Liver Regeneration and Tumor Stimulation—A Review of Cytokine and Angiogenic Factors
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- Christophi, C., Harun, N. & Fifis, T. J Gastrointest Surg (2008) 12: 966. doi:10.1007/s11605-007-0459-6
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Liver resection for metastatic (colorectal carcinoma) tumors is often followed by a significant incidence of tumor recurrence. Cellular and molecular changes resulting from hepatectomy and the subsequent liver regeneration process may influence the kinetics of tumor growth and contribute to recurrence. Clinical and experimental evidence suggests that factors involved in liver regeneration may also stimulate the growth of occult tumors and the reactivation of dormant micrometastases. An understanding of the underlying changes may enable alternative strategies to minimize tumor recurrence and improve patient survival after hepatectomy.
KeywordsColorectal carcinomaLiver resectionLiver regenerationCytokinesAngiogenesisGrowth factorsTumor recurrence
Long-term survival in patients with secondary liver tumors is achieved in selected patients by hepatic resection. Five-year survival rates in patients undergoing liver resection for colorectal cancer liver metastases range from 20% to 40%.1 Despite sophisticated staging techniques and adequate surgical clearance, local and systemic recurrences occur in the remaining patients. Recurrent disease in these patients usually appears within the first 12 to 18 months after resection at both hepatic and extrahepatic sites. Approximately 50% of recurrences occur in the liver only, while 15–20% occur in both hepatic and extrahepatic sites. Approximately 25–30%2 occur in extrahepatic sites only. Timing of the recurrences varies according to the organ involved. In general, extrahepatic recurrences occur later than hepatic recurrences and predominantly in the lung and lymph nodes indicating possible different causative mechanisms. The degree of liver resection is also a significant factor in the patterns of tumor recurrence.
Prognostic factors influencing recurrence after liver resection for colorectal metastases are several. The most significant adverse factors are involved resection margins and the presence of extrahepatic disease. The initial staging of the primary tumor, the number of metastases, timing to recurrence from the primary operation, the degree of differentiation and the presence of specific biological markers are also important prognostic parameters. The presence of angiogenic markers such as a high tumor vessel density and high preoperative serum levels of angiogenic growth factors such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), epidermal growth factor (EGF), and basic fibroblast growth factor (b-FGF)3,4 indicate a high propensity to tumor recurrence.
There is now accumulating clinical and experimental evidence that suggests specific factors involved in liver regeneration may influence the growth patterns of residual or dormant micrometastases after resection. The site of these micrometastases and sources of future recurrences remain controversial.
This review will assess evidence on the possible role of cytokine and angiogenic factors involved in liver regeneration on tumor recurrence.
Evidence for Recurrence of Metastases After Tumor Resection
Clinical evidence suggests that stimulation of tumor growth may occur after resection of liver tumors.5–7 Surgical strategies such as portal vein embolization and two-stage hepatectomy involving liver regeneration may also be associated with stimulation of tumor growth. Elias et al. performed studies, which assessed liver regeneration after right portal vain embolization of patients who had undergone hepatic resection. The growth rate of liver metastases exceeded that of the normal liver parenchyma by almost eight times, suggesting that the process of regeneration has significant proliferative effect on tumor cells.8 Kokudo et al. also reported that portal embolization before hepatic resection caused significant enhancement in the growth rate of colorectal cancer (CRC) metastases and poorer disease-free survival in these patients compared to those treated only with hepatic resection.9 Togo et al.10 have reported a high incidence of residual liver and lung metastases after two-stage hepatectomy and the need for protective measures such as chemotherapy during the liver regenerative phases. Adam et al.11 has emphasized the need of adjuvant chemotherapy during portal vein embolization and two-stage hepatectomy to prevent tumor proliferation during the liver regenerative phase. A report by von Schweinitz et al.12 found accelerated residual tumor growth in children with embryonal hepatoblastoma after liver resection compared to untreated patients. The accelerated growth correlated with increased HGF serum levels.
