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Defining ‘progression’ and triggers for curative intervention during active surveillance

Klotz, Laurence

doi: 10.1097/MOU.0000000000000158
ACTIVE SURVEILLANCE FOR FAVORABLE RISK PROSTATE CANCER: Edited by H. Ballentine Carter
Editor's Choice

Purpose of review Low-risk and many cases of low-intermediate risk prostate cancer have little or no metastatic potential, and do not pose a threat to the patient in his lifetime. Substantial recent evidence, reviewed in this article, has clarified who these patients are and supports the use of conservative management in such individuals.

Recent findings A key element of conservative management is the early identification of those ‘low-risk’ patients who harbour higher risk disease and benefit from definitive therapy. This represents about 30% of newly diagnosed low-risk patients. A further small proportion of patients with low-risk disease demonstrates true biological progression over time to higher grade disease (as distinct from grade increase on repeat biopsy due to resampling). Men with lower risk disease can defer treatment, in most cases for life. The results of active surveillance, embodying conservative management with selective delayed intervention for the subset who are reclassified as higher risk over time based on repeat biopsy, imaging or biomarker results, are associated with a 5% cancer-specific mortality at 15 years.

Summary Active surveillance for low-risk prostate cancer is well tolerated in the intermediate-long term time frame. Further refinement of the surveillance approach is ongoing, incorporating MRI, targeted biopsies and molecular biomarkers to improve appropriate patient selection and triggers for intervention.

Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

Correspondence to Laurence Klotz, Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave. #MG408, Toronto, ON M4N 3M5, Canada. E-mail: Laurence.klotz@sunnybrook.ca

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INTRODUCTION

The history of surgery has been one of progressive movement towards less invasive, painful and mutilating operations. The ultimate expression of this trend will be the management of disease without invasive procedures at all [1▪▪]. In prostate cancer, there has been a major shift towards tissue-conserving approaches, including active surveillance. Progress in defining ‘progression’ in men on active surveillance and in refining the accuracy of triggers for intervention will be reviewed in this study.

The United States Preventive Services Task Force (USPSTF) recommendation against prostate-specific antigen (PSA) screening in 2012 largely reflected concerns about overdiagnosis and overtreatment of nonlife-threatening or nonclinically significant disease (http://ww.uspreventiveservicestaskforce.org/uspstf12/prostate/prostateart.htm). Previously, most men with prostate cancer were treated by either radical prostatectomy or high-dose radiation treatment. The recommendations of the USPSTF, enhanced by evidence regarding the indolent nature of low-grade disease and the very low cancer-specific mortality outcome achieved with conservative management, have resulted in a more widespread adoption of this approach.

At the same time, it has become apparent that a significant proportion of patients diagnosed with apparent clinically insignificant prostate cancer, that is microfocal Gleason 6 disease, their prostate cancer is a wolf in sheep's clothing, in other words that there is coexistent, and potentially life-threatening, prostate cancer harboured elsewhere in the prostate. Another small group of patients evolve from sheep into wolves, that is their favourable looking Gleason 6 disease has adverse genetic features, which result in clonal evolution towards a more aggressive phenotype. Using systematic (blinded) biopsies to diagnose prostate cancer, the former (undersampling) is more common than the latter (biological progression).

Box 1

Box 1

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RATIONALE

In Caucasians and Blacks, the chance of harbouring prostate cancer is approximately one's age as a percentage; in other words, as many as 30% of men in their 30s, 40% in their 40s and 70% in their 70s have some histologic prostate cancer [2]. Most of these are microfoci only (<1 mm3) and low grade. A recent autopsy study in Japanese and Russian men, two groups in whom PSA testing was uncommon, found that in those who died of other causes, 35% of both groups had prostate cancer. Surprisingly, 50% of the cancers in Japanese men aged more than 70 years were Gleason score 7 or above [3▪]. This finding suggests that, particularly in men over 70 years of age, microfocal Gleason 3 + 4 might also represent ‘overdiagnosis’ of clinically insignificant cancer.

