|Year : 2018 | Volume
| Issue : 2 | Page : 78-83
Hypersensitivity reactions to paclitaxel with a modified dexamethasone intravenous premedication regimen
Vanita Noronha1, Deborah Enting2, Ravi Thippeswamy1, Amit Joshi1, Vijay Maruti Patil1, Kumar Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Oncology, Guy's and St. Thomas' NHS Foundation Trust, Guy's Hospital, London, UK
|Date of Web Publication||17-May-2019|
Department of Medical Oncology, Tata Memorial Hospital, Room 304, Homi Bhabha Block, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: The conventional paclitaxel premedication regimen consists of two oral dexamethasone doses of 20 mg each taken 12 h and 6 h before paclitaxel administration. For the sake of convenience, the premedication regimen has been modified with a single dose of dexamethasone administered intravenously 30–60 min before paclitaxel, omitting the oral doses. We assessed the rate of hypersensitivity reactions (HSRs) when a modified dexamethasone regimen was used.
Materials and Methods: This was an observational prospective cohort study in patients receiving paclitaxel chemotherapy. We recorded demographics, prior history of allergy and comorbidities, diagnosis, chemotherapy regimen with schedule, details of HSRs, and details of rechallenge. Descriptive analysis and simple percentages were performed.
Results: Between February 2011 and May 2011, 310 patients received 495 cycles of paclitaxel chemotherapy. The median age was 50 years, 77% of patients were female. Sixty-nine percent of patients had breast and gynecologic malignancies. Forty-four percent of patients were chemonaive. Sixty-eight percent of the paclitaxel cycles were once-in-3-week regimens; the remaining 32% were once a week. In all the paclitaxel cycles, a modified premedication regimen was administered. The dose of intravenous dexamethasone was 0 (n = 20), 8 mg (n = 210), 12 mg (n = 1), 16 mg (n = 56), and 20 mg (n = 163). The incidence of HSRs was 1.6%, with 1.2% incidence of severe hypersensitivity. No patient required hospitalization for the management of hypersensitivity. Three patients were rechallenged with paclitaxel after the development of hypersensitivity; all tolerated rechallenge without further infusion reactions.
Conclusion: A modified dexamethasone premedication regimen is a safe and convenient option with a low risk of hypersensitivity.
Keywords: Allergy, hypersensitivity, infusion reaction, intravenous, modified, paclitaxel, premedication, rechallenge
|How to cite this article:|
Noronha V, Enting D, Thippeswamy R, Joshi A, Patil VM, Prabhash K. Hypersensitivity reactions to paclitaxel with a modified dexamethasone intravenous premedication regimen. Cancer Res Stat Treat 2018;1:78-83
|How to cite this URL:|
Noronha V, Enting D, Thippeswamy R, Joshi A, Patil VM, Prabhash K. Hypersensitivity reactions to paclitaxel with a modified dexamethasone intravenous premedication regimen. Cancer Res Stat Treat [serial online] 2018 [cited 2019 Dec 15];1:78-83. Available from: http://www.crstonline.com/text.asp?2018/1/2/78/258544
| Introduction|| |
Paclitaxel is one of the most commonly used chemotherapeutic drugs, with proven efficacy in a wide variety of tumors including breast, ovarian, and lung cancer. Hypersensitivity reactions (HSRs) to paclitaxel itself or its excipient, polyoxyethylated castor oil (Cremophor EL) initially occurred in up to 42% of patients. This led to the routine use of prophylactic medications, including corticosteroids and histamine (H1 and H2) receptor antagonists before paclitaxel administration. The package insert for paclitaxel recommends that all patients should be premedicated with dexamethasone 20 mg orally 12 hours and 6 hours before intravenous (IV) paclitaxel, diphenhydramine (or its equivalent) 50 mg 30–60 min before paclitaxel, and cimetidine 300 mg or ranitidine 50 mg 30–60 min before the administration of paclitaxel.
For patients who are scheduled to receive paclitaxel chemotherapy in the morning, the pre-chemotherapy dexamethasone doses must be taken the night before and the morning of chemotherapy. These doses are sometimes forgotten by the patient, which may result in postponement of chemotherapy and dose delays. For ease of administration, a modified regimen with all three drugs given through IV injection 30–60 min before paclitaxel has been adopted in several centers worldwide. Varying rates of HSR have been reported using this modified premedication regimen.,,
At Tata Memorial Center (TMC) in Mumbai, India, a modified premedication regimen in which the steroid is administered IV along with other premedications 30–60 min before paclitaxel chemotherapy has been used for many years in a wide variety of tumor types and in a large number of patients. Although the estimated rate of HSR has not caused clinical concern, its actual frequency is not precisely known. Despite a hospital-wide acceptance of the modified protocol, a consensus on the dose of corticosteroids is lacking, with prescriptions varying between 8 and 20 mg. The literature lacks data on the association between corticosteroid dose and rate of HSR. Therefore, we conducted an observational study of patients treated with paclitaxel to understand the prophylactic regimen used and the rate of HSR. We aimed to add to the existing body of evidence supporting a simpler and modified prophylactic regimen and to provide useful data on corticosteroid dose, chemotherapy schedule, and rate of HSR.
