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1、结直肠癌肝转移新辅助化疗的共识与争议,第三军医大学西南医院肿瘤中心,梁后杰,Epidemiology of colorectal cancer(CRC),Results of Hepatic Resection for Metastatic Colorectal Cancer,Liver metastases of CRC,Management of MCRC:An Evolving Treatment Algorithm,Neoadj:where is the most controversy,Concept of resectability,手术的关注重点由“哪些可以切除”转变为“哪些可以
2、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;12:165192,No.of met and resectability,(A):不完全性切除患者的MST只有 14 月，而完全切除患者的MST为44
3、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 722724,Margin and resectability,Neo
4、adjuvant chemotherapy for resectable liver metastases of CRC,resectable,Preoperative chemotherapywhat are possible benefits?,Tumor shrinkage may facilite resection whith a hope for higher survival ratesTest chemoresponsiveness of matastasesSelect candidates for resection-Exclude tumors progressing w
5、hile on chemotherapy-Be more aggressive on responding tumors,EORTC 40983:Peri-operative chemotherapy,Size of lesions after pre-op chemotherapy,Phase 3 Trial of Perioperative FOLFOX4 and Surgery for Resectable CRC Liver Metastases(EORTC 40983):PFS,Rationale AGAINST neoadjuvant CT,Risk that metastases
6、 become unresectable if they progress during chemotherapyUncertainty about how to deal with“complete response”to chemotherapyLiver damage induced by chemotherapy,Preoperative chemotherapy:potential problems,Lost window of opportunity Tumor growth in a critical area may render metastases unresectable
7、 Chemotherapy induced portal vein thrombosis,1.Donadon M,et al.W J Gastroenteral 12:6556,2006,Survival 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 history of ATE(P0.01)Hurwiz et al,N Engl
8、 J Med 350:2335,2004Giantonio et al.ASCO,2005Cassidy et al,ESMO,2006Sandler et al,N Engl J Med 355:2542,2006Miller et al,SABCS,2005,Bevacizumab:Arterial Thromboembolic Events complicate subsequent liver resection,Preoperative chemotherapy:potential problems,Hinder detection of known metastases Radio
9、graphic complete response1 Frequency:6.5%Rare if initial tumor 4.5 cm Residual tumor identified:83%Chemotherapy reduces sensitivity of PET detection of matastases2,3Benoist S,et al,J Clin Oncol 24:3939,2006Akhurst T,et al,J Clin Oncol 23:8713,2005Tan,MCB et al,J Gastrointest Surg 11:1112,2007,“Compl
10、ete response”:does it cure?,Complete response,Preoperative chemotherapy:potential problems,Radiographic CR Pathologoc CR Radiographic CR Pathologoc CR1 Resection strategy must remove these lesions“Blind”removal sounds easy in conceptBenoist S,et al,JCO 24:3939,2006,Chemotherapy induces liver damage
11、The“blue”liver,The type of liver injury 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 chemotherapy,Sinusoidal lesions,Steatohepatitis,ASCO AMERICAN
12、SOCIETY OF CLINICAL ONCOLOGY,Vascular Change in Liver Post Systemic Chemotherapy,Clinical significance:impact on surgery,Clinical outcome related to liver damage,Steatosis associated with higher infection rate(Kooby et al,2003)Steatohepatitis associated with higher mortality rate due to liver failur
13、e after surgery(Vauthey et al.2006)Vascular injury associated with higher rate of operative bleeding and transfusion requirement(Vauthey et al.2006.Aloia et al.2006),Peroperative chemotherapy:potential problems,EORTC 40983:impact of pre-operative chemotherapy on surgery,B O S(Biologics,Oxaliplatin,S
14、urgery)EORTC 40051,Resectable CRC liver metastases:Unanswered Questions,Is peri-operative chemotherapy superior to post-operative chemotherapy?How much preoperative chemotherapy?How do you assess nature and extent of chemotherapy-induced liver injury?Do targeted agents modulate chemotherapy-induced
15、liver injury?,Neoadj for unresectable liver metastases of CRC,Chemotherapy for unresectable,Is 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 unresectable,Is there a benefit to add surgery to
16、 chemotherapy?To which patients?With what regimens?After how much duration of treatment?Take-home message,Downstaging UnresectableColorectal Metastases,Response to neoadjuvant chemothrapy,Survival after liver Resection of Non Resectable Colorectal Matastases after Systemic Chemotherapy,Survival afte
