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Initial approach to low- and very low-risk clinically localized prostate cancer
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Initial approach to low- and very low-risk clinically localized prostate cancer
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Literature review current through: Mar 2017. | This topic last updated: Mar 29, 2017.

INTRODUCTION — Most prostate cancers now are diagnosed while clinically localized, based in part upon the widespread use of serum prostate specific antigen (PSA) 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 or low-risk disease, active surveillance.

Key factors in choosing treatment for a man with 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 "Prostate cancer: Risk stratification and choice of initial treatment", section on 'Risk stratification'.)

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

(See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer".)

(See "Overview of the treatment of disseminated prostate cancer".)

RISK STRATIFICATION — The management of men with newly diagnosed prostate cancer needs to incorporate a consideration of the prolonged natural history of prostate cancer and the risk for progression to disseminated, potentially fatal disease.

Risk stratification uses the clinical stage of disease, baseline serum prostate specific antigen (PSA), the histologic grade group (based upon the Gleason score), and the extent of prostate involvement (including the number of biopsy cores containing cancer) to divide patients into prognostic stage groups (table 1 and table 2). Although there are fairly arbitrary boundaries between these prognostic categories, prostate cancer is a broad continuum. Risk stratification is combined with patient age, overall medical condition, the presence or absence of symptoms, and patient preferences in guiding initial therapy decisions. (See "Prostate cancer: Risk stratification and choice of initial treatment".)

Very low-risk prostate cancer – Patients with very low-risk clinically localized prostate cancer have disease detected by prostate biopsy only, without detectable abnormality on digital rectal examination or imaging. To be classified as very low-risk, such patients must have a histologic grade group 1 (Gleason score ≤6 on biopsy) and a serum PSA <10 ng/mL. Furthermore, the extent of disease within the prostate must be limited (ie, fewer than three positive biopsy cores with less than 50 percent involvement in any one core, and a PSA density less than 0.15 ng/mL/gram) [1].

Low-risk prostate cancer – Patients with low-risk, clinically localized prostate cancer either have disease limited to one lobe of the prostate (T2a) or no apparent tumor by digital rectal examination (T1; diagnosis based upon a biopsy only, with no abnormal findings on imaging or palpation), a serum PSA <10 ng/mL, and a histologic grade group 1 (Gleason score ≤6).

Intermediate-risk prostate cancer – Men with intermediate-risk clinically localized prostate cancer can have more extensive tumor in the prostate (ie, involving more than one-half of one lobe of the prostate [T2b] or with bilateral disease [T2c] on initial examination or imaging), but without extraprostatic extension or seminal vesicle involvement. In addition, patients with clinical stage T1 or T2a disease are classified as having intermediate-risk disease based upon a serum PSA ≥10 and <20 ng/mL or a histologic grade group 2 or 3 (Gleason score 7).

High-risk prostate cancer – Patients with high-risk, clinically localized prostate cancer may have more extensive disease, based upon the presence of extraprostatic extension (T3a). In addition, some patients with less extensive disease are classified as high risk because of a serum PSA ≥20 ng/mL or a histologic grade group 4 or 5 (Gleason score of 8 to 10).

Very high risk prostate cancer – Patients whose initial evaluation suggests locally advanced disease (T3b or T4) diagnosed based upon clinical staging but without lymph node involvement (N0) or distant metastases (M0) are at very high risk of local recurrence or distant metastases.

Patients with lymph node involvement or disseminated metastases are classified as having stage IV disease.

The initial approaches to treatment for men with very low or low-risk prostate cancer are discussed here. The management approaches to patients with intermediate or high-risk prostate cancer are discussed separately. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer".)

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

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 treatment option for some patients with prostate cancers that are small, have a low Gleason grade, and thus are thought to have a relatively low-risk of progression (TNM anatomic prognostic group I (table 1 and table 2)).

The goal of active surveillance is to avoid treatment-related complications for men whose cancers are not likely to progress. For many men, 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 men with low-risk, clinically localized prostate cancer", section on 'Rationale'.)

Active surveillance must be distinguished from "watchful waiting", which is based upon the premise that some men will not benefit from definitive treatment of their localized prostate cancer [2]. 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 men with short life expectancy based upon age and/or substantial comorbidity. (See "Prostate cancer in elderly patients" and "Radical prostatectomy for localized prostate cancer", section on 'Survival impact of radical prostatectomy'.)

