The Science Behind Active Surveillance
If every available candidate in North America and Europe pursued active surveillance, close to 300,000 men could be spared from unnecessary surgery and radiation every year. In one observational study of men on active surveillance with Gleason 3+3=6 or low-volume Gleason 3+4=7, men were ten times more likely to die of causes besides prostate cancer. In this study, 452 men on active surveillance were compared with 6,485 men having surgery, 2,264 men treated with external beam radiation, and 1,680 treated with seed radiation. There was no difference in prostate cancer mortality. To date, the published literature on surveillance includes 13 prospective studies, encompassing about 5,000 men. These studies, evaluating men who were mostly Gleason 3+3=6, fail to identify any increased risk of prostate cancer mortality, though one drawback is that the duration of observation in many of the studies is still short.
Active Surveillance Technique
The way men on surveillance are managed is evolving. Currently, most clinicians use the following approach or a variation of it: After the initial diagnosis of Gleason 6, a PSA blood test is performed every three months for the first two years, and then every six months thereafter. Another random biopsy is recommended within three to 12 months after the initial diagnostic biopsy. The second biopsy should target areas in the gland that are typically under-sampled on the initial diagnostic biopsy. If the biopsy is either negative or confirms a relatively small amount of Gleason 3+3, subsequent biopsies are performed every three to five years until the patient reaches age 80 or has a life expectancy under five years because of other maladies or serious medical issues.
Multiparametric MRI should be performed on patients whose PSA levels have changed over time in a way that suggests more aggressive disease (usually defined as a PSA-doubling time of less than three years); whose confirmatory biopsy shows substantial increase in the cancer’s size; or who are upgraded to Gleason 3+4 and who still desire surveillance as a management option. Identification of a lesion by multiparametric MRI (MP-MRI) that is suspected to be high grade should lead to a targeted biopsy. As quality MP-MRI centers become more widely available, it is possible that MP-MRI will replace random biopsy altogether.
Over time, in men who were initially diagnosed via random biopsy, one-third of patients will be reclassified as being at higher risk for progression and offered treatment. The rate of reclassification will vary depending on the type of criteria used for selecting active surveillance in the first place. An approach that offers surveillance to all patients with Gleason 6 and PSA less than 15, for example, will include more patients with undetected high grade disease than a policy restricted to the Epstein criteria (less than or equal to two positive biopsy cores, less than 50 percent cancer in any one core, and PSA density under 0.15). However, Epstein’s stringent eligibility requirements deny surveillance to many men with disease that is not life-threatening, that is, cancer that grows slowly. Experience shows that in men who are later upgraded, the majority (85 percent) will have Gleason 3+4. Many of these men who have low-volume grade 3+4=7 are still appropriate candidates to remain on active surveillance.
When Is There Too Much Grade 6 for Active Surveillance to Be Safe?
Men with larger quantities of Gleason 6 are at higher risk of harboring higher-grade cancer that may have been missed by the random biopsy. The exact threshold of what constitutes a “large quantity” of Gleason 6 is variable. Patients with higher-volume Gleason 6 need to be evaluated with multiparametric MRI and genetic tests such as Prolaris, Oncotype DX, or Decipher to exclude the presence of higher-grade cancer.
PSA Monitoring on Active Surveillance
PSA monitoring is helpful for identifying patients at higher risk. However, changes in PSA cannot be relied upon to make final decisions about treatment. This represents a shift in policy from earlier practice. Until MP-MRI became available, men on surveillance with rapidly rising PSA levels (with a doubling time under three years) were usually offered treatment. One multi-institutional surveillance registry reported that 20 percent of the men participating in the study were treated because their PSA doubling time was less than three years. Another report from a study of over 1,000 men, describes the cases of five men dying of metastatic prostate cancer, all five of whom had a PSA-doubling time under two years.
