Functional imaging in predicting response to antineoplastic agents and molecular targeted therapies in lung cancer: A review of existing evidence

Critical Reviews in Oncology/Hematology 83 (2012) 208–215

Functional imaging in predicting response to antineoplastic agents and molecular targeted therapies in lung cancer: A review of existing evidence S. Novello ∗ , M. Giaj Levra, T. Vavalà Thoracic Oncology Unit, Department of Clinical & Biological Sciences, University of Turin, AOU San Luigi Orbassano, Italy Accepted 28 September 2011

Contents 1. 2. 3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FDG-PET as a prognostic marker in non-small-cell lung cancer (NSCLC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . FDG-PET in monitoring NSCLC treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Cytotoxic chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Molecular targeted therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New biomarkers and functional imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract The increasing use of FDG-PET (18 F-2-fluoro-2-deoxy-d-glucose positron emission tomography) imaging in the staging of non-small-cell lung cancer (NSCLC) may result in a significant shift in stage distribution, with an increased percentage of patients staged as having metastatic disease and consequently a higher percentage of patients treated with systemic therapy. The amount of FDG-PET uptake in primary lung lesions has been shown to be correlated with tumour growth rate. Data suggest that tumours with increased glucose uptake are presumably more metabolically active and more biologically aggressive, and standardized uptake value (SUV) at PET may be regarded as a prognostic factor. Growing evidence suggests that PET may be used as a predictive marker to assess the activity of antineoplastic agents, allowing close monitoring of the efficacy of the treatment in order to be able to switch earlier to alternative therapies according to the individual chemosensitivity of the tumour. Currently the value of FDG-PET for monitoring response is complicated by the heterogeneity of the published data on the methods used for FDG quantification and the selection of the primary targets and clinical endpoints. As a result, objective validation of proposed thresholds of responsiveness is lacking. This article discusses the assessment of treatment response in NSCLC patients using functional imaging, and emphasizes advantages and limitations in clinical management. © 2011 Elsevier Ireland Ltd. All rights reserved. Keywords: Non-small-cell lung cancer; Functional imaging; Positron emission tomography; FDG-PET; Advanced disease; Personalized treatment

1. Introduction ∗

Corresponding author at: Thoracic Oncology Unit, Department of Clinical & Biological Sciences, University of Turin, AOU San Luigi, Regione Gonzole 10, 10043 Orbassano, Turin, Italy. Tel.: +39 0119026978; fax: +39 0119038616. E-mail address: [email protected] (S. Novello). 1040-8428/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.critrevonc.2011.09.009

Lung cancer remains one of the major causes of cancerrelated death throughout the developed world, with 1.5 million estimated new cases and 1.35 million deaths every

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year [1]. Currently, in clinical practice several clinical and molecular prognostic factors are considered to tailor therapies to different subgroups of patients; however, treatment responses are still being assessed by serial measurements of tumour size before and after treatment. The morphological criteria for the assessment of tumour response were formalized for the first time in 1981 by the World Health Organization (WHO), then revised in 2000 as “response evaluation criteria in solid tumours” (RECIST), and subsequently updated in 2009 with RECIST 1.1 [2,3]. Molecular imaging as a new technology and as a research and clinical tool was developed more than 30 years ago [3–6]. 18 F-2-fluoro-2-deoxy-d-glucose (18 FDG), a glucose analogue first tested in humans in 1976, is the most widely used metabolic tracer in the world [7]. It enters into cells through glucose transporters such as GLUT-1, and is subsequently phosphorylated by hexokinases [8]. The metabolic product FDG-6-phosphate is intracellularly trapped and cannot undergo further metabolism through the glycolytic pathway [9]. Following therapy, FDG-positron emission tomography (FDG-PET) seems to have superior prognostic value compared with computed tomography (CT) imaging, and the decrement in the FDG uptake between baseline and after one cycle of chemotherapy may predict outcome, the improvement in survival being directly related to the magnitude of the decreased uptake. However, there have been very few studies which considered the value of early FDG-PET in assessing tumour response while patients are still receiving therapy [10–13]. The rationale for using FDG-PET imaging in the evaluation of prognosis and therapeutic response relies on the relationship between FDG uptake and the proliferative activity of the tumour; changes may be assessed by several parameters, including standardized uptake value (SUV) [14]. New ligands such as 18 F-fluorothymidine (FLT) or its 11 C-labelled analogue, or techniques to monitor gene therapy of malignant tumours with PET (reporter gene imaging), receptor imaging, or imaging tumour hypoxia have been extensively studied in preclinical models and may become useful tools for response assessment in new anticancer treatments, even if these preliminary data need to be confirmed and validated in prospective clinical trials [15,16]. This review discusses the specific features of FDG-PET in predicting the response to antineoplastic agents in lung cancer, and emphasizes potential advantages and limitations of its use in the clinical management of patients with lung cancer.

