CAM 80147

Intensity-Modulated Radiotherapy of the Prostate

Category:Therapy   Last Reviewed:August 2019
Department(s):Medical Affairs   Next Review:August 2020
Original Date:August 2012    

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 
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.1-3 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 (PSA) recurrence or local recurrence after prostatectomy in the absence of metastatic disease.4 

RT TECHNIQUES
Conventional External-Beam Radiotherapy
Over the past several decades, methods to plan and deliver radiotherapy (RT) have evolved in ways that permit more precise targeting of tumors with complex geometries. Most early trials used 2-dimensional treatment planning, based on flat images and radiation beams with cross-sections of uniform intensity that were sequentially aimed at the tumor along 2 or 3 intersecting axes. Collectively, these methods are termed conventional external-beam radiotherapy

Three-Dimensional Conformal Radiotherapy
Treatment planning evolved by using 3-dimensional images, usually from computed tomography scans, to delineate the boundaries of the tumor and to discriminate tumor tissue from adjacent normal tissue and nearby organs at risk for radiation damage. Computer algorithms were developed to estimate cumulative radiation doses delivered to each volume of interest by summing the contribution from each shaped beam. Methods also were 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. Collectively, these methods are termed 3-dimensional conformal radiotherapy (3D-CRT). 

Intensity-Modulated Radiotherapy
Intensity-modulated radiotherapy (IMRT) offers better conformality than 3D-CRT, because it is able to modulate the intensity of the overlapping radiation beams projected on the target and to use multiple shaped treatment fields. Treatment planning and delivery are more complex, time consuming, and labor intensive for IMRT than for 3D-CRT. The technique uses a multileaf collimator [MLC]), which, when coupled with a computer algorithm, 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 thus may 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.

Technologic development has produced advanced techniques that 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.

IMRT methods to plan and deliver RT are not uniform. IMRT may use beams that remain on as MLCs move around the patient (dynamic MLC) or that are off during movement and turn on once the MLC reaches prespecified positions (“step and shoot” technique). A third alternative uses a very narrow single beam that moves spirally around the patient (tomotherapy). Each method uses different computer algorithms to plan treatment and yields somewhat different dose distributions in and outside the target. Patient position can alter target shape and thus affect treatment plans. Treatment plans are usually based on 1 imaging scan, a static 3D-CT image. Current methods seek to reduce positional uncertainty for tumors and adjacent normal tissues by various techniques. Patient immobilization cradles and skin or bony markers are used to minimize day-to-day variability in patient positioning. In addition, many tumors have irregular edges that preclude drawing tight margins on CT scan slices when radiation oncologists contour the tumor volume. It is unknown whether omitting some tumor cells or including some normal cells in the resulting target affects outcomes of IMRT.

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 Radiotherapy (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 considered INVESTIGATIONAL 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 MEDICALLY 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) 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]). 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.

NCCN 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]; and Xu et al [2011]).

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, extraprostatic extension, and Gleason scores of 8 to 10.

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 (Thompson et al [2013]) 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. Published randomized controlled trials have failed to demonstrate the superiority of hypofractionation in definitive RT for prostate cancer, either for efficacy or late toxicity. Ongoing phase 3 noninferiority trials might provide insight.

NCCN guidelines state that because, in the treatment of prostate cancer, moderately hypofractionated intensity-modulated radiotherapy (IMRT) regimens (2.4-4 Gy per fraction over 4-6 weeks) have been tested in randomized controlled trials, and efficacy and toxicity have been found similar to conventionally fractionated IMRT, hypofractionation may 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.

IMRT 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

50

47

70

70

NP

Myelitis, necrosis

Small intestine

50

NP

40

60

NP

55

Obstruction, perforation

Colon

55

NP

45

65

NP

55

Obstruction, perforation, ulceration, fistula

Rectum

NP

NP

60

NP

NP

80

Severe proctitis, necrosis, stenosis, 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 (2011). Radiation oncology. In DeVita, Lawrence, and Rosenberg, Cancer (p.308). Philadelphia: Lippincott Williams and Wilkins; 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.
NP: not provided; TD: tolerance dose.
a TD 5/5 is the average dose that results in a 5% complication risk within 5 years.
b TD 50/5 is the average dose that results in a 50% complication risk within 5 years. 

Table PG2. Radiation Dose Volume (1.8-2.0 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 et al. Radiation Oncology: A Question-Based Review. Lippincott Williams & Wilkins, 2010. 

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 & 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 a technology improves the net health outcome. Broadly defined, health outcomes are 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 to 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 a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses 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. RCTs 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 vs 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.