Animal studies have also confirmed that there is stimulation of tumor growth after liver resection. The degree of liver resection is a significant factor in the degree of tumor stimulation and the development of extrahepatic metastases.13 De Jong et al.14 demonstrated that liver regeneration may influence the growth of the remaining micrometastases in the liver by hepatotropic factors. Using rats induced with metastatic colorectal cancer, enhanced growth in the remnant liver after 70% partial hepatectomy was observed. Other studies in hepatectomized rats challenged with tumor cells found that the hepatic metastatic tumors grew faster than in sham hepatectomies.15 There was no difference in the growth rate of extrahepatic metastases between the two groups, suggesting a local paracrine stimulation by factor(s) related to liver regeneration. In a different study by Schindel and Grosfeld,6 both hepatic and extrahepatic metastases grew at a faster rate than those in the sham hepatectomized control rats, suggesting that factors induced by hepatectomy influence both local and distal tumor growth. Our studies have confirmed that 70% hepatic resection was associated with increased peritoneal and lung metastases as well as increased growth of intrahepatic metastases. The increase in growth in liver metastases occurred predominantly in the late phase of liver regeneration rather than the early phase.16 In a study with nude mice, it was found that even minimal liver resection results in a dramatic acceleration of recurring colorectal cancer liver metastases after hepatectomy.17
Studies by Ikeda18 and Slooter et al.13 suggest that the frequency of metastases after hepatectomy is proportional to the extent of resection. Mueller et al.19 using a rat model showed that portal branch ligation is associated with increased expression of genes known to promote tumor growth. Kollmar et al.20 showed that partial hepatectomy significantly increased tumor metastases when compared with nonresected controls or laparoscopy-treated animals and correlated with a significant increase in the expression of the macrophage-inflammatory protein-2 (MIP-2) receptor CXCR-2 on tumor cells and accelerated tumor angiogenesis.
Liver Regeneration After Hepatectomy
Adult hepatocytes are differentiated, metabolically active, and the majority is in the resting (G0) state.21 During liver regeneration, they undergo a “priming” phase to become “proliferatively competent” and move from G0 to G1. After the priming phase, growth factors and other mitogens stimulate cell proliferation, so that they undergo sufficient rounds of mitosis to restore the original mass of the liver.22,23 The molecular trigger to liver proliferation appears to be loss of functional hepatic mass. For example, in experimental partial hepatectomy, removal of one third of the liver evokes a poor proliferative response (only isolated hepatocytes proliferate), whereas two-thirds removal provokes 80% to 90% of hepatocytes to undergo coordinated rounds of mitosis.24 Sensors of such ideal “hepatic functional mass” remain unclear. From gene array and proteomic studies, numerous genes have shown alteration in their expression after hepatectomy.25–27 Some of the upregulated genes are absolutely necessary for regeneration to occur,28–30 whereas others show degrees of redundancy.28,31
Hepatocytes primed through these pathways become responsive to growth factors and enter into the second stage, the proliferative stage. The growth factors and their receptors that dominate this stage have proliferative and cytoprotective functions. The main factors involved are HGF, EGF receptor ligands such as EGF and TGF-α, heparin-binding EGF like growth factor (HB-EGF), amphiregulin,37 growth hormone (GH),38 and insulin growth factor binding protein-1 (IGFBP1).30 The increased metabolic demand on the remaining liver remnant after resection may be the sensor that dictates the extent of replication and also signal the termination onset. Proliferation inhibiting factors such as the transforming growth factor beta (TGF-β) superfamily, which includes TGF-β1, 2, and 3, activins, and inhibins among others, are involved in the termination stage of liver regeneration.39–41
Factors in Liver Regeneration that May Influence Tumor Growth and Metastasis
Tumor recurrence after hepatectomy may result from circulating tumor cells or dormant micrometastases. The source of these occult metastases is uncertain. Micrometastases are detectable on histological examination in resected specimens. These may reside in the portal vein, central vein, sinusoids, and the bile duct.48 Minimal residual disease in bone marrow may also be a source of tumor micrometastases49 A number of publications report positive tumor cell circulation after surgery.50 It has been shown, in animal models, that approximately 106 tumor cells per gram of tumor tissue may be shed daily into the systemic circulation.51 New metastases establish in selective tissues that express receptors that are able to recognize specific ligands such as integrin αvβ3 on the circulating tumor cells.52 These ligands must be activated for adhesion53,54 and maybe activated during liver regeneration through proteolytic cleavage of inactive surface ligands by MMPs.
