Medical Policy: 08.01.05 

Original Effective Date: April 2001 

Reviewed: August 2018 

Revised: August 2018 

 

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 or abnormalities. 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, PBT has been applied to treating tumors or abnormalities that require dose escalation to achieve a higher probability of care, requiring increased precision in dose deposition while protecting normal surrounding tissue. Proton beam therapy (PBT) 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 Planning

Proton beam radiation therapy (PBRT) can allow for radiation treatment plans that are highly conformal to the target volume. PBRT planning defines the necessary field sizes, gantry angles and beam energies needed to achieve the desired radiation dose distribution.

 

Proton beam radiation therapy (PBRT) treatment planning is a multi-step process and shares functions common to other forms of external beam radiotherapy planning:

  • Simulation and Imaging: Three-dimensional image acquisition of the target region by simulation employing CT, CT/PET and/or MRI scanning equipment is an essential prerequisite to PBRT treatment planning. If respiratory or other normal organ motion is expected to produce significant movement of the target region during radiotherapy delivery, the radiation oncologist may additionally elect to order multi-phasic treatment planning image sets to account for motion when rendering target volumes.  As in all forms of external beam radiation therapy, immobilization is critical. However, for PBRT, the immobilization system can impact the dose distribution and therefore these devices must be carefully designed.
  • Contouring: Defining the target and avoidance of structures is a multi-step process:
    • The radiation oncologist reviews the three dimensional images and outlines the treatment target on each slice of the image set. The summation of these contours defines the Gross Tumor Volume (GTV). For multiple image sets, the physician may outline separate GTVs on each image set to account for the effect of normal organ motion upon target location and shape. Some patients may not have GTVs if they have had previous treatment with surgery or chemotherapy, in which case treatment planning will be based on CTVs as described below.
    • The radiation oncologist draws a margin around the GTV to generate a Clinical Target Volume (CTV) which encompasses the areas at risk for microscopic disease (i.e. not visible on imaging studies). Other CTVs may be created based on the estimated volume of residual disease. For multiple image sets, the physician may draw this margin around an aggregate volume containing all image set GTV to generate an organ-motion CTV, or Internal Target Volume (ITV).
    • In x-ray therapy to account for uncertainties in the planning and delivery processes, a final margin is then added to create a Planning Target Volume (PTV). Similar to the approach used in x-ray therapy, a lateral target expansion guards against under-dosing the target in the presence of daily setup variation and/or organ and patient motion. With PBRT, however, the target expansion in the beam direction must also ensure coverage for uncertainties in the range of the proton beam which may not perfectly match the radiologic depth of the target.  The expansion in the beam direction may be different from the lateral expansion. Because the lateral and range expansions may differ for each beam, there is no longer a single PTV that is sufficient for a multi-field proton plan. Rather than prescribing a uniform dose to PTV, in PBRT the plan should be designed to cover the CTV in the presence of expected uncertainties.
    • Nearby normal structures that could potentially be harmed by radiation (i.e. “organs at risk”, or OARs) are also contoured.
  • Radiation Dose Prescribing:  The radiation oncologist assigns specific dose coverage requirements for the CTV which will be met even in the presence of expected positional and range uncertainties. A typical prescription may define a dose that will be delivered to at least 99% of the CTV. This coverage requirement is often accompanied by a minimum acceptable point dose delivered within the CTV in the presence of expected uncertainties and a constraint describing an acceptable range of dose homogeneity. Additionally, PBRT prescription requirements routinely include dose constraints for the OARs (e.g. upper limit of mean dose, maximum allowable point dose, and/or critical volume of the OAR that must not receive a dose above a specified limit). Doses to normal structures must also be evaluated in the presence of delivery and range uncertainties. A treatment plan that satisfies these requirements and constraints should maximize the potential for disease control and minimize the risk of radiation injury to normal tissue.
  • Dosimetric Planning and Calculations: The qualified medical physicist or a supervised dosimetrist calculates a treatment plan to deliver the prescribed radiation dose to the CTV and simultaneously satisfy the normal tissue dose constraints by delivering significantly lower doses to nearby organs. Delivery mechanisms vary, but through the use of scanning magnets or scattering devices PBRT plans spread protons laterally over the extent of a target volume. Additionally, multiple proton energies are combined, through the use of mechanical absorbers or accelerator energy changes, to deliver the planned dose distribution over the longitudinal extent of the target. Range compensation devices are sometimes used to match the range of the proton beam to the distal edge of the target. Regardless of the delivery technique, all delivery parameters and/or field specific hardware are developed by medical physicist or supervised dosimetrist and an expected dose distribution is calculated for the treatment plan. While PBRT plans may be more conformal than x-ray therapy plans, they may also be more susceptible to uncertainties in patient positioning or proton range in the patient.
  • Patient Specific Dose Verification: An independent dose calculation and/or measurement should confirm that the intended dose distribution for the patient is physically verifiable and feasible.         

 

Proton Beam Radiation Therapy Treatment Delivery

Proton delivery methods can be described in one of two forms: scattering or scanning.

 

In scattered deliveries, the beam is broadened by scattering devices, beam energies are combined by mechanical absorbers and the beam is shaped by placing material such as collimators and compensators into the proton path.

 

In scanning deliveries, the beam is swept laterally over the target with magnets instead of with scattering devices. Collimators and range compensators are still sometimes used for lateral and distal beam shaping, but field specific hardware is not always required because the scanning magnets allow the lateral extent of the beam to be varied with each energy level, a technique sometimes called intensity-modulated proton therapy (IMPT).

 

The basic requirement for all forms of 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.

 

Based on our criteria and review of the peer reviewed medical literature proton beam radiation therapy (PBRT) is considered investigational, including but not limited to the following indications as described below as the current published evidence does not allow for any definitive conclusions about the safety and efficacy of proton beam radiation therapy (PBRT) for these indications.

 

Combined Therapies 

New proton beam centers may use pencil beam scanning technology. This allows for more conformal treatment delivery and has also been termed intensity modulated proton therapy (IMPT). Long term follow-up with this technology is lacking. Additionally, there are significant uncertainties about the physics and biology of protons in this setting. These include complex interaction of scanning beams with moving tissues of different densities, and less predictable dose distributions during treatment of radiosensitive tumors. Clinical evidence is insufficient to support the combined use of these technologies in a single treatment plan (i.e. intensity modulated radiation therapy (IMRT) and proton beam radiation therapy (PBRT) also called intensity modulated proton therapy [IMPT]). No evidence was identified in the clinical literature supporting the combined use of proton beam radiation therapy (PBRT) and intensity modulated radiation therapy (IMRT) i.e. intensity modulated proton therapy (IMPT) in a single treatment plan. Comparative effectiveness studies including randomized controlled trials (RCTs) are needed to demonstrate the safety and long term efficacy of this combined therapy.

