HOLLYWOOD, FLA. – Updated prostate cancer guidelines from the National Comprehensive Cancer Network call for more stringent monitoring of low-risk and very-low-risk patients who have opted for active surveillance.

The more rigorous protocol should help allay patient anxiety about "watchful waiting," while minimizing the likelihood of overtreatment and its associated risks and side affects, Dr. James L. Mohler explained at the NCCN annual conference.

Based primarily on expert consensus rather than new evidence from clinical trials, the recommendations include the following:

• Prostate-specific antigen (PSA) testing at least every 6 months and as often as every 3 months.

• Digital rectal examination (DRE) at least every 12 months and as often as every 6 months.

• Repeat needle biopsy within 18 months for patients in whom the initial biopsy was 10 or more cores.

• Repeat initial biopsy within 6 months for patients in whom the initial biopsy was fewer than 10 cores.

• Consideration of a repeat biopsy for all patients as often as 12 months.

Previously, the NCCN had called for PSA testing and DREs as frequently as every 6 and 12 months, respectively, and deemed repeat needle biopsies to be optional within 6-18 months, depending on the number of cores initially biopsied, said Dr. Mohler.

Although the revised recommendations are more specific, they are still limited by the lack of quality evidence to support them, he said, noting that the first-ever North American phase III trial to compare active surveillance with mainstay prostate cancer treatments – the ongoing START (Surveillance Therapy Against Radical Treatment) study – is having trouble meeting enrollment goals because patients perceive active surveillance as "doing nothing."

In 2010, the NCCN prostate cancer guidelines recommended active surveillance as the only option for men with low-risk prostate cancer who had an estimated life expectancy less than 10 years and for men with very-low-risk prostate cancer (a newly defined patient subset) with a life expectancy less than 20 years, said Dr. Mohler, chair of the department of urology at Roswell Park Cancer Institute in Buffalo, N.Y.

Patients in the low-risk category are those with a stage T1-T2a tumor, a Gleason score of 2-6, and a PSA level less than 10 ng/mL, whereas very-low-risk patients are those with a stage T1a tumor, a Gleason score of 6 or less, a PSA level less than 10 ng/mL, fewer than three positive biopsy cores with no more than 50% cancer in each, and a PSA density below 0.15 ng/mL per gram, he explained.

Sipuleucel-T, Cabazitaxel included

The updated guidelines also outline new recommendations for systemic treatment of castration-recurrent metastatic prostate cancer, including salvage therapy with sipuleucel-T (Provenge) for asymptomatic or minimally symptomatic disease and cabazitaxel (Jevtana) as a second-line treatment option for patients who develop resistance to docetaxel (Taxotere), Dr. Mohler said.

The sipuleucel-T recommendation is based, in large part, on the recently reported findings of the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial that showed significantly improved overall survival – although not progression-free survival – among men who were randomized to the autologous active cellular immunotherapy, compared with placebo (N. Engl. J. Med. 2010;363:411-22), Dr. Mohler said. The category 1 recommendation applies to minimally symptomatic men with an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, a life expectancy greater than 6 months, and no visceral metastases. Sipuleucel-T is not recommended for men with symptomatic disease, for whom chemotherapy with docetaxel and prednisone remains appropriate, he said.

Men with advanced prostate cancer who are not helped by docetaxel may be candidates for treatment with cabazitaxel, a second-generation taxane, according to the revised guideline. In a phase III randomized trial, treatment with the microtubule inhibitor along with prednisone led to prolonged overall and progression-free survival and improved PSA and radiologic responses, compared with mitoxantrone (Novantrone) and prednisone, said Dr. Mohler (Lancet 2010;376:1147-54). Because of an increased risk of neutropenia and other adverse effects, "treatment should be reserved for patients without severe neuropathy or impaired liver, kidney, or bone marrow function," he said.

Denosumab an Option for Bone Mets

The revised guideline also updates the recommendation for the prevention of skeletal-related events in patients with advanced prostate cancer that has metastasized to the bone with the addition of the anti-RANKL (receptor-activated nuclear factor–kappaB ligand) monoclonal antibody denosumab (Xgeva) as an alternative to zoledronic acid (Zometa).

"In men with castration-recurrent prostate cancer who have bone metastases, denosumab was shown to be superior to zoledronic acid in preventing disease-related skeletal complications, including fracture, spinal cord compression, or the need for surgery or radiation therapy to bone," Dr. Mohler said, referring to the results of a phase III randomized study (Lancet. 2011;377:813-22).

Unlike zoledronic acid, which is administered intravenously and can potentially affect renal function, denosumab is given subcutaneously and does not affect kidney function, he said; as such, it represents a "novel treatment option."

The updated NCCN prostate cancer guidelines are available at www.nccn.org. Dr. Mohler is a cofounder and chief medical officer of AndroBioSys Inc. in Buffalo, N.Y.

NCCN Tightens Active Surveillance in Prostate Cancer Guidelines