The main limitation of using the rate of PSA elevation to guide therapy is the lack of specificity. Vickers, in an overview of every large active surveillance study (each study had a minimum of 200 patients), concluded that changes in PSA had no independent predictive value. In another study, traditional PSA “triggers” (doubling time less than three years, or PSA rising at a rate of more than two points per year) occurred in 50 percent of stable untreated patients, none of whom went on to develop progressive cancer, require treatment, or die of prostate cancer. These studies show that great care needs to be exercised when interpreting the significance of a rise in PSA, so that men with moderate changes don’t overreact and seek unnecessary aggressive treatment.
Active surveillance, with close monitoring and selective delayed intervention based on risk reclassification over time, is an appealing approach for Sky patients, and a welcome antidote for the 150,000 men in North America diagnosed every year with Gleason grade 6, who until now have been encouraged to undergo surgery or radiation. Furthermore, ongoing improvements in diagnostic accuracy of MP-MRI and genetic biomarkers will reduce the need for systematic biopsies and improve the early identification of occult, higher-risk disease.
References:
1. A Gawande. Two hundred years of surgery. New England Journal of Medicine 366: 1716, 2012.
2. W Sakr and others. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases. In Vivo 8: 439, 1994.
3. A Zlotta and others. Prevalence of prostate cancer on autopsy: cross-sectional study on unscreened Caucasian and Asian men. Journal of the National Cancer Institute 105: 1050, 2013.
4. D Hanahan and RA Weinberg. The hallmarks of cancer. Cell 100: 57, 2000.
5. D Hanahan and RA Weinberg. The hallmarks of cancer: the next generation. Cell 144: 646, 2011.
6. S Eggener and others. 20-year prostate cancer specific mortality after radical prostatectomy. Journal of Urology 185: 869, 2011.
7. S Eggener, personal communication.
8. HM Ross and others. Do adenocarcinomas of the prostate with Gleason Score (GS)<=6 have the potential to metastasize to lymph nodes? American Journal of Surgical Pathology 36: 1346, 2012.
9. A Stephenson and L Klotz. Comparative propensity analysis of active surveillance vs initial treatment. American Urological Association, 2013.
10. JH Hayes and others. Active surveillance compared with initial treatment for men with low-risk prostate cancer: a decision analysis. Journal of the American Medical Association 304: 2373, 2010.
11. B Carter and others. Early detection of prostate cancer: AUA guideline. American Urological Association https://www.auanet.org/education/guidelines/prostate-cancer-detection.cfm
12. O Bratt and others. Optimizing the definition of Very Low Risk prostate cancer. BJU International, accepted for publication 2014, presented at the European Association of Urology, Stockholm, March 2014.
13. T Wolters and others. A critical analysis of the tumor volume threshold for clinically insignificant prostate cancer using a data set of a randomized screening trial. Journal of Urology 185, 121, 2011.
14. J Cuzick and others. Prognostic value of a cell cycle progression signature for prostate cancer death in conservatively managed needle biopsy cohort. British Journal of Cancer 106: 1095, 2012.
15. D Knezevic and others. Analytical validation of the Oncotype DX prostate cancer assay - a clinical RT-PCR assay optimized for prostate needle biopsies. BMC Genomics 14: 690, 2013.
16. K. Robinson and others. Accurate prediction of repeat prostate biopsy outcomes by a mitochondrial DNA deletion assay. Prostate Cancer and Prostatic Diseases 16: 398, 2013.
17. A Loblaw and L Klotz. Gleason upgrading in a surveillance cohort is time dependent. American Urological Association, 2014.
18. D Sundi and others. African American men with very low-risk prostate cancer exhibit adverse oncologic outcomes after radical prostatectomy: should active surveillance still be an option for them? Journal of Clinical Oncology 31: 2991, 2013.
19. S Porten and others. Changes in prostate cancer grade on serial biopsy in men undergoing active surveillance. Journal of Clinical Oncology 29: 2795, 2011.
