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1、Highlights from the Tenth World Conference on lung cancer,Tracey L, Evans The oncologist 2004;9:232-238 The conference was held in Vancouver, Canada,ppt made by leeyong,Adjuvant Chemotherapy in non-small-cell lung cancer,International adjuvant lung cancer trial (IALT) from 1995-2000 1867 pts from 14
2、8 centers in 33 countries pts undergone complete resection of NSCLC chemotherapy arm vs observation arm,Chemotherapy used in IALT,Adjuvant chemotherapy regimen % of the pts,Cisplatin 300-400mg/m2 over 3-4 cycles with,etoposide,vinovelbine,vinblastin,vindesine,56,27,11,6,International adjuvant lung c
3、ancer trial (IALT),Thoracic radiotherapy was optional Chemotherapy was administered with 60 days 35% pts in each arm underwent pneuonectomy and the remainder had lobectomy 39% of pts in each arm had stage ,and 46% had scc,International adjuvant lung cancer trial (IALT),74% pts received at least 240m
4、g/m2 of DDP;8% pts assigned to the chemotherapy arm received no chemotherapy The lethal treatment-associated toxicity rate in the chemotherapy arm was 0.8%,Outcome data from IALT,Chemotherapy arm,Control,P value,Median survival,50.8 months,44.4 months,0.03,5-year survival rate,44.5%,40.4%,Median dis
5、ease-free survival,40.2 months,30.5 months,0.003,5-year disease-free survival rate,39.4%,34.3%,Lethal toxicity rate,0.8%,0,The overall survival hazard ratio for chemotherapy was 0.86 95% CI=0.76-0.98,Absolute 5-year survival benefit of 4.1%,Absolute 5-year disease-free survival benefit of 5.1%, and
6、hazard ratio was o.83%,The Big Lung Trial (BLT),Large, multicenter study in the UK All 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 chemotherapy DDP/VDS, MMC/IFO/DDP, MMC/VLB/DDP NVB/DD
7、P, or no chemotherapy,The Big Lung Trial (BLT),In the subgroup of pts receiving BSC as their primary modality, there was a statistically significant survival benefit for chemotherapy There was no benefit to chemotherapy in terms of overall survival or progression-free survival The overall survival h
8、azard ratio for chemotherapy was 1.02 (95%CI=0.77-1.35),Adjuvant 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 chemotherapy 69% of the pts assigned to the chemotherapy arm received all 3 c
9、ycles. Stage disease was present in 28%-29% of pts, while the remainder were stage or stage ,Adjuvant lung project ITALY(ALPI),43% of the pts in each group were schedule to have postoperative radiation therapy, and fewer in the chemotherapy group were able to complete it (65% vs 82%) There was no si
10、gnificant difference in overall survival (OR=o.96, 95% CI=0.81-1.13, p=0.589) between the two groups or progression-free survival (OR=0.89, 95% CI=0.76-1.03, p=0.128),commentary,Only 50% of the early-stage pts of NSCLC underwent surgical resection are alive 5 years later A meta-analysis of postopera
11、tive radiotherapy actually showed a survival decrement Individual randomized trials of adjuvant chemotherapy have been suboptimal due to the use of older, less effective chemotherapy regimens, poor chemotherapy compliance, and insufficient power to detect small benefits,commentary,NSCLCCG performed
12、a meta-analysis examining the benefit of adjuvant chemotherapy 17 trials were identified that compared surgery and chemotherapy with surgery alone There was a nonsignificant trend toward worse survival in the pts who received chemotherapy due primarily to the studies including alkylating agents, whi
13、ch consistently led to worse survival than with surgery alone (OR=1.15,p=o.oo5),commentary,Analysis limited to the 8 trials using DDP-based chemotherapy showed a trend toward better survival in the chemotherapy group that was nearly significant (OR=o.87,p=0.08) Absolute survival benefit of 5% at 5 y
14、ears,commentary,At 1867 pts, the IALT study remains the largest adjuvant trial presented to date The IALT study was large enough to determine that the very small benefits were statistically significant Why was the IALT study positive while the BLT and ALPI were not?,commentary,Size and hazard ratio
15、of overall survival in recent large adjuvant studies,Hazard ratio for chemotherapy,95% CI,n,NSCLCCG,1,394,o.87,0.74-1.02,ALPI,1,209,0.96,0.81-1.13,IALT,1,869,0.86,0.76-0.98,BLT,381,1.02,0.77-1.35,commentary,Some point to the better compliance with treatment in the IALT study 74% of the pts chemother
16、apy pts in the IALT study received at least 240mg/m2 of DDP In the BLT and ALPI, 64% and 69% of pts, respectively, received all 3 chemotherapy cycles. There may be a real benefit for adjuvant chemotherapy in NSCLC, but the magnitude of this benefit is likely quite small,commentary,Per IALT data, 25
17、pts must be treated to convert one person who otherwise would have died from the disease into a 5-year survivor One of every 125 pts treated experience lethal toxicity with the IALT regimens, and those pts die within 6 months of surgery, whereas pts who die of relapse usually live 1-2 year beyond su
18、rgical resection.,commentary,Lung cancer pts are not the same as breast cancer or colon cancer pts Lung cancer pts frequently have significant additional comorbidities that can complicate chemotherapy administration, and the chemotherapeutic regimens are usually more difficult There is at least some
