title: Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial Radiation therapy oncology group protocol 02-29: a phase II trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced non-small cell carcinoma of the lung. The role of post-operative radiotherapy in non-small-cell lung cancer: a multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease. Medical Research Council Lung Cancer Working Party. Pulmonary resection after concurrent chemotherapy and high dose (60Gy) radiation for non-small cell lung cancer is safe and may provide increased survival. Postoperative adjuvant therapy for stage II non-small-cell lung cancer. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. Effects of postoperative mediastinal radiation on completely resected stage II and stage III epidermoid cancer of the lung. Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: a single-center study. Postoperative radiotherapy for radically resected N2 non-small-cell lung cancer (NSCLC): randomised clinical study 1988-1992. Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Postoperative radiotherapy in radically resected non-small cell lung cancer. Postoperative radiation therapy in lung caner: a controlled trial after resection of curative design. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. A study of postoperative radiotherapy in patients with non-small-cell lung cancer: a randomized trial. A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma Long-term results of the international adjuvant lung cancer trial evaluating adjuvant Cisplatin-based chemotherapy in resected lung cancer.
abstract: PURPOSE Adjuvant cisplatin-based chemotherapy ( ACT ) is now an accepted st and ard for completely resected stage II and III A non-small-cell lung cancer ( NSCLC ) . Long-term follow-up is important to document persistent benefit and late toxicity . We report here up date d overall survival ( OS ) and disease-specific survival ( DSS ) data . PATIENTS AND METHODS Patients with completely resected stage IB ( T2N0 , n = 219 ) or II ( T1 - 2N1 , n = 263 ) NSCLC were r and omly assigned to receive 4 cycles of vinorelbine/cisplatin or observation . All efficacy analyses were performed on an intention-to-treat basis . Results Median follow-up was 9.3 years ( range , 5.8 to 13.8 ; 33 lost to follow-up ) ; there were 271 deaths in 482 r and omly assigned patients . ACT continues to show a benefit ( hazard ratio [ HR ] , 0.78 ; 95 % CI , 0.61 to 0.99 ; P = .04 ) . There was a trend for interaction with disease stage ( P = .09 ; HR for stage II , 0.68 ; 95 % CI , 0.5 to 0.92 ; P = .01 ; stage IB , HR , 1.03 ; 95 % CI , 0.7 to 1.52 ; P = .87 ) . ACT result ed in significantly prolonged DSS ( HR , 0.73 ; 95 % CI , 0.55 to 0.97 ; P = .03 ) . Observation was associated with significantly higher risk of death from lung cancer ( P = .02 ) , with no difference in rates of death from other causes or second primary malignancies between the arms . CONCLUSION Prolonged follow-up of patients from the JBR.10 trial continues to show a benefit in survival for adjuvant chemotherapy . This benefit appears to be confined to N1 patients . There was no increase in death from other causes in the chemotherapy arm BACKGROUND Whether adjuvant chemotherapy improves survival of patients with non-small-cell lung cancer ( NSCLC ) is not known . We aim ed to compare the effect of adjuvant vinorelbine plus cisplatin versus observation on survival in patients with completely resected NSCLC . METHODS 840 patients with stage IB-IIIA NSCLC from 101 centres in 14 countries were r and omly assigned to observation ( n=433 ) or to 30 mg/m(2 ) vinorelbine plus 100 mg/m(2 ) cisplatin ( n=407 ) . Postoperative radiotherapy was not m and atory and was undertaken according to every centre 's policy . The primary endpoint was overall survival . Analysis was by intention to treat . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N95053737 . FINDINGS 367 patients in the chemotherapy group and 431 in the control group received their assigned treatment . 