陳明+李堯+房曉+徐丹楓
(上海長(zhǎng)征醫(yī)院泌尿外科 上海 200003)
摘 要 目的:比較晚期前列腺癌患者分別采用國(guó)產(chǎn)亮丙瑞林藥物去勢(shì)與手術(shù)去勢(shì)治療的療效和安全性。方法:60例患者隨機(jī)采用國(guó)產(chǎn)亮丙瑞林藥物去勢(shì)或手術(shù)去勢(shì),并聯(lián)合比卡魯胺行全雄激素阻斷,觀察兩種治療方法的療效及不良反應(yīng)。結(jié)果:藥物去勢(shì)組與手術(shù)去勢(shì)組的有效率分別為86.6%和83.3%(P>0.05),90%藥物去勢(shì)和93%手術(shù)去勢(shì)患者的血清睪酮水平經(jīng)6個(gè)月治療后維持在去勢(shì)水平。兩組治療相關(guān)不良反應(yīng)主要表現(xiàn)為潮熱、乳房脹痛、疲勞等,兩組無(wú)統(tǒng)計(jì)學(xué)差異,但注射部位疼痛為藥物去勢(shì)所特有。結(jié)論:國(guó)產(chǎn)亮丙瑞林藥物去勢(shì)與手術(shù)去勢(shì)相比,短期療效確切,不良反應(yīng)小,能改善患者的生活質(zhì)量。
關(guān)鍵詞 前列腺癌 雄激素阻斷療法 療效分析
中圖分類號(hào):R977.12; R737.25 文獻(xiàn)標(biāo)識(shí)碼:B 文章編號(hào):1006-1533(2014)17-0017-03
Clinical comparative study on domestic leuprorelin and surgical castration
for the treatment of prostate cancer
CHEN Ming, LI Yao, FANG Xiao, XU Danfeng*
(Department of Urology, Shanghai Changzheng Hospital, Shanghai 200003, China)
ABSTRACT Objective: To compare the effectiveness and safety of domestic leuprorelin medical castration and surgical castration in patients with prostate cancer. Methods: Sixty patients were randomly divided into a medical castration group and a surgical castration group and meanwhile received bicalutamide for the blockade of total androgen. Efficacy and adverse reaction were compared between two groups. Testosterone concentrations, prostate-specific-antigen and treatment-related adverse events were recorded. Results: The effective rate was 86.6% in the medical castration group and 83.3% in the surgical castration group (P>0.05). Plasma testosterone concentration of 90% patients in the medical castration group and 93% patients in the surgical castration group was remained in the level of castration after 6-month treatment. The adverse events related to the treatment appeared as hot flash, swollen breast, fatigue and hyperhidrosis with insignificant difference though injection-site pain was special for medical castration. Conclusion: As compared with surgical castration, medical castration with domestic leuprorelin has a verified short-term efficacy, less adverse reaction and can improve the life quality of patients.
KEY WORDS prostate cancer; androgen deprivation therapy; effectiveness assessment
前列腺癌是我國(guó)男性最常見(jiàn)的惡性腫瘤之一,據(jù)統(tǒng)計(jì),我國(guó)2003-2007年前列腺癌的發(fā)病率和死亡率均明顯升高[1],因此,加強(qiáng)前列腺癌的防治顯得尤為重要。由于前列腺癌早期沒(méi)有特異性的臨床癥狀和體征,很大一部分患者發(fā)現(xiàn)時(shí)已失去根治手術(shù)的機(jī)會(huì),只能采取雄激素阻斷等治療,以延長(zhǎng)患者的生命,改善生活質(zhì)量。本文總結(jié)我科自2012年1月-2013年1月收治的無(wú)根治手術(shù)指征的前列腺癌患者60例,分別采用國(guó)產(chǎn)亮丙瑞林藥物去勢(shì)或手術(shù)去勢(shì),并聯(lián)合比卡魯胺行全雄激素阻斷,以此來(lái)評(píng)價(jià)兩種不同治療方案的療效和安全性。
