Proton Beam Therapy

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Title XVIII of the Social Security Act, Section 1833(e) states that no payment shall be made to any provider for any claim that lacks the necessary information to process the claim.

ABSTRACT

DESCRIPTION
Proton Beam Therapy (PBT) is a technology for delivering conformal external beam radiation with positively charged atomic particles to a well-defined treatment volume. PBT is approved by the U.S. Food and Drug Administration.

Due to its unique dose deposition characteristics, PBT can, in certain situations, deliver the prescribed target dose while giving a lower dose to normal tissues as compared to photon-based forms of external beam radiotherapy.

Photon beams deposit their greatest amount of energy beneath the patient's surface with a gradual reduction in energy deposition along the beam path as photons pass through the target and then through an exit point out of the body. In contrast, the physical profile of a beam of proton particles allows for the majority of its energy to be deposited over a very narrow range of tissue at a depth largely determined by the energy of the proton beam. A proton beam deposits relatively less radiation energy upon entering the body compared to a photon beam. The energy deposition of the proton beam then rapidly increases over a narrow range of tissue at a desired depth to produce an intense dose distribution pattern called the Bragg peak. Beyond the Bragg peak, energy and dose deposition rapidly decrease, resulting in the absence of any significant exit dose deposited in normal tissue beyond the target.

TREATMENT
PBT Treatment Planning
PBT can allow for radiation treatment plans that are highly conformal to the target volume. PBT planning defines the necessary field sizes, gantry angles and beam energies needed to achieve the desired radiation dose distribution.

An assessment of patient suitability for PBT is an important step in the process of care. Changes in the density and composition of tissues in the path of the beam have much greater impact on the delivered dose for protons than photons. Tissue interfaces, especially those with large differences in electron density, can lead to larger or unacceptable dosimetric uncertainties in PBT for certain patients.

PBT treatment planning is a multi-step process and shares functions common to other forms of external beam radiotherapy planning:

1. Simulation and Imaging: Three-dimensional image acquisition of the target region by simulation employing CT, CT/ PET and/or MR scanning equipment is an essential prerequisite to PBT treatment planning. If respiratory or other normal organ motion is expected to produce significant movement of the target region during radiotherapy delivery, the radiation oncologist may additionally elect to order multi-phasic treatment planning image sets to account for motion when rendering target volumes.
2. Contouring: Defining the target and avoidance structures is a multi-step process:
   
   1. The radiation oncologist reviews the three-dimensional images and outlines the treatment target on each slice of the image set. The summation of these contours defines the Gross Tumor Volume (GTV).
   2. The radiation oncologist draws a margin around the GTV to generate a Clinical Target Volume (CTV) which encompasses the areas at risk for microscopic disease (i.e., not visible on imaging studies).
   3. A final margin is then added to create a Planning Target Volume (PTV).
   4. Nearby normal structures that could potentially be harmed by radiation (i.e., "organs at risk'; or OARs) are also contoured.
   5. Radiation Dose Prescribing: The radiation oncologist assigns specific dose coverage requirements for the CTV which will be met even in the presence of expected positional and range uncertainties. A typical prescription may define a dose that will be delivered to at least 99% of the CTV. Additionally, PBT prescription requirements routinely include dose constraints for the OARs (e.g., upper limit of mean dose, maximum allowable point dose, and/or a critical volume of the OAR that must not receive a dose above a specified limit).
   6. Dosimetric Planning and Calculations: The qualified medical physicist or a supervised dosimetrist calculates a treatment plan to deliver the prescribed radiation dose to the CTV and simultaneously satisfy the normal tissue dose constraints by delivering significantly lower doses to nearby organs. Delivery mechanisms vary, but regardless of the delivery technique, all delivery parameters and/or field specific hardware are developed by a medical physicist or supervised dosimetrist and an expected dose distribution is calculated for the treatment plan.
   7. Patient Specific Dose Verification: An independent dose calculation and/or measurement should confirm that the intended dose distribution for the patient is physically verifiable and feasible.
   
   Documentation of all aspects of the treatment planning process is essential.
   
   PBT Treatment Delivery
   Proton delivery methods can be described in one of two forms: scattering or scanning.
   
   
   1. In scattered deliveries, the beam is broadened by scattering devices, beam energies are combined by mechanical absorbers and the beam is shaped by placing material such as collimators and compensators into the proton path.
   2. In scanning deliveries, the beam is swept laterally over the target with magnets instead of with scattering devices. Collimators and range compensators are still sometimes used for lateral and distal beam shaping, but field specific hardware is not always required because the scanning magnets allow the lateral extent of the beam to be varied with each energy level, a technique sometimes called intensity-modulated proton therapy (IMPT).
   
