Medical Policy: 08.01.05 

Original Effective Date: April 2001 

Reviewed: August 2020 

Revised: August 2020 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Proton beam radiation therapy (PBRT)/proton beam therapy (PBT) is a type of external beam radiotherapy that uses charged particles. These particles have unique characteristics, including limited lateral slide, scatter and tissue in a defined range, going for maximum dose delivery over the last few millimeters of the particles’ range. The maximum is called the Bragg peak. Proton beam therapy (PBT), when applied to treating cancer, uses different proton energy with Bragg peaks at various steps, enabling dose escalation to the tumor, minimizing excess dose to normal surrounding tissue.

 

Proton beam radiation therapy (PBRT) has been used in the treatment of two general categories of tumors. The first category includes tumors located near vital organs, such as intracranial lesions or those along the axial skeleton e.g. uveal melanoma, chordomas and other chondrosarcomas at the base of the skull and along the axial skeleton. The second category currently under investigation involves tumors with high rate of recurrence despite maximal doses of conventional radiation therapy (e.g. locally advanced prostate cancer). There are ongoing studies of proton beam radiation therapy (PBRT) for other malignancies including but not limited to breast cancer, genitourinary cancers, pancreatic cancer, gynecological cancers, gastrointestinal cancers, lung cancer, and head and neck cancers. Proton beam radiation therapy (PBRT) is not indicated for cancers that are widely disseminated or for cancers that have hematogenous (originating in the blood or spread through the blood system) metastases.

 

Over the years, PBRT has been applied to treating tumors or abnormalities (AVMs) that require dose escalation to achieve a higher probability of care, requiring increased precision in dose deposition while protecting normal surrounding tissue. Proton beam radiation therapy (PBRT) has an over 40 year history in treating cancer, yet to date, there have been few studies that show superiority to conventional photon beam radiation therapy such as 3-dimensional conformal radiotherapy, intensity modulated radiotherapy (IMRT) and stereotactic techniques, which allow for improved targeting of conventional radiation therapy that also minimize the dose delivery to surrounding normal tissues or organs at risk (OARs).

 

Proton Beam Radiation Therapy Treatment Delivery

Proton delivery methods can be described in one of two forms: passive scattering (also known as single and double scattering) or active scanning (also known as uniform and pencil beam scanning).

 

With passive scattering and uniform scanning, apertures and compensators are used to shape and fine tune the depth of the proton beam. With pencil beam scanning, there is generally no need for apertures and compensators, as the dose is "painted" in layers, producing more proximal conformity of the dose distribution as well as modulation of the dose within a field, referred to as intensity modulated proton therapy or IMPT.

 

The basic requirement for all forms of PBRT treatment delivery is that the technology must accurately produce the calculated dose distribution described by the PBRT plan. PBRT dose distributions are sensitive to changes in target depth and shape and thus, changes in patient anatomy during treatment may require repeat planning. Precise delivery is vital for proper treatment. Therefore, imaging guided radiation therapy (IGRT) should be used to verify accurate and consistent patient and target setup for every treatment fraction.

 

Proton beam radiation therapy (PBRT) is an outpatient procedure that is performed over the course of several days. The treatment regimen and duration vary depending on the type of cancer or abnormality being treated. Usually, treatment is given to a patient once daily, Monday through Friday, for up to eight weeks. The radiation doses are divided over this period to achieve the total dosage. After 2 initial planning sessions, each treatment session lasts between 20 to 40 minutes. Most of this time is spent aligning the patient for the prescribed treatment plan, while the actual delivery of the proton beam takes very little time.

 

Additional Information

In September 2013, as part of its national “Choosing Wisely” initiative, American Society for Radiation Oncology (ASTRO) listed proton beam therapy (PBT) for prostate cancer as one of 5 radiation oncology practices that should not be routinely used because they are not supported by evidence.

 

The American Society for Radiation Oncology (ASTRO) updated their Model Policy in 2017 on the use of Proton Beam Therapy (PBT): The model policy update was developed by ASTRO’s Payer Relations Subcommittee and states the model policies were developed to “communicate what ASTRO believes to be correct coverage policies for radiation oncology services.” It also states that the ASTRO model policies (do not serve as clinical guidelines” and are “recommendations for medical insurance coverage.”

 

Indications and Limitations of Coverage and/or Medical Necessity

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:

  • 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).
  • A decrease in the amount of dose inhomogeneity in a large treatment volume is required to avoid an excessive dose “hotspot” within the treatment volume to lessen the risk for excessive early or late normal tissue toxicity.
  • A photon based technique would increase the probability of clinically meaningful normal tissue toxicity by exceeding an integral dose based metric associated with toxicity.
  • 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. 

 

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 the 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
  • Hepatocellular cancer
  • Primary or benign solid tumors in children treated with curative intent and occasional palliative treatment of childhood tumors when at least one of 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
  • Malignant and benign primary CNS tumors
  • Advanced (e.g. T4) and/or unresectable head and neck cancers
  • Cancers of the paranasal sinuses and other accessory sinuses
  • Non-metastatic retroperitoneal sarcomas
  • Re-irradiation cases (where cumulative critical structure dose would exceed tolerance dose)

 

Group 2
Note: Please refer to the member’s benefit certificate language regarding clinical trials.

 

While PBT is not a new technology, there is a need for continued clinical evidence development and comparative effectiveness analysis for the appropriate use of PBT for various disease sites. All other indications not listed in Group 1 are suitable for Coverage with Evidence Development (CED). Radiation therapy for patients treated under CED paradigm should be covered by the insurance carrier as long as the patient is enrolled in either an IRB-approved (institution review board-approved) clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED. At this time, no indications are deemed inappropriate for CED and therefore Group 2 includes various systems such as, but not limited to, the following:

  • Non-T4 and resectable head and neck cancers
  • Thoracic malignancies, including non-metastatic primary lung and esophageal cancers, and mediastinal lymphomas
  • Abdominal malignancies, including non-metastatic primary pancreatic, biliary and adrenal cancers
  • Pelvic malignancies, including non-metastatic rectal, anal, bladder and cervical cancers
  • Non-metastatic prostate cancer
  • Breast cancer 

 

The model policy stated the following regarding PBT treatment of prostate cancer: “In the treatment of prostate cancer, the use of PBT is evolving as the comparative efficacy evidence is still being developed. In order for an informed consensus on the role of PBT for prostate cancer to be reached, it is essential to collect further data, especially to understand how the effectiveness or proton therapy compares to other radiation therapy modalities such as IMRT and brachytherapy. There is a need for more well-designed registries and studies with sizable comparator cohorts to help accelerate data collection. Proton beam therapy for primary treatment of prostate cancer should only be performed in the context of a prospective clinical trial or registry.”

 

Coverage under CED requirements will help expedite more permanent coverage decisions for all indications. Due to the numerous studies under way, proton coverage policies need to be reviewed on a frequent basis. As additional clinical data is published, this policy will be revised to reflect appropriate coverage.

 

Limitations of Coverage

PBT is not considered reasonable and medically necessary unless at least one of the criteria listed in the “Indications of Coverage” section of this policy is present.

 

Use of PBT is not typically supported by the following clinical scenarios:

  • Where PBT does not offer advantage over photon-based therapies that otherwise deliver good clinical outcomes and low toxicity
  • Spinal cord compression, superior vena cava syndromes, malignant airway obstruction, poorly controlled malignant bleeding and other scenarios of clinical urgency.
  • Inability to accommodate for organ motion
  • Palliative treatment in a clinical situation where normal tissue tolerance would not be exceeding in previously irradiated areas

 

Clinical Trials and Clinical Registry Trials

  • Proton beam radiation therapy (PBRT) is considered a non-covered benefit when it is the experimental arm or subject of the clinical trial (refer to the member’s benefit certificate language regarding clinical trials coverage).
  • When proton beam radiation therapy (PBRT) is studied as part of a clinical registry trial, Wellmark BCBS coverage criteria will be applied to determine the medical necessity of the proton beam radiation therapy (PBRT) services. When proton beam radiation therapy (PBRT) is part of a clinical registry trial and Wellmark BCBS criteria are not met, the proton beam radiation therapy (PBRT) will be considered not medically necessary.  
  • Clinical registry trials are observational and lack the basic underpinning of clinical equipoise as there is inherent bias among both patients and investigators.

 

Summary Evidence

In 2017, the American Society for Radiation Oncology (ASTRO) updated their Model Policy on the use of Proton Beam Therapy (PBT): The model policy update was developed by ASTRO’s Payer Relations Subcommittee and states the model policies were developed to “communicate what ASTRO believes to be correct coverage policies for radiation oncology services.” It also states that the ASTRO model policies (do not serve as clinical guidelines” and are “recommendations for medical insurance coverage.”

 

This medical policy addresses coverage criteria for those indications for which the role of proton beam radiation therapy (PBRT) lacks high-quality evidence comparing proton beam radiation therapy (PBRT) outcomes with photon-based (3D-conformal or intensity modulated radiation therapy [IMRT]) or stereotactic techniques based on the peer reviewed published medical literature in combination with National Comprehensive Cancer Network (NCCN) guidelines. Proton beam radiation therapy (PBRT) has not been proven to be more effective than other radiotherapy modalities for the treatment of these indications and will be considered not medically necessary.

 

Clinical Trials and Clinical Registry Trials 

  • Proton beam radiation therapy (PBRT) is considered a non-covered benefit when it is the experimental arm or subject of the clinical trial (refer to the member’s benefit certificate language regarding clinical trials coverage).
  • When proton beam radiation therapy (PBRT) is studied as part of a clinical registry trial, Wellmark BCBS coverage criteria will be applied to determine the medical necessity of the proton beam radiation therapy (PBRT) services. When proton beam radiation therapy (PBRT) is part of a clinical registry trial and Wellmark BCBS criteria are not met, the proton beam radiation therapy (PBRT) will be considered not medically necessary. 
  • Clinical registry trials are observational and lack the basic underpinning of clinical equipoise as there is inherent bias among both patients and investigators. 

 

Secondary Malignancies

A common argument by advocates for use of proton beam radiation therapy (PBRT) is the potential to reduce the risk of secondary malignancies further. A larger volume of normal tissue is exposed to low dose radiation with intensity modulated radiation therapy (IMRT), and this higher integral dose theoretically could cause a higher rate of secondary malignancies. There is a large body literature discussing the theoretical risks and benefits of proton beam radiation therapy (PBRT) with respect to secondary malignancies, based on modeling. While some studies may show promise, whether proton beam radiation therapy (PBRT) increases or reduces the risk of secondary malignancies is very much an unanswered issue, and as a result of the available published literature, the use proton beam is considered not medically necessary solely to reduce the risk of a secondary malignancy.

 

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

NCCN Guideline and VersionPrinciples of Radiation Therapy
Anal Carcinoma Version 2.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of anal carcinoma.
Bladder Cancer Version 6.2020 The NCCN guideline does not mention or indicate the use of proton beam  radiation therapy (PBRT) as a radiation treatment modality for the treatment of bladder cancer.
Bone Cancer Version 1.2020

Principles of Radiation Therapy
General Principles

  • Patients should be strongly encouraged to have RT at the same specialized center that is providing surgical and systemic interventions
  • Specialized techniques such as intensity modulated RT (IMRT); particle beam RT with protons, carbon ions, or other heavy ions; or stereotactic radiosurgery (SRS) should be considered as indicated in order to allow high dose therapy while maximizing normal tissue sparing.

Chrondrosarcoma: proton and/or photon beam RT may be useful for patients with chondrosarcomas of the skull base and axial skeleton with tumors in unfavorable location not amendable to resection.

 

Chordomas: For patients with resectable conventional or chondroid chordomas, wide exicision with or without RT is the primary treatment option for chordomas of the sacrum and mobile spine, whereas intralesional excision with or without RT is the treatment of choice for skull base tumors. Adjuvant RT can be considered for large extracompartmental tumors or for positive surgical margins following resection. RT is the primary treatment option for patient with unresectable chordomas, irrespective of location of the tumor.    

 

Ewing Sarcoma: Multiagent chemotherapy is the primary treatment and patients with disease that responds to primary treatment are treated with local control therapy (wide excision, definitive RT with chemotherapy, or amputation in selected cases) followed by adjuvant chemotherapy. Progressive disease is best managed with RT with or without surgery followed by chemotherapy or best supportive care.

 

Osteosarcoma: Osteosarcoma occurs mainly in children and young adults. Wide excision is the primary treatment for patients with low-grade osteosarcoma, whereas preoperative chemotherapy followed by wide excision is the preferred option for patients with high-grade osteosarcoma. Chemotherapy prior to wide excision can be considered for patients with periosteal lesions.   Following wide excision, postoperative chemotherapy is recommended for patients with low grade or periosteal sarcomas with pathologic findings of high grade disease and those with high grade sarcoma. RT followed by adjuvant chemotherapy is recommended if the sarcoma remains unresectable after preoperative chemotherapy. Progressive disease is managed with surgery, palliative RT, or best supportive care.

Breast Cancer Version 5.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of breast cancer.
Central Nervous System Cancers Version 2.2020

Intracranial and Spinal Ependymomas
Radiation Therapy

Proton beam craniospinal irradiation may be considered when clinically appropriate and when toxicity is a concern. SRS has been used as a boost after EBRT or to treat recurrent with some success, although data on long-term results are still lacking. 

 

Adult Medulloblastoma
Radiation Therapy

It reasonable to consider proton beam for craniospinal irradiation where available, as it is associated with less toxicity.

 

Meningiomas
Radiation Therapy

Conformal fractionated RT (e.g. 3D-CRT, IMRT, VMAT, proton therapy) may be used in patients with grade I meningiomas to spare critical structures and uninvolved tissue.

 

Anaplastic Glioma/Glioblastoma High Grade (Grades III/IV)

  • Simulation and Treatment Planning
    • Tumor volumes are best defined by using pre and postoperative MRI imaging using enhanced T1 with/without FLAIR/T2 sequences to define GTV. To account for sub-diagnostic tumor infiltration, the GTV is expanded 1-2 cm (CTV) for grade III, and up to 2-2.5 cm (CTV) for grade IV. Although trials in glioblastoma have historically used CTV expansion in the range of 2 cm, smaller CTV expansions are supported in the literature and can be appropriate. A planning target volume (PTV) of margin of 3-5 mm is typically added to the CTV to account for daily setup errors and imaging registration. Daily image guidance is required if smaller PTV margins are used (3mm or less). When edema as assessed by T2/FLAIR is included in the initial phase of treatment, fields are usually reduced for the last phase of the treatment (boost). The boost target volume will typically encompass only the gross residual tumor and the resection cavity. A range of acceptable clinical target volume margins exists. Both strategies appear to produce similar outcomes.
    • Consider proton therapy for patients with good long-term prognosis (grade III IDH-mutant tumors and grade III 1p19q co-deleted tumors) to better spare un-involved brain and preserve cognitive function.
Cervical Cancer Version 2.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of cervical cancer.
Colon Cancer Version 4.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of colon cancer.
Rectal Cancer Version 6.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for rectal cancer.
Esophageal and Esophagogastric Junction Cancers Version 4.2020

Simulation and Treatment Planning

 

CT simulation and conformal treatment planning should be used. Intensity modulated radiation therapy (IMRT) or proton beam therapya is appropriate in clinical settings where reduction in dose to organs at risk (e.g. heart, lungs) is required that cannot be achieved by 3-D techniques.

aData regarding proton beam therapy are early and evolving. Ideally, patients should be treated with proton beam therapy with a clinical trial.

Gastric Cancer Version 3.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of gastric cancer.
Head and Neck Cancers Version 2.2020

Proton Beam Therapy (PBT)

  • Achieving highly conformal dose distributions is especially important for patients whose primary tumors are periocular in location and/or invade the orbit, skull base, and/or cavernous sinuses; extend intracranially or exhibit extensive perineural invasion; and who are being treated with curative intent and/or who have long life expectancies following treatment. Nonrandomized single institution clinical reports and systematic comparisons demonstrate safety and efficacy of PBT in the above mentioned specific clinical scenarios.
  • Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy.

Cancer of the Oropharynx
Principles of Radiation Therapy
Definitive and Concurrent Systemic Therapy/RT:
Either IMRT (preferred) or 3D conformal RT is recommended for cancers of the oropharynx in order to minimize dose to critical structures. Use of proton therapy is an area of active investigation. Proton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy.

 

Postoperative: RT or concurrent systemic therapy. Either IMRT (preferred) or 3D conformal is recommended for cancers of the oropharynx in order to minimize does to critical structures. Use of proton therapy is an area of active investigation. Proton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy. 

 

Cancer of the Nasopharynx
Principles of Radiation Therapy

IMRT is recommended for cancers of the nasopharynx to minimize dose to critical structures. Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy.

 

Cancers of the Supraglottic Larynx
Principles of Radiation Therapy
 
Either IMRT or 3D conformal RT is recommended. Use of proton therapy is an area of active investigation. Proton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy.

 

Ethmoid Sinus Tumors
Principles of Radiation Therapy
Either IMRT or proton therapy is recommended for maxillary sinus or paranasal/ethmoid sinus tumors to minimize dose to critical structures.

 

Maxillary Sinus Tumors
Principles of Radiation Therapy
Either IMRT or proton therapy is recommended for maxillary sinus or paranasal/ethmoid sinus tumors to minimize dose to critical structures.

 

Occult Primary
Principles of Radiation Therapy
Either IMRT or 3D conformal RT is recommended when targeting the pharyngeal axis to minimize the dose to critical structures. Use of proton therapy is an area of active investigation. Proton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy.

 

Salivary Glands
Principles of Radiation Therapy

Either IMRT or 3D conformal RT is recommended. Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy

 

Mucosal Melanoma (MM)
Principles of Radiation Therapy

Either IMRT or 3D conformal RT is recommended. Proton therapy can be considered when normal tissue constraints cannot be met by photon-based therapy.

Hepatobiliary Cancers Version 5.2020

Hepatocellular Carcinoma (HCC)

  • Proton beam therapy (PBT) may be appropriate in specific situations.

In 2014, ASTRO released model policy supporting the use of proton beam therapy (PBT) in some oncology populations. In a recent phase II study 94.8% of patients with unresectable HCC who received high dose hypofractionated PBT demonstrated > 80% local control after two years, as defined by RECIST criteria. The panel advises that PBT may be considered and appropriate in select settings for treating HCC. Several ongoing studies are continue to investigate the impact of hypofractionated PBT on HCC outcomes (e.g. NCT02395523, NCT02632864) including randomized trials comparing PBT to RFA (NCT02640924) and PBT to TACE (NCT00857805).

 

NCCN guideline mentions the use of PBT in unresectable HCC but does not indicate or define what specific situations or select settings PBT should be utilized in unresectable HCC or the dosing.

 

Biliary Tract Cancers
Hypofractionated proton therapy may also be considered with patients with unresectable intrahepatic cholangiocarcinoma, but this treatment should only be administered at experienced centers.

