Urol Res (1997) 25 [Suppl 2]: $67-$71 © Springer-Verlag 1997 M. P. Wirth. S. E. Froschermaier The antiandrogen withdrawal syndrome Received: 15 July 1996/Accepted: 19 November 1996 Abstract In 1989 the unanticipated agonist effect of antiandrogens on LNCaP prostate cancer cells was de- tected. A "flutamide withdrawal syndrome" was first described by Kelly and Scher [15], who reported a de- crease in serum prostate-specific antigen (PSA) levels after the removal of flutamide from the treatment regi- men. In the last few years the paradoxical response to antiandrogens has also been reported for bicalutamide, chlormadinone acetate and others. Therefore the name of the syndrome has changed to "antiandrogen with- drawal syndrome." Several reasons such as mutations in the androgen receptor or a direct stimulatory effect of the antiandrogen for this effect have been discussed, but the exact molecular mechanism remains unclear. How- ever, in patients with hormonally relapsed prostate cancer, a trial of "withdrawal therapy" is required prior to the initiation of toxic therapies. Key words Antiandrogen withdrawal' Flutamide withdrawal. Prostate cancer. Androgen receptor Prostate cancer is the most frequently diagnosed cancer in men in the United States [4] and its incidence is ex- pected to rise in the next few years. For localized pro- state cancers cure can be achieved by surgery, but for advanced disease only palliative treatment is possible. So far hormonal manipulation has been the mainstay of treatment for advanced prostate cancer. Androgen deprivation can be achieved by castration, luteinizing hormone releasing hormone (LH-RH) analogs, antian- drogens, estrogens and gestagens. The blockade of the testosterone receptor by antiandrogens is one such widely used therapeutic principle. M. P. Wirth ([~). S. E. Froschermaier Dept. of Urology, Technical University of Dresden Fetscherstr, 74, D-01307 Dresden, Germany In 1989, however, an agonist effect of antiandrogens on LNCaP prostate cancer cells was first recognized. Initially the syndrome was named "flutamide with- drawal syndrome," but it soon became apparent that withdrawal responses represent a more generalized phenomenon and were not restricted to flutamide alone. Withdrawal responses to hormone antagonists are not restricted to patients with prostate cancer. In 1989 a case was reported in which the complete resolution of a lung mass in a patient with breast cancer was observed after withdrawal of tamoxifen, an antiestrogen [2]. The "antiandrogen withdrawal syndrome" Flutamide is a nonsteroidal antiandrogen, which blocks the binding of testosterone and dihydrotestosterone to its receptor. Despite its long period of therapeutic use, the clinical benefits of flutamide withdrawal in patients with progressive cancer on hormonal therapy were described only recently by Kelly and Scher [15], who reported three cases receiving complete androgen blockade with either gonadotropin-releasing hormone (GnRH) or orchiectomy and flutamide as antiandrogen. After initial response to hormonal therapy (duration 12 28 months), sequentially increasing prostate-specific antigen (PSA) values were documented. Therapy with flutamide was discontinued and sustained declines in serum PSA, ranging from 37% to 89%, were observed. In one patient with symptomatic bone lesions the decrease was associated with clinical improvement. Another study by the same authors [22] with more patients showed in 28% of 57 cases a decline in PSA which was greater than 50%. The median duration of response was 4 months. Dupont et al. [9] reported 40 patients with stage D2 prostate cancer, who showed progression of disease after an initial period of response to combination therapy with medical (luteinizing-hor- mone-releasing hormone agonist) or surgical castration and flutamide. Following withdrawal of flutamide, 1 patient showed a complete response, 3 patients had a
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`$68 partial response and 26 had stable disease. In ten pa- tients (25%) a progressive disease was observed. The combination of flutamide withdrawal and ami- noglutethimide treatment was studied in 29 patients 20 with hormone-resistant prostate cancer, who had re- ceived suramin and hydrocortisone previously. Amino- glutethimide 250 mg was given orally 4 times a day. When all 29 patients were evaluated, the median PSA value was 73% below the pre-withdrawal level. In 48% of the 29 cases the PSA decline was greater than 80% and lasted 4 weeks or longer. Twelve patients had soft tissue metastases, of whom three patients showed a measurable tumor shrinkage for 4 or more weeks. In three cases an improvement on bone scan was seen. In 1994 a case of a middle-aged man with pulmonary metastases of prostate cancer with focal neuroendocrine differentiation but no osseous involvement was reported 7. The patient had received endocrine combination therapy with the antiandrogen flutamide and an LH-RH agonist for 5.5 years, when PSA levels began