Surgical Approaches to Locally Advanced NSCLC. Kemp H. Kernstine, MD, PhD Professor and Chairman UT Southwestern Medical Center Dallas, TX

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1 Surgical Approaches to Locally Advanced NSCLC Kemp H. Kernstine, MD, PhD Professor and Chairman UT Southwestern Medical Center Dallas, TX

2 Keep it real simple. Do one thing and do it the best you can. -Harry Snyder, co-founder of In-N-Out Burger 1 1 In-N-Out Burger: A Behind-the-Counter Look at the Fast-Food Chain that Breaks All the Rules. Stacy Perman, Harper Collins, from Ca Cancer Jrnl 2010 av for Texas 88.3 and 51.2 for men and women respectively, 25% resectable; 4 est. 5/100,000 and 40% resectable; STS National Database Results for UTSW assumes all are cancer cases

3 Surgical Approaches to Locally Advanced NSCLC Kemp H. Kernstine, M.D., Ph.D. Division of Thoracic Surgery University of Texas Southwestern Medical Center Dallas, Texas August 11,

4 Disclosures None 4

5 Outline Definition of Locally Advanced Disease Not all resections are equal Evaluation Special circumstances 5

6 Locally-Advanced Disease (IIIA/IIIB): Definition UICC 7 UICC 6 IIIA (T 1-2 N 2, T 3 N 1-2 ) IIIB (T 1-3 N 3, T 4 N 0-3 ) Effusions excluded from trials T>7cm, M 1 (ipsilateral nodules) T 4(same lobe nodules)n 0 = IIB Pleural Eff = M1 a UICC 7 IIIA (T 1-2 N 2, T 3 N 1-2 ) IIIB (T 1-3 N 3, T 4 N 0-3 ) Clinical Stage, J T Oncol 2(8):

7 Quality Determinants of a Patient Factors Surgical Procedure? Surgeon Technique Surgical Team Hospital Management Team Rehab 1º MD Pulm Med Onc Rad Onc DFS Function QOL Hospital Morbidity Hospital Mortality

8 College Medical School 4 yrs Cardiothoracic Sub-Specialties 4 yrs Adult Cardiac 1 yr Great Vessels Valves Revascularization TMR Transplantation General Surgical Training 5 yrs Congenital Heart Heart Failure/LVAD 1 yr 1-2 yrs Cardiothoracic Surgical Training 2-3 yrs General Thoracic Transplantation 1 yr

9 Reasons to Refer to Specialist Surgeon 3-5 x lower Op Mortality 50% reduced morbidity 30% improved 5-year survival Potential Surgical Candidates 11 General Thoracic Track Programs PostCT Residency Training Programs 1-2 yrs addnl mostly at these locations Thorax 58:996, 2003 Lung Cancer 46:227, 2004 Ann Thor Surg 87, 995, 2009

10 2011: Surgical Patients Likely Insufficiently Staged % no CT, Mediastinal Staging or systematic node resection Mediastinoscopy used in 27.1% 46.6% no nodes in specimen no mediastinal nodes evaluated in 42% % had 3 nodal stations sampled % of node negative patients had no nodes examined 4 1 Thorax :3-5 2 Ann Thorac Surg : Lung Cancer : Ann Thorac Surg :1486

11 Surgery: NSCLC 11

12 Initial Assessment Labs, PFTs, Risk Assessment CT of the chest and upper abdomen Whole-body PET Bronchoscopy MRI Apex (MRI Angio) Brain MRI Mediastinoscopy (EBUS/EUS?)

