CAPER HCC Study Brief Summary:
Hepatocellular carcinoma (HCC) incidence has
been rising worldwide over the last 20 years. In 2012, liver cancer represents
the fifth most common cancer in men and the ninth in women and the second most
common cause of cancer-related death worldwide. Incidence is more in
underdeveloped countries of Africa and Asia compared to developed countries
correlating with the incidence of Hepatitis B (HBV) and Hepatitis C (HCV)
infection in most regions.
Hepatocellular carcinoma (HCC) usually occurs in
the setting of chronic liver disease and cirrhosis. Potentially curative
treatments include surgical tumor resection/ liver transplantation. However,
only a handful (<20%) of patients are able to undergo such treatments due to
the advanced nature of disease at the time of diagnosis.
The treatment options available to these
patients are limited and the prognosis is poor. Loco-regional therapies, such
as percutaneous ablation and radiofrequency ablation (RFA), arterial
chemoembolization (TACE), and conventional chemotherapies appear to offer
limited survival benefits in most cases.
Increased VEGF signaling leading to increased
tumor angiogenesis is one of the molecular alterations in HCC. Sorafenib, a
multikinase inhibitor (including VEGF signaling) has been approved for the
first line of treatment of HCC based on phase III trials showing significantly
improvement in progression free and overall survival (approximately by three
months) compared with placebo in patients with advanced HCC.
Recently multiple therapies have been approved
for second line therapy after sorafenib based on phase III trials, where there
was significant improvement in PFS and OS.
Unfortunately, regorafenib or other approved
second line therapy are not easily feasible for the majority of the population in
developing countries like India. There is thus a pressing need for easily
feasible, effective and tolerable
options to allow patients with advanced HCC to continue treatment after their
disease progresses on sorafenib.
EGFR and its ligands EGF and transforming growth
factor alpha (TGF-α) have been implicated in hepatocarcinogenesis and
overexpression of EGFR and EGF ligands is found in human HCC tissues. Erlotinib
is an orally active small-molecule tyrosine kinase inhibitor of EGFR approved
to treat patients with advanced non– small-cell lung and pancreatic cancers.
Erlotinib can inhibit invasion, metastasis, and angiogenesis in tumor cells
besides proliferation. Erlotinib 150 mg daily has demonstrated modest activity
but promising overall survival (OS) benefit in patients with unresectable HCC.
There are approximately 10 phase 2/3 trials (9 phase 2 trial and 1 phase 3
trial), showing a disease control rate of 42.5% to 79.6% and a median OS of
6.25 to 15.65 months. Also, the tolerance of erlotinib was not associated with
significant grade 3/4 toxicity in more than 10% of patients. Marie-José et al
results highlight that pathways controlled by EGFR/HER-3 are the driving force
for HCC cells to maintain proliferation under sorafenib. Therefore, EGFR
inhibitors are likely to be useful in the clinic in sorafenib resistant
patients.
Metronomic chemotherapy principally inhibits
angiogenesis by directly disrupting endothelial cell proliferation. Metronomic
chemotherapy may decrease the mobilization or viability of bone marrow-derived
circulating endothelial precursors, which contribute Hepatocellular carcinoma
(HCC) incidence has been rising worldwide over the last 20 years. In 2012,
liver cancer represents the fifth most common cancer in men and the ninth in
women and the second most common cause of cancer-related death worldwide.
Incidence is more in underdeveloped countries of Africa and Asia compared to
developed countries correlating with the incidence of Hepatitis B (HBV) and
Hepatitis C (HCV) infection in most regions.
Hepatocellular carcinoma (HCC) usually occurs in
the setting of chronic liver disease and cirrhosis. Potentially curative
treatments include surgical tumor resection/ liver transplantation. However,
only a handful (<20%) of patients are able to undergo such treatments due to
the advanced nature of disease at the time of diagnosis. The treatment options
available to these patients are limited and the prognosis is poor.
Loco-regional therapies, such as percutaneous ablation and radiofrequency
ablation (RFA), arterial chemoembolization (TACE), and conventional
chemotherapies appear to offer limited survival benefits in most cases.
Increased VEGF signaling leading to increased
tumor angiogenesis is one of the molecular alterations in HCC. Sorafenib, a multikinase
inhibitor (including VEGF signaling) has been approved for the first line of
treatment of HCC based on phase III trials showing significantly improvement in
progression free and overall survival (approximately by three months) compared
with placebo in patients with advanced HCC.