to rise. After withdrawal of flutamide (the LH-RH agonist was continued) the PSA level dropped from 9 to 2.8 ng/ml. In a study by Figg et al. 11, 21 patients with stage D2 prostate cancer and progressive disease despite medical or surgical castration and therapy with flut- amide were included. After withdrawal of flutamide seven patients experienced a mean decline in their PSA value of 72%. The mean duration of response was 112 days. The authors suggested that patients who showed a response to flutamide withdrawal appeared to have been receiving the agent for a longer period than had patients who did not respond (Table 1). Similar effects to those of flutamide withdrawal were shown for the withdrawal of other antiandrogens. In 1994 a response to withdrawal of bicalutamide, a non- steroidal antiandrogen, was reported 24. The patient was treated with bicalutamide for 32 months and 12 months with an LH-RH agent, when objective pro- gression of disease was seen. One month after with- drawal of bicalutamide, the PSA level decreased by 53%. A similar investigation was performed by Nieh 19, who reported three patients who received bicalutamide monotherapy for metastatic stage D2 carcinoma of the prostate. At the time of progression of clinical disease, therapy with an LH-RH agonist was added, with an improvement in symptoms. When progression of disease recurred, bicalutamide was withdrawn but the LH-RH agonist was continued. One patient remained stable after discontinuing bicalutamide, and two patients showed a decline in PSA levels of 42% and 75%, respectively, which was sustained for 3 and 6 months. The antiandrogen withdrawal syndrome was also found for the steroidal antiandrogens chlormadinone acetate (CMA) and megestrol acetate (Table 2). Aka- kura et al. 1 reported two cases with a decline in PSA and clinical improvement in prostate cancer after the withdrawal of CMA. The two patients had stage A2 and stage D2 prostate cancer and had been treated with hormonal therapy by combining orchiectomy and 100 mg CMA orally daily. In one patient after the withdrawal of CMA, PSA declined by 90%, with a duration of 10 months. The patient had an objective improvement of urethral obstruction, which had previ- ously appeared due to local progression of the prostate cancer. The second patient reported by the authors showed a decline of PSA of 69% and also an improve- ment of tumor-related symptoms. In the same year a similar case was described 8 in which a dramatic de- crease in PSA values was seen after discontinuing meg- estrol acetate. The patient had undergone radical prostatectomy, but at the time of surgery one positive lymph node was noted on permanent section. After a period of observation he was treated with pelvic irradi- ation and after metastases in the bone were detected bilateral orchiectomy was performed and the patient was treated with 80 mg megestrol acetate 4 times daily. A Table 1 PSA decline after the withdrawal of flutamide in patients with hormone-resistant prostate cancer Author Year n Mean Mean Remark PSA decline duration (days) Kelly and Scher 15 1993 3 61.3% 80 Dupont et al. 9 1993 40 53.3% 440 Sartor et al. 20 1994 29 73% 345 Cusan et al. 7 1994 1 69% 730 Figg et al. 11 1995 21 71.8% 111 All with clinical improvement With clinical improvement (n = 7) +Aminoglutethimide All with clinical improvement With clinical improvement Responders (n = 7) only Table 2 PSA decline after the withdrawal of other antiandro- gens than flutamide in patients with hormone-resistant prostate cancer Author Year n Mean PSA decline Mean duration (days) Small and Carroll 24 1993 1 53% 96 Nieh 19 1995 3 39% 110 Akakura et al. 1 1994 2 92.6% 300 Dawson and McLeod 8 1995 1 97.9% Antiandrogen Bicalutamide Bicalutamide Chlormadinone acetate Megestrol acetate
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`Table 3 Examples for muta- tions in the gene of the andro- gen receptor from human prostatic tissues Author Year n Hormonal status Codon Amino acid change Newmarket al. 18 1992 1/26 Naive 730 Val --+ Met Culig et al. 6 1993 1/7 Relapsed Val -+ Met Gaddipati et al. 12 1994 6/24 Independent 877 Thr --~ Ala Taplin et al. 26 1995 1/10 Independent 877 Thr -~ Ser Taplin et al. 26 1995 1/10 Independent 874 His --~ Tyr Taplin et al. 26 1995 1/10 Independent 902 Gln --~ Arg Taplin et al. 26 1995 1/10 Independent 721 Ala --~ Thr Taplin et al. 26 1995 1/10 Independent 647 Ser -~ Ash Taplin et al. 26 1995 1/10 Independent 724 Gly --~ Asp Taplin et al. 26 1995 1/10 Independent 880 Leu ~ Gln Taplin et al. 26 1995 1/10 Independent 896 Ala --~ Thr Evans et al. 10 1996 1/58 - 798 Gln -~ Glu $69 trial with ketoconazole was discontinued due to toxicity after 2 months. After withdrawal of megestrol acetate PSA levels decreased from 149 ng/ml to 3.1 ng/ml and remained stable until the end of observation. A complete remission of hormone refractory prostate cancer after withdrawal of diethylstilbestrol (DES) was reported by Bissada and Kaczmarek 3. After the withdrawal of