19、 indication that DDP may be a better drug than carboplatin in NSCLC,commentary,Should adjuvant chemotherapy for resected NSCLC become the standard of care? It depends on whom you you ask Only the most fit pts should be offered adjuvant chemotherapy Given the current state of the evidence, pts perfor
20、mance must factor strongly in the decision to administer,Second-Line Chemotherapy In Advanced NSCLC,Spanish Lung Cancer Group (SLCG) phase trial in which 259 pts who had prior chemotherapy for advanced NSCLC were randomized to receive either the traditional method of second-line docetaxel administra
21、tion or a weekly regimen of docetaxel Primary end point was 1 year survival, and secondary end points included OS, TTP, RR, toxicity profile, and QOL,Second-Line Chemotherapy In Advanced NSCLC,Comparison of every-3-weeks versus weekly docetaxel,Docetaxel 75mg/m2 every 3 weeks,Docetaxel 36mg/m2 weekl
22、y,P value,Response rate,8%,5%,NS,TTP,2.7 months,2.9 months,NS,1-year survival rate,29.2%,21.8%,NS,Median survival,7.1 months,5.4 months,o.o4,Second-Line Chemotherapy In Advanced NSCLC,The rates of grade 3/4/5 toxicities were similar in both arm More neutropenia, leukopenia, alopecia, and hepatic tox
23、icity in the every-3-weeks arm More diarrhea, mucositis, and dyspnea in the weekly arm There was no difference in quality-of-life measurements between the two arms,Comparison of every-3-weeks versus weekly docetaxel,Second-Line Chemotherapy In Advanced NSCLC,Regimens in pemetrexed versus docetaxel s
24、tudy Pemetrexed: 500mg/m2 iv every 3 weeks folic acid: 350-1,000g daily and vitB12 1mg 1/9ws Dexamethasone: 4 mg bid d -1,0,+1 Or Docetaxel: 75mg/m2 iv every 3 weeks Dexamethasone: 8mg twice a day on days -1,0,+1,Pemetrexed versus Docetaxel,Second-Line Chemotherapy In Advanced NSCLC,Efficacy of peme
25、trexed versus docetaxel,Median survival,Hazard ratio (95% CI),Pemetrexed (n=283),Docetaxel (n=288),1-year survival rate,Time to progression,Hazard ratio (95% CI),Response rate,8.3 months,7.9 months,o.99(0.8-1.2),29.7%,29.7%,2.9 months,2.9 months,0.97(0.8-1.2),9.1%,8.8%,Second-Line Chemotherapy In Ad
26、vanced NSCLC,Grade toxicity of pts of pemetrexed versus docexel,Pemetrxed n=285,Docetaxel N=276,P value,Neutropenia,Neutropenia fever,Thrombcytopenia,Neuropathy (grade 2-4),Hospitalization due to Fever and neutropenia,5%,2%,2%,3%,2%,40%,13%,1%,8%,16%,0.0001,0.0001,o.116,0.014,0.0001,commentary,Weekl
27、y regimens appear better tolerated, and assumption has been that they are likely similar in efficacy to the every-3-weeks regimens Spanish study demonstrated that there was a trend toward a higher 1-year survival rate in the every-3-weeks arm, and it is hard to ignore the statistically different ove
28、rall survival rate favoring the every-3-weeks docetaxel arm, with a 1.7 month longer median survival time and a p value of 0.04 The every-3-weeks schedule of choice, according to the study,commentary,Weekly regimens may be reasonable for pts in whom the toxicity profile of the every-3-weeks schedule
29、 is not desirable It now appear that pemetrexed has efficacy similar to that of docetaxel in the second-line treatment of advanced NSCLC The toxicity profile of pemetrexed is much better than that of the traditional method of docetaxel administration. Vitamin supplementation is critical to minimizin
30、g toxicity from pemetrexed,Second-Line Chemotherapy In Advanced NSCLC,Irresa was approved by the FDA in the May 2003 for the treatment of advanced NSCLC in the setting of progressive disease following platinum-based chemotherapy and docetaxel In Japan, Interstitial pneumonitis has been reported in 2
31、% of the pts, and 0.7% of the pts experienced fatal pneumonitis Of the pts outside Japan, o.33% developed pneumonitis and 0.1% developed fatal pneumonitis EAP in the US, pneumonitis occurred in 0.36% of pts and fatal pneumonitis occurred in 0.06%,Gefitinib (Irresa),Safety and Tolerability,Second-Lin
32、e Chemotherapy In Advanced NSCLC,Gefitinib (Irresa),Pts with BAC and never smoke,Pts with either non-smoker or BAC histology,Pts who were smoker with non- BAC histology,RR,MST,55%,14 months,26%,9 months,6%,4 months,Pts with nonadenocacinoma,0,Memorial Sloan-Kettering Cancer Center,Second-Line Chemot
33、herapy In Advanced NSCLC,None of the molecular markers (EGFR ERK p-Akt PTEN Her-2 P27 P53 k-Ras) were significant predictors of response Better performance status was predictive of better response rate in univariate analysis but was not an independent predictor in the multivariate analysis There was
34、 a trend toward a superior response rate in women (19% vs 8%, p=0.14),Gefitinib (Irresa),commentary,Now that gefitinib is available, how to use it? IDEAL2 showed a RR of 10.6% and a symptom improvement rate of 40% in pts with refractory NSCLC There has not been any randomized study demonstrating sup
35、erior survival rates for pts treated with gefitinib INTACT trials in which the combination of gefitinib and chemotherapy offered no better efficacy than chemotherapy alone,commentary,Interstitial pneumonitis is real but rare toxicity, and the reasons are not clear Gefinitib remains a remarkably tole
36、rable treatment, even in the pts with poor performance status Life-long non-smokers with BAC appear most likely to respond SWOG 0126 trial, evaluating gefitinib in BAC, demonstrated that RR in previously untreated pts was 19%, while the rate in previously treated pts was 12% A trial of erlotinib in BAC yielding a RR was 26%,谢谢大家！,