PROSTATE CANCER (Module 3 of Renal/Prostate Disease) Bill Lyons, M.D. UNMC Geriatrics & Gerontology Hello, my name is Bill Lyons with the Geriatrics Section at the University of Nebraska Medical Center. I would like to welcome you to Module 3 of the unit on Renal and Prostate Disease. This module will cover the subject of prostate cancer. As with other modules, this one will employ PowerPoint with voice overlay. After this module, you will try your hand at a case-based question, and we will provide you with the right answer and an explanation. We recommend that you complete this module before disengaging. When this module and question are completed, please click on “Mark Reviewed” on the main page of the minifellowship to indicate your completion.

PROSTATE CANCER: LEARNING OBJECTIVES Epidemiology and General Principles Treatment Approaches, Vigorous vs. Frail Androgen Deprivation Therapy: Benefits and Burdens This slide lists the learning objectives for this module on prostate cancer. After you have completed the module, you will be able to discuss briefly the epidemiology and general treatment principles for the disorder. You will also be able to explain how treatment approaches differ, depending on the stage of the cancer and on the characteristics of the patient. Last, you will be able to describe the pro’s and con’s of androgen deprivation therapy in managing older men with prostate cancer. You’ll note that this module does not discuss the subject of screening for prostate cancer; that issue is taken up in the unit on geriatric health care maintenance.

BACKGROUND Most common non-skin cancer in men Second-most-common cause of cancer mortality in American men Lifetime risk of prostate cancer: 16% Risk of dying of the disease 3.4% As you are no doubt aware, prostate cancer is a very common malignancy. Statistically, in fact, it is the most common cancer in men, aside from skin cancer. It is also a potentially serious disease, as it is number 2 on the list of causes of cancer deaths among American men. In the United States a man’s lifetime risk of being diagnosed with prostate cancer is 16%. On the other hand, the average American man’s risk of dying of the disease is only about 3%.

BACKGROUND, cont. Many/most elderly men die with, not of, prostate cancer Hence controversy regarding screening for and treating early-stage disease Damage done to normal tissue by treatment (radiation, surgery) may exceed that from untreated indolent cancer That disparity -- between the relatively high risk of being diagnosed with prostate cancer and the relatively low risk of dying from it – is what creates some of the clinical dilemmas we face. Put simply, although a lot of older men get prostate cancer, many or most of them will die with, not of, this disease. As a result, whether it is smart to screen men for prostate cancer is controversial, as is whether and how to treat early-stage disease. If an older man has an indolent prostate cancer that is never going to shorten his life or cause him suffering, he might be better off avoiding treatments, such as surgery or radiation, that inevitably damage normal as well as malignant tissue.

BACKGROUND, cont. Prostate cancer diagnosed Elevated PSA TURP pathology Local urologic symptoms Metastatic symptoms (esp. bone) Prostate cancer is diagnosed in a variety of clinical contexts. These generally reflect the cancer stage. Early-stage disease is diagnosed typically from elevated blood levels of prostate specific antigen, or from pathological examination of prostatic fragments taken at TURP. More advanced cancer may be diagnosed after a man presents with voiding complaints, such as hematuria, or the obstructive and irritative symptoms we discussed in the module on BPH. Occasionally men experience bone pain – typically in spine or pelvis – that leads to discovery of metastatic deposits of prostate cancer.

NATURAL HISTORY OF EARLY PROSTATE CANCER Johansson et al: population-based cohort Mean observation period 21 years N = 223 men Early stage: T0-T2 NX M0 Most early-stage tumors have indolent course Local progression, metastatic disease can arise over longer term “Findings  early radical treatment, notably among patients with estimated LE > 15 yr” Researchers are giving us a better understanding of the natural history of early-stage prostate cancer. In a recently-published study from Sweden, Johansson and his coworkers report on a population-based cohort of men who began with early stage prostate cancer. These men were followed for a mean period of 21 years, and the sample size contained 223 subjects. The researchers found that most of these early-stage tumors proved to have an indolent course for many years, although local progression and even metastatic disease does arise in some men after a long while. The authors concluded that their findings might justify early radical treatment of prostate cancer (that is, surgery or radiation), among patients whose life expectancy is thought to be at least 15 years. Conversely then, it seems, for elderly men with much reduced life expectancy, a more conservative approach might make more sense. In terms of your clinical decision making, it might be helpful to recall that the average 65 year old American man has a life expectancy of just over 15 years. The average 75 year old’s life expectancy is about 10 additional years.