Hodgkin Lymphoma Version 2.2020
  • Treatment with photons, electrons, or protons may all be appropriate depending on clinical circumstances.
  • Advanced radiation therapy (RT) technologies such as IMRT, breath hold or respiratory gating, image-guided RT or proton therapy may offer significant and clinically relevant advantages in specific instances to spare important OARs (organs at risk) such as the heart (including coronary arteries, valves, and left ventricle). Lungs, kidneys, spinal cord, esophagus, carotid artery, bone marrow, breasts, stomach, muscle/soft tissues, and salivary glands and decrease the risk for late, normal tissue damage while still achieving the primary goal of local tumor control.
  • The demonstration of significant dose sparing for these OARs reflects best clinical practice. Achieving highly conformal dose distributions is especially important for patients who are being treated with curative intent or who have long life expectations following therapy.
  • In mediastinal Hodgkin lymphoma (HL) the use of 4D-CT for simulation and the adoption of strategies to deal with respiratory motion and minimize dose to OARs are essential, especially deep inspiration breath hold techniques, respiratory gating, and image guided RT during treatment delivery.
  • Randomized studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which take 10 + years to develop. In light of that, the modalities and techniques that are found to best reduce the doses to the OARs in a clinically meaningful way without compromising target coverage should be considered.

 

Volumes

  • OARs should be outlined for optimizing treatment plan decisions.
  • The treatment plan is designed using conventional 3-D conformal, proton therapy, or IMRT techniques using clinical treatment planning considerations of coverage and dose reductions for OAR.

 

Principles of Radiation Therapy
RT can be delivered with photons, electrons, or protons, depending upon clinical circumstances. Although advanced RT techniques emphasize tightly conformal doses and steep gradients adjacent to normal tissues, the “low dose bath” to normal structures such as the breasts must be considered in choosing the final radiation therapy (RT) techniques. Therefore, target definition, delineation and treatment delivery verification require careful monitoring to avoid the risk of tumor geographic miss and subsequent decrease in tumor control. Initial diagnostic imaging with contrast enhanced CT, MRI, PET, ultrasound and other imaging modalities facilitate target definition. Preliminary results from single institution studies have shown that significant dose reduction to organs at risk (OARs; e.g. lungs, heart, breasts, kidneys, spinal cord, esophagus, carotid artery, bone marrow, stomach, muscle, soft tissue, salivary glands) can be achieved with advanced RT planning and delivery techniques such as four dimensional CT (4D-CT) simulation, intensity modulated RT (IMRT), image guided RT, respiratory gating, or deep inspiration breath hold. These techniques offer significant and clinically relevant advantages in specific instances to spare OARs and decrease the risk for normal tissue damage and late effects without compromising the primary goal of local tumor control. For optimal mediastinal treatment planning, organs or tissues to be contoured should include the lungs, heart, coronary arteries (including the left main, circumflex, left anterior descending and right coronary arteries with the priority placed on sparing the proximal over distal portions of the arteries) and left ventricle.

 

Randomized prospective studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which usually develop > 10 years after completion of treatment. Therefore, the guidelines recommend the RT delivery techniques that are found to best reduce the doses to the OARs in a clinically meaningful manner without compromising target coverage should be considered in these patients, who are likely to enjoy long life expectancies following treatment.

 

Involved- site RT (ISRT) and involved -node RT (INRT) are being used as alternatives to involved -field RT (IFRT) in an effort to restrict the size of the RT fields and to further minimize the radiation exposure to adjacent uninvolved organs and the potential long-term toxicities associated with radiation exposures. ISRT targets the originally involved nodal sites and possible extranodal extensions which generally defines a smaller field than the classical IFRT.

 

ISRT targets the initially involved nodal and extranodal sites as defined by the pre-treatment evaluation (physical examination, CT and PET imaging). However, it is intended to spare the adjacent uninvolved organs (such as lungs, bone, muscle, or kidney) when lymphadenopathy regresses following chemotherapy. Treatment planning for ISRT requires the use of CT-based simulation. The incorporation of additional imaging techniques such as PET and MRI often enhances the treatment planning. The optimized treatment plan for ISRT is designed using conventional 3-D conformal RT, proton therapy, or IMRT techniques using clinical treatment planning considerations of coverage and dose reductions for OARs.

Kidney Cancer Version 1.2021 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of kidney cancer.
Malignant Pleural Mesothelioma Version 2.2020
  • Use of conformal radiation technology intensity modulated radiation therapy (IMRT) is the preferred choice based on comprehensive consideration of target coverage and clinically relevant normal tissue tolerance.
  • CT simulation guided planning using either IMRT or conventional photon/electron RT is acceptable. IMRT is a promising treatment technique that allows for more conformal high dose RT and improved coverage to hemithorax. IMRT or other modern technology (such as tomotherapy or protons) should only be used in experienced centers or on protocol. When IMRT is applied, the NCI and ASTRO/ACR IMRT guidelines should be strictly followed. Special attention should be paid to minimize radiation to the contralateral lung, as the risk of fatal pneumonitis with IMRT is excessively high when strict limits are not applied.

 

NCCN guideline does not indicate or define what specific situations or select settings proton beam radiation therapy (PBRT) should be utilized or the dosing.

 

Cutaneous Melanoma Version 3.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for cutaneous melanoma.
Uveal Melanoma Version 1.2020

Principles of Radiation Therapy
Particle Beam Therapy
Treatment Information

  • Particle beam therapy is a common form of definitive radiotherapy for the primary tumor. A prospective trial found no difference in cause-specific survival among patients with tumors ≤ 15  mm in maximum basal diameter and ≤ 11 mm in apical height randomized to plaque brachytherapy or particle beam therapy
  • Particle beam therapy is appropriate as upfront therapy after initial diagnosis, after margin positive enucleation or for intraocular or orbital recurrence
  • Particle beam therapy should be performed by an experienced multidisciplinary team including an ophthalmic oncologist, radiation oncologist, and particle beam physicist
  • Tumor localization for particle beam therapy may be performed using indirect ophthalmoscopy, transillumination and/or ultrasound (intraoperative and/or preoperative) MRI and/or CT
  • Treatment Dosing Information: For intraocular tumors
    • Using protons 50-70 cobalt Gray equivalent (CGyE) in 4-5 fractions should be prescribed to encompass the planning target volume surrounding the tumor
    • Using carbon ions 60-85 CGyE in 5 fractions should be prescribed to encompass the planning target volume surrounding the tumor
    • Volumetric planning in 3 dimensions with or without CT and/or MRI is encouraged to maximize radiation delivery to tumor and minimize radiation delivery to organs and tissues at risk of injury from radiation 

Discussion section remains under development.

 

Neuroendocrine and Adrenal Tumors Version 2.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of neuroendocrine and adrenal tumors.
B-Cell Lymphomas Version 4.2020 (Also known as non-Hodgkin Lymphoma)
  • Treatment with photons, electrons or protons may all be appropriate, depending on clinical scenario.
  • Advanced radiation therapy technologies such as intensity modulated radiation therapy (IMRT)/VMAT, proton therapy, breath hold, or respiratory gating and/or image guided therapy may offer significant and clinically relevant advantages in specific instances to spare important organs at risk such as the heart (including coronary arteries and valves), lungs, kidneys, spinal cord, esophagus, bone marrow, breasts, stomach, muscle/soft tissue, and salivary glands and decrease the risk for late, normal tissue damage while still achieving the primary goal of local tumor control.
  • Reducing dose to normal tissues reduces the risk of late complications. Achieving highly conformal dose distribution is especially important for patients who are being treated with curative intent or who have long life expectancies following therapy.
  • For mediastinal and abdominal lymphoma, respiratory motion management such as gating or breath hold techniques may be advantageous. Breath-hold techniques have been shown to decrease incidental dose to the heart and lungs in many disease presentations. Similarly, for abdominal lymphomas, reduction in radiation exposures to liver and kidneys may be achieved by motion management techniques.
  • Randomized studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which take 10+ years to evolve. In light of that, the modalities and techniques that are found to best reduce the doses to the organs at risk (OAR) in a clinically meaningful way without compromising target coverage should be considered.

 

Volumes

Involved Site Radiation Therapy (ISRT) for Nodal Disease

  • ISRT is recommended as the appropriate field for NHL. Planning for ISRT requires modern CT based simulation and planning capabilities. Incorporating other modern imaging like PET and MRI often enhances treatment volume determination
  • ISRT targeting the site of the originally involved lymph nodes. The volume encompasses the original suspicious volume prior to chemotherapy or surgery. Yet, it spares adjacent uninvolved organs (like lungs, bone, muscle, or kidney) when lymphadenopathy regresses following chemotherapy.
  • The OAR (organs at risk) should be outlined by optimizing treatment plan decisions
  • The treatment plan is designed using conventional 3D conformal, or IMRT/VMAT, or proton therapy techniques using clinical treatment planning considerations of target coverage and dose reductions for OAR.  

ISRT for Exrtranodal Disease

  • Similar principles as for ISRT nodal sites above
  • For most organs and particularly for indolent disease, the whole organ comprises the CT (e.g. stomach, salivary gland, thyroid). For other organs, including orbit, lung, bone, localized skin and in some cases when RT is consolidation after chemotherapy partial organ RT may be appropriate
  • For most NHL subtypes no radiation is required for uninvolved lymph nodes

Principles of Radiation Therapy
Radiation therapy (RT) can be delivered with photons, electrons or protons depending upon clinical circumstances. Advanced RT techniques emphasize tightly conformal doses and steep gradients next to normal tissues. Therefore, target definition and delineation and treatment delivery verification require careful monitoring to avoid the risk of missing geographic location of the tumor and subsequent decrease in tumor control. Image guidance may be required to facilitate target definition. Preliminary results from single institution studies have shown that significant dose reduction to organs at risk (OAR; e.g. lungs, heart, breasts, kidneys, spinal cord, esophagus, carotid artery, bone marrow, stomach, muscle, soft tissue and salivary glands) can be achieved with advanced RT planning and delivery techniques such as 4D-CT simulation, intensity modulated RT (IMRT), image guided RT, respiratory gating or deep inspiration breath hold. These techniques offer significant and clinically relevant advantages in specific instances to spare OAR and reduce the risk of late complications from normal tissue damage. This is especially important for patients being treated with curative intent or how have long life expectancies following therapy.  In mediastinal lymphoma the use of 4D-CT simulation and the adoption of strategies to deal with respiratory motion such as inspiration breath hold techniques, and image guided RT during treatment delivery is also important.

 

Randomized prospective studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which usually develop > 10 years after completion of treatment. Therefore, the guidelines recommend that RT delivery techniques that are found to best reduce the doses to the OAR in a clinically meaningful manner without compromising target coverage should be considered.

 

Involved-site RT (ISRT) is recommended as the appropriate field for NHL as it limits the radiation exposure to adjacent uninvolved organs such as lungs, bone, muscle or kidney) when lymphadenopathy regresses following chemotherapy, thus minimizing the potential long term complications. ISRT targets the initially involved nodal and extra-nodal sites detectable at presentation. Larger RT fields should be considered for limited stage indolent NHL often treated with RT alone.

 

Treatment planning for ISRT requires the use of CT based simulation. The incorporation of additional imaging techniques such as PET and MRI often enhances the treatment planning. The OAR should be outlined for optimizing treatment plan decisions. The treatment plan is designed using conventional, 3D conformal, or IMRT techniques using clinical treatment planning considerations of coverage and dose reduction for OAR.

 

In the case of extranodal disease, particularly for indolent lymphoma, in most cases, the whole organ comprises the CTV (e.g. stomach, salivary gland and thyroid). For other organs, including orbit, breast, lung, bone, localized skin, and in some cases when RT is consolidation after chemotherapy, partial organ RT may be appropriate. No radiation is required for uninvolved lymph nodes for most NHL subtypes.

 

Pediatric Aggressive Mature B-Cell Lymphomas Version 2.2020

Pediatric Burkitt lymphoma and Pediatric diffuse large lymphoma

 

Radiation therapy rarely has a role in pediatric aggressive mature B-cell lymphomas due to the rapid lysis of tumor to chemotherapy and the avoidance of long-term side effects in children.

 

Primary Cutaneous B-Cell Lymphomas Version 2.2020

Principles of Radiation Therapy
The general intent of RT is to treat the evident skin disease with adequate margin both circumferentially and in depth.

 

Target Volumes

  • Involved-site radiation therapy (ISRT) for nodal disease
    • See Principals of Radiational Therapy for T-Cell lymphomas (Target Volumes: ISRT for nodal disease)
    • See Principals of Radiation Therapy for B-Cell lymphomas (Target Volumes: ISRT for nodal disease)

PBRT may be appropriate depending on clinical circumstances for ISRT and nodal disease.

 

Involved-site radiation therapy (ISRT) for cutaneous lesions
  • ISRT is recommended as the appropriate field for treating primary cutaneous lymphomas
T-Cell Lymphomas Version 1.2020
  • Advanced radiation therapy technologies such as IMRT, breath hold, or respiratory gating, image guided RT (IGRT), or proton therapy may offer significant and clinically relevant advantages in specific instances to spare important organs at risk such as the heart (including coronary arteries and valves), lungs, kidneys, spinal cord, esophagus, bone marrow, breasts, stomach, muscle/soft tissue, and salivary glands and decrease the risk for late, normal tissue damage while still achieving the primary goal of local tumor control. Achieving highly conformal dose distributions is especially important for patients who are being treated with curative intent or who have long life expectancies following therapy
  • The demonstration of significant dose sparing for these organs at risk reflects best clinical practice
  • In mediastinal lymphoma the use of 4D-CT for simulation and the adoption of strategies to deal with respiratory motion such as inspiration breath hold techniques, and image guided RT during treatment delivery is also important
  • Randomized studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which take 10+ years to evolve. In light of that, the modalities and techniques that are found to best reduce the doses to the organs at risk (OARs) in a clinically meaningful way without compromising target coverage should be considered.

 

Involved site Radiation Therapy (ISRT) for Nodal Disease

  • ISRT is recommended as the appropriate field for NHL. Planning for ISRT requires modern CT based simulation and planning capabilities.
  • ISRT targets the site of the originally involved lymph node(s). The volume encompasses the original suspicious volume prior to chemotherapy or surgery. Yet, it spares adjacent uninvolved organs (like lungs, bone, muscle, or kidney) when lymphadenopathy regresses following chemotherapy.
  • Possible movement of the target by respiration is determined by 4D-CT or fluoroscopy (internal target volume ITV) should also influence the final CTV.
  • The OAR should be outlined for optimizing treatment plan decisions.
  • The treatment plan is designed using conventional, 3-D conformal, or IMRT techniques using clinical treatment planning considerations of coverage and dose reductions for OAR.

ISRT for Extranodal Disease (excluding NK/T-cell lymphoma)

  • ISRT for extranodal disease (excluding NK/T-cell lymphoma)
    • Similar principles for ISRT nodal sites above
    • For most organs and particularly for indolent disease, the whole organ comprises the CT (e.g. stomach, salivary gland, thyroid). For other organs, including orbit, lung, bone, localized skin and in some cases when RT is consolidation after chemotherapy partial organ RT may be appropriate
    • Prophylactic irradiation is not required for uninvolved lymph nodes
  • ISRT for extranodal NK/T-Cell Lymphoma
    • For optimal treatment planning, both contrast enhanced CT and contrast enhanced MRI are essential. A PET/CT scan is necessary for defining the presence of nodal disease
    • The OARs should be outlined for optimizing treatment plan decisions
    • The treatment plan is designed using conventional 3-D conformal, or IMRT techniques using clinical treatment planning considerations of coverage and dose reductions for OARs

Treatment Modalities 
ISRT for Extranodal NK/T-Cell Lymphoma

  • Treatment with photons, electrons or protons may all be appropriate, depending on clinical circumstances

Principles of Radiation Therapy
Radiation therapy (RT) can be delivered with photons, electrons or protons depending on clinical circumstances. Advanced RT techniques emphasize tightly conformal doses and steep gradients next to normal tissues. Therefore, target definition and delineation and treatment delivery verification require careful monitoring to avoid the risk of missing geographic location of the tumor and subsequent decrease in tumor control. Image guidance may be required to facility target definition. Significant dose reduction to organs at risk (OAR; e.g. lungs, heart, breasts, kidneys, spinal cord, esophagus, carotid artery, bone marrow, stomach, muscle, soft tissue and salivary glands) can be achieved with advanced RT planning and delivery techniques such as 4D-CT simulation, intensity modulated RT (IMRT), image guided RT (IGRT), respiratory gating, or deep inspiration breath hold. These techniques offer significant and clinically relevant advantages in specific instances to spare OAR and decrease the risk for normal tissue damage and late effects without compromising the primary goal of local tumor control.   
    
Randomized prospective studies to test these concepts are unlikely to be done since these techniques are designed to decrease late effects, which usually develop > 10 years after completion of treatment. Therefore, the guidelines recommend that RT delivery techniques that are found to best reduce the doses to the OAR in a clinically meaningful manner without compromising target coverage should be considered.

 

Involved site RT (ISRT) is intended to limit radiation exposure to adjacent uninvolved organs (such as lungs, bone, muscle or kidney) when lymphadenopathy regresses following chemotherapy, thus minimizing the potential long- term complications. Extended field RT (EFRT) and involved field RT (IFRT) techniques have now been replaced by ISRT in an effort to restrict the size of the RT fields to smaller volumes. ISRT targets the initially involved nodal and extra-nodal sites detectable at presentation. Larger RT fields should be considered for limited stage indolent NHL often treated with RT alone.

 

Treatment planning for ISRT requires the use of CT- based simulation. The incorporation of additional imaging techniques such as PET and MRI often enhances the treatment planning. The OAR should be outlined for optimizing treatment plan decisions. The treatment plan is designed using conventional, 3D conformal, or IMRT techniques using clinical treatment planning considerations of coverage and dose reduction for OAR.

 

In the case of extranodal disease, (e.g. stomach, salivary gland and thyroid) comprises the CVT in most cases. For other organs, including orbit, breast, lung, bone, localized skin, and in some cases when RT is consolidation after chemotherapy, partial organ RT may be appropriate. No radiation is required for uninvolved lymph nodes for most NHL subtypes.

 

Basal Cell Skin Cancer Version 1.2020

The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of basal cell skin cancer.

 

Dermatofibrosarcoma Protuberans Version 1.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of Dermatofibrosarcoma Protuberans.
Merkel Cell Carcinoma Version 1.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of Merkel cell carcinoma.
Squamous Cell Skin Cancer Version 2.2020

The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of squamous cell skin cancer.