| Materials and Methods|| |
This was an observational prospective cohort study conducted in TMC, Mumbai, from February 2011 to May 2011. Two trainee medical oncology students visited the outpatient chemotherapy administration area daily and evaluated the files of patients receiving paclitaxel-based chemotherapy. The data collected from the files included comorbidities, diagnosis, stage, previous treatment details, previous history of HSR, the details of the current regimen with dose and schedule of paclitaxel, the medication used (original brand or generic), premedications used with doses, the height and weight of the patient, the cycle number of the present cycle, the duration of the cycle, details of any HSR with treatment taken, and further plan. HSR was graded according to the Common Terminology Criteria for Adverse Events, version 4.03 (U.S. National Cancer Institute). Specifically, an allergic infusion reaction was classified as Grade 1, if it was mild and transient, did not necessitate interruption of the infusion, and did not require intervention; Grade 2 if intervention was required, but the reaction responded promptly to therapy such as IV fluids and antihistamines and if prophylactic medications were required for up to 24 h; Grade 3 if the reaction was prolonged, did not promptly respond to therapy or infusion interruption, if the symptoms recurred after initially improving, or if hospitalization was needed for management of the allergic reaction; and Grade 4 if the reaction was life-threatening or necessitated urgent intervention.
Data were entered into an Excel sheet. The analysis was done in the Statistical Package for the Social Sciences, version 20 (IBM Corp.,). Descriptive statistics and simple percentages were used.
| Results|| |
Three hundred and ten patients received 495 cycles of paclitaxel-based chemotherapy during the period of the study. [Table 1] details the patient demographics, diagnosis, prior treatment, and current chemotherapy details. Two hundred and fifty-six patients had not received paclitaxel before the current cycle. Of the patients who had received prior paclitaxel, the number of cycles of paclitaxel received ranged from 1 to 40; the median number of cycles was 3.
|Table 1: Background information of the patients, including demographics, malignancy, prior therapy, and current chemotherapy details|
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The current chemotherapy regimens were broadly divided into two categories based on the paclitaxel schedule of administration: lower dose paclitaxel (50 mg/m2 – 80 mg/m2) given once a week and higher dose paclitaxel (175 mg/m2) given once in 3 weeks. The paclitaxel used was the original brand in 268 cycles (54.1%) and the generic version in 227 (45.9%). HSR-related premedications included IV dexamethasone, ranitidine (50 mg), and promethazine (12.5 mg or 25 mg). Dexamethasone was omitted in 20 cycles (4%). The dose of dexamethasone varied with values of 8 mg (n = 210), 12 mg (n = 1), 16 mg (n = 56), and 20 mg (n = 163); in 45 cycles, dexamethasone was given, but the dose was not recorded. IV ranitidine was administered in 482 cycles (97.4%), and IV promethazine was given in 440 cycles (88.9%).
In 495 paclitaxel cycles administered over the period of the study, eight episodes of HSR occurred in 7 patients; thus, the incidence of hypersensitivity was 1.6%. The HSR was Grade 2 in two patients (0.4%), Grade 3 in four patients (0.8%), and Grade 4 in two patients (0.4%). Thus, the rate of severe HSR (>/= Grade 3) was 1.2%.
The occurrence of hypersensitivity based on the dose of dexamethasone premedication was as follows: no dexa (20 cycles)-0 HSR/ 8 mg dexa (210 cycles)-1 HSR (0.5%)/ 12 mg dexa (1 cycle)-0 HSR/ 16–20 mg dexa (219 cycles)-6 HSR (2.7%)/ dexa dose not documented (45 cycles)-1 HSR (2.3%). The details of the HSR are provided in [Table 2].
|Table 2: Hypersensitivity reactions that occurred to paclitaxel-based chemotherapy during the period of the study|
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| Discussion|| |
The incidence of HSR to paclitaxel was 1.6%, with a 1.2% incidence of severe HSR when using a modified dexamethasone premedication regimen. The modified regimen consisted of dexamethasone administered IV 30-60min before chemotherapy, with no additional oral doses given 12 h and 6 h before chemotherapy. All the HSR resolved with standard medications including steroids or antihistamines and fluid hydration. No patient required hospitalization for HSR management, and none of the HSR were fatal. In the literature, the described incidence of HSR to paclitaxel in patients who have been premedicated ranges from 7% to 17%, with a 1%-2% incidence of severe HSR., 3, ,, Given the low rate of HSR with a modified schedule of dexamethasone premedication, this can be considered as an acceptable and convenient premedication option.
