A Phase III Randomized Trial of Combined Chemoradiotherapy Versus Radiotherapy Alone in Locally Advanced Non–Small-Cell Lung Cancer Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Experience with dose escalation using CHARTWEL (continuous hyperfractionated accelerated radiotherapy weekend less) in non-small-cell lung cancer. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. Uracil/Tegafur Plus Cisplatin with Concurrent Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer Radiosensitization with carboplatin for patients with unresectable stage III non-small-cell lung cancer: a phase III trial of the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer--report of a Canadian multicenter randomized trial. Interruptions of high-dose radiation therapy decrease long-term survival of favorable patients with unresectable non-small cell carcinoma of the lung: analysis of 1244 cases from 3 Radiation Therapy Oncology Group (RTOG) trials. Induction chemotherapy plus high-dose radiotherapy versus radiotherapy alone in locally advanced unresectable non-small-cell lung cancer. Hyperfractionated radiation therapy and concurrent low-dose, daily carboplatin/etoposide with or without weekend carboplatin/etoposide chemotherapy in stage III non-small-cell lung cancer: a randomized trial. Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. A phase II trial of concurrent chemoradiation therapy followed by consolidation chemotherapy with oral etoposide and cisplatin for locally advanced inoperable non-small cell lung cancers. A randomised phase III study of accelerated or standard fraction radiotherapy with or without concurrent carboplatin in inoperable non-small cell lung cancer: final report of an Australian multi-centre trial. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. 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 Radiotherapy alone versus chemotherapy with ifosfamide/vindesine followed by radiotherapy in unresectable locally advanced non-small cell lung cancer. A randomised phase III trial comparing consolidation treatment with further chemotherapy to chest irradiation in patients with initially unresectable locoregional non-small-cell lung cancer responding to induction chemotherapy. European Lung Cancer Working Party. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. Comparison of induction chemotherapy before radiotherapy with radiotherapy only in patients with locally advanced squamous cell carcinoma of the lung. The Swedish Lung Cancer Study Group. Phase II trial of hyperfractionated accelerated radiation therapy for nonresectable non-small-cell lung cancer: results of Eastern Cooperative Oncology Group 4593.
A phase III r and omized trial was conducted to investigate whether induction chemotherapy followed by radiation can influence survival as compared with radiation alone in unresectable , locally advanced non-small-cell lung cancer ( LADNSCLC ) . A total of 101 patients with unresectable stage IIIA or IIIB NSCLC were enrolled . Patients were stratified by performance status , weight loss , histology and stage , and then r and omized to receive combined chemoradiotherapy or radiotherapy alone . Radiotherapy was administered in 1.8 Gy to 2.0 Gy st and ard fractions daily 5 times weekly for a total dose of 60 Gy to 65 Gy . The combined group received induction of cisplatin , etoposide , and vinblastine ( PEV ) chemotherapy with cisplatin 20 mg/m2 on days 1 to 5 , etoposide 100 mg/m2 on days 2 to 4 , and vinblastine 6 mg/m2 on day 1 , which wasrepeated every 3 weeks for 3 courses , after which time the patients underwent radiotherapy .  Of 101 patients registered , 89 patients ( 43 combined , 46 radiotherapy alone ) were eligible for analysis . The response rates for the combined and radiotherapy groups were 65 % ( 28/43 ) and 70 % ( 32/46 ) , respectively . The median survival time ( MST ) showed a tendency to be more prolonged in the combined group than in the group receiving radiotherapy alone ( 13.8 vs. 8.5 months ) . The MST in patients with nonsquamous histology was strikingly prolonged in the combined group as compared with the radiotherapy group ( 14 vs. 3.6 months , p 0.027 ) . Likewise , the MST in patients with stage IIIB was significantly prolonged in the combined group as compared with the radiotherapy group ( 11.1 vs. 7.2 months , p 0.045 ) . Together , the MST of the high-risk group with nonsquamous or stage IIIB was significantly higher in the combined group than that seen in the radiotherapy group ( 11.6 vs. 8 months , p 0.046 ) , whereas the MST of the low-risk group , defined as having both squamous histology and stage IIIA , was similar in the two treatment groups ( 18.3 vs. 20.8 months , p = 0.293 ) . In conclusion , induction PEV chemotherapy plus radiotherapy is superior to radiotherapy alone in high-risk subsets of unresectable LAD-NSCLC and therapeutic strategy should be based on the identification of prognostic factors PURPOSE The superiority of chemoradiotherapy ( CRT ) over radiation alone in locally advanced non-small cell lung cancer ( NSCLC ) has been proven , but the relative merits of a concurrent schedule versus their sequential administration are less clear . This study compared the safety and efficacy of concurrent and sequential CRT , with chemotherapy ( CT ) consisting of a cisplatin and vinorelbine regimen , in patients with locally advanced NSCLC . PATIENTS AND METHODS One hundred and two previously untreated patients ( aged 42 - 75 years ) with locally advanced , stage IIIA ( n = 15 ) or stage IIIB ( n = 87 ) NSCLC were entered into the study . The CT schedule consisted of up to four cycles of cisplatin 80 mg/m(2 ) on day 1 , and vinorelbine 25 mg/m(2 ) at the first and fourth cycles ( 12.5 mg/m(2 ) during the 2nd/3rd cycles ) on days 1 , 8 , 15 of a 28-day cycle . Radiotherapy ( RT ) was prescribed at a dose of 60 Gy/30 fractions , given as five fractions per week for 6 weeks . In the concurrent arm ( arm A ) , RT was started on day 4 of cycle 2 ; whilst in the sequential arm ( arm B ) , RT started within 2 weeks after completion of CT . Fifty-two patients were r and omized to concurrent treatment and 50 to the sequential schedule . RESULTS Overall survival was significantly longer in arm A ( median survival 16.6 months ) versus arm B ( median survival 12.9 months ) ( P = 0.023 by means of log-rank test ; hazard ratio HR = 0.61 , 95 % CI of HR ( 0.39 - 0.93 ) ) , and time to progression ( TTP ) was also significantly longer in arm A ( median time to progression 11.9 months ) versus arm B ( median time to progression 8.5 months ) ( P = 0.024 by means of log-rank test ; HR = 0.62 , 95 % CI of HR ( 0.38 - 0.93 ) ) . Ninety-eight patients were evaluable for response and 101 for toxicity .  