 

Non-Small Cell Lung Cancer Version 6.2020

General Principles

  • Determination of the appropriateness of radiation therapy (RT) should be made by a board certified radiation oncologists who perform lung cancer RT as a prominent part of their practice
  • RT has a potential role in all stages of NSCLC, as either definitive or palliative therapy. Radiation oncology input as part of a multidisciplinary evaluation or discussion should be provided for all patients with stage IV disease that may benefit from local therapy
  • Critical goals of modern RT are to maximum tumor control and to minimize treatment toxicity. A minimum technologic standard is CT planned 3D-CRT
  • More advanced technologies are appropriate when needed to delivery curative RT safely. These technologies include (but are not limited to) 4D-CT and/or PET/CT simulation, IMRT/VMAT, IGRT, motion management, and proton therapy (https://www.astro.org/Daily-Practice/Reimbursement/Model-Policies/Model-Policies). Nonrandomized comparisons of using advanced technologies demonstrate reduced toxicity and improved survival versus older techniques.
  • Centers using advanced technologies should implement and document modality specific quality assurance measures. The ideal external credentialing of both treatment planning and delivery such as required for participation in RTOG clinical trials employing advance technologies. Useful references include the ACR practice parameters and technical standards.

Radiation Therapy Simulation, Planning and Delivery

  • IGRT including (but not limited to) orthogonal pair planar imaging and/or volumetric imaging (such as CBCT or CT on rails) is recommended when using SABR, 3D-CRT/IMRT, and proton therapy with steep dose gradients around the target, when OARs are in close proximity to high dose regions and when using complex motion management techniques.

 

Target Volumes, Prescription Doses and Normal Tissue Dose Constraints

  • Because risk of normal organ toxicity increases with dose, doses to normal organs should be kept as low as reasonably achievable rather than simply meeting nominal constraints. This is generally facilitated by more advanced techniques to achieve better dose conformity.

 

Palliative RT for Advanced/Metastatic NSCLC

The dose and fractionation of palliative RT should be individualized based on goals of care, symptoms, performance status, and logistical considerations. Shorter courses of RT are preferred for patients with poor performance status and/or shorter life expectancy because they provider similar pain relive as longer courses, although there is a higher potential need for retreatment. For palliation of thoracic symptoms higher dose/longer course thoracic RT is associated with moderately improved survival and symptoms, particularly in patients with good performance status. When higher doses (>30 Gy) are warranted, technologies to reduce normal tissue irradiation (at least 3D-CRT and including IMRT or proton therapy as appropriate) may be used.

 

For patients with advanced lung cancer (i.e. stage IV) with extensive metastases, systemic therapy is recommended; palliative RT can be used for symptom relief and potentially for prophylaxis at primary distant sites (such as pain. Bleeding or obstruction). Shorter courses of palliative RT are preferred for patients with symptomatic chest disease who have poor PS and/or shorter life expectancy (e.g. 17 Gy in 8.5 Gy fractions), because they provide similar pain relief as longer courses, although there is a higher potential need for retreatment. Higher doses and longer course thoracic RT (e.g. > 30 Gy in 10 fractions) are associated with modestly improved survival and symptoms, especially in patients with good PS. When higher doses (>30 Gy) are warranted, technologies to reduce normal tissue irradiation may be used (at least 3D-CRT and including IMRT or proton therapy as appropriate).

 

Occult Primary (Cancer of Unknown Primary [CUP]) Version 3.2020

The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of occult primary (cancer of unknown primary [CUP]).

 

Note: See Occult Primary under Head and Neck

 

Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 1.2020

 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of ovarian cancer including fallopian tube cancer and primary peritoneal cancer.   

Pancreatic Adenocarcinoma Version 1.2020

The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of pancreatic adenocarcinoma.

Penile Cancer Version 2.2020

The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of penile cancer.

 

Prostate Cancer Version 2.2020

Principles of Radiation Therapy

Definitive Radiation Therapy

General Principles

  • Highly conformal RT techniques should be used to treat localized prostate cancer.
  • Photon or proton EBRT are both effective at achieving highly conformal radiotherapy with acceptable and similar biochemical control and long term side effect profiles.
  • Brachytherapy boost when added to EBRT plus ADT in men with NCCN intermediate and high/very high risk prostate cancer, has demonstrated improved biochemical control over EBRT plus ADT alone in randomized trials but with higher toxicity.
  • SBRT is acceptable in practices with appropriate technology, physics and clinical expertise.

Proton Therapy
Proton beam RT has been used to treat patients with cancer since the 1950s. Proponents of proton therapy argue that this form of RT could have advantages over x-ray (photon) based radiation in certain clinical circumstances. Proton therapy and x-ray- based therapies like IMRT can deliver highly conformal doses to the prostate. Proton-based therapies will delivery less radiation dose to some of the surrounding normal tissues like muscle, bone, vessels and fat not immediately adjacent to the prostate. These tissues do not routinely contribute to the morbidity of prostate radiation and are relatively resilient to radiation injury, therefore, the benefit of decreased dose to these types of normal, non-critical tissues has not been apparent. The critical normal structures adjacent to the prostate that can create prostate cancer treatment morbidity include the bladder, rectum, neurovascular bundles and occasionally small bowel.

 

The weight of the current evidence about prostate cancer treatment morbidity supports the notion that the volume of the rectum and bladder that receives radiobiologically high doses of radiation near the prescription radiation dose accounts for the likelihood of long term treatment morbidity, as opposed to higher volume, lower dose exposures. Numerous dosimetric studies have been performed trying to compare x-ray based IMRT plans to proton therapy plans to illustrate how one or the other type of treatment can be used to spare the bladder or rectum from higher dose parts of the exposure. These studies suffer from biases and talents of the investigators who plan and create computer models of dose deposition for one therapy or the other. Although dosimetric studies in-silico can suggest that the right treatment planning can make an IMRT plan beat a proton therapy plan and vice-versa, they do not accurately predict clinically meaningful endpoints.

 

Comparative effectiveness studies have been published in an attempt to compare toxicity and oncologic outcomes between proton and photon therapies. Two comparisons between men treated with proton therapy or EBRT report similar toxicity rates. The largest retrospective comparative effectiveness analysis to date comparing IMRT to proton therapy was performed using SEER-Medicare claims data for the following long-term endpoints: gastrointestinal morbidity, urinary incontinence, non-incontinence urinary morbidity, sexual dysfunction, and hip fractures. With follow-up as mature as 80 months and using both propensity scoring and scoring and instrumental variable analysis, the authors concluded that men receiving IMRT therapy had statistically significantly lower gastrointestinal morbidity than patients receiving proton therapy, whereas rates of urinary incontinence, non-incontinence urine morbidity, sexual dysfunction, hip fractures and additional cancer therapies were statistically indistinguishable between the cohorts. However, firm conclusions regarding differences in toxicity or effectiveness of proton and photon therapy cannot be drawn because of the limitations inherent in retrospective/observational studies.

 

The costs associated with proton beam facility construction and proton beam treatment are high compared to the expense of building and using the more common photon linear accelerator- based practice. The American Society of Radiation Oncology (ASTRO) evaluated proton therapy and created a model policy to support the society’s position on payment coverage for proton beam therapy in 2014. This model policy was updated in 2017 and recommends coverage of proton therapy for the treatment of non-metastatic prostate cancer if the patient is enrolled in either an institutional review board (IRB) approved study or a multi-institutional registry that adheres to Medicare requirements for Coverage with Evidence Development (CED). The policy states “In the treatment of prostate cancer, the use of proton beam therapy is evolving as the comparative efficacy is still being developed. In order for an informed consensus on the role of proton beam therapy for prostate cancer to be reached, it is essential to collect further data, especially to understand how the effectiveness of proton therapy compares to other RT modalities such as IMRT and brachytherapy. There is a need for more well -designed registries and studies with sizeable comparator cohorts to help accelerate data collection. Proton beam therapy for primary treatment of prostate cancer should only be performed within the context of a prospective clinical trial or registry.”


An ongoing prospective randomized trial is accruing patients to compare prostate proton therapy and prostate IMRT.  The NCCN Panel believes no clear evidence supports a benefit or decrement to proton therapy over IMRT for either treatment efficacy or long term toxicity. Conventionally fractionated prostate cancer proton therapy can be considered a reasonable alternative to x-ray based regimens at clinics with appropriate technology, physics and clinical expertise.

 

Small Bowel Adenocarcinoma Version 2.2020

 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of small bowel adenocarcinoma.

Small Cell Lung Cancer Version 1.2021

The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of small cell lung cancer.

 

Soft Tissue Sarcoma Version 2.2020

Overview
Sarcomas constitute a heterogenous group of rare solid tumors of mesenchymal cell origin with distinct clinical and pathologic features; they are usually divided into two broad categories.

  • Sarcomas of soft tissues (including fat, muscle, nerve and nerve sheath, blood vessels, and other connective tissues); and
  • Sarcomas of bone

Sarcomas collectively account for approximately 1% of all adult malignancies and 15% of pediatric malignancies.

 

Radiation Therapy
RT can be administered either as primary, preoperative or postoperative treatment. Total RT doses are always determined based on the tissue tolerance. Newer RT techniques such as brachytherapy, intraoperative RT (IORT) and intensity modulated RT (IMRT) have led to the improvement of treatment outcomes in patients with STS. 

 

Soft Tissue Sarcomas of the Extremities, Superficial Trunk or Head and Neck
Radiation Therapy
 
Data from randomized studies and retrospective analyses support the use of preoperative and postoperative EBRT in appropriately selected patients. Brachytherapy (alone or in combination with EBRT) and IMRT have also been evaluated as an adjunct to surgery.

 

Panel Recommendations
When EBRT is used, sophisticated treatment planning with IMRT, tomotherapy and/or proton therapy can be used to improve therapeutic effect. RT is not a substitute for definitive surgical resection with negative margins, and re-resection to negative margins is preferable.Preoperative RT


Retroperitoneal/Intra-abdominal Soft Tissue Sarcoma
Radiation Therapy

RT can be administered either as preoperative treatment for patients with resectable disease or as primary treatment for those with unresctable disease. The panel discourages postoperative RT with the exception of highly selected cases of if LR would cause undue morbidity. The panel emphasizes that RT is not a substitute for definitive surgical resection with oncologically appropriate margins and re-resection may be necessary. If re-resection is not feasible, postoperative RT may be considered in highly selected patients who have not received preoperative RT, to attempt to control microscopic residual disease; however, this approach has not been validated in randomized trials.

 

Newer RT techniques such as IMRT and 3D conformal RT using protons or photons may allow tumor target coverage and acceptable clinical outcomes with normal tissue dose constraints to adjacent organs at risk. When EBRT is used, sophisticated treatment planning with IMRT, tomotherapy, and/or proton therapy can be used to improve therapeutic effect. However, the safety and efficacy of adjuvant RT techniques have yet to be evaluated in multicenter randomized controlled studies.

Testicular Cancer Version 3.2020

The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of testicular cancer.

 

Thymomas and Thymic Carcinomas Version 1.2020

Principles of Radiation Therapy
General Principles
 

  • Recommendations regarding RT should be made by a board-certified radiation oncologist with experience in managing thymomas and thymic carcinomas
  • Definitive RT should be given for patients with unresectable disease (if disease progresses on induction chemotherapy), incompletely resected invasive thymoma or thymic carcinoma, or as adjuvant therapy after chemotherapy and surgery for patients with locally advanced disease.
  • Radiation oncologists need to communicate with the surgeon to review the operative findings and to help determine the target volume at risk. They also need to communicate with the pathologist regarding the detailed pathology on histology, disease extent such as extracapsular extension, and surgical margins.
  • The review of preoperative imaging and co-registration of preoperative imaging into the planning system are helpful in defining treatment volumes.

Radiation Techniques

  • CT based planning is highly recommended.
  • RT should be given by 3-D conformal technique to reduce surrounding normal tissue damage (e.g. heart, lungs, esophagus, spinal cord). Intensity modulated RT (IMRT) may further improve the dose distribution and decrease the dose to the normal tissue as indicated. If IMRT is applied, the ASTRO/ACR IMRT guideline should be strictly followed
  • In addition to following the normal tissue constraints recommendations using the Principles of Radiation Therapy in the NCCN guidelines for Non-Small Cell Lung cancer, more conservative limits are recommended to minimize the dose volumes to all the normal structures. Since these patients are younger and mostly long term survivors, the mean total dose to the heart should be as low as reasonably achievable to potentially maximize survival.
  • Proton beam therapy (PBT) has been shown to improve the dosimetry compared to IMRT allowing better sparing of the normal organ (lungs, heart and esophagus). Additionally, favorable results in terms of both local control and toxicity have been obtained with PBT. Based on these data, PBT may be considered in certain circumstances.

Thymic Masses
Treatment

The optimal plan of care for patients with thymic malignancies should be developed before treatment after evaluation by radiation oncologists, thoracic surgeons, medical oncologists, and diagnostic imaging specialists. It is critical to determine whether the mass can be surgically resected; a board certified thoracic surgeon with primary focus on thoracic oncology should make this decision. Total thymectomy and complete surgical excision of the tumor are recommended whenever possible for resectable tumors.

 

Similar to thymomas patients with completely resected thymic carcinomas have longer survival than those who are either incompletely resected or unresectable. Patients who have R0 resection have a 5 year survival of about 60%. Thus management depends on the extent of resection. Patients with thymic. Patients with thymic carcinoma have a higher risks of recurrent disease, therefore, postoperative radiation is recommended to maximize local control. After resection of thymic carcinomas, postoperative management includes RT with or without chemotherapy, depending on the completeness of resection. For unresectable or metastatic thymic carcinomas, chemotherapy with or without RT is recommended.


Thymomas
Although thymomas can be locally invasive (e.g. pleura, lung) they uncommonly spread to regional lymph nodes or extrathoracic sites. Surgery (i.e. total thymectomy and complete excision of tumor) is recommended for all resectable thymomas for patients who can tolerate surgery.

 

Adjuvant therapy is not recommended for completely resected (R0) stage I thymomas. For incompletely resected thymomas, postoperative RT is recommended. CT based treatment planning is highly recommended before RT. RT should be given by the 3D conformal technique to reduce damage to surrounding normal tissue (e.g. heart, lungs, esophagus, spinal cord).

 

For locally advanced thymomas, induction chemotherapy is recommended followed by an evaluation for surgery; postoperative RT can be considered after surgical resection of the primary tumor and isolated metastases. For those with solitary metastasis or ipsilateral pleural metastases, options include 1) induction chemotherapy followed by surgery for resectable patients; or 2) surgery alone. After induction chemotherapy, imaging recommended (e.g. chest CT, MRI, PET/CT) as clinically indicated to determine whether resection is feasible. For patients with unresectable disease in both of these settings, RT with or without chemotherapy is recommended. It is difficult to specify RT dosing regimens for metastatic disease given the very broad range of metastatic scenarios that are possible. Stereotactic body radiation therapy (SBRT) may be appropriate for limited focal metastases, whereas conventional fractionation is appropriate for larger metastases. Highly conformal techniques may be appropriate for limited volume metastases, given the relatively long natural history of even metastatic thymoma.

 

Thyroid Carcinoma Version 2.2020

The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of thyroid carcinoma.

Uterine Neoplasms Version 2.2020

The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for uterine neoplasms.

Vulvar Cancer (Squamous Cell Carcinoma) Version 3.2020 The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) as a radiation treatment modality for the treatment of vulvar cancer.

 

American Urological Association (AUA)

In April 2017, American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) and Society of Urologic Oncology (SUO), issued a guideline on clinically localized prostate cancer. The guideline states the following regarding radiotherapy: "Clinicians should inform localized prostate cancer patients who are considering proton beam therapy that it offers no clinical advantage over other forms of definitive treatment." (Moderate Recommendation; Evidence Level: Grade C [RTCs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data]).

 

American College of Radiology (ACR)

The 2014 ACR Appropriateness Criteria Definitive External Beam Irradiation in Stage T1 and T2 Prostate Cancer states:

  • "There are only limited data comparing proton-beam therapy to other methods of irradiation or to radical prostatectomy for treating stage T1 and T2 prostate cancer. Further studies are needed to clearly define its role for such treatment."

 

 

Prior Approval:

Prior approval is required.

 

Policy:

  • See also medical policy 06.01.15 Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiation Therapy (SBRT)

 

Clinical Trials and Clinical Registry Trials

Proton beam radiation therapy (PBRT) is considered a non-covered benefit when it is the experimental arm or subject of the clinical trial (refer to the member’s benefit certificate language regarding clinical trials coverage).

 

When proton beam radiation therapy (PBRT) is studied as part of a clinical registry trial, Wellmark BCBS coverage criteria will be applied to determine the medical necessity of the proton beam radiation therapy (PBRT) services. When proton beam radiation therapy (PBRT) is part of a clinical registry trial and Wellmark BCBS criteria are not met, the proton beam radiation therapy (PBRT) will be considered not medically necessary

 

Clinical registry trials are observational and lack the basic underpinning of clinical equipoise as there is inherent bias among both patients and investigators.

  

Proton beam radiation therapy (PBRT) not meeting Wellmark BCBS medical necessity criteria will be considered not medically necessary as proton beam radiation therapy (PBRT) as not been proven effective outside of these indications.

 

Secondary Malignancies

Proton beam radiation therapy (PBRT) is considered not medically necessary solely to reduce the risk of secondary malignancy as the available published data on whether proton beam radiation therapy (PBRT) increases or reduces the risk of secondary malignancy remains unproven.

 

Prostate Cancer

Proton Beam radiation therapy (PBRT) is considered not medically necessary for the treatment of prostate cancer because it has not been proven to be more effective than other radiotherapy modalities for this indication.

