In this review, we summarize contemporary data pertaining to active surveillance, a safe and appropriate strategy for select patients with low-risk cancer characteristics who undergo monitoring at regular intervals.
ABSTRACT: The management of localized prostate cancer in an otherwise healthy male is complex, evolving, and largely consists of three modalities: surgery, radiation, and active surveillance. In this review, we summarize contemporary data pertaining to active surveillance, a strategy in which patients with low-risk cancer characteristics undergo monitoring at regular intervals. Treatment is initiated following evidence of cancer features associated with a higher risk of progression. Multiple clinical experiences suggest active surveillance is a safe and appropriate strategy for select patients. Most definitions of low-risk cancer include a variable combination of: prostate-specific antigen (PSA) ≤ 10 ng/mL, clinical stage T1–T2a, biopsy Gleason score ≤ 6, and three or fewer positive biopsy cores. Although older patients or those with significant competing medical risks typically are not treated with surgery or radiation, active surveillance should also be considered and explained to well-selected healthy patients otherwise considering primary therapy. Due to significant concerns about clinical understaging, eligible patients should consider a repeat biopsy prior to selecting active surveillance. Short- to intermediate-term follow-up suggests active surveillance is associated with favorable overall outcomes, including for those undergoing delayed treatment, and has a relatively low risk of leading to incurable prostate cancer.
There is no universally accepted strategy for the screening, diagnosis, and treatment of prostate cancer. However, once a patient is diagnosed, his risk of cancer progression may be estimated using serum prostate-specific antigen (PSA), biopsy findings, and clinical stage. For patients with low-volume and low-grade cancer characteristics associated with minimal risk of imminent cancer progression, controversy exists regarding the optimal treatment. This is exemplified by the multitude of management options available: surgery, radiation, active surveillance, watchful waiting, androgen deprivation, and experimental ablative therapies.
Active surveillance, distinct from watchful waiting, is dynamic and involves frequent evaluations of the cancer and overall health of the patient to determine if more concerning features warrant treatment. Watchful waiting, by the strictest definition, involves no additional cancer evaluation or therapy until symptoms of local or metastatic disease are present, thus excluding the concept of delayed intervention with curative potential. For patients with low-risk cancers, meaningful comparisons between treatment strategies are lacking and may never be available due to the large number of patients required, decades of necessary follow-up, and low incidence of cancer-related events. While watchful waiting is typically recommended for elderly patients with low-risk cancers or those with significant comorbidities, active surveillance may also be considered by those otherwise contemplating curative primary interventions. In the United States, active surveillance remains underutilized as only 10% of patients meeting common eligibility criteria ultimately select this option.[1,2] In this review of active surveillance, we summarize its rationale, criteria for eligibility, potential indications for therapeutic intervention, and contemporary outcomes.
In 2008, an estimated 28,660 men died of prostate cancer in the United States. The prevalence of the disease is much greater, with autopsy studies suggesting the presence of cancer in one-third of men over age 60 and up to 50% of men over 70. The disconnect between the 16% lifetime risk of being diagnosed with prostate cancer and 3% lifetime risk of a prostate cancer death highlights a significant challenge: accurately identifying patients whose prostate cancer may eventually metastasize over their lifetime so that prompt intervention may be instituted while simultaneously avoiding overtreatment of those whose cancer has an exceedingly low likelihood of adversely impacting their quality of life or longevity.
The adoption of PSA screening in the United States has resulted in significantly more men presenting with localized, organ-confined cancers with concomitantly decreasing rates of cancer-specific mortality. In 1988, 19% of patients presented with locally advanced disease vs 4% in 1998. At the time of diagnosis, deciding whether to treat a patient and by what modality is a complex task without robust comparative clinical data for reference.
The only available randomized trial analyzing two common management strategies was performed in Scandinavia, which showed that radical prostatectomy (RP) results in superior cancer-specific outcomes compared to observation alone for patients with higher-risk features (75% with digitally palpable cancers and 50% with PSA > 10 ng/mL). The absolute risk reduction of death at 12 years following treatment was 5.4%, translating to a number needed to treat of approximately 19. For the contemporary patient, likely diagnosed following an abnormally elevated PSA, the number needed to treat is estimated to be between 50 and 200.[8-9] This significant potential for overtreatment has generated enthusiasm for active surveillance.
