External beam radiation therapy for localized prostate cancer

INTRODUCTION — Standard options for the initial management of men with clinically localized prostate cancer include radiation therapy (RT; external beam [EBRT] and/or brachytherapy, with or without androgen deprivation therapy [ADT]), radical prostatectomy, or active surveillance in carefully selected patients. The choice of treatment is determined by a variety of factors, including risk stratification, patient preference, clinician judgment, and resource availability. (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

Although there are few randomized trials comparing RT with radical prostatectomy, the trials completed to date and observational data suggest that outcomes with either EBRT or brachytherapy (using adequate dosing schedules and contemporary treatment techniques) are similar to those with radical prostatectomy when men with clinically localized prostate cancer are stratified based on clinical tumor (T) stage, pretreatment serum prostate-specific antigen (PSA), and Gleason score [1,2].

The use of EBRT in the initial treatment of clinically localized prostate cancer will be reviewed here. The application of these techniques to men with low-, intermediate-, and high-risk prostate cancer is discussed separately, as is the role of brachytherapy for treatment of localized prostate cancer. (See "Initial approach to low- and very low-risk clinically localized prostate cancer" and "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement" and "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer".)

RISK STRATIFICATION AND THE SELECTION OF THE INITIAL TREATMENT APPROACH — The initial evaluation of men with suspected prostate cancer should include clinical staging based on a digital rectal examination by an experienced clinician to assess the extent of disease, a pretreatment serum prostate-specific antigen (PSA), the Gleason score/grade group in the initial biopsy, and the number and extent of cancer involvement in the biopsy cores. This information allows the stratification of men into clinical risk categories according to the primary tumor, as defined by the National Comprehensive Cancer Network (NCCN) (table 1). This risk stratification system has been utilized in guidelines for treatment of clinically localized prostate cancer from the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO), which have been largely endorsed by the American Society of Clinical Oncology (ASCO) [3-5].

Imaging studies (radionuclide bone scan, computed tomography [CT] of the abdomen and pelvis, multiparametric magnetic resonance imaging [MRI]) are used selectively to assess for extraprostatic extension, regional adenopathy, or distant metastases, depending on the initial clinical stage and estimate of risk. Imaging for distant disease is not routinely recommended for very low- and low-risk prostate cancer according to the clinical staging system described above, while skeletal scintigraphy and cross-sectional imaging (of the pelvis with or without abdominal imaging) are recommended for those with intermediate- and high-risk disease [3]. MRI of the prostate is often obtained in men with low- and very low-risk disease to ensure that high-grade disease has not been overlooked.

The Tumor, Node, Metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) uses the clinical stage of disease (or pathologic stage in those who have undergone prostatectomy), the baseline serum PSA, the histologic grade group (based on the Gleason score), and the extent of prostate involvement (as determined at the time of surgery) to divide patients into prognostic stage groups (table 2 and table 3). Among patients without distant metastases, these groups can also be used for selection of initial treatment according to risk, although we prefer to use the clinical risk categories as defined by the NCCN. It should be noted that detailed evaluation of histology, and the impact of tumor size (rather than just the number of positive cores) and gene expression profiling are not fully captured by these risk groups.

Guidelines from expert groups — In general, active surveillance is preferred for men with very low- or low-risk prostate cancer and a reasonable life expectancy, although definitive therapy could be offered to select patients with low-risk disease who may have a high probability of progression on active surveillance [3-5]. For men with higher risk disease and a reasonable life expectancy, definitive treatment using EBRT, with or without brachytherapy, or radical prostatectomy is an appropriate option.

The guidelines from the AUA/ASTRO/SUO and ASCO endorse shared decision making, which explicitly considers cancer severity (risk stratification), patient values and preferences, life expectancy, pretreatment general functional status and genitourinary symptoms, expected post-treatment functional status, and potential for salvage treatment [3-5].

Regarding the specific role of RT, the following recommendations are available from the AUA/ASTRO/SUO, which have largely been endorsed by ASCO [3-5]:

●Clinicians may offer single-modality EBRT or brachytherapy for patients who elect RT for low-risk prostate cancer.

●Clinicians may offer EBRT or brachytherapy, alone or in combination, for favorable intermediate-risk prostate cancer.

●Clinicians should offer androgen deprivation therapy (ADT) as an adjunct to either EBRT alone or EBRT combined with brachytherapy; clinicians should inform men that the addition of ADT increases the likelihood and severity of treatment-related effects on sexual function in most men and can cause other systemic side effects.

●Clinicians should inform men considering proton beam therapy that it offers no clinical advantage over other forms of definitive treatment.

●Clinicians should inform men with localized prostate cancer considering brachytherapy that it has similar effects to EBRT with regard to erectile dysfunction and proctitis but can exacerbate urinary obstructive symptoms. For men with intractable non-cancer-related obstructive lower urinary function, surgical approaches may be preferred. If RT is used for these patients or those with a previous significant transurethral resection of the prostate, low-dose-rate brachytherapy should be avoided.

Risk stratification and treatment options appropriate for each risk category are discussed in more detail separately. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer" and "Initial approach to low- and very low-risk clinically localized prostate cancer" and "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement".)

ANATOMIC CONSIDERATIONS — The goal of radiation therapy (RT) for men with localized prostate cancer is the delivery of a tumoricidal dose of radiation while minimizing radiation to the surrounding normal tissues [6].

RT planning must take into account the volume and anatomic distribution of both the tumor and the normal structures [7]. The prostate gland is a midline structure that lies in close proximity to the rectum and bladder. Thus, the major toxicities of normal tissue irradiation are gastrointestinal and genitourinary.

Definitive RT is usually delivered to the entire prostate gland because of the multifocal nature of prostate cancer and the inability to accurately localize all malignant areas within the gland by noninvasive means. Treatment fields are further individualized based on the estimated risk of seminal vesicle and regional lymph node involvement [8,9]. The lymphatic drainage of the prostate gland is through a periprostatic network that drains into both the external and internal iliac lymph nodes (together referred to as the pelvic nodes) [10,11].

Higher clinical stage, serum prostate-specific antigen (PSA) concentration, and Gleason score are associated with an increased risk of both seminal vesicle and pelvic lymph node involvement [12,13]. The serum PSA and Gleason score have been incorporated into the anatomic stage prognostic groups of the eighth (2017) Tumor, Node, Metastasis (TNM) staging system (table 2 and table 3). For patients at high risk of relapse, RT to the whole pelvis, which encompasses the bilateral lymph node regions, is sometimes utilized. (See "Localized prostate cancer: Risk stratification and choice of initial treatment" and "Initial staging and evaluation of males with newly diagnosed prostate cancer".)

