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Active surveillance for men with low-risk, clinically localized prostate cancer
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Active surveillance for men with low-risk, clinically localized prostate cancer
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Nov 28, 2016.

INTRODUCTION AND DEFINITION OF TERMS — Active surveillance for men with prostate cancer involves the avoidance or postponement of immediate therapy combined with careful surveillance; definitive treatment is then offered if there is evidence that the patient is at increased risk for disease progression. Active surveillance is the preferred option for the initial management of most men with localized low-risk prostate cancer [1,2].

Active surveillance differs from watchful waiting (observation), which is based upon the premise that men will not benefit from definitive treatment of clinically localized prostate cancer because of limited life expectancy, comorbidity, and the prolonged natural history of the prostate cancer [3]. For patients managed with watchful waiting, the decision is made at the outset to forego definitive treatment and to provide systemic or local treatment to palliate symptoms if disease progresses locally or at distant metastatic sites.

Key aspects of active surveillance for patients with localized low-risk prostate cancer will be reviewed here, including:

Rationale

Criteria for patient selection

Frequency and type of monitoring during active surveillance

Criteria for switching from surveillance to definitive therapy

Clinical outcomes

Other approaches to the management of patients with localized prostate cancer based upon risk of recurrence are discussed separately. (See "Prostate cancer: Risk stratification and choice of initial treatment" and "Initial approach to low- and very low-risk clinically localized prostate cancer".)

RATIONALE — The use of active surveillance as a treatment option in men with low-risk prostate cancer is based upon several assumptions [4]:

Prostate cancer is often detected when it is not clinically significant, and it may not become clinically significant during the patient's lifetime. The growth rate of many prostate cancers is slow, and the biologic propensity for metastasis is low in many cases. For many men, low-risk prostate cancer either never requires treatment or treatment can be postponed for a prolonged period without significantly decreasing the chance for cure.

Patients who have indolent prostate cancer can be distinguished by clinical and/or pathologic parameters from those who will have more aggressive disease that will lead to symptoms, metastases, or death.

Definitive treatments for patients with prostate cancer, including those directed at minimal disease, are associated with significant side effects and costs.

With appropriate surveillance, patients can be reclassified as being at higher risk for disease progression and receive definitive therapy without substantially decreasing the chance of cure.

The psychological burden of living with prostate cancer without active treatment is modest and certainly has less impact on quality of life than receiving definitive treatment.

Evidence supporting the concept that many men have asymptomatic prostate cancer that is indolent and does not require immediate treatment comes from a number of sources:

Autopsy studies have shown that there is a high incidence of occult cancer in the prostate of men dying without a known prostate cancer. The frequency of such tumors may be as high as 30 percent in men under 40 years, and may approach 70 to 80 percent in those 60 to 80 years of age. (See "Risk factors for prostate cancer", section on 'Age'.)

A high frequency of occult prostate cancer was observed in the Prostate Cancer Prevention Trial, in which men underwent routine prostate biopsy at the completion of the trial [5]. Among those who had received placebo, 15 percent of those without an elevated serum prostate-specific antigen (PSA) or abnormal digital rectal examination had occult prostate cancer. (See "Chemoprevention strategies in prostate cancer", section on 'Finasteride: Prostate Cancer Prevention Trial'.)

Epidemiologic studies since the introduction of PSA-based screening indicate that the number of cases of prostate cancer is substantially higher than was seen prior to the screening era. Extrapolations based upon the frequency of a serum PSA >2.5 ng/mL in men 50 to 70 years of age and the rate of a positive biopsy in that population subset suggest that there are over 500,000 undiagnosed cases of prostate cancer in this group [6].

The low risk of prostate cancer-specific mortality was illustrated by a series of 9557 patients with organ-confined disease and a Gleason score of 6 or less, in which only three patients died of prostate cancer [7]. The 15-year prostate cancer-specific mortality risk was approximately 1 percent.

PATIENT SELECTION — Identification of those patients whose disease is at low risk for progression for an extended period is a critical issue in the choice of active surveillance for men with prostate cancer [4].

Guideline recommendations — The use of active surveillance for patients with localized low-risk prostate cancer has been endorsed by key guideline-setting groups:

The Cancer Care Ontario (CCO) guidelines, which have been endorsed by the American Society of Clinical Oncology (ASCO), recommend active surveillance for most patients with low-grade (grade group 1 [Gleason 6]), localized prostate cancer [1]. Active surveillance may also be considered for patients with grade group 2 (Gleason score 7 [3+4]), who have low-volume and percentage Gleason 4 pattern pathology (<10 to 20 percent pattern 4), and/or age older than 75 years.

