Description:
Radiotherapy (RT) is an integral component of treatment for prostate cancer. Intensity-modulated radiotherapy (IMRT) has been proposed as a method of external-beam radiotherapy that delivers adequate radiation to the tumor volume, while minimizing the radiation dose to surrounding normal tissues and structures.

For individuals who have localized prostate cancer and are undergoing definitive RT who receive IMRT, the evidence includes several prospective comparative studies, retrospective studies, and systematic reviews of these studies. Relevant outcomes are overall survival, disease-free survival, quality of life, and treatment-related morbidity. Although there are few prospective comparative trials, the evidence has generally shown that IMRT provides tumor control and survival outcomes similar to 3-dimensional conformal radiotherapy (3D-CRT) while reducing gastrointestinal and genitourinary toxicity. These findings are supported by treatment planning studies, which have predicted that IMRT improves target volume coverage and sparing of adjacent organs compared with 3D-CRT. A reduction in clinically significant complications of RT is likely to improve the quality of life for treated patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have prostate cancer and are undergoing RT after prostatectomy who receive IMRT, the evidence includes retrospective comparative studies, single-arm phase 2 trials, and systematic reviews of these studies. Relevant outcomes are overall survival, disease-free survival, quality of life, and treatment-related morbidity. Although the comparative studies are primarily retrospective, the evidence has generally shown that IMRT provides tumor control and survival outcomes similar to 3D-CRT. Notably, a retrospective comparative study found a significant improvement in acute upper gastrointestinal toxicity with IMRT compared with 3D-CRT, mainly due to better bowel sparing with IMRT. Another retrospective comparative study found a reduction in genitourinary toxicity. A reduction in clinically significant complications of RT is likely to improve the quality of life for treated patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Background 
Prostate cancer is the second leading cause of cancer-related death among men in the U.S.⁶ Of the estimated 3.1 million new cases of prostate cancer reported during 2003 to 2017, localized, regional, distant, and unknown stage prostate cancer accounted for 77%, 11%, 5%, and 7% of cases, respectively. During this time period, the incidence of prostate cancer was highest for men aged 70 to 74 years of age and Black men. White men had lower percentages of distant (5%) and unknown stage prostate cancer (6%) than did any other race/ethnicity. With regard to survival for distant stage disease, 5-year survival was highest among Asian-Pacific islanders (42%), followed by Hispanics (37.2%), American Indian/Alaska natives (32.2%), Black (31.6%), and White (29.1%) men during a period from 2001 to 2016. Five-year survival for all stages combined was higher for White men as compared to Black or Hispanic men.

Prostate Cancer Treatment
For localized prostate cancer, radiotherapy (RT) is an accepted option for primary (definitive) treatment. Other options include surgery (radical prostatectomy), hormonal treatment, or active surveillance.

In the postoperative setting, RT to the prostate bed is an accepted procedure for patients with an increased risk of local recurrence, based on 3 randomized controlled trials that showed a significant increase in biochemical recurrence-free survival.^7,8,9 Professional society guidelines have recommended adjuvant RT to patients with adverse pathologic findings at the time of prostatectomy and salvage RT for patients with prostate-specific antigen recurrence or local recurrence after prostatectomy in the absence of metastatic disease.^10,5

Radiotherapy Techniques
Radiation therapy may be administered externally (i.e., a beam of radiation is directed into the body) or internally (i.e., a radioactive source is placed inside the body, near a tumor).¹¹ External RT techniques include "conventional" or 2-dimensional (2D) RT, 3-dimensional (3D) conformal RT, and intensity-modulated radiation therapy (IMRT).

Conventional External-Beam Radiotherapy
Methods to plan and deliver RT have evolved that permit more precise targeting of tumors with complex geometries. Conventional 2D treatment planning utilizes X-ray films to guide and position radiation beams.¹¹ Bony landmarks visualized on X-ray are used to locate a tumor and direct the radiation beams. The radiation is typically of uniform intensity.

Three-Dimensional Conformal Radiotherapy
Radiation treatment planning has evolved to use 3D images, usually from computed tomography (CT) scans, to more precisely delineate the boundaries of the tumor and to discriminate tumor tissue from adjacent normal tissue and nearby organs at risk for radiation damage. Three-dimensional conformal RT (3D-CRT) involves initially scanning the patient in the position that will be used for the radiation treatment.¹¹ The tumor target and surrounding normal organs are then outlined in 3D on the scan. Computer software assists in determining the orientation of radiation beams and the amount of radiation the tumor and normal tissues receive to ensure coverage of the entire tumor in order to minimize radiation exposure for at risk normal tissue and nearby organs. Other imaging techniques and devices such as multileaf collimators (MLCs) may be used to "shape" the radiation beams. Methods have also been developed to position the patient and the radiation portal reproducibly for each fraction and to immobilize the patient, thus maintaining consistent beam axes across treatment sessions.

Intensity-Modulated Radiotherapy
Intensity-modulated radiation therapy is the more recent development in external radiation. Treatment planning and delivery are more complex, time-consuming, and labor-intensive for IMRT than for 3D-CRT. Similar to 3D-CRT, the tumor and surrounding normal organs are outlined in 3D by a scan and multiple radiation beams are positioned around the patient for radiation delivery.¹¹ In IMRT, radiation beams are divided into a grid-like pattern, separating a single beam into many smaller "beamlets". Specialized computer software allows for “inverse” treatment planning. The radiation oncologist delineates the target on each slice of a CT scan and specifies the target's prescribed radiation dose, acceptable limits of dose heterogeneity within the target volume, adjacent normal tissue volumes to avoid, and acceptable dose limits within the normal tissues. Based on these parameters and a digitally reconstructed radiographic image of the tumor, surrounding tissues, and organs at risk, computer software optimizes the location, shape, and intensities of the beam ports to achieve the treatment plan's goals.

Increased conformality may permit escalated tumor doses without increasing normal tissue toxicity and is proposed to improve local tumor control, with decreased exposure to surrounding, normal tissues, potentially reducing acute and late radiation toxicities. Better dose homogeneity within the target may also improve local tumor control by avoiding underdosing within the tumor and may decrease toxicity by avoiding overdosing.

Other advanced techniques may further improve RT treatment by improving dose distribution. These techniques are considered variations of IMRT. Volumetric modulated arc therapy delivers radiation from a continuous rotation of the radiation source. The principal advantage of volumetric modulated arc therapy is greater efficiency in treatment delivery time, reducing radiation exposure and improving target radiation delivery due to less patient motion. Image-guided RT involves the incorporation of imaging before and/or during treatment to more precisely deliver RT to the target volume.

Regulatory Status
In general, IMRT systems include intensity modulators, which control, block, or filter the intensity of radiation; and, radiotherapy planning systems which plan the radiation dose to be delivered.

A number of intensity modulators have received marketing clearance through the FDA 510(k) process. Intensity modulators include the Innocure Intensity Modulating Radiation Therapy Compensators (Innocure) and decimal tissue compensator (Southeastern Radiation Products) FDA product code: IXI. Intensity modulators may be added to standard linear accelerators to deliver IMRT when used with proper treatment planning systems.

Radiotherapy treatment planning systems have also received FDA 510(k) marketing clearance. These include the Prowess Panther (Prowess), TiGRT (LinaTech), Ray Dose (Ray Search Laboratories), and the eIMRT Calculator (Standard Imaging). FDA product code: MUJ.

