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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Radiology
Policy Number:039
Effective Date: 09/21/2020
Original Policy Date:01/13/2009
Last Review Date:07/14/2020
Date Published to Web: 01/14/2009
Subject:
Radiation Therapy for Prostate Cancer

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.

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Brachytherapy is one type of radiation therapy used to treat prostate cancer. Unlike EBRT, in which high-energy x-ray beams generated by a machine are directed at the tumor from outside the body, brachytherapy involves placing radioactive material directly inside the prostate. This can be accomplished by performing a permanent seed implant by injecting radioactive seeds directly into the prostate gland, and typically using either Iodine or Palladium seeds. Alternatively, high dose rate brachytherapy uses temporary radioactive sources. Needles are placed into the prostate gland. A high activity radioactive seed (Iridium-192) is directed to predetermined positions in these needles for precalculated dwell times via a remote afterloading system, and after the appropriate dose is delivered, the needles are removed, usually within 24 hours.

Conventional External Beam Radiation Therapy (CRT) is a method for delivering a beam of high-energy x-rays to the location of the patient's tumor. The beam is generated outside the patient, usually by a linear accelerator and is targeted at the tumor site. With careful planning the tumor cells are destroyed and the surrounding tissue is spared from the harmful effects of the radiation. No sources are placed inside the patient's body. CRT refers to a treatment planning method wherein the prostate and other target tissues are identified by of surrounding anatomy such as bony landmarks and contrast enhanced viscera. This is considered “2D” planning (plain films are used) and is generally not considered appropriate for the definitive treatment of prostate cancer, especially in cases of locally advanced or higher risk prostate cancer where higher doses of radiation are usually delivered (ACR appropriateness Criteria).

Three-Dimensional Conformal Radiation Therapy (3D CRT) is an advanced form of external beam radiation that uses CT and computers to create a 3D picture of the tumor so that multiple radiation beams can be shaped exactly to the contour of the treatment.

Intensity Modulated Radiotherapy (IMRT) employs a very sophisticated computerized 3-D treatment planning system that accurately delivers a high dose of radiation to tumors of varying shapes with even more accurate sparing of surrounding tissue than can be accomplished with 3D CRT. IMRT evolved out of the inability of 3D CRT to irradiate tumors that are concave, surrounded by normal tissue, or in very close proximity to sensitive normal tissue, without causing excessive radiation exposure of adjacent normal tissue. IMRT incorporates two distinct features over 3D CRT; inverse treatment planning and computer-controlled intensity modulation of the photon radiation beam. IMRT is high precision radiotherapy that utilizes computer controlled linear accelerators to deliver precise radiation doses that conform to the 3D shape of the tumor. This results in sparing surrounding normal tissue and ultimately limiting side effects.

Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)

Radiation therapy for prostate cancer is considered medically necessary in the following situations:

I. Low-risk prostate cancer

    A. Low-risk prostate cancer is defined as having all of the following:
      1. Stage T1 to T2a
      2. Gleason score (GS) ≤ 6
      3. Prostate specific antigen (PSA) < 10 ng/mL

    B. The following treatments are considered medically necessary for treatment of low-risk prostate cancer
      1. Hypofractionation – 20 to 28 fractions of intensity-modulated radiation therapy (IMRT)
      2. Up to 5 fractions of stereotactic body radiation therapy (SBRT) alone (i.e. not as a boost)
      3. Low dose rate (LDR) brachytherapy (i.e. seed implant) alone
      4. High dose rate (HDR) brachytherapy alone

II. Intermediate-risk prostate cancer
    A. Intermediate-risk prostate cancer is defined as having any of the following:
      1. Stage T2b to T2c
      2. GS 7
      3. PSA 10 to 20 ng/mL

    B. The following treatments are considered medically necessary for treatment of intermediate-risk prostate cancer
      1. Hypofractionation – 20 to 28 fractions of IMRT
      2. Up to 5 fractions of SBRT alone (i.e. not as a boost)
      3. LDR brachytherapy (i.e. seed implant) alone for favorable intermediate-risk disease or for unfavorable intermediate-risk disease in combination with 25 to 28 fractions of 3DCRT or IMRT
      4. HDR brachytherapy alone for favorable intermediate-risk disease or for unfavorable intermediate-risk disease 1-2 implants in combination with 25 to 28 fractions of 3DCRT or IMRT

III. High-risk prostate cancer
    A. High-risk prostate cancer is defined as having any of the following:
      1. Stage ≥ T3a
      2. GS ≥ 8
      3. PSA > 20 ng/mL

    B. The following treatments are considered medically necessary for treatment of high-risk prostate cancer when not treating the pelvic lymph nodes:
      1. Hypofractionation – 20 to 28 fractions of IMRT
      2. Up to 5 fractions of SBRT alone (i.e. not as a boost)
      3, LDR brachytherapy (i.e. seed implant) in combination with 25 to 28 fractions of 3DCRT or IMRT
      4. 1-2 implants of HDR brachytherapy in combination with 25 to 28 fractions of 3DCRT or IMRT