It has been suggested that micrometastases remain dormant because proliferation and apoptosis rates of tumor cells are mutually antagonistic.55,56 Tumor growth requires the balance of growth factors and cytokines in the microenvironment to favor angiogenesis.57 Angiogenic inhibitors such as circulating angiostatin, ECM proteins such as thrombospondin,58 or ECM protein fragments such as endostatin59 are considered responsible for maintaining the dormant state. Major surgery including hepatectomy results in a major influx of angiogenic factors and cytokines that could alter the microenvironment of distant dormant tumor deposits causing their reactivation. In addition, the activation of the coagulation cascade,60 the temporary local and systemic immunosuppression after surgery,61 and the mobilization of EPC and other hematogenic cells have also been shown to enhance tumor metastases.62
ECM breakdown and remodeling at a smaller scale occurs also at the tumor interface. The factors involved (urokinase-type plasminogen activator (uPA), MMPs, HIF-1α, VEGF) are common to those of the liver ECM remodeling during liver regeneration. It has been shown that metastatic epithelial tumors undergo an epithelial to mesenchymal transition (EMT) to become invasive.63 Various stimuli within the tumor microenvironment also promote EMT transition of carcinoma cells. These include growth factors that bind to tyrosine-kinase receptors (TKR), such as b-FGF, EGF, and HGF, members of the TGF-β superfamily and ECM constituents including MPPs.64 These factors are upregulated by hepatectomy and in ECM remodeling and may account for increased metastases after liver resection (Fig. 3).
Growth factors such HGF, EGF, TGF-α, TGF-β, HIF-1α, VEGF, and MPPs have been shown in numerous studies (outlined in detail in the following sections) to be associated with tumor aggressiveness and metastasis. Therefore, additional upregulation of these factors during liver regeneration may enhance the metastatic process.
Hepatocyte growth factor (HGF) is one of the most important growth factors upregulated during liver regeneration. Expression of HGF increases 6 to 8 hours after partial hepatectomy. It is produced and secreted by stellate cells, sinusoidal endothelial cells, and Kupffer cells and acts in a paracrine manner.65,66 Studies using liver specific HGF receptor (c-Met) knockout mice showed that HGF/c-Met signaling is essential for liver regeneration after hepatectomy.67,68 HGF is a multifunctional factor. In cell culture, it induces strong mitogenic stimulation on hepatocytes and other cell types69,70 and exerts morphogenic, mitogenic, and proangiogenic effects on normal and neoplastic epithelial cells.71–73 It has functional roles in angiogenesis, wound healing, and carcinogenesis.74 Tamatani et al.75 reported that addition of exogenous HGF accelerated tumor migration and infiltration and increased MMP activity, suggesting an important role in tumor invasion and progression. HGF stimulates cell motility and the secretion of proteinases, which lyse the tumor basement membrane promoting metastasis.76,77 HGF is occasionally secreted by tumors, stimulating tumor growth in an autocrine manner.78
The HGF receptor belongs to the family of receptors of tyrosine kinases and is encoded by the c-Met protooncogene.79–81 HGF through c-Met and Mitogen-activated protein kinase (MAPK) signaling was shown to induce growth, invasion, and metastasis in hepatocellular carcinoma (HCC) tumors,82 and to be involved with high-grade invasive bladder cancer.75 The HGF/c-Met have also been implicated in CRC pathogenesis.83 HGF also cooperates with other receptors such as the insulin growth factor receptor (IGFR) in promoting tumor growth.84
EGFR and its Ligands
The EGFR, a tyrosine kinase receptor of the ErbB family, comprises the second major signaling system, after the HGF/c-Met, in liver regeneration.37 The EGFR belongs to a family of four closely related receptors: EGFR (ErbB-1), HER-2/neu (ErbB-2), HER-3 (ErbB-3), and HER-4 (ErbB-4). Ligand binding on the EGFR results in the activation of its tyrosine kinase (TK) activity. It initiates receptor-mediated signal transduction, cell mitogenesis, and cell transformation. EGFR ligands include EGF, TGF-α, amphiregulin, HB-EGF, epiregulin, and cellulin. The binding of these ligands to the receptor results in different function modulation for each of them, ranging from cell motility and proliferation to growth inhibition.37 A number of the EGFR ligands have been shown to be upregulated during liver regeneration (EGF, TGF-α, amphiregulin, and HB-EGF).
