Management of Advances Hepatocellular Carcinoma

Hepatocellular Carcinoma (HCC):
Management
PRATAP SAGAR TIWARI
Part 1: Managing Advanced HCC (past, present & future perspectives)
Part 2: Radiotherapy in HCC (is there any role ?)
Part 3: Locoregional Therapies in HCC (guidelines & beyond)
Part 4: Surgery in HCC (limit and limitations ?)
Part 5: Liver transplantation (HCC Perspective)

Part 1:
Managing Advanced
Hepatocellular Carcinoma
(HCC)Past, present and future Perspectives

Note
 This is only a compilation slide for academic purposes only. Please do not edit
or copy. All credit goes to those researchers whom I have made references in
the respective slides.

Introduction: Hepatocellular Carcinoma
 HCC is now the Sixth-mc cancer in the world (male: fifth, female: ninth) and the
fourth cause of cancer-related mortality as estimated by the WHO.[1]
 In all areas, males have a higher prevalence than females, the sex ratio usually
ranging between 2:1 and 4:1, and, in most areas, the age at diagnosis in females
is higher than in males.[2]
 Sex differences in sex hormones appear to be important as a RF for HCC.[3]
1. globacan.iarc.fr last accessed April1 2019
2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61:69.
3. Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007; 317:121.444

Estimated number of cases in 2018: WHO
Males: Mortality
1 Lung 1 184 947
2 Liver 548 375
Females: Mortaity
All 4 169 387
1 Breast 626 679
2 Lung 576 060
3 Colorectum 396 568
4 Cervix 311 365
5 Stomach 269 130
6 Liver 233 256
Males: incidence
All cancers 9 456 418
1 Lung 1 368 524
2 Prostate 1 276 106
3 Colorectum 1 026 215
4 Stomach 683 754
5 Liver 596 574
Overall: incidence
1 Lung 2 093 876
2 Breast 2 088 849
3 Colorectum 1 849 518
4 Prostate 1 276 106
5 Stomach 1 033 701
6 Liver 841 080
Females: Incidence
1 Breast 2 088 849
3 Lung 725 352
4 Cervix 569 847
5 Thyroid 436 344
6 Corpus uteri 382 069
7 Stomach 349 947
8 Ovary 295 414
9 Liver 244 506
Overall: Mortality
1 Lung 1 761 007
3 Stomach 782 685
4 Liver 781 631https://gco.iarc.fr/ last accessed April1 2019

Prognosis of Untreated HCC
1. Khalaf N, Ying J, Mittal S, et al. Natural history of untreated hepatocellular carcinoma in a US cohort and the role of cancer surveillance. Clin Gastroenterol Hepatol 2017;15:273–281.
2. Pawarode A, Voravud N, Sriuranpong V, et al: Natural history of untreated primary hepatocellular carcinoma: A retrospective study of 157 patients. Am J Clin Oncol 21:386-391, 1998
3. Pawarode A, Tangkijvanich P, Voravud N: Outcomes of primary hepatocellular carcinoma treatment: An 8-year experience with 368 patients in Thailand. J Gastroenterol Hepatol 15:860-864,
2000
4. Bialecki ES, Di Bisceglie AM: Clinical presentation and natural course of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 17:485-489, 2005
5. Barbara L, Benzi G, Gaiani S, et al: Natural history of small untreated hepatocellular carcinoma in cirrhosis: A multivariate analysis of prognostic factors of tumor growth rate and patient survival.
Hepatology 16:132-137, 1992
6. Cottone M, Virdone R, Fusco G, et al: Asymptomatic hepatocellular carcinoma in Child’s A cirrhosis: A comparison of natural history and surgical treatment. Gastroenterology 96:1566-1571, 1989
7. Farinati F, Marino D, De Giorgio M, et al: A reappraisal of the Barcelona Clinic Liver Cancer model: Natural history of untreated ‘intermediate stage’ hepatocellular carcinoma. J Intern Med 256:
529-530, 2004
8. Kim UB, Doo CJ, Baek SH, et al: Natural history and prognostic factors of primary hepatocellular carcinoma: Study of 70 untreated patients. Korean J Intern Med 4:136-141, 1989
1
• The 5-year survival of HCC is typically less than 5% without treatment.[2-8]

EXTRA NOTE
 5R's known as Response, Remission, Recovery, Relapse and Recurrence.
 Response: improvement
 Remission is clinically defined as the experience of being symptom-free from illness.
 Recovery is clinically defined as the absence of symptoms for at least 4 months following the
onset of remission.
 Relapse is defined as a full return of symptoms once remission has occurred - but before
recovery has taken hold.
 Recurrence refers to another episode after recovery has been attained.

Advanced HCC
 At the time of clinical DX, roughly 60%-70% of HCC pts present with
primary advanced, inoperable, disease [1].
 Moreover, tumor relapse (recurrence) following curative surgical MX
continues to be a substantial dilemma and is documented as high
as approx 70% at 5 years postoperatively [2].
 The standard of care MX for Advanced HCC remains a dilemma.
1. Llovet JM, Bruix J. Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol. 2008;48(Suppl 1):S20-37.
2. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology.
1999;30(6):1434-40.

AASLD surveillance and diagnostic algorithm
Surveillance USG with or without AFP
Diagnostic imaging for HCC with multiphase CT/MRI
Repeat USG with
or without AFP in
3-6 months
Interpretation
# Some high risk pts may undergo multiphase
CT/MRI for HCC surveillance (depending on pt body
habitus, visibility of liver at USG, being on LT waiting
list and other factors).
≥ 10 mm lesion or
AFP ≥ 20 ng/ml
<10 mm lesions Multiphase CT/MRI in selected
patients #
AASLD 2018

Negative LI-RADS NC LI-RADS 1 LI-RADS 2 LI-RADS 3
IntermediateProbably benignDefinitely benign
Non
categorizable#
No
Observation
Return to
Surveillance
in 6 months
Repeat or
alternate
diagnostic
imaging ≤ 3
months
Return to
Surveillance
imaging in 6
months
Return to
Surveillance
imaging in 6
months
Consider repeat
diagnostic
imaging ≤6
months
Repeat or alternate
diagnostic imaging
in 3-6 months
# usually due to technical problems

LI-RADS 4 LI-RADS 5 LI-RADS M
Malignant not
definitely HCC
Definite HCCProbably HCC
Recommend multidisciplinary
discussion for tailored workup that
may include biopsy (select
cases),or repeat or alternative
diagnostic imaging ≤ 3 months
HCC CONFIRMED
Recommend multidisciplinary
discussion for tailored workup that
may include biopsy (most cases),or
repeat or alternative diagnostic
imaging ≤ 3 months
If BiopsyIf Biopsy
Pathology
diagnosis
AASLD 2018
So,After HCC is diagnosed the next thing to do is
STAGING

LI-RADS (Liver Imaging Reporting and Data System)
 hepatic phase enhancement
 hyperenhancement: enhancement in the arterial phase is definitely greater than that of
background liver; if unsure, classify as isoenhancing
 "washout"
 a visual assessment of relative hypointensity of the lesion compared with background liver on the
portal venous and delayed phases
 capsule/pseudocapsule
 peripheral rim of smooth hyperenhancement seen in the portal venous or delayed phases
 threshold growth
 diameter increase ≥50% increase in ≤6 months
 other prior criteria are now considered subthreshold growth, an ancillary feature
 if prior exam >6 months, diameter ≥100% increase
 a new lesion ≥10 mm in <24 months
Taken from https://radiopaedia.org/articles/li-rads. Accessed 29 April 19

5 important things to note for staging
1. Size of the tumor ?
2. Number ?
3. Vascular invasion?
4. Child pugh class ?
5. Performance status ?

Barcelona Clinic Liver Cancer group
(BCLC) HCC staging system

Management : Advance HCC; Stage C
ESMO 2018 AASLD 2018 EASL 2018
5:EASL 2018
• As of 2017 sorafenib has been shown to be effective in first line,
• while regorafenib is effective in second line in case of radiological
progression under sorafenib.
• Lenvatinib has been shown to be non-inferior to sorafenib in first
line.
• Cabozantinib has been demonstrated to be superior to placebo in
2nd or 3rd line with an improvement of OS from eight months
(placebo) to 10.2 months (ASCO GI 2018).
• Nivolumab has been approved in second line by FDA but not EMA
based on uncontrolled phase II data.

HCC: APASL 2017
Sarin SK. Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017 Jul; 11(4): 317–370.

Advance HCC management: Overview
Systemic Chemotherapy
Targeted Chemotherapy
Immunotherapy
Combination therapies
Future perspectives

Advance HCC: Management options
Immunotherapy
Future perspectives
• The problem of using chemotherapy in HCC stems from the coexistence of
two conditions.
1. Cirrhosis can perturb the metabolism of chemotherapeutic drugs and
enhance their toxicity. In addition, some chemotherapy-related
complications, such as systemic infections, are particularly severe in
immunocompromised patients, like cirrhotics.
2. HCC has also been shown to be chemo-resistant to the most common
chemotherapies.[1]
1. Caruso ML, Valentini AM. Overexpression of p53 in a large series of patients with hepatocellular carcinoma: a clinicopathological correlation. Anticancer Res. 1999;19(5B):3853-6.

Immunotherapy
Future perspectives
STUDIES ON SYSTEMIC CHEMOTHERAPY
IN ADVANCE HCC

Cisplatin-based regimen
Author year Agent n
RR (%)
DS
(%)
TTP
(mon)
PFS
(mon)
OS
(mon)
Ref
Lee et al. 2004 Cisplatin plus doxorubicin 42 18.9 16.2 6.6 NR 7.3 1
Yang et al. 2004
Cisplatin, mitoxantrone, plus
continuous infusion 5-FU
63 23.8 NR 2.5 NR 4.9
2
Ikeda et al. 2005
Cisplatin, mitoxantrone, plus
continuous infusion 5-FU
51 27 NR NR 4 11.6
3
Boucher et al. 2002
Cisplatin, epirubicin plus
infusional 5-FU
21 14.5 NR 5.9 NR 10
4
n: sample size; RR: response rate; DS: disease stabilization; TTP: time to progression; PFS: progression-free
survival; OS: overall survival; NR: not reported; mon: months
1. Lee J, Park JO, Kim WS, Park SH, Park KW, Choi MS, et al. Phase II study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma. Cancer Chemother Pharmacol. 2004;54(5):385-90.
2. Yang TS, Chang HK, Chen JS, Lin YC, Liau CT, Chang WC. Chemotherapy using 5-fluorouracil, mitoxantrone, and cisplatin for patients with advanced hepatocellular carcinoma: an analysis of 63 cases. J Gastroenterol. 2004;39(4):362-9.
3. Ikeda M, Okusaka T, Ueno H, Takezako Y, Morizane C. A phase II trial of continuous infusion of 5-fluorouracil, mitoxantrone, and cisplatin for metastatic hepatocellular carcinoma. Cancer. 2005;103(4):756-62.
4. Boucher E, Corbinais S, Brissot P, Boudjema K, Raoul JL. Treatment of hepatocellular carcinoma (HCC) with systemic chemotherapy combining epirubicin, cisplatinum and infusional 5-fluorouracil (ECF regimen). Cancer Chemother Pharmacol.
2002;50(4):305-8.

