第十届世界肺癌会议（英文）

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 148 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 cancer 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 240mg/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 armControlP value Median survival 50.8 months 44.4 months0.03 5-year survival rate 44.5%40.4% Median disease-free survival 40.2 months 30.5 months0.003 5-year disease-free survival rate39.4%34.3% Lethal toxicity rate0.8%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 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/DDP, 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 hazard 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 cycles. 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 significant 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 postoperative 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 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, which 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 years 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 of overall survival in recent large adjuvant studies Hazard ratio for chemotherapy 95% CI n NSCLCCG 1,394o.87 0.74-1.02 ALPI1,209 0.960.81-1.13 IALT1,8690.86 0.76-0.98 BLT3811.020.77-1.35 commentary Some point to the better compliance with treatment in the IALT study 74% of the pts chemotherapy 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 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 surgical 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 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 performance 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 administration 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 weekly P value Response rate 8% 5%NS TTP2.7 months2.9 months NS 1-year survival rate29.2% 21.8% NS Median survival 7.1 months5.4 monthso.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 toxicity 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 study 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 pemetrexed 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 months7.9 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 Advanced 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 Weekly 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 overall 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 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 minimizing 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% 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-Line 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 RRMST 55%14 months 26%9 months 6%4 months Pts with nonadenocacinoma0 Memorial Sloan-Kettering Cancer Center Second-Line Chemotherapy 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 pe