经济简便改善早期乳腺癌患者生存

　　早期乳腺癌与晚期乳腺癌相比，患者生存率较高、生存期较长，而进一步提高生存率、延长生存期，已经达到瓶颈。多年来，不少晚期乳腺癌新药被尝试用于早期乳腺癌的研究大多失败，成功者寥寥无几，而且价格昂贵，其他“经济实用型”研究又以单中心、小样本、非对照为主。2022年9月，在欧洲肿瘤内科学会（ESMO）第47届大会，印度最大肿瘤医院孟买塔塔纪念中心主任兼肿瘤外科主任拉金德拉·阿希特·巴德韦医师口头报告了早期乳腺癌术前肿瘤周围局部注射利多卡因的全国多中心、大样本、随机对照研究结果，发现这种每支仅十几元人民币的常用局部麻醉药可将患者术后6年复发死亡率和总死亡率显著降低26%和29%。不过，该研究结果受到众多乳腺外科专家质疑。

　　时隔半年，2023年4月6日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表该研究全文，并配发哈佛大学医学院、布莱根医院和波士顿妇女医院、达纳法伯癌症研究院撰写的社论：肿瘤周围注射利多卡因——改善早期乳腺癌患者结局的低成本、易实施干预措施。本期《新见：月月谈》由山东省肿瘤医院乳腺外科副主任医师孙晓博士对该研究进行解读。

TMH902 (NCT01916317): Randomized Controlled Trial to Assess Blockade of Voltage Gated Sodium Channels During Surgery in Operable Breast Cancer

研究背景

　　随着对乳腺癌转移驱动机制的不断理解，部分学者开始关注局部麻醉药物作为治疗方案的可能性。利多卡因是临床最为常用的酰胺类局部麻醉药物，可通过阻止神经细胞膜的通透性，使细胞内外的钠钾离子交换通道受阻，从而抑制神经动作电位的传导，使神经细胞丧失兴奋性和传导性，产生局部麻醉作用。部分基础研究显示，利多卡因等局部麻醉药物可能通过抑制信号传导通路、诱导细胞凋亡、减少肿瘤细胞迁移、细胞周期介导效应、脱氧核糖核酸介导效应等途径减少肿瘤的复发和转移^[1-5]。

研究设计

　　该全国多中心非盲随机对照研究于2011年12月至2018年10从印度全国11家癌症中心入组早期乳腺癌术前未接受新辅助治疗患者1583例，按1∶1的比例随机分为两组：

• 有利多卡因组786例：手术前7～10分钟肿瘤周围注射0.5%利多卡因
• 无利多卡因组797例：手术前不用利多卡因，直接手术

　　术后全部给予标准的全身治疗和局部放疗。根据绝经状态和肿瘤大小对随机化进行分层，主要终点为无病生存，次要终点为总生存。

研究结果

　　中位随访68个月，有利多卡因组与无利多卡因组相比：

• 5年无病生存率：86.6%比82.6%（绝对获益4.0%）
• 5年复发死亡率：13.4%比17.4%
• 复发或死亡风险：降低26%（风险比：0.74，95%置信区间：0.58～0.95，P=0.017）
• 远处转移率：73.6%比75.2%
• 局部区域复发率：20.0%比17.6%
• 对侧乳腺癌或其他非乳腺原发癌发生率：6.3%比7.2%
• 5年总生存率：90.1%比86.4%（绝对获益3.7%）
• 5年总死亡率：9.9%比13.6%
• 总死亡风险：降低29%（风险比：0.71，95%置信区间：0.53～0.94，P=0.019）

无病生存曲线

总生存曲线

　　亚组分析表明，利多卡因对无病生存和总生存的影响，与患者是否绝经、肿瘤大小、淋巴结转移、激素受体和HER2状态都无显著相关性。

无病生存亚组分析

总生存亚组分析

　　该研究未出现利多卡因注射后不良反应。

临床意义

　　该多中心前瞻临床研究首次证实，术前肿瘤周围注射与未注射利多卡因相比，早期乳腺癌患者的无病生存和总生存显著改善，这些数据为围手术期使用局部麻醉药增加了新的循证医学证据。虽然该研究作者认为利多卡因获益的机制尚不明确，但是不可否认局部注射价格低廉的利多卡因是简单、经济、有效的干预措施，可以降低早期乳腺癌女性患者的复发率和死亡率。

　　需要注意的是，由于入组缓慢且无病生存事件数少于预期，该研究修改了统计学计划，由利多卡因组无病生存绝对获益7.0%（假设对照组5年无病生存率为60.0%，风险比：0.784）变更为利多卡因组无病生存绝对获益6.0%（假设对照组5年无病生存率为80.0%，风险比：0.676）。该研究目前仍未观察到上述获益，因此结果为阴性。然而，考虑到无病生存绝对获益4.0%和总生存绝对获益3.7%，以及局部注射利多卡因未发生任何不良事件的良好安全性，该研究结果对于临床工作存在一定指导意义。

　　印度是中低收入国家，医疗条件和中高收入国家不同。该研究对于HER2阳性乳腺癌患者仅有不到40%接受了靶向治疗，另外，接受腋窝淋巴结清扫术的患者比例较高，包括病理淋巴结阴性者。这些因素是否影响研究结果，我们不得而知。此外，对于部分早期乳腺癌患者，我们可能选择新辅助治疗，而该研究排除了新辅助治疗患者，那么这部分患者能否对局部注射利多卡因获益？因此，可能需要在不同国家开展设计更为严格的临床研究进行验证。

