Approach to Metastatic Colon Cancer

DR. BASSEM TOEMAMedical Oncology Specialist

Saad Specialist Hospital

Organ-Specific Metastatic Tumor Cell Adhesion and Extravasation of Colon Carcinoma Cells with Different Metastatic PotentialFrom Kerstin Schlu¨ ter, Peter Gassmann, et al; The American Journal of Pathology, Vol. 169, No. 3, September 2006, DOI: 10.2353/ajpath.2006.050566

1. Cell adhesion of circulating tumor cells occurred in metastatic target organs only, likely attributable to specific interactions between circulating carcinoma cells and the vessel wall of these metastatic target organs.

2. Colon carcinoma cells can arrest in target organs without size restriction.3. Migration into target organs correlated with their metastatic potential. Cell

extravasation of highly metastatic HT-29LMM and KM-12L4 colon carcinoma cells into liver parenchyma was significantly higher compared to low metastatic HT-29P cells (P < 0.05).

Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells: implication for a potential role in cancer metastasis from William Rengifo-Cam1, Akio Konishi1 et al; Oncogene (2004) 23, 289–297

• Modulation of SFK by Csk influences cell morphology, cell–cell interaction, cell motility and in vitro invasiveness in colon cancer cells• Modulation of SFK by Csk influences integrin-SFK-mediated cell adhesion signaling.• Modulation of SFK by Csk influences focal contact formation and actin cytoskeletal organization• Modulation of SFK by Csk does not affect the E-cadherin/b-catenin complex• Csk could control metastatic potential of cancer cells through regulating integrin-SFK-mediated cell adhesion signaling

Is CD133 a marker of metastatic colon cancer stem cells?Commentary From Mark A. LaBarge and Mina J. Bissell The Journal of Clinical Investigation, Volume 118 Number 6 June 2008

CD133 can no longer be considered a marker of CSCs in a metastatic context.

CD133 expression is not restricted to stem cells, and both CD133+ and CD133– metastatic colon cancer cells initiate tumorsFrom Sergey V. Shmelkov,1 Jason M. Butler et al; The Journal of Clinical Investigation, Volume 118 Number 6 June 2008Both CD133+ and CD133– subsets of human metastatic colon cancer exhibit long-term tumorigenic potential.

What is the target??

Best AchievableStatistical

Indices

Best Achievable

QualityOf Life

ESMO Minimum Clinical Recommendations 2008

Liver and lung metastasis

Synchronous Metachronous

Resectable Unresectable

Colon Surgery, liver resection or Lung metastatectomyand subsequent adjuvant systemic chemotherapy vs Hepatic artery infusion therapy ± systemic 5-FU and leucovorin

Limited colonresection if substantial risk of intestinal obstruction and/or if liver burden low ± Radiofrequency ablative therapy and palliative systemic chemotherapy

Resectable Unresectable

NCCN Guidelines

Liver resection or Lung metastasectomy and subsequent adjuvant systemic chemotherapy vs Hepatic artery infusion therapy ± systemic 5-FU and leucovorin

Palliative systemic chemotherapy

NCCN Guidelines updates

Determination of the KRAS gene status of either the primary tumor or a site of metastasis should be part of the pre-treatment work-up for all patients diagnosed with metastatic colorectal cancer.

Epidermal growth factor receptor (EGFR) inhibitors, cetuximab (Erbitux) and panitumumab (Vectibix) , either as single agents, or, in the case of cetuximab, in combination with other agents, are now recommended only for patients with tumors characterized by the wild-type KRAS gene.

ESMO Minimum Clinical Recommendations updates

•First-line palliative chemotherapy: fluoropyrimidine (i.v. 5-FU or oral) in various combinations and schedules. •Combination chemotherapy: 5-FU/LV/oxaliplatin (FOLFOX) or 5-FU/LV/irinotecan (FOLFIRI) provide better survival than 5-FU/LV. •The combination of capecitabine plus oxaliplatin has a similar activity to the combination 5-FU and leucovorin/Oxaliplatin.

Second-line chemotherapy: In patients refractory to FOLFOX an irinotecan-based regimen can be proposed and vice versa.

