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Initial approach to low- and very low-risk clinically localized prostate cancer

Initial approach to low- and very low-risk clinically localized prostate cancer
Literature review current through: Jan 2024.
This topic last updated: Mar 31, 2023.

INTRODUCTION — Most prostate cancers now are diagnosed while clinically localized, based mostly on the widespread use of serum prostate-specific antigen measurement. Treatment planning needs to incorporate the natural history of the disease and the risk of progression, since many of these cancers are biologically indolent and may never threaten the health or life of the patient.

For patients diagnosed with prostate cancer confined to the prostate, standard management options include radical prostatectomy, radiation therapy (external beam, brachytherapy), and for carefully selected patients with very low-risk, low-risk, or favorable intermediate-risk disease, active surveillance.

Key factors in choosing treatment for a male with very low- and low-risk prostate cancer include the likelihood of recurrence or metastasis following treatment (risk stratification), the patient's age and life expectancy, the presence or absence of significant comorbidity, and patient preferences. (See "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Risk stratification'.)

This topic discusses the initial management approach for males with very low- and low-risk prostate cancer. The approach to treatment of males with intermediate- and high-risk prostate cancer, locally advanced (very high-risk) disease, and stage IV disease (clinical lymph node involvement or disseminated metastases) is discussed separately:

(See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement".)

(See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer".)

RISK STRATIFICATION AND SELECTION OF THE INITIAL APPROACH — The initial evaluation of males 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 males 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) and the American Society of Clinical Oncology (ASCO) [1,2].

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 (including positron emission tomography scans using one of the new prostate-specific radiotracers) 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 [1]. MRI of the prostate is often obtained in males with low- and very low-risk disease to ensure that high-grade disease has not been overlooked. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer" and "The role of magnetic resonance imaging in prostate cancer".)

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 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 a 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. (See "Molecular prognostic tests for prostate cancer".)

In general, active surveillance is preferred for most males with very low-risk or low-risk prostate cancer and a reasonable life expectancy in the absence of certain histologic features (areas of cribriform or intraductal cancer) and low-risk gene expression profiles. (See "Molecular prognostic tests for prostate cancer" and "Interpretation of prostate biopsy", section on 'Gleason 8, grade group 4' and "Interpretation of prostate biopsy", section on 'Presence of a special subtype of cancer'.)

For males with higher risk disease and a reasonable life expectancy, definitive treatment using external beam radiation therapy, brachytherapy, or radical prostatectomy is an appropriate option. Guidelines from the AUA/ASTRO and ASCO endorse shared decision making that explicitly considers cancer severity (risk stratification), patient values and preferences, life expectancy, pretreatment general functional status and genitourinary symptoms, expected posttreatment functional status, and potential for salvage treatment [1,2].

TREATMENT APPROACHES — The relative advantages and disadvantages of different treatment approaches for males with newly diagnosed low-risk and very low-risk prostate cancer are discussed in this section. Standard treatment approaches include active surveillance, external beam radiation therapy (RT), brachytherapy, and radical prostatectomy.

Very low risk — For most males with clinically localized, very low-risk prostate cancer, we suggest active surveillance rather than immediate definitive therapy. However, this approach is associated with a need for close follow-up and may create significant anxiety, causing some patients to subsequently choose definitive intervention even in the absence of progressive disease. As such, this approach is appropriate for males who meet the biologic criteria of low risk for metastasis (in the absence of certain histologic features [areas of cribriform or intraductal cancer] and low-risk gene expression profiles) and have psychologic comfort with active surveillance. Some males may still choose to be treated (RT or radical prostatectomy) even in the presence of very low-risk disease.

Active surveillance — Active surveillance is defined as the postponement of immediate definitive therapy, with curative-intent treatment instituted if there is clinical evidence of disease progression. Active surveillance is an appropriate management option for most patients with prostate cancers that are small, have a low Gleason grade, and thus, have a relatively low risk of progression (National Comprehensive Cancer Network [NCCN] very low- and low-risk groups (table 1); tumor, node, metastasis [TNM] anatomic prognostic group I (table 2 and table 3)).

The goal of active surveillance is to avoid treatment-related complications for males whose cancers are not likely to progress. For many males, such disease either never requires treatment or treatment can be postponed for a prolonged period without significantly decreasing the chance of cure. (See "Active surveillance for males with clinically localized prostate cancer", section on 'Rationale for active surveillance'.)

Active surveillance must be distinguished from "watchful waiting," which is based on the premise that some males will not benefit from definitive treatment of their localized prostate cancer [3]. For patients managed with watchful waiting, the decision is made at the outset that the patient is not a candidate for definitive therapy and to provide palliative treatment (typically androgen deprivation therapy [ADT]) if and when symptomatic progression requires therapy. Watchful waiting may be an acceptable alternative for males with a short life expectancy based on age and/or substantial comorbidity. (See "Prostate cancer in older males" and "Radical prostatectomy for localized prostate cancer", section on 'Survival impact of radical prostatectomy'.)

The available evidence suggests that for appropriately selected males with very low- and low-risk prostate cancer that outcomes from active surveillance are similar to those in patients who undergo immediate definitive therapy, with better quality of life based on the avoidance of treatment-related side-effects. (See 'Evidence' below.)

Given these data, and because of the potential for side effects associated with aggressive treatment of indolent disease, active surveillance is the preferred option for patients with very low-risk prostate cancer and an estimated life expectancy >10 years in consensus-based guidelines from the NCCN [4]; these guidelines also state that observation (watchful waiting) is preferred for males with very low-risk prostate cancer and an estimated life expectancy <10 years. Guidelines 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), state that active surveillance is the best available care option for males with very low-risk localized prostate cancer [1,5].

