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Clinical Investigation |
1 Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 2 Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 3 Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 4 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands; and 5 Department of Medical Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Correspondence: For correspondence or reprints contact: Lioe-Fee de Geus-Oei, MD, Department of Nuclear Medicine (internal postal code 444), Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: L.degeus-oei{at}nucmed.umcn.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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MRGlu and SUV, the difference in overall survival (P = 0.017 for MRGlu, P = 0.018 for SUV) and progression-free survival (P = 0.002 for MRGlu, P = 0.0009 for SUV) was highly significant. When applying the predefined criteria for metabolic response, the cutoff levels as also used for size measurement (RECIST) showed significant differences for SUV between response categories in progression-free survival (P = 0.0003) as well as overall survival (P = 0.027). Conclusion: The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by 18F-FDG PET is highly predictive for patient outcome, stratifying patients into groups with widely differing overall survival and progression-free survival probabilities. The use of 18F-FDG PET for therapy monitoring seems clinically feasible, because simplified methods to measure tumor glucose use (SUV) are sufficiently reliable and can replace more complex, quantitative measures (MRGlu) in this patient population.
Key Words: chemotherapy response monitoring • 18F-FDG PET • non–small cell lung cancer • standardized uptake value • Patlak analysis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Nowadays, there is an increasing interest in the role of 18F-FDG PET beyond staging, such as the prediction of tumor response to therapy. Response assessment with morphologic imaging techniques has limitations in reliably distinguishing necrotic tumor or fibrotic scar from residual tumor tissue (8). Indeed, final treatment outcome will be determined more by the biologic aggressiveness of residual tumor than by its volume (9). Furthermore, some new therapies may be cytostatic instead of cytoreductive, in which case successful treatment may not lead to a decrease in tumor size and thus poses new demands on imaging modalities.
18F-FDG PET is ideally suited to overcome these kinds of problems. One of the advantages of 18F-FDG PET is that it not only can visualize but also can quantify 18F-FDG uptake to distinguish metabolically highly active from less-active tumor tissues. Furthermore, metabolic alterations of tumor cells, indicative of tumor response to therapy, may occur before alterations in tumor size. Early prediction of tumor response is of particular interest in patients with advanced stages of NSCLC. Tumor progression during first-line chemotherapy occurs in approximately 30% of patients (10). Because of relatively slow tumor shrinkage, as measured on morphologic imaging modalities, a significant percentage of patients will continue to undergo toxic therapy for weeks without benefit.
In the present prospective study, a design was used that allowed for comparative analysis of different quantitative PET methods to measure tumor glucose use at various levels of complexity. Furthermore, prospective as well as post hoc definitions for metabolic response were assessed to evaluate the value of 18F-FDG PET in therapy response monitoring of NSCLC.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Quantitative Dynamic 18F-FDG PET Data Acquisition and Reconstruction
Dynamic 18F-FDG PET was performed at baseline and after the second or third cycle of chemotherapy, depending on the chemotherapy regimen. The median interval between the clinical-staging 18F-FDG PET and the baseline dynamic 18F-FDG PET was 3 d. Patients fasted for at least 6 h before imaging. Intake of noncaloric beverages was permitted. All scans were acquired on an ECAT-EXACT47 PET scanner (Siemens Medical Solutions). The field of view for dynamic acquisition was based on whole-body 18F-FDG PET and CT scans performed for initial staging, including as many measurable tumor lesions as possible. A 20-min transmission scan was made, using the internal 68Ge/68Ga sources, to correct for photon attenuation. Approximately 200 MBq 18F-FDG were injected intravenously over a 1-min period, using a constant-infusion remote-controlled pump (Medrad). The dynamic data acquisition, performed in septa-extended (2-dimensional) mode, was started simultaneously with the injection of 18F-FDG and consisted of 16 time frames with variable frame length (10 x 30 s, 3 x 300 s, 3 x 600 s) for a total time of 50 min. A more detailed description of the data acquisition, reconstruction, and analysis methods was published previously (12).
