Monitoring Response to Therapeutic Interventions in Patients With Cancer

Monitoring Response to Therapeutic Interventions in Patients With Cancer Ken Herrmann, MD,* Bernd Joachim Krause, MD,* Ralph A. Bundschuh, PhD,* Tobias Dechow, MD,† and Markus Schwaiger, MD* Positron emission tomography (PET) and PET/computed tomography (CT) with the glucose analog 18F-fluorodeoxyglucose (FDG) are increasingly used to assess response to therapy in patients, and there is converging evidence that changes in glucose utilization during therapy can be used to predict clinical outcome. Today, integrated PET/CT systems have mainly replaced stand-alone PET devices, providing the opportunity to integrate morphologic information and functional information. However, the use of PET/CT systems also gives rise to methodological challenges for the quantitative analysis of PET scans for treatment monitoring. Recently published single-center studies demonstrate that FDG-PET and FDG-PET/CT have been successfully used for monitoring of tumor response to cytotoxic therapy in a variety of tumor entities. The potential early identification of nonresponding tumors provides an opportunity to alter treatment regimens according to the individual chemosensitivity of the tumor tissue. In this article, we review the methodological background to monitoring of cancer treatment with PET/CT, the diagnostic and prognostic performance of PET/CT for predicting tumor response with the glucose analog FDG in various tumor entities, and the clinical potential of new imaging probes. In addition, the future direction of research and clinical applications is discussed. Semin Nucl Med 39:210-232 © 2009 Elsevier Inc. All rights reserved.

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edical imaging methods have been advanced greatly during the last 100 years, with impressive clinical results. Through the use of imaging technologies with submillimeter resolution, early diagnosis of disease is now possible with high sensitivity and specificity. Besides improved visualization of morphology, newer strategies aim at the visualization of biologic processes, allowing the functional identification of pathology before tissue damage occurs. These advances have proven especially useful in the diagnostic and prognostic workup of patients with proven or suspected cancer. Early detection of malignant lesions and accurate staging of disease extent have positively affected patient outcome. In addition, the assessment of treatment response by imaging is increasingly recognized to provide important information for patient management. Currently, changes in tumor size are used to assess tumor response to therapy. The initially estab-

*Department of Nuclear Medicine, Technische Universität München, Munich, Germany. †Department of Internal Medicine III, Technische Universität München, Munich, Germany. Address reprint requests to Ken Herrmann, MD, Department of Nuclear Medicine, Technische Universität München, Ismaningerstr 22, D-81675 Munich, Germany. E-mail: [email protected]

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0001-2998/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.semnuclmed.2008.12.001

lished World Health Organization criteria of response based on 2 perpendicular diameters of tumor size1 have been replaced by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, which apply a unidimensional measurement model providing a combined assessment of all existing lesions.2,3 The limitations of these criteria are known: morphologic observations may not always be representative of tumor response because therapy-induced fibrosis, inflammation, or edema may mimic residual tumor and shrinking tumor masses may still contain viable tumor cells. With the introduction of molecular imaging, functional parameters of tumor biology can be visualized and tumor response defined more specifically.4-6 For example, decrease in tumor metabolism has been shown to precede tumor size reduction because morphologic changes associated with therapeutic success occur only during a prolonged period. As a consequence, tumor response may not be reliably assessed by anatomic imaging when only computed tomography (CT), magnetic resonance imaging (MRI), or endoscopic ultrasound are used.7-10 Positron emission tomography (PET) in combination with tumor-seeking radiopharmaceuticals has been shown to play a promising role in the clinical assessment of therapeutic interventions in tumor patients. Most clinical experience ex-

Monitoring response to therapeutic interventions in cancer ists with the glucose analog 18F-fluorodeoxyglucose (FDG), which has been correlated as marker of tumor metabolism with histopathologic and clinical outcome in a variety of tumor entities. First results suggest that this tracer can be successfully applied for monitoring tumor response to cytotoxic therapy and that changes in glucose utilization during therapy can be used to predict response and clinical outcome.11 Tumor FDG uptake as assessed quantitatively by PET has been shown to correlate with the number of viable tumor cells, whereas new experimental PET compounds target specific biologic processes, such as proliferation (18F-3=-fluoro3=-deoxy-L-thymidine [FLT]), angiogenesis (18F-galacto-arginine-glycine-aspartic acid [RGD]), apoptosis (Annexin-V), and hypoxia (18F-fluoromisonidazole [FMISO], 18F-fluoroazomycin arabinoside [FAZA]). These imaging targets represent key processes in oncogenesis and are expected to provide meaningful information for selection and monitoring of targeted therapy in an individual patient. On the basis of the in vivo characterization of tumor biology by imaging, personalized medicine may become possible in cancer patients. In parallel with the advances in molecular imaging, the introduction of multimodal imaging instrumentation is supporting the integration of anatomy and biology. PET/CT represents the first step in combining anatomic and metabolic information through almost simultaneous coregistered data acquisition.12 Besides having the logistical advantage of shortening the diagnostic process, whole-body PET/CT has been shown to be a superior diagnostic tool for the localization and characterization of malignant lesions. This advantage has been rapidly recognized by the imaging community and has revolutionized the clinical practice of PET in oncology. More recently the potential of PET/CT for therapy monitoring has been addressed in numerous investigations.5,6,11 The clinical success of multimodal imaging with PET/CT is expected to promote the combination of MRI and PET in the future, not only providing the integration of anatomy and biology but also adding physiologic parameters such as tumor blood volume, perfusion, and water diffusion. This article attempts to provide an overview of the currently available experience with PET and PET/CT for monitoring cancer therapy. We shall first address the methodological aspects of image acquisition and analysis, which are important for the required standardization of therapy monitoring by imaging approaches. Second, we shall discuss the diagnostic and prognostic performance of PET/CT in assessing and predicting tumor response with the metabolic marker FDG. Third, the clinical potential of new imaging probes will be presented in context with the expanding biologic understanding of the involved disease processes. Finally, future directions for research and clinical applications will be addressed.

Methodological Considerations Therapy monitoring requires a high level of standardization and reproducibility of imaging because it aims to assess changes in tracer uptake during a period of weeks to months.5,11 Additionally, imaging signals can only serve as a

211 surrogate endpoint if the results correlate with clinical outcome and patient survival. In contrast to morphologic parameters, biologic imaging markers are subject to considerable inter- and intraindividual variability and thus are more susceptible to physiologic variations that must be taken into consideration to design adequate imaging protocols. A guideline has recently been published for patient preparation, data acquisition, data processing, data analysis, and data interpretation.13 With respect to patient preparation, standardization of the following parameters has to be considered: physical activity (no strenuous exercise before PET scan), metabolic state (fasting before injection), blood glucose level at the time of injection, standardization of activity dose (body weight and/or body mass index dependence), hydration, stimulation of diuresis (for renal/pelvic imaging and reduction of bladder activity), medication (sedatives), comfortable surroundings (avoidance of temperature effects and muscular uptake), and time point of imaging (60 minutes vs 90 minutes postinjection).13 Despite the increasing use of PET/CT to predict therapeutic response, there is still little standardization of protocols for therapy response assessment. In 1999, the European Organisation for Research and Treatment of Cancer (EORTC) published the first guideline for therapy response assessment with FDG-PET.14 More recently, the National Cancer Institute published a guideline with consensus recommendations with the aim of standardizing the assessment of therapy response with PET.15 Specifications of different PET/CT systems that cause signal variations have to be taken into account to ensure reliable data acquisition. Signal variations can be minimized by using the same imaging instrumentation for serial imaging.16 Identical patient positioning in serial imaging is required to guarantee comparability of the data and to increase the validity of interscan comparisons.15 Another challenge of PET/CT imaging is the coregistration of imaging data as a result of the different acquisition characteristics of PET and CT (shallow free breathing vs mid-/end-expiratory breathing).17 One way to overcome this limitation is the use of respiratory gating, especially in small pulmonary lesions or lesions in the lower lung fields,18,19 or the application of motion correction algorithms.20 Because robustness of simple data acquisition is of major importance for therapy response assessment, especially with respect to multicenter studies, more complex coregistration techniques such as respiratory gating and motion correction are not implemented routinely in clinical applications. Attenuation correction is a prerequisite for the quantification of the PET signal. In the case of PET/CT, attenuation correction of PET emission data are based on a CT attenuation map measured with effective photon energies differing from PET transmission source energies (70-140 keV vs 511 keV). A bilinear rescaling of CT-derived attenuation coefficients is commonly used to create attenuation maps comparable with those obtained with 511-keV photons.21 Nevertheless, application of CT contrast media (oral and/or intravenous) may result in a regional overestimation of the activity concentration.22 Although a low-dose noncontrast-

