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Active surveillance for males with clinically localized prostate cancer

Active surveillance for males with clinically localized prostate cancer
Literature review current through: Jan 2024.
This topic last updated: Aug 24, 2022.

INTRODUCTION — Prostate cancer is the most common cancer among males in the United States [1] and other countries, as indicated in the World Health Organization GLOBOCAN database. However, a very large number of males are diagnosed with low-risk tumors that are unlikely to harm them if left untreated initially [2]. Furthermore, the treatment of prostate cancer often involves invasive therapy that often compromises sexual, urinary, or bowel-related quality of life [3]. As a result, active surveillance (AS) has emerged as a recommended management alternative to immediate treatment for carefully selected males with very low-, low-, and select patients with favorable intermediate-risk prostate cancer (table 1) [4-9]. AS is based on the assumption that initial assessment (particularly if it incorporates new tools such as prostate magnetic resonance imaging) is reasonably accurate for risk stratification, and that serial monitoring can successfully identify subclinical progression at a time when treatment is still curative in intent, and no more morbid than definitive treatment delivered at the time of diagnosis.

AS has grown rapidly over the last decade from an approach that was offered primarily at academic centers to worldwide adoption into clinical practice and incorporation into numerous guidelines [4-9], appropriately making it the preferred standard of care for males with very low- and low-risk prostate cancer [10]. However, the uptake of AS remains quite variable [11]. In addition, questions remain regarding who is and who is not an optimal candidate for AS.

Key aspects of AS for males with localized prostate cancer will be reviewed here, including the evidence supporting AS, optimal selection of patients for AS, approaches to tumor monitoring, and triggers for intervention. Other approaches to the management of patients with low- and intermediate-risk, localized prostate cancer are discussed separately. (See "Localized prostate cancer: Risk stratification and choice of initial treatment" and "Initial approach to low- and very low-risk clinically localized prostate cancer" and "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement".)

ACTIVE SURVEILLANCE VERSUS WATCHFUL WAITING — AS differs from watchful waiting (observation), which is based on the premise that males will not benefit from definitive treatment of clinically localized prostate cancer because of limited life expectancy, comorbidity, and the prolonged natural history of prostate cancer [12]. With AS, the treatment intent is cure, the follow-up schedule is predefined, and the aim is to minimize treatment-related toxicity without compromising survival, in a man with a reasonable (5 to 10 year) life expectancy and low- or favorable prognosis intermediate-risk disease. By contrast, there is no predefined schedule for watchful waiting, the aim is to minimize treatment-related toxicity and it may be applicable to patients at all stages of disease, especially if life expectancy is limited or significant comorbidity exists. While the age and health of the patient are always important considerations, AS is focused more on stratifying tumor risk and monitoring closely with the intent to provide timely definitive treatment if disease progresses.

RATIONALE FOR ACTIVE SURVEILLANCE — AS is based on the assumption that initial assessment (particularly if it incorporates new tools such as prostate magnetic resonance imaging [MRI]) is reasonably accurate for risk stratification, and that serial monitoring can successfully identify subclinical progression at a time when treatment is still curative in intent, and no more morbid than definitive treatment delivered at the time of diagnosis. The primary concerns with AS are twofold:

Disease may be misclassified at diagnosis, such that a patient with an aggressive cancer is incorrectly classified as having a low-risk cancer.

Favorable-risk cancer may evolve into higher-grade cancer during AS.

The rationale for AS as an alternative to definitive initial treatment for appropriately selected males with low-risk localized prostate cancer is as follows [2]:

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 males, low-risk prostate cancer either never requires treatment or treatment can be postponed for a prolonged period without significantly decreasing the chance for cure.

Evidence supporting the concept that many males 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 males dying without a known prostate cancer. The frequency of such tumors may be as high as 30 percent in males under 40 years, and it 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 males underwent routine prostate biopsy at the completion of the trial [13]. 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: PCPT'.)

The low risk of prostate cancer-specific mortality in males with low-risk disease (table 1) can be illustrated by data showing that males with grade group 1 disease (table 2) undergoing AS and followed long-term have less than a 1 percent risk of metastases, and a rate of prostate cancer mortality of 0.1 percent at 15 years [14].

Males 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. (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

Definitive treatments for patients with prostate cancer, including those directed at minimal disease, are associated with significant side effects and costs that are likely greater than the psychologic burden of living with prostate cancer without definitive treatment. (See 'Quality of life issues and psychologic comfort with surveillance' below.)

Prostatectomy data in patients otherwise meeting AS enrollment criteria suggest that the initial biopsy misclassification rate is on the order of 20 to 30 percent, and this may be lower if the initial biopsy includes MRI with MRI-targeted biopsy [15]. Furthermore, approximately one-third of AS patients show risk reclassification over time, and most do so within two to three years. With appropriate surveillance strategies, patients can be reclassified as being at higher risk for disease progression during AS, and receive definitive therapy without substantially decreasing the chance for cure. (See 'Outcomes' below.)

Quality of life issues and psychologic comfort with surveillance — A major advantage of AS is the avoidance or deferral of treatment-associated side effects. These advantages are difficult to quantify, with the exception of treatment-related side effects. An overview of the complications of radiation and surgical treatments for localized prostate cancer are presented elsewhere. (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'Outcomes and the choice of therapy'.)

However, a decision about whether to choose AS or immediate treatment for early prostate cancer also needs to consider factors other than treatment-related side effects that may affect quality of life. In a detailed decision analysis that focused on hypothetical, otherwise healthy 65-year-old males with low-risk, localized prostate cancer that used quality of life as the endpoint [16], AS was associated with a higher quality-adjusted life expectancy (QALE) than initial treatment with external beam radiation therapy, brachytherapy, or radical prostatectomy. However, the QALE gains and the optimal strategy were highly dependent on individual preferences for living under AS and for having been treated.

Males who are managed with AS have the psychosocial burden of living with an indolent cancer without active treatment [17,18]. This anxiety can be a significant factor in causing many patients who are being managed with AS to seek active treatment [19,20]. In the Toronto cohort, approximately one-third of patients sought active treatment for reasons other than disease progression [21].

On the other hand, males who are properly educated about the indolent course of good-risk prostate cancer may be better able to avoid some of the psychologic complications associated with AS [17]. Improved communication with the medical staff may improve both the acceptability of AS as an initial approach as well as the continuing participation in such a program [22,23]. (See 'Ensuring compliance with follow-up' below.)

Outcomes — 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 satisfy these criteria. However, taken together, the available data (mostly from older trials that compared definitive versus deferred initial therapy, usually watchful waiting) 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. [24-28]. Most of these data were derived in males with very low- and low-risk disease. These results are described in detail elsewhere. (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'Active surveillance'.)

Further evidence comes from the PROTECT trial that randomly assigned over 1600 males to "active monitoring," surgery, or radiation [29]. 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. Notably, MRI was not used to follow patients on active monitoring.

In the initial report of this trial (median follow-up 10 years), the development of metastases was significantly more frequent in patients managed with AS (33 males with metastatic disease versus 13 and 16 of those assigned to prostatectomy and radiation therapy, respectively), and the incidence of clinical progression was high (40 percent of males assigned to AS switched over to active therapy within five years). 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. Despite these findings, there were only a limited number of prostate cancer-related deaths in any of the groups, and there was no significant difference in the 10-year cancer-specific survival or all-cause mortality among the three treatments.

Additional support for AS in males with low-risk disease is provided by several single and multi-institutional series with intermediate- to long-term follow-up that have shown AS to be a safe alternative to immediate treatment with comparable survival in appropriately selected patients (table 3) [14,30-34].

