A dramatic, objective antiandrogen withdrawal response: case report and review of the literature
© Lau et al; licensee BioMed Central Ltd. 2008
Received: 24 July 2008
Accepted: 05 November 2008
Published: 05 November 2008
Antiandrogen withdrawal response is an increasingly recognized entity in patients with metastatic prostate cancer. To our knowledge, there have been no reports describing a durable radiologic improvement along with prostate-specific antigen (PSA) with discontinuation of the antiandrogen agent bicalutamide. We report a case in which a dramatic decline of serum PSA levels associated with a dramatic improvement in radiologic disease was achieved with bicalutamide discontinuation.
Cancer of the prostate is the most prevalent cancer of American men . At the time of diagnosis almost 50% of the patients have disease that extends beyond the prostate gland. Disseminated prostate cancer is primarily treated by local palliative measures and by testicular androgen ablation (medical or surgical). Non-steroidal antiandrogens are commonly used – either as short-term induction therapy to blunt the surge of testosterone that follows the initiation of luteinizing hormone-releasing hormone (LHRH) analogues, as long-term therapy with LHRH analogues or as single agent salvage treatment in men in whom LHRH analogues or surgical castration have ceased to control the disease. A phenomenon referred to as the antiandrogen withdrawal syndrome or antiandrogen withdrawal response (AAWR) occurring in men receiving non-steroidal antiandrogens was first described in 1993 [2–4]. The AAWR is defined as a 50% decline in prostate specific antigen (PSA) following cessation of an antiandrogen. The pathophysiology of the phenomenon is not completely understood. We report a very dramatic and prolonged antiandrogen withdrawal response and discuss the literature and recent information regarding the pathophysiology of the AAWR.
Prior case reports and clinical studies in antiandrogen withdrawal
Reports of antiandrogen withdrawal
No. of Patients
No. of patients with 50% PSA decline
Duration of Anti-androgen therapy (Months)
Duration of AAWR (Months)
16 months combined with LHRH agonist
10 and 15
7 and 6
The AAWR was first described by Kelly and Scher in 1993 . They described three metastatic prostate cancer patients in whom discontinuation of the flutamide resulted in PSA decrease (36% to 89% decline) and in some cases symptomatic improvement. In a second report by the same group, 36 men with metastatic prostate cancer who were receiving flutamide and had progressive disease were evaluated following flutamide discontinuation . Ten patients had a substantial decline (≥ 80% in 7 patients and ≥ 50% in 3) in the serum PSA level. The duration of decline was short, median of 5+ months. In a Canadian study, the median duration of response was 14.5 months . Other reports of flutamide withdrawal response are as noted in table 1[8, 9]. AAWR has also been described following bicalutamide and nilutamide withdrawal [10–13]. Small and colleagues compared antiandrogen withdrawal alone or in combination with ketoconazole in a randomized phase III trial in androgen-independent prostate cancer patients . This is the largest prospective study of AAWR. One hundred thirty-two patients were randomized to undergo androgen withdrawal alone or with ketoconazole and hydrocortisone. Eleven percent of patients undergoing antiandrogen withdrawal alone experienced PSA decline = 50%. The objective response rate in a measurable disease was 2%. The median time to PSA progression in PSA responders was 5.9 months (5.3 to 10.1 months). Of the patients had antiandrogen withdrawal and ketoconazole, 27% had a PSA response and 20% had objective responses. There were no differences in survival.
Sher and colleagues suggested that there was an association between duration of antiandrogen therapy and the likelihood of AAWR . The median duration of antiandrogen use for patients with a PSA decline greater than 50% from the baseline was 25 months versus 16 months of those nonresponders (p value = 0.012). Figg et al reported that patients who responded to flutamide withdrawal received the agent for a longer period (2.33 years) than the non-responders (1.54 years) . These differences were not statistically significant. The study from Herrade et al did not show the significant association between the duration of its use and withdrawal response . The median months for initial hormone therapy were 19 months for the responders and 16.5 months for the non-responders (p = 0.41). There are no clear "predictors" of AAWR.
