ACOSOG (NCCTG, CALGB) Alliance Thoracic Committeee-syllabus.gotoper.com/_media/_pdf/ILC12_Sat_12_Kernstine_Thoracic... · Alliance Thoracic Committee Kemp H. Kernstine, MD PhD

ACOSOG (NCCTG, CALGB) Alliance Thoracic Committee

Kemp H. Kernstine, MD PhD 7-12-12

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

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

Thoracic Committee Aims

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

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

Improve Local Control Aim #1

No Differences in Complications: Lymph Node Sampling vs MSLD

Ann Thorac Surg 2006 81:1013

J Thorac Cardiovasc Surg 2011, 141:662



No Difference within

T1 or T2 either



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

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

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

ACOSOG Z0040

• July, 1999 to March, 2004

• 1,047 acceptable patients (accrued 1310-20% 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%)

Z0040-Conclusions

• Positive Bone Marrow and Pleural Wash did not worsen survival

• Occult metastases in the LN did worsen the survival, HR 1.59-1.63

• There was no correlation between the number of IHC involved nodes and survival.

High-risk

patients with

suspected

or proven

NSCLC

Histological

confirmation

of NSCLC

Sublobar

resection

Sublobar

resection +

brachytherapy

R

A

N

D

O

M

I

Z

E

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


Placement of brachytherapy mesh


AATS 2010

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

Non-

resectable

candidates

Radiofrequency

ablation (RFA)

+ NSCLC

CT image to

document site

and approach

Improve Local Control: Z4033 Aim #1

Putnam JB et al: SPIE Proceedings 75:139, 2000

RFA effects on soft tissues

• Preclinical studies

• Acute porcine model

• Normal lung


Pre-Radiofrequency Ablation RFA Procedure

48 hrs post-RFA

Complete metabolic response (uptake equivalent to blood pool)


3 days post

RFA

Complete

Response

6 months post

RFA

Partial

Response

pre RFA

Preserve surgical effectiveness and minimize surgical morbidity for early stage NSCLC in the high-risk and more normal-risk patient

• From Z4032 – sublobar resection (+/- brachytherapy) vs. stereotactic body radiotherapy in high-risk patients

ACOSOG Z4099/RTOG 1021

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

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

Improve Local Control: ACOSOG Z4099 / RTOG 1021

18 Gy x 3


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.


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

ECOG 2202 – minimally invasive esophagectomy

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

Documents

ACOSOG (NCCTG, CALGB) Alliance Thoracic Committeee-syllabus.gotoper.com/_media/_pdf/ILC12_Sat_12_Kernstine_Thoracic... · Alliance Thoracic Committee Kemp H. Kernstine, MD PhD