High-risk prostate cancer brings new challenge

National Report-Advances in the diagnosis and treatment of prostate cancer are among the great medical accomplishments of the latter part of the 20th century and beginning of the 21st. Five-year survival rates for newly diagnosed loco-regional cancer advanced from 68% in 1975-’77 to 83% in 1987-’89 to nearly 100% in 2003-’09, according to the American Cancer Society. This victory, however impressive, is incomplete.

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In recent years, a number of leaders in the field of prostate cancer have identified a significant cohort of men who would likely benefit from aggressive treatment of their disease but are not getting it for a variety of reasons. Peter Carroll, MD, MPH, co-director of urologic cancer at the Helen Diller Comprehensive Cancer Center and chair of the department of urology at the University of California, San Francisco, is one of these specialists.

“There are two issues. There are patients who are being over-treated. That issue is being recognized and addressed. And then there are those who are undertreated. Few seem cognizant that there is under-treatment of high-risk disease,” Dr. Carroll told Urology Times.

“There is indeed under-treatment of high-risk disease,” said Laurence Klotz, MD, chief of the division of urology at Sunnybrook Health Sciences Center in Toronto, another specialist who is addressing this issue.

Urology Times readers tend to agree with Dr. Carroll and Dr. Klotz. A December 2014 reader poll on the UT website asked, “Are men with higher risk prostate cancer being treated aggressively enough?” More than half (57%) said no, while 43% said yes.

Next: 15% have high-risk disease

15% have high-risk disease

Epidemiologists are beginning to get a handle on the problem. Despite being able to diagnose and definitively treat prostate cancer in its early stages, the disease remains a leading killer, second only to skin cancer in American men. The American Cancer Society estimates that there are perhaps 3 million men living with the disease in the United States. The ACS further estimates that prostate cancer will have claimed 29,480 lives last year. Of the 233,000 men estimated to have presented with the disease in 2014, approximately 15% (or 34,950) will likely have high-risk disease, according to the ACS and findings published in Nature Reviews Clinical Oncology (2014; 11:308–23).

“If you look at the numbers, you will see that the majority of cancers are localized cancers. These constitute about 81% of the diagnoses. Regional disease constitutes about 11% and distant disease, about 4%,” Ahmedin Jemal, DVM, PhD, vice president of surveillance research at the American Cancer Society, told Urology Times.

One of the key findings of the 2014 ACS “Cancer Treatment & Survivorship” report is that a majority of men aged 75 years or older receive neither prostatectomy nor radiation for their disease.

“Older patients are more likely to be undertreated than younger patients,” said Dr. Carroll. “They are more likely to receive palliative rather than definitive treatment. We have found that older patients receiving palliative treatment such as hormonal therapy have twice the risk of dying of the disease as younger men treated with radiation or ­surgery.”

Dr. Klotz“I think radiation may be both under- and overused,” Dr. Klotz said. “My view, which is not universally accepted, is that the really high-risk young patient should be treated with surgery followed by radiation and hormones. It may be a form of under-treatment to treat a high-risk patient with radiation alone and deny him the benefit of surgical resection.

“It breaks down along specialty lines,” Dr. Klotz added. “The radiation oncologists think that these patients should get radiation and the urologists think they should get surgery. For most of my career, I viewed radiation and surgery as more or less equivalent, but I don’t hold that view anymore. There are now nine propensity studies that have been published. All show that mortality in patients treated with radiation alone is higher than in patients treated with surgery as the first modality. These findings are particularly applicable to high-risk patients.”

Next: Multi-modality therapies beneficial

Multi-modality therapies beneficial

There is a growing body of evidence that multi-modality therapies benefit high-risk patients.

“We found that patients who receive radiation therapy with androgen deprivation therapy have a better overall 5-year survival than those who received only ADT,” said Chun Chieh Anna Lin, PhD, MBA, senior epidemiologist, surveillance and health services research at the American Cancer Society.

Dr. Lin cited a study that she and colleagues presented at the American Society for Radiation Oncology’s 2014 annual meeting in San Francisco. The authors looked at 3,682 patients with lymph node-positive disease but no distant disease. One-third (1,204) received androgen deprivation therapy alone, while half (1,852) received combined ADT and radiation. Patients receiving combined therapy evidenced a 58% decreased risk of 5-year mortality compared to those who received hormonal therapy alone.

