1. Advanced Stage Prostate Cancer Management Michael E. Karellas Assistant Professor of Urologic Oncology May 15, 2010

2. Outline Defining advanced stage/high risk disease Treatment considerations Rising PSA after primary treatment Systemic therapies

3. Clinical Staging T1 T2 T3 T4 T1: Microscopic disease discovered by PSA T2: Tumor can be felt on rectal exam T3: Tumor spreads through the capsule T4: Spread to contiguous organs (bladder, rectum)

4. Advanced Stage Disease Generally defined by: –High grade/Gleason sum ≥ 8 –Serum PSA level > 20ng/mL –Clinical stage T3 disease or higher Patients are likely to have greater tumor volume, higher grade, and increased likelihood of regional spread

5. Cancer Specific Survival After Surgery (Data adapted from the series of Patrick C. Walsh, The Johns Hopkins Hospital, 1982-1999.)

6. Diagnostic Tools CT Scan –Assess for enlarged lymph nodes suggestive of disease spread Bone Scan –Assess for tumor spread to the bone

7. Trends in Diagnosis Fewer men are presenting with locally advanced prostate cancer ~10% of men with newly diagnosed prostate cancer have locally advanced disease (T3) There is an increasing use of treatment modalities other than surgery for high-risk prostate cancers

8. Trends Continued Currently, no consensus exists regarding the optimal management of locally advanced prostate cancer Treatment is individualized

9. Surgical Treatment Approaches Patients classified with high-risk prostate cancer by common definitions do not have a uniformly poor prognosis after surgery Radical prostatectomy with pelvic lymph node removal is usually reserved for those high-risk men with smaller tumors that can be completely removed

10. Surgical Considerations The most important pathologic criteria predicting prognosis after surgery –Gleason score –Surgical margin status –Non–organ-confined disease (extracapsular extension, seminal vesicle invasion, lymph node involvement)

11. Surgical Treatment Approaches For some high-risk patients, an integrated approach combining local and systemic therapy may be advantageous Without the use of secondary treatments after surgery, 5-year biochemical relapse can be higher than 60%

12. Secondary Treatments Radiation Therapy Early adjuvant radiation therapy was administered within 3 to 6 months of surgery with undetectable PSA Results showed patients had longer time until cancer progression and lower rates of metastasis at 5 years Treatment effects from radiation can affect quality of life

13. Secondary Treatments Hormonal Therapy Early androgen deprivation (hormone therapy) may improve survival Alternative methods of androgen manipulation (antiandrogen, intermittent) remain investigational Treatment effects may affect quality of life

14. Primary Treatment with Radiation Radiation therapy (RT) is an alternative treatment strategy for these men with locally advanced disease Overall survival after RT alone for locally advanced cancer is below 50% at 10 years Hormonal therapy typically started for 2 months prior and continued for 2 years after treatment in advanced/high risk cancers

15. PSA Recurrence PSA relapse or biochemical recurrence (BCR) after surgery or radiation occurs in approximately 50,000 men per year Management remains controversial as the course of their disease is highly variable

16. PSA Recurrence After Surgery PSA recurrence is defined as PSA ≥ 0.4ng/mL at least 8 weeks post-op with continued PSA rises Date of failure is date of first detectable PSA

17. PSA Recurrence After RT ASTRO Definition used for BCR after RT –Three consecutive PSA rises, optimally separated by 3 months between measurements after radiation therapy starting at least 2 years after the start of radiation –Time of failure defined as the midpoint between the nadir and first confirmed rise –“PSA Bounce” occurs in 12 to 61% of patients as long as 18 to 36 months after treatment

18. Nomograms The majority of patients will have a BCR far earlier than will be see on imaging studies 14 Nomograms (models) exist that attempt to predict clinically significant events in patients with rising PSA after surgery or radiation therapy

19. nomogram.org

20. mskcc.org

21. Local vs Distant Recurrence Imaging studies with CT scans or Bone Scans Often difficult to detect early (small) metastatic sites –Bone scan often required PSA > 20ng/mL PET scan and ProstScint scanning are considered investigational MRI scanning can be helpful in identifying local recurrence

22. Where is the Recurrent Disease? Local recurrence –Low PSA–Lower grade tumors –Low C/T stage–Long time from treatment –Long PSA doubling times Usually patients have a durable remission after salvage radiation to the prostate bed

23. Local Recurrence Salvage radiation is delivered to the prostate bed and pelvis Consider starting radiation when PSA >1.5ng/mL Treatment related effects –Bowel and bladder irritation/bleeding –Bladder neck contractures –Erectile dysfunction

24. Biopsies for BCR Abnormal DRE in post-surgery patient often leads to biopsies of the mass/nodule Most patients will not have a mass that can be felt on exam Abnormalities discovered on imaging are often biopsied

25. Where is the Recurrent Disease? Distant metastatic disease favored in –High grade disease –PSA recurs in less than 2 years –PSA doubling time less than 10 months Systemic therapy needed

26. Hormone Therapy for Rising PSA Also called androgen deprivation therapy Usually given for patients with a rising PSA from distant spread of CaP Can be given in combination with salvage radiation therapy for local recurrence

27. Hormonal Therapy Testosterone and its metabolites are responsible for growth of normal and cancerous prostate tissue Medications block the production of testosterone or can block its action on cells which prevents prostate cancer cells from growing Temporary solution, not intended to be curative

28. Hormonal Therapy Usual regimen is oral medication (biclutamide) for 14 days followed by monthly or every 3 month injections of another medication Orchiectomy

29. Side Effects of Hormonal Therapy Risk of impotence Gyencomastia Depression Weight gain Osteoporosis Fatigue Anemia Decreased mental acuity

30. Androgen (Testosterone) Independence Gasoline fuels the Hummer like Testosterone originally fueled the prostate cancer

31. Systemic Therapies Chemotherapy should be discussed and offered to all patients with hormone-refractory prostate cancer Chemotherapy Regimens –Docetaxel –Mitoxantrone –Clincal trials

32. Docetaxel Docetaxel is the standard treatment for hormone- refractory prostate cancer –prolongs progression-free and overall survival, improves pain, and improves quality of life Toxicity of docetaxel includes myelosuppression, fatigue, edema, moderate to modest neurotoxicity, and changes in liver function

34. Summary Rates of advanced stage/high risk prostate cancer have decreased Advanced stage prostate cancer treatment is individualized and often requires multiple methods of treatment Hormonal therapy is palliative and has associated side effects Systemic chemotherapy is indicated when hormonal therapy fails