Chemotherapy in Chemotherapy in Primary Liver CancersPrimary Liver Cancers

Hepatocellular Hepatocellular CarcinomaCarcinoma

Biliary Biliary adenocarcinomasadenocarcinomasJennifer J KnoxJennifer J Knox

Medical Oncology, Medical Oncology, Princess Margaret HospitalPrincess Margaret Hospital

Assistant Professor of Medicine,Assistant Professor of Medicine,University Of TorontoUniversity Of Toronto

ObjectivesObjectives

Appreciate the challenges in treating Appreciate the challenges in treating primary liver cancers and the limitations to primary liver cancers and the limitations to older trial dataolder trial data

Develop an approach to choosing Develop an approach to choosing appropriate patients who may benefit from appropriate patients who may benefit from therapiestherapies

Appreciate the recent advances in Appreciate the recent advances in systemic therapy for both HCC and biliary systemic therapy for both HCC and biliary cancers.cancers.

HCCHCC

Hepatocellular Hepatocellular CarcinomaCarcinoma

Fifth most common cancer Fifth most common cancer globallyglobally

5 year survivals < 10 %5 year survivals < 10 %

Incidence is risingIncidence is rising– NA: #8, (ahead of gastric/esophageal NA: #8, (ahead of gastric/esophageal

ca)ca)– Ontario incidence more than doubles Ontario incidence more than doubles

every decadeevery decade

HCC in TorontoHCC in TorontoN = 329 over 4 yearsN = 329 over 4 years

Risk FactorsRisk Factors Percentage Percentage HBVHBV 5555

HCVHCV 2525

Combined HBV & Combined HBV & HCVHCV

3.43.4

AlcoholAlcohol 1616

Other Known CausesOther Known Causes 22

UnknownUnknown 1111

Series from M. Series from M. ShermanSherman

Hepatocellular Hepatocellular Carcinoma: Carcinoma:

The ChallengeThe Challenge

Two diseases: Two diseases:

malignancy and chronic liver malignancy and chronic liver disease.disease.

a virulent cancer a virulent cancer andand a dysfunctional liver a dysfunctional liver

Heterogeneity: etiology & prognosisHeterogeneity: etiology & prognosisboth tumor and liver factors determine both tumor and liver factors determine survival in this highly variable patient survival in this highly variable patient population population

Heterogeneity: Heterogeneity: CLIP ScoreCLIP Score(Cancer of the Liver Italian (Cancer of the Liver Italian

programprogram))Calculate a score based on Calculate a score based on

cirrhosis: Child-Pugh: cirrhosis: Child-Pugh: (albumin Bili, PT, ascites, enceph)(albumin Bili, PT, ascites, enceph)

tumor size (>50% 0f liver)tumor size (>50% 0f liver)

single vs multinodular tumorssingle vs multinodular tumors

AFP (>400)AFP (>400)

portal vein thrombosis (presence)portal vein thrombosis (presence)

score:score: 11 22 33 44 5/65/6

med survivalmed survival 3232 16.516.54.54.5 2.52.5 1.01.0

(months)(months)

n = 435 n = 435 Gallo et al. 1998Gallo et al. 1998

New HCC case

UHN Tumor BoardsResection candidate?

Yes, resect

(10%)No

Transplant candidate?

YesTransplant (10%)

No

RFA candidate?

Yes, RFA

(10%)

No(70% !! )

TACE Candidate ?

•local ds•portal vein patent•Childs A•good PS

•extrahepatic ds•or aggressive local ds•Childs A•good PS

Trial Candidate?New Agents/ approaches

Recurrences

Supportive / palliative Care

NO

Hepatocellular CarcinomaHepatocellular Carcinoma

HCC’s are vascular tumors:HCC’s are vascular tumors:

TACETACETrans-Arterial ChemoembolizationTrans-Arterial Chemoembolization

•Specialised local therapy in HCC•Carefully selected patients

•Local disease•Child’ A•No PVT•Platelets > 50•Preserved organ function•Mod PS

•Interventional radiology and admission to hospital•High dose doxorubicin (75 mg / m2) and lipiodol,+/-gelfoam•Good f/u care

Hong KongHong Kong(HBV)(HBV)

BarcelonaBarcelona(HCV)(HCV)

TACE improves survival vs. best supportive careTACE improves survival vs. best supportive care

2 yr survival of 31% vs 11 %Lo et al.Hepatology 2002; 35: 1164-1171

2 yr survival 63% vs 27%Llovet et al. Lancet 2002; 359: 1734-1739

UHN/PMH experienceUHN/PMH experience

2 yr survival of 55%2 yr survival of 55%

Molinari et al. Clin Molinari et al. Clin Oncol 2006Oncol 2006

Patients:Patients:

