1. What to do in stage III non small-cell lung cancer? Miklos Pless 28. November 2013

2. 2 CRT: Concomitant vs. Sequential Meta-Analysis 2010 (HR 0.84, Cochrane 0.74) Auperin, JCO 2010

3. 3 CRT: Chemotherapy type not so important? CALGB 9431 (phase II) Vokes, JCO 2007

4. 4 CRT: Role of induction chemotherapy CALGB 39801

5. 5 Yamamoto S. et al., J. Clin. Oncol. 30, 2012, suppl. Abstr.7000 45 trials, 9 phase III, 36 phase II with 51 arms No difference between the two groups, med OS: CT 18.5 mo vs no CT 18.1 mo CRT: role of consolidation CT after CRT?

6. 6 HR 0.925 Curran, JNCI 2011 CRT: role of hyperfractionation RTOG 9410 Arm 3: 70 Gy: 1.2 Gy 2x/d Arm 2: 63 Gy: 1.8 Gy/d

7. 7 CRT: Role of high doses of RT RTOG 0617 Bradley, ASCO 2013

8. 8 Operable stage IIIA: Adjuvant Chemotherapy: OS better! Winton, NEJM 2005

9. 9 PORT Cochrane, 2010 Operable Stage IIIA Does adjuvant RT help? NO!

10. 10 Unresectable (?) N2 With response to Induction 3 x Cis/Carbo + X OP vs. RT (60 Gy) 1. EP: OS 50% complete resection! 41% downstaging to ≤ypN1 Unresectable (?) N2 With response to Induction 3 x Cis/Carbo + X OP vs. RT (60 Gy) 1. EP: OS 50% complete resection! 41% downstaging to ≤ypN1 JNCI, 2007

11. 11 Lancet 2009 PFS OS

12. 12 The activity of the SAKK group SAKK 16/96 (Phase II) 3 x Cisplatin/Taxotere neoadjuvant (Betticher, JCO 2003) Overall Survival (ITT population, n=90) 0.2.4.6.8 1 010203040 5060 Months Overall survival complete resection incomplete resection p<0.0001 all

13. 13 Is trimodal better than bimodal? SAKK 16/00 Presented by: Miklos Pless Chemotherapy Radiotherapy Surgery 3 weeks 3-4 weeks Stratification factors: Mediastinal bulk (≥5cm vs. <5cm), weight loss (≥5% vs. <5% in past 6 months), center Randomization Arm A: RT Arm B: no RT Surgery Chemotherapy 3-4 weeks CDDP 100mg/m 2 d1 x 3 cy q3w DXT 85mg/m 2 d1 x 3 cy q3w +G-CSF 44 Gy in 22 fractions in 3 weeks Accelerated conc. boost * ** * Staging: (PET-) CT: PD went off study

14. 14 Overall Survival TreatmentMedian OS (95% CI) RT27.1 (18.8, 42.8) no RT26.2 (21.0, 52.1) HR = 1.145 (95% CI: 0.786-1669) Pless ASCO 2013

15. 15 Stage III Very heterogeneous disease <30% can be cured (70-80% are NOT!) Both local and distant relapse are a problem! Requires bimodal treatment always Chemotherapy: minor effect Surgery vs. Radiotherapy? Trimodal treatment?

16. 16 Summary & Conclusions Which Chemotherapy?(Cis-)Platinum based, concurrent type and dose Which Radiotherapy?>60 Gy, less than 70 Gy type, dose, fraction Which combination? Surgery + ChemotherapyStage IIIA/N2 Radiotherapy + ChemotherapyStage IIIB/IIIA? all three?Probably not