 

Proton beam radiation therapy (PBRT) is considered not medically necessary, including but not limited to following indications in adults (over age 21), as there is lack of high quality evidence comparing proton beam radiation therapy (PBRT) outcomes with photon-based (3D-conformal or intensity modulated radiation therapy [IMRT]) or stereotactic techniques based on the peer reviewed published medical literature in combination with National Comprehensive Cancer Network (NCCN) guidelines. Proton beam radiation therapy (PBRT) has not been proven to be more effective than other radiotherapy modalities for the treatment of these indications:

  • Anal cancer
  • Basal cell skin cancer
  • Bladder cancer/genitourinary cancers (upper tract tumors, urothelial carcinoma, primary carcinoma of urethra)
  • Bone cancer (except the following which will require medical review: chondrosarcoma; chordoma; and osteosarcoma unresectable or incompletely resectable)
  • Breast cancer (except left sided invasive breast cancer which will require medical review)
  • Central nervous system (CNS) cancers (except for the following which will require medical review: Ependymoma by biopsy intracranial or spinal; Anaplastic Glioma/Glioblastoma by biopsy; Medulloblastoma by biopsy; and Meningiomas )
  • Cervical cancer
  • Colon cancer (includes colorectal cancer)
  • Cutaneous melanoma
  • Dermatofibrosarcoma Protuberans
  • Esophageal and esophagogastric junction cancers
  • Gastric cancers
  • Head and neck cancers (except the following which will require a medical review: Cancers of the oropharynx; mucosal melanoma; nasopharyngeal cancer; occult primary when targeting the pharyngeal axis; paranasal sinus cancer [maxillary sinus tumor, ethmoid sinus tumor, frontal sinus tumor, sphenoid sinus tumor]; salivary gland cancer; supraglottic larynx cancer; stage T4b disease; metastatic disease; recurrent persistent disease; unresectable nodal disease; and individual unfit for surgery)
  • Hepatobiliary cancers (except the following which will require a medical review: Hepatocellular carcinoma (HCC) and Intrahepatic cholangiocarcinoma) 
  • Intracranial arteriovenous malformations (AVM) (except for the following which will require a medical review: intracranial arteriovenous malformations (AVM) not amendable to surgical excision, embolization or standard stereotactic radiosurgery)
  • Kidney cancer
  • Lung cancer (including non-small cell and small cell and other lung cancers)
  • Lymphomas (Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma i.e. B-cell lymphomas, T-cell Lymphomas) (except when the Wellmark BCBS coverage criteria is met, will require medical review) 
  • Malignant pleural mesothelioma
  • Merkel cell carcinoma
  • Multiple myeloma
  • Neuroendocrine and adrenal tumors
  • Occult Primary – Cancer of Unknown Primary (CUP)
  • Ovarian cancer including fallopian tube and primary peritoneal cancer
  • Pancreatic cancer
  • Penile cancer
  • Prostate cancer (Note: see separate statement above for prostate cancer)
  • Rectal cancer
  • Small bowel adenocarcinoma
  • Soft tissue sarcomas (except the following which will require a medical review: retroperitoneal/intrabdominal soft tissue sarcoma)
  • Squamous cell skin cancer
  • Testicular cancer
  • Thymomas and thymic carcinomas (except when the Wellmark BCBS coverage criteria is met, will require medical review)
  • Uterine neoplasm
  • Vulvar cancer

 

Documentation Requirements for Proton Beam Radiation Therapy

The documentation requirements outlined below are used to assess whether the member meets the clinical criteria for coverage but does not guarantee coverage of the service requested.

 

Medical notes documenting all of the following:

  • History of medical condition requiring treatment; AND
  • Documentation that sparing the surrounding normal tissues/organs at risk (OARs) cannot be achieved with standard radiation therapy techniques; AND
  • Evaluation includes a comparison of treatment plans for proton beam radiation therapy (PBRT) and photon-based therapies such intensity modulated radiation therapy (IMRT) or 3D-conformal radiation therapy and when applicable stereotactic techniques (SBRT/SRS); AND
  • For hypofractionated radiation, provide the prescribed total dose and dose per fraction; AND
  • For delivery of radiation therapy course with standard fractionation, provided the dose prescription along with the documentation in the form of a clearly labeled, color comparative proton, and photon-based/ IMRT or stereotactic dose volume histogram and dose table, in absolute doses noting that sparing of the surrounding normal tissues/organs at risk (OARs) cannot be achieved with photon-based/IMRT or stereotactic techniques. Note: If citing an RTOG (Radiation Therapy Oncology Group) dose constraint, provide the RTOG protocol number; AND
  • Physician’s treatment plan. 

 

Definition

Curative Intent: treatment provided with the main intent being to improve or eliminate symptoms that the patient is experiencing and to extend the patient’s overall length of life.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.

  • 77520 Proton treatment delivery; simple, without compensation
  • 77522 Proton treatment delivery; simple, with compensation
  • 77523 Proton treatment delivery; intermediate
  • 77525 Proton treatment delivery; complex

 

Selected References:

