The increased accumulation of [18F]fluorodeoxyglucose in untreated prostate cancer

BACKGROUND: To evaluate the clinical usefulness of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) compared with histopathological grading, clinical stage and serum prostatic specific antigen (PSA) level in the detection and characterization of prostate cancer. METHODS: Forty-four patients with histologically proven prostate cancer and five control subjects with benign prostatic hyperplasia (BPH) were prospectively investigated with FDG-PET prior to treatment. RESULTS: By visual inspection, FDG accumulation was positive in 28 patients with prostate cancer (sensitivity 64%), whereas all were negative in the control group. FDG-PET in three patients with lymph node metastases did not show any high intrapelvic accumulations corresponding to metastatic sites. Among 12 patients with multiple bone metastases which were detected with 99m-HMDP bone scintigraphy, nine (75%) showed moderate to high FDG accumulation at the sites of bone metastases. Quantitatively, FDG accumulation in prostate cancer was significantly higher than in BPH and there was a tendency for FDG uptake of tumors to be higher with higher histological Gleason grades. Furthermore, FDG uptake in tumors with lymph node and/or bone metastasis was significantly higher than that of localized stages. However, the correlation between PSA and FDG uptake in the prostate cancer was very weak for clinical relevance. CONCLUSIONS: Although FDG-PET was not sensitive enough to detect prostate cancer in clinical use, it is suggested that glucose metabolism in prostate cancer tended to be higher in patients with tumors of advanced stages.     

Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging.

PURPOSE: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). (18)F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of (18)F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake. EXPERIMENTAL DESIGN: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue:blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane. RESULTS: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r = 0.24), with highly significant differences among the different tumor types (P < 0.005). CONCLUSIONS: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.     

11C] methionine and [18F] fluorodeoxyglucose PET in the follow-up of glioblastoma multiforme

Background The aim of this study was to evaluate the value of [11C] methionine (MET) and [18F] fluorodeoxyglucose (FDG) PET in the follow-up of glioblastoma multiforme (GBM). Patients and methods After surgical and/or conservative treatment, 28 patients (pts) with GBM underwent FDG and MET PET on average 12.7 months after the diagnosis had been established. Scans were evaluated visually and by calculating the maximal tumor SUV as well as the ratio of tumor vs. contralateral region (RTu). The degree of tracer uptake was compared with survival time, disease duration and MRI findings. Results The mean overall duration of survival was 12.7 months. The patients were divided into two groups: those that survived less than 12 months and those that survived longer than 12 months. Focally increased uptake was revealed by MET PET in 24 patients and by FDG PET in 2 patients. On MRI scans, viable tumor tissue was suspected in 18 patients. No correlations were registered between FDG/MET uptake and survival time or disease duration respectively; Kaplan–Meier calculations were negative in this regard. Similarly, negative results were obtained in subgroups of patients who had undergone microsurgical resection and whose disease was at least of 6 months’ duration, and additionally in a subgroup who had undergone their last treatment longer than 6 months ago. With respect to survival groups, a positive MET PET was associated with a sensitivity of 86% and a specificity of 8%. SUV and RTu values did not differ between patients with positive or negative MRI results. Conclusions In this study FDG PET seems to be of limited value in the work-up of recurrent GBM because of its lower sensitivity than MET PET and the fact that it allows no prediction of the outcome. MET PET visualizes viable tumor tissue without adding any prognostic information and appears to be in no way superior to conventional imaging.     

18F]fluorodeoxyglucose uptake by positron emission tomography predicts outcome of non-small-cell lung cancer.

PURPOSE: To determine whether the standardized uptake value (SUV) of [(18)F]fluorodeoxyglucose uptake by positron emission tomography could be a prognostic factor for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred sixty-two patients with stage I to IIIb NSCLC were analyzed. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and local-regional control (LRC) were calculated by the Kaplan-Meier method and evaluated with the log-rank test. The prognostic significance was assessed by univariate and multivariate analyses. RESULTS: There were 93 patients treated with surgery and 69 patients treated with radiotherapy. A cutoff of 5 for the SUV for the primary tumor showed the best discriminative value. The SUV for the primary tumor was a significant predictor of OS (P = .02) in both groups. Low SUVs ( 5.0; surgery group, P = .02; radiotherapy group, P = .0005). Low SUVs ( 5.0; stage I or II, P = .02; stage IIIa or IIIb, P = .004). However, using the same cutoff point of 5, the SUV for regional lymph nodes was not a significant indicator for DFS (P = .19), LRC (P = .97), or DMFS (P = .17). The multivariate analysis showed that the SUV for the primary tumor was a significant prognostic factor for OS (P = .03) and DFS (P = .001). CONCLUSION: The SUV of the primary tumor was the strongest prognostic factor among the patients treated by curative surgery or radiotherapy.     