Consistent with these guidelines, data from the Surveillance, Epidemiology, and End Results (SEER) database indicate that the use of active surveillance or watchful waiting for males with very low- and low-risk prostate cancer increased in the United States from 2010 to 2015, and this approach has now become the most commonly used treatment for very low- and low-risk localized prostate cancer (used in approximately 42 percent of patients, compared with approximately 31 percent undergoing radical prostatectomy and 27 percent undergoing RT) [6].

However, in our view, immediate definitive treatment with RT or radical prostatectomy remains an alternative for patients desiring a more definitive approach. Although active surveillance avoids side effects in the short term, it does induce significant concerns and anxiety. Many males who initially choose active surveillance decide on definitive treatment within one to two years despite the absence of progression.

The key issues for patients who may be candidates for active surveillance include:

Appropriate patient selection

The frequency and type of monitoring required during surveillance and the ability and desire to comply with a surveillance schedule

Criteria for initiating definitive therapy

These issues are discussed elsewhere. (See "Active surveillance for males with clinically localized prostate cancer".)

Low risk — For males with low-risk prostate cancer and a life expectancy greater than 10 years, definitive therapy (radical prostatectomy, brachytherapy, or external beam RT) or active surveillance may be an appropriate option. The choice of a specific approach requires a consideration of the benefits and risks associated with each approach, taking into account the patient's individual preferences and comorbidities, the histology of the tumor, and molecular testing.

For most patients, especially those with a limited life expectancy (less than 10 years), we suggest active surveillance rather than immediate definitive therapy. However, immediate definitive treatment with RT or radical prostatectomy remains an alternative for patients desiring a more aggressive approach who have a life expectancy >5 years.

Active surveillance — Because of the potential for side effects associated with aggressive treatment of indolent disease, active surveillance (as defined in the above paragraphs) is the preferred option for patients with low-risk prostate cancer and an estimated life expectancy ≥10 years in guidelines from the NCCN [4]; they also state that observation (watchful waiting) is preferred for males with low-risk prostate cancer and an estimated life expectancy <10 years. Guidelines from the AUA/ASTRO/SUO, which are endorsed by ASCO, state that active surveillance is a preferred care option for most males with low-risk prostate cancer, but that observation (watchful waiting) should be recommended for males with a life expectancy ≤5 years [1,5]. Active surveillance is a reasonable option, even for appropriately selected younger males [7,8]. (See "Active surveillance for males with clinically localized prostate cancer".)

As noted above, consistent with these guidelines, SEER data indicate that the use of active surveillance or watchful waiting for males with very low- and low-risk prostate cancer increased in the United States from 2010 to 2015, and this approach has now become the most commonly used treatment for very low- and low-risk localized prostate cancer [6].

Evidence — A definitive assessment of the role of AS for prostate cancer patients requires a direct comparison between immediate treatment and AS, which includes definitive treatment at the time when there is evidence of progression. There are no available randomized trials that meet these criteria. However, taken together, the available data suggest that outcomes in appropriately selected males with localized prostate cancer who are managed with initial observation appear to be similar to those undergoing immediate definitive therapy:

Two large older studies, the Scandinavian Prostate Cancer Group 4 (SPCG-4) trial [9,10] and the Prostate Cancer Intervention Versus Observation Trial (PIVOT) [11-13], compared immediate definitive therapy (radical prostatectomy) with delayed treatment for metastatic disease or symptomatic locoregional progression. Both trials provide insights into the natural history of prostate cancer, but neither trial utilized an active surveillance strategy with definitive therapy instituted if there was evidence of progression.

Nevertheless, in our view, the best evidence in support of AS comes from the PIVOT trial, for which long term results are available [11]. This study randomly assigned 731 males with localized prostate cancer to upfront radical prostatectomy versus delayed initial treatment and reported that after 22 years of follow-up, surgery had only a very small impact on reducing death from any cause (restricted mean survival in the surgery group was 13.6 versus 12.6 years in the delayed treatment group). When the analysis was restricted to males with low-risk disease, the benefit of surgery was much smaller, with no appreciable difference in mortality between those who had surgery and those who were initially observed. Notably, the risk of dying from a non-prostate cancer cause in PIVOT was higher than in many other prostate cancer studies, and because of this the results should be interpreted with caution because they may not reflect outcomes in a healthy population.

Further evidence comes from the PROTECT trial which randomly assigned over 1600 males to "active monitoring," surgery, or radiation [14]. Patients assigned to active monitoring had their prostate-specific antigen (PSA) monitored every three months during the first year and every six months thereafter. Additional testing was carried out as indicated, and the therapeutic plan was reassessed as clinically indicated. Notably, MRI was not used to follow patients on active monitoring.

In this trial, there were only a limited number of prostate cancer-related deaths in any of the groups, and there was no significant difference in the 15-year cancer-specific survival or all-cause mortality among the three treatments [15].

The development of metastases was significantly more frequent in patients managed with AS (9.4 percent versus 4.7 percent with surgery, and 5.0 percent with radiation), as discussed below. (See 'ProtecT trial' below.)

It is likely that these results were driven by the over 20 percent of males with intermediate- to high-risk disease who were randomized to the observation arm and, possibly, due to methods used for patient selection and surveillance. Unfortunately, the PROTECT trial was not powered appropriately for subgroup analyses, so a focused evaluation of low-risk patients was not possible.

Impact of tissue-based prognostic markers — An increased understanding of prostate cancer biology has led to the development of molecular tests that may provide some additional prognostic information, particularly when taken in conjunction with risk groups based on stage, Gleason score, and serum PSA. However, there is disagreement as to when and how to use these markers:

Consensus-based guidelines from the NCCN state that molecular testing should be considered for males with low-risk disease who are potential candidates for active surveillance and have a life expectancy >10 years [4].

