Castration-Resistant Prostate Cancer (CRPC)
Guidelines and review literature: (EAU Guidelines, Mottet et al, 2015) (S3-Leitlinie Prostatakarzinom der DGU) (Walsh-Campbell Urology 11th Edition).
Definition of Castration-Resistant Prostate Cancer
Castration-resistant prostate cancer (CRPC) is defined by a rising PSA concentration or disease progression despite a sufficient anti-androgen hormone therapy. Since castration-resistant prostate cancer is still amenable to hormonal treatment, the old term "hormone refractory prostate cancer (HRPC)" should be no longer used (Miller, 2011).
Mechanisms of Castration Resistance:
- Changes of the androgen receptor (gene amplification, overexpression)
- Overexpression of anti-apoptotic gene Bcl-2
- Activating of androgen-independent intracellular signal transduction for proliferation
- Co-factors of the androgen receptor which increase receptor activity
- Intracellular synthesis of testosterone from cholesterol
Prognosis of Castration-Resistant Prostate Cancer
In retrospective trials, the survival time is 40 months (with visible bone metastases) and 68 months (without visible bone metastases), calculated from the time of the first PSA rising under anti-androgen hormone therapy. Survival times in many chemotherapy trials of patients with CRPC is much worse (12–18 months), this is explained by patient selection.
Hormone Therapy for Castration-Resistant Prostate Cancer:
Hormonal treatment can be expanded to maximum androgen blockade (MAB), a significant PSA response can be expected in 60–80%. Furthermore, if progress is seen under maximum androgen blockade, the withdrawal of the antiandrogen (flutamide or bicalutamide) leads to a biochemical response of about 20–30%.
The continuation of the hormone therapy (with LHRH agonists) is recommended in CRPC despite disease progression, since prognosis is better with hormone therapy. The sequence of hormonal therapy for metastatic prostate cancer is presented in fig. sequence of hormonal therapy.
Hormonal therapy of advanced prostate cancer:
(*) Antiandrogens are given for the first two weeks of GnRH agonist therapy against the flare of LH and testosterone levels [see section pharmacology/hormone therapy]. Check the testosteron level if patients progress under GnRH therapy.
(**) See figure intermittend androgen suppression for details.
(***) No definitive evidence on the optimal mCRPC treatment sequence exists.
Abiraterone is a CYP-17 inhibitor and thus an inhibitor of testosterone biosynthesis. Abiraterone 1000 mg 1-0-0 p.o. prolonged survival in patients with CRPC (after docetaxel chemotherapy) in combination of prednisolone 10 mg/d (14.8 months vs. 10.9 months with placebo). Side effects are edema, hypokalemia and hypertension by increasing the mineralocorticoids (Bono et al, 2011). Abiraterone is also beneficial before docetaxel chemotherapy: an increase in progression-free survival (16.5 vs. 8.3 months) and overall survival has been demonstrated (Ryan et al, 2013). Treatment is stopped if the disease shows progression or the treatment is not tolerated. Since 2011 (USA) and 2013 (Germany), abiraterone is approved for patients with castration resistant prostate cancer before and after chemotherapy. Please see section pharmacology/abiraterone for side effects and pharmacological details. Further phase III studies are needed to identify the best sequencing of agents (e.g. docetaxel followed by abiraterone or abiraterone followed by docetaxel).
Enzalutamide is an androgen receptor antagonist with a higher binding affinity compared to e.g. bicalutamide. In addition, it prevents the translocation of activated androgen receptor to the nucleus. In phase III trials, enzalutamide significantly prolonged overall survival after docetaxel chemotherapy compared to placebo (18.4 vs. 13.6 months) with side effects comparable to the placebo group (Shear et al, 2012). In the PREVAIL trial, enzalutamide was effective before chemotherapy in castration-resistant prostate cancer (Beer et al, 2014).The dosage is 160 mg enzalutamide p.o. once a day. The additional administration of prednisolone is possible, but not necessary. Treatment is stopped if the disease shows progression or the treatment is not tolerated. See also section pharmacology/enzalutamide for side effects and pharmacological details.
Glucocorticoids in castration-resistant prostate cancer:
Glucocorticoids can cause a weak response, they are usually used in combination with above mentioned drugs or in palliative care. Dosage: Prednisolone 10 mg/d.
Chemotherapy for Castration-Resistant Prostate Cancer
Docetaxel: First-Line Chemotherapy of Castration-Resistant Prostate Cancer
In terms of overal survival time, chemotherapy offers only a moderate improvement. Chemotherapy, however, leads to an improvement of pain associated with advanced disease. The indication for chemotherapy in castration-resistant prostate cancer is symptomatic disease (pain) with a rapid biochemical progression (PSA doubling time of less than 3 months).
The most effective treatment schedule is docetaxel 75 mg/m2 every three weeks (21 day schedule) in combination with prednisolone. This improves overal survival by three months (19.2 vs. 16.3) compared to mitoxantrone chemotherapy. Benefit is especially proven for patients without visceral metastases, with a good PSA response and with a good Karnofsky index (Berthold et al, 2008). For pharmacology and side effects of docetaxel see section chemotherapy/docetaxel.
