Medical Policy: 08.01.05 
Original Effective Date: April 2001 
Reviewed: August 2016 
Revised: August 2016 


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 therapy (PBT) is a type of radiotherapy using protons rather than photons used in traditional external beam radiation therapy. PBT is used to treat solid tumors and is intended to minimize total radiation dose and side effects, including potential damage to surrounding healthy tissues. PBT can be used in conjunction with standard treatment strategies like surgery, chemotherapy and even conventional photon beam radiotherapy. Proton beam therapy (PBT), is also known as intensity-modulated proton therapy (IMPT), pencil beam scanning, proton therapy, proton beam radiotherapy, and spot scanning.

 

Proton 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, the physical profile of a beam of proton particles allows for the majority of its energy to be deposited over a very narrow range of tissue at a depth largely determined by the energy of the proton beam. A proton beam deposits relatively less radiation energy upon entering the body compared to a photon beam. The energy deposition of the proton beam than rapidly increases over a narrow range of tissue at a desired depth to produce an intense dose distribution pattern called 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 Therapy Treatment Planning

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

 

Proton beam therapy (PBT) 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 MR scanning equipment is an essential prerequisite to PBT treatment planning. If respiratory or other normal organ motion is expected to produce significant movement of the target region during radiotherapy delivery, the radiation oncologist may additionally elect to order to 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 PBT, 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 PBT, 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 PBT 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, PBT 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 PBT 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 PBT 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 Therapy Treatment Delivery

A proton beam can be delivered by two methods, passive or active spreading:

  • Passive Spreading: uses patient specific beam modifying devices (e.g., compensators, collimators) to scatter the proton beam before it enters the body. Compensators and collimators must be made for each patient to optimize scattering for specific tumor shapes and could require repositioning throughout treatment. When the proton beam passes through a beam modifying device, radioactive neutrons are released, possibly increasing the radioactive dose to patients or staff, and the beam modifying device becomes radioactive. Radioactive compensators and collimators must be stored for a few months after use while the radioactivity decays.  
  • Active Spreading: also known as spot scanning or pencil beam scanning, offers an alternative to passive spreading and reportedly provides more targeted treatment by sequentially focusing on smaller fields with narrower beams. Active spreading PBT might diffuse more rapidly than passive spreading PBT because active spreading potentially reduces scan time, minimizes radioactive exposure outside the target, and penetrates to deeper tumors.  

The basic requirement for all forms of PBT treatment delivery is that the technology must accurately produce the calculated dose distribution described by the PBT plan. PBT dose distributions are sensitive to changes in target depth and shape and thus, changes in patient anatomy during treatment may require repeat planning. Precise delivery is vital for proper treatment.

 

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 therapy has been proposed for the treatment of prostate cancer. The goal of proton beam therapy 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 therapy. 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 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 PBT. 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 3.2016

The (NCCN) guidelines for prostate cancer refer 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.” The costs associated with proton beam facility construction and proton beam treatment are high compared with the expense of building and using the more common photon linear accelerator based practice. 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.

 

Based on review of medical literature there is insufficient evidence to draw conclusions about the impact of proton beam therapy (PBT) for the treatment of prostate cancer.  A 2010 Blue Cross Blue Shield Association (BCBSA) TEC Assessment addressed the use of PBT for prostate cancer and concluded that it has not yet been extablished whether PBT improves outcomes in any setting for prostate cancer.  There are no randomized trials completed that directly compare 3D-CRT or IMRT with proton beam therapy (PBT), and rely mainly on single arm studies. Comparative clinical trials are warranted to determine the effectiveness on health outcomes. There is no evidence that this approach (PBT) offers any advantages over other radiotherapy modalities when measured by survival, tumor control or toxicity. Therefore, the use of proton beam therapy (PBT) for the treatment of prostate cancer is considered investigational. 

 

Non-Small Cell Lung Cancer

A 2010 Blue Cross Blue Shield Association (BCBSA) TEC Assessment assessed the use of PBT 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 SBRT, which is an accepted approach for using RT to treat NSCLC. Eight PBT case series were identified in the Assessment that included a total of 340 patients. No comparative studies, randomized or nonrandomized, were found.

 

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

 

National Comprehensive Cancer Network (NCCN) Non-Small Cell Lung Cancer Verrsion 4.2016

The goals of radiation therapy are to maximize tumor control and to minimize treatment toxicity. Advanced technologies such as 4D-conformal RT simulation, intensity modulated RT/volumetric modulated arc therapy (IMRT/VMAT), image guided RT, motion management strategies, and proton beam therapy (ASTRO Practice Management) have been shown to reduce toxicity and increase survival in nonrandomized trials. CT-planned 3D-conformal RT is now considered to be the minimum standard.

 

Note: See Practice Guideline and Position Statement below for the Emerging Technology Committee of American Society of Radiation Oncology (ASTRO) issued in 2012 and 2014 ASTRO model policy regarding the treatment of lung cancer and use of proton beam therapy.

 

It is not known whether the higher precision of proton beam therapy actually translates to better outcomes than other types of radiation treatment. There is limited clinical evidence that directly compares proton beam therapy with other types of radiation therapy. Comparative effectiveness studies including randomized controlled trials are needed to document the theoretical incremental advantages of proton beam therapy over other radiotherapies. Current published evidence also does not allow for any definitive conclusions about the safety and efficacy of proton beam therapy for this indication and therefore is considered investigational.

 

Small Cell Lung Cancer

National Comprehensive Cancer Network (NCCN) Small Cell Lung Cancer Version 1.2016: Radiation therapy has a potential role in all stages of SCLC as part of either definitive or palliative therapy. 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. Use of more advanced technologies is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints. Such technologies include (but are not limited to) 4D-CT and/or PET-CT simulation, IMRT/VMAT, IGRT, and motion management strategies. Brain metastases should be treated with whole brain radiation therapy.

 

The NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of small cell lung cancer. 

 

Head and Neck Tumors, Other than Skull Based

Proton beam therapy has been proposed for the treatment of head and neck tumors, other than skull based. Most head and neck cancers begin in the mucosal surfaces of the upper aerodigestive tract, and these are predominantly squamous cell carcinomas.

 

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

 

Human papillomavirus associated oropharyngeal cancer

Human papillomavirus (HPV) infection is a causative agent for many head and neck squamous cell carcinomas arising in the oropharynx (tonsils and base of tongue). HPV associated cancers have increased dramatically and have substantially altered the epidemiology of oropharyngeal squamous cell carcinoma. These tumors define a distinct subset of patients who have frequent lymph node involvement and an improved prognosis compared with HPV negative, tobacco-driven oropharynx cancers.

