs). Data about risk factors for BTRs during RDDs in patients with HSRs to taxanes are limited. This was a multicenter, retrospective study of patients with immediate-HSRs to taxanes. Initial HSRs were classified as grade 1, 2, or 3 based on severity. Prick/intradermal skin tests were performed with implicated taxanes. A 12-step protocol was used during RDD. The study comprised 75 patients (F/M: 63/12, mean age 49.92 ± 11.72 years, 43 HSRs to paclitaxel, 32 HSRs to docetaxel). The majority of reactions (86.7%) occurred during the first or second exposure. The prevalence of drug allergy history was higher in patients with paclitaxel HSR than in those with docetaxel HSR, although it was not statistically significant (23.3% vs. 6.3%). The initial HSRs were mostly grade 2 (n = 50, 66.7%) or grade 3 (n = 22, 29.3%). Skin tests with implicated taxanes were done on 48 patients, and the rate of positive response in patients with grade 1, 2, and 3 initial HSRs were 50%, 17.6%, and 16.7%, respectively. . A total of 255 RDDs were completely performed, although BTRs occurred in 27 (grade 1, 55.6%; grade 2, 40.7%; grade 3, 3.7%). There were no statistically significant correlations between the risk of BTR and age, drug cycle, gender, positivity of skin test or atopy. The step reduction was successfully done on 9 eligible patients with mild or moderate HSRs during the 12-step RDDs. Our experience demonstrates a 100% success rate in completing the 255 RDDs for taxanes, affirming the safety and efficacy of the RDD within the study population.

Impact of institutional interventions on the rate of paclitaxel hypersensitivity reactions.

Paclitaxel is associated with hypersensitivity reactions (HSRs). Intravenous premedication regimens have been devised to decrease the incidence and severity of HSRs. At our institution oral histamine 1 receptor antagonists (H1RA) and histamine 2 receptor antagonists (H2RA) were adopted as standard. Standardizations were implemented for consistent premedication use in all disease states. The purpose of this retrospective study was to compare the incidence and severity of HSRs before and after standardization. Patients who received paclitaxel from 20 April 2018 to 8 December 2020 having an HSR were included in analysis. An infusion was flagged for review if a rescue medication was administered after the start of the paclitaxel infusion. The incidences of all HSR prior to and post-standardization were compared. A subgroup analysis of patients receiving paclitaxel for the first and second time was performed. There were 3499infusions in the pre-standardization group and 1159infusions in the post-standardization group. After review, 100 HSRs pre-standardization and 38 HSRs post-standardization were confirmed reactions. The rate of overall HSRs was 2.9% in the pre-standardization group and 3.3% in the post-standardization group (p = 0.48). HSRs, during the first and second doses of paclitaxel, occurred in 10.2% of the pre-standardization and 8.5% of the post-standardization group (p = 0.55). This retrospective interventional study demonstrated that same-day intravenous dexamethasone, oral H1RA, and oral H2RA are safe premedication regimens for paclitaxel. No change in the severity of reactions was seen. Overall, better adherence to premedication administration was seen post-standardization.

Lessons learned from the investigation of a sustained increase in paclitaxel hypersensitivity reactions (P-HSR) at a large community oncology practice: A mystery not fully solved.

233 Background: Trillium Health Partners (THP) is a large community oncology practice that has a culture of quality and safety. An investigation was triggered by a perceived increase in the rate of P-HSR during a weekly quality huddle in the chemotherapy suite. At the time THP had no formal hypersensitivity reaction tracking process. A retrospective review of P-HSR over the preceding 18 months identified an increase in reaction rates from a baseline of 1% to 4.5% that started 3 months prior to the raised concern. Methods: A systematic quality review was undertaken to identify triggers for the change and to identify steps to decrease P-HSR to baseline. There was no identified change in premedication, administration or compounding practice and no association with drug or lot number was identified. The increase in P-HSR was coincident with a change in the intravenous (IV) pumps and tubing system across the hospital. The change in IV pumps introduced several potential triggers including: a change in the options for priming the IV tubing which introduced a potential for variable concentrations of drug reaching the patient at the outset of the infusion, an interaction between drug and IV tubing, and a doubling of the IV tubing length which could result in incomplete delivery of the premedication. Results: Sequential practice changes were introduced to address each potential driver including i) a slow infusion protocol for first 2 cycles, ii) alternative tubing sets, iii) practice alert regarding potential for under-delivery of premedication. Over time P-HSR trended down towards the historic baseline, no single intervention had a sustained impact, although the practice alert regarding the administration of premedication seemed to induce the most change. A step wise withdrawal of interventions that were felt to be non impactful is underway. Conclusions: Although no clear cause for the increase in P-HSR was identified the systematic quality review resulted in improved standardization of nursing practice for chemotherapy delivery and the methodical approach also lead to the establishment of a more comprehensive hypersensitivity reporting system at THP.

