Treatment for androgen-independent prostate cancer (AIPC) has been a challenge. During hormone therapy, prostate cancer initially responds well to androgen ablation; however, this response is gradually lost and the cancer becomes hormone-independent. Some patients with AIPC maintain hormone dependency but are resistant to androgen ablation (1). In this state, low-dose dexamethasone (DXM) therapy is thought to be effective in addition to second- or third-line anti-androgens, or anti-androgen withdrawal.

Glucocorticoids are used in the management of AIPC. In addition to their anti-inflammatory effects, these agents exhibit antitumor activity. However, their therapeutic role in AIPC remains unclear (2,3). A few studies have demonstrated negative effects for prostate cancer suppression with higher doses of DXM (4,5), or the antagonistic activity of DXM on prostate cancer cells with specific androgen receptor mutation (6). However, in most studies, DXM has exhibited an inhibitory effect on cell growth via intrinsic glucocorticoid receptors in androgen-independent prostate cancer cell lines such as PC-3 (3,7) or DU145 (8). In the present study, we retrospectively evaluated the outcome of oral low-dose DXM therapy for AIPC in the largest cohort of patients studied thus far.

We retrospectively studied 99 consecutive patients with prostate cancer who had been treated with hormone therapy (surgical castration or luteinizing hormone-releasing hormone agonist) and had shown biochemical failure [three consecutive increases in serum prostate-specific antigen (PSA) levels from the stabilized values]. These patients were treated either at Chiba University Hospital or Saiseikai Utsunomiya Hospital, and DXM therapy was started between January 1998 and April 2006. Patient characteristics are shown in Table I. Upon biochemical failure, patients were treated with oral low-dose DXM (initially 1.5 mg/day, then reduced every 2 weeks to 0.5–1.0 mg/day). After 1995, in patients treated with surgical or medical castration plus anti-androgen (AA) therapy, AA withdrawal syndrome was assessed for at least 4–8 weeks after the cessation of AA and prior to DXM being initiated. For these patients, luteinizing hormone-releasing hormone agonist was not discontinued (9). Docetaxel was not used in any of the patients since it was only approved in 2008 in Japan. Serum PSA levels were determined with the Tandem-R PSA Assay (Hybritech, Inc., San Diego, CA). The PSA test was performed every 2 weeks in the first two months, and then every month after the 3rd month of DXM administration in AIPC patients. Serum levels of interleukin (IL)-6 were measured in 18 patients before and after DXM administration using the chemiluminescent enzyme immunoassay (Cleia, SRL, Inc., Tokyo, Japan). The clinical effect of DXM was evaluated based on improvement of pain. Pain relief was defined as the ability of patients to discontinue the use of analgesics following DXM therapy. Pain scales were not used for assessment. Patients who showed a ≥50% decline in serum PSA levels were defined as PSA responders to DXM therapy. The remaining patients were defined as PSA non-responders. A decrease in PSA was confirmed with a second PSA level which was also <50%. Treatment failure was determined when patients showed three consecutive increases in PSA serum level. No routine bone or CT scans were performed during treatment.

In the present study, we retrospectively examined the efficacy of low-dose DXM therapy in the management of AIPC in a larger number of patients as compared with previous studies. Important characteristics of low-dose DXM include i) a relatively high response rate, ii) efficacy in the improvement of subjective symptoms, iii) the ability of DXM to be administered orally (helps maintain quality of life) and iv) lack of severe adverse effects. The PSA response to DXM was a strong independent prognostic factor. Younger patients with a longer history of hormone therapy and with slow-growing cancer appear to be favourable candidates for DXM therapy.

In previously reported outcomes of glucocorticoids for AIPC (3,11), the PSA response rate (≥50% decrease in PSA) ranged from 44 to 68%, and the median time to progression was approximately 9 months. Our results were comparable to these findings. The response rate itself was not significantly lower than that noted with other cytotoxic agents used for AIPC. Safety was achieved, although 5 patients (5.1%) experienced a fracture, which, in addition to DXM, may have been due to a relatively longer period of androgen deprivation therapy known to cause osteoporosis. Routine assessment of osteoporosis and its treatment using bisphosphonate such as zoledronic acid are recommended, although neither were performed in this study (12). Prophylactic anti-ulcerative agents should be prescribed simultaneously with DXM to prevent gastric ulcers as this adverse effect occurred relatively frequently in this study (6/99 patients, 6.1%), albeit in only one grade 3 case.

Even though docetaxel has become one of the most frequently used options for the management of AIPC in Western countries, our findings indicate that low-dose DXM is an important treatment option for urologists. This treatment is suitable particularly for patients who are not favourable candidates for cytotoxic agents.

Suppression of adrenal androgen secretion by DXM is believed to have a significant anti-tumor effect against prostate cancer. Glucocorticoids can inhibit prostate cancer cell growth by modulating cellular growth factors (11). Our previous report (13) demonstrated that serum levels of adrenal androgens such as dehydroepiandrosterone, dehydroepiandrosterone sulfate or androstendione were suppressed by DXM therapy irrespective of the response to this treatment.

Akakura et al (13) suggested that the significant suppression of IL-6 is another possible mechanism of dexamethasone action. IL-6 is known to be suppressed by glucocorticoids (6) and to stimulate the growth of prostate cancer cell lines through glucocorticoid receptors in an androgen-independent manner (3,14–17). In addition, IL-6 has been shown to activate the androgen receptor through a STAT3-dependent pathway (17–19). In this study, changes in serum IL-6 levels were significantly associated with the response to DXM in AIPC patients. Therefore, suppression of IL-6 has been accepted as a significant mechanism of DXM activity in AIPC.

The recent position of glucocorticoids in the management of prostate cancer is mainly found in the control arms or is for prophylactic use for adverse events in clinical trials for AIPC, in which prednisone is most frequently administered (20,21). On the other hand, results for DXM monotherapy have been less documented. DXM is thought to be a more potent agent than prednisone/prednisolone or hydrocortisone because of its stronger glucocorticoid activity and lower mineralocorticoid activity (3). In clinical practice, the PSA response rate for AIPC was 14–20% for hydrocortisone (40 mg/day), 27–38% for prednisone/prednisolone (7.5–10 mg/day) and 40–62% for dexamethasone (0.5–1.5 mg/day) (Table V) (3,11,13). Relatively higher doses of dexamethasone are currently used in an intermittent manner to reduce the hypersensitivity reactions and fluid retention associated with docetaxel (20,21). It was reported that DXM does not significantly contribute to the response rate of docetaxel and estramustine in AIPC (5), and that intermittent DXM results in a less profound suppression of adrenal androgens. Glucocorticoid receptors are generally down-regulated by glucocorticoids in a dose-dependent manner (22). Therefore, low-dose DXM is a reasonable choice of therapy for a longer duration of response as well as for reducing adverse events.

In conclusion, low-dose DXM therapy in the treatment of AIPC is well tolerated and safe, and may be one of the acceptable options in the management of AIPC, particularly for patients who are not favourable candidates for cytotoxic agents or in countries where docetaxel is not available.