Review

Antiangiogenic therapy and surgical practice A. R. John1,2 , S. R. Bramhall1 and M. C. Eggo2 1 Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, and 2 Division of Medical Sciences, The Medical School, University of Birmingham, Birmingham, UK Correspondence to: Mr A. R. John, Division of Medical Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UK (e-mail: [email protected])

Background: Antiangiogenic therapy has become a reality with the recent introduction of bevacizumab, a monoclonal antibody against vascular endothelial growth factor. Methods: Relevant medical literature from PubMed, National Institute for Health and Clinical Excellence and National Institutes of Health websites to August 2007 was reviewed. Results and conclusions: Although often described as the fourth modality of treatment after surgery, radiotherapy and chemotherapy, many antiangiogenic drugs have failed to live up to expectations. Nevertheless, research continues and there are reasons to believe that antiangiogenic therapy may yet have a future in the clinical setting.

Paper accepted 31 October 2007 Published online in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.6108

Introduction

The term angiogenesis, defined as the sprouting of new vessels from pre-existing vasculature, was first used by John Hunter in 1787 when describing the growth of blood vessels in a reindeer antler. It is only recently, however, that its importance in reproduction, development, wound healing and various disease states has been recognized. Today, over 20 angiogenic growth factors and over 300 angiogenesis inhibitors are known. These have the potential to be exploited clinically to regulate (reduce) the blood supply to cancers and so limit their growth.

Antiangiogenesis agents currently used in vivo

The principal regulators of angiogenesis are the vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). Table 1 shows the antiangiogenic compounds that are targeted at VEGFs and VEGFRs, and which have been used in vivo. The VEGFRs are receptor tyrosine kinases (RTKs) whose expression is largely confined to endothelial cells. Other RTKs with ubiquitous expression can, however, also stimulate angiogenesis, and inhibitors that inhibit these RTKs, in addition to VEGFRs, are likely to be of greater benefit than specific inhibitors. For example ZD6474, AEE788 and CP547 632 inhibit the receptor for epidermal growth factor (EGFR). Inhibition Copyright  2008 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

of EGFR will inhibit the growth of the tumour cells directly and inhibition of VEGFR will inhibit angiogenesis. Other receptors that are targeted include platelet-derived growth factor receptor, fibroblast growth factor receptor 1 and rearranged during transfection (RET) tyrosine kinase. Also shown in Table 1 is bevacizumab, a humanized form of a monoclonal antibody to VEGF, that binds to VEGF and inhibits its actions. Bevacizumab has been approved for use in human cancers; this is described in the next section. The other factors have shown promise in in vivo animal models of tumours, but have been less effective in humans, leading to termination of trials or their development. Table 2 shows compounds that are naturally occurring inhibitors of angiogenesis. Folkman28 postulated the existence of endogenous inhibitors of angiogenesis when he observed that metastases often flourished after removal of the primary tumour. He and his group have pioneered this area of research, with the discovery of endostatin and angiostatin as a result. These compounds apparently inhibit angiogenesis by several mechanisms, which are beginning to be characterized21,29 – 35 . They are usually smaller cleavage products of larger structural or extracellular matrix proteins. The importance of these naturally occurring inhibitors has been exemplified in Down’s syndrome, which is associated with a low incidence of solid organ tumours owing to the increased serum levels of endostatin36 . Zorick and colleagues37 proposed that an increase of British Journal of Surgery 2008; 95: 281–293

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Table 1

Antiangiogenic inhibitors that target vascular endothelial growth factor or its receptors

Antiangiogenic factor

Target

Effect

Reference

Inhibition of VEGF pathway Semaxanib (SU5416)

VEGFR1, VEGFR2

Inhibits EC growth, increases sensitivity to radiation therapy in in vivo models Apoptosis of ECs Apoptosis of ECs, inhibits tumour cell proliferation

1,2

Inhibits ECs; direct antitumour effect at higher concentrations? Inhibits EC proliferation, survival, migration, permeability and capillary sprouting Inhibits tumour cell proliferation and tumour angiogenesis

5

Inhibits tumour growth and angiogenesis Inhibits EC proliferation Inhibits proliferation, vessel area, length and branching Inhibits angiogenesis and tumour growth

