1、如何将不可切除的结直肠癌肝转移灶转为可手术切除,潘宏铭 浙江大学附属邵逸夫医院肿瘤内科,内容,序言 可切除肝转移灶的治疗 不可切除肝转移灶的治疗 总结,结肠癌肝转移发生率,肝脏是结肠癌转移的主要器官。 首诊时约 20 - 30%结肠癌患者发生仅有肝脏转移 复发时大约 30 - 40% 结肠癌患者发生仅有肝脏转移,结肠癌肝转移的治疗,结直肠癌肝转移后若不治疗，中位生存期仅8月，5年生存率几乎为0。 手术切除肝转移灶已经成为结直肠癌肝转移治疗的金标准，是肝转移患者目前唯一能达到治愈的治疗手段。 结直肠癌可手术切除肝转移灶患者的5年生存率达3040，中位生存期达2846个月。,DEFINITIONS
2、: ASCO 2006 LIVER THINK TANK,Neoadjuvant Therapy - Preoperative systemic therapy for resectable hepatic metastases followed by post resection therapy.Adjuvant Therapy - Systemic/regional therapy post hepatic resection.Conversion Therapy Systemic/regional therapy utilized for patients with unresectab
3、le hepatic metastases in an attempt to make the metastases resectable .,内容,序言 可切除肝转移灶的治疗 不可切除肝转移灶的治疗 总结,结直肠癌肝转移的切除指征,既往：异时性肝转移、转移灶局限于单个肝叶、数量少于4个、肿块小于5cm的患者，这样只有不到10的患者可以获得手术机会。 2006年美国肝胆胰协会大会讨论认为，只要转移灶能够完全切除，相邻的肝段可以共用足够的血流和胆汁通道，剩余的肝脏能够维持正常功能，那么转移灶就被认为是可切除的。,切缘距离,切缘距离是患者总生存率(P =0.003)和无病生存率(P 0.001)的
4、唯一独立预后因素。 切缘5mm的患者切缘复发率大大增加，总生存率和无病生存率明显下降。 切缘1cm以上是结直肠癌肝转移灶切除的追求标准，但是切缘1cm以内也不是肝转移灶切除的手术禁忌。,Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver metastases from colorectal cancer Final efficacy results of the EORTC Intergroup phase III study 40983.,B. Nordlinger, H. Sorbye, B. Glime
5、lius, G.J. Poston, P.M. Schlag, P. Rougier, W.O. Bechstein, J. Primrose, E.T. Walpole, T. Gruenberger Statistical analysis L. Collette For the EORTC GI Group, CR UK, ALMCAO, AGITG and FFCD,Trial Design and Objectives,R,FOLFOX4 x 6 cycles,Surgery,FOLFOX4 x 6 cycles,Surgery,364 patientsPotentially res
6、ectable (1-4) liver metastasesGoal: Improve progression-free survival to demonstrate a 40% increase in median PFS (HR=0.71) with 80% power and 2-sided significance level 5%,Pre-Operative Assessment,Outcome in chemotherapy arm CR: 3.3% PR: 35.2% Stable: 33.5% Progression 7.7% Not evaluable: 20.3%,Pro
7、gression-free survival in eligible patients,HR= 0.77; CI: 0.60-1.00, p=0.041,Periop CT,28.1%,36.2%,+8.1% At 3 years,(years),0,1,2,3,4,5,6,0,10,20,30,40,50,60,70,80,90,100,O,N,Number of patients at risk :,125,171,83,57,37,22,8,115,171,115,74,43,21,5,Surgery only,Adjuvant Chemotherapy - Current and Fu
8、ture Studies C-09: Metastasectomy followed by with Oxaliplatin and Capecitabine +/- FUDR,Resection of liver metastases (1-6),Capecitabine + Oxaliplatin,Capecitabine + Oxaliplatin alternating with HAI FUDR,Randomize,Open Planned Accrual 400,Trial 40051 (BOS),内容,序言 可切除肝转移灶的治疗 不可切除肝转移灶的治疗 总结,LIVER META
9、STASES,RESECTABLE 20-25%,NON RESECTABLE 75-80%,SURVIVAL BENEFIT 30-40% AT 5 YEARS,RESECTABLE 10-20%,Downsizing,size,location,number,OncoSurgical strategies in liver metastases from palliative to curative,Palliative,Curative,Survival,Time,Hepatic Artery Infusion (HAI) for Unresectable Liver Metastase
10、s,CALGB 9481: HAI FUDR versus Systemic 5FU and Leucovorin,Eligibility Liver-only, unresectable metastases from CRC No prior therapy for metastatic CRC,HAI FUDR 0.18 mg/kg + DEX 25 mg over 14 days Every 28 days (N = 68),5-FU 425 mg/m2 + LV 20 mg/m2 Daily x 5 every 4 weeks (N = 67),R,Kemeny NE et al.
