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Early prostate cancer survival similar after radical prostatectomy, observation
Radical prostatectomies for localized prostate cancer did not significantly reduce all-cause or prostate cancer–specific mortality compared with observation over 20 years of follow-up, according to study results published in The New England Journal of Medicine.
“Our study provides convincing evidence that supports at least three other large, long-term randomized trials in men with localized prostate cancer, demonstrating that observation or PSA–based active monitoring results in similar long-term overall and cancer-specific mortality for the large majority of men and especially for men with PSA–detected and low-risk disease or in older men with higher-risk disease,” Timothy Wilt, MD, MPH, professor of medicine at Veterans Affairs Center for Chronic Disease Outcomes Research in Minneapolis, told HemOnc Today. “Further, observation avoids large, long-term and sometimes serious treatment-related harms, including urinary, erectile and sexual dysfunction, treatment-related bother and reductions in daily activities.”
Researchers of the PIVOT trial randomly assigned 731 men (mean age, 67 years; median PSA value, 7.8 ng/mL) with localized prostate cancer and a life expectancy of at least 10 years to radical prostatectomy (n = 364) or observation (n = 367) from November 1994 through January 2002.
All-cause mortality and prostate-cancer mortality served as the primary endpoints. Researchers extended follow-up through August 2014 for the primary outcome.
After 19.5 years of follow-up (median, 12.7 years) death occurred in 223 men (61.3%) assigned surgery and in 245 (66.8%) assigned observation (absolute difference in risk, 5.5 percentage points; 95% CI, –1.5 to 12.4; HR = 0.84; 95% CI, 0.7-1.01).
Median survival was 13 years (95% CI, 12.5-13.5) with surgery compared with 12.4 years (95% CI, 11.4-12.8) with observation.
Death attributed to prostate cancer or its treatment occurred in 27 men (7.4%) assigned surgery and in 42 men (11.4%) assigned observation (absolute difference in risk, 4 percentage points; 95% CI, –0.2 to 8.3; HR = 0.63; 95% CI, 0.39-1.02).
Surgery reduced risk for all-cause mortality compared with observation among men with intermediate-risk disease (absolute difference, 14.5 percentage points; 95% CI, 2.8-25.6) but not among those with low-risk disease (absolute difference, 0.7 percentage points; 95% CI, –10.5 to 11.8) or high-risk disease (absolute difference, 2.3 percentage points; 95% CI, –11.5 to 16.1).
“My view when we started the study was that radical prostatectomy worked, but it didn’t work as well as everybody was saying,” study researcher Michael K. Brawer, MD, vice president of medical affairs at Myriad Genetics Laboratories, told HemOnc Today. “With these new data, we now see that there is some separation, particularly in the intermediate-risk group and in men with a PSA greater than 10. This is a case where we needed a very long follow-up to provide answers.”
Any progression occurred in 40.9% of men assigned surgery and 68.4% of men assigned observation.
Fewer men assigned surgery than observation experienced disease progression or received additional treatment, which mostly consisted of treatment for asymptomatic, local or PSA progression (33.5% vs. 59.7%; absolute difference, 26.2 percentage points; 95% CI, 19-32.9).
At 10 years’ follow-up, more men who underwent surgery experienced urinary incontinence (17.3% vs. 4.4%) and erectile and sexual dysfunction (14.6% vs. 5.4%).
“Physicians and patients now have high-quality information to confidently recommend and choose observation as a preferred treatment option for most men with PSA–detected localized prostate cancer, especially men with low-risk disease, older men or men with serious health conditions who have higher-risk disease, or those wishing to avoid treatment harms,” Wilt said. “Observation results in similar overall mortality, low and similar prostate cancer mortality and avoids early treatment harms. Observation is an excellent, wise and often preferred treatment choice.”
These findings are consistent with those of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) and the Prostate Testing for Cancer and Treatment (ProtecT) trial, according to the researchers.
“Clinical practice guidelines and performance incentives should be developed to encourage widespread use of observation or PSA–based active monitoring,” Wilt said. “Informed decision tools and media messages should support patient choice regarding observation as a wise and quality health care choice.”
The results of this study, along with the U.S. Preventive Services Task Force’s recommendation that clinicians speak to men about the benefits and harms of PSA screening, could lead more men to elect observation over surgery, Brawer said, especially if their cancers are diagnosed at earlier stages.
“It’s worth noting the cancers we have found have become more and more favorable,” Brawer said. “We’re starting to see the pendulum swing backward, and there is more testing and that would suggest we’ll find prostate cancers in an even more favorable stage than we saw in the early 1990s.”
There has been a slow adoption of observation, PSA–based monitoring and biopsy-based active surveillance in recent years. Wilt said his team’s findings — along with the recent ProtecT trial showing evidence that observation and PSA–based monitoring result in similar mortality to radical intervention — will result in greater awareness and increased implementation of observation.
