NCCN Guidelines® Updated
NCCN Flash Update sent July 9, 2013
NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer. These NCCN Guidelines® are currently available as Version 3.2013.
- Advanced disease: Additional systemic therapy for castration-recurrent prostate cancer (PROS-10):
- Added radium-223 as a first-line or second-line therapeutic option for symptomatic bone metastases (category 1).
- In addition, a new footnote was added to the guidelines stating: “Radium-223 is not approved for use in combination with docetaxel or any other chemotherapy. See Principles of Radiation Therapy (PROS-C, page 2 of 2).”
- Principles of Radiation Therapy (PROS-C, page 2 of 2) The following bullets were added:
- Radium-223 is an alpha-emitting radiopharmaceutical that has been shown to extend survival in men who have CRPC with symptomatic bone metastases, but no visceral metastases. Radium-223 differs from beta-emitting agents, such as samarium-153 and strontium-89, which are palliative and have no survival advantage. Radium-223 causes double-strand DNA breaks and has a short radius of activity. Grade 3-4 hematologic toxicity (2% neutropenia, 3% thrombocytopenia, 6% anemia) occurs at a low risk.
- Radium-223 is administered intravenously once a month for 6 months by an appropriately licensed facility, usually in nuclear medicine or radiation therapy departments.
- Prior to the initial dose, patients must have absolute neutrophil count ≥1.5 x 109/L, platelet count ≥100 x 109/L, and hemoglobin ≥10g/dL.
- Prior to subsequent doses, patients must have absolute neutrophil count ≥1 x 109/L and platelet count ≥50 x 109/L (per label, although this may be too low in practice). Radium-223 should be discontinued if a delay of 6-8 weeks does not result in the return of blood counts to these levels.
- Non-hematological side effects are generally mild, and include nausea, diarrhea, and vomiting. These symptoms are likely related to the fact that radium-223 is predominantly eliminated by fecal excretion.
- At the present time, except on a clinical trial, radium-223 is not intended to be used in combination with chemotherapy due to the potential for additive myelosuppression.
- Concomitant use of denosumab or zoledronic acid does not interfere with the beneficial effects of radium-223 on survival.
*For your reference, the announcement of the previous update (Version 2.2013) to the NCCN Guidelines for Prostate Cancer, distributed on March 12, 2013, is included below:
NCCN has published updates to the NCCN Guidelines and the NCCN Compendium for Prostate Cancer. These NCCN Guidelines are currently available as Version 2.2013.
- Page PROS-9
- Advanced disease: additional systemic therapy for castration-recurrent prostate cancer. Studies positive for metastatic disease, asymptomatic, secondary hormonal therapy; changed abiraterone acetate from a category 2A to a category 1 recommendation.
- Page PROS-E (2 of 3)
- Principles of Androgen Deprivation Therapy, revised the section detailing Secondary Hormonal Manipulation:
- Androgen receptor activation and autocrine/paracrine androgen synthesis are potential mechanisms of recurrence of prostate cancer during ADT (castration-recurrent prostate cancer [CRPC]). Thus, castrate levels of testosterone should be maintained while additional therapies are applied.
- Once ADT has failed, there are a variety of options that may afford clinical benefit. The available options are based on whether the patient is chemotherapy naive or already has been treated with docetaxel.
- In the setting in which patients are docetaxel naive and have no or minimal symptoms, administration of secondary hormonal manipulations including addition of, or switching to, a different anti-androgen (flutamide, bicalutamide, nilutamide, enzalutamide), addition of adrenal/paracrine androgen synthesis inhibitors (ketoconazole, abiraterone), or use of an estrogen, such as DES, can be considered.
- Abiraterone (1000 mg daily on an empty stomach) and low dose prednisone (5 mg BID) improved radiographic progression-free survival (rPFS), time to initiation of chemotherapy, time to onset or worsening of pain, and time to deterioration of performance status in a randomized controlled trial compared to prednisone alone. There was a trend toward improvement in overall survival. Use of abiraterone and prednisone in this setting is a category 1 recommendation. The side effects of abiraterone that require on-going monitoring include hypertension, hypokalemia, peripheral edema, atrial fibrillation, congestive heart failure, liver injury, and fatigue, as well as the known side effects of ADT and long-term corticosteroid use.
- In uncontrolled studies of docetaxel-naive men, enzalutamide resulted in significant PSA declines, but the use of enzalutamide in the setting is category 2A until effects on overall survival or rPFS from the on-going randomized, controlled trial in this setting are reported. The side effects of enzalutamide that require long-term monitoring include fatigue, diarrhea, hot flashes, headache, and seizures (reported in 0.9% of men on enzalutamide).
- Both randomized trials of abiraterone and enzalutamide in the pre-docetaxel setting were conducted in men who had no or minimal symptoms due to metastatic CRPC. How these agents compare to docetaxel for pain palliation in this population of patients is not clear. However, both drugs have palliative effects in the post docetaxel setting and are suitable options for men who are not good candidates to receive docetaxel.
- In the post-docetaxel CRPC population, enzalutamide and abiraterone plus prednisone have been shown to extend survival in randomized, controlled trials. Therefore, each agent has a category 1 recommendation.
- Evidence-based guidance on the sequencing of these agents in either pre- or post-docetaxel setting remains unavailable.
- The Discussion section has been updated to reflect the changes in the algorithm.
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