Medical Policy: 08.01.05 

Original Effective Date: April 2001 

Reviewed: August 2019 

Revised: August 2019 

 

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 body radiotherapy [SBRT]), 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.

 

This policy addresses those indications for which the role of proton beam radiation therapy (PBRT) remains unclear, and there is a lack of high-quality evidence demonstrating improved net health outcomes. Based on the insufficient published literature, proton beam radiation therapy (PBRT) will be considered not medically necessary.

 

Based on the 2017 ASTRO Model Policy on Proton Beam Therapy (PBT) the following indications are listed as Group 2 indication in which there is a need for continued clinical evidence and comparative effectiveness analyses. This model policy also goes on to state the patient should be enrolled in either an IRB approved clinical trial or in a multi-institutional patient registry adhering to Medicare requirements for CED.

  • Non-T4 and resectable head and neck cancers
  • Thoracic malignancies, including non-metastatic primary lung cancers, 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

 

Anal Cancer

There is limited evidence on the role of proton beam radiation therapy (PBRT) in the treatment of anal cancer. The evidence is primarily dosimetric studies comparing photon therapy and proton beam radiation therapy (PBRT). Wo et. al. (2018) reported on a multi-institutional pilot feasibility study that enrolled 25 patients with carcinoma of the anal canal and the use of pencil beam scanning proton beam radiation therapy (PBS-PT) with concurrent chemotherapy. This study found that proton beam radiation therapy (PBRT) may be feasible, however, the Grade 5 adverse events in this small study highlight potentially treatment related risks of this treatment regimen. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of anal cancer. The evidence is limited and the one clinical study was associated with Grade 5 adverse events, the use of proton beam radiation therapy (PBRT) in the treatment of anal cancer is unproven.

 

Bladder Cancer

There is limited evidence on the role of proton beam radiation therapy (PBRT) in the management of bladder cancer. In 2017, Takoka et. al. performed a retrospective review regarding the oncologic outcomes, prognostic factors and toxicities of proton beam radiation therapy (PBRT) in trimodal bladder-preserving therapy for muscle-invasive bladder cancer at their institution. Seventy patients were included in this study with cT2-3N0M0 muscle invasive bladder cancer and the trimodal bladder preserving therapy which consisted of transurethral resection of the bladder tumor, small pelvis photon irradiation, intra-arterial chemotherapy and proton beam therapy. The authors concluded that bladder preserving therapy with proton beam therapy was well tolerated and achieved favorable mortality rate. While this study was promising there remains to be limited evidence of efficacy on proton beam radiation therapy (PBRT) in the treatment of bladder cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of bladder cancer. The use of proton beam radiation therapy (PBRT) is unproven in the treatment of bladder cancer.

 

Breast Cancer

Note: This information may not apply to patients with left sided invasive breast cancer with nodal involvement.

 

Based on review of the available published literature for the treatment of invasive breast cancer a systematic review examined the current state of proton beam radiotherapy (PBRT) for treatment of breast cancer. Nine original investigations were analyzed and side effects were comparable to photon therapy. The authors noted definitive clinical experiences remain sparse and randomized trials comparing PBT to photon therapy in the treatment of breast cancer are underway and will further aid in providing robust conclusions. In retrospective and prospective studies using PBRT in the treatment of invasive breast cancer some of these studies may have shown promise but further studies are needed comparing proton beam radiation therapy (PBRT) with standard photon technologies like 3DCRT or IMRT to provide high quality evidence demonstrating the safety and efficacy of PBRT. The use of proton beam radiation therapy (PBRT) is unproven in the treatment of invasive breast cancer.

 

Esophageal Cancer

Based on review of the peer reviewed medical literature there have been several dosimetric studies comparing dose distributions in a limited number of patients using proton beam radiation therapy (PBRT) and photon radiation techniques. These have shown reduction in low dose radiation distribution to some structures such as the heart and lungs, and increased radiation dose to other structures, such as the spinal cord and skin. These studies also do not provide any clinical outcome data to show outcomes with PBRT compared to the photon based radiation techniques. Reported clinical experiences for PBRT for the treatment of esophageal cancer have generally been limited to single-institution studies. While results from these studies may be promising for improved clinical outcomes compared to standard of care photon-based therapies for esophageal cancer, further prospective trials are needed comparing proton beam radiation therapy (PBRT) with standard photon technologies like 3DCRT or IMRT to provide high quality evidence demonstrating the safety and efficacy of PBRT. NCCN Guideline recommends that patients with esophageal cancer be treated with proton beam therapy (PBT) within a clinical trial. The use of proton beam radiation therapy (PBRT) is unproven in the treatment of esophageal cancer.

 

Other considerations: The dose distribution using proton beam radiation therapy is affected to a much greater extent by changes in tissue density than photon beam radiation therapy (PBRT). As a result there is a concern about using PBRT in the presence of significant target motion. This especially pertains to targets in the thorax and upper abdomen, including the distal esophagus that move as a result of diaphragmatic excursion. Because the diaphragm moves during respiration, this results in changes to the tissues in the beam path, which can cause significant interplay effects and dose uncertainty. This could result in unanticipated overdose of normal tissues or under dose of target volumes. Therefore, direct comparative studies will be helpful to determine the safety and efficacy of PBRT compared photon radiation.

 

Gynecological Cancers (Cervical, Ovarian, Uterine, Vulvar)

There is limited evidence in the available published literature on proton beam radiation therapy (PBRT) in the treatment of gynecological cancers (cervical, ovarian, uterine and vulvar). The literature is primarily limited to dosimetric studies comparing photon therapy with proton therapy. While some studies for cervical cancer may show some dosimetric advantages with proton therapy compared to IMRT plan, there is limited clinical evidence on the efficacy of proton beam radiation therapy (PBRT) in the treatment of gynecological cancers (cervical, ovarian, uterine and vulvar) and is unproven. The NCCN guidelines do not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of gynecological cancers (cervical, ovarian, uterine and vulvar).

 

Hepatobiliary cancers

Note: This information may not apply to patients with unresectable hepatocellular carcinoma or intrahepatic cholangiocarcinoma.

 

Hepatobiliary cancers include cancers in the liver (hepatocellular carcinoma, HCC), gallbladder, and bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Gallbladder cancer and cholangiocarcinomas are collectively known as biliary tract cancers.

