Follow-up surveillance after definitive local treatment for prostate cancer

INTRODUCTION — Worldwide, prostate cancer is the second most common malignancy in males according to data from the GLOBOCAN database. Options for definitive local therapy include radical prostatectomy, external beam radiation therapy (RT) with or without androgen deprivation therapy (ADT), and brachytherapy. Some males with low- or very low-risk disease may be amenable to active surveillance. (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

Because of the prolonged natural history of prostate cancer, there are a large number of cancer survivors who are being followed after initial definitive treatment. One of the most important aspects of follow-up care for males who have undergone definitive local treatment for prostate cancer is the identification and management of therapy-related complications (particularly sexual and urinary dysfunction). The complications of radical prostatectomy, RT, and ADT are discussed elsewhere, as is an overview of the overall approach to prostate cancer survivors. (See "Radical prostatectomy for localized prostate cancer", section on 'Functional outcomes' and "External beam radiation therapy for localized prostate cancer", section on 'Complications' and "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer", section on 'Complications' and "Side effects of androgen deprivation therapy" and "Overview of approach to prostate cancer survivors", section on 'Treatment-related sequelae'.)

Males who have undergone definitive local treatment should also undergo periodic assessments for recurrent disease. This topic will discuss the approach to post-treatment surveillance to detect a recurrence after definitive local treatment for prostate cancer. The surveillance strategy for males with low-risk, localized prostate cancer who are managed with active surveillance, and recommendations for assessment during treatment for males with advanced prostate cancer are discussed elsewhere. (See "Active surveillance for males with clinically localized prostate cancer", section on 'Overview of our general approach to monitoring' and "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Assessment during treatment'.)

OUR APPROACH TO POST-TREATMENT SURVEILLANCE

●Serial evaluation of serum prostate-specific antigen (PSA) is the mainstay of surveillance testing in males who have undergone definitive therapy for localized prostate cancer. There are no clinical trials that define the optimal frequency for measuring serum PSA. We agree with guidelines from the National Comprehensive Cancer Network (NCCN), which recommend that serum PSA be monitored every 6 to 12 months for the first five years and annually thereafter [1]. (See 'Serum prostate-specific antigen' below.)

●Regular clinician visits may serve to reassure the patient, but they are of questionable utility in detecting recurrent tumor given that most recurrences manifest as a rise in serum PSA. Nevertheless, periodic evaluation by a health care provider is important to evaluate potential complications of therapy and for overall health care. The value of serial digital rectal examination (DRE) in this setting is unclear. DREs may have some value in detecting a local recurrence if the PSA becomes elevated.

●Imaging studies, such as bone scan, transrectal ultrasound (TRUS), computed tomography (CT), and positron emission tomography (PET) scanning, have no role as screening tests for recurrence of localized prostate cancer in the absence of a rising serum PSA or specific symptoms. These tests may be indicated to evaluate a rising PSA after definitive local treatment. (See 'Imaging studies' below.)

RISK OF RECURRENCE AND TIMING — In general, a recurrence is detected by a rise in serum prostate-specific antigen (PSA), a highly specific marker for prostate tissue, prior to any radiologic or symptomatic evidence of recurrence or progression. Most relapses after localized treatment happen within five years; however, late recurrences may also occur [2-5]. As an example, in a series of 4561 males who had undergone radical prostatectomy, 31 percent eventually developed a PSA recurrence [4]. Of these, approximately 10 percent occurred after five years. Patients with a pretreatment PSA <10 ng/mL and those with a Gleason score <7 were more likely to have a delayed recurrence. In contrast to a biochemical recurrence, the development of a clinically or radiologically overt local recurrence or distant metastases usually occurs significantly later in the natural history of the disease [6,7].