OVERVIEW OF THE APPROACH TO RADIATION THERAPY — For all men choosing EBRT for treatment of clinically localized prostate cancer, treatment should be administered using contemporary conformal techniques. Our specific recommendations for treatment are consistent with guidelines from the American Society for Radiation Oncology (ASTRO), the American Society of Clinical Oncology (ASCO), and the American Urological Association (AUA) [3,14]:

●If intensity-modulated radiation therapy (IMRT) is available, we suggest its use over three-dimensional conformal radiation therapy (3D-CRT), particularly in men in whom pelvic nodal irradiation is being considered (ie, those with a predicted risk of pelvic nodal metastases of 15 percent or higher) and in those undergoing hypofractionated or ultrahypofractionated therapy. (See 'Intensity-modulated radiation therapy' below.)

●Where available, we suggest the use of image-guided radiation therapy (IGRT) for daily localization of the prostate prior to each treatment. (See 'Benefit of image-guided radiation therapy' below.)

●An adequate dose of radiation is necessary for optimal tumor control. For men undergoing conventional fractionation RT (1.8 to 2 Gy per fraction), we prefer a dose of 76 Gy or higher. (See 'Dose' below.)

For most men who do not need pelvic nodal irradiation, we suggest prostate RT be delivered using moderate hypofractionation RT rather than conventional fractionation RT. Given the greater potential for toxicity, we prefer conventional fractionation EBRT regimens if pelvic nodal irradiation is needed. Another option is to use moderate hypofractionation to treat the prostate, and conventional fractionation to treat the pelvic lymph nodes. Either approach is acceptable.

The optimal regimen for hypofractionation has not been established; several are endorsed, including 60 Gy in 20 fractions and 70 Gy in 28 fractions. (See 'Moderate hypofractionation' below.)

●We consider stereotactic body radiation therapy (SBRT) to be an appropriate alternative to conventional fractionation RT for carefully selected men with low- or intermediate-risk prostate cancer who do not need nodal irradiation. Outside of the context of a clinical trial, we suggest not pursuing SBRT for men with high-risk prostate cancer who have chosen EBRT, unless whole-pelvis irradiation is contraindicated and the logistics prohibit a conventional course. (See 'Stereotactic body radiation therapy (ultrahypofractionation)' below.)

●A role for charged particle irradiation, such as proton irradiation, as an alternative to EBRT is not established, and we suggest not pursuing this strategy outside of the context of a clinical trial. (See 'Particle irradiation' below.)

EXTERNAL BEAM RADIATION THERAPY TECHNIQUES — Conformal techniques, particularly intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT), are the contemporary standard of care when EBRT is used to treat localized prostate cancer. These conformal techniques allow higher doses to the target while minimizing radiation to normal tissues compared with older two-dimensional approaches. This improved targeting permits a decrease in toxicity and an improvement in the therapeutic index [15].

Three-dimensional conformal radiation therapy — Three-dimensional conformal radiation therapy (3D-CRT) delivers radiation to a three-dimensional volume using imaging studies and computer software to precisely target RT delivery by delineating the prostate gland and its surrounding structures. Because treatment margins are smaller than those with older techniques, the volume of normal tissue receiving a clinically significant radiation dose is reduced.

The prostate, rectum, and bladder are identified on axial pelvic CT images. Treatment planning computers then calculate the dose in three dimensions, and the beam arrangements are planned to the prostate target volume (the gross tumor volume [GTV]) plus a margin of grossly normal surrounding tissue, termed the clinical target volume (CTV) [16]. The planning target volume (PTV) is the final treatment volume that encompasses the GTV, the CTV, and a margin for any error that results from daily setup and prostatic motion [8,17]. Either multileaf collimation or Cerrobend blocks are used to shape the treatment portals. Dose-volume histograms, which are the visual representation of the dose received by a particular target volume, permit the radiation oncologist to assign a specific RT dose to a particular volume of tissue, maximizing the delivery of the highest doses to the areas at highest risk.

Conventional schedules for RT using highly conformal techniques use a daily dose of 1.8 to 2 Gy for 38 to 45 fractions (total dose ≥76 Gy).

Intensity-modulated radiation therapy — If IMRT is available, we suggest its use, particularly in men in whom pelvic nodal irradiation is being considered (ie, those with a predicted risk of pelvic nodal metastases of 15 percent or higher) and in those undergoing hypofractionated or ultrahypofractionated therapy.

IMRT is an advanced form of 3D-CRT that can create a dose distribution around a complex and irregular target volume (image 1 and figure 1) [18]. In contrast to 3D-CRT, in which a uniform intensity is administered to a defined field, IMRT delivers nonuniform beam intensities to the target volume by changing the intensity of the beam. The nonuniform beam intensity can be generated by varying the opening of the RT beam (collimator) with a fixed gantry position or by changing the beam opening during an arc [19]. Alternatively, the beam intensity in IMRT can also be modulated by the gantry speed, as in rotational/arc delivery approaches. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

IMRT can safely escalate the dose to the prostate while reducing complications from irradiation of the surrounding normal tissue, especially the rectum. The high degree of conformality of the RT field permits further dose escalation to the tumor target compared with 3D-CRT.

IMRT versus 3D-CRT — Intensity-modulated radiation therapy (IMRT) is considered the standard of care in RT treatment centers; in both the United States and Europe, it has largely replaced older forms of non-modulated three-dimensional conformal radiation therapy (3D-CRT) [20-22], and it is specifically recommended over 3D-CRT in patients undergoing moderately hypofractionated or ultrahypofractionated EBRT in a combined American Society for Radiation Oncology (ASTRO)/American Society of Clinical Oncology (ASCO)/American Urological Association (AUA) guideline [14]. (See 'Moderate hypofractionation' below.)

Although there are no randomized trials comparing IMRT with 3D-CRT, IMRT appears to be less toxic at equivalent tumor doses of radiation by reducing the exposure of normal tissue to radiation. Furthermore, IMRT may have important dosimetric advantages in treating pelvic lymph nodes [18,23], where it allows better coverage while reducing radiation to the rectum, colon, small bowel, bladder, and penile structures [24,25].

The toxicity of IMRT was compared with that of 3D-CRT in the high-dose arm of the Radiation Therapy Oncology Group (RTOG) 0126 prostate cancer trial [26]. In that study, 763 patients were randomly assigned to receive 79.2 Gy; of these, 257 were treated with IMRT, and 492 were treated with 3D-CRT. Grade 2 or higher genitourinary or gastrointestinal toxicity was significantly less frequent with IMRT compared with 3D-CRT (15.1 versus 9.7 percent).

IMRT may have increased toxicity when the escalated radiation doses are compared with the lower doses with older 3D-CRT techniques. In a single-institution series of 1571 men treated for localized prostate cancer, IMRT was used to treat 741 patients to a dose of 81 Gy, while 830 men were treated with 3D-CRT at lower doses (358 at ≤70.2 Gy and 472 at 75.6 Gy) [27]. Acute urinary symptoms requiring treatment were significantly more frequent with IMRT than 3D-CRT (37 versus 22 percent), while acute rectal symptoms were uncommon with either modality (3 and 1 percent, respectively). Late urinary tract toxicity (frequency or urgency, incontinence, hematuria, stricture) was significantly more frequent in patients treated with IMRT (20 versus 12 percent). Patients treated with IMRT had a significantly decreased frequency of grade ≥2 gastrointestinal toxicity at 10 years (5 versus 13 percent with 3D-CRT).