Recently multiple therapies have been approved
for second line therapy after sorafenib based on phase III trials, where there
was significant improvement in PFS and OS.
Unfortunately, regorafenib or other approved
second line therapy are not easily feasible for the majority of the population
in developing countries like India. There is thus a pressing need for easily
feasible, effective and tolerable options to allow patients
with advanced HCC to continue treatment after their disease progresses on
sorafenib.
EGFR and its ligands EGF and transforming growth
factor alpha (TGF-α) have been implicated in hepatocarcinogenesis and
overexpression of EGFR and EGF ligands is found in human HCC tissues. Erlotinib
is an orally active small-molecule tyrosine kinase inhibitor of EGFR approved
to treat patients with advanced non– small-cell lung and pancreatic cancers.
Erlotinib can inhibit invasion, metastasis, and angiogenesis in tumor cells
besides proliferation. Erlotinib 150 mg daily has demonstrated modest activity
but promising overall survival (OS) benefit in patients with unresectable HCC.
There are approximately 10 phase 2/3 trials (9 phase 2 trial and 1 phase 3
trial), showing a disease control rate of 42.5% to 79.6% and a median OS of
6.25 to 15.65 months. Also, the tolerance of erlotinib was not associated with
significant grade 3/4 toxicity in more than 10% of patients. Marie-José et al
results highlight that pathways controlled by EGFR/HER-3 are the driving force
for HCC cells to maintain proliferation under sorafenib. Therefore, EGFR
inhibitors are likely to be useful in the clinic in sorafenib resistant
patients.
Metronomic chemotherapy principally inhibits
angiogenesis by directly disrupting endothelial cell proliferation. Metronomic
chemotherapy may decrease the mobilization or viability of bone marrow-derived
circulating endothelial precursors, which contribute to tumor
neovascularization. Metronomic chemotherapy even upregulates antiangiogenic
factors such as thrombospondin- 1 (TSP-1) and angiostatin, and down-regulates
angiogenic factors such as vascular endothelial growth factor (VEGF), basic
fibroblast growth factor (b-FGF), and hypoxia-inducible factor-1 (HIF-1). In
addition, metronomic chemotherapy reduces regulatory T cells and promote
dendritic cell maturation thereby stimulate the immune response. Tumor cells
may also be directly affected by the metronomic therapy.
HCCs are highly vascular tumors. HCC is
dependent on preexisting vasculature for its development and on
neovascularization and angiogenesis for its growth. Angiogenesis plays an
important role in the progression from cirrhosis to regenerative nodules,
dysplastic nodules, and ultimately to HCC. Therefore, antiangiogenic therapy is
an attractive approach in the treatment of HCC.
The optimal metronomic dose is known for only a
few drugs and diseases, Capecitabine 500 mg twice daily has shown to have
activity and antiangiogenic effectiveness in colorectal cancer, as demonstrated
by contrast-enhanced magnetic resonance imaging. Capecitabine, an
oral prodrug of 5- fluorouracil (5-FU), is rapidly and almost completely
absorbed from the gastrointestinal tract and it undergoes hydrolysis in the
liver and tissues to form active moiety fluorouracil. Fluorouracil is an antimetabolite
that inhibits thymidylate synthetase, blocking the methylation of deoxy
uridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree,
RNA synthesis. Multiple studies have shown that mild to moderate liver
dysfunction in patients with liver metastatic cancer did not significantly
affect Capecitabine pharmacokinetics as the predominant route of elimination is
via the kidney. Therefore, patients with liver dysfunction should be monitored
closely during treatment, but no dose adjustment is required for liver
dysfunction solely. Phase I and II studies suggest that Capecitabine 500mg BD
is safe and effective in HCC patients.
HCC is a complex, highly heterogeneous tumor,
which makes it unlikely that targeting any one pathway will achieve optimal
disease control. Also, resistance mechanisms to sorafenib in HCC are still
poorly understood. Proposed resistance mechanisms include upregulation of VEGF
and other growth factors, activation of alternate signaling pathways, co-option
of existing vessels, and transformation of the tumor vasculature to a more
mature, less VEGF-dependent phenotype. Thereby making metronomic capecitabine
based anti-angiogenesis a suitable therapy in sorafenib resistant patients.