Molecular mechanisms of antiandrogen withdrawal response
It has also been suggested that antiandrogens may stimulate a non-androgen receptor pathway. Lee et al showed that hydroxyflutamide can activate the mitogen-activated protein (MAP) kinase pathway independent of androgen receptor . They showed by immunohistochemical analysis a significant increase of activated MAP kinase in prostate tumors from patients receiving hydroxyflutamide. In vitro hydroxyflutmamide induced rapid activation of ras/MAP kinase pathway in human prostate cancer DU145 cells (which lack the androgen receptor) as well as in CWR22 and PC-3AR2 androgen receptor positive cells lines, indicating that the activation did not require androgen receptor. Furthermore, an epidermal growth factor receptor inhibitor or neutralizing antibody could obliterate this hydroxyflutamine-mediated activation of MAP kinase pathway. They suggested that antiandrogen, hydroxyflutamide could initiate the activation via a membrane-initiated, non-androgen receptor-mediated action, providing alternative pathway that might contribute to the withdrawal syndrome. However, there is no report of other nonsteroidal antiandrogen, bicalutamide and nilutamide, having such stimulatory effect on the MAP kinase pathway, limiting the generalizability of this finding.
Another mechanism could be over-expression of androgen receptor. Taplin et al showed that all metastatic androgen-independent tumors examined in her study expressed high levels of androgen receptor gene transcripts, relative to the levels expressed by an androgen dependent prostate cancer cell line, LNCaP . This raises the possibility of increasing androgen receptor expression may alter the prostate cancer cells' response to its ligand or even its antagonists. A report by Chen et al showed that mere 3-fold increase in androgen receptor will confer prostate cancer cells resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists . The study showed that when androgen receptors were over-expressed by transfection in the prostate cancer cell lines, LNCaP and LAPC4, the transfected cells were able to grow in low androgen concentrations. Importantly, the cell growth could also be enhanced by the antiandrogen, bicalutamide. The possible explanation could be an aberrant interaction between an androgen receptor coregulatory proteins and the receptor itself. They found that high androgen receptor levels could alter coactivator assembly with subsequent effects on transcriptional activity.
Most recently, studies of macrophage/cancer cell interaction have provided another possible explanation for hormone resistance in the androgen-independent prostate cancer and the AAWR . Zhu et al noted that all tumor samples they examined exhibited macrophage infiltration as well as stromal interactions with macrophages as compared to much less interaction between the macrophage and the normal areas . The findings suggest modulatory effects of macrophages on the cancer cells through the cytokines such as interleukin-1. They subsequently showed that IL-1 could convert androgen antagonists into agonists. The IL-1 stimulation of mitogen-activated protein/ERK kinase kinases (MEKK) results in phosphorylation of TAB2, an AR-interacting protein, which resulted in and release of the TAB2/N-CoR holocorepressor complex from the androgen receptor. Transcriptional activity of the androgen receptor, which was inhibited in the presence of bicalutamide, was then turned on.
In conclusion, we report here one of the first and to our knowledge most dramatic, and sustained antiandrogen withdrawal response. This case report emphasizes this subgroup of patients may have significant response to antiandrogen withdrawal and benefit from a non-cytotoxic intervention. Identification of this group of patients is important. Even though the exact mechanism of the antiandrogen withdrawal is not known, the molecular data suggest that androgen receptor still plays a crucial role in the phenomenon. Further understanding of the receptor biology is important.
Written informed consent could not be obtained in this case since the patient is deceased and the next of kin were untraceable. The Editors believe this case report contains a worthwhile clinical lesson, which could not be as effectively made in any other way. The Editors also expect the next of kin (or reasonable person) not to object to the publication since details of the patient remains anonymous.
prostate specific antigen.
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