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Active surveillance safe for favorable-risk prostate cancer
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Active surveillance appeared safe and feasible for patients with favorable-risk prostate cancer, according to long-term follow-up of a prospective single-arm cohort study.
Active surveillance has gained acceptance for patients with favorable-risk prostate cancer because it may reduce the risk for overtreatment of clinically insignificant disease, while still allowing for definitive therapy for patients whose risk appears to increase over time. However, long-term follow-up on this approach is lacking, according to background information provided by researchers.
In the current study, Laurence Klotz, MD, FRCS(C), chief of the division of urology at Sunnybrook Health Sciences Centre and professor in the department of surgery at the University of Toronto, and colleagues reported long-term outcomes of a large cohort of men who underwent active surveillance.
The study included 993 men (median age, 67.8 years; range, 41-89) with favorable- or intermediate-risk prostate cancer treated at a single academic health sciences center.
Researchers measured patients’ PSA levels in stable patients every 3 months for 2 years, and every 6 months thereafter. Intervention was offered for those whose PSA levels doubled in less than 3 years, those who demonstrated Gleason score progression and those who demonstrated unequivocal Gleason score progression.
About one-quarter of patients (28.6%; n=267) required intervention. The most common reasons for intervention were short PSA doubling time, grade progression and patient preference.
At the time of analysis, 149 (15%) patients had died, including 15 (1.5%) who died from prostate cancer. All 15 patients who died from prostate cancer had developed metastatic disease.
Another 25 patients were lost to follow-up. Of the 819 patients who were still alive at the time of analysis, median follow-up from first biopsy was 6.4 years (range, 0.2-19.8).
Researchers reported cause-specific survival rates of 98.1% at 10 years and 94.3% at 15 years.
Thirteen patients (1.3%) developed metastatic disease; of these patients, nine remained alive with confirmed metastases at the time of analysis and four had died of other causes.
The percentage of patients who remained untreated and on surveillance was 75.7% at 5 years, 63.5% at 10 years, and 55% at 15 years.
Researchers calculated a cumulative HR for nonprostate-to-prostate cancer mortality of 9.2 to 1.
“Active surveillance for favorable-risk and select early intermediate-risk prostate cancer is feasible and seems to be safe over 15 years,” Klotz and colleagues concluded. “This strategy provides the benefit of a personalized approach based on the demonstrated risk of clinical or biochemical progression with time … Although prostate cancer mortality increased with longer followup, only 2.8% of patients have developed metastatic disease and 1.5% have died of prostate cancer. These findings are consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.”
Although the results showed how many men in a surveillance cohort died of prostate cancer, they do not show how many ultimately died because they opted for surveillance and “thereby missed the window of opportunity for cure,” Matthew R. Cooperberg, MD, MPH, associate professor of urology, epidemiology and biostatistics at University of California, San Francisco, wrote in an accompanying editorial.
“Whatever this number truly is, it is greater than zero,” Cooperberg wrote. “These deaths by definition are preventable, and as sins of omission are particularly galling to cancer-focused clinicians. But in the alternative paradigm of immediate intervention for all low-risk tumors, they are vastly outnumbered by men harmed substantially by entirely avoidable treatments.”
The effort to reduce overtreatment must be balanced with attempts to identify patients with potentially lethal tumors while at a curable stage, Cooperberg wrote.
“The future of active surveillance — and of prostate cancer treatment in general — must be found at the frontiers of precision medicine,” Cooperberg said. “Both the timing and intensity of intervention should be customized based on maximal information reflecting clinical tumor characteristics; patient health and comorbidity; and, where appropriate, novel imaging and genomic assessment. Prostate cancer has evolved to a diagnosis now recognized to reflect an extraordinary range of biology and prognostic risk, and its management must reflect this diversity.”
Disclosure: See the full study for a list of the researchers’ relevant financial disclosures.
Perspective
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Maha Hussain
John Wei
The widespread use of PSA has been a “double-edged sword” for American men. On the one side of the blade, there has been a significant stage migration toward lower-risk, organ-confined disease. This likely is the reason why we have observed such a remarkable and continued reduction in prostate cancer mortality (Siegel R, et al. CA Cancer J Clin. 2014;doi:10.3322/caac.21208).
On the other side, there has been a significant increase in the number of what many refer to as “clinically insignificant” or latent prostate cancers. In the vast majority of these cases, reflexive, definitive therapy unlikely will improve survival for the majority, yet these patients are offered surgical or radiation therapies that may inflict physical harms and result in increased health care costs. Although this problem may someday be resolved through the use of early-detection panels of biomarkers (Prensner JR, et al. Sci Transl Med. 2012;doi:10.1126/scitraslmed.3003180. Prensner JR, et al. Curr Opin Genet Dev. 2009;doi:10.1016/j.gde.2008.11.008) and precise image-guided biopsies (Bjurlin MA, et al. J Urol. 2014;doi:10.1016/j.juro.2014.03.117), to date there are no such validated tools that can predict with high accuracy the disease’s natural history at an individual patient level.
To minimize overtreatment, passive strategies around the concept of “active surveillance” have been promulgated and it is now widely accepted as standard of care for low-grade, low-volume prostate cancer (Kawachi MH, et al. J Natl Compr Canc Netw. 2010;8:240-262). Indeed, the literature is full of variations on active surveillance strategies attesting to the lack of a validated standard. In general, men with newly diagnosed stage T1c, Gleason 6 disease will be monitored with regular PSA testing and serial biopsies until their comorbid risks exceed their cancer mortality risks. Although one could argue that such strategies are better than treating everyone with prostate cancer, long-term data on risks, benefits and cost-effectiveness from prospective clinical trials compared with immediate therapy are lacking (Perloth DJ, et al. J Natl Cancer Inst Monogr. 2012;doi:10.1093/jncimonographs/lgs037). It is within this context that we find the study by Klotz and colleagues very encouraging.
In this long-term follow-up study, there were few deaths related to prostate cancer (1.5%). The 10-year actuarial cause-specific survival rate was 98.1%, and the 15-year rate was 94.3%. Metastatic disease developed in only 2.8% of patients. The majority of patients remained untreated and on surveillance at 5 years (75.7%), 10 years (63.5%) and 15 years (55%). The authors concluded that “active surveillance for favorable-risk prostate cancer is feasible and seems safe within the 15-year time frame that the observed mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.” Although this Canadian experience may not be replicated in every setting, it may represent the best outcomes reported to date for active surveillance.
About the same time when this report was published, our cancer center was consulted on a gentleman in his 70s who was being actively followed for a low-grade, low-volume prostate cancer with a low PSA. He did well until late 2014, when his annual PSA increased from 1.3 ng/mL to 34 ng/mL and he was found to have locoregionally advanced cancer. In retrospect, his surveillance may have been not as “active” as it should have been, resulting in missed opportunities to treat the cancer when initial progression occurred. However, although this case initially fell within the parameters of the Klotz trial, this gentleman now faces an incurable — and likely morbid — cancer outcome.
The prudent clinician should remain wary of the highly variable nature of prostate cancer and — until we can precisely identify high-grade cancers when they occur, or can cure advanced cancers systemically — a large dose of caution is warranted.
Maha Hussain, MD, FACP, FASCO
HemOnc Today Editorial Board member
University of Michigan Comprehensive Cancer Center
John Wei, MD, MS
University of Michigan Comprehensive Cancer Center
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