Cisplatin-based regimen
Author year Agent n
RR (%)
DS
(%)
TTP
(mon)
PFS
(mon)
OS
(mon)
R
e
f
Park et al. 2006
Cisplatin, doxorubicin
plus capecitabine
29 24 20.7 3.7 NR 7.7
1
Shim et al. 2009
Cisplatin plus
capecitabine
178 19.7 45 NR 2.8 10.5
2
Lee et al. 2009
Cisplatin plus
capecitabine
32 6.3 34.3 2 NR 12.2
3
1. Park SH, Lee Y, Han SH, Kwon SY, Kwon OS, Kim SS, et al. Systemic chemotherapy with doxorubicin, cisplatin and capecitabine for metastatic hepatocellular carcinoma. BMC Cancer. 2006;6:3.
2. Shim JH, Park JW, Nam BH, Lee WJ, Kim CM. Efficacy of combination chemotherapy with capecitabine plus cisplatin in patients with unresectable hepatocellular carcinoma. Cancer Chemother Pharmacol. 2009;63(3):459-67.
3. Lee JO, Lee KW, Oh DY, Kim JH, Im SA, Kim TY, et al. Combination chemotherapy with capecitabine and cisplatin for patients with metastatic hepatocellular carcinoma. Ann Oncol. 2009;20(8):1402-7.

Gemcitabine-based regimen
Author year Agent n
RR (%)
DS
(%)
TTP
(mon)
PFS
(mon)
OS
(mon)
R
ef
Parikh et al. 2005
Gemcitabine and
cisplatin
30 20 43 4.5 NR 5.3
1
Chia et al. 2008
Gemcitabine and
cisplatin
15 6.7 20 NR 1.5 4.5
2
Lombardi et al. 2011
Gemcitabine plus
pegylated liposomal
doxorubicin
41 NR 24 NR 5.8 22.5
3
1. Parikh PM, Fuloria J, Babu G, Doval DC, Awasthy BS, Pai VR, et al. A phase II study of gemcitabine and cisplatin in patients with advanced hepatocellular carcinoma. Trop Gastroenterol. 2005;26(3):115-8.
2. Chia WK, Ong S, Toh HC, Hee SW, Choo SP, Poon DY, et al. Phase II trial of gemcitabine in combination with cisplatin in inoperable or advanced hepatocellular carcinoma. Ann Acad Med Singapore. 2008;37(7):554-8.
3. Lombardi G, Zustovich F, Farinati F, Cillo U, Vitale A, Zanus G, et al. Pegylated liposomal doxorubicin and gemcitabine in patients with advanced hepatocellular carcinoma: results of a phase 2 study. Cancer. 2011;117(1):125-33.

Oxaliplatin-based regimen
Author year Agent n
RR (%)
DS
(%)
TTP
(mon)
PFS
(mon
)
OS
(mo
n)
Ref
Louafi et al. 2007
Gemcitabine plus
oxaliplatin (GEMOX)
34 18 58 NR 6.3 11.5
1
Mir et al. 2012
Gemcitabine plus
oxaliplatin (GEMOX)
18 18.8 18.8 NR 3.2 4.7
2
Zaanan et al. 2013
Gemcitabine plus
oxaliplatin (GEMOX)
204 22 66 NR 4.5 11
3
Boige et al. 2007
Gapecitabine plus
oxaliplatin (XELOX)
50 6 72 NR 4.1 9.3
4
1. Louafi S, Boige V, Ducreux M, Bonyhay L, Mansourbakht T, de Baere T, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer. 2007;109(7):1384-90.
2. Mir O, Coriat R, Boudou-Rouquette P, Ropert S, Durand JP, Cessot A, et al. Gemcitabine and oxaliplatin as second-line treatment in patients with hepatocellular carcinoma pre-treated with sorafenib. Med Oncol. 2012;29(4):2793-9.
3. Zaanan A, Williet N, Hebbar M, Dabakuyo TS, Fartoux L, Mansourbakht T, et al. Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: a large multicenter AGEO study. J Hepatol. 2013;58(1):81-8.
4. Boige V, Raoul JL, Pignon JP, Bouche O, Blanc JF, Dahan L, et al. Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial. Br J Cancer. 2007;97(7):862-7.

Doxorubicin-based regimen
Author..et al (PD) N (phase) Agents Median Survival (months) Ref
Cartei G (2005) --- liposomal DOX 6.5 1
Dangoor A (2003) 16 (II) liposomal DOX 6.1 2
Hong RL (2003) 40 (II) liposomal DOX 3.0 3
Miller RL (2002) (II) liposomal DOX 5.1 4
Ruff P (2001) ---- liposomal DOX 5.3 5
1. Cartei G, Zustovich F, Murrone A, et al: A phase I-II study of liposomal doxorubicin (LD) in the treatment of hepatocellular carcinoma (HCC) not suitable for loco-regional therapy. J Clin
Oncol 23: 364s, 2005 (abstr 4227)
2. Dangoor A, Ranson M, Lee SM, et al: Treatment of inoperable hepatocellular carcinoma (HCC) with pegylated liposomal doxorubicin: A phase II study. Proc Am Soc Clin Oncol 21:361, 2003
(abstr 1450)
3. Hong RL, Tseng YL: A phase II and pharmacokinetic study of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma.Cancer Chemother Pharmacol 51:433-438,
2003
4. Miller RL, Bowen KE, Chun HG: A phase II study of liposomal doxorubicin (LD, Doxil) in patients with advanced hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC). Proc Am Soc Clin
Oncol 20:155b, 2002 (abstr 2324)
5. Ruff P, Moodley SD, Rapoport BL, et al: Long term follow-up of pegylated liposomal doxorubicin (CAELYX): A well tolerated and effective agent in advanced hepatocellular carcinoma (HCC).
Proc Am Soc Clin Oncol 19:167a, 2001 (abstr 667)

Doxorubicin combination-based regimen
Author..et al (PD) N (phase) Agents Median Survival
(months)
Ref
Lee J (2004) 29 (II) DOX, cisplatin and
Capecitabine
7.3 1
Lu YS (2004) 25 (II) DOX, interferon, and
tamoxifen
6.0 2
Yang TS (2001) 50 (I/II) DOX and gemcitabine 4.6 3
1. Lee J, Park JO, Kim WS, et al: Phase II study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma. Cancer Chemother Pharmacol 54:385-390, 2004
2. Lu YS, Hsu C, Li CC, et al: Phase II study of combination doxorubicin, interferon-alpha, and high-dose tamoxifen treatment for advanced hepatocellular carcinoma. Hepatogastroenterology
51:815-819, 2004
3. Yang TS, Wang CH, Hsieh RK, et al: A 2-stage phase II study of gemcitabine and doxorubicin in patients with advanced hepatocellular carcinoma. Proc Am Soc Clin Oncol 19:168a, 2001 (abstr
670)

PURPOSE: The study objective was to compare the OS of pts with unresectable or
metastatic HCC treated with nolatrexed (NOL) or doxorubicin (DOX).
PATIENTS AND METHODS: Pts from North America, Europe, and South Africa (N
= 444) with HCC were randomly assigned to receive NOL or DOX.
 Eligible pts had KPS > or = 60%,CLIP score < or = 3.
 Primary end point was OS.
 Secondary end points included progression-free survival (PFS), objective
response rates, and safety.
 The treatment groups were well-balanced with regards to age, sex, ethnic
origin, and underlying liver disease.
 Randomization was stratified according to KPS and CLIP score.

Overall survival Kaplan-Meier curve in the nolatrexed versus doxorubicin

Overall survival Kaplan-Meier curve in the nolatrexed versus doxorubicin
• Median OS was 22.3 weeks for NOL and 32.3 weeks for DOX (P = .0068).
• Objective response rate (complete response [CR] plus partial response
[PR]) was 1.4% for NOL and 4.0% for DOX.
• Median PFS was 12 weeks for NOL and 10 weeks for DOX (P = .7091).

 RESULTS: At the time of the final analysis, 377 pts had died.
 Median OS was 22.3 weeks for NOL and 32.3 weeks for DOX (P = .0068).
 The HR was 0.753 in favor of DOX.
 Objective response rate (complete response [CR] plus partial response [PR])
was 1.4% for NOL and 4.0% for DOX.
 Median PFS was 12 weeks for NOL and 10 weeks for DOX (P = .7091).
 Grade 3 and 4 stomatitis, vomiting, diarrhea, and thrombocytopenia were
more common in the NOL arm. Alopecia was more common in the DOX arm.
More patients were withdrawn from study for toxicity in the NOL arm than in
the DOX arm.
 CONCLUSION: NOL showed minimal activity in this phase III trial. Further
exploration at this dose and schedule in HCC is not warranted.

NOTE: THE CANCER OF THE LIVER ITALIAN PROGRAM
SCORE
Score of 4 -6 generally considered as Advanced disease.
Llovet JM, Bruix J: Prospective validation of the Cancer of the Liver Italian Program (CLIP) score: A new prognostic system for patients with cirrhosis and hepatocellular
carcinoma. Hepatology 32:679-680, 2000

NOTE: Karnofsky Performance Status
Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer. In Evaluation of chemotherapeutic agents. Edited by MacLeod CM. New York: Columbia University Press;
1949:191–205.

NOTE: Eastern Cooperative Oncology Group
(ECOG) Performance Status
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J
Clin Oncol 1982, 5(6):649–655.

A Randomized Phase III Study of Doxorubicin Vs Cisplatin/ Interferon α
-2b/Doxorubicin/Fluorouracil (PIAF) Combination CT for Unresectable
HCC
 A randomized PIII trial comparing doxo alone (n=94) with a combination CT regimen
consisting of cisplatin, interferon α-2b, doxo, and 5-fluorouracil (PIAF regimen)(n=94) was
conducted [1].
 The PEp was OS, and SEps were response rate and toxicity.
1. Yeo, W. et al. A randomized phase III study of doxorubicin versus cisplatin/interferon α-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for
unresectable hepatocellular carcinoma. J. Natl. Cancer Inst. 2005, 97, 1532–1538.
Neutropenia, thrombocytopenia,
and hypokalemia were statistically
significantly more common in pts
treated with PIAF than in pts treated
with doxo.

