ACOSOG Thoracic Committee Kemp H. Kernstine, MD PhD
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
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 Aim #3: Enhance therapeutic efficacy through biological and molecular markers
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
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
No Differences in Complications: Lymph Node Sampling vs MSLD Ann Thorac Surg 2006 81:1013
J Thorac Cardiovasc Surg 2011, 141:662
J Thorac Cardiovasc Surg 2011, 141:662
J Thorac Cardiovasc Surg 2011, 141:662 No Difference within T1 or T2 either
J Thorac Cardiovasc Surg 2011, 141:662
J Thorac Cardiovasc Surg 2011, 141:662
How Many More Lymph Nodes? Sampling vs Dissection Dissection 18 more lymph nodes, Right equaled Left Dissection 11-12 more N2 lymph nodes, Right equaled Left 90% of Dissection patients had 10 nodes harvested in each of 3 stations Chest 2011; 139:1124
Resectable NSCLC: The Problem 30-40% Stage I Recur and die of NSCLC Strategies to identify those at risk: Primary tumor evaluation Genome, Transcriptome and/or Proteome Peripheral Markers CTC, Cell Fragments, Proteome, Metabolisome, Circulating DNA/RNA Occult Disease Nodes, Lung, Pleura, Bone Marrow, Brain, etc. Stage I Adenocarcinoma Cleveland Clinic Ann Thorac Surg 2010; 90:1067 Circulating Tumor Cells Nature 2007; 450:1235
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.
Enhance Therapy / Biomarkers Aim #3 Z0040: Occult Metastases Resectable NSCLC. The study evaluated three indicators of occult metastases in patients with resectable NSCLC: cytology examination of pleural lavage IHC assay of micrometastatic deposits within lymph nodes IHC assay of micrometastases in rib bone marrow. IHC staining Mab to cytokeratin CAM5.2 and AE-1 Two blinded pathologists, third settles difference
Enhance Therapy / Biomarkers Aim #3 Does Occult Disease Impact Long-term Survival in Surgical NSCLC? Accrued 1310 over 7/99-3/04 1310-263 ineligible-114 lost to F/U = 933 (78%) eligible patients 95% R0 resection Wedge Acceptable, 10% of total 80% Lobectomies
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
Improve Local Control Aim #1 Placement of brachytherapy mesh
Improve Local Control Aim #1 1.0 0.8 Survival for NSCLC ( 2 cm ) 0.6 0.4 Lobar (n=80) 0.2 0.0 Sublobar (n=57) P=0.97 0 50 100 150 200 Follow-up (mo) Fernando HC et al: J Thorac Cardiovasc Surg 129:261, 2005
AATS 2010
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)
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
Improve Local Control: Z4033 Aim #1 Pre-Radiofrequency Ablation RFA Procedure 48 hrs post-rfa Complete metabolic response (uptake equivalent to blood pool)
F-18 FDG PET/CT in Stage IA NSCLC after RFA: Initial Report from a Cooperative Group Trial: American College of Surgeons Oncology Group Z4033 Don C Yoo, MD, Shauna Hillman, PhD, Homer A Macapinlac, MD; Hiran Fernando, MD; William S Rilling, MD; Jo-Anne O Shepard, MD, Damian E. Dupuy MD RSNA Annual meeting 2009
pre RFA 3 days post RFA Complete Response 6 months post RFA Partial Response
Results: Early post RFA PET/CT did not correlate with the findings on 6 month follow-up PET/CT (n=26) 6 Month Follow-up PET/CT Early PET/CT Complete Response Partial Response Progressive Response Complete Response Partial Response Progressive Response No follow-up 4 3 2 5 1 4 2 3 1 - - - No Response 1 - - -
Improve Local Control: Future Trials 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
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
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.
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.
Intergroup Participation ECOG 1505 postoperative adjuvant chemotherapy +/- bevacizumab (p stage IB >4 cm, II, select IIIA) CALGB 30506 metagene predictor model for adjuvant chemotherapy (p stage IA, IB <4 cm) CALGB 140503 - A Phase III trial of lobectomy versus sublobar resection for small ( 2 cm) NSCLC RTOG 1010 - A phase III trial evaluating Trastuzumab with trimodality therapy HER2-overexpressing EC ACOSOG Z4099 - Adjuvant Mediastinal Observation or Radiotherapy Evaluation for occult N2
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
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