This evidence review has been regularly updated with searches of the MEDLINE database. The most recent literature review was performed for the period through May 15, 2023. The following is a summary of key findings to date.
This evidence review includes systematic reviews that evaluate outcomes of intensity-modulated radiotherapy (IMRT) treatment in patients with prostate cancer, summarizes the data on adverse effects from these systematic reviews, and includes representative primary studies. A reduction in adverse effects is likely to be the greatest potential benefit of IMRT, and, in this regard, the most relevant studies are comparative trials of IMRT versus 3-dimensional conformal radiotherapy (3D-CRT) that report on rates of adverse events following treatment.
Primary (Definitive) Therapy for Localized Prostate Cancer
Systematic Reviews
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). 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 interval did not overlap 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 two treatments in acute rectal toxicity, late GU toxicity, and OS.
In 2012, Bauman et al 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. Based on a review of 11 published reports through March 2009 (9 retrospective cohort studies, 2 randomized clinical trials [RCTs]) including 4559 patients, the authors recommended IMRT over 3D-CRT for aggressive treatment of localized prostate cancer where an escalated radiation (>70 gray [Gy]) dose is required.
Nine of 11 studies reviewed by Bauman reported on adverse effects. Six of 9 studies reported on acute gastrointestinal (GI) effects.5 Four studies (3 retrospective cohort studies, 1 RCT) reported differences in adverse effects between IMRT and 3D-CRT. The RCT (N=78 patients) reported that acute GI toxicity was significantly less frequent in the IMRT group than in the 3D-CRT group. This was true for grade 2 or higher toxicities (20% vs 61%, p=0.001), grade 3 or higher 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 (Bauman, 2012).
Six of 9 studies reported on acute genitourinary (GU) effects. One study, a retrospective cohort study of 1571 patients, reported a difference in overall acute GU effects in favor of 3D-CRT (37% IMRT vs 22% 3D-CRT, p=0.001). For late GI toxicity, 4 of 9 studies, all retrospective cohort studies with a total of 3333 patients, reported differences between IMRT and 3D-CRT. One RCT, reporting on late GI toxicity, did not find any differences between IMRT and 3D-CRT. Five of 9 studies reported on late GU effects: only 1 reported a difference in late GU effects in favor of 3D-CRT (20% vs 12%, p=0.01). Two retrospective cohort studies reported mixed findings on quality-of-life outcomes.5 A subsequent economic analysis (based on this systematic review data) demonstrated that for radical radiation treatment (>70 Gy) of prostate cancer, suggested IMRT was cost-effective compared to an equivalent dose of 3D-CRT based on 2009 data from the Canadian health care system (Yong, 2012).
Similar findings were observed in a 2011 systematic review by Hummell et al of the clinical effectiveness of IMRT for the radical treatment of prostate cancer, undertaken by the U.K. Health Technology Assessment Programme (Hummel, 2011). The literature search through May 2009 identified 8 full-length, nonrandomized studies of IMRT versus 3D-CRT. Clinical outcomes were OS, biochemical (prostate-specific antigen [PSA]) relapse-free survival (RFS), toxicity, and health-related quality of life. The biochemical RFS was not affected by treatment received, except when doses differed between groups; in these 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 and 3D-CRT supported the theory that higher doses (up to 81 gray [Gy]) can improve biochemical survival for patients with localized prostate cancer. Most studies reported an advantage for IMRT in GI toxicity, particularly with regard to 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.
A 2007 review by the Institute for Clinical and Economic Review reached the following conclusions (Pearson, 2007):
“The literature on comparative rates of toxicity has serious methodological weaknesses. There are no prospective randomized trials or cohort trials, and the case series that exist are hampered by the lack of contemporaneous cohorts and/or by a failure to describe the selection process by which patients were assigned to IMRT vs. 3D-CRT. Published case series demonstrate consistent findings of a reduced rate of GI toxicity for IMRT at radiation doses from approximately 75–80 Gy [grays]. Data on GU toxicity have not shown superiority of IMRT over 3D-CRT, nor do the existing data suggest that IMRT provided a lower risk of erectile dysfunction.”
“The literature suggests that the risk of Grade 2 GI toxicity is approximately 14% with 3D-CRT and 4% with IMRT. Thus, the number of patients needed to treat to prevent one case of moderate-severe proctitis is 10, and for every 100 patients treated with IMRT instead of 3D-CRT, 10 cases of GI toxicity would be expected to be prevented.”