The overall response rate was significantly higher in arm A , 80 % ( with 21 % complete response ( CR ) ) compared with 47 % ( with 17 % CR ) in arm B ( P = 0.001 by means of chi(2)-test ) . WHO grade 3 or 4 toxicity was more frequent in arm A than in arm B , with a significantly greater incidence of leucopenia ( 53 % versus 19 % , P = 0.009 by means of chi(2 ) test ) and nausea/vomiting ( 39 % versus 15 % , P = 0.044 by means of chi(2 ) test ) . There were no treatment related deaths . CONCLUSION In this study population , concurrent CRT demonstrated significant benefit in terms of response rate , overall survival and time to progression over sequential CRT . The concurrent CRT schedule was associated with higher toxicity ; however , the adverse event profile was acceptable in both arms Results from the multicentre r and omized trial of CHART ( continuous , hyperfractionated , accelerated radiotherapy ) in non-small-cell lung cancer ( NSCLC ) showed a significant increase in survival ( P=0.004 ) compared with conventional radiotherapy and a therapeutic benefit relative to late radiation-induced morbidity . However , 60 % of patients died because of failure to control locoregional disease . These findings have stimulated interest in assessing the feasibility of dose escalation using a modified CHART schedule . Acute and late morbidity with a CHARTWEL ( CHART WeekEnd Less ) schedule of 54 Gy in 16 days was compared with that observed with 60 Gy in 18 days in patients with locally advanced NSCLC . The incidence and severity of dysphagia and of analgesia were scored using a semiquantitative clinical scale . Late radiation-induced morbidity , namely pulmonary , spinal cord and oesophageal strictures , were monitored using clinical and /or radiological criteria . Acute dysphagia and the analgesia required to control the symptoms were more severe and lasted longer in patients treated with CHARTWEL 60 Gy ( P < or = 0.02 ) . However , at 12 weeks , oesophagitis was similar to that seen with 54 Gy and did not lead to consequential damage . Early radiation pneumonitis was not increased but , after 6 months , there was a higher incidence of mild pulmonary toxicity compared with CHARTWEL 54 Gy . No cases of radiation myelitis , oesophageal strictures or of grade 2 or 3 lung morbidity have been encountered . CHARTWEL 60 Gy result ed in an enhancement of oesophagitis and grade 1 lung toxicity compared with CHARTWEL 54 Gy . These were of no clinical significance , but may be important if CHARTWEL is used with concomitant chemotherapy . These results provide a basis for further dose escalation or the introduction of concurrent chemotherapy BACKGROUND Human tumour cells can proliferate rapidly , and giving radiotherapy in many small fractions may reduce long-term normal-tissue morbidity . In response to these observations , we developed the CHART ( continuous hyperfractionated accelerated radiotherapy ) regimen , which uses thirty-six small fractions of 1.5 Gy given three times per day , to give 54 Gy in only 12 consecutive days . We report the long-term follow-up of a trial of CHART versus conventional radiotherapy in patients with locally advanced non-small-cell lung cancer ( NSCLC ) . METHODS 563 patients were entered by thirteen centres between April , 1990 , and March , 1995 . We included patients with NSCLC localised to the chest with a performance status of 0 or 1 in whom radical radiotherapy was chosen as the definitive management . Patients were r and omly allocated in a 3:2 ratio to CHART or conventional radiotherapy . The latter was thirty fractions of 2 Gy to a total dose of 60 Gy in 6 weeks . RESULTS The groups were well matched for possible prognostic factors . Overall there was a 24 % 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 = 0.004 , 95 % CI 0.63 - 0.92 ) . Subgroup analyses ( predefined ) suggest that the largest benefit occurred in patients with squamous cell carcinomas ( 82 % of the cases ) , in whom there was a 34 % reduction in the relative risk of death ( an absolute improvement at 2 years of 14 % from 19 % to 33 % ) . During the first 3 months , severe dysphagia occurred more often in the CHART group than in the group on conventional radiotherapy ( 19 vs 3 % ) . Otherwise , there were no important differences in short-term or long-term morbidity . INTERPRETATION CHART compared with conventional radiotherapy gave a significant improvement in survival of patients with NSCLC . Further improvement may be achieved with dose escalation in conformal radiotherapy , by the addition of cytotoxic chemotherapy , and by hypoxic cell radiosensitisation PURPOSE To evaluate new drugs in combination with cisplatin in unresectable stage III non-small-cell lung cancer , Cancer and Leukemia Group B ( CALGB ) conducted a r and omized phase II study of two cycles of induction chemotherapy followed by two additional cycles of the same drugs with concomitant radiotherapy . PATIENTS AND METHODS Eligible patients received four cycles of cisplatin at 80 mg/m(2 ) on days 1 , 22 , 43 , and 64 with arm 1 : gemcitabine 1,250 mg/m(2 ) on days 1 , 8 , 22 , and 29 and 600 mg/m(2 ) on days 