卡培他滨为常用于乳腺癌和胃肠癌的口服化疗药物，手足综合征为其常见副作用，发生率高达75%，其特征包括手掌足底皮肤疼痛、红肿、脱皮、脱屑、溃疡、开裂、麻木，虽然不会危及生命，但是影响生活质量，往往需要减少用药剂量甚至停药才能缓解。环氧合酶COX-2是催化花生四烯酸代谢产生前列腺素和血栓素的关键酶，对于手足综合征的红肿热痛等炎症反应发挥重要作用。COX-2抑制剂塞来昔布已被证实可以预防卡培他滨所致手足综合征，但是由于该口服药物可产生全身副作用，常规处方受到限制。双氯芬酸（大家更熟悉的原研药商品名：扶他林）也可抑制COX-2，通常用于治疗关节疼痛，局部外用制剂的全身副作用极小，故为非处方药。那么，局部外用双氯芬酸能否预防卡培他滨所致手足综合征？
　　2024年2月27日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表全印度医学科学院（印度卫生部辖下全印度20多家公立医学院、研究所和医院的总称，1956年由印度首任总理贾尼赫鲁创建，QS世界大学排名南亚地区最佳医学院）安贝德卡福利会（为纪念印度宪法起草委员会主席、首任法律和司法部部长而成立）扶轮肿瘤医院、印度理工学院、加拿大卡尔加里大学汤姆贝克癌症中心的D-TORCH研究报告，首次对局部外用双氯芬酸或安慰剂预防乳腺癌和胃肠癌卡培他滨化疗所致手足综合征的有效性和安全性进行双盲随机对照。
　　该单中心安慰剂双盲随机对照三期临床研究于2021年2月1日～2022年9月30日从全印度医学科学院安贝德卡福利会扶轮肿瘤医院入组计划接受卡培他滨治疗的乳腺癌（148例）和胃肠癌（115例）患者，按1∶1的比例随机分为两组，局部外用双氯芬酸（131例）或安慰剂（133例）凝胶治疗12周或出现手足综合征为止（以较早发生者为准）。主要终点为2或3级手足综合征（根据不良事件通用术语标准第5版）发生率，采用简单逻辑回归校正其他影响因素后对两组进行比较。
　　结果，双氯芬酸组与安慰剂组相比：
  • 2～3级手足综合征发生率：3.8%比15.0%（绝对值相差11.2%，95%置信区间：4.3～18.1，P=0.003）
  • 1～3级手足综合征发生率：6.1%比18.1%（绝对值相差11.9%，95%置信区间：4.1～19.6）
  • 坚持用药率：96.7%±19.1%比94.0%±28.3%
  • 卡培他滨剂量减少发生率：3.8%比13.5%（绝对值相差9.7%，95%置信区间：3.0～16.4）
  • 手足综合征所致生活质量恶化评分：3.5比12.4（绝对值相差8.9，95%置信区间：3.3～14.4）
　　亚组分析表明，无论男女、单药或联合化疗、体力状态评分、乳腺癌或胃肠癌，双氯芬酸与安慰剂相比，手足综合征发生率都显著较低。
　　因此，该双盲随机对照研究结果表明，对于接受卡培他滨治疗的乳腺癌或胃肠癌患者，局部外用双氯芬酸与安慰剂相比，手足综合征发生率、卡培他滨剂量减少发生率显著较低，生活质量显著较好，该研究支持选择局部外用双氯芬酸预防卡培他滨所致手足综合征，并有必要开展进一步研究对局部外用双氯芬酸与其他常用治疗方法预防卡培他滨化疗所致手足综合征的有效性和安全性进行比较。

J Clin Oncol. 2024 Feb 27. IF: 45.3

Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial.

Santhosh A, Sharma A, Bakhshi S, Kumar A, Sharma V, Malik PS, Pramanik R, Gogia A, Prasad CP, Sehgal T, Gund S, Dev A, Cheung WY, Pandey RM, Kumar S, Gupta I, Batra A; D-TORCH Trial Investigators.

Bhimrao Ramji Ambedkar Institute Rotary Cancer Hospital (BRAIRCH), All India Institute Of Medical Science (AIIMS), Delhi, India; Indian Institute of Technology, Delhi, India; Tom Baker Cancer Centre Calgary, Calgary, Canada.

PURPOSE: Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS.

METHODS: In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression.

RESULTS: In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4).

CONCLUSION: Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.

KEY OBJECTIVE: Hand-foot syndrome (HFS) is a dose-limiting adverse event associated with capecitabine, which leads to dose reductions and impairs the quality of life (QOL). In this double-blind, placebo-controlled study, we assessed the efficacy of topical diclofenac in preventing capecitabine-associated HFS in patients with breast or GI cancer.

KNOWLEDGE GENERATED: Our study demonstrated that topical diclofenac application is associated with a significantly lower rate of HFS in patients with breast or GI cancer. It was also associated with a lower rate of capecitabine dose reduction and a better QOL at 12 weeks compared with placebo.

RELEVANCE: Topical diclofenac should be considered when prescribing capecitabine-based treatment to patients with breast or GI cancer to prevent HFS. Further trials are needed to evaluate this treatment alongside other cancer treatments commonly associated with HFS.

PMID: 38412399

DOI: 10.1200/JCO.23.01730

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