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Imaging techniques as predictive and prognostic biomarkers in renal cell carcinoma:

Imaging techniques as predictive and prognostic biomarkers in renal cell carcinoma: 463624 TAM521758834012463624Therapeutic Advances in Medical OncologyP Nathan and A Vinayan Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Imaging techniques as predictive and (2013) 5(2) 119 –131 DOI: 10.1177/ prognostic biomarkers in renal cell 1758834012463624 © The Author(s), 2012. Reprints and permissions: carcinoma http://www.sagepub.co.uk/ journalsPermissions.nav Paul Nathan and Anup Vinayan Abstract: A number of imaging modalities are showing promise as predictive and prognostic biomarkers in advanced renal cell carcinoma. This review discusses progress to date in this exciting area and identifies areas of future promise. Keywords: biomarkers, imaging, prediction, prognosis, renal cell carcinoma Correspondence to: Introduction Predictive biomarkers Paul Nathan, PhD, FRCP Therapeutic options for patients with advanced Validated tools, which could predict clinical ben- Mount Vernon Cancer Centre – Medical Oncology, renal cell carcinoma (RCC) have dramatically efit from a therapy, would lead to significant Rickmansworth Road, improved over the last few years with the advent improvements in clinical management. Early Northwood, Middlesex HA6 2RN, UK of a number of novel agents targeting both tumour identification of responders, nonresponders or nathan.pd@gmail.com vasculature and tumour growth. Sunitinib [Motzer subpopulations of patients at risk for side effects Anup Vinayan, MRCP et al. 2007b], bevacizumab in combination with would help to identify patients who have great- Mount Vernon Cancer Centre – Medical interferon [Escudier et al. 2007b], temsirolimus est or least benefit from a specific intervention. Oncology, Northwood , [Motzer et al. 2007a], sorafenib and everolimus Predictive biomarkers would therefore help to Middlesex, UK [Motzer et al. 2008] have all become standard avoid exposing patients to the risk of unnecessary agents for the treatment of this disease. side effects from treatments from which they would be destined to derive little or no benefit. There is a clinical need to identify which patients are likely to derive most and least benefit from There are now a significant number of new thera- targeted therapies early in the course of treat- pies which have proven to be clinically effective, ment, that is, to predict response, and to identify but which have not succeeded in passing health– which patients have aggressive or indolent disease, economic assessments by reimbursement author- that is, to determine prognosis. ities. The cost-effectiveness analyses that bodies such as the National Institute for Health and RCC is highly vascular, driven at least in part by Clinical Excellence perform would be signifi- the frequent overexpression of vascular endothe- cantly impacted upon if it were possible to iden- lial growth factor (VEGF) [Nicol et al. 1997]. As tify subpopulations of patients who would derive all of the new therapeutic agents appear to have at most benefit from the drugs. This would lead to least some effect upon tumour vasculature, imag- a greater possibility that new therapies would be ing modalities that provide a quantitative assess- available for patients once efficacy had been ment of the change in vascularity may have a demonstrated. particular role in this disease. Imaging-defined response evaluation criteria in This review discusses imaging modalities that have solid tumours (RECIST) [Therasse et al. 2000] shown promise as either predictive or prognostic have been the basis of treatment response assess- tests in advanced RCC and identifies areas of ment in oncology since their introduction. The future opportunity. criteria were developed and validated to assess http://tam.sagepub.com 119 Therapeutic Advances in Medical Oncology 5 (2) responses to conventional therapies such as semiquantitative data related to blood flow and chemotherapy and radiotherapy rather than the some can also provide information on blood vol- new generation of targeted agents. RECIST crite- ume, cellularity or vessel permeability. DCE imag- ria are based upon change in size of target lesions. ing techniques such as DCE-MRI, DCE-CT and However, antivascular agents appear to be fre- DCE-US use exogenous contrast agents to differ- quently clinically active without inducing the sig- entiate vascular characteristics, while other MRI nificant size change required for a RECIST-defined techniques as ASL-MRI and DW-MRI use the response. No imaging modality has yet been vali- inherent changes in magnetic resonance between dated that can predict the treatment response of tissues without the use of an external contrast RCC treated with targeted therapies. agent. The latter group has a potential advantage as 20–30% of patients with RCC have impaired Primary RCC and its metastases are noted to be renal function, which increasingly precludes the highly vascular and are associated with an upreg- use of exogenous contrast agents. ulation of VEGF. Most sporadic and familial clear cell RCCs have an inactive VHL gene prod- Dynamic contrast-enhanced imaging techniques. uct either because of bi-allelic alterations in the Dynamic functional imaging using exogenous gene or post-transcriptional modification. Lack of contrast media centres on quantitative analysis of functional VHL gene product results in stabiliza- biodistribution of contrast media in tissues. These tion of hypoxia inducible factor (HIF) 1, 2 and techniques use the difference in pharmacokinetics increased transcription of factors such as VEGF of the contrast agent between tissues and tumour and platelet-derived growth factor. Activation of to provide tumour-specific and tissue-specific multiple pathways driven by these and other fac- information [Marcus et al. 2009]. tors results in increased angiogenesis in these tumours. This is thought to underpin the signifi- DCE-MRI as a biomarker of angiogenesis has cant clinical activity of antiangiogenic targeted been tested and validated over the last decade in therapies in RCC. Imaging techniques that can a variety of tumours. The gold standard correla- assess vascularity and changes in vascularity of tion was with immunohistochemical microves- these tumours may therefore have potential to be sel density measurements. Investigators have useful as predictive biomarkers. attempted to correlate imaging with tissue expres- sion of proangiogenic growth factors including VEGF (broad correlations in some studies and no Assessment of changes in vascularity correlations in others) [Padhani and Dzik-Jurasz, The gold standard for assessing vascularity and 2004; Schlemmer et al. 2004]. angiogenesis in a tumour is by measuring the mean vascular density, which is performed by counting The relationship between contrast concentration vascular structures directly with histology. This and signal intensity is complex and nonlinear in technique has limitations as it is invasive and can- DCE-MRI [Kiessling et al. 2007]. Along with the not be performed repeatedly to assess treatment concentration, it also depends on the imaging response in humans. Also, as it does not explore sequence used, machine setup, inherent hetero- the whole treatment volume, there is an increased geneity of the tumour and native relaxation rate chance of sampling error due to tumour heteroge- of the tissues [Padhani, 2003]. neity [Lebret et al. 2007; Renshaw et al. 1997]. The rate of delivery and washout of contrast media A number of clinically applicable functional imag- into the tumour vasculature bed depends on sev- ing techniques are capable of quantitatively assess- eral physiological characteristics of the tumour ing the vascularity of tumours in vivo pre and post vascular microenvironment. Depending on the treatment. These techniques include dynamic techniques used, parameters such as K (trans- trans contrast-enhanced magnetic resonance imag- fer constant, related to the influx of contrast agents ing (DCE-MRI), dynamic contrast-enhanced from plasma to the tumour interstitial space), Kep computed tomography (DCE-CT), dynamic (efflux of agents back to the vasculature), Ve contrast-enhanced ultrasound (DCE-US), dif- (effective volume of distribution), rBF (relative fusion-weighted MRI (DW-MRI), arterial spin blood flow), rBV (relative blood volume), IAUGC label MRI (ASL-MRI) and positron emission (initial area under gadolinium curve) can be tomography (PET) with oxygen-labelled water. obtained. The values are then fitted with statisti- Each of these techniques provides quantitative or cal models for analysis. 120 http://tam.sagepub.com P Nathan and A Vinayan In 2008, Flaherty and colleagues published a antiangiogenic agents. A total of 539 patients pilot study, which used DCE-MRI assessment with different tumour types including 157 patients in patients with metastatic RCC treated with with RCC were recruited from 19 centres in sorafenib. This study showed that inhibition of France. Perfusion parameters were collected from tumour vascular permeability by sorafenib, dem- these patients with DCE-US at baseline, on day onstrated by a reduction in K , was associated 7, day 14, day 30, day 60 and 2 monthly thereaf- trans with improved progression free survival (PFS) ter. This was correlated to the RECIST assess- (p = 0.01). Elevated baseline K was a statisti- ment performed 2 monthly. They showed that a trans cally significant predictive marker for favourable decrease in area under the curve (AUC) by more response to treatment (p < 0.02) [Flaherty et al. than 40% at 1 month was predictive of response 2008]. A prospective randomized phase II study for time to progression (TTP) (p < 0.01) and OS again with sorafenib in RCC by Stadler and col- (p < 0.04) [Lassau et al. 2012]. leagues also showed a good correlation of high baseline K with improved PFS (p < 0.027). In A simultaneous study with DCE-US from Toronto trans this study, however, change in K or IAUGC by Williams and colleagues in 17 patients with trans 90 were not significantly related to PFS [Hahn et al. metastatic RCC treated with sunitinib showed a 2008]. Further trials are underway to evaluate the decrease in median tumour fractional blood vol- use of DCE-MRI in RCC. ume by 73.2% after 2 weeks of treatment with a disruption-replenishment infusion method of Most modern MRI scanners have the ability to microbubble and a significant decrease in bolus perform these image acquisitions but there are peak with the bolus method. In this study no defi- several limitations to widespread use. Imaging nite correlation was noted with best response as protocols need to be optimized according to the assessed by RECIST [Williams et al. 2011]. area to be scanned and the type of tumour being analysed. The appropriate software needs to be US is a widely available and inexpensive technique. available and there also remain issues regarding Therefore performing frequent and serial examina- quantification, tumour heterogeneity and motion tions at short intervals is possible when using this artefact. Low molecular weight gadolinium, technique. However, the main problem with US is which is used as standard, has a limitation as the limited ability to penetrate through large areas these small agents rapidly leak out of the highly of tissue when trying to image deeply located permeable vasculature in the tumour. This in tumours, and more specifically, the inability to turn affects the data acquisition