Targeting angiogenesis in lung cancer-Pitfalls in drug development
Cite this article as: Hilbe W, Manegold C, Pircher A. Targeting angiogenesis in lung cancer - Pitfalls in drug development. Transl Lung Cancer Res 2012;1(2):122-128. DOI: 10.3978/j.issn.2218-6751.2012.01.01
Review Article
Targeting angiogenesis in lung cancer-Pitfalls in drug development
Wolfgang Hilbe1, Christian Manegold2, Andreas Pircher,1
1Department of Hematology and Oncology, Medical University Innsbruck, Austria; 2Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany
Wolfgang Hilbe, MD. Medical University Innsbruck, Department of Hematology and Oncology, Anichstrasse 35, A-6020 Innsbruck, Austria. Tel: 0043-512-504-81151; Fax: 0043-512-504-26299. Email: wolfgang.hilbe@i-med.ac.at.
Abstract
Jump to Section
Top
Abstract
Introduction
Tumor response but no prolongation of overall survival
Complexity of the biology of tumor angiogenesis
Reconsider the clinical development of anti-angiogenic drugs
Acknowledgement
References
In non-small-cell lung cancer, anti-angiogenic strategies like bevacizumab have developed into standard treatment options. New anti-angiogenic drugs like tyrosine kinase inhibitors generated optimistic results in phase II trials, but failed to translate into positive results in phase III trials. In this overview some critical aspects of the biology of tumor angiogenesis and potential pitfalls of anti-angiogenic drug development are discussed. These include the design of clinical trials, dosage of investigational drugs or the choice of combinational drugs, the lack of validated biomarkers and the complexity of the patho-biology of tumor angiogenesis. Future trials should also direct attention to the role of cigarette smoke and the stage of the disease, which is investigated.
Key words
VEGF; VEGFR; anti-antiangiogenic therapy; tyrosine kinase inhibitor (TKI); bevacizumab
Transl Lung Cancer Res Jan 04, 2012. DOI: 10.3978/j.issn.2218-6751.2012.01.01
Introduction
Jump to Section
Top
Abstract
Introduction
Tumor response but no prolongation of overall survival
Complexity of the biology of tumor angiogenesis
Reconsider the clinical development of anti-angiogenic drugs
Acknowledgement
References
In 1971, Judah Folkman hypothesized that tumor growth is dependent on angiogenesis and suggested that disrupting tumor angiogenesis would inhibit tumor growth, thus providing a method of controlling tumors (1). Thereby, tumor hypoxia is the key trigger to induce tumor angiogenesis and, in a simplified model, hypoxia and factors like epidermal growth factor (EGF), insulin-like growth factor (IGF) or platelet-derived growth factor (PDGF) lead to vascular-endothelial growth factor (VEGF)-secretion. Subsequently, VEGF activates VEGF receptors (VEGFR) which by means of dimerization induces the downstream signaling cascade of endothelial cells. Finally, proliferation, migration and permeability of endothelial cells are induced facilitating tumor growth and metastasis. During the following decades tumor angiogenesis has been the subject of extensive research and it is well known that angiogenesis is involved in early as well as in late carcinogenic processes and finally contributes to metastases (2).
Based on theoretical considerations, anti-angiogenic therapies could target either the VEGF itself by neutralization (Bevacizumab, VEGF-Trap (3)) or inhibition of the external epitope of the VEGF receptor with monoclonal antibodies. Further VEGF signaling can be blocked by VEGFR tyrosine kinase inhibitors (TKI) like sunitinib, sorafenib, pazopanib, cediranib, axitinib, motesanib and so on (4). In contrast to monoclonal antibodies, these TKIs are not specific for VEGFR 1-3 but also inhibit a plethora of tyrosine kinases and signaling pathways (5,6).
The anti-VEGF monoclonal antibody bevacizumab was the first successfully applied antiangiogenic drug in humans. By testing bevacizumab in advanced non-small-cell lung cancer (NSCLC), the well known Sandler trial proved efficacy in all evaluated end-points including overall survival (OS), progression-free survival (PFS) and doubling of response rates (RR) (7). This study was the basis for the approval of bevacizumab in NSCLC, a new "standard of care". Impressive effects seen in daily routine supported the enthusiasm for this new anticancer strategy (Figure 1).
