早期子宫内膜癌术后辅助治疗.pptx

早期子宫内膜癌术后早期子宫内膜癌术后辅助治疗辅助治疗子宫内膜癌分期（子宫内膜癌分期（FIGO2009FIGO2009）I 肿瘤限于子宫体 IA 肿瘤浸润深度1/2肌层 IB 肿瘤浸润深度1/2肌层II 肿瘤浸润宫颈间质，但无宫体外蔓延III 肿瘤局部和（或）区域扩散 IIIA 肿瘤累及浆膜层和（或附件）IIIB肿瘤累及阴道和（或）宫旁 IIIC盆腔淋巴结和（或）主动脉旁淋巴结转移 IIIC1盆腔淋巴结转移 IIIC2主动脉旁淋巴结转移伴有（或无）盆腔淋巴结转移IV肿瘤浸及膀胱和（或）直肠粘膜，和（或）盆腔淋巴结转移 IV1肿瘤浸及膀胱或直肠粘膜 IV2远处转移，包括腹腔内和（或）腹股沟淋巴结转移手术病理分期（手术病理分期（FIGOFIGO，19881988，20092009 ）Surgical StageSurgical Stage2009b2009 babcab2009 a手术病理分期（手术病理分期（FIGOFIGO，19881988，2009 2009）Surgical Surgical StageStagea期：癌瘤浸润膀胱或直肠粘膜期：癌瘤浸润膀胱或直肠粘膜b期：远处转移期：远处转移c2c1腹腔冲洗液腹腔冲洗液 a b c 早期子宫内膜癌GOG：仅考虑细胞分化程度和肌层浸润，5年生存率92.7%Relationgship between surgical-pathologic risk factors and outcome in stage I and II carcinoma of the endometrium:a Gynecologic Oncology Group study.Gynecol Oncol,1991,40:55-65.I期术后的辅助治疗II期术后辅助治疗问题n哪些需要术后辅助治疗n哪些腔内放疗足够n哪些的确需要盆腔放疗术后复发及转移的高危因素n高危因素：高危因素：细胞学分化程度 肌层浸润 病理类型n相对高危因素：相对高危因素：年龄 脉管瘤栓 肿瘤大小 子宫下段（宫颈腺体）受累 Prognostic FactorsEffect of individual prognostic factors on relative risk to survivalPrognostic factorRelative risknEndometrioid histology Grade 11.0Grade 21.6Grade 32.6nSerous histologyGrade 12.9Grade 24.4Grade36.6nMyometrial penetration endometrium only1.0inner 1/31.2inner 2/31.6outer 1/33.0nPositive washings 3.0nAge 45 years1.065 years3.4Lymphovascular space involvement 1.5 Keys et Al.A phase III trial of Surgery vs with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma:A Gynecologic Oncology Group study.Gynec.Oncology.92(3).744-751.2004Prognostic Factors危险因素 5年生存率多于2个 17%2个 66%无或1个 95%Creutzberg et Al.Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma;multicentric randomised trial.Lancet.355:1404-1411.2000危险度分组I（Risk Classification）n低危组（低危组（LRLR）:肿瘤限于子宫,侵犯肌层50%,高、中分化n中危组（中危组（IRIR）:侵犯子宫肌层50%,或G3,或宫颈受侵。再根据3个高危因素：脉管瘤栓,外1/3肌层受累,分化程度（G2，G3）中高危（中高危（HIRHIR）：3个高危因素，任何年龄；2个高危因素及50至69岁;1个高危因素及70岁以上.中低危（中低危（LIRLIR）：除上述中高危组以外的中危组 n高危组（高危组（HRHR）:子宫外或淋巴结转移。Relationgship between surgical-pathologic risk factors and outcome in stage I and II carcinomaof the endometrium:a Gynecologic Oncology Group study.Gynecol Oncol,1991,40:55-65.A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma:aGynecologic Oncology Group study.Gynecol Oncol.2004 Mar;92(3):744-51.危险度分组II（Risk Classification）n低危组（低危组（LRLR）:局限于子宫内膜的G1和G2期的子宫内膜样腺癌n中危组（中危组（IRIR）:病变局限于子宫，但肌层受侵或宫颈间质受侵，包括 部分IA期，全部IB期,部分II期。