Metastatic Colon CA Flashcards

Question

What are the options for patients with symptomatic primary in CLR CA?

Answer 1

``` Surgical: - primary resection - Defunctioning stoma Non-surgical: - stents - RT ```

Answer 2

Chemo if fit. Simmonds BJC 2000, colorectal cancer collaborative group. Meta-analysis 7 trials, 850 pts Results: 35% reduction in risk of death Absolute improvement in survival of 16%, median survival of 3.7m

Answer 3

In asymptomatic patients, one study for earlier, one study negative. ``` 1) Positive study: JCO 1992, Nordic group N=180 2 groups: - MTX/5FU/LV early - MTX/5FU/LV only when symptomatic ``` Results: - earlier treatment a/w improved OS 14m vs 9m - earlier treatment a/w improved med PFS (8vs 3m) and symptom-free interval (10vs 2m) 2) Negative trial: BJC 2005 Australasian group - Meta-analysis 2 RCTs n= 170 - early vs late 5FU - suspended early due to low accrual - results did not show difference in median survival, PFS nor QoL CAVEAT: old chemo regimens

Answer 4

Raltitrexed Lancet 2002 Pure Thymidylate synthetase inhibitor Raltitrexed vs deGramont vs Lokich regimen Real tittered has increased treatment-related deaths due to combined GI and haem toxicities. also has inferior QoL

Answer 5

Leucovorin (20) Bolus FU (425) Bolus D1-5 Q28days

Answer 6

Saltz NEJM 2000 IFL better PFS 7m vs 4m OS 15m vs 13m ORR 40% vs 20%

Answer 7

Doulliard Lancet 2000 FOLFIRI>5FU as 1st line Results: RR 40% vs 20% (5FU) TTP 7m vs 4m OS 17m vs 14m

Answer 8

1) Tegafur 2) Gimeracil (5-Chloro-2,4 dihydropyridine) - inhibits DPD activity 3) Oteracil DPD = Dihydropyrimidine Dehydrogenase

Answer 9

UFT = UFUR = Tegafur-uracil UFT is a 1st generation DPD inhibitory Fluoropyrimidine drug UFT is an oral agent = Uracil + Tegafur in 4:1 ratio Uracil = Competitive inhibitor of DPD excess uracil competes with 5FU for DPD, thereby inhibiting 5FU Catabolism. Tegafur is hence taken up by cancer cells and breaks Down into 5FU that kills cancer cells Uracil causes more 5FU to stay inside the cells and kill them

Answer 10

2nd line Met CLR CA, failed FU N=250 2 groups: - Irinotecan (300-350) q3weeks - infusion all 5 FU Results: 1y Survival 30% vs 45%(Irinotecan) OS 11m vs 8.5m (Irinotecan) PFS 4m vs 3m

Answer 11

FA (500) as 2-Hr infusion + CI-5FU (2.6g) over 24hours weekly x 6 weeks, then 2 week rest Q8weeks

Answer 12

1) Acute - cold-triggered sensory neuropathy that is temporary and rapidly reversible - no structural nerve damage 2) Chronic - dose-related, dose-limiting s/e No neuroprotective effect of IV Ca/Mg

Answer 13

Goldberg JCO 2004 ``` Met CLR CA, tx-naive N=800 3 groups: 1) IFL (control arm) 2) IROX 3) FOLFOX ``` Results: TTP: 6.9m vs 6.5m vs 8.7m RR 30% vs 35% vs 45% Med survival 15m vs 17m vs 19.5m FOLFOX with lower rates of severe n/v, diarrhea, FN, diarrhea CONCLUSION = FOLFOX emerged as new standard 1st-line therapy. Criticisms: - did not directly compare Ox and Irinotecan - compared 2 diff combination regimens with diff FU/Leu backbones - higher efficacy and better tolerability with infusion all FU/Leu may have contributed to differences in efficacy

Answer 14

``` A) 2005 JCO Colucci n=360 Tx-naive met CLR CA 2arms: - FOLFIRI - FOLFOX4 Results: - ORR 30%~ - TTP 7m~ - Duration of response 9-10m~ - OS 14m s 15m ``` ``` B) 2004 JCO Tournigand Met CLR CA treatment-naive, n=200 2arms: - FOLFIRI--> FOLFOX6 - FOLFOX6-->FOLFIRI Results: - Med survival 22m vs 21m - PFS 14m vs 11m - RR 56% vs 54% - Med PFS (1st line) 8.5m vs 8m - RR (2nd line) 15% vs 4% - med PFS (2nd line) 2.4m vs 2.5m --> If you use FOLFIRI as 2nd line after FOLFOX6, the 2nd PFS & RR is shorter, but OS similar. ```

Answer 15

Oxaliplatin (85) D1 + LV5FU2 regimen. LV5FU2 = Leucovorin (100) over 2 hours, Bolus FU (400), CI5FU (600) over 22hours D1-2

Answer 16

Irinotecan (180) D1 + LV5FU2 regimen LV5FU2: Leucovorin (100) over 2 hours D1 FU (400) Bolus FU (600) CI over 22 hours

Answer 17

2-hour infusion of Leucovorin FU Bolus (400) 46hr CI5FU (2400-3000) Oxaliplatin (100) Q2weeks

