The Stephen E. and Catherine Pappas Center for Neuro Oncology is a national leader in clinical research and the development of experimental therapeutics for adult malignant brain tumors. Massachusetts General Hospital is a founding member of the National Cancer Institute (NCI)-sponsored New Approaches to Brain Tumor Therapy (NABTT) clinical trials consortium and has entered its eleventh consecutive year of funding as part of this cooperative group. There are currently 18 open clinical trials for patients with newly diagnosed and recurrent malignant brain tumors. With more than 4,000 outpatient visits per year, the program is one of the largest in the U.S. Faculty members in the program also collaborate closely with colleagues at multiple institutions as part of Dana-Farber/Partners CancerCare. The Stephen E. & Catherine Pappas Center is supported by cooperative group grants (NABTT, RTOG), a program project grant (gene therapy), and multiple investigator-specific NIH grants.

Clinical trials
Most clinical trials in the program are NCI/NABTT-sponsored phase I and II studies, with our investigators currently serving as national chairs of three such studies. In addition, institution was designated as the Pharmacology Core Laboratory for NABTT in 2004. The Neuro-Oncology Program is also an active participant in studies of agents designed to enhance the sensitivity of tumor cells to ionizing radiation as part of the Radiation Therapy Oncology Group (RTOG). In addition to these approaches, the hospital is an international leader in the development of gene therapy for malignant gliomas. An NIH funded program project in the gene therapy of gliomas has led to a phase I trial of viral vector-based gene therapy for recurrent malignant gliomas.

Current efforts in the gene therapy program include:

• studying combinations of gene-based therapeutics with chemotherapy and/or radiation
• using oncolytic viruses to engender immunity to gliomas
• studying the effects of the innate immune response against virally treated gliomas
• designing improved versions of viral vectors, and increasing the selectivity of vectors by targeting gliomas

In addition to NCI/NABTT, RTOG, institutional and industry clinical trials, Neuro-Oncology Program investigators have collaborated with colleagues at Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Children's Hospital Boston to conduct ongoing clinical trials of anti-angiogenic therapies and a telomerase peptide vaccine trial.

Primary central nervous system lymphoma
The hospital investigators have established standard therapeutic approaches for primary central nervous system lymphoma (PCNSL) on the basis of national, multicenter studies. Two ongoing, national, multicenter studies of methotrexate and thio TEPA for newly diagnosed PCNSL and rituximab for recurrent PCNSL are chaired by the hospital investigators. In addition, our physicians have established useful prognostic markers in this disease. An international collaborative group to study PCNSL, chaired by an Massachusetts General Hospital investigator, has been established as part of the International Extranodal Lymphoma Study Group.

Neurofibromatosis
Investigators have a longstanding research interest in neurofibromatosis 1 and neurofibromatosis 2. Ongoing work includes characterization of the NF1 and NF2 genes and the development of an animal model for translational studies. The Neurofibromatosis Clinic provides comprehensive care for patients and recently was awarded a planning grant to design a multi-institutional clinical trials consortium for neurofibromatosis 1.

Molecular classification of brain tumors
Investigators at the institution have pioneered studies of the molecular classification of adult primary brain tumors. As a result of this work, chromosome 1p and chromosome 19q analysis are now routinely ordered as part of the diagnostic evaluation of patients with oligodendroglial tumors. Ongoing work utilizing gene-expression profiling has established distinct subsets of glioblastoma, and this information will be incorporated into future clinical trials. All new primary brain tumor patients are consented for entry into a clinical database and a brain tumor tissue bank at the hospital. More than 1500 primary brain tumor patients have been entered into the database since the inception of this resource in 1998. Correlative clinical-genetic studies are ongoing using these resources.

Neuroimaging of brain tumors
Investigators in the program have developed an active research imaging program for brain tumors utilizing spectroscopy and diffusion weighted images to predict chemosensitivity of brain tumors. This work, funded by NIH grant support, is ongoing.