   The basic requirement for all forms of PBT treatment delivery is that the technology must accurately produce the calculated dose distribution described by the PBT plan. PBT dose distributions are sensitive to changes in target depth and shape and thus, changes in patient anatomy during treatment may require repeat planning. Such a change must be documented.
   
   Precise delivery is vital for proper treatment. Therefore, imaging techniques such as stereoscopic X-ray or CT scan (collectively referred to as Image Guided Radiation Therapy or IGRT) should be utilized to verify accurate and consistent patient and target setup for every treatment fraction.
   
   Indications For Coverage
   
   PBT is considered reasonable in instances where sparing the surrounding normal tissue cannot be adequately achieved with photon-based radiotherapy and is of added clinical benefit to the patient. Examples of such an advantage might be:
   
   
   1. The target volume is in close proximity to one or more critical structures and a steep dose gradient outside the target must be achieved to avoid exceeding the tolerance dose to the critical structure(s).
   2. A decrease in the amount of dose inhomogeneity in a large treatment volume is required to avoid an excessive dose "hotspot" within the treated volume to lessen the risk of excessive early or late normal tissue toxicity.
   3. A photon-based technique would increase the probability of clinically meaningful normal tissue toxicity by exceeding an integral dose-based metric associated with toxicity.
   4. The same or an immediately adjacent area has been previously irradiated, and the dose distribution within the patient must be sculpted to avoid exceeding the cumulative tolerance dose of nearby normal tissue.
   
   PBT may offer dosimetric advantages as well as added complexity over conventional radiotherapy, 3D Conformal Radiation Therapy (3-D CRT) or Intensity Modulated Radiation Therapy (IMRT). Before applying PBT techniques, a comprehensive understanding of the benefits and consequences is required. In addition to satisfying at least one of the four selection criteria noted above, the radiation oncologist's decision to employ PBT requires an informed assessment of the benefits and risks including:
   
   • Determination of patient suitability for PBT allowing for reproducible treatment delivery
   • Adequate definition of the target volumes and OARs
   • Equipment capability, including ability to account for organ motion when relevant
   • Physician, physicist and staff training
   • Adequate quality assurance procedures.
   
   It is important to note that normal tissue dose volume histograms (DVHs) must be demonstrably improved with a PBT plan to validate coverage. Therefore, coverage decisions must extend beyond ICD-10 codes to incorporate additional considerations of clinical scenario and medical necessity with appropriate documentation. The final determination of the appropriateness and medical necessity for PBT resides with the treating radiation oncologist who should document the justification for PBT for each patient.
   
   Group 1
   On the basis of the above medical necessity requirements and published clinical data, disease sites that frequently support the use of PBT include the following:
   
   • Ocular tumors, including intraocular melanomas
   • Tumors that approach or are located at the base of skull, including but not limited to:
     
     • Chordoma
     • Chondrosarcomas
     • Primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated
   • Unresectable benign or malignant central nervous system tumors to include but not be limited to primary and variant forms of astrocytoma, glioblastoma, medulloblastoma, acoustic neuroma, craniopharyngioma, benign and atypical meningiomas, pineal gland tumors, and arteriovenous malformations
   • Primary hepatocellular cancer treated in a hypofractionated regimen
   • Primary or benign solid tumors in children treated with curative intent and occasional palliative treatment of childhood tumors when at least one of the four criteria noted above apply
   • Patients with genetic syndromes making total volume of radiation minimization crucial such as but not limited to NF-1 patients and retinoblastoma patients
   • Pituitary neoplasm
   • Advanced staged (e.g., T4) and/or unresectable malignant lesions of the head and neck
   • Malignant lesions of the paranasal sinus, and other accessory sinuses
   • Unresectable retroperitoneal sarcoma.
   
   PBT is one of the acceptable forms of external beam radiation therapy that may be used to administer Stereotactic Body Radiation Therapy (SBRT) or Stereotactic Radiosurgery (SRS). When PBT is used to administer SBRT or SRS, the delivery and management codes relevant for SBRT or SRS apply, and the same clinical indications apply as for those treatment strategies.
   
   Group 2
   Coverage of proton beam therapy in Group 2 is limited to providers who have demonstrated experience in data collection and analysis with a history of publication in the peer-reviewed medical literature.
   