The Evaluation of Paclitaxel Hypersensitivity Reactions (Hsrs) Following the Discontinuation of Prophylactic Pre-Medications

ABSTRACT Aim: Paclitaxel administration is associated with hypersensitivity reactions (HSRs), which are infrequent beyond the second dose. The incidence of HSRs is reported to range from 8-45%, (severe reactions occurring in 2%). Pre-medication with dexamethasone, diphenhydramine, and famotidine are typically administered to reduce the risk of HSRs, but are associated with adverse effects and longer visit time. In January 2014, our institution implemented a policy to discontinue pre-medications for all patients receiving paclitaxel-based regimens beyond paclitaxel dose two. We sought to evaluate this practice change and hypothesize that this policy is unlikely to result in an increased rate of HSRs. Methods: During a four-month period, pre-medications were discontinued in 187 patients receiving paclitaxel-based chemotherapy, who were HSR free on two previous pre-medicated doses. 111 patients received paclitaxel+platinum and 76 patients received paclitaxel +/- trastuzumab. 65 patients received weekly paclitaxel, 7 patients received dose-dense paclitaxel every 2 weeks and 115 patients received paclitaxel every 3 weeks. Surveys were administered to patients receiving weekly paclitaxel to evaluate adverse effects and patient preference. Time required to administer pre-medications was tracked. Results: Two of 111 patients receiving paclitaxel+platinum (1.80%) and 2 of 76 patients receiving paclitaxel +/- trastuzumab (2.63%) had non-severe HSRs (NCI CTCAE grade 2 or lower). An average of 92.6 minutes of chair time per patient (per clinic visit), was saved following the discontinuation of pre-medications. A total of 51, 856 minutes (864 hours) of chair time was saved during the four-month study. Of 52 surveys, 23 (44%) were returned and 86.9% of patients preferred treatment without pre-medications compared to the first two doses with pre-medications. Conclusions: In patients receiving paclitaxel+platinum regimens or paclitaxel +/- trastuzumab, the discontinuation of pre-medications is a safe and feasible option if a patient has not experienced an HSR during the first or second dose of paclitaxel. Disclosure: All authors have declared no conflicts of interest.

Anaphylactic Reaction Induced By Paclitaxel in the Treatment of Non-Small Cell Lung Cancer (NSCLC)

Most systemic chemotherapic agents used in lung cancer treatment can lead to hypersensitivity reactions, of varying degrees of severity. In absence of laboratory tests (such as elevated serum total tryptase or/and plasma histamine levels).Distinguishing between anaphylaxis and acute infusion reactions is impossible since their symptoms are identical. Few Paclitaxel hypersensitivity reactions described in literature are documented in the absence of standardized tests to chemotherapeutics drugs and since not all suspected patients undergo allergological tests. A 74 years old female patient, with history of Inobitriol induced laryn- geal angioedema and right middle lobe NSCLC, developed a moderate anaphylactic reaction during Paclitaxel second administration. Infusion suspension and symptomatic treatments led to rapid symptoms remission. Prick tests to Paclitaxel were negatives but the intradermal reaction was positive, as well as basophile activation test. The mechanism of paclitaxel-associated hypersensitivity reaction is uncertain and its solvent vehicle may be involved; in case of paclitaxel immediate hypersensitivity reaction, we recommend tryptase and/or histamine serum levels quantification to confirm the acute anaphylaxis episode and realization of allergologicals tests to Paclitaxel and its solvent vehicle (skin tests ± challenge test) 3 to 4 weeks after the incident. Rapid desensitization is possible for both Ig-E mediated and non-Ig-E mediated immediate hypersensitivity reactions to Paclitaxel.

