• No results found

Charged-Particle (Proton or Helium Ion) Radiotherapy

N/A
N/A
Protected

Academic year: 2021

Share "Charged-Particle (Proton or Helium Ion) Radiotherapy"

Copied!
14
0
0

Loading.... (view fulltext now)

Full text

(1)

MEDICAL POLICY

POLICY RELATED POLICIES POLICY GUIDELINES DESCRIPTION SCOPE BENEFIT APPLICATION RATIONALE REFERENCES CODING APPENDIX HISTORY

Charged-Particle (Proton or Helium Ion) Radiotherapy

Number 8.01.534 Effective Date August 11, 2015 Revision Date(s) N/A

Replaces 8.01.10

Policy

[TOP] 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 14mm 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 prostate cancer.

Note: Clinical outcomes for treating prostate cancer with charged-particle proton beam irradiation have not been shown to be superior to other approaches including intensity-modulated radiation therapy (IMRT) or conformal radiation therapy. (See the 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 non-central nervous system tumors,

• Tumors of the head and neck (other than skull-based chordoma or chondrosarcoma).

Related Policies

[TOP] 6.01.10 Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy

8.01.48 Intensity-Modulated Radiotherapy (IMRT): Cancer of the Head and Neck or Thyroid 8.01.49 Intensity-Modulated Radiation Therapy (IMRT): Abdomen and Pelvis

(2)

8.01.526 Intensity Modulated Radiation Therapy (IMRT) of the Prostate 8.01.527 Intensity Modulated Radiotherapy of the Breast and Lung

Policy Guidelines

[TOP] Evidence is unavailable 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 (less than 21 years of age).

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

Coding

CPT

Clinical Treatment Planning

77299 Unlisted procedure, therapeutic radiology clinical treatment planning Medical Radiation Physics

77399 Unlisted procedure, medical radiation physics, dosimetry, and treatment devices Treatment Delivery

77499 Unlisted procedure, therapeutic radiology treatment management 77520 Proton treatment delivery; simple, without compensation

77522 Proton treatment delivery; simple with compensation 77523 Proton treatment delivery; intermediate

77525 Proton treatment delivery; complex

Description

[TOP]

Background

Charged-particle beams consisting of protons or helium ions are a type of particulate radiation therapy (RT). They contrast with conventional electromagnetic (i.e., photon) RT 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 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 two 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

(3)

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 (i.e., 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

Note: The use of proton or helium radiation in conjunction with stereotactic guidance is addressed in a separate medical policy. (See Related Policies)

Scope

[TOP] Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

Benefit Application

[TOP] Charged particle radiation therapy is a specialized procedure that may need 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 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.

Rationale

[TOP] The policy was created in July, 2015 based on a literature search of the MEDLINE database through May 2015.

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.

(4)

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 e.g., 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

RT 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 (PBT) eliminates the exit dose to normal tissues and may eliminate about 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

(5)

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) MD Anderson Cancer Center and Methodist Hospital in Houston reported on 52 children treated at 2 centers in Texas; 21 received PBT and 31 received IMRT. (12) Patients received a median dose of 50.4 Gy. At 3 years, OS was 94.1% in the PBT group and 96.8% in the IMRT group (p=0.742). Three-year nodular and cystic failure-free survival rates were also similar between groups. Seventeen patients (33%) were found on imaging to have cyst growth within 3 months of RT and 14 patients had late cyst growth (>3 months after therapy); rates did not differ significantly between groups. In 14 of the 17 patients with early cyst growth,

enlargement was transient.

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. (13) 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. (14) 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.

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). (15) 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 RT, 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 RT 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. (16) As hearing loss is common following

chemoradiotherapy for children with medulloblastoma, the authors sought to compare whether proton RT led to a clinical benefit in audiometric outcomes (because, compared to photons, protons reduce radiation dose to the cochlea for these patients). The children underwent pre- and 1-year post-radiotherapy 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 post-radiation hearing thresholds at low-to-midrange frequencies; the rate of high-grade (high-grade 3 or 4) ototoxicity at 1 year was 5%. The authors compared this with a rate of high-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. (17) sought to determine whether proton RT has clinical advantages over photon RT 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

(6)

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 (e.g., cochlea and hypothalamus) were spared from radiation exposure when not adjacent to the primary tumor volume. Larger normal tissue volumes (e.g., 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 (18) and late toxicity outcomes in other solid tumors of childhood. (19, 20)

