| Coverage Policy Manual | |
| Policy #: | 2009034 |
| Category: | Radiology |
| Initiated: | September 2009 |
| Last Review: | September 2023 |
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| Intensity Modulated Radiation Therapy (IMRT), Prostate | |
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| Description: |
Prostate cancer is the second leading cause of cancer-related death among men in the U.S (U.S. Cancer Statistics Working Group, 2022). According to the most recent incidence data available from 2019, there were 224,733 reported new cases of prostate cancer among men in the United States. From 2015 to 2019, localized, regional, distant, and unknown stage prostate cancer accounted for 70.6%, 13.5%, 7.6%, 8.3% of new cases, respectively. In 2019, the incidence of prostate cancer was highest for men aged 70 to 74 years of age and Black men. White (non-Hispanic) men had lower percentages of distant (7.5%) and unknown stage prostate cancer (6.6%) than did any other race/ethnicity. With regard to survival for distant stage disease, 5-year survival was highest among Asian-Pacific islanders (44.1%), followed by Hispanics (38.2%), American Indian/Alaska natives (35.2%), Black (34.2%), and White (30.8%) men during a period from 2012 to 2018. 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 (Bolla 2005; Thompson, 2006; Wiegel, 2009). 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 (Thompson, 2013; Pisansky, 2019).
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) (Misher, 2022). 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 (Misher, 2022). 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 (Misher, 2022). 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 (Misher, 2022) 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
Risk of Recurrence
Low risk of recurrence (ALL must be present to qualify as low risk)
Intermediate risk of recurrence (ANY one characteristic)
High risk of recurrence (ANY one characteristic)
(Adapted from National Comprehensive Cancer Network guidelines for prostate cancer)
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 been cleared through the FDA 510(k) process. Intensity modulators include the Innocure Intensity Modulating Radiation Therapy Compensators (Innocure, LLC), cleared in 2006, and the decimal tissue compensator (Southeastern Radiation Products, Inc.), cleared in 2004. FDA product code: IXI. Intensity modulators may be added to standard linear accelerators to deliver IMRT when used with proper treatment planning systems.
Radiation therapy treatment planning systems have also been cleared for marketing by the FDA through the 510(k) process. These include the Prowess Panther (Prowess) in 2003, TiGRT (LinaTech) in 2009, Ray Dose (Ray Search Laboratories) in 2008, and the eIMRAT 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 cleared for marketing by the FDA through the 510(k) process is the Varian IMRT system (Varian Medical Systems). FDA product code: IYE
Information in this policy was formerly found in a general IMRT policy, 2003015. Coverage is unchanged with change to this individual policy.
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Policy/ Coverage: |
Effective August 1, 2021, for members of plans that utilize a radiation oncology benefits management program, Prior Approval is required for this service and is managed through the radiation oncology benefits management program.
Effective April 14, 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Intensity Modulated Radiation Therapy (IMRT) meets primary coverage criteria for effectiveness for treatment of non-metastatic localized prostate cancer for the following indications (see Description for definition of risk categories):
Image guidance or image-guided radiation therapy (IGRT), any modality, used with IMRT meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
IMRT for the treatment of localized prostate cancer in any circumstance other than specified above does not meet primary coverage criteria.
For members with contracts without primary coverage criteria, IMRT for the treatment of localized prostate cancer in any circumstance other than specified above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective March 13, 2022 to April 13, 2024
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Intensity Modulated Radiation Therapy (IMRT) meets primary coverage criteria for effectiveness for treatment of non-metastatic localized prostate cancer for the following indications (see Description for definition of risk categories):
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
IMRT for the treatment of localized prostate cancer in any circumstance other than specified above does not meet primary coverage criteria.
For members with contracts without primary coverage criteria, IMRT for the treatment of localized prostate cancer in any circumstance other than specified above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to March 13, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
IMRT meets primary coverage criteria for effectiveness for treatment of non-metastatic localized prostate cancer for the following indications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
IMRT for the treatment of localized prostate cancer in any circumstance other than specified above does not meet primary coverage criteria.
For members with contracts without primary coverage criteria, IMRT for the treatment of localized prostate cancer in any circumstance other than specified above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to September 2020
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
IMRT for treatment of localized prostate cancer meets primary coverage criteria for effectiveness when the patient has non-metastatic prostate cancer and will be treated with dose escalation greater than 75 Gy.
IMRT for treatment of localized prostate cancer meets primary coverage criteria for effectiveness when the patient has non-metastatic prostate cancer and will be treated with 70 Gy hypofractionation ( e.g. 28 fractions.)
Intensity Modulated Radiation Therapy, as adjuvant or salvage radiation therapy for men who are post-prostatectomy, with biochemical failure, without distant metastases, meets certificate primary coverage criteria when greater than 65 Gy to 72 Gy or more (dose escalation) will be given.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
IMRT for the treatment of localized prostate cancer for 1) doses of less than 75 Gy or 2) for doses less than 65 Gy for post-prostatectomy recurrent prostate cancer does not meet primary coverage criteria for cost effectiveness. There is no medical literature documenting improved outcomes with this dose of IMRT compared to radiation delivery by other, less expensive techniques.
For contracts without primary coverage criteria, IMRT for the treatment of localized prostate cancer for 1) doses of less than 75 Gy OR 2) for doses less than 65 Gy for post-prostatectomy recurrent prostate cancer, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to June 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
IMRT for treatment of localized prostate cancer meets primary coverage criteria for effectiveness when the patient has non-metastatic prostate cancer and will be treated with dose escalation greater than 75 Gy.
Intensity Modulated Radiation Therapy, as adjuvant or salvage radiation therapy for men who are post-prostatectomy, with biochemical failure, without distant metastases, meets certificate primary coverage criteria when greater than 65 Gy to 72 Gy or more (dose escalation) will be given.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
IMRT for the treatment of localized prostate cancer for 1) doses of less than 75 Gy or 2) for doses less than 65 Gy for post-prostatectomy recurrent prostate cancer does not meet primary coverage criteria for cost effectiveness. There is no medical literature documenting improved outcomes with this dose of IMRT compared to radiation delivery by other, less expensive techniques.
For contracts without primary coverage criteria, IMRT for the treatment of localized prostate cancer for 1) doses of less than 75 Gy OR 2) for doses less than 65 Gy for post-prostatectomy recurrent prostate cancer, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective November 2013- July 2015
IMRT for treatment of localized prostate cancer meets primary coverage criteria for effectiveness when the patient has non-metastatic prostate cancer and will be treated with dose escalation greater than 75 Gy.
IMRT for the treatment of localized prostate cancer. for doses of less than 75 Gy, does not meet primary coverage criteria for cost effectiveness. There is no medical literature documenting improved outcomes with this dose of IMRT compared to radiation delivery by other, less expensive techniques.
For contracts without primary coverage criteria, IMRT for the treatment of prostate cancer including, but not limited to, disease that is metastatic or a dose less than 75 Gy, is considered investigational. Investigational services are an exclusion in the member benefit certificate.
Intensity Modulated Radiation Therapy, as adjuvant or salvage radiation therapy for men who are post-prostatectomy, with biochemical failure, without distant metastases, meets certificate primary coverage criteria when 72 Gy or more (dose escalation) will be given.
For contracts without primary coverage criteria the use of Intensity Modulated Radiation Therapy, as adjuvant or salvage therapy, post-prostatectomy, is considered medically necessary when 72 Gy, or more, are given.
Effective August 2010-10/31/13
IMRT for treatment of localized prostate cancer meets primary coverage criteria for effectiveness when the patient has non-metastatic prostate cancer and will be treated with dose escalation greater than 75 Gy.
IMRT for the treatment of localized prostate cancer. for doses of less than 75 Gy, does not meet primary coverage criteria for cost effectiveness. There is no medical literature documenting improved outcomes with this dose of IMRT compared to radiation delivery by other, less expensive techniques.
For contracts without primary coverage criteria, IMRT for the treatment of prostate cancer including, but not limited to, disease that is metastatic or a dose less than 75 Gy, is considered investigational. Investigational services are an exclusion in the member benefit certificate.
Intensity Modulated Radiation Therapy, as adjuvant or salvage radiation therapy for men who are post-prostatectomy, with biochemical failure, without distant metastases, does not meet member benefit certificate primary coverage criteria. There are no studies reporting improved outcomes with dose escalation greater than 70 Gy for this subset of men and this is currently being studied in ongoing trials. A radiation dose of or less than 70Gy may be effectively administered by 3D-CRT or four-field technique.
For contracts without primary coverage criteria the use of Intensity Modulated Radiation Therapy, as adjuvant or salvage therapy, post-prostatectomy, is considered investigational. Investigational services are an exclusion in the member benefit certificate and are not covered.
Effective prior to August 2010
IMRT for treatment of prostate cancer meets primary coverage criteria for effectiveness when the patient has non-metastatic prostate cancer and will be treated with dose escalation greater than 75 Gy.
For contracts without primary coverage criteria, IMRT for the treatment of prostate cancer including, but not limited to, disease that is metastatic or a dose less than 75 Gy, is considered investigational. Investigational services are an exclusion in the members benefit certificate.
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| Rationale: |
For prostate cancer, external-beam radiation therapy (EBRT) is one accepted option for treatment. Over the past several decades, methods to plan and deliver radiation therapy have evolved in ways that permit more precise targeting of tumors with complex geometries. These methods 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 EBRT.
Treatment planning first evolved by using 3-dimensional images, usually from computed tomography (CT) scans, to delineate the tumor, its boundaries with adjacent normal tissue, and organs at risk for radiation damage. Radiation oncologists used these images, displayed from a “beam’s-eye view,” to shape each of several beams (e.g., with compensators, blocks, or wedges) to conform to the patient’s tumor geometry perpendicular to the beam’s axis. Computer algorithms were developed to estimate cumulative radiation dose 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 immobilize the patient, thus maintaining consistent beam axes across treatment sessions. However, “forward” planning used a trial and error process to select treatment parameters (the number of beams and the intensity, shape, and incident axis of each). The planner/therapist modified one or more parameters and re-calculated dose distributions, if analysis predicted underdosing for part of the tumor or overdosing of nearby normal tissue. Furthermore, since beams had uniform cross-sectional intensity wherever they bypassed shaping devices, it was difficult to match certain geometries (e.g., concave surfaces). Collectively, these methods are termed 3-dimensional conformal radiation therapy (3D-CRT).
Over the past decade, other methods were developed to permit beam delivery with non-uniform cross-sectional intensity. This technique often relies on a device (a multi-leaf collimator, MLC) situated between the beam source and patient, that moves along an arc around the patient. As it moves, a computer varies aperture size independently and continuously for each leaf. Thus, MLCs divide beams into narrow “beamlets,” with intensities that range from zero to 100% of the incident beam. With an alternative, termed tomotherapy, a small radiation portal emitting a single narrow beam moves spirally around the patient, with intensity varying as it moves. Each method (MLC-based or tomotherapy) is coupled to a computer algorithm for “inverse” treatment planning. The planner/radiotherapist 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 and surrounding tissues and organs at risk, computer software optimizes the location and shape of beam ports, and beam and beamlet intensities, to achieve the treatment plan’s goals. Collectively, these methods are termed intensity-modulated radiation therapy (IMRT).
Multiple studies have generated 3D-CRT and IMRT treatment plans from the same scans, then compared predicted dose distributions within the target and in adjacent organs at risk. Results of such planning studies show that IMRT improves on 3D-CRT with respect to conformality to, and dose homogeneity within, the target. Dosimetry using stationary targets generally confirms these predictions. Thus, radiation oncologists hypothesized that IMRT may improve treatment outcomes compared with those of 3D-CRT by one or more of the following mechanisms.