13 The Acceptable Surgical Evaluation & Treatment Anatomical resection- Lobectomy R0 Resection Resect hilar lymph nodes Resect/sample ipsilateral mediastinal lymph node stations > 4 1 contralateral station examined/resected >16 nodes examined 1-3 Preserve lung Segment > Wedge in hi risk (IMRT vs RFA?) 60-d mortality < 1% Ready for adjuvant w/i 4-6 weeks 1 Gajra JCO 2003, 2 Ludwig Chest 2005, 3 Ou J Thor Oncol 2008

14 Determination of Extent of Resection Wedge Resection Extended Segmentectomy Lobe + Wedge/Segmentectomy Pneumonectomy Segmentectomy Lobectomy Bilobectomy Lesion Size Solid Portion CT Border, Density Histology Tumor Location (Peripheral, Lobe) Presence of Other Lesions/Nodules Nodal Involvement FDG-PET Information Tissue and/or Serum Molecular Features Health Status of the Patient 14

15 Special Surgical Situations N2 N3 T4 Local Invasion 15

16 N2 Heterogeneity Good Prognosis Single node Microscopic Station 5 or 6 for LUL, 4R for RUL Poor Prognosis Gross disease Fixed to adjacent structures or Matted Nodes Multi-node Multi-station Bulky Station 7 > 4L > 9 Transcapsular Skip metastases 16 Adapted Govindan ASCO 2009, Kassis Thorac Surg Clin 18: 333, 2008

17 Prospective Trials (IIIA(pN2)): Comparison of Induction Chemotherapy Trial Results to Chemoradiotherapy Results Trial Patients R0 pcr Induction Chemotherapy Nodal pcr Local Failure Survival Betticher, 2003 SAKK Van Zandwijk, 2000 EORTC 8955 O'Brien, 2003 EORTC % 15% 31% 60% 38% (4 yr) 47 71% 6% 53% Not Stated 34% (2 yr) 52 Not Stated Not Stated 17% Not Stated 68% (1 yr) Induction Chemoradiotherapy Albain, 2009 INT % 18% 46% 16% 27% (5 yr) Choi, % 9.50% 24% 25% 37% (5 yr)

18 RCTs: Stage IIIA (N2) Surgery vs NonSurgical Treatment Trial Patients Treatment Johnstone, 2002 RTOG 8901 Shepherd, 1998 NCI-C 73 (54% bulky) Accrual Target Reached Specialty Surgeons Required Overall Survival CT S CT No No 22% CT RT(65 Gy) CT 22% (4 yr) 31 (62.5% R0) CT S CT Underpowered No 40% RT(60 Gy) 40% Albain, 2009 INT CT-RT(45 Gy) S Yes No 27% (2 yr) CT-RT (61 Gy) 20% van Meerbeeck, 2005 EORTC CT S +/- RT Yes No 16% (5 yr) CT RT (60 Gy) 14% (5 yr)

19 IIIB Bulky Disease: Parenchymal Sparing Induction ChemoRT E.M. PreChemoRT 4/13/06 PostChemoRT PreOp 6/12/06

20 N3 Disease Contralateral N3 no 5-year survivors in prior trials >30% of clinically N3 patients are incorrectly upstaged, confirm stage by biopsy Scalene node positive patients may have survival advantage Microscopic PET negative nodal disease may have survival advantage Bilateral lymphadenectomy w or w/o radical neck dissection may confer survival advantage Adjuvant CT or CT-RT may offer survival advantage

21 T4 Local Invasion Overall 8% 5-year survival with surgery in this group[i] T4 status must be clear and incontrovertible MIS exploration may be an opportunity to accurately stage Induction CT or CT-RT vs exploration w resection and adjuvant therapy 21 [i] Naruke et al. J Thorac Cardiovasc Surg 96:440, 1988.

22 Carina 13-30% operative mortality (prior radiation increases likelihood of death and complication) Op Mortality R carina pneumonectomy 16% vs L carina pneumonectomy 31% 20% 5-year survival in R0 resections Preserved for young, healthy, mediastinoscopy negative patients Grillo, JTCVS

23 Superior Vena Cava High morbidity 36%, mortality 12% Incomplete resection 20% 0[i]-29%[ii] 5-year survivors Differentiation of bulky N2 from T4 may be difficult T4, not bulky N2, may be curable w resection [i] Burt et al. Clin North Am 67:987, 1987 [ii] Spaggiari et al. Ann Thorac Surg 69: ,