   

Proton Beam Therapy (PBT) for Oncologic Indications 

Anal Carcinoma 

Proton beam therapy (PBT) has been proposed for the treatment of anal carcinoma.  Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of anal carcinoma. 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 and/or rectal cancer. The NCCN guideline does not mention or indicate the use of proton beam therapy for the treatment of anal carcinoma. The 2017 ASTRO Model-Policy guideline for proton beam therapy states, “pelvic malignancies, including non-metastatic rectal, anal, bladder and cervical cancers the patient should be enrolled in either IRB approved clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED (coverage with evidence development).” The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Bladder Cancer/Genitoruinary Cancers (Upper Tract Tumors, Urothelial Carcinoma, Carcinoma of Urethra)

Radiation therapy management is utilized in the treatment of invasive disease, proton beam therapy (PBT) has been proposed as a treatment option for bladder cancer and genitourinary cancers (upper tract tumors, urothelial carcinoma, carcinoma of urethra).

 

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of bladder cancer or genitourinary cancer (upper tract tumors, urothelial carcinoma, carcinoma of urethra). There are no randomized trials comparing PBT to other forms of external radiation. 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 bladder cancer or genitourinary cancer (upper tract tumors, urothelial carcinoma, carcinoma of urethra). The NCCN guideline does not mention or indicate the use of proton beam therapy (PBT) for the treatment of bladder or genitourinary cancers (upper tract tumors, urothelial carcinoma, carcinoma of urethra). The 2017 ASTRO Model-Policy guideline for proton beam therapy states, “pelvic malignancies, including non-metastatic rectal, anal, bladder, and cervical cancers the patient should be enrolled in either IRB approved clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED (coverage with evidence development).” The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Bone Cancer (Excluding Skull Based Chondrosarcoma and Chordoma and Unresectable Osteosarcoma) 

Primary bone tumors and selected metastatic tumors should be evaluated and treated by a multidisciplinary team of physicians with demonstrated expertise in the management of these tumors. Local control may be achieved either by limb sparing surgery or amputation. Radiation therapy (RT) is used as an adjuvant to surgery for patients with unresectable tumors or as definitive therapy in patients with tumors not amendable to surgery. Proton beam therapy (PBT) has been proposed in the treatment of bone cancer (excluding skull based chondrosarcoma and chordoma and unresectable osteosarcoma).   

 

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of bone cancer (excluding skull based chondrosarcoma and chordoma and unresectable osteosarcoma). 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 bone cancer (excluding skull based chondrosarcoma and chordoma and osteosarcoma that is unresectable or incompletely resectable). The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Breast Cancer 

Breast cancer is the most frequently diagnosed cancer globally and is the leading cause of cancer-related death in women. The etiology of the vast majority of breast cancer cases is unknown. However, numerous risk factors for the disease have been established. These risk factors include: female gender; increasing patient age; family history of breast cancer at a young age; early menarche; late menopause; older age at first live childbirth; prolonged hormone replacement therapy; previous exposure to therapeutic chest wall irradiation; benign proliferative breast disease; increased mammographic breast density; and genetic mutations such as BRCA 1 and 2 genes. 

 

Postoperative radiotherapy is considered standard of care after breast conserving surgery for breast cancer. After mastectomy, radiotherapy is required in case of intermediate or high risk of locoregional failure. Previous studies have shown that radiotherapy may be associated with an increased rate of major coronary events, especially in patients with left sided breast cancer. However, it should be noted that follow up period in these studies is relatively short. With improved survival more patients will be at risk for long-term radiation induced toxicity, thus making it even more important to reduce the dose to all organs at risk (OARs). Proton beam radiation therapy has been proposed for the treatment of breast cancer.

 

In left sided breast cancer radiotherapy, intensity modulated radiotherapy (IMRT) combined with breath-hold enable a dose reduction to the heart and left anterior descending (LAD) coronary artery. Intensity modulated proton therapy (IMPT) is being investigated with regard to decreasing the radiation to these structures. 

 

In 2013, MacDonald et al published a dosimetric planning study for the use of proton radiation therapy for locally advanced breast cancer. Twelve patients were enrolled in an institutional review board approved prospective clinical trial. Eleven of 12 patients had left sided breast cancer and one patient was treated for right sided breast cancer with bilateral implants. Five women had permanent implants at the time of RT, and seven did not have immediate reconstruction. The patients were assessed for skin toxicity, fatigue, and radiation pneumonitis during treatment and at 4 and 8 weeks after the completion of therapy.  All patients completed proton RT to a dose of 50.4 Gy (relative biological effectiveness (RBE)) to the chest wall and 45 to 50.4 Gy (RBE) to the regional lymphatics. No photon or electron component was used. The maximum skin toxicity during radiation was grade 2, the maximum CTCAE fatigue was grade 3, and there were no cases of pneumonitis reported. Concluded with the following “although we do not believe that proton radiation should become standard for all patients with locally advanced breast cancer, it may be appropriate for women with complex anatomy, including, but not limited to, patients with medial or inferior chest wall tumors, unfavorable cardiac anatomy, permanent bilateral implants, evidence of internal mammary node metastasis, and underlying cardiopulmonary risk factors. We continue to offer proton PMRT on trial for these patients.”  

 

In 2014, Mast et al reported on comparative planning study for left sided breast cancer radiotherapy with tangential intensity modulated radiotherapy (IMRT) combined with breast-hold and intensity modulated proton therapy (IMPT). Four treatment plans were generated in 20 patients; an IMPT plan and a tangential IMRT plan, both with breath-hold and free-breathing. At least 97% of the target volume had to be covered by at least 95% of the prescribed dose in all cases. Specifically with respect to the heart, the LAD and the target volumes. They analyzed the maximum doses, mean doses, and the volumes receiving 5-30 Gy. Compared to IMRT, IMPT resulted in significant dose reductions to the heart and LAD region even without breath hold. In the majority of IMPT cases, a reduction to almost zero to the heart and LAD region was obtained. IMPT treatment plans yielded the lowest dose to the lungs. They concluded with IMPT the dose to the heart and LAD region could be significantly decreased compared to tangential IMRT with breath-hold. The clinical relevance should be assessed individually based on the baseline risk of cardiac complications in combination with the dose to organs at risk (OARs). However, as IMPT for breast cancer is currently not widely available, IMPT should be reserved for patients remaining at high risk for major coronary events.

