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Management of Locally Advanced NSCLC
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Management of Locally Advanced NSCLC

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  1. Management of Locally Advanced NSCLC Shilpen Patel MD FACRO Department of Radiation Oncology, University of Washington, Seattle, WA

  2. Roadmap • Background • Evolution of therapy • Radiation alone • Sequential chemotherapy and radiation • Concurrent chemotherapy and radiation • Trimodality versus bimodality • Superior Sulcus Tumors • Imaging

  3. 9.8 13.8 17.7 Survival Improvement in Stage III NSCLC since 1980’s

  4. Evolution: Radiation Alone • In the 1970’s stage III NSCLC was an unresectable disease • Standard of care was radiation alone

  5. Evolution: Sequential chemotherapy and radiation

  6. Dillman et al. Improved Survival in Stage III NSCLC: 7yr f/u of CALGB #8433. JNCI Vol 88, No 17: 1210-14, 1990 & 1996 • 165 Pts w/ stage III NSCLC randomized to: Cisplatin + vinorelbine Radiation--60Gy Radiation--60Gy

  7. Dillman et al. Improved Survival in Stage III NSCLC: 7yr f/u of CALGB #8433. JNCI Vol 88, No 17: 1210-14, 1990 & 1996 • Median survival improved with chemotherapy • 9.7 months with radiation alone • 13.8 months with chemotherapy and radiation • OS improved at 7 years: • 6% with radiation alone • 13% with chemotherapy and radiation

  8. Evolution: Concurrent Chemoradiation

  9. RTOG 94-10: Curran, et al, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60 R A N D O M I Z A T I O N SEQ cDDP 100 mg/m2 d1, 29 Vlb 5 mg/m2 Q wk X 5 (d1, 8, 15, 22, 29) Standard fractionated RT (60 Gy) d 50 CON- QD cDDP 100 mg/m2 d1, 29 Vlb 5 mg/m2 Q wk X 5 (d1, 8, 15, 22, 29) Standard fractionated RT(60 Gy) d1 CON- BID cDDP 50 mg/m2 d1, 8, 29, 36 VP-16 50 mg/m2 d1-5, 8-12, 29-33, 36-40 Hyperfractionated RT (69.6 Gy) d1

  10. RTOG 94-10: Curran, et al, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60 Courtesy of Walter Curran, MD

  11. RTOG 94-10: Curran, et al, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60 Courtesy of Walter Curran, MD

  12. RTOG 94-10: Curran, et al, J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60 In Field failure rates • Sequential: 38% • Concurrent: 33% • Hyperfractionated: 25%

  13. Local Control 65% 65% 65%

  14. Evolution: Trimodality

  15. Intergroup 0139- Albain, et al., 2009 Median F/U 81 months Re-evaluate 2 to 4 weeks post RT; if no PD R A N D O M I Z E Cis/VP16 x 2 cycles w/concurrent XRT 45Gy Cis/VP16 x 2 cycles Stage IIIA (T1-3, pN2, M0) NSCLC N = 429 (396 eligible) Considered Resectable Surgery Cis/VP16 x 2 cycles w/concurrent XRT 45Gy Cis/VP16 x 2 cycles Continue RT to 61GY Re-evaluate 7 days prior to RT completion; if no PD

  16. Results: Intergroup 0139 Courtesy of Kathy Albain, MD

  17. Intergroup 0139/RTOG 9309 Progression-Free Survival by Treatment Arms 100 Trimodality ( n=201) Median 12.8 months 5-year 22.4% / / / 80 / Chemoradiation (n=191) Median 10.5 months 5-year 11.1% / 60 / / / / / / / / / PercentAlive / 40 / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / / 20 / / / / / / / / / Log rank p = 0.017 / / / 0 0 6 12 18 24 30 36 42 48 Months

  18. Intergroup 0139/RTOG 9309 Lancet 8/1/09Independent Favorable Survival Predictors • Female • No weight loss • Trimodality Arm • pN0 OS=41% • pN1-3 OS=24% • No Surgery OS=8%

  19. Joshua Sonett, MD, et al Pulmonary Resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in NSCLC. Ann Thor Surg 2004;78(4) • 40 consecutive patients who received high dose radiotherapy and concurrent platinum based chemotherapy between January 1994-May 2000 who then went on to undergo a lung resection. • Patients • Stage IIB – 7 patients • Stage IIIA – 21 patients • Stage IIIB – 10 patients • Stage IV – 2 patients

  20. Surgery • Median time to surgical resection 52.5 days (20-258 days) • Surgeries • 29 lobectomies • 11 pneumonectomies • No post-operative deaths • Median ICU time = 2 days • Overall length of stay = 6 days • One patient developed post pneumonectomy pulmonary edema • One patient developed a BP fistula

  21. Results • 34/40 patients (85%) were downstaged pathologically • 33/40 patients (82.5%) had no residual lymphadenopathy • 18/40 patients (45%) exhibited a complete pathologic response • 22/26 patients (85%) with N2 disease exhibited pathologic confirmed sterilization of their mediastinal disease

  22. Results • Median follow-up was 2.8 years • Overall survival at 1,2, and 5 years is 92%, 67%, 46% respectively. Median overall survival 53 months. • Disease free survival at 1, 2, and 5 years is 73%, 67%, 56%. Median disease free survival not reached • Failure Pattern • 14% Local and distant • 29% Brain only • 29% Distant only • 29% Local only

  23. RTOG 0229, Suntharalingam IJROBP 2012 CBDCA AUC =2.0, paclitaxel 50 mg/m2 q week x 6, 50.4 Gy to the mediastinum and primary tumor and boost of 10.8 Gy to gross dz Re-evaluate 2 to 4 weeks post RT; if no PD Stage III (pathologically proven N2 or N3) NSCLC N = 60 (57 eligible) CBDCA AUC =6, paclitaxel 200 mg/m2 q 21d x 2. Surgery Median follow-up is 20 months.

