Thoracic

Our Clinical Trials Continually updated listing of our clinical trials for thoracic cancers more

Our thoracic cancer clinical research team is developing new treatments for cancers that arise in the chest, especially lung cancer and mesothelioma. Our team's medical and radiation oncologists, pathologists, radiologists, and surgeons are at the forefront of developing many of the latest treatments for these cancers. We are also looking at new ways to improve lung function both during and after treatment for cancer.

Our researchers are investigating many leading-edge treatments, such as minimally invasive surgery for the removal of tumors and three-dimensional conformal radiation therapy. We have also pioneered the study of novel chemotherapy agents for thoracic cancers, including several of the latest "targeted therapy" agents.

Among our recent research accomplishments:

Detection, Diagnosis, and Prognosis

• Multiple retrospective and prospective studies conducted at Memorial Sloan-Kettering Cancer Center have demonstrated the value of positron emission tomography (PET) standardized uptake value for predicting prognosis in patients with resectable non-small cell lung cancer, mesothelioma, and small cell lung cancer. These studies were either the initial or most persuasive studies. Our results in patients with mesothelioma led directly to the incorporation of PET imaging into a multicenter trial of multimodality therapy for the initial staging, prognostic stratification, and assessment of response to induction chemotherapy. Ann Thorac Surg 2006;81:1076-1081. [PubMed Abstract]; J Thorac Cardiovasc Surg 2006;132:763-768. [PubMed Abstract]

Molecular Pathology

• The Lung Cancer Oncogenome Group (LCOG) at Memorial Sloan-Kettering Cancer Center focuses on the molecular pathogenesis and targeted therapy of lung adenocarcinoma in both human tumors and mouse models. This group meets weekly and brings together clinical researchers from multiple hospital departments and members of multiple laboratory groups in other programs. The work of the LCOG has been facilitated by the development of a high-quality tissue bank that now includes some 600 well-annotated primary lung cancers and paired benign lung specimens. LCOG interactions have led to the design of clinical trials exploring mutational status as a determinant of initial therapeutic approach; to funded participation of the group in a Director's Challenge grant in lung adenocarcinoma; and to our being a major contributor to the National Cancer Institute-funded Cancer Genome Atlas Lung Cancer Sequencing Project. We are developing a more prognostically accurate subtyping of adenocarcinoma based on gene expression profiling correlated to histopathologic and clinical features.

• Much of the current thrust in lung cancer relates to EGFR-directed therapy. The Lung Cancer Oncogenome Group has actively sought an improved understanding of the molecular determinants of sensitivity to and resistance of lung cancers to tyrosine kinase inhibitors (TKIs) targeting the EGFR pathway. Analyses of prospective clinical trials have revealed that response to both gefitinib and erlotinib correlate with smoking history and with EGFR mutation status; that EGFR and KRAS mutations appear to be mutually exclusive events in lung adenocarcinoma; that KRAS mutations are associated with resistance to EGFR TKIs; and that acquired resistance to EGFR TKIs is related, in part, to the development of a second mutation. The finding by investigators at Memorial Sloan-Kettering and in Boston of a clinically important relationship between EGFR mutation status and sensitivity to clinically available TKIs has led directly to a clinically available diagnostic tool and to clinical trials at both Memorial Sloan-Kettering and other centers testing novel agents (HKI-272, BIBW2992, dasatinib, DMAG, and ipilumumab) in patients with tumors that are resistant to gefitinib and erlotinib. J Clin Oncol 2006;24:1700-1704. [PubMed Abstract]; PLoS Med. 2005 Mar;2(3):e73. [PubMed Abstract]; PLoS Med. 2005 Jan;2(1):e17. [PubMed Abstract]

• Our investigators are leading studies evaluating DNA methylation and the levels of total circulating DNA in patients with early-stage and advanced non-small cell lung cancer. To improve the identification of patients at risk for cancer, prospective clinical trials are in progress to analyze DNA repair and genetic susceptibility to non-small cell lung cancer in current or former smokers and in nonsmokers.

