CME Author: Zeena Nackerdien
Study Authors: Anna Bill-Axelson, Lars Holmberg, et al.
Target Audience and Goal Statement:
Urologists and oncologists
The goal is to explore the survival benefit and association of histopathology with long-term prognosis of patients with localized prostate cancer enrolled in The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4).
Prostate cancer – usually a slow-growing disease — is the most common non-cutaneous tumor in American men. While it trails lung and colon cancer as the third-leading cause of death, the prognosis for many cancer survivors is excellent. These individuals are more likely to die from non-prostate-cancer-related causes. Due to widespread screening, most patients present with local or locoregional disease. Quality of life issues, including sexual dysfunction, are important to all patients, including prostate cancer survivors.
Active surveillance as currently defined includes a doctor visit with a prostate-specific antigen (PSA) blood test and digital rectal exam (DRE) about every 6 months plus repeat biopsies at selected time intervals; it is now considered an option for appropriate patients with low-risk prostate cancer confined to the gland. On the other hand, watchful waiting in current parlance is a less intensive type of follow-up that may mean fewer tests and relying more on changes in a man’s symptoms to decide if treatment is needed. Radical prostatectomy (RP) can also be a treatment option for select men with a life expectancy of at least 10 years.
An earlier Prostate Cancer Intervention vs Observation Trial (PIVOT) Study, conducted during the initial years of PSA screening, showed that RP vs active surveillance did not significantly reduce prostate cancer–specific or overall mortality after 12 years; however, a randomized trial of RP vs watchful waiting in men with localized prostate cancer initiated in the days before PSA screening (SPCG-4) showed a survival benefit for RP vs observation at 15 years of follow-up. An implied goal of the latter study was to maximize the possibilities for survival without overtreatment and data have been published approximately every three years since 2002.
Because of the good prognosis for patients with prostate cancer and morbidities associated with the surgery (side effects are less with newer treatment options such as prostate cancer ultrasound), the optimal role for RP in treatment is unclear. Continued outcomes through 2017, including the association of histopathology with long-term prognosis, have therefore been evaluated in the SPCG-4 study.
Synopsis and Perspective
Between 1989 and 1999, 695 men younger than age 75 with newly diagnosed prostate cancer in International Union against Cancer clinical stage T1b, T1c, or T2 were randomly assigned to RP (n=347) or to what the investigators characterized as watchful waiting (n=348) according to the protocol established at the study’s outset. In both groups, patients were examined every 6 months following initial assignment, including treatment in the RP group for the first 2 years, then annually thereafter. The primary outcome was death due to prostate cancer, and secondary outcomes were overall mortality, metastasis-free survival, and local progression.
The minimum follow-up time was 20 days and the maximum observed follow-up time was 28.0 years, with a calculated median follow-up time of 23.6 years. The current follow-up study was conducted 29 years after the start date, at which point 80% of the study participants had died, to see if a survival benefit from RP persisted.
Patients who underwent RP added a mean of 2.9 years to their life expectancy after 23 years, according to Anna Bill-Axelson, MD, PhD, Uppsala University in Sweden, and colleagues. Distant metastases were diagnosed in 92 men in the radical prostatectomy group and 150 men in the watchful waiting group. At 23 years, the cumulative incidence of metastases was 26.6% in the RP group and 43.3% in the watchful waiting group (difference 16.7 percentage points; 95% CI 9.6-23.7).
The cumulative incidence of death from all causes at 23 years was 71.9% in the radical prostatectomy group and 83.8% in the watchful waiting group (difference 12.0 percentage points; 95% CI 5.5-18.4). A total of 71 deaths in the RP group and 110 in the watchful waiting group were due to prostate cancer (relative risk 0.55; 95% CI 0.41-0.74). In the RP group, a Gleason score of more than 7 — about 40% of both treatment groups had scores in that range — was associated with a death risk that was 10 times as high as in patients with scores of 6 or lower. Compared to men without extracapsular extension in the RP group, the risk of death was 5 times as high in patients with extracapsular extension who had undergone the surgical procedure.
But a U.S. prostate cancer specialist told MedPage Today that the very length of the study complicates the interpretation, since current diagnosis and treatment is markedly different than when the trial began.
“It would be very difficult for a newly diagnosed patient to determine where he fits in this study,” said James Mohler, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York.
The researchers also did not report mortality for the two treatment groups stratified by baseline Gleason score. Adverse events such as incontinence and sexual dysfunction were not addressed in the current report; a 2011 publication from SPCG-4 indicated similar rates of erectile dysfunction in the two groups, but a nearly fourfold higher prevalence of urinary leakage in the patients who underwent RP.
Source Reference: New England Journal of Medicine, Dec. 13, 2018, DOI: 10.1056/NEJMoa1807801
Study Highlights: Explanation of Findings
“A mean of 2.9 years of life were gained with radical prostatectomy,” observed the authors. “The mean number of years gained is a crude measure, since any given man who is randomly assigned to undergo the procedure either might not benefit at all or might have a much greater benefit than the mean number for the whole group indicates. However, the measure puts in perspective what is risked by delaying intervention.”
“This remains the best randomized study of radical prostatectomy versus observation ever done,” Mohler told MedPage Today. “Its follow-up is long, it did not have PSA early detection bias, and even with the problems with Gleason grading and the determination of clinical pathologic stage, the group of patients seems to be largely devoid of who we would place on active surveillance today.”
But Mohler, who was not involved in the study, said that because of the way that prostate cancer diagnosis and management has changed since 1989, it’s unclear what the findings mean for current patients.
“The authors raise the concern that diagnosing cancer earlier – like it is done today – might fail to show this gain in life benefit because of contamination of modern-day patients with lots of patients that don’t really need to be treated,” he said. “And that’s a very legitimate concern, so it would be wrong for patients and urologists to say that this study proves that more men should have radical prostatectomy… That’s why this study is so hard to interpret in 2018.”
However, Mohler noted that if a patient does have an aggressive prostate cancer, the study shows that a patient “is better off having RP than observation, in terms of preventing the development of metastasis, dying of prostate cancer, and overall survival.”
Mike Bassett wrote the original story for MedPage Today.