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Metastatic prostate cancer.. a guide for treatment choice
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Metastatic prostate cancer.. a guide for treatment choice

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  • 1. By Osama Elzaafarany May 2014
  • 2. Stage IV prostate cancer : is defined by the American Joint Committee on Cancer's TNM classification system:  T4, N0, M0, any prostate-specific antigen (PSA), any Gleason.  Any T, N1, M0, any PSA, any Gleason.  Any T, any N, M1, any PSA, any Gleason Metas. dis.
  • 3. Approximately 10-20% of newly diagnosed prostate cancer cases involve locally advanced disease. Advanced disease is comparably less common, because more early stage cancer is being discovered d.t. PSA screening.
  • 4. Presentation Median survival Asymptomatic (limited) metastases ~18 to 24 months Asymptomatic (extensive) metastases ~18 months Symptomatic metastases ~9 to 16 months
  • 5. Manifestations of metastatic and advanced disease may include the following: • Anemia • Bone marrow suppression • Weight loss • Pathologic fractures • Spinal cord compression • Pain • Hematuria • Ureteral and/or bladder outlet obstruction • Urinary retention • Chronic renal failure • Urinary incontinence • Symptoms related to bony or soft-tissue metastases
  • 6.  Mainstay: “androgen suppression”.  It is a palliative tool, no cure.  Results of treatment: • median progression-free survival = 18-20 ms • overall survival = 24-36 ms.  All patients develop hormone-refractory disease.  Put in consideration the toxic effects of treatment. Any T, N1: Treatment includes ADT or radiation therapy (doses of 78-80+ Gy) with 3D-CRT/IMRT with IGRT plus long-term neoadjuvant/concomitant/adjuvant ADT for 2-3y Any T, any N, M1: Treatment includes only ADT for patients with M1
  • 7. Metas. prostate ca. Initial therapy CRPC Casteration-resistant ADT Androgen Deprivation Standard Supportive care. Bisphosphonates PSA doubling Symptoms Hormonal Chemo. 2 nd line
  • 8. Testosterone < 50 ng/dl Aim Surgical Medical Bilat orchiectomy • LHRH agonist: (e.g. goserelin, leuprolide) ( + oral antiandrogen ≥7 days to avoid testosterone flare). • LHRH antagonist. (e.g. degarelix ) • CAB: combined androgen blokade: LHRH agonist + oral antiandrogen How?
  • 9.  Patients who do not show an adequate suppression of serum testosterone (< 50 ng/dL) may be considered for CAB  Monotherapy of nonsteroidal antiandrogens are less effective but are associated with fewer hot flashes and fatigue and do not impair libido  If hormone therapy fails, that therapy should be continued into and through the next hormone manipulation.  Recent data showed that CAB is not superior to LHRH- agonists alone in treatment of metas PC.
  • 10. Gonadotropin-releasing hormone agonists: • Therapy with GnRH analogs may induce medical castration by suppressing LH production • These agonists can potentially cause a transient surge of LH when therapy is initiated before the LH levels fall (flare phenomenon) • GnRH agonists are offered in 1mo, 3mo, and once-yearly depots; it is necessary to premedicate with antiandrogen to prevent flare phenomenon • Leuprolide: 7.5 mg IM monthly or 22.5 mg IM every 3ms or 30 mg IM every 4ms or 45 mg IV every 6ms. • Histrelin: one 50mg implant SC every 12ms ; continue therapy until disease progression. • Goserelin: 3.6 mg implant SC monthly or a 10.8 mg implant SC every 3ms. • Triptorelin: 3.75 mg IM monthly or 11.25 mg IM every 3mo or 22.5 mg IM every 6ms.
  • 11. Gonadotropin-releasing hormone antagonists: • Pure GnRH antagonists suppress testosterone and avoid the flare phenomenon associated with GnRH agonists. • Degarelix: 120 mg SC x 2 doses (ie, 2 separate injections totaling 240 mg), and then, after 28 days, begin monthly maintenance dose of 80mg SC.
