18F-fluorothymidine PET for predicting survival in patients with resectable pancreatic cancer.

PURPOSE: The aim of this study was to correlate preoperative 3'-deoxy-3'-[18F] fluorothymidine (FLT) uptake with the clinical outcome and survival in these patients after surgery. MATERIALS AND METHODS: We performed a prospective analysis in 27 patients with adenocarcinoma of the pancreas (15 males, 12 females, mean age: 62 ± 13 years, range: 34 - 86 years). FLT PET (45 min p.i., 300 MBq FLT; ECAT HR+) images were acquired according to standard protocols. FLT uptake was quantified using standardised uptake values (SUV). Mean follow-up was 35 months (range 24-49). FLT uptake was correlated with survival using Martingale residual analysis. RESULTS: Twenty-two patients died during follow-up. Mean overall survival was 18.8 months (SD: 12.7 months, 95% CI: 7.7, 26.5). FLT PET showed a mean SUV of 2.5 (range: 1.1 - 6.5). Martingale residual analysis revealed significant correlation between survival and FLT uptake (p = 0.045). The corresponding estimated hazard ratio per one-point increment of SUVmean was 1.298 (95% CI: 1.001, 1.685; p < 0.05). CONCLUSIONS: FLT PET allows risk stratification for death in patients with resectable pancreatic cancer prior to surgery.

11C-choline PET/CT and whole-body MRI including diffusion-weighted imaging for patients with recurrent prostate cancer.

PURPOSE: To compare the detection efficacy of 11C-choline positron emission tomography and computed tomography (PET/CT) with whole-body magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) in patients with suspected recurrent prostate cancer. MATERIALS AND METHODS: Fifty-seven patients (mean age 68, range 54-80 years) underwent 11C-choline PET/CT and MRI using T1-weighted (T1w), short-tau inversion recovery (STIR), and DWI. Two readers visually rated suspicious lesions on a 5-point scale in 20 different regions. Clinical follow-up and histopathology served as the standard of reference (SOR). RESULTS: Fifty patients (mean PSA 29.9, range 1.0-670 ng/mL) had at least one positive lesion according to the SOR. Twenty-four patients had local recurrence (LR), 27 had lymph node (LN) involvement, and 22 had bone metastases. The overall detection rates for PET/CT and MRI on a patient basis were 94% and 88%, respectively (p = 0.07). The PSA level (>2 ng/mL vs ≤2 ng/mL) significantly influenced the overall performance of PET/CT (p = 0.003) and MRI (p = 0.03). PET/CT was significantly superior to MRI in detecting LR (p = 0.03) and bone metastasis (p = 0.02). We found no difference with respect to the detection of LN metastasis (p = 0.65). CONCLUSION: 11C-choline PET/CT was superior in the detection of local recurrence and bone metastasis on a regional basis. Whole-body MRI including DWI showed similar diagnostic accuracy only for detecting lymph node metastases. Compared with 11C-choline PET/CT, therefore, whole-body MRI including DWI cannot serve as alternative imaging modality for restaging prostate cancer.

99mTc-DPD SPECT/CT for localisation of inflammatory and chronic osteoarthritis of the foot and ankle. Comparison with planar imaging and SPECT as a clinical adjunct in radiosynovectomy.

AIM: The precise localisation of osteoarthritic and inflammatory changes is crucial for selective treatment planning of radiosynovectomy (RSV). The present study evaluated the diagnostic accuracy of planar bone imaging and SPECT for the detection of pathological bone metabolism and inflammation in joints of the foot and ankle, compared with SPECT/CT. PATIENTS, METHODS: 39 patients (mean age 65.6 ± 11.1 years) with suspected inflammatory osteoarthritis underwent SPECT/CT of the feet. After injection of approximately 500 MBq 99mTc DPD, all patients had three-phase planar bone imaging and late-phase hybrid SPECT/CT. late-phase SPECT, and CT of the foot. Increased bone metabolism and blood-pool was assigned to the respective joint of the fore-, mid-, and hindfoot, using SPECT/CT as the reference standard. RESULTS: Overall, SPECT had a higher sensitivity than planar imaging (0.80 vs 0.68, n.s.). The advantage of SPECT was most obvious in the anatomically complex midfoot area (0.63 vs 0.26, p < 0.05) and less obvious in the forefoot (0.85 vs 0.79, n.s.) and hindfoot (0.89 vs 0.89, n.s.). The overall concordance (Cohen`s Kappa) between SPECT/CT and planar (late-phase) imaging and SPECT was high for the forefoot and the hindfoot (planar: 0.78/0.81; SPECT 0.86/0.88) and comparatively low for the midfoot (planar: 0.27; SPECT 0.61). CONCLUSION: SPECT was significantly superior to planar bone imaging for the detection of joint lesions in the midfoot. The differences between SPECT and planar imaging in the fore- and hindfoot were not significant, most likely due to the inherently less complex anatomy. Compared with SPECT alone, a benefit from the use of SPECT/CT can be observed in the midfoot region where it facilitates the identification of the correct joint for RSV.