On the other hand, guidelines from the combined AUA/ASTRO/SUO, which are endorsed by ASCO, state that among most low-risk prostate cancers, tissue-based genomic biomarkers have not shown a clear role in the selection of candidates for active surveillance, and they specifically recommend against this practice [1,5].

Notably, more recent data published after the guidelines were developed suggest that gene expression assays can add unique information regarding biologic risk and natural history in higher volume Gleason 6 tumors and even in magnetic resonance imaging (MRI)-detected cancers [16-20]. Updated guidelines for the use of molecular and cellular diagnostics in localized prostate cancer are under development.

We would support active surveillance in this group with low-risk disease only in the absence of certain high-risk histologic features (eg, areas of cribriform or intraductal cancer) and low-risk gene expression profiles. (See "Interpretation of prostate biopsy" and "Molecular prognostic tests for prostate cancer", section on 'Tests based on molecular characteristics'.)

Definitive therapy — Although active surveillance is a preferred strategy for most patients, AUA/ASTRO/SUO guidelines for treatment of low-risk, clinically localized prostate cancer, which are endorsed by ASCO, suggest that clinicians may offer definitive treatment (radical prostatectomy or RT) to individuals with low-risk localized prostate cancer who have a high probability of progression on active surveillance [1,5]. Definitive treatment may also be an option for males who prefer more immediate treatment despite having low-risk disease, particularly if they are not comfortable with the psychosocial burden of living with an indolent cancer without active treatment, or are unable/unwilling to follow-through with recommended monitoring. (See "Active surveillance for males with clinically localized prostate cancer", section on 'Quality of life issues and psychologic comfort with surveillance' and "Active surveillance for males with clinically localized prostate cancer", section on 'Monitoring and triggers for intervention with treatment'.)

Radiation therapy — The goal of RT for males with localized prostate cancer is to deliver a therapeutic dose of radiation to the tumor while minimizing radiation to normal tissues. Both external beam RT and brachytherapy are widely used as a single modality for clinically localized, low-risk prostate cancer, and use of either as a single modality is supported by clinical practice guidelines [1,5]. When used as the primary treatment modality, disease control with RT is similar to that achieved with radical prostatectomy. (See "External beam radiation therapy for localized prostate cancer" and "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer" and "Radiation therapy techniques in cancer treatment".)

The definition of biochemical failure after RT is complex since some normal prostatic glandular tissue remains and serum PSA levels are unlikely to fall to undetectable levels following a course of RT. The Phoenix criteria define biochemical failure after either external beam RT or brachytherapy as a PSA rise of 2 ng/mL or more above the nadir PSA after treatment. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'After radiation therapy'.)

External beam radiation therapy — External beam RT utilizes an external source of radiation to treat the prostate gland and a margin of adjacent normal tissue. External beam RT is generally used alone (ie, without ADT or brachytherapy boost) for low-risk, clinically localized prostate cancer. (See "External beam radiation therapy for localized prostate cancer".)

Technique — Three-dimensional conformal radiation therapy (3D-CRT) techniques are considered standard and have replaced older two-dimensional approaches for the definitive treatment of localized prostate cancer. (See "External beam radiation therapy for localized prostate cancer", section on 'External beam radiation therapy techniques'.)

Multiple technical refinements of 3D-CRT may facilitate the administration of higher doses of radiation to the tumor and decrease toxicity to normal tissues:

Intensity-modulated radiation therapy (IMRT) is an advanced form of 3D-CRT that has replaced older 3D-CRT techniques in many areas [21]. IMRT utilizes a beam with varying intensity, in contrast to older forms of 3D-CRT techniques in which the dose rate is constant. Thus, IMRT can target a complex and irregular tumor volume more effectively. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

Image-guided radiation therapy (IGRT) uses two- or three-dimensional imaging prior to each treatment to precisely locate the tumor and surrounding organs. IGRT thus further minimizes the margin of normal tissue that would otherwise need to be irradiated to allow for changing anatomic relationships. (See "External beam radiation therapy for localized prostate cancer", section on 'Benefit of image-guided radiation therapy'.)

Accelerated courses of external beam RT have been demonstrated to achieve similar efficacy and toxicity with greater patient convenience because of the shorter time required for therapy. At least six large randomized trials 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 or 74 Gy in 28 fractions), and the conclusion of most is that efficacy is not inferior with moderate hypofractionation. There are conflicting data about whether hypofractionation increases overall treatment-related toxicity. Most trials demonstrate a small increased risk of acute gastrointestinal toxicity with moderate hypofractionation, and two identified a somewhat-increased risk of late toxicity. Even more accelerated therapy regimens (eg, five fractions given every other day) using stereotactic body radiation therapy (SBRT) are being explored in this setting, but the clinical trials are not mature. (See "External beam radiation therapy for localized prostate cancer", section on 'Moderate hypofractionation' and "External beam radiation therapy for localized prostate cancer", section on 'Stereotactic body radiation therapy (ultrahypofractionation)'.)

Proton-beam RT uses charged particles (protons) to deliver high doses of RT to the target volume while limiting the "scatter" dose received by surrounding tissues. Although proton-beam RT is being more widely used in males with prostate cancer as new treatment facilities become available, there is currently no evidence that this approach offers any advantages over IMRT or IGRT. (See "External beam radiation therapy for localized prostate cancer", section on 'Particle irradiation'.)

Complications — The morbidity of external beam RT is low with contemporary 3D-CRT techniques. The main complications are briefly reviewed here and discussed in detail elsewhere. (See "External beam radiation therapy for localized prostate cancer", section on 'Complications'.)

Gastrointestinal – Acute radiation proctitis of moderate or greater severity is reported in approximately 20 percent of men, depending on its definition, the radiation dose, and the treatment volume [22]. This estimate is supported by an analysis from the SEER database that found that approximately 17 percent of patients required a procedure such as colonoscopy following external beam RT for prostate cancer [21]. If the pelvic lymph nodes are included in the treatment volume, radiation enteritis may also be observed. (See "External beam radiation therapy for localized prostate cancer", section on 'Gastrointestinal' and "Radiation proctitis: Clinical manifestations, diagnosis, and management".)

