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Intermittent Androgen Deprivation Therapy for Prostate Cancer

Department of Medicine, Division of Hematology/Oncology, Medical University of South Carolina, Charleston, South Carolina, USA

Correspondence: Uzair B. Chaudhary, M.D., Medical University of South Carolina, Division of Hematology/Oncology, 96 Jonathan Lucas Street, 903 CSB, P.O. Box 250623, Charleston, South Carolina 29425, USA. Telephone: 843-792-4271; Fax: 843-792-0644; e-mail: chaudu{at}musc.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
After completing this course, the reader will be able to:

1. Explain the utility of intermittent androgen deprivation therapy in the management of patients with prostate cancer.
   
2. Describe the preclinical observations leading to the development of intermittent androgen deprivation therapy.
   
3. Identify the limitations in using intermittent androgen deprivation therapy for prostate cancer.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
Androgen deprivation therapy for prostate cancer is associated with several complications, including loss of libido, hot flashes, night sweats, psychological stress, osteoporosis, anemia, fatigue, loss of muscle mass, glucose intolerance, and changes in lipid profile. The natural history of prostate cancer while on such therapy is the attainment of an incurable androgen-independent state. Early diagnosis by prostate-specific antigen screening, longer life expectancies, and a penchant for immediate therapy pose a problem where clinicians have to balance the potential benefits of early hormonal therapy with the risks of development of these metabolic and psychological complications. Intermittent androgen deprivation offers clinicians a prospect to improve quality of life in patients with prostate cancer by harmonizing the benefits of androgen ablation with a reduction in treatment-related side effects and expenditure. In this review we discuss the challenges and opportunities of this mode of therapy and shed light on some of the underlying molecular mechanisms.

Key Words. Prostate cancer • Intermittent androgen deprivation • Hormonal therapy

	INTRODUCTION

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
Prostate cancer is the second leading cause of cancer-related death among men in the U.S. An estimated 220,900 men were projected to be diagnosed with this disease in 2003, with about 28,900 deaths [1].

It has been known for a long time that the growth of prostate cancer cells is driven by androgens. In males, androgens are synthesized by the testes and by the adrenal gland. The testes are the major source of testosterone, while the androgens produced by the adrenal gland are hormone precursors that are enzymatically converted to testosterone and dihydrotestosterone in prostatic and peripheral tissues [2]. The hormonal treatment of advanced prostate cancer gradually evolved with time. In the 1940s, Huggins et al. first showed that, in a significant number of patients with metastatic prostate cancer, castration dramatically improved clinical symptomatology and serum acid phosphatase levels [3]. In the 1970s, Labrie et al. [4] introduced the concept of total (and not merely testicular) androgen ablation by the use of nonsteroidal antiandrogens. In theory, this promised a more complete and resilient response. However, ensuing multiple randomized trials produced results that were not always congruous with expectations [5–7].

Despite a primary response rate of 80%–90% with hormonal ablation, almost all patients, in due course, advance to a state of androgen independence manifested by increasing prostate-specific antigen (PSA) levels, new lesions on bone scans, and worsening symptoms. This condition is also accompanied by the attainment of high resistance to cytotoxic drugs [8, 9]. The median survival time in patients with androgen-independent prostate cancer is about 18 months.

Androgen deprivation is associated with a variety of side effects, including hot flashes, loss of libido, fatigue, cognitive dysfunction, and depression. Long-term side effects like osteoporosis and anemia are also considerable. Androgen deprivation achieved by luteinizing hormone-releasing hormone (LHRH) with or without an antiandrogen is expensive. Many patients are now being diagnosed with early or progressive disease on the basis of a rising PSA level alone, and hormonal therapy is being employed earlier in the course of disease. As a consequence, many patients are being treated with hormonal therapy at the asymptomatic stage and, by virtue of the natural history of the disease, survive for years after diagnosis.

The observations that continuous androgen deprivation (CAD) is not curative and can significantly affect quality of life have led to the search for alternative hormonal manipulations. An ideal hormonal manipulation would lead to an improvement in side effect profile while enhancing antitumor efficacy and prolonging time to androgen independence.

	ACQUISITION OF HORMONE INDEPENDENCE

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
In an androgen-depleted environment, normal prostate epithelial cells never develop the ability to regenerate and grow [10, 11]. However, prostate cancer cells manage to break away from this and emerge as androgen independent. Several hypotheses have been put forth to explain this. Perhaps the two most important ones are the clonal selection hypothesis and the adaptation hypothesis.

