Lung Cancer R Zenhusern Lung cancer Epidemiology n

Lung Cancer R. Zenhäusern

Lung cancer: Epidemiology n Most common cancer in the world – 2. / 3. most cancer in men / women n 1. 2 million new cases / year n 1. 1 million deaths / year n Incidence – Men 1940 -80: 10 70/100000/J – Women 1965 -: 5 30/100000/J

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

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

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

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

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

Staging of Lung Cancer

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

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 (N 2): no clear evidence of an adverse effect

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.

Adjuvant Chemotherapy n n n 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)

Postoperative Chemo- and Radiotherapy n n n ECOG-Trial: 488 patients with stage II, IIIA RT alone (50. 4 Gy) versus RT + 4 x Cisplatin/Etoposid Median survival TRM Local recurrence 39 vs 38 months (ns) 1. 2 vs 1. 6% 13 vs 12% Keller et al. NEJM 2000; 343: 1217

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 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

Overall Survival (Panel A) and Disease-free Survival (Panel B) The International Adjuvant Lung Cancer Trial Collaborative Group, N Engl J Med 2004; 350: 351360

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

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

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

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

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

Sequential chemo- and radiotherapy n n Studies performed in the 1980 s 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

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)

Results: Sequential CT and RT Med. S 2 y-S 3 y-S 7 y-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

Results: Sequential CT and RT n US intergroup trial Sause W. JNCI 1995; 87: 198 n=458 Sause W. Chest 2000; 117: 351 RT 2 x Cis/Vbl hyper RT n MS (mo) 11. 4 13. 2 12 5 y-S (%) 5 8 6 French trial Le Chevalier JNCI 1992; 8: 58 N=353 3 x CT RT vs RT 3 y-S 12% vs 4%

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

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)

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

Sequential versus concomitant CT-RT n Japanese study: Furuse K et al. JCO 1999; 17: 2692 n= 320 n MS (mo) 5 y-DFS -2 cycles MVC RT 56 Gy 13. 3 19% -MCV/RT-10 days rest-MVC/RT 16. 5 27% RTOG 9410: n=611 2 x. CV RT(60 Gy) vs CV/RT Curran WJ. ASCO 2003; 22: a 621 OS: 4 vs 25% p= 0. 046

Neoadjuvant Therapy n Pancoast`s tumor, vertebral invasion – Combined neoadjuvant CT-RT should be considered n Tumors with ipsilateral mediastinal spread (N 2) – 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§

SAKK Studies n SAKK 16/00 – Preoperative CRT vs CT in NSCLC stage IIIA – CT: 3 cycles docetaxel and cisplatin (D 1, 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

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

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

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

New agents: Induction CT followed by concomitant CT-RT Induction (2 cycles) Concomitant Vinorelbine Cisplatin 25 mg/m 2 D 1, 8, (15) 80 mg/m 2 D 1 15 mg/m 2 D 1, 8 80 mg/m 2 D 1 Paclitaxel Cisplatin 225 mg/m 2 D 1 80 mg/m 2 D 1 135 mg/m 2 D 1 80 mg/m 2 D 1 Gemcitabine Cisplatin 1250 mg/m 2 D 1, 8 80 mg/m 2 D 1 600 mg/m 2 D 1, 8 80 mg/m 2 D 1 (2 cycles) CALGB study 9431: Vokes et al. JCO 2002; 20: 4191

New agents: Induction CT followed by concomitant CT-RT RR(CT) RR(CT-RT) 1 y. S 2 y. S 3 y. S (%) 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

Conclusion: Combined-Modality Therapy for Stage III Disease n n 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 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

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

SCLC n n n 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

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

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

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

SCLC Therapy n n 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

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

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