There is preclinical evidence to suggest that
inhibiting EGFR may make tumors more angiogenesis dependent, and therefore more
susceptible to anti-angiogenesis inhibitors. Factors such as fibroblast growth
factors (FGFs), insulin like growth factors (IGFs), angiopoietins, and
tumor-stromal interaction also contribute to sorafenib resistance. Hence
metronomic capecitabine based VEGF and other angiogenesis inhibition is worth
trying with anti EGFR inhibitor Erlotinib.
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HCC
(BCLC B or C stage) progressed or intolerant to sorafenib with CTP <=7
|
|
Capecitabine
500 mg BD with Erlotinib 100 mg OD continuously
|
|
Primary
endpoint
PFS
Secondary
endpoint
OS
Response rate
Toxicity
|
Patients of advanced HCC failing first line
sorafenib will be treated with Capecitabine and erlotinib combination as
follows
Tab Erlotinib 100 mg PO OD to continue
Tab Capecitabine 500mg PO BD to continue
Start of next cycle on D 28
(=1 cycle)
Treatment will be continued until unacceptable
toxicity, death, or consent withdrawal.
Study design:
Patients with unresectable or metastatic HCC who
have progression or are intolerant to sorafenib will be taken into study after
signing informed consent. Patient will be given capecitabine - erlotinib daily
until progression, unacceptable toxicity, consent withdrawal, death or lost to
follow up.
Sample size and statistical methods
Based on phase III second line regorafenib
trial, patients on placebo arm had a PFS of 10% at 6months. The hypothesis of
the study is based on the assumption that the PFS at 6 months would improve
from 10 to 30% by combination of metronomic capecitabine with erlotinib for the
treatment of advanced HCC post sorafenib failure, with a power of 80% and alpha of 0.1, a
Phase II study will require 29 patients with study accrual period of 2 years.
Follow up duration of the study will be 1-year post accrual of last patient.
Assuming an attrition rate of 10% per arm, a total of 32 patients will be
required to complete the study.
Duration of study
2.5 years (2years of recruitment; 6 months of
follow up)
Overview of advanced Hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) incidence has
been rising worldwide over the last 20 years and is expected to increase until
2030.([i],[ii],[iii]) In 2012, liver cancer represents the
fifth most common cancer in men and the ninth in women and the second most
common cause of cancer-related death worldwide.(3) Incidence is more
in underdeveloped countries of Africa and Asia compared to developed countries
correlating with the incidence of Hepatitis B (HBV) and Hepatitis C (HCV)
infection in most regions.([iv])
[i] Petrick JL, Kelly
SP, Altekruse SF et al. Future of hepatocellular carcinoma incidence in the
United States forecast through 2030. J Clin Oncol 2016; 34: 1787–1794.
[ii] White DL, Thrift
AP, Kanwal F et al. Incidence of hepatocellular carcinoma in all 50 United
States, from 2000 through 2012. Gastroenterology 2017; 152: 812–820.e5.
[iii] Globoscan.
http://globocan.iarc.fr/old/FactSheets/cancers/liver-new.asp
[iv] Ferlay J,
Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide:
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136:
e359–e386.
Hepatocellular carcinoma (HCC) usually occurs in
the setting of chronic liver disease and cirrhosis. Potentially curative
treatments include surgical tumor resection/ liver
transplantation. However, only a handful (<20%) of patients are able to
undergo such treatments due to the
advanced nature of disease at the time of
diagnosis. The treatment options available to these patients are limited and
the prognosis is poor. Loco-regional therapies, such as percutaneous ablation
and radiofrequency ablation (RFA), arterial chemoembolization (TACE), and
conventional chemotherapies appear to offer limited survival benefits in most
cases. ([i])
As the understanding of molecular alterations in
cancer is growing, more specific targeted therapies are taking shape and are
the future of cancer medicine. Increased VEGF signaling leading to increased
tumor angiogenesis is one of the molecular alterations in HCC. Sorafenib, a
multikinase inhibitor (including VEGF signaling) has been approved for the
first line of treatment of HCC based on phase III trials showing significantly
improvement in progression free and overall survival (approximately by three
months) compared with placebo in patients with advanced HCC.([ii],[iii])
[i] Rimassa, Lorenza
et al. The present and the future landscape of treatment of advanced hepatocellular
carcinoma. Digestive and Liver Disease, Volume 42, S273 - S280.