Several other groups have reported similarly low HSR rates when using the modified dexamethasone premedication regimen. Bookman et al. reported that in 283 patients treated with dexamethasone 10 mg or 20 mg IV 30 min before paclitaxel without additional oral dexamethasone, the incidence of all HSR was 4.6%, with a 0.7% incidence of serious HSR. Markman et al. reported a 9% incidence of HSR in over 200 patients treated with a similar modified dexamethasone IV regimen. Gilbar and Ridge reported no HSR in 35 patients treated with the modified regimen. In a phase II study by Yamada et al. in 60 patients with advanced gastric cancer who received modified dexamethasone premedication, 15% of patients developed HSR; all the reactions were Grade 1. Bookman et al. reported that there were no significant HSR in two prospective clinical trials in ovarian and lung cancer patients treated with carboplatin and paclitaxel, using the modified dexamethasone premedication schedule. Aoyama et al. reported that along with younger age and a prior history of allergy, the administration of short-course premedication was a predictive factor for the development of paclitaxel-related HSR in gynecologic patients, with an odds ratio (OR) of 14.1. Of note, all the patients in our study as well as the above-mentioned studies received short-course premedication, yet the incidence of HSR was low.
The modified dexamethasone prophylaxis regimen has been compared to the conventional oral regimen by several groups, with varying conclusions. Kwon et al. performed a retrospective historical cohort study and reported higher rates of HSR with the modified IV dose; the rates of overall and severe HSR when using the conventional regimen were 7.5% and 0.9% as compared to 17.3% and 7.3% with the modified regimen, P = 0.07. O'Cathail et al. also reported a higher rate of HSR when using the modified regimen; 5.4% HSR rate with conventional premedication versus 14.5% HSR rate with the modified regimen, P = 0.07. Conversely, Markman et al. reported that the incidence of HSR was 9% regardless of whether the dexamethasone regimen administered was modified or the conventional regimen. The question of whether the modified dexamethasone regimen led to a higher rate of HSR has been directly answered by two randomized controlled trials (RCTs). Yanaranop and Chaithongwongwatthana performed a double-blind RCT comparing conventional (oral) versus modified (IV) dexamethasone premedication in 288 patients with ovarian, Fallopian tube More Details, and peritoneal carcinoma receiving the first cycle of paclitaxel and carboplatin. The rates of HSR for the conventional and the modified dexamethasone regimens were 19.1% and 17.9%, respectively, P = 0.78; rates of severe HSR were 0 versus 0.7%, respectively, P = 0.498. Overall, there was no significant difference in the side effects between the two premedication regimens; however, significantly more patients developed acne (10.6%) with the conventional regimen compared to the modified IV regimen (2.1%), P = 0.004. Rosenberg et al. also reported no significant difference in HSR in 204 patients with relapsed ovarian cancer randomized in a bifactorial manner to once-a-week versus once-every-3-weeks paclitaxel and to oral conventional versus IV modified dexamethasone. A recent meta-analysis by Chen et al. found no difference in the overall rates of HSR between the conventional and modified regimen (OR 0.76, 95% confidence interval [CI] 0.55–1.06, P = 0.11) but a significantly lower rate of severe HSR with the conventional regimen (OR - 0.53, 95% CI, 0.28–0.99, P = 0.05).
Our study included seven patients who received 20 cycles of paclitaxel dosed between 50 mg/m2 and 80 mg/m2 once-a-week in which the dexamethasone premedication was omitted. No HSR were noted in these patients. In the literature, there are various approaches to handling dexamethasone premedication in patients receiving once-a-week paclitaxel regimens. Whereas some clinicians continue dexamethasone premedication as long as paclitaxel is being administered, other clinicians taper or omit the dexamethasone premedication in case the patient does not develop significant HSR during the first two cycles of chemotherapy. The rate of HSR using this approach has been reported to range between 0% and 6.25%.,,,,, Administering IV dexamethasone once-a-week for a prolonged period may put the patient at risk for various complications, including immune suppression, ophthalmologic, infectious, and metabolic complications; thus, the approach of omitting dexamethasone premedication is attractive since the risk of hypersensitivity in patients who do not develop initial HSR appears to be low.
We had data on the results of paclitaxel rechallenge in only three patients who developed HSR to paclitaxel. These patients tolerated paclitaxel well, with no further HSR episodes. Markman et al. reported that all 47 patients who had developed clinically relevant HSR to paclitaxel could be safely retreated with paclitaxel after following certain precautions such as desensitization procedures. Other authors have also reported that most patients who have developed HSR to paclitaxel can be safely rechallenged, with or without utilizing a desensitization strategy.,,,
| Conclusion|| |
The incidence of HSR to paclitaxel when using a modified IV dexamethasone regimen omitting the 12-h and 6-h oral pre-chemotherapy doses of dexamethasone was 1.6%, with a 1.2% incidence of severe HSR. Thus, a modified dexamethasone premedication regimen is safe and convenient and can be considered in patients receiving paclitaxel chemotherapy.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]