Japanese Journal of Clinical Oncology Advance Access published online on June 16, 2009
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyp062
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© The Author (2009). Published by Oxford University Press. All rights reserved
Anti-angiogenic Therapy Against Gastrointestinal Tract Cancers
Chugai Pharmaceutical Company, Ltd, Tokyo, Japan
For reprints and all correspondence: Junko Iwasaki, Lifecycle Management Unit, Chugai Pharmaceutical Company, Ltd, 2-1-1 Nihonbashi-Muromachi, Chuo-ku, Tokyo 103-8324, Japan. E-mail: jiwasaki{at}chugai-pharm.co.jp
Received January 15, 2009; accepted May 18, 2009
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Abstract |
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 TOP Abstract INTRODUCTIONTUMOR ANGIOGENESIS AND VEGFTARGETING VEGF PATHWAY AS...BIOMARKERS OF ANTI-ANGIOGENIC...CONCLUSIONConflict of interest statementAcknowledgementsReferences |
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Gastrointestinal tract cancers constitute a group of highest morbidity both in and outside Japan, and the prognosis still remains unfavorable when the disease has progressed to the unresectable stage. Since the late 1990s, a novel category of anti-cancer drugs, ‘molecular-targeted drugs’, has become available, and angiogenesis has been considered as one of the most important molecular targets for antitumor therapy since it is essential for tumor growth. Anti-angiogenic therapy inhibits tumor angiogenesis and promotes apoptosis of existing tumor blood vessels, thereby intercepting the supply of oxygen and nutrition essential for tumor growth and metastasis. It was also suggested that anti-angiogenic therapy effectively normalizes abnormal vascular permeability, and thereby decreases the interstitial pressure, which may improve delivery of concomitantly used chemotherapeutic agents to tumor cells. Vascular endothelial growth factor (VEGF) acts as one of the most potent stimulating agents of angiogenesis, and several strategies targeting the VEGF signaling pathway have been developed, including anti-VEGF antibodies, soluble receptors binding directly to VEGF ligand, anti-VEGF receptor (VEGFR) antibodies and VEGFR tyrosine kinase inhibitors. The breakthrough in the clinical development of anti-angiogenic therapy against colorectal cancer came in 2003 with a large prospective, randomized clinical trial of bevacizumab, a monoclonal antibody directed against VEGF. Anti-angiogenic therapy has introduced a highly effective, completely new mode of action in this area and is the new standard of care in advanced colorectal cancer, while still being tested in gastric cancer due to its convincing clinical benefit and its tolerability and combinability with multiple chemotherapeutic agents.
Key Words: angiogenesis • VEGF • bevacizumab • colorectal cancer • gastric cancer
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INTRODUCTION |
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TOPAbstractINTRODUCTIONTUMOR ANGIOGENESIS AND VEGFTARGETING VEGF PATHWAY AS...BIOMARKERS OF ANTI-ANGIOGENIC...CONCLUSIONConflict of interest statementAcknowledgementsReferences |
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According to the cancer incidence data estimated worldwide from regional registrations by the International Agency for Research on Cancer, gastrointestinal (GI) tract cancers constitute a group of highest morbidity (1). Prognosis of GI tract cancer differs depending on the disease stage at the time of diagnosis, and the survival was extended by early diagnosis and improved surgical techniques. However, still a considerable number of cases are diagnosed when the disease has progressed to the unresectable stage, and in these cases, the prognosis remains unfavorable (2,3). The treatment of unresectable GI tract cancers has mainly been developed and improved with chemotherapies based on 5-fluorouracil or its derivatives in the past decades, resulting in the prolongation of colorectal cancer patients' survival to
1 year (4). Since the late 1990s, a novel category of anti-cancer drugs, ‘molecular-targeted drugs’, has become available. Tremendous efforts of researchers and medical oncologists have focused in recent times on the development of these molecular-targeted drugs. The efficacy of molecular-targeted drugs has meanwhile also been demonstrated in the field of GI tract cancers. After many years of research, inhibition of tumor angiogenesis was proven as an effective anti-cancer treatment modality for the first time in 2003 in a large prospective, randomized clinical trial with bevacizumab (Avastin®), a monoclonal antibody directed against the vascular endothelial growth factor (VEGF), in patients with colorectal cancer (5). Bevacizumab was then approved in 2004 by the United States Food and Drug Administration for the treatment of colorectal cancer and is currently the only globally approved drug targeting the VEGF pathway in this indication. Thereafter, clinical development of anti-angiogenic therapy is proceeding at an accelerated pace in many different cancer types. This article outlines the current status in clinical development of anti-angiogenic therapy against GI tract cancers centering on the development of bevacizumab for colorectal cancer.
