Orig i nal Article J Chin Med Assoc 2003;66:735-740 Antiandrogen-associated Hepatotoxicity in the Man age ment of Ad vanced Pros tate Can cer Al pha DY Lin Kuang-Kuo Chen Alex TL Lin Yen-Hwa Chang Howard HH Wu Junne-Yih Kuo Wil liam JS Huang Yen-Shen Hsu Hsiao-Jen Chung Luke S Chang Di vi sion of Urol ogy, De part ment of Sur gery, Tai pei Vet erans Gen eral Hos pi tal, and De part ment of Urol ogy, School of Med i cine and Shu-Tien Uro log i cal Re search Cen ter, Na tional Yang-Ming Uni ver sity, Tai pei, Tai wan, R.O.C. Key Words antiandrogen; cyproterone acetate; flutamide; hepatotoxicity; prostate can cer Antiandrogens have been used to treat ad vanced pros tate can cer. Two types of antiandrogen are avail able, steroidal such as cyproterone ac e tate (CPA) and non-steroidal such as flutamide. Al though both types of antiandrogens have ef fi cacy, they have also been re - ported to in duce hepatotoxicity from mild liver func tion de te ri o ra tion to even fa tal liver fail ure. 1-4 Flutamide (4 -nitro-3-trifluoromethyl-isobutyranilide) Back ground. Antiandrogens avail able for pa tients with ad vanced pros tate can cer are re ported to cause hepatotoxicity. The aim of this study is to in ves ti gate the anti - androgen-associated hepatotoxicity in pa tients with ad vanced pros tate can cer. Methods. By ret ro spec tive charts re view, 229 pa tients (47-89 years old) with ad vanced pros tate can cer treated by to tal an dro gen block ade (TAB) with bi lat eral orchiectomy or LHRH (luteinizing hor mone-releasing hor mone) an a logues plus antiandrogen, or antiandrogen-radiotherapy were en rolled in this study. There were 124 pa tients tak ing flutamide 750 mg daily and 105 pa tients tak ing cyproterone ac e tate (CPA) 150 mg daily. Hepatotoxicity de fined by the In ter na tional Con sen sus Meet ing in 1990 and Food and Drug Ad min is tra tion, USA was used to eval u ate the hepatotoxicity (in clud - ing se ri ous hepat otoxicity). Results. There was a higher oc cur rence of hepatotoxicity in pa tients tak ing flutamide (15.3%) than tak ing CPA (9.5%) (p = 0.034). The occurrence of serious hepat - otoxicity of flutamide and CPA was 4.8% (6/124) and 3.8% (4/105), re spec tively. The mean latency pe riod of hepatotoxicity for CPA was 4.8 2.0 months for flutamide and 5.8 1.9 months for CPA, re spec tively. The 2 groups made no sig nif i - cant dif fer ence of liver en zyme (mean max i mal alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) = 284.2 99.3/300.6 58.5 U/L versus 341.8 67.1/301.6 80.5 U/L). All of the 19 pa tients (100%) and 9 of 10 pa tients (90%) with flutamide and CPA-induced hepatotoxicity got self-resolution af ter dis - con tinu a tion of the antiandrogens. The av er age time of self-resolution is 4.5 3.1 months and 6.3 4.7 months for flutamide and CPA, re spec tively. Five pa tients of flutamide-induced and 2 pa tients of CPA-induced hepatotoxicity got res o lu tion af ter chang ing to other antiandrogen. Con clu sions. Flutamide and CPA ap pear to cause hepatotoxic ef fects in some pa - tients. Dis con tinu a tion of the antiandrogens seems to be the res o lu tion of hepat - otoxicity. A change to other antiandrogen may be the al ter na tive strat egy to the antian dro gen-induced hepatotoxicity. The re sults of this study sug gest that all pa - tients re ceived flutamide and CPA should be mon i tored care fully for signs and symp - toms re fer able to hepatic in jury to pre vent the de vel op ment of se ri ous hepatic dys - function. is the first avail able nonsteroidal antiandrogen used for the treat ment of pros tate can cer. 5 The drug is an anilide that ap pears to block the ac tiv ity of dihydrotestosterone on an dro gen re cep tors in pros tate tis sue. 6 It could in hibit the up take and bind ing of an dro gens to nu clear re cep tors in the pros tate, so it is used for the treat ment of pa tients with metastatic carcinoma of the prostate. 7 Flutamide, approved by the US Food and Drug Administration in Re ceived: October 17, 2002. Ac cepted: July 16, 2003. Cor re spon dence to: Kuang-Kuo Chen, M.D., Ph.D, Di vi sion of Urol ogy, De part ment of Sur gery, Tai pei Vet erans Gen eral Hos pi tal, 201, Sec. 2, Shih-Pai Road, Tai pei 112, Tai wan. Fax: +886-2-2875-7540; E-mail: kkchen@vghtpe.gov.tw 735
