盆腔恶性肿瘤辅助放疗后放射性直肠损伤的发生现状:一项基于三期随机临床试验的报告

Chronic radiation-induced rectal injury after adjuvant radiotherapy for pelvic malignant tumors:report based on a phase 3 randomized clinical trial

目的放射治疗是盆腔恶性肿瘤主要的治疗手段。然而,既往对放射治疗后出现肠道的放射性损伤及患者生活质量的研究相对较少。本研究旨在分析盆腔恶性肿瘤辅助放疗后放射性直肠损伤的发生情况,以加强对放射性肠损伤研究的关注。方法本研究采用回顾性观察研究方法,分析STARS前瞻性随机对照试验(临床试验注册号:NCT00806117)数据库里中山大学附属肿瘤医院的病例数据。纳入2008年2月至2015年8月期间,在中山大学附属肿瘤医院接受根治性手术和术后治疗的848例确诊为宫颈癌的患者。纳入标准:(1)病理组织学确诊为宫颈鳞癌、宫颈腺癌及宫颈腺鳞癌;(2)行根治性子宫切除术和盆腔淋巴结清扫术;(3)术后病理检查证实至少有下列不良因素之一:盆腔淋巴结转移、宫旁切缘阳性、淋巴脉管浸润或宫颈肌层深部间质浸润;(4)术后接受过盆腔放射治疗;(5)同意并能够完成问卷调查。排除患有精神疾病及有智力或认知障碍的患者。全组848例患者在接受根治性子宫切除术和盆腔淋巴结清扫术后,均进行了放射治疗。盆腔放疗剂量为1.8 Gy/d或2.0 Gy/d,每周5次,总剂量45~50 Gy。563例患者在术后6周内开始放射治疗,其中282例患者采用单纯辅助放疗,281例患者采用同期放化疗方案(单药顺铂);285例患者采用序贯放化疗方案(TP方案,紫杉醇+顺铂)。观察术后辅助放疗期间的急性期不良事件发生情况、慢性期患者消化道不良反应发生情况和总体生活质量状况、以及慢性放射性直肠损伤发生情况。其中消化道症状及生活质量评估采用欧洲癌症治疗研究组织生命质量测定问卷3.0(EORTC QLQ-C30),功能领域和整体生活质量领域得分越高,说明生活质量越好;症状领域得分越高,表明症状或问题越多,生活质量越差;分别于患者放疗前(即手术治疗结束后1周)、术后辅助放疗期间、全部治疗结束后的12个月和24个月进行评估。慢性放射性直肠损伤定义为放疗结束后>3个月时消化道症状不能好转或者改善,分级标准参考美国国家癌症研究所不良事件通用标准4.0版(NCI-CTCAE 4.0版)中的胃肠道部分。结果848例患者放射总辐射剂量为(47.8±4.6)Gy。术后辅助放疗期间,急性期胃肠道反应症状包括恶心(46.0%,390/848)、呕吐(33.8%,287/848)、便秘(16.3%,138/848)及腹痛(10.3%,87/848)。治疗后12个月和24个月分别回收问卷346份和250份,QLQ-C30调查问卷显示,恶心或呕吐、食欲减退、腹泻、便秘等胃肠道症状得分均较放疗前(手术后1周)和术后放疗期间改善(均P<0.05)。随着随访时间的延长,患者总体生活质量评分逐步提高[放疗前,手术后1周:59.7(0.0~100.0)分,术后放疗期间:63.1(0.0~100.0)分,全部治疗结束后12个月:75.2(0.0~100.0)分,全部治疗结束后24个月:94.1(20.0~120.0)分,H=253.800,P<0.001]。完成全部治疗结束后12个月时,慢性放射性直肠损伤发生率为9.8%(34/346),其中97.1%(33/34)为1~2级不良事件,表现包括腹痛、便秘、便血、腹泻;1例(0.3%)出现频繁腹泻>8次/d,为3级不良事件。全部治疗结束后的24个月,慢性放射性直肠损伤发生率为9.6%(24/250),并未随着时间延长而明显下降(χ^(2)=0.008,P=0.927)。1例3级腹泻患者症状未见改善。结论盆腔恶性肿瘤患者术后辅助放疗期间,常见的治疗相关性胃肠道症状包括恶心、呕吐、便秘、腹痛和腹泻;治疗后12个月和24个月时各种消化道症状明显好转,但仍有少部分患者出现慢性放射性直肠损伤,且随时间延长不能明显改善,值得临床重视。

