Abstract：
OBJECTIVE: We determine the maximum tolerated tumor-focused dose (MTD) for the radical treatment of muscle invasive bladder cancer enabled by image guided adaptive radiation therapy and long-term clinical outcomes.
METHODS: Fifty-nine patients with T2 to T4aN0M0 unifocal urothelial muscle invasive bladder cancer suitable for daily radical radiation therapy were recruited prospectively to an ethics-approved protocol (NCT01124682). The uninvolved bladder (PTVbladder) was planned to 52 Gy in 32 fractions. The bladder tumor (PTVtumor) was planned to an assigned dose level of 68, 70, 72, or 74 Gy. If organ at risk dose constraints were violated, then PTVtumor was planned to 64 Gy. Dose level allocation was determined by concurrent toxicity assessment of all previous patients recruited. Acute toxicity was evaluated using Common Terminology Criteria for Adverse Events v3.0; late toxicity was evaluated using Radiation Therapy Oncology Group criteria. The MTD was predefined as the highest dose level with an estimated probability of ≤ 15% ≥ G3 late toxicity and an observed rate of <50% acute G3 and <10% acute G4 toxicity.
RESULTS: Twenty-six patients were assigned to 68 Gy, of whom 6 were planned to 64 Gy; 29 patients were assigned to 70 Gy of whom 1 was planned to 68 Gy, 2 patients were assigned and planned to 72 Gy; no patients were assigned to 74 Gy. Three patients did not complete the treatment as planned, of whom only 1 patient stopped treatment because dose-limiting toxicity occurred. The MTD was 70 Gy. Acute genito-urinary and gastro-intestinal G3 acute toxicity was seen in 19% and 7% of patients, respectively. No acute G4 genito-urinary or gastro-intestinal toxicity was seen. Late toxicity (any) G3 and G4 was seen in 14% and 2% of patients, respectively. The 5-year overall survival was 58% (95% CI, 44%-71%). The bladder preservation rate was 89% (95% CI, 88%-96%) with 6 patients not retaining native bladder function.
CONCLUSIONS: Bladder tumor-focused dose escalation to 70 Gy using image guided adaptive radiation therapy is feasible with acceptable toxicity. This dose level has been evaluated in a phase II randomized control trial (RAIDER NCT02447549).
METHODS: Fifty-nine patients with T2 to T4aN0M0 unifocal urothelial muscle invasive bladder cancer suitable for daily radical radiation therapy were recruited prospectively to an ethics-approved protocol (NCT01124682). The uninvolved bladder (PTVbladder) was planned to 52 Gy in 32 fractions. The bladder tumor (PTVtumor) was planned to an assigned dose level of 68, 70, 72, or 74 Gy. If organ at risk dose constraints were violated, then PTVtumor was planned to 64 Gy. Dose level allocation was determined by concurrent toxicity assessment of all previous patients recruited. Acute toxicity was evaluated using Common Terminology Criteria for Adverse Events v3.0; late toxicity was evaluated using Radiation Therapy Oncology Group criteria. The MTD was predefined as the highest dose level with an estimated probability of ≤ 15% ≥ G3 late toxicity and an observed rate of <50% acute G3 and <10% acute G4 toxicity.
RESULTS: Twenty-six patients were assigned to 68 Gy, of whom 6 were planned to 64 Gy; 29 patients were assigned to 70 Gy of whom 1 was planned to 68 Gy, 2 patients were assigned and planned to 72 Gy; no patients were assigned to 74 Gy. Three patients did not complete the treatment as planned, of whom only 1 patient stopped treatment because dose-limiting toxicity occurred. The MTD was 70 Gy. Acute genito-urinary and gastro-intestinal G3 acute toxicity was seen in 19% and 7% of patients, respectively. No acute G4 genito-urinary or gastro-intestinal toxicity was seen. Late toxicity (any) G3 and G4 was seen in 14% and 2% of patients, respectively. The 5-year overall survival was 58% (95% CI, 44%-71%). The bladder preservation rate was 89% (95% CI, 88%-96%) with 6 patients not retaining native bladder function.