Nevertheless, the challenges, experienced during the clinical development in lung cancer, have to be kept in mind. When bevacizumab was evaluated in a randomized phase II trial in an unselected NSCLC cohort, 4 out of 66 treated patients experienced fatal bleedings (8). By defining a clear risk profile and by excluding "high-risk" patients, bevacizumab application proved to be tolerable in subsequent phase III trials (7,9).
Furthermore, first reports evaluating orally available kinase inhibitors also proved to be effective (10). These first positive results initiated a great engagement of the pharmaceutical industry to develop a number of similar products targeting VEGFR1, 2, 3 or other angiogenic cascades (11) (see Table 1). However, these optimistic results generated in phase II trials did not translate into positive results in phase III trials. In the following, some critical aspects of the biology of tumor angiogenesis and potential pitfalls of anti-angiogenic drug development are discussed.
Figure 1. A 72-years old male patient, suffering from advanced NSCLC (adeno-carcinoma). After a pretreatment period of 23 months with erlotinib as monotherapy, bevacizumab was added at the time of progression in January 2009 resulting in a dramatic response within two months.
Table 1. Relevant phase III trials introducing anti-angiogenic agents in NSCLC.
Drug Class Target Clinical Phase Combination PFS OS Ref (or clin.trials gov.)
Bevacizumab MoAb VEGF III
III		 Carboplatin/PXL
Cisplatin/Gemcitabine		 positive
positive		 positive
negative		 Sandler et al. (7)
Reck et al. (9)
Aflibercept Soluble decoy receptor VEGF III DXL positive negative Novello et al. (42)
ASA4040 VDA unknown III Carboplatin/PXL negative negative Lara et al. (15)
BIBF1120 TKI VEGFR-1, 2, 3, FGFR, PDGFR III
III		 DXL
Pemetrexed		 pending
pending		 pending
pending		 NCT00805194
NCT00806819
Cediranib TKI VEGFR-1, 2, 3, c-kit, Flt-3 III
II/III		 Carboplatin/PXL
Carboplatin/PXL		 pending
negative		 pending
negative		 NCT00795340
Goss et al. (43)
Motesanib TKI VEGFR-1, 2, 3, PDGFR, RET, kit III Carboplatin/PXL positive negative Scagliotti et al. (44)
Sorafenib TKI Raf, Kit, Flt-3, VEGFR-2 & 3, PDGFR-β III
III
III		 Carboplatin/PXL
Cisplatin/Gemcitabine
Monotherapy		 negative
negative
pending		 negative
negative
pending		 Scagliotti et al. (45)
Gatzemeier et al. (46)
NCT00863746
Sunitinib TKI VEGFR-1, 2, 3, PDGFR-α, PDGFR-β, Flt-3, c-kit III Monotherapy pending pending NCT00693992
Vandetanib TKI VEGFR-2 & 3, RET, EGFR III
III
III		 Docetaxel
Pemetrexed
Monotherapy		 positive
negative
positive		 negative
negative
negative		 Herbst et al. (47)
De Boer et al. (48)
Lee et al. (49)
MoAb: monoclonal antibody; VDA: vascular disrupting agent; DXl: docetaxel; PXL: paclitaxel; TKI: tyrosine kinase inhibitor.
Tumor response but no prolongation of overall survival
Jump to Section
Top
Abstract
Introduction
Tumor response but no prolongation of overall survival
Complexity of the biology of tumor angiogenesis
Reconsider the clinical development of anti-angiogenic drugs
Acknowledgement
References
Throughout the last years, most of the phase III studies evaluating anti-angiogenic drugs failed to prove a survival benefit despite improvement of PFS. A heavily discussed study, for example, is the AVAIL trial testing chemotherapy plus minus bevacizumab (9). By addition of bevacizumab in two different dosages, PFS improved significantly from 6.1 to 6.5 or 6.7 months, the median OS, however, failed to prove a beneficial effect of bevacizumab (13.1 vs. 13.6 or 13.4 months).
Afterwards, a series of phase III trials, evaluating kinase inhibitors, vascular disrupting agents or new molecules like the VEGF-trap, failed to improve overall survival despite optimistic results as far as PFS was concerned (12). Why does a drug, which proves efficacy in terms of tumor response or prolongation of PFS, not change patient’s outcome? Possible answers for that question are manifold.
