|MP 8.01.10||Charged-Particle (Proton or Helium Ion) Radiation Therapy|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/3:2014
|Return to Medical Policy Index|
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Charged-particle beams consisting of protons or helium ions are a type of particulate radiation therapy (RT). They contrast with conventional electromagnetic (ie, photon) RT due to several unique properties, including minimal scatter as particulate beams pass through tissue, and deposition of ionizing energy at precise depths (ie, the Bragg peak). Thus, radiation exposure of surrounding normal tissues is minimized. The theoretical advantages of protons and other charged-particle beams may improve outcomes when the following conditions apply:
- Conventional treatment modalities do not provide adequate local tumor control;
- Evidence shows that local tumor response depends on the dose of radiation delivered; and
- Delivery of adequate radiation doses to the tumor is limited by the proximity of vital radiosensitive tissues or structures.
The use of proton or helium ion RT has been investigated in 2 general categories of tumors/abnormalities. However, advances in photon-based RT such as 3-D conformal RT (3D-CRT), intensity-modulated RT (IMRT), and stereotactic body radiotherapy (SBRT) allow improved targeting of conventional therapy:
1. Tumors located near vital structures, such as intracranial lesions or lesions along the axial skeleton, such that complete surgical excision or adequate doses of conventional RT are impossible. These tumors/lesions include uveal melanomas, chordomas, and chondrosarcomas at the base of the skull and along the axial skeleton.
2. Tumors associated with a high rate of local recurrence despite maximal doses of conventional RT. One tumor in this group is locally advanced prostate cancer (ie, stages C or D1 [without distant metastases], also classified as T3 or T4).
Proton-beam therapy (PBT) can be given with or without stereotactic techniques. Stereotactic approaches are frequently used for uveal tract and skull-based tumors. For stereotactic techniques, 3 to 5 fixed beams of protons or helium ions are used.
Charged-particle irradiation with proton or helium ion beams may be considered medically necessary in the following clinical situations:
- primary therapy for melanoma of the uveal tract (iris, choroid, or ciliary body), with no evidence of metastasis or extrascleral extension, and with tumors up to 24 mm in largest diameter and 14 mm in height;
- postoperative therapy (with or without conventional high-energy x-rays) in patients who have undergone biopsy or partial resection of chordoma or low-grade (I or II) chondrosarcoma of the basisphenoid region (skull-base chordoma or chondrosarcoma) or cervical spine. Patients eligible for this treatment have residual localized tumor without evidence of metastasis.
- in the treatment of pediatric central nervous system tumors.
Charged-particle irradiation with proton beams using standard treatment doses is considered not medically necessary in patients with clinically localized prostate cancer because the clinical outcomes with this treatment have not been shown to be superior to other approaches including intensity-modulated radiation therapy (IMRT) or conformal radiation therapy, yet proton-beam therapy is generally more costly than these alternatives. (See Benefit Application section for contractual items that may impact use in this condition.)
Other applications of charged-particle irradiation with proton beams are considered investigational. This includes, but is not limited to:
- non-small-cell lung cancer (NSCLC) at any stage or for recurrence,
- pediatric noncentral nervous system tumors,
- tumors of the head and neck (other than skull-based chordoma or chondrosarcoma).
There are no data to define age parameters for the use of proton-beam therapy in pediatric patients. Some studies using proton beam therapy in pediatric central nervous system (CNS) tumors mostly included patients younger than 3 years of age. However, experts cite the benefit of proton beam therapy in pediatric patients of all ages (<21 years of age).
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: Unlisted procedure, medical radiation physics, dosimetry, and treatment devices
Clinical Treatment Planning
77299: Unlisted procedure, therapeutic radiology clinical treatment planning
The codes used for treatment delivery will depend on the energy source used, typically either photons or protons. For photons (ie, 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 (ie, codes 77402-77416). When proton beam therapy is used, the following specific CPT codes are available:
77520: Proton treatment delivery; simple, without compensation
77522: Proton treatment delivery; simple with compensation
77523: Proton treatment delivery; intermediate
77525: Proton treatment delivery; complex
Note: Codes for treatment delivery primarily reflect the costs related to the energy source used, and not physician work.
Clinical Treatment Management
77499: Unlisted procedure, therapeutic radiology clinical treatment management
Stereotactic charged particle radiosurgery would be reported with the following CPT codes:
61796: Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); 1 simple cranial lesion
61797: Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); each additional cranial lesion, simple (List separately in addition to code for primary procedure)
61798: Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); 1 complex cranial lesion
61799: Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); each additional cranial lesion, complex (List separately in addition to code for primary procedure)
63620: Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); 1 spinal lesion
63621: Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); each additional spinal lesion (List separately in addition to code for primary procedure)
BlueCard/National Account Issues
Charged particle radiation therapy is a specialized procedure that may require out of network referral.