Whole-pelvis versus prostate-only radiation therapy — The pathologic status of the regional lymph nodes is typically unknown (pNX) in men with clinically localized prostate cancer who are managed with RT. Various clinical and pathologic parameters have been used to estimate the likelihood of regional lymph node involvement and thus select patients for whole-pelvis radiation therapy (WPRT) [28,29]. Based on currently available results, WPRT may be considered in cases with clinical lymph node involvement or in some cases where there is no clinical suspicion but the estimated risk of lymph node involvement is greater than 15 percent. There is no consensus on what tool to use to estimate which men have a risk of nodal involvement that exceeds 15 percent. Options include the Partin tables [30], the Roach formula [31], or other methods [32]. At some institutions, all men with grade group 4 or 5 disease (table 4) or a prostate-specific antigen (PSA) >20 mg/mL are referred for WPRT. However, this is a controversial area, and many radiation oncologists do not treat the pelvic lymph nodes electively, although most phase III trials conducted by the RTOG included WPRT (eg, RTOG 8531, 8610, 9202, and 9408 [75 percent of patients]).

The role of WPRT for men with intermediate- or high-risk disease is discussed in detail separately. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Whole-pelvis versus prostate-only radiation therapy'.)

Moderate hypofractionation — For most men who have chosen EBRT for treatment of localized prostate cancer, we suggest moderate hypofractionation RT over conventional fractionation RT if nodal irradiation is not needed. This recommendation is consistent with professional guidelines from ASTRO, ASCO, and the AUA [14]. Given the potential for greater toxicity with hypofractionated RT when the field includes the pelvic lymph nodes, we prefer conventional fractionation RT in these patients. Another option is to use moderate hypofractionation to treat the prostate, and conventional fractionation to treat the pelvic lymph nodes.

Men considering moderate hypofractionation RT should be counseled about the small increased risk of gastrointestinal, and possibly genitourinary, toxicity associated with this approach, which may not be clinically meaningful [33]. Furthermore, while acute genitourinary and late gastrointestinal/genitourinary toxicities appear to be similar, there is limited follow-up beyond five years for most of the randomized trials evaluating moderate hypofractionation. Some men who place a higher value on minimizing treatment-related toxicity and who are not bothered by the inconvenience of longer duration treatment might reasonably choose conventional fractionation RT.

The optimal regimen for hypofractionation has not been established; the AUA/ASTRO/ASCO guideline endorsed either 60 Gy in 20 fractions or 70 Gy in 28 fractions because these schedules were supported by the largest evidence base [14].

Preclinical studies suggest that prostate cancer differs from most other tumors in that larger fractions of EBRT might be more effective than conventional smaller fractions.

Multiple large randomized trials and a meta-analysis have evaluated the potential role of hypofractionated RT (in which a larger dose per fraction is given over a shorter time period, such as 60 Gy in 20 fractions), and the conclusion of most was that efficacy is not inferior with moderate hypofractionation [34-40]; only one trial has shown increased efficacy with hypofractionation [41].

There are conflicting data about whether hypofractionation increases overall treatment-related toxicity. A year 2019 Cochrane review of 10 randomized trials concluded that there is uncertainty as to the effect of hypofractionation on late gastrointestinal toxicity, and that there is probably little to no difference in late genitourinary toxicity or in acute genitourinary toxicity for hypofractionation versus conventional fractionation RT [38]. Most trials have shown a small increased risk of acute gastrointestinal toxicity with moderate hypofractionation [35-37,42], and two identified a somewhat-increased risk of late toxicity (HYpofractionated irradiation for PROstate cancer [HYPRO] and RTOG 0415):

●In the RTOG 0415 trial, 1115 patients with low-risk prostate cancer were randomly assigned to RT with conventional fractionation (73.8 Gy in 41 fractions over 8.2 weeks) or a hypofractionated regimen (70.8 Gy in 28 fractions over 5.6 weeks) [34]. The trial was designed to demonstrate the noninferiority of hypofractionation based on five-year disease-free survival, with hypofractionation being no more than 7.65 percent worse than conventional fractionation. At a median follow-up of 5.9 years, hypofractionation met the predefined criteria for noninferiority, with a five-year disease-free survival rate of 86.3 versus 85.3 percent with conventional fractionation (hazard ratio [HR] 0.85, 95% CI 0.64-1.14). However, hypofractionation was associated with a significantly increased rate of physician-reported, late, grade 2 and 3, gastrointestinal and genitourinary toxicity. Despite this, there were no significant differences in patient-reported prostate cancer-specific (eg, bowel, bladder, sexual) or general quality of life measures at 6, 12, 24, and 60 months after study entry [43].

●In the Dutch HYPRO trial, 820 patients with intermediate- or high-risk localized prostate cancer were randomly assigned to RT with conventional fractionation (39 fractions of 2 Gy over eight weeks) or hypofractionation (19 fractions of 3.4 Gy in 6.5 weeks) [40]. At a median follow-up of 60 months, there was no statistically significant difference in the five-year relapse-free survival rate (77.1 and 80.5 percent, respectively, for conventional and hypofractionated treatment; HR 0.86, 95% CI 0.63-1.16). Grade ≥2 gastrointestinal toxicity up to 120 days post-RT was more common with hypofractionation (42 versus 31 percent). The rate of grade ≥2 gastrointestinal toxicity at three years was higher in the hypofractionation group (22 versus 18 percent), as was that of high-grade (grade ≥3) genitourinary toxicity (19 versus 13 percent).

●On the other hand, additional data are available from the randomized phase II CHIRP trial in which 96 individuals with high-risk prostate cancer were randomly assigned to conventional (78 Gy in 39 fractions) versus hypofractionated (68 Gy in 25 fractions) RT; all received pelvic nodal RT [44,45]. At 24 months, there were no significant differences in patient-reported quality of life, and earlier significant differences in bowel bother and SF-12 physical component scores (some of which favored conventional fractionation, and some favoring hypofractionation) were no longer present.

Stereotactic body radiation therapy (ultrahypofractionation) — We consider stereotactic body radiation therapy (SBRT) to be an appropriate alternative to conventional fractionation RT for carefully selected men with low- or intermediate-risk prostate cancer who do not need nodal irradiation. This recommendation is consistent with published consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [46], as well as joint guidelines from ASTRO/ASCO and the AUA [14]. Patients may choose this treatment over conventional fractionation EBRT if they value a shorter treatment duration and are willing to accept a potentially higher toxicity profile, especially in the short term. Outside of the context of a clinical trial, we suggest not pursuing SBRT for men with high-risk prostate cancer who have chosen EBRT because of the potential for greater toxicity with SBRT to the prostate and whole pelvis as compared with prostate only SBRT [47].