301 ( 36 % ) patients had stage IB disease , 203 ( 24 % ) had stage II disease , and 325 ( 39 % ) had stage IIIA disease . Tolerance to chemotherapy mainly included neutropenia in 335 ( 92 % ) patients and febrile neutropenia in 34 ( 9 % ) ; seven ( 2 % ) toxic deaths were also recorded . Compliance was greater with cisplatin than with vinorelbine ( median dose intensity 89 % [ range 17 - 108 ] vs 59 % [ 17 - 100 ] ) . After a median follow-up of 76 months ( range 43 - 116 ) , median survival was 65.7 months ( 95 % CI 47.9 - 88.5 ) in the chemotherapy group and 43.7 ( 35.7 - 52.3 ) months in the observation group . Adjusted risk for death was significantly reduced in patients assigned chemotherapy compared with controls ( hazard ratio 0.80 [ 95 % CI 0.66 - 0.96 ] ; p=0.017 ) . Overall survival at 5 years with chemotherapy improved by 8.6 % , which was maintained at 7 years ( 8.4 % ) . INTERPRETATION Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC , better defining indication of adjuvant chemotherapy BACKGROUND Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases ( N2 ) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival . We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with st and ard concurrent chemotherapy and definitive radiotherapy without resection . METHODS Patients with stage T1 - 3pN2M0 non-small-cell lung cancer were r and omly assigned in a 1:1 ratio to  concurrent induction chemotherapy  ( two cycles of cisplatin [ 50 mg/m(2 ) on days 1 , 8 , 29 , and 36 ] and etoposide [ 50 mg/m(2 ) on days 1 - 5 and 29 - 33 ] ) plus radiotherapy ( 45 Gy ) in multiple academic and community hospitals . If no progression , patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy . Two additional cycles of cisplatin and etoposide were given in both groups . The primary endpoint was overall survival ( OS ) . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00002550 . FINDINGS 202 patients ( median age 59 years , range 31 - 77 ) were assigned to group 1 and 194 ( 61 years , 32 - 78 ) to group 2 .  Median OS was 23.6 months ( IQR 9.0-not reached ) in group 1 versus 22.2 months ( 9.4 - 52.7 ) in group 2 ( hazard ratio [ HR ] 0.87 [ 0.70 - 1.10 ] ; p=0.24 ) . Number of patients alive at 5 years was 37 ( point estimate 27 % ) in group 1 and 24 ( point estimate 20 % ) in group 2 ( odds ratio 0.63 [ 0.36 - 1.10 ] ; p=0.10 ) . With N0 status at thoracotomy , the median OS was 34.4 months ( IQR 15.7-not reached ; 19 [ point estimate 41 % ] patients alive at 5 years ) . Progression-free survival ( PFS ) was better in group 1 than in group 2 , median 12.8 months ( 5.3 - 42.2 ) vs 10.5 months ( 4.8 - 20.6 ) , HR 0.77 [ 0.62 - 0.96 ] ; p=0.017 ) ; the number of patients without disease progression at 5 years was 32 ( point estimate 22 % ) versus 13 ( point estimate 11 % ) , respectively . Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 ( 77 [ 38 % ] and 20 [ 10 % ] , respectively ) and group 2 ( 80 [ 41 % ] and 44 [ 23 % ] , respectively ) . In group 1 , 16 ( 8 % ) deaths were treatment related versus four ( 2 % ) in group 2 . In an exploratory analysis , OS was improved for patients who underwent lobectomy , but not pneumonectomy , versus chemotherapy plus radiotherapy . INTERPRETATION Chemotherapy plus radiotherapy with or without resection ( preferably lobectomy ) are options for patients with stage IIIA(N2 ) non-small-cell lung cancer . FUNDING National Cancer Institute , Canadian Cancer Society , and National Cancer Institute of Canada PURPOSE To evaluate mediastinal nodal clearance ( MNC ) rates after induction chemotherapy and concurrent , full-dose radiation therapy ( RT ) in a phase II trimodality trial ( Radiation Therapy Oncology Group protocol 0229 ) . PATIENTS AND METHODS Patients ( n=57 ) with stage III non-small cell lung cancer ( pathologically proven N2 or N3 ) were eligible .  Induction chemotherapy consisted of weekly carboplatin ( AUC = 2.0 ) and paclitaxel 50 mg/m(2 ) . Concurrent RT was prescribed , with 50.4 Gy to the mediastinum and primary tumor and a boost of 10.8 Gy to all gross disease . The mediastinum was pathologically reassessed after completion of chemoradiation . The primary endpoint of the study was MNC , with secondary endpoints of 2-year overall survival and postoperative morbidity/mortality . RESULTS The grade 3/4 toxicities included hematologic 35 % , gastrointestinal 14 % , and pulmonary 23 % . Forty-three patients ( 75 % ) were evaluable for the primary endpoint . Twenty-seven patients achieved the primary endpoint of MNC ( 63 % ) . Thirty-seven patients underwent resection . There was a 14 % incidence of grade 3 postoperative pulmonary complications and 1 30-day , postoperative grade 5 toxicity ( 3 % ) . With a median follow-up of 24 months for all patients , the 2-year overall survival rate was 54 % , and the 2-year progression-free survival rate was 33 % . The 2-year overall survival rate was 75 % for those who achieved nodal clearance , 52 % for those with residual nodal disease , and 23 % for those who were not evaluable for the primary endpoint ( P=.0002 ) . CONCLUSIONS This multi-institutional trial confirms the ability of neoadjuvant concurrent chemoradiation with full-dose RT to sterilize known mediastinal nodal disease The role of post-operative radiotherapy for patients with non-small-cell lung cancer ( NSCLC ) is unclear despite five previous r and omised trials . One deficiency with these