Because proton beam therapy is generally more costly than alternative therapies but has not been shown to lead to improved outcomes compared to those obtained with alternatives, it is considered not medically necessary using the MPRM medical necessity definition.
For contracts that do not use this definition of medical necessity, other contract provisions including contract language concerning use of out of network providers and services may be applied. That is, if the alternative therapies (e.g., IMRT or conformal treatments) are available in-network but proton beam therapy is not, proton beam therapy would not be considered an in-network benefit. In addition, benefit or contract language describing the 'least costly alternative' may also be applicable for this choice of treatment.
The policy was created in 1996 and updated regularly with searches of the MEDLINE database. The most recent literature review was conducted on February 6, 2014.
Uveal Melanomas and Skull-Based Tumors
The available evidence 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 reached the same conclusions.(2) A systematic review of charged-particle therapy found that local tumor control rate and 5-year overall survival (OS) for skull base chordomas treated with proton therapy were 63% and 81%, respectively, compared with postsurgical treatment with conventional photon therapy with reported local tumor control rates and 5-year OS of 25% and 44%, respectively, and compared with surgery followed by fractionated stereotactic radiotherapy, which resulted in a 5-year local tumor control rate of 50%.(3) A summary of tumor control in published proton therapy studies of chondrosarcoma of the skull base was 95% 5-year local tumor control, similar to the results of conventional therapy.
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. For example, in 1992, Suit and Urie combined data from 3 centers and reported local control in 96% and a 5-year survival of 80%, results considered equivalent to enucleation.(1) A 2005 summary of results from the United Kingdom reported 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.(4)
In 2013, Wang et al published a systematic review on charged-particle (proton, helium or carbon ion) radiation therapy for uveal melanoma.(5) The review included 27 controlled and uncontrolled studies that reported health outcomes eg, mortality, local recurrence. Three of the studies were randomized controlled trials (RCTs). One of the RCTs compared helium ion therapy with an alternative treatment (in this case, brachytherapy). The other 2 RCTs compared different proton beam protocols so cannot be used to draw conclusions about the efficacy of charged-ion particle therapy relative to other treatments. The overall quality of the studies was low; most of the observational studies did not adjust for potential confounding variables. The analysis focused on studies of treatment-naïve patients (all but one of the identified studies). In a pooled analysis of data from 9 studies, there was not a statistically significant difference in mortality with charged-particle therapy compared with brachytherapy (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.01 to 1.63). However, there was a significantly lower rate of local control with charged-particle therapy compared with brachytherapy in a pooled analysis of 14 studies (OR=0.22; 95% CI, 0.21 to 0.23). There were significantly lower rates of radiation retinopathy and cataract formation in patients treated with charged-particle therapy compared with brachytherapy (pooled rates of 0.28 vs 0.42 and 0.23 vs 0.68, respectively). According to this review, there is low-quality evidence that charged-particle therapy is at least as effective as alternative therapies as primary treatment of uveal melanoma and is better at preserving vision.
Pediatric Central Nervous System Tumors
Radiation therapy is an integral component of the treatment of many pediatric central nervous system (CNS) tumors including high-grade gliomas, primitive neuroectodermal tumors (PNETs), medulloblastomas, ependymomas, germ cell tumors, some craniopharyngiomas and subtotally resected low-grade astrocytomas.(6) Children who are cured of their tumor experience long-term sequelae of RT, which may include developmental, neurocognitive, neuroendocrine, and hearing late effects. Radiation to the cochlea may lead to loss of hearing at doses greater than 35 to 45 Gy in the absence of chemotherapy, and the risk of ototoxicity is increased in children who receive ototoxic platinum-based chemotherapy regimens.(7) Craniospinal irradiation, most commonly used in the treatment of medulloblastoma, has been reported to lead to thyroid dysfunction and damage to the lungs, heart and gastrointestinal tract.(7) In addition, patients who receive radiation at a young age are at an increased risk of developing radiation-induced second tumors compared with their adult counterparts.(7)
The development of more conformal radiation techniques has decreased inadvertent radiation to normal tissues; however, while intensity-modulated radiation therapy (IMRT) decreases high doses to nearby normal tissues, it delivers a larger volume of low- and intermediate-dose radiation. Proton-beam radiotherapy eliminates the exit dose to normal tissues and may eliminate ~50% of radiation to normal tissue.