in dynamic imag- penetrate through air or bone. Because RCC fre- ing as this is defined by vascular permeability and quently metastasizes to the lung and mediastinum, tumour perfusion. Gadolinium in higher molecu- the use of DCE-US in large cohorts of patients is lar weight conjugates could be used to overcome unknown. A potential advantage of DCE-US is the this problem, as these are less sensitive to vascular fact that the microbubbles are intravascular and permeability. therefore, in theory, the quantification of tumour perfusion should not be affected by vessel perme- Lamuraglia and colleagues used DCE-US along ability. However, the technique tends to be more with a new perfusion software as a predictive operator dependent and those with the relevant tool in metastatic RCC [Lamuraglia et al. 2006]. skills are not available in all locations. Thirty patients who were enrolled in a randomized clinical trial comparing sorafenib with placebo To date, no studies have been published using were recruited. DCE-US examination was per- DCE-CT as a tool for treatment response predic- formed at baseline, week 3 and week 6. The good tion in RCC. This technique does hold promise responders were defined by a combination of a as the concentration kinetics of the contrast are decrease in contrast uptake greater than 10% and a related directly and linearly to enhancement and stable or decrease in tumour size. The responders analysis is therefore relatively straight forward identified at week 3 had a statistically significant [Miles, 2002]. However, there is little general improvement in PFS (p < 0.0004) and overall sur- agreement about the techniques to use for model- vival (OS) (p < 0.0004) over the nonresponders. ling and further quantitative analysis. Evidence from rectal carcinoma showed that baseline blood A recent prospective multicentre study by Lassau flow and blood volume were significantly lower in and colleagues investigated the use of DCE-US nonresponders compared with responders treated as a predictive biomarker in patients treated with with chemoradiotherapy [Bellomi et al. 2007]. http://tam.sagepub.com 121 Therapeutic Advances in Medical Oncology 5 (2) The study also showed a significant decrease in diffusion depending on the Brownian motion of blood flow, blood volume and permeability sur- the water molecules in tissues. Desar and col- face area product post treatment. CT scanning is leagues noted that sunitinib-induced antiangio- the commonest tool used at present to monitor genic effects in RCC can be reliably measured treatment response, therefore it would be a prac- with DW-MRI as early as 3–10 days after starting tical and easy option to incorporate DCE-CT the treatment [Desar et al. 2011]. This needs fur- protocols in almost all centres once a general ther evaluation before it can be reliably used as a agreement is obtained and the technique is vali- predictive biomarker. There are as yet no pub- dated further. lished data with either of these techniques to pre- dict responses in RCC to targeted therapies. Imaging techniques that use no external contrast agent. A number of MRI techniques which do not resort to an external contrast agent have been Assessment of change in metabolic activity developed and are being assessed as biomarkers Fluorodeoxyglucose (FDG)-PET/CT scan is a of treatment response. Between 20% and 30% valuable tool, which has already established its of patients with RCC are unable to have exter- role in the assessment and management of many nal contrast due to renal impairment and tech- tumour types. By combining a short-lived radioac- niques that do not resort to external contrast are tive tracer with a biologically active molecule, thus valuable[Nathan et al. 2010]. These tech- PET scan provides a functional map of the disease niques use the magnetic field to modify the investigated. The most common biological mole- magnetic properties of the tissue including the cule used in oncology is FDG. This glucose ana- tumour. logue is rapidly and preferentially taken up by the rapidly growing malignant cells, thus leading to ASL-MRI uses the inherent nuclear spin of intense radiolabelling of that tissue. A combined endogenous water protons to label arterial blood. CT and PET scan provides a combination of met- Quantitative images of blood flow to the tissue can abolic activity with anatomical localization of tis- be generated by differential labelling inside and sues. The use of FDG-PET/CT in treatment outside the tissue of interest. The technique has response assessment, that is, as a predictive marker potential to be used as a quantitative marker for in RCC, looks promising but has not been fully response assessment to antivascular treatment. evaluated. A recent study by Powles and col- The feasibility of this technique to monitor leagues looked at the use of sequential FDG-PET response to antiangiogenic therapy in RCC scanning as a correlative marker of OS in patients metastases was demonstrated by de Bazelaire with RCC treated with sunitinib [Powles et al. and colleagues [de Bazelaire et al. 2005]. In a 2010]. A total of 44 patients were enrolled in phase II trial of 10 patients, ASL-MRI and this phase II study. Patients had three FDG- DCE-MRI were used to assess the treatment PET scans: before treatment, at 4 and 16 weeks. response in patients with metastatic RCC Reduction in maximum standardized uptake value treated with an antiangiogenic agent (PTK787/ (SUVmax) by 20% was considered a response and ZK222584). The study showed that changes in was correlated with OS. The study showed that blood flow detected by ASL-MRI at 1 month high baseline SUVmax suggested a trend towards correlated with the change in tumour size low OS [hazard ratio (HR) 3.30; 95% confidence measured at 4 months or at disease progression interval (CI) 1.36–8.45]. Metabolic response was (p < 0.01) [de Bazelaire et al. 2008]. If validated noted on the PET scan after 4 weeks. However, in larger studies, ASL-MRI thus might prove to disease progression according to the 16-week scan be an important biomarker in early assessment correlated with a decreased OS (HR –5.96; 95% of treatment response. CI –2.43 to +19.02). Techniques such as blood oxygen level dependent Similar results were noted in smaller trials of 12 MRI (BOLD-MRI) and DW-MRI which use no patients and 14 patients by Minamimoto and external contrast are other methods with poten- Revheim and colleagues respectively [Minamimoto tial to predict treatment response. BOLD-MRI et al. 2010; Revheim et al. 2011]. Using a 20% uses the difference in magnetic properties of oxy- reduction in FDG-PET uptake, Minamimoto and haemoglobin and deoxyhaemoglobin and hence colleagues were able to separate good responders BOLD signals are related to tumour hypoxia. with a mean PFS of 233.8 days and poor respond- DW-MRI evaluates the property of water ers with a PFS of 75 days. 122 http://tam.sagepub.com P Nathan and A Vinayan A pharmacodynamic study using serial 3deoxy3’ progressive disease. According to the Choi crite- fluorothymidine PET (FLT-PET) scans on ria, these numbers were 36, 6 and 13 respectively. patients at baseline, during treatment with suni- In patients having a partial response, the Choi cri- tinib and after withdrawal of drug within cycle 1 teria had a significantly better predictive value for showed an increase in cellular proliferation dur- PFS and OS (p < 0.001 for both) than RECIST ing sunitinib withdrawal [Liu et al. 2011]. This is (p = 0.689 and 0.191 respectively). The predic- noted to associate with VEGF ligand levels and tive value of RECIST increased to a statistically early exploratory analysis suggests that the extent significant level only when best response during of flare could predict poorer clinical benefit from treatment was taken into account. the drug. The Choi criteria and RECIST were again com- pared with a smaller cohort of 22 patients treated New criteria for response assessment with sorafenib reported by Hittinger and colleagues RECIST criteria depend upon the change in sum [Hittinger et al. 2011]. Even though the Choi cri- of the unidimensional measurements of target teria defined more patients as responders, they lesions. However, the clinical benefit does not did not differentiate between patients who did always correlate with change in size alone in and those who did not have therapeutic improve- tumours treated with targeted therapies. Emerging ments in PFS or OS. evidence shows that some patients continue to derive clinical benefit from continuation of suni- ’Modified’ Choi criteria. We proposed a modifi- tinib after documented disease progression based cation of the Choi criteria in the assessment of on RECIST criteria [Teo et al. 2012]. This retro- treatment response to targeted therapy in meta- spective analysis of 39 patients treated with suni- static RCC in which both a change in size and tinib showed that such use of a tyrosine kinase density are required [Nathan et al. 2010]. The inhibitor (TKI) beyond progression gives pro- standard Choi criteria require a decrease in size longed disease control and is safe. The use of by 10% or a decrease in CT contrast enhance- RECIST alone as a measure of treatment response ment by 15% for a response. We suggested a is therefore arguable. modification of the Choi criteria in which both a minimum 10% size decrease and a 15% reduc- Choi criteria. Choi proposed an alternative set of tion in enhancement are required to define a criteria for the assessment of gastrointestinal stro- response. We performed a retrospective study of mal tumours (GIST) treated with the targeted 32 patients with metastatic RCC treated with agent imatinib [Choi, 2008; Choi et al. 2007]. TKIs. Twelve patients were excluded as they did The Choi criteria require either a change in size not have contrast-enhanced scans due to renal or a change in density (contrast enhancement) to dysfunction. Both baseline and 12-week post- predict a response. They have been found to be treatment contrast-enhanced scans were collected more reliable than RECIST in monitoring GIST and analysed. According to the response obtained responses to treatment using PET-CT as a gold on the 12-week scan, patients were assigned to standard. It has been suggested that the Choi cri- progressive disease, stable disease or partial teria could be suitable for assessment of targeted response using RECIST, Choi and modified therapies in other cancers, but this has not yet Choi criteria, correlated with TTP. Patients who been extensively evaluated. had a partial response according to the modified Choi criteria had a statistically significant longer In renal cancer, van der Veldt and colleagues have TTP than those who were deemed to have sta- analysed the use of Choi criteria in treatment ble disease (mean 448 versus 89 days, p = 0.002). response assessment in RCC and found them to Neither RECIST nor Choi criteria defined par- correlate better to TTP than RECIST [van der tial responders went on to have a significant Veldt et al. 2010]. A total of 55 patients with meta- improvement in TTP compared with those static RCC treated with sunitinib were analysed who had stable disease. Further larger trials are retrospectively. The pretreatment and first evalua- planned to validate these results. CT enhance- tion post-treatment scan were analysed with ment was measured in the arterial phase rather RECIST and Choi criteria separately and corre- than in the more usual portovenous phase in this lated with PFS and OS. At first evaluation, study. This may be relevant