IV. Treatment of the pelvic lymph nodes
    A. The following treatments are considered medically necessary for the treatment of prostate cancer when treating the pelvic lymph nodes (i.e. for high-risk or node-positive disease):
      1. Conventional fractionation - when delivering 1.8 to 2.0 Gy/fraction, 36 to 45 fractions of IMRT
      2. Hypofractionation - 20 to 28 fractions of IMRT
      3. LDR brachytherapy (i.e. seed implant) in combination with 25 to 28 fractions of 3DCRT or IMRT
      4. HDR brachytherapy in combination with 25 to 28 fractions of 3DCRT or IMRT

V. Adjuvant (postoperative) or salvage radiation therapy is considered medically necessary in any of the following settings:
    A. Positive surgical margins
    B. Extracapsular extension
    C. Seminal vesicle involvement
    D. Positive lymph nodes
    E. Detectable or rising postoperative PSA level

A dose of 64-72 Gy in 32 to 40 fractions of IMRT is considered medically necessary .

VI. Metastatic Disease
    A. Low-volume disease
      1. In members with castration naive metastatic prostate cancer with 3 or fewer bone metastases and no visceral disease, IMRT to a dose of 55 Gy in 20 fractions to the prostate in conjunction with androgen deprivation therapy (ADT) is considered medically necessary only when the use of NCCN category I systemic regimens (i.e. abiraterone, docetaxel, enzalutamide, apalutamide) are contraindicated.
    B. Radiation to the prostate is considered not medically necessary for high-volume disease.

VII. Palliative
    A. For treatment of obstructive symptoms or hematuria due to tumor, a dose of 30 Gy in 10 fractions or 37.5 Gy using 3DCRT in 15 fractions is considered medically necessary.

VIII. Proton beam therapy
    (Please refer to a separate policy on 'Proton Beam Therapy' - Policy #011 in the Radiology Section.)

IX. Injection or implantation of bulking/spacer material (SpaceOAR Hydrogel) in conjunction with IMRT and other forms of radiation delivery for prostate cancer is considered investigational. There is very limited published clinical evidence on the safety and efficacy of this procedure. Clinical trials were primarily performed in conjunction with IMRT.


Medicare Coverage:
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for External beam photon radiation therapy (EBRT), Stereotactic body radiation therapy (SBRT) or 3DCRT. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy for Radiation Treatment of Prostate Cancer.

Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has issued a determination for Intensity-Modulated Radiation Therapy (IMRT). Medicare Advantage Products will follow LCD L36711 for Intensity Modulated Radiation Therapy (IMRT). For additional information and eligibility, refer to Local Coverage Determination (LCD): Intensity Modulated Radiation Therapy (IMRT) (L36711). Available at: https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=36711&ver=18&name=314*1&UpdatePeriod=749&bc=AAAAEAAAAAAAAA%3d%3d&.


Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP Coverage:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

    [INFORMATIONAL NOTE:

    I. External beam radiation


      The American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and the American Urological Association (AUA) published an evidence-based guideline for the performance of hypofractionated radiation therapy. Moderate hypofractionation was defined as a radiation fraction size between 240 cGy and 340 cGy. Ultra-hypofractionation was defined as a radiation fraction size greater or equal to 500 cGy. For an individual with localized prostate cancer who declines active surveillance, an individual with intermediate-risk prostate cancer, or an individual with high-risk prostate cancer in whom the pelvic lymph nodes are not being treated, hypofractionation radiation therapy received a strong recommendation based on high quality evidence. The recommendation was made regardless of whether the seminal vesicles are included in the treatment field, patient age, comorbidities, anatomy, and/or urinary function. These recommendations were based on reviews of large multi-center clinical trials, including the Conventional or Hypofractionated High-Dose Intensity-Modulated Radiotherapy (CHHiP) trial, Prostate Fractionated Irradiation Trial (PROFIT), Radiation Therapy Oncology Group (RTOG) 0415 trial, and the Dutch Hypofractionated versus Conventionally Fractionated Radiotherapy for Patients with Prostate Cancer (HYPRO) trial. Regimens of 6000 cGy in 20 radiation treatment fractions and 7000 cGy in 28 radiation treatment fractions are suggested by the guideline based on their review of the largest database. This recommendation has a consensus of 100%, but the quality of evidence was noted as moderate, and the recommendation strength was noted as conditional. The panel stated that most of the published fractionation schedules have not been studied in comparative clinical trials, thus, an optimal regimen has not yet been determined.

      Based on this data, NCCN Guidelines have stated that moderate hypofractionation (i.e. 20 to 28 fractions) is preferred for the treatment of low-, intermediate-, and high-risk disease.

      UK CHHiP

      In this phase III multicenter, non-inferiority trial, 3216 patients were randomized to conventional fractionation (74 Gy in 37 fractions) or to one of two moderate hypofractionation arms (60 Gy in 20 fractions or 59 Gy in 19 fractions). Most patients included in this trial had low- or intermediate-risk disease. The primary outcome was time to biochemical or clinical failure. At a median follow up of 62.6 months, the 5-year biochemical or clinical failure-free rates was 88.3%, 90.6% and 85.9% in the conventional, 60 Gy and 57 Gy arms respectively. However, only the 60 Gy arm was statistically non-inferior to the 74 Gy arm. There was no difference in overall survival among the groups. At 5-years, the frequency of clinician- or patient-reported late GI, GU or sexual toxicity was also similar among the groups.