SBRT is an extreme form of hypofractionation in which the entire dose of radiation is administered in five or fewer fractions when used as monotherapy, or typically in two fractions when used as a boost. This approach may be particularly useful for patients who benefit logistically from a very shortened, hypofractionated course (eg, patients who have a long commute to the center or a poor support system). (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

The available data on the efficacy and toxicity of SBRT for treatment of localized prostate cancer are as follows:

●In the Scandinavian HYPO-RT-PC trial, 1200 men with intermediate-risk or high-risk (11 percent of the total) prostate cancer were randomly assigned to conventional fractionation EBRT (78 Gy in daily 2 Gy fractions) or to SBRT (42.7 Gy in seven sessions of 6.1 Gy each, administered over 2.5 weeks) [48]. At a median follow-up of five years, the proportion of patients who were free of biochemical or clinical failure was similar (84 percent in both groups at five years). Patient-reported early side effects were more pronounced with hypofractionation, and physician-scored grade 2 or worse urinary toxicity was higher in this group at the end of RT (28 versus 23 percent). No significant increases in late, grade 2 or worse urinary or bowel toxicities were found, with the exception of a small increase in urinary toxicity at one year with hypofractionation (6 versus 2 percent).

On the other hand, a later analysis of patient-reported quality of life (QOL) concluded that SBRT was as well tolerated as conventional fractionation up to six years after completion of treatment [49]. There were no statistically significant differences in the proportion of men with clinically relevant acute urinary symptoms or problems of sexual function at the end of radiotherapy, although bowel problems were more pronounced and this had a small temporary adverse effect on QOL. Thereafter, there were no clinically relevant differences in urinary, sexual, or bowel function between the groups. At six-year follow-up, there was no difference in the incidence of clinically relevant deterioration between the two groups for urinary bother, overall bowel bother, overall sexual bother, or in global health/QOL scores.

●In the phase 3 noninferiority PACE-B trial, 874 men with low- or intermediate-risk prostate cancer were randomly assigned to fractionated IMRT or SBRT [50]. In contrast to the HYPO-RT-PC trial, SBRT was not associated with greater acute or longer duration genitourinary or gastrointestinal toxicities up to two years post-enrollment. Oncologic endpoints were not reported.

●Another report included 1100 patients who were treated in phase II protocols from eight institutions between 2003 and 2011 [51]. Low-, intermediate-, and high-risk patients constituted 58, 30, and 11 percent of cases. With a median follow-up of 36 months, the five-year actuarial biochemical relapse-free survival rates for the low-, intermediate-, and high-risk groups were 95, 84, and 81 percent, respectively. Among men with at least five years of follow-up, the five-year biochemical relapse-free survival rates for men with low- and intermediate-risk disease were 99 and 93 percent, respectively. Treatment-related toxicity was not reported.

Despite these favorable reports, median follow-up has been generally limited to three to five years in these and other reports [52,53], and concerns have been raised as to long-term outcomes and especially whether SBRT increases late genitourinary toxicity compared with IMRT.

Long-term outcomes and late toxicity have been addressed in the following studies:

●A cohort study analyzed individual patient data from 2142 men enrolled in 10 single-institution phase II trials and two multi-institutional phase II trials of SBRT for low- and intermediate-risk prostate cancer between January 2000 and December 2013 [54,55]. The median follow-up was 6.9 years. Seven-year cumulative rates of biochemical recurrence for low-risk disease (55 percent of those enrolled), favorable intermediate-risk disease, and unfavorable intermediate-risk disease were 4.5, 8.6, and 14.9 percent, respectively. The seven-year cumulative incidence of late, grade 3 or higher, genitourinary toxic events was 2.4 percent, and that of late, grade 3 or higher, gastrointestinal toxic events was 0.4 percent. These rates compare favorably with historical reports of long-term gastrointestinal and genitourinary toxicity after standard fractionation EBRT. (See 'Gastrointestinal' below and 'Urinary symptoms' below.)

●A systematic review of SBRT for localized prostate cancer included 38 trials and prospective series, totaling 6116 patients; the median follow-up was 39 months [52]. A meta-analysis of the 14 studies reporting biochemical recurrence-free survival indicated an overall five-year biochemical recurrence-free survival rate of 95.4 percent (95% CI 91.3-97.5). Of the studies that reported biochemical recurrence-free survival by risk group, five-year biochemical recurrence-free survival rates for low- and intermediate-risk disease were 96.7 (95% CI 95.2-97.8) and 92.1 (95% CI 89.2-94.3) percent, respectively. Estimated, late, grade ≥3 genitourinary and gastrointestinal toxicity rates were 2 (95% CI 1.4-2.8) and 1.1 (95% CI 0.6-2.0) percent, respectively. Increasing the dose of SBRT was associated with improved biochemical control but worse late genitourinary toxicity.

Taken together, these data support the safety and efficacy of SBRT as an alternative to conventional fractionation RT for carefully selected men. However, no study has directly compared SBRT with moderate hypofractionation RT, and a true understanding of the relative benefits and risks of SBRT compared with conventional fractionation or moderate hypofractionation regimens requires published results from randomized trials. Two ongoing randomized clinical trials are comparing SBRT versus conventional or moderately hypofractionated RT (NCT01794403 and NCT03367702). Eligible patients should be encouraged to enroll.

Benefit of image-guided radiation therapy — For men receiving EBRT for clinically localized prostate cancer, we suggest the use of IGRT rather than non-image-guided RT.

When RT is administered to the prostate, it is important to provide accurate localization of the prostate gland, which can vary on a day-by-day basis. IGRT is a technique that can be used either with 3D-CRT or IMRT and that acquires two- or three-dimensional images prior to each treatment, thus tracking the location of the tumor and the surrounding organs. IGRT is universally recommended when delivering IMRT, especially hypofractionated RT [14]. (See 'Moderate hypofractionation' above and 'Stereotactic body radiation therapy (ultrahypofractionation)' above.)

Commonly used imaging approaches to evaluate and track prostate position for IGRT include gold marker (fiducial) tracking with megavoltage portal imaging, kilovoltage imaging, abdominal ultrasound, cone beam CT, four-dimensional and cine magnetic resonance imaging, and radiofrequency transponder systems. Definitive benefit of one modality over another has not been shown [14].

Over the last several years, the use of IGRT in prostate cancer RT has grown substantially. Clinical evaluations comparing the benefits on local control and/or reduced toxicity with IGRT have been mixed; however, most reports suggest that patients treated with IGRT have less RT-related morbidity than those treated without IGRT [42,56-62]. As examples:

●IGRT was compared with non-image-guided therapy using older 3D-CRT techniques in 475 patients from the control arms of two randomized trials, both of which administered 78 Gy in 39 fractions [42,56,57]. Analyses of dose contours found a decrease in radiation dose to the bladder and anorectum with IGRT compared with non-image-guided 3D-CRT (33 versus 43 and 24 versus 45 Gy, respectively). During the first year post-treatment, IGRT was associated with a decrease in both grade ≥2 urinary and gastrointestinal toxicity (38 versus 48 and 29 versus 49 percent, respectively).