[ii] Pinter M, Sieghart
W, Graziadei I, et al. Sorafenib in unresectable hepatocellular carcinoma from
mild to advanced stage liver cirrhosis. Oncologist 2009;14:70–6.
[iii] Wörns MA, Weinmann
A, Pfingst K, et al. Safety and efficacy of sorafenib in patients with advanced
hepatocellular carcinoma in consideration of concomitant stage of liver
cirrhosis. J Clin Gastroenterol 2009; 43:489–95.
Treatment of advanced HCC post sorafenib.
Recently multiple therapies have been approved
for second line therapy after sorafenib based on phase III trials, where there
was significant improvement in PFS and OS.
Regorafenib, oral multikinase inhibitor is the
first drug approved as second line treatment in HCC patients who have
tolerated sorafenib but progressed on sorafenib based on survival
benefit in a phase III RESORCE study. ([i]) Points to note
are median time on treatment being 3.5 months, 51% patient required dose
reductions and 10% required treatment discontinuation due to AEs. Regorafenib
is not suitable for the treatment of patients intolerant to sorafenib
or CTP -B, and a second-line treatment for this subgroup of patients remains an
unmet need.
Cabozantinib, another multikinase inhibitor is
approved in second line and beyond in patients with well-preserved liver
function and ECOG PS 0–1 based on CELESTIAL trial (again 62%
[i] Bruix J, Qin S,
Merle P, Granito A, Huang YH, Bodoky G, 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.
patients required dose reductions and 16%
treatment discontinuation).([i]) Cabozantinib is still
not available in many countries (including India).
Ramucirumab, a human immunoglobulin G1 (IgG1)
monoclonal antibody that inhibits ligand activation of VEGFR2, is approved as a
second line therapy in a specific subset of HCC with baseline AFP >= 400
ng/mL, well preserved liver function and ECOG PS 0–1 based on survival benefit
in phase III REACH 2 trial. ([ii]) However, cost of
ramucirumab is around 1.6 lakh rupees per month in developing countries like
India.
Nivolumab, a fully human molecular antibody
anti-PD-1 has been approved in second line based on impressive result of
Checkmate 040 study in patients with intermediate or advanced HCC and preserved
liver function (CP-A). ([iii]) However, the cost of
therapy is around Rs 2 lakh per month in India.
Unfortunately, regorafenib or other approved
second line therapy are not easily feasible for the majority of the population
in developing countries like India. There is thus a pressing need for easily
feasible, effective and tolerable
options to allow patients with advanced HCC to continue treatment after their
disease progresses on sorafenib.
[i] 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.
[ii] Zhu AX, Kang Y-K,
Yen C-J et al. REACH-2: a randomized, doubleblind, placebo-controlled phase 3
study of ramucirumab versus placebo as second-line treatment in patients with
advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein
(AFP) following first-line sorafenib. J Clin Oncol 2018; 36: 4003–4003.
[iii] 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;389:2492-502.
Role of anti EGFR therapy in HCC.
EGFR and its ligands EGF and transforming growth
factor alpha (TGF-α) have been implicated in many malignancies including HCC;
overexpression of EGFR and EGF ligands is found in human HCC tissues. ([i],[ii]). Erlotinib is an
orally active small-molecule tyrosine kinase inhibitor of EGFR approved to
treat patients with advanced non– small-cell lung and pancreatic cancers.([iii]) Erlotinib can inhibit
invasion, metastasis, and angiogenesis in tumor cells besides proliferation.([iv]) Erlotinib 150 mg daily
has demonstrated modest activity but promising overall
[i] Hisaka T, Yano H,
Haramaki M et al (1999) Expressions of epidermal growth factor family and its
receptor in hepatocellular carcinoma cell lines: relationship to cell
proliferation. Int J Oncol 14:453–460.
[ii] Ito Y, Takeda T,
Higashiyama S et al (2001) Expression of heparin binding epidermal growth
factor-like growth factor in hepatocellular carcinoma: an immunohistochemical
study. Oncol Rep 8:903–907.
[iii] Astellas Pharma
US, Genentech: Tarceva (erlotinib tablets, oral): Prescribing information.