8

Inhibits cell proliferation, survival, permeability, migration and nitric oxide production Inhibits EC proliferation

12

Cytotoxic activity, release of cytokines in the milieu of tumour Reduces VEGFR1 expression, cell cycle arrest in G1 mRNA degradation, reduces viability of cells Binds to and inactivates circulating VEGF

14

SU6668 SU011248 ZD6474 Vatalanib (PTK787/ZK222584) Sorafenib (BAY 43-9006) CP 547 632 AG013736 AZD2171 AEE788 Monoclonal antibodies Bevacizumab

PDGFR, VEGFR2, FGFR1 VEGFR1, PDGFR, c-Kit, FGFR1 VEGFR2, EGFR, RET tyrosine kinase VEGFR1, VEGFR2, PDGFR-β, C-kit tyrosine kinase Raf kinase, VEGFR2, PDGFR-β, VEGFR3 VEGFR2, EGFR, PDGFR-β VEGFR, PDGFR, c-Kit VEGFR, PDGFR-β, c-Kit EGFR, VEGFR VEGF

IMC-1C11 Other mechanisms of VEGF pathway inhibition Cellular immunotherapy (CD8-positive cytotoxic lymphocytes) Aplidine Antisense oligonucleotides VEGF-AS VEGF trap

VEGFR2

VEGFR VEGFR1 VEGF VEGF

3 4

6

7

9 10 11

13

15 16,17 18

VEGF(R), vascular endothelial growth factor (receptor); EC, endothelial cell; PDGFR, platelet-derived growth factor receptor; FGFR, fibroblast growth factor receptor; EGFR, epidermal growth factor receptor; RET, rearranged during transfection.

Table 2

Endogenous inhibitors of angiogenesis

Antiangiogenic factor

Target

Endostatin

Broad spectrum; VEGFR2, integrin α5β1, others?

Angiostatin

ATP synthase, integrin αvβ3, angiomotin, annexin II

Thrombospondin 1

MMP-9, CD36

PEX Interleukin 12 Arresten Canstatin

MMP-2 VEGF, MMP-9, TIMP-1 α1β1 integrin Cell surface integrin?

Effect

Reference

Inhibits proliferation and migration of ECs, and direct antitumour effect Inhibits EC migration and proliferation, and induces apoptosis Inhibits EC proliferation and migration, and induces apoptosis Regulates invasive behaviour of new vessels Inhibits EC proliferation and migration Inhibits EC tube formation, EC proliferation and migration Inhibits EC migration, tube formation, and induces apoptosis

19,20

21,22

23

24 25 26 27

VEGF(R), vascular endothelial growth factor (receptor); EC, endothelial cell; ATP, adenosine 5
-triphosphate; MMP, matrix metalloproteinase; PEX, C-terminal haemopexin fragment of MMP-2; TIMP, tissue inhibitor of metalloproteinase.

about a third of endostatin levels in serum was enough to inhibit the development of solid tumours in affected individuals. Despite Folkman’s inspired hypothesis and the hopes of the stock market, endostatin has failed to live up to its early expectations in clinical trials38 . Several explanations have been put forward for this: the protein is difficult to work

with; it aggregates easily and loses bioactivity; and problems exist with mode of delivery, biphasic dose response39 and bioavailability. Modified forms of endostatin are being developed in Folkman’s laboratory to allow large-scale production of a stable, active form of the protein, but clinical trials are at least a couple of years away. A modified form of endostatin, Endostar (Medgenn Bioengineering,

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Table 3

283

Putative antiangiogenic inhibitors

Antiangiogenic factor

Target

Effect

Reference

MMP inhibitor TIMP-2

MMP-2, integrin α3β1

Inhibits bFGF-induced EC growth and angiogenesis, blocks VEGF-induced EC proliferation via integrins and MMP-independent action Blocks binding of VEGF to VEGFR and stabilizes death receptor, resulting in apoptosis of ECs Broad-spectrum inhibitors of MMP activity, leading to suppression of both EC and tumour cell migration and invasion As for batimastat

