PET tracers in musculoskeletal disease beyond FDG.

Musculoskeletal tumors comprise a multitude of tumor entities with different grades of malignancy, biological behavior, and therapeutic options. Positron emission tomography (PET) using the glucose analog [18F]fluorodeoxyglucose (FDG) is an established imaging modality for detection and staging of cancer, despite some shortcomings. Numerous studies have evaluated the role of PET imaging musculoskeletal tumors beyond FDG. The use of more specific novel PET radiopharmaceuticals such as the proliferation marker [18F]fluorodeoxythymidine (FLT), the bone-imaging agent [18F]sodium fluoride, amino acid tracers ([11C]methionine, [18F]fluoroethyltyrosine), or biomarkers of neoangiogenesis ([18F]galacto-RGD) can potentially provide insights into the biology of musculoskeletal tumors with focus on tumor grading, treatment monitoring, posttherapy assessment, and estimation of individual prognosis. In this article, we review the potential role of these alternative PET tracers in musculoskeletal disorders with emphasis on oncologic applications.

Molecular imaging of proliferation and glucose utilization: utility for monitoring response and prognosis after neoadjuvant therapy in locally advanced gastric cancer.

BACKGROUND: Metabolic imaging of gastric cancer is limited due to the 30% of primary tumors that are not (18)F-fluorodeoxyglucose (FDG) avid. In contrast, the proliferation marker (18)F-fluorothymidine (FLT) has been shown to visualize also non-FDG-avid gastric tumors. In this study we tested whether FLT-positron emission tomography (PET) can improve the predictive potential of molecular imaging for assessing response to neoadjuvant therapy in gastric cancer compared with FDG-PET. METHODS: 45 patients with gastric cancer underwent FDG- and FLT-PET before and 2 weeks after initiation of chemotherapy. FDG/FLT-PET findings and Ki67 immunohistochemistry were correlated with clinical and histopathological response and survival. RESULTS: 14 patients had non-FDG-avid tumors, whereas all tumors could be visualized by FLT-PET. No significant association of clinical or histopathological response with any of the analyzed metabolic parameters [initial standardized uptake value (SUV), SUV after 2 weeks, change of SUV for FDG/FLT] was found. Univariate Cox regression analysis for Ki67 and metabolic parameters revealed significant prognostic impact for survival only for FLT SUV(mean) day 14 (p=0.048) and Ki67 (p=0.006). Multivariate Cox regression analysis (including clinical response, Lauren type, ypN category, and FLT SUV(mean) day 14) revealed Lauren type and FLT SUV(mean) day 14 as the only significant prognostic factors (p=0.006, p=0.002). CONCLUSIONS: FLT uptake 2 weeks after initiation of therapy was shown to be the only imaging parameter with significant prognostic impact. Neither FLT-PET nor FDG-PET were correlated with histopathological or clinical response. However, these data must be interpreted with caution due to the single-center trial study design, relatively short follow-up, poor response rates, and unfavorable prognosis.

Imaging of proliferation in hepatocellular carcinoma with the in vivo marker 18F-fluorothymidine.