212 enhanced CT scan for attenuation correction before PET avoids this problem,5 attenuation correction is increasingly performed with diagnostic CT scans in clinical practice. Moreover, attenuation correction may lead to artifacts as the result of misalignment between PET and CT, especially in the vicinity of the liver/lung border as the attenuation correction factors of lung and soft tissue differ significantly.23 Optimal image reconstruction depends on the PET scanner and the injected activities; hence, a general parameter setting cannot be defined. To minimize interstudy variability, a number of different parameters—image reconstruction methods and parameters, filters, and application of the attenuation map— have to be consistent across serial scans in a patient.15 Alternatively, as proposed by Weber and Figlin,5 standardization of data acquisition also can be achieved by requesting phantom measurements for the calibration of different imaging instrumentation. Methodological evaluation is recommended for each implementation of new reconstruction algorithms (point-spread function, time-of-flight), which have not yet been validated for quantification in larger studies. Besides the standardization of imaging parameters, biologic understanding of the imaging probe is required to interpret the imaging result. Increased consumption of glucose is a characteristic of most tumor cells and is partially related to overexpression of the glucose transporter-1 (Glut-1) and increased hexokinase activity. This principle enables the visualization of tumor tissue with high sensitivity. However, the specificity is reduced as a result of physiologic glucose tissue uptake (brown fat, colonic and gynecologic activity, infections and inflammations, and rebound thymic hyperplasia). Nonspecific FDG accumulation in inflammatory lesions is of major importance for therapy monitoring. False overestimation of FDG uptake might occur in tumors with an inflammatory component or, more often, because of radiationmediated inflammatory processes (that may persist from weeks up to months), potentially influencing the assessment of changes in glucose metabolism during therapy response assessment. The authors of several studies have proven a correlation of FDG uptake with expression of Glut-1 and/or hexokinase activity by using immunohistochemical parameters.24-27 Recently published data suggest that increased glycolytic rates of cancer cells are not only secondary to cellular proliferation and intratumoral hypoxia but also are caused by genetic alterations in various oncogenic signaling pathways that result in resistance to apoptosis, shutdown of oxidative phosphorylation, and activation of glycolysis.28 Additionally, reduction of FDG uptake is not necessarily associated with cell death, but also can be induced by a translocation of glucose transporters from the plasma membrane to the cytosol.29 Clinical confirmation of these experimental observations underlines the promising value of FDG-PET for monitoring inhibition of these signaling pathways by targeted drugs. The standardized uptake value (SUV) has been introduced as a simple method to standardize the FDG uptake in a semiquantitative way. Injected activity is normalized to patient characteristics (body weight,30 lean body mass,31 or body

K. Herrmann et al surface area32). As an additional correction factor for the SUV, the plasma glucose level of the patient has been suggested.33 Hoekstra and colleagues34 correlated the different SUVs with the metabolic glucose rate obtained by linear regression of dynamic data as the gold standard and showed that the intraindividual variance in the plasma glucose level had the greatest influence on SUV calculation. The combination of normalization to body weight and correction for differences in interstudy plasma glucose level is recommended. For the assessment of a lesion SUV, the use of the SUVmax is the simplest method, with low interobserver variability. The disadvantage of SUVmax, however, is its sensitivity to statistical noise, leading to high fluctuations in the uptake value. To reduce statistical fluctuations, the SUVmean within a defined region of interest (ROI) centered around the voxel with the SUVmax was introduced.35 Weber and coworkers.36 showed that glucose utilization can be assessed with high reproducibility by the use of a 2D ROI with a diameter of 1.5 cm around the hottest voxel. The authors investigated 16 patients with a total of 50 lesions who underwent 2 PET scans within 10 days and showed that there was a high reproducibility for the SUV measurements.36 The fixed size 2D ROI approach has been established and validated in a number of studies.9,37-43 Recently, other techniques have been described, including circular 3D ROI around the hottest pixel,36 volumes of interest (VOIs), thresholding techniques (isocontours44), and freehand drawing. These approaches have not been validated yet and must be assessed with respect to their robustness and their practicability in multicenter trials.15 Kinetic modeling of glucose utilization with nonlinear regression techniques13 (2- or 3-compartment models) represents the most accurate way to analyze dynamic PET data. However, Weber and coworkers36 showed that there was no significant difference for prediction of response to therapy for SUVmean in comparison with tracer kinetic approaches (FDG net influx constants [ki] and influx constants [ki,gluc]) and glucose-normalized SUVmean. Because of its complexity, including the requirement of an arterial input function (arterial blood sampling45 or image derived46), kinetic modeling remains mainly limited to scientific investigations. Several studies have investigated the possibility of analyzing dynamic data with simplified methods such as linearized Patlak analysis47,48 or other approaches.33 Furthermore, dual-time point imaging was introduced to obtain a minimum of dynamic information. Despite promising results for diagnosis or staging (eg, differentiation between malignancies and inflammatory processes),49,50 the role of dual-time point imaging for therapy monitoring remains to be determined. Partial volume effects have to be taken into account when performing SUV measurements as well as when analyzing dynamic PET data to quantitatively assess therapy response. Partial volume effects occur if the lesion size is smaller than three times the spatial resolution of the PET scanner51,52 and may lead to underestimation of the glucose uptake in small lesions. Such underestimation has the potential to result in an overestimation of the SUV decrease after therapy in a shrinking lesion and subsequently in a wrong classification as a metabolic responder. To overcome these effects, several cor-

Monitoring response to therapeutic interventions in cancer rection strategies can be used.53 For most of them the lesion size needs to be defined. Therefore, combined PET/CT acquisition offers advantages as the lesion size can be measured with high resolution and used to correct the PET data.54,55 One major challenge is the clinical validation of response assessment by PET/CT. Histopathologic response is considered the gold standard, but complete resection of the tumor is necessary for a complete histopathologic response analysis. Thus, histopathologic response can only be determined in the case of preoperative (radio-) chemotherapy, as previously performed in numerous studies.9,42,43,54 In esophageal cancer, histopathologic regression can be assessed according to the classification published by Becker and coworkers. Histopathologic response (regression grade I) is defined as less than 10% vital tumor cells in the operative specimen after neoadjuvant chemotherapy, whereas histopathologic nonresponding tumors show 10-50% (regression grade II) or ⬎50% (regression grade III) remaining vital tumor cells.56 The use of imaging as a surrogate endpoint requires demonstration of a significant relationship between imaging results and clinical outcome.5,57 In the era of evidence-based medicine, prospective randomized trials are mandatory for this purpose. To our knowledge, no prospective randomized trial involving PET or PET/CT in therapy monitoring has been published as yet. A number of single-center studies have been performed, with promising results (Tables 1 and 2). There is no question that randomized trials are needed to firmly establish the clinical role of PET and PET/CT in therapy monitoring, but the logistical and financial requirements have to be addressed. Cooperation between the pharmaceutical and the instrumentation industry is needed to support such trials, and attempts have to be made to obtain funding from national and international funding agencies (National Institutes of Health, European Union, etc). For the preparation of such trials, the diagnostic performance of a chosen surrogate endpoint has to be carefully defined. The relationship of sensitivity and specificity of the selected imaging criteria may vary depending on the response pattern of the investigated tumor entity. In lymphoma patients—with expected response rates greater than 50%—it is important to identify patients responding to the treatment with high sensitivity and high positive predictive value. However, in solid tumors, the expected treatment response rates are significantly lower. Therefore, the clinical task of imaging in this setting is to correctly identify nonresponding patients early during therapy to avoid toxic, expensive, and ineffective treatment; this demands a high negative predictive value of the test. This different response pattern has to be considered when selecting imaging time points during therapy for response assessment. Different protocols have been applied for the evaluation of response to therapy (single vs serial scans, early vs late assessment). Single-scan approaches are based on the assumption that residual FDG uptake after chemo(radio)therapy is a specific marker for viable residual tumor tissue.8,58 This approach is subject to variance of biologic imaging signals which causes difficulties in defining an absolute SUV cut-off for prediction of therapy response. Conversely, several stud-

213 ies have investigated the prognostic relevance of quantitative changes in FDG uptake late and early after start of therapy compared with baseline values before treatment.37,42 After completion of therapy, low residual FDG uptake comparable to background is expected in responding patients; therefore, remaining focal uptake most probably represents viable tumor tissue. However, early after the start of therapy, FDG uptake is expected to decrease at different slopes in responders and nonresponders. Therefore, quantitative analysis of SUV changes between baseline scan and follow-up scan is used to differentiate between responding and nonresponding patients. Performance of serial scans using standardized preparation and acquisition setup is expected to be less susceptible to systematic errors as compared with the singlescan approach. To differentiate metabolic responders from nonresponders, metabolic thresholds for the changes in SUV have to be defined. In a first step these thresholds have to be established. They may depend on various factors, including tumor entity, time point (late vs early), and therapy. Values in a range of 20-70% have been published for therapy-associated decreases in SUV. Once a threshold has been established for one tumor entity, it cannot be easily extrapolated to other tumor entities. As an example, for early therapy response assessment in esophageal cancer a threshold of 30% has been established for squamous cell cancer,43 whereas the threshold is 35% for adenocarcinoma.40,42 In the next step, established thresholds need to be validated in prospective clinical studies or, more importantly, in randomized multicenter trials. In summary, from a methodological point of view, the most important issue in therapy monitoring using PET/CT is the standardization of patient preparation, data acquisition and processing, and data interpretation, especially for the purpose of prospective randomized multicenter studies. Validation should be done using correlation with clinical outcome. Because of the high variability in biomarker uptake and the different mechanisms of antitumor therapy, it may be necessary for therapy response criteria to be established and validated for different tumor entities and for different therapy regimens.

Therapy Monitoring with 18F-FDG-PET/CT Numerous clinical studies have evaluated the role of FDGPET for assessment of early and late therapy response (Tables 1 and 2), tumor control, and prediction of prognosis. Especially the evaluation of response to therapy appears to be one of the most promising future indications for 18F-FDGPET/CT imaging in clinical routine. The following section gives an overview of the role of 18F-FDG-PET/CT in the assessment of therapy response and prognosis, with special emphasis on early therapy response evaluation.

