Flashcards in Metastatic Colon CA Deck (142):
What is the advantage of CI 5FU>Bolus 5FU?
- loading Bolus: stomatitis, myelosupprssion
- weekly plus: diarrhea
- continuous infusion: PPE
What is Irinotecan metabolized into?
Irinotecan --> SN38
SN38 - active compound
Metabolized by UGT1A1
If there is UGT1A1*28 polymorphism, there is increased risk of neutropenia
What is the evidence for Irinotecan >BSC?
Cunningham Lancet 1998
Irinotecan+BSC > BSC
Survival is better
What is the evidence for IFL 1st line?
1) Saltz et al NEJM 2000
A) q6weeks each given weekly for 4 weeks
- Irinotecan (125) IV over 90min
- Leucovorin (20) IV Bolus
- 5FU (500) Bolus
B) Daily X 5 days, Q4w
- Leucovorin (20) IV Bolus
- 5FU (425) IV Bolus
C) weekly X 4weeks Q6w
- Irinotecan alone (125) over 90min
IFL vs 5FU/LV
- PFS 7m vs 4m
- RR 40% vs 20%
- OS 15m vs 13m
2) Douillard Lancet 2000
- Irinotecan + 5FU + LV
- RR 35% vs. 20% (ITT arm)
- TTP 7m vs 4m
- OS 17m vs 14m
3) EORTC 40986, Kohne et al
- FA (500)/5FU (2.6g/m2 over 24h) weekly x6, Q8w = AIO arm
- Irinotecan (80) --> FA (500)/5FU (2.6g/m2/24h)
MPFS 8.5m vs 6.5m (AIO)
Med OS 17m to 20m (p not sig)
ORR 60% vs 30%
FOLFOX vs CAPOX
Arkenau et al JCO 2008, meta-analysis
N=3500, 6RCTs PH II and III
CAPOX vs FOLOFX
Lower RR with CAPOX, but similar PFS and OS
- lesser G3/4 HFS, thrombocytopenia, diarrhea
- less G3/4 neutropenia
What are the Fluorouracil regimens?
1) MAYO clinic regimen
- Q4w to Q5w
- 5FU (425) D1-5
- Leucovorin (20) D1-5
2) Roswell Park
- Q8weeks, 6 weeks on/2 weeks off
- Leucovcorin (500)
3) de Gramont --> French LV5FU2
- Leucovorin (200) over 2 hours --> Bolu 5FU(400) -->5FU (600) over 22 hours X 2 days
- De Gramont with Oxaliplatin added on ?
4) German AIO
- 5FU as protracted infusion for 24 hours
- FU (425) + Leu (20) D1-5 Q28days
- FU (2600) as 24 hour infusions +/- Leu (500) weekly x6
- 6 weeks on, 2 weeks off
Any evidence for Bev in 2nd line?
E3200 Giantonio JCO 2007
Single agent Bev activity is 3%, little/no activity as a single agent.
Addition of Bev to FOLFOX improves survival of those refractory to Irinotecan.
How about Bev beyond progression?
Tell me about ML18147
ML18147 Arnold ASCO 2012
Bev+ Standard 1st line chemo
1st line chemo = Ox- or Iri-based
Upon progression, randomized to 2 arms:
A) standard 2nd line chemo until PD
B) Bev (2.5mg/kg/week) + standard 2nd-line chemo
** CT switch upon PD: Ox--> Iri, Iri-->Ox)
- PFS in favor of Bev+CT: HR 0.7 5.7m vs 4m
- OS HR 0.8 11m vs 10m
What are the studies supporting Bev beyond progression?
Tell me about the GONO-BEBYP study:
1st line chemo +Bev
Chemo: FOLFIRI/FOLFOX/FOLFOXIR/Fluoropyrimidine mono-tx
Randomized to 2 arms:
A) Second-line CT
B) Second-line CT + Bev
2nd-line CT = FOLFIRI/mFOLFOX-6
- PFS 7m vs 5m (CT); HR 0.65
Tell me about the BRiTE study:
Axel Grothey JCO 2008
An observational study
After 1st PD, physician decision with no random assignment into 3 arms:
A) No post-PD treatment
B) PostPD Tx w/o Bev
C) PostPD Tx with Bev
BBP (Bev beyond PD) > No BBP> No Tx
~ 1 yr: 75% > 50% > 25%
Any evidence to back up using Bev in the elderly?