  24. RTOG 0229, Suntharalingam IJROBP 2012 • Grade 3/4 toxicities: heme 35%, GI 14%, pulmonary 23%. • 43 pts (75%) were evaluable for the primary endpoint; 36 pts underwent resection. 7 pts had residual mediastinal dz. 27/43 (63%) achieved mediastinal clearance. • There was a 14% (5/37) incidence of grade 3 postoperative pulmonary complications. There was only one postop grade 5 toxicity (3%).

  25. RTOG 0229, Suntharalingam IJROBP 2012 • With a median follow-up of 24 months for all patients, the 2-year overall survival rate was 54%, and the 2-year progression-free survival rate was 33%. The 2 year survival rate was 75% for those who achieved nodal clearance. • Next steps? RTOG 0839

  26. Thomas M, Macha HN, Ukena D, et al. Cisplatin/etoposide followed by twice daily chemoradiation versus cisplatin/etoposide alone before surgery in Stage III NSCLC: A randomized Phase III trial of the GermanLung Cancer Cooperative Group. Lancet Oncology 2008

  27. Thomas M, Macha Et al. Lancet Oncology 2008. • Only 54-57% of Stage IIIA patients in either arm underwent a complete resection (R0) • MST was not different between the arms (15.5 mo. in chemoradiotherapy and 16.8 mo. in chemotherapy only arm, p=0.97) • Radiation was delivered in a non standard form (and we know from RTOG 9410 that BID is inferior!) • Pneumonectomy contributed to mortality (14% versus 6%)

  28. Van Meerbeeck et al JNCI 99(6) p 442-450 EORTC 08941 • 579 pts stage IIIA N2 NSCLC randomized: Platinum based chemo Surgical Resection Radiation--60Gy Radiation

  29. Van Meerbeeck et al JNCI 99(6) p 442-450 EORTC 08941 • In the XRT arm, g 3/4 acute and late esophageal and pulmonary toxicity was 4% and 7% • Median and 5 y Overall survival (resection versus XRT) was 16.4 versus 17.5 mo and 15.7% versus 14%

  30. Is long term survival predicted by pathologic response?/Does mediastinal clearance matter? • Rusch VW, Albain KS, Crowley JJ, et al Surgical Resection of Stage IIIA/IIIB NSCLC after induction chemoradiotherapy. J. Thorac Cardiovasc Surgery 1993;105:96-106 • Sugarbaker DJ, Herdon J, Kohman LJ, Krasna MJ, Green MR, CALGB Thoracic Surgery Group. Results of CALGB 8935. A multiinstitutional phase II trimodality trial for Stage IIIA NSCLC. J Thorac Cardiovasc Surg 1995; 109; 473-83 • Voltoni L, Luca L, Ghiribelli C, Paladini P, Di Bisceglie M, Gotti G. Results of induction chemotherapy followed by surgical resection in patients with stage IIIA NSCLC; the importance of nodal down staging after chemotherapy. Eur J Cardiothoracic Surg 2001;20:1106-12. • Betticher DC, Schmitts S, Totsch M, et al Mediastinal lymph node clearance after docetaxol-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 NSCLC:a multicenter phase II trial JCO 21:1752-9.

  31. What about superior sulcus tumors?

  32. SWOG 9416 Re-evaluate 2 to 4 weeks post RT; if no PD 2 cycles of chemo Pancoast tumors (n=83) Cis/Etoposide + XRT 45 Gy Surgery

  33. Kwong KF, et al High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete response rates and excellent long-term survival. J Thorac Cardiovasc Surg. 2005 Jun;129(6):1250-7 • 36 patients with Pancoast tumor • Stage IIB-IV • R0 resection was achieved in 36 (97.3%) patients • High-dose radiotherapy (mean 56.9Gy; range, 30-70.2 Gy) was successfully tolerated in all but 1 patient • Pathologic complete response was found in 40.5% (n = 15) of patients

  34. Kwong KF, et al . J Thorac Cardiovasc Surg. 2005 Jun;129(6):1250-7 • Operative mortality rate was 2.7% (n=1/37). • Significant morbidities occurred in 10 patients (n=10/37, 27% patients) but were variable and without a dominant pattern

  35. Kwong KF, et al . J Thorac Cardiovasc Surg. 2005 Jun;129(6):1250-7 • Recurrences occurred in 50% of patients • Distant recurrence accounted for the majority of recurrences (13 patients / 36.1%) • Local recurrences in the lung-mediastinum occurred in 5 patients (13.8%)

  36. Kwong KF, et al . J Thorac Cardiovasc Surg. 2005 Jun;129(6):1250-7

  37. New technology requires careful planning • Treatment planning cannot make up for drawing the wrong volumes • The most radioresistant tumor cell is the one that’s not in the field!

  38. What about PET?

  39. Assessing Gross Tumor Volume