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 : 10  70/100000/J
Women : 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%

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

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

9. 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

10. 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

11. Staging of Lung Cancer

12. 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 ?

13. 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

14. 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.

15. 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)

16. 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 vs 1.6%
Local recurrence 13 vs 12%
Keller et al. NEJM 2000;343:1217

17. 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

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

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

20. 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%

21. 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

22. 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..
Combined Strategies
Primary and concomitant CT C...
C C.. R R R R R

23. Therapeutic Strategies
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

24. 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

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. S 2y-S 3y-S 7y-S (%)
CT-RT 14 mo
RT 10 mo
Dillman etal. NEJM 1990;329:940
Dillman et al. JNCI 1996;88:1210

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

28. Concomitant Chemo- and Radiotherapy
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

29. 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)

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

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

33. 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§

34. SAKK Studies SAKK 16/00 SAKK 16/01
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

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

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

37. NSCLC: chemotherapy combinations
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

38. 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 80 mg/m2 D mg/m2 D1
Paclitaxel 225 mg/m2 D mg/m2 D1
Cisplatin 80 mg/m2 D1 80 mg/m2 D1
Gemcitabine 1250 mg/m2 D1, mg/m2 D1,8
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) 1yS 2yS 3yS
(%)
V+C 44% 73%
P+C 33% 67%
G+C 40% 74%
CALGB study 9431: Vokes et al. JCO 2002;20:4191

40. 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

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

42. 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

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

44. 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

45. 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

46. 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

47. SCLC Results Limited Disease: Remission rate 80-90% CR 50-60%
Median Survival months
2-year Survival 40%
5-year Survival %

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