Metastatic prostate cancer.. a guide for treatment choice


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Metastatic prostate cancer.. a guide for treatment choice

  1. 1. By Osama Elzaafarany May 2014
  2. 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. 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. 4. Presentation Median survival Asymptomatic (limited) metastases ~18 to 24 months Asymptomatic (extensive) metastases ~18 months Symptomatic metastases ~9 to 16 months
  5. 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. 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. 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. 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. 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. 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. 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. 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. 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. 14. 1) Hot flushes. 2) Osteoporosis. 3) Fractures. 4) Obesity. 5) Insulin resistance. 6) DM. 7) Alteration in lipids. 8) Cardiovascular dis.
  15. 15. pain Bone health Diabetes Cardio-vascular Calcium + Vit-D Denusomab / 6ms Dexa scan / 1y RTx. strontium-89 samarium-153
  16. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 28. ALSYMPCA, NEGM 2013
  29. 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. 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. 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. 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. 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].