INDICATIONS

Males at low risk of disease progression — Identification of males whose disease is at a low risk for progression is a critical issue in the choice of AS. Tumor grade, volume, and prostate-specific antigen (PSA) levels are the most common factors influencing the choice of AS, but other factors such as age, comorbidity and life expectancy, results of prostate magnetic resonance imaging (MRI) and genomic testing, the absence of certain histologic features on prostate biopsy (areas of cribriform or intraductal histology), psychologic comfort with AS, and the ability/willingness to follow-through with recommended monitoring during AS need to be considered. (See 'Tools to refine the selection of males for AS' below.)

Very low- and low-risk tumors – Guidelines from expert groups (including the National Comprehensive Cancer Network [NCCN], combined guidelines from the American Urological Association [AUA]/American Society for Radiation Oncology [ASTRO], and the American Society of Clinical Oncology [ASCO] [5-9]) all state that AS is the preferred approach for males with very low-risk prostate cancer, as defined by tumor grade volume, and PSA level (table 1). NCCN, AUA/ASTRO, and ASCO also consider AS an appropriate alternative to immediate definitive treatment for males with low-risk disease [5-8]. (See "Initial approach to low- and very low-risk clinically localized prostate cancer".)

Intermediate-risk tumors – Although controversial, AS is an option for males with favorable intermediate-risk disease (table 1), especially those who are older or have significant comorbidity and are willing to accept a potentially higher risk of developing metastases. AS is not indicated for males with unfavorable intermediate-risk disease, unless they are an older adult and/or have a limited life expectancy. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Options for intermediate-risk disease'.)

Unfortunately, there is no clear consensus as to how to substratify those who fall into a "more favorable" versus "less favorable" intermediate-risk category, nor whether all males in the favorable intermediate-risk category are good candidates for AS. Guidelines from the AUA/ASTRO, ASCO, Cancer Care Ontario, NCCN, and a combined guideline from the European Association of Urology/European Association of Nuclear Medicine/European Society for Radiotherapy and Oncology/ European Society of Urogenital radiology/International Society of Geriatric Oncology all endorse AS as a management option for carefully selected patients with intermediate-risk disease, but each defines that population of "favorable" intermediate-risk differently. Current guideline-based definitions of intermediate-risk prostate cancer and recommendations for AS from expert groups are outlined in the table (table 4). We consider that any of these definitions are appropriate.

Decision-making in a patient with favorable intermediate-risk disease who is considering AS rather than definitive local therapy must be carefully individualized. The main concern for intermediate-risk disease managed with AS is the possibility that outcomes may be worse, as was suggested in the PROTECT trial, described above. (See 'Outcomes' above.)

An important point is that being at an increased risk of progression based on a classification of intermediate risk disease compared with low-risk and very low-risk tumor does not mean AS is not an option [35,36]. Risk is measured on a continuous spectrum that requires a careful balance between avoiding overtreatment and ensuring cancer control. Other factors influencing the decision to pursue AS in this population include:

We tend to prefer upfront definitive treatment rather than AS for males with grade group 3 disease (table 2), and for those with high volume grade group 2 disease (three or more involved cores).

We discourage individuals with intraductal or cribriform histology subtypes from AS unless they are an older adult or have lower life expectancy, given the greater risk of progression and concern for undersampled higher-grade tumors. (See 'Histology' below.)

Tissue-based genomic prognostic markers can be used in males with favorable intermediate-risk disease to discover those who might have more aggressive disease, and better served by definitive therapy. However, while these tests are currently being used for treatment decision-making, better evidence is needed before they can be considered a standard component of the decision-making process for or against AS. (See 'Tissue-based genomic prognostic markers' below.)

The impact of these and other factors, including the results of tissue-based genomic testing and prostate MRI are discussed below. (See 'Tools to refine the selection of males for AS' below.)

Tools to refine the selection of males for AS — Tumor grade, volume, and PSA still represent the most common factors that are considered in the choice of AS for males with low-risk or favorable-intermediate risk prostate cancer. In the last decade, other factors, including multiparametric prostate (mp) MRI, histology, and tissue based genomic markers have emerged as helpful tools to select and monitor patients for AS, but more research is needed to understand how to best utilize these tools.

Future studies focusing on the prospective serial evaluation of these tests in all males undergoing surveillance will help us to better understand how to best use these tests and for whom they benefit the most. As an example, the Miami MRI for Active Selection of Treatment (MAST) trial is a single-institution study of males with very low- to intermediate-risk prostate cancer who are undergoing AS on a prospective National Cancer Institute (NCI) sponsored protocol [37]. Participants undergo an mpMRI and MRI targeted and template biopsy within 18 months of diagnosis and annually thereafter for the next three years, with blood and urine collected annually for biomarker assessment and cancer positive cores sent to Decipher Biosciences for expression profiling. We anticipate this trial will provide helpful information on serial biomarker assessment and its association with tumor progression, which may be useful for tailoring surveillance intensity to provide risk appropriate management.

Histology

Intraductal and cribriform histology – Intraductal histology (picture 1), which is not a component of the Gleason grade group classification system, is enriched for mutations in homologous recombination DNA repair genes (eg, BRCA2). Germline mutations in BRCA1, BRCA2, ATM, and CHEK2 have been associated with lethal prostate cancer [38,39], and males found to have BRCA or ATM mutations have a higher risk of grade reclassification among males undergoing AS [40]. As a result, some guidelines specifically exclude males with intraductal histology from AS protocols. (See "Genetic risk factors for prostate cancer", section on 'Prognostic impact' and "Interpretation of prostate biopsy", section on 'Intraductal carcinoma of the prostate'.)

Invasive cribriform patterns in prostatic adenocarcinoma (picture 2), represent Gleason 4 disease and have been recognized as a morphologic biomarker for poor prognosis of prostate cancer. It has even been suggested that the large expansile cribriform patterns (now defined as Gleason pattern 4) in prostatic adenocarcinoma should be distinguished from other Gleason pattern 4 lesions and possibly categorized as Gleason pattern 5. Some guidelines specifically exclude patients with cribriform histology from AS protocols [41]. (See "Interpretation of prostate biopsy", section on 'Modifications to the Gleason grading system'.)

Quantitative Gleason grading – One of the most important factors in the decision to proceed with AS versus definitive local treatment is the grade of cancer found on prostate biopsy. The best outcomes with AS are in males with grade group 1 disease. In fact, for males being managed with AS the emergence of grade group 2 (Gleason 3+4, (table 2)) cancer is often the most common trigger for stopping surveillance and intervening with definitive therapy [2]. (See 'Triggers for treatment intervention' below.)

Among males considering AS for intermediate-risk prostate cancer who have grade group 2 tumors (table 2), the amount of grade group 2 disease is important. As an example, a man with a biopsy core interpreted as grade group 2 cancer may have anywhere from as little as <5 percent Gleason pattern 4 to as much as 49 percent Gleason pattern 4; however, these patients are likely to behave very differently. The first patient is likely to have a risk of progression that is similar to males with low-risk disease; however, the second patient may behave more like a grade group 3 cancer.

A study of close to 500 males with grade group 2 cancer, matching biopsy, and radical prostatectomy tissue found that all methods of quantifying the extent of grade group 2 cancer in the biopsy specimen enhanced the prediction of adverse pathology in the radical prostatectomy specimen [42]. However, using the total length of Gleason pattern 4 cancer in the cores appeared to add the most value to predicting risk.

While most pathologists report the percentage of total cancer in each specimen core, only some report the actual amount of grade group 2 or higher cancer; the component on which a decision to treat is usually being based. If at all possible, pathology reports should include the percent of the higher Gleason score component, especially for males with grade groups 2 cancer. (See "Interpretation of prostate biopsy", section on 'Gleason grading system'.)

Multiparametric MRI of the prostate — Where feasible, multiparametric magnetic resonance imaging (mpMRI) of the prostate should be obtained in males with very low-, low-, and intermediate-risk disease who are considering AS to ensure that higher-grade disease has not been overlooked. However, in our view, for regions where MRI is not widely available or affordable, AS can be performed safely without the inclusion of prostate MRI. The role of prostate MRI for the confirmatory biopsy and for monitoring patients while on an AS protocol are addressed below. (See 'Confirmatory biopsy' below and 'Role of repeat biopsy and MRI during longitudinal follow-up' below.)

