镭-223治疗转移性去势抵抗性前列腺癌的有效性与安全性初步分析

目的 探讨镭-223治疗转移性去势抵抗性前列腺癌(mCRPC)患者的有效性和安全性。 方法 回顾性分析2021年1月至2022年1月重庆大学附属肿瘤医院采用镭-223治疗的22例mCRPC患者的临床资料。年龄(70.7±1.3)岁;美国东部肿瘤协作组(ECOG)评分1分7例,2分15例;骨转移分级Ⅱ级7例,Ⅲ级15例。针对mCRPC,既往行一线治疗1例(4.6%),二线治疗4例(18.2%),三线治疗10例(45.5%),四线治疗4例(18.2%),五线治疗3例(13.6%);平均经历三线治疗。从诊断mCRPC至开始镭-223治疗的中位时间为29(20,34)个月。治疗前中位碱性磷酸酶(ALP)为147.0(101.8,212.5)U/L,中位前列腺特异性抗原(PSA)为44.7(20.2,99.1)ng/ml;6例(27.27%)合并1~2级贫血,血红蛋白中位值115.0(103.8,122.5)g/L,中性粒细胞计数(3.0±0.3)× 10 ⁹/L,血小板计数(169.8±17.0) ×10 ⁹/L。患者每4周静脉注射镭-223(剂量为55kBq/kg),最多6个周期。统计分析总生存时间(OS)、影像学无进展生存时间(rPFS)、PSA进展时间、PSA缓解率、疼痛缓解率、疼痛进展时间,根据镭-223治疗前经历的治疗线数分层分析OS、rPFS、PSA进展时间等。同时分析镭-223治疗的主要不良反应。 结果 本组22例采用镭-223治疗平均2.7(1~6)个周期,共4例完成6个周期;12例(54.6%)治疗≥3个周期,10例(45.5%)治疗<3个周期。13例(59.1%)单独采用镭-223治疗,9例(40.9%)联合其他治疗(其中多西他赛化疗1例,恩扎卢胺2例,奥拉帕利3例,磷酸雌莫司汀3例)。本组所有患者均未使用双磷酸盐治疗。本组中10例(45.5%)死亡,均死于疾病进展;22例中位生存时间11.0(2.2,19.8)个月。3例(13.6%)、7例(31.8%)、3例(13.6%)、1例(4.5%)分别于治疗后2、3、4、10个月出现影像学进展,余8例(36.4%)均未出现影像学进展,22例中位rPFS为4.0(3.1,4.9)个月。4例(18.2%)出现PSA缓解,其中3例(13.6%)后期PSA再次升高,1例(4.5%)PSA持续稳定下降;22例中位PSA进展时间为3.6(2.2,5.1)个月。15例(68.2%)治疗1个月疼痛缓解,其中5例(22.7%)后期出现疼痛加重,10例(45.5%)疼痛持续缓解;22例疼痛进展时间中位值5.5(3.5,7.6)个月。本组无骨折患者,无因疼痛行放疗或手术患者。7例(31.8%)治疗后ALP较基线下降≥30%。镭-223治疗主要不良反应为恶心(15例,68.2%)、呕吐(7例,3.8%)、血小板减少(8例,36.4%)、贫血(6例,27.3%)、中性粒细胞减少(4例,4.6%),均为1~2级,无≥3级不良反应;无因不良事件导致治疗中断者。 结论 镭-223治疗mCRPC患者疼痛缓解率高,可延长OS、rPFS及PSA进展时间;治疗期间无严重不良反应,患者耐受性好。结论尚需进一步扩大样本量及延长随访时间以验证。     

去势抵抗性前列腺癌的治疗进展

临床上去势抵抗性前列腺癌（castrationresistant prostate cancer,CRPC）是前列腺癌死亡的重要原因,近年来美国FDA批准了多种新药用于CRPC的治疗,如新型雄激素合成抑制剂（阿比特龙,TAK-700）、雄激素受体拮抗剂（MDV3100）以及新的免疫疗法（Sipuleucel-T）等.本文就CRPC治疗进展作一综述.     

