Undeterred by initial data that favor immediate surgery over surveillance, U.S. prostate cancer investigators continue to explore the watchful waiting strategy as a viable option for selected patients. The latest findings suggest the effort has yet to stem the tide of anxious patients who are abandoning surveillance in favor of more aggressive treatment.
Between one-third and one-half of patients on surveillance with localized prostate cancer pursue interventions within 5 years, according to several studies reported earlier this year at the annual meeting of the American Urological Association (AUA). In certain subgroups, as many as three-fourths drop out of surveillance within 4 to 5 years.
Rising prostate-specific antigen (PSA) levels appear to be the driving force behind many patients decision to seek intervention.
"The men just cant stand to see their PSA values going up," said Judd Moul, M.D., director of the Department of Defense Center for Prostate Disease Research. "Either the patients, their doctors, or a combination of both get cold feet."
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However, results of the Swedish study left the door open for continued evaluation of surveillance. Despite the improved disease-specific survival, prostatectomy patients had similar overall survival as patients on surveillance. The surgery group also had more sexual impotence and symptoms of urinary incontinence. Additionally, a majority of patients in both treatment arms were alive and free of metastases at 6 years.
"I think it might be possible to look at the Swedish data and carve out low-risk patients who did not accrue as much benefit from surgery and who might be appropriate for prospective studies of watchful waiting," said Tomasz Beer, M.D., assistant professor of medicine and director of the prostate cancer research program at Oregon Health and Science University (OHSU) in Portland.
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Moul and colleagues found that about half of more than 1,000 patients on surveillance had interventions within 5 years. PSA velocity was the major predictor of active therapy.
"We were kind of surprised to find that PSA was driving the train much more than anything else, including Gleason score, age, and even comorbidities," said Moul, also a professor of surgery at the Uniformed Services University of the Health Sciences in Bethesda, Md.
Moul and his associates did a separate analysis of patients with low-risk characteristics: lower PSA, Gleason score, and clinical stage. The analysis also was limited to patients younger than 70. Within 4 to 5 years, three-fourths had pursued some form of active therapy. Rising PSA again was the driving force.
Another report at the AUA meeting involved 402 low-risk surveillance patients enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE). After a median follow up of 1.7 years, 171 (43%) had received some form of active treatment for prostate cancer. In patients who had interventions, the mean PSA rose from 11 ng/mL at baseline to 19 ng/mL at the time of intervention. Those who remained on watchful waiting had a decline in PSA from 8.5 ng/mL to 7.9 ng/mL. Patients who had a PSA increase of more than 5 ng/mL were almost four times as likely to seek intervention as those who had increases of 2.4 ng/mL to 4.9 ng/mL, according to Peter Carroll, M.D., professor of urology at the University of California at San Francisco (UCSF).
An evaluation of 72 low-risk patients (stage T1-2, Gleason score of 7 or less) showed that one-third of patients had interventions after a median follow up of 4 years. Intervention was equally likely in patients who entered surveillance because of low-risk characteristics or because of substantial co-morbidities, reported Young Kang, M.D., a clinical fellow at Columbia University in New York. Initial PSA was the only significant predictor of intervention-free survival.
The implications of the studies for watchful waiting are open to interpretation. Moul sees one possible interpretation of his data as indicating that "we have no idea how to do watchful waiting." If an active therapy, such as prostatectomy or radiation, resulted in a 50% failure rate at 5 years for localized prostate cancer, physicians "would probably be put in jail for offering that treatment to men." Alternatively, offering patients surveillance might have delayed secondary morbid therapy for a period of time, during which the patients had good quality of life.
The fact that one-third of the patients in the Columbia study had interventions does not indicate that patients and physicians should not consider surveillance, said Mitchell Benson, M.D., professor of urology and lead collaborator in the study along with urologist James McKiernan, M.D. The positive side of the data is that two-thirds of the patients did not require intervention.
"I still think surveillance is a viable option and an appropriate option for some people," said Benson. "The onus is on the surgeon to be certain that a patient is an appropriate candidate for surveillance to begin with. In my hands, that often involves repeat prostate biopsies to make sure that clinical understaging has not occurred."
A major challenge for the future is to develop better criteria to identify candidates for watchful waiting, Benson added.
Carroll emphasized that studies of watchful waiting have to be considered within the context of contemporary medical practice. Widespread PSA screening has led to increased detection of low-volume, low-grade tumors, many of which are likely to be clinically insignificant. Patients who have low-risk disease, defined by a PSA of less than 10 ng/mL, no Gleason 4-5 pathology, and clinical stage T1c-2a disease, probably constitute 40% to 45% of all prostate cancer detection, and the proportion continues to increase, he said.
"My personal feeling is that watchful waiting should be increasing," said Carroll. "I think urologists will be judged by how they treat this disease. If we dont become more open minded, I think we could be in real trouble. We have to pay attention to what is happening. Overdetection will become a more important issue. Within that context, we risk being too aggressive with some patients and not aggressive enough with others. We need to change the paradigm, or we will lose control of these patients."
Additionally, surveillance needs to be an active regimen. UCSF, Johns Hopkins University, and the University of Toronto have ongoing studies of surveillance. At each of these institutions, surveillance includes PSA assessment every 3 to 4 months, repeat imaging every 6 months, and repeat biopsy every 12 to 24 months, said Carroll.
Beer thinks the watchful waiting data could be used to make a case for a clinical trial evaluating delayed intervention as a specific strategy for treating localized prostate cancer. Such a study could add a new dimension to watchful waiting by making it more proactive. Carroll said that the ongoing studies have incorporated intervention at disease progression. Thus far, hormonal therapy has been the preferred intervention.
Benson already counsels his patients that watchful waiting does not rule out the possibility of intervention at some point, merely the fact that intervention will not occur immediately. He also makes periodic repeat biopsy a standard component of surveillance as a means of documenting disease progression.
"Biological progression is less objective [than clinical progression] but in many ways more anxiety provoking for patients because they get fixated in PSA results," said Benson. "PSA has no predictive ability; it just tells us what has happened. I think there is some predictive ability of biopsy, where we can see more extensive cancer in the face of a PSA that is relatively stable."
Watchful waiting also raises the issue of whether delayed intervention harms patients. Carroll and Moul have data that point in somewhat different directions. Overall, Mouls data indicate that delayed intervention does not adversely affect disease-free survival. However, after stratifying patients by PSA, Gleason score, and clinical stage, he and his colleagues have seen some evidence that patients at higher risk tend to have lower recurrence-free survival when treatment is delayed.
Carroll said his data show that most men who go off watchful waiting to interventions maintain their risk categories, such that low-risk patients tend to remain low risk.
"We rarely see a major change in risk," he said. "That suggests that even though patients frequently require treatment, the disease can still be effectively treated."
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