In this recent conversation, internationally recognized expert Stacy Loeb, MD, professor of urology and population health at New York University and a urologist at Manhattan Veterans Affairs Hospital, offers a brief review of the history of active surveillance for patients with prostate cancer. She discusses its established use for patients with low and very-low-risk diseases and offers insights into considerations for its application to treatment of those with intermediate-risk disease, including the profile of appropriate patients, risk stratification, and use of genetic testing in this heterogeneous population. She also explains the critical importance of actively engaging patients as partners in their own care by attending to their mental health and lifestyle practices.
In addition to her significant contributions to the literature and presentations at national and international conferences, Dr. Loeb is the recipient of the 2021 Gold Cystoscope award for outstanding research to enhance the value of prostate cancer screening and active surveillance. She is also the host of the Men’s Health Show on Sirius XM 110 satellite radio.
Dr David Ambinder: Active surveillance (AS) has been the standard of care for patients with very-low-risk and low-risk prostate cancer for many years, and its utilization has been increasing. Please describe the history of AS and the earliest clinical data supporting its implementation.
Dr Stacy Loeb: Some of the landmark trials of AS were conducted at Johns Hopkins in Baltimore, Maryland, and Sunnybrook Hospital in Toronto, Ontario, Canada, where long-term results from some of the earliest AS populations were published. The findings showed that the patients had a very low risk of metastasis or prostate cancer-related mortality that remained steady over 10 to 15 years. The publication of these trials was instrumental in converting AS from its previous status as an investigational approach to the standard of care for patients with very low- and low-risk prostate cancer.
More recently, AS has been applied to patients with intermediate-risk prostate cancer. This is exciting, but its use in this context raises more questions than in the setting of very low- and low- risk populations. The intermediate-risk group of individuals with prostate cancer has a more diverse patient profile. Indeed, current guidelines endorse categorizing these patients as favorable or unfavorable risk.1
It is clear that certain patients are at higher risk for developing metastatic prostate cancer and probably would benefit from more definitive therapy. Please describe the ideal patient with intermediate-risk prostate cancer who would benefit from AS, and conversely, which patients you would discourage from pursuing this approach.
AS is an option for select patients with intermediate-risk prostate cancer. It’s important to consider that this is a heterogeneous risk group. First, as you note, patients with intermediate-risk prostate cancer are divided into those with favorable and unfavorable intermediate-risk disease. Patients with favorable intermediate-risk disease are the ones we would consider for potential AS; patients considered to have unfavorable intermediate risk would not be ideal candidates. Furthermore, even within the favorable intermediate-risk category, there is quite a lot of heterogeneity. For example, a patient can be considered intermediate risk with a prostate-specific antigen (PSA) level >10 but have Gleason 6 (Gleason grade group [GGG] 1) disease.
These patients have a more favorable prognosis compared to patients with GGG2 disease. Patients considered to be at intermediate risk exclusively by virtue of having a PSA of 10-15 ng/mL with GGG1 prostate cancer would be potentially good candidates for AS. Another consideration is the percent of Gleason pattern 4 disease in patients with GGG2 prostate cancer, because a higher percentage of pattern 4 is associated with a greater risk of recurrence and less favorable prognosis. Other considerations are the type of histology found on biopsy.
For example, patients with intraductal and cribriform histology have a less favorable prognosis, and that should be considered when deciding on whether to pursue AS. Finally, genetic factors can play a role. For example, patients with pathogenic variants (e.g., BRCA2) have a greater risk of progression with AS, and are not ideal candidates for AS, particularly in intermediate-risk disease.
Do you routinely obtain genetic testing and genomic testing prior to placing patients on AS?
We do not obtain germline genetic testing for all patients with prostate cancer, but there are subsets of potential candidates for AS who would meet the criteria for germline testing. These include patients who have intraductal or cribriform histology, Ashkenazi Jewish ancestry, a family history of a high-risk germline mutation (such as BRCA2), or a strong family cancer history suggestive of a possible hereditary cancer syndrome. Any of those factors would make patients with low- or intermediate-risk prostate cancer eligible for germline testing.
