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.