 

Based on review of the peer reviewed medical literature regarding radiation therapy for the treatment of breast cancer, there is a concern in regards to adverse effects to the heart and lungs. The problem arises when radiation exits the breast and passes through the heart and lungs, and deposits enough energy to permanently damage the heart and lungs. It is proposed that proton beam therapy (PBT) deposits most of the energy in the breast and therefore theoretically there should be less energy delivered and less complications to the heart and lungs. However, photon radiation therapy is delivered with much safer techniques today. Better planning with CT scanners and more accurate delivery with intensity modulated radiation therapy (IMRT) can lead to significantly less radiation energy to the heart and lungs. Therefore, proton beam therapy (PBT) may not prove to be safer than standard photon radiation therapy. There are very few clinical trials that have been done using PBT for the treatment of breast cancer, computer models predict less radiation to unwanted organs with PBT, but few clinical studies have examined these models. Further comparative effectiveness studies including randomized controlled trials are needed to document the advantages of proton beam therapy (PBT) including intensity modulated proton therapy (IMPT) over other radiotherapies such as intensity modulated radiation therapy (IMRT). The NCCN guideline does not mention or indicate the use of proton beam radiation therapy for the treatment of breast cancer. The 2017 ASTRO Model-Policy guideline for proton beam therapy states, “for breast cancer the patient should be enrolled in either IRB approved clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED (coverage with evidence development).” Current published evidence does not allow for any definitive conclusions that proton beam therapy (PBT) is more beneficial than the standard of care alternatives (photon radiation) for the treatment of breast cancer. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Central Nervous System (CNS) Cancers – Adults (Other than CNS Cancers not Adjacent to Critical Structures such as the Optic Nerve, Brain Stem or Spinal Cord) 

Radiation therapy is commonly used to treat central nervous system (CNS) cancers, and  proton beam therapy (PBT) has been proposed for the treatment of CNS cancers. 

 

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 therapy (PBT) for the treatment of central nervous system (CNS) cancers other than those CNS cancers not adjacent to critical structures such as the optic nerve, brain stem or spinal cord. Some of the studies regarding PBT 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 PBT, however, the magnitude of effect of PBT 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, PBT was used in combination with other therapies so results do not reflect the outcome of PBT 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. NCCN guideline states standard external beam radiation therapy (EBRT) is the most common approach for radiation therapy in the treatment of CNS tumors. NCCN guideline does not mention or indicate the use of proton beam therapy for the treatment of CNS cancers. The evidence is insufficient to determine the effects of the technology on net health outcomes for the treatment of central nervous system (CNS) cancers that are not adjacent to critical structures such as the optic nerve, brain stem or spinal cord.

 

Colon Cancer and Rectal Cancer 

Proton beam therapy (PBT) has been proposed for the treatment of colon and/or rectal cancer.

 

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of colon and/or rectal 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 and/or rectal cancer. The NCCN guideline does not mention or indicate the use of proton beam therapy for the treatment of colon and/or rectal cancer. The 2017 ASTRO Model-Policy guideline for proton beam therapy states, “pelvic malignancies, including non-metastatic rectal, anal, bladder and cervical cancers the patient should be enrolled in either IRB approved clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED (coverage with evidence development).” The evidence is insufficient to determine the effects of the technology on net health outcomes. 

   

Esophageal and Esophagogastric Junction Cancers 

Proton beam therapy (PBT) has been proposed for the treatment of esophageal and esophagogastric junction cancers. There have been few reports of PBT to treat esophageal and esophagogastric junction tumors. There are no prospective randomized trials. Wang et. al. published a retrospective report of complications after trimodality therapy looking at intensity modulated radiation therapy (IMRT) and PBT compared to conformal radiation. A total of 444 patients were reported. Both IMRT and PBT were associated with reduced risk of complications compared to 3D conformal radiation. No direct comparison of IMRT vs PBT was performed. Several phase II trials are underway but there is insufficient evidence to draw conclusion on how PBT compares to photon based therapy for esophageal and esophagogastric junction cancers. 2017 ASTRO Model Policy for Proton Beam Therapy, states “thoracic malignancies, including non-metastatic primary lung and esophageal cancers, and mediastinal lymphomas PBT should be performed in either an IRB-approved clinical trial or in a multi-institutional patient registry adhering to Medicare requirements for CED (coverage with evidence development). National Comprehensive Cancer Network (NCCN) guidelines states that data regarding proton beam therapy are early and evolving. Ideally patients should be treated with proton beam therapy within a clinical trial. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Gastric Cancers 

Proton beam therapy (PBT) has been proposed for the treatment of gastric cancer.

Based on review of the peer reviewed medical literature there are no moderate or high quality studies comparing PBT to 3D conformal radiotherapy or IMRT for gastric cancer.  Further 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 gastric cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy for gastric cancer. The evidence is insufficient to determine the effects of the technology on net health outcomes.  

  

Gynecological Cancers (Cervical, Uterine, Ovarian, Vulvar) 

Proton beam radiation therapy has been proposed for the treatment of gynecologic cancers (cervical, ovarian, uterine and vulvar).  

 

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of gynecologic cancers (cervical, uterine, ovarian or vulvar). There are no randomized trials comparing PBT to other forms of external radiation. 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 gynecologic cancers. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy for the treatment of gynecological cancers (cervical, uterine, ovarian and vulvar). The 2017 ASTRO Model-Policy guideline for proton beam radiation therapy states, “pelvic malignancies including non-metastatic rectal, anal, bladder, and cervical cancers the patient should be enrolled in either IRB approved clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED (coverage with evidence development).” The evidence is insufficient to determine the effects of the technology on net health outcomes.

   

Head and Neck Cancers 

Note: This does not apply to patients whose primary tumors are periocular in location and/or invade the orbit, skull base, and/or cavernous sinus; extend intracranially or exhibit extensive perineural invasion.   

     

There has been interest in the use of proton beam therapy (PBT) for the treatment of selected patients with head and neck cancer. Although there are several trials currently underway, there are currently no published randomized studies comparing proton therapy to intensity modulated radiation therapy (IMRT) in the treatment of 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 PBT. They concluded there was insufficient evidence comparing PBT to other modalities. This report was updated in 2014 with the same conclusion. 

 

For individuals who have head and neck tumors other than patients whose primary tumors are periocular in location and/or invade the orbit, skull base, and/or cavernous sinus; extend intracranially or exhibit extensive perineural invasion, who receive proton beam therapy (PBT) the evidence includes cases series and a systematic review. The systematic review noted that the studies on proton beam therapy were heterogenous in terms of the type of particle and delivery techniques; further, there are no head to head trials comparing proton beam therapy with other treatments. The evidence is insufficient to determine the effects of the technology of net health outcomes.

