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Positron Emission Tomography in Non–Small-Cell Lung Cancer: Prediction of Response to Chemotherapy by Quantitative Assessment of Glucose Use

From the Departments of Nuclear Medicine, Internal Medicine III, and Radiology, Technische Universität München, München, Germany.

Address reprint requests to Wolfgang A. Weber, MD, Nuklearmedizinische Klinik, Klinikum Rechts der Isar, Ismaning Straße 22, 81675 München, Germany; email: w.weber{at}lrz.tum.de.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To prospectively evaluate the use of positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) to predict response to chemotherapy in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods: Patients with stage IIIB or IV NSCLC scheduled to undergo platinum-based chemotherapy were eligible for this study. Patients were studied by FDG-PET before and after the first cycle of therapy. Based on previous studies, a reduction of tumor FDG uptake by more than 20% as assessed by standardized uptake values (SUV) was used as a criterion for a metabolic response. Furthermore, changes in tumor SUVs were compared with changes in FDG net-influx constants (Ki) and tumor/muscle ratios (t/m).

Results: Fifty-seven patients were included in the study. There was a close correlation between metabolic response and best response to therapy according to Response Evaluation Criteria in Solid Tumors (P < .0001; sensitivity and specificity for prediction of best response, 95% and 74%, respectively). Median time to progression and overall survival were significantly longer for metabolic responders than for metabolic nonresponders (163 v 54 days and 252 days v 151 days, respectively). Similar results were obtained when Ki was used to assess tumor glucose use, whereas changes in t/m showed considerable overlap between responding and nonresponding tumors.

Conclusion: In NSCLC, reduction of metabolic activity after one cycle of chemotherapy is closely correlated with final outcome of therapy. Using metabolic response as an end point may shorten the duration of phase II studies evaluating new cytotoxic drugs and may decrease the morbidity and costs of therapy in nonresponding patients.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN RECENT years, positron emission tomography (PET) has become an established method for staging of patients with non–small-cell lung cancer (NSCLC). Glucose use is markedly accelerated in NSCLC, resulting in high tumor uptake of the radiolabeled glucose analog fluorine-18 fluorodeoxyglucose (FDG). PET imaging with FDG has been shown to be significantly more sensitive and specific than conventional methods for detection of lymph node and distant metastases.¹ Thus the addition of FDG-PET to the diagnostic work-up of patients with potentially resectable NSCLC has been shown to significantly reduce the number of futile thoracotomies.²

In addition to tumor staging, PET imaging can also be used to assess changes in tumor glucose use during chemo- and radiotherapy. In untreated tumors, quantitative measurements of tumor glucose use have been shown to be highly reproducible.^3,4 Furthermore, several studies in malignant lymphoma,⁵ osteosarcoma,⁶ breast,^7–11 and esophageal cancer^12,13 have indicated that the reduction of tumor glucose use after chemo- or radiotherapy as assessed by PET imaging is well correlated with histopathologic tumor regression and patient outcome. Moreover, changes in glucose metabolism may allow prediction of subsequent response after only a few days of therapy.^7–11,14 This suggests that PET imaging may be used to personalize the use of chemotherapy for individual patients.

Early prediction of tumor response is of particular interest in patients with advanced NSCLC. The majority of patients present with unresectable disease (stage IIIB, IV) and undergo palliative therapy with platinum-based chemotherapy regimens. Palliative chemotherapy has been demonstrated to improve quality of life and to prolong median overall survival by approximately 2 months.¹⁵ The objective response rate of various combination regimens is in the range of 20% to 40%.^16,17 Tumor progression during first-line chemotherapy occurs in approximately one third of the patients.¹⁶ Thus a significant percentage of the patients undergo several weeks of toxic therapy without benefit. Second-line chemotherapy regimens for treatment of NSCLC have been established^18,19 and new targeted therapies such as tyrosine kinase inhibitors have shown activity in patients who progressed after platinum-based chemotherapy.^20,21 Early prediction of tumor response would allow physicians to offer patients with nonresponding tumors these alternative forms of treatment early in the course of therapy.

