Treating prostate cancer, Part III: Active surveillance

Although cancer remains the second leading cause of death in the United States, doctors have made steady progress in controlling the dreaded disease. Many experts believe that we are on the verge of dramatic improvements based on blockbuster research that is deciphering the basic biology and genetics of malignancy. Even without these insights, early diagnosis and aggressive therapy have produced enormous gains.

The well-known benefit of "catching it early" is responsible for the enthusiastic embrace of screening tests that detect cancers before they cause symptoms. In most cases, it's a great thing, but prostate cancer may be an exception. The limitations of the prostate-specific antigen (PSA) test and the variable behavior of prostate cancers mean that randomized clinical trials are needed to tell if PSA screening is beneficial and which men are most likely to gain from it.

The benefits of "getting it all out" and "hitting it hard" explain why most patients who are diagnosed with cancer press for prompt and aggressive treatment. But here, too, prostate cancer may be an exception. Researchers have already learned that there is no need to rush into treatment. Because most prostate cancers grow slowly, men can delay treatment for many months without harm. But postponing treatment for months is one thing, deferring it for years, quite another. Is there ever an advantage to deferring treatment for prostate cancer?

Deferred treatment

Diagnosing cancer but not trying to cure it sounds bizarre, even criminal. But it's been an acceptable option for some men with prostate cancer, particularly in Scandinavia. The reasons are simple: many more men die with prostate cancer than from it, and the side effects of treatment (especially sexual and urinary problems) may impair the quality of a man's life without extending its length.

Deferred treatment goes by many names, including observation, expectant treatment, and watchful waiting. It never means denying treatment. Instead, the strategy has usually involved declining potentially curative surgery or radiation for asymptomatic disease, then using hormonal treatment, sometimes with radiation, to treat symptoms that may occur down the road. And in a new wrinkle, the active surveillance approach calls for intense monitoring during the "waiting" phase, so potentially curative treatment can begin as soon as needed.

Two studies illustrate the potential benefits and hazards of watchful waiting, and both illustrate the crucial importance of tumor grade and long-term follow-up.

A 2004 study from Sweden evaluated 223 men diagnosed with early prostate cancer between 1977 and 1984, when PSA testing was not available. Of these cases, 117 were detected when the tumors were already large enough to produce a lump in the prostate that showed up on a doctor's digital rectal exam, while 106 cases were detected when pathologists examined tissue removed during surgery for a different condition, benign prostatic hyperplasia. CT scans and MRIs were also unavailable, but clinical criteria suggested that all the men had early disease confined to the prostate itself. Only 4% had poorly differentiated (aggressive-looking) tumors with an aggressive appearance.

Although none of the men received treatment initially, all were followed with clinical exams and bone scans, and 80% of the patients had additional prostate biopsies.

During a follow-up period that averaged 21 years, only 17% of patients had repeat biopsies showing cancer cells that had a different degree of differentiation than their initial specimens did. And during the first 15 years, just 14% of the men developed clinically progressive disease, and only 12% died from prostate cancer. But beyond 15 years, the risk of progressive disease climbed, and the prostate cancer death rate tripled. Both in the early years and beyond, men with low-grade tumors fared much better than men with aggressive-looking cancers.

A 2005 American study agreed that tumor grade is an important predictor of survival without curative treatment, but did not find any disease acceleration beyond 15 years. The subjects were 767 men with an average age of 69 when they were diagnosed with prostate cancer between 1971 and 1984. All the men had clinically localized disease at the time of diagnosis. Doctors did not perform surgery or administer radiation therapy to try to cure any of the patients, but 42% began hormonal treatment within six months of diagnosis.

The patients were followed for an average of 24 years. Throughout that time, the prostate cancer death rate remained low for men with well-differentiated (nearly normal-looking) tumors that had Gleason scores of 2 through 4 (six deaths per 1,000 person-years). In contrast, men with poorly differentiated tumors that had Gleason scores of 8 through 10 had a high risk of dying within just 10 years (121 deaths per 1,000 person-years). Men with intermediate Gleason scores had an intermediate risk of dying from prostate cancer throughout the study.