镭-223治疗48例骨转移去势抵抗性前列腺癌的疗效及安全性

目的 探讨镭-223在骨转移去势抵抗性前列腺癌(mCRPC)中的疗效及安全性。 方法 回顾性分析2021年2月至2022年5月复旦大学附属肿瘤医院采用镭-223治疗的48例mCRPC患者的临床资料。平均年龄70.5(49~90)岁,中位前列腺特异性抗原(PSA) 44.70(0.15~1 864.00)ng/ml,中位血清碱性磷酸酶(ALP)162(43~1 589)U/L。患者均有骨痛症状,均存在骨转移且不伴内脏转移(骨转移数量>1处,分期ⅣB期)。自诊断mCRPC至开始使用镭-223的中位时间为10(3~47)个月。9、18、11例患者既往分别接受一线、二线、三线针对mCRPC的药物治疗,10例曾接受至少四线治疗。38例(79.1%)、31例(64.5%)、30例(62.5%)、7例(14.6%)患者既往分别使用过阿比特龙、恩扎卢胺、多西他赛、奥拉帕利。48例均行镭-223治疗(55 kBq/kg,每4周注射1次,计划使用6周期)。分析PSA较基线水平下降>30%的比率、ALP较基线水平下降>30%的比率、症状减轻率、中位总体生存期(OS)等疗效指标,以及治疗相关不良反应情况、中途停止治疗的原因等。 结果 本研究48例中位随访时间8(1~16)个月,11例完成6个疗程治疗,中位治疗4(1~6)个疗程。27例(56.2%)使用镭-223的同时使用骨保护药物(双磷酸盐/地舒单抗)。10例(20.8%)治疗期间PSA下降>30%,25例(52.1%)ALP下降>30%。23例(47.9%)骨痛症状减轻。9例既往仅接受一线针对mCRPC治疗者中,6例(66%)骨痛症状减轻,4例(44%)PSA下降>30%。18例既往接受二线治疗者中,11例(61%)骨痛症状减轻,4例(22%)PSA下降>30%。21例既往接受三线及以上治疗者中,6例(28.5%)骨痛症状减轻,2例(9.5%)PSA下降>30%。48例中位OS未达到,使用Kaplan-Meier法预估中位OS为12.5个月。最常见的血液学不良反应为血小板下降(15例,31.2%;其中3级6例,4级0例),其次为白细胞下降(11例,22.9%;其中3级4例,4级1例)和贫血(8例,16.7%;其中3级3例,4级0例)。非血液学不良反应包括：发热1例(2.1%),便秘4例(8.3%),恶心呕吐10例(20.8%),腹泻7例(14.6%),头晕1例(2.1%)和乏力11例(22.9%)。因无法耐受不良反应导致治疗终止7例(中位治疗2个疗程),因疾病进展/死亡导致治疗终止14例(中位治疗2个疗程),因其他原因自主终止治疗5例(中位治疗1个疗程)。 结论 对于既往接受一线或二线治疗的mCRPC患者,镭-223在症状控制方面表现良好。因血液学不良反应发生率较高,治疗过程中应密切关注血常规变化,及时对症处理,以提高患者对药物的耐受能力。     

镭-223治疗骨转移性去势抵抗性前列腺癌的研究进展

世界范围内,前列腺癌(prostate cancer,PCa)是男性第二大常见癌症,2012年新诊断的PCa患者为110万,约占新增癌症病例总数的15%[1].在我国,随着生活方式、饮食结构的逐渐西化和人口老龄化的加剧,Pca的发病率近年来呈持续快速增长趋势[2].10%~20%的Pca发生远处转移,其中以骨转移最多见[3].大多数转移性Pca患者最初对雄激素去势疗法或手术去势治疗有效[4],10%~20%的患者最终发展为去势抵抗性Pca(castration-resistant prostate cancer, CRPC)[5].一旦发展为CRPC,很难治愈,中位生存期不到2年[6].且超过90%的CRPC患者存在骨转移,骨转移可导致骨相关事件((skeletal related events,SREs),如病理性骨折、脊髓压迫、肿瘤相关的外科手术干预及外放射治疗等,不仅降低了生活质量和总生存期(overall survival,OS),还增加了治疗负担[3,7-8].针对转移性CRPC,一些新的治疗方法和手段逐步进入临床验证或使用,镭-223是唯一对有骨转移症状但无已知内脏转移的CRPC患者能带来生存获益的新药.美国FDA于2013年5月批准拜耳公司研发的二氯化镭(通用名:镭-223;商品名:Xofigo)注射液上市.本文对镭-223治疗骨转移性CRPC的进展及安全性和有效性进行了评述.     