Increased conformality may permit escalated tumor doses without increasing normal tissue toxicity (e.g., proctitis), and may thus improve local tumor control. Better dose homogeneity within the target may also improve local tumor control by avoiding underdosing (cold spots) within the tumor and may decrease toxicity by avoiding overdosing (hot spots). Finally, enhanced conformality for standard doses may reduce dose outside the target volume and thus decrease toxicity.
However, IMRT aims radiation at the tumor from many more directions, and thus subjects more normal tissue to low-dose radiation than occurs with conventional EBRT or 3D-CRT. This may increase late effects of radiation therapy. Furthermore, treatment planning and delivery are more complex, time-consuming, and labor-intensive for IMRT than for 3D-CRT. Thus, clinical studies must test whether IMRT improves tumor control or reduces acute and late toxicities, when compared with 3D-CRT. Testing this hypothesis requires direct comparative data on outcomes for separate groups of similar patients treated with each method.
As noted in the Description section, intensity-modulated radiation therapy (IMRT) detects the areas of radiation and adjusts the dose weighting and delivery to process the radiation plan. In contrast to 3-dimensional conformal radiation that is accurate to within 7 to 10 mm, IMRT restricts the dose and provides accuracy within 1 to 3 mm.
Recent systematic reviews have evaluated the use of IMRT in patients with prostate cancer.
The most recent published review is a comparative effectiveness study of therapies for clinically localized prostate cancer (Wilt, 2008). Based on review of the data, this analysis reached the following conclusions:
Another recent review by the Institute for Clinical and Economic Review (Pearson, 2007) stated:
The policy was updated with a literature search using MEDLINE through January 2009. Zelefsky and colleagues (2008) reported on the incidence and predictors of treatment-related toxicity at 10 years after 3D-CRT and IMRT for localized prostate cancer. Between 1988 and 2000, 1,571 patients with stages T1-T3 prostate cancer were treated with 3D-CRT or IMRT with doses ranging from 66 to 81 Gy. Twenty-two percent were considered to be at low risk, as based on NCCN guidelines. The median follow-up was 10 years. The actuarial likelihood at 10 years for the development of Grade 2 or higher gastrointestinal (GI) toxicities was 9%. The use of IMRT significantly reduced the risk of GI toxicities compared with patients treated with conventional 3D-CRT (13% to 5%; p<0.001). Among patients who experienced acute symptoms, the 10-year incidence of late toxicity was 42%, compared with 9% for those who did not experience acute symptoms. The 10-year incidence of late Grade 2 or higher genitourinary (GU) toxicity was 15%. Patients treated with 81 Gy (IMRT) had a 20% incidence of GU symptoms at 10 years, compared with 12% for patients treated with lower doses (p=0.01). Among patients who had developed acute symptoms during treatment, the incidence of late toxicity at 10 years was 35%, compared with 12%. The incidence of Grade 3 GI and GU toxicities was 1% and 3%, respectively. The authors concluded that serious late toxicity was unusual despite the delivery of high radiation dose levels in these patients. They also noted that higher doses were associated with increased GI and GU Grade 2 toxicities, but the risk of proctitis was significantly reduced with IMRT.
Cohlon and colleagues (2008) reported on preliminary biochemical outcomes and toxicity with high-dose IMRT to a dose of 86.4 Gy for localized prostate cancer. For this study, 478 patients were treated between August 1997 and March 2004 with 86.4 Gy using a 5- to 7-field IMRT technique. The median follow-up was 53 months. Thirty-seven patients (8%) experienced acute Grade 2 GI toxicity; none had acute Grade 3 or 4 GI toxicity; 105 patients (22%) experienced acute Grade 2 GU toxicity; and 3 patients (0.6%) had Grade 3 GU toxicity. Sixteen patients (3%) developed late Grade 2 GI toxicity; 2 patients (<1%) developed late Grade 3 GI toxicity; 60 patients (13%) had late Grade 2 GU toxicity; and 12 (<3%) experienced late Grade 3 GU toxicity. The 5-year actuarial PSA relapse-free survival, according to the nadir plus 2 ng/mL definition, was 98%, 85%, and 70% for the low-, intermediate-, and high-risk NCCN prognostic groups. The authors concluded that treatment with ultra-high radiation dose levels of 86.4 Gy using IMRT for localized prostate cancer is well tolerated and the early excellent biochemical control rates are encouraging. These results based on a case series should be considered as preliminary.
Many of the reports in medical literature continue to address dosimetric studies but there are some clinical studies being reported. Some are at 5=plus years follow-up. The technique of radiation therapy delivery is not specified but CPT codes to report IMRT did not exist until 2002. There are multiple ongoing studies of radiation therapy for the treatment of prostate cancer and many of the trials use “3DCRT/IMRT” in their descriptions.
Kuban, 2008, reported results of 301 patients followed for a median of 8.7 years. Freedom from biochemical or clinical failure, computed at 8-years post treatment, was 78% for those in the 78-Gy arm vs 59% for those in the 70-Gy arm, using Kaplan-Meier analysis. Gastrointestinal toxicity, grade 2 or higher, occurred twice as often in the high dose patients (26& vs 13%) but there was no statistical difference in genitourinary toxicity of grade 2 or higher (13% vs 8%).
Michalski and colleagues (2009), in writing for the American College of Radiology’s Expert Panel on Radiation Oncology-Prostate, review multiple issues with the use of 3DCRT/IMRT for the treatment of prostate cancer. Many of the studies reviewed report better results of dose escalation for those men at intermediate to high-risk. The ACR Appropriateness Criteria gives a rating of 8 to IMRT and 7 to 3DCRT on a scale of 9 with 9 being the most appropriate.
