资生丸方治疗恶性肿瘤靶向药物相关性腹泻脾胃虚弱证的随机对照研究

Zisheng Pill Formula(资生丸方)in Treating Malignant Tumor Targeted Therapy-induced Diarrhea with Spleen-stomach Weakness Syndrome:A Randomized-controlled Trial

目的评价资生丸方治疗恶性肿瘤靶向药物相关性腹泻脾胃虚弱证的临床疗效及安全性。方法采用前瞻性随机对照研究,纳入67例患者随机分为治疗组34例和对照组33例。治疗组予口服资生丸方中药汤剂每日1剂,分为2次,每次200 ml;对照组予口服蒙脱石散每日3次,每次3 g,首剂加倍,疗程均为2周。比较两组患者治疗前后腹泻次数、大便性状、腹泻常见不良事件评价标准(CTCAE)分级、中医证候疗效、欧洲癌症治疗研究组织生活质量测定量表(EORTC QOL C30)评分以及血清肠道功能指标[二胺氧化酶(DAO)、D-乳酸(D-LA)、内毒素(ET)]水平,并进行安全性评价。结果本研究纳入符合方案集(PPS)患者治疗组33例、对照组32例。治疗组与对照组腹泻总有效率(84.85%vs 37.50%)、中医证候总有效率(93.94%vs 34.38%),差异均有统计学意义(P<0.01)。与本组治疗前比较,两组治疗后腹泻次数减少,腹泻CTCAE分级降低,大便性状好转,总体健康状况评分升高,DAO、D-LA、ET水平降低;治疗组腹泻次数、大便性状、畏寒肢冷、乏力、纳呆、恶心呕吐、腹胀、腹痛中医症状评分均降低,躯体功能评分升高;对照组腹泻次数、大便性状、腹痛评分降低(P<0.05或P<0.01)。除恶心呕吐及腹痛评分、总体健康状况及躯体功能评分、ET水平外,治疗组其余各指标改善情况均优于对照组(P<0.05或P<0.01)。研究过程中治疗组发生消化道感染、便秘各1例不良事件,对照组1例肿瘤进展。结论资生丸方能有效改善恶性肿瘤靶向药物相关性腹泻脾胃虚弱证患者的临床症状,提高生活质量,降低血清DAO、D-LA、ET水平,且安全性较好,其作用机制可能与修复肠道黏膜屏障功能有关。

Objective To evaluate the clinical efficacy and safety of Zisheng Pill Formula(资生丸方,ZPF)in the treatment of malignant tumor targeted drugs-related diarrhea with spleen-stomach weakness syndrome.Methods This was an randomized controlled study,involving 34 cases in the treatment group and 33 cases in the control group.The treatment group was given ZPF decoction,one dose daily by twice,200 ml each time,while the control group was given montmorillonite powder,three times per day,3 g each time,with the first dose doubled,both groups for two weeks.The diarrhea frequency,stool characteristics,common terminology criteria for adverse events(CTCAE)for diarrhea,traditional Chinese medicine(TCM)syndrome score,the European organization for research on treatment of cancer(EORTC)quality of life questionnaire(EORTC QOL-C30)score,levels of serum intestinal functional indicators including diamine oxidase(DAO),D-lactic acid(D-LA),endotoxin(ET)levels were evaluated before and after treatment,and the safety was assessed.Results There were 33 cases in the treatment group and 32 cases in the control group in terms of the per-protocol set(PPS).The total effective rate of diarrhea of the treatment group and control group was 84.85%and 37.50%,respectively,and the total effective rate of TCM syndromes was 93.94%and 34.38%,with statistically significant differences between the groups(P<0.01).After treatment,the frequency of diarrhea and CTCAE grade decreased in both groups,with improved stool characteristics,increased overall health score,and decreased DAO,D-LA and ET levels;in the treatment group,the frequency of diarrhea,the TCM symptom scores in terms of stool characteristics,fear of cold and cold limbs,fatigue,numbness,nausea and vomiting,abdominal distension and abdominal pain were reduced,while the physical function score increased;in the control group,the frequency of diarrhea,stool characteristics and abdominal pain score decreased(P<0.05 or P<0.01).The results favored the treatment group than the control group in all the outcomes except for the nausea and vomiting score,abdominal pain score,overall health score,physical function score,and ET level(P<0.05 or P<0.01).During the treatment,one case of gastrointestinal infection and one case of constipation occurred in the treatment group,while one case of tumor progression in the control group.Conclusion ZPF can effectively improve the clinical symptoms,increase quality of life,decrease serum DAO,D-LA and ET levels,and is safe when treating malignant tumor targeted drug-related diarrhea with spleen-stomach weakness syndrome.The possible mechanism may be related to the repair of intestinal mucosa barrier function.