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1、结直肠癌肝转移新辅助结直肠癌肝转移新辅助化疗的共识与争议化疗的共识与争议第三军医大学西南医院肿瘤中心第三军医大学西南医院肿瘤中心梁后杰梁后杰Epidemiology of colorectal cancer(CRC)Results of Hepatic Resection for Metastatic Colorectal CancerLiver metastases of CRCManagement of MCRC:An Evolving Treatment Algorithm Neoadj:where is the most controversyConcept of resectabil
2、ity手术的关注重点由“哪些可以切除”转变为“哪些可以保留”Timothy M. Pawlik 2008只要能够完全切除，转移灶的个数与长期生存率无关Altendorf-Hofmann A, Scheele J. A critical review of the major indicators of prognosis after resection of hepatic metastases from colorectal carcinoma. Surg Oncol Clin N Am 2003;12:165192No.of met and resectability(A):不完全性切除患
3、者的MST只有14月，而完全切除患者的MST为44月。Altendorf-Hofmann A, et al. Surg Oncol Clin N Am 2003;12:165192.(B): 只要能够完全切除，切除边界的宽度对生存时间无明显影响。Pawlik TM, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005;241:715722; discussion 722
4、724Margin and resectability Neoadjuvant chemotherapy for resectable liver metastases of CRCresectablePreoperative chemotherapywhat are possible benefits?Tumor shrinkage may facilite resection whith a hope for higher survival ratesTest chemoresponsiveness of matastasesSelect candidates for resection
5、-Exclude tumors progressing while on chemotherapy -Be more aggressive on responding tumorsEORTC 40983:Peri-operative chemotherapySize of lesions after pre-op chemotherapyPhase 3 Trial of Perioperative FOLFOX4 and Surgery for Resectable CRC Liver Metastases (EORTC 40983):PFSRationale AGAINST neoadjuv
6、ant CTRisk that metastases become unresectable if they progress during chemotherapyUncertainty about how to deal with “complete response” to chemotherapyLiver damage induced by chemotherapyPreoperative chemotherapy:potential problems Lost window of opportunity Tumor growth in a critical area may ren
7、der metastases unresectable Chemotherapy induced portal vein thrombosis 1. Donadon M, et al. W J Gastroenteral 12:6556, 2006Survival according to response to neoadjuvant chemotherapy ATE：cerebral infact, myocardial infarction, TIA, angina Risk factors for developing ATE Age 65 y (P=0.01) Prior histo
8、ry of ATE (P 4.5 cm Residual tumor identified: 83% Chemotherapy reduces sensitivity of PET detection of matastases2,31.Benoist S, et al, J Clin Oncol 24:3939,20062.Akhurst T,et al, J Clin Oncol 23:8713, 20053.Tan, MCB et al, J Gastrointest Surg 11:1112, 2007“Complete response”:does it cure?Complete
9、responsePreoperative chemotherapy:potential problemsRadiographic CR Pathologoc CR Radiographic CR Pathologoc CR1 Resection strategy must remove these lesions “Blind” removal sounds easy in conceptBenoist S, et al, JCO 24:3939, 2006Chemotherapy induces liver damage The “blue” liverThe type of liver i
10、njury depends on drug administered Vascular lesions: Oxaliplatin (Rubbia-Brandt et al, 2004) Steatosis: 5FU, Irinotecan? (Parikh et al, 2003) Steatohepatitis: Irinotecan (Vauthey et al, 2006)Liver damage induced by chemotherapySinusoidal lesionsSteatohepatitisASCO AMERICAN SOCIETY OF CLINICAL ONCOLO
11、GYVascular Change in Liver Post Systemic Chemotherapy Clinical significance:impact on surgery Clinical outcome related to liver damageSteatosisassociatedwithhigherinfectionrate(Koobyetal,2003)Steatohepatitisassociatedwithhighermortalityrateduetoliverfailureaftersurgery(Vautheyetal.2006)Vascularinjur
12、yassociatedwithhigherrateofoperativebleedingandtransfusionrequirement(Vautheyetal.2006.Aloiaetal.2006)Peroperative chemotherapy:potential problemsEORTC 40983:impact of pre-operative chemotherapy on surgeryB O S (Biologics,Oxaliplatin,Surgery)EORTC 40051Resectable CRC liver metastases: Unanswered Que
13、stionsIsperi-operativechemotherapysuperiortopost-operativechemotherapy?Howmuchpreoperativechemotherapy?Howdoyouassessnatureandextentofchemotherapy-inducedliverinjury?Dotargetedagentsmodulatechemotherapy-inducedliverinjury?Neoadj for unresectable liver metastases of CRC Chemotherapy for unresectableI
14、s there a benefit to add surgery to chemotherapy?To which patients?With what regimens?After how much duration of treatment?Take-home message Chemotherapy for unresectableIs there a benefit to add surgery to chemotherapy?To which patients?With what regimens?After how much duration of treatment?Take-h
15、ome messageDownstaging UnresectableColorectal MetastasesResponse to neoadjuvant chemothrapySurvival after liver Resection of Non Resectable Colorectal Matastases after Systemic Chemotherapy Survival after liver Resection of Colorectal MatastasesSurvival After Chemotherapy For CRLMEffective Preoperat
16、ive Therapy+Hepatic Resection:Long-term Results in “unresectable” Patients Chemotherapy for unresectableIs there a benefit to add surgery to chemotherapy?To which patients?With what regimens?After how much duration of treatment?Take-home message A Model to predict Survival after Liver resection of N