A proposed benefit of IMRT is to reduce toxicity to adjacent structures, allowing dose escalation to the target area and fewer breaks in treatment courses due to a reduction in side effects. However, this may come with a loss of locoregional control and overall survival (OS) due to factors discussed above. Thus, outcomes of interest are toxicity, quality of life, locoregional recurrence, and OS. The following is a summary of the literature to date

This evidence review includes systematic reviews that have evaluated outcomes of IMRT treatment in patients with prostate cancer, summarizes the data on adverse events from these systematic reviews, and includes additional primary studies. Because a reduction in adverse events is likely to be the greatest potential benefit of IMRT, the most relevant trials compare IMRT with 3D-CRT and report on adverse event rates following treatment. 

INTENSITY-MODULATED RADIOTHERAPY FOR INDIVIDUALS UNDERGOING PRIMARY (DEFINITIVE) THERAPY FOR LOCALIZED PROSTATE CANCER

Clinical Context and Test Purpose
The purpose of IMRT in patients who have localized prostate cancer 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 net health outcomes for individuals who have localized prostate cancer and are undergoing definitive therapy?

The following PICOTS were used to select literature to inform this review.

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

Interventions
The test being considered is IMRT.

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

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

Timing
Time of treatment is not uniform. Follow-up times of interest may vary from weeks to months after treatment

Setting
Patients with prostate cancer are actively managed by radiation oncologists.

Systematic Reviews
A meta-analysis by Yu et al (2016) included 23 studies (total N=9,556 patients) that compared IMRT with 3D-CRT for gastrointestinal (GI), genitourinary (GU), and rectal toxicity, biochemical control, and OS.5 The meta-analysis included 16 retrospective comparisons and 5 prospective cohort studies published before July 2015. The relative risk for the pooled analysis was considered significant if the 95% confidence intervals did not overlap at 1 at the p<0.05 level. IMRT resulted in less acute and late GI toxicity, less rectal bleeding, and improved biochemical control (see 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 IMRT vs 3D-CRT 95% CI

Acute GI toxicity

12 4,142 0.59

0.44 to 0.78

Late GI toxicity

13 6,519 0.54

0.38 to 0.78

Acute rectal toxicity

4 2,188 1.03

0.45 to 2.36

Late rectal bleeding

5 1,972 0.48

0.27 to 0.85

Acute GU toxicity

14 4,603 1.08

1.00 to 1.17

Late GU toxicity

12 5,608 1.03

0.82 to 1.30

Biochemical control

6 2,416 1.17

1.08 to 1.27

Overall survival

3 924 1.07

0.96 to 1.19

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

Bauman et al (2012) published a systematic review that examined the evidence for IMRT in the treatment of prostate cancer to quantify its potential benefits and to make recommendations for radiation treatment programs considering adopting this technique within the province of Ontario, Canada.6 Based on a review of 11 published reports through March 2009 (9 retrospective cohort studies, 2 randomized controlled trials [RCTs]) including 4,559 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=0.001), grade 3 or 4 toxicity (0% vs 13%, p=0.001), and for acute proctitis (15% vs 38%, p=0.03). 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 (total 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 one reported a difference in late GU effects in favor of 3D-CRT. Two retrospective cohort studies reported mixed findings on quality of life outcomes.6 A economic analysis (based on this systematic review data) by Yong et al (2012) suggested IMRT was more cost-effective than an equivalent dose of 3D-CRT based on 2009 data from the Canadian health care system.7

A systematic review by Hummel et al (2010) on the clinical effectiveness of IMRT for the radical treatment of prostate cancer was undertaken for the U.K. Health Technology Assessment Programme.8 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, which can be more easily achieved with IMRT than with 3D-CRT.  

Primary Studies Reporting on Outcomes and Adverse Events
Additional studies not included in the 2016 Yu meta-analysis5 are described next.  

