Bradley Jeffrey, Graham Mary V, Winter Kathryn, Purdy James A, Komaki Ritsuko, Roa Wilson H, Ryu Janice K, Bosch Walter, Emami Bahman
Department of Radiation Oncology, Washington University Siteman Cancer Center, St. Louis, MO 63110, USA.
Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):318-28. doi: 10.1016/j.ijrobp.2004.06.260.
To evaluate prospectively the acute and late morbidities from a multiinstitutional three-dimensional radiotherapy dose-escalation study for inoperable non-small-cell lung cancer.
A total of 179 patients were enrolled in a Phase I-II three-dimensional radiotherapy dose-escalation trial. Of the 179 patients, 177 were eligible. The use of concurrent chemotherapy was not allowed. Twenty-five patients received neoadjuvant chemotherapy. Patients were stratified at escalating radiation dose levels depending on the percentage of the total lung volume that received >20 Gy with the treatment plan (V(20)). Patients with a V(20) <25% (Group 1) received 70.9 Gy in 33 fractions, 77.4 Gy in 36 fractions, 83.8 Gy in 39 fractions, and 90.3 Gy in 42 fractions, successively. Patients with a V(20) of 25-36% (Group 2) received doses of 70.9 Gy and 77.4 Gy, successively. The treatment arm for patients with a V(20) > or =37% (Group 3) closed early secondary to poor accrual (2 patients) and the perception of excessive risk for the development of pneumonitis. Toxicities occurring or persisting beyond 90 days after the start of radiotherapy were scored as late toxicities. The estimated toxicity rates were calculated on the basis of the cumulative incidence method.
The following acute Grade 3 or worse toxicities were observed for Group 1: 70.9 Gy (1 case of weight loss), 77.4 Gy (nausea and hematologic toxicity in 1 case each), 83.8 Gy (1 case of hematologic toxicity), and 90.3 Gy (3 cases of lung toxicity). The following acute Grade 3 or worse toxicities were observed for Group 2: none at 70.9 Gy and 2 cases of lung toxicity at 77.4 Gy. No patients developed acute Grade 3 or worse esophageal toxicity. The estimated rate of Grade 3 or worse late lung toxicity at 18 months was 7%, 16%, 0%, and 13% for Group 1 patients receiving 70.9, 77.4, 83.8, or 90.3 Gy, respectively. Group 2 patients had an estimated late lung toxicity rate of 15% at 18 months for both 70.9 and 77.4 Gy. The prognostic factors for late pneumonitis in multivariate analysis were the mean lung dose and V(20). The estimated rate of late Grade 3 or worse esophageal toxicity at 18 months was 8%, 0%, 4%, and 6%, for Group 1 patients receiving 70.9, 77.4, 83.8, 90.3 Gy, respectively, and 0% and 5%, respectively, for Group 2 patients receiving 70.9 and 77.4 Gy. The dyspnea index scoring at baseline and after therapy for functional impairment, magnitude of task, and magnitude of effort revealed no change in 63%, functional pulmonary loss in 23%, and pulmonary improvement in 14% of patients. The observed locoregional control and overall survival rates were each similar among the study arms within each dose level of Groups 1 and 2. Locoregional control was achieved in 50-78% of patients. Thirty-one patients developed regional nodal failure. The location of nodal failure in relationship to the RT volume was documented in 28 of these 31 patients. Twelve patients had isolated elective nodal failures. Fourteen patients had regional failure in irradiated nodal volumes. Two patients had both elective nodal and irradiated nodal failure.
The radiation dose was safely escalated using three-dimensional conformal techniques to 83.8 Gy for patients with V(20) values of <25% (Group 1) and to 77.4 Gy for patients with V(20) values between 25% and 36% (Group 2), using fraction sizes of 2.15 Gy. The 90.3-Gy dose level was too toxic, resulting in dose-related deaths in 2 patients. Elective nodal failure occurred in <10% of patients.
前瞻性评估一项针对不可切除非小细胞肺癌的多机构三维放射治疗剂量递增研究中的急性和晚期发病率。
共有179例患者参加了一项I-II期三维放射治疗剂量递增试验。179例患者中，177例符合条件。不允许同时使用化疗。25例患者接受了新辅助化疗。根据治疗计划中接受>20 Gy的全肺体积百分比（V(20)），将患者分层至递增的放射剂量水平。V(20)<25%的患者（第1组）依次接受33次分割的70.9 Gy、36次分割的77.4 Gy、39次分割的83.8 Gy和42次分割的90.3 Gy。V(20)为25%-36%的患者（第2组）依次接受70.9 Gy和77.4 Gy。V(20)≥37%的患者（第3组）的治疗组因入组不佳（2例患者）以及认为发生肺炎的风险过高而提前关闭。放疗开始后90天以上发生或持续的毒性反应被评为晚期毒性反应。基于累积发病率法计算估计的毒性发生率。
第1组观察到以下急性3级或更严重毒性反应：70.9 Gy（1例体重减轻）、77.4 Gy（各1例恶心和血液学毒性）、83.8 Gy（1例血液学毒性）和90.3 Gy（3例肺部毒性）。第2组观察到以下急性3级或更严重毒性反应：70.9 Gy时无，77.4 Gy时有2例肺部毒性。没有患者发生急性3级或更严重的食管毒性。接受70.9、77.4、83.8或90.3 Gy的第1组患者在18个月时3级或更严重晚期肺部毒性的估计发生率分别为7%、16%、0%和13%。接受70.9和77.4 Gy的第2组患者在18个月时晚期肺部毒性估计发生率均为15%。多因素分析中晚期肺炎的预后因素是平均肺剂量和V(20)。接受70.9、77.4、83.8、90.3 Gy的第1组患者在18个月时3级或更严重晚期食管毒性的估计发生率分别为8%、0%、4%和6%，接受70.9和77.4 Gy的第2组患者分别为0%和5%。基线时以及治疗后针对功能损害、任务难度和努力程度的呼吸困难指数评分显示，63%的患者无变化，23%的患者有功能性肺功能丧失，14%的患者有肺功能改善。在第1组和第2组的每个剂量水平内，各研究组观察到的局部区域控制率和总生存率均相似。50%-78%的患者实现了局部区域控制。31例患者发生区域淋巴结失败。这31例患者中有28例记录了淋巴结失败部位与放疗体积的关系。12例患者有孤立的选择性淋巴结失败。14例患者在照射的淋巴结体积内有区域失败。2例患者既有选择性淋巴结失败又有照射淋巴结失败。
使用三维适形技术，对于V(20)值<25%的患者（第1组），放射剂量安全递增至83.8 Gy；对于V(20)值在25%-36%之间的患者（第2组），放射剂量安全递增至77.4 Gy，分割剂量为2.15 Gy。90.3 Gy剂量水平毒性过大，导致2例患者因剂量相关死亡。<10%的患者发生选择性淋巴结失败。
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