Answer 18

5FU Leucovorin Irinotecan Oxaliplatin High activity, increased toxicity Reserved for specific situations eg. Substantial tumor shrinkage Falcone JCO 2007 ``` N=250 treatment-naive Unresectable met CLR CA 2 groups: - FOLFOXIRI - FOLFIRI ``` ``` Results: CR 8% vs 6% PR 60% vs 40% ORR 70% vs 50% R0 resection rate 15% vs 6% MPFS 10m vs 7m MOS 23m vs 17m ``` Tox: G2/3neurotox 20% vs 0% G3/4 neutropenia 50% vs 30%

Answer 19

``` Hypertension Bleeding GI Perforations (1-2%) Arterial thrombotic events (4-5%) ?Venous thrombotic events ```

Answer 20

Yes AVEX trial Cunningham Lancet Onco 2013 N=300 Elderly pts, >70yo Treatment-naive, Unresectable, met CLR CA Deemed not candidates for Ox-based or Irinotecan-based chemo 2 groups: A) Cape (1000) BD D1-14 B) Cape (1000) BD D1-14 + Bev (7.5mg/kg) D1 Q21 days Results: - PFS 9m vs 5m (cape alone) - ARE 40% vs 20% - med OS 21m vs 17m (Cape alone) * study underpowered to demonstrate stat significant improvement in OS

Answer 21

Yes, negative and in fact harmful. ``` A) JCO 2009 Hecht et al 1st line tx, met CRC 2 arms: - Panitumumab + Bev + Chemo - Bev + Chemo Chemo = Ox- and Irinotecan-based Results: - med PFS 10m (Pani) vs 11m - med survival 19m vs 24.5m - G3/4 adverse events 36% vs 1% (no pani) ``` ``` B) NEJM 2009 Tol et al Treatment-naive, met CLR Ca N=750 2 arms: - Cape + Ox + Bev - Cape + Ox + Bev + Cetuximab Results: - med PFS 11m s 9m (Cetuximab) - QoL scores lower in CBC group - OS and RR ~ - those with KRAS mutation + Cetuximab had decreased PFS ```

Answer 22

``` Acne-like rash, predominantly on face, upper tors Asthenia Fatigue Malaise Lethargy ```

Answer 23

Yes. Saltz et al. JCO 2004 Phase II Aim: to evaluate the anti-tumor activity and toxicity of single-agent Cetuximab in chemo-refractory CLR cancer whose tumor express EGFR S/p Irinotecan (either alone or in combination), with demonstrated clinical failure N=60 Cetuximab weekly - 1st dose 400 mg/m2 over 2 hours - subsequent weekly tx at 250mg/m2 over 1 hour Results: 10% with PR (5 patients) 21 patients with SD/minor responses Median survival 6months

Answer 24

Yes NEJM 2004 Cunningham N=300 Met CLR CA Refractory to tx with Irinotecan 2 arms: A) Cetuximab + Irinotecan B) Cetuximab If PD, addition of Irinotecan to Cetuximab mono therapy was permitted. Results: RR 20% vs 10% (monotherapy) TTP 4m vs 1.5m (monotherapy) Median survival 9m vs 7m - Trend

Answer 25

JCO 2007 Van Cutsem ``` Met CLR CA PD after std tx N=450 1% or more EGFR staining Measurable dz Radiologic PD during or within 6m of most recent chemo ``` 2 arms: - Panitumumab + BSC >> Panitumumab 6mg/kg Q2w - BSC RESULTS: PFS 8w vs 7w (BSC) ORR 10% vs 0% OS~ (likely contributed by cross-over)

Answer 26

Jonker NEJM 2007 N=575 CLR CA EGFR+ S/p Fluoropyrimidine, Irinotecan, Oxaliplatin OR had contraindications to tx with these drugs 2 groups: A) Cetuximab (400) 1st dose; 250mg/m2+BSC 2nd dose onwards weekly B) BSC alone RESULTS: OS HR 0.77, in favor of Cetuximab PFS HR 0.7 in favor of Cetuximab Med OS 6m (Cetuximab) vs 4.5m (BSC alone)

Answer 27

IgG1 chimeric monoclonal Antibody against Epidermal growth factor receptor

Answer 28

ASPECCT trial Price et al, Lancet Onco 2014 N=1000 ``` Chemo refractory wt KRAS exon2 Met CLR CA 2 arms: A) Panitumumab 6mg/kg Q2weeks B) Cetuximab 400 mg /m2 --> 240mg/me Qweekly ``` Results: OS ~ 10.4m (Pani) vs 10m

Answer 29

KRAS is a homolog of the transforming gene Kirsten rat sarcoma-2 virus Pts with advanced CLR CA must have wt KRAS for EGFR Ab to be effective KRAS is a phosphorylated signal transducer that self-inactivates via intrinsic GTPase activity Several KRAS oncogene mutations result in the production of proteins with reduced GTPase activity and hence unable to self-inactivate. In CLR Ca, mainly in exon 2, codons 12 and 13.