17、on Resectable Colorectal MetastasesComparison of patient characteristics between cured and non-cured patientsAdam R ,ASCO 2008 abstr 4023 Clinical risk scoring system ( Fong et al) disease-free interval 1 pre-operative CEA level 200 IU per ml, size of largest tumor 5 cm lymph node positive primary t
18、umor. 0 5y survival 60%35y survival 20%ASCO 2008 abstr 4076 Survival after resection of liver metastases from colorectal cancer with poor clinical risk factors using adjuvant systemic plus hepatic arterial therapy Chemotherapy for unresectableIs there a benefit to add surgery to chemotherapy?To whic
19、h patients?With what regimens?After how much duration of treatment?Take-home messageResectability correlates with rsponseOverall survival curves (Kaplan-Meier) of patients with and without complete pathologic response (CPR) 完全缓解患者术后10年生存率约68，而部分缓解者约29Ren Adam, Dennis A，et al. J. Clin. Oncol., 2008,2
20、6(10): 1635-1641Liver Resection after chemotherapy in initially unresectable patientslFOLFOXIRIlEGFRantibodiesCrystal:FOLFIRI+/-CetuximabOPUS:FOLFOX+/-CetuximablVEGFinhibitionSafetyofbevicizumabIs there a better treatment than FOLFOXLong-term Outcome of Unresectable Metastatic Colorectal Cancer(MCRC
21、) Patients(Pts) Treated With First-line FOLFOXIRI Followed by R0 Surgical Resection of MetastasesResection after combinaton of cytotoxics and targeted agentsOPUS trial:response rates by subgroupOPUS tiral: secondary endpointsCRYSTAL trial: Surgery with curative intent Cetuximab Studies in Non-Resect
22、able Liver Metastases(non-selected patients)Rosenberg AH, et al. Proc ASCO 2002;20 (Abstract No. 536); Peeters M, et al. Eur J Cancer Suppl 2005;3:188 (Abstract No.664); Folprecht G, et al. Ann Oncol (2005); Cervantes A, et al. Eur J Cancer Suppl 2005;3:181 (Abstract No. 642) 爱必妥爱必妥+FOLFIRI爱必妥爱必妥+AI
23、O/伊立替康伊立替康Erbitux+FOLFOX-4患者数患者数422142有效率（）有效率（）6267（10CR)72（10CR)疾病稳定（）疾病稳定（）212917疾病控制率疾病控制率839595肝转移切除率肝转移切除率()242423Response rate and resectability 有效率和切除率有效率和切除率 (%)有效率有效率切除率切除率ERBITUXFOLFOX41ERBITUXAIO IRI2ERBITUX+FOLFIRI3FOLFIRI4AIO + IRI5FOLFOX41Cervantes A, et al. ECCO (2005); 2Folprecht G,
24、 et al. Ann Oncol (2005); 3Rougier P, et al. ECCO (2005); 4Tournigand, et al. J Clin Oncol (2004); 5Khne C-H, et al. EORTC-Study 40986 (2005)EMR 604-CELIM研究研究: 肝转移灶不可切除的肝转移灶不可切除的mCRC患者患者治疗治疗 8 个周期个周期 (4 个月个月)不可切除不可切除可切除可切除4继续治疗继续治疗4个周期个周期可切除可切除切除切除继续治疗继续治疗6个周期个周期(3个月个月)主要终点主要终点: 有效率有效率54 例患者例患者/组组随机
25、随机FOLFOX + ERBITUXFOLFIRI + ERBITUXEGFR阳性阳性/未检测未检测手术无法切除手术无法切除 / 5 个肝转移灶个肝转移灶无肝外转移无肝外转移 Bevacizumab in unresectable liver metastases of CRC ASCO 2008 Abr 4022 Surgery with curative intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer: FIRST BEAT a
26、nd NO16966 Chemotherapy for unresectableIs there a benefit to add surgery to chemotherapy?To which patients?With what regimensAfter how much duration of treatment?Take-home messageRisks of Prolonged Chemotherapy In potential candidates for Surgeryl Comlete Clinical Response : a paradoxl Progression
27、after initial responsel Hepatotoxic effect CCR: To achieve or to avoid?1. A complete radiological reaponse dose not mean cure in 83% of the lesions (1) and 94% of the patients (2)2. Although rare and conceptually valorizing, this situation should be avoided and resection performed as soon as resecta
28、bility is obtained3. What is a dream for medical oncologists could be a nightmare for surgeonsl Preoperation Chmotherapy 1990s Steatosis Elias, JACS 1995; Behms JGIS 1998 With intrarterial chmotherapy 2000s Vascular lesiors Rubbia-Brandt, Ann oncol 2004 Centrolobular necrosis Adam, Ann Surg 2004 Reg
29、enerative nobular hyperplasia Steatohepatitis (Irinotecan) Vauthey, JCO 2006l Impact on postop. Complications - Nortality : No except steatohepatitis Vauthey, JCO 2006 - Norbidity : Yes Nordlinger, ASCO 2005 - Relationship duration of chemo : Yes Karroui, BJS 2006 Aloia, JCO 2006 HepatoToxic Effects
30、 of ChemotherapyAs soon as the matastases become resectable Not to miss thegoodtherapeutic window: If tumoral progression, Surgery even potentially curative, has poor resulits Not toovertreatthe patient Complete response: a major problem for the surgeon with however a minority of pathology-proven ne
31、crosis Need for good collaboration Oncologist - SurgeonTiming of Surgery after Chemotherapy Chemotherapy for unresectableIs there a benefit to add surgery to chemotherapy?To which patients?With what regimensAfter how much duration of treatment?Take-home messages Resectability is becoming a new end-p
32、oint in strategies invoving chemotherapy in non resectable patients 15-30% patients could be switched to resectability The more efficient the chemotherapy, the best the chance for surgery The faster the response, the lesser the risk of liver toxicity As soon resectability is obtained, surgery should be envisaged Cure is possible with actual survival at more than 10 yearsTake-Home messages
