Preclinical efficacy of the c-Met inhibitor CE-355621 in a U87 MG mouse xenograft model evaluated by 18F-FDG small-animal PET.

The purpose of this study was to evaluate the efficacy of CE-355621, a novel antibody against c-Met, in a subcutaneous U87 MG xenograft mouse model using (18)F-FDG small-animal PET. METHODS: CE-355621 or control vehicle was administered intraperitoneally into nude mice (drug-treated group, n = 12; control group, n = 14) with U87 MG subcutaneous tumor xenografts. Drug efficacy was evaluated over 2 wk using (18)F-FDG small-animal PET and compared with tumor volume growth curves. RESULTS: The maximum %ID/g (percentage injected dose per gram of tissue) of (18)F-FDG accumulation in mice treated with CE-355621 remained essentially unchanged over 2 wk, whereas the %ID/g of the control tumors increased 66% compared with the baseline. Significant inhibition of (18)F-FDG accumulation was seen 3 d after drug treatment, which was earlier than the inhibition of tumor volume growth seen at 7 d after drug treatment. CONCLUSION: CE-355621 is an efficacious novel antineoplastic chemotherapeutic agent that inhibits (18)F-FDG accumulation earlier than tumor volume changes in a mouse xenograft model. These results support the use of (18)F-FDG PET to assess early tumor response for CE-355621.     

PET predicts prognosis after 1 cycle of chemotherapy in aggressive lymphoma and Hodgkin's disease.

Early identification of chemotherapy-refractory lymphoma patients provides a basis for alternative treatment strategies. Metabolic imaging with (18)F-FDG PET offers functional tissue characterization that is useful for assessing response to therapy. Our objective was to determine the predictive value of (18)F-FDG PET early during chemotherapy (after 1 cycle) and at the completion of chemotherapy for subsequent progression-free survival (PFS) in patients with aggressive non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). METHODS: (18)F-FDG PET (dual-head coincidence camera with attenuation correction) was performed before and after 1 cycle of chemotherapy on 30 patients (17 NHL, 13 HD; mean age, 52.3 +/- 16.0 y). For 23 of the 30 patients, (18)F-FDG PET data were also obtained after the completion of chemotherapy. The patients had a median follow-up of 19 mo (range, 18-24 mo). Follow-up of PFS was compared between patients with positive and negative (18)F-FDG PET results obtained after the first cycle of chemotherapy and at the completion of chemotherapy. RESULTS: Positive (18)F-FDG PET results obtained both after the first cycle and at the completion of therapy were associated with a shorter PFS (median, 5 and 0 mo, respectively) than were negative (18)F-FDG PET results (PFS medians not reached). A statistically significant difference in PFS between positive and negative (18)F-FDG PET results was obtained both after the first cycle and at the completion of chemotherapy (P < or = 0.001). The PFS and (18)F-FDG PET results obtained after the first cycle correlated better than those obtained after the completion of chemotherapy (r(2) = 0.45 vs. 0.17). (18)F-FDG PET had more false-negative results after the last cycle (6/17 cases, or 35%) than after the first cycle (2/13 cases, or 15%). Thus, (18)F-FDG PET had greater sensitivity and positive predictive values after the first cycle (82% vs. 45.5% and 90% vs. 83%, respectively) than after the last cycle. CONCLUSION: (18)F-FDG PET after 1 cycle of chemotherapy is predictive of 18-mo outcome in patients with aggressive NHL and HD and may earlier identify patients who would benefit from more intensive treatment programs.     

Early prediction of response to chemotherapy in metastatic breast cancer using sequential 18F-FDG PET.

Chemotherapy is currently the treatment of choice for patients with high-risk metastatic breast cancer. Clinical response is determined after several cycles of chemotherapy by changes in tumor size as assessed by conventional imaging procedures including CT, MRI, plain film radiography, or ultrasound. The aim of this study was to evaluate the use of sequential 18F-FDG PET to predict response after the first and second cycles of standardized chemotherapy for metastatic breast cancer. METHODS: Eleven patients with 26 metastatic lesions underwent 31 (18)F-FDG PET examinations (240-400 MBq of 18F-FDG; 10-min 2-dimensional emission and transmission scans). Clinical response, as assessed by conventional imaging after completion of chemotherapy, served as the reference. 18F-FDG PET images after the first and second cycles of chemotherapy were analyzed semiquantitatively for each metastatic lesion using standardized uptake values (SUVs) normalized to patients' blood glucose levels. In addition, whole-body 18F-FDG PET images were viewed for overall changes in the 18F-FDG uptake pattern of metastatic lesions within individual patients and compared with conventional imaging results after the third and sixth cycles of chemotherapy. RESULTS: After completion of chemotherapy, 17 metastatic lesions responded, as assessed by conventional imaging procedures. In those lesions, SUV decreased to 72% +/- 21% after the first cycle and 54% +/- 16% after the second cycle, when compared with the baseline PET scan. In contrast, 18F-FDG uptake in lesions not responding to chemotherapy (n = 9) declined only to 94% +/- 19% after the first cycle and 79% +/- 9% after the second cycle. The differences between responding and nonresponding lesions were statistically significant after the first (P = 0.02) and second (P = 0.003) cycles. Visual analysis of 18F-FDG PET images correctly predicted the response in all patients as early as after the first cycle of chemotherapy. As assessed by 18F-FDG PET, the overall survival in nonresponders (n = 5) was 8.8 mo, compared with 19.2 mo in responders (n = 6). CONCLUSION: In patients with metastatic breast cancer, sequential 18F-FDG PET allowed prediction of response to treatment after the first cycle of chemotherapy. The use of 18F-FDG PET as a surrogate endpoint for monitoring therapy response offers improved patient care by individualizing treatment and avoiding ineffective chemotherapy.     