•CPT A CPT A

•No PVTNo PVT

•PS 0-2PS 0-2

53 yo woman, HBV, CPT A, multifocal HCC. no PVT, good PS

On transplant list...waiting

TACE as a bridge to transplant

Catheterization of R hepatic artery and injection with•Doxorubicin 75/mg/m2•Lipiodol 10cc in 20cc total volume Disease control at 10 months

Should patients with HCC, not Should patients with HCC, not suitable for radical treatments, be suitable for radical treatments, be

considered for systemic considered for systemic treatments?treatments?

Older series suggest theseOlder series suggest these

patients have med OS of 3 patients have med OS of 3 months - chemo has no role. months - chemo has no role.

But heterogeneity within patient But heterogeneity within patient population studied not population studied not

recognizedrecognized

Single agent Single agent doxorubicindoxorubicin

16 trials, 734 patients, 16 trials, 734 patients, ORR: 18%ORR: 18%– myelosuppression, myelosuppression, ↑↑ hyperbilirubin hyperbilirubin

1 RCT doxo vs BSC (n=60)1 RCT doxo vs BSC (n=60)– Med surv 10.6 wks vs 7.5 wksMed surv 10.6 wks vs 7.5 wks – Rx-related death of 25%. Rx-related death of 25%. Lai et al. Cancer Lai et al. Cancer

1998. 1998.

Other anthracyclinesOther anthracyclines– mitoxantrone, epirubicin are similar, mitoxantrone, epirubicin are similar,

? improved toxicity? improved toxicity– Liposomal doxo - 2 trials - disappointingLiposomal doxo - 2 trials - disappointing

CLIP ScoreCLIP ScoreWhat patients were enrolled What patients were enrolled

on these trials ?on these trials ?Calculate a score based on Calculate a score based on

cirrhosis: Child-Pugh: cirrhosis: Child-Pugh: (albumin Bili, PT, ascites, (albumin Bili, PT, ascites, enceph)enceph)

tumor size (>50% 0f liver)tumor size (>50% 0f liver)

single vs multinodular tumorssingle vs multinodular tumors

AFP (>400)AFP (>400)

portal vein thrombosis (presence)portal vein thrombosis (presence)

score:score: 11 22 33 44 5/65/6

med survivalmed survival 3232 16.516.54.54.5 2.52.5 1.01.0

(months)(months)

Gish et al JCO July 2007

Phase III trial of Nolatrexed vs. Doxorubicin in advanced HCC

•1st Modern trial in HCC (CLIP 0-3) •Med surv of 8 months with Doxo !

Doxorubicin Doxorubicin combinationscombinations

Numerous combinations – toxicNumerous combinations – toxic

470 patients : RR 14%470 patients : RR 14%

Exception: Exception: PIAF (cisplatin, INFPIAF (cisplatin, INFαα doxo, 5-FU doxo, 5-FU))

– Phase II RR 26% Phase II RR 26% 9 patients downstaged to surgery9 patients downstaged to surgery4 of 9 had path CRs!4 of 9 had path CRs! Leung et al. Clin Can Res Leung et al. Clin Can Res 1999.1999.

chemosensitivity and radiological chemosensitivity and radiological underestimation true responseunderestimation true response

significant toxicity: Rx-related deathssignificant toxicity: Rx-related deaths

Phase III Trial of Phase III Trial of PIAF vs Doxo in inoperable PIAF vs Doxo in inoperable

HCCHCCYeo et al. J Natl Cancer Inst 2005Yeo et al. J Natl Cancer Inst 2005

180 patients:180 patients: one of the largest chemo trials in one of the largest chemo trials in HCCHCC

DoxoDoxo PIAFPIAFORRORR 11%11% 20%20% p=0.09 p=0.09SDSD 40%40% 31%31%

Med surv Med surv 7.1 mo7.1 mo 8.4 mo 8.4 mo p=0.87p=0.87

*PIAF: Septic death rate of 4 %, *PIAF: Septic death rate of 4 %, febrile neutropenia > 40%febrile neutropenia > 40%

Other CytotoxicsOther CytotoxicsNo other drug appears better. All RRs < 10%No other drug appears better. All RRs < 10%

FluoropyrimidinesFluoropyrimidines– Infusional or capecitabine maybe bestInfusional or capecitabine maybe best

