ACOSOG (NCCTG, CALGB) Alliance Thoracic Committee Kemp H. Kernstine, MD PhD

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1 ACOSOG (NCCTG, CALGB) Alliance Thoracic Committee Kemp H. Kernstine, MD PhD

2 ACOSOG Thoracic Committee Chair: Bryan Meyers, M.D., MPH Vice Chairs: Malcolm Brock, MD Tom DiPetrillo, M.D. Ramaswamy Govindan, M.D. Carolyn Reed, MD

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5 Thoracic Committee Aims Aim #1: To individualize the care of thoracic malignancies through novel and local ablative therapies Aim #2: To apply neoadjuvant and adjuvant therapeutic strategies for NSCLC and esophageal cancers Aim #3: Enhance therapeutic efficacy through biological and molecular markers

6 Outline of ACOSOG Lung Cancer Trials Z0030 Early Dx Lymphatic Sampling v Dissection Z0040 Occult Metastases and Effect On Survival Z4032 Wedge vs Wedge BrachyThx in Hi Risk Early Disease Z4033 RFA in Hi Risk Early Disease Z4099/RTOG-1041 IMRT vs Wedge in Hi Risk

7 Improve Local Control Aim #1 Z0030 Randomized Trial of Mediastinal Lymph Node Sampling versus Complete Lymphadenectomy During Pulmonary Resection in the Patient with N0 or N1 (less than hilar) Non-Small Cell Carcinoma

8 No Differences in Complications: Lymph Node Sampling vs MSLD Ann Thorac Surg :1013

9 J Thorac Cardiovasc Surg 2011, 141:662

10 J Thorac Cardiovasc Surg 2011, 141:662

11 J Thorac Cardiovasc Surg 2011, 141:662 No Difference within T1 or T2 either

12 J Thorac Cardiovasc Surg 2011, 141:662

13 J Thorac Cardiovasc Surg 2011, 141:662

14 How Many More Lymph Nodes? Sampling vs Dissection Dissection 18 more lymph nodes, Right equaled Left Dissection more N2 lymph nodes, Right equaled Left 90% of Dissection patients had 10 nodes harvested in each of 3 stations Chest 2011; 139:1124

15 Enhance Therapy / Biomarkers Aim #3 Z0040: A Prospective Study of the Prognostic Significance of Occult Metastases in the Patient with Resectable Non-small Cell Lung Carcinoma.

16 Occult Metastases in Lymph Nodes Predict Survival in Resectable Non Small-Cell Lung Cancer: Report of the ACOSOG Z0040 Trial Determine prevalence of occult metastases and it s relationship to survival Eligible: previously untreated and potentially resectable NSCLC Nodes reexamined after routine exam and w cytokeratin IHC; saline lavage prior to and after resection; bone marrow examined

17 ACOSOG Z0040 July, 1999 to March, ,047 acceptable patients (accrued % excluded), median age 67.2 years 66% Stage I Pleural lavage positive in 29 (3.3%) Bone marrow positive in 66 (8%) N0 lymph nodes positive (anticytokeratin antibodies CAM 5.2 and AE-1) in 130 (22.4%)

18 Z0040-Conclusions Positive Bone Marrow and Pleural Wash did not worsen survival Occult metastases in the LN did worsen the survival, HR There was no correlation between the number of IHC involved nodes and survival.

19 Improve Local Control Aim #1 Z4032: A randomized phase III study of sublobar resection versus sublobar resection plus brachytherapy in high-risk patients with non-small cell lung cancer (NSCLC), 3cm High-risk patients with suspected or proven NSCLC Histological confirmation of NSCLC R A N D O M I Z E Sublobar resection Sublobar resection + brachytherapy

20 Improve Local Control Aim #1 Placement of brachytherapy mesh

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25 AATS 2010

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27 Improve Local Control: Z4033 Aim #1 Z4033: A pilot study of radiofrequency ablation in high-risk patients with stage IA non-small cell lung cancer High-risk patients with suspected or proven NSCLC Nonresectable candidates + NSCLC CT image to document site and approach Radiofrequency ablation (RFA)

28 Improve Local Control: Z4033 Aim #1 RFA effects on soft tissues Preclinical studies Acute porcine model Normal lung Putnam JB et al: SPIE Proceedings 75:139, 2000

29 Improve Local Control: Z4033 Aim #1 Pre-Radiofrequency Ablation RFA Procedure 48 hrs post-rfa Complete metabolic response (uptake equivalent to blood pool)

30 pre RFA 3 days post RFA Complete Response 6 months post RFA Partial Response

31 ACOSOG Z4099/RTOG 1021 Preserve surgical effectiveness and minimize surgical morbidity for early stage NSCLC in the highrisk and more normal-risk patient From Z4032 sublobar resection (+/- brachytherapy) vs. stereotactic body radiotherapy in high-risk patients

32 A Randomized Phase III Study of Sublobar Resection (+/- Brachytherapy) versus Stereotactic Body Radiation Therapy in High Risk Patients with Stage I Non- Small Cell Lung Cancer (NSCLC) ACOSOG Z4099/RTOG 1021 Same group of patients as in Z4032 Inclusion: FEV1 < 50% or DLCO < 50%; Minor (need 2): Age > 75, FEV1 DLCO, Pulm HTN sys > 40mmHG, LVEF < 40%, PaO2 < 55, PaCO2 45 mmhg, MMRC score > 3

33 Improve Local Control: ACOSOG Z4099 / RTOG 1021 A Randomized Phase III Study of Sublobar Resection versus Stereotactic Body Radiation Therapy in High Risk Patients with Stage I Non- Small Cell Lung Cancer. PI Chrish Fernando / Bob Timmerman 18 Gy x 3

34 Improve Local Control: ACOSOG Z4099 / RTOG 1021 Primary objective: To ascertain whether patients treated by SBRT have 3-year overall survival (OS) rate that is no more than 10% less than patients treated with SR.

35 Improve Local Control: ACOSOG Z4099 / RTOG 1021 Secondary objective(s): To compare loco-regional recurrence-free survival and disease-free survival between study arms. Locoregional recurrence includes recurrence within the same lobe or hilum (N1 nodes), or progression within 1cm of the staple line after SR, or within 1cm of the PTV after SBRT (local progression) after treatment effects such as scarring have subsided. To compare treatment-related specific adverse event profiles at 1, 3 and 12 months post therapy. To compare pulmonary function between arms To determine morbidity in each arm for patients with low or high Charlson comorbidity index scores, and whether this index can be used to select patients for SBRT or SR.

36 Intergroup Participation ECOG 1505 postoperative adjuvant chemotherapy +/- bevacizumab (p stage IB >4 cm, II, select IIIA) CALGB metagene predictor model for adjuvant chemotherapy (p stage IA, IB <4 cm) CALGB A Phase III trial of lobectomy versus sublobar resection for small ( 2 cm) NSCLC ECOG 2202 minimally invasive esophagectomy RTOG A phase III trial evaluating Trastuzumab with trimodality therapy HER2-overexpressing EC ACOSOG Z Adjuvant Mediastinal Observation or Radiotherapy Evaluation for occult N2

37 Translational Studies Adjuvant therapy in early or locally advanced stage (resected) NSCLC based on a selected high-risk molecular characteristic such as metagene model DNA methylation lymph nodes Simple (e.g. 2-gene) prognostic model

38 Summary Novel large thoracic surgical studies with innovative therapeutic aims completed which will impact choice and extent of care of patients with NSCLC Multidisciplinary participation embraced with rapid expansion of protocols. Engaging other cooperative groups as a strategic plan to complete high-priority surgical studies