A 2012, 5-year update of a systematic review(3) drew similar conclusions to the original review, that except for rare indications such as childhood cancer, the gain from proton RT in clinical practice remains controversial.(8)
A 2012 review of the literature on the use of proton radiotherapy for solid tumors of childhood, the most common of which are CNS tumors, offered the following summaries of studies and conclusions.(7)
Experience with the use of proton-beam therapy (PBT) for medulloblastoma, the most common malignant CNS tumor in the pediatric population, is relatively large. Although data on the late effects comparing proton with photon therapy are still maturing, dosimetric studies suggest that proton therapy in medulloblastoma should lead to decreased long-term toxicity.
Gliomas in locations where surgical resection can lead to unacceptable morbidity (eg, optic nerves or chiasm, brainstem, diencephalon, cervical-medullary junction), are often treated with chemotherapy in young patients in order to delay radiation, with radiation to a dose of 54 Gy being reserved for unresectable lesions.
Loma Linda University Medical Center reported on proton radiation in the treatment of low-grade gliomas in 27 pediatric patients.(9) Six patients experienced local failure; acute side effects were minimal. After a median follow-up of 3 years, all of the children with local control maintained performance status. A dosimetric comparison of protons with photons for 7 optic pathway gliomas treated at Loma Linda showed a decrease in radiation dose to the contralateral optic nerve, temporal lobes, pituitary gland and optic chiasm with the use of protons.(10)
Massachusetts General Hospital reported on the use of protons in 17 children with ependymoma.(11) Radiation doses ranged from 52.2 to 59.4 cobalt Gy equivalent. Median follow-up was 26 months, and local control, progression-free survival, and OS rates were 86%, 80%, and 89%, respectively. Local recurrences were seen in patients who had undergone subtotal resections. No deleterious acute effects were noted; the authors stated that longer follow-up was necessary to assess late effects. In the same study, 2 IMRT plans were generated to measure for dosimetric advantages with the use of protons for the treatment of infratentorial and supratentorial ependymomas. In both locations, the use of proton radiation provided significant decrease in dose to the whole brain, and specifically the temporal lobes. In addition, as compared with IMRT, proton radiation better spared the pituitary gland, hypothalamus, cochlea, and optic chiasm, while providing equivalent target coverage of the resection cavity.
Craniopharyngiomas are benign lesions, which occur most commonly in children in the late first and second decades of life.(7) Massachusetts General Hospital reported on 5 children treated with combined photon/proton radiation or proton radiation alone with a median follow-up of 15.5 years.(12) All 5 patients achieved local control without evidence of long-term deficits from radiation in endocrine or cognitive function. Loma Linda reported on the use of proton radiation in 16 patients with craniopharyngioma who were treated to doses of 50.4 to 59.4 cobalt Gy equivalent.(13) Local control was achieved in 14 of the 15 patients with follow-up data. Follow-up was 5 years; 3 patients died, 1 of recurrent disease, 1 of sepsis, and 1 of a stroke. Among the survivors, 1 patient developed panhypopituitarism 36 months after debulking surgeries and radiation, a second patient had a cerebrovascular accident 34 months after combined primary treatment, and a third patient developed a meningioma 59 months after initial photon radiation, followed by salvage resection and proton radiation.
Massachusetts General Hospital reported on the use of protons in the treatment of germ cell tumors in 22 patients, 13 with germinoma and 9 with nongerminomatous germ cell tumors (NGGCTs).(14) Radiation doses ranged from 30.6 to 57.6 cobalt Gray equivalents. All of the NGGCT patients received chemotherapy before radiation therapy. Twenty-one patients were treated with cranial spinal irradiation, whole ventricular radiation therapy, or whole brain radiation followed by an involved field boost; 1 patient received involved field alone. Median follow-up was 28 months. There were no CNS recurrences and no deaths. Following radiation therapy, 2 patients developed growth hormone deficiency, and 2 patients developed central hypothyroidism. The authors stated that longer follow-up was necessary to assess the neurocognitive effects of therapy. In the same study, a dosimetric comparison of photons and protons for representative treatments with whole ventricular and involved field boost was done. Proton radiotherapy provided substantial sparing to the whole brain and temporal lobes, and reduced doses to the optic nerves.
