Retooling a Blood-Based Biomarker: Phase I Assessment of the High-Affinity CA19-9 Antibody HuMab-5B1 for Immuno-PET Imaging of Pancreatic Cancer.

PURPOSE: In patients with cancer who have an abnormal biomarker finding, the source of the biomarker in the bloodstream must be located for confirmation of diagnosis, staging, and therapy planning. We evaluated if immuno-PET with the radiolabeled high-affinity antibody HuMab-5B1 (MVT-2163), binding to the cancer antigen CA19-9, can identify the source of elevated biomarkers in patients with pancreatic cancer. PATIENTS AND METHODS: In this phase I dose-escalating study, 12 patients with CA19-9-positive metastatic malignancies were injected with MVT-2163. Within 7 days, all patients underwent a total of four whole-body PET/CT scans. A diagnostic CT scan was performed prior to injection of MVT-2163 to correlate findings on MVT-2163 PET/CT. RESULTS: Immuno-PET with MVT-2163 was safe and visualized known primary tumors and metastases with high contrast. In addition, radiotracer uptake was not only observed in metastases known from conventional CT, but also seen in subcentimeter lymph nodes located in typical metastatic sites of pancreatic cancer, which were not abnormal on routine clinical imaging studies. A significant fraction of the patients demonstrated very high and, over time, increased uptake of MVT-2163 in tumor tissue, suggesting that HuMab-5B1 labeled with beta-emitting radioisotopes may have the potential to deliver therapeutic doses of radiation to cancer cells. CONCLUSIONS: Our study shows that the tumor antigen CA19-9 secreted to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. This significantly broadens the number of molecular targets that can be used for PET imaging and offers new opportunities for noninvasive characterization of tumors in patients.

qPSMA: Semiautomatic Software for Whole-Body Tumor Burden Assessment in Prostate Cancer Using 68Ga-PSMA11 PET/CT.

Our aim was to introduce and validate qPSMA, a semiautomatic software package for whole-body tumor burden assessment in prostate cancer patients using 68Ga-prostate-specific membrane antigen (PSMA) 11 PET/CT. Methods: qPSMA reads hybrid PET/CT images in DICOM format. Its pipeline was written using Python and C++ languages. A bone mask based on CT and a normal-uptake mask including organs with physiologic 68Ga-PSMA11 uptake are automatically computed. An SUV threshold of 3 and a liver-based threshold are used to segment bone and soft-tissue lesions, respectively. Manual corrections can be applied using different tools. Multiple output parameters are computed, that is, PSMA ligand-positive tumor volume (PSMA-TV), PSMA ligand-positive total lesion (PSMA-TL), PSMA SUVmean, and PSMA SUVmax Twenty 68Ga-PSMA11 PET/CT data sets were used to validate and evaluate the performance characteristics of qPSMA. Four analyses were performed: validation of the semiautomatic algorithm for liver background activity determination, assessment of intra- and interobserver variability, validation of data from qPSMA by comparison with Syngo.via, and assessment of computational time and comparison of PSMA PET-derived parameters with serum prostate-specific antigen. Results: Automatic liver background calculation resulted in a mean relative difference of 0.74% (intraclass correlation coefficient [ICC], 0.996; 95%CI, 0.989;0.998) compared with METAVOL. Intra- and interobserver variability analyses showed high agreement (all ICCs > 0.990). Quantitative output parameters were compared for 68 lesions. Paired t testing showed no significant differences between the values obtained with the 2 software packages. The ICC estimates obtained for PSMA-TV, PSMA-TL, SUVmean, and SUVmax were 1.000 (95%CI, 1.000;1.000), 1.000 (95%CI, 1.000;1.000), 0.995 (95%CI, 0.992;0.997), and 0.999 (95%CI, 0.999;1.000), respectively. The first and second reads for intraobserver variability resulted in mean computational times of 13.63 min (range, 8.22-25.45 min) and 9.27 min (range, 8.10-12.15 min), respectively (P = 0.001). Highly significant correlations were found between serum prostate-specific antigen value and both PSMA-TV (r = 0.72, P < 0.001) and PSMA-TL (r = 0.66, P = 0.002). Conclusion: Semiautomatic analyses of whole-body tumor burden in 68Ga-PSMA11 PET/CT is feasible. qPSMA is a robust software package that can help physicians quantify tumor load in heavily metastasized prostate cancer patients.