 

A revised classification/staging system has been proposed for HPV related oropharyngeal cancers. This new system recategorizes many of the patients previously staged as 4a to 1, 2, or 3 with much better prognostic accuracy; the therapeutic approach for patients with HPV associated oropharyngeal cancer has not changed. Because of the better prognosis for patients with HPV associated oropharyngeal cancer, clinical trials that include de-intensification of treatment are underway to define the optimal approach for these patients, with the goal of maximizing long-term cure rates while minimizing toxicity. Currently, however, the approach to these patients outside of a clinical trial setting is the same as for patients with oropharyngeal cancer not associated with HPV.

 

Definitive RT approaches for head and neck tumors other than skull based include external beam RT and brachytherapy. Curative RT treatment requires a three-dimensional conformal technique at a minimum. Highly conformal radiation techniques, such as intensity-modulated RT (IMRT) and image-guided RT (IGRT), have demonstrated reduced morbidity and represent the current standard of care. 


In 2016, Blanchard, et. al. performed a case matched analysis which was a 1:2 matching of intensity modulated proton beam therapy (IMPT) to intensity modulated radiation therapy (IMRT) used for patients with oropharyngeal carcinoma and the ability to reduce the dose to organs at risk while maintaining adequate tumor control. The goal was to compare the clinical outcomes of these two treatment modalities. The study cohort consisted of IMPT patients from a prospective quality of life study and consecutive IMRT patients treated at a single institution during the period of 2010-2014. Patients were matched on unilateral/bilateral treatment, disease site, human papillomavirus status, T and N status, smoking status, and receipt of concomitant chemotherapy. Survival analysis were performed using a Cox model and binary toxicity endpoints using logistic regression analysis. Fifty IMPT and 100 IMRT patients were included. The median following up time was 32 months. There were no imbalance in patient/tumor characteristics except for age (mean age 56.8 years for IMRT patients and 61.2  1 years for IMPT patients, p-value=0.010). Statistically significant differences were not observed in overall survival (hazard ration (HR) = 0.55; 95% confindence interval (CI); 0.12-2.50, p-value = 0.44) or in progression free survival (HR = 1.02; 95% CI: 0.41-2.54; p-value = 0.96). The age adjusted odds ratio (OR) for the presence of gastrostomy tube (G-tube) during treatment for IMPT vs IMRT were OR = 0.53; 95% CI: 0.24-1.15; p-value = 0.11 and OR = 0.43; 95% CI: 0.16 -1.17; p-value = 0.10 at 3 months after treatment. When considering the pre-planned composite endpoint of grade 3 weight loss or G-tube presence, the ORs were OR = 0.44; 95% CI:0.19-1.0; p-value = 0.05 at 3 months after treatment and OR = 0.23; 95% CI 0.07-0.73; p-value = 0.01 at 1 year of treatment. The results suggest that IMPT is associated with reduced rates of feeding tube dependency and severe weight loss jeopardizing outcome. However, prospective multicenter randomized trials are needed to validate such findings.       

 

National Comprehensive Cancer Network (NCCN) Head and Neck Cancers Version 1.2016

Intensity modulated radiation therapy (IMRT) is now widely used in head and neck cancers and is the predominant technique 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.

 

Brachytherapy has been used less often in recent years because of improved local control obtained with concurrent chemoradiation. However, brachytherapy still has a role for lip and oral cavity cancers.

 

NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of head and neck cancers (other than skull based tumors).  

 

Based on the peer-reviewed medical literature there is insufficient evidence to support the use of PBT of the head and neck, other than skull based tumors. There is lack of clinical outcome studies comparing PBT to other types of radiation treatment. What few comparative studies exist are limited to dosimetric planning studies and not studies of clinical outcomes. Comparative effectiveness studies including randomized controlled trials are needed to document the advantages of proton beam therapy over other radiotherapies. Current published evidence also does not allow for any definitive conclusions about the safety and efficacy of proton beam therapy for the treatment of head and neck tumors other than skull based and therefore is considered investigational.     

 

Central Nervous System Cancers

Proton beam therapy has been proposed for the treatment of central nervous system cancers.

National Comprehensive Cancer Network (NCCN) Central Nervous System Cancers Version 1.2015

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 dose of RT administered varies depending on the pathology.  

 

Pediatric Non-CNS Tumors

Proton beam therapy 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 therapy over other radiotherapies. Current published evidence also does not allow for any definitive conclusions about the safety and efficacy of proton beam therapy for this indication and therefore is considered investigational.

 

Esophageal Cancer

Proton beam therapy has been proposed for the treatment of esophageal cancer. Based on review of medical literature studies of the clinical effectiveness of primary PBT in the treatment of esophageal cancer are based on retrospective design and case series. Evidence is limited and inadequate to compare the potential harms of PBT relative to other radiation modalities in patients with esophageal cancer, particularly in comparison to IMRT. Prospective comparative effectiveness studies including randomized controlled trials are needed to document the incremental advantages of proton beam therapy (PBT) or other radiotherapies and determine the safety and efficacy of PBT for this indication. Therefore, proton beam radiation therapy is considered investigational for this indication.    

 

In 2015, Wang et. al. published a retrospective study comparing passive-scatter proton beam therapy (PBT) 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 PBT 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 PBT 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. Howevcer, IMRT may be superior to PBT 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 PBT 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.

 

National Comprehensive Cancer Network (NCCN) Esophageal and Esophagogastric Junction Cancers Version 2.2016

Principles of Radiation Therapy (RT): Use of CT simulation and 3D treatment planning is strongly encouraged. IMRT is appropriate in clinical settings where reduction in dose to organs at risk (e.g. heart, lungs) is required that cannot be achieved by 3D techniques.

 

The panel recommends that RT alone should generally be reserved for palliation or for patients who are medically unable to receive chemotherapy.

 

Alternative RT techniques such as hypoxic cell sensitizers and hypofractionation have not resulted in clear survival advantage. Experience with intraoperative RT (IORT) as an alternative to external beam radiation therapy (EBRT) is limited. IMRT is currently being investigated. Restrospective studies comparing three dimensional 3D conformal vs IMRT with esophageal cancer have generally shown superior dose conformity and homogeneity with IMRT and reduction of RT dose of the lungs and heart.

 

NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of esophageal and esophagogastric junction cancers.     

 

Gastrointestinal Cancers

Proton beam therapy has been proposed for the treatment of gastrointestinal cancers. A systematic review concluded that there is insufficient evidence to recommend proton beam therapy outside of clinical trials for gastrointestinal malignancies. Based on the peer reviewed medical literature there is insufficient evidence to draw any definitive conclusions as to whether PBT has any advantages over traditional therapies or the safety and efficacy for this indication and therefore is considered investigational.   

