BlueCross and BlueShield of Montana Medical Policy/Codes
Charged-Particle (Proton or Helium Ion) Radiation Therapy
Chapter: Radiology
Current Effective Date: December 27, 2013
Original Effective Date: March 01, 2010
Publish Date: September 27, 2013
Revised Dates: March 7, 2012; January 30, 2013; September 5, 2013
Description

Charged-particle beams consisting of protons or helium ions are a type of particulate radiation therapy. They contrast with conventional electromagnetic (i.e., photon) radiation therapy due to several unique properties, including minimal scatter as particulate beams pass through tissue, and deposition of ionizing energy at precise depths (i.e., the Bragg peak). Thus, radiation exposure of surrounding normal tissues is minimized. The theoretical advantages of proton beam therapy (PBT) are that it may improve outcomes and decrease toxicitywhen the following conditions apply:

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

Participating Providers are required to Prior authorize radiation oncology/therapy for Blue Cross Blue Shield of Montana (BCBSMT) Members eligible for the CareCore Program. To authorize, Utilize CareCore National’s website: http://www.carecorenational.com/  or call 1-866-668-7446, option1. Services that are not prior authorized will be denied. For benefit questions call (BCBSMT) Customer Service at 1-800-447-7828.

For Non-Eligible Members, Out of State Providers, and Non-participating providers Prior authorization is recommended. To authorize, call Blue Cross and Blue Shield of Montana (BCBSMT) Customer Service at 1-800-447-7828 or fax your request to the Medical Review Department at 406-441-4624. A retrospective review is performed if services are not prior authorized.

Medically Necessary

BCBSMT may consider charged-particle irradiation with proton or helium ion beams medically necessary in the following clinical situations:

  • Uveal melanoma when PBT is considered preferential compared to brachytherapy
  • Chordomas and Chondrosarcomas of the base of the skull, localized and in the postoperative setting
  • Localized unresectable hepatocellular carcinoma when considered preferential to stereotactic body radiation therapy (SBRT) or radiofrequency ablation
  • Pediatric CNS and spinal tumors.

Investigational

For all other tumors, PBT is considered experimental, investigational, or unproven.  PBT in combination with photon therapy for any tumor is considered investigational.  Since PBT has not been proven to lower the incidence of second malignancies compared to photon therapy, PBT is considered investigational when the sole reason for its use is to theoretically decrease the risk of second malignancy.

PBT for accelerated partial breast or wholebreast irradiation is considered experimental, investigational and unproven.

Policy Guidelines

The use of proton beam or helium ion radiation therapy typically consists of a series of CPT codes describing the individual steps required: medical radiation physics, clinical treatment planning, treatment delivery, and clinical treatment management. It should be noted that the code for treatment delivery primarily reflects the costs related to the energy source used and not physician work. The following CPT codes have been used:

Medical Radiation Physics

77399

Clinical Treatment Planning

77299

Treatment delivery

The codes used for treatment delivery will depend on the energy source used, typically either photons or protons. For photons (i.e., with a Gamma Knife or LINAC device) nonspecific radiation therapy treatment delivery CPT codes may be used based on the voltage of the energy source (i.e., codes 77402–77416). When proton beam therapy is used, the following specific CPT codes are available:

77520, 77522, 77523, 77525

Note: Codes for treatment delivery primarily reflect the costs related to the energy source used, and not physician work.

Clinical Treatment Management

77499

Stereotactic charged particle radiosurgery would be reported with the following CPT codes:

61796, 61797, 61798, 61799, 63620, 63621

Rationale

Charged-particle beam radiation therapy has been most extensively studied in uveal melanomas, in which the focus has been to provide adequate local control while still preserving vision. Pooling data from 3 centers, Suit and Urie reported local control in 96% and 5-year survival of 80%, results considered equivalent to enucleation. (1) A recent summary of results from the United Kingdom reports 5-year actuarial rates of 3.5% for local tumor recurrence, 9.4% for enucleation, 61.1% for conservation of vision of 20/200 or better, and 10.0% death from metastasis. (2) The available evidence also suggested that charged-particle beam irradiation is at least as effective as, and may be superior to, alternative therapies, including conventional radiation or resection to treat chordomas or chondrosarcoma of the skull base or cervical spine. (1) A TEC Assessment completed in 1996 (3) reached the same conclusions.

