NCCN Continues to Modify Prostate Cancer Guidelines

Plea for Surveillance Research Funds

Nick Mulcahy

March 15, 2011

March 15, 2011 (Hollywood, Florida) — "More rigorous" monitoring of active surveillance and "completely revamped" systemic therapy for metastatic disease are the big changes to the prostate cancer guidelines from the National Comprehensive Cancer Network (NCCN), said James Mohler, MD, chair of the NCCN prostate cancer panel.

Dr. Mohler, who is from the Roswell Park Cancer Institute in Buffalo, New York, told the audience here at the NCCN 16th Annual Conference that although prostate-specific antigen (PSA) screening for prostate cancer continues to be problematic, it is also vitally necessary.

"We don't want to go back to the 1980s," he said, referring to the time before widespread PSA screening, when 16% of all prostate cancers were diagnosed at the metastatic stage, compared with only 4% as of 2002.

The problem with PSA screening is the overtreatment of screen-detected disease. "We clearly don't need to treat every man with prostate cancer," he said. "Up to 50% of men in America are overtreated."

Active surveillance is a strategy to reduce the overtreatment of prostate cancer and its related morbidity, said Dr. Mohler.

Dr. James Mohler

In 2010, the NCCN issued a new prostate cancer guideline that called for active surveillance as the sole initial treatment for all men with very-low-risk and low-risk disease. The guideline was "ahead of its time," Dr. Mohler told the meeting last year. Now, the revised guidance has tightened up the recommendations on monitoring, he said. Much is unknown about the watch-and-wait strategy, and some new data from active surveillance cohorts in North America are troubling, Dr. Mohler reported.

The NCCN guideline now advises clinicians that, when the initial biopsy is more than 10 cores, repeat biopsy may be performed within 18 months. When the initial biopsy is fewer than 10 cores, a repeat biopsy may be performed within 6 months of diagnosis. However, for all patients, physicians should "consider" a repeat prostate biopsy as often as 12 months as part of ongoing active surveillance. The guideline also suggests that a PSA test be performed as often as every 3 months, but at least every 6 months. In addition, a digital rectal exam should be performed as often as every 6 months, and at least every 12 months.

In terms of biopsies, the guidance now says that a repeat prostate biopsy should be "considered" as often as annually "to assess for disease progression, because PSA kinetics may not be reliable as monitoring parameters to determine progression of disease." This insight about PSA kinetics comes from research at Johns Hopkins, in Baltimore, Maryland, one of the active surveillance cohorts in the United States, and was previously reported by Medscape Medical News.

An ongoing observational study of another active surveillance cohort, in Toronto, Ontario, has found that PSA doubling time appears to be unreliable for the identification of progressive disease that remains curable, reported Dr. Mohler. As a result, this finding is also now in the guideline.

Dr. Mohler noted that all of this new monitoring guidance is based on "consensus recommendations" — in other words, not based on level 1 evidence from randomized trials.

"It's very hard to provide concrete guidance because of the lack of evidence," he admitted. As it currently stands, the guidance for active surveillance has a long way to go, Dr. Mohler said.

"We hope to do more for patients and urologists to establish the best possible schedule to detect prostate cancer progression," he said. Some such evidence will eventually come from the Surveillance Therapy Against Radical Treatment (START) trial, the first-ever North American phase 3 trial comparing active surveillance with mainstay treatments. The trial is still enrolling patients, but the enrolment is going "horribly," said Dr. Mohler, because of patient apprehensions about active surveillance.

Because of the many unknowns in active surveillance, the new prostate cancer guideline contains a "plea" for more research in this area, said Dr. Mohler.

Systemic Therapy for Metastatic Disease

"We have completely revamped systemic therapy for castration-resistant metastatic prostate cancer," Dr. Mohler told Medscape Medical News in an interview before the NCCN meeting. The revamping includes 2 new treatments and a new agent for the prevention of skeletal-related events.

One of the new treatments — sipuleucel-T (Provenge, Dendreon) — is an immunotherapy, which, according to the NCCN, should be considered for asymptomatic men with castration-resistant metastatic prostate cancer.

These men should have a good performance status, an estimated life expectancy of more than 6 months, and no visceral disease.

Sipuleucel-T has been shown in a phase 3 trial to extend survival; mean survival was 25.8 months in the treatment group and 21.7 months in the control group (a 22% reduction in mortality risk).

Interestingly, men who benefited from sipuleucel-T showed no clinical response, and the PSA responses were few, noted Dr. Mohler.

Symptomatic men in this setting, who are by definition not candidates for sipuleucel-T, should still first be considered for chemotherapy (docetaxel and prednisone every 3 weeks), according to the guideline.

For a man who fails docetaxel, there is a new second-line option — cabazitaxel (Jevtana, Sanofi-Aventis).

"It is impressive that cabazitaxel produced a significant survival benefit in patients who had progressed despite docetaxel, a drug that has a very similar mechanism," said Philip Saylor, MD, from Massachusetts General Hospital Cancer Center in Boston, who did not attend the NCCN meeting.

Dr. Saylor was referring to the fact that cabazitaxel has been shown in a phase 3 trial to prolong overall survival; median survival was 15.1 months in the cabazitaxel group and 12.7 months in the mitoxantrone group.

There are limitations to who can be prescribed cabazitaxel, according to the NCCN. Patients selected for treatment should be without severe neuropathy and have adequate liver, kidney, and bone marrow function, "given the high risk of neutropenia and other side effects in this population."

"Patients who tolerated first-line docetaxel chemotherapy without experiencing substantial side effects are the most likely to be interested in subsequent treatment with cabazitaxel," Dr. Saylor told Medscape Medical News in an email.

Finally, for men with castration-resistant metastatic prostate cancer, the NCCN panel now recommends denosumab (Xgeva, Amgen) as an alternative to zoledronic acid for the prevention of skeletal-related events. A phase 3 study showed denosumab to be the superior agent in delaying the time to first skeletal-related event and other measures, said Dr. Mohler. All patients receiving denosumab should be treated with vitamin D and calcium and undergo periodic monitoring of serum calcium levels because of the risk for hypocalcemia.

Dr. Mohler is the chief medical officer of Androbiosys, Inc.

National Comprehensive Cancer Network (NCCN) 16th Annual Conference. Presented March 12, 2011.