Monoclonal antibodies: Bevacizumab in first-line treatment in combination with an irinotecan based regimen. Cetuximab and panitumumabin chemorefractory metastatic colorectal cancer.

Management of MetastaticColon Cancer

Results of hepatic resection for metastatic colorectal cancer

Author and Year Number of patients 5 yr OS, percent Median survival, months

Hughes, KS; 1986 607 33 NR

Scheele, J; 1995 434 33 40

Nordlinger, B; 1996 1568 28 NR

Jamison, RL; 1997 280 27 33

Fong, Y; 1999 1001 37 42

Iwatsuki, S; 1999 305 32 NR

Choti, M; 2002 133 58 NR

Abdalla, E; 2004 190 58 NR

Fernandez, FG; 2004 100 58 NR

Wei, AC; 2006 423 47 NR

Rees, M; 2008 929 36 42.5

Clinical risk score*

Survival at: Median survival,

mos1 yr 2 yr 3 yr

0 93 79 60 741 91 76 44 512 89 73 40 473 86 67 20 334 70 45 25 205 71 45 14 22

•Derived from the presence of node-positive primary tumor, relapse-free interval <12 months, multiple rather than solitary hepatic tumors, serum CEA >200 within one month of surgery, and largest hepatic tumor >5 cm. •From: Fong, Y, et al Ann Surg 1999; 230:309.

Neoadjuvant Chemotherapy for Metastatic ColonCancer: A Cautionary NoteFrom Anton J. Bilchik, John Wayne et al; Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp 9073-9078

• The use of FOLFOX to downstage unresectable tumors was first introduced in 1998 by Bismuth and Adam. In their study, tumors were downsized and became resectable in 16% of patients; the 5-year postoperative survival rate in these resected patients was 40%.• In a larger study, 1,104 patients with tumors deemed unresectable received oxaliplatin; 335 (23%) subsequently underwent primary hepatic resection, with a survival rate similar to the rate after primary hepatectomy in patients presenting with resectable disease.• More recently, Delaunoit et al reported curative resection in 24 (3.3%) of 795 randomly assigned patients who had received neoadjuvant chemotherapy for initially unresectable metastatic colon cancer; most of these patients (92%) received an oxaliplatin-based regimen. The median overall survival time in the resected group was 42.4 months, and the median time to relapse was 18.4 months.

Agents with Proof of Efficacy in Colorectal Cancer

Conventional chemotherapy Targeted therapy

Fluoropyrimidines VEGF inhibition

5-FU (+ LV)* Bevacizumab*

Capecitabine* EGF receptor inhibition

UFT (+ LV) Cetuximab*

S1 Panitumumab

Raltitrexed Matuzumab

Pemetrexed

Mitomycin*

Irinotecan*

Oxaliplatin*

*FDA Approved for treatment of advanced CRC (August 2005).

Regimen Irinotecan Oxaliplatin Leucovorin 5-FU/Capecitabine Schedule

FOLFIRI 180 mg/m2 d1

400 mg/m2 over 2 hr d1

FU 400 mg/m2 bolus d1, followed by 2400-3000 mg/m2 over 46

hours, continuous infusionEvery 2 weeks

Douillard regimen

180 mg/m2 d1

100 mg/m2* over 2 hr d1,2 before 5-FU

FU 400 mg/m2 bolus then 600 mg/m2 over 22 hours d1,2 Every 2 weeks

FOLFOX 4 85 mg/m2 d1

200 mg/m2 over 2 hr d1,2 before 5-FU

FU 400 mg/m2 bolus then 600 mg/m2 over 22 hours d1,2 Every 2 weeks

FOLFOX 6 100 mg/m2 d1

400 mg/m2 over 2 hr d1

FU 400 mg/m2 bolus d1, followed by 2400-3000 mg/m2 over 46

hours, continuous infusionEvery 2 weeks

Modified FOLFOX 6

85 mg/m2 d1

400 mg/m2 over 2 hr d1

FU 400 mg/m2 bolus d1, followed by 2400 mg/m2 over 46 hours Every 2 weeks

FOLFOX 7 130 mg/m2 d1

400 mg/m2 over 2 hr d1

FU 400 mg/m2 bolus, then 2400 mg/m2 over 46 hours

Every 2 weeks

Modified FOLFOX 7 (Optimox)