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TUMOR ANGIOGENESIS AND VEGF |
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TOPAbstractINTRODUCTIONTUMOR ANGIOGENESIS AND VEGFTARGETING VEGF PATHWAY AS...BIOMARKERS OF ANTI-ANGIOGENIC...CONCLUSIONConflict of interest statementAcknowledgementsReferences |
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Constitutive physiological angiogenesis is essential for growth and development and plays important roles in processes such as embryogenesis, development in the early post-natal stage, skeletal growth during childhood and adolescence, ovarian luteinization, uterine vascularization etc. Contrary to this, angiogenesis during adulthood plays limited roles and is mainly involved in pathological angiogenesis. Cancer, retinopathy, psoriasis, endometriosis etc. are known as diseases involving pathological angiogenesis, but research into tumor angiogenesis has advanced the farthest (6).
Tumor angiogenesis is known to be different from the physiological angiogenesis and has been shown to lead to the development of abnormal vascular architecture, changes in interaction between endothelial cells and perivascular cells, enhanced vascular permeability etc. Blood supply through newly generated tumor blood vessels is considered essential for tumor growth beyond a diameter of 1–2 mm, and a process called ‘angiogenic switch’ is considered to be involved. Once switched on, angiogenesis and tumor growth and metastasizing go hand in hand. Tumors produce a series of angiogenic factors, and VEGF is considered to be the major factor in this angiogenic switch (7). Expression of the VEGF-encoding gene is regulated by various factors and stimuli, including hypoxia (8). When VEGF is secreted by these factors and binds to VEGF receptor (VEGFR), the VEGFR activation leads to survival of immature endothelial cells by suppression of apoptosis, growth/migration of vascular endothelial cells and promotion of capillary vascular permeability. It is believed that through vascular leakage plasma proteins leak out into the extravascular space and the interstitial pressure in the tumor stroma and surrounding tissue increases, thereby delivery of chemotherapeutic agents to the tumor is significantly impaired (9).
Although Folkman (10) published a paper in 1971 postulating that angiogenesis is essential for tumor growth and inhibition of such angiogenesis processes may lead to novel antitumor therapy, it took many years to discover VEGF. In 1983, Senger et al. (11) isolated a partially purified protein from model animals which was shown to enhance vascular permeability and called it ‘vascular permeability factor’. In 1989, Ferrara and Henzel (12) independently isolated VEGF from cultures of pituitary gland-derived cells. Ultimately, it could be shown that all these substances were, in fact, the same protein.
VEGF is a glycoprotein with a molecular weight of 34–46 kDa produced by normal cells and tumor cells. It serves as soluble ligand to VEGFR proteins on the surface of vascular endothelial cells etc. as homodimers. VEGF acts as one of the most potent stimulating agents of angiogenesis through the induction of endothelial cell growth by binding to VEGFR (13). At the present time point, six ligands have been identified as a family. VEGF-A acts specifically on vascular endothelial cells together with VEGF-B, VEGF-E and placental growth factor, and VEGF-C and VEGF-D act on lymphatic vessel endothelial cells. Among those, VEGF-A is considered to be the most important factor (13–15). At present, three types of VEGFR (VEGFR-1, -2 and -3) have been identified, which constitute the VEGFR family. Most of the biological activity of VEGF-A is exerted through binding to VEGFR-2 (15,16).
Overexpression of VEGF has been detected in almost all human cancers investigated, such as colorectal cancer, gastric cancer, lung cancer, breast cancer, renal cancer, ovarian cancer etc. (17–22). It was also reported that there is a correlation between high levels of VEGF in patients with colorectal cancer and angiogenesis/metastasis/growth of tumor (17,23). Also, in patients with gastric cancer, the correlation between high levels of VEGF and unfavorable prognosis was suggested (18,24). It is therefore considered that inhibition of VEGF is a rational strategy to treat cancer.
