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1、2009ASCO结肠癌进展,南昌大学第一附属医院肿瘤科 黎军和,分子指标预测期结肠癌高危复发大型研究结果Ceteximab疗效的预测结肠癌辅助化疗终点Oxaliplatin相关synchronous stage IV colorectal cancer 化疗策略和方案的调整其它,分子指标预测结肠癌高危复发及指导化疗,Abr4000 高通量 Abr4001MSIAbr 4002 Abr 4012 18q LOH,Background:NSABP C-01/C-02、CCF、C-04、C-06 48 genes significantly associated with recurrence ri
2、sk and 66 genes predictive of 5FU/LV benefit.Multivariate analysis yielded 18 genes(7 prognostic genes,6 predictive genes,5 reference genes)and separate prognostic recurrence score(RS)and predictive treatment score(TS)algorithms.Methods:Gene expression was quantitated by RT-PCR.Recurrence-free inter
3、val(RFI),disease-free survival(DFS),and overall survival(OS)were analyzed using Cox regression Results:In the QUASAR validation study the RS predicted recurrence risk(p=0.004).The RS also predicted DFS(p=0.01)and OS(p=0.04).Recurrence risk increased monotonically with increasing RS.In multivariate a
4、nalyses,RS retained prognostic significance(p=0.008)independent of mismatch repair(MMR),T stage,nodes examined,grade,and lymphovascular invasion.MMR deficiency(p0.001)and T4 stage(p=0.005).However,TS was not validated as a predictor of 5FU/LV benefitConclusions:RS is a validated,independent predicto
5、r of individualized recurrence risk for stage II colon cancer,Kerr etl.2009 ASCO Abstract No:4000,To investigate the incidence of MSI-H in stage II(n=395)and stage III(n=859)COC,its association with histopathological variables and its prognostic and predictive impact。Patients：PETACC 3-EORTC 40993-SA
6、KK 60/00 trial Results：MSI H was present in 22%(85)of Stage II and 12%(103)of Stage III colon cancer.Microsatellite instability is a strong prognostic factor for RFS and OS when considering Stage II and Stage III COC.Subgroup analysis suggests a stronger effect in Stage II than in Stage III.There is
7、 no evidence for an effect of the addition of IRI.,Tejpar etl.2009ASCO Abstract No:4001,Object:To compare the incidence of molecular markers in stage II(SII)and III(SIII)colon cancer and tested their prognostic value per stage 1564Patients：PETACC 3-EORTC 40993-SAKK 60/00 trial P53,SMAD4,thymidylate
8、synthetase(TS)and hTERT,mutations of KRAS and BRAF,microsatellite instability(MSI)and 18qLOH Results Conclusions:Molecular markers in colon cancer have a stage specific prognostic value.The possibility that the stages represent different diseases,rather than sequential steps in the evolution of a si
9、ngle disease,needs to be considered.,Tejpar etl.2009ASCO Abstract No:4002,This prospective study investigated the role of 18qLOH among patients with low-risk stage II colon cancer.1738 stage II patients In Cancer and Leukemia Group B(CALGB)protocol 9581 chemotherapy-naiveResults:A significantly lowe
10、r proportion of patients with 18qLOH-positive tumors had proximal tumors(46.5%vs 65.5%;p=0.02).Significantly decreased DFS and OS were observed in patients with 18qLOH-positive tumors.Five-year DFS among patients with 18qLOH-positive tumors was 0.78 vs 0.93 among patients with 18qLOH-negative tumors
11、 HR 0.39;95%CI(0.16,0.94);logrank p=0.03 based on 33 events.Five-year OS among patients with 18qLOH-positive tumors was 0.85 vs 0.98 among patients with 18qLOH-negative tumors HR 0.25;95%CI(0.07,0.83);logrank p=0.01.Conclusions:LOH at 18q was prognostic for DFS and OS among patients with low risk st
12、age II colon cancer.,Bertagnolli et al.2009ASCO Abstract No:4012,大型研究结果,Results of NSABP Protocol C-08 Impact of older age on the efficacy of newer adjuvant therapies：Findings from the ACCENT Database.Final results of the AGITG MAX trial A quality-of-life(QoL)analysis of the CRYSTAL trial.Interim sa
13、fety analysis of DREAM study.,A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon:Results of NSABP Protocol C-08.Results:Conclusions:The addition of bevacizumab to mFF6 did not result in an overall statistically significant prolongation in DFS.
