如何将不可切除的结直肠癌肝转移灶转为可手切除

1、内容l序言l可切除肝转移灶的治疗l不可切除肝转移灶的治疗l总结结肠癌肝转移发生率l肝脏是结肠癌转移的主要器官。l首诊时约 20 - 30%结肠癌患者发生仅有肝脏转移l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l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。l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。l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: asco 2006 liver think tank内容l序言l可切除肝转移灶的治疗l不可

2、切除肝转移灶的治疗l总结 l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。l2006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l切缘距离是患者总生存率(p =0.003)和无病生存率(p 0.001)的唯一独立预后因素。l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。l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-operati

3、ve folfox4 chemotherapy and surgery for resectable liver metastases from colorectal cancerb. nordlinger, h. sorbye, b. glimelius, g.j. poston, p.m. schlag, p. rougier, w.o. bechstein, j. primrose, e.t. walpole, t. gruenbergerstatistical analysis l. collettetrial design and objectivesrfolfox4 x 6 cyc

4、lessurgeryfolfox4 x 6 cyclessurgery 364 patients potentially resectable (1-4) liver metastases goal: 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 assessmentloutcome in chemotherapy armprogression

5、-free survival in eligible patientshr= 0.77; ci: 0.60-1.00, p=0.041periop ct28.1%36.2%+8.1%at 3 years (years)01234560102030405060708090100onnumber of patients at risk :125 171835737228115 1711157443215surgery onlyadjuvant chemotherapy - current and future studiesopen planned accrual 400folfox6 modif

6、ied+ cetuximab6 cyclesrandomizationresectableliver metastases from colorectal cancer no extrahepatic diseasewho ps 0,1no previous chemo for metsfolfox6 modified+ cetuximab+ bevacizumab6 cycles(no bevacizumab in cycle #6)folfox6 modified+ cetuximab6 cyclesfolfox6 modified+ cetuximab+ bevacizumab6 cyc

7、lesfollow upfollow upsurgerysurgerytrial 40051 (bos)内容l序言l可切除肝转移灶的治疗l不可切除肝转移灶的治疗l总结downsizingsizelocationnumberpalliativecurativesurvivaltimehepatic artery infusion (hai)for unresectable liver metastaseseligibilityhai fudr 0.18 mg/kg + dex 25 mg over 14 daysevery 28 days (n = 68)5-fu 425 mg/m2 + lv

8、20 mg/m2daily x 5 every 4 weeks (n = 67)rkemeny ne et al. j clin oncol 24:1395-1403, 2006calgb 9481: overall survival hai 5fu/lvmed os (months) 24.420.0 (p=0.034)thp (months) 9.8 7.3 (p=0.034)tep (months) 7.714.8 (p=0.029)rr 47% 24%hai5fu/lvkemeny et al. j clin oncol. 2006;24:1395.hepaticnonhepatich

9、aisystemic, p=0.034years from trial entryproportion hepatic progressionfree012300.20.40.60.81.0012300.20.40.60.81.0haisystemic, p=0.029proportion nonhepatic progressionfreeyears from trial entrypotential limitationsrole of neoadjuvant systemic chemotherapy for liver-only metastasesresection of non-r

10、esectable liver metastases after systemic chemotherapypublished seriesauthorslevi fowlerbismuthgiachettiadamweinrivoireyear1992199219961999200120012002no pts98-33038970153131type chemofu-fol-oxalifu-folfu-fol-oxali fu-fol-oxali*fu-fol-oxalifu-folfu-fol-oxali no resect18 (19%)1153 (16%)77 (20%)95 (14

11、%)6 (11%)57 (43%)5-yr surv-40%50%39%-fu-fol-oxali : chronomodulated* liver only metastasessurvival after liver resection of colorectal metastasespaul brousse hospital - 473 patients (apr. 88 - jul. 99)years20406080100012345678910survival (%)91%48%30%66%33%23%52%p= 0.01adam r et al. ann surg 2004no s

12、urgeryresectable : 335initially non resectable : 138collaboration : oncologists - surgeons for non resectable metastases1- 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

13、- resectability: a new end point for treatment strategyneoadjuvant oxaliplatin paul brousse hospital studyadam r. et al., ann. surg. oncol., 2001; 8: 347-353chemo: 701 (80%)14%9008007006005004003002001000resection: 266 (31%)86%36%64%95872 patients1988 - 1996initially non-resectablenon-resectablerese

14、ctable14% of 701 ct-treated patients achieved a response permitting resection chemotherapyrole of neoadjuvant treatmentpatient status at a mean follow-up of 4.2 years56 dead (59%)39 alive (41%)25 alive disease free (26%)14 alive with disease (15%)survival after primary or secondaryresection of liver

15、 metastasesstrictly confidential. for internal use only. non-promotional material.acrobatacrobat 研究设计研究设计folfox + folfox + 西妥昔单抗一线治疗西妥昔单抗一线治疗转移性结直肠癌转移性结直肠癌acrobatacrobat 研究设计研究设计folfox + folfox + 西妥昔单抗一线治疗西妥昔单抗一线治疗转移性结直肠癌转移性结直肠癌(n=43)入组入组入组入组主要终点主要终点主要终点主要终点: : : : rrrrrrrrcetuximabcetuximab (400 mg