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. (21) A total of 9 studies were included in the review; 4 were comparative and 5 were noncomparative. There were 2 RCTs and only one of these included a comparison group of patients who did not receive PBT. This study, published in 1995 by Shipley et al, compared treatment with EBRT using photons and either a photon or proton beam boost. (22) After a median follow-up of 61 months, the investigators found no statistically significant differences in OS, disease-specific survival, or recurrence-free survival. In a subgroup of patients with poorly differentiated tumors, there was superior local control with proton beam versus photon boost; but survival outcomes did not differ. Actuarial incidence of urethral stricture and freedom from rectal bleeding were significantly better in the photon boost group. The TEC Assessment noted that higher doses were delivered to the proton beam boost group and thus better results on survival and tumor control outcomes would be expected. Moreover, the study was published in the mid-1990s and used 2D methods of RT that are now outmoded. The other RCT, known as Proton Radiation Oncology Group (PROG)/ACR 95-09, compared 3D conformal EBRT with either a high-dose or conventional-dose proton beam boost. (23) After a median follow-up of 8.9 years, there was not a statistically significant difference between groups in survival. Biochemical failure, an intermediate outcome, was significantly lower in the high-dose proton beam group than the conventional-dose proton beam group. The TEC Assessment authors stated that the outcome, biochemical failure, has an unclear relationship to the more clinically important outcome, survival. The rate of acute gastrointestinal (GI) tract toxicity was worse with the high-dose proton beam boost. Taking into account data from all 9 studies included in the review, the authors of the TEC Assessment concluded that there was inadequate evidence from comparative studies to permit conclusions about the impact of PBT on health outcomes. Ideally, RCTs would report long-term health outcomes or intermediate outcomes that

consistently predict health outcomes.

No RCTs have been published since the TEC Assessment that compared health outcomes in patients treated with PBT versus patients treated by other RT modalities.

An RCT compared different protocols for administering hypofractionated proton therapy, but because there was no comparison with an alternative intervention, conclusions cannot be drawn about the efficacy and safety of PBT. This study was published in 2013 by Kim et al. in Korea and included men with androgen-deprivation therapy-naive stage T1-T3 prostate cancer. (24) The 5 proton beam 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 GI toxicity. In 2014, the Agency for Healthcare Research and Quality published a review of therapies for localized prostate cancer, that is defined as cancer confined to the prostate gland. (25) This report was an update of a 2008 comparative effectiveness review. (26) The authors compared risk and benefits of a number of treatments for

(7)

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

From the published literature, it appears that dose escalation is an accepted concept in treating organ-confined prostate cancer. (27) PBT, using 3D-conformal RT [CRT] planning or IMRT, is 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 RT 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. (28)

Three published 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. (29) 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. (30) 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. (31) 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). (32) 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

(8)

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. (33) 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. (34) 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.

To date, 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. (35) 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

A 2014 systematic review evaluated the literature on charged particle therapy versus photon therapy for the treatment of paranasal sinus and nasal cavity malignant disease. (36) The authors identified 41 observational studies that included 13 cohorts treated with charged particle therapy (total N=286 patients) and 30 cohorts treated with photon therapy (total N=1186 patients). There were no head-to-head trials. In a meta-analysis, the pooled event rate of OS was significantly higher with charged particle therapy than photon therapy at the longest duration of follow-up (RR=1.27; 95% CI: 1.01 to 1.59). Findings were similar for the outcome survival at 5 years (RR=1.51; 95% CI: 1.14 to 1.99). Findings were mixed for the outcomes locoregional control and disease-free survival; photon therapy was significantly better for only 1 of the 2 timeframes (longest up or 5-year follow-up). In terms of adverse effects, there were significantly more neurologic toxic effects with charged particle therapy compared with photon therapy (p<0.001) but other toxic adverse event rates eg, eye, nasal and

hematologic did not differ significantly between groups. The authors noted that the charged particle studies were heterogeneous, eg, type of charged particles (carbon ion, proton), and delivery techniques. It should also be noted that comparisons were indirect, and none of the studies included in the review actually compared the 2 types of treatment in the same patient sample.

(9)

Also in 2014, Zenda et al. reported on late toxicity in 90 patients after PBT for nasal cavity, paranasal sinuses, or skull base malignancies. (37) Eighty seven of the 90 patients had paranasal sinus or nasal cavity cancer. The median observation period was 57.5 months. Grade 3 late toxicities occurred in 17 patients (19%) and grade 4 occurred in 6 patients (7%). Five patients developed cataracts, and 5 had optic nerve disorders. Late toxicities (other than cataracts) developed a median of 39.2 months after PBT.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 1.