      At 8-years and a median follow up of 9.2 years, the 60 Gy arm remained non-inferior to the 74 Gy arm while clinical assessments of late toxicity also remained the same across all groups. The authors concluded that moderate hypofractionation remained the “standard of care for men with localized PCa”.

      RTOG 0415

      In another phase III non-inferiority trial, 1115 patients were randomized to conventional fractionation (73.8 Gy in 41 fractions) or to hypofractionation (70 Gy in 28 fractions). Only men with low-risk disease were enrolled and none received hormonal therapy. It is noted that approximately 21% of both arms were treated using a 3D conformal technique. The primary outcome was disease-free survival (DFS). At a median follow up of 5.8 years, the 5-yr DFS was 86.3% vs. 85.3% in the hypofrac vs. conventional arms respectively confirming non-inferiority of hypofractionation (p<0.001). Further, with respect to biochemical recurrence and overall survival at 5 years, the hypofractionated arm was also statistically non-inferior (p<0.001 and p=0.008). Though there were no differences in early GI or GU toxicity, hypofractionated radiation was associated with a significant increase in maximum grade 2 late GI (18.3% vs. 11.4%) and GU (26.2% vs. 20.5%) toxicity.

      In a separate publication reporting on the QOL (Bruner et al.), the authors confirmed that statistical noninferiority of hypofractionated radiation as compared to conventional radiation in patient-reported urinary symptoms scores and bowel-symptoms scores at 6, 24 and 60 months. At 12 months, hypofractionated radiation had a significant decline in the bowel domain score though this difference did not meet the prior threshold for clinical significance.

      PROFIT

      In this phase III multicenter noninferiority trial of intermediate-risk prostate cancer, 1206 patients were randomized to conventional fractionation (78 Gy in 39 fractions) or to hypofractionation (60 Gy in 20 fractions). The use of hormonal therapy was not allowed. The primary outcome was biochemical-clinical failure (BCF). At a median follow up of 6.0 years, the 5-year BCF disease-free survival was 85% in both arms confirming noninferiority of the hypofractionated arm. There was no difference in overall survival or in late grade 3 or greater GI or GU toxicity. It is noted, however, that there was a significant increase in acute grade 2 or greater GI toxicity in the hypofractionated arm (p=0.003) with a significant increase in late grade 2 or greater GI toxicity in the conventional arm (p=0.006).

      Dutch HYPRO

      820 patients with intermediate- or high-risk disease were randomized in this multicenter phase III trial to either hypofractionation (64.6 Gy in 19 fractions) or to conventional fractionation (78 Gy in 39 fractions), and 67% of patients received concurrent androgen deprivation therapy. The primary outcome was relapse free survival (RFS). At a median follow up of 89 months, 7-year RFS was 71.7% in the hypofractionated arm vs. 67.6% in the conventional arm (p=0.47). There was no difference in overall survival. In a separate publication reporting on quality of life (QOL) at 3 years, the incidence of urinary and GI symptoms were similar among both groups, though noninferiority of the hypofractionated arm could not be statistically confirmed.

      Regina Elena National Cancer Institute

      In another randomized study evaluating high-risk patients, 168 patients were randomized to hypofractionation (62 Gy in 20 fractions) or to conventional fractionation (80 Gy in 40 fractions). The hypothesis was that hypofractionation would lower rates of late complications; hence the primary outcome was late toxicity. It is noted that patients were treated with 3D conformal radiation and all received 9 months of ADT. At a median follow up of 9 years, there was no significant difference in late G2 or greater GI or GU toxicity. Improvements in freedom from biochemical failure favored hypofractionation, though not statistically significant.

      MDACC

      In this single institution dose-escalated randomized trial, 222 men were randomized to hypofractionation (72 Gy in 30 fractions) or to conventional fractionation (75.6 Gy in 42 fractions). At a median follow up of 8.5 years, in an intent-to-treat analysis, time to failure was improved with hypofractionation (p=0.01). Among men who did not receive ADT, hypofractionation was less likely to develop failure (p=0.033). Among men with PSA of 10 or under, hypofractionation were associated with fewer failures at 8 years (p=0.042). There was no difference in survival. The 8-yr incidence of late grade 2 or 3 GI or GU toxicity was not statistically different between both groups (12.6% hypofractionation vs. 5% conventional); it is noted that with a rectal V65 of 15% or under, late grade 2-3 GI toxicity was lowered further to 8.6% at 8-years.

      Cleveland Clinic

      In another single institution study, 854 consecutive patients with localized prostate cancer were treated with hypofractionation. At a medium follow up of 11.3 years, 10-year control rates for low- and intermediate-risk were similar to conventional rates. The authors note that high-risk patients “had relatively poorer biochemical control” though this could have been overcome with longer ADT and/or with elective nodal irradiation. Grade 3 or greater late GU and GI toxicity was 2% and 1% respectively.

