Medical Policy: 08.01.05 

Original Effective Date: April 2001 

Reviewed: August 2016 

Revised: May 2017 

 

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) is a type of radiotherapy using protons rather than photons used in traditional external beam radiation therapy. Proton beam radiation therapy (PBRT) can be used in conjunction with standard treatment strategies like surgery, chemotherapy and even conventional photon beam radiotherapy. Treatment using proton beam radiation therapy (PBRT) has been proposed for the treatment of tumors or abnormalities, more often for the treatment of tumors that would benefit from the delivery of a high dose of radiation with a limited scatter.  Proton beam radiation therapy (PBRT), is also known as intensity-modulated proton therapy (IMPT), proton therapy and proton beam radiotherapy.

 

Photon beams deposit their greatest amount of energy beneath the patient’s surface with a gradual reduction in the energy deposition along the beam path as photons pass through the target and then through an exit point out of the body. In contrast, protons are positively charged, subatomic particles that deposit the bulk of their radiation energy at the end of their range of penetration (e.g. into the tumor). This peak of energy deposition is referred to as the Bragg peak. Beyond the Bragg peak, energy and dose deposition rapidly decrease, resulting in the absence of any significant exit dose deposited in normal tissue beyond the target.  Proton beam radiation therapy (PBRT) allows for targeted dosing of proton radiation to a particular tumor site or abnormality, with minimal dose delivery to surrounding normal tissue, theoretically offering an advantage over the delivery of photons. The theoretical advantages of proton beam radiation therapy (PBRT) may improve outcomes when the following conditions apply:

  • Conventional treatment modalities do not provide adequate local tumor control;
  • Evidence shows that local tumor response depends on the dose of radiation delivered; and
  • Delivery of adequate radiation doses to the tumor is limited by the proximity of vital radiosensitive tissue or structures.

However, 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).

     
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; it is also not indicated for use as a short term palliative procedure.

 

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. 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.

 

Prostate Cancer

Prostate cancer is typically detected based on digital rectal examination and screening with serum prostate specific antigen (PSA). Prostate cancer is diagnosed by biopsy and evaluated (staged) to determine the extent of disease (local, regional or distant metastatic). The most appropriate treatment options may include active surveillance, radical prostatectomy or radiation therapy using x-ray (photon) external beam radiotherapy and brachytherapy.

 

Proton beam radiation therapy (PBRT) has been proposed for the treatment of prostate cancer. The goal of proton beam radiation therapy (PBRT) 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 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, 3D-conformal RT, IMRT 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.    

 

National Comprehensive Cancer Network (NCCN), Prostate Cancer 2.2017

Principles of Radiation Therapy 

  • External Beam Radiation Therapy: Over the past several decades, radiation therapy (RT) techniques have evolved to allow higher doses of radiation to administer safely. Three dimensional (3D) conformal radiation therapy (3D-CRT) uses computer software to integrate CT images of the patient’s internal anatomy in the treatment position, which allows higher cumulative doses to be delivered with lower risk of late effects. The second generation 3D technique IMRT is used increasingly in practice because IMRT reduced the risk of gastrointestinal toxicities and rates of salvage therapy compared to 3D CRT in some but not all studies.   
    • EBRT is one of the principal treatment options for clinically localized prostate cancer. NCCN Guidelines Panel consensus was that modern EBRT and surgical series show similar progression free survival in patients with low risk disease treated with radical prostatectomy or EBRT.   
    • EBRT has demonstrated efficacy in patients at high risk and very high risk.
  • Brachytherapy: Brachytherapy is used traditionally for low risk cases since earlier studies found it less effective than EBRT for high risk disease. However, increasing evidence suggests that technical advancements in brachytherapy may provide a role for contemporary brachytherapy in high-risk localized and locally advanced prostate cancer. Brachytherapy involves placing radioactive sources into the prostate tissue. There are currently two methods for prostate brachytherapy: low dose rate (LDR) and high dose rate (HDR).
  • Proton Therapy: Proton therapy and x-ray based therapies like IMRT can deliver highly conformal doses to the prostate. Proton based therapies will deliver less radiation dose to some of the surrounding normal tissues like muscle, bone, vessels, and fat not immediate adjacent to the prostate. These tissues do not routinely contribute to the morbidity of prostate radiation, are relatively resilient to radiation injury, and so the benefit of decreased dose to these types of normal, non-critical tissues has not been apparent. The critical normal structures adjacent to the prostate that can create prostate cancer treatment morbidity include bladder, rectum, neurovascular bundles, and occasionally small bowel.

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

 

The NCCN guideline regarding proton therapy for prostate cancer refers to ASTRO’s current position which states that “proton beam therapy for primary treatment of prostate cancer should only be performed within the context of a prospective clinical trial or within prospective registries.”  The NCCN panel believes there is no clear evidence supporting a benefit or decrement to proton therapy over IMRT for either treatment efficacy or long term toxicity.

 

Summary 

Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of prostate cancer.  A 2010 Blue Cross Blue Shield Association (BCBSA) TEC Assessment addressed the use of PBRT for prostate cancer and concluded that it has not yet been extablished whether PBRT 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 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 radiation therapy (PBRT) offers any advantages over other radiotherapy modalities when measured by survival, tumor control or toxicity. The 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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of prostate cancer and therefore is considered investigational. 

 

Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death in the United States. However, much progress has been made recently for lung cancer such as screening, minimally invasive techniques for diagnosis and treatment, and advances in radiation therapy (RT) including stereotactic ablative radiotherapy (SABR), targeted therapies and immunotherapies. The primary risk factor for lung cancer is smoking tobacco, which accounts for most lung cancer related deaths. Other possible risk factors for lung cancer include disease history (e.g. COPD), cancer history, family history of lung cancer, and exposure to other carcinogens. Proton beam radiation therapy (PBRT) 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 PBRT 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.

 

National Comprehensive Cancer Network (NCCN) Non-Small Cell Lung Cancer Version 5.2017

Principles of Radiation Therapy 

  • Determination of the appropriateness of radiation therapy (RT) should be made by board certified radiation oncologists who perform lung cancer RT as a prominent part of their practice.
  • RT has a potential role in all states of NSCLC as either definitive or palliative therapy.
  • The critical goals of modern RT are to maximize tumor control and to minimize treatment toxicity.
  • 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, intensity modulated radiation therapy (IMRT)/volumetric modulated Arc Therapy (VMAT), image guided RT (IGRT), motion management, and proton therapy. Nonrandomized comparisons of using advanced technologies versus older technologies demonstrate reduced toxicity and improved survival.
  • SABR (stereotactic ablative radiation therapy, also known as stereotactic body radiation therapy SBRT) is recommended for patients who are medically inoperable or who refused to have surgery after thoracic surgery evaluation. SABR is also an appropriate option for patients with high surgical risk (able to tolerate sublobar resection but not lobectomy (e.g. age ≥ 75 years; poor lung function).

Radiation Therapy Stimulation, Planning and Delivery 

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

Summary
Based on review of the peer reviewed medical literature there is insufficient evidence to draw conclusions about the safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of non-small cell lung cancer (NSCLC). A 2010 Blue Cross Blue Shield Association (BCBSA) TEC Assessment addressed the use of PBRT for non-small cell lung cancer and concluded that it has not yet been established whether PBRT 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 states for thoracic malignancies 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). 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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of non-small cell lung cancer (NSCLC). 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with non-small cell lung cancer. Therefore, proton beam radiation therapy (PBRT) for the treatment of non-small cell lung cancer is considered investigational.

 

Small Cell Lung Cancer

Neuroendocrine tumors account for approximately 20% of lung cancers; most (approximately 14%) are small cell lung cancer (SCLC). In 2017, an estimated 31,000 new cases of SCLC will occur in the United States. Nearly all cases of SCLC are attributed to cigarette smoking. Although the incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1. SCLC is characterized by a rapid doubling time, high growth fraction, and early development of widespread metastases. Most patients with 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 radiation therapy (PBRT) has been proposed for the treatment of small cell lung cancer (SCLC).

 

National Comprehensive Cancer Network (NCCN) Small Cell Lung Cancer Version 3.2017

Principles of Radition Therapy 

  • Radiation therapy has a potential role in all stages of SCLC as part of either definitive or palliative therapy.  Radiation oncology input, as part of a multidisciplinary evaluation of discussion, should be provided for all patients in the determination of the treatment strategy. 
  • To maximize tumor control and to minimize treatment toxicity, critical components of modern RT include appropriate simulation, accurate conformal RT planning, and ensuring accurate delivery of the planned treatment.  A minimum standard is CT-planned 3D conformal RT. Multiple fields should be used with all fields treated each day. 
  • 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, intensity modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT), image guided radiation therapy (IGRT), and motion management strategies. 

 

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of small cell lung cancer (SCLC). 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and 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 for thoracic malignancies 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). Therefore, proton beam radiation therapy (PBRT) for the treatment of small cell lung cancer (SCLC) is considered investigational. 

 

Head and Neck Cancers, (Other than Skull Based Chordoma or Chondrosarcoma)

In 2017, it is estimated that about 63,030 new cases of oral cavity, pharyngeal, and laryngeal cancers will occur, which account for about 3.7% of new cancer cases in the United States. An estimated 13,360 deaths from head and neck cancers will occur during this time period. Squamous cell carcinoma or a variant is the histologic type in more than 90% of these tumors. Alcohol and tobacco abuse are common etiologic factors in cancers of the oral cavity, oropharynx, hypopharynx, and larynx. Because the entire aerodigestive tract epithelium may be exposed to these carcinogens, patients with head and neck cancers are at risk for developing second primary neoplasms of the head and neck, lung, esophagus, and other sites that share these risk factors.     