Table 1. Summary of Key Active Trials

NCT No. Trial Name Planned

Enrollment

Completion Date NCT01617161 Proton Therapy vs. IMRT for Low or Intermediate Risk

Prostate Cancer (PARTIQoL)

400 Jan 2016

NCT01230866 Study of Hypo-fractionated Proton Radiation for Low Risk Prostate Cancer

192 Dec 2018

NCT01993810 Comparing Photon Therapy To Proton Therapy To Treat Patients With Lung Cancer

560 Dec 2020

NCT: national clinical trial

Summary of Evidence

Charged-particle beams consisting of protons or helium ions are a type of particulate radiotherapy (RT). A summary of the evidence by indication follows.

• Chordomas or chondrosarcoma – 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. (Medically necessary)

• Head and neck cancer – In treating head and neck cancer, other than skull-based tumors (see

chordomas/chondrosarcoma above), the data from comparative studies are lacking and noncomparative data are insufficient. Moreover, support from clinical input was mixed. (Investigational)

• Lung cancer – In treating lung cancer, definite evidence showing superior outcomes with charged

particle-beam RT versus SBART an accepted approach for treating lung cancer with radiation, is lacking. (Investigational)

• Pediatric central nervous system (CNS) tumors – For pediatric 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. (Medically necessary)

• Pediatric non-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. (Investigational)

• Clinically localized prostate cancer – There is insufficient evidence to draw conclusions about the impact of charged-particle RT on the net health outcome for treatment of clinically 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 for clinically localized prostate cancer. (Not medically necessary)

• Uveal melanoma – 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. (Medically necessary)

Practice Guidelines and Position Statements

American College of Radiology Appropriateness Criteria

A 2014 guideline on external beam irradiation in stage T1 and T2 prostate cancer states:

• There are only limited data comparing proton-beam therapy to other methods of irradiation or to radical prostatectomy for treating stage T1 and T2 prostate cancer. Further studies are needed to clearly define

(10)

its role for such treatment.

• There are growing data to suggest that hypofractionation at dose per fraction <3.0 Gy per fraction is reasonably safe and efficacious, and although the early results from hypofractionation/ SBRT (stereotactic body radiation therapy) studies at dose per fraction >4.0 Gy seem promising, these approaches should continue to be used with caution until more mature, ongoing phase II and III randomized controlled studies have been completed. (38)

National Comprehensive Cancer Network (NCCN) guidelines

Prostate Cancer: NCCN guidelines for Prostate Cancer (v.1.2015) refer to American Society for Radiation Oncology’s (ASTRO) current position which states that “proton beam therapy for primary treatment of prostate cancer should only be performed within the context of a prospective clinical trial.” The costs associated with proton beam facility construction and proton beam treatment are high compared with the expense of building and using the more common photon linear accelerator based practice. The NCCN panel believes there is no clear evidence supporting a benefit or decrement to proton therapy over IMRT for either treatment efficacy or long-term toxicity. (39)

Non-Small Cell Lung Cancer: NCCN guidelines for Non-Small-Cell Lung Cancer (v.1.2015) 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.” (40)

Bone Cancer: NCCN guidelines for Bone Cancer (v1.2015) 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.”(41)

American Society for Radiation Oncology (ASTRO)

The Emerging Technology Committee of 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.” (42)

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.(43)

In June 2014, ASTRO published a model policy on use of PBT. (44) The document stated that ASTRO supports PBT for the treatment of the following conditions:

• Ocular tumors, including intraocular melanomas

• Tumors that approach or are located at the base of the skull, including but not limited to:

o Chordoma o Chondrosarcoma

• Primary or metastatic tumors of the spine (selected patients)

• Primary hepatocellular cancer treated in a hypofractionated regimen

• Primary or benign solid tumors in children (selected patients)

• Patients with genetic syndromes making total volume of radiation minimization crucial such as but not limited to NF-1 patients and retinoblastoma patients.

The model policy stated the following regarding PBT for treating prostate cancer:

(11)

compares to other radiation therapy modalities such as IMRT and brachytherapy. There is a need for more well-designed registries and studies with sizable comparator cohorts to help accelerate data collection. Proton beam therapy for primary treatment of prostate cancer should only be performed within the context of a prospective clinical trial or registry.”