Because of the potential for side effects associated with aggressive treatment of indolent disease, active surveillance is an option for patients with very low-risk prostate cancer and an estimated life expectancy less than 20 years [1]. Immediate definitive treatment with radiation therapy or radical prostatectomy is an alternative for patients desiring a more aggressive approach. Active surveillance may also be an option for patients with low-risk disease and a life expectancy of less than ten years.

Although active surveillance avoids side effects in the short term, it does induce significant concerns and anxiety. Many men 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

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 men with low-risk, clinically localized prostate cancer".)

Radiation therapy — The goal of RT for men 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. When used as the primary treatment modality, disease control with RT is similar to that with radical prostatectomy. (See "External beam radiation therapy for localized prostate cancer" and "Brachytherapy for 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 RT — 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 androgen deprivation therapy or brachytherapy boost) for low-risk clinically localized prostate cancer. (See "External beam radiation therapy for localized prostate cancer".)

Technique — Three-dimensional conformal RT (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 RT 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 RT (IMRT) is an advanced form of 3D-CRT that has replaced older 3D-CRT techniques in many areas [3]. 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 RT – Image-guided RT (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.

Proton-beam RT – 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 therapy is being more widely used in men 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 upon its definition, the radiation dose, and treatment volume [4]. This estimate is supported by an analysis from the Surveillance, Epidemiology, and End Results (SEER) database that found that approximately 17 percent of patients required a procedure such as colonoscopy following external beam RT for prostate cancer [3]. 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 "Clinical manifestations, diagnosis, and treatment of radiation proctitis".)

Symptoms can include abdominal cramping, tenesmus, urgency, and frequent defecation. They can usually be controlled with antidiarrheal agents or topical antiinflammatory 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 "Clinical manifestations, diagnosis, and treatment of radiation proctitis" 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 "Cystitis in patients with cancer", section on 'Radiation cystitis'.)

Erectile dysfunction – The frequency of erectile dysfunction increases over time. By two years after external beam RT, 60 to 70 percent of men report moderate or more severe difficulties with sexual functioning [4]. 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 a one or a limited number of treatments, rather than the daily therapy required by external beam RT. (See "Brachytherapy for 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 90 minute outpatient procedure.

Patient selection — The appropriateness of brachytherapy for individual patients is based upon technical feasibility, the absence of coexistent urinary conditions, and the ability to adequately irradiate all disease. Brachytherapy alone is an appropriate option for men with low or intermediate-risk disease [5,6] (table 1 and table 2). Its suitability for high-risk patients is being expanded. Clinical trials that have completed enrollment are maturing, and at least one single-institution report demonstrates that the results of low dose rate brachytherapy are similar to those of other modalities [7]. (See "Brachytherapy for localized prostate cancer", section on 'Patient selection'.)

A large prostate gland (>60 g) is associated with a higher rate of treatment-related complications, including acute urinary retention, and is a relative contraindication to brachytherapy (table 3). A course of ADT prior to brachytherapy is sometimes used prior to brachytherapy to reduce the volume of the prostate gland, although there is no evidence to demonstrate that this approach adds value and has the down side of exposing patients to the acute side effects of ADT. (See "Brachytherapy for localized prostate cancer", section on 'Patient selection'.)

Complications — The main complications following brachytherapy are genitourinary and gastrointestinal. (See "Brachytherapy for 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 men who were potent prior to brachytherapy (table 4). The patient-reported frequency of erectile dysfunction is time dependent and similar to that for RT and radical prostatectomy [4]. (See "Brachytherapy for localized prostate cancer", section on 'Sexual dysfunction'.)

GI 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 [4].

Radical prostatectomy

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

The most widely used surgical techniques are the open retropubic radical prostatectomy and a minimally invasive radical prostatectomy. (See "Radical prostatectomy for localized prostate cancer".)

All prostate tissue is removed during a successful radical prostatectomy. Postoperatively, detectable serum PSA using standard immunoassays is indicative of residual prostatic tissue, which presumably represents residual tumor tissue. The most widely accepted criterion for defining biochemical failure after radical prostatectomy is that of the American Urological Association (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 [8]. Biochemical recurrence has a variable natural history, and not all men with a detectible PSA after RP require therapy. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'After radical prostatectomy'.)

Pathologic T3, margin positive disease, and microscopic lymph node involvement — Clinical staging based upon 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 upon pathologic staging is discussed separately. (See "Prostate cancer: Pathologic stage T3 disease or positive surgical margins following radical prostatectomy".)

