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the Lebanese Society of Medical Oncology commitment to cure cancer november 13-15, 2008 Beirut adjuvant therapy in non-small cell lung cancer Dominique H. Grunenwald, MD Professor in Thoracic and Cardiovascular Surgery Hopital Tenon, University of Paris. France IS NATURAL HISTORY OF NON-SMALL CELL LUNG CANCER IN ACCORDANCE TO TNM STAGING SYSTEM ? Grunenwald DH, et al. J Thorac Oncol 2007;2 Suppl.4:S574-S575 TN staging for 392 M1 nsclc T1 T2 T3 T4 total % N0 12 40 18 16 86 22 N1 2 25 3 16 46 12 N2 14 75 34 39 162 41 N3 3 49 11 35 98 25 total 31 189 66 106 392 % 8 48 17 27 100 among patients with stage IV metastatic nsclc : % no. N0-1 34 N status 132 T1-2 56 T status 220 % no. N2-3 260 T3-4 172 66 44 T1-2N0 = 13% metastatic spreading is not the privilege of locally advanced disease in nsclc let's remember year 1995 ! the only curative treatment is surgery post-operative radiotherapy is a paradigm ct is something for metastatic disease "new" drugs are emerging … for stage IV vinorelbine taxanes gemcitabine induction ct is coming out … in stage IIIA remember year 1995 ! Non-Small Cell Lung Cancer Collaborative Group Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials Br Med J 1995;311:899-909 postoperative cisplatin regimen could improve the overall survival of patients resected for nonsmall cell cancer adjuvant ct in nsclc NSCLC Collaborative Group BMJ 311:899,1995 Surgery vs Surgery + CT (cisplatin-based trials) 1.0 S U 0.9 Surgery+CT Surgery 0.8 R 0.7 V 0.6 I 0.5 V 0.4 A 0.3 L 0.2 5% 0.1 Patients at risk Surgery+CT Surgery 0.0 Events Total 298 706 688 316 0 12 24 706 688 590 548 462 433 Months 36 48 60 371 353 295 258 206 177 phase III trials management of early stage nsclc Trial Stage CT IB, IIA vinorelbine - CDDP I, II, IIIA, complete resection Platinum based, RT II, IIIA EPx4 + RT vs. RT I-IV Various, vs. BSC ALPI I, II, IIA Cisplatin, MMC, vindesine x 3 ANITA I, II, IIIA vinorelbine - CDDP T2N0 Paclitaxel-CBDCA NCIC CTG BR.10 IALT ECOG BIG Lung Trial CALGB 9633 remember year 1998 ! paradigm explodes PORT meta-analysis published in the Lancet post-operative radiotherapy is detrimental … in early stages questionable in stage IIIA remember year 2002 ! Adjuvant Lung Project Italy (ALPI) presented at ASCO "negative" "death of adjuvant therapy!!!" Dr. Scagliotti is disappointed… results of ialt and anita are about to come ... others are smiling ... remember year 2003 ! ALPI is published "negative" Scagliotti GV, et al. J Natl Cancer Inst 2003 International Adjuvant Lung cancer Trial (IALT) presented at ASCO "positive" Japan Lung Cancer Research Group (UFT) presented at ASCO "positive" IALT cisplatin combined with a "new" drug in 30% of cases Japanese study adjuvant ct without platinum salts IALT outcomes N patients Events MST Median DFS 5-year survival* 5-year DFS** Chemo Control P value 932 469 50.8 mos 40.2 mos 44.5% 39.4% 935 504 44.4 mos 30.5 mos 40.4% 34.3% 0.03 0.003 * HR = 0.86 (95% CI 0.76-0.98) ** HR = 0.83 (95% CI 0.74-0.94) planned 3.300 patients; enrolled 1867 IALT Collaborative Group NEJM 2004; 350: 351-360 Overall survival Probability of survival (%) 100 90 80 70 60 50 40 30 20 10 0 0 No. at risk Control 488 UFT 491 UFT Control No. of cases 5 YS (%) Control 488 85.4 UFT 491 87.9 H.R.