TURKISH THORACİC SOCIETY 9 th ANNUAL CONGRESS

1. TURKISH THORACİC SOCIETY 9 th ANNUAL CONGRESS Neoadjuvant Therapy in Early Stage Lung Cancer Prof. Metin GORGUNER gorguner@atauni.edu.tr 19 – 23 April 2006, Sungate Port Royal, Kemer/Antalya/TÜRKİYE

2. In memory of our dear colleague…

3. Lung Cancer: Still a major problem ! • Every year approx.; 800.000 – 1.000.000 death • Of all cancer deaths; Man: 31%, Woman: 25% • Median survival; Approximately 8 month • Total 5-year survival ; % 8 % 15

4. Survival According to the Stage * Extrathoracic micrometastatic involvement with no determined by available diagnostic methods is present approx. 60% of patients. Silvestri GA et al. Chest 2003; 123: 147-56s.

5. Goldie and Coldman Hypothesis • Drug resistance in tumors exposed to cytotoxic agents • Drug-resistant mutations arise spontaneously at a measurable frequency • The larger the tumor burden, the more likely a mutation will occur • Early, highest dose use of all agents is most likely to prevent multiply resistant clones and, thus, to effect a cure Goldie JH, Coldman AJ. Cancer Treat Rep. 1983; 67:923-31.

6. Induction / Neoadjuvant Therapy “The use of systemic therapy before definitive local regional therapy”

7. Induction chemotherapy is based on the Goldie and Coldman Hypothesis: • Less the tumor size • More the tumoral response • Fewer are chemo-resistant cells Souquet PJ, Geriniere L. Lung Cancer2001; 34: S155-S158.

8. Theoretical Advantages of Neoadjuvant Therapy • Early control of micrometastasis • Reduction in size of primary tumor, thereby improving resectability rates • Can be given at full dosage • Usually better tolerated than adjuvant chemotherapy Ukena U. Lung Cancer2001; 33 (Suppl. 1): S25-S28. Crino L. Lung Cancer 2002; 38: S31-S32.

9. Disadvantages of Neoadjuvant Therapy Increased morbidity and mortality Ineffective induction regimen Progression of resectable disease

10. Neoadjuvant Therapy in Early Stage NSCLC “The role of neoadjuvant chemotherapy, with or without radiotherapy, in stage-I, -II, and minimal stage-III disease is controversial, Not routinely recommended, For only clinical study ” Betticher DC, Rosell R. Lung Cancer2004; 46 (Suppl. 2): S23-S32.

11. Superior Sulcus Tumours “Superior sulcus tumours must be regarded as a separate category” ASCO Guideline 2004

12. Neoadjuvant Therapy in NSCLC • Which has long been investigated for stage III NSCLC • The first studies were small (< 600 pts), mostly phase II, and frequently lacked surgical staging • Was also recently explored in stage I/II

13. In a Pilot Randomized British Study Phase III Study Design RANDOMIZE ELIGIBLE MVP X 3 cycles SURGERY SURGERY • Clinical stage IB, II, IIIA (resectable 1 pt) • Mediastinoscopy not routinely performed de Boer RH, et al. Br J Cancer1999; 79: 1514-18.

14. In a Pilot Randomized British StudyIn Conclusion • Objective tumour response was 55% • No severe toxicities • No significant deterioration in QoL • Feasible in early stage NSCLC BUT Only 22 patients ! de Boer RH, et al. Br J Cancer1999; 79: 1514-18.

15. BLOT (Bimodality Lung Oncology Team) Trial Phase II Study Design Paclitaxel/Carboplatin x 2 Surgery Paclitaxel/Carboplatin x 3 Follow-up • Mediastinoscopy routinely Pisters KMW et al. J Thorac Cardiovasc Surg2000; 119: 429-39.

16. Patients Characteristics

17. Induction Chemotherapy Response

18. BLOT Trial • 1 induction chemotherapy death • 88 patients underwent surgery (94%) • 86% completely resected • S-Stage; 42p (48%) less, 32p (36%) more • 2 postoperative deaths Pisters KMW et al. J Thorac Cardiovasc Surg2000; 119: 429-39.

19. Overall Survival Curve

20. Phase II BLOT Trial • n=133, c-stage T2N0, T1-2,N1, T3,N0-1 • 94% planned induction therapy delivered compared to 45% postoperative • 5-year overall survival 45% • Basis for SWOG 9900 trial Pisters KM et al. Proc ASCO2003; 22: 633.

21. SWOG 9900 Trial:Preliminary ResultsObjectives • Determine if 3 cycles of preoperative paclitaxel/carboplatin chemotherapy improves survival compared to surgery alone in clinical stage IB, II and IIIA NSCLC • Evaluate response rate and toxicities associated with preoperative chemotherapy • Compare operative mortality and toxicities Pisters K, et al. ASCO2005, Abstract No. 7012

22. SWOG 9900 Trial Phase III Study Design RANDOMIZE ELIGIBLE Paclitaxel/Carboplatin X 3 cycles SURGERY SURGERY • Clinical stage T2N0, T1-2N1, T3N0-1 • Mediastinoscopy if LN > 1 cm on CT

23. SWOG 9900 Trial Eligibility • Clinical Stage T2N0, T1-2N1, T3N0-1 • Performance Status 0 – 1 • Predicted post-resection FEV1 ≥ 1.0 L • Appropriate candidate for chemotherapy Pisters K, et al. ASCO2005, Abstract No. 7012