A variety of factors have been evaluated in an attempt to identify males at high risk of a disease recurrence following radical prostatectomy or radiation therapy (RT). In multivariate models, the most important determinants of outcome are the pretreatment serum PSA and Gleason score, as well as the anatomic extent of disease. These are the factors that are used in risk stratification models, including those of the National Comprehensive Cancer Network (NCCN), which categorize males with newly diagnosed prostate cancer into different levels of risk (table 1). (See "Localized prostate cancer: Risk stratification and choice of initial treatment".)

Increasingly, models are being developed and validated that can be used to predict individualized estimates of biochemical recurrence [6,8-11] and prostate cancer-specific survival [11-13] after definitive local treatment of prostate cancer, based on clinicopathologic factors. One such model, the PREDICT Prostate model, is an individualized web-based prognostic tool for males with newly diagnosed nonmetastatic prostate cancer that estimates the likelihood of survival at 10 and 15 years postdiagnosis [12].

Models such as these do not take into account genomic tests or molecular markers. Multiple molecular prognostic tests are emerging specifically with the aim of better risk stratifying males treated for localized prostate cancer. However, the role of these tests in males who have undergone definitive treatment for prostate cancer is not yet as a standard approach. (See "Molecular prognostic tests for prostate cancer".)

Natural history of PSA-only recurrence — Although biochemical relapse is an independent risk factor for the development of distant metastases and prostate cancer-specific mortality [14], a prostate-specific antigen (PSA) relapse does not necessarily predict the development of metastases or death [15-17]. Several models or nomograms to predict outcome following a PSA recurrence are available. Some are based only on pretreatment factors, while others incorporate the pathologic examination of the surgical specimen and, in one case, the duration of time that a man has remained free of progression since surgery. As examples:

●Data from an analysis of 1997 males treated at Johns Hopkins were initially used to construct the "Pound tables" to predict the likelihood of being free of metastases following a biochemical failure after radical prostatectomy [18]. A later analysis of a cohort from this same institution (450 males with a biochemical recurrence after radical prostatectomy who did not receive adjuvant or salvage therapy before the development of metastatic disease) provided information about 5- and 10-year metastasis-free survival, stratified by pathologic Gleason score and PSA doubling time [16]. A somewhat more clinically useful table combining Gleason score and PSA doubling time was presented by this group in 2003 based on 312 males, but it was never published (table 2) [19]. A preliminary report of a later analysis of a slightly larger cohort (513 men) treated at this same institution attempted to identify a PSA cutpoint that indicates the imminent emergence of metastases among males with a PSA doubling time <12 months [20].

A comparable table to estimate the 10-year risk of prostate cancer-related death in males with a rising PSA after radical prostatectomy, based on 379 such males derived from the same institution, was published in 2005 (table 3) [15].

●Others have published a nomogram predicting prostate cancer-specific mortality for males with a biochemical recurrence after radical prostatectomy that is based on preoperative PSA, pathologic Gleason score, extraprostatic extension, seminal vesicle invasion, time to biochemical recurrence, PSA level at biochemical recurrence, and PSA doubling time [21]. This nomogram is available online.

●Memorial Sloan Kettering also has a nomogram to predict the risk of dying of prostate cancer in males with a rising PSA after radical prostatectomy.

In some cases, the diagnostic evaluation will reveal a localized recurrence for which salvage local therapy may be appropriate and potentially curative. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation" and "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy" and "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)

Androgen deprivation therapy (ADT) is the key component of treatment for males with documented distant metastases. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer".)

The natural history of prostate cancer in males with a PSA-only recurrence (without an identifiable locoregional recurrence or distant metastases) after definitive local therapy is often prolonged, and a biochemical recurrence alone is not necessarily an indication for therapy. If a "PSA-only failure" occurs, other clinical characteristics, such as time to biochemical recurrence or PSA doubling time, can be used to counsel patients and to help guide treatment decisions regarding secondary therapy. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification" and "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Specific prognostic factors'.)

However, in many cases, early intervention is pursued if a recurrence is detected, since many recurrences following initial treatment can be successfully treated. Furthermore, treatment of PSA-only recurrences when the PSA is very low can prolong survival. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'When to initiate ADT-based therapy'.)