as renal tumours are according to the RECIST criteria, seven patients highly vascular and enhance well in the arterial had a response, 38 had stable disease and 10 had phase [Lee et al. 2005; Raptopoulos et al. 2001]. http://tam.sagepub.com 123 Therapeutic Advances in Medical Oncology 5 (2) Size and attenuation CT criteria/morphology, attenu- changes, which did not fit in with these criteria ation, size and structure criteria. Another study were classified as an indeterminate response. The exploring the use of a combination of change in MASS criteria showed an increased sensitivity of size and CT attenuation to predict treatment 86% and specificity of 100% in recognizing good response in metastatic RCC was published by responders (TTP and improved disease specific Smith and colleagues [Smith et al. 2010a]. Con- survival p < 0.0001). trast-enhanced CT scans of 53 patients with met- astatic RCC treated with either sunitinib or The group further recommended that the combi- sorafenib were analysed. In calculating the attenu- nation of memorial sloan kettering cancer centre ation data, Smith and colleagues used volumetric (MSKCC) criteria and MASS criteria together mean attenuation of target lesions in place of mean could give a high overall accuracy in identifying attenuation in the most representative axial image. patients with PFS less than 1 year or at least 1 They proposed new imaging criteria, size and year [Smith et al. 2011]. attenuation CT (SACT) criteria. The criteria defined favourable response as any of the follow- Tumour burden and growth rate. Basappa and ing: a decrease in tumour size of at least 20%; a colleagues investigated the effect of tumour bur- decrease in tumour size of at least 10% and at least den (TB) with treatment with VEGF-targeted half of nonlung target lesions with decreased mean therapy. Sixty-nine patients were retrospectively attenuation of at least 20 Hounsefield units (HU); analysed. Median TB and site of metastasis were or one or more lung lesions with decreased mean examined. With multivariate analysis, at baseline, attenuation by at least 40 HU. Unfavourable the total number of metastases (<10) and the TB response was defined as any of the following: an above the diaphragm (<6.5 cm) were independent increase in tumour size of at least 20%; new metas- positive predictors of OS [Basappa et al. 2011]. tasis; marked central fill in of a target lesion; or new TB (p = 0.003) and total metastases (≤12) were enhancement in a homogenously hypoattenuating noted as predictors of OS at TTP. nonenhancing mass. A comparison was made between the SACT criteria, RECIST criteria and a Initial tumour size and the rate of size reduction modification of the Choi criteria (with volumetric in response to targeted therapy were predictive attenuation data of the whole tumour rather than markers reported by Yuasa and colleagues[Yuasa mean attenuation in an axial slice) in predicting a et al. 2011]. In this 139-patient retrospective PFS greater than 250 days in this patient popula- analysis, a linear, moderate to strong association tion. The favourable response defined by the SACT was noted between the pretreatment tumour size criteria had a sensitivity of 75% and a specificity of and reduction in growth rate on therapy (correla- 100% in identifying patients with PFS greater than tion coefficient –0.441, p < 0.001). When a thresh- 250 days. These values were 16% and 100%, and old value of 23.9 mm was applied, it was noted 93% and 44% for the RECIST criteria and volu- that the smaller tumours showed a better rate of metric modified Choi criteria, respectively. shrinkage (p < 0.001). The same group attempted to improve on the Use of tumour growth rate (TGR) was retrospec- SACT criteria by including specific morphologic tively analysed by Ferte and colleagues [Ferte or structural changes (e.g. necrosis) and eliminat- et al. 2012]. Images from patients recruited to ing the need for volumetric three-dimensional large phase III trials with sorafenib (TARGET) analysis in their new criteria [referred to as mor- and everolimus (RECORD) were assessed (n = phology, attenuation, size and structure (MASS) 902). TGR was defined as the value obtained by criteria] [Smith et al. 2010b]. According to the dividing tumour shrinkage by time between two MASS criteria, favourable response was defined as evaluations. All treatment periods, including no new lesion and any of the following: a decrease before, under treatment (at first cycle), at pro- in tumour size of at least 20%; one or more pre- gression and after treatment interruption, were dominantly solid enhancing lesions with marked noted. The results showed that the TGR under central necrosis or marked decreased attenuation treatment was significantly decreased with both (≥40 HU). An unfavourable response was defined sorafenib and everolimus. High TGR under treat- as an increase in tumour size of at least 20% in the ment was associated with poor PFS (HR 2.6) and absence of marked necrosis or marked decreased OS (HR 2.3) in patients treated with sorafenib attenuation; and new metastasis, marked central and poor OS (HR 1.2) in the smaller everolimus fill-in, or new increased enhancement. Other cohort. TGR after interruption was significantly 124 http://tam.sagepub.com P Nathan and A Vinayan higher in both sorafenib and everolimus cohorts intermediate-risk group (one or two risk factors) than TGR at progression (14.6 versus 31 and 17.9 and the poor prognostic group (more than two versus 32.1, respectively). The inclusion of TGR risk factors) were 10 months and 4 months respec- thus allows the practitioner to evaluate the tumour tively [Motzer et al. 1999]. The MSKCC criteria response more carefully. have been widely used in many phase III trials of RCC evaluating antiangiogenic agents either to The threshold of tumour response as change in stratify patients in trial analysis [Escudier et al. sum of longest diameter (∆SLD) to mammalian 2007b; Motzer et al. 2007b, 2008] or to define target of rapamycin inhibitor everolimus was entry criteria in other trials [Escudier et al. 2007a; investigated by Oudard and colleagues [Oudard Hudes et al. 2007]. et al. 2012]. The data from the phase III RECORD-1 trial were analysed and a series of Evidence from these trials showed that the benefi- arbitrary thresholds were identified to attempt to cial effects of these drugs were maintained across distinguish responders from nonresponders. With prognostic groups but were significantly greater response defined by the optimal threshold of in good and intermediate prognostic groups. –5%∆SLD, the median PFS was 8.4 months for Hence prognostic grouping of RCC has an impor- the responders and 5.0 months for the nonre- tant role in selection of treatment and also in sponders (HR 2.4). determining the time of introduction of systemic treatment. Imaging techniques can potentially act as noninvasive tools in identifying these prognos- Prognostic biomarkers tic factors. These include assessment of histologi- Imaging biomarkers that provide an insight into cal subtype, nuclear grading and in the accurate the natural course of the disease are of potential staging of disease. use in identifying patients who are most or least likely to benefit from treatment as well as in inter- preting clinical trials. The prognosis of any malig- Assessment of histological subtypes nancy could be related to a variety of factors. There has been debate as to whether prognosis of RCC is a heterogeneous group of diseases. There RCC varies significantly with histological sub- are a number of histological subtypes and within type. Studies have in part been hampered by each subtype there is a widely varying natural his- small numbers of the rarer subtypes and associ- tory between patients. Some tumours are very ated lack of control for other prognostic factors. aggressive while others remaining indolent. Some RCC can be subclassified according to histology patients experience stable metastatic disease for a as clear cell, papillary type I and II, chromophobe, significant period of time that does not require sarcomatoid, collecting duct and a variety of systemic treatment until progression is seen. very rare and unclassified subtypes(World Health Organization classification) [Ebele et al. 2004; Several clinicopathological prognostic models are Kovacs et al. 1997]. The clear cell (conventional) designed to assess survival in the postnephrec- subtype is the most common and accounts for tomy [Leibovich score, University of California, approximately 70% of cases. The papillary sub- Los Angeles (UCLA) score] [Leibovich et al. type accounts for around 15–20% of cases. The 2005; Zisman et al. 2001] and metastatic setting type II papillary and other subtypes are less (Motzer score, UCLA score) [Motzer et al. 1999]. common. There is good evidence that tumours These prognostic models use histological fea- with sarcomatoid elements have a poorer prog- tures, including Fuhrman grade and necrosis, nosis than the majority of tumours without performance status and a variety of biochemical [Cangiano et al. 1999]. markers for categorization into prognostic groups. With the emerging possibility that treatment deci- The MSKCC (Motzer) criteria classified patients sions may be influenced by histological subtype, into good, intermediate and poor prognostic together with the fact that core biopsy is associ- groups depending on five factors: primary ated with diagnostic inaccuracy [Lebret et al. tumour remaining in situ, Eastern Cooperative 2007] a noninvasive technique to assess histologi- Oncology Group performance status, anaemia, cal subtype would be of potential clinical value. A lactate dehydrogenase level and hypercalcaemia. number of different imaging modalities have been Median survival in patients with zero risk fac- assessed for this purpose. These include multi- tors was 20 months but median survival in the slice CT, DW-MRI and DCE-MRI. http://tam.sagepub.com 125 Therapeutic Advances in Medical Oncology 5 (2) Sheir and colleagues attempted to use multislice the papillary subtype with good sensitivity (80%) CT to differentiate histological subtypes. They and specificity (94%). reviewed 87 CT images of patients with RCC ret- rospectively and compared them with histopathol- Sun and colleagues explored the use of DCE-MRI ogy. Biphasic CT scans of the kidneys were as a tool in predicting the histopathological sub- performed using unenhanced, corticomedullary type of RCC. They compared the difference in phase (CMP) and excretory phase (EP) (30 and enhancement pattern in CMP and nephrographic 300 s after contrast injection respectively) proto- phase images with histopathology. In both the cols. It was noted that the degree of enhancement CMP and nephrographic phase, clear cell tumours in the CMP and EP was the most valuable param- showed maximum signal intensity change and eter in attempting to differentiate between histo- papillary tumours the least. Signal intensity change logical subtypes (p < 0.001). Mean CT attenuation in the CMP was the most effective parameter dif- (+2 standard deviations) in the CMP was 138.2 ± ferentiating clear cell and papillary subtypes with a 38.0 HU for clear cell, 89.2 ± 31.4 HU for papil- sensitivity of 93% and a specificity of 96% [Sun lary and 55.17 ± 24.0 HU for chromophobe et al. 2009]. DCE-MRI was also useful in predict- tumours. In the excretory phase, clear cell tumours ing the nuclear grade of the tumour as reported by showed an enhancement of 73.0 ± 17.6 HU while Palmowski and colleagues. Twenty-one