TaxanesTaxanes– Not well studied…but appear toxicNot well studied…but appear toxic

Topoisomerase inhibitorsTopoisomerase inhibitors– CPT-11 toxicCPT-11 toxic– Etoposide betterEtoposide better

Nucleoside analoguesNucleoside analogues– Gemcitabine inactive alone / combinations (?SD)Gemcitabine inactive alone / combinations (?SD)– Gem/ cisplatin combo more promisingGem/ cisplatin combo more promising

TS inhibitorsTS inhibitors– Nolatrexed stable disease in phase IINolatrexed stable disease in phase II– ...phase III worse than single agent doxo...phase III worse than single agent doxo

Other Agents in HCCOther Agents in HCC

Anti-hormonal Agents

Tamoxifen Anti-

androgen

3 x RCT: neg large RCT :neg

Immuno-therapy

IFN others

several RCT-contradictory results

Somatostatin 41% HCC

Octreotide

Sandostatin LAR

1 RCT: pos 2 RCT neg

HCC: Promise of Targeted AgentsHCC: Promise of Targeted Agents

appropriate to test new agentsappropriate to test new agents

better tolerated in patients with liver better tolerated in patients with liver dysfunctiondysfunction

promising targets:promising targets:

– angiogenesis inhibitors ( angiogenesis inhibitors ( sorafenibsorafenib, , Avastin)Avastin)

– growth factor inhibitors (EGFR, Ras ,Raf)growth factor inhibitors (EGFR, Ras ,Raf)– apoptosis and cell cycle modifiersapoptosis and cell cycle modifiers– unique antigens or receptors (HGF)unique antigens or receptors (HGF)

low grade low grade dysplasticdysplastic

high grade high grade dysplasticdysplastic

HCCHCC

H/EH/E

SMSMactinactin

CD34CD34

Vascularity and Angiogenesis in Multistep HCC Carcinogenesis

Park et al. Arch Pathol Lab Med 2000; 124:1061

Sorafenib (Nexavar) in HCCSorafenib (Nexavar) in HCCFew responses seen in early trials

TTP of 6 months in phase II thought encouraging (most phase IIs in HCC TTP is 2 months)

3 randomised trials completed

Phase III: 1)Nexavar vs BSC (SHARP trial)

:2) Asian-Pacific

Phase II: 3) Doxo vs Doxo + Nexavar

SHARP: Sorafenib Hepatocellular SHARP: Sorafenib Hepatocellular Phase III Study Design Phase III Study Design

Sorafenib400 mg bidSorafenib400 mg bid

PlaceboPlacebo

Major endpoints• Survival • PFS• QOL

(1:1) Randomization

Stratification

Eligibility criteria• Histologically/cytologically

confirmed, unresectable and/or metastatic disease

• Child-Pugh A• Measurable disease• ECOG PS 0 or 1• Good organ function• Prior TACE allowed

Opened 2005

Hand–foot skin reactionHand–foot skin reaction palmar plantar erythrodysethesias (PPE) palmar plantar erythrodysethesias (PPE)

Acral Erythema◦painful, edematous,◦ erythematous◦parathesias◦hyperkeratosis ◦desquamation

SHARP HCV subgroupSHARP HCV subgroup

Sorafenib placebo

n 99 98

OS (mo) 14HR 0.58

7.9

TTP 7.6 2.8

Bolondi et al. GI ASCO 2008

c/w SHARP : OS 10.7 vs 7.9 mo, HR 0.69

20% HBV subset?

Asia-Pacific phase III Asia-Pacific phase III

Cheng et al ASCO 2008

Cheng et al ASCO 2008

22ndnd trial: trial:Doxorubicin +/- sorafenib Doxorubicin +/- sorafenib

randomized phase IIrandomized phase II

Study DesignStudy Design

Doxorubicin total allowed 360 mg/m2 and in approved circumstances 450 mg/m2, after which sorafenib versus placebo can be continued as single agent

Eligibility

Child-Pugh A

ECOG PS: 0, 1, 2

(1:1

) R

and

om

izat

ion

(N~

96)

Period 1 Period 2

Continue

until

withdrawal,

PD, or death

6 cycles of:• Doxorubicin 60 mg/m2 IV*

Day 1 in 21-day cycles• Sorafenib 400 mg po bid

6 cycles of:• Doxorubicin 60 mg/m2 IV*

Day 1 in 21-day cycles• Placebo 2 tablets po bid

Placebo2 tablets po bid

Sorafenib400 mg po bid

ResultsResultsDXR/sorafenibDXR/sorafenib

(n=47)(n=47)