41,42

Inhibits migration and survival of ECs mediated by PGE and VEGF Inhibits angiogenesis through reduction of VEGF expression, apoptosis of tumour cells Defective vascular assembly

45

Inhibits bFGF-induced angiogenesis, induces apoptosis in new ECs Inhibition of VEGF-induced EC proliferation and tumour growth in animal models

49

Cell cycle arrest, apoptosis, inhibition of angiogenesis, cell invasion and metastasis Inhibits EGF-induced migration and tube formation, blocks EGF-induced upregulation of VEGF and IL-8, inhibits cellular proliferation, and promotes apoptosis

51

EGFR

Induction of apoptosis, G0/G1 cell cycle arrest, inhibition of tumour cell proliferation, inhibition of angiogenesis and metastasis with enhancement of radiosensitivity

54

Unknown

Inhibitor of FGF-2 and VEGF-induced angiogenesis and tube formation Inhibits EC migration and tube formation Inhibits EC proliferation, tube formation and vascular permeability Inhibits angiogenesis by suppressing VEGF production Induces apoptosis in ECs and rapidly dividing tumour cells Induces EC apoptosis

55

TIMP-3

VEGFR

Batimastat (BB94)

MMP

Marimastat (BB2516) COX-2 inhibitors Celecoxib Indomethacin

MMP

SC236 Integrin blockers VitaxinTM

COX-2

SCH 22153 EGFR inhibitors Small molecules Erlotinib (OS1574/TarcevaTM ) Gefitinib (ZD1839/IressaTM )

Monoclonal antibody Cetuximab (C225)

Others Thalidomide Cerivastatin TNP-470 Perindopril Methoxyoestradiol NeovastatTM

COX-2 receptor COX-1, COX-2

αvβ3 integrin αvβ3 and αvβ5 integrins

EGF EGFR

HMG-CoA reductase Methionine aminopeptidase 2 Angiotensin I-converting enzyme Microtubules MMP, VEGF, others

43

44

44

46,47

48

50

52,53

56 57,58 59 60,61 62

MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; (b)FGF, (basic) fibroblast growth factor; EC, endothelial cell; VEGF(R), vascular endothelial growth factor (receptor); COX, cyclo-oxygenase; PGE, prostaglandin E; EGF(R), epidermal growth factor (receptor); IL, interleukin; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A. VitaxinTM (Medlmmune, Gaithersburg, Maryland, USA), TarcevaTM (Hoffman-La Roche, Basle, Switzerland), IressaTM (Astrazeneca, Macckesfield, UK), NeovastatTM (Aeterna Laboratories, Quebec, Canada).

Yantai, China), has been developed in China. It has been approved for non-small cell cancer of the lung by the Chinese state food and drug administration after successful phase III trials in China40 . This news has been received with scepticism in the West, particularly as it is uncertain that the trial meets US and European standards. Licensing issues have also been a major obstacle to conducting trials of Endostar in the USA as patents for the endostatin protein are held by the Children’s Hospital, Boston. Other putative antiangiogenic factors are shown in Table 3. Matrix metalloproteinease (MMP) inhibitors may be effective because MMPs can release growth factors from

the cell matrix and because matrix dissolution is essential for the invading tumour and its vasculature. Integrin blockers and cyclo-oxygenase 2 inhibitors have also been shown to abrogate the effects of VEGF on angiogenesis. As noted above, inhibitors of EGFR signalling (such as cetuximab) block a receptor that is frequently overexpressed in solid tumours. This should inhibit both tumour growth and endothelial cell growth. Drugs such as thalidomide, angiotensin-converting enzyme inhibitors and 3-hydroxy3-methyl-glutaryl-coenzyme A reductases have somewhat surprisingly been shown to have antiangiogenic properties. Whether many of these commonly used drugs will actually

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reduce the incidence of cancers in long-term users remains to be determined. Angiogenesis inhibitors in clinical practice

