Reuters Health Information

Study Confirms Safety of Active Surveillance in Low-Risk Prostate Cancer

By Reuters Staff

July 07, 2016

NEW YORK (Reuters Health) – After a decade of follow-up in the Prostate Cancer Research International Active Surveillance (PRIAS) study, researchers have confirmed that active surveillance is a safe treatment option for men with low-risk prostate cancer.

“However,” they say, “some changes could be made to the follow-up protocol to safely increase the number of men who remain on active surveillance.”

Dr. Leonard P. Bokhorst of Erasmus University Medical Center in Rotterdam, the Netherlands, and colleagues analyzed data on more than 5,000 men in 18 countries followed in PRIAS, including 622 who were followed more than five years and 107 were followed more than 7.5 years.

The median age at diagnosis was 65.9 years.

Original inclusion criteria included Gleason score 3+3 or lower, stage cT2c or lower, and prostate-specific antigen (PSA) 10 ng/ml or lower. PSA tests were scheduled every three months and digital rectal examinations were scheduled every six months during the first two years of study, then less often later. Criteria to recommend starting active treatment include Gleason score higher than 3+3, more than two positive cores, and stage higher than cT2.

Median PSA for the study population was 5.7 ng/ml. Most men (69%) had one positive biopsy core, with Gleason score of 3+3 (99%) and a clinical stage of T1c (88%).

Almost 3,400 men received at least one repeat biopsy during follow-up and some received up to five biopsies.

Overall, 1,768 men discontinued active surveillance during follow-up, 1,102 due to protocol-based reclassification. Other reasons for discontinuations included anxiety, switch to watchful waiting, death, and loss to follow-up. Two-thirds (67%) of the men were treated with either radical prostatectomy or radiation therapy after discontinuation. Only 3% received hormonal therapy.

Almost half (48%) of the patients were still on active surveillance after five years and 27% were on active surveillance at 10 years, the researchers reported online June 19 in European Urology.

The team had pathology data on 360 men who had radical prostatectomy. Of the men who switched to treatment because of protocol-based reclassification, 82 (30%) had favorable pathological outcomes, 85 (34%) had intermediate outcomes, and 100 (36%) had unfavorable outcomes.

Mortality from prostate cancer was less than 1% during follow-up.

Because of the higher rate of unfavorable treatment outcomes, the researchers recommended a change in the PRIAS protocol.

“Instead of an immediate switch to active treatment if more than two cores are positive, men should receive further investigation to confirm higher risk disease,” the researchers write. They recommend examination by magnetic resonance imaging because its negative predictive value for Gleason upgrading is near 100%.

They concluded, “Criteria used to recommend a switch to active treatment do not seem selective enough to avoid unnecessary switches to active treatment.”

Dr. Bokhorst did not respond to a request for comment.

The Prostate Cancer Research Foundation, Rotterdam, supports the PRIAS study. The authors made no disclosures.

SOURCE: http://bit.ly/28Q5Cd3

Eur Urol 2016.

https://www.canceractive.com/cancer-active-page-link.aspx?n=3187

http://www.independent.co.uk/life-style/health-and-families/health-news/study-raises-doubts-over-treatment-for-prostate-cancer-7685310.html

http://www.itv.com/news/story/2012-04-28/doubts-over-prostate-cancer-treatment/

http://www.netdoctor.co.uk/conditions/cancer/news/a13750/prostate-cancer-treatment-unnecessary/

http://www.spiritofhealthkc.com/wp/wp-content/uploads/2014/03/PROSTATE-CANCER-Study-Raises-Doubts-over-Treatment-for-Pro.pdf

https://www.canceractive.com/stored-files/wttr_prostate_cancer.pdf

Medscape Medical News > Oncology

Time to Abandon the Digital Rectal Exam?

Fran Lowry

September 15, 2016

In men with a normal prostate specific antigen (PSA) level, the digital rectal examination (DRE) rarely assists in diagnosing clinically significant prostate cancer, yet it is an invasive, uncomfortable examination with very little gain, according to a new study.

In an analysis of data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), DRE screening in the setting of normal PSA levels captured an additional 2% of men with clinically significant prostate cancer.

It may be time to abandon the DRE, suggest the authors of an article published in Current Medical Research and Opinion.

“A lot of men will comment that they are dreading the visit because they fear the digital rectal exam, so through conversation with patients and also through the literature, we recognized that the thought of the DRE keeps some men from coming to our office,” author Ryan P. Terlecki, MD, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, told Medscape Medical News.

Dr Ryan Terlecki

In 2012, the United States Preventive Services Task Force (USPSTF) released recommendations against routine PSA screening for prostate cancer in healthy men.

The recommendation was controversial, but physicians did reduce routine PSA screening. However, there has been less focus on DRE screening, and it has been unclear whether DREs improve cancer detection, Dr Terlecki said.

He and his team decided to look at how useful DRE screening was in the PLCO trial.

The nationwide, population-based trial evaluated cancer screening programs and their impact on cancer mortality. In the screening arm, 38,340 men received annual PSA testing and DREs during the first 3 years; they continued to undergo PSA for screening an additional 2 years, for a total of 5 years. The control arm consisted of patients who received usual care. Participants were followed for up to 13 years.

Those with an abnormal test result were referred to their individual healthcare provider for biopsy.

Dr Terlecki and his group focused on the men who received both screening tests in the first 3 years.

Using National Comprehensive Cancer Network prostate cancer guidelines, the researchers defined a clinically significant prostate cancer as a tumor associated with PSA level > 10 ng/ml, a Gleason score ≥7, or clinical stage ≥T2b in men aged 75 years or younger During that time, the men received 129,028 PSA tests and 124,694 DREs.

Of PSA tests, 10,490 (8.1%) were abnormal and resulted in 3422 (32.6% of abnormal screens) biopsies.

Those biopsies identified 1317 men with prostate cancer; of these cases, 680 (19.9%) were considered to be clinically significant prostate cancer.

Of the DRE tests, 9362 (7.5%) were abnormal and were suspicious for prostate cancer; these tests led to the performance of 2024 biopsies.

For each year studied, men with isolated abnormal DREs were significantly (P < .05) less likely to undergo biopsy than those with isolated abnormal PSA levels.

The biopsies that were triggered by an isolated abnormal DRE result identified 616 men with prostate cancer, and of those, 317 men were considered to have clinically significant prostate cancer.

The analysis showed that the rate of prostate cancer detection with DRE was significantly lower than that associated with isolated abnormal PSA results for each year and overall (P < .01), with the exception for year 2 (P = .12).

Maximal Pain, Minimal Gain

“Our analysis reemphasizes the superiority of PSA as an independent screen for prostate cancer that is clinically significant, compared to DRE,” Dr Terlecki said.

“An abnormal PSA led to the detection of 680 cases of clinically significant prostate cancer, compared to 317 cases from an abnormal DRE, and most of those, 69%, also had an abnormal PSA. So the digital rectal exam did not appear to be useful in detecting cases of clinically significant disease if men were going to have PSA anyway,” he said.

“This is interesting, because a lot of people don’t realize, urologists especially, that our governing association, the American Urological Association, states that there is no evidence that the digital rectal exam is beneficial and that it should not be in primary screening, but that it could potentially be useful as a secondary test in men who have elevated PSA,” Dr Terlecki said.

“Also, the American Cancer Society continues to recommend PSA but doesn’t require the rectal exam,” he said.

The PLCO data also showed that one would have to perform well over 1000 DREs to find one case of significant prostate cancer, Dr Terlecki said.

“The data did suggest that if both PSA and digital rectal exam were both abnormal, there may be a higher chance of significant prostate cancer, but if you are going to biopsy someone on the basis of an abnormal blood test anyway, doing the digital rectal exam seems not to add anything,” he said.

However, Dr Terlecki did note that the conclusions from his study are based on data derived from the PLCO study. That study has been criticized for a number of factors; these include inconsistent use of biopsy following positive screening tests, lack of end-of-study biopsies to determine population disease burden, and low numbers of black men in the study.