Complications — The complications of most concern to men 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 depend in part upon the experience and expertise of the surgeon, and not whether the technique is performed by the open or minimally invasive approach. (See "Radical prostatectomy for localized prostate cancer", section on 'Complications and quality of life'.)

Urinary incontinence — The incidence of urinary incontinence following radical prostatectomy depends upon 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 physician reported). Based upon 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 [4]. (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 men with significant persistent incontinence, options include a urethral sling procedure or artificial urinary sphincter.

Erectile dysfunction — The frequency of erectile dysfunction following retropubic radical prostatectomy depends upon the patient's age, preoperative level of sexual functioning, and whether or not nerve-sparing surgery was performed (table 5). Erectile dysfunction is nearly universal if the erectile nerves are not preserved at surgery. (See "Radical prostatectomy for localized prostate cancer", section on 'Impotence'.)

The return of potency following a nerve-sparing procedure is gradual, and men may benefit from regular use of a phosphodiesterase-5 (PDE5) inhibitor. Although potency rates as high as 80 percent have been reported from 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 physician-reported data.

Erectile dysfunction can be treated with PDE-5 inhibitors, penile injection therapy, vacuum erection devices (VED), 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 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 these ablative approaches to treatment remains uncertain. Potential advantages in men with localized disease include the ability to destroy cancer cells using a relatively noninvasive procedure. As such, these procedures are associated with minimal blood loss and pain. There is also a more rapid posttreatment convalescence.

Whether the long-term outcomes are equivalent to those with definitive surgery or RT is uncertain however. Additional experience and longer follow-up are required to compare the rate of disease control and side effects profiles with other treatment modalities.

Androgen deprivation therapy alone — Guidelines from the National Comprehensive Cancer Network (NCCN) and the AUA both recommend that primary androgen deprivation therapy (ADT) alone not be included among standard options for the initial treatment of men with localized prostate cancer [1,6].

Androgen deprivation therapy (ADT) alone has been advocated for patients seeking active therapy but wishing to avoid the side effects of radical prostatectomy or RT. Studies advocating ADT alone for localized prostate cancer are retrospective, include limited patient numbers, have a short follow-up duration, and lack critical assessment of the side effects associated with ADT [9].

Large database studies have found an increase in all-cause mortality when primary ADT is used to treat prostate cancer:

A study from the Surveillance, Epidemiology, and End Results (SEER) database included over 46,000 men diagnosed with localized prostate cancer between 1992 and 2009 and not treated with either RT or radical prostatectomy [10]. In this cohort, 39 percent were managed with primary ADT and 61 percent with observation. Treatment with ADT was associated with a significant increase in all-cause mortality compared with those not given ADT (hazard ratio [HR] 1.37, 95% CI 1.20-1.56).

A similar conclusion was drawn from a cohort from the National Center for Prostate Disease Research database, which included 2313 men with biopsy-confirmed, clinically localized (T1-T2) prostate cancer, of whom 569 chose ADT and 1744 chose expectant management [11]. In a preliminary report, treatment with ADT was a significant predictor of all-cause death after controlling for follow-up time, year of diagnosis, age, race, PSA level, tumor characteristics, comorbidity, and secondary treatment.

Antiandrogen monotherapy — Primary antiandrogen monotherapy is not recommended for localized prostate cancer. Antiandrogen monotherapy was most extensively evaluated in the Early Prostate Cancer program in which 8113 men with localized (T1, T2) or locally advanced (T3, T4) nonmetastatic prostate cancer were randomly assigned to bicalutamide or placebo in addition to standard care (watchful waiting, RP, or RT) [12]. At a median follow-up of 10 years, the improvement in progression-free survival in men with localized (T1, T2) disease was not statistically significant regardless of the initial management approach. In addition, there was no statistically significant difference in overall survival. In men with locally advanced (T3, T4) disease, PFS was improved but there was no statistically significant difference in overall survival.

PROGNOSIS — The prognosis with different treatment modalities is illustrated by a very large observational series, as well as by the results of the Prostate Testing for Cancer and Treatment (ProtecT) trial [13,14]. (See 'ProtecT trial' below.)

Radical prostatectomy, external beam radiation therapy (RT), and brachytherapy all provide biochemical relapse free survival of 80 percent or more in studies with 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 men 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 men with low-risk prostate cancer who were treated at the Mayo Clinic between 1987 and 2003 [15]. 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 men 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 the 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 men who underwent radical prostatectomy for prostate cancer [16]. In an analysis based upon 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 men treated over a 30 year period [17].

