-
摘要:
哌柏西利作为第一个上市的细胞周期蛋白依赖性激酶4和6抑制剂,显著改善了激素受体阳性、人表皮生长因子受体-2阴性乳腺癌的生存。哌柏西利的开发是抗肿瘤药物发展的一个重要里程碑。本文回顾了哌柏西利作用机制,总结了药物相关临床试验、相关不良反应以及药物应用等问题。
-
关键词:
- 哌柏西利 /
- 乳腺癌 /
- 细胞周期蛋白依赖性激酶 /
- 激素受体
Abstract:As the first cyclin-dependent kinases 4 and 6 inhibitors, palbociclib significantly improved the survival of the patients with the hormone receptor-positive and human epidermal growth factor receptor-2 negative breast cancer. Palbociclib is a crucial landmark in the development history of antineoplastic drugs. This article reviews the mechanism of palbociclib, and summarizes the clinical trials, side effects, and the application of palbociclib.
-
Key words:
- Palbociclib /
- Breast cancer /
- Cyclin-dependent kinases 4/6 /
- Hormone-receptor
-
0 引言
约16%~23%的局部中晚期直肠癌患者合并侧方淋巴结(LPLN)转移[1-2]。侧方淋巴结清扫术(LPLND)作为直肠癌LPLN转移的主要治疗手段之一,其疗效已被广泛证实[3-5]。日本临床肿瘤学组(JCOG)0212试验表明,与单独的全直肠系膜切除术(TME)相比,TME联合LPLND的应用并不会改善Ⅱ期和Ⅲ期直肠癌患者的总体生存率(OS),但在抑制包括LPLN在内的侧盆壁区域的局部复发有着明显积极作用[3]。此外,一项纳入来自日本两个大容量中心的1 191例行TME+LPLND的直肠癌患者的研究显示,髂内淋巴结和闭孔淋巴结转移与直肠上动脉淋巴结转移清扫后的治疗效果相当,而单侧LPLND术后局部复发的风险是双侧LPLND的两倍[4]。然而,上述研究探讨的是预防性LPLND在局部中晚期直肠癌的疗效,JCOG0212试验排除了近20%的术前影像学评估LPLN转移的患者,这与临床实际情况不符。因此,本研究旨在探讨LPLND在LPLN转移患者中的治疗效果及预后意义。
1 资料与方法
1.1 资料来源
回顾性分析2012年1月—2020年12月在中国医学科学院肿瘤医院和北京大学第一医院行TME联合LPLND的中低位直肠癌患者的临床病例资料。纳入标准:(1)病理证实LPLN转移;(2)病理类型为腺癌;(3)肿瘤下缘位于腹膜返折以下。排除标准:(1)同时性远处转移;(2)既往合并其他恶性肿瘤病史;(3)未按照日本大肠癌协会(JSCCR)指南进行规范化LPLND。所有患者签署手术知情同意,本研究设计与开展经过医院伦理委员会审批通过。
1.2 诊断与治疗
所有入组患者术前均完善实验室检查、胸腹盆CT、直肠MRI与肠镜。入组患者的治疗策略(例如是否行新辅助放化疗、开腹或腹腔镜)均是由多学科会诊讨论制定的结果与患者主观意愿共同决定。新辅助放化疗采用长程同步放化疗(50 Gy/25 f/ 2 Gy),放疗期间口服卡培他滨。新辅助放化疗结束后6~8周进行TME+LPLND。采用第八版AJCC分期系统进行TNM分期[6]。侧方淋巴结分为5个区域,分别为髂内淋巴结近端、髂内淋巴结远端、闭孔淋巴结、髂外淋巴结与髂总淋巴结[7]。上述区域出现的淋巴结转移定义为LPLN转移,LPLND的清扫范围定义为上述整个区域淋巴与脂肪组织的剔除。两家机构均采用保留盆腔自主神经的LPLND。
1.3 随访
术后病理证实LPLN转移的患者均推荐于术后4~6周后行辅助化疗。对于术前接受新辅助放化疗的患者,术后无论病理分期均推荐行共6个月的围手术期化疗。患者术后采用门诊的方式进行随访。前两年每三个月随访一次,两年后每6个月进行一次。每次随访需完善体格检查、肿瘤标志物以及胸腹盆CT。肠镜每1年完善一次。本研究的随访截止日期为2021年12月31日。本研究的终点是3年OS与3年无瘤生存率(DFS)。
1.4 统计学方法
用SPSS24.0软件对数据进行统计分析。计数资料以例数(%)表示,计量资料符合正态分布以平均数表示,否则采用中位数表示,Kaplan-Meier法进行生存曲线绘制,Long rank法进行生存时间比较,将有意义的因素纳入Cox比例风险回归模型进行多因素分析。P < 0.05为差异有统计学意义。
2 结果
2.1 临床资料
共102例病理LPLN转移的患者纳入本研究。其中男57例、女45例,平均年龄(56.5±12.6)岁。35例患者接受了新辅助放化疗。术后病理结果提示,LPLN转移的患者中,T分期与N分期分别以T3~T4(n=89, 87.3%)和N1~N2(n= 87, 85.3%)为主。低分化腺癌/黏液腺癌/印戒细胞癌的患者比例为44.1%(n=45)。LPLN常见转移部位依次为髂内淋巴结(n=68, 66.7%)、闭孔淋巴结(n=44, 43.1%)和髂总/髂外淋巴结(n=12, 11.8%)。10例(9.8%)患者出现双侧LPLN转移,平均LPLN转移数量为2.2±2.4,其中16例(15.7%)患者LPLN转移数量 > 2。手术入路主要以腹腔镜LPLND为主(n=75, 73.5%),其中行直肠前切除术者44例(43.1%),腹会阴联合切除术者44例(43.1%),Hartmann术者8例(7.8%),全盆腔脏器切除术者6例(5.9%)。中位手术时间与术中出血量分别为277 min和100 ml。术后恢复方面,有31例(30.4%)患者出现术后并发症,1例(1.0%)患者围手术期死亡。术后平均住院时间为(12.9±10.2)天。共有82例(78.4%)患者接受了术后辅助化疗,见表 1。
