Curative radiotherapy of early operable non-small cell lung cancer. Randomized versus historical controls for clinical trials. Radical radiotherapy of inoperable non-small cell lung cancer. Irradiation techniques and tumor characteristics in relation to local control and survival. The effect of radiotherapy on the survival of non-small cell lung cancer patients. High-dose, hyperfractionated, accelerated radiotherapy using a concurrent boost for the treatment of nonsmall cell lung cancer: unusual toxicity and promising early results. Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. Choosing between randomised and non-randomised studies: a systematic review Long‐term observations of the patterns of failure in patients with unresectable non‐oat cell carcinoma of the lung treated with definitive radiotherapy report by the radiation therapy oncology group
The results of 44 patients with early operable non-small cell lung cancer treated from January 1975 through 1981 are retrospectively analysed . All were proven by pathology and /or cytology and denied surgery in our joint Chest Clinic for various reasons . 55 - 70 Gy/6 - 7 weeks was delivered by conventional fractionation through A-P portals by telecobalt and /or 25 - 35 MeV high energy electron beam or 8 MV X-ray . 40 Gy/4 weeks was given prophylactically to the mediastinum . The 1- , 3- , and 5-year survival rates , 93 , 55 , and 32 % , are superior to what is reported in the literature . In the present series , the favorable factors are : ( 1 ) patients without any intercurrent disease but refused operation ; ( 2 ) T1 lesions ; ( 3 ) complete regression of the lesion at the conclusion of radiotherapy ; ( 4 ) doses ranging from 69 to 70 Gy . It is shown that early non-small cell lung cancer can be cured by radiotherapy alone giving survival rates comparable to surgery . Prospect i ve r and omized clinical trials are warranted To compare the use of  r and omized controls ( RCTs ) and historical controls ( HCTs )  for clinical trials , we search ed the literature for therapies studied by both methods . We found six therapies for which 50 RCTs and 56 HCTs were reported . Forty-four of 56 HCTs  ( 79 percent ) found the therapy better than the control regimen , but only 10 of 50 RCTs ( 20 percent ) agreed . For each therapy , the treated patients in RCTs and HCTs of the same therapy was largely due to differences in outcome for the control groups , with HCT control patients generally doing worse than the RCT control groups . Adjustment of the outcomes of the HCTs for prognostic factors , when possible , did not appreciably change the results . The data suggest that biases in patient selection may irretrievably weight the outcome of HCts in favor of new therapies . RCTs may miss clinical ly important benefits because of inadequate attention to sample size . The predictive value of each might be improved by reconsidering the use of p less than 0.05 as the significance level for all types of clinical trials , and by the use of confidence intervals around estimates of treatment effects The relation between tumor characteristics , irradiation technique , local tumor control and survival was retrospectively studied in 323 patients with non-small cell lung cancer who started radical radiotherapy in 1974 - 1981 . At that time three non-r and omized different fractionation schedules were used : 16 x 3.25 Gy , total dose 52 Gy , 3 fractions/week ( schedule 1 ) , 11 x 4 Gy , total dose 44 Gy , 2 fractions/week ( schedule 2 ) and 25 x 2 Gy , total dose 50 Gy , 5 fractions/week ( schedule 3 ) . The highest survival rates were observed in the patient group treated according to schedule 2 . The 2-year survival rate was 30 % compared with 18 % and 6 % in the patients treated according to schedule 1 and 3 respectively . However , this can at least partly be explained by patient selection . A correlation between size of the tumor , target volume and survival was observed : the larger the tumor , the poorer the survival . Pleural effusion showed to be an unfavorable prognostic factor . The prognosis of inoperable lung cancer on the whole remained poor : the 1-year survival rate was 43 % and 2-year survival rate 16 % . Only 3 % of the patients lived at least five years PURPOSE To determine if thoracic radiotherapy improves the survival of non-small cell lung cancer ( NSCLC ) patients . METHODS AND MATERIAL S A Cox proportional hazards model with prognostic and treatment covariates was