1. Approach to Metastatic Colon Cancer DR. BASSEM TOEMAMedical Oncology Specialist Saad Specialist Hospital
2. Organ-Specific Metastatic Tumor Cell Adhesion and Extravasationof 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• 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.• Colon carcinoma cells can arrest in target organs without size restriction.• 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).
3. 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 adhesionsignaling.• Modulation of SFK by Csk influences focal contact formation and actincytoskeletal organization• Modulation of SFK by Csk does not affect the E-cadherin/b-catenin complex• Csk could control metastatic potential of cancer cells through regulatingintegrin-SFK-mediated cell adhesion signaling
4. CD133 expression is not restricted to stem cells, andboth CD133+ and CD133– metastatic colon cancer cellsinitiate tumorsFrom Sergey V. Shmelkov,1 Jason M. Butler et al; The Journal of Clinical Investigation, Volume 118Number 6 June 2008Both CD133+ and CD133– subsets of human metastatic colon cancerexhibit long-term tumorigenic potential.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 June2008CD133 can no longer be considered a marker of CSCs in ametastatic context.
5. What is the target?? Best BestAchievable AchievableStatistical Quality Indices Of Life
6. ESMO Minimum ClinicalRecommendations 2008
7. NCCN Guidelines Liver and lung metastasis Synchronous Metachronous Resectable Unresectable Resectable UnresectableColon Surgery, Limited colon Liver resection Palliativeliver resection resection if or Lung systemicor Lung substantial risk metastasectomy chemotherapymetastatectomy of intestinal and subsequentand subsequent obstruction adjuvantadjuvant and/or if liversystemic systemic burden low ±chemotherapy chemotherapy Radiofrequencyvs Hepatic vs Hepatic ablative therapyartery infusion artery infusion and palliativetherapy ± therapy ± systemicsystemic 5-FU systemic 5-FUand leucovorin chemotherapy and leucovorin
8. Management of Metastatic Colon Cancer ESMO Minimum Clinical NCCN Guidelines updates Recommendations updates •First-line palliative chemotherapy:Determination of the KRAS gene status of fluoropyrimidine (i.v. 5-FU or oral) in variouseither the primary tumor or a site of combinations and schedules.metastasis should be part of the pre- •Combination chemotherapy: 5-treatment work-up for all patients FU/LV/oxaliplatin (FOLFOX) or 5-diagnosed with metastatic colorectal FU/LV/irinotecan (FOLFIRI) provide bettercancer. survival than 5-FU/LV. •The combination of capecitabine plus oxaliplatin has a similar activity to the combination 5-FUEpidermal growth factor receptor (EGFR) and leucovorin/Oxaliplatin.inhibitors, cetuximab (Erbitux) and Second-line chemotherapy: In patients refractorypanitumumab (Vectibix) , either as single to FOLFOX an irinotecan-based regimen can beagents, or, in the case of cetuximab, in proposed and vice versa.combination with other agents, are now Monoclonal antibodies: Bevacizumab in first-linerecommended only for patients with tumors treatment in combination with an irinotecancharacterized by the wild-type KRAS gene. based regimen. Cetuximab and panitumumab in chemorefractory metastatic colorectal cancer.
9. 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 NRFernandez, FG; 2004 100 58 NR Wei, AC; 2006 423 47 NR Rees, M; 2008 929 36 42.5
10. Clinical risk Survival at: Median score* 1 yr 2 yr 3 yr survival, mos 0 93 79 60 74 1 91 76 44 51 2 89 73 40 47 3 86 67 20 33 4 70 45 25 20 5 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 hepatictumor >5 cm.•From: Fong, Y, et al Ann Surg 1999; 230:309.
11. 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 firstintroduced in 1998 by Bismuth and Adam. In their study, tumors weredownsized and became resectable in 16% of patients; the 5-yearpostoperative survival rate in these resected patients was 40%.• In a larger study, 1,104 patients with tumors deemed unresectablereceived oxaliplatin; 335 (23%) subsequently underwent primary hepaticresection, with a survival rate similar to the rate after primaryhepatectomy 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 neoadjuvantchemotherapy for initially unresectable metastatic colon cancer; most ofthese patients (92%) received an oxaliplatin-based regimen. The medianoverall survival time in the resected group was 42.4 months, and themedian time to relapse was 18.4 months.
12. Agents with Proof of Efficacy in Colorectal CancerConventional chemotherapy Targeted therapyFluoropyrimidines VEGF inhibition5-FU (+ LV)* Bevacizumab*Capecitabine* EGF receptor inhibitionUFT (+ LV) Cetuximab*S1 PanitumumabRaltitrexed MatuzumabPemetrexedMitomycin*Irinotecan*Oxaliplatin* * FDA Approved for treatment of advanced CRC (August 2005).