 

All patients should be evaluated for potentially curative therapies including resection, transplantation, and ablative treatments. Ablative treatments include radiofrequency ablation and cryoablation. Radiation therapy is considered for patients who are not candidates for resection, transplant or other alternative therapies. There is growing evidence for the use of stereotactic body radiation therapy (SBRT) in the treatment of HCC, however, proton beam radiation therapy (PBRT) has also been used in the treatment of hepatobiliary cancers. While there may be a role for PBRT in certain circumstances for hepatobiliary cancers, further randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of proton beam therapy for the treatment of patients with hepatobiliary cancers. The use of proton beam radiation therapy (PBRT) in the treatment of hepatobiliary cancers is unproven.

 

Head and Neck Cancers

Note: This information may not apply to patients with mucosal melanoma, nasopharyngeal cancer, paranasal sinus cancer and salivary gland cancer.

 

There has been interest in the use of proton beam radiation therapy (PBRT) for the treatment of selected patients with head and neck cancers. In 2010, the Agency for Healthcare Research and Quality (AHRQ) conducted a systematic review of different radiation modalities used in the treatment of head and neck malignancies including 2D radiation, 3D conformal radiation, IMRT (intensity modulated radiation therapy) and PBRT. They concluded there was insufficient evidence comparing PBRT to other modalities. This report was updated in 2014 with the same conclusion. For individuals who have head and neck tumors who receive proton beam radiation therapy (PBRT) the evidence includes cases series and a systematic review. The systematic review noted that the studies on proton beam radiation therapy (PBRT) were heterogenous in terms of the type of particle and delivery techniques; further, there are no head to head trials comparing proton beam radiation therapy (PBRT) with other alternative treatments. Further studies are needed comparing protons with photons to determine the long term efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with head and neck cancers. There is limited clinical evidence on the efficacy of proton beam radiation therapy (PBRT) in the treatment of head and neck cancer and is unproven.

 

Lung Cancers

The available published literature on proton beam radiation therapy (PBRT) in the treatment of lung cancers is limited. Based on the review of the limited randomized studies regarding proton beam radiation therapy (PBRT) for the treatment of lung cancer the evidence does not show improved outcomes with protons. The dosimetric studies may show the potential for radiation dose reduction, however, larger prospective studies are needed to define these critical dosimetric points for PBRT in the treatment of lung cancer. There is limited clinical evidence on the efficacy of proton beam radiation therapy (PBRT) in the treatment of lung cancer and is unproven.

 

Lymphomas

There is considerable interest in use of proton beam radiation therapy (PBRT) for the treatment of Hodgkin’s and Non-Hodgkin’s lymphoma (B-cell and T-cell lymphomas). These individuals often have relatively good prognoses, with 10 year survival rate of Hodgkin’s lymphoma (HL) of approximately 90% and somewhat lower rates for Non-Hodgkin’s lymphoma (NHL) (B-cell and T-cell lymphomas). Therefore, there is concern that this patient population has a longer duration of survival, allowing sufficient time for very late side effects of radiation for curative treatment to emerge and affect quality of life (QOL). However, the doses of radiation that are typically delivered for lymphoma are low or moderate compared to most solid tumors, and these doses often do no approach the established tolerance doses for organs at risk (OAR) in the treated volume. The dosimetric advantage of proton beam radiation therapy (PBRT) is primarily in the volume of tissue receiving low doses of radiation relative to the prescribed dose, and since the prescribed dose is already low in this setting, it is not clear that the reduction in the volume of organs at risk (OAR) exposed to these relatively low doses is clinically meaningful.

 

There are several studies of dosimetric comparisons between proton beam radiation therapy (PBRT) and photon therapy which demonstrate modest reductions in radiation doses to organs at risk in lymphomas, however, these studies have not demonstrated a difference in clinical outcomes related to this dosimetric reduction. In contrast to the large number of dosimetric studies comparing dose distributions, there are relatively few studies of patients with lymphoma treated with PBRT that report patient outcomes. Further studies are needed comparing protons with photons to determine the long term efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with lymphomas. There is limited clinical evidence on the efficacy of proton beam radiation therapy (PBRT) in the treatment of lymphomas and is unproven.

 

Pancreatic Cancer

There is limited evidence demonstrating outcomes for patients with pancreas cancer treated with proton beam radiation therapy (PBRT). Reported clinical experiences for PBRT have generally been limited to single-institution studies. The dose distribution using PBRT is affected to a much greater extent by changes in tissue density than photon radiation therapy. As a result there is concern about using PBRT in the presence of significant target motion. This especially pertains to targets in the thorax and upper abdomen, including the pancreas, which move as a result of diaphragmatic excursion. Because the diaphragm moves during respiration, this results in changes to the tissues in the beam path, which can cause significant interplay effects and dose uncertainty. This could result in unanticipated overdose of normal tissues or under dose of target volumes. Prospective trials comparing PBRT with standard photon therapy like 3DCRT or IMRT are necessary to provide high quality evidence demonstrating the value of PBRT for the treatment of locally advanced pancreatic cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of pancreatic cancer. The use of proton beam radiation therapy (PBRT) in the treatment of pancreatic cancer is unproven.

 

Prostate Cancer

There is significant consensus among radiation oncologists that there is lack of comparative effectiveness research on proton beam radiation therapy (PBRT) for prostate cancer. Multiple evidence based reviews on this topic have concluded, that no clear evidence supports a benefit of proton therapy over intensity modulated radiation therapy (IMRT) in terms of efficacy or long-term toxicity. These include reports from AHRQ, the American Urologic Association, and the American College of Radiology and ASTRO subcommittee on emerging technology. In the 2017 update of the model policy on proton beam therapy (PBT), ASTRO maintains:

 

"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 of proton therapy compares to other radiation 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 within the context of a prospective clinical trial or registry."

 

The body of evidence on proton beam radiation therapy (PBRT) for prostate cancer largely consists of retrospective studies performed at tertiary centers. The evidence quality is low and there is insufficient evidence to determine how PBRT compares to standard of care photon-based therapies, which are able to achieve outcomes with low toxicity. The use of proton beam radiation therapy (PBRT) in the treatment of prostate cancer is unproven.

 

Rectal Cancer

The available published literature on proton beam radiation therapy (PBRT) and rectal cancer is limited to dosimetric studies. There is no readily available published data on clinical studies of proton beam therapy and rectal cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of rectal cancer. The use of proton beam radiation therapy (PBRT) in the treatment of rectal cancer is unproven.

 

Bone Cancer

Note: This information may not apply to patients with skull based chondrosarcoma; chordoma; or unresectable or incompletely resectable osteosarcoma.