Tumor-specific positron emission tomography imaging in patients: [18F] fluorodeoxyglucose and beyond.

Biochemical and molecular imaging of cancer using positron emission tomography (PET) plays an increasing role in the care of cancer patients. Most clinical work to date uses the glucose analogue [(18)F]fluorodeoxyglucose (FDG) to detect accelerated and aberrant glycolysis present in most tumors. Although clinical FDG PET has been used largely to detect and localize cancer, more detailed studies have yielded biological insights and showed the utility of FDG as a prognostic marker and as a tool for therapeutic response evaluation. As cancer therapy becomes more targeted and individualized, it is likely that PET radiopharmaceuticals other than FDG, aimed at more specific aspects of cancer biology, will also play a role in guiding cancer therapy. Clinical trials designed to test and validate new PET agents will need to incorporate rigorous quantitative image analysis and adapt to the evolving use of imaging as a biomarker and will need to incorporate cancer outcomes, such as survival into study design.     

Combined uptake of [18F]FDG and [18F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients.

PURPOSE: FDG PET is frequently used for radiotherapy (RT) planning to determine the tumour extent. Similarly, FMISO is used to assess the hypoxic sub-volume. The relationship between the volumes determined on the basis of FDG and FMISO was investigated. Additionally, the quantitative correlation of the tracers on a voxel basis was studied. METHODS: Twelve head-and-neck cancer (HNC) patients underwent FDG and FMISO PET examinations prior to RT treatment. The tumour volumes assessed by the two tracers and also the voxel-based joint uptake values were investigated. The characteristic shapes and patterns of the determined scatter plots were analyzed. A number of different variables such as the maximum uptake values of FDG and FMISO, the FDG and FMISO positive volumes, the slope m of the regression line and the scatter width sigma of the scatter plots were tested for their ability to stratify the patient group with respect to treatment outcome. RESULTS: A diversity of characteristic FDG-FMISO distributions was observed in the patient group. However, no general correlation of enhanced glucose metabolism and FMISO uptake was observed. The maximum uptake of FMISO (p=0.045) showed borderline significance for stratifying the patient group. FDG positive tumour volume, hypoxic fraction, maximum FDG uptake and m were not significant. Sigma turned out to be the most significant variable (p=0.008) to predict treatment success probabilities. CONCLUSION: FMISO and FDG PET data provide independent information about the examined tumour. A quantification of the correlated tracer uptake seems to be meaningful.     

Frequent impact of [18F]fluorodeoxyglucose positron emission tomography on the staging and management of patients with indolent non-Hodgkin's lymphoma

[18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful in staging aggressive non-Hodgkin's lymphoma (NHL). However, its role in indolent NHL has not been established. This retrospective study assessed the sensitivity and clinical impact of PET findings in patients with indolent NHL. Patients with indolent NHL who underwent FDG-PET scanning between May 1997 and August 2001 were identified. Case records were reviewed for FDG-PET and conventional staging/restaging results and compared for concordance. Forty-seven patients were identified. Twelve staging FDG-PET scans and 37 restaging FDG-PET scans were obtained. The FDG-PET case sensitivity rate was 98%. Forty-two percent of staging FDG-PET scans were concordant with conventional staging, with the remaining patients exhibiting more extensive disease on PET. At progression, FDG-PET and conventional assessments were discordant in 46% of cases. Positron emission tomography findings downstaged disease in 30% of these patients and upstaged disease in 16%. Computed tomography (CT) and FDG-PET identified 150 and 146 individual sites of disease, respectively. Among "definite" sites on structural imaging, 74% were also seen on PET. For equivocal lesions, only 19% were seen on both modalities. Clinical management was changed in 34% of patients as a result of FDG-PET findings. Of 22 discordant lesions in which true disease status could be evaluated, the PET findings were confirmed to be correct in 21 (95%; P < 0.0001). These findings demonstrate that FDG-PET has a high sensitivity for indolent NHL and often leads to alteration of disease staging and management. This high accuracy of FDG-PET in assessing discordant lesions suggests a greater diagnostic utility compared with CT.     

Lung cancer proliferation correlates with [F-18]fluorodeoxyglucose uptake by positron emission tomography.