Fully integrated IMRT systems also are available. These devices are customizable, and support all stages of IMRT delivery, including planning, treatment delivery, and health record management. One such device to receive FDA 510(k) clearance is the Varian IMRT system (Varian Medical Systems). FDA product code: IYE.

Related Policies
80114 Brachytherapy for Clinically Localized Prostate Cancer Using Permanently Implanted Seeds
80133 High-Dose Rate Temporary Prostate Brachytherapy
80146 Intensity-Modulated Radiotherapy of the Breast and Lung
80148 Intensity-Modulated Radiotherapy: Cancer of the Head and Neck or Thyroid
80149 Intensity-Modulated Radiation Therapy (IMRT): Abdomen and Pelvis
80159 Intensity-Modulated Radiotherapy: Central Nervous System Tumors

Policy: 
Intensity-modulated radiotherapy (IMRT) may be considered MEDICALLY NECESSARY in the treatment of localized prostate cancer (see Policy Guidelines).

IMRT may be considered MEDICALLY NECESSARY after radical prostatectomy as:

• Adjuvant therapy when there are adverse pathologic findings at prostatectomy or with a persistently detectable prostate-specific antigen level after prostatectomy (see Policy Guidelines)
• Salvage therapy when there is evidence of biochemical or local recurrence when there is no evidence of distant metastatic disease (see Policy Guidelines).

IMRT is investigational and/ or unproven and therefore considered NOT MEDICALLY NECESSARY for the treatment of prostate cancer when the above criteria are not met.  

If medical necessity criteria for IMRT of the prostate are met, then SpaceOAR (CPT 55874) would be considered MEDICLALLY NECESSARY as well.

Policy Guidelines   
Localized Prostate Cancer: Radiotherapy as Definitive Treatment
Localized prostate cancer can be defined as cancer confined to the prostate gland T1-T2N0-NXM0 or as locally advanced cancer. Locally advanced cancer is confined to adjacent structures and includes T3a-T3bN0-NXM0. The presence of tumor invasion beyond extracapsular extension or other than seminal vesicles, or with evidence of regional lymph node involvement, in the absence of distant metastases T4N0-N1M0, does not necessarily preclude definitive therapy.

The National Comprehensive Cancer Network (NCCN)¹ has recommended a dose of 75.6 to 79.2 gray (Gy) in conventional fractions (with or without seminal vesicles) for patients with low-risk cancers (based on findings from Kuban et al. [2008]²). Low-risk features in localized prostate cancer are defined as stage T1 to T2a, a Gleason score of 6 or less, and a prostate-specific antigen (PSA) level less than 10 ng/mL.

The NCCN¹ has recommended doses up to 81.0 Gy for patients with intermediate- and high-risk cancers, defined as: intermediate risk: stage T2b to T2c or Gleason score of 7 or PSA levels between 10 ng/mL and 20 ng/mL; and high-risk: stage T3a or Gleason score of 8 to 10 or PSA level greater than 20 ng/mL (based on Eade et al. [2007]³; and Xu et al. [2011]⁴).

Post Prostatectomy: Radiotherapy as Adjuvant or Salvage Therapy
Radiotherapy (RT) after prostatectomy is used as adjuvant therapy in patients at a higher risk of recurrence. In the adjuvant setting, adverse pathologic findings at prostatectomy include positive surgical margins, seminal vesicle invasion, and extraprostatic extension.

Use of RT as salvage therapy included treating the prostate bed and possibly surrounding tissues, including lymph nodes, in a patient with locoregional recurrence after surgery. In the salvage setting, biochemical recurrence is defined as a detectable or rising PSA level of 0.2 ng/mL or more after surgery, with a confirmatory test level of 0.2 ng/mL or higher.

American Urological Association and American Society for Radiation Oncology (Pisansky et al. [2019]⁵) guidelines recommend a minimum dose of 64 to 65 Gy in the post-prostatectomy setting.

Fractionation
In the treatment of prostate cancer, conventional RT applies total doses in excess of 74 Gy over up to 9 weeks, whereas hypofractionated RT involves daily doses greater than 2 Gy and has an overall shorter treatment time.

The NCCN guidelines¹ state that in the treatment of prostate cancer, moderately hypofractionated intensity-modulated radiotherapy (IMRT) regimens (2.4 to 4 Gy per fraction over 4 to 6 weeks) have been tested in randomized trials, and their efficacy has been similar or non-inferior to conventionally fractionated IMRT, with 1 trial showing fewer treatment failures with a moderately fractionated regimen. Toxicity was similar between moderately hypofractionated and conventional regimens in some but not all of the trials. Overall, the panel believes that hypofractionated IMRT techniques, which are more convenient for patients, can be considered as an alternative to conventionally fractionated regimens when clinically indicated.

Radiation Tolerance of Normal Tissue
Organs at risk are defined as normal tissues whose radiation sensitivity may significantly influence treatment planning and/or prescribed radiation dose. Organs at risk may be particularly vulnerable to clinically important complications from radiation toxicity.

Intensity-modulated radiotherapy should be considered when a tumor is near organs at risk, and 3-dimensional conformal radiotherapy planning does not meet dose-volume constraints for normal tissue tolerance.

Tables PG1 and 2 outline radiation doses generally considered tolerance thresholds for these normal structures in the pelvis.

Table PG1. Radiation Tolerance Doses for Normal Tissues of the Pelvis  

Site	TD 5/5, Graya			TD 50/5, Grayb			Complication End Point
	Portion of Organ Involved			Portion of Organ Involved
	1/3	2/3	3/3	1/3	2/3	3/3
Spinal cord	50 (5 cm)	50 (10 cm)	47 (20 cm)	70 (5 cm)	70 (10 cm)	NP	Myelitis, necrosis
Small intestine	50	NP	40	60	NP	55	Obstruction, perforation, fistula
Colon	55	NP	45	65	NP	55	Obstruction, perforation, ulceration, fistula
Rectum	NP	NP	60	NP	NP	80	Severe proctitis, necrosis, fistula
Bladder	NP	80	65	NP	85	80	Symptomatic bladder contracture and volume loss
Femoral head	NP	NP	52	NP	NP	65	Necrosis

Compiled from 2 sources: (1) Morgan MA, Ten Taken RK, Lawrence TS. Essentials of radiation therapy. In DeVita, Hellman, and Rosenberg, Cancer: Principles & Practice of Oncology. Philadelphia: Lippincott Williams and Wilkins; 2019; and (2) Kehwar TS, Sharma SC. Use of normal tissue tolerance doses into linear quadratic equation to estimate normal tissue complication probability.

http://www.rooj.com/Radiation%20Tissue%20Tolerance.htm. Accessed May 25, 2021.
NP: not provided; TD: tolerance dose.
^aTD 5/5 is the average dose that results in a 5% complication risk within 5 years.
^bTD 50/5 is the average dose that results in a 50% complication risk within 5 years.

Table PG2. Radiation Dose Volume (1.8 to 2.0 Gray per Fraction) for Normal Tissues of the Pelvis 

Site	Radiation Dose Volume
Rectum	V75 < 15%, V70 < 20%, V65 < 25%, V60 < 35%, V50 < 50%
Bladder	V80 < 15%, V75 < 25%, V70 < 35%, V65 < 50%
Femoral head	V50 < 5%

Compiled from: Hristov B, Lin SH, Christodouleas JP, editors. Radiation Oncology: A Question-Based Review. Philadelphia: Lippincott Williams & Wilkins; 2011.