Clonal Selection Hypothesis
Prostate epithelium is made up of three different types of cells. The largest portion is secretory epithelial cells. Others are basal epithelial cells and endocrine-paracrine cells. Normal secretory epithelial cells require androgens to survive, while basal cells can endure without them. Basal cells are understood to be the stem cells of the prostate, or cells that generate secretory epithelial cells [12, 13]. Only epithelial cells undergo apoptosis upon androgen withdrawal and not basal or stromal cells [14]. The clonal selection hypothesis relates to the selective survival of preexisting androgen-independent cells within the tumor by hormonal deprivation [15]. These clonal cells are thought to be poorly differentiated and akin to basal or stem cells.

	ADAPTATION HYPOTHESIS

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
This hypothesis puts across the suggestion that androgen independence may be an intrinsic, but dormant, property of some prostate cancer cells that is activated in response to androgen deprivation [16]. This could happen through one or more of several proposed mechanisms:

• Attainment of increased sensitivity of androgen receptors to very low serum levels of androgen [17].
  
• Acquisition of mutations in the androgen receptor protein eventually proceeding to activation of the androgen-signaling axis with ligands other than testosterone [18]. These newer ligands may be exogenous molecules such as drugs. It has been suggested that, to a mutated receptor, flutamide may act as such an alternative ligand. Indeed, in some patients with progressive disease while on flutamide, withdrawal of this drug can lead to paradoxical declines in serum PSA levels.
  
• Acquisition of an effectual circumvention where steroid hormone receptors are activated without a ligand. Three growth factors—insulin-like growth factor, keratinocyte growth factor, and epidermal growth factor—have been shown to activate receptor tyrosine kinases (RTKs) [17]. After RTKs are activated, the androgen receptor is phosphorylated by either protein kinase B (Akt) or mitogen-activated protein kinase, resulting in ligand-independent androgen receptor activation [19].
  
• Unmasking of pathways that can facilitate proliferation and inhibit apoptosis. The bcl-2 gene is a bypass candidate that can block apoptosis. bcl-2 is not expressed in normal prostate cells, but it is present in androgen-independent prostate cancer [20].
  

It is generally believed that more than one possible mechanism operates in any given case of androgen insensitivity.

	INTERMITTENT ANDROGEN DEPRIVATION

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
Prolonged androgen deprivation provides the stimulus for activating dormant nonandrogen-mediated signaling pathways. Intermittent replacement of androgen may, therefore, inhibit the biochemical switch leading to activation of such pathways with resultant clinical benefits.

Experiments involving hormone-dependent breast cancer in the Nb rat model revealed that, with a moderate reduction in hormone levels, tumor growth diminished and the emergence of a hormone-independent state was delayed. Castration in the same rat model actually accelerated progression to the hormone-independent state and hastened the death of the animal [21].

The effects of intermittent androgen deprivation (IAD) were investigated using the Shionogi tumor model, and it was noticed that time to progression to androgen independence was prolonged threefold, from 50 to 150 days [10]. Similarly, in studies on LNCaP human prostate cancer sublines, it was found that IAD helped maintain androgen-regulated PSA gene expression and prolonged the time to androgen-independent PSA regulation [22].

	INTERMITTENT ANDROGEN DEPRIVATION IN HUMANS

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
The above preclinical data, coupled with the desire to minimize the side effects and cost of therapy, has resulted in a number of clinical trials exploring the utility of IAD. The majority of these studies are single-institution phase II studies, but they do provide valuable information regarding the usefulness of IAD.

Klotz et al. described IAD therapy in a group of 20 patients with advanced prostate cancer who had received androgen deprivation therapy for a median period of 10 months (diethylstilbestrol in 19 patients and flutamide in one patient) prior to abandonment of all such treatment [23]. Disease progression occurred after a median interlude of 8 months. Nine of 10 patients who had been rendered impotent by androgen deprivation therapy resumed sexual activity within this interval. Importantly, all patients who relapsed had a rapid clinical response following resumption of androgen deprivation therapy.