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GENETIC FEATURES OF LOW-GRADE PROSTATE CANCER

For most molecular pathways that characterize cancer cells that invade and metastasize, the genetic aberrations that characterize these pathways are normal in Gleason pattern 3 and abnormal in pattern 4 and 5 [4,5]. There are exceptions to this, including TMPRSS2-ERG (commonly translocated in all grades of prostate cancer) [6] and pTEN (absent in about 10% of Gleason pattern 3, and 50% or more of higher grade cancers) [7]. Given the normal limits of histology at predicting genetic abnormalities, this heterogeneity is not surprising. However, isolated genetic alterations do not appear to translate into an aggressive metastatic phenotype.

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METASTATIC POTENTIAL

A natural limitation of the conservative (no treatment) management series is that, as the diagnosis is based on needle biopsy, there is no way to exclude the possibility that the patients who progress to metastasis had occult higher grade cancer at the time of diagnosis. About 25% of men initially diagnosed with Gleason 6 on biopsy have occult higher grade cancer, and these appear to be responsible for most of the prostate cancer deaths reported in series of conservative management. One multicentre study of 24 000 men with long-term follow-up after surgery included 12 000 with surgically confirmed Gleason 6 cancer (i.e. precluding the possibility of occult higher grade disease lurking in the unsampled prostate) [8]. The 20-year prostate cancer mortality was 0.2%. About 4000 of these were treated at Memorial Sloan Kettering Cancer Centre (MSKCC); of these, one died of prostate cancer; a pathological review of this patient revealed Gleason 4 + 3 disease (Scott Eggener, personal communication). A second study of 14 000 men with surgically confirmed Gleason 6 disease found only 22 with lymph node metastases; a review of these cases showed that all had higher grade cancer in the primary tumour. The rate of node-positive disease in the patients with no Gleason 4 or 5 disease in their prostates was therefore zero [9].

Occasional genetic mutations that confer an aggressive phenotype may be prehistologic or may develop as a result of the accumulation of genetic alterations in normal cells or low-grade cancers. A recent genetic analysis of multiple metastatic sites from a patient who had extensive Gleason 4 + 3 pT3a N1 disease resected at age 47, and died 17 years later of metastatic castrate resistance prostate cancer, reported that the metastatic lesions appeared to derive from a microfocus of Gleason pattern 3 disease, rather than, as expected, from the high-grade cancers elsewhere in the prostate [10]. A second case report from the same group described a patient on active surveillance with 12 annual biopsies that were negative or showed Gleason 6 cancer only. Biopsies were discontinued for 5 years, until a repeat biopsy performed for a rise in PSA showed Gleason 9 cancer, which had metastasized. Molecular characterization of the biopsies in this patient showed no homology at all between the earlier low-grade cancer and the high-grade cancer [11▪]. These case reports are a challenge to the view that Gleason pattern 3 does not behave like a malignancy. It has been proposed that in the first patient, the low-grade cancer that shared genetic homology with the metastases, and was present in a sea of higher grade cancer, may have developed as a ‘redifferentiated’ clonal offspring of a higher grade cancer cell that had metastasized [12▪]. Key points raised by these informative cases are that biology is complex, dynamic and not 100% predictable; these are single case reports, and should be viewed in that context; and it is possible that histological Gleason pattern 3, particularly when it coexists with higher grade cancer, may harbour prehistological genetic alterations that confer a more aggressive phenotype. This is the conceptual basis for genetically based predictive assays that disaggregate low-grade cancer into low and higher risk groups. Importantly, concerns about the risks exemplified by these cases should be balanced against the extensive clinical evidence supporting the absence of metastatic potential in the vast majority of pure Gleason pattern 3 cancers.

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OUTCOME OF SURVEILLANCE

Cardiovascular disease is the commonest cause of death in men with favourable risk prostate cancer. In the most mature surveillance cohort [13▪▪], with a median follow-up of 8 years, the cumulative hazard ratio (or relative risk) of nonprostate cancer death was 10 times that for prostate cancer. The first publication to explicitly describe a cohort managed with expectant management with selective delayed intervention was published in 2002 [14]; currently, the published literature on surveillance includes 13 distinct prospective studies, encompassing about 5000 men [13▪▪,14–26]. Most of these studies have a follow-up duration that is insufficient to identify an increased risk of prostate cancer mortality as a result of surveillance. Long-term follow-up is essential to address this critical question. For example, a pivotal Swedish study reported that the risk of prostate cancer mortality in patients managed by watchful waiting was low for many years, but tripled after 15 years of follow-up [27,28]. (‘Watchful waiting’ meant no opportunity for selective delayed intervention, whereas about 30% of patients in most surveillance series have had radical treatment.) In the Toronto experience, 70 patients have been followed for 14 years or more; 1.5% have had late disease progression to metastatic disease (after 7 years), but there is no evidence of a sharp increase in mortality in those with longer follow-up [15]. Table 1 summarizes the overall results of the 13 prospective series. The key outcome measures include the proportion of patients treated, overall and cause-specific survival. About one-third of patients are treated; most series have few or no prostate cancer deaths. In the Toronto series, the actuarial prostate cancer mortality at 15 years is 5%.

