We investigated the endocrinological effects of pretreatment with chlormadinone acetate (CMA) in preventing the initial testosterone surge induced by a luteinizing hormone-releasing hormone (LH-RH) analogue. A total of 25 patients with previously untreated prostate cancer were included in this study. The patients were randomly assigned to 2 treatment groups:Group1;CMA therapy was begun 4 weeks before the initial LH-RH analogue injection. Group 2;CMA therapy was begun 2 weeks before the initial LH-RH analogue injection. After the initial LH-RH analogue injection, CMA was administered during this study. After LH-RH analogue application, the mean values of serum luteinizing hormone (LH) and testosterone increased in both groups on day 3. However, LH and testosterone levels remained beneath pretreatment values in both groups. The mean relative PSA levels did not significantly increased on day 3 and day 7in both groups. Our results indicate that pretreatment with CMA for 2 weeks was sufficient to prevent the initial testosterone surge in the maximal androgen blockade which was associated with CMA

Kagawa, Susumu

Kanayama, Hiro-omi

Miyake, Noriaki

Sumiyoshi, Yoshiteru

Yamamoto, Akihiro

Yokozeki, Hideaki

Tokushima University Institutional Repository

INTRODUCTIONThe luteinizing hormone-releasing hormone(LH-RH) analogue induces a transient release ofluteinizing hormone (LH) with a consecutive in-crease in testosterone, and this increase results inexacerbation of clinical signs and symptoms in someprostate cancer patients [1, 2]. Several studies havedemonstrated that this disease flare can be effec-tively eliminated by the use of antiandrogens incombination with or before initiation of LH-RHanalogue therapy [3-6]. However, the optimalduration of pretreatment is rather difficult to deter-mine. We herein report the endocrinological effectsof pretreatment with the steroidal antiandrogen,chlormadinone acetate (CMA ; 6-chloro-3,20-dioxo-4,6-pregnadien-17-yl acetate, Teikoku Hormone MFGCo. Tokyo, Japan) for the prevention of this initialtestosterone surge.PATIENTS AND METHODSA total of 25 patients with previously untreatedprostate cancer (stage B, C, D) proved by biopsy wereincluded in this study. All patients gave informedPrevention of the initial testosterone surge induced bya luteinizing hormone-releasing hormone analogue inprostate cancer patients : the endocrinological effectsof pretreatment with chlormadinone acetateAkihiro Yamamoto, Yoshiteru Sumiyoshi＊, Noriaki Miyake＊＊, Hideaki Yokozeki†,Hiro-omi Kanayama‡, and Susumu Kagawa‡Department of Urology, Kochi Takasu Hospital, Kochi, Japan; ＊Department of Urology, NationalShikoku Cancer Center Hospital, Ehime, Japan; ＊＊Department of Urology, Yashima General Hospital,Kagawa, Japan ; †Department of Urology, Tokushima Municipal Hospital, Tokushima, Japan ; and‡Department of Urology, The University of Tokushima School of Medicine, Tokushima, JapanAbstract : We investigated the endocrinological effects of pretreatment with chlormadinoneacetate (CMA) in preventing the initial testosterone surge induced by a luteinizinghormone-releasing hormone (LH-RH) analogue. A total of 25 patients with previouslyuntreated prostate cancer were included in this study. The patients were randomlyassigned to 2 treatment groups : Group 1 ; CMA therapy was begun 4 weeks before theinitial LH-RH analogue injection. Group 2 ; CMA therapy was begun 2 weeks before theinitial LH-RH analogue injection. After the initial LH-RH analogue injection, CMA wasadministered during this study. After LH-RH analogue application, the mean values ofserum luteinizing hormone (LH) and testosterone increased in both groups on day 3.However, LH and testosterone levels remained beneath pretreatment values in bothgroups. The mean relative PSA levels did not significantly increased on day 3 and day 7in both groups. Our results indicate that pretreatment with CMA for 2 weeks was sufficientto prevent the initial testosterone surge in the maximal androgen blockade which wasassociated with CMA. J. Med. Invest. 