Because prostate cancer is often indolent and its treatment can negatively affect quality of life, active surveillance is an attractive disease management option for many patients with early-stage, low-risk disease. But the optimal selection criteria for active surveillance remain undefined. An ongoing clinical trial at The University of Texas MD Anderson Cancer Center may uncover prognostic factors for disease progression and clarify which patients are likely to benefit from active surveillance.
“Over the past decade, the proportion of patients with low-risk prostate cancer whose disease is managed by active surveillance rather than surgery, radiation, or other treatments has gone from 10% to 40%,” said Jeri Kim, M.D., a professor in the Department of Genitourinary Medical Oncology. “But there are no established selection criteria for active surveillance.”
Dr. Kim and John Davis, M.D., an associate professor in the Department of Urology, are the co-principal investigators of an ongoing trial designed to help define these criteria. The trial recently completed its enrollment of more than 1,100 patients, and the investigators have begun analyzing preliminary data.
In 2006, the trial began enrolling patients with recently diagnosed, early-stage (i.e., clinically localized) prostate cancer who expressed a preference for active surveillance. All patients underwent baseline PSA (prostate-specific antigen) tests and, since 2007, transrectal ultrasound-guided biopsies of 11 cores.
Favorable-risk disease was defined as a PSA level below 4 ng/mL and a biopsy core with either (a) a tumor length less than 3 mm and a Gleason score less than or equal to 6 or (b) a tumor length less than 2 mm, a Gleason score of 7, and no dominant Gleason grade 4 (i.e., poorly differentiated) component. Patients with favorable-risk disease were classified as group 1. Patients who did not meet the criteria for favorable-risk disease were placed in group 2 if they were candidates for surgery or radiation therapy but chose active surveillance or in group 3 if they had comorbidities that precluded surgery or radiation therapy.
The trial’s endpoints include 5- and 10-year progression-free survival rates as well as quality of life as measured by questionnaires. Concurrent studies of biomarkers for disease progression also are under way.
“There’s no standard monitoring schedule for active surveillance,” Dr. Kim said. “Different active surveillance studies worldwide may use different schedules and even different surveillance tests.” The tests and monitoring schedule for the trial were based on the active surveillance schedule that is typically used at MD Anderson.
In the trial, patients undergo a digital rectal examination and a blood draw for PSA testing every 6 months; at this time patients also answer a quality-of-life questionnaire. Transrectal ultrasound-guided biopsies of 11 cores are performed at the end of the first year and then every 1–2 years, depending on disease characteristics.
Patients in the trial will continue this surveillance schedule until disease progression, or “reclassification,” occurs. Indications for disease reclassification are a 30% increase in PSA level or biopsy findings that indicate progression, such as an increase in Gleason score, increase in tumor length or volume in a positive biopsy core, or additional positive cores. If a patient’s disease is reclassified, the patient will be offered surgery or radiation therapy.
Predictors of disease reclassification
To evaluate variables as sociated with disease reclassification in patients with the favorable-risk profile, Drs. Kim and Davis and their colleagues conducted a preliminary analysis of outcomes for 191 patients from group 1. At a median follow-up of 3 years, disease remained stable in 159 (83%) of the 191 patients and was reclassified in 32 (17%). All 32 of these patents had their disease reclassified on the basis of biopsy results. A multivariable analysis of baseline characteristics found that tumor length of 1 mm or greater in a biopsy core was a significant predictor (P = .007), older age was a marginal predictor (P = .05), and PSA level was not a predictor of disease reclassification.
More recently, the researchers analyzed the outcomes of 808 patients: 246 from group 1 and 562 from group 2. The study’s results are not yet published, but Dr. Kim said that multivariable analysis showed that tumor length of 1 mm or greater in a core from the diagnostic or confirmatory biopsy performed at enrollment and assignment to group 2 were predictors of reclassification. As in the previous analysis, PSA level was not a predictor of disease reclassification. Over a 5-year surveillance period, patients with more than one positive biopsy core with a tumor length of 3 mm or more and a Gleason score of 6 or 7 at enrollment were twice as likely as patients in the favorable-risk group to have their disease reclassified.
If confirmed by analyses that include 5- and 10-year survival data, the findings from these two preliminary analyses could lead to less stringent and less invasive monitoring for patients without predictors of disease reclassification. “Our preliminary data indicate that patients with certain tumor characteristics can have less frequent biopsies,” Dr. Kim said. “We’re learning a lot from this study, including how to reduce the use of invasive procedures while maintaining safety.”
Quality of life
Another goal of the trial is to document changes in patients’ quality of life during active surveillance for prostate cancer. Drs. Kim and Davis and their colleagues analyzed the scores of quality-of-life questionnaires completed over 2.5 years by 180 patients in group 1. These questionnaires assessed disease-specific and general quality of life as well as anxiety and illness uncertainty.
The mean overall scores for both disease-specific and general quality of life remained stable; only the scores regarding sexual function decreased. Dr. Kim noted that this decrease was statistically but not clinically significant. Scores for anxiety and illness uncertainty improved over time. “These findings suggest that patients tend to maintain their quality of life during active surveillance,” Dr. Kim said. “But we need data for longer follow-up times.”
Drs. Kim and Davis are planning another study that will compare quality of life in patients undergoing different prostate cancer treatments with that of patients undergoing active surveillance.
A biomarker analysis of blood samples from 542 patients from groups 1 and 2 showed that high baseline levels of caveolin-1, a component of the caveolae and cellular membrane that is secreted by prostate cancer cells, were associated with disease reclassification during active surveillance. If validated, this finding—which Drs. Kim and Davis and their colleagues reported at the 2016 meeting of the American Society of Clinical Oncology—could lead to the use of caveolin-1 levels, in conjunction with baseline clinical and pathological parameters, to select patients for active surveillance.
Future diagnostic and surveillance tools
Although the potential prognostic factors and biomarkers for disease reclassification revealed in the trial’s preliminary analyses are a few years away from validation and clinical use, some existing techniques could be applied to improve patient selection for active surveillance. For example, Dr. Kim said that multiparametric magnetic resonance imaging (MRI), which combines functional MRI with anatomical T1-weighted and T2-weighted MRI, and MRI-ultrasound fusion biopsy have improved the detection of clinically significant prostate cancers.
She added that commercially available genetic tests can give information about the aggressiveness of a patient’s disease, a patient’s 10-year mortality risk, or—used in conjunction with the patient’s National Comprehensive Cancer Network risk stratification—the likelihood of finding favorable pathology results at prostatectomy. These techniques could soon become standard risk assessment tools for prostate cancer.
“The newer technologies will help improve the initial risk stratification to filter out those patients who may need active treatment,” Dr. Kim said. “But for the most part, men on active surveillance with current technology are doing well. Men with low-risk prostate cancer should consider active surveillance as a management option.”
For more information, contact Dr. Jeri Kim at 713-563-7237 or firstname.lastname@example.org.
Parker PA, Davis JW, Latini DM, et al. Relationship between illness uncertainty, anxiety, fear of progression and quality of life in men with favourable-risk prostate cancer undergoing active surveillance. BJU Int. 2016;117:469–477.
Davis JW, Ward JF III, Pettaway CA, et al. Disease reclassification risk with stringent criteria and frequent monitoring in men with favourable-risk prostate cancer undergoing active surveillance. BJU Int. 2016;118:68–76.
OncoLog, July 2017, Volume 62, Issue 7