2010 Update
Prostate fossa
In 2005 Vargas and colleagues published a study 617 men who had a radical prostatectomy. Thirty-four of those men received adjuvant or salvage (n=99) radiation therapy after prostatectomy. Both groups received a median dose of 59.4 Gy using a four-field or bilateral arc technique. The adjuvant group had pathological features consistent with high risk of recurrence. In the salvage group 44% had an initial undetectable postoperative PSA level that later became detectable. The 5-y BC was 47 % for all patients who did not receive radiation therapy and 57% for the group that did receive adjuvant radiation.
The American College of Radiology, in the Appropriateness Criteria for Postradical Prostatectomy Irradiation in Prostate Cancer, updated in 2009, lists three indications for radiation therapy after radical prostatectomy:
Adjuvant radiotherapy for men with an undetectable or barely detectable PSA (<0.2 ng/mL) who have high risk pathologic features;
Salvage radiotherapy for men who had an undetectable or barely detectable PSA (<0.2 ng/mL) immediately after surgery, but whose PSA rises at some late date;
Salvage radiotherapy for men whose PSA remains at 0.2 ng/mL or above after surgery.
The document summarizes:
Pasquier and Ballereau (2008) reported a literature review for adjuvant and salvage radiotherapy after prostatectomy. Immediate postoperative RT improved biochemical and clinical progression-free survival but had little effect on metastasis-free or overall survival. They concluded that prospective randomized trials were needed to compare immediate post-operative radiotherapy with salvage radiotherapy and that these trials should also study the value of androgen therapy deprivation in these settings.
Until 2010 there was no definition of what the appropriate target volume should be for the administration of post-prostatectomy radiation therapy. In order to promote uniformity in defining prostate fossa clinical target volume (PF-CTV) the RTOG (Michalski et al, 2010) published consensus guidelines intended to be used in current and future RTOG clinical trials. The CTV defined by this group represents a minimum volume to be irradiated in a typical postoperative scenario.
Nielson et al., 2010, noted difficulty in counseling men about treatment options postprostatectomy. Should all men with adverse pathological features undergo immediate adjuvant radiation or should initial observation with more selective, but early, salvage radiation therapy be recommended. They noted three ongoing trials that might help answer that question:
Radiotherapy and Androgen Deprivation in Combination After Local Surgery, RADICALS trial, in the United Kingdom and Canada - NCT00541047: This is a randomized trial with patients undergoing immediate RT or early salvage RT. These men are then randomized into no hormone therapy, short-term or long-term hormone therapy. The RT dosage and administration technique is not specified.
A phase II trial of Short Term Androgen Deprivation with Pelvic Lymph Node or Prostate Bed Only Radiotherapy (SPPORT) in prostate cancer patients with a rising PSA after radical prostatectomy – NCT00567580 (RTOG0534): Arm I receives prostate bed radiotherapy (PBRT) alone, 64.8 – 70.2 Gy, technique not specified; Arm II receives the same RT dose but also neoadjuvant and concurrent short-term androgen deprivation starting 2 months before RT; Arm III receives PBRT to 64.8 – 20.2 Gy, pelvic lymph node RT to 45 Gy, and neoadjuvant and concurrent short-term androgen deprivation starting 2 months before RT.
A phase III trial of radiation therapy with or without Casodex in patients with PSA elevation following radical prostatectomy for pT3n0 carcinoma of the prostate – NCT 00002874 (RTOG9601): Patients will receive 64.8 Gy to the original prostate volume, the tumor resection bed and the proximal membranous urethra. They will receive Casodex 150 mg or placebo daily for two years beginning immediately upon, or just prior to, the initiation of RT.
There are other ongoing trials that might include different drugs, may incorporate brachytherapy, different RT doses or different schedules but they are not all listed here.
October 2012 Update
PubMed search from October 2010 through September 2012 performed to identify results of clinical trials to support the use of IMRT in the treatment of prostate cancer. There were many dosimetric trials and reports of comparisons that are not considered here since they do not report improved patient outcomes.
NCCN Prostate Cancer Guidelines Version 3.2012, Principles of Radiation recommends a dose of 75.6-79.2 Gy in conventional fractions to the prostate, w or w/o seminal vesicles, for patients for low-risk cancers. Intermediate- and high-risk patients should receive doses up to 81 Gy. 3D conformal and IMRT techniques should be employed and IGRT is required for a dose of 78 Gy or higher.
Ip and colleagues, for the Tufts Evidence-based Practice Center, did an update of an assessment for radiation therapy for localized prostate cancer in August 2010. At that time they made the following conclusion: “Definitive benefits of radiation treatments compared to no treatment or no initial treatment for localized prostate cancer could not be determined because available data were insufficient. Data on comparative effectiveness between different forms of radiation treatments (BT, EBRT, SBRT) are also inconclusive whether one form of radiation therapy is superior to another form in terms of overall or disease-specific survival. Studies suggest that higher EBRT dose results in increased rates of long-term biochemical control than lower EBRT dose. EBRT administered as a standard fractionation of moderate hypofractionation does not appear to differ with respect to biochemical control and late genitourinary and gastrointestinal toxicities. Available data suggest that BT might be associated with an increase in genitourinary toxicity compared with EBRT. BT appears to be largely comparable to EBRT in the rates of gastrointestinal toxicity. However, more and better quality studies are needed to either confirm or refute these suggested findings. “
Hummel et al., 2010, performed a systematic review and economic evaluation of IMRT for treatment of prostate cancer. They did not identify any randomized controlled trials comparing IMRT with 3DCRT. They found 13 non-randomized trials, 5 available as abstracts only. Most studies reported an advantage for IMRT in GI toxicity though there was some indication GU toxicity might be worse. QOL improved for both groups following radiotherapy and any differences in the groups resolved by 6 months after treatment. They were uncertain that differences in GI toxicity between IMRT and 3DCRT are sufficient for IMRT to be cost-effective, that it would depend on the incidence of GI toxicity and its duration and the cost difference between IMRT and 3DCRT.