Firstly, the design of clinical trials could be an answer. Subsequent lines of treatment, including cross-over to similar products in later lines, might hide the absolute benefit of a drug (13). In that context the establishment of adequate criteria for response is warranted, since standard RECIST criteria measure tumor reduction in diameter but not the development of necrosis (14).
Secondly, the dosage of the investigational drug and the choice of combinational drugs might be other reasons. At the WCLC meeting in 2011, the presenting author of the ATTRACT study (15) therefore suggested that a suboptimal dosage of the investigational drug could be responsible for the negative outcome of the trial.
Thirdly, due to the absence of valuable biomarkers for antiangiogenic drugs (16), a proper selection of patients was impossible.
In the fourth place, another explanation supported by prominent preclinical data suggested that anti-angiogenic drugs might influence the biology of the disease. This was pointed out by Ebos et Kerbel (12) stating that "Antiangiogenic therapies might initiate an array of stromal and microenvironmental defense mechanisms that contribute to eventual drug inefficacy and, more provocatively, may lead to a more aggressive and invasive tumor phenotype-one with an increased ability to metastasize". Their considerations were based on previous critical publications. In 2009, Ebos et al. (17) showed that sunitinib/SU11248 can accelerate metastatic tumor growth and decrease OS in mice receiving short-term therapy in various metastasis assays. Interestingly, mice, receiving sunitinib prior to intravenous implantation of tumor cells, also experienced an acceleration of metastases, suggesting possible "metastatic conditioning" by VEGFR inhibitors in various organs. At the same time, Paez-Ribes et al. (18) observed increased numbers of metastases in distant organs after VEGF-pathway inhibition in a mouse model. Despite an initial benefit, this mechanism could lead to limited OS benefits.
Complexity of the biology of tumor angiogenesis
Jump to Section
Top
Abstract
Introduction
Tumor response but no prolongation of overall survival
Complexity of the biology of tumor angiogenesis
Reconsider the clinical development of anti-angiogenic drugs
Acknowledgement
References
Angiogenesis is dependent on a complex network of different cell compartments regulated by a balance of angiogenic and anti-angiogenic factors, which is much more complicated than described in the early days of the development of anti-angiogenic therapies (6). In pathologic angiogenesis the tumor cells themselves produce VEGF and other angiogenic factors such as beta-fibroblast growth factor (bFGF), angiopoietins, interleukin-8 and placental-derived growth factor (PlGF), which leads to an overweight of proangiogenic factors promoting the angiogenic switch. These factors stimulate resident endothelial cells to proliferate, loose cell interactions and migrate. An additional source of angiogenic factors is the adjacent tumor stroma , which is a heterogeneous compartment, comprising of fibroblastic, inflammator y and immune cells. Tumorassociated fibroblasts produce chemokines such as stromal cell-derived factor-1 (SDF-1), which may recruit bonemarrow- derived angiogenic cells (BMC) (19). Tumor cells may also release stromal cell-recruitment factors, such as PDGF-A, PDGF-C or transforming growth factor (TGF). A well established function of tumor-associated fibroblasts is the production of growth factors such as EGFR ligands, hepatocyte growth factors and heregulin. Endothelial cells produce PDGF-B, which promotes recruitment of pericytes in the microvasculature after activation of PDGFR (20). A crucial paper, discussing resistance to a VEGF inhibitor, has been recently published and analyzes the influence of the tumor stroma in the development of resistance against anti-angiogenic therapies (21). They showed, that in a bevacizumab resistant mouse model, multiple genes (components of the EGFR and FGFR pathways) were upregulated, and most of them occurred predominantly in stromal and not in tumor cells. Similarly, Solinas et al. (22) found that alterations of the endothelial microenvironment (e.g. by chemotherapy or radiation) leads to an induction of inflammatory mechanisms which increases the metastatic potential. Others stressed the key role of mast cells (23) which are involved in angiogenic switch, production of pro-angiogenic compounds and the induction of neovascularization. These data support the special role of the stromal tissue not only in promoting tumor angiogenesis but also in the development of evasive resistance mechanisms against therapies. From the clinical point it is well known that tumors exposed to antiangiogenic therapies will mostly become resistant thus leading to a re-growth of the tumor (for review see Jubb AM et al. (24) and Bergers G et al. (25)). Various mechanisms are being discussed. On the one hand, other angiogenic factors like bFGF or PDGF could be up-regulated; on the other hand tumor vessels could be protected by an increased coverage of pericytes. A third option would be that tumor cells increase their invasiveness by an accumulation of mutations (26). Finally, endothelial progenitor cells, attracted from the bone marrow, could play a role in inducing resistance (27).