46 : 55-58, 1999Key words : Prostate cancer, Luteinizing hormone-releasing hormone analogue, Disease flare, ChlormadinoneacetateReceived for publication November 17, 1998 ; accepted December25, 1998.Address correspondence and reprint requests to Dr. AkihiroYamamoto, Department of Urology, Kochi Takasu Hospital,Takasu-shin-machi, Kochi 780-8122, Japan and Fax : +81-888-84-1892.The Journal of Medical Investigation Vol.46 1999５５consent to participate in the study. The patients wereassigned randomly to 2 treatment groups. Group 1patients were treated with the depot LH-RH ana-logue (leuprorelin acetate 3.75 mg or goserelin 3.6mg) plus CMA. CMA therapy was begun 4 weeksbefore the initial LH-RH analogue injection at adosage of 100 mg/day orally. Group 2 patients weretreated with the LH-RH analogue plus CMA at thesame dosages used in group 1 with the exceptionthat CMA therapy was begun 2 weeks before theinitial LH-RH analogue injection. After the initialLH-RH analogue injection, CMA was administeredto both groups.Serum LH, testosterone, and prostate specificantigen (PSA) were measured in each patient beforethe initial CMA administration, and on days 0, 3, 7,and 28 of LH-RH analogue therapy. Serum LH(Spack-S LH kit, Daiichi Radioisotope LaboratoriesLtd., Tokyo, Japan) and testosterone (Total Testos-terone, Diagnostic Products Corporation, Los Angels,USA) levels were measured by radioimmunoassay.PSA assay was performed by themonoclonal HybritechTandem-R immuno-radiometric technique (Tandem-RPSA, Hybritech. Inc., San Diego, USA). Due to thewide variation of the initial values of serum PSA, weinvestigated the mean relative PSA levels. Relativevalues were expressed as a percentage of the initialvalue for each patient before therapy started, whichwas considered 100%.Histologically, differentiation of adenocarcinomawas evaluated according to the criteria of the GeneralRules for Clinical and Pathological Studies onProstatic Cancer [7]. Data are presented as means±SD (standard deviation). For statistical analysis,the Wilcoxon one sample analysis, paired Wilcoxontest and Mann-Whitney U test were used and a Pvalue below 0.05 was considered to indicate statisticalsignificance.RESULTSThe characteristics of the patients are shown intable 1. There were no significant differences be-tween the 2 treatment groups in the initial age,histopathological grade, clinical stage, serum LH,testosterone and PSA levels at the start of treat-ment.The mean absolute values of serum LH and tes-tosterone in both groups are shown in figures 1and 2. Pretreatment with CMA decreased serumLH levels. Compared to day 0 (the initial injectionFig.1. Effects of CMA pretreatment on serum LH in prostatecancer patients. LH-RH analogue was administered on day 0.Values are mean±S.D. ; Closed circle, Group 1, n=12 ; Opencircle, Group 2, n=13. *p<0.05, **p<0.01, ***p<0.001 vs. day 0.Fig. 2. Effects of CMA pretreatment on serum testosterone inprostate cancer patients. LH-RH analogue was administered onday 0. Values are mean±S.D. ; Closed circle, Group 1, n=12 ;Open circle, Group 2, n=13. **p<0.01, ***p<0.001 vs. day 0.Table 1. Patient characteristicsGroup 1(n=12)Group 2(n=13)Age (years) 75.5±8.0 75.4±7.0Histopathological gradeWellModeratePoor453247StageB 1B 2CD 222443361LH (mIU/ml) 5.9±2.6 12.7±9.5Testosterone (ng/dl) 422.2±152.7 528.2±173.7PSA (ng/ml) 129.0±176.8 60.0±63.7Values are means±S.D.A. Yamamoto et al. Prevention of Testosterone Surge by Chlormadinone Acetate５６of the LH-RH analogue), the serum LH levels wereincreased on day 3 (Group 1 ; 2.83±2.22 vs. 4.06±2.05mIU/ml, Group 2 ; 4.92±3.61 vs.7.95±5.23mIU/ml), and then decreased. However, the serumLH levels on day 3 did not reach pretreatment levelsin either group. There were no significant differ-ences in serum LH levels between the groups ondays 0, 3, 7, and 28. The serum testosterone levelsshowed a parallel decrease with LH until day 0,and reached castration levels below 100 ng/dl inboth groups. Temporary