A Randomized Phase III Study of Doxorubicin Vs Cisplatin/ Interferon α
-2b/Doxorubicin/Fluorouracil (PIAF) Combination CT for Unresectable
HCC
 A randomized PIII trial comparing doxo alone (n=94) with a combination CT regimen
consisting of cisplatin, interferon α-2b, doxo, and 5-fluorouracil (PIAF regimen)(n=94) was
conducted [1].
 The PEp was OS, and SEps were response rate and toxicity.
Neutropenia, thrombocytopenia,
and hypokalemia were statistically
significantly more common in pts
treated with PIAF than in pts treated
with doxo.
• Although pts on PIAF had a higher ORR and better survival than
pts on doxo, the differences were not statistically significant.
• PIAF was also a/with increased treatment related toxicity.

A randomized PIII trial of doxo vs. combined CT with 5-FU, leucovorin,
and oxaliplatin (FOLFOX4) in Advanced HCC/
EACH Study
 Another randomized PIII trial of Doxo (N=187) vs. combined CT with 5-
fluorouracil, leucovorin, and oxaliplatin (FOLFOX4)(N=184) conducted in pts
with advanced HCC.
1. Qin S, et al. Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: A subgroup analysis of
the EACH study. Oncologist 2014, 19, 1169–1178.
• Median OS was 5.9 months with FOLFOX4 and 4.3
months with doxo (HR: 0.75; 95% CI:0.58–0.98; p=.03).

Doxo combination-based regimen: Phase III Studies
Author.et al (PD) N (phase) Median Survival
(months)
Re
f
Yeo W (2004) 94 vs 94 DOX vs PIAF 6.8 vs 8.6 (p=0.83) 1
Qin S (2010)
EACH Study
187 Vs 184 DOX Vs FOLFOX4 4.3 vs 5.9 (p=0.03) 2
2. Qin, S.; Cheng, Y.; Liang, J.; Shen, L.; Bai, Y.; Li, J.; Fan, J.; Liang, L.; Zhang, Y.; Wu, G.; et al. Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in
Chinese patients with advanced hepatocellular carcinoma: A subgroup analysis of the EACH study. Oncologist 2014, 19, 1169–1178.

Hormonal Therapy
 Several HCCs express sex-hormone receptors such as estrogen (ER),
progesterone (PR), and androgen receptors [1] as well as somatostatin
receptors [2,3].
 The most frequently employed hormonal agents for the management of HCC
include tamoxifen, megestrol, octreotide, and lanreotide.
1. Boonyaratanakornkit V, Edwards DP. Receptor mechanisms mediating non-genomic actions of sex steroids. Semin Reprod Med. 2007;25(3):139-53.
2. Cebon J, Findlay M, Hargreaves C, Stockler M, Thompson P, Boyer M, et al. Somatostatin receptor expression, tumour response, and quality of life in patients
with advanced hepatocellular carcinoma treated with long-acting octreotide. Br J Cancer. 2006;95(7):853-61.
3. Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON. Treatment of hepatocellular carcinoma with octreotide: a randomised
controlled study. Gut. 1998;42(3):442-7.

Hormonal Therapy: Tamoxifen
 Multiple studies including single-center and multicenter prospective
randomized controlled trials, systematic reviews, and meta-analyses
investigated the role of tamoxifen for the MX of pts with advanced
unresectable HCC [1-5].
 These studies were unsatisfactory and failed to demonstrate improved survival
advantages (disease-free survival [DFS] and overall survival [OS] rates) or
enhanced quality of life (functional status).
1. Castells A, Bruix J, Bru C, Ayuso C, Roca M, Boix L, et al. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients. Gastroenterology.
1995;109(3):917-22.
2. Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. CLIP Group (Cancer of the Liver Italian Programme). Lancet. 1998;352(9121):17-20.
3. Chow PK, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, et al. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial.
Hepatology. 2002;36(5):1221-6.
4. Nowak A, Findlay M, Culjak G, Stockler M. Tamoxifen for hepatocellular carcinoma. Cochrane Database Syst Rev. 2004(3):Cd001024.
5. Barbare JC, Bouche O, Bonnetain F, Raoul JL, Rougier P, Abergel A, et al. Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol. 2005;23(19):4338-46.

Hormonal Therapy: Tamoxifen
 Multiple studies including single-center and multicenter prospective
randomized controlled trials, systematic reviews, and meta-analyses
investigated the role of tamoxifen for the MX of pts with advanced
unresectable HCC [1-5].
 These studies were unsatisfactory and failed to demonstrate improved survival
advantages (disease-free survival [DFS] and overall survival [OS] rates) or
enhanced quality of life (functional status).
1. Castells A, Bruix J, Bru C, Ayuso C, Roca M, Boix L, et al. Treatment of hepatocellular carcinoma with tamoxifen: a double-blind placebo-controlled trial in 120 patients. Gastroenterology.
1995;109(3):917-22.
2. Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. CLIP Group (Cancer of the Liver Italian Programme). Lancet. 1998;352(9121):17-20.
3. Chow PK, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, et al. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: a multicenter randomized controlled trial.
Hepatology. 2002;36(5):1221-6.
4. Nowak A, Findlay M, Culjak G, Stockler M. Tamoxifen for hepatocellular carcinoma. Cochrane Database Syst Rev. 2004(3):Cd001024.
5. Barbare JC, Bouche O, Bonnetain F, Raoul JL, Rougier P, Abergel A, et al. Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol. 2005;23(19):4338-46.
Thus, this treatment with Tamoxifen is discouraged in
advanced HCC.

Hormonal Therapy: Tamoxifen based
 A phase II study by Cheng AL et al [1] enrolled 36 pts with advanced HCC. Pts received high-
dose tamoxifen plus doxorubicin. Only 33.3% attained partial remission with a median PFS of
roughly 7 months.
1. Cheng AL, Yeh KH, Fine RL, Chuang SE, Yang CH, Wang LH, et al. Biochemical modulation of doxorubicin by high-dose tamoxifen in the treatment of advanced hepatocellular carcinoma.
Hepatogastroenterology. 1998;45(24):1955-60.
2. Melia WM, Johnson PJ, Williams R. Controlled clinical trial of doxorubicin and tamoxifen versus doxorubicin alone in hepatocellular carcinoma. Cancer Treat Rep. 1987;71(12):1213-6.
Tamoxifen + Doxo
Doxo Vs Tamoxifen + Doxo
 Melia et al. [2] enrolled 60 advanced inoperable HCC pts who were then randomized to two
groups: (1) doxo alone (60 mg/m2 at 3-week intervals) and (2) combined doxorubicin plus
tamoxifen (10 mg twice daily). Drug response happened only in 3 (11%) and 4 (16%) pts of the
above-mentioned groups, respectively, without statistical significant difference.

Hormonal Therapy: Tamoxifen based
 Moreover, Lu et al. [1] (Phase II) studied the Triple combination therapy in 25 pts with advanced
unresectable HCC. Partial remission was achieved in 5 pts (20%) with median PFS of 7 months.
Overall, median OS was 6 months, whereas the 1-year survival rate was roughly 16%.
1. Lu YS, Hsu C, Li CC, Kuo SH, Yeh KH, Yang CH, et al. Phase II study of combination doxorubicin, interferon-alpha, and high-dose tamoxifen treatment for advanced hepatocellular carcinoma.
Hepatogastroenterology. 2004;51(57):815-9.
2. Cheng AL, Chen YC, Yeh KH, Chuang SE, Chen BR, Chen DS. Chronic oral etoposide and tamoxifen in the treatment of far-advanced hepatocellular carcinoma. Cancer. 1996;77(5):872-7.
3. Raderer M, Pidlich J, Muller C, Pfeffel F, Kornek GV, Hejna M, et al. A phase I/II trial of epirubicin and high dose tamoxifen as a potential modulator of multidrug resistance in advanced
hepatocellular carcinoma. Eur J Cancer. 1996;32a(13):2366-8.
Tamoxifen + Doxo + IFNa
Tamoxifen + Others
 Furthermore, the combination of tamoxifen with oral etoposide [2] and epirubicin [3] have
been conducted with only modest antitumor outcomes.

Hormonal Therapy: Megestrol
Yr
1997 Chow et al Phase II 46 No single patient attained partial or complete
response.
1
2001 Villa et al Phase III (vs
Placebo)
21 Vs 24 MS: 18 mnths vs 7 mnths p= 0.0090 2
2011 Chow et al Phase III (Vs
Placebo)
135 VS 69 Placebo group had higher (statistically NS) OS than
the treated group (2.14 vs. 1.88 months, respectively).
3
1. Chao Y, Chan WK, Wang SS, Lai KH, Chi CW, Lin CY, et al. Phase II study of megestrol acetate in the treatment of hepatocellular carcinoma. J Gastroenterol Hepatol. 1997;12(4):277-81.
2. Villa E, Ferretti I, Grottola A, Buttafoco P, Buono MG, Giannini F, et al. Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors.
Br J Cancer. 2001;84(7):881-5.
3. Chow PK, Machin D, Chen Y, Zhang X, Win KM, Hoang HH, et al. Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma. Br J
Cancer. 2011;105(7):945-52.

Somatostatin Analogues
Author.et al (PD) N (phase) Agents
Numbers
Median Survival (months) Ref
Kouroumalis et al
1998
II Octreotide Vs Placebo
n=28 Vs 30
13 vs. 4
P = 0.002
1
Raderer et al.
2000
II Lanreotide
n=21
4.2 2
Cebon et al.
2006
II Lanreotide
n=63
8 3
Barbare et al.
2009
III Lanreotide Vs Placebo
n=135 vs 137
6.5 vs 7.1
p=0.3
4
1. Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled
study. Gut. 1998;42(3):442-7.
2. Raderer M, Hejna MH, Muller C, Kornek GV, Kurtaran A, Virgolini I, et al. Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide
in vitro and in vivo. Int J Oncol. 2000;16(6):1197-201.
4. Barbare JC, Bouche O, Bonnetain F, Dahan L, Lombard-Bohas C, Faroux R, et al. Treatment of advanced hepatocellular carcinoma with long-acting octreotide: a
phase III multicentre, randomised, double blind placebo-controlled study. Eur J Cancer. 2009;45(10):1788-97.