trials was that they did not include adequate TNM staging , and so the present r and omised trial was design ed to compare surgery alone ( S ) with surgery plus post-operative radiotherapy ( SR ) in patients with pathologically staged T1 - 2 , N1 - 2 . M0 NSCLC . Between July 1986 and October 1993 , 308 patients ( 154 S , 154 SR ) were entered from 16 centres in the UK . The median age of the patients was 62 years , 74 % were male , > 85 % had normal or near normal levels of general condition , activity and breathlessness , 68 % had squamous carcinoma , 52 % had had a pneumonectomy , 63 % had N1 disease and 37 % N2 disease . SR patients received 40 Gy in 15 fractions starting 4 - 6 weeks post-operatively . Overall there was no advantage to either group in terms of survival , although definite local recurrence and bony metastases appeared less frequently and later in the SR group . In a subgroup analysis , in the N1 group no differences between the treatment groups were seen , but in the N2 group SR patients appeared to gain a one month survival advantage , delayed time to local recurrence and time to appearance of the bone metastases . There is , therefore , no clear indication for post-operative radiotherapy in N1 disease , but the question remains unresolved in N2 disease BACKGROUND We have used doses of 60Gy or higher for neoadjuvant chemoradiotherapy for select patients with advanced non-small cell lung cancer ( NSCLC ) , including patients with N2 disease and those with Pancoast lesions , to avoid gaps in radiotherapy in case surgery is ultimately not offered . METHODS A retrospective cohort study using a prospect i ve data base . Patients underwent initial staging with CT , PET/CT and lymph node biopsy ( mediastinoscopy , endoscopic esophageal ultrasound and endobronchial ultrasound ) and then received neoadjuvant high dose radiotherapy and chemotherapy , followed by thoracotomy with intent to cure . RESULTS Between January 1998 and June 2008 there were 216 patients who were eligible for this study . The median dose of radiation was 60Gy ( range 60 - 72Gy ) . Lobectomy was performed in 152 patients ( 70 % ) about 7 weeks after radiotherapy finished ( mean 51 days , range 34 - 89 days).The bronchus was buttressed with an intercostal muscle flap in 97 % patients . Median hospital stay was 4.5 days ( range 2 - 57 ) . Major morbidity occurred in 17 % . There were five ( 2.3 % ) deaths . There were no bronchial-pleural fistulas after lobectomy , but two occurred after right pneumonectomy . Predictors of morbidity were FEV(1 ) < 50 % ( p<0.001 ) , DLCO < 60 % ( p<0.001 ) and age > 75 years ( p=0.008 ) . The overall 5-year Kaplan-Meier survival was 34 % . It was 42 % for those who underwent R0 resection , 38 % for those with initial N2 disease and 45 % for the 71 complete responders . CONCLUSIONS Pulmonary resection after high dose ( > /=60Gy ) neoadjuvant chemoradiotherapy is safe . Lobectomy can be safely performed and bronchopleural fistula prevented . Sixty Gy allows for maximal medical therapy in case resection is not offered . Since complete response rates may be higher than when 45Gy is used and since surgery is safe , its use deserves further investigation BACKGROUND Stage II non-small-cell lung cancer is regarded as one of the early lung cancers . Although resection , including the mediastinal lymph nodes , is currently regarded as the st and ard treatment , the survival rate of this disease is not encouraging . It is well known that the most common causes of death are locoregional recurrences or distant metastases , or both . However , the best adjuvant treatment to improve survival is as controversial an issue as ever . METHODS This study was design ed as a r and omized , blinded , two-armed study with operation and adjuvant radiotherapy in one arm , versus operation and adjuvant mitomycin C ( 10 mg/m2 ) , vinblastine ( 6 mg/m2 ) , and cisplatin ( 100 mg/m2 ) ( MVP ) chemotherapy in the other arm . We assigned 57 resected patients with pathologic proven stage II non-small cell lung cancer to the groups according to our eligibility criteria . RESULTS The most common pattern of recurrence was distant metastases , and nearly all the recurrences ( 17 of 18 patients ) in both groups were found within 2 years after operation . The rates of the locoregional and distant metastases were 3.6 % and 46.4 % in the adjuvant radiotherapy group and 6.9 % and 10.3 % in the adjuvant chemotherapy group ( p = 0.018 ) . The 5-year disease-free survival rates were 52.0 % in the adjuvant radiotherapy group and 74.0 % in the adjuvant chemotherapy group ( p = 0.16 , log-rank test ) . The 2-year , 5-year , and 6-year survival portions were 60.3 % , 56.5 % , and 28.3 % in the adjuvant