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Active monitoring, treatment confer comparable prostate cancer–specific survival
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Active monitoring demonstrated comparable rates of disease-specific mortality but worse rates of disease progression and metastases compared with surgery and radiotherapy for localized prostate cancer, according to the results of the randomized ProtecT trial.
Further, patient-reported outcomes varied considerably across the three treatment platforms.
“Men with newly diagnosed, localized prostate cancer need to consider the clinical trade-off between the short-term and long-term effects of radical treatments on urinary, bowel and sexual function and the higher risks [for] disease progression with active monitoring, as well as the effects of each of these options on quality of life,” Freddie C. Hamdy, MBChB, MD, FRCS, FMedSci, professor of surgery and professor of urology at University of Oxford’s Nuffield Department of Surgical Sciences, and colleagues wrote.
Treatment outcomes
Approximately 180,000 men in the United States will be diagnosed with prostate cancer by PSA testing in 2016, and 26,000 men will die of the disease.
However, the appropriate treatment platform for men diagnosed based on PSA levels is controversial.
“The widespread use of PSA testing has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer, but many men do not benefit from intervention because the disease is either indolent or disseminated at diagnosis,” Hamdy and colleagues wrote. “Prostate cancer often progresses slowly, and many men die of competing causes. In addition, interventions for prostate cancer can have adverse effects on sexual, urinary or bowel function.”
Hamdy and colleagues conducted the Prostate Testing for Cancer and Treatment (ProtecT) trial to observe disease-specific outcomes based on treatment platform in men with newly diagnosed localized prostate cancer.
A total of 82,249 men received a PSA test between 1999 and 2009, of whom 2,664 received a diagnosis of localized prostate cancer.
Sixty-two percent (n = 1,643; median age, 62 years; range, 50-69) of diagnosed men consented to enter the ProtecT study. The researchers randomly assigned men to active monitoring (n = 545), radical prostatectomy (n = 553) or external-beam radiotherapy (n = 545).
Active monitoring consisted of serum PSA level testing every 3 months in the first year on study, followed by testing every 6 months to 12 months thereafter. Men with an increase of at least 50% during the previous 12 months received a review and were presented with management options, including continued monitoring with further testing, radical prostatectomy or radiotherapy, or palliative services.
Prostate cancer–specific mortality — defined as death definitely or probably caused by prostate cancer — at a median of 10 years’ follow-up served as the primary endpoint.
Seventeen prostate cancer–specific deaths occurred during follow-up. This included eight men in the active monitoring arm (1.5 deaths per 1,000 person-years; 95% CI, 0.7-3), five men assigned surgery (0.9 deaths per 1,000 person-years; 95% CI, 0.4-2.2) and four men assigned radiotherapy (0.7 deaths per 1,000 person-years; 95% CI, 0.3-2).
Additionally, the rates of death by any cause did not significantly differ by group (active monitoring, n = 59; surgery, n = 55; radiotherapy, n = 55).
Two hundred four men experienced disease progression, most of whom had been assigned active monitoring (n = 112). Forty-six men in each treatment arm progressed (P < .001 for comparison).
Thirty-three men assigned active monitoring experienced disease progression with metastases, compared with 13 men assigned surgery and 16 men assigned radiotherapy (P = .004 for comparison).
No men died due to surgical complications; however, nine developed thromboembolic or cardiovascular events, and 14 required a transfusion of more than three units of blood. Other surgical complications included rectal injury (n = 1) and anastomotic problems requiring intervention (n = 9).
Three men died within 90 days after completing radiotherapy.
A total of 291 men initially assigned active monitoring received a radical intervention (surgery, n = 142; radiotherapy, n = 97; brachytherapy, n = 22).
“Further follow-up of the ProtecT participants with longer-term survival data will be crucial to evaluate this trade-off in order to fully inform decision-making for physicians and patients considering PSA testing and treatment options for clinically localized prostate cancer,” Hamdy and colleagues wrote.
Variations in incontinence, sexual health
Because few patient-reported outcomes data exist with regard to localized prostate cancer treatment options, the ProtecT trial also included an analysis of patient-reported outcomes based on therapy assignment.
“Systematic reviews and studies involving large, prospective cohorts have shown particular effects on urinary, bowel and sexual function and little effect on general quality of life after radical treatments, but clear comparisons among contemporary treatments have been hindered by differences in outcome definitions, limited use of validated outcome measures, mostly short-term follow-up, and sparse data on radiotherapy or active surveillance programs,” the researchers wrote. “Randomized clinical trials have not included the full range of validated patient-reported outcome measures.”
Men enrolled in the ProtecT trial completed initial questionnaires at diagnosis, at 6 months and 12 months following random assignment, and annually thereafter.
The response rate remained higher than 85% throughout follow-up for most outcome measures. Fifty-five men (3.3%) ceased returning questionnaires, and some men failed to complete all questions.
Men assigned prostatectomy reported the greatest negative effect on urinary continence at 6 months and had worse urinary incontinence at all time points (P < .001).