At least 20 other studies of watchful waiting have been reported; most are from Europe, some from the U.S. The details and results vary, but they generally agree that low-grade tumors are likely to remain indolent for at least 10 to 15 years, while high-grade tumors are likely to be dangerous within five to 10 years. These studies have helped sketch out the natural course of prostate cancers that do not receive treatment with curative intent, but they don't answer the $64,000 question: can early treatment improve outcome? Only randomized clinical trials can provide that answer, and a 2005 study does just that. It's an important step forward, but like most progress prostatic, it has limitations of its own.

Watchful waiting vs. surgery

In 2005, 100 years after the radical prostatectomy was introduced by Dr. Hugh Young, researchers from Scandinavia were the first to demonstrate that the operation can indeed prolong life. The subjects were 695 men who were diagnosed with prostate cancer between 1989 and 1999. The volunteers were randomly assigned to receive surgery or to be followed without active treatment (watchful waiting). Over 10 years of follow-up, 14% of the watchful waiting group died from prostate cancer, and 30% died from all causes, while 9% of the surgical group died from prostate cancer, and 24% died from all causes. Although modest, the benefit of surgery was statistically significant. However, it was confined to men age 65 years or younger at the time of randomization. In fact, this trial suggests that among men age 65 and over, 300 patients would have to undergo surgery to prevent one death from prostate cancer within 10 years.

Although experts often disagree about prostate cancer, they agree that this is an important, high-quality trial. Does it mean that all men with organ-confined prostate cancer should opt for surgery? A look at the fine print tells us the answer is no — or, at least, not yet.

Most patients in the Scandinavian study had locally advanced disease with PSAs of about 13 nanograms per milliliter (ng/mL), while most American men who are diagnosed by PSA screening have much earlier disease that may act differently. Among other things, it may take around 10 years for a prostate cancer detected at a PSA of 5 ng/mL to grow large enough to boost the PSA to 13 or produce a lump in the gland — and patients feel and function perfectly well without treatment during this long latent period. In addition, men with other medical problems likely to limit their lifespan to 10 years or less were excluded from the trial, as were men with aggressive, high-risk prostate cancers. And until 2003, men in the watchful waiting group who developed progressive prostate cancer were not offered any treatment. In contrast, most American men who select deferred treatment are monitored closely and are treated actively if their disease progresses. Men facing a therapeutic decision should also remember that the trial did not compare surgery with radiation therapy.

Despite these limitations, the study provides long-awaited evidence that surgery can improve survival in some men. And it has also helped refine the approach to deferred treatment. In the past, it often merited the designation of observation or watchful waiting; as in the Scandinavian study, doctors kept an eye on their patients but held off on treatment until symptoms developed. Now, it's a much more active process, with closer surveillance to detect changes that trigger treatment even in the absence of symptoms.

Active surveillance

As with so many areas of prostate cancer, active surveillance is a work in progress. Although there are many variations, the theme of close monitoring to detect abnormalities that trigger treatment is universal.

One appealing approach uses multiple criteria to select men who are likely to do well with deferred treatment. For men younger than 70, these include a PSA of 10 ng/mL or less, a Gleason score of 6 or lower, and a PSA velocity (a measure of the rate at which PSA levels have risen) below 2. For men with life expectancy of more than 15 years, low tumor volume (cancer found in no more than three of the cores of tissue obtained at prostate biopsy and in less than 50% of any one core) is also important for eligibility. Because older men have shorter life expectancies, these standards can be modified for men over 70 to include PSAs up to 15 and Gleason scores up to 7.

Since 1995, a Canadian study has been evaluating 299 patients who met these strict eligibility criteria. The patients had PSA tests and digital rectal exams every three months for the first two years, then every six months if the results were stable. They also had a repeat prostate biopsy after one year and then every three years until age 80.

Patients were converted to active treatment if their PSAs rose rapidly enough to double within two to three years or if their biopsies showed grade progression to a Gleason score of 7 or higher. In addition, patients were entirely free to choose active treatment at any time.

After an average follow-up of just over five years, two-thirds of the patients remained clinically well without active treatment. Among the 101 patients who switched to active therapy, only two died from prostate cancer during that time period. All in all, the risk of dying from prostate cancer within eight years of diagnosis was less than 1% in these low-risk patients.