Symptoms can include abdominal cramping, tenesmus, urgency, and frequent defecation. They can usually be controlled with antidiarrheal agents or topical anti-inflammatory preparations. After RT is completed, acute symptoms usually subside within three to eight weeks.

Long-term intestinal side effects persist in a low percentage of patients, manifested by persistent diarrhea, tenesmus, rectal urgency, or hematochezia. Rectal or anal strictures, ulcers, and perforation are rare. (See "Radiation proctitis: Clinical manifestations, diagnosis, and management" and "Overview of gastrointestinal toxicity of radiation therapy".)

Urinary – Approximately one-half of patients experience urinary frequency, dysuria, or urgency due to cystitis, urethritis, or both during external beam RT. Symptoms typically resolve within several weeks after the completion of therapy. Late side effects are uncommon. (See "External beam radiation therapy for localized prostate cancer", section on 'Urinary symptoms' and "Chemotherapy and radiation-related hemorrhagic cystitis in cancer patients", section on 'Radiation therapy'.)

Erectile dysfunction – The frequency of erectile dysfunction increases over time. By two years after external beam RT, 60 to 70 percent of males report moderate or more severe difficulties with sexual functioning [22]. Other factors that can contribute to erectile dysfunction in this population include older age, intercurrent diseases (hypertension, cardiovascular disease, diabetes), and the use of neoadjuvant ADT. (See "External beam radiation therapy for localized prostate cancer", section on 'Sexual dysfunction'.)

Brachytherapy — Brachytherapy directly implants a radioactive source within the prostate to treat the cancer, thus providing the highest dose of radiation over a very limited distance. Brachytherapy maximizes irradiation of the tumor while minimizing radiation to normal structures. Brachytherapy requires only one or a limited number of treatment(s), rather than the daily therapy required by external beam RT. (See "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer".)

The radiation source is inserted into the prostate using a transperineal approach under transrectal ultrasound guidance.

Low-dose rate brachytherapy is delivered with permanently implanted radioactive seeds, typically using either iodine-125 or palladium-103.

High-dose rate brachytherapy uses a temporary radiation source, such as iridium-192, which is inserted into the prostate through hollow catheters or needles that have been appropriately positioned and later removed. This form of brachytherapy typically requires a 48-hour hospitalization, in contrast to low-dose rate brachytherapy, which can be completed in a single 60- to 90-minute outpatient procedure.

Patient selection — The appropriateness of brachytherapy for individual patients is based on technical feasibility, the absence of coexistent intractable non-cancer-related urinary conditions, and the ability to adequately irradiate all disease. Brachytherapy alone is an appropriate option for males with very low-, low-, or favorable intermediate-risk disease (table 2 and table 3) [23,24].

The available data suggest that males with bothersome lower urinary tract symptoms are more likely to be improved with radical prostatectomy than with either brachytherapy or external beam RT, and this should be a factor in decision making. The incidence of incontinence after brachytherapy is higher in males with a prior transurethral resection of the prostate (TURP). Furthermore, a large prostate gland (>60 g) is associated with a higher rate of treatment-related complications, including acute urinary retention, and it is a relative contraindication to brachytherapy (table 4) [25]. Although a course of ADT prior to brachytherapy is sometimes used to reduce the volume of the prostate gland, there is no evidence to demonstrate that this approach adds value, and it has the downside of exposing patients to the acute side effects of ADT. (See "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer", section on 'Patient selection'.)

For these reasons, guidelines from the AUA/ASTRO/SUO and ASCO suggest that low-dose rate brachytherapy be discouraged for males with intractable non-cancer-related lower urinary tract symptoms or a prior significant TURP [1,5].

Complications — The main complications following brachytherapy are genitourinary and gastrointestinal. (See "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer", section on 'Complications'.)

Urinary symptoms – Transient urinary frequency, urgency, and dysuria occur in the majority of patients, generally developing several days after implantation. Acute prostatic swelling causing urinary retention and requiring catheterization is uncommon. Late complications can include incontinence, urethral strictures, and urinary retention.

Erectile dysfunction – The reported incidence of erectile dysfunction varies widely among males who were potent prior to brachytherapy (table 5). The patient-reported frequency of erectile dysfunction is time dependent and similar to that for RT and radical prostatectomy [22]. (See "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer", section on 'Sexual dysfunction'.)

Gastrointestinal symptoms – Gastrointestinal toxicity is less common than genitourinary toxicity following brachytherapy. Late gastrointestinal complications of brachytherapy are seen in less than 10 percent of patients and include rectal urgency, bleeding or ulceration, bowel frequency, and prostatorectal fistulas [22].

Radical prostatectomy — Radical prostatectomy is an established option to treat localized prostate cancer, based on high rates of long-term cancer control, acceptable perioperative morbidity and mortality, and an acceptable side effect profile.

The most widely used surgical technique is robotic-assisted minimally invasive radical prostatectomy. Pelvic lymph node dissection can usually be omitted in males with low-risk disease. (See "Radical prostatectomy for localized prostate cancer".)

In general:

Younger or healthier males (<65 years of age or life expectancy >10 years) are more likely to experience cancer control benefits from prostatectomy than are older males [12].

Older males experience higher rates of permanent erectile dysfunction and urinary incontinence after prostatectomy than do younger men. (See 'Complications' below.)

Open and robot-assisted radical prostatectomies offer similar cancer control, continence recovery, and sexual recovery outcomes.

Robot-assisted laparoscopic or perineal techniques are associated with less blood loss than open retropubic prostatectomy, although perioperative transfusion rates are similar.