Thus the aim of the present study was to determine whether changes in tumor glucose use measured by FDG-PET allow prediction of tumor response and patient outcome after the first cycle of platinum-based chemotherapy. Because there is currently no consensus for which methods of data acquisition and analysis are best suited to monitor tumor glucose use by PET imaging, we also compared several techniques with respect to their ability to predict response to chemotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Patients with advanced NSCLC who were scheduled to undergo palliative chemotherapy with a platinum-based regimen were eligible for this study. All patients underwent contrast-enhanced helical computed tomography (CT) of the chest and abdomen for tumor staging. If clinical symptoms suggested the presence of brain or bone metastases, then cerebral magnetic resonance imaging or bone scintigraphy was performed. Eligibility criteria included histologically or cytologically proven NSCLC, tumor stage IIIB (with malignant pleural effusion) or IV, measurable primary tumor according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria,²² a performance status of 0 to 2 on the Eastern Cooperative Oncology Group scale. Patients were excluded when they were diabetic, had received previous chemo- or radiotherapy, when the primary tumor was not well delineated because of surrounding atelectasis, or when there were clinical or radiographic signs of postobstructive pneumonia. The study protocol was approved by the institutional review board at the Technische Universität München, and written informed consent was obtained from all patients.

Chemotherapy
The chemotherapy regimens used in this study were carboplatin/paclitaxel, cisplatin/vinorelbine, cisplatin/docetaxel, and cisplatin/etoposide. These chemotherapy regimens are known to possess similar activity and effectiveness for treatment of NSCLC.²³ Paclitaxel 200 mg/m² body-surface area (BSA) and carboplatin area under the curve (AUC) 6 mg/mL/min were administered every 3 weeks. The cisplatin/vinorelbine regimen included cisplatin at a dose of 70 mg/m² BSA on day 1 and vinorelbine 35 mg/m² BSA on days 1 and 15 of each 4-week cycle. Cisplatin/docetaxel was administered every 3 weeks (75 mg/m² BSA of cisplatin and 75 mg/m² BSA of docetaxel). Treatment with cisplatin/etoposide included 60 mg/m² BSA of cisplatin on days 1 and 8 and etoposide 150 mg/m² BSA on days 3 to 5 of each 3-week cycle. Patients received standard premedication with dexamethasone and antihistaminergic drugs for treatment with paclitaxel or docetaxel and were hydrated with saline for treatment with cisplatin. Patients with disease progression received second-line chemotherapy or palliative radiotherapy.

PET Imaging
PET imaging was performed with an ECAT EXACT full-ring PET scanner (CTI/Siemens, Knoxville, TN).²⁴ A baseline FDG-PET was performed within 1 week before initiation of chemotherapy. FDG-PET was repeated on day 21 of the first chemotherapy cycle. Patients fasted at least 6 hours before PET imaging to ensure standardized glucose metabolism. After a transmission scan of 15 minutes’ duration for attenuation correction, patients were injected with 300 to 400 MBq of FDG, and a dynamic emission scan of the tumor region was acquired (5 x 1 minute frames, 11 x 5 minutes frames). Attenuation-corrected emission data were reconstructed by filtered back projection using a Hanning filter with a cutoff frequency of 0.4 cycles/pixel. In patients who were not sure whether they were able to tolerate the 75-minute data acquisition protocol, only a static emission scan of 15 minutes’ duration followed by a 15-minute transmission scan was performed 45 minutes after tracer injection.

For quantitative assessment of tumor FDG uptake, regions of interest (ROIs) were placed semiautomatically over all primary tumors as previously described.¹⁰ Tumor glucose use was assessed by standardized uptake values, tumor/muscle ratios, and FDG net-influx constants. Standardized uptake values (SUV) normalized to injected activity and patients’ body weight were calculated from the mean activity concentration in the tumor ROIs between 45 and 60 minutes postinjection. For determination of tumor/muscle ratios (t/m), circular ROIs with a diameter of 1.5 cm were additionally placed in paraspinal muscles on both sides of the vertebral column in three consecutive slices. The t/m was calculated by dividing the mean activity concentration between 45 and 60 minutes postinjection within the tumor ROIs by the mean activity concentration in the muscle ROIs. FDG net-influx constants (Ki) were calculated as previously described using a time-activity curve derived from the ascending aorta as the input function.⁴ For all patients, the analysis of PET scans was completed and recorded before response evaluation by CT.

Response Evaluation and Follow-Up
CT scans of chest and abdomen were repeated after every two cycles of chemotherapy. Tumor response was evaluated according to RECIST criteria²² without knowledge of the results of the PET studies. Patients without tumor progression underwent further therapy with the same chemotherapy regimen. The best overall response achieved during treatment with the first-line chemotherapy regimen was determined and correlated with changes in FDG uptake. Patients with progressive disease underwent second-line chemotherapy with or without symptomatic radiotherapy. Overall survival and time to progression were calculated from the start of the first chemotherapy cycle.

Statistical Analysis
The primary end point of the study was the correlation between early changes in glucose use of the primary tumor and subsequent best response to first-line chemotherapy. A decrease of baseline metabolic activity by more than 20% was prospectively used as a threshold for a metabolic response in PET imaging. This threshold was based on previous studies on the reproducibility of the FDG signal in malignant tumors, which have indicated that PET imaging can reliably measure changes by more than 20% of the baseline value.^3,4 All quantitative data are expressed as mean ± one SD. Differences in quantitative parameters were analyzed by Mann-Whitney and Wilcoxon signed rank test for unpaired and paired observations, respectively. Linear regression and Spearman’s rank correlation coefficient (rho) was used to describe the correlation between quantitative parameters. The diagnostic accuracy of changes in t/m, SUV, and Ki to predict subsequent response was compared by receiver operating characteristic (ROC) curves.²⁵ Median overall survival and time to progression were estimated according to the Kaplan-Meier method. Survival in patients with and without a metabolic response was compared by the log-rank test. Statistical computations were performed with the StatView software package version 5.0 (SAS Institute, Cary, NC) and Rockit 0.9B (C.E. Metz, Department of Radiology, University of Chicago, Chicago, IL).

	RESULTS

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Changes of Metabolic Activity During Chemotherapy and Tumor Response
A total of 57 patients were included in the study and underwent the baseline and follow-up PET scans. Patient characteristics are listed in Table 1. Dynamic PET scans were acquired in 32 patients. Blood glucose levels at the first and second PET scan were 106 ± 15 mg/dL and 103 ± 15 mg/dL, respectively. The chemotherapy regimen was carboplatin/paclitaxel in 31 patients, cisplatin/vinorelbine in 22 patients, cisplatin/docetaxel in three patients, and cisplatin/etoposide in one patient. Patients received one to eight cycles of chemotherapy (median, four cycles). Two patients died before response assessment by CT. The cause of death was pulmonary embolism in one patient and unknown in the other patient. In the 55 patients who were assessable for response, the overall response rate was 38% (21 of 35 patients; Table 1).

View larger version (124K): [in this window] [in a new window]   Fig 1. Fluorodeoxyglucose (FDG) positron emission tomography and computed tomography scans of a responding (A) and a nonresponding tumor (B). In the responding tumor, there is a 61% decrease in FDG uptake 3 weeks after initiation of chemotherapy. In contrast, tumor FDG uptake is almost unchanged in the nonresponding tumor.

The relative changes of Ki and SUV were closely correlated (Table 3; rho = 0.88; slope of the regression line, 0.77; Fig 2A). The correlation between the t/m ratio and SUV or Ki demonstrated a higher scattering (rho = 0.77 for both comparisons; Fig 2B). Figure 3 shows the relative changes of all three parameters in relation to best overall response to first-line chemotherapy. The ROC curves (Fig 4) demonstrate that changes in Ki and SUV provided a similar accuracy for differentiation of responding and nonresponding tumors (area under the ROC curve, 0.92 and 0.91, respectively). In contrast, the t/m ratios of responding and nonresponding tumors showed considerably more overlap (area under the ROC curve, 0.77; P = .01 for comparison with ROC curve for changes in SUV).

View larger version (17K): [in this window] [in a new window]   Fig 2. Correlation between changes in (A) net-influx constants (Ki) and standardized uptake values (SUV) and (B) tumor/muscle ratio (t/m) and SUV (B). Although there is a close correlation between Ki and SUV (Spearman’s rank correlation coefficient [rho] = 0.88), the correlation between t/m and SUV shows considerable scattering (rho = 0.77).

View larger version (16K): [in this window] [in a new window]   Fig 3. Changes in tumor metabolic activity and best response to therapy. (), Changes in tumor/muscle ratio; (•), changes in standardized uptake values; (), changes in net-influx constants.

View larger version (17K): [in this window] [in a new window]   Fig 4. Receiver operating characteristic curves for prediction of best overall response by changes in tumor/muscle ratio (t/m), standardized uptake values (SUV), and net-influx constants (Ki).

View larger version (20K): [in this window] [in a new window]   Fig 5. Kaplan-Meier plots showing (A) progression-free and (B) overall survival. For both parameters, there is a significant difference between patients with and without a metabolic response in fluorodeoxyglucose positron emission tomography (P = .0003 and P = .005, respectively).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

To our knowledge, monitoring of tumor response in lung cancer by FDG-PET has only been evaluated in a limited number of studies. In these studies, patients were imaged before or after completion of therapy. The results suggested that PET imaging allows differentiation of viable tumor and fibrotic tissue after completion of radiotherapy.^26–28 No systematic studies on identification of tumor response early during the course of therapy have been reported so far. However, findings of a case report that included two patients with NSCLC and four patients with small-cell lung cancer have indicated that in responding tumors, FDG uptake decreases rapidly during therapy.²⁹

Our data are consistent with recent studies in breast and esophageal cancer, which also indicated that early metabolic changes during chemotherapy are predictive of subsequent tumor response and outcome of therapy.^10,11,14 In addition to confirming these results in metastatic NSCLC, strengths of the present study include the use of a prospective definition of a metabolic response and a systematic comparison of three parameters for assessment of metabolic changes by PET imaging.

Previous studies have used a posthoc definition of criteria for prediction of response to therapy.^10,11,14 This definition is likely to overestimate the diagnostic accuracy of PET imaging. To avoid this bias, we applied a prospective definition of a metabolic response that was based on independent studies on the reproducibility of parameters derived from FDG-PET scans. A metabolic response was defined as a decrease of FDG uptake that is larger than two times the SD of spontaneous changes of tumor glucose use as measured by FDG-PET.^3,4 The present study demonstrates that a metabolic response according to this definition correlates well with subsequent decrease of tumor size as assessed by standard response criteria.

Tumor glucose use has been assessed by PET imaging using a variety of techniques, which vary widely in the required scanning time and the complexity of data analysis.³⁰ Therefore, the methods required to monitor tumor glucose use during chemotherapy are not only interesting from a methodologic point of view, but they also determine how readily PET imaging can be implemented as a routine clinical test. t/m ratios and SUVs can be derived from PET scans acquired for tumor staging. Determination of t/m ratios does not require any further measurements. For calculation of SUVs, only the amount of radioactivity injected and the body weight of the patient need to be measured additionally. These two parameters are used to normalize the measured activity concentration within the tumor between different patients and scans. In contrast, Patlak-Gjedde analysis generally requires dynamic data acquisition. This means that multiple images of the tumor region are recorded to measure the time course of FDG accumulation by the tumor tissue. In addition, the clearance of FDG from the blood is determined by taking multiple blood samples or by measuring the activity concentration in large blood vessels located in the field of view of the PET scanner. From these data, the net rate of FDG phosphorylation (Ki) is calculated.³⁰ In contrast, t/m ratios and SUVs do not differentiate between metabolized and nonmetabolized intracellular or extracellular FDG. In addition, Patlak-Gjedde analysis takes into account differences in the whole-body distribution of FDG at the time of the baseline and the follow-up scan, which may affect the accumulation of the tracer in the tumor tissue. Therefore, Ki is in principle a more reliable measure of tumor glucose use than SUV or t/m.

However, in the present study, we observed a close correlation between changes in SUV and Ki. The ROC curves for prediction of response by changes in Ki and SUV showed an almost identical diagnostic accuracy of both parameters. Furthermore, changes in SUV and Ki demonstrated a similar correlation with patient survival. Therefore, in monitoring chemotherapy of advanced NSCLC it seems feasible to use SUVs for prediction of therapy response. In addition, only an axial field of view of 15 to 20 cm can be studied during the dynamic data acquisition required for Patlak-Gjedde analysis, whereas SUVs can also be calculated from whole-body PET studies. As metastatic lesions in different parts of the body may respond differently to chemotherapy, this represents a principal advantage of SUV compared with Ki. In the present study, we observed a partial response of the primary tumor in three patients, whereas lymph and distant metastases remained stable or progressed.

Compared with SUV and Ki, the reduction of t/m showed a considerable overlap between responding and nonresponding tumors. Thus t/m seems to be less suited than SUV and Ki for monitoring tumor response. This can probably be explained by a relatively low and variable FDG uptake in paraspinal muscles. Muscle activity may vary between the baseline and follow-up scan, thereby increasing or decreasing the FDG accumulation within the paraspinal muscles. Because FDG uptake by paraspinal muscles is generally low, small absolute changes in muscular tracer accumulation may cause large changes in t/m.

Several clinical parameters such as performance status have been shown to be statistically correlated with the probability of tumor response to chemotherapy.³¹ However, their accuracy to predict response is too low to be useful for making a decision in an individual patient. More recently, molecular markers, such as p53, tubulin, and p-glycoprotein have been evaluated for prediction of response to chemotherapy.^32,33 However, we are not aware of studies that prospectively demonstrate that molecular markers can be used to predict response to combination chemotherapy with the clinically required accuracy. This can probably be explained by the fact that the mechanisms for chemotherapy resistance are complex and likely to depend on the interactions of several factors, such as intracellular drug uptake, drug metabolism, and defects in apoptosis. Therefore, it seems unlikely that analysis of the expression of a limited number of proteins is sufficient to predict response to chemotherapy. Development of cDNA microarray technology has facilitated the problem to analyze simultaneously a large number of genes in clinical material.³⁴ However, chemosensitivity may be governed by mechanisms that are not readily revealed at the transcriptional level, such as posttranscriptional regulation, posttranslational modification, or protein-protein interactions. Furthermore, proteins or RNA obtained from biopsy specimens may not be representative of the whole tumor mass, especially in patients with advanced NSCLC.

The clinical use of FDG-PET for prediction of response to chemotherapy requires confirmation of the results of the present study by other groups. Studies of larger number of patients are necessary to narrow the confidence intervals for the sensitivity and specificity of FDG-PET to predict best response to chemotherapy. Nevertheless, the present study indicates that FDG-PET may provide unique means to use chemotherapy more efficiently in patients with advanced NSCLC. In patients without a metabolic response, the drug regimen may be changed to second-line therapy after the first therapy cycle, thereby significantly reducing the morbidity and costs resulting from ineffective therapy. The use of FDG-PET for therapy monitoring seems clinically feasible, because PET imaging is becoming increasingly available and our data demonstrate that no sophisticated methods for data analysis are required to detect a metabolic response to chemotherapy. It is also attractive to include FDG-PET in phase II studies evaluating new drug regimens for treatment of NSCLC. Patients with a metabolic response have a high probability for achieving a partial response or at least disease stabilization. Hence the new drug regimen can safely be continued in these patients, followed by a standard response evaluation. In contrast, the experimental drug should be stopped in patients without a metabolic response. Because patients without a metabolic response are unlikely to achieve an objective response, this approach is not expected to miss new active drug regimens. However, the time during which patients are exposed to an inactive new drug can be significantly shortened.

	ACKNOWLEDGMENTS

 
We thank R. Busch, Department of Medical Statistics, TU-Muenchen, for statistical consultation. Furthermore, we thank the cyclotron staff and the technologists at our institution for their excellent support.

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Submitted December 2, 2002; accepted April 24, 2003.

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				S. Ben-Haim and P. Ell 18F-FDG PET and PET/CT in the Evaluation of Cancer Treatment Response J. Nucl. Med., January 1, 2009; 50(1): 88 - 99. [Abstract] [Full Text] [PDF]

				W. A. Weber The Use of Positron Emission Tomography versus Computerized Tomography Scans in the Assessment of Response to Therapy ASCO Educational Book, January 1, 2009; 2009(1): 474 - 478. [Abstract] [Full Text] [PDF]

				S. Holdenrieder, J. von Pawel, E. Dankelmann, T. Duell, B. Faderl, A. Markus, M. Siakavara, H. Wagner, K. Feldmann, H. Hoffmann, et al. Nucleosomes, ProGRP, NSE, CYFRA 21-1, and CEA in Monitoring First-Line Chemotherapy of Small Cell Lung Cancer Clin. Cancer Res., December 1, 2008; 14(23): 7813 - 7821. [Abstract] [Full Text] [PDF]

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				M. R. Benz, V. Evilevitch, M. S. Allen-Auerbach, F. C. Eilber, M. E. Phelps, J. Czernin, and W. A. Weber Treatment Monitoring by 18F-FDG PET/CT in Patients with Sarcomas: Interobserver Variability of Quantitative Parameters in Treatment-Induced Changes in Histopathologically Responding and Nonresponding Tumors J. Nucl. Med., July 1, 2008; 49(7): 1038 - 1046. [Abstract] [Full Text] [PDF]

				C. Plathow and W. A. Weber Tumor Cell Metabolism Imaging J. Nucl. Med., June 1, 2008; 49(Suppl_2): 43S - 63S. [Abstract] [Full Text] [PDF]

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				F.-M. S. Kong, K. A. Frey, L. E. Quint, R. K. T. Haken, J. A. Hayman, M. Kessler, I. J. Chetty, D. Normolle, A. Eisbruch, and T. S. Lawrence A Pilot Study of [18F]Fluorodeoxyglucose Positron Emission Tomography Scans During and After Radiation-Based Therapy in Patients With Non Small-Cell Lung Cancer J. Clin. Oncol., July 20, 2007; 25(21): 3116 - 3123. [Abstract] [Full Text] [PDF]

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				K. Ott, W. A. Weber, F. Lordick, K. Becker, R. Busch, K. Herrmann, H. Wieder, U. Fink, M. Schwaiger, and J.-R. Siewert Metabolic Imaging Predicts Response, Survival, and Recurrence in Adenocarcinomas of the Esophagogastric Junction J. Clin. Oncol., October 10, 2006; 24(29): 4692 - 4698. [Abstract] [Full Text] [PDF]

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				H. Su, C. Bodenstein, R. A. Dumont, Y. Seimbille, S. Dubinett, M. E. Phelps, H. Herschman, J. Czernin, and W. Weber Monitoring Tumor Glucose Utilization by Positron Emission Tomography for the Prediction of Treatment Response to Epidermal Growth Factor Receptor Kinase Inhibitors. Clin. Cancer Res., October 1, 2006; 12(19): 5659 - 5667. [Abstract] [Full Text] [PDF]

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				W A Weber PET for response assessment in oncology: radiotherapy and chemotherapy Br. J. Radiol., November 1, 2005; Supplement_28(1): 42 - 49. [Abstract] [Full Text] [PDF]

				N. Avril, S. Sassen, B. Schmalfeldt, J. Naehrig, S. Rutke, W. A. Weber, M. Werner, H. Graeff, M. Schwaiger, and W. Kuhn Prediction of Response to Neoadjuvant Chemotherapy by Sequential F-18-Fluorodeoxyglucose Positron Emission Tomography in Patients With Advanced-Stage Ovarian Cancer J. Clin. Oncol., October 20, 2005; 23(30): 7445 - 7453. [Abstract] [Full Text] [PDF]

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				W. A. Weber Use of PET for Monitoring Cancer Therapy and for Predicting Outcome J. Nucl. Med., June 1, 2005; 46(6): 983 - 995. [Abstract] [Full Text] [PDF]

				L. K. Shankar and D. C. Sullivan Functional Imaging in Lung Cancer J. Clin. Oncol., May 10, 2005; 23(14): 3203 - 3211. [Abstract] [Full Text] [PDF]

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				C. Waldherr, I. K. Mellinghoff, C. Tran, B. S. Halpern, N. Rozengurt, A. Safaei, W. A. Weber, D. Stout, N. Satyamurthy, J. Barrio, et al. Monitoring Antiproliferative Responses to Kinase Inhibitor Therapy in Mice with 3'-Deoxy-3'-18F-Fluorothymidine PET J. Nucl. Med., January 1, 2005; 46(1): 114 - 120. [Abstract] [Full Text] [PDF]

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				F. C. Detterbeck, J. F. Vansteenkiste, D. E. Morris, C. A. Dooms, A. H. Khandani, and M. A. Socinski Seeking a Home for a PET, Part 3: Emerging Applications of Positron Emission Tomography Imaging in the Management of Patients With Lung Cancer Chest, November 1, 2004; 126(5): 1656 - 1666. [Abstract] [Full Text] [PDF]

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