43 , 50 , 64 , and 71 ; arm 2 : paclitaxel 225 mg/m(2 ) for 3 hours on days 1 and 22 and 135 mg/m(2 ) on days 43 and 64 ; and arm 3 : vinorelbine 25 mg/m(2 ) on days 1 , 8 , 15 , 22 , and 29 and 15 mg/m(2 ) on days 43 , 50 , 64 , and 71 . Radiotherapy was initiated on day 43 at 2 Gy/d ( total dose , 66 Gy ) . RESULTS One hundred seventy-five eligible patients were analyzed . Toxicities during induction chemotherapy consisted primarily of grade 3 or 4 granulocytopenia . Grade 3 or 4 toxicities during concomitant chemoradiotherapy consisted of thrombocytopenia , granulo-cytopenia , and esophagitis . Response rates after completion of radiotherapy were 74 % , 67 % , and 73 % for arms 1 , 2 , and 3 , respectively . Median survival for all patients was 17 months . One- , 2- , and 3-year survival rates for the patients on the three arms were 68%/37%/28 % , 62%/29%/19 % , and 65%/40%/23 % . CONCLUSION Four cycles of gemcitabine , vinorelbine , or paclitaxel in combination with cisplatin can be administered at these doses and schedules . The observed survival rates exceed those of previous CALGB trials and may be attributable to the use of concomitant chemoradiotherapy . Induction chemotherapy added to concomitant chemoradiotherapy is being evaluated in a phase III r and omized trial PURPOSE Chemotherapy for non-small-cell lung cancer ( NSCLC ) remains controversial . We describe the two largest reported , r and omized , parallel trials design ed to determine whether the addition of chemotherapy influences duration and quality of life in localized , unresectable ( mitomycin , ifosfamide ,  cisplatin [MIC]1 trial ) and extensive ( MIC2 trial ) disease . PATIENTS AND METHODS Ambulatory patients with NSCLC , aged 75 years or younger , with localized disease , were r and omized in MIC1 to receive up to four cycles of chemotherapy ( CT : mitomycin 6 mg/m(2 ) , ifosfamide 3 g/m(2 ) , and cisplatin 50 mg/m(2 ) ) every 21 days , followed by radical radiotherapy ( CT + RT ) or radiotherapy ( RT ) alone . Extensive-stage patients were r and omized in MIC2 to identical chemotherapy plus palliative care ( CT + PC ) or palliative care ( PC ) alone . Short-term change in quality of life ( QOL ) was assessed in a subgroup of patients . Data from the two trials were combined to allow multivariate and stratified survival analyses . RESULTS Seven hundred ninety-seven eligible patients were r and omized , 446 in MIC1 and 351 in MIC2 . MIC CT improved survival in both trials ( significantly in MIC2 ) . The median survival time in MIC1 was 11.7 months ( CT + RT ) versus 9.7 months ( RT alone ) ( P = .14 ) ; whereas in MIC2 , median survival time was 6.7 months ( CT + PC ) compared with 4 . 8 months ( PC alone ) ( P = .03 ) . QOL , assessed in 134 patients from start of trial to week 6 , showed improvement with chemotherapy and deterioration with st and ard treatment . In the combined analysis of 797 r and omized patients , the positive effect of MIC on survival was significant overall ( P = .01 ) and after adjusting for prognostic factors ( P = .01 ) . CONCLUSION MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL Purpose : To evaluate the efficacy and toxicity of a novel combination treatment using concurrent radiotherapy with cisplatin plus UFT , which is comprised of uracil and tegafur , in locally advanced non-small cell lung cancer ( NSCLC ) patients . Experimental Design : In this Phase II trial , patients with unresectable stage III NSCLC were treated with the oral administration of UFT ( 400 mg/m2/d tegafur ) on days 1–14 and days 29–42 whereas 80 mg/m2 cisplatin was administered i.v . on days 8 and 36 . Radiotherapy , with a total dose of 60 Gy , was delivered in 30 fractions from day 1 . Results : Seventy patients were enrolled and eligible , as follows : 57 males/13 females ; mean age 61 ranging from 36 to 74 ; performance status 0/1:45/25 ; stage IIIA/IIIB , 14/56 . A complete response was observed in two patients and a partial response in 54 patients , and the overall response rate was 81 % ( 95 % confidence interval ; 70–89 % ) . The median survival , the 1- and 2-year survival rates were 16.5 months , 67 % and 33 % , respectively . Grade 3/4 leukopenia occurred in 14%/1 % of the patients . Grade s 3 non-hematological toxicities were only reported in three patients with nausea , two with esophagitis and one with pneumonitis whereas no grade 4 non-hematological toxicity was observed . Conclusions : UFT plus cisplatin with concurrent radiotherapy is considered to be a feasible and effective treatment for locally advanced NSCLC patients . Additional study of this concurrent chemoradiotherapy is warranted PURPOSE To determine whether the administration of carboplatin concurrently with radiation treatment improves survival in patients with inoperable stage III non-small-cell lung cancer . PATIENTS AND METHODS Two hundred eighty-three patients with inoperable stage III non-small-cell lung cancer were entered onto a r and omized trial by the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group . R and omization was performed before initiation of any therapy . All patients received an induction chemotherapy program with vinblastine and cisplatin for 5 weeks , followed by 6,000 cGy of radiation therapy over 6 weeks . One hundred thirty-seven patients were r and omized to this therapy regimen alone ; 146 patients were r and omized to receive carboplatin at 100 mg/m2/wk concurrent with the radiation therapy . RESULTS The complete response was 18 % with concurrent carboplatin versus 10 % with radiotherapy alone ( P = .101 ) . There was no difference with respect to failure-free survival ( 10 % with carboplatin and 9 % with radiotherapy alone ) or overall survival ( 13 % with carboplatin and 10 % with radiotherapy alone ) at 4 years . In patients not receiving carboplatin , the relapse rate was 69 % within the field of radiation and 53 % in the boost volume . In patients receiving