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Highlights from the Tenth World Conference on lung cancerTracey L,EvansTracey L,EvansThe oncologist 2004;9:232-238The oncologist 2004;9:232-238The conference was held in Vancouver,CanadaThe conference was held in Vancouver,Canadappt made by leeyongHighlights from the Tenth Worl1 1Adjuvant Chemotherapy in non-small-cell lung cancerInternational adjuvant lung cancer trial(International adjuvant lung cancer trial(IALTIALT)from 1995-2000from 1995-2000 1867 pts from 148 centers in 33 countries1867 pts from 148 centers in 33 countries pts undergone complete resection of NSCLC pts undergone complete resection of NSCLC chemotherapy arm chemotherapy arm vsvs observation arm observation arm Adjuvant Chemotherapy in non-s2 2Chemotherapy used in IALT Adjuvant chemotherapy regimen%of the ptsCisplatin 300-400mg/m2 over 3-4 cycles withetoposidevinovelbinevinblastinvindesine5627116Chemotherapy used in IALT Adju3 3International adjuvant lung cancer trial(IALT)Thoracic radiotherapy was optionalChemotherapy was administered with 60 days35%pts in each arm underwent pneuonectomy and the remainder had lobectomy39%of pts in each arm had stage,and 46%had sccInternational adjuvant lung ca4 4International adjuvant lung cancer trial(IALT)74%pts received at least 240mg/m2 of DDP;8%pts assigned to the chemotherapy arm received no chemotherapyThe lethal treatment-associated toxicity rate in the chemotherapy arm was 0.8%International adjuvant lung ca5 5Outcome data from IALTChemotherapy armControlP valueMedian survival50.8 months44.4 months0.035-year survival rate44.5%40.4%Median disease-free survival40.2 months 30.5 months0.0035-year disease-free survival rate39.4%34.3%Lethal toxicity rate0.8%0The overall survival hazard ratio for chemotherapy was 0.86 95%CI=0.76-0.98Absolute 5-year survival benefit of 4.1%Absolute 5-year disease-free survival benefit of 5.1%,and hazard ratio was o.83%Outcome data from IALTChemothe6 6The Big Lung Trial(BLT)Large,multicenter study in the UKAll pts with NSCLC received primary therapy as determined by stage(surgery,radiation,or BSC)Pts randomized to receive either three 3-weekly cycles of DDP-based chemotherapyDDP/VDS,MMC/IFO/DDP,MMC/VLB/DDP NVB/DDP,or no chemotherapyThe Big Lung Trial(BLT)Large,7 7The Big Lung Trial(BLT)In the subgroup of pts receiving BSC as their primary modality,there was a statistically significant survival benefit for chemotherapyThere was no benefit to chemotherapy in terms of overall survival or progression-free survivalThe overall survival hazard ratio for chemotherapy was 1.02(95%CI=0.77-1.35)The Big Lung Trial(BLT)In the8 8Adjuvant lung project ITALY(ALPI)1209 pts with completely resected NSCLC were randomly assigned to received either MMC,VDS,and DDP every 3 weeks for 3 cycles or no chemotherapy69%of the pts assigned to the chemotherapy arm received all 3 cycles.Stage disease was present in 28%-29%of pts,while the remainder were stage or stage Adjuvant lung project ITALY(AL9 9Adjuvant lung project ITALY(ALPI)43%of the pts in each group were schedule43%of the pts in each group were schedule to have postoperative radiation therapy,and fewer in to have postoperative radiation therapy,and fewer in the chemotherapy group were able to complete it the chemotherapy group were able to complete it(65%vs 82%)(65%vs 82%)There was no significant difference in There was no significant difference in overalloverall survival survival(OR=o.96,95%CI=0.81-1.13,p=0.589)(OR=o.96,95%CI=0.81-1.13,p=0.589)between the two groups or between the two groups or progression-free survivalprogression-free survival (OR=0.89,95%CI=0.76-1.03,p=0.128)(OR=0.89,95%CI=0.76-1.03,p=0.128)Adjuvant lung project ITALY(AL1010commentaryOnly 50%of the early-stage pts of NSCLC underwent Only 50%of the early-stage pts of NSCLC underwent surgical resection are alive 5 years latersurgical resection are alive 5 years laterA meta-analysis of postoperative radiotherapy actually A meta-analysis of postoperative radiotherapy actually showed a survival decrementshowed a survival decrementIndividual randomized trials of adjuvant chemotherapy Individual randomized trials of adjuvant chemotherapy have been suboptimal due to the use of older,less have been suboptimal due to the use of older,less effective chemotherapy regimens,poor chemotherapy effective chemotherapy regimens,poor chemotherapy compliance,and insufficient power to detect small compliance,and insufficient power to detect small benefitsbenefitscommentaryOnly 50%of the earl1111commentaryNSCLCCG performed a meta-analysis examining the NSCLCCG performed a