ASCO 2010-ACTIVE SURVEILLANCE SAFE IN EARLY PROSTATE CANCER

June 18, 2010 (Chicago Illinois) — The results of 2 new studies of men with low-risk prostate cancer on active surveillance should provide some confidence for the clinicians using this disease management approach.

The 2 studies, one published in a major journal and the other presented here at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting, differ in design and the outcomes they measure. However, in both cases, their findings shed light on the risks involved when low-risk men forgo active treatment.

The first study is a nationwide population-based cohort from Sweden published online June 18 in the Journal of the National Cancer Institute.

The observational study compared low-risk and intermediate-risk men treated with active surveillance or watchful waiting with men who underwent either radical prostatectomy or radiation therapy.

The Swedish investigators retrospectively found that in men with low-risk localized prostate cancer (T1, Gleason score ≤6, and prostate-specific antigen [PSA] <10 ng/mL), 10-year prostate-cancer-specific mortality was 2.4% (95% confidence interval [CI], 1.2% - 4.1%) in the 1085 patients in the surveillance group and 0.7% (95% CI, 0.3% - 1.4%) in the 1601 patients in the treatment group.

The study "adds to the growing list of population-based studies with data on long-term outcomes" for men with localized disease, note Siu-Long Yao, MD, and Grace Lu-Yao, PhD, in an editorial that accompanies the study. Dr. Yao is from Merck Research Laboratories in Kenilworth, New Jersey, and Dr. Lu-Yao is from the Cancer Institute of New Jersey at the University of Medicine and Dentistry of New Jersey in New Brunswick.

"Probably the most remarkable finding from this study and several previous studies, however, is the realization that survival in most (e.g., Gleason ≤7 disease), but not all (e.g., Gleason 8–10), patients with localized disease managed conservatively is now similar to that of age-matched control subjects," write the editorialists, referring to men managed with active surveillance compared with low-risk men treated with either surgery or radiotherapy.

A higher proportion of healthy patients were assigned to treatment and therefore might have produced worse outcomes in the active surveillance group, suggest the authors, led by Pär Stattin, MD, PhD, from Umeå University Hospital in Sweden. "Patients with a short life expectancy were more often selected for surveillance than for surgery or radiation therapy," they write.

Nevertheless, attempts to adjust for this in the statistical analyses did not produce risk estimates that were "materially different" from unadjusted analyses, report the authors.

The Swedish investigators conclude that the strategy of active surveillance "appears to be suitable for many of these men," referring to those with low-risk disease.

However, Dr. Stattin and colleagues warn that the median follow-up in the study was 8.2 years and because "most patients currently diagnosed with localized prostate cancer are aged 60 to 70 years and have a life expectancy of more than 15 years, longer follow-up is needed."

Study of Surgical Outcomes in Men on Active Surveillance

Another study of men with low-risk prostate cancer was presented at the ASCO meeting.

The single-center study (Johns Hopkins in Baltimore, Maryland) compared the surgical outcomes of low-risk men treated with active surveillance who eventually underwent a delayed radical prostatectomy for their disease with the surgical outcomes of low-risk men who underwent immediate surgery.

In this study, investigators asked whether active surveillance compromises the likelihood of cure in men with low-risk prostate cancer who choose this strategy initially but eventually undergo radical prostatectomy.

The answer depends on the circumstances that cause a man to eventually undergo surgery, explained Bruce Trock, PhD, MPH, from Johns Hopkins University School of Medicine.

Since 1995, 772 men have enrolled in the active surveillance program at Johns Hopkins, which is the largest cohort in the United States, said Dr. Trock.

He explained that the program has one of the "most conservative criteria" among these cohorts. Namely, eligible men must have a biopsy Gleason score of 6 or less, 2 or fewer positive cores, 50% or less involvement of any core with cancer, and a PSA density of less than 0.15.

The men are rebiopsied annually and any increase in the above biopsy parameters triggers a recommendation for treatment.

At a median follow-up of 2 years, 116 (15%) men have undergone delayed surgery — 43 because of a higher Gleason score at repeat biopsy, 48 because of some other biopsy change, and 25 because of a personal decision to switch.

The surgical pathology of these 116 patients was compared with the surgery outcomes of 348 men who underwent surgery immediately.

The investigators found that the 116 men initially managed with active surveillance who then switched to surgery were significantly more likely to have a nonorgan-confined tumor (P = .009) and a high-grade tumor (P = .0001) than matched men who underwent surgery immediately.

However, this apparent bad news is largely explainable and is balanced out by another finding in the study, Dr. Trock reported.

"When men with low-risk disease have surgery at any time, we have found historically that about 25% of them will actually have a higher-grade tumor than found by biopsy," he said.

This happens because a "biopsy is the result of randomly sticking needles into the prostate" he said. "The portion of the prostate being biopsied is a very small portion of the whole organ," he explained, adding that breast cancer biopsies, for example, are much more accurate because they are guided by imaged or palpable lesions.

So the Johns Hopkins investigators did an additional analysis: they excluded 43 of the 116 men who had upgraded Gleason scores of 7 or more at a follow-up biopsy. The found that the remaining 73 men had "surgical pathology outcomes similar to the immediate radical prostatectomy patients."

This is good news about active surveillance, noted Dr. Trock.

"Men in active surveillance who continue to show a low-grade tumor by Gleason score at follow-up biopsies have about the same risk of finding a higher-grade tumor at surgery as those men who have immediate surgery," he explained.

Dr. Trock reported that in the entire cohort of the 772 men on active surveillance at Johns Hopkins, the risk of a high-grade tumor at follow-up biopsy or radical prostatectomy is 7.3% per year of follow-up.

Because there was a median follow-up of 2 years among the men who switched to surgery, there is another important finding here, said Dr. Trock. "The risk of a high-grade tumor does not increase with the length of time a man is in the active surveillance program prior to surgery," he said.

The study suggests, said Dr. Trock, that "most high-grade tumors found in [active surveillance] men at surgery were present at the time of diagnosis but were undergraded by their diagnostic biopsy, as opposed to progressing from a lower-grade tumor during the delay prior to surgery." However, Dr. Trock noted that it is not clear whether disease progression took place and, if it did, in what percentage of men.

The Swedish Study was funded by the Swedish Research Council, the Swedish Cancer Foundation, and the Västerbotten County Council. The editorial was funded by a grant from the National Institutes of Health. Dr. Yao is an employee of Merck. Dr. Trock has disclosed no relevant financial relationships.

J Natl Cancer Inst. Published online June 18, 2010.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract 4506. Presented June 6, 2010.