Coding
The following CPT codes for simple and complex intensity-modulated radiotherapy delivery are available:

77385: Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple
77386: complex. 

The Centers for Medicare and Medicaid Services (CMS) did not implement this change for 2015; instead CMS created HCPCS G codes for the radiotherapy codes being deleted 12/31/14. CMS continues to maintain the G codes for 2016. So the following codes may be used for IMRT:

G6015: Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session 

G6016: Compensator-based beam modulation treatment delivery of inverse planned treatment using 3 or more high resolution (milled or cast) compensator, convergent beam modulated fields, per treatment session.

Code 77301 remains valid:

77301: Intensity-modulated radiotherapy plan, including dose-volume histograms for target and critical structure partial tolerance specifications.

Effective in 2010, a new code was added:

77338: Multi-leaf collimator (MLC) device(s) for intensity-modulated radiation therapy (IMRT), design and construction per IMRT plan.

Code 77338 is to be reported only once per IMRT plan.

Effective 01012018 a new code was added:

55874 Transperineal placement of biodegradable material, periprostatic, single or multiple injection(s), including image guidance, when performed

Benefit Application
BlueCard^®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale     
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Multiple-dose planning studies have generated 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) treatment plans from the same scans, and then compared predicted dose distributions within the target and adjacent organs at risk. Results of such studies have shown that IMRT improves on 3D-CRT on conformality to, and dose homogeneity within, the target. Dosimetry using stationary targets generally confirms these predictions. Thus, radiation oncologists have hypothesized that IMRT may provide better treatment outcomes than 3D-CRT. However, these types of studies offer indirect evidence for IMRT treatment benefit, and it is difficult to relate dosing study results to actual effects on health outcomes.

Comparative studies of radiation-induced adverse events from IMRT versus alternative radiation delivery would constitute definitive evidence of establishing the benefit of IMRT. Single-arm series of IMRT can give insights into the potential for benefit, particularly if an adverse event that is expected to occur at high rates is shown to decrease by a large amount. Studies of treatment benefit are also important to establish whether IMRT is at least as good as other types of delivery, but, absent such comparative trials, it is likely that benefit from IMRT is at least as good as with other types of delivery.

In general, when the indication for IMRT is to avoid radiation to sensitive areas, dosimetry studies have been considered sufficient evidence to demonstrate that harm would be avoided using IMRT. For other indications, such as using IMRT to provide better tumor control, comparative studies of health outcomes are needed to demonstrate such a benefit.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African American, Asian, Black, Latino and Native American]; LGBTQIA (lesbian, gay, bisexual, transgender, queer, intersex, asexual); women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Intensity-Modulated Radiotherapy for Primary (Definitive) Therapy for Localized Prostate Cancer
Clinical Context and Therapy Purpose
The purpose of IMRT in patients who have localized prostate cancer and undergoing definitive radiotherapy (RT) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does IMRT improve the net health outcome for individuals who have localized prostate cancer and are undergoing definitive therapy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who have localized prostate cancer and are undergoing definitive therapy.

Interventions
The therapy being considered is IMRT. Radiotherapy is an integral component of prostate cancer treatment. Intensity-modulated radiotherapy has been proposed as a method of external-beam RT that delivers adequate radiation to the tumor volume while minimizing the radiation dose to surrounding normal tissues and structures.

Comparators
The following therapy is currently being used to make decisions about the treatment of localized prostate cancer: 3D-CRT.

Outcomes
The general outcomes of interest are overall survival (OS), locoregional recurrence, quality of life, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A meta-analysis by Yu et al. (2016) included 23 studies (N = 9556 patients) that compared IMRT with 3D-CRT for gastrointestinal (GI), genitourinary (GU), and rectal toxicity, biochemical control, and OS.¹² Reviewers included 16 retrospective comparisons and 5 prospective cohort studies published before July 2015. The relative risk (RR) for the pooled analysis was considered significant if the 95% confidence interval (CI) did not overlap at 1 at the p < .05 level. Intensity-modulated radiotherapy resulted in less acute and late GI toxicity, less rectal bleeding, and improved biochemical control (Table 1). There was a modest increase in acute GU toxicity, and no significant differences between the treatments in acute rectal toxicity, late GU toxicity, and OS.

Table 1. Outcomes for IMRT Compared With 3D-CRT

Comparison	No. of Studies	No. of Patients	RR for IMRT vs 3D-CRT	95% CI
Acute GI toxicity	12	4142	0.59	0.44 to 0.78
Late GI toxicity	13	6519	0.54	0.38 to 0.78
Acute rectal toxicity	4	2188	1.03	0.45 to 2.36
Late rectal bleeding	5	1972	0.48	0.27 to 0.85
Acute GU toxicity	14	4603	1.08	1.00 to 1.17
Late GU toxicity	12	5608	1.03	0.82 to 1.30
Biochemical control	6	2416	1.17	1.08 to 1.27
Overall survival	3	924	1.07	0.96 to 1.19

3D-CRT: 3-dimensional conformal radiotherapy; CI: confidence interval; GI: gastrointestinal, grade 2-4 toxicity; GU: genitourinary, grade 2-4 toxicity; IMRT: intensity-modulated radiotherapy; RR: relative risk.

Bauman et al. (2012) published a systematic review that assessed IMRT in the treatment of prostate cancer to quantify its potential benefits and to make recommendations for RT programs considering adopting this technique within Ontario, Canada.¹³ Based on a review of 11 published reports through March 2009 (9 retrospective cohort studies, 2 RCTs) including 4559 patients, reviewers recommended IMRT over 3D-CRT for aggressive treatment of localized prostate cancer where an escalated radiation (> 70 gray [Gy]) dose would be required. Four studies (3 retrospective cohort studies, 1 RCT) reported differences in adverse events between IMRT and 3D-CRT. The RCT (N = 78 patients) reported significantly less frequent acute GI toxicity in the IMRT group than in the 3D-CRT group. This was true for grade 2, 3, or 4 toxicity (20% vs. 61%, p = .001), grade 3 or 4 toxicity (0% vs. 13%, p = .001), and for acute proctitis (15% vs. 38%, p = .03). A second RCT included in this systematic review reported no differences in toxicity between IMRT and 3D-CRT. For late GI toxicity, 4 of 9 studies, all retrospective cohort studies (N = 3,333 patients), reported differences between IMRT and 3D-CRT. One RCT, reporting on late GI toxicity, did not find any differences between IMRT and 3D-CRT. Five of 9 studies reported on late GU effects: only 1 reported a difference in late GU effects in favor of 3D-CRT. Two retrospective cohort studies reported mixed findings on quality of life outcomes.¹³

A systematic review by Hummel et al. (2010) conducted for the Health Technology Assessment Programme evaluated the clinical effectiveness of IMRT for the radical treatment of prostate cancer.¹⁴ The literature search through May 2009 identified 8 nonrandomized studies comparing IMRT with 3D-CRT. Clinical outcomes were OS, biochemical (prostate-specific antigen [PSA]) relapse-free survival, toxicity, and health-related quality of life. The biochemical relapse-free survival was not affected by treatment received, except when doses differed between groups. In those cases, a higher dose with IMRT was favored over lower doses with 3D-CRT. There was some indication that GU toxicity was worse for patients treated with dose-escalated IMRT. However, any group difference resolved by 6 months after treatment. Data comparing IMRT with 3D-CRT supported the theory that higher doses (up to 81 Gy) can improve biochemical survival for patients with localized prostate cancer. Most studies reported an advantage for IMRT in GI toxicity, particularly for the volume of the rectum treated, because toxicity can be reduced by increasing conformality of treatment.