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TARGETING VEGF PATHWAY AS ANTI-ANGIOGENIC THERAPY AGAINST GI TRACT CANCERS |
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TOPAbstractINTRODUCTIONTUMOR ANGIOGENESIS AND VEGFTARGETING VEGF PATHWAY AS...BIOMARKERS OF ANTI-ANGIOGENIC...CONCLUSIONConflict of interest statementAcknowledgementsReferences |
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Anti-VEGF therapy inhibits tumor angiogenesis and promotes apoptosis of existing tumor blood vessels, thereby intercepting the supply of oxygen and nutrition essential for tumor growth and metastasis (25–27). It was also suggested that anti-VEGF therapy effectively normalizes abnormal vascular permeability, and thereby decreases the interstitial pressure (28,29). Jain (30) argues that these effects may improve delivery of concomitantly used chemotherapeutic agents to tumor cells and asserted that it may be important to balance chemotherapy and anti-VEGF therapy in dose and timing.
Figure 1 shows the drugs targeting the VEGF pathways. These drugs can be categorized into four groups: anti-VEGF antibodies represented by bevacizumab, soluble receptors binding directly to VEGF ligand such as VEGF-Trap, anti-VEGFR antibodies and VEGFR tyrosine kinase inhibitors. Although all of these induce inhibition of VEGF pathways, the molecular targets and their mode of action are different from one another. The summary of anti-VEGF agents under development in GI tract cancers are shown in Table 1. In the following sections, each representative drug is described in detail.
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Anti-VEGF Antibodies
Bevacizumab is a humanized monoclonal antibody against VEGF-A and inhibits binding between VEGF-A and VEGFR as a result of specific binding between bevacizumab and VEGF-A. Bevacizumab suppresses tumor growth and metastasis by inhibiting the biological functions of VEGF-A.
By immunizing mice with human VEGF165, the anti-human VEGF-A mouse monoclonal antibody A4.6.1 was first isolated, and it was shown to act as a neutralizing antibody against human VEGF-A and to exhibit anti-tumor activity in some mouse xenograft models engrafted with different human tumor cell lines (31). However, antigenicity, triggered in the human immune system by application of mouse antibodies, was a significant hurdle to taking this antibody into clinical use in patients. To reduce the antigenicity and to avoid the antibody generation against mouse monoclonal antibodies, ‘humanization’ of mouse monoclonal antibody is used. ‘Bevacizumab’ was created by the genetically engineered ‘humanization’ technology applied to the mouse antibody, A4.6.1 (32). In the bevacizumab molecule, 93% is derived from human IgG1, and only 7% from mouse antibody, A4.6.1, and the elimination half-life of plasma bevacizumab in the end phase is 17–21 days. It was also clarified that bevacizumab can recognize and bind to not only VEGF165 but also most of human VEGF-A isoforms.
In several studies using nude mice transplanted with human tumor cells of various tumor types, it was shown that administration of A4.6.1 antibody or bevacizumab suppressed tumor growth by 25–95% compared with the control group (33). It was also shown that chemotherapy combined with A4.6.1 antibody or bevacizumab gave a more pronounced antitumor effect than chemotherapy alone. Also, in clinical development, bevacizumab was administered to patients with colorectal cancer, breast cancer, lung cancer, renal cancer etc. in Phase I and II studies, and a favorable safety and tolerability profile was established as well as its anti-tumor efficacy when used in combination with various chemotherapeutic agents (34–36).
In 2003, the result of a double-blind, randomized, Phase III study of bevacizumab was presented at the conference of American Society of Clinical Oncology (ASCO). In this study, the IFL therapy (irinotecan + bolus intravenous injection of 5-fluorouracil/folinic acid), a standard therapy in the USA at the time of the study design, was compared with the IFL + bevacizumab 5 mg/kg (biweekly administration) therapy in 815 patients as first-line treatment of colorectal cancer. In the final analysis, the addition of bevacizumab to IFL extended the survival period [overall survival (OS)] from 15.6 to 20.3 months [hazard ratio (HR) 0.66, P < 0.001]. This study was perceived as groundbreaking for a new standard of care in advanced colorectal cancer incorporating an anti-angiogenic therapeutic agent in combination with chemotherapy to significantly extend patients lives. The IFL + bevacizumab therapy was generally well tolerated, and although there was an apparent higher incidence in the IFL + bevacizumab group than in the IFL alone group in Grade 3 hypertension (IFL + bevacizumab group 11.0% vs. IFL alone group 2.3%), it was controllable with standard oral antihypertensive agents. GI perforation, hemorrhage, thromboembolism were also seen, although very rare. It is therefore necessary to pay sufficient attention to occurrence of such adverse reactions, but from the viewpoint that the adverse reaction profile is different from that of chemotherapy, bevacizumab is considered to be an ideal drug for combination with chemotherapy.