 

Human papillomavirus (HPV) infection is now well accepted as a cause of squamous cancers of the oropharynx (particularly cancers of the tonsils and tongue base). The overall incidence of HPV-positive head and neck cancers is increasing in the United States, while the incidence of HPV-negative (primarily tobacco and alcohol related) cancer is decreasing. Patients with HPV-associated head and neck cancer tend to be younger. Oral HPV type 16 and infection increases risk of oropharyngeal cancer and a strong causal relationship has been established. HPV types of 18, 31 and 33 are responsible for the vast majority of the remaining fraction.

 

Treatment is complex for patients with head and neck cancers. The specific site of disease, stage, and pathologic findings guide treatment (e.g. the appropriate surgical procedure, radiation targets, dose and fractionation, indications for systemic therapy). Single modality treatment with surgery or radiation therapy (RT) is generally recommended for the approximately 30% to 40% of patients who present with early stage disease (stage I or II). The two most commonly employed modalities, surgery and RT, result in similar survival in these individuals. Proton beam radiation therapy (PBRT) has been proposed for the treatment of head and neck cancers, (other than skull based tumors chordoma or chondrasarcoma). 

 

Head and neck cancers arise from a variety of sites within the head and neck region, which is divided into five basic areas:

  • The oral cavity includes the lips, buccal mucosa, anterior tongue, floor of the mouth, hard palate, upper gingiva, lower gingiva, and retromolar trigone.
  • The pharynx is divided into the oropharynx, the nasopharynx, and the hypopharynx.
    • The nasopharynx, the narrow tubular passage behind the nasal cavity, is the upper part of the pharynx.
    • The oropharynx, the middle part of the pharynx, includes the tonsillar area, tongue base, soft palate, and posterior pharyngeal wall.
    • The hypopharynx, the lower part of the pharynx, includes the pyriform sinuses, the posterior surface of the larynx (postcricoid area), and the inferoposterior and inferolateral pharyngeal walls.
  • The larynx contains the vocal cords and epiglottis. It is divided into three anatomic regions: the supraglottic larynx, the glottic larynx (true vocal cords, and the anterior and posterior commissures), and the subglottic larynx.
  • The nasal cavity and the paranasal sinuses include the maxillary, ethmoid, sphenoid, and frontal sinuses.
  • The major salivary glands (parotid, submandibular, and sublingual) and the minor salivary glands are located throughout the submucosa of the mouth and upper aerodigestive tract, including the oral cavity (especially the palate), paranasal sinuses, larynx, and pharynx 

National Comprehensive Cancer Network (NCCN) Head and Neck Cancers Version 2.2017

  • The NCCN guidelines for head and neck cancers address tumors arising in the lip, oral cavity, pharynx, larynx and paranasal sinuses; occult primary cancer, salivary gland cancer, and mucosal melanoma are also addressed.
  • The initial evaluation and development of a plan for treating the patient with head and neck cancer requires a multidisciplinary team of health care providers with expertise in caring for these patients.

Radiation Techniques 

  • Target delineation and optimal dose distribution experience in head and neck imaging and thorough understanding of patterns of disease spread. Intensity modulated radiation therapy (IMRT) or other conformal techniques (3-D conformal, 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.
  • 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 (volume modulated arc therapy) are advanced forms of IMRT.
  • Proton Beam Therapy (PBT): Achieving highly conformal dose distributions is especially important for patients who primary tumors are periocular in location and/or invade the orbit, skull base, and/or cavernous sinus; extend intracranially or exhibit extensive perineural invasion; and who are being treated with curative intent and/or who have long life expectancies following treatment. Non-randomized single institution clinical reports and systematic comparisons demonstrate safety and efficacy of proton beam therapy in the above mentioned specific clinical scenarios.    

Intensity modulated radiation beam (IMRT) can be modulated to decrease doses to normal structures without compromising the doses to the cancer targets. Over the last 15 years, IMRT has displaced other techniques in the treatment of most head and neck malignancies. IMRT is an advanced form of conformal RT permitting more precise cancer targeting while reducing dose to normal tissues. IMRT is now widely used in head and neck cancers and is the predominant techniques used at NCCN member institutions. It is useful in reducing long term toxicity in oropharyngeal, paranasal sinus, and nasopharyngeal cancers by reducing the dose to one or more major salivary glands, temporal lobes, mandible, auditory structures (including cochlea), and optic structures.

 

At present, proton beam therapy is the predominant particle therapy under active clinical investigation in the United States. Proton therapy has been used to treat oropharyngeal cancers, sinonasal malignancies, adenoid cystic carcinomas and MMs (mucosal melanomas). A systematic review and meta-analysis of non-comparative observation studies concluded that patients with malignant diseases of the nasal cavity and paranasal sinuses who received proton therapy appears to have better outcomes than those receiving photon therapy. A review of proton therapy in patients with head and neck cancers included 14 retrospective reviews and 4 prospective nonrandomized studies. The 2 to 5 year local control rates were as low as 17.5% for T4 or recurrent paranasal sinus cancers and as high as 95% in other types of tumors.

 

In institutional reports, outcomes for proton therapy have been reported. Recent reports show that proton beam therapy (PBT) for the treatment of sinonasal cancer is associated with good locoreginal control, freedom from distant metastasis, and acceptable toxicity. Another recent institutional report (N=41) showed that PBT may be associated with greater normal tissue sparing without sacrificing target coverage, which may be associated with reduced toxicity compared to IMRT.

 

Results from retrospective study comparing 40 patients with cancer of the nasopharynx, nasal cavity, or paranasal sinuses who received either PBT or IMRT to the head and neck (with or without chemotherapy) showed that PBT was associated with lower mean doses to the oral cavity, esophagus, larynx, and parotid glands, regardless of nodal status and compared to IMRT. PBT was also associated with less dependence on opioid pain medication and gastrostomy tube placement, compared to IMRT.

 

Occasional fatal outcomes have been reported with proton therapy include 3 deaths to brainstem injury. Long term toxicities have been reported after proton therapy with nasal cavity, paranasal sinus or skull based malignancies.

 

As described above, nonrandomized institutional reports and a small number of systemic reviews have shown that PBT may be safe to use in some settings for head and neck cancers. In patients with tumors that are periocular in location and/or invade the orbit, skull base, and/or cavernous sinus, and tumors that extend intracranially or exhibit extensive perineural invasion, as well as in patients being treated with curative intent and/or have long life expectancies, achieving highly conformal dose distribution is crucial. An accurate comparison of benefits to other RT options should ideally take place in the controlled setting of randomized clinical trials.

 

Summary

There has been interest in the use of proton beam radiation therapy (PBRT) for the treatment of selected patients with head and neck cancer over the last decade with several trials published in peer reviewed medical literature over this period of time describing the safety and efficacy of this treatment modality in this patient population. The initial data are encouraging with good local control rates and low toxicity rates reported in most patients. However, the data is difficult to interpret due to a variety of treatment techniques and doses used as well as small patient numbers with limited follow-up times and outcomes reporting. Therefore, most investigators recommend additional study of the long-term safety and efficacy of protons in this clinical setting before adopting this technology as a standard treatment option for the treatment of patients with head and neck cancers (other than skull based tumors chordoma or chondrosarcoma). There is insufficient evidence to permit conclusions as to whether or not the use of protons in this specific clinical setting improves net health outcomes in comparison with standard radiation therapy techniques with photons. The ASTRO Model-Policy guideline for proton beam therapy states for head and neck malignancies 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 current published evidence does not allow for any definitive conclusions about the safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of head and neck cancers (other than skull based chordoma and chondrasarcoma) and therefore is considered investigational.

 

Note: Based on the NCCN guideline version 2.2017, non-randomized single institution clinical reports and systematic comparisons found proton beam radiation therapy (PBRT) to be considered safe and effective in patients with primary tumors that are periocular in location and/or invade the orbit, skull base, and/or cavernous sinus; extend intracranially or exhibit extensive perineural invasion; and who are being treated with curative intent and/or who have long life expectancies following treatment. Therefore, proton beam radiation therapy (PBRT) may be considered medically necessary for the treatment of head and neck cancers that meet the above criteria. However, proton beam radiation therapy (PBRT) for the treatment of all other head and neck cancers (other than skull based chordoma and chondrasarcoma) that do not meet this criteria will be considered investigational as stated above.  

 

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

Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. Primary brain tumors range from pilocytic astrocytomas, which are very uncommon, noninvasive, and surgically curable, to glioblastoma multiforme, the most common intraparenchymal brain tumor in adults, which is highly invasive and virtually incurable. Likewise, patients with metastatic brain disease may have rapidly progressive systemic disease or no systemic cancer at all. These patients may have one or dozens of brain metastases, and they may have a malignancy that is highly responsive or, alternatively, highly resistant to radiation therapy (RT) or chemotherapy. Because of this marked heterogeneity, the prognostic features and treatment options for brain tumors must be carefully reviewed on an individual basis and communicated to each patient. In addition, CNS tumors are associated with a range of symptoms and complications such as edema, seizures, endocrinopathy, fatigue, psychiatric disorders, and venous thromboembolism that can seriously impact patients’ quality of life. The involvement of an interdisciplinary team including neurosurgeons, RT therapists, oncologists, neurologists, or neurodiologists, is a key factor in the appropriate management of these patients.  Proton beam radiation therapy (PBRT) has been proposed for the treatment of central nervous system cancers.