11、J Clin Oncol 24:1395-1403, 2006,CALGB 9481: Overall Survival,HAI 5FU/LV Med OS (months) 24.4 20.0 (p=0.034) THP (months) 9.8 7.3 (p=0.034) TEP (months) 7.7 14.8 (p=0.029) RR 47% 24%,HAI,5FU/LV,CALGB 9481: Hepatic vs Nonhepatic Disease Progression,Kemeny et al. J Clin Oncol. 2006;24:1395.,Hepatic,Non
12、hepatic,HAI,Systemic, P=0.034,Years from trial entry,Proportion hepatic progressionfree,HAI,Systemic, P=0.029,Proportion nonhepatic progressionfree,Years from trial entry,HAI as Neoadjuvant Therapy for Initially Unresectable Disease,Potential Limitations Invasive Percutaneously placed catheters have
13、 a high rate of complications Surgical placement may delay systemic therapy Lack of treatment for potential extrahepatic disease Limited studies,Role of Neoadjuvant Systemic Chemotherapy for Liver-only Metastases,Resection of non-resectable liver metastases after systemic chemotherapy Published seri
14、es,AuthorsLevi Fowler Bismuth Giachetti Adam Wein Rivoire,Year1992 1992 1996 1999 2001 2001 2002,No Pts98 - 330 389 701 53 131,Type ChemoFu-Fol-Oxali Fu-Fol Fu-Fol-Oxali Fu-Fol-Oxali* Fu-Fol-Oxali Fu-Fol Fu-Fol-Oxali,No Resect18 (19%) 11 53 (16%) 77 (20%) 95 (14%) 6 (11%) 57 (43%),5-yr Surv- - 40% 5
15、0% 39% - -,Fu-Fol-Oxali : Chronomodulated,*,Liver only metastases,Survival after Liver Resection of Colorectal Metastases Paul Brousse Hospital - 473 patients (Apr. 88 - Jul. 99),91%,48%,30%,66%,33%,23%,52%,P= 0.01,Adam R et al. Ann Surg 2004,No Surgery,Resectable : 335 Initially non resectable : 13
16、8,Collaboration : Oncologists - Surgeons For Non Resectable Metastases,1- Current chemotherapy allows at least 20% of patients to be rescued by liver surgery2- The survival benefit of these patients is substantial(30% and 20% rate at 5 and 10 years)3- Resectability: a new end point for treatment str
17、ategy,Neoadjuvant Oxaliplatin Paul Brousse Hospital Study,Adam R. et al., Ann. Surg. Oncol., 2001; 8: 347-353,Chemo: 701 (80%),14%,900,800,700,600,500,400,300,200,100,0,Resection: 266 (31%),86%,36%,64%,95,171,872 patients 1988 - 1996,Initially non-resectable Non-resectable Resectable,14% of 701 CT-t
18、reated patients achieved a response permitting resection,171,Chemotherapy,Role of Neoadjuvant Treatment,Patient status at a mean follow-up of 4.2 years,56 dead (59%),Survival after primary or secondary resection of liver metastases,C225 + FOLFIRI 用于mCRC一线治疗,Peeters et al. Eur J Cancer 2005;Supplemen
19、t 3:Abstract 664,Phase III Trial of FOLFOXIRI vs FOLFIRI as First-Line Therapy of Advanced Colorectal CancerG.O.N.O.Study Design -,Stratification Center PS 0/1 vs 2 Adj. Ctx,R,FOLFIRI CPT-11 180 mg/m2 d1 LV 100 mg/m2 d1,2 5-FU 400 mg/m2 bolus d1,2 5-FU 600 mg/m2 22h inf d1,2 q 2 wks x 12 cycles,FOLF
20、OXIRI CPT-11 165 mg/m2 d1 Oxali 85 mg/m2 d1 LV 200 mg/m2 d1 5-FU 3200 mg/m2 48h inf d1 q 2 wks x 12 cycles,Falcone et al.,ASCO4026,JCO 2007,Phase III Trial of FOLFOXIRI vs FOLFIRI as First-Line Therapy of Advanced CRC,* externally reviewed: 67% 2nd line FOLFOX,Falcone.,ASCO4026,JCO 2007,*CMH test,n=