The most important trigger of the production of proangiogenic factors is the induction of tumor hypoxia. The role of hypoxia has already been elucidated by Carmeliet et al. (2). Hypoxic tumor cells switch to a pro-angiogenic phenotype. One key mediator in that regulation is the hypoxia-inducible factor 1 (HIF-1), which is a hetero-dimeric protein that activates the transcription of many genes that code for proteins involved in angiogenesis, glucose metabolism, cell proliferation/survival and invasion/metastasis (2,28). HIFs increase transcription of several angiogenic genes (for example, genes encoding VEGF, PDGF and nitricoxide species). HIFs also affect cellular survival/apoptosis pathways. In that particular setting, the role of anti-angiogenic therapies was investigated by M. Franco, showing that they increase the hypoxic tumor fraction (29). After a threeweek treatment period using DC101 (VEGFR2 monoclonal antibody) the authors found a reduction in micro-vascular density, blood flow and perfusion, but also an increase in the hypoxic tumor fraction (measured with pimonidazole) and an elevation in HIF-1A expression. Tumors can cope with hypoxia by selection of hypoxia-tolerant clones and more malignant metastatic cells, which are less sensitive to antiangiogenic therapies (30,31). Furthermore, tumor cells might undergo an epithelial-mesenchymal transition to escape hypoxic conditions (31).
Reconsider the clinical development of anti-angiogenic drugs
Jump to Section
Top
Abstract
Introduction
Tumor response but no prolongation of overall survival
Complexity of the biology of tumor angiogenesis
Reconsider the clinical development of anti-angiogenic drugs
Acknowledgement
References
Facing the complexity of tumor-angiogenesis together with the failure of phase III drug combination studies the traditional pharmaceutical development strategies have to be reconsidered. Planning of clinical trials evaluating anti-angiogenic drugs should consider the following points.
-Choice and dose of combinational drugs matter (26,32-34). Evidently, a combination of a platinum plus one of the third generation cytostatics with one of the anti-angiogenic kinase inhibitors does not seem to add any benefit. However, monotherapy with for example sorafenib revealed efficacy in single cases (10). We also learned that chemotherapies such as cyclophosphamide, administered at maximum tolerated doses, can mobilize circulating endothelial progenitor cells, which could contribute to re-growth of the tumor (26,27,32). On the other side metronomic therapy (closely spaced, less toxic doses of chemotherapy) can prevent mobilization of circulating endothelial progenitor cells (33,34).
-As a second point, the stage of the disease, in which the clinical trial is performed, could be an essential question. It is known that cancer can develop due to mechanisms evolved by tumors to escape from surveillance of immune cells (35) and that the immune defense mechanism are altered in late stage diseases (36,37). Still, the majority of preclinical studies with anti-VEGF inhibitors were performed in early tumor stages whereas the majority of clinical phase III trials were done in advanced metastatic disease. Preclinical evaluations are dominated by mouse models analyzing early tumor stages with tumor response or progression as primary endpoints. In the clinical setting, patients are treated in an advanced stage of the disease and the primary end-point has to be overall survival (38). These discrepant stages of disease evaluating different end-points could be responsible for misleading interpretations of results. Therefore, there is an absolute need to develop appropriate cancer models for the development of anti-angiogenic drugs.
-Thirdly, every trial using anti-angiogenic drugs should include some kind of biomarker program. Since adequate in vivo models are missing, the biological role of these substances in humans has to be closely monitored (14,16,39). For example, the MD Anderson group around John V. Heymach (39) performed an extensive hypothesis generating biomarker program in 123 patients who were treated in a randomized phase II trial evaluating vandetanib (40). A large number of cytokines and angiogenic factors were evaluated at different days of the treatment and were correlated with progression risk. For example, plasma levels of VEGF increased and soluble VEGFR-2 decreased by day 43. Increase of VEGF was correlated with an increased risk of progression. However, validation of such biomarkers is warranted.
-Finally, cigarette smoke induces oxidative/nitrosative stress, which increases the nitration of tyrosine residues on VEGFR2, rendering it inactive for downstream signaling. Active smoking could be responsible for an endothelial dysfunction (41). Therefore, a stratification of smoking behavior should be included.