Paclitaxel hypersensitivity reactions: Prevalence and outcomes.

e16518 Background: Paclitaxel is an effective and commonly used chemotherapeutic. Severe hypersensitivity reactions (HSRs) to this drug are characterized by a combination of erythroderma, chest/bac...

Phase I/feasibility trial of dose-dense carboplatin (C) and paclitaxel (P) in patients (pts) with ovarian cancer: A Gynecologic Oncology Group study

5544 Background: Dose-dense regimens improve outcome for women with breast cancer. We investigated the feasibility of dose-dense CP for women with ovarian cancer. Methods: Pts with untreated stage III/IV ovarian cancer received C AUC 5 and P 175 mg/m2 day 1, pegfilgrastim 6 mg day 2 every 2 weeks for 6 cycles. Dose-limiting toxicity (DLT) was defined as: febrile neutropenia, grade 4 neutropenia ≥7 days, grade 4 thrombocytopenia (tcp), grade 3 tcp with bleeding, dose delay >2 weeks, grade 3/4 non-hematologic toxicity (excluding fatigue, hypersensitivity, nausea/vomiting, alopecia, constipation, diarrhea or bone pain), and any treatment related death. The study utilized a 2-stage sequential design (20 pts/stage) with DLTs in 6 cycles determining regimen feasibility. Results: Between September 2006 and September 2008, 43 pts enrolled. Twenty and 17 patients were evaluable for toxicity over 6 cycles in stages 1 and 2 respectively. Six DLT's were observed for both stages. Thirty pts completed treatment and 12 did not [DLTs (6), paclitaxel hypersensitivity reactions (2), progression (1), patient choice (1), infection (1) and death unrelated to treatment (1)]. One pt remains on treatment. The 6 DLTs resulting in treatment discontinuation included grade 3 neuropathy (2), grade 4 neuropathy (1), grade 4 tcp (1), grade 4 tcp/grade 3 febrile neutropenia (1), and grade 4 SVT (1). Six other DLTs not preventing treatment completion included grade 3 infection (1), grade 3 AST/ALT elevation (1), grade 3 confusion (1), grade 3 dehydration (1), grade 3 neuropathy (1) and grade 4 tcp (1). Other toxicities resulting in treatment delays included grade 3 tcp (1), grade 3 fatigue (1) and grade 2 neuropathy (2). There were 5 P dose reductions and 4 C dose reductions. Conclusions: Seventy-two percent pts completed 6 cycles of dose-dense CP. Based on DLTs (at least 12 in 37 evaluable pts), this regimen is not feasible. Given the neuropathy and tcp, we do not recommend further investigation in a phase III trial. No significant financial relationships to disclose.

Retrospective evaluation of weekly paclitaxel hypersensitivity reactions reported utilizing an electronic medical record system at a tertiary cancer center

This is a retrospective observational study evaluating hypersensitivity reactions captured by an electronic medical record (EMR) system for weekly paclitaxel infusions. The study evaluates the demographics, co-morbidities, premedications, chemotherapy agents, and postmedications of patients reporting a hypersensitivity reaction to weekly infusions of paclitaxel at a major cancer center, from June 2006 to December 2007. Data were analyzed using descriptive statistics and logistic regression. P values <0.05 were considered significant. There were 51 hypersensitivity reactions in 36 patients during this time period that were documented in the allergy section of the EMR. Reactions occurred in patients with an average age of 55 years (SD = 10.77); 47 (92%) of the reactions occurred in females, and 42 (82%) of the reactions occurred with orders on the breast medical/surgical service. Thirty-two (63%) reactions occurred with either the first or second dose of weekly paclitaxel infusion. The most common premedication was dexamethasone (50 infusions), followed by diphenhydramine (18 infusions), and cimetidine (14 infusions). Thirty-three (65%) infusions had only one premedication. Postreaction, 41 (80%) cases had diphenhydramine and 30 (59%) cases had hydrocortisone administered prior to restarting the infusion. Logistic regression analysis did not indicate any relationship between history of previous allergies, hypertension, coronary disease, or chronic obstructive pulmonary disease and the number of premedications. The results indicate that there is substantial variability in the type and number of premedications utilized in the management of paclitaxel hypersensitivity reactions. Interventions are needed to decrease the rate of hypersensitivity reactions from weekly paclitaxel infusions.

