**6. Perfusion CT**

**4.3. VEG/PF**

12 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

of proteins [58].

growing tumor mass [59].

ing techniques.

Vascular endothelial growth/permeability factor (VEG/PF) is a 40 kda disulphide-linked dimeric glycoprotein that is active in increasing blood vessel permeability, endothelial cell growth and angiogenesis. These properties suggest that the expression of VEG/PF by tumor cells could contribute to the increased neovascularization and vessel permeability that are associated with tumor vasculature. The cDNA sequence of VEG/PF from human U937 cells was shown to code for a 189-amino acid polypeptide that is similar in struc‐ ture to the B chain of PDGF-B and other PDGF-B-related proteins. The overall identity with PDGF-B is 18%. However, all eight of the cysteines in PDGF-B were conserved in human VEG/PF, an indication that the folding of the two proteins is probably similar. Clusters of basic amino acids in the COOH-terminal halves of human VEG/PF and PDGF-B are also prevalent. Thus, VEG/PF appears to be related to the PDGF/v-sis family

Neoangiogenesis, the formation of new blood vessels from a pre-existing vascular net‐ work, is essential for tumor growth, tumor proliferation and metastasis. The angiogene‐ sis process is regulated by different proangiogenic and antiangiogenic factors, being the primary stimulus of new vessel formation the hypoxia induced by expansion of the

Tumor angiogenesis is an attractive target for anticancer therapy, and a wide range of novel therapies directed against tumor vascularity has been developed. Because many antiangiogenic agents are not cytotoxic but instead produce disease stabilization, meas‐ urement of tumor size alone may be not informative regarding therapeutic effects. For that reason, there has been great interest in the use of physiologic, rather than solely anatomic, imaging techniques [60]. Tumor vascularity has different features that are char‐ acteristic of malignancy, such as spatial heterogeneity, chaotic structure, fragility and high permeability to macromolecules. These structural abnormalities of new tumor ves‐ sels lead to pathophysiologic changes within the neoplastic tissue, including an increase in capillary permeability, volume of extravascular-extracellular space, and tumor perfu‐ sion, that permit distinction of malignant from benign vascularity with functional imag‐

Several commonly available imaging modalities, including magnetic resonance (MR), com‐ puted tomography (CT), ultrasound and positron emission tomography (PET), have been used to indirectly assess the angiogenic status of human tumors [61]. But perfusion imaging with MR, and specially CT, are the most useful in clinical practice. They have the advantage of good spatial resolution, minimal invasiveness and rapid acquisition of data. Both techni‐ ques sequentially demonstrate passage of a bolus of contrast medium through a region of

interest and allow quantification of the profile of tissue enhancement.

**5. Angiogenesis and radiological assessment techniques**

The fundamental principle of perfusion CT is based on the temporal changes in tissue at‐ tenuation after intravenous administration of iodinated contrast material (CM). This en‐ hancement depends on the tissue iodine concentration, existing a direct linear relationship between contrast concentration and CT enhancement [62].

Recent progress in multidetector CT technology has enabled the rapid scanning of large ana‐ tomic volumes with high resolution. In perfusion CT, repeated series of images of the vol‐ ume analyzed are performed in quick succession before, during and after intravenous administration of CM. The ensuing tissue enhancement can be divided into two phases based on CM distribution: a initial phase where the enhancement is attributable to the distri‐ bution of contrast within the intravascular space ("first pass", lasting 40-60 secs. from the contrast arrival), and a second phase as contrast diffuses from the intravascular to the ex‐ travascular compartment across the capillary basement membrane (2-5 minutes duration). To objectively quantify the "real" perfusion parameters of tissues from the density differ‐ ence produced by the contribution of contrast material, a mathematic model is applied to the dynamic CT data. The quantitative parameters generated include blood volume (BV), blood flow (BF), mean transit time and capillary permeability surface.

Perfusion CT is a biomarker for angiogenesis that have been validated with other surrogate markers, such as VEGF levels, tumor perfusion and microvascular density (Fig 4) [63]. There has been a gradual increase of its use in oncology, ranging the wide spectrum of clinical ap‐ plications of this technique, from lesion characterization, (differentiation between benign and malignant lesions), to prognostic information based on tumor vascularity and monitor‐ ing therapeutic effects of chemoradiation and antiangiogenic drugs. In a recent study using a 320-detector row CT, Ohno et al. concluded that perfusion CT has the potential to be more specific and accurate than PET/CT for differentiating malignant from benign pulmonary nodules [64]. Another study have also shown that in patients with NSCLC treated with sora‐ fenib and erlotinib, early changes in tumor blood flow were predictive of objective response and tended to indicate a longer progression-free survival [65].