Primary Studies Reporting on Outcomes and Adverse Effects
Sujenthiran et al (2017) published a retrospective cohort study of 23,222 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 was available in various databases serving the English National Health Service. 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 9300 procedures. The most commonly diagnosed GI toxicity was radiation proctitis (n=5962 [68.5%] of 8701 diagnoses). For GU toxicity, the most prevalent procedure was unspecified endoscopic examination of the bladder, undertaken in 1470 (40.6%) of 3625 procedures; of 4061 GU toxicity diagnoses, 1265 (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.
In 2016, Viani et al reported a pseudorandomized trial (sequential allocation) that compared toxicity between IMRT and 3D-CRT in 215 men who had localized prostate cancer. 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 endpoint of the trial was toxicity, defined as any symptom 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 study 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/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 after treatment.
A 2013 study by Michalski et al reported comparative data for IMRT and 3D-CRT from the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial (Michalski, 2013). In this trial, the initial protocol was for 3D-CRT, but during the trial, the protocol was amended to provide 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 or greater late GI toxicity for IMRT on univariate analysis (p=0.039). On multivariate analysis, there was a 26% reduction in grade 2 or higher 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.
In 2013, Vora et al reported on 9-year tumor control and chronic toxicities observed in 302 patients treated with IMRT for clinically localized prostate cancer at 1 institution(Vora, 2013). 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 (log rank, p=0.05). At last follow-up, none had persistent GI and only 0.7% had persistent GU toxicities of grade 3 or higher. The high-risk group was associated with a higher distant metastasis rate (p=0.02) and death from prostate cancer (p=0.001) (Vora, 2013).
In 2011, Alicikus et al. reported on 10-year outcomes in 170 patients treated after high-dose IMRT (81 Gy). The 10-year actuarial PSA-RFS rates were 81% for the low-risk group, 78% for the intermediate-risk group, and 62% for the high-risk group. The 10-year distant metastases-free rates were 100%, 94%, and 90%, respectively, and cause-specific mortality rates were 0%, 3%, and 14%, respectively. The 10-year likelihood of developing grade 2 and 3 late GU toxicity was 11% and 5%, respectively, and the likelihood of developing grade 2 and 3 late GI toxicity was 2% and 1%, respectively. No grade 4 toxicities were observed.
In 2009, Wong et al reported on a retrospective study of radiation dose escalation in 853 patients with localized (T1c-T3N0M0) prostate cancer. 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 EBRT plus brachytherapy boost (n=44). All patients were followed for a median of 58 months (range, 3-121 months). The 5-year OS for the entire group was 97%. The 5-year biochemical control (bNED) 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 EBRT plus brachytherapy. The bNED rates for 3D-CRT were significantly lower than those of the other higher dose modalities (p<.001).
In 2008, Cahlon et al 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. Median follow-up was 53 months. Thirty-seven (8%) patients experienced acute grade 2 GI toxicity; none had acute grade 3 or 4 GI toxicity; 105 (22%) patients experienced acute grade 2 GU toxicity; and 3 (0.6%) patients had grade 3 GU toxicity. Sixteen patients (3%) developed late grade 2 GI toxicity; 2 patients (<1%) developed late grade 3 GI toxicity; 60 (13%) patients had late grade 2 GU toxicity; and 12 (<3%) experienced late grade 3 GU toxicity. The 5-year actuarial PSA-RFS rates, according to the nadir plus 2 ng/mL definition, were 98%, 85%, and 70% for the low-, intermediate-, and high-risk NCCN prognostic groups, respectively.
NCCN Recommendations for RT Dose for Low-Risk vs Intermediate- to High-Risk Prostate Cancer
NCCN has made recommendations for 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 include the use of IMRT as the mode of RT and others that did not.
In 1993, the University of Texas M.D. Anderson Cancer Center activated an RCT to compare toxicity and patient outcomes after 78 Gy using 3D-CRT and 70 Gy using conventional (2-dimensional) in patients with localized prostate cancer. The long-term results were reported by Kuban et al in 2008. 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 groups in the 70 and 78 Gy groups were low risk (n=31 and n=30), intermediate risk (n=71 and n=68), and high risk (n=48 and n=53), respectively. When analyzed by risk group, patients with low-risk disease treated to 78 Gy versus 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 divided by PSA level, only those patients with a PSA level greater than 10 ng/mL showed a difference in FFF based on dose level.
NCCN guidelines cite the 2008 Kuban study in addition to Kalbasi et al (2015) as evidence for a dose of 75.6 to 79.2 Gy (with or without 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 cites the following studies.
