crpc
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crpc
- 1. Castration-Resistant Prostate Cancer (CRPC): AUA Guideline Michael S. Cookson, MD, MMHC Vice Chairman and Hart Professor of Urologic Surgery Vanderbilt University Medical Center Nashville, Tennessee
- 2. Header. Arial 48. Prostate cancer remains the 2nd leading cause of cancer deaths in American men This year alone, more than 28,000 men will die from prostate cancer Historically, the median survival for men with mCRPC was less than 2 years…but, we are beginning to impact on this and extend survival The recent surge of new treatment agents for men with mCRPC has improved survival, but unfortunately it remains an incurable disease Scope of the Problem Siegel R, et al: CA Cancer J Clin 2012; 62:10.
- 3. Header. Arial 48.Treatment Evolution 2004: Docetaxel Tannock et al. (TAX 327) 2010: Cabazitaxel de Bono et al. (TROPIC) 2010: Sipuleucel-T Kantoff et al. (IMPACT) 2011: Abiraterone de Bono et al. (COU-AA-301) 2012: Enzalutamide Scher et al. (AFFIRM) 2013: Abiraterone Ryan et al. (COU-AA-302) Since the FDA approval of docetaxel, four additional agents with survival benefit have been FDA approved based on RCT’s While greater availability of effective agents benefits patients, multiple options and sequencing may complicate decision-making 2003 2005 2007 2009 2011 2013
- 4. Header. Arial 48. Consistent with the AUA guideline methodology, a comprehensive systematic review of the published literature on therapies for CRPC from January 1996 through February 2013: 5376 potential studies 303 qualified included in the final analysis Guideline statements and a treatment algorithm were formed based on this literature review. Systematic Review
- 5. Methodology: Rating of Evidence Strength and Quality A • Well conducted RCT’s • Exceptional observational studies B • RCT’s and/or observational studies with some weaknesses C • Observational studies that are inconsistent -difficult to interpret
- 6. • Standard • Benefits are >or< than the harms • Level of evidence A or B • Recommendation • Benefits are >or< than the harms • Level of evidence C • Option • Benefits = harms • Level of evidence A, B, or C Methodology: Linking of Evidence to Statement Type
- 7. Header. Arial 48. To assist in clinical decision-making, six index patients were developed representing the most common clinical scenarios that are encountered in clinical practice These index patients were created based on the following: 1. Presence or absence of metastatic disease 2. Degree and severity of symptoms 3. Patients’ performance status (ECOG scale) 4. Prior docetaxel chemotherapy Index Patients
- 8. Header. Arial 48. 1. Asymptomatic non-metastatic CRPC and a rising PSA 2. Asymptomatic or minimally symptomatic, metastatic (mCRPC) without prior docetaxel chemotherapy 3. Symptomatic, mCRPC and no prior docetaxel chemotherapy with good performance status 4. Symptomatic, mCRPC and no prior docetaxel chemotherapy with poor performance status 5. Symptomatic, mCRPC and prior docetaxel chemotherapy with good performance status 6. Symptomatic, mCRPC and prior docetaxel chemotherapy with poor performance status Index Patients
- 9. Header. Arial 48.Clinical Algorithm Staging/ H&P/Imaging Index Patient 1 Index Patient 2 Index Patient 3 Index Patient 4 Index Patient 5 Index Patient 6 Non-metastatic CRPC and rising PSA Metastatic CRPC No prior docetaxel Prior docetaxel Asymptomatic or mildly symptomatic Symptomatic Good performance status Poor performance status Good performance status Poor performance status
- 10. Header. Arial 48. Asymptomatic non-metastatic CRPC Clinicians should recommend observation with continued androgen deprivation. (Recommendation; Evidence Level Grade C) Clinicians may offer treatment with first- generation anti- androgens (flutamide, bicalutamide and nilutamide) or first- generation androgen synthesis inhibitors (ketoconazole + steroid) to select patients who are unwilling to accept observation. (Option; Evidence Level Grade C) Index Patient 1
- 11. Header. Arial 48. Asymptomatic non-metastatic CRPC Clinicians should NOT offer systemic chemotherapy or immunotherapy to patients outside the context of a clinical trial. (Recommendation; Evidence Level Grade C) Index Patient 1