 

Hepatobiliary Cancers 

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. Proton beam therapy (PBT) has been used for the treatment of hepatobiliary cancers.

 

Hepatocellular carcinomas (HCC) are aggressive primary malignancies in the liver. All patients should be evaluated for potentially curative therapies including resection, transplantation, and ablative treatment. Radiation therapy (RT) is considered for patients who are not candidates for resection. There is growing evidence for the use of stereotactic body radiation therapy (SBRT). Proton beam therapy (PBT) has also been used in the treatment of hepatocellular carcinoma. There are no randomized trials comparing PBT to other forms of external radiation. A systematic review and meta-analysis comparing PBT to conventional radiation and SBRT have been reported. Overall survival, progression- free survival, and local control were equivalent for PBT and SBRT. Both PBT and SBRT were superior to conventional radiation.

 

Proton beam therapy (PBT) has been compared to transarterial chemoembolization (TACE) for HCC in a randomized trial. A total of 69 subjects were reported. The primary endpoint was progression-free survival (48% vs 31%, p=0.06) favoring protons but no significant difference in overall survival with a median overall survival of 30 months. Total days of hospitalization within 30 days of treatment was 166 days for the 36 TACE patients and 24 days for the proton patients (p<0.001).        

 

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of hepatobiliary cancers (liver [hepatocellular carcinoma, HCC], gallbladder, and bile ducts [intrahepatic and extrahepatic cholangiocarcinoma]). There are no randomized trials comparing PBT to other forms of external radiation. Randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of proton beam therapy (PBT) for the treatment of patients with hepatobiliary cancers. There are  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 does not indicate or define what specific situations or select settings PBT should be utilized or the dosing. The evidence is insufficient to determine the effects of the technology on net health outcomes. 

   

Hodgkin’s Lymphoma and Non-Hodgkin’s Lymphoma (B-Cell Lymphomas) 

Hodgkin lymphoma (HL) is a malignancy involving the lymph nodes and the lymphatic system. The WHO (World Health Organization) classification divides HL into 2 main types: classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominate Hodgkin lymphoma (NLPHL).

 

Non-Hodgkin’s lymphomas (NHL) (B-cell lymphomas) are a heterogeneous group of lymphoproliferative malignancies with differing patterns of behavior and response to treatment. Like Hodgkin lymphoma (HL), NHL usually originates in the lymphoid tissues and can spread to other organs. NHL, however, is much less predictable than Hodgkin lymphoma and has a greater predilection to disseminate to extranodal sites.

 

Proton beam therapy (PBT) has been studied and used for the treatment of Hodgkin’s lymphoma and non-Hodgkin lymphoma (B-cell lymphomas). 

 

In 2014, the International Lymphoma Radiation Oncology Group (ILROG) issued guidelines regarding radiation therapy for Hodgkin lymphoma and non-Hodgkin lymphoma.

  • Hodgkin’s lymphoma: Radiation therapy is the most effective single modality for local control of Hodgkin lymphoma (HL) and an important component of therapy for many patients. These guidelines have been developed to address the use of RT in HL in the modern era of combined modality treatment.
    • Newer treatment techniques, including intensity modulated radiation therapy, breath-hold, image guided radiation therapy, and 4-dimensional imaging, should be implemented when their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control.
  • Non-Hodgkin lymphoma: Radiation therapy is the most effective single modality for local control of non-Hodgkin lymphoma (NHL) and is an important component of therapy for many patients. Many of the historic concepts of dose and volume have recently been challenged by the advent of modern imaging and RT planning tools. The International Lymphoma Radiation Oncology Group (ILROG) has developed these guidelines after multinational meetings and analysis of available evidence. The guidelines represent an agreed consensus view of the ILROG steering committee on the use of RT in NHL in the modern era.
    • The roles of reduced volume and reduced doses are addressed, integrating modern imaging with 3-dimensional planning and advanced techniques for RT delivery.
    • In the modern era, in which combined-modality treatment with systemic therapy is appropriate, the previously applied extended-field and involved field RT techniques that targeted nodal regions have now been replaced by limiting the RT to smaller volumes based solely on detectable nodal involvement at presentation.
    • A new concept, involved site RT, defines the clinical target volume.
    • For indolent NHL, often treated with RT alone, larger fields should be considered.
    • New treatment techniques, including intensity modulated radiation therapy (IMRT), breath-holding, image guided RT, and 4-dimensional imaging should be implemented, and their use is expected to decrease significantly the risk for normal tissue damage while still achieving the primary goal of local tumor control.

 

The International Lymphoma Radiation Oncology Group guidelines does not mention the use of proton beam therapy (PBT)for the treatment of Hodgkin’s lymphoma or non-Hodgkin lymphoma (B-cell lymphomas). 

 

Data on proton beam therapy (PBT) for the treatment for lymphoma are limited. A recent review examined the use of consolidative PBT after chemotherapy for Hodgkin lymphoma. A total of 138 patients enrolled on tracking protocols or registry studies were reviewed. Forty-two percent of the patients were pediatric and received a median dose of 21 Gy equivalent. Adult patients received a median dose of 30.6 Gy equivalent. With a median follow-up of 32 months, three year relapse free survival was 92%. The authors concluded that early survival rates were similar to photon based therapy and continued follow-up to assess for late effects is needed.

 

Data on proton beam therapy (PBT) for non-Hodgkin lymphoma (NHL) (B-cell lymphomas) are limited. A small retrospective cohort has been reported. Eleven patients were treated between 2008 and 2014. Follow-up was 38 months. Two-year local control was 91%. Toxicities were grade 2 or less. The study concluded that longer-term follow-up and more patients are needed to confirm their findings. 

  

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of Hodgkin’s lymphoma and non-Hodgkin lymphoma (B-cell lymphomas). 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 Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) (B-cell lymphomas). The NCCN guideline regarding the use of proton beam therapy (PBT) for the treatment of Hodgkin’s lymphoma and B-cell lymphomas does not include a discussion of specific dose or length of treatment considering the disease stage. The 2017 ASTRO Model Policy for proton beam therapy states, “thoracic malignancies, including non-metastatic primary lung and esophageal cancers, and mediastinal lymphomas the patient should be enrolled in either IRB approved clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED (coverage with evidence development).” The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Kidney Cancer 

Proton beam radiation therapy has been proposed for the treatment of kidney cancer.  Based on review of the peer reviewed medical literature, there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) 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 for the treatment of kidney cancer. There are no randomized trials comparing PBT 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 for the treatment of patients with kidney cancer. The evidence is insufficient to determine the effects of the technology on net health outcomes.    

