Chemotherapy in Primary Liver Cancers

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Chemotherapy in Primary Liver Cancers

• Hepatocellular Carcinoma
• Biliary adenocarcinomas

Jennifer J Knox Medical Oncology, Princess
Margaret Hospital Assistant Professor of
Medicine, University Of Toronto
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Objectives

• Appreciate the challenges in treating primary
  liver cancers and the limitations to older trial
  data
• Develop an approach to choosing appropriate
  patients who may benefit from therapies
• Appreciate the recent advances in systemic
  therapy for both HCC and biliary cancers.

HCC
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Hepatocellular Carcinoma

• Fifth most common cancer globally
• 5 year survivals lt 10
• Incidence is rising
• NA 8, (ahead of gastric/esophageal ca)
• Ontario incidence more than doubles every decade

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HCC in TorontoN 329 over 4 years
Risk Factors Percentage
HBV 55
HCV 25
Combined HBV HCV 3.4
Alcohol 16
Other Known Causes 2
Unknown 11
Series from M. Sherman
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Hepatocellular Carcinoma The Challenge

• Two diseases
• malignancy and chronic liver disease.
• a virulent cancer and a dysfunctional liver
• Heterogeneity etiology prognosis
• both tumor and liver factors determine survival
  in this highly variable patient population

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Heterogeneity CLIP Score(Cancer of the Liver
Italian program)

• Calculate a score based on
• cirrhosis Child-Pugh (albumin Bili, PT,
  ascites, enceph)
• tumor size (gt50 0f liver)
• single vs multinodular tumors
• AFP (gt400)
• portal vein thrombosis (presence)
• score 1 2 3 4 5/6
• med survival 32 16.5 4.5 2.5 1.0
• (months)
• n 435 Gallo et al. 1998

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New HCC case
UHN Tumor Boards
Resection candidate?
Yes, resect (10)
No
Transplant candidate?
No
Yes Transplant (10)
RFA candidate?
No (70 !! )
Yes, RFA (10)
Recurrences
Trial Candidate? New Agents/ approaches
TACE Candidate ?

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

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

NO
Supportive / palliative Care
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Hepatocellular Carcinoma
HCCs are vascular tumors
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TACE

• Trans-Arterial Chemoembolization

• Specialised local therapy in HCC
• Carefully selected patients
• Local disease
• Child A
• No PVT
• Platelets gt 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

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TACE improves survival vs. best supportive care
Hong Kong (HBV)
2 yr survival of 31 vs 11 Lo et al.Hepatology
2002 35 1164-1171

• Patients
• CPT A
• No PVT
• PS 0-2

UHN/PMH experience 2 yr survival of 55 Molinari
et al. Clin Oncol 2006
2 yr survival 63 vs 27 Llovet et al. Lancet
2002 359 1734-1739
Barcelona (HCV)
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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
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Should patients with HCC, not suitable for
radical treatments, be considered for systemic
treatments?

• Older series suggest these
• patients have med OS of 3 months - chemo has
  no role.
• But heterogeneity within patient population
  studied not recognized

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Single agent doxorubicin

• 16 trials, 734 patients, ORR 18
• myelosuppression, ? hyperbilirubin
• 1 RCT doxo vs BSC (n60)
• Med surv 10.6 wks vs 7.5 wks
• Rx-related death of 25. Lai et al. Cancer
  1998.
• Other anthracyclines
• mitoxantrone, epirubicin are similar,
• ? improved toxicity
• Liposomal doxo - 2 trials - disappointing

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CLIP ScoreWhat patients were enrolled on these
trials ?

• Calculate a score based on
• cirrhosis Child-Pugh (albumin Bili, PT,
  ascites, enceph)
• tumor size (gt50 0f liver)
• single vs multinodular tumors
• AFP (gt400)
• portal vein thrombosis (presence)
• score 1 2 3 4 5/6
• med survival 32 16.5 4.5 2.5 1.0
• (months)

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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 !