The Thought of the DRE Keeps Some Men From Screening

“We are not challenging screening at all. We’re just talking about the digital rectal exam. For those who are in favor of screening, our report might be a welcome addition to the literature, because it has already been shown that the DRE is a barrier for men to actually participate in screening,” Dr Terlecki said.

“For example, a little over 40% of African American men reported fears of discomfort and embarrassment from the exam in one study,” he said

“The DRE isn’t even useful to evaluate for an enlarged prostate, rectal tone in trauma cases, and things of this sort, as we found when we searched the literature. It used to be used for screening for colon cancer, but as of 2002, the USPSTF no longer advocates its use for that either,” Dr Terlecki said.

He added: “If somebody already has diagnosed prostate cancer and is being treated with radiation or certain types of surgery, that is a different story, and this study was not designed to challenge that. But if we think about the DRE in terms of screening and looking for an initial problem, I don’t really see a role. Overall, I think that this most common clinical examination for me, the digital rectal exam, should be largely abandoned, based on the evidence before us.”

Dr Terlicki continued: “Traditionally it was just something that the doctor would do, like a knee jerk reaction, during a routine physical, and it is such an uncomfortable part of the exam for most men. So if it’s not providing useful information, why go through it?”

Don’t Abandon the DRE

However, some researchers disagree.

As reported in Medscape Medical News, once a man decides to undergo screening for prostate cancer, then both PSA testing and the DRE should be carried out, according to David Penson, MD, MPH, chair of the Department of Urologic Surgery at Vanderbilt University Medical Center, Nashville, Tennessee.

The Medscape article mentions a patient who was diagnosed after an internist felt what he described as a hard nodule in the prostate during a DRE, despite the patient’s having a low PSA level.

Asked to comment on this study by Medscape Medical News, Marc B. Garnick, MD, Beth Israel Deaconess Medical Center and Gorman Brothers Professor of Medicine at Harvard Medical School, Boston, Massachusetts, warned: “Family and primary care physicians should not mistakenly interpret the results of this study by endorsing the elimination of performing DREs.”

Dr Garnick said that the arguments that the authors make for discontinuing use of the DRE as a method of screening for prostate cancer are “compelling.”

My personal practice will never abandon DRE. Dr Marc Garnick

“Their data, as well as earlier data, suggest limited utility of DRE alone as a screening modality for prostate cancer, regardless of whether it is indolent or clinically significant. However, my personal practice will never abandon DRE as an integral part of the physical examination beyond screening considerations,” he said.

“It is an important portion of the exam for men with urinary symptoms. Does my examination suggest BPH [benign prostatic hyperplasia] or something more nefarious? There are other anatomic considerations evaluated during a DRE, for instance, the distal rectum and anus,” Dr Garnick said.

“In following patients with a rising PSA post radical prostatectomy, DRE can be extremely helpful in identifying anastomotic or local recurrences. For those who have an elevation in PSA post radiation, DRE is helpful in post radiation treatment considerations,” he said.

“Finally, appreciate that in the current study, of all of the men with abnormal DREs, only a small proportion underwent biopsy, hence weakening the otherwise cogent arguments made by the authors. And even if there is less evidence-based information about DRE utility for screening for prostate cancer, there are a multitude of other reasons for continuing to keep it as an integral part of the physical examination,” Dr Garnick said.

Weighing in with his opinion, J. Brantley Thrasher, MD, William L. Valk Distinguished Professor, Department of Urology, University of Kansas Medical Center, Kansas City, told Medscape Medical News he would not abandon the DRE.

“Given the limitations of this study, as mentioned by the authors, and the fact that DRE is a relatively benign exam with very few, if any, complications, I would continue to offer DRE as a part of screening,” Dr Thrasher said.

“Additionally, more information from diverse populations should be available before I will abandon this simple and safe exam. I have found numerous abnormalities in the face of normal PSAs over the years,” he said.

Dr Terlecki, Dr Garnick, and Dr Thrasher report no relevant financial relationships.

Curr Med Res Op. Published online July 4, 2016. Abstract

 

Medscape Medical News > Oncology

10-Year Prostate Cancer Results From Landmark ProtecT Trial

Alexander M. Castellino, PhD

September 14, 2016

CORRECTED September 15, 2016 // In a landmark study, prostate-cancer survival was not significantly different among men with localized disease in the 3 different treatment groups (prostatectomy, radiation, and monitoring), according to 10-year results published today in the New England Journal of Medicine.

However, prostatectomy and radiotherapy had lower rates of disease progression and metastases in the Prostate Testing for Cancer and Treatment (ProtecT) trial.

“This is the first time that radiotherapy, surgery, and active monitoring for prostate cancer have been directly compared in a large randomized trial, with a 10-year follow-up,” lead author Freddie Hamdy, MBChB, MD, a professor of surgery and urology at the University of Oxford, United Kingdom, told Medscape Medical News.

The primary endpoint of prostate cancer–specific mortality was approximately 1% in each study group, which had a median follow-up of 10 years.

“This was lower than the expected rate,” he said.

“Although radical treatment is effective in reducing disease progression and metastases, this does not translate into survival,” Dr Hamdy added.

The new comparative effectiveness results are accompanied by a companion study of patient-reported outcomes that reveal varying rates of adverse events by treatment type and may help clinicians and patients in decision making.

“The ProtecT trial is an important study that provides additional support for utilizing conservative management for select patients,” said Rahul Tendulkar, MD, a radiation oncologist from the Cleveland Clinic, Ohio, who was not associated with the study and was asked for comment.

He pointed out that active surveillance has become an increasingly accepted treatment strategy for men with early-stage prostate cancer since the study started.

“While this trial may not be practice changing, it certainly adds validity to the notion that treatment of prostate cancer can lead to some patient harm (particularly sexual dysfunction and urinary incontinence after radical prostatectomy and rectal bleeding after radiation therapy),” he added.

However, Dr Tendulkar said that “there remain some important lingering questions” with regard to the higher rates of cancer progression and distant metastases with active monitoring.

The ProtecT population came from 82,429 men aged 50 to 69 years who received a prostate-specific antigen (PSA) test between 1999 and 2009. Of these, 2664 were diagnosed with early prostate cancer, including low-risk and intermediate-risk disease according to the D’Amico classification.

A total of 1643 men eventually enrolled in the study and were randomly assigned to active monitoring (n = 545), surgery (n = 553), or radiotherapy with hormones (n = 545). The radiation therapy group received neoadjuvant androgen-deprivation therapy 3 to 6 months before and three-dimensional conformal radiotherapy (total dose, 74 Gy in 37 fractions). Review appointments were held to determine PSA levels. Management options were provided if they rose 2.0 ng/mL above the nadir.

Men receiving surgery had PSA measurements every 3 months for the first 2 years, every 6 months for the third year, and annually thereafter.

Table. Prostate Cancer–Specific Death and Metastases

Outcome	Patients (n)	Event Rate per 1000 Person-Years	P Value for Overall Comparison
Prostate cancer–specific death
Active monitoring	8	1.5	.48
Surgery	5	0.9
Radiation therapy	4	0.7
Metastases
Active monitoring	33	6.3	.004
Surgery	13	2.4
Radiation therapy	16	3.0

Of the 17 total prostate cancer–specific deaths, some were in men with low-risk disease, and that is troublesome, Dr Hamdy noted. “We cannot describe lethal disease well at diagnosis. We need new markers to tell us that,” he said.

Also, all-cause mortality did not statistically significantly differ across the three groups (169 total deaths; P = 0.87).

Monitoring Protocol Is Not Contemporary

An important aspect of the study design is that the active monitoring protocol used in this study is different from how it is done today, said Stacy Loeb, MD, a urologist at New York University’s Langone Medical Center, who was not involved with the study.

“Overall, the protocol of active monitoring used in ProtecT is different from that used in contemporary active surveillance programs,” she said.