  • Nilsson S, Norlen BJ, Widmark A.  A systematic overview of radiation therapy effects in prostate cancer. Acta Oncol. 2004;43(4):316-81.
  • Yeboah C Sandison GA. Optimized treatment for prostate cancer comparing IMPT, VHEET and 15 MV IMXT.  Phys Med Biol. 2002;47(13):2247-61
  • Gardner BG, et al. Late normal tissue sequelae in the second decade after high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer.  J Urol. 2002 Jan;167(1)123-6
  • Thurman SA et al. Radiation therapy for the treatment of locally advanced and metastatic prostate cancer. Hematol Oncol Clin North Am. 2001 Jun;15(3): 423-43
  • Rossi CJ, et al. Particle beam radiation therapy in prostate cancer: is there an advantage?  Semin Radiat Oncol. 1998 Apr;8(2): 115-23.
  • Zietman AL, DeSilvio ML, Slater JD et al. Comparison of Conventional-Dose vs High-Dose Conformal Radiation Therapy in Clinically Localized Adenocarcinoma of the Prostate. JAMA 2005; 294(10):1233-9.
  • ECRI Institute. Health Technology Information Service. Emerging Technology Report. (May 2007). Proton beam radiation therapy (overview). Retrieved December 18, 2007 from ECRI Institute.
  • Trikalinos TA, Terasawa T, Ip S et al. Particle Beam Radiation Therapies for Cancer. Technical Brief No. 1. (Prepared by Tufts Medical Center Evidence-based Practice Center under Contract No. HHSA-290-07-10055.) Rockville, MD: Agency for Healthcare Research and Quality. September 2009.
  • Brada M, Pijls-Johannesma M, De Ruysscher D. Proton Therapy in Clinical Practice: Current Clinical Evidence. J Clin Oncol. 2007 Mar 10; 25(8):965-70.
  • Wilt TJ, MacDonald R, Rutks I et al. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med 2008; 148:435-48.
  • Wilt TJ, Shamliyan T, Taylor B et al. Comparative Effectiveness of Therapies for Clinically Localized Prostate Cancer. Comparative Effectiveness Review No. 13. (Prepared by Minnesota Evidence-based Practice Center under Contract No. 290-02-00009.) Rockville, MD: Agency for Healthcare Research and Quality; 2008.
  • Schulz-Ertner D, Tsujii H. Particle radiation therapy using proton and heavier ion beams. J Clin Oncol 2007; 25:953-64.
  • Goetein M, Cox JD. Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol 2008; 26:175-6.
  • Grutters JP, Kessels AG, Pijls-Johannesma M et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother Oncol. 95(1):32-40.
  • Iwata H, Murakami M, Demizu Y et al. High-dose proton therapy and carbon-ion therapy for stage I non-small cell lung cancer. Cancer. 116(10):2476-85.
  • Pijls-Johannesma M, Grutters JP et al. Do we have enough evidence to implement particle therapy as standard treatment in lung cancer? A systematic literature review. Oncologist. 1591):93-103.
  • Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Proton Beam Therapy for Non-small Cell Lung Cancer. TEC Assessments 2010;  Volume 25, Tab 7
  • TARGET [database online]. Plymouth Meeting (PA):ECRI Institute; 2010 Nov 1. Proton beam radiation therapy (overview).
  • Kagan AR, Schulz RJ. Proton-beam therapy for prostate cancer. Cancer J 2010; 16(5):405-9.
  • Zietman AL, Bae K, Slater JD et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/American College of Radiology 95-09. J Clin Oncol. Mar 1 2010; 28(7):1106-11. doi: 10.1200/JCO.2009.25.8475.
  • Talcott JA, Rossi C, Shipley WU et al. Patient-reported long-term outcomes after conventional and high-dose combined proton and photon radiation for early prostate cancer. JAMA. Mar 17; 303(11):1046-53.
  • Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Proton Beam Therapy for Prostate Cancer. TEC Assessments 2011; Volume 25, Tab 10.
  • Emerging Technology Evidence Report. Proton Beam Therapy (overview). Plymouth Meeting (PA): ECRI Institute; 2011 Oct.
  • Coen JJ, Zietman AL, Rossi CJ et al. Comparison of high-dose proton radiotherapy and brachytherapy in localized prostate cancer: a case-matched analysis. Int J Radiat Oncol Biol Phys. 2012 Jan 1; 82(1):e25-31. Epub 2011 Apr 4.
  • Coen JJ, Paly JJ, Niemierko A et al. Long-term quality of life outcome after proton beam monotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Jan 1; 82(1):213-21. Epub 2010 Nov 17.
  • Kahn J, Loeffler JS, Niemierko A et al. Long-term outcomes of patients with spinal cord gliomas treated by modern conformal radiation techniques. Int J radiat Oncol Biol Phys. 2011; 81(1):232-38.
  • Ramaekers BL, Pijls-Johannesma M, Joore MA et al. Systematic review and meta-analysis of radiotherapy in various head and neck cancers: comparing photons, carbon-ions and protons. Cancer treat Rev. 2011; 37(3):185-201.
  • ECRI Institute. Proton Beam Radiation Therapy (Overview). Plymouth Meeting (PA): ECRI Health Technology Assessment Information Service. August 2012. [Emerging Technology Evidence Report].
  • Allen AM, Pawlicki T, Dong L, Fourkal E, et al. An evidence based review of proton beam therapy: the report of ASTRO’s emerging technology committee. Radiother Oncol 2012 Apr;103(1):8-11. 
  • UpToDate. Radiation Therapy Techniques in Cancer Treatment. Timur Mitin, M.D., PhD. Topic last updated August 14, 2017.
  • ASTRO. Practice Management-Proton Beam Therapy for Prostate Cancer Position Statement.
  • ASTRO. News and Medical Releases 2013. Encouraging Outcomes for Pediatric Brain Tumor Patients Treated with Proton Therapy. September 22, 2013.
  • American Brain Tumor Association. Pituitary Tumors.
  • ECRI Institute. Emerging Technology Evidence Report. Proton Beam Radiation Therapy (Overview). January 2013.
  • American Brain Tumor Association: Proton Therapy.
  • UpToDate. Overview of Multimodality Treatmentfor Primary Soft Tissue Sarcoma of the Extremities and Chest Wall. Thomas F. DeLaney, M.D., Mark C. Gebhardt, M.D., Christopher W Ryan M.D..  Topic last updated: February 6, 2017.
  • National Cancer Institute. Childhood Craniopharyngioma Treatment. Last modified August 2013.
  • National Cancer Institute. Intraocular (Uveal) Melanoma Treatment. Last modified November 2012.
  • Agency for Healthcare Research and Quality (AHRQ). Proton Beam Radiation Therapy. March 2013.
  • ECRI Institute. Hotline Response. Proton Beam Radiation Therapy for Cancers of the Brain, Head, Neck and Skull Base. May 2013.
  • UpToDate. Brain Arteriovenous Malformation. Robert J. Singer, M.D., Christopher S. Ogilvy, M.D., Guy Rordorf, M.D. Topic last updated November 7, 2016.
  • UpToDate. Chordoma and Chondrosarcoma of the Skull Base. Carol Snyderman, M.D., MBA, Derrick Lin, M.D. Topic last updated August 1, 2016.
  • UpToDate. Uveal and Conjunctival Melanoma. Evangelos S. Gragoudas, M.D., Anne Marie Lane, MPH, Helen A. Shih, M.D., Richard D. Carvajal, M.D.. Topic last updated April 27, 2017.
  • UpToDate. External Beam Radiation Therapy for Localized Prostate Cancer. Steven J. DiBiase, M.D., Mack Roach, III, M.D.. Topic last updated April 10, 2017.
  • American Cancer Society. Radiation Therapy for Pituitary Tumors. Last reviewed January 2013.
  • ASTRO Model Policies – Proton Beam Therapy (PBT) June 2014.
  • ECRI. Health Technology Forecast. Proton Beam Therapy for Treating Cancer, July 2014.
  • F. Daniel Armstrong, University of Miami Miller School of Medicine; and Holtz Children’s Hospital, Univerity of Miami/Jackson Memorial Medical Center, Miami, FL. Proton Beam Radiation Therapy and Health Related Quality of Life in Children with CNS Tumors. Journal of Clinical Oncology, Volume 30, Number 17, June 10, 2010.  
  • American College of Radiology (ACR) Appropriateness Criteria for External Beam Radiation Therapy Treatment Planning for Clinically Localized Prostate Cancer, Last reviewed in 2016.
  • American Society for Radiation Oncology (ASTRO) Model Policies: Proton Beam Therapy (PBT) 2014.
  • American Society for Radiation Oncology (ASTRO) Recommends Five Radiation Oncology Treatments to Question as Part of Choosing Wisely Campaign, September 2013.
  • National Cancer Institute. Health Professional PDQ Prostate Cancer Treatment.
  • ECRI. Health Technology Forecast. Proton Beam Therapy Systems for Treating Cancer, Published June 2015.
  • Cancer.Net. Brain Tumor Overview and Treatment Options.
  • Cancer.Net. Central Nervous System Tumors - Childhood Overview and Treatment Options.
  • Blanchard P, Garden A, Gunn G.B., et. al Intensity modulated proton beam therapy (IMPT) versus intensity modulated photon therapy (IMRT) for patients with oropharynx cancer – a case matched analysis. Journal Radiotherapy and Oncology May 2016.
  • Wang J, Palmer M, Bilton S, et. al. Comparing proton beam to intensity modulated radiation therapy planning in esophageal cancer. International Journal of Particle Therapy 2015;1(4):866-877
  • Wang J, Wei C, Tucker S, et.al. Predictors of postoperative complications after trimodality therapy for esophageal cancer. Int J Radiat Oncol Biol Phys 2013 Aug 1; 86(5): 885-891
  • Sio T, Lin HK, Shi Q, et. al. Intensity modulated proton therapy versus intensity modulated photon radiation therapy for oropharyngeal cancer: First comparative results of patient-reported outcomes. Int J Radiation Oncol Biol Phys Vol. 95, No. 4 pp 1107-1114
  • Holliday E, Garden A, Rosenthal D, et. al. Proton therapy reduces treatment-related toxicities for patients with nasopharyngeal cancer: A case match control study of intensity-modulated proton therapy and intensity-modulated photon therapy. International Jounr of Particle Therapy 2015;2(1):19-28
  • Gunn GB, Blanchard P, Garden A, et. al. Clinical outcomes and patterns of disease recurrence after intensity modulated proton therapy for oropharyngeal squamous carcinoma. Int J Radiation Oncol Biol Phys. Vol. 95, No. 1, pp. 360-367, 2016  
  • Frank S, Cox James, Gillin M, et. al. Multifield optimization intensity modulated proton therapy for head and neck tumors: A translation to practice. Int J Radiation Oncol Biol Phys, Vol. 89, No. 4, pp. 846-853, 2014
  • Slater J, Yonemoto L, Mantik D, et. al. Proton radiation for treatment of cancer of the oropharynx: Early experience at Loma Linda University Medical Center using a concomitant boost technique. Int J. Radiation Oncology Biol. Phys. Vol. 62. No.2, pp. 494-500, 2005
  • Patel S, Wang Z, Wong William, et. al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity-malignant diseases: a systematic review and meta-analysis. Lancet Oncol 2014;15:1027-38
  • Welsh J, Gomez D, Palmer M, 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 Radiat Oncol Biol Phys 2011 Dec 1; 81(5):1336-1342
  • Zhang X, Zhao K, Guerrero T. et. al. 4D CT-based treatment planning for intensity modulated radiation therapy and proton therapy for distal esophagus cancer. Int J Radiat Oncol Biol Phys. 2008 September 1; 72(1):278-287
  • Batra S, Comisar L, Lukens JN, et. al. Lower rates of acute gastrointestinal toxicity with pencil beam proton therapy relative to IMRT in neoadjuvant chemoradiation for rectal cancer. J Clin Oncol 2015;33:696
  • MacDonald S, Patel S, Hickey S, et. al. Proton therapy for breast cancer after mastectomy: Early outcomes of a prospective clinical trial. Int J Radiation Oncol Biol Phys. Vol 86. No. 3. Pp. 484-490, 2013
  • Mast M, Vredeveld E, Credoe H, et. al. Whole breast proton irradiation for maximal reduction of heart dose in breast cancer patients. Breast Cancer Res Treat (2014) 148-33-39
  • Darby S, Ewertz M, McGale P, et. al. Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer. The New England Journal of Medicine, March 14, 2013 Vol. 368. No. 11
  • Correa C, Litt H, Weit-Ting H, et. al. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. Journal of Clinical Oncology Volum 25 Number 21 July 2007
  • Harris ER, Correa C, Wei-Ting H, et. al. Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. Journal of Clinical Oncology Volume 24 Number 25 September 2006
  • UpToDate. Overview of treatment for head and neck cancer. Bruce E. Brockstein M.D., Kerstin M. Stenson, M.D., FACS, Shiu Song, M.D., PhD. Topic last updated July 12, 2016.
  • UpToDate. Age Related Macular Degeneration Treatment and Prevention. Jorge G Arroyo M.D., MPH. Topic last updated March 8, 2017.
  • UpToDate. Radiation Therapy, Chemotherapy, Neoadjuvant Approaches, and Postoperative Adjuvant Therapy for Localized Cancers of the Esophagus. Noah C Choi, M.D., Michael K. Gibson M.D., PhD, FACP. Topic last updated July 10, 2017.
  • UpToDate. Management of Locally Advanced Unresectable and Inoperable Esophageal Cancer. Dwight E. Heron M.D., MBA, FACRO, FACR, Michael K. Gibson M.D, PhD, FACP. Topic last updated December 13, 2016.
  • UpToDate. Initial approach to low and very low risk clinically localized prostate cancer. Eric A. Klein M.D., Jay P. Ciezki M.D, Topic last updated March 29, 2017.
  • UpToDate. Initial Management of Regionally Localized Intermediate, High and Very High Risk Prostate Cancer. John F. Ward, M.D., FACS, Nicholas Vogelzang, M.D., Brian Davis, M.D., PhD. Topic last updated May 12, 2017.  
  • UpToDate. Clinical Features, Evaluation, and Treatment of Retroperitoneal Soft Tissue Sarcoma. John T. Mullen M.D., FACS, Thomas F. DeLaney, M.D. Topic last updated March 10, 2017.
  • UpToDate. Treatment of Locally Recurrent and Unresectable, Locally Advanced Soft Tissue Sarcoma of the Extremities. Thomas F. DeLaney M.D., David C. Harmon, M.D., Mark C. Gebhardt, M.D.. Topic last updated April 25, 2017.
  • UpToDate. Overview of the Treatment of Newly Diagnosed, Non-Metastatic Breast Cancer. Alphose Taghian, M.D., PhD, Moataz N. El-Ghamry, M.D., Sofia D. Merajver, M.D., PhD. Topic last updated August 15, 2017.
  • UpToDate. Overview of Treatment Approaches for Hepatocellular Carcinoma. Eddie K. Abdalla, M.D., Keith E. Stuart, M.D.. Topic last updated December 13, 2016.   
  • Sen S. Arteriovenous Malformations Treatment and Management. MedScape. Updated May 27, 2014.
  • Cotter SE, McBride SM, Yock TI. Proton radiotherapy for solid tumors of childhood. Technol Cancer Res Treat 2012 Jun;11(3):267-78. PMID 22417062
  • Leroy R, Benahmed N, Hulstaert F, et al. Proton therapy in children: a systematic review of clinical effectiveness in 15 pediatric cancers. Int J Radiat Oncol Biol Phys. May 1 2016;95(1):267-278. PMID 27084646
  • Merchant TE. Proton beam therapy in pediatric oncology. Cancer J. Jul-Aug 2009;15(4):298-305. PMID 19672146
  • Kim YJ, Cho KH, Pyo HR, et al. A phase II study of hypofractionated proton therapy for prostate cancer. Acta Oncol. Apr 2013;52(3):477-485. PMID 23398594
  • Sun F, Oyesanmi O, Fontanarosa J, et al. Therapies for Clinically Localized Prostate Cancer: Update of a 2008 Systematic Review. Comparative Effectiveness Review No. 146). AHRQ Publication No. 15-EHC004-EF. Rockville (MD): Agency for Healthcare Research and Quality;Dec 2014.
  • Grutters JP, Kessels AG, Pijls-Johannesma M, et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother Oncol. Apr 2010;95(1):32-40. PMID 19733410
  • Pijls-Johannesma M, Grutters JP, Verhaegen F, et al. Do we have enough evidence to implement particle therapy as standard treatment in lung cancer? A systematic literature review. Oncologist. 2010;15(1):93-103. PMID 20067947
  • Zenda S, Kawashima M, Arahira S, et al. Late toxicity of proton beam therapy for patients with the nasal cavity, para-nasal sinuses, or involving the skull base malignancy: importance of long-term follow-up. Int J Clin Oncol. Jun 2015;20(3):447-454. PMID 25135461
  • Chang JY, Jabbour SK, De Ruysscher D, et al. Consensus statement on proton therapy in early-stage and locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. May 1 2016;95(1):505-516. PMID 27084663
  • Nguyen PL, Aizer A, Assimos DG, et al. ACR Appropriateness Criteria(R) Definitive External-Beam Irradiation in stage T1 and T2 prostate cancer. Am J Clin Oncol. Jun 2014;37(3):278-288. PMID 25180754
  • Ojerholm E, Kirk ML, Thompson RF, et.al. Pencil-beam scanning proton therapy for anal cancer. a dosimetric comparison with intensity modulated radiotherapy. Acta Oncol 2015;54(8):1209-17. PMID 25734796
  • Specht L, Yahalorn J, Illidge T. et. al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the International Lymphoma Radiation Oncology Group (ILROG). Int J Radiat Oncol Biol Phys 2014 July 15;89(4):854-62. PMID 23790512
  • Illidge T, Specht L. Yahalom J. et. al. Modern radiation for nonal non-Hodgkin lymphoma target definition and dose guidelines from the Internationl Lymphoma Radiation Oncology Group (ILROG). Int J Radiat Oncol. Biol Phys 2014 May 1;89(1):49-58. PMID 24725689   
  • American Academy of Ophthlamology (AAO). Age Related Macular Degeneration Preferred Practice Pattern Guidelines 2015.
  • National Imaging Assocation (NIA) Guidelines for Proton Beam Radiation Therapy.
  • Qi WX, Fu S, Zhang Q, et. al. Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: a systematic review and meta-analysis. Radiother Oncol 2015 Mar:114(3):289-95. PMID 25497556
  • Kim B, Chen YL, Kirsch DG, et. al. An effective preoperative three-dimensional radiotherapy target volume for extremity soft tissue sarcoma and the effect of margin width on local control. Int J Radiat Oncol Biol Phys 2010 Jul 1;77(3):843-50. PMID 20005638
  • Yoon SS, Chen YL, Kirsch DG, et. al. Proton-beam, intensity modulated, and/or intraoperative electron radiation therapy combined with aggressive anterior surgical resection for retroperitoneal sarcomas. Ann Surg Oncol 2010 Jun;17(6):1515-29. PMID 20151216
  • Swanson EL, Indelicato DJ, Louis D, et. al. Comparison of three-dimensional (3D)  conformal proton radiotherapy (RT), 3D conformal photon RT, and intensity-modulated RT for retroperitoneal and intra-abdominal sarcomas. Int J Radiat Oncol Biol Phys 2012 Aug 1;83(5):1549-57. PMID 22270176
  • Vogel J, Berman AT, Lin L, et. al. Prospective study of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma: early response and toxicity assessment. Radiother Oncol 2016 Mar:118(3):504-9. PMID 26895711
  • Parikh RR, Rhome R, Hug E, et. al. Adjuvant proton beam therapy in the management of thymoma: a dosimetric comparison and acute toxicities. Clin Lung Cancer 2016 Sep;27(5):362-366. PMID 27372386
  • Gray PJ, Paly JJ, Yeap BY, et. al. Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer 2013 May 1:119(9):1729-35. PMID 23436283
  • Mendenhall NP, Hoppe BS, Nichols RC, 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. PMID 24521677
  • Hoppe BS, Michalski JM, Mendenhall NP, et. al. Comparative effectiveness study of patient-reported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer 2014 Apr 1;120(7):1076-82. PMID 24382757
  • Henderson RH, Hoppe BS, Marcus RB Jr, et. al. Urinary functional outcomes and toxicity five years after proton therapy for low and intermediate-risk prostate cancer: results of two prospective trials. Acta Oncol 2013 Apr52(3):463-9. PMID 23477359
  • Holliday EB, Frank SJ. Proton radiation therapy for head and neck cancer: a review of the clinical experience to date. Int J Radiat Oncol Biol Phys 2014 Jun 1;89(2):292-302. PMID 24837890
  • Mendenhall NP, Malyapa RS, Su Z, et. al. Proton Therapy for head and neck cancer: rationale, potential indications, practical considerations, and current clinical evidence. Acta Oncol 2011 Aug;50(6):763-71. PMID 21767172
  • Bui M, Frank SJ, Nasser QJ, et. al. Multidisciplinary management of primary adenoid cystic carcinoma of the eyelid with perineural invasion. Ophthal Plast Reconstr Surg 2013 Nov-Dec;29(6):e143-6. PMID 23446295
  • Jakobi A, Bandurska-Luque A, Stutzer K, et. al. Identification of patient benefit from proton therapy for advanced head and neck cancer patients based on individuals and subgroup normal tissue complication probability analysis. Int J Radiat Oncol Biol Phys 2015 Aug 1;92(5):1165-1174. PMID 26194685
  • Jakobi A, Stutzeer K, Bandurska-Luque A, et. al. NTCP reduction for advanced head and neck cancer patients using proton therapy for complete for sequential boost treatment versus photon therapy. Acta Oncol 2015;54(9):1658-64. PMID 26340301
  • Kandula S, Zhu X, Garden AS, et. al. Spot-scanning beam proton therapy vs intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison. Med Dosim 2013 Winter 38(4):390-4. PMID 23916884
  • Lukens JN, Lin A, Hahn SM. Proton therapy for head and neck cancer. Curr Opin Oncol 2015 May;27(3):165-71. PMID 25811343
  • Orlandi E, lacovelli NA, Bonora M, et. al. Salivary gland photon beam and particle radiotherapy: present and future. Oral Oncol 2016 Sep;60:146-56. PMID 27394087
  • Ramaekers BL, Grutters JP, Piils-Johannesma M, et. al. Protons in head-and-neck cancer: bridging the gap of evidence. Int J Radiat Oncol Biol Phys 2013 Apr 1:85(5):1282-8. PMID 23273998
  • Simone CB 2nd, Ly D, Dan TD, et. al. Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, adaptive proton radiotherapy for treatment of locally advanced head and neck cancer. Radiother Oncol 2011 Dec:101(3):376-82. PMID 21663988
  • Verma V, Mishra MV, Mehta MP. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer 2016 May15;(10):1483-501. PMID 26828647
