Active surveillance and focal therapy for low-intermediate risk prostate cancer

Low risk and many cases of low-intermediate risk prostate cancer, are indolent, have little or no metastatic potential, and are not life threatening. Major advances have been made in understanding who these patients are, and in encouraging the use of conservative management in such individuals. Conservative management incorporates the early identification of those ‘low risk’ patients who harbor higher risk disease, and benefit from definitive therapy. Based on the current algorithm of PSA followed by systematic biopsy, this represents about 30% of newly diagnosed low risk patients. A further small proportion of patients with low risk disease demonstrate biological progression to higher grade disease. Men with lower risk disease can defer treatment, usually for life. Men with higher risk disease that can be localized to a relatively small volume of the prostate may be candidates for focal, prostate sparing therapy. The results of active surveillance, embodying conservative management with selective delayed intervention for the subset who are re-classified as higher risk over time based on repeat biopsy, imaging, or biomarker results, have shown that this approach is safe in the intermediate to long term, with a 1-5% cancer specific mortality at 15 years. Further refinement of the surveillance approach is ongoing, incorporating MRI, targeted biopsies, and molecular biomarkers.     

Active surveillance as a practical strategy to differentiate lethal and non-lethal prostate cancer subtypes

Differentiation between lethal and non-lethal prostate cancer subtypes has become a very important issue in avoiding excessive treatment in an era when prostate-specific antigen (PSA) screening has reduced the rate of prostate cancer deaths by more than 20%. However, it is difficult to determine the patients who may or may not benefit from immediate treatment interventions at the time of the initial diagnosis. The selection of candidate patients who can postpone immediate treatment and undergo follow-ups with a specific surveillance program, or ‘active surveillance,'' is a practical way to minimize overtreatment. In this review, the benefits and risks of active surveillance are discussed. Future perspectives, including imaging and new biomarkers for improving the outcomes of active surveillance programs, are also discussed.     

Active surveillance for prostate cancer

Many men diagnosed with localized prostate cancer can postpone definitive treatment without raising their risk of metastasis or death from disease. Active surveillance (AS) is a method of monitoring select men, with the option of switching to active treatment upon signs of progression, thereby avoiding the well-known side-effects of surgery and radiotherapy. This review analyzes the data from long-running AS cohorts to determine the safety and efficacy of AS. We conducted a narrative review of recently published data, including 14 articles from 13 AS cohorts. The cohorts used varying inclusion criteria, with reported differences in clinical T stage and Gleason Score (Grade Group), among other features. Some studies (n=5) limited their cohorts to low-risk patients, while others (n=8) also included intermediate-risk patients. The heterogeneity of the cohorts produced mixed results, with the risk of prostate cancer metastasis ranging from 0.1–1.0% at 10 years and the risk of prostate cancer mortality ranging from 0–1.9% at 10 years. However, the majority of studies reported risks of less than 0.5% at 10 years for both metastasis and death. For most cohorts, half of men remained untreated for 5–10 years, with estimates ranging from 37% receiving active treatment in the Toronto cohort to 73% in the Prostate Cancer Research International AS (PRIAS) study. Current data do not support the use of negative magnetic resonance imaging (MRI) to avoid scheduled biopsy. Taken together, the data collected from these AS cohorts suggests that AS is a safe approach for men with low-grade prostate cancer and some men with intermediate risk disease. AS should be more broadly implemented for eligible patients to avoid the decreases in quality of life from undergoing active treatment. Studies expanding the inclusion criteria and further defining a subset of men with favorable intermediate-risk prostate cancer who might safely benefit from AS are needed to assess the long-term outcomes of using AS in intermediate-risk groups.     

Identifying intermediate-risk candidates for active surveillance of prostate cancer

Purpose

Although already established for very-low and low-risk (LR) prostate cancer (PCa), controversy remains around offering active surveillance (AS) to men with intermediate-risk (IR) PCa. As IR represents a broad spectrum of disease biology, there is a critical need to define eligibility criteria that will enable both patient and physician to accept AS as the best balance of competing risks. In this study, we aimed to identify predictors of progression to enable optimal patient selection.

Association of prostate cancer risk alleles with unfavourable pathological characteristics in potential candidates for active surveillance

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Men fail active surveillance for a variety of reasons; however, no single reliable biomarker has been found to date which will identify these men from the outset. We know that there are about 35 prostate cancer risk alleles which have been discovered to influence risk of prostate cancer, from large‐scale genome‐wide association studies. Some of these have been associated with aggressive prostate cancer. Nobody has examined the potential for these risk alleles to predict men who might fail active surveillance. This study adds to the growing evidence that single nucleotide polymorphisms may be able to identify men who have aggressive prostate cancers, and that this could be part of a risk algorithm used in active surveillance protocols.