One if the earliest published trials on proton beam therapy to treat prostate cancer was a randomized clinical trial published in 1995 comparing outcomes of conventional radiation therapy with versus without an additional radiation “boost” of proton beam therapy (PBT). (4) Patients treated in the control arm received a total of 67.2 Gy, while those in the “high-dose” arm received a total of 75.6 Gy. (These doses are below those often currently given.) This study, initiated in 1982, was designed to determine if this dose escalation of 12.5% would increase the 5- and 8-year rates of local control, disease-specific survival, overall survival, or total tumor-free survival with acceptable adverse effects. There was no statistically significant difference in any of the outcomes measured. On subgroup analysis, patients with poorly differentiated cancer, achieved a statistically significant improvement in the rate of local control but not in other outcomes, such as overall survival or disease-specific survival. Patients in the high-dose arm experienced a significantly increased rate of complications, most notably rectal bleeding. Subsequently, new sophisticated treatment planning techniques, referred to as 3-dimensional conformal radiotherapy (3D-CRT) or image-modulated radiation therapy (IMRT), have permitted dose escalation of conventional radiation therapy to 80 Gy, a dose higher than that achieved with proton therapy in the above study. (5,6) Furthermore, these gains were achieved without increasing radiation damage to adjacent structures.

Many of the reports published document the experience of the Loma Linda University Medical Center (Loma Linda, CA). In 2004, investigators at Loma Linda reported their experience with 1,255 patients with prostate cancer who underwent 3D-CRT-proton beam radiation therapy. (7) Outcomes were measured in terms of toxicity and biochemical control, as evidenced by prostate specific antigen (PSA) levels. The overall biochemical disease-free survival rate was 73% and was 90% in patients with initial PSA less than or equal to 4.0. The long-term survival outcomes were comparable with those reported for other modalities intended for cure.

From the published literature, it appears that dose escalation is an accepted concept in treating organ-confined prostate cancer. (8) Proton beam therapy, using 3-D CRT planning or IMRT, is one technique used to provide dose escalation to a more well-defined target volume. However, dose escalation is more commonly offered with conventional external beam radiation therapy using 3-D CRT or IMRT. The morbidity related to radiation therapy of the prostate is focused on the adjacent bladder and rectal tissues; therefore, dose escalation is only possible if these tissues are spared. Even if IMRT or 3-D CRT permits improved delineation of the target volume, if the dose is not accurately delivered, perhaps due to movement artifact, the complications of dose escalation can be serious, as the bladder and rectal tissues are now exposed to even higher doses. The accuracy of dose delivery applies to both conventional and proton beam therapy. (9) Ongoing randomized studies are examining the outcomes of dose escalation for conventional external beam radiation therapy (EBRT). (10)

2006 Update

Additional data have been published concerning use of proton beam therapy in localized prostate cancer. (11) While there have not been randomized studies, reports from treating large numbers of patients with prostate cancer using this modality have demonstrated results comparable to those obtained with alternative techniques.

A number of case series describe initial results using proton beam therapy in hepatocellular cancer, non-small-cell lung cancer, metastatic tumors of the choroid, and recurrent uveal melanoma. However, these results are not sufficient to determine whether proton beam therapy offers any advantage over conventional treatments for these conditions.

2007–2008 Update

The policy was updated with a literature search using MEDLINE in January 2008. None of the publications identified lead to a change in the policy statement. Publications describe initial, preliminary results of using proton beam radiotherapy in other malignancies such as breast cancer. In addition, the combination of proton beam radiotherapy with transpupillary thermotherapy in the treatment of ocular melanoma is being studied. (12) A recent Agency for Healthcare Research and Quality (AHRQ) comparative effectiveness review of therapies for clinically localized prostate cancer indicated that, based on nonrandomized comparisons, the absolute rates of outcomes after proton radiation appear similar to other treatments. (13)

August 2008 Update

The policy was updated on treatment of prostate cancer with a literature search using MEDLINE through July 2008. No studies were identified that would alter the conclusions of the AHRQ report which noted that results of proton beam therapy appear similar to results of other treatments for clinically localized prostate cancer. (13) Given these conclusions, along with information that proton beam therapy is generally more costly than alternative treatments, proton beam therapy is considered not medically necessary.