radiotherapy group , and 82.8 % , 70.1 % , and 60.1 % in the adjuvant chemotherapy group ( p = 0.01 , p = 0.17 , and p = 0.03 , Z-test ) . The difference of the actuarial survival between these two groups was somewhat significant ( p = 0.09 , log-rank test ) . CONCLUSIONS Our results suggest that the addition of adjuvant MVP chemotherapy may reduce the distant metastasis rates and prolong the survival of the surgically resected stage II non-small-cell lung cancer patients BACKGROUND Surgery is the primary treatment for patients with stage I , II , or IIIA non-small-cell lung cancer ( NSCLC ) . However , long-term survival of NSCLC patients after surgery alone is largely unsatisfactory , and the role of adjuvant chemotherapy in patient survival has not yet been established . METHODS Between January 1994 and January 1999 , 1209 patients with stage I , II , or IIIA NSCLC were r and omly assigned to receive mitomycin C ( 8 mg/m2 on day 1 ) , vindesine ( 3 mg/m2 on days 1 and 8) , and cisplatin ( 100 mg/m2 on day 1 ) every 3 weeks for three cycles ( MVP group ; n = 606 ) or no treatment ( control group ; n = 603 ) after complete resection . R and omization was stratified by investigational center , tumor size , lymph-node involvement , and the intention to perform radiotherapy . The primary endpoint was overall survival and secondary endpoints were progression-free survival and toxicity associated with adjuvant treatment . Survival curves were analyzed using the log-rank test . All statistical tests were two-sided . RESULTS After a median follow-up time of 64.5 months , there was no statistically significant difference between the two patient groups in overall survival ( hazard ratio = 0.96 , 95 % confidence interval = 0.81 to 1.13 ; P = .589 ) or progression-free survival ( hazard ratio = 0.89 , 95 % confidence interval = 0.76 to 1.03 ; P = .128 ) . Only 69 % of patients received the three planned cycles of MVP . Grade s 3 and 4 neutropenia occurred in 16 % and 12 % , respectively , of patients in the MVP arm . Radiotherapy was completed by 65 % of patients in the MVP arm and by 82 % of patients in the control group . In the multivariable analysis , only disease stage and sex were associated with survival . CONCLUSION This r and omized trial failed to prospect ively confirm a statistically significant role for adjuvant chemotherapy in completely resected NSCLC . Given the poor compliance with the MVP regimen used in this study , future studies should explore more effective treatments BACKGROUND We undertook to determine whether adjuvant vinorelbine plus cisplatin prolongs overall survival among patients with completely resected early-stage non-small-cell lung cancer . METHODS We r and omly assigned patients with completely resected stage IB or stage II non-small-cell lung cancer to vinorelbine plus cisplatin or to observation . The primary end point was overall survival ; principal secondary end points were recurrence-free survival and the toxicity and safety of the regimen . RESULTS A total of 482 patients underwent r and omization to vinorelbine plus cisplatin ( 242 patients ) or observation ( 240 ) ; 45 percent of the patients had pathological stage IB disease and 55 percent had stage II , and all had an Eastern Cooperative Oncology Group performance status score of 0 or 1 . In both groups , the median age was 61 years , 65 percent were men , and 53 percent had adenocarcinomas . Chemotherapy caused neutropenia in 88 percent of patients ( including grade 3 febrile neutropenia in 7 percent ) and death from toxic effects in two patients ( 0.8 percent ) . Nonhematologic toxic effects of chemotherapy were fatigue ( 81 percent of patients ) , nausea ( 80 percent ) , anorexia ( 55 percent ) , vomiting ( 48 percent ) , neuropathy ( 48 percent ) , and constipation ( 47 percent ) , but severe ( grade 3 or greater ) toxic effects were uncommon ( < 10 percent ) . Overall survival was significantly prolonged in the chemotherapy group as compared with the observation group ( 94 vs. 73 months ; hazard ratio for death , 0.69 ; P=0.04 ) , as was relapse-free survival ( not reached vs. 46.7 months ; hazard ratio for recurrence , 0.60 ; P<0.001 ) . Five-year survival rates were 69 percent and 54 percent , respectively ( P=0.03 ) . CONCLUSIONS Adjuvant vinorelbine plus cisplatin has an acceptable level of toxicity and prolongs disease-free and overall survival among patients with completely resected early-stage non-small-cell lung cancer BACKGROUND On the basis of a previous meta- analysis , the International Adjuvant Lung Cancer Trial was design ed to evaluate the effect of cisplatin-based adjuvant chemotherapy on survival after complete resection of non-small-cell lung cancer . METHODS