OVERALL APPROACH TO TREATMENT Mortimer & McElhaney’s Schema Approach depends on function, co-morbidity Continuing with this theme, let’s consider a schema for prostate cancer treatment proposed by Drs. Joanne Mortimer and Janet McElhaney. They suggest that the treatment approach for a man with prostate cancer be determined not only by the cancer stage, but by intrinsic characteristics of the patient. A man who is highly functional and who has low comorbidity – like the fellow on the left with the barbell -- would be treated in one way. Another man who has functional impairments and serious comorbidities – as suggested by the gentleman on the right leaning on a cane -- would be treated in a second way. Here are Mortimer and McElhaney’s recommendations.

GENERAL SCHEMA: CANCER CONFINED TO GLAND Good Function, Low Comorbidity: Prostatectomy vs. radiation treatment Poor Function, High Comorbidity: Consider watchful waiting Let’s start first with low-stage cancer, in which the malignancy is confined to the prostate gland. This might arise in the setting of PSA screening or pathologic examination after a TURP. Vigorous men with low comorbidity should be advised to consider prostatectomy or radiation treatment, in the hopes of achieving cure. On the other hand, men with poor function and high comorbidity might better be served with a watchful-waiting approach. This more conservative approach might serve the frail patient better, as he is more likely to die from a disease other than prostate cancer, and is more likely to suffer complications of radical prostate cancer treatment.

GENERAL SCHEMA: LOCAL EXTENSION OF DISEASE To capsule, seminal vesicle, bladder, rectum, or pelvic nodes Good Function, Low Comorbidity: Radiation + GnRH agonist Poor Function, High Comorbidity: Consider GnRH agonist alone When prostate cancer has spread locally, a different approach is taken Local extension of disease includes spread to the prostatic capsule, to the seminal vesicle, to the urinary bladder or rectum, or to pelvic lymph nodes. Men with good function and low comorbidity are probably best treated with a combination of radiation therapy and medical castration, using a gonadotropin-releasing-hormone agonist. (I will discuss this hormonal treatment at greater length in a few minutes.) Frail men with poor function and high comorbidity are probably better off without radiation treatment, and might receive a gonadotropin-releasing-hormone agonist alone.

GENERAL SCHEMA: DISEASE OUTSIDE THE PELVIS Initial approach: Good Function, Low Comorbidity: Castration (androgen deprivation therapy) + antiandrogen (eg, flutamide) AKA “Combined androgen blockade” Poor Function, High Comorbidity: Same The initial approach for prostate cancer that has spread outside the pelvis does not depend on whether the patient is highly functional and with few comorbidites, or functionally dependent and with many other diseases. In either case, Mortimer and McElhaney recommend what is known as combined androgen blockade. This involves use of both castration (such as with a GnRH agonist) and an androgen blocker, such as flutamide.

GENERAL SCHEMA: DISEASE OUTSIDE THE PELVIS If disease has progressed: Good Function, Low Comorbidity: Stop antiandrogen treatment Poor Function, High Comorbidity: Same Most prostate cancers eventually become androgen-independent over time. Therefore, if a man with prostate cancer outside the pelvis is treated with combined androgen blockade, and he eventually shows progression of his disease despite this treatment, the next step is to stop antiandrogen treatment and monitor him. This approach does not depend on the patient’s functional status or level of comorbidity.

GENERAL SCHEMA: DISEASE OUTSIDE THE PELVIS If disease progresses still further: Good Function, Low Comorbidity Consider chemotherapy Poor Function, High Comorbidity Symptomatic management If his prostate cancer continues to progress, the patient and his care team have a decision to make. Mortimer and McElhaney suggest that, for men with good function and low comorbidity, chemotherapy be a consideration. On the other hand, men with poor function and high levels of comorbidity are not likely to benefit from chemotherapy, and their care should focus on management of symptoms, such as with opiates and NSAIDs for treatment of bone pain. Another attractive therapy for men with prostate cancer metastatic to bone is the bisphosphonate, zoledronic acid. A randomized, controlled trial looking at treatment of metastatic prostate cancer found that zoledronic acid, compared to placebo, reduced the number of skeletal-related events, such as pathologic fractures, need for radiation or surgery, and spinal cord compression.