Multiparametric prostate MRI has emerged as the best method of localizing cancer within the prostate gland. A negative transrectal ultrasound (TRUS)-guided biopsy in the face of clinically determined need or indication for a prostate biopsy is the most validated and accepted indication for prostate MRI and MRI-targeted biopsy. However, accumulating evidence suggests that incorporation of prebiopsy MRI into the diagnostic pathway for any clinically suspected prostate cancer improves the diagnosis of clinically significant disease, reduces adverse effects from biopsy, and can potentially prevent unnecessary biopsies in some individuals. (See "Prostate biopsy", section on 'Choice of biopsy method by indication' and "The role of magnetic resonance imaging in prostate cancer", section on 'Initial presentation with no prior biopsy'.)

MRI of the prostate has emerged as an important component of optimizing patient selection for AS. The limitations of the conventional approach to risk stratification, as described above, in males being considered for AS has been the misclassification of risk in 25 to 30 percent of males, based on the presence of higher-grade prostate cancer in males whose TRUS-guided biopsy shows only grade group 1 disease. Prostate MRI may aid in the identification of occult higher grade tumors, even among patients with known clinically low-risk disease.

While MRI has a moderate diagnostic accuracy for detecting otherwise missed grade group 2 or higher disease, the strength of MRI in this setting comes from its high negative predictive value (NPV; 68 to 100 percent) for clinically significant disease (defined as grade group ≥2 disease (table 2)) [43-52]. As an example, a meta-analysis of seven studies, encompassing 1028 males on AS for low-risk prostate cancer found that mpMRI had a moderate diagnostic accuracy for grade group 2 or higher cancer with a sensitivity and specificity of 69 and 78 percent, respectively [44]. For a pretest probability of 20 percent, the positive predictive value was 44 percent, but the NPV was 91 percent. Thus, a negative MRI provides reassurance to patients that their disease is truly low risk, and it may improve retention in an AS strategy. This subject is discussed in more detail elsewhere. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Males choosing active surveillance'.)

The data are less robust on whether MRI is beneficial as a component of the confirmatory biopsy or thereafter, as a monitoring tool for males undergoing AS, and it remains uncertain whether the addition of MRI adds value to systematic biopsy and clinical variables in longitudinal follow-up. These data are discussed in detail below. (See 'Confirmatory biopsy' below and 'Role of repeat biopsy and MRI during longitudinal follow-up' below.)

Impact of PI-RADS classification on selection of candidates for AS — All of these series described above on use of MRI to select patients for AS predated the development of the Prostate Imaging Reporting and Data System (PI-RADS) for MRI classification of the likelihood of clinically significant cancer. Data examining whether MRI PI-RADS category can predict eligibility for AS or subsequent upgrading during AS are conflicting. However, we do not exclude males with an MRI PI-RADS 5 lesion from AS, but we do ensure that they undergo a confirmatory biopsy with MRI targeting plus systemic biopsies to exclude clinically significant cancer before considering this approach. (See 'Confirmatory biopsy' below and 'Role of repeat biopsy and MRI during longitudinal follow-up' below.)

MRI definitions for a clinically significant cancer are based on PI-RADS, which was developed by the International Prostate MRI Working Group to standardize prostate MRI examination performance and reporting. Developed in 2015, the most recent version, PI-RADS v2.1, which was published in 2019, revises the technical parameters for image acquisition and modifies the interpretation criteria for MRI data, among other changes [53].

PI-RADS categorizes prostate lesions based on the likelihood of cancer according to a five-point scale, defined as follows:

PI-RADS 1 – Clinically significant cancer is highly unlikely to be present.

PI-RADS 2 – Clinically significant cancer is unlikely to be present.

PI-RADS 3 – The presence of clinically significant cancer is equivocal.

PI-RADS 4 – Clinically significant cancer is likely to be present.

PI-RADS 5 – Clinically significant cancer is highly likely to be present.

In two separate studies, the probability of finding a clinically significant cancer (ie, lesion that is predicted to have a grade group of 2 or higher (table 2) with either a volume ≥0.5 mL or extraprostatic extension) in males with PI-RADS 3, 4, or 5 lesions was 12 and 23 percent, 60 and 49 percent, and 83 and 77 percent, respectively [54,55]. Although most studies measuring the diagnostic performance of prostate MRI have defined PI-RADS ≥3 lesions as indicative of a clinically significant cancer, the published literature regarding the significance of a PI-RADS 3 lesion is conflicting. This subject is discussed in more detail elsewhere. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Prostate imaging reporting and data system (PI-RADS)'.)

Data examining whether PI-RADS category on the baseline MRI can predict subsequent progression of disease while on AS (and therefore suitability for AS) are conflicting:

One retrospective analysis included 442 patients referred to the NCI for evaluation of prostate cancer, including mpMRI, and who met eligibility for AS (which included grade group 1 or 2 disease on confirmatory MRI-targeted biopsy in addition to systematic biopsy without concerning features [eg, T3 disease] on MRI) [56]. Of the 344 males who had at least one PI-RADS score documented, among those with an index lesion PI-RADS category 3 or lower, 17 percent (22 of 131) had progression to grade group 3 or greater while on AS, with a median time to progression of 76 months. For those with an index PI-RADS 4 lesion, 18 percent (29 of 162) had progression, with a median time to progression of 74 months, and for those with PI-RADS 5 lesions, 33 percent progressed (17 of 51), with a median time to progression of 31 months.

On the other hand, another analysis of males with clinically low-risk prostate cancer prospectively enrolled on AS at a single institution between 2000 and 2016 failed to show that a higher PI-RADS score was associated with an increased risk of progression to higher grade disease while on AS [57]. In multivariate analysis, biopsy reclassification was associated with higher PSA density, a greater percentage of biopsy cores positive and a high genomic prostate score (GPS), but PI-RADS score 4 or 5 was not associated with biopsy reclassification at any time point.

Tissue-based genomic prognostic markers — Molecular prognostic tests that are based on analysis of prostate cancer tissue for specific biomarkers are emerging, specifically with an aim to better risk stratify both untreated and treated males with localized prostate cancer. Several of these tests have been validated and are clinically available. (See "Molecular prognostic tests for prostate cancer", section on 'Available tests'.)

Three of these tests (Oncotype Dx Genomic Prostate Score [GPS], Myriad Genetics Polaris score, and Decipher Genomic classifier) have been studied for their utility for decision-making regarding initial definitive treatment versus AS in males with localized prostate cancer. Both the Decipher and Prolaris tests were developed initially for predicting metastasis after radical prostatectomy; their utility was subsequently evaluated for predicting adverse pathology in males considering AS. On the other hand, the GPS score was specifically designed to address heterogeneity and multifocality issues related to prostate biopsy in order to be useful for decision-making regarding the need for treatment versus AS on the basis of initial needle biopsies. These data are presented separately. (See "Molecular prognostic tests for prostate cancer", section on 'Genomic prostate score (Oncotype Dx Genomic Prostate Score)' and "Molecular prognostic tests for prostate cancer", section on 'Genomic classifier (Decipher)' and "Molecular prognostic tests for prostate cancer", section on 'Cell-cycle progression score (Prolaris)'.)

Although each of these tests has evidence supporting their role as a predictor of adverse pathology and/or cancer progression in males managed initially with AS, use remains variable and not widely accepted for the following reasons:

None of these tests has been validated for this use in a prospective randomized controlled trial. Furthermore, in the absence of head-to-head trials, there is no data on how best to equate results from one test to another, or to select one test over another.