Sujenthiran et al (2017) published a retrospective cohort study of 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 was available in various databases serving the English National Health Service.9 Dosage was similar between treatment types: patients in both groups received a median 2 Gy per fraction for a median total dose of 74 Gy. Gastrointestinal (GI) and genitourinary (GU) toxicities were comparable to grade 3 or above according to 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% confidence interval [CI], 0.61 to 0.72; p<0.01). The rate of GU toxic events was similar between treatment groups: for IMRT, 2.3 GU events per 100 person-years; for 3D-CRT, 2.4 GU events per 100 person-years (HR=0.94; 95% CI, 0.84 to 1.06; p=0.31). For GI toxicity, the most common procedure was diagnostic fiber optic sigmoidoscopy, representing 3607 (38.8%) of 9,300 procedures. The most commonly diagnosed GI toxicity was radiation proctitis (n=5,962 [68.5%] of 8,701 diagnoses). For GU toxicity, the most prevalent procedure was unspecified endoscopic examination of the bladder, undertaken in 1,470 (40.6%) of 3,625 procedures; of 4,061 GU toxicity diagnoses, 1,265 (31.1%) were of hematuria. Overall, in the cohort of 23, 222 men, IMRT saw a notable increase in use between 2010 and 2013 (3.1% vs 64.7%, respectively). Limitations included therapeutic differences and baseline GI and GU symptoms that were unaccounted for in analysis, as well as limited follow-up on GI and GU toxicity. Reviewers concluded that IMRT showed a significant improvement for severe GI toxicity over 3D-CRT, and similar severe GU toxicity.

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.10 Treatment consisted of hypofractionated radiotherapy (RT) at a total dose of 70 Gy at 2.8 Gy per fraction using either IMRT or 3D-CRT. The primary end point 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 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 post-treatment.

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

Comparison 3D-CRT (n=109), % IMRT (n=106), % p

Acute gastrointestinal toxicity, grade 2

24 7 0.001

Acute genitourinary toxicity, grade 2

27 9 0.001

Late gastrointestinal toxicity, grade 2

21.7 6.4 0.001

Late genitourinary toxicity, grade 2

12.3 3.7 0.02

Biochemical control

94.3 95.4 0.678

 IMRT: intensity-modulated radiotherapy; 3D-CRT: 3-dimensional conformal radiotherapy.   

 A study by Michalski et al (2013) reported comparative data for IMRT and 3D-CRT from the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial.11 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 grade 2, 3, and 4 late GI toxicity for IMRT on univariate analysis (p=0.039). 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=0.099). 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.12 Median dose delivered was 76 Gy (range, 70-77 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=0.05). 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=0.02) and death from prostate cancer (p=0.001).12 

Wong et al (2009) reported on a retrospective study of radiation dose escalation in 853 patients with localized (T1c-T3N0M0) prostate cancer.13 RTs 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 radiotherapy plus brachytherapy boost (n=44). All patients were followed for a median of 58 months (range, 3-121 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 radiotherapy plus brachytherapy. The biochemical no evidence of disease rates for 3D-CRT were significantly lower than those of the other higher dose modalities (p<0.001).

Cahlon et al (2008) reported on preliminary biochemical outcomes and toxicity with high-dose IMRT (86.4 Gy) for localized prostate cancer.14 For this study, 478 patients were treated between 1997 and 2004 with 86.4 Gy using a 5- to 7-field IMRT technique. Median follow-up was 53 months. Thirty-seven (8%) patients experienced acute grade 2 GI toxicity, with no acute grade 3 or 4 GI toxicity; 105 (22%) patients experienced acute grade 2 GU toxicity, with 3 (0.6%) patients having grade 3 GU toxicity. Sixteen (3%) patients developed late grade 2 GI toxicity while 2 patients (<1%) developed late grade 3 GI toxicity; 60 (13%) patients had late grade 2 GU toxicity while 12 (<3%) experienced late grade 3 GU toxicity. The 5-year actuarial relapse-free survival rates (using PSA nadir + 2 ng/mL) were 98%, 85%, and 70% for the low-, intermediate-, and high-risk National Comprehensive Cancer Network (NCCN) prognostic groups, respectively.

Evidence Supporting NCCN Recommendations for RT Dose for Low-Risk vs Intermediate- to High-Risk Prostate Cancer
NCCN has made recommended the use of RT for patients with prostate cancer based on risk stratification by clinical and pathologic findings. These recommendations are based on some 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).15 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 vs 70 Gy, had a freedom from biochemical or clinical failure (FFF) of 88% and 63%, respectively (p=0.042). The intermediate-risk patients showed no statistically significant difference in FFF based on dose level (p=0.36). Patients with high-risk disease showed a significant difference in FFF based on dose (63% vs 26%, p=0.004), 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 FFF.