100 mg/m2 d1

400 mg/m2 over 2 hr d1 FU 3000 mg/m2 over 46 hours Every 2 weeks

Modified FOLFOX 7 (ConcePT)

85 mg/m2 d1

200 mg/m2 over 2 hr d1 FU 2400 mg/m2 over 46 hours Every 2 weeks

XELOX 130 mg/m2 d1

Capecitabine 2000 mg/m2 daily days 1 to 14

Every 2 weeks

XELOX 85 mg/m2 d1

Capecitabine 2000 mg/m2 daily days 1 to 14

Every 2 weeks

FOLFOXIRI 165 mg/m2 d1

85 mg/m2 d1

200 mg/m2 over 2 hr d1 3200 mg/m2 over 48 hours Every 2 weeks

Irinotecan Combinations as First-line Therapy in Advanced Colorectal Cancer

Study and number Protocol RR, % PFS, mo OS, mo

Saltz et al.,

n = 457

5-FU/LV bolus (Mayo) 21 4.3 12.6

IFL 39 7 14.8

P value < 0.001 0.004 0.04

Douillard et al.,

n = 338

5-FU/LV infusional 31 4.4 14.1

FOLFIRI ("Douillard") 49 6.7 17.4

P value < 0.001 < 0.001 0.031

Kohne et al.,

n = 430

5-FU/LV infusional 34.3 6.4 16.9

FOLFIRI (AIO2.0) 62.2 8.5 20.1

P value < 0.0001 < 0.0001 ns

Oxaliplatin Combinations as First-line Therapy in Advanced Colorectal Cancer

Study and number

Protocol RR, % PFS, mo OS, mo

Giacchetti et al., n = 200

5-FU/LV infusional 16 6.1 19.9

cm FOLFOX 53 8.7 19.4

P value < 0.0001 0.048 ns

de Gramont et al.,

n = 420

5-FU/LV infusional 22.3 6.2 14.7

FOLFOX4 50.7 9 16.2

P value 0.000 < 0.0001 ns

Grothey et al.,

n = 252

5-FU/LV bolus (Mayo) 22.6 5.3 16.1

FUFOX 49.1 7.8 19.7

P value < 0.0001 0.0001 ns

NCCTG/Intergroup Trial N9741 Efficacy (From Goldberg et al; JCO, 2004)

IFL FOLFOX P value

OS 15.0 mo 19.5 mo 0.0001

TTP 6.9 mo 8.7 mo 0.0014

RR 31% 45% 0.002

NCCTG/Intergroup Trial N9741 Five year data and prognostic factor analysis (From Goldberg et al; JCO 2008 Dec 10;26(35):5721-7)

IFL FOLFOX IROX P value

OS 14.6 mo 20.2 mo 17.3 mo < .001

TTP 6.1 mo 8.9 mo 6.7 mo < .001

5-year survival

rate3.7% 9.8% 5.1%

0.04 (FOLFOX with IFL ) .128 (FOLFOX with

IROX)

Cetuximab as Salvage Therapy of Colorectal Cancer After Failure of Irinotecan

ASCO 2001 ASCO 2002 ASCO 2003

Phase II Phase II Randomized phase II

C225 + CPT C225 C225 + CPT C225

Number 121 57 218 111

RR, % 22.5 11 23* 11

RR + SD, % 46 35 56* 32

Median TTP, mo 4.1* 1.5

Median overall survival, mo

> 4 8.6 6.9

*P < 0.05.