Pooled analysis by Cassidy ESMO 2008
NO16966: 1st line FOLFOX4/XELOX + Bev
AVF2108g: 1st line IFL + Bev
AVF2192g: 1st line FL +Bev
E4300: 2nd line FOLFOX4 = Bev
Bev provides consistent PFS benefit in those >65 and those 65, Bev provided a similar OS benefit to young and old
What are the 3 VEGF receptor functions?
- Migration, invasion, survival
Proliferation, survival, Permeability
What are the 3 general mechanisms of angiogenesis inhibitors ?
- Block VEGF expression
- Erlotinib, Cetuximab Panitumumab
- Neutralize VEGF
- Aflibercept, Bevacizumab
- Block VEGF Receptor (VEGFR-2)
- Anti-VEGFR-2 TKIs: Sunitinib, Sorafenib, Pazopanib
Tell me about the evidence for Aflibercept?
Aflibercept is a VEGF-TRAP, and works extracellularly to neutralize the activity of VEGF
Evidence for its usage comes from the VELOUR trial
Phase III study
Met CRC after failure of an Ox-based regimen. Randomized into 2 groups:
A) Aflibercept 4mg/kg + FOLFIRI Q2weeks
B) Placebo + FOLFIRI Q2 weeks
30% with prior Bev
OS: 12m vs 13.5m (with Alfibercept) HR 0.8
PFS: 4.7 m vs 7m HR 0.75
What about evidence for Regorafenib ?
CORRECT study by Grothey et al ASCO GI 2012
Met CRC after standard therapy, randomized into 2 groups:
A) Regorafenib 160mg OM 3w/1w +BSC
B) Placebo + BSC
OS = 6.5m vs 5m (Placebo) HR 0.8
PFS = 1.9m vs 1.7 (Placebo) HR 0.5
Any evidence for Cetuximab alone?
NCI-CO.17 study by Cunningham NEJM 2004 and Jonker NEJM 2007
Cetuximab showed single agent activity of 10% in BOND1
Improved OS (6.1m can 4.6m) when compared against BSC in pretreated met CRC (CO.17)
What is the EPIC study?
Cetuximab/Irinotecan vs Irinotecan
Sobrero JCO 2008
Failed 1st line FU/OX
Improved RR and PFS
How about Cetuximab in 1st line ?
CRYSTAL study by Van Cutsem NEJM 2009
Untreated met CRC n=1200
- Improved RR and PFS
>> RR 50% vs 40%
>> PFS 9m vs 8m
- In wt-KRAS patients:
>> RR 60% vs 40%
>> PFS 10m vs 9m
- In those undergoing surgery with curative intent, more had successful resection
>> mPFS 7.4 vs 7.7 (FOLFIRI alone)
>> mOS 16.2m vs 16.7m
What are the factors that increase the risk of colon cancer?
A) Polyposis Syndromes
- Familial Polyposis
- Peutz-Jeghers Syndrome
- Juvenile polyposis
B) Non-Polyposis syndromes
C) Other medical conditions
- Inflammatory bowel disease
- Hx of colon cancer
- prior polyps
- 1st degree relative Dx
What are the genetic aberrations in the development of colon cancer ?
5q loss --> APC, Beta-Catenin --> Adenoma
18q loss--> KRAS --> Late adenoma
17q loss --> BAT-26, p53 --> Early cancer
8q loss --> late cancer
** 5q, 18q,17q, 8q
What is the RR for the following?
2) addition of Ox or Irinotecan to FU+Leu
1) 20%, median survival 1 year
2) 24 months
What is the evidence for bi-monthly high-dose Leucovorin + FU + CI5FU in advanced Ca?
De Gramont study, JCO 1997 French study
Advanced CLR Ca
A) IV LV (20) + Bolus 5FU (425) D1-5 q28days
B) IV LV (200) + Bolus 5FU (400) + 22hr CI 5FU (600) D1-2 q2weeks
RR 15% (A) vs 30% (B)
PFS 22w (A) vs 28w
Med survival 57w vs 62 weeks (not sig)
G3/4 tox 24% vs 10%
What is the evidence for Cape = 5Fu/Leu
1) 2001 JCO Hoff et al
Met CLR CA, 1st line tx
A) Oral Cape D1-14 q21days
B) 5FU/LV Bolus D1-5 q28days
RR 25% vs 15% (5FU/LV)
Med TTP 4.3m vs 4.7m
Med OS 12.5m vs 13m (non-sig)
Cape with lower diarrhea, stomatitis, nausea and alopecia.