We r and omly assigned patients either to three or four cycles of cisplatin-based chemotherapy or to observation . Before r and omization , each center determined the pathological stages to include , its policy for chemotherapy ( the dose of cisplatin and the drug to be combined with cisplatin ) , and its postoperative radiotherapy policy . The main end point was overall survival . RESULTS A total of 1867 patients underwent r and omization ; 36.5 percent had pathological stage I disease , 24.2 percent stage II , and 39.3 percent stage III . The drug allocated with cisplatin was etoposide in 56.5 percent of patients , vinorelbine in 26.8 percent , vinblastine in 11.0 percent , and vindesine in 5.8 percent . Of the 932 patients assigned to chemotherapy , 73.8 percent received at least 240 mg of cisplatin per square meter of body-surface area . The median duration of follow-up was 56 months . Patients assigned to chemotherapy had a significantly higher survival rate than those assigned to observation ( 44.5 percent vs. 40.4 percent at five years [ 469 deaths vs. 504 ] ; hazard ratio for death , 0.86 ; 95 percent confidence interval , 0.76 to 0.98 ; P<0.03 ) . Patients assigned to chemotherapy also had a significantly higher disease-free survival rate than those assigned to observation ( 39.4 percent vs. 34.3 percent at five years [ 518 events vs. 577 ] ; hazard ratio , 0.83 ; 95 percent confidence interval , 0.74 to 0.94 ; P<0.003 ) . There were no significant interactions with prespecified factors . Seven patients ( 0.8 percent ) died of chemotherapy-induced toxic effects . CONCLUSIONS Cisplatin-based adjuvant chemotherapy improves survival among patients with completely resected non-small-cell lung cancer We r and omly assigned 230 patients with resected Stage II or III epidermoid ( squamous-cell ) lung cancer to receive postoperative adjuvant radiotherapy or no adjuvant treatment . Careful intraoperative staging had been performed in all patients . Before r and omization , patients were stratified according to stage , weight loss , age , and institution . Prognostic variables , such as stage , weight loss , age , nodal-disease status , and tumor status , were equally distributed between the two groups . The mean time from r and omization to analysis was 3.5 years among the 210 eligible patients . There was no evidence that radiotherapy improved survival , and although recurrence rates appeared to be somewhat reduced among patients assigned to radiotherapy , these decreases were not statistically significant . However , radiotherapy did produce a striking and significant reduction in recurrences to the ipsilateral lung and mediastinum . Moreover , overall recurrence rates were reduced by radiotherapy in patients with N2 disease ( P less than 0.05 ) , although even this subgroup had no evidence of improved survival . We conclude that radiotherapy can reduce local recurrences after resection of epidermoid carcinoma of the lung , but that it does not increase survival rates PURPOSE We started a phase II trial of induction chemotherapy and concurrent hyperfractionated chemoradiotherapy followed by either surgery or boost chemoradiotherapy in patients with advanced , stage III disease . The purpose is to achieve better survival in the surgery group with minimum morbidity and mortality . PATIENTS AND METHODS Patients treated from 1998 to 2002 with neoadjuvant chemoradiotherapy and surgical resection for stage III NSCLC were analyzed . The treatment consisted of four cycles of induction chemotherapy with carboplatin/paclitaxel followed by chemoradiotherapy with a reduced dose of carboplatin/paclitaxel and accelerated hyperfractionated radiotherapy with 1.5 Gy twice daily up to 45 Gy . After restaging , operable patients underwent thoracotomy . Inoperable patients received chemoradiotherapy up to 63 Gy . Study end points included resectability , pathologic response , and survival . Results One hundred twenty patients were enrolled ; 25 % patients had stage IIIA , 73 % had stage IIIB , and 2 % stage IV . After treatment , 47.5 % had downstaging , 29.2 % had stable disease , and 23.3 % had progressive disease . Thirty patients ( 25 % ) were not eligible for operation because of progressive disease , stable disease , and /or functional deterioration with one treatment-related death . The 30-day mortality was 5 % in patients who underwent operation . The 5-year survival rate for 120 patients was 21.7 % , and it was 43.1 % in patients with complete resection . In postoperative patients with stage N0 disease , 5-year survival was 53.3 % ; if stage N2 or N3 disease was still present , 5-year survival was 33.3 % . CONCLUSION Staging and treatment with chemoradiotherapy and complete