Intermittent androgen deprivation therapy for prostate cancer

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.     

Intermittent androgen deprivation for patients with recurrent/metastatic prostate cancer

This study was designed to assess the duration of response to intermittent androgen deprivation therapy (IAD) in patients with recurrent and/or metastatic prostate cancer. Between January 1993 and March 2000, 74 patients with recurrent and/or metastatic prostate cancer had IAD with either luteinizing hormone-releasing hormone agonist (LHRH) or an LHRH with an oral antiandrogen. Forty-one patients were treated for an increasing prostate-specific antigen (PSA) level after primary local treatment. Of the remaining 33 patients, 17 patients were treated for metastases (9 for bone metastases, 8 for lymph nodes metastases, and 16 for local recurrence). Patients who had undergone IAD completed between 1 and 6 cycles. A cycle was defined as the period during which the patient was actively taking the hormone medication. Seventy-four patients completed the first cycle, 49 completed the second cycle, and 23 completed the third cycle. The pattern of PSA changes with each cycle, the length of each cycle, and the time interval between successive cycles were studied. The time to progression (defined as an increasing PSA level on two consecutive measurements or radiologic evidence of progression of disease while the patient was on androgen deprivation) was also studied. The median PSA before the IAD was 11.4 ng/mL (range 0.12-378). The median PSA nadir at the end of each cycle increased progressively (0.1 ng/mL after the first cycle to 3.3 ng/mL after the fifth cycle). The time interval between the cycles progressively decreased from 9.5 months between the first and second cycles to 6 months between the third and fourth cycles. The 4-year actuarial androgen-independent free survival was 71%. For the subgroups of patients treated for biochemical failure, locoregional recurrence, and bone metastases, the 4-year actuarial progression-free survival rates were 80%, 67%, and 45% respectively (P = 0.018). The median time of 18 months to progression in patients with bone metastases is similar to that reported with continuous hormonal therapy. In patients with biochemical failure, the median time to progression (more than 5 years) suggests that the IAD approach may be a viable option for this group of patients.     

Intermittent versus continuous androgen deprivation therapy to biochemical recurrence after external beam radiotherapy: a phase 3 GICOR study

Purpose

We compared biochemical control and quality of life with intermittent (6 months) versus continuous (36 months) androgen deprivation therapy (ADT) in a non-inferiority randomized phase 3 trial in patients with biochemical failure (BF) after external beam radical radiotherapy (EBRT).

Materials and methods

Patients were stratified according to the Gleason score (GS) and were classified as low risk with a GS < 6 and 7 (3 + 4) and high risk with a GS of 7 (4 + 3) and >7. Patients were followed with PSA determinations and quality-of-life assessments (QLQ C-30 and QLQ PR-25) every 6 months for a period of 3 years. BF after radiation was defined as a PSA level of nadir +2 ng/ml. Disease progression (DP) after ADT was defined as PSA ≥4 ng/ml (BF) and/or metastases.

Results

Seventy-seven patients were included in this multicenter phase 3 trial from 2005 to 2009. Thirty-eight and 39 patients were included in the intermittent and continuous groups, respectively. The median follow-up for both groups was 48 months (40–68). DP after ADT in the intermittent group was seen in three patients (distant metastases in one patient) versus 0 in the continuous group. The QLQ-C30 and QLQ PR-25 scores did not show any statistically difference between the two ADT groups.

Conclusions

No significant differences were seen in DP and QLQ between intermittent (6 months) and continuous (36 months) ADT in patients with BF after EBRT.

     