From observations made on a group of 47 patients, Goldenberg et al. first helped define the optimal trigger points in IAD using PSA level [24]. Patients were treated with combined androgen suppression for 24–32 weeks until a PSA nadir in the normal range (4.0 ng/ml) was attained. Medication was then stopped until the serum PSA level increased to a mean value between 10 ng/ml and 20 ng/ml. The first two cycles were of 73 and 75 weeks’ duration, with mean percentages of time off therapy of 41% and 45%, respectively. Serum testosterone normalized within 8 weeks after stopping androgen suppression, and the off-treatment phase was associated with an increased sense of well-being and recovery of libido and potency. The mean and median overall survival times were 210 weeks and 166 weeks, respectively. The results of this study laid a foundation for phase III trials now under way that are being conducted by the Southwest Oncology Group (SWOG) and the National Cancer Institute of Canada (NCIC).

Since the development of LHRH agonists, many studies have examined this modality (Table 1) [23–29]. Most of the studies used a treatment schema whereby patients were treated with an LHRH agonist (with or without antiandrogens) until PSA became undetectable or a nadir was reached, at which time, androgen deprivation was stopped. Androgen deprivation was resumed once the PSA level had climbed to an arbitrarily fixed level (often 50% of the initial pretreatment value or an absolute value greater than 5–10 ng/ml).

From one study, Strum et al. derived that those hormone-naïve patients who achieved and maintained an imperceptible PSA level for at least 1 year during androgen deprivation could anticipate a prolonged off-therapy phase duration [28]. Attainment of a serum testosterone level 150 ng/dl in 4 months after antiandrogen withdrawal was another predictor of a prolonged off-therapy phase. There seems to be a wide variation in the amount of time spent in the off-treatment phase, as patients may experience treatment holidays lasting 3 years or longer, especially those with localized disease or serological progression after definitive local therapy.

IAD does not avert the emergence of androgen independence. Grossfeld et al. demonstrated a progressive decline in the duration of the off-therapy phase and an increase in the duration of the on-therapy phase in subsequent cycles. Patients spent an average of 45% of the time not receiving therapy. Furthermore, 5 of 61 patients (8.1%) demonstrated progressive disease, with a median time to progression of 48 months [29].

	QUALITY-OF-LIFE ISSUES

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
A significant finding consistent among all seven studies outlined in Table 1 was the recovery of libido during the time off treatment in men who had normal libidos prior to the initial androgen deprivation therapy. There was also a subjective improvement in overall sense of well-being during the off-treatment phase.

Information from several randomized trials suggests that quality of life is enhanced by total androgen blockade in terms of metastatic pain, overall performance status, and urinary symptoms [30, 31]. da Silva thoroughly explained that there may be a discrepancy between the physician’s and the patient’s assessments of potency and pain [32]. A study of 47 patients undergoing treatment for prostate cancer, assessed with validated self-administered quality-of-life questionnaires, revealed that patients treated with androgen deprivation fared worse with respect to psychological distress, hot flashes, loss of energy, and reduced sexual enjoyment [33]. Grossfeld et al. evaluated self-reported health-related quality of life (HRQOL) in 10 patients undergoing IAD [34]. These 10 patients undertook 14 treatment cycles in which HRQOL data were available for both the on-therapy and off-therapy phases. All patients experienced clinically significant improvements in vitality/fatigue, sexual function, and sexual bother during the off-therapy phase. Patients younger than 71 also reported clinically significant improvements in physical role and health compared with 1 year ago. Additionally, patients older than 71, reported significant improvements in physical function, general health, and urinary function.

Age-related osteopenia and osteoporosis are common in men with prostate cancer, and there is proof of a further reduction in bone mineral density with androgen deprivation. Bone mineral density loss is 3%–5% in the first year of androgen blockade therapy, with an increase in osteoporotic fracture incidence [35]. Jiang and Higano reported the dynamics of bone mineral density during IAD in prostate cancer patients without bone metastases. Bone mineral density changes seemed to parallel the on- and off-treatment periods. The maximum loss of bone mineral density occurred during the first cycle. There was less loss during the off-treatment periods [36].

Anemia related to androgen deficiency can be significant and occurs commonly in men receiving total androgen blockade. It is normochromic, normocytic, starts at the beginning of androgen blockade, and usually resolves after androgen blockade is discontinued [37]. Since anemia is reversible, IAD can improve quality of life by reducing the degree and duration of anemia.