carboplatin , the relapse rate was 59 % within the field of radiation and 43 % in the boost volume . Patients with cancers more than 70 cm2 in size had significantly poorer survival ( P = .01 ) . CONCLUSION Carboplatin at the dose and schedule used did not significantly impact on disease control or survival . The relapse rate within the chest remained more than 50 % . More effective regimens will be required to impact on local disease control and survival The survival benefit of combination chemotherapy to patients with advanced non-small-cell carcinoma of the lung ( NSCLC ) is controversial . To study this question , the National Cancer Institute of Canada ( NCIC ) Clinical Trials Group conducted a prospect i ve r and omized trial comparing best supportive care ( BSC ) to two chemotherapy regimens , vindesine and cisplatin ( VP ) , and cyclophosphamide , doxorubicin , and cisplatin ( CAP ) .  Between February 1983 and January 1986 , 23 centers across Canada entered 251 patients on study . Eighteen centers participated in the three-arm schema ( 150 patients ) ; centers choosing not to participate in a study with a no-chemotherapy arm followed a two-arm schema comparing VP with CAP ( 101 additional patients ) . Altogether , 233 patients were eligible . Patients had measurable or evaluable disease , with either distant metastases ( 82.5 % ) or bulky limited disease considered inoperable or unsuitable for radical radiotherapy . The treatment groups were comparable in terms of age , sex , performance status , histology , disease extent , and weight loss . The overall response rates ( complete response [ CR ] plus partial response [ PR ] ) on the chemotherapy arms were CAP , 15.3 % , and VP , 25.3 % ( P = .06 ) . Patients on the three-arm portion of the trial had a median survival of 32.6 weeks when treated with VP , 24.7 weeks with CAP , and 17 weeks with BSC . The significance of the differences in survival , adjusted for prognostic factors , is as follows : chemotherapy v BSC , P = .02 ; VP v BSC , P = .01 ; and CAP v BSC , P = .05 . Toxicity on the chemotherapy arms was significant , with leukopenia of severe or greater degree occurring in 37.8 % ( CAP ) and 40.0 % ( VP ) , severe vomiting in 12.2 % ( CAP ) and 23.3 % ( VP ) , and severe neurotoxicity in 15.6 % ( VP ) PURPOSE To determine if prolonged treatment time adversely affects survival for patients with inoperable non-small cell carcinoma of the lung . METHODS AND MATERIAL S Patients enrolled on three r and omized studies ( RTOG 8311 , 8321 , 8403 ) between 1983 - 1989 formed the data base . Previous analyses found that the addition of thymosin ( 8321 ) or prophylactic cranial irradiation ( 8403 ) failed to prolong survival : both studies used thoracic irradiation with st and ard fractionation to 55 - 60 Gy in 30 fractions . In 8311 , patients were treated by hyperfractionated radiation therapy to r and omly assigned total doses of 60.0 Gy , 64.8 Gy , 69.6 Gy , 74.4 Gy or 79.2 Gy , 1.2 Gy twice daily , 5 days per week . Patients analyzed received + /- 4 % of the assigned total dose and lived > 90 days ( to ensure that all patients would have completed treatment ) . Completion < 5 days beyond protocol specifications was classified as " per protocol . " Elapsed treatment time exceeding specifications by 5 - 9 days was a minor deviation , 10 - 13 days was a major deviation-acceptable , and > or = 14 days was a major deviation-unacceptable . Absolute survival was the endpoint to evaluate the effect of delays . The log rank statistic was used to test for survival differences in the univariate setting , the Cox regression model was used in the multivariate setting . RESULTS Of 293 patients treated with st and ard fractionation , eight ( 2.7 % ) had deviations from the specified treatment time ( six minor , two major-acceptable ) . With hyperfractionation , 90 ( 15 % ) patients had deviations ( 40 minor , 21 major-acceptable , 29 major-unacceptable ) . As the assigned dose increased , the deviation rate increased ( 9.7 % for 60.0 Gy vs. 20.8 % for 79.2 Gy ) . Survivals for hyperfractionation patients with any deviations in treatment time were significantly shorter than those treated " per protocol " ( p = 0.16 ) : estimated 2- and 5-years rates were 24 % and 10 % versus 13 % and 3 % , respectively . Multivariate analyses showed the delay effect to be entirely in patients treated with 69.6 Gy or higher ; there was also dependence upon the patients ' prognosis . In patients with favorable prognosis ( KPS 90 - 100 , weight loss < or = 5 % , no N3 ) , the difference in survival was pronounced ( 33 % and 15 % vs. 14 % and 0 % at 2- and 5-years , respectively ) . Such differences were not found in patients with unfavorable prognostic factors . CONCLUSIONS Interruptions delaying completion of planned radiation therapy were more frequent with higher total doses ( > or = 69.6 Gy ) . Favorable patients ( high KPS , little weight loss , < N3 nodal metastasis ) had markedly adverse effects on long-term survival associated with delays to completion of the planned total dose BACKGROUND High-dose radiation therapy is generally recommended as st and ard treatment in regionally advanced unresectable non-small-cell lung cancer ( NSCLC ) , but median- and long-term survival remain poor . Some reports have recently shown an improvement of results in advanced NSCLC when cisplatin was included in the chemotherapy regimens . Therefore , we design ed a r and omized trial to determine whether induction chemotherapy before high-dose radiotherapy improves response rate and survival in stage III NSCLC over that achieved with radiotherapy alone . PATIENTS AND METHODS From March , 1984 to December , 1988 , 66 consecutive patients with stage III unresectable NSCLC were r and omized to one of two treatment arms ; 61 were evaluable for survival and 58 for response and toxicity . Patients r and omly assigned to arm A received cisplatin ( CDDP 