Gish et al JCO July 2007
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Doxorubicin combinations

• Numerous combinations toxic
• 470 patients RR 14
• Exception PIAF (cisplatin, INFa doxo, 5-FU)
• Phase II RR 26
• 9 patients downstaged to surgery
• 4 of 9 had path CRs! Leung et al. Clin Can
  Res 1999.
• chemosensitivity and radiological underestimation
  true response
• significant toxicity Rx-related deaths

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Phase III Trial of PIAF vs Doxo in inoperable
HCC Yeo et al. J Natl Cancer Inst 2005

• 180 patients one of the largest chemo trials in
  HCC
• Doxo PIAF
• ORR 11 20 p0.09
• SD 40 31
• Med surv 7.1 mo 8.4 mo p0.87
• PIAF Septic death rate of 4 ,
• febrile neutropenia gt 40

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Other Cytotoxics

• No other drug appears better. All RRs lt 10
• Fluoropyrimidines
• Infusional or capecitabine maybe best
• Taxanes
• Not well studiedbut appear toxic
• Topoisomerase inhibitors
• CPT-11 toxic
• Etoposide better
• Nucleoside analogues
• Gemcitabine inactive alone / combinations (?SD)
• Gem/ cisplatin combo more promising
• TS inhibitors
• Nolatrexed stable disease in phase II
• ...phase III worse than single agent doxo

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Other Agents in HCC
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HCC Promise of Targeted Agents

• appropriate to test new agents
• better tolerated in patients with liver
  dysfunction
• promising targets
• angiogenesis inhibitors ( sorafenib, Avastin)
• growth factor inhibitors (EGFR, Ras ,Raf)
• apoptosis and cell cycle modifiers
• unique antigens or receptors (HGF)

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Vascularity and Angiogenesis in Multistep HCC
Carcinogenesis
low grade dysplastic
high grade dysplastic
HCC
H/E
SMactin
CD34
Park et al. Arch Pathol Lab Med 2000 1241061
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Sorafenib (Nexavar) in HCC

• Few 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

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SHARP Sorafenib Hepatocellular Phase III Study
Design

• Major endpoints
• Survival
• PFS
• QOL

Sorafenib400 mg bid
Placebo
Opened 2005
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Handfoot skin reaction palmar plantar
erythrodysethesias (PPE)

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

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SHARP HCV subgroup
Sorafenib placebo
n 99 98
OS (mo) 14 HR 0.58 7.9
TTP 7.6 2.8
c/w SHARP OS 10.7 vs 7.9 mo, HR 0.69 20 HBV
subset?
Bolondi et al. GI ASCO 2008
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Asia-Pacific phase III
Cheng et al ASCO 2008
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Cheng et al ASCO 2008
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2nd trialDoxorubicin /- sorafenib randomized
phase II
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Study 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
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Results
DXR/sorafenib (n47) DXR/placebo (n49)
TTP (months) 8.6 4.8
OS (months) 13.7 6.5
PFS (months) 6.9 2.8
Response (CRPR) n() 2 (4) 1 (2)
Response (SD) 36 (77) 27 (55)
Definitive analysis (data from March 2007 cutoff,
independent assessment, TTP 38 events, OS 50
events, PFS 70 events )
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Exploratory Comparison Per Protocol Overall
Survival
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
1.00
0.75
0.50
Survival Distribution Function
0.25
0.00
20.0 months
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
Months From Randomization
Doxorubicin plus sorafenib
Censored treatment Doxorubicin sorafenib
STRATA
Censored treatment Doxorubicin placebo
Doxorubicin placebo
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Percent Change in Target Lesion From Baseline
(Independent Assessment)
Doxorubicin sorafenib (n47)
100
Doxorubicin placebo (n49)
80
60
62
40
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Change in Target Lesion From Baseline ()
0
-20
-40
-60
-80
-100

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

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Safety and Study Drug Administration
DXR/sorafenib (n47) DXR/placebo (n49)
All cause adverse events (AE) () 100 100
Drug-related AE () 92 88
Serious all cause AE (SAE) () 38 40
Drug related SAE () 21 17
AE leading to discontinuation () 36 33
Death within 30 days () 11 21
Median daily dose study drug (mg) 708 763
Median total doxorubicin dose (mg/m2) 165 120
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CALGB 80802 Phase III trial of sorafenib
Doxorubicin in advanced HCC

• PI Ghasan Abou-Alfa
• 600 patient trial, same patient population....
• randomized sorafenib vs sorafenib/doxorubicin
  combination.
• Primary endpoint is OS
• Includes radiological correlate
• protocol at CTEP review, ? NCIC.