  • 12. Nonsteroidal antiandrogens: • Antiandrogens bind to androgen receptors and competitively inhibit their interaction with testosterone and dihydrotestosterone • These agents do not decrease LH levels and androgen production • Antiandrogens are usually used in combination with a GnRH agonist in order to prevent a disease flare caused by the transient increase in testosterone levels.  Flutamide 250 mg PO TID.  Bicalutamide 50 mg PO daily; patients refractory to other antiandrogen agents may start with 150 mg PO daily.  Nilutamide 300 mg PO daily for 30 days, and then 150 mg PO daily.
  • 13. SWOG trial, NEGM 2013 Metas Prostate Ca. 7 ms induction ADT RAND If PSA ≤ 4 Intermittent VS continous Survival results are inconclusive According to NCCN guidelines: You can consider intermittent ADT when the adverse effects of ADT is a matter
  • 14. 1) Hot flushes. 2) Osteoporosis. 3) Fractures. 4) Obesity. 5) Insulin resistance. 6) DM. 7) Alteration in lipids. 8) Cardiovascular dis.
  • 15. pain Bone health Diabetes Cardio-vascular Calcium + Vit-D Denusomab / 6ms Dexa scan / 1y RTx. strontium-89 samarium-153
  • 16. Definition: hormone-refractory prostate cancer is defined as 2-3 consecutive rises in prostate-specific antigen (PSA) levels obtained at intervals of > 2 weeks and/or Documented disease progression based on:  Findings from CT scan and/or bone scan.  Bone pain.  Obstructive voiding symptoms. With castration levels of Testosterone: ( < 50 ng/dl)
  • 17. Maintain the castration Asymptomatic Symptomatic Docetaxel / 3ws + Prednisone 5mg x 2 daily Imaging studies +ve or PSA DT < 10 ms Secondary hormone therapy Denosumab or Zomita / month
  • 18.  Aberaterone Acetate. (® Zytiga 250 mg tab)  Enzalutamide. (® Xtandi 40 mg caps)  Ketoconazole. (® Nizoral 100 mg tab)  DES: diethylstilbesterol. (® Stilphostrol 1mg tab)  Coricosteroids. (e.g: prednisone 5 mg tab)  Anti-androgens: non-steroidal:  Bicalutammide. (® Casodex 50 mg caps, 1 X1)  Flutamide. (® Eulexin 250 mg tab, 1 X 3)  Nilutamide
  • 19.  4 tabs once daily, on empty stomach.  Androgen synthesis inhibitor  To be taken with prednisone tab (5mg 1 x 2).  FDA approval as first line therapy in asympt CRPC and as second line therapy after failure of Docetaxel.  Precautions: Monitor Bld pressure / month.  Most common S.E: Fatigue, back+joint pain, periphr edema., HTN  Serious S.E: hepatic, cardiac and electrolytes. • Monitor liver functions, K+, Phosphorus / month. • Monitor Bld pressure / month.
  • 20. COU-AA-301 trial: De Bono et al, NEGM, 2011 ~ 1200 pts. Progression on Docetaxel. PS ≤ 2. Testosterone ≤ 2nmol/liter Excluded if: •Liver enz ≥ 2.5 times norm. •Chr liver dis. •Active hepatitis. •Uncontrolled HTN. •Prevoius Ketoconazole. •Signif cardiac dis. RAND Zytiga + prednisone Prednisone Increase OS: 15 ms VS 11 ms (P < 0.001) More SE : HTN, edema, K+
  • 21. Phase III trial by Ryan CJ et al, NEGM, 2013 Aberaterone acetate as first line in asymptomatic CRPC ~ 1080 pts. Metas CRPC Asympt or minimal sympt. RAND Zytiga + prednisone Placebo + Prednisone Improvement of radiograph PFS: 16.5 ms VS 8 ms (P<0.001)
  • 22.  Anti-androgen: Inhibit signaling of androgen receptor at multiple levels.  Dose: 4 caps once daily, +/- food.  Not necessary to take prednisone with it.  Could be used in pts with poor PS.  Less S.E than Abiraterone.  Given with GnRH agonists.  Seroius S.E: Seizures. (0.6 %)
  • 23. ~ 1200 pts. Progression on chemo. Any PS Visceral metas. RAND Enzalutamide Placebo. Increase MS: 13.5 ms VS 18.5 ms (P < 0.001) SE mild : Fatigue, diarrhea, hot flushes Ongoing PREVAIL trial to asses the role of Enzalutamide in pre-docetaxel settings
  • 24. Provenge ®: IV over 60 min / 2 weeks x 3 cycles. Immunotherapy. Autologous cancer vaccine. 1) Collect bld from pt. 2) Separate APC (Ag-presenting cells) 3) Exposure to (PAP-GM-CSF recombinant fusion gene) ; “prostatic acid phosphatase” 4) Re-infuse in the same pt.