100 mg/m2 on day 1 ) and etoposide ( VP 16 120 mg/m2 on days 1 , 2 , 3 ) every 3 wks for 3 courses followed by radiotherapy 56 Gy on pre-treatment tumor volume and 40 Gy on mediastinum and bilateral supraclavicular nodes . Patients assigned to arm B received only the same radiotherapy . The 61 eligible patients were comparable in terms of age , performance status , histology and treatment . RESULTS Response rate was 53 % in arm A and 32 % in arm B. The median survival was 52 wks for the combined treatment arm and 36 wks for the radiation therapy arm . At six years of follow-up all the patients were dead . Toxicity was mild and no treatment-related deaths were recorded . CONCLUSION Induction chemotherapy produced a better response rate and a trend of improved survival ( 4 months ) but a significant survival advantage was not achieved ( p < 0.11 ) , probably because of the small number of patients enrolled in the trial PURPOSE To investigate whether the addition of weekend chemotherapy consisting of carboplatin/etoposide to hyperfractionated radiation therapy ( Hfx RT ) and concurrent daily carboplatin/etoposide offers an advantage over the same Hfx RT/daily carboplatin/etoposide . METHODS AND MATERIAL S A total of 195 patients ( Group I , 98 ; Group II , 97 ) were treated with either Hfx RT to a total tumor dose of 69.6 Gy via 1.2 Gy b.i.d . fractionation and daily 50 mg each of carboplatin and etoposide during the RT course ( Group I ) or the same Hfx RT with daily carboplatin/etoposide consisting of 30 mg each of carboplatin and etoposide and with weekend ( Saturdays and Sundays ) 100 mg each of carboplatin and etoposide during the RT course ( Group II ) . RESULTS No difference was found regarding median survival time and 5-year survival rates ( 20 vs. 22 months and 20 % vs. 23 % ; p = 0.57 ) . Median time to local progression was 20 and 19 months , respectively , while 5-year local progression-free survival rates were 28 % and 27 % , respectively ( p = 0.66 ) . Also , there was no difference regarding either median time to distant metastasis and 5-year distant metastasis-free survival ( 21 vs. 25 months and 29 % vs. 34 % , p = 0.29 ) . There was no difference in the incidence of various nonhematologic toxicities between the two treatment groups , but patients treated with the weekend CHT had significantly more high- grade ( > or = 3 ) hematologic toxicity ( p = 0.0046 ) . Late high- grade toxicity was not different between the two treatment groups . CONCLUSION The addition of weekend carboplatin/etoposide did not improve results over those obtained with Hfx RT and concurrent low-dose , daily carboplatin/etoposide , but it led to a higher incidence of acute high- grade hematologic toxicity STUDY OBJECTIVES The purpose of this phase III clinical trial was to test whether chemotherapy followed by radiation therapy result ed in superior survival to either hyperfractionated radiation or st and ard radiation in surgically unresectable non-small cell lung cancer . DESIGN Patients were prospect ively r and omized to 2 months of cisplatin , vinblastine chemotherapy followed by 60 Gy of radiation at 2.0 Gy per fraction or 1.2 Gy per fraction radiation delivered twice daily to a total dose of 69.6 Gy , or 2.0 Gy per fraction of radiation once daily to 60 Gy . Patients were enrolled from January 1989 through January 1992 , and followed for a potential minimum period of 5 years . SETTING This trial was an intergroup National Cancer Institute-funded trial within the Radiation Therapy Oncology Group , the Eastern Cooperative Oncology Group , and the Southwest Oncology Group . PATIENTS Patients with surgically unresectable non-small cell lung cancer , clinical stage II , IIIA , and IIIB , were required to have a Karnofsky Performance Status of > or = 70 and a weight loss of < 5 % for 3 months before study entry . Four hundred ninety patients were registered on trial , of which 458 patients were eligible . CONCLUSION Overall survival was statistically superior for the patients receiving chemotherapy and radiation vs the other two arms of the study . The twice-daily radiation therapy arm , although better , was not statistically superior in survival for those patients receiving st and ard radiation .  Median survival for st and ard radiation was 11.4 months ; for chemotherapy and irradiation , 13.2 months ; and for hyperfractionated irradiation , 12 months . The respective 5-year survivals were 5 % for st and ard radiation therapy , 8 % for chemotherapy followed by radiation therapy , and 6 % for hyperfractionated irradiation We report a phase II study to evaluate the survival rate , response rate and toxicity of concurrent chemoradiation therapy ( CCRT ) followed by consolidation chemotherapy ( CT ) with oral etoposide and cisplatin for patients with locally advanced inoperable non-small cell lung cancer ( NSCLC ) . Fifty-four patients with locally advanced inoperable NSCLC who had received no prior therapy were enrolled into this trial between May 1995 and December 2000 . Treatment consisted of two cycles of concurrent CT and four cycles of consolidation CT with oral etoposide ( 50 mg/m2 ) on days 1 - 14 during the CCRT courses and on days 1 - 21 during the consolidation CT courses , plus cisplatin ( 75 mg/m2 i.v . ) on day 1 of a 28-day cycle . Conventional radiotherapy ( 1.8 Gy/fraction , 63 Gy over 7 weeks ) was delivered from day 1 of the CT . Fifty-two patients were evaluable for response . Twelve patients ( 22 % ) achieved complete responses , and 32 patients ( 60 % ) achieved partial responses , for an overall response rate of 82 % with a median duration of response of 9.1 months . Forty-three per cent developed grade 4 haematological toxicity , 11 % grade 3 or 4 oesophagitis and 7 % grade 3 or 4 lung toxicity . There were two treatment-related deaths , one from radiation pneumonitis and the other from sepsis . After a median follow-up duration of 50 months ( range 20 - 85 ) , the median overall survival time was 15.3 months ( 95 % CI , 9.7 - 20.8 ) , and the 1- , 2- , 3- , and 5 year overall survival rates were 62 , 40 , 30 and 16 % , respectively . The duration of median progression-free survival was 12.3 months ( 95 % CI , 7.4 - 17.3 ) , and the 1- , 2- , 3- , and 5-year progression-free survival rates were 47 , 40 , 29 and 23 % , respectively . Thus , concurrent conventional chest radiotherapy with oral etoposide plus cisplatin followed by consolidation CT led to an encouraging survival rate and prolongation of the time to progression , with moderate toxicity in patients with locally advanced inoperable NSCLC PURPOSE To investigate the effects separately and together of ( a ) shortening overall treatment time and ( b ) giving concurrent carboplatin in patients having radical radiotherapy for inoperable non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Between April 1989 and May 1995 , 204 patients with medically inoperable or technically unresectable NSCLC localised to the primary site and regional lymph nodes were r and omised to receive one of four treatments using a 2 x 2 factorial design : st and ard radiotherapy , 60 Gy in 30 fractions in 6 weeks ( R6 ) ; accelerated radiotherapy , 60 Gy in 30 fractions in 3 weeks ( R3 ) ; st and ard radiotherapy as in R6 with carboplatin 70 mg/m2/day for 5 days during weeks 1 and 5 of radiotherapy ( R6C ) ; accelerated radiotherapy as in R3 with carboplatin 70 mg/m2/day for 5 days during week 1 of radiotherapy ( R3C ) . RESULTS The estimated median survival of all r and omised patients was 15.7 months and estimated 2-year survival was 31 % . The longest survival was seen in patients r and omised to R6C ( median 20.3 months , 41 % surviving at 2 years ) but there were no statistically significant differences between treatment arms or treatment factors ( carboplatin versus no carboplatin , accelerated versus conventional radiotherapy ) . Haematological toxicity was significantly greater in patients treated with carboplatin and oesophageal toxicity was significantly greater and more protracted in patients treated with accelerated radiotherapy . CONCLUSIONS This study failed to show a significant survival advantage for any of the treatment arms or factors . Halving overall treatment time result ed in significantly greater oesophageal toxicity with no suggestion of a survival advantage PURPOSE A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy ( RT ) and chemotherapy ( CT ) improves survival in unresectable stage III non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients were assigned to the two treatment arms . In the concurrent arm , chemotherapy consisted of cisplatin ( 80 mg/m(2 ) on days 1 and 29 ) , vindesine ( 3 mg/m(2 ) on days 1 , 8 , 29 , and 36 ) , and mitomycin ( 8 mg/m(2 ) on days 1 and 29 ) . RT began on day 2 at a dose of 28 Gy ( 2 Gy per fraction and 5 fractions per week for a total of 14 fractions ) followed by a rest period of 10 days , and then repeated . In the sequential arm , the same CT was given , but RT was initiated after completing CT and consisted of 56 Gy ( 2 Gy per fraction and 5 fractions per week for a total of 28 fractions ) . RESULTS Three hundred twenty patients were entered onto the study . Pretreatment characteristics were well balanced between the treatment arms . The response rate for the concurrent arm was significantly higher ( 84 . 0 % ) than that of the sequential arm ( 66 % ) ( P = .0002 ) . The median survival duration was significantly superior in patients receiving concurrent therapy ( 16.5 months ) , as compared with those receiving sequential therapy ( 13.3 months ) ( P = .03998 ) . Two- , 3- , 4- , and 5-year survival rates in the concurrent group ( 34.6 % , 22.3 % , 16.9 % , and 15.8 % , respectively ) were better than those in the sequential group ( 27.4 % , 14.7 % , 10.1 % , and 8.9 % , respectively ) . Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm ( P = .0001 ) . CONCLUSION In selected patients with unresectable stage III NSCLC , the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach BACKGROUND For many years , high dose radiation therapy was the st and ard treatment for patients with locally or regionally advanced non-small-cell lung cancer ( NSCLC ) , despite a 5-year survival rate of only 3%-10 % following such therapy . From May 1984 through May 1987 , the Cancer and Leukemia Group B ( CALGB ) conducted a r and omized trial that showed that induction chemotherapy before radiation therapy improved survival during the first 3 years of follow-up . PURPOSE This report provides data for 7 years of follow-up of patients enrolled in the CALGB trial . METHODS The patient population consisted of individuals who had clinical or surgical stage III , histologically documented NSCLC ; a CALGB performance status of 0 - 1 ; less than 5 % loss of body weight in the 3 months preceding diagnosis ; and radiographically visible disease . Patients were r and omly assigned to receive either 1 ) cisplatin ( 100 mg/m2 body surface area intravenously on days 1 and 29 ) and vinblastine ( 5 mg/m2 body surface area intravenously weekly on days 1 , 8 , 15 , 22 , and 29 ) followed by radiation therapy with 6000 cGy given in 30 fractions beginning on day 50 ( CT-RT group ) or 2 ) radiation therapy with 6000 cGy alone beginning on day 1 ( RT group ) for a maximum duration of 6 - 7 weeks . Patients were evaluated for tumor regression if they had measurable or evaluable disease and were monitored for toxic effects , disease progression , and date of death . RESULTS There were 78 eligible patients r and omly assigned to the CT-RT group and 77 r and omly assigned to the RT group . Both groups were similar in terms of sex , age , histologic cell type , performance status , substage of disease , and whether staging had been clinical or surgical . All patients had measurable or evaluable disease at the time of r and om assignment to