 

National Comprehensive Cancer Network (NCCN) Central Nervous System Cancers Version 1.2016

Treatment Principles

  • Radiation oncologists use several different treatment modalities in patients with primary brain tumors, including brachytherapy, fractionated stereotactic RT, and stereotactic radiosurgery (SRS). Standard fractionated external beam radiation therapy (EBRT) is the most common approach, while hypofractionation is emerging as an option for select patients (i.e. elderly and patients with compromised performance). RT for patients with primary brain tumors is administered within a limited field (tumor and surround), while whole brain RT (WBRT) and SRS are used primarily for brain metastases.  

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of central nervous system cancers. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with central nervous system cancers. Therefore, proton beam radiation therapy (PBRT) for the treatment of central nervous system cancers tumors or lesions that are not adjacent to critical structures such as the optic nerve, brain stem or spinal cord is considered investigational.

 

Pediatric Non-CNS Tumors

Proton beam radiation therapy (PBRT) has been proposed for treatment of pediatric non-CNS tumors. For pediatric non-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 proton beam radiation therapy (PBRT) over other radiotherapies. Current published evidence also does not allow for any definitive conclusions about the safety and efficacy of proton beam radiation therapy (PBRT) for this indication and therefore is considered investigational.

 

Esophageal Cancer

Esophageal cancer is the 6th most common cause of cancer death worldwide and is more common in men.  Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma. SCC seems to be more sensitive to chemotherapy, chemoradiation, and radiation therapy than adenocarcinoma, but the long term outcomes appear to be the same. Tobacco and alcohol abuse are major risk factors for SCC, whereas the use of tobacco is moderate established risk factor for adenocarcinoma. Obesity and high body mass index (BMI) have been established as strong risk factors for adenocarcinoma of the esophagus. Gastroesophageal reflux disease (GERD) and Barrett’s esophagus are the other two major risk factors for adenocarcinoma of the esophagus. Patients with adenocarcinoma and SCC of the esophagus are also at increased risk of developing second primary cancers such as head and neck and lung cancers.  Proton beam radiation therapy (PBRT) has been proposed for the treatment of esophageal cancer.     

 

In 2015, Wang et. al. published a retrospective study comparing passive-scatter proton beam radiation therapy (PBRT) versus intensity modulated radiation therapy (IMRT) for reducing heart/lung dose in espophageal cancer, and to identify anatomy and treatment planning parameters that can lead to suboptimal proton plans. Passive scatter PBRT versus IMRT mean doses and coverage to the lung/heart were evaluated for 55 patients with esophageal cancer from 2007 to 2010. In conclusion, the study suggests that passive-scattering PBRT using a left lateral/PA beam approach with 1:2 weighting is superior to IMRT for lowing both mean heart and lung doses and should be considered as a treatment planning approach for reducing radiation-induced cardiopulmonary toxicities in esophageal cancer. However, IMRT may be superior to PBRT for smaller normal tissue volumes receiving higher doses of radiation. Future studies evaluating which dosimetric parameters (V5, V40, or mean heart/lung dose, among others) have the greatest effect on late cardiopulmonary morbidity are needed to determine whether IMRT versus PBRT should be used on an individualized patient basis. Long term clinical data on pulmonary/cardiac toxicities are also needed to validate these theoretic dosimetric advantages.

 

Retrospective studies comparing three dimensional (3D) conformal vs. IMRT for patients with esophageal cancer have generally shown superior dose conformity and homogeneity with IMRT and reduction of RT dose to the lungs and heart.

 

National Comprehensive Cancer Network (NCCN) Esophageal and Esophagogastric Junction Cancers Version 1.2017

Principles of Radiation Therapy (RT) 

  • Treatment recommendations should be made after joint consultation and/or discussion by a multidisciplinary team including surgical, radiation and medical oncologists, radiologists, gastroenterologists, and pathologists.
  • CT scan, barium swallow, endoscopic ultrasound (EUS), endoscopy reports, and PET or PET/CT scans, when available should be reviewed by the multidisciplinary team. This will allow an informed determination of treatment volume and field borders prior to simulation.
  • All available information from pre-treatment diagnostic studies should be used to determine the target volume.

Simulation and Treatment Planning 

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

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of esophageal cancer. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with esophageal cancer. The NCCN guideline states that proton beam radiation therapy (PBRT) is early and evolving, ideally, patients with esophageal cancer should be treated with proton beam radiation therapy (PBRT) within a clinical trial. The ASTRO Model – Policy guideline for proton beam therapy states for head and neck malignancies and gastrointestinal carcinomas 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). Therefore, proton beam radiation therapy (PBRT) for the treatment of esophageal cancer is considered investigational.

 

Gastric Cancers

Upper gastrointestinal (GI) tract cancers originating in the esophagus, esophagogastric junction (EGJ), and stomach constitute a major health problem around the world. A dramatic shift in the location of upper GI tract tumors has occurred in the United States,  the proximal lesser curvature, cardia and the EGJ are the most common sites of gastric cancer. In 2016 it was estimated 26, 370 people would be diagnosed and 10,730 people would eventually die of the disease in the United States. Gastric cancer is often diagnosed at an advanced stage. It continues to pose a major challenge for health care professionals. Environmental risk factors include Helicobacter pylori (H. pylori) infection, smoking, high salt intake, and other dietary factors. In a recent meta-analysis there was no appreciable association between moderate alcohol drinking and gastric cancer risk; however, there was a positive association with heavy alcohol drinking, particularly for non-cardia gastric cancers.

 

While most gastric cancers are considered sporadic, it is estimated that 5% to 10% have a familial component and 3% to 5% are associated with inherited cancer predisposition syndromes. The most common hereditary cancer predisposition syndromes include the following: hereditary diffuse gastric cancer (HDGC), Lynch syndrome, juvenile polyposis syndrome (JPS), Peutz Jeghers syndrome (PFS), and familial adenomatous polyposis.

 

Radiation therapy (RT) has been assessed in randomized trials in both the preoperative and post-operative setting in patients with resectable gastric cancer. Intensity modulated radiation therapy (IMRT) has the potential to reduce radiation related toxicity by delivering large doses of RT to target tissues. Several retrospective studies have demonstrated the feasibility of IMRT in the treatment of localized and advanced gastric cancer. Radiation therapy (preoperative, postoperative, or palliative) can be an integral part of treatment for gastric cancers.  Proton beam radiation therapy (PBRT) has been proposed for the treatment of gastric cancers.

 

National Comprehensive Cancer Network (NCCN) Gastric Cancer Version 1.2017

Principles of Radiation Therapy

  • Treatment recommendations should be made after joint consultation and/or discussion by a multidisciplinary team including surgical, radiation, medical oncologists, gastroenterologists, and pathologists.
  • CT scans, EUS endoscopy reports, and PET or PET/CT scans, when available should be reviewed by the multidisciplinary team. This will allow an informed determination of treatment volume and field borders prior to simulation.
  • All available information from pre-treatment diagnostic studies should be used to determine the target volume.
  • Image guidance may be used appropriately to enhance clinical targeting.

Simulation and Treatment Planning

  • CT simulation and conformal treatment planning should be used. Intensity modulated radiation therapy (IMRT) may be used in clinical settings where 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 device 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.

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of gastric cancer. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with gastric cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for gastric cancer.   The ASTRO Model-Policy guideline for proton beam therapy states for gastrointestinal carcinomas and abdominal malignancies 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). Therefore, proton beam radiation therapy (PBRT) for the treatment of gastric cancer is considered investigational.  

 

Pancreatic Adenocarcinoma

During the year of 2017 in the United States, an estimated 53,670 people will be diagnosed with pancreatic cancer and approximately 43,090 people will die of pancreatic cancer. This disease is the fourth most common cause of cancer-related death among United States men (after lung, prostate and colorectal cancer) and women (after lung, breast and colorectal cancer). Although incidence is roughly equal in both sexes, African Americans have a higher incidence of pancreatic cancer than white Americans. Furthermore, the incidence of pancreatic cancer in the United States has increased, possibly because of the increasing prevalence of obesity, an aging population and other unknown factors. Mortality rates have remained largely unchanged.

 

Risk factors associated with pancreatic cancer include cigarette smoking, exposure to chemicals and heavy metals, heavy alcohol consumption, an increased body mass index (BMI), chronic pancreatitis, and diabetes. Pancreatic cancer is thought to have a familial component in approximately 10% of cases, and familial excess of pancreatic cancer is associated with high risk.

 

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 (PBRT) has been proposed for the treatment of pancreatic cancer.

 

National Comprehensive Cancer Network (NCCN) Pancreatic Adenocarcinoma Version 2.2017

Principles of radiation therapy

  • Patients with pancreatic cancer are best managed by a multidisciplinary team.
  • Stereotactic body radiotherapy (SBRT) should be avoided if direct invasion of bowel or stomach is observed on CT, MRI or endoscopy.
  • Recommendations for radiation therapy (RT) for such patients are typically based upon five clinical scenarios:
    • Resectable/borderline resectable (neoadjuvant)
    • Locally advanced/unresectable (definitive)
    • Resectable (adjuvant)
    • Palliative (non-metastatic and metastatic)
    • Recurrent
  • In all scenarios, the goal of delivering RT is to sterilize vessel margins, and enhance the likelihood of a margin-negative resection, and provide adequate local control to prevent or delay progression of local disease while minimizing the risk of RT exposure to surrounding organs 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.

