Ask the Experts – Hiten D Patel

Question 1. Is there a place for active surveillance in the management of men with intermediate-risk prostate cancer?

Intermediate-risk prostate cancer is a heterogeneous risk group. We know that these are the men that may derive the most benefit from intervention, and so it becomes a challenge to clearly identify men who might benefit from considering active surveillance. For older men with significant comorbidities, watchful waiting may be appropriate as this would help avoid morbidity from both treatment as well as repeat testing and biopsies. However, I do think there is a place for active surveillance for men on the lower end of the risk spectrum with intermediate-risk prostate cancer. Very few, if any, subtypes of men with intermediate-risk prostate cancer will have outcomes similar to low-risk prostate cancer as our prior research studies have shown. Still, the absolute increase in risk for adverse pathology and death is small enough for some subtypes (e.g. type 1 intermediate-risk) that well-informed men should be able to participate in shared decision making with their urologist if they would like to consider active surveillance.

Question 2.  What concerns, if any, do you have about recommending active surveillance for these patients?

Answer
One concern in recommending active surveillance for patients with intermediate-risk prostate cancer is the increased risk for adverse pathology – the potential that a patient has even worse prostate cancer than we thought. Although a patient may make a decision given their biopsy pathology, there is a chance the biopsy is discordant with their “true” disease state. Most of the time, the biopsy is either accurate or could even overestimate the burden of cancer. However, 20-25% of the time, patients with Grade Group 2 (Gleason 3+4) prostate cancer who fall into the category of type 1 intermediate risk disease will have adverse features such as Grade Group 3 disease, seminal vesicle invasion, or positive lymph nodes. Another concern is whether healthy patients may miss a window of curability if their intermediate-risk prostate cancer progresses from a potentially localized state to a more advanced state. While patients who are reclassified from low to intermediate risk on active surveillance usually have the same treatment options available to them, treatment options change more significantly from intermediate to high risk disease.

Question 3. Which patients with intermediate-risk PCa would be optimal candidates for active surveillance?

Answer
Patient factors may ultimately determine who is an optimal candidate for active surveillance. Type 1 intermediate risk patients (Grade Group 2 or less) are potential candidates, but additional data including the percentage of pattern 4 disease is important as there is some thought that 5% or less pattern 4 involvement may minimize risk of adverse outcomes. Unfortunately, few patients appear to meet this criteria of 5% from the large segment of patients with type 1 intermediate risk disease, and so it may not help the majority of patients make their decision. Therefore, patient factors will be important with active surveillance only offered to patients willing to accept the increased risk of harboring adverse pathology and subsequent potential for adverse outcomes. Additional tests for risk-stratification such as MRI may also be prime modalities to reduce the risk pool and increase confidence in offering active surveillance to type 1 intermediate risk patients, but studies have not parsed this out yet.

Question 4. Does the new Grade Group system help clarify which men with intermediate-risk PCa are good candidates for active surveillance?

Answer
The Grade Group system has helped create clinically useful prognostic groups. The categories of 1 through 5 provide a more intuitive assessment of risk when advising patients. However, Grade Group 1 patients which have Gleason 3+3 disease are still generally the best candidates for active surveillance. The NCCN risk classification system remains a useful modality to further characterize patients into low, intermediate, and high beyond Grade Group alone. Therefore, the Grade Group system has not directly helped clarify how we can potentially select intermediate-risk patients for active surveillance. We do know that the main population of interest is Grade Group 2 patients because our studies have demonstrated Grade Group 1 patients who meet the NCCN intermediate-risk classification certainly do better than similar patients with Grade Group 2 disease. The larger group of men where there is uncertainty is in the Grade Group 2 stratum, and this is where additional study is needed.

Question 5. Should active surveillance be more intense for men with intermediate-risk PCa than for those with low-risk disease? If so, how?

Answer
For appropriately-informed patients, I would argue active surveillance does not need to be more intense compared to men with low-risk prostate cancer. First, the initial workup may be most important to consider with additional testing including MRI to ensure no MRI-identifiable lesions are un-sampled by biopsy. While the data for this indication, of MRI differentiating Grade Group 2 and Grade Group 3 disease, is not yet established, we know MRI generally picks up higher risk cancers and may translate well into this indication. Repeat MRIs, conversely, will likely be of limited value. Second, patients with type 1 intermediate risk disease opting for active surveillance are inherently accepting an increased risk in the oncologic domain for benefits in other aspects of quality of life. Therefore, increasing the intensity of active surveillance would counteract the intended benefits. Patients who are uncomfortable with the inherent risks should not opt for active surveillance and instead consider immediate intervention. An important area of research will be the rate at which patients are reclassified from Grade Group 2 to Grade Group 3; a short treatment-free interval would further argue against the utility of active surveillance for these patients.