Answer 30

JCO 2010 Doulliard et al PRIME: Panitumumab Randomized trial In combination with chemotherapy for Metastatic Colorectal cancer to determine Efficacy Treatment naive Met CLC CA N=1200 2 arms: A) Panitumumab + FOLFOX4 B) FOLFOX4 Results: Non-significant increase in OS 24m vs 20m (FOLFOX4) PFS 9.6m vs 8m IF mutant KRAS: - PFS reduced significantly in Pani-folfox4 arm HR 1.29 - med OS 15.5m vs 19m

Answer 31

Lancet Oncol 2014 Heinemann Aim: compare Cetuximab + FOLFIRI vs Bev+ FOLFIRI N=600 KRAS Exon2 wt Metastatic treatment naive 2 arms: A) FOLFIRI + Cetuximab B) FOLFIRI + Bevacizumab Results: Objective response ~ 62% (Cetuximab) 58% (Bev) Med PFS ~ 10m OS 29m (Cetuximab) vs 25m (Bev) HR 0.8 p significant ** Updated analysis accounted for additional mutations in KRAS Exon3 and NRAS. This demonstrated an even larger difference in OS of 33m (Cetuximab) vs 26m Toxcities: Hematotoxicities 20%~ Skin reactions 26% vs 2%(Bev) Diarrhea 10% ~

Answer 32

Yes Mutations of BRAF (5-10%) of patients with advanced CLR CA, are mutually exclusive with KRAS mutations

Answer 33

Patients with BRAF mutations in Adv CLR CA are mutually exclusive with KRAS mutations A/w very poor prognosis Median survival 12-14m Aggressive 1st line approach may at least partially counteract the poor prognosis Think if pt can take FOLFOXIRI+Bev

Answer 34

Fuchs et al JCO 2003 FU-refractory CLR CA N=300 ``` 2 arms: A) Weekly x4, off 2 week - 125m/2 B) Q3weekly - 350mg/m2 - 300mg/m2 in those 70 and older, ECOG 2, prior pelvic RT ``` ``` RESULTS: Med f/u 16m 1y OS similar 40-50% Med OS 10m Med TTP 3-4m QoL not statistically different ``` Toxicities: G3/4 diarrhea in 40% of weekly pts vs 20% in Q3w tx. Tx-related mortality in 5% of the weekly regimen vs 2% of those in Q3weekly

Answer 35

Camptothecin derivative Also known as CPT-11 Topoisomerase-I inhibitor Single agent activity in adv CLR CA and other solid tumors ~10%-15%, median survival ~8m Active metabolite = SN-38 SN-38 binds to and stabilizes the Top-I DNA complex, preventing the re-ligation of DNA during replication and transcription. Subsequent collision between this stable complex and an advancing replication fork results in dsDNA breaks and apoptosis

Answer 36

Yes. Trifluridine-Tipiracil Mayer NEJM 2015 RECOURSE Study Tx-refractory with previous exposure to 5FU/Irinotecan/Oxaliplatin N=800 2arms: A) Trifluridine-Tipiracil - 35mg/m2 BD 5 days a week with 2 days rest X 2weeks --> 2 week rest B) Placebo Results: Med OS 5m vs 7m Med time to worsening PS 5.7m (TAS) vs 4m

Answer 37

Leucovorin

Answer 38

Folinic Acid

Answer 39

FU has been combined with Folinic Acid to enhance the capacity of FU to bind to thymidylate synthase.

Answer 40

Orally administered combination of: - Trifluridine - Tipiracil Hydrochloride Trifluridine = active cytotoxic component of TAS-102 - It is a thymidine-based nucleic acid analogue - Triphosphate forms gets incorporated into the DNA, resulting in anti-tumor effects. Tipiracil Hydrochloride = Thymidine phosphorylase inhibitor - Prevents the rapid degradation of Trifluridine - allows for maintenance of adequate plasma levels of the active drug.

Answer 41

RECOURSE Study by Mayer et al NEJM 2015 N=800 Known KRAS status Prior chemo with Fluoropyrimidine ,Oxaliplatin, Irinotecan, Bevacizumab, +/- Cetuximab/Panitumumab ``` RESULTS: Med OS 5m (Placebo) vs 7m (HR 0.7) Med time to worsening PS 4m (placebo) vs 6m Med PFS ~ 2m ORR 1.6% (TAS-102) vs 0.4% (Placebo) ```

Answer 42

JCO 2004 by Grothey 7 phase III trials in adv CRC Median OS is strongly correlated with exposure to all 3 active chemo drugs. Only exposure to all 3 drugs but not to initial doublet chemo was significantly a/w OS Pts who received doublet chemo as 1st line have higher chances of receiving all 3 active agents Use of combination protocols a/w sig improvement in med survival of 3.5months

Answer 43

Second only to colorectal cancer as a common cause of death among patients with FAP Heterogeneous presentation - asymptomatic abdominal mass to bowel obstruction or urethral obstruction Sporadic Desmoid tumors also occur Possible palliative options include: - Chemotherapy - Hormonal therapy - Targeted therapy such as imatinib

Answer 44

Multiple colon cancers | Multiple cutaneous neoplasia, including sebaceous adenomas

