) It is estimated that between 20-80 percent of patients treated for locally advanced epithelial or mesenchymal tumors will die secondary to the failure of photon therapy and/or surgery to achieve local control. Furthermore, these aggressive local therapies are themselves often associated with significant acute and late morbidity. There are other tumors, particularly pediatric tumors, for which local control is often satisfactory but treatment-related late effects are high. It is the primary aim of this Program Project to exploit the superior dose distributions of proton beams to improve clinical outcomes for patients with a variety of solid tumors both in terms of cancer control and treatment-related morbidity. We have treated over 5,000 cancer patients with proton therapy at the Harvard Cyclotron Laboratory since 1974. We have achieved significant gains in clinical outcomes for a number of disease sites including chondrosarcomas and chordomas of the skull base and cervical spine (95 percent and 50 percent local control, respectively), paranasal sinus tumors (87 percent local control), and ocular melanomas (97 percent local control). We propose to carry out clinical trials using proton beams in additional tumor sites where photon therapy has provided suboptimal treatment outcomes. The two basic hypotheses for this Program Project are that, using the superior dose distributions of proton beams, we can (in subproject 5) escalate tumor dose and improve local control without increasing damage to non-target normal tissues and (in subproject 6) maintain high rates of local control while decreasing treatment related morbidity. We will assess clinical gains in terms of five endpoints: 1) local control, 2) distant metastasis-free survival, 3) overall survival, 4) treatment-related morbidity, and 5) quality-of-life (QOL) We also hypothesize that proton irradiation will decrease the comorbidity between radiation therapy and chemotherapy thus improving compliance and intensity of treatment. We will use well-designed prospective phase I/II/III trials to test these hypotheses. The proposed research program consists of three closely related projects. In subproject 5 we will carry out phase I/II/III dose escalation studies for prostate, lung, paranasal sinus, nasopharynx and hepatocellular cancers. The goals of these trials are to improve local control and survival. In subproject 6 we will carry out phase II/III studies designed to reduce treatment-related morbidity for pediatric cancers including medulloblastoma, retinoblastoma, and soft tissue sarcomas, and adult tumors including rectal carcinoma and choroidal melanoma. In the prostate clinical trial we will collaborate with the Loma Linda University Medical Center in protocol design and patient accrual. In subproject 4 we will develop treatment delivery and planning systems, and design and carry out dosimetry and quality assurance programs to support the proposed clinical trials. The Northeast Proton Therapy Center (NPTC), jointly funded by the NCI and the MGH, has been built on the MGH campus. The NPTC will provide the increased capacity and new technologies needed to conduct the clinical trials proposed in this application. With our experience in conducting proton clinical trials, and the resources offered by the NPTC, we have unique capabilities to carry out the proposed research. It is our expectation that these clinical trials will show improved cancer control rates, reduced treatment morbidity and improved QOL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA021239-24A1
Application #
6228281
Study Section
Subcommittee G - Education (NCI)
Program Officer
Stone, Helen B
Project Start
1995-08-31
Project End
2007-03-31
Budget Start
2002-04-11
Budget End
2003-03-31
Support Year
24
Fiscal Year
2002
Total Cost
$3,747,755
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Pulsifer, Margaret B; Duncanson, Haley; Grieco, Julie et al. (2018) Cognitive and Adaptive Outcomes After Proton Radiation for Pediatric Patients With Brain Tumors. Int J Radiat Oncol Biol Phys 102:391-398
Liao, Zhongxing; Lee, J Jack; Komaki, Ritsuko et al. (2018) Bayesian Adaptive Randomization Trial of Passive Scattering Proton Therapy and Intensity-Modulated Photon Radiotherapy for Locally Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 36:1813-1822
Jeter, Melenda D; Gomez, Daniel; Nguyen, Quynh-Nhu et al. (2018) Simultaneous Integrated Boost for Radiation Dose Escalation to the Gross Tumor Volume With Intensity Modulated (Photon) Radiation Therapy or Intensity Modulated Proton Therapy and Concurrent Chemotherapy for Stage II to III Non-Small Cell Lung Cancer: A P Int J Radiat Oncol Biol Phys 100:730-737
Frank, Steven J; Blanchard, Pierre; Lee, J Jack et al. (2018) Comparing Intensity-Modulated Proton Therapy With Intensity-Modulated Photon Therapy for Oropharyngeal Cancer: The Journey From Clinical Trial Concept to Activation. Semin Radiat Oncol 28:108-113
Lin, Yu-Fen; Chen, Benjamin P; Li, Wende et al. (2018) The Relative Biological Effect of Spread-Out Bragg Peak Protons in Sensitive and Resistant Tumor Cells. Int J Part Ther 4:33-39
Ning, Matthew S; Tang, Linglong; Gomez, Daniel R et al. (2017) Incidence and Predictors of Pericardial Effusion After Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 99:70-79
Chang, Joe Y; Zhang, Wencheng; Komaki, Ritsuko et al. (2017) Long-term outcome of phase I/II prospective study of dose-escalated proton therapy for early-stage non-small cell lung cancer. Radiother Oncol 122:274-280
Sanford, Nina N; Yeap, Beow Y; Larvie, Mykol et al. (2017) Prospective, Randomized Study of Radiation Dose Escalation With Combined Proton-Photon Therapy for Benign Meningiomas. Int J Radiat Oncol Biol Phys 99:787-796
Taylor, Paige A; Kry, Stephen F; Followill, David S (2017) Pencil Beam Algorithms Are Unsuitable for Proton Dose Calculations in Lung. Int J Radiat Oncol Biol Phys 99:750-756
Yock, Torunn I; Yeap, Beow Y; Ebb, David H et al. (2016) Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol 17:287-98

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