1. Lung Cancer R. Zenhäusern

2. Lung cancer: Epidemiology n Most common cancer in the world –2./ 3. most cancer in men / women 1.2 million new cases / year 1.1 million deaths / year Incidence –Men 1940-80: 10  70/100000/J –Women 1965-: 5  30/100000/J

3. Lung cancer: Epidemiology n 13% of cancers, n 18% of cancer deaths Switzerland 3500 new cases / year n 80% die during the first year n Prognosis remains dismal: –five-year survival 10-14%

6. Non-Small-Cell Lung Cancer n 75 % of all lung cancers n Majority of patients present with stage III and IV

7. NSCLC: Histology n Squamos-cell carcinoma20-25% n Adenocarcinoma40% n Large cell carcinoma10%

9. NSCLC: Staging n Staging Locoregional Disease: –Chest x-ray and chest CT scan (including liver and adrenal glands) –No evidence of distant metastatic disease: FDG-PET ist recommended –Biopsy of mediastinal LN ist recommended: CT-scan > 1.0 cm or positive on PET neg. PET scanning does not preclude biopsy ASCO Guideline 2004;22:330

10. NSCLC: Staging n Staging Distant Metastatic Disease: –No evidence of distant metastatic disease on CT scan of the chest: PET ist recommended –A bone scan is optional –Resectable primary lung lesion and bone lesion on PET/bone scan: MRI/CT and biopsy –Brain: CT or MRI if symptoms, patients with stage III considered for aggressive local Th. –Isolated adrenal mass: biopsy –Isolated liver mass: biopsy ASCO Guideline 2004;22:330

11. Staging of Lung Cancer

12. Local NSCLC: Stage I, II n Standard of care = Surgery n Relapse rate35%-50% in St. I n Relapse rate40%-60% in St. II n Adjuvant radiotherapy ? n Adjuvant chemotherapy ?

13. Adjuvant Radiotherapy n Port meta-analysis Trialist Group. Lancet 1998;352:257 –9 randomised trials of postoperative RT versus surgery (2128 patients) –21% relative increase in the risk of death with RT –Reduction of OS from 55% to 48% (at 2 years) –Adverse effect was greatest for Stage I,II –St.III (N2): no clear evidence of an adverse effect

14. Adjuvant Radiotherapy n Conclusion –Postoperative RT should not be used outside of a clinical trial in Stage I, II lung cancer, unless surgical margins are positive and repeated resection is not feasible.

15. Adjuvant Chemotherapy n Undetectable microscopic metastasis at diagnosis n Individual trials have not shown a significant benefit n Meta-analysis BMJ 1995;311:899: –Alkylating agents had an adverse effect –Cisplatin-based therapy: 13% reduction in risk of death (not significant)

16. Postoperative Chemo- and Radiotherapy n ECOG-Trial: 488 patients with stage II, IIIA n RT alone (50.4 Gy) versus RT + 4x Cisplatin/Etoposid n Median survival39 vs 38 months (ns) n TRM 1.2 vs 1.6% n Local recurrence13 vs 12% Keller et al. NEJM 2000;343:1217

17. Cisplatin-based Adjuvant Chemotherapy (International Adjuvant Lung Cancer Trial Collaboratvie Group) n Randomised trial of 3-4 cycles of cisplatin-based CT vs observation in patients with St. II, III LC CTno CT 5-Y. DFS39.4%34.3% p <0.03 5-y. OS44.5%40.4% p <0.03 IALT. NEJM 2004;350:351

18. The International Adjuvant Lung Cancer Trial Collaborative Group, N Engl J Med 2004;350:351- 360 Overall Survival (Panel A) and Disease-free Survival (Panel B)

19. Adjuvant Chemotherapy n Conclusion: –One should consider the use of adjuvant platinum-based chemotherapy in patients with stage I,II or IIA NSCLC

20. Locally advanced NSCLC n Thoracic irradiation is the mainstay of treatment for inoperable stage III disease n Its curative potential is extremely poor 5-year survival rates 3-5%

