1. Optimal use of adjuvant chemotherapy for patients with stage I, II, or IIIA disease Francesco Grossi Oncologia Medica A Disease Management Team - Lung Cancer Istituto Nazionale per la Ricerca sul Cancro Genova Highlights in the management of NSCLC Roma, 14 Giugno 2008

2. 1995 meta-analysis Clinical trials post 1995 meta-analysis 2006 LACE meta-analysis 2007 meta-analysis Trials and meta-analysis with UFT Adjuvant chemotherapy in NSCLC: evidence from literature

3. 1995 Meta-Analysis Results 15% increase in the risk of death with alky. agents 13% reduction in the risk of death with P-based CT Absolute benefit for CT of 3% at 2 years and 5% at 5 years (HR:0.87) Non-small Cell Lung Cancer Collaborative Group, BMJ 1995

4. LIMITS OF THE 1995 META-ANALYSIS FOR ADJUVANT CHEMOTHERAPY Number of patients rather small (1,394 pts in the cisplatin-treated group) Patient characteristics often heterogeneous Difference in survival of borderline statistical significance

5. Post 1995 meta-analysis trials: results Study# Pts StageCT 5YS gain p US Interg.488 II-IIIPE/RT-6% 0.56 ALPI1209 Ib-IIIAMVP +1% 0.58 CALGB344 IbCT+2% 0.1 IALT1868 Ib-IIIAPV/PE+4% 0.03 NCIC482 Ib-IIPV+15% 0.02 ANITA840 Ib-IIIAPV+9% 0.01

6. LACE Meta-Analysis Pignon JP, ASCO 2006 OS by trial

7. UFT meta-analysis +5% Hamada C, JCO 2005

8. 2007 meta-analysis IPD of 8147 patients 15 RCTs with CDDP without UFT, 8 with UFT without CDDP and 7 with both CDDP and UFT Survival: CT benefit (HR=0.86, p<0.000001); 4% at 5 years (from 60% to 64%) Stewart LA, ASCO 2007

9. The benefit of adjuvant treatment in several other cancers in adults CancerStageReference5-years (%)10-years (%) Breast Early (Chemo) EBCTCG, Lancet 1992 3.26.3 Breast Early (Tamoxifen) EBCTCG, Lancet 1992 3.66.2 Ovarian Early (Platinum) Trimbos JB, JNCI 2003 8- Colorectal Dukes B,C (5-FU + LV) IMPACT, Lancet 1995 5- Lung Stage I-IIIAStewart, ASCO 2007 45 (8-yrs)

10. IALT: OS at 8 years Le Chevalier, ASCO 2008

11. IALT: DFS at 8 years Le Chevalier, ASCO 2008

12. Cause of death

13. Adjuvant NSCLC chemotherapy in Clinical Practice Lynch T et al. ‘‘Early Stage Lung Cancer - New Approaches to Evaluation and Treatment,’’ Cambridge, MA, October 1 - 2, 2004 - Clin Cancer Res 2005

14. Trial PNX RT Compliance TOX IALT 35 30 74 ++ NCIC 23 0 65 +++ ANITA 37 25 56 +++ BLT ? 14 64 +++ ALPI 25 43 69 +++ CALGB 10 0 84 + Post 1995 meta-analysis trials: toxicity and compliance

15. Now what? Should we use adjuvant chemotherapy in all patients with resected NSCLC?

16. Post-surgical treatment Clinical patient selection Biological patient selection

17. Post-surgical treatment Clinical patient selection Biological patient selection

18. Patient selection criteria Stage Good performance status Rapid postoperative recovery Few comorbid illnesses Age < 70 years

19. Patient selection criteria Stage Good performance status Rapid postoperative recovery Few comorbid illnesses Age < 70 years

20. IAIBIIIIIA ALPI IALT NCI-C CALGB ANITA CT effect and stage Positive Negative Not tested

21. Cancer Care Ontario and ASCO guideline Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stages IIA, IIB, and IIIA disease Although there has been a statistically significant overall survival benefit seen in several randomized clinical trials (RCTs) enrolling a range of people with completely resected NSCLC, results of subset analyses for patient populations with stage IB disease were not significant, and adjuvant chemotherapy in stage IB disease is not currently recommended for routine use Pisters KMW, JCO 2007

22. ESMO Clinical Recommendations D’Addario G, Ann Oncol 2008

23. CALGB 9633: OS in patients with tumor ≥ 4 cm

25. Japanese clinical practice guideline Adjuvant chemotherapy with UFT for patients with stage IB and some IA (tumor size: 2 cm or more) In Japan, about 70% of patients with stage IB disease receive UFT adjuvant treatment in practice Tsuboi M, 1° European Lung Cancer Conference – Geneva 2008, abstract 152 O

26. Efficacy of adjuvant CT in stage IB UFT studies (and meta-analysis) positive CALGB study positive for PFS CALGB subgroup analysis shows survival advantage for T> 4 cm (JBR10 too) Although not statistically significant LACE meta- analysis shows HR of 0.92 in favour of CT