Nerve-sparing approaches are associated with better erectile function recovery than non-nerve-sparing procedures.

Surgery may be preferred over RT for males with obstructive non-cancer-related lower urinary function.

All prostate tissue is removed during a successful radical prostatectomy.

However, not all males have an undetectable PSA after radical prostatectomy, and if it is detectable, not all require therapy:

Approximately 3 to 4 percent of patients treated with radical prostatectomy have a detectable and non-rising PSA over many years, usually <0.4 ng/mL.

Postoperatively, detectable serum PSA levels that are progressively rising presumably represent residual tumor tissue. The most widely accepted criterion for defining biochemical failure after radical prostatectomy is that of the AUA, which defines a biochemical recurrence as a serum PSA ≥0.2 ng/mL that is confirmed by a second determination with a PSA ≥0.2 ng/mL [26].

Biochemical recurrence has a variable natural history, and not all males require therapy. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'After radical prostatectomy'.)

Adjuvant therapy — Clinical staging based on the digital rectal examination and potentially supplemented by imaging may fail to detect extraprostatic extension, seminal vesicle involvement, or lymph node involvement. The management of patients with more extensive disease or positive surgical margins based on pathologic staging after radical prostatectomy is discussed separately. (See "Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy".)

Complications — The complications of most concern to males who undergo prostatectomy are urinary incontinence and impotence, which are due to damage to the urinary sphincter and penile nerves. The frequency of incontinence and erectile dysfunction depends on the extent of the tumor, and the experience and expertise of the surgeon, and not whether the technique is performed using the open or minimally invasive approach. (See "Radical prostatectomy for localized prostate cancer", section on 'Functional outcomes'.)

Urinary incontinence — The incidence of urinary incontinence following radical prostatectomy depends on the definition of incontinence, the time elapsed since surgery, whether or not a nerve-sparing approach was used, and the source of the data (patient or clinician reported). Based on patient queries, some symptoms may be present in up to 25 percent or more of patients at one year and later, and 5 to 10 percent consider this to be a moderate or more severe problem [22]. (See "Radical prostatectomy for localized prostate cancer", section on 'Urinary incontinence'.)

Urinary incontinence is most common immediately after surgery, and there is a gradual return of function thereafter. Conservative measures (eg, pelvic floor muscle training and biofeedback) are often used in the months following radical prostatectomy in an effort to control symptoms while sphincter function is returning. For males with significant persistent incontinence, options include a urethral sling procedure or an artificial urinary sphincter.

Erectile dysfunction — The frequency of erectile dysfunction following retropubic radical prostatectomy depends on the patient's age, the preoperative level of sexual functioning, and whether or not nerve-sparing surgery was performed (table 6). Erectile dysfunction is nearly universal if the erectile nerves are not preserved at surgery. (See "Radical prostatectomy for localized prostate cancer", section on 'Erectile dysfunction'.)

The return of potency following a nerve-sparing procedure is gradual, and males may benefit from regular use of a phosphodiesterase-5 (PDE5) inhibitor. Although potency rates as high as 80 percent have been reported in individual centers performing nerve-sparing surgery on carefully selected men, the potency rates in broader populations are substantially lower. Furthermore, patient estimates of the frequency of erectile dysfunction are generally higher than in clinician-reported data.

Erectile dysfunction can be treated with PDE-5 inhibitors, penile injection therapy, vacuum erection devices, and implantation of a penile prosthesis. (See "Treatment of male sexual dysfunction" and "Surgical treatment of erectile dysfunction".)

Other approaches

Ablation therapy — Cryotherapy, high-intensity focused ultrasound (HIFU), and photodynamic therapy have been used to selectively destroy prostate tissue. These ablation techniques can be applied either to the entire prostate gland or to focally destroy the part of the prostate gland thought to be involved by tumor. (See "Cryotherapy and other ablative techniques for the initial treatment of prostate cancer".)

The role of cryotherapy in the management of patients with localized disease remains uncertain despite the technologic advances that have been made. Even among males with low-risk disease (table 1), it is not clear that results with cryotherapy are comparable with those that can be achieved with other therapeutic approaches.

We suggest that cryotherapy not be used routinely as an alternative to standard treatment approaches (ie, radical prostatectomy, external beam RT, brachytherapy, or active surveillance) for localized prostate cancer. In keeping with guidelines from ASCO [1], whole-gland cryosurgery should be limited to males with low-risk (table 1), clinically localized prostate cancer who are not suitable for either radical prostatectomy or RT due to comorbidities yet who have a life expectancy >10 years. (See "Cryotherapy and other ablative techniques for the initial treatment of prostate cancer", section on 'Cryotherapy'.)

HIFU uses sonic waves to create thermal energy that destroys the target tissue within the prostate. HIFU has not been compared with other standard treatment approaches in randomized trials, nor is it included in guidelines for the initial management of males with prostate cancer from expert groups [1,2]. Clinicians should inform patients considering HIFU that this treatment option lacks robust evidence of efficacy, and that even though HIFU was approved by the US Food and Drug Administration (FDA) as "existing technology" for destruction of prostate tissue, it is not approved for the treatment of prostate cancer given the lack of long-term data on outcomes [1,27]. (See "Cryotherapy and other ablative techniques for the initial treatment of prostate cancer", section on 'High-intensity focused ultrasound'.)

Photodynamic therapy has been studied for the focal treatment of low-risk prostate cancer as an alternative to active surveillance. Longer follow-up and comparisons with other treatment modalities will be required to assess the role of this approach in males with prostate cancer. Photodynamic therapy is currently experimental in the United States and Europe, and it should only be applied within the context of a formal clinical trial. (See "Cryotherapy and other ablative techniques for the initial treatment of prostate cancer", section on 'Photodynamic therapy'.)