   
   • Unresectable lung cancers and upper abdominal/peri-diaphragmatic cancers
   • Advanced stage, unresectable pelvic tumors including those with peri-aortic nodes or malignant lesions of the cervix
   • Breast cancers
   • Unresectable pancreatic and adrenal tumors
   • Skin cancer with macroscopic perineural/cranial nerve invasion of skull base
   • Unresectable malignant lesions of the liver, biliary tract, anal canal and rectum
   • Prostate cancer, without distant metastases
   • Hodgkin or Non-Hodgkin Lymphoma involving the mediastinum or in non-mediastinal sites where PBT has the potential to reduce the risk of pneumonitis or late effects of radiation therapy (secondary malignancy, cardiovascular disease, or other chronic health conditions)
   • Re-irradiation where prior radiation therapy to the site is the governing factor necessitating PBT in lieu of other radiotherapy.
   
   Prostate Cancer
   Coverage and payments of proton beam therapy for prostate cancer will require:
   
   1. Physician documentation of patient selection criteria (stage and other factors as represented in the NCCN guidelines);
   2. Documentation and verification that the patient was informed of the range of therapy choices, including risks and benefits.

N/A

N/A

GENERAL

Aetna Clinical Policy Bulletin: Proton Beam and Neutron Beam Radiotherapy. Number 270. Last review 11/21/2014.

Agency for Healthcare Research and Quality; AHRQ; Particle beam radiation therapies for cancer. Publication No. 09-EHC019-EF. Revised November 2009, www.ahrq.gov.

Anthem Intensity Modulated Radiation Therapy (IMRT): RAD 00041.Last reviewed 5/15/2014.

Anthem Proton Beam Radiation Therapy: RAD 00015.Last reviewed 11/13/2014.

ASTRO Model Policy: Proton Beam Therapy (PBT). Approved 5/20/2014.

ASTRO/ACR Guide to Radiation Oncology 2010.

HealthNet National Medical Policy: Proton Beam Radiotherapy. NMP141. Updated October 2014.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®), Melanoma, Version I.2018. October II, 2017, NCCN.org

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) Version 3.2017 for Pheochromoctyoma/Paraganglioma. NCCN.org

Other Contractor Policies: Highmark, First Coast Service Options, Cahaba Benefit Administrators

Proton Therapy Consortium, Particle Therapy Cooperative Group- North America. Model Policy: Coverage of Proton Beam Therapy. March 31, 2014.

United Healthcare Medical Policy: Proton Beam Radiation Therapy. 2015T0132R. Effective January 1, 2015.

U.S. Food and Drug Administration (FDA) 510(k) summary; Hitachi's PROBEAT k053280; Mar 9, 2006; www.fda.gov

Washington State Health Care Authority, Health Technology Assessment. Proton Beam Therapy. April 11,2014.

LUNG

Liao Z et al. Analysis of clinical and dosimetric factors associated with radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with concurrent chemotherapy (ConChT) and three dimensional conformal radiotherapy (3D-CRT) Unknown date. Presented at 47th Annual ASTRO Meeting.

LYMPHOMA

NCCN Clincal Practice Guidelines in Oncology: Hodgkin Lymphoma. Version 2.2015. NCCN Clincal Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas. Version 2.2015.

PROSTATE

Agency for Healthcare Research and Quality; Comparative effectiveness of therapies for clinically localized prostate cancer. Feb 2008. www.ahrq.gov.

Agency for Healthcare Research and Quality; Comparative effectiveness review Number 146. Therapies for clinically localized prostate cancer: update of a 2008 systematic review.

GENERAL

Chung CS, Keating N, Yock T, Tarbell N. Comparative analysis of second malignancy risk in patients treated with proton therapy vs. conventional photon therapy. Int. J. Radiation Oncology Biol. Phys. 2008;72(1):S8

Foote RL, Stafford SL, Petersen IA, et al. The clinical case for proton beam therapy. Radiation Oncology. 2012;7(174):1-10.

Gagliardi G, Costine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int. J. Radiation Oncology Biol. Phys. 2010;76(3):S77-S85.

Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-volume effects in the spinal cord. Int. J. Radiation Oncology Biol. Phys. 2010;76(3):S42-S49.

MacDonald, SM, et al. Proton beam radiation therapy. Cancer Invest. 2006;24(2):199-208.

Moslehi J. The cardiovascular perils of cancer survivorship. NEJM. 2013;368(11):1055-1056.