Much of the literature surrounding these tests focuses on surgical patients who were candidates for AS and subsequently had prostatectomy with tissue available for profiling from the whole prostate gland. Less evidence is available in actual AS patients, for whom these tests are being used. One problem is that that different biopsy cores from the same prostate may yield different results on genomic testing [58].

Although molecular tests such as these have been shown to predict the risk of higher-grade and higher-stage disease in those thought to be good candidates for AS, not all studies confirm this [59]. As an example, a study from the multi-institutional Canary PASS prospective cohort found that GPS testing was unable to improve the prediction of males with low-risk prostate cancer who were likely to be pathologically upstaged at confirmatory biopsy, compared with a model based on clinical factors alone [60]. However, this study had a significant selection bias in that it only included the 432 out of 1041 males who had a GPS test available for evaluation. Furthermore, while the test may not have been able to predict pathologic reclassification, its ability to predict more relevant long-term endpoints (eg, survival, disease recurrence) remains uncertain.

In our view, while these tests are currently being used for treatment decision-making [61,62], better evidence is needed before any of these tests can be considered a standard component of the decision-making process for or against AS, particularly for males with low-risk disease. (See "Molecular prognostic tests for prostate cancer", section on 'Clinical utility and guidelines from expert groups' and "The role of magnetic resonance imaging in prostate cancer", section on 'Males choosing active surveillance'.)

In patients considering AS, we typically use genomic testing of tumor tissue selectively in cases where it might change management. This recommendation is consistent with guidelines from the NCCN and ASCO, which both support use of one of these genomic molecular assays to improve risk stratification in males considering AS who have low-risk or favorable intermediate-risk disease if the results of the assay might change clinical management [6,63]. The ASCO guideline also addressed the relative value of prostate MRI versus tissue biomarkers in this setting, concluding that each of these approaches can provide clinically relevant information regarding the likelihood of upgrading on subsequent biopsy or prostatectomy [63]. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Males choosing active surveillance'.)

Molecular markers of prostate cancer detection — Serum biomarkers such as the 4K score, and Prostate Health Index and urinary biomarkers such as SelectMDx prostate cancer antigen 3 and the Mi-prostate score are available to assist in the detection of clinically significant prostate cancer in order to help decide if a prostate biopsy is warranted.

There is very limited evidence supporting a role for any of these molecular markers for decision-making related to suitability for AS, and we suggest not using them for this purpose. Although some markers have been evaluated for predicting reclassification and may have some benefit in helping to select appropriate patients for surveillance versus treatment [64]; none of the studies have examined the relative benefit of any these markers compared with other tests that are more commonly used in AS, such as mpMRI or tissue-based genomic markers.

Confirmatory biopsy — For most patients considering AS for low-risk or favorable intermediate-risk prostate cancer, we advise a confirmatory biopsy at 6 to 18 months that incorporates a prostate MRI, where feasible, to permit MRI targeting of suspicious regions during the procedure, and reducing uncertainty regarding the presence of a missed higher-grade tumor. Patients with unfavorable clinical parameters (eg, extensive grade group 1 disease (table 2), high PSA density, African American ethnicity, or a family history of early prostate cancer mortality) should have a confirmatory biopsy even if the MRI is negative.

Most urologists believe in the value of a subsequent "confirmatory" biopsy to be performed anywhere from 6 to 18 months after initial diagnosis before committing to a plan for AS in order to identify patients in whom the original biopsy may have missed evidence of higher-risk disease [65]. Contemporary studies would suggest that upgrading or reclassification on subsequent biopsy would occur in as many as 20 to 35 percent of cases with low-risk disease at diagnosis. Rates of misclassification are lower (10 to 20 percent) when prostate mpMRI-targeted biopsy approaches are utilized during the diagnostic biopsy [66]. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Initial presentation with no prior biopsy'.)

The rationale for pursuing a confirmatory biopsy is that based on systematic biopsies, misattribution of grade (finding only grade group 1 disease on the initial biopsy when disease of grade group 2 or greater is present (table 2)) occurs in up to 35 percent of males who are being considered for AS [15,67,68].

Multiple guidelines recommend MRI prior to the confirmatory biopsy in an effort to reduce sampling error [6,8,41]. Furthermore, prospective studies have also evaluated the use of serial MRI for the monitoring of males on AS, with most providing evidence of improved sensitivity for upgrading when a combined approach is used [69-73]. (See 'Role of repeat biopsy and MRI during longitudinal follow-up' below.)

The available data addressing whether the addition of MRI to systematic biopsies leads to less missed detection of clinically significant cancer than systematic biopsy alone for the confirmatory biopsy are conflicting:

The prospective Canary PASS study found that neither mpMRI nor genomic profiling with GPS scores improved upon clinical models in predicting reclassification from grade group 1 to 2 cancer on confirmatory biopsy [45,60]. However, others have found both GPS and PIRADS version 2 scores to be independently associated with biopsy upgrade in males undergoing monitoring during AS at UCSF [61]. While both of these studies provide insight into the utility of mpMRI and genomic profiling in AS, they are based only on a subgroup of patients who were able to get the tests during clinical practice, which may explain the discordant findings.

On the other hand, in a randomized trial in males undergoing AS for low-risk prostate cancer in whom a confirmatory biopsy was indicated, the addition of MRI with targeted biopsies to systematic TRUS-directed biopsies did not significantly increase the upgrading rate compared with systematic biopsy alone. After central pathology review, upgrading was observed in 36 of 132 males in the systematic biopsy arm and 42 of 127 males in the MRI arm (27 versus 33 percent, p = 0.3) [52]. However, there were significant differences among the three sites participating in the study, and at the site with the most experience with the MRI fusion biopsy system, the upgrading rate on targeted biopsy plus systematic biopsy was actually higher than the upgrading rate with 12-core systematic biopsy alone. Notably, both systematic and targeted biopsy (alone) missed clinically significant cancer in 6 and 8 percent of patients, respectively, suggesting that a combined approach would minimize the risk of missing clinically significant disease.

A later analysis of this trial that addresses repeat biopsies with extended follow-up is discussed below. (See 'Role of repeat biopsy and MRI during longitudinal follow-up' below.)

Is a negative MRI sufficient to forego a confirmatory biopsy? — As noted above, we generally perform magnetic resonance imaging (MRI) prior to the confirmatory biopsy; if a lesion is seen on MRI, a targeted biopsy is performed in addition to systematic biopsies. We also perform systematic confirmatory biopsies if the MRI is negative, or if MRI is not feasible.

At least some data, mostly derived from series incorporating MRI into serial monitoring during AS, suggest that a negative MRI in this setting is sufficient to forego a confirmatory biopsy [69]. However, others suggest that systematic biopsy can reveal clinically significant cancer, regardless of the MRI findings in this situation. In the randomized ASIST trial described above, in the MRI arm, five of the 45 patients with MRI negative findings (11 percent) had clinically significant cancers detected on systematic biopsy, and in the entire cohort, targeted biopsy missed clinically significant cancer in 8 percent of patients [52]. The authors concluded that patients at high risk for occult higher-grade disease should undergo systematic biopsies regardless of the MRI findings. (See 'Confirmatory biopsy' above.)

This issue is currently the subject of several prospective trials. In these trials, subsequent biopsies and/or MRI are repeated to look for evidence of biologic progression to grade group 2 (table 2)) disease or higher. Until the results of these trials are known, in our view, systematic biopsy should still be done for the confirmatory biopsy, even if MRI is negative.

Other factors — AS has been established as a safe management strategy for carefully selected males with prostate cancer, yet specific subgroups are perceived to be at greater risk of poor outcomes, which may influence decision making about AS as an option. This section will review the data on age and life expectancy, race/ethnicity, and the results of germline genetic testing.