Cabazitaxel: Second-Line Chemotherapy of Castration-Resistant Prostate Cancer
Cabazitaxel, a taxane, is an effective chemotherapeutic agent for patients with CRPC in progression under or after chemotherapy with docetaxel. Overall survival was 15.1 vs. 12.7 months in phase III comparison with a mitoxantrone chemotherapy (Bono et al, 2010). Dosage: cabazitaxel 25 mg/m2 i.v. every three weeks, in addition prednisolone 10 mg/d.
Prevention of Osseous Complications of Castration-Resistant Prostate Cancer
30–50% of patients with advanced prostate cancer suffer from pathological fractures due to bone metastases. The regular administration of a bisphosphonate (zoledronic acid) or a RANK ligand inhibitor (denosumab) inhibits osteoclasts and reduces morbidity from bone metastases.
Zoledronic acid reduced skeletal complications in Phase III trials: 33% skeletal related events (SRE) with zoledronic acid vs. 44% SRE in the placebo group (Saad et al 2004). Serious complications include renal side effects and osteonecrosis of the jaw (2–5%). Dosage: 4 mg zolendronic acid i.v. every 4 weeks. Please see section pharmacology/zoledronic acid for pharmacological details.
Denosumab is a human monoclonal antibody, which interactions via RANKL and RANK inhibit osteoclasts. Denosumab has been tested in a phase III trial advantageous compared zolendronic acid: 20.7 months vs. 17.1 months until the onset of skeletal complications. Denosumab is administered subcutaneously, the dosage is 120 mg every 4 weeks. The risk of the osteonecrosis of the jaw is comparable to zoledronic acid (Fizazi et al, 2011). For the prevention of osteoporosis, the dosage of denosumab is 60 mg s.c. every 6 months. Please see section pharmacology/denosumab for pharmacological details.
Radiotherapy of Prostate Cancer Bone Metastases
Irradiation of Painful Lesions:
Palliative percutaneous radiotherapy is the treatment of choice for a single or few well localized painful bone metastases. The dosage is around 30 Gy, which are administered in 10 fractions. A single fraction with a dose of 8 Gy is also possible.
Intravenous radionuclides for painful bone metastases:
Intravenous radionuclides are a treatment possibility for disseminated painful bone metastases. 223Ra (radium-223) is a modern radiopharmaceutical with alpha radiation, which was approved in 2013 by the FDA. Radium-223 is preferentially absorbed by bone (and thus in bone metastases) because of its chemical similarity to calcium. Due to the low range of an alpha emitter, only minor side effects on the bone marrow and other tissues have to be expected. The half-life of radium-223 is 11 days. In the pivotal study, patients with osseous metastatic castration-resistant prostate cancer and without visceral metastases were treated with six 223Ra injections every four weeks versus placebo (Parker et al, 2013). Significant differences were observed in survival time (15 vs. 11 months) and time to first skeletal complication of bone metastases (16 vs. 10 months). The rate of side effects was low: mild nausea and diarrhea. The treatment group had less bone pain (10 vs. 16%), anemia (8 vs. 9%) or spinal cord compression (4 vs. 5%).
Alternatively available radionuclides such as 89Sr (strontium-89) and 153Sm (Samarium-153) are beta emitters with a greater range and thus higher myelotoxicity. Other isotopes such as 188Re-HEDP (rhenium-188) are tested in clinical trials.
Future Prospects in the Treatment of Castration-Resistant Prostate Cancer
Many new agents for the treatment of castration-resistant prostate cancer are currently tested in clinical trials.
Sipuleucel-T is an immunotherapeutic agent to treat castration-resistant prostate carcinoma. Leukocytes from patients are obtained by plasmapheresis. Antigen-presenting cells are incubated with a specific fusion protein (containing PAP protein and growth factors). The activated leukocytes are retransfused (Three transfusions every two weeks). A significantly better survival rates with low toxicity has been reported in the pivotal trial (tested against placebo): median survival 25.8 vs. 21.7 months, three years survival rate 32% versus 23% (Kantoff et al, 2010). The drug has been approved in the USA in 2010. Sipuleucel-T is not approved in the EU or Germany. Criticism exists because of the high cost of Sipuleucel-T as well as Sipuleucel-T was not tested in comparison to another therapeutic agent such as docetaxel.
TAK-700 is a non-steroidal androgen biosynthesis inhibitor of the testicular and adrenal CYP17A1 enzyme. TAK-700 did not improve the survival in phase III trials.
Cabozantinib is a tyrosine kinase inhibitor with activity against MET and VEGFR. Phase II trials showed a good response. Phase III trials did not improve survival.
OGX-011 blocks the formation of clusterin, an upregulated protein in CRPC. The combination of docetaxel with OGX-011 was in phase II trials more effective than docetaxel alone (24 vs. 17 months). Survival was not improved in phase III trials.
The inhibition of heat shock protein 27 (HSP27) enables apoptosis of tumor cells. Phase III trial is planned.
