J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Overview of Colorectal Cancer, Recent...

J. Macdonald, CRC Symposium, 1.23.2001J. Macdonald, CRC Symposium, 1.23.2001OncologyOncology Spectrums Spectrums, NYC, NYC

Overview of Colorectal Cancer, Overview of Colorectal Cancer, Recent Studies, and Recent Studies, and

Trial DesignTrial Design

John S. Macdonald, MDJohn S. Macdonald, MD

Saint Vincent’s Comprehensive Saint Vincent’s Comprehensive Cancer CenterCancer Center


Cancer Incidence/DeathCancer Incidence/Death

IncidenceIncidence DeathDeathTotal (all cancers)Total (all cancers) 1,220,1001,220,100 552,200552,200

GI cancersGI cancers1.1. Large bowelLarge bowel 133,600 133,600

56,20056,2002.2. PancreasPancreas 28,300 28,300 28,200 28,2003.3. StomachStomach 21,500 21,500 13,000 13,0004.4. LiverLiver 15,300 15,300

13,80013,8005.5. EsophagusEsophagus 12,300 12,300 12,100 12,1006.6. BiliaryBiliary 6,900 6,900

3,4003,400

Greenlee RT, Greenlee RT, et al. et al. Cancer Statistics 2000. Cancer Statistics 2000. CA: A Journal for Clinicians. 2000;50:7-33. CA: A Journal for Clinicians. 2000;50:7-33.


Colorectal CancerColorectal CancerEtiologyEtiology

Population risk:Population risk: Lifestyle Lifestyle Dietary Dietary

Personal risk:Personal risk: GeneticGenetic

Prevention:Prevention: Long-term dietary modificationLong-term dietary modificationMedical model: Medical model:

NSAIDs/ASA/othersNSAIDs/ASA/others

APCAPCFNPCCFNPCC


Genetic Alterations Most Genetic Alterations Most Commonly Associated With Commonly Associated With

Colorectal CancerColorectal CancerDominant oncogenesDominant oncogenes••c-srcc-src•K-rasK-ras•C-mycC-myc

Tumor suppressor genesTumor suppressor genes•MCC (mutated in colorectal cancer)MCC (mutated in colorectal cancer)•DCC (deleted in colorectal cancer)DCC (deleted in colorectal cancer)•APC (adenomatosis polyposis coli)APC (adenomatosis polyposis coli)•p53p53

DNA repair genesDNA repair genes•MSH2MSH2

PrognosisPrognosis•MSIMSI


Phase III Study Phase III Study Colon CancerColon Cancer

683683AdvancedAdvanced

Colon Colon CancerCancerCasesCases

RRAANNDDOOMM

CPT-11CPT-115-FU5-FULeucovorin (222 cases)Leucovorin (222 cases)

5-FU5-FULeucovorin (221 cases)Leucovorin (221 cases)

CPT-11 (223 cases)CPT-11 (223 cases)

Saltz, Saltz, et al.et al. NEJM 2000;343:905. NEJM 2000;343:905.


Phase III Colon CancerPhase III Colon Cancer

ToxicityToxicityGr 3Gr 3

RegimenRegimen CasesCases RRRR PFSPFS DiarrheaDiarrhea MucositisMucositis ANCANC SurvivalSurvival (N) (N) (%) (%) (%) (%) (%) (%) (%) (%) (months)(months)

CPT-11/CPT-11/ 5-FU/LV5-FU/LV 231 231 39* 7.0**39* 7.0** 22 22 2.2 2.2 54 54 14.8 *** 14.8 ***

5-FU/LV5-FU/LV 226 226 21 4.321 4.3 13 13 16.9 16.9 66 66 12.6 12.6

CPT-11CPT-11 226 226 18 4.218 4.2 31 31 2.2 2.2 31 31 12.0 12.0

* * PP<0.001<0.001 ** ** PP =0.004 =0.004 *** *** PP =0.04 =0.04

Saltz, Saltz, et al.et al. NEJM 2000;343:905. NEJM 2000;343:905.


Colorectal CancerColorectal CancerCurrent Adjuvant StudyCurrent Adjuvant Study

5-FU 500 mg/m5-FU 500 mg/m22

Leucovorin 500 mg/mLeucovorin 500 mg/m22 weekly x6 weekly x6 followed by 2 weeks rest followed by 2 weeks rest (4 cycles=32 weeks)(4 cycles=32 weeks)

5-FU 500 mg/m5-FU 500 mg/m22

Leucovorin 20 mg/mLeucovorin 20 mg/m22

CPT-11 125 mg/mCPT-11 125 mg/m2 2 weekly x4weekly x4followed by 2 weeks restfollowed by 2 weeks rest(5 cycles=30 weeks)(5 cycles=30 weeks)

