Everything You Need to Know About Prostate Cancer Basic Research

Donald Vander Griend Ph.D. Huggins Lecture Series February 12, 2005 QUESTIONS? Email me at dvguofc@yahoo.com Access these lectures on the web: http://ben-may.bsd.uchicago.edu then click on “Presentations” Lecture Outline 1. Jan 15 - The Problem, The Prostate, and The Man 2. Jan 22 - What is Cancer? 3. Jan 29 - The Causes of Prostate Cancer 4. Feb 5 - Diagnosing Prostate Cancer 5. TODAY - Treating Prostate Cancer 6. Feb 19 - Prostate Cancer Metastasis 7. Feb 26 - Hormones and Prostate Cancer 8. March 5 - Emerging and Novel Treatment Techniques - Hope for the Future Treating Prostate Cancer Early Disease • • • • • Surgery Radiation and Brachytherapy Cryotherapy Watchful Waiting Risks, Pros and Cons of each Advanced Disease • Hormone Therapy • Chemotherapy • Pain Management If You Recall…Lecture 4 Diagnosing Prostate Cancer Diagnosis: Yes or No PSA, DRE, Biopsy Staging: The extent of the disease Tumor-Node-Metastasis (TNM) Classification, Gleason Scoring, Surgical Margin, Bone Scan The Decision Discussion between patient and doctor. Thoroughly discuss various options available. Thoroughly discuss the procedure. Patient should be fully aware of risks and potential complications. Considerations Prior to Treatment  Patient’s general medical condition and age.  Tumor Grade (Gleason Score) and serum PSA.  Disease Stage and the likelihood of the cancer being confined to the prostate gland and thus potentially curable.  Estimation of outcome compared to other treatments.  Side effects from various treatments. Goals of Treatment (In Order of Priority) 1. Cancer Control 2. Preservation of Urinary Control (Continence) 3. Preservation of Sexual Function (Potency) Early Disease: Confined to the Prostate  If staging parameters indicate a good chance that the tumor has not spread outside of the prostate, then removal or destruction of the prostate gland should be curative.  Surgery – Radical Prostatectomy removes the prostate gland.  Radiation and Cryotherapy – Destroys the prostate gland. History of the Prostatectomy Hugh Hampton Young (Johns Hopkins) pioneered a systematic technique and performed the first radical perineal prostatectomy in 1904. 1943 - Theodore Millin introduced the retropubic prostatectomy approach. 1983 – Patrick Walsh described a modified “nerve-sparing” retropubic approach to preserve potency. Radical Retropubic Prostatectomy (RRP)  “Nerve Sparing” procedure developed by Walsh consisted of modified surgical technique to control blood and enhance visibility within surgical site.  Allowed for the identification and potential preservation of the nerves that control erectile function (potency).  Two neurovascular bundles on either side of the prostate that control erectile function. The Nerve Bundles Cross-Section of Prostate Urethra Prostate Neurovascular Bundles of Walsh Rectum RRP: The Surgical Approach 1.5-4 hours, usually epidural anesthesia. Incision: Begins just below navel and extends to pubic bone. Remaining Urethra is sewn to bladder neck over a catheter. Surgical Approach Pelvic Bone (Pubis) Bladder Rectum Urethra Prostate RRP: Complications  Severe or life-threatening complications are rare.  Incontinence (Urinary Control): complete incontinence is uncommon, although a significant number of patients experience some stress-incontinence. Usually improves with time.  Impotence (Erectile Dysfunction): if both neurovascular bundles were spared, potency rates range from 30-86%, depending on institution. Usually improves over time, and other ED treatments can work. RRP: Advantages  Whole prostate - and thus the entire tumor can be examined histologically.  Surgeon has access to regional lymph nodes to test if prostate cancer cells have left the tumor.  Surgical margin can be examined. T OR T Not all of tumor removed Negative Surgical Margin Positive Surgical Margin Radical Perineal Prostatectomy Very similar to Retropubic protocol Pelvic (nerve sparing, sewing Bone of urethra, etc.) Incision: Between Anus and base of Scrotum. Prostate Bladder Rectum (Pubis) Urethra Surgical Approach Perineal Prostatectomy Comparison with RRP: Comparable cure rates as well as similar urinary and potency complications. Disadvantages: Cannot access regional lymph nodes Slight increase in risk of rectal injury and associated complications. Emerging Therapy: Laparoscopic Radical Prostatectomy  Eliminates the need for a large incision by using a telescopic instruments called a laparoscopes.  Small camera attached to the laparoscope allows the surgeon to view inside the abdomen. Laparoscopic Prostatectomy  Advantages: – Less blood loss. – No large incision. – Shorter hospital stay and earlier return to activities.  Disadvantages: – – – – Longer procedure Variable surgical margins rates. Slower return of urinary continence. Variable potency rates. The Da Vinci Robot Surgeon operates from a console with a 3-D screen. Grasp controls to manipulate surgical tools within the patient. Robotic arms translate finger, hand, and wrist movements. Very High-Precision http://www.intuitivesurgical.com ? Radiation Therapy (RT)  High-Powered X-Rays that damage DNA and kill prostate cancer cells. 1. External Beam Radiation Therapy (EBRT): X-rays aimed at prostate. 2. Brachytherapy: Radioactive seed implants into prostate. General Procedure: EBRT and Brachytherapy  EBRT: 1. Map precise area that will receive radiation. 2. Multiple treatments ~5 days/week for ~8 weeks. Each treatment takes about 10 minutes and no anesthesia is required. 40-100 rice-sized radioactive seeds are implanted into the prostate via ultrasound-guided needles. Anesthesia is required. 2. All radiation inside the pellets is generally exhausted within a year. 1.  