=0.709 [0.515-0.978] 1 2 3 4 Logrank test 0.0350 5 6 7 8 Years after resection 481 482 469 471 445 442 423 416 378 368 219 96 221 105 T1N0 T2N0 UFT Control UFT Control despite smaller subset of pT2 (130 vs 360), all benefit comes from pT2 patients acceptance of CT according to tumor size is unavailable overall compliance relatively poor (53%) IALT & ALPI common features large scale randomised clinical trials across all resectable stages (I-IIIA) cisplatin-based ct sequential adjuvant rt allowed sample size calculation around the survival advantage indicated by 1995 nsclc meta-analysis ALPI - Overall Survival Eve nts/Total CT Control 278/548 288/540 HR=0.96 (0.81 - 1.13) P<0.03 100 80 p=0.585 60 survival (%) P R O B A B I L I T Y ialt overall survival 40 adjuvant ct 20 0 control 0 • • 1 775 774 2 624 450 308 602 432 286 3 4 5 years 181 164 N Engl J med 2004;350:351-60 YEARS Scagliotti GV et al. JNCI 2003; 95 (19) : 1453-61 initial toxicity affects the results ALPI - Overall Survival P R O B A B I L I T Y Events/Total CT 278/548 Control 288/540 HR=0.96 (0.81 - 1.13) p=0.585 Scagliotti GV et al. JNCI 2003; 95 (19) : 1453-61 YEARS ialt overall survival P<0.03 100 survival (%) 80 60 adjuvant ct 40 control 20 0 0 1 932 2 775 933 3 624 774 602 4 450 432 5 years 308 286 181 164 N Engl J med 2004;350:351-60 remember year 2004 ! IALT1 and JLCRG2 (UFT) published 1. IALT collaborative group. N Engl J Med 2004;350(4):351-60 2. Kato H, et al. N Engl J Med 2004;350(17):1713-21 NCI Canada JBR.10 (cisplatin + vinorelbine) presented at ASCO "positive" CALGB 9633 (carboplatin + paclitaxel) presented at ASCO "positive" JBR.10 stage IB & II cisplatin combined with a "new" drug CALGB 9633 stage IB "new" combination Intergroup JBR.10 National Cancer Institute of Canada SWOG JBR10; ECOG JBR10; CALGB 9795 Vin/Cis Observation phase III randomised trial of adjuvant VINORELBINE and CISPLATIN in completely resected stage IB and II nsclc Winton T, et al., ASCO 2004 summary • overall survival vinorelbine-cisplatin = 15 % improvement of 5-yr OS (p = 0.0022) = 30 % reduction in risk of death (p = 0.012) • 5-yr recurrence-free survival NVB-CDDP control 61 % 48 % (p = 0.012) • tolerability NVB-CDDP well tolerated (59 % > 3 cycles) negligeable negative impact on qol CALGB 9633 only stage I B (approx. 1/3 of early nsclc) median follow up time : 34 months only!! a lot of censored patients!!! trial stopped early CALGB 9633 (stage IB only) 0.8 0.6 0.4 0.2 ----Chemotherapy ---chemotherapy ----Observation ---observation p=0.028 0.0 Probability 1.0 OVERALL SURVIVAL 0 20 40 60 Survival Time (Months) 80 Review by ASCO* adjuvant chemotherapy trials from ASCO 2003-2004 IALT CALGB n JBR 10 1867 344 482 5-yr rfs I, II and III different CDDPbased CT ± RT 39.4% vs 34.3% IB and II NVB + CDDP without RT 61% vs 48% 5-yr surv. 44.5% vs 40.4% IB PCT+CBDCA without RT 61% vs 50% (4 yrs f.-up) 71% vs 59% (4 yrs f.