27. Number of patients needed to treat to detect an OS benefit at 5 years Pisters KMW, JCO 2007 Abbreviations: OS, overall survival; HR, hazard ratio; ARR, absolute risk reduction; NNT, number needed to treat to prevent one death;

28. Estimated absolute risk and benefit for 100 patients with NSCLC treated with surgery and adjuvant CT Pisters KMW, JCO 2007

29. Patient selection criteria Stage Good performance status Rapid postoperative recovery Few comorbid illnesses Age < 70 years

30. Role of PS in the post-surgery treatment decision KPS of <70 is an important prognostic factors in Stage I NSCLC. Therefore, KPS assessment is recommended when analyzing the prognostic effects of tumor or treatment-related factors on OS. Firat S, Int J Radiat Oncol Biol Phys 2002 p=0.001

31. Patient selection criteria Stage Good performance status Rapid postoperative recovery Few comorbid illnesses Age < 70 years

32. Patient selection criteria Stage Good performance status Rapid postoperative recovery Few comorbid illnesses Age < 70 years

33. Differential prognostic impact of comorbidity The highest levels of comorbidity (moderate and severe) were found among the lung cancer patients (38.9%), whereas the least amount was among prostate (13.3%) and breast (18.3%) cancer patients. Comorbidities have little impact on the survival of patients with aggressive tumors Read WL, JCO 2004

34. Impact of comorbidity on survival after surgical resection Comorbidity has a significant impact on survival after surgical resection of patients with stage I NSCLC These data may help to explain the lower than expected survival results for patients after surgical resection for stage I NSCLC Battafarano RJ, JTCS 2002 Survival at 3 years for each level of comorbidity (stage I NSCLC): none, 85.6% mild, 74.8% moderate, 68.8% severe, 70.0% (p <.002)

35. Patient selection criteria Stage Good performance status Rapid postoperative recovery Few comorbid illnesses Age < 70 years

36. Post-surgical treatment Clinical patient selection Biological patient selection

37. Hypothesis A genomic strategies refines prognosis in early stage non-small cell lung carcinoma A genomic strategy to refine prognosis in early stage non-small cell lung carcinoma (NSCLC). Potti A, NEJM 2006

38. Methods 89 Early stage NSCLC 44 adenocarcinoma 45 squamous cell carcinoma Age 66 (range 32-83) Gender39 female, 52 male Follow-up6 years ~ 50% had disease recurrence within 2.5 years and 50% had disease-free survival of > 5 years Gene expression using Affymetrix U133-2.0 plus Potti A, NEJM 2006

39. Genomic predictor of recurrence Early stage NSCLC (n= 89) Accuracy ~ 90% Metagene (mgene) 79 Alive Disease recurrence/death High risk Low risk Potti A, NEJM 2006

40. NSCLC – Recurrence predictor Genomic vs Clinical (n= 89) Lung Metagene Predictor (LMP) Clinical Model Accuracy ~ 90%Accuracy ~ 60% Potti A, NEJM 2006

41. Estimates based on predictions from the lung metagene model and clinical model NSCLC Survival LMP NSCLC Survival – Clinical variables NSCLC Survival by T alone NSCLC Survival by stage of disease Potti A, NEJM 2006

42. Trial Design: Clinical Stage I NSCLC Low-Risk; N=150 High-risk; N=300 Adjuvant Chemotherapy Observation 80% 4-year Total population=500 (450+10% poor RNA) Observation Randomize

43. Signature is prognostic in observation but not in CT treated patients Tsao M, ASCO 2008

44. 15-gene signature is prognostic in stage I and II observation patients Tsao M, ASCO 2008

45. CT benefits JBR.10 high risk but not low risk patients Tsao M, ASCO 2008

46. CALGB 30506 Stage IA NSCLC patients Surgery Gene Expression Analysis Lung Metagene Predictor ObservationRandomize ObservationChemotherapy Six gene classifier Proteomics ERCC1 RRM1 EGFR FISH or IHC EGFR TKI FISH+ &/or IHC+ Prognostic tests: Predictive tests: Low High

47. ERCC1 in Early Stage NSCLC & Adjuvant CT Olaussen KA, NEJM 2006 N= 761; ERCC1 negative= 56%, benefit of adjuvant chemotherapy only in ERCC1 negative tumors (HR for death 0.65, CI95% 0.50-0.86). In surgery alone ERCC1 positive tumors survived longer

48. ERCC1 Positive ERCC1 Negative HR=1.14 [0.84-1.55], p = 0.40 ERCC1: IALT Bio, n= 761 pts HR=0.65 [.50-.86], p = 0.002

49. Proposed Adjuvant Trial: NSCLC Stage II, IIIA ERCC 1 Expression Docetaxel + Vinorelbine Cisplatin + Docetaxel RRM1 Expression Cisplatin + Gemcitabine Simon, Bepler 2007 High Low HighLow

50. C onclusions For any patient there is a balance between side effects and clinical benefit It is important to discuss with patients the reality of treatment and the associated risks and benefits Benefits Risks

51. Thank you for your attention! francesco.grossi@istge.it