Al pha DY Lin et al. Jour nal of the Chi nese Med i cal As so ci a tion Vol. 66, No. 12 1989, is also used af ter orchiectomy or in com bi na tion with various luteinizing hor mone-releasing hormone (LHRH) agonists. 8 Nev er the less, hepatotoxicity from mild liver func tion deterioration, hep a ti tis with bridg ing ne cro sis or cho les tasis, fulminant hep a ti tis and even mor tal ity due to liver fail ure have been re ported in west ern coun tries. The oc cur rence of hepatotoxicity re - ported ranged from 1 to 5%. 9 Gomez et al. have re - ported an oc cur rence of hepatotoxicity in 0.36% of 1,091 con sec u tively patients treated with prostate cancer (as de fined by an in crease in se rum transaminase ac tiv ity 4 folds or more above the up per nor mal limit). 10 Cyproterone ac e tate (CPA) is a widely used drug in the treat ment of ad vanced pros tatic car ci noma. It ex erts a di rect antiandrogenic effect on the tumor cells and its metastases, and has an ad di tional neg a tive feed back ef - fect on the hy po tha lamic re cep tor, thus lead ing to re duce in go nad o tro pin re lease and to di min ish testicular an dro - gen pro duc tion. 2 The in ci dence of CPA-induced hepat - otoxicity was noted as 4.5% in the Eu ro pean or ga ni za - tion for re search and treatment of cancer (EORTC) study. 11 The num ber of pa tients with prostate cancer in - creased dra mat i cally in re cent few years in our coun try. Antiandrogens were also used fre quently in pa tients with lo cally ad vanced or met a static pros tate can cer. The pur - pose of this study is to in ves ti gate the hepatotoxicity in - duced by flutamide and CPA. METHODS From Jan u ary 1994 to June 2000, a to tal of 229 con - sec u tive patients with advanced pros tate carcinoma (stage C or D) were treated with flutamide 750 mg or CPA 150 mg daily in com bi na tion with LHRH ag o nist, orchiectomy or radiotherapy. The patients treated with antiandrogen alone (monotherapy) were also in cluded. Ex cluded were the pa tients with his tory of hep a ti tis, gall stone, fatty liver, liver cir rho sis, habits of al co hol con - sump tion, and medication that may cause liver in jury. Se rum alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) were checked before treat - ment, and then monthly for 3 months and ev ery 3-6 months there af ter. Some pa tients also had se rum al ka line phos phatase (Alk. P), -glutamyl transpeptidase (GGT) and to tal bil i ru bin (TB) eval u ated be fore and af ter antia - ndrogen treat ment. The pa tients char ac ter is tics are showed in Ta ble 1. Hepatotoxicity was de fined as: mild-to-moderate (liver en zymes el e va tion 2-6 folds of up per nor mal limit) and se ri ous hepatotoxicity (liver en zymes elevation greater than 6 folds of up per nor mal limit). Drug-induced liver in jury was de fined uti liz ing the cri te ria re ported by the In ter na tional Consensus Meet ing in 1990. 12 The signs and symp toms of liver dis ease are gen er ally non spe cific. The term liver in jury is more pre ferred than hep a ti tis, ne cro sis or cho lestasis in the de scrip tion of drug-induced liver dis ease. The con sen sus meet ing de fined liver in jury as an in crease of more than twice the upper limit of the nor mal range of ALT or con ju gated bil i ru bin, or a com - bined in crease in AST, Alk. P and TB, pro vided any one of them is more than twice nor mal. 12 The di ag no sis of chem i cally in duced liver in jury de - pends on 2 fac tors: (1) the ap pro pri ate clin i cal set ting and (2) the ex clu sion of the other causes of the liver dis ease. Sup port for the di ag no sis can be ob tained from the clin i - cal response to discontinuation or re-administration of the drug. 13 Pearson Chi-Square test was used to compare the dif fer ence of hepatotoxicity be tween flutamide and CPA. Independent t-test was used to com pare the dif fer ence of Table 1. Characteristics of patients Flutamide (No. = 124) CPA (No. = 105) Age (yrs) 73.6 10.1 (50-89) a 76.1 9.5 (47-88) a Pre-treatment mean ALT/AST (U/L) 19.9 13.1/17.2 11.4 b 22.8 16.1/15.7 11.9 b CPA = cyproterone acetate; Age data expressed as mean SD (range). a p = 0.352, comparison between flutamide and CPA group; b p = 0.227, comparison between flutamide and CPA group. 736