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 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.

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.

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.

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.

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.

18F-FDG PET and 18F-FDG PET/CT for assessing response to therapy in esophageal cancer.

In patients with locally advanced esophageal cancer, preoperative chemotherapy or chemoradiotherapy has been shown to improve outcome with respect to survival. Patients who respond to induction therapy have a significantly improved survival, compared with patients who do not respond to the therapy. However, surrogate markers that predict response or prognosis-especially early in the course of therapy-are not available in clinical routine. In patients with esophageal cancer, PET with the glucose analog (18)F-FDG can be used for assessing response to therapy. Therapy response can be assessed with (18)F-FDG PET and (18)F-FDG PET/CT late, that is, after completion of therapy, and early in the course of therapy. In adenocarcinomas of the esophagogastric junction, (18)F-FDG has been established and validated in several studies as a surrogate marker that allows prediction of response and prognosis, whereas in other studies (18)F-FDG PET was not predictive of response and prognosis. The MUNICON study was an initial unicenter trial showing that a PET-guided treatment algorithm was feasible in patients with adenocarcinomas of the esophagogastric junction. The results of this study are important toward individualization of multimodal treatment. The use of (18)F-FDG PET and PET/CT for therapy monitoring in esophageal cancer is the subject of intense discussion, underlining the need for randomized multicenter studies. From a methodologic point of view, the most important issue in therapy monitoring using (18)F-FDG PET and PET/CT is the standardization of patient preparation, data acquisition and processing, and data interpretation, especially for prospective randomized multicenter studies. In conclusion, single-center studies investigating response assessment in patients with esophageal cancer have provided promising results. In the future, prospective randomized multicenter trials will have to be performed and research will address new imaging probes and innovative therapy regimens.

Evaluation of dual-phase multi-detector-row CT for detection of intestinal bleeding using an experimental bowel model.

To evaluate dual-phase multi-detector-row computed tomography (MDCT) in the detection of intestinal bleeding using an experimental bowel model and varying bleeding velocities. The model consisted of a high pressure injector tube with a single perforation (1 mm) placed in 10-m-long small bowel of a pig. The bowel was filled with water/contrast solution of 30-40 HU and was incorporated in a phantom model containing vegetable oil to simulate mesenteric fat. Intestinal bleeding in different locations and bleeding velocities varying from zero to 1 ml/min (0.05 ml/min increments, constant bleeding duration of 20 s) was simulated. Nineteen complete datasets in arterial and portal-venous phase using increasing bleeding velocities, and seven negative controls were measured using a 64 MDCT (3-mm slice thickness, 1.5-mm reconstruction increment). Three radiologists blinded to the experimental settings evaluated the datasets in a random order. The likelihood for intestinal bleeding was assessed using a 5-point scale with subsequent ROC analysis. The sensitivity to detect bleeding was 0.44 for a bleeding velocity of 0.10-0.50 ml/min and 0.97 for 0.55-1.00 ml/min. The specificity was 1.00. The area under the curve was calculated to be 0.73, 0.88 and 0.89 for reader 1, 2 and 3, respectively. Dual-phase MDCT provides high sensitivity and specificity in the detection of intestinal bleeding with bleeding velocities of 0.5-1.0 ml/min. Therefore, MDCT should be considered as a primary diagnostic technique in the management of patients with suspected intestinal bleeding.

Early metabolic response evaluation by fluorine-18 fluorodeoxyglucose positron emission tomography allows in vivo testing of chemosensitivity in gastric cancer: long-term results of a prospective study.

PURPOSE: We prospectively evaluated the predictive value of positron emission tomography using fluorine-18 fluorodeoxyglucose (FDG-PET) for in vivo testing of chemosensitivity in locally advanced gastric cancer using an a priori definition of metabolic response (a decrease of >35% of the standard uptake value). The goal of the study was the definition of biologically different groups of patients prior to or early during induction therapy, with special emphasis on FDG non-avid tumors. EXPERIMENTAL DESIGN: Based on our data, which was published in 2003, at least 36 patients with metabolic response or FDG non-avid tumors had to be recruited for an analysis of the group of FDG non-avid tumors with sufficient statistical power. Seventy-one patients (32 metabolic nonresponders, 17 metabolic responders, and 22 patients with FDG non-avid tumors) underwent FDG-PET at baseline. In FDG-avid tumors, FDG-PET was repeated 14 days after the initiation of chemotherapy. RESULTS: Metabolic responders (17 of 49) showed a high histopathologic response rate (69%) and a favorable prognosis (median survival not reached), whereas metabolic nonresponders (32 of 49) had a poor prognosis (median survival, 24.1 months) and showed a histopathologic response in 17%. The histopathologic response rate (24%) for FDG-PET non-avid patients showed no significant difference compared with FDG-avid nonresponders (P=0.72). Survival of FDG non-avid patients was 36.7 months (not significantly different from FDG-avid nonresponders, 24.1 months, P=0.46). CONCLUSION: In locally advanced gastric cancer, three different metabolic groups exist. Response and survival was predicted by PET in FDG-avid tumors. Metabolic response assessment was not possible in FDG non-avid tumors; however, due to unfavorable outcome, therapy modification might also be considered in FDG non-avid tumors.