Answer 45

Chromosomal instability due to mutations in the APC tumor suppressor gene

Answer 46

MSI caused by mutations in the DNA MMR genes Most common hereditary syndrome predisposing to CLR CA Lifetime risk for developing colon cancer among patients with HNPCC approaches 80% Also a/w other malignancies: - endometrial - gastric - ampullary - biliary - urinary tract cancers

Answer 47

``` Colon cancers Endometrial cancers Gastric cancers Ampullary cancers Biliary cancers Urinary tract cancers ```

Answer 48

``` Demonstration of MSI-H phenotype + Germline mutation in any of the DNA MMR genes: - MLH1 on chr 3p - MSH2 on chr 2p - MSH6 on chr 2p - PMS1 on 2q - PMS2 on 7q ``` Germline mutations involving MSH2 and MLH1 genes account for >60% of the known mutations present in HNPCC NCCN recommends: 1) Tumor screening with MSI 2) Lack of expression of MMR protein expression by IHC 3) MMR mutation testing

Answer 49

>80% eliminated via the DPD enzyme DPD enzyme deficiencies are at high risk of 5FU toxicities

Answer 50

``` Severe neutropenia FN Diarrhea, mucositis Cerebellar ataxia, neurotoxicity Death ``` Most common mutation = IVS14 + 1G>A, DPYD*2A mutation

Answer 51

TSER *3/*3 genotype is a/w higher levels of thymidine synthase and Lower tumor response to 5FU therapy

Answer 52

``` AR disease MYH Gene, a base-excision repair Gene Deficiency in MYH leads to somatic mutations in APC Gene - not Germline Clinical features similar to FAP ```

