Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy

PURPOSE: The aim of this study was to determine the maximum tolerated dose (MTD) delivered within 6 weeks in patients with non-small-cell lung cancer (NSCLC). The impact of tumor volume and delivered dose on failure-free interval (FFI) and overall survival (OS) were also studied. METHODS AND MATERIALS: A Phase I/II trial was performed including inoperable NSCLC patients. According to the relative mean lung dose (rMLD), five risk groups with different starting doses were defined: Group 1, rMLD 0.0 to 0.12; Group 2, rMLD 0.12 to 0.18; Group 3, rMLD 0.18 to 0.24; Group 4, rMLD 0.24 to 0.31; and Group 5, rMLD 0.31 to 0.40. Patients underwent irradiation with 2.25 Gy per fraction and a fixed overall treatment time of 6 weeks. The dose was escalated with 6.75 Gy after 6 months follow-up without dose-limiting toxicity. If more than 30 fractions were prescribed, twice-daily irradiation was performed with at least a 6-h interval. RESULTS: A total of 88 patients were included. Tumor Stage I or II was found in 53%, IIIA in 31%, and IIIB in 17%. The MTD was not achieved in risk Group 1 (reached dose, 94.5 Gy). For risk Groups 2 and 3 the MTD was 81 Gy. The 74.3-Gy dose was determined to be safe for Group 4 and the 60.8-Gy dose for Group 5. In 2 patients (5%) an isolated nodal relapse occurred. Based on multivariable analysis, higher doses significantly increased the FFI (p = 0.02) for the total group. The OS was increased in the lower risk groups (p = 0.05) but not in the higher risk groups (p = 0.4). CONCLUSION: Dose escalation is safe up to 94.5 Gy in 42 fractions in 6 weeks in patients with an MLD 13.6 Gy or less. Higher doses are associated with a better FFI and OS for smaller tumor volumes. Involved-field irradiation results in a low percentage of isolated nodal relapses.     

Three-dimensional conformal radiation therapy for non-small-cell lung cancer: a phase I/II dose escalation clinical trial

PURPOSE: 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). MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

91例非小细胞肺癌三维适形放疗的临床分析

目的分析三维适形放疗(3DCRT)在非小细胞肺癌(NSCLC)治疗中的效果和放射损伤情况，并分析其预后因素。方法接受3DCRT的91例NSCLC中男73例，女18例，中位年龄66岁。放疗中位单次剂量2Gy，5次／周，中位总剂量60Gy，中位随访期17个月。结果完全缓解11．0％(10／91)，部分缓解46、2％(42／91)，稳定33．0％(30／91)，进展1．1％(1／91)，有效率57．1％(52／91)。1、2年总生存率分别为67．0％、32．6％，中位生存期16个月。1、2年的无局部进展生存率分别为82．6％、53．0％。单因素和多因素分析都显示，体重下降≥5％预后不良。急性放射性肺炎2级2例，3级4例；晚期放射性肺炎2级1例，3级1例。急性放射性食管炎2级8例。急性2级骨髓毒性5例。结论3DCRT治疗NSCLC有很好的近期疗效，放射损伤在可接受范围。放疗总剂量还有提升的空间。     

Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial.

PURPOSE: High-dose radiation may improve outcomes in non-small-cell lung cancer (NSCLC). By using three-dimensional conformal radiation therapy and limiting the target volume, we hypothesized that the dose could be safely escalated. MATERIALS AND METHODS: A standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes >or= 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely. More recently, selected patients received neoadjuvant cisplatin and vinorelbine. RESULTS: At the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions. CONCLUSION: Dose escalation in NSCLC has been accomplished safely in most patients using three-dimensional conformal radiation therapy, limiting target volumes, and segregating patients by the volume of normal lung irradiated.     