Although not comprehensive, a list of angiogenesis inhibitors currently in clinical trials is available from the US National Cancer Institute website (www.cancer.gov/clinicaltrials/developments/anti-angiotable). Antiangiogenic therapy became a reality with the approval of bevacizumab (also known as avastatin) by the US Food and Drug Administration in February 2004 for use in combination with standard chemotherapy for colorectal cancer. The median survival in one phase III trial of 813 patients using bevacizumab was 20·3 months in the treatment group compared to 15·6 months in the group receiving chemotherapy alone (irinotecan, bolus fluorouracil and leucovorin) (P < 0·001). The median progression-free survival was 10·6 and 6·2 months respectively (P < 0·001)63 . Separately, the Eastern Cooperative Oncology Group has studied the effect of bevacizumab alone, in combination with 5-fluorouracil (5-FU), leucovorin and oxaliplatin (FOLFOX-4), and FOLFOX-4 alone in 829 patients who had previously undergone chemotherapy (fluoropyrimidine and irinotecan)64 . The overall and progression-free survival were found to be significantly longer after combination treatment. The overall survival times were 12·9, 10·8 and 10·2 months respectively with combination treatment, chemotherapy and bevacizumab alone; respective values for progression-free survival were 7·3, 4·7 and 2·7 months. Bevacizumab has been used as a first line of treatment for locally advanced, recurrent or metastatic non-small cell cancer of the lung in combination with platinum-based chemotherapy (median survival 12·3 months with paclitaxel and carboplatin plus bevacizumab versus 10·3 months with paclitaxel and carboplatin alone; P < 0·003)63,65,66 . Encouraging reports are also emerging from the use of bevacizumab and paclitaxel in previously untreated patients with metastatic breast cancer67 ; adding bevacizumab doubles progressionfree survival. Unfortunately, addition of bevacizumab to chemotherapy did not increase survival in patients with previously treated and refractory breast cancer68 . Antiangiogenic factors that target the receptors for VEGFs, for example semaxanib (SU5416) and vatalanib, have shown promising results in animal studies. However, they have not produced clinical benefit in several phase III studies, which has resulted in the termination of their development. Sorafenib (BAY 43–9006, Nexavar ; Bayer, Leverkusen, Germany)69 and sunitinib (SU11 248, Sutent ; Pfizer Oncology, New York, USA)70 , which act to Copyright  2008 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

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inhibit signalling pathways downstream of receptors, have been approved for advanced renal cell carcinoma; sunitinib is also used in imatinib–mesylate-resistant gastrointestinal stromal tumours70 . Oral sorafenib, a multikinase inhibitor, is currently licensed for advanced renal cell carcinoma as second-line therapy. It also appears to increase the overall survival of patients with advanced hepatocellular carcinoma71 . A worldwide multicentre trial, which included five centres in the UK, randomized 602 patients with advanced hepatocellular cancer to receive either sorafenib or placebo. The median overall survival was 10·7 months with the active agent and 7·9 months for placebo. Sorafenib is the first agent to show any statistically significant overall survival benefit in this disease. Although the results of these clinical trials are encouraging as proof of principle, the effects are undeniably modest. In the UK, guidelines issued by the National Institute for Health and Clinical Excellence (NICE) in 2007 do not recommend the use of bevacizumab in combination with 5-FU as a first-line treatment for metastatic colorectal cancer based on a cost–benefit analysis72 . NICE used quality-adjusted life years (QALY), a measure of quantity and quality of life lived, to quantify the cost of intervention. Using a one-way sensitivity analysis of the base case, the cost per QALY gained was £60 430–76 831 for bevacizumab in combination with irinotecan, bolus fluorouracil and leucovorin. For bevacizumab in combination with 5-FU and leucovorin this was found to be at least £51 355. Further analysis with a willingness-to-pay threshold at £30 000 showed that the chance of bevacizumab being cost effective was zero. This drug, or a related derivative, may still have a market in the treatment of age-related macular degeneration. Preliminary reports show dramatic improvements in proliferative neovascular eye diseases73,74 and results from clinical trials are awaited. Why does antiangiogenic therapy not work better?