In an editorial, Zeitman comments that while proton beam therapy has been used in prostate cancer for some time, and there is a growing body of evidence confirming clinical efficacy, apart from some comparative planning studies, there is no proof that it is superior to alternatives such as 3-D CRT or IMRT. (14) The editorial notes that proton beam therapy could show benefit by either allowing greater dose escalation (if improved outcomes were demonstrated) or by allowing certain doses of radiation therapy to be delivered with fewer adverse effects compared to other modalities. In terms of dose escalation, the editorial reports on a model (proposed by Konski) that speculates delivering 91.8 Gy could yield a 10% improvement in 5-year freedom from biochemical failure for men with intermediate risk (15% to 20% of those with prostate cancer) of disease. The editorial also comments that the ability to deliver this dose of radiation has yet to be studied. In terms of proton beam therapy leading to reduced side effects, the editorial notes that work is just beginning. The author comments that we do not know whether there would be gains by treating with proton beam therapy to the doses currently used in IMRT therapy (around 79 to 81 Gy); this is a topic for which studies are needed.

2009-2010 Update

The policy was updated with a literature search using MEDLINE through November 2009. No randomized trials of charged particle radiation therapy for cancer were identified. Case series are reporting early results for use of proton beam therapy in cancer involving the lung and the liver. A recent systematic review of charged-particle radiation therapy for cancer concluded “evidence on the comparative effectiveness and safety of charged-particle radiation therapy in cancer is needed to assess the benefits, risks, and costs of treatment alternatives.” (15) Thus, the policy statements are unchanged.

October 2010 Update

The policy was updated following a TEC Assessment on use of proton beam therapy for non-small-cell lung cancer (NSCLC). (16)

This TEC Assessment addressed the key question of how health outcomes (overall survival, disease-specific survival, local control, disease-free survival, and adverse events) with proton beam therapy (PBT) compare with outcomes observed for stereotactic body radiotherapy (SBRT), which is an accepted approach for using radiation therapy 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. For these studies, stage I comprised 88.5% of all patients, and only 39 patients were in other stages or had recurrent disease. Among 7 studies reporting 2-year overall survival, probabilities ranged between 39% and 98%. At 5 years, the range across 5 studies was 25% to 78%. It is unclear if the heterogeneity of results can be explained by differences in patient and treatment characteristics.

A recent indirect meta-analysis reviewed in the Assessment found a nonsignificant difference of 9 percentage points between pooled 2-year overall survival estimates favoring SBRT over PBT. (17) The nonsignificant difference of 2.4 percentage points at 5 years also favored SBRT over PBT. Based on separate groups of single-arm studies on SBRT and PBT, it is unclear if this indirect meta-analysis adequately addressed the possible influence of confounding on the comparison of SBRT and PBT. The Assessment noted that adverse events reported after PBT generally fell into the following categories: rib fracture, cardiac, esophageal, pulmonary, skin, and soft tissue. Adverse events data in PBT studies are difficult to interpret due to lack of consistent reporting across studies, lack of detail about observation periods and lack of information about rating criteria and grades.

The report concluded that the evidence is insufficient to permit conclusions about the results of PBT for any stage of NSCLC. All PBT studies are case series; there are no studies directly comparing PBT and 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 were similar in patient age, 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 whether the heterogeneity of results can be explained by differences in patient and treatment characteristics. In addition, indirect comparisons between PBT and SBRT, comparing separate sets of single-arm studies on PBT and SBRT may be distorted by confounding. In the absence of randomized controlled trials, the comparative effectiveness of PBT and SBRT is uncertain.

Since the published data do not allow conclusion about the results of PBT on health outcomes for any stage of NSCLC, this is considered investigational. Details regarding this application are added to the investigational policy statement.

