Men With High-Risk Prostate Cancer Undergoing More Prostatectomies

Matthew R. Cooperberg, MD, MPH

It has been recognized that treatment outcomes for men with high-risk prostate cancer are widely variable. Endpoints, such as biochemical failure—free survival, distant metastasis–free survival, prostate cancer–specific survival, and even overall survival (OS), vary according to the high-risk characteristics the patient presents with at the time of diagnosis.

Managing the patient with high-risk, localized prostate cancer has been a challenge for urologists. These patients have less than positive outcomes when compared with other patients with more favorable clinical characteristics. The National Comprehensive Cancer Network and the American Urological Association define this patient as having an increased Gleason score (Gleason 8 to 10) and a PSA over 20 ng/ml.

In addition, these patients are characterized by “a clinical tumor stage greater than T2c in the case of the AUA system or T3a in the NCCN system,” said Matthew Cooperberg, MD, associate professor in the departments of Urology and Epidemiology & Biostatistics, Helen Diller Family Chair in Urology, University of California San Francisco. “I think there are many of us that would argue that the AUA or NCCN classifications are not a very good way to define high-risk disease because there’s a tremendous amount of prognostic heterogeneity within high-risk groups.”

Prostate cancer’s characteristic slow growth pattern and the potential toxicity of current treatments makes risk stratification of patients all the more important to clinicians and researchers. But how these patients should be stratified, in clinical practice and for research trials, is increasingly complex.

There are a number of risk prediction tools at the clinician’s disposal. An effective tool will be able to provide a prediction of a positive biopsy with or without a prior negative biopsy; prediction before surgery of pathologic outcomes; prediction before and after surgery of biochemical and clinical endpoints; prediction before radiotherapy of biochemical and clinical endpoints; and prediction of metastases and survival among patients with recurrent disease after primary treatment.¹

Standard of Care

Currently, the only risk assessment tool endorsed by the AUA is a 3-level classification described by D’Amico et al.² This system uses PSA level (blood test), Gleason grade (microscopic appearance of the cancer cells), and T stage (size of the tumor on rectal exam and/or ultrasound) to group men as low-, intermediate-, or high-risk. There are significant limitations associated with this classification. Multivariable instruments such as a variety of nomograms and the CAPRA score are able to provide much more precise estimates of risk, and some have been well validated at this point. But with the emergence of prostate cancer biomarkers, it is hoped that validation of risk stratification tools will elucidate, for clinicians, which clinically based instruments to use and in which settings.The standard of care for the high-risk patient population is either combined radiation therapy with hormonal therapy or radical prostatectomy (RP) with pelvic lymph node dissection. Surgery in this patient group was historically avoided, potentially based on the perception of ostensibly higher complication rates associated with inferior functional and oncological outcomes. But that trend may be shifting according to emerging research.

Recent studies suggest that RP is not only appropriate for this population but also may be a more optimal initial treatment, given that many of these patients require multimodal therapy to manage their disease. The question about radiation versus surgery lies in the details, with treatment tailored to each patient. The decision is usually made after considering the patient’s overall health, life expectancy, and the disease risk, ie, PSA, tumor extent, and grade, said Cooperberg.

“If surgery is chosen, it should include lymph node dissection in high-risk disease. If radiation is the first treatment option, the next question to consider is external beam versus brachytherapy versus a combination and how much hormonal therapy should be given together with the radiation therapy,” Cooperberg said.

Recent trends suggest a shift away from radiation therapy and more towards RP for patients with high-risk prostate cancer, said Stacy Loeb, MD, assistant professor of Urology and Population Health, New York University School of Medicine, NYU Langone Medical Center. “The shift may be attributed to multiple observational studies, rather than prospective, randomized studies,” said Loeb. No randomized data comparing different therapy approaches have been reported. In addition, continence rates in patients who have undergone RP for high-risk disease seem to be unaffected. In many patients, a nerve-sparing procedure can be performed to improve the chances of potency without a significant negative impact on surgical margin rates.

Because of the lack of a randomized trial comparing these therapies, clinicians can only say that “surgery is better than watchful waiting and that hormonal therapy plus radiation is better than hormonal therapy alone,” added Cooperberg. There is a growing body of evidence that suggests a survival benefit associated with RP over external beam radiation therapy, specifically for high-risk disease.

“When we look at combined external beam radiation therapy with brachytherapy and long-term hormonal therapy, I think the gap narrows, but it does not close altogether,” said Cooperberg. “So there does appear to be a benefit for surgery in this setting of high-risk disease.”

The other reason that surgery may be preferable initially, said Loeb, is that it is possible to give radiation and hormonal therapy at a later date, after the patient undergoes a RP.

“It’s very difficult to perform RP after a patient has had radiation, and it is only offered at select hospitals around the world,” said Loeb. “The prostate tissues are affected by radiation therapy, and there is a much higher risk of complications if you perform surgery after radiation.” This is a factor to consider, especially if the high-risk patient needs multimodality therapy. After the patient undergoes a RP, radiation therapy can be administered more easily than the other way around.

The other benefit surgery offers the patient is a one-time procedure. Radiation therapy requires administration over several weeks. Though less invasive, radiation therapy is time consuming. Prostate-specific antigen levels should drop to zero within 2 months after surgery, but with radiation therapy, PSA levels may fall up to 2 years and ultimately hover between 0 and 3. In either case, PSA requires monitoring and tracking.

“A patient might prefer undergoing surgery because the prostate is out of the body and once it’s removed, it gives some patients peace of mind if the PSA remains zero,” said Loeb.

Loeb noted that both treatments have risks associated with them. For surgery, there are problems with erection and urination. In addition, the adverse effects come on immediately and often improve over time. With radiation, the adverse effects come on slowly over time, so the timing for side effects is different for each course of treatment.

There is no definitive course of action for the high-risk patient, but Cooperberg does recommend that high-risk cancer patients be taken care of in a high-volume, multidisciplinary care setting. “Ideally, these patients should at least be offered the opportunity to talk to a radiation oncologist,” he said. Generally speaking, it is going to be the urologist that provides patient counseling and will likely discuss all treatment options with the patient. “The fact is, every patient is different, and there is no definitive course of treatment yet.”

Though much of the debate around prostate cancer centers around low-risk disease and the benefits of active surveillance, the high-risk prostate cancer patients are best managed in “referral centers with a radiation and medical oncologist on site, with a urologist on site, and with the ability to get patients into clinical trials when appropriate,” said Cooperberg. “These really are patients that should be treated by high-volume surgeons in conjunction with a multidisciplinary team.”

References

1. Cooperberg MR. Prostate cancer risk assessment: choosing the sharpest tool in the shed. Cancer. 2008;113(11):3062-3066.
2. American Urological Association Prostate Cancer Clinical Guidelines Panel. Guideline for the Management of Clinically Localized Prostate Cancer: 2007 Update. Linthicum, Md: American Urological Association Education and Research, Inc.; 2007.