Answer 53

``` AR disease MYH Gene, a base-excision repair Gene Deficiency in MYH leads to somatic mutations in APC Gene - not Germline Clinical features similar to FAP ```

Answer 54

KRAS mutation | BRAF V600E mutation

Answer 55

Matthew Seymour Lancet 2007 One of the trials that showed sequential chemotherapy was a viable option as cf to combination chemo in treatment naive met colorectal cancer ``` N=2000 Advanced CLR CA 3 arms: A = control group = CI FU/LV 48hr q2w --> Irinotecan B = FU --> Combination chemo C = Combination chemo ``` Combination chemo = FU/Iri or FU/Ox = B-ir and C-ir = B-Ox and C-ox Results: Median survival = 14m (A); B-ir 15m, B-Ox 15m, C-ir 17m C-Ox 15m

Answer 56

1) CAIRO-1 2) MRC-FOCUS 3) FFCD-2000-05

Answer 57

Ducreux Lancet Oncol 2011 Aim: to evaluate if combination Tx > Sequential Tx in adv CLR CA N=400 Advanced CLR CA Treatment-naive 2arms: A) Simplified LV5FU2 regimen --> FOLFOX6 --> FOLFIRI - Bolus 5FU (400) + CI 5FU(2400)+ Leucovorin (400) --> L5FU2+Ox (100) --> LV5FU2+Iri (180) B) FOLFOX6-->FOLFIRI Both Q2w RESULTS: Med PFS after 2lines 10.5m (Sequential) vs 10.3m (Comb) 6 deaths due to toxic effects of treatment occurred in combination go up Fewer G3/4 SE significantly in sequential groups for hematological and non-hematological. Conclusion --> Upfront Combination chemo more toxic and not more effective than sequential

Answer 58

FOLFOX, FOLFIRI largely comparable 1) JCO Colucci 2005 2) JCO Tournigand 2004

Answer 59

OPTIMOX-1 OPTIMOX-2 MRC COIN CAIRO3

Answer 60

Tournigand JCO 2006 Aim: To evaluate the efficacy of intermittent Oxaliplatin Tx as opposed to continuous Tx. N=600 + exploratory cohort of 100 elderly/poor prognosis 2arms: A) FOLFOX4 - Leucovorin + FU Bolus (400) + 22hr CI5FU (600) D1-2 - Ox (85) D1 - q2weeks B) 6 FOLFOX7 -->12# (s)LV5FU2 --> 6FOLFOX7 - FOLFOX7= 2hr Leucovorin + CI5FU (2400) 46hours + Ox (130) on D1 q2w - (s)LV5FU2 = Leucovoin/Bolus 5FU(400) + CI5FU(3000) over 46hr q2w ``` RESULTS: Med PFS 9m (A) vs 9m (B) Med OS 20m (A) vs 21m (B) RR ~60% G3 sensory neuropathy 18% (A) vs 13% (B) ``` Conclusion: Ox can be safely stopped after 6# in a FOLFOX regimen

Answer 61

Chibaudel JCO 2009 Aim: To compare chemo discontinuation vs maintenance therapy after 6#FOLFOX N=200 Met CLR CA Tx-naive 2arms: 1) Arm 1 = maintenance arm = 6mFOLFOX7 --> Leucovorin+Bolus & Infusional 5FU until PD -->mFOLFOX7 2) Arm 2 = CFI arm = 6#mFOLFOX7--> complete Stop --> reintroduction of mFOLFOX7 after tumor PD ``` RESULTS: Median duration of disease control (DDC) 13m v 9m (CFI) Med PFS 9m (maintenance) vs 7m (CFI) Med OS 24m (maintenance) vs 20m (CFI) ORR ~60% ```

Answer 62

Richard Adams Lancet Oncol 2011 Aim: assess if OS on intermittent Tx was non-inferior to that of continuous chemo N=1600 Txt naiive ``` 3 arms: A): Continuous Ox+5FU B): Continuous Tx + Cetuximab C): Intermittent chemotherapy - Chemo x12 weeks---> CFI until PD --> Chemo ``` RESULTS: Median survival ITT: 16m (A) vs 14m (C) Raised baseline platelet a/w poor survival with intermittent chemo G3/worse hematological Toxic effect 15% vs 12% N/V more common on intermittent therapy G3/worse peripheral neuropathy 30% vs 5% G3/worse HFS 4% vs 3% Conclusion: - did not show non-inferiority of intermittent tx - but remains a Tx option as it decreases time on chemo, reduced cumulative toxic effects and improved QoL.

Answer 63

Simkens Lancet 2015 Aim: to determine the efficacy of maintenance txt with Cape+Bev vs observation N=550 Previously untreated met CLR Ca with stable disease or better after induction treatment Induction Tx: 6#Cape/Ox/Bev q21days 2arms: A) Maintenance : Cape/Bev B) Observation group On 1st PD = PFS1, patients then receive CAPOX-B until 2nd PD = PFS2 RESULTS: - median f/u 4 years - PFS2 better with maintenance 12m vs 9m - Med OS 18m vs 22m (maintenance) - trend

Answer 64

Douillard et al Lancet 2000 Aim: To investigate the efficacy of Irinotecan+FU as first-line tx. N=400 Met CLR CA, treatment-naive 2 arms: A) Irinotecan + 5FU/Leu B) 5FU/Leu Results: RR 50% (Iri) vs 30% TTP 7m vs 4m OS 17m vs 14m

Answer 65

Fuchs et al JCO 2007. BICC-C study Aim: To compare 3 different Irinotecan-containing regimens in 1st line setting of previously untreated met CLR CA patients ``` N=400 3arms: A) FOLFIRI B) mIFL C) CapeIRI * initially a double-blind treatment with celecoxib/placebo ** Protocol amendment: >> add Bevacizumab >> CapeIRI arm discontinued, because of greater toxicity of CapeIRI + paucity of safety data for combination of CapeIRI+Bev. ``` RESULTS: Med PFS 8m (FOLFIRI) vs 6m (IFL) vs 6m (CapeIRI) Med OS 23m (FOFIRI) vs 18m (mIFL) vs 19m (CapeIRI) ORR ORR~ 47% (FOLFIRI) 43%(mIFL) 29% (CapeIRI)

Answer 66

Arkenau JCO 2008 Pooled analysis of 6 randomized phase II and III trials Aim: investigated role of Ox in combination with Capecitabine or Infusional FU in met CRC. Meta-analysis to compare the efficacy N=3500 RESULTS: Higher RR for FU-based regimens PFS and OS similar

Answer 67

Yes. HORG study by Souglakos in BJC 2006 N=280 2 arms: A) FOLFOXIRI B) FOLFIRI RESULTS: No difference in OS/TTP/RR But observed med OS of 21.5m is one of the best ever reported

Answer 68

FOLFOXIRI A) HORG study - Day 1: Irinotecan (150mg/m2 30min infusion) - Day 2: Oxaliplatin (65) as 2h infusion at same time as LV - Day 2+3: LV (200) +Bolus 5FU (400) +22h CI5FU (600) B) FALCONE - Day1: Irinotecan (165) over 1hour + Oxaliplatin (85) over 2 hours + LV (200) over 2 hours - Day 1-3: CI5FU (3200)

Answer 69

Recombinant chimeric IgG1 monoclonal Ab to EGFR Competitive inhibitor of EGFR Binds specifically to EGFR and with greater affinity than EGF or other Ligands (eg. TGF alpha) Possible IgG1 related ADCC anti-tumor effects shown in vitro

Answer 70

``` 1) Van Cutsem ASCO 2007 - CRYSTAL phase 3 study N=1200, previously treated EGFR+patients 2arms: - FOLFIRI + Cetuximab - FOLFIRI PFS 9m vs 8m 1yPFS 30% s 20% RR 50% vs 40% ``` 2)Tabenero JCO 2007 Phase 2 n=40 EGFR+ FOLFOX4 + Cetuximab RR 70%, PFS 12m, OS 30m 3) Venook ASCO 2006 CALGB Phase 3 - Tx-naive, regardless of EGFR - n=240 - 2 X 2 factorial: >> FOLFOX or FOLFIRI >> Cetuximab or no Cetuximab - RR 50% vs 30% 4) OPUS Study by Bokemeyer ASCO 2007 2008 - randomized phase 2 - n=340 EGFR+ - 2 arms: >> FOLFOX4 + Cetuximab >> FOLFOX4 - RR 46% vs 36% 5) Borner Ann Oncol 2008 - phase 2 randomized, n=74 previously untreated, EGFR+ - XELOX +/- Cetuximab - PR 40% vs 15% - SD 35% vs 60% - TTF 7m vs 6m - OS 21m vs 17m