Also thereafter, reproducible results were reported in several Phase III studies conducted in patients with metastatic colorectal cancer, verifying the clinical efficacy of bevacizumab in combination with various kinds and treatment line of chemotherapy (Table 2). From these results, bevacizumab has now become the standard therapeutic drug against metastatic colorectal cancer in the world. At present, a global Phase III study (AVANT trial) on post-operative adjuvant chemotherapy with bevacizumab against colon cancer is ongoing, and several Japanese hospitals have joined this study and are collaborating with the Western countries toward simultaneous development.
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Phase I and II developmental studies were also conducted in Japanese patients with colorectal cancer. The efficacy results were favorable, comparing well with the international experience (Table 3) (39). Pharmacokinetic parameters were similar to those obtained in the USA, and there were no additional safety risks observed in Japanese patients. In addition, a post-marketing surveillance observational trial of bevacizumab has been conducted since the launch of bevacizumab in Japan to confirm the favorable safety profile in Japanese patients in daily practical clinical use conditions by registering all patients up to a total of 2500 patients. The rationales of this kind of survey are: (i) important unexpected rare adverse reactions if any can be picked up by collecting safety data of such a larger number of unselected patients compared with the clinical studies conducted before approval and (ii) safety data of an unselected patient population under every day clinical practice conditions can be collected and compared with the different clinical study populations. The results of this safety surveillance will be presented in ASCO Gastrointestinal Cancers Symposium in 2009.
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In terms of clinical development in gastric cancer, no angiogenesis inhibitor has yet been approved globally, but the results of some Phase II studies suggest clinical efficacy also in this tumor entity. In a Phase II study with irinotecan + cisplatin therapy in combination with bevacizumab, Shah et al. (40) reported favorable results {response rate (RR): 65% [95% confidence interval (CI): 46–80%], progression-free survival (PFS): 8.3 months (95% CI: 5.5–9.9 months), OS: 12.3 months (95% CI: 11.3–17.2 months)}. A Phase II study with docetaxel + bevacizumab therapy was conducted in patients treated in second-line, and complete response was noted in 1 of 23 patients, partial response (PR) in 5 and stable disease (SD) in 7 patients (41). A randomized, global Phase III study with bevacizumab in combination with capecitabine + cisplatin (the AVAGAST study) is now being conducted in EU countries, the USA and Asia-Pacific region, including Japan. Japan and Korea are playing a central role in global development efforts in gastric cancer because of the similarities in epidemiology (42,43) and in standard of care in both countries. Japanese investigators with plenty of clinical study experience have been participating in the planning of the AVAGAST trial and this is one of the very first trials where Japanese investigators are driving a large international study initiative.
At present, bevacizumab has already been approved in numerous overseas countries for the treatment of colorectal cancer, non-small cell lung cancer, breast cancer, renal cancer etc. In Japan, bevacizumab was approved for colorectal cancer in April 2007, and clinical development studies other than GI tract cancers are also under way or completed in advanced lung cancer, in early- and in advanced-stage breast cancer and in glioblastoma multiforme.
Soluble VEGFRs
Aflibercept is a soluble VEGFR designed to bind to VEGF in the circulating blood. The molecule has developed by new engineering technique of antibody and is a fusion of the ligand-binding site of the extracellular domain of VEGFR-1 with the Fc domain of IgG1. It was reported that aflibercept showed anti-tumor effect against both primary lesions and pulmonary metastatic lesions in non-clinical studies using tumor-bearing nude mice (44). In the Phase I study conducted in patients with solid tumor or lymphoma which had been resistant to previous chemotherapy, SD was attained for at least 10 weeks in 17 of 35 patients and the tolerability was favorable. Adverse reactions reported in this study were proteinuria, hypertension etc., being similar to those reported with the other anti-VEGF drugs (45). In Japan, a Phase I study using aflibercept in combination with S-1 or docetaxel is ongoing in patients with solid tumors.