Moeller et al reported on 23 children who were enrolled in a prospective observational study and treated with PBT for medulloblastoma between the years 2006-2009.(15) As hearing loss is common following chemoradiotherapy for children with medulloblastoma, the authors sought to compare whether proton radiotherapy led to a clinical benefit in audiometric outcomes (since, compared to photons, protons reduce radiation dose to the cochlea for these patients). The children underwent pre- and 1-year postradiotherapy pure-tone audiometric testing. Ears with moderate-to-severe hearing loss before therapy were censored, leaving 35 ears in 19 patients available for analysis. The predicted mean cochlear radiation dose was 30 60Co-Gy Equivalents (range, 19-43). Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (p<0.05). There was partial sparing of mean postradiation hearing thresholds at low-to-midrange frequencies; the rate of high-grade (grade 3 or 4) ototoxicity at 1 year was 5%. The authors compared this with a rate of grade 3-4 toxicity following IMRT of 18% in a separate case series. The authors concluded that preservation of hearing in the audible speech range, as observed in their study, may improve both quality of life and cognitive functioning for these patients.
Merchant et al(16) sought to determine whether proton radiotherapy has clinical advantages over photon radiotherapy in childhood brain tumors. Three-dimensional imaging and treatment-planning data, which included targeted tumor and normal tissues contours, were acquired for 40 patients. Histologic subtypes in the 40 patients were 10 each with optic pathway glioma, craniopharyngioma, infratentorial ependymoma, or medulloblastoma. Dose-volume data were collected for the entire brain, temporal lobes, cochlea, and hypothalamus, and the data were averaged and compared based on treatment modality (protons vs photons) using dose-cognitive effects models. Clinical outcomes were estimated over 5 years. With protons (compared with photons), relatively small critical normal tissue volumes (eg, cochlea and hypothalamus) were spared from radiation exposure when not adjacent to the primary tumor volume. Larger normal tissue volumes (eg, supratentorial brain or temporal lobes) received less of the intermediate and low doses. When these results were applied to longitudinal models of radiation dose-cognitive effects, the differences resulted in clinically significant higher IQ scores for patients with medulloblastoma and craniopharyngioma and academic reading scores in patients with optic pathway glioma. There were extreme differences between proton and photon dose distributions for the patients with ependymoma, which precluded meaningful comparison of the effects of protons versus photons. The authors concluded that the differences in the overall dose distributions, as evidenced by modeling changes in cognitive function, showed that these reductions in the lower-dose volumes or mean dose would result in long-term, improved clinical outcomes for children with medulloblastoma, craniopharyngioma, and glioma of the optic pathway.
Pediatric Non-CNS Tumors
There are scant data on the use of PBT in pediatric non-CNS tumors and includes dosimetric planning studies in a small number of pediatric patients with parameningeal rhabdomyosarcoma(17) and late toxicity outcomes in other solid tumors of childhood.(18,19)
Localized Prostate Cancer
A 2010 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 in prostate cancer.(20) 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, 1 study included a mix of patients with separate results for those given only protons and those given x-rays plus protons, 1 mixed study lacked separate results, and 2 studies only included patients receiving PBT without x-ray external beam radiotherapy. Among studies using proton beam boost, only 1 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, RCTs would report long-term health outcomes or intermediate outcomes that consistently predict health outcomes. Of the 4 comparisons, there was 1 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 OS. 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 OS 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.
A 2008 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. (21)
One if the earliest published trials on PBT to treat prostate cancer was an RCT published in 1995 comparing outcomes of conventional radiation therapy with versus without an additional radiation “boost” of PBT.(22) 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, OS, 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 OS 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 IMRT, have permitted dose escalation of conventional radiation therapy to 80 Gy, a dose higher than that achieved with proton therapy in the previous study.(23,24) Furthermore, these gains were achieved without increasing radiation damage to adjacent structures.
Subsequently, a 2005 RCT treated 393 patients with prostate cancer using either a conventional-dose or a high-dose PBT and found results comparable with those obtained with conventional techniques.(25)
A 2013 RCT by Kim et al in Korea compared 5 protocols for administering hypofractionated proton therapy in men with androgen-deprivation therapy-naïve stage T1-T3 prostate cancer.(26) The protocols were as follows: arm 1, 60 CGE (cobalt gray equivalent/20 fractions for 5 weeks; arm 2, 54 CGE/15 fractions for 5 weeks; arm 3, 47 CGE/10 fractions for 5 weeks; arm 4, 35 CGE/5 fractions for 2.5 weeks; or arm 5, 35 CGE/5 fractions for 5 weeks. Eighty-two patients were randomized, and there was a median follow-up of 42 months. Patients assigned to arm 3 had the lowest rate of acute genitourinary toxicity and those assigned to arm 2 had the lowest rate of late gastrointestinal toxicity. In this study, proton therapy was not compared with an alternative prostate cancer treatment.