In the ProtecT study, prostate biopsies were not part of regular scheduled monitoring but could be used as part of the clinical assessment of disease progression, she said.

Dr Loeb pointed out that this differs from modern active surveillance programs, which include serial PSA testing and digital rectal examination, as well as serial prostate biopsies to check for increases in the grade or volume of the cancer.

She also noted that in the Johns Hopkins active surveillance program, patients with very-low-risk and low-risk prostate cancer are monitored with PSA testing and prostate exams every 6 months, as well as yearly prostate biopsies.

Dr Loeb pointed out that since the inception of this program in 1995, approximately 1300 patients have been enrolled and only 2 have died of prostate cancer. The 15-year prostate cancer–specific survival rate was 99.9% and metastasis-free survival rate was 99.4%.

“This suggests a very low risk of developing incurable disease for low-risk patients who are monitored closely,” she said.

The Case for Active Treatment

In an accompanying editorial, Anthony V. D’Amico, MD, chief of Genitourinary Radiation Oncology at the Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts, notes that there was a trend toward decreased death from prostate cancer for men assigned to surgery or radiation vs active monitoring, particularly in men older than 65 years of age.

“Although further follow-up will determine whether these trends become significant, causality between an increase in metastatic disease and the use of active monitoring versus treatment was established,” he writes.

“The clinical significance of this finding is that with the use of active monitoring, more men will have metastasis and the side effects of salvage treatment (meaning at least lifelong intermittent androgen-deprivation therapy), which are not inconsequential,” he adds.

Dr D’Amico indicates that the adverse events experienced from surgery or radiation were similar to what has been previously reported.

He notes that the incidence of metastases and death from prostate cancer was similar between patients receiving radiation or surgery. “From the information provided from the patient-reported outcomes, patients can now choose which treatment they are willing to take based on which side effects they are willing to possibly sustain without fear of selecting an inferior treatment in terms of cancer control,” he writes.

“For today, we can conclude on the basis of level 1 evidence, that PSA monitoring, as compared with treatment of early prostate cancer, leads to increased metastases,” Dr D’Amico says.

“[I]f a man wishes to avoid metastatic prostate cancer and the side effects of its treatment, monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study,” he writes.

In his editorial, Dr D’Amico also notes that there was a near-significant interaction between age and cancer-related mortality and that “men 65 years and older were more likely to die from prostate cancer if assigned to active monitoring than if assigned to treatment.”

“Should the interaction between age and death from prostate cancer among men assigned to treatment versus monitoring become significant, it would support recommending treatment as opposed to monitoring to otherwise healthy men 65 years of age or older with early prostate cancer who today are increasingly being placed on active surveillance,” he writes.

The underlying pain and suffering from metastatic disease are significant, as are the side effects for lifelong androgen-deprivation treatment for metastatic disease, Dr D’Amico explained. “Most importantly, for men who experience metastases, prostate cancer is incurable and even if they die of another cause (eg, heart attack) before prostate cancer they are at risk for suffering pain from bone fractures from the metastasis and side effects from life-long androgen-deprivation therapy. They may regret for not having being treated initially,” he told Medscape Medical News.

The Case for Active Monitoring/Surveillance

In the ProtecT trial, Dr Hamdy and colleagues point out that active monitoring was undertaken to minimize the risk for overtreatment, including the experience of treatment side effects. Disease progression was monitored regularly so that radical treatment with curative intent could be provided.

In two other studies — one comparing watchful waiting to surgery (SPCG-4 study) and the other comparing observation to surgery (PIVOT study) — the protocols did not have curative intervention in place following disease progression

In ProtecT, trial design called for PSA to be measured periodically every 3 months in the first year and every 6 to 12 months thereafter. If PSA levels increased at least 50% over the previous 12 months, it triggered a review and opportunities for the patient to have other tests and to discuss with the clinician the treatment of their choice: continued monitoring or radical treatment. If the PSA reached 10 ng/mL or more, an isotope bone scan was advised.

“The goal of contemporary active surveillance is to identify evidence of ‘disease reclassification’ (changes in grade or extent of disease) while the cancer is still localized to the prostate (ie, before it has spread or become incurable),” Dr Loeb said.

“For men where serial testing show an increasing grade or volume of cancer, definitive treatment can be offered within the window of curability,” she added.

Dr Loeb also noted that current guidelines from the American Society of Clinical Oncology indicate active surveillance as the recommended option for most patients with low-risk prostate cancer. Active surveillance recommendations include follow-up biopsy at 6 to 12 months to confirm eligibility, then every 2 to 5 years thereafter (J Clin Oncol. 2016;34:2181-2190).

She noted that active surveillance is more controversial for intermediate-risk patients with a higher risk of developing metastatic disease.

“These patients should be counseled on a higher risk of the cancer progressing without treatment,” she noted.

Dr Loeb also pointed out that other tests, such as biomarkers and MRI, are being integrated into active surveillance, which were not available when ProtecT started.

Dr Hamdy explained that he would not stop offering active monitoring to his patients, but the methods to follow them up need to be revised. “Men need to be counseled about the risk of metastases and disease progression over time, as well as side effects of treatments,” he said.

The ProtecT Patient-Reported Outcomes Study

Patient-reported outcome measures were prespecified endpoints of a separate study from ProtecT and were measured by using validated questionnaires across four key domains: urinary function, sexual function, bowel function, and health-related quality of life.

The validated questionnaires were completed at baseline (ie, at the time of biopsy before diagnosis was made), at 6 and 12 months after randomization, and after that annually, say the authors, led by Jenny Donovan, PhD, professor of social medicine at the University of Bristol, United Kingdom.

Complete 6-year data were analyzed on the basis of the intention-to-treat population. Rate of questionnaire completion was 85% during follow-up for most measures.

Prostatectomy was reported to have the greatest negative effect on urinary incontinence at 6 months; some recovery was seen over time, but at all time points, it was highest in men who underwent prostatectomy (P < .001 at each measure).

“After 6 years, about 1 out of 5 men still needed to use pads for urinary incontinence,” Dr Donovan said about the surgery group. “Some men recover, but some have longer and more lasting effects,” she added. At 6 years, this 17% compared unfavorably with the 8% of the active monitoring group who needed pads and 4% of the radiation therapy group.

In terms of sexual function, 67% of the study population reported erections firm enough for intercourse, but at 6 months, this fell to 52% of the monitoring group, 22% of the radiotherapy group, and 12% of the prostatectomy group.

Erectile function was worse at all time points in the prostatectomy group. By year 6, there was not much difference in the rate of men who had sufficient erections in the monitoring and radiation groups (30% and 27%, respectively). But the prostatectomy group was at 17% by that point.

Radiation therapy had the most negative effect on bowel function at 6 months compared with the other two groups, and some bowel symptoms developed over time.

Men who stayed on active monitoring avoided these side effects related to functioning, but half changed to radical treatments and so some sexual and urinary difficulties increased gradually over time.

Quality of life was not a differentiator between groups in this study.

“Importantly, across all the three groups, including active monitoring, there were no significant differences in anxiety or depression or in general health-related or cancer-related quality of life,” Dr Donovan noted.

“Patient-reported outcomes have been directly compared for the first time in this randomized study using validated instruments,” she told Medscape Medical News.

“Results of patient-reported outcomes provide clinicians and patients detailed information of each of the three treatments over 6 years. This study should allow them to take their time and make an informed decision about which treatment to seek, balancing the risks of disease progression against the real and sometimes lasting impact of side effects,” she said.

The ProtecT investigators indicated that men in the study would be followed for a longer time to determine whether treatment may translate into survival benefits. “This follow-up is important to determine the ‘trade-off’ that patients need to make between cancer outcomes, survival and quality of life,” Dr Hamdy said.

The study was supported by the UK National Institute for Health Research Health Technology Assessment Program. Dr Hamdy and coauthors and Dr Tendulkar have disclosed no relevant financial relationships. Dr Loeb reports serving as an advisor to Bayer.