Folkman’s view of angiogenesis as ‘an organizing principle’ to simplify therapeutic options in many angiogenesisdependent conditions is attractive75 . It is clear, however, that in practice things are more complicated. The process of angiogenesis is highly regulated, and controlled by the balance of proangiogenic and antiangiogenic stimuli. In tumours, there are many stimuli that can alter this balance. These include tumour hypoxia, glucose deprivation, mechanical stress, growth factors secreted by the tumours themselves and genetic changes (activation of oncogenes or inactivation of tumour suppressor genes)76 . The predominant angiogenic and antiangiogenic www.bjs.co.uk

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factors responsible for the angiogenic switch vary in different lesions. This suggests that determination of the predominant angiogenic factor and its targeted therapy could lead to a useful response, especially if combined with an antiangiogenic agent with a broader spectrum of action. What follows is a summary of the mechanism of angiogenesis and the therapeutic strategies that are now evolving.

Steps in angiogenesis

The progression of tumour from a dormant to an active state depends on a series of events, including a switch to an angiogenic phenotype (Fig. 1). This can be triggered by various signals, including genetic mutation, hypoxia, metabolic stress, mechanical stress and immune/inflammatory response86 . The ‘spike’ hypothesis

Surgery o rn o

Antiang rapy iog he t en ic Primary tumour

ssion gre pro

Antiang iog en

The angiogenic switch and antiangiogenesis

rapy the ic

Angio gen ic

n ho itc

Cancers start off as small groups of abnormal cells. These proliferate rapidly and enlarge, eventually producing symptoms and signs. This process is angiogenesis dependent, as a tumour cannot grow beyond 1–2 mm in size without its own blood supply. Folkman80 used in vivo models to show the cessation of tumour growth in the absence of an adequate blood supply. Until the tumour cell acquires the ability to produce its own, or to modify its environment to produce angiogenic stimulators de novo, its cells may remain dormant or even disappear owing to other host factors. It is now widely accepted that every increment of tumour growth requires an increment of vascular growth and that survival rates are inversely proportional to the microvessel density81 . Besides its requirement for tumour growth, angiogenesis aids tumour dissemination82 – 85 .

al rm

sw

This complex process involves cells, soluble polypeptides, haemodynamic factors and extracellular matrix components77 . It leads to the eventual development of the neovascular network. Interactions between oncogenes, suppressor genes, environmental factors, proangiogenic and antiangiogenic factors, along with several key proteases, play a role in the angiogenic pathway78,79 . Four steps are involved in this pathway: degradation of basement membrane; migration and proliferation of endothelial cells; intercellular and cell–matrix interactions; and maturation of the neovasculature. Interventions can be applied at any of the four steps to abrogate angiogenesis.

Angiogenesis and cancer

Unknown primary Dormant tumour

Metastasis/advanced tumour Antiangiogenic therapy Cure/tumour dormancy

Progression of tumour from dormant stage to metastasis. Antiangiogenic therapy applied at an appropriate time during progression can reverse tumour growth, prevent metastasis or even result in cure

Fig. 1

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proposed by Indraccolo and co-workers87 suggests that a transient angiogenic switch can interrupt tumour dormancy and prime tumour growth. This switch can also be thrown by loss of antiangiogenic factors with or without an increase in the release of angiogenic factors. Antiangiogenic therapy inhibits the sprouting of blood vessels and acts to arrest the angiogenic switch. Several integrated steps occur during tumour angiogenesis, which depend on angiogenic and antiangiogenic promoters. A balance is required for a healthy endothelium. Imbalances in angiogenic factors lead to a haphazard development of blood vessels88 ; thin-walled vessels with an abnormal pericyte coat or an incomplete basement membrane are examples89,90 . This, coupled with loss of adhesion between endothelial cells, leads to a hyperpermeable ‘leaky’ state. The extravasation of proteins is essential for the migration of endothelial cells91 . This characteristic, coupled with changes at the molecular and functional level, produces a distinct advantage for the survival and spread of tumour cells. Oncogenes play an important role in angiogenesis. The ras oncogene that is commonly found in tumours helps tumour growth through a direct effect on proliferation and indirectly by inducing angiogenesis through upregulation of VEGF92,93 . Along with the c-myc oncogene, ras can also turn on the angiogenic switch by downregulating the antiangiogenic factor thrombospondin94 . Fleming and colleagues95 have shown that RNA interference directed towards mutant k-ras, which is a feature of pancreatic adenocarcinoma, can reduce the angiogenic potential of certain cancer cell lines, either by increasing the level of thrombospondin 1 or by reducing production of VEGF. Folkman and Ryeom96 have proposed an ‘endothelial centric hypothesis of oncogene addiction’ reflecting the requirement of activated oncogenes for tumour growth. These workers have demonstrated that oncogene activation alone cannot sustain tumour growth beyond a microscopic size96 . The importance of a concerted effort in the development of cancer is exemplified in chronic inflammatory conditions, especially those without a known infective cause. The production of inflammatory cytokines and prostaglandins may suppress cell-mediated immunity and promote angiogenesis in these circumstances. The reactive oxygen species and other metabolites produced may result in DNA damage and mutations97,98 . The mediators themselves may induce cell proliferation and inhibition of apoptosis. This, coupled with the stimulation of angiogenesis, can provide the ideal microenvironment for the angiogenic switch, leading to tumour development and growth.

