Longer-term follow-up data from a major trial has confirmed the initial observation that for men with low-risk early-stage prostate cancer, surgery does not reduce the risk for death compared with observation.
The new results come from longer follow-up of the Prostate cancer Intervention Versus Observation Trial (PIVOT) and show that surgery was not associated with significantly lower all-cause or prostate cancer mortality than was observation in men initially diagnosed with early-stage prostate cancer.
Although men undergoing surgery — in this case radical prostatectomy — had a 16% decreased risk for death from any cause and a 37% decreased risk for death from prostate cancer or its treatment, the difference between this and outcomes in the observation group was not statistically significant.
However, surgery was associated with a higher incidence of adverse events necessitating treatment than was observation: urinary incontinence (17.3% after surgery vs 4.4% with observation) and erectile and sexual dysfunction (14.6% vs 5.4%, respectively).
The new findings come after a median follow-up of 12.7 years (range, 12.0 to 19.5 years) of PIVOT and were published in the July 13 issue of The New England Journal of Medicine.
"Our results, together with those of SPCG-4, the ProtecT trial, and two earlier trials that showed no mortality benefits of surgery or radiation as compared with observation, have clinical implications," the study authors write.
"PIVOT provides high-quality scientific evidence supporting the use of observation in most men with localized prostate cancer," corresponding author, Timothy J. Wilt, MD, MPH, from the Minneapolis Veterans Affairs Health System and Center for Chronic Disease Outcomes Research, Minneapolis, told Medscape Medical News.
"Cancer is a fearful word, and the immediate reaction from a patient is that 'I've got to do something,'" he commented. "Based on these data, physicians can now confidently recommend observation as the preferred treatment option for most men with early prostate cancer, especially men with low-risk disease," he said.
However, an expert approached for comment suggested that the trial did not show a significant difference between surgery and observation because it was underpowered.
"PIVOT is an important study and is the only observation-vs-treatment study with a significant proportion of African American men," Anthony D'Amico, MD, PhD, chief of genitourinary radiation oncology at the Dana-Farber Cancer Center and Brigham and Women's Hospital, Boston, Massachusetts, told Medscape Medical News.
It did not show a statistically significant difference between surgery and observation, but it "almost did," he commented.
The 19.5-year cumulative incidence of death was 61.3% for men assigned to surgery and 66.8% for those assigned to observation (hazard ratio [HR], 0.84; P = .06). A similar trend was reported for incidence in death from prostate cancer or its treatment: 7.4% vs 11.4% (HR, 0.63; P = .06).
Dr D'Amico pointed out that the P value was .06 for the endpoint of all-cause and prostate cancer–specific mortality — and this is only 1/100th of a point away from statistical significance (a P value is considered to indicate statistical significance when According to Dr D'Amico, this is extremely noteworthy given the shorter life expectancy of men in PIVOT compared with men of average health in the United States.
"This [and] the fact that PIVOT did not reach its accrual goal are both factors that should have caused it to be underpowered to measure a significant difference between the two randomized arms. Yet it almost did," Dr D'Amico said.
Dr Wilt explained why accrual to this trial was difficult. "Accrual was hampered by widespread belief in the medical and scientific community that surgery would have mortality benefits that would be very large and would appear early, and thus randomization to surgery vs observation would be unethical," he said. "Thus, there was strong discouragement from many not associated with this trial to enroll," he added.
Because of difficulties in accruing, the sample size for PIVOT was revised. Initially, the investigators had planned to enroll 2000 men. But they downsized the trial after calculating that 740 men enrolled over 7 years, with an additional 8 years of follow-up, would provide 91% power to detect a 25% relative reduction in all-cause mortality, assuming a median survival of 10 years.
Dr Wilt said the final sample size was based on input and approval from the data safety and monitoring board and permitted accurate assessments of overall and disease-specific mortality. is less than .05).
Dr Wilt elaborated that men enrolled in PIVOT were healthy, with few coexisting medical conditions, had a life expectancy of at least 10 years, and were judged by their physician to be a candidate for surgery. Nearly 85% of men rated their health as very good or better. "Our results were similar in younger and healthier men and in men of black race," Dr Wilt said.
"Our results convincingly demonstrate that any mortality benefit due to surgery is small at best and not present in men with low-risk disease," he added.
Dr Wilt told Medscape Medical News that it was important to focus on the absolute differences, which over nearly 20 years were less than 6 percentage points for all-cause and 4 percentage points for prostate cancer–specific mortality. "Absolute differences were small and not significant," he said
However, Dr D'Amico argued that the absolute differences are deflated because of the large proportion of men (about 40%) with low-risk prostate cancer, in whom immediate treatment has not been shown to prolong life compared with observation. "This is the reason why it is important to look at subgroups who had higher-risk prostate cancer [ie, intermediate and high risk]," he said.
In men with intermediate-risk disease, surgery was associated with a significant 32% relative reduction in mortality, while in men with high-risk disease PIVOT showed a near-significant 22% relative reduction, Dr D'Amico observed.