N Engl J Med. Published online September 14, 2016. Hamdy study, Donovan study, Editorial

Editor’s note: Dr Loeb was incorrectly paraphrased about disease-specific survival in metastases data in an earlier version of this story.

 

Almost all men with early prostate cancer survive 10 years, regardless of treatment

Laurie McGinley, The Washington Post

Published 3:43 pm, Wednesday, September 14, 2016

Men with early prostate cancer who choose to closely monitor their disease are just as likely to survive at least 10 years as those who have surgery or radiation, finds a major study that directly tested and compared these options. (Sept. 14)

Media: associatedpress
The survival rate for early-stage prostate cancer is 99 percent after 10 years, regardless of whether men undergo surgery, radiation or are “actively monitored,” according to studies published Wednesday. Researchers hailed the results as good news, saying they had been expecting a survival rate of 90 percent.

The two new studies, published in the New England Journal of Medicine, also illustrated the complicated treatment equations facing men with early-stage prostate cancer, and they immediately set off a debate among physicians about how to interpret the results.

Researchers from the universities of Oxford and Bristol found no difference in survival rates among men who were randomly assigned to surgery, radiation or monitoring; it is the largest study of its kind. Those who underwent surgery or radiation cut in half the risk that their disease would spread to bones and lymph nodes, compared with those who were simply monitored. Although the treatment didn’t extend life during the first 10 years, a survival benefit might yet emerge in the next five or 10 years, the researchers said. The scientists also found that the surgery and radiation treatments sometimes caused severe side effects, including sexual dysfunction, incontinence and bowel problems, that hurt the patients’ quality of life.

“Men with newly diagnosed, localized prostate cancer need to consider the critical trade-off between the short-term and long-term effects of radical treatments on urinary, bowel and sexual function and the higher risks of disease progression” that comes with monitoring, the researchers wrote.

Freddie Hamdy, a professor of surgery and urology at the University of Oxford who was the lead researcher, said his advice to patients is that they should not “rush to receive treatment, but to really digest and really look at the side effects that the treatments produce.”

Otis Brawley, chief medical officer for the American Cancer Society, who had no role in the study, agreed. “We have already had an increased number of men in the United States who choose to be observed after diagnosis, and I would hope this would encourage more of that,” he said of the study. But he also acknowledged that there would be differences of opinions about the study, adding, “There’s a little something for everybody.”

Indeed, in an editorial that accompanied the studies, Anthony D’Amico, chief of genitourinary radiation oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, emphasized the studies’ finding that surgery and radiation reduced the risk of metastasis and disease progression. “If a man wishes to avoid metastatic prostate cancer and the side effects of its treatment, monitoring should be considered only if he has life-shortening coexisting disease” that might prevent him from living for much longer than 10 years.

Jim Hu, a urologic oncologist at Weill Cornell Medicine, said he was struck by the “significant differences in the likelihood of metastatic disease,” which he said could eventually translate into a survival benefit for the men who got surgery or radiation.

But other physicians said that might not be the case, and that men who got the treatments might die first from other causes, such as heart attacks.

For the British study, more than 82,000 men between 1999 and 2009, ages 50 to 69 were tested with a blood test called PSA, for prostate-specific antigen. About 1,600 were diagnosed with early-stage cancer and agreed to take part in the study. They were randomly assigned to one of three groups: Those who got surgery to remove the prostate, called a radical prostatectomy; those who got radiation; and those who got active monitoring, which researchers described as “less passive” than the “watchful waiting” stance used by many doctors in the United States. Researchers studied mortality rates at 10 years and whether the cancer progressed and spread; a second study addressed the impact of the treatments reported by the men.

Their conclusion was that the three approaches did not translate into “significant differences” in deaths caused by prostate cancer or other causes. “Thus,” they concluded, “longer-term follow-up is necessary.”

Part of the conundrum facing researchers and clinicians is that prostate cancer is both overtreated and undertreated. For years, many doctors say, men were overtreated based on the results of a PSA test. The test can result in “false positives,” or encourage aggressive treatment of malignancies that are so slow-growing that they aren’t a threat. In many cases, men no longer get PSA tests as a routine matter.

However, men still die from prostate cancer – because doctors don’t know which cases will turn into a lethal, metastatic form of the disease. More than 180,000 men in the United States will be diagnosed with prostate cancer this year, and more than 26,000 will die from the disease.

“Everybody is searching for the key to identifying cancers that will progress,” or spread, said Jenny Donovan, a researcher at the University of Bristol who took part in the studies. “We all want to do that.”

Brawley, of the American Cancer Society, noted: “This study has just 10 years of data, and it may take 20 or 25 years to see survival improvements from treatment, so we cannot say yet with certainty whether and how much of an advantage treatment has over no treatment. We can only say that at 10 years, there is no difference.”

 

T he New England Journal of  Medicine 13/7/17

Follow-up of Prostatectomy versus Observation for Early Prostate  Cancer

Timothy J. Wilt, M.D., M.P.H., Karen M. Jones, M.S., Michael J. Barry, M.D., Gerald L. Andriole, M.D., Daniel Culkin, M.D., Thomas Wheeler, M.D., William J. Aronson, M.D., and Michael K. Brawer, M.D.

From the Minneapolis Veterans Affairs (VA) Health Care System and Center for Chronic Disease Outcomes Research and the Section of General Medicine, Univer- sity of Minnesota School of Medicine, Minneapolis (T.J.W.); the VA Cooperative Studies Program Coordinating Center, Perry Point, MD (K.M.J.); the General Medicine Division, Massachusetts Gen- eral Hospital, Boston (M.J.B.); the Divi- sion of Urology, Washington University School of Medicine, St.  Louis  (G.L.A.);  the Department of Urology, University of Oklahoma College of Medicine, Oklahoma City (D.C.); the Department of Pathology and Immunology, Baylor College of Medi- cine, Houston (T.W.); VA Medical Center, Greater Los Angeles Healthcare System, Los Angeles (W.J.A.); and Myriad Genet- ics Laboratories, Salt Lake City (M.K.B.). Address reprint requests to Dr. Wilt  at  the Minneapolis VA Center for Chronic Disease Outcomes Research, 1 Veterans Dr. (111-0), Minneapolis, MN 55417, or at [email protected].

N Engl J Med 2017;377:132-42. DOI: 10.1056/NEJMoa1615869

Copyright © 2017 Massachusetts Medical Society.

BACKGROUND

We previously found no significant differences in mortality between men who under- went surgery for localized prostate cancer and those who were treated with observation only. Uncertainty persists regarding nonfatal health outcomes and long-term mortality.

METHODS

From November 1994 through January 2002, we randomly assigned 731 men with local- ized prostate cancer to radical prostatectomy or observation. We extended follow-up through August 2014 for our primary outcome, all-cause mortality, and the main sec- ondary outcome, prostate-cancer mortality. We describe disease progression, treatments received, and patient-reported outcomes through January 2010 (original follow-up).

RESULTS

During 19.5 years of follow-up (median, 12.7 years), death occurred in 223 of 364 men (61.3%) assigned to surgery and in 245 of 367 (66.8%) assigned to observation (absolute difference in risk, 5.5 percentage points; 95% confidence interval [CI], −1.5 to 12.4; hazard ratio, 0.84; 95% CI, 0.70 to 1.01; P=0.06). Death attributed to prostate cancer or treatment occurred in 27 men (7.4%) assigned to surgery and in 42 men (11.4%) as- signed to observation (absolute difference in risk, 4.0 percentage points; 95% CI, −0.2 to 8.3; hazard ratio, 0.63; 95% CI, 0.39 to 1.02; P=0.06). Surgery may have been associ- ated with lower all-cause mortality than observation among men with intermediate-risk disease (absolute difference, 14.5 percentage points; 95% CI, 2.8 to 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) (P=0.08 for interaction). Treatment for disease progression was less frequent with surgery than with observation (absolute difference, 26.2 percentage points; 95% CI, 19.0 to 32.9); treatment was primarily for asymptomatic, local, or biochemical (prostate- specific antigen) progression. Urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation through 10 years. Disease-related or treatment-related limitations in activities of daily living were greater with surgery than with observation through 2 years.

