Wu Kai-Liang, Jiang Guo-Liang, Liao Yuan, Qian Hao, Wang Li-Juan, Fu Xiao-Long, Zhao Shen
Department of Radiation Oncology, Cancer Hospital, Fudan University, Shanghai, China.
Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1336-44. doi: 10.1016/s0360-3016(03)01385-3.
A prospective Phase I/II dose escalation study was conducted to determine the maximum tolerated dose (MTD) in three-dimensional conformal radiation therapy (3D-CRT) for non-small-cell lung cancer (NSCLC).
MTD would be reached via a dose escalation study. After 42 Gy/21 fractions, 4.2 weeks by conventional fractionated irradiation through anteroposterior/posteroanterior fields, the 3D-CRT technique was used as boost. The planned total dose escalation depended on lung volume irradiated. According to the percentage of lung volume receiving >20 Gy, the patients were divided into three subgroups (i.e., <25%, 25%-37%, and >37%). The scheduled dose escalation began with 69 Gy and continued to 78 Gy. The boost doses were delivered at 3 Gy per fraction, once per day, five fractions per week. Each dose level includes 5 patients. Besides radiotherapy, all patients received neoadjuvant and adjuvant chemotherapy with MVP regimen (Mitomycin, Vindesine, cis-platium). The criterion for stopping further dose escalation was > or =20% of patients with > or =RTOG Grade 3 radiation pneumonitis.
Between June 1999 and February 2001, 50 patients had been enrolled in this study, including 4 with Stage II disease, 31 with Stage IIIa disease, and 15 with Stage IIIb disease. The dose escalation plan has been completed. All subgroups reached the highest predetermined dose levels (i.e., 78 Gy for the <25% subgroup, 78 Gy for the 25-37% subgroup, and 75 Gy for the >37% subgroup). Although none of the subgroups developed more than 20% of >/=Grade 3 acute pneumonitis, dose escalation was terminated because long-term follow-up was needed to observe late complications. Median follow-up time (MFT) for the entire group was 18 months (6-37 months). The most common acute complication was esophagitis in 56% of patients with RTOG Grade 1-2, and in 4% with Grade 3. Acute radiation pneumonitis developed in 36% of patients with RTOG Grade 1-2. Only 1 patient had Grade 3 pneumonitis, which was in the 25-37% subgroup at 75 Gy. The hematopoietic toxicity appeared in 58% of patients with Grade 1-2, and 8% with Grade 3. As to late complications, only 30% of patients developed pulmonary fibrosis of RTOG Grade 1-2. The median survival time for the entire group was 18 months. Two-year overall survival, locoregional progression-free rate, and distant metastasis rate were 44%, 40%, and 41%, respectively.
Although MFT was 18 months, it had not yet been declared because a longer follow-up was needed to observe the late complications. The 2-year overall survival of 44% was very encouraging and implied that 3D-CRT combined with chemotherapy would improve the outcome for locally advanced NSCLC.
开展一项前瞻性I/II期剂量递增研究，以确定非小细胞肺癌（NSCLC）三维适形放疗（3D-CRT）中的最大耐受剂量（MTD）。
通过剂量递增研究确定MTD。经前后野常规分割照射42 Gy/21次，历时4.2周后，采用3D-CRT技术进行追加放疗。计划的总剂量递增取决于受照射的肺体积。根据接受>20 Gy肺体积的百分比，将患者分为三个亚组（即<25%、25%-37%和>37%）。预定的剂量递增从69 Gy开始，持续至78 Gy。追加放疗剂量为每次3 Gy，每天1次，每周5次。每个剂量水平纳入5例患者。除放疗外，所有患者均接受MVP方案（丝裂霉素、长春地辛、顺铂）的新辅助和辅助化疗。停止进一步剂量递增的标准是≥20%的患者发生≥RTOG 3级放射性肺炎。
1999年6月至2001年2月，本研究共纳入50例患者，其中II期4例，IIIA期31例，IIIB期15例。剂量递增计划已完成。所有亚组均达到了预定的最高剂量水平（即<25%亚组为78 Gy，25%-37%亚组为78 Gy，>37%亚组为75 Gy）。虽然没有一个亚组发生超过20%的≥3级急性肺炎，但由于需要长期随访以观察晚期并发症，剂量递增终止。全组的中位随访时间（MFT）为18个月（6-37个月）。最常见的急性并发症是食管炎，56%的患者为RTOG 1-2级，4%为3级。36%的患者发生RTOG 1-2级急性放射性肺炎。仅l例患者发生3级肺炎，该患者在25%-37%亚组，接受75 Gy照射。58%的患者出现1-2级血液学毒性，8%为3级。至于晚期并发症，仅30%的患者发生RTOG 1-2级肺纤维化。全组的中位生存时间为18个月。两年总生存率、局部区域无进展率和远处转移率分别为44%、40%和41%。
虽然MFT为18个月，但由于需要更长时间的随访以观察晚期并发症，尚未宣布研究结果。44%的两年总生存率非常令人鼓舞，表明3D-CRT联合化疗可改善局部晚期NSCLC的治疗效果。