“There remains skepticism of the scientific facts from these studies, fear regarding a cancer diagnosis, and widely held treatment beliefs and incentives that will make widespread adoption of these best practices challenging,” Wilt said. “However, the fact that men with tumors detected currently by PSA testing have lower PSA and smaller-volume tumors with better long-term natural history than those enrolled in our study makes observation even a better option for more men currently diagnosed with localized cancer.” – by Chuck Gormley
For more information:
Michael K. Brawer, MD, can be reached at Myriad Genetics, Inc., 320 Wakara Way, Salt Lake City, UT 84108; email: mbrawer@myriad.com.
Timothy Wilt, MD, MPH, can be reached at Minneapolis VA Health Care System Center for Chronic Disease Outcomes Research (CCDOR), Mail code: 152, Bldg. 9, One Veterans Drive, Minneapolis, MN 55417; email: tim.wilt@va.gov.
Disclosure: The Department of Veterans Affairs, the Agency for Healthcare Quality and Research, and the NCI funded this study. Wilt reports no relevant financial disclosures. Brawer is vice president of medical affairs at Myriad Genetics Laboratories. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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This study provides long-term results from PIVOT, a randomized trial comparing prostatectomy and observation for U.S. men diagnosed with prostate cancer during the early PSA era. At a median follow-up of 12.7 years, researchers observed no statistically significant difference in OS between the two groups. However, men who underwent surgery had a greater risk for incontinence and erectile dysfunction. There are numerous limitations to PIVOT, but the overall findings are consistent with the ProtecT trial from the United Kingdom. That study randomly assigned screen-detected patients to surgery, radiation therapy or active monitoring, and found no significant difference in survival at 10 years’ follow-up, but did find significant differences in functional outcomes.
In the guidelines, management decisions about prostate cancer are determined based on life expectancy and the stage of disease. Both ASCO and American Urological Association (AUA) recommend active surveillance as the preferred management option for low-risk prostate cancer. Subgroup analysis from PIVOT found no difference in survival for men with low-risk disease who had surgery compared with observation, affirming current management recommendations. Nevertheless, active surveillance continues to be underused in U.S. men with low-risk disease, with less than 50% choosing this option as of 2013. This is in stark contrast to data from Sweden, where 91% of very low-risk and 74% of low-risk patients choose active surveillance. The reasons for underutilization of active surveillance in the United States appear to be multifactorial, with barriers at the patient and physician level.
The use of active surveillance in intermediate-risk disease continues to be controversial. Both ASCO and AUA guidelines state that active surveillance can be offered to select patients with low-volume Gleason 3 + 4 disease. Subgroup analysis in PIVOT showed a survival benefit from prostatectomy over observation in intermediate-risk patients. It is noteworthy that PIVOT was not powered for subgroup analysis and did not use a modern active surveillance protocol. Although we cannot generalize the results from PIVOT to the use of a careful surveillance protocol in highly selected patients with low-volume intermediate-risk disease, continued caution should be exercised in this population.
The results from PIVOT lend further support to the use of active surveillance for most patients with low-risk prostate cancer. For patients at the high end of the low-risk category or low end of the intermediate-risk category, additional testing options are now available that can be used to guide management decisions. For example, Prolaris (Myriad Genetics), OncotypeDx (Genomic Health) and Decipher (GenomeDx) are three tissue-based marker tests which provide prognostic information beyond the traditional risk classification and can be used to assist in management decisions for borderline cases. Multiparametric MRI also is increasingly used for local staging and to inform decisions about active surveillance vs. upfront treatment.
Hamdy FC, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1606220.
Although widely hailed in the press as showing that treatment had no impact on overall or prostate cancer-specific survival, the PIVOT trial is deeply flawed and should be interpreted with caution. Because the trial did not complete its planned accrual, it was severely underpowered to answer the question it posed. It also included predominantly older men who had substantial comorbidities and would not generally be considered for definitive treatment.
Overall, 223 of 364 men (61%) assigned to surgery and 245 of 367 (67%) assigned to observation died. Death due to prostate cancer occurred in 27 patients (7.4%) managed with surgery and 42 (11.4%) managed with observation. Despite the lack of differences in overall and disease-specific survival, disease progression — local, regional or systemic — occurred significantly less frequently in those managed with radical prostatectomy (41% vs. 68%; HR = 0.39; 95% CI, 0.32-0.48). Also, fewer men who underwent radical prostatectomy needed additional treatment for recurrent or progressive disease (33.5% vs. 59.7%). When stratified by disease aggressiveness, those with intermediate-risk disease had a trend toward improved survival.
The most that can be concluded from PIVOT is that older men with significant comorbidities and low-grade disease — rated by National Comprehensive Cancer Network as very low and low risk — did not benefit from surgery, which is already widely recognized and has led to management of such patients by active surveillance. Concluding that surgery has no benefit in younger, healthier men with more aggressive disease is not supported by the reported data.