Age and life expectancy – The suitability of AS for younger males has been questioned out of concerns surrounding the safety, durability of surveillance, and eventuality of definitive treatment. Younger age (eg, <60 years) has empirically served as a major driver in decision-making for localized prostate cancer, favoring early treatment in younger males [74,75]. However, increasing age is a risk factor for prostate cancer-specific mortality, and younger patients have higher baseline urinary and sexual function at the time of diagnosis and, therefore, stand to lose the most with immediate treatment [76,77].

Some (but not all [78]) data suggest that younger males may be actually less likely to upgrade while on AS than older males [79-85]:

In one report, the five-year incidence of biopsy grade reclassification Gleason score ≥4+3 in males undergoing AS who were <60, 60 to 69, and ≥70 years of age was 4, 7, and 14 percent, respectively [80].

In another AS cohort of 1433 males in which 42 percent were <60 years old, younger age was associated with a lower risk of Gleason score upgrade (hazard ratio [HR] 0.969, 95% CI 0.956-0.983), but there was no association between younger age and risk of definitive treatment while on AS or risk of biochemical recurrence after delayed prostatectomy [81].

AS is an option across all levels of life expectancy depending on the risk of the tumor. However, for those with an expected life expectancy of less than ten years (or as males undergoing AS get older or develop additional comorbidities), the intensity of monitoring during AS may decrease. In some cases, the strategy may transition to more of a watchful waiting approach. (See 'Active surveillance versus watchful waiting' above and 'Overview of our general approach to monitoring' below.)

Race/ethnicity – Some (but not all) data suggest that AS for Black males carries a greater risk for poor outcomes than is seen in males of other races/ethnicities, although these differences are likely multifactorial in etiology, and may be a consequence of race-based differences in care [86,87]:

The potentially increased risk with AS in Black males can be illustrated by the outcomes of a series in which Black males who chose radical prostatectomy for very low-risk prostate cancer were compared with a comparable group of males of other races [88]. All males met the NCCN criteria for very low-risk disease (table 1). In the radical prostatectomy specimens, the Black males had significantly higher rates of upgrading of their Gleason pathology (33 versus 13 percent) and positive surgical margins (19 versus 6 percent). On multivariate analysis, the increased risk of unfavorable findings at prostatectomy was statistically significant compared with the combined results for other races. These data suggest that outcomes would have been worse had these males chosen AS rather than prostatectomy. This raises questions of the quality of the initial biopsy and under-sampling at time of diagnosis, which are known sequelae of race-based differences in care.

Others, using data from the Surveillance, Epidemiology, and End Results prostate AS/watchful waiting cohort, have shown racial disparities in mortality from prostate cancer, which were greatest in Gleason score 6 disease [89]. Although the absolute difference was small, Black males with Gleason score 6 (but not Gleason score 7 to 10) disease were twice as likely to die of prostate cancer compared with males of other race/ethnicity (0.4 versus 0.22 percent, HR 1.95, 95% CI 1.42-2.67). Critiques on this work focus on the likelihood of under-sampling and underdiagnosed disease as contributing factors rather than inherent biologic differences in Gleason score 6 disease between races.

A retrospective cohort study in the US Veterans Health Administration Health Care System compared outcomes among 2280 Black males versus 6446 non-Hispanic White Americans who were diagnosed with low-risk prostate cancer and managed with AS [90]. At a median follow-up of 7.6 years, Black males had a significantly higher cumulative risk of disease progression (59.9 versus 48.3, difference 11.6 percent, 95% CI 9.2-13.9 percent, p <0.001) and definitive treatment (54.8 versus 41.4, difference 13.4 percent (95% CI 11.0-15.7 percent, p <0.001), but no differences in metastases (1.5 versus 1.4 percent) or prostate cancer-specific mortality (1.1 versus 1.0 percent).

On the other hand, results from the large, prospective multi-institutional, Canary PASS study do not suggest that Black males are at increased risk for pathologic reclassification while on AS, or for adverse pathology findings at prostatectomy [91]. From this study the authors argue that in the setting of standardized access, equal quality of care and adequate follow-up, previously observed racial disparities can be reduced considerably.

A greater acknowledgment and understanding of systemic differences in access, treatment, and post-treatment management can further elucidate the relative contribution of biologic and nonbiologic factors that impact oncologic outcomes in Black males.

Germline testing – Because of the greater risk of aggressive disease, clinicians may consider excluding males with germline homologous recombination DNA repair pathogenic or likely pathogenic variants from AS. However, until further information is available, we do not exclude these males from AS, but we discuss the potential risks in greater detail, and individualize decision making based on patient values, goals, and preferences.

Germline testing for alteration in homologous recombination DNA repair genes (eg, BRCA1, BRCA2, ATM, CHEK2) is generally recommended for males with very low-risk, low-risk, and intermediate-risk disease if family history is positive for an inherited cancer predisposition syndrome or if there is intraductal or cribriform histology. Intraductal/cribriform histology is enriched for pathogenic or likely pathogenic variants in homologous recombination DNA repair genes (especially BRCA2). (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Germline genetic testing and tumor tissue testing' and "Genetic risk factors for prostate cancer", section on 'Who needs referral for genetic evaluation' and "Risk factors for prostate cancer", section on 'Family history and genetic factors'.)

Germline pathogenic or likely pathogenic variants in BRCA1, BRCA2, ATM, and CHEK2 have been associated with lethal prostate cancer [38,39], and males found to have BRCA or ATM variants also have a higher risk of grade reclassification among males undergoing AS [40]. These data suggest that germline pathogenic or likely pathogenic variants in at least some of these genes may inform decision making for AS [92]. However, there is no widespread consensus on this point. A major problem is that few studies of AS have included individuals with germline or somatic pathogenic or likely pathogenic variants in DNA repair genes, so that the impact of having such a mutation remains somewhat unclear.

MONITORING AND TRIGGERS FOR INTERVENTION WITH TREATMENT — Careful monitoring is required during AS to identify disease progression and the need for definitive therapy. The available data on progression rates are variable, with some population-based series suggesting that approximately one-half of males on AS will undergo definitive treatment within five years of initiating AS, mostly for disease progression [93-95], while single institution academic centers report a broader range of discontinuation rates (24 to 50 percent) [96,97].

There is no single widely accepted AS monitoring strategy, and protocols need to be tailored to the risk of progression, the individual values, goals, and preferences of each patient, and competing comorbidities. Criteria for disease progression are not well defined, and they require clinician judgment. A change in risk group (table 2) on biopsy may reflect progression to clinically significant disease and the need for definitive therapy, although some males with a change in category from low-risk to favorable intermediate risk disease (table 1) may still be appropriate for continued AS.

AS involves monitoring for prostate cancer growth with the goal of timely, curative therapy for tumors that appear to be progressing. Since these patients are untreated, grade progression occurs in some patients over time and higher-grade cancer exposes the patient to the risk of metastatic disease. Long-term close follow-up is needed to prevent late, lethal disease progression.

Protocols for monitoring AS vary significantly by institution and have evolved over time, relating to the dynamic nature of surveillance and the diversity in goals and approaches to prostate cancer observation [91,98,99]. Typically, AS involves serial measurement of prostate-specific antigen (PSA), physical examination, imaging and periodic biopsy for histologic assessment of progression. Notably, serum PSA and digital rectal examination (DRE) have limited sensitivity for detecting progression [2]. However, a significant rise in serum PSA, a worsening abnormality on DRE, or progression of disease on multiparametric prostate magnetic resonance imaging (mpMRI) should serve as the basis for more detailed evaluation (typically prostate biopsy). A change in risk group (table 2) on biopsy strongly implies progression to clinically significant disease and the need for definitive therapy.

Ensuring compliance with follow-up — Identifying barriers to follow-up and compliance is critical to ensure optimal AS. The generally good results reported in males who choose AS are predicated on close longitudinal monitoring and a transition to definitive local therapy in the event of disease progression. Identifying barriers to follow-up and compliance is critical to ensure the success of AS. The available data suggest that adherence to guideline-recommended monitoring in the community is less than ideal [100], that between 10 and 50 percent of males will be lost to follow-up during AS [101-103], and patients in lower socioeconomic strata, African Americans, and those with extensive comorbidity may be at a relatively higher risk for less than ideal surveillance.