17、r liver Resection of Colorectal Matastases,Survival After Chemotherapy For CRLM,Effective Preoperative Therapy+Hepatic Resection:Long-term Results in“unresectable”Patients,Chemotherapy for unresectable,Is there a benefit to add surgery to chemotherapy?To which patients?With what regimens?After how m
18、uch duration of treatment?Take-home message,A Model to predict Survival after Liver resection of Non Resectable Colorectal Metastases,Comparison of patient characteristics between cured and non-cured patients,Adam R,ASCO 2008 abstr 4023,Clinical risk scoring system(Fong et al),disease-free interval
19、1 pre-operative CEA level 200 IU per ml,size of largest tumor 5 cm lymph node positive primary tumor.0 5y survival 60%3 5y 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 arteri
20、al therapy,Chemotherapy for unresectable,Is there a benefit to add surgery to chemotherapy?To which patients?With what regimens?After how much duration of treatment?Take-home message,Resectability correlates with rsponse,Overall survival curves(Kaplan-Meier)of patients with and without complete path
21、ologic 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.,2008,26(10):1635-1641,Liver Resection after chemotherapy in initially unresectable patients,FOLFOXIRIEGFR antibodies Crystal:FOLFIRI+/-Cetuximab OPUS:FOLFOX+/-Cetuximab VEGF inhibition Safety of bevicizumab,Is ther
22、e a better treatment than FOLFOX,Long-term Outcome of Unresectable Metastatic Colorectal Cancer(MCRC)Patients(Pts)Treated With First-line FOLFOXIRI Followed by R0 Surgical Resection of Metastases,Resection after combinaton of cytotoxics and targeted agents,OPUS trial:response rates by subgroup,OPUS
23、tiral:secondary endpoints,CRYSTAL trial:Surgery with curative intent,Cetuximab Studies in Non-Resectable 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);Cerv
24、antes A,et al.Eur J Cancer Suppl 2005;3:181(Abstract No.642),Response rate and resectability,有效率和切除率(%),有效率切除率,ERBITUXFOLFOX41,ERBITUXAIO IRI2,ERBITUX+FOLFIRI3,FOLFIRI4,AIO+IRI5,FOLFOX4,1Cervantes A,et al.ECCO(2005);2Folprecht G,et al.Ann Oncol(2005);3Rougier P,et al.ECCO(2005);4Tournigand,et al.J C
25、lin Oncol(2004);5Khne C-H,et al.EORTC-Study 40986(2005),EMR 604-CELIM研究:肝转移灶不可切除的mCRC患者,治疗 8 个周期(4 个月),不可切除,可切除,4继续治疗4个周期,可切除,切除,继续治疗6个周期(3个月),主要终点:有效率54 例患者/组,随机,FOLFOX+ERBITUX,FOLFIRI+ERBITUX,EGFR阳性/未检测,手术无法切除/5 个肝转移灶无肝外转移,Bevacizumab in unresectable liver metastases of CRC,ASCO 2008 Abr 4022 Surg
26、ery with curative intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer:FIRST BEAT and NO16966,Chemotherapy for unresectable,Is there a benefit to add surgery to chemotherapy?To which patients?With what regimensAfter how much duration of treatment?
27、Take-home message,Risks of Prolonged Chemotherapy In potential candidates for Surgery,Comlete Clinical Response:a paradox Progression after initial response Hepatotoxic effect,CCR:To achieve or to avoid?,A complete radiological reaponse dose not mean cure in 83%of the lesions(1)and 94%of the patient
28、s(2)Although rare and conceptually valorizing,this situation should be avoided and resection performed as soon as resectability is obtained What is a dream for medical oncologists could be a nightmare for surgeons,Preoperation Chmotherapy 1990s Steatosis Elias,JACS 1995;Behms JGIS 1998 With intrarte
29、rial chmotherapy 2000s Vascular lesiors Rubbia-Brandt,Ann oncol 2004 Centrolobular necrosis Adam,Ann Surg 2004 Regenerative nobular hyperplasia Steatohepatitis(Irinotecan)Vauthey,JCO 2006 Impact on postop.Complications-Nortality:No except steatohepatitis Vauthey,JCO 2006-Norbidity:Yes Nordlinger,ASC
30、O 2005-Relationship duration of chemo:Yes Karroui,BJS 2006 Aloia,JCO 2006,HepatoToxic Effects of Chemotherapy,As soon as the matastases become resectable Not to miss thegoodtherapeutic window:If tumoral progression,Surgery even potentially curative,has poor resulits Not toovertreatthe patient Comple
31、te response:a major problem for the surgeon with however a minority of pathology-proven necrosis,Need for good collaboration Oncologist-Surgeon,Timing of Surgery after Chemotherapy,Chemotherapy for unresectable,Is there a benefit to add surgery to chemotherapy?To which patients?With what regimensAft
32、er how much duration of treatment?Take-home messages,Resectability is becoming a new end-point 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 years,Take-Home messages,