Phase I study of paclitaxel with standard dose ifosfamide in children with refractory solid tumors: A Pediatric Oncology Group study (POG 9376)

A dose-escalation Phase I study of taxol (paclitaxel) administered in combination with standard dose ifosfamide was conducted in children with relapsed or refractory solid tumors. Primary objectives were to estimate the maximum tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs). Paclitaxel was administered as a 6-hr continuous infusion (hr 0-6), followed by intravenous ifosfamide (2 g/m(2)/day x 3 days) over 1 hr at hours 6-7, 24-25, and 48-49. Patients at dose level 1 received 250 mg/m(2) paclitaxel. Subsequent dose escalation proceeded using a standard 3 x 3 Phase I design. Fifteen patients received a combined 46 courses of therapy. The median age was 14.5 years (range, 2-19 years), and diagnoses included sarcoma (7), neuroblastoma (3), and other (5). Three patients received paclitaxel at 250 mg/m(2) (10 courses), six at 325 mg/m(2) (19 courses), three at 425 mg/m(2) (8 courses), and three at 550 mg/m(2) (9 courses). DLTs occurred in 2/3 patients at 550 mg/m(2) paclitaxel during cycle 1, including grade 3 hypotension and grade 4 anaphylaxis in 1 patient each. Common non-dose-limiting toxicities included bone marrow suppression and peripheral neuropathy. Response was evaluable in 14 patients and included mixed response (3), stable disease (5), and progressive disease (6). Paclitaxel hypersensitivity reactions were dose limiting when the drug was administered as a 6-hr infusion. The MTD and recommended Phase II dose of paclitaxel administered as a 6-hr continuous intravenous infusion followed by standard dose intravenous ifosfamide is 425 mg/m(2) paclitaxel.

Oral premedication for the prevention of hypersensitivity reactions to paclitaxel

Premedication with dexamethasone, H1 and H2 receptor antagonists given intravenously prior to paclitaxel are highly successful in preventing life-threatening hypersensitivity reactions. We conducted a prospective study to assess the availability and safety of the administration of promethazine and dexamethasone per os in the premedication of paclitaxel hypersensitivity reactions. Of 180 eligible cancer patients, 100 patients received paclitaxel weekly and 80 patients, every 3 weeks. Patients received premedication with promethazine 25 mg per os, dexamethasone 2-20 mg per os and cimetidine 300 mg intravenously. One hundred patients in the weekly group received 940 cycles of paclitaxel. Hypersensitivity reactions occurred in one (1%) patient. There were no hypersensitivity reactions in 99% of patients. Eighty patients in the 3 weekly group received 464 cycles of paclitaxel. Hypersensitivity reactions occurred in (3) 4% of patients while 96% of patients had no hypersensitivity reactions. Two of these three patients had no further hypersensitivity reactions after receiving premedication intravenously. In the two groups 40 min/cycle reduction in treatment duration was observed. In conclusion, this study shows that drugs used for premedication prior to paclitaxel can be given orally. This strategy is feasible, gives excellent results in reducing hypersensitivity reactions and shortens the time of treatment for patients and treating staff.