meta-analysis examining the benefit of adjuvant chemotherapybenefit of adjuvant chemotherapy17 trials were identified that compared surgery and 17 trials were identified that compared surgery and chemotherapy with surgery alonechemotherapy with surgery aloneThere was a nonsignificant trend toward worse survival in There was a nonsignificant trend toward worse survival in the pts who received chemotherapy due primarily to the the pts who received chemotherapy due primarily to the studies including alkylating agents,which consistently led studies including alkylating agents,which consistently led to worse survival than with surgery alone to worse survival than with surgery alone(OR=1.15,p=o.oo5)(OR=1.15,p=o.oo5)commentaryNSCLCCG performed a 1212commentaryAnalysis limited to theAnalysis limited to the 8 trials using DDP-based 8 trials using DDP-based chemotherapy showed a trend toward better chemotherapy showed a trend toward better survival in the chemotherapy group that was survival in the chemotherapy group that was nearly significant(OR=o.87,p=0.08)nearly significant(OR=o.87,p=0.08)Absolute survival benefit of 5%at 5 yearsAbsolute survival benefit of 5%at 5 yearscommentaryAnalysis limited to 1313commentaryAt 1867 pts,the At 1867 pts,the IALTIALT study remains the largest study remains the largest adjuvant trial presented to dateadjuvant trial presented to dateThe IALT study was large enough to determine The IALT study was large enough to determine that the very small benefits were statistically that the very small benefits were statistically significantsignificantWhy was the IALT study positive while the BLT Why was the IALT study positive while the BLT and ALPI were not?and ALPI were not?commentaryAt 1867 pts,the IAL1414commentarySize and hazard ratio of overall survival in recent large adjuvant studiesHazard ratio for chemotherapy95%CInNSCLCCG1,394o.870.74-1.02ALPI1,2090.960.81-1.13IALT1,8690.860.76-0.98BLT3811.020.77-1.35commentarySize and hazard rati1515commentarySome point to the better compliance with treatment Some point to the better compliance with treatment in the IALT studyin the IALT study74%of the pts chemotherapy pts in the IALT study 74%of the pts chemotherapy pts in the IALT study received at least 240mg/mreceived at least 240mg/m2 2 of DDP of DDPIn the BLT and ALPI,64%and 69%of pts,In the BLT and ALPI,64%and 69%of pts,respectively,received all 3 chemotherapy cycles.respectively,received all 3 chemotherapy cycles.There may be a real benefit for adjuvant There may be a real benefit for adjuvant chemotherapy in NSCLC,but the magnitude of this chemotherapy in NSCLC,but the magnitude of this benefit is likely quite smallbenefit is likely quite smallcommentarySome point to the be1616commentaryPer IALT data,25 pts must be treated to convert Per IALT data,25 pts must be treated to convert one person who otherwise would have died from one person who otherwise would have died from the disease into a 5-year survivorthe disease into a 5-year survivorOne of every 125 pts treated experience lethal One of every 125 pts treated experience lethal toxicity with the IALT regimens,and those pts toxicity with the IALT regimens,and those pts die within 6 months of surgery,whereas pts who die within 6 months of surgery,whereas pts who die of relapse usually live 1-2 year beyond die of relapse usually live 1-2 year beyond surgical resection.surgical mentaryPer IALT data,25 pt1717commentaryLung cancer pts are not the same as breast cancer Lung cancer pts are not the same as breast cancer or colon cancer ptsor colon cancer ptsLung cancer pts frequently have significant Lung cancer pts frequently have significant additional comorbidities that can complicate additional comorbidities that can complicate chemotherapy administration,and the chemotherapy administration,and the chemotherapeutic regimens are usually more difficultchemotherapeutic regimens are usually more difficultThere is at least some indication that DDP may be a There is at least some indication that DDP may be a better drug than carboplatin in NSCLC better drug than carboplatin in NSCLC commentaryLung cancer pts are 1818commentaryShould adjuvant chemotherapy for resected Should adjuvant chemotherapy for resected NSCLC become the standard of care?NSCLC become the standard of care?It depends on whom you you askIt depends on whom you you askOnly the Only the most fit ptsmost fit pts should be offered adjuvant should be offered adjuvant chemotherapychemotherapyGiven the current state of the evidence,pts Given the current state of the evidence,pts performance must factor strongly in the decision