DXR/placeboDXR/placebo

(n=49)(n=49)

TTP (months)TTP (months) 8.68.6 4.84.8

OS (months)OS (months) 13.713.7 6.56.5

PFS (months)PFS (months) 6.96.9 2.82.8

ResponseResponse

(CR+PR) n(%)(CR+PR) n(%)

2 (4)2 (4) 1 (2)1 (2)

Response (SD)Response (SD) 36 (77)36 (77) 27 (55)27 (55)

Definitive analysis (data from March 2007 cutoff, independent assessment, TTP: 38 events, OS: 50 events, PFS: 70 events )

Exploratory Comparison Per Protocol: Exploratory Comparison Per Protocol: Overall SurvivalOverall Survival

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

0.00

0.25

0.50

0.75

1.00

Months From Randomization

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 months

STRATA: Doxorubicin plus sorafenib Censored treatment: Doxorubicin + sorafenibDoxorubicin + placebo Censored treatment: Doxorubicin + placebo

Median OS: Doxorubicin + sorafenib: 13.7 (95% CI: 10.4-can not be estimated) Doxorubicin + placebo: 6.5 (95% CI: 4.9-9.5) Hazard Ratio: 0.45 p= 0.0049 Total # of events: 50

•March 2007 data cut-off•Based on independent radiological assessment population: subjects valid for ITT

-100

-80

-60

-40

-20

0

20

40

60

80

100

Doxorubicin + placebo (n=49)

Doxorubicin + sorafenib (n=47)

Percent Change in Target Lesion From Baseline Percent Change in Target Lesion From Baseline (Independent Assessment)(Independent Assessment)

Ch

ang

e in

Tar

get

Les

ion

F

rom

Bas

elin

e (%

)

62% 29%

Safety and Study Drug AdministrationSafety and Study Drug Administration

DXR/sorafenib DXR/sorafenib (n=47)(n=47)

DXR/placebo DXR/placebo (n=49)(n=49)

All cause adverse events (AE) (%)All cause adverse events (AE) (%) 100100 100100

Drug-related AE (%)Drug-related AE (%) 9292 8888

Serious all cause AE (SAE) (%) Serious all cause AE (SAE) (%) 3838 4040

Drug related SAE (%)Drug related SAE (%) 2121 1717

AE leading to discontinuation (%)AE leading to discontinuation (%) 3636 3333

Death within 30 days (%)Death within 30 days (%) 1111 2121

Median daily dose study drug (mg)Median daily dose study drug (mg) 708708 763763

Median total doxorubicin dose (mg/mMedian total doxorubicin dose (mg/m22)) 165165 120120

CALGB 80802 : Phase III trial of sorafenib ± CALGB 80802 : Phase III trial of sorafenib ± Doxorubicin in advanced HCC Doxorubicin in advanced HCC

PI: Ghasan Abou-AlfaPI: Ghasan Abou-Alfa

600 patient trial, same patient 600 patient trial, same patient population....population....

randomized sorafenib vs randomized sorafenib vs sorafenib/doxorubicin combinationsorafenib/doxorubicin combination..– Primary endpoint is OS Primary endpoint is OS – Includes radiological correlate Includes radiological correlate – protocol at CTEP review, ? NCIC.protocol at CTEP review, ? NCIC.

72 yo woman, HBV+, recurrent biopsy-proven multifocal 72 yo woman, HBV+, recurrent biopsy-proven multifocal HCC, +PVT, 8 months post resection. Child A, good PS. HCC, +PVT, 8 months post resection. Child A, good PS.

Enrolled on phase II trial of Doxorubicin + SorafenibEnrolled on phase II trial of Doxorubicin + Sorafenib

Baseline triphasic CT

72 yo woman, HBV+, recurrent biopsy-proven multifocal HCC, +PVT, 8 72 yo woman, HBV+, recurrent biopsy-proven multifocal HCC, +PVT, 8 months post resection. Child A, good PS. Enrolled on phase II trial of months post resection. Child A, good PS. Enrolled on phase II trial of

Doxorubicin + SorafenibDoxorubicin + Sorafenib

baseline

C-2, slight progression, SD

C-4, SDDox held

C-6, hypodenseminor response,SD by RECIST

C8, ongoing SD

C-10, all more hyperdensePD by RECIST

What is the mechanism of drug resistance ?