Simulation, Motion Management and Treatment Planning 

  • For localized pancreatic cancer (neoadjuvant, borderline, and unresectable) placement of 1-5 (preferably ≥ 3) gold fiducial markers is recommended for targeting purposes.
  • CT simulation should be done with IV and oral contrast.
  • For body and tail lesions it may be ideal to simulate with an empty stomach to increase the separation from the tumor. Ideally, the patient should be given the same volume of water prior to treatment each day to mimic simulation anatomy.
  • Respiratory motion should be accounted for determining the internal target volume during a 4D-CT scan, breath-hold with active breathing control (ABC) or compression device.
  • Motion management using respiratory gating or breath-hold, respiratory tracking, or abdominal compression should be used to reduce cranio-caudal fiducial location during treatment.
  • 3-D conformal RT (3D-CRT), intensity modulated radiation therapy (IMRT), and stereotactic body radiation therapy (SBRT) with breath-hold/gating techniques can result in improved planning target volume (PTV) coverage with decreased dose to OARs.

Dose and Fractionations 

  • It is imperative to evaluate the dose-volume histogram (DVH) of the PRV and the critical OARs such as the duodenum, stomach, liver, kidneys, spinal cord, and bowel. No clear dose constraints for SBRT currently exist but are emerging.

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of pancreatic cancer. 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, however, the magnitude of effect of PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with pancreatic cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of pancreatic cancer. The ASTRO Model-Policy guideline for proton beam therapy states for abdominal malignancies 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). Therefore, proton beam radiation therapy (PBRT) for the treatment of pancreatic cancer is considered investigational.

 

Hepatocellular Carcinoma

Hepatobiliary cancers are highly lethal cancers including a spectrum of invasive carcinomas arising 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.

 

Risk factors for the development of HCC, the most common of the hepatobiliary malignancies, include viral infections caused by hepatitis B virus (HBV) and/or hepatitis C virus (HCV), particular comorbidities or conditions, and certain external sources. Non-viral causes associated with an increased risk for HCC include alcoholic cirrhosis, inherited errors of metabolism (relatively rare) such as hereditary hemochromatosis, porphyria cutanea tarda, and alpha-1 antitrypsin deficiency, Wilson’s disease, and stage IV primary biliary cirrhosis.

 

The incidence of HCC is increasing in the United States, particularly in the population infected with HCV. Approximately 4 million individuals in the United States are chronically infected with HCV, and the annual incidence rate of HCC among patients with HCV related cirrhosis has been estimated between 2% and 8%.  Although it has been reported that the number of cases of hepatitis C infection diagnosed per year in the United States is declining, it is likely that the observed increase in the number of cases of HCV related HCC is associated with the often prolonged period between viral infection and the manifestation of HCC.

 

All patients with HCC should be carefully evaluated for treatment considerations. The management of patients with HCC is complicated by the presence of underlying liver disease. The treatment of patients with HCC often necessitates the involvement of hepatologists, cross-sectional radiologists, interventional radiologists, transplant surgeons, pathologists, medical oncologists, and surgical oncologists.  Proton beam radiation therapy has been proposed for the treatment of hepatocellular carcinoma (HCC).

 

National Comprehensive Cancer Network (NCCN) Hepatobiliary Cancers Version 1.2017

Principles of Locoregional Therapy

  • External beam radiation therapy (EBRT) is a treatment option (category 2B) for patients with unresectable disease, or for those who are medically inoperable due to comorbidity.
  • All tumors, irrespective of their location, may be amendable to radiation therapy (3D conformal radiation therapy, intensity modulated radiation therapy (IMRT), or stereotactic body radiation therapy (SBRT).
  • Hypofractionation with photons or protons is an acceptable option for intrahepatic tumors, though treatment at centers with experience is recommended.
  • SBRT is an advanced technique of hypofractionated EBRT with photons, there is a growing evidence for the usefulness of SBRT in the management of patients with HCC.
  • Proton beam therapy (PBT) may be appropriate in specific situations. 
  • Palliative EBRT is appropriate for symptom control and/or prevention of complications from metastatic HCC lesions, such as bone or brain.

NCCN Recommendation for Locoregional Therapies

The consensus of the panel is that liver resection or transplantation, if feasible, is preferred for patients who meet surgical or transplant selection criteria since these are established potentially curative therapies. Locoregional therapy (e.g. ablation, arterially-directed therapies, and EBRT) is the preferred treatment approach for patients who are not amendable to surgery or liver transplantation. Systemic therapy with sorafenib can also be considered. The panel recommends that SBRT can be considered as an alternative to ablation and/or embolization techniques or when these therapies have failed or are contraindicated (in patients with unresectable disease characterized as extensive or otherwise not suitable for liver transplantation and those with local disease but who are not considered candidates for surgery due to performance status or comorbidity). Palliative EBRT is appropriate for symptom control and/or prevention of complications from metastatic HCC lesions in bone or brain.       

 

The NCCN recommendation regarding the use of proton beam radiation therapy (PBRT) for the treatment of hepatocellular carcinoma does not include a discussion of specific dose, length of treatment or the specific situations in which proton beam radiation therapy (PBRT) may be appropriate in a patient with hepatocellular carcinoma.

  

Summary

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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of hepatocellular carcinoma (HCC). 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with hepatocellular carcinoma (HCC). The NCCN recommendation regarding the use of proton beam radiation therapy (PBRT) for the treatment of hepatocellular carcinoma does not include a discussion of specific dose or length of treatment. Therefore, proton beam radiation therapy (PBRT) for the treatment of hepatocellular carcinoma (HCC) is considered investigational. 

 

Kidney Cancer

Renal cell carcinoma (RCC) comprises approximately 3.8% of all new cancers, with a median age at diagnosis of 64 years. Approximately 90% of renal tumors are renal cell carcinoma, and approximately 80% of these are clear cell tumors. Smoking and obesity are established risk factors for RCC development. Several hereditary types of RCC also exist, with von Hippel-Lindau (VHL) disease being the most common.

 

Surgical resection remains an effective therapy for clinically localized renal cell carcinoma (RCC), with options including radical nephrectomy and nephron sparing surgery. Active surveillance and ablative techniques such as cryo or radiofrequency ablation are alternative strategies for selected patients, particularly the elderly and those with competing health risks. Proton beam radiation therapy (PBRT) has been proposed for the treatment of kidney cancer.

 

National Comprehensive Cancer Network (NCCN) Kidney Cancer Version 2.2017

Treatment of Localized Disease

  • Surgical resection remains an effective therapy for clinically localized RCC, with options including radical nephrectomy and nephron-sparing surgery.
  • Active surveillance and ablative techniques such as cyro or radiofrequency ablation are alternative strategies for selected patients, particularly the elderly and those with competing health risks.

Management of Advanced or Stage IV Disease

  • Patients with stage IV disease also may benefit from surgery.
  • Primary treatment of relapsed or stage IV disease and surgically unresectable disease – cytoreductive nephrectomy before systemic therapy is generally recommended in patients with a potentially resectable primary tumor mass.    

Supportive Care

  • Supportive care remains the mainstay of therapy for all patients with metastic renal cell carcinoma (RCC). This includes surgery for patients with solitary brain metastasis whose disease is well controlled extracranially. Stereotactic radiotherapy, if available, is an alternative to surgery for limited brain metastasis, and whole brain irradiation is recommended for patients with multiple brain metastasis.
  • Bone metastasis occurs in 30% to 40% of patients with advanced RCC. Bone lesions in patients with RCC are typically osteolytic and cause considerable morbidity, leading to skeletal-related events (SREs), including bone pain with need for surgery or radiotherapy, hypercalcemia, pathologic fractures, and spinal cord compression. Two studies of patients with bone metastases showed an improvement in bone pain using different radiotherapy modalities.     

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of kidney cancer. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with kidney cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of kidney cancer. The ASTRO Model-Policy guideline for proton beam therapy states for abdominal malignancies 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). Therefore, proton beam radiation therapy (PBRT) for the treatment of kidney cancer is considered investigational.

 

Gynecological Cancers  (Cervical, Uterine, Ovarian, Vulvar)

Cervical Cancer

Cervical cancer rates are decreasing among women in the United States, although incidence remains high among Hispanic/Latino, Black and Asian women. Cervical cancer is a major health problem for women, it is the fourth most common cancer in women worldwide. Persistent human papillomavirus (HPV) infection is the most common factor in the development of cervical cancer. Other epidemiologic risk factors associated with cervical cancer are a history of smoking, oral contraceptive use, early age of onset of coitus, larger number of sexual partners, history of sexually transmitted disease, certain autoimmune diseases, and chronic immunosuppression.

 

Squamous cell carcinomas account for approximately 80% of all cervical cancers and adenocarcinomas accounts for approximately 20%. Adenocarcinoma of the cervix has increased over the past 3 decades, probably because cervical cytology screening methods are less effective for adenocarcinoma. Screening methods for HPV testing may increase detection of adenocarcinoma. Vaccination with HPV vaccines may also decrease the incidence of both squamous cell carcinoma and adenocarcinoma.   

 

The primary treatment for early-stage cervical cancer is either surgery or radiation therapy. Proton beam radiation therapy (PBRT) has been proposed for the treatment of gynecologic cancers (cervical, ovarian, uterine and vulvar).