In 2004, investigators at Loma Linda, CA reported their experience with 1255 patients with prostate cancer who underwent 3D-conformal radiotherapy (3D-CRT) PBT.(27) 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 prostate specific antigen 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.(28) PBT, using 3D-CRT planning or IMRT, is 1 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 (EBRT) using 3D-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 3D-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 PBT.(29) Ongoing randomized studies are examining the outcomes of dose escalation for conventional EBRT.(30)
In a 2007 editorial, Zeitman comments that while PBT 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 3D-CRT or IMRT.(31) The editorial notes that PBT could show benefit by either allowing greater dose escalation (if improved outcomes were demonstrated) or by allowing certain doses of RT to be delivered with fewer adverse effects compared with 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%-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 PBT 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 PBT to the doses currently used in IMRT therapy (around 79-81 Gy); this is a topic for which studies are needed.
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.(32) They note that while projected dose distribution for PBT suggests reduced rates of bladder and rectal toxicity, toxicity reports for PBT in prostate cancer are similar to those for 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 et al 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.(33) 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 et al 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.(34) 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.
Non-Small-Cell Lung Cancer
A 2010 TEC Assessment assessed the use of PBT for non-small-cell lung cancer (NSCLC).(35) This TEC Assessment addressed the key question of how health outcomes (OS, disease-specific survival, local control, disease-free survival, and adverse events) with 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.
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 RCTS, the comparative effectiveness of PBT and SBRT is uncertain.
The 2010 TEC 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.
A 2010 indirect meta-analysis reviewed in the TEC Assessment found a nonsignificant difference of 9 percentage points between pooled 2-year OS estimates favoring SBRT over PBT for treatment of NSCLC.(36) 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.
Pijls-Johannesma et al conducted a 2010 systematic literature review through November 2009 examining the evidence on the use of particle therapy in lung cancer.(37) Study inclusion criteria included that the series had at least 20 patients and a follow-up period of 24 months or more. Eleven studies, all dealing with NSCLC, mainly stage I, were included in the review, 5 investigating protons (n=214) and 6, C-ions (n=210). The proton studies included 1 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% to 87%. The 2- and 5-year OS and 2- and 5-year cause-specific survival (CSS) rates were 31% to 74% and 23% and 58% to 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.
A 2010 systematic review of charged-particle radiation therapy for cancer concluded “evidence on the comparative effectiveness and safety of charged-particle radiation therapy in NSCLC cancer is needed to assess the benefits, risks, and costs of treatment alternatives.”(38)
As of February 2014, no RCTs or non-RCTs reporting health outcomes in patients treated with PBT versus an alternative treatment have been published. In 2013, Bush et al published data on a relatively large series of patients (n=111) treated at 1 U.S. facility over 12 years.(39) Patients had NSCLC that was inoperable (or refused surgery) and were treated with high-dose hypofractionated PBT to the primary tumor. Most patients (64%) had stage II disease and the remainder had stage 1 disease. The 4-year actuarial OS rate was 51% and the CSS rate was 74%. The subgroup of patients with peripheral stage I tumors treated with either 60 or 70 Gy had an OS of 60% at 4 years. In terms of adverse events, 4 patients had rib fractures determined to be related to treatment; in all cases, this occurred in patients with tumors adjacent to the chest wall. The authors noted that a 70-Gy regimen is now used to treat stage I patients at their institution. A limitation of the study was a lack of comparison group.
Head and Neck Tumors, Other Than Skull-Based
The literature on the use of PBT for head and neck tumors (other than skull-based) is scant and consists of dosimetric planning studies for nasopharyngeal carcinoma,(40) and a case series of 91 patients who received combined proton and photon radiotherapy for advanced paranasal sinus tumors.(41)
Ongoing Clinical Trials
Two phase 3 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 (NCT01182779). A Phase III trial is comparing photon versus proton and carbon ion radiotherapy in patients with skull Base meningioma (NCT01795300).
A phase 3 trial is comparing photon and proton therapy in patients with inoperable non-small-cell lung cancer (NCT01993810)
Two phase 3 trials examining proton therapy for treating prostate cancer. In one, proton therapy is being compared with IMRT in patients with stages T1c to T2b disease (NCT01616161). The other phase 3 trial is comparing hypofractionated proton radiation versus standard dose for prostate cancer (NCT01230866).
