ABSTRACT: Androgen deprivation therapy (ADT) has been used in the management of prostate cancer for more than four decades. Initially, hormone therapy was given largely for palliation of symptomatic metastases. Following several randomized trials of patients with intermediate- to high-risk prostate cancer that demonstrated improvements in biochemical control and survival with the addition of ADT to external beam radiotherapy, there was a dramatic increase in the use of hormone therapy in the definitive setting. More recently, the safety of ADT has been questioned, as some studies have suggested an association of hormone therapy with increased cardiovascular morbidity and mortality. This is particularly worrisome in light of practice patterns that show ADT use extrapolated to situations for which there has been no proven benefit. In the setting of dose escalation with modern radiotherapy, in conjunction with the latest concerns about cardiovascular morbidity with ADT, the magnitude of expected benefit along with potential risks of ADT use must be carefully considered for each patient.
There is mounting evidence that androgen deprivation therapy (ADT) for prostate cancer carries significant health risks. General awareness of the unpleasant but typically tolerable side effects of androgen suppression is not lacking. Recent studies, however, have reported clinically significant cardiovascular morbidity and increased mortality, calling into question the safety of androgen suppression. In the mid-1990s there was a precipitous rise in the use of ADT in the face of emerging data indicating improved disease control, as well as preliminary results of a randomized trial that demonstrated an overall survival (OS) benefit with ADT. What followed was a dramatic expansion in the role of hormone therapy—from primarily palliation of symptomatic metastases, to a component of definitive treatment. It is estimated that more than 600,000 men in the United States receive ADT. A recent report on practice patterns suggested that almost 70% of hormone therapy is prescribed to patients for whom there is no proven benefit.
The role of androgen suppression in the primary treatment of prostate cancer is most clear for locally advanced disease. Patients with high-risk features (prostate-specific antigen [PSA] > 20 ng/mL, Gleason score ≥ 8, T3–4) are typically treated with external beam radiotherapy (EBRT) with ADT, radical prostatectomy, or prostate seed implant plus supplemental EBRT with or without ADT (Figure 1). It has now been more than 20 years since the standard use of ADT for locally advanced disease was first established. Given the latest concerns regarding hormone therapy, its overall effect on survival must be scrutinized. This review will re-examine the impact of ADT on survival as well as the available evidence in the context of issues that have come to light in the last two decades.
Modalities and Mechanism of Action
The Nobel Prize in medicine was awarded to Charles Huggins in 1966 for his discoveries regarding the androgen dependence of prostate cancer. Dr. Huggins’ work demonstrated that orchiectomy led to clinical improvement in patients with metastatic disease and, conversely, that androgen injections caused worsening of symptoms. Androgens promote the growth of both benign glandular epithelial cells and malignant cells in the prostate. Depriving cancer cells of their stimulant causes regression that can be translated into symptomatic control in metastatic disease and possible improvement in cure rates in the definitive-treatment setting. After prolonged hormone therapy, prostate cancer can develop independence from androgens and become refractory to ADT.
Orchiectomy as the primary means of ADT has largely been replaced with pharmacologic agents because of both their reversibility and data from 10 randomized trials and meta-analysis showing equivalence to surgical castration. Leuprolide and goserelin(Drug information on goserelin)— gonadotropin-releasing hormone (GnRH) agonists, are the two most commonly used drugs. Under normal conditions, GnRH is released by the hypothalamus in a pulsatile fashion, stimulating the pituitary to secrete leutinizing hormone, which, in turn, promotes testosterone production in the testes. Over time, GnRH agonists induce downregulation of its receptors in the pituitary, thus leading to castrate levels of testosterone. Combined androgen blockade can be achieved by adding anti-androgens—bicalutamide or flutamide(Drug information on flutamide), which act directly at the prostate gland and decrease the adrenal contribution of androgens. In conjunction with radiotherapy, ADT is thought to reduce disease burden and therefore augment cell kill and improve tumor control. Androgen suppression has also been shown to promote apoptosis[6,7] and decrease hypoxia, thereby producing a synergistic effect with concurrent ionizing radiation. In vivo experiments have also shown induction of an immune response. Systemically, ADT may serve to eliminate micrometastases. The biologic mechanism of androgen deprivation in combination with radiotherapy and their interactions have not been fully elucidated. Further clarity is expected with ongoing investigations.
Although there are clear advantages to the reversibility of drugs and dampened psycho-physical insult compared with orchiectomy, the development of pharmacologic therapies with its financial incentives and ease of use has led to cavalier and inappropriate application, as evidenced by the millions of men who have received androgen suppression for nonproven indications.[10,11] In Medicare patients alone, more than $1 billion was spent on GnRH agonists in 2001, leading to a federal act instituted in 2004 that cut reimbursement such that, by 2005, reimbursement for GnRH agonists had decreased 40% to 50% compared with that in 2003. Notably, from 2004 to 2005, coinciding with the year following the mandate to reduce reimbursement, there was a decline in the use of GnRH agonists and a corresponding increase in surgical castration, although not of equal magnitude. One can hope that this imbalance is a result of more judicious ADT use and not a consequence of withholding proper treatment in the face of diminishing financial returns.
Androgen Deprivation Therapy and External Beam Radiotherapy
Numerous phase III randomized trials have been completed investigating the role of ADT with EBRT in high-risk patients (Table 1). Three trials demonstrated an OS benefit and all studies found an improvement in prostate cancer mortality—these trials form the basis for the current standard use of ADT in the high-risk setting. One of the landmark studies was a European collaborative trial that randomized 415 patients with high-grade and/or T3–4 prostate cancer to EBRT alone or EBRT plus concurrent and adjuvant ADT for 3 years. At 5 years, there was a 26% statistically significant OS benefit in patients who received hormone therapy. Recent key updates of two Radiation Therapy Oncology Group (RTOG) studies provided 10-year outcomes that remarkably also showed improvement in OS of 26%.[14,15] Given that it has been 10–20 years since the inception of these trials, it is important to note the changes in practice over this period in order to appropriately apply these data to current times. First, with the exception of one trial, these studies primarily used clinical staging as eligibility criteria and represent a more locally advanced group than what is commonly diagnosed today as high-risk. For example, in the EORTC trial, 91% of patients had T3–T4 tumors and 33% had PSA > 40ng/mL; currently this currently this is not a typical presentation. A more common high-risk patient in the modern era is one with a moderately elevated PSA, normal digital rectal exam, and Gleason score of 8; such a patient was in the minority of historic trials. In the setting of gross tumor and higher disease burden seen in earlier studies, ADT likely played a more critical role as EBRT alone at conventional doses was likely to be insufficient.
The second major change in the landscape of prostate cancer is that in recent years, a number of dose escalation trials have shown improvement in biochemical control rates with radiation doses greater than 70 Gy,[17-20] and as a result, the doses of 65–70 Gy utilized in all of the ADT trials are considered inadequate by today’s standards. Therefore, there is debate regarding the role of androgen suppression with higher doses of radiation, and the question arises as to whether ADT was simply compensating for inadequate dose. Retrospective data have suggested that the benefit of an escalated dose is greater than that from addition of ADT to conventional doses, suggesting that ADT cannot replace dose escalation. To date, however, there has been no survival benefit shown with dose escalation, so one can argue that even with increasing radiation doses, ADT may still confer an additional benefit in highly selected patients. This question remains to be answered in a randomized trial.