表 1 102例直肠癌侧方淋巴结转移患者的临床病理资料(n(%))Table 1 Clinicopathological data of 102 rectal cancer patients with lateral pelvic lymph node metastases (n(%))2.2 生存预后
本研究中位随访时间为30个月,总体队列的3年OS与3年DFS分别为50.6%和32.4%,见图 1。单因素分析显示LPLN转移区域、LPLN转移位置、LPLN转移数量和术后并发症显著影响OS(P < 0.05)。此外,术前CEA水平、病理N分期、LPLN转移区域、LPLN转移位置、LPLN转移数量和术后并发症显著影响DFS(P < 0.05)。多因素分析显示LPLN转移至髂外/髂总是影响OS(HR=3.53; 95%CI: 1.50~8.31; P=0.004)和DFS(HR=2.40; 95%CI: 1.05~5.47; P=0.037)的共同独立危险因素,见表 2。LPLN转移至髂外/髂总淋巴结的患者的3年OS(66.8% vs. 7.7%, P < 0.001)与DFS(39.1% vs. 10.5%, P=0.012)明显低于转移至髂内/闭孔淋巴结转移的患者,见图 2。
表 2 102例直肠癌侧方淋巴结转移患者的预后单因素及多因素Cox回归分析Table 2 Univariate and multivariate Cox regression analyses for prognosis of 102 rectal cancer patients with lateral pelvic lymph node metastases3 讨论
LPLN转移是中低位直肠癌常见的转移途径之一,其治疗手段在东西方国家间仍存在争议。西方国家将LPLN转移视为远处转移(髂内淋巴结转移除外),不常规推荐LPLND,依靠新辅助放化疗来清除盆腔侧方转移灶。相反,日本学者认为LPLN转移为局部淋巴结转移,JSCCR推荐局部中晚期(cT3、T4/N+)的直肠癌患者进行标准的预防性LPLND来降低局部复发率,JCOG0212试验显示与单独TME相比,TME联合LPLND的应用并不会改善Ⅱ期和Ⅲ期直肠癌患者的OS,但在抑制包括LPLN在内的侧盆壁区域的局部复发有着明显积极作用[3]。然而,目前针对病理LPLN转移患者,治疗性LPLND的疗效与有效清扫范围仍存在争议。本研究分析了102例病理诊断LPLN转移的患者,LPLN转移区域主要局限于髂内淋巴结(n=68, 66.7%)与闭孔淋巴结(n=44, 43.1%),双侧LPLN转移率为9.8%(n=10)。预后分析发现,LPLN转移至髂外或髂总是OS和DFS的独立不良预后危险因素。
LPLN转移患者能否通过LPLND达到生存获益取决于转移灶是局部可切除治愈的还是无法控制的远处转移。日本等相关研究甚至显示LPLN转移的患者即使进行LPLND后,其远期预后亦未达到明显改善[5, 8-10]。一方面,这可能是由于LPLN转移的患者多合并肝、肺等远处微转移灶,初次就诊时难以发现,是导致LPLND术后复发转移的主要因素。另一方面,需术前对LPLN转移患者精确评估,严格把握LPLND指征。LPLN转移数量、位置往往是影响预后的关键因素[1, 11-13]。日本一项全国性多机构研究纳入了5 789例行LPLND的患者,结果显示髂内淋巴结转移预后较好,其预后与N2b期相似[1]。Kanemitsu等进行了一项纳入两个中心1 191例直肠癌患者的回顾性研究显示,髂内淋巴结和闭孔淋巴结转移在LPLND后与直肠上动脉淋巴结转移清扫后的治疗效果相当[4]。同样,Yokoyama等纳入了一项131例LPLN转移患者的回顾性研究显示,局限于髂内或者闭孔的单个LPLN转移的患者在LPLND后可以取得较好的远期预后[11]。与上述研究相似,本研究发现即使进行LPLND,髂外和髂总淋巴结转移患者的OS与DFS仅为7.7%和10.5%,明显低于髂内与闭孔转移的患者。此外,我们将LPLN转移区域、位置、数量等因素纳入Cox回归分析显示,髂外和髂总淋巴结转移是OS(HR=3.53; 95%CI: 1.50~8.31; P=0.004)和DFS(HR=2.40; 95%CI: 1.05~5.47; P=0.037)的独立不良预后因素。因此,我们认为髂外淋巴结或髂总淋巴结转移可视为全身性转移,此类患者无法通过LPLND中达到生存获益,全身综合性治疗往往是此类患者最佳的治疗选择[8]。
LPLND清扫范围直接决定了肿瘤根治性效果与预后,同时较大范围的额外清扫也会引起相应副损伤。《日本大肠癌处理规约》第9版中,将髂内血管近端、髂内血管远端、闭孔区域、髂总血管、髂外血管、骶外侧、骶正中、髂总血管规定为LPLND范围[7]。文献报道95%以上的LPLN转移发生于髂内血管与闭孔区域[14],本研究发现,88.2%的患者LPLN转移局限于髂内血管与闭孔区域。同时,LPLN转移超过闭孔和髂内血管范围后,其发生同时性转移的比例明显升高,即使行LPLND后,其5年OS依然较低[10, 13]。因此,除非在术前影像学提示有明确转移的情况下,推荐行LD2(髂内动脉近端、髂内动脉远端、闭孔区域)淋巴结清扫,在保证肿瘤根治性效果的前提下,尽可能降低手术风险与副损伤。
综上所述,LPLN转移主要位于髂内血管与闭孔区域。此外,转移至髂外或髂总淋巴结患者的生存预后无法通过LPLND改善,全身性综合治疗往往是此类患者的最佳治疗选择。随着进一步的临床实践,结论仍需大样本研究证实。
Competing interests: The authors declare that they have no competing interests.作者贡献:郑方超:论文构思与撰写杜丰、刘昊琳、王雪、岳健:论文修改、文献整理袁芃:论文指导 -