  • 25. • Metas CRPC. • First line in asympt or minimal sympt pts. • Good PS. • Life expectancy > 6 ms. • No visceral metas. It was resulted in 22% reduction in mortality when compared to placebo in a phase III trial, which was published by Kantoff PW et al, NEGM 2010. Common S.E: chills. pyrexia and headache.
  • 26. Semi-synthetic taxane derivative. Dose: 25 mg/m2 over 1 hr / 3weeks. After failure of Docetaxel. TROPIC trial, Lancet 2010. Updated Ann Oncol, 2013 755 pts. CRPC Progression on Docetaxel. RAND Cabazitaxel + prednisone Mitoxantrone + prednisone. 2.5ms Improv. in OS
  • 27. Xofigo ® alpha particle-emitting radioactive therapeutic agent (half life~11 day) I.V injection over 1 min. Every 4 weeks X 6 cycles. Dose: 1.35 micro-curie / Kg. Symptomatic CRPC + Bone metas – no visceral metas The most common adverse drug reactions (≥ 10%) were nausea,diarrhea, vomiting, and peripheral edema. The most common hematologic laboratory abnormalities (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia
  • 28. ALSYMPCA, NEGM 2013
  • 29. ADT associated with 20-50% relative increase of fracture risk. ADT decrease bone menial density. Longer treatment duration greater fracture risk. Fracture risk can be assessed using algorithm FRAX® NCCN recommendations: (with ADT)  Supplemental Calcium (1200 mg daily) + vit-D (1000 IU daily).  Base line DEXA scan then annually.  Denosumab: 60 mg / 6ms : phase III trial in non-metas PC showed that Denosumab increase bone menial density by 6.7% and reduces the risk of fracture ( from 3.9% to 1.5%); Smith MR et al, NEGM 2009; 361(8):745-55.  Or Zoledronic acid (5mg/12 ms).
  • 30. Bone health in metas PC: JNCI,2002 Updated in 2004 643 pts CRPC: Asympt. Or minimal sympt. Zometa VS Placebo Increase median time To SRE No effect on OS.
  • 31. Phase III trial, Lancet 2011. CRPC pts: (Good PS + no previous bisphosphonates + life expectancy > 6ms. ) Denosumab: 120 mg / month Zoledronic acid : 4 mg / 4 weeks. Hypocalcaemia more with Denosumab: (13% VS 6%) SREs were similar Median time to first SRE increase with Denosumab: (21 ms VS 17 ms)
  • 32.  Considering the possible minimal survival benefit together with the cost and toxicity of the additional anti-androgen, first-line hormonal management of metastatic prostate cancer should be based on chemical or surgical castration only [I, B].  Patients who develop castration-resistant prostate cancer (CRPC) should continue androgen suppression and be considered for further hormone therapies; • Chemotherapy might be preferable in those with poor initial hormone response or severe symptoms. • In patients progressing following docetaxel, treatment with abiraterone, or enzalutamide, should be discussed if not used previously [II, A].
  • 33.  Docetaxel using a 3-weekly schedule should be considered for symptomatic, castration-resistant disease [I, A].  Cabazitaxel is more effective than mitoxantrone in patients previously treated with docetaxel [I, B].  External beam RT should be offered for patients with a moderate number of painful bone metastases (1×8 Gy has equal pain-reducing efficacy to multifraction schedules) [I, A].  Bone targeted therapy with one of the beta particle emitting radionuclides (strontium-89 and samarium-153) should be considered for patients with painful bone metastases [II, B].  In patients with bone metastases from CRPC at high risk for clinically relevant SREs, denosumab or zoledronic acid can be recommended, and a large trial found that denosumab delayed SREs for longer than zoledronic acid. Neither agent has been shown to prolong survival [I, B].  MRI of the spine to detect subclinical cord compression should be considered in men with CRPC with vertebral metastases and back pain [III, B].