Prostate Cancer

Three recent review articles comment that current data do not demonstrate improved outcomes with use of PBT for prostate cancer. In a 2010 review, Kagan and Schulz comment about the lack of data related to improved outcomes and make a number of additional, important comments. (18) They note that while projected dose distribution for PBT suggests reduced rated of bladder and rectal toxicity, toxicity reports for PBT in prostate cancer are similar to those for intensity-modulated radiation therapy (IMRT). They also comment that the role of dose escalation and the optimum doses and dose rates are yet to be established. Finally, they note that the potential for treatment errors with PBT is much greater than with photons. Brada and colleagues reported on an updated systematic review of published peer-reviewed literature for PBT and concluded it was devoid of any clinical data demonstrating benefit in terms of survival, tumor control, or toxicity in comparison with best conventional treatment for any of the tumors so far treated, including prostate cancer. (19) They note that the current lack of evidence for benefit of protons should provide a stimulus for continued research with well-designed clinical trials. In another review article, Efstathiou and colleagues concluded that the current evidence does not support any definitive benefit to PBT over other forms of high-dose conformal radiation in the treatment of localized prostate cancer. (20) They also comment on uncertainties surrounding the physical properties of PBT, perceived clinical gain, and economic viability. Thus, the policy statement regarding use for prostate cancer is unchanged.

2011 update

Lung Cancer

Pijls-Johannesma and colleagues conducted a systematic literature review through November 2009 examining the evidence on the use of particle therapy in lung cancer. (21) Study inclusion criteria included that the series had at least 20 patients and a follow-up period ≥24 months. Eleven studies were included in the review, five investigating protons (n=214) and six C-ions (n=210). The proton studies included one phase 2 study, 2 prospective studies and 2 retrospective studies. The C-ion studies were all prospective and conducted at the same institution in Japan. No phase 3 studies were identified. Most patients had stage 1 disease, however, a wide variety of radiation schedules were used making comparisons of results difficult, and local control rates were defined differently across studies. For proton therapy, 2- to 5-year local tumor control rates varied in the range of 57%–87%. The 2- and 5-year overall survival (OS) and 2- and 5-year cause-specific survival (CSS) rates were 31%–74% and 23% and 58%–86% and 46%, respectively. These local control and survival rates are equivalent to or inferior to those achieved with stereotactic radiation therapy. Radiation-induced pneumonitis was observed in about 10% of patients. For C-ion therapy, the overall local tumor control rate was 77%, but it was 95% when using a hypofractionated radiation schedule. The 5-year OS and CSS rates were 42% and 60%, respectively. Slightly better results were reported when using hypofractionation, 50% and 76%, respectively. The authors concluded that the results with protons and heavier charged particles are promising, but that because of the lack of evidence, there is a need for further investigation in an adequate manner with well-designed trials.

Prostate Cancer

A 2010 TEC Assessment addressed the use of proton beam therapy for prostate cancer, and concluded that it has not yet been established whether proton beam therapy improves outcomes in any setting in prostate cancer. (22) The following is a summary of the main findings.

A total of 9 studies were included in the review; 4 were comparative and 5 were noncomparative. Five studies included patients who received x-ray external-beam radiotherapy plus proton beam boost, one study included a mix of patients with separate results for those given only protons and those given x-rays plus protons, one mixed study lacked separate results and 2 studies only included patients receiving proton beam therapy without x-ray external beam radiotherapy. Among studies using proton beam boost, only one study provided survival outcome data for currently applicable methods of x-ray external-beam radiotherapy. Thus, data on survival outcomes were insufficient to permit conclusions about effects. Three studies on proton beam boost and 2 studies on proton beam alone gave data on biochemical failure. Prostate cancer symptoms were addressed in 2 studies and quality of life in one. Eight of 9 studies report on genitourinary and gastrointestinal toxicity.

There was inadequate evidence from comparative studies to permit conclusions for any of the comparisons considered. Ideally, randomized, controlled trials would report long-term health outcomes or intermediate outcomes that consistently predict health outcomes. Of the 4 comparisons, there was one good quality randomized trial each for 2 of them. One showed significantly improved incidence of biochemical failure, an intermediate outcome of uncertain relation to survival, for patients receiving high-dose proton beam boost compared with conventional dose proton boost. No difference between groups has been observed in overall survival. Grade 2 acute gastrointestinal toxicity was significantly more frequent in the group receiving high-dose proton beam boost but acute genitourinary toxicity and late toxicities did not significantly differ. The other trial found no significant differences between patients receiving x-ray versus proton beam boost on overall survival or disease-specific survival, but rectal bleeding was significantly more frequent among patients who had a proton beam boost. Good quality comparative studies were lacking for other comparisons addressed in the Assessment.