PET/CT with Gluc-Lys-([(18)F]FP)-TOCA: correlation between uptake, size and arterial perfusion in somatostatin receptor positive lesions.

PURPOSE: Somatostatin receptor (sstr) positive tumours vary widely in uptake of radiolabelled somatostatin (sst) analogues. This study determinates variability in lesion uptake of the glycosylated sst analogon N(alpha)-(1-deoxy-D-fructosyl)-N(epsilon)-(2-[(18)F]fluoropropionyl)-Lys(0)-Tyr(3)-octreotate (Gluc-Lys([(18)F]FP)-TOCA) and correlates it with lesion size and arterial perfusion as measured on computed tomography (CT). METHODS: Ten patients with metastasized neuroendocrine carcinomas were investigated with positron emission tomography PET/CT (Biograph 16, Siemens, Germany). Lesion standardized uptake values (SUVs) were determined at approximately 50 min post tracer injection according to a 60% isocontour volume of interest around each lesion. Lesion size and enhancement in the arterial phase (hounsfield units, HUs) were derived from CT. RESULTS: 114 lesions in the upper abdomen had a correlate on both, PET and CT. Variability in lesion SUVs was high (SUV(mean) 22 +/- 13). Intraindividually, there was a sigmoid positive correlation between lesion SUV and lesion diameter indicating partial volume effects. Residual variability in lesions > or =3 cm (> or =2.5 cm) ranged down to about half (third) of the maximum lesion uptake and remained unexplained by partial volume effects. No correlation with measured HU in the arterial phase was found, neither intraindividually nor interindividually. CONCLUSION: Partial volume effects were a major source of intraindividual variability in tumour tracer uptake. Lesions below 2.5 to 3 cm should thus be used with caution when performing dose calculations. In larger lesions residual variability in uptake must be considered; it may be due to variable sstr2 expression on the tumours' cell surfaces.

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 to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial.

BACKGROUND: In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18-fluorodeoxyglucose-PET ([(18)F]FDG-PET) during neoadjuvant chemotherapy is predictive of histopathological response and survival. We aimed to assess the feasibility of a PET-response-guided treatment algorithm and its potential effect on prognosis. METHODS: Between May 27, 2002, and Aug 4, 2005, 119 patients with locally advanced adenocarcinoma of AEG type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) were recruited into this prospective, single-centre study. All patients were assigned to 2 weeks of platinum and fluorouracil-based induction chemotherapy (evaluation period). Those with decreases in tumour glucose standard uptake values (SUVs), predefined as decreases of 35% or more at the end of the evaluation period and measured by PET, were defined as metabolic responders. Responders continued to receive neoadjuvant chemotherapy of folinic acid and fluorouracil plus cisplatin, or folinic acid and fluorouracil plus cisplatin and paclitaxel, or folinic acid and fluorouracil plus oxaliplatin for 12 weeks and then proceeded to surgery. Metabolic non-responders discontinued chemotherapy after the 2-week evaluation period and proceeded to surgery. The primary endpoint was median overall survival of metabolic responders and non-responders. Secondary endpoints were median event-free survival, postoperative complications and mortality, number of residual tumour-free (R0) resections, and histopathological responses. This study has been registered in the European Clinical Trials Database (EudraCT) as trial 2007-003356-11. FINDINGS: 110 patients were evaluable for metabolic responses. 54 of these patients had metabolic responses (ie, decrease of 35% or more in tumour glucose SUV) after 2 weeks of induction chemotherapy, corresponding to a response of 49% (95% CI 39-59). 104 patients had tumour resection (50 in the responder group and 54 in the non-responder group). After a median follow-up of 2.3 years (IQR 1.7-3.0), median overall survival was not reached in metabolic responders, whereas median overall survival was 25.8 months (19.4-32.2) in non-responders (HR 2.13 [1.14-3.99, p=0.015). Median event-free survival was 29.7 months (95% CI 23.6-35.7) in metabolic responders and 14.1 months (7.5-20.6) in non-responders (hazard ratio [HR] 2.18 [1.32-3.62], p=0.002). Major histological remissions (<10% residual tumour) were noted in 29 of 50 metabolic responders (58% [95% CI 48-67]), but no histological response was noted in metabolic non-responders. INTERPRETATION: This study confirmed prospectively the usefulness of early metabolic response evaluation, and shows the feasibility of a PET-guided treatment algorithm. These findings might enable tailoring of multimodal treatment in accordance with individual tumour biology in future randomised trials.

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.

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.

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.