Michalski et al, 2010, updated long-term toxicity following 3DCRT from the RTOG 9406 dose escalation study of 1,084 men in this phase I/II study.
Level I: 68.4 Gy in 1.8 Gy fractions, prostate only
Level II: 73.8 Gy in 1.8 Gy fractions, prostate + SV with prostate boost
Level III: 79.2 Gy in 1.8 Gy fractions, prostate + SV
Level IV: 74 Gy in 2.0 Gy fractions
Level V: 78 Gy in 2.0 Gy fractions
Group 1: prostate only Group II: prostate + SV + prostate boost Group III: prostate + SV
Significantly more grade 2 or greater toxicity with 78 Gy at 2 Gy/fraction than with 68.4-79.2 at 1.8 Gy/fraction and with 74 Gy at 2 Gy/fraction.
Postprostatectomy: adjuvant or salvage therapy
ACR Appropriatenss Criteria, 2010, considers 3DCRT and IMRT as 8 (usually appropriate) and still states the recommended radiation dose to the fossa is 66-70.2 Gy in either the adjuvant or salvage setting. "The addition of pelvic radiotherapy to prostate fossa radiation is generally discouraged, although it may be appropriate in certain clinical situations (absence of lymph node dissection, evidence of nodal involvement at prostatectomy or on imaging studies, etc).
The AUA has a 2011 update of their 2007 guideline for Prostate Cancer which did not mention IMRT. The 2007 guideline has nothing on it to indicate it has been validated and confirmed in 2011, that statement is found only in the list of guidelines. (http://www.auanet.org/content/clinical-practice-guidelines/clinical-guidelines.cfm#1)
Thompson et al., 2009, reported results of 425 men, post radical prostatectomy, randomized to observation (n=211) and adjuvant radiation, 10 – 64 Gy (n=214). Metastasis-free survival was significantly better in the RT group, 93 of 214 events, compared to 114 of 211 events in the observation group. There was significant improvement in the survival, 88 deaths of 214 for the RT group compared to 110 deaths of 211 in the observation group.
NCCN Principles of Radiation in Prostate Cancer Guidelines Version 3.2012, does not list a recommended dose for post-prostatectomy radiation therapy.
There are a number of ongoing trials, some comparing IMRT to proton beam therapy, some involving brachytherapy, some with or without hormone therapy. Results from the following trials may help resolve some of the long-standing questions about radiation therapy for the treatment of prostate cancer in several different circumstances.
NCT01685190 A phase 2 trial comparing IMRT of the prostate alone with IMRT of the prostate & pelvis.
NCT00326638 A phase 3 trial comparing 3DCRT with helical tomotherapy.
NCT00033631 A phase 3 trial comparing high-dose 3DCRT with standard dose 3DCRT/IMRT for treatment of localized prostate cancer.
NCT003317773 A phase 3 trial of 3DCRT, IMRT and hypofractionated radiation therapy.
NCT00936390 A phase 3 trial of 3DCRT or IMRT, with or without androgens.
No new evidence has been identified that would warrant a change in the coverage statement.
2013 Update
There are multiple ongoing trials of IMRT and conformal RT, usually hypofractionated, as well as SBRT and brachytherapy to treat all stages of prostate cancer. Some are of particular interest:
Sharma, et al., 2010, studied men who received a mean dose of 76 Gy by IMRT or 3DCRT with androgen deprivation. The authors concluded use of IMRT significantly decreased the acute and late GI toxicity. It should be noted that the treatment field for 92% of the 3DCRT group and 58% of the IMRT group included prostate, SVs and lymph nodes. A photon energy (MV) > 14 was used for 72% of the 3DCRT group and only 11% of the IMRT group.
Dose escalation in 3DCRT was reported by Beckendorf et al., 2010. This was a randomized trial comparing 70 and 80 Gy radiotherapy for prostate cancer. Five years after treatment only 103 of the 306 patient sample were available and there were no differences in quality of life in the 2 arms despite slightly higher rates of rectal and urinary toxicity in the 80 Gy arm.
Jacobs et al., 2012, reported comparative effectiveness of external beam radiation approaches for prostate cancer. A large number of Medicare patients were studied. For the subset of higher risk patients, IMRT appeared to show benefit in terms of reduced salvage therapy without an increase in complications. For patients in other risk groups the risks of salvage therapy and complications were comparable between the two modalities.
The Agency for Healthcare Research and Quality (AHRQ) posted their intent to update their 2008 Comparative Effectiveness Review of Therapies for Clinically Localized Prostate Cancer. This update is not on the AHRQ website as of 10/31/2013.
Spratt et al., 2013, reported the use of high-dose radiation to 86.4 Gy using 5-7 field IMRT; 59% were also treated with neoadjuvant and concurrent androgen deprivation therapy. The median follow-up for the entire cohort was 5.5 years (range 1 – 14 years). For low-, intermediate-, and high-risk groups the 7-year biochemical relapse-free survival rates were 98.8%, 85.6% and 67.9% respectively. In intermediate- and high-risk groups grade 2 or higher late GI and GU toxicities were 4.4% and 21.1% while late grade 3 toxicity was experienced by 0.7% and 2.2% respectively.
Ost et al., 2010, reported results of 144 patients with high-risk disease at prostatectomy referred for adjuvant IMRT (A-IMRT) and 134 men referred for salvage IMRT (S-IMRT) for biochemical failure post- prostatectomy. Median doses of 74 Gy and 76 Gy respectively were given. A total of 178 patients were matched 89:89) with a median follow-up of 36 months. The 3-year bRFS was 91% for A-IMRT compared to 79% for S-IMRT.
ACR Appropriateness Criteria Post Radical Prostatectomy (Rossi, 2011) gave a rating of 8 (usually appropriate) for prostate bed irradiation in both the adjuvant and early salvage circumstance for IMRT at a dose of 6660 cGy in 37 fractions. Radiation therapy is not recommended in the setting of a fast-rising PSA.