Somatostatin Analogues
Author.et al (PD) N (phase) Agents
Numbers
Median Survival (months) Ref
Kouroumalis et al
1998
II Octreotide Vs Placebo
n=28 Vs 30
13 vs. 4
P = 0.002
1
Raderer et al.
2000
II Lanreotide
n=21
4.2 2
Cebon et al.
2006
II Lanreotide
n=63
8 3
Barbare et al.
2009
III Lanreotide Vs Placebo
n=135 vs 137
6.5 vs 7.1
p=0.3
4
1. Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON. Treatment of hepatocellular carcinoma with octreotide: a randomised controlled
study. Gut. 1998;42(3):442-7.
2. Raderer M, Hejna MH, Muller C, Kornek GV, Kurtaran A, Virgolini I, et al. Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide
in vitro and in vivo. Int J Oncol. 2000;16(6):1197-201.
4. Barbare JC, Bouche O, Bonnetain F, Dahan L, Lombard-Bohas C, Faroux R, et al. Treatment of advanced hepatocellular carcinoma with long-acting octreotide: a
phase III multicentre, randomised, double blind placebo-controlled study. Eur J Cancer. 2009;45(10):1788-97.
 In a RCT involving 70 pts, Yuen and colleagues[1] reported no survival benefit
compared with placebo for long-acting octreotide (1.9 vs 2 months).
 In a European RCT involving 120 pts, Becker and colleagues[2] also reported no
survival benefit for long-acting octreotide compared with placebo (4.7 versus
5.3 months).
1. Yuen MF, Poon RT, Lai CL, et al. A randomized placebocontrolled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology 2002;36:687–91.
2. Becker G, Allgaier HP, Olschewski M, Za¨hringer A, et alHECTOR Study Group. Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind
study. Hepatology 2007;45:9–15.

Other treatments
 A large RCT compared seocalcitol – a vitamin-D like anti-proliferative molecule
– with placebo in 746 pts and showed no differences in OS (9.6 months
seocalcitol vs. 9.2 months placebo).[1]
 In a small Indian study(N=23 VS 19) treatment of advanced HCC with high dose
vitamin K3 produced objective response in 17% pts with improved survival in
pts achieving objective response; however, it did not affect the overall
survival.[2]
1. Beaugrand M, Sala M, Degos F, Sherman M, Bolondi L, Evans T, et al. Treatment of advanced hepatocellular carcinoma by seocalcitol (a vit D analogue): an
International randomized double-blind placebo-controlled study in 747 patients. J Hepatol 2005;42:17A.
2. Sarin SK, Kumar M, Garg S, Hissar S, Pandey C, Sharma BC. High dose vitamin K3 infusion in advanced hepatocellular carcinoma. J Gastroenterol Hepatol.
2006;21(9):1478–1482. http://dx.doi.org/10.1111/j.1440-1746.2006.04383.x.

Hormonal therapy: Summary
 All studies examining the role of single-agent tamoxifen or in
combination with diverse chemotherapeutic drugs were
unsatisfactory and failed to yield substantial worthy survival
advantages.
 Similar discouraging results occurred with megestrol as well as
somatostatin analogs (octreotide and lanreotide).

Hormonal therapy: Summary
 All studies examining the role of single-agent tamoxifen or in
combination with diverse chemotherapeutic drugs were
unsatisfactory and failed to yield substantial worthy survival
advantages.
 Similar discouraging results occurred with megestrol as well as
somatostatin analogs (octreotide and lanreotide).
• It can be concluded that the use of hormonal therapy for the MX of
advanced inoperable HCC is not recommended.
• Its use may be only recommended within the context of clinical trials.
• Further research is needed.

Summary for CT in Advanced HCC
 APASL17: NOT MENTIONED
 AASLD18: NOT MENTIONED
 Chemotherapy for HCC in non-cirrhotic pts is an underexplored area.
Chemotherapy for HCC in non-cirrhotic pts needs to be further investigated. [1]
1. Edeline J, Raoul JL, Vauleon E. Guillygomac’h A, Boudjema K, Boucher E. Systemic chemotherapy for hepatocellular carcinoma in non-cirrhotic liver: a
retrospective study. World J Gastroenterol 2009;15:713–716.

NOTE: INASL 2014 HCC GUIDELINE
 The use of systemic chemotherapy has not been found to be effective in MX of
HCC in RCTs.
 Two phase II studies from India have evaluated the role of cytotoxic CT in HCC.
 Parikh et al found that a regimen containing gemcitabine and cisplatin in pts
with advanced HCC was well tolerated in a phase II study.[1]
 Subsequently Pande et al reported a partial response rate in 25%, and stable
disease in an additional 50% to three or more cycles of CT with gemcitabine
and cisplatin, with a median OS of 7.5 months (95% CI, 4.5–10.5) from their
retrospective study of 24 pts of HCC.[1]
1. Parikh PM, Fuloria J, Babu G, et al. A phase II study of gemcitabine and cisplatin in patients with advanced hepatocellular carcinoma. Trop Gastroenterol. 2005;26(3):115–118.
2. Pande SB, Doval DC, Pavithran K, Sharma JB, Shirali R, Jena A. Gemcitabine and cisplatin-based combination chemotherapy in advanced hepatocellular carcinoma: an Indian experience. Indian
J Med Paediatr Oncol. 2012;33(1):42–47. http://dx.doi.org/10. 4103/0971-5851.96968.

Consensus Statements
 There is no evidence that combination Sorafenib with other cytotoxic agents or
targeted agents or hormonal therapy is superior to Sorafenib alone. (Evidence-
4,Grade-C)
 In case of progression or intolerance to Sorafenib, BSC is preferred or pts
should be included in clinical trials. (Evidence-1b, Grade-A)

Consensus Statements
 There is no evidence that combination Sorafenib with other cytotoxic agents or
targeted agents or hormonal therapy is superior to Sorafenib alone. (Evidence-
4,Grade-C)
 In case of progression or intolerance to Sorafenib, BSC is preferred or pts
should be included in clinical trials. (Evidence-1b, Grade-A)Use of systemic cytotoxic CT, immunotherapy, or hormonal therapy
(such as tamoxifen, anti-androgens, somatostatin analogs) are not
recommended for the clinical management of HCC, either alone or in
combination or as adjuvant or neoadjuvant therapies. (Evidence-
1b,Grade-A)

Immunotherapy
Future perspectives
• Sorafenib
• Lenvatinib
• Regorafenib
• Cabozantinib

Sorafenib
 It acts by inhibiting the serine–threonine kinases involved in RAF/MEK/ERK
pathway, and the receptor tyrosine kinase activity of vascular endothelial
growth factor receptors (VEGFRs) 1, 2, and 3 and platelet-derived growth factor
receptor β (PDGFR-β).[1-4]
 Cellular signaling that is mediated by the Raf-1 and VEGF pathways has been
implicated in the molecular pathogenesis of HCC, providing a rationale for
investigating sorafenib for this indication.
• Inhibits tumor-cell proliferation
• Inhibits Tumor angiogenesis
• Increases the rate of apoptosis
1. Wilhelm SM, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099-7109
2. Chang YS, et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 2007; 59: 561-574
3. Wilhelm SM, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther 2008; 7: 3129-3140
4. McDermott U, et al. Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling. Proc Natl Acad Sci USA 2007; 104:19936-19941

Summary of major phase I/II studies on Sorafenib for
the MX of pts with advanced HCC
Author.. et al year Phase n Child class (%) Hepatitis DCR
(%)
TTP
(mon)
OS
(mon)
R
ef
A B C
B C
Furuse 2008 I 27 48 52 0 15 74 83 4.9 15.6 1
Castrogudin 2008 I 13 92 NR NR 0 23 62 NR 2 2
Abou-Alfa 2006 II 137 72 28 0 17 48 36 4,2 9.2 3
Massa 2008 II 16 NR NR NR NR NR 64 3 15 4
Yau 2008 II 51 71 26 3 90 6 26 3 5 5
n: sample size;; DCR: disease control rate; TTP: time to progression; OS: overall survival; NR: not reported;
mon: months
1. Furuse J. Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci. 2008;99(1):159-65.
2. Castroagudin JF. Short-term efficacy and safety of treatment of advanced hepatocellular carcinoma with sorafenib. Journal of Hepatology. 2008;48(362 Suppl 2):s141-s142.
3. Abou-Alfa GK,, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24(26):4293-300.
4. Massa ESC, et al. Efficacy, safety and impact on quality of life of a treatment with sorafenib in elderly cancer patients with advanced hepatocellular carcinoma. Result of a phase II study. Ann
Oncol. 2009;20 (Suppl 8):s65.
5. Yau T,, et al. Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts
poor response. Cancer. 2009;115(2):428-36.

Sorafenib in Advanced HCC: SHARP TRIAL[1]
Josep M. Llovet, Sergio Ricci, Vincenzo Mazzaferro. N Engl J Med 2008; 359:378-390 DOI: 10.1056/NEJMoa0708857
 METHODS: In this multicenter, phase 3, double-blind, placebo-controlled trial,
602 pts with advanced HCC randomly assigned who had not received previous
systemic RX to receive either sorafenib (n=299) (400 mg BID) or placebo
(n=303).
 Primary outcomes: OS and the time to symptomatic progression.
 Secondary outcomes: time to radiologic progression and safety.
1. Llovet JM, Ricci S, Mazzaferro V et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378–390.
• OS was measured from the date of randomization until the date of death from any cause.
• The time to symptomatic progression was measured from the date of randomization until the first
documented event of symptomatic progression. Symptomatic progression was defined as either a ↓ of ≥4
points from the baseline score on pts' responses to the FHSI8 questionnaire, a change that was confirmed
3 weeks later , a deterioration in ECOG performance status to 4, or death.

Kaplan–Meier Analysis of Overall
Survival
Among 602 pts (of whom
299 received sorafenib and
303 received placebo), the
median OS was 10.7
months in the S group, as
compared with 7.9
months in the P group
(HR for death in the S
group, 0.69; 95% CI, 0.55 to
0.87)p<0.001.

 RESULTS: Median OS was 10.7 mnths in the sorafenib group and 7.9 mn in the
placebo gp (HR in the sorafenib gp, 0.69; 95% CI, 0.55-0.87; P<0.001).
 The median time to symptomatic progression: 4.1 mn vs. 4.9 mn, P=0.77.
 The median time to radiologic progression: 5.5 mn Vs 2.8 mnths (P<0.001).
 7 pts in the sorafenib gp (2%) and 2 pts in the placebo gp (1%) had a PR; no
pts had a CR.
 The overall incidence of treatment-related adverse events was 80% in the
sorafenib group and 52% in the placebo groupDiarrhea, wt loss, HFSR, and
hypophosphatemia were more frequent in the sorafenib gp.

 RESULTS: Median OS was 10.7 mnths in the sorafenib group and 7.9 mn in the
placebo gp (HR in the sorafenib gp, 0.69; 95% CI, 0.55-0.87; P<0.001).
 The median time to symptomatic progression: 4.1 mn vs. 4.9 mn, P=0.77.
 The median time to radiologic progression: 5.5 mn Vs 2.8 mnths (P<0.001).
 7 pts in the sorafenib gp (2%) and 2 pts in the placebo gp (1%) had a PR; no
pts had a CR.
 The overall incidence of treatment-related adverse events was 80% in the
sorafenib group and 52% in the placebo groupDiarrhea, wt loss, HFSR, and
hypophosphatemia were more frequent in the sorafenib gp.
CONCLUSIONS: In pts with advanced HCC, MS and the time
to radiologic progression were nearly 3 months longer for pts
RX with sorafenib than for those given placebo.