patients papillary and chromophobe had an enhancement were analysed with DCE-MRI presurgically; of 70.0 ± 10.4 and 33.9 ± 12.1 HU respectively. tumour perfusion and tissue–blood ratio were The difference between subtypes in both the CMP noted for the entire tumour and also for the most and EP was statistically significant (p < 0.001). highly vascularized area in the tumour. Higher The cutoff value for highest accuracy for diagnosis grade tumours had significantly higher perfusion of clear cell carcinoma was 83.5 HU for CMP and values (p < 0.05) in the most vascular area [2.14 ± 64.5 HU for EP. Other factors such as presence or 0.89 versus 1.40 ± 0.49 ml/g/min) and the entire absence of cystic degeneration, tumour vascularity tumour (1.59 ± 0.44 versus 1.08 ± 0.38 ml/g/min) and pattern of enhancement also supplemented [Palmowski et al. 2009]. this differentiation [Sheir et al. 2005]. These imaging techniques are of interest, how- Pedrosa and colleagues attempted evaluation of ever their use in clinical practice will require much malignant renal tumours with the help of noncon- more robust validation and they are unlikely to trast-enhanced and contrast-enhanced MRI and replace the use of histological diagnosis in the correlated this with histology. The study cohort near future. consisted of 76 patients who had both MRI and histological confirmation [Pedrosa et al. 2008]. Renal masses were analysed for size, location, Staging of renal cell carcinoma necrosis, haemorrhage, signal intensity and uni- Accurate staging of RCC is an important factor formity of signal intensity, type and extent of fat influencing the prognosis. While CT, MRI, PET and contrast enhancement, peri-renal fat invasion and bone scans all are used routinely in staging a and renal vein thrombosis. They were then assigned variety of different cancers, there is debate regarding to one of eight different groups defined according the usefulness of some of these techniques in RCC. to MRI appearance. The results were compared with the histological analysis and the sensitivity Assessment of skeletal metastasis. Nuclear and specificity of these MRI groups were calcu- medicine (NM) bone scans with Tc99 provide lated to predict the histological diagnosis and limited anatomical detail and only provide infor- nuclear grade. The MRI classification had a sen- mation about tumour deposits where an osteoblas- sitivity of 93% and specificity of 75% for the diag- tic reaction has occurred. RCC bony metastases nosis of clear cell subtype, using the presence of are predominantly osteoclastic, resulting in a low solid enhancing mass with or without necrosis. sensitivity of conventional bone scans. Stauden- Retroperitoneal collaterals, intravoxel fat signal herz and colleagues showed that the sensitivity of and necrosis all correlated directly with clear cell bone scintigraphy varied from 10% to 60% in subtype. MRI features such as hemorrhagic cyst RCC [Staudenherz et al. 1999]. with peripheral enhancing growth in the wall and solid hypo-enhancing homogeneous masses with MRI has been suggested as a more sensitive tool low SI on T2-weighted images were predictors of in the assessment of skeletal metastasis than NM 126 http://tam.sagepub.com P Nathan and A Vinayan bone scan. A recent study by Sohaib and col- CT had a better outcome (overall median survival leagues compared the efficacy of whole body MRI not reached versus 23 months, scan and NM bone scan in the assessment of p = 0.05). Patients with a median value of SUVmax bony RCC metastasis. This prospective study of greater than 5.7 had a short PFS and OS (3 47 patients showed that even though both bone months versus 9 months, p = 0.03) and (23.3 months scan and MRI were highly specific (94% versus versus 9.1 months). Another observation in the 97%), the sensitivity of whole body MRI scan was study was that in eight patients the early PET/CT much superior (94%) to bone scan (62%) in the findings were consistent with the later CT results. detection of renal metastasis to bone (p = 0.007). MRI also had the advantage of assessment of soft A recent as yet unpublished study from Japan by tissue disease simultaneously [Sohaib et al. 2009]. Nakaigawa and colleagues examined whether SUVmax from the pretreatment FDG-PET scan Assessment of visceral disease. For assessment could be used as a prognostic marker for survival of lymph node and visceral disease, FDG-PET [Nakaigawa et al. 2012]. In 67patients enrolled and scan has been found to be extremely sensitive in monitored in this study, the researchers noted that characterizing metastases from a variety of tumour the SUVmax varied widely in RCC tumours from types. However, there is a significant incidence of an undetectable level increasing to 16.6 (mean 7.6 false-positive results, which is perhaps not surpris- ± 3.6) with an increasing trend towards poorer ing given that FDG is not a cancer-specific tracer prognosis (p < 0.001, HR –1.289). The results were [Antoch et al. 2003; Schmidt et al. 2006]. Small further analysed with SUVmax results stratified as lesions in the lung and liver may remain FDG less than 7.0, between 7.0 and 12 and greater than occult due to smearing of the signal as a result of 12.0. Median OS for patients was 1229 ± 991 days, organ motion. Use of PET-CT is also inferior to 446 ± 202 days and 95 ± 43 days respectively. whole body MRI in cancers with a frequent meta- static spread to the bone, liver and central ner- In a separate study of 35 patients, this group sug- vous system [Antoch et al. 2003; Schmidt et al. gested that an FDG-PET scan 1 month after 2005]. Poor uptake of FDG has also been noted treatment initiation could be used as a predictive in tumour types such as RCC, prostatic malig- marker for therapeutic response to TKIs based on nancy and low-grade soft tissue malignancies whether the tumour size had increased and [Schmidt et al. 2006]. SUVmax had decreased by less than 20% or by at least 20% [Ueno et al. 2012]. The value of FDG PET scans in RCC diagnosis is debated with multiple small studies showing sensi- Assessment of mechanism of drug action and role tivity ranging from 32% to 100% for initial diagno- in drug development. Imaging biomarkers have sis and staging of primary RCC [Montravers et al. an increasing role in early phase drug develop- 2000; Nakatani et al. 2011]. The largest of these ment. The phase I trial end points have now series, published by Kang and colleagues, included moved away from the traditional end points of 66 patients with RCC and showed a sensitivity of maximum tolerated dose and toxicity assessment 60% [Kang et al. 2004]. Nakatani and colleagues to also incorporate pharmacodynamic end points suggested a higher FDG sensitivity for RCC metas- which evaluate the mechanism of drug action and tasis but this has not yet been validated [Nakatani also to aid evaluation of the therapeutic window et al. 2011]. Larger series of studies are required to of these targeted agents. validate the use of FDG-PET scan in RCC but as the specificity of this technique was higher than With a view to streamlining the drug development conventional imaging in previous studies, its use process, the US Food and Drug Administration would be limited at present as a tool to help resolve has approved performing exploratory investigator dilemmas in selected cases with equivocal conven- new drug (IND) studies (termed as phase 0 tri- tional imaging but high suspicion. als). The purpose of these early studies is to assist in the go versus no-go decision for a product In a retrospective study by Le Moulec and col- using human models than relying on inconsist- leagues, 21 patients with metastatic RCC who ent animal data. Functional imaging has an received FDG-PET/CT study at baseline and after important role in this setting as it can provide evi- 2 months were evaluated [Le Moulec et al. 2010]. dence of drug activity as well as help in selection of The study noted that patients with a negative PET/ the functional dose of the drug. http://tam.sagepub.com 127 Therapeutic Advances in Medical Oncology 5 (2) and radiation therapy in rectal carcinoma: initial Discussion experience. Radiology 244(2): 486–493. RCC appears to be more sensitive to treatment with antiangiogenic drugs than many other tumours Cangiano, T., Liao, J., Naitoh, J., Dorey, F., Figlin, R. due to the high vascularity of the tumour and its and Belldegrun, A. (1999) Sarcomatoid renal cell dependence on the VHL pathway in pathogene- carcinoma: biologic behavior, prognosis, and response sis. With an increasing number of therapeutic to combined surgical resection and immunotherapy. J Clin Oncol 17: 523–528. agents in development, the need for biomarkers is more critical than ever for analysing efficacy and Choi, H. (2008) Response evaluation of potentially improving the cost–benefit ratio of gastrointestinal stromal tumors. Oncologist 13 treatment. There are now emerging data about (Suppl. 2): 4–7. how these newer techniques could fit into the Choi, H., Charnsangavej, C., Faria, S., paradigm of RCC management, starting from ini- Macapinlac, H., Burgess, M., Patel, S. et al. (2007) tial diagnosis and staging to therapeutic response Correlation of computed tomography and positron assessment. These early data need extensive and emission tomography in patients with metastatic robust validation. Functional imaging with DCE- gastrointestinal stromal tumor treated at a single MRI and DCE-CT holds promise as predictive institution with imatinib mesylate: proposal of new and prognostic biomarkers in treatment response computed tomography response criteria. J Clin Oncol in patients with RCC. DW-MRI can give insight 25: 1753–1759. into histological subtypes and in the diagnosis of De Bazelaire, C., Alsop, D., George, D., Pedrosa, I., skeletal metastasis, which is appealing and may Wang, Y., Michaelson, M. et al. (2008) Magnetic have utility in clinical practice. Evidence needs to resonance imaging measured blood flow change after be generated about the use of other techniques in antiangiogenic therapy with PTK787/ZK 222584 RCC, such as ASL-MRI and MR spectroscopy. correlates with clinical outcome in metastatic renal cell carcinoma. Clin Cancer Res 14: 5548–5554. In conclusion, in an area in which biomarker De Bazelaire, C., Rofsky, N., Duhamel, G., development is the focus of international research Michaelson, M., George, D. and Alsop, D. (2005) activity, imaging as a biomarker in RCC holds Arterial spin labeling blood flow magnetic resonance most promise in making an impact upon the clini- imaging for the characterization of metastatic renal cell carcinoma1. Acad Radiol 12: 347–357. cal management of this disease. Desar, I., ter Voert, E., Hambrock, T., van Asten, J., Funding van Spronsen, D., Mulders, P. et al. (2011) This research received no specific grant from any Functional MRI techniques demonstrate early funding agency in the public, commercial, or not- vascular changes in renal cell cancer patients treated with sunitinib: a pilot study. Cancer Imaging 11: for-profit sectors. 259–265. Conflict of interest statement Ebele, J., Sauter, G., Epstein, J. and Sesterhenn, I. The authors declare no conflict of interest in pre- (eds) (2004) World Health Organization Classification paring this article. of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC. 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BMC prognostication of renal cell carcinoma using an Cancer 12: 162. SAGE journals integrated staging system. J Clin Oncol 19: 1649–1657. http://tam.sagepub.com 131 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Medical Oncology SAGE