Rationale for antiangiogenic treatment

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The rationale for antiangiogenic therapy stems from the observation that the target cells, that is endothelial cells, are genetically stable, diploid and homogeneous, unlike cancer cells. This reduces their chance of mutation and the problem of drug resistance. One endothelial cell is estimated to support the growth of 50–100 tumour cells. Hence the death of one endothelial cell ‘amplifies’ any antitumour effect99 – 101 . In addition, angiogenic endothelium is known to overexpress angiogenic factors102 . Targeting these distinct angiogenesis-specific factors may produce maximal efficacy with the chance of reduced toxicity. The ease of administration of most antiangiogenic agents makes it an even more attractive option. The various components of a tumour include, in addition to the neoplastic cells, stromal cells such as pericytes, endothelial cells, mast cells, lymphocytes, dendritic cells, fibroblasts and myofibroblasts. These are enmeshed in the extracellular matrix. The various components contribute to a unique microenvironment, which allows the tumour cells to grow. The tumoral vascular architecture, which provides the nutrients required for cell growth, is disorganized owing to uncontrolled VEGF signalling and mechanical forces, leading to formation of saccular, dilated, tortuous vessels with trifurcations and branches of uneven diameter103 . Changes also occur in the factors that contribute to the rheological properties of blood in patients with cancer104 . These include increases in the aggregation and rigidity of red blood cells, raised fibrinogen and globulin concentrations, and a decreased albumin to fibrinogen ratio105,106 . These changes cause an unpredictable rate and direction of flow, leading to a variation in the distribution of nutrients. This has implications for therapeutic strategies107 . Hypoxia may be a persistent feature in the tumour microenvironment because of the inability of the host vasculature and angiogenesis to keep up with demand. Hypoxia can promote angiogenesis and metastasis through the release of hypoxia inducible factor α. It can also confer chemoresistance and radioresistance to tumours. Jain108 has shown that antiangiogenic therapy can prune some tumoral vessels, while normalizing the structure and function of the rest, resulting in changes in the tumour microenvironment with respect to oxygenation and pH. It may prove possible to exploit these while using radiation or chemotherapy to allow better penetration. Vascular targeting therapy

Vascular targeting therapy destroys existing tumour vasculature rather than preventing new growth by British Journal of Surgery 2008; 95: 281–293

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sprouting109 . Three different classes of vascular targeting therapy have been described. First, there are liganddirected vascular targeting agents, such as cationic nanoparticles bound to an integrin αvβ3-directed ligand, that deliver a mutant gene to tumour blood vessels110 . Second come small molecule vascular targeting agents, for example combretastatin analogues, that disrupt the tubulin cytoskeleton, inducing rapid morphological changes in endothelial cells to cause thrombosis of the vasculature111 . Finally, there is cationic liposome-based vascular targeting therapy, which relies on a selective propensity for targeting activated tumour endothelium112 . All three types of molecule can carry a variety of drugs to target tumour endothelial cells selectively. Problems with antiangiogenic therapy

