Active Surveillance Key to Limiting PSA-Related Overtreatment, but Remains Difficult Sell

E. David Crawford, MD

Active surveillance for low-grade prostate cancer has long been considered the elusive “holy grail” for mitigating the overtreatment effect of PSA screening. At the 2013 IPCC®, E. David Crawford, MD, provided an overview of active surveillance and discussed a few potential methods for increasing its use.

Patients commonly misinterpret active surveillance as “doing nothing.” In actual clinical practice, “[It] means that you’re going to individualize management, you’re going to follow these patients, and if you need to, you’re going to jump in early with the idea that you’re going to cure them,” explained Crawford, professor of Surgery and Radiation Oncology, and head of the Section of Urologic Oncology at the University of Colorado Denver School of Medicine, as well as associate director of the University of Colorado Comprehensive Cancer Center, also in Denver.

Crawford said that one of the difficulties with convincing patients to choose active surveillance is that treatment is highly effective. A seminal paper by Eggener et al found that in a population of over 12,000 men with low-grade prostate cancer (usually Gleason 6) treated with radical prostatectomy, the 20-year prostate cancer specific mortality was 0.2% (J Urol. 2011. 185[3];869-875). However, the key issue, according to Crawford, is whether all of these patients actually needed the surgery. The treatment is associated with serious comorbidities (eg, urinary incontinence and sexual dysfunction), and research has demonstrated that active surveillance can be equally effective in the appropriate patients.

In the PIVOT trial, men with localized prostate cancer were randomized to radical prostatectomy or observation. The results showed that there was no significant difference between the two approaches in terms of prostate-cancer mortality (N Engl J Med. 2012;367[3]:203-213). Additionally, Crawford said, “If you look at the hazard ratios [in the PIVOT data] and focus on who might benefit, what is seen is that with most low-risk cancers…[outcomes were] powerfully in favor of observation.”

Other clinical trial results have supported use of active surveillance, as well. According to Crawford, if you pool the results from the key active surveillance trials, you can collect data from nearly 3000 men with a reasonable follow-up period. Among these men, the cancer-specific survival rate at 10 years is 99.7%.

Identifying Candidates for Active Surveillance

The one drawback with this evidence, Crawford noted, is that the data are retrospective. A definitive randomized trial was attempted by US and Canadian researchers; however, the study failed due to an inability to accrue patients.Crawford said that patient selection is paramount to successful outcomes with active surveillance. Although there are no standard guidelines for identifying ideal candidates, a few widely-used methodologies have emerged.

One is the D’Amico classification, developed by Anthony V. D’Amico, MD, PhD, Dana-Farber/Harvard Cancer Center. D’Amico’s criteria include a Gleason score ≤6, a PSA ≤10, and a tumor stage of T1c-2a (JAMA. 1998;280[11]:969-974).

Another popular set of criteria was developed by Jonathan Epstein, MD, at The James Buchanan Brady Urological Institute at Johns Hopkins. Epstein’s more refined standards include a Gleason score ≤6, stage T1c cancer, a PSA density <0.15, <3 cores with cancer, “and/ or cancer involving no more than 50% of any core on at least a 12 core biopsy.”

The NCCN Prostate Cancer Guidelines factor age into these classifications as well: life expectancy <10 years when using D’Amico criteria and <20 years when using Epstein criteria.

Table. When Is Active Surveillance Appropriate?¹

Risk

Expected Survival

Initial Therapy

Very Low (Epstein Criteria)²

Low (D’Amico Criteria)³

<20 years

<10 years

Active Surveillance Preferred⁴

Very Low (Epstein Criteria)²

Low (D’Amico Criteria)

≥20 years

≥10 years

1. Active Surveillance⁵

2. Radiotherapy

3. Radical Prostatectomy

¹Based on NCCN Guidelines.

²Stage T1c; Gleason ≤6; PSA <10 ng/mL; <3 positive prostate biopsy cores, ≤50% cancer in any core; PSA density <0.15 ng/mL/g.

