Medical Management of Colorectal Cancer - Abramson Cancer Center

Medical Management ofColorectal CancerBruce J. Giantonio, MD

The Good News• More people with early disease can be cured:- Improved adjuvant therapy• People with advanced disease live longer withtreatment:- 4-5 times longer than NO treatment- YEARS instead of MONTHS• Many new therapies currently in clinical trials

The Bad News• Few people undergo screening• Not all people with advanced disease benefitfrom treatment- Need to further refine our ability to ‘tailor’ treatmentbased on risk• Only 2-3% of adults with cancer in the USparticipate in clinical trials• Side effects remain a problem

Stage at Diagnosis2008 new cases:colon cancer: 108,070rectal cancer: 40,7403 rd leading cancer diagnosis2 nd leading cause of cancer death21% Stage IV14% Stage I37% Stage III28% Stage IICancer Statistics: Jemal et al; CA Cancer J Clin 2008

Staging of Colorectal CancerSTAGE:1 2 3INSIDE orLUMENMUCOSAMUSCULARIS MUCOSASUBMUCOSAWALLUSCULARIS PROPRIASEROSAFATLYMPH NODESOUTSIDEAdapted from Skarin. Slide Atlas of Diagnostic Oncology. Gower Medical Publishing; 1997:Fig 5.98.

Colon Cancer TreatmentStage ISURGERYStage IV21%Stage I14%Stage III37%Stage II28%Cancer Statistics: Jemal et al; CA Cancer J Clin 2005;55:10-30

Colon Cancer TreatmentStage ISURGERYStage IV21%Stage I14%Stage III37%Stage II28%Stage IISURGERY+/- chemoCancer Statistics: Jemal et al; CA Cancer J Clin 2005;55:10-30

Colon Cancer TreatmentStage ISURGERYStage IV21%Stage I14%Stage IIIStage III37%SURGERY →chemotherapyStage IISURGERY+/- chemoStage II28%Cancer Statistics: Jemal et al; CA Cancer J Clin 2005;55:10-30

Colon Cancer TreatmentStage IVCHEMOTHERAPY+/- surgeryStage IV21%Stage ISURGERYStage I14%Stage IIIStage III37%SURGERY →chemotherapyStage IISURGERY+/- chemoStage II28%Cancer Statistics: Jemal et al; CA Cancer J Clin 2005;55:10-30

Impact of Family History6Relative Risk543211.722.755.370First-DegreeRelativeTwoRelatives≥ 1 First-DegreeRelatives &Age < 45 yFuchs et al. N Engl J Med. 1994;331:1669-1674.1674.

Medical Management ofColorectal CancerChemotherapy and Targeted Therapy

Chemo• Interrupts machinery ofcell division- Prevents cellular replication• Not specific to cancercells• Side effects

Chemo vs Targeted• Interrupts machinery ofcell division- Prevents cellular replication• Not specific to cancercells• Side effects• Interrupts machinery ofmalignancy- Growth signals for tumor cells- Blood supply for tumor cells• More specific to cancercells• Fewer side effects

Medical Management ofColorectal CancerChemotherapy

Key Therapeutic Agents in CRC:Historical Perspective~1960: 5-FU

Key Therapeutic Agents in CRC:Historical Perspective~1960: 5-FU40 YEARS!1998: IRINOTECAN

Key Therapeutic Agents in CRC:Historical Perspective~1960: 5-FU40 YEARS!1998: IRINOTECAN2001: CAPECITABINE2002: OXALIPLATIN2004: CETUXIMAB2004: BEVACIZUMAB2006: PANITUMUMAB

Combination ChemotherapyFOLFOX vs XELOX vs FOLFIRI

Infusional 5-FU/LV Regimens5FU BolusLV5FU2LV5FU 46 hrsEvery 2 weeks5FU= 5-FluorouracilLV= leucovorin

Infusional 5-FU/LV RegimensX = OxaliplatinX = IrinotecanFOLFOX65FU BolusLV 5FU 46 hrsFOLFIRI+ BiologicXBEvery 2 weeks+ BiologicL = leucovorinB = anti-vegf or anti-egfrX = oxaliplatin OR irinotecan5FU= 5-Fluorouracil