The results of a Phase II monotherapy study in previously treated patients with colorectal cancer were presented at the 2008 ASCO conference. In this study, hypertension, proteinuria, fatigue and headache were reported as most prominent Grade 3/4 toxicities with acceptable tolerability. PFS was 2.0 months in 20 patients untreated with bevacizumab and 3.4 months in 26 patients previously treated with bevacizumab (46). At present, a Phase III randomized comparative study is being conducted to compare FOLFIRI with FOLFIRI + aflibercept (biweekly administration) in second-line patients. In addition, global Phase III study in gastric cancer is being planned for aflibercept.
Anti-VEGFR Antibodies
IMC-1121B is a recombinant humanized IgG1 monoclonal antibody against VEGFR-2 and inhibits the biological functions of VEGF by binding specifically to VEGFR-2. In non-clinical studies, IMC-1121B showed anti-tumor effects in various models of leukemia and solid tumors. In a Phase I study conducted in 37 patients with solid tumors, the maximum tolerated dose was reached at 13 mg/kg. Hypertension and deep vein thrombosis were noted as dose-limiting toxicities. Other adverse reactions reported were proteinuria, arterial thrombotic events, anorexia, fatigue, headache etc., but the tolerability was reported as acceptable. PR was noted in four patients including one patient with gastric cancer and SD persisting for at least 6 months was noted in nine patients including two patients with colorectal cancer, suggesting also the efficacy (47). At present, a Phase II study is planned in the USA in patients with colorectal cancer, and a Phase III study as second-line treatment is also being planned in patients with gastric cancer. However, the clinical development in Japan has not started as yet.
VEGFR Tyrosine Kinase Inhibitors
At present, a number of Phase III studies with different VEGFR tyrosine kinase inhibitors are under way around the world. The feature of these agents is that they have multi-molecular targets, which we may expect the increase in power of anti-tumor effects, although they also may have risks for increasing side effects due to their biology.
Among them, vatalanib is one of the drugs reaching most rapidly to Phase III stage, and it has been developed against various cancers including colorectal cancer, lung cancer and gastrointestinal stromal tumor (GIST). Vatalanib is a tyrosine kinase inhibitor acting on VEGFR-1, -2 and -3, and its secondary targets are also platelet-derived growth factor receptor β (PDGFR-β) and c-kit. It was reported that in the non-clinical studies, vatalanib decreased microvessel density as an indicator of effective inhibition of angiogenesis and improved survival in a mouse brain tumor model (48,49). In the Phase I study, the toxicities noted were lightheadedness, ataxia, nausea, diarrhea, vomiting, hypertension etc., but all were controllable. When used as monotherapy in patients with various cancers who had previously received standard therapy, SD persisting for at least 56 days was noted in 13 of 21 patients, suggesting a favorable risk benefit relation (50). Also in Japan, a Phase I monotherapy study was conducted to confirm the tolerability in Japanese patients.
In a Phase I/II study using FOLFOX4 (oxaliplatin + intravenous infusion of 5-fluorouracil/folinic acid) in combination with vatalanib, RR in 35 patients with colorectal cancer was 48.6% (95% CI: 31.4–66.0%) and PFS was 11.4 months (95% CI: 8.8–13.6 months) (51). On the basis of these results, two Phase III randomized comparative studies were conducted to compare the FOLFOX4 therapy with the combination of FOLFOX4 and vatalanib in first-line and in second-line patients (CONFIRM1 and CONFIRM2 studies). However, in the first-line patient sample, PFS was identical in both treatment groups, with 7.7 months in the FOLFOX4 + vatalanib group and 7.6 months in the FOLFOX4 group (HR 0.88, P = 0.12), which failed to reach primary endpoint (52). Also in the patients treated in second-line, a clinical benefit could not be shown in OS as a primary endpoint (HR 0.94, P = 0.51) (53).
Cediranib is currently been tested in a Phase III trial based on a favorable Phase I and II results. It is a tyrosine kinase inhibitor acting selectively on VEGFR-1, -2 and -3. In the Phase I study conducted in 83 patients with solid cancer, toxicities such as diarrhea, dysphonia and hypertension were noted, but the tolerability was acceptable at dose levels of 
45 mg, and PR was noted in 2 patients and SD in 22 patients, indicating clinical efficacy (54). Also in Japan, a Phase I monotherapy study was conducted in 40 patients with solid tumors. Proteinuria, diarrhea and thrombocytopenia were noted in three patients as dose-limiting toxicities at 45 mg, and the maximum tolerated dose was set to be 30 mg. In the efficacy evaluation, PR was noted in 2 of 32 patients and SD at least 8 weeks in 24 of 32 patients (55).