In conclusion anti-angiogenic therapies are already used successfully in daily clinical practice. But there are still many questions to be answered about mode of action and optimal use of anti-angiogenic drugs. Further scientific efforts are necessary to analyze signal pathways and regulatory mechanisms which could possibly help to identify new targets and biomarkers. Special attention should be directed to the following points: Pivotal role of hypoxia, modes of resistance/microenvironment, need for optimal (mouse) models, role of cigarette smoke, choice of chemotherapy combination and the stage of the disease, which is evaluated.
Acknowledgement
Jump to Section
Top
Abstract
Introduction
Tumor response but no prolongation of overall survival
Complexity of the biology of tumor angiogenesis
Reconsider the clinical development of anti-angiogenic drugs
Acknowledgement
References
This work was supported by the "Association of Cancer Research -Innsbruck (Verein für Tumorforschung, Innsbruck)".
References
Jump to Section
Top
Abstract
Introduction
Tumor response but no prolongation of overall survival
Complexity of the biology of tumor angiogenesis
Reconsider the clinical development of anti-angiogenic drugs
Acknowledgement
References
  • Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-6.[LinkOut]
  • Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249-57.[LinkOut]
  • Lockhart AC, Rothenberg ML, Dupont J, et al. Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 2010;28:207-14.[LinkOut]
  • Scagliotti G, Govindan R. Targeting angiogenesis with multitargeted tyrosine kinase inhibitors in the treatment of non-small cell lung cancer. Oncologist 2010;15:436-46.[LinkOut]
  • Auberger J, Loeffler-Ragg J, Wurzer W, et al. Targeted therapies in nonsmall cell lung cancer: proven concepts and unfulfilled promises. Curr Cancer Drug Targets 2006;6:271-94.[LinkOut]
  • Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967-74.[LinkOut]
  • Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542- 50.[LinkOut]
  • Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184-91.[LinkOut]
  • Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatingemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010;21:1804-9.[LinkOut]
  • Blumenschein GR Jr, Gatzemeier U, Fossella F, et al. Phase II, multicenter, uncontrolled trial of single-agent sorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer. J Clin Oncol 2009;27:4274-80.[LinkOut]
  • Ulahannan SV, Brahmer JR. Antiangiogenic agents in combination with chemotherapy in patients with advanced non-small cell lung cancer. Cancer Invest 2011;29:325-37.[LinkOut]
  • Ebos JM, Kerbel RS. Antiangiogenic therapy: impact on invasion, disease progression, and metastasis. Nat Rev Clin Oncol 2011;8:210-21.[LinkOut]
  • Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57.[LinkOut]
  • Jain RK, Duda DG, Willett CG, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 2009;6:327-38.[LinkOut]
  • Lara PN Jr, Douillard JY, Nakagawa K, et al. Randomized phase III placebocontrolled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer. J Clin Oncol 2011;29:2965-71.[LinkOut]
  • Pircher A, Hilbe W, Heidegger I, et al. Biomarkers in tumor angiogenesis and anti-angiogenic therapy. Int J Mol Sci 2011;12:7077-99.[LinkOut]
  • Ebos JM, Lee CR, Cruz-Munoz W, et al. Accelerated metastasis after shortterm treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009;15:232-9.[LinkOut]
  • Pàez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15:220-31.[LinkOut]
  • Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005;121:335-48.[LinkOut]
  • Gaengel K, Genové G, Armulik A, et al. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 2009;29:630-8.[LinkOut]
  • Cascone T, Herynk MH, Xu L, et al. Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitorresistant human lung adenocarcinoma. J Clin Invest 2011;121:1313-28.[LinkOut]
  • Solinas G, Marchesi F, Garlanda C, et al. Inflammation-mediated promotion of invasion and metastasis. Cancer Metastasis Rev 2010;29:243- 8.[LinkOut]
  • Maltby S, Khazaie K, McNagny KM. Mast cells in tumor growth: angiogenesis, tissue remodelling and immune-modulation. Biochim Biophys Acta 2009;1796:19-26.
