PCa Commentary | Volume 138 – September 2019

Posted by Edward Weber | September 2019

ACTIVE SURVEILLANCE: UPDATE and NEW DEVELOPMENTS

The first study of active surveillance (AS) was started in 1996 at the University of Toronto by Dr. Laurence Klotz. It was first reported in the literature in 2002. In the ensuing 20 years, AS has become increasingly accepted as a management approach to biopsy-diagnosed low-risk prostate cancer. Approximately 40% of men with low-risk cancers during the period from 2010-2013 were managed with AS. Since AS was first reported, the basic goal has remained the same: defer treatment and avoid the associated morbidities while preserving the chance for cure when intervention is indicated. Extensive study has resulted in refinements in the important areas of patient selection and monitoring.

The essential requirement for optimal active surveillance outcome is limiting eligibility to those men with ‘true’ Gleason score 6 cancers, i.e., patterns 3+3. Tumors diagnosed with this histology are thought to lack the molecular capability to support metastases. As reported by Eggener et al.,J Urol. 2011, “Stratified by patient age, 15-year PCSM (prostate cancer-specific mortality) for Gleason score < 6 ranged from 0.2-1.2%, and for Gleason 3+4 the range was 4.2% to 6.5%.” 

The challenge, however, is ensuring that no occult higher grade cancer is present in the biopsy specimen. Studies have found that in repeat ‘confirmation’ biopsies taken following a diagnosis of Gleason score 6 cancer in the original TRUS (‘transrectal ultrasound’) biopsy, higher grade cancer was found in 20-30%. This reclassification is attributed to ‘undersampling.’ The ‘true’ grade progression due to mutations has been estimated at 1-2% per year. 

There is an effort to widen eligibility for AS and allow a low percentage of pattern 4 (say <5%) in Gleason score 3+4 cancers. Gleason score 6 tumors associated with PSA levels of 10-20 ng/mL may also be acceptable.

The state of the art as of 2017 was reviewed by Klotz et al., in an article with the catchy title: “Active Surveillance for Prostate Cancer: How to Do It Right” (Oncology. May 15, 2017). Dr. Laurence Klotz, Professor of Surgery at the University of Toronto, continues to be recognized as one of the gurus in the practice and research of active surveillance. This comprehensive review is still quite up to date.

Two examples of eligibility criteria:

Johns Hopkins: Stage T1c (i.e., no lumps on the prostate), Gleason score < 6, PSA density <0.15 (i.e., PSA divided by prostate size), < 2 positive biopsy cores, < 50% involvement by cancer in any biopsy core. (Note no mention of PSA level.)

Dr. Klotz’s institution allows one palpable prostatic nodule (i.e., stage T2a), PSA < 10-15 ng/mL, and no mention of number of positive cores or PSA density. Men with Gleason score 7 (3+4) may be eligible if the amount of Gleason pattern 4 is minimal.

The PRIAS national trial studying AS allowed PSA density < 0.2 but reported results inferior to the Johns Hopkins data.

It has been recognized that men with prostate cancer carrying a germline BRCA2 mutation have more aggressive disease than suggested by the Gleason score and may not be good candidates for AS. Carter et al., Eur Urol. 2019 May, reported that men with germline mutations in BRCA 1/2 and ATM are 2-3X more likely to be reclassified than non-carriers.

What outcomes have been reported using careful selection of participants?

For men undergoing active surveillance, two important clinical end-points are:

1. Metastases-free survival (MFS), i.e., the interval from the start of AS to metastases subsequent to any intervention; and, 
2. Prostate cancer-specific survival (PCSS). Overall survival is not as relevant since this figure includes death from other causes, e.g., heart disease, the most common cause of death in men with low-risk prostate cancer.

Data on MFS and PCSS:  * 

In the Johns Hopkins study of 1298 men, MFS at 10 years was 99.4%; PCSS, 99.9%. At 15 years, 99.4% and 99.9%, respectively. The median treatment-free period was 8.5 years. Based on studies carried out at Johns Hopkins, Dinz et al. concluded “Patients on active surveillance reclassified to grade groups 2 [Gleason 3+4=7] or greater are at no greater risk for treatment failure than men newly diagnosed with similar grades” (J Urol. 2017).

In the original Klotz study of 993 men, in the low-risk group MFS at 10 and 15 years was 96% and 95%. In the intermediate-risk group (including some Gleason score 3+4), MFS was 91% and 82% at 10 and 15 years.

From the Klotz study: “…patients with Gleason 3+4=7 disease at baseline had a 3.8X greater risk of metastases at 15 years (20% vs 5%).”