Imaging techniques as predictive and prognostic biomarkers in renal cell carcinoma:

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463624 TAM521758834012463624Therapeutic Advances in Medical OncologyP Nathan and A Vinayan Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Imaging techniques as predictive and (2013) 5(2) 119 –131 DOI: 10.1177/ prognostic biomarkers in renal cell 1758834012463624 © The Author(s), 2012. Reprints and permissions: carcinoma http://www.sagepub.co.uk/ journalsPermissions.nav Paul Nathan and Anup Vinayan Abstract: A number of imaging modalities are showing promise as predictive and prognostic biomarkers in advanced renal cell carcinoma. This review discusses progress to date in this exciting area and identifies areas of future promise. Keywords: biomarkers, imaging, prediction, prognosis, renal cell carcinoma Correspondence to: Introduction Predictive biomarkers Paul Nathan, PhD, FRCP Therapeutic options for patients with advanced Validated tools, which could predict clinical ben- Mount Vernon Cancer Centre – Medical Oncology, renal cell carcinoma (RCC) have dramatically efit from a therapy, would lead to significant Rickmansworth Road, improved over the last few years with the advent improvements in clinical management. Early Northwood, Middlesex HA6 2RN, UK of a number of novel agents targeting both tumour identification of responders, nonresponders or nathan.pd@gmail.com vasculature and tumour growth. Sunitinib [Motzer subpopulations of patients at risk for side effects Anup Vinayan, MRCP et al. 2007b], bevacizumab in combination with would help to identify patients who have great- Mount Vernon Cancer Centre – Medical interferon [Escudier et al. 2007b], temsirolimus est or least benefit from a specific intervention. Oncology, Northwood , [Motzer et al. 2007a], sorafenib and everolimus Predictive biomarkers would therefore help to Middlesex, UK [Motzer et al. 2008] have all become standard avoid exposing patients to the risk of unnecessary agents for the treatment of this disease. side effects from treatments from which they would be destined to derive little or no benefit. There is a clinical need to identify which patients are likely to derive most and least benefit from There are now a significant number of new thera- targeted therapies early in the course of treat- pies which have proven to be clinically effective, ment, that is, to predict response, and to identify but which have not succeeded in passing health– which patients have aggressive or indolent disease, economic assessments by reimbursement author- that is, to determine prognosis. ities. The cost-effectiveness analyses that bodies such as the National Institute for Health and RCC is highly vascular, driven at least in part by Clinical Excellence perform would be signifi- the frequent overexpression of vascular endothe- cantly impacted upon if it were possible to iden- lial growth factor (VEGF) [Nicol et al. 1997]. As tify subpopulations of patients who would derive all of the new therapeutic agents appear to have at most benefit from the drugs. This would lead to least some effect upon tumour vasculature, imag- a greater possibility that new therapies would be ing modalities that provide a quantitative assess- available for patients once efficacy had been ment of the change in vascularity may have a demonstrated. particular role in this disease. Imaging-defined response evaluation criteria in This review discusses imaging modalities that have solid tumours (RECIST) [Therasse et al. 2000] shown promise as either predictive or prognostic have been the basis of treatment response assess- tests in advanced RCC and identifies areas of ment in oncology since their introduction. The future opportunity. criteria were developed and validated to assess http://tam.sagepub.com 119 Therapeutic Advances in Medical Oncology 5 (2) responses to conventional therapies such as semiquantitative data related to blood flow and chemotherapy and radiotherapy rather than the some can also provide information on blood vol- new generation of targeted agents. RECIST crite- ume, cellularity or vessel permeability. DCE imag- ria are based upon change in size of target lesions. ing techniques such as DCE-MRI, DCE-CT and However, antivascular agents appear to be fre- DCE-US use exogenous contrast agents to differ- quently clinically active without inducing the sig- entiate vascular characteristics, while other MRI nificant size change required for a RECIST-defined techniques as ASL-MRI and DW-MRI use the response. No imaging modality has yet been vali- inherent changes in magnetic resonance between dated that can predict the treatment response of tissues without the use of an external contrast RCC treated with targeted therapies. agent. The latter group has a potential advantage as 20–30% of patients with RCC have impaired Primary RCC and its metastases are noted to be renal function, which increasingly precludes the highly vascular and are associated with an upreg- use of exogenous contrast agents. ulation of VEGF. Most sporadic and familial clear cell RCCs have an inactive VHL gene prod- Dynamic contrast-enhanced imaging techniques. uct either because of bi-allelic alterations in the Dynamic functional imaging using exogenous gene or post-transcriptional modification. Lack of contrast media centres on quantitative analysis of functional VHL gene product results in stabiliza- biodistribution of contrast media in tissues. These tion of hypoxia inducible factor (HIF) 1, 2 and techniques use the difference in pharmacokinetics increased transcription of factors such as VEGF of the contrast agent between tissues and tumour and platelet-derived growth factor. Activation of to provide tumour-specific and tissue-specific multiple pathways driven by these and other fac- information [Marcus et al. 2009]. tors results in increased angiogenesis in these tumours. This is thought to underpin the signifi- DCE-MRI as a biomarker of angiogenesis has cant clinical activity of antiangiogenic targeted been tested and validated over the last decade in therapies in RCC. Imaging techniques that can a variety of tumours. The gold standard correla- assess vascularity and changes in vascularity of tion was with immunohistochemical microves- these tumours may therefore have potential to be sel density measurements. Investigators have useful as predictive biomarkers. attempted to correlate imaging with tissue expres- sion of proangiogenic growth factors including VEGF (broad correlations in some studies and no Assessment of changes in vascularity correlations in others) [Padhani and Dzik-Jurasz, The gold standard for assessing vascularity and 2004; Schlemmer et al. 2004]. angiogenesis in a tumour is by measuring the mean vascular density, which is performed by counting The relationship between contrast concentration vascular structures directly with histology. This and signal intensity is complex and nonlinear in technique has limitations as it is invasive and can- DCE-MRI [Kiessling et al. 2007]. Along with the not be performed repeatedly to assess treatment concentration, it also depends on the imaging response in humans. Also, as it does not explore sequence used, machine setup, inherent hetero- the whole treatment volume, there is an increased geneity of the tumour and native relaxation rate chance of sampling error due to tumour heteroge- of the tissues [Padhani, 2003]. neity [Lebret et al. 2007; Renshaw et al. 1997]. The rate of delivery and washout of contrast media A number of clinically applicable functional imag- into the tumour vasculature bed depends on sev- ing techniques are capable of quantitatively assess- eral physiological characteristics of the tumour ing the vascularity of tumours in vivo pre and post vascular microenvironment. Depending on the treatment. These techniques include dynamic techniques used, parameters such as K (trans- trans contrast-enhanced magnetic resonance imag- fer constant, related to the influx of contrast agents ing (DCE-MRI), dynamic contrast-enhanced from plasma to the tumour interstitial space), Kep computed tomography (DCE-CT), dynamic (efflux of agents back to the vasculature), Ve contrast-enhanced ultrasound (DCE-US), dif- (effective volume of distribution), rBF (relative fusion-weighted MRI (DW-MRI), arterial spin blood flow), rBV (relative blood volume), IAUGC label MRI (ASL-MRI) and positron emission (initial area under gadolinium curve) can be tomography (PET) with oxygen-labelled water. obtained. The values are then fitted with statisti- Each of these techniques provides quantitative or cal models for analysis. 120 http://tam.sagepub.com P Nathan and A Vinayan In 2008, Flaherty and colleagues published a antiangiogenic agents. A total of 539 patients pilot study, which used DCE-MRI assessment with different tumour types including 157 patients in patients with metastatic RCC treated with with RCC were recruited from 19 centres in sorafenib. This study showed that inhibition of France. Perfusion parameters were collected from tumour vascular permeability by sorafenib, dem- these patients with DCE-US at baseline, on day onstrated by a reduction in K , was associated 7, day 14, day 30, day 60 and 2 monthly thereaf- trans with improved progression free survival (PFS) ter. This was correlated to the RECIST assess- (p = 0.01). Elevated baseline K was a statisti- ment performed 2 monthly. They showed that a trans cally significant predictive marker for favourable decrease in area under the curve (AUC) by more response to treatment (p < 0.02) [Flaherty et al. than 40% at 1 month was predictive of response 2008]. A prospective randomized phase II study for time to progression (TTP) (p < 0.01) and OS again with sorafenib in RCC by Stadler and col- (p < 0.04) [Lassau et al. 2012]. leagues also showed a good correlation of high baseline K with improved PFS (p < 0.027). In A simultaneous study with DCE-US from Toronto trans this study, however, change in K or IAUGC by Williams and colleagues in 17 patients with trans 90 were not significantly related to PFS [Hahn et al. metastatic RCC treated with sunitinib showed a 2008]. Further trials are underway to evaluate the decrease in median tumour fractional blood vol- use of DCE-MRI in RCC. ume by 73.2% after 2 weeks of treatment with a disruption-replenishment infusion method of Most modern MRI scanners have the ability to microbubble and a significant decrease in bolus perform these image acquisitions but there are peak with the bolus method. In this study no defi- several limitations to widespread use. Imaging nite correlation was noted with best response as protocols need to be optimized according to the assessed by RECIST [Williams et al. 2011]. area to be scanned and the type of tumour being analysed. The appropriate software needs to be US is a widely available and inexpensive technique. available and there also remain issues regarding Therefore performing frequent and serial examina- quantification, tumour heterogeneity and motion tions at short intervals is possible when using this artefact. Low molecular weight gadolinium, technique. However, the main problem with US is which is used as standard, has a limitation as the limited ability to penetrate through large areas these small agents rapidly leak out of the highly of tissue when trying to image deeply located permeable vasculature in the tumour. This in tumours, and more specifically, the inability to turn affects the data acquisition in dynamic imag- penetrate through air or bone. Because RCC fre- ing as this is defined by vascular permeability and quently metastasizes to the lung and mediastinum, tumour perfusion. Gadolinium in higher molecu- the use of DCE-US in large cohorts of patients is lar weight conjugates could be used to overcome unknown. A potential advantage of DCE-US is the this problem, as these are less sensitive to vascular fact that the microbubbles are intravascular and permeability. therefore, in theory, the quantification of tumour perfusion should not be affected by vessel perme- Lamuraglia and colleagues used DCE-US along ability. However, the technique tends to be more with a new perfusion software as a predictive operator dependent and those with the relevant tool in metastatic RCC [Lamuraglia et al. 2006]. skills are not available in all locations. Thirty patients who were enrolled in a randomized clinical trial comparing sorafenib with placebo To date, no studies have been published using were recruited. DCE-US examination was per- DCE-CT as a tool for treatment response predic- formed at baseline, week 3 and week 6. The good tion in RCC. This technique does hold promise responders were defined by a combination of a as the concentration kinetics of the contrast are decrease in contrast uptake greater than 10% and a related directly and linearly to enhancement and stable or decrease in tumour size. The responders analysis is therefore relatively straight forward identified at week 3 had a statistically significant [Miles, 2002]. However, there is little general improvement in PFS (p < 0.0004) and overall sur- agreement about the techniques to use for model- vival (OS) (p < 0.0004) over the nonresponders. ling and further quantitative analysis. Evidence from rectal carcinoma showed that baseline blood A recent prospective multicentre study by Lassau flow and blood volume were significantly lower in and colleagues investigated the use of DCE-US nonresponders compared with responders treated as a predictive biomarker in patients treated with with chemoradiotherapy [Bellomi et al. 2007]. http://tam.sagepub.com 121 Therapeutic Advances in Medical Oncology 5 (2) The study also showed a significant decrease in diffusion depending on the Brownian motion of blood flow, blood volume and permeability sur- the water molecules in tissues. Desar and col- face area product post treatment. CT scanning is leagues noted that sunitinib-induced antiangio- the commonest tool used at present to monitor genic effects in RCC can be reliably measured treatment response, therefore it would be a prac- with DW-MRI as early as 3–10 days after starting tical and easy option to incorporate DCE-CT the treatment [Desar et al. 2011]. This needs fur- protocols in almost all centres once a general ther evaluation before it can be reliably used as a agreement is obtained and the technique is vali- predictive biomarker. There are as yet no pub- dated further. lished data with either of these techniques to pre- dict responses in RCC to targeted therapies. Imaging techniques that use no external contrast agent. A number of MRI techniques which do not resort to an external contrast agent have been Assessment of change in metabolic activity developed and are being assessed as biomarkers Fluorodeoxyglucose (FDG)-PET/CT scan is a of treatment response. Between 20% and 30% valuable tool, which has already established its of patients with RCC are unable to have exter- role in the assessment and management of many nal contrast due to renal impairment and tech- tumour types. By combining a short-lived radioac- niques that do not resort to external contrast are tive tracer with a biologically active molecule, thus valuable[Nathan et al. 2010]. These tech- PET scan provides a functional map of the disease niques use the magnetic field to modify the investigated. The most common biological mole- magnetic properties of the tissue including the cule used in oncology is FDG. This glucose ana- tumour. logue is rapidly and preferentially taken up by the rapidly growing malignant cells, thus leading to ASL-MRI uses the inherent nuclear spin of intense radiolabelling of that tissue. A combined endogenous water protons to label arterial blood. CT and PET scan provides a combination of met- Quantitative images of blood flow to the tissue can abolic activity with anatomical localization of tis- be generated by differential labelling inside and sues. The use of FDG-PET/CT in treatment outside the tissue of interest. The technique has response assessment, that is, as a predictive marker potential to be used as a quantitative marker for in RCC, looks promising but has not been fully response assessment to antivascular treatment. evaluated. A recent study by Powles and col- The feasibility of this technique to monitor leagues looked at the use of sequential FDG-PET response to antiangiogenic therapy in RCC scanning as a correlative marker of OS in patients metastases was demonstrated by de Bazelaire with RCC treated with sunitinib [Powles et al. and colleagues [de Bazelaire et al. 2005]. In a 2010]. A total of 44 patients were enrolled in phase II trial of 10 patients, ASL-MRI and this phase II study. Patients had three FDG- DCE-MRI were used to assess the treatment PET scans: before treatment, at 4 and 16 weeks. response in patients with metastatic RCC Reduction in maximum standardized uptake value treated with an antiangiogenic agent (PTK787/ (SUVmax) by 20% was considered a response and ZK222584). The study showed that changes in was correlated with OS. The study showed that blood flow detected by ASL-MRI at 1 month high baseline SUVmax suggested a trend towards correlated with the change in tumour size low OS [hazard ratio (HR) 3.30; 95% confidence measured at 4 months or at disease progression interval (CI) 1.36–8.45]. Metabolic response was (p < 0.01) [de Bazelaire et al. 2008]. If validated noted on the PET scan after 4 weeks. However, in larger studies, ASL-MRI thus might prove to disease progression according to the 16-week scan be an important biomarker in early assessment correlated with a decreased OS (HR –5.96; 95% of treatment response. CI –2.43 to +19.02). Techniques such as blood oxygen level dependent Similar results were noted in smaller trials of 12 MRI (BOLD-MRI) and DW-MRI which use no patients and 14 patients by Minamimoto and external contrast are other methods with poten- Revheim and colleagues respectively [Minamimoto tial to predict treatment response. BOLD-MRI et al. 2010; Revheim et al. 2011]. Using a 20% uses the difference in magnetic properties of oxy- reduction in FDG-PET uptake, Minamimoto and haemoglobin and deoxyhaemoglobin and hence colleagues were able to separate good responders BOLD signals are related to tumour hypoxia. with a mean PFS of 233.8 days and poor respond- DW-MRI evaluates the property of water ers with a PFS of 75 days. 122 http://tam.sagepub.com P Nathan and A Vinayan A pharmacodynamic study using serial 3deoxy3’ progressive disease. According to the Choi crite- fluorothymidine PET (FLT-PET) scans on ria, these numbers were 36, 6 and 13 respectively. patients at baseline, during treatment with suni- In patients having a partial response, the Choi cri- tinib and after withdrawal of drug within cycle 1 teria had a significantly better predictive value for showed an increase in cellular proliferation dur- PFS and OS (p < 0.001 for both) than RECIST ing sunitinib withdrawal [Liu et al. 2011]. This is (p = 0.689 and 0.191 respectively). The predic- noted to associate with VEGF ligand levels and tive value of RECIST increased to a statistically early exploratory analysis suggests that the extent significant level only when best response during of flare could predict poorer clinical benefit from treatment was taken into account. the drug. The Choi criteria and RECIST were again com- pared with a smaller cohort of 22 patients treated New criteria for response assessment with sorafenib reported by Hittinger and colleagues RECIST criteria depend upon the change in sum [Hittinger et al. 2011]. Even though the Choi cri- of the unidimensional measurements of target teria defined more patients as responders, they lesions. However, the clinical benefit does not did not differentiate between patients who did always correlate with change in size alone in and those who did not have therapeutic improve- tumours treated with targeted therapies. Emerging ments in PFS or OS. evidence shows that some patients continue to derive clinical benefit from continuation of suni- ’Modified’ Choi criteria. We proposed a modifi- tinib after documented disease progression based cation of the Choi criteria in the assessment of on RECIST criteria [Teo et al. 2012]. This retro- treatment response to targeted therapy in meta- spective analysis of 39 patients treated with suni- static RCC in which both a change in size and tinib showed that such use of a tyrosine kinase density are required [Nathan et al. 2010]. The inhibitor (TKI) beyond progression gives pro- standard Choi criteria require a decrease in size longed disease control and is safe. The use of by 10% or a decrease in CT contrast enhance- RECIST alone as a measure of treatment response ment by 15% for a response. We suggested a is therefore arguable. modification of the Choi criteria in which both a minimum 10% size decrease and a 15% reduc- Choi criteria. Choi proposed an alternative set of tion in enhancement are required to define a criteria for the assessment of gastrointestinal stro- response. We performed a retrospective study of mal tumours (GIST) treated with the targeted 32 patients with metastatic RCC treated with agent imatinib [Choi, 2008; Choi et al. 2007]. TKIs. Twelve patients were excluded as they did The Choi criteria require either a change in size not have contrast-enhanced scans due to renal or a change in density (contrast enhancement) to dysfunction. Both baseline and 12-week post- predict a response. They have been found to be treatment contrast-enhanced scans were collected more reliable than RECIST in monitoring GIST and analysed. According to the response obtained responses to treatment using PET-CT as a gold on the 12-week scan, patients were assigned to standard. It has been suggested that the Choi cri- progressive disease, stable disease or partial teria could be suitable for assessment of targeted response using RECIST, Choi and modified therapies in other cancers, but this has not yet Choi criteria, correlated with TTP. Patients who been extensively evaluated. had a partial response according to the modified Choi criteria had a statistically significant longer In renal cancer, van der Veldt and colleagues have TTP than those who were deemed to have sta- analysed the use of Choi criteria in treatment ble disease (mean 448 versus 89 days, p = 0.002). response assessment in RCC and found them to Neither RECIST nor Choi criteria defined par- correlate better to TTP than RECIST [van der tial responders went on to have a significant Veldt et al. 2010]. A total of 55 patients with meta- improvement in TTP compared with those static RCC treated with sunitinib were analysed who had stable disease. Further larger trials are retrospectively. The pretreatment and first evalua- planned to validate these results. CT enhance- tion post-treatment scan were analysed with ment was measured in the arterial phase rather RECIST and Choi criteria separately and corre- than in the more usual portovenous phase in this lated with PFS and OS. At first evaluation, study. This may be relevant as renal tumours are according to the RECIST criteria, seven patients highly vascular and enhance well in the arterial had a response, 38 had stable disease and 10 had phase [Lee et al. 2005; Raptopoulos et al. 2001]. http://tam.sagepub.com 123 Therapeutic Advances in Medical Oncology 5 (2) Size and attenuation CT criteria/morphology, attenu- changes, which did not fit in with these criteria ation, size and structure criteria. Another study were classified as an indeterminate response. The exploring the use of a combination of change in MASS criteria showed an increased sensitivity of size and CT attenuation to predict treatment 86% and specificity of 100% in recognizing good response in metastatic RCC was published by responders (TTP and improved disease specific Smith and colleagues [Smith et al. 2010a]. Con- survival p < 0.0001). trast-enhanced CT scans of 53 patients with met- astatic RCC treated with either sunitinib or The group further recommended that the combi- sorafenib were analysed. In calculating the attenu- nation of memorial sloan kettering cancer centre ation data, Smith and colleagues used volumetric (MSKCC) criteria and MASS criteria together mean attenuation of target lesions in place of mean could give a high overall accuracy in identifying attenuation in the most representative axial image. patients with PFS less than 1 year or at least 1 They proposed new imaging criteria, size and year [Smith et al. 2011]. attenuation CT (SACT) criteria. The criteria defined favourable response as any of the follow- Tumour burden and growth rate. Basappa and ing: a decrease in tumour size of at least 20%; a colleagues investigated the effect of tumour bur- decrease in tumour size of at least 10% and at least den (TB) with treatment with VEGF-targeted half of nonlung target lesions with decreased mean therapy. Sixty-nine patients were retrospectively attenuation of at least 20 Hounsefield units (HU); analysed. Median TB and site of metastasis were or one or more lung lesions with decreased mean examined. With multivariate analysis, at baseline, attenuation by at least 40 HU. Unfavourable the total number of metastases (<10) and the TB response was defined as any of the following: an above the diaphragm (<6.5 cm) were independent increase in tumour size of at least 20%; new metas- positive predictors of OS [Basappa et al. 2011]. tasis; marked central fill in of a target lesion; or new TB (p = 0.003) and total metastases (≤12) were enhancement in a homogenously hypoattenuating noted as predictors of OS at TTP. nonenhancing mass. A comparison was made between the SACT criteria, RECIST criteria and a Initial tumour size and the rate of size reduction modification of the Choi criteria (with volumetric in response to targeted therapy were predictive attenuation data of the whole tumour rather than markers reported by Yuasa and colleagues[Yuasa mean attenuation in an axial slice) in predicting a et al. 2011]. In this 139-patient retrospective PFS greater than 250 days in this patient popula- analysis, a linear, moderate to strong association tion. The favourable response defined by the SACT was noted between the pretreatment tumour size criteria had a sensitivity of 75% and a specificity of and reduction in growth rate on therapy (correla- 100% in identifying patients with PFS greater than tion coefficient –0.441, p < 0.001). When a thresh- 250 days. These values were 16% and 100%, and old value of 23.9 mm was applied, it was noted 93% and 44% for the RECIST criteria and volu- that the smaller tumours showed a better rate of metric modified Choi criteria, respectively. shrinkage (p < 0.001). The same group attempted to improve on the Use of tumour growth rate (TGR) was retrospec- SACT criteria by including specific morphologic tively analysed by Ferte and colleagues [Ferte or structural changes (e.g. necrosis) and eliminat- et al. 2012]. Images from patients recruited to ing the need for volumetric three-dimensional large phase III trials with sorafenib (TARGET) analysis in their new criteria [referred to as mor- and everolimus (RECORD) were assessed (n = phology, attenuation, size and structure (MASS) 902). TGR was defined as the value obtained by criteria] [Smith et al. 2010b]. According to the dividing tumour shrinkage by time between two MASS criteria, favourable response was defined as evaluations. All treatment periods, including no new lesion and any of the following: a decrease before, under treatment (at first cycle), at pro- in tumour size of at least 20%; one or more pre- gression and after treatment interruption, were dominantly solid enhancing lesions with marked noted. The results showed that the TGR under central necrosis or marked decreased attenuation treatment was significantly decreased with both (≥40 HU). An unfavourable response was defined sorafenib and everolimus. High TGR under treat- as an increase in tumour size of at least 20% in the ment was associated with poor PFS (HR 2.6) and absence of marked necrosis or marked decreased OS (HR 2.3) in patients treated with sorafenib attenuation; and new metastasis, marked central and poor OS (HR 1.2) in the smaller everolimus fill-in, or new increased enhancement. Other cohort. TGR after interruption was significantly 124 http://tam.sagepub.com P Nathan and A Vinayan higher in both sorafenib and everolimus cohorts intermediate-risk group (one or two risk factors) than TGR at progression (14.6 versus 31 and 17.9 and the poor prognostic group (more than two versus 32.1, respectively). The inclusion of TGR risk factors) were 10 months and 4 months respec- thus allows the practitioner to evaluate the tumour tively [Motzer et al. 1999]. The MSKCC criteria response more carefully. have been widely used in many phase III trials of RCC evaluating antiangiogenic agents either to The threshold of tumour response as change in stratify patients in trial analysis [Escudier et al. sum of longest diameter (∆SLD) to mammalian 2007b; Motzer et al. 2007b, 2008] or to define target of rapamycin inhibitor everolimus was entry criteria in other trials [Escudier et al. 2007a; investigated by Oudard and colleagues [Oudard Hudes et al. 2007]. et al. 2012]. The data from the phase III RECORD-1 trial were analysed and a series of Evidence from these trials showed that the benefi- arbitrary thresholds were identified to attempt to cial effects of these drugs were maintained across distinguish responders from nonresponders. With prognostic groups but were significantly greater response defined by the optimal threshold of in good and intermediate prognostic groups. –5%∆SLD, the median PFS was 8.4 months for Hence prognostic grouping of RCC has an impor- the responders and 5.0 months for the nonre- tant role in selection of treatment and also in sponders (HR 2.4). determining the time of introduction of systemic treatment. Imaging techniques can potentially act as noninvasive tools in identifying these prognos- Prognostic biomarkers tic factors. These include assessment of histologi- Imaging biomarkers that provide an insight into cal subtype, nuclear grading and in the accurate the natural course of the disease are of potential staging of disease. use in identifying patients who are most or least likely to benefit from treatment as well as in inter- preting clinical trials. The prognosis of any malig- Assessment of histological subtypes nancy could be related to a variety of factors. There has been debate as to whether prognosis of RCC is a heterogeneous group of diseases. There RCC varies significantly with histological sub- are a number of histological subtypes and within type. Studies have in part been hampered by each subtype there is a widely varying natural his- small numbers of the rarer subtypes and associ- tory between patients. Some tumours are very ated lack of control for other prognostic factors. aggressive while others remaining indolent. Some RCC can be subclassified according to histology patients experience stable metastatic disease for a as clear cell, papillary type I and II, chromophobe, significant period of time that does not require sarcomatoid, collecting duct and a variety of systemic treatment until progression is seen. very rare and unclassified subtypes(World Health Organization classification) [Ebele et al. 2004; Several clinicopathological prognostic models are Kovacs et al. 1997]. The clear cell (conventional) designed to assess survival in the postnephrec- subtype is the most common and accounts for tomy [Leibovich score, University of California, approximately 70% of cases. The papillary sub- Los Angeles (UCLA) score] [Leibovich et al. type accounts for around 15–20% of cases. The 2005; Zisman et al. 2001] and metastatic setting type II papillary and other subtypes are less (Motzer score, UCLA score) [Motzer et al. 1999]. common. There is good evidence that tumours These prognostic models use histological fea- with sarcomatoid elements have a poorer prog- tures, including Fuhrman grade and necrosis, nosis than the majority of tumours without performance status and a variety of biochemical [Cangiano et al. 1999]. markers for categorization into prognostic groups. With the emerging possibility that treatment deci- The MSKCC (Motzer) criteria classified patients sions may be influenced by histological subtype, into good, intermediate and poor prognostic together with the fact that core biopsy is associ- groups depending on five factors: primary ated with diagnostic inaccuracy [Lebret et al. tumour remaining in situ, Eastern Cooperative 2007] a noninvasive technique to assess histologi- Oncology Group performance status, anaemia, cal subtype would be of potential clinical value. A lactate dehydrogenase level and hypercalcaemia. number of different imaging modalities have been Median survival in patients with zero risk fac- assessed for this purpose. These include multi- tors was 20 months but median survival in the slice CT, DW-MRI and DCE-MRI. http://tam.sagepub.com 125 Therapeutic Advances in Medical Oncology 5 (2) Sheir and colleagues attempted to use multislice the papillary subtype with good sensitivity (80%) CT to differentiate histological subtypes. They and specificity (94%). reviewed 87 CT images of patients with RCC ret- rospectively and compared them with histopathol- Sun and colleagues explored the use of DCE-MRI ogy. Biphasic CT scans of the kidneys were as a tool in predicting the histopathological sub- performed using unenhanced, corticomedullary type of RCC. They compared the difference in phase (CMP) and excretory phase (EP) (30 and enhancement pattern in CMP and nephrographic 300 s after contrast injection respectively) proto- phase images with histopathology. In both the cols. It was noted that the degree of enhancement CMP and nephrographic phase, clear cell tumours in the CMP and EP was the most valuable param- showed maximum signal intensity change and eter in attempting to differentiate between histo- papillary tumours the least. Signal intensity change logical subtypes (p < 0.001). Mean CT attenuation in the CMP was the most effective parameter dif- (+2 standard deviations) in the CMP was 138.2 ± ferentiating clear cell and papillary subtypes with a 38.0 HU for clear cell, 89.2 ± 31.4 HU for papil- sensitivity of 93% and a specificity of 96% [Sun lary and 55.17 ± 24.0 HU for chromophobe et al. 2009]. DCE-MRI was also useful in predict- tumours. In the excretory phase, clear cell tumours ing the nuclear grade of the tumour as reported by showed an enhancement of 73.0 ± 17.6 HU while Palmowski and colleagues. Twenty-one patients papillary and chromophobe had an enhancement were analysed with DCE-MRI presurgically; of 70.0 ± 10.4 and 33.9 ± 12.1 HU respectively. tumour perfusion and tissue–blood ratio were The difference between subtypes in both the CMP noted for the entire tumour and also for the most and EP was statistically significant (p < 0.001). highly vascularized area in the tumour. Higher The cutoff value for highest accuracy for diagnosis grade tumours had significantly higher perfusion of clear cell carcinoma was 83.5 HU for CMP and values (p < 0.05) in the most vascular area [2.14 ± 64.5 HU for EP. Other factors such as presence or 0.89 versus 1.40 ± 0.49 ml/g/min) and the entire absence of cystic degeneration, tumour vascularity tumour (1.59 ± 0.44 versus 1.08 ± 0.38 ml/g/min) and pattern of enhancement also supplemented [Palmowski et al. 2009]. this differentiation [Sheir et al. 2005]. These imaging techniques are of interest, how- Pedrosa and colleagues attempted evaluation of ever their use in clinical practice will require much malignant renal tumours with the help of noncon- more robust validation and they are unlikely to trast-enhanced and contrast-enhanced MRI and replace the use of histological diagnosis in the correlated this with histology. The study cohort near future. consisted of 76 patients who had both MRI and histological confirmation [Pedrosa et al. 2008]. Renal masses were analysed for size, location, Staging of renal cell carcinoma necrosis, haemorrhage, signal intensity and uni- Accurate staging of RCC is an important factor formity of signal intensity, type and extent of fat influencing the prognosis. While CT, MRI, PET and contrast enhancement, peri-renal fat invasion and bone scans all are used routinely in staging a and renal vein thrombosis. They were then assigned variety of different cancers, there is debate regarding to one of eight different groups defined according the usefulness of some of these techniques in RCC. to MRI appearance. The results were compared with the histological analysis and the sensitivity Assessment of skeletal metastasis. Nuclear and specificity of these MRI groups were calcu- medicine (NM) bone scans with Tc99 provide lated to predict the histological diagnosis and limited anatomical detail and only provide infor- nuclear grade. The MRI classification had a sen- mation about tumour deposits where an osteoblas- sitivity of 93% and specificity of 75% for the diag- tic reaction has occurred. RCC bony metastases nosis of clear cell subtype, using the presence of are predominantly osteoclastic, resulting in a low solid enhancing mass with or without necrosis. sensitivity of conventional bone scans. Stauden- Retroperitoneal collaterals, intravoxel fat signal herz and colleagues showed that the sensitivity of and necrosis all correlated directly with clear cell bone scintigraphy varied from 10% to 60% in subtype. MRI features such as hemorrhagic cyst RCC [Staudenherz et al. 1999]. with peripheral enhancing growth in the wall and solid hypo-enhancing homogeneous masses with MRI has been suggested as a more sensitive tool low SI on T2-weighted images were predictors of in the assessment of skeletal metastasis than NM 126 http://tam.sagepub.com P Nathan and A Vinayan bone scan. A recent study by Sohaib and col- CT had a better outcome (overall median survival leagues compared the efficacy of whole body MRI not reached versus 23 months, scan and NM bone scan in the assessment of p = 0.05). Patients with a median value of SUVmax bony RCC metastasis. This prospective study of greater than 5.7 had a short PFS and OS (3 47 patients showed that even though both bone months versus 9 months, p = 0.03) and (23.3 months scan and MRI were highly specific (94% versus versus 9.1 months). Another observation in the 97%), the sensitivity of whole body MRI scan was study was that in eight patients the early PET/CT much superior (94%) to bone scan (62%) in the findings were consistent with the later CT results. detection of renal metastasis to bone (p = 0.007). MRI also had the advantage of assessment of soft A recent as yet unpublished study from Japan by tissue disease simultaneously [Sohaib et al. 2009]. Nakaigawa and colleagues examined whether SUVmax from the pretreatment FDG-PET scan Assessment of visceral disease. For assessment could be used as a prognostic marker for survival of lymph node and visceral disease, FDG-PET [Nakaigawa et al. 2012]. In 67patients enrolled and scan has been found to be extremely sensitive in monitored in this study, the researchers noted that characterizing metastases from a variety of tumour the SUVmax varied widely in RCC tumours from types. However, there is a significant incidence of an undetectable level increasing to 16.6 (mean 7.6 false-positive results, which is perhaps not surpris- ± 3.6) with an increasing trend towards poorer ing given that FDG is not a cancer-specific tracer prognosis (p < 0.001, HR –1.289). The results were [Antoch et al. 2003; Schmidt et al. 2006]. Small further analysed with SUVmax results stratified as lesions in the lung and liver may remain FDG less than 7.0, between 7.0 and 12 and greater than occult due to smearing of the signal as a result of 12.0. Median OS for patients was 1229 ± 991 days, organ motion. Use of PET-CT is also inferior to 446 ± 202 days and 95 ± 43 days respectively. whole body MRI in cancers with a frequent meta- static spread to the bone, liver and central ner- In a separate study of 35 patients, this group sug- vous system [Antoch et al. 2003; Schmidt et al. gested that an FDG-PET scan 1 month after 2005]. Poor uptake of FDG has also been noted treatment initiation could be used as a predictive in tumour types such as RCC, prostatic malig- marker for therapeutic response to TKIs based on nancy and low-grade soft tissue malignancies whether the tumour size had increased and [Schmidt et al. 2006]. SUVmax had decreased by less than 20% or by at least 20% [Ueno et al. 2012]. The value of FDG PET scans in RCC diagnosis is debated with multiple small studies showing sensi- Assessment of mechanism of drug action and role tivity ranging from 32% to 100% for initial diagno- in drug development. Imaging biomarkers have sis and staging of primary RCC [Montravers et al. an increasing role in early phase drug develop- 2000; Nakatani et al. 2011]. The largest of these ment. The phase I trial end points have now series, published by Kang and colleagues, included moved away from the traditional end points of 66 patients with RCC and showed a sensitivity of maximum tolerated dose and toxicity assessment 60% [Kang et al. 2004]. Nakatani and colleagues to also incorporate pharmacodynamic end points suggested a higher FDG sensitivity for RCC metas- which evaluate the mechanism of drug action and tasis but this has not yet been validated [Nakatani also to aid evaluation of the therapeutic window et al. 2011]. Larger series of studies are required to of these targeted agents. validate the use of FDG-PET scan in RCC but as the specificity of this technique was higher than With a view to streamlining the drug development conventional imaging in previous studies, its use process, the US Food and Drug Administration would be limited at present as a tool to help resolve has approved performing exploratory investigator dilemmas in selected cases with equivocal conven- new drug (IND) studies (termed as phase 0 tri- tional imaging but high suspicion. als). The purpose of these early studies is to assist in the go versus no-go decision for a product In a retrospective study by Le Moulec and col- using human models than relying on inconsist- leagues, 21 patients with metastatic RCC who ent animal data. Functional imaging has an received FDG-PET/CT study at baseline and after important role in this setting as it can provide evi- 2 months were evaluated [Le Moulec et al. 2010]. dence of drug activity as well as help in selection of The study noted that patients with a negative PET/ the functional dose of the drug. http://tam.sagepub.com 127 Therapeutic Advances in Medical Oncology 5 (2) and radiation therapy in rectal carcinoma: initial Discussion experience. Radiology 244(2): 486–493. RCC appears to be more sensitive to treatment with antiangiogenic drugs than many other tumours Cangiano, T., Liao, J., Naitoh, J., Dorey, F., Figlin, R. due to the high vascularity of the tumour and its and Belldegrun, A. (1999) Sarcomatoid renal cell dependence on the VHL pathway in pathogene- carcinoma: biologic behavior, prognosis, and response sis. With an increasing number of therapeutic to combined surgical resection and immunotherapy. J Clin Oncol 17: 523–528. agents in development, the need for biomarkers is more critical than ever for analysing efficacy and Choi, H. (2008) Response evaluation of potentially improving the cost–benefit ratio of gastrointestinal stromal tumors. Oncologist 13 treatment. There are now emerging data about (Suppl. 2): 4–7. how these newer techniques could fit into the Choi, H., Charnsangavej, C., Faria, S., paradigm of RCC management, starting from ini- Macapinlac, H., Burgess, M., Patel, S. et al. (2007) tial diagnosis and staging to therapeutic response Correlation of computed tomography and positron assessment. These early data need extensive and emission tomography in patients with metastatic robust validation. Functional imaging with DCE- gastrointestinal stromal tumor treated at a single MRI and DCE-CT holds promise as predictive institution with imatinib mesylate: proposal of new and prognostic biomarkers in treatment response computed tomography response criteria. J Clin Oncol in patients with RCC. DW-MRI can give insight 25: 1753–1759. into histological subtypes and in the diagnosis of De Bazelaire, C., Alsop, D., George, D., Pedrosa, I., skeletal metastasis, which is appealing and may Wang, Y., Michaelson, M. et al. (2008) Magnetic have utility in clinical practice. Evidence needs to resonance imaging measured blood flow change after be generated about the use of other techniques in antiangiogenic therapy with PTK787/ZK 222584 RCC, such as ASL-MRI and MR spectroscopy. correlates with clinical outcome in metastatic renal cell carcinoma. Clin Cancer Res 14: 5548–5554. In conclusion, in an area in which biomarker De Bazelaire, C., Rofsky, N., Duhamel, G., development is the focus of international research Michaelson, M., George, D. and Alsop, D. (2005) activity, imaging as a biomarker in RCC holds Arterial spin labeling blood flow magnetic resonance most promise in making an impact upon the clini- imaging for the characterization of metastatic renal cell carcinoma1. Acad Radiol 12: 347–357. cal management of this disease. Desar, I., ter Voert, E., Hambrock, T., van Asten, J., Funding van Spronsen, D., Mulders, P. et al. (2011) This research received no specific grant from any Functional MRI techniques demonstrate early funding agency in the public, commercial, or not- vascular changes in renal cell cancer patients treated with sunitinib: a pilot study. Cancer Imaging 11: for-profit sectors. 259–265. Conflict of interest statement Ebele, J., Sauter, G., Epstein, J. and Sesterhenn, I. The authors declare no conflict of interest in pre- (eds) (2004) World Health Organization Classification paring this article. of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon: IARC. 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Journal

Therapeutic Advances in Medical Oncology – SAGE

Published: Nov 20, 2012

Keywords: biomarkers; imaging; prediction; prognosis; renal cell carcinoma

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