16、/m(400 mg/m2 2week 1 and week 1 and 250 mg/m250 mg/m2 2weekly thereafter)weekly thereafter)folfox4 folfox4 方案直至疾病进展或不能耐受毒性方案直至疾病进展或不能耐受毒性次要终点次要终点次要终点次要终点: : : : 安全性、安全性、安全性、安全性、 耐受性耐受性耐受性耐受性 、 ttp ttp ttp ttp 、osososos初筛了初筛了6262例病人例病人(ecog ps 0 (ecog ps 0 ? ? 2); 52 (84%)2); 52 (84%)例是有例是有egfregfr过度

17、表达的转移性过度表达的转移性病人病人; 43; 43例入组例入组 ( (安全性和疗效均可评估安全性和疗效均可评估) )+e diaz-rubio et al, 2005 asco abs 3535strictly confidential. for internal use only. non-promotional material.acrobatacrobat 研究有效率高达研究有效率高达8181acrobatacrobat 研究有效率高达研究有效率高达81819 9 例病人例病人 (21%)(21%)获得了二次手术获得了二次手术r0 r0 ( (完全切除完全切除) :7(17%) ) :

18、7(17%) e diaz-rubio et al, 2005 asco abs 353587 87 ? ? 99%99%98%98%4141疾病控制疾病控制 (or +sd)(or +sd)66 66 ? ? 91%91%81%81%3434总有效率总有效率 (cr + pr)(cr + pr)7 7 ? ? 31%31%17%17%7 7疾病稳定疾病稳定(sd)(sd)55 55 ? ? 84%84%71%71%3030部分缓解部分缓解(pr)(pr)3 3 ? ? 23%23%10%10%4 4完全缓解完全缓解(cr)(cr)可信区间可信区间95% ci95% ci百分比百分比病例数病例

19、数n=42n=42c225 + folfiri 用于mcrc一线治疗best overall responsepartial responsestable disease disease control中位疗效持续时间 中位生存期 c225 + folfiri (high-dose)% (n=42)6221831024%(10例)23peeters et al. eur j cancer 2005;supplement 3:abstract 664phase iii trial of folfoxiri vs folfiri as first-line therapy of advanced

20、colorectal cancerstratificationcenterps 0/1 vs 2adj. ctxrfolfiricpt-11 180 mg/m2 d1lv100 mg/m2 d1,25-fu400 mg/m2 bolus d1,25-fu600 mg/m2 22h inf d1,2q 2 wks x 12 cyclesfolfoxiricpt-11 165 mg/m2 d1oxali 85 mg/m2 d1lv200 mg/m2 d15-fu 3200 mg/m2 48h inf d1q 2 wks x 12 cyclesfalcone et al.,asco4026,jco

21、2007phase iii trial of folfoxiri vs folfiri as first-line therapy of advanced crcfolfirifolfoxirirr* (%)34600.0001cr+pr+sd* (%)6881r0 resection (%) (all patients)6150.033r0 resection (%) (liver limited)12360.017pfs (mos)6.99.80.0006os (mos)16.722.60.032* externally reviewed: 67% 2nd line folfoxfalco

22、ne.,asco4026,jco 2007*cmh testn=599 / groupn=599 / groupn=134 / n=122p=0.0034*odds ratio 3.0 95% ci: 1.4 - 6.5 folfiri alone erbitux + folfirino residual tumor in patients with liver metastasesitt populationliver-limited disease populationvan cutsem et al, asco 2007 liver toxicity of neoadjuvant the

23、rapyno chemotherapy5-fu/lv5-fu/lv + irinotecan5-fu/lv + oxaliplatinother1.904.318.9098.110095.781.1100nsns0.00001ns8.916.610.63.88.391.183.489.496.291.7nsnsnsns4.44.820.26.3095.695.279.893.6100ns0.0001nsns patients with steatohepatitis had an increased 90-day mortality compared with patients who did

24、 not have steatohepatitis (p=0.001)*comparison of each group vs no chemotherapy.vauthey et al. j clin oncol. 2006;24:2065.vasodilation & congestionpeliosis:hemorrhagic centrilobular necrosis nodular regenerative hyperplasia vascular changes in liver post systemic chemotherapy aloia et al, j clin

25、 oncol 24: 4983,2006hepatic atrophy & sinusoidal congestioncollaboration oncologists - surgeons for timing of surgery after chemotherapyas soon as the metastases become resectable not to miss the good therapeutic window: tumoral progression: surgery even potentially curative, has poor results no

26、t to overtreat the patient complete response: a major problem for the surgeon with however a minority of pathology-proven necrosis hepatotoxicity: a clinical impact related to durationstudies including nonselected patients with mcrc (solid line) (r=0.74; p0.001)studies including selected patients(li

27、ver metastases only, no extrahepatic disease)(r=0.96; p=0.002)phase iii studies including nonselected patients with mcrc (dashed line)(r=0.67; p=0.024)folprecht g, et al. ann oncol 2005;16:13111319response rate0.90.80.70.60.50.40.3resection rate0.60.50.40.30.20.10impact of increasing response rates 射频消融（rfa）l操作简单易行；l创伤小；l既可治疗原发灶又可治疗转移灶；l 耗时短并发症少；l安全可靠, 病人易耐受 ；l可重复治疗，适用于多个病灶；l缩短住院时间，术后12天可出院；l尤其适用于不能耐受手术者；l部分肿瘤可达到根治目的 。lrfa对于直径大于3cm的病灶疗效不佳，局部复发率高。l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。lrfa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