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adjuvant therapy in non-small cell lung cancer

adjuvant therapy in non-small cell lung cancer. the Lebanese Society of Medical Oncology commitment to cure cancer november 13-15, 2008 Beirut. Dominique H. Grunenwald, MD Professor in Thoracic and Cardiovascular Surgery Hopital Tenon, University of Paris. France.

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adjuvant therapy in non-small cell lung cancer

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  1. adjuvant therapy in non-small cell lung cancer the Lebanese Society of Medical Oncology commitment to cure cancer november 13-15, 2008 Beirut Dominique H. Grunenwald, MD Professor in Thoracic and Cardiovascular Surgery Hopital Tenon, University of Paris. France

  2. 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 metastatic spreading is not the privilege of locally advanced disease in nsclc

  3. 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

  4. 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 non-small cell cancer

  5. adjuvant ct in nsclc NSCLC Collaborative Group BMJ 311:899,1995

  6. Surgery vs Surgery + CT (cisplatin-based trials) Surgery+CT Surgery 1.0 0.9 Events Total S U R V I V A L Surgery+CT 298 706 0.8 Surgery 688 316 0.7 0.6  5% 0.5 0.4 0.3 0.2 0.1 Patients at risk 0.0 0 12 24 36 48 60 Months 706 590 462 371 295 206 688 548 433 353 258 177

  7. phase III trials management of early stage nsclc

  8. remember year 1998 ! paradigm explodes PORT meta-analysis published in the Lancet post-operative radiotherapy is detrimental … in early stages questionable in stage IIIA

  9. remember year 2002 ! Adjuvant Lung Project Italy (ALPI) presented at ASCO "negative" "death of adjuvant therapy!!!"

  10. Dr. Scagliotti is disappointed…

  11. results of ialt and anita are about to come ... others are smiling ...

  12. 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"

  13. IALT cisplatin combined with a "new" drug in 30% of casesJapanese study adjuvant ct without platinum salts

  14. IALT outcomes * 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

  15. Overall survival 100 90 80 70 UFT Control 60 Probability of survival (%) 50 40 30 20 H.R.=0.709 [0.515-0.978] 10 0 0 1 2 3 4 5 6 7 8 Years after resection No. at risk Control 488 481 469445 423 378 219 96 UFT 491 482 471442 416 368 221 105

  16. 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%) UFT Control UFT Control T1N0 T2N0

  17. 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 Together enrolled more than 3.000 patients

  18. initial toxicity affects the results

  19. Events/Total CT 278/548 Control 288/540 HR=0.96 (0.81 - 1.13) p=0.585 ALPI - Overall Survival PROBABILITY YEARS Scagliotti GV et al. JNCI 2003; 95 (19) : 1453-61

  20. ialt overall survival P<0.03 100 80 60 40 20 0 adjuvant ct survival (%) control 0 1 2 3 4 5 years • 775 624 450 308 181 • 774 602 432 286 164 N Engl J med 2004;350:351-60

  21. 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"

  22. JBR.10 stage IB & IIcisplatin combined with a "new" drug CALGB 9633 stage IB"new" combination

  23. Intergroup JBR.10National Cancer Institute of CanadaSWOG JBR10; ECOG JBR10; CALGB 9795 phase III randomised trial of adjuvant VINORELBINE and CISPLATIN in completely resected stage IB and II nsclc Vin/Cis Observation Winton T, et al., ASCO 2004

  24. summary JBR.10 ASCO 04 • 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

  25. 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 ----- Chemotherapy ----- Observation ---- chemotherapy ---- observation

  26. Review by ASCO* adjuvant chemotherapy trials from ASCO 2003-2004 IALT CALGB JBR 10 n 1867 344 482 stages I, II and III IB IB and II adj. ct different CDDP-based CT ± RT PCT+CBDCAwithout RT NVB + CDDPwithout RT 5-yr rfs 39.4% vs 34.3% 61% vs 50% (4 yrs f.-up) 61% vs 48% 5-yr surv. 44.5% vs 40.4% 71% vs 59% (4 yrs f.-up) 69% vs 54% *from review by K. Pisters, ASCO 2004

  27. 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"

  28. 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 NavelbineInternational TrialistsAssociation