表 1 哌柏西利治疗乳腺癌的Ⅱ期临床试验结果
Table 1 Phase Ⅱ clinical trials' results of palbociclib in treatment of breast cancer
表 2 哌柏西利治疗乳腺癌的Ⅲ期临床试验结果
Table 2 Phase Ⅲ clinical trials' results of palbociclib in treatment of breast cancer
-
[1] Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study[J]. Lancet Oncol, 2015, 16(1): 25-35. doi: 10.1016/S1470-2045(14)71159-3
[2] Cardoso F, Paluch-Shimon S, Senkus E, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5)[J]. Ann Oncol, 2020, 31(12): 1623-1649. doi: 10.1016/j.annonc.2020.09.010
[3] 国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会乳腺癌专业委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. 中国晚期乳腺癌规范诊疗指南(2020版)[J]. 中华肿瘤杂志, 2020, 42(10): 781-797. doi: 10.3760/cma.j.cn112152-20200817-00747 Breast Cancer Expert Committee of National Cancer Quality Control Center; Breast Cancer Expert Committee of China Anti-Cancer Association, Cancer Drug Clinical Research Committee of China Anti-Cancer Association. Guidelines for clinical diagnosis and treatment of advanced breast cancer in China (2020 Edition)[J]. Zhonghua Zhong Liu Za Zhi, 2020, 42(10): 781-797. doi: 10.3760/cma.j.cn112152-20200817-00747
[4] Moy B, Rumble RB, Come SE, et al. Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update[J]. J Clin Oncol, 2021, 39(35): 3938-3958. doi: 10.1200/JCO.21.01374
[5] Weinberg RA. The retinoblastoma protein and cell cycle control[J]. Cell, 1995, 81(3): 323-330. doi: 10.1016/0092-8674(95)90385-2
[6] Roberts PJ, Bisi JE, Strum JC, et al. Multiple Roles of Cyclin-Dependent Kinase 4/6 Inhibitors in Cancer Therapy[J]. J Nat Cancer Inst, 2012, 104(6): 476-487. doi: 10.1093/jnci/djs002
[7] Spring LM, Wander SA, Andre F, et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future[J]. Lancet, 2020, 395(10226): 817-827. doi: 10.1016/S0140-6736(20)30165-3
[8] Schwartz GK, Lorusso PM, Dickson MA, et al. PhaseⅠ study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1)[J]. Br J Cancer, 2011, 104(12): 1862-1868. doi: 10.1038/bjc.2011.177
[9] Flaherty KT, Lorusso PM, Demichele A, et al. PhaseⅠ, Dose-Escalation Trial of the Oral Cyclin-Dependent Kinase 4/6 Inhibitor PD 0332991, Administered Using a 21-Day Schedule in Patients with Advanced Cancer[J]. Clin Cancer Res, 2012, 18(2): 568-576. doi: 10.1158/1078-0432.CCR-11-0509
[10] Tamura K, Mukai H, Naito Y, et al. Phase Ⅰ study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients[J]. Cancer Sci, 2016, 107(6): 755-763. doi: 10.1111/cas.12932