Intra-prostatic fiducial markers and concurrent androgen deprivation

AimsTo document the case of a man with adenocarcinoma of the prostate treated with external beam radiotherapy and concurrent androgen deprivation.Materials and methodsThe man, who received 79.8 Gy in 42 fractions of radiotherapy over 8.5 weeks using three intra-prostatic gold fiducial markers for on-line set-up correction, started an anti-androgen 2.5 weeks before radiotherapy, on the day of his planning computed tomography, and a gonadotropin-releasing hormone agonist on his first day of radiotherapy.ResultsIn the sixth week of radiotherapy, the distance between the fiducial markers had diminished: superior to posterior-mid (from 19 to 11 mm), posterior-mid to inferior (from 19 to 15 mm), and superior to inferior (from 31 to 22 mm), so the patient was rescanned. Between the two planning computed tomographies, the prostate volume had decreased from 44.3 to 28.3 cm³ (−36%). Had the planned radiotherapy been delivered to the anatomy of the rescan, the dose to the rectal wall would have exceeded the planned dose–volume histogram constraints. However, with the patient set up to the fiducial markers, the dose–volume histogram constraints for the rectal wall and bladder wall were met throughout the course of radiotherapy.ConclusionInvolution of the prostate owing to concurrent androgen deprivation may cause in-migration of implanted fiducial markers and excessive dose to the rectal wall. With concurrent androgen deprivation, daily on-line set-up correction to fiducial markers can aid in safe dose escalation.     

Complications of androgen deprivation therapy: prevention and treatment

Androgen deprivation, as a form of treatment for prostate cancer, has been used for decades. Within the last decade, however, its use has increased significantly. Therefore, it is incumbent upon the physician to be familiar with the side effects associated with this treatment. Some of these side effects (eg, osteoporosis, changes in lipid profiles, and anemia) may be associated with significant morbidity, whereas others (eg, impotence, decreased libido, fatigue, and hot flashes) primarily affect the patient's quality of life. Prevention strategies and treatments exist for many of these side effects. In addition, alternative forms of antiandrogen therapy such as intermittent hormone ablation and antiandrogen monotherapy may be effective, with the added benefit of minimizing side effects. This review focuses on the wide range of side effects associated with androgen ablation as well as preventive and treatment strategies.     

Lack of prostate cancer radiosensitization by androgen deprivation.

PURPOSE: The majority of clinical trials have shown that high-grade prostate cancer patients treated with androgen deprivation (AD) plus radiation (RT) have a survival advantage over those treated with RT alone. One possible mechanism for such a favorable interaction is that AD sensitizes cells to radiation. Animal model studies have provided suggestive evidence that AD sensitizes cells to radiation, but this mechanism is difficult to confirm conclusively in vivo. This question was investigated in LNCaP cells grown in vitro. METHODS AND MATERIALS: LNCaP cells were cultured in vitro in Dulbecco's modified Eagle's medium (DMEM)-F12 medium, containing 10% fetal bovine serum (complete medium [CM]). AD was achieved by culture in charcoal-stripped serum (SS)-containing medium. Replacement of androgen was done by adding the synthetic androgen R1881 at 1 x 10(-10) M to SS. Apoptosis was measured with a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Clonogenic survival was used to determine overall cell death, and the results were corrected for differences in plating efficiency from the various growth conditions. RESULTS: LNCaP cells were grown in CM, SS, or SS + R1881 medium, and cell counts obtained at 3, 4, and 5 days. Cell number increased exponentially in CM, whereas no increase in cell number was observed in SS medium. Cell counts from growth in SS + R1881 were intermediate between these extremes. Apoptosis was measured to determine if the combination of AD + RT in vitro resulted in supra-additive cell death, as has been previously described in an in vivo model system. The cells were cultured for 3 days before RT and apoptosis quantified 24 h after RT. There was a consistent supra-additive increase in apoptosis in cells exposed to AD + RT (2 or 8 Gy), as compared to either treatment given individually. In contrast, significant radiosensitization by AD was not observed by clonogenic survival even when the conditions of AD were varied. No radiosensitization was observed upon incubation in SS medium for 3, 4, or 5 days before RT, or extending AD after RT for 6 h before plating or 24 h after plating. CONCLUSION: The results show that in LNCaP prostate tumor cells supra-additive apoptosis does not translate into radiosensitization by clonogenic survival. Because clonogenic survival is a measure of overall cell death, either the level of apoptosis is too small a component of overall cell death or the increases in apoptosis occurred in a subpopulation that would have been killed by other mechanisms. Although the findings indicate that AD does not act by sensitizing prostate cancer cells to RT, the additive cell death and growth inhibitory effects of AD + RT are clinically meaningful.     