CONCLUSIONS

After nearly 20 years of follow-up among men with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression. (Funded by the Department of Veter- ans Affairs and others; PIVOT  ClinicalTrials.gov number, NCT00007644.

Prostatectomy vs. Observation for Prostate Cancer

 

We previously reported that rad- ical prostatectomy was not associated with significantly lower all-cause or prostate-cancer mortality than observation with noncurative palliative interventions through 12 years among men with localized prostate cancer detected during the early era of prostate-specific antigen (PSA) testing.1 In light of the protracted disease course and extended survival of many patients, treatment decisions often require infor- mation about additional treatments received, patient-reported outcomes, and very-long-term mortality. Three other randomized trials com- pared radical prostatectomy with observation or PSA-based active monitoring. One older trial showed no significant difference in overall mor- tality.2 Another trial, also conducted before the widespread use of PSA screening, showed differ- ences favoring surgery in all-cause and prostate- cancer mortality of 12.7 and 11.0 percentage points, respectively, with similar differences in the risk of distant metastases at a median follow- up of 13.4 years.3 The most recent trial, involving men with disease detected by PSA screening, showed no significant difference in all-cause or prostate-cancer mortality after a median of 10 years of follow-up among radiation therapy, sur- gery, and PSA-based active monitoring and de- layed radical intervention.4 We report all-cause and prostate-cancer mortality through nearly 20 years of follow-up and describe disease progres- sion, treatments received, and patient-reported outcomes during the original follow-up.

Trial Design

We previously described the design, methods, and baseline results of the Prostate Cancer Interven- tion versus Observation Trial (PIVOT).1,5 The trial was approved by the institutional review board at each site. Patients provided written informed consent. After completion of follow-up through January 2010, we amended the protocol to assess extended all-cause and prostate-cancer mortality. The original and revised protocols, including the statistical analysis plan, are available with the full text of this article at NEJM.org.

Patients

From November 1994 through January 2002, we randomly assigned 731 men with localized pros- tate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatec- tomy or observation at Department of Veterans Affairs and National Cancer Institute medical centers.1,5 Patients had to be medically fit for radical prostatectomy and have histologically confirmed, clinically localized prostate cancer (stage T1-T2NxM0 in the tumor–node–metasta- sis classification system according to the Ameri- can Joint Committee on Cancer6) of any grade diagnosed within the previous 12 months. Pa- tients had to have a PSA value of less than 50 ng per milliliter, an age of 75 years or younger, negative results on a bone scan for metastatic disease, and a life expectancy of at least 10 years. Trial sites assessed eligibility on the basis of lo- cal PSA values and biopsy readings. One of the authors, who is a pathologist, reviewed and re- classified biopsy specimens at a central location. The pathologist was unaware of the long-term fate of the patient and of the original Gleason score assessment at the local center.

Follow-up and Clinical Outcomes

We assessed all-cause and prostate-cancer mor- tality through August 2014, for a minimum of 12 years and a maximum of 19.5 years or until the patient died. Logistic and analytic difficul- ties, including difficulty in obtaining informa- tion about and adjudicating the cause of death, delayed the reporting of findings. An end-points committee whose members were unaware of the trial-group assignments determined the cause of death on the basis of information extracted from the patients’ medical records.1,7 Data on disease progression, treatment received, and patient- reported health outcomes were based on follow- up through January 2010. After January 2010, data on treatment and follow-up were not system- atically collected. We classified progression as local, regional, systemic, or biochemical (PSA) and as symptomatic or asymptomatic (Table S1 in the Supplementary Appendix, available at NEJM.org). We defined treatments as “definitive intervention” (Fig. S1 in the Supplementary Appen- dix), any surgery (including radical prostatectomy), radiation therapy, hormone therapy, chemother- apy, or immunotherapy, and we report treat- ments according to type of disease progression.

Statistical Analysis

Our primary outcome was all-cause mortality. Our secondary outcome was prostate-cancer mortality, which was defined as death that was definitely

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Competing risks, because the Kaplan–Meier method for unadjusted survival analysis yields unreliable results for survival estimates in the presence of competing risks.8-10 We assessed the cumulative incidence of death, between-group differences, and relative risks at 4, 8, 12, and 16 years and at the end of follow-up. P values of less than 0.05 were considered to indicate statistical signifi- cance, with no adjustment for multiple compari- sons. We prespecified seven subgroups accord- ing to baseline characteristics, as described previously1: age, race, coexisting conditions,11 self- reported performance status, PSA level, Gleason score,12 and D’Amico tumor risk score.13 We also assessed mortality outcomes on the basis of central histopathological reclassification. Patient- reported outcomes were analyzed at baseline, 6 months, 1 year, 2 years, 5 years, and 10 years with the use of Fisher’s exact test for categorical outcomes or a t-test for continuous measures. We used SAS software, versions 9.3 and 9.4 (SAS Institute), for the  analyses.14 or probably due to prostate cancer or definitely or probably due to treatment for prostate cancer. End points through January 2010 included the following: local, regional, systemic, and bio- chemical (PSA) progression; additional treat- ments; adverse events requiring treatment; and patient-reported outcomes of urinary inconti- nence, erectile and sexual dysfunction, worry about health, “bother” due to prostate cancer or treatment, physical discomfort, satisfaction with sexual functioning, and functional limitations due to prostate cancer or treatment.

Analyses were performed according to the intention-to-treat principle with the use of Kaplan– Meier methods and corresponding 95% confi- dence intervals. We used the Fine and Gray method to compare groups with respect to prostate-cancer mortality in the presence of  com-

All-Cause and Prostate-Cancer Mortality

As of August 2014, a total of 468 of 731 men (64.0%) had died. The vital status of all the par- ticipants was available, although we were unable to ascertain the cause of death in 7 men (2 as- signed to surgery and 5 to observation). The median follow-up from randomization to death or the end of follow-up was 12.7 years (inter- quartile range, 7.3 to 15.5). All-cause mortality was not significantly lower with surgery than with observation (hazard ratio, 0.84; 95% confi- dence interval [CI], 0.70 to 1.01; P=0.06) (Fig. 1A). The 19.5-year cumulative incidence of death was 61.3% among men assigned to radical prostatec- tomy and 66.8% among those assigned to obser- vation (relative risk, 0.92; 95% CI, 0.82 to 1.02) (Table 1). Absolute differences in risk, although not significant, increased from 3.1 percentage points at 8 years to 5.5 percentage points at the end of follow-up (Table S3 in the Supplementary Appendix). The median survival was 13.0 years (95% CI, 12.5 to 13.5) with surgery and 12.4 years

(95% CI, 11.4 to 12.8) with observation.

Death attributed to prostate cancer or treat- ment occurred in 69 men (9.4%); 65 deaths were attributed to prostate cancer and 4 to treatment. Prostate-cancer mortality was not significantly