Plasma Time–Activity Curves
To measure the blood clearance of 18F-FDG, plasma time–activity curves were derived from arterial blood sampling when feasible. Arterial blood samples were taken manually at set times to provide an arterial plasma input function as described previously (12). When arterial cannulation was contraindicated or not feasible, an image-based input function was determined by measuring 18F-FDG counts in a volume of interest (VOI) over the ascending aorta, which accurately determines 18F-FDG blood levels (12).
Tumor Time–Activity Curves
Tumor time–activity curves were obtained by placing VOIs semiautomatically over the tumor and metastases using a threshold of 50% of the maximum pixel value within the lesion. Necrotic areas were excluded from the VOIs. A volume-weighted mean value of tumor glucose use (metabolic rate of glucose [MRglu]) of all lesions in each PET scan was derived to provide one value for each study. VOIs drawn on the first 18F-FDG PET (before initiation of chemotherapy) were copied to the second 18F-FDG PET (after 2 or 3 cycles of chemotherapy).
Patlak Graphical Analyses
For quantitative measurement of glucose metabolism, Patlak graphical analysis was used to calculate the MRGlu (expressed in µmol.mL–1. min–1) in tumor tissue (13,14). A detailed description of the Patlak graphical analyses and its assumptions have been published elsewhere (12,13). In brief, the Patlak approach takes into account differences in the whole-body distribution of 18F-FDG at the time of scanning, which may affect the accumulation of 18F-FDG in the tumor tissue. Furthermore, the MRGlu in tumor was calculated by multiplication of the slope of the Patlak plot and the basic blood glucose level (expressed in µmol.mL–1). Blood glucose level was measured (hexokinase method, Aeroset; Abbott Diagnostics) before 18F-FDG injection. The fractional change in MRGlu between 18F-FDG PET at baseline and after 2 or 3 cycles of chemotherapy was calculated.
Standardized Uptake Value (SUV)
18F-FDG PET scans were also evaluated semiquantitatively by SUV analysis. SUVs normalized to injected activity and patients' body weight were calculated from the mean activity concentration in the tumor VOIs between 40 and 50 min after injection, which is the last time frame of the dynamic scan. A volume-weighted mean value of each PET scan was derived from all lesions to give one average SUV (SUVavg; hereafter referred to as SUV) for each PET scan. The percentage change in SUV between the 18F-FDG PET at baseline and after 2 or 3 cycles of chemotherapy was calculated.
Clinical Follow-up
During and after treatment, patients were monitored with clinical examination at regular intervals, chest CT, radiography, and other imaging studies as clinically indicated. Tumor response was evaluated according to RECIST criteria without knowledge of the results of the PET studies. When recurrence was suspected or proven, patients were always restaged. The progression/relapse pattern and cause of death were determined in all cases. The date of local or distant progression was defined as the earliest date at which disease progression was confirmed, either clinically or by imaging or biopsy. Patients who were progression free at the closeout date (November 1, 2006) or who had died from any cause had their time to progression censored at that date. Survival was measured from the date of the baseline PET scan to the date of death. Patients who were still alive at the closeout date had their survival censored to that date.
Statistical Analysis
Survival and progression-free survival served as the standard of reference. Cox proportional hazards regression analysis was used to assess the predictive value of response evaluation with 18F-FDG PET, as expressed in the percentage change in MRGlu and SUV between the 18F-FDG PET at baseline and after 2 or 3 cycles of chemotherapy. The data have been adjusted for tumor stage at the time of the baseline PET scan. Statistical significance was assessed using the Wald 
2 test. The overall survival and progression-free survival with respect to MRGlu and SUV were calculated using Kaplan–Meier estimates. The percentage change in measurements between the first and second scan were stratified by the median value to avoid data-driven significance for the cutoff level. However, stratification at the median value is still a post hoc definition for metabolic response. To avoid this bias, also some predefined, prospective definitions of metabolic response were used. For that purpose the population was categorized according to the definitions for metabolic response of The European Organization for Research and Treatment of Cancer (EORTC), into a group with complete response (CR) or partial response (PR) ( < –25%), a group with stable disease (SD) ( –25% to +25%), and a group with progressive disease (PD) ( > +25%) (15). Furthermore, the population was categorized according to the cutoff values also used for size measurement (RECIST), for which < –30% is CR or PR, –30% to +20% is SD, and > +20% is PD (16). Groups were compared using the Breslow test, which counts losses that occur early in the survival distribution more heavily than losses that occur late, because sample sizes are larger in early months relative to late months. Spearman 
-correlations were used to determine the comparability between the different methods to measure glucose metabolism. Statistical tests were based on a 2-sided significance level, and the level of significance was set at 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Patient Follow-up
No patients were lost to follow-up. Median follow-up time was overall 13 mo (range, 2–48 mo), for surviving patients 20 mo (range, 9–45 mo), and for deceased patients 9 mo (2–48 mo). During this time period, 38 patients had died and tumor progression was diagnosed in 45 of the 51 patients. Median time to progression was 7 mo (range, 0–39 mo). Overall survival after baseline 18F-FDG PET at 1 y was 57%, at 2 y 36%, and at 3 y 22%. Progression-free survival after baseline 18F-FDG PET at 1 y was 26%, at 2 y 17%, and at 3 y 8%.