2013 UPDATE

Risk of Second Malignancies

There has been a suggestion that there may be a lower risk of second malignancies with PBT compared to IMRT. A larger volume of normal tissue is exposed low dose radiation with IMRT, and this higher integral dose theoretically could cause a higher rate of second malignancies. However, many Proton facilities in the U.S. use passive scattering PBT, producing secondary neutrons, which may in turn also increase the risk of second malignancies. There is a large body of data discussing the theoretic risks and benefits of PBT with respect to second malignancies, based on modeling.23-27Both sides of the argument can be supported based on this data. It is best summed up by a comprehensive review from the NIH published in June 2013. The publication concluded that “…to date, no observational studies have directly assessed the second cancer risks after IMRT or proton therapy.  Until sufficient follow-up is available to conduct such studies, assessment of the risks relies on risk projection studies or theoretical models.”28

There is also a recent publication from the Massachusetts General Hospital (MGH) proton facilitywhich looks at the risk of second malignancies in their patient population.29The authors admit to several significant limitations of their study, including having lost 26% of the patients to follow-up. While their data shows a lower risk of second malignancies in the proton group (5.2%) compared to a National Cancer Institute Surveillance, Epidemiology and End Results (SEER) database matched a photon control group (7.5%) at a median follow-up of 6.7 years, their conclusion of the study is that “…these findings are reassuring that the risk of second tumors was at least not increased when using protons compared with photons…” and that “…given the limitations of the study, the reduced second tumor rate in the proton cohort that we observed should be viewed as hypothesis generating.”  There is also debate about the reliability of the SEER database matched cohort in determining the risk of second malignancies from photon therapy. An editorial by Bekelman et al accompanying this publication30 concludes that in light of a clear difference in subsequent malignancy rates in the critical longer-term period after treatment and the early differences suggesting study design limitations, hypotheses about the relative benefits or harms of PBT remain unquestionably 2-sided: PBT may be associated with increased or decreased subsequent malignancies compared with photon therapy. A publication by Zelefsky et al. from Memorial Sloan-Kettering Cancer Center on the rate of second malignancies after treatment of prostate cancer with radical prostatectomy, brachytherapy and external beam radiotherapy yielded a different outcome related the conventional radiotherapy.31  Two thousand fifty-eight (2658) patients treated over 3 years were followed over 10 years.  The study found that, when adjusted for age and smoking history, the incidence of second malignancies after radiotherapy was not significantly different from that after radical prostatectomy.  Regarding the risk of second malignancy after cranial irradiation with stereotactic radiosurgery, a study with 5000 patients showed no increased risk.32The authors conclude “Pragmatically, in advising patients, the risks of malignancy would seem small, particularly if such risks are considered in the context of the other risks faced by patients with intracranial pathologies requiring radiosurgical treatments.”

Whether PBT increases or reduces the risk of second malignancies is very much an unanswered issue, and this argument cannot currently play a role in determining the appropriate or inappropriate use of PBT for any patient.

National Cancer Institute Clinical Trials

Two phase III trials are comparing photon versus carbon ion radiation therapy in patients with low and intermediate grade chondrosarcoma of the skull base (NCT01182753) and chordoma of the skull base (CT01182779).

A phase III trial is comparing hypofractionated proton radiation versus standard dose for prostate cancer (NCT01230866).

Summary

  • Studies on the use of charged-particle beam radiation therapy to treat uveal melanomas have shown local control and survival rates considered equivalent to enucleation. Therefore, it is considered medically necessary for this indication.
  • Available evidence suggests that charged-particle beam irradiation is at least as effective as, and may be superior to, alternative therapies, including conventional radiation or resection to treat chordomas or chondrosarcoma of the skull base or cervical spine. Therefore, it is considered medically necessary for this indication.
  • Results of proton beam studies for clinically localized prostate cancer have shown similar results and outcomes when compared to other radiation treatment modalities. Currently, the evidence does not support any definitive benefit to PBT in the treatment of prostate cancer.  Therefore it is considered experimental, investigational, and unproven for treatment of prostate cancer.
  • In treating lung cancer, definite evidence showing superior outcomes with proton beam radiation therapy versus stereotactic body radiation therapy (an accepted approach for treating lung cancer with radiation), is lacking. Therefore, this indication is considered investigational.  There is insufficient evidence proving efficacy and safety using PBT for locally advanced lung cancer, and therefore PBT is considered investigational for this indication.