RRAANNDDOOMM


StructureStructureWater-soluble platinum derivative with an oxalato Water-soluble platinum derivative with an oxalato ligand and a 1,2-diaminocyclohexane (DACH) carrierligand and a 1,2-diaminocyclohexane (DACH) carrier

The DACH carrier ligand can exist in 3 stereochemical The DACH carrier ligand can exist in 3 stereochemical conformations:conformations:

oxaliplatin (I-OHP)oxaliplatin (I-OHP)Pt(oxalato)(trans-I-dach)Pt(oxalato)(trans-I-dach)Pt(oxalato)(1R,2R-dach)Pt(oxalato)(1R,2R-dach) MW 397.3 MW 397.3


Colorectal CancerColorectal Cancer

• De Gramont survival and responseDe Gramont survival and response

SurvivalSurvival PFS PFS ResponseResponse (Months)(Months) ((Months)Months) ( (%)%)

5-FU/Leucovorin5-FU/Leucovorin 14.7 14.7 6.0 6.0 28.6 28.6

5-FU/Leucovorin/5-FU/Leucovorin/ OxaliplatinOxaliplatin 16.2 16.2 8.2 8.2 49.5 49.5

PP=NS=NS PP=0.0001=0.0001

De Gramont, et al.: JCO 2000;18:2968.De Gramont, et al.: JCO 2000;18:2968.

PP=0.0003=0.0003


NSABP C07NSABP C07

ARM 1ARM 1• LeucovorinLeucovorin

– 500 mg/m500 mg/m22/2 hours/2 hours

• 5FU5FU– 500 mg/m500 mg/m22 bolus bolus

– 1 hour into leucovorin1 hour into leucovorin

• (GITSG schedule)(GITSG schedule)• Weekly, 6 weeks/8Weekly, 6 weeks/8• Total of 3 cyclesTotal of 3 cycles

ARM 2ARM 2• 5FU/leucovorin5FU/leucovorin

– Same as Arm 1Same as Arm 1– Weeks 1 though 6 Weeks 1 though 6

of 8of 8

• OxaliplatinOxaliplatin– 85 mg/m85 mg/m22

– Weeks 1, 3, and 5Weeks 1, 3, and 5

• Total of 3 cyclesTotal of 3 cycles


Oral Fluorinated PyrimidinesOral Fluorinated Pyrimidines

AdvantagesAdvantages

Oral RouteOral RoutePharmacokineticsPharmacokinetics

Radiation SensitizationRadiation Sensitization


Oral Fluorinated Oral Fluorinated PyrimidinesPyrimidines

UFTUFT

5-FU/7765-FU/776

S-1S-1

CapecitabineCapecitabine

5'-deoxy-5-5'-deoxy-5-fluorouridinefluorouridine

DPDDPDinhibitioninhibition

ProdrugsProdrugs


0

0.2

0.4

0.6

0.8

1

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

MONTHS

Updated SurvivalUpdated Survival

UFT/LV 5-FU/LVN 409 407No. deaths 349 351Median 12.4 13.4

HR*: 0.96 (95.6%; CI=0.83-1.13)HR*: 0.96 (95.6%; CI=0.83-1.13)

* Ratio 5-FU/LV:UFT/LV* Ratio 5-FU/LV:UFT/LV


Phase III StudyPhase III Study Capecitabine Capecitabine

ResponseResponseRegimenRegimen CasesCases PRPR DurationDuration PFSPFS SAESAE

(N)(N) % % months months monthsmonths % %CapecitabineCapecitabine2500 mg/m2500 mg/m22/d /d 26.6 26.6 x14 daysx14 days 301 (2.3% CR) 301 (2.3% CR) 7.3 7.3 5.3 5.3 12.512.5

5-FU/LV5-FU/LVMayo Mayo 17.9 17.9 RegimenRegimen 301 (2.3% CR) 301 (2.3% CR) 9.6 9.6 4.8 4.8 17.717.7

Twelves, Twelves, et al.et al. Proc ASCO.Proc ASCO. 1999;18:263. 1999;18:263.


Cusp of the futureCusp of the futureCyanidesCyanidesArsenicalsArsenicalsHeavy metalsHeavy metals

XRTXRTAlkylatorsAlkylators AntimetabolitesAntimetabolites

Tumor suppressorTumor suppressor gene products gene productsEGFREGFRAnti-angiogenesisAnti-angiogenesisAnti-RASAnti-RASAnti-senseAnti-senseGene RxGene Rx

PenicillinPenicillinID - 1900ID - 1900

Oncology - Oncology - 20002000

J. Macdonald, CRC Symposium, 1.23.2001 Oncology Spectrums, NYC Overview of Colorectal Cancer, Recent...

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