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Lung Cancer. R. Zenhäusern. Lung cancer: Epidemiology. 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. Lung cancer: Epidemiology.

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Lung Cancer


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    1. Lung Cancer R. Zenhäusern

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

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

    5. NSCLC: Histology • Squamos-cell carcinoma 20-25% • Adenocarcinoma 40% • Large cell carcinoma 10%

    6. NSCLC: Staging • 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

    7. NSCLC: Staging • 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

    8. Staging of Lung Cancer

    9. Local NSCLC: Stage I, II • Standard of care = Surgery • Relapse rate 35%-50% in St. I • Relapse rate 40%-60% in St. II • Adjuvant radiotherapy ? • Adjuvant chemotherapy ?

    10. Adjuvant Radiotherapy • 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

    11. Adjuvant Radiotherapy • 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.

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

    13. Postoperative Chemo- and Radiotherapy • ECOG-Trial: 488 patients with stage II, IIIA • RT alone (50.4 Gy) versus RT + 4x Cisplatin/Etoposid • Median survival 39 vs 38 months (ns) • TRM 1.2 vs 1.6% • Local recurrence 13 vs 12% Keller et al. NEJM 2000;343:1217

    14. Cisplatin-based Adjuvant Chemotherapy(International Adjuvant Lung Cancer Trial Collaboratvie Group) • Randomised trial of 3-4 cycles of cisplatin-based CT vs observation in patients with St. II, III LC CT no CT 5-Y. DFS 39.4% 34.3% p <0.03 5-y. OS 44.5% 40.4%p <0.03 IALT. NEJM 2004;350:351

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

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

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

    18. Locally advanced NSCLC • 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

    19. Combined chemotherapy and radiation • Sequential strategies • Primary CT C C.. R R R R R • Primary and adjuvant CT C C.. R R R R R C C • Concomitant Strategies • Daily CT C C C C C C C C C C R R R R R R R R R R • Intermittent CT C.. C.. R R R R R R R R R R • Combined Strategies • Primary and concomitant CT C... C C.. R R R R R

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

    21. Sequential chemo- and radiotherapy • Studies performed in the 1980s did not show an advantage • 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

    22. 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)

    23. Results: Sequential CT and RT Med. S 2y-S 3y-S 7y-S (%) CT-RT 14 mo 26 23 17 RT 10 mo 13 11 6 Dillman etal. NEJM 1990;329:940 Dillman et al. JNCI 1996;88:1210

    24. Results: Sequential CT and RT • US intergroup trialSause W. JNCI 1995;87:198 n=458Sause W. Chest 2000;117:351 MS (mo) 5y-S (%) RT 11.4 5 2x Cis/Vbl 13.2 8 hyper RT 12 6 • French trialLe Chevalier JNCI 1992;8:58 N=353 3x CT  RT vs RT 3y-S 12% vs 4%

    25. Simultaneous CT / RT is beneficial in: Head and neck cancer Anal cancer Cervical cancer Cisplatin is effective as a radiosensitiser 6-8 mg/m2 daily 30 mg/m2 weekly 70 mg/m2 3-weekly Concomitant Chemo- and Radiotherapy

    26. Concomitant CT-RT: EORTC Trial • 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/m2) • RT + weekly cisplatin (30 mg/m2)

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

    28. Sequential versus concomitant CT-RT • Japanese study:Furuse K et al. JCO 1999;17:2692 n= 320 MS (mo) 5y-DFS -2 cycles MVC  RT 56 Gy 13.3 19% -MCV/RT-10 days rest-MVC/RT 16.5 27% • RTOG 9410: Curran WJ. ASCO 2003;22:a621 n=611 2xCVRT(60Gy) vs CV/RT OS: 4 vs 25% p= 0.046

    29. Neoadjuvant Therapy • Pancoast`s tumor, vertebral invasion • Combined neoadjuvant CT-RT should be considered • 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§

    30. SAKK Studies • 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) • SAKK 16/01 • Preoperative CRT in NSCLC pts with operable stage IIIB disease • The same regimen as 16/00

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

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

    33. Regimes Cisplatin+Paclitaxel Cisplatin+Gemcitabine Cisplatin+Docetaxel Carboplatin+paclitaxel Results (n=1155 pts.) Response rate 19% Median survival 8 months 1-year survival 33% 2-year survival 11% Schiller et al. NEJM 2002;346:92 NSCLC: chemotherapy combinations

    34. New agents: Induction CT followed by concomitant CT-RT Induction (2 cycles) Concomitant (2 cycles) Vinorelbine 25 mg/m2 D1,8,(15) 15 mg/m2 D1,8 Cisplatin 80mg/m2 D1 80mg/m2 D1 Paclitaxel 225 mg/m2 D1 135 mg/m2 D1 Cisplatin 80mg/m2 D1 80mg/m2 D1 Gemcitabine 1250 mg/m2 D1,8 600 mg/m2 D1,8 Cisplatin 80mg/m2 D1 80mg/m2 D1 CALGB study 9431: Vokes et al. JCO 2002;20:4191

    35. New agents: Induction CT followed by concomitant CT-RT RR(CT) RR(CT-RT) 1yS 2yS 3yS (%) V+C 44% 73% 65 40 23 P+C 33% 67% 62 29 19 G+C 40% 74% 68 37 28 CALGB study 9431: Vokes et al. JCO 2002;20:4191

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

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

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

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

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

    41. SCLC Therapy • 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 • Early use of RT with CT improves cure rates

    42. SCLC Therapy • The actuarial risk of CNS metastasis developing 2 years after CR of SCLC is 35%-60% • 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

    43. SCLC Results • Limited Disease: • Remission rate 80-90% • CR 50-60% • Median Survival 18-20 months • 2-year Survival 40% • 5-year Survival 15-25%

    44. SCLC Results • Extensive Disease: • Remission rate 70-80% • CR 20-30% • Median Survival 8-10 months • 2-year Survival < 10%