One percent of men assigned prostatectomy reported use of absorbent pads at baseline, which increased to 46% at 6 months; 4% of men assigned active monitoring and 5% of men assigned radiotherapy reported using pads at 6 months.
Seventeen percent of men who underwent prostatectomy reported using pads at year 6 of follow-up, compared with 8% of men on active monitoring and 4% of men who underwent radiotherapy.
Although the effect of urinary incontinence on quality of life was initially worse for men assigned prostatectomy, the effect became similar to other groups after 2 years. All groups reported an increase in nocturia.
Sixty-seven percent of men reported the ability to sustain an erection firm enough for intercourse at baseline; at 6 months, the percentage decreased to 52% among men assigned active monitoring, 22% of men assigned radiotherapy and 12% of men assigned prostatectomy (P < .001).
Erection rates remained lowest among men who underwent prostatectomy, decreasing to 17% after 6 years of follow-up.
Men in the radiotherapy and active monitoring arms also reported declines in erectile functioning. Twenty-seven percent of men in the radiotherapy group and 30% of men on active monitoring reported erections firm enough for intercourse at 6 years.
Men assigned radiotherapy reported worse outcomes related to bowel function and bother at 6 months, whereas men assigned prostatectomy and active monitoring did not report significant changes from baseline.
Although the percentage of men reporting fecal incontinence and loose stools remained similar in all groups, a greater percentage of men assigned radiotherapy reported bloody stool from year 2 of follow-up onward (P < .001).
The researchers did not observe a significant difference in health-related quality of life between treatment groups at year 5 of follow-up.
“[U]nderstanding the effects of the treatments and how the treatments affect men’s lives [is] crucial for decision making,” Hamdy and colleagues wrote. “The patient-reported outcome measures in the ProtecT trial included key domains that were recommended by international groups, and we followed reporting guidelines to provide unbiased comparisons of the effects of standardized prostatectomy, radiotherapy and active monitoring strategies for PSA–detected clinically localized prostate cancer.”
Individual treatment preferences
Although definitive answers to the best approaches for prostate cancer have not been reached, these reports can help guide clinicians and patients as they plan treatment, Anthony V. D’Amico, MD, PhD, professor of radiation oncology at Harvard Medical School and chief of genitourinary radiation oncology at Dana-Farber Cancer Institute, wrote in an accompanying editorial.
“For today, we can conclude on the basis of level-one evidence that PSA monitoring, as compared with treatment of early prostate cancer, leads to increased metastasis,” D’Amico wrote. “Therefore, 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 such that his life-expectancy is less than the 10-year median follow-up of the current study.”
Because prostate cancer with surgery compared with radiation conferred no significant difference in death, “men with low-risk or intermediate-risk prostate cancer should feel free to select a treatment approach using the data on health-related quality of life and without fear of possibly selecting a less effective cancer therapy,” he added. – by Cameron Kelsall
References:
D’Amico AV. N Engl J Med. 2016;doi:10.1056/NEJMoa1610395.
Donovan JL, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1606221.
Hamdy FC, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1606220.
Disclosures: Hamdy reports grant support from the National Institute for Health Research, Health Technology Assessment Programme during the conduct of the study. Please see the full study for a list of all other researchers’ relevant financial disclosures. D’Amico reports no relevant financial disclosures.
Perspective
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Jay Ciezki
Prostate cancer is different from so many other cancers, because it has a very long natural history. Recent coverage has tried to respond to PSA screening studies, whereas other coverage has attempted to suggest every treatment option is essentially the same in terms of outcomes. The biggest outcomes difference is the metastatic disease burden, which was very different in each of the arms of this study. This is so important because people are focusing on OS and disease-specific mortality — which will probably be eventually affected by the differences in metastatic burden — but because of the long history of prostate cancer, it will probably take years for that data to show itself.
Before then, there are important issues that could probably be better addressed in future publications. The difference in metastatic burden by treatment arm has a lot to do with quality-of-life outcomes that have not been assessed. The toxicity analysis presented here deals with gastrointestinal and genitourinary adverse events, but because metastatic disease is treated with systemic therapies like hormone therapy and chemotherapy, there are additional adverse events that go well beyond these domains. So, the main issue at this point is probably not going to be related to mortality at this point, but really should address the effects on overall quality of life. Future studies should focus on domains such as hematologic toxicity, performance status and other factors associated with long-term systemic therapy.
Further, any real-world analysis needs to address cost. Because many patients with prostate cancer are going to live for a long time, and receive many drug courses, this needs to be taken into account when deciding the best treatment options. Certain maintenance and systemic therapies can cost much more than an upfront therapy, especially when repeated over time.
It would be wonderful to see a cost analysis added to the literature, because it could help address how overall treatment is approached. When a patient makes a choice today, we do not necessarily know what is going to happen 10 years from now. If they are not cured of their disease, what downstream ramifications will there be for additional therapies, and what effects will they have on the medical system in terms of cost and quality of life? Prostate cancer is a disease that begs these questions, and it would be extremely beneficial to have an answer.
Disclosure: Ciezki reports no relevant financial disclosures.
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