Epidermal growth factor receptor (EGF-R) inhibitors for metastatic colorectal cancer Rebecca A Herbertson, Chris Karapetis, Nick Pavlakis, Tim Price, Niall Tebbutt published in The Cochrane Library 2009, Issue 1

A protocol for a review to determine the benefits and harms of EGFR inhibitors in the treatment of metastatic colorectal cancer when given alone, in combination with chemotherapy, or with other biological agents. Primary endpoints• Progression free survivalSecondary endpoints• Overall survival• Tumour response• Toxicity/adverse events• Quality of life• Cost-effectivenessSubgroup analysis will be performed according to;• Measures of EGFR expression• Known patient related prognostic factors such as age, performance status, number of organs involved with metastatic disease• The presence and grade of skin toxicity

Common Side Effects of Agents Used to Treat Colorectal Cancer

Toxicity5-FU bolus

5-FU continuous

infusionCapecitabine Irinotecan Oxaliplatin Bevacizumab Cetuximab

Neutropenia +++ (+) (+) ++ +

Mucositis +++ + + (+) +

Diarrhea ++ +++ +++ +++ + (+)

Hand-and-foot syndrome

+ ++ +++

Nausea

/vomiting+ (+) (+) ++ ++

Neuropathy +++

Hypersensitivity + (+) ++

Alopecia + (+) (+) ++ (+)

Hypertension ++

Skin rash +++

Rare side effects IHD IHD IHDCholinergic syndrome

HemolysisBleeding, GI perforation, proteinuria

Pulmonary

A case report of 53-year-old male patient, with metastatic colon cancer to the liver, who received First-line chemotherapy on palliative basis oxaliplatin 45 mg/m2, 5-fluorouracil 450 mg/m2 and folinic acid 200 mg/m2, all given on the same day weekly for 6 consecutive weeks followed by a 2-week rest. after the first week of the third cycle he developed Guillain-Barre´ Syndrome as a result of treatment with oxaliplatin. From C. Christodouloua, D. Anastasopoulosb et al; Anti-Cancer Drugs 2004, 15:997–999

A case report of 63 years old woman with Locally recurrent breast cancer While being treated with liposomal doxorubicin and bevacizumab, she experienced after 1 month of therapy Bevacizumab-associated osteonecrosis of the jaw. From S. Greuter*, F. Schmid et al; Annals of Oncology Volume 19: No. 2, December 2008.

Molecular Predictors of Response to Oxaliplatin-based Therapy Name of gene

involvedType of genetic variation Functional significance Clinical consequence

XRCC-1Polymorphism in exon 10 causing an Arg 300 to Gln substitution

Increased ability for repair of DNA damage caused by platinum adducts

Fivefold increased risk to fail 5-fluorouracil / oxaliplatin therapy in patients with metastatic colorectal cancer with at least one Gln mutant allele

ERCC-1 Increased mRNA levelsIncreased ability to repair DNA damage through the nucleotide excision repair (NER) pathway

Higher expression levels associated with shorter survival in patients with metastatic colorectal cancer

ERCC-1

Silent polymorphism C to T at position 118 with no corresponding amino acid change

Unknown but possible trend towards higher ERCC-1 expression with higher number of T alleles

T/T and C/T genotypes associated with shortened survival in patients with metastatic colorectal cancer

XPDPolymorphism in exon 23 causing a Lys 751 to Gln substitution

Unknown but possible decreased NER efficacy with Lys allele

Decreased response rate to 5-fluorouracil / oxaliplatin in metastatic colorectal cancer patients with at least one Gln allele (10% vs 24% in patients with Lys/Lys)

GSTP-1Polymorphism at position 313 causing an isoleucine to valine substitution

Diminished enzymatic activity of GSTP-1-105 Val, a detoxifying enzyme involved in platinum resistance

Increased survival in patients homozygous for the val/val genotype compared with patients with one or two Ile alleles

EGFRVariation in number of CA dinucleotide repeats in intron 1

EGFR transcription activity declines with increasing number of CA repeats

Higher response rate to 5- fluorouracil / oxaliplatin with increasing number of CA repeats in patients with metastatic colorectal cancer

Examples of Molecular Predictors of Toxicity to Irinotecan and Oxaliplatin in the Treatment of Gastrointestinal Cancers