再根据3个高危因素：脉管瘤栓,外1/3肌层受累,分化程度（G2，G3）中高危（HIR）：3个高危因素，任何年龄；2个高危因素及50至69岁;1个高危因素，70岁以上.中低危（LIR）：除上述中高危组以外的中危组 n高危组（高危组（HRHR）:包括任何分化程度的宫颈大肿瘤受累，III期，IVA期,及特殊病理类型如papillary serous or clear cell uterine tumors Contemporary management of endometrial cancer.Lancet.2012 Apr 7;379(9823):1352-60.危险度分组III（Risk Classification）n低危组（低危组（LRLR）:I期子宫内膜样腺癌，G1和G2期，肌层受侵50%n中危组（中危组（IRIR）:其它的I期子宫内膜样腺癌。中低危（LIR）：年龄50%；G3肌层受侵60岁；G1或G2且肌层受累50%；G3肌层受侵50%，II期，III期的子宫内膜样腺癌,及特殊病理类型如papillary serous or clear cell uterine tumors.Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma:multicentre randomised trial.PORTEC Study Group.Post Operative Radiation Therapy in Endometrial Carcinoma.Lancet.2000 Apr 22;355(9213):1404-11.The Role of Radiotherapy in Endometrial Cancer:Current Evidence and Trends。Curr Oncol Rep(2011)13:472478低危组子宫内膜样腺癌IA期，肌层受侵50%，G1和G2期n5年生存率达95%以上；n放疗不能改善局控率（包括阴道残端），总复发率及总生存率；n增加治疗相关并发症n局部复发后治疗仍取得高生存率。结论：不需要辅助治疗结论：不需要辅助治疗nElliott P,Green D,Coates A,et al.The efficacy of postoperative vaginal irradiation in preventing vaginal recurrence in endometrial cancer.Int J Gynecol Cancer 1994;4:8493.n Karolewski K,Kojs Z,Urbanski K,et al.The effi ciency of treatment in patients with uterine-confined endometrial cancer.Eur J Gynaecol Oncol 2006;27:57984.nTouboul E,Belkacemi Y,Buff at L,et al.Adenocarcinoma of the endometrium treated with combined irradiation and surgery:study of 437 patients.Int J Radiat Oncol Biol Phys 2001;50:8197.nMariani A,Webb MJ,Keeney GL,Haddock MG,Calori G,Podratz KC.Low-risk corpus cancer:is lymphadenectomy or radiotherapy necessary?Am J Obstet Gynecol 2000;182:150619.nSorbe B,NordstromB,Maenpaa J,et al.Intravaginal brachytherapy in FIGO stage I low-risk endometrial cancer:a controlled randomized study.Int J Gynecol Cancer 2009;19:87378.中危组及高危组（早期子宫内膜癌）目前无令人信服的研究证实辅助治疗提高生存率。n中低危组n中高危组Contemporary management of endometrial cancer.2012 Apr 7;379(9823):1352-60术后辅助放疗The Norwegian trial方法方法:540 患者,手术+镭腔内放疗后，随机分为不加盆腔放疗组及加盆腔淋巴结放疗.随访3-10年。结果结果:1.盆腔放疗组阴道残端及盆腔的复发率明显下降(1.9 vs 6.9%,P .01)2.盆腔放疗组远处转移率则增加(9.9 vs 5.4%).3.5年生存率无差异（91%vs 89%）4.G3，肌层浸润大于50%的患者在局控率和总生存率上可能受益（18%vs 27%），但样本量小，无统计意义。Aalders J,Abeler V,Kolstad P,Onsrud M.Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma:clinical and histopathologic study of 540 patients.Obstet Gynecol.1980 Oct;56(4):419-27.PORTEC-1方法方法:715I期子宫内膜样腺癌，G1肌层浸润大于50%，G2，G3肌层浸润小于50%.TAH-BSO，随机分为术后体外放疗（46Gy/2Gy）和不加治疗组。结果结果:1.局部复发率：5年 4%vs 14%(p0.001)，10年 5%vs 14%(p0.001)2.OS:5年 81%vs 85%（p=0.31）.10年：68%vs 73%（p=0.14）。3.肿瘤相关死亡率：5年 9%vs 6%(p=0.37).10年 10%vs 8%(p=0.47).4.治疗相关并发症：25%vs 6%(p0.0001).5.阴道复发后5年生存率64%,盆腔复发及远处转移11%。6.未加放疗组局部复发75%位于阴道残端，治疗后5年生存率70%。7.局部复发相关高危因素：G3，大于60岁，肌层浸润大于50%。Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma:multicentre randomised trial.PORTEC Study Group.Post Operative Radiation Therapy in Endometrial Carcinoma.Lancet.2000 Apr 22;355(9213):1404-11.Postoperative radiotherapy for Stage 1 endometrial carcinoma:long-term outcome of the randomized PORTEC trial with central pathology review.Int J Radiat Oncol Biol Phys.2005;63:8348.(Postoperative Radiation Therapy in Endometrial Carcinoma)PORTEC-1结论结论:nI期子宫内膜癌，术后放疗可降低局部复发率，但不提高总生存率.n放疗增加治疗相关并发症.n60 岁以下和G2肌层浸润小于50%的I期患者不建议术后放疗.Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma:multicentre randomised trial.PORTEC Study Group.Post Operative Radiation Therapy in Endometrial Carcinoma.Lancet.2000 Apr 22;355(9213):1404-11.Postoperative radiotherapy for Stage 1 endometrial carcinoma:long-term outcome of the randomized PORTEC trial with central pathology review.Int J Radiat Oncol Biol Phys.2005;63:8348.GOG99方法：方法：448 IR（IB,IC,and II），其中HIR 33%，TAH-BSO+淋巴结切除术，随机分成盆腔放疗（50.4Gy/1.8Gy）和不加治疗组。结果结果:1.OS无差异：4年 92%（放疗组）vs 86%（对照组）(RH:0.86;P=0.557).2.放疗减少局部（阴道及盆腔）复发：18（对照组）and 3（放疗组）；3.HIR组CIR（累积复发率）：2-year 26%（对照组）versus 6%（放疗组）;4年27%vs 13%；4.HIR组复发率增加；5.LVSI与淋巴结转移，远处转移强相关。6.治疗相关严重并发症：4年13%；A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma:a Gynecologic Oncology Group study.Gynecol Oncol.2004 Mar;92(3):744-51.GOG99结论结论:1.早期子宫内膜癌中危组，术后辅助放疗降低复发风险，不提高总生存率2.术后辅助放疗限于HIR。3.术后放疗增加治疗相关并发症。A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma:a Gynecologic Oncology Group study.Gynecol Oncol.2004 Mar;92(3):744-51.ASTEC and EN5 trials方法方法:905，FIGO stage IA and IB G3;IC 和IIA all grades;特殊病理类型，手术（淋巴结是否切除不限），随机体外放疗（40-46Gy）或观察.腔内治疗不限，包括观察组。结果结果:1.OS：5年两组均为84%,hazard ratio 1.05(95%CI 0.75-1.48;p=0.77).2.观察组53%进行腔内治疗,5 years 局部复发率 6.1%.