Lymphoma Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) are malignancies with a high potential for cure using

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Table 1 Overview of Studies Regarding Early Evaluation of Therapy Response With FDG-PET and FDG-PET/CT Tumor

First Author

Year

No. Patients

Criteria

Time Point

Lymphoma

Haioun Hutchings Weber Hoekstra Weber Wieder Ott Lordick Ott Ott Cascini Rosenberg Schelling Smith Dose Schwarz¶ Avril Strobel Brun Stroobants Goerres Holdsworth Choi

2005 2006 2003 2005 2001 2004 2006 2007 2003 2008 2006 2008 2000 2000 2005 2005 2008 2002 2003 2005 2007 2007

90 77 57 56 37 22 65 110 35 71 33 29 22 30 11 33 25 47 17 28 63 40

Visual Visual ⴚ20% ⴚ35% ⴚ35% ⴚ30% ⴚ35% ⴚ35% ⴚ35% ⴚ35% ⴚ52% ⴚ35% ⴚ55% ⴚ20% Visual ⴚ20% ⴚ30% Median ⴚ25% Visual ⴚ40% ⴚ70%

2 cycles 2 cycles 2 weeks 2 weeks 2 weeks 2 weeks 2 weeks 2 weeks 2 weeks 2 weeks 12 days 2 weeks 2 weeks 2 weeks 3 weeks 2 weeks 3 cycles 5 to 10 days 8 days 19 days 1 month 2 months

Lung Esophagus

Gastric Colorectal Breast

Ovarian Melanoma Head and neck GIST

Responders 90% 96% 9 43 >48 >38 >42 >36 >48 >35 100% 74% 100% 90% 19.2 38 80% >120 92% >48 26 70%

Nonresponders

P Value

Comment

61% 0% 5 18 20 18 18 26 17 24 100% 70% 85% 74% 8.8 23 40% 40 12% 22 3 30%

0.006 <0.001 0.005 0.04 0.04 0.011 0.01 0.015 0.001 0.037 NA NA NA NA NS 0.008 0.048 0.004 0.001 0.001 0.002 0.01

2-year estimates of overall survival* 2-year progression-free survival† Median survival‡ Median survival‡ Median survival‡ Median survival‡ Median survival‡ Median survival‡ Median survival‡ Median survival‡ Histopathologic response prediction§ Histopathologic response prediction§ Histopathologic response prediction§ Histopathologic response prediction§ Overall survival‡ Median survival‡ 1-year overall survival㥋 Median survival‡ 1-year progression-free survival** Median survival‡ Time to treatment failure‡ 2-years progression-free survival†

NS, not significant; NA, not available. *Percentage of patients with 2-year overall survival. †Percentage of patients with 2-year progression-free. ‡Survival in months. §Sensitivity and specificity for prediction of histopathologic response. ¶Metastatic disease. 㥋Percentage of patients with 1-year overall survival. **Percentage of patients showing 1-year progression-free survival.

K. Herrmann et al

Tumor Lymphoma Lung

Esophagus

Colorectal

Cervix Head and neck Sarcoma

First Author

Year

No.

Criteria

Responders

Nonresponders

P Value

Comment

Spaepen* Juweid‡ MacManus Hellwig Pottgen Brucher Flamen Downey Kim Port Swisher Calvo Guillem Capirci Rosenberg Grigsby Nishiyama** Kunkel Connell Schuetze Hawkins Evilevitch

2001 2005 2003 2004 2006 2001 2002 2003 2007 2007 2004 2003 2004 2007 2008 2004 2008 2003 2007 2005 2005 2007

54 60 73 47 37 27 36 17 62 62 103 21 15 45 29 152 21 35 30 46 36 42

Visual Visual Visual SUV > 4 Visual ⴚ52% Visual ⴚ60% ⴚ80% ⴚ50% SUV > 4 SUV > 2.5 ⴚ62.5% ⴚ66.2% ⴚ57.5% Visual ⴚ65% SUV > 4 Visual ⴚ40% SUV > 2.5 ⴚ60%

31 >48 >36 56 >24 23 >34 63% 31 36 >24 86% >55 81% 79% >60 90% >60 †† >100 72% 100%

10 12 12 19 15 9 8 38% 17 18 15 80% 39 79% 70% 30 82% 18 †† 40 27% 71%

<0.001 0.003 <0.0001 <0.001 0.03 <0.0001 0.005 0.055 0.025 0.03 0.01 NS 0.02 NA NA <0.001 NA 0.046 0.037 0.02 0.01 NA

Median progression-free survival† Progression-free survival† Median survival† Median surviva† Progression-free survival† Median survival† Median survival† 2-year disease-free survival rate§ Disease-free survival† Disease-free survival† Median survival† 3-year survival rate¶ Recurrence-free survival† Histopathologic response prediction㥋 Histopathologic response prediction㥋 Median survival† Histopathologic response prediction㥋 Median survival† Overall survival† Median survival† 4-year progression-free survival‡‡ Histopathologic response prediction㥋

Monitoring response to therapeutic interventions in cancer

Table 2 Overview of Studies Regarding Late Evaluation of Therapy Response With FDG-PET and FDG-PET/CT

NS, not significant; NA, not available. *Hodgkin’s disease. †Survival in months. ‡NHL. §Percentage of patients with 2-year disease-free survival. ¶Percentage of patients with 3-year survival. 㥋Sensitivity and specificity for prediction of histopathologic response. **Ovarian and uterine cancer. ††Not given. ‡‡Percentage of patients with 4-year progression-free survival.

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K. Herrmann et al

216 chemotherapy and/or radiotherapy. In general, the prognosis of high-risk disease defined, for example, by advanced stage, performance status, and specific serum parameters is worse than that of low-risk disease, and high-risk disease thus requires more aggressive therapy regimens.59 Selection of highrisk patients is crucial because more intensive treatments, such as the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for HD or dose-escalated CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone), are associated with greater toxicity, treatment-related deaths, and secondary malignancies.60-62 An important clinical question is how to determine response early in patients undergoing cytotoxic treatment and to adapt dosing and intensity to the individual disease through the use of imaging techniques. In recent years, numerous studies have investigated different approaches to the assessment of treatment response with FDG-PET.63-79 Use of FDG-PET for early assessment of therapy response in lymphoma, for both HD and aggressive NHL, has been studied after 1 to 4 cycles of chemo- and chemoimmunotherapy. In contrast to currently used pretreatment clinical prognostic indices for NHL such as the International Prognostic Index (IPI) and the follicular lymphoma IPI (FLIPI) and molecular genetic profiling,74,76 PET has been used to assess treatment response during and after treatment. The first correlation of PET results with clinical outcome was published by Romer and coworkers,73 who showed that standard chemotherapy of patients with NHL causes a rapid decrease in tumor FDG uptake as early as 7 days after treatment initiation making FDG-PET a promising tool for early prediction of response to chemotherapy. As discussed in a review by Seam and coworkers,75 midtreatment PET has been confirmed to predict clinical outcome in numerous studies.65,66,68,69,71,72,77,79 In a recent publication by Haioun and coworkers,66 early PET results predicted complete response rate, event-free survival, and overall survival irrespective of IPI risk group in 90 patients with aggressive NHL. In a study of 77 patients with HD by Hutchings and coworkers,68 FDGPET was found to predict treatment failure and progressionfree survival (Table 1). For prediction of progression-free survival, early FDG-PET was as accurate after 2 cycles as later during treatment and was superior to CT at all times. A positive early FDG-PET scan proved to be highly predictive of progression in patients with advanced stage or extranodal disease. However, so far no clinical trials in patients with lymphoma have demonstrated a clinical benefit through the change of therapy on the basis of interim PET results. Seam and coworkers therefore proposed that midtreatment PET scans should be reserved for trials investigating clinical outcome prospectively. The use of FDG-PET for assessment of residual masses after completion of therapy and for restaging has also been extensively studied. In the recently published recommendations on the use of FDG-PET in oncology, Fletcher and coworkers80 conclude that FDG-PET should routinely be added to the conventional workup for restaging or detecting recurrence in both NHL and HD patients. This conclusion was

mainly based on 2 systematic reviews.64,67 FDG-PET proved to be beneficial for differentiation of necrotic or scar tissue from active disease in patients with a residual mass. Regarding HD patients, Facey and coworkers64 reviewed 8 PET and 6 CT studies showing that patients with a residual mass after completion of treatment and a negative PET scan are unlikely to experience relapse. Because of a relatively high false-positive rate, Facey and coworkers recommended histologic verification before reinitiating treatment. Terasawa and coworkers78 recently published a systematic review on the role of FDG-PET for posttherapy assessment of HD and aggressive NHL. This review included 19 studies with a total of 474 HD patients and 254 NHL patients, and the reported sensitivity and specificity of FDG-PET for predicting disease relapse ranged from 0.50 to 1.00 and from 0.67 to 1.00, respectively, for HD, and from 0.33 to 0.77 and from 0.82 to 1.00, respectively, for NHL. Terasawa and coworkers concluded that FDG-PET has a good diagnostic accuracy for assessing residual HD at the completion of firstline treatment, even though available evidence is still limited. A recently published study investigated the negative predictive value of FDG-PET for prediction of progression or early relapse in patients presenting residual masses (diameter ⬎2.5 cm) after the end of BEACOPP chemotherapy.81 The negative predictive value of PET was 94% and the corresponding progression-free survival for PET-negative patients was 96% (vs 86% for PET-positive patients, P ⫽ 0.011). The authors concluded that consolidation radiotherapy can be omitted in PET-negative patients with residual disease without increasing the risk for progression or early relapse compared with patients in complete remission. Regarding NHL, clinical data are quite limited and prospective studies are needed. Nevertheless, after the promising results reported by Juweid and coworkers,70 demonstrating that use of FDG-PET in addition to the International Working Group criteria for response assessment of NHL increased the number of complete remissions and the hazard ratio between partial and complete remission, FDG-PET is now an integral part of the recently revised response criteria63 (Table 2). In conclusion, patient stratification based on PET and PET/CT contributes significantly to the optimization of patient management and therapy in lymphoma. Posttherapy assessment has proven to have a high diagnostic accuracy for assessing residual disease.63 The predictive role of midtreatment PET/CT and early, quantitative response assessment remains to be validated in multicenter trials.

