Lung cancer is the leading cause of cancer-related mortality in the United States. Despite great advances in the understanding of lung cancer biology, only 15% of patients are alive five years after diagnosis. The research program of the Center for Thoracic Cancers is a multifaceted effort designed to understand thoracic cancer biology, discover novel agents, and improve treatment.

A major focus of our research effort has been molecular epidemiology. Why do only 15% of patients with a smoking history develop lung cancer? Can we explain the variance in outcomes to treatment by looking at differences in the genome? In the laboratory of Dr. David Christiani at the Harvard School of Public Health, Dr. Geoffrey Liu has investigated the relationship between germ line polymorphisms and the development of lung cancer. His work has been particularly insightful in the development of lung cancer in women. An important extension of this work will be to look at esophageal cancers using a similar approach with related genes. Working with Drs. Christiani and Liu, Dr. Sarada Gurubhagavatula is investigating the role that polymorphisms in DNA repair enzymes might play a role in determining the response to platinum-based chemotherapy. Dr. Rebecca Suk is examining the role of these same DNA repair enzymes in predicting toxicity from chemotherapy. The ultimate goal of this work is to make possible a more rationale selection of treatment for patients with lung cancer.

Novel agents hold great promise for lung cancer patients. The Center for Thoracic Cancers, along with our partners at the Dana-Farber/Brigham and Women's Cancer Center, have played a major role in the development of new treatments for advanced lung cancer. Gefitinib is the first molecularly targeted agent to show activity against NSCLC and was approved by the FDA in 2003 for the treatment of advanced lung cancer. Bevicuzimab is a monoclonal antibody that targets VEGF. We are actively investigating the role that bevicuzimab might play along with standard chemotherapy in both patients with early lung cancer and in those with more advanced disease. Finally, antisense oligonucleotides are a promising class of agents. The largest trial to date of an agent that targets protein kinase C was presented at the American Society of Clinical Oncology this year by our group.

Treating early stage lung cancer is also a major focus of our group. Under the leadership of Dr. Douglas Mathisen, the Division of Thoracic Surgery has become a leading center for complex airway surgery as well as resection of thymic and esophageal cancers. Dr. Noah Choi recently obtained R01 funding for his work on integrating dynamic biologic imaging with radiation treatment. At the Francis H. Burr Proton Therapy Center, Dr. Choi is combining intensity modulated proton (and photon) radiation therapy along with chemotherapy for patients with locally advanced lung cancer.

Treating special populations is an important part of the care of lung cancer patients. Lung cancer is essentially a disease of the elderly; nearly 40% of patients with lung cancer are over 70 at the time of diagnosis. We know that elderly patients desire prolongation of life to the same extent as younger patients, yet often older patients are not offered aggressive treatment for their disease. Dr. Panos Fidias has recently published work showing that single agent paclitaxel can have excellent activity in patients over 70. Dr. Fidias' study included pharmacokinetic correlations performed in the laboratory of Dr. Jeffrey Supko at the Cancer Center, which showed that paclitaxel seems to have a similar pharmacokinetic profile in the elderly. Since joining our group this year, Dr. Lecia Sequist is pioneering a novel geriatric assessment tool to determine if we can select patients who should be treated with single agents vs. combination therapy. This work has involved a new collaboration between the Cancer Center and the MGH Geriatrics group.

How do we know which agents make sense to bring forward from phase I to phase III testing? Who is going to pay for this? How do we consider the economic consequences of our treatments of patients with lung cancer? Dr. Thomas Roberts has researched the key decision to proceed to phase III trial testing in the era of targeted therapy. Working with Dr. Scott Gazelle, Dr. Roberts is developing economic models that will help us predict the impact of new drugs and new technologies in the treatment of lung cancer.

The successful treatment of the lung cancer patient requires that we care for the whole patient. Toward that end, Dr. Jennifer Temel focuses her work on the care of lung cancer patients at the end of life, as well as novel approaches to improve quality of life in all lung cancer patients. In association with Massachusetts General Hospital and Dana-Farber Cancer Institute's Palliative Care Services, Dr. Temel has begun a trial of early intervention of a palliative care service for patients with metastatic lung cancer. She is also investigating the impact that a structured exercise program can have on outcomes of patients with advanced lung cancer.

Selected Clinical Research Protocols

Phase III trial of carboplatin/ gemcitabine followed by immediate or delayed docetaxel for patients with advanced NSCLC

A pilot study of early intervention with palliative care in the treatment of patients with advanced lung cancer

Phase II study of C225 in patients with advanced lung cancer

Phase I/II study of chemotherapy with dose-escalated IMRT for patients with locally advanced NSCLC

Phase I study of gefitinib and oral vinorelbine in patients with advanced previously treated NSCLC

Faculty
Thomas J. Lynch Jr., MD
Medical Director

James Allan, MD
Noah Choi, MD
David Christiani, MD
Dean Donahue, MD
Panos Fidias, MD
Henning Gaissert, MD
David Kanerek, MD
Michael Lanuti, MD
Geoffrey Liu, MD
Douglas Mathisen, MD
Thomas Roberts, MD
Jennifer Temel, MD
John Wain, MD
Cameron Wright, MD

Selected Publications
Kris M, Natale R, Herbst R, Lynch T, Prager D, et al. Efficacy of gefitinib, an inhibitor of the epidermal receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. J Am Med Assoc 2003; 290:2149 2158.

Roberts T, Lynch T, Chabner B. The Phase III trial in the era of targeted therapy: Unraveling the "go or no go" decision. J Clin Oncol 2003; 21:3683-3695.

Roof K, Fidias P, Lynch T, Ancukiewicz M, Choi N. Radiation dose escalation in limited-stage small-cell lung cancer. Int J Radiat Oncol Biol Phys 2003; 57: 701-708.

Su L, Liu G, Zhou W, Xu L, Miller DP, Park S, Lynch TJ, Wain JC, Christiani DC. No association between the p21 codon 31 serine-arginine polymorphism and lung cancer risk. Cancer Epidemiology, Biomarkers & Prevention 2003;12:174-5.

Salgia R, Lynch T, Skarin A, et al . Vaccination with irradiated autologous tumor cells engineered to secrete granulocytemacrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small cell lung carcinoma. J Clin Oncol 2003; 21:624-630.

Choi NC, Fischman AJ, Niemierko A, Ryu J-S, Lynch T, Wain J, Wright C, Fidias P, Mathisen D. Dose-response relationship between probability of pathologic tumor control and glucose metabolic rate measured with FDG PET after preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002; 54:1024-1035.

Wright CD, Menard MT, Wain JC, Donahue DM, Grillo HC, Lynch TJ, Choi NC, Mathisen DJ. Induction chemoradiation compared with induction radiation for lung cancer involving the superior sulcus. Ann Thorac Surg 2002; 75:1541-4.

Miller DP, Liu G, De Vivo I, Lynch TJ, Wain JC, Su L, Christiani DC. Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. Cancer Res 2002; 62:2819-23.

Wang LI, Miller DP, Sai Y, Liu G, Su L, Wain JC, Lynch TJ, Christiani DC. Manganese superoxide dismutase alanine-9 to valine polymorphism and lung cancer risk. J Natl Cancer Inst 2001; Dec 5:93(23):1818-1821.

Fidias P, Supko J, Martins R, Boral A, Skarin A, Johnson B, Carey R, Grossbard M, Vasconcelles M, Shapiro G, Lynch T. A phase II clinical and pharmacokinetic study of weekly paclitaxel in elderly patients with non-small cell lung cancer. Clin Cancer Res 2001; 7(12):3942-9.