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72 yo woman, HBV, recurrent biopsy-proven
multifocal HCC, PVT, 8 months post resection.
Child A, good PS. Enrolled on phase II trial of
Doxorubicin Sorafenib
Baseline triphasic CT
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72 yo woman, HBV, recurrent biopsy-proven
multifocal HCC, PVT, 8 months post resection.
Child A, good PS. Enrolled on phase II trial of
Doxorubicin Sorafenib
C-2, slight progression, SD
C-4, SD Dox held
baseline
C-6, hypodense minor response, SD by RECIST
C-10, all more hyperdense PD by RECIST
C8, ongoing SD
What is the mechanism of drug resistance ?
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HCC Sorafenib Trials Summary
Phase II Rand Phase II Rand Phase II SHARP Phase III SHARP Phase III Asia-Pacific Phase III Asia-Pacific Phase III
sorafenib Dox sorafenib Dox placebo sorafenib placebo sorafenib placebo
n 136 47 49 299 303 150 76
CPT A/B 72/28 A A A A A A
OS (mo) 9.2 13.7 6.5 10.7 HR 0.69 P0.00058 7.8 6.5 HR 0.68 P0.014 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
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Sorafenib in HCC

• Body of evidence supports sorafenib as the new
  reference standard of care in advanced HCC
  (Child A, good PS)
• This has launched many new studies
• Adjuvant setting ( surgery/ RFA)
• ECOG 1207 Peri TACE (/- sorafenib)
• Combinations with other targeted agents and dox
• Other HCC populations (Child B, post transplant)

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Erlotinib (Tarceva) in HCC

• Targeting EGFR in HCC
• Phase II, n38Philip et al, JCO 2005
• 88 EGFR
• 32 progression-free at 6 months
• 10 PR
• Med OS 13 months (encouraging)

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Bevacizumab in HCC

• Phase II, n 46Seigel 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 enhancement by DCE MRI and reductions in
  circulating VEGF-A levels
• Early studies combining erlotinib and bevacizumab
  suggest synergism in HCC.. Phase III in
  planning Thomas et al ASCO 2007

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Patient ( cryptogenic cirrhosis, 2 HCC lesions
(largest 11.3 cm))
March 2003, arterial phase
March 2003, venous phase

• Avastin phase II
• Grade 1 fatigue epistaxis onlyOff study at
  7.2 monthssecondary to ileac (bone) met

Bevacizumab x 6 months
Oct 2003, arterial phase
Oct 2003, venous phase
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Targeted Therapy in HCC
Target/ agent VEGF VEGFR PDGF EGFR Raf M-Tor IGF HGF status
Bev Phase II completed , combination studies planned
Sunitinib Phase II completed Phase 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
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The near Future A new HCC case
Multidisplenary Tumor Boards
Provincial Coverage (CCO)
Curative approaches
Adjuvant Trial !
No (70 !! )
Yes (30)
Sorafenib Rx vs. Trial Candidate Sorafenib
combinations, novel agents, radiation/ targeted
therapy, novel approaches
TACE Candidate?

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

Adjuvant Trial !

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

NO
Recurrences
Supportive / palliative Care
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Conclusions

• larger randomized studies are now being done
• Evaluate patients of uniform and intermediate
  prognosis
• Survival, PFS as the primary endpoint.
• Systemic therapy new reference standard with
  sorafenib
• Appropriate patients should be referred for
  clinical trials when available.