**15. Conclusions**

treated patients with advanced NSCLC. The secondary endpoint of OS was not significantly different between the two arms [88]. Another phase II trial showed that vandetanib in com‐ bination with docetaxel was superior to docetaxel alone in pretreated NSCLC patients with

The phase III ZODIAC trial randomized patients with advanced NSCLC to receive either docetaxel/vandetanib or docetaxel/placebo as second-line treatment. Although vandetanib improved ORR (17 versus 10%, p= 0.0001) and PFS (HR: 0.79, p< 0.0001), OS was not signifi‐ cantly improved (HR: 0.91, p= 0.196) [90]. In the ZEAL trial, vandetanib was investigated in combination with pemetrexed also in the second-line setting. Despite an improvement in ORR (19 versus 8%, p < 0.001), this study did not meet its primary endpoint of PFS (HR: 0.86, p = 0.108) [91]. In another phase III trial (ZEPHYR), patients who had progressed after chemotherapy and erlotinib were randomized to vandetanib versus placebo. PFS was im‐ proved (HR: 0.63, p < 0.0001), but not OS (HR: 0.95, p = 0.527) [92]. The above phase III trials did not carry out stratified analysis on the EGFR gene status and therefore were not able to

regard to PFS (18.7 weeks versus 12 weeks; HR = 0.64, p = 0.037) [89].

18 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

further identify the potential populations that may benefit from vandetanib.

Sunitinib is an oral TKI of VEGFR-1, -2, -3, PDGFR-α/β, c-kit, Flt-3 and RET.

weeks (95%CI: 8.6-14.1) and 37.1 weeks (95%CI: 31.1-69.7), respectively [94].

CALGB 30607 study of sunitinib as maintenance therapy.

mous NSCLC (AGILE1038: with cisplatin/gemcitabine).

**14. Other multi-targeted TKIs**

**13. Sunitinib**

These results led to withdrawal of the application for approval of vandetanib in NSCLC.

It has been studied in advanced NSCLC in two phase II trials. In the first one, 63 pretreated patients received sunitinib as single agent, achieving an ORR of 11.1% (95%CI: 4.6–21.6), me‐ dian PFS of 12 weeks (95%CI: 10.0-16.1) and median OS of 23.4 weeks (95%CI: 17.0-28.3) [93]. In the other phase II trial, 47 pretreated patients received sunitinib on a continuousdosing schedule (37.5 mg/day). The ORR was only 2.1%, but median PFS and OS were 11.9

There are ongoing studies investigating sunitinib in patients with NSCLC, including the phase II CALGB 30704 trial evaluating sunitinib as second-line therapy and the phase III

Axitinib, with VEGFR, PDGFR-β and c-Kit as its main targets, is currently the most potent TKI in inhibiting VEGFR signal pathways. In a phase II study in advanced NSCLC, in which 28% of patients had received no prior chemotherapy, ORR was 9.4%, with PFS and OS of 4.9 and 14.8 months, respectively [95]. Currently, three ongoing phase II studies are exploring the effectiveness and safety of axitinib-based combination therapies in non-squamous (AGILE1030: with paclitaxel/carboplatin; AGILE1039: with pemetrexed/cisplatin) and squa‐

In recent years, we have acquired a lot of information regarding the role of angiogenesis and its pathophysiological relationship with some types of neoplasias, engaging in proc‐ esses such as tumour growth and dissemination capacity as loco-regional as distant. In lung cancer, we know that neoangiogenesis is the result of the action of several growth factors (mainly VEGF, TGF-alpha, EGF, VEG/PF and PDGF) whose output is controlled by transcription factors hypoxia-induced such as HIF-1, whose expression has been asso‐ ciated as an independent factor of poor prognosis. Acquired knowledge has allowed de‐ signing therapeutic strategies aimed at blocking the action of various pro-angiogenic factors and thereby altering the disease natural course. Some drugs acting against VEGF, as bevacizumab, have demonstrated clinical efficacy improving OS and PFS although with treatment-related toxicities expected with blocking this pathway, as showed some trials, particularly in patients subsets with a known clinical profile that when is present makes it more susceptible to those complications. Another line of research has been that of small-molecule tyrosine kinase inhibitors (sorafenib, vandetanib, sunitinib, axitinib, pa‐ zopanib and motesanib), showing some benefits in PFS but without a positive impact in OS when were applied non-selectively among NSCLC patients, so in the future probably we will need identify populations with a right profile that allows us to predict who have more chance to benefit from this therapy. Structural abnormalities in tumor neovasculari‐ zation lead to pathophysiological changes within the neoplastic tissue. The study of these functional changes have allowed to develop imaging techniques that, not only differenti‐ ate a benign lesion from other malignant, but also provide prognostic information and monitor the therapeutic effects of drugs used. Thus, techniques such as perfusion CT and dynamic MR allow anatomical and functional assessment of neoplasia, based on the characteristics and changes of intratumoral capillary network.