increases were observedon day 3 (Group 1 ; 138.12±95.82 ng/dl, Group 2 ;202.58±81.70 ng/dl), but did not reach pretreat-ment levels. On day 7, serum testosterone levelsdecreased to castration levels in both groups. Therewere no significant differences in serum testosteronelevels between the groups on days 0, 3, 7, and 28.The mean relative values of serum PSA are shownin figure 3. CMA pretreatment significantly reducedserum PSA. On day 0, the mean relative values ofserum PSA in group 2 (45.31±24.76%) were higherthan those in group 1 (24.92±11.89%). There wereno significant differences among the groups on days3, 7, and 28. In group 2, the mean relative values ofserum PSA were significantly lower on day 3 (38.26±19.71%) and day 7 (35.25±19.62%) than on day 0(45.31±24.76%). However, the mean relative PSAlevels were not lower on day 3 (25.26±12.34%) orday 7 (27.68±12.31%) than on day 0 (24.92±11.89%) in group 1. In 3 cases in group 1, the meanrelative values of serum PSA decreased in a linearfashion after the initial injection of the LH-RH ana-logue, and all 3 cases exhibited well differentiatedadenocarcinoma. In contrast, increases in the meanrelative values of serum PSA on day 7 compared todays 0 or 3 were observed in 9 cases. The adeno-carcinoma was well differentiated in 1 case, mod-erate in 5, and poor in 3. Increases in the meanrelative values of serum PSA on day 7 were morefrequently seen in the patients with high histopatho-logical grade (p<0.05). There was no correlationbetween the change in mean relative values ofserum PSA and the clinical stage.No signs or symptoms of disease flare were ob-served in either group.DISCUSSIONSince disease flare is considered to be due to theinitial increase in serum testosterone, the use ofantiandrogens in combination with or before ini-tiation of a LH-RH analogue has been advocated.Labrie et al. [3] reported that the concomitantadministration of the nonsteroidal antiandrogen,flutamide, completely eliminated the risk of diseaseflare. On the other hand, Schulze et al . [4] indicatedthat pretreatment with flutamide for only 1 day maynot be sufficient to prevent tumor flare, and shouldbegin 1 week before the LH-RH analogue injection.However, from an endocrinological viewpoint, theeffects of nonsteroidal antiandrogens in preventingdisease flare are rather difficult to determine dueto their mode of action [6]. Pretreatment with thesteroidal antiandrogen, cyproterone acetate, for 1week prevented the LH-RH analogue induced tes-tosterone surge and an initial increase in prostaticacid phosphatase beyond the pretreatment levels[4]. The administration of estramustine phosphate560mg daily for 3 weeks prior to goserelin acetatedepot therapy was also considered sufficient toprevent tumor flare [6].The steroidal antiandrogen CMA was reportedto reduce serum testosterone levels and block thebinding of androgens to androgen receptors inprostatic carcinoma tissue [8]. Nishimura et al . [9]reported that the plasma testosterone concentrationdecreased to levels of normal females after 4-6weeks of CMA administration, but increased to anaverage level of 109ng/dl after 8 -10 weeks of CMAadministration. Yoshida et al . [5] investigated theefficacy of 2-week and 4-week pretreatment with 100mg/day CMA to prevent disease flare in patientswith metastatic carcinoma of the prostate. Sinceserum PSA levels significantly increased in the2-week pretreatment group but showed a linearFig. 3. Effects of CMA pretreatment on mean relative valuesof serum PSA in prostate cancer patients. LH-RH analogue wasadministered on day 0. Values are mean±S.D. ; Closed circle,Group 1, n=12 ; Open circle, Group 2, n=13. **p<0.01, ***p<0.001vs. day 0.