体外放疗组为3.2%结论结论:早期子宫内膜癌体外放疗既不能减少局部复发，也不能提高生存率。Blake P,Swart AM,Orton J,et al.Adjuvant external beam radiotherapy in the treatment of endometrial cancer(MRC ASTEC and NCIC CTG EN.5 randomised trials):pooled trial results,systematic review,and meta-analysis.Lancet.2009;373:13746.Largest randomized trial comparing pelvic EBRT to no adjuvant treatment after surgery for stage I EC.术后辅助放疗术后辅助放疗样本人群：样本人群：21,249 patients，stage IA-IC，node-negative endometrial adenocarcinoma。19.2%接受放疗，包括EBRT(62.5%)，VBT(17.9%)，both(26.4%)结论：结论：IC期患者，术后辅助放疗提高了总生存率和相对生存率（p0.001）Lee CM,Szabo A,Shrieve DC,Macdonald OK,Gaff ney DK.Frequency and effect of adjuvant radiation therapy among women with stage I endometrial adenocarcinoma.JAMA 2006;295:38997.MetaMeta分析分析1 1分析对象：分析对象：5个临床实验比较EBRT对I期子宫内膜癌的作用。.结果结果:低危组(IA,IBG1，G2)：OR for overall survival 0.71;95%CI 0.52-0.96).中危组(IC G1/2 and IBG3)：OR 0.97;95%CI 0.69-1.35.高危组（IC G3）：DFS OR 1.76;95%CI 1.07-2.89结论结论:中低危组(IA,IBG1，G2)不能从术后EBRT获益。高危组（IC G3）：DFS可获益10%。Survival and recurrent disease after postoperative radiotherapy for early endometrial cancer:systematic review and meta-analysis.BJOG.2007 Nov;114(11):1313-20.Epub 2007 Sep 5.MetaMeta分析分析2 2分析对象：分析对象：8个随机临床研究比较I期子宫内膜癌术后辅助放疗（EBRT或/和VBT），单纯VBT和观察组。其中6个研究为高质量研究。结论结论:1.低危患者不建议术后辅助放疗。2.EBRT(with or without VBT)减少局部复发风险，但总生存率，肿瘤相关死亡率及远处转移率未获益。3.HIR亚组，EBRT不能提高OS，VBT可有效控制阴道残端复发。4.由于HR亚组入组有限，不排除EBRT生存率获益可能。5.EBRT增加治疗相关并发症，降低生活质量。6.未来增加对高危因素的定义及研究Adjuvant radiotherapy for stage I endometrial cancer。Cochrane Database Syst Rev.2012 Apr 18;4:CD003916.术后辅助放疗术后辅助放疗n辅助放疗减少局部复发，但不影响总生存率。n放疗后相关并发症尤其是严重并发症增加。n局部复发率与高危因素相关。nLIR辅助放疗局控率无明显改善(5%)。n辅助放疗建议限于有局部复发高位因素如HIR和HR亚组。放疗方式选择放疗方式选择nEBRTnVBTnBothPORTEC-2(EBRT VS VBT)方法方法:427，HIR（stage I or IIA endometrial carcinoma），手术，pelvic EBRT(46 Gy in 23 fractions;n=214)or VBT(21 Gy high-dose rate in three fractions,or 30 Gy low-dose rate;n=213).结果结果:1.预计5年阴道复发率：1.8%for VBT and 1.6 for EBRT(HR 0.78,95%CI 0.17-3.49;p=0.74).2.5年局部复发率：5.1%for VBT and 2.1%for EBRT(HR 2.08,0.71-6.09;p=0.17).3.5年盆腔复发率：1.5%(0.5-4.5)versus 0.5%(0.1-3.4)(HR 3.10,0.32-29.9;p=0.30),4.远处转移率：8.3%5.1-13.4 vs 5.7%3.3-9.9;（HR 1.32,0.63-2.74;p=0.46).5.OS：84.8%95%CI 79.3-90.3 vs 79.6%71.2-88.0;（HR 1.17,0.69-1.98;p=0.57)6.DFS：82.7%76.9-88.6 vs 78.1%69.7-86.5;（HR 1.09,0.66-1.78;p=0.74).7.