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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
2、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;12:165192,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
3、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 722724,Margin and
4、 resectability,Neoadjuvant chemotherapy for resectable liver metastases of CRC,resectable,Preoperative chemotherapy what are possible benefits?,Tumor shrinkage may facilite resection whith a hope for higher survival rates Test chemoresponsiveness of matastases Select candidates for resection -Exclud
5、e tumors progressing while 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 neoadjuvan
6、t CT,Risk that metastases become unresectable if they progress during chemotherapy Uncertainty about how to deal with “complete response” to chemotherapy Liver damage induced by chemotherapy,Preoperative chemotherapy: potential problems,Lost window of opportunity Tumor growth in a critical area may
7、render metastases unresectable 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 h
8、istory of ATE (P0.01) Hurwiz et al, N Engl J Med 350:2335,2004 Giantonio et al. ASCO, 2005 Cassidy et al, ESMO, 2006 Sandler et al, N Engl J Med 355:2542, 2006 Miller et al, SABCS, 2005,Bevacizumab:Arterial Thromboembolic Events complicate subsequent liver resection,Preoperative chemotherapy: potent
9、ial problems,Hinder detection of known metastases Radiographic complete response1 Frequency: 6.5% Rare if initial tumor 4.5 cm Residual tumor identified: 83% Chemotherapy reduces sensitivity of PET detection of matastases2,3 Benoist S, et al, J Clin Oncol 24:3939,2006 Akhurst T,et al, J Clin Oncol 2
10、3:8713, 2005 Tan, MCB et al, J Gastrointest Surg 11:1112, 2007,“Complete 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 co
11、ncept Benoist S, et al, JCO 24:3939, 2006,Chemotherapy induces liver damage 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, 20
12、06),Liver damage induced by chemotherapy,Sinusoidal lesions,Steatohepatitis,ASCO AMERICAN 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
13、(Kooby et al, 2003) Steatohepatitis associated with higher mortality rate due to liver failure 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: potent
14、ial problems,EORTC 40983:impact of pre-operative chemotherapy on surgery,B O S (Biologics,Oxaliplatin,Surgery) EORTC 40051,Resectable CRC liver metastases: Unanswered Questions,Is peri-operative chemotherapy superior to post-operative chemotherapy? How much preoperative chemotherapy? How do you asse
15、ss 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 what regimens? After how
16、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 message,Downstaging Unresectable Colorectal Metastases,Response to neoadjuvant chemoth
17、rapy,Survival after liver Resection of Non Resectable Colorectal Matastases after Systemic Chemotherapy,Survival after liver Resection of Colorectal Matastases,Survival After Chemotherapy For CRLM,Effective Preoperative Therapy+Hepatic Resection: Long-term Results in “unresectable” Patients,Chemothe
18、rapy 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 Metastases,Comparison of patient characteristics betw
19、een cured and non-cured patients,Adam 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 5y survival 20%,ASCO 2008 abstr 4076,Survival afte
20、r 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 of treatment? T
21、ake-home message,Resectability correlates with rsponse,Overall 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29 Ren Adam, Dennis A，et al. J. Clin. Oncol., 2008,26(10): 1635-1641,Liver Resection after chemotherapy in initially
22、unresectable patients,FOLFOXIRI EGFR antibodies Crystal: FOLFIRI +/- Cetuximab OPUS: FOLFOX +/- Cetuximab VEGF inhibition Safety of bevicizumab,Is there a better treatment than FOLFOX,Long-term Outcome of Unresectable Metastatic Colorectal Cancer(MCRC) Patients(Pts) Treated With First-line FOLFOXIRI
23、 Followed by R0 Surgical Resection of Metastases,Resection after combinaton of cytotoxics and targeted agents,OPUS trial: response rates by subgroup,OPUS tiral: secondary endpoints,CRYSTAL trial: Surgery with curative intent,Cetuximab Studies in Non-Resectable Liver Metastases(non-selected patients)
24、,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),Response rate and resectability,有效率和切除率 (%),有效率 切除率,ERBITUX FOLFOX
25、41,ERBITUX AIO 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 Clin 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
26、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 Surgery with curative intent in patients treated with first-line chemotherapy plus bevacizuma
27、b 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 message,Risks of Prolonged Chemotherapy In potential candidates for Surger
28、y,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 patients (2) Although rare and conceptually valorizing, this situation should be avo
29、ided 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 intrarterial chmotherapy 2000s Vascular lesiors Rubbia-Brandt, Ann oncol 2004 Ce
30、ntrolobular 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, ASCO 2005 - Relationship duration of chemo : Yes Karroui, B
31、JS 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 Complete response: a major problem for the surgeon wi
32、th 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 regimens After how much duration of treatment? Take-h
33、ome 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,