OBJECTIVE

• ? To assess whether the carrier status of 35 risk alleles for prostate cancer (CaP) is associated with having unfavourable pathological features in the radical prostatectomy specimen in men with clinically low risk CaP who fulfil commonly accepted criteria as candidates for active surveillance.

PATIENTS AND METHODS

• ? We studied men of European ancestry with CaP who fulfilled the commonly accepted clinical criteria for active surveillance (T1c, prostate‐specific antigen <10 ng/mL, biopsy Gleason ≤6, three or fewer positive cores, ≤50% tumour involvement/core) but instead underwent early radical prostatectomy.
• ? We genotyped these men for 35 CaP risk alleles. We defined ‘unfavourable’ pathological characteristics to be Gleason ≥7 and/or ≥ pT2b in their radical prostatectomy specimen.

RESULTS

• ? In all, 263 men (median age 60 [46–72] years) fulfilled our selection criteria for active surveillance, and 58 of 263 (22.1%) were found to have ‘unfavourable’ pathological characteristics.
• ? The frequencies of three CaP risk alleles (rs1447295 [8q24], P= 0.004; rs1571801 [9q33.2], P= 0.03; rs11228565 [11q13], P= 0.02) were significantly higher in men with ‘unfavourable’ pathological characteristics.
• ? Two other risk alleles were proportionately more frequent (rs10934853 [3q21], P= 0.06; rs1859962 [17q24], P= 0.07) but did not achieve nominal statistical significance.
• ? Carriers of any one of the significantly over‐represented risk alleles had twice the likelihood of unfavourable tumour features (P= 0.03), and carriers of any two had a sevenfold increased likelihood (P= 0.001).
• ? Receiver–operator curve analysis demonstrated an area under the curve of 0.66, suggesting that the number of single nucleotide polymorphisms carried provided discrimination between men with ‘favourable’ and ‘unfavourable’ tumour features in their prostatectomy specimen.

CONCLUSION

• ? In potential candidates for active surveillance, certain CaP risk alleles are more prevalent in patients with ‘unfavourable’ pathological characteristics in their radical prostatectomy specimen.

     

Active surveillance; a reasonable management alternative for patients with prostate cancer: the Miami experience

OBJECTIVE

To examine the outcome of patients diagnosed with ‘low‐risk’ prostate cancer managed by active surveillance (AS).

PATIENTS AND METHODS

In all, 157 men with localized prostate cancer were followed on AS. The inclusion criteria for AS included: Gleason score of ≤ 6, a serum prostate‐specific antigen (PSA) level of ≤15 ng/mL, stage ≤ T2, low‐volume disease and >12 months of follow‐up. The follow‐up was rigorous, with PSA tests and a digital rectal examination every 3 months for 2 years, and a repeat biopsy 6–12 months after the initial diagnosis and yearly when indicated. Continuance of AS was based on the PSA doubling time, re‐biopsy score, Gleason score, tumour volume, stage progression and patient preference.

RESULTS

In all 99 patients met the inclusion criteria; their mean age at diagnosis was 66 years, their mean PSA level 5.77 ng/mL and the mean follow‐up 45.3 months. On initial repeat biopsy, 63% had no cancer and 34% had a Gleason sum of ≤ 6. Eight patients were treated (three with hormones; five with curative intent); two had radical prostatectomy (one had pT2c pNO Gleason 7 disease); three had radiotherapy. The probability is that 85% would remain treatment‐free at 5 years; no patient died from prostate cancer. The PSA doubling time and clinical stage at diagnosis were predictive of progression.

CONCLUSION

Patients who are followed on AS must be selected using narrowly defined inclusion criteria and closely followed with a standard regimen of PSA testing, digital rectal examination and repeat biopsy.     

Repeat prostate biopsies predict location of index cancer in an active surveillance cohort

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? The accuracy of TRUS‐guided biopsies in identifying the location of an index cancer at surgery is low. When two biopsies show cancer in the same location, the concordance between the biopsy and surgical location of the cancer increases.

OBJECTIVE

? To evaluate the ability of repeat prostate biopsies to determine the location of the index cancer for men on prostate cancer surveillance.

PATIENTS AND METHODS

? Forty‐five men on active surveillance had a record of the locations of their positive diagnostic biopsy, repeat surveillance biopsy and index cancer (i.e. largest cancer) from prostatectomy specimens. ? Logistic regression analysis was used to evaluate the association between two consecutive needle biopsies showing cancer in an identical location and the outcome of finding the index cancer at the same location as the initial diagnostic biopsy.