 

Non-Small Cell Lung Cancer 

Proton beam therapy (PBT) has been proposed as a radiation therapy modality for the treatment of non-small cell lung cancer.  

 

A 2010 Blue Cross Blue Shield Association (BCBSA) TEC Assessment assessed the use of PBT (proton beam therapy) for non-small cell lung cancer (NSCLC). This TEC Assessment addressed the key question on how health outcomes (OS, disease-specific survival, local control, disease free survival, and adverse events) with PBT compared with outcomes observed for stereotactic body radiotherapy (SBRT), which is an accepted approach for using RT to treat NSCLC. Eight PBT case series were identified in the Assessment that included a total of 340 patients. No comparative studies, randomized or nonrandomized, were found.

 

The report concluded that the evidence is insufficient to permit conclusions about the results of PBT for any state of NSCLC. All PBT studies are case series; there are no studies directly comparing PBT with SBRT. Among study quality concerns, no study mentioned using an independent assessor of patient reported adverse events, adverse events were generally poorly reported, and details were lacking on several aspects of PBT treatment regimens. The PBT studies had similar patient ages, but there was great variability in percent within stage Ia, sex ratio, and percent medically inoperable. There is a high degree of treatment heterogeneity among the PBT studies, particularly with respect to planning volume, total dose, number of fractions, and number of beams. Survival results are highly variable. It is unclear if the heterogeneity of results can be explained by differences in patient and treatment characteristics. Indirect comparisons between PBT and SBRT, comparing separate sets of single arm studies on PBT and SBRT, may be distorted by confounding variables. In the absence of randomized controlled trials, the comparative effectiveness of PBT and SBRT is uncertain. Whether PBT for non-small cell lung cancer improves outcomes in any setting has not yet been established. PBT for treatment of non-small cell lung cancer at any stage or for recurrent non-small cell lung cancer does not meet the TEC criteria.

 

Based on review of medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of non-small cell lung cancer (NSCLC). A 2010 Blue Cross Blue Shield Association (BCBSA) TEC Assessment addressed the use of PBT for non-small cell lung cancer and concluded that it has not yet been established whether PBT improves outcomes in any setting for NSCLC. The NCCN guideline for non-small cell lung cancer includes proton therapy as an advanced radiation technology in the principles of radiation therapy for the treatment of non-small cell lung cancer, however, the guideline refers to the ASTRO Model Policy guideline for proton beam therapy which the 2017 model policy guideline states, “thoracic malignancies including non-metastatic primary lung and esophageal cancers, and mediastinal lymphomas the patient should be enrolled in either IRB approved clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED (coverage with evidence development).” Further 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 non-small cell lung cancer. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Pancreatic Adenocarcinoma 

In patients with pancreatic cancer, radiation therapy is usually given concurrently with chemotherapy. Chemotherapy is used as a radiosensitizer, increasing the toxicity of radiation to tumor cells. A major goal of radiation therapy (RT) is to sterilize vessel margins and increase the likelihood of margin-negative resection. It also may be used to enhance local control and prevent disease progression, while minimizing the risk of RT exposure to surrounding organs at risk. Proton beam radiation therapy has been proposed for the treatment of pancreatic cancer.

 

Based on review of the peer reviewed medical literature there are no moderate or high quality studies comparing PBT to 3D conformal radiotherapy or IMRT for pancreatic cancer. Further 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 pancreatic cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy for the treatment of pancreatic cancer. The 2017 ASTRO Model-Policy guideline for proton beam therapy states, “abdominal malignancies, including non-metastatic primary pancreatic, biliary and adrenal cancers  the patient should be enrolled in either IRB approved clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED (coverage with evidence development).” The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Pediatric Non-Central Nervous System (CNS) Tumors 

Proton beam therapy (PBT) has been proposed for treatment of pediatric non-central nervous system (CNS) tumors. For pediatric non-central nervous system (CNS) tumors, scant data exist and consist of dosimetric planning studies and a few case series in a small number of patients.  Comparative effectiveness studies including randomized controlled trials are needed to document the theoretical advantages of PBT therapy over other radiotherapies. Current published evidence also does not allow for any definitive conclusions about the efficacy of PBT for this indication. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Prostate Cancer 

Proton beam therapy (PBT) has been proposed for the treatment of prostate cancer. The goal of proton beam therapy (PRT) is to achieve higher doses to small targets, with possibly greater benefit, and create similar to lower risk of adverse events compared with other treatments. In spite of the theory that protons cause less damage to normal tissue, there is at present no convincing evidence that urinary (bladder problems), gastrointestinal (rectal leakage or bleeding), or sexual (erectile dysfunction), complication rates are lower following proton beam radiation therapy (PBRT). A few studies suggest that rates of some side effects might even be higher.

 

A 2010 Blue Cross Blue Shield Association (BCBSA) TEC Assessment addressed the use of PBT (proton beam therapy) for prostate cancer and concluded that it has not yet been established whether PBT improves outcomes in any setting for clinically localized prostate cancer. A total of 9 studies were included in the review; 4 were comparative and 5 were non-comparative. There were 2 RCTs, and only one of these included a comparison group of patients who did not receive PBRT. Taking into account data from all 9 studies included in the review, the authors of the TEC Assessment concluded that there was inadequate evidence from comparative studies to permit conclusions about the impact of PBT on health outcomes. Ideally, RCTs would report long term health outcomes or intermediate outcomes that consistently predict health outcomes. No RTCs have been published since the TEC Assessment that compared health outcomes in patients treated with PBT versus patients treated by other RT modalities.

 

In 2014, the Agency of Healthcare Research and Quality (AHRQ) published a review of therapies for localized prostate cancer. This report was an update of a 2008 comparative effectiveness review. The authors compared risk and benefits of a number of treatments for localized prostate cancer including radical prostatectomy, EBRT (standard therapy as well as PBT (proton beam therapy), 3D-conformal RT (radiation therapy), IMRT (intensity modulated radiation therapy) and stereotactic body radiotherapy (SBRT)), interstitial brachytherapy, cryotherapy, watchful waiting, active surveillance, hormonal therapy, and high intensity focused ultrasound. The review concluded that the evidence for most treatment comparisons is inadequate to draw conclusions about comparative risks and benefits. Limited evidence appeared to favor surgery over watchful waiting or EBRT, and RT plus hormonal therapy over RT alone. The authors noted that there are advances in technology for many of the treatment options for clinically localized prostate cancer; for example, current RT protocols allows higher doses than those administered in many of the trials included in the report. Moreover, the patient population has changed since most of the studies were conducted. In recent years, most patients with localized prostate cancer are identified via prostate specific antigen (PSA) testing and may be younger and healthier than prostate cancer patients identified in the pre-PSA era. Thus, the authors recommend additional studies to validate the comparative effectiveness of emerging therapies such as PBT, robotic assisted surgery and SBRT.    