 

Studies of proton beam radiation therapy (PBRT) in bone cancer are limited, with the exception of skull based chondrosarcoma; chordoma and for local control in patients with unresectable or incompletely resectable osteosarcoma. Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam radiation therapy (PBRT) for the treatment of bone cancer (excluding skull based chondrosarcoma and chordoma and osteosarcoma that is unresectable or incompletely resectable). Randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with bone cancer (excluding skull based chondrosarcoma and chordoma and osteosarcoma that is unresectable or incompletely resectable). The use of proton beam radiation therapy (PBRT) in the treatment of bone cancer (excluding skull based chondrosarcoma and chordoma and osteosarcoma that is unresectable or incompletely resectable) is unproven.

 

Central Nervous System (CNS) Tumors not Adjacent to Critical Structures Such as the Optic Nerve, Brain Stem or Spinal Cord > 21 Years of Age

Radiation therapy is commonly used to treat central nervous system (CNS) malignant tumors. Also, benign central nervous system (CNS) tumors including meningiomas, acoustic neuromas and pituitary adenomas have also been treated with proton beam radiation therapy (PBRT). Based on review of the peer reviewed medical literature which includes meta-analysis, systematic reviews, small retrospective and prospective studies and case series the evidence is insufficient for any definitive conclusions about the efficacy of proton beam radiation therapy (PBRT) for the treatment of central nervous system (CNS) cancers not adjacent to critical structures such as the optic nerve, brain stem or spinal cord. Some of the studies regarding PBRT primarily focus on treatment planning and dosimetric data comparing tumor coverage and tissue sparing; others compared external beam radiation therapy (EBRT) using intensity modulated radiation therapy (IMRT) and PBRT, however, the magnitude of effect of PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of proton beam therapy for the treatment of patients with central nervous system (CNS) cancers. The use of proton beam radiation therapy (PBRT) in the treatment of central nervous system (CNS) tumors not adjacent to critical structures such as optic nerve, brain stem or spinal cord is unproven.

 

Colon cancer (Includes Colorectal Cancer)

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam radiation therapy (PBRT) for the treatment of colon (colorectal) cancer. Randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of proton beam radiation therapy for the treatment of patients with colon (colorectal) cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of colon (colorectal) cancer. The use of proton beam radiation therapy (PBRT) in the treatment of colon (colorectal) cancer is unproven.

 

Gastric cancers

Based on review of the peer reviewed medical literature a study was found describing the potential dosimetric advantage of proton beam therapy, however, there is no moderate or high quality studies comparing proton beam radiation therapy (PBRT) to 3D conformal radiotherapy or intensity modulated radiation therapy (IMRT) for gastric cancer. Treatment with protons is dependent on tissue density and changes in patterns of gas make the treatment of gastric cancer with proton beam radiation therapy (PBRT) challenging. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy for the treatment of gastric cancer. Therefore, the use of proton beam radiation therapy (PBRT) in the treatment of gastric cancer is unproven.

 

Kidney cancer

Based on review of the peer reviewed medical literature, there is insufficient evidence to draw conclusions about the use of proton beam radiation therapy (PBRT) for the treatment of kidney cancer. Per NCCN guidelines the use of conformal radiation technology using intensity modulated radiation therapy (IMRT) is the preferred choice based on comprehensive consideration of target coverage and clinically relevant normal tissue tolerance. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of kidney cancer. There are no randomized trials comparing PBRT to other forms of external radiation. Randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with kidney cancer. The use of proton beam radiation therapy (PBRT) in the treatment of kidney cancer is unproven.

 

Small Bowel Adenocarcinoma

Based on the NCCN guidelines radiation treatment is the following for the treatment of small bowel adenocarcinoma:

  • Duodenum: treatment can be delivered using 3-D conformal radiation therapy. When appropriate advanced treatment planning, such as intensity modulated radiation therapy (IMRT) should be considered to limit toxicity to adjacent normal organs.
  • Jejunum/Ileum: radiation therapy is not generally indicated for lesions arising in these sites. Any consideration for such therapy must be made on a highly selected basis by a multidisciplinary team.

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

 

Soft tissue sarcomas

Note: This information may not apply to patients with non-metastatic retroperitoneal soft tissue sarcoma.

 

Studies of proton beam radiation therapy (PBRT) in soft tissue sarcomas are limited, with the exception of retroperitoneal sarcomas. For soft tissue sarcomas other than retroperitoneal sarcomas the studies on proton beam radiation therapy (PBRT) are primarily dosimetric comparisons. In a dosemetric analysis of 5 patients with paraspinal sarcoma they found that the intensity modulated radiation therapy (IMRT) plan and the intensity modulated proton plan produced equal homogenous levels of tumor coverage. There was also a reduction in the integral dose to the organs at risk with the intensity modulated radiation therapy (IMRT) plan. There is limited clinical evidence on the efficacy of proton beam radiation therapy (PBRT) in the treatment of soft tissue sarcomas (except for non-metastatic retroperitoneal sarcomas) and is unproven.

 

Testicular Cancer

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam radiation therapy (PBRT) for the treatment of testicular cancer. Randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with testicular cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of testicular cancer. The use of proton beam radiation therapy (PBRT) in the treatment of testicular cancer is unproven.

 

Thymomas and Thymic Carcinomas

The optimal plan of care for patients with thymic malignancies should be developed prior to treatment, after evaluation by radiation oncologists, thoracic surgeons, medical oncologists and diagnostic imaging specialists. Total thymectomy and complete surgical excision of the tumor are the gold standard of treatment and are recommended whenever possible for most resectable tumors. For unresectable or metastatic thymic carcinomas, chemotherapy with or without radiation therapy is recommended.

 

For incompletely resected thymomas postoperative radiation therapy is recommended. Radiation therapy (RT) should be given by the 3D conformal technique to reduce damage to surrounding normal tissue (e.g. heart, lungs, esophagus, and spinal cord).

 

Based on review of medical literature retrospective and prospective studies have been completed evaluating the use of proton beam radiation therapy (PBRT) in the treatment of thymomas and thymic carcinomas. These studies may have shown that proton beam radiation therapy (PBRT) is well tolerated with a reduction in dose to critical structures, however, the authors concluded further studies are needed to evaluate and assess clinical outcomes and late toxicities which needs to include longer follow up periods regarding the use of PBRT for the treatment of thymomas and thymic carcinomas. The current published evidence does not allow for any definitive conclusions about the efficacy of proton beam radiation therapy (PBRT) for the treatment of thymomas and thymic carcinomas. The use of proton beam radiation therapy (PBRT) in the treatment of thymomas and thymic carcinomas is unproven.

