紫杉醇化疗前激素用药简化方案

　　紫杉醇是最常用的乳腺癌化疗药物之一，由于其过敏反应发生率高达30%，故给药前需要给予抗组胺药（组胺H1受体抑制剂苯海拉明、组胺H2受体抑制剂西咪替丁或雷尼替丁）和皮质激素（地塞米松）预防过敏。不过，地塞米松等皮质激素大剂量或长期用药副作用较多。那么，紫杉醇化疗前激素用药能否简化？

　　2021年9月2日，美国转化肿瘤学会《肿瘤学家》在线发表美国哈佛大学达纳法伯癌症研究所、米尔福德肿瘤医院、南韦茅斯肿瘤医院、伦敦德里肿瘤医院、圣伊丽莎白医疗中心、哈佛大学公共卫生学院、巴西叙利亚黎巴嫩医院、法国古斯塔夫鲁西研究所的研究报告，对早期乳腺癌剂量密集多柔比星＋环磷酰胺化疗4轮→紫杉醇化疗2轮后去掉皮质激素的安全性进行了探讨。

　　该多中心前瞻单组二期临床研究于2016年5月～2018年11月入组I～III期乳腺癌术前或术后患者127例，首先完成4轮剂量密集多柔比星＋环磷酰胺化疗，随后完成4轮每2周紫杉醇175mg/m²化疗。患者前2轮紫杉醇化疗前接受地塞米松＋苯海拉明＋组胺H2受体抑制剂的标准预防过敏用药方案。如果前2轮紫杉醇化疗未发生过敏反应，那么第3轮和第4轮紫杉醇化疗前去掉地塞米松。最后，对3～4级过敏反应发生率进行推算。

　　结果，125例患者接受了大于1次方案治疗并被纳入分析，紫杉醇化疗共计486轮，其中14例患者（11.2%，90%置信区间：6.9～20.0%）发生22次（4.5%，90%置信区间：3.1～6.4%）任何级别过敏反应。

　　各轮紫杉醇化疗后，任何级别过敏反应发生率：

• 第1轮：1.6%（90%置信区间：0.3～5.0%）

• 第2轮：6.5%（90%置信区间：3.3～11.3%）

• 第3轮：7.4%（90%置信区间：3.9～12.5%）

• 第4轮：2.6%（90%置信区间：0.7～6.6%）

　　第3轮和第4轮紫杉醇化疗前地塞米松用药率减少92.8%。

　　第3轮和第4轮紫杉醇化疗仅1例患者出现3级过敏反应，237次紫杉醇输注仅发生3或4级过敏反应1次，发生率为0.4%（0.02～2.0%）。该患者第2轮紫杉醇化疗期间出现2级过敏反应，虽然紫杉醇化疗前常规给予地塞米松，但是随后仍然发生3级过敏反应。

　　对第3轮和第4轮紫杉醇化疗前不知接受地塞米松的患者进行敏感性分析，任何级别过敏反应发生率：

• 第3轮：2.7%（3/111，0.7～6.8%）

• 第4轮：0.9%（1/109，0.05～4.3%）

　　因此，该多中心小样本非前瞻研究结果表明，对于早期乳腺癌术前或术后患者，如果剂量密集紫杉醇化疗第1轮和第2轮未见过敏反应，那么第3和第4轮可以安全地去掉皮质激素。

Oncologist. 2021 Sep 2. Online ahead of print.

Prospective Study Testing a Simplified Paclitaxel Premedication Regimen in Patients with Early Breast Cancer.

Barroso-Sousa R, Vaz-Luis I, Di Meglio A, Hu J, Li T, Rees R, Sinclair N, Milisits L, Leone JP, Constantine M, Faggen M, Briccetti F, Block C, Partridge A, Burstein H, Waks AG, Tayob N, Trippa L, Tolaney SM, Hassett MJ, Winer EP, Lin NU.

Dana-Farber Cancer Institute, Boston, MA, USA; Dana-Farber Cancer Institute, Milford, MA, USA; Dana-Farber Cancer Institute at South Shore Hospital, South Weymouth, MA, USA; Dana-Farber Cancer Institute/New Hampshire Oncology-Hematology, Londonderry, NH, USA; Dana-Farber Cancer Institute at St. Elizabeth's Medical Center, Boston, MA, USA; Harvard School of Public Health, Boston, MA, USA; Hospital Sírio-Libanês, Brasília, Brazil; Institut Gustave Roussy, Villejuif, France.

BACKGROUND: In early trials, hypersensitivity reactions (HSRs) to paclitaxel were common, thus prompting the administration of antihistamines and corticosteroids before every paclitaxel dose. We tested the safety of omitting corticosteroids after cycle 2 during the paclitaxel portion of the dose-dense (DD) doxorubicin-cyclophosphamide (AC)-paclitaxel regimen.

PATIENTS AND METHODS: In this prospective, single-arm study, patients who completed 4 cycles of DD-AC for stage I-III breast cancer received paclitaxel 175 mg/m2 every two weeks for 4 cycles. Patients received a standard premedication protocol containing dexamethasone, diphenhydramine and a histamine H2 blocker prior to the first two paclitaxel cycles. Dexamethasone was omitted in cycles 3 and 4 if there were no HSRs in previous cycles. We estimated the rate of grade 3-4 HSRs.

RESULTS: Among 127 patients enrolled, 125 received >1 dose of protocol therapy and are included in the analysis. Fourteen (11.2%, 90%CI: 6.9-20.0%) patients had any-grade HSRs, for a total of 22 (4.5%, 3.1-6.4%) HSRs over 486 paclitaxel cycles. Any-grade HSRs occurred in 1.6% (0.3-5.0%), 6.5% (3.3-11.3%), 7.4% (3.9-12.5%), and 2.6% (0.7-6.6%) of patients after paclitaxel cycles 1, 2, 3, and 4, respectively. Dexamethasone use was decreased by 92.8% in cycles 3 and 4. Only one patient experienced grade 3 HSR in cycles 3 or 4, for a rate of grade 3/4 HSR 0.4% (0.02-2.0%)(1/237 paclitaxel infusions). That patient had grade 2 HSR during cycle 2, and the subsequent grade 3 event occurred despite usual dexamethasone premedication. A sensitivity analysis restricted to patients not known to have received dexamethasone in cycles 3 and 4 found that any-grade HSRs occurred in 2.7% (3/111, 0.7-6.8%) and 0.9% (1/109, 0.05-4.3%) of patients in cycle 3 and 4, respectively.

CONCLUSION: Corticosteroid premedication can be safely omitted in cycles 3 and 4 of dose-dense paclitaxel if HSRs are not observed during cycles 1 and 2.

IMPLICATIONS FOR PRACTICE: Due to the potential for hypersensitivity reactions (HSR) to paclitaxel, corticosteroids are routinely prescribed prior to each dose, on an indefinite basis. In this prospective study including 125 patients treated with 486 paclitaxel cycles, we demonstrate that corticosteroids can be safely omitted in future cycles if HSRs did not occur during cycles 1 and 2 of paclitaxel, and that this strategy reduces the use of corticosteroids in cycles 3 and 4 by 92.8% relative to current standard-of-care.

KEYWORDS: breast cancer; dose-dense chemotherapy; hypersensitivity; paclitaxel; premedication

PMID: 34472667

DOI: 10.1002/onco.13960