The results of the Phase II randomized study comparing FOLFOX6 + cediranib (20 mg/day) with FOLFOX6 + cediranib (30 mg/day) therapy and FOLFOX6 + bevacizumab (10 mg/kg, biweekly administration) involving 215 patients with previously treated colorectal cancer were presented at the 2008 ASCO conference. In this study, the incidence of thrombocytopenia, hypertension and malaise was higher in the cediranib 30 mg group, but there was no significant difference in PFS as the primary endpoint between cediranib and bevacizumab (56). An ongoing phase III randomized comparative trial is comparing FOLFOX6 + bevacizumab (5 mg/kg, biweekly administration) therapy with FOLFOX6 + cediranib (20 mg/day) therapy in first-line patients. Also in Japan, a Phase I/II study with the FOLFOX6 + cediranib regimen is underway.
Sunitinib is a multi-target type tyrosine kinase inhibitor targeting VEGFR-1, -2, -3, PDGFR-
, -β, c-kit etc. In a Phase I monotherapy study conducted in 28 patients with solid tumors, dose-limiting toxicities such as fatigue, hypertension, bullous skin disorders, perforation etc. were noted, but tolerability was confirmed at the recommended dosage of 50 mg/day. PR was noted in six patients and SD in five patients, suggesting clinical efficacy (57). Also in Japan, a Phase I/II monotherapy study was conducted in 30 GIST patients, and the same dosage regimen as in the Western countries (4-week once-daily administration of 50 mg/day followed by 2-week drug cessation) was tested. In the efficacy evaluation, PR was noted in four patients and SD persisting for at least 4 weeks was noted in eight patients. Sunitinib was approved for the treatment of GIST and renal cell carcinoma in the USA (January 2006) and in Japan (April 2008).
The results of a Phase I/II study with FOLFIRI (irinotecan + intravenous infusion of 5-fluorouracil/folinic acid) + sunitinib therapy conducted in 37 patients with colorectal cancer was presented at the 2008 ASCO conference. In this study, the most serious adverse events were bone marrow toxicity, nausea and vomiting, but the maximum-tolerated dose regimen was a cycle of 4-week administration of 37.5 mg/day followed by 2-week drug pause. PR was noted in 8 of 19 patients and SD in another 10 patients (58). On the basis of these results, a Phase III randomized comparative trial was started to compare the FOLFIRI with FOLFIRI + sunitinib therapy. In Japan, a Phase I study with mFOLFOX6 + sunitinib therapy and a Phase II study with FOLFIRI + sunitinib are currently being conducted in first-line colorectal cancer patients.
Sunitinib has also been under investigation in gastric cancer, and in the interim report of the Phase II trial with sunitinib as single agent conducted in patients with gastric cancer treated after standard therapy, PR was noted in 2 of 72 patients and SD in 17 patients, PFS was 11.1 weeks and OS was 47.7 weeks (59). A Phase I/II study combining chemotherapy with sunitinib in this indication is ongoing.
Sorafenib is another multi-target type tyrosine kinase inhibitor. In the early stage of development, inhibition of Raf-1 kinase was targeted, but in pre-clinical xenograft models of various solid tumors, inhibitory effects on VEGFR-2, -3, PDGFR-β, Flt-3 and c-kit were detected. In a Phase I monotherapy study conducted in 19 patients with solid tumors, the dose-limiting toxicities were rash and hypertension, but the maximum-tolerated dose was reached at 600 mg b.i.d. The toxicities were mild to moderate, with acceptable tolerability. SD was also noted in five patients (60). Also in the Japanese Phase I study conducted in 31 patients with solid tumors, the tolerability was acceptable, although the dose-limiting toxicities were diarrhea and fatigue (61). In the Western countries, sorafenib was already approved for the treatment of renal cell carcinoma and hepatocellular carcinoma, and in Japan, sorafenib was approved for the treatment of renal cell carcinoma in January 2008.