Genomic testing involves the use of Oncotype DX® (Precision Oncology), Prolaris® (Myriad), or Decipher® (Veracyte); these are optional tests that can be used in the tumor tissue of patients with newly diagnosed prostate cancer to assist with risk stratification. For most patients with very low- or low-risk prostate cancer, I don’t think these tests are necessary. However, for those with borderline features such as high-volume Gleason 6 prostate cancer, or at the low end of the spectrum of favorable intermediate-risk disease, the genomic markers could be used to provide additional risk information and aid in decision making.
In many of the current prostate cancer guidelines, AS protocols can be quite rigorous and there is debate about the deintensification of AS follow-up. Can you speak to that? Do you modify your protocol based on patient-specific risk factors?
The optimal protocol for AS was the subject of my first NIH grant, which included developing a Markov model comparing different testing frequencies and intensities of follow-up during AS. The results of our model are published in European Urology, and basically show that for patients with low-risk prostate cancer, there was very little difference between patients who underwent biopsies every year or every 5 years in terms of their lifetime projected outcomes for metastasis and prostate cancer mortality. I think the current protocols represent overactive surveillance, particularly for older men with low-risk or very low-risk disease.
There is a major effort under way to deintensify AS protocols when appropriate for patients with low-risk disease. Conversely, for patients with intermediate-risk prostate cancer, a systematic review did show worse metastasis-free and cancer-specific survival compared to patients with low-risk disease. These patients continue to require closer follow up than the patients with very low- or low-risk disease. A risk-adapted protocol for AS is important. AS protocols should not be the same for every patient and should be individualized to the patient’s preferences and individual circumstances, including life expectancy, general health, and prostate cancer features.
There is concern that putting patients on AS may have a negative prostate cancer-related psychological impact, leading to anxiety or depression. How necessary is it to discuss and counsel patients about their emotional well-being when starting them on AS?
I think it is very important to assess the patient’s emotional health and take it into consideration when discussing the patient’s preferences. At the same time, we have a responsibility to counsel patients with low-risk prostate cancer that AS is the preferred option, and to provide reassurance that studies show it is a safe management approach supported by long-term data. There are other types of cancer-such as basal cell skin cancer-that do not elicit the same level of fear in patients, so I believe that by providing sufficient education, in many cases, we can help our patients become more comfortable with AS.
You recently published a report on how diet may affect prostate cancer risk.2 Do you counsel your patients on lifestyle changes and advise them on what they can do outside of therapy to reduce the risk of developing aggressive prostate cancer?
This is extremely important. We have ample data showing that patients with low-risk prostate cancer on AS are much more likely to die from other causes, especially cardiovascular disease, than they are to die from prostate cancer. This is a critical teachable moment for our patients, and we can greatly improve their overall health and longevity by providing lifestyle advice. There is level 1 evidence that patients with low-risk prostate cancer who adopt a vegan diet and moderate physical activity have a reduced risk of progression on AS.
The good news is the same strategies for a plant-based diet and physically active lifestyle also align with overall health recommendations: what’s good for the prostate is also good for the heart and many other health issues. Also, patients like to feel that they are actively contributing to improving their health and reducing their risk of progression. It’s great to be able to have evidence-based advice to give them about what they can do for themselves. Some recommendations I discuss with my patients include eating more plant-based food, avoiding red meat and dairy products, and engaging in ideally 150 minutes a week of moderately intense aerobic physical activity, as well as resistance and flexibility exercises at least twice a week. Healthy sleep is also very important, and mindfulness activities such as yoga and meditation can be very helpful.
Are there any educational resources that you find beneficial to give to your patients?
There are a lot of great resources and support groups available. The Prostate Cancer Foundation has a patient guide that is updated every year with input from prostate cancer experts; it contains a lot of information about prostate cancer across the management spectrum. ZERO – The End of Prostate Cancer also has information for patients, as well as UsToo support groups in which patients with prostate cancer can participate in. Other groups include Fans for the Cure and for AS specifically there’s the Active Surveillance Patients International group.
Is there anything specific that you would like to see improve over the next 10 years?
My greatest hope is that the uptake of AS will continue to increase over the next 10 years, because utilization is still heterogeneous in the United States and across the world. I expect there will be significant improvement in patient selection, risk stratification, and follow-up protocols for AS. Currently, AS is still ultimately biopsy-based in 2022, but with continued improvements in imaging, biomarkers, and other noninvasive tests, hopefully, we can decrease our reliance on prostate biopsies for follow-up during AS in the future.