[11] Finn RS, Boer K, Bondarenko I, et al. Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1, TRIO-18)[J]. Breast Cancer Res Treat, 2020, 183(2): 419-428. doi: 10.1007/s10549-020-05755-7
[12] Johnston S, Puhalla S, Wheatley D, et al. Randomized Phase Ⅱ Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial[J]. J Clin Oncol, 2019, 37(3): 178-189. doi: 10.1200/JCO.18.01624
[13] Masuda N, Nishimura R, Takahashi M, et al. Palbociclib in combination with letrozole as first-line treatment for advanced breast cancer: A Japanese phaseⅡ study[J]. Cancer Sci, 2018, 109(3): 803-813. doi: 10.1111/cas.13507
[14] Takahashi M, Masuda N, Nishimura R, et al. Palbociclib-letrozole as first-line treatment for advanced breast cancer: Updated results from a Japanese phase 2 study[J]. Cancer Med, 2020, 9(14): 4929-4940. doi: 10.1002/cam4.3091
[15] Albanell J, Martínez MT, Ramos M, et al. Randomized phaseⅡstudy of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2-advanced breast cancer: GEICAM/2014-12 (FLIPPER)[J]. Eur J Cancer, 2022, 161: 26-37. doi: 10.1016/j.ejca.2021.11.010
[16] Park YH, Kim TY, Kim GM, et al. Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial[J]. Lancet Oncol, 2019, 20(12): 1750-1759. doi: 10.1016/S1470-2045(19)30565-0
[17] Yuan Y, Lee JS, Yost SE, et al. PhaseⅠ/Ⅱ trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer[J]. Eur J Cancer, 2021, 154: 11-20. doi: 10.1016/j.ejca.2021.05.035
[18] Gianni L, Bisagni G, Colleoni M, et al. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study[J]. Lancet Oncol, 2018, 19(2): 249-256. doi: 10.1016/S1470-2045(18)30001-9
[19] Martin M, Zielinski C, Ruiz-Borrego M, et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase Ⅲ randomised controlled trial-PEARL[J]. Ann Oncol, 2021, 32(4): 488-499. doi: 10.1016/j.annonc.2020.12.013
[20] Demichele A, Clark AS, Tan KS, et al. CDK 4/6 Inhibitor Palbociclib (PD0332991) in Rb+Advanced Breast Cancer: Phase Ⅱ Activity, Safety, and Predictive Biomarker Assessment[J]. Clin Cancer Res, 2015, 21(5): 995-1001. doi: 10.1158/1078-0432.CCR-14-2258
[21] Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer[J]. N Engl J Med, 2016, 375(20): 1925-1936. doi: 10.1056/NEJMoa1607303
[22] Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial[J]. Lancet Oncol, 2016, 17(4): 425-439. doi: 10.1016/S1470-2045(15)00613-0
[23] Turner NC, Slamon DJ, Ro J, et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer[J]. N Engl J Med, 2018, 379(20): 1926-1936. doi: 10.1056/NEJMoa1810527