Prospective comparison of 18F-FDG PET with conventional imaging modalities (MRI, CT, and 67Ga scintigraphy) in assessment of combined intraarterial chemotherapy and radiotherapy for head and neck carcinoma.

To preserve the oral organs and functions in patients with head and neck carcinoma, accurate determination of the appropriate treatment after neoadjuvant chemotherapy and radiotherapy is of critical importance. We evaluated the diagnostic accuracy of (18)F-FDG PET relative to that of other conventional imaging modalities in the assessment of therapeutic response after combined intraarterial chemotherapy and radiotherapy as an organ preservation protocol. METHODS: The study was prospectively performed on 23 consecutive patients with head and neck squamous cell carcinoma who completed the treatment regimen and underwent 2 (18)F-FDG PET studies before and after neoadjuvant chemoradiotherapy. (67)Ga scintigraphy (only before therapy) as well as MRI and CT (both before and after therapy) were also performed. All images were blindly and independently interpreted without knowledge of histologic findings. The level of confidence in image interpretation was graded by means of a 5-point rating system (0 = definitely no tumor to 4 = definite tumor). RESULTS: Before treatment, (18)F-FDG PET detected primary tumors in all 23 patients and was more sensitive (100%) than MRI (18/23; 78.3%), CT (15/22; 68.2%), and (67)Ga scintigraphy (8/20; 40%), with a confidence level of 3 or 4 as a positive tumor finding. After chemoradiotherapy, residual tumors were histologically confirmed in 4 patients (pathologic complete response rate, 19/23; 82.6%). Although posttreatment (18)F-FDG PET showed almost equal sensitivity (4/4; 100%) compared with MRI (3/3; 100%) or CT (3/4; 75%), its specificity (17/19; 89.5%) was superior to MRI (7/17, 41.2%) and to CT (10/17; 58.8%) for primary lesions. Regarding metastases to neck lymph nodes, only specificity for posttreatment images was calculated because no metastasis was confirmed in any patients after treatment. Six subjects had (18)F-FDG PET-positive lymph nodes, which had pathologically no tumor cells and suggested an inflammatory reactive change after therapy. Therefore, the specificity of posttreatment (18)F-FDG PET (17/23; 73.9%) was almost identical to that of MRI (17/20; 85%) and CT (16/21; 76.2%) for neck metastasis. With combined chemoradiotherapy monitored with (18)F-FDG PET, 8 patients avoided surgery and the remaining 15 patients underwent a reduced form of surgery. CONCLUSION: (18)F-FDG PET facilitates differentiation of residual tumors from treatment-related changes after chemoradiotherapy, which may be occasionally difficult to characterize by anatomic images. (18)F-FDG PET has a clinical impact for the management of patients with head and neck cancers after neoadjuvant chemoradiotherapy by optimizing surgical treatment for each patient and contributes to the improvement of the patient's quality of life.     