Practice Guidelines and Position Statements

2013 March ASTRO Board of Directors

ASTRO does not support the routine use of PBT for prostate cancer. “While proton beam therapy is not a new technology, its use in the treatment of prostate cancer is evolving.“ is the statementreleased by ASTRO’s Board of Directors on March 13, 2013. “The comparative efficacy evidence of proton beam therapy is still being developed,” said Michael L. Steinberg, MD, FASTRO, ASTRO Chairman. “We look forward to new and innovative research that will more clearly define the role of proton beam therapy for localized prostate cancer among the currently available treatment options.

2011 National Comprehensive Cancer Network (NCCN) guidelines

NCCN guidelines for prostate cancer (v 4.2011) state that proton therapy is not recommended for routine use at this time since clinical trials have not yet yielded data that demonstrates superiority to, or equivalence of, proton beam and conventional external beam for the treatment of prostate cancer.

NCCN guidelines for non-small cell lung cancer (v 3.2011) state that under strictly defined protocols, proton therapy may be allowed.

NCCN guidelines for bone cancer (v 2.2011) state that proton beam radiation therapy has been associated with excellent local tumor control and long-term survival in patients with low-grade base of skull chondrosarcomas.

Medicare National Coverage

There is no national coverage determination.

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. Blue Cross and Blue Shield of Montana recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply, drug or device will be covered, please note that member contract language will take precedence over medical policy when there is a conflict. 