Sorafenib is currently under development in gastric cancer indication. The results of a Phase II study with docetaxel + cisplatin in combination with sorafenib (ECOG5203 study) were presented at ASCO 2008 conference, and RR of 38.6% (95% CI: 26.3–52.2%), PFS of 5.8 months (95% CI: 5.4–7.2 months) and OS of 14.9 months (95% CI: 8.6–15.2 months) are suggestive of clinical efficacy (62). In addition, global Phase III study is being planned for sorafenib.
Numerous other clinical trials in GI tract cancer area are active presently with different new angiogenesis inhibiting agents.
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BIOMARKERS OF ANTI-ANGIOGENIC THERAPY |
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TOPAbstractINTRODUCTIONTUMOR ANGIOGENESIS AND VEGFTARGETING VEGF PATHWAY AS...BIOMARKERS OF ANTI-ANGIOGENIC...CONCLUSIONConflict of interest statementAcknowledgementsReferences |
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Translational research is becoming extremely important also in anti-angiogenic therapy and when selecting patient for individualized therapy. Despite intense efforts, no validated biomarker for anti-angiogenic therapy has been discovered so far. Also in the research accompanying the Phase III study testing bevacizumab in addition to the IFL therapy, no correlation could be established between the therapeutic effect and the presence/absence of genetic markers such as k-ras, b-raf and others (63,64). In addition to ongoing further research into tissue and blood markers, other non-invasive methods are being explored such as analysis of tumor blood vessel imaging using diagnostic instruments such as dynamic magnetic resonance imaging, computed tomography and positron emission tomography (26,50,54,65,66). However, these methods remain experimental for the time being and are not yet suited for routine use in clinical practice.
It is considered that there are some advantages in GI tract cancers for biomarker exploration. One advantage is that the technology related to endoscopic instruments is progressing remarkably in this field (67,68). Non-invasive approaches using endoscopic instruments may become one of the attractive methods in the future. Another advantage is that tumor tissues can be taken from the GI tract organs by endoscopic biopsy more easily than from other organs. The test to compare biomarker activity in the tumor tissues between before and after treatment is feasible in the case of GI tract cancers. It is considered urgently necessary to carry out biomarker exploration with GI tract cancers utilizing these advantages and discover effective biomarkers for safety and efficacy.
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CONCLUSION |
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TOPAbstractINTRODUCTIONTUMOR ANGIOGENESIS AND VEGFTARGETING VEGF PATHWAY AS...BIOMARKERS OF ANTI-ANGIOGENIC...CONCLUSIONConflict of interest statementAcknowledgementsReferences |
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We have outlined the history and current status of development of anti-angiogenic therapy against GI tract cancers, in and outside Japan. Anti-angiogenic therapy has introduced a highly effective, completely new mode of action in this area and is the new standard of care in advanced colorectal cancer, while still being tested in gastric cancer due to its convincing clinical benefit and its tolerability and combinability with multiple chemotherapeutic agents. Still, not all patients draw the same benefit from this new treatment and clinical or translational biomarkers are needed to better target this therapy. Ongoing clinical development will soon answer the question whether the addition of anti-angiogenic agents to chemotherapy in early disease stages (adjuvant treatment) will be effective in extending patients' lives and increasing the cure rates after initial surgical tumor removal.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONTUMOR ANGIOGENESIS AND VEGFTARGETING VEGF PATHWAY AS...BIOMARKERS OF ANTI-ANGIOGENIC...CONCLUSIONConflict of interest statementAcknowledgementsReferences |
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Both J.I. and S.-i.N. are employees of Chugai Pharmaceutical Company, LTD.
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Acknowledgements |
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TOPAbstractINTRODUCTIONTUMOR ANGIOGENESIS AND VEGFTARGETING VEGF PATHWAY AS...BIOMARKERS OF ANTI-ANGIOGENIC...CONCLUSIONConflict of interest statementAcknowledgementsReferences |
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We thank Dr Stefan Manth (Chugai Pharmaceutical Co., Ltd), Dr Florin Sirzén, Dr Ulrich-Peter Rohr and Dr Niko Andre (F. Hoffman-La Roche Ltd) for valuable scientific advice.
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References |
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TOPAbstractINTRODUCTIONTUMOR ANGIOGENESIS AND VEGFTARGETING VEGF PATHWAY AS...BIOMARKERS OF ANTI-ANGIOGENIC...CONCLUSIONConflict of interest statementAcknowledgementsReferences |
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