Sorafenib: Asia-Pacific trial (ORIENTAL)
 In Asia-Pacific trial [1], 226 pts were randomized in a 2:1 ratio
between sorafenib and placebo.
1. Cheng AL, Kang YK, Chen Z et al (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind,
placebo-controlled trial. Lancet Oncol 10:25–34
Median overall survival was 6.5 months
(95% CI, 5.56–7.56) in pts treated with
sorafenib, compared with 4.2 months
(3.75–5.46) in those who received
placebo (HR 0.68 [95% CI, 0.50–0.93]; P
= 0.014).
Time to progression, was significantly
higher in the Sorafenib group (2.8 mo vs
1.4 mo, P = 0.0005).

Sorafenib: CP class B/C & Elderly ??
 Regarding liver function, available data come from retrospective studies[1-5], that evaluated RX
with sorafenib in pts with C-P B, showing shorter OS, compared with pts with C-P A.
 In addition, two studies[2-5] showed an ↑ incidence of severe A/E in C-P B pts, that led to dose
reduction or discontinuation of RX.
 Thus, in the latest available guidelines there is no clear CI about sorafenib administration in pts
with C-P B, but caution is advised due to the ↑ risk of A/E [6].
 Sorafenib RX in elderly (age > 70 yrs) was evaluated only in a retrospective study[7], which
reported a PFS and OS similar to younger pts, associated to a higher incidence of some A/E
(neutropenia, malaise and mucositis); anyway, no clear indication about RX of older pts was
given in last guidelines.
References are at the end of the slides

Sorafenib: notes
 The recommended daily dose : 800mg.
 Median treatment duration is estimated to be 5–6months, but early prevention
of toxicities can enhance tolerability.
 Treatment is a/with manageable AEs, such as diarrhoea, hand–foot skin
reactions, fatigue, HTN, weight loss, hypophosphatemia.
 Around 15% of pts are intolerant to sorafenib, and thus treatment needs to be
withdrawn, while another 35% of pts require dose reduction. Treatment related
liver failure or life-threatening complications are marginal.
 Clinically symptomatic vascular disease—either coronary or peripheral—is
considered a formal contraindication.

Ikeda M, et al. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Japanese Journal of Clinical Oncology, Volume 48, Issue 2,
February 2018, Pages 103–114, https://doi.org/10.1093/jjco/hyx180

Sunitinib: SUN1170 trial
 Sunitinib is MKI which targets VEGFR,
PDGFR and c-kit.
Cheng AL, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III
trial. J Clin Oncol 2013; 31: 4067-4075

Sunitinib: SUN1170 trial
 Sunitinib is MKI which targets VEGFR,
PDGFR and c-kit.
Cheng AL, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III
trial. J Clin Oncol 2013; 31: 4067-4075
• OS with sunitinib was not superior or equivalent but was significantly inferior
to sorafenib regarding OS (7.9 mo vs 10.2 mo, P =0.0014).
• Based on current evidence, sunitinib is not to be considered as a viable
therapeutic alternative to sorafenib.

Brivanib : BRISK-FL & BRISK-PS trial
 Brivanib is a small molecule acting as dual tyrosine kinase inhibitor (TKI) of
VEGFR and FGFR.
 The drug, administrated orally (800 mg OD), was initially evaluated as first line
RX in comparison with sorafenib in the BRISK-FL trial[1](n= 577 VS 578), then as
second line RX in comparison with placebo in pts who complained intolerance
or lack of response to sorafenib in BRISK-PS trial[2](n=363 VS 162).
1. Johnson PJ, Cheng AL et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the
randomized phase III BRISK-FL study. J Clin Oncol 2013; 31: 3517-3524
2. Llovet JM, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the
randomized phase III BRISK-PS study. J Clin Oncol 2013; 31:3509-3516

Brivanib : BRISK-FL & BRISK-PS trial
 BRISK-FL trial[1] showed no difference regarding OS between brivanib and
sorafenib (9.5 mo vs 9.9 mo, HR = 1.06, 95%CI: 0.93-1.22, P = 0.311).
 Even as second-line therapy, in comparison with BSC, Brivanib failed: BRISK-
PS[2] trial showed no significant difference regarding OS between the two
approaches (9.4 mo vs 8.2 mo, P = 0.3307).
1. Johnson PJ, Cheng AL et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the
randomized phase III BRISK-FL study. J Clin Oncol 2013; 31: 3517-3524
2. Llovet JM, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the
randomized phase III BRISK-PS study. J Clin Oncol 2013; 31:3509-3516
Thus, at this time evidences do not allow to consider brivanib an effective
alternative to Sorafenib.

Erlotinib: SEARCH trial
 Erlotinib is a TKI targeting EGFR, which was evaluated in combination with
sorafenib vs sorafenib alone in SEARCH phase III trial[1](n=362 vs 358).
1. Zhu AX, Llovet JM, et al. SEARCH: a phase III, randomized, doubleblind, placebo-controlled trial of sorafenib plus erlotinib in patients with
advanced hepatocellular carcinoma. J Clin Oncol 2015; 33:559-566
This combination did not lead to an increased OS (9.5 mo vs 8.5 mo,
P = 0.408) and was related to potent toxicity.

Linifanib : LIGHT trial
 Linifanib is a dual TKI targeting VEGFR and PDGFR.
 LIGHT phase III trial[1] (n= 514 vs 521 )compared the drug to sorafenib as first-
line RX, but OS between the two groups was similar (9.1 vs 9.8) (95%CI: 8.3-
11.0, HR = 1.046, 95%CI: 0.896-1.221 p=ND) and linifanib group showed higher
rate of adverse events (e.g., HTN and HE).
1. Cainap C, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin
Oncol 2015; 33: 172-179

Linifanib : LIGHT trial
 Linifanib is a dual TKI targeting VEGFR and PDGFR.
 LIGHT phase III trial[1] (n= 514 vs 521 )compared the drug to sorafenib as first-
line RX, but OS between the two groups was similar (9.1 vs 9.8) (95%CI: 8.3-
11.0, HR = 1.046, 95%CI: 0.896-1.221 p=ND) and linifanib group showed higher
rate of adverse events (e.g., HTN and HE).
1. Cainap C, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin
Oncol 2015; 33: 172-179
OS between the two groups was similar (9.1 vs 9.8) (95%CI: 8.3-11.0, HR = 1.046,
95%CI: 0.896-1.221 p=ND) and linifanib group showed higher rate of adverse
events (e.g., HTN and HE).

SILIUS trial
 Background: Aimed to compare continuous HAIC plus sorafenib with sorafenib alone in pts
with advanced, unresectable HCC. Randomly assigned (1:1) to receive 400 mg sorafenib orally
twice daily or 400 mg sorafenib orally BD plus HAIC (cisplatin 20 mg/m 2 on days 1 and 8 and
fluorouracil 330 mg/m 2 continuously on days 1–5 and 8–12 of every 28-day cycle via an
implanted catheter system).
 The primary endpoint was overall survival.
 Median OS was similar in the S + HAIC group(n=102) and sorafenib monotherapy (n=103)
groups (11·8 months [95% CI 9·1–14·5] vs 11·5 months [8·2–14·8]; HR 1·009 [95% CI 0·743–1·371];
p=0·955).
1. Kudo M,et al. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced
hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial.Lancet VOLUME 3, ISSUE 6, P424-432, JUNE 01, 2018

SILIUS trial
 Background: Aimed to compare continuous HAIC plus sorafenib with sorafenib alone in pts
with advanced, unresectable HCC. Randomly assigned (1:1) to receive 400 mg sorafenib orally
twice daily or 400 mg sorafenib orally BD plus HAIC (cisplatin 20 mg/m 2 on days 1 and 8 and
fluorouracil 330 mg/m 2 continuously on days 1–5 and 8–12 of every 28-day cycle via an
implanted catheter system).
 The primary endpoint was overall survival.
 Median OS was similar in the S + HAIC group(n=102) and sorafenib monotherapy (n=103)
groups (11·8 months [95% CI 9·1–14·5] vs 11·5 months [8·2–14·8]; HR 1·009 [95% CI 0·743–1·371];
p=0·955).
1. Kudo M,et al. Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced
hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial.Lancet VOLUME 3, ISSUE 6, P424-432, JUNE 01, 2018
Addition of hepatic arterial infusion chemotherapy to sorafenib did not
significantly improve overall survival in pts with advanced HCC.

 Context In a RCT, 400 mg of sorafenib twice daily prolonged overall survival of
pts with advanced HCC and CP A disease.
 Objective To evaluate the efficacy and safety of doxorubicin plus sorafenib
compared with doxorubicin alone in pts with advanced HCC and CP A disease.

 Design, Setting, and Patients In a double-blind phase 2 multinational study,
conducted from April 2005 to October 2006, 96 pts (76% male; median age, 65
years [range, 38-82 years]) with advanced HCC, ECOG PS 0 to 2, CP A status,
and no prior systemic therapy were randomly assigned to receive 60 mg/m2 of
doxorubicin intravenously every 21 days plus either 400 mg of sorafenib or
placebo orally twice a day. The date of the last patient’s follow-up was April
2008.
 Main Outcome Measure Time to progression.

• Median OS was 13.7 months (95% CI, 8.9-not reached) and
6.5 months (95% CI, 4.5-9.9; P=.006), and
• PFS was 6.0 months (95% CI, 4.6-8.6) and 2.7 months (95%
CI, 1.4-2.8) in these groups, respectively (P=.006).

Conclusions In summary, among pts with advanced HCC, RX with sorafenib
+ doxo compared with doxo plus placebo resulted in greater median time to
progression, OS, and PFS.
The degree to which this improvement may represent synergism between
sorafenib and doxorubicin remains to be defined. This trial has served as the
basis for the phase 3 trial of sorafenib plus doxorubicin vs sorafenib alone.[1]
1. https://clinicaltrials.gov/ct2/show/NCT01015833

Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients
with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). Abou-Alfa GK,et
al. Journal of Clinical Oncology 34, no. 4_suppl (February 1 2016) 192-192.
 Background: The results of Phase II appeared promising compared to the
historic outcomes seen in the pivotal sorafenib (S) trials. CALGB 80802 was
designed to determine if D+S improved survival compared to S alone.
 Methods: Pts [346 patients (173 on each of D+S and S)] with histologically
proven advanced HCC, no prior systemic therapy and CP A were randomized
to receive D 60 mg/m2 every 21 days plus S 400 mg PO twice daily (D+S) or S
alone.