 

Other Indications

Intracranial Arteriovenous Malformations (AVM) (Except for Intracranial Arteriovenous Malformations not Amendable to Surgical Excision, Embolization or Standard Stereotactic Radiosurgery)

Intracranial arteriovenous malformations (AVMs) is an abnormal vascular structure in which an artery is directly connected to a vein without the normally intervening smaller arterioles, capillaries, and veins. Individuals with AVMs of the brain may be subject to disabling or fatal recurrent hemorrhage, seizures, severe headaches, and progressive neurological deficits. Management decisions are most appropriately made by a multidisciplinary team of experienced clinicians who consider size, location and vascular features of the AVM.

 

Treatment modalities include surgery; radiosurgery is useful option in lesions deemed at high risk for surgical therapy; and endovascular embolization can be useful in adjunct to these techniques.

 

Based on review of the peer reviewed medical literature successful intracranial AVM obliteration with radiosurgery using proton beam radiation therapy (PBRT) depends upon the lesion size and dose of radiation, also the associated risk based on anatomic location or feeding vessel anatomy. Complete cure is considerably higher with smaller lesions; an overall 80 percent obliteration rate by three years with lesions that are 3 cm or smaller. Therefore, the use of proton beam radiation therapy (PBRT) is considered unproven for the treatment of intracranial arteriovenous malformations (AVMs) for other than small lesion(s) when surgery may be associated with increased risk based on anatomic locations or feeding vessel anatomy.

 

Summary

While proton beam radiation therapy (PBRT) has been used to treat cancer since the 1950’s, there is currently insufficient clinical outcomes reported in the peer reviewed medical literature to allow one to make a definitive conclusion about the role of proton beam radiation therapy (PBRT) for the indications addressed in this medical policy. It is unclear whether a mild-moderate reduction in low dose exposure will translate into a clinically meaningful benefit and there is no proven superiority for proton beam radiation therapy (PBRT) over photon radiation therapy (3D conformal, intensity modulated radiation therapy (IMRT) or stereotactic radiation therapy). Further studies are needed to define comparative effectiveness of proton radiation therapy versus photon radiation therapy. Therefore, the indications outlined below in the policy criteria will be considered not medically necessary.

 

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 1.2019
  • Consensus of the panel is that intensity modulated radiation therapy (IMRT) is preferred over 3-D conformal RT (radiation therapy) in the treatment of anal carcinoma.
  • With IMRT, dose to small bowel, bladder, pelvic/femoral bones and external genitalia can be sculpted and minimized despite close proximity of these organs to target volumes.

 

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

Bladder Cancer Version 4.2019

Invasive Disease

  • Carcinoma of the bladder and carcinoma of the urethra:
  • External Beam Radiation Therapy (EBRT)

 

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

Bone Cancer Version 2.2020

Osteosarcoma

  • Combined photon/proton or proton beam RT has been shown to be effective for local control in some patients with unresectable or incompletely resected osteosarcoma.

 

Ewing Sarcoma and Giant Cell Tumor of Bone

  • The NCCN guideline does not mention or indicate the use of proton beam therapy (PBT) as a radiation treatment modality.
Breast Cancer Version 2.2019

Invasive Breast Cancer
Optimizing Delivery of Individual Therapy

  • It is important to individualize radiation therapy planning and delivery CT-based treatment planning is encouraged to delineate target volumes and adjacent organs at risk. Greater target dose homogeneity and sparing of normal tissues can be accomplished using compensators such as wedges, forward planning using segments, and intensity modulated radiation therapy (IMRT)
  • Respiratory control techniques including deep inspiration breath hold and prone positioning may be used to try to further reduce dose to adjacent normal tissues, in particular heart and lung. Boost treatment in the setting of breast conservation can be delivered using enface electrons, photons or brachytherapy. Chest wall scar boost when indicated typically treated with electrons or photons
  • Whole breast radiation
  • Chest wall radiation (including breast reconstruction)
  • Regional nodal radiation
  • Accelerated partial breast irradiation (APBI)

 

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

Central Nervous System Cancers Version 1.2019

Radiation oncologists use several different treatment modalities in patients with primary brain tumors including:

  • Brachytherapy
  • Fractionated stereotactic radiotherapy (FSRT)
  • Stereotactic radiotherapy
  • Standard fractionated external beam radiation therapy (EBRT) is the most common approach, while hypofractionation is emerging as an option for selected patients (i.e. elderly and patients with compromised performance)

 

Adult Intracranial and Spinal Ependymoma

  • Craniospinal: to reduce toxicity from craniospinal irradiation (CSI) in adults, consider the use of intensity modulated radiotherapy or protons if available

 

Adult Medulloblastoma

  • To reduce risk from craniospinal irradiation in adults, consider the use of intensity modulated radiotherapy or protons if available

 

Menigiomas

  • Highly conformal fractional RT techniques (e.g. 3D-CRT, IMRT, VMAT, proton therapy) are recommended to spare critical structures and uninvolved tissue
Cervical Cancer Version 4.2019
  • External beam radiation therapy (EBRT) using multiple conformal fields or intensity modulated volumetric techniques, such as intensity modulated radiation therapy (IMRT)/volumetric-modulated arc therapy (VMAT)/tomotherapy.
    • IMRT may be helpful in minimizing dose to the bowel and other critical structures in the post-hysterectomy setting and in treating the para-aortic nodes when necessary. These techniques can also be useful when high doses are required to treat gross disease in regional lymph nodes.
    • SBRT is an approach that allows for delivery of very high doses of focused EBRT
  • Brachytherapy
  • Intraoperative radiation therapy (IORT)

 

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

Colon Cancer Version 2.2019
  • If radiation therapy is used, conformal external beam radiation therapy (EBRT) should be used and intensity modulated radiation therapy (IMRT) should be reserved only for unique clinical situation as reirradiation of previously treated patients with recurrent disease or unique anatomical situations.
  • Intraoperative radiation therapy (IORT) if available may be considered for patients with T4 or recurrent cancers as an additional boost. If IORT is not available, additional external beam radiation and/or brachytherapy could be considered to a limited volume.
  • In patients with a limited number of liver or lung metastases, radiotherapy to the metastatic site can be considered in highly selected cases or in the setting of a clinical trial. Radiotherapy should not be used in the place of surgical resection. Radiotherapy should be delivered in a highly conformal manner. The techniques can included 3-D conformal radiation therapy, IMRT or SBRT (stereotactic body radiotherapy).