20. L Klotz and others. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. Journal of Clinical Oncology 28: 126, 2010.
21. M Bul and others. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. European Urology 63: 597, 2013.
22. MA Dall'Era and others. Active surveillance for the management of prostate cancer in a contemporary cohort. Cancer 112: 2664, 2008.
23. Y Kakehi and others. Prospective evaluation of selection criteria for active surveillance in Japanese patients with stage T1cN0M0 prostate cancer. Japanese Journal of Clinical Oncology 38: 122, 2008.
24. J Tosoian and others. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. Journal of Clinical Oncology 29: 2185, 2011.
25. S Roemeling and others. Active surveillance for prostate cancers detected in three subsequent rounds of a screening trial: characteristics, PSA doubling times, and outcome. European Urology 51: 1244, 2007.
26. MS Soloway and others. Careful selection and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the need for treatment. European Urology 58: 831, 2010.
27. MI Patel and others. An analysis of men with clinically localized prostate cancer who deferred definitive therapy. Journal of Urology 171: 1520, 2004.
28. GA Barayan and others. Factors influencing disease progression of prostate cancer under active surveillance: a McGill University Health Center cohort. BJU International 114: E99, 2014.
29. J Rubio-Briones and others. Obligatory information that a patient diagnosed of prostate cancer and candidate for an active surveillance protocol must know. Actas Urológicas Españolas 40: 88, 2014.
30. R Godtman and others. Outcome following active surveillance of men with screen-detected prostate cancer. Results from the Göteborg randomised population-based prostate cancer screening trial. European Urology 63: 101, 2013.
31. F Thomsen and others. Active surveillance can reduce overtreatment in patients with low-risk prostate cancer. Danish Medical Journal 60: A4575, 2013.
32. ED Selvadurai and others. Medium-term outcomes of active surveillance for localised prostate cancer. European Urology 64: 981, 2013.
33. M Popiolek and others. Natural history of early, localized prostate cancer: a final report from three decades of follow-up. European Urology 63: 428, 2013.
34. HA Vargas and others. Magnetic resonance imaging for predicting prostate biopsy findings in patients considered for active surveillance of clinically low risk prostate cancer. Journal of Urology 188: 1732, 2012.
35. Y Krakowsky and others. Prostate cancer death of men treated with initial active surveillance: clinical and biochemical characteristics. Journal of Urology 184: 131, 2010.
36. AJ Vickers and others. Systematic review of pretreatment PSA velocity and doubling time as PCA predictors. Journal of Clinical Oncology 27: 398, 2008.
37. A Loblaw and others. Comparing prostate specific antigen triggers for intervention in men with stable prostate cancer on active surveillance. Journal of Urology 184: 1942, 2010.
Laurence Klotz, MD is the past Chief of Urology at Sunnybrook Health Sciences Centre and Professor of Surgery at the University of Toronto. He is also Chairman of the World Uro-Oncology Federation and a past president of the Urological Research Society and the Canadian Urological Association. Dr. Klotz was the Founding Editor-in-Chief of both the Canadian Journal of Urology and the Canadian Urology Association Journal (CUAJ), and is now Editor Emeritus of the CUAJ. He was the founder and is chairman of the Canadian Urology Research Consortium. Dr. Klotz obtained his medical degree from the University of Toronto and completed his residency at the University of Toronto Gallie Program in Surgery. Dr. Klotz continued his postgraduate studies with a special fellowship at Memorial Sloan Kettering Cancer Centre in New York, in uro-oncology and tumour biology. Dr. Klotz is a widely published uro-oncologist with over 300 publications and 4 books. His main research interest has been prostate cancer. He serves on the boards of many medical/scientific organizations and journals, including the SUO[1] , Prostate Cancer Canada, the journals Prostate Cancer and Prostatic Diseases, Brazilian Journal of Urology, Italian Journal of Urology, and World Journal of Urology. He was recently awarded the Queen’s Jubilee Medal for meritorious public service.