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Management of Locally Advanced NSCLC. Shilpen Patel MD FACRO Department of Radiation Oncology, University of Washington, Seattle, WA. Roadmap. Background Evolution of therapy Radiation alone Sequential chemotherapy and radiation Concurrent chemotherapy and radiation

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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