 

National Comprehensive Cancer Network (NCCN) Cervical Cancer Version 1.2017

Principles of Radiation Therapy

External Beam Radiation Therapy (EBRT)

  • The use of CT-based treatment planning and conformal blocking is considered the standard of care for EBRT. MRI is the best imaging modality for determining soft tissue and parametrial involvement in patients with advanced tumors. In patients who are not surgically staged, PET imaging is useful to help define the nodal volume of coverage.

  • Intensity modulated radiation therapy (IMRT) and similar highly conformal methods of dose delivery may be helpful in minimizing the dose to the bowel and other critical structures in the IMRT post-hysterectomy setting and in treating the para-aortic nodes when necessary. These techniques can also be useful when high doses are required to treat gross disease in regional lymph nodes. However, conformal external beam therapies (such as IMRT) should not be used as routine alternatives to brachytherapy for treatment of central disease in patients with intact cervix. Very careful attention to detail and reproducibility (including consideration of target and normal tissue definition, patient and internal organ motion, soft tissue deformation, and rigorous dosimetric and physics quality assuarance) is required for proper delivery of IMRT and related highly conformal technologies. Routine image guidance, such as cone-beam CT (CBCT) may be helpful in defining daily internal soft tissue positioning.

  • Concepts regarding the gross target volume (GTV), clinical target volume (CTV), planning target volume (PVT), organs at risk (OARs) and dose volume histogram (DVH) have been defined for use in conformation radiotherapy, especially IMRT.

  • Stereotactic body radiotherapy (SBRT) is an approach that allows delivery of very high doses of focused external beam radiation in 1-5 fractions and may be applied to isolated metastatic sites.

Brachytherapy

  • Brachytherapy is a critical component of definitive therapy for all patients with primary cervical cancer who are not candidates for surgery.  Brachytherapy may be combined with EBRT.
  • In selected post-hysterectomy patients (especially those with positive or close vaginal mucosal surgical margins), vaginal cylinder brachytherapy may be used as a boost to EBRT.
  • SBRT is not considered an appropriate routine alternative to brachytherapy. 

Intraoperative Radiation Therapy (IORT)

  • IORT is a specialized technique that delivers single, highly focused dose or radiation to a tumor bed at risk, or isolated unresectable residual, during an open surgical procedure. It is particularly useful in patients with recurrent disease within a previously radiated volume.

 

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

 

Ovarian Cancer

Ovarian neoplasms consist of several histopathologic entities and the treatment depends on the specific tumor types. Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country’s fifth most common cause of cancer mortality in women. The incidence of ovarian cancer increases with age and is most prevalent in the sixth and seventh decades of life. The median age at the time of diagnosis is 63 years, and more than 70% of patients present with advanced disease.

 

Epidemiologic studies have identified risk factors in the etiology of ovarian cancer. A 30% to 60% decreased risk for cancer is associated with younger age at pregnancy and first birth (≤ 25 years), the use of oral contraceptives and/or breastfeeding. Conversely, nuliparity or older age (> 35 years) at pregnancy and first birth confers an increased risk for ovarian cancer. The risk for borderline epithelial tumors (also known as low malignant potential tumors) may be increased after ovarian stimulation for in vitro fertilization. Obesity does not appear to be associated with the most aggressive types of ovarian cancer. Environmental factors have been investigated, but so far they have not been conclusively associated with the development of this neoplasm.

 

Family history (primary patients having 2 or more first-degree relatives with ovarian cancer) including linkage with BRCA 1 and BRCA 2 genotypes (hereditary breast and ovarian cancer (HBOC) syndrome) or families effected with Lynch Syndrome (hereditary nonpolyposis colorectal cancer (HNPCC) syndrome) is associated with early onset disease.

 

Primary treatment for presumed ovarian cancer consists of appropriate surgical staging and cytoreduction, followed in most (but not all) patients by systemic chemotherapy. Proton beam radiation therapy (PBRT) has been proposed in the treatment of gynecologic cancers (cervical, ovarian, uterine and vulvar).

 

National Comprehensive Cancer Network (NCCN) Ovarian Cancer  1.2017

Radiation Therapy
Whole abdominal radiation therapy is rarely used for epithelial ovarian, primary peritoneal and fallopian tube cancers. It is not included as a treatment recommendation in the NCCN guidelines for ovarian cancer. Palliative localized RT is an option for symptom control in patients with recurrent disease.        

 

NCCN guidelines do not mention or indicate the use of proton beam radiation therapy (PBRT) as a treatment modality for the treatment of ovarian cancer.

 

Uterine Neoplasms

Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 61,380 new uterine cancer cases will occur in 2017, with 10,920 deaths resulting from the disease.

 

Risk factors for uterine neoplasms include increased levels of estrogen (caused by obesity, diabetes, and high-fat diet), early age at menarche, nuliparity, late age at menopause, Lynch syndrome, older age (≥ 55 years), and tamoxifen use. The incidence of endometrial cancer is increasing because of increased life expectancy and obesity.

 

For patients with known or suspected uterine neoplasms, the initial preoperative evaluation/workup for known or suspected malignancy includes a history and physical examination, expert pathology review with additional endometrial biopsy as indicated, imaging, consideration of genetic evaluation and other studies. Most patients with endometrial cancer have stage I disease at presentation, and surgery is recommended for medically operable patients. External beam radiation therapy and brachytherapy is a recommended treatment for individuals not suited for primary surgery. Proton beam radiation therapy (PBRT) has been proposed for the treatment of gynecologic cancers (cervical, ovarian, uterine and vulvar). 

 

National Comprehensive Cancer Network (NCCN) Version 2.2017 Uterine Neoplasms

Principles of Radiation Therapy

  • Radiation therapy (RT) is directed at sites of known or suspected tumor involvement, and may include external beam radiation therapy (EBRT) and/or brachytherapy.
  • Evidence supports the use of combined modality radiation and chemotherapy as adjuvant treatment for patients with extrauterine disease.

  • Palliative EBRT should be individualized to disease extent and patient performance status. 

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

 

Vulvar Cancer

Vulvar cancer accounts for 4% of gynecologic malignancies. Ninety percent of vulvar cancers are squamous cell carcinoma (SCC) histology. Risk factors for the development of vulvar neoplasia include increasing age, infection with human papillomavirus (HPV), cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. After careful clinical evaluation and staging, the standard primary treatment of early stage vulvar SCC is conservative, individualized tumor excision with IFLN (inguinofemoral lymph node) evaluation and the use of external beam radiation therapy (EBRT). Proton beam radiation therapy (PBRT) has been proposed in the treatment of gynecologic cancers (cervical, ovarian, uterine and vulvar).

 

National Comprehensive Cancer Network (NCCN) Vulvar Cancer (Squamous Cell Carcinoma) Version 1.2017

Principles of Radiation Therapy

  • Radiation therapy (RT) is often used in the management of patients with vulvar cancer, as adjuvant therapy following initial surgery, as part of 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 radiation therapy (RT) refers to RT directed at sites of known or suspected tumor involvement. In general, tumor-directed external beam radiation therapy (EBRT) is directed to the vulva and/or inguinofemoral, external and internal iliac node 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 involvement.
  • Target tissues should be treated once daily, 5 days per week. Breaks from treatment should be minimized. 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.
  • Ensure coverage of gross tumor burden with margin. In highly selected cases where only a superficial vulvar target is to be treated, an enface electron beam may be used.

3D Conformal/Anterior-Posterior/Posterior-Anterior (AP/PA) Fields

  • The target is best defined by both physical examination and CT based treatment planning; contouring of the target structures is recommended. When an AP/PA technique is primarily used, often wide AP and narrower PA fields are used with electrons supplementing the dose in the inguinal region, if the depth of the inguinal nodes allow for electron coverage.  More conformal techniques such as three or four field approaches may allow for greater sparing of the bowel and/or bladder, depending on tumor extent and patient anatomy.

 

Intensity Modulated Radiation Therapy (IMRT)

  • Consider use of image-guided IMRT in select cases – to account for vulva edema or marked tumor regression.
  • Planning should be taken with care to respect normal tissue tolerance such as rectum, bladder, small bowel and femoral head and neck.
     

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

 

Summary for Gynecologic Cancers (Cervical, Uterine, Ovarian and Vulvar)
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of gynecologic cancers (cervical, uterine, ovarian and vulvar). 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with gynecologic cancers (cervical, uterine, ovarian and vulvar). The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of gynecological cancers (cervical, uterine, ovarian and vulvar). The ASTRO Model-Policy guideline for proton beam therapy states for pelvic malignancies including gynecologic carcinomas 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). Therefore, proton beam radiation therapy (PBRT) for the treatment of gynecologic cancers (cervical, uterine, ovarian and vulvar) is considered investigational.

 

Genitourinary Cancer/Bladder Cancer

An estimated 79, 030 new cases of urinary bladder cancer (60,490 men and 18,450 women) will be diagnosed in the United States in 2017 with approximately 16, 870 deaths (12,240 men and 4630 women) occurring during the same period. Bladder cancer, the sixth most common cancer in the United States is rarely diagnosed in individuals younger than 40 years of age. Given the median age at diagnosis is 65 years, medical comorbidities are a frequent consideration in patient management.

 

The goal of therapy is to determine whether the bladder should be removed or it can be preserved without compromising survival, and to determine if the primary lesion can be managed independently or if patients are at high risk for distant spread requiring systemic approaches to improve the likelihood of cure. Radiation therapy management is utilized in the treatment of invasive disease, proton beam radiation therapy (PBRT) has been proposed as a treatment option for genitourinary cancer/bladder cancer.