  29. type of surgery, pTNM, histology OBS NVB+CDDP Type of surgery n= 433 n= 407 Pneumonectomy 35.8% 38.1% Lobectomy 58.4% 57.2% Stage n= 433 n= 407 I (pT2 N0) 34.2% 35.4% II 30.5% 29.2% IIIA 35.3% 35.4% Histology n= 433 n= 407 Squamous 58.9% 60.0% Non Squamous 41.1% 40.0% PORT 33.3% 21.6% Chemotherapy at relapse 48% 39.2% ANITA

  30. overall survival 1.00 0.75 0.50 Survival Distribution Function Obs 0.25 NVB + CDDP 0 0 20 40 60 80 100 120 months ANITA

  31. survival: Cox univariate analysis covariatesunivariate P value HR [95% CI] age >55 years 0.04 1 < 55 years 0.81 [0.67 - 0.99] WHO ps 0 0.012 1 1-2 1.27 [1.05 - 1.52] surg. pneumonectomy 0.001 1 other 0.73 [0.60 - 0.88] radiotherapy no 0.003 1 yes 1.34 [1.10 - 1.63] stage IIIA < 0.001 1 IB-II 0.54 [0.45 - 0.65] N status N+ < 0.001 1 N0 0.53 [0.44 - 0.65] histology adk 0.733 1 other 0.97 [0.80 - 1.17] ANITA

  32. survival: Cox univariate analysis covariatesunivariate P value HR [95% CI] age >55 years 0.04 1 < 55 years 0.81 [0.67 - 0.99] WHO ps 0 0.012 1 1-2 1.27 [1.05 - 1.52] surg. pneumonectomy 0.001 1 other 0.73 [0.60 - 0.88] radiotherapy no 0.003 1 yes 1.34 [1.10 - 1.63] stage IIIA < 0.001 1 IB-II 0.54 [0.45 - 0.65] N status N+ < 0.001 1 N0 0.53 [0.44 - 0.65] histology adk 0.733 1 other 0.97 [0.80 - 1.17] ANITA

  33. 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

  34. adjuvant ct as a standard ? • issues : • which drug combination ? • which patients (stages) ? • role of PostOperativeRT • perspectives

  35. 1,0 0,8 0,6 0,4 0,2 2 4 6 8 3 1 7 5 Lung Adjuvant Cisplatin Evaluation (LACE) Probability individual patient data from 5 trials (4,584 patients) postoperative cisplatin-based ct significantly improves survival in patients with nsclc HR translates into an absolute benefit of 5.4% at 5 years Time (years) 0 0 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 Pignon JP, et al. J Clin Oncol 2008;26:3552-9

  36. 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

  37. Study 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% 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

  38. which patients (stages) ? "cisplatin-based ct is certainly effective for stages II and III" Pignon JP, et al. J Clin Oncol 2006;24:18S 7008

  39. adjuvant paclitaxel plus carboplatin vs. observation in stage IB non-small-cell lung cancer (CALGB 9633) 344 patients randomly assignedmedian follow-up 74 monthspredominant 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

  40. Goldstraw P, et al. J Thorac Oncol 2007;2:706-14

  41. Goldstraw P, et al. J Thorac Oncol 2007;2:706-14

  42. adjuvant Mountain CF Goldstraw P, et al. J Thorac Oncol 2007;2:706-14

  43. Vancouver 2002

  44. impact of postoperative radiation therapy (ANITA)adjuvant cisplatin and vinorelbine ct vs. observation completely resected nsclc stages IB to IIIAPORT recommended for pN+ disease unplanned subgroup analysis observation chemotherapyPORT 33% 22%impact on surv.overall deleterious deleterious pN1 improved detrimentalpN2 improved improved Douillard JY, et al. Int J Rad Oncol Biol Phys 2008

  45. Role of PORT: ANITA subset analysis 5YS (%) Chemotherapy Control PORT noRT PORT noRT N1 40% 56% 43% 31% N2 47% 34% 21% 17% PORT 232 pts N0 13% N1 37% N2 50% Rosell, IASLC 2005 Douillard J, et al. (ANITA), Lancet Oncology, 2006;7(9):719-27 Possible benefit for PORT in N2 patients to be confirmed by a phase III trial

  46. don't forget to join LungART trial(all resected N2 nsclc)http://www.ifct.fr

  47. 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, …)

  48. convenience age quality of life administration

  49. 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 ctgroup age no. % young < 65 3,269 71 midcategory 65 to 69 901 20elderly  70 414 9 survival & event-free survival ns Früh M, et al. J clin Oncol 2008;26:3573-81

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