Randomized Controlled Trials
Studies not included in the Yu et al. (2016) meta-analysis12, are summarized below.

Viani et al. (2016) reported on a pseudorandomized trial (sequential allocation) that compared toxicity levels between IMRT and 3D-CRT in 215 men who had localized prostate cancer.¹⁵ Treatment consisted of hypofractionated RT at a total dose of 70 Gy in 2.8 Gy per fraction for either IMRT or 3D-CRT. The primary endpoint was toxicity, defined as any symptoms up to 6 months after treatment (acute) or that started 6 months after treatment (late). Quality of life was assessed with a prostate-specific module. The trial was adequately powered, and the groups were comparable at baseline. However, blinding of patients and outcome assessors was not reported. As shown in Table 2, the 3D-CRT group reported significantly more incidence of acute and late GI and GU toxicity, with similar rates of biochemical control (PSA nadir + 2 ng/mL). The combined incidence of acute GI and GU toxicity was 28% for the 3D-CRT group compared with 11% for the IMRT group. Prostate-specific quality of life was reported to be worse in the 3D-CRT group at 6, 12, and 24 months, but not at 36 months posttreatment.

Table 2. Acute and Late Toxicity Rates With 3D-CRT and IMRT

Comparison	3D-CRT (n = 109), %	IMRT (n = 106), %	p
Acute GI toxicity, grade ≥ 2	24	7	.001
Acute GU toxicity, grade ≥ 2	27	9	.001
Late GI toxicity, grade ≥ 2	21.7	6.4	.001
Late GU toxicity, grade ≥ 2	12.3	3.7	.02
Biochemical control	94.3	95.4	.678

3D-CRT: 3-dimensional conformal radiotherapy; GI: gastrointestinal; GU: genitourinary; IMRT: intensity-modulated radiotherapy.

Nonrandomized Studies
Sujenthiran et al. (2017) published a retrospective cohort study evaluating 23,222 men who were treated for localized prostate cancer with IMRT (n = 6,933) or 3D-CRT (n = 16,289) between January 2010 and December 2013 and whose data were available in various databases within the English National Health Service.16, Dosage was similar between treatment types: patients in both groups received a median of 2 Gy per fraction for a median total dose of 74 Gy. Gastrointestinal and GU toxicities were categorized as grade 3 or above using National Cancer Institute Common Terminology Criteria. On average, patients in the IMRT group experienced fewer GI toxic events per 100 person-years (4.9) than patients in the 3D-CRT group, who saw an average 6.5 GI events per 100 person-years (adjusted hazard ratio [HR], 0.66; 95% CI, 0.61 to 0.72; p < .01). The rate of GU toxicity events was similar between treatment groups (IMRT, 2.3 GU events per 100 person-years vs 3D-CRT, 2.4 GU events per 100 person-years; HR, 0.94; 95% CI, 0.84 to 1.06; p = .31). The most commonly diagnosed GI toxicity event was radiation proctitis (n = 5,962 [68.5%] of 8,701 diagnoses). Of 4061 GU toxicity diagnoses, the most common was hematuria (1265 [31.1%]). Study limitations included therapeutic differences and baseline GI and GU symptoms unaccounted for in the analysis, as well as a limited follow-up on GI and GU toxicity. Reviewers concluded that IMRT showed a significant reduction in GI toxicity severity over 3D-CRT and similar levels of GU toxicity severity.

Michalski et al. (2013) reported on comparative data for IMRT and 3D-CRT from the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial.17, In this trial, the initial protocol only included 3D-CRT, but during the trial, the protocol was amended to include IMRT. As a result, 491 patients were treated with 3D-CRT and 257 were treated with IMRT. Patients treated with 3D-CRT received 55.8 Gy to the prostate and seminal vesicles and then 23.4 Gy to the prostate only. All IMRT patients received 79.2 Gy to the prostate and seminal vesicles. Radiation exposure for the bladder and rectum were significantly reduced with IMRT. There was a significant decrease in the incidence of grades 2, 3, and 4 late GI toxicity for IMRT on univariate analysis (p = .039). On multivariate analysis, there was a 26% reduction in grade 2, 3, and 4 GI toxicity for the IMRT group but this difference was not statistically significant (p = .099). There were no differences in early or late GU toxicity between groups.

Vora et al. (2013) reported on 9-year tumor control and chronic toxicities observed in 302 patients treated with IMRT for clinically localized prostate cancer at a single institution.¹⁸ Median dose delivered was 76 Gy (range, 70 to 77 Gy), and 35% of patients received androgen deprivation therapy. Local and distant recurrence rates were 5% and 8.6%, respectively. At 9 years, biochemical control rates were 77% for low-risk, 70% for intermediate-risk, and 53% for high-risk patients (p = .05). At last follow-up, none had persistent GI and only 0.7% had persistent GU toxicities of grade 3 or 4. The high-risk group was associated with a higher distant metastasis rate (p = .02) and death from prostate cancer (p = .001).

Wong et al. (2009) reported on a retrospective study of radiation dose escalation in 853 patients with localized (T1c-T3N0M0) prostate cancer.¹⁹ Radiotherapies used included conventional dose (71 Gy) 3D-CRT (n = 270), high-dose (75.6 Gy) IMRT (n = 314), permanent transperineal brachytherapy (n = 225), and external-beam RT plus brachytherapy boost (n = 44). All patients were followed for a median of 58 months (range, 3 to 121 months). The 5-year OS rate for the entire group was 97%. The 5-year biochemical no evidence of disease rates, local control rates, and distant control rates were 74%, 93%, and 96%, respectively, for 3D-CRT; 87%, 99%, and 97%, respectively, for IMRT; 94%, 100%, and 99%, respectively, for brachytherapy alone; and 94%, 100%, and 97%, respectively, for external-beam RT plus brachytherapy.

Dosing for Low-Risk versus Intermediate- to High-Risk Prostate Cancer
The National Comprehensive Cancer Network (NCCN) has recommended use of RT for patients with prostate cancer based on risk stratification by clinical and pathologic findings. These recommendations are based on studies that did and did not include IMRT as the mode of RT.

In 1993, a U.S. cancer research center initiated an RCT comparing toxicity levels with outcomes after 3D-CRT (at 78 Gy) and 2-dimensional RT (at 70 Gy) in patients with localized prostate cancer. The long-term results were reported by Kuban et al. (2008).² The trial included 301 patients with stage T1b to T3 disease who received 70 Gy (n = 150) or 78 Gy (n = 151). Median follow-up was 8.7 years. Patient risk levels in the 70- and 78-Gy groups were low (n = 31 and n = 30), intermediate (n = 71 and n = 68), and high (n = 48 and n = 53), respectively. When analyzed by risk group, patients with low-risk disease treated to 78 Gy versus 70 Gy, had freedom from a biochemical or clinical failure of 88% and 63%, respectively (p = .042). The intermediate-risk patients showed no statistically significant difference in freedom from biochemical or clinical failure based on dose level (p = .36). Patients with high-risk disease showed a significant difference in freedom from biochemical or clinical failure based on dose (63% vs. 26%, p = .004), although when these high-risk patients were stratified by PSA level, only those patients with a PSA level greater than 10 ng/mL showed a difference in freedom from biochemical or clinical failure.

