Guideline for Management of Castration-Resistant Prostate Cancer

A very useful up to date Guideline


Guideline for Management of Castration-Resistant Prostate Cancer
Author: Nick Mulcahy
CME Author: Charles P. Vega, MD, FAAFP
CME Released: 06/19/2013

This article is intended for primary care clinicians, urologists, oncologists, radiation oncologists, and other specialists who care for patients with castration-resistant prostate cancer.

There are 240,000 new diagnoses of prostate cancer in the United States annually, and most men who die of prostate cancer have metastatic castration-resistant prostate cancer (mCRPC). The median survival time of patients with mCRPC has traditionally been less than 2 years, and androgen receptors appear to remain active among these patients despite circulating levels of androgens consistent with castration.

Treatment with medications such as docetaxel has changed how CRPC is treated during the past decade. The current guideline from the American Urological Association (AUA) describes the best practice for the management of CRPC.

Study Synopsis and Perspective
The AUA has issued a new guideline for the management of CRPC that provides a "rational basis" for treatment decisions.

Those decisions are now "complex" because a group of treatment options for metastatic disease has emerged in a short period of time, according to a press release issued at AUA 2013 Annual Scientific Meeting, held in San Diego, California.

The treatment options in mCRPC include 4 new therapies that have been approved since 2010: sipuleucel-T, cabazitaxel, abiraterone, and enzalutamide. These therapies, along with docetaxel (approved in 2004), have all been shown to improve overall survival time in metastatic disease.

"Prior to 2004, once patients failed primary androgen deprivation, treatments were administered solely for palliation," write the guideline authors, led by Michael S. Cookson, MD, from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

The guidelines are much needed, according to a clinician not involved with their writing. "There is a lack of clarity as to the best method for treating castration-resistant prostate cancer," said Willie Underwood III, MD, MPH, from the Roswell Park Cancer Institute in Buffalo, New York.

The guidance is especially important given the publicity that has accompanied the new therapies, as well as their cost, he told Medscape Medical News in an interview. "When a drug comes out with a lot of hype, every patient wants that drug."

A large part of the new guideline is recommendations for 6 different types of patients. These "index" patients represent the most common clinical scenarios in men whose prostate cancer is not responsive to traditional androgen-deprivation therapy.

The profiles of the index patients comprise symptoms, performance status, the presence or absence of metastases, and whether or not docetaxel has been administered.

The guideline authors acknowledge that treatment is rapidly changing, and advise clinicians to use it in conjunction with the "current literature" and an individual patient's treatment goals.

The following are the index patients and the associated recommendations.

Index Patient 1: Asymptomatic Nonmetastatic CRPC

Profile
The typical patient has a rising prostate-specific antigen (PSA) level and no radiologic evidence of metastatic prostate cancer. He is also required to have castrate levels of testosterone (< 50 ng/mL). Treatment recommendations
Observation with continued androgen deprivation (preferred)
First-generation antiandrogens (flutamide, bicalutamide, and nilutamide) or first-generation androgen-synthesis inhibitors (ketoconazole plus steroid) to patients unwilling to accept observation
Discussion
No treatment has been shown to improve overall survival duration in these men. "Since all agents have potential side effects...we must first do no harm," write the authors.


Index Patient 2: Asymptomatic or Minimally Symptomatic mCRPC Without Previous Docetaxel Chemotherapy

Profile
These patients have "a rising PSA in the setting of castrate levels of testosterone" and metastatic disease documented on radiographic imaging.
Treatment recommendations
Abiraterone plus prednisone, docetaxel, or sipuleucel-T (preferred)
First-generation antiandrogen therapy or ketoconazole plus steroid or observation to patients who do not want or cannot have one of the standard therapies
Discussion
The 3 standard therapies are approved by the US Food and Drug Administration for this indication and improved overall survival time in randomized clinical trials. There are no direct comparison studies to inform optimal sequencing. "As a general principle, it is preferable to give the least toxic agent first," the authors note.


Index Patient 3: Symptomatic mCRPC With Good Performance Status and No Previous Docetaxel Chemotherapy

Profile
These patients have a rising PSA level in the setting of castrate levels of testosterone. Their symptoms should be related to prostate cancer alone (and not to other conditions) and might include pain.
Treatment recommendations
Docetaxel (preferred)
Abiraterone plus prednisone (alternative)
Ketoconazole plus steroid, mitoxantrone, or radionuclide therapy for patients who do not want or cannot have one of the standard therapies
Discussion
Sipuleucel-T immunotherapy is not recommended in symptomatic disease, the authors note.


Index Patient 4: Symptomatic mCRPC With Poor Performance Status and No Previous Docetaxel Chemotherapy

Profile
Clinical trials have generally excluded patients with a poor performance status (ECOG 3 or 4); as a result, data guiding their management are extrapolated from randomized trials of healthier patients.
Treatment recommendations
Abiraterone plus prednisone (preferred)
Ketoconazole plus steroid or radionuclide therapy to patients who are unable or unwilling to receive abiraterone plus prednisone
Docetaxel or mitoxantrone chemotherapy in select cases, specifically when performance status is directly related to the cancer


Index Patient 5: Symptomatic mCRPC With Good Performance Status and Previous Docetaxel Chemotherapy

Profile
A focus of therapy should be to maintain the excellent performance status without significant toxicity from additional therapy.
Treatment recommendations
Abiraterone plus prednisone, cabazitaxel, or enzalutamide (preferred)
If the patient received abiraterone plus prednisone before docetaxel chemotherapy, offer cabazitaxel or enzalutamide.
Ketoconazole plus steroid if abiraterone plus prednisone, cabazitaxel, or enzalutamide is unavailable
Re-treatment with docetaxel for patients who were benefiting from but discontinued treatment with docetaxel because of reversible adverse effects
Discussion
Abiraterone plus prednisone and enzalutamide appear to provide clinical benefit equivalent to (if not superior to) additional intravenous chemotherapy with an agent such as cabazitaxel. These 2 therapies have "significantly less acute toxicity and no apparent cumulative toxicity" during prolonged periods, say the authors.


Index Patient 6: Symptomatic mCRPC With Poor Performance Status and Previous Docetaxel Chemotherapy

Profile
"Treatment given in the last months of life may delay access to end-of-life care, increase costs, and add unnecessary symptom management. Patients with poor performance status (ECOG 3 or 4) should not be offered further treatment," write the authors.
Treatment recommendations
Palliative care (preferred)
For selected patients, offer treatment with abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid, or radionuclide therapy
Discussion
There is insufficient evidence demonstrating a treatment benefit in this patient population.


Because the skeletal system is the most common site for prostate cancer metastasis, the guideline also makes recommendations regarding bone health.

Bone Health

Treatment recommendations
Offer preventive treatment (eg, supplemental calcium, vitamin D) for fractures.
Choose either denosumab or zoledronic acid as preventive treatment of skeletal-related events.

"Prostate cancer deaths are typically the result of mCRPC, a painful disease," said Dr. Cookson in a press statement. "In recent years, a number of new treatments and therapeutic agents have entered the market that have been shown to minimize adverse effects and pain and prolong survival in some patients, but the fact remains that mCRPC is the terminal stage of prostate cancer."

Castration-Resistant Prostate Cancer: AUA Guideline