UNLABELLED: We determined the ability of PET with the thymidine analog 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) to detect hepatocellular carcinoma (HCC). METHODS: In this pilot study, (18)F-FLT PET was performed in 18 untreated patients with clinically suspected HCC. Routine diagnostic procedures included ultrasound, MRI, or contrast-enhanced spiral CT of the upper gastrointestinal tract in all patients. At 45-60 min after the intravenous injection of approximately 270-340 MBq of (18)F-FLT, emission and transmission scanning was performed with a high-resolution PET scanner. Tracer uptake in the tumor and surrounding liver tissue was evaluated semiquantitatively by calculation of mean and maximum standardized uptake values (SUVs). Results were correlated with those of the conventional imaging methods. RESULTS: A total of 13 of 18 tumors (sensitivity, 72%; 95% confidence interval [CI], 47%-90%) showed focal (18)F-FLT uptake higher than surrounding liver activity and were detectable as hot lesions. Five tumors were characterized as photopenic lesions or contained a mixture of hot and cold lesions exhibiting a comparable or lower (18)F-FLT uptake than the surrounding liver tissue. When all lesions were considered, the mean (18)F-FLT SUV was 7.8 (range, 2.5-11.1), and the maximum (18)F-FLT SUV was 9.3 (range, 2.9-14.3). Histology and clinical follow-up revealed HCC in 16 patients and cholangiocarcinoma in 2 patients. In the subgroup of HCC, the sensitivity for tumor detection was 69% (11/16; 95% CI, 41%-89%). Correlation analysis demonstrated a significant positive relationship between the proliferation marker MIB-1 and the mean SUV (r = 0.66, P = 0.02). Survival analysis (Cox proportional hazards regression) for initial (18)F-FLT uptake (mean and maximum SUVs) revealed increased hazard ratios (mean SUV, 1.20; maximum SUV, 1.12), but because of the small number of events, these results were not statistically significant. CONCLUSION: In this pilot study, HCC tumors showed a mixed uptake pattern for the in vivo proliferation marker (18)F-FLT. A total of 69% of the HCC lesions showed (18)F-FLT uptake higher than that of the surrounding liver tissue, whereas the remaining lesions were photopenic or contained a mixture of hot and cold lesions. High initial (18)F-FLT uptake seems to be associated with reduced overall survival and could be an important prognostic factor if this tendency can be confirmed in a larger prospective trial.

Early response assessment using 3'-deoxy-3'-[18F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin's lymphoma.

PURPOSE: To evaluate 3'-deoxy-3'-[(18)F]fluorothymidine-positron emission tomography (FLT-PET) for early monitoring response of high-grade non-Hodgkin's lymphoma to treatment with cyclophosphamide-adriamycin-vincristine-prednisone chemotherapy with or without rituximab immunotherapy (R-CHOP/CHOP). EXPERIMENTAL DESIGN: Twenty-two patients with histologically proven high-grade non-Hodgkin's lymphoma scheduled to undergo first line treatment with R-CHOP/CHOP were included. All patients received baseline imaging before therapy with FLT-PET. For noninvasive assessment of treatment response, FLT-PET was repeated at following time points: group 1 (n = 6), 1 and 6 weeks after R-CHOP/CHOP; group 2 (n = 16), 2 days after rituximab and 2 days after CHOP application. Emission images were acquired 45 min after injection of 300 to 370 MBq of FLT. FLT uptake was quantified by region-of-interest technique on a lesion basis. Maximum standardized uptake values (SUV) for FLT were calculated using circular region of interest (diameter, 1.5 cm). RESULTS: In all patients, morphologically proven lesions showed initially high FLT uptake (mean SUV, 8.1 +/- 3.9). In group 1, mean FLT SUV decreased 7 days after R-CHOP/CHOP by 77% (P < 0.001), the reduction in FLT SUV from baseline was 85% after 40 days (P = 0.003). In group 2, FLT uptake in patients without dexamethasone pretreatment revealed no significant reduction after rituximab (P = 0.3) but significantly decreased 2 days after CHOP to 32% compared with the baseline value (P = 0.004). CONCLUSIONS: Administration of R-CHOP/CHOP is associated with an early decrease in lymphoma FLT uptake. Interestingly, there was no reduction of FLT uptake after rituximab alone, indicating no early antiproliferative effect of immunotherapy. FLT-PET seems to be promising for early evaluation of drug effects in lymphoma.

Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment.