Serum testosterone levels often return to within the normal range after a median of 4–6 months after the termination of androgen deprivation therapy, which is coincident with the reduction in symptomatology noticed during the off-treatment period in patients undergoing IAD [25, 26]. In a recently reported prospective analysis, serum testosterone levels were measured at 3-month intervals in 68 men after the withdrawal of androgen deprivation therapy. The median time to normalization of testosterone levels was 7 months (range 1–58 months). At 3, 6, and 12 months, 28%, 48%, and 74% of men, respectively, had normal testosterone levels [38]. Central obesity is commonly associated with increased cortisol levels, increased plasma-free fatty acids, insulin resistance, and increased cardiovascular risk. An increase in adipose deposition in the truncal subcutaneous and muscle areas is a well-recognized feature of testosterone insufficiency [39–41]. Androgen deprivation therapy may also have important, but yet understudied, implications with regard to cardiovascular health and reduced muscle performance. This may be another area where IAD therapy has potential benefits.

	UNRESOLVED ISSUES

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
Survival
The most important question is the potential impact on survival of IAD in comparison with CAD. Tunn et al. reported results from a phase III study comparing IAD with CAD in patients with PSA relapse after radical prostatectomy [42]. In that study, 83 patients received IAD and 68 patients received CAD. In the IAD group, the PSA value to terminate the off-treatment phase was set at 3 ng/ml. The mean follow-up was 24 months. There was no statistically significant difference in time to progression between the two arms of the study. However, in the off-treatment phase of IAD, greater than 90% of patients recovered normal testosterone levels. Mean off-therapy phase durations were 9.9 months in the first cycle and 6.1 months in the second cycle.

Another international randomized clinical trial reported by Schasfoort et al. compared IAD with CAD in patients with advanced prostate cancer [43]. There were 97 and 96 patients in the two arms, respectively. The criteria to start therapy in patients randomized to IAD were a PSA level 20 mg/ml, for patients with disease stage N0-3 M1, or a PSA level 10 mg/ml, for patients with disease stage N1-3 M0. The median observation time in the study was 24.5 months. The median times to clinical progression or PSA relapse were 18 months in the IAD arm and 24.1 months in the CAD arm. The median time to survival had not been reached at the time of reporting. Thirty-five patients in the IAD arm and 50 patients in the CAD arm withdrew early, before the observation period ended, and the main reasons given were patients’ wishes, adverse events, and lack of efficacy. Long-term follow-up is needed from these randomized trials to assess the impact on survival (beneficial or adverse).

A randomized prospective clinical trial comparing IAD with CAD has been initiated in men with PSA relapse without clinical evidence of metastatic disease following radiotherapy for prostate cancer through the NCIC. This trial, JPR 7, is now a cancer trials support unit-listed trial and is open to participation by all. The SWOG initiated a randomized clinical trial comparing IAD with CAD in men with distant metastatic disease, and that trial has enrolled over 1,000 patients so far with a target accrual of 1,512 patients. These trials will give crucial information for defining the precise role of IAD in the management of patients with prostate cancer.

Patient Selection
Another unresolved issue is the appropriate selection of patients for IAD therapy. Initial PSA level, Gleason score, extent of disease, PSA doubling time, and time to relapse after definitive therapy may influence the utility of IAD. De La Taille et al. recently reported the results of a study of 146 patients who were treated with IAD, 24 of whom developed biochemical progression. Using multivariate analysis, a Gleason score 8, metastatic disease or positive lymph nodes at the time of initiation, and age <70 years were strong predictive factors for biochemical progression [44]. In another study by Sciarra et al., IAD was employed in patients with biochemical failure after radical retropubic prostatectomy. Patients with Gleason scores 8 fared less well than those who had combined Gleason scores <7 [45].

We consider the use of IAD for patients with localized disease who are not appropriate candidates for definitive local therapy but are at a significant risk for disease progression and for patients with PSA relapse after definitive local therapy. It is essential to pay close attention to quality of life and to recovery of normal testosterone levels during off-treatment periods [38]. When PSA is undetectable in a patient whose serum testosterone level has normalized, one can be optimistic that the treatment of prostate cancer was effectual [38]. Recovery of serum testosterone is also of psychological and physiological advantage to patients.

	CONCLUSION

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 
IAD can ameliorate some of the short- and long-term side effects associated with CAD. IAD can be considered a reasonable approach for patients with prostate cancer, provided they are fully informed of the investigational nature of the therapy, until mature results are available from randomized clinical trials. It is a safe treatment modality that can be easily implemented in the clinical setting; however, close clinical follow-up is required.

	REFERENCES

Top Learning Objectives Abstract Introduction Acquisition of Hormone... Adaptation Hypothesis Intermittent Androgen... Intermittent Androgen... Quality-of-Life Issues Unresolved Issues Conclusion References

 

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