³Stage T1-T2a; Gleason ≤6; PSA <10 ng/mL.

⁴Monitor patient’s PSA at least every 6 months and do DRE at least every 12 months. For Very Low risk also do a repeat prostate biopsy as often as every 12 months.

⁵Monitor patient’s PSA at least every 6 months, do DRE at least every 12 months, and do a repeat prostate biopsy as often as every 12 months.

Source: Crawford ED. Active surveillance: pros, cons, and optimal candidates. Presented at: 6th Annual Interdisciplinary Prostate Cancer Congress; March 16, 2013; New York, NY.

Following Patients and Triggers for Intervention

Other factors involved when considering active surveillance include the general health of the patient, side effects associated with treatment, and the patient’s personal preference.There are no standard guidelines for how to follow patients on active surveillance or when to intervene with treatment.

The NCCN Prostate Cancer Guidelines suggest monitoring strategies correlating to both the D’Amico and the Epstein classifications (Table). Regarding intervention triggers, the NCCN Guidelines state that treatment is “recommended in most men who demonstrate a Gleason grade of 4 or 5 on repeat biopsy, have cancer in a greater number or greater extent of prostate biopsies, or have a PSA doubling time of less than 3 years.”1

Laurence Klotz, MD, chief of Urology at Sunnybrook Health Sciences Centre and professor of Surgery at the University of Toronto, established another well-known list of intervention trigger points for patients on active surveillance: PSA doubling time <3 years, Gleason score progression to ≥4+3, or unequivocal clinical progression.

Crawford noted that PSA kinetics can be unreliable and should be used as a guide only in monitoring patients. He said several studies have gone even further and questioned any use of PSA kinetics.

What Causes Active Surveillance Failure?

For example, Vickers et al conducted a systematic review of 87 studies and wrote in their conclusion, “There is little evidence that calculation of PSA velocity or doubling time in untreated patients provides predictive information beyond that provided by absolute PSA level alone” (J Clin Oncol. 2009;27[3]:398-403).Crawford described several issues that can lead to the failure of active surveillance.

He said that the transrectal biopsies that are used to stage patients lack sufficient accuracy and specificity. “We do random transrectal biopsies and we base life and death decisions on them…We need more information— people fail because they are inaccurately staged to begin with.”

Inadequate biopsy sampling of the anterior region of the prostate has been associated with active surveillance failure (J Urol. 2009;182(5):2274-2278). Transrectal ultrasound (TRUS)—guided prostate biopsies are usually directed at the posterior region, explained Crawford, so “missed significant cancers are usually anterior.”

Crawford said that several new methods are being employed to enhance the consistency and accuracy of biopsies to get a better idea of what is happening in the patient’s prostate.

In his practice, Crawford has been using the template biopsy. In this procedure, a grid template covers the perineum, and, guided by transrectal ultrasound, biopsies (40-80 cores) are obtained from specific areas of the prostate. The results are used to reconstruct a 3D image of the prostate that shows the location of the tumor cells.

Increasing Use of Active Surveillance

Crawford said that in the future, genetic markers will be used in screening, prognosis, and treatment selection to improve the overall management of prostate cancer.Crawford said that despite the positive evidence and the serious comorbidities associated with treatment, it remains difficult to convince a newly diagnosed patient that active surveillance may be his best option.

Part of the problem may be with communication. “If you tell someone they are on fire, they run for a fire extinguisher. We need to communicate a different message,” said Crawford. He noted that consideration is being given to renaming low-grade prostate cancer (Gleason ≤6); not using the term cancer might reduce patients’ fear and make them more willing to choose active surveillance.

Treatment of patients by multidisciplinary teams has also been shown to increase rates of active surveillance. “[With] multidisciplinary clinics versus individual practice, twice as many people undergo active surveillance,” Crawford said.

1. National Comprehensive Cancer Network. NCCN Guidelines Version 2.2013: Prostate Cancer. http://bit.ly/NCCN_ Prostate. Accessed April 14, 2013