Pathophysiology, present and future treatments

Are some men more susceptible to prostate cancer than others and why?
Prostate cancer (PC) is the most common cancer in American men and is the second leading cause of male cancer deaths with 35,000 deaths annually. Autopsy studies have demonstrated histological evidence of PC in 15% of men in the 6th decade; that rate increases to 50% in the 9th decade. Recent studies demonstrate higher rates with up to 30% of men age 30-39 showing microscopic foci of PC. This prevalence is constant worldwide so that the rate of histological PC is independent of place of birth and of race. In contrast, death rates of PC vary from country to country suggesting that environmental influences might be crucial in developing clinical PC. Studies of migrating populations have further supported this viewpoint. Men moving from Asia, where PC death is uncommon, to the United States gradually achieve the same death rates from PC as the general population in the United States.

The pathogenesis of PC, is poorly understood. Men castrated before puberty almost never have clinical PC. Therefore androgens are thought to have a permissive role. Other factors influencing the rate of clinical PC are:

Genetics - Prostate cancer in a first degree relative doubles the risk for PC and this risk increases as more relatives are affected.

Race - African-American men in the United States are among the most susceptible in the world. Their risk for developing PC is 120 times higher than for Chinese men and 1 1/3 higher than for Caucasian men of a similar educational and socioeconomic class.

Dietary fat - High intake of saturated fat from animal sources, especially red meat, elevates the relative risk for development of clinically evident PC. Some studies have demonstrated a correlation with intake of dairy products, obesity and PC.

Vasectomy - The overall relative risk for men of developing PC following a vasectomy is found to be elevated in some studies; however, this association is very controversial and remains under investigation. Most likely further study will show that vasectomy will have no influence on PC.

What are the treatments and their effectiveness?
Prostate cancer can be divided into clinical stages on the basis of tumor volume and anatomical extension (Fig. 1). Each clinical stage has different treatment options and prognosis (Table 1).

The prognosis depends on the stage as well as on the histological grade of the tumor. A poorly differentiated tumor tends to metastasize more often than a well- or moderately differentiated tumor. The prognosis of PC without initial treatment is not clear, but a few studies have found that the 10 year disease-specific survival for men with a clinical diagnosis of organ-confined PC is approximately 86%, and for regional PC (not organ-confined) the 5 year survival rate is approximately 50%.

Organ-confined disease
Treatment is intended to be curative, which in the United States includes either radical prostatectomy or radiation therapy. A watchful-waiting policy is preferred in elderly (age >70 or >75 years) men with an asymptomatic organ-confined PC. In the elderly, the disease-specific survival may approach 100% because elderly patients generally die of causes other than PC.

Radical prostatectomy has been preferred throughout the last decade after new techniques like nerve sparing surgery and autologous transfusions decreased morbidity and mortality. The mortality after radical prostatectomy is 0-2%. Morbidity primarily consists of impotence (20-80%), incontinence (5%) and urethral stricture (10%). Radical prostatectomy is generally reserved for men with more than 10 years life expectancy. Radiation therapy is performed most often as external beam radiation. The therapy is associated with side effects consisting primarily of impotence (10-20%), incontinence (1%), rectal injury (2%), lymphedema (10%) and urethral stricture (6%). A major concern with radiation therapy is the fact that up to 50% of patients will have a positive prostate biopsy 18-24 months after treatment, indicating recurrent or persistent PC.

The ten year survival for both therapies is approximately 60%, being perhaps slightly better in the surgically treated group. However, a prospective study randomizing patients to either radiation therapy or radical prostatectomy is not available making any comparison between the two treatment options and between treatment and watchful waiting difficult.

Regional but not organ-confined disease
Untreated regional PC causes local complications due to growth into adjacent structures, e.g., urethra, bladder, ureters, nerves and rectum, leading to bleeding, obstructive symptoms of bowel and bladder, and pain. A common approach to regional disease is radiation therapy, but therapy varies from watchful waiting to radical prostatectomy, radiation therapy or hormonal treatment. The 10 year survival is approximately 40% and does not differ essentially from one therapy to another.