resection performed in experienced centers achieve acceptable morbidity and mortality In the period 1988 - 1992 , 74 consecutive radically resected patients with NSCLC were r and omised to postoperative radiotherapy or surgery alone in order to evaluate the influence of postoperative radiotherapy on survival . There were 61 males and 13 females , aged 35 - 80 years , median 59 years . Their distribution by stage was as follows : pT1N2 = 19 , pT2N2 = 54 , pT3N2 = one patient ; histology : 32 squamous , 32 adeno and 10 large cell carcinomas ; surgery : atypical resection in six , lobectomy in 27 , bilobectomy in ten , and pneumonectomy in 31 patients . In 27 patients , only one lymph node in a single mediastinal lymph node site was affected ; in 31 patients more than one lymph node in one site ; in 16 patients more sites were affected . In 35/74 patients radiotherapy of hilar and mediastinal sites with 3000 cGy in 2 weeks was performed . On December 31 , 1994 , 19 patients ( 26 % ) were still alive ; 39/55 patients died of the following causes : locoregional failure-10(26 % ) , distant metastases- 25 ( 64 % ) , other tumor-unrelated causes-four patients ( 10 % ) . Five-year survival rates did not show statistically significant differences between the irradiated and surgically treated patients only with respect to sex , pTNM stage , histology and frequency of locoregional failure . The number of metastatic mediastinal lymph nodes was the only significant prognostic factor ( P < 0.005 ) in both r and omised groups OBJECTIVES Stage III non-small cell lung cancer ( NSCLC ) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable , bulky nodal disease . This review up date s the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients . METHODS Systematic search es were conducted through MEDLINE , Embase , and the Cochrane Data base for Systematic Review up to December 2011 , focusing primarily on r and omized trials , selected meta-analyses , practice guidelines , and review s. RESULTS For individuals with stage IIIA or IIIB disease , good performance scores , and minimal weight loss , treatment with combined chemoradiotherapy results in better survival than radiotherapy alone . Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported . Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation . Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy ; however , weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate . The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery . Postoperative radiotherapy  improves local control without improving survival . CONCLUSIONS Multimodality therapy is preferable in most subsets of patients with stage III lung cancer . Variability in the patients included in r and omized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios . Future trials are needed to investigate the roles of individualized chemotherapy , surgery in particular cohorts or setting s , prophylactic cranial radiation , and adaptive radiation PURPOSE To evaluate the value of adjuvant postoperative external-beam radiation ( EBR ) in patients with radically resected non-small cell lung cancer ( NSCLC ) pT1 - 3 pN0 - 2 compared to patients with resected NSCLC without adjuvant EBR . MATERIAL S AND METHODS In 155 patients ( 121 male , 34 female ; mean age , 59 years ) 105 lobectomies , 12 bilobectomies , and 38 pneumonectomies with radical lymph node dissection of the contralateral [ corrected ] side were performed . Postoperative staging was done according to the TNM system and was as follows : pT1 ( n=38 ) , pT2 ( n=89 ) , pT3 ( n=28 ) ; pN0 ( n=39 ) , pN1 ( n=67 ) and pN2 ( n=49 ) . Histopathologic study revealed 68 squamous cell carcinomas , 53 adenocarcinomas , 21 large cell carcinomas , 6 adenosquamous cell carcinomas , and 7 bronchioloalveolar cell carcinomas . All patients were r and omly assigned into two treatment groups : 72 patients with no further treatment ( control group ) , and 83 patients ( EBR group ) with adjuvant postoperative EBR of the bronchial stump and mediastinum ( 50 to 56 Gy , 8 or 23 MV photons , 2 Gy/d , 5 d/wk ) beginning 4 to 6 weeks after surgery . RESULTS The overall 5-year survival rate ( median observation time , 43 months ) of all patients was 24.1 % ( EBR group , 29.7 % ; control group , 20.4 % ; p>0.05 , not significant ) . The relative risk of the EBR group was 0.85 with a two-sided confidence interval of 0.66 to 1.09 . The overall 5-year recurrence-free survival was 20.6 % ( EBR , 27.1 % ; control group , 15.6 % ; p=0.07 ) . The relative risk of the EBR group was 0.80 with a confidence interval of 0.63 to 1.01 . The rate of local recurrences at the bronchial stump and /or mediastinum was significantly smaller in the EBR