 

National Comprehensive Cancer Network Version 2.2017 for Bladder Cancer

Principles of Radiation Management of Invasive Disease

 

Carcinoma of the Bladder
  • Precede radiation therapy alone or concurrent chemoradiotherapy by maximum TUR (transuretheral resection) of the tumor when safely possible.
  • Use multiple fields from high energy linear accelerated beams.
  • For invasive tumors consider low-dose preoperative radiation therapy prior to segmental cystectomy (category 2B)
  • Concurrent chemoradiotherapy or radiation therapy alone is most successful for patients without hydronephrosis and without extensive carcinoma in-situ associated with their muscle-invading tumor
  • For patients with stage Ta, T1 or Tis, external beam radiation therapy (EBRT) alone is rarely appropriate.
  • Treat the whole bladder with or without pelvic nodal radiotherapy using conventional or accelerated hypofractionation.
  • Concurrent chemoradiotherapy is encouraged for added tumor cytotoxicity.
  • Concurrent chemoradiotherapy or radiation therapy alone should be considered as potentially curative therapy for medically inoperable patients or local palliation in patients with metastatic disease.
Carcinoma of the Urethra
  • Data support the use of radiation therapy for urothelial carcinoma and squamous cell carcinoma of the urethra (case series and experience in treating these carcinomas arising from other disease sites); radiation can also be considered for adenocarcinoma of the urethra.
  • Definitive radiation therapy (organ preservation) using external beam radiation therapy (EBRT).  
Non-Urothelial Carcinomas of the Bladder

Approximately 10% of bladder tumors are non-urothelial (non-transitional cell) carcinoma. These individuals are often treated based on the identified histology. In general patients with non-urothelial invasive disease are treated with cystectomy.

 

Upper Genitourinary Tract Tumors

Upper tract tumors, including those that originate in the renal pelvis or in the ureter, are relatively uncommon. The primary treatment for renal pelvic tumors is surgery. If metastatic disease is documented or associated comorbid conditions are present, treatment should include systemic chemotherapy with regimens similar to those used for metastatic urothelial bladder tumors.    

 

In the settings of positive upper tract cytology but negative imaging and biopsy studies, treatment remains controversial and appropriate management is currently poorly defined. Frequent monitoring for disease is necessary in these patients.

 

Urothelial Carcinoma of the Ureter

Ureteral tumors may develop de novo or in patients who have undergone successful treatment for superficial tumors that originate in the bladder. For resectable ureteral tumors the primary management is surgery. Neoadjuvant chemotherapy should be considered in select patients.

 

Urothelial Carcinoma of the Prostate

Urothelial carcinoma of the prostate may occur de novo or more typically concurrently or after treatment of bladder cancer. Similar to tumors originating in other sites of the urothelium, management of prostate urothelial carcinomas is based on the extent of disease with particular reference to the urethra, duct, acini, and stroma. 

 

Pending histologic confirmation, tumors that are limited to the prostatic urethra with no acina or stromal invasion can be managed with TURP and intraprostatic BCG. If local recurrence is seen, cystoprostatectomy with or without urethrectomy is recommended. Patients with tumors that invade the ducts, acini or stroma should undergo cystoprostatectomy with or without urethrectomy. Neoadjuvant chemotherapy may be advised for stromal invasion.  

 

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of genitourinary/bladder cancers. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with genitourinary/bladder cancers. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of bladder/genitourinary cancer. The ASTRO Model-Policy guideline for proton beam therapy states for genitourinary carcinomas 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). Therefore, proton beam radiation therapy (PBRT) for the treatment of genitourinary/bladder cancers is considered investigational.

 

Soft Tissue Sarcomas

Sarcomas 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

Sarcomas account for approximately 1% of all adult malignancies and 15% of pediatric malignancies. In 2017, an estimated 12,390 people will be diagnosed with soft tissue sarcoma (STS) in the United States, with approximately 4,990 deaths. The most common subtypes STS are undifferentiated pleomorphic sarcoma, GISTs, liposarcoma, leiomyosarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors (MPNSTs). The anatomic site of the primary disease represents an important variable and influences treatment outcomes. Extremities (43%), the trunk (10%), visceral (19%), retroperitoneum (15%), or head and neck (9%) are the most common primary sites. STS most commonly metastasize to the lungs; tumors arising in the abdominal cavity more commonly metastasize to the liver and peritoneum. Rhabdomyosarcoma (RMS) is the most common STS of children and adolescents and is less common in adults.

 

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 primary, preoperative or postoperative treatment.  Proton beam radiation therapy (PBRT) has been proposed for the treatment of soft tissue sarcomas.

 

National Comprehensive Cancer Network (NCCN) Soft Tissue Sarcoma Version 2.2017

Radiation Therapy

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

 

Soft Tissue Sarcomas of the Extremities, Superficial Trunk, or Head and Neck 
Data from randomized studies and retrospective analyses support the use of preoperative or postoperative external beam radiation therapy (EBRT) in appropriately selected patients. Brachytherapy (alone or in combination with EBRT) and IMRT has also been evaluated as an adjunct to surgery. The main advantage of IMRT is its ability to more closely contour the high-dose radiation volume thereby minimizing the volume of high-dose radiation to the surrounding normal tissues, further minimizing toxicity. 

 

Panel Recommendations
When EBRT is used, sophisticated planning with IMRT, tomotherapy, and/or proton therapy can be used to improve therapeutic effect.

     

Retroperitoneal/Intra-abdominal Soft Tissue Sarcomas
Surgical resection of localized tumor with negative margins remains the standard. Radiation therapy (RT) can be administered either as preoperative or postoperative treatment for patients with resectable disease and primary treatment for those with unresectable disease. New RT 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 the therapeutic effect. However, the safety and efficacy of adjuvant RT techniques have yet to be evaluated in multicenter randomized controlled studies.   


Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of soft tissue sarcomas. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with soft tissue sarcomas. The NCCN guideline states that the safety and efficacy adjuvant radiation techniques which includes proton therapy have yet to be evaluated in multicenter randomized controlled studies. Therefore, proton beam radiation therapy (PBRT) for the treatment of soft tissue sarcomas is considered investigational.

 

Thymomas and Thymic Carcinoma

Thymic epithelial tumors originate in the thymus and include thymomas and thymic carcinomas. Thymomas are a common primary tumor in the anterior mediastinum, although they are rare. Although thymomas can spread locally, they are much less invasive then thymic carcinomas. Thymic carcinomas are very rare. Patients with thymomas have a 5 year survival rate of approximately 90% while patients with thymic carcinomas are only approximately 55%.

 

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.

 

Thymomas typically occur in adults 40 to 70 years of age, they are rare in children and adolescents. The etiology of thymomas is unknown. The incidence of thymomas is higher in African-Americans as well as Asians and Pacific Islanders, which suggest there may be a genetic component. Surgery i.e. total thymectomy and complete excision of tumor is recommended for all resectable thymomas for patients who can tolerate surgery. 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). Proton beam radiation therapy (PBRT) has been proposed for the treatment of thymomas and thymic carcinomas.

 

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.

  

National Comprehensive Cancer Network (NCCN) Thymomas and Thymic Carcinomas Version 1.2017

General Principles

  • Recommendations regarding radiation therapy should be made by a board-certified radiation oncologist.

  • Definitive radiation therapy (RT) should be given to patients with unresectable disease, incompletely resected invasive thymoma or thymic carcinoma, or as adjuvant therapy after chemotherapy and surgery for patients with locally advanced disease.

  • Radiation oncologists need to communicate with the surgeon to review the operative findings and to help determine the target volume at risk. 

Radiation Techniques

  • CT based planning is highly recommended.
  • 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.
  • Radiation therapy (RT) should be given by 3D conformal technique to reduce surrounding normal tissue damage (e.g. heart, lungs, esophagus and spinal cord). Intensity modulated radiation therapy (IMRT) may further improve the dose distribution and decrease the dose to the normal tissue as indicated.
  • Proton beam radiation therapy (PBRT) has been shown to improve 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 PBRT. Based on these data, PBRT may be considered in certain circumstances.

 

Summary
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 thymoma and thymic carcinomas. These studies may have shown that proton beam radiation therapy (PBRT) is well tolerated with a reduction in dose to critical structures, however, the authors concluded further studies are needed to evaluate and assess clinical outcomes and late toxicities which needs to include longer follow up periods regarding the use of proton beam radiation therapy (PBRT) for the treatment of thymoma and thymic carcinomas. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with thymoma and thymic carcinomas. The current published evidence does not allow for any definitive conclusions about the safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of thymoma and thymic carcinomas and therefore is considered investigational.

 

Colon Cancer and Rectal Cancer

Colorectal cancer is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Approximately 20% of colon cancer cases are associated with familial clustering, and first-degree relatives of patients with colorectal adenomas or invasive colon cancer are at increased risk for colorectal cancer. Genetic susceptibility to colorectal cancer includes well-defined inherited syndromes, such as Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) and familial adenomatous polyposis.  

 

Primary treatment is surgical management with colectomy with en bloc removal of the regional lymph nodes. If the cancer is locally unresectable or the patient is medically inoperable, chemotherapy or chemoradiation is recommended, possibly with the goal of converting the lesion to a resectable state. Proton beam radiation therapy (PBRT) has been proposed for the treatment of colon and/or rectal cancer.