Quantitative Changes in 18F-FDG Uptake
Mean MRglu at baseline was 0.146 ± 0.079 µmol.mL–1.min–1 (range, 0.028–0.356) and during evaluation was 0.084 ± 0.072 µmol.mL–1.min–1 (range, 0.009–0.355). The median fractional change of MRglu as compared with baseline was –47% ± 55% (range, –93% to +226%). Mean SUV at baseline was 5.27 ± 2.51 (range, 1.37–16.66) and during evaluation was 3.72 ± 2.75 (range, 0.71–16.64). The median fractional change of SUV as compared with baseline was –35% ± 42% (range, –73% to +125%).
Figure 1 shows a typical example of a patient with stage IV NSCLC and tumor lesions who responded to chemotherapy. There is an 82% decrease in MRglu and a 65% decrease in SUV relative to baseline.
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Prediction of Survival by 18F-FDG PET
To generate Kaplan–Meier survival curves, the decrease in tumor glucose metabolism was dichotomized at the median value, which was –47% and –35% for MRGlu and SUV, respectively. The Kaplan–Meier survival curves for overall survival are shown in Figure 2A (MRGlu) and Figure 2B (SUV). The difference in survival between both strata was highly significant for both MRGlu and SUV (P = 0.017 for MRGlu and P = 0.018 for SUV; Table 2 and Figs. 2A and 2B). For patients with a decrease in MRGlu lower than the median value, median overall survival was only 8 mo, whereas it was 17 mo for patients with a more pronounced decrease in MRGlu.
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MRGlu (P = 0.002) and of SUV (P = 0.0009) (Table 2). Patients with a decrease of MRGlu by >47% were characterized by a significantly longer time to progression (median, 10 vs. 3 mo; P = 0.002). The results obtained for SUV were also evident: median progression-free survival, 11 versus 3 mo. The corresponding Kaplan–Meier curves for progression-free survival are shown in Figure 3A (MRGlu) and Figure 3B (SUV). There was a highly significant increase in the rates of progression associated with worsening response as assessed by PET on Cox proportional regression analysis adjusting for disease stage at the time of commencement of treatment (P = 0.018 for MRGlu and P = 0.028 for SUV).
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SUV (P = 0.027).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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MRGlu and SUV, the difference in overall survival between both strata was highly significant (P = 0.017 for MRGlu and P = 0.018 for SUV). Also, a difference in progression-free survival was seen (P = 0.002 for MRGlu and P = 0.0009 for SUV).
The strength of the present study is that also some predefined, prospective definitions of metabolic response were evaluated, comparing 3 strata for assessment of metabolic changes by 18F-FDG PET. One of these prospective definitions was proposed by the EORTC (15) to provide a framework for comparison between studies and to facilitate assessment of the technique. A >25% decrease in glucose metabolism was estimated to be a sign of partial metabolic response after 2 or more cycles of chemotherapy. According to this EORTC definition, the present study demonstrated highly significant differences in progression-free survival between each stratum (P = 0.007 for MRGlu and P = 0.0003 for SUV). The same significant results were found when using the cutoff levels that are proposed for evaluation after 1 cycle of chemotherapy, for which a metabolic response is defined by a decrease in tumor glucose metabolism of >15%. However, for prediction of overall survival using these EORTC criteria, no statistical significance was reached; only a trend was found (P = 0.0504). This is probably due to the limited number of patients in each stratum: more censored patients for overall survival compared with progression-free survival in combination with smaller groups due to categorization into 3 groups (CR or PR, SD, and PD) instead of 2. The EORTC PET response criteria were developed by consensus between a range of PET experts and currently represent the most authoritative SUV-based recommendations. Also, when applying the same cutoff levels that are used for size measurement in standard clinical response assessment with conventional methods according to RECIST (16,17), significant differences between the strata were found in progression-free survival as well as overall survival with respect to SUV.
These results imply that measurement of treatment-induced changes in tumor glucose metabolism with PET is quite robust. There is even more considerable evidence for this, as simplified 18F-FDG PET measures (SUV) and the more complex, quantitative measures, derived from Patlak graphical analysis (MRGlu), show comparable highly significant results indicative for treatment outcome. Given the high correlation between SUV and MRGlu (r = 0.94, P < 0.0001), there is no obvious need to apply the more complex dynamic imaging protocols (necessary for MRGlu calculation) for prediction of therapy response in monitoring chemotherapy of NSCLC. This indicates that 18F-FDG PET can be readily implemented as a routine clinical tool for response monitoring when some basic requirements of quality assurance are met (18). Multiple follow-up scans encourage a simplified approach to improve patient compliance, an important feature of successful clinical trials. Another advantage of the SUV is that it can be calculated from static whole-body 18F-FDG PET studies. In quantitative dynamic scans, only one axial field of view of typically 15–20 cm can be studied during the dynamic data acquisition. As metastatic lesions in different parts of the body may respond differently to chemotherapy, this represents a principal advantage of SUV.
The results of the present study are in line with other studies on the predictive value of 18F-FDG PET in locally advanced NSCLC. Several studies indicated a possible role for PET in assessment of response during or after radiotherapy (19), induction chemotherapy (20–22), or a combination thereof (8,23–27). The earliest study, performed in 1996 by Ichiya et al. (19), showed a more prominent decrease in 18F-FDG uptake in patients with a radiotherapy response on CT compared with those with no change in tumor size on CT. In the pilot study of Vansteenkiste et al. (20), a reduction in 18F-FDG uptake of >50% in the primary tumor or mediastinal clearance after induction chemotherapy proved to be a better predictor of long-term survival compared with the World Health Organization criteria (28,29) used as the standard for response assessment on CT. Another study that evaluated response monitoring of induction chemotherapy (21) showed that 18F-FDG PET identified prognostically different strata in patients considered responsive according to CT. In this prospective multicenter study, 18F-FDG PET was performed before and after 1 and 3 cycles of induction chemotherapy. The residual metabolic rate of glucose after 1 cycle selected patients with different outcomes. The residual metabolic rate of glucose after completion of induction chemotherapy proved to be the best prognostic factor. The other 6 studies (8,23–27) showed that 18F-FDG PET was also predictive with respect to therapy outcome of combined modality therapy. Metabolic response proved to be associated with pathologic response (23,24,26,27). A study performed by Mac Manus et al. (25) showed a significantly longer median survival for patients with complete metabolic response than for patients with incomplete metabolic response (31 vs. 11 mo).
The experience with 18F-FDG PET on therapy response monitoring in advanced stages of NSCLC is limited. So far, a single well-designed study on response assessment in advanced stages (stage IIIB or IV), using serial PET scans, was performed by Weber et al. (30). Fifty-seven patients scheduled to undergo platinum-based chemotherapy were studied before and after the first cycle of therapy. A decrease in SUV of 20% or more after 1 cycle of chemotherapy was associated with a longer time to progression (163 vs. 54 d) and longer median overall survival time (252 vs.151 d). The 1-y survival rate was also significantly higher in metabolic responders compared with nonresponders (44% vs. 10%). This study showed that a reduction of metabolic activity already after 1 cycle of chemotherapy is closely correlated with final outcome of therapy.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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FOOTNOTES |
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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