PURPOSE: To evaluate the time course of therapy-induced changes in tumor glucose use during chemoradiotherapy of esophageal squamous cell carcinoma (ESCC) and to correlate the reduction of metabolic activity with histopathologic tumor response and patient survival. PATIENTS AND METHODS: Thirty-eight patients with histologically proven intrathoracic ESCC (cT3, cN0/+, cM0) scheduled to undergo a 4-week course of preoperative simultaneous chemoradiotherapy followed by esophagectomy were included. Patients underwent positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) before therapy (n = 38), after 2 weeks of initiation of therapy (n = 27), and preoperatively (3 to 4 weeks after chemoradiotherapy; n = 38). Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUVs). Results Mean tumor FDG uptake before therapy was 9.3 +/- 2.8 SUV and decreased to 5.7 +/- 1.9 SUV 14 days after initiation of chemoradiotherapy (-38% +/- 18%; P <.0001). The preoperative scan showed an additional decrease of metabolic activity to 3.3 +/- 1.1 SUV (P <.0001). In histopathologic responders (< 10% viable cells in the resected specimen), the decrease in SUV from baseline to day 14 was 44% +/- 15%, whereas it was only 21% +/- 14% in nonresponders (P =.0055). Metabolic changes at this time point were also correlated with patient survival (P =.011). In the preoperative scan, tumor metabolic activity had decreased by 70% +/- 11% in histopathologic responders and 51% +/- 21% in histopathologic nonresponders. CONCLUSION: Changes in tumor metabolic activity after 14 days of preoperative chemoradiotherapy are significantly correlated with tumor response and patient survival. This suggests that FDG-PET might be used to identify nonresponders early during neoadjuvant chemoradiotherapy, allowing for early modifications of the treatment protocol.

Comparison of changes in tumor metabolic activity and tumor size during chemotherapy of adenocarcinomas of the esophagogastric junction.

UNLABELLED: We evaluated the temporal relationship between chemotherapy-induced changes in tumor glucose use and tumor size. METHODS: Twenty patients with adenocarcinoma of the esophagogastric junction (AEG) were studied by 18F-FDG PET and CT scans before neoadjuvant chemotherapy, 14 d after the initiation of therapy, and 4 wk after the completion of therapy. RESULTS: The relative change in 18F-FDG uptake was more than 2 times larger than the decrease in tumor size at all time points (P<0.01). At 14 d after the initiation of chemotherapy, there was no correlation between the reduction in 18F-FDG uptake and tumor wall thickness. The change in 18F-FDG uptake after 14 d of therapy was significantly correlated with the reduction in tumor size after the completion of therapy. CONCLUSION: In AEG, changes in tumor metabolism are a more sensitive parameter for assessing the effects of chemotherapy than are changes in tumor size. Early changes in metabolic activity predict the subsequent reduction in tumor size.

Clinical use of bone-targeting radiopharmaceuticals with focus on alpha-emitters.

Various single or multi-modality therapeutic options are available to treat pain of bone metastasis in patients with prostate cancer. Different radionuclides that emit ß-rays such as (153)Samarium and (89)Strontium and achieve palliation are commercially available. In contrast to ß-emitters, (223)Radium as a α-emitter has a short path-length. The advantage of the α-emitter is thus a highly localized biological effect that is caused by radiation induced DNA double-strand breaks and subsequent cell killing and/or limited effectiveness of cellular repair mechanisms. Due to the limited range of the α-particles the bone surface to red bone marrow dose ratio is also lower for (223)Radium which is expressed in a lower myelotoxicity. The α emitter (223)Radium dichloride is the first radiopharmaceutical that significantly prolongs life in castrate resistant prostate cancer patients with wide-spread bone metastatic disease. In a phase III, randomized, double-blind, placebo-controlled study 921 patients with castration-resistant prostate cancer and bone metastases were randomly assigned. The analysis confirmed the (223)Radium survival benefit compared to the placebo (median, 14.9 mo vs 11.3 mo; P < 0.001). In addition, the treatment results in pain palliation and thus, improved quality of life and a delay of skeletal related events. At the same time the toxicity profile of (223)Radium was favourable. Since May 2013, (223)Radium dichloride (Xofigo(®)) is approved by the US Food and Drug Administration.

PET and PET-CT in esophageal and gastric cancer.

Esophageal cancer ranks among the ten most common malignancies in the world and is a frequent cause of cancer-related death. Almost all therapeutic modalities for esophageal cancer are associated with considerable mortality and morbidity. Consequently, there has been growing concern regarding effective management of esophageal cancer. Imaging plays an important role in the initial selection of patients. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is playing an increasing role in the management of esophageal cancer. The role of FDG-PET in diagnosis, preoperative staging, monitoring of response to neoadjuvant therapy, and detection of disease recurrence is evaluated in this chapter.

Predictive value of initial 18F-FLT uptake in patients with aggressive non-Hodgkin lymphoma receiving R-CHOP treatment.