Phase III randomized study of Sorafenib plus Doxorubicin versus Sorafenib in
patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance).
Abou-Alfa GK,et al. Journal of Clinical Oncology 34, no. 4_suppl (February 1 2016) 192-192.
 Results: The Alliance DSMB halted the study after accrual of 346 patients (173 on each of D+S
and S) when a futility boundary was crossed at a planned interim analysis.
 With 107 events in each arm, median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5
months (95% CI 7.4-14.3) for S with a HR 1.06 (95% CI 0.8-1.4) for D+S vs. S.
 Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1), respectively (HR = 0.90,
95% CI 0.72-1.2).
 There were 38 deaths on treatment: 18 on D+S and 20 on S. Among these 8 [sepsis (1),
dysphagia (1), pneumonia (1), cardiac (2), hepatic failure (2), and not otherwise specified (1)] on
D+S, and 3 [fatigue (1), hepatic failure (1), and a secondary malignancy (1)] on S, were at least
possibly related to treatment.
 A maximum grade 3 or 4 only hematologic adverse events (AE) occurred in 37.8% of patients
on D+S and 8.1% of patients on S. Non-hematologic AEs were comparable, in 63.6% and 61.5%
of patients, respectively.
 Conclusions:The addition of D to S resulted in higher toxicity and did not improve OS or PFS.
The S median OS of about 10 months is consistent with previous reports.

Phase III randomized study of Sorafenib plus Doxorubicin versus Sorafenib in
patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance).
Abou-Alfa GK,et al. Journal of Clinical Oncology 34, no. 4_suppl (February 1 2016) 192-192.
 Results: The Alliance DSMB halted the study after accrual of 346 patients (173 on each of D+S
and S) when a futility boundary was crossed at a planned interim analysis.
 With 107 events in each arm, median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5
months (95% CI 7.4-14.3) for S with a HR 1.06 (95% CI 0.8-1.4) for D+S vs. S.
 Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1), respectively (HR = 0.90,
95% CI 0.72-1.2).
 There were 38 deaths on treatment: 18 on D+S and 20 on S. Among these 8 [sepsis (1),
dysphagia (1), pneumonia (1), cardiac (2), hepatic failure (2), and not otherwise specified (1)] on
D+S, and 3 [fatigue (1), hepatic failure (1), and a secondary malignancy (1)] on S, were at least
possibly related to treatment.
 A maximum grade 3 or 4 only hematologic adverse events (AE) occurred in 37.8% of patients
on D+S and 8.1% of patients on S. Non-hematologic AEs were comparable, in 63.6% and 61.5%
of patients, respectively.
 Conclusions:The addition of D to S resulted in higher toxicity and did not improve OS or PFS.
The S median OS of about 10 months is consistent with previous reports.
The study was halted after after accrual of toxicity.
Median OS was 9.3 months (95%CI 7.1-12.9) for D+S, and 10.5 months (95%
CI 7.4-14.3) for S with a HR 1.06 (95% CI 0.8-1.4) for D+S vs. S.
Median PFS was 3.6 (95% CI 2.8-4.6) and 3.2 months (95% CI 2.3-4.1),
respectively (HR = 0.90, 95% CI 0.72-1.2).
Conclusions:The addition of D to S resulted in higher toxicity and did not
improve OS or PFS. The S median OS of about 10 months is consistent with
previous reports.

Vandetanib in pts with inoperable HCC: a phase II, randomized,
double-blind, placebo-controlled study.
 BG/AIM: The present study evaluated the efficacy and safety of vandetanib, an oral inhibitor of
both VEGFR and EGFR, in patients with unresectable advanced HCC.
 vandetanib 300mg/day(n=19), vandetanib 100mg/day(n=25), or placebo (n=23)
 The primary objective : to evaluate tumor stabilization rate (CR+PR+SD ⩾4months).
Vandetanib (Hsu C, et al) 2012
Results:
• In both vandetanib arms, tumor stabilization rate was not significantly different from placebo: 5.3%
(vandetanib 300mg), 16.0% (vandetanib 100mg) and 8.7% (placebo).
• The MC A/E were diarrhea and rash, whose incidence did not differ significantly between treatment
groups.
• CONCLUSIONS: Vandetanib has limited clinical activity in HCC. The safety profile was consistent with
previous studies.
1. Hsu C, et al. Vandetanib in patients with inoperable hepatocellular carcinoma: a phase II, randomized, double-blind, placebo-controlled study.J Hepatol. 2012
May;56(5):1097-103. doi: 10.1016/j.jhep.2011.12.013. Epub 2012 Jan 13.

Efficacy and safety of Nintedanib versus sorafenib in Asian pts with advanced
HCC: A randomized phase II trial.
1. Cheng AL. Efficacy and safety of nintedanib versus sorafenib in Asian patients with advanced hepatocellular carcinoma (HCC): A randomized phase II trial.Journal
of Clinical Oncology 33, no. 3_suppl (January 20 2015) 339-339.
 To evaluate the efficacy and safety of N versus sorafenib (S) in Asian pts with advanced HCC.
 Primary endpoint was TTP (RECIST 1.0) and secondary endpoints were OS and investigator-
assessed (IA) TTP.
 Results: Pts (N=95) were randomized to receive N (n=63) or S (n=32)
 N and S had comparable TTP (median 2.8 vs 3.0 months; HR 1.39 [95% CI: 0.87–2.23]) and OS
(median 10.2 vs 10.7 months; HR 0.94 [95% CI: 0.59–1.49]).
Nintedanib (Cheng AL, et al) 2015
Conclusions:
• N shows similar efficacy to S for TTP and OS.
• N was better tolerated than S and AEs were generally manageable.
• Further studies of N in Asian patients with advanced HCC are warranted.

Randomized, open-label phase 2 study comparing frontline dovitinib versus
sorafenib in pts with advanced HCC.
1. Cheng AL. Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular
carcinoma.Hepatology. 2016 Sep;64(3):774-84. doi: 10.1002/hep.28600. Epub 2016 May 17.
 BG: In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Oral dovitinib
(500 mg/day,; n = 82) versus sorafenib (400 mg BD; n = 83) was evaluated .
 The PEp and SEp were OS and TTP, respectively.
 The median OS (95% [CI]) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-
11.3) months for sorafenib.
 The median TTP (95% CI) was 4.1 (2.8-4.2) months and 4.1 (2.8-4.3) months for
dovitinib and sorafenib, respectively.
Dovitinib (Cheng AL, et al) 2016
CONCLUSION:
Dovitinib was well tolerated, but activity was not greater than sorafenib as a
frontline systemic therapy for HCC.
Based on these data, no subsequent phase 3 study has been planned.

Anti-mTOR (mammalian target of rapamycin) agents
year phase Agent n
RR (%)
DS
(%)
TTP
(mon)
PFS
(mon)
OS
(mo
n)
Re
f
Blaszkowsky et al. 2011 I/II Everolimus 28 4 44 NR 3.8 8.4 1
Rizell et al. 2008 II Sirolimus 21 4.8 23.8 NR NR 6.5 2
1. Blaszkowsky LS, Abrams TA, Miksad RA, Zheng H, Meyerhardt JA, Schrag D, Kwak EL, Fuchs C, Ryan DP, Zhu AX. Phase I/II study of everolimus in patients with advanced hepatocellular
carcinoma (HCC) J Clin Oncol. 2010;28(Suppl 15S):Ae14542.
2. Rizell M, Andersson M, Cahlin C, Hafstrom L, Olausson M, Lindner P. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol.
2008;13(1):66-70.

Anti-EGFR (Epidermal growth factor receptor) agents
year phase Agent n
RR (%)
DS
(%)
TTP
(mon)
PFS
(mon)
OS
(m
on)
Ref
Philip et al. 2005 II Erlotinib 38 7.9 59 NR 3.2 13 1
Thomas et al. 2007 II Erlotinib 40 0 43 NR 3.1 11 2
O’Dwyer et al. 2006 II Gefitinib 31 3 22.5 NR 2.8 6.5 3
Ramanathan et al. 2009 II Lapatinib 57 5 35 NR 2.3 6.2 4
Lin et al. 2008 II Imatinib 15 0 13.3 NR NR NR 5
Zhu et al. 2007 II Cetuximab 30 0 17 NR 1.4 9.6 6
Gruenwald et al. 2007 II Cetuximab 32 0 44 1.9 2 NR 7

Antiangiogenic agents
year phase Agent n
RR (%)
DS
(%)
TTP
(mon)
PFS
(mon
)
OS
(mo
n)
Ref
Schwartz et al. 2006 II Bevacizumab 30 6.7 57 6.4 NR NR 1
Malka et al. 2007 II Bevacizumab 30 12.5 54 NR 3.5 NR 2
Siegel et al. 2008 II Bevacizumab 46 13 NR NR 6.9 12.4 3
Hoda et al. 2008 II Sunitinib 23 6 35 NR NR NR 4
Zhu et al. 2009 II Sunitinib 34 2.9 47 4.1 3.9 9.8 5
Faivre et al. 2009 II Sunitinib 37 2.7 35 5.3 3.7 8 6
Koeberle et al. 2010 II Sunitinib 45 2 40 2.8 2.8 9.3 7
Finn et al. 2012 II Brivanib 46 4.3 41.3 2.7 NR 9.79 8

Antiangiogenic agents
year phase Agent n
RR
(%)
DS
(%)
TTP
(mon
)
PFS
(mon)
OS
(mo
n)
Ref
Yau et al. 2009 I Pazopanib 27 7 41 4.6 NR NR 9
Toh et al. 2009 II Inifanib 44 8.7 NR 3.7 3.7 9.8 10
Alberts et al. 2007 II Cediranib 28 0 NR 2.8 NR 5.8 11
O’Neil et al. 2009 II Selumetinib 19 0 37.5 2 NR NR 12
Kanai et al. 2010 I/II Orantinib 35 8.6 42.8 2.1 NR 13.1 13
Zhu et al. 2010 II Ramucirumab 42 NR 50 NR 4.3 NR 14
Koch et al. 2007 I Vatalanib 18 0 50 NR NR 7.3 15
Llovet et al.
BRISK-PS
2013 III
Brivanib + BSC
VS Placebo +
BSC
363
vs
162
9.4
vs
8.2
(ns)
16

Sorafenib Phase III trials
Agents n
RR
(%)
DCR
(%)
TTP/PFS
(Median:
months)
OS
(Median:
months)
P
value
Phase/Na
me of
trial
Authors reported
year
Ref
No.
Sorafeni
b
Placebo
299
303
2.3
0.7
43
32
5.5
2.8
10.7
7.9
<0.001
SHARP
Llovet JM
2008
1
Sorafeni
b
Placebo
150
76
3*
1
35.3
15.8
2.8
1.4
6.5
4.2 0.014
Asia-
Pacific
Cheng AL
2009 2
Sunitinib
Sorafeni
b
530
542
6.6
6.1
50.8
51.5
3.6
3.0
7.9
10.2
0.0014
SUN1170
Cheng AL
2013 3
Brivanib
Sorafeni
b
577
578
12*
9
66%*
65
4.2
4.1
9.5
9.9
0.3730
BRISK-FL
Johnson P
2013 4
Linifanib
Sorafeni
b
514
521
13.0
6.9
ND
ND
5.4
4.0
9.1
9.8 ND LiGHT
Cainap C
2015 5
RR, response rate; DCR, disease control rate; TTP, time to progression; PFS, progression-free survival; OS, overall survival; Ref, reference; ND,
no data;*Modified RECIST.
1. Llovet JM , Ricci S, Mazzaferro V, et al. . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90.
2. Cheng AL , Kang YK, Chen Z, et al. . Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25–34.
3. Cheng AL , Kang YK, Lin DY, et al. . Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013;31:4067–75.
4. Johnson PJ , Qin S, Park JW, et al. . Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol 2013;31:3517–24.
5. Cainap C , Qin S, Huang WT, et al. . Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015;33:172–9.