The NCCN guideline also cites the Kuban et al. (2008) study,² in addition to Kalbasi et al. (2015),²⁰ as evidence for a dose of 75.6 to 79.2 Gy (with or without the inclusion of the seminal vesicles) as appropriate for patients with low-risk cancers and that the conventional dose of 70 Gy is no longer considered adequate.

For patients with intermediate- and high-risk prostate cancer, the NCCN has cited the following studies. Xu et al. (2011) reported on a toxicity analysis of dose escalation from 75.6 to 81.0 Gy in 189 patients receiving definitive RT for prostate cancer.⁴ Patients were at high, intermediate, and low risk according to NCCN definitions, and were dosed at physician discretion. A total of 119 patients received 75.6 Gy and 70 received 81.0 Gy. Patients were followed at intervals of 3 to 6 months for 5 years and yearly after that (median follow-up, 3 years). The 81.0 Gy group had higher rates of grade 2 acute GU toxicity (p < .001), late GU toxicity (p = .001), and late GI toxicity (p = .082) but a lower rate of acute GI toxicity (p = .002). There were no notable differences in final GU (p = .551) or final GI (p = .194) toxicity levels compared with the 75.6 Gy group.

Eade et al. (2007) reported on the results of 1,530 consecutive patients treated for localized prostate cancer with 3D-CRT between 1989 and 2002.³ Patients were grouped by dose level: less than 70 Gy (n = 43), 70 to 74.9 Gy (n = 552), 75 to 79.9 Gy (n = 568), and 80 Gy or more (n = 367). Median follow-up ranged from 46 to 86 months, with the group receiving 80 Gy or more having a median follow-up of 45.6 months. Adjusted 5-year estimates of freedom from biochemical failure for the 4 groups were 60%, 68%, 76%, and 84% using the American Society for Radiation Oncology criteria and 70%, 81%, 83%, and 89% using Phoenix criteria, respectively. Adjusted 5- and 10-year estimates of freedom from distant metastases for the 4 groups were 96% and 93%, 97% and 93%, 99% and 95%, and 98% and 96%, respectively. The authors concluded that a pronounced RT dose-response by freedom from biochemical failure was seen after adjusting for pretreatment PSA level, Gleason score, and tumor stage and that the vast majority of patients should receive 80 Gy or more, although a subgroup of patients might be adequately treated with a lower dose of radiation.

Section Summary: Intensity-Modulated Radiotherapy for Primary (Definitive) Therapy for Localized Prostate Cancer
The evidence on IMRT for definitive treatment of localized prostate cancer includes several prospective comparative studies, retrospective comparative studies, and systematic reviews. Results generally showed that IMRT consistently reduced the risk of GI and GU toxicities with similar survival outcomes as compared to 3D-CRT. A reduction in clinically significant complications of RT is likely to improve the quality of life for treated patients.

Intensity-Modulated Radiotherapy for Prostate Cancer After Prostatectomy
Clinical Context and Therapy Purpose
The purpose of IMRT in patients who have prostate cancer and are undergoing RT after prostatectomy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does IMRT improve the net health outcome in patients who have prostate cancer and are undergoing RT after prostatectomy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals who have prostate cancer and are undergoing RT after prostatectomy.

Interventions
The therapy being considered is IMRT.

Comparators
The following therapy is currently being used to make decisions about the treatment of localized prostate cancer after prostatectomy: 3D-CRT.

Outcomes
The general outcomes of interest are OS, locoregional recurrence, quality of life, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
The joint American Urological Association and the American Society for Radiation Oncology (2013) guideline on the use of adjuvant and salvage RT after prostatectomy was based on a systematic review conducted by Thompson et al. (2013), who searched the literature from 1990 to 2012 and selected 294 articles.¹⁰ Reviewers attempted to determine which RT technique and doses produced optimal outcomes, but found it impossible to answer these questions because most available data came from observational studies and approximately one-third treated patients with conventional 2-dimensional external-beam modalities. Of the literature assessed in the review, less than 5% of studies reported using IMRT. Reviewers stated that 64 to 65 Gy is the minimum dose that should be delivered after prostatectomy but that dosage should be individualized to the patient. A 2019 amendment to the guidelines, incorporating 155 references published between January 1990 and December 2017, affirmed that determining which RT techniques and doses produced optimal outcomes in the adjuvant and salvage RT contexts was "not possible".⁵

Nonrandomized Comparative Studies
Massaccesi et al. (2013) reported preliminary acute toxicity results from a phase 2 trial of hypofractionated IMRT with a simultaneous integrated boost to the pelvic nodes and prostate bed after prostatectomy.²¹ Between 2008 and 2012, 49 patients considered to be at a high-risk of relapse after radical prostatectomy, or who had biochemical relapse, received 45 Gy in 1.8-Gy fractions to the whole pelvis and 62.5 Gy in 2.5-Gy fractions (equivalent dose, 68.75 Gy) to the prostate bed. The toxicity findings were compared with those of 52 consecutive patients selected from an electronic database who underwent adjuvant or salvage 3D-CRT with standard 2-Gy fractionation to the prostatic bed and regional pelvic nodes. Grade 1, 2, 3, and 4 acute GU toxicity occurred in 71.2% of all patients without a significant difference between the groups (hypofractionated IMRT vs. conventionally fractionated 3D-CRT; p = .51). Grade 2 acute GU toxicity, reported in 19.8% of all patients, was less frequent in patients in the IMRT group (9.6% vs. 28.8%, p = .02). There were no cases of grade 3 acute GU toxicity. Thirty (29.7%) patients developed grade 2 acute GI toxicity; the difference between groups was not statistically significant. No cases of grade 3 acute GI toxicity were reported. The study concluded that the acute toxicity profile for hypofractionated high-dose simultaneous integrated boost IMRT after prostatectomy compared favorably with that of conventionally fractionated high-dose 3D-CRT.

Alongi et al. (2009) reported on acute toxicity results of whole pelvis irradiation for 172 consecutive patients with clinically localized prostate cancer treated with IMRT or 3D-CRT as adjuvant (n = 100) or salvage (n = 72) therapy after radical prostatectomy and pelvic lymph node dissection.²² Whole pelvis radiation was considered in patients with a limited lymphadenectomy and/or in the presence of a high-risk of nodal involvement, in patients with positive lymph nodes and/or in the presence of adverse prognostic factors (Gleason score > 7 and/or preoperative PSA level > 10 ng/mL). Eighty-one patients underwent 3D-CRT, and 91 underwent IMRT. No grade 3 or 4 acute GU or lower GI side effects were observed. Acute grade 2 GU and acute lower GI grade 2 events did not differ significantly between treatment groups (Table 3). There was a higher incidence of acute upper GI grade 2, 3, and 4 toxicity, in the 3D-CRT group. The authors concluded that acute toxicity following postoperative whole pelvis irradiation was reduced with IMRT compared with 3D-CRT; this effect was most significant for upper GI symptoms, owing mainly to better bowel sparing with IMRT.