If focal therapy fails, salvage radical prostatectomy may be feasible, but cancer outcomes may be poor [28].

Androgen deprivation therapy alone — Guidelines from the NCCN [4], AUA/ASTRO, and ASCO do not include primary ADT as a standard option for the initial treatment of males with low-risk localized prostate cancer unless for palliation of local symptoms in select patients with a limited life expectancy for whom definitive therapy is not advised [1,2].

Outcomes and the choice of therapy — For males with low-risk, clinically localized prostate cancer, brachytherapy, external beam RT, and radical prostatectomy all provide an extremely high degree of freedom from local or distant recurrence with prolonged follow-up. For carefully selected patients with a low or very low risk of recurrence, active surveillance, with delayed definitive treatment if necessary, is also an appropriate option, but there may be an increased risk of clinical progression and metastatic disease in males who undergo active surveillance rather than initial definitive therapy, as suggested in the randomized Prostate Testing for Cancer and Treatment (ProtecT) trial. (See 'ProtecT trial' below.)

The choice of a therapeutic approach depends on an informed patient decision incorporating knowledge about the potential advantages and disadvantages associated with each approach, along with personal preferences. Important associated advantages, disadvantages, and contraindications are summarized in the tables (table 7 and table 8 and table 9). In addition to these issues, some males without cancer recurrence will require surgery to deal with treatment-related urinary issues [29], and the evaluation of posttreatment toxicity must take this fact into account.

Cost has become more important in the choice of treatment because of changes in the finances of health care. A study evaluating each of these options using time-driven activity-based costing has demonstrated important differences among the various modalities [30]. In this analysis, external beam RT with IMRT was more expensive than prostatectomy, and all were more expensive than low-dose rate brachytherapy. The cost-effectiveness of active surveillance is not necessarily better than that of immediate definitive treatment; in one report of males with low-risk localized prostate cancer, the cost-effectiveness of active surveillance was dependent on the "trigger" for radical prostatectomy and the quality of life issues for males undergoing active surveillance [31].

Outcomes after treatment with different treatment modalities have been described in the randomized ProtecT trial, as well as in several very large observational series. (See 'ProtecT trial' below.)

Randomized trials

ProtecT trial — The most extensive data comparing different treatment options come from the Prostate Testing for Cancer and Treatment (ProtecT) trial, which was conducted in the United Kingdom [14,15,32]. In the ProtecT trial, 1643 patients were randomly assigned to one of three regimens: active monitoring, radical prostatectomy, or external beam RT (74 Gy in 37 fractions) with neoadjuvant and concurrent ADT for three to six months. Active monitoring used serum PSA levels measured every three months in the first year and every 6 to 12 months thereafter to trigger patient reassessment and consideration of a change in clinical management. Active monitoring is different from active surveillance in that it relies primarily on grade progression, rather than an increase in serum PSA, to prompt therapeutic intervention. Notably, prostate MRIs and genomic testing were not available; prostate biopsies were not done in the active surveillance group, and the trigger to consider a change in management was largely driven by PSA results.

The patients were recruited from a PSA screening population aged 50 to 69 years and included mainly males with low-risk disease (76 percent with stage T1c disease; the Gleason score was 6 in 77 percent of cases and was 7 in 21 percent of cases; the median serum PSA was 4.6 ng/mL). Approximately 1 percent of the population had African or Caribbean ethnicity.

Based on a median follow-up of 15 years [15]:

The primary endpoint of the trial was cancer-specific survival. Death from prostate cancer occurred in 45 males (2.7 percent): 17 (3.1 percent) in the active monitoring group, 12 (2.2 percent) in the prostatectomy group, and 16 (2.9 percent) in the radiotherapy group.

The differences between groups in cancer-specific survival were not statistically significant.

The development of metastases (bone, lymph node, or visceral metastases, or a serum PSA >100 ng/mL), a secondary endpoint in the trial, was significantly more frequent in patients managed with active monitoring (at 15 years of follow-up, metastases developed in 9.4 percent in the active monitoring group, 4.7 percent in the prostatectomy group, and in 5.0 percent in the radiotherapy group).

Death from any cause occurred in 22 percent, with similar rates in all three groups.

The incidence of clinical progression was also significantly more frequent in those managed with active monitoring, and 40 percent of males assigned to active monitoring underwent active therapy within five years [32]. Clinical progression included the development of metastatic disease, the diagnosis of clinical T3 or T4 disease, long-term ADT treatment, ureteral obstruction, rectal fistula, or the need for a urinary catheter due to local tumor growth. Clinical progression occurred in 26 percent, 10.5 percent, and 11.0 percent of males assigned to active monitoring, radical prostatectomy, or RT, respectively [15]. The criteria for the detection of clinical progression (especially PSA progression) differed significantly between the three modalities, and this may have influenced the results.

Prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse over time in this group [32]. The negative effect of RT on sexual function was greatest at six months, but sexual function then recovered somewhat and was stable thereafter; RT had little effect on urinary continence. Bowel function was worse in the RT group at six months than in the other groups, but then it recovered somewhat, except for the increasing frequency of bloody stools. Effects on quality of life mirrored the reported changes in function.

The results of this trial are subject to several limitations. The applicability of the results of this trial to older males (≥70 years at diagnosis) or those of African or Caribbean ethnicity is unclear, and results may differ. Both RT and surgical techniques have improved since the trial was initiated, as have the criteria for patient selection for active surveillance. As noted above, prostate MRIs and genomic testing were not available; prostate biopsies were not done in the active surveillance group, and the trigger to consider a change in management was largely driven by PSA results. This "surveillance" strategy is largely outdated. (See "Active surveillance for males with clinically localized prostate cancer", section on 'Monitoring and triggers for intervention with treatment'.)