In 2011, Xu et al reported a toxicity analysis of dose escalation from 75.6 to 81.0 Gy in 189 patients receiving definitive RT for prostate cancer. Patients were at high, intermediate, and low risk according to NCCN definitions, and received 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 thereafter (median follow-up, 3.0 years). The method of RT was at the discretion of the treating physician, and included IMRT in 60% and conventional RT in 40%. 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 when compared with the 75.6-Gy group.
In 2007, Eade et al reported the results of 1530 consecutive patients treated for localized prostate cancer with 3D-CRT between 1989 and 2002. Patients were grouped by dose: <70 Gy (n=43), 70-74.9 Gy (n=552), 75-79.9 Gy (n=568), and =80 Gy (n=367). Median follow-up ranged from 46 to 86 months. The =80-Gy group had a median follow-up of 45.6 months. That group was mixed, with 64 (17%) patients having low-risk cancer, 247 (67%) intermediate-risk, and 56 (16%) high-risk. Intermediate- and high-risk patients made up 44%, 46%, and 48% of the <70 Gy, 70-74.9 Gy, and 75-79.9 Gy groups, respectively. Adjusted 5-year estimates of freedom from biochemical failure (FFBF) for the 4 groups were 60%, 68%, 76%, and 84% using ASTRO 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 FFBF 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.
Therapy for Prostate Cancer After Prostatectomy
The 2012 Bauman systematic review found insufficient data to recommend IMRT over 3D-CRT after prostatectomy.
A 2013 joint American Urological Association and ASTRO guideline on 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 (Thompson, 2013). The panel’s comments on RT technique 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% 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.
Alongi et al 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 (Alongi, 2009). 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 higher acute GU or lower GI side effects were observed. Acute grade 2 GU occurred in 10 (12.3%) of 81 patients in the 3D-CRT group and in 6 (6.6%) of 91 in the IMRT group (p=0.19). For acute lower GI grade 2 events, the incidence was 7 (8.6%) of 81 patients in the 3D-CRT group versus 3 (3.3%) of 91 in IMRT (p=0.14) group. Acute upper GI grade 2 or higher toxicities were 18 (22.2%) of 81 patients and 6 (6.6%) of 91 patients in 3D-CRT and IMRT group, respectively (p=0.004). The authors concluded that acute toxicity following postoperative whole pelvis irradiation was reduced with IMRT compared to 3D-CRT; this effect was most significant for upper GI symptoms, owing mainly to better bowel sparing with IMRT.
Leite et al (2021) conducted a single-arm, phase 2 study that evaluated the safety and feasibility of postoperative hypofractionated RT with intensity-modulated and image-guided RT to the prostate bed in 61 patients who had undergone radical prostatectomy. Of these patients, 57 received salvage RT and 4 received adjuvant RT. The dose prescribed to the prostate bed was 51 Gy in 3.4 Gy daily fractions using IMRT and imaging guidance; all patients were treated with IMRT with volumetric arch therapy. After a median follow-up of 16 months, results revealed that 11.5% of patients experienced acute grade =2 GU symptoms and 13.1% experienced acute grade =2 GI symptoms. Late grade =2 GU and GI toxicity occurred at a rate of 8.2% and 11.5%, respectively. Three patients experienced a biochemical recurrence and the median time to the PSA nadir was 9 months. The actutimes biochemical failure-free survival was 95.1%.
In 2013, Massaccesi et al reported preliminary results of acute toxicities during a phase 2 trial of hypofractionated IMRT with simultaneous integrated boost (SIB) to the pelvic nodes and prostate bed after prostatectomy. Between November 2008 and February 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) to the prostate bed.
In 2014, initial results of the PLATIN 3 trial (Prostate and Lymph Node Irradiation with Integrated-Boost-IMRT after Neoadjuvant Antihormonal Treatment) were published (Katayama, 2014). This phase 2 trial evaluated the safety and feasibility of irradiating the pelvic lymph nodes simultaneously with a boost to the prostate bed. From 2009 to 2011, 40 patients with high-risk features or inadequate lymphadenectomy after radical prostatectomy were enrolled; 39 patients finished treatment. Treatment consisted of 2 months of antihormonal treatment before IMRT of the pelvic lymph nodes (51.0 Gy) with a SIB 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.
In 2014, acute toxicity results from the PRIAMOS1 (Hypofractionated Radiotherapy of the Prostate Bed With or Without the Pelvic Lymph Nodes) trial were reported (Katayama, Striecker, 2014) This prospective phase 2 trial assessed 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.
In 2013, Corbin et al reported adverse effects in high-risk men 2 years after IMRT post prostatectomy (Corbin, 2013). Between 2007 and 2010, 78 consecutive men received either adjuvant RT (n=17 [22%]) or salvage RT (n=61 [78%]). 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).