estimated using prospect i ve data for 129 NSCLC patients presenting at the Victoria Clinic ( ViCC ) of the British Columbia Cancer Agency ( BCCA ) 1990 - 1991 . The estimated model was simulated to predict survival curves for groups of patients with and without treatment . The difference between the predicted median survival with treatment and without treatment is the gain in survival attributable to treatment . RESULTS After adjusting for the effect of TNM staging , Karnofsky performance status , weight loss , tumor size , and tumor histology on survival , high-dose palliative radiotherapy ( RT ) ( 30 - 50 Gy in 10 - 20 fractions ) increased median survival by 79 days ( 95 % confidence interval : 31 - 106 days ) , and lowered the relative risk of death rate to 0.53 ( 95 % confidence interval : 0.35 - 0.85 ) . Radical RT ( 50 or more Gy , in 20 or more fractions ) increased median survival by 424 days ( 95 % confidence interval : 302 - 488 days ) , and lowered the relative risk of death to 0.24 ( 95 % confidence interval : 0.14 - 0.43 ) . CONCLUSION Our results support the hypothesis that the increased survival of patients receiving aggressive palliative , or radical , RT  is due not solely to patient selection , but also partly to a response to treatment PURPOSE The treatment of nonsmall cell lung cancer ( NSCLC ) with conventional radiotherapy ( RT ) results in inadequate local tumor control and survival . We report results of a Phase II trial design ed to treat patients with a significantly increased total dose administered in a reduced overall treatment time using a hyperfractionated , accelerated treatment schedule with a concurrent boost technique . METHODS AND MATERIAL S A total of 49 patients with unresectable Stage IIIA/IIIB ( 38 patients ) or medically inoperable Stage I/II ( 11 patients ) NSCLC were prospect ively enrolled in this protocol . Radiation therapy was administered twice daily , 5 days/week with > 6 h between each treatment . The primary tumor and adjacent enlarged lymph nodes were treated to a total dose of 73.6 Gy in 46 fractions of 1.6 Gy each . Using a concurrent boost technique , electively irradiated nodal regions were simultaneously treated with a dose of 1.25 Gy/fraction for the first 36 fractions to a total dose of 45 Gy . RESULTS Median survival for the entire group of 49 patients is 15.3 months . Actuarial survival at 2 years is 46 % : 60 % for 11 Stage I/II patients , 55 % for 21 Stage IIIA patients , and 26 % for 17 Stage IIIB patients . The actuarial rate of freedom from local progression at 2 years is 64 % for the entire group of 49 patients : 62 % for Stage I/II patients , 70 % for Stage IIIA patients , and 55 % for Stage IIIB patients . Patients who underwent serial bronchoscopic reevaluation ( 4 Stage I/II , 8 Stage IIIA , and 6 Stage IIIB ) have an actuarial rate of local control of 71 % at 2 years . The median total treatment time was 32 days . Nine of 49 patients ( 18 % ) experienced Grade III acute esophageal toxicity . The 2-year actuarial risk of Grade III or greater late toxicity is 30 % . The 2-year actuarial rate of severe-late pulmonary and skin-subcutaneous toxicity is 20 % and 15 % , respectively . CONCLUSION This treatment regimen administers a substantially higher biologically effective dose compared with conventional and pure hyperfractionation treatment schedules . The overall rate of acute and late toxicity was acceptable . Preliminary rates of overall survival and local control and freedom from local progression compare favorably to results reported with pure hyperfractionated radiotherapy and chemoradiotherapy BACKGROUND AND METHOD A r and omised controlled trial in locally advanced non-small cell lung cancer ( NSCLC ) , compared CHART which employs 36 fractions of 1.5 Gy 3 times per day to give 54 Gy in 12 consecutive days with conventional radiotherapy-30 fractions of 2 Gy to a total dose of 60 Gy in 6 weeks . A total of 563 patients were entered between April 1990 and April 1995 . This report is based upon the data up date d to 1 April 1998 . RESULTS The analysis of the mature data shows that the benefits previously reported have been maintained . Overall there was a 22 % reduction in the relative risk of death , which is equivalent to an absolute improvement in 2 year survival of 9 % from 20 to 29 % ( P = 0.008 ) and a 21 % reduction in the relative risk of local progression ( P = 0.033 ) . In the large subgroup of patients with squamous cell cancer which