ICD-9 Codes
92.26, 170.0, 170.2, 170.9, 190.0 – 190.9, 192.2, 198.5
ICD-10 Codes
C41.0, C41.2, C41.9, C49.0, C69.00-C69.92, C72.0, D8004ZZ, D0014ZZ, D0064ZZ
Procedural Codes: 77399, 77299, 77520, 77522, 77523, 77525, 77499
References
  1. Suit H, Urie M. Proton beams in radiation therapy. J Natl Cancer Inst 1992; 84(3):155-64.
  2. Damato B, Kacperek A, Chopra M et al. Proton beam radiotherapy of choroidal melanoma: the Liverpool-Clatterbridge experience. Int J Radiat Oncol Biol Phys 2005; 62(5):1405-11.
  3. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Charged particle (proton or helium ion) irradiation for uveal melanoma and for chordoma or chondrosarcoma of the skull base or cervical spine. TEC Assessments 1996; Volume 11, Tab 1.
  4. Shipley WU, Verhey LJ, Munzenrider JE. Advanced prostate cancer: the results of a randomized comparative trail of high dose irradiation boosting with conformal photons compared with conventional dose irradiation using protons alone. Int J Radiat Oncol Biol Phys 1995; 32(1):3-12.
  5. Hanks GE. A question filled future for dose escalation in prostate cancer. Int J Radiat Oncol Biol Phys 1995; 32(1):267-9.
  6. Cox JD. Dose escalation by proton irradiation for adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1995; 32(1):265-6.
  7. Slater JD, Rossi CJ, Yonemoto LT et al. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int J Radiat Oncol Biol Phys 2004; 59(2):348-52.
  8. Nilsson S, Norlen BJ, Widmark A. A systematic overview of radiation therapy effects in prostate cancer. Acta Oncologica 2004; 43(4):316-81.
  9. Kuban D, Pollack A, Huang E et al. Hazards of dose escalation in prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys 2003; 57(5):1260-8.
  10. Michalski JM, Winter K, Purdy JA et al. Toxicity after three-dimensional radiotherapy for prostate cancer with RTOG 9406 dose level IV. Int J Radiat Oncol Biol Phys 2004; 58(3):735-42.
  11. 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: a randomized controlled trial. JAMA 2005; 294(10):1233-9.
  12. Desjardins L, Lumbroso-Le Rouic L, Levy-Gabriel C et al. Combined proton beam radiotherapy and transpupillary thermotherapy for large uveal melanomas: a randomized study of 151 patients. Ophthalmic Res 2006; 38(5):255-60.
  13. Wilt TJ, Shamliyan T, Taylor B et al. Comparative effectiveness of therapies for clinically localized prostate cancer. Comparative Effectiveness Review No. 13. Agency for Healthcare Research and Quality. February 2008. Available online at: http://effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=9&DocID=79  . Last accessed February 2008.
  14. Zietman AL. The Titanic and the iceberg: prostate proton therapy and health care economics. J Clin Oncol 2007; 25(24):3565-6.
  15. Terasawa T, Dvorak T, Ip S et al. Systematic review: charged-particle radiation therapy for cancer. Ann Intern Med 2009; 151(8):556-65.
  16. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Proton beam therapy for non-small-cell lung cancer. TEC Assessments 2010; Volume 25, Tab 7.
  17. 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 2010; 95(1):32-40.
  18. Kagan AR, Schulz RJ. Proton-beam therapy for prostate cancer. Cancer J 2010; 16(5):405-9.
  19. Brada M, Pijls-Johannesma M, De Ruysscher D. Current clinical evidence for proton therapy. Cancer J 2009; 15(4):319-24.
  20. Efstathiou JA, Trofimov AV, Zietman AL. Life, liberty, and the pursuit of protons: an evidence-based review of the role of particle therapy in the treatment of prostate cancer. Cancer J 2009; 15(4):312-8.
  21. Pijls-Johannesma M, Grutters J, 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.
  22. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Proton beam therapy for prostate cancer. TEC Assessments 2010; Volume 25, Tab 10.
  23. ZacharatouJarlskog C, Paganetti H. Risk of developing second cancer from neutron dose in proton therapy as function of field characteristics, organ, and patient age. Int J RadiatOncolBiol Phys. 2008 Sep 1;72(1):228-35.
  24. Athar BS, Paganetti H. Neutron equivalent doses and associated lifetime cancer incidence risks for head & neck and spinal proton therapy. Phys Med Biol. 2009 Aug 21;54(16):4907-26.
  25. Moteabbed M, Geyer A, et al. Comparison of whole-body phantom designs to estimate organ equivalent neutron doses for secondary cancer risk assessment in proton therapy. Phys Med Biol. 2012 Jan 21;57(2):499-515.
  26. Brenner DJ, Hall EJ. Secondary neutrons in clinical proton radiotherapy: a charged issue. RadiotherOncol. 2008 Feb;86(2):165-70.
  27. Shih HA, Arvold ND Arvold, Niemierko A, et al. Second Tumor Risk and Projected Late Effects after Proton vs. Intensity Modulated Photon Radiotherapy for Benign Meningioma: A Dosimetric Comparison. International Journal of Radiation Oncology * Biology * Physics Vol. 78, Issue 3, Supplement, Page S272.
  28. Berrington de Gonzalez,A, et al. Second Solid Cancers After Radiation Therapy: A Systematic Review of the Epidemiologic Studies of the Radiation Dose-Response Relationship. International Journal of Radiation Oncology * Biology * Physics Volume 86, Issue 2 , Pages 224-233, 1 June 2013 http://www.redjournal.org/article/S0360-3016(12)03512-2/fulltext.
  29. Chung CS, Yock TI, et al. Incidence of Second Malignancies Among Patients Treated With Proton Versus Photon Radiation. Int J RadiatOncolBiol Phys. 2013 Sept 1 : 87(1) : 46-52. 
  30. Bekelman  JE et al. Subsequent Malignancies After Photon versus Proton Radiation Therapy. Int J RadiatOncolBiol Phys. 2013 Sept 1: 87(1):10-12
  31. Zelefsky MJ, Pei X, et al. Secondary cancers after intensity-modulated radiotherapy, brachytherapy and radical prostatectomy for the treatment of prostate cancer: incidence and cause-specific survival outcomes according to the initial treatment intervention. BJU Int. 2012 Dec;110(11):1696-701. http://www.ncbi.nlm.nih.gov/pubmed/22889401.
  32. Rowe J, Grainger A, et al. Risk of Malignancy after Gamma Knife Stereotactic Radiosurgery. Neurosurgery 2007 Jan;60(1):60-5.
History
March 2012 Policy updated with literature search, reference numbers 16-27 added, use for NSCLC added as a specific indication to the investigational statement, other policy statements unchanged 
January 2013 Removed treatment of localized prostate cancer from the Medically Necessary statement. 
September 2013 Simplified wording of medical necessity criteria.  Move prostate cancer to be included in the investigational policy statement.  Added combination proton and photon therapy to investigational statement.  Updated practice guideline statement with ASCO information.
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Charged-Particle (Proton or Helium Ion) Radiation Therapy