21. Locally advanced NSCLC n A meta-analysis of 22 randomised studies showed a beneficial effect of CT added to RT –10% reduction in risk of death per year –Small absolute survival benefit: 4% after 2 years 2% after 5 years NSCLC Collaborative Group. BMJ 1995;311:899

22. Combined chemotherapy and radiation n Sequential strategies –Primary CTC C.. R R R R R –Primary and adjuvant CTC C.. R R R R R C C n Concomitant Strategies –Daily CTC C C C C C C C C C R R R R R –Intermittent CTC.. C.. R R R R R n Combined Strategies –Primary and concomitant CT C... C C.. R R R R R

23. Therapeutic Strategies n Sequential CT–RT + CT in standard dose  of micrometastasis  volume of primary tumor - longer treatment time delay of RT n Concomittant C-RT + Improvement of local control (radiosensitisation) - greater toxic effects Reduced dose of CT

24. Sequential chemo- and radiotherapy n Studies performed in the 1980s did not show an advantage n Three large phase III trials gave pos. Results –Dillman etal. NEJM 1990;329:940 –Sause et al. JNCI 1995;87:198 –Le Chevalier et al. JNCI 1992;8:58

25. Sequential chemo- and radiotherapy Dillman etal. NEJM 1990;329:940 (CALGB 8433) 2 cycles of Cis / Vbl  RT (60 Gy/6 w) R RT (60 Gy/6 w)

26. Results: Sequential CT and RT Med. S2y-S3y-S7y-S (%) CT-RT14 mo262317 RT10 mo13116 Dillman etal. NEJM 1990;329:940 Dillman et al. JNCI 1996;88:1210

27. Results: Sequential CT and RT n US intergroup trial Sause W. JNCI 1995;87:198 n=458 Sause W. Chest 2000;117:351 MS (mo)5y-S (%) RT11.45 2x Cis/Vbl13.28 hyper RT126 n French trial Le Chevalier JNCI 1992;8:58 N=353 3x CT  RT vs RT3y-S12% vs 4%

28. Concomitant Chemo- and Radiotherapy n Simultaneous CT / RT is beneficial in: –Head and neck cancer –Anal cancer –Cervical cancer n Cisplatin is effective as a radiosensitiser –6-8 mg/m 2 daily –30 mg/m 2 weekly –70 mg/m 2 3-weekly

29. Concomitant CT-RT: EORTC Trial n Schaake-Koning C. NEJM 1992;326:524 331 patients randomised to one of three regimens: –RT alone: 30 Gy in 10 fractions, 3-week rest period, 25 Gy in 10 fractions –RT + daily cisplatin (6-8 mg/m 2 ) –RT + weekly cisplatin (30 mg/m 2 )

30. EORTC Trial: Results 2-year Survival n RT alone:13% n RT + daily cisplatin:26% n RT + weekly cisplatin:18% Schaake-Koning C. NEJM 1992;326:524

32. Sequential versus concomitant CT-RT n Japanese study: Furuse K et al. JCO 1999;17:2692 n= 320 MS (mo)5y-DFS - 2 cycles MVC  RT 56 Gy13.319% -MCV/RT-10 days rest-MVC/RT16.527% n RTOG 9410: Curran WJ. ASCO 2003;22:a621 n=611 2xCV  RT(60Gy) vs CV/RTOS:4 vs 25% p= 0.046

33. Neoadjuvant Therapy n Pancoast`s tumor, vertebral invasion –Combined neoadjuvant CT-RT should be considered n Tumors with ipsilateral mediastinal spread (N2) –Poor survival with surgery alone –2 small randomised trials showed a benefit of neoadjuvant combined CT-RT –Roth et al. JNCI 1994;86:673 –Phase II trials report good results of neoadjuvant CT§

34. SAKK Studies n SAKK 16/00 –Preoperative CRT vs CT in NSCLC stage IIIA –CT: 3 cycles docetaxel and cisplatin (D1,22,43) –RT: 3 weeks of RT (44 Gy in 22 fractions) n SAKK 16/01 –Preoperative CRT in NSCLC pts with operable stage IIIB disease –The same regimen as 16/00