      Fox Chase

      In this single institution study, 303 men with low-, intermediate- and high-risk disease were randomized to hypofractionation (70.2 Gy in 26 fractions) vs. conventional fractionation (76 Gy in 38 fractions). At a median follow up of 122.9 months, the 10-year incidence of biochemical and/or clinical disease failure (BDCF) was 25.9% in the conventional arm and 30.6% in the hypofractionated arm (p=0.25). There was also no statistical difference between the arms with respect to local recurrence, prostate-cancer specific mortality and overall mortality. The rate of distant metastases at 10 years was 6.4% conventional fractionation vs. 14.3% with hypofractionation (p=0.08) with the rate difference of 7.8% considered statistically significant.

      Long-term toxicity with hypofractionation remains low as described by Lieng et al. In a single institution study of 96 men evaluating two different hypofractionated regimens (66 Gy and 60 Gy in 20 fractions), the authors reported 5- and 8-year incidence of late grade 2 or greater GI toxicity of 4% and 4% vs. 21% and 21% in the 60 Gy and 66 Gy arms respectively (p<0.01). Grade 2 or greater GU toxicity at 5 and 8 years was 9% and 12% vs. 4% and 4% in the 60 Gy and 66 Gy arms respectively (p=0.68).

      COVID-19 Pandemic of 2020

      The use of hypofractionation has taken an even greater role during the pandemic of 2020. Recently published guidelines for the treatment of prostate cancer recommend that for definitive therapy, “the shortest fractionation schedule that has evidence of safety and efficacy should be adopted.” This includes the use of SBRT or a 20-fraction regimen to a dose of 60-62 Gy.

      Given the recommendations made by ASTRO and the NCCN Guidelines and the wealth of data supporting the use of hypofractionation for localized prostate cancer, only hypofractionated regimens (i.e. 20 to 28 fractions) will be considered medically necessary. Conventional fractionation will be considered not medically necessary.


    II. Combination therapy (external beam and brachytherapy)

      For individuals with intermediate- or high-risk disease, combination external beam combined with brachytherapy is considered medically necessary. Combination therapy is considered not medically necessary for individuals with low-risk disease. Guidelines on prostate cancer from the NCCN indicate that an external beam dose of up to 50.4 Gy is recommended. Therefore, up to 28 fractions will be considered medically necessary.

      Recently, the American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and the American Urological Association (AUA) published an evidence-based guideline for the performance of hypofractionated radiation therapy. Moderate hypofractionation was defined as a radiation fraction size between 240 cGy and 340 cGy. Ultra-hypofractionation was defined as a radiation fraction size greater or equal to 500 cGy. For an individual with localized prostate cancer who declines active surveillance, an individual with intermediate-risk prostate cancer, or an individual with high-risk prostate cancer in whom the pelvic lymph nodes are not being treated, hypofractionation radiation therapy received a strong recommendation based on high quality evidence. The recommendation was made regardless of whether the seminal vesicles are included in the treatment field, patient age, comorbidities, anatomy, and/or urinary function. These recommendations were based on reviews of large multi-center clinical trials, including the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy (CHHiP) trial, Prostate Fractionated Irradiation Trial (PROFIT), Radiation Therapy Oncology Group (RTOG) 0415 trial, and the Dutch Hypofractionated versus Conventionally Fractionated Radiotherapy for Patients with Prostate Cancer (HYPRO) trial. Regimens of 6000 cGy in 20 radiation treatment fractions and 7000 cGy in 28 radiation treatment fractions are suggested by the guideline based on their review of the largest database. This recommendation has a consensus of 100%, but the quality of evidence was noted as moderate, and the recommendation strength was noted as conditional. The panel stated that most of the published fractionation schedules have not been studied in comparative clinical trials, thus, an optimal regimen has not yet been determined.


    III. SBRT

      In addition to the recommendations noted for hypofractionation, the new guideline reviewed SBRT, also called ultra-hypofractionation. In men with low-risk prostate cancer who declined active surveillance, ultra-hypofractionation was suggested as an alternative to conventional fractionation with a conditional recommendation based on a moderate quality of evidence. For an individual with intermediate-risk prostate cancer, the consensus also suggested that ultra-hypofractionation could be used as an alternative to conventional fraction but strongly encouraged that these individuals be treated as part of a clinical trial or a multi-institutional registry. The strength of the recommendation was conditional and was based on a low quality of evidence. For an individual with high-risk prostate cancer, it was suggested that ultra-hypofractionation not be offered outside of a clinical trial or a multi-institutional registry as data was lacking on a comparative basis. The quality of evidence was felt to be low for this conditional recommendation. On the other hand, NCCN Guidelines considers ultra-hypofractionation as an acceptable regimen for high-risk disease. As such, SBRT is considered medically necessary for low-,intermediate-, and high-risk prostate cancer when not irradiating the pelvic lymph nodes. It should be noted that SBRT (ultra-hypofractionation) is defined as an entire treatment course consisting of five or fewer fractions. Thus, SBRT cannot be billed as a boost.