The role of 18F-FDG PET in staging and early prediction of response to therapy of recurrent gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are gaining the interest of researchers because of impressive metabolic response to the targeted molecular therapeutic drug imatinib mesylate. Initial reports suggest an impressive role for (18)F-FDG PET in follow-up of therapy for these tumors. However, the role of (18)F-FDG PET versus that of CT has not been established. Therefore, we compared the roles of (18)F-FDG PET and CT in staging and evaluation of early response to imatinib mesylate therapy in recurrent or metastatic GIST. METHODS: The study included 54 patients who underwent (18)F-FDG PET and CT scans within 3 wk before initiation of imatinib mesylate therapy. Forty-nine of these patients underwent repeat scans 2 mo after therapy. The numbers of sites or organs containing lesions on (18)F-FDG PET and CT scans were compared. Corresponding lesions on (18)F-FDG PET and CT scans or those confirmed to be malignant in appearance by other imaging modalities or on follow-up were considered true positives. Lesions seen on (18)F-FDG PET or CT scans but not seen or confirmed to be of benign appearance with other imaging modalities or on follow-up were considered false positives. Measurements of the maximum standard uptake value (SUV) on (18)F-FDG PET scans and tumor size on CT scans were used for quantitative evaluation of early tumor response to therapy. RESULTS: A total of 122 and 114 sites and/or organs were involved on pretherapy (18)F-FDG PET and CT scans, respectively. The sensitivity and positive predictive values (PPVs) for CT were 93% and 100%; whereas these values for (18)F-FDG PET were 86% and 98%. However, the differences between these values for CT and (18)F-FDG PET were not statistically significant (P = 0.27 for sensitivity and 0.25 for PPV). This suggests comparable performance of (18)F-FDG PET and CT in staging GISTs. Repeat scans at 2 mo after therapy showed agreement between (18)F-FDG PET and CT scans in 71.4% of patients (57.1% having a good response to therapy and 14.3% lacking a response). Discrepant results between (18)F-FDG PET and CT were recorded for 28.6% of the patients. (18)F-FDG PET predicted response to therapy earlier than did CT in 22.5% of patients during a longer follow-up interval (4-16 mo), whereas CT predicted lack of response to therapy earlier than (18)F-FDG PET in 4.1%. One patient did not undergo long-term follow-up. These findings suggest that (18)F-FDG PET is superior to CT in predicting early response to therapy in recurrent or metastatic GIST patients. CONCLUSION: The performances of (18)F-FDG PET and CT are comparable in staging GISTs before initiation of imatinib mesylate therapy. However, (18)F-FDG PET is superior to CT in predicting early response to therapy. Thus, (18)F-FDG PET is a better guide for imatinib mesylate therapy.     

Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922.

For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. METHODS: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E(max) and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was determined at different doses and different time points. RESULTS: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of (18)F-FDG per viable tumor volume was minimally affected by the treatment, whereas the (18)F-FLT uptake decreased in correlation with the growth inhibition. CONCLUSION: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. (18)F-FLT is a suitable tracer for the monitoring of effect, and the (18)F-FLT PET study might be performed within 3 d after dosing.     

Use of PET for monitoring cancer therapy and for predicting outcome.

PET with the glucose analog (18)F-FDG is increasingly used to monitor tumor response in patients undergoing chemotherapy and chemoradiotherapy. Numerous studies have shown that (18)F-FDG PET is an accurate test for differentiating residual viable tumor tissue from therapy-induced fibrosis. Furthermore, quantitative assessment of therapy-induced changes in tumor (18)F-FDG uptake may allow the prediction of tumor response and patient outcome very early in the course of therapy. Treatment may be adjusted according to the chemosensitivity and radiosensitivity of the tumor tissue in an individual patient. Thus, (18)F-FDG PET has an enormous potential to reduce the side effects and costs of ineffective therapy. This review focuses on the practical aspects of (18)F-FDG PET for treatment monitoring and on how to perform a quantitative assessment of tumor (18)F-FDG uptake in clinical studies.     

Early response to treatment with Glivec detected with 18F-FDG PET in a patient with gastrointestinal stromal tumor

We present the case of a male patient with gastrointestinal stromal tumor (GIST) in whom we conducted two (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) studies, the first one prior to beginning the treatment with Glivec and the second after one month of treatment. The first (18)F-FDG PET scan detected multiple FDG avid foci in distal esophagus, liver and in an interaortocava lymph node. The second (18)F-FDG PET showed very good response to therapy, with an almost complete disease remission. After 23 months of follow-up, the early response to treatment detected by (18)F-FDG PET was confirmed. The utility of (18)F-FDG PET in the evaluation of response to treatment in GIST is discussed and compared with CT.     

Monitoring therapeutic response of human ovarian cancer to 17-DMAG by noninvasive PET imaging with <Superscript>64</Superscript>Cu-DOTA-trastuzumab