資料與方法
資料
60例患者均行血常規(guī)、肝腎功能、前列腺特異抗原(PSA)、骨掃描等檢查,并經(jīng)前列腺穿刺活檢獲得明確病理診斷。兩組患者的一般情況、治療前血清PSA值、睪酮值和穿刺標(biāo)本Gleason評(píng)分見(jiàn)表1。
治療方法
所有患者按照隨機(jī)化原則分別采用醋酸亮丙瑞林微球(上海麗珠制藥有限公司,商品名:貝依)3.75 mg肌肉注射(1次/28 d)或者雙側(cè)睪丸切除術(shù),并同時(shí)給予比卡魯胺50 mg口服(1次/d)行全雄激素阻斷。4周為1個(gè)治療周期,共6個(gè)治療周期,每個(gè)治療周期末檢查記錄兩組患者的血清PSA值、睪酮值以及臨床癥狀的改善情況。
療效評(píng)價(jià)標(biāo)準(zhǔn)
前列腺癌客觀療效判定標(biāo)準(zhǔn):CR指血清PSA下降至正常值以下,即<4 ng/ml,持續(xù)超過(guò)1個(gè)月;PR指血清PSA下降至治療前數(shù)值的50%以下,持續(xù)1個(gè)月以上;SD是指血清PSA值下降不足50%,或下降雖超過(guò)50%但持續(xù)不足1個(gè)月;PD是指血清PSA值較治療前升高。
統(tǒng)計(jì)方法
用SPSS 13.0軟件進(jìn)行t檢驗(yàn)和χ2檢驗(yàn),以P<0.05為差異有統(tǒng)計(jì)學(xué)意義。
結(jié)果
療效
57例(95%)患者的血清睪酮水平在第一個(gè)治療周期末均降至去勢(shì)水平,治療過(guò)程中血清睪酮水平均無(wú)明顯波動(dòng)。在6個(gè)治療周期結(jié)束后,27例(90%)藥物去勢(shì)患者和28例(93%)手術(shù)去勢(shì)患者的血清睪酮水平不超過(guò)0.02 ng/ml(P>0.05)。
所有患者的血清PSA值在第一個(gè)治療周期末均降低至初始值50%以下,至6個(gè)治療周期結(jié)束后兩組患者中PSA不超過(guò)0.2 ng/ml的分別為15例和13例。按照前列腺癌客觀療效判定標(biāo)準(zhǔn),藥物去勢(shì)組和手術(shù)去勢(shì)組的有效率分別為86.6%和83.3%(P>0.05),結(jié)果見(jiàn)表2。
安全性
在6個(gè)治療周期過(guò)程中,31例患者出現(xiàn)治療相關(guān)不良反應(yīng),主要包括潮熱(25例),乳房脹痛(9例),疲勞(8例),多汗(5例)和注射部位疼痛(3例)等,但均為輕度不適,給予對(duì)癥處理后緩解,未發(fā)現(xiàn)心腦血管意外及不可逆性肝腎功能損害等嚴(yán)重并發(fā)癥。兩組治療相關(guān)不良反應(yīng)見(jiàn)表3。
討論
前列腺癌起病隱匿,部分患者就診時(shí)疾病已進(jìn)展至中晚期,已經(jīng)失去了根治手術(shù)的最佳時(shí)機(jī),而只能接受內(nèi)分泌治療。自1941年Huggins等[2]首次提出內(nèi)分泌治療以來(lái),手術(shù)去勢(shì)一直是中晚期前列腺癌患者的首選治療方式[3]。它可以使患者睪酮迅速且持續(xù)下降至去勢(shì)水平,但該種治療方式對(duì)患者心理狀態(tài)及生活質(zhì)量會(huì)產(chǎn)生較大的影響[4],而且治療中無(wú)法靈活調(diào)節(jié)治療方案,因此,2013版《中國(guó)泌尿外科疾病診斷治療指南》推薦有條件的患者應(yīng)該首先考慮藥物去勢(shì)。
黃體生成激素釋放激素類似物(LHRH-a)是目前常用的藥物去勢(shì)制品,已上市的品種有亮丙瑞林、戈舍瑞林和曲普瑞林,緩釋劑型為1、2、3或6個(gè)月注射1次[5]。我國(guó)原來(lái)臨床應(yīng)用的LHRH-a緩釋劑均為國(guó)外公司生產(chǎn),價(jià)格昂貴,限制了一部分患者的使用。上海麗珠制藥有限公司自主研制的貝依,打破了國(guó)外企業(yè)在該領(lǐng)域長(zhǎng)達(dá)20多年的壟斷地位,以媲美國(guó)外藥品的品質(zhì)和相對(duì)低廉的價(jià)格,給中國(guó)患者帶來(lái)了福音。
初次注射LHRH-a時(shí)有睪酮一過(guò)性升高[6],所以在注射當(dāng)日開(kāi)始給予比卡魯胺抗雄激素治療,以對(duì)抗睪酮一過(guò)性升高所導(dǎo)致的病情加劇。同時(shí),研究表明,合用比卡魯胺的最大限度雄激素阻斷(MAB)與單純?nèi)?shì)相比可延長(zhǎng)總生存期3~6個(gè)月,平均5年生存期提高2.9%,對(duì)于局限性前列腺癌,應(yīng)用MAB治療時(shí)間越長(zhǎng),PSA復(fù)發(fā)率越低,可使死亡風(fēng)險(xiǎn)降低20%,并可相應(yīng)延長(zhǎng)無(wú)進(jìn)展生存期[7]。