 

National Comprehensive Cancer Network Colon Cancer Version 2.2017 and Rectal Cancer Version 3.2017

Principles of Radiation Therapy

  • If radiation therapy is used, conformal external beam radiation should be routinely used and intensity modulated radiation therapy (IMRT) should be reserved only for unique clinical situation such as reirradiation of previously treated patients with recurrent disease or unique anatomical structures.
  • 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 external beam radiation therapy (EBRT) 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 a 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 3D conformal radiation therapy, IMRT, or stereotactic body radiation therapy (SBRT).  


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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of colon and/or rectal cancer. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with colon and/or rectal cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of colon and/or rectal cancer. The ASTRO Model-Policy guideline for proton beam therapy states for gastrointestinal carcinomas and abdominal malignancies 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). Therefore, proton beam radiation therapy (PBRT) for the treatment of colon and/or rectal cancer is considered investigational.

 

Anal Carcinoma

An estimated 8200 new cases (2950 men and 5250 women) of anal cancer involving the anus, anal canal, or anorectum will occur in the United States in 2017. It has been estimated that 1100 deaths due to anal cancer will occur in the United States in 2017. Although considered to be a rare type of cancer, the incidence in the United States has increased. Anal carcinoma is associated with human papillomavirus (HPV) infection; a history of receptive anal intercourse or sexually transmitted disease; a history of cervical, vulvar or vaginal cancer; immunosuppression after solid organ transplantation or HIV infection; hematologic malignancies; certain autoimmune disorders; and smoking.

 

Primary treatment of non-metastatic anal carcinoma includes chemotherapy with radiation therapy support. Proton beam radiation therapy (PBRT) has been proposed for the treatment of anal carcinoma.

 

National Comprehensive Cancer Network (NCCN) Anal Carcinoma Version 2.2017

Principles of Radiation Therapy

  • The consensus of the panel is that intensity modulated radiation therapy (IMRT) is preferred over 3-D conformal RT in the treatment of anal carcinoma. IMRT requires expertise and careful target design to avoid reduction in local control by so-called “marginal-miss.”
  • PET/CT should be considered for treatment planning.
  • For 3D conformal RT, the inguinal nodes and the pelvis, anus and perineum should be included in the initial radiation fields.

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of anal carcinoma. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with colon and/or rectal cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of colon and/or rectal cancer. The ASTRO Model-Policy guideline for proton beam therapy states for gastrointestinal carcinomas and abdominal malignancies 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). Therefore, proton beam radiation therapy (PBRT) for the treatment of anal carcinoma is considered investigational.

 

Testicular Cancer

Germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes. These tumors also occur occasionally in extragonadal primary sites, but they are still managed the same as testicular GCTs. GCTs are relatively uncommon tumors and account for 1% of all male tumors. Testicular GCTs constitute the most common solid tumor in men between the ages of 20 and 34 years, and the incidence of testicular GCTs has been increasing in the past two decades. GCTs are classified as seminoma or nonseminoma.

 

Several risk factors for GCT development have been identified including prior history of GCT, positive family history, cryptorchidism, testicular dysgenesis, and Klinefelter’s syndrome.   

 

Radical inguinal orchiectomy is considered the primary treatment for most patients who present with testicular mass that is concerning for malignancy on ultrasound. Proton beam radiation therapy (PBRT) has been proposed for the treatment of testicular cancer.

 

National Comprehensive Cancer Network (NCCN) Testicular Cancer Version 2.2017

Principles of Radiation Therapy: Pure Testicular Seminoma

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

 

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of testicular cancer. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with testicular cancer. The NCCN guideline does not mention or indicate the use of proton beam radiation therapy (PBRT) for the treatment of testicular cancer. Therefore, proton beam radiation therapy (PBRT) for the treatment of testicular cancer is considered investigational.  

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 (PBRT) 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, secifically 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.

 

National Comprehensive Cancer Network (NCCN) Breast Cancer Version 2.2017

Principles of Radiation 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 is typically treated with electrons or photons.
  • Whole breast radiation is utilized for most women treated with breast conserving surgery.  CT based treatment planning is recommended to limit radiation exposure to the heart and lungs, and to assure adequate coverage of the breast lumpectomy site. For greater homogeneity of target dose and to spare normal tissues using compensators such as tissue wedges, forward planning using segments, and IMRT may be used. Respiratory control techniques including deep inspiration breath-hold and prone positioning may be used to try to further reduce dose to adjacent normal tissues, particularly heart and lungs. Radiation boost treatment in the setting of breast conservation can be delivered using enface electrons, photons, or brachytherapy.
  • Chest wall radiation (including breast reconstruction), the target includes the ipsilateral chest wall, mastectomy scar, and drain sites when indicated. Depending on whether the patient has had breast reconstruction or not, several techniques using photons and/or electrons are appropriate. CT based treatment planning is encouraged in order to identify lung and heart volumes and minimize exposure of these organs.
  • Regional node radiation target delineation is best achieved by the use of CT based treatment planning especially when treating the internal mammary lymph nodal volume to evaluate dose to normal tissues, especially the heart and lung.
  • Accelerated partial breast irradiation (APBI) preliminary studies of APBI suggest that rates of local control in selected patients with early-stage breast cancer may be comparable to the those treated with standard whole breast RT. However, compared to standard whole breast irradiation, several recent studies document an inferior cosmetic outcome with APBI. Follow up is limited and studies are ongoing.  

 

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

 

Summary
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 radiation therapy (PBRT) 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 radiation therapy (PBRT) may not prove to be safer than standard photon radiation therapy. There are very few clinical trials that have been done using proton beam radiation therapy (PBRT) for the treatment of breast cancer, computer models predict less radiation to unwanted organs with proton beam radiation therapy (PBRT), 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 radiation therapy (PBRT) over other radiotherapies such as intensity modulated radiation therapy (IMRT). The NCCN guideline does not mention or indicate the use of proton beam radiation radiation therapy (PBRT) for the treatment of breast cancer.  Current published evidence does not allow for any definitive conclusions about the safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of breast cancer and therefore is considered investigational.

 

 

Hodgkin’s Lymphoma and Non-Hodgkin’s Lymphoma

Hodgkin lymphoma (HL) is an uncommon malignancy involving the lymph nodes and the lymphatic system. Most patients are diagnosed between 15 and 30 years of age, following by another peak in adults aged 55 years or older. In 2017, an estimated 8,260 people will be diagnosed with HL in the United States and 1,070 people will die from the disease. The WHO (World Health Organization) classification divides HL into 2 main types: classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominate Hodgkin lymphoma (NLPHL).

 

The past few decades have seen significant progress in the management of patients with HL; it is now curable in at least 80% of patients. The advent of more effective treatment options has improved the 5 year survival rates. Radiation therapy is a treatment modality utilized in the treatment of Hodgkin lymphoma (HL) and proton beam radiation therapy (PBRT) has been proposed for the treatment of Hodgkin lymphoma (HL).

 

Non-Hodgkin’s lymphomas (NHL) 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.

 

The prognosis depends on the histologic type, stage and treatment. NHL can be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas. In general modern treatment of patients with NHL, overall survival at 5 years is over 60%. Of patients with aggressive NHL, more than 50% can be cured. The vast majority of relapses occur in the first 5 years after therapy. The risk of late relapse is higher in patients who manifest both indolent and aggressive histologies.  Radiation therapy is a treatment modality utilized in the treatment of Non-Hodgkin’s lymphoma (NHL) and proton beam radiation therapy (PBRT) has been proposed for the treatment of NHL.

 

In 2014, the International Lymphoma Radiation Oncology Group (ILROG) issued guidelines regarding radiation therapy for Hodgkin lymphoma and Non-Hodgkin’s 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’s lymphoma: Radiation therapy is the most effective single modality for local control of non-Hodgkin’s 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 radiation therapy (PBRT) for the treatment of Hodgkin’s lymphoma or Non-Hodgkin’s lymphoma. 

 

 

National Comprehensive Cancer Network Hodgkin Lymphoma Version 1.2017

Principles of Radiation Therapy

  • Treatment with photons, electrons or protons may all be appropriate depending upon clinical circumstances.
  • Advanced radiation therapy (RT) technologies such as intensity modulated radiation therapy (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 organs at risk (OARs) such as the heart (including coronary arteries, valves and left ventricle), lungs, kidneys, spinal cord, esophagus, carotid artery, 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.
  • 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 expectancies following therapy.
  • In mediastinal Hodgkin lymphoma the use of 4D-CT simulation and the adoption of strategies to deal with respiratory motion such as respiratory gating, inspiration breath-hold techniques, and image-guided RT during treatment delivery may be necessary.
  • 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 original involved lymph node(s). It 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 3D conformal, or IMRT techniques using clinical treatment planning considerations of coverage and dose reduction to OAR.

Preliminary results from single-institution studies have shown that significant dose reduction to organs at risk (OARs; e.g. lungs, heart, breasts, kidneys, spinal cord, esophagus, carotid artery, bone marrow, stomach, muscle/soft tissue and salivary glands) can be achieved with advanced radiation therapy (RT) planning and delivery techniques such as four dimensional CT (4D-CT) simulation, image guided RT, respiratory gating or deep inspiration breath-hold. These techniques offer significant and clinically relevant advantages in specific instances to spare OARs and decrease the risk for normal tissue damage and late effects without compromising the primary goal of local tumor control.  

 

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

  

National Comprehensive Cancer Network Non-Hodgkin’s Lymphoma Version 3.2016

Principles of Radiation Therapy

  • Treatment with photons, electrons, or protons, depending upon clinical circumstances.
  • Advanced RT techniques emphasize tightly conformal doses and steep gradients next to normal tissues. Therefore, target definition and delineation and treatment delivery verification require careful monitoring to avoid the risk of missing geographic location of the tumor and subsequent decrease in tumor control. Image guidance may be required to facilitate target definition.