RISING PSA AFTER LOCAL TREATMENT After RRP, typically check PSA q 3 mo Rising PSA, short doubling time predict disease progression After radiation treatment, PSA declines Typically nadir < 1.0 ng/mL reached Three consecutive increases from nadir signifies biochemical failure Let’s return to the case of a man who has undergone so-called radical therapy for management of early-stage prostate cancer. Men who undergo radical retropubic prostatectomy are usually followed with serial measurements of serum PSA, measured every three months. It is desired that such men have undetectable PSA after their surgery, and that the PSA values remain so. Evidence of cancer recurrence or progression would be a rising PSA, and men with shorter PSA doubling times have worse prognoses. Men whose prostate cancer is treated with radiation should also have very low post-treatment PSA levels, although it is not necessarily undetectable. Typically, a nadir value of less than 1 nanogram per mL is reached. Men whose prostate cancer is cured by radiation have persistently very low PSA values; men who show three consecutive increases in serum PSA values, on the other hand, are demonstrating biochemical failure.

ANDROGEN DEPRIVATION THERAPY Generally first-line therapy for advanced prostate cancer, also used as adjuvant for local treatment of high-risk disease Medical now more common than orchiectomy, outcomes similar Let’s look more in depth at the subject of androgen deprivation therapy. This approach is generally regarded as first-line therapy for advanced prostate cancer, and is also commonly used as an adjuvant treatment for local therapy of high-risk disease. Androgen deprivation therapy is the same as castration, but sounds less intimidating to most men. It can be accomplished either with drugs, such as GnRH agonists, or via orchiectomy. Outcomes for medical and surgical approaches are pretty similar, but the medical approach is now used more often.

ANDROGEN DEPRIVATION THERAPY, cont. GnRH agonists – leuprolide, goserelin Depot injections, subcutaneous implants Decrease pituitary release of LH Castration levels of testosterone w/in 3 wks Initial testosterone surge Flare of metastatic disease, bone pain Some start androgen receptor blocker beforehand Leuprolide and goserelin are gonadotropin releasing hormone agonists available for prostate cancer treatment. GnRH agonist therapy is available as depot injections or as subcutaneous implants. These agents act by decreasing the release of luteinizing hormone from the pituitary gland. Typically, they result in castration levels of serum testosterone within 3 weeks of initiating treatment. However, it is important to remember that when these drugs are started, there can be an initial testosterone surge, which can spark a flare of metastatic disease, reflected by a surge of worsening bone pain. To prevent or minimize this, many clinicians start an androgen receptor blocker before starting a GnRH agonist, and continue the androgen receptor blocker for 2-4 weeks to provide protection against the testosterone surge. I will talk a bit more about androgen receptor blockers shortly.

ANDROGEN DEPRIVATION THERAPY: BENEFITS In advanced prostate cancer: Reduced bone pain Fewer pathologic fractures Reduced incidence of spinal cord compression Reduced incidence of ureteral obstruction Survival? Unclear Androgen deprivation therapy has been shown to confer a number of benefits for patients with advanced prostate cancer. It reduces bone pain in men with skeletal metastases, and reduces the number of pathologic fractures. It also reduces the incidence of both spinal cord compression and obstruction of the ureters. On the whole, it probably improves quality of life. Whether it also prolongs life, in the setting of advanced prostate cancer, is not yet certain.

ANDROGEN DEPRIVATION THERAPY: ADVERSE EFFECTS Decreased libido and erectile dysfunction Hot flashes in up to 80% Osteoporosis with increased risk of fracture Mood and cognitive effects Body composition: lean  fat Increased fasting glucose, cholesterol Anemia Gynecomastia Of course, androgen deprivation therapy has its down side. It is definitely associated with a number of adverse effects. Sexual side effects, such as reduced libido and erectile dysfunction, are extremely common. So are hot flashes, which can be seen in up to 80% of men on this treatment. Osteoporosis, with its associated increased fracture risk, can develop, and we will return to this subject shortly. Many men experience problems with mood or cognition after starting androgen deprivation therapy. Changes in body composition are seen as well. Muscle mass declines, and fat mass increases. Metabolic changes such as increases in fasting glucose or cholesterol have been noted. Reductions in serum hemoglobin, and frank anemia, can develop as well. Finally, some men show growth of breast tissue, or gynecomastia, on treatment.