Factors such as younger age (<55 years), high-volume disease, patient preference, and/or African-American ethnicity should be taken into account. For patients with a limited life expectancy (<5 years) and low-risk prostate cancer, watchful waiting may be more appropriate than active surveillance.

The National Comprehensive Cancer Network (NCCN) guidelines define a very low-risk group, which includes the criteria for the tumor, node, metastasis (TNM) prognostic stage group I in the 2017 TNM staging system [2]. In addition, these patients must have fewer than three positive biopsy cores, with ≤50 percent cancer in each core, and a prostate-specific antigen (PSA) density <0.15 ng/mL/g. In this very low-risk group, the NCCN recommends active surveillance as the preferred option for those with a life expectancy less than 20 years.

For the low-risk group (prognostic stage group I), the NCCN considers active surveillance an option, along with radical prostatectomy and radiation therapy, for those with a life expectancy >10 years. For those with a life expectancy <10 years, these guidelines recommend observation, with the expectation to deliver palliative therapy for the development of symptoms, or a change in exam or PSA that suggests symptoms are imminent.

The distinction between low and very low risk, based on volume of histologic grade group 1 (Gleason 6) cancer and PSA density, is based on several studies, which demonstrate a correlation between higher volume low-grade cancer and the presence of occult higher grade cancer. There is a consensus, however, that in the absence of higher grade cancer, the metastatic potential of grade group 1 is virtually zero. Thus, patients with higher volume grade group 1 (Gleason 6) may warrant more intensive evaluation (ie, multiparametric magnetic resonance imaging [MRI] and/or more extensive biopsies).

NCCN guidelines also consider active surveillance an option for patients with favorable intermediate-risk prostate cancer.

The American Urological Association (AUA) considers active surveillance, interstitial brachytherapy, external beam radiation therapy, and radical prostatectomy appropriate treatment options for patients with low and intermediate-risk prostate cancer [8]. These guidelines concluded that the available data on outcomes and complications were insufficient to recommend any one form of treatment over another for any risk category of disease. These guidelines recommend that all men with clinically localized prostate cancer be informed about all four of these treatment strategies, with a discussion of estimated benefit as well as harm from each intervention.

Particular caution should be exercised if active surveillance is being considered in men with intermediate-risk prostate cancer. An analysis of 945 of patients compared outcomes in 237 patients with intermediate-risk disease versus the 708 patients with low-risk disease [9]. Cancer specific survival was significantly poorer at 15 years for those with intermediate-risk disease (88.5 versus 96.3 percent, hazard ratio [HR] 3.75, 95% CI 1.37-10.28), and there was an increased risk of developing metastatic disease (4.6 percent versus 0.8 percent). Overall survival for intermediate-risk patients was also worse (15-year overall survival 50 versus 69 percent, HR 2.08, 95% CI 1.49-2.89), although this may reflect differences in the patient populations [10].

Guideline criteria — Although definitive criteria for patient selection have not been established in formal clinical trials, large case series have been used to establish guidelines for patients at low risk of disease progression.

Key elements of the CCO guidelines, which have been endorsed by ASCO and NCCN, include the following:

Clinically localized disease (≤T2a).

Gleason score 6 (3+3), grade group 1 (table 1). Some patients with Gleason score 7 (3+4), grade group 2, may also be considered for active surveillance if there are only focal areas of pattern 4 disease comprising ≤10 percent of the biopsy area.

Serum PSA <10 ng/mL.

The application of these criteria or of nomograms for helping a patient to decide whether to pursue active surveillance must be carefully individualized. Active surveillance for intermediate-risk disease may be particularly appropriate in patients who are older and/or those with significant comorbidity. Treatment-related toxicity (impotence, incontinence, acute surgical complications) appears to be more frequent in older men, making a more inclusive approach to active surveillance more attractive [11]. (See "Prostate cancer: Risk stratification and choice of initial treatment", section on 'Nomograms'.)

Other parameters — A number of other factors may influence the decision of whether to manage a specific patient with active surveillance.

Multiparametric MRI of the prostate is rapidly evolving and has promise as a diagnostic test that may optimize patient selection for active surveillance as well as for monitoring those already on active surveillance. The strength of MRI in the setting of surveillance is data from numerous sources reporting a high negative predictive value (between 85 and 100 percent) for clinically significant disease. The limitation of the conventional approach to surveillance has been the misclassification of risk in 25 to 30 percent of patients, based on the presence of occult higher grade cancer in men whose biopsy shows only Gleason 6. MRI appears to be accurate at identifying many of these patients, which should improve the long-term mortality rate. A negative MRI also provides reassurance to patients that their disease is truly low risk and, thus, may improve retention of an active surveillance approach. (See "The role of magnetic resonance imaging in prostate cancer".)