Preliminary results from single institution studies have shown that significant dose reduction to organs at risk (OAR, eg. lungs, heart, breasts, kidney, 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, IMRT, image guided RT, respiratory gating or deep inspiration breath hold. These technique 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.  

 

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

 

Summary
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of Hodgkin lymphoma (HL) and Non-Hodgkin’s lymphoma (NHL). 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with Hodgkin lymphoma (HL) and Non-Hodgkin’s lymphoma (NHL). The NCCN guideline regarding the use of proton beam radiation therapy (PBRT) for the treatment of Hodgkin lymphoma and Non-Hodgkin’s lymphoma does not include a discussion of specific dose or length of treatment considering the disease stage. Therefore, proton beam radiation therapy (PBRT) for the treatment of Hodgkin lymphoma (HL) and Non-Hodgkin’s lymphoma (NHL) is considered investigational.

 

Bone Cancer (excluding skull based chondrosarcoma and chordoma)

Primary bone cancers are extremely rare neoplasms and account for less than 0.2% of all cancers, although the true incidence is difficult to determine secondary to the rarity of these tumors. The pathogenesis and etiology of bone cancers remain unclear. Gene rearrangements between EWS and ETS family of genes have been implicated in the pathogenesis of Ewing sarcoma. Specific germline mutations have also been implicated in the pathogenesis of osteosarcoma. Li-Fraumeni syndrome characterized by a germline mutation in the TP53 gene is associated with a high risk of developing osteosarcoma. Osteosarcoma is the most common second primary malignancy in patients with retinoblastoma, characterized by a mutation in the retinoblastoma gene RB1. Osteosarcoma is also the most common radiation-induced bone sarcoma.  

 

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 radiation therapy (PBRT) has been proposed in the treatment of bone cancer.   

 

National Comprehensive Cancer Network Bone Cancer Version 2.2017

Principles of Radiation Therapy

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

Osteosarcoma

Osteosarcoma occurs mainly in children and young adults. Wide excision is the primary treatment in patients with low-grade osteosarcomas, whereas preoperative chemotherapy followed by wide excision is the preferred option for patients with high grade osteosarcoma. Combined photon/proton beam RT has been shown to be effective for local control in some patients with unresectable or incompletely resectable osteosarcoma.   

 

Summary (excluding skull based chondrosarcoma and chordoma)
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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of bone cancer (excluding skull based chondrosarcoma and chordoma and osteosarcoma that is unresectable or incompletely resectable). 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of patients with bone cancer (excluding skull based chondrosarcoma and chordoma and osteosarcoma that is unresectable or incompletely resectable). Therefore, proton beam radiation therapy (PBRT) for the treatment of bone cancer (excluding skull based chondrosarcoma and chordoma and osteosarcoma that is unresectable or incompletely resectable) is considered investigational.

 

Other Abnormalities

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.    

 

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 radiation therapy (PBRT) 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 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.  Therefore, proton beam radiation therapy (PBRT) for the treatment of age related macular degeneration is considererd investigational.

 

In 2015, the American Academy of Ophthalmology (AAO) preferred practice patterns do not address proton beam radiation therapy (PBRT) 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.  

 

Summary of Evidence

Proton beam radiation therapy (PBRT) 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 safety and 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; hepatocellular; lung, Hodgkin and Non-Hodgkin’s lymphoma; soft tissue sarcomas; colon/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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) 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

American College of Radiology (ACR)

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 Society for Radiation Oncology (ASTRO)

The Emerging Technolgogy Committee of American Society of Radiation Oncology (ASTRO) published 2012 evidence-based recommendations declaring a lack of evidence for proton beam therapy for malignancies outside of large ocular melanomas and chordomas:

 

“Current data do not provide sufficient evidence to recommend proton beam therapy (PBT) outside of clinical trials in lung cancer, head and neck cancer, GI (gastrointestinal) malignancies. In hepatocellular carcinoma and prostate cancer, there is evidence for the efficacy of PBRT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies, there is a suggestion from the literature that PBT is superior to photon approaches, but there is currently insufficient data to support a firm recommendation for PBRT. In the setting of craniospinal irradiation for pediatric patients, protons appear to offer a dosimetric benefit over photons, but more clinical data are needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. In all fields, however, further clinical trials are needed and should be encouraged. “

 

In September 2013, as part of its national “Choosing Wisely” initiative, 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 2014, the American Society for Radiation Oncology (ASTRO) published a Model Policy on the use of Proton Beam Therapy (PBT):

 

Indications and Limitations of Coverage and/or Medical Necessity

Indications for Coverage

PBT is considered reasonable in instances where sparing the surrounding normal tissue cannot be adequately achieved with photon based radiotherapy and is of added clinical benefit to the patient. Examples of such an advantage might be:

  • 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
  • Primary hepatocellular cancer treated in a hypofractionated regimen
  • Primary or benign solid tumors in children treated with curative intent and occasional palliative treatment of childhood tumors when at least one of four criteria are met.
  • Patients with genetic syndromes making total volume of radiation minimization crucial such as but not limited to NF-1 patients and retinoblastoma patients.
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 above 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). At this time, no indications are deemed inappropriate for CED and therefore the below group of indications includes various systems such as, but not limited to the following:

  • Head and neck malignancies
  • Thoracic malignancies
  • Abdominal malignancies
  • Pelvic malignancies, including genitourinary, gynecologic and gastrointestinal carcinomas

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.

 

American Urological Assocation (AUA)

In 2007, reviewed and validity confirmed in 2011, the American Urological Association (AUA) issued a guideline on management of clinically localized prostate cancer which includes the following treatment options:

  • Watchful waiting and active surveillance
  • Interstitial prostate brachytherapy
  • External beam radiation therapy using intensity modulated radiation therapy (IMRT) and image guidance radiotherapy either with transabdominal ultrasound or intraprostatic placement of fiducial markers for further refined treatment delivery, resulting in dose accuracy and escalation to provide proven improvements in local tumor elimination and reduction in late-radiation-related complications
  • Radical prostatectomy
  • Primary hormonal therapy  

Guideline does not include or indicate the use of proton beam radiation therapy (PBRT) in the treatment of localized prostate cancer. 

 

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 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 10.01.18 Clinical Trials Coverage of Routine Patient Care Costs
  • See also medical policy 06.01.15 Stereotactic Surgery and Stereotactic Radiosurgery

 

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

  • Prostate Cancer
  • Bladder cancer/genitourinary cancers
  • Gastric cancers
  • Pancreatic cancer (pancreatic adenocarcinomas)
  • Abdominal malignancies (colorectal, liver, pancreatic, kidney and stomach) 
  • Gynecological cancers (cervical, ovarian, uterine, vulvar)
  • Hepatocellular carcinoma (HCC)
  • Lung cancer (including non-small cell and small cell and other lung cancers)
  • Non-Hodgkin’s and Hodgkin lymphomas (lymphomas of the thorax)
  • Soft tissue sarcomas
  • Colon and rectal cancer
  • Anal cancer
  • Breast cancer
  • Thymomas and Thymic carcinomas
  • Testicular cancer
  • Head and neck cancers (except for chordoma and chondrasarcoma; and 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)
  • Esophageal cancer
  • Non-uveal melanomas
  • Bone cancer (except for chordoma or chondrosarcoma; and combined photon/proton radiation therapy for local control in patients with unresectable or incompletely resectable osteosarcoma)
  • Pediatric non central nervous system tumors
  • Central nervous system tumors/lesions for adults (> 18 years of age) that are not adjacent to critical structures such as the optic nerve, brain stem or spinal cord
  • Kidney cancer
  • Age related macular degeneration (AMD)
  • Intracranial ateriovenous malformations (AVM) (except for intracranial AVM, small lesion(s) (3cm or less) when surgery may be associated with increased risk based on anatomic locations or feeding vessel anatomy)

Proton beam radiation therapy (PBRT) 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 safety and efficacy of proton beam radiation therapy (PBRT) for the treatment of certain cancers and other abnormalities. 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 PBRT on local tumor control or survival cannot be determined as studies lacked control or comparison groups. Other study limitations also include small sample sizes, changes in protocol or treatment site and heterogeneous study groups. Furthermore, PBRT was used in combination with other therapies so results do not reflect the outcome of PBRT alone. Further randomized controlled trials comparing protons with photons are needed to determine the long term safety and efficacy of proton beam radiation therapy (PBRT) and therefore proton beam radiation therapy (PBRT) 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).

 

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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  • Jakobi A, Stutzeer K, Bandurska-Luque A, et. al. NTCP reduction for advanced head and neck cancer patients using proton therapy for complete for sequential boost treatment versus photon therapy. Acta Oncol 2015;54(9):1658-64. PMID 26340301
  • Kandula S, Zhu X, Garden AS, et. al. Spot-scanning beam proton therapy vs intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison. Med Dosim 2013 Winter 38(4):390-4. PMID 23916884
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  • Orlandi E, lacovelli NA, Bonora M, et. al. Salivary gland photon beam and particle radiotherapy: present and future. Oral Oncol 2016 Sep;60:146-56. PMID 27394087
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  • Verma V, Mishra MV, Mehta MP. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer 2016 May15;(10):1483-501. PMID 26828647
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Policy History:

  • 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.