内镜下注射标记纳米碳在进展期结直肠癌治疗中的应用研究

目的探讨内镜下注射标记纳米碳在进展期结直肠癌治疗中的应用。方法采用随机对照研究方法。病例纳入标准:(1)年龄>18岁首次发现并且肠镜及活检病理证实为结直肠癌患者;(2)进展期结直肠癌(术前TNM分期为T3或N1以上)、局部无法切除、M1期同时性转移灶可切除并同意行新辅助治疗的患者;(3)进展期结直肠癌(T3或N1以上分期)、同时性转移灶不可切除或不同意行外科手术而选择放化疗的患者。排除既往腹部外科手术史和放化疗史者、急需手术或内镜支架置入治疗者以及严重过敏体质者。根据以上标准,前瞻性纳入2016年1月至2017年12月期间在联勤保障部队第九○○医院消化内科确诊为进展期结直肠癌的患者共120例;采用随机数字表法分为纳米碳标记组和非标记组。纳米碳标记组均于放化疗前1~7 d内进行标记,病灶标记点位置:(1)若肠镜能顺利通过者,在肿瘤口侧、肛侧旁开1 cm处分别予相对两侧肠壁注射4个点;(2)若肠腔严重狭窄、肠镜无法通过者,仅在距肿瘤肛侧的1 cm处予四象限行4个点的注射。每个注射点注射0.1 ml纳米碳原液,并依据病灶纳米碳黑染范围测量病灶大小。放化疗治疗8周后评估患者的疗效,经评估为可行外科手术的患者于放化疗结束后6周手术,比较两组术中探查病灶时间、手术时间、术中出血量、远端切缘距病灶长度、保肛率、首次切缘阳性率等术中和术后情况。经评估为无手术指征的患者中,放化疗有效者继续原方案化疗,治疗无效则更换化疗方案,半年后最终评估疗效参照修订版RECIST指南(1.1版)]。结果有3例患者脱落本试验,最终共有117例患者纳入本研究。纳米碳标记组59例,非标记组58例,两组患者基线资料的比较,差异均无统计学意义(均P>0.05)。所有患者术前放化疗不良反应较轻微,通过对症处理后均能耐受,所有患者未因不良反应而中断治疗。纳米碳标记组所有患者均未出现发热、腹痛、腹胀、便血等不适。被标记后的肠黏膜均黑染清晰。评估为有手术指征的患者共77例,其中纳米碳标记组39例(纳米碳标记组可手术),非标记组38例(非标记组可手术);两组基线资料的比较,差异均无统计学意义(均P>0.05);无手术指征继续放化疗的患者共40例,其中纳米标记组20例(纳米碳标记组非手术),非标记组20例(非标记组非手术);两组基线资料的比较,差异均无统计学意义(均P>0.05)。纳米碳标记组可手术术中均能够轻易快速地在直肠浆膜面发现黑染的纳米碳标记点,被标记的肠段均未发现明显的水肿、坏死、脓肿等。与非标记组可手术相比,纳米碳标记组可手术术中探查病灶时间(3.4±1.4)min比(11.8±3.4)min,t=-14.07,P<0.001]和总手术时间更短(155.7±44.5)min比(177.2±30.2)min,t=-2.48,P=0.015],术中出血量更少(101.3±36.7)ml比(120.2±38.2)ml,t=-2.22,P=0.029],远端切缘距病灶长度更短(3.7±1.0)cm比(4.6±1.7)cm,t=-2.20,P=0.034],差异均有统计学意义(均P<0.05);保肛率相对较高66.7%(16/24)比45.5%(10/22),χ^2=2.10,P=0.234],首次切缘阳性率较低0比4.5%(1/22),χ^2=0.62,P=0.480],但差异未达到统计学意义(均P>0.05)。两组术后肿瘤分化程度及术后病理TNM分期的差异均无统计学意义。经评估为无手术指征的患者,半年后再次评估放化疗疗效,纳米碳标记组非手术完全缓解(CR)者1例,部分缓解(PR)者8例,疾病稳定(SD)者10例,疾病进展(PD)者1例,疾病好转率45.0%(9/20);非标记组非手术CR者0例,PR者6例,SD者11例,PD者3例,疾病好转率30.0%(6/20);两组疾病好转率的差异均无统计学意义(P=0.514)。结论内镜下注射纳米碳标记法用于结直肠肿瘤定位安全可靠,能够辅助新辅助治疗后行手术时快速探查到病灶,精准地进行切除,明显缩短手术时间,减少手术创伤;能辅助肠镜精确测量放化疗前后病灶大小,增加评估疗效的手段,以指导后续治疗方案;值得临床推广应用。

Application of endoscopic tattooing with carbon nanoparticlet in the treatment for advanced colorectal cancer