Clinical practice guidelines from the American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and American Society of Clinical Oncology (ASCO) recommend that clinicians monitor patients with localized prostate cancer post-therapy with serial PSA measurements, with the specific intervals tailored to disease risk based on clinicopathologic features [22,23]. The duration and interval of follow-up beyond 10 years for patients with an undetectable PSA at that time should be a shared decision based on patient disease risk, age, comorbidity status, and preference.

SURVEILLANCE STRATEGIES — There are no randomized trials that have defined the optimal follow-up strategy to detect a local or distant recurrence in males following initial definitive treatment for localized prostate cancer. Regular monitoring of serum prostate-specific antigen (PSA), a highly specific marker for prostate tissue, is widely practiced following definitive therapy. In general, a recurrence is detected by a rise in serum PSA prior to any radiologic or symptomatic evidence of recurrence or progression. The development of a clinically or radiologically overt local recurrence or distant metastases usually occurs significantly later in the natural history of the disease. As such, imaging studies, such as bone scan, transrectal ultrasound (TRUS), computed tomography (CT), and positron emission tomography (PET) scanning, have no role as screening tests to detect a recurrence in the absence of a rising serum PSA or specific symptoms. These tests may be indicated to evaluate a rising PSA after definitive local treatment. (See 'Serum prostate-specific antigen' below and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation".)

An important point is that when considering post-treatment surveillance strategies, the impact of therapy for recurrent disease on both overall survival and quality of life should be discussed with the patient, with shared decision making on whether and how to perform post-treatment surveillance. The patient's individual preferences and overall health status are of primary importance in choosing a surveillance strategy after treatment for localized prostate cancer. If a man would not desire additional treatment in the event of a disease recurrence, or if his life expectancy is severely limited due to comorbid conditions, early detection of recurrent disease would only cause psychological distress and could detract from quality of life while not affecting overall survival. In this situation, it may be appropriate to forego some or all components of the post-treatment surveillance strategy.

Serum prostate-specific antigen — Serial evaluation of serum PSA is the mainstay of surveillance testing in males who have undergone definitive therapy for localized prostate cancer. There are no clinical trials that define the optimal frequency for measuring serum PSA. We agree with guidelines from the National Comprehensive Cancer Network (NCCN), which recommend that serum PSA be monitored every 6 to 12 months for the first five years and annually thereafter [1].

Serum PSA is a sensitive marker for recurrent prostate adenocarcinoma and is elevated in 95 percent of males with recurrent disease. While the use of PSA for cancer screening is controversial, there is little debate that it is an excellent tumor marker in males with an established diagnosis of prostate cancer. (See "Screening for prostate cancer" and "Measurement of prostate-specific antigen".)

Definition — The definition of a PSA (biochemical) recurrence depends on the initial treatment:

●Surgery – All prostate tissue is removed during a successful radical prostatectomy. Thus, any detectable PSA in the serum using the standard immunoassay (the typical limit of detection is 0.1 ng/mL) theoretically indicates remaining prostate tissue and might represent persistent or recurrent disease. Ultrasensitive PSA assays may detect lower levels of PSA, but the utility of basing treatment decisions on the much lower levels of PSA detected with these assays remains unclear. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'After radical prostatectomy'.)

●Radiation therapy – The definition of a biochemical failure following radiation therapy (RT) is more complicated since there is benign prostate tissue remaining after RT. The American Society for Radiation Oncology (ASTRO) has established guidelines to define a PSA recurrence following RT. In the 2005 Phoenix criteria, a PSA rise of 2 ng/mL or more above the nadir PSA is considered the standard definition of a biochemical failure after external beam RT [24]. These criteria are discussed in more detail separately. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'After radiation therapy'.)