UNLABELLED: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy is the standard therapy in aggressive B-cell lymphoma. (18)F-FDG PET has high prognostic implications at treatment completion but is limited as an early predictor. Here, we present the results of a prospective study correlating the initial uptake of the in vivo proliferation marker 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) with the clinical outcome of patients with aggressive non-Hodgkin lymphoma treated with R-CHOP. METHODS: Sixty-six eligible patients were evaluated prospectively with (18)F-FLT PET before R-CHOP. PET was performed 45 min after injection of 300-370 MBq of (18)F-FLT. Mean and maximum standardized uptake values (SUVs) were calculated on a lesion-by-lesion basis. Response was assessed at the end of therapy. International Prognostic Index (IPI) scores and clinical parameters (Ann Arbor stage, lactate dehydrogenase, performance status, extranodal disease) were determined in all patients. Response was assessed according to revised response criteria after the end of therapy. After treatment, patients were followed in intervals from 4 wk to 6 mo (mean follow-up, 23.1 mo [range, 1-63 mo]), and progression-free and overall survival were determined. RESULTS: All lymphoma lesions identified by a reference method ((18)F-FDG PET/CT or multislice CT of the trunk) showed increased focal tracer uptake (mean (18)F-FLT SUV, 7.3 ± 2.5). Response assessment revealed progressive disease in 4, partial response in 3, and complete response (CR) in the remaining 55 patients. The IPI score was predictive for achieving CR (P = 0.034). Importantly, initial mean SUV was also significantly higher in patients who showed progressive disease and partial response than in patients who achieved CR (P = 0.049). In addition, we found a significant correlation between IPI score and initial (18)F-FLT uptake. CONCLUSION: Taken together, high (18)F-FLT uptake is a negative predictor of response to R-CHOP treatment in aggressive B-cell non-Hodgkin lymphoma and correlates with the IPI score. Thus, (18)F-FLT PET may represent a useful tool for implementing risk-adapted treatment in these patients.

Comparison of different SUV-based methods for response prediction to neoadjuvant radiochemotherapy in locally advanced rectal cancer by FDG-PET and MRI.

PURPOSE: The aim of this study was to compare different analysis methods of 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) data for prediction of histopathological response (HPR) to neoadjuvant radiochemotherapy (RCTx) in patients with advanced rectal cancer. PROCEDURES: Twenty-eight patients of a previously published clinical trial underwent serial FDG-PET/computed tomography scans at baseline, 14 days after initiation, and after completion of RCTx. In addition, MRI was performed at baseline and after the end of therapy. Response prediction was correlated with different image analysis algorithms comprising pure metabolic parameters taking into account the FDG uptake, volume-based parameters measuring the lesion volume in either MRI or PET data, and integrated parameters combining metabolic and volumetric information. The established two-dimensional (2D) regions of interest (ROI; diameter 1.5 cm) served as standard of reference. Changes between the parameters at the defined time points were calculated and analyzed for their potential to predict HPR to RCTx using receiver operating characteristic (ROC) analysis. Additionally, the interobserver reliability of fixed-size algorithms was analyzed. RESULTS: Histopathology classified eight of 28 patients as non-responders and 20 patients as responders to RCTx. ROC analysis of the standard 2D ROI technique revealed areas under the curve (AUCs) of 0.64 and 0.71 for the early and late time points. Corresponding AUCs for three-dimensional (3D) volume of interest technique resulted in AUCs of 0.75 for both early and late time points, respectively. Volumetric parameters showed AUCs ranging from 0.52 to 0.57 (early time points) and 0.46 to 0.76 (later time points), respectively. Corresponding AUCs for the integrated parameters were ranging between 0.70 and 0.73 (early time points) and 0.66 and 0.76 (late time points). Analysis of intra-class correlation coefficients (ICC) for three different readers resulted in the best intra-class correlation values for the changes of 3D standard uptake value (SUV(3D)), for both early (ICC = 0.96) and late (ICC = 0.96) time points, respectively. CONCLUSIONS: Our study emphasizes that 3D-based approaches for assessing SUV values consistently belonged to the group of parameters with the highest AUC values for prediction of HPR to neoadjuvant RCTx in patients with rectal cancer. MRI was not a good predictor for therapy response; hence, the MRI information derived from combined anatomic and metabolic parameters showed unsatisfying results too.

