By: Dan Sperling, MD

The last decade has witnessed a slow but dramatic trend away from whole gland or radical prostate cancer treatments in favor of active surveillance (AS) as a disease management strategy. This shift is heavily influenced by accumulating evidence of the harms done by radical therapies to patients’ urinary and sexual function. In addition, new insight into the natural history of prostate cancer cells suggests that not all cancer progresses to lethality. Likewise, ongoing advances in genomic research and the development of refined biomarker tests are enabling the identification of cell lines most likely to become highly aggressive. Finally, imaging allows monitoring of tumors which alters the standard repeat biopsy protocol for AS patients, which patients often refuse to comply with. Bolstered by these developments, physicians and patients are more confident in choosing AS as an alternative to risk-laden surgical and radiation therapies.

In order to qualify patients for AS, the consideration uppermost in a doctor’s mind is the clinical nature of his patient’s prostate cancer. According to Ploussard et al. (2011), insignificant prostate cancer (Ins-PCa) is defined as Gleason score 6 without Gleason pattern 4 or 5, organ-confined disease, and tumor volume < 0.5 cm3. The authors wrote, “The exciting challenge of obtaining the pretreatment diagnostic tools that can really distinguish insignificant from significant PCa should be one of the main objectives of urologists in the following years to decrease the risk of overtreatment of Ins-PCa.” [i]

One of those tools is a new blood test called the 4K Score. The blood sample is used to measure the levels of 4 tumor biomarkers (total PSA, free PSA, intact PSA, and human kallikrein-2). An algorithmic calculation that includes those biomarkers as well as patient age, digital rectal exam result, and previous biopsy status, results in a score indicating a pre-biopsy risk of aggressive cancer. At the 2015 European Association of Urology Congress (Madrid, Spain; Mar. 20-24) Punnen et al. presented their study of 306 men whose underwent prostate biopsies that initially revealed Gleason 6 disease, and who also had 4K Score results.[ii] The men were being considered for AS. However, there was a correlation between higher 4K scores and larger amounts of prostate cancer in their biopsies. Eventually, 51 patients had radical prostatectomy; the men whose PCa was upgraded on histopathology to Gleason 7 or higher had “a significantly higher pre-biopsy 4Kscore in comparison to those patients whose disease was not upgraded.” Thus, the high 4K scores accurately predicted which men were not qualified for AS.

Diagnostic imaging is another promising tool for distinguishing patients who can safely choose AS. Very recent research from a Korean team provides evidence that mpMRI is on the threshold of successfully addressing that challenge. Kim et al. (2015) studied the ability of one of the MRI functional parameters, diffusion-weighted imaging (DWI), to improve the detection of insignificant prostate cancer as a way to qualify men for AS.[iii] (For more information on DWI, see https://sperlingprostatecenter.com/mri-imaging-prostate-cancer-two-parameters/)

The authors retrospectively evaluated 287 active surveillance candidates who had DWI-MRI prior to radical prostatectomy. Acquiring the post-surgery prostate specimens allowed microscopic evaluation (histopathology) in order to compare the actual disease with the images. Patients were stratified into two groups:

• Group A included 243 patients (84.7%) with no visible tumor on imaging, or suspected tumor of higher ADC value, which is the measure of diffusion of water molecules in tissue used to differentiate healthy from cancer tissue.
• Group B included 44 patients (15.3%) with a suspected lower ADC value tumor.

The lowest ADC values indicate a need for biopsy.

According to the results, Group A (higher ADC value) had a much greater proportion (61.3%) of organ-confined Gleason???6 disease and insignificant prostate cancer than Group B (38.6%). Statistical analysis showed that a high ADC value was an independent predictor of organ-confined insignificant prostate cancer. The team concluded, “… ADC values may be a useful marker for predicting insignificant prostate cancer in candidates for AS.”

Active surveillance depends on a high degree of confidence that the patient has insignificant disease. Both the 4K Score and mpMRI are resources that can ease the minds of physicians and patients when considering this alternative to radical treatments.

[i] Ploussard G, Epstein J, Montironi R et al. The contemporary concept of significant versus insignificant prostate cancer. Eur Urol 60 (2011):291–303.

[ii] Punnen M, Steine S,. Zappala J et al. Among men with low-grade prostate cancer on prostate biopsy, the 4Kscore predicts the presence of more aggressive prostate cancer.  Presented at the Congress of the European Association of Urology, Madrid, Spain. 2015.

[iii] Kim TH, Jeong JY, Lee SW et al. Diffusion-weighted magnetic resonance imaging for prediction of insignificant prostate cancer in potential candidates for active surveillance. vEur Radiol. 2015 Jan 31. Epub ahead of print. doi: 10.1007/s00330-014-3566-2