Other — A German phase III trial (PREFERE, NCT01717677) is currently enrolling patients to compare prostate cancer-specific survival after radical prostatectomy, external beam RT, brachytherapy, and active surveillance in patients with low- or intermediate-risk prostate cancer [33]. The trial is designed to enroll 7600 patients, and results are not anticipated until approximately 2030.

Observational series — Radical prostatectomy, external beam RT, and brachytherapy all provide biochemical relapse-free survival of 80 percent or more in studies with a follow-up of 5 to 10 years. Furthermore, more than 95 percent of patients remain free of local recurrence and distant metastases. Representative large observational studies illustrate the results in males with limited-risk prostate cancer.

Radical prostatectomy — The results using radical retropubic prostatectomy to treat prostate cancer are illustrated by a retrospective series of 3283 males with low-risk prostate cancer who were treated at the Mayo Clinic between 1987 and 2003 [34]. Approximately two-thirds of these cases had clinical stage T1c disease, and the remainder had T2a primary tumors; the mean pretreatment PSA was 5.4 ng/mL. Median follow-up was 7.7 years.

At five years, 90 percent of males were free from biochemical relapse, and at 10 years, 82 percent remained progression free. Even among those who experienced a biochemical relapse, the prognosis for these low-risk patients was highly favorable. The overall rates of freedom from local recurrence at 5 and 10 years were 98 and 97 percent, respectively, and freedom from systemic progression at 5 and 10 years was 99.6 and 99 percent, respectively.

Additional data on the efficacy of radical prostatectomy come from a multi-institutional series of over 23,000 males who underwent radical prostatectomy for prostate cancer [35]. In an analysis based on surgical staging, the prostate cancer-specific mortality for those with Gleason 6 or less lesions was approximately 1 percent at 15 years; similarly, for those with pathologic T2N0 lesions, prostate cancer-specific mortality was 0.8 to 1.5 percent at 15 years. Similar results have been reported in a large single-institution experience with 4478 males treated over a 30-year period [36].

External beam RT — The outcomes with external beam RT as a single modality are illustrated by a single-institution series of 2047 males treated between 1998 and 2004 [37]. The series included 446 patients with low-risk disease. RT was administered by either 3D-CRT or IMRT, with doses ranging from 66 to 86 Gy.

The seven-year PSA relapse-free survival rate for patients with low-risk disease was 90 percent. Both the distant metastasis-free and the cause-specific survival rates at seven years for the males with low-risk disease were 99 percent. There was no statistically significant difference in outcome as a function of radiation dose.

Brachytherapy — The results with low-dose rate brachytherapy using permanent seed implantation are illustrated by a multi-institutional series of 2693 patients treated between 1988 and 1998 [38]. Median follow-up was five years. Within this series, 1444 patients had low-risk disease. Two-thirds of patients were treated with iodine-125, and the remainder were treated with palladium-103.

The eight-year PSA relapse-free survival rate was 82 percent according to the ASTRO definition (three successive increases in PSA after nadir was reached) and 74 percent according to the Phoenix (nadir +2 ng/mL) definition. The eight-year distant metastasis-free survival rate for the low-risk patients was 98 percent. Multivariate analysis confirmed the importance of an adequate dose of radiation. Unfortunately, the intensity and quality of follow-up were not stated in this paper.

A more recent single-institution series with longer follow-up in all risk groups where the intensity of follow-up was recorded and adequate found that results with low-dose rate brachytherapy were competitive with other modalities (1082 of 1989 patients were low risk). The 5- and 10-year biochemical relapse-free survival (Phoenix definition), metastases-free survival, overall survival, and prostate cancer-specific mortality rates were 95.5 and 86.7, 99.0 and 94.6, 95.0 and 77.6, and 0.29 and 2.07 percent, respectively [39].

High-dose rate brachytherapy reports with adequate follow-up and good attention to follow-up quality are rare. One study with a median follow-up of 6.5 years analyzed 448 cases, including 288 with low-risk disease, but did not report the intensity of follow-up [40]. The 10-year biochemical relapse-free (Phoenix definition), metastases-free, overall, and prostate cancer-specific survival rates were 97.8, 98.9, 76.7, and 99.1 percent, respectively.

Quality of life issues — External beam RT, brachytherapy, radical prostatectomy, and active surveillance can all be effective in appropriately selected patients in terms of control of disease, but there are important differences in terms of their impact on quality of life. Three large prospective studies that relied on patient-reported outcome measures provide important insights and can help guide the decision-making process [22,41,42]. These results are consistent with the quality of life results from the ProtecT trial [32], as well as those from a contemporary systematic review [43]. As examples:

In a study of 1141 males with localized prostate cancer who were managed with radical prostatectomy, external beam RT, brachytherapy, or active surveillance (469, 249, 109, and 314 cases, respectively) quality of life was assessed for two years using the Prostate Cancer Symptom Indices instrument [41]. Sexual function in males with excellent baseline function was decreased more markedly with radical prostatectomy than with external beam RT or brachytherapy compared with active surveillance. External beam RT was associated with acute worsening of urinary obstructive and bowel symptoms; however, the differences in all of these symptoms had largely disappeared by 24 months.

In a study of 1201 males treated for clinical T1/T2 prostate cancer at several United States centers, treatment included radical prostatectomy, external beam RT, or brachytherapy (in 603, 292, and 306 cases, respectively) [22].

Urinary symptoms – Symptoms of urinary irritation or obstruction (dysuria, weak stream, frequency) were seen after RT and were more common after brachytherapy than external beam RT. The incidence of these symptoms peaked at two months and was less common by two years after treatment. By contrast, incontinence was frequent after radical prostatectomy, with approximately two-thirds of patients requiring at least some pad use after two months. By two years, symptoms had resolved in most patients, although 20 percent still required some use of pads. Incontinence was much less common in patients treated with external beam RT or brachytherapy.

