MOST MEN WITH LOW RISK PROSTATE CANCER GET HIGH RISK TREATMENT

July 26, 2010 — A majority of men with newly diagnosed low-risk prostate cancer choose to undergo aggressive local intervention with either radical prostatectomy or radiation therapy, despite the high risk for complications and adverse effects and the availability of active surveillance as an alternative.

These conclusions, drawn from a study published in the July 26 issue of the Archives of Internal Medicine, once again illustrate the problems of overtreatment of prostate cancer, say experts contacted by Medscape Medical News.

In the study, Grace L. Lu-Yao, PhD, and colleagues from the Cancer Institute of New Jersey, in New Brunswick, analyzed data from the Surveillance, Epidemiology, and End Results database and found 123,934 men with prostate cancers that were newly diagnosed between 2004 and 2006.

The researchers found that 14% of the men had prostate-specific antigen levels lower than 4.0 ng/mL — the widely accepted threshold for recommending biopsy. Of this group, 54% had low-risk disease features, including disease confined within one half of 1 lobe of the prostate (stage T2a or less), Gleason score of 6 or less, and a PSA of 10 ng/mL or less.

Yet more than three fourths of all patients with PSAs lower than 4.0 ng/mL elected to undergo radical prostatectomy or radiation therapy. The team found that 44% of men with PSAs lower than 4.0 ng/mL underwent radical prostatectomy, and 33% had radiation.

"Our study found that aggressive local therapy was provided to most patients diagnosed as having prostate cancer," Dr. Lu-Yao and colleagues write.

"These results underscore the fact that PSA level, the current biomarker, is not a sufficient basis for treatment decisions. Without the ability to distinguish indolent from aggressive cancers, lowering the biopsy threshold might increase the risk of overdiagnosis and overtreatment," the investigators write.

Men with cancers detected by screening had a significantly lower risk of having high-grade disease compared with men with cancers detected by other means (odds ratio [OR] for screening, 0.67; 95% confidence interval [CI], 0.60 - 0.76), but the screen-detected cancers in men with PSAs lower than 4 were significantly more likely to be treated with either surgery (OR, 1.49; 95% CI, 1.38 - 1.62) or radiation (OR, 1.39; 95% CI, 1.30 - 1.49).

The same group of researchers has previously reported that conservative management of prostate cancer diagnosed in the age of PSA — from the 1990s on — had better outcomes than conservative management of disease diagnosed in the 2 previous decades, possibly because of "additional lead time, overdiagnosis related to PSA testing, grade migration, or advances in medical care" (JAMA. 2009;302(11):1202-1209).

Informed Discussions Best Antidote to Overdiagnosis, Overtreatment

An informed discussion between physician and patient is the best means for ensuring that patients get the appropriate treatment for their disease stage and grade, says coauthor Robert S. DiPaola, MD, from the Cancer Institute of New Jersey, and associate dean for oncology programs and professor of medicine at University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School in Piscataway, in an interview with Medscape Medical News.

"It's not because we would say there's some cutoff here, because there are men diagnosed with prostate cancer who have PSAs less than 2 or 2.5 [ng/mL]. I think it really needs to be an informed discussion over biopsy vs no biopsy, based on a number of different parameters, including exam, prostate size, perhaps ultrasound, PSA velocity, and PSA level related to age," he said.

Armed with that information, the clinician can then discuss with the patient his prognosis and his options for therapy.

"For example: A man 75 [years old] or so with an average, say, stage T1c tumor would have about a 10% chance of dying from prostate cancer in his lifetime, and based on that they can discuss whether that warrants for him radical prostatectomy or radiation. Obviously, for younger men we tend to err on the side of local therapy," Dr. DiPaola says.

He cautions, however, that there are as yet no reliable means for accurately determining risks for individual patients, which is why many men who might otherwise die from other causes still undergo aggressive therapies.

"A Frightening Piece of Information"

A proponent of active surveillance of low-risk prostate cancer patients tells Medscape Medical News that overdiagnosis and overtreatment of prostate cancer is a major problem for urologists, oncologists, and patients today.

"I think if you look around the country at what's happening with prostate cancer management in general, young men have surgery, and they're overwhelmingly more likely to have surgery than radiation treatment, and what we're trying to do is find those who don't need either," says Donald S. Kaufman, MD, director of the Claire and John Bertucci Center for Genitourinary Cancers at Massachusetts General Hospital in Boston.

"The business of taking people who are younger with PSAs that are lower and have biopsies that show cancer and then have surgery is actually a piece of frightening information which we're all aware of, and this paper brings it out very nicely," he says.

Lowering guideline-recommended PSA cutoffs to 2.5 or 2.0 ng/mL, as has been proposed in recent years, would make a bad situation even worse, and could result in an additional 400,000 cases of prostate cancer, "and God knows who's going to take care of them, except that if they did nothing it would be better," Dr. Kaufman adds.

Philip Kantoff, MD, director of the genitourinary cancer program at the Dana-Farber Cancer Institute in Boston, agrees.

"There is a changing tide in the field through the recognition of a variety of studies, including this one, that a substantial number of people, particularly in the good-risk category with good-risk features, don't require treatment but have been getting treatment, and we need to improve our ability to identify these people and to figure out reasonable strategies for following them," Dr. Kantoff tells Medscape Medical News.

Not "Watchful Waiting" but "Active Surveillance"

Although many men balk at the idea of waiting around for something to happen — a common perception of traditional "watchful waiting" — active surveillance, with yearly or biannual biopsies, digital rectal exams, and PSA testing every 3 to 6 months, can be an effective alternative for many men with low-risk prostate cancers, say Richard M. Hoffman, MD, MPH, from the New Mexico VA Health Care System and University of New Mexico School of Medicine in Albuquerque, and Steven B. Zeliadt, PhD, from the VA Puget Sound Health Care System and University of Washington in Seattle, in an accompanying editorial.

"Active surveillance is considered an acceptable alternative for men with cancers at low risk for progression as defined by a PSA level of 10 ng/mL or lower, a Gleason score of 6 or lower, and a clinical stage of T1c or T2a," they write. "For men who select active surveillance, the choice to undergo deferred treatment remains available and can be based on evidence of disease progression (rising PSA level, increasing Gleason score, and/or an abnormal [digital rectal exam] finding) and/or patient preference."

Active surveillance should not be restricted to men 65 years and older, because many younger men will also have biopsy-proven cancer that would otherwise not cause them problems during their lives, Dr. Kaufman says.

"I see so many highly intelligent young men who come in having had a biopsy which shows a minimal amount of Gleason 6 cancer, and they'll say 'I have cancer and I want it out — I don't want to hear about it and I don't want to talk about it,' " Dr. Kaufman says. "A lot of those patients listen to us and end up having active surveillance."

His center recommends active surveillance in about 25% to 30% of men with newly diagnosed prostate cancer, and "if you follow a precise active surveillance program, as we have our patients do, nobody gets into trouble," he says.

The study was sponsored by grants from the National Cancer Institute, Cancer Institute of New Jersey, and Robert Wood Johnson Foundation. The authors, editorialists, Dr. Kaufman, and Dr. Kantoff have disclosed no relevant financial relationships.

Arch Intern Med. 2010;170:1256-1261.