The prognosis for patients found to have tumor involvement of one or more regional lymph nodes is less favorable, with a biochemical recurrence rate at 15 years of 52 percent and a clinical recurrence rate of 33 percent [18]. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer", section on 'Prognosis'.)

External beam RT — The outcomes with external beam RT as a single modality are illustrated by a single institution series of 2047 men treated between 1998 and 2004 [19]. The series included 446 patients with low-risk disease. RT was administered either by 3D-CRT or IMRT, with doses ranging from 66 to 86 Gy.

The seven-year PSA relapse-free survival rate for low-risk disease patients was 90 percent. Both the distant metastasis-free and the cause-specific survival rates at seven years for the men 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-institution series of 2693 treated between 1988 and 1998 [20]. Median follow-up was five years. Within this series, 1444 had low-risk disease. Two-thirds of patients were treated with iodine-125 and the remainder with palladium-103.

The eight-year PSA relapse-free survival rate was 82 percent according to the American Society for Radiation Oncology (ASTRO) definition (three successive increases in the PSA after nadir reached) and 74 percent according to the Phoenix (nadir +2 ng/mL) definition. The eight-year distant metastasis free survival 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 was not stated in this paper.

A more recent low dose rate 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 [7].

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 [21]. The 10-year biochemical relapse-free survival (Phoenix definition), metastases-free survival, overall survival, and prostate cancer-specific survival rates were 97.8, 98.9, 76.7, and 99.1 percent, respectively.

CHOICE OF THERAPY — For men with low-risk clinically localized prostate cancer, brachytherapy, external beam radiation therapy (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 low or very low-risk of recurrence, active surveillance with delayed definitive treatment if necessary is also an appropriate option. The most extensive data comparing these approaches come from the Prostate Testing for Cancer and Treatment (ProtecT) trial. (See 'ProtecT trial' below.)

The choice of therapeutic approach depends upon an informed patient decision incorporating knowledge about the potential advantages and disadvantages associated with each approach along with personal preferences. Important advantages, disadvantages, and contraindications associated are summarized in the appended tables (table 6 and table 7 and table 8). In addition, a contemporary study based upon the Surveillance, Epidemiology, and End Results (SEER)-Medicare database analyzed the differences in the need for procedural repair of posttreatment toxicity [22]. Importantly, this study includes a cohort of patients without cancer who were age-matched with the treated patients; some men without prostate cancer will require surgery to deal with urinary issues, and evaluation of posttreatment toxicity must take this fact into account.

The importance of cost has become more important because of changes in the finances of healthcare. A study evaluating each these options using time-driven activity-based costing has demonstrated important differences among the various modalities [23]. In this analysis, external beam radiation with intensity-modulated RT (IMRT) was more expensive than prostatectomy, and all were more expensive than low dose rate brachytherapy.

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 [13,14]. 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 androgen deprivation therapy (ADT) for three to six months. Active monitoring used serum prostate-specific antigen (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 upon grade progression, rather than an increase in serum PSA, to prompt therapeutic intervention.

The patients were recruited from a PSA screening population aged 50 to 69 years and included 76 percent with stage T1c disease. The Gleason score was 6 in 77 percent of cases, and the Gleason score 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.

Results from the ProtecT trial have been published based upon a median follow-up of 10 years:

The primary endpoint of the trial was cancer-specific survival. The 10-year cancer-specific survival rates for active monitoring, radical prostatectomy, and RT were 98.8, 99.0, and 99.6 percent, respectively. There also was no significant difference in all-cause mortality, with all-cause death rates per 1000 person-years of 10.9, 10.1, and 10.3, respectively.

The differences between groups in cancer-specific survival were not statistically significant (hazard ratio [HR] for surgery versus active monitoring 0.63, 95% CI 0.21-1.93; HR for RT versus active monitoring 0.51, 95% CI 0.15-1.69; and HR for surgery versus RT 0.80, 95% CI 0.22-2.99). However, there were only 8, 5, and 4 prostate cancer-related deaths, and longer follow-up may eventually reveal significant differences.

The development of metastases (bone, lymph node, visceral, or a serum PSA >100 ng/mL), a secondary endpoint in the trial, was significantly more frequent in patients managed with active monitoring (33 men with metastatic disease versus 13 and 16 for those assigned to radical prostatectomy or RT, respectively, 6.3 versus 2.4 and 3.0 per 1000 person-years).