本組30例使用貝依行藥物去勢(shì)的患者中,90%的患者血清睪酮持續(xù)處于較低水平,用藥6個(gè)月時(shí)客觀有效率達(dá)86.6%,與手術(shù)去勢(shì)的療效相當(dāng)。但是所有接受內(nèi)分泌治療的前列腺癌患者都將進(jìn)展為去勢(shì)抵抗性前列腺癌(CRPC),此時(shí)內(nèi)分泌治療雖有助于改善相關(guān)癥狀,但大多不能控制疾病的進(jìn)展[8]。由于本次研究觀察期較短,未觀察到大量去勢(shì)抵抗性轉(zhuǎn)變,但藥物去勢(shì)和手術(shù)去勢(shì)組各有1例在6個(gè)月觀察期內(nèi)出現(xiàn)PSA較治療前升高的病例。對(duì)于此類病情進(jìn)展的患者,可考慮聯(lián)合放療、改用二線內(nèi)分泌治療或化療等其他治療方法。此外,內(nèi)分泌治療還能縮小前列腺體積,改善前列腺癌患者下尿路梗阻癥狀[9]。經(jīng)12周治療后,前列腺體積較基線縮小35%~36%,國(guó)際前列腺癥狀評(píng)分下降至少3分,平均下降27%~37%。在本組患者中,既往有排尿癥狀者經(jīng)治療后也觀察到梗阻癥狀得到部分緩解。
內(nèi)分泌治療的主要不良反應(yīng)包括:潮熱、多汗、乳房發(fā)育、疲勞等[10],藥物去勢(shì)和手術(shù)去勢(shì)均有出現(xiàn),但癥狀均為輕度,經(jīng)對(duì)癥處理后多能緩解。注射部位局部反應(yīng)為藥物去勢(shì)所特有[11],這可能與藥物微球的局部刺激有關(guān)。微球平均粒徑越小,微球釋放越穩(wěn)定,也能采用更小的針頭注射,患者治療的不適感更少。本組患者中出現(xiàn)3例注射部位硬結(jié)、腫痛。
綜上所述,內(nèi)分泌治療對(duì)中晚期前列腺癌短期療效佳,有效改善臨床癥狀。藥物去勢(shì)與手術(shù)去勢(shì)相比,在保證治療效果的前提下,不良反應(yīng)小,改善患者的生活質(zhì)量,值得臨床推廣。
參考文獻(xiàn)
韓仁強(qiáng), 武鳴, 陳萬(wàn)青, 等. 2003-2007年中國(guó)前列腺癌發(fā)病與死亡分析[J]. 中國(guó)腫瘤, 2012, 21(11): 805-811.
Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate[J]. CA Cancer J Clin,1972, 22(4): 232-240.
Iversen P, McLeod DG, See WA, et al. Antiandrogen monotherapy in patients with localized or locally advanced prostate cancer: final results from the bicalutamide Early Prostate Cancer programme at a median follow-up of 9.7 years[J]. BJU Int,2010, 105(8): 1074-1081.
Kato T, Komiya A, Suzuki H, et al. Effect of androgen deprivation therapy on quality of life in Japanese men with prostate cancer[J]. Int J Urol, 2007, 14(5): 416-421.
Wex J, Sidhu M, Odeyemi I, et al. Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: evidence review and economic evaluation[J]. Clinicoecon Outcomes Res, 2013, 24(5): 257-269.
Msaouel P, Diamanti E, Tzanela M, et al. Luteinising hormone-releasing hormone antagonists in prostate cancer therapy[J]. Expert Opin Emerg Drugs, 2007, 12(2): 285-299.
Klotz L, Schellhammer P, Carroll K. A re-assessment of the role of combined androgen blockade for advanced prostate cancer[J]. BJU Int, 2004, 93(9): 1177-1182.
Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA Guideline[J]. J Urol, 2013, 190(2): 429-438.
Mason M, Maldonado Pijoan X, Steidle C, et al. Neoadjuvant androgen deprivation therapy for prostate volume reduction, lower urinary tract symptom relief and quality of life improvement in men with intermediate- to high-risk prostate cancer: a randomised non-inferiority trial of degarelix versus goserelin plus bicalutamide[J]. Clin Oncol , 2013, 25(3): 190-196.