Similar studies are ongoing in the United States and the United Kingdom. Doctors in San Francisco have been using active surveillance to manage 240 low-risk patients with an average age of 64 and an average PSA of 6.5 ng/mL. The five-year risk of requiring active treatment was below 10%, and there were no deaths from prostate cancer at the time of their report. The British study is managing 80 low-risk patients with a similar active surveillance plan; after an average follow-up of three and a half years, 20% of the patients converted to active treatment, but there have been no prostate cancer deaths in the group.

More research is needed to learn if active surveillance holds up in the long run and to refine the eligibility criteria. Above all, there is a need for randomized clinical trials that compare active surveillance with early surgery or radiation. Several trials are under way, including the Prostate Cancer Intervention Versus Observation Trial (PIVOT) and the Standard Treatment Against Restricted Treatment (START) study.

Randomized clinical trials are essential, but in the case of prostate cancer they are very slow. The landmark Scandinavian trial took 10 years to find that radical prostatectomy is superior to no treatment in men with locally advanced disease who are younger than 65 years of age. Because the men who now volunteer for trials of active surveillance have much earlier disease, it will take much longer to see if they are better off with surveillance or early treatment.

Why wait?

Deferred treatment is not for everyone. Men with high-grade or high-volume tumors can spend a few months lining up expert care and deciding what treatment they want, but they should not delay active treatment for prolonged periods. Most high-risk men with organ-confined cancers chose surgery, but those with more widespread prostate cancer should choose radiation or hormone treatment.

In contrast, men with low-grade, small-volume prostate cancer do face a choice between active surveillance and active treatment. Until research tells us which is best, and for which patients, it's a personal decision for each patient in consultation with his doctors and family.

Active surveillance is a reasonable option for men with early, low-grade (Gleason score of 6 or less), localized prostate cancer (stages T1 and T2) who do not have symptoms from the disease. Men with larger or higher grade tumors are likely to develop symptoms that require treatment.

Active surveillance is most appropriate for older men, particularly those above 65. Younger men with a disease that limits their life expectancy to 10 years or less are also reasonable candidates for deferred treatment.

Active surveillance is reasonable for men who understand the potential advantages and disadvantages of deferred treatment and who are comfortable with the approach. Many men, particularly Americans, expect that a diagnosis of cancer will be followed promptly by treatment; surveillance is not appropriate for men who want to "get it all out" or "get on with it." But men of a certain age who can live comfortably with a diagnosis of cancer should consider the option, providing they have early, asymptomatic disease. In fact, deferred treatment may allow select men with prostate cancer to avoid the side effects of treatment and live more comfortably without sacrificing life expectancy.

Most patients view a diagnosis of cancer as a matter of life and death, and most treatment trials agree, focusing on the length of survival as a measure of success. But the quality of life is important as well, particularly when the disease is as slow growing as many prostate cancers.

Although the quality of life is harder to measure than the length of life, some studies suggest that deferred treatment has an edge over aggressive therapy. Unless it causes anxiety, surveillance has no side effects, while surgery and radiation can have many, ranging from temporary pain and diarrhea to permanent impotence and incontinence. A California report, for example, found that men who deferred treatment for localized prostate cancer had a better disease-related quality of life than men treated with either surgery or radiation. Faced with therapeutic options, men with prostate cancer should consider survival first, but all patients should also consider comfort and function as they arrive at a decision.

Not many men choose deferred treatment, but those who do should choose active surveillance rather than simply waiting for symptoms. And men who elect deferred treatment should watch themselves, reporting to their physicians if they develop pain, urinary symptoms, impotence, weakness, fatigue, or weight loss. Some men may also elect to follow a diet low in saturated fat but rich in whole grains, tomatoes and other vegetables, and fish, and to take supplements such as selenium, vitamin D, soy, lycopene, or vitamin E. Red wine and pomegranates also have advocates. None of these has a proven role in prostate cancer, but each shows some promise, at least for prevention.

Every man who receives a diagnosis of prostate cancer should think about active surveillance. Many won't be eligible, and most of those who are will choose active treatment. But which treatment?