Overview of our general approach to monitoring — Our general approach to monitoring in males on AS is as follows:

As noted above, for most patients we advise a confirmatory biopsy at 6 to 18 months that incorporates a prostate MRI and MRI-targeted biopsy of suspicious regions to reduce uncertainty regarding the presence of a missed higher-grade tumor. Patients with unfavorable clinical parameters (eg, extensive grade group 1 disease (table 2), high PSA density, African American ethnicity, or a family history of early prostate cancer mortality) should have a confirmatory biopsy even if the MRI is negative. (See 'Confirmatory biopsy' above.)

Subsequent MRI and/or repeat biopsies should be performed every two to five years. Even if the MRI is negative or stable, we believe that patients should have periodic repeat biopsies, albeit as infrequently as every five years. For patients who cannot undergo MRI (eg, those with pacemakers or other hardware), we perform repeat systematic biopsies every two to four years depending on their risk parameters.

Consistent with guidelines from the National Comprehensive Cancer Network, we perform assay of PSA no more often than every six months and repeat DRE no more often than every 12 months unless clinically indicated.

Sustained increases in serum PSA (especially a PSA doubling time of <3 years or a rise in PSA of >10 to 15 ng/mL) or worsening abnormalities on DRE should serve as an indicator for more detailed evaluation (typically prostate MRI with targeted biopsies of regions of interest with or without systematic biopsies). For males followed serially with prostate MRI, a biopsy may be recommended for clear-cut growth of a Prostate Imaging Reporting and Data System (PI-RADS) 4 or 5 lesion, or evolution of a prior PI-RADS 3 lesion into a PI-RADS 4 or 5 lesion. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Prostate imaging reporting and data system (PI-RADS)'.)

For many males there is a de-escalation of AS with aging, and following their cancer with less invasive measures (eg, periodic assay of PSA and/or MRI) and foregoing subsequent biopsy, or becoming even less active in their surveillance monitoring strategy may move them towards true "watchful waiting." (See 'Active surveillance versus watchful waiting' above.)

Role of repeat biopsy and MRI during longitudinal follow-up — For males who are still candidates for AS after the confirmatory biopsy, periodic repeat biopsies are important to detect grade group progression and the need for definitive therapy; a negative follow-up biopsy is associated with a lower risk of future reclassification and upgrading. There is controversy regarding the timing of subsequent biopsies, and the role of serial magnetic resonance imaging (MRI). While serial MRI may help delay and significantly reduce the frequency and number of biopsies performed during AS in those who maintain a stable MRI, it is unlikely that MRI will allow males to avoid subsequent biopsies completely as the ability of mpMRI to confidently exclude cancer progression is far from perfect [98]. Our general approach for most males is to perform an MRI every one to two years, and biopsy every 3 to 5 years if the MRI and PSA are stable.

Repeat biopsy – The rationale for repeat prostate biopsy is that a change in risk group (table 2) on serial biopsies may reflect progression to clinically significant disease and the need for definitive therapy, particularly for males with a change in category from low-risk to intermediate-risk disease (table 1). (See 'Triggers for treatment intervention' below.)

Furthermore, a negative follow-up biopsy is associated with an approximately 50 percent decrease in the risk of future reclassification and upgrading [104]. This may allow for tailoring of the future monitoring strategy.

There is no consensus on the optimal timing or frequency of repeat biopsy. For many males, a strategy of biennial biopsies after the initial confirmatory biopsy is appropriate. A comparative analysis of individual patient data from four major centers with long-term experience using AS [105] concluded that a strategy of biennial biopsies after an initial confirmatory biopsy was consistent with treatment delays of no more than six to eight months in detecting progression, which are unlikely to have a significant effect on long-term treatment outcomes.

However, the biopsy strategy should be tailored to the estimated risk of disease progression. As an example, a man with one core of grade group 1 cancer with a negative mpMRI and negative confirmatory biopsy could safely spread out their biopsies to every three to five years. However, a man with intermediate-risk disease may require more frequent biopsies to ensure his cancer does not progress to a level that would compromise his opportunity for cure while being observed.

Regardless of the timing and frequency of repeat biopsy during AS some consideration should be paid to the approach. With the increasing risk of sepsis associated with transrectal approaches, there has been an increased utilization of the transperineal approach to biopsy. This approach does not require passing a needle through the rectum to sample the prostate, resulting in a much lower risk of biopsy associated sepsis [106]. Contemporary evidence suggest that detection rates of significant cancer, incorporation of MRI targeting, and side effect profiles in the transperineal setting are equivalent to, if not better than transrectal approaches [107]. These issues are described in detail elsewhere. (See "Prostate biopsy".)

Role of MRI – The role of serial prostate MRI in males on AS for prostate cancer is debated. The available data are mixed on whether the addition of MRI adds value to systematic biopsy and clinical variables in the longitudinal follow-up of males on AS [44,45,69,108-117]. As examples:

One study conducted in a large, and well-known multi-institutional AS cohort (the CANARY PASS study) found no benefit from mpMRI in detecting upgrading during surveillance [45].

The benefits of MRI at the time of confirmatory biopsy were addressed in an analysis of the randomized ASIST trial discussed above. (See 'Confirmatory biopsy' above.)

A later analysis included the 199 males who did not have upgrading at the one-year confirmatory biopsy and continued AS for a further two years [110]. There were fewer failures of AS (defined as grade progression, clinical progression, subject choice, clinical judgment, initiation of treatment, or loss to follow-up) in the MRI arm (19 of 98, 19 percent) than in the transrectal ultrasound arm (35 of 101, 35 percent), and fewer males were upgraded to grade group 2 in the MRI arm (10 versus 23 percent). While these data suggest that mpMRI may have helped to select the patients who were unlikely to progress during observation, significant differences in failure of AS were detected in the MRI arm across the three centers participating in the trial (ranging from 4.2 to 27 percent), complicating interpretation of these results. Furthermore, the trial enrolled only males with low-grade cancers and it is unclear whether this benefit will translate to males with favorable intermediate-risk tumors.

The prospective Stockholm3 Active Surveillance study was designed to evaluate whether MRI could reduce biopsy intensity in a population of males undergoing AS; eligible males (n = 280) were diagnosed with low-risk (grade group 1, (table 2)) prostate cancer after being enrolled on a diagnostic screening by invitation study, all underwent prostate MRI and blood sampling for prognostic biomarkers at study baseline, followed by prostate biopsy [69]. The median time on AS at the time of analysis was 4.6 years prior to study entry. Most patients (63 percent) had undergone one or more previous biopsies, and 36 percent had previously undergone prostate MRI. The primary outcomes were reclassification to grade group 2 disease or to high- or very high-risk prostate cancer, which included unfavorable intermediate-risk prostate cancer or higher based on the National Comprehensive Cancer Network (NCCN) guidelines (table 1).

Adding an MRI-targeted biopsy to systematic biopsies was 52 percent more sensitive for finding grade group 2 disease relative to systematic biopsy alone (95% CI 1.28-1.85), and was 65 percent more sensitive for detecting high- or very high-risk cancer (95% CI 1.27-2.45). Omitting biopsies in MRI-negative males reduced the number of biopsy procedures by 49 percent, and still detected 30 percent more grade group 2 tumors, and 53 percent more clinically significant cancers compared with systematic biopsies, while missing 7.2 percent (10 of 138) of grade group 2 tumors, and 1.4 percent (2 of 138) of high- or very high-risk cancers.