The Impact That Number of Analyzed Metastatic Breast Cancer Lesions Has on Response Assessment by 18F-FDG PET/CT Using PERCIST.

UNLABELLED: The PET Response Criteria in Solid Tumors (PERCIST) are not specific regarding the number of lesions that should be analyzed per patient. This study evaluated how the number of analyzed lesions affects response assessment in metastatic breast cancer. METHODS: In 60 patients, response was assessed by the change in SUVpeak, normalized to lean body mass, of the most (18)F-FDG-avid lesion (PERCIST 1) and by the change in the sum of normalized SUVpeak for up to 5 lesions (PERCIST 5). The correlation between response by PERCIST and progression-free and disease-specific survival was evaluated. RESULTS: In responders and nonresponders, the respective progression-free survival at 2 y was 37.26% and 6.43% for PERCIST 1 (P < 0.0001) and 33.65% and 7.14% for PERCIST 5 (P < 0.0001) and the respective disease-specific survival at 4 y was 58.96% and 25.44% for PERCIST 1 (P < 0.012) and 59.12% vs 20.01% for PERCIST 5 (P < 0.002). CONCLUSION: The number of analyzed lesions does not appear to have a major impact on the prognostic value of response assessment with (18)F-FDG PET/CT in metastatic breast cancer.

Repeatability of 18F-FDG PET/CT in Advanced Non-Small Cell Lung Cancer: Prospective Assessment in 2 Multicenter Trials.

UNLABELLED: PET/CT with the glucose analog (18)F-FDG has several potential applications for monitoring tumor response to therapy in patients with non-small cell lung cancer (NSCLC). A prerequisite for many of these applications is detailed knowledge of the repeatability of quantitative parameters derived from (18)F-FDG PET/CT studies. METHODS: The repeatability of the (18)F-FDG signal was evaluated in 2 prospective multicenter trials. Patients with advanced NSCLC (tumor stage III-IV) underwent two (18)F-FDG PET/CT studies while not receiving therapy. Tumor (18)F-FDG uptake was quantified by measurement of the maximum standardized uptake value within a lesion (SUVmax) and the average SUV within a small volume of interest around the site of maximum uptake (SUVpeak). Analysis was performed for the lesion in the chest with the highest (18)F-FDG uptake and a size of at least 2 cm (target lesion) as well as for up to 6 additional lesions per patient. Repeatability was assessed by Bland-Altman plots and calculation of 95% repeatability coefficients (RCs) of the log-transformed SUV differences. RESULTS: Test-retest repeatability was assessed in 74 patients (34 from the ACRIN 6678 trial and 40 from the Merck MK-0646-008 trial). SUVpeak was 11.57 ± 7.89 g/mL for the ACRIN trial and 6.89 ± 3.02 for the Merck trial. The lower and upper RCs were -28% (95% confidence interval [CI], -35% to -23%) and +39% (95% CI, 31% to 54%) in the ACRIN trial, indicating that a decrease of SUVpeak by more than 28% or an increase by more than 39% has a probability of less than 2.5%. The corresponding RCs from the Merck trial were -35% (95% CI, -42% to -29%) and +53% (95% CI, 41% to 72%). Repeatability was similar for SUVmax of the target lesion, averaged SUVmax, and averaged SUVpeak of up to 6 lesions per patient. CONCLUSION: The variability of repeated measurements of tumor (18)F-FDG uptake in patients with NSCLC is somewhat larger than previously reported in smaller single-center studies but comparable to that of gastrointestinal malignancies in a previous multicenter trial. The variability of measurements supports the definitions of tumor response according to PET Response Criteria in Solid Tumors.

Assessment of striatal dopamine D2/D3 receptor availability with PET and 18F-desmethoxyfallypride: comparison of imaging protocols suited for clinical routine.