**Figure 4.** Parametric maps of perfusion CT studies representing blood flow in two different patients with NSCLC. (A) Tumor with very low perfusion depicted in blue and (B) a highly vascularized neoplasm showing yellow and red zones (scale at left).

Radiation exposure, the requirement of long breath holding during chest imaging acquisi‐ tion and lack of standardized protocols, remain potential drawbacks of this technique. How‐ ever, implementation of low-dose scanning strategies may allow a more widespread use in the future.

After proving the improvement in the response rate (RR) and progression free survival (PFS) of bevacizumab together with chemotherapy in first line in a randomized phase II study in which 99 patients with advanced or metastatic NSCLC were included [68], the ECOG group undertook a phase III trial (ECOG 4599) in first line, in which patients with brain metastasis, hemoptysis, and squamous histology were excluded, due to the risk of hemoptysis observed in the previous study with this histology [69]. The studied random‐ ized 878 patients with recurrent or advanced NSCLC to receive carboplatin/paclitaxel with or without bevacizumab on a dose of 15 mg/kg every 21 days and crossover was not allowed. The main objective, overall survival (OS), was improved in the trial arm: 12.3 months vs 10.3 months, with a hazard ratio (HR): 0.79 (95% CI: 0.67-0.92; p=0.003). In addition, the RR was also improved (35 vs 15% (p<0.001)) and the PFS went from 4.5 to 6.2 months (HR: 0.66; 95% CI: 0.57-0-77, p<0.001). However, adding bevacizumab to the chemotherapy also increased toxicity; there were 15 toxic deaths (2 in the arm of che‐ motherapy alone) due to pulmonary hemorrhage, digestive bleeding, febrile neutropenia, ictus and lung embolism. A subgroup analysis found that patients over 70 had a higher

Angiogenesis and Lung Cancer http://dx.doi.org/10.5772/54309 15

The AVAiL study [70] randomized 1043 patients to receive cisplatin and gemcitabine with or without bevacizumab in a dose of 7.5 or 15 mg/kg each 21 days. In this study the main goal was PFS, which was higher in patients which received the drug than those who took placebo, both in small dose arm (6.7 months vs 6.1 months; HR: 0.75, p=0.003) as well as in higher one (6.5 months vs 6.1 months, HR: 0.82, p=0.03). Nevertheless, OS didn't improve, which could be explained by the high percentage of patients who received treatment after‐ wards (more than 60%). Regarding toxicity, 7 patients died due to lung hemorrhage in the trial arm (2 in the control trial), although it was observed that in patients who were under

The SAiL safety study, which included more than 2000 patients, showed the effectiveness of combining other doublets of chemotherapy; in terms of safety it displayed a grade 3 or high‐

An efficiency meta-analysis published in 2011 confirms effectiveness in terms of PFS, pre‐

A meta-analysis published recently with 2210 patients evaluated the bevacizumab toxicity profile with high dose of bevacizumab (15 mg/kg), and stated that bevacizumab is related to a higher risk of toxicity deaths (HR: 2.04; 95% CI: 1.18-3.52), but it was not the case in lower doses of 7.5 mg/kg (HR: 1.20; 95% CI: 0.60-2.41). In addition, bevacizumab was associated to

More studies have been conducted in sub-populations, for example, the PASSPORT study in 109 patients with brain metastasis, subgroup that had not been included in previous studies, and which proved that bevacizumab can be administrated in patients with controlled brain metastasis [74]. Another review on the incidence of bleeding in patients with brain metasta‐ sis treated with antiangiogenic drugs proved to be safe when it is administered to treated

a greater incidence of grade 3-4 toxicities, especially in the group of high doses [73].

patients as well as patients with metastasis that appears during treatment [75].

incidence of grade 3-5 toxicities (87 vs 61%).

anticoagulant treatment there was no lung hemorrhage.

senting uncertainty in terms of improvement of OS [72].

er lung hemorrhage incidence only in 1% of the patients [71].