Salonen AJ, Taari K, Ala-Opas M, et al. Advanced prostate cancer treated with intermittent or continuous androgen deprivation in the randomised FinnProstate Study VII: quality of life and adverse effects[J]. Eur Urol, 2013, 63(1): 111-120.
Marberger M, Kaisary AV, Shore ND, et al. Effectiveness, pharmacokinetics, and safety of a new sustained-release leuprolide acetate 3.75 mg depot formulation for testosterone suppression in patients with prostate cancer: a Phase III, open-label, international multicenter study[J]. Clin Ther, 2010, 32(4): 744-757.
(收稿日期:2014-05-29)
Kato T, Komiya A, Suzuki H, et al. Effect of androgen deprivation therapy on quality of life in Japanese men with prostate cancer[J]. Int J Urol, 2007, 14(5): 416-421.
Wex J, Sidhu M, Odeyemi I, et al. Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: evidence review and economic evaluation[J]. Clinicoecon Outcomes Res, 2013, 24(5): 257-269.
Msaouel P, Diamanti E, Tzanela M, et al. Luteinising hormone-releasing hormone antagonists in prostate cancer therapy[J]. Expert Opin Emerg Drugs, 2007, 12(2): 285-299.
Klotz L, Schellhammer P, Carroll K. A re-assessment of the role of combined androgen blockade for advanced prostate cancer[J]. BJU Int, 2004, 93(9): 1177-1182.
Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA Guideline[J]. J Urol, 2013, 190(2): 429-438.
Mason M, Maldonado Pijoan X, Steidle C, et al. Neoadjuvant androgen deprivation therapy for prostate volume reduction, lower urinary tract symptom relief and quality of life improvement in men with intermediate- to high-risk prostate cancer: a randomised non-inferiority trial of degarelix versus goserelin plus bicalutamide[J]. Clin Oncol , 2013, 25(3): 190-196.
Salonen AJ, Taari K, Ala-Opas M, et al. Advanced prostate cancer treated with intermittent or continuous androgen deprivation in the randomised FinnProstate Study VII: quality of life and adverse effects[J]. Eur Urol, 2013, 63(1): 111-120.
Marberger M, Kaisary AV, Shore ND, et al. Effectiveness, pharmacokinetics, and safety of a new sustained-release leuprolide acetate 3.75 mg depot formulation for testosterone suppression in patients with prostate cancer: a Phase III, open-label, international multicenter study[J]. Clin Ther, 2010, 32(4): 744-757.
(收稿日期:2014-05-29)
Kato T, Komiya A, Suzuki H, et al. Effect of androgen deprivation therapy on quality of life in Japanese men with prostate cancer[J]. Int J Urol, 2007, 14(5): 416-421.
Wex J, Sidhu M, Odeyemi I, et al. Leuprolide acetate 1-, 3- and 6-monthly depot formulations in androgen deprivation therapy for prostate cancer in nine European countries: evidence review and economic evaluation[J]. Clinicoecon Outcomes Res, 2013, 24(5): 257-269.
Msaouel P, Diamanti E, Tzanela M, et al. Luteinising hormone-releasing hormone antagonists in prostate cancer therapy[J]. Expert Opin Emerg Drugs, 2007, 12(2): 285-299.
Klotz L, Schellhammer P, Carroll K. A re-assessment of the role of combined androgen blockade for advanced prostate cancer[J]. BJU Int, 2004, 93(9): 1177-1182.
Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA Guideline[J]. J Urol, 2013, 190(2): 429-438.
Mason M, Maldonado Pijoan X, Steidle C, et al. Neoadjuvant androgen deprivation therapy for prostate volume reduction, lower urinary tract symptom relief and quality of life improvement in men with intermediate- to high-risk prostate cancer: a randomised non-inferiority trial of degarelix versus goserelin plus bicalutamide[J]. Clin Oncol , 2013, 25(3): 190-196.
Salonen AJ, Taari K, Ala-Opas M, et al. Advanced prostate cancer treated with intermittent or continuous androgen deprivation in the randomised FinnProstate Study VII: quality of life and adverse effects[J]. Eur Urol, 2013, 63(1): 111-120.
Marberger M, Kaisary AV, Shore ND, et al. Effectiveness, pharmacokinetics, and safety of a new sustained-release leuprolide acetate 3.75 mg depot formulation for testosterone suppression in patients with prostate cancer: a Phase III, open-label, international multicenter study[J]. Clin Ther, 2010, 32(4): 744-757.
(收稿日期:2014-05-29)