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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.


The Multi-Modality Approach to Stage III NSCLC: Current State of Knowledge


GOAL
To provide physicians and oncology nursing professionals with up-to-date information on the treatment and management of patients with non-small cell lung cancer.

TARGET AUDIENCE
This activity is designed for physicians and oncology nursing professionals. No prerequisites required.

LEARNING OBJECTIVES
The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing take responsibility for the content, quality, and scientific integrity of this CE activity. At the conclusion of this activity, the participant should be able to:

  • Recognize the impact and clinical guidelines of treating stage III non-small cell lung cancer (NSCLC).
  • Describe the issues and trends of using adjuvant and neoadjuvant chemotherapy for stage III NSCLC.
  • Understand the mechanism of action of current and emerging therapies in the treatment and management of stage III NSCLC.
  • Compare and contrast the latest clinical trial results of multimodal therapies that have used chemotherapy and/or chemoradiotherapy before and/or after surgery.

ACCREDITATION STATEMENT
The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Institute for Johns Hopkins Nursing is accredited as a provider of continuing nursing education by the American Nurses' Credentialing Center's Commission on Accreditation.

CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The Institute for Johns Hopkins Nursing designates this educational activity for a maximum of 2.4 contact hours. Claim only those contact hours actually spent in the activity.

The estimated time to complete this educational activity: 2 hours.

Release date: April 15, 2006.
Expiration date: April 15, 2008.

DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing name implies review of educational format, design, and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an educational grant from sanofi-aventis U.S.

Full Disclosure Policy Affecting CE Activities:
As a provider accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of the Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Directors and Participating Faculty reported the following:

PROGRAM DIRECTORS

Julie R. Brahmer, MD
Assistant Professor
Department of Oncology
The Sidney Kimmel Comprehensive  Cancer Center
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Brahmer reports receiving grants/research support from AstraZeneca and Wyeth; and receiving honoraria from Sanofi-Aventis.

Denise J. Dianna, RN, BSN, OCN
Oncology Nurse Clinician
The Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins Hospital
Baltimore, Maryland
Ms Dianna reports having no financial or advisory relationships with corporate organizations related to this activity.

David S. Ettinger, MD
Alex Grass Professor of Oncology
Otolaryngology, Head and Neck Surgery
Gynecology and Obstetrics
Radiation Oncology and Molecular Radiation Sciences
The Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr Ettinger reports receiving grants/research support from Eli Lilly and Company, Novartis, and Sanofi-Aventis; serving as a consultant for AstraZeneca, Aventis, Bristol-Myers Squibb Company, Cell Therapeutics, Eli Lilly and Company, GlaxoSmithKline, Merck and Company, MGI Pharma, and Pfizer, Inc; and receiving honoraria from AstraZeneca, Aventis, Bristol-Myers Squibb Company, Eli Lilly and Company, GlaxoSmithKline, Merck and Company, MGI Pharma, and Pfizer, Inc.

PARTICIPATING FACULTY

Royce Calhoun, MD
Assistant Professor
SurgeryÐCardiothoracic
University of California Davis Cancer Center
Sacramento, California
• Dr Calhoun reports having no financial or advisory relationships with corporate organizations related to this activity.

David R. Gandara, MD
Professor of Medicine
Division of Hematology/Oncology
Associate Director for Clinical Research
Director, Thoracic Oncology Program
University of California Davis Cancer Center
Sacramento, California
Dr Gandara reports receiving grants/research support from Bristol-Myers Squibb Company and Sanofi-Aventis; and serving as a consultant for Genentech and Sanofi-Aventis.

Oliver Gautschi, MD
Visiting Clinician
University of California Davis Cancer Center
Sacramento, California
Dr Gautschi reports having no financial or advisory relationships with corporate organizations related to this activity.

Zelanna Goldberg, MD
Associate Professor
Department of Radiation Oncology
University of California Davis Cancer Center
Sacramento, California
Dr Goldberg reports having no financial or advisory relationships with corporate organizations related to this activity.

Wayne L. Hofstetter, MD
Assistant Professor
Department of Thoracic and Cardiovascular Surgery
University of Texas MD Anderson Cancer Center
Houston, Texas
Dr Hofstetter reports having no financial or advisory relationships with corporate organizations related to this activity.