Several angiogenic molecules have been described and the factor predominating depends on the location and type of tumour. With tumour progression, the number of proangiogenic factors tends to increase113 . This would limit the use of single agents with a narrow spectrum of action and might lead to resistance or tolerance. The dose and schedule of dosing for antiangiogenic therapy is still uncertain. Unlike conventional chemotherapy in which the maximal tolerated dose (MTD) is the preferred effective dose, a non-linear response curve in the case of antiangiogenic therapy means that responses in the laboratory setting may not easily be replicated clinically. Many antiangiogenic agents are already known to show a biphasic response, depending on the tumour; variation is from very low to very high dose39,114 . In some situations in which an initial response has occurred, continued administration of the agent has resulted in a diminished effect, resembling an acquired resistance to the drug. Whether this is a real drug resistance, or an effect resulting from concentrations of the drug falling beyond its therapeutic efficacy owing to cumulative toxicity, is a matter of conjecture. Current laboratory evidence favours the administration of a prolonged or frequent low-dose therapy (metronomic), which results in the apoptosis of dividing endothelial cells without any effect on quiescent endothelial cells115 . This has resulted in a renewed interest in conventional chemotherapeutic agents that have been shown to have antiangiogenic properties at doses considerably less than the MTD. Combination strategies have also been evolved to have maximal effect. Klement and co-workers116 have shown that human neuroblastoma cell lines inoculated into immunodeficient mice respond better with a combination of vinblastine (below its MTD) and the antiangiogenic agent DC101, a monoclonal antibody targeting VEGFR2. Copyright  2008 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

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There was a complete and sustained regression of these tumours. Similarly Kamat and colleagues117 have shown the efficacy of metronomic dosing schedules of taxanes in combination with AEE788, a dual EGFR and VEGFR inhibitor, in an orthotopic murine model of ovarian cancer. It seems clear that an understanding of the pharmacodynamic properties of the drug is essential before any meaningful results can be obtained. Recognizing the precise dose and scheduling may not necessarily be the critical step. Some studies have focused on the differences in endothelial cells in varying microenvironments to explain the nonresponse to antiangiogenic therapy. Factors determining the angiogenic balance in different tumours, as described above, may vary, making certain antiangiogenic drugs ineffective. Furthermore, mechanisms independent of angiogenesis might exist to sustain tumour growth. These phenomena have been demonstrated by several investigators, and include vascular co-option (recruitment of pre-existing vessels by tumours)118 , vasculogenesis (endothelial cells from bone marrow contributing to new vessel formation)119 , vascular mimicry (small vessel-like structure with cluster of tumour cells)120 and vascular mosaicism (endothelial cells interspersed with tumour cells reported in implantation models of colonic carcinoma)121 . These additional mechanisms might contribute to the nonresponse of certain tumours to antiangiogenic therapy. Widespread opinion has been that the ‘angiogenic’ receptors, that is VEGFRs and tyrosine kinase receptors for angiopoietins, are endothelial cell specific. However, several publications now describe their expression on non-endothelial cells, both normal and cancerous. What their role is on these cells remains to be ascertained but interventions that inhibit angiogenic growth factor signalling may not be as specific as first thought. This may explain the side-effects encountered with some drugs. Surgery and antiangiogenic therapy

Currently, surgery offers the only chance of a ‘cure’ in most solid organ tumours. Whether surgery actually contributes to the development of metastatic foci by mechanical seeding during manipulation of tumour, or by removal of a source of antiangiogenic factors, has not been determined, although a combination of these two is also possible. A notouch isolation technique has been advocated for colorectal malignancies to reduce the risk of mechanical seeding. A prospective randomized trial from the Netherlands using such a technique for large bowel cancers showed a tendency for reduction in the number of, and time to, occurrences of liver metastasis (P = 0·14)122 . This effect was most www.bjs.co.uk