The interpretation of an increase in serum PSA following RT is further complicated by the observation that serum PSA levels can fluctuate ("bounce") significantly after RT (particularly brachytherapy) before reaching the post-treatment nadir. Thus, increases in PSA must be interpreted with caution, and they do not necessarily indicate a recurrence. The PSA bounce phenomenon is discussed separately. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'PSA bounce'.)

Notably, because PSA is a highly specific tumor marker for prostate adenocarcinoma, the absence of a rise in PSA over time (regardless of the initial form of treatment) can provide significant psychological reassurance to males following definitive local treatment that the disease has not recurred.

Once a biochemical recurrence is diagnosed, potential approaches include salvage local treatment, systemic therapy, and observation, depending on the site and extent of recurrent disease, and other factors, such as PSA doubling time. The diagnostic evaluation for males with a rising serum PSA after definitive local therapy for prostate cancer is discussed in detail elsewhere. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation".)

Even if the site of a recurrence cannot be identified, there may be a prolonged period after the documentation of a PSA recurrence before there is any clinical evidence of disease.

While biochemical relapse is an independent risk factor for the development of distant metastases and prostate cancer-specific mortality, a PSA relapse does not necessarily predict the development of metastases or death, and not all biochemical-only recurrences require aggressive therapy. (See 'Natural history of PSA-only recurrence' above.)

History and physical examination — The majority of recurrences following radical prostatectomy or RT for localized prostate cancer are asymptomatic and manifested only by a rising serum PSA. While regular clinician visits may serve to reassure the patient, they are of questionable utility in detecting recurrent tumor. Nevertheless, periodic evaluation by a health care provider is important to evaluate potential complications of therapy and for overall health care.

Digital rectal examination — Monitoring serum PSA, rather than a digital rectal examination (DRE), is the "gold standard" for early detection of a recurrence following definitive local therapy in patients with localized prostate cancer. The value of serial DRE in this setting is unclear. DREs may have some value in detecting a local recurrence if the PSA becomes elevated.

Following radical prostatectomy, the prostatic fossa should be empty on DRE. However, DRE is not sensitive enough to detect a local recurrence early [25-28]. As an example, in a retrospective analysis of 501 males who had undergone radical prostatectomy, 72 had a rising PSA [25]. Only 4 of the 501 males (0.8 percent) had an abnormal DRE, and the PSA was elevated in each of these cases.

In males treated initially with RT, the role of DRE is also unclear. DRE was used routinely prior to the availability of PSA, but this outcome is now seldom reported. Moreover, the clinical significance of a change in DRE following RT is unclear. Furthermore, there is considerable intraobserver variability in assessing change in DRE, which limits the utility of this endpoint.

Imaging studies — Imaging studies, including bone scans, TRUS, CT, and PET scans, do not have a routine role in surveillance for recurrence in patients who have undergone definitive therapy for localized prostate cancer in the absence of a rising serum PSA or specific symptoms.

A variety of imaging studies are potentially useful for identifying the specific sites of recurrence in males with biochemical evidence of a recurrence (a rising PSA) or for evaluating symptoms suggestive of recurrent disease. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation" and "Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)

Bone scan — The technetium-99 radionuclide bone scan is a sensitive and reliable test for detecting the presence of skeletal metastases in symptomatic patients. In the absence of symptoms, bone scan has been replaced by PSA testing for the early detection of an asymptomatic recurrence.

Bone scans are more likely to detect metastases when the serum PSA level is markedly elevated (especially >10 ng/mL) [29]. However, almost all males who have a biochemical recurrence after definitive local treatment will have a serum PSA that is much lower (often <1 ng/mL). In this setting, the bone scan is unlikely to identify bony metastases in the absence of symptoms referable to bone. The limited yield of bone scan in this setting can be illustrated by a series of 239 males in whom 414 bone scans were performed [30]. The frequency with which positive bone scans were identified increased progressively with the level of serum PSA. For patients with a PSA <10, 10 to 20, 20 to 50, and >50 ng/mL, the frequency of a positive bone scan was 4, 36, 50, and 79 percent, respectively. This subject is discussed in detail separately. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Accuracy of individual tests and procedures' and "Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)

Guidelines from expert groups differ as to the indications for bone scan following definitive local therapy:

●NCCN guidelines suggest bone imaging for males who develop symptoms, and bone imaging as often as every 6 to 12 months for those with node-positive disease who are receiving androgen deprivation therapy (ADT) [1].