去势抵抗性前列腺癌药物治疗的新策略

大部分进展性前列腺癌患者初始对内分泌治疗敏感,最终会对内分泌治疗产生抵抗.近几年来治疗去势抵抗性前列腺癌取得了很大的进展,本文就药物阻断雄激素的合成、免疫治疗、靶向治疗、二线化疗药物及化疗药物耐药机制研究方面进行综述.     

转移性去势抵抗性前列腺癌免疫治疗的现状和研究进展

理想的免疫疗法具有对肿瘤的高度杀伤性和对自身组织机体的无害性,因此被用于治疗高致死性的转移性去势抵抗性前列腺癌.前列腺癌的免疫疗法当前主要包括疫苗疗法、免疫检查点阻断疗法、免疫调节剂疗法以及联合疗法,这些疗法分别通过不同的免疫机制治疗前列腺癌.被称作Sipuleucel-T的疫苗早已被美国食品和药品监督管理局批准治疗转...     

转移性去势抵抗性前列腺癌免疫治疗的现状和研究进展

理想的免疫疗法具有对肿瘤的高度杀伤性和对自身组织机体的无害性,因此被用于治疗高致死性的转移性去势抵抗性前列腺癌。前列腺癌的免疫疗法当前主要包括疫苗疗法、免疫检查点阻断疗法、免疫调节剂疗法以及联合疗法,这些疗法分别通过不同的免疫机制治疗前列腺癌。被称作Sipuleucel-T的疫苗早已被美国食品和药品监督管理局批准治疗转移性去势抵抗性前列腺癌,而其他免疫药物的研究尚在进行。本文对转移性去势抵抗性前列腺癌各种免疫疗法的现状及最新进展进行综述。     

177Lu-PSMA治疗转移性去势抵抗性前列腺癌的研究进展

前列腺癌是全世界男性发病率居第二位的恶性肿瘤,虽然在亚洲人群中的发病率较低,但近年来也出现了较快的增长 ^{[ 1]} 。其中局限性前列腺癌治疗效果较好,但仍有部分患者在接受内分泌治疗后,癌细胞从激素依赖性转变为激素非依赖性并发生转移,被称为转移性去势抵抗性前列腺癌(metastatic castration resistant prostate cancer, mCRPC),此时患者的预期生存时间很少超过20个月 ^{[ 2]} ,目前mCRPC主流的治疗方案有化疗、新型内分泌治疗(阿比特龙、恩杂鲁胺) ^{[ 3]} 、核素治疗 ^{[ 3]} 及免疫疫苗(如Sipuleucel T) ^{[ 4]} 等。最近的研究结果表明由镓-68( ⁶⁸Ga)及镥-177( ¹⁷⁷Lu)标记的前列腺特异性膜抗原(prostate membrane-specific antigen,PSMA)可用于mCRPC患者的放射性核素显像及治疗 ^{[ 5]} 。 ¹⁷⁷Lu-PSMA治疗具有诊疗同期、高度靶向、不良反应小等特点 ^{[ 6]} ,是国际上前列腺癌诊疗的一个新方向,具有良好的应用前景。     

177Lu-PSMA放射性配体治疗在转移性去势抵抗性前列腺癌的应用初探

目的:评估¹⁷⁷Lu-PSMA放射性配体治疗在转移性去势抵抗性前列腺癌的安全性及初步疗效。方法:收集2017—2020年空军军医大学西京医院收治并接受¹⁷⁷Lu-PSMA放射性配体治疗的转移性去势抵抗性前列腺癌患者,对其中3例典型患者的临床资料进行回顾性分析。结果:病例1确诊前列腺癌后,分别先后予以前列腺癌根治术、双侧睾丸切除术、放疗、转移灶切除+粒子植入术,PSA有效控制10余年后持续上升,⁶⁸Ga-PSMA PET/CT提示多发淋巴结及骨转移,行2个周期¹⁷⁷Lu-PSMA放射性配体治疗后,PSA由2092 ng/mL下降至920 ng/mL,治疗前后血红蛋白、白细胞、肝肾功无明显变化。病例2术前行⁶⁸Ga-PSMA PET/CT发现2处骨转移灶,新辅助内分泌治疗6个月后行前列腺癌根治术,术后PSA逐渐升高,影像学检查发现转移灶增加,行3个周期¹⁷⁷Lu-PSMA放射性配体治疗,复查⁶⁸Ga-PSMA PET/CT转移灶缩小,病灶...     