The study authors made another observation that has troubled prostate cancer experts for many years without resolution. Non-clinical factors can have significant impact on therapy selection and outcomes.

Dr. Lin, Dr. Jemal, and collaborators at Massachusetts General Hospital in Boston reported that, “Prior to propensity score matching, patients who were aged 65 or younger, those with private insurance, lower comorbidity scores, higher Gleason scores, lower PSA values, and higher clinical T-stage were significantly more likely to receive combined therapy” (Int J Radiat Oncol Biol Phys 2014; 90:S13-14).

High degree of treatment variation

“Treatment varies a lot. I would say that variations in approach, particularly among radiation oncologists, is greater for high-risk patients than for any other aspect of this field,” Dr. Klotz said.

“We have also shown that there is a great deal of variability in the treatment of prostate cancer, variability that is not related to patient demographics such as age, comorbidity, or disease characteristics such as PSA, tumor stage, or grade,” said Dr. Carroll. “About a third of variance in treatment appears to be related to practice site. That is a higher degree of variability than you would see with hip fracture treatment or coronary bypass procedures. And I see no reason not to think there isn’t variability among academic medical centers.”

Dr. Carroll co-authored a 2010 paper with colleagues Matthew Cooperberg, MD, MPH, and Jeanette M. Broering, PhD, that looked at factors influencing clinical decisions (J Clin Oncol 2010; 28:1117-23). Although the study was not powered to identify these factors definitively, the authors stated that, “Explanations for the observed variations are speculative, but presumably reflect variable physician training, experience, and personal outcomes; payor mix, reimbursement patterns, and other financial incentives; the local medicolegal environment; uneven penetrance of novel technologies; impact of local culture on patient beliefs and preferences; and many other factors.”

Comorbidities appear as one of the primary factors weighed in treatment decisions. Timothy Daskivich, MD, and colleagues at the David Geffen School of Medicine at UCLA looked at treatments in men with multiple comorbidities and early-stage prostate cancer in a study recently published in Cancer (2014; 120:3642-50). In comparing 516 men with low-risk disease, 475 men with intermediate-risk, and 432 men with high-risk disease, they found that men with high-risk disease had a lower probability of aggressive treatment regardless of comorbidity.

The researchers also found that aggressive treatment was not associated with a survival benefit in men with low- and intermediate-risk disease, but a trend toward benefit was seen in men with high-risk disease. They concluded that in men with significant comorbidities, aggressive treatment was poorly matched with tumor risk, and that while conservative management may be applicable in men with low- and intermediate-risk disease, aggressive treatment may benefit men with high-risk disease.

Dr. CarrollDr. Carroll said that identifying risk accurately is one path toward effective treatment of men with high-risk prostate cancer.

“Those who assess risk most accurately have a better understanding of the disease and treat more appropriately. In other words, those who evaluate a patient more precisely and in greater detail get it right more often than not,” he said.

One of the aspects of the issue seldom mentioned is the range of definitions used to identify high-risk patients. There are at least five, including those from the AUA, European Association of Urology, Radiation Therapy Oncology Group, National Comprehensive Cancer Network, and the University of California, San Francisco, which developed the Cancer of the Prostate Risk Assessment. While the differences are subtle, they can influence studies of outcomes, handicap comparisons of treatments, and have profound influence on decisions being made with individual patients.

Next: Questions persist

Questions persist

Questions surrounding the diagnosis and treatment of high-risk disease are likely to persist, at least into the near future.

“There are no randomized trials comparing surgery to radiation, and that is the problem. It then becomes a question of which data you choose to believe. To my mind, it is a little bit like the Middle East where Israelis and Palestinians both have their own narratives. It sounds as if they are talking about two different situations, but in fact it is the same situation,” said Dr. Klotz.

Dr. Carroll finds parallels between the evolution of active surveillance, which is reducing overtreatment of low-risk disease, and the current status of under-treatment of high-risk disease.

“There has probably been a tripling of the utilization of surveillance in the last few years,” Dr. Carroll said. “It was put front and center before urologists and they responded by changing practice patterns. We are not where we need to be, but there has been a remarkable uptake. That is what happens when you call attention to an issue. Things fall into place.

“What we are seeing now is a migration toward the more appropriate treatment of low-risk disease and a more aggressive approach to high-risk disease.”

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