Lee Grace, Nelson Bailey, Koenig Julie, Plastaras John P, Metz James M, Yeap Beow Y, Zhang Yongbin, Drapek Lorraine C, Baglini Christian, Ryan David P, Parikh Aparna R, Allen Jill N, Clark Jeffrey W, Blaszkowsky Lawrence S, Ben-Josef Edgar, Hong Theodore S, Kharofa Jordan R, Wo Jennifer Y
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Radiation Oncology, University of Cincinnati, Cincinnati, Ohio.
Int J Radiat Oncol Biol Phys. 2025 May 1;122(1):52-62. doi: 10.1016/j.ijrobp.2024.12.034. Epub 2025 Jan 10.
Although definitive chemoradiation therapy (CRT) with 5-fluorouracil (5-FU) and mitomycin-C (MMC) (5-FU/MMC) remains the standard of care for localized anal cancer, treatment is associated with significant acute and late toxicity. Proton radiation therapy (RT) may potentially reduce such toxicity. Here, we assess the long-term outcomes of patients with anal cancer treated with CRT using proton RT in 2 prospective pilot studies.
Patients with stage I to III anal cancer treated with proton RT (pencil beam scanning or intensity modulated proton therapy) per Radiation Therapy Oncology Group (RTOG) 0529 dose schema with concurrent 5-FU/MMC (2 cycles) in 2 prospective, single-arm trials were followed. Locoregional failure, distant metastases, colostomy-free survival, disease-free survival, and overall survival were assessed. Physician-graded late toxicity (>90 days from CRT) was assessed per National Cancer Institute Common Terminology Criteria for Adverse Events version 4. Late toxicities were compared with RTOG 0529 via Fisher exact test. Patient-reported outcomes were analyzed.
Between 2013 and 2020, 39 patients were treated; 37 (95%) patients completed treatment per protocol. The median follow-up was 63 months. The 5-year locoregional failure, distant metastases, colostomy-free survival, disease-free survival, and overall survival were 21%, 19%, 72%, 69%, and 75%, respectively. The worst late treatment toxicities were grade 1 in 38%, grade 2 in 24%, grade 3 in 19%, grade 4 in 3%, and no grade 5. Compared to RTOG 0529, rates of overall grade 2+ late toxicities were significantly lower (46% vs 75%, P = .01), attributed to lower dermatologic toxicities (0% vs 25%, P < .01), but there was no significant difference in overall grade 3+ toxicities (22% vs 20%, P = 1.00). No statistically significant correlations between organ-at-risk dosimetry and late toxicities were noted. Available patient-reported outcomes demonstrated that significant proportion of patients had persistent gastrointestinal symptoms at long term.
Definitive CRT with proton RT with concurrent 5-FU/MMC for the treatment of anal cancer resulted in comparable long-term disease control and grade 3+ late toxicities compared to RTOG 0529. Future studies should evaluate additional measures to minimize treatment toxicity and subsets of patients who are most likely to benefit from proton RT.
尽管含5-氟尿嘧啶（5-FU）和丝裂霉素-C（MMC）的确定性放化疗（CRT）（5-FU/MMC）仍是局部晚期肛管癌的标准治疗方案，但该治疗会带来显著的急性和晚期毒性。质子放射治疗（RT）可能会降低此类毒性。在此，我们在两项前瞻性试点研究中评估了采用质子RT进行CRT治疗的肛管癌患者的长期疗效。
在两项前瞻性单臂试验中，对按照放射治疗肿瘤学组（RTOG）0529剂量方案接受质子RT（笔形束扫描或调强质子治疗）并同时接受5-FU/MMC（2个周期）治疗的I至III期肛管癌患者进行随访。评估局部区域失败、远处转移、无结肠造口术生存率、无病生存率和总生存率。根据美国国立癌症研究所不良事件通用术语标准第4版评估医生分级的晚期毒性（自CRT起>90天）。通过Fisher精确检验将晚期毒性与RTOG 0529进行比较。分析患者报告的结果。
2013年至2020年期间，共治疗了39例患者；37例（95%）患者按方案完成治疗。中位随访时间为63个月。5年局部区域失败、远处转移、无结肠造口术生存率、无病生存率和总生存率分别为21%、19%、72%、69%和75%。最严重的晚期治疗毒性为1级的占38%，2级的占24%，3级的占19%，4级的占3%，无5级。与RTOG 0529相比，2级及以上晚期毒性的总体发生率显著更低（46%对75%，P = 0.01），这归因于更低的皮肤毒性（0%对25%，P < 0.01），但3级及以上毒性的总体发生率无显著差异（22%对20%，P = 1.00）。未发现危及器官剂量测定与晚期毒性之间存在统计学显著相关性。现有的患者报告结果表明，很大一部分患者长期存在持续的胃肠道症状。
与RTOG 0529相比，采用质子RT联合5-FU/MMC进行确定性CRT治疗肛管癌可带来相当的长期疾病控制和3级及以上晚期毒性。未来的研究应评估其他措施以尽量减少治疗毒性，以及最可能从质子RT中获益的患者亚组。