镭-223治疗转移性去势抵抗性前列腺癌的有效性与安全性初步分析

目的探讨镭-223治疗转移性去势抵抗性前列腺癌(mCRPC)患者的有效性和安全性。方法回顾性分析2021年1月至2022年1月重庆大学附属肿瘤医院采用镭-223治疗的22例mCRPC患者的临床资料。年龄(70.7±1.3)岁;美国东部肿瘤协作组(ECOG)评分1分7例, 2分15例;骨转移分级Ⅱ级7例, Ⅲ级15例。针对mCRPC, 既往行一线治疗1例(4.6%), 二线治疗4例(18.2%), 三线治疗10例(45.5%), 四线治疗4例(18.2%), 五线治疗3例(13.6%);平均经历三线治疗。从诊断mCRPC至开始镭-223治疗的中位时间为29(20, 34)个月。治疗前中位碱性磷酸酶(ALP)为147.0(101.8, 212.5)U/L, 中位前列腺特异性抗原(PSA)为44.7(20.2, 99.1)ng/ml;6例(27.27%)合并1～2级贫血, 血红蛋白中位值115.0(103.8, 122.5)g/L, 中性粒细胞计数(3.0±0.3)× 109/L, 血小板计数(169.8±17.0) ×109/L。患者每4周静脉注射镭-223(剂量为55kBq/kg), 最...     

A prospective analysis of time to normalization of serum testosterone after withdrawal of androgen deprivation therapy

PURPOSE: Patients with prostate cancer are treated with neoadjuvant, adjuvant and intermittent androgen deprivation therapy. Prostate specific antigen (PSA) is altered during androgen deprivation therapy, and as a result the prognostic significance and accuracy of PSA values measured before serum testosterone has normalized are questionable because the patient is still effectively on androgen deprivation therapy. We determine the time it takes for serum testosterone to return to normal after withdrawal of androgen deprivation therapy. MATERIALS AND METHODS: Serial serum testosterone was prospectively measured at 3-month intervals in 68 men after withdrawal of androgen deprivation therapy. The number of months to return to normal serum testosterone 270 ng./dl. or greater, was calculated for each patient. Patients were stratified according to duration of androgen deprivation, age and type of luteinizing hormone releasing hormone agonist used. RESULTS: Median patient age was 71 years (range 46 to 88). Median time to normalization of testosterone was 7 months (range 1 to 58). At 3, 6 and 12 months 28%, 48% and 74% of men had normal serum testosterone, respectively. Serum testosterone took significantly longer to return to normal in patients on androgen deprivation therapy for 24 months or greater compared to those on therapy for less than 24 months (log-rank p = 0.0034). There was no statistical significance based on age or type of luteinizing hormone releasing hormone agonist used. CONCLUSIONS: Androgen deprivation has an effect on serum testosterone that extends beyond the cessation of treatment. Serum testosterone should be measured in all men until normalization. These results should be applied to the interpretation of PSA levels after withdrawal of androgen deprivation therapy. In addition, these data have implications regarding dose scheduling and definition of biochemical (PSA) failure after primary therapy.     