 

National Comprehensive Cancer Network (NCCN) gastric cancer version 2.2016

The principles of radiation therapy includes IMRT (3-D planning or 4D-CT planning), the NCCN guidelines does not mention the use of proton beam radiation therapy as a therapeutic option for the treatment of gastrointestinal cancers.  

 

Pancreatic Adenocarcinoma

Proton beam therapy has been proposed for the treatment of pancreatic adenocarcinoma.

 

National Comprehensive Cancer Network (NCCN) Pancreatic Adneocarcinoma Version 1.2016

Principles of radiation therapy states 3-D conformal RT (3D-CRT) or IMRT, IORT (intraoperative radiation therapy) delivered with electron beam RT or high dose rate brachytherapy, or fractionated RT.

 

Advanced Radiation Techniques:

  • IMRT is increasingly being applied for therapy for locally advanced pancreatic adenocarcinoma and in the adjuvant setting with the aim of increasing radiation dose to the gross tumor while minimizing toxicity to surrounding tissues. While authors concluded that IMRT plans would allow for significant increase in target volume dose with substantial dose reductions to local organs at risk, there is no clear consensus on the appropriate maximum dose of radiation when IMRT is used.
  • Stereotactic body radiotherapy is another technique aimed at increasing dose to the tumor while sparring radiation to nearby healthy tissue.
  • Intraoperative radiation therapy (IORT) can allow for higher doses of radiation because of sensitive structures can be excluded from radiation fields.

The NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of pancreatic adenocarcinoma. 

 

Hepatocellular Carcinoma

Proton beam therapy has been proposed for the treatment of hepatocellular carcinoma.

 

National Comprehensive Cancer Network (NCCN) Hepatobiliary Cancers Version 2.2016

Locoregional therapies for hepatocellular carcinoma (HCC): External beam radiation therapy (EBRT) allows focal administration of high dose radiation to liver tumors while sparring surrounding liver tissue, thereby limiting the risk of radiation-induced liver damage in patients with unresectable or inoperable HCC. Advances in EBRT, such as intensity modulated radiation therapy (IMRT), have allowed for enhanced delivery of higher radiation doses to the tumor while sparring surrounding critical tissue. Stereotactic body radiation therapy (SBRT) is an advanced technique of EBRT that delivers large ablative doses of radiation. There is growing evidence (primary from non-RCTs) supporting the usefulness of SBRT for patients with unresectable, locally advanced, or recurrent HCC.

 

All tumors, irrespective of their location, may be amendable to SBRT, IMRT, or 3D conformal RT. SBRT is often used for patients with 1 to 3 tumors with minimal or no extrahepatic disease. There is no strict size limit, so SBRT may be used for larger lesions if there is sufficient uninvolved liver and liver radiation tolerance can be respected. The majority of safety and efficacy on the use of SBRT are available for patients with HCC and Child-Pugh A liver function; limited safety data are available for the use of SBRT in patients with Child-Pugh B or poorer liver function. Those with Child-Pugh B cirrhosis can safely be treated, but they may require dose modifications and strict dose constraint adherence. The safety of SBRT for patients with Child-Pugh C cirrhosis has not been established, as there are not likely to be clinical trials available for this group of patients with a very poor prognosis.

 

In 2014, ASTRO (American Society for Radiation Oncology) released a model policy supporting the use of proton beam therapy (PBT) in some oncology populations. In a recent meta-analysis including 70 studies charged particle therapy (mostly including PBT) was compared to SBRT and conventional radiotherapy. OS (RR, 25.9; 95% CI, 1.64-408.5; P = .02), PFS (RR, 1.86; 95% CI, 1.08-3.22; P = .013) and locoregional control (RR, 4.30; 95% CI, 2.09-8.84; P < .001) through five years was greater for charged particle therapy than conventional radiotherapy. There were no significant differences between charged particle therapy and SBRT for these outcomes. The panel advises that PBT may be considered and appropriate in select setting for treating HCC.    

 

NCCN recommendations for locoregional therapies

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 to control and/or prevention of complications from metastatic HCC lesions in bone or brain. The panel encourages prospective clinical trials evaluating the role of SBRT in patients with unresectable, locally advanced, or recurrent HCC.  

 

Comparative effectiveness studies including randomized controlled trials are needed to document the theoretical incremental advantages of proton beam therapy over other radiotherapies (e.g. SBRT). Based on meta-analysis including 70 studies there is no evidence that this approach (PBT) offers any advantages over other radiotherapy  modalities (SBRT) when measured by survival, tumor control or toxicity. Therefore, the use of proton beam therapy (PBT) for the treatment of hepatocellular cancer is considered investigational.           

 

Kidney Cancer

Proton beam therapy has been proposed for the treatment of kidney cancer. 

 

National Comprehensive Cancer Network (NCCN)Kidney Cancer Version 3.2016

Surgical resection remains an effective therapy with options including radical nephrectomy, partial nephrectomy or nephron sparring surgery.

 

NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of kidney cancer. 

 

Gynecological Cancers  (Cervical, Uterine, Ovarian, Vulvar)

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

 

Cervical Cancer

National Comprehensive Cancer Network (NCCN) Cervical Cancer Version 1.2016

The principles of radiation therapy for cervical cancer include external bean radiation therapy (EBRT); intensity modulated radiation therapay (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 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 an intact cervix; brachytherapy and intraoperative radiation therapy (IORT) which is useful in patients with recurrent disease within previously radiated volume.

 

NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of cervical cancer.

 

Ovarian Cancer

National Comprehensive Cancer Network (NCCN) Version 1.2016 Ovarian Cancer

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 the use of proton beam therapy as a therapeutic option for the treatment of ovarian cancer.

 

Uterine Neoplasms

National Comprehensive Cancer Network (NCCN) Version 2.2016 Uterine Neoplasms

Principles of radiation therapy states tumor directed radiation therapy (RT) refers to RT directed at sites of known or suspected tumor involvement, and may include external beam radiation therapy (EBRT) and/or brachytherapy.

 

NCCN guideline does not mention the use proton beam therapy as a therapeutic option for the treatment of uterine cancer.

 

Vulvar Cancer

National Comprehensive Cancer Network (NCCN) Vulvar Cancer (Squamous Cell Carcinoma) Version 1.2016

Principles of radiation therapy states tumor directed radiation therapy (RT) directed at sites of known or suspected tumor involved. 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.

 

NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of vulvar cancer.

 

Genitourinary Cancer

Proton beam therapy has been proposed for the treatment of genitourinary cancer.

 

National Comprehensive Cancer Network Version 2.2016 for Bladder Cancer includes the following: bladder, upper genitourinary tract tumors, ureteral tumors, urothelial carcinomas of the prostate, primary carcinoma of the urethra and non-urothelial carcinomas of the bladder. 