Objective To explore the application of endoscopic tattooing with carbon nanoparticles in the treatment of advanced colorectal cancer(ACRC).Methods A randomized controlled study was used.Inclusion criteria:(1)age more than 18 years old,and colorectal cancer was found for the first time and confirmed by colonoscopy and biopsy;(2)advanced colorectal cancer(preoperative TNM stage of T3/N1 or above,local unresectable lesion,M1 stage and simultaneously resectable metastatic lesion),and patients agreed to receive neoadjuvant therapy;(3)advanced colorectal cancer(TNM stage of T3/N1 or above)with simultaneous unresectable metastatic lesion,and patients refused operation and consented to chemoradiotherapy.Patients with previous abdominal surgery history,radiotherapy and chemotherapy history,urgent need for surgery or endoscopic stent placement and those with severe allergic constitution were excluded.Based on the above criteria,120 patients diagnosed with ACRC in No.900 Hospital of the Joint Logistics Team from January 2016 to December 2017 were prospectively enrolled and randomly divided into tattoo group and non?tattoo group by random number table method.Tattoo group were tattooed within 1?7 days before chemoradiotherapy.The labeling location of the lesions:(1)if the colonoscopy could pass smoothly,4 points were injected into the intestinal wall of the both opposite sides 1 cm cephalad and caudad of the tumor;(2)if the colorectal cavity was severely narrow and the colonoscopy could not pass,only 4 points were injected in 4 quadrants at 1 cm caudad of the tumor.Each injection point was injected with 0.1 ml carbon nanoparticles,and the size of the tumor was measured according to the range of carbon nanoparticles staining.The efficacy was evaluated after 8 weeks of chemoradiotherapy.Patients who were defined to be suitable for operation underwent operation 6 weeks after chemoradiotherapy.The following parameters were compared between two groups:lesion identification time,operation time,blood loss,distance from lesion to distal margin,the rate of first positive margin and the rate of anal sphincter preservation(rectal cancer).Among patients who had been evaluated as having no indication for surgery,those who were effective in chemoradiotherapy continued to receive chemotherapy in the original regimen;if the treatment failed,the chemotherapy regimen was replaced,and the efficacy was finally evaluated after six monthsreferring to the revised RECIST guidelines(version 1.1)].Results Three patients withdrew from this study,and 117 patients were enrolled in this study finally,including 59 cases in tattoo group and 58 cases in the non?tattoo group.There were no significant differences in baseline data between two groups(all P>0.05).All the patients had slight adverse reactions of radiotherapy and chemotherapy before operation,and could tolerate after symptomatic management without interruption of treatment.All the patients in the tattoo group had no discomfort such as fever,abdominal pain,abdominal distention,hematochezia,etc.and the intestinal mucosa could be seen clearly with black staining after being tattooed.A total of 77 patients were evaluated with surgical indications,including 39 cases in the tattoo group(tattoo?operable)and 38 cases in the non?tattoo group(non?tattoo?operatable).There were no significant differences in baseline data between the two groups(all P>0.05).Forty patients without operation indications continued chemoradiotherapy,including 20 cases in tattoo group(tattoo?inoperable)and 20 cases in non?tattoo group(non?tattoo?inoperable),whose differences in baseline data between the two groups were not significant as well(all P>0.05).No obvious edema,necrosis or abscess were found in the tattooed segments and the black spots could be seen quickly and clearly on the serosa of rectum in tattoo?operable patients.As compared to non?tattoo group,tattoo group had significantly shorter lesion identification time(3.4±1.4)minutes vs.(11.8±3.4)minutes,t=-14.07,P<0.001],shorter operation time(155.7±44.5)minutes vs.(177.2±30.2)minutes,t=-2.48,P=0.015],less blood loss(101.3±36.7)ml vs.(120.2±38.2)ml,t=-2.22,P=0.029],shorter distance from lesion to distal margin(3.7±1.0)cm vs.(4.6±1.7)cm,t=-2.20,P=0.034],while tattoo group had slightly higher rate of anal sphincter preservation66.7%(16/24)vs.45.5%(10/22),χ^2=2.10,P=0.234]and lower rate of first positive resection margin0 vs.4.5%(1/22),χ^2=0.62,P=0.480],but their differences were not significant.There were no significant differences in the degree of tumor differentiation and TNM stage between two groups.Patients without operative indication were evaluated for efficacy of chemoradiotherapy again after half a year.One case of complete response(CR),8 of partial response(PR),10 of stable disease(SD)and 1 of progressive disease(PD)were found and the improvement rate was 45.0%(9/20)in tattoo?inoperable patients.No case of CR,6 of PR,11 of SD and 3 of PD were found and the improvement rate was 30.0%(6/20)in non?tattoo?inoperable patients.There was no significant difference in the improvement rate between the two groups(P=0.514).Conclusions Endoscopic tattooing with carbon nanoparticles injection is safe and reliable for colorectal tumor positioning.It can assist rapid detection of lesions during surgery after neoadjuvant treatment,perform accurate resection,significantly shorten the operation time and reduce surgical trauma;can assist colonoscopy accurately to measure the size of the lesions before and after chemoradiotherapy,and increase the means of assessing the efficacy to guide the follow?up treatment plan.This technique is worth clinical promotion and application.