Xelox or CapOxXELOX : 21-day cycleOxaliplatinCAPECITABINE twice a dayRestD1 D2 D15 D21OX = oxaliplatin; LV = leucovorin; BV = bevacizumab; PL = placebo; 5-FU = 5-fluorouracil

Medical Management ofColorectal CancerTargeted Therapy

A Model Antibody

Avastin (Bevacizumab, rhuMAb-VEGF)• Binds to vascular endothelialgrowth factor (VEGF)• 93% human, 7% murine

Endothelial Cell Activation:VEGF Signal TransductionVEGFPPPPSurvivalMigrationEndothelial CellProliferation29

Endothelial Cell Activation:VEGF Signal TransductionAnti-VEGFantibodiesbevacizumabVEGFEndothelial Cell30

Cetuximab (Erbitux)• Binds Epidermal growth factorreceptor (EGFR)• Approx 70% human, 30%murine

EGFR Signal TransductionRASRAFPI3-KSOSpY K K pYGRB2pYMEKPTENAKTSTATMAPKGene transcriptionCell-cycle progressionG2MSG1Proliferation/MaturationSurvival/ApoptosisAngiogenesisMetastasis

Agents Targetingthe Epidermal Growth Factor PathwayEGFAnti-EGFRantibodiesCetuximab,panitumumabPPPPTumor cell

The Good News• People with advanced disease live longer withtreatment:- 4-5 times longer than NO treatment- YEARS instead of MONTHS

Clinical Trials:The Key to New Discoveries•Phase I:•what are the toxicities?•what should the dosage be?•Phase II:•does the new treatment have a positive effect againsta specific type of cancer?•Phase III:•how does the new treatment compare with the bestexisting treatment?

N9741 Phase III Trial ofFirst-line IFL vs FOLFOX4 vs IROXSchemaRANDOMIZATIONN=245Bolus IFL(5-FU/LV + Irinotecan)Goldberg RN et al. JCO 1/1/04.

N9741 Phase III Trial ofFirst-line IFL vs FOLFOX4 vs IROXSchemaRANDOMIZATIONN=245N=250N=246Bolus IFL(5-FU/LV + Irinotecan)FOLFOX4(5-FU/LV + Oxaliplatin)IROX(Irinotecan/Oxaliplatin)Goldberg RN et al. JCO 1/1/04.

N9741: Overall Survival% Alive1009080706050403020100FOLFOX4 vs IFL (P=.0001; HR=0.66)IROX vs IFL (P=.04)0 1 2YearsIFLFOLFOX4IROXGoldberg et al. J Clin Oncol. 2004;22:23.

N9741: Overall Survival% Alive100908070605040302010NOTreatmentFOLFOX4 vs IFL (P=.0001; HR=0.66)IROX vs IFL (P=.04)IFLFOLFOX4IROX00 1 2YearsGoldberg et al. J Clin Oncol. 2004;22:23.

N9741: Safety ProfilePercent5045403530252015105014411Febrileneutropenia2912Grade 3/4 Adverse Events*25Diarrhea15619Nausea13423Vomiting228 8IFLFOLFOX4IROX219Infections Overallneuropathies7P≤.002 for all comparisons of IFL and IROX vs FOLFOX.*Observed in >10% of patients in any treatment arm.Goldberg et al. J Clin Oncol. 2004;22:23.

C80405: Intergroup 1 st -line TrialmFOLFOX6orFOLFIRI(PhysicianChoice)RandomizationBevacizumabCetuximabBevacizumab +Cetuximab

Medical Management ofColorectal CancerAdjuvant Therapy

Adjuvant therapy is treatment given aftersurgery to reduce the risk of recurrence

CRC: 5-Year Survival by Stage10090%Without any adjuvant therapy% Survival80604070%50%200Stage I Stage II Stage III

The Good News• More people with early disease can be cured:- Improved adjuvant therapy

CRC: 5-Year Survival by Stage% Survival10080604090%With adjuvant therapy?81%200Stage I Stage II Stage III

MOSAIC Phase III TrialStage II CRC (40%)Stage III CRC (60%)RANDOMIZEn=1,100n=1,100FOLFOX4LV5FU2Primary end point: 3-year DFSSecondary end points: safety, OSde Gramont et al. Proc Am Soc Clin Oncol. 2003;22:253. Abstract 1015.