But has higher HFS and G3/4 hyperbilirubinemia
2) Van Cutsem JCO 2001
Cape (2500/d) vs Mayo regimen
RR 19 vs 15%
OS 12m vs 13m (5FU)
What are the options for patients with symptomatic primary in CLR CA?
- primary resection
- Defunctioning stoma
Chemo vs BSC in Stage IV CRC?
Chemo if fit.
Simmonds BJC 2000, colorectal cancer collaborative group.
7 trials, 850 pts
35% reduction in risk of death
Absolute improvement in survival of 16%, median survival of 3.7m
What do you know about chemotherapy timing in asymptomatic adv CLR CA? Earlier better?
In asymptomatic patients, one study for earlier, one study negative.
1) Positive study: JCO 1992, Nordic group
- MTX/5FU/LV early
- MTX/5FU/LV only when symptomatic
- 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
What can be used in patients with DPD deficiency?
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
What is the Mayo Regimen?
Leucovorin (20) Bolus
FU (425) Bolus
IFL better or Mayo regimen better?
Saltz NEJM 2000
PFS 7m vs 4m
OS 15m vs 13m
ORR 40% vs 20%
FOLFIRI better or 5FU better as first line?
Doulliard Lancet 2000
FOLFIRI>5FU as 1st line
RR 40% vs 20% (5FU)
TTP 7m vs 4m
OS 17m vs 14m
What is S-1?
2)Gimeracil (5-Chloro-2,4 dihydropyridine)
- inhibits DPD activity
DPD = Dihydropyrimidine Dehydrogenase
What is UFT?
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
What is the evidence of 2nd-line Irinotecan>CI 5FU?
Met CLR CA, failed FU
- Irinotecan (300-350) q3weeks
- infusion all 5 FU
1y Survival 30% vs 45%(Irinotecan)
OS 11m vs 8.5m (Irinotecan)
PFS 4m vs 3m
What is the standard AIO FU/FA regimen?
FA (500) as 2-Hr infusion + CI-5FU (2.6g) over 24hours
weekly x 6 weeks, then 2 week rest
What are the side-effects of Oxaliplatin?
- cold-triggered sensory neuropathy that is temporary and rapidly reversible
- no structural nerve damage
- dose-related, dose-limiting s/e
No neuroprotective effect of IV Ca/Mg
What is the NCCTG/Intergroup N9741 trial?
Goldberg JCO 2004
Met CLR CA, tx-naive
1) IFL (control arm)
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.
- 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
FOLFOX = FOLIRI. Evidence?
A) 2005 JCO Colucci
Tx-naive met CLR CA
- ORR 30%~
- TTP 7m~
- Duration of response 9-10m~
- OS 14m s 15m
B) 2004 JCO Tournigand
Met CLR CA treatment-naive, n=200
- FOLFIRI--> FOLFOX6
- 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.
What is the FOLFOX4 regimen?
Oxaliplatin (85) D1 + LV5FU2 regimen.
LV5FU2 = Leucovorin (100) over 2 hours, Bolus FU (400), CI5FU (600) over 22hours D1-2
What is the FOLFIRI Regimen?
Irinotecan (180) D1 + LV5FU2 regimen
Leucovorin (100) over 2 hours D1
FU (400) Bolus
FU (600) CI over 22 hours
What is the FOLFOX6 regimen?
2-hour infusion of Leucovorin
FU Bolus (400)
46hr CI5FU (2400-3000)
What is FOLFOXIRI and what is the evidence?
High activity, increased toxicity
Reserved for specific situations eg. Substantial tumor shrinkage
Falcone JCO 2007
Unresectable met CLR CA
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
G2/3neurotox 20% vs 0%
G3/4 neutropenia 50% vs 30%
What are the side-effects of Bevacizumab?
GI Perforations (1-2%)
Arterial thrombotic events (4-5%)
?Venous thrombotic events
Any evidence for Capecitabine + Bev?
AVEX trial Cunningham Lancet Onco 2013
Elderly pts, >70yo
Treatment-naive, Unresectable, met CLR CA
Deemed not candidates for Ox-based or Irinotecan-based chemo
A) Cape (1000) BD D1-14
B) Cape (1000) BD D1-14 + Bev (7.5mg/kg) D1
- 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
Any evidence for EGFR Ab + Bev + chemo?
