Surgery Versus Watchful Waiting in Early Prostate Cancer
Key Words
Prostate cancer, prostatectomy, watchful waiting. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
Men with localized prostate cancer who underwent radical prostatectomy were less likely to have their cancer spread and less likely to die (from the disease or any cause) than men who were managed by “watchful waiting.” This is the first large phase III trial to show an overall survival benefit for this kind of surgery.
Source
The New England Journal of Medicine, May 12, 2005 (see the journal abstract).
Background
Prostate cancer is the second most common type of cancer among American men, and accounts for a third of all their cancers. An estimated 232,090 men will be newly diagnosed with the disease in the United States in 2005 and about 30,350 men will die from it.
However, because most prostate tumors are found in older men and grow slowly, many patients will eventually die of causes other than prostate cancer. If a man’s tumor is found early and before it has spread (metastasized), his doctor may recommend “watchful waiting” instead of surgery or radiotherapy – treatments that carry certain risks. With watchful waiting (also known as “expectant management”), doctors actively and carefully monitor the patient for signs that the cancer has worsened, treating symptoms of the disease when they occur.
Primary surgery to remove the prostate and related lymph nodes is called radical prostatectomy; the procedure can damage nearby nerves, which poses risks of incontinence and impotence.
The Study
In this study, researchers enrolled 695 men between 1989 and 1999 at 14 medical centers throughout Sweden, Finland, and Iceland. The majority of men had been diagnosed with early prostate cancer due to symptoms, urinary tract disease, or abnormal results from a digital rectal examination (DRE). The men, whose average age was 65, were randomly assigned to one of two groups. Half of them (347) received a radical prostatectomy and the other half (348) were monitored through watchful waiting.
In 2002, researchers with the study released preliminary results after following men in both groups for a median of 6.2 years, a relatively short time given how long men with early-stage prostate cancer live with their disease. At that time, researchers found that the surgery group was 50 percent less likely to die of prostate cancer than the watchful waiting group, and were 37 percent less likely to see their cancer spread to distant parts of their bodies. However, there was no statistically significant difference in terms of overall survival – that is, men in one group were living about as long as men in the other group.
In the New England Journal of Medicine article described here, researchers presented a second analysis of the data after an additional three years of follow-up. By following the patients for a longer time, researchers hoped to discover whether one or the other approach led to a better rate of overall survival.
The study’s lead author is Anna Bill-Axelson, M.D., Ph.D., University Hospital, Upsala, Sweden.
Results
After a median follow-up of 8.2 years, the advantages of receiving surgery as compared to watchful waiting were more evident, and a small though statistically significant advantage in overall survival emerged: 83 men in the surgery group versus 106 men in the watchful waiting group died (of any cause), which amounts to a 26 percent advantage. Death specifically from prostate cancer was 44 percent less likely among those who received surgery: 30 men versus 50 men in the watchful waiting group.
Men receiving surgery were 40 percent less likely to have their cancer spread to distant sites in the body, and 66 percent less likely to have it spread locally. In the surgery group, this meant the reappearance of a local tumor; for the watchful waiting group, local spread meant either a detectable tumor or problems urinating that required intervention.
Comments
Significantly, these are the first results from a large study to demonstrate that radical prostatectomy increases overall survival, relative to watchful waiting, in men with clinically detected prostate cancer. For all endpoints studied, the advantages have increased over time, and “we expect that the benefits of this surgery will increase during longer periods of follow-up,” said the study’s authors.
They also point out that the possible complications of the surgery (impotence, incontinence) must “be weighed against the increasing incidence of symptoms and use of treatments after the progression of disease in the watchful waiting group.”
Limitations
The men in this study do not match the typical profile of newly diagnosed prostate cancer patients in the United States, said Alison Martin, M.D., senior investigator with NCI’s Cancer Therapy Evaluation Program.
“Due to the widespread use of PSA screening in the United States, most patients here are diagnosed at an earlier stage of disease, before the disease is palpable and before symptoms,” she said. “At this very early stage, it is unknown whether radical prostatectomy would have the same impact. While this is a landmark study that estimates the benefit of radical prostatectomy in the appropriate patient, important questions that remain include whether we can develop molecular profiles and clinical paradigms that identify the early prostate cancer detected by PSA that needs any intervention, and if so, which kind.”
Some of these answers, she said, may come from the Prostate Cancer Intervention Versus Observation Trial (PIVOT), which completed accrual in 2002. Half of the patients in PIVOT were diagnosed on the basis of an elevated PSA level when their cancers were too small to be clinically detected. As in the Scandinavian trial, patients were randomly assigned to surgery or watchful waiting. Early results from PIVOT may be available in the next several years.
Martin also noted that the Standard Treatment Against Restricted Treatment (START) trial, to be led by the National Cancer Institute of Canada and scheduled to begin in 2006, will compare standard treatment (choice of surgery, brachytherapy, or external beam radiotherapy) to "active surveillance" in men diagnosed with early-stage, low-risk prostate cancer typical of the population in the U.S.
Watchful waiting, which treats symptoms (usually from metastatic disease) as they develop, is fundamentally different from active surveillance, said Martin. With this approach, patients randomized to active surveillance will be closely followed by measures of prostate biology such as PSA doubling time and Gleason score on repeat prostate biopsies. Intervention, such as surgery or radiotherapy, would be tailored to the subset of individuals who exhibit changes in these parameters over time. Tumor samples will be collected for analysis of molecular signatures that indicate the risk of progression.
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