Purpose  17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat-shock protein 90 (Hsp90) inhibitor, has been intensively investigated for cancer therapy and is undergoing clinical trials. Human epidermal growth factor receptor 2 (HER-2) is one of the client proteins of Hsp90 and its expression is decreased upon 17-DMAG treatment. In this study, we aimed to noninvasively monitor the HER-2 response to 17-DMAG treatment in xenografted mice. Methods  The sensitivity of human ovarian cancer SKOV-3 cells to 17-DMAG in vitro was measured by MTT assay. HER-2 expression in SKOV-3 cells was determined by flow cytometry. Nude mice bearing SKOV-3 tumors were treated with 17-DMAG and the therapeutic efficacy was evaluated by tumor size measurement. Both treated and control mice were imaged with microPET using ⁶⁴Cu-DOTA-trastuzumab and ¹⁸F-FDG. Biodistribution studies and immunofluorescence staining were performed to validate the microPET results. Results  SKOV-3 cells are sensitive to 17-DMAG treatment, in a dose-dependent manner, with an IC₅₀ value of 24.72 nM after 72 h incubation. The tumor growth curve supported the inhibition effect of 17-DMAG on SKOV-3 tumors. Quantitative microPET imaging showed that ⁶⁴Cu-DOTA-trastuzumab had prominent tumor accumulation in untreated SKOV-3 tumors, which was significantly reduced in 17-DMAG-treated tumors. There was no uptake difference detected by FDG PET. Immunofluorescence staining confirmed the significant reduction in tumor HER-2 level upon 17-DMAG treatment. Conclusion  The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using ⁶⁴Cu-DOTA-trastuzumab. This approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment.     

18F-FDG PET for evaluation of the treatment response in patients with gastrointestinal tract lymphomas.

(18)F-FDG PET is highly sensitive and specific for evaluation of the treatment response of nodal and extranodal diseases in patients with malignant lymphomas. However, no data are available in the literature with regard to (18)F-FDG PET for evaluation of the treatment response in patients with lymphomas with gastrointestinal tract (GIT) involvement. This study was undertaken to investigate the usefulness of (18)F-FDG PET in monitoring the response to the treatment of lymphomas in this setting. METHODS: We retrospectively analyzed 19 patients with different types of lymphomas (10 diffuse large B-cell lymphomas, 4 follicular lymphomas, 3 mantle cell lymphomas, and 2 Hodgkin's disease) involving GIT. Among 19 patients, 4 had gastric involvement, 13 had small bowel involvement, and 2 had small bowel plus colon involvement by lymphomas. All patients underwent (18)F-FDG PET before and after the completion of therapy. The results of (18)F-FDG PET were compared with the results of CT and clinical outcome; the presence of relapse was determined on the basis of positive biopsy results or clinical follow-up data. RESULTS: Of the 19 posttreatment PET scans, 13 showed no pathologic (18)F-FDG uptake, whereas 6 showed persistent (18)F-FDG uptake. Among the 13 patients who had negative PET scans, only 1 patient (7.7%) relapsed, whereas all 6 patients (100%) who had persistent abnormal (18)F-FDG uptake on posttherapy PET scans relapsed. Posttreatment CT scans were negative for 10 patients but showed persistent disease in the remaining 9 patients. Among the 10 patients who had negative CT scans, 9 remained in remission and 1 (10%) relapsed. Of the 9 patients who showed persistent disease, 6 (67%) relapsed and 3 (33%) remained in remission after the mean follow-up of 20 mo. The sensitivity, specificity, positive and negative predictive values, and accuracy of posttherapy (18)F-FDG PET were 86%, 100%, 100%, 92%, and 95%, respectively. The corresponding values for CT were 67%, 75%, 75%, 90%, and 79%, respectively. Patients with positive (18)F-FDG PET results had statistically significantly lower disease-free survival (DFS) (0%) than did those with positive CT results (33%) (P = 0.04). There was no statistically significant difference in DFS between patients with negative (18)F-FDG PET results and patients with negative CT results. CONCLUSION: A positive (18)F-FDG PET scan after the completion of chemotherapy in patients with lymphomas with GIT involvement is a strong predictor of relapse. (18)F-FDG PET has higher diagnostic accuracy than CT in the detection of residual disease after therapy. Despite the mild physiologic (18)F-FDG uptake in the GIT, (18)F-FDG PET has potential value in monitoring the response to treatment in patients with GIT lymphomas, particularly when pretreatment PET results are positive.     

68Ga-labeled bombesin studies in patients with gastrointestinal stromal tumors: comparison with 18F-FDG.