Metastatic disease
Initial metastasis is often to pelvic lymph nodes. Another prime metastatic site is to bone, especially vertebrae, pelvis, ribs and femur, causing isolated or diffuse pain due to bone fractures. Neurologic symptoms also occur due to compression of the spinal cord and brain metastasis. Anemia may be seen because of reduced hematopoiesis.

Many patients present with metastatic disease or eventually progress to advanced stage disease. Therapy may target a specific complication, e.g., transurethral resection of the prostate to relieve urinary obstruction or hematuria, or radiation therapy to painful bony metastases. Hormonal therapy attempts to control metastatic growth by androgen depletion since growth of PC is androgen dependent in most cases. When to start androgen suppression is controversial, but recent investigations have reported a slightly better survival rate when therapy is started immediately after metastatic disease is identified, compared with when symptoms from metastases begin.

Bilateral orchiectomy reduces androgen concentrations by approximately 95% with the remaining amount produced by the adrenal glands. Orchiectomy is still widely used as a safe, cost-effective method. The major concern is the permanent loss of potency and libido, and the occurrence of hot flushes in approximately 40% of patients. An alternative is therapy with a luteinizing hormone-releasing hormone (LH-RH) analog that inhibits testosterone production in the testes by decreasing (LH) release from the pituitary gland. In the past, diethylstilbestrol was widely prescribed but its association with congestive heart failure and thromboembolism has led to a decline in its use.

To obtain maximum androgen blockade, it is necessary to add an antiandrogen (e.g., flutamide) to either orchiectomy or LH-RH therapy. An antiandrogen exerts its effect by competing with the remaining androgens for the intracellular androgen receptor in the target organs. This approach improves longevity by a matter of months in selected groups of men.

What are the possibilities for improvements in therapy?
Prostatic cancer is the most prevalent cancer in men and the second leading cause of cancer death. Despite intensified efforts to improve the diagnosis and treatment of PC, the death rate has remained unchanged for decades. While it is hoped that new screening approaches, including PSA testing, and increased use of radical prostatectomy will drop the death rate, the impact of these approaches on survival will not be known for another 10-15 years. A large scale prospective clinical trial is necessary to decide the relative benefits of potentially curative treatment such as radical prostatectomy and radiation therapy versus observation. Plans for such trials are now underway.

It has been 50 years since a Nobel Prize was awarded for the demonstration that PC responds to androgen deprivation, knowledge that led to treatment (orchiectomy) which has palliated and perhaps modestly improved the survival of untold thousands. Unfortunately there has been little progress in the area of treatment of metastatic disease since then, although the concept of total androgen blockade using an androgen receptor blocker has imparted some modest gains. Trials of chemotherapeutic agents applied early in the course of PC, when metastasis is first noticed, have not resulted in any improvement. Prostate cancer is a slow growing tumor and the hope for newer chemotherapeutic agents improving survival is slight.

In the near future, management of PC should focus on patient selection. Patients with localized cancer which is likely to pro gress need to be identified and targeted for treatment. The notion that there is considerable benefit to aggressive diagnosis and treatment in men beyond the age of 70 or 75 years is not supported by the literature and this approach needs to be reassessed. Finally, a long-term study to examine the drug finasteride for prevention of prostate cancer by the reduction of prostate glandular activity has been initiated by the National Cancer Institute; however, these results are at least 5 years in the future.

Suggested Reading

Pienta KJ, Esper PS. Risk factors for prostate cancer. Annals of Internal Medicine. 1993;118:793-802.

Garnick MB. Prostate cancer: screening, diagnosis, and management. Annals of Internal Medicine. 1993;118:804-818.

Lynch JH. Treatment of advanced prostate cancer. The Journal of Family Practice. 1993;37(5):448-493.

Stanley T, McNeal J. Adenocarcinoma of the Prostate. In: Walsh PC, Retik AB, Stamey TA, Vaughan ED, eds. Campbell's Urology, 6th edition, Vol. 2. Philadelphia: W. B. Saunders Company; 1992:1159-1222.