The data on radiation or chemoradiation following cystectomy are scarce and further prospective studies are needed to evaluate their efficacy and potential toxicity. Because local recurrence rates are high for some patients after cystectomy, adjuvant radiotherapy is reasonable to consider in these patients.

 

NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of bladder cancer.

 

NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of upper genitourinary tract tumors, ureteral tumors, urothelial carcinomas of the prostate, primary carcinoma of the urethra and non-urothelial carcinomas of the bladder.

 

Soft Tissue Sarcomas (Extremity/Trunk/Head-Neck or Retroperitoneal/Intra-Abdominal Sarcoma)

Proton beam therapy has been proposed for the treatment of soft tissue sarcomas.

 

National Comprehensive Cancer Network (NCCN) Soft Tissue Sarcoma Version 2.2016

The guideline indicates a potential role for proton therapy in retroperitoneal/intra-abdominal soft tissue sarcomas in persons who did not receive preoperative radiotherapy. The guideline states: Newer RT techniques such as intensity-modulated radiation therapy (IMRT), 3D conformal RT using protons or photons may allow tumor target coverage and acceptable clinical outcomes within normal tissue does constraints to adjacent organs at risk. When ERBT is used, sophisticated treatment planning with IMRT, tomotherapy, and/or proton therapy can be used to improve therapeutic effect. However, the safety and efficacy of adjuvant RT techniques is yet to be evaluated in multicenter randomized controlled studies.     

 

It is not known whether the higher precision of proton beam therapy actually translates to better clinical outcomes than other types of radiation treatment. There is limited clinical evidence that directly compares proton beam therapy with other types of radiation therapy. Comparative effectiveness studies including randomized controlled trials are needed to document the incremental advantages of proton beam therapy over other radiotherapies. Current published evidence also does not allow for any definitive conclusions about the safety or efficacy of proton beam therapy for soft tissue sarcomas and therefore is considered investigational. 

 

Thymomas and Thymic Carcinoma

Proton beam therapy has been proposed for the treatment of thymomas and thymic carcinoma.

 

National Comprehensive Cancer Network (NCCN) Thymomas and Thymic Carcinomas Version 3.2016

  • Thymic Masses:  Total thymectomy and complete surgical excision of the tumor are the gold standard of treatment and recommended whenever possible for most resectable tumors.
  • Thymomas: Surgery (total thymectomy and complete excision of tumor) is recommended for all resectable thymomas for patients who can tolerate surgery. Adjuvant therapy is not recommended for completely resected state I thymomas. For incompletely resected thymomas, postoperative radiation therapy (RT) is recommended. RT should be given by the 3-D conformal technique to reduce damage to surrounding normal tissue (e.g. heart, lungs, esophagus, spinal cord). Use of intensity modulated radiation therapy (IMRT) may decrease the dose to the normal tissues.

NCCN guideline does not mention the use of proton beam therapy as a therapeutic option for the treatment of thymomas and thyic carcinoma.   

 

Colon Cancer and Rectal Cancer

Proton beam therapy has been proposed for the treatment of colon and rectal cancer.

 

National Comprehensive Cancer Network (NCCN) Colon Cancer and Rectal Cancer Version 2.2016

Radiation therapy fields should include the tumor bed, which should be preoperative radiological imaging and/or surgical clips. If radiation therapy is to be used, conformal external beam radiation therapy (EBRT) should be routinely used and intensity modulated radiation therapy (IMRT) should be reserved only for unique clinical situations such as reirradiation of previously treated patients with recurrent disease or unique anatomical situations.

 

NCCN guidelines does not mention the use of proton beam therapy as a therapeutic option for the treatment of colon cancer or rectal cancer.

 

Anal Carcinoma

Proton beam therapy has been proposed for the treatment of anal carcinoma.

 

National Comprehensive Cancer Network (NCCN) Anal Carcinoma Version 2.2016

The consensus of the panel is the IMRT is preferred over 3-D conformal RT in the treatment of anal carcinoma.

 

NCCN guidelines does not mention the use of proton beam therapy as a therapeutic option for the treatment of anal cancer.

 

Testicular Cancer

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

 

National Comprehensive Cancer Network (NCCN) Testicular Cancer Version 2.2016

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 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 guidelines does not mention the use of proton beam therapy as a therapeutic option for the treatment of testicular cancer.

Breast Cancer

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 therapy has been proposed for the treatment of breast cancer.

 

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

 

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

 

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

 

National Comprehensive Cancer Network (NCCN) Breast Cancer Version 2.2016

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 should receive a dose 46-50 Gy in 23-25 fractions or 4.-42.5 Gy in 15-16 fractions (hypofractionation is preferred).

 

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 nodes to evaluate dose to normal tissues, especially the heart and lung.

 

Accelerated partial breast irradiation (APBI) may be used in patients with early stage breast cancer. However, compared to standard whole breast radiation several recent studies document an inferior cosmetic outcome with APBI. APBI can be delivered with brachytherapy or with external beam radiation therapy (EBRT).

 

NCCN guidelines does not mention the use of proton beam therapy as a therapeutic option for the treatment of breast cancer.

 

Based on review of the peer reviewed medical literature further comparative effectiveness studies including randomized controlled trials are needed to document the advantages of proton beam therapy (i.e. IMPT) over other radiotherapies. Current published evidence does not allow for any definitive conclusions about the safety and efficacy of proton beam therapy for the treatment of breast cancer and therefore is considered investigational.     

 

Hodgkin’s Lymphoma and Non-Hodgkin’s Lymphoma

Proton beam therapy has been proposed for the treatment of lymphomas. Per review of the medical literature published studies for proton beam therapy for the treatment of lymphomas (Hodgkin’s or Non-Hodgkin’s) are limited to dosimetric planning studies, there is lack of published clinical outcome studies of proton beam therapy demonstrating improvements over photon therapy modalities.

 

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 therapy for the treatment of Hodgkin’s lymphoma or Non-Hodgkin’s lymphoma. 

 

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

Radiation therapy can be delivered with photons, electrons, or protons, depending upon clinical circumstances. Advanced RT techniques emphasize tightly conformal doses and steep gradients next to normal tissues. Therefore, target definition and delineation and treatment delivery verification require careful monitoring to avoid the risk of missing geographic location of the tumor and subsequent decrease in tumor control. Image guidance may be required to facilitate target definition. Preliminary results from single institution studies have shown that significant dose reduction to organs at risk (OAR, 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.

 

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

  

National Comprehensive Cancer Network Version 3.2016 Hodgkin Lymphoma

Radiation therapy can be delivered with photons, electrons, or protons, depending upon clinical circumstances. Advanced RT techniques emphasize tightly conformal doses and steep gradients next to normal tissues. Therefore, target definition and delineation and treatment delivery verification require careful monitoring to avoid the risk of missing geographic location of the tumor and subsequent decrease in tumor control. Image guidance may be required to facilitate target definition. Preliminary results from single institution studies have shown that significant dose reduction to organs at risk (OAR, 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.