Objective Radiotherapy is one of the standard treatments for pelvic malignant tumors.However,researches associated with intestinal radiation injury and the quality of life(QoL)of patients receiving radiotherapy were lacking in the past.This study aims to analyze the occurrence of radiation-induced rectal injury after adjuvant radiotherapy for pelvic malignant tumors and call for more attention on this issne.Methods A retrospectively observational study was conducted.Case data of cervical cancer patients from the database of STARS phase 3 randomized clinical trial(NCT00806117)in Sun Yat-sen University Cancer Center were analyzed.A total of 848 cervical cancer patients who received adjuvant radiation following hysterectomy and pelvic lymphadenectomy in Sun Yat-sen University Cancer Center from February 2008 to August 2015 were recruited.The pelvic radiation dosage was 1.8 Gy/day or 2.0 Gy/day,five times every week,and the total dosage was 40-50 Gy.Among 848 patients,563 patients received radiation six weeks after surgery,of whom 282 received adjuvant radiation alone and 281 received concurrent chemoradiotherapy(weekly cisplatin);other 285 patients received sequential chemoradiotherapy(paclitaxel and cisplatin).Acute adverse events,chronic radiation damage of rectum,and QoL were collected and analyed.The digestive tract symptoms and QoL were evaluated based on EORTC QLQ-C30 questionnaires at one week after surgery(M0),during adjuvant therapy period(M1),and at 12 months and 24 months after the completion of treatments(M12 and M24),respectively.Higher scores in the functional catalog and overall quality of life indicated better quality of life,while higher scores in the symptom catalog indicated severe symptoms and worse QoL.Chronic radiation rectal injury was defined as digestive symptoms that were not improved within three months after radiotherapy.Grading standard of acute adverse events and chronic radiation rectal injury was according to the gastrointestinal part of National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0(NCI-CTCAE Version 4.0).Results The mean total radiation dosage of 848 patients was(47.8±4.6)Gy.During adjuvant therapy,the common symptoms of acute intestinal dysfunction were nausea(46.0%,390/848),vomiting(33.8%,287/848),constipation(16.3%,138/848)and abdominal pain(10.3%,87/848).At M12 and M24,the number of 0 QLQ-C30 questionnaires collected was 346 and 250,respectively.QLQ-C30 questionnaires showed that the scores of nausea or vomiting,appetite decrease,diarrhea,constipation,etc.were improved obviously at M12 or M24 compared with those at M0 or during M1(all P<0.05).As the extension of the follow-up time,the score of the overall QoL of patients gradually increased[M0:59.7(0.0-100.0);M1:63.1(0.0-100.0);M12:75.2(0.0-100.0);M24:94.1(20.0-120.0);H=253.800,P<0.001].Twelve months after the completion of treatments,the incidence of chronic radiation rectal injury was 9.8%(34/346),mainly presenting as abdominal pain,constipation,stool blood,diarrhea,mostly at level 1 to 2 toxicity(33/34,97.1%).One patient(0.3%)developed frequent diarrhea(>8 times/d),which was level 3 toxicity.Twenty-four months after all treatments,the incidence of chronic radiation rectal injury was 9.6%(24/250),which was not decreased significantly compared to that in the previous period(χ^(2)=0.008,P=0.927).The symotoms of one patient with level 3 toxicity was not relieved.Conclusions The common symptoms of patients with pelvic maligant tumors during postoperative adjuvant radiotherapy include nausea,vomiting,constipation,abdominal pain and diarrhea.These symptoms are alleviated obviously at 12 and 24 months after adjuvant radiotherapy,and the QoL is significantly improved.However,a few patients may develop chronic radiation rectal injury which is not improved for years or even decades,and deserves attention in clinical practice.