The activity of EGFR is abnormally elevated in most human solid tumors85 including CRC86 and human HCC.87–89 EGFR overexpression correlates with early tumor recurrence90 and extrahepatic metastasis. The EGFR signaling also induces VEGF upregulation and the induction of angiogenesis.91–93 Cetuximab or gefitinib therapy (EGFR inhibitors), in a colon carcinoma model, results in a decrease of VEGF, b-FGF, and TGF-α expression and a reduction in microvessel count.94,95 Another EGFR family ligand upregulated in liver regeneration, HB-EGF, binds to ErbB1 and ErbB2 receptors. It plays a major role in angiogenesis by stimulating ErbB receptor phosphorylation and migration of smooth muscle cells (SMCs).96,97 TGF-α, another EGFR ligand is also upregulated in liver regeneration and is associated with adverse predictors of survival when upregulated in tumor.98
Angiogenic growth factors such as VEGF that promote new vasculature formation from preexisting blood vessels are increased during liver regeneration. Most solid tumors overexpress and secrete VEGF.99 It is also secreted by infiltrating immune cells such as monocytes.100,101 Solid tumors are generally hypoxic, resulting in HIF-1α upregulation, which in turn induces angiogenic factors such as VEGF production.102 VEGF is also induced through EGFR and c-Met signaling.97,103 VEGF also plays a role in vasculogenesis by recruiting endothelial progenitor cells from the bone marrow for endothelial vessel formation. Tumors producing high levels of VEGF are associated with increased tumor vascularity, metastasis, chemoresistance, and poor prognosis.104
VEGF has several other associated actions, which enhance tumor angiogenesis and metastatic potential, including the upregulation of the VEGF receptor FLK-1 in tumor cells.105 VEGF also induces the synthesis of a stroma-derived factor (SDF-1) that recruits circulating cells from the periphery to the tumor site where they differentiate into cancer-associated fibroblasts (CAFs). These produce b-FGF and many other factors associated with ECM remodeling, angiogenesis, and cancer-cell EMT.64 Basic FGF induces endothelial cell proliferation, migration, and capillary tube formation.106
Transforming growth factor beta (TGF-β), upregulated in liver regeneration, enhances angiogenesis and metastases by promoting accumulation of ECM glycoproteins and adhesion proteins.107 Serum TGF-β levels correlate with the development of liver metastasis after potentially curative hepatic resection.4,108 Changes in expression and mutations in the genes for TGF-β, the TGF-β receptors, and the SMAD proteins also correlate with metastatic cancers of the colon, liver, and pancreas.107 Loss of the TGF-β receptors, TGFβR2 and TGFβR1, occurs often in human liver cancer, disrupting the TGF-β signaling pathway.109,110 Similar loss of these receptors has been reported in preneoplastic and malignant cells from rats, mice, and humans, indicating that loss of the antiproliferative TGF-β signaling results in tumorogenesis.111
IGF-I and IGFR
Insulin growth factor I (IGF-I) has not been shown to be upregulated during hepatectomy by gene arrays,25 and no function has been attributed to it in the regeneration process. However, liver regeneration after hepatectomy is disrupted in male mice that do not express the IGFR in the liver.112 It is possible that IGF-I is modulated as a byproduct of growth hormone upregulation.38 GH is upregulated during liver regeneration and it has been shown to be important for the regeneration process. It is the primary regulator of IGF-I synthesis and secretion in hepatocytes. IGF-I in turn regulates GH secretion through a negative feedback loop.113 IGF-I levels in circulation are modulated by the IGF-binding proteins (IGFBPs) and only 5% of IGF-I circulates unbound.114,115 The majority of IGF-I in the body is manufactured by the liver116. Although it is not clear if IGF-I has a role in liver regeneration, there is able evidence that IGF-I and its tyrosine kinase receptor play important roles in the development and progression of a variety of human cancers including CRC.117 IGF-I induces CRC proliferation, and high IGF-R expressing tumors colonize the liver more readily than low IGF-IR expressing tumors.118 This may be the reason that the majority of CRC metastases are found in the liver. Epidemiological studies have established a correlation between circulating levels of IGF-I and IGFBP-3 and the relative risk for developing colon, breast, prostate, and lung cancer.119,120 High levels of IGF-I and low levels of IGFBP-3 are independently associated with an increased risk of colorectal cancer. Warren et al.121 showed that IGF-I induces VEGF expression in cultured colorectal carcinoma cells. Wu et al.117 also demonstrated VEGF upregulation in tumors by IGF-I addition. Similar to HGF/c-Met, IGF-I/IGFR signaling is known to induce tumor cell migration, invasion, and angiogenesis by stimulating endothelial cell VEGF expression122 and promoting endothelial cell migration.123 Using plasmid-mediated IGF-I therapy, Rabinovsky et al.124 demonstrated increased expression of VEGF and activation of the VEGF receptors FLK-1 (VEGFR-2) and FLT-1 (VEGFR-1). FLK-1 receptor signaling induces endothelial cell proliferation and increases permeability, whereas FLT-1 receptor is implicated in vascular remodeling.125
IGF-I and HGF have been shown to function as co-mitogens in a rat hepatoma cell line126. In addition, Bauer et al.84 demonstrated a tyrosine kinase receptor cooperation between IGFR and c-Met in human CRC. IGF-I appears to be an upstream regulator of the angiogenic cascade. Even if there is no increase in IGF-I growth factor during liver regeneration, the increase of many other tumor promoting factors that have been shown to cooperate in IGF-I/IGFR signaling suggests that IGF-I is an important contributor to accelerated tumor growth and metastatic activity associated with hepatectomy.