  • Jubb AM, Oates AJ, Holden S, et al. Predicting benefit from anti-angiogenic agents in malignancy. Nat Rev Cancer 2006;6:626-35.[LinkOut]
  • Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8:592-603.[LinkOut]
  • Kerbel RS. Tumor angiogenesis. N Engl J Med 2008;358:2039-49.[LinkOut]
  • Resch T, Pircher A, Kähler CM, et al. Endothelial Progenitor Cells: Current Issues on Characterization and Challenging Clinical Applications. Stem Cell Rev 2011. [Epub ahead of print]
  • Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell 2011;146:873-87.[LinkOut]
  • Franco M, Man S, Chen L, et al. Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia. Cancer Res 2006;66:3639-48.[LinkOut]
  • Yu JL, Rak JW, Coomber BL, et al. Effect of p53 status on tumor response to antiangiogenic therapy. Science 2002;295:1526-8.[LinkOut]
  • Brahimi-Horn MC, Chiche J, Pouysségur J. Hypoxia and cancer. J Mol Med (Berl) 2007;85:1301-7.[LinkOut]
  • Bertolini F, Paul S, Mancuso P, et al. Maximum tolerable dose and low dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 2003;63:4342-6.
  • Shaked Y, Emmenegger U, Man S, et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 2005;106:3058-61.[LinkOut]
  • Belotti D, Vergani V, Drudis T, et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 1996;2:1843-9.
  • Griffioen AW. Anti-angiogenesis: making the tumor vulnerable to the immune system. Cancer Immunol Immunother 2008;57:1553-8.[LinkOut]
  • Fridman WH, Galon J, Dieu-Nosjean MC, et al. Immune infiltration in human cancer: prognostic significance and disease control. Curr Top Microbiol Immunol 2011;344:1-24.[LinkOut]
  • Talmadge JE, Fidler IJ. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res 2010;70:5649-69.[LinkOut]
  • Fojo T, Parkinson DR. Biologically targeted cancer therapy and marginal benefits: are we making too much of too little or are we achieving too little by giving too much? Clin Cancer Res 2010;16:5972-80.[LinkOut]
  • Hanrahan EO, Lin HY, Kim ES, et al. Distinct patterns of cytokine and angiogenic factor modulation and markers of benefit for vandetanib and/ or chemotherapy in patients with non-small-cell lung cancer. J Clin Oncol 2010;28:193-201.[LinkOut]
  • Heymach JV, Paz-Ares L, De Braud F, et al. Randomized phase II study of vandetanib alone or with paclitaxel and carboplatin as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 2008 ;26:5407-15.[LinkOut]
  • Edirisinghe I, Rahman I. Cigarette smoke-mediated oxidative stress, shear stress, and endothelial dysfunction: role of VEGFR2. Ann N Y Acad Sci 2010;1203:66-72.[LinkOut]
  • Novello S, Ramlau R, Gorbunova VA, et al. Aflibercept in combination with docetaxel for second-line treatment of locally advanced or metastatic nonsmall- cell lung cancer (NSCLC): Final results of a multinational placebocontrolled phase III trial (EFC10261-VITAL). 14th World Conference of Lung Cancer 2011, O43.06. Available online: http://abstracts.webges.com[LinkOut]
  • Goss GD, Arnold A, Shepherd FA, et al. Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. J Clin Oncol 2010;28:49-55.[LinkOut]
  • Scagliotti G, Vynnychenko I, Ichinose Y, et al. An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) [abstract]. J Clin Oncol 2011;29:s7512.
  • Scagliotti G, Novello S, von Pawel J, et al. Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:1835-42.[LinkOut]
  • Gatzemeier U, Eisen T, Santoro A., et al. Sorafenib (S)/ Gemcitabine/ Cisplatin (GC) vs GC alone in the first-line treatment of advanced nonsmall cell lung cancer (NSCLC): phase III NSCLC research experience utilizing Sorafenib (NEXUS) trial. Ann Oncol 2010;21:viii7(LBA 16).
  • Herbst RS, Sun Y, Eberhardt WE, et al. Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-smallcell lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 2010;11:619-26.[LinkOut]
  • De Boer R, Arrieta Ó, Gottfried M, et al. Vandetanib plus pemetrexed versus pemetrexed as second-line therapy in patients with advanced nonsmall cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZEAL) [abstract]. J Clin Oncol 2009;27:s8010.
  • Lee J, Hirsh V, Park K, et al. Vandetanib versus placebo in patients with advanced non-small cell lung cancer (NSCLC) after prior therapy with an EGFR tyrosine kinase inhibitor (TKI): A randomized, double-blind phase III trial (ZEPHYR) [abstract]. J Clin Oncol 2010;28:s7525.

Article Options

Download Citation

Share