RESULTS

? Eighteen of 45 (40%) men ultimately had an index cancer at the same location as their diagnostic biopsy. ? Thirteen men had two consecutive biopsies that showed cancer at the same location each time; nine of these men ultimately had an index cancer at that same location. ? In multivariable logistic regression analysis of men with at least two biopsies, having two initial consecutive biopsies with the same location increased the odds (odds ratio 5.9; 95% CI 1.1–31, P= 0.037) of having an index cancer at the same location as the initial biopsy in a cohort of men on active surveillance.

CONCLUSIONS

? A substantial proportion of men in an active surveillance cohort who undergo prostatectomy ultimately have evidence of an index cancer at the same location as their initial biopsy. ? This is more likely to be the case when a repeat biopsy shows evidence of cancer at the same location.     

Cause-specific mortality of low and selective intermediate-risk prostate cancer patients with active surveillance or watchful waiting

BackgroundActive surveillance or watchful waiting (AS/WW) is increasingly being used as an alternative strategy to radical prostatectomy or radiation therapy for appropriately selected patients with prostate cancer (PCa). However, the prognosis of low-risk and selective intermediate-risk PCa patients after AS/WW is poorly defined. In this study we reviewed the patients registered in the Surveillance, Epidemiology, and End Results (SEER) Program to establish a competing risk nomogram for the prediction of prostate cancer-specific mortality (PCSM).MethodsThe information of patients undergoing AS/WW in the SEER program from 2004 to 2015 was obtained. All patients were ISUP (International Society of Urological Pathology) grade 1 or 2 PCa and also fulfilled the National Comprehensive Cancer Network’s definition of low-risk PCa [prostate specific antigen (PSA) <10 ng/mL and cT2aN0M0 or less)]. A competing risk nomogram was used to analyze the association of tumor characteristics with PCSM and non-PCSM among the PCa patients with AS/WW. All cases were randomly divided into a training cohort and a validation cohort (1:1). A competing risk nomogram was constructed to predict PCSM in PCa patients with AS/WW. The performance of the PCSM nomogram was evaluated using the concordance index (C-index) and calibration curve.ResultsA total of 30,538 PCa patients were identified as low risk or selective intermediate risk with AS/WW. The 10-year cumulative incidence of death from prostate cancer and death from other cause were 2.8% (95% CI: 2.4–3.1%) and 19.3% (95% CI: 17.8–20.5%), respectively. Variables associated with PCSM included age, marital status, PSA, and ISUP grade. The PCSM nomogram had a good performance in both the training and validation cohorts, with a C-index of 0.744 (95% CI: 0.700–0.781, P<0.001) and 0.738 (95% CI: 0.700–0.777, P<0.001), respectively.ConclusionsOverall, the prognosis was favorable for the low- and selective intermediate-risk PCa patients with AS/WW. The competing risk nomogram yielded a good performance in identifying subgroups of patients with a higher risk of PCSM and potential candidates for AS/WW.     

Transatlantic Consensus Group on active surveillance and focal therapy for prostate cancer

Study Type – Prognosis (inception cohort) Level of Evidence 2a What's known on the subject? and What does the study add? There is little data on the utility of digital rectal examination (DRE) as a diagnostic tool in the era of prostate‐specific antigen (PSA) testing. Using a population‐based database, we found that detection of prostate cancer while still localized among men with high‐grade PSA‐occult disease may result in survival benefit.

OBJECTIVE

• ? To determine whether detection of high‐grade prostate cancer while still clinically localised on digital rectal examination (DRE) can improve survival in men with a normal prostate‐specific antigen (PSA) level.

PATIENTS AND METHODS

• ? From the Surveillance, Epidemiology and End Results database, 166 104 men with prostate cancer diagnosed between 2004 and 2007 were identified.
• ? Logistic regression was used to identify factors associated with the occurrence of palpable, PSA‐occult (PSA level of <2.5 ng/mL), Gleason score 8–10 prostate cancer.
• ? Fine and Gray's and Cox multivariable regressions were used to analyse whether demographic, treatment, and clinicopathological factors were associated with the risk of prostate cancer‐specific mortality (PCSM) and all‐cause mortality (ACM), respectively.

RESULTS

• ? Both increasing age (adjusted odds ratio [aOR] 1.02, 95% confidence interval (CI) 1.01–1.03; P < 0.001) and White race (aOR 1.26, 95% CI 1.03–1.54; P= 0.027) were associated with palpable, Gleason 8–10 prostate cancer. Of 166 104 men, 685 (0.4%) had this subset of prostate cancer.
• ? Significant factors associated with risk of PCSM included PSA level (adjusted hazard ratio [aHR] 0.71, 95% CI 0.51–0.99; P= 0.04), higher Gleason score (aHR 2.20, 95% CI 1.25–3.87; P= 0.006), and T3–T4 vs T2 disease (aHR 3.11, 95% CI 1.79–5.41; P < 0.001).
• ? Significant factors associated with risk of ACM included age (aHR 1.03, 95% CI 1.01–1.06; P= 0.006), higher Gleason score (aHR 2.05, 95% CI 1.36–3.09; P < 0.001), and T3–T4 vs T2 disease (aHR 2.11, 95% CI 1.38–3.25, P < 0.001)

CONCLUSIONS

• ? Clinically localised disease on DRE among men with PSA‐occult high‐grade prostate cancer was associated with improved PCSM and ACM, suggesting that DRE in this cohort (older age and White race) may have the potential to improve survival.