Olsen DR, Bruland OS, Frykholm G, Norderhaug IN. et al;. Proton therapy - a systematic review of clinical effectiveness. Radiother Oncol. 2007;83:123-132.

Patel S, Kostaras X, Parliament M, et al. Recommendations for the referral of patients for proton-beam therapy, an Albert Health Services report: a model for Canada? Curr Oncol. 2014;21(5):251-262.

Schneider U, Lomax A, Pemler P, et al. The impact of IMRT and proton radiotherapy on secondary cancer incidence. Strahlenter Onckol. 2006;182:647-652.

Seppenwoolde Y, Lebesque JV, de Jaegar K, et al. Comparing different NTCP models that predict the incidence of radiation pneumonitis. Int. J. Radiation Oncology Biol. Phys. 2003;55(3):724-35.

Slater, J. Clinical applications of proton irradiation treatment at Loma Linda University: review of a fifteen year experience. Technology in Cancer Research and Treatment. 2006;5(2):81-89.

Smith RP, Heron DE, Hug MS, Yue NJ. Modern radiation treatment planning and delivery from Röntgen to real time. Hematol Oncol Clin North Am. 2006;20(1):45-62.

BREAST

Ares C, Khan S, MacArtain AM, et al. Postoperative proton radiotherapy for localized and locoregional breast cancer: potential for clinically relevant improvements? Int J Rad Oncol. 2010;76(3):685-697.

Bush DA, Do S, Lum S, et al. Partial Breast Radiation therapy with proton beam: 5-year results with cosmetic outcomes. Int. J. Radiation Oncology Biol. Phys. 2014;90(3):501-505.

Bush DA, Slater JD, Garberoglio C, Do S, Lum S, Slater JM. Partial breast irradiation delivered with proton beam: results of a phase II trial. Clin Breast Cancer. 2011;11(4):241-245.

Bush DA, Slater JD, Garberoglio C, Yuh G, Hocko JM, Slater JM. A technique of partial breast irradiation utilizing proton beam radiotherapy: comparison with conformal x-ray therapy. The Cancer Journal. 2007;13(2):114-118.

Chang JH, Lee NK, Kim JY, et al. Phase II trial of proton beam accelerated partial breast irradiation in breast cancer. Rad and Oncol. 2013;108:209-214.

Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. NEJM. 2013;368(11):987-998.

Darby SC, McGale P, Taylor CW, Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300 000 women in US SEER cancer registries. Lancet Oncol. 2005;6:557-565.

Depauw N, Batin E, Daartz J, et al. A novel approach to posmastectomy radiation therapy using scanned proton beams. Int J Rad. Oncol. 2015;91(2):427-434.

Kozak KR, Smith BL, Adams J, et al. Accerlated partial-breast irradiation using proton beams: initial clinical experience. Int. J. Rad. Oncology. 2006;66(3):691-698.

MacDonald SM, Patel SA, Hickey S, et al. Proton therapy for breast cancer after mastectomy: early outcomes of a prospective clinical trial. Int J Rad Oncol. 2013;886(3):484-490.

Xu N, Ho MW, Li Z, Morris CG, Mendenhall NP. Can proton therapy improve the therapeutic ratio in breast cancer patients at risk for nodal disease? Am J of Clin Oncol. 2014;37(6):568-574.

ESOPHAGUS

Chuong MD, Hallemeier CL, Jabbour SK, et al. Improving outcomes for esophageal cancer using proton beam therapy. Int J Rad Oncol.2016;95(1):488-497.

Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer- long term follow-up of a prospective randomized trial (RTOG 85-01). JAMA.1999;281(17):1623-1627.

Echeverria AE, McCurdy M, Castillo R, et al. Proton therapy radiation pneumonitis local dose-response in esophagus cancer patients. Radiotherapy and Oncology. 2013;106:124-129.

Fernandes A, Berman AT, Mick R, et al. A prospective study of proton beam reirradiation for esophageal cancer. Int J Radiation Oncol Biol Phys. 2016;95(1):483-487.

Gayed IW, Liu HH, Wamique S, et al. The prevalence of myocardial ischemia after concurrent chemoradiation therapy as determined by gated myocardial perfusion imaging in patients with esophageal cancer. J. Nucl. Med. 2006;46:1756-62.

Koyama S, Tsujii H. Proton beam therapy with high-dose irradiation for superficial and advanced esophageal carcinomas. Clinical Cancer Research. 2003;9:3571-3577.