●A retrospective review of 275 men with prostate cancer treated before and after implementation of a fiducial marker IGRT program and dose escalation from 74 Gy in 37 fractions to 78 Gy in 39 fractions revealed fewer cases of severe urinary frequency (7 versus 23 percent), diarrhea (3 versus 15 percent), and fatigue (8 versus 23 percent) with IGRT [58]. Prostate cancer-specific endpoints were not reported.

These data are all from retrospective reports. Definitive evidence that IGRT reduces morbidity and improves the efficacy of prostate cancer treatment compared with older techniques will require carefully conducted clinical trials. Few are available:

●In one such example, daily IGRT control was significantly better than the use of weekly control in men undergoing RT for clinically localized prostate cancer in terms of both efficacy and toxicity endpoints [63].

●Data are also available from an analysis of the randomized phase II CHHiP trial (comparing conventional versus moderate hypofractionation) in which there was a second randomization of 293 men to IGRT with standard margins (IGRT), IGRT with reduced radiotherapy margins (IGRT-R), or no IGRT [62]. (See 'Moderate hypofractionation' above.)

The rectal and bladder dose volume were significantly lower with IGRT-R compared with IGRT-S. Although long-term toxicity rates were low overall, the cumulative proportion of patients with RTOG grades ≥2 bowel and urinary toxicity at two years was lowest for IGRT-R.

Clinical practice guidelines state that IGRT is recommended when delivering moderately hypofractionated or ultrahypofractionated RT regimens.

PARTICLE IRRADIATION — A role for particle irradiation as an alternative to EBRT is not established. Clinical practice guidelines from the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) and American Society of Clinical Oncology (ASCO) conclude that proton beam therapy offers no clinical advantage over other forms of definitive treatment [3,64].

Particle beams interact with tissue similarly to X-rays, but heavier particles, such as neutrons or carbon, cause greater levels of ionization per unit length and an increased radiobiologic effect compared with photons, which lack mass. The most extensive data are available for particle beams using protons; there is more limited, ongoing research with carbon ions. (See "Radiation therapy techniques in cancer treatment", section on 'Particle therapy'.)

Proton beam — The theoretical advantage of proton beam therapy is in its dose distribution. The physical characteristics of the proton beam result in the majority of the energy being deposited at the end of a linear track, in what is called the Bragg peak. The radiation dose then falls rapidly to zero beyond the Bragg peak. However, there can be some uncertainty about the exact location of the Bragg peak due to tissue inhomogeneities (eg, bone, air). Proton beam therapy thus permits the delivery of high doses of RT to the target volume while limiting the "scatter" dose received by surrounding tissues.

Versus external beam radiation therapy — Use of proton beam RT is expanding as more proton beam treatment centers open. However, there are no randomized trials comparing proton beam therapy with photon therapy or brachytherapy in men with clinically localized prostate cancer. A systematic review of the available evidence from ASTRO on efficacy and toxicity concluded that outcomes were similar with proton beam therapy and intensity-modulated radiation therapy (IMRT) using photons but did not demonstrate a benefit for the proton beam approach [65].

Results from large observational series include the following:

●An analysis from the Medicare-Surveillance, Epidemiology, and End Results (SEER) database identified 684 men treated with proton beam therapy between 2002 and 2007 and compared them with a cohort treated using IMRT [20]. IMRT was associated with significantly less gastrointestinal morbidity. However, there were no statistically significant differences in other toxicities, nor was there a significant difference in the frequency with which patients required additional cancer therapy.

●A retrospective analysis of early toxicity compared 421 men treated for prostate cancer with proton beam therapy with 842 matched controls treated with IMRT in the Medicare database [66]. Patients were treated from 2008 to 2009. There was a statistically significant decrease in genitourinary toxicity at six months, but this difference had disappeared by one year. There were no other significant differences in toxicity between the two techniques at either six months or one year. The costs associated with proton beam therapy were approximately 75 percent higher compared with those associated with IMRT.

●Another analysis compared outcomes in patients with localized prostate cancer treated between 1996 and 1999 with high-dose RT using photons plus proton beam therapy or brachytherapy [67]. There was no difference in the primary outcome, biochemical progression-free survival.

Carbon ion — Carbon ion RT is being evaluated, primarily in a series of studies in Japan, as an alternative form of particle irradiation to treat men with prostate cancer. In an analysis of 2157 patients treated at four institutions, the five-year biochemical relapse-free survival rates for low-, intermediate-, and high-risk disease were 92, 89, and 92 percent, respectively [68]. No grade 3 toxicities were observed, and the rates of grade 2 genitourinary and gastrointestinal toxicities were 4.6 and 0.4 percent, respectively. Others report less favorable results for high-risk disease [69].

One potential advantage of carbon ion over photon RT is a possible reduction in the risk of subsequent primary cancers (especially rectal cancers [70]), although the data are limited due to the small risk of subsequent primary malignancies in men receiving treatment for localized prostate cancer overall and the limited availability of carbon ion RT. However, this study was susceptible to huge selection bias.

ENDPOINTS FOR TREATMENT EFFICACY — A rising serum prostate-specific antigen (PSA) following radiation therapy (RT) is almost universally used as an endpoint for treatment failure and is termed a "biochemical recurrence." Men without a rise in serum PSA following treatment are considered to be biochemically with no evidence of disease (bNED). For men undergoing EBRT, the Phoenix criteria are used, which define biochemical recurrence as a rise in PSA of 2 ng/mL or more above the nadir, regardless of whether or not the patient receives androgen deprivation therapy (ADT). The date of failure is defined as the time the rise in PSA of ≥2 ng/mL is noted. Rebiopsy is only indicated if the serum PSA is rising and further local therapy is being considered.

Definition of biochemical recurrence — The definition of biochemical failure after definitive RT is complicated by the presence of the normal prostatic glandular tissue that remains following RT. Furthermore, the decline in serum PSA following RT is gradual, and the mean time for the PSA to reach its nadir is 18 months or longer. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'After radiation therapy'.)

In an effort to standardize the criteria used to define progression, a consensus panel convened by the American Society for Radiation Oncology (ASTRO) in 1996 established criteria for defining biochemical failure in patients who had been treated with EBRT [71]. These criteria were modified by ASTRO in 2005 into the so-called Phoenix criteria, which are now widely used for patients treated with RT [72]. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Definition of biochemical progression'.)

The Phoenix criteria define biochemical (PSA) failure as a rise in serum PSA of 2 ng/mL or more above the nadir, regardless of whether or not the patient receives ADT. The date of failure is defined as the time the rise in PSA of ≥2 ng/mL above the nadir is observed. This definition, however, was not designed to determine cure rates but rather the presence of a clinically significant recurrence, and thus, it should not be used to compare RT with other modalities.

Another commonly used surrogate endpoint is the interval to biochemical failure (IBF) [73-75]. Both time to biochemical failure and the PSA doubling time are useful surrogate endpoints for prostate cancer-specific mortality in men undergoing prostate RT with or without ADT [73,74,76].