     

The role of transperineal template prostate biopsies in restaging men with prostate cancer managed by active surveillance

Study Type – Diagnostic (exploratory cohort) Level of Evidence 3b What's known on the subject? and What does the study add? The optimal method of active surveillance in prostate cancer remains unknown. This study is one of the first to report on the role of transperineal template prostate biopsies in active surveillance. It demonstrates that around one third of men are reclassified with more significant prostate cancer at an early stage in their management. This is a higher proportion than reported in contemporary cancers using standard transrectal biopsies for restaging.

OBJECTIVE

• ? To evaluate the role of transperineal template prostate biopsies in men on active surveillance.

PATIENTS AND METHODS

• ? In all, 101 men on active surveillance for prostate cancer underwent restaging transperineal template prostate biopsies at a single centre.
• ? Criteria for active surveillance were ≤75 years, Gleason ≤3+3, prostate‐specific antigen (PSA) ≤15 ng/mL, clinical stage T1–2a and ≤50% ultrasound‐guided transrectal biopsy cores positive for cancer with ≤10 mm of disease in a single core.
• ? The number of men with an increase in disease volume or Gleason grade on transperineal template biopsy and the number of men who later underwent radical treatment were assessed.
• ? The role of PSA and PSA kinetics were studied.

RESULTS

• ? In all, 34% of men had more significant prostate cancer on restaging transperineal template biopsies compared with their transrectal biopsies.
• ? Of these men, 44% had disease predominantly in the anterior part of the gland, an area often under‐sampled by transrectal biopsies.
• ? In the group of men who had their restaging transperineal template biopsies within 6 months of commencing active surveillance 38% had more significant disease.
• ? There was no correlation with PSA velocity or PSA doubling time.
• ? In total, 33% of men stopped active surveillance and had radical treatment.

CONCLUSIONS

• ? Around one‐third of men had more significant prostate cancer on transperineal template biopsies.
• ? This probably reflects under‐sampling by initial transrectal biopsies rather than disease progression.

     

Early outcomes of active surveillance for localized prostate cancer

OBJECTIVE: To describe the preliminary clinical outcomes of active surveillance (AS), a new strategy aiming to individualize the management of early prostate cancer by selecting only those men with significant cancers for curative therapy, and illustrate the contrast with a policy of watchful waiting (WW). PATIENTS AND METHODS: Eighty men with early prostate cancer began AS at the authors' institution between 1993 and 2002. Eligibility included histologically confirmed prostatic adenocarcinoma, fitness for radical treatment, clinical stage T1/T2, N0/X, M0/X, a prostate specific antigen (PSA) level of < or = 20 ng/mL, and a Gleason score of < or = 7. PSA was measured and a digital rectal examination conducted at 3-6 month intervals. The decision between continued monitoring or radical treatment was informed by the rate of rise of PSA, and was made according to the judgement of each patient and clinician. During the same period, 32 men with localized prostate cancer (any T stage, N0/X, M0/X, any PSA, Gleason score < or = 7) were managed by WW; hormonal treatment was indicated for symptomatic prostate cancer progression. The PSA doubling time (DT) was calculated using linear regression of ln(PSA) against time, using all pretreatment PSA values. RESULTS: At a median follow-up of 42 months, 64 (80%) of the 80 patients on AS remained under observation, 11 (14%) received radical treatment and five (6%) died from other causes. No patient developed evidence of metastatic disease, none started palliative hormone therapy, and there were no deaths from prostate cancer. Of the 11 patients who received radical treatment all remained biochemically controlled with no clinical evidence of recurrent disease. The median PSA DT while on AS was 12 years. Twenty (62%) of the 32 patients on WW remained on observation, eight (25%) received palliative hormonal therapy and four (12%) died, including one from prostate cancer. CONCLUSIONS: AS is feasible in selected men with early prostate cancer. The natural history of this disease often appears extremely indolent, and most men on AS will avoid radical treatment. There is a marked contrast between AS (with radical treatment for biochemical progression) and WW (with palliative treatment for symptomatic progression). Ongoing studies are seeking to optimize the AS protocol, and to compare the long-term outcomes with those of immediate radical treatment.