Edward S. Kim, MD
Assistant Professor
Department of Thoracic/Head and Neck Medical Oncology
University of Texas MD Anderson Cancer Center
Houston, Texas
Dr Kim reports receiving grants/research support from AstraZeneca, Eli Lilly and Company, Genentech, ImClone, and Sanofi-Aventis.

Primo N. Lara, Jr, MD
Associate Professor
Department of Hematology/Oncology
University of California Davis Cancer Center
Sacramento, California
Dr Lara reports serving on the speaker's bureau for Sanofi-Aventis.

Alex Metzger, MD
Senior Fellow
Department of Hematology/Oncology
University of California Davis Cancer Center
Sacramento, California
Dr Metzger reports having no financial or advisory relationships with corporate organizations related to this activity.

Notice: The audience is advised that the articles in this CE activity contain no reference(s) to unlabeled or unapproved uses of drugs or devices.

Johns Hopkins Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Johns Hopkins Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Multimodality Approach To Stage III NSCLC: Current State Of Knowledge
David S. Ettinger, MD, Julie R. Brahmer, MD,  and Denise J. Dianna, RN, BSN, OCN

Non-small cell lung cancer (NSCLC) requires a multimodality approach for optimal patient treatment. NSCLC accounts for 80% of all lung cancers and more than 130 000 deaths in the United States alone each year.1 Multimodality therapy involves the use of chemotherapy, radiation therapy, and surgery in 1 of several different approaches, such as sequential, concurrent, induction-first, or concurrent-first combinations. Clinical teams comprised of 1 or more medical oncologists, thoracic surgeons, radiation oncologists, pulmonologists, and other radiologists or other personnel lend their expertise to the process of determining the best course of treatment per patient and his/her stage of disease. Patients with NSCLC are classified at diagnosis into 3 major treatment groups based on the stage of disease: patients with surgically resectable tumors (stages I and II), patients with locally (T3ÐT4) or regionally (N2ÐN3) advanced lung cancer (stage III), and patients with distant metastases (M1; stage IV). Thefocus of this monograph is stage III NSCLC, and more specific, stage IIIA and stage IIIB disease are addressed.

Combined-modality treatment for stage III NSCLC is the subject of robust and global clinical research and it continues to evolve rapidly with more widely available venues for dissemination of clinical trial results. Chemotherapy before surgery is now an established form of treatment for resectable stage IIIA NSCLC. Since the 1990s, data from randomized clinical trials and surveys of institutional databases has indicated that survival is much improved with induction chemotherapy plus surgical resection, rather than with resection alone, in patients with stage IIIA disease.2-4 However, controversy continues to exist regarding which combined treatments are optimal for stage IIIA and stage IIIB subsets, given that stage III is a heterogeneous set of disease states that can clinically range from tumors rated as apparently resectable (with occult microscopic nodal metastases) to unresectable (multistation nodal disease), in addition to tumors (T3 and T4) that invade a variety of structures (ie, chest wall, mediastinum, heart, and proximal airways). Ongoing complexities in staging (and possible restaging after therapy) can further complicate accurate diagnosis and treatment decisions.

These and many other unresolved issues present an ongoing challenge for clinicians using combined-modality approaches. Despite a multitude of clinical advances in chemotherapy, radiotherapy, chemoradiotherapy, and/or newer imaging technologies, there are many facets of multimodality treatment that need to be resolved. A major issue at present is whether surgical resection is desirable for some patients with stage III disease. Other major questions that need to be answered include the following: Is there an ideal sequence of radiotherapy and chemotherapy for specific subsets of patients? How can existing and emerging molecular agents be "customized" for a stage III patient, based on their individual genotype, coupled with their tumor subtype? Can the issue of micrometastases in the distant sanctuary of the brain be addressed during early administration of combined-modality treatment? These questions and others are discussed in the articles of this monograph.