Lung Cancer Lung cancer is the leading cause of cancer-related death in both men and women in the United States.82 The prognosis of locally advanced and metastatic disease is poor and therefore new therapeutic approaches have been evaluated in numerous studies. Particularly in non-small cell lung cancer (NSCLC), targeting the epidermal growth factor receptor (EGFR) by antibodies (eg, cetuximab) or EGFR kinase inhibitors (eg, gefitinib, erlotinib) has been shown to improve survival and/or clinical symptoms.83-86 Notably, in the case of EGFR inhibitors, only a sub-

Monitoring response to therapeutic interventions in cancer group of patients seems to benefit considerably from the costly treatment. In locally advanced/metastatic NSCLC, the addition of cetuximab to standard chemotherapy prolonged the median survival from 10.1 to 11.3 months.83 However, the annual costs of cetuximab per patient exceed half a million U.S. dollars. To avoid both ineffective therapies and unnecessary expenses, biomarkers and imaging will be required to provide early prediction of response to treatment and to define distinct subgroups of patients. Early prediction of response to chemotherapy in NSCLC was first studied by Weber and coworkers. Metabolic responders, defined as those with a reduction in SUVmean of more than 20% 2 weeks after the start of chemotherapy, showed a significantly longer time to progression and higher overall survival than metabolic nonresponders (P ⫽ 0.0003 and P ⫽ 0.005, respectively)9 (Table 1). Similar results were obtained by Hoekstra and coworkers in 56 patients; these authors demonstrated that reduction in tumor FDG uptake by more than 35% after one cycle of chemotherapy (compared with baseline) was significantly correlated with better survival (P ⫽ 0.04).87 Quantitative analysis of a postinduction therapy scan showed a similar predictive value as early response evaluation. Regarding response assessment after completion of therapy, MacManus and coworkers compared FDG-PET with CT in 73 patients undergoing radical radiotherapy or chemoradiotherapy8 (Table 2). PET not only classified more complete responders (normalization of FDG uptake in all initially FDG-avid lesions) but also decreased the number of nonassessable patients. In a multifactor analysis including CT response, performance status, weight loss, and stage, only PET response was significantly associated with longer survival (P ⬍ 0.0001). These results have been validated by other studies revealing significantly better median survival for responders versus nonresponders.7,54 In a more recent study, chemotherapy response evaluation after 2 or 3 cycles of chemotherapy revealed a significant difference in survival if patients were dichotomized using median change in metabolic rate of glucose and SUVmean (P ⫽ 0.017 and P ⫽ 0.018, respectively).88 Dooms and coworkers combined primary tumor response by FDG-PET after completion of induction chemotherapy with morphometric tissue analysis of mediastinal lymph nodes for prognostic risk stratification.89 In the group of patients with cleared or persistent minor mediastinal involvement, decrease in primary FDG uptake by more than 60% (decrease in SUVmax after completion of chemotherapy) was correlated with a significantly better 5-year overall survival (62% vs 13%, P ⫽ 0.002). However, patients with persistent major mediastinal disease had a poor prognosis and should not be considered for surgery (5-year overall survival rate: 0%). In summary, for lung cancer, promising data exist for both early and late therapy response assessment.

Esophageal Cancer (Adenocarcinomas and Squamous Cell Carcinomas) Esophageal cancer ranks among the 10 most common malignancies and is a frequent cause of cancer-related death. How-

217 ever, carcinomas of the esophagus represent a heterogeneous group of tumors in terms of etiology, histopathology, and epidemiology. In the upper two-thirds of the esophagus, squamous cell carcinomas (SCC) predominate, whereas carcinomas of the distal esophagus/esophagogastric junction are mostly adenocarcinomas (AEG). It has been shown that neoadjuvant cytotoxic therapy in patients with operable lower esophageal AEG significantly improves progression-free and overall survival.90,91 Besides cytotoxic agents, targeted approaches such as EGFR antibodies are currently under investigation. However, many patients do not respond to neoadjuvant therapy. Early response assessment with FDG-PET/CT might be important in distinguishing responders from nonresponders, thereby avoiding unnecessary toxicity, a lack of clinical benefit, and additional costs. Early therapy monitoring in patients with esophageal cancer was investigated by Weber and coworkers42 in a study cohort of 40 patients with locally advanced AEG, showing that prediction of histopathologic response is possible by metabolic imaging with 18F-FDG as early as 2 weeks after start of induction chemotherapy. Application of the criterion metabolic response— defined as a reduction in baseline SUV of more than 35%—allowed prediction of clinical response with a sensitivity of 93% and a specificity of 95%. Metabolic responders were also characterized by significantly longer time to progression/recurrence (P ⫽ 0.01) and longer overall survival (P ⫽ 0.04; Table 1). The aforementioned 35% SUV threshold was evaluated by Ott and coworkers40 in a prospective study in a total of 65 patients. Histologic responders were detected by PET with a sensitivity of 80% and a specificity of 95%. Metabolic response was also associated with a better 3-year survival rate (70% vs 35%, P ⫽ 0.01). In the subgroup of patients who underwent complete resection (R0), multivariate analysis (covariates: ypT and ypN category, histopathologic response) revealed metabolic response to be the only factor predictive of recurrence (P ⬍ 0.018). On the basis of these findings, in the recently published MUNICON trial,92 treatment was tailored to the individual patient based on the PET results. Metabolic responders (after 2 weeks of induction chemotherapy) continued to receive chemotherapy for a maximum of 12 weeks before undergoing surgery, whereas chemotherapy was discontinued in metabolic nonresponders, and immediate resection performed. In this trial, 110 patients were evaluable for metabolic response and 49% were classified as metabolic responders; 104 patients had resections. Histopathologic response was achieved in 58% of the metabolic responders, but in none of the metabolic nonresponders. Survival analysis revealed better event-free and overall survival for metabolic responders than for nonresponders (respectively: 29.7 vs 14.1 months, P ⫽ 0.002, and not reached vs 25.8, P ⫽ 0.015) (Table 1). Wieder and coworkers43 evaluated the time course of therapy-induced changes in tumor glucose metabolism during chemoradiotherapy in a cohort of 38 patients with esophageal SCC. Early metabolic response, defined as a reduction in baseline SUV of more than 30% at 2 weeks after start of induction chemotherapy, predicted histopathologic re-

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218 sponse with a sensitivity of 93% and a specificity of 88%. Changes in tumor metabolic activity early in the course of preoperative chemoradiotherapy were also significantly correlated with patient survival (P ⬍ 0.011). In a more recent publication by Gillham and coworkers, response evaluation was performed as early as 1 week after the start of chemoradiation.93 However, PET failed to predict histomorphologic tumor response in this study cohort of 32 patients (5 SCC, 27 AEG). The role of FDG-PET after chemo- and chemoradiotherapy as a specific marker for viable residual tumor, associated with a poor prognosis, has also been studied by several groups. In 2001, Brucher and coworkers94 showed in 27 patients with SCC that a threshold of 52% decrease in SUVmean not only was a strong prognostic factor but also differentiated histopathologic responders from nonresponders with a sensitivity and specificity of 100% and 55%, respectively (Table 2). In this study, patients with a reduction in FDG uptake of less than 52% had a significantly shorter median survival (8.8 months vs 22.5 months, P ⬍ 0.0001) compared with patients with a SUV decrease of 52% or more. Comparable results have been reported in other recently published studies. Flamen and coworkers showed that a reduction in the tumor-to-liver FDG uptake ratio of ⬎80% 3 to 4 weeks after completion of neoadjuvant chemoradiation detected response to therapy in a cohort of 36 patients with a sensitivity and specificity of 71% and 82%, respectively.58 In a smaller group of 17 patients, Downey and coworkers95 demonstrated that a reduction in SUVmax of more than 60% after completion of induction chemotherapy compared with baseline scan was correlated with a better 2-year disease-free survival (67% vs 38%, P ⫽ 0.055). In another study by Kim and coworkers in 62 patients, complete metabolic PET response (reduction of SUVmax by ⬎80%) after completion of preoperative chemoradiotherapy correlated significantly with histopathologic response and predicted long-term outcome96 (Table 2). In 62 patients with esophageal carcinoma, Port and coworkers97 compared PET response and clinical response with respect to prediction of pathologic downstaging and disease-free survival. A reduction in SUVmax of more than 50% compared with baseline was more closely associated with improved disease-free survival than was clinical response. Regarding prediction of pathologic downstaging, the two methods appeared of equivalent accuracy. However, Port and coworkers97 showed that a complete absence of residual FDG uptake is not necessarily associated with a complete pathologic response. This observation confirmed an earlier published study by Swisher and coworkers in 103 patients, showing that PET failed to rule out residual microscopic disease. FDG uptake in the tumor bed was not different in patients with no residual viable tumor cells as compared with patients with up to 10% viable tumor cells.98 Swisher and coworkers also investigated the prognostic relevance of residual FDG uptake after completion of neoadjuvant chemoradiation, and claimed that a SUVmax ⬍4 was the best long-term predictor of survival (hazard ratio 3.5, P ⫽ 0.04). The accuracy of FDG-PET for prediction of histopathologic response was comparable to that of CT and

ultrasound. In contrast to these results, Smithers and coworkers found no correlation between PET response and histopathologic response in 45 patients undergoing neoadjuvant chemotherapy or chemoradiation.99 These conflicting results underline the need for randomized multicenter studies with standardized imaging protocols, as recently initiated by EORTC.100 Future approaches may combine metabolic information determined by PET with in vivo tissue characterization obtained by biopsies. Westerterp and coworkers assessed FDG uptake in 26 patients as well as immunohistochemical stains of tumor sections (angiogenic markers [VEGF, CD31], Glut-1, hexokinase [HK] isoforms, proliferation marker [Ki-67], macrophage marker [CD68], and apoptosis marker [cleaved caspase-3]).27 The only parameters associated with FDG uptake were Glut-1 expression and tumor size. In summary, single-center studies investigating quantitative response assessment in patients with esophageal cancer have provided promising results. Based on these studies, the use of PET for modification or potential intensification of perioperative therapy regimens has been suggested—MUNICON I being the first study to show the feasibility of a PET responseguided treatment algorithm. However, the reported results have been the subject of intense debate, underlining the need for randomized multicenter studies with standardized imaging protocols.