2. FDG-PET as a prognostic marker in non-small-cell lung cancer (NSCLC) The amount of FDG uptake in the primary site of lung cancer has been shown to have a direct relationship to tumour growth [17], and the immunohistochemical assessment of

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over-expression of cell-membrane glucose transporter protein (Glut1 and Glut3) has been correlated with poor outcome [18]. These data suggest that tumours with increased glucose uptake are presumably more metabolically active and more biologically aggressive. However, the precise mechanism through which cancer treatment induces alterations in these cellular processes and leads to changes in FDG uptake is incompletely understood, and may differ for different tumour types or treatments. FDG uptake in focal pulmonary abnormalities has been shown to correlate with the doubling time of the pulmonary lesion. Duhaylongsod et al. demonstrated that the standardized uptake ratio was significantly correlated with the doubling time of the tumour (r = −0.89; P = 0.002): in 34 patients with cancer the mean standardized uptake ratio (±SD) was 5.9 ± 2.7, versus 2.0 ± 1.7 in 19 patients with benign disease (P < 0.001) [18]. Using a criterion of standardized uptake ratio ≥2.5 for malignancy, the accuracy of PET was 92%. These data suggest that the amount of FDG uptake in malignant lesions at baseline and during follow-up after therapy may be used to provide prognostic information [19]. Ahuja et al. [20], surveying 155 patients with NSCLC, reported that 118 patients (76%) had tumours with SUV <10, and in this group the median survival was 24.6 months (95% confidence interval [CI]: 20.9–41.1). Thirty-seven patients (24%) had tumours with SUVs >10 and a median survival of 11.4 months (95% CI: 9.3–19.4). An SUV >10 correlated with poorer survival (P = 0.0049). Patients with primary lesions >3 cm and an SUV >10 had the worst prognosis, with a median survival of 5.7 months (95% CI: 4.0–13.1). Multivariate analysis demonstrated that an SUV >10 provided prognostic information regardless of clinical stage and tumour size. A recent meta-analysis performed by the European Lung Cancer Working Party as part of the International Association for the Study of Lung Cancer (IASLC) Lung Cancer Staging Project concluded that, in patients with NSCLC, the metabolic activity of the primary tumour as determined by the SUV on FDG-PET imaging is a prognostic factor. The metaanalysis identified 13 eligible studies with a total of 1474 patients, and 11 of these studies identified the high SUV as a poor prognostic factor for survival; the overall hazard ratio for death when all 13 studies were considered was 2.27 (95% CI: 1.70–3.02) [21]. This meta-analysis suggests that in NSCLC the SUV measurement of the primary tumour generates prognostic information, but again these results need to be confirmed by meta-analysis of an individual patient’s data. In a retrospective study by Goodgame et al., a threshold SUV of 5.5 was used to evaluate the prognostic significance of FDG uptake in 136 patients with stage-I NSCLC who underwent curative surgical resection [22]. 32 out of 136 developed recurrence of malignancy after a mean follow-up time of 46 months. Patients with a primary tumour with high FDG uptake (SUV > 5.5) had a three times higher likelihood of having recurrence of their disease. In 22 patients (33%) with a

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high SUV (>5.5) the disease recurrence had already occurred, whereas only ten patients with a low SUV (<5.5.) had recurrence (14%). At the multivariate analysis including SUV, T-classification, age and histology, high SUV was independently associated with recurrence (P = 0.002) and mortality (0.041). Recently Gulenchyn et al. presented a case series of early stage NSCLC in which patients underwent surgical resection, and for all patients considered a preoperative FDG-PET was available. It was shown that the SUV was inversely correlated with survival, even after adjusting for tumour stage and performance status [23].