 

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

Rectal Cancer Version 2.2019
  • Positioning and other techniques to minimize the volume of small bowel in the fields should be encouraged.
  • Intensity modulated radiation therapy (IMRT) should only be used in the setting of a clinical trial or in a unique clinical situations such as reirradiation of previously treated patients with recurrent disease or unique anatomical situations.
  • Image guidance radiation therapy (IGRT) and cone beam CT imaging should be routinely used during their course of treatment with IMRT and SBRT (stereotactic body radiotherapy).
  • Intraoperative radiation therapy (IORT) if available may be considered for very close or positive margins after resection, as an additional boost, especially patients with T4 or recurrent cancers. If IORT is not available, external beam radiation therapy and/or brachytherapy to a limited volume could be considered soon after surgery, prior to adjuvant chemotherapy.
  • In patients with a limited number of liver and lung metastases, radiotherapy to the metastatic site can be considered in highly selected cases or in the setting of a clinical trial. Radiotherapy should not be used in the place of surgical resection. Radiotherapy should be delivered in a highly conformal manner. The techniques can include 3-D conformal radiation therapy, IMRT or SBRT.

 

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

Esophageal and Esophagogastric Junction Cancers Version 2.2019
  • In general, Siewart I and II tumors should be managed with radiation therapy guidelines applicable to esophageal and EGJ cancers. Siewert III tumor patients may receive perioperative chemoradiation depending on institutional preference, and are more generally appropriately managed with radiation according to guidelines applicable to gastric cancers. These recommendations may be modified depending on the location of the bulk of the tumor.

 

Simulation and Treatment Planning

  • CT simulation and conformal treatment planning should be used. Intensity modulated radiation therapy (IMRT) or proton beam therapy 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.

 

Data regarding proton beam therapy(PTB) are early and evolving. Therefore, the NCCN Guidelines recommend that patients with esophageal cancer be treated with proton beam therapy (PTB) within a clinical trial.

  • Use of immobilization device is strongly recommended for reproducibility daily setup
  • Respiratory motion may be significant for distal esophagus and EGJ lesions. When 4D-CT planning or other motion management techniques are used, margins may be modified to account for observed motion and may also be reduced if justified.
  • Target volumes need to be carefully defined and encompassed while designing IMRT plans. Uncertainties from variations in stomach filling and respiratory motion should be taken into account. For structures such as the lungs, attention should be given to the lung volume receiving low to moderate doses, as well as the volume receiving high doses. Attention should be paid to sparing the uninvolved stomach that may be used for future reconstruction (i.e. anastomosis site)

 

Normal Tissue Tolerance Dose-Limits

  • Treatment planning is essential to reduce unnecessary dose to organs at risk including liver.
  • Lung dose may require particular attention, especially in a preoperatively treated patient.

 

The NCCN guideline recommends that patients with esophageal cancer be treated with proton beam therapy (PBT) within a clinical trial.

Gastric Cancer Version 2.2019

Simulation and Treatment Planning

  • CT simulation and conformal treatment planning should be used. Intensity modulated radiation therapy (IMRT) may be used in clinical settings were reduction in dose to organs at risk (e.g. heart, lungs, liver, kidneys, small bowel) is required, which cannot be achieved by 3-D techniques.
  • Use of immobilization devices is strongly recommended for reproducibility of daily setup.
  • 4D-CT planning or other motion management may be appropriately utilized in select circumstances where organ motion with respiration may be significant.
  • Target volumes need to be carefully defined and encompassed while designing IMRT plans. Uncertainties from variations in stomach filling and respiratory motion should be taken into account.

 

Normal Tissue Tolerance Dose Limits

  • Treatment planning is essential to reduce unnecessary dose to organs at risk

 

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

Head and Neck Cancers Version 2.2019

Radiation Techniques

  • IMRT or other conformal techniques (3D conformal RT, helical tomotherapy, volumetric modulated arc therapy (VMAT), and proton beam therapy (PBT) may be used as appropriate depending on the stage, tumor, location, physician training/experience, and available physics support.
  • Advanced radiation therapy technologies such as IMRT, tomotherapy, VMAT, image-guided radiation therapy (IGRT), and PBT may offer clinically relevant advantages in specific instances to spare important organs at risk (OARs), such as the brain, brain stem, cochlea, semicircular canals, optic chiasm and nerves, other cranial nerves, retina, lacrimal glands, cornea, spinal cord, brachial plexus, mucosa, salivary glands, bone (skull based and mandible), pharyngeal constrictors, larynx, and esophagus, and decrease the risk of late, normal tissue damage while sill achieving the primary goal of local tumor control. The demonstration of significant dose-sparing of these OARs reflects best clinical practice.
  • Randomized studies to test these concepts are unlikely to be done since the above specific clinical scenarios are relatively rare. In light of that, the modalities and techniques that are found best to reduce the doses to the OARs in a clinically meaningful way without compromising target coverage should be considered.

 

Intensity Modulated Radiation Therapy (IMRT)

  • IMRT has been shown to be useful in reducing long term toxicity in oropharyngeal, paranasal sinus, and nasopharyngeal cancers by reducing the dose to salivary glands, temporal lobes, auditory structures (including cochlea), and optic structures. The application of IMRT to other sites (e.g. oral cavity, larynx, hypopharynx, salivary glands) is evolving and may be used at the discretion of treating physicians. Helical tomotherapy and VMAT are advanced forms of IMRT.

 

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.
Hepatobiliary Cancers Version 3.2019

Hepatocellular Carcinoma (HCC)

  • EBRT (external beam radiation therapy) is a treatment option for patients with unresectable disease, or for those who are medically inoperable due to comorbidity.
  • All tumors irrespective of the location may be amendable to radiation therapy (3D conformal radiation therapy, intensity modulated radiation therapy (IMRT), or stereotactic body radiation therapy (SBRT) to improve treatment accuracy and reduce treatment related toxicity.
  • Hypofractionation with photons or protons is an acceptable option for intrahepatic tumors, though treatment of centers with experience is recommended.
  • There is growing evidence for the usefulness of SBRT in management of patients with HCC.
  • Proton beam therapy (PBT) may be appropriate in specific situations.
  • Palliative EBRT is appropriate for symptom control and/or prevention of complications from metastatic HCC lesions, such as bone or brain.

 

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.

 

Gallbladder Cancer

  • Image guided radiotherapy is strongly recommended when using EBRT, IMRT, and SBRT to improve treatment accuracy and reduce treatment related toxicity.