Clinical Input Received Through Physician Specialty Society and Academic Medical Center
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 2 physician specialty societies (4 responses) and 4 academic medical centers while this policy was under review for March 2013. There was uniform support for the use of PBT in pediatric CNS tumors. Two reviewers expressed support for the use of PBT in pediatric non-CNS tumors; data for this use are scant. Input on head and neck tumors (nonskull based) was mixed.
- Studies on the use of charged-particle beam radiation therapy (RT) 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.
- For pediatric central nervous system (CNS) tumors, there is a small body of literature on long-term outcomes with the use of proton-beam therapy (PBT). This modality of treatment of pediatric CNS tumors has the potential to reduce long-term side effects, as dosimetric studies of proton therapy compared with best available photon-based treatment have shown significant dose-sparing to developing normal tissues. Clinical input uniformly supported this use of PBT. Therefore, PBT may be considered medically necessary in the treatment of pediatric CNS tumors.
- For pediatric non-CNS tumors, scant data exists and consists of dosimetric planning studies and a few case series in a small number of patients. Therefore, this indication is considered investigational.
- Results of proton beam studies for clinically localized prostate cancer have shown similar results and outcomes when compared with other radiation treatment modalities. Given these conclusions, along with information that PBT is generally more costly than alternative treatments, PBT is considered not medically necessary for treating prostate cancer.
- In treating lung cancer, definite evidence showing superior outcomes with PBT versus stereotactic body radiation therapy (an accepted approach for treating lung cancer with radiation), is lacking. Therefore, this indication is considered investigational.
- In treating head and neck cancer (other than skull-based tumors), the data are scant and support from clinical input was mixed. Therefore, this indication is considered investigational.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) guidelines
Prostate Cancer: NCCN guidelines for Prostate Cancer (V1.2014) state that “proton beams can be added as an alternative radiation source. The costs associated with proton beam facility construction and proton beam treatment are high. However, theoretically, protons may reach deeply located tumors with less damage to surrounding tissues… 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 treatment of prostate cancer.”(42)
Non-Small-Cell Lung Cancer: NCCN guidelines for Non-Small-Cell Lung Cancer (V3.2014) state that “more advanced technologies are appropriate when needed to deliver curative RT safely. These technologies include….proton therapy. Nonrandomized comparisons of using advanced technologies versus older techniques demonstrate reduced toxicity and improved survival.”(43)
Bone Cancer: NCCN guidelines for Bone Cancer ( V1.2014) state that “specialized techniques such intensity-modulated radiation therapy (IMRT), particle beam RT with protons, carbon ions or other heavy ions, stereotactic radiosurgery or fractionated stereotactic RT should be considered as indicated in order to allow high-dose therapy while maximizing normal tissue sparing.”(44)
American Society for Radiation Oncology
The Emerging Technology Committee of American Society for Radiation Oncology (ASTRO) published 2012 evidence-based recommendations declaring a lack of evidence for PBT for malignancies outside of large ocular melanomas and chordomas:
“Current data do not provide sufﬁcient evidence to recommend PBT outside of clinical trials in lung cancer, head and neck cancer, GI [gastrointestinal] malignancies (with the exception of hepatocellular) and pediatric non-CNS 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.”(45)
ASTRO published a position statement in February 2013 which states the following: “At the present time, ASTRO believes the comparative efficacy evidence of proton beam therapy with other prostate cancer treatments is still being developed, and thus the role of proton beam therapy for localized prostate cancer within the current availability of treatment options remains unclear.”(46)
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.(47)
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
- Suit H, Urie M. Proton beams in radiation therapy. J Natl Cancer Inst 1992; 84(3):155-64.
- 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.
- Lodge M, Pijls-Johannesma M, Stirk L et al. A systematic literature review of the clinical and cost-effectiveness of hadron therapy in cancer. Radiother Oncol 2007; 83(2):110-22.
- 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.
- Wang Z, Nabhan M, Schild SE et al. Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys 2013; 86(1):18-26.
- Hoffman KE, Yock TI. Radiation therapy for pediatric central nervous system tumors. J Child Neurol 2009; 24(11):1387-96.
- Cotter SE, McBride SM, Yock TI. Proton radiotherapy for solid tumors of childhood. Technol Cancer Res Treat 2012; 11(3):267-78.