24 Other Organ Invasion Extended operations w induction chemotherapy, w or w/o RT 3-year survival 54% improved, but higher complications[i] Esophageal 1/7 reported 5-year survivors L Atrium, SVC, vertebra may be resected and reconstructed w 19-25%[i], [ii] 5-year survival in selected R0 resections Aorta Advential better survival Atrium 22% 5-year survival[i] [i] Lung Cancer 29:135, 2000 [ii] J Neurosurg 91:74, [i] Macchiarini et al. Ann Thorac Surg 57: , [i] Tsuchiya et al. Ann Thorac Surg 57: ,

25 NSCLC that involves at the least the parietal pleura of the superior sulcus above the 2 nd rib level Frequency is estimated to be less than 3% 40% symptomatic, usually due to local invasion rather than typical NSCLC symptoms Pancoast

26 Surgical Techniques Posterior Approach Shaw-Paulson Posterolateral thoracotomy Conventional approach Advantage Excellent exposure for posterior structures Feasible for vertebral resection Disadvantage Difficult to dissect thoracic inlet structure (esp. vessels) 2004, Thorac Surg Clin, Kent

27 Surgical techniques anterior approach Transclavicular approach Initially proposed by Dartevelle et al Advantage Excellent exposure All type of lung resections feasible without accessory thoracotomy Disadvantage Resection of the clavicle Risk of winged scapula 2004, Thorac Surg Clin, Macchiarini

28 Surgical techniques anterior approach Trans-sternal approach Hemiclamshell incision Trap-door incision Advantage Excellent exposure for anterior structures Disadvantage Difficult posterior dissection Risk of flail chest Excessive incision for true apical tumors Resection of the clavicle (trap-door) 2004, Thorac Surg Clin, Macchiarini

29 Surgical techniques anterior approach Trans-scapular approach Advantage Adequate exposure Disadvantage Very long (ischemic) incision Time-consuming closure Increased shoulder girdle dysfunction 2004, Thorac Surg Clin, Macchiarini

30 Brief Review of Data Guiding Clinical Management T3 > T4 Resect Lobe > Wedge R0 a must! Meta-Analysis Induction CRT vs Induction RT vs Adj RT Meta-Analysis Induction CRT Better than other Options

31 Historical: What we know Without treatment, survival is months Advanced T, N, M status worsens the prognosis Without surgery, long term survival is uncommon, <5% > Lobectomy provides survival advantage Induction chemotherapy and radiation combined are synergistic R1 and R2 resections do not appear to provide a survival advantage Induction therapy increases resection and R0 rate Combined chemotherapy and radiation appear to provide better response than either alone Platinum based double drug therapy appears to improve survival >45 Gy appears to be effective to achieve pcr pcr after induction increases survival

32 3 Phase II Pancoast Trials Compared Trial Group and Name SWOG 9416 Author Special Section and Date Criteria Rusch, 2007 T3N0-1 or T4N0-1 NSCLC, Mediastinoscopy All Special Exclusions PS >2 PET Included in w/u and % No # Patients 110, 78 T3, 32 T4 (116 entered trial) How Long to Reach? April 1995 to November 1999 Tumor Size PreRx (median) 6 cm ( cm) Chemo Regimen w dose Cisplatin 50 mg/m2 d1,8,29,36 Etoposide 50 mg/m2 d1-5,29-33 # Cycles # (%) Completing Induction Therapy Radiatio n Dose (Gy) (95%) 45 Radiation to Include Mediastin um? patients excluded Concurre nt? Yes IMRT Technique Included% No Determinan t for Surgical Intervention Stable or Responding to Induction JCOG 9806 Kunitoh, 2008 ipsilateral N3 eligible, no mediastinosc opy, if node < 1 cm considered negative No 76 (20 w T4) May 1999 to November 2002 mitomycin 8 mg/m2 on day 1, vindesine 3 mg/m2 on days 1 and 8, and cisplatin 80 mg/m2 on day 1 Q 4wks 2 45 (1 wk split) patients excluded Yes No SWOG 0220 Kraut TBA T3N0-1 or T4N0-1 NSCLC, Mediastinoscopy All No 44 Cisplatin 50 mg/m2 d1,8,29,36 Etoposide 50 mg/m2 d1-5,29-33 then 3 cycles of docetaxel 75mg/m² Q 21 days 2 45 patients excluded Yes No Stable or Responding to Induction