- 12. Header. Arial 48. Asymptomatic or minimally symptomatic, mCRPC without prior docetaxel chemotherapy Clinicians should offer abiraterone + prednisone, docetaxel or sipuleucel-T to patients with good performance status. [Standard; Evidence Level Grade A (abiraterone) / B (docetaxel) /B (sipuleucel-T)] Clinical Principle: As there are no direct studies comparing the agents to inform optimal sequencing, it is preferable to give the least toxic agent first and other considerations including ease of administration Index Patient 2
- 13. Header. Arial 48. Asymptomatic or minimally symptomatic, mCRPC without prior docetaxel chemotherapy Clinicians may offer first-generation anti-androgen therapy, ketoconazole + steroid or observation to patients with good performance status and no prior docetaxel chemotherapy who do not want or cannot have one of the standard therapies. (Option; Evidence Level Grade C) Index Patient 2
- 14. Header. Arial 48. Symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy Clinicians should offer docetaxel to patients with symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy. (Standard; Evidence Level Grade B) Clinicians may offer abiraterone + prednisone to patients with symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy. (Recommendation; Evidence Level Grade C) Index Patient 3
- 15. Header. Arial 48. Symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy Clinicians may offer ketoconazole + steroid, mitoxantrone or radionuclide therapy to patients who do not want or cannot have one of the standard therapies. [Option; Evidence Level Grade C (ketoconazole) /B (mitoxantrone) / C (radionuclide therapy)] Clinicians should NOT offer treatment with either estramustine or sipuleucel-T. (Recommendation; Evidence Level Grade C) Index Patient 3
- 16. Header. Arial 48. Symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy Clinicians may offer treatment with abiraterone + prednisone to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy. (Option; Evidence Level Grade C) Clinicians may offer treatment with ketoconazole + steroid or radionuclide therapy who are unable or unwilling to receive abiraterone + prednisone. (Option; Evidence Level Grade C) Index Patient 4
- 17. Header. Arial 48. Symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy Clinicians may offer docetaxel or mitoxantrone chemotherapy to patients in select cases, specifically when the performance status is directly related to the cancer. (Expert Opinion) Clinicians should NOT offer sipuleucel-T to patients with symptomatic mCRPC with poor performance status and no prior docetaxel. (Recommendation; Evidence Level Grade C) Index Patient 4
- 18. Header. Arial 48. Symptomatic, mCRPC with good performance status and prior docetaxel chemotherapy Clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or enzalutamide. If the patient received abiraterone + prednisone prior to docetaxel chemotherapy, he should be offered cabazitaxel or enzalutamide. [Standard; Evidence Level Grade A (abiraterone) /B (cabazitaxel) /A (enzalutamide)] Index Patient 5
- 19. Header. Arial 48. Symptomatic, mCRPC with good performance status and prior docetaxel chemotherapy Clinicians may offer ketoconazole + steroid if abiraterone + prednisone, cabazitaxel or enzalutamide is unavailable. (Option; Evidence Level Grade C) Clinicians may offer retreatment with docetaxel to patients with mCRPC with good performance status who were benefitting at the time of discontinuation (due to reversible side effects) of docetaxel chemotherapy. (Option; Evidence Level Grade C) Index Patient 5
- 20. Header. Arial 48. Symptomatic, mCRPC with poor performance status and prior docetaxel chemotherapy Clinicians should offer palliative care to patients with mCRPC with poor performance status who received prior docetaxel chemotherapy. Alternatively, for selected patients, clinicians may offer treatment with abiraterone + prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy. (Expert Opinion) Index Patient 6