-up) stages adj. ct 69% vs 54% *from review by K. Pisters, ASCO 2004 what about year 2005? NCI C JBR.10 : cddp + vinorelbine published Winton TL, al. N Engl J Med 2005;352:2589-97 Adjuvant Navelbine International Trialists Association (ANITA) : cddp + vinorelbine presented at ASCO "positive" ANITA: Phase III Adjuvant Vinorelbine and Cisplatin versus Observation in Completely Resected Non-Small-Cell Lung Cancer Patients JY. Douillard, et al. on behalf of the Adjuvant Navelbine International Trialists Association type of surgery, pTNM, histology Type of surgery Pneumonectomy Lobectomy Stage I (pT2 N0) II IIIA Histology Squamous Non Squamous PORT Chemotherapy at relapse OBS n= 433 35.8% 58.4% n= 433 34.2% 30.5% 35.3% n= 433 58.9% 41.1% 33.3% 48% NVB+CDDP n= 407 38.1% 57.2% n= 407 35.4% 29.2% 35.4% n= 407 60.0% 40.0% 21.6% 39.2% ANITA overall survival Median months 1.00 Survival Distribution Function P-value OBS. NVB + CDDP 43.8 65.8 0.013 Hazard Ratio 0.79 [0.66 - 0.95] 0.75 0.50 Obs 0.25 NVB + CDDP 0 0 20 40 60 80 100 120 months ANITA survival: Cox univariate analysis covariates univariate P value age > 55 years < 55 years WHO ps 0 1-2 surg. pneumonectomy other radiotherapy no yes stage IIIA IB-II N status N+ N0 histology adk other ANITA HR [95% CI] 0.04 0.81 0.012 1.27 0.001 0.73 0.003 1.34 < 0.001 0.54 < 0.001 0.53 0.733 0.97 1 [0.67 - 0.99] 1 [1.05 - 1.52] 1 [0.60 - 0.88] 1 [1.10 - 1.63] 1 [0.45 - 0.65] 1 [0.44 - 0.65] 1 [0.80 - 1.17] survival: Cox univariate analysis covariates univariate P value age > 55 years < 55 years WHO ps 0 1-2 surg. pneumonectomy other radiotherapy no yes stage IIIA IB-II N status N+ N0 histology adk other ANITA HR [95% CI] 0.04 0.81 0.012 1.27 0.001 0.73 0.003 1.34 < 0.001 0.54 < 0.001 0.53 0.733 0.97 1 [0.67 - 0.99] 1 [1.05 - 1.52] 1 [0.60 - 0.88] 1 [1.10 - 1.63] 1 [0.45 - 0.65] 1 [0.44 - 0.65] 1 [0.80 - 1.17] what about year 2006? Adjuvant Navelbine International Trialists Association (ANITA) : cddp + vinorelbine published Douillard JY, et al. Lancet Oncol 2006;7:719-27 Update of CALGB 9633 (stage IB, PCT-CBDCA) presented at ASCO negative!!!! LACE adjuvant meta-analysis presented adjuvant ct as a standard ? issues : 1. which drug combination ? 2. which patients (stages) ? 3. role of PostOperativeRT 4. perspectives Probability Lung Adjuvant Cisplatin Evaluation (LACE) 1,0 0,8 0,6 0,4 HR translates into an absolute benefit of 5.4% at 5 years 0,2 Time (years) 0 0 1 2 3 4 5 6 7 8 Patients at risk Surg alone 4068 3585 3043 2539 2034 1548 779 358 103 Surg+CT 4079 3607 3074 2584 2137 1665 835 389 108 individual patient data from 5 trials (4,584 patients) postoperative cisplatin-based ct significantly improves survival in patients with nsclc Pignon JP, et al. J Clin Oncol 2008;26:3552-9 which drug combination ? Lung Adjuvant Cisplatin Evaluation (LACE) 5 randomized clinical trials including 4,584 patients Pignon JP, et al. J Clin Oncol 2006;24:18S 7008 vinorelbine associated with 320 to 400 mg/m2 of cisplatin appears the most promising drug combination Pignon JP, et al. J Clin Oncol 2006;24:18S 7008 Rx N 5yr surv. (%) Absolute benefit JBR.10 IB-II (ASCO 04) Surgery vinorelbine-CDDP 241 241 54 69 + 15% ANITA IB, II, IIIA (ASCO 05) Surgery vinorelbine-CDDP 433 407 43 51 + 8% LACE NVB Meta-analysis (ESMO 06) Surgery vinorelbine-CDDP 1888 46.1 55 + 8.9% Study which patients (stages) ? uft survival: Cox univariate analysis covariates univariate P value age > 55 years < 55 years WHO ps 0 1-2 surg. pneumonectomy other radiotherapy no yes stage IIIA IB-II N