- Published in Everyday Urology - Oncology Insights: Volume 4, Issue 4
A 65-year-old man presents with skeletal pain. His PSA is 101 ng per mL, computed tomography (CT) reveals pelvic lymphadenopathy, a 99mTc bone scan shows extensive bone metastases, and prostate biopsy cores are interpreted as Gleason score 9 with intraductal features. The patient starts long-term androgen-deprivation therapy (ADT) and completes five cycles of docetaxel. His pain resolves. His PSA declines but remains persistently elevated at 2.6 ng per mL, so the decision is made to add enzalutamide, a next-generation androgen receptor (AR)-targeted therapy, to ADT.
The patient’s PSA level continues to fall steadily and measures near 0 ng per mL over a three-year period. During this time, his liver function tests remain within normal limits and he is asymptomatic and active. However, four years after his initial diagnosis of metastatic hormone-sensitive prostate cancer (mHSPC), a routine follow-up CT of chest, abdomen, and pelvis reveals multiple new liver lesions measuring <2 cm. This occurs in the absence of a PSA rise.
As this case illustrates, patients with M1 prostate can experience metastatic progression during treatment with no concurrent change in PSA, symptoms, or performance status. Studies of patients with high-risk localized prostate cancer or metastatic (M1) castration-resistant prostate (mCRPC) who develop radiographic progression indicate that nearly 25% do not have a concurrent rise PSA, a phenomenon known as PSA discordance.1, 2 Although it is unclear how often PSA-discordant radiographic progression occurs in the setting of mHSPC, a post hoc analysis of the PREVAIL trial showed that it occurred among 65 (24.5%) of 265 patients with mCRPC and radiographic progression on enzalutamide.2
While these data might seem to justify more frequent imaging for all patients with mHSPC, the question is not so simple. Theoretically, frequent imaging could help us prevent unnecessary costs and toxicities from ineffective treatment and control disease better by switching patients earlier to a more effective therapy. But it also increases healthcare costs and could prompt us to prematurely abandon a therapy if we misinterpret a healing response (flare) as progression3 or conclude that a clinically insignificant progression as significant. Most crucially, there is no strong evidence that earlier detection of treatment failure ultimately benefits patients.
So how often should we image these patients? The National Comprehensive Cancer Network (NCCN) guidelines on prostate cancer provide limited recommendations on how often patients should be scanned while on ADT, stating that “bone scans should be performed as often as every 6 to 9 months to monitor ADT. The need for soft tissue imaging remains unclear.”4 It is not clear that these recommendations are standard or supported by evidence. Bone scans in mHSPC are typically performed in the setting of a rising PSA on ADT, but routine bone scans every 6 to 9 months have no evidence for support. In addition, soft tissue imaging is critical when monitoring metastatic prostate cancer and may be even more important than routine bone scans, as suggested by the case above.
The RADAR III recommendations are a consensus statement on frequency and type of imaging in advanced prostate cancer.5 For patients on treatment for M1 prostate cancer, the RADAR III guidance recommends monitoring with traditional imaging (CT and bone scan) modalities (or next-generation imaging if these are negative) if the patient’s symptomatology has changed, his performance status has changed, his PSA has doubled since his last date of imaging, or every 6 to 9 months in the absence of a PSA rise.
In summary, we have no clear consensus regarding the frequency or type of imaging to perform when monitoring patients undergoing treatment for mHSPC. We also do not know how the earlier use of novel androgen receptor (AR)-targeted therapies might affect the biology of prostate cancer recurrence. Based on studies of PSA-discordant prostate cancer, we should take care not to over-rely on PSA to rule out progression. We should not assume that our patients are not progressing just because they appear to have stable symptomatology and performance status.
A 66-year-old man presents with rectal pain. During the preceding 12 months, his PSA has risen from 2.0 to 7.1 ng per mL. Bone and CT scans now reveal metastases to multiple bones and to pelvic lymph nodes. His core biopsies are all scored as Gleason 8. His medical history includes hypertension currently controlled by two medications and a distant history of a seizure disorder. The patient is started on ADT and abiraterone-prednisone, and his PSA subsequently declines. However, after 6 months, he develops chest spams and a chest CT shows multivessel coronary disease. Abiraterone-prednisone is stopped, and three cardiac stents are placed. His PSA subsequently rises, and he resumes a half-dose of abiraterone-prednisone.
This case illustrates the potentially serious risks of adding a potent direct AR-targeted agent such as abiraterone, enzalutamide, or apalutamide to ADT. While these agents are life-prolonging for our patients with high-risk mHSPC, the results of a large randomized phase 3 trials indicate that they also can cause serious cardiovascular toxicities, accelerated bone loss, osteoporotic fractures, falls, and cognitive impairment.6-9 These toxicities are probably most common in the setting of relevant comorbidities but also can develop in otherwise healthy men. Furthermore, when we consider that a direct AR-targeted agent such as enzalutamide has up to eight times more AR binding affinity as bicalutamide,10 we need to ask, how does this affect known rates of complications with ADT alone? In addition, what is the impact of duration of therapy, and what happens in the real world, outside the carefully controlled setting of a clinical trial? We know that patients are receiving next-generation AR-targeted agents for years in these clinical scenarios.
Unfortunately, we currently have no way to reliably predict which patients will develop serious toxicities from AR-targeted therapy, although at least one biomarker study (in cognitive impairment) is underway.11 My approach is to discuss side effects with patients so that they are informed and know to report them to me if they emerge. Regarding treatment-emergent cognitive impairment, is can be helpful to explain that it is not the same as dementia and appears (thus far) to be reversible if treatment is stopped. To date, we have no robust prospective data confirming that androgen deprivation contributes to dementia. An association was identified by a retrospective analysis of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database,12 but such studies are limited by the known potential for miscoding errors (which has been documented for PSA!)13 and because it is impossible in these observational studies to completely control for the potential effects of confounding variables.
Some patients with mHSPC may ask about intermittent ADT as a strategy to reduce the risk of toxicities. So far, no randomized study in mHSPC has shown that intermittent ADT is equivalent to continuous ADT, and it is important for patients to understand this. In addition, combining ADT with docetaxel or next generation AR-targeted therapy produces an “unprecedented survival impact,” as a recent review noted.14 Just as we should individualize the frequency of monitoring within a reasonable timeframe based on patients’ known risk factors, we also should tailor treatment to balance the risks of prolonged exposure to these newer therapies and therapeutic combinations with the risk of cancer progression to try to optimize individual patient outcomes in mHSPC.
Written by: William Oh, MD, Chief of the Division of Hematology and Medical Oncology at the Mount Sinai Health System and Deputy Director of The Tisch Cancer Institute, an NCI-designated cancer center, at the Icahn School of Medicine at Mount Sinai. He is also Professor of Medicine, and Urology, and is the Ezra M. Greenspan, MD Professor in Clinical Cancer Therapeutics.
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2. Bryce A.H., Alumkal J.J., Armstrong A., Higano C.S., Iversen P., Sternberg C.N., et al. Radiographic progression with nonrising psa in metastatic castration-resistant prostate cancer: Post hoc analysis of prevail. Prostate cancer and prostatic diseases. 2017;20:221-227.
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11. Prostate cancer foundation. Challenge awards-class of 2017.
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14. Shevach J., Sydes M.R., Hussain M. Revisiting intermittent therapy in metastatic prostate cancer: Can less be more in the "new world order"? Eur Urol Focus. 2019;5:125-133.