放化疗(综合治疗 [combined-modality treatment, CMT])现已成为肛门鳞状细胞癌的标准诊疗方法。直到 20 世纪 70 年代末,肛管癌的常规治疗一直是腹会阴联合切除术 (abdominoperineal resection, APR)。之后,单组 II 期研究证实,约 80%-90% 的患者经过初始 CMT 可获得完全缓解。尽管临床试验尚未显示 CMT 在总生存率方面的显著优势,但与单独行放疗比较,其改善了局部控制疾病的局部控制和缓解率:高质量的证据显示,综合治疗 (CMT) 与单独放疗相比,可显著改善局部控制(3 年后为 61% vs 39%;[23]UKCCCR Anal Cancer Trial Working Party. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet. 1996;348:1049-1054.http://www.ncbi.nlm.nih.gov/pubmed/8874455?tool=bestpractice.com[24]Northover J, Glynne-Jones R, Sebag-Montefiore D, et al. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer. 2010;102:1123-1128.http://www.ncbi.nlm.nih.gov/pubmed/20354531?tool=bestpractice.com5 年后为 68% vs 50%[25]Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer radiotherapy and gastrointestinal cooperative groups. J Clin Oncol. 1997;15:2040-2049.http://www.ncbi.nlm.nih.gov/pubmed/9164216?tool=bestpractice.com)。该方法与单独放疗相比也可改善缓解率(80% vs 54%)。[25]Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer radiotherapy and gastrointestinal cooperative groups. J Clin Oncol. 1997;15:2040-2049.http://www.ncbi.nlm.nih.gov/pubmed/9164216?tool=bestpractice.com系统评价或者受试者>200名的随机对照临床试验(RCT)。和未进行结肠造口术的生存率。无结肠造口的生存率:高质量的证据显示,综合治疗 (CMT) 与单独放疗相比可显著改善无结肠造口术的生存率(72% vs 40%)。[25]Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer radiotherapy and gastrointestinal cooperative groups. J Clin Oncol. 1997;15:2040-2049.http://www.ncbi.nlm.nih.gov/pubmed/9164216?tool=bestpractice.com系统评价或者受试者>200名的随机对照临床试验(RCT)。[26]Glynne-Jones R, Lim F. Anal cancer: an examination of radiotherapy strategies. Int J Radiat Oncol Biol Phys. 2011;79:1290-1301.http://www.ncbi.nlm.nih.gov/pubmed/21414513?tool=bestpractice.com诱导化疗或放疗剂量强化无法改善未进行结肠造口术患者的生存率。[27]Peiffert D, Tournier-Rangeard L, Gérard JP, et al. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol. 2012;30:1941-1948.http://www.ncbi.nlm.nih.gov/pubmed/22529257?tool=bestpractice.com
手术(最常用 APR )被保留用于挽救治疗。尽管对于体积较大的原发肿瘤 (>5 cm) 患者,其完全缓解率更低 (50%-75%),但大部分患者仍然可不用结肠造口术,而且该方法的总生存情况极好。一些大便失禁或肛瘘患者可能需要进行治疗前转向结肠造口术,治疗成功后再将其还纳。
CMT 方案
CMT 的疗效是公认的,而且最近的随机临床试验都专注于探寻理想的治疗方案。已经确定丝裂霉素作为 CMT 必要组成部分的作用,即放疗 + 氟尿嘧啶 + 丝裂霉素的效果优于放疗 + 氟尿嘧啶。无病生存率和无结肠造口的生存率:高质量的证据显示,与单独放疗+ 丝裂霉素相比,放疗 + 丝裂霉素 + 氟尿嘧啶可达到较高的无病生存率和无结肠造口术的生存率。[28]Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol. 1996;14:2527-2539.http://www.ncbi.nlm.nih.gov/pubmed/8823332?tool=bestpractice.com系统评价或者受试者>200名的随机对照临床试验(RCT)。两项随机试验发现,与基于氟尿嘧啶/顺铂的放化疗方案相比,基于氟尿嘧啶/丝裂霉素的放化疗方案可显著改善患者的无病生存及总生存情况。[29]Gunderson LL, Winter KA, Ajani JA, et al. Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol. 2012;30:4344-4351.http://www.ncbi.nlm.nih.gov/pubmed/23150707?tool=bestpractice.com[30]James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol. 2013;14:516-524.http://www.ncbi.nlm.nih.gov/pubmed/23578724?tool=bestpractice.com控制糖尿病患者心血管风险行动 (ACCORD) 3 试验发现,诱导化疗或标准放化疗后用短距离放射治疗强化,并未改善无结肠造口的生存率。[27]Peiffert D, Tournier-Rangeard L, Gérard JP, et al. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol. 2012;30:1941-1948.http://www.ncbi.nlm.nih.gov/pubmed/22529257?tool=bestpractice.com
因此,放疗 + 双重药物化疗(氟尿嘧啶和丝裂霉素)仍是标准治疗。[30]James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol. 2013;14:516-524.http://www.ncbi.nlm.nih.gov/pubmed/23578724?tool=bestpractice.com盆腔放疗,5日/周,持续治疗5周。放疗的第 1 周和第 5 周要联合化疗:在第 1-4 天和 29-33 天持续输注氟尿嘧啶,在第 1 和 29 天单次静脉推注丝裂霉素。对于 T3 或 T4 和/或 N1 病变,大部分肿瘤医生添加 2 个周期的诱导化疗,并增加总放疗剂量,尽管尚不清楚是否可改善患者结局。
治疗可在门诊进行。但对于 3 +级急性毒性反应(中性粒细胞减少、血小板减少症、皮肤破溃、肛门/直肠疼痛)者,可能需要间断治疗。约 5% 的患者治疗的毒性反应可能进展为重度(4 度),因而可能需要住院以治疗脱水和脓毒症的风险。
治疗后评估以及不完全缓解的管理
在完成治疗后的第 6 周,对患者进行体格检查,并通过直肠检查和肛门镜检查评估肿瘤治疗效果。应仅在肿瘤对治疗无反应或体积增大时进行活检。
未达完全缓解的患者可接受挽救治疗,即对原发肿瘤进行额外的 9 Gy 放疗,同时联合氟尿嘧啶/顺铂进行化疗。
在完成该挽救治疗后 6 周若仍未达到完全缓解,则可进行 APR,并行永久性结肠造口术。