 

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

 

Based on review of the medical literature there is limited clinical evidence that directly compares proton beam therapy with other types of radiation therapy. Comparative effectiveness studies including randomized controlled trials are needed to document the incremental advantages of proton beam therapy over other radiotherapies. Current published evidence also does not allow for any definitive conclusions about the safety and efficacy of proton beam therapy for the treatment of lymphomas (NH or NHL) and therefore is considered investigational.    

 

Other Indications

Brain Arteriovenous Malformations

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. Conventional treatment (e.g. craniotomy with excision, embolization) of AVM may be unsuitable because of the location, size, or operative risk of the lesion.

 

Based on review of medical literature, successful brain AVM obliteration with radiosurgery using proton beam therapy 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.    

 

Age Related Macular Degeneration (AMD)

Age related macular degeneration (AMD) is a degenerative disease of the central portion of the retina (the macula) that results primarily in loss of central vision. AMD is classified as dry (atrophic) or wet (neovascular or exudative). Radiation therapy i.e. proton beam therapy has been proposed for the treatment of AMD. 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.

 

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

 

Summary

It is not known whether the higher precision of proton beam therapy actually translates to better clinical outcomes than other types of radiation treatment of many common cancers or for other indications. There is limited clinical evidence that directly compares proton beam therapy with other types of radiation therapy. Comparative effectiveness studies including randomized controlled trials are needed to document the theoretical incremental advantages of proton beam therapy over other radiotherapies (e.g., IMRT, conventional radiotherapy or stereotactic photon radiosurgery). Current published evidence also does not allow for any definitive conclusions about the safety and efficacy of proton beam therapy including but not limited to the indications listed above and therefore, proton beam radiation therapy is considered investigational.

Practice Guidelines and Position Statements

American College of Radiology

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 PBT 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 PBT. 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 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, ASTRO published a model policy on use of 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. 

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
    • Chondrosarcoma
  • 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.

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.”

 

American Academy of Ophthalmology

In 2015, the American Academy of Ophthalmology issued preferred practice pattern guidelines regarding age related macular degeneration which states: “Radiation therapy, acupuncture, electrical stimulation, macular translocation surgery, and adjunctive use of intravitreal corticosteroids with verteporfin (PDT) are not recommended: III, Moderate; Strong


Prior Approval:

 

Prior approval is required.


Policy:

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

  • Prostate cancer
  • Bladder cancer
  • Gastrointestinal cancers
  • Genitourinary cancer
  • Pancreatic cancers
  • Abdominal malignancies
  • Gynecological cancers
  • Hepatocellular carcinoma
  • Lung cancer
  • Non-Hodgkin’s and Hodgkin's 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 skull-based tumors)
  • Esophageal cancer
  • Non-uveal melanomas
  • Osteosarcoma except for patients with unresectable or incompletely resected osteosarcoma following post-operative chemotherapy
  • 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 AVMs, small lesions when surgery may be associated with increased risk based on anatomic locations or feeding vessel anatomy 

It is not known whether the higher precision of proton beam therapy actually translates to better clinical outcomes than other types of radiation treatment of many common cancers or for other indications. There is limited clinical evidence that directly compares proton beam therapy with other types of radiation therapy. Comparative effectiveness studies including randomized controlled trials are needed to document the theoretical incremental advantages of proton beam therapy over other radiotherapies (e.g., IMRT, conventional radiotherapy or stereotactic photon radiosurgery). Current published evidence also does not allow for any definitive conclusions about the safety and efficacy of proton beam therapy including but not limited to the indications listed above and therefore, proton beam radiation therapy is considered investigational.



Procedure Codes and Billing Guidelines:

  • To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 77520 Proton treatment delivery; simple, without compensation
  • 77522 Proton treatment delivery; simple, with compensation
  • 77523 Proton treatment delivery; intermediate
  • 77525 Proton treatment delivery; complex

Selected References:

  • Nilsson S, Norlen BJ, Widmark A. A systematic overview of radiation therapy effects in prostate cancer. Acta Oncol. 2004;43(4):316-81. 
  • Yeboah C Sandison GA. Optimized treatment for prostate cancer comparing IMPT, VHEET and 15 MV IMXT.  Phys Med Biol. 2002;47(13):2247-61
  • Gardner BG, et al. Late normal tissue sequelae in the second decade after high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer.  J Urol. 2002 Jan;167(1)123-6
  • Thurman SA et al. Radiation therapy for the treatment of locally advanced and metastatic prostate cancer. Hematol Oncol Clin North Am. 2001 Jun;15(3): 423-43
  • Rossi CJ, et al. Particle beam radiation therapy in prostate cancer: is there an advantage?  Semin Radiat Oncol. 1998 Apr;8(2): 115-23.
  • Zietman AL, DeSilvio ML, Slater JD et al. Comparison of Conventional-Dose vs High-Dose Conformal Radiation Therapy in Clinically Localized Adenocarcinoma of the Prostate. JAMA 2005; 294(10):1233-9.
  • ECRI Institute. Health Technology Information Service. Emerging Technology Report. (May 2007). Proton beam radiation therapy (overview). Retrieved December 18, 2007 from ECRI Institute.
  • Trikalinos TA, Terasawa T, Ip S et al. Particle Beam Radiation Therapies for Cancer. Technical Brief No. 1. (Prepared by Tufts Medical Center Evidence-based Practice Center under Contract No. HHSA-290-07-10055.) Rockville, MD: Agency forHealthcare Research and Quality External SiteSeptember 2009.
  • Brada M, Pijls-Johannesma M, De Ruysscher D. Proton Therapy in Clinical Practice: Current Clinical Evidence. J Clin Oncol. 2007 Mar 10; 25(8):965-70.
  • Wilt TJ, MacDonald R, Rutks I et al. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med 2008; 148:435-48.
  • Wilt TJ, Shamliyan T, Taylor B et al. Comparative Effectiveness of Therapies for Clinically Localized Prostate Cancer. Comparative Effectiveness Review No. 13. (Prepared by Minnesota Evidence-based Practice Center under Contract No. 290-02-00009.) Rockville, MD: Agency for Healthcare Research and Quality; 2008.
  • Schulz-Ertner D, Tsujii H. Particle radiation therapy using proton and heavier ion beams. J Clin Oncol 2007; 25:953-64.
  • Goetein M, Cox JD. Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol 2008; 26:175-6.
  • Grutters JP, Kessels AG, Pijls-Johannesma M et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother Oncol. 95(1):32-40.
  • Iwata H, Murakami M, Demizu Y et al. High-dose proton therapy and carbon-ion therapy for stage I non-small cell lung cancer. Cancer. 116(10):2476-85.
  • Pijls-Johannesma M, Grutters JP et al. Do we have enough evidence to implement particle therapy as standard treatment in lung cancer? A systematic literature review. Oncologist. 1591):93-103.
  • Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Proton Beam Therapy for Non-small Cell Lung Cancer. TEC Assessments 2010; Volume 25, Tab 7.
  • TARGET [database online]. Plymouth Meeting (PA):ECRI Institute External Site2010 Nov 1. Proton beam radiation therapy (overview).
  • Kagan AR, Schulz RJ. Proton-beam therapy for prostate cancer. Cancer J 2010; 16(5):405-9.
  • Zietman AL, Bae K, Slater JD et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from proton radiation oncology group/American College of Radiology 95-09. J Clin Oncol. Mar 1 2010; 28(7):1106-11. doi: 10.1200/JCO.2009.25.8475.
  • Talcott JA, Rossi C, Shipley WU et al. Patient-reported long-term outcomes after conventional and high-dose combined proton and photon radiation for early prostate cancer. JAMA. Mar 17; 303(11):1046-53.
  • Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Proton Beam Therapy for Prostate Cancer. TEC Assessments 2010; Volume 25, Tab 10.
  • Emerging Technology Evidence Report. Proton Beam Therapy (overview). Plymouth Meeting (PA): ECRI Institute External Site2011 Oct.
  • Coen JJ, Zietman AL, Rossi CJ et al. Comparison of high-dose proton radiotherapy and brachytherapy in localized prostate cancer: a case-matched analysis. Int J Radiat Oncol Biol Phys. 2012 Jan 1; 82(1):e25-31. Epub 2011 Apr 4.
  • Coen JJ, Paly JJ, Niemierko A et al. Long-term quality of life outcome after proton beam monotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Jan 1; 82(1):213-21. Epub 2010 Nov 17.
  • Kahn J, Loeffler JS, Niemierko A et al. Long-term outcomes of patients with spinal cord gliomas treated by modern conformal radiation techniques. Int J radiat Oncol Biol Phys. 2011; 81(1):232-38.
  • Ramaekers BL, Pijls-Johannesma M, Joore MA et al. Systematic review and meta-analysis of radiotherapy in various head and neck cancers: comparing photons, carbon-ions and protons. Cancer treat Rev. 2011; 37(3):185-201.
  • ECRI Institute. Proton Beam Radiation Therapy (Overview). Plymouth Meeting (PA): ECRI Institute External SiteAugust 2012. [Emerging Technology Evidence Report].
  • Allen AM, Pawlicki T, Dong L, Fourkal E, et al. An evidence based review of proton beam therapy: the report of ASTRO's emerging technology committee. Radiother Oncol 2012 Apr;103(1):8-11.
  • National Comprehensive Cancer Network External Site(NCCN). Soft Tissue Sarcoma Version 1.2013.
  • National Comprehensive Cancer Network External Site(NCCN). Bone Cancer Version 1.2014.
  • National Comprehensive Cancer Network External Site(NCCN). Prostate Cancer Version 1.2014. National Comprehensive Cancer Network (NCCN). Non Small Cell Lung Cancer Version 2.2014.
  • National Comprehensive Cancer Network External Site(NCCN). Central Nervous System Cancers Version 2.2013.
  • UpToDate External SiteRadiation Therapy Techniques in Cancer Treatment. Timur Mitin, M.D., PhD. Topic last updated: September 9, 2013.
  • ASTRO External SitePractice Management-Proton Beam Therapy for Prostate Cancer Position Statement.
  • ASTRO External SiteNews and Medical Releases 2013. Encouraging Outcomes for Pediatric Brain Tumor Patients Treated with Proton Therapy. September 22, 2013.
  • American Brain Tumor Association External SitePituitary Tumors.
  • ECRI Institute External SiteEmerging Technology Evidence Report. Proton Beam Radiation Therapy (Overview). January 2013.
  • American Brain Tumor Association External SiteProton Therapy.
  • UpToDate External SiteLocal Treatment for Primary Soft Tissue Sarcoma of the Extremities and Chest Wall. Thomas F. DeLaney, M.D., David C. Harmon, M.D., Mark C. Gebhardt, M.D.. Topic last updated: February 5, 2016.
  • National Cancer Institute External SiteChildhood Craniopharyngioma Treatment. Last modified August 2013.
  • National Cancer Institute External SiteIntraocular (Uveal) Melanoma Treatment. Last modified November 2012.
  • Agency for Healthcare Research and Quality (AHRQ). Proton Beam Radiation Therapy. March 2013.
  • ECRI Institute External SiteHotline Response. Proton Beam Radiation Therapy for Cancers of the Brain, Head, Neck and Skull Base. May 2013.