Although controversial, several sites have recommended a repeat prostate biopsy before committing to a plan for active surveillance in order to identify patients in whom the original biopsy may have missed evidence of increased risk [12]. Delaying this biopsy for six months to a year is unlikely to have an impact on long-term outcome, even if higher grade disease is eventually identified. In most such patients, upgrading is to Gleason 3+4, and delayed treatment is still effective. (See 'Prostate biopsy' below.)

Some groups have incorporated the number of positive cores on the original biopsy, the percentage of positive cores, the extent of tumor involvement within a biopsy core, the PSA density, and PSA kinetics, but these parameters have not been shown to add discriminatory value and have not been incorporated into patient selection guidelines [1,2,13].

In older patients, a comprehensive geriatric assessment may be useful in determining whether a definitive intervention, active surveillance, or watchful waiting is most appropriate. (See "Comprehensive geriatric assessment for patients with cancer".)

Molecular prognostic tests are emerging, specifically with an aim to better risk stratify both untreated and treated men with localized prostate cancer. Such tests may eventually offer additional information on the appropriate selection of patients for active surveillance. (See "Molecular prognostic tests for prostate cancer".)

Ethnicity — African American ethnicity may be an additional factor to consider in deciding whether or not to use active surveillance as the initial treatment approach in men with low-risk prostate cancer.

African American ethnicity is associated with an increased incidence of prostate cancer. In this population, prostate cancer has a significantly earlier age of onset, higher PSA levels, worse Gleason scores, and more advanced stage of disease at presentation. These associations are multi-factorial, and may also reflect issues of access to care and early detection as well as inherent genetic and environmental factors. (See "Risk factors for prostate cancer", section on 'Ethnicity'.)

The potential increased risk with active surveillance is illustrated by the outcomes in which a series of African American men who chose radical prostatectomy for very low-risk prostate cancer were compared with a comparable group of men of white or other races [14]. All men had clinical stage T1c disease, biopsy Gleason score ≤6 using contemporary Gleason criteria, no more than two positive biopsy cores, less than 50 percent involvement in any one core, PSA ≤10 ng/mL, and a PSA density ≤0.15 ng/mL/cm3. In the radical prostatectomy specimens, the African American men had significantly higher rates of upgrading of their Gleason pathology (33 versus 13 percent) and positive surgical margins (19 versus 6 percent). On multivariable analysis, the increased risk of unfavorable findings at prostatectomy was statistically significant compared with the combined results for white and other races.

However, the majority of black men who choose active surveillance are able to avoid overtreatment. Ethnicity is only one of many factors that should be taken into consideration in the selection of active surveillance or active treatment. MRI and/or molecular biomarkers may facilitate the confidence with which patients with Gleason 6 cancer and other risk factors (race, family history) can be offered surveillance, as well as those with favorable intermediate-risk disease. (See "Molecular prognostic tests for prostate cancer".)

SURVEILLANCE STRATEGY — Careful surveillance is required to identify men whose disease manifests an increased risk of progression and, therefore, requires definitive therapy.

The primary parameters available for monitoring include the serum prostate-specific antigen (PSA), digital rectal examination, and repeat prostate biopsy, but no clinical studies have defined the appropriate testing intervals and the criteria to trigger active intervention. Increases in serum PSA or abnormalities on digital rectal examination should serve as an indicator for more detailed evaluation.

Serum PSA — Serum prostate-specific antigen PSA should be repeated every three to six months. Different series have advocated different criteria for re-assessment. While there are no hard cutoffs for PSA, in our series a PSA doubling time of <3 years or a rise of PSA >10 to 15 should trigger re-assessment, either with biopsy or magnetic resonance imaging (MRI).  

Digital rectal examination — Digital rectal examination should be repeated yearly in an effort to detect any clinical evidence of progression. Serum PSA and repeat prostate biopsy may be repeated more frequently if there is clinical suggestion of progression on digital rectal examination.

Prostate biopsy — A repeat prostate biopsy is generally performed within the first year to rule out higher grade disease that may have been missed on the original biopsy. A negative MRI in men who are very low risk may be sufficient to avoid a confirmatory biopsy; this question is currently the subject of several prospective trials.