the drug, PSA decreased from 84 ng/ml to 1.3 ng/ml and remained normal for more than 3 years of follow up. The induration of the right lobe of the prostate which was detected at the time of diagnosis was no longer palpable after DES withdrawal, and the lesion in the left occipital region which was reported on the bone scan remained unchanged. Prognostic factors The response to antiandrogen withdrawal depends pos- sibly on the kind of prior treatment, baseline PSA and duration of antiandrogen exposure. Patients treated with surgical castration and flutamide had a better response to flutamide withdrawal than patients treated with gonadotropin-releasing hormone (GnRH) analog and flutamide or monotherapy as initial treatment 17. Scher et al. 23 compared the response to the anti- androgen withdrawal of 42 patients, who were pre- treated with maximal androgen blockade and 15 patients with monotherapy as pretreatment. None of the 15 patients with previous monotherapy met the criteria for response of antiandrogen withdrawal. It was con- cluded that patients with a lower androgen level have a greater likelihood of response to antiandrogen with- drawal. These results correspond well to the results of Herrada et al. 13, who showed a lower dehydroepi- androsterone level in patients with good response to antiandrogen withdrawal when compared to patients with no response. A review of the cases of response to antiandrogen withdrawal in the literature reveals that nearly all patients who had a good response to with- drawal had previously had complete androgen blockade. Sartor et al. 20 pointed out that the baseline PSA was higher in responding patients than in nonresponding patients. In a study by Scher et al. 23 of 57 consecutive patients with progressive prostate cancer, a longer duration of flutamide exposure was observed in responders than in nonresponders. These findings are, however, in contrast to the results of Dupont et al. 9, who found no difference between responders and non- responders regarding the duration of flutamide therapy. Initial tumor histology was also not predictive of out- come 23. Explanations for the withdrawal syndrome The mechanism of the withdrawal phenomon remains unclear. However, speculation has centered on possible mutations of the androgen receptor. Other explanations are altered biosynthesis of androgens in the prostatic gland, which might lead to an increased cellular con- centration of dihydrotestosterone. Scher and Kelly 22 suggested that flutamide might stimulate the growth of prostate cancer cells by itself from the beginning. Wilding et al. 28 reported that the growth of LNCaP cells but not of DU 145 cells, which do not express the androgen receptor, can be enhanced by adding hydroxyflutamide, nilutamide or cyproterone acetate. One year later, Veldscholte et al. 27 discovered a mutation in the androgen receptor of the LNCaP cell line. They used the polymerase chain reaction (PCR) technique to detect a point mutation at position 3157 of exon 8 in the hormone-binding domain of the androgen receptor. The mutation led to a change in hormone binding and produced growth stimulation with antian- drogens. In an investigation by Taplin et al. 26, a mutation in the same codon as found by Veldscholte et al. 27 in LNCaP cells was detected in bone marrow samples of patients with advanced prostate cancer. In contrast to Veldscholte et al., the mutation resulted in a different amino acid change (threonine to serine instead of threonine to alanine). The wild-type androgen receptor was only weakly stimulated by estrogen or progesterone, but the mutant androgen receptors were stimulated by estrogen and progesterone. Newmarket al. 18 were the first to report a rate of 3.9% mutations in the androgen receptor of prostate cancer specimens from patients with localized prostate cancer. By using the PCR technique, a guanidine -~
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`$70 adenine substitution in codon 730, changing valine to methionine, was detected. The mutation was not present in normal lymphocytes from the same patient, thus indicating a somatic mutation. Culig et al. 6 investigated seven tumor specimens derived from patients with metastatic prostate cancers. In one specimen from a patient with a progression of disease in spite of endocrine and cytotoxic therapy, they detected a point mutation at nucleotide 2671 that re- sulted in a change valine ~ methionine at position 715. The authors were able to show that the activity of the mutant receptor was fourfold that of the wild-type receptor when progesterone was added. They also demonstrated that dehydroepiandrosterone and andro- stendione were more effective with the mutant receptor than with the wild type. Some authors, however, were unable to detect androgen receptor mutations even in patients who had died from hormone refractory prostate cancer, whereas others reported mutation rates of up to 50% 10, 14, 17, 23, 25, 26. So far it has not been proved that the antiandrogen