 

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of prostate cancer.  A 2010 Blue Cross Blue Shield Association (BCBSA) TEC Assessment addressed the use of PBT for prostate cancer and concluded that it has not yet been extablished whether PBT improves outcomes in any setting for prostate cancer.  Comparative effectiveness studies have been published in an attempt to compare toxicity and oncologic outcomes between photon and proton therapies. The largest retrospective comparative effectiveness analysis to date comparing IMRT (intensity modulated radiation therapy) to proton therapy was performed using SEER Medicare claims data for the following long-term endpoints: gastrointestinal morbidity, urinary incontinence, non-incontinence urinary morbidity, sexual dysfunction and hip fractures. With follow up as mature as 80 months and using both propensity scoring and instrumental variable analysis, the authors concluded that men receiving IMRT therapy had statistically significantly lower gastrointestinal morbidity than patients receiving proton therapy, whereas rates of urinary incontinence, non-incontinence urinary morbidity, sexual dysfunction, hip fractures, and additional cancer therapies were statistically undistinguishable between the cohorts. However, firm conclusions regarding differences in toxicity or effectiveness of proton and photon therapy cannot be drawn because of the limitations inherent in retrospective/observational studies.  There is no evidence that proton beam therapy (PBT) offers any advantages over other radiotherapy modalities when measured by survival, tumor control or toxicity. The 2017 ASTRO Model Policy guideline for proton beam therapy states, “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 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 within the context of prospective clinical trial or registry.” The current published evidence does not allow for any definitive conclusions regarding the efficacy of proton beam radiation therapy (PBRT) for the treatment of prostate cancer.  The evidence is insufficient to determine the effects of the technology on net health outcomes. 

 

Small Cell Lung Cancer 

Most patients with small cell lung cancer (SCLC) present with limited disease confined to the chest. SCLC is highly sensitive to initial chemotherapy and radiotherapy; however, most patients eventually die of recurrent disease. Proton beam therapy (PBT) has been proposed for the treatment of small cell lung cancer (SCLC).

 

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 small cell lung cancer (SCLC). Some of the studies regarding PBT 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 proton beam therapy, however, the magnitude of effect of PBT 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, PBT was used in combination with other therapies so results do not reflect the outcome of PBT alone. Further 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 small cell lung cancer (SCLC). The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of small cell lung cancer (SCLC). The ASTRO Model-Policy guideline for proton beam therapy states, 'thoracic malignancies including non-metastatic primary lung and esophageal cancers, and mediastinal lymphomas, the patient should be enrolled in either IRB approved clinical trial or in a multi-institutional patient registry adhering to the Medicare requirements for CED (coverage with evidence development). The evidence is insufficient to determine the effects of the technology on net health outcomes. 

 

Soft Tissue Sarcomas 

Soft tissue sarcomas (STS) constitute a heterogeneous group of solid tumors of mesenchymal cell origin with the distinct clinical and pathologic features; they are usually divided into two broad categories:

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

 

Prior to initiation of treatment, all patients should be evaluated and managed by a multidisciplinary team with extensive expertise and experience in the treatment of STS. Surgical resection is the standard of primary treatment for most patients with STS, and  radiation therapy may be administered either as preoperative or postoperative treatment.  Proton beam therapy (PBT) has been proposed for the treatment of soft tissue sarcomas (STS), specifically related to retroperitoneal and intra-abdominal soft tissue sarcomas (STS).

 

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) for the treatment of soft tissue sarcomas. 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 soft tissue sarcomas. The NCCN guideline states “new techniques such as intensity modulated radiation therapy (IMRT) and 3D conformal radiation therapy using protons or photons may allow tumor target coverage and acceptable clinical outcomes within normal tissue dose constraints to adjacent organs at risk. When external beam radiation therapy (EBRT) is used, sophisticated treatment planning with IMRT, tomotherapy and/or ptoon therapy can be used to improve therapeutic effect. However, the safety and efficacy adjuvant radiation techniques which includes proton therapy have yet to be evaluated in multicenter randomized controlled studies.” The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Testicular Cancer 

Proton beam therapy (PBT) has been proposed for the treatment of testicular cancer.

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the use of proton beam therapy (PBT) 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 for the treatment of patients with testicular cancer. The NCCN guideline does not mention or indicate the use of proton beam therapy for the treatment of testicular cancer. The evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Thymomas and Thymic Carcinoma 

Proton beam therapy (PBT) has been proposed for the treatment of 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).

 

In 2016 Vogel, et. al completed a prospective study of proton beam radiation therapy (PBRT) for adjuvant and definitive treatment of thymoma and thymic carcinoma: early response and toxicity assessment. Radiation is an important modality in treatment of thymic tumors, and toxicity may reduce its overall effect. They hypothesized that double-scattering proton beam therapy (DS-PT) can achieve excellent local control with limited toxicity in patients with thymic malignancies. Patients with thymoma or thymic carcinoma treated with DS-PT between 2011 and 2015 were prospectively analyzed for toxicity and patterns of failure on an IRB-approved study. Twenty-seven consecutive patients were evaluated. Patients were a median of 56 years and had thymoma (85%). They were treated with definitive (22%), salvage (15%) or adjuvant (63%) DS-PT to a median of 61.2/1.8 Gy [CGE]. No patient experienced grade 3 toxicity. Acute grade 2 toxicities included dermatitis (37%), fatigue (11%), esophagitis (7%), and pneumonitis (4%). Late grade 2 toxicity was limited to a single patient with chronic dyspnea. At a median follow-up of 2 years, 100% local control was achieved. Three-year regional control, distant control, and overall survival rates were 96% (95% CI 76-99%), 74% (95% CI 41-90%), and 94% (95% CI 63-99%), respectively. They concluded that this was the first cohort and prospective series of proton therapy to treat thymic tumors, demonstrating low rates of early toxicity and excellent initial outcomes.