Koyama S, Tsujii H, Yokota H, et al. Proton beam therapy for patients with esophageal carcinoma. Jpn J Clin Oncol. 1994;24:144-153.

Lin S, Komaki R, Liao Z, et al. Proton beam therapy and concurrent chemotherapy for esophageal cancer. Int. J. Radiation Oncology Biol. Phys. 2012:83(3):e334-e351

Ling TC, Slater JM, Nookala P, et al. Analysis of Intensity-Modulated Radiation Therapy (IMRT), Proton and 3D Conformal Radiotherapy (3D-CRT) for Reducing Perioperative Cardiopulmonary Complications in Esophageal Cancer Patients. Cancers (Basel). 2014;6(4):2356-68. doi: 10.3390/cancers6042356. PMID: 25489937.

Mizumoto M, Sugahara S, Nakayama H, et al. Clinical results of proton-beam therapy For locoregionally advanced esophageal cancer. Strahlenter Onkol. 2010;186(9):482-488.

Mizumoto M, Sugahara S, Okumura T, et al. Hyperfractionated concomitant boost proton beam therapy for esophageal carcinoma. Int. J. Radiation Oncology Biol. Phys. 2011;81(4)e601-6.

Pan X, Zhang X, Li Y, Mohan R, Liao Z. Impact of using different four-dimensional computed tomography data sets to design proton treatment plans for distal esophageal cancer. Int. J. Radiation Oncology Biol. Phys. 2009;73(2):601-9. doi: 10.1016/j.ijrobp.2008.09.042. PMID: 19147024.

Shirai K, Tamaki Y, Kitamoto Y, et al. Dose-volume histogram parameters and clinical factors associated with pleural effusion after chemoradiotherapy in esophageal cancer patients. Int. J. Radiation Oncology Biol. Phys. 2011;80(4):1002-7.

Sugahara S, Tokuuyh K, Okumura T, et al. Clinical results of proton beam therapy for cancer of the esophagus. Int. J. Radioation Oncology. 2005;61: 76-84.

Takada A, Nakamura T, Takayama K, et al. Preliminary treatment results of proton beam therapy with chemoradiotherapy for stage I–III esophageal cancer. Cancer Med. 2016:506-515.

Vosmik M, Petera J, Sirak I, et al. Technological advances in radiotherapy for esophageal cancer. World Journal of Gastroenterology. 2010;16(44)5555-5564.

Wang J, Wei C, Tucker SL, et al. Predictors of postoperative complications after trimodality therapy for esophageal cancer. Int. J. Radiation Oncology Biol. Phys. 2013;86(5):885-891.

Wang SL, Liao Z, Vaporciyan AA, et al. Investigation of clinical and dosimetric factors associated with postoperative pulmonary complications in esophageal cancer patients treated with concurrent chemoradiotherapy followed by surgery. Int. J. Radiation Oncology Biol. Phys. 2006;64(3):692-9. Epub 2005 Oct 19. PMID: 16242257.

Wei X, Liu HH, Tucker SL, et al. Risk factors for pericardial effusion in inoperable esophageal cancer patients treated with definitive chemoradiation therapy. Int. J. Radiation Oncology Biol. Phys. 2008;70(3):707-14. doi: 10.1016/j.ijrobp.2007.10.056. Epub 2008 Jan 11. PMID:18191334.

Welsh J, Gomez D, Palmer MB, et al. Intensity-modulated proton therapy further reduces normal tissue exposure during definitive therapy for locally advanced distal esophageal tumors: a dosimetric study. Int. J. Radiation Oncology Biol. Phys. 2011;81(5):1336-1342.

Zhang X, Zhao KL, Guerrero TM, et al. Four-dimensional computed tomography-based treatment planning for intensity-modulated radiation therapy and proton therapy for distal esophageal cancer. Int. J. Radiation Oncology Biol. Phys. 2008;72(1):278-287.

HEAD AND NECK

Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-sell carcinoma of the head and neck. N Engl J Med. 2004;350:1937-44.

Dagan R, Bryant CM, Bradley JA, et al. A prospective evaluation of acute toxicity from proton therapy for targets of the parotid region. International Journal of Particle Therapy. 2016:1-6.

Gomez D, Komaki R. Technical advances of radiation therapy for thymic malignancies. J of Thoracic Oncology. 2010;5(10):Suppl 4)S336-S343.

Machtay M, Moughan J, Trotti A, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. Journal of Clinical Oncology. 2008;26(21):3582-3589.

