Martin Allen-Auerbach

Reduction of Glucose Metabolic Activity Is More Accurate than Change in Size at Predicting Histopathologic Response to Neoadjuvant Therapy in High-Grade Soft-Tissue Sarcomas

Purpose: Change in tumor size as classified by Response Evaluation Criteria in Solid Tumors poorly correlates with histopathologic response to neoadjuvant therapy in patients with soft-tissue sarcomas. The aim of this study was to prospectively evaluate whether positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET) allows for a more accurate evaluation of histopathologic response. Experimental Design: From January 2005 to January 2007, 42 patients with resectable biopsy-proven high-grade soft-tissue sarcoma underwent a FDG-PET/computed tomography scan before and after neoadjuvant treatment. Relative changes in tumor FDG uptake and size from the baseline to the follow-up scan were calculated, and their accuracy for assessment of histopathologic response was compared by receiver operating characteristic curve analysis. Histopathologic response was defined as ≥95% tumor necrosis. Results: In histopathologic responders (n = 8; 19%), reduction in tumor FDG uptake was significantly greater than in nonresponders (P < 0.001), whereas no significant differences were found for tumor size (P = 0.24). The area under the receiver operating characteristic curve for metabolic changes was 0.93, but only 0.60 for size changes (P = 0.004). Using a 60% decrease in tumor FDG uptake as a threshold resulted in a sensitivity of 100% and a specificity of 71% for assessment of histopathologic response, whereas Response Evaluation Criteria in Solid Tumors showed a sensitivity of 25% and a specificity of 100%. Conclusion: Quantitative FDG-PET was significantly more accurate than size-based criteria at assessing histopathologic response to neoadjuvant therapy. FDG-PET should be considered as a modality to monitor treatment response in patients with high-grade soft-tissue sarcoma.

FDG-PET/CT Imaging Predicts Histopathologic Treatment Responses after the Initial Cycle of Neoadjuvant Chemotherapy in High-Grade Soft-Tissue Sarcomas

Purpose: In patients with soft-tissue sarcoma (STS), the early assessment of treatment responses is important. Using positron emission tomography/computed tomography (PET/CT) with [18F]fluorodeoxyglucose (FDG), we determined whether changes in tumor FDG uptake predict histopathologic treatment responses in high-grade STS after the initial cycle of neoadjuvant chemotherapy. Experimental Design: From February 2006 to March 2008, 50 patients with resectable high-grade STS scheduled for neoadjuvant therapy and subsequent tumor resection were enrolled prospectively. FDG-PET/CT before (baseline), after the first cycle (early follow-up), and after completion of neoadjuvant therapy (late follow-up) was done. Tumor FDG uptake and changes were measured by standardized uptake values. Histopathologic examination of the resected specimen provided an assessment of treatment response. Patients with ≥95% pathologic necrosis were classified as treatment responders. FDG-PET/CT results were compared with histopathologic findings. Results: At early follow-up, FDG uptake decreased significantly more in 8 (16%) responders than in the 42 (84%) nonresponders (−55% versus −23%; P = 0.002). All responders and 14 of 42 nonresponders had a ≥35% reduction in standardized uptake value between baseline and early follow-up. Using a ≥35% reduction in FDG uptake as early metabolic response threshold resulted in a sensitivity and specificity of FDG-PET for histopathologic response of 100% and 67%, respectively. Applying a higher threshold at late follow-up improved specificity but not sensitivity. CT had no value at response prediction. Conclusion: A 35% reduction in tumor FDG uptake at early follow-up is a sensitive predictor of histopathologic tumor response. Early treatment decisions such as discontinuation of chemotherapy in nonresponding patients could be based on FDG-PET criteria.

Quantitative F18-fluorodeoxyglucose positron emission tomography accurately characterizes peripheral nerve sheath tumors as malignant or benign

Correct pretreatment classification is critical for optimizing diagnosis and treatment of patients with peripheral nerve sheath tumors (PNSTs). The aim of this study was to evaluate whether F18‐fluorodeoxyglucose positron emission tomography (FDG PET) can differentiate malignant (MPNST) from benign PNSTs.