The incidence of clinical progression was also significantly more frequent in those managed with active monitoring, and 40 percent of men assigned to active monitoring underwent active therapy within five years. 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 112, 46, and 46 men assigned to active monitoring, radical prostatectomy, or RT, respectively (22.9, 8.9, and 9.0 per 1000 person-years). The criteria for the detection of clinical progression (especially PSA progression) between the three modalities differ significantly and may have influenced these results.

Longer follow-up will be required to know whether the higher incidence of metastatic disease with active monitoring compared with radical prostatectomy or RT can affect cancer-specific or overall mortality and what the impact of subsequent treatment for metastatic disease has on quality of life and survival.

The results of the trial are subject to several additional limitations. The applicability of the results of this trial to older men (≥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. Furthermore, the management of metastatic disease is evolving rapidly and may result in improvements in patient survival for patients who do develop metastatic disease.

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 [24]. The trial is designed to enroll 7600 patients, and results are not anticipated until approximately 2030.

Quality of life — 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 upon patient-reported outcome measures provide important insights and can help guide the decision-making process [4,25,26].

In one study, 2550 men with localized prostate cancer were treated with radical prostatectomy, external beam RT, or active surveillance (1523, 598, and 429 cases, respectively) [25]. Outcomes were assessed at 36 months after treatment using the Expanded Prostate Cancer Index Composite (EPIC-26). Radical prostatectomy was associated with a greater decrease in sexual function and more urinary incontinence than either RT or active surveillance. However, irritative urinary symptoms were less common with radical prostatectomy than with either RT or active surveillance.

In another study, 1141 men with localized prostate cancer were managed with radical prostatectomy, external beam RT, brachytherapy, or active surveillance (469, 249, 109, and 314 cases, respectively) [26]. Quality of life was assessed for two years using the Prostate Cancer Symptoms Indices instrument. Sexual function in men with excellent 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 these symptoms had largely disappeared by 24 months.

In a study of 1201 men treated for clinical T1/T2 prostate cancer, treatment included radical prostatectomy, external beam RT, or brachytherapy (in 601, 292, and 306 cases, respectively) [4].

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. In 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 [14]. These results were consistent with other studies, showing somewhat worse urinary symptoms and sexual function related to surgery, and more bowel symptoms related to RT. There were no meaningful differences in overall health-related quality of life, and differences in specific parameters decreased with time.

POST-TREATMENT SURVEILLANCE — Follow-up surveillance after initial definitive 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.

With the availability of sensitive testing for serum PSA, 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 during and after treatment for 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: Prostate cancer treatment; stage I to III cancer (Beyond the Basics)" and "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

The clinical assessment of the anatomic extent of disease, serum prostate specific antigen (PSA), and biopsy Gleason score are used for risk stratification which then guides the initial choice of therapy in conjunction with patient age, comorbidity, and personal preferences (table 1 and table 2). (See "Prostate cancer: Risk stratification and choice of initial treatment".)

For men with clinically localized, very low-risk prostate cancer and a life expectancy of less than 20 years, 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, causing many patients to subsequently choose definitive intervention even in the absence of progressive disease. Radiation therapy and radical prostatectomy are acceptable alternatives for patients preferring immediate definitive therapy. (See 'Active surveillance' above.)

For men with low-risk prostate cancer and a life expectancy of greater than 10 years, definitive therapy (radical prostatectomy, brachytherapy, or external beam radiation therapy [RT]), or active surveillance may all be appropriate options. 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. (See 'Radiation therapy' above and 'Radical prostatectomy' above and 'Active surveillance' above.)

For patients with a more limited life expectancy (less than 10 years) we suggest active surveillance (Grade 2C). (See 'Active surveillance' above.)

Although disease control with radical prostatectomy and radiation therapy are similar, there are important differences in the patterns of toxicity associated with these treatments. The advantages, disadvantages, and contraindications with each treatment modality are summarized in the attached tables (table 6 and table 7 and table 8) (See 'Choice of therapy' above.)

Irritative and obstructive urinary symptoms are more common after RT, particularly brachytherapy. Incontinence is more frequent after radical prostatectomy, but generally improves gradually after surgery.

Bowel symptoms (urgency, frequency) are more common after external beam RT and brachytherapy than with 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. At 24 months, sexual symptom scores are similar among men treated with RP, RT, and brachytherapy.

Follow-up surveillance after initial definitive treatment is an important component of patient management since salvage may be feasible if recurrence is detected early. (See "Follow-up surveillance during and after treatment for prostate cancer".)

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REFERENCES

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