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Treatment of advanced metastatic prostate cancer
This document provides an overview of treatment options for advanced or metastatic prostate cancer. It discusses that androgen deprivation therapy (ADT) is usually the first line treatment and can involve medical or surgical castration. For patients where ADT is not suitable or becomes ineffective, there are secondary hormonal treatments and newer agents available, as well as chemotherapy. The document outlines considerations for intermittent versus continuous ADT and treatments after disease becomes castrate-resistant or progresses on docetaxel, including newer agents like abiraterone and enzalutamide. Symptom management is addressed in a separate resource.
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Treatment of advanced metastatic prostate cancer
- 1. Part of the“Enhancing Prostate Cancer Care” MOOC Catherine Holborn Senior Lecturer in Radiotherapy & Oncology Sheffield Hallam University
- 2. Definition Disease thathas spread distant to the prostate This can include clinical evidence of spread to the pelvic lymph nodes (N1) It can also include distant metastases that have spread via the circulatory system (M1) The most common site of distant metastases is the bone
- 3. Aim of presentation To provide an overview of the treatment of advanced/ metastatic prostate cancer Detail on the different methods of Androgen Deprivation Therapy (ADT) has been provided in a previous presentation Symptom management/treatment will also be covered in a separate presentation
- 4. First line treatmentwith ADT Androgen Deprivation Therapy (ADT) is the first line treatment for advanced/metastatic prostate cancer For N1,M0 patients, this may be combined with radical radiotherapy to treat the local disease and pelvic lymph nodes (benefits investigated as part of the ‘Stampede’ trial) ADT using either medical or surgical castration methods i.e. stopping the production of testosterone in the testes, is the preferred approach Can be achieved with either a bilateral orchidectomy (removal of testes) or more commonly the use of LHRH agonists Anti-androgen therapy (a different method that blocks the testosterone from reaching the growth receptors on the cell surface) is used to counteract any tumour flare that is possible in the first 1-2 weeks of LHRHa use.
- 5. Alternatives For menwho are symptomatic and/or at risk of complications e.g. spinal cord compression, LHRHa’s may not be appropriate (risk of tumour flare). The use of an LHRH antagonist e.g. Degarelix, or anti-androgen therapy may be considered as an alternative Anti-androgens as an alternative monotherapy to castration (high dose Bicalutamide 150mg), may also be considered for men who wish to retain their sexual function. However, anti-androgen therapy is less effective than LHRHa therapy and can compromise survival. The man must be aware of its potential impact on survival and be prepared to revert to LHRHa if sexual function is not preserved.
- 6. Timing of firstline treatment There is no question that ADT should be started immediately for men with symptomatic metastatic disease. For asymptomatic men, immediate ADT will delay progression to the symptomatic stage and avoid/decrease the risk of cancer related complications such as a spinal cord compression or pathological fracture. No clear differences in survival have been observed between immediate vs. deferred ADT for asymptomatic men. Some men may wish to avoid the side effects of ADT and a watchful waiting approach may be considered, delaying treatment until symptoms occur. However, they must be well informed about the risks of early symptomatic progression.
- 7. Intermittent ADT Sideeffects associated with long terms use of ADT can be extensive and have a significant impact on a mans quality of life. It is also thought that a resistance to lowered levels of testosterone, or an androgen independent clone, may develop over time. Cycles of alternating ‘off’ and ‘on’ periods may be used to limit side effects and may also delay the onset of resistance (keeping the cells ‘sensitised’ and ‘reliant’ on testosterone). It is mostly recommended for men who achieve an adequate PSA response with initial therapy. This is less likely in men with high pre-treat PSA, a more advanced clinical stage and a higher metastatic burden. Men on an intermittent regime must be monitored closely.