Bowel function – Bowel symptoms, primarily urgency and frequency, were reported by 10 to 20 percent of patients treated with either external beam RT or brachytherapy. Although the incidence was highest at two months after treatment, symptoms persisted at two years in 7 to 16 percent of cases. Bowel symptoms were rare after radical prostatectomy.

Sexual function – In patients managed with radical prostatectomy, some sexual dysfunction was present in approximately 90 percent of patients after two months and was a moderate or major problem in 60 percent. Some problems persisted in 60 percent after two years, and it was a moderate or big problem in 43 percent. For patients treated with RT (either external beam RT or brachytherapy), approximately 60 percent had some sexual dysfunction at two months, which persisted at two years.

In the ProtecT trial, patient-reported quality of life parameters were assessed through six years for urinary, sexual, and bowel function, as well as overall well-being [32]. These results were consistent with other studies, showing somewhat worse urinary symptoms and sexual function related to surgery, and worse bowel symptoms related to RT. There were no meaningful differences in overall health-related quality of life, and although differences in specific parameters decreased with time, males undergoing prostatectomy still had worse sexual function and urinary continence than the other groups throughout the trial. (See 'ProtecT trial' above.)

FOLLOW-UP TESTING

Posttreatment surveillance — Follow-up surveillance after initial definitive local treatment is an important component of patient management. Although most patients with low-risk, clinically localized prostate cancer will remain disease free, a minority will relapse with local and/or distant disease.

Serial evaluation of serum prostate-specific antigen (PSA) is the mainstay of surveillance testing. This may result in detection of recurrence at a time when successful salvage therapy is feasible.

Follow-up after definitive treatment is discussed separately. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)

Males undergoing active surveillance — Careful monitoring is required during active surveillance to identify disease progression and the need for definitive therapy. Typically, this involves serial measurement of serum PSA, physical examination, imaging and periodic biopsy for histologic assessment of progression. There is no single widely accepted monitoring strategy, and surveillance protocols need to be tailored to the risk of progression; the individual values, goals, and preferences of each patient; and competing comorbidities. This subject is discussed in detail elsewhere. (See "Active surveillance for males with clinically localized prostate cancer", section on 'Monitoring and triggers for intervention with treatment'.)

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 5th to 6th 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 10th to 12th 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: Prostate cancer (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

The initial clinical staging is based on a digital rectal examination, pretreatment serum prostate-specific antigen (PSA), the Gleason grade group in the initial biopsy, and the number and extent of cancer involvement in the biopsy cores. This information allows the stratification of males into clinical risk categories according to the primary tumor, as defined by the National Comprehensive Cancer Network (NCCN) (table 1). (See 'Risk stratification and selection of the initial approach' above.)

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. Imaging for distant disease is not routinely recommended for very low- and low-risk disease. MRI of the prostate is often obtained in males with low- and very low-risk disease to ensure that high-grade disease has not been overlooked.

Treatment selection

For most individuals with clinically localized, very low-risk prostate cancer, we suggest active surveillance rather than immediate definitive therapy (Grade 2C). However, this approach is associated with a need for close follow-up and may create significant anxiety. As such, this approach is most appropriate for males who meet the biologic criteria of low risk for metastasis in the absence of certain histologic features (areas of cribriform or intraductal cancer) and low-risk gene expression profiles and who have psychologic comfort with active surveillance. Some patients may still choose active treatment (radiation therapy [RT] or radical prostatectomy) even in the presence of very low-risk disease. (See 'Very low risk' above.)

For individuals with low-risk prostate cancer and a life expectancy >10 years, definitive therapy (radical prostatectomy, brachytherapy, or external beam RT) or active surveillance are all appropriate options. The choice of the specific approach requires a consideration of the benefits and risks associated with each approach, taking into account the patient's individual preferences and comorbidities. (See 'Low risk' above.)

For patients with a more limited life expectancy (<10 years), we suggest active surveillance rather than immediate definitive therapy in the absence of certain histologic features (areas of cribriform or intraductal cancer) and low-risk gene expression profiles (Grade 2C). (See 'Active surveillance' above.)

For patients who choose definitive therapy for very-low or low-risk prostate cancer, surgery is generally preferred over RT for individuals with obstructive non-cancer-related lower urinary function. Otherwise, either RT or radical prostatectomy may be chosen for definitive local therapy. The following issues may also inform this choice.

Comparing outcomes with radical prostatectomy versus RT, disease control rates are similar for most males, but there are important differences in the patterns of toxicity associated with these treatments. The advantages, disadvantages, and contraindications associated with each treatment modality are summarized in the tables (table 7 and table 8 and table 9). (See 'Outcomes and the choice of therapy' above.)

In general:

-Early irritative and obstructive urinary symptoms are more common after RT, particularly brachytherapy. Incontinence is more frequent after radical prostatectomy, but it generally improves gradually with time.

-Bowel symptoms (urgency, frequency) are more common after external beam RT and brachytherapy than radical prostatectomy.

-Erectile dysfunction is most frequent immediately after radical prostatectomy. Bilateral nerve-sparing surgery diminishes but does not eliminate this risk. Erectile dysfunction is also common after both external beam RT and brachytherapy, and the incidence rises gradually following treatment. Although there is recovery over time, some of these differences persist long-term.

Follow-up testing

Follow-up surveillance after initial definitive treatment is an important component of patient management since salvage may be feasible if recurrence is detected early. Serial PSA testing is the mainstay of posttreatment surveillance. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)

For males who choose active surveillance, careful monitoring is required to identify disease progression and the need for definitive therapy. Typically, this involves serial measurement of serum PSA, physical examination, and imaging and periodic biopsy for histologic assessment of progression.

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Eric A Klein, MD, who contributed to earlier versions of this topic review.

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.

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Topic 6940 Version 67.0

References

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