Although biochemical failure is a surrogate for prostate cancer-specific death, a PSA relapse does not necessarily predict the development of metastases or death. In many cases, the natural history of disease is very prolonged, and overt metastatic disease may not become evident for many years after a rising serum PSA is detected. The natural history of disease in men with an isolated rising serum PSA and without clinical evidence of metastases is discussed separately. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Risk of metastases or death'.)

Post-treatment biopsy — Prostate rebiopsy is not a routine component of follow-up after primary treatment with RT. Rebiopsy is only indicated if the serum PSA is rising and further local therapy is being considered, since some of these men are curable with salvage retreatment (eg, surgery, brachytherapy). (See "Follow-up surveillance after definitive local treatment for prostate cancer" and "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)

The time course of the disappearance of viable cancer from the prostate following RT can be prolonged. This is thought to be due to the long doubling time of many prostate tumors and the observation that cell death following RT is a postmitotic event. As a result, false-positive biopsies may be due to delayed tumor regression, and indeterminate biopsies (showing either atypical cells or a radiation effect in tumor cells) are of uncertain significance. Nonetheless, the persistence of viable-appearing tumor cells beyond 18 months does appear to predict a greater likelihood of treatment failure [77-80].

The histologic changes induced by RT and the difficulty of accurate interpretation of a prostate biopsy following RT are discussed separately.

FACTORS AFFECTING OUTCOME

Dose — Conformal radiation therapy (RT) techniques permit escalation of radiation doses to the prostate gland beyond the lower doses used with older techniques. (See 'External beam radiation therapy techniques' above.)

Conventional schedules for RT using highly conformal techniques use a daily dose of 1.8 to 2 Gy for 38 to 45 fractions. Multiple trials have examined the importance of dose and have confirmed the added benefit of dose escalation in preventing biochemical failure after definitive RT.

The most comprehensive data on the impact of dose when conformal techniques are used come from the Radiation Therapy Oncology Group (RTOG) 0126 trial, in which 1499 eligible patients with localized prostate cancer were randomly assigned to treatment with either 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions, using either three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) [81]. With a median follow-up of 8.4 years, the eight-year biochemical failure rates using the Phoenix criteria were 20 and 35 percent for the 79.2 and 70.2 Gy regimens, respectively. The eight-year distant metastasis rates were 4 and 6 percent, respectively. However, there were no statistically significant differences in overall survival (eight-year overall survival 76 versus 75 percent). The five-year rates of late, grade ≥2, gastrointestinal or genitourinary toxicity were greater with the higher dose of RT (21 versus 15 and 12 versus 7 percent, respectively).

Newer techniques using image-guided radiation therapy (IGRT), proton beam irradiation, hypofractionation, and combined EBRT plus brachytherapy have allowed further dose escalation, and doses greater than 81 Gy can be safely administered to the prostate gland [82]. These different approaches have not been compared in randomized trials. Whether these higher doses further improve efficacy remains uncertain [82-84].

Benefit of an intraprostatic boost — The benefit of dose escalation using a focal boost to the intraprostatic tumor was addressed in the phase III FLAME trial in which 571 men with intermediate- or high-risk cancer undergoing image-guided IMRT or volumetric modulated arc therapy (77 Gy in daily 2.2 Gy fractions over seven weeks) were randomly assigned to receive or not receive a simultaneous integrated focal boost up to 95 Gy to the macroscopic tumor as visible on multiparametric magnetic resonance imaging (resulting in 35 fractions of up to 2.7 Gy each) [85]. At a median follow-up of 72 months, biochemical disease-free survival (bDFS), the primary endpoint, was significant longer in those who received the boost (hazard ratio 0.45, 95% CI 0.28-0.71; five-year bDFS 92 versus 85 percent). The cumulative incidence of late grade ≥2 genitourinary or gastrointestinal toxicity was slightly but not significantly higher in the boost group (28 versus 23, and 13 versus 12 percent, respectively), and health-related quality of life was similar.

While these data provide some support for boost strategies, treatment delivery over seven weeks is outdated, and this approach cannot be recommended.

Schedule

Treatment delays — Treatment delays that increase the overall treatment time may be a significant factor influencing the rate of biochemical failure:

●In a multicenter retrospective analysis of 4338 men treated with EBRT for T1 or T2 prostate cancer in the prostate-specific antigen (PSA) era, a statistical increase in biochemical failure was seen with longer overall treatment duration [86]. This effect was limited to cases in which the total radiation dose was ≥70 Gy.

●Similar conclusions were drawn in a separate analysis of 1796 men with prostate cancer treated with RT alone [87]. Treatment breaks resulting in a nontreatment day ratio of ≥33 percent (eg, four or more breaks during a 40-fraction treatment five days per week) significantly worsened the 10-year rate of freedom from biochemical failure.

Delays should be avoided during treatment if at all possible.

Hypofractionation — A moderately hypofractionated schedule (a larger dose per fraction given over a shorter time period, such as 60 Gy in 20 fractions) appears to offer similar efficacy to conventional schedules (eg, 76 Gy in 38 fractions), without an increase in late toxicity. The trials that support this point of view are discussed above. (See 'Moderate hypofractionation' above.)

Ultrahypofractionated RT is also referred to as stereotactic body radiation therapy (SBRT). SBRT is an appropriate alternative to conventional fractionation RT for carefully selected men with low- or intermediate-risk prostate cancer who choose EBRT and do not need pelvic nodal RT. There are no published data comparing SBRT with moderate hypofractionation regimens.

Rectal separation — Minimizing the radiation dose to the rectum while maintaining a full dose of therapy to the prostate is important to limit gastrointestinal complications. (See 'Gastrointestinal' below.)

The injection of a hydrogel spacer to increase the distance between the rectum and prostate has been used to decrease the dose of radiation to the rectum. In a randomized, single-blinded trial, the use of a hydrogel spacer in conjunction with image-guided IMRT did decrease late rectal toxicity (5 percent fewer grade 1 toxicities; of dubious value) as well as improve bowel function quality of life [88,89]. There were no reported adverse events related to the use of rectal separation in this trial.

Despite these favorable reports, more recent data from a review of the Manufacturer and User Facility Device Experience (MAUDE) database have raised concerns about the potential for severe complications in proximity to gel injections [90].

Given the modest degree of benefit and the conflicting data regarding toxicity, we can neither support nor refute the use of this device.

Concurrent androgen deprivation therapy — The use of androgen deprivation therapy (ADT) in combination with EBRT has become the standard of care for men receiving RT for high- and intermediate-risk prostate cancer, based on improvements in cancer-specific and overall survival observed in multiple randomized trials. The optimal duration and timing (ie, starting before RT versus concurrently) are controversial areas. The results supporting the role of ADT in these patients and the specific details regarding the duration and timing of ADT are discussed separately. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Role of concurrent ADT'.)

COMPLICATIONS — The morbidity of EBRT is low in patients treated with contemporary techniques. In order to quantify treatment-related morbidity, the Radiation Therapy Oncology Group (RTOG) has developed clinician-report-based acute and late morbidity scales (table 5) [91]. Morbidity based on patient-reported scores usually exceeds that reported by clinicians [92].