status N+ N0 histology adk other ANITA HR [95% CI] 0.04 0.81 0.012 1.27 0.001 0.73 0.003 1.34 < 0.001 0.54 < 0.001 0.53 0.733 0.97 1 [0.67 - 0.99] 1 [1.05 - 1.52] 1 [0.60 - 0.88] 1 [1.10 - 1.63] 1 [0.45 - 0.65] 1 [0.44 - 0.65] 1 [0.80 - 1.17] "cisplatin-based ct is certainly effective for stages II and III" Pignon JP, et al. J Clin Oncol 2006;24:18S 7008 adjuvant paclitaxel plus carboplatin vs. observation in stage IB non-small-cell lung cancer (CALGB 9633) 344 patients randomly assigned median follow-up 74 months predominant toxicity = gr. 3 to 4 neutropenia no treatment-related deaths survival not different (p = .12) significant survival difference in favor of adjuvant ct for tumors 4 cm (p = .043) Strauss GM, et al. J Clin Oncol 2008;26:5043-51 Goldstraw P, et al. J Thorac Oncol 2007;2:706-14 Goldstraw P, et al. J Thorac Oncol 2007;2:706-14 Mountain CF Goldstraw P, et al. J Thorac Oncol 2007;2:706-14 Vancouver 2002 impact of postoperative radiation therapy (ANITA) adjuvant cisplatin and vinorelbine ct vs. observation completely resected nsclc stages IB to IIIA PORT recommended for pN+ disease unplanned subgroup analysis observation 33% PORT impact on surv. overall deleterious pN1 improved pN2 improved chemotherapy 22% deleterious detrimental improved Douillard JY, et al. Int J Rad Oncol Biol Phys 2008 Role of PORT: ANITA subset analysis PORT 232 pts Overall Survival in N2 patients Med. survival OVERALL: 47.4 m. 1.00 N1 37% N2 50% Survival Distribution Function N0 13% 32.6 m. CT 20 m. OBS 0.75 23.8 m. 22.7 m. 12.7 m. CT + PORT CT PORT OBS 0.50 Chemotherapy Control 0.25 5YS (%) PORT noRT PORT noRT 0.00 0 20 40 60 80 100 120 DURATION OF SURVIVAL (MONTHS) N1 40% 56% 43% 31% N2 47% 34% 21% 17% Douillard J, et al. (ANITA), Lancet Oncology, 2006;7(9):719-27 Rosell, IASLC 2005 Possible benefit for PORT in N2 patients to be confirmed by a phase III trial don't forget to join LungART trial (all resected N2 nsclc) http://www.ifct.fr perspectives in adjuvant strategy for resected nsclc better convenience (oral ct?) non studied drugs (gemcit., pemetr., taxanes, …) combinations without cisplatine adjuvant immunotherapy (Mage A3) tailored therapies (ERCC1, BCRA1, RRM1, EGFR, p53, RAS mutations) targeted therapies (tki, mc ab, …) convenience • age • quality of life • administration effect of age on adjuvant cisplatin-based ct for completely resected nsclc (LACE) individual patient data from 4,584 patients 5 trials of cisplatin-based ct group age no. % young < 65 3,269 71 midcategory 65 to 69 901 20 elderly 70 414 9 survival & event-free survival ns Früh M, et al. J clin Oncol 2008;26:3573-81 quality-of-life outcomes for adjuvant ct (JBR.10) adjuvant cisplatin + vinorelbine vs. observation completely resected stages IB to II nsclc (n=482) QOL assessments: - 173 patients in observation arm - 186 in ct arm effects of adjuvant ct on QOL temporary return to baseline in most patients Beziak A, et al. J Clin Oncol 2008;26:5052-9 vinorelbine D1, D8 + cddp every 3 weeks optimises with respect of planned dose intensity Similar efficacy Improved Tolerance “The combination of VNR on day 1,8 plus CDDP every 3 weeks may be considered as a reference regimen” Gebbia et al, Lung Cancer 2008 better convenience ? oral ct? adjuvant