Yes, negative and in fact harmful.
A) JCO 2009 Hecht et al
1st line tx, met CRC
- Panitumumab + Bev + Chemo
- Bev + Chemo
Chemo = Ox- and Irinotecan-based
- 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
- Cape + Ox + Bev
- Cape + Ox + Bev + Cetuximab
- med PFS 11m s 9m (Cetuximab)
- QoL scores lower in CBC group
- OS and RR ~
- those with KRAS mutation + Cetuximab had decreased PFS
Tell me some common side effects of Cetuximab
Acne-like rash, predominantly on face, upper tors
Any evidence for Cetuximab as onto therapy?
Yes. Saltz et al. JCO 2004
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
- 1st dose 400 mg/m2 over 2 hours
- subsequent weekly tx at 250mg/m2 over 1 hour
10% with PR (5 patients)
21 patients with SD/minor responses
Median survival 6months
Any role in continuing Irinotecan beyond PD with Cetuximab?
NEJM 2004 Cunningham
Met CLR CA
Refractory to tx with Irinotecan
A) Cetuximab + Irinotecan
If PD, addition of Irinotecan to Cetuximab mono therapy was permitted.
RR 20% vs 10% (monotherapy)
TTP 4m vs 1.5m (monotherapy)
Median survival 9m vs 7m - Trend
What is the evidence for Panitumumab?
JCO 2007 Van Cutsem
Met CLR CA
PD after std tx
1% or more EGFR staining
Radiologic PD during or within 6m of most recent chemo
- Panitumumab + BSC
>> Panitumumab 6mg/kg Q2w
PFS 8w vs 7w (BSC)
ORR 10% vs 0%
OS~ (likely contributed by cross-over)
How about Cetuximab in chemo-refractory CLR CA?
Jonker NEJM 2007
S/p Fluoropyrimidine, Irinotecan, Oxaliplatin OR had contraindications to tx with these drugs
A) Cetuximab (400) 1st dose; 250mg/m2+BSC 2nd dose onwards weekly
B) BSC alone
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)
What is Cetuximab
IgG1 chimeric monoclonal Antibody against Epidermal growth factor receptor
What do you know about Panitumumab vs Cetuximab?
Price et al, Lancet Onco 2014
Chemo refractory wt KRAS exon2
Met CLR CA
A) Panitumumab 6mg/kg Q2weeks
B) Cetuximab 400 mg /m2 --> 240mg/me Qweekly
OS ~ 10.4m (Pani) vs 10m
Tell me about KRAS
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.
What is the frequency of KRAS exon 2 mutations in CLR CA?
What is the PRIME Study about?
Doulliard et al
PRIME: Panitumumab Randomized trial In combination with chemotherapy for Metastatic Colorectal cancer to determine Efficacy
Met CLC CA
A) Panitumumab + FOLFOX4
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
Tell me about the FIRE-3 trial
Lancet Oncol 2014 Heinemann
Aim: compare Cetuximab + FOLFIRI vs Bev+ FOLFIRI
KRAS Exon2 wt
Metastatic treatment naive
A) FOLFIRI + Cetuximab
B) FOLFIRI + Bevacizumab
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
Skin reactions 26% vs 2%(Bev)
Diarrhea 10% ~
Are BRAF mutually exclusive with KRAS?
Mutations of BRAF (5-10%) of patients with advanced CLR CA, are mutually exclusive with KRAS mutations
Tell me about BRAF-associated advanced CLR CA
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
Tell me what you know about the scheduling of Irinotecan?
Fuchs et al JCO 2003
FU-refractory CLR CA
A) Weekly x4, off 2 week
- 300mg/m2 in those 70 and older, ECOG 2, prior pelvic RT
Med f/u 16m
1y OS similar 40-50%
Med OS 10m
Med TTP 3-4m
QoL not statistically different
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
Tell me about Irinotecan
Also known as CPT-11
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
Are there any treatment options beyond 5FU/Irinotecan/Oxaliplatin?
Mayer NEJM 2015 RECOURSE Study
Tx-refractory with previous exposure to 5FU/Irinotecan/Oxaliplatin
- 35mg/m2 BD 5 days a week with 2 days rest X 2weeks --> 2 week rest
Med OS 5m vs 7m
Med time to worsening PS 5.7m (TAS) vs 4m
What is Folinic Acid?