Mishra et al., 2011, authored a review article to evaluate evidence for and distinguish between ART and early SRT. They concluded early ART provides improved biochemical relapse-free survival, and potentially overall survival, for patients with adverse pathological features (APFs) following prostatectomy compared with observation. However, it is unknown if early SRT is equivocal to ART.
Goenka et al., 2011, reported results of treatment with SRT with 3DCRT (n=109) or IMRT (n=176),mean follow-up 60 months. 88% of men treated with doses > 70Gy were treated with IMRT while 86% of men treated with < 70 Gy received 3DCRT. IMRT was associated with a reduction in grade ≥ 2 GI toxicity compared to 3DCRT but not associated with a reduction of risk of grade ≥ 2 GU toxicity, urinary incontinence, or grade 3 erectile dysfunction.
Bauman et al., 2012, authored a guideline intended to promote evidence-based practice in Ontario, Canada. Their recommendations are:
Goldin et al., 2013, authored an article published in JAMA. Data was obtained from the Surveillance, Epidemiology, and End Results-Medicare linked database. They looked at comparative effectiveness of IMRT and conventional conformal therapy but data does not have information about radiation therapy dosage. An invited commentary by Cooperberg in the same issue addresses cost-effectiveness issues related to IMRT services.
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2009, Wong et al reported on a retrospective study of radiation dose escalation in 853 patients with localized (T1c-T3N0M0) prostate cancer (Wong, 2009). Radiation therapies used included conventional dose (71 Gy) 3D-CRT (n=270), high-dose (75.6 Gy) IMRT (n=314), permanent transperineal brachytherapy (n=225), and EBRT plus brachytherapy boost (n=44). All patients were followed for a median of 58 months (range, 3 to 121 months). The authors reported:
Intermediate- and high-risk prostate cancer patients in this study had significantly improved 5-year bNED rates with dose escalation. However, in low-risk prostate cancer patients, bNED rates with dose escalation were not improved compared with conventional dose 3D-CRT. The authors also found acute and late grade-2 and -3 GU toxicities were fewer with IMRT than brachytherapy or EBRT plus brachytherapy.
A randomized ongoing Phase III trial studying the adverse effects of 3 schedules of IMRT in treating patients with localized prostate cancer is being undertaken by the U.K. Institute of Cancer Research (NCT00392535). This is a multicenter trial (n=26 centers) with an estimated enrollment of 2163 patients. The primary outcome measures are acute and late radiation-induced adverse effects and freedom from prostate cancer recurrence. This study completion date was September 2012, but final results are not published. Preliminary results of this study have been published which report that hypofractionated IMRT (57-60 Gy) seems equally well-tolerated as conventionally fractionated treatment (74 Gy) at 2 years of follow-up (Dearnaley, 2012).
2015 Update
A literature search conducted through March 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Primary Studies Reporting on Outcomes and Adverse Effects
In a non-randomized retrospective study, a total of 553 patients with prostate cancer were treated with 3D-CRT at a dose of 70 or 74 Gy (3D-CRT 70, 3D-CRT 74, respectively) or IMRT at a dose of 78 Gy or a total dose of 82 Gy that included a simultaneous integrated boost (SIB) (IMRT 78, IMRT/SIB 82, respectively) (Dolezel, 2015). Late toxicity was scored according to the Fox Chase Modification of the Radiation Therapy Oncology Group and late Effects Normal Tissue Task Force (FC-RTOG/LENT) late toxicity criteria. Biochemical failure was defined using the Phoenix and American Society for Therapeutic Radiation Oncology (ASTRO) definitions.
The 5-year risk of grade 2-4 genitourinary toxicity was 26% in the 3D-CRT 70 group, 27% in the 3D-CRT 74 group, 17% in the IMRT 78 group, and 25% in the IMRT/SIB 82 group, with no intergroup statistical differences. The 5-year risk of grade 2-4 gastrointestinal toxicity was 19% (3D-CRT 70), 42% (3D-CRT 74), 20% (IMRT 78), and 27% (IMRT/SIB 82); the differences between the 3D-CRT 74 and 3D-CRT 70 and between 3D-CRT 74 and IMRT 78 groups were statistically significant (log rank p = 0.03). The 5-year Phoenix prostate specific antigen (PSA) relapse-free survival (PSA-RFS) in low-risk, intermediate-risk, and high-risk patients treated using 3D-CRT were 89%, 66%, and 58 %, respectively. Among patients treated with IMRT, the 5-year PSA-RFS was 91%, 89%, and 84% among low-, intermediate-, and high risk patients, respectively. Among patients treated using 3D-CRT versus IMRT for the aforementioned risk groups, clinical relapse-free survival rates (C-RFS) were 95% versus 100%; 87% versus 99%; and, 84% versus 94%, respectively. Disease-free survival (DFS) rates for low-, intermediate- and high-risk patients treated using 3D-CRT were 83%, 71%, and 72%, respectively. For those categories, the IMRT group had DFS rates of 96%, 89%, and 88%, respectively. The differences in PSA-RFS rates for intermediate- and high-risk patients were statistically significant compared to low-risk patients, while C-RFS and DFS rate differences were not statistically different. This study provides some comparative data that supports lower toxicity for IMRT and improved oncologic outcomes compared to 3D-CRT, but it is limited by the retrospective design, lack of statistical significance on some of the main outcomes, and the nonrandomized design that may have led to noncomparability of treatment groups.
