奥沙利铂辅助化疗老年结直肠癌患者的周围神经病变研究

背景　在结直肠癌辅助化疗方案中使用奥沙利铂已被证明能以增加毒副作用为代价提高总生存率。奥沙利铂对老年患者的毒副作用发生率和严重程度可能更高，而老年患者的获益可能更少。目的　评估奥沙利铂辅助化疗与老年结直肠癌患者周围神经病变的关系。方法　本研究为回顾性队列研究，2012—2015年海南省人民医院、海南医学院第二附属医院胃肠外科收治行手术治疗的65岁以上结直肠癌患者38 085例，接受辅助化疗的Ⅱ期和Ⅲ期患者3 607例，其中1 541例（42.72%）接受奥沙利铂辅助化疗方案，2 066例（57.28%）单独使用氟尿嘧啶化疗方案。根据年龄分为66~69岁（987例）和≥70岁（2 620例）。收集患者的临床资料，随访3年，截至2018-02-01，记录周围神经病变发生率、神经性疼痛药物使用率、死亡发生率。周围神经病变发生率及神经性疼痛药物使用率构建多变量原因别风险模型，使用累积发病率函数估计周围神经病变发生率、神经性疼痛药物使用率、死亡发生率。结果　66~69岁与≥70岁患者性别、病理分期、合并痴呆症状、脑卒中比例、Charlson合并症（CCI）指数比较，差异均有统计学意义（P<0.05）。66~69岁应用奥沙利铂辅助化疗患者病理分期Ⅲ期、肿瘤位于结肠比例较未应用奥沙利铂辅助化疗患者升高，合并糖尿病比例、CCI指数较未应用奥沙利铂辅助化疗患者降低（P<0.05）。≥70岁应用奥沙利铂辅助化疗患者男性、病理分期Ⅲ期、肿瘤位于结肠比例较未应用奥沙利铂辅助化疗患者升高，年龄、合并痴呆症状比例、CCI指数较未应用奥沙利铂辅助化疗患者降低（P<0.05）。在全体患者中，奥沙利铂辅助化疗与周围神经病变风险增加相关（P<0.05）；在66~69岁患者中，奥沙利铂辅助化疗与周围神经病变风险增加不相关（P>0.05）；在≥70岁患者中，奥沙利铂辅助化疗与周围神经病变风险增加相关（P<0.05）。在全体患者中，奥沙利铂辅助化疗与加巴喷丁、三环类抗抑郁药、度洛西汀使用增加相关（P<0.05）；在66~69岁患者中，奥沙利铂辅助化疗与三环类抗抑郁药使用增加相关（P<0.05）；在≥70岁患者中，奥沙利铂辅助化疗与加巴喷丁、三环类抗抑郁药使用增加相关（P<0.05）。接受奥沙利铂辅助化疗患者3年周围神经病变发生率为6.63%〔95%CI（5.44%，7.97%）〕，神经性疼痛药物使用率为15.43%〔95%CI（13.61%，17.37%）〕，死亡发生率为14.72%〔95%CI（13.04%，16.67%）〕。结论　奥沙利铂辅助化疗老年结直肠癌患者可导致周围神经病变，尤其是年龄≥70岁患者的周围神经病变和需要神经性疼痛药物进行治疗的风险较高，因此对于老年结直肠癌患者辅助化疗时，需充分考虑周围神经病变。

Peripheral Neuropathy in Elderly Patients with Colorectal Cancer Treated with Oxaliplatin-assisted Chemotherapy

Background　The addition of oxaliplatin to adjuvant chemotherapy for colorectal cancer has been shown to improve overall survival at the expense of increased toxicity.The incidence and severity of toxicity might be greater among older patients who might also derive less benefit from oxaliplatin.Objective　To evaluate the association between oxaliplatin-assisted chemotherapy and peripheral neuropathy in elderly patients with colorectal cancer.Methods　This study was a retrospective cohort study.A total of 38 085 patients aged 66 or above who underwent surgery for colorectal malignancies in the Department of Gastrointestinal Surgery of Hainan General Hospital and the Second Affiliated Hospital of Hainan Medical University from 2012 to 2015 were included in the study.Among 3 607 stage Ⅱ and Ⅲ patients receiving adjuvant chemotherapy，1 541 （42.72%） patients received oxaliplatin-assisted chemotherapy and 2 066 （57.28%） patients received fluorouracil chemotherapy alone.According to age，patients were divided into 66-69 years old group（n=987） and ≥70 years old group（n=2 620）.The clinical data were collected in the three-year follow up.As of 1 February 2018，the incidence of peripheral neuropathy，drug use rate of neuropathic pain and mortality rate were recorded.A multi-variable hazard modelling was constructed by the incidence of peripheral neuropathy and drug use rate of neuropathic pain.The cumulative incidence function was used to estimate the incidence of peripheral neuropathy，drug use rate of neuropathic pain，and mortality rate.Results　There were significant differences in gender，pathological stages，complication rate of dementia and stroke，Charlson's complications index （CCI） between two groups （P<0.05）.The proportion of pathological stageⅢ and colon cancer in patients aged 66-69 with oxaliplatin-assisted chemotherapy was higher than those without oxaliplatin-assisted chemotherapy，while the complication rate of diabetes mellitus and CCI were lower （P<0.05）.The proportion of male，pathological stageⅢ and colon cancer in patients aged 70 or above with oxaliplatin-assisted chemotherapy was higher than those without oxaliplatin-assisted chemotherapy，while the age，complication rate of dementia and CCI were lower （P<0.05）.Oxaliplatin-assisted chemotherapy was associated with an increased risk of peripheral neuropathy in all patients （P<0.05）.Oxaliplatin-assisted chemotherapy was not associated with an increased risk of peripheral neuropathy in patients aged 66-69 （P<0.05）.Oxaliplatin-assisted chemotherapy was associated with an increased risk of peripheral neuropathy in patients aged 70 or above（P<0.05）.Oxaliplatin-assisted chemotherapy was associated with increased use of gabapentin，tricyclic antidepressants and duloxetine in all patients （P<0.05）.Oxaliplatin-assisted chemotherapy was associated with increased use of tricyclic antidepressants in patients aged 66-69（P>0.05）.Oxaliplatin-assisted chemotherapy was associated with increased use of gabapentin and tricyclic antidepressants in patients aged 70 or above （P<0.05）.The incidence of peripheral neuropathy was 6.63% 〔95%CI（5.44%，7.97%）〕，the drug use rate of neuropathic pain was 15.43% 〔95%CI（13.61%，17.37%）〕 and the mortality rate was 14.72% 〔95%CI（13.04%，16.67%）〕 in patients receiving oxaliplatin-assisted chemotherapy for three years.Conclusion　Oxaliplatin-assisted chemotherapy in elderly patients with colorectal cancer can lead to peripheral neuropathy，especially in patients aged 70 and above who have a higher risk of peripheral neuropathy and drug use of neuropathic pain.Therefore，for adjuvant chemotherapy in elderly patients with colorectal cancer，it is necessary to fully consider the peripheral neuropathy.