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摘要
目的探讨淋巴靶向化疗在食管癌切除术中的应用价值。方法采用前瞻性研究方法。选取2013年1—12月四川大学华西医院收治的117例行经左胸食管切除及区域淋巴结清扫术的食管中段或下段癌(未累及食管胃结合部)患者的临床资料。采用半随机对照方法,将患者分为4组:CPL组,行经左胸食管切除及区域淋巴结清扫术中采用纳米活性炭吸附紫杉醇行淋巴靶向化疗;CFL组,行经左胸食管切除及区域淋巴结清扫术中采用纳米活性炭吸附氟尿嘧啶行淋巴靶向化疗;FV组,行经左胸食管切除及区域淋巴结清扫术前采用氟尿嘧啶行静脉化疗;对照组,直接行经左胸食管切除及区域淋巴结清扫术。CPL组和CFL组:术前配制纳米活性炭-化疗药物混悬液,术中用1 mL注射器在胸段食管肿瘤下缘黏膜下注射相应混悬液。FV组:氟尿嘧啶用100 mL生理盐水配制后,在术前行静脉滴注,30 min输注完毕。食管癌组织切取后,取胃左动脉旁淋巴结送药物浓度检测。上述3组患者在食管胃吻合术开始时,采集外周静脉血约3 mL,进行血清药物浓度检测。对照组:同期行经左胸食管切除及区域淋巴结清扫术,无需采集血样、食管组织标本。观察指标:(1)化疗患者淋巴结和血清药物浓度比较。(2)随访和生存情况:4组患者的4年累积生存率比较。术后采用门诊和电话方式进行随访,了解患者生存情况。随访时间截至2017年12月。正态分布且方差齐的计量资料用x±s表示,多组间比较采用方差分析;偏态分布的计量资料以M(P25,P75)表示,多组间比较采用Cruskal-Wallis秩和检验,两组间采用Mann-Whitney U检验或Wilcoxon符号秩和检验。计数资料比较采用χ2检验或Fisher确切概率法。等级资料比较采用Kruskal-Wallis检验。采用Kaplan-Meier法绘制患者术后生存曲线,Log-rank检验进行生存分析。结果筛选出符合研究条件的患者117例,男90例,女27例;年龄37～84岁,平均年龄62岁。117例患者中,CPL组41例,CFL组41例,FV组9例,对照组26例。纳入患者均康复出院,未发生骨髓抑制、严重腹泻、吻合口瘘、重症肺炎等并发症。(1)化疗患者淋巴结和血清药物浓度比较:CPL组、CFL组、FV组淋巴结药物浓度分别为2.16μg/g(1.14μg/g,4.39μg/g)、0.44μg/g(0.11μg/g,1.18μg/g)、0.11μg/g(0,0.28μg/g),上述3组血清药物浓度分别为0(0,0)、0(0,0.31μg/mL)、0(0,0.30μg/mL)。CPL组和CFL组淋巴结药物浓度均高于同组血清药物浓度,同组两者比较,差异均有统计学意义(Z=-5.579,-3.069,P<0.05)。而FV组淋巴结药物浓度与血清药物浓度比较,差异无统计学意义(Z=-0.365,P>0.05)。3组化疗患者淋巴结药物浓度比较,差异有统计学意义(H=33.458,P<0.05);血清药物浓度比较,差异也有统计学意义(H=10.356,P<0.05)。进一步两两比较发现:CFL组淋巴结氟尿嘧啶浓度高于FV组,两组比较,差异有统计学意义(Z=82.500,P<0.05),而CFL组与FV组血清氟尿嘧啶浓度比较,差异无统计学意义(Z=160.500,P>0.05)。CPL组淋巴结紫杉醇浓度高于CFL组淋巴结氟尿嘧啶浓度,两组比较,差异有统计学意义(Z=351.000,P<0.05);而CPL组血清紫杉醇浓度低于CFL组血清氟尿嘧啶浓度,两组比较,差异有统计学意义(Z=577.000,P<0.05)。(2)随访和生存情况:117例患者中,21例失访。96例获得随访患者的随访时间为6.0～58.0个月,中位随访时间为20.0个月。CPL组、CFL组、FV组、对照组患者的4年累积生存率分别为46.2%、27.8%、33.3%、17.1%。4组患者生存情况比较,差异无统计学意义(χ2=5.166,P>0.05)。结论食管癌切除术中淋巴靶向化疗使化疗药物浓集于食管癌区域淋巴结,药物对载体的亲和力可能与疗效有关,但其单独、单次应用不能提高患者术后生存率。【Abstract】Objective To investigate the application value of lymph node-targeted chemotherapy in resection of esophageal carcinoma.Methods The prospective study was conducted.The clinical data of 117patients with middle and low esophageal carcinoma(without involving esophagogastric junction)who underwent left transthoracic esophagectomy and regional lymph node dissection in the West China Hospital of Sichuan University between January 2013 and December 2013 were collected.All patients were allocated into the 4 groups by semi-randomized control method:CPL group received intraoperatively carbon nanoparticles-paclitaxel for lymph node-targeted chemotherapy,CFL group received intraoperatively carbon nanoparticles-fluorouracil for lymph nodetargeted chemotherapy,FV group received preoperative fluorouracil intravenous chemotherapy,and control group underwent left transthoracic esophagectomy and regional lymph node dissection.CPL and CFL groups:suspensions of carbon nanoparticles and chemotherapy drugs were preoperatively prepared,and were intraoperatively injected under mucosa of lower edge of thoracic esophageal tumor using 0.1 mL syringes.FV group:fluorouracil with 100mL of saline were mixed,and then were preoperatively injected by intravenous drip within 30 minutes.After cutting tissues of esophageal carcinoma,lymph nodes of left gastric arteria were removed,and drug level in lymph nodes was measured.At the beginning of esophagogastrostomy in the CPL,CFL and FV groups,3 mL peripheral venous blood were collected and measured for serum drug level.Control group:patients underwent left transthoractic esophagectomy and regional lymph node dissection(no blood sample and esophageal specimen).Observation