UNLABELLED: Assessment of striatal dopamine receptor availability with (18)F-desmethoxyfallypride PET is of high diagnostic utility in parkinsonism. The present study was undertaken to define the optimal clinical scan protocol with regard to quantification accuracy and scan time. METHODS: Fourteen patients with parkinsonian syndromes underwent (18)F-desmethoxyfallypride PET over 90 min. Volume-of-interest analyses were performed after spatial normalization, with the right and left caudate nuclei and putamina as target regions and the cerebellum as reference region. The estimate of target region binding potential (relative to nondisplaceable radioligand in tissue) (BP(ND)) provided by the 2-step simplified reference tissue model (SRTM2) served as the reference standard. Additional analyses included the multilinear reference tissue model 2 (MRTM2), noninvasive graphical analyses, and single-scan analyses (peak-equilibrium analysis at 35-65 min [PEA]; pseudoequilibrium analysis at 60-90 min [PsEA]). RESULTS: SRTM2 and MRTM2 yielded virtually identical results (mean BP(ND) difference = 0.1% ± 0.5%, r(2) = 1.0). Noninvasive graphical analyses with and without inclusion of the k(2)' term were affected by a small BP(ND) bias (2.5% ± 3.6% and -5.0% ± 6.7%, respectively), although correlations with SRTM2 were still excellent (r(2) = 1.0 and 0.98, respectively). In turn, single-scan analyses suffered from limited precision (PEA, mean BP(ND) bias = 0.7% ± 13.0%, r(2) = 0.90) or a considerable positive bias (PsEA, 19.2% ± 7.1%, r(2) = 0.98). Shortening scan time to 70 and 60 min resulted in an acceptable average BP(ND) change (<5% decline) for SRTM2/MRTM2 and graphical analysis with inclusion of the k(2)' term, respectively. CONCLUSION: Kinetic reference tissue model analyses of (18)F-desmethoxyfallypride PET data offer the least biased results at a well-tolerable scan duration and should thus be pursued whenever possible. Single-scan analyses may be pragmatic alternatives that, however, suffer from a relevant positive bias (PsEA) or limited precision (PEA).

3'-deoxy-3'-[18F]fluorothymidine positron emission tomography for response assessment in soft tissue sarcoma: a pilot study to correlate imaging findings with tissue thymidine kinase 1 and Ki-67 activity and histopathologic response.

BACKGROUND: This study sought to determine whether [(18)F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging allows assessment of tumor viability and proliferation in patients with soft tissue sarcomas who are treated with neoadjuvant therapy. METHODS: Twenty patients with biopsy-proven, resectable, high-grade soft tissue sarcoma underwent [(18)F]FLT PET/CT imaging before and after neoadjuvant therapy. Histologic subtypes included sarcomas not otherwise specified (n = 5), malignant peripheral nerve sheath tumors (n = 3), gastrointestinal stromal tumors (n = 3), leiomyosarcomas (n = 3), angiosarcomas (n = 2), and others (n = 4). Changes in [(18)F]FLT peak standardized uptake value (SUVpeak) were correlated with percent necrosis in excised tissue, whereas posttreatment [(18)F]FLT tumor uptake was correlated with thymidine kinase 1 (TK1) expression and Ki-67 staining indices in excised tumor tissue. RESULTS: Tumor FLT SUVpeak averaged 7.1 ± 3.7 g/mL (range, 1.9-16.1 g/mL) at baseline and decreased significantly to 2.7 ± 1.6 g/mL (range, 0.8-6.0 g/mL) at follow-up (P < .001); however, marked reductions in SUV were not specific for histopathological response. The posttreatment SUVpeak did not correlate with TK1 (P = .27) or Ki-67 expression (P = .21). CONCLUSIONS: Marked reductions in [(18)F]FLT tumor uptake in response to neoadjuvant treatment were observed in most patients with sarcoma. However, these reductions were not specific for histopathologic response to neoadjuvant therapy. Furthermore, posttreatment [(18)F]FLT tumor uptake was unrelated to tumor proliferation by Ki-67 and TK1 staining. These results question the value of [(18)F]FLT PET imaging for treatment response assessments in patients with soft tissue sarcoma.

Generating evidence for clinical benefit of PET/CT in diagnosing cancer patients.