微血管血流(MV-Flow)成像鉴别诊断子宫附件良、恶性肿瘤

目的 评价微血管血流(MV-Flow)成像鉴别诊断子宫附件良、恶性肿瘤的价值。方法 前瞻性纳入107例附件肿块患者、共115个肿块,经阴道超声采集MV-Flow图像,测量血管指数(VI);绘制受试者工作特征曲线,评价其鉴别诊断子宫附件良、恶性肿瘤的价值。结果 115个子宫附件肿瘤中, 33个恶性肿瘤,82个良性肿瘤。MV-Flow条件下,子宫附件恶性肿瘤血流多呈条状、中心型分布,良性肿瘤血流多呈点状分布或少量条状血流呈周围型分布;恶性肿瘤VI明显高于良性肿瘤(P<0.001)。MV-Flow成像鉴别诊断子宫附件良、恶性肿瘤的曲线下面积为0.918;以VI≥7.15为截断值,其诊断子宫附件恶性肿瘤的准确率为89.57%,敏感度为84.85%,特异度为91.46%。结论 MV-Flow成像鉴别诊断子宫附件良、恶性肿瘤具有较高效能。     

单纯前列腺上皮内瘤回顾性分析(附142例病例分析)

目的通过对前列腺上皮内瘤(PIN)临床资料分析,探讨PIN的生物特性及应对策略。方法对31例无前列腺癌PIN(NPCaPIN)改变患者(其中1级23例,2、3级8例)的临床资料(包括患者血清PSA、fPSA/tPSA、PSA密度等区域计数资料以及穿刺标本免疫组织化学染色结果)进行回顾性分析,以同期确诊为前列腺癌(PCa)、良性前列腺增生(BPH)患者资料作为对照,分析低级别PIN(LGPIN)和高级别PIN(HGPIN)改变之间及NPCaPIN临床特征与PCa、BPH患者临床特征的差异。结果LGPIN和HGPIN改变的患者之间血清PSA水平和年龄存在差异(P<0.05);LGPIN和PCa患者之间血清PSA水平、前列腺体积、fPSA存在显著差异(P<0.01),PSA密度、fPSA/tPSA比值存在差异(P<0.05),和BPH患者之间各项均无明显差异;HGPIN改变和PCa患者之间前列腺体积、fPSA水平和年龄存在差异(P<0.05),和BPH患者之间血清PSA水平差异显著(P<0.01),fPSA/tPSA比值和年龄(P<0.05)存在差异;NPCaPIN和PCa患者之间血清前列腺体积、fPSA水平和年龄、血清PSA水平、PSA密度存在显著差异(P<0.01),和BPH患者之间fPSA/tPSA比值(P<0.05)存在差异。P63、AE1、AE3、P504S、PSA免疫组织化学结果NPCaPIN组类似于BPH而完全异于PCa。结论LGPIN的临床和病理特征与BPH相似,而HGPIN的临床和病理方面具有一定的前列腺恶性肿瘤特征,需要积极的临床追踪观察。     

Bone-Turnover Metabolites as Clinical Markers of Bone Metastasis in Patients with Prostatic Carcinoma

Background : Candidate markers of prostatic metastases to bone, urinary deoxypyridinoline, serum carboxy-terminal propeptide of type 1 procollagen (P1CP), and pyridinoline cross-linked carboxy-terminal telopeptide of type 1 collagen (1CTP), were measured to evaluate their prognostic efficacy.
Methods : Urinary levels (mean ± SD) of deoxypyridinoline were measured by a competitive immunoassay, and serum levels of P1CP and 1CTP were measured by radioimmunoassay in 30 patients with benign prostatic hyperplasia, 18 patients with prostatic carcinoma without bone metastases, and 27 patients with prostatic carcinoma and bone metastases.
Results : Urinary concentrations of deoxypyridinoline (pmol/μmol creatinine) in patients with prostatic carcinoma and bone metastases (10.4 ± 7.7) were significantly higher than those in similar patients without bone metastases (4.3 ± 1.3) and those in patients with benign prostatic hyperplasia (3.8 ± 1.2). Serum levels of P1CP and 1CTP (ng/mL) in patients with prostatic carcinoma and bone metastases (262.6 ± 188.7 and 10.3 ± 9.5, respectively) were significantly higher than those in similar patients without bone metastases (118.1 ± 30.2 and 4.3 ± 1.4, respectively) and those in patients with benign prostatic hyperplasia (93.9 + 25.1 and 3.3 ± 1.1, respectively). Serial measurements of urinary deoxypyridinoline and serum P1CP and 1CTP were correlated with a positive response to treatment (reduced measurements) and with the clinical progression of disease (increased measurements) before detection of new bone lesions by bone scintigram.
Conclusion :Urinary deoxypyridinoline, serum P1CP, and serum 1CTP should be useful markers in confirming and monitoring prostatic carcinoma metastases to bone.     

Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer

PURPOSE: A multicenter double-blind, randomized, placebo controlled clinical trial was performed to assess the effect of zoledronic acid, a potent new bisphosphonate, on bone mineral density during androgen deprivation therapy for nonmetastatic prostate cancer. MATERIALS AND METHODS: Men with M0 (no distant metastases) prostate cancer beginning androgen deprivation therapy were randomly assigned to receive 4 mg. zoledronic acid or placebo intravenously every 3 months for 1 year. The primary efficacy variable was the percent change from baseline to 1 year in bone mineral density of the lumbar spine as measured by dual energy x-ray absorptiometry. RESULTS: A total of 106 men were enrolled in the trial. Mean bone mineral density in the lumbar spine increased by 5.6% in men receiving zoledronic acid and decreased by 2.2% in those given placebo (mean difference 7.8%, 95% confidence interval 5.6%-10.0%, p <0.001). Mean bone mineral density of the femoral neck, trochanter and total hip also increased in the zoledronic acid group and decreased in the placebo group. Zoledronic acid was well tolerated. CONCLUSIONS: Zoledronic acid increases bone mineral density in the hip and spine during androgen deprivation therapy for nonmetastatic prostate cancer.     

Incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease: predictive role of bone resorption and formation markers evaluated at baseline

PURPOSE: We evaluated the incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease. We also assessed the predictive role of bone turnover markers determined at baseline. MATERIALS AND METHODS: A total of 112 patients were consecutively enrolled in our study from July 1990 to July 1998 and followed until death or the last followup. Bone pain, disease extent in bone, serum prostate specific antigen, hemoglobin, and a panel of bone formation and resorption markers were assessed at baseline before any second line treatment. RESULTS: Skeletal complications in 34 patients (30.3%, estimated yearly incidence 12.3%) involved vertebral deformity or collapse requiring spinal orthosis in 20 (17.9%), spinal cord compression in 7 (6.2%), pathological bone fracture in 10 (8.9%), symptomatic hypercalcemia in 1 (0.9%) and symptomatic hypocalcemia in 1 (0.9%). Median time to the evidence of the initial skeletal complication was 9.5 months. These adverse events did not influence overall survival. At baseline patients with eventual skeletal complications had greater bone pain (p = 0.02), a heavier tumor load in bone (p = 0.005), lower performance status (p = 0.05), and higher serum alkaline phosphatase (p <0.02) and urinary deoxypyridoline (p <0.05) than their counterparts. Multivariate analysis revealed that only urinary deoxypyridinoline was independently associated with the onset of these events (p <0.02). The scatterplot of urinary deoxypyridinoline values in patients with and without skeletal complications enabled us to detect a cutoff of 38 pM./mM. for predicting 51% of skeletal events with only an 8% false-positive rate. CONCLUSIONS: Skeletal complications are common in patients with prostate cancer and hormone refractory disease. Bone loss is the major cause of onset. Baseline deoxypyridinoline at the cutoff point noted had moderate sensitivity but high specificity for predicting these adverse skeletal events.     

对比观察不可逆电穿孔与射频消融治疗肝癌

目的 对比观察不可逆电穿孔(IRE)与射频消融治疗肝癌的安全性及疗效。方法 前瞻性纳入48例肝癌患者,随机将其分为试验组及对照组,每组24例。对试验组于全身麻醉下行CT引导下IRE消融;对照组于局部麻醉下行CT引导下射频消融;记录术中及术后不良反应,对比评价疗效。结果 对2组患者均顺利完成治疗,试验组1例死于对比剂过敏性休克,其余患者均未发生治疗相关3～4级严重不良反应及并发症。组间术后7天肿瘤消融成功率(96.43%vs. 96.97%)、术后30天(96.43%vs. 93.94%)及90天(89.29%vs. 90.91%)局部无复发率差异均无统计学意义(P均>0.05);术后各时间点总缓解率及疾病控制率差异亦无统计学意义(P均>0.05)。结论 IRE消融治疗肝癌效果明确、安全性高、不良反应轻,其局部控制肿瘤效果与射频消融治疗相当。