Answer 71

1) JCO 2004 Saltz et al - phase 2, EGFR+ who failed Irinotecan n=60 - PR 9%, SD 36% OS 6m 2) EPIC study Sobrero JCO 2008 - Phase 3, s/p 5FU and Ox failure - n=1300 EGFR + - 2 arms: >> Cetuximab+ Irinotecan >> Irinotecan - OS 10.7m vs 10, - PFS 4m vs 2.m - CR 1.4% vs 0.2% - 47% on Irinotecan arm go on to receive Cetuximab, this may explain lack of difference in OS 3) 2nd and 3rd Line Cunningham NEJM 2004 - s/p Irinotecan failure - n=330 (regardless of EGFR status) - 2 arms: >> Cetuximab+ Irinotecan >> Cetuximab alone - PR 23% s 11% ; SD 30% vs 20% - TTP 4m vs 1.5m - OS 9m vs 7m

Answer 72

1) Cunningham NEJM 2005 - Phase 3 - Cetuximab+Iri vs Cetuximab alone - previous Irinotecan failure N=330 - PR 23% vs 11% - SD 30% vs 20% - TTP 4m vs 1.5m - OS 9m vs 7m 2) Jonker NEJM 2007- NCIC CTG phase 3 - n= 580 EGFR + patients - prev tx with or contraindicated to 5FU, Irinotecan and Oxaliplatin - Randomised to: Cetuximab vs BSC - OS 6m vs 4.6m - PR 8% vs 0% 3) Lenz JCO 2006 - Phase 2 n=350 EGFR positive patients refractory to 5FU/Oxaliplatin and Irinotecan, - all patients received Cetuximab monotherapy - PR 12% - PFS 1.5m - OS 6.6m

Answer 73

Activating K-RAS mutations in exon 2 are found in 40-45% of met CLR Ca

Answer 74

1) resectable mets | 2) initially Unresectable disease rendered suitable for resection

Answer 75

Treatment is seen as a continuum of care. ``` Prolongation of survival Cure Improving tumor-elated symptoms Stopping tumor progression Maintaining QoL ```

Answer 76

1) Cytotoxic agents 2) Biological targeted agents - Anti-VEGF strategies - Anti-EGFR strategies - Multi-kinase inhibitors

Answer 77

Higher RR Longer PFS Better OS

Answer 78

Anti-VEGF A recombinant fusion protein Blocks: VEGF-A, VEGF-B, Placenta Growth factor Improves OS, PFS and RR when combined in 2nd line with FOLFIRI in Oxaliplatin-pretreated patients - regardless of whether Bev was given in first line Similar toxicity pattern as Bev: - mucosal bleeding, Arterial thrombosis, hypertension, intestinal peforation, proteinuria, wound healing problems - **unlike Bev, Aflibercept increases chemo-related side-effects such as diarrhea, neutropenia, Asthenia and stomatitis

Answer 79

Detection of mutations in: Exon3 of KRAS Gene Exon4 of KRAS Gene Exon2-4 of NRAS Gene In addition to KRAS Exon 2

Answer 80

Specific HFS Fatigue Transaminitis

Answer 81

1) Group 0 - primarily technically R0-resectable liver/lung mets + no biological relative contraindications - Upfront resection 2) Group 1 - Potentially resectable met disease with curative intention - Downsize disease by chemo - enable secondary surgery to allow disease-free status - -> most active induction chemo - Anti-EGFR Ab appear to be more effective in tumor shrinkage than Bev-based combinations 3) Group 2 - disseminated disease, technically "never"/unlikely resectable intermediate intensive treatment - Treatment intent is palliative largely - in those who are symptomatic/more aggressive biology/extensive disease, very active 1st-line Tx with high likelihood to induce mets regression in short time - -> Consider cytotoxic doublet + Targeted agent - In oligometastatic patients ablative methods should be additionally considered, as they may allow a progression-free interval even without systemic treatment. 4) Group 3 - Never-resectable metastatic disease - non-intensive/sequential treatment - Maximal shrinkage of mets is NOT the primary aim - Aim is prevention of tumor progression & prolongation of life with minimal treatment burden - -> Combination cytotoxic+/- biological targeted agent OR escalation strategy may start with FP+ Bev

Answer 82

1) Post-op adjuvant chemo with FOLFOX for 6 months 2) Peri-op chemo - 3 months before and 3 months after resection of mets

Answer 83

Oxaliplatin = sinusoidal liver lesions | Irinotecan - steatohepatitis

Answer 84

(Histology, Invasion, Perforation, Margins, Obstruction, LN) poorly differentiated Histology lymphatic / vascular / perineural Invasion localized Perforation Margins - close/indeterminate/positive bowel Obstruction

Answer 85

No consensus as to the definition but: | 1) Tumor

Answer 86

Placement of a hepatic arterial port or implantable pump during surgery for liver resection with subsequent infusion of chemo directed to the liver mets through the hepatic artery.