What is Leucovorin
Why is Leucovorin added to Fluorouracil?
FU has been combined with Folinic Acid to enhance the capacity of FU to bind to thymidylate synthase.
What is TAS-102?
Orally administered combination of:
- 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.
What is the evidence for TAS-102?
RECOURSE Study by Mayer et al NEJM 2015
Known KRAS status
Prior chemo with Fluoropyrimidine ,Oxaliplatin, Irinotecan, Bevacizumab, +/- Cetuximab/Panitumumab
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)
What is Grothey's 3-Drug hypothesis?
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
Tell me about Desmoid tumors
Second only to colorectal cancer as a common cause of death among patients with FAP
- asymptomatic abdominal mass to bowel obstruction or urethral obstruction
Sporadic Desmoid tumors also occur
Possible palliative options include:
- Hormonal therapy
- Targeted therapy such as imatinib
Describe Muir-Torre syndrome
Multiple colon cancers
Multiple cutaneous neoplasia, including sebaceous adenomas
FAP is characterized by...?
Chromosomal instability due to mutations in the APC tumor suppressor gene
What is HNPCC characterized by?
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:
- urinary tract cancers
What are the other associated cancers with HNPCC?
Urinary tract cancers
How can HNPCC be confirmed by?
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
1) Tumor screening with MSI
2) Lack of expression of MMR protein expression by IHC
3) MMR mutation testing
How is 5FU eliminated?
>80% eliminated via the DPD enzyme
DPD enzyme deficiencies are at high risk of 5FU toxicities
What are the 5FU Toxicities, esp related to DPD enzyme deficiencies
Cerebellar ataxia, neurotoxicity
Most common mutation = IVS14 + 1G>A, DPYD*2A mutation
What is TSER *3/*3 genotype a/w ?
TSER *3/*3 genotype is a/w higher levels of thymidine synthase and Lower tumor response to 5FU therapy
Tell me about MYH-associated Polyposis
MYH Gene, a base-excision repair Gene
Deficiency in MYH leads to somatic mutations in APC Gene
- not Germline
Clinical features similar to FAP
Tell me about MYH-associated Polyposis
MYH Gene, a base-excision repair Gene
Deficiency in MYH leads to somatic mutations in APC Gene
- not Germline
Clinical features similar to FAP
Which genetic change is a/w resistance to treatment with Cetuximab?
BRAF V600E mutation
Tell me about the MRC FOCUS study
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
Advanced CLR CA
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
Median survival = 14m (A); B-ir 15m, B-Ox 15m, C-ir 17m C-Ox 15m
What are the 3 trials that support sequential use over combination use of chemo agents in met CLR CA?
Tell me about the FFCD 2000-05 trial
Ducreux Lancet Oncol 2011
Aim: to evaluate if combination Tx > Sequential Tx in adv CLR CA
Advanced CLR CA
A) Simplified LV5FU2 regimen --> FOLFOX6 --> FOLFIRI
- Bolus 5FU (400) + CI 5FU(2400)+ Leucovorin (400) --> L5FU2+Ox (100) --> LV5FU2+Iri (180)
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
Re: Sequencing of agents, which trials tell us what?
FOLFOX, FOLFIRI largely comparable
1) JCO Colucci 2005
2) JCO Tournigand 2004
What are the studies that discuss re: maintenance vs intermittent chemo?
What is the OPTIMOX-1 study?
Tournigand JCO 2006
Aim: To evaluate the efficacy of intermittent Oxaliplatin Tx as opposed to continuous Tx.
+ exploratory cohort of 100 elderly/poor prognosis
- Leucovorin + FU Bolus (400) + 22hr CI5FU (600) D1-2
- Ox (85) D1
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
Med PFS 9m (A) vs 9m (B)
Med OS 20m (A) vs 21m (B)
G3 sensory neuropathy 18% (A) vs 13% (B)
Conclusion: Ox can be safely stopped after 6# in a FOLFOX regimen
Tell me about the OPTIMOX2
Chibaudel JCO 2009
Aim: To compare chemo discontinuation vs maintenance therapy after 6#FOLFOX
Met CLR CA
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
Median duration of disease control (DDC) 13m v 9m (CFI)
Med PFS 9m (maintenance) vs 7m (CFI)
Med OS 24m (maintenance) vs 20m (CFI)
Tell me about the MRC COIN trial
Richard Adams Lancet Oncol 2011
Aim: assess if OS on intermittent Tx was non-inferior to that of continuous chemo
A): Continuous Ox+5FU
B): Continuous Tx + Cetuximab
C): Intermittent chemotherapy
- Chemo x12 weeks---> CFI until PD --> Chemo
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%
- 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.