- De Ruysscher D, Mark Lodge M, Jones B et al. Charged particles in radiotherapy: a 5-year update of a systematic review. Radiother Oncol 2012; 103(1):5-7.
- Hug EB, Muenter MW, Archambeau JO et al. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol 2002; 178(1):10-7.
- Fuss M, Hug EB, Schaefer RA et al. Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique. Int J Radiat Oncol Biol Phys 1999; 45(5):1117-26.
- MacDonald SM, Safai S, Trofimov A et al. Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys 2008; 71(4):979-86.
- Fitzek MM, Linggood RM, Adams J et al. Combined proton and photon irradiation for craniopharyngioma: long-term results of the early cohort of patients treated at Harvard Cyclotron Laboratory and Massachusetts General Hospital. Int J Radiat Oncol Biol Phys 2006; 64(5):1348-54.
- Luu QT, Loredo LN, Archambeau JO et al. Fractionated proton radiation treatment for pediatric craniopharyngioma: preliminary report. Cancer J 2006; 12(2):155-9.
- MacDonald SM, Trofimov A, Safai S et al. Proton radiotherapy for pediatric central nervous system germ cell tumors: early clinical outcomes. Int J Radiat Oncol Biol Phys 2011; 79(1):121-9.
- Moeller BJ, Chintagumpala M, Philip JJ et al. Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy. Radiat Oncol 2011; 6:58.
- Merchant TE, Hua CH, Shukla H et al. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer 2008; 51(1):110-7.
- Kozak KR, Adams J, Krejcarek SJ et al. A dosimetric comparison of proton and intensity-modulated photon radiotherapy for pediatric parameningeal rhabdomyosarcomas. Int J Radiat Oncol Biol Phys 2009; 74(1):179-86.
- Merchant TE. Proton beam therapy in pediatric oncology. Cancer J 2009; 15(4):298-305.
- Timmermann B. Proton beam therapy for childhood malignancies: status report. Klin Padiatr 2010; 222(3):127-33.
- Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Proton beam therapy for prostate cancer. TEC Assessments 2010; Volume 25, Tab 10.
- Wilt TJ, Shamliyan T, Taylor B et al. Comparative effectiveness of therapies for clinically localized prostate cancer. Comparative Effectiveness Review No. 13. 2008. Available online at: http://effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=9&DocID=79. Last accessed February, 2008.
- 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.
- Cox JD. Dose escalation by proton irradiation for adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1995; 32(1):265-6.
- Hanks GE. A question filled future for dose escalation in prostate cancer. Int J Radiat Oncol Biol Phys 1995; 32(1):267-9.
- 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.
- Kim YJ, Cho KH, Pyo HR et al. A phase II study of hypofractionated proton therapy for prostate cancer. Acta Oncol 2013; 52(3):477-85.
- 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.
- Nilsson S, Norlen BJ, Widmark A. A systematic overview of radiation therapy effects in prostate cancer. Acta Oncol 2004; 43(4):316-81.
- 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.
- 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.
- Zietman AL. The Titanic and the iceberg: prostate proton therapy and health care economics. J Clin Oncol 2007; 25(24):3565-6.
- Kagan AR, Schulz RJ. Proton-beam therapy for prostate cancer. Cancer J 2010; 16(5):405-9.
- Brada M, Pijls-Johannesma M, De Ruysscher D. Current clinical evidence for proton therapy. Cancer J 2009; 15(4):319-24.
- 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.
- 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.
- 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.
- 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.
- Terasawa T, Dvorak T, Ip S et al. Systematic review: charged-particle radiation therapy for cancer. Ann Intern Med 2009; 151(8):556-65.
- Bush DA, Cheek G, Zaheer S et al. High-dose hypofractionated proton beam radiation therapy is safe and effective for central and peripheral early-stage non-small cell lung cancer: results of a 12-year experience at Loma Linda University Medical Center. Int J Radiat Oncol Biol Phys 2013; 86(5):964-8.
- Taheri-Kadkhoda Z, Bjork-Eriksson T, Nill S et al. Intensity-modulated radiotherapy of nasopharyngeal carcinoma: a comparative treatment planning study of photons and protons. Radiat Oncol 2008; 3:4.
- Weber DC, Chan AW, Lessell S et al. Visual outcome of accelerated fractionated radiation for advanced sinonasal malignancies employing photons/protons. Radiother Oncol 2006; 81(3):243-9.
- National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Prostate Cancer V1 2014. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Last accessed February, 2014.
- National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer V3 2014. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Last accessed February, 2014.
- National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Bone Cancer V1 2014. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. Last accessed February, 2014.