Table 1

Table 1

The annual rate of intervention in most published surveillance series is about 3–5% per year. (Fig. 1). The slope of the curve flattens out at around 10 years. The shape of this time to intervention curve points to the opportunities for improvement in defining triggers for intervention. Knowing that most upgrading reflects more accurate sampling rather than true grade progression, the higher grade cancers should preferably be identified early, that is within the first year, and the subsequent rate of grade progression and intervention would then be closer to 1% per year (red line in Fig. 1).

FIGURE 1

FIGURE 1

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DEFINING PROGRESSION

Progression in men on surveillance, in most cases, means reclassification to a higher risk of true disease progression (i.e. metastasis or locally advanced disease). (This is an important distinction to the meaning of progression, as it is usually used in oncology, that is where a change to more advanced disease has already occurred.) Risk reclassification has been accomplished by one of the following observations:

  1. Rapid PSA rise or short PSA doubling time
  2. Grade progression on repeat biopsy
  3. Volume progression (of Gleason 6) on repeat biopsy
  4. T stage progression on digital rectal exam
  5. Increase in cancer size or worsening in appearance on imaging (usually MRI)
  6. Worsening of genetic features on molecular evaluation.
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SURVEILLANCE FOLLOW-UP

Following the initial diagnosis of Gleason 6 prostate cancer on 10 or more core systematic biopsies, PSA is performed every 3 months for 2 years to establish a baseline of PSA kinetics and every 6 months indefinitely after that. A confirmatory biopsy must be carried out within 6–12 months of the initial diagnostic biopsy on which cancer was identified. This confirmatory biopsy should target the areas that are typically undersampled on the initial diagnostic biopsy. This includes the anterior prostate, and the prostatic apex and base. If the confirmatory biopsy is either negative or confirms microfocal Gleason 3 + 3 disease, subsequent biopsies are performed every 3–5 years until the patient reaches age 80, or has a life expectancy of less than 5 years because of comorbidity. Some groups have utilized more frequent biopsies (as often as annually) [18], and some controversy exists as to what biopsy frequency is optimal. The confirmatory biopsy is considered mandatory, as it samples areas of the prostate that are often missed on the initial biopsy; following this, most men are adequately monitored by serial biopsies every 4–5 years. It is likely that the increasing use of MRI and molecular markers will further reduce biopsy requirements in men with favourable results (i.e. negative MRI). Table 2 summarizes the triggers for intervention employed in the published series to date. These are very much in evolution.

Table 2

Table 2

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LIMITATIONS OF PSA KINETICS AS A TRIGGER FOR INTERVENTION

In the early days of active surveillance, PSA kinetics was an appealing trigger for intervention. This was based on the simple observation that most patients with advanced prostate cancer had an elevated PSA, and, therefore, a stable PSA likely implied stable disease and vice versa. Until multiparametric MRI became available, men on active surveillance (AS) with poor PSA kinetics (doubling time <3 years) were offered treatment. In the PRIAS multi-institutional AS registry, 20% of men being treated had intervention based on a PSA doubling time less than 3 years [26]. Indeed, in a report of the five men dying of metastatic prostate cancer in the Toronto cohort, all had a PSA doubling time of less than 2 years [29]. However, PSA kinetics turned out to have a crucial limitation: lack of specificity. The liability of PSA, and the high prevalence of inflammatory causes of a sharp transient rise in PSA, severely limits the reliability of PSA kinetics as a trigger [30]. In a study of PSA kinetics in a large surveillance cohort, false-positive PSA triggers (doubling time <3 years, or PSA velocity >2 ng/year) occurred in 50% of stable untreated patients, none of whom went on to progress, require treatment or die of prostate cancer [31]. Vickers [32], in an overview of all of the studies of more than 200 patients examining the predictive value of PSA kinetics in localized prostate cancer, concluded that kinetics had no independent predictive value beyond the absolute value of PSA. Currently, PSA kinetics are used as a guide to identify patients at a higher risk, but not to drive the decision to treat.