展望与启示

　　随着影像技术的不断进步和乳腺癌筛查体系的不断完善，早期乳腺癌患者的比例不断增加。局部区域治疗技术和全身治疗方案的不断进步，显著降低了早期乳腺癌患者的复发和死亡风险。但是，仍然大约30%的早期乳腺癌患者出现远处转移。根据APHINITY研究8年随访结果，曲妥珠单抗±帕妥珠单抗相比，辅助治疗HER2阳性乳腺癌患者无病生存获益2.6%^[6]。根据monarchE研究4年随访数据，将阿贝西利作为高风险激素受体阳性乳腺癌患者的辅助强化治疗，无浸润病变生存获益6.4%^[7]。根据KEYNOTE-522研究，帕博利珠单抗用于早期高风险三阴性乳腺癌术前新辅助治疗，3年无事件生存率获益约7%^[8]。然而，印度研究证实，每支十几元的利多卡因，无病生存获益4.0%、总生存获益3.7%，性价比似乎更高。因此，该研究作为首个证实肿瘤周围注射利多卡因可以改善乳腺癌生存的多中心大样本前瞻随机对照临床研究，小小举动便可经济简便地改善早期乳腺癌患者生存，成为最接地气的早期乳腺癌临床研究之一。

参考文献

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7. Johnston SRD, Toi M, O'Shaughnessy J, et al. Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): Results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol. 2023;24:77-90.
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J Clin Oncol. 2023 Apr 6. IF: 50.717

Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer.

Badwe RA, Parmar V, Nair N, Joshi S, Hawaldar R, Pawar S, Kadayaprath G, Borthakur BB, Rao Thammineedi S, Pandya S, Balasubramanian S, Chitale PV, Neve R, Harris C, Srivastava A, Siddique S, Vanmali VJ, Dewade A, Gaikwad V, Gupta S.

Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India; Kolhapur Cancer Centre, Kolhapur, India; Max Superspeciality Hospital, Patparganj, New Delhi, India; B. Borooah Cancer Institute, Guwahati, India; Basavatarakam Indo-American Cancer Hospital and Research Centre, Hyderabad, India; Gujarat Cancer & Research Institute, Ahmedabad, India; Malabar Cancer Centre (MCC), Kodiyeri, Thalassery, Kannur, India; Siddhivinayak Ganapati Cancer Hospital, Miraj, India; Sterling Multi-Speciality Hospital, Pune, India; North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS), Shillong, India; All India Institute of Medical Sciences, New Delhi, India.

PURPOSE: Preventing metastases by using perioperative interventions has not been adequately explored. Local anesthesia blocks voltage-gated sodium channels and thereby prevents activation of prometastatic pathways. We conducted an open-label, multicenter randomized trial to test the impact of presurgical, peritumoral infiltration of local anesthesia on disease-free survival (DFS).

METHODS: Women with early breast cancer planned for upfront surgery without prior neoadjuvant treatment were randomly assigned to receive peritumoral injection of 0.5% lidocaine, 7-10 minutes before surgery (local anesthetics [LA] arm) or surgery without lidocaine (no LA arm). Random assignment was stratified by menopausal status, tumor size, and center. Participants received standard postoperative adjuvant treatment. Primary and secondary end points were DFS and overall survival (OS), respectively.

RESULTS: Excluding eligibility violations, 1,583 of 1,600 randomly assigned patients were included in this analysis (LA, 796; no LA, 804). At a median follow-up of 68 months, there were 255 DFS events (LA, 109; no LA, 146) and 189 deaths (LA, 79; no LA, 110). In LA and no LA arms, 5-year DFS rates were 86.6% and 82.6% (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95; P = .017) and 5-year OS rates were 90.1% and 86.4%, respectively (HR, 0.71; 95% CI, 0.53 to 0.94; P = .019). The impact of LA was similar in subgroups defined by menopausal status, tumor size, nodal metastases, and hormone receptor and human epidermal growth factor receptor 2 status. Using competing risk analyses, in LA and no LA arms, 5-year cumulative incidence rates of locoregional recurrence were 3.4% and 4.5% (HR, 0.68; 95% CI, 0.41 to 1.11), and distant recurrence rates were 8.5% and 11.6%, respectively (HR, 0.73; 95% CI, 0.53 to 0.99). There were no adverse events because of lidocaine injection.

CONCLUSION: Peritumoral injection of lidocaine before breast cancer surgery significantly increases DFS and OS. Altering events at the time of surgery can prevent metastases in early breast cancer (CTRI/2014/11/005228).

KEY OBJECTIVE: There is preclinical and clinical evidence of surgical dissemination leading to metastases. Surgery-induced acute hypoxia can activate prometastatic pathways through voltage-gated sodium channels, which can be blocked by local anesthetics (LA).

KNOWLEDGE GENERATED: To our knowledge, this is the first randomized trial to show that peritumoral injection of a LA, lidocaine, significantly increases disease-free survival (DFS) and overall survival (OS) in women with operable breast cancer. DFS and OS increased by 4% (hazard ratio [HR], 0.74; P = .017) and 3.7% (HR, 0.71; P = .019), respectively. The large sample size, multicenter design, consistency of results across subgroups, ease of implementation, and low cost allow the results to be generalizable worldwide, saving over 100,000 lives annually.

RELEVANCE: This study challenges assumptions, suggesting that small, inexpensive changes in technical aspects of surgery may reduce metastasis.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01916317

PMID: 37023374

DOI: 10.1200/JCO.22.01966

J Clin Oncol. 2023 Apr 6. IF: 50.717

Peritumoral Lidocaine Injection: A Low-Cost, Easily Implemented Intervention to Improve Outcomes in Early-Stage Breast Cancer.

Higgins T, Mittendorf EA.

Brigham and Women's Hospital, Boston, MA; Dana-Farber Brigham Cancer Center, Boston, MA; Harvard Medical School, Boston, MA.

PMID: 37023390

DOI: 10.1200/JCO.23.00418

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