Dynamic PET studies with a 68Ga-bombesin analog, DOTA-PEG2-[d-Tyr6, beta-Ala11,Thi13,Nle14] BN(6-14) amide (68Ga-BZH3; DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid, and PEG is ethylene glycol [2-aminoethyl-carboxymethyl ether]), were performed on patients with gastrointestinal stromal tumors (GIST) to investigate the impact of complementary receptor scintigraphy on diagnosis and the potential of a radionuclide treatment. Furthermore, dynamic 18F-FDG studies were performed on the same patients. METHODS: This study comprised 17 patients with GIST. All patients were scheduled for therapy with imatinib because of unresectable primary or recurrent GIST or because of metastatic disease. Dynamic PET scans using 68Ga-BZH3 and 18F-FDG were obtained on 2 consecutive days. Multivariate analysis was used to evaluate the kinetic data. Standardized uptake values (SUVs) were calculated, and a compartmental model (2-tissue) and noncompartmental model were used for data evaluation of both tracers. RESULTS: Fourteen of 17 patients (25/30 lesions) were positive for uptake on 18F-FDG imaging, whereas 68Ga-BZH3 demonstrated an enhanced accumulation in 7 of 17 patients (8/30 lesions). Thirteen lesions were confirmed by histologic examination, and the remaining 17 were confirmed by follow-up. One recurrent tumor in the stomach could not be delineated on 18F-FDG imaging but showed enhanced 68Ga-BZH3 uptake. The median SUV for 68Ga-BZH3 was 3.3, in comparison with 7.9 for 18F-FDG. Best-subset analysis demonstrated that the global SUV (55-60 min after injection) for 18F-FDG was primarily dependent on k3, followed by k1. Multivariate analysis did not show a significant correlation between the kinetic parameters (k1-k4, fractional blood volume, and SUV) for 18F-FDG and bombesin. CONCLUSION: 68Ga-BZH3 may be helpful for diagnostic reasons in a subgroup of patients with GIST, as in the case of negative 18F-FDG findings and suspicion of viable tumor tissue. The meaning of the enhanced 68Ga-BZH3 uptake is open at the moment.     

Time course of early response to chemotherapy in non-small cell lung cancer patients with 18F-FDG PET/CT.

PET and (18)F-FDG have the potential to follow the early metabolic response to chemotherapy in patients with non-small cell lung cancer and to predict success or failure of the therapy. METHODS: We studied 16 patients with non-small cell lung cancer as they followed 2 courses of docetaxel and carboplatin. Each patient was studied weekly for 7 wk, and tissue activity was assessed by the amount of radioactivity retained 90 min after the intravenous injection of (18)F-FDG. In a prospective analysis, the linear least-squares method was used to evaluate the time course of metabolic activity in tumor and liver, bone marrow, and unaffected lung tissues; a metabolic response was defined as a response in which the slope of the regression was negative and significantly different from zero. Our hypothesis was that patients who exhibited a tumor metabolic response would survive longer than those who did not. In a retrospective examination of our data, we grouped our patients into those who survived <6 mo and those who survived longer and calculated the difference in the standardized uptake value (SUV) between day 7 and subsequent time points to determine the most appropriate timing of 2 PET studies in predicting response to therapy. RESULTS: Fifteen of 16 patients completed the study. In the prospective study, 8 patients were classified as nonresponders as the slope of the regression of tumor SUV versus time was not different from zero; they all died within 35 wk of the end of their study. Seven patients were classified as responders; 5 survived and 2 died, one at 25 wk and the other at 76 wk. In the retrospective study, a decrease of 0.5 SUV between studies performed at 1 and 3 wk after the initiation of chemotherapy was predictive of those patients who survived >6 mo and in whom chemotherapy was presumably successful. CONCLUSION: Patients with non-small cell lung cancer who had a positive outcome, as exhibited by prolonged survival, were those who showed a tumor metabolic response assessed using weekly (18)F-FDG PET studies. (18)F-FDG PET studies performed at 1 and 3 wk after the initiation of chemotherapy allowed prediction of the response to therapy.     

Small-animal PET imaging of human epidermal growth factor receptor type 2 expression with site-specific 18F-labeled protein scaffold molecules.

Human epidermal growth factor receptor type 2 (HER2) is a well-established tumor biomarker that is overexpressed in a wide variety of cancers and that serves as a molecular target for therapeutic intervention. HER2 also serves as a prognostic indicator of patient survival and as a predictive marker of the response to antineoplastic therapy. The development of (18)F-labeled biomolecules for PET imaging of HER2 (HER2 PET) is very important because it may provide a powerful tool for the early detection of HER2-positive tumor recurrence and for the monitoring of HER2-based tumor treatment. METHODS: In this study, anti-HER2 monomeric and dimeric protein scaffold molecules [Z(HER2:477) and (Z(HER2:477))(2), respectively] were radiofluorinated at a reasonable radiochemical yield (13%-18%) by use of site-specific oxime chemistry. The resulting radiofluorinated protein scaffold molecules were then evaluated as potential molecular probes for small-animal HER2 PET by use of a SKOV3 tumor-bearing mouse model. RESULTS: The 4-(18)F-fluorobenzaldehyde conjugated aminooxy-protein scaffolds [(18)F-N-(4-fluorobenzylidene)oxime (FBO)-Z(HER2:477) and (18)F-FBO-(Z(HER2:477))(2)] both displayed specific HER2-binding ability in vitro. Biodistribution and small-animal PET imaging studies further revealed that (18)F-FBO-Z(HER2:477) showed rapid and high SKOV3 tumor accumulation and quick clearance from normal tissues, whereas (18)F-FBO-(Z(HER2:477))(2) showed poor in vivo performance (low tumor uptake and tumor-to-normal tissue ratios). The specificity of (18)F-FBO-Z(HER2:477) for SKOV3 tumors was confirmed by its lower uptake on pretreatment of tumor-bearing mice with the HER2-targeting agents Z(HER2) and trastuzumab. Moreover, small-animal PET imaging studies revealed that (18)F-FBO-Z(HER2:477) produced higher-quality tumor imaging than (18)F-FBO-(Z(HER2:477))(2). (18)F-FBO-Z(HER2:477) could clearly identify HER2-positive tumors with good contrast. CONCLUSION: Overall, these data demonstrate that (18)F-FBO-Z(HER2:477) is a promising PET probe for imaging HER2 expression in living mice. It has a high potential for translation to clinical applications. The radiofluorination method developed can also be used as a general strategy for the site-specific labeling of other proteins with (18)F. The protein scaffold molecules used here are attractive for the further development of PET probes for other molecular targets.     