indicators:(1)comparison of drug levels in lymph node and serum of patients with chemotherapy;(2)follow-up and survival:4-year cumulative survival rate in 4 groups.Follow-up using outpatient examination and telephone interview was performed to detect patients’survival up to December 2017.Measurement data with normal distribution and homogeneity of variance were represented as x±s,and comparisons among groups were analyzed using the ANOVA.Measurement data with skewed distribution were described as M(P25,P75),and comparisons among groups and between groups were respectively analyzed using the Kruskal-Wallis rank test and Mann-Whitney U test or Wilcoxon signed rank test.Comparisons of count data were analyzed using chi-square test or Fisher exact probability.Ordinal data were compared by the Kruskal-Wallis test.The survival curve was drawn by the Kaplan-Meier method,and Log-rank test was used for survival analysis.Results One hundred and seventeen patients were screened for eligibility,including 90 males and 27 females,and age was 37-84 years old,with an average age of 62 years old.Of 117 patients,41,41,9 and 26 were respectively allocated into the CPL,CFL,FV and control groups.Eligible patients recovered and were discharged from hospital,without bone marrow depression,severe diarrhea,anastomotic leakage and severe pneumonia.(1)Comparison of drug levels in lymph node and serum of patients with chemotherapy:drug levels in the CPL,CFL and FV groups were respectively 2.16μg/g(1.14μg/g,4.39μg/g),0.44μg/g(0.11μg/g,1.18μg/g),0.11μg/g(0,0.28μg/g)in lymph nodes and 0(0,0),0(0,0.31μg/mL),0(0,0.30μg/mL)in serum.Drug levels of lymph node in the CPL and CFL groups were higher than those of serum,with statistically significant differences(Z=-5.579,-3.069,P<0.05).There was no statistically significant difference in drug levels of lymph node and serum of FV group(Z=-0.365,P>0.05).There was a statistically significant difference in drug levels of lymph node among CPL,CFL and FV groups(H=33.458,P<0.05),and in drug levels of serum among CPL,CFL and FV groups(H=10.356,P<0.05).Further analysis showed that fluorouracil level of lymph node in the CFL group was higher than that in the FV group,with a statistically significant difference(Z=82.500,P<0.05),and there was no statistically significant difference in fluorouracil level of serum between CFL group and FV group(Z=160.500,P>0.05).Paclitaxel level of lymph node in the CPL group was higher lhan fluorouracil level of lymph node in the CFL group,with a statistically significant difference(Z=351.000,P<0.05),and paclitaxel level of serum in the CPL group was lower than fluorouracil level of serum in the CFL group,showing a statistically significant difference(Z=577.000,P<0.05).(2)Follow-up and survival:of 117 patients,21 lost follow-up,and 96 were followed up for 6.0-58.0 months,with a median time of 20.0 months.The 4-year cumulative survival rate in the CPL,CFL,FV and control groups was respectively 46.2%,27.8%,33.3%and 17.1%.There was no statistically significant difference in the survival of 4 groups(χ2=5.166,P>0.05).Conclusions The lymph node-targeted chemotherapy can promote chemotherapy drugs to aggregate in the lymph nodes during resection of esophageal carcinoma.The affinity of chemotherapy drugs on carrier is involved in clinical effects,and single use of chemotherapy drug cannot improve postoperative survival rate of patients.
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单位四川大学华西医院; 四川大学