非小细胞肺癌三维适形放射治疗临床Ⅰ和Ⅱ期剂量递增试验结果分析

目的：通过剂量递增试验试图获得非小细胞肺癌（NSCLC）病例三维适形放射的最大耐受剂量并观察其疗效。方法：50例Ⅱ－ⅢB期非小细胞肺癌病例先用前胸和后背后相对野常规分割放射治疗，剂量42Gy，21分次，4．2周完成，然后再用三维适形放射治疗进行肿瘤增加量，3Gy／次，1次／d,5d／周，剂量递增次数为9－12次，肿瘤总剂量递增水平为69、72、75和78Gy，以≥15％的患者出现美国肿瘤放射治疗协作组织（RTOG）3级或以上急性放射性肺损伤为限制剂量递标准。所有组病例给予以铂类药为基础的化疗，结果：50例NSCLC随访15－31个月，已完成剂量递增计划。近期疗效中完全缓解（CR）率为16％，部分缓解（PR）70％，无进展（NR）率为14％，总有效率（CR＋PR）为86％，1＋2级急性放射性食管炎发生率为56％，3例为10％，1＋2级急性放射性肺炎发生率为36％，3级为2％；1＋2级急性骨髓抑制发生率为58％，3级为8％，1＋2级放射性肺炎发生率为30％，全组中位生存时间2个月，1、2年生存率分别为70％、47％，1、2年局部控制率分别为80％、62％，结论：该剂量递增的方法和剂量能为大多数患者所耐受，在进一步随访晚期毒副作用后可获得最大耐受剂量，近期疗效令人鼓舞，远期疗效有效待进一步观察。     

非小细胞肺癌立体适形放疗的Ⅰ期临床剂量递增试验

目的 建立非小细胞肺癌适形放疗技术,试图获得患者适形放疗的最大耐受剂量（ＭＴＤ）,并观察其即期疗效。方法 １９９９年６月至２０００年６月,３８例Ⅱ～ⅢＢ期非小细胞肺癌患者进入本研究。常规放疗４２Ｇｙ后用适形放疗做肿瘤剂量递增。根据接受２０Ｇｙ照射的总肺体积面分比,计划的肿瘤剂量递增水平分别为６９、７２、７５、７８和８１Ｇｙ。大于ＲＴＯＧⅢ级放射性肺损伤为停止剂量递增的标准。结果 已完成放疗计划者有     

非小细胞肺癌术后三维适形放疗疗效分析

目的 分析非小细胞肺癌(NSCLC)术后接受三维适形放射治疗(3DCRT)的初步结果.方法 84例NSCLC患者术后接受3DCRT,其中肺叶切除65例(77.4%),全肺切除19例(22.6%);完整的R0切除54例(64.3%),镜下切缘阳性的R1切除15例(17.9%),肉眼残存的R2切除15例(17.9%).术后病理分期为Ⅰ B期1例,ⅡB期7例,ⅢA期52例,ⅢB期24例.全组术后中位放疗剂量为60 Gy(40～70 Gy,2 Gy/次).术后37例患者接受中位3个周期的辅助化疗.中位随访时间为35.5个月.结果 全组患者的3年生存率为58.6%,4年生存率为43.9%.有43例(53.1%)出现复发转移,其中胸内复发8例(9.9%),远处转移38例(46.9%).单因素分析显示,患者性别、年龄、体重下降、肿瘤大小、病理类型和分期与预后无关.接受R1、R2切除的患者预后较差.随访中,有9例(11.1%)患者出现2级以上放射性肺炎.结论 NSCLC患者术后采用3DCRT放疗效果较好,不良反应发生率较低,安全可靠.     

Rapidly alternating radiotherapy and high dose cisplatin chemotherapy in stage IIIB non-small cell lung cancer: results of a phase I/II study.

Alternating radiotherapy and chemotherapy increases tumor cure rates in some animal models with reduced normal tissue damage compared to sequential use of these modalities. To test this concept in non-small cell lung cancer, 23 patients with predominantly Stage IIIB disease were treated on a Northern California Oncology Group pilot study of alternating radiotherapy and high dose cisplatin. Radiotherapy consisted of 6000 cGy delivered in three separate 10-day courses of 200 cGy/fraction/day during weeks 1 and 2, 5 and 6, and 9 and 10. High dose cisplatin, 100 mg/m2 in 3% saline, was administered on weeks 3 and 4, 7 and 8, 11 and 12, and 15 and 16. The response rate in 22 eligible patients is 73% (16/22) with four complete responses and 12 partial responses. Feasibility of this approach is demonstrated by 20/22 patients completing radiotherapy and a median of 2.5 courses of chemotherapy administered. Median survival time is 14.2 months (range 2-40+ months). One- and 2-year survival rates are 64% (14/22) and 41% (9/22), respectively. Hematologic, renal, and radiation-related toxicities were significant but manageable. We conclude that rapid alternation of radiotherapy and a high dose intensity cisplatin regimen is feasible in Stage IIIB non-small cell lung cancer, with a high response rate and acceptable toxicity. The long-term impact on local control and survival remains unclear, although preliminary survival data are encouraging in this poor prognosis population. Further studies of this concept are warranted.     