Merchant TE, Hua CH, Shukla H, et al. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer. 2008;51(1):110-117.

Patel SH, Wang Z, Wong WW, et at. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. 2014;15:1027-1038.

Petit, JH, Biller BMK, Yock TI, et al. Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. J Clin Endocrinol Metab. 2008;93(2):393-399.jcem.endojournals.org.

Romesser PB, Cahlon O, Scher E, et al. Proton beam radiation therapy results in significantly reduced toxicity compared with intensity-modulated radiation therapy for head and neck tumors that require ipsilateral radiation. Radiotherapy and Oncology. 2016;118:286-292.

LIVER

Hata M, Tokuuye K, Sugahara S, et al. Proton beam therapy for aged patients with hepatocellular carcinoma. Int J Rad. Oncol. 2007;69(3):805-812.

Mizumoto M, Okumura T, Hashimoto T, et al. Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols. Int. J. Radiation Oncology. 2011;81(4):1039-1045.

Wei-Xiang Q, Fu S, Zhang Q, Guo XM. Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: A systematic review and meta-analysis. Radiotherapy and Oncology. 2015;114:289-295.

LUNG

Allen A, Czerminska M, Janne PA, et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int. J. Radiation Oncology Biol. Phys. 2006;65(3):640-5.

Allen A, Czerminska M, Janne PA, et al. Fatal pneumonitis associated with intensity-modulated radiation therapy for mesothelioma. Int. J. Radiation Oncology Biol. Phys. 2006;65(3):640-5.

Bradley J, Bae K, Graham MV, et al. Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG0117. J. Clin Oncology. 2010;28(14):1475-80.

Bradley J, Moughan J, Graham MV, et al. A phase I/II radiation dose escalation study with concurrent chemotherapy for patients with inoperable stages I to II non-small-cell lung cancer: phase I results of RTOG 0117. Int. J. Radiation Oncology Biol. Phys. 2010;77(2):367-72.

Chang J, Komake R, Lu C, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III non-small cell lung cancer. Cancer. 2011;117(20):4707-13.

Chang J, Komaki R, Wen HY, et al. Toxicity and patterns of failure of adaptive/ablative proton therapy for early-stage, medically inoperable non-small cell lung cancer. Int. J. Radiation Oncology Biol. Phys. 2011;80(5):1350-7.

Chang J, Zhang X, Wang X, et al., Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in stage I or Stage III non-small-cell lung cancer. Int. J. Radiation Oncology Biol. Phys. 2006;65(4):1087-96.

Hata M, Tokuuye K, Kagei K, et al. Hypo-fractionated high-dose proton beam therapy for stage I non-small-cell lung cancer: preliminary results of a phase I/II clinical study. Int. J. Radiation Oncology Biol. Phys. 2007;68(3):786-93.

Hoppe B, Huh S, Flampouri S, et al. Double-scattered proton-based stereotactic body radiotherapy for stage I lung cancer: a dosimetric comparison with photon-based stereotactic body radiotherapy. Radiotherapy and Oncology. 2010;97:425-30.

Komaki R. Does proton beam radiotherapy (PBT) reduce treatment related pneumonitis (TRP) compared to intensity modulated radiation therapy (IMRT) in patients with locally advanced non-small cell lung cancer (NCLC) treated with concurrent chemotherapy? Presentation at Abramson Cancer Center of Univ. of PA. May 23, 2008.

Komaki R, Sejpal S, Wei X, et al. Reduction of bone marrow suppression for patients with stage III NSCLC treated by proton and chemotherapy compared With IMRT and chemotherapy. Vol. 14. (O10) Jacksonville, Florida: PTCOG 47; 2008.

Marks LB, Bentzen SM, Deasy JO, et al. Radiation dose-volume effects in the lung.Int. J. Radiation Oncology Biol. Phys. 2010;76(3):S70-S76.

Nakayama H, Sugahara S, Tokita M, et al. Proton beam therapy for patients with medically inoperable stage I non-small cell lung cancer at the University of Tsukuba. Int. J. Radiation Oncology Biol. Phys. 2010:78(2):467-71.

Nihei K. Ogina T, Ishikura S, Nishimura H. et al., High-dose proton beam therapy for stage I non-small-cell lung cancer.Int. J. Radiation Oncology Biol. Phys. 2006;65(1):107-111.

Register SP, Zhang X, Mohan R, Chang JY. et al., Proton stereotactic body radiation therapy for clinically challenging cases of centrally and superiorly located stage I non-small cell lung cancer. Int. J. Radiation Oncology Biol. Phys. 2011;80(4):1015-22.