National Association for Proton Therapy

In March 2015, National Association for Proton Therapy published a model coverage policy. (45) This organization is a nonprofit corporation that “promotes the therapeutic benefits of proton therapy for cancer treatment….” (46) Their model policy was not endorsed by ASTRO or NCCN. Prostate carcinoma was an indication considered medically necessary in this document. The model policy did not include a discussion of the published evidence.

U.S. Preventive Services Task Force Recommendations

Not applicable.

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.

References

[TOP] 1. Suit H, Urie M. Proton beams in radiation therapy. J Natl Cancer Inst. 1992;84(3):155-164. PMID1311773 2. 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.

3. 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. May 2007;83(2):110-122. PMID 17502116 4. 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):1405-1411. PMID

5. 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. May 1 2013;86(1):18-26. PMID 23040219

6. Hoffman KE, Yock TI. Radiation therapy for pediatric central nervous system tumors. J Child Neurol. Nov 2009;24(11):1387-1396. PMID 19841427

7. Cotter SE, McBride SM, Yock TI. Proton radiotherapy for solid tumors of childhood. Technol Cancer Res Treat. Jun 2012;11(3):267-278. PMID 22417062

8. De Ruysscher D, Mark Lodge M, Jones B, et al. Charged particles in radiotherapy: a 5-year update of a systematic review. Radiother Oncol. Apr 2012;103(1):5-7. PMID 22326572

9. Hug EB, Muenter MW, Archambeau JO, et al. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol. Jan 2002;178(1):10-17. PMID 11977386

10. 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. Dec 1 1999;45(5):1117-1126. PMID 10613303

11. 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. Jul 15 2008;71(4):979-986. PMID 18325681

12. Bishop AJ, Greenfield B, Mahajan A, et al. Proton beam therapy versus conformal photon radiation therapy for childhood craniopharyngioma: multi-institutional analysis of outcomes, cyst dynamics, and toxicity. Int J Radiat Oncol Biol Phys. Oct 1 2014;90(2):354-361. PMID 25052561

13. 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. Apr 1 2006;64(5):1348-1354. PMID 16580494

14. Luu QT, Loredo LN, Archambeau JO, et al. Fractionated proton radiation treatment for pediatric craniopharyngioma: preliminary report. Cancer J. Mar-Apr 2006;12(2):155-159. PMID 16630407

(12)

15. 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. Jan 1 2011;79(1):121-129. PMID 20452141

16. 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. PMID 21635776

17. 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. Jul 2008;51(1):110-117. PMID 18306274

18. 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. May 1 2009;74(1):179-186. PMID 19019562

19. Merchant TE. Proton beam therapy in pediatric oncology. Cancer J. Jul-Aug 2009;15(4):298-305. PMID 19672146

20. Timmermann B. Proton beam therapy for childhood malignancies: status report. Klin Padiatr. May 2010;222(3):127-133. PMID 20514614

21. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Proton beam therapy for prostate cancer. TEC Assessments 2010;Volume 25, Tab 10.

22. 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.

23. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294(10):1233-1239. PMID 16160131

24. Kim YJ, Cho KH, Pyo HR, et al. A phase II study of hypofractionated proton therapy for prostate cancer. Acta Oncol. Apr 2013;52(3):477-485. PMID 23398594

25. Sun F, Oyesanmi O, Fontanarosa J, et al. Therapies for Clinically Localized Prostate Cancer: Update of a 2008 Systematic Review. 2014;

http://effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=2022. Accessed July, 2015.

26. Wilt TJ, Shamliyan T, Taylor B, et al. Comparative effectiveness of therapies for clinically localized prostate cancer. Comparative Effectiveness Review No. 13. 2008;

http://effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=9&DocID=79. Accessed July, 2015

27. Nilsson S, Norlen BJ, Widmark A. A systematic overview of radiation therapy effects in prostate cancer. Acta Oncologica. 2004;43(4):316-381. PMID 15303499

28. 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):1260-1268. PMID 14630260

29. Kagan AR, Schulz RJ. Proton-beam therapy for prostate cancer. Cancer J 2010; 16(5):405-409. PMID 20890135

30. Brada M, Pijls-Johannesma M, De Ruysscher D. Current clinical evidence for proton therapy. Cancer J 2009; 15(4):319-324. PMID 19672149

31. 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):312-318. PMID 19672148

32. 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.