In this issue of Johns Hopkins Advanced Studies in Medicine, Oliver Gautschi, MD, Zelanna Goldberg, MD, Royce Calhoun, MD, and  David R. Gandara, MD, provide the collective "voices" of the medical oncologist, the thoracic surgeon, and the radiation oncologist in their detailed overview of current approaches to multimodality treatment in devising strategies for patients with stage III NSCLC. The first half of the review article discusses details of the multimodality approach, and provides background and discussion of the following: epidemiology and the complexities of clinical staging and diagnosis; treatment-related considerations; treatment of potentially resectable and unresectable disease, including a historical treatise, biological and clinical considerations, and an analysis of different treatment paradigms that have evolved. The article also highlights new treatment regimens, such as incorporation of prophylactic cranial irradiation to address potential micrometastasis to the brain, evolving approaches to radiotherapy, and integration of molecular targeted agents into combined-modality therapy.

The clinician interview with David S. Ettinger, MD, Julie R. Brahmer, MD, and Edward S. Kim, MD, discusses in detail many of the contemporary issues and future directions in multimodality treatment. Topics discussed include ongoing issues of clinical staging, including the current International Association for the Study of Lung Cancer staging project, its mission and timeline, and its clinical ramifications; whether there is a role for surgery in stage IIIA (N2) disease; optimization of multimodality therapy of resectable versus unresectable tumors; comparison of neoadjuvant therapies; molecular targeted therapies in practice and emerging from the laboratory; and the outlook for future approaches to treating stage III NSCLC.

The case study by Edward S. Kim, MD, and Wayne L. Hofstetter, MD, focuses on the importance of staging and accurate diagnosis for patients with stage IIIA T2N2M0. Emphasized here are the important stepwise decisions that must be made by the multimodality team members to provide the best-fit provision of treatment that may be the most efficacious per patient. Issues that are mentioned include the role of positron emission tomography/computed tomography scanning, mediastinoscopy, neoadjuvant chemotherapy versus other therapy, nonsurgery versus surgery (ie, resectable vs nonresectable; pneumonectomy vs lobectomy), and potential for disease downstaging after treatment.

The case study by Alex Metzger, MD, and Primo N. Lara, Jr, MD, focuses on effective treatment strategies for stage IIIA (N2) NSCLC, including the importance of placing patients into best-fit clinical trials to determine the best treatment regimen. The hypothetical patient is placed into a clinical trial designed to compare induction chemotherapy alone versus concurrent chemotherapy and induction radiotherapy. The rationale for the patient's entry into the clinical trial (Radiation Therapy Oncology Group 0412 or Southwest Oncology Group 0332) is discussed in detail, as is the schema for the protocol design. This case study also highlights the major controversy as to whether there is a role for neoadjuvant and adjuvant therapy in unresectable stage IIIA patients.

Collectively, the articles in this monograph provide a thorough discussion of major controversies, advances, and emerging concepts regarding multimodality treatment for stage III NSCLC. The contents of this monograph will help clinicians, researchers, fellows-in- training, and oncology nurses broaden their understanding of key issues and existing complexities in determining the best multimodality approach per individual patient with stage III NSCLC.

REFERENCES

1. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: looking to the future. J Clin Oncol. 2005;23:3175-3185.
2. Roth JA, Fossella F, Komaki R, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994;86:673-680.
3. Rosell R, Gomez-Codina J, Camps C, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med. 1994;330:153-158.
4. Martin LW, Correa AM, Hofstetter W, et al. The evolution of treatment outcomes for resected stage IIIA non-small cell lung cancer over 16 years at a single institution. J Thorac Cardiovasc Surg. 2005;130:1601-1610.

*Alex Grass Professor of Oncology, Otolaryngology, Head and Neck Surgery, Gynecology and Obstetrics, Radiation Oncology and Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
 Assistant Professor, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Oncology Nurse Clinician, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, Maryland.
Address correspondence to: David S. Ettinger, MD, Department of Oncology, The Sidney Kimmel
Comprehensive Cancer Center, Johns Hopkins University School of Medicine, CRB-G88, 1650 Orleans Street, Baltimore, MD. E-mail: ettinda@jhmi.edu.

The content in this monograph was developed with the assistance of a staff medical writer. Each author had final approval of his/her article and all its contents.





Johns Hopkins Advanced Studies in Medicine (ISSN-1558-0334), is published by Galen Publishing, LLC, d/b/a ASiM, PO Box 340, Somerville, NJ 08876. (908) 253-9001. Copyright ©2012 by Galen Publishing. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, without first obtaining permission from the publisher. ASiM is a registered trademark of The Healthcare Media Group, LLC.