Roelofs E, Engelsman M, Rasch C, et al. Results of a multicentric in silico clinical trial (ROCOCO). Comparing radiotherapy with photons and protons for non-small cell lung cancer. Journal of Thoracic Oncology. 2012;7(1)165-176.

Sejpal S, Komaki R, Tsao A, et al. Early findings on toxicity of proton beam therapy with concurrent chemotherapy for non-small cell lung cancer. Cancer. 2011:3004-3013.

Vogelius I, Westerly DC, Aznar MC, et al. Estimated radiation pneumonitis risk, after photon versus proton therapy alone or combined with chemotherapy for lung cancer. Acta Oncologica. 2011;50:772-6.

Zhang X, Li Y, Pan X, et al. Intensity-modulated proton therapy reduces the dose to normal tissue compared with intensity-modulated radiation therapy or passive scattering proton therapy and enables individualized radical radiotherapy for extensive stage IIIB non-small cell lung cancer: a virtual clinical study. Int. J. Radiation Oncology Biol. Phys. 2010;77(2):357-366.

LYMPHOMA

Andolino DL, Hoene T, Lu X, Buchsbaum J, Chang AL. Dosimetric comparison of involved-field three-dimensional conformal photon radiotherapy and breast-sparing proton therapy for the treatment of Hodgkin’s lymphoma in female pediatric patients. Int. J. Radiation Oncology. 2011;81(4):e667-e671.

Chera B, Rodrigues C, Morris CG, et al. Dosimetric comparison of three different involved nodal irradiation techniques for stage II Hodgkin’s lymphoma patients: conventional radiotherapy, intensity-modulated radiotherapy, and dimensional proton radiotherapy. Int. J. Radiation Oncology Biol. Phys. 2009;75(4):1173-80.

Heidenreich PA, Schnittger I, Strauss HW, et al. Screening of coronary artery disease after mediastinal irradiation of Hodgkin’s disease. J. Clin. Oncol. 2007;25:43-49.

Hodgson D, Dong L. Proton therapy for Hodgkin lymphoma: does a case report make the case? Leukemia & Lymphoma. 2010;51(8):1397–1398.

Hoppe B et al. Cardiac sparing with proton therapy in consolidative radiation therapy for Hodgkin lymphoma. Leukemia & Lymphoma. 2010;51(8):1559-62 Hoppe B, Flampouri S, Su Z, et al. Effective dose reduction to cardiac structures using proton compared with 3DCRT and IMRT in mediastinal Hodgkin lymphoma. Int. J. Radiation Oncology Biol. Phys. 2012;84(2):449-455:1-7.

Hoppe BS, Flampouri S, Lynch J, Slayton W, Zaiden R, Zuofeng L. Improving the therapeutic ratio in Hodgkin lymphoma through the use of proton therapy. Oncology. 2012;26(5) 456-9, 462-5.

Hoppe BS, Flampouri S, Su Z, et al. Consolidative involved-node proton therapy for stage IA-IIIB mediastinal Hodgkin lymphoma: preliminary dosimetric outcomes from a phase II study. Int. J. Radiation Oncology Biol. Phys. 2012;83(1):260-267.

Hoppe BS, Flampouri S, Zaiden R, et al. Involved-node proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2 study. Int. J. Radiation Oncology Biol. Phys. 2014;89(5):1053-1059.

Jorgensen AYS, Maraldo MV, Brodin NP, et al. The effect on esophagus after different radiotherapy techniques for early stage Hodgkin’s lymphoma. Acta Oncologica. 2013;52:1559-1565.

Li J, Dabaja B, Reed V, et al. Rationale for and preliminary results of proton beam therapy for mediastinal lymphoma. Int. J. Radiation Oncology Biol. Phys. 2011.;81(1):167-74.

MacDonald SM, Jimenez R, Paetzold P, et al. Proton radiotherapy for chest wall and regional lymphatic radiation; dose comparisons and treatment delivery. Rad Oncol. 2013;8(71):1-7.

Maraldo MV, Brodin NP, Aznar MC, et al. Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma. Annals of Oncology. 2013;24:2113-2118.

OCULAR MELANOMA

Wang Z, Nabhan M, Schild SE, et al. Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int. J. Radiation Oncology Biol. Phys. 2013;86(1):18-26.