18F-FET PET compared with 18F-FDG PET and CT in patients with head and neck cancer.

Recent studies suggest a somewhat selective uptake of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in cerebral gliomas and in squamous cell carcinoma (SCC) and a good distinction between tumor and inflammation. The aim of this study was to investigate the diagnostic potential of 18F-FET PET in patients with SCC of the head and neck region by comparing that tracer with 18F-FDG PET and CT. METHODS: Twenty-one patients with suspected head and neck tumors underwent 18F-FET PET, 18F-FDG PET, and CT within 1 wk before operation. After coregistration, the images were evaluated by 3 independent observers and an ROC analysis was performed, with the histopathologic result used as a reference. Furthermore, the maximum standardized uptake values (SUVs) in the lesions were determined. RESULTS: In 18 of 21 patients, histologic examination revealed SCC, and in 2 of these patients, a second SCC tumor was found at a different anatomic site. In 3 of 21 patients, inflammatory tissue and no tumor were identified. Eighteen of 20 SCC tumors were positive for both 18F-FDG uptake and 18F-FET uptake, one 0.3-cm SCC tumor was detected neither with 18F-FDG PET nor with 18F-FET PET, and one 0.7-cm SCC tumor in a 4.3-cm ulcer was overestimated as a 4-cm tumor on 18F-FDG PET and missed on 18F-FET PET. Inflammatory tissue was positive for 18F-FDG uptake (SUV, 3.7-4.7) but negative for 18F-FET uptake (SUV, 1.3-1.6). The SUVs of 18F-FDG in SCC were significantly higher (13.0 +/- 9.3) than those of 18F-FET (4.4 +/- 2.2). The ROC analysis showed significantly superior detection of SCC with (18)F-FET PET or 18F-FDG PET than with CT. No significant difference (P = 0.71) was found between 18F-FDG PET and 18F-FET PET. The sensitivity of 18F-FDG PET was 93%, specificity was 79%, and accuracy was 83%. 18F-FET PET yielded a lower sensitivity of 75% but a substantially higher specificity of 95% (accuracy, 90%). CONCLUSION: 18F-FET may not replace 18F-FDG in the PET diagnostics of head and neck cancer but may be a helpful additional tool in selected patients, because 18F-FET PET might better differentiate tumor tissue from inflammatory tissue. The sensitivity of 18F-FET PET in SCC, however, was inferior to that of 18F-FDG PET because of lower SUVs.     

Findings on 18F-FDG PET scans after neoadjuvant chemoradiation provides prognostic stratification in patients with locally advanced rectal carcinoma subsequently treated by radical surgery.

Predicting outcome after aggressive therapy for advanced rectal cancer remains difficult. (18)F-FDG PET has emerged as a valid method for predicting patient outcomes after therapy in an increasing number of cancers. We evaluated the prognostic information obtained from the degree of change in tumor (18)F-FDG PET uptake induced by chemoradiation before radical curative surgery in patients with T3/T4 rectal cancer. METHODS: The study included 34 consecutive patients with T3/T4 Nx M0 rectal cancer on structural imaging, who underwent staging and postchemoradiation (18)F-FDG PET before planned curative surgery. Change in (18)F-FDG uptake was graded visually as complete (CMR), partial (PMR), or no (NoMR) metabolic response. Pre- and postchemoradiation (18)F-FDG PET-derived standardized uptake values (SUVs) were then obtained for PMR patients to determine whether SUV further stratified this subgroup. Operative findings were available in 30 patients (3 excluded because of (18)F-FDG PET-defined M1 disease, 1 refused surgery). Clinical status at study closeout (alive free from disease, FFD; alive with disease, AWD; or died of disease, DOD) was available for all patients. RESULTS: A pathologic complete response was found in only 6 of 30 patients (5 CMR, 1 false-positive PMR). However, after an estimated median 3.1 y of follow-up, all 17 CMR patients were FFD, 6 of 10 PMR patients were FFD, 2 of 10 had DOD, and 2 of 10 were AWD. All 3 NoMR patients DOD. PET response was highly significantly associated with overall survival duration (P < 0.0001) and time to progression (P < 0.0001). Pathologic complete response was the only other statistically significant prognostic factor (P < 0.03). The percentage of maximum SUV change after chemoradiation was not predictive of survival in PMR patients. CONCLUSION: Using a simple qualitative assessment, postchemoradiation (18)F-FDG PET scintigraphy provides good medium-term prognostic information in patients with advanced rectal cancer undergoing radical surgery with curative intent.     