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Table 1. Cumulative Incidence of Death from Any Cause through 19.5 Years.*
Variable	Radical Prostatectomy   No. of Events/ Total No.                % (95% CI)		No. of Events/ Total No.	Observation     % (95% CI)	Absolute Difference in  Risk  (95% CI)         percentage points	Relative Risk (95% CI)
Overall	223/364	61.3 (56.2 to 66.1)	245/367	66.8 (61.8 to 71.4)	5.5 (−1.5 to 12.4)	0.92 (0.82 to 1.02)
Age at diagnosis
<65 yr	58/122	47.5 (38.9 to 56.3)	78/131	59.5 (51.0 to 67.6)	12.0 (−0.3 to 23.8)	0.80 (0.63 to 1.01)
≥65 yr	165/242	68.2 (62.1 to 73.7)	167/236	70.8 (64.7 to 76.2)	2.6 (−5.7 to 10.8)	0.96 (0.86 to 1.09)
Race†
White	150/232	64.7 (58.3 to 70.5)	155/220	70.5 (64.1 to 76.1)	5.8 (−2.8 to 14.3)	0.92 (0.81 to 1.04)
Black	64/111	57.7 (48.4 to 66.4)	75/121	62.0 (53.1 to 70.1)	4.3 (−8.2 to 16.7)	0.93 (0.75 to 1.15)
PSA
≤10 ng/ml	140/238	58.8 (52.5 to 64.9)	151/241	62.7 (56.4 to 68.5)	3.8 (−4.9 to 12.5)	0.94 (0.81 to 1.08)
>10 ng/ml	83/126	65.9 (57.2 to 73.6)	93/125	74.4 (66.1 to 81.2)	8.5 (−2.8 to 19.6)	0.89 (0.75 to 1.04)
Risk category‡
Locally assessed
Low	82/148	55.4 (47.4 to 63.2)	83/148	56.1 (48.0 to 63.8)	0.7 (−10.5 to 11.8)	0.99 (0.81 to 1.21)
Intermediate	77/129	59.7 (51.1 to 67.8)	89/120	74.2 (65.7 to 81.2)	14.5 (2.8 to 25.6)	0.80 (0.67 to 0.96)
High	55/77	71.4 (60.5 to 80.3)	59/80	73.8 (63.2 to 82.1)	2.3 (−11.5 to 16.1)	0.97 (0.80 to 1.17)
Centrally assessed
Low	58/111	52.3 (43.0 to 61.3)	67/122	54.9 (46.1 to 63.5)	2.7 (−10.0 to 15.2)	0.95 (0.75 to 1.21)
Intermediate	97/155	62.6 (54.7 to 69.8)	99/139	71.2 (63.2 to 78.1)	8.6 (−2.2 to 19.1)	0.88 (0.75 to 1.03)
High	55/78	70.5 (59.6 to 79.5)	63/85	74.1 (63.9 to 82.2)	3.6 (−10.0 to 17.2)	0.95 (0.79 to 1.15)

* PSA  denotes  prostate-specific antigen.

† Race was reported by the participants.

‡ The risk category was determined according to the D’Amico risk score, which is based on tumor stage, histologic score, and PSA level. lower with radical prostatectomy than with observation (hazard ratio, 0.63; 95% CI, 0.39 to 1.02; P= 0.06) (Fig. 1B). The cumulative incidence of death due to prostate cancer or treatment was 7.4% with surgery and 11.4% with observation (absolute  difference, 4.0  percentage points; 95% CI, −0.2 to 8.3) (Table 2). Relative and absolute differences in risk remained stable after 12 years (Table S4 in the Supplementary Appendix). Death that was considered to be definitely due to prostate cancer or treatment occurred in 18 men (4.9%) assigned to surgery and 22 men (6.0%) assigned to observation.

 

Subgroup Analyses

The effect of surgery on mortality did not differ significantly according to baseline patient characteristics (Fig. 2A and 2B and Tables 1 and 2, and Tables S3 and S4 in the Supplementary Appendix). Among men younger than 65 years of age, the absolute difference in all-cause mortal- ity between the surgery group and the observation group increased from −1.5 percentage points (95% CI, −11.7 to 8.5) at 8 years to 12.0 percent- age points (95% CI, −0.3 to 23.8) at the end of follow-up. Among men 65 years of age or older, the absolute difference at the end of follow-up was 2.6 percentage points (95% CI, −5.7 to 10.8). The effect of surgery on all-cause mortality may have differed according to baseline PSA value (P = 0.06 for interaction) and tumor risk category (P= 0.08 for interaction) (Fig. 2A and Table 1, and Table S3 in the Supplementary Appendix). Surgery was not associated with lower

 

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Table 2. Cumulative Incidence of Death from Prostate Cancer through 19.5 Years.   Variable   Radical Prostatectomy   No. of Events/ Total No.              % (95% CI)       No. of Events/ Total No.   Observation     % (95% CI) Absolute Difference in  Risk  (95% CI)         percentage points Relative Risk (95% CI) Overall 27/364 7.4 (5.2 to 10.6) 42/367 11.4 (8.6 to 15.1) 4.0 (−0.2 to 8.3) 0.65 (0.41 to 1.03) Age at diagnosis <65 yr 9/122 7.4 (3.9 to 13.4) 15/131 11.5 (7.1 to 18.0) 4.1 (−3.4 to 11.5) 0.64 (0.29 to 1.42) ≥65 yr 18/242 7.4 (4.8 to 11.5) 27/236 11.4 (8.0 to 16.1) 4.0 (−1.3 to 9.4) 0.65 (0.37 to 1.15) Race White 17/232 7.3 (4.6 to 11.4) 28/220 12.7 (9.0 to 17.8) 5.4 (−0.2 to 11.1) 0.58 (0.32 to 1.02) Black 8/111 7.2 (3.7 to 13.6) 11/121 9.1 (5.2 to 15.6) 1.9 (−5.6 to 9.2) 0.79 (0.33 to 1.90) PSA ≤10 ng/ml 16/238 6.7 (4.2 to 10.6) 23/241 9.5 (6.4 to 13.9) 2.8 (−2.2 to 7.9) 0.70 (0.38 to 1.30) >10 ng/ml 11/126 8.7 (4.9 to 15.0) 19/125 15.2 (10.0 to 22.5) 6.5 (−1.7 to 14.7) 0.57 (0.29 to 1.16) Risk category Locally assessed Low 6/148 4.1 (1.9 to 8.6) 8/148 5.4 (2.8 to 10.3) 1.4 (−3.9 to 6.7) 0.75 (0.27 to 2.11) Intermediate 11/129 8.5 (4.8 to 14.6) 19/120 15.8 (10.4 to 23.4) 7.3 (−0.9 to 15.7) 0.54 (0.27 to 1.08) High 10/77 13.0 (7.2 to 22.3) 15/80 18.8 (11.7 to 28.7) 5.8 (−5.9 to 17.2) 0.69 (0.33 to 1.45) Centrally assessed Low 1/111 0.9 (0.2 to 4.9) 8/122 6.6 (3.4 to 12.4) 5.7 (0.5 to 11.6) 0.14 (0.02 to 1.08) Intermediate 14/155 9.0 (5.5 to 14.6) 12/139 8.6 (5.0 to 14.5) −0.4 (−7.0 to 6.5) 1.05 (0.50 to 2.18) High 10/78 12.8 (7.1 to 22.0) 20/85 23.5 (15.8 to 33.6) 10.7 (−1.3 to 22.3) 0.54 (0.27 to 1.09)

all-cause mortality than observation among men with a PSA value of 10 ng per milliliter or less or among those with low-risk or high-risk cancers but may have been associated with lower mortal- ity among men with a PSA value of more than 10 ng per milliliter or among those with intermedi- ate-risk disease. Among men with low-risk dis- ease, the absolute difference in risk between the trial groups was 0.7 percentage points (95% CI, −10.5 to 11.8). Among men with intermediate- risk tumors, the absolute difference in risk was 14.5 percentage points (95% CI, 2.8 to 25.6). The absolute difference in risk was smaller and not significant among men with disease that was determined to be intermediate-risk on the basis of central (rather than local) Gleason  grading.