De cem ber 2003 Antiandrogen-associated Hepatotoxicity in Pros tate Can cer Pa tients la tency pe riod and res o lu tion du ra tion of hepatotoxicity be tween flutamide and CPA. A p value of less than 0.05 was con sid ered sta tis ti cally sig nif i cant. RESULTS Oc cur rence of hepatotoxicity of flutamide and CPA was 15.3% (19/124) and 9.5% (10/105), re spec tively (p = 0.034). The mean max i mal ALT and AST are showed in Ta ble 2. The oc cur rence of CPA-induced hepatotoxicity is sig nif i cantly lower than that of flutamide. In CPA group, the lev els of se rum ALT/ AST/ Alk. P/ GGT/ TB were checked in 3 of 10 pa tients with hepatotoxicity; in - cluding 1 with mild-to-moderate hepatotoxicity and 2 with se vere hepatotoxicity. The re cords were 78 U/L /93 U/L /143 U/L /21 U/L /0.3 mg/dl, 244 U/L /193 U/L /143 U/L /21 U/L /0.5 mg/dl, and 1132 U/L /992 U/L /210 U/L /127 U/L /7.6 mg/dl in 3 pa tients, re spec tively. In flutamide group, Alk. P, GGT and TB were checked in 4 of 19 pa tients with hepatotoxicity when it oc curred; one was with mild-to-moderate hepatotoxicity and 3 were with se ri ous hepatotoxicity. The ALT/ AST/ Alk. P/ GGT/ TB were re corded as 103 U/L /111 U/L /78 U/L /19 U/L /0.8 mg/dl, 382 U/L /313 U/L /29 U/L /22 U/L /0.2 mg/dl, 1035 U/L /745 U/L /145 U/L /140 U/L /7.0 mg/dl, and 216 U/L /201 U/L /92 U/L /77 U/L /0.7 mg/dl in them, re spec tively. The re sults of this study im - plied that the Alk. P, GGT and TB may be ab nor mal in pa tients with se ri ous hepatotoxicity. La tency pe riod of hepatotoxicity and res o lu tion du - ra tion af ter dis con tinu a tion of antiandrogen are showed in Ta ble 3. Neither of them showed sig nif i cant dif fer ence be tween flutamide and CPA. The dis tri bu tion of non-hepatotoxic and hepatotoxic group in pa tients tak ing antiandrogen is showed in Fig. 1 (flutamide) and Fig. 2 (CPA). Four of the 6 pa tients with flutamide-induced se ri ous hepatotoxicity were orig i nally treated in com bi na tion with orchiectomy. An other one had flutamide and ra dio - ther apy. The other 1 was treated with LHRH ag o nist and flutamide. One pa tient (ra dio ther apy and flutamide) was lost to fol low-up. Five of them re solved af ter dis con tinu - a tion of the antiandrogen for 7.9 4.1 months. Three of the 5 pa tients changed to di eth yl stil bes trol, and the other 2 took CPA af ter the liver func tion re cov ered. All the 5 pa tients had loss of li bido and po tency af ter the al ter na - tive treatment. None of them had fur ther liver func tion de te ri o ra tion dur ing the fol low-up pe riod. Nine of the 13 pa tients with flutamide-induced mildto-moderate hepatotoxicity were originally treated with orchiectomy and flutamide; an other 2 with ra dio ther apy and flutamide; and the other 2 with LHRH agonist and flutamide. All of them had resolved liver function af ter dis con tinu a tion of antiandrogen. In the fol low-up pe riod, five of them (38.4%) had their dose ta per ing; 3 changed to CPA, and 2 dis con tin ued antiandrogen. The re main ing 3 pa tients changed to di eth yl stil bes trol, and 2 of them sub - se quently changed to bicalutamide due to the side ef fects of di eth yl stil bes trol. These pa tients showed no re cur rence of hepatotoxicity in the fol low-up pe riod. A case of pathologically proved flutamide-induced se ri ous hepatotoxicity was in cluded. 