35. Metastasis 40-50% at diagnosis 70% during follow-up

36. Chremotherapy for NSCLC n Old agents –Cisplatin –Carboplatin –Etoposid –Vinblastin n New agents –Docetaxel –Paclitaxel –Vinorelbine –Gemcitabine –Irinotecan

37. NSCLC: chemotherapy combinations n Regimes –Cisplatin+Paclitaxel –Cisplatin+Gemcitabine –Cisplatin+Docetaxel –Carboplatin+paclitaxel n Results (n=1155 pts.) n Response rate 19% n Median survival 8 months n 1-year survival33% n 2-year survival11% Schiller et al. NEJM 2002;346:92

38. New agents: Induction CT followed by concomitant CT-RT Induction (2 cycles) Concomitant (2 cycles) Vinorelbine 25 mg/m 2 D1,8,(15) 15 mg/m 2 D1,8 Cisplatin80 mg/m 2 D1 80 mg/m 2 D1 Paclitaxel225 mg/m 2 D1135 mg/m 2 D1 Cisplatin80 mg/m 2 D180 mg/m 2 D1 Gemcitabine1250 mg/m 2 D1,8600 mg/m 2 D1,8 Cisplatin80 mg/m 2 D180 mg/m 2 D1 CALGB study 9431: Vokes et al. JCO 2002;20:4191

39. New agents: Induction CT followed by concomitant CT-RT RR (CT) RR (CT-RT) 1yS2yS3yS (%) V+C 44% 73%654023 P+C 33% 67%622919 G+C 40% 74%683728 CALGB study 9431: Vokes et al. JCO 2002;20:4191

40. Conclusion: Combined-Modality Therapy for Stage III Disease n Adding CT to radiation therapy improves survival and alters the course of this disease n Phase III studies suggest improvement in both local control and survival with concomitant CT-RT n Combined CT-RT should be the standard of care of patients with good PS and minimal weight loss n The absolute gain from combined CT-RT is still modest n The role of surgery following induction CT-RT is for patients with unresectable Cancer is being explored

41. Small-cell Lung Cancer (SCLC) n 15-20% of all lung cancer n Incidence:15/100000/year n Men : women = 5 : 1

42. SCLC n Rapid local and metastatic spread n Mediastinal lymph node metastasis in most cases n Median Survival in untreated patients 2-3 months n Superior vena caval obstruction and paraneoplastic syndromes (SIADH, Cushing) n Association with smoking

43. SCLC Staging n Limited Disease Confined to: –One hemithorax –Mediastinum –Ipislateral hilar and supraclavicular nodes n Extensive Disease –Malignant pleura and pericard effusion –Contralateral hilar and supraclavicular nodes

44. SCLC Therapy n No surgery; SCLC is a systemic disease n Chemotherapy is the standard of care –Cisplatin+Etoposid n Limited stage SCLC: Bimodality therapy with chemotherapy and radiotherapy

45. SCLC Therapy n The addition of thoracic RT significantly improves survival in patients with LS-SCLC –Meta-analysis. Pignon et al. NEJM 1992;327:1618 –14% reduction in the mortality rate –5.4% benefit in terms of OS at 3 years n Early use of RT with CT improves cure rates

46. SCLC Therapy n The actuarial risk of CNS metastasis developing 2 years after CR of SCLC is 35%-60% n Prophylactic cranial Irradiation is recommended for pts. With LS-SCLC in CR –Meta-analysis: Auperin et al. NEJM;1999:341:475 –PCI: 5.4% greater absolute survival at 3 years

47. SCLC Results n Limited Disease: –Remission rate80-90% –CR50-60% –Median Survival18-20 months –2-year Survival40% –5-year Survival15-25%

48. SCLC Results n Extensive Disease: –Remission rate70-80% –CR20-30% –Median Survival8-10 months –2-year Survival< 10%