withdrawal syndrome is mainly caused by mutations in the androgen receptor. Mutations of the androgen re- ceptor are rare in early-stage prostate cancers, but may be more important in the advanced stages. It might also be possible that in the early stages only few tumor cells contain mutant androgen receptors but these cells might underlay a preferential growth in a low androgen envi- ronment. Conclusions About 30-75% of the patients with hormone-insensitive, advanced prostate cancer could have a significant decline in PSA which is in most cases associated with an objective complete or partial response in soft tissue and bony metastases by antiandrogen withdrawal. It is not clear what cut-off value of the PSA can be regarded as "significant," some authors suggesting a decline greater than 50% in three consecutive measurements, others suggesting a decline greater than 90%. The mean dura- tion of the response is, according to the literature, about 320 days and ranges between 80 and 730 days. There- fore, antiandrogen withdrawal is a reasonable thera- peutic maneuver to consider for patients whose prostate cancer has become "hormone independent" before the exploration of alternative and more toxic therapies. A review of the results of antiandrogen withdrawal reveals different clinical outcomes, even when the same antian- drogen was used. The effect of PSA decline after anti- androgen withdrawal is also important if patients participate in a clinical trial with PSA as success-param- eter. Many physicians consider additional hormonal ther- apy to have no efficacy when progression is documented after first-line hormonal treatment. Observation of the antiandrogen withdrawal syndrome has shown that pa- tients do not necessarily become completely refractory to hormone manipulation after initial therapy. Sasagawa et al. 21 reported an effect of high-dose medroxyprog- esterone acetate as second-line hormonal treatment of the pain relief in patients with advanced prostate cancer. In a recent study a benefit of bicalutamide after with- drawal of flutamide was documented in four out of eight patients 16. However, until now there have been very few reports of second-line hormonal treatment and work needs to continue to clarify the situations in which fur- ther hormonal manipulation after effective antiandrogen withdrawal could be of clinical benefit. The precise molecular mechanisms for the response following discontinuation of antiandrogen therapy are not clear. The mutant receptor hypothesis seems to be most likely. However, further investigation is necessary to clarify the role of mutated androgen receptors, which might become useful targets for new drugs for the treatment of advanced prostate cancer. Another inter- esting point is whether the new concept of intermittent androgen suppression, introduced by Bruchovsky et al. 5, can take advantage of the withdrawal phenomenon. References 1. Akakura K, Akimoto S, Ohki T, Shimazaki J (1995) Antian- drogen withdrawal syndrome in prostate cancer after treatment with steroidal antiandrogen chlormadinone acetate. Urology 45:700 2. Belani CP, Pearl P, Whitley NO, Aisner J (1989) Tamoxifen withdrawal response. Arch Intern Med 149:449 3. Bissada NK, Kaczmarek AT (1995) Complete remission of hormone refractory adenocarcinoma of the prostate in response to withdrawal of diethylstilbestrol. J Urol 153:1944 4. Boring CC, Squires TS, Tong T (1992) Cancer statistics. CA Cancer J Clin 42:19 5. Bruchovsky N, Goldenberg SL, Rennie PS, Gleave M (1995) Theoretische Oberlegungen und erste klinische Ergebnisse mit intermittierender Hormonbehandlung bei Patienten mit einem fortgeschrittenen Prostatakarzinom. Urologe A 34:389 6. Culig Z, Hobisch A, Cronauer MV, Cato AC, Hittmair A, Radmayr C, Eberle J, Bartsch G, Klocker H (1993) Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endrocrinol 7:1541 7. Cusan L, Gomez JL, Dupont A, Diamond P, Lemay M, Moore S, Labrie F (1994) Metastatic prostate cancer pulmo- nary nodules: beneficial effects of combination therapy and subsequent withdrawal of flutamide. Prostate 24:257 8. Dawson NA, McLeod DG (1995) Dramatic prostate specific antigen decrease in response to discontinuation of megestrol acetate in advanced prostate cancer: expansion of the antian- drogen withdrawal syndrome. J Urol 153:1946 9. Dupont A, Gomez JL, Cusan L, Koutsilieris M, Labrie F (1993) Response to ftutamide withdrawal in advanced prostate cancer in progression under combination therapy. J Urol 150:908 10. Evans BAJ, Harper ME, Daniells CE, Watts CE, Matenhelia S, Green J, Griffiths K (1996) Low incidence of androgen receptor gene mutations in human prostatic tumors using single strand conformation polymorphism analysis. Prostate 28:162 11. Figg WD, Sartor O, Cooper MR, Thibault A, Bergan RC, Dawson N, Reed E, Myers CE (1995) Prostate specific antigen decline following the discontinuation of flutamide in patients with stage D2 prostate cancer. Am J Med 98:412
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