Research Article: Redefining Hormone Sensitive Disease in Advanced Prostate Cancer

Date Published: February 25, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Xiaoyu Hou, Thomas W. Flaig.


Prostate cancer is the most common cancer among men in the United States. For decades, the cornerstone of medical treatment for advanced prostate cancer has been hormonal therapy, intended to lower testosterone levels, known as Androgen Deprivation Therapy (ADT). The development of hormone-resistant prostate cancer (now termed castration-resistant prostate cancer:CRPC) remains the key roadblock in successful long-term management of prostate cancer. New advancements in medical therapy for prostate cancer have added to the hormonal therapy armamentarium. These new therapeutic agents not only provide a survival benefit but also show potential for reversing hormonal resistance in metastatic CRPC, and thus redefining hormonally sensitive disease.

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Prostate cancer is the 2nd most frequently diagnosed cancer and the 6th leading cause of death among males worldwide [1]. In 2011, it is estimated that there will be 240,890 new cases of prostate cancer and an estimated 33,720 deaths due to prostate cancer in the USA [2]. A variety of primary treatment modalities exist to treat localized cancer of the prostate including surgery, external beam radiation therapy, brachytherapy, cryosurgery, and High Intensity Focused Ultrasound (HIFU). However, for metastatic prostate cancer, the initial treatment has traditionally been hormonal therapy. ADT is effective for 2-3 years on average, and when hormonal therapy fails, chemotherapy provides a survival and palliative benefit, at the cost of considerable side effects. ADT has been given standalone and as an adjunct with other treatment modalities such as chemotherapy, radiation, and surgery [3].

Hormonal therapy has long been an integral part of prostate cancer treatment. In 1811, Scottish surgeon John Hunter (1728–1793) observed the relationship between prostate growth and testicular function for the first time in his textbook Practical Observations on the Treatment of Diseases of the Prostate Gland [4]. Louis Auguste Mercier (1811–1882) of France first performed orchiectomy for the treatment of an enlarged prostate in 1857 [4]. In 1941, Huggins first used estrogen to treat metastatic prostate cancer, which led to a Nobel prize in 1966, representing one of the first successful systemic therapies for cancer [5].

Historically, a serum testosterone level of <50 ng/dL (<1.74 nmol/L) has been used as the benchmark to assess the efficiency of hormonal therapy, as comparable to the level of suppression achieved with surgical castration [26]. Subsequently, disease progression after achieving castration levels of serum testosterone has been used as the definition of CRPC. For many years, clinicians lacked rigorously proven therapeutic hormonal options for the treatment of prostate cancer after the development of castration-resistant disease, with only docetaxel chemotherapy providing a clear survival benefit in this setting [27, 28]. However, the introduction of several new hormonal agents has challenged the traditional definition of CRPC. The phase III, landmark findings of the abiraterone acetate study by de Bono et al. have drawn into question our traditional definition of CRPC. Previously, phase I/II clinical trials of the CYP17 inhibitor abiraterone acetate demonstrated clinical activity in CRPC [31, 32]. This phase III study demonstrates a clear survival benefit from additional hormonal manipulation in a prostate cancer population previously described as hormone refractory. Clearly, simply defining CRPC as progressive disease with a serum testosterone level of less than 50 ng/dL is no longer adequate. The findings of de Bono et al. are consistent with other investigations showing ongoing androgen-related activity in the post-chemotherapy setting. Going forward, the definition of hormone-sensitive prostate cancer will need to incorporate the use of a potent CYP17 enzyme inhibitor such as abiraterone acetate. Accordingly, a much lower level of systemic testosterone, beyond the traditional 50 ng/dL benchmark and closer to the 1-2 ng/dL level, must be targeted to achieve “complete” androgen deprivation. New investigational agents such as TAK-700 and TOK-001 represent addition agents in this class of CYP17 inhibitors, currently undergoing clinical testing in CRPC [33, 35]. Additionally, the use of new generation antiandrogens, such as MDV3100, must also be integrated into our definition of hormone-sensitive prostate cancer. The available clinical trial data with this drug, although early and limited, suggests substantial activity in a traditionally defined CRPC population [48].   Source: