**3. New techniques in imaging of renal tumors**

The introduction of functional imaging techniques have allowed us to study in vivo physio‐ logical processes of tissues and tumors. Techniques such as computed tomography (CT) or magnetic resonance (MR) allow us to study tumor perfusion (angiogenesis). Positron emis‐ sion tomography (PET) scan or spectroscopy RM is useful in the evaluation of tumor metab‐ olism while difusion RM allows the study of the diffusion of water molecules through the diffusion sequences (cellularity) to assess hypoxia phenomena or changes in the lymph no‐ des function. All these techniques can obtain information on the tumor microenvironment, including levels of oxygenation, tumor cell proliferation or vascularization and open a dif‐ ferent dimension in the study of patients: diagnosis, staging, treatment planning, evaluation of response or follow-up [42] [43].

For example, dynamic techniques (MRI or CT) seem most appropriate for assessing antivas‐ cular drug response or acting in the VEGF/ PDGFR pathway, such as bevacizumab, whose mechanism of action appears to focus on normalization of tumor vascularization [Jain 2005], while the PET appears to do better in the case of drugs such as cetuximab, acting in the EGFR pathway [44] [45] [46].

### **3.1. Perfusion-CT**

Perfusion CT is based on the temporal change of the attenuation of tissues after intravenous administration of iodinated contrast. This study consists of two phases. The first phase lasts between 40 and 60 seconds in which the enhancement is mainly due to the contrast distribu‐ tion in the intravascular space and its rapid passage to the extracellular space. This phase requires high temporal resolution (one acquisition per second). In the second phase the con‐ trast enhancement depends on its distribution between intra-and extravascular compart‐ ments. In this period the acquisition in more spaced and lasts between 2 and 5 minutes [47] [48] [49,50].

This functional technique can be used to measure a number of parameters including vascu‐ lar blood flow, blood volume, mean transit time, peak enhancement, time to peak enhance‐ ment and capillary permeability. Several studies have validated functional CT data as a biomarker of angiogenesis [47] [51]. There is growing interest on the use of CT perfusion in oncology with multiple applications that may be helpful: differential diagnosis between be‐ nign and malignant neoplasms, identifying tumors of unknown origin (with impaired liver perfusion with occult metastatic disease), definition of prognosis (with best response in tu‐ mors with more perfusion), monitoring response to treatment and development of new drugs (Figures 8 and 9) [50]. The technique is being applied in multiple tumor types: head and neck, lung, liver, pancreas, colorectal cancer, lymphoma and prostate.

**Figure 9.** Renal Cancer with diffuse metastatic disease (black arrows) in a 58 year-old female patient. Pre-therapy (left column) and 10 days post-sunitinib (right column). Axial CT images, blood flow (BF) parametric maps, and curves timedensity show a partial response with disappearance of some metastatic foci, necrotic changes in many of them, a change in enhancement curve (white arrows) and a BF decrease by 95% in tumor. Courtesy Dr. García Figueiras.

Imagen Thecniques in Renal-Cell Carcinoma http://dx.doi.org/10.5772/54190 57

Other functional imaging techniques not specifically focused on the study of angiogenesis, such as diffusion MRI, enabling the study of tumor cellularity and having quantitative pa‐ rameters such as the apparent diffusion coefficient (ADC). Thus, tumors with high cellulari‐ ty show low ADC [52] [53]. Moreover, since tumor response is associated with destruction of tumor cells, it is generally associated with increased ADC tumor lesions. The diffusion thus evaluate the apoptotic and necrotic effect but not angiogenesis, main target of new

Preliminary studies have shown significant changes very early in the flow, blood volume and perfusion with tumor therapy. There is a relationship between changes in Ktrans, Kep and the area under the curve and the response in different tumors, showing a very marked functional changes in the vascular supply to the tumor [54] [55]. Therefore these techniques could be worth to select those patients who will respond to drugs with an early evaluation

In a subgroup of patients enrolled in the phase II study discontinuation of sorafenib, DCE-MRI was performed before and after initiation of treatment. Radiological response by RE‐ CIST criteria was observed in 4/17 patients (ORR 24%), and time to progression was 12.9 months. Ktrans decreased significantly during treatment with sorafenib (60.3% decrease,

**3.2. DCE-MRI**

drugs.

of the response using functional imaging.

**Figure 8.** Renal Cancer. Liver metastasis treated with temsirolimus. Axial CT image (A) and blood volume (B) and blood flow (C) parametric maps show low perfusion parameters in metastasis. Courtesy Dr. García Figueiras.

**Figure 9.** Renal Cancer with diffuse metastatic disease (black arrows) in a 58 year-old female patient. Pre-therapy (left column) and 10 days post-sunitinib (right column). Axial CT images, blood flow (BF) parametric maps, and curves timedensity show a partial response with disappearance of some metastatic foci, necrotic changes in many of them, a change in enhancement curve (white arrows) and a BF decrease by 95% in tumor. Courtesy Dr. García Figueiras.

## **3.2. DCE-MRI**

For example, dynamic techniques (MRI or CT) seem most appropriate for assessing antivas‐ cular drug response or acting in the VEGF/ PDGFR pathway, such as bevacizumab, whose mechanism of action appears to focus on normalization of tumor vascularization [Jain 2005], while the PET appears to do better in the case of drugs such as cetuximab, acting in the

Perfusion CT is based on the temporal change of the attenuation of tissues after intravenous administration of iodinated contrast. This study consists of two phases. The first phase lasts between 40 and 60 seconds in which the enhancement is mainly due to the contrast distribu‐ tion in the intravascular space and its rapid passage to the extracellular space. This phase requires high temporal resolution (one acquisition per second). In the second phase the con‐ trast enhancement depends on its distribution between intra-and extravascular compart‐ ments. In this period the acquisition in more spaced and lasts between 2 and 5 minutes [47]

This functional technique can be used to measure a number of parameters including vascu‐ lar blood flow, blood volume, mean transit time, peak enhancement, time to peak enhance‐ ment and capillary permeability. Several studies have validated functional CT data as a biomarker of angiogenesis [47] [51]. There is growing interest on the use of CT perfusion in oncology with multiple applications that may be helpful: differential diagnosis between be‐ nign and malignant neoplasms, identifying tumors of unknown origin (with impaired liver perfusion with occult metastatic disease), definition of prognosis (with best response in tu‐ mors with more perfusion), monitoring response to treatment and development of new drugs (Figures 8 and 9) [50]. The technique is being applied in multiple tumor types: head

**Figure 8.** Renal Cancer. Liver metastasis treated with temsirolimus. Axial CT image (A) and blood volume (B) and

blood flow (C) parametric maps show low perfusion parameters in metastasis. Courtesy Dr. García Figueiras.

and neck, lung, liver, pancreas, colorectal cancer, lymphoma and prostate.

EGFR pathway [44] [45] [46].

**3.1. Perfusion-CT**

56 Renal Tumor

[48] [49,50].

Other functional imaging techniques not specifically focused on the study of angiogenesis, such as diffusion MRI, enabling the study of tumor cellularity and having quantitative pa‐ rameters such as the apparent diffusion coefficient (ADC). Thus, tumors with high cellulari‐ ty show low ADC [52] [53]. Moreover, since tumor response is associated with destruction of tumor cells, it is generally associated with increased ADC tumor lesions. The diffusion thus evaluate the apoptotic and necrotic effect but not angiogenesis, main target of new drugs.

Preliminary studies have shown significant changes very early in the flow, blood volume and perfusion with tumor therapy. There is a relationship between changes in Ktrans, Kep and the area under the curve and the response in different tumors, showing a very marked functional changes in the vascular supply to the tumor [54] [55]. Therefore these techniques could be worth to select those patients who will respond to drugs with an early evaluation of the response using functional imaging.