 

 

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A Death from Any Cause
Radical			P Value for
Subgroup                  Observation          Prostatectomy	Hazard Ratio (95% CI)		Interaction
no. of events/total no.
Overall                        245/367              223/364		0.84 (0.70–1.01)
Age			0.56
<65 yr                        78/131                58/122		0.73 (0.52–1.02)
≥65 yr                       167/236              165/242		0.88 (0.71–1.09)
Race			0.87
White                       155/220              150/232		0.82 (0.66–1.03)
Black                         75/121                64/111		0.87 (0.62–1.22)
Other                         15/26                   9/21		0.64 (0.28–1.46)
PSA			0.06
≤10 ng/ml                 151/241              140/238		0.91 (0.72–1.14)
>10 ng/ml                  93/125                83/126		0.73 (0.54–0.98)
Risk			0.08
Low                           83/148                82/148		0.98 (0.72–1.33)
Intermediate                  89/120                77/129		0.68 (0.50–0.92)
High                          59/80                  55/77		0.78 (0.54–1.13)
Charlson score			0.79
0                             128/220              117/224		0.84 (0.65–1.07)
≥1                            117/147              106/140		0.85 (0.65–1.10)
Performance status			0.55
0                             200/310              184/312		0.84 (0.69–1.03)
1–4                            45/57                  39/52		0.83 (0.54–1.28)
Gleason score			0.84
<7                            167/261              145/254		0.82 (0.65–1.02)
≥7                             63/86                  68/98		0.83 (0.59–1.17)
	0.1                        0.5                  1.0                 1.5
	Radical Prostatectomy Better  Observation Better
B Death from Prostate Cancer
Radical			P Value for
Subgroup                  Observation          Prostatectomy	Hazard Ratio (95% CI)		Interaction
no. of events/total no.
Overall                         42/367                27/364		0.63 (0.39–1.02)
Age			0.99
<65 yr                        15/131                 9/122		0.63 (0.28–1.43)
≥65 yr                        27/236                18/242		0.63 (0.35–1.15)
Race			0.49
White                        28/220                17/232		0.55 (0.30–1.01)
Black                         11/121                 8/111		0.78 (0.32–1.91)
Other                         3/26                   2/21		0.82 (0.14–4.65)
PSA			0.62
≤10 ng/ml                  23/241                16/238		0.70 (0.37–1.32)
>10 ng/ml                  19/125                11/126		0.54 (0.26–1.13)
Risk			0.89
Low                            8/148                  6/148		0.74 (0.26–2.13)
Intermediate                  19/120                11/129		0.53 (0.25–1.11)
High                          15/80                  10/77		0.64 (0.29–1.41)
Charlson score			0.44
0                              25/220                19/224		0.72 (0.40–1.31)
≥1                             17/147                 8/140		0.49 (0.21–1.13)
Performance status			0.61
0                              35/310                24/312		0.66 (0.40–1.11)
1–4                             7/57                   3/52		0.47 (0.12–1.80)
Gleason score			0.97
<7                             20/261                12/254		0.60 (0.30–1.24)
≥7                             21/86                  15/98		0.59 (0.30–1.13)
	0.1                         0.5         1.0        2.0             5.0
	Radical Prostatectomy Better  Observation Better

 

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Table 3. Disease Progression and Treatment for Disease Progression or Adverse Events (Original Follow-up).
Variable	Radical Prostatectomy                   Observation (N= 364)                                 (N= 367)   number (percent)		Absolute Difference (95%  CI)   percentage points	Hazard Ratio (95% CI)
Disease progression*
Local, regional, or systemic  progression
Any	149 (40.9)	251 (68.4)	27.5 (20.4 to 34.2)	0.39 (0.32 to 0.48)
Asymptomatic	89 (24.4)	161 (43.9)	19.4 (12.6 to 26.0)	0.46 (0.35 to 0.59)
Local progression
Any	124 (34.1)	227 (61.9)	27.8 (20.7 to 34.5)	0.37 (0.29 to 0.46)
Asymptomatic	61 (16.8)	119 (32.4)	15.7 (9.5 to 21.7)	0.43 (0.32 to 0.59)
Regional progression
Any	33 (9.1)	52 (14.2)	5.1 (0.4 to 9.8)	0.60 (0.39 to 0.92)
Asymptomatic	22 (6.0)	30 (8.2)	2.1 (−1.7 to 6.0)	0.69 (0.40 to 1.20)
Systemic progression
Any	37 (10.2)	54 (14.7)	4.5 (−0.3 to 9.4)	0.64 (0.42 to 0.97)
Asymptomatic	25 (6.9)	38 (10.4)	3.5 (−0.6 to 7.6)	0.62 (0.37 to 1.03)
Treatment for disease progression†
For any reason	122 (33.5)	219 (59.7)	26.2 (19.0 to 32.9)	0.45 (0.36 to 0.56)
For increasing or persistently elevated PSA value	74 (20.3)	139 (37.9)	17.5 (11.0 to 23.9)	0.46 (0.34 to 0.61)
For local progression	45 (12.4)	93 (25.3)	13.0 (7.3 to 18.5)	0.44 (0.31 to 0.63)
For regional progression	2 (0.5)	3 (0.8)	0.3 (−1.3 to 1.9)	0.64 (0.11 to 3.82)
For systemic progression	17 (4.7)	32 (8.7)	4.0 (0.4 to 7.8)	0.49 (0.27 to 0.88)
Adverse events requiring treatment‡
Erectile dysfunction	53 (14.6)	20 (5.4)	−9.1 (−13.5 to −4.8)	2.77 (1.65 to 4.63)
Incontinence	63 (17.3)	16 (4.4)	−12.9 (−17.5 to −8.6)	4.22 (2.44 to 7.30)
Other	45 (12.4)	41 (11.2)	−1.2 (−5.9 to 3.5)	1.08 (0.71 to 1.65)

* Disease progression was defined according to the trial protocol as the time to evidence of disease progression or persistence. Progression  was classified according to clinical stage (local, regional, or systemic) and whether asymptomatic or causing clinical signs or symptoms.

† Data reflect recorded treatments and indications for treatment on the basis of clinical stage, including an increasing or persistently elevated PSA level. A patient could be counted as having received treatment for more than a single type of disease progression.

‡ Data are based on treatments with a known start date.

Exploratory analyses in men with T1c (nonpal- pable, PSA-detected) tumors, including those with a PSA value of more than 10 ng per milliliter or a Gleason score of 7 or more (on a scale from 2 to 10, with 10 indicating the most poorly differen- tiated tumors), showed nonsignificant differ- ences in all-cause and prostate-cancer mortality between the surgery group and the observation group (Tables S3 and S4 in the Supplementary Appendix). Few deaths from prostate cancer or treatment occurred among men with T1c tumors, and confidence intervals were wide (Tables S3 and S4 in the Supplementary Appendix).

Disease Progression and Additional Treatments

Fewer men assigned to surgery had disease pro- gression or received additional treatment than men assigned to observation (Table 3, and Figs. S2 through S4 in the Supplementary Appendix). Any progression occurred in 40.9% of the men assigned to surgery versus 68.4% of the men as- signed to observation. Most disease progression was local, and approximately half the cases of local progression were asymptomatic. Definitive treatment occurred in 20.4% of the men assigned to observation, rarely after 5 years of follow-up,

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and in 85.5% of the men assigned to surgery, almost all occurring within 1 year (Fig. S1 in the Supplementary Appendix). Treatment for cancer progression, mostly for asymptomatic, local, or PSA progression, occurred in 33.5% of the men assigned to surgery and in 59.7% of the men as- signed to observation (Table 3, and Fig. S3 in the Supplementary Appendix). Androgen-deprivation therapy was less frequent among men assigned to surgery than among those assigned to obser- vation (21.7% vs. 44.4%). The absolute difference in the risk of systemic progression or treatment for systemic progression was approximately 4 per- centage points, in favor of surgery.

The frequency of treatment for local progres- sion was lower with surgery than with observa- tion in all tumor risk groups. Among men with low-risk disease, treatment for regional or sys- temic disease was infrequent and did not differ significantly between the surgery group and the observation group. Among men with intermedi- ate-risk disease, the frequency of treatment for systemic progression was lower with surgery than with observation (5.4% vs. 11.7%). Among men with high-risk disease, the frequency of treat- ment for an increasing or persistently elevated PSA value was lower with surgery than with observation (33.8% vs. 52.5%), but there was no significant difference with respect to treatment for regional or systemic progression. (Details re- garding treatment according to progression type and tumor risk category are provided in Fig. S4 in the Supplementary Appendix.) Physician-pre- scribed treatment for erectile dysfunction and urinary incontinence due to prostate-cancer pro- gression or treatment was more common with surgery than with observation (Table  3).