 

In 2016 Parikh, et. al. completed a study on adjuvant proton beam therapy in the management of thymoma: a dosimetric comparison and acute toxicities. They evaluated the dosimetric differences between proton beam therapy (PBRT) and intensity modulated radiation therapy for resected thymoma and simultaneously reported an early clinical experience with PBRT in this cohort. They identified 4 patients with thymoma or thymic carcinoma treated at their center from 2012 to 2014 who completed adjuvant PBRT to a median dose of 57.0 cobalt Gy equivalents (CGE; range, 50.4-66.6 CGE) after definitive resection. Adjuvant radiation was indicated for positive (n = 3) or close margin (n = 1). Median age was 45 (range, 32-70) years. Stages included II (n = 2), III (n = 1), and IVA (n = 1). Analogous IMRT plans were generated for each patient for comparison, and preset dosimetric endpoints were evaluated. Early toxicities were assessed according to retrospective chart review.  Compared with IMRT, PBRT was associated with lower mean doses to the lung (4.6 vs. 8.1 Gy; P = .02), esophagus (5.4 vs. 20.6 Gy; P = .003), and heart (6.0 vs. 10.4 Gy; P = .007). Percentages of lung, esophagus, and heart receiving radiation were consistently lower in the PBRT plans over a wide range of radiation doses. There was no difference in mean breast dose (2.68 vs. 3.01 Gy; P = .37). Of the 4 patients treated with PBRT, 3 patients experienced Grade 1 radiation dermatitis, and 1 patient experienced Grade 2 dermatitis, which resolved after treatment. With a median follow-up of 5.5 months, there were no additional Grade ≥ 2 acute or subacute toxicities, including radiation pneumonitis. They concluded PBRT is clinically well tolerated after surgical resection of thymoma, and is associated with a significant reduction in dose to critical structures without compromising coverage of the target volume. Prospective evaluation and longer follow-up is needed to assess clinical outcomes and late toxicities.

   
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 therapy (PBT) 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 PBT for the treatment of thymomas and thymic carcinomas. Further randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of PBT for the treatment of patients with 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 evidence is insufficient to determine the effects of the technology on net health outcomes.

 

Proton Beam Therapy (PBT) for Other Abnormalities

Age Related Macular Degeneration (AMD) 

Age related macular degeneration (AMD) is a degenerative disease of the central portion of the retina (the macula) that results primarily in loss of central vision. AMD is classified as dry (atrophic) or wet (neovascular or exudative). Radiation therapy i.e. proton beam therapy has been proposed for the treatment of AMD as adjuvant therapy or as an alternative for individuals who decline or are not appropriate for approved therapies for AMD. External beam radiation therapy has also been studied in patients with AMD. A meta-analysis of randomized, controlled trials concluded that there was no consistent evidence of benefit, the long term safety and radiation therapy is unknown. The evidence is insufficient to determine the effects on net health outcomes, and therefore, proton beam radiation therapy for the treatment of age related macular degeneration is considered investigational.  

 

In 2015, the American Academy of Ophthalmology (AAO) preferred practice patterns do not address proton beam radiation therapy as a treatment option for age related macular degeneration (AMD), but does state that there is insufficient data to demonstrate clinical efficacy of radiation therapy in general.

 

Intracranial Arteriovenous Malformations

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 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 investigational for the treatment of intracranial arteriovenous malformations for other than small lesion(s) when surgery may be associated with increased risk based on anatomic locations or feeding vessel anatomy.    

 

Summary of Evidence

Proton beam radiation therapy (PBRT)/proton beam therapy (PBT) has been used to treat cancer since the 1950’s. Proponents of proton beam radiation therapy (PBRT) argue that this form of radiation therapy could have advantages over x-ray (photon) based radiation in certain clinical circumstances. However, based on review of the peer reviewed medical literature including 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 certain cancers, including but not limited to the following: prostate; bladder/genitourinary; gastric; pancreatic; abdominal; gynecologic (cervical, ovarian, uterine, vulvar); hepatobiliary (hepatocellular HCC, gallbladder, intrahepatic and extrahepatic cholangiocarcinoma); lung (non-small cell and small cell), Hodgkin's lymphoma and non-Hodgkin lymphoma (B-cell lymphomas); soft tissue sarcomas; colon and/or rectal; anal; breast; thymomas and thymic; testicular;  head and neck (except as indicated below in the policy criteria;  esophageal; non-uveal melanomas; bone (except as indicated below in the policy criteria); pediatric non-central nervous system tumors; central nervous system tumors (except as indicated below in the policy criteria); kidney and other abnormalities, including but not limited to the following: intracranial arteriovenous malformations (except as indicated below in the policy criteria) and age related macular degeneration.  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 using intensity modulated radiation therapy (IMRT) and proton beam radiation therapy (PBRT), however, the magnitude of effect of PBT 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, PBT was used in combination with other therapies so results do not reflect the outcome of PBT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of proton beam radiation therapy (PBRT).  The evidence is insufficient to determine the effects of the technology on net health outcomes and therefore is considered investigational including but not limited to those indications listed above. 

 

Also, advances in photon-based radiation therapy, such as  3-dimensional conformal radiotherapy, intensity modulated radiotherapy (IMRT), and stereotactic body radiotherapy, do allow for improved targeting of conventional radiation therapy that also minimize the dose delivery to surrounding normal tissues or organs at risk (OARs).

 

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) 

NCCN Guideline and VersionPrinciples of Radiation Therapy

Aids Related Kaposi Sarcoma Version 1.2018

For most skin lesions, electrons or superficial x-rays can be used to deliver optimal dosimetry and minimize dose to underlying structures. To ensure sufficient dose is delivered for deeper or larger lesions, conformal photon therapy or mixed photon-electron treatment plans may be utilized, IMRT (intensity modulated radiation therapy) with or without image guidance may be useful for larger lesions.

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

Anal Carcinoma Version 2.2018

  • 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.

 

  • SBRT (stereotactic body radiation therapy) after systematic therapy may be appropriate depending on response. SBRT can also be considered for treatment of primary nodal recurrence in the setting of low volume metastatic disease.

 

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

Bladder Cancer Version 5.2018

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 treatment modality.

Bone Cancer Version 1.2019

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 treatment modality.

Breast Cancer Version 1.2018

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 treatment modality.  

Central Nervous System Cancers Version 1.2018

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)

 

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

Cervical Cancer Version 1.2019

  • External beam radiation therapy (EBRT)
  • Brachytherapy
  • Intraoperative radiation therapy (IORT)

 

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

Colon Cancer Version 3.2018

  • 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 treatment modality.    

Rectal Cancer Version 3.2018

  • 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 ther 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 treatment modality.        

 

Esophageal and Esophagogastric Junction Cancers Version 2.2018

  • 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 therapya is appropriate in clinical settings where reduction in dose to organs at risk (e.g. heart, lungs) is required that cannot be achieved by 3-D techniques.

 

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

 

Gastric Cancer Version 2.2018

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 treatment modality.     

Head and Neck Cancers Version 2.2018

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, 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 sinsus; 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 2.2018

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). Image guided radiotherapy is strongly recommended when using EBRT, IMRT and 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.
  • 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.