Undoubtedly, early radical intervention for all patients will lead to further decreases in mortality but would occur with significant financial, psychological, and functional burdens. Estimations of overdiagnosis rates range from 23% to 42% for screen-detected prostate cancers with estimated overtreatment rates of 10% for RP and 45% for radiation therapy.. Further, each modality is associated with varying risks and degrees of erectile, urinary, and gastrointestinal dysfunction. A comprehensive quality-of-life evaluation using validated instruments among treated prostate cancer survivors suggests: (1) RP has the greatest adverse effect of all monotherapies on sexual function and incontinence; (2) external-beam radiation and brachytherapy have the greatest gastrointestinal impact; (3) brachytherapy patients report long-lasting irritative bowel and urinary symptoms; (4) addition of hormones to radiation therapy results in worse outcomes across most measured functional domains; and (5) symptoms worsen with increasing prostate size, PSA, age, and obesity. The optimal strategy, still poorly defined, balances the likelihood of long-term oncologic success and treatment-related impairment, recommending interventions to those most likely to benefit.
With widespread use of PSA screening, an estimated lead time of 5 to 8 years exists compared to when the cancer is diagnosed by digital rectal examination or symptoms. Early clinical experiences suggest that modest delays in the application of treatment do not compromise outcomes compared to immediate intervention. Two studies have shown that low-risk patients who delayed prostatectomy for medians of 6 and 22 months did not experience more adverse pathologic outcomes, although more extensive follow-up is necessary.[13,14]
Recent multi-institutional data with follow-up as long as 20 years following RP has shown the 15-year risk of cancer-specific mortality in patients with Gleason 6 or less cancers to be less than 1%, as only 1 of 3,700 men with organ-confined, Gleason 6 or less cancers died from the disease. Based on these data, it appears that the accurate identification of cancer grade and stage at the time of diagnosis is the primary obstacle limiting the more widespread adoption of active surveillance.
Within the confines of current diagnostic and imaging capabilities, optimizing patient selection is directly related to the ultimate oncologic success of any active surveillance program. Berglund et al sought to determine the risk of prostate cancer understaging in patients meeting the inclusion criteria of an active surveillance program by examining pathologic findings of repeat prostate biopsies within 3 months of the initial diagnostic biopsy. An increased grade and/or stage was identified in 27% (28/104) of patients on repeat biopsy.
Sheridan et al reviewed biopsies from 241 men on active surveillance who underwent at least one subsequent biopsy. Pathologic progression was noted in 45 (19%) patients, with 24 cases occurring within 2 years of diagnosis.
For both studies, pathologic upgrading occurring over such a brief period of time is highly likely to reflect undersampling of the prostate rather than true progression, further highlighting the limitations of prostate cancer clinical staging. Therefore, for patients considering active surveillance, repeat biopsy following an initial prostate cancer diagnosis appears to improve the staging evaluation, ultimately improving the success of patients remaining on active surveillance.
Definitions of Pathologically Insignficant Prostate Cancer
Attempts have been made to define the pathologic features of “indolent” or “insignificant” cancers that harbor an exceedingly low risk of progression. Conceptually, if full characterization of the prostate can be achieved at the time of diagnosis, tailored recommendations regarding the need for treatment could be more effectively determined. Perhaps the most widely recognized definition is that of Epstein (Table 1).