Gastric Cancer The prognosis of gastric cancer is highly dependent on tumor stage at the time of diagnosis.101 Patients with locally advanced tumors in the Western world who do not receive perioperative treatment have a poor prognosis, with a 5-year survival rate of 20-30%.102 In addition to early response assessment by FDG-PET/CT in the neoadjuvant setting, metabolic imaging may help to overcome the therapeutic limitations in disseminated disease by guiding the development of new therapy regimens. Clinical studies are evaluating novel therapeutic approaches using new therapeutic agents comprising taxanes, monoclonal antibodies (cetuximab, bevacizumab), and inhibitors (sorafenib, lapatinib). However, the clinical benefit of these regimens has not yet been finally determined. As recently summarized by Ott and coworkers,101 current imaging modalities or in vitro molecular markers cannot reliably predict the therapy response of patients with gastric cancer. Nonresponding patients need to be identified early after the start of therapy to change the therapeutic management and avoid unnecessary side-effects.90 Early assessment of response to neoadjuvant chemotherapy was first studied by Ott and coworkers39 in 44 patients with locally advanced gastric cancer, 35 of whom proved assessable (Table 1). Using the same criterion for differentiating metabolic responders and nonresponders as defined by Weber and coworkers42 for patients with AEG, early response assessment by 18FFDG-PET was able to predict histopathologic response with a sensitivity of 77% and a specificity of 86% (Figs. 1 and 2). Median survival and 2-year survival rate were significantly

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Figure 1 Example of an FDG-PET/CT study in a patient with locally advanced gastric cancer undergoing neoadjuvant chemotherapy. FDG-PET/CT studies were performed before therapy (A-C) and 14 days after the start of neoadjuvant chemotherapy (D-F). (A and D) Transaxial PET; (B and E) transaxial CT; (C and F) fused PET/CT images. Semiquantitative analysis showed a 52% decrease in SUVmean as early as 14 days after start of therapy; histopathology after surgery revealed a histopathological response.

better for metabolic responders (not reached and 90%) than for nonresponders (18.9 months and 25%; P ⫽ 0.002). In this study approximately one-third of gastric cancer patients had initially low FDG uptake. Further analysis showed that FDG-negative tumors were associated with diffuse Lauren classification, small tumor size, good differentiation, mucinous content, and localization in the distal third of the stomach.39 Recently published long-term results have revealed that in locally advanced gastric cancer, three different response patterns exist.41 Metabolic responders had a higher histopathologic response rate (69%) than metabolic nonresponders (17%) and initially FDG-negative patients (24%). Survival of FDG-negative patients was not significantly different from that of FDG-avid nonresponders (36.7 months vs 24.1 months; P ⫽ 0.46), whereas for FDG-avid responders median overall survival had not yet been reached. Ott and coworkers therefore assumed that even though metabolic response assessment is not possible in FDG-negative tumors, a

therapy modification might be considered in this patient subgroup. Another group investigated a different time point and threshold in 41 patients with gastric cancer.103 In this retrospective study, a decrease in the initial SUV of more than 45% after 35 days proved to be the best criterion for predicting response and prognosis to preoperative chemotherapy. Metabolic response was significantly correlated with histopathologic response (less than 50% residual tumor; P ⫽ 0.007) and disease-free survival (P ⫽ 0.01). Again, routine use of these parameters in a clinical setting cannot be recommended before standardization of the imaging procedure, and a prospective evaluation in a multicenter trial has been performed. Because one-third of gastric carcinomas are FDG-negative and therefore not suitable for response monitoring using FDG-PET, FLT-PET has been studied for detection of locally advanced gastric cancer by our group.104 Although absolute uptake values were lower for FLT than for FDG, FLT-PET revealed a higher sensitivity than FDG-PET and might serve

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Figure 2 Example of an FDG-PET/CT study in a patient with locally advanced gastric cancer undergoing neoadjuvant chemotherapy. FDG-PET/CT studies were performed before therapy (A-C) and 14 days after the start of neoadjuvant chemotherapy (D-F). (A and D) Transaxial PET; (B and E) transaxial CT; (C and F) fused PET/CT images. FDG uptake 14 days after the start of chemotherapy is almost unchanged (SUVmean decrease, 24%) in this histopathologically nonresponding tumor.

as a useful diagnostic adjunct reflecting the quantitative assessment of proliferation. In conclusion, quantitative assessment of early response to chemotherapy has been shown to distinguish responding from nonresponding patients in single-center studies in gastric cancer patients. Further studies are needed to confirm these promising findings.

Colorectal Cancer Colorectal cancer is a common neoplasm in Western countries, with an incidence ranked second for men and women.105 In locally advanced tumors, preoperative chemoradiotherapy is an established standard procedure. Prediction

of response before or early in the course of preoperative chemo(radio)therapy remains crucial and has been investigated with FDG-PET and PET/CT.106-112 In the metastatic situation, survival has improved from 10 to 20 months over recent years.113 This therapeutic success can be ascribed to the addition of both new chemotherapeutic drugs such as oxiliplatin and irinotecan and antibodies, eg, cetuximab and bevacizumab, to the fluorouracil/folic acid backbone. Because various costly treatment combinations are available, with variable efficacy, response monitoring using biologic imaging markers might be very helpful in defining the best regimen for the individual patient. Furthermore, early response assessment might be critical to evaluate response to systemic

Monitoring response to therapeutic interventions in cancer chemotherapy before resection of metastasis with curative intent. Therapy response was first evaluated by Findlay and coworkers in liver metastases of colorectal cancer, showing that changes in FDG uptake during the first month of therapy correlate with the chemotherapeutic effects.109 Early response assessment after initiation of chemoradiotherapy was studied by Cascini and coworkers107 in 33 patients with locally advanced rectal cancer. Patients underwent FDG-PET scans before and 12 days after the start of treatment. Half of the recruited patients had a third FDG-PET scan before surgery (Table 1). Retrospective receiver operating characteristic (ROC) analysis revealed that a threshold of 52% decrease in SUVmean separated histologic responders from nonresponders with a high sensitivity, specificity, and accuracy (100%, 87%, and 94%, respectively). PET after completion of chemoradiotherapy has also been investigated in recently published studies. Calvo and coworkers106 investigated the prognostic value of the SUVmax 4 to 5 weeks after completion of chemoradiotherapy in patients with locally advanced rectal cancer. Presurgical SUVmax below or above 2.5 did not predict recurrence or patient outcome (Table 2). In contrast, initial SUVmax ⬍6 was correlated with significantly better 3-year overall survival than an initial SUVmax ⱖ6 (93% vs 60%, P ⫽ 0.04). In a study by Guillem and coworkers,111 15 patients with locally advanced rectal cancer underwent a FDG-PET scan before and 4 to 5 weeks after completion of neoadjuvant chemoradiotherapy. A reduction in SUVmean of more than 62.5% was defined as a metabolic response and correlated significantly with better recurrence-free survival (P ⫽ 0.02). In a more recently published study, 44 patients with primary rectal cancer and 4 patients with pelvic recurrence underwent PET scans before the start of neoadjuvant bevacizumab-based chemoradiotherapy and 5 to 6 weeks after completion of treatment.110 ROC analysis revealed a 66.5% decrease in SUVmax compared with baseline to be the optimal threshold, resulting in a sensitivity of 81%, a specificity of 79%, and an overall accuracy of 80%. The results of these studies suggest the potential utility of FDG-PET as a complementary diagnostic and prognostic procedure in the assessment of response of locally advanced rectal cancer to neoadjuvant chemoradiotherapy. FDG-PET has also been evaluated for response assessment of palliative chemotherapy in 50 patients with metastatic colorectal cancer. FDG-PET scans were performed initially and after 2 and 6 months of treatment.108 Correlation with overall survival showed significant differences for the early PET scan for both metabolic rate of glucose (cut-off: 65% decrease) and SUV (cut-off: 20% decrease) (P ⫽ 0.009 and P ⫽ 0.021, respectively). Similar results were found in a more recently performed study by Rosenberg and coworkers in 30 patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy.112 Metabolic response evaluation by PET/CT was performed 2 weeks after the start of chemoradiotherapy and after completion of chemoradiotherapy before surgery (Tables 1 and 2). ROC analysis resulted in optimal cut-offs of

221 35% and 57.5% SUV decrease for the early and the late time point respectively, leading to a sensitivity of 74% and 79% respectively (Figs. 3 and 4). Corresponding specificity was 70% for both time points. Rosenberg and coworkers attributed the reduced sensitivity to nonmalignant FDG uptake due to therapy-induced inflammation. Evaluation of early metabolic response assessment, with the potential to lead to modification or avoidance of ineffective treatments, should be performed in larger patient groups. In conclusion, recently published studies demonstrate that histopathologic response to neoadjuvant chemoradiotherapy can be predicted by quantitative FDG-PET/CT with a satisfying accuracy. In the future there is a need not only to establish and validate optimal cut-off values, but also to investigate modification or intensification of treatment in this patient population.