14、,Tejpar etl.2009ASCO Abstract LBA4,Impact of older age on the efficacy of newer adjuvant therapies in 12,500 patients(pts)with stage II/III colon cancer:Findings from the ACCENT Database.Background:to determine the impact of pts age 70 do not receive the same benefit from combination and/or oral FU
15、as those 70.Any benefit,if present,compared to IV FU/LV would not be clinically meaningful.,Tejpar etl.2009ASCO Abstract LBA4,International randomized phase III study of capecitabine(Cap),bevacizumab(Bev),and mitomycin C(MMC)in first-line metastatic colorectal cancer(mCRC):Final results of the AGITG
16、 MAX trial.patients:either unfit for or who do not require initial oxaliplatin/irinotecan.Methods:arm A Cap(Cap 2000mg/m2/d or 2500mg/m2 d1-14 q21d),arm B Cap Bev(Bev 7.5mg/kg q3w)arm C Cap Bev MMC(MMC 7mg/m2 q6w).ResultsConclusions:The addition of BevMMC to Cap significantly improved PFS without si
17、gnificant additional toxicity.OS was similar for all arms.Cap BevMMC is an active,low toxicity regimen that may be considered as a treatment option for pts with mCRC.,Tebbutt etl.2009ASCO Abstract 4023,In phase III CRYSTAL trial，QoL was a secondary endpoint Methods:EORTC QLQ-C30(v3.0)questionnaire R
18、esults：In pts with mCRC,cetuximab plus FOLFIRI first-line significantly prolongs PFS compared with FOLFIRI alone while preserving QoL.The PFS benefit is even more pronounced for pts with KRAS wt tumors.,Folprecht etl.2009ASCO Abstract 4076,mFOLFOX-bevacizumab or XELOX-bevacizumab then bevacizumab(B)
19、alone or with erlotinib(E)in first-line treatment of patients with metastatic colorectal cancer(mCRC):Interim safety analysis of DREAM study.Results:induction with mFOLFOX-B or XELOX-B as well as maintenance with B or B+E appears to be well-tolerated,without unexpected side effects,Tournigand etl.20
20、09ASCO Abstract 4077,Ceteximab疗效的预测,EGFR ligand:amphiregulin epiregulin insulin-like growth factor 1(IGF-1)BRAF-1皮疹EGFR polymorphisms,Background:Gene expression of the EGFR ligand epiregulin(EREG)may further predict benefit from cetuximab Methods:CRC tumour samples were analyzed from a phase III cli
21、nical trial of cetuximab plus BSC vs BSC alone(NEJM 2007;357(20)Results:In the K-ras WT subset,OS was better for cetuximab than BSC among patients with high EREG(HR 0.43;p0.0001)but not for low EREG patients(HR 0.77,p=0.28).High EREG AND K-ras WT status(Combimarker)was present in 139(36%).Within the
22、 Combimarker positive group the median PFS was 5.4 vs 1.9 months(HR,0.31;p0.0001),and median OS 9.8 vs 5.1 months(HR,0.43;p0.001)in the cetuximab vs BSC arms Conclusions:patients with both high EREG gene expression and K-ras wild-type status may benefit from cetuximab therapy.Determination of EREG g
23、ene expression levels should be prospectively evaluated in patient selection for EGFR targeted therapy.,Jonker et al.2009ASCO Abstract 4016,Background:70%to 40%of patients with K-RAS wild type does not seem to benefit from Cetuximab.Colorectal cancer cells with IGF-1 system activation may escape ant
24、i-EGFR mediated cell death Methods:IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab Results:IGF-1 was overexpressed in 41 cases(66%).IGF-1 negative IGF-1 positive progressive disease 6(29%)26(63%)Median TTP 7.7 months 2.3
25、 months Among K-RAS wild type patients,IGF-1 negative and positive tumors showed a partial response to cetuximab-irinotecan in 7(50%)and 1(5%)cases respectively(p=0.004).Median TTP in IGF-1 negative tumors was 11 months and 3.2 months in IGF-1 positive colorectal cancers(p=0.03).Conclusions:IGF-1 pr