Answer 87

Aim: To assess efficacy and safety of adding SIRT to standard FOLFOX-based chemo in treatment-naive patients Treatment-naive, liver mets +/- limited extra hepatic mets. 2x2 factorial design: - mFOLFOX6 + SIRT +/- Bev - mFOLFOX6 - SIRT RESULTS: - PFS (any site): no difference ~10-11m - PFS (Liver): 13m vs 21m (in favor of FOLFOX+Bev+SIRT) - ORR (any site): trend: 67% vs 72% - ORR (Liver) 70% vs 80%

Answer 88

Gastric/duodenal ulcer (4%) Ascites (3%) Hepatic failure (1%) aviation hepatitis (1%)

Answer 89

Selective Internal Radiation Therapy Employs Yttrium-90 (Y-90) labeled resin microspheres as liver-directed therapy. Hepatic artery injection Delivers a single large radiation dose to liver tumors with radiation deposited over 3 weeks FDA approved in 2002 for Unresectable CRCLMs

Answer 90

1) Hepatic Arterial Infusion 2) Arterially Directed Embolic Therapy - TACE 3) Liver-Directed Radiation - Radioembolization 4) Tumor Ablation - RFA - Microwave ablation - Cryoablation - Percutaneous ethanol injection - Electro-coagulation

Answer 91

Pre operative portal vein embolization of the involved liver can be performed to expand the future live remnant

Answer 92

Earlier treatment of micro mets disease Determination of responsiveness to chemotherapy (which can be prognostic, and help in planning postop therapy) Avoidance of local therapy for those with early PD

Answer 93

Missing "window of opportunity" for resection due to PD Achieve tent of CR, making it difficult to identify areas for resection Potential for development of liver steatohepatitis/sinusoidal injury

Answer 94

Crigler-Najjar Types I and II | Gilbert Syndrome

Answer 95

Yes. TRIBE trial Phase III Unresectable met CLR CA FOLFOXIRI/Bev vs FOLFIRI/Bev RESULTS: FOLFOXIRI/Bev significantly increase PFS 12m vs 10m HR 0.75 RR 65% vs 50% Updated analysis : Median OS 30m vs 26m Subgroup analysis: 60% had adjuvant Oxaliplatin. In this group, no benefit to addition of Ox

Answer 96

Recombinant protein that has part of the human VEGF Receptors 1 and 2 fused to the Fc portion of human IgG1 Designed to function as a VEGF trap to prevent activation of VEGF receptors and thus inhibit angiogenesis

Answer 97

Tested 2nd-line Ziv-Alfibercept in met CLR CA who had PD after one Ox-containing regimen 2 arms: - FOLFIRI-ziv-Aflibercept - FOLFIRI/placebo Results: OS 13.5m vs 12m

Answer 98

Anti-angiogenic agent | Human monoclonal antibody that targets the extracellularly domain of VEGFR-2 --> Blocking VEGF signaling.

Answer 99

RAISE Study Phase III=1000 Met CLR CA PD on 1st-line Tx: FU/Ox/Bev Randomized to: - FOLFIRI+Ramucirumab - FOLFIRI+Placebo Results: - OS: 13m vs 12m HR 0.8 - PFS 6m vs 4.5m HR 0.8

Answer 100

``` VEGFR Fibroblast growth factor receptors (FGF) PDGFR BRAF KIT RET ```

Answer 101

1) CORRECT - n= 760, phase III - PD on standard therapy - 2 arms: Placebo or Regorafenib - OS 6.4m vs 5m HR 0.8 - PFS 1.9m vs 1.7m 2) CONCUR trial - China/HK/S.Korea/Taiwan/Vietnam - progressive met CLR Ca, PD after 2 or more lines - Regorafenib vs placebo - OS 9m vs 6m HR 0.55

Answer 102

Pembrolizumab is a humanized, IgG4 monoclonal Ab Binds to PD-1 with high affinity This prevents PD-1 from interacting with PD-L1 and PD-L2, allowing immune recognition and response

Answer 103

Fuchs et al JCO 2007 N=400 Treatment-naive ``` 3 arms: 1) FOLFIRI 2) mIFL 3) CapeIRI Protocol amendment : additional 100 pts added and randomized to FOLFIRI+ Bev vs mIFL+Bev, CapeIRI stopped ``` RESULTS: med PFS 7.5m FOLFIRI, 6m mIFL, 6m CapeIRI Med OS 23m FOLFIRI, 17.5m mIFL, 19m CapeIRI CapeIRI a/w higher rates of vomiting/diarrhea/dehydration After amendment, med survival time for FOLFIRI+Bev not reached, but 19m for mIFL+Bev Conclusion: - FOLFIRI and FOLFIRI+Bev offered superior activity to comparators, and were safe - Infusional schedule of 5FU should be the preferred Irinotecan-based regimen in first-line met CLR CA

Answer 104

Yes Hurwitz NEJM 2004 Untreated met CLR CA, n=800 2 arms: - IFL + Placebo - IFL + Bev RESULTS: - med OS 20m vs 15.5m (Placebo) - med PFS 10.5m vs 6m - RR 45% vs 35%

Answer 105