Another nonrandomized study compared acute and subacute urinary and rectal toxicity in patients with localized prostate cancer who received treatment with one of the following four RT techniques: IMRT, 3DCRT, low-dose-rate permanent implant brachytherapy using I-125 seeds (LDRB), and high-dose-rate brachytherapy (HDRB) (Morimoto, 2014). Among 156 patients with localized prostate cancer, 57 underwent IMRT; 35 underwent 3D-CRT; 37 underwent I-125 LDRB implant, and 27 underwent HDRB. The prescribed doses were 70-74 Gy/35-37 fractions, 70 Gy/35 fractions, 145 Gy, and 45.5 Gy/7 fraction/4 days for IMRT, 3DCRT, LDRB, and HDRB respectively. Toxicities (≤6 months) were retrospectively evaluated using the Common Terminology Criteria for Adverse Events version 4.03. The frequency of grade 1 or 2 urinary toxicities using 3D-CRT (33/35 [94%]) was significantly higher than that with HDRB (18/27 [67%]) or IMRT (37/57 [65%]) (p<0.05). The frequency of grade 1 or 2 urinary toxicities using LDRB was 31 of 37 (84%). The frequency of grade 1 or 2 gastrointestinal toxicities using 3D-CRT (17/35 [49%]) was significantly higher than that using LDRB (4/37 [11%]) or HDRB (0/27 [0%]) (p<0.05). With IMRT, the frequency of grade 1 or 2 gastrointestinal toxicities was 18/57 (32%), which was significantly higher than that using HDRB (0/27 [0%]) (p<0.05). Grade 3 or greater adverse events were not observed. This evidence shows that acute and subacute genitourinary toxicities were observed more frequently after 3D-CRT than after IMRT. However, the limitations of the study are similar to other non-randomized studies reviewed in this Policy, including the possibility of noncomparability of treatment groups.
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov through March 2015 identified currently. These trials are:
Ongoing
Unpublished
The American College of Radiology (ACR) Appropriateness Criteria® indicates IMRT is the standard for definitive external beam RT of the prostate (Nguyen, 2014).
2015 Update
This policy is being updated based on a literature search focusing on the use of IMRT as adjuvant salvage radiation therapy for the treatment of post-prostatectomy recurrent prostate cancer. The policy statement has been revised based on the following literature identified.
The National Comprehensive Cancer Network (NCCN) (NCCN, 2015) recommends >64Gy to 72Gy for post-prostatectomy recurrent prostate ca (biochemical recurrence). In addition, the American Society for Therapeutic Radiology and Oncology (ASTRO) AUA Guidelines supports the use of >64 Gy with higher range doses if recurrent disease is documented by biopsy (Thompson, 2014).
The following published studies support the use of IMRT as adjuvant salvage radiation therapy for the treatment of post-prostatectomy recurrent prostate cancer at doses greater than 64 Gy.
Bernard and colleagues reported on a study to evaluate the association between external beam radiotherapy dose and biochemical failure of prostate cancer in patients who received salvage prostate bed EBRT for a rising PSA level after radical prostatectomy (Bernard, 2010). A total of 364 men met study selection criteria and were followed up for a median of 6.0 years (range, 0.1-19.3 years). Median pre-EBRT PSA level was 0.6 ng/mL. The estimated cumulative rate of BcF at 5 years after EBRT was 50% overall and 57%, 46%, and 39% for the low-, moderate-, and high-dose groups, respectively. In multivariable analysis adjusting for potentially confounding variables, there was evidence of a linear trend between dose and BcF, with risk of BcF decreasing as dose increased (relative risk [RR], 0.77 [5.0-Gy increase]; p = 0.05). Compared with the low-dose group, there was evidence of a decreased risk of BcF for the high-dose group (RR, 0.60; p = 0.04), but no difference for the moderate-dose group (RR, 0.85; p = 0.41). The others conclude doses higher than 66.6 Gy result in decreased risk of biochemical failure.
Results of a retrospective study to assess the effectiveness of early salvage radiotherapy (RT) for patients with prostate-specific antigen (PSA) relapse after radical prostatectomy (RP) was published in 2009 (Tomita, 2009). Fifty-one patients underwent salvage RT for biochemical relapse of prostate cancer initially treated with RP. All patients had persistent or rising PSA>0.20 ng/ml at some point after surgery, or three successive PSA elevations after a postoperative nadir if PSA was<or =0.20 ng/ml. Most (96%) of pre-RT PSA were less or equal to 0.50 ng/ml, and median value was 0.25 ng/ml (range, 0.05-0.90 ng/ml). Median RT dose was 60 Gy (range, 50-66 Gy). Multivariate Cox regression analysis was performed for PSA before RP and salvage RT, margin status, seminal vesicle involvement, extracapsular invasion, Gleason score, PSA doubling time (PSADT), and RT dose to identify significant predictors of biochemical outcome. The authors concluded, “Although a total dose of 60 Gy was effective at a low pre-RT PSA levels with short follow-up, an RT dose>or =60 Gy resulted in superior biochemical outcomes even in patients with a pre-RT PSA<or =0.50 ng/ml” (Tomita, 2009).
In 2012, King published a systematic review on the timing of salvage radiotherapy after radical prostatectomy (King, 2012). A systematic review of all published SRT studies was performed to identify the pathologic, clinical, and treatment factors associated with relapse-free survival (RFS) after SRT. A total of 41 studies encompassing 5597 patients satisfied the study entry criteria. Radiobiologic interpretation of biochemical tumor control was used to provide the framework for the observed relationships. Prostate-specific antigen (PSA) level before SRT (P<.0001) and RT dose (P=.0052) had a significant and independent association with RFS. There was an average 2.6% loss of RFS for each incremental 0.1 ng/mL PSA at the time of SRT (95% CI,∼2.2-3.1). With a PSA level of 0.2 ng/mL or less before SRT, the RFS approached 64%. The dose for salvage RT in the range of 60-70 Gy seemed to be on the steep part of the sigmoidal dose-response curve, with a dose of 70 Gy achieving 54% RFS compared with only 34% for 60 Gy. There was a 2% improvement in RFS for each additional Gy (95% CI,∼0.9-3.2). The observed dose-response was less robust on sensitivity analysis.
November 2017
A literature search using the MEDLINE database through October 2017 did not reveal any new literature that would prompt a change in the coverage statement.