Farmingdale,NY, Astellas Pharma US, Genentech, 2012.
[iv] Van den Eynde M,
Baurain JF, Mazzeo F, Machiels JP. Epidermal growth factor receptor targeted
therapies for solid tumours. Acta Clin Belg 2011; 66: 10-17, Hirte HW. Profile
of erlotinib and its potential in the treatment of advanced ovarian carcinoma.
Onco Targets Ther 2013; 6: 427-435.
survival (OS) benefit in patients with
unresectable HCC.([i],[ii]) There are
approximately 10 phase 2/3 trials (9 phase 2 trial and 1 phase 3 trial),
showing a disease control rate of 42.5% to 79.6% and a median OS of 6.25 to
15.65 months. Also the tolerance of erlotinib was not associated with
significant grade 3/4 toxicity in more than 10% of patients.([iii]) Marie-José et al
results highlight that pathways controlled by EGFR/HER-3 are the driving force
for HCC cells to maintain proliferation under sorafenib.([iv]) Therefore, EGFR
inhibitors are likely to be useful in the clinic in sorafenib resistant
patients.
[i] Philip PA, Mahoney
MR, Allmer C, et al: Phase II study of erlotinib (OSI-774) in patients with
advanced hepatocellular cancer. J Clin Oncol 23:6657-6663, 2005.
[ii] Thomas MB, Chadha
R, Glover K, et al: Phase 2 study of erlotinib in patients with unresectable
hepatocellular carcinoma. Cancer 110:1059-1067, 2007.
[iii] Zhang J, Zong Y,
Xu GZ, et al. Erlotinib for advanced hepatocellular carcinoma. A systematic
review of phase II/III clinical trials. Saudi Med J.
2016;37(11):1184-1190.
[iv] Blivet-Van
Eggelpoël, Marie-José et al. Epidermal growth factor receptor and HER-3
restrict cell response to sorafenib in hepatocellular carcinoma cells. Journal
of Hepatology, Volume 57, Issue 1, 108 – 115.
Rationale of Metronomic capecitabine
Metronomic chemotherapy principally inhibits
angiogenesis by directly disrupting endothelial cell proliferation. Metronomic
chemotherapy may decrease the mobilization or viability of bone marrow-derived
circulating endothelial precursors, which contribute to tumor
neovascularization. ([i]) Metronomic
chemotherapy even upregulates antiangiogenic factors such as thrombospondin- 1
(TSP-1) and angiostatin, and down-regulates angiogenic factors such as vascular
endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), and
hypoxia-inducible factor-1 (HIF-1). ([ii]) In addition,
metronomic chemotherapy reduces regulatory T cells and promote dendritic cell
maturation thereby stimulate the immune response. ([iii],[iv]) Tumor cells may
also be directly affected by the metronomic therapy. ([v])
HCCs are highly vascular tumors. HCC is
dependent on preexisting vasculature for its development and on
neovascularization and angiogenesis for its growth. Angiogenesis plays an
important role in the progression from cirrhosis to regenerative nodules,
dysplastic nodules, and ultimately to HCC. ([vi]) Therefore,
antiangiogenic therapy is an attractive approach in the treatment of HCC.
[i]Bertolini F, Paul S,
Mancuso P, Monestiroli S, Gobbi A, Shaked Y, et al. Maximum tolerable dose and
low-dose metronomic chemotherapy have opposite effects on the mobilization and
viability of circulating endothelial progenitor cells. Cancer Res.
2003;63:4342–6.
[ii] Torimura T,
Iwamoto H, Nakamura T, Koga H, Ueno T, Kerbel RS, et al. Metronomic
chemotherapy: possible clinical application in advanced hepatocellular
carcinoma. Transl Oncol. 2013;6:511–9.
[iii] Lutsiak MEC,
Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of
CD4(+)25+T regulatory cell function implicated in enhanced immune response by
low-dose cyclophosphamide. Blood. 2005;105:2862–8.
[iv] Tanaka H,
Matsushima H, Mizumoto N, Takashima A. Classification of chemotherapeutic
agents based on their differential in vitro effects on dendritic cells. Cancer
Res. 2009;69:6978–86.
[v] Shaked Y,
Emmenegger U,Man S, Cervi D, Bertolini F, Ben- David Y, Kerbel RS: Optimal
biologic dose of metronomic chemotherapy regimens is associated with maximum
antiangiogenic activity. Blood, 106: 3058-3061, 2005.
