PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Treatment of stage II non-small cell lung cancer. 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. Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer: mature results of a phase II trial. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC Durvalumab after Chemoradiotherapy in Stage III Non–Small‐Cell Lung Cancer
PURPOSE The phase III PROCL AIM study evaluated overall survival ( OS ) of concurrent pemetrexed-cisplatin and thoracic radiation therapy ( TRT ) followed by consolidation pemetrexed , versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy . PATIENTS AND METHODS Patients with stage IIIA/B unresectable nonsquamous non-small-cell lung cancer r and omly received ( 1:1 ) pemetrexed 500 mg/m(2 ) and cisplatin 75 mg/m(2 ) intravenously every 3 weeks for three cycles plus concurrent TRT ( 60 to 66 Gy ) followed by pemetrexed consolidation every 3 weeks for four cycles ( arm A ) , or st and ard therapy with etoposide 50 mg/m(2 ) and cisplatin 50 mg/m(2 ) intravenously , every 4 weeks for two cycles plus concurrent TRT ( 60 to 66 Gy ) followed by two cycles of consolidation platinum-based doublet chemotherapy ( arm B ) . The primary objective was OS . The study was design ed as a superiority trial with 80 % power to detect an OS hazard ratio of 0.74 with a type 1 error of .05 . RESULTS Enrollment was stopped early because of futility . Five hundred ninety-eight patients were r and omly assigned ( 301 to arm A , 297 to arm B ) and 555 patients ( 283 in arm A , 272 in arm B ) were treated . Arm A was not superior to arm B in terms of OS ( hazard ratio , 0.98 ; 95 % CI , 0.79 to 1.20 ; median , 26.8 v 25.0 months ; P = .831 ) . Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events ( 64.0 % v 76.8 % ; P = .001 ) , including neutropenia ( 24.4 % v 44.5 % ; P < .001 ) , during the overall treatment period . CONCLUSION Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to st and ard chemoradiotherapy for stage III unresectable nonsquamous non-small-cell lung cancer 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 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Based on clinical assessment alone , patients with stage II non-small cell lung cancer ( NSCLC ) comprise only 5 % of all patients with NSCLC . In addition , patients with stage II NSCLC represent a heterogeneous group , since stage II consists of patients with T1 - 2N1 or T3N0 tumors . By definition , patients with tumor invading the chest wall apex , mediastinum , diaphragm , or even the mainstem bronchus may all have T3 tumors . The extent of the data available regarding treatment of each of these different groups is therefore limited . The quality of the data is limited as well , because information often comes from small series of patients . Studies of adjuvant therapy after complete resection of stage II NSCLC are an important exception to this generalization , since data from large , r and omized studies of adjuvant radiation therapy , chemotherapy , or a combination of the two are available for analysis . Superior sulcus tumors are discussed elsewhere in these guidelines 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 feasibility and efficacy of an intensive multimodality approach with combination chemotherapy , hyperfractionated accelerated chemoradiotherapy , and definitive surgery in prognostically unfavorable subgroups of locally advanced non-small-cell lung cancer stages IIIA and IIIB ( LAD-NSCLC ) . PATIENTS AND METHODS Following staging , including mediastinoscopy , 94 patients with inoperable LAD-NSCLC were treated preoperatively with chemotherapy ( three courses of split-dose cisplatin and etoposide [ PE ] ) followed by concurrent chemoradiotherapy ( one course of PE combined with 45 Gy hyperfractionated accelerated radiotherapy ) . After repeat mediastinoscopy , patients underwent surgery 4 weeks postradiation . RESULTS Of 94 consecutive patients ( 52 stage IIIA [ > or = two lymph node levels involved ] and 42 stage IIIB [ no pleural effusion , no supraclavicular nodes ] ) , 62 ( 66 % ) completed induction and underwent surgery . Complete resection ( R0 ) was achieved in 50 ( 53 % of all patients ) and pathologic complete response ( PCR ) in 24 ( 26 % ) . After a median follow-up of 43 months , the median survival time was 20 months for IIIA , 18 months for IIIB , and 42 months for R0 patients . Calculated survival rates at 4 years were 31 % , 26 % , and 46 % . Two patients died of sepsis preoperatively and four died postoperatively of pleural empyema ( n = 1 ) , stump insufficiency ( n = 2 ) , and cardiac failure ( n = 1 ) . Other toxicities were acceptable-mainly hematologic during chemotherapy or chemoradiotherapy and esophagitis during chemoradiotherapy . CONCLUSION This intensive multimodality treatment is feasible and demonstrates high efficacy in prognostically unfavorable LAD-NSCLC subgroups with high R0 rates and improved long-term survival compared with historical BACKGROUND We aim ed to compare overall survival after st and ard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer . METHODS In this open-label r and omised , two-by-two factorial phase 3 study in 185 institutions in the USA and Canada , we enrolled patients ( aged ≥ 18 years ) with unresectable stage III non-small-cell lung cancer , a Zubrod performance status of 0 - 1 , adequate pulmonary function , and no evidence of supraclavicular or contralateral hilar adenopathy . We r and omly assigned ( 1:1:1:1 ) patients to receive either 60 Gy ( st and ard dose ) , 74 Gy ( high dose ) , 60 Gy plus cetuximab , or 74 Gy plus cetuximab . All patients also received concurrent chemotherapy with 45 mg/m(2 ) paclitaxel and carboplatin once a week ( AUC 2 ) ; 2 weeks after chemoradiation , two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel ( 200 mg/m(2 ) ) and carboplatin ( AUC 6 ) . R and omisation was done with permuted block r and omisation methods , stratified by radiotherapy technique , Zubrod performance status , use of PET during staging , and histology ; treatment group assignments were not masked . Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy . The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary . For patients assigned to receive cetuximab , 400 mg/m(2 ) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2 ) , and was continued through consolidation therapy . The primary endpoint was overall survival . All analyses were done by modified intention-to-treat . The study is registered with Clinical Trials.gov , number NCT00533949 . FINDINGS Between Nov 27 , 2007 , and Nov 22 , 2011 , 166 patients were r and omly assigned to receive st and ard-dose chemoradiotherapy , 121 to high-dose chemoradiotherapy , 147 to st and ard-dose chemoradiotherapy and cetuximab , and 110 to high-dose chemoradiotherapy and cetuximab . Median follow-up for the radiotherapy comparison was 22.9 months ( IQR 27.5 - 33.3 ) . Median overall survival was 28.7 months ( 95 % CI 24.1 - 36.9 ) for patients who received st and ard-dose radiotherapy and 20.3 months ( 17.7 - 25.0 ) for those who received high-dose radiotherapy ( hazard ratio [ HR ] 1.38 , 95 % CI 1.09 - 1.76 ; p=0.004 ) . Median follow-up for the cetuximab comparison was 21.3 months ( IQR 23.5 - 29.8 ) . Median overall survival in patients who received cetuximab was 25.0 months ( 95 % CI 20.2 - 30.5 ) compared with 24.0 months ( 19.8 - 28.6 ) in those who did not ( HR 1.07 , 95 % CI 0.84 - 1.35 ; p=0.29 ) . Both the radiation-dose and cetuximab results crossed protocol -specified futility boundaries . We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups . By contrast , the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects ( 205 [ 86 % ] of 237 vs 160 [ 70 % ] of 228 patients ; p<0.0001 ) . There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups ( radiotherapy comparison : eight vs three patients ; cetuximab comparison : ten vs five patients ) . There were no differences in severe pulmonary events between treatment groups . Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received st and ard-dose treatment ( 43 [ 21 % ] of 207 patients vs 16 [ 7 % ] of 217 patients ; p<0.0001 ) . INTERPRETATION 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer , and might be potentially harmful . Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients . FUNDING National Cancer Institute and Bristol-Myers Squibb PURPOSE Concurrent chemoradiotherapy with or without surgery are options for stage IIIA(N2 ) non-small-cell lung cancer . Our previous phase II study had shown the efficacy of induction chemotherapy followed by chemoradiotherapy and surgery in patients with IIIA(N2 ) disease and with selected IIIB disease . Here , we compared surgery with definitive chemoradiotherapy in resectable stage III disease after induction . PATIENTS AND METHODS Patients with pathologically proven IIIA(N2 ) and selected patients with IIIB disease that had medical/functional operability received induction chemotherapy  , which consisted of three cycles of cisplatin 50 mg/m(2 ) on days 1 and 8 and paclitaxel 175 mg/m(2 ) on day 1 every 21 days , as well as concurrent chemoradiotherapy to 45 Gy given as 1.5 Gy twice daily , concurrent cisplatin 50 mg/m(2 ) on days 2 and 9 , and concurrent vinorelbine 20 mg/m(2 ) on days 2 and 9 . Those patients whose tumors were reevaluated and deemed resectable in the last week of radiotherapy were r and omly assigned to receive a chemoradiotherapy boost that was risk adapted to between 65 and 71 Gy in arm A or to undergo surgery ( arm B ) . The primary end point was overall survival ( OS ) . RESULTS After 246 of 500 planned patients were enrolled , the trial was closed after the second scheduled interim analysis because of slow accrual and the end of funding , which left the study underpowered relative to its primary study end point . Seventy-five patients had stage IIIA disease and 171 had stage IIIB disease according to the Union for International Cancer Control TNM classification , sixth edition . The median age was 59 years ( range , 33 to 74 years ) . After induction , 161 ( 65.4 % ) of 246 patients with resectable tumors were r and omly assigned ; strata were tumor-node group , prophylactic cranial irradiation policy , and region . Patient characteristics were balanced between arms , in which 81 were assigned to surgery and 80 were assigned to a chemoradiotherapy boost . In arm B , 81 % underwent R0 resection . With a median follow-up after r and om assignment of 78 months , 5-year OS and progression-free survival ( PFS ) did not differ between arms . Results were OS rates of 44 % for arm B and 40 % for arm A ( log-rank P = .34 ) and PFS rates of 32 % for arm B and 35 % for arm A ( log-rank P = .75 ) . OS at 5 years was 34.1 % ( 95 % CI , 27.6 % to 40.8 % ) in all 246 patients , and 216 patients ( 87.8 % ) received definitive local treatment . CONCLUSION The 5-year OS and PFS rates in r and omly assigned patients with resectable stage III non-small-cell lung cancer were excellent with both treatments . Both are acceptable strategies for this good-prognosis group BACKGROUND An earlier analysis in this phase 3 trial showed that durvalumab significantly prolonged progression‐free survival , as compared with placebo , among patients with stage III , unresectable non – small‐cell lung cancer ( NSCLC ) who did not have disease progression after concurrent chemoradiotherapy . Here we report the results for the second primary end point of overall survival . METHODS We r and omly assigned patients , in a 2:1 ratio , to receive durvalumab intravenously , at a dose of 10 mg per kilogram of body weight , or matching placebo every 2 weeks for up to 12 months . R and omization occurred 1 to 42 days after the patients had received chemoradiotherapy and was stratified according to age , sex , and smoking history . The primary end points were progression‐free survival ( as assessed by blinded independent central review ) and overall survival . Secondary end points included the time to death or distant metastasis , the time to second progression , and safety . RESULTS Of the 713 patients who underwent r and omization , 709 received the assigned intervention ( 473 patients received durvalumab and 236 received placebo ) . As of March 22 , 2018 , the median follow‐up was 25.2 months . The 24‐month overall survival rate was 66.3 % ( 95 % confidence interval [ CI ] , 61.7 to 70.4 ) in the durvalumab group , as compared with 55.6 % ( 95 % CI , 48.9 to 61.8 ) in the placebo group ( two‐sided P=0.005 ) . Durvalumab significantly prolonged overall survival , as compared with placebo ( stratified hazard ratio for death , 0.68 ; 99.73 % CI , 0.47 to 0.997 ; P=0.0025 ) . Up date d analyses regarding progression‐free survival were similar to those previously reported , with a median duration of 17.2 months in the durvalumab group and 5.6 months in the placebo group ( stratified hazard ratio for disease progression or death , 0.51 ; 95 % CI , 0.41 to 0.63 ) . The median time to death or distant metastasis was 28.3 months in the durvalumab group and 16.2 months in the placebo group ( stratified hazard ratio , 0.53 ; 95 % CI , 0.41 to 0.68 ) . A total of 30.5 % of the patients in the durvalumab group and 26.1 % of those in the placebo group had grade 3 or 4 adverse events of any cause ; 15.4 % and 9.8 % of the patients , respectively , discontinued the trial regimen because of adverse events . CONCLUSIONS Durvalumab therapy result ed in significantly longer overall survival  than placebo . No new safety signals were identified . ( Funded by AstraZeneca ; PACIFIC Clinical Trials.gov number , NCT02125461 . Background Most patients with locally advanced , unresectable , non – small‐cell lung cancer ( NSCLC ) have disease progression despite definitive chemoradiotherapy ( chemotherapy plus concurrent radiation therapy ) . This phase 3 study compared the anti – programmed death lig and 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum‐based chemoradiotherapy .  Methods We r and omly assigned patients , in a 2:1 ratio , to receive durvalumab ( at a dose of 10 mg per kilogram of body weight intravenously ) or placebo every 2 weeks for up to 12 months . The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy . The co primary end points were progression‐free survival ( as assessed by means of blinded independent central review ) and overall survival ( unplanned for the interim analysis ) . Secondary end points included 12‐month and 18‐month progression‐free survival rates , the objective response rate , the duration of response , the time to death or distant metastasis , and safety . Results Of 713 patients who underwent r and omization , 709 received consolidation therapy ( 473 received durvalumab and 236 received placebo ) . The median progression‐free survival from r and omization was 16.8 months ( 95 % confidence interval [ CI ] , 13.0 to 18.1 ) with durvalumab versus 5.6 months ( 95 % CI , 4.6 to 7.8 ) with placebo ( stratified hazard ratio for disease progression or death , 0.52 ; 95 % CI , 0.42 to 0.65 ; P<0.001 ) ; the 12‐month progression‐free survival rate was 55.9 % versus 35.3 % , and the 18‐month progression‐free survival rate was 44.2 % versus 27.0 % . The response rate was higher with durvalumab than with placebo ( 28.4 % vs. 16.0 % ; P<0.001 ) , and the median duration of response was longer ( 72.8 % vs. 46.8 % of the patients had an ongoing response at 18 months ) . The median time to death or distant metastasis was longer with durvalumab than with placebo ( 23.2 months vs. 14.6 months ; P<0.001 ) . Grade 3 or 4 adverse events occurred in 29.9 % of the patients who received durvalumab and 26.1 % of those who received placebo ; the most common adverse event of grade 3 or 4 was pneumonia ( 4.4 % and 3.8 % , respectively ) . A total of 15.4 % of patients in the durvalumab group and 9.8 % of those in the placebo group discontinued the study drug because of adverse events . Conclusions Progression‐free survival was significantly longer with durvalumab than with placebo . The secondary end points also favored durvalumab , and safety was similar between the groups . ( Funded by AstraZeneca ; PACIFIC Clinical Trials.gov number , NCT02125461 .
Background Chemoradiation with curative intent is considered the st and ard of care in patients with locally advanced , stage iii non-small-cell lung cancer ( nsclc ) .
However , some patients with stage iii ( N2 or N3 , excluding T4 ) nsclc might be eligible for surgery .
The objective of the present systematic review was to investigate the efficacy of surgery after chemoradiotherapy compared with chemoradiotherapy alone in patients with potentially resectable locally advanced nsclc .