Table 3. Acute and Late Toxicity Rates With 3D-CRT and IMRT

Comparison	3D-CRT, n (%)	IMRT, n (%)	p
Acute lower GI toxicity, grade ≥ 2	7 (8.6)	3 (3.3)	.14
Acute upper GI toxicity, grade ≥ 2	18 (22.2)	6 (6.6)	.004
Acute GU toxicity	10 (12.3)	6 (6.6)	.19

Single-Arm Studies
Several prospective single-arm, phase 2 studies have evaluated the safety and efficacy of different methods of delivering IMRT (e.g., integrated boost, hypofractionation) in this clinical context.

Leite et al. (2021) conducted a single-arm, phase 2 study that evaluated the safety and feasibility of postoperative hypofractionated RT with intensity-modulated and image-guided RT to the prostate bed in 61 patients who had undergone radical prostatectomy.²³ Of these patients, 57 received salvage RT and 4 received adjuvant RT. The dose prescribed to the prostate bed was 51 Gy in 3.4 Gy daily fractions using IMRT and imaging guidance; all patients were treated with IMRT with volumetric arch therapy. After a median follow-up of 16 months, results revealed that 11.5% of patients experienced acute grade ≥ 2 GU symptoms and 13.1% experienced acute grade ≥ 2 GI symptoms. Late grade ≥ 2 GU and GI toxicity occurred at a rate of 8.2% and 11.5%, respectively. Three patients experienced a biochemical recurrence and the median time to the PSA nadir was 9 months. The actutimes biochemical failure-free survival was 95.1%.

PLATIN 3 Trial
Initial results of the phase 2, Prostate and Lymph Node Irradiation With Integrated Boost-IMRT After Neoadjuvant Antihormonal Treatment (PLATIN) trial were published by Katayama et al. (2014).²⁴ This trial evaluated the safety and feasibility of irradiating the pelvic lymph nodes simultaneously with a boost to the prostate bed in 40 patients with high-risk features or inadequate lymphadenectomy after radical prostatectomy. Treatment consisted of 2 months of antihormonal treatment before IMRT of the pelvic lymph nodes (51.0 Gy) with a simultaneous integrated boost to the prostate bed (68.0 Gy). No incidence of acute grade 3 or 4 toxicity occurred. Nearly 23% of patients experienced acute grade 2 GI and GU toxicity, 10% late grade 2 GI toxicity, and 5% late grade 2 GU toxicity. One patient developed late grade 3 proctitis and enteritis. At a median of 24 months, 89% of patients were free of a PSA recurrence.

PRIAMOS1 Trial
Acute toxicity results from the Hypofractionated RT of the Prostate Bed With or Without the Pelvic Lymph Nodes (PRIAMOS1) trial were reported by Katayama et al. (2014).²⁵ This prospective phase 2 trial assessed the safety and toxicity of hypofractionated RT of the prostate bed with IMRT as a basis for further prospective trials. Forty patients with indications for adjuvant or salvage therapy (pathologic stage T3 and/or R1/2 or with a PSA recurrence after prostatectomy) were enrolled from February to September 2012; 39 were evaluated. All patients received a total dose of 54.0 Gy to the prostate bed, 28 for salvage and 11 in the adjuvant setting. Based on preoperative staging, patients were risk-stratified as low (n = 2), intermediate (n = 27), or high (n = 10). Ten weeks after completing therapy, there were no adverse events exceeding grade 3. Acute GI toxicity rates were 56.4% and 17.9% for grade 1 and 2, respectively, and acute grade 1 GU toxicity was recorded in 35.9% of patients.

Corbin et al. (2013) reported on the adverse events in men at high-risk of recurrence 2 years after prostatectomy and IMRT.²⁶ Between 2007 and 2010, 78 consecutive men received adjuvant RT (n = 17 [22%]) or salvage RT (n = 61 [78%]). The median IMRT dose was 66.6 Gy (range, 60 to 72 Gy). Quality of life data were collected prospectively at 2, 6, 12, 18, and 24 months, and included urinary incontinence, irritation or obstruction, bowel or rectal function, and sexual function. No significant changes were observed from baseline through 2-year follow-up, with global urinary irritation or obstruction scores unchanged or improved over time from baseline, global urinary incontinence improved from baseline to 24 months in the subset of patients receiving adjuvant therapy, and global bowel and sexual domain scores improved or were unaffected over follow-up (though initially lower at 2 months).

Section Summary: Intensity-Modulated Radiotherapy for Prostate Cancer After Prostatectomy
The evidence on the use of IMRT for prostate cancer after prostatectomy includes nonrandomized comparative studies, single-arm phase 2 trials, and systematic reviews. Although the comparative studies are primarily retrospective, the evidence has generally shown that IMRT compared favorably to 3D-CRT with regard to GI and GU toxicity. Notably, a retrospective comparative study found a significant reduction in acute GI toxicity with IMRT compared with 3D-CRT, mainly due to better bowel sparing with IMRT. Another retrospective comparative study found a reduction in GU toxicity. A reduction in clinically significant complications of RT is likely to improve the quality of life for treated patients.

Summary of Evidence
For individuals who have localized prostate cancer and are undergoing definitive RT who receive IMRT, the evidence includes several prospective comparative studies, retrospective studies, and systematic reviews. Relevant outcomes are OS, DFS, disease specific survival, quality of life, and treatment-related morbidity. Although there are few prospective comparative trials, the evidence has generally shown that IMRT provides survival outcomes similar to 3D-CRT while reducing GI and GU toxicity. These findings are supported by treatment planning studies, which have predicted that IMRT improves target volume coverage and sparing of adjacent organs compared with 3D-CRT. A reduction in clinically significant complications of RT is likely to improve the quality of life for treated patients. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have prostate cancer and are undergoing RT after prostatectomy who receive IMRT, the evidence includes retrospective comparative studies, single-arm phase 2 trials, and systematic reviews. Relevant outcomes are OS, DFS, disease specific survival, quality of life, and treatment-related morbidity. Although the comparative studies are primarily retrospective, the evidence has generally shown that IMRT compared favorably to 3D-CRT with regard to GI and GU toxicity. Notably, a retrospective comparative study found a significant reduction in acute upper GI toxicity with IMRT compared with 3D-CRT, mainly due to better bowel sparing with IMRT. Another retrospective comparative study found a reduction in GU toxicity. A reduction in clinically significant complications of RT is likely to improve the quality of life for treated patients. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network
The National Comprehensive Cancer Network guidelines (v.4.2022) on prostate cancer indicate that highly conformal radiotherapy (RT) should be used in conventional fraction doses of 75.6 to 79.2 Gy for low-risk prostate cancer and up to 81 Gy for intermediate- and high-risk prostate cancer.¹ For adjuvant and salvage external-beam RT, the recommended dose ranged from 64 to 72 Gy in standard fractionation. The Network guideline also indicates that intensity-modulated radiotherapy (IMRT) is used increasingly in clinical practice and states that IMRT "reduced the risk of gastrointestinal toxicities and rates of salvage therapy compared to 3D-CRT in some but not all older retrospective and population-based studies, although treatment cost is increased." The NCCN also notes that more recent data have revealed that "moderately hypofractionated image-guided IMRT regimens (2.4 to 4 Gy per fraction over 4 to 6 weeks) have been tested in randomized trials, and their efficacy has been similar or non-inferior to conventionally fractionated IMRT. Overall, the panel believes that hypofractionated IMRT techniques, which are more convenient for patients, can be considered as an alternative to conventionally fractionated regimens when clinically indicated."