``` 1) Hecht et al JCO 2008 2 arms, n=1000: - Chemo/Bev/Pani - Chemo/Bev RESULTS: - Med PFS 10m vs 11.5m(control) - Med survival 19.5m vs 24.5m - Increased toxicity in Panitumumab of Irinotecan cohort. ``` ``` 20 NEJM 2009 Tol et al N=750 2 arms: - Chemo/Bev/Cetuximab - Chemo/Bev RESULTS: - med PFS 11m (CB) vs 9m (CBC) - QoL lower in CBC group, more G3/4 events ```

Answer 106

Presence of pre-existing serum IgE Ab to oligosaccharide, galactose-alpha-1,3-galactose

Answer 107

1) Cancer in the family tt fulfills the Amsterdam criteria - FAP excluded - 3 or more family members with CLR CA, at least 2 of whom must be 1st degree relatives. - At last 2 successive generations affected - Development of CLR Ca must occur before 50yo 2) CLR Ca or endometrial Ca Dx before 45 yo 3) R sided colon CA it's an undifferentiated pattern on histo evaluation, Dx 45 yo 4) Signet ring cell-type colorectal cancer Dx before 45 yo 5) Adenoma diagnosed before 40yo 6) Development of 2 HNPCC-related extracolonic cancers in one individual (I.e. Endometrial, small intestine, ovarian, gastric) 7) Development of CLR ca in an individual who has a first-deg relative with CLR ca and/or HNPCC-related extracolonic cancer and/or colorectal Adenoma. - Ca Dx before 45 yo and Adenoma before 40

Answer 108

Van Cutsem JCO 2011 (update) Original NEJM 2009 Aim: Invx efficacy of FOLFIRI+Cetuximab as 1st line treatment for mCLR CA - Also to check associations between KRAS mutation status and clinical response to Cetuximab. N=1200 2 arms: 1) FOLFIRI 2) FOLFIRI + Cetuximab RESULTS: (a) 2009: No Significant differences in OS btwn the 2 groups - HR for PFS among wtKRAS = 0.7 in favor of the Cetuximab group. - med OS in wtKRAS group 25m vs 21m - med OS in mtKRAS group 17.5 ad 17.7m (FOLFIRI) (b) Median OS 23.5m (Cetuximab) vs 20m PFS 10m vs 8.5m RR 57% vs 40% CONCLUSIONS: KRAS mutation status was confirmed as a powerful predictive bio marker for Cetuximab+FOLFIRI efficacy. BRAF tumor mutation was a strong indicator of poor prognosis The CRYSTAL study results are consistent with the updated data from the OPUS study which confirmed that: KRAS tumor mutation status as an effective bio marker for the efficacy of Cetuximab + Oxaliplatin/LV/CI 5FU in first-line TC of patients with KRAS wtype mCRC

Answer 109

JCO 2008, Bokemeyer Update Ann Onco 2011 N= 300 Met CLR Ca treatment-naive 2 arms: 1) FOLFOX4 + Cetuximab 2) FOLFOX4 ``` RESULTS: - ORR 46% vs 36% (FOLFOX4) - wtKRAS: ORR 60% vs 37% (FOLFOX4) - wtKRAS: lower risk of disease progression HR 0.57 - ITT population: OS not different. Median survival 18m~ - wtKRAS group: >> RR 60% vs 35% >> med PFS 8m vs 7m >> OS 23m vs 18.5m (trend) - mtKRAS group: >> RR 35% vs 55%(FOLFOX) >> Med PFS 5.5 vs 8.5m >> Med OS 17.5m vs 13.5m - Comparing wt vs mt + received Cetuximab >> OS 23m vs 13.5m - Comparing wt vs mt + NO Cetuximab: >> OS 18.5m vs 17.5m ```

Answer 110

Alberto Sobrero JCO 2008 N=1300 Met CLR CA Previously s/p Fluoropyrimidine+Oxaliplatin 2arms: 1) Cetuximab + Irinotecan 2) Irinotecan (350 mg/m2 Q3w) ``` RESULTS: - Med OS comparable 10.7m vs 10m (Iri) >> 45% of those assigned to Irinotecan alone eventually received Cetuximab - Med PFS 4m vs 2.5m - RR 16.5% vs 4% - improve QoL ```

Answer 111

Douillard et al JCO 2010 Aim: To evaluate efficacy and safety of Panitumumab + FOLFIRI in First line setting for met CLR CA. - Panitumumab already approved as monotherapy for chemo-refractory met CLR CA N=1200 2 arms: 1) Panitumumab + FOLFOX4 2) FOLFOX4 ``` RESULTS: (A) wt KRAS: - improved PFS 9.6m vs 8m HR 0.8 - OS 24m vs 20m (Trend) (B) mt KRAS: - med OS 15.5m vs 19m (no Pani) ```

Answer 112

Primrose Lancet Oncology 2014 B/g: Surgery for liver met result in OS of 40% at 5 years. Aim: To assess benefit of adding Cetuximab to standard chemotherapy in those with resectable CLR liver met N=250 KRAS exon 2wt Resectable or sub optimally resectable CLR Liver met 2 arms: 1) Chemo 2) Chemo+ Cetuximab before and after liver liver resection Chemo: FOLFOX or XELOX or FOLFIRI (if adjuvant Ox given) RESULTS: PFS: 14m vs 20.5m(without Cetuximab)

Metastatic Colon CA Flashcards

(142 cards)