CONCLUSIONS: Bladder tumor-focused dose escalation to 70 Gy using image guided adaptive radiation therapy is feasible with acceptable toxicity. This dose level has been evaluated in a phase II randomized control trial (RAIDER NCT02447549).
摘要：
目的：我们确定了通过图像引导自适应放疗（IGART）和长期临床结果实现的肌层浸润性膀胱癌（MIBC）根治性治疗的最大耐受肿瘤聚焦剂量（MTD）。
方法：59例适用于每日根治性放疗的T2-T4aN0M0单灶性尿路上皮MIBC患者被前瞻性招募到伦理批准的方案（XX）。未受累的膀胱（PTVbindle）计划在32个部分中达到52Gy（f）。计划将膀胱肿瘤（PTV肿瘤）的指定剂量水平为68、70、72或74Gy。如果违反了危险器官（OAR）剂量限制，然后PTV肿瘤计划为64Gy。通过对所有以前招募的患者的并发毒性评估来确定剂量水平分配。使用CTCAEv3.0评估急性毒性；使用RTOG标准评估晚期毒性。MTD预定为最高剂量水平，估计概率≤15%≥G3晚期毒性，观察率<50%急性G3和<10%急性G4毒性。
结果：26名患者被分配到68Gy，其中6例计划为64Gy；29例患者被分配为70Gy，其中1例计划为68Gy，2例患者被分配并计划到72Gy；没有患者被分配到74Gy。三名患者未按计划完成治疗，其中只有1例患者因发生剂量限制性毒性而停止治疗。MTD为70Gy。急性泌尿生殖道（GU）和胃肠道（GI）G3急性毒性分别在19％和7％的患者中观察到。没有看到4级GU或GI毒性。晚期毒性(任何)G3和G4分别见于14%和2%的患者中。5年总生存率为58%（95%CI44-71%）。膀胱保存率为89％（95％CI，88％至96％），其中6例患者未保留天然膀胱功能。
结论：使用IGART将膀胱肿瘤聚焦剂量递增至70Gy是可行的，毒性可接受。该剂量水平已在II期随机对照试验（XXXXX）中进行了评估。
方法：59例适用于每日根治性放疗的T2-T4aN0M0单灶性尿路上皮MIBC患者被前瞻性招募到伦理批准的方案（XX）。未受累的膀胱（PTVbindle）计划在32个部分中达到52Gy（f）。计划将膀胱肿瘤（PTV肿瘤）的指定剂量水平为68、70、72或74Gy。如果违反了危险器官（OAR）剂量限制，然后PTV肿瘤计划为64Gy。通过对所有以前招募的患者的并发毒性评估来确定剂量水平分配。使用CTCAEv3.0评估急性毒性；使用RTOG标准评估晚期毒性。MTD预定为最高剂量水平，估计概率≤15%≥G3晚期毒性，观察率<50%急性G3和<10%急性G4毒性。
结果：26名患者被分配到68Gy，其中6例计划为64Gy；29例患者被分配为70Gy，其中1例计划为68Gy，2例患者被分配并计划到72Gy；没有患者被分配到74Gy。三名患者未按计划完成治疗，其中只有1例患者因发生剂量限制性毒性而停止治疗。MTD为70Gy。急性泌尿生殖道（GU）和胃肠道（GI）G3急性毒性分别在19％和7％的患者中观察到。没有看到4级GU或GI毒性。晚期毒性(任何)G3和G4分别见于14%和2%的患者中。5年总生存率为58%（95%CI44-71%）。膀胱保存率为89％（95％CI，88％至96％），其中6例患者未保留天然膀胱功能。
结论：使用IGART将膀胱肿瘤聚焦剂量递增至70Gy是可行的，毒性可接受。该剂量水平已在II期随机对照试验（XXXXX）中进行了评估。