A phase II trial of accelerated hypofractionated three-dimensional conformal radiation therapy in locally advanced non-small cell lung cancer

Purpose

The aim of this study is to evaluate the safety and efficacy of accelerated hypofractionated radiotherapy (HypoRT) combined with sequential chemotherapy in locally advanced non-small cell lung cancer (NSCLC).

Materials and methods

A total of 34 patients with stage III NSCLC were enrolled. All patients received accelerated HypoRT (initially 50 Gy/20 fractions, then a fraction dose of 3 Gy) using three-dimensional conformal radiation therapy (3D-CRT), omitting elective nodal irradiation (ENI), to a total dose of 65-68 Gy. All patients received two cycles of induction chemotherapy; 1-2 cycles of consolidation chemotherapy were given to 31 patients. The primary outcome measure was a profile of radiation toxicity. The secondary endpoints included overall survival (OS), progression-free survival (PFS), locoregional PFS (LR-PFS) and the pattern of initial failure.

Results

Radiation toxicity was minimal. The median and 3-year OS, PFS were 19.0 months, 32.1%; 10.0 months, 29.8%, respectively. The 1-, 2-, and 3-year LR-PFS were 69.6%, 60.9% and 60.9%, respectively. No patient experienced isolated elective nodal failure as the first site of failure.

Conclusion

This study suggests that accelerated HypoRT using 3D-CRT omitting ENI can be used in combination with sequential chemotherapy in locally advanced NSCLC.     

Clinical research on three-dimensional conformal radiotherapy of non-small cell lung cancer

OBJECTIVE To investigate the clinical efficacy and toxic effect of the 3-dimensional conformal radiation therapy (3DCRT) for non-small cell lung cancer (NSCLC).METHODS Fifty-two patients with the Stage-I and W NSCLC were treated with 3DCRT. Cross analysis of the clinical data was conducted in the comparison between the 52 cases with 3DCRT and the other 50 cases with the conventional radiation therapy (CRT). In the 3DCRT group, only the primary tumor and positive lymph-node draining area were included in the clinical target area, setting 4 to 6 coplanar or non-coplanar irradiation fields, with 2 Gy or 3 Gy/fraction, 1 fraction a day and 5 fractions per week.The total dose ranged from a test dose (DT) of 66 Gy to 72 Gy. In the CRT group, the field area contained the primary tumor plus the homolateral hilum of the lung, the mediastinum superior or hol-mediastinum, and opposed anteroposterior irradiation. When the dosage reached DT 36～40 Gy, an oblique portal administered radiation was conducted in order to avoid injuring the spinal cord.The DT was 1.8～2.0 Gy/fraction, 1 fraction a day, 5 fractions per week, with a total dose of 60 Gy to 70 Gy.RESULTS The therapeutic effect (CR PR) was 90.4% in the 3DCRT group, and was 72% in the CRT group. There was statistically significant difference between the two groups, P <0.01.There was a clinical symptom improvement attained by 96.5% and 86.4% respectively in the two groups, and there was a statistically significant difference between the groups, P <0.01. The 6-month,1 and 2-year overall survival rates were 92.3%, 75.0% and 42.3% in the 3DCRT group, and 76%, 60% and 30% in the CRT group,respectively. There was a significant difference in the 6-month overall survival rate between the groups, P < 0.05. There was no obvious significant difference in the 1 and 2-year overall survival rates between the two groups, P > 0.05. The toxic reaction was 12.5% and 23.7% respectively in the 3DCRT and CRT groups.Acute radioactive esophagitis and leucopenia were markedly lower in the 3DCRT group than in the CRT group. There was a statistically significant difference between the groups, P <0.05. Notoxic reaction of Stage-Ⅲ and over was found in the 3DCRT group during radiation therapy.CONCLUSION The 3DCRT method has a satisfactory short-term efficacy and improvement of clinical symptoms in treating NSCLC, with a mild toxic reaction and good tolerance in patients.It can be used for enhancing the tumor-control rate and bettering the quality of life.     

