Systemic Chemotherapy ECIV

Question 1

Infusional x Bolus
JCO 1997
De Grammont

LV is a reduced folate (tetrahydrofolate) that increases the affinity of fluorouracil for thymidylate synthase.

Answer 1

448 patients - Infusional x Mayo clinic

Bimonthly regimen:

• More effective (response rate of measurable lesions 32,6% x 14,4%)
• Median PFS (62 weeks x 56,8 weeks)
• Less GI toxicity (mucositis and diarrhea) and granulocytopenia
• No evidence of increased survival

Question 2

Capecitabine x 5FU/LV
BJCancer 2004
Van Cutsem

Capecitabine - 2xday, 1-14 every 21 days
generates 5FU preferentially in tumour tissue through exploitation of higher intratumoral concentrations of thymidine phosphorylase.

Answer 2

1207 patients - Capecitabine x 5FU/LV

Lower incidence of GI (diarrhea, stomatitis, nausea), alopecia and neutropaenia.
Obs.: hand-foot sd ( 53,5% x 6,2%)

Capecitabine:

• Superior response rate
• Equivalent TTP and OS
• Improved safety profile
• Improved convenience

Question 3

Irinotecan (IFL)
NEJM, 2000
Saltz

Irinotecan:
Potent inhibitor of topoisomerase I (nuclear enzyme involved in the unwinding of DNA during replication

Answer 3

IFL x 5FU/LV (Mayo) x Irinotecan
683 patients

IFL - significantly longer PFS
       higher RR
       longer OS
       more grade 3 diarrhea
       less grade 3 or 4 mucositis
       less grade 4 neutropenia

Question 4

Infusional 5FU/LV x Infusional 5GU/LV/Ir.
(once weekly AIO regimen or every 2 weeks)
Lancet 2000, Douillard

Answer 4

385 patients

Increased RR, TTP, OS
More diarrhea and neutropenia

Question 5

FOLFOX 4
De Grammont, JCO 2000

Platinum based drug, forms cross-linking adducts, blocking DNA replication and transcription.

Answer 5

420 patients

Significantly longer PFS (9 x 6,2 months)
Better RR (50,7% x 22,3%)
No significant difference in OS
More neutropenia, diarrhea and neuro

Question 6

FOLFOX4 x IROX x IFL

IROX - oxaliplatin + irinotecan every 3 weeks

Answer 6

795 patients

FOLFOX4

• superior TTP, RR, median survival
• lower rates of GI toxicity (nausea, vomiting, diarrhea, dehydration) and neutropenia.

Question 7

FOLFIRI x FOLFOX4

2005 JCO Colucci

Answer 7

360 patients

no difference in ORR, TTP, OS
more gastrointestinal toxicity in FOLFIRI
more thrombocytopenia and neuro in FOLFOX

Question 8

XELOX x FOLFOX4
2008, JCO Cassidy
(+ bev / placebo)

Answer 8

2034 patients

XELOX is not inferior in terms of PFS.
FOLFOX4 - more neutropenia and granulocytopenia
XELOX - more diarrhea and H-F Sd.

Question 9

FOLFOXIRI x FOLFIRI

BJC 2006 Souglakos

Answer 9

283 patients

No difference in terms of
OS, TTP, RR
Higher incidence of alopecia, diarrhea, neuro

Question 10

FOLFOXIRI x FOLFIRI

JCO 2007 Falcone

Answer 10

244 patients

FOLFOXIRI
Improved RR, PFS and OS
more neuro and neutropenia

Question 11

FOLFIRI - FOLFOX6
vs.
FOLFOX6 - FOLFIRI

JCO 2004 Tournigand

Answer 11

Similar PFS, RR
FOLFIRI - more GI and alopecia
FOLFOX6 - more neuro and neutropenia

Question 12

IFL x IFL+Bev
NEJM 2004, Hurwitz

Humanized recombinant monoclonal antinbody which binds and blocks the activity of all isoforms of VEGF-A

Answer 12

813 patients

IFL + Bev - increased OS, PFS and RR
               - more hypertension
OS: 20,3 x 15,6 months
PFS: 10,6 x 6,2 months
RR: 44,8% x 34,8%
Grade 3 hypertension was more common during the experimental group treatment.

Question 13

XELOX x FOLFOX4
Bev x placebo
JCO 2008 Saltz

Answer 13

1401 patients
Bev is associated with improved RR and PFS
No difference in OS

Question 14

NEJM 2007, Jonker
Cetuximab x BSC
(Chemo refractory cases)

Cetuximab: chimeric monoclonal antibody against epidermal growth factor receptor (EGFR)

Answer 14

572 patients

Improved OS, PFS
OS 6,1 x 4,6 months

Question 15

NEJM, 2008
Karapetis (reevaluation of Jonker 2007)

K-ras: small G-protein downstream of EGFR and an essential component of the EGFR signaling cascade, can acquire activating mutations in exon 2, thus isolating the pathway from the effect of EGFR and rendering EGFR inhibitors ineffective.

Answer 15

Patients with K-ras mutation did not benefit from cetuximab.

The mutation status of the K-ras gene had no influence on survival among patients treated with BSC alone.

Question 16

FOLFIRI + CETUX X FOLFIRI
Association with K-ras status
NEJM 2009, Van Cutsem

CRYSTAL trial

The clinical activity of cetuximab was shown in a retrospective analysis to be limited to wild-type tumors at codons 12 and 13 of K-ras gene (64% of K-ras evaluable population)

Answer 16

599 patients

Improved PFS
No difference in OS
Association with K-ras status for tumor response, but not for PFS or OS
The benefit was limited to patients with K-ras wild-type tumors

Skin reactions

Question 17

FOLFIRI + CETUX X FOLFIRI
Association with K-ras status
JCO 2011, Van Cutsem

The ascertainment of patients analysed for K-ras status increased from 45% to 89%, with mutations detected in 37% of tumors.

Answer 17

K-ras wild-type:
Significant improvement in OS (23,5 x 20 m)
PFS (9,9 x 8,4m)
RR (57,3 x 39,7%)
BRAF tumor mutation was a strong indicator of poor prognosis

Question 18

JCO 2012, Tveit

FLOX + CETUX x FLOX

Answer 18

571 patients
K-ras mutation were present in 39%
BRAF mutations were present in 12% (strong negative prognostic factor)
Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC
Obs.: ITT design

Question 19

FOLFOX4 + PMab x FOLFOX4
JCO 2010, Douillard
(PRIME trial)

Panitumumab - fully human anti-EGFR monoclonal antibody

Answer 19

1183 patients
KRAS results were available for 93%
KRAS wild-type
-improved PFS
-non significant improment in oS

Question 20

Chemo (oxa or iri)+bev+PMab x Chemo+bev

JCO 2009, Hecht

Answer 20

-Increased toxicity and decreased PFS