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

Hodgkin Lymphoma (Age > 18) Version 2.2019
  • 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

  • ISRT (involved site radiation therapy) is recommended as the appropriate field for HL. Planning for ISRT requires modern CT-based simulation and planning capabilities. Incorporating other modern imaging such as PET and MRI often enhances treatment volume determination.
  • ISRT targets the site of the originally involved lymph node(s). The volume encompasses the original suspicious volume prior to chemotherapy or surgery. Yet is spares adjacent uninvolved organs (such as lungs, bone, muscle, or kidney) when lymphadenopathy regresses following chemotherapy.
  • 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 OAR.

 

Preliminary results from single institution studies have shown that significant does 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 decrease the risk for normal tissue damage and late effects without compromising the primary goal of local tumor control. 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.

NCCN guideline regarding the use of proton beam radiation therapy (PBRT) for the treatment of Hodgkin lymphoma does not include a discussion of specific dose or length of treatment considering the disease stage.

Kidney Cancer Version 2.2020

Surgical resection remains an effective therapy for localized RCC (renal cell carcinoma) with options including radical nephrectomy and nephron sparing surgery.

 

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

Malignant Pleural Mesothelioma Version 2.2019
  • 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 2.2019
  • Definitive external beam radiation therapy (EBRT) should be delivered using a technique judged optimal by the treating radiation oncologist.
  • There are insufficient data to support the use of electronic surface brachytherapy in the management of cutaneous melanoma.

 

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

Neuroendocrine and Adrenal Tumors Version 1.2019

Neuroendocrine Tumors

  • Chemoradiation is thought to have most efficacy for tumors with atypical histology or tumors with higher miotic and proliferative indices (e.g. Ki-67). There are limited data on the efficacy of chemoradiation for unresectable IIIA or IIIB low grade lung neuroendocrine tumors; however, some panel members consider chemoradiation in this situation.

 

Adrenocortical Carcinoma

  • Localized Disease
  • Treatment
  • Consider external beam RT to tumor bed
  • Metastatic Disease
  • Consider local therapy
  • RFA (radiofrequency ablation)
  • RT (radiation therapy)

 

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

B-Cell Lymphomas Version 4.2019
  • Treatment with photons, electrons or protons may all be appropriate, depending on clinical circumstances.
  • Advanced radiation therapy technologies such as intensity modulated radiation therapy (IMRT), breath hold, or respiratory gating, image guided therapy 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 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 (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 techniques using clinical treatment planning considerations of coverage and dose reductions for OAR.

 

Preliminary results from single institution studies have shown that significant does 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 decrease the risk for normal tissue damage and late effects without compromising the primary goal of local tumor control. 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.

 

NCCN guideline regarding the use of proton beam radiation therapy (PBRT) for the treatment of non-Hodgkin lymphoma (B-cell lymphomas) does not include a discussion of specific dose or length of treatment considering the disease stage.

Primary Cutaneous B-Cell Lymphomas Version 2.2019

PCMZL (primary cutaneous marginal zone lymphoma) and PCFCL (primary cutaneous follicle center lymphoma)

  • Optimal management for solitary/regional PCMZL and PCFCL is the external beam RT.
  • For relapsed or refractory disease external beam RT may be adequate.

 

RT is very effective when used as an initial local therapy as well as cutaneous relapses in most patients with indolent PCBCL (primary cutaneous B-cell lymphomas).

 

Low dose involved field RT (4 Gy in two fractions) is an effective treatment option for palliation of symptoms in patients with persistent (initial) lesions or recurrent symptomatic disease.

 

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

T-Cell Lymphomas Version 2.2019
  • Advanced radiation therapy technologies such as IMRT, breath hold, or respiratory gating, image guided therapy, 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.

 

Image guidance may be required to facilitate 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 control.

 

Involved site RT (ISRT) is intended to limit radiation exposure to adjacent uninvolved organs (e.g. lungs, bone, muscle, kidney) when lymphadenopathy regresses following chemotherapy, thus minimizing the potential long term complications. The treatment plan is designed using conventional 3D conformal or IMRT techniques using clinical treatment planning considerations of coverage and dose reductions for OAR.

 

NCCN guideline regarding the use of proton beam therapy (PBT) for the treatment of T-cell lymphomas does not include a discussion of specific dose or length of treatment considering the disease stage.

Basal Cell Skin Cancer Version 1.2019
  • Electron Beam Radiation Therapy (EBRT)
  • Radioisotope brachytherapy could be considered in highly selected cases.

 

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

Merkel Cell Carcinoma Version 1.2019
  • After surgery, patients may undergo postoperative RT of the primary site.
  • Adjuvant RT to the primary site is generally recommended for all other cases, especially for patients with microscopic or grossly positive margins or other risk factors for recurrence. Efforts should be made to avoid delay of adjuvant RT if planned, because delay between the time of surgery and RT initiation is associated with worse outcomes. Adjuvant RT to the primary site depends on the success of the prior surgery.

 

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

Squamous Cell Skin Cancer Version 2.2019

Although surgery is the mainstay of local treatment for SCC, patient preference and other factors may lead to the choice of RT as primary therapy for local disease without lymph node involvement. Radiation is an effective treatment option for selected patients with SCC in situ who have large or multiple lesions and those who refuse surgery.

 

NCCN panel recommends adjuvant radiotherapy for any SCC that shows evidence of extensive perineural or large nerve involvement. Adjuvant RT is also recommended option if tissue margins are positive after definitive surgery.

 

Selection of target area margins and RT modality is left to clinical judgement and based on the experience and expertise available at the treating institution. A variety of external beam options have been shown to be effective for treating cSCC and similar cosmetic/safety results and are generally accepted as standard of care.

 

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

Non-Small Cell Lung Cancer Version 6.2019
  • More advanced technologies are appropriate when needed to deliver 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.

 

The goals of RT are to maximize tumor control and to minimize treatment toxicity. Advanced technologies such as 4D conformal RT simulation, intensity modulated RT/volumetric modulated arc therapy (IMRT/VMAT), image-guided RT, motion management strategies, and proton therapy have been shown to reduce toxicity and increase survival in nonrandomized trials.

 

NCCN guideline does not indicate or define what specific situations or select settings PBT should be utilized or the dosing.

Occult Primary (Cancer of Unknown Primary [CUP]) Version 2.2019

Localized Disease

  • Consider definitive radiotherapy for patients with localized disease.
  • Consider stereotactic ablative radiotherapy (SABR) for limited (1-3) metastases and pulmonary metastases.

 

Adjuvant Therapy

  • Consider adjuvant radiation therapy after lymph node dissection if the disease is limited to a single nodal site with extranodal extension or inadequate nodal dissection with multiple positive nodes.