 

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 does not indicate or define what specific situations or select settings PBT should be utilized 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 treatment modality. 

Hodgkin Lymphoma (Age > 18) Version 3.2018

  • 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 therapy (PBT) 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 4.2018

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 treatment modality.

Malignant Pleural Mesothelioma Version 2.2018

  • 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 therapy (PBT) should be utilized or the dosing.

Melanoma Cutaneous Version 3.2018

  • 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 treatment modality.     

Neuroendocrine and Adrenal Tumors Version 2.2018

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 treatment modality.     

B-Cell Lymphomas Version 4.2018

  • 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 therapy (PBT) 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 2.2018

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 treatment modality.     

T-Cell Lymphomas Version 5.2018

  • Treatment with photons, electrons, or protons may be appropriate, depending on the clinical circumstances
  • 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 non-Hodgkin lymphoma (B-cell lymphomas) does not include a discussion of specific dose or length of treatment considering the disease stage. _

Basal Cell Skin Cancer Version 1.2018

  • 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 (PBT) as a treatment modality.  

Merkel Cell Carcinoma Version 2.2018

  • 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 treatment modality.     

Squamous Cell Skin Cancer Version 2.2018

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 treatment modality.   

Non-Small Cell Lung Cancer Version 6.2018

  • 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 1.2019

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 treatment modality.     

Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 2.2018

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 treatment modality.    

Pancreatic Adenocarcinoma Version 2.2018

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 treatment modality.   

Penile Cancer Version 2.2018

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 treatment modality.

Prostate Cancer Version 4.2018

  • Highly conformal RT techniques should be used to treat localized prostate cancer.
  • Photon or proton beam radiation 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 Cell Lung Cancer Version 2.2018

  • 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 treatment modality.

Soft Tissue Sarcoma Version 2.2018

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

  • 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 2.2018

  • 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 treatment modality.

Thymomas and Thymic Carcinomas Version 2.2018

  • 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 paln.
  • 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 1.2018

  • 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 treatment modality.

Uterine Neoplasms Version 2.2018

  • 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 treatment modality.

Vulvar Cancer (Squamous Cell Carcinoma) Version 1.2018

  • 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.
  • Adequate dosing is crucial and can be accomplished with either 3D conformal approaches or intensity modulated radiation therapy (IMRT) as long as care is given to assure adequate dosing and coverage of tissues at risk for tumor involvement. 

 

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

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 Assocation (AUA)

In April 2017, American Urological Assocation (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.”

 

American Academy of Ophthalmology

In 2015, the American Academy of Ophthalmology issued preferred practice pattern guidelines regarding age related macular degeneration which states: “Current therapies that have insufficient data to demonstrate clinical efficacy include radiation therapy, acupuncture, electrical stimulation, macular translocation surgery, and adjunctive use of intravitreal corticosteroids with verteporfin PDT.  Therefore at this time these therapies are not recommended."

 

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)/proton beam therapy (PBT) is considered investigational, including but not limited to following indications:

  • Age related macular degeneration (AMD)
  • Anal carcinoma
  • Bladder cancer/genitourinary cancers (upper tract tumors, urothelial carcinoma, primary carcinoma of urethra)
  • Bone cancer (except for skull based chordoma or chondrosarcoma; and combined photon/proton radiation therapy for local control in patients with unresectable or incompletely resectable osteosarcoma)
  • Breast cancer
  • Central nervous system (CNS) cancers > 18 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 whose primary tumors are periocular in location and/or invade the orbit, skull base and/or cavernous sinus; extend intracranially or exhibit extensive perineural invasion)   
  • Hepatobiliary cancers
    • Hepatocellular carcinoma (HCC)
    • Gallbladder cancer
    • Intrahepatic and extrahepatic cholangiocarcinoma
  • Hodgkin’s lymphoma
  • Intracranial arteriovenous malformations (AVM) (except for
  • Kidney cancer
  • Lung cancer (including non-small cell and small cell and other lung cancers)
  • Non-Hodgkin Lymphoma (B-cell lymphomas)
  • Non-uveal melanomas
  • Pancreatic cancer
  • Pediatric non-central nervous (CNS) system tumors
  • Prostate cancer
  • Rectal cancer
  • Soft tissue sarcomas
  • Testicular cancer
  • Thymomas and thymic carcinomas 
  • Thyroid carcinomas

Proton beam radiation therapy (PBRT)/proton beam therapy (PBT) has been used to treat cancer since the 1950’s. Proponents of proton therapy argue that this form of radiation therapy could have advantages over photon based radiation in certain clinical circumstances. However, based on review of the peer reviewed medical literature including meta-analysis, systematic reviews, small retrospective and prospective studies and case series the evidence is insufficient, proton beam therapy (PBT) is not proven to be more beneficial than the standard of care alternatives (photon radiation) for the treatment of certain cancers and other abnormalities. Advances in photon-based radiation therapy, such as  3-dimensional conformal radiotherapy, intensity modulated radiotherapy (IMRT), and stereotactic body radiotherapy (SBRT), do allow for improved targeting of conventional radiation therapy that also minimize the dose delivery to surrounding normal tissues or organs at risk (OARs). Studies regarding PBRT/PBT primarily focus on treatment planning and dosimetric data comparing tumor coverage and tissue sparing; others compared external beam radiation therapy using intensity modulated radiation therapy (IMRT) and proton beam therapy, however, the magnitude of effect of PBRT/PBT 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/PBT was used in combination with other therapies so results do not reflect the outcome of PBRT/PBT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term efficacy of proton beam therapy (PBT). NCCN guidelines do not include or indicate the use of proton beam therapy as a radiation treatment modality for the majority of the indications listed above. If proton beam therapy is mentioned as a radiation treatment modality in an NCCN guideline recommendation the information may not indicate or define what specific situations or select setting PBRT/PBT should be utilized or the dosing. The evidence is insufficient to determine the effects of the technology on net health outcomes including but not limited to those indications listed above. 

 

Combined Therapies 

Proton beam radiation therapy (PBRT)/proton beam therapy (PBT) used in conjunction with intensity modulated radiation therapy (IMRT) known as intensity modulated proton therapy (IMPT) is considered investigational.

 

The clinical evidence is insufficient to support the combined use of these technologies in a single treatment plan. Comparative effectiveness studies including randomized controlled trials (RCTs) are needed to demonstrate safety and long-term efficacy of combined therapy. The evidence is insufficient to determine the effects of this technology on net health outcomes.

 

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

 

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  • 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
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    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   

 

Policy History:

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

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

 

*CPT® is a registered trademark of the American Medical Association.