18F-FDG PET evaluation of the response to therapy for lymphoma and for breast, lung, and colorectal carcinoma.

PET is a unique form of diagnostic imaging that observes in vivo biologic changes using radiopharmaceuticals that closely mimic endogenous molecules. (18)F-FDG, which allows the evaluation of glucose metabolism, is the most commonly used tracer in oncology because of the practical half-life of (18)F (110 min), compared with other short-lived positron emitters. (18)F-FDG uptake in tumors is proportional to the glycolytic metabolic rate of viable tumor cells indicating the increased metabolic demand of tumors for glucose. (18)F-FDG PET significantly improves the accuracy of imaging tumors in initial staging, management of recurrent cancer, and monitoring of therapy response. The information provided by this technique is more sensitive and specific than that provided by anatomic imaging modalities. (18)F-FDG PET is particularly superior to CT or MRI in the ability to evaluate the effectiveness of various treatment regimens early during therapy or after therapy. In this review, we discuss the role of (18)F-FDG PET in evaluating the response to therapy and the impact of this information on patient management.     

18F-FLT PET for visualization of laryngeal cancer: comparison with 18F-FDG PET.

The feasibility of (18)F-3'-fluoro-3'-deoxy-L-thymidine PET (FLT PET) for detecting laryngeal cancer was investigated and compared with (18)F-FDG PET. METHODS: Eleven patients diagnosed with or strongly suspected of having recurrent laryngeal cancer and 10 patients with histologically proven primary laryngeal cancer underwent attenuation-corrected (18)F-FLT PET imaging 60 min after injection of a median of 213 MBq (range, 175-400 MBq) (18)F-FLT and attenuation-corrected (18)F-FDG PET imaging 90 min after injection of a median of 340 MBq (range, 165-650 MBq) (18)F-FDG. All patients were staged by endoscopy and CT according to the Union Internationale Contre la Cancer TNM staging system. All patients underwent biopsy of the laryngeal area after imaging. Lesions seen on (18)F-FDG PET and (18)F-FLT PET were compared with histopathologic results. Mean SUVs, maximum SUVs, and tumor-to-nontumor (TNT) ratios were calculated for (18)F-FLT and (18)F-FDG. Wilcoxon nonparametric testing was used for comparison of (18)F-FDG with (18)F-FLT uptake. The Spearman correlation coefficient was used to correlate mean SUVs, maximum SUVs, and TNT ratios of (18)F-FDG PET and (18)F-FLT PET. Two-tailed P values < 0.05 were considered significant. RESULTS: (18)F-FDG PET and (18)F-FLT PET detected laryngeal cancer correctly in 15 of 17 patients. One lesion judged as positive on (18)F-FDG PET turned out to be normal tissue. Of 2 lesions judged as positive on (18)F-FLT PET, 1 turned out to be inflammation and the other to be normal tissue. Maximum SUVs were 3.3 (range, 1.9-8.5) for (18)F-FDG and 1.6 (range, 1.0-5.7) for (18)F-FLT (P < 0.001). Mean SUVs were 2.7 (range, 1.5-6.5) for (18)F-FDG and 1.2 (range, 0.8-3.8) for (18)F-FLT (P < 0.001). TNT was 1.9 (range, 1.3-4.7) for (18)F-FDG and 1.5 (range, 1.1-3.5) for (18)F-FLT (P < 0.05). CONCLUSION: The numbers of laryngeal cancers detected with (18)F-FLT PET and (18)F-FDG PET were equal. In laryngeal cancer, the uptake of (18)F-FDG is higher than that of (18)F-FLT.     

PET in the assessment of therapy response in patients with carcinoma of the head and neck and of the esophagus.