 

Palliative Therapy

  • Consider palliative radiotherapy for symptomatic patients. Hypofractionated RT can be used as palliative treatment for uncontrolled pain, for impending pathologic fracture, or for impending cord compression.

 

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

Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 1.2019

Primary treatment for presumed ovarian cancer consists of appropriate surgical staging and debulking surgery followed in most (but not all) patients by systemic chemotherapy.

 

Whole abdominal radiation therapy is rarely used for epithelial ovarian primary peritoneal, and fallopian tube cancers in NCCN member institutions. It is not included as treatment recommendation in the NCCN guidelines for Ovarian Cancer. Palliative localized RT is an option for symptom control in patients with recurrent disease. Patients who receive radiation are prone to vaginal stenosis, which can impair sexual function. Woman can use vaginal dilators to prevent or treat vaginal stenosis. Dilator use can start 2 to 4 weeks after RT is completed and can be done indefinitely.

 

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

Pancreatic Adenocarcinoma Version 3.2019

In all scenarios, the goal of delivering RT is to sterilize vessel margins, enhance the likelihood of a margin negative resection, and provide adequate control to prevent or delay progression of local disease while minimizing the risk of RT exposure to surrounding organ at risk (OARs). Radiation can also be used to palliate pain and bleeding or relieve obstructive symptoms in patients who have progressed or recurred locally.

  • 3-D conformal RT (3D-CRT), intensity modulated RT (IMRT) and SBRT with breath-hold/gating techniques can result in improved planning target volume (PTV) coverage with decreased dose to OARs.
  • It is imperative to evaluate the dose-volume histogram (DVH) of the PTV and the critical OARs such as the duodenum, stomach, liver, kidneys, spinal cord, and bowel. No clear OAR dose constraints for SBRT current exist but are emerging.

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

Penile Cancer Version 3.2019

If tumor < 4 cm

  • Brachytherapy alone (category 2B) (should be performed with interstitial implant)
  • EBRT (category 2B)
  • EBRT with concurrent chemotherapy (category 3)
  • Consider prophylactic EBRT to inguinal lymph nodes in patients who are not surgical candidates or who decline surgical management

 

If tumor > 4 cm

  • EBRT with concurrent chemotherapy (category 3)
  • Brachytherapy alone (category 2B) in select cases with careful post treatment surveillance

 

T3-4 or N+ (surgically unresectable)

  • EBRT with concurrent chemotherapy (category 3)

 

Primary

Site Margin Positive Following Penectomy

  • Postsurgical EBRT
  • Brachytherapy may be considered in select cases

 

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

Prostate Cancer Version 3.2019
  • 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.

 

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 1.2020
  • Duodenum: treatment can be delivered using 3-D conformal radiation therapy. When appropriate advanced treatment planning, such as intensity modulated radiation therapy (IMRT) should be considered to limit toxicity to adjacent normal organs.

 

Jejunum/Ileum: radiation therapy is not generally indicated for lesions arising in these sites. Any consideration for such therapy must be made on a highly selected basis by a multidisciplinary team.

 

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

Small Cell Lung Cancer Version 2.2019
  • Use of more advanced technologies is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints. Such technologies include (but are not limited to) 4D-CT and/or PET/CT simulation, IMRT/VMAT, IGRT, and motion management strategies. IMRT is preferred over 3D conformal external beam RT (CRT) on the basis of reduced toxicity in the setting of concurrent chemotherapy/RT.

 

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

Soft Tissue Sarcoma Version 3.2019

Preoperative RT

  • External beam radiation therapy
  • If an R1 or R2 resection is anticipated, clips to high risk areas for recurrence is encouraged. When external beam RT is used, sophisticated treatment planning with IMRT and/or protons can be used to improve the therapeutic ratio
  • Brachytherapy (low dose rate [LDR]/high dose rate [HDR]) – data is still limited on the use of HDR brachytherapy for sarcomas
  • IORT (intraoperative radiation therapy)

 

Postoperative RT following surgery with clips

  • External beam radiation therapy
  • If an R1 or R2 resection is anticipated, clips to high risk areas for recurrence is encouraged. When external beam RT is used, sophisticated treatment planning with IMRT and/or protons can be used to improve the therapeutic ratio
  • IORT (intraoperative radiation therapy)
  • Brachytherapy (low dose rate [LDR]/high dose rate [HDR]) – data is still limited on the use of HDR brachytherapy for sarcomas

 

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).

 

Retroperiotoneal/Intra-Abdominal Soft Tissue Sarcomas

  • RT can be administered as either preoperative treatmeant for patients with resectable disease or as primary treatment for those with unresectable disease.
  • Newer techniques such as IMRT and 3D conformal RT using protons or photons may allow tumor target coverage and acceptable clinical outcomes within 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.

 

NCCN guideline does not indicate or define what specific situations or select settings PBT should be utilized or the dosing.

Testicular Cancer Version 1.2019

Principles of Radiotherapy for Pure Testicular Seminoma

  • Linear accelerators with > 6 MV photons should be used when possible
  • The mean dose (Dmean) and dose delivered to 50% of the volume (D50%) of the kidneys, liver, and bowel are lower with CT based anteroposterior-posteroanterior (AP-PA) three dimensional conformal radiation therapy (3D-CRT) than intensity-modulated radiation therapy (IMRT). As a result, the risk of second cancers arising in the kidneys, liver or bowel may be lower with 3D-CRT than IMRT, and IMRT is not recommended.

 

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

Thymomas and Thymic Carcinomas Version 2.2019
  • CT-based planning is highly recommended. Simulations of target motion are encouraged whenever possible.
  • Radiation beam arrangements should be selected based on the shape of PTV aiming to confine the prescribed high dose to the target and minimize dose to adjacent critical structures. Anterior-posterior and posterior-anterior ports weighing more anteriorly, or wedge pair technique may be considered. These techniques, although commonly used during the traditional 2-D era, can generate an excessive dose to normal tissue. A dose volume histogram of the lungs, heart, and cord need to be carefully reviewed for each plan.
  • 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 guidelines should be strictly followed
  • Proton beam therapy (PBT) has been shown to improve the dosimetry compared to IMRT allowing better sparing of the normal organs (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.

 

Thymomas

  • Use of intensity-modulated RT (IMRT) may decrease the dose to normal tissue. If IMRT is used, guidelines from the NCI Advanced Technology Center (ATC) and ASTRO/ACT should be followed. Because these patients are younger and usually longer term survivors, the mean dose to the heart should be as low as reasonably achievable.

