Proceed With Caution Is the Message on Active Surveillance

Mitchell C. Benson, MD, PhD

Active surveillance is increasingly employed in men diagnosed with low-risk prostate cancer despite a lack of high-level clinical trial evidence supporting this approach, and physicians should engage in careful patient selection before recommending the strategy, according to Mitchell C. Benson, MD.

That note of caution was among the key points that Benson stressed during a presentation on localized prostate cancer that he delivered at the 8th Annual Interdisciplinary Prostate Cancer Congress in New York City.

“In terms of local therapies, radiation therapy and radical surgery remain effective treatments but it’s the active surveillance that we have to be most careful of if we want to do no harm to our patients,” said Benson, who is the Herbert and Florence Irving Professor at Columbia University Medical Center, New York-Presbyterian Hospital.

“The question is, can we delay treatment without compromising curability and that’s the dilemma,” Benson said in an interview. “We need to make sure that we are not compromising curability and we don’t know that with 100% certainty.”

Treatment Patterns and Evidence

Benson said that the proportion of newly diagnosed patients who do not undergo radiation or surgery has increased dramatically in recent years. Researchers who examined two large US databases found that noncurative initial management for patients with low-risk disease increased from 13%-21% in 2004, depending on the database, to 20%-32% in 2010.¹

Yet although the use of the strategy has increased, the supporting evidence is derived primarily from expert opinion or bench research and not from randomized clinical trials, said Benson.

“Although there is a tremendous amount of information and stress and urgency to not treat, the reality is that we don’t have a lot of level 1 evidence that no treatment is the appropriate thing,” he said. “We’re being pushed toward active surveillance and we really don’t know with any degree of certainty that we’re not doing harm.”

Indolent prostate cancer has been defined since 1994 as a Gleason score ≤6, PSA density <0.150 ng/mL/g, <3 cores involved, and <50% of any single core involved,² Benson noted.

Several studies have supported active surveillance for this patient population, Benson noted. He said Dall’Era et al³ found a low rate of prostate cancer—specific mortality ranging from 0.2% to 1% in a study of patient outcomes from seven institutions. However, Benson said the median follow-up was short, ranging from 1.8 years to 6.8 years.

Benson pointed instead to a study of long-term outcomes of 945 patients with low- or intermediate-risk prostate cancer who were managed with an active surveillance protocol at Sunnybrook Health Sciences Centre in Toronto between 1995 and 2013.⁴ Intermediate risk was defined as a PSA >10ng/ml, Gleason score 7, or clinical stage T2b/2c.

Patients with an intermediate risk experienced lower rates of overall survival compared with low-risk patients at 10 years (68.4% vs 83.6%, respectively) and at 15 years (50.3% vs 68.8%, respectively).

Notably, Benson said, intermediate-risk patients had a lower rate of prostate cancer—specific survival (CSS). The CSS rates for intermediate-risk patients were 95.5% at 10 years and 88.5% at 15 years, compared with 98.2% at 10 years and 96.3% at 15 years for low-risk patients. That translated into a CSS risk that was 3.75 times higher for patients in the intermediate group, Benson said.

“We can do a good job even with intermediate-risk disease as it relates to prostate cancer specific survival but the numbers are getting small, the confidence intervals are stretching, so we have to be careful,” said Benson.

Benson sharply criticized the conclusions of another study, the PIVOT trial, which found that radical prostatectomy did not significantly reduce all-cause mortality compared with observation among men with localized prostate cancer through 12 years’ follow-up.⁵ He said the conduct of the trial and the patient selection were seriously flawed. “This study should never have been accepted for publication,” he said.

Selection Strategies

Benson said genetic analysis of the “true biologic behavior” of prostate cancer would eventually help clarify which patients should appropriately be recommended for active surveillance. Gene signature tests that assess risk can be used to help support decisions, he added.

As it stands now, Benson said clinicians could improve patient selection by augmenting the standard evaluation through more extensive biopsies. He said a single transrectal ultrasonography should not be used to select patients for active surveillance. “Saturation biopsy improves risk stratification,” he said, adding that he performs an immediate confirmatory biopsy at presentation.

Benson and colleagues conducted a study of confirmatory biopsies in 60 patients with low-grade prostate cancer and found that 31.7% (19 patients) would not be candidates for active surveillance based on the results.⁶

Words of Caution

In an interview, Benson offered succinct advice for clinicians. “My main take-home message is: Choose your patients wisely and do it with a dialogue.”

He said he goes through a PowerPoint presentation with his patients to help them understand the factors in choosing active surveillance versus active treatment, including their biological and chronological age and the details of their disease. “Going on active surveillance is a risk assessment,” said Benson. “Active surveillance doesn’t mean no treatment ever. It just means no treatment now and that’s an important thing for the patient to understand.”

Benson also noted that some patients will choose active surveillance against the advice of their doctors. “You have to have a long informed consent with that patient. And if the patient is insistent on active surveillance and you think that that patient is not a good candidate for active surveillance, I think you have to very carefully document that in your medical record—that the patient chose that active surveillance against best medical advice,” said Benson.

References

1. Weiner AB, Patel SG, Etzioni R, Eggener SE. National trends in the management of low and intermediate risk prostate cancer in the United States [published online August 5, 2014]. J Urol. 2015;193(1):95-102.
2. Epstein JI, Walsh PC, Brendler CB. Radical prostatectomy for impalpable prostate cancer: the Johns Hopkins experience with tumors found on transurethral resection (stages T1A and T1B) and on needle biopsy (stage T1C). J Urol. 1994;152(5 Pt 2):1721-1729.
3. Dall’Era MA, Albertsen PC, Bangma C, et al. Active surveillance for prostate cancer: a systematic review of the literature [published online June 7, 2012]. Eur Urol. 2012;62(6):976-983.
4. Musunuru HB, Klotz L, Vespirini D, et al. Cautionary tale of active surveillance in intermediate-risk patients: overall and cause-specific survival in the Sunnybrook experience. J Clin Oncol. 2015;33(suppl 7;abstr163).
5. Witt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer (PIVOT). N Engl J Med. 2012;367(3):203-213.
6. Motamedinia P, RiChard JL, McKiernan JM, et al. Role of immediate confirmatory prostate biopsy to ensure accurate eligibility for active surveillance. Urology. 2012;80(5):1070-1074.

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