group ( n=5 ) than in the control group ( n=17 ) ( p<0.01 ) . Multivariate analysis ( chi2 test ) demonstrated an independent influence of postoperative EBR on the incidence of local recurrences . The incidence of distant metastases was slightly but not significantly higher in patients without EBR ( 38 patients ) compared to those who had EBR ( 32 patients ) . CONCLUSION High-dose postoperative EBR to the mediastinum significantly reduces the risk of local recurrence at the bronchial stump and /or mediastinum . Age , sex , histologic subtype , tumor size , surgical approach , or extent of lymph node involvement had no prognostic value -- only postoperative EBR had an independent influence on the risk of local recurrence . The effect of postoperative EBR was on the verge of significance with respect to recurrence-free survival and showed the same tendency in overall survival , however with an attenuated relative risk Abstract Postoperative supervoltage radiotherapy was tested in a controlled clinical trial in an attempt to improve the survival for patients with bronchogenic carcinoma .  Radiation therapy began 3 to 4 weeks after surgery ; three fields were used giving a dose of 6,000 rad in six weeks to the mediastinum from a Co 60 unit . Between 1966 and 1975 , 224 patients were included in this study . All had a resection of curative design . 175 patients were evaluable . No increase in survival time was noticed in the irradiated group . The 5 year survival rate was lower in this group ( 24 % versus 43 % for the control group ) but the difference was not statistically significant . For squamous cell carcinoma , the analysis showed a detrimental effect of radiation therapy in the T 2 group ( BACKGROUND Preoperative chemotherapy improves survival in patients with stage III non-small-cell lung cancer ( NSCLC ) amenable to resection . We aim ed to assess the additional effect of preoperative chemoradiation on tumour resection , pathological response , and survival in these patients . METHODS Between Oct 1 , 1995 , and July 1 , 2003 , patients with stage IIIA-IIIB NSCLC and invasive mediastinal assessment from 26 participating institutions of the German Lung Cancer Cooperative Group ( GLCCG ) were r and omly assigned to one of two treatment groups . The intervention group were scheduled to receive three cycles of cisplatin and etoposide , followed by twice-daily radiation with concurrent carboplatin and vindesine , and then surgical resection ( those with positive resection margins or unresectable disease were offered further twice-daily radiotherapy ) . The control group were scheduled to receive three cycles of cisplatin and etoposide , followed by surgery , and then further radiotherapy . The primary endpoint was median progression-free survival ( PFS ) in patients eligible for treatment after r and omisation . Secondary endpoints in patients eligible for treatment after r and omisation were overall survival ( OS ) and the proportion of patients undergoing surgery . Secondary endpoints in patients with tumour resection were the proportion with negative resection margins , the proportion with complete resection , the proportion with histopathological response , and the proportion with mediastinal downstaging . Additionally , exploratory ( not prespecified ) post-hoc analyses in terms of PFS and OS were done on patients not amenable to resection and on further subgroups of patients undergoing resection . Analyses were by intention to treat . This trial is registered on the Clinical Trials.gov website , number NCT 00176137 . FINDINGS 558 patients were r and omly assigned . 34 patients did not meet inclusion criteria and were excluded . Of 524 eligible patients , 142 of 264 ( 54 % ) in the interventional group and 154 of 260 ( 59 % ) in the control group underwent surgery ; 98 of 264 ( 37 % ) and 84 of 260 ( 32 % ) underwent complete resection . In patients with complete resection , the proportion of those with mediastinal downstaging ( 45 of 98 [ 46 % ] and 24 of 84 [ 29 % ] , p=0.02 ) and pathological response ( 59 of 98 [ 60 % ] and 17 of 84 [ 20 % ] , p<0.0001 ) favoured the interventional group . However , there was no difference in PFS ( primary endpoint ) between treatment groups-either in eligible patients ( median PFS 9.5 months , range 1.0 - 117.0 [ 95 % CI 8.3 - 11.2 ] vs 10.0 months , range 1.0 - 111.0 [ 8.9 - 11.5 ] , 5-year PFS 16 % [ 11 - 21 ] vs 14 % [ 10 - 19 ] , hazard ratio ( HR ) 0.99 [ 0.81 - 1.19 ] , p=0.87 ) , in those undergoing tumour resection , or in patients with complete resection . In both groups , 35 % of patients undergoing surgery received a  pneumonectomy  ( 50/142 vs 54/154 ) . In patients receiving a pneumonectomy , treatment-related