Sorafenib Phase III trials
Agents n
RR
(%)
DCR
(%)
TTP/PFS
(Median:
months)
OS
(Median:
months)
P
value
Phase/Name of
trial
Authors
reporte
d year
Ref
No.
Sorafenib + Erlotinib
Sorafenib + Placebo
362
358
6.6
3.9
43.9
52.5
3.2
4.0
9.5
8.5 0.408 SEARCH
Zhu AX
2015 1
Sorafenib +
Doxorubicin
Sorafenib
180
176
ND
ND
ND
ND
4.0
3.9
10.5
8.9 0.24
CALGB
80 802
Abou-
Alfa GK
2016 2
Lenvatinib
Sorafenib
478
476
24*
9
75.6*
60.5
8.9
7.4
13.6
12.3 ND REFLECT
Cheng
AL
2017 3
RR, response rate; DCR, disease control rate; TTP, time to progression; PFS, progression-free survival; OS,
overall survival; Ref, reference; ND, no data;*Modified RECIST.
1. Zhu AX , Rosmorduc O, Evans TR, et al. . SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J
Clin Oncol 2015;33:559–66.
2. Abou-Alfa GK , Niedzwieski D, Knox JJet al. . Phase III randomized study of Sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC)- CALGB 80802
(Alliance). J Clin Oncol 2016;34:(suppl; abstr 4003).
3. Cheng AL , Finn RS, Qin Set al. . Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol
2017;35:(suppl; abstr 4001).

Lenvatinib:
 Several phase III trials have been conducted to challenge sorafenib in front line
(testing sunitinib, brivanib, erlotinib, linifanib or doxorubicin), but lenvatinib has
only recently shown non-inferior clinical efficacy [1].
 Lenvatinib is an oral multikinase inhibitor that targets VEGFR1–3 and fibroblast
growth factor receptor (FGFR)1–4, among others.
1. Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular
carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018; 391: 1163–1173.

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable
HCC: a randomised phase 3 non-inferiority trial/REFLECT
1. Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
Lancet 2018; 391: 1163–1173.
 This multicentre, phase 3, randomised, open-label, noninferiority study was
done at 154 sites in 20 countries throughout the Asia-Pacific, European, and
North American regions.
 Patients received oral lenvatinib 12 mg/day (for bodyweight ≥60 kg) or 8
mg/day (for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day
cycles.
 The PEp was OS. SEp were PFS, TTP, ORR, QoL.

HCC: a randomised phase 3 non-inferiority trial
1. Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
Lancet 2018; 391: 1163–1173.

The study met its PEp of non-inferiority
in OS [HR 0.92; 95% CI 0.79–1.06; mOS
lenvatinib, 13.6 months vs sorafenib,
12.3 months].
SEp such as PFS, TTP and ORR (24% vs
9.2% for sorafenib, mRECIST ORR) were
significantly better for lenvatinib.
Lenvatinib-related mc any-grade A/Es compared with sorafenib were as follows: HTN (42% vs 30%), diarrhoea
(39% vs 45%) and HFSR (27% vs 52%).

The study met its PEp of non-inferiority
in OS [HR 0.92; 95% CI 0.79–1.06; mOS
lenvatinib, 13.6 months vs sorafenib,
12.3 months].
SEp such as PFS, TTP and ORR (24% vs
9.2% for sorafenib, mRECIST ORR) were
significantly better for lenvatinib.
Lenvatinib-related mc any-grade A/Es compared with sorafenib were as follows: HTN (42% vs 30%), diarrhoea
(39% vs 45%) and HFSR (27% vs 52%).
Lenvatinib demonstrated non-inferiority results compared with
sorafenib .
These results position lenvatinib as an option in first-line treatment for
advanced HCC, once the drug is approved by regulatory agencies.

EVOLUTION of Chemotherapy in A-HCC
Ikeda M, et al. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Japanese Journal of Clinical Oncology, Volume 48, Issue 2,
February 2018, Pages 103–114, https://doi.org/10.1093/jjco/hyx180

Phase III trials for Second Line Drug
Agents
Trial (year)
n (Number
of pts)
OS (Median:
months)
Authors(et al) Ref No.
Brivanib + BSC Vs Placebo + BSC
BRISK-PS (2013)
363 vs 162
9.4 Vs 8.2
P=NS
Llovet JM
1
Everolimus Vs Placebo
EVOLVE-1 (2014) 362 Vs 184
7.6 Vs 7.3
P= NS Zhu AX 2
Ramucirumab Vs Placebo
REACH-2 (2019) 197 Vs 95
8.5 Vs 7.3
P=0.01
Zhu AX
3
S-1 Vs Placebo
S-CUBE (2017) 223 Vs 111
11.1 Vs 11.2
P=0.2 Kudo M 4
OS, overall survival; Ref, reference
1. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed:
results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31(28):3509-16.
2. Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.
JAMA. 2014;312(1):57-67.
3. Zhu AX,et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-
controlled, phase 3 trial. The Lancet 2019 VOLUME 20, ISSUE 2, P282-296
4. Kudo M,et al. S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial.Lancet Gastroenterol
Hepatol 2017; 2: 407–17

Phase III trials for Second Line Drug
Agents
Trial (year)
n
RR
(%)
OS (Median:
months)
Author(et al)
Ref
No.
ADI-PEG 20 Vs Placebo 424 Vs 211 ND
7.8 Vs 7.4
P=0.8 Abou-Alfa GK 1
Regorafenib Vs Placebo
RESORCE (2016) 379 Vs 194 10
10.6 Vs 7.8
p<0·0001 Bruix J 2
Tivanitinib Vs Placebo
METIV-HCC
226 Vs 114 ND
8.4 Vs 9.1
P=0.8 Rimassa 3
Cabozantinib Vs Placebo
CELESTIAL (2018) 470 Vs 237 4
10.2 Vs 8.0
p-=0.004 Abou-Alfa GK 4
RR, response rate; OS, overall survival; Ref, reference; ND, no data.
1. GK Abou-Alfa, et al. Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular
carcinoma.Ann Oncol. 2018 Jun 1;29(6):1402-1408.
2. Bruix J, Qin S, Merle P et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3
trial. Lancet 2017; 389: 56–66.
3. Rimassa L et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet
Oncol. 2018 May;19(5):682-693
4. Abou-Alfa GK, Meyer T, Cheng AL et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: results from the
randomized phase III CELESTIAL trial. J Clin Oncol 2018; 36(Suppl 4): 207.

Targeted second-line therapies
 Regorafenib is the standard of care for pts with advanced HCC who have tolerated sorafenib
but progressed. It is recommended in pts with well preserved liver function and ECOG PS 0–1 [I,
A].
 Cabozantinib can be considered for pts who had progressive disease on one or two systemic
therapies with well-preserved liver function and ECOG PS 0–1, pending EMA approval [I, A].
 Ramucirumab (RAM) can be considered for pts in second-line treatment with baseline AFP ≥
400 ng/mL, well preserved liver function and ECOG PS 0–1, pending EMA approval [I, A].

Future of Advance HCC MX: Role of Immunotherapies
Immune
System
MAb Targeted
Therapy
Immune
checkpoint
inhibition
PD-1/PD-L1 and CTLA-4 pathways
Programmed death-ligand 1 (PD-L1) (found on the surface of cancer cells and stromal cells) and Programmed cell
death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) (found on the surface of T cells) have
been shown to play particularly important roles in the suppression of T cell activation by cancer cells.
For eg ; Tremelimumab is a Mab that blocks cytotoxic T-lymphocyte-associated
antigen 4 (CTLA-4), an inhibitory co-receptor that interferes with T cell activation
and proliferation.
Source of the cliparts/images are listed in the end of slides

Nivolumab: CheckMate 040
 More recently, a large single-arm phase I/II trial of the PD-1 inhibitor Nivolumab,Checkmate 040
(n=262) has been reported [1].
 The ORR was 20% (RECIST v1.1) and the PFS and 9-month OS were 4.0 months and 74%,
respectively.
1. El-Khoueiry AB, Sangro B, Yau T et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative,
phase 1/2 dose escalation and expansion trial. Lancet 2017; 389: 2492–2502.
The first-line phase III trial comparing sorafenib with
nivolumab, CheckMate 459, is expected to report in 2019
and, if positive, will position Nivolumab as a first-line
treatment option.

RATIONALE 301 study: Tislelizumab Vs sorafenib as first-line
RX for unresectable HCC (PHASE III)
 Tislelizumab is an anti-PD-1 antibody .
 After its safety was confirmed in a phase I trial involving 61 pts with solid cancers, including HCC,
a global phase III trial was started in December 2017; pts were allocated to two groups,
tislelizumab or sorafenib, as a first-line treatment.[1]
1. Qin S, Finn RS, Kudo M, et al. A phase 3, randomized, open-label, multicenter study to compare the efficacy and safety of tislelizumab,an anti-PD-1 antibody,
versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma. J Clin Oncol 2018;36(15_suppl):TPS3110.

Pembrolizumab : KEYNOTE-224[1]
 Meanwhile, a phase II trial of the anti-PD-1 antibody Pembrolizumab as second-line treatment
(KEYNOTE-224) has recently been reported.
 The 16.3% response rate and mOS was 12.9 months (95% CI 9.7–15.5) .
1. Zhu AX, Finn RS, Edeline J et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-
randomised, open-label phase 2 trial. Lancet Oncol 2018; 19:940–952.

Camrelizumab
 Camrelizumab (SHR-1210) is an anti-PD-1 antibody .
 A phase I trial was performed in 58 pts with solid cancers (including HCC), with one of the three
pts with HCC exhibiting a response.[1]
 At present, a phase II/III trial is underway in China involving pts who failed to respond or were
intolerant to prior systemic treatment (NCT02989922). [II]
1. Huang J, Mo H, Wu D, et al. Phase I study of the anti-PD-1 antibody SHR-1210 in patients with advanced solid tumors. J Clin Oncol 2017;35(15_suppl):e15572.
2. Qin SK, Ren ZG, Meng ZQ, et al. LBA27A randomized multicentered phase II study to evaluate SHR-1210 (PD-1 antibody) in subjects with advanced
hepatocellular carcinoma (HCC) who failed or intolerable to prior systemic treatment. Ann Oncol 2018;29(suppl_8).
According to the interim results of the phase II part reported at a
meeting of the ESMO in 2018, the RR as 13.8% and 6-month OS rate
was 74.7%.