HCC Sorafenib Trials SummaryHCC Sorafenib Trials Summary

Phase II Rand Phase II SHARPPhase III

Asia-PacificPhase III

sorafenib Dox + sorafenib

Dox + placebo

sorafenib placebo sorafenib placebo

n 136 47 49 299 303 150 76CPT A/B

72/28%

A A A A A A

OS (mo)

9.2 13.7 6.5 10.7HR 0.69P=0.00058

7.8 6.5HR 0.68P=0.014

4.2

TTP 5.5 8.6 4.8 5.5 2.8 2.8 1.4

PFS 6.9 2.8 NR NR HR 0.62

PR +SD

- 81 57 73 68 57 28

TTSP - - - No diff No diff

Sorafenib in HCCSorafenib in HCC

Body of evidence supports sorafenib as the Body of evidence supports sorafenib as the new reference standard of care in advanced new reference standard of care in advanced HCC (Child A, good PS)HCC (Child A, good PS)This has launched many new studies…This has launched many new studies…

Adjuvant setting ( surgery/ RFA)Adjuvant setting ( surgery/ RFA) ECOG 1207: Peri TACE (+/- sorafenib)ECOG 1207: Peri TACE (+/- sorafenib) Combinations with other targeted agents and doxCombinations with other targeted agents and dox Other HCC populations (Child B, post transplant)Other HCC populations (Child B, post transplant)

Erlotinib (Tarceva) in HCC

Targeting EGFR in HCC

Phase II, n=38…Philip et al, JCO 2005– 88% EGFR+ – 32% progression-free at 6 months– 10% PR– Med OS 13 months (encouraging)

Bevacizumab in HCCPhase II, n = 46…Seigel et al, JCO 2008– 65% progression-free at 6 months– 14% PR (good single agent activity)– Med OS 13 months (encouraging) – Bev associated with significant reductions in tumor Bev associated with significant reductions in tumor

enhancement by DCE MRI and reductions in circulating enhancement by DCE MRI and reductions in circulating VEGF-A levels VEGF-A levels

Early studies combining erlotinib and Early studies combining erlotinib and bevacizumab suggest synergism in HCC….. bevacizumab suggest synergism in HCC….. Phase III in planningPhase III in planning Thomas et al ASCO 2007Thomas et al ASCO 2007

Patient : ( Patient : ( cryptogenic cirrhosis, 2 HCC lesions (largest 11.3 cm))cryptogenic cirrhosis, 2 HCC lesions (largest 11.3 cm))

March 2003, arterial phaseMarch 2003, arterial phase March 2003, venous phaseMarch 2003, venous phase

Oct 2003, arterial phaseOct 2003, arterial phase Oct 2003, venous phaseOct 2003, venous phase

Bevacizumab x 6 monthsBevacizumab x 6 months

Avastin phase IIAvastin phase II

•Grade 1 fatigueGrade 1 fatigue& epistaxis only& epistaxis only

Off study Off study at 7.2 monthsat 7.2 monthssecondary to secondary to ileac (bone) metileac (bone) met

Targeted Therapy in HCCTargeted Therapy in HCCTarget/ agent

VEGF VEGFR PDGF EGFR Raf M-Tor

IGF HGF status

Bev + Phase II completed , combination studies planned

Sunitinib + + Phase II completedPhase III planned

Sorafenib + + + Phase IIIs completed

Abbott + + Phase I/II underway

Erlotinib + Phase II complete

Genfitinib + Phase II complete

Lapatinib + Phase II complete

Cetux + Phase II complete

Temsirol. + Phase I/ II underway

Rad001 + Phase I/II planned

Thalid + Phase III underway

The near Future: A new HCC case

Multidisplenary Tumor Boards

Curative approaches

Yes(30%)

No(70% !! )

TACE Candidate?TACE Candidate? •local ds

•portal vein patent•Childs A, good PS

•extrahepatic ds•or aggressive local ds•Childs A/B, good PS

Sorafenib Rx vs.Sorafenib Rx vs.Trial Candidate : Trial Candidate : Sorafenib combinations, novel agents, radiation/ targeted therapy, novel approaches

Recurrences

Supportive / palliative Care

NO

Adjuvant Trial !

Adjuvant Trial !

Provincial Coverage (CCO)

ConclusionsConclusionslarger randomized studies are now being donelarger randomized studies are now being done– Evaluate patients of uniform and Evaluate patients of uniform and

intermediate prognosis intermediate prognosis – Survival, PFS as the primary endpoint. Survival, PFS as the primary endpoint.

Systemic therapy: new reference Systemic therapy: new reference standard with sorafenib standard with sorafenib

Appropriate patients should be referred Appropriate patients should be referred for clinical trials when available. for clinical trials when available.