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- American Society for Radiation Oncology (ASTRO). ASTRO Position Statement: Use of Proton Beam Therapy for Prostate Cancer. 2013. Available online at: https://www.astro.org/uploadedFiles/Main_Site/Practice_Management/Reimbursement/ProtonProstateStatement.pdf. Last accessed February, 2014.
- American Society for Radiation Oncology (ASTRO). ASTRO releases list of five radiation oncology treatments to question as part of national Choosing Wisely® campaign. Available online at: https://www.astro.org/uploadedFiles/Main_Site/News_and_Media/News_Releases/2013/Choosing_Wisely_PR_FINAL_091713.pdf. Last accessed February, 2014.
|CPT||See Policy Guidelines|
|ICD-9 Procedure||92.26||Teleradiotherapy of other particulate radiation|
|ICD-9 Diagnosis||170.0||Malignant neoplasm of skull|
|170.2||Chondrosarcoma of cervical spine|
|170.9||Chondrosarcoma, basisphenoid region (skull)|
|190.0-190.9||Malignant neoplasm of eye code range (190.0 includes vueal tract)|
|192.0-192.3||Malignant neoplasm of other and unspecified parts of the nervous system (192.2 is specific to the spinal cord)|
|198.5||Secondary malignant neoplasm of skull|
|ICD-10-CM (effective 10/1/15)||C41.0||Malignant neoplasm of bones of skull and face|
|C41.2||Malignant neoplasm of vertebral column|
|C41.9||Malignant neoplasm of bone and articular cartilage, unspecified|
|C49.0||Malignant neoplasm of connective and soft tissue of head, face and neck|
|C69.00-C69.92||Malignant neoplasm of eye and adnexa code range (C69.30-C69.42 are specific to the uveal tract)|
|C71.0-C71.9||Malignant neoplasm of the brain code range|
|C72.0||Malignant neoplasm of spinal cord|
|ICD-10-PCS (effective 10/1/15)||ICD-10-PCS codes are only used for inpatient services.|
|D8004ZZ||Radiation oncology, eye, beam radiation, eye, heavy particles (protons, ions)|
|D0014ZZ, D0064ZZ||Radiation oncology, central and peripheral nervous system, beam radiation, brain stem or spinal cord, heavy particles (protons, ions)|
|Type of Service||Therapy|
|Place of Service||Outpatient|
Charged Particle (Proton or Helium Ion) Irradiation
Helium Ion or Proton Beam Radiotherapy
Irradiation, Charged Particle (Proton or Helium Ion)
Proton or Helium Ion Beam Radiotherapy
|07/31/96||Add to Therapy section||New policy|
|01/30/98||Replace policy||Reviewed with changes; new indications|
|11/15/98||Coding update||99 CPT coding release|
|11/01/99||Replace policy||New CPT code; policy unchanged|
|10/15/00||Replace policy||New CPT codes|
|4/29/03||Replace policy||Policy updated with literature search; no change in policy statement; references added|
|04/1/05||Replace policy||Policy updated with literature search with specific focus on proton beam therapy for prostate cancer; no change in policy statement, reference numbers 6–9 added|
|7/20/06||Replace policy||Policy updated to state proton beam is an alternative in localized prostate cancer. New reference numbers 2 and 11 added and other references renumbered|
|02/14/08||Replace policy||Policy updated with literature search; no change in policy statements. Reference numbers 12 and 13 added.|
|08/14/08||Replace policy||Policy updated related to localize prostate cancer; reference number 14 added. Policy statement changed to indicate that proton beam therapy is not medically necessary in the treatment of localized prostate cancer.|
|02/11/10||Replace policy||Policy updated with literature search, reference 15 added, no changes to policy statements|
|10/08/10||Replace policy||Policy updated with literature search, reference numbers 16-20 added, use for NSCLC added as a specific indication to the investigational statement, other policy statements unchanged|
|10/04/11||Replace policy||Policy updated with literature search, references 21 and 22 added, no changes to policy statements|
|03/14/13||Replace policy||Policy updated with literature search. References 1, 5-18, 38-39 and 43 added. References 40-42 updated. Change to policy statement that proton radiotherapy may be considered medically necessary for the treatment of pediatric CNS tumors. Investigational policy statements added for pediatric non-CNS tumors and head and neck tumors (non-skull based).|
|3/13/14||Replace policy||Policy updated with literature search through February 6, 2014. References 5, 26, 39, 46, and 47 added. No change in policy statements.|