The PI-RADS criteria as utilized in these studies were not designed for following patients with a known cancer. One group developed specific criteria for interpretation of MRI in males undergoing AS (the PRECISE criteria) [118]. Several studies (all retrospective analyses of prospectively collected data) have used these criteria to evaluate prostate cancer progression during AS [119-122]. However, the negative predictive value (range 70 to 100 percent) and positive predictive value (range 24 to 66 percent) from these studies are not sufficient to conclude that MRI can be used as a sole factor for excluding disease progression in males followed on AS, and the changes on MRI are also not sufficiently accurate to indicate prostate cancer progression [117].

Given the disparate data, it is not surprising that clinical practice is variable. Many clinicians are performing serial prostate MRI scans every one to three years and recommending biopsy only for clear-cut growth of a PI-RADS 4 or 5 lesion, or evolution of a prior PI-RADS 3 lesion into a PI-RADS 4 or 5 lesion. Other institutions, including that of the authors associated with this topic review, are still performing a prostate biopsy every two to five years, even in the presence of a stable PSA and reassuring MRI findings [123].

Guidelines for treatment of clinically localized prostate cancer from the combined American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) and American Society of Clinical Oncology (ASCO) suggest that clinicians may "consider" multiparametric prostate MRI as a component of AS for localized prostate cancer, but that this should not replace periodic surveillance biopsy [7,9]. Consensus-based guidelines from NCCN suggest repeat mpMRI no more often than every 12 months unless clinically indicated [124].

Triggers for treatment intervention — Most males who discontinue AS do so because of disease progression. The criteria for progression during AS are not well defined, and they require clinician judgment. Sustained increases in serum PSA (especially a PSA doubling time of <3 years) or worsening abnormalities on DRE should serve as an indicator for more detailed evaluation (typically prostate MRI with targeted biopsies of regions of interest with or without systematic biopsies). For males followed serially with prostate MRI, a biopsy may be recommended for clear-cut growth of a PI-RADS 4 or 5 lesion, or evolution of a prior PI-RADS 3 lesion into a PI-RADS 4 or 5 lesion. A change in risk group (table 2) on biopsy may reflect progression to clinically significant disease and the need for definitive therapy, particularly for a relatively healthy man with a change in category from low-risk to intermediate-risk disease (table 1).

Most males who discontinue AS do so because of disease progression, although in some cases it is unrelated to disease progression [94,125]. The reasons for discontinuing AS were analyzed in a series of 1729 males in a Swedish database who were followed for a minimum of five years [94]. At five years, 64 percent of the males remained on AS. Discontinuation of AS was due to PSA progression, biopsy progression, or personal preference in 52, 24, and 20 percent of cases, respectively.

Upgrading on repeat biopsy - From a biopsy standpoint, often the criteria used to determine eligibility for AS are used as a trigger for intervening with treatment. As an example, groups that used very low-risk prostate cancer as criteria to select patients for surveillance might intervene with treatment if a subsequent biopsy showed that the cancer had surpassed that definition. However, as noted above, this definition correlates well with indolent disease at the time of surgery, but would result in overtreatment of many males who did not require immediate treatment.

While there has been an increased acceptance in observing larger volumes of low-risk (grade group 1) cancer, there is no real consensus on how much is too much. Many feel that a finding of less than one-third of the cores positive would be very reasonable to observe; however, more than one-half the cores positive may be too much, primarily for concern for an unfound grade group 2 or higher cancer [126].

Currently, the most common reason for stopping surveillance in favor of treatment is the emergence of a grade group 2 or higher cancer on subsequent biopsy. However, males with grade group 2 cancer display variable rates of progression and quantifying the exact amount of pattern 4 cancer that is likely to impact progression is helpful to enhance risk assessment and decision-making. Furthermore, while observing a grade group 2 cancer may in general incur more risk than observation of a grade group 1 tumor, this must be considered in regard to the patient's age, comorbidities, and competing risk of mortality.

For males with grade group 2 cancer (ie, intermediate-risk disease) who choose surveillance, there is no accepted threshold or amount of Gleason pattern 4 cancer that is used as a cut off to decide on the need for treatment. In evaluating such males for treatment or continued surveillance, it may be important to consider other factors that may predict progression such as PSA density, the volume and subtype of pattern 4 disease, genomic testing and the results of mpMRI. (See 'Role of repeat biopsy and MRI during longitudinal follow-up' above.)

While the emergence of a grade group 3 cancer is more universally accepted as a point at which surveillance should be discontinued, it depends highly on the sampling of the prostate, which may not appropriately reflect the true risk of cancer progression. Clearly more research is needed to identify the ideal protocols for monitoring and triggers for intervention in males with intermediate-risk prostate cancer to prevent a compromise in cancer control.

Consensus-based guidelines from the NCCN indicate that cancer progression may have occurred during AS if Gleason grade 4 or 5 cancer is found on a repeat prostate biopsy, or if prostate cancer is found in a greater number of prostate biopsies, or occupies a greater extent of the prostate biopsy.

MRI – For males followed serially with prostate MRI, a biopsy may be recommended for clear-cut growth of a PI-RADS 4 or 5 lesion, or evolution of a prior PI-RADS 3 lesion into a PI-RADS 4 or 5 lesion.

PSA and DRE – As noted above, for most males, we recommend a repeat PSA no more often than every six months, and repeat DRE no more often than once yearly. In our view, sustained increases in serum PSA (especially a PSA doubling time of <3 years) or worsening abnormalities on DRE should serve as an indicator for more detailed evaluation (typically prostate MRI with targeted biopsies of regions of interest with or without systematic biopsies).

Guidelines from the AUA/ASTRO, which have been endorsed by the ASCO, do not specify the level of change in the PSA or DRE that should prompt consideration for active intervention [7,9]. Consensus-based guidelines from the suggest that repeat biopsy be considered if prostate examination changes, or PSA increases, but there is no parameter [6].

PREVENTION OF PROGRESSION — For patients undergoing AS for localized prostate cancer, we suggest against the use of 5-alpha reductase (5-AR) inhibitors or enzalutamide for the purpose of delaying progression. While limited data suggest that patients receiving such treatments are less likely to crossover to definitive treatment, there isn't sufficient evidence that these treatments reduce progression to higher grade cancer. On the other hand, males undergoing AS for localized prostate cancer should be encouraged to pursue lifestyle interventions such as structured aerobic exercise, that may improve psychologic and emotional health and cardiorespiratory fitness, and possibly, slow disease progression.

5-alpha reductase inhibitors — At least in theory, treatment with dutasteride or finasteride, 5-AR inhibitors, may benefit males on AS, particularly those with symptomatic benign prostatic hyperplasia and lower urinary tract symptoms. 5-AR inhibitors improve lower urinary tract symptoms by blocking the conversion of testosterone into the more potent androgen dihydrotestosterone, and androgens such as these are potent drivers of prostate tumorigenesis. Although limited, at least some data in males undergoing AS for prostate cancer suggests that use of 5-AR inhibitors might reduce reclassification and crossover to treatment compared with not taking these drugs [127]. The lack of randomization and a placebo control limits interpretation because of the potential for confounding and selection bias.

Notably, cytoreduction of low-grade (grade group 1 (table 2)) cancer was the only benefit of dutasteride in the randomized REDEEM trial; these drugs do not appear to reduce the rate of progression to higher grade cancer. Furthermore, these drugs have associated side effects, particularly loss of libido. For all of these reasons, a 5-AR inhibitor is not currently recommended by any guideline group solely for the purpose of reducing the likelihood of risk reclassification during AS. Chemoprevention strategies using 5-AR inhibitors are discussed in detail elsewhere. (See "Chemoprevention strategies in prostate cancer", section on '5-Alpha reductase inhibitors'.)

Enzalutamide — Enzalutamide is a potent oral androgen receptor inhibitor with activity in localized and more advanced stages of prostate cancer. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Neoadjuvant ADT approaches' and "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Enzalutamide, apalutamide, and darolutamide' and "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer", section on 'Enzalutamide or apalutamide plus ADT'.)