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

Measurements of tumor glucose use by 18F-FDG PET need to be standardized within and across institutions. Various parameters are used for measuring changes in tumor glucose metabolic activity with 18F-FDG PET in response to cancer treatments. However, it is unknown which of these provide the lowest variability between observers. Knowledge of the interobserver variability of quantitative parameters is important in sarcomas as these tumors are frequently large and demonstrate heterogeneous 18F-FDG uptake. Methods: A total of 33 patients (16 men, 17 women; mean age, 47 ± 18 y) with high-grade sarcomas underwent 18F-FDG PET/CT scans before and after neoadjuvant chemotherapy. Two independent investigators measured the following parameters on the pretreatment and posttreatment scans: maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), mean SUV (SUVmean), SUVmean in an automatically defined volume (SUVauto), and tumor-to-background ratio (TBR). The variability of the different parameters was compared by concordance correlation coefficient (CCC), variability effect coefficient, and Bland–Altman plots. Results: Baseline SUVmax, SUVpeak, SUVmean, SUVauto, and TBR averaged 10.36, 7.78, 4.13, and 6.22 g/mL and 14.67, respectively. They decreased to 5.36, 3.80, 1.79, and 3.25 g/mL and 6.62, respectively, after treatment. SUVmax, SUVpeak, and SUVauto measurements and their changes were reproducible (CCC ≥ 0.98). However, SUVauto poorly differentiated between responding and nonresponding tumors. The high intratumoral heterogeneity of 18F-FDG resulted in frequent failure of the thresholding algorithm, which necessitated manual corrections that in turn resulted in a higher interobserver variability of SUVmean (CCCs for follow-up and change were 0.96 and 0.91, respectively; P < 0.005). TBRs also showed a significantly higher variability than did SUVpeak (CCCs for follow-up and change were 0.94 and 0.86, respectively; P < 0.005). Conclusion: SUVmax and SUVpeak provided the most robust measurements of tumor glucose metabolism in sarcomas. Delineation of the whole-tumor volume by semiautomatic thresholding did not decrease the variability of SUV measurements. TBRs were significantly more observer-dependent than were absolute SUVs. These findings should be considered for standardization of clinical 18F-FDG PET/CT trials.

Performance of 2-Deoxy-2-[F-18]fluoro-d-glucose Positron Emission Tomography and Integrated PET/CT in Restaged Breast Cancer Patients

PurposeThis study was conducted to compare the clinical stage derived from 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) positron emission tomography (PET) to that of integrated PET/computed tomography (CT) in restaged breast cancer patients.ProceduresFifty-eight female patients (age range 29–80 years, mean age ±SD, 53.3 ± 11.7 years) underwent PET/CT restaging for breast cancer. Two experienced nuclear medicine physicians interpreted PET images. A radiologist was added for reading PET/CT studies. A patient-based analysis was performed. Histopathological findings, correlative imaging studies, changes in number, size, and hypermetabolic activity of suspicious lesions and/or patient outcome served as standard of reference for determining the diagnostic accuracy of both modalities.ResultsPET staged 79.3% (46/58) of the patients correctly, overstaged seven (12.1%), and understaged five patients (8.6%). Integrated PET/CT staged 89.7% (52/58) of the patients correctly, overstaged four (6.9%), and understaged two patients (3.4%). The staging accuracy of PET/CT was not significantly better than that of PET alone (p = 0.059). Lesions exhibiting mild hypermetabolic activity, benign inflammatory lesions, and physiological variants largely explained incorrect PET findings.ConclusionIntegrated PET/CT only marginally improves the restaging accuracy over PET alone (p = 0.059) in breast cancer patients.