Following this, subsequent biopsies and/or MRI are repeated to look for evidence of biologic progression to Gleason 4+3 (grade group 2 (table 1)) or higher. The optimal frequency for subsequent biopsies is not well established. The Cancer Care Ontario guideline recommends serial biopsies every two to five years, while the National Comprehensive Cancer Network (NCCN) guidelines indicate that biopsy should be repeated no more often than every 12 months unless clinically indicated.  

Many men who ultimately require active intervention actually represent a subset of patients who were undersampled originally. In a series of 470 men initially included in an active surveillance program at Johns Hopkins, patients underwent annual prostate biopsies to identify evidence of progression [15]. Overall, 51 patients (11 percent) underwent radical prostatectomy. Three-fourths of those who progressed did so within one to two years after the original diagnosis, suggesting undersampling of more aggressive tumor rather than progression of indolent tumor.

Prevention of progression — Treatment with dutasteride, a 5-alpha reductase inhibitor, may benefit men on surveillance. (See "Chemoprevention strategies in prostate cancer", section on '5-Alpha reductase inhibitors'.)

In the multicenter REDEEM trial, treatment with dutasteride significantly decreased or delayed the risk of pathologic or therapeutic progression (an increase in volume or grade of disease, or treatment of prostate cancer for any reason) compared with placebo [16]. There was no evidence of an increase in the number of patients with high grade prostate cancer on the final biopsy.

These results require confirmation in larger numbers of patients with longer follow-up. The trial was relatively short term, and there are no data on clinical progression.

OUTCOMES — The available data on patient outcomes with active surveillance come from observation studies [4]. Large, randomized trials that compare active surveillance with immediate intervention are in progress. (See 'Randomized trials' below.)

Observational studies — Multiple observational studies provide important information about the clinical course of patients managed with active surveillance, although additional longer-term follow-up is needed. These studies consistently have found a low rate of progression to metastatic disease or death from prostate cancer with active surveillance; in addition, the majority of patients did not require definitive therapy within the time frame of these studies [13,17-22]. These results are illustrated by the following large studies:

In the multicenter international PRIAS study, 5302 patients with low-risk prostate cancer were managed prospectively with active surveillance according to a predefined protocol consistent with other active surveillance protocols; 622 patients were followed on active surveillance for >5 years and 107 for >7.5 years [13]. For the entire cohort, 99 percent of patients had Gleason 6 (grade group 1) disease, 88 percent had clinical T1 disease, and 11 percent had clinical T2a disease.

At five and 10 years of follow-up, 52 and 73 percent, respectively, of men had discontinued active surveillance. Of those discontinuing active surveillance, 62 percent did so because of reclassification as higher risk. Among the patients subsequently treated with radical prostatectomy, one-third were found to still have favorable pathologic features (Gleason 6, pT2). As of the 2016 report, 30 men in the entire study had a biochemical recurrence following definitive treatment, 10 had local recurrence, eight developed metastases, and one died of prostate cancer.

An analysis of the criteria used to initiate definitive treatment found that only Gleason upgrading (Gleason ≥7) or clinical T3 disease was predictive of unfavorable pathologic features. A prostate-specific antigen (PSA) doubling time of zero to three years and the presence of more than two positive cores, which were originally criteria for definitive treatment, were not predictive of unfavorable pathology on subsequent radical prostatectomy.

A prospective database from Toronto included men who were initially managed with active surveillance beginning in 1995 [22]. The patient population included those with low-risk disease (Gleason score ≤6 and serum PSA ≤10 ng/mL) and those with favorable intermediate-risk disease (serum PSA ≤15 ng/mL or a Gleason score 7 [3+4]) who had significant comorbidity or a life expectancy less than 10 years.

The most recent analysis of this database included 945 patients, 732 with low-risk disease and 213 with intermediate-risk disease. With a median follow-up of approximately 6.5 years, metastasis-free survival at 10 and 15 years was 96 and 95 percent, respectively for those with low-risk disease. For those with intermediate-risk disease, the 10- and 15-year metastasis-free survival rates were 91 and 82 percent. The worse outcome in those with intermediate-risk disease was primarily associated with Gleason 7 (3+4) disease.

In the Johns Hopkins experience, 1298 men have been followed for a median of five years [23]. Planned follow-up included annual repeat prostate biopsy. The cumulative incidences of grade reclassification at 10 and 15 years were 26 and 31 percent, respectively; factors associated with an increased incidence of grade reclassification included older age, PSA density, and number of positive cores. The 10- and 15-year rates of curative intervention were 50 and 57 percent, respectively; increased PSA density and a greater number of positive biopsy cores were associated with an increased incidence of definitive therapy. Their more stringent approach to active surveillance eligibility (confined to very low risk for men <70 in younger men, and low risk in older men) was associated with a 15-year prostate-cancer-mortality of only 0.4 percent. This emphasizes both the extremely low risk of active surveillance as a management strategy and the trade-offs involved in a more inclusive approach.