The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor

Despite an initial response to androgen deprivation therapy, prostate cancer (PCa) progresses eventually from an androgen-dependent to an androgen-independent phenotype. One of the mechanisms of relapse is antiandrogen withdrawal phenomenon caused by mutation of 877th amino acid of androgen receptor (AR). In the present study, we established a method to measure the concentration of androstenediol (adiol) in prostate tissue. We found that adiol maintains a high concentration in PCa tissue even after androgen deprivation therapy. Furthermore, adiol is a stronger activator of mutant AR in LNCaP PCa cells and induces more cell proliferation, prostate-specific antigen (PSA) mRNA expression, and PSA promoter than dihydrotestosterone (DHT). Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR. However, high concentration of bicalutamide was necessary to block completely adiol activity. These effects were specific to LNCaP cells because adiol had less effect in PC-3 PCa cells transfected with wild-type AR than DHT and had similar effect in PC-3 cells transfected with mutant AR. The mechanism that adiol activates mutant AR in LNCaP cells did not result from the increased affinity to mutant AR or from AR's association with coactivator ARA70. However, low concentration of adiol induced more AR nuclear translocation than DHT in LNCaP cells and not PC-3 cells transfected with AR. These results indicate that adiol may cause the progression of PCa even after hormone therapy.     

Pathologic changes associated with androgen deprivation therapy for prostate cancer

Prostate glands exposed to androgen deprivation with leuprolide +/- flutamide were evaluated for pathologic changes which might be related to therapy. Comparing pretreatment and posttreatment tissue by visual discrimination using light microscopic study revealed treatment-related alterations in the size and distribution of neoplastic glands in 60% of cases. Quantitative measurements documented glandular changes in an even greater percentage of cases. Although distinctive, the histologic pattern was not specific for leuprolide/flutamide. The absence of appreciable degeneration and necrosis in tumor cells suggests that this type of androgen deprivation may act through suppression rather than ablation of prostatic cancers. The relationship between treatment-related histologic effects and initial tumor grade and clinical stage as well as expression of prostate-specific antigen was studied. Accurate histologic assessment of leuprolide/flutamide-treated prostate glands should not be a problem so long as specimens are thoroughly examined and drug-related variations in tumor morphologic features are appreciated.     

Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy

Androgen deprivation therapy induces apoptosis or cell cycle arrest in prostate cancer (PCa) cells. Here we set out to analyze whether MCL1, a known mediator of chemotherapy resistance regulates the cellular response to androgen withdrawal. Analysis of MCL1 protein and mRNA expression in PCa tissue and primary cell culture specimens of luminal and basal origin, respectively, reveals higher expression in cancerous tissue compared to benign origin. Using PCa cellular models in vitro and in vivo we show that MCL1 expression is upregulated in androgen-deprived PCa cells. Regulation of MCL1 through the AR signaling axis is indirectly mediated via a cell cycle-dependent mechanism. Using constructs downregulating or overexpressing MCL1 we demonstrate that expression of MCL1 prevents induction of apoptosis when PCa cells are grown under steroid-deprived conditions. The BH3-mimetic Obatoclax induces apoptosis and decreases MCL1 expression in androgen-sensitive PCa cells, while castration-resistant PCa cells are less sensitive and react with an upregulation of MCL1 expression. Synergistic effects of Obatoclax with androgen receptor inactivation can be observed. Moreover, clonogenicity of primary basal PCa cells is efficiently inhibited by Obatoclax. Altogether, our results suggest that MCL1 is a key molecule deciding over the fate of PCa cells upon inactivation of androgen receptor signaling.     

Complications of androgen deprivation therapy in men with prostate cancer

Androgen deprivation therapy (ADT) is indicated for the treatment of metastatic prostate cancer and locally advanced disease. In addition to sexual side effects, long-term ADT results in several other changes, including hot flashes; gynecomastia; changes in body composition, metabolism, and the cardiovascular system; osteoporosis; anemia; psychiatric and cognitive problems; and fatigue and diminished quality of life. This review discusses these complications of ADT and treatments aimed at reducing them. It is important for clinicians to anticipate these effects and to initiate measures to prevent or minimize them in order to maintain quality of life in prostate cancer survivors.