Combined Assessment of Metabolic and Volumetric Changes for Assessment of Tumor Response in Patients with Soft-Tissue Sarcomas

By allowing simultaneous measurements of tumor volume and metabolic activity, integrated PET/CT opens up new approaches for assessing tumor response to therapy. The aim of this study was to determine whether combined assessment of tumor volume and metabolic activity improves the accuracy of 18F-FDG PET for predicting histopathologic tumor response in patients with soft-tissue sarcomas. Methods: Twenty patients with locally advanced high-grade soft-tissue sarcoma (10 men and 10 women; mean age, 49 ± 17 y) were studied by 18F-FDG PET/CT before and after preoperative therapy. CT tumor volume (CTvol) was measured by delineating tumor borders on consecutive slices of the CT scan. Mean and maximum 18F-FDG standardized uptake value within this volume (SUVmean and SUVmax, respectively) were determined. Two indices of total lesion glycolysis (TLG) were calculated by multiplying tumor volume by SUVmean (TLGmean) and SUVmax (TLGmax). Changes in CTvol, SUVmean, SUVmax, TLGmean, and TLGmax after chemotherapy were correlated with histopathologic tumor response (≥95% treatment-induced tumor necrosis). Accuracy for predicting histopathologic response was compared by receiver-operating-characteristic (ROC) curve analysis. Results: Baseline SUVmax, SUVmean, CTvol, TLGmean, and TLGmax were 11.22 g/mL, 2.84 g/mL, 544.1 mL, 1,619.8 g, and 8852.9 g, respectively. After neoadjuvant therapy, all parameters except CTvol showed a significant decline (ΔSUVmax = −51%, P < 0.001; ΔSUVmean = −40%, P < 0.001; ΔCTvol = −14%, P = 0.37; ΔTLGmean = −44%, P = 0.006; and ΔTLGmax = −54%, P = 0.001). SUV changes in histopathologic responders (n = 6) were significantly more pronounced than those in nonresponders (n = 14) (P = 0.001). Histopathologic response was well predicted by changes in SUVmean and SUVmax (area under ROC curve [AUC] = 1.0 and 0.98, respectively) followed by TLGmean (AUC = 0.77) and TLGmax (AUC = 0.74). In contrast, changes in CTvol did not allow prediction of treatment response (AUC = 0.48). Conclusion: In this population of patients with sarcoma, TLG was less accurate in predicting tumor response than were measurements of the intratumoral 18F-FDG concentration (SUVmax, SUVmean). Further evaluation of TLG in larger patient populations and other tumor types is necessary to determine the value of this conceptually attractive parameter for assessing tumor response.

18F-FDG PET/CT for Monitoring Treatment Responses to the Epidermal Growth Factor Receptor Inhibitor Erlotinib

Response rates of unselected non–small cell lung cancer (NSCLC) patients to the epidermal growth factor receptor inhibitor erlotinib are low and range from 10% to 20%. Early response assessments are needed to avoid costs and side effects of inefficient treatments. Here we determined whether early changes in tumor uptake of 18F-FDG can predict progression-free and overall survival in NSCLC patients who are treated with erlotinib. Methods: Twenty-two patients (6 men, 16 women; mean age ± SD, 64 ± 13 y) with stage III or stage IV NSCLC who received erlotinib treatment were enrolled prospectively. 18F-FDG PET/CT was performed before the initiation of treatment (n = 22), after 2 wk (n = 22), and after 78 ± 21 d (n = 11). Tumor maximum standardized uptake values were measured for a maximum of 5 lesions for each patient. Tumor responses were classified using modified PET Response Criteria in Solid Tumors (use of maximum standardized uptake values). Median overall survival by Kaplan–Meier analysis was compared between groups using a log-rank test. Results: The overall median time to progression was 52 d (95% confidence interval, 47–57 d). The overall median survival time was 131 d (95% confidence interval, 0–351 d). Patients with progressive metabolic disease on early follow-up PET showed a significantly shorter time to progression (47 vs. 119 d; P < 0.001) and overall survival (87 vs. 828 d; P = 0.01) than patients classified as having stable metabolic disease or partial or complete metabolic response. Conclusion: These data suggest that 18F-FDG PET/CT performed early after the start of erlotinib treatment can help to identify patients who benefit from this targeted therapy.

(18)F-FDOPA PET for differentiating recurrent or progressive brain metastatic tumors from late or delayed radiation injury after radiation treatment.