performance must factor strongly in the decision to administerto administercommentaryShould adjuvant chem1919Second-Line Chemotherapy In Advanced NSCLCSecond-Line Chemotherapy In Advanced NSCLC Spanish Lung Cancer Group(SLCG)phase Spanish Lung Cancer Group(SLCG)phase trial in trial in which 259 pts who had prior chemotherapy for which 259 pts who had prior chemotherapy for advanced NSCLC were randomized to receive either advanced NSCLC were randomized to receive either the traditional method of second-line docetaxel the traditional method of second-line docetaxel administration or a weekly regimen of docetaxeladministration or a weekly regimen of docetaxelPrimary end point was 1 year survival,and secondary Primary end point was 1 year survival,and secondary end points included OS,TTP,RR,toxicity profile,and end points included OS,TTP,RR,toxicity profile,and QOL QOL Second-Line Chemotherapy In Ad2020Second-Line Chemotherapy In Advanced NSCLCSecond-Line Chemotherapy In Advanced NSCLCComparison of every-3-weeks versus weekly docetaxelDocetaxel 75mg/m2every 3 weeksDocetaxel 36mg/m2weeklyP valueResponse rate8%5%NSTTP2.7 months2.9 monthsNS1-year survival rate29.2%21.8%NSMedian survival7.1 months5.4 monthso.o4Second-Line Chemotherapy In Ad2121Second-Line Chemotherapy In Advanced NSCLCSecond-Line Chemotherapy In Advanced NSCLCThe rates of grade 3/4/5 toxicities were similar The rates of grade 3/4/5 toxicities were similar in both armin both armMore neutropenia,leukopenia,alopecia,and More neutropenia,leukopenia,alopecia,and hepatic toxicity in the every-3-weeks armhepatic toxicity in the every-3-weeks armMore diarrhea,mucositis,and dyspnea in the More diarrhea,mucositis,and dyspnea in the weekly armweekly armThere was no difference in quality-of-life There was no difference in quality-of-life measurements between the two armsmeasurements between the two armsComparison of every-3-weeks versus weekly docetaxelSecond-Line Chemotherapy In Ad2222Second-Line Chemotherapy In Advanced NSCLCSecond-Line Chemotherapy In Advanced NSCLCRegimens in pemetrexed versus docetaxel studyRegimens in pemetrexed versus docetaxel study Pemetrexed:500mg/m Pemetrexed:500mg/m2 2 iv every 3 weeks iv every 3 weeks folic acid:350-1,000g daily and vitB folic acid:350-1,000g daily and vitB1212 1mg 1/9ws 1mg 1/9ws Dexamethasone:4 mg bid d-1,0,+1 Dexamethasone:4 mg bid d-1,0,+1OrOrDocetaxel:75mg/mDocetaxel:75mg/m2 2 iv every 3 weeks iv every 3 weeks Dexamethasone:8mg twice a day on days-1,0,+1 Dexamethasone:8mg twice a day on days-1,0,+1 Pemetrexed versus DocetaxelSecond-Line Chemotherapy In Ad2323Second-Line Chemotherapy In Advanced NSCLCSecond-Line Chemotherapy In Advanced NSCLCEfficacy of pemetrexed versus docetaxelMedian survivalHazard ratio(95%CI)Pemetrexed(n=283)Docetaxel(n=288)1-year survival rateTime to progressionHazard ratio(95%CI)Response rate8.3 months7.9 monthso.99(0.8-1.2)29.7%29.7%2.9 months2.9 months0.97(0.8-1.2)9.1%8.8%Second-Line Chemotherapy In Ad2424Second-Line Chemotherapy In Advanced NSCLCSecond-Line Chemotherapy In Advanced NSCLCGrade toxicity of pts of pemetrexed versus docexelPemetrxedn=285DocetaxelN=276P valueNeutropeniaNeutropenia feverThrombcytopeniaNeuropathy(grade 2-4)Hospitalization due to Fever and neutropenia5%2%2%3%2%40%13%1%8%16%0.00010.0001o.1160.0140.0001Second-Line Chemotherapy In Ad2525commentaryWeekly regimens appear better tolerated,and Weekly regimens appear better tolerated,and assumption has been that they are likely similar in assumption has been that they are likely similar in efficacy to the every-3-weeks regimensefficacy to the every-3-weeks regimensSpanish study demonstrated that there was a trend Spanish study demonstrated that there was a trend toward a higher 1-year survival rate in the every-3-toward a higher 1-year survival rate in the every-3-weeks arm,and weeks arm,and it is hard to ignoreit is hard to ignore the statistically the statistically different overall survival rate favoring the every-3-different overall survival rate favoring the every-3-weeks docetaxel arm,with a 1.7 month longer weeks docetaxel arm,with a 1.7 month longer median survival time and a p value of 0.04 median survival time and a p value of 0.04 The every-3-weeks schedule of choice,according to The every-3-weeks schedule of choice,according to the studythe studycommentaryWeekly regimens appe2626commentaryWeekly regimens may be reasonable for pts in Weekly regimens may be reasonable for pts in whom the toxicity profile of the every-3-weeks whom the toxicity profile of the every-3-weeks schedule is not desirableschedule is not desirableIt now appear