Tell me about the CAIRO3
Simkens Lancet 2015
Aim: to determine the efficacy of maintenance txt with Cape+Bev vs observation
Previously untreated met CLR Ca with stable disease or better after induction treatment
Induction Tx: 6#Cape/Ox/Bev q21days
A) Maintenance : Cape/Bev
B) Observation group
On 1st PD = PFS1, patients then receive CAPOX-B until 2nd PD = PFS2
- median f/u 4 years
- PFS2 better with maintenance 12m vs 9m
- Med OS 18m vs 22m (maintenance) - trend
What is the evidence for Irinotecan as first-line in met CLR CA?
Douillard et al Lancet 2000
Aim: To investigate the efficacy of Irinotecan+FU as first-line tx.
Met CLR CA, treatment-naive
A) Irinotecan + 5FU/Leu
RR 50% (Iri) vs 30%
TTP 7m vs 4m
OS 17m vs 14m
Why is an Infusional-based schedule of 5FU is preferred when using with Irinotecan?
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
* 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.
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)
Tell me about the Arkenau pooled analysis
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
Higher RR for FU-based regimens
PFS and OS similar
Any evidence AGAINST FOLFOXIRI?a
HORG study by Souglakos in BJC 2006
No difference in OS/TTP/RR
But observed med OS of 21.5m is one of the best ever reported
What is the difference in regimen of FOLFOXIRI in the Falcone study and HORG study?
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)
- Day1: Irinotecan (165) over 1hour + Oxaliplatin (85) over 2 hours + LV (200) over 2 hours
- Day 1-3: CI5FU (3200)
What is Cetuximab?
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
What are the trials with Cetuximab as 1st line?
1) Van Cutsem ASCO 2007 - CRYSTAL phase 3 study
N=1200, previously treated EGFR+patients
- FOLFIRI + Cetuximab
PFS 9m vs 8m
1yPFS 30% s 20%
RR 50% vs 40%
2)Tabenero JCO 2007 Phase 2
FOLFOX4 + Cetuximab
RR 70%, PFS 12m, OS 30m
3) Venook ASCO 2006 CALGB Phase 3
- Tx-naive, regardless of EGFR
- 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
- 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
What are the 2nd line studies for Cetuximab?
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
- 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
What are the 3rd Line evidence for Cetuximab?
1) Cunningham NEJM 2005
- Phase 3
- Cetuximab+Iri vs Cetuximab alone
- previous Irinotecan failure
- 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
How common is K-RAS mutation?
Activating K-RAS mutations in exon 2 are found in 40-45% of met CLR Ca
What are the 2 conditions in which met CLR CA can be treated?
1) resectable mets
2) initially Unresectable disease rendered suitable for resection
What are the goals of treatment in Unresectable mCRC?
Treatment is seen as a continuum of care.
Prolongation of survival
Improving tumor-elated symptoms
Stopping tumor progression
What is systemic treatment of mCRC comprised of?
1) Cytotoxic agents
2) Biological targeted agents
- Anti-VEGF strategies
- Anti-EGFR strategies
- Multi-kinase inhibitors
What is the benefit of combination chemo?
Tell me about Aflibercept
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
What is the expanded RAS analysis?
Detection of mutations in:
Exon3 of KRAS Gene
Exon4 of KRAS Gene
Exon2-4 of NRAS Gene
In addition to KRAS Exon 2
Name me the side-effects of Regorafenib
What are the 4 clinically defined groups in deciding treatment strategy as per ESMO Guidelines?
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
What is considered sufficient remnant liver?
What is the 5-yr survival rates in R0-resectable colorectal liver mets?
What is th 5-yr survival rates in R0-resectable colorectal lung mets?
What are the 2 potential strategies for (neo)- adjuvant therapy in those with resectable liver mets?
1) Post-op adjuvant chemo with FOLFOX for 6 months
2) Peri-op chemo
- 3 months before and 3 months after resection of mets
What are the different histological changes in liver parenchyma that Oxaliplatin and Irinotecan may cause?