American Society for Radiation Oncology et al.
The American Society for Radiation Oncology, American Society of Clinical Oncology, and the American Urological Association (2019) published guidelines on hypofractionated external beam RT in localized prostate cancer with the following recommendations:²⁷

Table 4. Recommendations on Hypofractionated EBRT in Localized Prostate Cancer

Statement	RS	QOE	Consensus
“In men with low-risk PC who decline active surveillance and receive EBRT to the prostate with or without radiation to the seminal vesicles, moderate hypofractionation should be offered.”	Strong	High	100%
“In men with intermediate-risk PC receiving EBRT to the prostate with or without radiation to the seminal vesicles, moderate hypofractionation should be offered.”	Strong	High	100%
“In men with high-risk PC receiving EBRT to the prostate, but not including pelvic lymph nodes, moderate hypofractionation should be offered.”	Strong	High	94%
“In patients who are candidates for EBRT, moderate hypofractionation should be offered regardless of patient age, comorbidity, anatomy, or urinary function. However, physicians should discuss the limited follow-up beyond 5 years for most existing RCTs evaluating moderate hypofractionation.”	Strong	High	94%
“Men should be counseled about the small increased risk of acute gastrointestinal toxicity with moderate hypofractionation.”	Strong	High	100%
“Regimens of 6000 cGy delivered in 20 fractions of 300 cGy and 7000 cGy delivered in 28 fractions of 250 cGy are suggested since they are supported by the largest evidentiary base.”	Conditional	Moderate	100%

cGY: centigray; EBRT: external beam radiation therapy; PC: prostate cancer; QOE: quality of evidence; RCT: randomized controlled trial; RS: recommendation strength.

In 2019, the American Society for Radiation Oncology and American Urological Association published an amendment to their 2013 guideline on adjuvant and salvage RT after prostatectomy.^5,10 The guideline contains statements (Table 5) that provide direction to clinicians and patients regarding the use of RT in this setting. The amendment included an additional statement (Statement 9) on the use of hormone therapy with salvage RT and long-term data were used to update an existing statement (Statement 2) on adjuvant RT.⁵

Table 5. Recommendations for Adjuvant and Salvage Radiotherapy after Prostatectomy.

Statement	Evidence Strength
Statement 1: "Patients who are being considered for management of localized prostate cancer with radical prostatectomy should be informed of the potential for adverse pathologic findings that portend a higher risk of cancer recurrence and that these findings may suggest a potential benefit of additional therapy after surgery."	Clinical principle
Statement 2: "Patients with adverse pathologic findings including seminal vesicle invasion, positive surgical margins, and extraprostatic extension should be informed that adjuvant radiotherapy, compared to radical prostatectomy only, reduces the risk of biochemical recurrence, local recurrence, and clinical progression of cancer. They should also be informed that the impact of adjuvant radiotherapy on subsequent metastases and overall survival is less clear; one of three randomized controlled trials that addressed these outcomes indicated a benefit but the other two trials did not demonstrate a benefit. However, these two trials were not designed to identify a significant reduction in metastasis or death with adjuvant radiotherapy."	Clinical principle
Statement 3: "Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy including seminal vesicle invasion, positive surgical margins, or extraprostatic extension because of demonstrated reductions in biochemical recurrence, local recurrence, and clinical progression."	Grade A
Statement 4: "Patients should be informed that the development of a PSA recurrence after surgery is associated with a higher risk of development of metastatic prostate cancer or death from the disease. Congruent with this clinical principle, physicians should regularly monitor PSA after radical prostatectomy to enable early administration of salvage therapies if appropriate."	Clinical principle
Statement 5: "Clinicians should define biochemical recurrence as a detectable or rising PSA value after surgery that is ≥ 0.2 ng/ml with a second confirmatory level ≥ 0.2 ng/ml."	Grade C
Statement 6: "A restaging evaluation in the patient with a PSA recurrence may be considered."	Grade C
Statement 7: "Physicians should offer salvage radiotherapy to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease."	Grade C
Statement 8: "Patients should be informed that the effectiveness of radiotherapy for PSA recurrence is greatest when given at lower levels of PSA."	Clinical principle
Statement 9: "Clinicians should offer hormone therapy to patients treated with salvage radiotherapy (postoperative PSA ≥ 0.20 ng/mL) Ongoing research may someday allow personalized selection of hormone or other therapies within patient subsets."	Grade A
Statement 10: "Patients should be informed of the possible short-term and long-term urinary, bowel, and sexual side effects of radiotherapy as well as of the potential benefits of controlling disease recurrence."	Clinical principle

PSA: prostate specific antigen.
Grade A: well-conducted and highly generalizable RCTs or exceptionally strong observational studies with consistent findings.
Grade B: RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings.
Grade C: observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data.
Clinical principle: statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature.

American College of Radiology
The American College of Radiology Appropriateness Criteria (2014) have indicated IMRT is the standard for definitive external-beam RT of the prostate.²⁸

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing trials that might affect this review are listed in Table 6.

Table 6. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03526510	Randomized Trial of Concomitant Hypofractionated IMRT Boost Versus Conventional Fractionated IMRT Boost for Localized High Risk Prostate Cancer	178	Dec 2024
Unpublished
NCT00326638	Randomized Phase III Trial of 3D Conformal Radiotherapy Versus Helical Tomotherapy IMRT in High-Risk Prostate Cancer	72	Jun 2020

IMRT: intensity-modulated radiotherapy;NCT: national clinical trial.

References:  