9 In 4 pa tients with CPA-induced se ri ous hepatotoxicity, 3 were orig i nally treated with orchiectomy and CPA, and 1 was treated with LHRH and CPA. All of them got re - Table 3. Latency period and resolution duration after discontinuation Flutamide CPA p value Treatment time (months) 2-68 2-43 0.841 a Latency period (months) 4.8 2.0 5.8 1.9 0.862 b Resolution duration (months) 4.5 3.1 6.3 4.7 0.622 c CPA = cyproterone acetate; a,b,c Independent t-test. Table2. Incidenceof hepatotoxicity Flutamide CPA p value Mean [max. ALT/AST (U/L)] 284.2 99.3/300.6 58.5 341.8 67.1/301.6 80.5 0.744 a Incidence of hepatotoxicity 15.3% (19/124) 9.5% (10/105) 0.034 b Mean [max ALT/ASTU/L] = mean SD of maximal alanineaminotransaminase (ALT) and aspartateaminotransaminase (AST); CPA = cyproterone acetate; a,b Pearson Chi-Square test 737
Al pha DY Lin et al. Jour nal of the Chi nese Med i cal As so ci a tion Vol. 66, No. 12 cov ered from that hepatotoxicity in a mean of 6.9 months af ter dis con tinu a tion of the CPA. Two of the 4 pa tients no lon ger re quired antiandrogen; 1 changed to di eth yl - stil bes trol and the other one switched to bicalutamide. In the fol low ing days, no other ep i sode of drug-induced hepat otoxicity was found to oc cur in them. In the 6 patients with CPA-induced mild-to-moderate hepatotoxicity, 3 were orig i nally treated with orchiectomy and CPA, 2 received ra dio ther apy and CPA, and 1 re - ceived LHRH ag o nist and CPA. No hepatotoxicity was found to oc cur in these 6 pa tients in the fol low-up pe riod. There was no cor re la tion be tween the du ra tion of antiandrogen treatment (flutamide or CPA) and the el e - va tion of liver en zyme. There was no sig nif i cant dif fer - ence in age be tween the groups of pa tients with flutamideand CPA-induced hepatotoxicity. Also, there was no sig - Flutamide n = 124 Non-hepatotoxicity n = 105 (84.7%) ean [max ALT/AST] a = 29.4 13.5/19.3 11.2 Hepatotoxocity n = 19 (15.3%) mean [max ALT/AST] = 284.2 99.3/300.6 58.5 ALT or AST > Normal value n = 6 6 b S/S + (ALT/AST > Normal value n = 13 2) c n = 6* Switch to CPA n = 13 Switch to CPA n = 3 n = 5 *including 1 patient had liver enzyme returned to normal after antiandrogen discontinuation at other hospital Fig. 1. Dis tri bu tion of non-hepatotoxic and hepatotoxic group in de tail of flutamide; mean [max ALT/AST] a : mean SD value of max i mal ALT and max i mal AST; ALT or AST > Nor mal value 6 b : ALT or AST greater than six times of the up per limit of nor mal; S/S + (ALT/AST > Nor mal value 2) c : symp toms or signs of liver func tion de te ri o ra tion with ALT or AST greater than two times of the up per limit of nor mal. CPA n = 105 Non-hepatotoxicity n = 95 (90.5%) mean [max ALT/AST] a = 32.4 19.4/25.1 9.2 Hepatotoxocity n = 10 (9.5%) mean [max ALT/AST] = 341.8 67.1/301.6 80.5 ALT or AST > Normal value n = 4 6 b S/S + (ALT/AST > Normal value n = 6 2) c n = 4 Switch to flutamide n = 5 Switch to flutamide n = 2 n = 1 Fig. 2. Dis tri bu tion of non-hepatotoxic and hepatotoxic group in de tail of CPA; mean [max ALT/AST] a : mean SD value of max i mal ALT and max i mal AST; ALT or AST > Nor mal value 6 b : ALT or AST greater than 6 times of the up per limit of nor - mal; S/S + (ALT/AST > Nor mal value 2) c : symp toms or signs of liver func tion de te ri o ra tion with ALT or AST greater than 2 times of the up per limit of nor mal. 738
De cem ber 2003 Antiandrogen-associated Hepatotoxicity in Pros tate Can cer Pa tients nif i cant dif fer ence of age in hepatotoxic and non-hepat - otoxic groups of pa tients hav ing ei ther flutamide or CPA. DISCUSSION Both flutamide and CPA play a certain role in the man age ment of ad vanced pros tate cancer, and hepat - otoxicity oc curs in both of them. Flutamide and CPA may cause liver in jury from mild liver func tion de te ri o ra tion, hep a ti tis with cholestatic or hepatocelluar injury, to fulminant hepatitis and even mortality. 