  • UpToDate External SiteBrain Arteriovenous Malformation. Robert J. Singer, M.D., Christopher S. Ogilvy, M.D., Guy Rordorf, M.D. Topic last updated: February 28, 2014.
  • UpToDate External SiteChordoma and Chondrosarcoma of the Skull Base. Carol Snyderman, M.D., MBA, Derrick Lin, M.D. Topic last updated July 30, 2013.
  • UpToDate External SiteUveal and Conjunctival Melanoma. Evangelos S. Gragoudas, M.D., Anne Marie Lane, MPH, Helen A. Shih, M.D., Richard D. Carvajal, M.D.. Topic last updated October 29, 2013.
  • UpToDate External SiteExternal Beam Radiation Therapy for Localized Prostate Cancer. Steven J. DiBiase, M.D., Mack Roach, III, M.D.. Topic last updated June 29, 2016.
  • American Cancer Society. Radiation Therapy for Pituitary Tumors. Last reviewed January 2013.
  • ASTRO External SiteModel Policies – Proton Beam Therapy (PBT) June 2014.
  • National Comprehensive Cancer Network External Site(NCCN) Version 2.2016 Soft Tissue Sarcoma.
  • National Comprehensive Cancer Network External Site(NCCN) Version 4.2016 Non-Small Cell Lung Cancer.
  • National Comprehensive Cancer Network External Site(NCCN) Version 2.2016 Bone Cancer.
  • National Comprehensive Cancer Network External Site(NCCN) Version 2.2016 Anal Cancer.
  • National Comprehensive Cancer Network External Site(NCCN) Version 2.2016 Bladder Cancer.
  • National Comprehensive Cancer Network External Site(NCCN) Version 2.2016 Colon Cancer.
  • National Comprehensive Cancer Network External Site(NCCN) Version 2.2016 Rectal Cancer.
  • National Comprehensive Cancer Network External Site(NCCN) Version 2.2016 Esophageal and Esophoagogastric Junction Cancers.
  • National Comprehensive Cancer Network External Site(NCCN) Version 2.2016 Hepatobillary Cancers.
  • National Comprehensive Cancer Network External Site(NCCN) Version 3.2016 Hodgkin Lymphoma.
  • National Comprehensive Cancer Network External Site(NCCN) Version 1.2016 Ovarian Cancer.
  • National Comprehensive Cancer Network External Site(NCCN) Version 1.2016 Pancreatic Adenocarcinoma.
  • National Comprehensive Cancer Network External Site(NCCN) Version 2.2016 Uterine Neoplasms.
  • ECRI External SiteHealth Technology Forecast. Proton Beam Therapy for Treating Cancer, July 2014.
  • F. Daniel Armstrong, University of Miami Miller School of Medicine; and Holtz Children’s Hospital, Univerity of Miami/Jackson Memorial Medical Center, Miami, FL. Proton Beam Radiation Therapy and Health Related Quality of Life in Children with CNS Tumors. Journal of Clinical Oncology, Volume 30, Number 17, June 10, 2010.
  • National Comprehensive Cancer Network External Site(NCCN). Non-Hodgkin’s Lymphomas Version 132016.
  • National Comprehensive Cancer Network External Site(NCCN) Prostate Cancer Version 3.20156
  • American College of Radiology (ACR) Appropriateness Definitive External Beam Irradiation in Stage T1 and T2 Prostate Cancer, Am J Clin Oncol 2014;37:278-288
  • American Society for Radiation Oncology External Site(ASTRO) Model Policies: Proton Beam Therapy (PBT) 2014.
  • American Society for Radiation Oncology (ASTRO) Recommends Five Radiation Oncology Treatments to Question as Part of Choosing Wisely Campaign External SiteSeptember 2013.
  • National Cancer Institute External SiteHealth Professional PDQ Prostate Cancer Treatment.
  • ECRI External SiteHealth Technology Forecast. Proton Beam Therapy Systems for Treating Cancer, Published June 2015.
  • Cancer.Net External SiteBrain Tumor Overview and Treatment Options.
  • Cancer.Net External SiteCentral Nervous System Tumors - Childhood Overview and Treatment Options.
  • National Comprehensive Cancer Network External Site(NCCN) Central Nervous System Tumors Version 1.2015.
  • National Comprehensive Cancer Network External Site(NCCN) Gastric Cancer Version 2.2016.
  • National Comprehensive Cancer Network External Site(NCCN) Head and Neck Cancer Version 1.2016.
  • National Comprehensive Cancer Network External Site(NCCN) Kidney Cancer Version 3.2016.
  • National Comprehensive Cancer Network External Site(NCCN) Melanoma Version 3.2015.
  • National Comprehensive Cancer Network External Site(NCCN) Malignant Pleural Mesothelioma Version 2.2015.
  • National Comprehensive Cancer Network External Site(NCCN) Multiple Myeloma Version 4.2015.
  • National Comprehensive Cancer Network External Site(NCCN) Neuroendocrine Tumors Version 1.2015.
  • National Comprehensive Cancer Network External Site(NCCN) Occult Primary Version 1.2015.
  • National Comprehensive Cancer Network External Site(NCCN) Small Cell Lung Cancer Version 1.2016.
  • National Comprehensive Cancer Network External Site(NCCN) Testicular Cancer Version 2.20165.
  • National Comprehensive Cancer Network External Site(NCCN) Thymomas and Thymic Conditions Version 3.2016.
  • National Comprehensive Cancer Network External Site(NCCN) Thyroid Carcinoma Version 1.2016.
  • Blanchard P, Garden A, Gunn G.B., et. al Intensity modulated proton beam therapy (IMPT) versus intensity modulated photon therapy (IMRT) for patients with oropharynx cancer – a case matched analysis. Journal Radiotherapy and Oncology May 2016.
  • Wang J, Palmer M, Bilton S, et. al. Comparing proton beam to intensity modulated radiation therapy planning in esophageal cancer. International Journal of Particle Therapy 2015;1(4):866-877
  • Wang J, Wei C, Tucker S, et.al. Predictors of postoperative complications after trimodality therapy for esophageal cancer. Int J Radiat Oncol Biol Phys 2013 Aug 1; 86(5): 885-891
  • Sio T, Lin HK, Shi Q, et. al. Intensity modulated proton therapy versus intensity modulated photon radiation therapy for oropharyngeal cancer: First comparative results of patient-reported outcomes. Int J Radiation Oncol Biol Phys Vol. 95, No. 4 pp 1107-1114
  • Holliday E, Garden A, Rosenthal D, et. al. Proton therapy reduces treatment-related toxicities for patients with nasopharyngeal cancer: A case match control study of intensity-modulated proton therapy and intensity-modulated photon therapy. International Jounr of Particle Therapy 2015;2(1):19-28
  • Gunn GB, Blanchard P, Garden A, et. al. Clinical outcomes and patterns of disease recurrence after intensity modulated proton therapy for oropharyngeal squamous carcinoma. Int J Radiation Oncol Biol Phys. Vol. 95, No. 1, pp. 360-367, 2016  
  • Frank S, Cox James, Gillin M, et. al. Multifield optimization intensity modulated proton therapy for head and neck tumors: A translation to practice. Int J Radiation Oncol Biol Phys, Vol. 89, No. 4, pp. 846-853, 2014
  • Slater J, Yonemoto L, Mantik D, et. al. Proton radiation for treatment of cancer of the oropharynx: Early experience at Loma Linda University Medical Center using a concomitant boost technique. Int J. Radiation Oncology Biol. Phys. Vol. 62. No.2, pp. 494-500, 2005