1. National Comprehensive Cancer Network. Prostate Cancer. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed May 23, 2023.
2. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys. Jan 01 2008; 70(1): 67-74. PMID 17765406
3. Eade TN, Hanlon AL, Horwitz EM, et al. What dose of external-beam radiation is high enough for prostate cancer?. Int J Radiat Oncol Biol Phys. Jul 01 2007; 68(3): 682-9. PMID 17398026
4. Xu N, Rossi PJ, Jani AB. Toxicity analysis of dose escalation from 75.6 gy to 81.0 gy in prostate cancer. Am J Clin Oncol. Feb 2011; 34(1): 11-5. PMID 20101167
5. Pisansky TM, Thompson IM, Valicenti RK, et al. Adjuvant and Salvage Radiation Therapy After Prostatectomy: ASTRO/AUA Guideline Amendment, Executive Summary 2018. Pract Radiat Oncol. 2019; 9(4): 208-213. PMID 31051281
6. U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on 2021 submission data (1999-2019): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; https://www.cdc.gov/cancer/dataviz, released in November 2022. Accessed May 16, 2023.
7. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet. Aug 2005; 366(9485): 572-8. PMID 16099293
8. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. Nov 15 2006; 296(19): 2329-35. PMID 17105795
9. Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol. Jun 20 2009; 27(18): 2924-30. PMID 19433689
10. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. Aug 2013; 190(2): 441-9. PMID 23707439
11. Misher C. Radiation therapy: which type is right for me? Last reviewed: March 16, 2022. https://www.oncolink.org/cancer-treatment/radiation/introduction-to-radiation-therapy/radiation-therapy-which-type-is-right-for-me. Accessed May 16, 2023.
12. Yu T, Zhang Q, Zheng T, et al. The Effectiveness of Intensity Modulated Radiation Therapy versus Three-Dimensional Radiation Therapy in Prostate Cancer: A Meta-Analysis of the Literatures. PLoS One. 2016; 11(5): e0154499. PMID 27171271
13. Bauman G, Rumble RB, Chen J, et al. Intensity-modulated radiotherapy in the treatment of prostate cancer. Clin Oncol (R Coll Radiol). Sep 2012; 24(7): 461-73. PMID 22673744
14. Hummel S, Simpson EL, Hemingway P, et al. Intensity-modulated radiotherapy for the treatment of prostate cancer: a systematic review and economic evaluation. Health Technol Assess. Oct 2010; 14(47): 1-108, iii-iv. PMID 21029717
15. Viani GA, Viana BS, Martin JE, et al. Intensity-modulated radiotherapy reduces toxicity with similar biochemical control compared with 3-dimensional conformal radiotherapy for prostate cancer: A randomized clinical trial. Cancer. Jul 01 2016; 122(13): 2004-11. PMID 27028170
16. Sujenthiran A, Nossiter J, Charman SC, et al. National Population-Based Study Comparing Treatment-Related Toxicity in Men Who Received Intensity Modulated Versus 3-Dimensional Conformal Radical Radiation Therapy for Prostate Cancer. Int J Radiat Oncol Biol Phys. Dec 01 2017; 99(5): 1253-1260. PMID 28974414
17. Michalski JM, Yan Y, Watkins-Bruner D, et al. Preliminary toxicity analysis of 3-dimensional conformal radiation therapy versus intensity modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial. Int J Radiat Oncol Biol Phys. Dec 01 2013; 87(5): 932-8. PMID 24113055
18. Vora SA, Wong WW, Schild SE, et al. Outcome and toxicity for patients treated with intensity modulated radiation therapy for localized prostate cancer. J Urol. Aug 2013; 190(2): 521-6. PMID 23415964
19. Wong WW, Vora SA, Schild SE, et al. Radiation dose escalation for localized prostate cancer: intensity-modulated radiotherapy versus permanent transperineal brachytherapy. Cancer. Dec 01 2009; 115(23): 5596-606. PMID 19670452
20. Kalbasi A, Li J, Berman A, et al. Dose-Escalated Irradiation and Overall Survival in Men With Nonmetastatic Prostate Cancer. JAMA Oncol. Oct 2015; 1(7): 897-906. PMID 26181727
21. Massaccesi M, Cilla S, Deodato F, et al. Hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost after radical prostatectomy: preliminary results of a phase II trial. Anticancer Res. Jun 2013; 33(6): 2785-9. PMID 23749942
22. Alongi F, Fiorino C, Cozzarini C, et al. IMRT significantly reduces acute toxicity of whole-pelvis irradiation in patients treated with post-operative adjuvant or salvage radiotherapy after radical prostatectomy. Radiother Oncol. Nov 2009; 93(2): 207-12. PMID 19766338
23. Leite ETT, Ramos CCA, Ribeiro VAB, et al. Hypofractionated Radiation Therapy to the Prostate Bed With Intensity-Modulated Radiation Therapy (IMRT): A Phase 2 Trial. Int J Radiat Oncol Biol Phys. Apr 01 2021; 109(5): 1263-1270. PMID 33346091
24. Katayama S, Habl G, Kessel K, et al. Helical intensity-modulated radiotherapy of the pelvic lymph nodes with integrated boost to the prostate bed - initial results of the PLATIN 3 Trial. BMC Cancer. Jan 14 2014; 14: 20. PMID 24422782
25. Katayama S, Striecker T, Kessel K, et al. Hypofractionated IMRT of the prostate bed after radical prostatectomy: acute toxicity in the PRIAMOS-1 trial. Int J Radiat Oncol Biol Phys. Nov 15 2014; 90(4): 926-33. PMID 25216858
26. Corbin KS, Kunnavakkam R, Eggener SE, et al. Intensity modulated radiation therapy after radical prostatectomy: Early results show no decline in urinary continence, gastrointestinal, or sexual quality of life. Pract Radiat Oncol. 2013; 3(2): 138-44. PMID 24674317
27. 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. J Urol. Mar 2019; 201(3): 528-534. PMID 30759696
28. Nguyen PL, Aizer A, Assimos DG, et al. ACR Appropriateness Criteria® Definitive External-Beam Irradiation in stage T1 and T2 prostate cancer. Am J Clin Oncol. Jun 2014; 37(3): 278-88. PMID 25180754

Coding Section 

Codes	Number	Description
CPT	55874 (effective 01/01/2018)	Transperineal placement of biodegradable material, periprostatic, single or multiple injection(s), including image guidance, when performed.
	77301	Intensity modulated radiotherapy plan, including dose-volume histograms for target and critical structure partial tolerance specification
	77338	Multileaf collimator (MLC) device(s) for intensity-modulated radiation therapy (IMRT), design and construction, per IMRT plan
	77385	Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple (new code 01/01/15)
	77386	complex (new code 01/01/15)
	77418	Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session (code deleted 12/31/14)
ICD-9 Diagnosis	185	Malignant neoplasm of prostate
HCPCS	G6015	Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session (new code 01/01/15)
	G6016	Compensator-based beam modulation treatment delivery of inverse planned treatment using 3 or more high resolution (milled or cast) compensator, convergent beam modulated fields, per treatment session (new code 01/01/15)
ICD-10-CM (effective 10/01/15)	C61	Malignant neoplasm of prostate
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this imaging.
Type of Service
Place of Service

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.   

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

08/11/2023	Annual review, no change to policy intent. Updating background, rationale, references, and coding
08/15/2022	Annual review, no change to policy intent. Updating rationale and references.
08/06/2021	Annual review, no change to policy intent. Updating background, guidelines, rationale and references.
08/04/2020	Annual review, no change to policy intent. Updating rationale and references.
08/01/2019	Annual review, no change to policy intent. Updating guidelines and references.
08/27/2018	Annual review, no change to policy intent. Updating rationale and references.
02/12/2018	Interim review adding medical necessity criteria for 55874 SpaceOAR. No other changes made.
09/06/2017	Interim Review to remove medical necessity criteria for CPT 0438T. No other changes made.
09/06/2017	Interim Review to add medical necessity criteria for CPT 0438T. No other changes made.
08/10/2017	Annual review, no change to policy intent. Updating background, description, rationale, references and coding.
08/08/2016	Annual review, removing radiation dose constraints for definitive therapy of localized prostate cancer with guidelines with details regarding dosing for low-risk vs intermediate to high risk prostate cancer. A statement was also added to address IMRT post prostatectomy. Updating background, description, guidelines, rationale and references.
08/18/2015	Annual review, no change to policy intent. Updated title, background, description, guidelines, rationale and references. Added regulatory status and coding.
08/06/2014	Annual review. Added related policy and policy guidelines. Updated policy verbiage to include uses that do not meet the stated criteria are investigational. Updated rationale and references. No change to policy intent.