4. 1989-1992: 458 patients, KPS  70%, wt loss  5% in 3 months Sause W. 2000 Use of 2D radiotherapy Outcomes in stage III nsclc (1990’s)

5. Best outcomes per patient subgroup Median survival in phase III trials of Chemo-RT 17-17.9 months Curran ‘02, Movsas 05 22.2 months Albain ‘05 Subgroups modified from Ruckdeschel JC. 1997 Median survival after RT alone = 11.4-12 months (Sause 2000) T4 – N3 IIIB Bulky or fixed multi-station N2 disease IIIA 4 Nodal metastases identified during p re-thoracotomy staging (mediastinoscopy; EUS, EBUS, PET scan) IIIA 3 Nodal metastases (single station) found intraoperatively IIIA 2 Nodal metastases found incidentally on the final pathological examination of resected surgical specimen IIIA 1 Description Subset

7. CTC for Adverse Events v3.0 Toxicity of chemo-radiotherapy Severely altered eating/swallowing; IV fluids, tube feedings, or TPN indicated >24 hrs Interfering with ADL; Oxygen indicated Grade 3 Life-threatening consequences (e.g. obstruction, perforation) Esophagitis Life-threatening; ventilatory support needed Pneumonitis Grade 4

10. INT 0139: Toxicity of 2D CT-RT Albain 2005

11. Outcomes depending on RT planning Major errors : when part of tumor was missed by  1 beams Unacceptable target coverage using 2D RT Modified from Rosenman JG, 2002 15 % 332 ‘ 91 EORTC 8844 INT 0139 CALGB 8433 RTOG 8311 SWOG 7628 RTOG 7301 Study 19 % 194 ‘ 03 23 % 155 ‘ 90 6 % 832 ‘ 93 31% 140 ‘ 82 12% 316 ‘ 82 major errors Patients Year

12. INT 0139: Treatment-related mortality Albain 2005

15. Advances in RT planning & delivery 3D CRT PET PET-CT Cone-beam CT 4DCT

20. Minimise disease progression during treatment Stage III nsclc progressing from potentially curable  incurable Trials with surgical arm Chemo-RT only 43 % off-study after induction chemotherapy Van Meerbeeck 05 19 % did not have thoracotomy 20 % did not have def. CT-RT Albain ASCO 05 Drop-out rates Author 16 % progression in concurrent and sequential CT-RT arms Fournel JCO 05 Drop-out rates Author

22. Stage III-N2 : EORTC 08941 vs INT 0139 Chemo-RT completed in 33 days INT 0139 EORTC 08941 Mean 52 days (range 17-113) Median 43 days Chemo-radiotherapy completed in 137 days # 43% drop-out # Median interval chemo-surgery = 49 days (22-86) (Albain 2005; van Meerbeeck 2007) Patient preference for short schemes? Treatment and indirect costs ?

24. Toxicity & survival in SWOG 0023 Gaspar ASTRO 2006

25. Dose-volume histograms Dose Organ volume Volume of both lungs minus PTV tumour 66 Gy 20 Gy 0% 100% V 20 = 30% V 20 to predict risk of radiation pneumonitis

26. Impact of V 20 on toxicity & survival SWOG 0023 analysis (Gaspar L. 2006) 12 mo 24 mo Median survival 10 % 4 % Radiation pneumonitis ≥ Grade 3 V 20 >35% V 20 ≤ 35%

27. Impact of V 5 on toxicity after CT-RT Relative volumes of lung receiving more than a threshold dose of 5 Gy (rV5) was the most significant factor associated with treatment-related pneumonitis. 1-year actuarial incidences of G≥3 pneumonitis in group V5 ≤42% = 3% And in group V5 >42% = 38% respectively ( p = 0.001). 223 patients treated with concurrent CT-RT at MDAH (Wang S, 2007)

31. 4DCT based respiration-gated RT Radiation beam ‘on’ Treatment beam fixed in space and gated to turn on only when the target (or surrogate signal) comes into the pre-planned area

32. Respiratory gating to reduce V 20 V 20 reductions achieved in stage III NSCLC (Underberg 2006) 16.2% reduction when single CT & std margins used 7.0% reduction when compared to a 4DCT-based ITV

38. Two Compartment Model of Combined Modality Therapy for Locally Advanced Lung Cancer Local-Regional Disease Distant Micrometastases Surgery/Radiotherapy Chemotherapy Brain Sanctuary Gandara D. JCO 2003