Epstein et al used the Johns Hopkins’ radical prostatectomy experience to retrospectively define a subset of patients whose pathologic features were deemed “insignificant”: organ-confined, Gleason score of 6 or less, and a total tumor volume < 0.2 cm3. Subsequently, preoperative parameters were assessed to predict which patients were likely to harbor cancers with these relatively indolent features. A PSA density (PSAD) < 0.15 ng/mL, clinical stage ≤ T2a, and no biopsy Gleason grade 4 or 5 led to a 73% predictive accuracy. A recent review by Dall’Era et al. cites the most commonly used parameters suggestive of pathologic insignificance: PSA < 10 ng/mL, stable PSA kinetics (low PSA velocity or long PSA doubling time), no Gleason 4 or 5 component, no single positive biopsy core with > 50% tumor involvement, and percent positive biopsy cores ≤ 33%. While the cumulative accuracy supersedes reliance of any single feature, it remains suboptimal.
Observational experiences from patients initiating watchful waiting many decades ago serve as an educational guide regarding the natural history of localized prostate cancer. Their relevance to a contemporary PSA-screened patient remains unclear as diagnoses were largely made following an abnormal digital rectal examination or transurethral resections for benign prostatic hyperplasia. Additionally, pathologists presently are more likely to assign a higher grade to cancers than they were historically, resulting in an upward migration of Gleason grades over the past few decades.
Watchful Waiting Trials in Prostate Cancer
Utilizing a population-based database of men electing watchful waiting, Albertsen et al showed that those with low-grade prostate cancers have a minimal risk of dying from prostate cancer during 20 years of follow-up (6 deaths per 1,000 person-years), with death rates stable at 15 years and beyond (Table 2). Johansson et al followed 223 patients with clinical stage T1–T2 prostate cancers, treating tumor progression with delayed androgen deprivation. They similarly found a low risk of cancer-related death for those with low-grade cancers (10 per 1,000 person-years) but, in contrast to Albertsen, noted a decreased cancer-specific survival (89% to 72%) between 15 and 20 years follow-up, suggesting that watchful waiting may not be the ideal strategy for those with a particularly long estimated life expectancy.
In a prospective randomized evaluation of watchful waiting compared to RP, Bill-Axelson et al enrolled 695 patients between 1989 and 1999. Patients were low-risk, defined as clinical stage T1–T2 with moderately or well-differentiated cancers, an estimated life expectancy >10 years, a normal bone scan, and PSA < 50 ng/mL. With a median follow-up of 12 years, 13% of patients who underwent RP vs 18% of those on watchful waiting died of prostate cancer, for a relative risk of 0.65. These differences in disease-specific death remained stable beyond 10 years of follow-up. While this study provides invaluable information, it primarily included patients with higher-stage disease than are typically seen in modern, PSA-screened cohorts-approximately 10% of patients were diagnosed by PSA screening, 75% had palpable tumors at diagnosis, and 50% had PSA values > 10 ng/mL. As such, its generalizability to contemporary patients is unclear.
Active Surveillance Trials in Prostate Cancer
Early- to intermediate-term data for appropriately selected active surveillance patients suggests metastasis rates consistently below 1%, with follow-ups ranging from 2 to 8 years.[24-29] The outcomes in any active surveillance program are directly related to patient age and overall health, cancer-specific inclusion criteria, frequency and type of surveillance, and indications for recommending intervention. The available studies represent a heterogeneous group of patients with a variety of eligibility criteria and varying thresholds for subsequent interventions, thereby making any cross-comparisons difficult, if not impossible (Table 3). Some commonalities do exist, as all studies included a relatively older population (median ages 63–70 years) with clinical stage ≤ T2. However, eligibility criteria regarding Gleason grade, PSA, PSA kinetics, and number of positive biopsy cores varied.[24-29]
When counseling a patient considering active surveillance, several findings based on available series may be offered (Table 3). First, a small percentage of patients on active surveillance exhibit disease progression, with an estimated risk of metastasis of < 1% at 2 to 8 years while on surveillance.[25,28,29] Second, patients with low-risk features (PSA < 10 ng/mL, clinical stage T1–T2a, and biopsy Gleason sum 6 or less) who select active surveillance have an estimated disease-specific mortality of 1% at 8 years. Third, active surveillance patients who undergo delayed intervention within 2 years do not harbor worse pathologic features compared to patients who undergo immediate RP.[13,14,24] Fourth, the rates of remaining on active surveillance and outcomes following delayed intervention rely heavily on the inclusion criteria. The obvious and inherent benefits of active surveillance are avoiding or delaying treatment and its potential side effects, but these must be seriously balanced against the low but real risks of disease progression, delayed intervention, and cancer-related morbidity or mortality.