  • Leroy R, Benahmed N, Hulstaert F, et. al. Proton therapy in children: a systematic review of clinical effectiveness in 15 pediatric cancers. Int J Radiat Oncol Biol Phys 2016 May 1;95(1):267-78. PMID 27084646
  • Patel SH, Wang Z, Wong WW, et. al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol 2004 Aug;15(9):2017-38. PMID 24980873
  • Zenda S, Kawashima M, Arahira S, et. al. Late toxicity of proton beam therapy for patients with nasal cavity, para-nasal sinuses, or involving the skull base malignancy: importance of long term follow up. Int J Clin Oncol 2015 Jun;20(3):447-54. PMID 25135461
  • Chang JY, Jabbour SK, De Ruysscher D, et. al. Consensus statement on proton therapy in early-stage and locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys 2016 May 1;95(1):505-16. PMID 2708466
  • Ciernik IF, Niemierko A, Harmon DC, et. al. Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer 2011 Oct 1;117(19):4522-30. PMID 21448934    
  • Holliday E, Bhattasali O, Kies M, et. al. Postoperative intensity modulated proton therapy for head and neck adenoid cystic carcinoma. International Journal of Particle Therapy published Mar 2016    
  • ECRI. Health Technology Assessment. Proton Beam Radiation Therapy Systems for Treating Cancer. Published March 2017.
  • American Urological Association (AUA) Guideline on the Management of Clinically Localized Prostate Cancer.
  • National Cancer Institute: Comprehensive Cancer Information Non-Hodgkin’s Lymphoma Health Professional Version.
  • Hutcheson K, Lewin AS, Garden DI, et. al. Early experience with IMPT for the treatment of oropharyngeal tumors: acute toxicities and swallowing related outcomes. International Journal of Radiation Oncology Biology Physics October 2013 Volume 87, Issue 2 Supplement Page S604
  • Miller RC, Lodge M, Murad MH, Jones B. Controversies in clinical trials in proton radiotherapy: the present and the future. Semin Radiat Oncol 2013 Apr 23(2):127-33. PMID 23473690
  • Zenda S, Kawashima M, Nishio T, et. al. Proton beam therapy as a nonsurgical approach to mucosal melanoma of the head and neck: a pilot study. Int J Radiat Oncol Biol Phys 2011 Sep 1;81(1):135-9. PMID 20950948
  • Fukumitsu N, Okumura T, Mizumoto M, et. al. Outcome of  T4 (International Union Against Staging System, 7th edition) or recurrent nasal cavity and paranasal sinus carcinoma treated with proton beam. Int J Radiat Oncol Biol Phys 2012 Jun 1;83(2):704-11. PMID 22099036
  • Demizu Y, Fujji O, Terashima K, et. al. Particle therapy for mucosal melanoma of the head and neck. A single-institution retrospective comparison of proton and carbon ion therapy. Strahlenther Onkol 2014 Feb;190(2):186-91. PMID 24362502
  • Fuji H, Yoshikawa S, Kasami M, et. al. High-dose proton beam therapy for sinonasal mucosal malignant melanoma. Radiat Oncol 2014 Jul 23;9:162. PMID 25056641
  • Allen AM, Pawlicki T, Doug L, et. al. An evidence based review of proton beam therapy: the report of ASTRO’s emerging technology committee. Radiother Oncol 2012 Apr;103(1):8-11. PMID 22405807
  • Bhattasali O, Holliday E, Kies MS, et. al. Definitive proton radiation therapy and concurrent cisplatin for unresectable head and neck adenoid cystic carcinoma: A series of 9 cases and a critical review of the literature. Head Neck 2016 Apr 38 Suppl 1: E1472-80. PMID 26561041
  • 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. Radiother Oncol 2016 Feb;118(2):286-92. PMID 26867969
  • Russo AL, Adams JA, Weyman EA, et. al. Long-term outcomes after proton beam therapy for sinonasal squamous cells carcinoma. Int J Radiat Oncol Biol Phys 2016 May 1;95(1):368-76. PMID 27084654
  • Dagan R, Bryant C, Li Z, et. al. Outcomes of sinonasal cancer treated with proton therapy. Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):377-85. PMID 27084655
  • McDonald MW, Liu Y, Moore MG, Johnstone PA. Acute toxicity in comprehensive head and neck radiation for nasopharynx and paranasal sinus cancer: cohort comparison of 3D conformal proton therapy and intensity modulated radiation therapy.  Radiat Oncol 2016 Feb 27;11:32. PMID 26922239
  • UpToDate. Nonsurgical therapies for localized hepatocellular carcinoma: transarterial embolization, radiotherapy and radioembolization. Steven A. Curley M.D., FACS, Keith E. Stuart M.D., Jonathan M. Schwartz M.D., Robert L. Carithers Jr, M.D., Klaudia U. Hunter M.D., Topic last updated March 16, 2017
  • National Comprehensive Caner Network (NCCN) Anal Carcinoma Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Bladder Cancer Version 6.2020
  • National Comprehensive Cancer Network (NCCN) Bone Cancer Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Breast Cancer Version 5.2020
  • National Comprehensive Cancer Network (NCCN) Central Nervous System Cancers Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Cervical Cancer Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Colon Cancer Version 4.2020
  • National Comprehensive Cancer Network (NCCN) Rectal Cancer Version 6.2020
  • National Comprehensive Cancer Network (NCCN) Esophageal and Esophagogastric Junction Cancers Version 4.2020
  • National Comprehensive Cancer Network (NCCN) Gastric Cancer Version 3.2020
  • National Comprehensive Cancer Network (NCCN) Head and Neck Cancers Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Hepatobiliary Cancers Version 5.2020
  • National Comprehensive Cancer Network (NCCN) Hodgkin Lymphoma Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Kidney Cancer Version 1.2021
  • National Comprehensive Cancer Network (NCCN) Malignant Pleural Mesothelioma Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Cutaneous Melanoma Version 3.2020
  • National Comprehensive Cancer Network (NCCN) Uveal Melanoma Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Multiple Myeloma Version 4.2020. 
  • National Comprehensive Cancer Network (NCCN) Neueroendocrine and Adrenal Tumors Version 2.2020
  • National Comprehensive Cancer Network B-Cell Lymphomas Version 4.2020
  • National Comprehensive Cancer Network (NCCN) Pediatric Aggressive Mature B-Cell Lymphoma Version 2.2020.
  • National Comprehensive Cancer Network (NCCN) Primary Percutaneous B-Cell Lymphomas Version 2.2020
  • National Comprehensive Cancer Network (NCCN) T-Cell Lymphomas Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Basal Cell Skin Cancer Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Dermatofibrosarcoma Protuberans Version 1.2020.
  • National Comprehensive Cancer Network (NCCN) Merkel Cell Carcinoma Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Squamous Cell Skin Cancer Version 2.2020
  • National Comprehensive Cancer Network Non-Small Cell Lung Cancer Version 6.2020 
  • National Comprehensive Cancer Network (NCCN) Occult Primary (Cancer of Unknown Primary [CUP] Version 3.2020
  • National Comprehensive Cancer Network  (NCCN) Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Pancreatic Adenocarcinoma Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Penile Cancer Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Prostate Cancer Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Small Bowel Adenocarcinoma Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Small Cell Lung Cancer Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Soft Tissue Sarcoma Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Testicular Cancer Version 3.2020
  • National Comprehensive Cancer Network (NCCN) Thymomas and Thymic Carcinomas Version 1.2020
  • National Comprehensive Cancer Network (NCCN) Thyroid Carcinoma Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Uterine Neoplasm Version 2.2020
  • National Comprehensive Cancer Network (NCCN) Vulvar Cancer (Squamous Cell Carcinoma) Version 3.2019
  • Chung CS, Tock TI, Nelson K, et al. Incidence of second malignancies among patients treated with proton versus photo radiation. Int J Radiat Oncol Biol Phys. 2013; 87(1): 46-52. PMID 23778197
  • Foote RL, Stafford SL, Petersen IA, et al. The clinical case for proton beam therapy. Radiat Oncol. 2012; 7:174. doi: 10.1186/1748-717X-7-174 PMID 23083010
  • Radu C, Norrlid O, Braendengen M, et al. Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients. Acta Oncol. 2013; 52(3): 528-37 PMID 23113591
  • Wolff HA, Wagner DM, Conradi L, et al. Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: A planning study with clinical implications. Radiother Oncol. 2012; 102(1): 30-7.
  • Bush, David A. et al. Partial Breast Radiation Therapy With Proton Beam: 5-Year Results With Cosmetic Outcomes. Int J Radiat Oncol Biol Phys. 2014;90(3): 501-505. PMID 25084608
  • Bush DA, Slater JD, Garberoglio C, et al. Partial breast irradiation delivered with proton beam: results of a phase II trial. Clin Breast Cancer. 2011; 11(4):241-245  
  • Chang JH, Lee NK, Kim JY, et al. Phase II trial of proton beam accelerated partial breast irradiation in breast cancer. Radiother Oncol. 2013; 108(2):209-214 PMID 23891102
  • MacDonald SM, Patel SA, Hickey S, et al. Proton therapy for breast cancer after mastectomy: early outcomes of a prospective clinical trial. Int J Radiat Oncol Biol Phys. 2013; 86(3): 484-90. PMID 23523326
  • Brown AP, Barney CL, Grosshans DR, et al. Proton Beam Craniospinal Irradiation Reduces Acute Toxicity for Adults With Medulloblastoma. Int J Radiat Oncol Biol Phys. 2013; 86(2): 277-84 PMID 23433794
  • Dinh J, Stoker J, Georges RH, et al. Comparison of proton therapy techniques for treatment of the whole brain as a component of craniospinal radiation. Radiation Oncology (London, England). 2013;8:289 PMID 24344645
  • Giantsoudi, Drosoula et al. Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury. Int J Radiat Oncol Biol Phys. 2016;95(1):287-296 PMID 26691786
  • Hattangadi JA, Chapman PH, Bussiere MR, et al. Planned Two-Fraction Proton Beam Stereotactic Radiosurgery for High-Risk Inoperable Cerebral Arteriovenous Malformations. Int J Radiat Oncol Biol Phys. 2012; 83(2): 533-41 PMID 22099050
  • Hauswald H, Rieken S, Ecker S, et al. First experiences in treatment of low-grade glioma grade I and II with proton therapy. Radiat Oncol. 2012; 7:189 PMID 23140402
  • Moignier, Alexandra et al. Theoretical Benefits of Dynamic Collimation in Pencil Beam Scanning Proton Therapy for Brain Tumors: Dosimetric and Radiobiological Metrics. Int J Radiat Oncol Biol Phys. 2016;95(1):171-180 PMID 26614424
  • Weber DC, Schneider R, Goitein G, et al. Spot scanning-based proton therapy for intracranial meningioma: long-term results from the Paul Scherrer Institute. Int J Radiat Oncol Biol Phys 2012;83(3):865-871 PMID 22138457
  • Doyen, Jérôme, Falk AT, Floquet V, Hérault J, Hannoun-Lévi JM. Proton beams in cancer treatments: Clinical outcomes and dosimetric comparisons with photon therapy. J Gastro Hepat. 2016;30(5)957-963 PMID 26827698
  • Echeverria A, McCurdy M, Castillo R, et al. Proton therapy radiation pneumonitis local dose–response in esophagus cancer patients. Radiother Oncol. 2013; 106: 124-9 PMID 23127772
  • Hong TS, Wo JY, Yeap BY, et al. Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. Journal of Clinical Oncology. 2016;34(5):460-468 PMID 26668346
  • Lin SH, Komaki R, Liao Z, et al. Proton Beam Therapy and Concurrent Chemotherapy for Esophageal Cancer. Int J Radiat Oncol Biol Phys. 2012. 83(3): e345-51 PMID 22417808
  • Mizumoto M, Sugahara S, Nakayama H, et al. Clinical Results of Proton-Beam Therapy for Locoregionally Advanced Esophageal Cancer. Strahlenther Onkol. 2010; 186(9): doi: 10.1007/s00066-010-2079-4 PMID 20803187
  • Mizumoto M, Sugahara S, Okumura T, et al. Hyperfractionated concomitant boost proton beam therapy for esophageal carcinoma. Int J Radiat Oncol Biol Phys. 2011; 81(4): e601-6 PMID 21511402
  • Clivio A, Kluge A, Cozzi L, et al. Intensity Modulated Proton Beam Radiation for Brachytherapy in Patients with Cervical Carcinoma. Int J Radiat Oncol Biol Phys. 2013; 87(5): 897-903 PMID 24119834
  • A Jakobi, et. al., NTCP reduction for advanced head and neck cancer patients using proton therapy for complete or sequential boost treatment versus photon therapy. Acta Oncologica 2015;54:1658-1664 PMID 26340301
  • Dagan, Roi et al. Outcomes of Sinonasal Cancer Treated With Proton Therapy. Int J Radiat Oncol Biol Phys. 2016;95(1):377-385 PMID 27084695
  • El-Sawy T, et. al., Multidisciplinary Management of Lacrimal Sac/nasolacrimal Duct Carcinomas. Ophthal Plast Reconstr Surg. 2013;29:454-457 PMID 24195987
  • Fukumitsu N, Okumura T, Mizumoto M, et al. Outcome of T4 (International Union Against Cancer Staging System, 7th edition) or recurrent nasal cavity and paranasal sinus carcinoma treated with proton beam. Int J Radiat Oncol Biol Phys. 2012; 83(2):704-11 PMID 22099036
  • Hojo H, Zenda S, Akimoto T, et al. Impact of early radiological response evaluation on radiotherapeutic outcomes in the patients with nasal cavity and paranasal sinus malignancies. J Radiat Res. 2012; 53(5):704-9 PMID 22843360
  • Holliday, Emma B. et al. Proton Radiation Therapy for Head and Neck Cancer: A Review of the Clinical Experience to Date. Int J Radiat Oncol Biol Phys. 2014;89(2):292-302 PMID 24837890
  • Ramaekers BL, Grutters JP, Pijls-Johannesma M, et al. Protons in Head-and-Neck Cancer: Bridging the Gap of Evidence. Int J Radiat Oncol Biol Phys. 2013; 85(5): 1282-8 PMID 23273998
  • Romesser PB, Cahlon O, Scher ED, Hug EB, Sine K, DeSelm C, Fox JL, Mah D, Garg MK, Chang JH, Lee NY. Proton beam reirradiation for recurrent head and neck cancer: multi-institutional report on feasibility and early outcomes. Int J Radiat Oncol Biol Phys. 2016;95(1): 386-395 PMID 27084656
  • Sio, Terence T. et al. Intensity Modulated Proton Therapy Versus Intensity Modulated Photon Radiation Therapy for Oropharyngeal Cancer: First Comparative Results of Patient-Reported Outcomes. Int J Radiat Oncol Biol Phys. 2016;95(4): 1107-1114 PMID 27354125
  • Zenda S, Kawashima M, Nishio T, et al. Proton Beam Therapy as a nonsurgical approach to mucosal melanoma of the head and neck: a pilot study. Int J Radiat Oncol Biol Phys. 2011; 81(1): 135-9 PMID 20950948
  • Zenda S, Kohno R, Kawashima M, et al. Proton beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys. 2011; 81(5): 1473-8 PMID 20961697
  • Bush DA, Kayali R, Slater JH. The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial. Cancer 2011;117:3053-3059 PMID 21264826
  • Fukumitsu N, Hashimoto T, Okumura T, et al. Investigation of the geometric accuracy of proton beam irradiation in the liver. Int J Radiat Oncol Biol Phys. 2012; 82(2): 826-33 PMID 21236603
  • Hong TS, DeLaney TF, Mamon HJ et al. A prospective feasibility study of respiratory gated proton beam therapy. Pract Radiat Oncol 2014;4(5):316-322 PMID 25194100
  • Ja Young Kim, et al. Normal liver sparing by proton beam therapy for hepatocellular carcinoma: Comparison with helical intensity modulated radiotherapy and volumetric modulated arc therapy. Acta Oncologica. 2015;54(10): 1827-1832 PMID 25765526
  • Mizumoto M, Okumura T, Hashimoto T, et al. Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols. Int J Radiat Oncol Biol Phys. 2011; 81(4): 1039-45 PMID 20888707
  • Nakayama H, Sugahara S, Fukuda K, et al. Proton beam therapy for hepatocellular carcinoma located adjacent to the alimentary tract. Int J Radiat Oncol Biol Phys. 2011; 80(4): 992-5 PMID 21543162
  • Sugahara S, Oshiro Y, Nakayama H, et al. Proton Beam Therapy for Large Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys. 2010; 76(2): 460-6 PMID 19427743
  • Bush DA, Cheek G, Zaheer S, et al. High-Dose Hypofractionated Proton Beam Radiation Therapy Is Safe and Effective for Central and Peripheral Early-Stage Non-Small Cell Lung Cancer: Results of a 12-Year Experience at Loma Linda University Medical Center. Int J Radiat Oncol Biol Phys. 2013; 86(5): 964-98 PMID 23845845
  • Chang JY, Komaki R, Lu C, et al. Phase 2 Study of High-Dose Proton Therapy With Concurrent Chemotherapy for Unresectable Stage III Nonsmall Cell Lung Cancer. Cancer. 2011; 117(20): 4707-13 PMID 21437893
  • Chang JY, 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 Radiat Oncol Biol Phys. 2011; 80(5): 1350-1357 
  • Colaco, Rovel J. et al. Dosimetric rationale and early experience at UFPTI of thoracic proton therapy and chemotherapy in limited-stage small cell lung cancer. Acta Oncologica. 2013;52(3): 506-513 PMID 23438357
  • Gomez DR, Gillin M, Liao Z, et al. Phase 1 Study of Dose Escalation in Hypofractionated Proton Beam Therapy for Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2013; 86(4): 665-70 PMID 23688815
  • Hoppe BS. Phase II trial of concurrent chemotherapy and proton therapy for stage 3 NSCLC. Int J Particle Ther 2014;2:58
  • Hoppe, Bradford S. et al. A Phase 2 Trial of Concurrent Chemotherapy and Proton Therapy for Stage III Non-Small Cell Lung Cancer: Results and Reflections Following Early Closure of a Single-Institution Study. Int J Radiat Oncol Biol Phys. 2016;95(1): 517-522 PMID 26774428
  • Iwata H, Murakami M, Demizu Y, et al. High-dose proton therapy and carbon-ion therapy for stage I nonsmall cell lung cancer. Cancer. 2010; 116(10): 2476-85 PMID 20225229
  • Iwata H, Demizu Y, Fujii O, et al. Long-term outcome of proton therapy and carbon-therapy for large (T2a-T2bN0M0) non-small-cell lung cancer. J Thorac Oncol. 2013; 8(6): 726-35 PMID 23459403
  • Koay EJ, Lege D, Mohan R, et al. Adaptive/Nonadaptive Proton Radiation Planning and Outcomes in a Phase II Trial for Locally Advanced Non-small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2012; 84(5): 1093-100 PMID 22543217
  • Krayenbuehl J, Hartmann M, Lomax AJ, et al. Proton therapy for malignant pleural mesothelioma after extrapleural pleuropneumonectomy. Int J Radiat Oncol Biol Phys. 2010; 78(2): 628-34 PMID 20385451
  • Nakayama H, Satoh H, Sugahara S, et al. Proton Beam Therapy Of Stage II and III Non-Small-Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2011; 81(4): 979-84.
  • Nguyen QN, Ly NB, Komaki R, et al. Long-term outcomes after proton therapy, with concurrent chemotherapy, for stage II-III inoperable non-small cell lung cancer. Radiother Oncol 2015; 115:367-372 PMID 26028228
  • Oshiro Y, Mizumoto M, Okumura T, et al. Results of Proton Beam Therapy without Concurrent Chemotherapy for Patients with Unresectable Stage III Non-small Cell Lung Cancer. J Thorac Oncol. 2012; 7(2): 370-5 PMID 22157368
  • Oshiro Y, Okumura T, Kurishima K, et al. High-dose concurrent chemo-proton therapy for stage III NSCLC: Preliminary results of a phase II study. J Radiat Res 2014;55:959-965 PMID 24864278
  • Schild S, et al. Proton beam therapy for locally advanced lung cancer: A review. World J Clin Oncol 2014; 5(4): 568-575 PMID 25302161
  • Sejpal S, Komaki R, Tsao A, et al. Early Findings on Toxicity of Proton Beam Therapy With Concurrent Chemotherapy for Nonsmall Cell Lung Cancer. Cancer. 2011; 117(13): 3004-13 PMID 21264827
  • Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al. Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol 2003;21:3431-3439 PMID 21459527
  • Bhakta N, Liu Q, Yeo F, et al. Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an analysis from the St Jude Lifetime Cohort Study. Lancet Oncol 2016;17:1325-1334 PMID 27470081
  • Bhatti P, Veiga LH, Ronckers CM, et al. Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res 2010;174:741-752 PMID 21128798
  • Boukheris H, Stovall M, Gilbert ES, et al. Risk of salivary gland cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Int J Radiat Oncol Biol Phys 2013;85:776-783  
  • Castellino SM, Geiger AM, Mertens AC, et al. Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 2011;117:1806-1816 PMID 22836059
  • Cella L, Conson M, Pressello MC, et al. Hodgkin's lymphoma emerging radiation treatment techniques: trade-offs between late radio-induced toxicities and secondary malignant neoplasms. Radiat Oncol 2013;8:22 PMID 23360559
  • Cutter DJ, Schaapveld M, Darby SC, et al. Risk of valvular heart disease after treatment for Hodgkin lymphoma. J Natl Cancer Inst 2015;107 PMID 25713164
  • Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013;368:987-998 
  • Dietz AC, Chen Y, Yasui Y, et al. Risk and impact of pulmonary complications in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Cancer 2016;122:3687-3696
  • Dores GM, Curtis RE, van Leeuwen FE, et al. Pancreatic cancer risk after treatment of Hodgkin lymphoma. Ann Oncol 2014;25:2073-2079 PMID 25185241
  • Fox AM, Dosoretz AP, Mauch PM, et al. Predictive factors for radiation pneumonitis in Hodgkin lymphoma patients receiving combined-modality therapy. Int J Radiat Oncol Biol Phys 2012;83:277-283 PMID 22019238
  • Hoppe BS, Flampouri S, Lynch J, et al. Improving the Therapeutic Ratio in Hodgkin Lymphoma Through the Use of Proton Therapy. Oncology (Williston Park). 2012; 26(5): 456-9, 462-5 PMID 22730602