33 3 Phase II Pancoast Trials Compared- Early Results Trial Group and Name Author and Date Chemo Regimen w dose Induction Rx Related Deaths # (%) Inoperable Due to Disease Progressio n # (%) Surgically- Treated % Sublobar % Open and Closed % R0 CR% CR+Min% # (%) No Chest Wall Resection Necessary p Induction Hospital Lengthof-Stay (d) PostOp Morbidity % PostOp 30-d Mortality % PostOp Therapy Planned #(%) Completing Planned Postop Therapy SWOG 9416 Rusch, 2007 Cisplatin 50 mg/m2 d1,8,29,36 Etoposide 50 mg/m2 d1-5, (2.7%) 9 (8.2%) 88 (80%) 83 (76%), surgically- Rx 83/88 (94%) 32/88 (36%) 61 (56%) 13/88 (15%) 7 (3-64) 52% 2 (2.3%) wrong in abstract 2 more cycles of Cist/Etop 59/88 (67%) started Chemo, 45% completed, no mention of what % or # surgical JCOG 9806 Kunitoh, 2008 mitomycin 8 mg/m2 on day 1, vindesine 3 mg/m2 on days 1 and 8, and cisplatin 80 mg/m2 on day 1 Q 4wks 1/76 (1.3%), 83-84% hematologic Gr 3-4 Toxicity 57/75 (76%) 3/57 (5.3%) 1/57 (1.8%) 51/57 (89%) 12/57 (21%) 12/75 (16%) SWOG 0220 Kraut TBA Cisplatin 50 mg/m2 d1,8,29,36 Etoposide 50 mg/m2 d1-5,29-33 then 3 cycles of docetaxel 75mg/m² Q 21 days 29 (66%) 29 (100%) 8 (28%) 23 (79%) 3 cycles Docetaxel 45% initiated

34 3 Phase II Pancoast Trials Compared- Long Term Results Trial Group and Name Author and Date Chemo Regimen w dose MST (mo) 2 yr Overall Survival % 2-yr Overall Survival for those surgicallyresected % 3-yr DFS (%) 3-yr OS (%) 5-yr Disease Free Survival % 5-yr Overall Survival % If pcr, 5- yr Survival % LR # (%) Systemic Recurrenc e # (%) Brain Recurren ce # (%) SWOG 9416 Rusch, 2007 Cisplatin 50 mg/m2 d1,8,29,36 Etoposide 50 mg/m2 d1-5, , 94 mo if R0 not reached 55% 70% % 54%, T3=T4 (10 local only + 7 Local + systemic) /57 (30%) 19 distant + 7 L +D /57 (46%) 19 of 57 who recurred (41%) JCOG 9806 Kunitoh, 2008 mitomycin 8 mg/m2 on day 1, vindesine 3 mg/m2 on days 1 and 8, and cisplatin 80 mg/m2 on day 1 Q 4wks PFS 28 mo, median OS not reached % 61% 45% 56% T3 better outcome Resected, 2+4/20 recurred (30%) Resected, 14+4/20 (20%) Resected, 4/20 (20%) SWOG 0220 Kraut TBA Cisplatin 50 mg/m2 d1,8,29,36 Etoposide 50 mg/m2 d1-5,29-33 then 3 cycles of docetaxel 75mg/m² Q 21 days

35 Summary of Conclusions from 3 Phase II Trials to Date Induction-related deaths 1-3% Induction progression 8% Resectability is 70-80% R0 rate is 90% pcr 20-35% 10-20% avoid chest wall resection Postoperative mortality 2% Postoperative morbidity ~50% pcr and R0 risk factors for survival 5-yr OS is ~50%

36 N2 Disease in Pancoast Estimates are 10-20% None of the phase II trials included PET in the analysis All 3 of them excluded N2 disease, 1 clinical by criteria There was no standardization of mediastinoscopy or lung resection-related lymphadenectomy quality

37 Locally Advanced Patients are a Heterogeneous Group Surgical Quality is Varied and Often Inadequate Trimodality in selected Patients appears to improve survival Summary

38 Question and Answer Session Kemp H. Kernstine, MD, PhD Professor and Chairman UT Southwestern Medical Center Dallas, TX