In patients with carcinoma of the head and neck and of the esophagus, metabolic and functional imaging by PET with (18)F-FDG has a pivotal role in the evaluation of tumor response to therapy, specifically, in the prediction of progression-free survival and overall survival. Metabolic imaging allows the detection of biochemical changes within tumor cells as opposed to identifiable morphologic changes. Anatomic imaging modalities do not reliably differentiate between responders and nonresponders early during the course of follow-up. The correlation between histopathologic tumor response after preoperative therapy and clinical prognosis is well established for many cancers. Squamous carcinoma of the head and neck and esophageal carcinoma demonstrate avid (18)F-FDG uptake. For these cancers, (18)F-FDG PET parallels histopathologic findings in its ability to detect residual viable tumor; therefore, it is a valuable tool for the noninvasive assessment of histopathologic tumor response in advanced-stage cases after neoadjuvant therapy before surgery. Early determination of nonresponders is of prime importance, as timely therapy modification can be accomplished for patients who do not demonstrate a response to therapy. This determination is exceptionally important for head and neck and esophageal malignancies, both of which are known for their unfavorable prognosis, as early modifications in therapy regimens for nonresponders may improve patient outcome. There is now evidence that (18)F-FDG PET is a sensitive and specific method for determining therapy response and for providing important prognostic information for these cancers. Therefore, (18)F-FDG PET may change patient management and lead to improved survival for a selected group of patients with carcinoma of the head and neck and of the esophagus.     

Whole-body (18)F-FDG PET improves the management of patients with small cell lung cancer.

The aim of this study was to evaluate the impact of whole-body (18)F-FDG PET on staging and managing patients with small cell lung cancer (SCLC). METHODS: The treatment records of 42 consecutive patients (27 men, 15 women; mean age, 62 y; age range, 45-83 y) with SCLC were reviewed. Whole-body (18)F-FDG PET was performed for initial staging in 24 patients and for restaging after chemotherapy or radiation treatment in 20 patients. Two patients of the initial staging group were restaged with PET after therapy. PET findings were correlated with clinical and radiologic findings (CT of the chest and abdomen, bone scan, and CT or MRI of the brain). The impact of PET on staging and management decisions was determined. RESULTS: For 12 of 42 patients (29%), PET results changed the patient's management. In 8 patients (19%), PET resulted in a change of radiation therapy because of the detection of previously unknown tumor foci. Adjuvant radiation therapy was cancelled in 3 patients. A change of radiation field and volume was necessary in 5 patients. In 1 patient, PET results excluded extensive disease, which permitted surgical resection of the tumor. Chemotherapy was discontinued in 2 patients and restarted in 1 patient on the basis of the PET findings. In 5 patients (12%), PET excluded malignancy as the suspicious lesions found with conventional cross-sectional imaging did not take up (18)F-FDG. CONCLUSION: The results of this study show that (18)F-FDG PET has a major impact on the management of patients with SCLC, influencing both the stage and the management in 29% of patients. PET is a highly valuable tool for accurate target definition of radiation treatment by reducing the probability of overlooking involved areas.     

Bispecific antibody pretargeting PET (immunoPET) with an 124I-labeled hapten-peptide.

We previously described a highly flexible bispecific antibody (bs-mAb) pretargeting procedure using a multivalent, recombinant anti-CEA (carcinoembryonic antigen) x anti-HSG (histamine-succinyl-glycine) fusion protein with peptides radiolabeled with 111In, 90Y, 177Lu, and 99mTc. The objective of this study was to develop a radioiodination procedure primarily to assess PET imaging with 124I. METHODS: A new peptide, DOTA-D-Tyr-D-Lys(HSG)-D-Glu-D-Lys(HSG)-NH2 (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid), was synthesized and conditions were established for radioiodination with yields of approximately 70% for 131I and 60% for 124I. Pretargeting with the 131I- and 124I-labeled peptide was tested in nude mice bearing LS174T human colonic tumors that were first given the anti-CEA x anti-HSG bs-mAb. Imaging (including small-animal PET) and necropsy data were collected at several intervals over 24 h. Comparisons were made between animals given 124I-anti-CEA Fab', 18F-FDG, the same peptide radiolabeled with 111In and pretargeted with the bs-mAb, and the radioiodinated peptide alone. RESULTS: The radioiodinated peptide alone cleared quickly from the blood with no evidence of tumor targeting, but when pretargeted with the bs-mAb, tumor uptake increased 70-fold, with efficient and rapid clearance from normal tissues, allowing clear visualization of tumor within 1-2 h. Tumor uptake measured at necropsy was 3- to 15-fold higher and tumor-to-blood ratios were 10- to 20-fold higher than those for 124I-Fab' at 1 and 24 h, respectively. Thyroid and stomach uptake was observed with the radioiodinated peptide several hours after injection (animals were not premedicated to reduce uptake in these tissues), but gastric uptake was much more pronounced with 124I-Fab'. Tumor visualization with 18F-FDG at approximately 1.5 h was also good but showed substantially more uptake in several normal tissues, making image interpretation in the pretargeted animals less ambiguous than with 18F-FDG. CONCLUSION: Bispecific antibody pretargeting has a significant advantage for tumor imaging over directly radiolabeled antibodies and could provide additional enhancements for oncologic imaging, particularly for improving targeting specificity as compared with 18F-FDG.