immunotherapy ? immunotherapy MAGE A3 nsclc express MAGE-A3 antigen in 35% of cases MAGE-A3 expression has poor prognosis randomized phase II in Stage IB/II MAGE-A3+ (n=182) postop. MAGE-A3 (5 x q3w, then 8 x q3 mo.) vs. Placebo good tolerance and treatment compliance 27% relative improvement of DFI & DFS in the MAGE-A3 arm (ns) ongoing phase III (MAGRIT) Vansteenkiste, ASCO 2007 – Abs 7554 post-surgical adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells from tissue culture of tumor-draining lymph nodes in primary lung cancer N2 lung cancer no. of patients = 28 immunotherapy no. of courses = 313 4 x ct + immunotherapy / 2 mo. for 2 years fever/chill on the day of cell transfer # 80% 5-yr survival 53% CONCLUSION adoptive transfer is feasible and safe Kimura H, et al. Anticancer Res 2008;28:1229-38 biomarkers ? DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy patients with completely resected nsclc and ERCC1-negative tumors appear to benefit from adjuvant cisplatin-based ct, whereas patients with ERCC1-positive tumors do not Olaussen KA, et al. N Engl J Med 2006;355:983-91 prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer (JBR. 10) stage IB and II nsclc adjuvant cisplatin plus vinorelbine or observation p53 expression (IHC) predictive and prognostic p53 mutations (sequencing) ns RAS mutations (hybridization) ns p53 overexpression 52% obs. arm: p53-positive < p53-negative (P = .03) progn. ct arm: p53-positive > p53-negative (P = .02) predict. Tsao MS, et al. J Clin Oncol 2007;25:5240-7 targeted therapies ? ongoing studies bevacizumab cetuximab pazopanib ... Cancer Care Ontario and ASCO guideline adjuvant cisplatin-based ct - recommended in stages IIA, IIB, and IIIA - not currently recommended in stage IB disease - not recommended in stage IA adjuvant radiation therapy - appears detrimental to survival in stage IB and II - may possibly confer a modest benefit in stage IIIA Pisters KM, et al. J Clin Oncol 2007;25:5506-18 long-term results of the IALT ialt was positive after a median follow-up of 56 months, but the significant effect was no longer present after a median follow-up of 90 months significant difference between the results of overall survival before and after 5 years (p-value for interaction 0.006) possible late adjuvant ct-related over-mortality need for long-term follow-up of adjuvant lung cancer trials Le Chevalier T, et al. 2008 ASCO Annual Meeting overall survival Median months OBS. NVB + CDDP 43.8 65.8 1-year survival + 3.1% 80.4% 83.5% 2-year survival + 5.1% 62.8% 67.9% 5-year survival + 8.6% 42.6% 51.2% 7-year survival + 8.4% 36.8% 45.2% logrank p value = 0.013 ANITA take home messages • the adjuvant debate is not closed down • however adjuvant cisplatin-based ct is recommended for stages II and IIIA • adjuvant ct can be proposed to stage IB patients with resected T2 > 4 cms • the only evidence-based "new drug" doublet is cisplatin-vinorelbine •better convenience could be obtained with oral ct there is still no evidence for... • any other drug combination • the assimilation of ct for advanced disease to adjuvant ct for early stages • the role of PORT in resected N2 disease • the role of biomarkers • the role of immune or targeted therapies thank you ...