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  
  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 and metastases data in an earlier version of this story.

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