  • Patel S, Wang Z, Wong William, et. al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity-malignant diseases: a systematic review and meta-analysis. Lancet Oncol 2014;15:1027-38
  • Welsh J, Gomez D, Palmer M, et. al. Intensity-modulated proton therapy further reduces normal-tissue exposure during definitive therapy for locally advanced distal esophageal tumors: A dosimetric study. Int J Radiat Oncol Biol Phys 2011 Dec 1; 81(5):1336-1342
  • Zhang X, Zhao K, Guerrero T. et. al. 4D CT-based treatment planning for intensity modulated radiation therapy and proton therapy for distal esophagus cancer. Int J Radiat Oncol Biol Phys. 2008 September 1; 72(1):278-287
  • Batra S, Comisar L, Lukens JN, et. al. Lower rates of acute gastrointestinal toxicity with pencil beam proton therapy relative to IMRT in neoadjuvant chemoradiation for rectal cancer. J Clin Oncol 2015;33:696
  • MacDonald S, Patel S, Hickey S, et. al. Proton therapy for breast cancer after mastectomy: Early outcomes of a prospective clinical trial. Int J Radiation Oncol Biol Phys. Vol 86. No. 3. Pp. 484-490, 201
  • Mast M, Vredeveld E, Credoe H, et. al. Whole breast proton irradiation for maximal reduction of heart dose in breast cancer patients. Breast Cancer Res Treat (2014) 148-33-39
  • Darby S, Ewertz M, McGale P, et. al. Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer. The New England Journal of Medicine, March 14, 2013 Vol. 368. No. 11
  • UpToDate External SiteOverview of treatment for head and neck cancer. Bruce E. Brockstein M.D., Kerstin M. Stenson, M.D., FACS, Shiu Song, M.D., PhD. Topic last updated July 12, 2016.
  • UpToDate External SiteAge Related Macular Degeneration Treatment and Prevention. Jorge G Arroyo M.D., MPH. Topic last updated March 2, 2016.
  • UpToDate External SiteRadiation Therapy, Chemotherapy, Neoadjuvant Approaches, and Postoperative Adjuvant Therapy for Localized Cancers of the Esophagus. Noah C Choi, M.D., Michael K. Gibson M.D., PhD, FACP. Topic last updated April 22, 2016.
  • UpToDate External SiteManagement of Locally Advanced Unresectable and Inoperable Esophageal Cancer. Dwight E. Heron M.D., MBA, FACRO, FACR, Michael K. Gibson M.D, PhD, FACP. Topic last updated November 24, 2015.
  • UpToDate External SiteInitial approach to low and very low risk clinically localized prostate cancer. Eric A. Klein M.D., Jay P. Ciezki M.D, Topic last updated March 21, 2016.
  • UpToDate External SiteInitial Management of Regionally Localized Intermediate, High and Very High Risk Prostate Cancer. John F. Ward, M.D., FACS, Nicholas Vogelzang, M.D., Brian Davis, M.D., PhD. Topic last updated June 2, 2016.    
  • UpToDate External SiteClinical Features, Evaluation, and Treatment of Retroperitoneal Soft Tissue Sarcoma. John T. Mullen M.D., FACS, Thomas F. DeLaney, M.D. Topic last updated July 8, 2016.
  • UpToDate External SiteTreatment of Locally Recurrent and Unresectable, Locally Advanced Soft Tissue Sarcoma of the Extremities. Thomas F. DeLaney M.D., David C. Harmon, M.D., Mark C. Gebhardt, M.D.. Topic last updated March 24, 2016.
  • UpToDate External SiteOverview of the Treatment of Newly Diagnosed, Non-Metastatic Breast Cancer. Alphose Taghian, M.D., PhD, Moataz N. El-Ghamry, M.D., Sofia D. Merajver, M.D., PhD. Topic last updated March 29, 2016.
  • UpToDate External SiteOverview of Treatment Approaches for Hepatocellular Carcinoma. Eddie K. Abdalla, M.D., Keith E. Stuart, M.D.. Topic last updated April 14, 2016.
  • UpToDate External SiteRadiation Therapy Techniques in Cancer Treatment. Timur Mitin M.D., PhD. Topic last updated January 14, 2016.
  • National Comprehensive Cancer Network (NCCN) External SiteCervical Cancer Version 1.2016.
  • National Comprehensive Cancer Network (NCCN) External SiteVulvar Cancer (Squamous Cell Carcinoma) Version 1.2016.
  • Sen S. Arteriovenous Malformations Treatment and Management. MedScape External SiteUpdated May 27, 2014.
  • Cotter SE, McBride SM, Yock TI. Proton radiotherapy for solid tumors of childhood. Technol Cancer Res Treat 2012 Jun;11(3):267-78. PMID 22417062
  • Leroy R, Benahmed N, Hulstaert F, et al. Proton therapy in children: a systematic review of clinical effectiveness in 15 pediatric cancers. Int J Radiat Oncol Biol Phys. May 1 2016;95(1):267-278. PMID 27084646
  • Merchant TE. Proton beam therapy in pediatric oncology. Cancer J. Jul-Aug 2009;15(4):298-305. PMID 19672146
  • Kim YJ, Cho KH, Pyo HR, et al. A phase II study of hypofractionated proton therapy for prostate cancer. Acta Oncol. Apr 2013;52(3):477-485. PMID 23398594
  • Sun F, Oyesanmi O, Fontanarosa J, et al. Therapies for Clinically Localized Prostate Cancer: Update of a 2008 Systematic Review. Comparative Effectiveness Review No. 146). AHRQ Publication No. 15-EHC004-EF. Rockville (MD): Agency for Healthcare Research and Quality;Dec 2014.
  • Grutters JP, Kessels AG, Pijls-Johannesma M, et al. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis. Radiother Oncol. Apr 2010;95(1):32-40. PMID 19733410
  • Pijls-Johannesma M, Grutters JP, Verhaegen F, et al. Do we have enough evidence to implement particle therapy as standard treatment in lung cancer? A systematic literature review. Oncologist. 2010;15(1):93-103. PMID 20067947
  • Zenda S, Kawashima M, Arahira S, et al. Late toxicity of proton beam therapy for patients with the nasal cavity, para-nasal sinuses, or involving the skull base malignancy: importance of long-term follow-up. Int J Clin Oncol. Jun 2015;20(3):447-454. PMID 25135461
  • Chang JY, Jabbour SK, De Ruysscher D, et al. Consensus statement on proton therapy in early-stage and locally advanced non-small cell lung cancer. Int J Radiat Oncol Biol Phys. May 1 2016;95(1):505-516. PMID 27084663
  • Nguyen PL, Aizer A, Assimos DG, et al. ACR Appropriateness Criteria(R) Definitive External-Beam Irradiation in stage T1 and T2 prostate cancer. Am J Clin Oncol. Jun 2014;37(3):278-288. PMID 25180754
  • Ojerholm E, Kirk ML, Thompson RF, et.al. Pencil-beam scanning proton therapy for anal cancer. a dosimetric comparison with intensity modulated radiotherapy. Acta Oncol 2015;54(8):1209-17. PMID 25734796
  • Specht L, Yahalorn J, Illidge T. et. al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the International Lymphoma Radiation Oncology Group (ILROG). Int J Radiat Oncol Biol Phys 2014 July 15;89(4):854-62. PMID 23790512
  • Illidge T, Specht L. Yahalom J. et. al. Modern radiation for nonal non-Hodgkin lymphoma target definition and dose guidelines from the Internationl Lymphoma Radiation Oncology Group (ILROG). Int J Radiat Oncol. Biol Phys 2014 May 1;89(1):49-58. PMID 24725689   
  • American Academy of Ophthlamology (AAO) External SiteAge Related Macular Degeneration Preferred Practice Pattern Guidelines 2015.

Policy History:

  • 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.

*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.