that pemetrexed has efficacy similar It now appear that pemetrexed has efficacy similar to that of docetaxel in the second-line treatment of to that of docetaxel in the second-line treatment of advanced NSCLCadvanced NSCLCThe toxicity profile of pemetrexed is much better The toxicity profile of pemetrexed is much better than that of the traditional method of docetaxel than that of the traditional method of docetaxel administration.administration.Vitamin supplementation is critical to minimizing Vitamin supplementation is critical to minimizing toxicity from pemetrexedtoxicity from pemetrexedcommentaryWeekly regimens may 2727Second-Line Chemotherapy In Advanced NSCLCSecond-Line Chemotherapy In Advanced NSCLCIrresa was approved by the FDA in the May 2003 for the Irresa was approved by the FDA in the May 2003 for the treatment of advanced NSCLC in the setting of progressive treatment of advanced NSCLC in the setting of progressive disease following platinum-based chemotherapy and docetaxeldisease following platinum-based chemotherapy and docetaxelIn Japan,Interstitial pneumonitis has been reported in 2%of In Japan,Interstitial pneumonitis has been reported in 2%of the pts,and 0.7%of the pts experienced fatal pneumonitisthe pts,and 0.7%of the pts experienced fatal pneumonitisOf the pts outside Japan,o.33%developed pneumonitis and Of the pts outside Japan,o.33%developed pneumonitis and 0.1%developed fatal pneumonitis0.1%developed fatal pneumonitisEAP in the US,pneumonitis occurred in 0.36%of pts and fatal EAP in the US,pneumonitis occurred in 0.36%of pts and fatal pneumonitis occurred in 0.06%pneumonitis occurred in 0.06%Gefitinib(Irresa)Safety and TolerabilitySecond-Line Chemotherapy In Ad2828Second-Line Chemotherapy In Advanced NSCLCSecond-Line Chemotherapy In Advanced NSCLCGefitinib(Irresa)Pts with BAC and never smokePts with either non-smoker or BAC histology Pts who were smoker with non-BAC histologyRRMST55%14 months26%9 months6%4 months Pts with nonadenocacinoma0Memorial Sloan-Kettering Cancer CenterSecond-Line Chemotherapy In Ad2929Second-Line Chemotherapy In Advanced NSCLCSecond-Line Chemotherapy In Advanced NSCLCNone of the molecular markers(EGFR ERK p-Akt PTEN Her-2 None of the molecular markers(EGFR ERK p-Akt PTEN Her-2 P27 P53 k-Ras)were significant predictors of responseP27 P53 k-Ras)were significant predictors of responseBetter performance status was predictive of better response Better performance status was predictive of better response rate in univariate analysis but was not an independent predictor rate in univariate analysis but was not an independent predictor in the multivariate analysisin the multivariate analysisThere was a trend toward a superior response rate in women There was a trend toward a superior response rate in women(19%vs 8%,p=0.14)(19%vs 8%,p=0.14)Gefitinib(Irresa)Second-Line Chemotherapy In Ad3030commentaryNow that gefitinib is available,how to use it?Now that gefitinib is available,how to use it?IDEAL2 IDEAL2 showed a RR of 10.6%and a symptom showed a RR of 10.6%and a symptom improvement rate of 40%in pts with improvement rate of 40%in pts with refractory NSCLCrefractory NSCLCThere has not been any randomized study There has not been any randomized study demonstrating superior survival rates for pts treated demonstrating superior survival rates for pts treated with gefitinibwith gefitinibINTACTINTACT trials in which the combination of gefitinib and trials in which the combination of gefitinib and chemotherapy offered no better efficacy than chemotherapy offered no better efficacy than chemotherapy alone chemotherapy alone commentaryNow that gefitinib i3131commentaryInterstitial pneumonitis is real but rare toxicity,and Interstitial pneumonitis is real but rare toxicity,and the reasons are not clearthe reasons are not clearGefinitib remains a remarkably tolerable treatment,Gefinitib remains a remarkably tolerable treatment,even in the pts with poor performance statuseven in the pts with poor performance statusLife-long non-smokers with BAC appear most likely to Life-long non-smokers with BAC appear most likely to respondrespondSWOG 0126 trialSWOG 0126 trial,evaluating gefitinib in BAC,evaluating gefitinib in BAC,demonstrated that RR in previously untreated pts was demonstrated that RR in previously untreated pts was 19%,while the rate in previously treated pts was 12%19%,while the rate in previously treated pts was 12%A trial of erlotinib in BAC yielding a RR was 26%A trial of erlotinib in BAC yielding a RR was 26%commentaryInterstitial pneumon3232谢谢大家！3333
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