Oxaliplatin = sinusoidal liver lesions
Irinotecan - steatohepatitis
What are the high-risk factors for recurrence?
(Histology, Invasion, Perforation, Margins, Obstruction, LN)
poorly differentiated Histology
lymphatic / vascular / perineural Invasion
Margins - close/indeterminate/positive
On pathology review, what is considered as a Positive margin for endoscopic ally removed malignant polyps ?
No consensus as to the definition but:
What is the minimum number of LN that needs to be evaluated?
What is hepatic artery infusion?
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.
Tell me about the SIRFLOX trial
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
- 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%
What're are the SIRT-associated events?
Gastric/duodenal ulcer (4%)
Hepatic failure (1%)
aviation hepatitis (1%)
What is SIRT?
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
What are the liver-directed therapies that you know about in CLR CA?
1) Hepatic Arterial Infusion
2) Arterially Directed Embolic Therapy
3) Liver-Directed Radiation
4) Tumor Ablation
- Microwave ablation
- Percutaneous ethanol injection
When the remnant liver is insufficient in size based on cross-sectional imaging volume tricks, what can be done?
Pre operative portal vein embolization of the involved liver can be performed to expand the future live remnant
What are the advantages to pre-op chemo?
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
Potential disadvantages of pre-op chemo
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
What syndromes are a/w deficiencies in UGT 1A1?
Crigler-Najjar Types I and II
Any evidence for FOLFOXIRI + Bev?
Yes. TRIBE trial
Unresectable met CLR CA
FOLFOXIRI/Bev vs FOLFIRI/Bev
FOLFOXIRI/Bev significantly increase PFS 12m vs 10m HR 0.75
RR 65% vs 50%
Updated analysis : Median OS 30m vs 26m
60% had adjuvant Oxaliplatin. In this group, no benefit to addition of Ox
What is the Half-life of Bev?
What is Ziv-Aflibercept?
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
What is the VELOUR trial
Tested 2nd-line Ziv-Alfibercept in met CLR CA who had PD after one Ox-containing regimen
OS 13.5m vs 12m
What is Ramucirumab?
Human monoclonal antibody that targets the extracellularly domain of VEGFR-2 --> Blocking VEGF signaling.
What is the evidence for Ramucirumab in met CLR CA?
Met CLR CA PD on 1st-line Tx: FU/Ox/Bev
- OS: 13m vs 12m HR 0.8
- PFS 6m vs 4.5m HR 0.8
What does Regorafenib inhibit
Fibroblast growth factor receptors (FGF)
What is the evidence of Regorafenib?
- 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
- progressive met CLR Ca, PD after 2 or more lines
- Regorafenib vs placebo
- OS 9m vs 6m HR 0.55
How does Pembrolizumab work?
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
What did the BICC-C study conclude?
Fuchs et al JCO 2007
Protocol amendment : additional 100 pts added and randomized to FOLFIRI+ Bev vs mIFL+Bev, CapeIRI stopped
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
- 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
Any evidence to show Bevacizumab improves OS and PFS?
Hurwitz NEJM 2004
Untreated met CLR CA, n=800
- IFL + Placebo
- IFL + Bev
- med OS 20m vs 15.5m (Placebo)
- med PFS 10.5m vs 6m
- RR 45% vs 35%
What is the evidence to show the antagonistic effect of EGFR Ab and Bevacizumab when used concurrently?
1) Hecht et al JCO 2008
2 arms, n=1000:
- 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
- med PFS 11m (CB) vs 9m (CBC)
- QoL lower in CBC group, more G3/4 events
What has anaphylaxis to Cetuximab been correlated to?
Presence of pre-existing serum IgE Ab to oligosaccharide, galactose-alpha-1,3-galactose
What is the Bethesda Criteria?
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
Tell me about the CRYSTAL Study
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.
2) FOLFIRI + Cetuximab
(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%
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
Tell me about the OPUS study
JCO 2008, Bokemeyer
Update Ann Onco 2011
Met CLR Ca treatment-naive
1) FOLFOX4 + Cetuximab
- 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
Tell me about the EPIC study
Alberto Sobrero JCO 2008
Met CLR CA
Previously s/p Fluoropyrimidine+Oxaliplatin
1) Cetuximab + Irinotecan
2) Irinotecan (350 mg/m2 Q3w)
- 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
Tell me about the PRIME study
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
1) Panitumumab + FOLFOX4
(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)