MDACC 2018: Problems in the Diagnosis and Treatment of Prostate Cancer
Further, the Prostate Cancer Prevention Trial demonstrated a similar finding in patients with PSA values of 2.1-3 ng/ml. PSA kinetics similarly has been shown to offer little to clinical decision making as a predictor of cancer or the presence of high-grade cancer. Ultimately, Dr. Studer asserts that PSA screening “betrays men” with a normal PSA [and aggressive disease] and “terrorizes men” with an elevated PSA [and benign or indolent disease].
Pathology reports also pose problems for clinicians treating and researching prostate cancer. While prostate biopsy is more reliable than PSA, there is a lack of concordance among pathologists regarding the appropriate Gleason scoring of biopsy samples. Pathologists have changed the relevant criteria over time and this has resulted in a lack of consistency in the interpretation of many important trials.
While the ERSPC trial, at 11-year follow up, demonstrated a 21% relative reduction in prostate-cancer-specific mortality in the screening group compared to observation, it is notable that prostate cancer deaths in the screening group only represents 6.1% of the patients. This means that 94% of patients had to live with a cancer diagnosis, 85% of whom received immediate treatment and were thus exposed to the treatment-related risks and toxicities. According to Dr. Studer, this highlights that disease-specific mortality may not be an adequate endpoint in trials such as these because it does not take into account the patients who died as a result of the treatment (earlier than would be expected). This leads to misleading computations of the number of patients needed to treat based on the disease-specific mortality endpoint. Dr. Studer goes on to highlight the Goteborg prostate cancer screening trial2 as a further example of this problem, citing the 30% higher disease-specific mortality in the control vs. screening groups is seemingly impressive, it must be noted that the difference in the absolute number of deaths from all-cause mortality was only n=13.
An important example of death due to the treatment of prostate cancer is death related to the toxicities associated with androgen deprivation therapy (ADT). Notably, patients treated with ADT for localized well- or moderately-differentiated prostate cancer have unfavorable outcomes. Toxicity associated with ADT led to an interest in intermittent as opposed to continuous ADT to mitigate these concerns, however, intermittent ADT was found to demonstrate similar long-term adverse effects as continuous administration.
Another important question in the prostate cancer space is whether intensified treatment of prostate cancer has resulted in decreased mortality. The Scandinavian Prostate Cancer Group (SPCG-4)3 trial demonstrated a survival advantage to radical prostatectomy over watchful waiting, but the vast majority of patients in this trial presented with advanced disease (88% had a palpable disease at diagnosis). The American counterpart, PIVOT, found that surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation at nearly 20-year follow-up [4]. Dr. Studer points out that the prostate-cancer mortality curves in the PIVOT trial do overlap for the initial two years of follow up and then begin to separate at the two-year point, remaining parallel for most of the ensuing 18 years. He suggests that this is because patients in the observation arm felt to be higher risk due to a rising PSA was placed on ADT therapy thereby improving prostate-cancer specific outcomes in the short-term.
Finally, Dr. Studer asserts that an apparently impressive decrease in prostate cancer mortality is likely, to a large extent, not due to PSA screening or improvements in prostate cancer treatment. Rather, this is a reflection of increasing treatment intensity of an indolent disease that went largely undetected in the pre-PSA era. That is, we saw a prostate cancer incidence spike following the introduction of PSA screening that resulted in a dilution of the prostate cancer mortality pool with a disease that likely never needed treatment. Dr. Studer notes, finally, that it is likely that most aggressive prostate cancers disseminate early, before we diagnose it, and are hardly curable with local treatments alone.
Presented by: Urs E. Studer, MD, University Hospital, Department of Urology, Bern, Switzerland
References
1. Schroder, F.H., et al., Prostate-cancer mortality at 11 years of follow-up. N Engl J Med, 2012. 366(11): p. 981-90.
2. Hugosson, J., et al., Eighteen-year follow-up of the Goteborg Randomized Population-based Prostate Cancer Screening Trial: effect of sociodemographic variables on participation, prostate cancer incidence and mortality. Scand J Urol, 2018. 52(1): p. 27-37.
3. Bill-Axelson, A., et al., Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med, 2014. 370(10): p. 932-42.
4. Wilt, T.J., et al., Follow-up of Prostatectomy versus Observation for Early Prostate Cancer. N Engl J Med, 2017. 377(2): p. 132-142.
Written by Justin T. Matulay, MD, Urologic Oncology Fellow and Ashish M. Kamat, MD (@UroDocAsh), Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX at the 13th Update on the Management of Genitourinary Malignancies, The University of Texas (MDACC - MD Anderson Cancer Center) November 9-10, 2018, Dan L. Duncan Building, Houston, TX