In PIVOT, for men with intermediate-risk disease, incidence of all-cause mortality was 59.7% for surgery and 74.2% for observation (absolute difference, 14.5 percentage points; HR, 0.80 [95% confidence interval (CI), 0.67 - 0.96]). Corresponding rates for death from prostate cancer or its treatment were 8.5% vs 15.8% (absolute difference, 7.3 percentage points; HR, 0.54 [95% CI, 0.27 - 1.08]). Similar trends were reported for men aged 65 years and younger.
Surgery may have benefits that justify harm in younger men (ie, men with very long life expectancies) and men with intermediate-risk disease, Dr Wilt admitted. "However, any benefit should be balanced with treatment harms," he said.
Men currently detected with prostate cancer are likely to have a better prognosis with observation than men enrolled in PIVOT because they typically have smaller volume and lower PSA [prostate-specific antigen] results and thus more indolent disease, Dr Wilt noted. "Therefore, any possible mortality benefit would be smaller in absolute terms and require longer to accrue," he said.
However, Dr D'Amico noted that, given the decline in PSA screening in the US, men presenting with early-stage prostate cancer actually have disease similar to men who included in PIVOT.
Other Outcomes From PIVOT
Several other clinical outcomes that favored surgery were also reported in PIVOT. Men randomly assigned to surgery had a lower incidence of disease progression (40.9% vs 68.4%) and a lower incidence of local (40.9% vs 68.4%), regional (9.1% vs 14.2%), and systemic (10.2% vs 14.7%) progression. In addition, in the surgery cohort, fewer men needed treatment for disease progression (33.5% vs 59.7%), with nearly twice as many men in the observation group requiring treatment for local (25.3% vs 12.4%) and systemic (8.7% vs 4.7%) progression.
Dr D'Amico referred to data in the supplemental appendix in PIVOT that reported a significant 36% relative reduction in metastasis among men undergoing surgery. "This is a clinically relevant endpoint given the pain and suffering that can be associated with metastatic disease and the side effects of treatment that include at least life-long intermittent androgen deprivation therapy," Dr D'Amico said (J Clin Oncol. 2017;35:1638-1640).
Observation vs Active Surveillance
Medscape Medical News asked Dr Wilt whether these results are relevant in an era of active surveillance. "Yes," he said. "Men enrolled and treatments they received in PIVOT are similar to men currently diagnosed with prostate cancer and considering treatment options."
He explained that unlike observation, active surveillance involves periodic lab tests, digital rectal examinations, and prostate biopsies. On the basis of changes in these test results, delayed treatments intended for cure may be recommended even if patients do not have signs or symptoms from prostate cancer.
However, the PIVOT authors admit that active surveillance is the predominant active-monitoring practice in the United States. "Prostate biopsy–based active surveillance has not been evaluated [in the United States] and remains of uncertain benefit, but results in substantial harms related to surveillance biopsies and delayed radical intervention," Dr Wilt said.
"For many men, PIVOT indicates that observation is a preferred treatment option because it leads to similar overall and prostate cancer morality and avoids treatment-related harms," Dr Wilt said.
Moreover, Dr Wilt pointed out that patient-reported outcomes, such as overall health, physical, or mental health, did not differ between the two groups. "It is important to note that worry and anxiety were not significant in men undergoing observation," he said.
Men assigned to surgery were likely to report "bother" due to prostate cancer or treatment, physical discomfort, and limitations in activities of daily living through 2 years, but not subsequently, the study authors noted.
Debate Between Intervention and No Intervention
Dr Wilt appreciated the ongoing debate on treatment vs observation for early-stage prostate cancer. In his own practice, he discusses the risks and benefits of intervention with his patients. He counsels against intervention for patients with low-risk disease. Patients with high-risk disease have poor prognosis and are also unlikely to do better with surgery or radiation, he noted. "These patients require better treatment options," he said. Patients with intermediate- risk disease and young men detected with early-stage prostate cancer need to know the trade-offs between intervention and no intervention before deciding on a management approach, he no
In contrast, Dr D'Amico noted that, despite its potential limitations, the results of PIVOT argue strongly for immediate treatment of men with intermediate-risk and high-risk prostate cancer where significant and near significant signals for mortality reductions were reported.
Given that PIVOT, SPCG-4, and the ProtecT trial support observation/active surveillance over intervention, Dr Wilt noted that the burden of proof remains on others to design, conduct, and complete a larger, longer-term study to assess the effectiveness and harms of various treatment options.
"Until then, results from PIVOT along with those of other recently completed randomized trials suggest that radical intervention results in small to no mortality benefit and substantial harms compared to observation or PSA-based monitoring for the large majority of men with early-stage prostate cancer," he told Medscape Medical News.
Dr Wilt and Dr D'Amico have disclosed no relevant financial relationships.
N Engl J Med. Published online July 13, 2017. Abstract
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