The role of MMPs is to maintain homeostasis in the extracellular environment. In liver regeneration, they play central roles in promoting growth factor upregulation or activation, and in the breakdown and remodeling of the ECM.40 There are several classes of MMPs, and the biological roles of the majority have not been fully elucidated. MMPs are part of an extensive “protease web” where individual members may also be substrates of other proteases, releasing activated ligands or inhibitors in many signaling pathways.127 Several studies have linked MMPs with numerous types and stages of cancer. They have been implicated in the base membrane alterations leading to tumor metastasis.128,129 Overexpression of particular MMPs has been correlated with tumor progression, and mouse transgenic models overexpressing MMPs support this finding.130 In addition to ECM degradation, MMPs promote tumor progression by modulating the generation and active states of key molecules in various signaling pathways including growth factors and chemokines.127
Over 50% of patients who undergo resection for colorectal cancer liver metastases will ultimately have recurrent disease in the liver and/or extrahepatic sites. The major adjunct to surgery has been systemic chemotherapy in the neoadjuvant or postoperative situation. Several studies have now confirmed that conventional combination systemic chemotherapy associated with potential curative liver resection has been associated with increased survival rates.131,132 The major areas of concern with the use of chemotherapy have been compromised liver function (steatohepatitis, sinusoidal obstructive syndromes), coagulation disorders, and impaired wound healing. In addition, the regenerative ability of the liver may be compromised, leading to limited surgical options.133 Portal vein embolization and two-stage hepatectomy are used in these situations.
There is now accumulating evidence and strong theoretical considerations that the process of liver regeneration after liver resection stimulates tumor recurrence. The specific pathways, including upregulated growth factors and signaling molecules responsible for tumor stimulation and recurrence, remain undefined. Our own evidence suggests that the late phase of liver regeneration is the key process where this occurs. This would suggest that growth factors and cytokines involved in angiogenesis and ECM remodeling are the key processes in liver regeneration involved in tumor growth and metastases.
Selective targeting of these processes in the late phase of liver regeneration may be beneficial in reducing tumor recurrence, without compromising the early phase of liver regeneration.
Cancer Therapies Targeting Angiogenesis and Metastasis Promoting Factors
Reported Clinical Effects
mAb Bevacizumab (Avastin)
Survival benefit, disease stabilization, partial regression
FDA approval for metastatic CRC in combination with CT
Some clinical activity
VEGF trap (soluble hybrid VEGFR-1–2 decoy)
Significant radiographic improvement in one patient
Phase I/ II
Inhibits tumor growth and lymphangiogenesis,
SM TKI AZD2171
VEGFR-1, -2, -3
SM TKI GW786034
Partial regression, disease stabilization
SM TKI vatalinib PTK787
Significant clinical effect in a subgroup of patients with high LDH levels
VEGFR-1, -2, PDGFR
SM TKI SU11248 (sunitunib)
Partial regression, complete response
FDA approval for metastatic RCC and GIST
Some problems with bleeding
VEGFR-1, -2, bFGFR
SM TKI CP-547632
No additional clinical benefit in combination with CT
Phase I/ II
VEGFR-1, -2, -3, PDGFR, c-kit, Raf
SM TKI Bay 43-9006 sorafenib
Prolongs progression-free survival
FDA approved monotherapy metastatic RCC
SM TKI Imatinib (STI-571)
Significant improvement in survival
FDA approval for treatment of CML and GIST.
VEGFR-1, -2, -3, EGFR
SM TKI ZD6474
Prologed progression-free survival
SM TKI AEE788
Significant reduction of tumor growth and metastasis
EGFR, bFGFR, FGFR
SM TKI SU6668
SM TKI AG1478
Inhibits EGFR activity
SM erlotinib (OSI-774)
Significant improvement in median survivalnon-small cell lung cancer.