NCCN guidelines also cite the 2008 Kuban study 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, NCCN has cited the following studies. For example, 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.16 Patients were at high, intermediate, and low risk according to NCCN definitions, and received a dose 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 method of RT was at the discretion of the treating physician The 81.0-Gy group had higher rates of grade 2 acute GU toxicity (p<0.001), late GU toxicity (p=0.001), and late GI toxicity (p=0.082), but a lower rate of acute GI toxicity (p=0.002). There were no notable differences in final GU (p=0.551) or final GI (p=0.194) 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 2002.17 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. The group receiving 80 Gy or more had a median follow-up of 45.6 months. That group was mixed, with 64 (17%) patients having a low risk of cancer, 247 (67%) having an intermediate risk, and 56 (16%) having a high risk. Intermediate- plus high-risk patients made up 44%, 46%, and 48% of the less than 70 Gy, 70 to 74.9 Gy, and 75 to 79.9 Gy groups, respectively. 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%. The authors concluded that a pronounced RT dose-response by freedom from biochemical failure was seen after adjusting for pretreatment PSA, Gleason score, and tumor stage and that the vast majority of patients should receive 80 Gy or more, although a subgroup of patients may be adequately treated with less radiation.

Section Summary: Primary (Definitive) RT 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 of these studies. Results generally show that IMRT provides tumor control and survival outcomes similar to 3D-CRT, with reductions in GI and GU toxicity. A reduction in clinically significant complications of RT is likely to improve quality of life for treated patients.

IMRT IN INDIVIDUALS WITH PROSTATE CANCER AFTER PROSTATECTOMY
Clinical Context and Test Purpose
The purpose of IMRT in patients who have prostate cancer and are undergoing radiotherapy 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 net health outcomes in patients who have prostate cancer and are undergoing radiotherapy after prostatectomy?

The following PICOTS were used to select literature to inform this review.

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

Interventions
The test being considered is IMRT.

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

Outcomes
The general outcomes of interest are OS, disease-specific survival, quality of life, and treatment-related morbidity

Timing
Time of treatment is not uniform. Follow-up times of interest vary from weeks to months after treatment.

Setting
Patients with prostate cancer are actively managed by radiation oncologists.

Systematic Reviews 
The 2012 Bauman systematic review (discussed earlier) found insufficient data to recommend IMRT over 3D-CRT after prostatectomy.6   

The 2013 joint American Urological Association and the American Society for Radiation Oncology guidelines on the use of adjuvant and salvage RT after prostatectomy was based on a systematic review of the literature from 1990 to 2012, which yielded 294 articles.4 The panel’s comments on RT techniques stated that it attempted to determine which technique and doses produced optimal outcomes, but that it was not possible to answer these questions from available data because most data came from observational studies and approximately one-third treated patients with conventional (2D) external-beam modalities. Of the literature included in the review, less than 5% of studies reported using IMRT. The panel 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.   

Nonrandomized Comparative Studies 
Alongi et al (2009) reported results of acute toxicity of whole pelvis irradiation in 172 consecutive patients with clinically localized prostate cancer treated with IMRT or 3D-CRT as adjuvant (n=100) or salvage (n=72) RT after radical prostatectomy and pelvic lymph node dissection.18 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 (see Table 3). There was a higher incidence of acute upper GI grade 2, 3, and 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 gastrointestinal toxicity, grade 2

7 (8.6) 3 (3.3) 0.14

Acute upper gastrointestinal toxicity, grade 2

18 (22.2) 6 (6.6) 0.004

Acute genitourinary toxicity

10 (12.3) 6 (6.6) 0.19

IMRT: intensity-modulated radiotherapy; 3D-CRT: 3-dimensional conformal radiotherapy. 

Massaccesi et al (2013) reported preliminary acute toxicity results from a phase 2 trial of hypofractionated IMRT with simultaneous integrated boost to the pelvic nodes and prostate bed after prostatectomy.19 Between 2008 and 2012, 49 patients considered to be at 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=0.51). 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=0.02). 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.

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). 

PLATIN 3 Trial
In 2014, initial results of the phase 2 Prostate and Lymph Node Irradiation With Integrated Boost-IMRT After Neoadjuvant Antihormonal Treatment (PLATIN 3) trial were published.20 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 acute grade 3 or 4 toxicity occurred. Nearly 23% of patients experienced acute grade 2 GI and GU toxicity and 10% late grade 2 GI 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
In 2014, acute toxicity results from the Hypofractionated RT of the Prostate Bed With or Without the Pelvic Lymph Nodes (PRIAMOS1) trial were reported.21 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 completion of therapy, there were no adverse events exceeded grade 3. Acute GI toxicity rates were 56.4% and 17.9% for grade 1 and 2, respectively, and acute GU toxicity was recorded in 35.9% of patients at a maximum grade of 1.

Corbin et al (2013) reported on the adverse events in high-risk men 2 years after IMRT and prostatectomy.22 Between 2007 and 2010, 78 consecutive men received either adjuvant RT (n=17 [22%]) or salvage RT (n=61 [78%]). The median IMRT dose was 66.6 Gy (range, 60-72 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 unaffected over follow-up (though initially lower at 2 months).  