mortality increased in the interventional group compared with the control group ( 7/50 [ 14 % ] vs 3/54 [ 6 % ] ) . INTERPRETATION In patients with stage III NSCLC amenable to surgery , preoperative chemoradiation in addition to chemotherapy increases pathological response and mediastinal downstaging , but does not improve survival . After induction with chemoradiation , pneumonectomy should be avoided . FUNDING German Cancer Aid ( Bonn , Germany ) PURPOSE To study the value of postoperative radiotherapy for non-small-cell lung cancer ( NSCLC ) with positive regional lymph metastases ( NI or N2 ) after radical surgery . MATERIAL S AND METHODS From February 1982 to October 1995 , 366 patients with NSCLC and N1 or N2 disease were r and omized into  postoperative radiotherapy ( S + R ) ( 183 patients ) and no further treatment ( S alone ) ( 182 patients ) . Postoperative radiotherapy ( RT ) was administrated 3 - 4 weeks after radical operation . Irradiated fields covered the bronchial stump , ipsilateral hilum , and most of the mediastinum . The midplane dose was 6000 cGy/30 fractions/6 weeks , with the spinal cord limited to 4000 cGy/20 fractions/4 weeks or less . One hundred thirty-four patients in S + R group and 162 patients in S alone group were evaluated . Clinical data were comparable in both arms , except for the numbers of N2 patients . RESULTS The 3-year and 5-year overall survival rates were 51.9 % and 42.9 % in the S + R group and 50.2 % and 40.5 % in the S alone Group ( p = 0.56 ) . The 3-year and 5-year disease-free survival rates were 50.7 % + /- 4.7 % and 42.9 % + /- 5.2 % in the S + R group vs. 44.4 % + /- 4.3 % and 38.2 % + /- 4.5 % in the S alone group ( p = 0.28 ) , respectively . In the patients with NI or T3 - 4 tumors , there was a trend toward improved survival in the S + R group , especially in the patients with T3 - 4N1M0 . These patients demonstrated 20 % improvement in overall survival ( p = 0.092 ) and greater than 20 % better disease-free survival ( p = 0.057 ) . Postoperative RT reduced local recurrence but had no impact on distant metastases . CONCLUSION Postoperative RT significantly reduced local relapses , but did not improve overall survival , due to a high frequency of distant metastases in this patient group Postoperative radiotherapy is commonly used to treat patients with completely resected nonsmall cell lung carcinoma , but its effect on overall survival has not been established PURPOSE Based on 5-year or shorter-term follow-up data in recent r and omized trials , adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients with non-small-cell lung cancer ( NSCLC ) . We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up . PATIENTS AND METHODS Patients with completely resected NSCLC were r and omly assigned to three or four cycles of cisplatin-based chemotherapy or to observation . Cox models were used to evaluate treatment effect according to follow-up duration . Results The trial included 1,867 patients with a median follow-up of 7.5 years . Results showed a beneficial effect of adjuvant chemotherapy on overall survival ( hazard ratio [ HR ] , 0.91 ; 95 % CI , 0.81 to 1.02 ; P = .10 ) and on disease-free survival ( HR , 0.88 ; 95 % CI , 0.78 to 0.98 ; P = .02 ) . However , there was a significant difference between the results of overall survival before and after 5 years of follow-up ( HR , 0.86 ; 95 % CI , 0.76 to 0.97 ; P = .01 v HR , 1.45 ; 95 % CI , 1.02 to 2.07 ; P = .04 ) with P = .006 for interaction . Similar results were observed for disease-free survival . The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 ( 95 % CI , 0.99 to 1.81 ; P = .06 ) . CONCLUSION These results confirm the significant efficacy of adjuvant chemotherapy at 5 years . The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy
target: RESULTS For patients who have undergone surgical resection , high-level evidence suggests that use of postoperative RT does not influence survival , but optimizes local control for patients with N2 involvement , and its use in the setting of positive margins or gross primary /nodal residual disease is recommended .
  No high-level evidence exists for the routine use of preoperative induction chemoradiation therapy ; however , modern surgical series and a post-hoc Intergroup 0139 clinical trial analysis suggest that a survival benefit may exist if patients are properly selected and surgical techniques/postoperative care is optimized .
background: PURPOSE To provide guidance to physicians and patients with regard to the use of adjuvant external beam radiation therapy ( RT ) in locally advanced non-small cell lung cancer ( LA NSCLC ) based on available medical evidence complemented by consensus-based expert opinion .