- 21. Header. Arial 48. The following statements apply to all index patients: Clinicians should offer preventative treatment (e.g., supplemental calcium, Vitamin D) for fractures and skeletal related events to CRPC patients. (Recommendation; Evidence Level Grade C) Clinicians may choose either denosumab or zoledronic acid when selecting a preventative treatment for skeletal related events for mCRPC patients with bony metastases. (Option; Evidence Level Grade C) Bone Health
- 22. Staging/ H&P/Imaging Index Patient 1 Index Patient 2 Index Patient 3 Index Patient 4 Index Patient 5 Index Patient 6 • Clinicians should recommend observation with continued androgen deprivation • Clinicians may offer treatment with first- generation anti- androgens (flutamide, bicalutamide and nilutamide) or first-generation androgen synthesis inhibitors (ketoconazole+steroid) to select patients unwilling to accept observation • Clinicians should NOT offer systemic chemotherapy or immunotherapy outside the context of a clinical trial Non-metastatic CRPC Metastatic CRPC No prior docetaxel Prior docetaxel • Clinicians should offer abiraterone + prednisone, docetaxel systemic chemotherapy or sipuleucel-T immunotherapy • Clinicians may offer first- generation anti-androgen therapy, ketoconazole + steroid or observation to patients who do not want or cannot have one of the previously listed standard treatments. Asymptomatic or mildly symptomatic Symptomatic Good performance status • Clinicians should offer palliative care • Clinicians may offer treatment with abiraterone + prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy • Clinicians should NOT offer systemic chemotherapy or immunotherapy Good performance status Poor performance status • Clinicians should offer docetaxel • Clinicians may offer abiraterone + prednisone • Clinicians may offer ketoconazole + steroid, mitoxantrone or radionuclide therapy to patients who do not want or cannot have one of the previously listed treatments • Clinicians should NOT offer treatment with either estramustine or sipuleucel-T • Clinicians may offer treatment with abiraterone + prednisone • Clinicians may offer treatment with ketoconazole + steroid or radionuclide therapy to patients who are unable or unwilling to receive abiraterone + prednisone • Clinicians may offer docetaxel or mitoxantrone chemotherapy in select cases, specifically when performance status is directly related to the cancer • Clinicians should NOT offer sipuleucel-T • Clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or enzalutamide; if the patient received abiraterone + prednisone prior to docetaxel chemotherapy, cabazitaxel or enzalutamide should be offered • Clinicians may offer ketoconazole + steroid if one of the previously listed standard treatments is unavailable • Clinicians may offer retreatment with docetaxel to patients who were benefitting at the time of discontinuation (due to reversible side effects) of docetaxel treatment Guideline Statements on Bone Health for all Index Patients • Clinicians should offer preventative treatment (e.g. supplemental calcium, Vitamin D) for fractures and skeletal related events to CRPC patients • Clinicians may choose either denosumab or zoledronic acid when selecting a preventative treatment for skeletal related events for CRPC patients with bony metastases Poor performance status
- 23. Acknowledgements CRPC Panel Michael S. Cookson, MD (Chair) Adam S. Kibel, MD (Vice Chair) Philipp Dahm, MD, MHSc Christine Engstrom, PhD, CRNP, AOCN Stephen J. Freedland, MD Maha Hussain, MD, FACP Daniel W. Lin, MD William T. Lowrance, MD William K. Oh, MD David F. Penson, MD Bruce J. Roth, MD Methodology Hassan Murad, MD, MPH Osama Altayar, MD Mohammed Nabhan, MD AUA Guidelines Staff . Acknowledgements FOR MORE INFORMATION, PLEASE ATTEND: Detection of Prostate Cancer & Castration-Resistant Prostate Cancer Course May 6, Noon-130pm San Diego Convention Center 6C
Hinweis der Redaktion
- Good morning Mr. President, Mr. Secretary, Members and Guests. Today I will present to you the newly developed CRPC Guidelines. I will point out that this is the first time the AUA has addressed the management of this disease state, and given the current state of health care it is both timely and imperative for our memberswho treat men with APC to be familiar with this information.