Brain metastases are frequently treated with radiation. It is critical to distinguish recurrent or progressive brain metastases (RPBM) from late or delayed radiation injury (LDRI). The purpose of this study was to examine the diagnostic accuracy as well as the prognostic power of 6-18F-fluoro-l-dopa (18F-FDOPA) PET for differentiating RPBM from LDRI. Methods: Thirty-two patients who had 83 previously irradiated brain metastases and who underwent 18F-FDOPA PET because of an MR imaging–based suggestion of RPBM were studied retrospectively. PET studies were analyzed semiquantitatively (lesion-to-striatum and lesion-to-normal brain tissue ratios based on both maximum and mean standardized uptake values) and visually (4-point scale). The diagnostic accuracy of PET was verified by histopathologic analysis (n = 9) or clinical follow-up (n = 74) on a lesion-by-lesion basis. Receiver operating characteristic curve analysis was used to identify the best diagnostic indices. The power of 18F-FDOPA PET to predict disease progression was evaluated with the Kaplan–Meier and Cox regression methods. Results: The best overall accuracy was achieved by visual scoring, with which a score of 2 or more (lesion uptake greater than or equal to striatum uptake) resulted in a sensitivity of 81.3% and a specificity of 84.3%. Semiquantitative 18F-FDOPA PET uptake indices based on lesion-to-normal brain tissue ratios were significantly higher for RPBM than for LDRI. Among the various predictors tested, 18F-FDOPA PET was the strongest predictor of tumor progression (hazard ratio, 6.26; P < 0.001), and the lesion-to-normal brain tissue ratio or visual score was the best discriminator. The mean time to progression was 4.6 times longer for lesions with negative 18F-FDOPA PET results than for lesions with positive 18F-FDOPA PET results (76.5 vs. 16.7 mo; P < 0.001). 18F-FDOPA PET findings tended to predict overall survival. Conclusion: Metabolic imaging with 18F-FDOPA PET was useful for differentiating RPBM from LDRI. Semiquantitative indices, particularly lesion-to-normal uptake ratios, could be used. A visual score comparing tumor 18F-FDOPA uptake and striatum 18F-FDOPA uptake provided the highest sensitivity and specificity and was predictive of disease progression.

Measuring Response with FDG-PET: Methodological Aspects

The use of fluorodeoxyglucose positron emission tomography (FDG-PET) for the evaluation of tumor response to chemotherapy and radiation therapy has been studied in a number of malignancies. By imaging tumor metabolism and therapy-related changes, FDG-PET has demonstrated advantages over anatomical imaging in the assessment of treatment response. More recent investigations have indicated that FDG-PET can predict tumor response early during the course of therapy, potentially allowing for early treatment adjustments. The aim of this review is to provide oncologists with a basic knowledge of the practical aspects of PET quantification for treatment.

PET/CT imaging: The incremental value of assessing the glucose metabolic phenotype and the structure of cancers in a single examination

PET/CT with the glucose analogue FDG is emerging as the most important diagnostic imaging tool in oncology. More than 2000 PET/CT scanners are operational worldwide and its unique role for diagnosing, staging, restaging and therapeutic monitoring in cancer is undisputed. Studies conducted in thousands of cancer patients have clearly indicated that the combination of molecular PET with anatomical CT imaging provides incremental diagnostic value over PET or CT alone. State of the art imaging protocols combine fully diagnostic CT scans with quality whole body PET surveys. The current review briefly describes the biological alterations of cancer cells that result in their switch to a strongly glycolytic phenotype. Different whole body imaging protocols are discussed. We summarize the evidence for the incremental value of PET/CT over CT and PET alone using imaging of sarcoma as an example. Following this section we discuss the performance of FDG-PET/CT imaging for staging, restaging and monitoring of head and neck cancer, solitary lung nodules and lung cancer, breast cancer, colorectal cancer, lymphoma and unknown primary tumors. Finally, the recently emerging evidence of a substantial impact of PET/CT imaging on patient management is presented.