Pemirolast potently attenuates paclitaxel hypersensitivity reactions through inhibition of the release of sensory neuropeptides in rats

The effects of anti-allergic agents on the hypersensitivity reactions to paclitaxel, an anti-cancer agent, were examined in rats. Intravenous injection of paclitaxel (15 mg/kg) caused a marked extravasation of plasma protein in lungs and a transient decrease in arterial partial oxygen pressure ( PaO 2 ). The paclitaxel-induced protein extravasation was inhibited by low doses (0.1–1 mg/kg) of pemirolast or high doses (30–100 mg/kg) of cromoglycate. However, ketotifen was not effective. The decrease in PaO 2 induced by paclitaxel was also significantly reversed by pemirolast. On the other hand, the paclitaxel-induced plasma extravasation was not attenuated by a histamine H 1 blocker diphenhydramine or an H 2 blocker famotidine, but was significantly reduced by a neurokinin NK 1 antagonist LY303870 (0.5 mg/kg) and an NK 2 antagonist SR48968 (1 mg/kg). The concentrations of proteins and sensory peptides such as substance P, neurokinin A and calcitonin gene-related peptide but not histamine in the rat bronchoalveolar lavage fluid were elevated by paclitaxel injection. Both cromoglycate and pemirolast reduced the paclitaxel-induced rise in proteins and sensory peptides. Therefore, we demonstrated for the first time that sensory nerve peptides are involved in paclitaxel hypersensitivity and that an anti-allergic agent pemirolast attenuates the paclitaxel response by inhibiting the release of sensory nerve peptides.

Paclitaxel hypersensitivity reactions related to bee-sting allergy

Patients with a history of beesting allergy may have a higher risk of a hypersensitivity reaction with paclitaxel treatment. We suggest careful screening of patients for allergies.

Single-Dose Dexamethasone Paclitaxel Premedication

Paclitaxel is one of the most active chemotherapy agents for the treatment of ovarian and other gynecologic cancers. Hypersensitivity reactions (HSR) remain one of the major clinical concerns in the use of paclitaxel. This report deals with 183 consecutive patients treated with paclitaxel chemotherapy. A total of 1010 cycles were administered. Premedication consisted of single-dose intravenous decadron, benadryl, and cimetidine administered immediately prior to chemotherapy. Four hypersensitivity reactions occurred. All patients recovered uneventfully from these reactions. Two of these patients received additional oral decadron followed by the standard premedication and were successfully retreated with multiple courses of paclitaxel therapy without reaction. Our findings confirm other reports that paclitaxel chemotherapy hypersensitivity reactions can be decreased with a single-dose intravenous decadron premedication regimen and that patients who do have paclitaxel HSRs may be safely retreated with paclitaxel.

Phase II study of paclitaxel in relapsed non-Hodgkin's lymphomas.

To assess the efficacy and toxicity of paclitaxel administered as a 96-hour infusion to patients with relapsed non-Hodgkin's lymphomas (NHLs). Eligible patients had relapsed NHL and measurable disease and were considered incurable. Paclitaxel was infused at a dose of 140 mg/m2 every 3 weeks. Premedications to prevent paclitaxel hypersensitivity reactions were not administered and no patients received corticosteroids. Expression of the multidrug resistance (mdr-1) gene was determined in tumor from 17 patients by mRNA quantitative polymerase chain reaction (PCR). Thirty-one patients received a total of 99 cycles of paclitaxel. Two patients were not assessable for response. The median age was 50 years, 71% had stage IV disease, and intermediate/high-grade histology was present in 65% of patients. Patients had received a median of three prior chemotherapy regimens, and 68% of patients had responded to the previous chemotherapy (chemotherapy-sensitive). Of 29 assessable patients, five (17%) achieved a partial response (PR). With a median potential follow-up time of 17 months, the median event-free and overall survival durations were 1.6 and 7.5 months, respectively. No correlation was found between response to paclitaxel and extent of prior treatment or response. The mdr-1 gene was easily detectable in 14 of 17 tumor biopsies, but was low in all but one sample. The most serious toxicity was grade 4 neutropenia, which occurred during 14% of cycles. Paclitaxel was well tolerated, but had a low response rate in patients with relapsed NHLs. There was no clear association between response to paclitaxel and extent of our response to prior treatment. Most patients had chemotherapy-sensitive disease, which suggests that the low response rate to paclitaxel was probably not due to general chemotherapy resistance. Paclitaxel provided good palliation in a minority of patients and is a reasonable agent to consider for use in patients who have failed to respond to standard chemotherapy.