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obvious in the sigmoid colon with angioinvasive growth. More recent data from Japan using both no-touch isolation and extensive intraperitoneal lavage in pancreatectomies have also shown positive results. These were statistically significant, although the number studied was small123 . Mean survival time was almost doubled to 41·5 months with this procedure (P = 0·018). Whether a combination of prophylactic preoperative metronomic antiangiogenic therapy would have aided in the delay or prevention of the development of local and regional recurrences is unknown at present, but is an exciting prospect. If it does, the extension of this kind of therapy to patients with different types of cancer might be possible. Retsky et al.124 have suggested that surgical wounding itself can cause a release of proangiogenic factors. This has been hypothesized as one of the reasons why nearly 27 per cent of premenopausal, node-positive women with breast cancer develop distant relapses within the first 10 months following resection. Adjuvant chemotherapy improves outcomes in such cases, probably because it inhibits the growth of the rapidly dividing cells, both tumour and vasculature125 . When considering preoperative antiangiogenic therapy, its potential to inhibit wound healing must be considered, especially with respect to bowel anastomosis. This would need to be assessed against any putative beneficial effects. Studies on animal models of wound healing concurrent with antiangiogenic therapy have been inconclusive. Results seem to be dependent on the agents used126,127 . Hypoxia can occur during surgery as a consequence of blood loss or temporary vascular exclusion in liver surgery. This can induce angiogenesis and so affect the prognosis in cancer situations128 . Several studies have shown the adverse effect of blood transfusion on longterm survival and tumour recurrence129,130 . Intraoperative blood transfusion may represent an indirect indicator of the amount of hypoxic injury and may be directly proportional to the angiogenic response. Recent studies also point to the depletion of nitric oxide in stored blood, resulting in impaired vasodilatory ability of red blood cells. This can compromise blood flow and further accentuate the hypoxic state, with release of proangiogenic factors131 . Intermittent perioperative administration of antiangiogenic factors may seem an attractive possibility for dealing with the proangiogenic factors released, as well as to balance the negative impact, if any, on wound healing. Fig. 1 shows the progression of tumour from a dormant to an advanced state. Antiangiogenic therapy administered during this phase could prevent the activation of the angiogenic switch, allowing sustained dormancy. It may also limit the progression of primary tumour, potentially Copyright  2008 British Journal of Surgery Society Ltd Published by John Wiley & Sons Ltd

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resulting in a cure. When combined with surgery, antiangiogenic therapy administered before and after removal of the primary tumour may prevent the seeding and growth of metastases. It may also act to inhibit angiogenic factors released during the wounding response at surgery. Finally, it may replace the antiangiogenic factors that the primary tumour may have been releasing. Future directions

Recent advances allowing identification of proteins by mass spectrometry (proteomics) has resulted in attempts to use this information in the clinical setting. Oncoproteomics, the application of proteomics technology in oncology, has the prospect of identifying novel tumour biomarkers as well as new biomarkers that can reliably predict outcomes during cancer therapy. This may hold the key to the individualized selection of appropriate antiangiogenic therapy. The urinary proteome and techniques for standardizing urine specimens have therefore been the subject of intense investigation. Areas of research include the presence of modified proteins and low concentrations of proteins of interest132 as well as extrinsic factors related to sample preparation. The widespread availability of these techniques will provide a valuable guide to the appropriate selection and monitoring of antiangiogenic therapy. Other emerging imaging techniques can assess the function of tumour microvessels. This can be done by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and dynamic contrast-enhanced computed tomography (perfusion CT). Low molecular weight gadolinium-based contrast media have been used to qualify and quantify the rate of intercompartmental transfer (intravascular to extravascular and back) of the dye after a bolus injection. These are different in normal and tumour tissues133 . Needless to say these kinetic variables need to be made reproducible. Perfusion CT with iodinated contrast media, which can visualize vessels less than 1 mm in diameter, has been able to demonstrate the antiangiogenic effects of bevacizumab in patients with rectal cancer134 . Reports emerging from several phase I studies suggest that DCE-MRI and perfusion CT can estimate the biologically active dose of antiangiogenic agents135 . The widespread availability of these techniques will promote the optimization of antiangiogenic therapies. This, coupled with the development of surrogate markers of tumour response, will determine the future of antiangiogenic therapy. Moreover, the role of antiangiogenic therapy in the early stages of tumour formation, before the angiogenic balance shifts heavily towards the angiogenic side, is another area for future investigation. www.bjs.co.uk

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Acknowledgements

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