Brachytherapy History of Radiation Therapy  1898 – The first use of newly discovered “Xrays” was to alleviate the pain of pelvic bone metastases.  Early use of external beam radiation therapy was limited because of power necessary to reach deep-seated cancers such as prostate cancer.  1950’s – New and more powerful isotopes and machines were discovered and built.  Today – Computers and improved radiation technologies allow high-dose and highprecision treatment of prostate tumors. External Beam Radiation Goal: Maximize damage to the prostate and minimize damage to surrounding tissues (i.e. bladder and rectum) Seminal Vesicles Prostate History of Brachytherapy  1909 – Minet first placed a radium tube in a catheter to irradiate prostate cancer.  1970’s – Real interest occurred when Whitmore described an implant technique using I-125. Inconsistent dose distribution was a problem.  1985 – Holm and Ragde used TransRectal UltraSound (TRUS) to position Pd-103 implants and established a national brachytherapy implant course. Brachytherapy: Distribution Cross-Section of Prostate Urethra Uneven Distribution Ultrasound-guided bead placement for even distribution Image of Prostate With Radioactive Bead Implants RT: Complications EBRT  Most symptoms occur during treatments and subside after completion.  Diarrhea, rectal irritation, fatigue, frequent and painful urination, blood in the urine.  Erectile dysfunction: less common than radical prostatectomy following treatment but slower recovery. RT: Complications Brachytherapy  High initial dose of radiation that slowly fades over 1 year.  Prostate inflammation and swelling, sometimes with severe urinary symptoms.  Other, more rare symptoms include persistent urinary and bowel frequency and urgency.  Erectile dysfunction: similar to EBRT. Cryotherapy  Destroys prostate cells by freezing tissue.  Old idea that is making a comeback due to greater precision and better methods of imaging and temperature monitoring.  Method: insertion of sub-zero cryoprobes into prostate perineally (between scrotum and anus).  As yet unresolved how effective cryotherapy is compared to surgery or radiation. Cryotherapy: The Procedure Urethra Cryoprobes Rectum Prostate Watchful Waiting A.K.A. observation, expectant therapy or deferred therapy. Diagnosis of an early-stage (T1-T2), low-grade tumor. No medical treatment is provided. Patient receives regular follow-up to monitor tumor. Why Wait?  PSA and DRE can detect prostate cancer at a very early stage.  Average doubling time of a prostate tumor is quite slow (2-4 years).  Immediate radical therapy may constitute overtreatment and an introduce unnecessary urinary and potency risks.  May be appropriate if the patient is elderly and/or in poor health, and will live out their life spans without the cancer causing problems.  May also be appropriate for a younger patient who is willing to be vigilant and accept the risk of the cancer spreading. ? Advanced Prostate Cancer If the prostate cancer is no longer confined to the prostate. 12-28% of newly diagnosed prostate cancers extend outside the prostate gland or involve the regional lymph nodes (stage T3 tumors). Transition from cure to disease management. Hormone Therapy  Prostate cells and prostate cancer cells are dependant upon androgens (male sex hormones) for survival and growth.  Removal of androgens kills a majority of prostate cancer cells. Testosterone Adrenal Androgen 5% 95% Testes Prostate Growth and Function Adjuvant Hormone Therapy Hormone therapy (androgen ablation) is a standard method of treating advanced and metastatic prostate cancer. However, for newly-diagnosed advanced cancers, androgen ablation may be performed prior to prostatectomy or radiation in order to shrink the tumor. The effectiveness of this technique is still under debate. Removing Androgens 1. Orchiectomy (castration): surgical removal of the testicles. 2. Oral drug which has the same effect as castration. Blocks testosterone production. Include LHRH agonists and antagonists and oral estrogens. 3. Anti-androgens which block the effects of testosterone. 4. Combination therapies. Results of Androgen Removal Impotence Loss of sexual desire (libido) Hot flashes Weight gain Fatigue Reduced brain function Loss of muscle and bone mass Some cardiovascular risks Hormone-Refractory Prostate Cancer (HRPC)  Despite initial response rates of 80-90%, nearly all men with advanced prostate cancer develop hormone-resistant prostate cancer after 18-24 months.  These “hormone-refractory” (HR) prostate cancer cells can grow in the absence of androgens.  The behavior of HR prostate cancers differ widely between patients. Chemotherapy  What is it: using anti-cancer drugs to kill hormone-refractory prostate cancers.  More side effects than hormone therapy.  Problem: high variability between HRPCs.  A large number of studies have been conducted using numerous chemotherapies with very poor response rates (<10%).  Difficulty: criteria used to measure response.  Recently, newer agents and combination therapies have shown promising results. Management of Prostate Cancer Bone Metastases Goal: prevent pain, improve mobility, prevent complications such as fractures or compression. Goal: Maintain acceptable quality of life. Methods: bis-phosphonates, radiation of detected metastatic lesions, surgery. ? I Want to Know More…  Internet: – www.urologyhealth.org – www.prostate.com – www.ucurology.org – www.prostate-cancer-institute.org  Books: – Dr. Patrick Walsh's Guide to Surviving Prostate Cancer. By Patrick C. Walsh, Janet Farrar Worthington – Prostate Cancer for Dummies. By Paul H. Lange, et al. – The Best Options for Diagnosing and Treating Prostate Cancer: Based on Research, Clinical Trials, and Scientific and Investigational Studies. By James Jr., Ph.D. Lewis