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
PRIMARY (DEFINITIVE) THERAPY FOR LOCALIZED PROSTATE CANCER
A 2016 meta-analysis by Yu et al included 23 studies (total N=9556 patients) that compared IMRT with 3D-CRT for gastrointestinal (GI), genitourinary (GU), and rectal toxicity, biochemical control, and overall survival (OS) (Yu, 2016). 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. 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.
In 2016, Viani et al reported on a pseudorandomized trial (sequential allocation) that compared toxicity levels between IMRT and 3D-CRT in 215 men who had localized prostate cancer (Viani, 2016). 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. 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 posttreatment.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
IMRT for Primary (Definitive) Therapy for Localized Prostate Cancer
Sujenthiran et al published a retrospective cohort study evaluating 23222 men who were treated for localized prostate cancer with IMRT (n=6933) 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 (Sujenthiran,2017). 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. GI 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, 0.66; 95% CI, 0.61 to 0.72; p<0.01). 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; hazard ratio, 0.94; 95% CI, 0.84 to 1.06; p=0.31). The most commonly diagnosed GI toxicity events were radiation proctitis (n=5962 [68.5%] of 8701 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 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.
May 2020 Update
A literature search was conducted through May 2020. There was no new information identified that would prompt a change in the coverage statement.
September 2020 Update
There is a trend toward hypofractionation (fewer treatments to deliver the same biologic dose) which allows patients to be treated with less disruption of their daily lives. There have been several randomized clinical trials comparing conventionally fractionated external radiotherapy with hypofractionated regimens.
RTOG 0415 was designed to evaluate the non-inferiority of hypofractionated treatment (70.8 Gy in 28 fractions) compared to conventional fractionation (73.8 Gy in 42 fractions) (Lee et al, 2016). There were 1092 participants. At a median follow-up of 5.9 years, the estimated 5-year disease-free survival rate was 85.3% in the conventional radiotherapy arm and 86.3% in the hypofractionated radiotherapy arm. The hypofractionated arm was associated with a significant increase in late grade 2 and 3 gastrointestinal and genitourinary adverse events. Based on the DFS rates, hypofractionated radiotherapy was found to be non-inferior.
In the HYPRO trial, patients with intermediate to high-risk prostate cancer were randomized to receive 78 Gy in 38 fractions or 64.6 Gy in 19 fractions (Incrocci et al, 2016). At 5years, the relapse free survival rates for conventional fractionation versus hypofractionation were 77.1% and 80.5% respectively. Since the goal of the trial was to prove superiority of hypofractionation, the authors concluded that hypofractionation had not been proven superior to standard fractionation. Hypofractionation does appear non-inferior in this study.
In the PROFIT trial, investigators randomly assigned patients with intermediate-risk prostate cancer to receive 78 Gy in 39 fractions or 60 Gy in 20 fractions (Catton et al, 2017). With 6 years of followup, biochemical disease free survival was the same in both groups. There were no differences in ≥ grade 3 late GI or GU toxicities reported.
Five-year results of the CHHip trial were recently published (Dearnaley et al, 2016). This was an open label, randomized study looking at both effectiveness and toxicities. A total of 3216 men were included. They compared 74 Gy in 37 fractions over a period of 7.4 weeks with hypofractionated radiotherapy at 60 Gy in 20 fractions over a period of 4 weeks or 57 Gy in 19 fractions over a period of 3.8 weeks. At the 5 year follow-up, biochemical or clinical failure-free rates were 88.3% in the conventional 74-Gy group, 90.6% in the hypofractionated 60-Gy group, and 85.9% in the hypofractionated 57-Gy group. While bladder and bowel symptoms peaked sooner in the hypofractionated groups (4-5 vs 7-8 weeks), at 18 weeks, rates were similar for all groups. Long-term adverse effects were similar among the treatment groups. The authors concluded that the hypofractionated approach using 60 Gy in 20 fractions was non-inferior to standard fractionation using 74 Gy in 37 fractions.
In 2018, ASTRO, ASCO, and AUA published an evidence-based guideline on hypofractionated radiation therapy for localized prostate cancer. They defined moderate hypofractionation as daily fractions ranging from 240 cGy to 340 cGy and ultrahypofractionation as daily fractions > 500 cGy. The latter is given in up to 5 fractions of SBRT. In comparing moderately fractionated IMRT with conventionally fractionated treatment, the panel has recommended that hypofractionated therapy should be offered to men with low- or intermediate-risk prostate cancer who opt for active treatment. These recommendations were both considered strong, were based on high-quality evidence, and had 100% consensus. Moderate hypofractionation should also be offered for highrisk prostate cancer where pelvic nodes will not be treated based on 94% consensus. They recommended that men be counselled of a small increased risk of temporary GI toxicity with hypofractionated regimens but noted that late GI and GU toxicities were similar in hypofractionated and conventional treatments. The suggested fractionation patterns are either 6,000 cGy in 20 fractions or 7,000 cGy in 28 fractions.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The NCCN guideline also cites the Kuban et al study, in addition to Kalbasi et al, 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. (Kuban, 2008; Kalbasi, 2015).
A 2019 amendment to the joint guidelines of the American Urological Association and the American Society for Radiation Oncology on the use of adjuvant and salvage RT after prostatectomy incorporated 155 references published between January 1990 and December 2017. The amendment affirmed that determining which RT techniques and doses produced optimal outcomes in the adjuvant and salvage RT contexts was "not possible" (Pisansky, 2019).
The National Comprehensive Cancer Network guidelines (v.2.2021) 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 (NCCN, 2021). 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."
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 (Pisansky, 2019; Thompson, 2014). The guideline contains statements that provide direction to clinicians and patients regarding the use of RT in this setting. The amendment included an additional statement [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."] on the use of hormone therapy with salvage RT and long-term data were used to update an existing statement (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.") on adjuvant RT (Pisansky, 2019).
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.
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