Fellowship training
A fellowship program in Neuro-Oncology has existed at Massachusetts General Hospital for three decades. Over the past three years, the program has expanded significantly and was awarded an NCI-sponsored K12 training grant in 2001. There are currently seven trainees in the program, five of whom hold both MD and PhD degrees. Graduates of the training program hold leadership positions in multiple academic centers across the U.S.

Selected Clinical Research Protocols

Phase II study of intravenous methotrexate and thiotepa in patients with newly diagnosed primary central nervous system lymphoma

Phase I/II trial of oxaliplatin as neoadjuvant treatment in adults with newly diagnosed glioblastoma multiforme

ST 1481 in adults with malignant glioma: A phase I-II clinical trial

Phase II study of AZD2171 for recurrent glioblastoma

Faculty
Tracy T. Batchelor, MD
Executive Director
Robert L. Martuza, MD
Director
Jay S. Loeffler, MD
Chief, Department of Radiation Oncology

Fred Barker, MD
Arnab Chakravarti, MD
William Curry, MD
E. Tessa Hedley Whyte, MD
John Henson, MD
Fred Hochberg, MD
David Louis, MD
Mia Maccollin, MD
Robert Ojemann, MD
Alison O'Neill, MD
Scott Plotkin, MD, PhD
Nancy Tarbell, MD
Halyna Vitagliano, MD

Selected Publications
Batchelor TT, Carson K, O'Neill A, Alavi J, New P, Grossman SA, Hochberg F, Priet R. for the NABTT CNS Consortium. The treatment of primary central nervous system lymphoma (PCNSL) with methotrexate and deferred radiotherapy: NABTT 96-07. J Clin Oncol 2003; 21:1044-1049.

Braaten KM, Betensky RA, de Leval L, Okada Y, Hochberg F, Louis DN, Harris NL, Batchelor TT. Bcl-6 expression predicts improved survival in patients with primary central nervous system lymphoma. Clin Cancer Res 2003; 9:1063-1069.

Hampl JA, Camp SM, Mydlarz WK, Hampl M, Ichikawa T, Chiocca EA, Louis DN, Sena-Esteves M, Breakefield XO. Potentiated gene delivery to tumors using HSV/EBV/RV tribrid amplicon vectors. Human Gene Therapy 2003; 14:611-626.

Baehring JM, Damek D, Martin EC, Betensky RA, Hochberg FH. Neurolymphomatosis. Neurooncol 2003; 5:104-115.

MacCollin M, Willet C, Heinrich B, Jacoby LB, Acierno JS, Perry A, Louis DN. Familial schwannomatosis: Exclusion of the NF2 locus as the germline event. Neurology 2003; 60:1968 1974.

Nutt CL, Mani DR, Betensky DA, Tamayo P, Cairncross JG, Ladd C, Pohl U, Hartmann C, McLaughlin ME, Batchelor TT, Black PM, von Deimling A, Pomeroy SL, Golub TR, Louis DN. Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res 2003; 63:1602-1607.

Chakravarti A, Noll E, Black PM, Finkelstein DF, Finkelstein DM, Dyson NJ, Loeffler JS. Quantitatively determined surviving expression levels are of prognostic value in human gliomas. J Clin Oncol 2002; 20:1063-1068.

Ino Y, Betensky RA, Zlatescu MC, Sasaki H, Macdonald DR, Stemmer-Rachamimov AO, Ramsay DA, Cairncross JG, Louis DN. Molecular subtypes of anaplastic oligodendroglioma: Implications for patient management at diagnosis. Clinical Cancer Res 2001; 7:839-845.

Barker FG, Simmons ML, Chang SM, Prados MD, Larson DA, Sneed PK, Wara WM, Berger MS, Chen P, Israel MA, Aldape KD. EGFR overexpression and radiation response in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2001; 51:410-418.

Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN. Specific chromosomal losses predict chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998; 90:1473-1479.