Breast Cancer Breast cancer is a leading cause of cancer death in women in the industrialized world, with around 12% of women developing breast cancer at some stage during their lifetime. Resection of the tumor is the only option for cure. In the case of advanced tumors, primary resection may require prior neoadjuvant chemotherapy.114-116 However, these therapeutic approaches need to be closely monitored to distinguish responders from nonresponders, who do not benefit from the cytotoxic treatment. Around 30% of patients who present initially with locoregional disease develop metastases. Patients with visceral metastasis will receive chemotherapy with a palliative intention. However, monitoring response may be crucial both in choosing the right therapeutic strategy and in detecting patients who might qualify for resection of visceral metastasis. The first study to evaluate FDG-PET for the assessment of therapy response was published by Wahl and coworkers as early as 1993.117 Seven years later, 2 studies investigating the role of FDG-PET for early prediction of response to chemotherapy in patients with locally advanced breast cancer were published.118,119 In a cohort of 22 patients with a total of 24 breast carcinomas, Schelling and coworkers118 defined metabolic response as a decrease of more than 45% in baseline SUV. This threshold led to a high accuracy (88%) in predicting histopathologic response after only one cycle of chemotherapy; related sensitivity and specificity were 100% and 85% respectively (Table 1). In the second study by Smith and coworkers, PET after a single administration of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%.119 The predictive value of FDG-PET has also been studied in patients with metastatic breast cancer.119-121 Gennari and coworkers observed a significant decrease in tumor SUV as early as day 8 after start of treatment in 6 patients who responded to chemotherapy, whereas the 3 nonresponders showed no significant change in FDG uptake.122 In another study by Dose Schwarz and coworkers121 investigating 11 patients with metastatic breast cancer, patients with a negative 18F-FDGPET scan after the first cycle of chemotherapy showed a

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Figure 3 Example of a patient with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy before surgery. FDG-PET/CT studies were performed before therapy (A-C) and 14 days after the start of neoadjuvant chemoradiotherapy (D-F). (A and D) Transaxial CT; (B and E) transaxial PET; (C and F) fused PET/CT images. Semiquantitative analysis showed a 68% decrease in SUVmean as early as 14 days after the start of therapy; histopathology after surgery revealed a histopathological response.

longer overall survival than nonresponders (19.2 vs 8.8 months; Table 1). Comparison of responding and nonresponding lesions revealed a statistically significant difference in SUV uptake at both time points, after the first and the second cycle (P ⫽ 0.02 and P ⫽ 0.003, respectively). In contrast to these 2 studies, recently published results by Couturier and coworkers120 showed that a decline in SUV after one cycle of therapy was not predictive for treatment response. However, FDG-PET after 3 cycles of therapy predicted treatment response and was correlated with improved overall survival. Interestingly, visual image analysis alone was insufficient to make this determination and SUV measurements were necessary to obtain significant results. In summary, promising data exist demonstrating that response to therapy can be predicted by quantitative assessment of FDG-PET/CT in patients with locoregional and metastatic breast cancer.

Ovarian and Cervical Cancer In gynecologic tumors other than breast cancer, so far only limited data are available. Regarding ovarian cancer, Avril and coworkers38 evaluated sequential 18F-FDG-PET scans after the first and third cycles of neoadjuvant chemotherapy for prediction of patient outcome in 33 patients with advancedstage ovarian cancer. A significant correlation was observed between metabolic response after the first (P ⫽ 0.008) and the third (P ⫽ 0.005) cycle of chemotherapy and overall survival. After the first cycle, a threshold of 20% decrease in SUV for differentiation of metabolic responders and nonresponders revealed the following median overall survival: 38.3 months for metabolic responders and 23.1 months for metabolic nonresponders (Table 1). Grigsby and coworkers123 performed an FDG-PET study in 152 patients with cervical cancer before and after completion of chemoradiotherapy. Patients with no residual FDG uptake (n ⫽ 114) showed a significantly

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Figure 4 Example of an FDG-PET/CT study in a patient with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy before surgery. FDG-PET/CT studies were performed before therapy (A-C) and 14 days after the start of neoadjuvant chemoradiotherapy (D-F). (A and D) Transaxial CT; (B and E) transaxial PET; (C and F) fused PET/CT images. FDG uptake 14 days after the start of chemoradiotherapy is almost unchanged (SUVmean decrease, 24%) in this histopathologically nonresponding tumor.

better 5-year cause-specific survival estimate than patients with persistent uptake (n ⫽ 20; 80% vs 32%) (Table 2). None of the subgroup of 18 patients with new anatomic sites of abnormal FDG uptake was alive after 5 years. These initial results were evaluated by the same group in a prospective trial including 92 patients.124 After chemoradiotherapy, all patients underwent a second PET scan and were again divided into those with a complete metabolic response (n ⫽ 65), a partial metabolic response (n ⫽ 15), or progressive disease (n ⫽ 12). Corresponding 3-year progression-free survival rates were 78%, 33%, and 0%. Multivariate analysis demonstrated that the hazard ratio (HR) for risk of recurrence based on the posttherapy metabolic response showing progressive disease was 32.57; a partial metabolic response had an HR of 6.30. Posttherapeutic PET assessment was more predictive of survival outcome than the pretreatment lymph node status (HR of 3.54).124

Nishiyama and coworkers investigated FDG-PET for prediction of response in a mixed study cohort of 21 patients with uterine (n ⫽ 13) and ovarian (n ⫽ 8) cancer who were undergoing chemo- and chemoradiotherapy. Posttherapy SUV was significantly lower in responders than in nonresponders (P ⬍ 0.005)125 (Table 2). An arbitrary reduction in SUVmax of 65% for differentiation of responders from nonresponders resulted in a sensitivity of 90%, a specificity of 82%, and an accuracy of 86%.

Melanoma Although FDG-PET and FDG-PET/CT are widely used for staging, restaging, and therapy control, so far only limited data are available regarding the assessment of response in melanoma patients. In a recently published study, Strobel and coworkers investigated 25 patients with stage IV mela-

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224 noma, comparing changes in FDG uptake and S-100B tumor marker levels after three cycles of chemotherapy. PET/CT response defined by visual criteria was significantly correlated with a longer progression-free survival (P ⫽ 0.002) and a better 1-year overall survival (80% vs 40%, P ⫽ 0.048)126 (Table 1). Previously, the same group compared changes in SUVmax before and after therapy with serial measurements of the tumor marker S-100B in 41 patients with proven melanoma metastases.127 S-100B changes were only assessable in 26 patients; in the other 15 patients, S-100B values were not suitable for response assessment since they were normal before and after therapy. Among the 26 assessable patients, a complete agreement in PET/CT and tumor marker changes was found in 22. In the other four patients, subsequent S100-B measurements matched with the earlier observed changes in FDG uptake.

Head and Neck Cancer Early assessment of therapy response and prediction of therapy outcome in 47 patients with locally advanced head and neck squamous cell carcinoma (HNSCC) was studied by Brun and coworkers128 in 2002. As early as 5 to 10 days after initiation of radiotherapy, determination of the metabolic rate was correlated with 5-year survival. Patients with a metabolic rate lower than the median turned out to have a significantly higher 5-year survival (72% vs 35%, P ⫽ 0.004), whereas determination of SUV at this time point showed no correlation with survival (Table 1). Kunkel and coworkers investigated the role of FDG-PET after neoadjuvant radiotherapy in 35 patients.129 Patients with presurgical FDG uptake with a SUV of less than 4 had a better 3-year survival rate than patients with higher uptake (80% vs 43%). It was also shown that postirradiation FDG uptake significantly predicted survival (P ⫽ 0.046) and local tumor control (P ⫽ 0.0017; Table 2). In a more recent publication by Connell and coworkers, 30 patients with head and neck mucosal squamous cell cancer underwent FDG-PET/CT after completion of radiotherapy.130 Compared with metabolic nonresponse, metabolic response was associated with a significantly better overall (P ⫽ 0.037) and disease-free survival (P ⫽ 0.046).

Gastrointestinal Stromal Tumors (GIST) Use of PET and PET/CT imaging in the treatment of GIST has been evaluated in several studies. The first study was published by Stroobants and coworkers,131 who investigated the role of FDG-PET in early evaluation of response to treatment with imatinib in a group of 21 patients with GIST (n ⫽ 17) or other soft tissue sarcomas (n ⫽ 4). FDG-PET response (defined according to the European Organization for Research on Treatment of Cancer [EORTC] FDG-PET recommendations) as early as at day 8 after initiation of imatinib treatment was associated with a significant longer progression-free survival (1 year progression-free survival: 92% vs 12%, P ⫽ 0.001; Table 1). Response evaluation by FDG-PET preceded CT response by a median of 7 weeks (range, 4-48 weeks).

Gayed and coworkers132 compared PET with CT 2 months after completion of imatinib therapy in 49 patients. PET proved to predict response to therapy earlier than CT in 22.5% of patients during a longer follow-up interval (4-16 months), whereas CT predicted lack of response to therapy earlier than FDG-PET in 4.1% of patients. In 20 patients with GIST, Antoch and coworkers133 reported that PET diagnosed tumor response more accurately than CT at all investigated time points (after 1, 3, and 6 months). However, best results were found by a side-by-side evaluation of PET and CT images. Goerres and coworkers134 investigated 28 patients with GIST who underwent a PET/CT study 1 month after the start of imatinib treatment. Patients without suspicious FDG uptake at this early time point had a significantly better 2-year survival rate (100% vs 49%, P ⫽ 0.001) and a longer median time to progression interval (32.2 vs 9.3 months, P ⫽ 0.002) than patients with residual FDG uptake (Table 1). In contrast, contrast-enhanced CT criteria provided insufficient prognostic power. Similar results were described in a recently published study by Holdsworth and coworkers, with 63 patients undergoing PET and CT after 1 month of treatment.135 In this patient group, time-to-treatment failure was best predicted by an optimized PET SUVmax threshold of 3.4 (P ⫽ 0.0001), a reduction in the SUVmax of 40% (P ⫽ 0.002), and an optimized CT bidimensional measurement threshold (P ⫽ 0.0001). On the basis of these observations, Choi and coworkers136 evaluated 172 lesions of 40 patients with GIST by PET and CT before therapy with imatinib and 2 months into treatment. Small changes in tumor size and tumor density (Hounsfield units in the portal venous phase) on the CT scans proved to be more accurate in identifying PET responders than the RECIST criteria. The authors therefore suggested that these new criteria should be employed in future GIST studies.

Sarcoma Early response assessment with FDG-PET in sarcoma patients was described by Stroobants and coworkers.131 In 4 patients with soft-tissue sarcoma forming a subgroup among a total of 21 patients undergoing imatinib therapy, FDG-PET was used to assess treatment response as early as 8 days after treatment (for details, see the section “Gastrointestinal Stromal Tumors”). Of the 4 patients with nonGIST soft-tissue sarcomas, none revealed a metabolic response according the EORTC PET response criteria. Evaluation of treatment response after completion of neoadjuvant chemotherapy has been investigated in a number of studies.137-144 Schuetze and coworkers included 46 patients with high-grade soft-tissue sarcomas who underwent PET scans before and after therapy.138 A decrease in FDG uptake of more than 40% compared with baseline was correlated with a significantly lower risk of disease recurrence (P ⫽ 0.01) and of metastasis (P ⫽ 0.02). Survival analysis revealed that patients with a SUVmax reduction of less than 40% showed poorer recurrence-free (P ⫽ 0.01) and overall survival (P ⫽ 0.02)

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than patients with a higher reduction in FDG uptake (Table 2). Hawkins and coworkers investigated 36 patients with tumors of the Ewing sarcoma family.140 A SUVmax of less than 2.5 after completion of neoadjuvant chemotherapy was associated with a significantly better 4-year progression-free survival (72% vs 27%; P ⫽ 0.01). In a more recent publication by Evilevitch and coworkers, 42 patients with biopsy-proven high-grade soft-tissue sarcomas underwent PET/CT scans before and after neoadjuvant chemotherapy.144 Metabolic parameters were correlated with RECIST criteria as well as histopathologic response. Decrease in SUV was significantly greater in histopathologic responders than in nonresponders (P ⬍ 0.001), in contrast to changes in tumor size (P ⫽ 0.24). Regarding quantitative values, a decrease in FDG uptake of greater than 60% depicted all histopathologic responders (sensitivity: 100%), and the corresponding specificity was 71% (Table 2). Application of RECIST criteria resulted in a sensitivity of 25% and a specificity of 100%. Considering that quantitative FDG-PET parameters were significantly more accurate than size-based criteria for prediction of histopathologic response, Evilevitch and coworkers suggested the introduction of FDG-PET for monitoring of treatment response in patients with high-grade soft tissue sarcomas.

Therapy Monitoring with 18F-FLT-PET PET with the use of the glucose analog FDG is an established imaging modality for predicting tumor response to therapy and patient survival.145 However, FDG is not tumor specific and can also accumulate in inflammatory lesions such as tuberculosis (granulomas), inflammation, and sarcoidosis, reducing its specificity and diagnostic accuracy.146,147 For assessment of proliferative activity and better differentiation of inflammation from malignant tissue, measurement of tumor growth and DNA synthesis might be appropriate. So far, several DNA precursors have been investigated, including 11C-thymidine, which represents the native pyrimidine base used for DNA synthesis in vivo.148 Owing to the short half-life

of 11C and the rapid degradation of 11C-thymidine, this tracer has been considered less suitable for clinical use. Recently, the thymidine analog FLT has been suggested for noninvasive assessment of proliferation and more specific tumor imaging.149 The complexity of FLT synthesis is similar to that of the standard radiotracer FDG.150 FLT, which is derived from the cytostatic drug azidovudine, has been reported to be stable in vitro and to accumulate in proliferating tissues and malignant tumors.148 Thymidine kinase 1 was identified as the key enzyme responsible for the intracellular trapping of FLT.151,152 FLT is not incorporated into DNA (⬍2%) and therefore does not provide a direct measure of proliferation.153 In vitro studies have indicated that FLT uptake is closely related to thymidine kinase 1 (TK1) activity and TK1 protein levels.151,152 FLT is therefore considered to reflect TK1 activity and, hence, S-phase fraction rather than DNA synthesis. Although FLT is a poor substrate for type 1 equilibrative nucleoside transporters, cellular uptake of FLT is further facilitated by redistribution of nucleoside transporters to the cellular membrane after inhibition of endogenous synthesis of thymidylate (TMP; de novo synthesis of TMP).154 However, the detailed uptake mechanism of FLT is as yet unknown, and the influence of membrane transporters and various nucleoside-metabolizing enzymes remains to be determined. Recently, a significant correlation of tumoral proliferation and FLT uptake in various malignant tumors has been described, including breast cancer,155,156 esophageal and gastric cancer,104,157 colorectal cancer,158 pancreatic cancer,159 lung cancer,104,160-164 glioma,165,166 melanoma,167 head and neck cancer,168,169 sarcoma,170,171 and lymphomas153 (for review, see also Salskov and coworkers172). As a consequence of these promising results, it has been suggested that FLT could be used for therapeutic monitoring in various clinical settings. FLT-PET for prediction of response to chemotherapy was first studied by Pio and coworkers in 14 patients with metastatic breast cancer.173 Decrease in FLT uptake between the initial study and the second PET scan 2 weeks after the start of chemotherapy correlated strongly with the late CA27.29

Table 3 Overview of Studies Regarding Response Evaluation With FLT-PET Tumor

First Author

Year

No.

Description

Lymphoma

Herrmann

2007

22

Breast cancer

Pio

2003

14

Kenny

2007

13

Glioblastoma Colorectal carcinoma

Chen Wieder

2007 2006

21 10

Sarcoma

Been

2007

10

Monitoring of R-CHOP with FLT-PET ¡ significant decrease in FLT uptake detectable as early as 2 days after CHOP FLT scan 2 weeks after start of chemotherapy correlated well with late changes in tumor marker and tumor size Decreases in SUV (90 min) and Ki on FLT scan 1 week after start of chemotherapy discriminated between clinical responders and stable disease Response to chemotherapy in patients with recurrent glioblastoma Comparison of responders and nonresponders after neoadjuvant treatment ¡ no correlation between histological response and FLT decrease FLT-PET before and after HILP ¡ significant decrease in FLT uptake after therapy; initial high FLT uptake showed better therapy response

K. Herrmann et al

226 tumor marker levels (P ⫽ 0.001) and the late CT size changes (P ⫽ 0.01; Table 3). In a second study investigating the role of FLT-PET for therapy monitoring in breast cancer patients, Kenny and coworkers included 13 patients with a total of 17 lesions. FLT scans were performed before therapy and 1 week after the start of chemotherapy.174 PET findings were correlated with clinical response defined according the RECIST criteria assessed at day 60 after the start of treatment. The authors found that decreases in both the semiquantitative parameter SUV at 90 minutes postinjection and the fully quantitative net irreversible plasma to tumor transfer constant discriminated between clinical response and stable disease and preceded tumor size changes assessed by CT. Although both studies involved only small numbers of patients, FLT-PET seems to be a valuable tool for assessment of early response to chemotherapy in breast cancer patients. In 22 patients with aggressive NHL we investigated the ability of FLT-PET to monitor response to immunochemotherapy. We showed that administration of (immuno)chemotherapy is associated with an early decrease in lymphoma FLT uptake.175 Interestingly, there was no reduction in FLT uptake if patients initially received rituximab alone, indicating no early antiproliferative effect of immunotherapy (Table 3). Even though correlation between residual FLT uptake or decrease in FLT uptake and overall outcome was not attempted owing to the small number of patients experiencing relapse, FLTPET seemed to be a promising tool for early evaluation of drug effects in patients with aggressive high-grade lymphoma. Because of the negligible background uptake of FLT in the brain, specific imaging of proliferation may be appropriate for detection and monitoring of tumors or metastases in the central nervous system. In 21 patients with recurrence of glioma, Chen and coworkers investigated the use of FLT-PET for monitoring of treatment response to chemotherapy (bevacizumab and irinotecan).176 FLT-PET imaging was performed before therapy and at 1 to 2 weeks and 6 weeks after the start of treatment. Metabolic response, defined as a reduction in SUVmax of more than 25%, was correlated with survival and MRI findings. Metabolic responders (n ⫽ 9) survived 3 times as long (10.8 vs 3.4 months; P ⫽ 0.003) as nonresponders (n ⫽ 10), and tended to have a prolonged progression-free survival (P ⫽ 0.061). Both early and late FLT-PET responses were more significant predictors of overall survival (P ⫽ 0.006 and P ⫽ 0.002) compared with the MRI response (P ⫽ 0.060 for both time points). The authors therefore concluded that FLT-PET seems to be predictive of overall survival in patients receiving chemotherapy of recurrent gliomas. Been and coworkers studied the role of FLT-PET for monitoring hyperthermic isolated limb perfusion (HILP) in 10 patients with locally advanced soft-tissue sarcoma. After HILP, both semiquantitative FLT uptake parameters SUVmean and SUVmax decreased significantly (P ⫽ 0.002 and P ⫽ 0.008, respectively).177 Changes in FLT uptake have not been correlated with survival. Wieder and coworkers assessed FLT-PET for therapy monitoring in ten patients with rectal cancer undergoing neoadjuvant chemoradiotherapy and cor-

related changes in FLT uptake with histopathologic response (Table 3). FLT uptake 2 weeks after the start of chemoradiotherapy was significantly decreased compared with the initial scan and showed a further decrease after completion of chemoradiotherapy. However, the degree of change in FLT uptake 2 weeks after initiation of neoadjuvant therapy and after its completion did not correlate with histopathologic tumor regression. Therefore the authors suggested that, in contrast to the other mentioned studies, FLT-PET is not a promising approach for assessment of tumor response to neoadjuvant chemoradiotherapy in patients with rectal cancer. Although that the majority of the cited results indicate FLT-PET to be a valuable tool for assessment of treatment response, so far published data are preliminary and clinical trials are needed to further validate FLT as a marker for therapy response. Moreover, the lower uptake of FLT compared with FDG may result in a reduced sensitivity for the detection of residual disease after treatment. As previously reported for the standard radiotracer FDG, false positive findings may also occur at FLT-PET because an increased proliferation rate is not specific for malignant tumors. Troost and coworkers described false positive FLT uptake in nonmetastatic reactive cervical lymph nodes, attributing the FLT uptake to reactive B-lymphocyte proliferation.169

Therapy Monitoring with Hypoxia Tracers PET and PET/CT offer the possibility of in vivo mapping of regional tumor hypoxia with adequate anatomic resolution as well as monitoring of therapy through follow-up mapping of hypoxia. Derivatives of misonidazole—an azomycin-based hypoxic cell sensitizer that was introduced in radiation oncology decades ago— have been successfully labeled with positron emitters. FMISO is a radiopharmaceutical directly derived from misonidazole and is the most extensively studied PET agent for hypoxia mapping among these derivatives. FMISO shows a high accumulation in hypoxic tissue that is proportional to the hypoxic fraction of the tumor. Under hypoxic conditions, FMISO accumulation is much higher than under normoxic conditions. FMISO is a highly stable radiopharmaceutical that can be used to visualize and to quantify hypoxia.178 To date, FMISO is the most widely used PET imaging agent for tumor hypoxia (for reviews see Krause and coworkers179 and Lee and coworkers180). Alternative nitroimidazole radiopharmaceuticals for PET imaging have been developed by changing the properties of the tracers, especially with respect to blood clearance.181,182 Fluoroazomycin arabinoside (FAZA) PET imaging for the detection of tumor hypoxia has recently been shown to be slightly superior in terms of an increased tumor/muscle ratio in head and neck cancer patients.183 Molecular imaging with hypoxia-specific PET tracers has great potential as a tool to identify patients who may benefit from changes in their therapeutic regimen because hypoxia has been identified as a major adverse prognostic factor for tumor progression and for resistance to anticancer treatment.

Monitoring response to therapeutic interventions in cancer Numerous PET studies evaluating hypoxia in different tumor types have been conducted in recent years, including cervical cancer, head and neck cancer, lung cancer, soft tissue carcinoma, colorectal cancer, breast cancer, brain tumors, renal cancer, and prostate cancer (for reviews see Krause and coworkers179 and Lee and coworkers180). PET hypoxia imaging has also been used for therapy monitoring.184-187 Hicks and coworkers investigated FMISO/ FDG-PET in advanced head and neck cancer during hypoxiatargeting therapy.186 Fifteen patients with advanced head and neck cancer underwent FDG and FMISO PET in a phase I trial of chemoradiation plus tirapazamine. FMISO-PET was positive in 13 of the 15 patients at baseline. Twelve of the 15 primary sites and 8 of the 13 neck nodes were scored as positive. Median follow-up was 6.9 years. All sites with corresponding FDG and FMISO abnormalities at baseline showed a marked reduction in uptake within 4 weeks of therapy onset. The clinical use of hypoxia-targeted therapies is, however, limited by their toxicity and so they should only be used in patients with significantly hypoxic tumors. Issues such as narrow therapeutic windows underscore the importance of being able to reliably identify and quantify regional hypoxia. Data reported by Hicks and coworkers indicate that FMISO PET may be potentially useful in selecting patients or disease types that would benefit from hypoxia-targeting therapy.186 Given that FMISO uptake represents significant hypoxia, the results of Hicks and coworkers are consistent with effective hypoxia-targeted therapy (in their patient population). Hypoxia imaging may thus guide the selection or risk stratification of patients in trials evaluating hypoxia-targeting chemotherapeutic agents such as tirapazamine. In a study by Koh and coworkers, 7 patients with locally advanced NSCLC underwent sequential FMISO-PET imaging while receiving primary radiotherapy.185 Fractional hypoxic volume was calculated for each study as the percentage of pixels within the analyzed imaged tumor volume. Five of the 7 patients showed a reduction in FMISO uptake after therapy. Gagel and coworkers187 examined 8 patients with nonsmall cell lung cancer with FMISO- and FDG-PET for therapy response assessment after chemoradiotherapy. The authors discussed the potential usefulness of changes in FMISO accumulation for therapy monitoring. In a study by Rajendran and coworkers of soft tissue sarcoma patients,184 significant hypoxia was found in 76% of tumors imaged before therapy. Ten patients receiving neoadjuvant chemotherapy were also imaged after therapy but before surgical resection. Most tumors showed evidence of reduced uptake of both FMISO and FDG after chemotherapy. Ten patients were reimaged following their third cycle of chemotherapy. Five of these 10 patients demonstrating pretreatment hypoxia (83%) had lower hypoxic volumes post chemotherapy (suggesting improvement in oxygenation); in these patients FDG SUVmax also was reduced. In summary, imaging of hypoxia has been shown to be a promising approach for therapy monitoring. However, a direct comparison of various hypoxia tracers has to be performed to select the best and to assure reproducibility. To

227 date, assessment of therapy response with hypoxia tracers is still experimental.

Outlook Despite the very promising results of recently published and ongoing trials evaluating the role of FDG-PET for response assessment, future validation of FDG-PET/CT for monitoring tumor response is mandatory. From our perspective, the following main aspects should be the focus of future research activities: (1) randomized multicenter trials and standardization of response assessment by PET and (2) assessment and evaluation of oncologic therapies employing new imaging probes. The MUNICON trial was one of the first clinical trials to provide evidence that FDG-PET can be used to individualize neoadjuvant therapy in patients with locally advanced esophageal cancer.92 These promising results can serve as a model for response-guided trials in other malignant diseases, such as lung, head and neck, or ovarian cancer, in which induction treatment plays a potential role. However, these results were obtained in a single-center study and need to be confirmed in prospective randomized multicenter trials. This would be an important step in view of the possible implementation into clinical practice of FDG-PET/CT for therapy response assessment in patients undergoing neoadjuvant therapy. Regarding esophageal cancer, the “NEOadjuvant therapy monitoring with PET and CT in Esophageal Cancer” multicenter trial initiative (NEOPEC-trial) has recently been launched as part of a randomized multicenter Dutch trial comparing neoadjuvant chemoradiotherapy for 5 weeks followed by surgery versus surgery alone for esophageal cancer. In this trial, 150 patients in six centers will be included within 3 years. Primary end points will be a difference in accuracy and in negative predictive value between FDG-PET and CT. Based on the results of the MUNICON trial, the EORTC GI group has recently started an initiative for a multicenter study investigating a PET-guided treatment algorithm in patients with locally advanced esophageal cancer.100 In addition to the need for multicenter trials, it is also important to assess new, more specific tracers. Future studies will have to evaluate whether new tracers such as the highly ␣v␤3-selective tracer 18F-galacto-RGD, the in vivo proliferation marker 18F-FLT, or the hypoxia tracer 18F-MISO are suitable for use in therapeutic response assessment. New oncologic treatment regimens comprise targeted drugs inhibiting specific signaling pathways. Such targeted drugs have recently been introduced for a wide spectrum of human solid tumors, including breast cancer, colorectal cancer, and NSCLC as well as GIST. Because the diverse signaling pathways involved in the development and progression of malignancies are genetically heterogeneous, an efficacious response is often achieved in only a small percentage of patients. High costs of targeted therapy approaches and the considerable toxic side-effects call for a specific patient stratification strategy identifying potential responders. Further work needs to be done on the integration of molecular imaging into the process of drug development and how molecular

K. Herrmann et al

228 imaging can address key questions in the preclinical and clinical evaluation of new targeted drugs with special regard to the imaging of expression and inhibition of drug targets, noninvasive tissue pharmacokinetics, and early assessment of the tumor response.6 Major challenges of these new targeted therapy approaches comprise identification of the correct, biologically active concentration and dose schedule, selection of those patients likely to benefit from treatment, monitoring of inhibition of the target protein or pathway, and assessment of the response of the tumor to therapy.

Acknowledgments We appreciate the excellent contributions made by our colleagues PD Dr. Andreas Buck, PD Dr. Ambros Beer, PD Dr. Hinrich Wieder, Dr. Michael Souvatzoglou, and Mrs. Christine Praus.

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