Patient-Reported Outcomes

Patient-reported overall health, physical or men- tal health assessed with the use of the Medical Outcomes Study 12-Item Short-Form General Health Survey (SF-12), and worry about health did not differ significantly between the groups. As compared with men assigned to observation, men assigned to surgery were more likely to re- port bother due to prostate cancer or treatment, physical discomfort, and limitations in activities of daily living through 2 years but not at later time points. The use of absorbent pads because of incontinence was greater through 10 years in men treated with surgery than in those assigned

to observation; absolute differences exceeded 30 percentage points at all time points. Erectile dys- function as well as decreases in sexual function, activity, interest, and satisfaction were much greater through 5 years in men assigned to sur- gery than in those assigned to observation. De- tails on patient-related outcomes are provided in Figures S5 through S9 and Tables S5 through S7 in the Supplementary Appendix.

After nearly 20 years, the absolute difference in all-cause mortality between men assigned to sur- gery and those assigned to observation was less than 6 percentage points, and the absolute dif- ference in prostate-cancer mortality was 4 per- centage points. The extended follow-up yielded slightly greater differences in mortality favoring surgery than those described earlier, although the differences remained nonsignificant.1,14-16 The frequencies of disease progression and treatment for disease progression were lower with surgery than with observation, although most events of progression were asymptomatic, local, or bio- chemical. There were large, long-term differ- ences in urinary incontinence and erectile and sexual dysfunction in favor of observation and smaller, shorter-term differences in adverse ef- fects with respect to physical function and activi- ties of daily living.

Although relative differences in prostate-cancer mortality between the trial groups appeared to be larger, absolute differences were small, both relative and absolute differences were nonsignifi- cant, and statistical measures were not adjusted for multiple comparisons; such an adjustment would have further reduced the levels of signifi- cance of the differences.17 We encourage readers to focus on absolute differences in risk and cor- responding confidence intervals.14-16 The differ- ence was 1 percentage point when the end point was death that was considered to be definitely due to prostate cancer or treatment. Using all- cause mortality as our primary end point avoid- ed pitfalls in cause-of-death  ascertainment.7,18

We urge caution in interpreting subgroup effects.19 Our trial was not powered to detect small differences between subgroups, but significant results may be due to multiple analyses.17 If differences in all-cause mortality exist, they were confined to men with intermediate-risk disease

 

 

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and depend on histopathological classification methods. For men with low-risk or high-risk disease, differences in all-cause mortality were 3 percentage points or less and were not signifi- cant. Surgical effects on mortality did not vary according to patient factors.

Most treatment for disease progression was for local, asymptomatic reasons, especially in- creasing or persistently elevated PSA values. Among men assigned to surgery, 41% had dis- ease progression and 34% received treatment for disease progression. There were few differences in quality of life and worry about health between the surgery group and the observation group. Long-term erectile and sexual dysfunction and urinary incontinence and physician-directed treat- ment were substantially greater with surgery than with observation. Functional limitations and bother due to prostate cancer or treatment were greater with surgery than with observation through at least 2 years, whereas worry about health was less at 10 years.

Our findings are generally consistent with those of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4)3,20 and the Prostate Testing for Cancer and Treatment (ProtecT) trial.4,21 SPCG-4, like PIVOT, compared surgery with ob- servation, whereas the ProtecT trial compared surgery or radiation with active monitoring and delayed radical intervention based primarily on PSA results without surveillance biopsies. Data from randomized trials are lacking to assess biopsy-based active surveillance, the predominant active-monitoring practice in the United States. PIVOT involved men who received a diagnosis of prostate cancer, and who used treatments avail- able, in the United States during the early era of PSA testing,1,5 a midpoint between the era before PSA testing (SPCG-4) and the later era of PSA testing (the ProtecT trial). Mortality differences across these studies may reflect differences in patient age and coexisting conditions but more likely reflect differences in the natural history of prostate cancer that are related to detection methods and possibly treatment approaches, including improvements in medical treatment for progressive disease. Only 9.4% of PIVOT participants died from prostate cancer. The absolute difference in all-cause mortality between the trial groups was 5.5 percentage points in favor of surgery, and the absolute difference in prostate-cancer mortality was 4.0  percentage points. In the ProtecT trial, mortality and the incidence of metastatic disease (which included asymptomatic disease detected by surveillance imaging and biochemical [PSA] testing) as well as absolute differences between the trial groups in favor of radical intervention (1 percentage point for mortality and 4 percentage points for metastatic-disease incidence) were much lower through 10 years than in SPCG-4 or PIVOT.

Our results, together with those of SPCG-4, the ProtecT trial, and two earlier trials that showed no mortality benefits of surgery2 or radia- tion22 as compared with observation, have clini- cal implications. First, they show that long-term prostate-cancer mortality remains low among most men with localized prostate cancer who are treated with observation and that death from prostate cancer is very uncommon among men with low-risk and low-PSA disease. Reducing over- treatment is needed. Men with low-risk and PSA- based screening–detected disease can safely avoid harms and costs of early radical intervention or of biopsy-guided active surveillance with delayed radical treatment.4,21,23 Observation, PSA-based monitoring, and active surveillance with delayed radical intervention remain infrequently used, even among older men,24-26 despite a frequency of metastatic progression of less than 3%,27 prostate- cancer mortality of 1% or less,28-31 and cost-effec- tiveness that is superior to that with early radical intervention.23,32 PSA-based monitoring and biopsy- based active-surveillance programs should reduce the frequency of surveillance biopsy and increase biopsy and PSA thresholds that trigger radical interventions.

Second, surgery may have mortality benefits in some men, particularly those with intermediate risk prostate cancer who have long life expectancies. However, the comparative effects of active surveillance and PSA-based monitoring in many men with intermediate-risk disease should be examined. In addition, the risk of progression or death as well as the absolute treatment benefit diminish while overtreatment harms increase in men with smaller-volume, screening-detected lower-risk cancers. Beneficial effects depend on proper histopathological grading, which is fraught with interobserver and intraobserver variation. Revisions in Gleason grading and risk-score clas- sification systems have resulted in an upgrading of prostate cancers that are classified today, as compared with those in men enrolled in PIVOT.

 

 

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Prostatectomy vs. Observation for Prostate Cancer

This has led to more men being classified with intermediate-risk or high-risk disease, resulting in fewer men being considered eligible for ob- servation or active  monitoring.33-36

Third, although men with high-risk disease have a poor prognosis, surgery may not provide large benefits with respect to mortality. Safer and more effective options are needed. Fourth, surgery is associated with a decreased risk of disease progression and treatment for disease progression. However, most progression is asymptomatic, local, or biochemical, for which the treatment benefit is uncertain. Among men with low-risk disease in our trial, the frequency of treatment for regional or systemic progression was not significantly lower with surgery than with observation. Reducing treatment for asymptomatic progression would decrease harms and costs, with little, if any, effect on mortality. Fifth, surgery causes perioperative and longer- term adverse effects, some requiring treatment. Nonetheless, regardless of the initial treatment, we found few differences between the trial groups in long-term bother, physical discomfort, worry about health, overall health, or limitations in activities due to prostate cancer or treatment.

Differences in satisfaction with sexual functioning remained significant through 5 years.

In conclusion, radical prostatectomy was not associated with significantly lower all-cause or prostate-cancer mortality than observation through 20 years of follow-up among men with localized prostate cancer that was diagnosed during the early era of PSA testing. Absolute differences remained below 6 percentage points. Death from prostate cancer was very uncommon among men with low-risk disease who were assigned to observation. Surgery may be associated with de- creased mortality among men with intermediate- risk prostate cancer, depending on the pathological classification. Surgery resulted in substantially greater long-term urinary incontinence and erec- tile and sexual dysfunction than observation and was associated with a significantly lower risk of disease progression and additional treatments, most for local or asymptomatic biochemical progression.

Supported by the Department of Veterans Affairs, the Agency for Healthcare Quality and Research, and the National Cancer Institute.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org

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