treatment groups . Both groups received a similar quantity and quality of radiation therapy . As previously reported , the rate of tumor response , as determined radiographically , was 56 % for the CT-RT group and 43 % for the RT group ( P = .092 ) . After more than 7 years of follow-up , the median survival remains greater for the CT-RT group ( 13.7 months ) than for the RT group ( 9.6 months ) ( P = .012 ) as ascertained by the logrank test ( two-sided ) . The percentages of patients surviving after years 1 through 7 were 54 , 26 , 24 , 19 , 17 , 13 , and 13 for the CT-RT group and 40 , 13 , 10 , 7 , 6 , 6 , and 6 for the RT group . CONCLUSIONS Long-term follow-up confirms that patients with stage III NSCLC who receive 5 weeks of chemotherapy with cisplatin and vinblastine before radiation therapy have a 4.1-month increase in median survival . The use of sequential chemotherapy-radiotherapy increases the projected proportion of 5-year survivors by a factor of 2.8 compared with that of radiotherapy alone . However , inasmuch as 80%-85 % of such patients still die within 5 years and because treatment failure occurs both in the irradiated field and at distant sites in patients receiving either sequential chemotherapy-radiotherapy or radiotherapy alone , the need for further improvements in both the local and systemic treatment of this disease persists STUDY OBJECTIVE To compare the survival of patients with locally advanced non-small cell lung cancer treated with  single-agent vindesine , thoracic radiotherapy , or both treatment modalities . DESIGN R and omized , prospect i ve , phase III trial . SETTING Multi-institutional , university-based national cooperative oncology group . PATIENTS The study included 319 patients with locally advanced , unresectable non-small cell lung cancer who had no evidence of extrathoracic metastases . All patients were ambulatory and had measurable disease . Some patients could not have surgery because of coexisting medical conditions . INTERVENTION Patients were r and omly assigned to receive vindesine , 3 mg/m2 body surface area weekly ; st and ard thoracic radiotherapy , 60 Gy over 6 weeks ; or both vindesine and thoracic radiotherapy . Vindesine was administered for 6 weeks and then every other week to patients who had no disease progression . Patients who developed progressive disease while receiving vindesine or radiotherapy alone were crossed over to radiotherapy or vindesine , respectively . Response assessment took place at week 6 . RESULTS The overall response rate was superior in the radiotherapy arms ( radiotherapy alone , 30 % ; radiotherapy plus vindesine , 34 % ; vindesine alone , 10 % ; P = 0.001 ) . However , with a minimum follow-up of 42 months , no improvement in survival has been seen with radiotherapy . The median survival was 8.6 months for patients receiving radiotherapy alone , 9.4 months for those receiving radiotherapy plus vindesine , and 10.1 months for those receiving vindesine ( P = 0.58 ) . Radiotherapy also failed to improve long-term survival . The 5-year survivals were 3 % , 3 % , and 1 % , respectively ( P = 0.56 ) . CONCLUSION Patients with non-small cell lung cancer who have inoperable , nonmetastatic disease gain no clinical ly meaningful survival advantage with immediate thoracic irradiation , even when modern megavoltage radiation therapy techniques and equipment are used 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 In a German multicenter trial , previously untreated patients with unresectable stages IIIA and IIIB non-small cell lung cancer were r and omly assigned to receive either radiotherapy alone ( arm A ) or chemotherapy followed by radiotherapy ( arm B ) . Chemotherapy in arm B consisted of ifosfamide 1,500 mg/m2 intravenously on days 1 to 5 and 29 to 33 , and vindesine 3 mg/m2 intravenously on days 1 and 5 and 29 and 33 . Radiotherapy started on day 1 in arm A and on day 56 in arm B. Single doses of 2 Gy were given 5 days a week for 3 weeks and after a 2-week interval for an additional 2 weeks . The total radiation dose was 50 Gy . Concurrent to radiotherapy , cisplatin was given as a radiosensitizer at a dose of 20 mg/m2 once a week . From July 1986 to March 1989 , 85 patients were r and omized , of whom 78 were evaluable . Main prognostic factors were well balanced . Of the patients receiving chemotherapy , 25 % had a partial remission after two cycles , 46 % showed no change , and 29 % had progressive disease . After radiotherapy , response rates were 49 % in arm A and 58 % in arm B , including a 10 % complete remission rate in both groups . After two thirds of the projected sample size had been included , an analysis of survival was performed and showed a statistically significant advantage for the treatment group including chemotherapy ( P = .016 ) . Median survival was 9.0 months versus 13.7 months and 2-year survival was 12 % versus 24 % , both in favor of the group receiving chemotherapy . These results caused premature discontinuation of patient accrual according to the study protocol and the recommendations of the Ethics Review Board of the Philipps-University Hospital . The results of this trial indicate that chemotherapy is able to prolong survival of patients with locally advanced unresectable non-small cell lung cancer and should be considered for treatment of these patients PURPOSE A phase III r and omised trial was conducted in patients with non-metastatic unresectable non-small-cell lung cancer in order to compare , in responders to induction chemotherapy , consolidation treatment by further chemotherapy to chest irradiation . PATIENTS AND METHODS A total of 462 untreated NSCLC patients were eligible for three courses of induction chemotherapy ( MIP ) consisting of cisplatin ( 50 mg/m2 ) , ifosfamide ( 3 g/m2 ) and mitomycin C ( 6 mg/m2 ) . It was proposed that objective responders be r and omised to either three further courses of MIP or to chest irradiation ( 60 Gy ; 2 Gy per fraction given over six weeks ) . RESULTS An objective response rate of 35 % was achieved ; 115 patients ( including 52 % with initial stage IIIA and 44 % with initial stage IIIB ) were r and omised to consolidation treatment , 60 of them to further chemotherapy and 55 to chest radiotherapy . There was no significant difference in survival between the two arms , with a respective median and two-year survival of 42 weeks ( 95 % confidence intervals ( 95 % CI : 35 - 51 ) and 18 % ( 95 % CI : 8 - 28 ) for chemotherapy and 54 weeks ( 95 % CI : 43 - 73 ) and 22 % ( 95 % CI : 11 - 33 ) for irradiation . There was also no statistical difference for response duration between the two arms but chest irradiation was associated with a significantly greater duration of local control than chemotherapy ( median duration times : 158 vs. 31 weeks , P = 0.0007 ) . CONCLUSIONS For non-metastatic unresectable NSCLC treated by an induction chemotherapy regimen containing cisplatin and ifosfamide , if an objective response is obtained , consolidation treatments by further chemotherapy or by chest irradiation result in non-statistically different survival distributions , although a better local control duration is observed with radiotherapy PURPOSE To test the concept of taxane sequencing in combined-modality therapy , this phase II trial ( S9504 ) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB non-small-cell lung cancer ( NSCLC ) . Results were compared with those of the predecessor study ( S9019 ) with identical eligibility , staging criteria , and treatment , excepting docetaxel consolidation . PATIENTS AND METHODS Treatment consisted of cisplatin 50 mg/m2 on days 1 , 8 , 29 , and 36 , etoposide 50 mg/m2 on days 1 through 5 and 29 through 33 , and concurrent thoracic radiotherapy ( total dose of 61 Gy ) . Consolidation docetaxel started 4 to 6 weeks after chemoradiotherapy at an initial dose of 75 mg/m2 . RESULTS Stage subsets ( tumor-node-metastasis system ) in 83 eligible patients were as follows : T4N0/1 , 31 patients ( 37 % ) ; T4N2 , 22 patients ( 27 % ) , and T1 - 3N3 , 30 patients ( 36 % ) . Concurrent chemoradiotherapy was generally well tolerated , but two patients died from probable radiation-associated pneumonitis . Neutropenia during consolidation docetaxel was common ( 57 % with grade 4 ) and most frequent during escalation to 100 mg/m2 . Median progression-free survival was 16 months , median survival was 26 months , and 1- , 2- , and 3-year survival rates were 76 % , 54 % , and 37 % , respectively . Brain metastasis was the most common site of failure . In S9019 , median survival was 15 months and 1- , 2- , and 3-year survival rates were 58 % , 34 % , and 17 % , respectively . CONCLUSION Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable , and results compare favorably with the predecessor trial S9019 . Nevertheless , this study remains hypothesis-generating and does not provide definitive evidence of the benefit of this approach . Phase III trials evaluating the S9504 regimen have been initiated to vali date these results The aim of this r and omised trial was to investigate the effect of induction chemotherapy before radiotherapy on survival in 302 patients with non-resectable squamous cell carcinoma of the lung .  Radiotherapy , 56 Gy to the chest , was given to 154 patients and combined treatment , with chemotherapy preceding the radiotherapy , to 148 patients .  Chemotherapy consisted of three courses of cisplatin ( 120 mg/m2 ) and etoposide ( 100 mg/m2 i.v . for 3 days ) administered every fourth week . Median survival was 10.5 months in the radiotherapy arm and 11 months in the combined treatment arm . The 2-year survival rate was 17 % in the radiotherapy arm and 21 % in the combined treatment arm . Addition of chemotherapy seemed to significantly improve survival , according to the Cox multivariate analysis ( P = 0.04 ) , but as only a trend according to life-table analysis ( P = 0.11 ) . Chemotherapy also accomplished a trend towards improved local control ( P = 0.08 ) and towards decreased metastatic disease ( P = 0.10 ) . 2 patients in the combined treatment arm , but none in the radiotherapy arm , died from toxicity . The conclusion was that the value of the chemotherapy used in this study was very modest , but the results strongly support further research for more efficient drugs and combinations PURPOSE To assess the feasibility , toxicity , and efficacy of hyperfractionated accelerated radiation therapy ( HART ) for non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Thirty patients from six institutions with stage IIIA or IIIB NSCLC were enrolled between November 1993 and August 1995 .  Radiation therapy ( total dose , 57.6 Gy in 36 fractions ) was delivered over 15 days with the use of three daily fractions with a 4-hour interval between fractions and an 8-hour interval between on-cord fields . Patients were not treated on weekends . RESULTS Twenty-eight patients ( 93 % ) completed radiation therapy . Treatment-related toxicities of grade 3 or greater included esophagitis in six patients and grade 3 skin reaction in three patients . The overall objective response rate was 54 % , and the response rate within the radiation field was 64 % . With a minimum follow-up of 19 months in surviving patients , the median survival and 1-year survival rate are 13 months and 57 % , respectively . The median relapse-free survival and 1-year relapse-free survival rate are 7 months and 23 % , respectively . No transverse myelitis or late toxicities of grade 4 or greater have been observed . CONCLUSION HART , delivered to a total dose of 57.6 Gy over 15 total days , is practical and well tolerated . Survival appears similar to that seen with modern combined modality regimens . A phase III trial is under way
AIM To define the best sequence of radiotherapy and chemotherapy for inoperable stage III non-small cell lung ( NSCL ) tumours .