[4] Gerber HP, Kowalski J, Sherman D, Eberhard DA, Ferrara N. Complete inhibition of rhabdomyosarcoma xenograft growth and neovascularization requires blockade of both tumor and host vascular endothelial growth factor. Cancer Res 2000, Nov

Angiogenesis and Lung Cancer http://dx.doi.org/10.5772/54309 21

[5] Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch

[6] Kaelin WG. The von hippel-lindau protein, HIF hydroxylation, and oxygen sensing.

[7] Imoto H, Osaki T, Taga S, Ohgami A, Ichiyoshi Y, Yasumoto K. Vascular endothelial growth factor expression in non-small-cell lung cancer: Prognostic significance in

[8] Herbst RS, Fidler IJ. Angiogenesis and lung cancer: Potential for therapy. Clin Cancer

[9] Cox G, Jones JL, Walker RA, Steward WP, O'Byrne KJ. Angiogenesis and non-small

[10] Tamura M, Ohta Y, Kajita T, Kimura K, Go T, Oda M, et al. Plasma VEGF concentra‐ tion can predict the tumor angiogenic capacity in non-small cell lung cancer. Oncol

[11] Takigawa N, Segawa Y, Fujimoto N, Hotta K, Eguchi K. Elevated vascular endothe‐ lial growth factor levels in sera of patients with lung cancer. Anticancer Res

[12] Linder C, Linder S, Munck-Wikland E, Strander H. Independent expression of serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bfgf)

[13] Matsuyama W, Hashiguchi T, Mizoguchi A, Iwami F, Kawabata M, Arimura K, Osame M. Serum levels of vascular endothelial growth factor dependent on the stage

[14] Choi JH, Kim HC, Lim HY, Nam DK, Kim HS, Yi JW, et al. Vascular endothelial growth factor in the serum of patients with non-small cell lung cancer: Correlation

[15] Laack E, Köhler A, Kugler C, Dierlamm T, Knuffmann C, Vohwinkel G, et al. Pre‐ treatment serum levels of matrix metalloproteinase-9 and vascular endothelial growth factor in non-small-cell lung cancer. Ann Oncol 2002, Oct;13(10):1550-7.

[16] Jäger R, List B, Knabbe C, Souttou B, Raulais D, Zeiler T, et al. Serum levels of the angiogenic factor pleiotrophin in relation to disease stage in lung cancer patients. Br J

in patients with carcinoma and sarcoma. Anticancer Res 1998;18(3B):2063-8.

progression of lung cancer. Chest 2000, Oct;118(4):948-51.

with platelet and leukocyte counts. Lung Cancer 2001;33(2-3):171-9.

squamous cell carcinoma. J Thorac Cardiovasc Surg 1998, May;115(5):1007-14.

during tumorigenesis. Cell 1996, Aug 9;86(3):353-64.

cell lung cancer. Lung Cancer 2000, Feb;27(2):81-100.

Biochem Biophys Res Commun 2005, Dec 9;338(1):627-38.

15;60(22):6253-8.

Res 2000, Dec;6(12):4604-6.

Rep 2001;8(5):1097-102.

1998;18(2B):1251-4.

Cancer 2002, Mar 18;86(6):858-63.