24. SWOG 9900 Trial Accrual • Initial plan:………. 600 patients • Start:………………. October 1999 • Closed:……………. July 2004 • Final accrual:……. 354 pts; 19 ineligible* * Stage, histology, nonmeasurable disesase, staging Pisters K, et al. ASCO2005, Abstract No. 7012

25. Characteristics of 355 Patients

26. Induction Chemotherapy Compliance n=168 • Completed 3 Cycles 77% • Less than 3 Cycles • Adverse effects 8% • Refusal 4% • Progression 3% • Death 2% • Other 5% • N/A 1% Pisters K, et al. ASCO2005, Abstract No. 7012

27. Induction Chemotherapy Response n=168 Complete Response ……….. 3% Partial Response …………… 38% Stable Disease ……………… 43% Progression ………………….. 7% Assesment Inadequate ….. 9% Pisters K, et al. ASCO2005, Abstract No. 7012

28. Progression-Free Survival Curve

29. Overall Survival Curve

30. FrenchThoracic Cooperative Group Trial Objective and Eligibility • Evaluate whether PCT could improve survival • Clinical Stage I (except for T1N0), II, IIIA • 75 years old or less • WHO Performance Status 2 or less Depierre A, et al. J Clin Oncol 2002; 20: 247-53.

31. FrenchThoracic Cooperative GroupTrialPhase III Study Design RANDOMIZE ELIGIBLE MIC X2 cycles MIC* X2 cycles SURGERY * Responding pts SURGERY • Clinical stage IB, II, IIIA • Mediastinoscopy not routinely performed • pT3 and pN2 received radiotherapy

32. Characteristics of 355 Patients

33. French Thoracic Cooperative Group TrialResults Median survival 37 vs. 26 mo, (P = .15) Disease free survival 27 vs. 13 mo (P = .033) OR to MIC: 64% 2 x preop toxic deaths (hemoptysis, sepsis) Postop mortality: 6.7% (CT) vs. 4.5% (S) 3-year survival rates: 52% (CT) vs. 41% (S) Depierre A, et al. J Clin Oncol 2002; 20: 247-53.

34. Overall Survival Curve

35. Survival by Stage

36. Probabilities of Relapse

37. 5-Year Results of Study Arm 1yr % 3yr % 5yr % PCT 76.5 52 41.3 Surgery 73.3 41.5 31.6 Difference 3.2 10.5 9.7 P 0,48 0,04 0,06 Depierre A, et al. World Conference of Lung Cancer, 2003

38. Comparison – Overall Survival SWOG 9900 FRENCH BLOT Preop Control Preop Control Median OS 4347 40 37 26 (months) 1 year (%)8482 79 77 73 2 year (%)6869 63 59 52

39. 11th World Conference on Lung CancerJuly 3 – 6, 2005, Barcelona, Spain • Bepler G, et al. Neoadjuvant gemcitabine and pemetrexed (NeoGP) in resectableNSCLC. (phase II, 15 pts, IB-IIIA, selected IIIB) • Socinski M, et al. Induction chemotherapy with gemcitabine-containing regimens in stage I-IINSCLC: initial results of the GINEST Project. (phase II, 83 pts, 1 year Survival 85%) • Sorenson J, et al. Scandinavian randomised trial of neoadjuvant chemotherapy in stages IB-IIIA (N2 -). (phase III, 44 pts, MS and 5 year Survival: 34.4 mo and 36% in PCT, 22.5 mo and 24% in Surgery - NS) Lung Cancer 2005; 49 (suppl 2): s39, s40 and s41.

40. Ongoing Phase III Trials in Early Stage

41. IFCT TrialStudy Design Depierre A, et al.

42. NATCH (NeoAdj. TaxCarbo Hope) TrialStudy Design Rosell R, et al.

43. NATCH TrialGenetic Studies • Genetic markers in serum DNA at baseline, 6 months and 1 year • To prognosis and/or chemoresistance Rosell R, et al.

44. What about Neoadjuvant Therapy in SCLC ? “The Study of neoadjuvant chemotherapy, in Small Cell Lung Carcinoma is limited”

45. Wada and colleagues;Surgical TreatmentofSCLC: Advantage of Preoperative Chemotherapy • 46 pts who underwent surgery • 17 pts (37%) neoadjuvant therapy group • 23 pts (50.5%) adjuvant therapy group • The 5-year survival rate of patients with c-Stage I or II disease in the neoadjuvant therapy group was as high as 80.0% (but with no statistical significance, P = 0.10) • Failure to employ preoperative CTx was the strongest poor prognostic factor (P = 0.01) Wada H, et al. Lung Cancer 1995; 13: 45-56.

46. Nakamura and colleagues;Outcome of Surgery for SCLC – Responseto Induction ChemotherapyPredictsSurvival • 69 pts who underwent complete resection • 32 pts (46%) received induction CT • Overall Response Rate to CTx was 71.9% • Downstaging after induction chemotherapy conferred a survival benefit Nakamura H, et al. Thorac Cardiovasc Surg 2004; 52: 206-10.

47. Conclusion (1) • Neoadjuvant therapy seems promising • Feasibility and safety in selected stage I and II disease was demonstrated • Good patient tolerance and compliance to the chosen chemotherapy • A trend for a survival benefit particularly in early stages I and II • A low rate of primary progression during induction treatment (between 3 and 5%)

48. Conclusion (2) • No study has yet compared the utility of adjuvant versus neoadjuvant approach • The role of chemotherapy in stage IA ? • The comparison of various CT regimes ? • Molecularly targeted approaches with neoadjuvant therapy in early stage ? • More work is needed to evaluate and optimize this approach

49. Most Effective and Cheapest Therapy in Lung Cancer

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