PANCREAS

Ding X, Dionisi F, Tang S, Ingram M, Hung CY, Prionas E, et al. A comprehensive dosimetric study of pancreatic cancer treatment using three-dimensional conformal radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), volumetric-modulated radiation therapy (VMAT), and passive-scattering and modulated-scanning proton therapy (PT). Med Dosim. 2014;39(2):139-45. doi: 10.1016/j.meddos.2013.11.005. Epub 2014 Mar 21.PMID: 24661778.

Hong TS, Ryan DP, Borger DR, Blaszkowsky LS, Yeap BY, Ancukiewicz M, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int. J. Radiation Oncology Biol. Phys. 2014;89(4):830-8. doi:10.1016/j.ijrobp.2014.03.034. Epub 2014 May 24.PMID: 2486754.

Lee RY, Nichols RC Jr, Huh SN, Ho MW, Li Z, Zaiden R, et al. Proton therapy may allow for comprehensive elective nodal coverage for patients receiving neoadjuvant radiotherapy for localized pancreatic head cancers. J Gastrointest Oncol. 2013;4(4):374-9. doi: 10.3978/j.issn.2078-6891.2013.043.PMID:24294509.

Lukens JN, Mick R, Demas KI, et al. Acute toxicity of proton versus photon chermoradiation therapy for pancreatic adenocarcinoma: a cohort study. Int J Rad Oncol. 2013;887:S311.

Nichols RC Jr, George TJ, Zaiden RA Jr, Awad ZT, Asbun HJ, Huh S, et al. Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity. Acta Oncol. 2013;52(3):498-505. doi: 10.3109/0284186X.2012.762997.PMID: 23477361.

Nichols Jr RC, Huh SN, Prado KL, et al. Protons offer reduced normal-tissue exposure for patients receiving postoperative radiotherapy for resected pancreatic head cancer. Int J of Rad. Oncol. 2012;83(1):159-163.

Thompson RF, Mayekar SU, Zhai H, Both S, Apisarnthanarax S, Metz JM, et al. A dosimetric comparison of proton and photon therapy in unresectable cancers of the head of pancreas. Med Phys. 2014;41(8):081711. doi: 10.1118/1.4887797. PMID: 25086521.

PROSTATE

Bryant CL, et al. Five-Year Biochemical Results, Toxicity, and Patient-Reported Quality of Life Following Delivery of Dose-Escalated Image-Guided Proton Therapy for Prostate Cancer. Int J Radiat Oncol Biol Phys. May 1, 2016. 10.1016/j.ijrobp.2016.02.038

Chera BS, et al. Dosimetric Study of Pelvic Proton Radiotherapy for High-Risk Prostate Cancer. Int J Radiat Oncol Biol Phys. 2009.75:994-1002.

Fang P, Mick R, Deville C, et al. A Case-matched study of toxicity outcomes after proton therapy and intensity-modulated radiation therapy for prostate cancer. Cancer. April 2015:1118-1127.

Holtzman AL, et al. Proton Therapy as Salvage Treatment for Local Relapse of Prostate Cancer Following Cryosurgery or High-Intensity Focused Ultrasound. Int J Radiat Oncol Biol Phys. May 1, 2016. 10.1016/j.ijrobp.2015.12.351.

Mendenhall et al. Five-year outcomes from 3 prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014 Mar 1;88(3):596-602;

Mendenhall et al. Proton beam therapy for localized prostate cancer 101: Basics, Controversies, and Facts Rev Urol. 2014; 16(2): 67–75.

Nguyen Pl, Trofimov A, Zietman AL. et al; Proton-beam vs intensity-modulated radiation therapy: which is best for treating prostate cancer? ONCOLOGY. 2008;22(7):754-757.

Sheets N, Goldin G, Meyer A, et al. Intensity-modulated radiation therapy, proton therapy radiation therapy and morbidity and disease control in localized prostate cancer. JAMA. 2012;307(15):1611-9.

Shipley WU et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys. 1995 Apr 30;32(1):3-12.

Wisenbaugh ES, Andrews PE, Ferrigni RG, et al. Proton Beam Therapy for Localized Prostate Cancer 101: Basics, Controversies, and Facts. Rev Urol. 2014;16(2):67-75 doi:10.3909/riu0601.

STOMACH

Van den Belt-Dusebout AW, Aleman BMP, Besseling G, et al. Roles of radiation dose and chemotherapy in the etiology of stomach cancer as a second malignancy. Int. J. Radiation Oncology Biol. Phys. 2009;75(5):1420-1429.