How to follow men on active surveillance?

The conventional mode of follow-up has familiar elements: digital rectal exam annually, PSA test every 3-6 months (trigger for biopsy undefined), and 12-core systematic biopsies cued by physical findings, PSA rise, or as stipulated by protocol (i.e., 3-5 years) or anxiety. The multiparametric MRI has evolved as a major component of follow-up—although the exact protocol for employing the MRI is still research-in-progress.

The role of the mpMRI in patient selection and follow-up:

The mpMRI-based targeted biopsy, together with the 12-core systematic biopsy, is gaining consensus as the preferred pre-AS selection tool. The combination significantly reduces the approximately 20-30% misclassification rate associated with the 12-core biopsy alone. The baseline MRI study provides a comparison for further MRI follow-up. Such a follow-up study may show an increase in size and/or density of the index lesion suggesting grade progression, and perhaps, additional tumors—all indicators for re-biopsy with a targeted MRI guided biopsy combined with a systematic 12-core biopsy. Primary intervention would follow if Gleason grade worsening were diagnosed.

The question that is frequently asked is whether men on AS can be followed with only MR imaging. There is little support for MRI-only follow-up even though an unsuspicious MRI (i.e., PI-RAD score 1 or 2 in a 1-5 scale) carries a strong ‘negative predictive value,’ suggesting that no progression has evolved. There is strong literature support for periodic ‘protocol’ prescribed biopsies even when there is no suspicion of progression. 

A report by Thurtle et al., BJU Int. 2018, Cambridge, UK, described their protocol for AS management as follows: 

• pre-AS baseline mpMRI-targeted and 12-core biopsies
• confirmatory combination biopsy at year 1
• MRI at year 2
• MRI and protocol biopsy at year 3
• MRI at year 4, and
• MRI and protocol biopsy at year 5

Of the 145 men in the study, in 104 a biopsy was triggered. Gleason score progression was confirmed by biopsy in 16%. In four, the biopsy was prompted by three consecutive rises in PSA, in 10 by changes in MRI, and in 6 per protocol only.

In a review article, Stavrinides et al. Prostate Cancer and Prostatic Diseases. 2019, outlined their protocol schema:

• a combination MRI and 12-core biopsy at AS entry
• a repeat combination biopsy at 1 year
• biopsies for visible MRI lesions in 1-2 years, and 
• for unsuspicious MRI findings (PI-RAD 1 and 2), biopsies in 2-3 years

Can genomic testing panels, e.g., OncotypeDx or Decipher, improve on patient selection for AS?

The literature addressing this question is limited. A pertinent article is: “The Clinical Utility of the Genomic Prostate Score (i.e. OncotypeDx) in Men with Very Low- to Intermediate-Risk Prostate Cancer,” Gaffney et al., J Urol. 2019.

No benefit was found in doing genomic testing on men with very low-risk cancer. Of the 45 men out of 134 with low-risk disease, in 19 the risk category was lowered to very low-risk and 4 men were upgraded to intermediate-risk. 

“Validation of the Decipher Test for predicting adverse pathology in candidates for prostate cancer active surveillance,” Kim et al., Prostate Cancer and Prostatic Diseases. 2019, examined the predictive usefulness of this genomic classifier to identify men suitable for AS with very low-, low-, and favorable intermediate-risk cancer on biopsy. Decipher’s risk scale spans 0 to 1 with a higher risk of clinical metastases at 5 years associated with higher values. Values of < 0.45 and < 0.2 suggest a 91% and 96% likelihood of freedom from adverse pathology which would disqualify men for AS participation.

Unanswered is the question as to the utility of genomic testing in men who met the stringent eligibility requirements and had undergone MRI guided biopsies. It may be established that these gene expression classifiers will serve as ‘tie breakers’ for men marginally qualified for AS.

BOTTOM LINE:

When carefully selected and monitored, men choosing active surveillance can experience a safe delay of primary treatment and excellent outcomes. 

[Corrigendum: In Vol. 136 on the Natural History of Prostate Cancer, there was confusing data about the percentage of metastases occurring in men with PSADT of <6 and < 10 months: 

The copy should read: “Of the 172 men whose PSADT was < 6 months, 61% developed metastases; of the 260 men with PSADT <10 months, 55% developed metastases during a median follow-up of 10 years.”

“I want to thank Dawn Scott, Staffperson, Tumor Institute Radiation Oncology Group, & Mike Scully, Librarian, Swedish Medical Center for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible.”