The complications of EBRT are discussed here.

Gastrointestinal — Acute gastrointestinal toxicity during RT can manifest as proctitis or enteritis. The reported incidence of radiation proctitis ranges from 5 to 30 percent depending on the definition used, the dose of radiation, and the treatment volume.

Symptoms include abdominal cramping, tenesmus, urgency, and frequency of defecation. They can usually be controlled with antidiarrheal agents or topical anti-inflammatory preparations. After RT is completed, acute symptoms usually resolve within three to eight weeks. (See "Radiation proctitis: Clinical manifestations, diagnosis, and management" and "Overview of gastrointestinal toxicity of radiation therapy".)

Long-term gastrointestinal side effects persist in a low percentage of patients and can manifest as persistent diarrhea, tenesmus, rectal urgency, or hematochezia [93,94]. Rectal or anal strictures, fecal incontinence, ulcers, and perforation are rare. In several large trials, the incidence of grade 3 or greater toxicity in men treated with high-dose RT (≥74 Gy) was 1 to 5 percent [95-99].

However, when highly conformal RT beams are used and the dose to the rectum is limited, the rate of moderate to severe gastrointestinal effects with high-dose RT approaches is similar to that seen among men who receive lower doses of RT [96-98,100].

Urinary symptoms — During EBRT, approximately one-half of patients experience urinary symptoms, which may include frequency, dysuria, and/or urgency due to cystitis, urethritis, or both [95-99]. Symptoms typically resolve within four weeks after the completion of therapy.

Late urinary tract side effects are relatively uncommon in contemporary series. The incidence of urinary incontinence is probably approximately 1 percent in men without a history of prior prostate surgery, although this may vary depending on the definition [92,93,101-103]. In patients who had severe obstructive or irritative symptoms prior to treatment, EBRT may eventually improve functional status, presumably by decreasing prostate size [104].

Other long-term genitourinary toxicities include urethral strictures, cystitis, hematuria, and bladder contracture [105]. In a review of two RTOG randomized trials of EBRT for prostate cancer, the incidence of late, grade 3 or worse, genitourinary toxicity was 8 percent [106]. One-half of these were attributed to urethral stricture that could be managed with outpatient dilation.

Risk of hemorrhage in anticoagulated patients — Men who are on anticoagulation appear to be at increased risk of hemorrhage from either radiation cystitis or radiation proctitis. In a single-institution retrospective series of 568 men treated with definitive EBRT (either three-dimensional conformal radiation therapy [3D-CRT] or intensity-modulated radiation therapy [IMRT]), the four-year risk of grade 3 or worse bleeding was significantly higher among the 79 men on either warfarin or clopidogrel compared with those not anticoagulated (15.5 versus 3.6 percent) [107]. Gastrointestinal bleeding was more common than urinary tract bleeding. Such bleeding is generally self-limited and rarely requires transfusion. The evaluation and management of hemorrhagic cystitis after cancer treatment are addressed in detail elsewhere. (See "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients".)

Sexual dysfunction — The assessment of the frequency of erectile dysfunction in men treated with RT has been studied extensively.

A validated model has been developed to help predict the probability of erectile function two years after EBRT; significant factors in this analysis included planned neoadjuvant hormone therapy (yes or no), pretreatment prostate-specific antigen (PSA) level (<4 versus ≥4 ng/mL), and pretreatment sexual health-related quality of life [108]. (See "Epidemiology and etiologies of male sexual dysfunction" and "Approach to older males with low testosterone" and 'Concurrent androgen deprivation therapy' above.)

The frequency of new-onset impotence following EBRT depends in part on the definition of potency and on the time frame of assessment [92]. In contemporary series, 30 to 45 percent of men who are potent prior to RT become impotent after therapy, with the frequency increasing over time [101,102,109].

Technical aspects of RT delivery may contribute to radiation-induced impotence [110-114]. The literature suggests that the risk of impotence is significantly reduced if penile structures (particularly the corpus spongiosum) are avoided [110]. More sophisticated forms of RT delivery, such as IMRT, may limit the dose to the penile bulb and corporal bodies compared with 3D-CRT [115]. (See 'Intensity-modulated radiation therapy' above.)

Phosphodiesterase inhibitors (sildenafil, vardenafil, tadalafil) are more effective than placebo in treating erectile dysfunction in men treated with EBRT [116-119]. (See "Treatment of male sexual dysfunction", section on 'Initial therapy: PDE5 inhibitors'.)

The daily use of phosphodiesterase inhibitors for penile rehabilitation during and after RT has been studied in two relatively large randomized trials, but the value of this approach remains uncertain. (See "Radical prostatectomy for localized prostate cancer", section on 'Penile rehabilitation'.)

●In one trial, 242 patients were assigned to either tadalafil or placebo for 24 weeks beginning with and continuing after RT (either EBRT or brachytherapy) [120]. Although the frequency of spontaneous erections with tadalafil was increased at 28 to 30 weeks compared with placebo (79 versus 74 percent), the difference was not statistically significant, and there was essentially no difference between the two groups at one year (72 versus 71 percent).

●In a second trial, 279 men were randomly assigned in a 2:1 ratio to either sildenafil or placebo, and 202 received treatment [121]. Patients were treated with EBRT and/or brachytherapy, and 10 percent of patients received neoadjuvant androgen deprivation therapy (ADT). Daily sildenafil or placebo was continued for six months. The primary endpoint of the trial was erectile function at 24 months. There was a statistically significant improvement in erectile function at 12 months with sildenafil, but this difference was no longer present at 18 and 24 months.

Fatigue — Fatigue is common following RT. Prospective studies have shown that fatigue is present prior to treatment in men with prostate cancer and that its incidence and severity increase during treatment [122,123]. Two randomized trials found that aerobic and resistance exercise ameliorated fatigue in the short term, and resistance exercise may offer additional conditioning benefits [124,125]. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment", section on 'Radiation therapy'.)

Insufficiency fractures — Insufficiency fractures are a subtype of stress fracture that can result from physiologic stress to weakened bone. These uncommonly occur following EBRT for prostate cancer. These fractures are thought to be due to radiation injury to the microcirculation in bone.

In a retrospective series of 134 patients treated for prostate cancer, clinically symptomatic insufficiency fractures were diagnosed in eight (6 percent) [126]. All had been treated with whole-pelvis 3D-CRT or IMRT for locally advanced disease or positive regional lymph nodes. Seven of the eight had also been treated with ADT, which may have contributed to the risk of insufficiency fractures. (See "Side effects of androgen deprivation therapy", section on 'Osteoporosis and bone fractures'.)

Patients presented with low back or pelvic pain and were diagnosed at a median of 20 months after RT. On imaging studies, all had fractures in the sacrum, and pubic bone involvement was present as well in two cases. All patients were managed with rest and analgesics.