13. 5-FU/ Regimen Irinotecan Oxaliplatin Leucovorin Schedule Capecitabine FU 400 mg/m2 bolus d1, followed 180 400 mg/m2 over 2 FOLFIRI by 2400-3000 mg/m2 over 46 Every 2 weeks mg/m2 d1 hr d1 hours, continuous infusion Douillard 180 100 mg/m2* over 2 FU 400 mg/m2 bolus then 600 Every 2 weeks regimen mg/m2 d1 hr d1,2 before 5-FU mg/m2 over 22 hours d1,2 85 mg/m2 200 mg/m2 over 2 FU 400 mg/m2 bolus then 600 FOLFOX 4 Every 2 weeks d1 hr d1,2 before 5-FU mg/m2 over 22 hours d1,2 FU 400 mg/m2 bolus d1, followed 100 mg/m2 400 mg/m2 over 2 FOLFOX 6 by 2400-3000 mg/m2 over 46 Every 2 weeks d1 hr d1 hours, continuous infusionModified FOLFOX 85 mg/m2 400 mg/m2 over 2 FU 400 mg/m2 bolus d1, followed Every 2 weeks 6 d1 hr d1 by 2400 mg/m2 over 46 hours 130 mg/m2 400 mg/m2 over 2 FU 400 mg/m2 bolus, then 2400 mg/ FOLFOX 7 Every 2 weeks d1 hr d1 m2 over 46 hoursModified FOLFOX 100 mg/m2 400 mg/m2 over 2 FU 3000 mg/m2 over 46 hours Every 2 weeks 7 (Optimox) d1 hr d1Modified FOLFOX 85 mg/m2 200 mg/m2 over 2 FU 2400 mg/m2 over 46 hours Every 2 weeks 7 (ConcePT) d1 hr d1 130 mg/m2 Capecitabine 2000 mg/m2 daily XELOX Every 2 weeks d1 days 1 to 14 85 mg/m2 Capecitabine 2000 mg/m2 daily XELOX Every 2 weeks d1 days 1 to 14 165 85 mg/m2 200 mg/m2 over 2 FOLFOXIRI 3200 mg/m2 over 48 hours Every 2 weeks mg/m2 d1 d1 hr d1
14. Irinotecan Combinations as First-line Therapy in Advanced Colorectal CancerStudy and number Protocol RR, % PFS, mo OS, mo 5-FU/LV bolus (Mayo) 21 4.3 12.6 Saltz et al., IFL 39 7 14.8 n = 457 P value < 0.001 0.004 0.04 5-FU/LV infusional 31 4.4 14.1 Douillard et al., FOLFIRI ("Douillard") 49 6.7 17.4 n = 338 P value < 0.001 < 0.001 0.031 5-FU/LV infusional 34.3 6.4 16.9 Kohne et al., FOLFIRI (AIO2.0) 62.2 8.5 20.1 n = 430 P value < 0.0001 < 0.0001 ns
15. Oxaliplatin Combinations as First-line Therapy in Advanced Colorectal Cancer Study and Protocol RR, % PFS, mo OS, mo number 5-FU/LV infusional 16 6.1 19.9Giacchetti et al., n cm FOLFOX 53 8.7 19.4 = 200 P value < 0.0001 0.048 ns 5-FU/LV infusional 22.3 6.2 14.7de Gramont et al., FOLFOX4 50.7 9 16.2 n = 420 P value 0.000 < 0.0001 ns 5-FU/LV bolus (Mayo) 22.6 5.3 16.1 Grothey et al., FUFOX 49.1 7.8 19.7 n = 252 P value < 0.0001 0.0001 ns
16. 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
17. NCCTG/Intergroup Trial N9741 Five year data and prognostic factoranalysis (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 0.04 (FOLFOX with survival 3.7% 9.8% 5.1% IFL ) .128 (FOLFOX with rate IROX)
18. 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 >4 8.6 6.9 survival, mo* P < 0.05.
19. 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 1A protocol for a review to determine the benefits and harms of EGFRinhibitors 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
21. A case report of 53-year-old male patient, with metastatic colon cancer to theliver, who received First-line chemotherapy on palliative basis oxaliplatin 45mg/m2, 5-fluorouracil 450 mg/m2 and folinic acid 200 mg/m2, all given on thesame day weekly for 6 consecutive weeks followed by a 2-week rest. after thefirst week of the third cycle he developed Guillain-Barre´ Syndrome as a resultof treatment with oxaliplatin. From C. Christodouloua, D. Anastasopoulosb et al; Anti-Cancer Drugs2004, 15:997–999
22. A case report of 63 years old woman with Locally recurrent breast cancerWhile being treated with liposomal doxorubicin and bevacizumab, sheexperienced after 1 month of therapy Bevacizumab-associated osteonecrosisof the jaw. From S. Greuter*, F. Schmid et al; Annals of Oncology Volume 19: No. 2, December 2008.