DFS by Treatment Arm (ITT)Probability10.90.80.723% risk reduction in the FOLFOX-4 armHazard ratio: 0.77 (0.65-0.92), P

What’s the next Phase III Study?RANDOMIZATIONFOLFOXFOLFOX + ?

NSABP C-08Phase III: Stage II & IIIRANDOMIZATIONFOLFOXFOLFOX + Bevacizumab

N0147Phase III: Stage II & IIIRANDOMIZATIONFOLFOXFOLFOX + Cetuximab

Managing Cancer TreatmentSide Effects

Chemotherapy Side EffectsIrinotecan:• Early and late diarrhea• Neutropenia• Hair lossCapecitabine:• Hand foot syndrome• Nausea• Diarrhea• Mucositis• NeutropeniaOxaliplatin:• neuropathy• Decreased WBC’s• Cold hypersensitivity• Nausea and vomiting• Hair thinning5FU:• Diarrhea• Mucositis• Myelosuppression• Hand foot syndrome

Hand-Foot Syndrome• Keep hands & feet clean and moist• Apply topical alcohol free emollients andcreams (Aveeno, Lubriderm,Udder Cream,Bag Balm)- AVOID topical anesthetics or creamscontaining diphenhydramine (Benadryl) →Can worsen toxicity• Periodically Immerse hands and feet in coolwater• Use mild soap and no rubbing

Peripheral Neuropathy• Sense of touch is distorted- ordinary touch can beunpleasant or painful.• Burning or prickling feeling without stimulus• Decreased touch sensation• Difficulty sensing the position, location, orientation,and movement of the body and its parts(Proprioception)• Important to report ANY of these symptoms to healthcare provider

Targeted Therapies: SideEffectsBevacizumab (Avastin)• Hypertension• Bleeding• Delayed wound healing• Arterial blood clots• Gastrointestinal perforation (rare)• Dumping protein into urine (Proteinuria)

Targeted Therapies: SideEffectsCetuximab (Erbitux)• Infusion reactions (occurs in 3% of patients)• Interstitial lung disease: scarring of the lungs (rare)• Acneform rash• Low magnesium and calcium levels (electrolytesmust be monitored)

Acneiform Rash•Avoid sun, heat &humidity•Use mild soaps•Water based makeup isgenerally well toleratedPharmacologic Mgmt.• Topical and/orantibiotics• Topical and/or oralantihistamines• Cool compresses• Petroleum jelly,silver sulfadiazineointment forulcerative lesions

The Good News• More people with early disease can be cured:- Improved adjuvant therapy• People with advanced disease live longer withtreatment:- 4-5 times longer than NO treatment- YEARS instead of MONTHS• Many new therapies currently in clinical trials

The Bad News• Few people undergo screening• Not all people with advanced disease benefitfrom treatment- Need to further refine our ability to ‘tailor’ treatmentbased on risk• Only 2-3% of adults with cancer in the USparticipate in clinical trials

Good ResourcesAbramson Cancer Center ofthe University of Pennsylvaniawww.ONCOLINK.comThe National Cancer Institute (NCI)1-800-4-CANCERwww.cancer.gov*The Coalition of Cancer CooperativeGroupswww.TrialCheck.orgAmerican Cancer Society1-800-ACS-2345www.cancer.orgNational Comprehensive CancerNetwork (NCCN)1-888-909-NCCNwww.nccn.orgThe Wellness Community:1-888-793-WELLwww.thewellnesscommunity.org.*not www.nci.gov that’s for the NUCLEAR CONTROL INSTITUTE

YO!THANKYOU!

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