急性胃肠道毒性：12.6%27/215 vs 53.8%112/208).Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2):an open-label,non-inferiority,randomised trial.Lancet.2010 Mar 6;375(9717):816-23.PORTEC-2(EBRT VS VBT)结论：结论：nVBT与EBRT在局部复发，远处转移及生存率无差异。nVBT相对EBRT可减少治疗相关并发症，提高生活质量。nVBT建议作为HIR的术后辅助治疗。Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2):an open-label,non-inferiority,randomised trial.Lancet.2010 Mar 6;375(9717):816-23.The Norwegian trial(VBT VS EBRT+VBT)方法方法:540 患者,手术+镭腔内放疗后，随机分为不加盆腔放疗组及加盆腔淋巴结放疗.随访3-10年。结果结果:1.盆腔放疗组阴道残端及盆腔的复发率明显下降(1.9 vs 6.9%,P .01)2.盆腔放疗组远处转移率则增加(9.9 vs 5.4%).3.5年生存率无差异（91%vs 89%）4.G3，肌层浸润大于50%的患者在局控率和总生存率上可能受益（18%vs 27%），但样本量小，无统计意义。Aalders J,Abeler V,Kolstad P,Onsrud M.Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma:clinical and histopathologic study of 540 patients.Obstet Gynecol.1980 Oct;56(4):419-27.VBT VS EBRT+VBT方法方法:527 IR，VBT 或VBT联合EBRT结果：结果：5年局部复发率：1.5%（VBT+EBRT）vs 5%（VBT）(p=0.013),阴道复发：1.9%vs 2.7%，p=0.555盆腔复发（除外阴道复发）：0.4 vs 5.3，p=0.0006.联合放疗减少93%盆腔复发。远处转移：4.6%vs 6.5%，p=0.3345-year OS：89%VS 90%，p=0.548.肌层浸润大于50%是局部复发的高危因素。放疗相关并发症（肠道，尿道等）明显增加，p0.01。External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma-a prospective randomized study Int J Radiat Oncol Biol Phys.2012 Mar 1;82(3):1249-55.Epub 2011 Jun 14.VBT VS EBRT+VBT结论：结论：nIR患者，局控率上EBRT+VBT 优于单纯VBT，但无统计意义。n结合总生存率，治疗并发症及成本效益，VBT作为IR术后辅助放疗选择。nEBRT+VBT可做为高危组（2个或更多高危因素）的选择External pelvic and vaginal irradiation versus vaginal irradiation alone as postoperative therapy in medium-risk endometrial carcinoma-a prospective randomized study Int J Radiat Oncol Biol Phys.2012 Mar 1;82(3):1249-55.Epub 2011 Jun 14.MetaMeta分析分析分析对象：分析对象：8个随机临床研究比较I期子宫内膜癌术后辅助放疗（EBRT或/和VBT），单纯VBT和观察组。其中6个研究为高质量研究。结论结论:1.低危患者不建议术后辅助放疗。2.EBRT(with or without VBT)减少局部复发风险，但总生存率，肿瘤相关 死亡率及远处转移率未获益。3.HIR亚组，EBRT不能提高OS，VBT可有效控制阴道残端复发。4.由于HR亚组入组有限，不排除EBRT生存率获益可能。5.EBRT增加治疗相关并发症，降低生活质量。6.未来增加对高危因素的定义及研究Adjuvant radiotherapy for stage I endometrial cancer。Cochrane Database Syst Rev.2012 Apr 18;4:CD003916.复发复发n局部复发为主，75%位于阴道残端。n未辅助放疗组阴道残端复发后治疗CR 89%，5年生存率65%。