老年非小细胞肺癌50例三维适形放疗的临床分析

目的 探讨三维适形放疗(3DCRT)治疗老年非小细胞肺癌(NSCLC)的临床疗效.方法 50例老年NSCLC的患者全部接受WDVE-XKY808立体定向适形放射治疗系统治疗.3DCRT处方剂量为DT40～60 Gy,中位剂量为60 Gy,参考剂量曲线选定为70%～90%.分割方式:2～4 Gy/次,每次间隔1～3 d.结果 肿瘤完全缓解15例(30%),部分缓解23例(46%),总有效率为76%.1、2、3年生存率为66.3%、45.7%,30.3%.结论 3DCRT对老年NSCLC患者有较好的局部控制效果和较高的安全性,是治疗老年NSCLC的有效方法之一.     

ⅢA期非小细胞肺癌术后三维适形放疗与常规放疗的初步比较

目的回顾性比较ⅢA期非小细胞肺癌（NSCLC）术后三维适形放疗（3DCRT组）和常规放疗（CRT组）的近期疗效及放疗反应.方法对美国安德森癌症中心收治的114例ⅢA期NSCLC患者的术后放疗资料进行回顾性分析.CRT组63例,3DCRT组51例.CRT组放疗中位剂量为53.5Gy分27次,3DCRT组的为52.8Gy分26次,均在5～6周内完成.结果CRT、3DCRT组中位随访时间分别为28、13个月.两组近期放疗反应、局部控制率及无远处转移生存率等无差异.1、2年总生存率CRT组为80%、62%,3DCRT组为93%、70%.1、2年无瘤生存率CRT组为62%、44%,3DCRT组为58%、32%.两组死亡原因有统计学差异,CRT组有4例死于与心脏损伤有关的并发症,而3DCRT组则无.结论ⅢA期NSCLC术后三维适形放疗可取得与常规放疗类似的近期疗效而并不增加局部复发和远处转移的危险性,对心脏的损伤有降低趋势,对生存率影响则有待更长时间的随访结果.     

非小细胞肺癌术后三维适形放疗与常规放疗结果比较

目的 回顾性比较非小细胞肺癌术后三维适形放疗(3DCRT)和常规放疗的疗效、失败模式及副反应.方法 分析3年余接受术后放疗的ⅠB～ⅢB期非小细胞肺癌患者162例,其中86例采用3DCRT,76例采用常规放疗.结果 总随访率91.5%,3DCRT和常规放疗的中位随访时间分别为29.4个月和33.8个月.3DCRT和常规放疗的1、2、3年无局部进展生存率分别为97.5%、83.2%、83.2%和84.3%、76.0%、65.6%(χ2=5.46,P=0.019),总生存率、无疾病进展生存率和无远转生存率均相似;总局部区域失败率分别为14.5%和33.3%(χ2=7.70 P=0.006),远处转移率两组相似.2～3级放射性肺炎发生率3DCRT显著低于常规放疗(11.6%:23.7% χ2=4.10,P=0.043).结论 术后放疗采用3DCRT技术比常规放疗技术能提高局部控制率,降低放疗相关副反应发生率.     

Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial.

BACKGROUND AND PURPOSE: To evaluate the benefits and the drawbacks of post-operative radiotherapy in completely resected Stage I (a and b) non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with pathological Stages Ia and Ib NSCLC have been randomized into two groups: Group 1 (G1) received adjuvant radiotherapy, Group 0 (G0) the control group did not receive any adjuvant therapy. Local control, toxicity and survival have been evaluated. RESULTS: Between July 1989 and June 1997, 104 patients with pathological stage I NSCLC have been enrolled in this study. Fifty-one patients were randomized to G1 and 53 to G0. Six patients have been excluded from the study due to incomplete follow-up data. Regarding local control, one patient in the G1 group had a local recurrence (2.2%) while in the G0 12 local recurrences have been observed (23%). Seventy-one percent of patients are disease-free at 5 years in G1 and 60% in G0 (P=0.039). Overall 5-year survival (Kaplan-Meier) showed a positive trend in the treated group: 67 versus 58% (P=0.048). Regarding toxicity in G1, six patients experienced a grade 1 acute toxicity. Radiological evidence of long-term lung toxicity, with no significant impairment of the respiratory function, has been detected in 18 of the 19 patients who have been diagnosed as having a post-radiation lung fibrosis. CONCLUSIONS: Adjuvant radiotherapy gave good results in terms of local control in patients with completely resected NSCLC with pathological Stage I. Overall 5-year survival and disease-free survival showed a promising trend. Treatment-related toxicity is acceptable.     