Section Summary: RT for Prostate Cancer After Prostatectomy
The evidence on IMRT for prostate cancer after prostatectomy includes nonrandomized comparative studies, single-arm phase 2 trials, retrospective series, and systematic reviews of these studies. 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 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 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.

PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network
Recent National Comprehensive Cancer Network guidelines (v.3.2018) for prostate cancer indicate that highly conformal radiotherapy should be used in conventional fraction doses of 75.6 to 79.2 gray (Gy) for low-risk prostate cancer and up to 81 Gy for intermediate- and high-risk prostate cancer.23 For adjuvant and salvage external-beam radiotherapy, the recommended doses are 64 to 72 Gy in standard fractionation. The Network guidelines also indicate that intensity-modulated radiotherapy is used increasingly in clinical practice because of reduced risk of gastrointestinal toxicities and rates of salvage therapy in some studies.  

American Urological Association and American Society for Radiation Oncology
The 2013 American Urological Association and American Society for Radiation Oncology guidelines addressed the use of adjuvant and salvage RT after radical prostatectomy.4 The guidelines stated that adjuvant RT should be given to patients with adverse pathologic findings at prostatectomy and salvage RT to patients with prostate-specific antigen recurrence or local recurrence after prostatectomy if there is no evidence of distant metastases. However, the available data did not identify which RT technique and dose produce optimal outcomes in this setting. 

American Society of Clinical Oncology
American Society of Clinical Oncology endorsed the American Urological Association and the American Society for Radiation Oncology clinical practice guidelines for adjuvant and salvage RT after prostatectomy.24 An update of this guideline is scheduled for publication mid-2017.  

American College of Radiology
The American College of Radiology Appropriateness Criteria (2014) have indicated intensity-modulated radiotherapy is the standard for definitive external-beam radiotherapy of the prostate.25 

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable. 

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might affect this review are listed in Table 4.

Table 4. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date

Ongoing

NCT00331773

A Phase III Randomized Study of Hypofractionated 3D-CRT/MRT vs. Conventionally Fractionated 3D-CRT/MRT With Favorable-Risk Prostate Cancer

1,115

Jul  2015 (ongoing)

NCT00033631 

A Phase III Randomized Study Of High Dose 3D-CRT/IMRT Versus Standard Dose 3D-CRT/IMRT In Patients Treated For Localized Prostate Cancer 

1,532 

Apr 2014 

NCT: national clinical trial.  

References:  

  1. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet. Aug 13-19 2005;366(9485):572-578. PMID 16099293
  2. Thompson IM, Jr., Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. Nov 15 2006;296(19):2329-2335. PMID 17105795
  3. 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):2924-2930. PMID 19433689
  4. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. Aug 2013;190(2):441-449. PMID 23707439
  5. 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. May 2016;11(5):e0154499. PMID 27171271
  6. 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):461-473. PMID 22673744
  7. 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
  8. 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):2004-2011. PMID 27028170
  9. 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 1 2017;99(5):1253-1260. PMID 28974414
  10. 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 1 2013;87(5):932-938. PMID 24113055
  11. 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):521-526. PMID 23415964
  12. Wong WW, Vora SA, Schild SE, et al. Radiation dose escalation for localized prostate cancer: intensity-modulated radiotherapy versus permanent transperineal brachytherapy. Cancer. Dec 1 2009;115(23):5596-5606. PMID 19670452
  13. 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 1 2008;70(1):67-74. PMID 17765406
  14. 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):11-15. PMID 20101167
  15. 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 1 2007;68(3):682-689. PMID 17398026
  16. 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):207-212. PMID 19766338
  17. 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):2785-2789. PMID 23749942
  18. 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
  19. 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):926-933. PMID 25216858
  20. 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. Apr-Jun 2013;3(2):138-144. PMID 24674317
  21. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate cancer. Version 3.2018. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed July 2, 2018.
  22. Freedland SJ, Rumble RB, Finelli A, et al. Adjuvant and salvage radiotherapy after prostatectomy: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol. Dec 1 2014;32(34):3892-3898. PMID 25366677
  23. Nguyen PL, Aizer A, Assimos DG, et al. ACR Appropriateness Criteria(R) definitive external-beam irradiation in stage T1 and T2 prostate cancer. Am J Clin Oncol. Jun 2014;37(3):278-288. PMID 25180754

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 and Blue Shield Association technology assessment program (TEC) and other non-affiliated 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     

08/01/2019 

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 on 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.


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