6,17-19 Be cause the pos si bil ity of dose-related hepatotoxicity in both flutamide and CPA, 20 early ta per - ing of the dose or discontinuation of the antiandrogen may be a good res o lu tion to pre vent se ri ous hepatotoxicity. The oc cur rence of hepatotoxicity, de fined as an el e - vation of serum aminotransaminase con cen tra tion 4 folds or more above the up per nor mal limit, was 0.36% in 1,091 con sec u tive pros tate can cer pa tients treated with flutamide. 10 Using this definition, the occurrence of hepatotoxicity in this study was 5.6% and 5.7% for flutamide and CPA, re spec tively. How ever, the pa tients with liver en zyme el e va tion less than 4 folds would be missed. In the EORTC pro to col 30892 study, the oc cur - rence of he patotoxicity is 10.0% and 4.5% for flutamide and CPA, re spec tively. 11 Lundgren re ported one of 10 pa - tients (10%) who had liver injury as so ci ated with flutamide. 16 Lund et al. reported the re ver sal of se vere hepatotoxicity af ter dis con tinu a tion of flutamide use in 1 of 20 pa tients. 17 Con se quently, the def i ni tion of hepato - toxicity would af fect the eval u a tion of in ci dence and the re sults of man age ment. Liver func tion de te ri o ra tion with bio chem i cal ab nor - mal ity would be nec es sary to con firm the di ag no sis. All clinical and bi o log i cal man i fes ta tions of hepatotoxicity caused by flutamide or CPA pro gres sively dis ap peared upon dis con tinu a tion. It seems to be re vers ible. Flutamide seems to have more chance to cause hapatotoxicity than CPA. Ac cord ing to our data, in con sid er ation of max i mal antidrogen block ade, the side ef fect of antiandrogen can be solved by switch ing flutamide to CPA or vice versa. No hepatotoxicity oc curred with the al ter na tive change in the sub group with mild-to-moderate hepatotoxicity. As showed in our data, ta per ing the dose of flutamide or CPA could resolve the hepatotoxicity. Dose-related hepatotoxicity may be pos si ble in flutamide and CPA. It has also been re ported in the long-term use of CPA. 20 To pre vent the de vel op ment of se ri ous hepatic dys func tion, all patients treated with flutamide or CPA should be mon i tored clin i cally for signs and symp toms re fer able to hepatic in jury. ALT and AST could provide 100% sen si tiv ity and spec i fic ity of hepatotoxicity as shown in our data. This is also de scribed in the study of Gomez et al. 10 The mech a nism of hepatotoxicity caused by flutamide and CPA is still not fully un der stood. Flutamide-induced hep a ti tis is cholestsatic and/or cytolytic, and fulminant hep a ti tis is pos si ble. 19 Fau et al. re ported that flutamide is toxic to the rat hepatocytes as a re sult of the cytochrome P-450 (3A and also 1A)-mediated for ma tion of elec - trophic me tab o lites, whose dam ag ing ef fects are fur ther ag gra vated by the in hib i tory ef fect of flutamide on mi to - chon drial respiration and adenosine triphosphate (ATP) formation. 19 CPA-induced hepatic dys func tion is due to di rect or to re ac tive met a bolic tox ic ity. 15 Our laboratory data showed that antiandrogen-as - sociated hepatotoxicity could induce cytolytic and/or cholestsatic liver in jury. The re sults of this study im plied that the Alk.P and TB may be ab nor mal in pa tients with se ri ous hepatotoxicity. Based on these find ings, we may sug gest urol o gists to check Alk. P and TB be fore and af - ter antiandrogen treatment even though ALT and AST could provide 100% sen si tiv ity and specificity of flut - amide- associated hepatotoxicity. 10 In con clu sion, the re sults of this study sug gest that flutamide and CPA appear to cause hepatotoxicity in some pa tients with advanced prostatic car ci noma. To pre vent the tox ic ity and its pro gres sion, care ful fol - low-up of the liver func tion be fore and af ter anti - androgen treatment is highly rec om mended. Tapering the dose, dis con tinu a tion of antiandrogen, or switch ing to other antia ndrogen may re solve the hepatotoxicity. REFERENCES 1. Johnason JE, Andersson SO, Beckman KW, Lingardh G, 739
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