５７The Journal of Medical Investigation Vol.46 1999decrease in the 4-week pretreatment group, theyconcluded that the 4-week regimen was more effec-tive than the 2-week regimen [5]. However, thereare two major differences from our study. First,CMA was discontinued after the LH-RH analoguetherapy in their study. Second, they investigated theefficacy in patients with metastatic carcinoma of theprostate.In recent meta-analyses, maximal androgenblockade (MAB) continues to be debated, with ad-vocates both for and against its efficacy [10, 11]. Inthe present study, CMA was continued after theLH-RH analogue therapy for the purpose of MAB.The serum LH and testosterone levels were in-creased on day 3 compared to day 0, but did notreach pretreatment levels in either group. The meanrelative values of serum PSA were significantlylower on day 3 and day 7 than on day 0 in group 2.However, the mean relative PSA levels were notlower on days 3 or 7 than on day 0 in group 1, de-spite the longer pretreatment. These results suggestthat pretreatment for 2 weeks is sufficient to pre-vent the initial testosterone surge in the MAB whichis associated with CMA. PSA change induced by atransient testosterone increase may be different ineach case, and it seems to be difficult to identify thecorrelation factor. However, as shown in our resultsthe histopathological grade may contribute to thedifference. A larger prospective trial is necessaryto elucidate this factor.REFERENCES1. Faure N, Lemay A, Laroche B, Robert G,Plante R, Jean C, Thabet M, Roy R, FazekasATA : Preliminary results on the clinical efficacyand safety of androgen inhibition by an LHRHagonist alone or combined with an antiandrogenin the treatment of prostatic carcinoma. Prostate4 : 601-624, 19832. Kahan A, Delrieu F, Amor B, Chiche R, StegA : Disease flare induced by D-Trp6-LHRHanalogue in patients with metastatic prostaticcancer. Lancet 1 : 971-972, 19843. Labrie F, Dupont A, Belanger A, Lachance R :Flutamide eliminates the risk of disease flarein prostatic cancer patients treated with aluteinizing hormone-releasing hormone agonist.J Urol 138 : 804- 806, 19874. Schulze H, Senge T : Influence of differenttypes of antiandrogens on luteinizing hormone-releasing hormone analogue-induced testoster-one surge in patients with metastatic carcinomaof the prostate. J Urol 144 : 934-941, 19905. Yoshida K, Takeuchi S : Pretreatment withchlormadinone acetate eliminates testoster-one surge induced by a luteinizing -hormone-releasing hormone analogue and the risk ofdisease flare in patients with metastatic car-cinoma of the prostate. Eur Urol 27 : 187-191,19956. Shimizu T, Shibata Y, Jinbo H, Satoh J, YamanakaH : Estramustine phosphate for presrventingflare-up in luteinizing hormone-releasing hor-mone analogue depot therapy. Eur Urol 27 :192-195, 19957. Japanese Urological Association and the Japa-nese Pathological Society : General Rules forClinical Pathological Studies on ProstaticCancer, ed 2. Kanehara Shuppan, Tokyo, 19928. Shida K : Fundamental and clinical study onanti-androgen-androgen dependency of pros-tatic tumors and clinical application of anti-androgens. Asian Med J 24 : 747-776, 19819. Nishimura R, Shida K : Antiandrogenic therapyfor the treatment of early stage prostatic cancer.Prostate 1 (suppl) : 27-34, 198110. Prostate Cancer Trialists’Collaborative Group :Maximum androgen blockade in advancedprostate cancer : an overview of 22 randomizedtrials with 3283 deaths in 5710 patients. Lancet346 : 265-269, 199511. Caubet JF, Tosteson TD, Dong EW, NaylonEM, Whiting GW, Ernstoff MS, Ross SD :Maximum androgen blockade in advancedprostate cancer : A meta-analysis of publishedrandomized controlled trials using nonsteroidalantiandrogens. Urology 49 : 71-78, 1997A. Yamamoto et al. Prevention of Testosterone Surge by Chlormadinone Acetate５８

Prevention of the initial testosterone surge induced by a luteinizing hormone-releasing hormone analogue in prostate cancer patients:the endocrinological effects of pretreatment with chlormadinone acetate

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Prevention of the initial testosterone surge induced by a luteinizing hormone-releasing hormone analogue in prostate cancer patients:the endocrinological effects of pretreatment with chlormadinone acetate

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