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GRADE PROGRESSION ON REPEAT BIOPSY

Most cases that are upgraded on the confirmatory or subsequent biopsies are thought to be upgraded on the basis of resampling (about 25% of patients). Of those who are upgraded, in up to 98%, the upgrading is to Gleason 3 + 4 only [33]. Upgrading to Gleason 8 or higher is uncommon; in the Toronto series, this was 13%. Biological grade progression (Gleason 3 cells giving rise to Gleason 4 or 5 progeny) occurs over time, but is uncommon. In the Toronto surveillance cohort, we observed that the likelihood of grade progression increased approximately 1% per year from the time of the original biopsy [34]. The implication is that long-term follow-up is required, although in most cases, the Gleason grade remains stable.

We have developed a risk calculator (Fig. 2) that incorporates the important clinical parameters associated with grade progression in a surveillance cohort [34]. On the basis of simple clinical and pathological factors, a patient's likelihood of upgrading varies from 10 to 70%.

FIGURE 2

FIGURE 2

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VOLUME PROGRESSION

Many studies have demonstrated that men with high-volume Gleason pattern 3 have a higher risk of harbouring higher grade cancer. A threshold of more than 8 mm of total cancer on systematic biopsy has recently been described [35]. The management of patients found to have higher volume Gleason 6 is to exclude the presence of higher grade cancer as rigorously as possible (based on MRI, targeted/template biopsies and biomarkers). A finding of higher grade cancer in most cases warrants intervention; the remainder are unlikely to require treatment.

Low prostate volume, and more specifically a high PSA density (PSA: prostate volume ratio), has been demonstrated in many studies to be a predictor for risk progression. A high PSA density in some Gleason 6 surveillance candidates reflects PSA arising from a large occult cancer. Increased caution is warranted in these cases.

A few young men (age <50 years) are found to have extensive Gleason 6 cancer on biopsy. In these patients, uncertainty exists about the risk of true tumour progression over time, as well as the risk of harbouring occult high-grade disease. These patients are outliers and it is reasonable to offer them treatment. Where exactly to draw the line in terms of age and cancer volume is a matter of clinical judgement and risk tolerance.

African-Americans on AS have a higher rate of risk reclassification, and PSA failure when treated, than Caucasian men [36]. Black men who are surveillance candidates also have a higher rate of large anterior cancers than Caucasians [37]. However, black patients diagnosed with low-grade prostate cancer include many men who have little or no probability of a prostate cancer related death during their remaining lives, and active surveillance is still an appealing option for those who have been appropriately risk-stratified.

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Biomarkers

Two biomarkers have recently been approved by the US Food and Drug Administration (FDA) on the basis of their ability to predict progression in low-grade prostate cancer patients: the Prolaris assay [38] (Myriad Genetics Inc., Salt Lake City, Utah), which looks for abnormal expression of cell cycle related genes; and the Oncotype DX assay (Genome Health Inc., Redwood City, California), which identifies a panel of genes linked to a more aggressive phenotype [39]. The Decipher assay, a tissue-based 22-marker genomic classifier evaluating noncoding RNA sequences, has been demonstrated to accurately predict the risk of biochemical progression after radical prostatectomy [40]. The Mitomics assay, which identifies the presence of a functional mitochondrial DNA deletion associated with aggressive prostate cancer [41], is not yet FDA approved. These tests hold the promise of interrogating the microfocus of Gleason 6 found on biopsy for accurate information about the presence of higher grade cancer elsewhere in the prostate, or the future likelihood of progression to aggressive disease. That the biomarkers can achieve this confirms the interrelationship of heterogeneous multifocal cancers.