The toxicity findings were compared to 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 or greater 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 significant. No cases of grade 3 acute GI toxicity were reported. The authors concluded that the acute toxicity profile for hypofractionated high-dose SIB-IMRT after prostatectomy compared favorably with that of conventionally fractionated high-dose 3D-CRT.
Ongoing and Unpublished Clinical Trials
- NCT00326638 - Randomized Phase III Trial of 3D Conformal Radiotherapy Versus Helical Tomotherapy IMRT in High-Risk Prostate Cancer
- NCT03526510 - Randomized Trial of Concomitant Hypofractionated IMRT Boost Versus Conventional Fractionated IMRT Boost for Localized High Risk Prostate Cancer.
SUMMARY OF EVIDENCE
For individuals who have localized prostate cancer and are undergoing definitive radiotherapy (RT) who receive intensity-modulated radiotherapy (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 with regard to GI and GU toxicity. 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
The National Comprehensive Cancer Network guidelines (v.2023) 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. 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." NCCN also notes that more recent data have revealed that "moderately hypofractionated image-guided IMRT regimens (2.4 to 4 Gy per fraction over 4 to 6 weeks) have been tested in randomized trials, and their efficacy has been similar or non-inferior to conventionally fractionated IMRT. Overall, the panel believes that hypofractionated IMRT techniques, which are more convenient for patients, can be considered as an alternative to conventionally fractionated regimens when clinically indicated."
American Urological Association and American Society for Radiation Oncology
2013 American Urological Association (AUA) and American Society for Radiation Oncology (ASTRO) guidelines address the use of adjuvant and salvage radiotherapy (RT) after radical prostatectomy (Thompson, 2013). The guidelines state that adjuvant RT should be given to patients with adverse pathologic findings at prostatectomy and salvage RT to patients with prostate-specific antigen or local recurrence after prostatectomy if there is no evidence of distant metastases. However, the available data do not answer which RT technique and dose produces optimal outcomes in this setting.
American Society of Clinical Oncology
In 2019, the American Society for Radiation Oncology, American Society of Clinical Oncology, and American Urological Association published guidelines on hypofractionated EBRT in localized prostate cancer with the following recommendations (Morgan et al, 2019):
Recommendations on Hypofractionated EBRT in Localized Prostate Cancer
[RS: recommendation strength; QOE: quality of evidence; PC: prostate cancer]“In men with low-risk PC who decline active surveillance and receive EBRT to the prostate with or without radiation to the seminal vesicles, moderate hypofractionation should be offered.” RS: Strong. QOE: High. Consensus:100%
- “In men with intermediate-risk PC receiving EBRT to the prostate with or without radiation to the seminal vesicles, moderate hypofractionation should be offered.” RS: Strong. QOE: High. Consensus:100%
- “In men with high-risk PC receiving EBRT to the prostate, but not including pelvic lymph nodes, moderate hypofractionation should be offered.” RS: Strong. QOE: High. Consensus:94%
- “In patients who are candidates for EBRT, moderate hypofractionation should be offered regardless of patient age, comorbidity, anatomy, or urinary function. However, physicians should discuss the limited
- follow-up beyond 5 years for most existing RCTs evaluating moderate hypofractionation.” RS: Strong. QOE: High. Consensus:94%
- “Men should be counseled about the small increased risk of acute gastrointestinal toxicity with moderate hypofractionation.” RS: Strong. QOE: High. Consensus:100%
- “Regimens of 6000 cGy delivered in 20 fractions of 300 cGy and 7000 cGy delivered in 28 fractions of 250 cGy are suggested since they are supported by the largest evidentiary base.” RS: Conditional. QOE: Moderate. Consensus:100%
In 2019, the American Society for Radiation Oncology and American Urological Association published an amendment to their 2013 guideline on adjuvant and salvage radiation therapy after prostatectomy (Pisansky et al, 2019; Thompson et al, 2013). 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) on the use of hormone therapy with salvage RT and long-term data were used to update an existing statement (Statement 2) on adjuvant RT.
American College of Radiology
The American College of Radiology Appropriateness Criteria indicates IMRT is the standard for definitive external beam radiotherapy of the prostate (Nguyen, 2014).
REGULATORY STATUS
In general, intensity-modulated radiotherapy (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 for marketing by the U.S. Food and Drug Administration (FDA) through the 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 been cleared for marketing by FDA through the 510(k) process. They 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 cleared for marketing by FDA through the 510(k) process is the Varian IMRT system (Varian Medical Systems). FDA product code: IYE.