●Contemporary guidelines from the European Association for Urology (EAU) suggest that for asymptomatic males with a suspected PSA relapse after definitive local therapy, bone scan can be omitted until the PSA is greater than 20 ng/mL, although there is not uniform agreement on this recommendation [31].

Links to additional society guidelines can be found elsewhere. (See 'Society guideline links' below.)

We generally do not perform bone scans in asymptomatic males unless the PSA is over 5 to 10 ng/mL.

Evaluation of the prostate or prostatic fossa — There is no role for transrectal ultrasound of the prostate or prostatic fossa, or multiparametric prostate magnetic resonance imaging as a screening test for recurrence of localized prostate cancer.

However, for males with a suspected biochemical recurrence and no evidence of systemic disease, prostate biopsy may be useful in confirming a local recurrence and in planning secondary treatment. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Prostate evaluation'.)

Pelvic computed tomography — Pelvic CT is not indicated for routine surveillance of males who have received definitive treatment for localized prostate cancer because of the limited sensitivity of CT in detecting low-volume recurrent disease [32].

Positron emission tomography/computed tomography — There is no role for PET scanning using either standard F-18 fluorodeoxyglucose (FDG) or any more sensitive prostate cancer-specific PET tracer (eg, F-18 fluciclovine, F-18/C-11 choline, or G-68 or F-18 prostate-specific membrane antigen [PSMA]) to screen for a recurrence after definitive local therapy of localized prostate cancer.

Use of these imaging studies should be limited to males who are documented to have a rising serum PSA after definitive local therapy [33]. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Next-generation imaging'.)

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

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

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

●Beyond the Basics topic

SUMMARY AND RECOMMENDATIONS

●Goals of follow-up care – Follow-up care for males who have undergone definitive local treatment for prostate cancer includes surveillance for disease recurrence and early identification and management of therapy-related complications (particularly sexual and urinary dysfunction). The complications of radical prostatectomy, radiation therapy (RT), and androgen deprivation therapy (ADT) are discussed elsewhere, as is an overview of the overall approach to prostate cancer survivors. (See "Radical prostatectomy for localized prostate cancer", section on 'Functional outcomes' and "External beam radiation therapy for localized prostate cancer", section on 'Complications' and "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer", section on 'Complications' and "Side effects of androgen deprivation therapy" and "Overview of approach to prostate cancer survivors", section on 'Treatment-related sequelae'.)

●Risk of recurrence and timing – In general, a recurrence is detected by a rise in serum prostate-specific antigen (PSA), a highly specific marker for prostate tissue, prior to any radiologic or symptomatic evidence of recurrence or progression. Most relapses after localized treatment happen within five years; however, late recurrences may also occur. (See 'Risk of recurrence and timing' above.)

●Surveillance strategies

•Serial evaluation of serum prostate-specific antigen (PSA) is the mainstay of surveillance testing in males who have undergone definitive therapy for localized prostate cancer. We recommend that serum PSA be monitored every 6 to 12 months for the first five years and annually thereafter. (See 'Serum prostate-specific antigen' above.)

•Periodic evaluation by a health care provider is important to evaluate potential complications of therapy and for overall health care. The value of serial digital rectal examination (DRE) in this setting is unclear. DREs may have some value in detecting a local recurrence if the PSA becomes elevated. (See 'History and physical examination' above.)

•Imaging studies, such as bone scan, transrectal ultrasound (TRUS), multiparametric prostate magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) scanning, have no role as screening tests for recurrence of localized prostate cancer in the absence of a rising serum PSA or specific symptoms. (See 'Imaging studies' 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.