Tumor proliferation has prognostic value in resected early-stage non-small cell lung cancer (NSCLC). We evaluated whether [F-18]fluorodeoxyglucose (FDG) uptake of NSCLC correlates with tumor proliferation and, thus, could noninvasively grade NSCLCs (refining patient prognosis and therapy). Thirty-nine patients with potentially resectable NSCLC underwent whole-body FDG positron emission tomography (PET) 45 min after i.v. injection of 10 mCi of FDG. Tumor FDG uptake was quantitated with the maximum pixel standardized uptake value (maxSUV). The lesion diameter from computed tomography was used to correct the maxSUV for partial volume effects using recovery coefficients determined for the General Electric Advance PET scanner. Thirty-eight patients underwent complete surgical staging (bronchoscopy and mediastinoscopy, with or without thoracotomy). One stage IV patient by PET underwent bronchoscopic biopsy only. Immunohistochemistry for Ki-67 (proliferation index marker) was performed on all of the 39 NSCLC specimens (35 resections, 1 percutaneous, and 3 surgical biopsies). The specimens were reviewed for cellular differentiation (poor, moderate, well) and tumor type. Lesions ranged from 0.7 to 6.1 cm. The correlation found between uncorrected maxSUV and lesion size (Rho, 0.56; P = 0.0006) disappeared when applying the recovery coefficients (Rho, -0.035; P = 0.83). Ki-67 expression (percentage of positive cells) correlated strongly with FDG uptake (corrected maxSUV: Rho, 0.73; P < 0.0001). The correlation was stronger for stage I lesions (11 stage IA, 15 stage IB): Rho, 0.79; P < 0.0001) and strongest in stage IB (Rho, 0.83; P = 0.0019). A significant association (P < 0.0001) between tumor differentiation and corrected SUV was noted. FDG PET may be used to noninvasively assess NSCLC proliferation in vivo, identifying rapidly growing NSCLCs with poor prognosis that could benefit from preoperative chemotherapy.     

A large-scale study of bone marrow involvement in patients with Hodgkin's lymphoma

This study was designed to identify variables that can predict bone marrow involvement (BMI) in Hodgkin's lymphoma (HL), and to analyze the benefit of bilateral over unilateral bone marrow trephine biopsy (BMB). From 1982 to 2000, BMB had been performed at diagnosis in 1161 patients with HL who had been followed from the institutions participating in the Piemonte Hodgkin's Disease Registry. Six hundred and sixteen patients (53%) had received bilateral BMB, and the remaining 545 patients (47%) received unilateral BMB. The relationships between BMB results and other clinical features were retrospectively studied with both univariate and multivariate analyses. Ninety-two patients (8%) showed BMI: 51 of them were staged with bilateral and 41 with unilateral BMB. Among the 92 patients with BMI, a second extranodal involvement was present in only 25 patients (27%). In multivariate analysis, the 5 independent factors that predicted for BMI were B symptoms, infradiaphragmatic involvement, mixed cellularity (MC) and lymphocyte depleted (LD) histology, involvement of > or = 4 lymphatic areas, and liver involvement. The probability of BMI according to the presence of these variables was distributed as follows: 0.3%, 2.5%, 7.6%, and 27% in patients positive for 0, 1, 2, and > or = 3 factors, respectively. Among 51 patients staged with bilateral BMB, BMI was shown in both specimens in 33 cases (65%), whereas the positivity was limited to only 1 of the 2 specimens in the remaining 18 cases (35%). A score based on 5 variables can predict the probability of BMI, and BMB could be avoided in patients with a score of 0 and a probability of BMI of < 0.5%. When BMB is needed, the superiority of bilateral over unilateral biopsy is suggested.     

Sequential positron emission tomography using [18F]fluorodeoxyglucose for monitoring response to chemotherapy in metastatic breast cancer.

PURPOSE: To evaluate the clinical value of positron emission tomography (PET) for monitoring chemotherapy in metastatic breast cancer. EXPERIMENTAL DESIGN: Twenty patients with hormonorefractory or hormonoreceptor-negative multimetastatic breast cancer were prospectively included. PET studies were done at baseline, at day 21 after the first cycle and at day 21 after the third cycle of chemotherapy. Metabolic response was defined based on visual and various modes of standardized uptake value (SUV) analysis of sequential PET studies. RESULTS: After one cycle, PET indicated a partial response in 12 patients, stable disease in 7 patients, and progressive disease in 1 patient, according to the visual analysis. After three cycles, PET showed a complete response in 5 patients, partial response in 11 patients, stable disease in 3 patients, and progressive disease in 1 patient. Seventy-five percent of the patients showing a metabolic response on visual analysis effectively responded to the treatment. The average SUV decreased on both the second and the third PET study, but only changes measured after three cycles of chemotherapy predicted the clinical response to chemotherapy and the overall survival. All methods for calculating the SUV (normalized for body weight, body surface area, or lean body mass) provided similar results. CONCLUSION: Semiquantitative analysis of [18F]fluorodeoxyglucose-PET studies done after three cycles of chemotherapy is useful for monitoring the response to chemotherapy in metastatic breast cancer.     