33. 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. PMID 19733410

34. 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. PMID 20067947

35. 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. Aug 1 2013;86(5):964-968. PMID 23845845

36. Patel SH, Wang Z, Wong WW, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. Aug

2014;15(9):1027-1038. PMID 24980873

37. Zenda S, Kawashima M, Arahira S, et al. Late toxicity of proton beam therapy for patients with the nasal cavity, para-nasal sinuses, or involving the skull base malignancy: importance of long-term follow-up. Int J Clin Oncol. Aug 20 2014. PMID 25135461

(13)

38. Nguyen PL, Aizer A, Assimos DG, et al. ACR Appropriateness Criteria(R) Definitive External-Beam Irradiation in stage T1 and T2 prostate cancer. Am J Clin Oncol. Jun 2014;37(3):278-288. PMID 25180754

39. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Prostate Cancer V1 2015. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed July, 2015. 40. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Non-Small

Cell Lung Cancer V1 2015. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed July, 2015.

41. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Bone Cancer V1 2015. http://www.nccn.org/professionals/physician_gls/pdf/bone.pdf. Accessed July, 2015.

42. Allen AM, Pawlicki T, Dong L, et al. An evidence based review of proton beam therapy: the report of ASTRO's emerging technology committee. Radiother Oncol. Apr 2012;103(1):8-11. PMID 22405807 43. American Society for Radiation Oncology (ASTRO). ASTRO releases list of five radiation oncology

treatments to question as part of national Choosing Wisely® campaign.

https://www.astro.org/uploadedFiles/Main_Site/News_and_Media/News_Releases/2013/Choosing_Wisel y_PR_FINAL_091713.pdf. Accessed July, 2015.

44. American Society for Radiation Oncology (ASTRO). Model Policy: Proton Beam Therapy.

http://www.astro.org/uploadedFiles/Main_Site/Practice_Management/Reimbursement/ASTRO%20PBT% 20Model%20Policy%20FINAL.pdf. Accessed July, 2015.

45. National Association for Proton Therapy (NAPT). Medical Policy: Coverage of Proton Beam Therapy. 2015; http://www.proton-therapy.org/documents/Final_2015_Model_Policy.pdf. Accessed July, 2015. 46. National Association for Proton Therapy (NAPT). Background: The Voice of the Proton Community.

http://www.proton-therapy.org/backgrou.htm. Accessed July, 2015.

47. Blue Cross and Blue Shield Association. Charged-particle (proton or helium ion) radiotherapy. Medical Policy Reference Manual, Policy 8.01.10, 2015.

Coding

[TOP]

Codes Number Description

CPT 77299 Unlisted procedure, therapeutic radiology, clinical treatment planning 77399 Unlisted procedure, medical radiation physics, dosimetry, and treatment

devices, and special services

77499 Unlisted procedure, therapeutic radiology treatment management 77520 Proton treatment delivery, simple, without compensation

77522 simple, with compensation 77523 Intermediate

77525 Proton treatment delivery, complex Type of Service Therapy

Place of Service Outpatient

Appendix

[TOP] N/A

History

[TOP] Date Reason

08/11/15 New Policy. Replaces 8.01.10 (now deleted). Policy created with literature review through May, 2015. Charged particle proton/helium beam radiotherapy may be considered medically necessary when criteria are met. Proton beam radiotherapy is considered not medically necessary for prostate cancer and investigational for all other indications. Policy was created to retain not medically necessary statement in support of local plan coverage.

(14)

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).

References

Related documents

The philosophical criterion focuses on the theoretical, methodological and value positions of the curriculum. A module should be a means to enhance the intellectual development

The dramatic increase in workers’ compensation medical costs has all stakeholders — researchers, policymakers, insurers, managed care providers, and employers — seeking

™ Promote special features of INIS Database, including key milestones and/aspects, such as free access. ™ Cooperate with the Secretariat on national and regional seminars, as well

The airway epithelial barrier comprises ciliated cells, olfactory cells (in olfactory.. FIGURE 1 | Epithelial dynamics in upper and lower airway epithelium; normal epithelium

Abstract | Agonists of seven-transmembrane receptors, also known as G protein- coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a

In addition to the basic model, we also present a variant that produces a topic hierarchy, by modeling the vocabulary only at the leaf level and considering topics in the inner

The IT product NXP MIFARE DESFire EV1 MF3ICD81 (Target of Evaluation, TOE) has been evaluated at an approved evaluation facility using the Common Methodology for IT Security

In question 1, respondents were asked, “In the future I would be willing to bicycle GTSR with motor vehicles on the road.” It was found that summer bicyclists were