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INCIDENCE

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Prostate cancer is the most commonly diagnosed cancer in men and a leading cause of cancer death. In the United States, there were approximately 238,590 new prostate cancer cases and 29,790 deaths in 2013 (1). Incidence and mortality rates for prostate cancer are highly variable worldwide.

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Prostate cancer incidence in the United States increased steadily throughout the second half of the 20th century. This increase appears related to the increase in life expectancy and associated rise in number of older men at risk for prostate cancer. Other factors including widespread use of prostate-specific antigen (PSA) screening also appear to have contributed to the increase in annual prostate cancer incidence. PSA screening identified a large number of prevalent cases of asymptomatic prostate cancer. The annual incidence of prostate cancer peaked at approximately 350,000 cases in 1993. After declining in the late 1990s, the annual incidence of prostate cancer has slowly increased. In contrast to the striking variations in annual rates of prostate cancer diagnosis, prostate cancer mortality rates have declined since 1990.

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SPECTRUM OF ADVANCED DISEASE

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Prostate cancer preferentially spreads to regional lymph nodes and bone. Clinically significant metastases to liver, lung, or other visceral organs are less common. Bone scans using technetium-99m methylene diphosphonate (99mTc MDP) are routinely used to assess skeletal involvement. Computed tomography scans or magnetic resonance imaging scans are used to assess regional lymph nodes.

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The spectrum of advanced disease has markedly changed in recent decades. Prostate cancer screening with serum PSA has been accompanied by a dramatic stage migration, and now less than 10% of men in the United States have radiographic evidence of metastases at initial diagnosis. Additionally, PSA testing is routinely used for surveillance after surgery or radiation therapy for early stage disease. As a result, advanced prostate cancer now includes men with rising serum PSA levels as the only indication of disease progression after prior treatment for early stage disease.

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ANDROGEN DEPRIVATION THERAPY

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HYPOTHALAMIC-PITUITARY-GONADAL AXIS

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Prostate cancers ubiquitously express the androgen receptor and require androgens for growth and survival. Testosterone synthesized by the Leydig cells of the testis is the primary source of androgens in men. Leydig cell synthesis of testosterone is regulated by luteinizing hormone (LH) of pituitary origin.

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The release of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. Levels of circulating testosterone are maintained within normal limits by negative feedback at the level of the hypothalamus and pituitary.

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Approximately 98% of plasma testosterone is present in a biologically inactive protein bound form. Free testosterone enters cells by diffusion across the cell membrane. In some tissues, including the brain, pituitary, and kidney, unmodified testosterone is bound by the androgen receptor. In other tissues, including the prostate, seminal vesicles, epididymis, adrenals, liver, and skin, testosterone is efficiently converted ...

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