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 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%

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

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

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

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

Staging of Lung Cancer

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 ?

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

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.

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)

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

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

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

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

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%

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

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

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

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

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 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

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 11.4 5 2x Cis/Vbl 13.2 8 hyper RT 12 6 French trial Le Chevalier JNCI 1992;8:58 N=353 3x CT  RT vs RT 3y-S 12% vs 4%

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

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)

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

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

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§

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

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

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

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

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 D1 80 mg/m2 D1 Paclitaxel 225 mg/m2 D1 135 mg/m2 D1 Cisplatin 80 mg/m2 D1 80 mg/m2 D1 Gemcitabine 1250 mg/m2 D1,8 600 mg/m2 D1,8 CALGB study 9431: Vokes et al. JCO 2002;20:4191

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

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

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

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

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

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

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

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

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%

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