FDA approval for metastatic lung and pancreatic cancers
Significant improvement in median survival in non-small cell lung cancer: selected patients
Promising as monotherapy or in combination with cytotoxic treatment for CRC
FDA approval for metastatic CRC
Improved progression free survival
FDA approval for metastatic CRC
SM TKI AG879
Inhibits tumor in combination with AG1478
SM TKI GW572016
Inhibits tumor xenografts
Suppression of tumor growth and metastasis
Significant tumor growth inhibition and longer survival.
MMP-2, 3, 9
SM Tanomastat (BAY 12-9566)
No clinical benefit
MMP-1, 2, 8, 9, 13
No clinical benefit
MMP-2, 3, 9, 13, 14 collagenase III
Discontinued because of adverse complications
MMP-1, 2, 3, 7, 9, 12
Broad spectrum MMPs
No improvement, toxic
Endostatin combined with radiotherapy
Blocks tumor revascularization in mouse xenografts. No significant tumor regression in cancer patients
Preclinical, Phase II
High disease control
EMD-121974 Blocks an endothelial integrin
Tumor and endothelial cell apoptosis not reach significance
TNP-470 Fumagillin analogue inhibits endothelial cell proliferation
Some clinical benefit. Not effective in colonic carcinoma
Phase I, Preclinical
MAb Vitaxin MEDI-523
MAb Abergrin MEDI-522
Well tolerated, some clinical activity
αvβ3 and αvβ5integrin
Cilengitide (EMD 121974)
Well tolerated. Tumor and endothelial cell apoptosis did not reach significance
Neutralizing pan-TGF-β mAb
Inhibits metastases when used with other anticancer treatments
TGF-β1, TGFβ2 antisense oligonucleotides
Increased progression free time
Dominant negative receptor (DNRII)
Inhibits tumor. Prolongs survival
Soluble domain of TGF-b
Inhibits tumor growth
SM drugs : SB-505124, SD-208, LY580276
Inhibits tumor growth
SM drug Rofecoxib
Increases levels of endostatin
Inhibition of tumor growth and metastasis
uPA peptide antagonist
Inhibition of tumor xenografts
Antisense HIF-1a oligonucleotide
Significant tumor growth delays or total tumor suppression
SM inhibitor PX-478
Significant antitumor activity tumor xenografts
Inhibition of tumor xenografts
Inhibits tumor growth, invasion, metastasis and angiogenesis.
c-met small-interfering RNA adenovirus
Downregulation of c-Met. Inhibition of tumor in mouse model
A number of monoclonal antibodies such as bevacizumab, cetuximab, panitumumab, trastuzumab, and small-molecule tyrosine kinase inhibitors, ZD-1839, OSI-774/CP358774, Sorafenib (Bay 439006) Sunitinib (SU11248), STI-571, have FDA approval for cancer treatments, including CRC (Table 1). Angiogenesis has been specifically targeted through VEGF and its receptors. This treatment is thought to be tumor specific as angiogenesis does not occur in adult tissues with the exception of wound healing, ischemia, menstruation, and pregnancy.134 Recent studies, however, indicate that inhibition of VEGF signaling could lead to vascular disturbances in normal tissues and even regression of normal blood vessels.135 Wound healing complications increased from 3.4% to 13% in patients receiving bevacizumab when surgery was performed within 60 days after the last treatment.136 As bevacizumab has a relatively long half life, hepatectomy for tumor downstaging should not be performed for at least 28 days.136 In advanced CRC disease, bevacizumab in combination with other chemotherapies137 has shown significant improvement in overall survival.138 Antiangiogenic drugs in general, however, including bevacizumab, have not proven beneficial as monotherapies in the clinical situation. In advanced tumors, angiogenesis is under the influence of several factors in addition to VEGF,139 which may account for the limited efficacy of anti-VEGF treatments.
Antiangiogenic treatment to prevent recurrence after potentially curative hepatectomy requires further evaluation. A multitargeting inhibitor such as Sorafenib, administered orally, in combination with conventional chemotherapy, may prove to be the most efficacious. The timing of administration of these agents is uncertain and needs investigation.
Tumor recurrence after hepatectomy for liver tumors is a significant clinical problem resulting in long-term mortality. Strategies for the removal of liver tumors have focused on aggressive surgical resection to achieve clear margins, including techniques such as portal vein embolization and two-stage hepatectomy. Accumulating clinical and experimental evidence suggests that factors involved in liver regeneration may stimulate residual micrometastases. A clear understanding of the underlying processes may allow adjuvant therapies to be used at specific time points after resection to minimize the risk of recurrent disease.
Financial support for this project was provided by the Austin Health Medical Research Foundation.