26、oved to be a reliable predictive factor for resistance to anti-EGFR monoclonal antibodies in K-RAS wild type colorectal cancer,Scartozzi et al.2009ASCO Abstract 4017,Background:To study the power of epiregulin(EREG)and amphiregulin(AREG)expression in primary tumors to predict the outcome in patients
27、 with chemorefractory metastatic colorectal cancer(cmCRC)treated with the combination of cetuximab plus irinotecan.Methods:amphiregulin and epiregulin mRNA expression Results:In KRAS wild-type(WT)patients,there was a significant association between log-transformed ligand expression and response In a
28、 Cox-regression model log-transformed ligand expression was significantly associated to progression-free survival(PFS)and overall survival(OS)There was no predictive power of ligand expression in KRAS mutant patients.Conclusions:Expression of EGFR ligands in primary tumors significantly predicts fav
29、orable outcome in KRAS WT mCRC treated with cetuximab and irinotecan,Prenen et al.2009ASCO Abstract 4019,Abstract 4021 retrospectively assessed KRAS mutational status and Amphiregulin expression by immunohistochemistry(IHC)in 86 irinotecan-refractory EGFR-positive mCRC patients treated with cetuxima
30、b plus irinotecan,Results:AR-low patients reported a significantly worse RR(2/22,9%)compared with AR-high(10/27,37%)(p=0.024)and a trend toward shorter PFS(3.5 vs 5.3 months,HR 0.88 95%CI:0.46-1.60,p=0.628)and OS(8.8 vs 15.1 months,HR 0.60 95%CI:0.30-1.10,p=0.106).Conclusions:Absent or low AR expres
31、sion at IHC may be related to resistance to cetuximab plus irinotecan.,Loupakis et al.2009ASCO Abstract 4021,Background:re-assessing the impact of KRAS status and other possible predictive factors for OS Results:OS in pts with KRAS wt tumors was significantly improved compared to pts with KRAS mt tu
32、mors(median 20.8 vs 15.9 mo;hazard ratio(HR)=1.62;p=0.0296).Cox proportional hazard analysis showed that as well as KRAS wt status(vs KRAS mt),an acne-like rash of grade 2/3(vs grade 0/1)in the first 6 weeks and no prior treatment(vs prior neo-/adjuvant treatment)were the strongest independent predi
33、ctors for prolonged survival(each p0.005).,Koza et al.2009ASCO Abstract 4055,Abstract 4058：In KRAS wild-type patients,BRAF mutations are confirmed to predict resistance to cetuximab treatment Abstract 4060：EGFR SNP is not a predictive marker of efficacy to EGFR-inhibitors.Our study suggest that pts
34、with WT KRAS and 1xULN levels of LDH,have major benefit to anti-EGFR therapy in second-third line therapy.Abstract 4063：Co-expression of pIGF-1R and MMP7 is associated with resistance to anti-EGFR therapy in WTRAS pts.,结肠癌辅助化疗观测终点Abstract 4011,Object(1)2yr DFS predicts 5yr OS?(2)a stronger relations
35、hip between DFS and OS in stage III pts?(3)6 or 7 yrs are necessary to demonstrate DFS and OS?association in future trials due to extended survival following recurrence 12,676 patients from MOSAIC,X-ACT,PETACC-3,NSAPB C-06 and C-07,and C89803Methods:Concordance between 2 and 3yr DFS,and 5 and 6yr OS
36、 was examined in 6 randomized phase III trials from 1997-2002.Results Conclusions:In recent trials in stage III pts,DFS HRs based on 2yr median f-up are highly predictive of 5 and 6yr OS HRs.In all pts the association between DFS and OS HRs is stronger for 6yr OS,but 7yr follow-up may be required.Th
37、ese data support 3yr DFS as a primary endpoint for modern stage III trials,and indicate that 2yr DFS would also be an appropriate primary endpoint.,Sargent et al.2009ASCO Abstract 4011,Oxaliplatin相关,To define the sensitivity to oxaliplatin reintroduction CaMg on chronic and acute neurotoxicity assoc
38、iated with oxaliplatin Picoplatin,Background:To define the sensitivity to oxaliplatin reintroduction based on the oxaliplatin-free interval Patients:Stage IV pts entered in the OPTIMOX1 and 2 studies Results:Conclusions:A prolonged interval between two FOLFOX therapies or a prolonged PFS at first-li