There have not been any prospectively validated markers of disease status or progression for men electing active surveillance. Most investigators have decided that upgrading on repeat biopsy, pathologic or radiographic evidence of an increasing tumor burden, a more concerning digital rectal examination, or a continuously rising PSA should all prompt consideration of primary therapy.
Regarding pathologic findings, the presence of cancer on a repeat biopsy prior to starting active surveillance has been associated with an increased risk of subsequent intervention. A multi-institutional, retrospective analysis of 262 men on active surveillance suggested that those with cancer on repeat biopsy and a higher sum of positive cores on initial and repeat biopsies were more likely to undergo delayed intervention. Another group has similarly shown that the number of positive biopsies at diagnosis correlates with time to delayed treatment.
Among PSA parameters, absolute PSA at diagnosis,[24,27,30] PSA doubling time (PSADT),[30-33] PSA density (PSAD),[24-25,27] and PSA velocity (PSAV)[19,24] have all been suggested as prognosticators for disease progression and the need for treatment. A PSADT < 2 years has correlated with disease progression on digital rectal examination. A PSAD > 0.15 ng/mL/cm3 predicted those more likely to receive active treatment after enrollment in active surveillance. These studies suggest PSA kinetics may retrospectively identify patients at elevated risk of disease progression and subsequent intervention.
However, there are also potential pitfalls and false-positives associated with a reliance on PSA kinetics, as many noncancer etiologies can lead to PSA variability. Intuitively, and perhaps incorrectly, clinicians place undue importance on PSA and PSA kinetics when assessing patients on active surveillance. Fall et al examined whether baseline PSA and PSAV could predict disease progression in their prospective database of 267 men on active surveillance, of which 34 have died of prostate cancer. At 6 and 10 years after the initiation of active surveillance, neither baseline PSA nor PSAV reliably distinguished patients who developed lethal disease vs those who did not. As such, the value of absolute PSA and PSA kinetics in early decision-making for prostate cancer patients remains debatable.
Finally, cancer anxiety scores of men on active surveillance have been shown to significantly predict future treatment. When selective inclusion criteria are employed, 60% to 90% of patients remain on active surveillance for 2 years, and up to 75% for 5 years.[24,27,29] Up to 10% of this attrition rate, and perhaps higher, may be directly attributed to anxiety.
Prospective, randomized active surveillance studies are underway in Canada, the United Kingdom, and the Netherlands and will ultimately provide valuable information. Any meaningful advance in clinical staging (eg, novel biomarker, imaging, biopsy techniques) has the ability to improve the utility and application of active surveillance. Potential examples that remain to be completely evaluated in this setting include magnetic resonance imaging with higher Tesla magnets, urine-based prostate cancer gene 3 (PCA3) levels that may correlate with tumor volume, and evaluation of TMPRSS2/ERG fusion messenger RNA, whose isoform expression profiles have been associated with more aggressive pathologic findings.
Active surveillance provides a simple, safe, and durable treatment alternative for appropriately selected, low-risk prostate cancer patients. The risk of disease progression is low and delayed treatment outcomes appear promising, although longer follow-up is still needed. The recognition of potentially unnecessary overtreatment should reemphasize our duty to educate patients of all available treatment options, including the option for delayed active intervention when deemed necessary. If improvements in the imaging and staging of prostate cancer occur, treatment can be better allocated for patients most likely to benefit and limited or avoided for those with a low likelihood of benefit but similar risk of treatment-related morbidity.
Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Editor’s Note:This article is part of a special series, Controversies in the Management of Localized Prostate Cancer, which began in the September issue of ONCOLOGY. Guest edited by Dr. Derek Raghavan, each article in the series takes a particular position on optimal patterns of care for early-stage prostate cancer.
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