The benefit of enzalutamide in patients undergoing AS was directly addressed in the phase II ENACT trial in which 227 males with low- or favorable intermediate-risk prostate cancer undergoing AS were randomly assigned to receive or not receive one year of enzalutamide (160 mg daily) [128]. The primary endpoint was time to pathologic or therapeutic prostate cancer progression, which was defined as a ≥1 increase in the primary or secondary Gleason pattern or ≥15 percent increased cancer-positive cores, or earliest occurrence of primary therapy for prostate cancer. At a median follow-up of approximately 480 days, the median time to progression was not reached in either group; however, disease progression was observed in 46 percent fewer patients receiving enzalutamide (28 versus 37 percent, HR 0.54, 95% CI 0.33-0.89), While the incidence of prostate cancer progression was lower with enzalutamide at one year (7.9 versus 23 percent), it was similar at two years (16 versus 16.4 percent). Other secondary endpoints also favored enzalutamide at one year but not later. As an example, the odds of a negative biopsy at one year was 3.5-fold higher with enzalutamide (35 versus 14.2 percent, OR 3.5, 95% CI 1.76-6.92), but the difference was no longer statistically significant at two years (19 versus 12 percent, OR 1.6, 95% CI 0.66-4.0). The number of patients who went on to receive primary therapy in each group was not reported. The time to PSA rise was delayed by six months, but the total number of patients with PSA progression through the end of the observation period was not different (84.2 versus 84.1 percent).

The most commonly reported adverse events during enzalutamide therapy were fatigue (55 percent), gynecomastia (37 percent), breast tenderness (26 percent), and erectile dysfunction (18 percent). Although drug-related adverse events were reported by almost 90 percent of individuals, only 2.7 percent were considered serious, and 7 percent led to study discontinuation. Treatment with enzalutamide was associated with clinically meaningful declines in sexual and physical function, which resolved by month 24 after treatment cessation.

Can exercise help? — We encourage males to pursue lifestyle interventions such as exercise that may improve psychologic and emotional health [129] and cardiorespiratory fitness, and possibly, slow disease progression. This recommendation is consistent with guidelines from the American Cancer Society Nutrition and Physical Activity Guideline for Cancer Survivors that suggest that survivors without physical limitations or contraindications should aim for at least 150 minutes per week of moderate-intensity exercise or 75 minutes per week of vigorous-intensity aerobic physical activity or an equivalent combination of moderate- and vigorous-intensity aerobic physical activity, which should also include routine resistance exercises [130].

Observational studies have shown an association between physical activity patterns after cancer diagnosis and prognosis in individuals diagnosed with early-stage cancers of the breast, colon, and prostate. However, there are limited data from randomized trials evaluating the impact of increased physical activity on rates of cancer recurrence or mortality. (See "The roles of diet, physical activity, and body weight in cancer survivors", section on 'Prostate cancer'.)

New data from a small randomized clinical trial suggest the possibility that high-intensity interval training might slow disease progression in males undergoing AS for localized prostate cancer. In the ERASE trial, 52 males under AS for mostly low-risk localized disease were randomly assigned to high-intensity interval training (HIIT; which consisted of 12 weeks of thrice weekly supervised aerobic sessions at 85 to 95 percent of peak oxygen consumption), or usual care (which included maintaining normal exercise levels) [131]. Compared with the usual care group, those randomized to HIIT experienced a decreased PSA level (mean change -0.4 microgram/L, 95% CI -0.8 to 0.0) while PSA level increased in the control group (mean change 0.3 microgram/L, 95% CI -0.7 to 1.3); adjusted between group difference was -1.1 microgram/L (95% CI -2.1 to 0.0). Males in the HIIT group also had slower PSA velocity (adjusted between group difference -1.3 microgram/L per year, 95% CI -2.5 to -0.1), although there were no significant differences in PSA doubling time.

Confirmation of these results is needed in larger trials before definitive conclusions can be drawn as to the influence of structured aerobic exercise on outcomes from AS. (See "Overview of approach to prostate cancer survivors", section on 'General principles guiding follow-up'.)

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: Choosing treatment for low-risk localized prostate cancer (The Basics)")

Beyond the Basics topics

SUMMARY AND RECOMMENDATIONS

Definition and rationale – Active surveillance (AS) for males with clinically localized prostate cancer defers curative-intent treatment until there is evidence of subclinical disease progression. (See 'Active surveillance versus watchful waiting' above.)

AS relies on accurate risk stratification and assumes that treatment of subclinical progression identified by serial monitoring in appropriately selected patients is as effective and no more morbid than immediate definitive treatment. (See 'Rationale for active surveillance' above and 'Outcomes' above.)

Indications

AS is the preferred approach for males with very low-risk prostate cancer, as defined by tumor grade volume and prostate-specific antigen (PSA) level (table 1). AS an appropriate alternative to immediate definitive treatment for males with low-risk disease. Specific recommendations for management of very low-risk and low-risk prostate cancer are discussed elsewhere. (See "Initial approach to low- and very low-risk clinically localized prostate cancer".)

Although controversial, AS is an option for males with favorable intermediate-risk disease (table 1), especially those who are older or have significant comorbidity and are willing to accept a potentially higher risk of developing metastases. AS is not indicated for males with unfavorable intermediate-risk disease, unless they are an older adult and/or have a limited life expectancy. Definitions of favorable and unfavorable intermediate-risk prostate cancer vary (table 4). The management of intermediate-risk prostate cancer is discussed in detail elsewhere. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Options for intermediate-risk disease'.)

For most patients considering AS for either very low-, low-, or favorable intermediate-risk disease, we advise a confirmatory biopsy at 6 to 18 months that incorporates prostate magnetic resonance imaging (MRI; where feasible), to reduce the chance of a missed higher-grade tumor. Patients with unfavorable clinical parameters (eg, extensive grade group 1 disease (table 2), favorable intermediate-risk disease, high PSA density, African American ethnicity, or a family history of early prostate cancer mortality) should have a confirmatory biopsy even if the MRI is negative. (See 'Confirmatory biopsy' above.)

Monitoring during AS – AS monitoring strategies are tailored to the risk of progression, and the individual values, goals, and preferences of each patient. Criteria for disease progression are not well defined, and require clinician judgment. However, a change in risk group (table 2) may reflect progression to clinically significant disease and the need for definitive therapy, particularly for an otherwise healthy man with a change in category from low-risk to intermediate-risk disease (table 1). (See 'Monitoring and triggers for intervention with treatment' above.)

Our general approach is as follows (see 'Overview of our general approach to monitoring' above):

We assay PSA no more often than every six months and repeat digital rectal examination (DRE) no more often than every 12 months unless clinically indicated. Prostate biopsy is performed for sustained PSA increases (especially a PSA doubling time of <3 years) or worsening abnormalities on DRE.

Even if PSA and DRE are stable, we advise periodic rebiopsy to detect grade group progression. For most males, we perform MRI annually, with biopsy for clear-cut growth of a Prostate Imaging Reporting and Data System (PI-RADS) 4 or 5 lesion, or progression of a prior PI-RADS 3 lesion to PI-RADS 4 or 5. Even if the MRI is negative or stable, or if MRI is not feasible, we advise periodic repeat biopsy every two to five years depending on risk parameters. (See 'Role of repeat biopsy and MRI during longitudinal follow-up' above.)

Prevention of progression

For patients undergoing AS for localized prostate cancer, we suggest against the use of 5-alpha reductase inhibitors or enzalutamide to delay disease progression (Grade 2C). (See 'Prevention of progression' above.)

We encourage individuals to pursue lifestyle interventions such as exercise that may improve psychologic and emotional health and cardiorespiratory fitness, and possibly, slow disease progression. (See 'Can exercise help?' above.)

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

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Topic 6922 Version 78.0

References

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