Creutzberg CL,van Putten WL,Koper PC,et al.Survival after relapse in patients with endometrial cancer:results from a randomized trial.Gynecol Oncol 2003;89:20109.Huh WK,Straughn JM Jr,Mariani A,et al.Salvage of isolated vaginal recurrences in women with surgical stage I endometrial cancer:a multiinstitutional experience.Int J Gynecol Cancer 2007;17:88689放疗方式选择放疗方式选择HIR术后辅助治疗：VBTHR(存在多个高危因素):EBRT或EBRT+VBT术后辅助化疗n盆腔放疗改善局控率，但不影响OSnHR治疗后局部复发30%，远处转移达88%。Gyn oncol 2002,Gyn oncol 2007.术后辅助化疗术后辅助化疗术后辅助化疗术后辅助化疗nCT VS RT 在OS，PFS，RR无差异n放疗+额外的化疗OS无差异JGOG2033（CT VS RT）中危及高危患者，比较术后辅助放疗及化疗。HIR亚组行辅助化疗组PSF及OS获益。两组副反应无明显差异。Susumu N,Sagae S,Udagawa Y,et al.Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate-and high-risk endometrial cancer:a Japanese Gynecologic Oncology Group study.Gynecol Oncol 2008;108:22633.JGOG2033：JGOG2033：NSGO-9501/EORTC 55991 trailnHR：I，II，III期n比较RT+4 CT/RTn早期数据：PSF：79%VS 72%，P=0.03 OS：74%VS 82%，P=0.08A randomized phase-III study on adjuvant treatment with radiation(RT)chemotherapy(CT)in early-stage high-risk endometrial cancer(NSGO-EC-9501/EORTC 55991).ASCO web.MaNgo ILIADE-III trial结果类似。结果类似。Hogberg T,Signorelli M,de Oliveira CF,et al.Sequential adjuvant chemotherapy and radiotherapy in endometrial cancerresults from two randomised studies.Eur J Cancer 2010;46:242231.NSGO/EORTC+MaNgo ILIADE-III联合分析结果：联合分析结果：the estimate of risk for relapse or death：HR 0.63,CI 0.44-0.89;P=0.009；cancer-specific survival(CSS)：HR 0.55,CI 0.35-0.88;P=0.01。OS：HR 0.69,CI 0.46-1.03;P=0.07；结论结论:放化疗联合提高HR患者PSF，OS也可能受益。Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer-results from two randomised studies.Eur J Cancer.2010 Sep;46(13):2422-31.Epub 2010 Jul 7.METAMETA分析分析1 1汇总5项临床研究n术后+铂类化疗可能在会略提升PSF，减少远处转移，n但OS与术后辅助放疗无差异。n可考虑作为一种治疗的选择，或联合放疗。Adjuvant chemotherapy for endometrial cancer after hysterectomy.Cochrane Database Syst Rev.2011 Oct 5;(10):CD003175.Meta Meta 分析分析2 27临床研究，早期子宫内膜癌或晚期术后无肉眼残留子宫内膜癌结论：结论：单纯化疗或联合放化疗对生存率无影响。只有某些高危组可能获益。Adjuvant chemotherapy for endometrial cancer.Int J Gynecol Cancer.2011 Jul;21(5):885-95.术后辅助化疗n中低危不需辅助化疗。n高危：进一步评价进行中的临床研究进行中的临床研究nGOG249GOG249：HIR患者EBRT vs VBT+3TP（紫杉醇，卡铂）化疗nPORTEC-3PORTEC-3：HIR及HR患者EBRT vs EBRT+化疗：放疗期间2DDP，放疗后4TP：紫杉醇+卡铂nRTOG-GOG9905RTOG-GOG9905：病变局限于子宫的高危患者，放疗及期间2DDP，续4TP（紫杉醇，顺铂）总结总结术后辅助放疗适应症术后辅助放疗适应症术后辅助放疗局限于HIR和HR组放疗方式的选择放疗方式的选择nHIR，VBT相对EBRT可获得良好的局部控制率，并减少治疗相关并发症，取得更好的生活质量。nHR，生存率可能通过EBRT获益。术后辅助化疗术后辅助化疗n中低危组：无获益n中高危组：联合化疗可能PFS受益，需进一步评价。谢谢