Moonen L, vd Voet H, de Nijs R, Horenblas S, Hart A A, Bartelink H
Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Amsterdam.
Int J Radiat Oncol Biol Phys. 1998 Oct 1;42(3):525-30. doi: 10.1016/s0360-3016(98)00263-6.
To evaluate and eventually quantify a possible influence of tumor proliferation during the external radiation course on local control in muscle invasive bladder cancer.
The influence of total dose, overall treatment time, and treatment interruption has retrospectively been analyzed in a series of 379 patients with nonmetastasized, muscle-invasive transitional cell carcinoma of the urinary bladder. All patients received external beam radiotherapy at the Netherlands Cancer Institute between 1977 and 1990. Total dose varied between 50 and 75 Gy with a mean of 60.5 Gy and a median of 60.4 Gy. Overall treatment time varied between 20 and 270 days with a mean of 49 days and a median of 41 days. Number of fractions varied between 17 and 36 with a mean of 27 and a median of 26. Two hundred and fourty-four patients had a continuous radiation course, whereas 135 had an intended split course or an unintended treatment interruption. Median follow-up was 22 months for all patients and 82 months for the 30 patients still alive at last follow-up. A stepwise procedure using proportional hazard regression has been used to identify prognostic treatment factors with respect to local recurrence as sole first recurrence.
One hundred and thirty-six patients experienced a local recurrence and 120 of these occurred before regional or distant metastases. The actuarial local control rate was 40.3% at 5 years and 32.3% at 10 years. In a multivariate analysis total dose showed a significant association with local control (p = 0.0039), however in a markedly nonlinear way. In fact only those patients treated with a dose below 57.5 Gy had a significant higher bladder relapse rate, whereas no difference in relapse rate was found among patients treated with doses above 57.5 Gy. This remained the case even after adjustment for overall treatment time and all significant tumor and patient characteristics. The Normalized Tumor Dose (NTD) (alpha/beta = 10) and NTD (alpha/beta = 15) were not significantly related to local control (p = 0.96 and p = 0.053, respectively). Only weak evidence was found for an association between local control and overall treatment time (p = 0.067). No difference in bladder relapse rate was found among patients treated with a continuous course and patients who had treatment interruptions (p = 0.099). Neither the length of the interruption, nor the actual number of treatment days has a significant influence on local control (p = 0.04 and p = 0.09, respectively).
In contrast to two earlier, but smaller reports, in this study no significant effect of treatment prolongation on outcome after radiotherapy could be demonstrated and thus no support was found for an important role for tumor proliferation as the cause of treatment failure in muscle-invasive bladder cancer. Results of large-sized phase III trials will have to be awaited to show any benefit from reduction of the overall treatment time and to quantify the potential effect of tumor proliferation.
评估并最终量化肌肉浸润性膀胱癌外照射过程中肿瘤增殖对局部控制的可能影响。
回顾性分析了379例非转移性肌肉浸润性膀胱移行细胞癌患者，分析了总剂量、总治疗时间和治疗中断的影响。1977年至1990年间，所有患者均在荷兰癌症研究所接受了外照射放疗。总剂量在50至75 Gy之间，平均为60.5 Gy，中位数为60.4 Gy。总治疗时间在20至270天之间，平均为49天，中位数为41天。分次次数在17至36次之间，平均为27次，中位数为26次。244例患者接受了连续放疗疗程，而135例患者有计划的分割疗程或意外的治疗中断。所有患者的中位随访时间为22个月，最后一次随访时仍存活的30例患者的中位随访时间为82个月。采用比例风险回归的逐步程序来确定关于局部复发作为唯一首次复发的预后治疗因素。
136例患者出现局部复发，其中120例发生在区域或远处转移之前。5年时的精算局部控制率为40.3%，10年时为32.3%。在多变量分析中，总剂量与局部控制显示出显著关联（p = 0.0039），然而呈明显的非线性关系。实际上，只有那些接受低于57.5 Gy剂量治疗的患者膀胱复发率显著更高，而接受高于57.5 Gy剂量治疗的患者之间复发率没有差异。即使在调整了总治疗时间以及所有显著的肿瘤和患者特征后，情况仍然如此。归一化肿瘤剂量（NTD）（α/β = 10）和NTD（α/β = 15）与局部控制无显著相关性（分别为p = 0.96和p = 0.053）。仅发现微弱证据表明局部控制与总治疗时间之间存在关联（p = 0.067）。接受连续疗程治疗的患者与有治疗中断的患者之间膀胱复发率没有差异（p = 0.099）。中断时间的长短以及实际治疗天数均对局部控制没有显著影响（分别为p = 0.04和p = 0.09）。
与两项早期但规模较小的报告不同，本研究未证明治疗延长对放疗后结局有显著影响，因此未发现肿瘤增殖作为肌肉浸润性膀胱癌治疗失败原因的重要作用的支持证据。必须等待大型III期试验的结果，以显示缩短总治疗时间的任何益处并量化肿瘤增殖的潜在影响。