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ROLE OF MRI

Systematic serial transrectal ultrasound-guided biopsy, the mainstay of active surveillance monitoring to date, has significant limitations, including undersampling, urosepsis, patient discomfort and erectile dysfunction. MRI has an emerging role in the management of AS patients and offers the potential to address these limitations. The key metric is the negative predictive value (NPV). This has been reported to be 97% for a group of about 300 surveillance candidates at [42]. This observation requires validation. An MRI lesion characterized as PiRADS (Prostate Imaging Reporting and Data System) score of 4 or 5/5 has a 90% positive predictive value for high-grade cancer. This abnormality is characterized by a hypodense lesion on T2-weighted image, with both restricted diffusion and enhanced contrast. These lesions are very significant and should lead at least to a targeted biopsy, if not definitive intervention. An equivocal lesion (PiRADS 3/5) should trigger a targeted biopsy. The diagnostic usefulness of MRI and targeted biopsy compared with systematic biopsy has recently been reported to be optimized in men with a PSA of more than 5.2 [43▪]. As most men on surveillance have a PSA that is at least mildly elevated (i.e. above 5), this reinforces the potential value of MRI.

The favourable results of active surveillance reported to date have been achieved without MRI. It is thus, currently, an adjunct to surveillance and not a requirement. In centres in which access to MRI is limited by either availability or resource restrictions, it should be used selectively. However, it is plausible that an MRI performed at diagnosis in all newly diagnosed prostate cancer patients would enhance the results of surveillance further, by identifying most of the covert ‘wolves’ several years earlier. This approach is currently the subject of prospective trials.

Currently, multiparametric MRI is indicated in men on surveillance whose PSA kinetics suggests more aggressive disease (usually defined as a PSA doubling time <3 years), whose biopsy shows substantial volume increase or who are upgraded to Gleason 3 + 4 wherein surveillance is still desired as a management option. Identification of an MRI target suspicious for high-grade disease should warrant a targeted biopsy, or if the lesion is large and unequivocal, intervention.

A further area for research is to better understand how to integrate the results of genetic biomarker tests and MRI. For example, optimal management of the patient in whom results are discrepant (i.e. genetic test indicates high risk but MRI is negative) is unknown. False-positive and false-negative results occur with both diagnostic approaches, but how commonly is unknown. Although the molecular assays may meet the unmet need of better risk assignment, further validation of their performance is needed before they are widely adopted in the surveillance scenario.

There is an increasing recognition that patients with Gleason 3 + 4 = 7, in which the component of pattern 4 is small (<10%), have a very similar natural history to those with Gleason 3 + 3, perhaps reflecting the stage migration phenomenon associated with grade reclassification [44]. These patients are surveillance candidates. MRI to confirm the absence of large volume, high-grade cancer is particularly important in these patients.

Although there is a general consensus on the principles of surveillance amongst most practitioners, the optimal surveillance strategy and triggers for intervention are not agreed upon. This mainly reflects differences in treatment philosophy and risk tolerance. An inclusive approach means that the benefits of surveillance are available to many more patients, but will likely mean a small increased risk of metastasis. One recent study compared the outcome of the Hopkins approach, using grade or volume progression based on annual biopsies, vs. the PRIAS approach, based on PSA kinetics and biopsy every 3 years [45]. About 6% of patients would have had a delay in diagnosis (median 2 years) using the PRIAS approach, and 12% would have avoided misclassification using the Hopkins approach. Neither of these strategies employed MRI, which would likely have influenced the results considerably.

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CONCLUSION

Active surveillance is an appealing approach for low-risk patients and an effective solution to the widely recognized problem of overtreatment. Ongoing improvements in diagnostic accuracy based on multiparametric MRI and genetic biomarkers should reduce the need for systematic biopsies, improve the early identification of occult higher risk disease and enhance the ability to detect patients destined to have grade progression over time. Adverse PSA kinetics, although sensitive for more aggressive disease, are an unreliable trigger for intervention due to lack of specificity. Existing nomograms employing clinical and pathological parameters permit patient stratification for the risk of subsequent upgrading. A confirmatory biopsy targeting the anterolateral horn and anterior prostate must be performed within 6–12 months. PSA should be performed every 6 months and subsequent biopsies every 3–5 years until the patient is no longer a candidate for definitive therapy. MRI is indicated for men with a grade or volume increase, or adverse PSA kinetics. Genetic characterization of cancer will likely have an increasing role in identifying patients at risk. Treatment should be offered for most patients with an upgraded disease.

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Acknowledgements

None.

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Financial support and sponsorship

This work was supported by the Genito-Urinary Oncology site group, Sunnybrook Health Sciences Centre and Prostate Cancer Canada.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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Keywords:

active surveillance; biomarkers; MRI; progression; prostate cancer; triggers

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