    IV. Postoperative radiation therapy

      In the setting of postoperative prostate cancer, external beam photon radiation therapy may be beneficial in the setting of positive margins, extracapsular extension, seminal vesicle involvement, lymph node involvement, or prostate cut-through. In addition, an individual with a detectable or rising postoperative PSA level may benefit from postoperative radiotherapy. In the postoperative setting, a dose of 64 to 72 Gy (i.e. up to 40 fractions) is recommended by the NCCN.

      A retrospective review of 112 patients evaluating the role of hypofractionation was recently published. In this study, the authors reported the 10-year results of 52.5 Gy in 20 fractions using 3D conformal radiation. The authors concluded that hypofractionation provided results comparable to conventional regimens. Further, early salvage radiation (at or before a PSA 0.2 ng/mL) yielded improved disease control. Specifically, the freedom from biochemical failure (FFBF) was 81% (vs. 66%) at 5 years and 68% (vs. 49%) at 10 years. These results have led to recommendations to use hypofractionation during the COVID-19 pandemic by the NCCN risk group.


    V. Palliative radiation therapy

      Per the NCCN Guidelines, a dose of 30 Gy in 10 fraction or 37.5 Gy in 15 fractions is recommended for “…treatment of the primary site in men with metastatic disease…to palliate obstructive symptoms due to tumor.”

    VI. Metastatic Prostate Cancer and Radiation Therapy

      In castration-nave metastatic prostate cancer, the current stand of care is systemic therapy with androgen deprivation therapy (ADT) usually in combination with docetaxel or abiraterone with prednisone (Morris et al, 2018). There has been debate in the scientific literature on the role of local therapy to the prostate gland in the setting of metastatic disease with some studies suggesting a benefit while other studies have not found a similar benefit (Rusthoven et al., 2016; Steuber et al., 2017). There is particular interest in the role of local therapy in patients with low metastatic burden. Recent randomized trials have been published evaluating the role of local treatment to the prostate in the setting of metastatic disease.

      In 2018, Bouve et al. reported the results of the HORRAD trial which is a multi-institution randomized controlled trial evaluating the role of definitive radiation therapy to the prostate in combination with androgen deprivation therapy for patients with metastatic prostate cancer. Four hundred thirty-two men with newly diagnosed, previously untreated prostate cancer with bone metastases were randomized to ADT alone or ADT with radiation therapy. Participants received 70 Gy in 35 fractions or 57.76 Gy in 19 fractions to the prostate with or without the seminal vesicles. There was no statistically significant difference in median overall survival between the ADT alone arm (43 months) vs. the ADT with radiation therapy arm (45 months) p=0.4. There was no significant difference in overall survival when stratified by number of bone metastases: <5 bone metastases (HR 0.68; 95% CI: 0.42–1.10) vs. >5 bone metastases (HR 1.06; 95% CI: 0.80–1.39). As this trial did not demonstrate an overall survival benefit to adding radiation therapy to the prostate gland to androgen deprivation therapy, the authors conclude that local therapy to the prostate gland in patients with metastatic prostate cancer at diagnosis should not be performed outside of a clinical trial.

      The STAMPEDE trial, a multi-institutional randomized phase III trial, randomized 2061 men with newly diagnosed metastatic prostate cancer with no previous treatment to standard of care (androgen deprivation therapy with or without docetaxel) or standard of care and radiotherapy between January 2013 and September 2016 (Parker et al., 2018). Radiation therapy was delivered to the prostate gland as 36 Gy in 6 fractions weekly or 55 Gy of 20 fractions daily. In May 2018, the authors decided to do a prespecified subgroup analysis for survival by metastatic burden. Low metastatic burden was defined as 3 or fewer bone metastases. High metastatic burden was defined as four or more bone metastases with one or more outside the vertebral bodies or pelvis, or visceral metastases, or both. While there was a difference in failure free survival, there was no difference in overall survival with the addition of radiation therapy. When analyzing the data by metastatic burden, the authors found an improvement overall survival in patients with a low metastatic burden (HR 0.68, 95% CI 0.52–0.90; p=0.007; 3-year survival 73% with control vs. 81% with radiotherapy). There was an improvement in failure free survival with the addition of radiation therapy for patients with low metastatic burden (HR 0.76, 95% CI 0.68–0.84; p<0.0001). The authors concluded that while radiation therapy to the prostate did not improve overall survival to unselected patients with newly diagnosed prostate cancer there was an improvement in overall survival in patients with low metastatic burden in a prespecified subgroup analysis.

      Taken together, the HORRAD trial and the STAMPEDE trial both demonstrate that there is no overall survival advantage to the addition of radiation therapy to hormonal therapy in newly diagnosed prostate cancer which was the primary endpoint to both trials. These trials raise the question of a role for radiation therapy to the prostate in selected patients with a limited number of bone metastases. It is important to note that the HORRAD trial did not find a benefit in the low metastatic setting and the STAMPEDE trial only found a benefit in a subgroup analysis that was prespecified in May 2018. As this endpoint was not initially defined, the authors had to ascertain metastatic burden by retrospectively collecting baseline data. Therefore, as the survival benefit was only seen on subgroup analysis, this finding must be interpreted with caution (Boeri et al., 2018). Furthermore, as noted by the authors in the STAMPEDE trial, the systemic therapy regimens used in treatment of metastatic prostate cancer have evolved. Currently, most patients with metastatic prostate cancer are usually treated upfront with androgen deprivation therapy (ADT) in combination with docetaxel or in combination with abiraterone with prednisone. Most patients in the STAMPEDE trial received upfront treatment with androgen deprivation therapy alone. Only 18% of patients received androgen deprivation therapy and docetaxel. The value of radiation therapy to the prostate in men with metastatic prostate cancer receiving abiraterone is unknown. Therefore, the benefit of local radiation therapy in the setting of more modern systemic therapy regimens is unknown and is being evaluated in the PEACE1 trial (NCT01957436). The PEACE1 trial (NCT01957436) is an ongoing multi-center phase III study evaluating the clinical benefit of androgen deprivation therapy (+ docetaxel) with or without local radiotherapy with or without abiraterone acetate and prednisone in patients with metastatic hormone-nave prostate cancer. Additionally, the radiation dose used in the STAMPEDE trial (36 Gy in 6 fractions or 55 Gy in 20 fractions) is a dose lower than the > 70 Gy that is commonly used in current practice and 6 Gy/fraction each week is not a tumoricidal dose. This further calls into question the results of the subgroup analysis. On the other hand, it is recognized that there remains a small cohort of patients in whom the NCCN category 1 systemic therapies (i.e. abiraterone, docetaxel, enzalutamide, and apalutamide) are contraindicated or cannot otherwise be given due to intolerances. In this low-volume metastatic cohort, the use of radiation therapy to the primary is considered medically necessary.]

    ________________________________________________________________________________________

    Horizon BCBSNJ Medical Policy Development Process:

    This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

    ___________________________________________________________________________________________________________________________

    Index:
    Radiation Therapy for Prostate Cancer
    Radiation Treatment of Prostate Cancer
    Prostate Cancer, Radiation Treatment
    Radiotherapy of Prostate Cancer
    SpaceOAR Prostate-Rectum Spacer
    Augmenix Inc., SpaceOAR Prostate-Rectum Spacer
    Prostate-Rectum Spacer
    Hydrogel Prostate-Rectum Spacer
    Stereotactic Radiotherapy of Prostate Cancer
    Prostate Cancer, Stereotactic Radiotherapy
    SBRT, Prostate Cancer

    References:
    1. Abu-Gheida I, Chandana AR, Kotecha R, Weller MA, Shah C, Kupelian PA, et al. Ten-year outcomes of moderately hypofractionated (70 Gy in 28 fractions) intensity modulated radiation therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2019;104(2):325-333. doi: 10.1016/j.ijrobp.2019.01.091.

    2. Agazaryan N, Tenn S, Chow P, et al. Volumetric modulated arc therapy treatment protocol for hypo-fractionated stereotactic body radiotherapy for localized prostate cancer. Int J Clin Oncol Biol Phys. 2010 Nov 1; 78(3):S844. Abstract 3431.

    3. Aluwini S, van Rooji P, Hoogeman M, et al. CyberKnife stereotactic radiotherapy as monotherapy for low- to intermediate-stage prostate cancer: Early experience, feasibility, and tolerance. J Endourol. 2010 May 17; 24(5):865-869.

    4. Arcangeli G, Saracino B, Arcangeli S, Gomellini S, Grazia Petrongari M, Sanguineti G, et al. Moderate hypofractionation in high-risk, organ-confined prostate cancer: Final results of a phase III randomized trial. J Clin Oncol. 2017;35(17): 1891-1897. doi: 10.1200/JCO.2016.70.4189.

    5. ASTRO Model Policies – Stereotactic Body Radiation Therapy (SBRT) Approved 8-2-10. Updated 4-17-13.

    6. Avkshtol V, Ruth KJ, Ross EA, Hallman MA,Greenberg RE, Price Jr RA, et al. Ten-year update of a randomized, prospective trial of conventional fractionated versus moderate hypofractionated radiation therapy for localized prostate cancer. J Clin Oncol. 2020;38:1676-1684. doi: 10.1200/JCO.19.01485.

    7. Bekelman JE, Rumble RB, Chen C, et al. Clinically localized prostate cancer: ASCO clinical practice guideline endorsement of an American Urological Association/American Society for Radiation Oncology/Society of Urologic Oncology guideline. Published online before print. 2015 Sep 5.

    8. Boeri L. Sharma V, Karnes RK. Radiotherapy for newly diagnosed oligometastatic prostate cancer. Lancet. 2018 Oct 18. pii: S0140-6736(18)32598-4. doi: 10.1016/S0140-6736(18)32598-4.

    9. Boev LMS, Hulshof MCCM, Vis AN, Zwinderman AH, Twisk JWR, Witjes WPJ, Delaere KPJ, Moorselaar RJAV, Verhagen PCMS, van Andel G. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2018. https://doi.org/10.1016/j.eururo.2018.09.008.

    10. Boike TP, Lotan Y, Cho LC, et al. Phase I dose-escalation study of stereotactic body radiation therapy for low-and intermediate-risk prostate cancer. J Clin Oncol. 2011 May 20; 29(15):2020-2026.

    11. Bolzicco G, Favretto MS, Scremin E, et al. Image-guided stereotactic body radiation therapy for clinically localized prostate cancer: Preliminary clinical results. Technol Cancer Res Treat. 2010 Oct; 9(5):473-477.

    12. Bruner DW, Pugh SL, Lee WR, et al. Quality of Life in Patients With Low-Risk Prostate Cancer Treated With Hypofractionated vs Conventional Radiotherapy: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019;5(5):664–670. doi:10.1001/jamaoncol.2018.6752.

    13. Buyyounski MK, Price RA, Harris EER, et al. Stereotactic body radiotherapy for primary management of early stage, low- to intermediate-risk prostate cancer: Report of the ASTRO Emerging Technology Committee. Int J Radiat Oncol Biol Phys. 2010 Apr: 76(5):1297-1304.

    14. Catton CN, Lukka H, Gu C-S, Martin JM, Supiot S Chung PWM, et al. Radonmized trial of a hypofractionated radiation regimen for the treatment of localized prostate cancer. J Clin Oncol. 2017;35(17):1884-1890. doi: 10.1200/JCO.2016.71.7397.

    15. Chin S, Fatimilehin A, Walshaw R, Argarwal A, Mistry H, Elliott T, et al. Ten-year outcomes of moderately hypofractionated salvage postprostatectomy radiation therapy and external validation of a contemporary multivariable nomogram for biochemical failure. Int J Radiat Oncol Biol Phys. 2020;107(2):288-296. doi: 10.1016/j.ijrobp.2020.01.008.

    16. Coakley FV, Oto A, Alexander LF, et al. ACR Appropriateness Criteria. Prostate cancer—pretreatment detection, staging, and surveillance. Date of origin: 1995. Last review date: 2016.

    17. Copp H, Bissonette EA, Theodorescu D. Tumor control outcomes of patients treated with trimodality therapy for locally advanced prostate cancer. Urology. 2005 Jun; 65(6):1146-1151.

    18. D’Amico AV, Cote K, Loffredo M, et al. Determinants of prostate cancer-specific survival after radiation therapy for patients with clinically localized prostate cancer. J Clin Oncol. 2002, 20(23):4567-4573.

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    20. Davis BJ, Taira AV, Nguyen PL, et al. ACR Appropriateness Criteria. Permanent source brachytherapy for prostate cancer. Date of origin: 1996. Last review date: 2016.

    21. Dearnaley DP, Griffin C, Syndikus S, Khoo V, Birtle AJ, Choudhury A, et al. Eight-year outcomes of a phase III randomized trial of conventional versus hypofractionated high-dose intensity modulated radiotherapy for prostate cancer (CRUK/06/016): Update from the CHHiP trial. J Clin Oncol. 2020;38(6 suppl):325-325. doi: 10.1200/JCO.2020.38.6_suppl.325.

    22. Dearnaley D, Syndikus I, Mossop, Khoo V, Birtle A, Bloomfield D, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomized, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17:1047-60. doi: 10.1016/S1470-2045(16)30102-4.

    23. Demanes DJ, Rodriguez RR, Schour L, et al. High-dose- rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California endocurietherapy’s 10-year results. Int J Radiat Oncol Biol Phys. 2005 Apr 1; 61(5):1306-1316.

    24. De Vries KC, Wortel RC, Oomen-de-Hoop E, Heemsbergen WD, Pos FJ, Incrocci L. Hypofractionated versus conventionally fractionated radiation therapy for patients with intermediate- or high-risk, localized, prostate cancer: 7-year outcomes for the randomized, multicenter, open-label, phase 3 HYPRO trial. Int J Radiat Oncol Biol Phys. 2020;106(1):1085-1158. doi: 10.1016/j.ijrobp.2019.09.007.

    25. Freeman DE, King CR. Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes. Radiation Oncology. 2011 Jan 10; 6(3).

    26. Friedland JL, Freeman DE, Masterson-McGary ME, et al. Stereotactic body radiotherapy: An emerging treatment approach for localized prostate cancer. Technol Cancer Res Treat. 2009 Oct; 8(5):387-392.

    27. Fuller DB, Mardirossian G, Wong D, et al. Prospective evaluation of stereotactic body radiotherapy for low- and intermediate-risk prostate cancer: Emulating high-dose-rate brachytherapy dose distribution. Int J Radiat Oncol Biol Phys. 2012 Nov 1; 84(3):S149. Abstract 368.

    28. Galalae RM, Martinez A, Mate T, et al. Long-term outcome by risk factors using conformal high-dose-rate brachytherapy (HDR-BT) boost with or without neoadjuvant androgen suppression for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004 Mar 15; 58(4):1048-1055.

    29. Gustafson GS, Nguyen PL, Assimos DG, et al. ACR Appropriateness Criteria. Postradical prostatectomy irradiation in prostate cancer. Date of origin: 1996. Last review date: 2014.