[24] Rugo HS, Cristofanilli M, Loibl S, et al. Prognostic Factors for Overall Survival in Patients with Hormone Receptor-Positive Advanced Breast Cancer: Analyses From PALOMA-3[J]. Oncologist, 2021, 26(8): e1339-e1346. doi: 10.1002/onco.13833
[25] Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study[J]. Lancet Oncol, 2021, 22(2): 212-222. doi: 10.1016/S1470-2045(20)30642-2
[26] Gnant M, Dueck AC, Frantal S, et al. Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03)[J]. J Clin Oncol, 2022, 40(3): 282-293. doi: 10.1200/JCO.21.02554
[27] Loibl S, Marmé F, Martin M, et al. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial[J]. J Clin Oncol, 2021, 39(14): 1518-1530. doi: 10.1200/JCO.20.03639
[28] Rugo HS, Turner NC, Finn RS, et al. Palbociclib plus endocrine therapy in older women with HR+/HER2– advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies[J]. Eur J Cancer, 2018, 101: 123-133. doi: 10.1016/j.ejca.2018.05.017
[29] Ettl J, Im SA, Ro J, et al. Hematologic adverse events following palbociclib dose reduction in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: pooled analysis from randomized phase 2 and 3 studies[J]. Breast Cancer Res, 2020, 22(1): 27. doi: 10.1186/s13058-020-01263-0
[30] Masuda N, Mukai H, Inoue K, et al. Neutropenia management with palbociclib in Japanese patients with advanced breast cancer[J]. Breast Cancer, 2019, 26(5): 637-650. doi: 10.1007/s12282-019-00970-7
[31] O'Leary B, Cutts RJ, Huang X, et al. Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer[J]. J Nat Cancer Institute, 2021, 113(3): 309-317.
[32] Darrigues L, Pierga JY, Bernard-Tessier A, et al. Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients[J]. Breast Cancer Res, 2021, 23(1): 31.
[33] Kettner NM, Vijayaraghavan S, Durak MG, et al. Combined Inhibition of STAT3 and DNA Repair in Palbociclib-Resistant ER-Positive Breast Cancer[J]. Clin Cancer Res, 2019, 25(13): 3996-4013.
[34] Dowsett M, Kilburn L, Rimawi MF, et al. Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ER+/HER2- Breast Cancer[J]. Clin Cancer Res, 2022, 28(1): 163-174.
-
期刊类型引用(5)
1. 贾欢欢,陈东辉,李白莲. 哌柏西利联合来曲唑在HR+/HER2-复发转移性乳腺癌患者中的应用. 黑龙江医药科学. 2025(05): 153-154+157 . 百度学术
2. 侯兰,代引海,王哲,焦扬驰,常可欣,王茂,吴少锋,齐婧,张聚良. METTL3介导的CCNE1 m~6A修饰调控乳腺癌细胞对哌柏西利敏感性的研究. 现代肿瘤医学. 2024(05): 787-791 . 百度学术
3. 陈静静,系祖斌,裴小卉,李明磊,白首龙,姚立成. 哌柏西利、来曲唑及氟维司群联合用药治疗晚期HR~+/HER2~-乳腺癌的疗效与安全性观察. 现代肿瘤医学. 2024(05): 838-842 . 百度学术
4. 罗开伟,何鑫,徐骥,汪伟,胡彬彬. 高纯度哌柏西利合成工艺研究. 浙江化工. 2023(03): 23-27+33 . 百度学术
5. 孙彩红,全香花,张金铭,元海丹. 阿贝西利在HR+/HER2-乳腺癌治疗中的应用研究进展. 延边大学医学学报. 2023(03): 226-231 . 百度学术
其他类型引用(1)
计量
- 文章访问数: 2270
- HTML全文浏览量: 3796
- PDF下载量: 3293
- 被引次数: 6