None of the patients had biochemical or imaging evidence of metastatic disease when they presented with insufficiency fractures or during subsequent follow-up (median 40 months). Characteristic findings on imaging studies may be useful in distinguishing insufficiency fractures from bone metastases [127].

Secondary malignancies — Although RT appears to be associated with a small increase in the incidence of bladder and rectal cancer, the risk of dying from a secondary malignancy at 10 to 15 years is very small and appears to be of similar magnitude to that seen after radical prostatectomy [128-131].

The most extensive data come from a systematic review of the literature that incorporated data from 19 tumor registry studies, 21 institutional studies, and 6 studies that reported mortality due to second primary malignancies [128]. Although the results varied from study to study, the authors concluded that there was a small increase in the risk of both bladder and rectal cancer in patients treated with EBRT when compared with prostate cancer patients not receiving RT. However, these differences were not consistently present in studies comparing the cancer incidence with that in the general population. In addition, since most of these studies used surgically treated patients as a control group to patients treated with EBRT, and patients treated with radical prostatectomy have a hazard ratio of 0.45 for second cancers, this may have led to gross overestimation of the true risk of radiation-induced cancer [129].

The systemic review found significant heterogeneity between the different reports, and the interpretation of the data was complicated by a number of factors, including the use of older RT techniques with larger treatment fields in many series, the variable duration of follow-up, and the use of different comparators (general population versus prostate cancer patients not treated with RT).

There are limited data regarding the risk with more modern techniques that use smaller fields. A retrospective cohort study of patients with prostate cancer found similar rates of secondary malignancies in patients treated with IMRT compared with 3D-CRT. This study used data from the Surveillance, Epidemiology, and End Results (SEER) program that included males diagnosed with prostate cancer between 2002 and 2013 and reported an overall hazard ratio of secondary malignancy for IMRT versus 3D-CRT of 0.91 (95% CI 0.83-0.99) [132].

The risk of therapy-related myeloid neoplasms was analyzed in a retrospective analysis of 10,924 patients treated for prostate cancer between 1986 and 2011 [133]. Therapy consisted of EBRT, brachytherapy, or radical prostatectomy in 2183 (20 percent), 2936 (27 percent), and 5805 (53 percent) cases, respectively. Myelodysplastic syndrome was diagnosed in 31 cases; there was no statistically significant difference between the treatment groups, nor was there an increased incidence compared with population-based registries. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

SURVEILLANCE AFTER TREATMENT — Surveillance strategies after treatment for localized prostate cancer are discussed separately. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of prostate cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Radiation therapy (The Basics)" and "Patient education: Choosing treatment for low-risk localized prostate cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Risk stratification and choice of treatment

•Clinical staging based on a digital rectal examination by an experienced clinician, serum prostate-specific antigen (PSA), the Gleason score/grade group in the initial biopsy, and the extent of cancer involvement in the biopsy cores allows the stratification of men into clinical risk categories according to the primary tumor, as defined by the National Comprehensive Cancer Network (NCCN) (table 1). (See 'Risk stratification and the selection of the initial treatment approach' above.)

Imaging studies (radionuclide bone scan, CT of the abdomen and pelvis, prostate MRI) and positron emission tomography scans are used selectively to assess for extraprostatic extension, regional adenopathy, or distant metastases, depending on the initial clinical stage and estimate of risk.

•In general, active surveillance (AS) is preferred for men with very low- or low-risk prostate cancer and a reasonable life expectancy, although definitive therapy could be offered to select patients with low-risk disease who may have a high probability of progression on AS. For men with higher risk disease and a reasonable life expectancy, definitive treatment using external beam radiation therapy (EBRT), with or without brachytherapy, or radical prostatectomy is appropriate.

The choice of EBRT is largely a matter of patient preference. Long-term outcomes with contemporary EBRT techniques that use high radiation doses and conformal treatment planning, combined with androgen deprivation therapy (ADT) for those with higher risk disease, appear similar to those with radical prostatectomy. (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

●General principles of EBRT

•For all men choosing EBRT, treatment should be administered using contemporary conformal techniques (see 'External beam radiation therapy techniques' above):

-We suggest use of intensity-modulated RT, where available, particularly if pelvic nodal irradiation is being considered and in those undergoing hypofractionated or ultrahypofractionated RT (Grade 2C). (See 'Intensity-modulated radiation therapy' above.)

-Where available, we suggest the use of image-guided radiation therapy for daily localization of the prostate prior to each treatment (Grade 2C). (See 'Benefit of image-guided radiation therapy' above.)

-For men who choose conventional fractionation RT, the dose should be ≥76 Gy given using 1.8 to 2 Gy daily fractions. (See 'Dose' above.)

-For most men who do not need whole-pelvis radiation therapy to treat the pelvic lymph nodes, we suggest moderate hypofractionation RT over conventional fractionation RT (Grade 2B). Given the potential for greater toxicity with hypofractionated RT when the field includes the pelvic lymph nodes, we prefer conventional fractionation RT in these patients. Another option is to use moderate hypofractionation to treat the prostate, and conventional fractionation to treat the pelvic lymph nodes. Either approach is acceptable.

Men considering moderate hypofractionation RT should be counseled about the possible small increased risk of acute gastrointestinal toxicity associated with this approach, and the limited available information beyond five years for most of the randomized trials. Some men who place a higher value on minimizing treatment-related toxicity and who are not bothered by the inconvenience of longer duration treatment might reasonably choose conventional fractionation rather than hypofractionated RT.

The optimal regimen for hypofractionation treatment of the prostate has not been established; several are endorsed, including 60 Gy in 20 fractions and 70 Gy in 28 fractions. (See 'Moderate hypofractionation' above.)

-Stereotactic body radiation therapy (SBRT; ultrahypofractionated RT) is an appropriate alternative to conventional fractionation RT for carefully selected men with low- or intermediate-risk prostate cancer who do not need nodal irradiation. Patients may choose this option if they value a shorter treatment duration and are willing to accept a potentially higher toxicity profile, especially in the short term. Outside of the context of a clinical trial, we do not offer SBRT to men with high-risk prostate cancer. (See 'Stereotactic body radiation therapy (ultrahypofractionation)' above.)

•A role for particle irradiation as an alternative to external beam RT is not established, and we suggest not pursuing this strategy outside of the context of a clinical trial (Grade 2C). (See 'Particle irradiation' above.)

●Endpoints for treatment efficacy

•The efficacy of EBRT is assessed using the Phoenix criteria, which define biochemical recurrence as a rise in serum PSA of 2 ng/mL or more above the nadir, regardless of whether or not the patient receives ADT. The date of failure is defined as the time the rise in PSA of ≥2 ng/mL is noted. (See 'Definition of biochemical recurrence' above.)

•Rebiopsy is only indicated if the serum PSA is rising and further local therapy is being considered.

●Complications – The most frequent complications due to EBRT are gastrointestinal (radiation proctitis and enteritis), urinary (frequency, dysuria, and/or urgency due to cystitis, urethritis, or both), and sexual dysfunction. (See 'Complications' above.)

ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.