Name of

drugTarget gene

Function of target gene

Genetic variation identified

Functional significance

Clinical impact

Irinotecan UGT1A1

Metabolism of SN-38, the active

form of irinotecan

UGT1A1*28 2 bp (TA) insertion in the TATA

box in promoter region

Reduced protein

expression

Increased toxicity in homozygous and

heterozygous patients

Irinotecan UGT1A1

Metabolism of SN-38, the active

form of irinotecan

SNP G to A change in exon1

Not determined

Increased toxicity in heterozygous

patients

Irinotecan UGT1A1

Metabolism of SN-38, the active

form of irinotecan

SNP T-3263 T>G in promoter region

Decreased transcriptional

activity

Increased toxicity in homozygous

patients who also had UGT1A1*28

Oxaliplatin GSTP-1Protection of

cells from free radical injury

I105V SNP C>TNot clearly determined

Examples of Molecular Predictors of Toxicity to 5-Fluorouracil-based Therapy

Target gene Function of target geneGenetic variation

identifiedFunctional

significanceClinical impact

DPD 5-FU catabolism

G to A mutation in the invariant GT splice donor

site flanking exon 14 (IVS14+1G>A)

Decreased activity of DPD

Severe, potentially lethal toxicity

OPRT

Activation of 5-FU into FUMP with subsequent incorporation into RNA or inhibition of TS via conversion into FUDP

and FdUMP

SNP in exon 3 G213AIncreased activity of

OPRT

Increased frequency of grade 2 or more

diarrhea and leucopenia in

patients with G213A allele

TSTarget of 5-FU; source

of de novo thymidine in cell

Presence of tandem repeats 2R or 3R in 5'

UTR region

Three repeats associated with

increased TS activity

Increased frequency of grade 2 or more

diarrhea and leucopenia in

patients with 2R genotype

Deleted in Colon Cancer Protein Expression in Colorectal Cancer Metastases: A Major Predictor of Survival in Patients With Unresectable Metastatic Disease Receiving Palliative Fluorouracil-Based ChemotherapyFrom Carlo Aschele, Domizia Debernardis et al; J Clin Oncol 22:NUMBER 18, 3758-3765, SEPTEMBER 15 2004

42 patients with metastatic CRC homogeneously treated by methotrexate-modulated bolus FU alternated to 6-S-leucovorin–modulated infused FU and retrospectively correlated with patient characteristics and clinical outcome.DCC protein expression was assessed immunohistochemically on archival specimens of CRC metastasis. Positive immunoreactivity in 45% of patients. The median survival time was 14.3 months in patients without DCC expression and 21.4 months in patients with DCC-positive tumors(log-rank test, P .04); The 2-year survival rates were 8.5% and 42.5%, respectively.Response rates to chemotherapy were not significantly different between the two groups.By multivariate analysis, DCC protein expression maintained its prognostic value and showed to be the single best predictor of survival, with a relative risk of 2.16

Genetic testing for UGT1A1*28 and *6 in Japanese patients who receive irinotecan chemotherapy.Y. Akiyama, K. Fujita et al; Annals of Oncology 19: 2089–2094, 2008

Genotype n (%) 95% confidence interval (%)

UGT1A1*1/*1 135 (45.0) 39.3–50.8

UGT1A1*1/*28 47 (15.7) 11.7–20.3

UGT1A1*1/*6 88 (29.3) 24.1–34.8

UGT1A1*28/*28 2 (0.7) 0.1–2.4

UGT1A1*6/*6 17 (5.7) 3.3–8.9

UGT1A1*6/*28 11 (3.7) 1.8–6.5

Prospective study. Aim is to examine the distributions of UGT1A1*28 and UGT1A1*6 polymorphisms of the UDP-glucuronosyltransferase (UGT) 1A1 gene.No: of Japanese patients is 300 (male/female, 172/128) with various solid tumors (200 CRC, 43 gastric, 15 ovarian, 14 breast, 10 lung, and 18 others). The combined frequency of patients with two ‘risk alleles’ (i.e. *28/*28, *6/*6, and *6/*28) was 10.1% (95% confidence interval, 6.8% to 14.0%). Such patients might be at increased risk for irinotecan-related neutropenia. Given the genotype frequencies of UGT1A1*28 and UGT1A1*6, genetic testing for UGT1A1 is useful for identifying homozygotes for UGT1A1*6 as well as heterozygotes for UGT1A1*6 andUGT1A1*28, thereby avoiding severe irinotecan-induced toxicity in Japanese patients.

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