The reasons men discontinue active surveillance were analyzed in a series of 1729 men in a Swedish database who were followed for a minimum of five years [24]. At five years, 64 percent of the men remained on active surveillance. Discontinuation of active surveillance was due to PSA progression, biopsy progression, or personal preference in 52, 24, and 20 percent of cases, respectively.

Randomized trials — A definitive assessment of the role of active surveillance in favorable-risk prostate cancer patients requires a direct comparison between immediate treatment and active surveillance including definitive treatment for evidence of progression.

Two large older studies, the Scandinavian Prostate Cancer Group 4 trial [25] and the PIVOT trial [26], 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. (See "Radical prostatectomy for localized prostate cancer", section on 'Survival impact of radical prostatectomy'.)

In the Prostate Testing for Cancer and Treatment (ProtecT) trial that is being conducted in the United Kingdom (NCT00632983), patients were randomly assigned to active monitoring, radical prostatectomy, or definitive radiation therapy [27,28]. Patients assigned to active monitoring had their 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.

In the initial report of this trial, there was no significant difference in the 10-year cancer-specific survival or overall survival rates. However, there was an increased frequency of metastatic disease and clinical progression, and there were only a very limited number of deaths related to prostate cancer.

Detailed results and limitations of the ProtecT trial are discussed separately. (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'ProtecT trial'.)

Quality of life — The main advantage of active surveillance is the avoidance or deferral of treatment-associated side effects. These advantages are difficult to quantify. A detailed decision analysis that focused on hypothetical, otherwise healthy 65-year-old men with low-risk, localized prostate cancer used quality of life as the endpoint [29]. In this analysis, active surveillance was associated with a higher quality-adjusted life expectancy than initial treatment with external beam radiation therapy, brachytherapy, or radical prostatectomy. (See "Initial approach to low- and very low-risk clinically localized prostate cancer".)

A decision about whether to choose active surveillance or immediate treatment for early prostate cancer also needs to consider other factors that may affect quality of life:

Patients who are managed with active surveillance have the psychosocial burden of living with an indolent cancer without active treatment [30,31]. This anxiety can be a significant factor in causing many patients who are being managed with active surveillance to seek active treatment [32]. In the Toronto cohort, approximately one-third of patients sought active treatment for reasons other than disease progression [33]. (See 'Observational studies' above.)

Patients who are properly educated about the indolent course of good-risk prostate cancer may be better able to avoid some of the psychological complications associated with active surveillance [31]. Improved communication with the medical staff may improve both the acceptability of active surveillance as an initial approach as well as continuing participating in such a program [34,35].

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: 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)")

SUMMARY AND RECOMMENDATIONS

Active surveillance for men with low-risk, clinically localized prostate cancer utilizes observation rather than immediate therapy, with curative-intent treatment deferred, in most cases indefinitely or until there is evidence of an increased risk for disease progression. This approach is based upon the prolonged natural history of the prostate cancer and is an attempt to balance the risks and side effects of overtreatment against the possibility of disease progression and a lost opportunity for cure. (See 'Rationale' above.)

Outcomes for appropriately selected patients managed with active surveillance are similar to those in patients who receive immediate definitive therapy. (See 'Outcomes' above.)

Guidelines from the major guideline-setting bodies consider active surveillance the preferred option for men with low-risk, clinically localized prostate cancer and a potential option for those with favorable intermediate-risk disease. (See 'Guideline recommendations' above and "Prostate cancer: Risk stratification and choice of initial treatment".)

Identification of patients whose disease is at low risk for progression for an extended period is a critical issue in the choice of active surveillance for men with prostate cancer. Key criteria include clinically localized disease (≤T2a), grade group 1 (Gleason grade 6), and serum prostate-specific antigen (PSA) ≤10 ng/mL. (See 'Patient selection' above.)

For patients being managed with active surveillance, careful monitoring is required to detect early evidence of an increased risk of progression. (See 'Surveillance strategy' above.)

Repeat prostate biopsy is generally recommended within the first year to rule out high-grade disease missed on the original biopsy. Repeat subsequent biopsies should be performed every two to five years.

Serum PSA should be monitored every three to six months.

Digital rectal examination is recommended on an annual basis.

An increase in the pathologic grade, a significant rise in serum PSA, or an abnormality on digital rectal examination should serve as the basis for more detailed evaluation.

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