Durvalumab
 A phase I/II trial of Durvalumab monotherapy for solid cancers, including HCC, has been
completed, with a 10% response rate and a median OS of 13.2 months observed for a cohort
of 40 pts with HCC.[1]
 Durvalumab plus tremelimumab (an anti-CTLA-4 antibody) combination therapy has also
been developed, and a phase III trial is now underway to evaluate the efficacy of both
durvalumab monotherapy and durvalumab plus tremelimumab combination therapy.[2]
1. Wainberg ZA, Segal NH, Jaeger D, et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J Clin Oncol
2017;35(15_suppl):4071.
2. Abou-Alfa GK, Chan SL, Furuse J, et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with
unresectable hepatocellular carcinoma (HCC): HIMALAYA study. J Clin Oncol 2018;36(15_suppl):TPS4144.

Immune checkpoint inhibitors under evaluation in main clinical trials for
HCC (as of September 2018)
Okusaka T, Ikeda M. Immunotherapy for hepatocellular carcinoma: current status and future perspectives.ESMO Open. 2018 Dec 10;3(Suppl 1):e000455

Main trials for immune checkpoint inhibitors under evaluation in pts with
HCC (as of September 2018)
Okusaka T, Ikeda M. Immunotherapy for hepatocellular carcinoma: current status and future perspectives.ESMO Open. 2018 Dec 10;3(Suppl 1):e000455

Response assessment by RECIST v1.1 and mRECIST for HCC

These were not covered in this presentation
 Thalidomide studies
 Irinotecan studies
 IFN a, monotherapy and combination regime studies
 Role of Sorafenib POST-LT/POST SURGERY/POST LOCOREGIONAL THERAPIES
 Role of Surgery in Advance HCC
 Role of radiation therapy in Advanced HCC
Thankyou pic src: https://www.pinterest.com/FungiStaaan/thank-you-images-pics/
Sad picart src: https://www.kisspng.com/png-redwood-city-electronic-arts-logo-ea-sports-sad-758947/

References
 Ikeda M, et al. Systemic Chemotherapy for Advanced Hepatocellular Carcinoma: Past, Present, and
Future. Diseases. 2015 Dec; 3(4): 360–381.
 Ikeda M, et al. Chemotherapy for hepatocellular carcinoma: current status and future perspectives.
Japanese Journal of Clinical Oncology, Volume 48, Issue 2, February 2018, Pages 103–114,
https://doi.org/10.1093/jjco/hyx180
 Abu-Zaid A, et al. Past, Present, and Future Perspectives on the Systemic Therapy for Advanced
Hepatocellular Carcinoma (HCC) — A Comprehensive Review. Recent Advances in Liver Diseases and
Surgery. DOI: 10.5772/60991. Available at https://www.intechopen.com/books/recent-advances-in-liver-
diseases-and-surgery/past-present-and-future-perspectives-on-the-systemic-therapy-for-advanced-
hepatocellular-carcinoma-h last assessed may 2 2019.
 Note: The other references are included in their respective slides.
1st slide Liver pic taken from : https://fixhepc.com/blog/item/85-direct-acting-antivirals-and-liver-cancer-risk.html

References to cliparts/images in slide;
Future of Advance HCC MX: Role of Immunotherapies
 Antibody clipart Src:
https://www.roche.com/research_and_development/what_we_are_working_on/research_tech
nologies/antibodies-at-roche.htm
 James Allison/honjo pic src: From Wiki
 MAB clipart: https://lymphoma-action.org.uk/about-lymphoma-treatment-
lymphoma/antibody-therapy-lymphoma-including-rituximab

INASL : EVIDENCE GRADING
 The Task-Force adopted the Oxford Center for Evidence
Based Medicine—Levels of Evidence of 2009[1] for
developing an evidence-based approach. The group
assessed the level of existing evidence and accordingly
ranked the recommendations [i.e., level of evidence from 1
(highest) to 5 (lowest); grade of recommendation from A
(strongest) to D (weakest)].
1. CEBM > EBM Tools > Finding the Evidence > Levels of Evidence 2 > Levels of Evidence 1. Available at:
http://www.cebm.net/index.aspx?o=1025. Accessed 02.05.19.

References: Anti-EGFR agents
1. Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of erlotinib (OSI-774)
in patients with advanced hepatocellular cancer. J Clin Oncol. 2005;23:6657-63.
2. Thomas MB, Chadha R, Glover K, Wang X, Morris J, Brown T, et al. Phase 2 study of erlotinib in patients
with unresectable hepatocellular carcinoma. Cancer. 2007;110(5):1059-67.
3. O’Dwyer, O’Neil BH, Williams-Goff LW, Kauh J, Bekaii-Saab T, Strosberg JR, Lee R, Deal AM, Sullivan D,
Sebti SM. A phase II study of AZD6244 in advanced or metastatic hepatocellular carcinoma. J Clin
Oncol. 2009;27(Suppl):Ae15574. 2006.
4. Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz HJ, Yen Y, et al. A phase II study of lapatinib in
patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol.
2009;64:777-783.
5. Lin AY, Fisher GA, So S, Tang C, Levitt L. Phase II study of imatinib in unresectable hepatocellular
carcinoma. Am J Clin Oncol. 2008;31(1):84-8.
6. Zhu AX, Stuart K, Blaszkowsky LS, Muzikansky A, Reitberg DP, Clark JW, et al. Phase 2 study of cetuximab
in patients with advanced hepatocellular carcinoma. Cancer. 2007;110(3):581-9.
7. Gruenwald V, Wilkens LGM, Greten TF, Kubicka S, Ganser A, Manns MP, Malek NP. A phase II open-label
study of cetuximab in unresectable hepatocellular carcinoma: final results. J Clin Oncol. 2007;(Suppl
15S):25 [18S], 4598.

References: Antiangiogenic agents
1. Schwartz JD, Schwartz M, Sung M, Lehrer D, Cohen E, Kinkhabwala M, Holloway SB, Siegel A, Ocean A, Wadler S. Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without
invasion of the portal vein. Gastrointestinal Cancers Symposium. 2006:A210. 2006.
2. Malka D, Dromain C, Farace F, Horn S, Pignon J, Ducreux M, Boige V. Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): preliminary results of a phase II study with circulating endothelial cell
(CEC) monitoring. J Clin Oncol. 2007;25(18S):4570.
3. Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26(18):2992-8.
4. Hoda D, Catherine C, Strosberg J, Valone T, Jump H, Campos T, Halina G, Wood G, Hoffe S, Garrett CR. Phase II study of sunitinib malate in adult pts (pts) with metastatic or surgically unresectable hepatocellular carcinoma
(HCC). Proceedings of the 2008 Gastrointestinal Cancers Symposium. Abstract: 267.
5. Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol.
2009;27(18):3027-35.
6. Faivre S, Raymond E, Boucher E, Douillard J, Lim HY, Kim JS, et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study. Lancet Oncol.
2009;10(8):794-800.
7. Koeberle D, Montemurro M, Samaras P, Majno P, Simcock M, Limacher A, et al. Continuous sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and
Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06). Oncologist. 2010;15(3):285-92.
8. Finn RS, Kang YK, Mulcahy M, Polite BN, Lim HY, Walters I, et al. Phase II, openlabel study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2012;18:2090-8.
9. Yau CC, Chen PJ, Curtis CM, Murphy PS, Suttle AB, Arumugham T, Hodge JP, Dar MM, Poonet R. A phase I study of pazopanib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2009;27(Suppl):3561.
10. Toh H, Chen P, Carr BI, Knox J, Gill S, Steinberg J, Carlson DM, Qian J, Qin Q, Yong W. A phase II study of ABT-869 in hepatocellular carcinoma (HCC): interim analysis. J Clin Oncol. 2009;27(Suppl):4581.
11. Alberts SR, Fitch TR, Kim GP, Morlan BW, Dakhil SR, Gross HM, et al. Cediranib (AZD2171) in patients with advanced hepatocellular carcinoma: a phase II North Central Cancer Treatment Group Clinical Trial. Am J Clin
Oncol. 2012;35(4):329-33.
12. O’Neil BH, Williams-Goff LW, Kauh J, Bekaii-Saab T, Strosberg JR, Lee R, Deal AM, Sullivan D, Sebti SM. A phase II study of AZD6244 in advanced or metastatic hepatocellular carcinoma. J Clin Oncol.
2009;27(Suppl):Ae15574.
13. Kanai F, Yoshida H, Tateishi R, Sato S, Kawabe T, Obi S, et al. A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2011;67(2):315-24.
14. Zhu AX, Finn RS, Mulcahy MF, Gurtler JS, Sun W, Schwartz, P Rojas, A.Dontabhaktuni, H. Youssoufian, Stuart KE. A phase II study of ramucirumab as first-line monotherapy in patients (pts) with advanced hepatocellular
carcinoma (HCC). J Clin Oncol. 2010;28(15s):4083.
15. Koch I, Baron A, Roberts S. Influence of hepatic dysfunction on safety, tolerability, and pharmacokinetics (PK) of PTK787/ZK 222584 in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol.
2007;23(Suppl):4134.
16. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized
phase III BRISK-PS study. J Clin Oncol. 2013;31(28):3509-16.

References: Sorafenib: CP class B/C & Elderly ??
1. Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate
marker for efficacy. Am J Clin Oncol 2013; 36: 319-324
2. Chiu J, et al. The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with
underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits. Cancer 2012;
118: 5293-5301
3. Lencioni R, et al. First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular
carcinoma and of its treatment with sorafeNib) non-interventional study. Int J Clin Pract 2012; 66: 675-683
4. Lencioni R, et al. GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its
treatment with sorafeNib): second interim analysis. Int J Clin Pract 2014; 68: 609-617
5. Marrero JA, et al. Final analysis of GIDEON (Global Investigation of therapeutic decision in hepatocellular carcinoma
[HCC] and of its treatment with sorafenib [sor]) in > 3000 Sor-treated patients (pts):Clinical findings in pts with liver
dysfunction. J Clin Oncol 2013;31 (15, suppl): 4126
6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary cancers.
Accessed version 2, 2015. Available from: URL: http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf
7. Wong H, Tang YF, Yao TJ, Chiu J, Leung R, Chan P, Cheung TT, Chan AC, Pang RW, Poon R, Fan ST, Yau T. The outcomes
and safety of single-agent sorafenib in the treatment of elderly patients with advanced hepatocellular carcinoma
(HCC). Oncologist 2011; 16: 1721-1728

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