- 8. Castrate Resistant ProstateCancer Men are defined as having Castrate Resistant Prostate Cancer (CRPC) once their cancer has shown signs of progression, despite first line attempts to deprive the cells of testosterone through either medical or surgical castration Several consecutive rises in the PSA level from the initial PSA nadir (lowest level reached), is a common indication. There may also be clinical signs e.g. symptoms or radiographic evidence of progression
- 9. Hormone Refractory? Theterm hormone refractory prostate cancer (HRPC) was, until recently, a more commonly used term It was thought that the cancer cells began to grow despite a lack of testosterone i.e. they were androgen ‘independent’. This isn’t necessarily the case. It is now thought that the cancer cells still require testosterone to activate the growth receptor sites Testosterone produced by the testes has been stopped but an intra-prostatic androgen synthesis still occurs, which converts testosterone that has been secreted by the adrenal glands, into the more potent Dihydrotestosterone (DHT).
- 10. Secondary ADT options For those patients who are hormone ‘naive’ i.e. not had previous ADT, they can expect some quite spectacular results. However; When first line treatment does not achieve an adequate suppression of testosterone (typically levels of <20ng/ml) or if CRPC develops, additional methods of hormone manipulation may then be tried: Addition of an anti-androgen (Combined Androgen Blockade – CAB) Use of dexamethasone (0.5mg daily) and possibly ketoconazole (drugs that can help to stop adrenal glands producing testosterone) Use of oestrogens
- 11. More recent agents Abiraterone Acetate An inhibitor of an enzyme responsible for the intra-prostatic androgen synthesis previously described Enzalutamide (MDV3100) Blocks the androgen growth receptors and has been found to be 8-10 times more effective than bicalutamide (conventional anti-androgen)
- 12. Use in chemonaive patients Second line ADT with Abiraterone Acetate has been shown to improve overall survival and radiographic progression free survival*, and also delay the need for chemotherapy However, the use of Abiraterone Acetate and Enzalutamide prior to the use of any chemotherapy is not always available/recommended in certain countries e.g. NHS/NICE in the UK** * Arguably a more reliable measure of treatment response at this stage, than PSA response alone ** At time of writing – Sept 2014
- 13. Other agents Sipuleucel-Tis another promising agent and is a form of immunotherapy which initiates an immune response against cells expressing the enzyme Prostatic Acid Phosphatase (PAP). May be an option for men who are asymptomatic or with minimal symptoms.
- 14. CRPC and chemotherapy If disease progression occurs despite the second and third line attempts mentioned previously then ADT should continue as the androgen receptor is know to remain active. However, chemotherapy should also now be considered. In particular for those men with: Detectable metastases Symptoms of metastases and progression Rapidly rising PSA (may be asymptomatic) It is not used for men who do not have CRPC outside of a clinical trial.
- 15. History of Chemotherapy A number of studies have been conducted in this area. Research continues and is essential! Mitoxantrone plus prednisone vs. prednisone only Mitoxantrone regime improved pain control and QOL but no improvement in survival Doxetaxel based therapy then researched Superior in PSA reduction and small survival benefit Docetaxel plus prednisone now the first line standard (delivered every 3 weeks for up to 10 cycles) But side effects can be substantial. A good performance status is needed e.g. >60% Karnofsky Performance Status (KPS)
- 16. Progression after docetaxel If the disease should progress following treatment with docetaxel then Abiraterone Acetate and Enzalutamide may then be tried. Second line chemotherapy options may also be considered. Much more research and innovation is needed and is ongoing in this area
- 17. Second line chemotherapy Mitoxantrone may be used but with minimal effect Re-treatment with docetaxel may be considered if a good response was found the first time around, but some may not recommend this Another promising drug is Cabazitaxel which has shown survival advantages but has significant side effects and may be contraindicated in men with liver problems Cabozanitab is a drug type known as a tyrosine kinase inhibitor. It works to stop the action of tyrosine kinase which is a protein on the cells surface that signals the cell to grow, divide and form new blood vessels. Research is underway regarding its effectiveness.
- 18. Treatment of symptoms Treatment may be needed if the disease becomes symptomatic and begins to affect the patients quality of life. A range of treatments and therapies, underpinned by a holistic approach to care, is required.
- 19. The principles ofsymptom management and an overview of the possible symptoms associated with advanced prostate cancer and how these might be managed, is covered in a separate learning resource.