18F]FDG and [18F]FLT uptake in human breast cancer cells in relation to the effects of chemotherapy: an in vitro study

Increased 2'-deoxy-2'-[18F]fluoro-D-glucose (FDG) uptake is the most commonly used marker for positron emission tomography in oncology. However, a proliferation tracer such as 3'-deoxy-3'-[18F]fluorothymidine (FLT) might be more specific for cancer. 3'-deoxy-3'-[18F]fluorothymidine uptake is dependent on thymidine kinase 1 (TK) activity, but the effects of chemotherapeutic agents are unknown. The aim of this study was to characterise FDG and FLT uptake mechanisms in vitro before and after exposure to chemotherapeutic agents. The effects of 5-fluorouracil (5-FU), doxorubicin and paclitaxel on FDG and FLT uptake were measured in MDA MB231 human breast cancer cells in relation to cell cycle distribution, expression and enzyme activity of TK-1. At IC50 concentrations, 5-FU resulted in accumulation in the G1 phase, but doxorubicin and paclitaxel induced a G2/M accumulation. Compared with untreated cells, 5-FU and doxorubicin increased TK-1 levels by >300. At 72 h, 5-FU decreased FDG uptake by 50% and FLT uptake by 54%, whereas doxorubicin increased FDG and FLT uptake by 71 and 173%, respectively. Paclitaxel increased FDG uptake with >100% after 48 h, whereas FLT uptake hardly changed. In conclusion, various chemotherapeutic agents, commonly used in the treatment of breast cancer, have different effects on the time course of uptake of both FDG and FLT in vitro. This might have implications for interpretation of clinical findings.     

Posttherapy [18F] fluorodeoxyglucose positron emission tomography in carcinoma of the cervix: response and outcome.

PURPOSE: The aim of this study was to evaluate response to therapy using posttherapy molecular imaging with [(18)F] fluorodeoxyglucose (FDG), and to compare the response with patient outcome. PATIENTS AND METHODS: This was a retrospective medical record review of 152 patients with carcinoma of the cervix. All patients underwent a pre- and posttreatment whole-body positron emission tomography (PET) imaging scan with FDG. Patients were treated with external irradiation and intracavitary brachytherapy, and most received concurrent weekly cisplatin. Posttherapy whole-body FDG-PET was performed 1 to 12 months (mean, 3 months) after completion of treatment. RESULTS: The posttherapy PET did not show any abnormal FDG uptake in 114 patients, and their 5-year cause-specific survival estimate was 80%. There was persistent (in the irradiated region) abnormal FDG uptake in the cervix or lymph nodes in 20 patients. Their 5-year cause-specific survival estimate was 32%. New anatomic sites (in unirradiated regions) of abnormal FDG uptake were present in 18 patients, and none were alive at 5 years. A Cox proportional hazards model of survival outcome indicated that any abnormal posttherapy FDG uptake (persistent or new) was the most significant prognostic factor for developing metastatic disease and death from cervical cancer when compared with pretreatment- and treatment-related prognostic factors (P <.0001). CONCLUSION: Posttherapy abnormal FDG uptake (persistent or new) as detected by whole-body PET measures tumor response and might be predictive of tumor recurrence and death from cervical cancer. Prospective validation of these results is warranted.     

Impact of [18f] fluorodeoxyglucose positron emission tomography on staging and management of early-stage follicular non-hodgkin lymphoma

PURPOSE: Accurate staging is critical to select patients with early-stage (I-II) follicular lymphoma (ESFL) suitable for involved-field radiotherapy (IFRT) and to define the radiotherapy portal. We evaluated the impact of fluorodeoxyglucose (FDG) PET on staging, treatment, and outcome for patients with ESFL on conventional staging. METHODS AND MATERIALS: Forty-two patients with untreated ESFL (World Health Organization Grade I-IIIa, or "low grade") following a minimum of physical examination, computerized tomography, and bone marrow examination (conventional assessment) and who had staging PET from June 1997 to June 2006 were studied retrospectively. Stage allocation was based on routine imaging reports. Disease sites, stage, and management plan were recorded based on conventional assessment or conventional assessment plus PET. RESULTS: FDG avidity was demonstrated in 97% of patients in whom disease was evident on conventional assessment after biopsy. PET findings suggested a change of stage or management in 19 patients: 13 (31%) who were upstaged to Stage III-IV, altering ideal management from IFRT to systemic therapy, and 6 (14%) who had the involved field enlarged, including 4 upstaged from Stage I to II. Of these 19 cases, PET findings were considered true positive in 8 patients, indeterminate in 10, and false positive in only 1 patient. CONCLUSIONS: Our data confirm that ESFL is usually FDG-avid. In routine practice, PET has the potential to upstage and thereby alter management in a high proportion of patients with apparent ESFL.     