In a subgroup of patients enrolled in the phase II study discontinuation of sorafenib, DCE-MRI was performed before and after initiation of treatment. Radiological response by RE‐ CIST criteria was observed in 4/17 patients (ORR 24%), and time to progression was 12.9 months. Ktrans decreased significantly during treatment with sorafenib (60.3% decrease, 95% CI 46.1 to 74.6%). The percentage decrease in Ktrans and change in tumor size was sig‐ nificantly associated with progression-free survival (p = 0.01 and 0.05, respectively).

The functional and molecular imaging techniques could offer clear opportunities in the study of renal tumors, but nevertheless, we must not forget that, for validation as bio‐ markers, would require completing a qualification and validation process, which would pass through standardization in the collection and analysis of the images and the correlation of the parameters obtained with patient outcomes. Once this is ach‐ ieved, functional-molecular techniques, especially perfusion CT, could become promis‐ ing tools in the selection of patients for targeted drug therapy and the assessment of

Imagen Thecniques in Renal-Cell Carcinoma http://dx.doi.org/10.5772/54190 59

Classically, oncology response evaluation is based on comparison of pre and post-treatment tumor volume by studying changes in the diameter of the tumors. RECIST criteria in its original version and its 2009 Update 1.1 are applied routinely in oncology practice [2]. How‐ ever, it is recognized that the response evaluation focused exclusively on size changes have important limitations, including the importance of excluding changes in tumor metabolism or not considering the appearance of necrosis or fibrosis as a factor which may be related to response to treatment. Furthermore, the introduction of new drugs creates the need for a

The limitations of traditional approaches, as the criteria of the World Health Organiza‐ tion (WHO) or Response Evaluation Criteria in Solid Tumors (**RECIST**) in the evaluation of targeted therapies have been widely documented [64] [65] [57]. Therapies that act on tumor vascularity may have underestimated clinical benefit by tumor size change since their mechanism of action (more cytostatic that cytotoxic), produces more stabilization

Without abandoning the use of size criteria as a key element in the assessment of patients with metastatic renal cancer, some authors have attempted to obtain early information (**EP‐ TIC**, Early English Post-herapy Imaging Changes) [66] on the prognosis of patients treated with therapy acting at the VEGF pathway. In this regard, it was demonstrated that a 10% decrease in the sum of the largest diameters of the lesions in the first control, provides infor‐ mation on the subsequent course of patients. Using only tumor size as endpoint criterion

Subsequently it was observed a relationship between the degree of tumor enhancement be‐ fore therapy and the likelihood of response (being higher in those tumors with greater pre‐ treatment enhancement). Many of these new drugs induce tumor necrosis, causing a dramatic drop in the enhancement of metastatic lesions in the post-therapy evaluation [67]. Based on these observations and on previous experience with gastrointestinal stromal tu‐ mors treated with imatinib, a set of tumor response criteria based on changes in size and / or density tumor was established: Choi criteria, modified Choi criteria, MASS criteria and

the response [57] [58].

than tumoral responses.

SACT criteria (Table 1) [56].

would leave aside the use of IV contrast.

**5. Criterios RECIST/MASS/CHOI**

different evaluation of the tumor and treatment response [46].

### **3.3. PET**

Finally, molecular techniques such as PET show a limited role in the study of metastatic re‐ nal cancer, since this tumor usually has a low activity of glucose metabolism (pathway as‐ sessed by 18F-fluorodeoxyglucose, the most widely used radiotracer). Only in cases where the tumor shows an increased metabolism of glucose, PET may be useful in the assessment of the disease and its response to therapy. Other radiotracers that allow the study of impor‐ tant characteristics such as tumor hypoxia, cell proliferation or angiogenesis itself, are still under evaluation and implementation in clinical practice [56]. In an experimentally way it is evaluating the introduction of functional imaging techniques in clinical studies, to develop translational research in oncology imaging applications. In a NCI trial, Dr. Hoffman (Uni‐ versity of Utah) is using DCE-MRI and various types of PET (H2150-PET, FDG-PET, FDL-PET) in monitoring response to multi-targeted treatment in renal cancer patients.