Ipilimumab is an antibody against CTLA-4, which is an antigen on cytotoxic lymphocytes.
Lenalidomide is an immunomodulator.
Aflibercept is an inhibitor of angiogenesis.
Follow-Up Care for Prostate Cancer
Follow Up After Curative Therapy
Follow-up care consist of evalutation of treatment side effects (micturition, sexuality, ...) and measuring of the PSA concentration. Digital rectal examination can be omitted, if biochemical progress is ruled out. Imaging with PMSA-PET is only useful if local recurrence or disease progression is suspected and if imaging has an influence on the further therapy. For further details of the diagnosis and treatment of prostate cancer recurrence see corresponding sections of radical prostatectomy or radiation therapy.
The schedule of follow-up examinations have not been systematically studied. The EAU guidelines recommend: three times in the first year (3, 6 and 12 months after therapy), every 6 months in the second and third year after therapy, thereafter every year.
Follow-up with Hormone Therapy
Three and six months after the start of hormone therapy tolerability and clinical success (complaints, PSA concentration) should be determined. Measuring of the testosterone concentration is optional, but mandatory if the treatment response with GnRH analogues is insufficient.
Further follow-up is planned individually. In patients with stage M0 and a good response of hormone therapy, PSA monitoring and clinical investigations shoud be done every 3–6 months. Patients with clinical metastases require frequent examinations with additional measurement of blood count, creatinine and AP. Imaging should be performed individually based on symptoms and clinical consequences.
Prevention of Prostate Cancer
5α-reductase Inhibitors and Prostate Cancer Risk
In long-term randomized studies with 5α-reductase inhibitors to treat benign prostate hyperplasia, the incidence of prostate cancer was reduced (compared to placebo). For finasteride, the reduction of prostate cancer incidence was shown in one randomized study. However, the rate of undifferentiated tumors was higher in the verum group. For dutasteride, the reduced prostate cancer incidence was shown in the REDUCE trial. After 4 years of treatment with dutasteride 0.5 mg/d, the prostate cancer incidence in patients with increased risk was reduced to 20% (dutasteride) vs. 25% (placebo) (Andriole et al, 2010). The effect of dutasteride on the prostate cancer mortality remains unclear, neither agent was recommended by the FDA for use for chemoprevention of prostate cancer.
Selenium and Prostate Cancer Risk
Randomized trials and case-control studies could partly demonstrate a preventive effect of selenium on the development of prostate carcinoma. The meaningful SELECT study (see below) failed to demonstrate any preventive effect.
Antioxidants and Prostate Cancer Risk:
Both vitamin C and vitamin E have antioxidant properties, which are associated with a reduction of cancer risk. The Physicians Health Study II (randomized, n=14& nbsp;600) could not prove any protective effect of vitamin C or vitamin E (Gaziano et al, 2009). This result is contrary to the results of SU.VI.MAX study (see below).
Inhibition of Cyclooxygenase (COX) and Prostate Cancer Risk
Several studies have demonstrated a lower prostate cancer risk in patients with regular intake of acetylsalicylic acid. The non-specific inhibition of cyclooxygenase leads to a problematic side effect profile. Prevention trials with COX-2 inhibitors are still pending.
Studies with the Combination of Several Substrates for the Prevention of Prostate Cancer
The study data is contradictory.
Substitution with selenium, vitamin E, the combination of selenium with vitamin E or placebo (randomized, n=36 000 men). No differences between treatment groups and placebo (Lippman et al, 2009)
The daily substitution with vitamin C, vitamin E, beta-carotene, selenium and zinc reduces the incidence rate of PCA (randomized, n=5141, follow-up 8 years): prostate cancer risk halved (HR 0.52) in patients with a PSA below 3 ng/ml. However, the PSA concentration did not change due to the substitution and is therefore not a suitable biochemical marker for future prevention trials. In patients with pathological PSA levels, the reduction of prostate cancer risk was low (HR 0.88) (Meyer et al, 2005).
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- N. Mottet (Chair), J. Bellmunt, E. Briers (Patient Representative), R.C.N. van den Bergh (Guidelines Associate),
M. Bolla, N.J. van Casteren (Guidelines Associate), P. Cornford, S. Culine, S. Joniau, T. Lam, M.D. Mason, V. Matveev, H. van der Poel, T.H. van der Kwast, O. Rouvière, T. Wiegel
- Guidelines on Prostate Cancer of the European Association of Urology (EAU), https://uroweb.org/guideline/prostate-cancer/.
- Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe,
- Interdisziplinäre Leitlinie der Qualität S3 zur Früherkennung, Diagnose und Therapie der verschiedenen Stadien des Prostatakarzinoms, Langversion 3.1, 2014 AWMF Registernummer: 034/022OL, http://www.awmf.org/leitlinien/detail/ll/043-022OL.html (Zugriff am: 07.02.2016)
- Wein, A. J.; Kavoussi, L. R.; Partin, A. P. & Peters, C. A.
- Campbell-Walsh Urology
. Elsevier, 2015. ISBN 978-1455775675.