23. Molecular Predictors of Response to Oxaliplatin-based TherapyName of gene Type of genetic variation Functional significance Clinical consequence involved Fivefold increased risk to fail 5-fluorouracil / Polymorphism in exon 10 Increased ability for repair of oxaliplatin therapy in patients with metastatic XRCC-1 causing an Arg 300 to Gln DNA damage caused by platinum colorectal cancer with at least one Gln mutant substitution adducts allele Increased ability to repair DNA Higher expression levels associated with shorter ERCC-1 Increased mRNA levels damage through the nucleotide survival in patients with metastatic colorectal excision repair (NER) pathway cancer Silent polymorphism C to Unknown but possible trend T/T and C/T genotypes associated with T at position 118 with no towards higher ERCC-1 ERCC-1 shortened survival in patients with metastatic corresponding amino acid expression with higher number colorectal cancer change of T alleles Decreased response rate to 5-fluorouracil / Polymorphism in exon 23 Unknown but possible decreased oxaliplatin in metastatic colorectal cancer XPD causing a Lys 751 to Gln NER efficacy with Lys allele patients with at least one Gln allele (10% vs 24% substitution in patients with Lys/Lys) Diminished enzymatic activity of Polymorphism at position Increased survival in patients homozygous for GSTP-1-105 Val, a detoxifying GSTP-1 313 causing an isoleucine the val/val genotype compared with patients enzyme involved in platinum to valine substitution with one or two Ile alleles resistance Variation in number of CA EGFR transcription activity Higher response rate to 5- fluorouracil / EGFR dinucleotide repeats in declines with increasing number oxaliplatin with increasing number of CA repeats intron 1 of CA repeats in patients with metastatic colorectal cancer
24. Examples of Molecular Predictors of Toxicity to Irinotecan and Oxaliplatin in the Treatment ofGastrointestinal Cancers Name of Function of Genetic variation Functional Target gene Clinical impact drug target gene identified significance Metabolism of UGT1A1*28 2 bp (TA) Increased toxicity in Reduced SN-38, the active insertion in the TATA homozygous and Irinotecan UGT1A1 protein form of box in promoter heterozygous expression irinotecan region patients Metabolism of SN-38, the active Increased toxicity in Irinotecan SNP G to A change in Not UGT1A1 form of heterozygous irinotecan exon1 determined patients Metabolism of Increased toxicity in SN-38, the active Decreased Irinotecan SNP T-3263 T>G in homozygous UGT1A1 form of transcriptional irinotecan promoter region patients who also activity had UGT1A1*28 Protection of Not clearly Oxaliplatin GSTP-1 cells from free I105V SNP C>T determined radical injury
25. Examples of Molecular Predictors of Toxicity to 5-Fluorouracil-based Therapy Genetic variation FunctionalTarget gene Function of target gene Clinical impact identified significance G to A mutation in the invariant GT splice donor Decreased activity of Severe, potentially DPD 5-FU catabolism site flanking exon 14 DPD lethal toxicity (IVS14+1G>A) Activation of 5-FU into Increased frequency FUMP with subsequent of grade 2 or more incorporation into RNA Increased activity of diarrhea and OPRT SNP in exon 3 G213A or inhibition of TS via OPRT leucopenia in conversion into FUDP patients with G213A and FdUMP allele Increased frequency of grade 2 or more Target of 5-FU; source Presence of tandem Three repeats diarrhea and TS of de novo thymidine in repeats 2R or 3R in 5 associated with leucopenia in cell UTR region increased TS activity patients with 2R genotype
26. Deleted in Colon Cancer Protein Expression in Colorectal CancerMetastases: A Major Predictor of Survival in Patients WithUnresectable 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
27. Genetic testing for UGT1A1*28 and *6 in Japanese patientswho 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) 1.8–6.5Prospective study. Aim is to examine the distributions of UGT1A1*28 and UGT1A1*6polymorphisms of the UDP-glucuronosyltransferase (UGT) 1A1 gene.No: of Japanese patients is 300 (male/female, 172/128) with various solid tumors (200CRC, 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 beat increased risk for irinotecan-related neutropenia.Given the genotype frequencies of UGT1A1*28 and UGT1A1*6, genetic testing forUGT1A1 is useful for identifying homozygotes for UGT1A1*6 as well asheterozygotes for UGT1A1*6 andUGT1A1*28, thereby avoiding severe irinotecan-induced toxicity in Japanese patients.