39、ne FOLFOX predict the efficacy of oxaliplatin reintroduction.,de Gramont et al.2009ASCO Abstract 4024,Background:to investigate whether CaMg reduced acute and/or chronic,cumulative sNT.Methods:104 patients FOLFOX+CaMg VS FOLFOX+placebo Results:acute sNT:no difference(sensitivity to cold,swallowing o
40、f cold liquids,throat discomfort)cumulative sNT:significantly reduce numbness in fingers(p=0.02),impaired ability to button shirts(p=0.05),tingling in fingers(p=0.06),and muscle cramps over the course of therapy(p=0.01).,Grothey et al.2009ASCO Abstract 4025,Background:Picoplatin(Pico)was designed to
41、 overcome platinum resistance and has the potential for improved safety The incidence of grade(G)3-4 neurotoxicity with single-agent Pico across studies was 2%Methods:Pico Q4W(150 mg/m2)with Q2W FU and LV(FOLPI)vs.modified(m)FOLFOX-6(FOLFOX)as 1st line treatment for patients(pts)with advanced CRC Re
42、sults:Neurotoxicity was observed in 65%of pts on FOLFOX(10%G 3/4)and 28%of pts on FOLPI(no G 3/4).Most frequent G 3/4 AEs on FOLPI were neutropenia(60%),thrombocytopenia(40%)and anemia(14%).In the FOLFOX arm,other than neuropathy,the most frequent G 3/4 AEs were neutropenia(20%)and thrombocytopenia(
43、12%).Disease control(CR+PR+SD)was 76%for FOLPI and 76%for FOLFOX.In the FOLPI arm there were 1 CR(2%)and 11 PR(22%).In the FOLFOX arm there were no CRs and 13 PR(26%).Conclusions:FOLPI with Pico Q4W shows comparable disease control with less frequent Neurotoxicity.,Earhart et al.2009ASCO Abstract 40
44、26,synchronous stage IV colorectal cancer,是否需要切除原发灶？是否需要修改CRC分期标准？,Background:In the absence of symptoms(bleeding,perforation,obstruction)or resectable metastatic disease,primary tumor resection in patients who present with synchronous metastatic colorectal cancer(CRC)is of uncertain benefit.Methods
45、：prospective 233patients initial treatment：oxaliplatin-or irinotecan-based,triple-drug chemotherapy(FOLFOX,IFL,or FOLFIRI)with or without bevacizumab。Results：217(93%)never required surgical palliation of their primary tumor.16(7%)required emergent surgery for primary tumor obstruction or perforation
46、 10(4%)required nonoperative intervention(stent or radiotherapy 213(89%)never required any direct symptomatic management for their intact primary Conclusions:Most patients with synchronous stage IV CRC who receive up-front modern combination chemotherapy never require palliative surgery for their in
47、tact primary.These data support the use of chemotherapy,without routine prophylactic resection neither obstructed nor hemorrhaging,Background:AJCC V.6(2002)places patients with inoperable hepatic MCRC can be made operable with curative intent with chemotherapy yet remaining in Stage 4.Results：1998-2
48、001 68,307 individuals 5-year survival of patients who underwent HPX was 41.6%better than that for both Stage 3(38.6%(95%CI 37.9%-39.2%,P0.01)and 4(6.1%95%CI 5.3-6.9%,P0.01)overall.Conclusions:5-year survival following HPX for MCRC is better than that seen overall for all Stage 3 patie.Our data supp
49、ort the hypothesis that all MCRC that is potentially resectable with curative intent should be stratified within Stage 3,and Stage 4 should only contain those MCRC patients for whom surgery is not an option.,Morris et al.2009ASCO Abstract 4099,化疗方案和策略的调整,Abstract No4078：Phase III study of standard t
50、riweekly versus dose-dense biweekly capecitabine(C)+oxaliplatin(O)+bevacizumab(B)as first-line treatment for metastatic colorectal cancer(mCRC):XELOX-A-DVS(dense versus standard):Interim analysis.Abstract No4125：Poker schedule of weekly alternating 5-fluorouracil,irinotecan,bevacizumab,and oxaliplat