Therapy Monitoring with Fluorine-18 FDG-PET and Fluorine-18 FDG-PET/CT.

PET with the glucose analog [18F]-FDG is increasingly used to monitor tumor response in patients undergoing chemotherapy and chemoradiotherapy. The clinical value of FDG PET for differentiation of residual tumor and therapy-induced fibrosis has been documented for gastrointestinal cancer. Furthermore, quantitative assessment of therapy-induced changes in tumor [18F]-FDG uptake may allow the prediction of tumor response and patient outcome very early in the course of therapy. This suggests that FDG PET may be used to identify nonresponders early during neoadjuvant chemoradiotherapy, allowing for early modifications of the treatment protocol.

PET imaging with [18F]3'-deoxy-3'-fluorothymidine for prediction of response to neoadjuvant treatment in patients with rectal cancer.

PURPOSE: Positron emission tomography (PET) using 18F-labelled 3'-deoxy-3'-fluorothymidine (FLT) was assessed for therapy monitoring in patients with rectal cancer undergoing neoadjuvant chemoradiotherapy. METHODS: Ten patients with locally advanced rectal cancer were included and underwent long-course preoperative chemoradiotherapy (total dose 45 Gy, 1.8 Gy/day, concomitant 250 mg/m2 5-fluorouracil) followed by surgery. FLT-PET was performed prior to chemoradiotherapy, 2 weeks after initiation of chemoradiotherapy and preoperatively (3-4 weeks post chemoradiotherapy). FLT uptake was correlated with histopathological tumour regression and changes in T stage. RESULTS: Mean tumour FLT uptake was 4.2+/-1.0 SUV before therapy and decreased significantly to 2.9+/-0.6 SUV 14 days after initiation of chemoradiotherapy (-28.6%+/-10.7%, p=0.005). The preoperative scan showed a further decrease to 1.9+/-0.4 SUV (-54.7%+/-7.6%, p=0.005). However, the degree of change in FLT uptake 2 weeks after initiation and after completion of neoadjuvant therapy did not correlate with histopathological tumour regression. CONCLUSION: FLT-PET did not seem to be a promising method for assessment of tumour response in the studied chemoradiotherapy regimen in patients with rectal cancer.

Prediction of tumor response by FDG-PET: comparison of the accuracy of single and sequential studies in patients with adenocarcinomas of the esophagogastric junction.

PURPOSE: Positron-emission-tomography with the glucose analog fluorodeoxyglucose (FDG-PET) has shown encouraging results for prediction of tumor response to chemotherapy. However, there is no consensus as to what time after initiation of therapy FDG-PET should be performed. To address this question we studied the time course of changes in tumor FDG-uptake in patients with locally advanced adenocarcinomas of the esophagogastric junction (AEG) treated with preoperative chemotherapy. METHODS: Twenty-four patients with AEG were included and underwent FDG-PET prior to therapy (PET1), 2 weeks after initiation of therapy (PET2), and preoperatively (PET3). Tumor metabolic activity was assessed by standardized uptake values (SUV) and correlated with histopathologic response and patient survival. RESULTS: Baseline tumor SUV was 8.3 +/- 3.5 and decreased to 5.0 +/- 1.8 at PET2 (p < 0.0001). At PET3 there was further decrease to 3.5 +/- 1.9 (p < 0.0001). The relative decrease of tumor FDG-uptake from PET1 to PET2 and from PET1 to PET3 were both significantly correlated with histopathologic response. Reduction of tumor SUV from PET1 to PET2 was significantly correlated with survival (p = 0.03) and there was a similar trend for changes from PET1 to PET3 (p = 0.09). In contrast, absolute SUVs did not demonstrate a significant correlation with histopathological response or patient survival at any of the studied time points. CONCLUSION: In patients with AEG, relative changes in tumor FDG uptake are better predictors for treatment outcome than absolute SUVs. Metabolic changes within the first 2 weeks of therapy are at least as efficient for prediction of histopathologic response and patient survival as later changes.