- Prostate cancer is the most commonly diagnosed malignancy in American men and remains the second leading cause of cancer deaths. In 2012, approximately 240,000 men were diagnosed and over 28,000 died of the disease. Prostate cancer deaths are typically the result of metastatic castration resistant prostate cancer (mCRPC), and historically the median survival for men with mCRPC was < 2 years.
- The treatment of CRPC has undergone a dramatic change over the past decade. Prior to 2004, once patients failed primary androgen deprivation, all treatments were palliative. Landmark studies in demonstrated that docetaxel improved survival for these patients. Since then, 4 additional agents that show a survival benefit have been FDA approved on the basis of randomized clinical trials. These agents have been tested in multiple disease states to determine which patients benefit from each treatment. While greater availability of effective agents benefits patients, multiple options and sequencing may complicate decision-making
- 1.TheAUA conducts rigorous systematic reviews in accordance with the Institute of Medicine’s standards for trustworthy guidelines.2. The systematic review encompassed publications from January 1, 1996 to February 14 20133. This yielded 5376 potentially relevant studies of which 303 qualified through inclusion/exclusion criteria and were included in the final analysis.4.The multidisciplinary expert panel then developed Guideline statements and a treatment algorithmbased on this literature review.
- The quality of the evidence was assessed according to standard methodology,and studies were categorized by Grade based on the certainty of the results as a High, Moderate or Low.
- The AUA nomenclature system explicitly links statement types to the body of evidence according to Grade and the Panels judgment regarding the balance between the benefits risk or harms of the treatment.
- These Guidelines were developed to provide a rational basis for treatment of patients with CRPC based on our current understanding of the data. To this end, six index patients were developed representing the most common clinical scenarios that are encountered based on:the presence or absence of metastatic disease,the degree and severity of symptomsthe patients’ performance status, and the pretreatment with docetaxel-based chemotherapy.
- 8. Based on our current understanding of the data, 6 index patients were developed representing the most common clinical scenarios that are encountered.
- This rationale based on the most common clinical presentations of men with CRPC were used as the rationale for development of a user friendly management algorithm.
- In men with non-metastatic CRPC, no treatment has been shown to prolong overall survival. As all agents have potential side effects, we must first do no harm. As such, it was the panel judgment that observation be the recommended. There was a strong panel judgment that patients should be encouraged to enter clinical trials when available. However, some patients may still choose to forego this approach in favor of first generation anti-androgens or first generation androgen synthesis inhibitors.
- While multiple agents have been shown to prolong survival for men with metastatic CRPC, none of the agents are FDA-approved in the non-metastatic setting. Thus, the panel strongly recommended against this practice for multiple reasons, clinicians should NOT offer systemic chemotherapy or immunotherapy to patients outside the context of a clinical trial.
- As a standard, Abiraterone and docetaxel (both with prednisone) and sipuleucel-T are currently the only agents that have an FDA indication for use in men with mCRPC who have not yet received docetaxel chemotherapy. For each agent, there is a randomized clinical trial that has shown a benefit for the drug. Unfortunately, there are no direct studies comparing the agents that can be used to inform optimal sequencing. As a general principle, it is preferable to give the least toxic agent first, particularly given the lack of head-to-head data, but this must be considered in light of other considerations, including convenience of administration. As such, patients should be informed of all options and be allowed to make an informed decision based upon their own preferences and goals related to therapy.