Radiation pneumonitis: local dose versus [18F]-fluorodeoxyglucose uptake response in irradiated lung

PURPOSE: To quantify the relationship between the local radiation dose received and the posttreatment positron emission tomography/computed tomography (PET/CT) [(18)F]2-fluoro-2-deoxyglucose (FDG) uptake in the lung. METHODS AND MATERIALS: The data from 36 patients treated for esophageal cancer with thoracic radiotherapy who underwent restaging PET/CT imaging between 4 and 12 weeks after radiotherapy completion were evaluated. Their treatment planning CT was registered with the restaging PET/CT. Using histogram analysis, the voxel average FDG-PET uptake vs. radiation dose was obtained for each case. Hierarchical linear regression models for each patient were applied to study the variation in the linear trends between cases. Deviation of the dose-response curve from a linear model was tested. RESULTS: The median time between radiotherapy completion and FDG-PET imaging was 40 days (range, 26-70 days). The median of the mean standard uptake value in the lung that received 0-5 Gy was 0.63 (range, 0.36-1.27), 5-10 Gy was 0.77 (range, 0.40-1.35), 10-20 Gy was 0.80 (range, 0.40-1.72), and >20 Gy was 1.08 (range, 0.44-2.63). A hierarchical linear regression model of the radiation dose and normalized FDG uptake per case found an adequate fit with the linear model, and the addition of quadratic and logarithmic functions did not improve the fit. The 36 cases had a posterior mean of slopes range of 0.0048-0.069. CONCLUSION: The regional dose vs. radiation pneumonitis response was evaluated with FDG-PET/CT imaging. Statistical modeling found a linear relationship. The slope of this relationship varied over an order of magnitude, reflecting the range of the underlying biological response to radiation among the study population.     

Value of [18F]fluorodeoxyglucose-positron emission tomography in managing patients with aggressive non-Hodgkin's lymphoma

An increased glucose metabolic rate is observed with various degrees of intensity in different subtypes of aggressive lymphomas. [(18)F]Fluorodeoxyglucose (FDG)-positron emission tomography (PET; FDG-PET) allows functional imaging of this phenomenon through 3-dimensional tomographic slices, which are now easily fused with computed tomography (CT) images. [(18)F]Fluorodeoxyglucose-PET staging appears superior to conventional staging modalities for detecting nodal and extranodal lymphoma. When performed after first-line chemotherapy, FDG-PET is more efficient than CT and conventional diagnostic methods to predict the disease outcome. Some studies have reported that the relapse rate is 100% in patients with positive PET findings after treatment and 17% in patients with negative PET findings. This imaging modality can also assess early response after 1-2 cycles of chemotherapy, thus identifying responders from patients whose cancer will fail to respond to first-line therapy or will relapse shortly after having exhibited a partial or complete remission. [(18)F]Fluorodeoxyglucose-PET also seems useful for an accurate selection of patients who will benefit from highly intensive treatment.     

In vitro 2-deoxy-2-[18F]fluoro-D-glucose uptake: practical considerations

In oncology 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]-FDG), a glucose analogue, is the most used positron emission tomography (PET) tracer. There are however some limitations due to low metabolic activity or high surrounding physiological uptake in several tumors or regions. Investigating new tracers or methods is expensive and elaborative when animal experiments or phase I clinical trials are used. In vitro experiments can overcome these limitations. We analyzed the influence of incubation time, cell medium conditions, administered activity, and cell density on [(18)F]-FDG uptake in six different cell cultures. Glucose transporter 1 (GLUT1)- and hexokinase 2 (HK2)-expression at high and low cell density was analyzed using immunocytochemistry. FDG-uptake increases over time and absence of glucose in the incubation medium increases uptake. By increasing the administered activity, uptake per protein also increases and tracer uptake per protein is lower at higher cell densities. Immunocytochemical analysis reveals a lower expression of both GLUT1 and HK2 at higher cell concentrations. All investigated parameters influenced FDG uptake and therefore we can conclude it is of utmost importance to keep administered activity, incubation medium, and time constant and to correct uptake when cell density changes due to environmental conditions, such as therapy.