  • 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 Radiat Oncol Biol Phys. 2012; 83(1): 260-7 PMID 22014950
  • Hoppe BS, Flampouri S, Su Z, et al. Effective Dose Reduction to Cardiac Structures Using Protons Compared With 3DCRT and IMRT in Mediastinal Hodgkin Lymphoma. Int J Radiat Oncol Biol Phys. 2012; 84(2): 449-55  PMID 22386373
  • 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 Radiat Oncol Biol Phys 2014;89:1053-1059 PMID 24928256
  • Hoppe BS, Hill-Kayser CE, Tseng YD, et al. The Use of Consolidative Proton Therapy After First-Line Therapy Among Patients With Hodgkin Lymphoma at Academic and Community Proton Centers. Int J Radiat Oncol Biol Phys 2016;96:S39
  • Hoppe BS, Tsai H, Larson G, et al. Proton therapy patterns-of-care and early outcomes for Hodgkin lymphoma: results from the Proton Collaborative Group Registry. Acta Oncol 2016;55:1378-1380
  • Horn S, Fournier-Bidoz N, Pernin V, et al. Comparison of passive-beam proton therapy, helical tomotherapy and 3D conformal radiation therapy in Hodgkin's lymphoma female patients receiving involved-field or involved site radiation therapy. Cancer Radiother 2016;20:98-103 PMID 26992750
  • Inskip PD, Sigurdson AJ, Veiga L, et al. Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects. Int J Radiat Oncol Biol Phys 2016;94:800-807 PMID 26972653
  • Jorgensen AY, Maraldo MV, Brodin NP, et al. The effect on esophagus after different radiotherapy techniques for early stage Hodgkin's lymphoma. Acta Oncol 2013;52:1559-1565
  • Knausl B, Lutgendorf-Caucig C, Hopfgartner J, et al. Can treatment of pediatric Hodgkin's lymphoma be improved by PET imaging and proton therapy? Strahlenther Onkol 2013;189:54-61 PMID 23161118
  • Li J, Dabaja B, Reed V, et al. Rationale for and preliminary results of proton beam therapy for mediastinal lymphoma. Int J Radiat Oncol Biol Phys. 2011; 81(1):167-74 PMID 20643518
  • 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. Ann Oncol 2013;24:2113-2118 PMID 23619032
  • Morton LM, Gilbert ES, Stovall M, et al. Risk of esophageal cancer following radiotherapy for Hodgkin lymphoma. Haematologica 2014;99:e193-196
  • Ng AK. Review of the cardiac long-term effects of therapy for Hodgkin lymphoma. Br J Haematol 2011;154:23-31 PMID 21539537
  • Pinnix CC, Smith GL, Milgrom S, et al. Predictors of radiation pneumonitis in patients receiving intensity modulated radiation therapy for Hodgkin and non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2015;92:175-182 PMID 25863764
  • Plastaras JP, Vogel J, Elmongy H, et al. First Clinical Report of Pencil Beam Scanned Proton Therapy for Mediastinal Lymphoma. Int J Radiat Oncol Biol Phys 2016;96:E497 
  • Schaapveld M, Aleman BM, van Eggermond AM, et al. Second Cancer Risk Up to 40 Years after Treatment for Hodgkin's Lymphoma. N Engl J Med 2015;373:2499-2511
  • Swerdlow AJ, Cooke R, Bates A, et al. Breast cancer risk after supradiaphragmatic radiotherapy for Hodgkin's lymphoma in England and Wales: a National Cohort Study. J Clin Oncol 2012;30:2745-2752 PMID 22734026
  • Toltz A, Shin N, Mitrou E, et al. Late radiation toxicity in Hodgkin lymphoma patients: proton therapy's potential. J Appl Clin Med Phys 2015;16:5386 PMID 26699298
  • Tukenova M, Diallo I, Anderson H, et al. Second malignant neoplasms in digestive organs after childhood cancer: a cohort-nested case-control study. Int J Radiat Oncol Biol Phys 2012;82:e383-390  
  • Tukenova M, Guibout C, Hawkins M, et al. Radiation therapy and late mortality from second sarcoma, carcinoma, and hematological malignancies after a solid cancer in childhood. Int J Radiat Oncol Biol Phys 2011;80:339-346 PMID 20646844 
  • van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma. J Clin Oncol 2016;34:235-243
  • van Nimwegen FA, Schaapveld M, Janus CP, et al. Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk. JAMA Intern Med 2015;175:1007-1017 PMID 25915855
  • Veiga LH, Holmberg E, Anderson H, et al. Thyroid Cancer after Childhood Exposure to External Radiation: An Updated Pooled Analysis of 12 Studies. Radiat Res 2016;185:473-484. PMID 27128740
  • Voong KR, McSpadden K, Pinnix CC, et al. Dosimetric advantages of a "butterfly" technique for intensity-modulated radiation therapy for young female patients with mediastinal Hodgkin's lymphoma. Radiat Oncol 2014;9:94 PMID 24735767
  • Winkfield KM, Gallotto S, Adams JA, et al. Proton Therapy for Mediastinal Lymphomas: An 8-year Single-institution Report. Int J Radiat Oncol Biol Phys 2015;93:E461 
  • Wray J, Flampouri S, Slayton W, et al. Proton Therapy for Pediatric Hodgkin Lymphoma. Pediatr Blood Cancer 2016;63:1522-1526 PMID 27149120
  • Zeng C, Plastaras JP, James P, et al. Proton pencil beam scanning for mediastinal lymphoma: treatment planning and robustness assessment. Acta Oncol 2016;55:1132-1138 PMID 27332881
  • Hong TS, Ryan DP, Blaszkowsky LS, et al. Phase I study of preoperative short-course chemoradiation with proton beam therapy and capecitabine for resectable pancreatic ductal adenocarcinoma of the head. Int J Radiat Oncol Biol Phys. 2011; 79(1): 151-7 PMID 20421151
  • Nichols RC Jr, George TJ, Zaidden RA Jr, et al. Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity. Acta Oncologica. 2013; 52: 498-505 PMID 23477361
  • Nichols RC Jr, Huh SN, Prado KL, et al. Protons Offer Reduced Normal Tissue Exposure for Patients Receiving Postoperative Radiotherapy for Resected Pancreatic Head Cancer. Int J Radiat Oncol Biol Phys. 2012; 83(1): 158-63 PMID 22245197
  • Terashima K, Demizu Y, Hashimoto N, et al. A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis. Radiother Oncol. 2012; 103(1): 25-31 PMID 22300608
  • Amsbaugh MJ, Grosshans DR, McAleer MF, et al. Proton therapy for spinal ependymomas: planning, acute toxicities, and preliminary outcomes. Int J Radiat Oncol Biol Phys. 2012;83(5):1419-24 PMID 22245209
  • Childs SK, Kozak KR, Friedmann AM, et al. Proton radiotherapy for parameningeal rhabdomyosarcoma: clinical outcomes and late effects. Int J Radiat Oncol Biol Phys. 2012;82(2):635-642
  • Cotter SE, Herrup DA, Friedmann A, et al. Proton Radiotherapy for Pediatric Bladder/ Prostate Rhabdomyosarcoma: clinical Outcomes and Dosimetry Compared to Intensity Modulated Radiation Therapy. Int J Radiat Oncol Biol Phys. 2011; 81(5): 1367-73 PMID 20934266
  • De Amorim Bernstein K, Sethi R, Trofimov, et al. Early clinical outcomes using proton radiation for children with central nervous system atypical teratoid rhabdoid tumors. Int J Radiat Oncol Biol Phys. 2013; 86(1):114-20 PMID 23498870
  • Hattangadi JA, Rombi B, Yock TI, et al. Proton radiotherapy for high-risk pediatric neuroblastoma: early outcomes and dose comparison. Int J Radiat Oncol Biol Phys. 2012; 83(3):1015-22 PMID 22138463
  • Hill-Kayser C, Tochner Z, Both S, et al. Proton versus photon radiation therapy for patients with high-risk neuroblastoma: the need for a customized approach. Pediatr Blood Cancer. 2013; 60(10):1606-11 PMID 23737005
  • Jimenez RB, Sethi R, Depauw N, et al. Proton radiation therapy for pediatric medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for very young children treated with upfront chemotherapy. Int J Radiat Oncol Biol Phys. 2013; 87(1):120-06 PMID 23790826
  • Kuhlthau KA, Pulsifer MB, Yeap BY, et al. Prospective study of health-related quality of life for children with brain tumors treated with proton radio- therapy. J Clin Oncol. 2012; 30(17): 2079-86 PMID 22565004
  • MacDonald SM, Sethi R, Lavally B, et al. Proton radiotherapy for pediatric central nervous system ependymoma: clinical outcomes for 70 patients. Neuro Oncol. 2013; 15(11): 1552-9 PMID 24101739
  • Oshiro Y, Mizumoto M, Okumura T, et al. Clinical results of proton beam therapy for advanced neuroblastoma. Radiat Oncol. 2013;8(1):142 PMID 23758770
  • Bryant, Curtis et al. Five-Year Biochemical Results, Toxicity, and Patient-Reported Quality of Life After Delivery of Dose-Escalated Image Guided Proton Therapy for Prostate Cancer. Int J Radiat Oncol Biol Phys. 2016;95(1);422-434 PMID 27084658
  • Coen JJ, Bae K, Zietman AL, et al. Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology phase II study 03-12. Int J Radiat Oncol Biol Phys. 2011; 81(4):1005-9 PMID 20932675
  • Coen JJ, Paly JJ, Niemierko A, et al. Long-term quality of life outcome after proton beam monotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012; 82(2):e201-9 PMID 21621343
  • Henderson RH, Hoppe BS, Marcus RB Jr, et al. Urinary functional outcomes and toxicity five years after proton therapy for low- and intermediate- risk prostate cancer: results of two prospective trials. Acta Oncol. 2013; 52(3):463-9 PMID 23477359
  • Hoppe BS, Michalski JM, Mendenhall NP, et al. Comparative effectiveness study of patient-reported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer. 2013. [Epub ahead of print] PMID 24382757
  • Hoppe BS, Nichols RC, Henderson RH, et al. Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger. Cancer. 2012; 118(18):4619-26 PMID 22253020
  • Johansson S, Astrom L, Sandin F, Isacsson U, Montelius A, Turesson I. Hypofractionated proton boost combined with external beam radiotherapy for treatment of localized prostate cancer. Prostate Cancer. 2012; 654861 PMID 22848840
  • Yu JB, Soulos PR, Herrin J, et al. Proton Versus Intensity-Modulated Radiotherapy for Prostate Cancer: Patterns of Care and Early Toxicity. J Natl Cancer Inst. 2013; 105(1): 25-32 PMID 23243199
  • Ciernik IF, Niemierko A, Harmon DC, et al. Proton based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer. 2011; 117(19): 4522-30.
    PMID 21448934 
  • ASTRO (American Society of Radiation Oncology) Model Policies. Proton Beam Therapy (PBT) Approved June 2017.
  • Romesser P, 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. Radiother Oncol 2016 Feb 118(2):286-292. PMID 26867969
  • Frisch S, Timmermann B. The evolving role of proton beam therapy for sarcomas. Clin Oncol (R Coll Radiol) 2017 Aug;29(8):500-506. PMID 28506520
  • Verma V, Shah C, Mehta MP. Clinical outcomes and toxicity of proton radiotherapy for breast cancer. Clin Breast Cancer 2016 Jun;16(3):145-54
  • Bradley JA1, Dagan R2, Ho MW, et. al. Initial report of a prospective dosimetric and clinical feasibility trial demonstrates the potential of protons to increase the therapeutic ratio in breast cancer compared with protons. Int J Radiat Oncol Biol Phys 2016 May 1;95(1):411-21. PMID 26611875
  • Johannes A, Langendiijka PL, De Dirk R, et. al. Selction of patients for radiotherapy with protons aiming at reduction of side effects: the model based approach. Radiotherapy and Oncology Volume 107, Issue 3, June 2013 pages 267-273. PMID 23759662  
  • Mondlane G, Gubanski M, Lind PA, et. al. Comparative study of the calculated risk of radiation-induced cancer after photon and proton beam based radiosurgery of liver metastases. Phys Med 2017 Oct42:263-270. PMID 28366554
  • Klein J, Dawson LA. Hepatocellular carcinoma radiation therapy: review of evidence and future opportunities. Int J Radiat Oncol Biol Phys 2013 Sep 1;88(2):461-2. PMID 23219567
  • Bush DA, Smith JC, Slater JD, et. al. Randomized clinical trial comparing proton beam radiation therapy with transarterial chemoembolization for hepatocellular carcinoma: results of an interim analysis. Int J Radiat Oncol Biol Phys 2016 May 1;95(1):477-82. PMID 27084661
  • Fukumitsu M, Sugahara S, Nakayam H, et. al. A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma. Int J Radit Oncol Biol Phys 2009 Jul 1;74(3):831-6. PMID 19304408
  • Hashimoto T, Tokuuye K, Fukumitsu N, et. al. Repeated proton beam therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2006 May 1;65(1):196-202. PMID 16563656
  • Hata M, Tokuuye K, Sugahara S, et. al. Proton beam therapy for aged patients with hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2007 Nov 1;69(3):805-12. PMID 17524568
  • Kawashima M, Furuse J, Nishio T, et. al. Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 2005 Mar 20;23(9):1839-46. PMID 15774777
  • Qi WX, Fu S, Zhang Q, et. al. Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: a systematic review and meta-analysis. Radiothera Oncol 2015 Mar 114(3):289-95. PMID 25497556 
  • ACR-ASTRO Practice Parameters for the Performance of Proton Beam Radiation Therapy. Revised 2018
  • The National Proton Association for Proton Therapy Model Policy. Last Revised February 2019  
  • Vogel J, Berman AT, Lin L, et. al. Prospective study of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma: early response and toxicity assessment. Radiothera Oncol 2016 Mar;118(3):504-9. PMID 26895711
  • Taylor CW, Wang Z, Macaulay E,et. al. Exposure of the heart in breast cancer radiation therapy: a systematic review of heart doses published during 2003 to 2013. Int J Radiat Oncol Biol Phys 2015 Nov 15;93(4):845-53. PMID 26530753
  • Sanda MG, Cadeddu JA, Kirkby E, et. al. Clinically Localiz ed Prostate Cancer: AUA/ASTRO/SUO Guideline Part I: Risk Stratification, Shared Decision Making, and Care Options. J Urol 2018 Mar;199(3):683-690. PMID 29203269
  • Thorpe CS, Niska JR, Girardo ME, et. al. Proton beam therapy reirradiation for breast cancer: multi-institutional prospective PCG registry analysis. Breast J 2016 Jul 23. PMID 31338974
  • Hansen TM, Bartlett GK, Mannina Jr. EM, et. al. Dosimetric comparison of treatment techniques: brachytherapy, intensity modulated radiation therapy and proton beam in partial breast irradiation. Int J Part Ther 2015;2(2):376-384.
  • Lin LL, Vennarini S, Dimofte D, et. al. Proton beam versus photon beam dose to the heart and left anterior descending artery for left sided breast cancer. Acta Oncol 2015;54(7):1032-9. PMID 25789715
  • Lischalk JW, Chen H, Repka MC, et. al. Definitive hypofractionated radiation therapy for early stage breast cancer: dosimetric feasibility of stereotactic ablative radiotherapy and proton beam therapy for intact breast tumors. Adv Radiat Oncol 2018 Jun 11;3(3):447-457
  • Luo L, Cuaron J, Braunstein L, et. al. Early outcomes of breast cancer patients treated with post-mastectomy uniform scanning proton therapy. Radiother Oncol 2019 Mar;132:250-256. PMID 30414757
  • Mast ME, Vredeveld EJ, Credoe HM, et. al. Whole breast proton irradiation for maximal reduction of heart dose in breast cancer patient. Breast Cancer Res Treat 2014 Nov;148(1):33-9. PMID 25266130
  • Stick LB, Yu J, Maraldo MV, et. al. Joint estimation of cardiac toxicity and recurrence risks after comprehensive nodal photon versus proton therapy for breast cancer. Int J Radiot Oncol Biol Phys 2017 Mar 15;97(4):754-761. PMID 28244411
  • Teichman SL, Do S, Lum S, et. al. Improved long term patient reported health and well-being outcomes of early stage breast cancer treated with partial breast proton therapy. Cancer Med 2018 Dec;7(12):6064-6076. PMID 30453388
  • Verma V, Shah C, Mehta MP. Clinical outcomes and toxicity of proton radiotherapy for breast cancer. Clin Breast Cancer 2016 Jun;16(3):145-54. PMID 26995159
  • Baues C, Martinez S, Engert A, et. al. Proton versus photon deep inspiration breath hold techniques in patients with Hodgkin lymphoma and mediastinal radiation. Radiat Oncol 2018;13:122. PMID 29970105
  • Bergom C, Currey A, Desai N, et. al. Deep Inspiration hold: tehcniques and advantages for cardiac sparing during breast cancer irradiation. Front Oncol 2018;8:87. PMID 29670854
  • Combs SE. Does proton therapy have a future in CNS tumors? Curr Treat Neurol 2017 Mar;19(30:12. PMID 28365895
  • Combs SE. Proton and carbon ion therapy of intracranial gliomas. Prog Neurol Surg 2018;32:57-65. PMID 29990974
  • Anand A, Bues M, Rule WG, et. al. Scanning proton beam therapy reduces normal tissue exposure in pelvic radiotherapy for anal cancer. Radiother Oncol 2015 Dec;117(3):505-8. PMID 26597231
  • Ojerholm E, Kirk ML, Thompson RF, et. al. Pencil beam scanning proton therapy for anal cancer: a dosimetric comparison with intensity modulated radiotherapy. Acta Oncol 2015;54(8):1209-17. PMID 25734796
  • Chuong MD, Hallemeier CL, Jabbour SK, et. al. Improving outcomes for esophageal cancer using proton beam therapy. Int J Radiat Oncol Biol Phys 2016 May 1;95(1):488-97. PMID 27084662
  • Fang P, Shiraishi Y, Verma V, et. al. Lymphocyte-sparing effect of proton therapy in patients with esophageal cancer treated with definitive chemoradiation. Int J Part Ther 2018 Winter 4(3):23-32. PMID 30079369
  • Fernandes A, Berman AT, Mick R, et. al. A prospective study of proton beam reirradiation for esophageal cancer. Int J Radiat Oncol Biol Phys 2016 May 1;95(1):483-7. PMID 26847847
  • Hirano Y, Onozawa M, Hojo H, et. al. Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced esophageal squamous cell carcinoma. Radiat Oncol 2018;13:23. PMID 29426342
  • Haque W, Verma V, Butler EB, et. al. Utilization of neoadjuvant intensity-modulated radiation therapy and proton beam therapy for esophageal cancer in the United States. J Gastrointest Oncol 2018 Apr;9(2):282-294. PMID 29755767
  • Patel SA, Edgington SK, Adams J,e t. al. Novel use of proton beam therapy for neoadjuvant treatment of radiation associated squamous cell carcinoma of the esophagus. J Gastrointest Oncol 2019 Feb;10(1):155-160. PMID 30788171
  • Prayongrat A, Xu C, Li H, et. al. Clinical outcomes of intensity modulated proton therapy and concurrent chemotherapy in esophageal carcinoma: a single institutional experience. Adv Radiat Oncol 2017 Jun 13;2(3):301-307. PMID 29114596
  • Takada A, Nakamura T, Takavama K, et. al. Preliminary treatment results of proton beam therapy with chemoradiotherapy for stage I-III esophageal cancer. Cancer Med 2016 Mar;5(3):506-515. PMID 26806272
  • Xi M, Xu C, Liao Z, et. al. Comparative outcomes after definitive chemotherapy using proton beam therapy versus intensity modulated radiation therapy for esophageal cancer: a retrospective single institutional analysis. Int J Radiat Oncol Biol Phys 2017 Nov 1;99(3):667-676. PMID 29280461
  • Maemura K, Mataki Y, Kurahara H, et. al. Comparison of proton beam radiotherapy and hyper-fractionated accelerated chemoradiotherapy for locally advanced pancreatic cancer. Pancreatology 2017Sep-Oct 17(5):833-838. PMID 28778480
  • Thompson RF, Mayekar SU, Zhai H, et. al. A dosemetric comparison of proton and photon therapy in unresectable cancers of the head of pancreas. Med Phys 2014 Aug;41(8):081711. PMID 25086521
  • Calaco R, Nichols R, Huh S, et. al. Protons offers reduced bone marrow, small bowel, and urinary bladder exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer. J Gastrointest Oncol 2014 Feb;5(1):3-8. PMID 24490037
  • Plastaras JP, Dionisi F, Wo JY. Gastrointestinal cancer: nonliver proton therapy for gastrointestinal cancers. Cancer J 2014 Nov-Dec 20(6):378-86. PMID 25415682
  • Marnitz S, Wlodarczyk W, Neumann O, et. al. Which technique for radiation is most beneficial for patients with locally advanced cervical cancer? Intensity modulated proton therapy versus intensity modulated photon treatment, helical tomotherapy and volumetric arc therapy for primary radiation and intra-individual comparison. Radiat Oncol 2015 Apr 17 10:91. PMID 25896675
  • Verma V, Simone CB, Wahl AO, et. al. Proton radiotherapy for gynecological neoplasms. Acta Oncol 2016 Nov;55(11):1257-1265. PMID 27500710
  • Blanchard P, Gunn GB, Lin A, et. al. Proton therapy for head and neck cancers. Semin Radiat Oncol 2018 Jan;28(1):53-63. PMID 29173756
  • Blanchard P, Frank SJ. Proton therapy for head and neck cancers. Cancer Radiother 2017 Oct 21 (6-7) 515-520. PMID 28869195
  • Blanchard P, Garden AS, Gunn GB, et. al. Intensity modulated proton beam therapy (IMPT) versus intensity modulated proton therapy (IMRT) for patients with oropharynx cancer – a case matched analysis. Radiother Oncol 2016 Jul 120 (1) 48-55. PMID 27342249   
  • Holliday EB, Kocak-Uzel E, Feng L, et. al. Dosimetric advantages of intensity modulated proton therapy for oropharyngeal cancer compared with intensity modulated radiation: a case matched control analysis. Med Dosim 2016 Autumn;41(3):189-94. PMID 27158021
  • Sio TT, Lin HK, Shi Q, et. al. Intensity modulated proton therapy versus intensity modulated photon radiation therapy for oropharyngeal cancer: First comparative results of patient reported outcomes. Int J Radiat Oncol Biol Phys 2016 Jul 15;95(4):1107-14. PMID 27354125
  • Patel SH, Wang Z, Wong WW, et. al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol 2014 Aug;15(9):1027-38. PMID 24980873   
  • Russo AL, Adams JA, Weyman EA, et. al. Long term outcomes after proton beam therapy for sinonasal squamous cell carcinoma. Int J Radiat Oncol Bio Phys 2016 May 1;95(1):368-76. PMID 27084654
  • Arts T, Breedveld S, de Jong MA et. al. The impact of treatment accuracy on proton therapy patient selection for oropharyngeal cancer patients Radiother Oncol. 2017 Dec;125(3):520-525. PMID 29074078