Rectal cancer: MR imaging before neoadjuvant chemotherapy and radiation therapy for prediction of tumor-free circumferential resection margins and long-term survival.

PURPOSE: To retrospectively evaluate the prognostic importance of involvement of the circumferential resection margin predicted by using magnetic resonance (MR) imaging before neoadjuvant treatment in patients with rectal cancer. MATERIALS AND METHODS: The local institutional review board approved the retrospective analysis of the data and waived informed consent. Sixty-eight patients (52 men, 16 women; mean age +/- standard deviation, 58.9 years +/- 9.4) with cT3 NX M0 tumors were included. T2-weighted MR images were analyzed in consensus by two radiologists with respect to the shortest distance between the outermost parts of the tumor to the adjacent mesorectal fascia (as the potential circumferential resection margin in total mesorectal excision). Histopathologic and follow-up data were available for all patients (mean follow-up time, 54 months; range, 31-77 months). To compare local recurrence and survival rates, the population was divided into three groups categorized according to the minimum distance of the tumor to the mesorectal fascia (group 1, 1 to 5 mm; group 3, >5 mm). Univariate Cox and multivariate proportional hazard regression models were used to test the prognostic importance of clinical, histopathologic regression, and histopathologic tumor parameters. RESULTS: MR imaging led to accurate prediction of a histologically involved circumferential resection margin (sensitivity, 100%; specificity, 88%). The rates for local recurrence (group 1, 33%; group 2, 5%; group 3, 6%; P<.02) and 5-year overall survival (group 1, 39%; group 2, 70%; group 3, 90%; P<.001) differed significantly among the predefined groups. The distance to the mesorectal fascia was an independent prognostic parameter in multivariate analysis (P<.001), and histopathologic response to treatment provided no additional information. CONCLUSION: Prediction of the tumor-free circumferential resection margin assessed with MR imaging before initiation of neoadjuvant chemotherapy and radiation therapy proved to be a prognostic factor in rectal cancer.

Adenocarcinomas of esophagogastric junction: multi-detector row CT to evaluate early response to neoadjuvant chemotherapy.

PURPOSE: To prospectively evaluate multi-detector row computed tomography (CT) in the assessment of early response during neoadjuvant chemotherapy for adenocarcinoma of the esophagogastric junction (AEG). MATERIALS AND METHODS: The study protocol was approved by the local ethics committee. Written informed consent was obtained from all patients. Thirty-one patients with an AEG (stage T3 N0/1 M0 or T4 N0/1 M0) were examined with multi-detector row CT before and 2 weeks after the initiation of chemotherapy. There were seven women and 24 men with a mean age of 62 years +/- 8.1 (standard deviation). The maximal transverse tumor diameter was measured and tumor volumetry was performed by three independent readers. The resulting changes were correlated with the histopathologic grade of regression in 21 patients. The differentiation of responders from nonresponders was assessed with receiver operating characteristic analysis in these 21 patients. Interobserver variability was determined in all 31 patients with the Spearman rank correlation. Survival without disease progression was estimated in all patients according to the Kaplan-Meier method. Statistical comparisons between different groups of patients were performed with the log-rank test. RESULTS: The interobserver variability for the diameter measurements (R = 0.13-0.20) was higher than that for the volumetric measurements (R = 0.70-0.82). The correlation of histopathologic grades of regression with changes in diameter was not statistically significant for the three readers, whereas the correlation of volume changes with histopathologic grades of regression was statistically significant for two of the three readers (P = .01, .05, and .08). Results of receiver operating characteristic analysis revealed an optimal cutoff level for tumor volumetry at a reduction of volume of 14.8%, which resulted in a sensitivity of 100% (six of six patients) and a specificity of 53% (eight of 15 patients). Although the probability of progression was higher in the nonresponder group than in the responder group (61% vs 40%, respectively), the differences were not statistically significant. CONCLUSION: Tumor volumetry based on multi-detector row CT can help predict early response to treatment 2 weeks after the initiation of neoadjuvant chemotherapy in patients with AEG; however, the classic approach of tumor diameter measurement failed to show significant correlation with histopathologic tumor regression.