 

Thymic Carcinomas

  • Postoperative RT with or without chemotherapy depending on the completeness of resection. For unresectable or metastatic thymic carcinomas chemotherapy with or without RT is recommended.

 

NCCN guideline does not indicate or define what specific situations or select settings PBT should be utilized or the dosing.

Thyroid Carcinoma Version 1.2019
  • External beam radiation therapy (EBRT)
  • Intensity modulated radiation therapy (IMRT)
  • Stereotactic body radiation therapy (SBRT)

 

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

Uterine Neoplasms Version 3.2019
  • RT is directed at sites of known or suspected tumor involvement and may include external beam RT (EBRT) and/or brachytherapy.

 

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

Vulvar Cancer (Squamous Cell Carcinoma) Version 2.2019
  • RT is often used in the management of patients with vulvar cancer as adjuvant therapy following initial surgery as part of the primary therapy in locally advanced disease, or for secondary therapy/palliation in recurrent/metastatic disease
  • Radiation technique and doses are important to maximize tumor control while limiting adjacent normal tissue toxicity
  • Tumor directed RT refers to RT directed at sites of known or suspected tumor involvement. In general, tumor-directed external beam RT (EBRT) is directed to the vulva and/or inguinofemoral, external and internal iliac nodal regions. Brachytherapy can sometimes be used as a boost to anatomically amendable primary tumors. Careful attention should be taken to ensure adequate tumor coverage by combining clinical examination, imaging findings, and appropriate nodal volumes at risk to define the target volume. For example invasion into the anus above the pectinate line would necessitate coverage of the perirectal nodes.
  • Image guided IMRT is an essential component (to account for vulva edema or marked tumor regression). Planning should be taken with care to respect normal tissue tolerances such as rectum, bladder, small bowel, and femoral head and neck.

 

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

 

American Society for Radiation Oncology (ASTRO)

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.

 

In 2017, the American Society for Radiation Oncology (ASTRO) updated their Model Policy on the use of Proton Beam Therapy (PBT):

 

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 lanquage 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

 

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)

 

Proton beam radiation therapy (PBRT) is considered not medically necessary, including but not limited to following indications:

  • Anal cancer
  • Bladder cancer/genitourinary cancers (upper tract tumors, urothelial carcinoma, primary carcinoma of urethra)
  • Bone cancer (except for skull based chondrosarcoma; chordoma and combined photon/proton radiation therapy for local control in patients with unresectable or incompletely resectable osteosarcoma)
  • Breast cancer (except for left sided invasive breast cancer and curative intent and requires node irradiation i.e. internal mammary, supraclavicular and/or axillary nodes and documentation is provided that sparring the adjacent critical structures (heart/left anterior descending artery) to avoid cardiac toxicity that cannot be achieved with standard photon radiation therapy in individuals with expected long term survival)
  • Central nervous system (CNS) cancers > 21 years of age that are not adjacent to critical structures such as the optic nerve, brain stem or spinal cord
  • Colon cancer (includes colorectal cancer)
  • Esophageal and esophagogastric junction cancers
  • Gastric cancers
  • Gynecological cancers (cervical, ovarian, uterine, vulvar)
  • Head and neck cancers (except for those patients with mucosal melanoma, nasopharyngeal cancer, paranasal sinus cancer and salivary gland cancer; based on clinical stage, pathology results, concurrent chemotherapy and when documentation is provided that sparing of the surrounding normal tissues/organs at risk cannot be achieved with standard photon radiation therapy)
  • Hepatobiliary cancers
    • Hepatocellular carcinoma (HCC) (except for localized unresectable disease and ineligible for liver transplant and not amendable to other forms of ablative treatment [radiofrequency or cryoablation] and transarterial therapy (chemoembolization) is contraindicated or not technically feasible and no extrahepatic disease and no metastatic disease and in the curative setting when documentation is provided that sparing of the surrounding normal tissues [organs at risk] cannot be achieved with standard photon radiation therapy)
    • Gallbladder cancer
    • Intrahepatic cholangiocarcinoma (except for confirmed by biopsy intrahepatic cholangiocarcinoma that is unresecatable disease or metastatic disease and no extrahepatic disease and documentation supports proton radiation therapy will reduce the impact to the surrounding liver tissue)
    • Extrahepatic cholangiocarcinoma
  • Intracranial arteriovenous malformations (AVM) (except for intracranial arteriovenous malformations 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)
  • Pancreatic cancer
  • Prostate cancer
  • Rectal cancer
  • Small bowel adenocarcinoma
  • Soft tissue sarcomas (except non-metastatic retroperitoneal soft tissue sarcomas and documentation is provided that proton radiation therapy will reduce the impact to the surrounding organs at risk that cannot be achieved with standard photon radiation therapy)
  • Testicular cancer
  • Thymomas and thymic carcinomas

 

While proton beam radiation therapy (PBRT) has been used to treat cancer since the 1950’s, there is currently insufficient clinical outcomes reported in the peer reviewed medical literature to allow one to make a definitive conclusion about the role of proton beam radiation therapy (PBRT) for the above indications. It is unclear whether a mild-moderate reduction in low dose exposure will translate into a clinically meaningful benefit and there is no proven superiority for proton beam radiation therapy (PBRT) over photon radiation therapy (3D conformal, intensity modulated radiation therapy (IMRT) or stereotactic radiation therapy). Further studies are needed to define comparative effectiveness of proton radiation therapy versus photon radiation therapy.

 

Secondary Malignancies

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

 

Documentation Requirements for Proton Beam Radiation Therapy

  • Include a treatment prescription that defines the goals of the treatment plan, including specific dose-volume parameters for the target and nearby critical structures as well pertinent details of beam delivery, such as method of beam modulation, field arrangement, and expected positional and range uncertainties.
  • Include a treatment plan, signed by a physician, which meets the prescribed dose-volume parameters for the clinical target volume (CTV) and surrounding organs at risk (OARs) in the presence of expected uncertainties. Documentation should include clinical rational that the higher levels of precision associated with proton beam radiation therapy compared to other radiation treatments (i.e. photon therapy) are clinically necessary to spare nearby tissue and OARs.
  • Describing the target setup verification methodology, including patient positioning, immobilization and use of image guidance.
  • Include verification of planned dose distribution via independent dose calculation or physical measurement.

 

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
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  • 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 2019 - Annual Review, Policy Revised
  • November 2018 - Interim Review, Policy Revised
  • August 2018 - Annual Review, Policy Revised
  • August 2017 - Annual Review, Policy Renewed
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  • May 2015 - Interim Review, Policy Revised
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  • January 2012 - Annual Review, Policy Renewed
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