    30. Hoffman KE, Voong KR, Levy LB, Allen PK, Choi S, Schlemback PJ. Et al. Radomized trial of hypofractionated, dose-escalated, intensity-modulated radiation therapy (IMRT) versus conventionally fractionated IMRT for localized prostate cancer. J Clin Oncol. 2018;36(29):2943-2949. doi: 10.1200/JCO.2018.77.9868.

    31. Hossain S, Xia P, Huang K, et al. Dose gradient near target–normal structure interface for nonisocentric CyberKnife and isocentric intensity-modulated body radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010 Sep 1; 78(1):58-63.

    32. Hsu ICJ, Yamada Y, Assimos DG, et al. ACR Appropriateness Criteria. High-dose-rate brachytherapy for prostate cancer. Date of origin: 2013.

    33. Jabbari S, Weinberg VK, Kaprealian T, et al. Stereotactic body radiotherapy as monotherapy or post-external beam radiotherapy boost for prostate cancer: technique, early toxicity, and PSA response. Int J Radiat Oncol Biol Phys. 2012 Jan 1; 82(1):228-234.

    34. Kang JK, Cho CK, Choi CW, et al. Image-guided stereotactic body radiation therapy for localized prostate cancer. Tumori. 2011; 97(1):43-48.

    35. Katz AJ. CyberKnife Radiosurgery for Prostate Cancer. Technol Cancer Res Treat. 2010 Oct; 9(5):463-472.

    36. Katz AJ and Kang J. Quality of life and toxicity after SBRT for organ-confined prostate, a 7-year study. Front Oncol. 2014 Oct 28; 4(31):1-6.

    37. Katz AJ and Kang J. Stereotactic body radiotherapy with or without external beam radiation as treatment for organ confined high-risk prostate carcinoma: a six year study. Radiation Oncol. 2014 Jan 1; 9(1):1-10.

    38. Katz AJ, Santoro M. Quality of life and efficacy for stereotactic body radiotherapy for treatment of organ confined prostate cancer. Int J Radiat Oncol Biol Phys. 2010 Nov 1; 78(3):S58. Abstract 123.

    39. Katz AJ, Santoro M, Ashley R, et al. Stereotactic body radiotherapy for organ-confined prostate cancer. BMC Urology. 2010; 10:1.

    40. King CR, Brooks JD, Gill H, et al. Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Feb 1; 82(2):877-882.

    41. King CR, Brooks JD, Gill H, et al. Stereotactic body radiotherapy for localized prostate cancer: Interim results of a prospective phase II clinical trial. Int J Radiat Oncol Biol Phys. 2009 Mar 15; 73:1043-1048.

    42. King CR, Freeman D, Kaplan I, et al. Stereotactic body radiotherapy for localized prostate cancer: pooled analysis from a multi-institutional consortium of prospective phase II trials. Radiation Oncol. 2013 Nov; 109(2):217-221.

    43. Lee WR, Dignam JJ, Amin MB, Bruner DW, Low D, Swanson GP, et al. Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol. 2016;34(20):2325-2332. doi: 10.1200/JCO.2016.67.0448.

    44. Lin Y-W, Lin L-C, and Lin K-L. The early result of whole pelvic radiotherapy and stereotactic body radiotherapy boost for high-risk localized prostate cancer. Front Oncol. 2014 Oct; 4(278):1-8.

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    46. Mantz CA, Fernandez E, Zucker I, et al. A phase II trial of real-time target tracking SBRT for low-risk prostate cancer utilizing the Calypso 4D localization system: Patient reported health-related quality of life and toxicity outcomes. Int J Radiat Oncol Biol Phys. 2010 Nov 1; 78(3):S57-S58. Abstract 121.

    47. Martinez AA, Gustafson G, Gonzalez J, et al. Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer. Int J Radiat Oncol Biol Phys. 2002 Jun 1; 53(2):316-327.

    48. Martinez A, Gonzalez J, Spencer W, et al. Conformal high dose rate brachytherapy improves biochemical control and cause specific survival in patients with prostate cancer and poor prognostic factors. J Urol. 2003 Mar; 169(3):974-979.

    49. McLaughlin PW, Liss, AL, Nguyen PL, et al. ACR Appropriateness Criteria. Locally advanced (high-risk) prostate cancer. Date of origin: 1996. Last review date: 2016.

    50. Meier R, Beckman A, Kaplan I, et al. Stereotactic radiotherapy for organ-confined prostate cancer: Early toxicity and quality of life outcomes from a multi-institutional trial. Int J Radiat Oncol Biol Phys. 2010 Nov 1; 78(3):S57. Abstract # 120.

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    52. Merrick GS, Wallner KE, Butler WM. Permanent interstitial brachytherapy in the management of carcinoma of the prostate gland. J Urol. 2003 May; 169(5):1643-1652.

    53. Merrick GS, Wallner KE, Butler WM. Minimizing prostate brachytherapy-related morbidity. Urology. 2003 November; 62(5):786-792.

    54. Morgan SC, Hoffman K, Loblaw DA, et al. Hypofractionated radiation therapy for localized prostate cancer: Executive summary of an ASTRO, ASCO, and AUA evidence-based guideline. Pract Radiat Oncol. 2018. In press.

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    Codes:
    (The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

    CPT*

      HCPCS
        C9743

      * CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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