Annals of Oncology Advance Access originally published online on December 20, 2007
Annals of Oncology 2008 19(2):395-396; doi:10.1093/annonc/mdm568
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letters to the editor |
Prolonged control of progressive castration-resistant metastatic prostate cancer with testosterone replacement therapy: the case for a prospective trial
After the seminal observations of Huggins and Hodges [1] had laid the basis for the hormonal therapy of prostate cancer, Pearson [2] described two patients with castration-resistant prostate cancer that responded to testosterone with relief of symptoms and declines in serum acid phosphatase. The particular molecular context for this seeming paradox has not been established but the biphasic effects of sex steroids as mediators of cell proliferation and cell death have since been characterized in diverse laboratory models [3]. Androgen-dependent prostate cancer cells subjected to long-term androgen deprivation in vitro can emerge from quiescence with proliferative capacity and an androgen-suppressible phenotype [4] mediated via the androgen receptor. The subsequent reappearance of an androgen-stimulated phenotype in these cells under the influence of androgen can be managed with renewed castration [5]. Although there are no prospective studies that demonstrate prolonged disease control and quality-of-life benefit in men with progressive castration-resistant prostate cancer following optimal initial castration response, similar to the laboratory model, the following case report is instructive.A 78-year-old man underwent radical prostatectomy for a pT3N1 Gleason 7 adenocarcinoma of the prostate in 1989. Preoperative serum prostate-specific antigen (PSA) was 80 ng/ml. He received prolonged luteinizing hormone-releasing hormone therapy and remained with castrate levels of testosterone and undetectable PSA until 2004 when his PSA rose progressively to 1.4 ng/ml. Radiological studies showed common iliac adenopathy. He complained of fatigue, reduced physical endurance, loss of libido, diminished concentration span and urinary incontinence. He was started on parenteral testosterone replacement therapy (Figure 1, T1) at his request with the serum testosterone level titrated into the normal reference range (240–827 ng/dl). His PSA rose rapidly, then declined gradually but persistently >18 months. Urinary incontinence resolved rapidly and he reported improvement in muscle strength, endurance, libido and intellectual function, attention span and concentration over the next 6 months. Restaging scans after 12 months showed stable adenopathy. After 27 months, rising serum PSA to 8.4 ng/ml was accompanied by radiological evidence of progressive retroperitoneal and pelvic adenopathy; testosterone replacement therapy was discontinued (Figure 1, T2) with decline in the PSA to 2.1 ng/ml, testosterone into the castrate range and uniform regression in adenopathy at 3 months.
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This narrative illustrates prolonged disease control and subjective improvement in androgen deprivation symptoms in a man with progressive castration-resistant prostate cancer receiving testosterone replacement therapy. Given the observations from the preclinical models [3–5], men with prolonged and optimal castration response before castration-resistant progression may be a subset more likely to benefit from testosterone replacement therapy with prolonged disease control and amelioration of attendant androgen deprivation symptoms. Subsequent progression may be androgen dependent and disease control retrievable with renewed castration therapy.
While the specific molecular and cellular epithelial–stromal determinants of tumor-suppressive effects of testosterone therapy remain to be determined, this report offers proof of principle that prolonged clinical benefit is feasible. Intermittent androgen therapy may thus have a beneficial role in biological subsets of castration-resistant prostate cancer. Conversely, disease acceleration with testosterone may be anticipated in other subsets and caution is necessary. A clinical trial of testosterone replacement therapy that assesses survival and quality-of-life outcomes in men with progressive castration-resistant prostate cancer with prior optimal castration response should be considered.
Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, 1155 Herman P. Pressler, Houston, TX 77030-3721, USA
(E-mail: pmathew{at}mdanderson.org)
References
1. Huggins C, Hodges CV. The effect of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res (1941) 1:293–297.
2. Pearson OH. Discussion of Dr Huggins' paper "control of cancers of man by endocrinological methods". Cancer Res (1957) 17:473–479.
3. Soto AM, Sonnenschein C. The two faces of Janus: sex steroids as mediators of both cell proliferation and cell death. J Natl Cancer Inst (2001) 93:1673–1675.
4. Kokontis JM, Hay M, Liao S. Progression of LNCaP cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and a role for p27kip1 in androgen-induced cell cycle arrest. Mol Endocrinol (1998) 12:941–953.
5. Chuu CP, Hiipakka RA, Fukuchi J, et al. Androgen causes growth suppression and reversion of androgen-independent prostate cancer xenografts to an androgen-stimulated phenotype in athymic mice. Cancer Res (2005) 65:2082–2084.
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