- In patients who elect not to receive the standard therapies for whatever reason, there are a number of other options available. Data to support the use of these options in the setting of asymptomatic or minimally symptomatic prostate cancer is limited and generally of lesser strength than the standard treatments. Some have suggested that the removal of anti-androgen therapy may have a beneficial effect on mCRPC.Manipulation with existing first generation anti-androgen agentscan only be considered an option in this setting, if only because they offer patients who do not want or cannot have one of the standard therapies (for whatever reason) a relatively simple, non-toxic therapeutic option.
- In Index Patient 3, the symptomatic, metastatic CRPC with good performance status and no prior docetaxel chemotherapy, the Panel recommendedAs a Standard,clinicians should offer Docetaxel+Prednisone should be offered Based on results of 2 RCT’s (TAX 327 and SWOG 9916)As a Recommendation, clinicians may offer abiraterone + prednisone to these patients prior to docetaxel chemotherapy.
- As an Option, clinicians may offer ketoconazole + steroid, mitoxantrone or radionuclide therapy to patientswho do not want or cannot have one of the standard therapies.Finally, it it recommended by the Panel that clinicians should NOT offer treatment with either estramustine or sipuleucel-T in this setting.
- In Index Patient 4, symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy, the Panel recommendedAs an option, clinicians may offer treatment with abiraterone+prednisoneAnd, clinicians may offer as an option treatment with ketoconazole + steroid or radionuclide therapy for those who are unable or unwilling to receive abiraterone + prednisone.
- Also in Index Patient 4, it was the Expert Opinion of the Panel that clinicians may offer docetaxel or mitoxantrone chemotherapy to patients in select cases, specifically when the performance status is directly related to the cancer. The Panel recommended that clinicians should NOT offer sipuleucel-T to patients in this clinical scenario based on the fact that patients with very symptomatic disease and poor performance status would be unlikely to gain significant survival benefit from use of immunotherapy.______________________
- Index Patient 5, the Symptomatic, metastatic CRPC with good performance status and prior docetaxel chemotherapy, The Panel recommended:As a Standard, clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or enzalutamide. If the patient received abiraterone + prednisone prior to docetaxel chemotherapy, he should be offered cabazitaxel or enzalutamide.
- In Index Patient 5, the Symptomatic, metastaticCRPC with good performance status and prior docetaxel chemotherapy As an Option, clinicians may offer ketoconazole + steroid if abiraterone + prednisone, cabazitaxel or enzalutamide is unavailable.Also as an Option, clinicians may offer retreatment with docetaxel to patients with mCRPC with good performance status who were benefitting at the time of discontinuation (due to reversible side effects) of docetaxel chemotherapy.
- Palliative care is an interdisciplinary, holistic approach to managing advanced disease such as prostate cancer with a limited prognosis. It can include controlling symptoms that are physical, psychological, spiritual and social. The goal of palliation is to prevent and relieve suffering and to support the best possible quality of life for the patient and family.As such, for Index Patient 6 Symptomatic, metastatic CRPC with poor performance status and prior docetaxel chemotherapy, the Panel felt that based on expert opinion, clinicians should offer palliative care.Alternatively, for selected patients, clinicians may offer treatment with abiraterone + prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy is selected cases.
- The Guideline also includes statements on bone health that apply to all index patients with CRPC. These include the recommendation that clinicians should offer supplemental calcium, Vitamin D for preventative treatment of fractures and skeletal related events. As an Option, clinicians may choose either denosumab or zoledronic acid when selecting a preventative treatment for skeletal related events for metastatic CRPC patients with bony metastases.
- This demonstrates the Clinical Algorithm that was based on the Panel’s methodology and approach to patients with CRPC and will be available via Internet and Pocket Guide.
- I wish to acknowledge the dedication and determination of my esteemed panel. This was truly a group project that could not have been completed without the cooperation of all involved. This included not only Urologists, Urologic Oncologists, Medical Oncologists with special expertise in GU Oncology and Palliative care, Nursing and Methodologist. Special thanks to Dr. Adam Kibel, Vice Chair, who’s contribution was especially impactful.