结直肠癌肝转移新辅助化疗的共识与争议课件.ppt

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手术的关注重点由手术的关注重点由“ “哪些可以切除哪些可以切除” ”转变为转变为“ “哪些可以保留哪些可以保留” ”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 A

3、m 2003;12:165192 No.of met and resectability(A): (A): 不完全性切除患者的不完全性切除患者的MSTMST只有只有 14 14 月，而完全切除患者的月，而完全切除患者的MSTMST为为44 44 月。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。的宽度对生存时间无明显影响。Pawlik TM, et al. Effect of surgical margin status

4、 on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 2005;241:715722; discussion 722724Margin and resectability Neoadjuvant chemotherapy for resectable liver metastases of CRC resectablePreoperative chemotherapywhat are possible benefits? Tumor shrinkage ma

5、y facilite resection whith a hope for higher survival rates Test chemoresponsiveness of matastases Select candidates for resection -Exclude tumors progressing while on chemotherapy -Be more aggressive on responding tumorsEORTC 40983:Peri-operative chemotherapySize of lesions after pre-op chemotherap

6、yPhase 3 Trial of Perioperative FOLFOX4 and Surgery for Resectable CRC Liver Metastases (EORTC 40983):PFSRationale AGAINST neoadjuvant CT Risk that metastases become unresectable if they progress during chemotherapy Uncertainty about how to deal with “complete response” to chemotherapy Liver damage

7、induced by chemotherapyPreoperative chemotherapy:potential problems Lost window of opportunity Tumor growth in a critical area may render metastases unresectable Chemotherapy induced portal vein thrombosis 1. Donadon M, et al. W J Gastroenteral 12:6556, 2006Survival according to response to neoadjuv

8、ant chemotherapy ATE：cerebral infact, myocardial infarction, TIA, angina Risk factors for developing ATE Age 65 y (P=0.01) Prior history 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.

9、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 responsePreoperative chemotherapy:potential problemsRadiographic CR Pathologoc CR Radiographic CR Pathologoc CR1 Resection strategy must remove these lesions “Blin

10、d” removal sounds easy in conceptBenoist S, et al, JCO 24:3939, 2006Chemotherapy induces liver damage The “blue” liverThe type of liver injury depends on drug administered Vascular lesions: Oxaliplatin (Rubbia-Brandt et al, 2004) Steatosis: 5FU, Irinotecan? (Parikh et al, 2003) Steatohepatitis: Irin

11、otecan (Vauthey et al, 2006)Liver damage induced by chemotherapySinusoidal lesionsSteatohepatitisASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGYVascular Change in Liver Post Systemic Chemotherapy Clinical significance:impact on surgery Clinical outcome related to liver damage SteatosisSteatosis associate

12、d with higher infection rate associated with higher infection rate (Kooby (Kooby et al, 2003) et al, 2003) SteatohepatitisSteatohepatitis associated with higher mortality rate due associated with higher mortality rate due to liver failure after surgery to liver failure after surgery (Vauthey (Vauthe

13、y et al. 2006) et al. 2006) Vascular injury associated with higher rate of operative Vascular injury associated with higher rate of operative bleeding and transfusion requirementbleeding and transfusion requirement (Vauthey et al. 2006. Aloia(Vauthey et al. 2006. Aloia et al. 2006 ) et al. 2006 )Per

14、operative chemotherapy:potential problemsEORTC 40983:impact of pre-operative chemotherapy on surgeryB O S (Biologics,Oxaliplatin,Surgery)EORTC 40051Resectable CRC liver metastases: Unanswered Questions Is peri-operative chemotherapy superior to post-operative chemotherapy? How much preoperative chem

15、otherapy? How do you assess nature and extent of chemotherapy-induced liver injury? Do targeted agents modulate chemotherapy-induced 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 w

16、hat regimens? After how much duration of treatment? Take-home message 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 messageDownstaging UnresectableColorectal MetastasesResponse t

17、o neoadjuvant chemothrapySurvival after liver Resection of Non Resectable Colorectal Matastases after Systemic Chemotherapy Survival after liver Resection of Colorectal MatastasesSurvival After Chemotherapy For CRLMEffective Preoperative Therapy+Hepatic Resection:Long-term Results in “unresectable”

18、Patients 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 A Model to predict Survival after Liver resection of Non Resectable Colorectal MetastasesComparison of patient char

19、acteristics 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 tumor. 0 5y survival 60% 3 3 5y survival 20%ASCO 2008 abstr 40

20、76 Survival after resection of liver metastases from colorectal cancer with poor clinical risk factors using adjuvant systemic plus hepatic arterial therapy Chemotherapy for unresectable Is there a benefit to add surgery to chemotherapy? To which patients? With what regimens? After how much duration

21、 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., 2008,26(10): 1635-1641Liver Resection after chemotherapy i

22、n initially unresectable patientsl FOLFOXIRIl EGFR antibodies Crystal: FOLFIRI +/- Cetuximab OPUS: FOLFOX +/- Cetuximabl VEGF inhibition Safety of bevicizumabIs there a better treatment than FOLFOXLong-term Outcome of Unresectable Metastatic Colorectal Cancer(MCRC) Patients(Pts) Treated With First-l

23、ine 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-Resectable Liver Metastases(non-selected p

24、atients)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 + + FOLFIRIFOLFIRI爱必妥爱必妥 + + AIO/ AIO/ 伊立替康伊立替康Erbit

25、uxErbitux + + FOLFOX-4FOLFOX-4患者数患者数424221214242有效率（）有效率（）62626767（1010CR)CR)7272（1010CR)CR)疾病稳定（）疾病稳定（）212129291717疾病控制率疾病控制率838395959595肝转移切除率肝转移切除率( () ) 242424242323Response 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 + IRI5FOLFO

26、X41Cervantes A, et al. ECCO (2005); 2Folprecht G, 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

27、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 bevacizum

28、ab 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 regimens After how much duration of treatment? Take-home messageRisks of Prolonged Chemotherapy In potential candidates for Surger

29、yl Comlete Clinical Response : a paradoxl Progression 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

30、 be avoided and resection performed as soon as resectability 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 onc

31、ol 2004 Centrolobular necrosis Adam, Ann Surg 2004 Regenerative 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

32、 Karroui, BJS 2006 Aloia, JCO 2006 HepatoToxic Effects 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

33、surgeon with however a minority of pathology-proven necrosis Need for good collaboration Oncologist - SurgeonTiming of Surgery after Chemotherapy Chemotherapy for unresectable Is there a benefit to add surgery to chemotherapy? To which patients? With what regimens After how much duration of treatmen

34、t? 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 yearsTake-Home messages