Acute esophageal toxicity in non-small cell lung cancer patients after high dose conformal radiotherapy.

BACKGROUND AND PURPOSE: To correlate acute esophageal toxicity with dosimetric and clinical parameters for non-small cell lung cancer (NSCLC) patients treated with radiotherapy (RT) alone or with chemo-radiotherapy (CRT). PATIENTS AND METHODS: We analyzed the data of 156 patients with medically inoperable or locally advanced NSCLC. Seventy-four patients were irradiated with high dose RT only, 45 patients with sequential CRT (Gemicitabine/Cisplatin) and 37 patients with concurrent CRT (Cisplatin daily 6 mg/m(2)). The radiation dose delivered ranged from 49.5 to 94.5 Gy (2.25-2.75 Gy per fraction) with an overall treatment time of 5-6 weeks. For all patients the maximal acute esophageal toxicity (RTOG/EORTC criteria) was scored and related to dose-volume parameters, as well as to clinical and treatment-related parameters. All parameters were tested univariable and multivariable in a binary logistic regression model. The toxicity data of a homogeneous subgroup was fitted to the Lyman-Kutcher-Burman model. RESULTS: Grade 2 acute esophageal toxicity or higher occurred in 27% (n=42) of the patient population of which nine patients developed grade 3 toxicity and one patient grade 4. All 10 patients with grade>or=3 esophageal toxicity received concurrent CRT. At multivariable analysis, the most significant clinical parameter to predict acute esophageal toxicity was the concurrent use of CRT. The most significant dosimetric parameter was the esophagus volume that received at least 35 Gy. The data of the patients who did not receive concurrent CRT were well described by the Lyman-Kutcher-Burman normal tissue complication probability model. The optimal fit of the data of non-concurrent treated patients to this model was obtained using the following values for the parameters: TD(50)=47 Gy (41-60 Gy), n=0.69 (0.18-6.3) and m=0.36 (0.25-0.55) where the numbers between brackets denote the 95% confidence interval. Acute esophageal toxicity was not significantly increased for patients treated with sequential CRT. CONCLUSION: Both concurrent CRT and the volume that receives at least 35 Gy were predictors of acute esophageal toxicity.     

三维适形放疗治疗非小细胞肺癌所致放射性食管炎的多因素分析

目的 观察三维适形放疗治疗非小细胞肺癌所致放射性食管炎的发生情况,探讨影响放射性食管炎发生的临床和物理因素.方法 选取未手术、经缩野增量三维适形放疗的非小细胞肺癌患者106例,收集全部患者临床资料及三维适形放疗计划物理参数.单因素分析采用方差分析、x2 检验和x2线性趋势检验;多因素分析采用多因素非条件Logistic回归分析.结果 发生放射性食管炎47例,其中1级31例,2级l1例,3级5例,总发生率为44.3％ (47/106).KPS评分、放疗增敏和病灶位置与放射性食管炎的发生密切相关(x2=11.30、8.45、7.67,均P＜0.05).照射野内食管受照长度、照射野内食管受照平均剂量与放射性食管炎的发生密切相关(F=20.82、83.08,均P＜0.05).随着受照射体积百分数V20、V30、V40和V50的增加,放射性食管炎的发生率明显增高,且具有线性趋势(x2=38.36、33.29、38.18、54.62,均P＜0.05).Logistic回归模型显示,放疗增敏、照射野内食管受照长度、照射野内食管受照平均剂量和V50与放射性食管炎的发生相关(OR=0.321、2.850、7.307、8.558,均P＜0.05).结论 放疗增敏、照射野内食管受照长度、照射野内食管受照平均剂量和V50是影响放射性食管炎发生的独立因素,V50对判断放射性食管炎的发生具有较高的价值.