Early Identification of Metastatic Disease in Prostate Cancer: RADAR Group Recommendations

An Interview with E. David Crawford, MD, and Daniel P. Petrylak

Please expand on the current lack of consensus regarding eligibility criteria, type of imaging modality, and frequency of scanning, particularly for M0 CRPC patients.

Dr. Crawford:

The transition to metastatic disease in men with prostate cancer is a seminal event in the management of these patients. Recent data suggest that approximately 33% of men with M0 CRPC actually have metastatic disease (Yu et al, J Urol. 2012 Jul;188(1):103-109). This is particularly relevant because we have a number of new and effective treatments for this stage of disease that are proven to extend life. If we can identify metastatic disease earlier, we have the opportunity to intervene with these new therapeutic options and hopefully improve outcomes. Most of the men are under the care of urologists at the time they are diagnosed with advanced prostate cancer. Unfortunately, there are no clear cut guidelines as to when imaging should be employed and what type of scan to perform to identify metastatic disease.

What are the limitations of available imaging modalities?

Dr. Crawford:

The traditional imaging modalities, such as bone scans, lack sensitivity and specificity and it is unclear as to the appropriate timing to order these scans. Newer and more advanced imaging options include sodium fluoride PET scans. They are more sensitive and specific, but they are limited in their availability or by insurance coverage.

What are the implications of the recommendations for clinical practice? For payers (private and government)?

Dr. Crawford:

We have tried to develop a consensus to aid clinicians as to when to do bone scans, CT scans, and to consider the newer modalities such as NaF PET scans. Our goal is to provide a framework for physicians that will help improve consistency of patient care and lead to earlier identification of metastatic disease. We hope these recommendations will support insurance coverage for the appropriate patients.

Dr. Petrylak:

This publication gives payers a framework to work with urologists, radiation oncologists, and medical oncologists regarding the optimal timing and imaging modality for staging patients.

What are the implications for treatment and prognosis?

Dr. Crawford:

Hopefully we will be able to implement these new effective treatments earlier in the course of the disease and improve survival. Recent data (Schellhammer et al, Urology. 2013 Jun;81(6):1297-1302) suggest that starting Provenge® (sipuleucel-T) immunotherapy early, in patients with lower PSA levels and fewer mets, increases the treatment effect and prolongs survival out to 13.1 months.

Why is early identification of M0 CRPC so important for patients?

Dr. Crawford:

While we need more studies in this area to provide level 1 evidence that correlates early intervention with prolonged survival, existing data suggest that early identification of M0 CRPC and appropriate treatment leads to improved outcomes.

Dr. Petrylak:

The early identification of metastases is important to the early implementation of treatments such as Provenge® (sipuleucel-T), Zytiga® (abiraterone/prednisone) and enzalutamide, which are only indicated for those patients with metastatic disease.

What data exist to support early intervention for an M0 CRPC patient?

Dr. Crawford:

There are no Phase 3 studies in M0 patients that demonstrate clinically meaningful benefits. We need to look at the newer therapies earlier in the course of disease and the M0 patient population is the best place to start.

Dr. Petrylak:

A retrospective analysis of patients treated with Provenge® has found that patients in the lowest PSA quartile have the (PSA<22.1) have a 13 month improvement in median survival when compared to those in the highest quartile (PSA>134) who have a 2.8 month improvement in median survival.  Thus, since Provenge® is only indicated for those patients with metastatic disease, earlier identification of patients with metastatic disease in the MO state could potentially lead to earlier initiation of treatment.

Why do the RADAR recommendations add screening before change-of-therapy?

Dr. Crawford:

Screening measures the progression of disease. If we can detect progression earlier, then we can better adapt our treatment approach. The sooner we can detect that the disease is advancing, the better.

Dr. Petrylak:

The assessment of the efficacy of a treatment is multifactorial, and includes changes in PSA, quality of life parameters, and objective measurements by imaging. Imaging performed prior to initiating a new therapy serves as a new baseline to assess the effect of a new treatment.

Compare the efficacy of F-Sodium Fluoride (NaF) PET/CT imaging to conventional bone scans.

Dr. Crawford:

Sodium Fluoride (NaF) is more sensitive and has been shown to detect micrometastases up to 12 months sooner than standard bone scans. However, there have been cases of false positives.

Dr. Petrylak:

Studies have demonstrated a greater sensitivity as well as specificity when NaF PET scans are compared to conventional bone scans. An analysis of data taken from National Oncologic PET registry published in the Journal of Nuclear Medicine found that use of NaF-PET shifted management plans to treatment for 77% of patient with an initial diagnosis of prostate cancer, 52% of men with suspected first osseous metastases, and 71% of those with suspected progression of osseous metastases. There were definite findings of bone metastasis in 14%, 29%, and 76% of the patients in the 3 groups, respectively.

How can the RADAR guidelines increase the rate of early detection of metastases in patients with PC?

Dr. Crawford:

The framework in the manuscript provides recommendations from a multi-disciplinary team of prostate cancer specialists in urology, oncology, and radiation oncology. They recommend screening for metastatic disease at lower PSA levels in the M0 population (when PSA level ≥ 2 ng/mL, scanning again when PSA=5 ng/mL, and every doubling of PSA levels thereafter).

Dr. Petrylak:

The guidelines help to identify those patients at risk, using absolute PSA values, PSA doubling time, as well as clinical parameters.

How will disease management be guided with the RADAR recommendations?

Dr. Crawford:

We believe that mets are seminal event and signal a new stage of disease. In the past, there were not many options for patients with advanced prostate cancer so identifying metastatic disease didn’t change the course of treatment. Now with the approval of several novel therapies, we believe that earlier detection will provide an opportunity to intervene earlier on behalf of the patient and hopefully slow down the disease progression and improve outcomes.

Should community oncologists and urologists implement the screening guidelines in their practice for CRPC patients?

Dr. Crawford:

We hope so. Providing a framework should make it easier for physicians to implement guidelines that work for their individual practice.

Dr. Petrylak:

Yes, these guidelines will help to identify those patients who would benefit from imaging, and thus direct treatment appropriately.

Can you tell us anything about RADAR II? What can we expect from that meeting?

Dr. Crawford:

We are excited about expanding on the work done in RADAR I and are meeting now to look at how to implement management strategies. We would like to offer recommendations on sequencing treatment options based on currently available data even though sequencing studies are not available at present and those underway will take some time for results. There is not good clarity on how to implement all of the new treatments and we hope we can provide some guidance for clinicians and patients who need this information urgently.

Dr. Petrylak:

The RADAR II meeting focused on other measures of outcome such as PSA circulating tumor cells, and patient reported outcomes and their validity as potential surrogate end points.

E. David Crawford, MD, is the Distinguished Endowed Professor of Surgery, Urology, and Radiation Oncology, and head of the Section of Urologic Oncology at the University of Colorado Anschutz Medical Campus in Aurora, Colorado. He also serves as the Practice Director for the Urologic Oncology clinic. He was the lead author on the report from the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Group published online in Urology.

Daniel P. Petrylak, MD, is Professor of Medicine (medical oncology) and Urology, Yale School of Medicine, and Leader of Prostate Medical Oncology at the Yale Cancer Center, New Haven, Connecticut. He was a member of the RADAR Group and coauthor of the report from the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Group published in Urology.