accounted for 81 % of the cases , there was a 30 % reduction in the relative risk of death , which is equivalent to an absolute improvement in 2 year survival of 13 % from 20 to 33 % ( P = 0.0007 ) and a 27 % reduction in the relative risk of local progression ( P = 0.012 ) . Furthermore , in squamous carcinoma there was a 25 % reduction in the relative risk of local and /or distant progression ( P = 0.025 ) and 24 % reduction in the relative risk of metastasis ( P = 0.043 ) . There was no evidence that CHART gave more or less benefit in any other subgroup . CONCLUSION This analysis of mature data confirms that CHART is superior to conventional radiotherapy in achieving local tumour control and survival in locally advanced NSCLC . This demonstrates the importance of cellular re population as a cause of failure in the radiotherapy of NSCLC . The reduction in the risk of metastasis confirms that improved local tumour control , even in lung cancer , can reduce the incidence of metastasis . This trial shows that control of local tumour can lead to an improvement in long term survival ! [ ] [ 1 ] Rating : R and omised controlled trials are often held up as the “ gold st and ard ” of medical research , and it is commonly believed that the size of a treatment effect is exaggerated in non-r and omised studies . In these days of evidence based medicine , however , where is the empirical evidence that this is so ? A widespread criticism of r and omised controlled trials is that they are based on highly selected individuals . Are there systematic differences between patients included and excluded in such trials , and do these influence the measured treatment effect ? These are just a few … [ 1 ] : This report details the patterns of tumor recurrence in two prospect i ve r and omized studies involving 551 patients with histologically proven unresectable or medically inoperable non‐oat cell carcinoma of the lung treated with definitive radiotherapy .  Patients were treated according to two protocol s , depending on the stage of the tumor : ( 1 ) Patients with T1 , 2 , 3‐NO , 1 , 2 tumors were r and omized to four different regimens : 4000 cGy split course ( 2000 cGy in five fractions , per 1 week , 2 weeks rest and additional 2000 cGy in five fractions , per 1 week ) or 4000 , 5000 , or 6000 cGy continuous courses , five fractions per week . ( 2 ) Patients with T4 , any N or N3 , any T stage tumors were r and omized to be treated with 3000 cGy tumor dose ( TD ) , ten fractions in 2 weeks , 4000 cGy split course ( described above ) , or 4000 cGy continuous course . In the patients with less advanced tumors ( Study 1 ) the intrathoracic failure rate within the irradiated volume was 48 % with 4000 cGy continuous , 38 % with 4000 cGy split course or 5000 cGy continuous , and 27 % for patients receiving 6000 cGy continuous course . The failure rate in the nonirradiated lung ranged from 25 % to 30 % in the various groups . Patients with adenocarcinoma or large cell undifferentiated carcinoma had better intrathoracic tumor control ( 35 % ) than those with squamous cell carcinoma ( 20 % ) . The incidence of distant metastases was 75 % to 80 % in all histologic groups . Distant metastases appeared sooner after therapy in the patients with adenocarcinoma or large cell undifferentiated carcinoma . The initial failure rate in the brain was 7 % in patients with squamous cell carcinoma , 19 % with adenocarcinoma , and 13 % in patients with large cell carcinoma .  The ultimate incidence of brain metastases was 16 % in squamous cell carcinoma , and 30 % for adenocarcinoma or large cell undifferentiated carcinoma . Higher doses of irradiation will be necessary in order to improve the intrathoracic tumor control . Clinical trials by the Radiation Therapy Oncology Group , some of them involving multiple daily fractionation , are in progress . Furthermore , because of the high incidence of distant metastases , effective systemic cytotoxic agents are critically needed to improve survival of lung cancer patients . The high frequency of brain metastases suggests that , as in small cell carcinoma of the lung , elective irradiation of the brain may be necessary , if not to improve survival to enhance the quality of life of patients with adenocarcinoma and large cell carcinoma
OBJECTIVES To determine the effectiveness of radical radiotherapy in medically inoperable stage I/II non-small cell lung cancer ( NSCLC ) and the extent of treatment related morbidity .