[vi] Theise ND.
Macroregenerative (dysplastic) nodules and hepatocarcinogenesis: theoretical
and clinical considerations. Semin Liver Dis. 1995;15:360–371.
The optimal metronomic dose is known for only a
few drugs and diseases, Capecitabine 500 mg twice daily has shown to have
activity and antiangiogenic effectiveness in colorectal cancer, as demonstrated
by contrast-enhanced magnetic resonance imaging.([i]) Capecitabine, an oral
prodrug of 5- fluorouracil (5-FU), is rapidly and almost completely absorbed
from the gastrointestinal tract and it undergoes hydrolysis in the liver and
tissues to form active moiety fluorouracil. Fluorouracil is an antimetabolite
that inhibits thymidylate synthetase, blocking the methylation of deoxy
uridylic acid to thymidylic acid, interfering with DNA, and to a lesser degree,
RNA synthesis. ([ii]) Multiple studies have
shown that mild to moderate liver dysfunction in patients with liver metastatic
cancer did not significantly affect Capecitabine pharmacokinetics as the
predominant route of elimination is via the kidney. Therefore, patients with
liver dysfunction should be monitored closely during treatment, but no dose
adjustment is required for liver dysfunction solely. ([iii]) Phase I and II studies
suggest that Capecitabine 500mg BD is safe and effective in HCC patients. ([iv],[v])
[i] Steinbild S,
Arends J,MedingerM, Häring B, Frost A, Drevs J, Unger C, Strecker R, Hennig J,
Mross K: Metronomic antiangiogenic therapy with capecitabine and celecoxib in
advanced tumor patients -- results of a phase II study. Onkologie, 30: 629-635,
2007
[ii] Walko CM, Lindley
C. Capecitabine: a review. Clinical Therapeutics 2005;27:23–44.
[iii] Twelves C,
Glynne-Jones R, Cassidy J, Schuller J, Goggin T, Roos B, Banken L,Utoh M,
Weidekamm E, Reigner B. Effect of hepatic dysfunction due to liver metastases
on the pharmacokinetics of Capecitabine and its metabolites. ClinCancer
Res. 1999 Jul;5(7):1696-702.
[iv] Omar Abdel-Rahman.
Sorafenib versus Capecitabine in the management of advanced hepatocellular
carcinoma.
[v] Metronomic
Capecitabine as second-line treatment in hepatocellular carcinoma after
sorafenib failure Alessandro Granitoa.
Rationale of proposed study combination
HCC is a complex, highly heterogeneous tumour,
which makes it unlikely that targeting any one pathway will achieve optimal
disease control. Also, resistance mechanisms to sorafenib in HCC are still
poorly understood. Proposed resistance mechanisms include upregulation of VEGF
and other growth factors, activation of alternate signaling pathways, co-option
of existing vessels, and transformation of the tumor vasculature to a more
mature, less VEGF-dependent phenotype.([i],[ii]) Thereby making
metronomic capecitabine based anti-angiogenesis a suitable therapy in sorafenib
resistant patients.
There are preclinical evidence to suggest that
inhibiting EGFR may make tumors more angiogenesis dependent, and therefore
more susceptible to anti-angiogenesis inhibitors15 Factors such as
fibroblast growth factors (FGFs), insulin like growth factors (IGFs),
angiopoietins, and tumor-stromal interaction also contribute to sorafenib
resistance.([iii]) Hence metronomic
capecitabine based VEGF and other angiogenesis inhibition is worth trying with
anti EGFR inhibitor Erlotinib.
5. Hypothesis
The combination of Capecitabine and Erlotinib in
advanced HCC patients after sorafenib failure would lead to an increase in PFS
from 10% to 30% at 6 months.
[i] Glade Bender J,
Cooney EM, Kandel JJ, Yamashiro DJ. Vascular remodeling and clinical resistance
to antiangiogenic cancer therapy. Drug Resist Updat. 2004 Aug-Oct;7(4-5)
289-300.
[ii]Casanovas O, Hicklin DJ,
Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of
VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell.
2005;8(4):299–309.
[iii] Bergers G, Hanahan
D. Modes of resistance to antiangiogenic therapy. Nat Rev Cancer.
2008;8:592–603.
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