21、599 / group,n=599 / group,n=134 / n=122,p=0.0034* odds ratio 3.0 95% CI: 1.4 - 6.5,No residual tumor in patientswith liver metastases,ITT population,Liver-limited disease population,Van Cutsem et al, ASCO 2007,CRYSTAL Trial: Surgery with Curative Intent,Specific Chemotherapy Associated Hepatic Toxic
22、ity,Irinotecan Steatohepatitis Oxaliplatin Sinusoidal/vascular injuryAcute & chronic clinical sequelae Biologics - ?Bevacizumab 6 to 8 wks before resectionLiver regeneration & hemorrhage Morbidity is increased with prolonged course of chemotherapy (Aloia et al, J Clin Oncol, 2006),Liver Toxicity of
23、Neoadjuvant Therapy,Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis (P=0.001),*Comparison of each group vs no chemotherapy.Vauthey et al. J Clin Oncol. 2006;24:2065.,Vasodilation & Congestion,Peliosis:,Hemorrhagic Centrilobular
24、Necrosis,Nodular Regenerative Hyperplasia,Vascular Changes in Liver Post Systemic ChemotherapyAloia et al, J Clin Oncol 24: 4983,2006,Hepatic atrophy & sinusoidal congestion,Collaboration Oncologists - Surgeons for Timing of Surgery after Chemotherapy,As soon as the metastases become resectableNot t
25、o miss the good therapeutic window:Tumoral progression: Surgery even potentially curative, has poor results Not to overtreat the patientComplete response: a major problem for the surgeonwith however a minority of pathology-proven necrosisHepatotoxicity: a clinical impact related to duration,Folprech
26、t G, et al. Ann Oncol 2005;16:13111319,Response rate,0.9,0.8,0.7,0.6,0.5,0.4,0.3,Resection rate,0.6,0.5,0.4,0.3,0.2,0.1,0,Impact of Increasing Response Rates,N014A: Resection of Unresectable CRC Limited to the Liver Using FOLFOX6 + Cetuximab,CR/PR resectable O.R. CT x 2 PR, unresectable Rx to Prog/T
27、olerabilityProg Off Study, Rx per M.D.Endpoints: Resectability, Response Rate, Survival,Evaluation,Oxaliplatin+5-FU/LV (FOLFOX6) + C225,射频消融（RFA）,操作简单易行； 创伤小； 既可治疗原发灶又可治疗转移灶；耗时短并发症少； 安全可靠, 病人易耐受 ； 可重复治疗，适用于多个病灶； 缩短住院时间，术后12天可出院； 尤其适用于不能耐受手术者； 部分肿瘤可达到根治目的 。,潘宏铭,金伟.中国癌症杂志.2006,16(10):781-784.,射频消融（RFA
28、）,RFA对于直径大于3cm的病灶疗效不佳，局部复发率高。 因此多数情况下，局部消融只可作为姑息性治疗或辅助性治疗。 RFA在提高手术切除率上得到了很好的应用，多被用于那些转移灶双叶分布、靠近切缘和无法切除的肝内复发的患者。,9 MH,患者，男，43岁。2004年8月6日肠镜诊为：“直肠癌”，8月10日行“直肠癌根治术”。术后病理示：高分化腺癌，侵出浆膜外，LNs9/19。CT示3个肝转移灶，患者于04.8.26行肝转移灶射频治疗。后行“MOSAIC”方案化疗12次。,根治+RFA术后辅助化疗,新辅助化疗后射频治疗,患者，男，49岁。2004年9月肠镜诊为：乙状结肠癌。行乙状结肠癌手术切除。术
29、后病理：“肿块64cm,溃疡型，粘液性腺癌，切缘阴性， LNS (2+/3)。”术后复查CT示“肝脏多发肿块”。穿刺活检病理为转移性腺癌。2004-10-8起“FOLFOX4方案”化疗8次。肝内肿块缩小。2005-1-6行肝转移灶射频治疗。,内容,序言 可切除肝转移灶的治疗 不可切除肝转移灶的治疗 总结,总结,Options available for patients in the adjuvant, perioperative, and neoadjuvant settings Patients amenable to surgery have a better outcome, even
30、 if recurrence Studies support role for adjuvant therapy in resectable liver metastases,value of HAI-based therapy to be assessed,总结,Patients with liver metastases benefit from chemotherapy followed by surgery Oxaliplatin-containing regimens render an additional 10% or more patients resectable Use of CPT-11 less well studied Role of HAI remains uncertain Response-enhancing agents needed Potential for chemotherapy-induced liver disease,总结,Management requires multidisciplinary approach Medical Oncology Surgery Radiology Development of practice guidelines,