ANDROGEN DEPRIVATION THERAPY: ADVERSE EFFECTS Check BMD at baseline; start Ca + D Bisphosphonates Osteoporosis Bony metastases of androgen-independent prostate cancer Because of the significant risk of adverse effects on the skeleton in men who are prescribed androgen deprivation therapy, it is recommended that a bone mineral density determination be made at baseline, before treatment is begun. Calcium and vitamin D supplementation should be provided to men who begin androgen deprivation therapy. Those men who are found to have or who develop osteoporosis should be considered for bisphosphonate treatment. And, as I mentioned earlier, bisphosphonates like zoledronic acid can be helpful as well for men who have skeletal deposits of androgen-independent prostate cancer.

ADVANCED PROSTATE CANCER …almost always becomes androgen- independent after some time on ADT Duration of ADT response in metastatic disease typically 14-20 months Options: Hormone receptor blockers (flutamide, bicalutamide, nilutamide) Ketoconazole – decreases adrenal androgen synthesis As I said before, it’s an unfortunate fact that almost all cases of advanced prostate cancer eventually become androgen-independent after some time on treatment with androgen deprivation therapy. The duration of response to castration in treatment of metastatic disease is on the order of 14 to 20 months. When cancer progresses after treatment with androgen deprivation therapy, some options remain. Hormone receptor blockers – such as flutamide, bicalutamide, and nilutamide – can be employed. Or, ketoconazole may be helpful; in addition to its antifungal action, this agent also decreases androgen synthesis by the adrenal gland.

REFERENCES AND READINGS Baum N. Clinical Geriatrics 2005;13(5):23-26. Johansson JE et al. JAMA 2004; 291:2713-2719 Mortimer JE, McElhaney J. Cancers in the Geriatric Population. Chapter 30 in: Landefeld CS et al. Current Geriatric Diagnosis and Treatment, 2004, McGraw-Hill. The next two slides list some of the major references used to create this presentation. If you are interested in learning more about the subject of prostate cancer, these sources make excellent reading, and their bibliographies are helpful as well.

REFERENCES AND READINGS Sharif N et al. JAMA 2005;294:238-244. Stoller ML, Carroll PR. Urology. Chapter 23 in: Tierney LM Jr, McPhee SJ, Papadakis MA, Current Medical Diagnosis & Treatment, 2004, McGraw-Hill. This completes Module 3 of kidney and prostate disease, covering prostate cancer. To proceed to the question, close this window, advance to page two in this learning unit and click on “Module 3 question.” Don’t forget to complete your evaluation in order to receive credit.

Post test 1 An 82-year-old patient of yours is diagnosed with prostate cancer, and pelvic imaging strongly suggests he has extensive involvement of pelvic lymph nodes. Because of his functional dependence (he requires assistance for bathing and dressing, and he ambulates with a walker) and comorbidity (he has poorly-controlled diabetes mellitus, advanced heart failure, and mild dementia), he is started on leuprolide injections as sole therapy. All of the following statements regarding his androgen deprivation therapy (ADT) are true EXCEPT:

All of the following statements regarding his androgen deprivation therapy (ADT) are true EXCEPT: Flutamide should be started before the GnRH agonist, leuprolide. (b) ADT is expected to reduce his risk of pathologic fractures. (c) ADT is expected to prolong his survival. (d) ADT may exacerbate his cognitive problems. (e) His bone mineral density should be checked before treatment begins, and he should be considered for treatment with a bisphosphonate.

Correct Answer: (c) ADT is expected to prolong his survival. Feedback:(c) is not necessarily a true statement (and therefore is the correct answer); it is not yet clear that ADT prolongs survival in men with prostate cancer, although it does reduce the risk of many complications. Statement (a) is true, because androgen blockers reduce the odds of GnRH-induced flares. Statement (b) is true pathologic fractures are one complication that occur less frequently when GnRH agonists are employed. Statement (d) is true, and should be remembered in the care of patients like this one who already have cognitive deficits. Finally, statement (e) is true, because ADT places patients at risk of treatment-induced osteoporosis.