  • Lewis GD, Holliday EB, Kocak-Uzel E et. al. Intensity-modulated proton therapy for nasopharyngeal carcinoma: Decreased radiation dose to normal structures and encouraging clinical outcomes Head Neck. 2016 Apr;38 Suppl 1:E1886-95. PMID 26705956
  • Mark W. McDonald, Yuan Liu, Michael G. Moore, et.al. Acute toxicity in comprehensive head and neck radiation for nasopharynx and paranasal sinus cancers: cohort comparison of 3D conformal proton therapy and intensity modulated radiation therapy Radiat Oncol. 2016; 11: 32 PMID 26922239
  • Gunn GB, Blanchard P, Garden AS, et.al.  Clinical Outcomes and Patterns of Disease Recurrence After Intensity Modulated Proton Therapy for Oropharyngeal Squamous Carcinoma Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):360-7 PMID 27084653
  • Holliday EB, Kocak-Uzel E, Feng L, et. al.  Dosimetric advantages of intensity-modulated proton therapy for oropharyngeal cancer compared with intensity-modulated radiation: A case-matched control analysis. Med Dosim. 2016 Autumn;41(3):189-94. PMID  27158021
  • Sio TT1, Lin HK2, Shi Q et. al. Intensity Modulated Proton Therapy Versus Intensity Modulated Photon Radiation Therapy for Oropharyngeal Cancer: First Comparative Results of Patient-Reported Outcomes Int J Radiat Oncol Biol Phys. 2016 Jul 15;95(4):1107-14 PMID 27354125
  • Dagan R, Bryant C, Li Z, Yeung D, et. al.  Outcomes of Sinonasal Cancer Treated With Proton Therapy Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):377-85 PMID 27084655
  • Fuji H1, Yoshikawa S, Kasami M et. al. High-dose proton beam therapy for sinonasal mucosal malignant melanoma Radiat Oncol. 2014 Jul 23;9:162 PMID 25056641
  • Holliday EB, Frank SJ Proton radiation therapy for head and neck cancer: a review of the clinical experience to date Int J Radiat Oncol Biol Phys. 2014 Jun 1;89(2):292-302 PMID 24837890
  • Leeman JE, Romesser PB, Zhou Y et. al. Proton therapy for head and neck cancer: expanding the therapeutic window Lancet Oncol. 2017 May;18(5):e254-e265 PMID 28456587
  • Linton OR, Moore MG, Brigance JS Proton therapy for head and neck adenoid cystic carcinoma: initial clinical outcomes Head Neck. 2015 Jan;37(1):117-24 PMID 25646551
  • McKeever MR, Sio TT, Gunn GB et. al. Reduced acute toxicity and improved efficacy from intensity-modulated proton therapy (IMPT) for the management of head and neck cancer Chin Clin Oncol. 2016 Aug;5(4):54 PMID 27506808
  • Phan J, Sio TT, Nguyen TP, Takiar V et. al. Reirradiation of Head and Neck Cancers With Proton Therapy: Outcomes and Analyses Int J Radiat Oncol Biol Phys. 2016 Sep 1;96(1):30-41. PMID 27325480
  • 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 Radiat Oncol Biol Phys. 2014 Aug 1;89(5):1053-1059 PMID 24928256   
  • Adeberg S, Harrabi SB, Bougatf N, et al. Intensity-modulated proton therapy, volumetric-modulated arc therapy, and 3D conformal radiotherapy in anaplastic astrocytoma and glioblastoma: a dosimetric comparison. Strahlenther Onkol. 2016 Nov;192(11):770-779. 
  • Allen AM, Pawlicki T, Dong L, et al. An evidence based review of proton beam therapy: the report of ASTRO’s emerging technology committee. Radiother Oncol. 2012 Apr; 103(1):8-11
  • Arvold ND, Niemierko A, Broussard GP, et al. Projected second tumor risk and dose to neurocognitive structures after proton versus photon radiotherapy for benign meningioma. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):e495-e500
  • Bekelman JE, Schultheiss T, Berrington De Gonzalez A. Subsequent malignancies after photon versus proton radiation therapy. Int J Radiat Oncol Biol Phys. 2013 Sep 1; 87(1):10-12
  • Berrington de Gonzalez A, Gilbert E, Curtis R, et al. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship. Int J Radiat Oncol Biol Phys. 2013 Jun 1; 86(2):224-233
  • Bradley JA, Dagan R, Ho, MW, et al. Initial report of a prospective dosimetric and clinical feasibility trial demonstrates the potential of protons to increase the therapeutic ratio in breast cancer compared with photons. Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):411-421
  • Cella L, Conson M, Pressello MC, et al. Hodgkin’s lymphoma emerging radiation treatment techniques: trade-offs between late-night radio-induced toxicities and secondary malignant neoplasms. Radiat Oncol. 2013 Dec;8:22
  • Chang JY, Komaki R, Lu C, et al. Phase 2 study of high-dose proton therapy with concurrent chemotherapy for unresectable stage III nonsmall cell lung cancer. Cancer. 2011 Oct 15; 117(20):4707-4713
  • Chang JY, Verma V, Li M, et al. Proton beam radiotherapy and concurrent chemotherapy for unresectable Stage III non-small cell lung cancer. JAMA Oncol. 2017 Aug;3(8):e172032
  • Chung CS, Yock TI, Nelson K, et al. Incidence of second malignancies among patients treated with proton versus photon radiation. Int J Radiat Oncol Biol Phys. 2013 Sep 1; 87(1):46-52
  • Coen JJ, Bae K, Zietman AL, et al. Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology Phase II study 03- 12. Int J Radiat Oncol Biol Phys. 2011 Nov 15; 81(4):1005-1009
  • Coen JJ, Paly JJ, Niemierko A, et al. Long-term quality of life outcome after proton beam monotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):e201-209
  • Coeh JJ, Zietman AL, Rossi CJ, et al. Comparison of high-dose proton radiotherapy and brachytherapy in localized prostate cancer: a case-matched analysis. Int J Radiat Oncol Biol Phys. 2012 Jan 1;82(1):e25-e31
  • DÄ›dečková, K, Móciková, H, Marková, J, et al. T011: Proton radiotherapy for mediastinal Hodgkin lymphoma: single institution experience (abstract). Haematologica. 2016;101(Suppl 5):12-13
  • 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. 2015 Apr 1;121(7):1118-1127
  • Georg D, Hopfgartner J, Gòra J, et al. Dosimetric considerations to determine the optimal technique for localized prostate cancer among external photon, proton, or carbon-ion therapy and high-dose-rate or low-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys. 2014 Mar 1;88(3):715-722
  • Gray PJ, Paly JJ, Yeap BY, et al. Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer. 2013 Jay 1;119(9):1729-1735
  • Greenberger BA, Pulsifer MG, Ebb DH, et al. Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2014 Aug 1;89(5):1060- 1068
  • Grutters JPC, Kessels AGH, Pijls-Johannesma M, et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother Oncol 2010 Apr; 95(1):32-40
  • Hauswald H, Rieken S, Ecker S, et al. First experiences in treatment of low-grade glioma grade I and II with proton therapy. Radiation Oncol. 2012 Dec;7:189
  • Hoppe BS, Mamalui-Hunter M, Mendenhall NP, et al. Improving the therapeutic ratio by using proton therapy in patients with stage I or stage II seminoma. Am J Clin Oncol. 2013 Feb; 36(1):31-37
  • Hoppe BS, Michalski JM, Mendenhall NP, et al. Comparative effectiveness study of patient-reported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer. 2014 Apr 1; 120(7):1076- 1085
  • Hutcheson K, Lewin JS, Garden AS, et al. Early experience with IMPT for the treatment of oropharyngeal tumors: acute toxicities and swallowing-related outcomes. Int J Radiat Oncol Biol Phys. 2013 Oct 1; 87(2 Suppl):S605
  • Horn S, Fournier-Bidoz N, Pernin V, et al. Comparison of passive-beam proton therapy, helical tomotherapy and 3D conformal radiation therapy in Hodgkin’s lymphoma female patients receiving involved-field or involved site radiation therapy. Cancer Radiother. 2016 Apr;20(2):98-103
  • Horwich A, Fossa SD, Huddart R, et al. Second cancer risk and mortality in men treated with radiotherapy for stage I seminoma. Brit J Cancer. 2014 Jan; 110 (1): 256-263
  • Houweling AC, Crama K, Visser J, et al. Comparing the dosimetric impact of interfractional anatomical changes in photon, proton and carbon ion radiotherapy for pancreatic cancer patients. Phys Med Biol. 2017 Mar 21;62(8):3051-3064
  • Hutcheson K, Lewin JS, Garden AS, et al. Early experience with IMPT for the treatment of oropharyngeal tumors: acute toxicities and swallowing-related outcomes. Int J Radiat Oncol Biol Phys. 2013 Oct 1; 87(2 Suppl):S605
  • Ishikawa H, Hashimoto T, Moriwaki T, et al. Proton beam therapy combined with concurrent chemotherapy for esophageal cancer. Anticancer Res. 2015 Mar;35(3):1757-1762
  • Jorgensen AYS, Maraldo MV, Brodin NP, et al. The effect on esophagus after different radiotherapy techniques for early stage Hodgkin’s lymphoma. Acta Oncolog. 2013 ;52(7):1559-1565
  • Jiang ZQ, Yang K, Komaki R, et al. Long-term clinical outcome of intensity-modulated radiotherapy for inoperable non-small cell lung cancer: The MD Anderson experience. Int J Radiat Oncol Biol Phys. 2012 May 1; 83(1):332-339
  • Kim S, Shen S, Moore DF, et al. Late gastrointestinal toxicities following radiation therapy for prostate cancer. Europ Urol. 2011 Nov;60(5):908-916
  • Kollmeier MA, Fidaleo A, Pei X, et al. Favourable long-term outcomes with brachytherapy-based regimens in men ≤60 years with clinically localized prostate cancer. BJU Int. 2013 Jun; 111(8):1231-1236
  • Kotecha R, Yamada Y, Pei X, et al. Clinical outcomes of high-dose-rate brachytherapy and external beam radiotherapy in the management of clinically localized prostate cancer. Brachytherapy. 2013 Jan-Feb; 12(1):44-49
  • Lee RY, Nichols Jr RC, Huh SN, 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 Dec;4(4):374-379
  • Lewinshtein D, Gulati R, Nelson PS et al. Incidence of second malignancies after external beam radiotherapy for clinical stage I testicular seminoma. BJU International. 2012 Mar; 109(5): 706-712
  • Liao Z, Lee JJ, Komaki R, et al. 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. 2018 Jan 20;36(18):1813-1822
  • Liao ZX, Lee JJ, Komaki R, et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced non-small cell lung cancer. J Clin Oncol. 2016; 34(15_suppl), 8500
  • Lin LL, Kirk M, Scholey J, Taku N, Kiely JB, White B, Both S. Initial Report of Pencil Beam Scanning Proton Therapy for Posthysterectomy Patients With Gynecologic Cancer. Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):181-9. doi: 10.1016/j.ijrobp.2015.07.2205. Epub 2015 Jul 11
  • Lin SH, Komaki R, Liao Z, et al. Proton beam therapy and concurrent chemotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):e345-351.
  • 115. Lin SH, Merrell KW, Shen J, et al. Multi-institutional analysis of radiation modality use and postoperative outcomes of neoadjuvant chemoradiation for esophageal cancer. Radiother Oncol. 2017 Jun;123(3):376-381
  • Linton OR, Moore MG, Brigance JS, et al. Proton therapy for head and neck adenoid cystic carcinoma: initial clinical outcomes. Head & Neck. 2015 Jan 1;37(1):117-124
  • Lukens JN, Mick R, Demas KL, et al. Acute toxicity of proton versus photon chemoradiation therapy for pancreatic adenocarcinoma: a cohort study. Int J Radiat Biol Phys. 2013 Oct 1;87(2 Suppl):S311
  • MacDonald SM, Patel SA, Hickey S, et al. Proton therapy for breast cancer after mastectomy: early outcomes of a prospective clinical trial. Int J Radiat Oncol Biol Phys. 2013 Jul 1;86(3):484-490
  • Maemura K, Mataki Y, Kurahara H, et al. Comparison of proton beam radiotherapy and hyper-fractionated accelerated chemoradiotherapy for locally advanced pancreatic cancer. Pancreatology. 2017 Sep-Oct;17(5):833-838
  • Makishima H, Ishikawa H, Terunuma T, et al. Comparison of adverse effects of proton and x-ray Chemoradiotherapy for esophageal cancer using an adaptive dose-volume histogram analysis. J Radiat Research. 2015 May 1;56(3):568-576
  • Maraldo MV, Brodin NP, Aznar MC, et al. Doses to head and neck normal tissues for early stage Hodgkin lymphoma after involved node radiotherapy. Radiother Oncol. 2014 Mar;110(3):441-447
  • 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. Ann Oncol. 2013 Aug;24(8):2113-2118
  • Mazonakis M, Berris T, Lyraraki E et al. Radiation therapy for stage IIA and IIB testicular seminoma: peripheral dose calculations and risk assessments. Physics in Medicine and Biology. 2015 Mar 21; 60(6):2375-2390
  • McDonald MW, Liu Y, Moore MG, et al. Acute toxicity in comprehensive head and neck radiation for nasopharynx and paranasal sinus cancers: cohort comparison of 3D conformal proton therapy and intensity modulated radiation therapy. Radiat Oncol. 2016;11(32)
  • McDonald MW, Zolali-Meybodi O, Lehnert SJ, et al. Reirradiation of recurrent and second primary head and neck cancer with proton therapy. Int J Radiat Oncol Biol Phys. 2016 Nov 15;96(4):808-819
  • Mendenhall NP, Hoppe BS, Nichols RC, 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; 88(3):596-602
  • Mizumota M, Yamamoto Y, Takano S, et al. Long-term survival after treatment of glioblastoma multiforme with hyperfractionated concomitant boost proton beam therapy. Pract Radiat Oncol. 2015 Jan-Feb;5(1):e9-e16 
  • Mohan R, Grosshans D. Proton therapy – present and future. Adv Drug Deliv Rev. 2017 Jan 15; 109:26-44
  • Moteabbed M, Geyer A, Drenkhahn R, et al. Comparison of whole-body phantom designs to estimate organ equivalent neutron doses for secondary cancer risk assessment in proton therapy. Phys Med Biol. 2012 Jan 21; 57(2):499-515
  • Murphy ES, Suh JH. Radiotherapy for vestibular schwannomas: a critical review. Int J Radiat Oncol Biol Phys. 2011 Mar 15; 79(4):985-997
  • Nichols Jr RC, George TJ, Zaiden Jr RA, et al. Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a lower incidence of gastrointestinal toxicity. Acta Oncologica. 2013;52(3):498-505
  • 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 Radiat Oncol Biol Phys. 2012 May 1;83(1):148-163
  • Niedzielski JS, Yang J, Mohan R, et al. Differences in normal tissue response in the esophagus between proton and photon radiation therapy for non-small cell lung cancer using in vivo imaging biomarkers. Int J Radiat Oncol Biol Phys. 2017 Nov 15;99(4):1013-1020
  • Ojerholm E, Kirk ML, Thompson RF, Zhai H, Metz JM, Both S, Ben-Josef E, Plastaras JP. Pencil-beam scanning proton therapy for anal cancer: a dosimetric comparison with intensity-modulated radiotherapy. Acta Oncol. 2015;54(8):1209-17. doi: 10.3109/0284186X.2014.1002570. Epub 2015 Mar 3
  • Patel SH, Want Z, Wong WW, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. 2014 Aug:15(9):1027-1038
  • Peeler CR, Mirkovic D, Titt U, et al. Clinical evidence of variable proton biological effectiveness in pediatric patients treated for ependymoma. Radiother Oncol; 2016 Dec; 121(3):395-401
  • Prayongrat A, Xu C, Li H, et al. Clinical outcomes of intensity modulated proton therapy and concurrent chemotherapy in esophageal carcinoma: a single institutional experience. Adv Radiat Oncol. 2017 Jul-Sep;2(3):301-307
  • Phan J, Sio TT, Nguyen TP, et al. Reirradiation of head and neck cancer with proton therapy: outcomes and analyses. Int J Radiat Oncol Biol Phys. 2016 Sep 1;96(1):30-41
  • Plastaras JP, Vogel J, Elmongy H, et al. First clinical report of pencil beam scanned proton therapy for mediastinal lymphoma. Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2 Suppl):E497
  • Raldow AC, Hong TS. Will There Be a Clinically Significant Role for Protons in Patients With Gastrointestinal Malignancies? Semin Radiat Oncol. 2018 Apr;28(2):125-130. doi: 10.1016/j.semradonc.2017.11.006
  • Ramakrishna NR, Harper B, Burkavage R, et al. A comparison of brain and hippocampal dosimetry with protons or intensity modulated radiation therapy planning for unilateral glioblastoma. Int J Radiat Oncol Biol Phys. 2016 Oct 1;96(2 Suppl):e134-e135
  • Radiation Therapy Oncology Group (RTOG). RTOG 1308 Protocol Information. Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC
  • Richie JP. Editorial Comment. Re: Incidence of second malignancies after external beam radiotherapy for clinical stage I testicular seminoma. J of Urology. 2012 Dec; 188(6):2231-2232
  • 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. Radiother Oncol. 2016 Feb;118(2):286-292
  • Russo AL, Adams, JA, Weyman EA, et al. Long-term outcomes after proton beam therapy for sinonasal squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):358-376
  • Sachsman S, Flampouri S, Li Z, et al. Proton therapy in the management of non-Hodgkin lymphoma. Leuk Lymphoma. 2015;56(9):2608-2612
  • Sachsman S, Hoppe BS, Mendenhall NP, et al. Proton therapy to the subdiaphragmatic region in the management of Hodgkin lymphoma. Leuk Lymphoma. 2015;56(7):2019-2024
  • Sachsman S, Nichols Jr RC, Morris CG, et al. Proton therapy and concomitant capecitabine for non-metastatic unresectable pancreatic adenocarcinoma. Int J Particle Therapy 2014 Winter;1(3):692-701
  • Schild ST, Rule WG, Ashman JB, et al. Proton beam therapy for locally advanced lung cancer: a review. World J Clin Oncol. 2014 Oct 10;5(4):568-575
  • Sejpal S, Komaki R, Tsao A, et al. Early findings on toxicity of proton beam therapy with concurrent chemotherapy for nonsmall cell lung cancer. Cancer. 2011 Jan 11;117(13):3004-3013
  • Sheets NC, Goldin GH, Meyer AM, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA. 2012 Apr 18; 307(15):1611-1620
  • Shih HA, Arvold ND, Niemierko A, et al. Second tumor risk and projected late effects after proton vs. intensity modulated photon radiotherapy for benign meningioma: a dosimetric comparison. Int J Radiat Oncol Biol Phys. 2010 Nov 1; 78(3): S272. Shih HA, Sherman JC, Nachtigall LB, et al. Proton therapy for low-grade gliomas: results from a prospective trial. Cancer. 2015 Jan 13;121(10):1712-1719
  • Simone II CB, Kramer K, O’Meara WP et al. Predicted rates of secondary malignancies from proton versus photon radiation therapy for stage I seminoma. Int J Radiat Oncol Biol Phys. 2012 Jan 1; 82(1): 242-249
  • Sio TT, Lin H-K, Shi Q, et al. Intensity modulated proton therapy versus intensity modulated photon radiation therapy for oropharyngeal cancer: first comparative results of patient-reported outcomes. Int J Radiat Oncol Biol Phys. 2016 Jul 15;95(4):1107-1114
  • Spratt DE, Pei X, Yamada J, et al. Long-term survival and toxicity in patients treated with high-dose intensity modulated radiation therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2013 Mar 1; 85(3):686-92
  • Sugahara S, Oshiro Y, Nakayama H, et al. Proton beam therapy for large hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2010 Feb 1; 76(2):460-466
  • Takatori K, Terashima K, Yoshida R, et al. Upper gastrointestinal complications associated with gemcitabineconcurrent proton radiotherapy for inoperable pancreatic cancer. J Gastroenterol. 2014 Jun;49(6):1074-1080
  • Takaoka EI, Miyazaki J, Ishikawa H, Kawai K, Kimura T, Ishitsuka R, Kojima T, Kanuma R, Takizawa D, Okumura T, Sakurai H, Nishiyama H. Long-term single-institute experience with trimodal bladder- Preserving therapy with proton beam therapy for muscle-invasive bladder cancer. Jpn J Clin Oncol. 017 Jan;47(1):67-73. doi: 10.1093/jjco/hyw151. Epub 2016 Oct 13
  • Terashima K, Demizu Y, Jin D, et al. A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis. Radiother Oncol. 2012 Apr;103(1):25-31
  • Thompson RF, Mayekar SU, Zhai H, et al. A dosimetric comparison of proton and photon therapy in unresectable cancers of the head of pancreas. Medical Physics. 2014 Aug;41(8Part1):081711-1-081711-10
  • Tolz A, Shin N, Mitrou E, et al. Late radiation toxicity in Hodgkin lymphoma patients: proton therapy’s potential. J Appl Clinic Med Physics; 2015 Sept 8;16(5):167-178
  • Trofimov A, Nguyen PL, Efstathiou JA, et al. Interfractional variations in the setup of pelvic bony anatomy and soft tissue, and their implications on the delivery of proton therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2011 Jul 1;80(3):928-937
  • Tseng YD, Cutter DJ, Plastaras JP, et al. Evidence-based review on the use of proton therapy in lymphoma from the Particle Therapy Cooperative Group (PTCOG) Lymphoma Subcommittee. Int J Radiat Oncol Biol Phys. 2017 Nov 15;99(4):825-842
  • van de Schoot AJ, Visser J, van Kesteren Z, Janssen TM, Rasch CR, Bel A. Beam configuration selection for robust intensity-modulated proton therapy in cervical cancer using Pareto front comparison. Phys Med Biol. 2016 Feb 21;61(4):1780-94. doi: 10.1088/0031-9155/61/4/1780. Epub 2016 Feb 8

 

Policy History:

  • August 2020 - Annual Review, Policy Revised
  • August 2019 - Annual Review, Policy Revised
  • November 2018 - Interim Review, Policy Revised
  • August 2018 - Annual Review, Policy Revised
  • August 2017 - Annual Review, Policy Renewed
  • May 2017 - Interim Review, Policy Revised
  • August 2016 - Annual Review, Policy Revised
  • September 2015 - Annual Review, Policy Revised
  • May 2015 - Interim Review, Policy Revised
  • January 2015 - Policy Revised
  • October 2014 - Annual Review, Policy Renewed
  • January 2014 - Annual Review, Policy Revised
  • January 2013 - Annual Review, Policy Renewed
  • January 2012 - Annual Review, Policy Renewed
  • January 2011 - Annual Review, Policy Revised

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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