3. FDG-PET in monitoring NSCLC treatment The initial observation that patients with a significant tumour response frequently show a negative PET scan after completion of therapy, despite significant residual morphological abnormalities, has led to the hypothesis that measurable quantitative changes in tumour metabolism may occur early during therapy, and these may be used as an early indicator for tumour response. This hypothesis was initially evaluated by Jansson et al. in patients with breast cancer and by Findlay et al. for colorectal cancer [24,25]. These studies indicated that, in responding tumours, metabolic activity markedly changed within the first weeks of therapy. In NSCLC, the interpretation of SUV changes following neo-adjuvant chemotherapy, particularly if the preoperative approach includes radiotherapy, can be confounded by different factors, including tumour cell differentiation and macrophage infiltration. Animal studies have shown that up to 30% of the FDG uptake in a tumour may be related to the accumulation of the tracer in the macrophage/monocyte system, and some tumours retain high SUV at the completion of therapy even when post-resection pathological assessment reveals a complete remission [11]. In vitro studies suggest that chemotherapy and radiotherapy may cause a “metabolic flare” phenomenon secondary to the activation of energy-dependent cellular repair mechanisms [26,27]. Based on these in vitro data it has been recommended that the assessment of tumour response should not be performed immediately after the completion of therapy. However, in these in vitro studies, FDG uptake was measured “per surviving cells”. This differs from the clinical situation, in which PET changes result from a combination of decreased FDG uptake caused by cancer cell death plus potentially increased FDG uptake by surviving tumour cells. In the clinical setting, a temporary increase of tumour FDG uptake in response to chemo- or radiotherapy has been observed only in the first hours after high-dose radiotherapy of brain tumours [28,29]. Currently available information supports the recommendation that post-treatment FDG-PET imaging should be performed at least 2 weeks after the end of the chemotherapy cycle. It may be assumed that the transient and non-durable

changes in FDG uptake that can occur in tumours during the immediate post-treatment period will be minimized using this approach [29]. Data on treatment interval after the completion of radiotherapy are even less conclusive. Acute inflammatory changes with subsequent alterations in FDG uptake in both tumour and surrounding tissue have been documented [30]. Newer radiation therapies – such as gamma-knife and focal high-dose radiation – are associated with enhanced inflammatory reactions, confounding the interpretation of post-treatment FDG-PET scan if performed within a short period after completion of these therapies [31]. A delay of 6–8 weeks or longer after radiation therapy has been recommended before a post-treatment FDG-PET scan is performed. In order to achieve standardization in the assessment of the response to FDG-PET, in 1999 the European Organization for Research and Treatment of Cancer (EORTC) proposed guidelines; these were followed more recently by those of the National Cancer Institute [32,33]. Unfortunately, both consensus statements have failed to resolve ongoing debate regarding the parameters that should be measured at the time of the assessment of the therapeutic response, when they should be measured, and how a response should be defined. In fact, most of the available studies have used different criteria to classify patients as metabolic responders or non-responders. Frequently these criteria were defined retrospectively, and this may potentially be responsible for an overestimation of the predictive value of FDG-PET for tumour response or patient survival [14] (Table 1). A potential pragmatic approach may limit the comparative assessment to the intra-individual comparison of tumour FDG uptake. If this is the case, many of the confounding factors will be eliminated, especially if the baseline and follow-up scans are acquired and analysed according to the same protocol. Data from two small clinical studies evaluating the test/retest reproducibility of FDG-PET suggest that a relative decrease in the SUV of the tumour by more than 20%, a coefficient of variation of approximately 10%, and an absolute decrease by more than one-fold could be used as a definition for a metabolic response in phase-II studies [17,34]. 3.1. Cytotoxic chemotherapy In local NSCLC, Ichiya et al. published the first trial assessing the potential role of FDG-PET in predicting the response to therapy. Thirty untreated patients with NSCLC were included in the study. At baseline no significant differences in the FDG uptake were observed according to the histological types and extent of the primary tumour. Tumours with a higher SUV (≥7) responded better to therapy than those with a lower SUV (P < 0.05). The decrease in the uptake after therapy tended to be more relevant among responders than in patients with disease stabilization. The authors concluded that FDG-PET can predict tumour response to induction therapy, and that changes in FDG uptake before,

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Table 1 Studies evaluating the role of 18 F-FDG-PET for therapeutic response assessment in non-small-cell lung cancer (NSCLC). Study

Year

Stage

Criteria for response on FDG-PET

Design

P-value

MacManus Tanvetyanon de Geus-Oei Hellwig Vansteenkiste Hoekstra Dooms

2003 2008 2007 2004 1998 2005 2008

I–III IB–IIIB IB–IV IIB–IV IIIA IIIA IIIA

Prospective Prospective Prospective Prospective Prospective Prospective Retrospective

0.0004 NS 0.017 <0.001 0.03 0.0003

Decoster Pottgen Eschman Weber Nahmias

2008 2006 2007 2003 2007

IIIA–IIIB III III IIIB–IV IIIB–IV

Complete metabolic response Complete metabolic response or partial metabolic response Rate of glucose metabolism > 47% 35% decrease in SUV SUV < 4 50% decrease in SUV Rate of glucose metabolism < 0.13 ␮mol/mL/min Pathological response in mediastinal lymph node and > 60% decrease in SUV in primary tumour Complete metabolic response 50% decrease in SUV Complete metabolic response or 80% decrease in SUV 20% decrease in SUV Decrease in SUV at weeks 1 and 3

Retrospective Retrospective Retrospective Prospective Prospective

0.004 <0.005 <0.005 0.005 0.0016

Modified from Hicks [59].

during or after neo-adjuvant treatment correlates with the outcome [35]. In a prospective study of 47 patients with locally advanced, potentially resectable stage-IIIA N2 NSCLC treated with neo-adjuvant chemotherapy, a reassessment with FDG-PET performed after one cycle of chemotherapy showed that a decrease in FDG uptake ≥35% correlated with an increased survival (P = 0.03). In this study, the monitoring of therapeutic response with FDG-PET was better than with CT, and also enabled an early prediction of survival during the preoperative treatment [12]. Lee et al. retrospectively considered 44 patients with locally advanced NSCLC treated with neo-adjuvant chemotherapy followed by surgery. The aim of the study was to assess the value of tumour response using combined FDG-PET and CT scan data for the prediction of clinical outcome and pathological response. Radiological-metabolic responders had a longer time to recurrence (TTR) than nonresponders: mean TTR, 58.7 months versus 22.3 months (P = 0.001) with ≥30% reduction of size and ≥50% reduction of maximum SUV (SUVmax ), and mean TTR, 49.4 months versus 23.5 months (P = 0.022) with ≥30% reduction of size and ≥25% reduction of SUVmax , respectively. The TTR of radiological responders (≥30% reduction in size) and metabolic responders (≥25% reduction in SUVmax ) did not differ from the TTR of non-responders (P > 0.05). The accuracy of the prediction of pathological response was 70% in radiological responders, 75% in metabolic responders, and 82% in radiological-metabolic responders. This study may not be considered conclusive because of its retrospective design and the small number of patients included [36]. In a recent prospective study of 57 patients with stage-IIIB or -IV unresectable NSCLC – who underwent restaging with FDG-PET after one cycle of platinum-based chemotherapy – a decrease in SUV ≥ 20% in the primary tumour was an independent predictor of long-term survival [13]. The metabolic response was highly correlated with best response to therapy according to RECIST as assessed by serial CT scans, and was associated with a higher overall survival than in

non-responders (median survival time of 252 days versus 151 days for patients without a metabolic response at restaging with FDG-PET). Nahmias et al. reported a small study aimed at assessing the early response to chemotherapy with FDG-PET performed weekly in patients with stage-IIIB and -IV NSCLC. Sixteen patients were enrolled, and they were assessed weekly for 7 weeks while they received front-line chemotherapy with carboplatin and docetaxel. Tissue activity was assessed by the amount of radioactivity retained 90 min after the intravenous injection of 18 FDG. The linear least-squares method was used to evaluate the time course of metabolic activity in tumour and liver, bone marrow, and unaffected lung tissues; a metabolic response was defined as a response in which the slope of the regression was negative and significantly different from zero. Eight patients were classified as non-responders as the slope of the regression of tumour SUV versus time was not different from zero, and the median overall survival time in this group of patients was 20 weeks. Seven patients were classified as responders; five survived and two died, one at week 25 and the other at week 76. There was no statistically significant difference between the SUV obtained on day 1 and on day 7 either in the overall group or when the responders and non-responders were considered separately [37]. The authors concluded that although the study was conducted in an extremely limited sample of patients, it demonstrated that patients who respond to chemotherapy can be identified early in the course of chemotherapy with FDG-PET. Currently FDG-PET imaging should not still be considered in therapeutic decisions concerning eligibility for surgical resection or dose-escalated radiotherapy after neoadjuvant treatment of NSCLC. This recommendation is supported by the findings of a study by Poettgen et al. that correlated PET/CT imaging and histopathology after neoadjuvant therapy. Forty-six patients with stage-IIIA and -IIIB NSCLC were resected after neo-adjuvant therapy. Pathological complete response of the primary tumour was observed in 19 patients (41%) with a broad range of SUV (mean)

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(0.4–9.8, mean 3.0) after neo-adjuvant therapy. A high rate of histopathological complete remissions (44%) was observed in tumours with a post-induction SUV > 2.5 and volumes larger than the median (7.9 cm3 ) before resection. Mean SUV was positively correlated with the macrophage score (r = 0.39, P = 0.007) and tumour cell density (r = 0.32, P = 0.03). These observations suggest that post-induction FDG uptake should be interpreted with caution in larger residual tumour volumes since, as also reported above, high SUV levels may be due to macrophage infiltration and not viable tumour tissue [38]. This note of caution is actually supported by the results of a systematic review by Rebollo-Aguirre et al. about the role of FDG-PET for evaluating response after neo-adjuvant therapy; for the final analysis they considered nine of 497 published papers. The authors observed a lack of standardized protocols for patient preparation, image acquisition, and imaging interpretation; the ranges of sensitivity, specificity, and positive and negative predictive values for primary tumour response assessment were 80–100%, 0–100%, 42.9–100%, and 66.7–100%, respectively. FDG-PET seems to be an accurate non-invasive method to predict long-term outcome and may be an important step towards patient-tailored induction therapy response in NSCLC, but the results of the analysis do not support the use of FDG-PET as the only reassessment tool for mediastinal lymph-node evaluation for routine clinical use [39,40].

3.2. Molecular targeted therapies Two phase-III clinical trials which tested the role of the epidermal growth factor receptor (EGFR) tyrosine inhibitors erlotinib and gefitinib in patients with refractory or relapsed NSCLC after platinum-based chemotherapy indicate the need for new criteria to evaluate therapeutic responses in solid tumours [17,41,42]. In a placebo-controlled phase-III study treatment with erlotinib prolonged median overall survival of chemotherapyrefractory patients. The objective tumour response rate as measured by CT scan was only 9%. In a similar phase-III study gefitinib induced a comparable response rate of 8% by CT; however, in this study CT response was not associated with an additional statistically significant survival benefit. These data imply that tumour size reduction by CT is a poor predictor of patient survival after treatment with EGFR kinase inhibitors. Potentially, FDG-PET is attractive for monitoring treatment with protein kinase inhibitors, because many signalling pathways targeted by protein kinase inhibitors have a well-established role also in regulating tumour glucose metabolism. The protein kinase Akt is a central regulator of cellular apoptosis, but it is also involved in regulation of glucose metabolism both in normal tissues and in cancer cells [43–48].

Treatment with EGFR kinase inhibitors has been shown to inhibit Akt phosphorylation in gefitinib-sensitive but not gefitinib-resistant tumours [49]. Su et al. measured early changes in tumour glucose consumption in gefitinib-sensitive cell lines to predict early tumour response. FDG uptake per viable tumour cell decreases as early as 2 h after exposure to gefitinib. These data suggest that the decrease in the FDG signal is not caused by cell death, but reflects changes in glucose metabolic activity of viable tumour cells; in sensitive cell lines, gefitinib led to the translocation of glucose transporters from the plasma membrane to the cytosol. The functional consequences of this translocation determine a 50% decrease in initial transport rates and a 25% decrease in uptake at equilibrium and precedes cell death [50,51]. Recently Mileshkin et al. reported the results of a prospective international study which evaluated whether ontreatment 18 F-deoxyglucose (FDG) and 18 F-deoxythymidine (FLT) PET responses predict improved progression-free survival (PFS) and overall survival (OS) following treatment in second/third-line NSCLC with erlotinib. The study confirmed that partial metabolic response at day 14 FDG-PET is positively associated with improved PFS and OS, even in the absence of a later morphological response by RECIST. An early FDG-PET response may be particularly useful in the wild-type EGFR group or other clinical subgroups in which the likelihood of a response to EGFR-TKIs is low [52]. Choi et al. prospectively compared FLT- and FDG-PET in 20 patients with NSCLC for early prediction of response to erlotinib. After 6 weeks of therapy, they reported six partial responders, disease stabilization in one and progressive disease in 13 patients. The baseline SUVmax of the primary tumour did not significantly differ between responders and non-responders with FLT (6.2 ± 1.4 versus 6.5 ± 2.1, P = 0.765) and FDG-PET (14.1 ± 6.2 versus 12.7 ± 4.6, P = 0.565). On day 7 after therapy, the percentage change in SUVmax was significantly different between responders and non-responders in FLT- (−38.7 ± 3.4% versus 3.9 ± 20.4%, P < 0.001) and FDG-PET (−38.0 ± 16.5% versus 0.1 ± 14.1%, P = 0.001). The sensitivity, specificity, and positive and negative predictive values of percentage change in SUVmax were all 100.0% in FLT-PET (cut-off value, ≤34.6%), and 92.9%, 100%, 100%, 85.7% in FDGPET (cut-off value, ≤20.3%), respectively. The time to progression was significantly longer in responders than in non-responders (P < 0.001). The authors concluded that the SUVmax percentage change in the primary tumour as assessed by FLT- or FDG-PET after 7 days of therapy with erlotinib was a promising predictive variable of the response [53]. Few data are available about the role of FDG-PET and other targeted agents. In a prospective trial involving eight patients with advanced relapsed NSCLC treated with singleagent everolimus, FDG-PET was suggested as a possible method for the early evaluation of pharmacodynamic effects of mTOR inhibition in this setting [54].

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4. New biomarkers and functional imaging The thymidine analogue FLT has been evaluated in several studies as a marker of tumour cell proliferation [55]. Initial preclinical and clinical studies in untreated tumours have confirmed that tumour FLT uptake is well correlated with histological markers of neoplastic cell proliferation [17]. FLT-PET has been used preclinically to test the activity of histone deacetylase (HDAC) inhibitors, an expanding class of growth-inhibiting compounds targeting DNA and RNA. A variety of PET imaging probes for imaging angiogenesis, and hence potentially anti-angiogenic effects, has been synthesized [56]. These include perfusion tracers such as 15 O-labelled H O, hypoxia markers such as 18 FHX4 [57], 2 monoclonal antibodies against vascular endothelial growth factor (VEGF) and ligands for the ␣v␤3 integrins [17]. Reporter gene imaging can be used non-invasively to assess the expression of a variety of genes and the modulation of gene expression by alternative therapies. The feasibility of this concept has been demonstrated for several genes critical for the growth of malignant tumours [58]. Finally, the use of therapeutic compounds themselves as imaging tools to test whether the compound hits the designated targeted sites is another way through which functional imaging can be used to improve drug development [10]. 5. Conclusion The strength of FDG-PET when compared with nonimaging predictors of response to treatment relies on its ability to image a biochemical process in a living organism. Data about FDG-PET in the assessment of the therapeutic response strongly indicate that a reduction of 18 F-FDG tissue retention, however it is measured and whatever time after treatment it is performed, is more likely to be associated with both a pathological response and improved survival than the absence of any change in the metabolic response. Nevertheless, the lack of reproducibility and standardization of the measurement of the response, and poor harmonization of response criteria, are currently strong limiting factors to the qualification of FDG-PET as a predictive marker. In conclusion, based on the preliminary evidence reviewed in this paper, prospective multi-institutional studies aimed at the standardization of PET imaging protocols and with prospectively predefined response criteria are urgently awaited. Conflict of interest statement None of the named authors have any financial relationships that might bias the work or interfere with objective judgment. Role of the funding source Sponsors have not been involved in study design, collection, analysis or interpretation of data, in the writing of the

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Biography Dr. Novello is currently Assistant Professor in Respiratory Medicine at the University of Turin, Department of Clinical & Biological Sciences. Graduated in Medicine at the

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University of Torino in 1995, she is also postgraduted in Respiratory Medicine (1995–99) and in Medical Oncology (2006–2010). She has been fellow at the Gustave Roussy Institute – Service de Medicine (Chef de Service Dr. Thierry Le Chevalier) and research fellow at the Department of Clinical & Biological Sciences, University of Torino (2001–04). Dr. Novello obtained a PhD in Medical Oncology at the same University (2002–06). From 2004 to 2010 has been appointed as physician on staff at the Thoracic Oncology Unit at S. Luigi Hospital, Orbassano (Torino). Member of ASCO, International Association for the Study of Lung Cancer (IASLC), she is board member of the Scientific Committee of National Lung Cancer Partnership, of the Scientific Committee of WELAS (a IARC program approved by CEE) and president of WALCE (Women Against Lung Cancer in Europe). Recently elected as a IASLC Board of Director member (4 years mandate). Research interest: Lung Cancer, Supportive Care, Screening, Women and Lung Cancer, Translational Research.