Novel Therapeutic Agents

• The Thoracic Disease Management Team has been at the forefront of efforts to understand how EGFR kinase inhibition leads to tumor killing in lung cancer. A prospective trial is evaluating induction and adjuvant gefitinib in patients with resectable lung adenocarcinoma with a bronchoalveolar component and a minimal or no smoking history. This study aims to confirm prospectively our prior observation that the presence of EGFR mutations correlates with response to gefitinib.

• Using surgical resection specimens, we will study the mechanisms that permit persistence of EGFR-mutant cells after initial treatment. The demonstration that mutations in EGFR underlie sensitivity to EGFR TKIs has fostered clinical efforts to identify more effective inhibitors of EGFR (such as HKI-272 and XL647) and pathways parallel to or downstream of EGFR, such as mTOR (targeted by the drug everolimus).

• Despite rapid and dramatic regressions with EGFR TKIs in patients with tumors bearing mutations in EGFR, all patients relapse. In a study designed to permit re-biopsy of such patients, we have discovered two new mutations responsible for acquired resistance: T790M and D761Y. Clinical trials are underway to assess the effectiveness of HKI-272 and everolimus in these patients. We have learned that 48-hour pretreatment with EGFR TKIs greatly enhances the ability of chemotherapy to cause regressions in human tumor xenografts; escalating the TKI dose causes additional regression. Our investigators have designed a randomized phase II clinical trial to replicate this experiment in patients. Clin Cancer Res 2005;11:1983-1989. [PubMed Abstract]

• In national extensions of our efforts, we are co-chairing a randomized phase II CALGB trial comparing chemotherapy plus erlotinib with erlotinib alone in patients with lung adenocarcinomas and a minimal smoking history. This trial is a direct outgrowth of our translational research efforts and of previous clinical research studies and multicenter trials. J Clin Oncol 2006;24:1700-1704. [PubMed Abstract]

• Based on the results of several trials testing multimodality approaches to resectable malignant pleural mesothelioma, extrapleural pneumonectomy (EPP) and adjuvant high-dose hemithoracic radiation (HDRT) has emerged as a standard treatment. Investigators have also established the feasibility of induction cisplatin-based chemotherapy before EPP and HDRT. These results motivated a recently completed phase II multicenter trial of this strategy evaluating induction cisplatin and pemetrexed in this multimodal sequence. Brachytherapy 2005;4:30-33. [PubMed Abstract]; J Thorac Onco1 2006;1:289-295. [PubMed Abstract]

• We are evaluating the effectiveness of suberoylanilide hydroxamic acid (SAHA, also known as vorinostat), a drug developed at Memorial Sloan-Kettering, for the treatment of mesothelioma. In 2006, the FDA approved vorinostat for the treatment of cutaneous T-cell lymphoma (under the brand name Zolinza), and the drug is now being assessed for the treatment of other types of cancer. Following our identification of aurora kinase overexpression in mesothelioma, we are now conducting a phase I trial of the aurora kinase inhibitor AZD1152 in patients with mesothelioma. Clin Lung Cancer 2006;7:257-261. [PubMed Abstract]

Radiation Therapy

• Our radiation oncologists have been investigating ways of effecting more precise delivery of high-dose radiation through better control of tumor motion and the integration of PET and cone-beam imaging. Integrating PET into treatment planning improves the reproducibility of tumor delineation. A phase I dose-escalation trial using 3D conformal radiotherapy for inoperable non-small cell lung cancer established that a dose of 84 Gy can be safely delivered in patients and reported very favorable survival and local control rates in patients receiving greater than 80 Gy. Int J Rad Oncol Biol Phys 2005;62:70-75. [PubMed Abstract]; Cancer 2005;103:2118-2127. [PubMed Abstract]