For diagnostic methods such as PET/CT, not only diagnostic accuracy but also clinical benefit must be demonstrated. However, there is a lack of consensus about how to approach this task. Here we consider 6 clinical scenarios to review some basic approaches to demonstrating the clinical benefit of PET/CT in cancer patients: replacement of an invasive procedure, improved accuracy of initial diagnosis, improved accuracy of staging for curative versus palliative treatment, improved accuracy of staging for radiation versus chemotherapy, response evaluation, and acceleration of clinical decisions. We also develop some guidelines for the evaluation of clinical benefit. First, it should be clarified whether there is a direct benefit of the use of PET/CT or an indirect benefit because of improved diagnostic accuracy. If there is an indirect benefit, then decision modeling should be used initially to assess the benefit expected from the use of PET/CT. Only if decision modeling does not allow definitive conclusions should randomized controlled trials be planned.

Combined assessment of metabolic and volumetric changes for assessment of tumor response in patients with soft-tissue sarcomas.

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

Evaluation of [(18)F]gefitinib as a molecular imaging probe for the assessment of the epidermal growth factor receptor status in malignant tumors.

PURPOSE: Gefitinib, an inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK), has shown potent effects in a subset of patients carrying specific EGFR-TK mutations in advanced non-small-cell lung cancer. In this study, we asked whether PET with [(18)F]gefitinib may be used to study noninvasively the pharmacokinetics of gefitinib in vivo and to image the EGFR status of cancer cells. MATERIALS AND METHODS: Synthesis of [(18)F]gefitinib has been previously described. The biodistribution and metabolic stability of [(18)F]gefitinib was assessed in mice and vervet monkeys for up to 2 h post injection by both micropositron emission tomography (PET)/computed tomography (CT) scans and postmortem ex vivo tissue harvesting. Uptake levels of radiolabeled gefitinib in EGFR-expressing human cancer cell lines with various levels of EGFR expression or mutation status were evaluated both in vivo and in vitro. RESULTS: MicroPET/CT scans in two species demonstrated a rapid and predominantly hepatobiliary clearance of [(18)F]gefitinib in vivo. However, uptake levels of radiolabeled gefitinib, both in vivo and in vitro, did not correlate with EGFR expression levels or functional status. This unexpected observation was due to high nonspecific, nonsaturable cellular uptake of gefitinib. CONCLUSION: The biodistribution of the drug analogue [(18)F]gefitinib suggests that it may be used to assess noninvasively the pharmacokinetics of gefitinib in patients by PET imaging. This is of clinical relevance, as insufficient intratumoral drug concentrations are considered to be a factor for resistance to gefitinib therapy. However, the highly nonspecific cellular binding of [(18)F]gefitinib may preclude the use of this imaging probe for noninvasive assessment of EGFR receptor status in patients.

Monitoring cancer treatment with PET/CT: does it make a difference?

PET with the glucose analog 18F-FDG is increasingly being used to monitor the effectiveness of therapy in patients with malignant lymphomas and a variety of solid tumors. The use of integrated PET/CT instead of stand-alone PET for treatment monitoring poses some methodologic challenges for the quantitative analysis of PET scans but also provides the opportunity to integrate morphologic information and functional information. This integration may allow the definition of new parameters for assessment of the tumor response and will also facilitate the use of PET in research studies as well as in clinical practice. This review addresses how CT-based attenuation correction may affect the quantitative analysis of 18F-FDG PET scans and summarizes the results of recent studies with PET/CT for treatment monitoring for lung cancer and gastrointestinal stromal tumors. The review concludes with an outlook on how PET/CT could make a difference in drug development and clinical management for patients.

Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma.

PURPOSE: To develop guidelines for performing and interpreting positron emission tomography (PET) imaging for treatment assessment in patients with lymphoma both in clinical practice and in clinical trials. METHODS: An International Harmonization Project (IHP) was convened to discuss standardization of clinical trial parameters in lymphoma. An imaging subcommittee developed consensus recommendations based on published PET literature and the collective expertise of its members in the use of PET in lymphoma. Only recommendations subsequently endorsed by all IHP subcommittees were adopted. RECOMMENDATIONS: PET after completion of therapy should be performed at least 3 weeks, and preferably at 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Visual assessment alone is adequate for interpreting PET findings as positive or negative when assessing response after completion of therapy. Mediastinal blood pool activity is recommended as the reference background activity to define PET positivity for a residual mass > or = 2 cm in greatest transverse diameter, regardless of its location. A smaller residual mass or a normal sized lymph node (ie, < or = 1 x 1 cm in diameter) should be considered positive if its activity is above that of the surrounding background. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow are also proposed. Use of attenuation-corrected PET is strongly encouraged. Use of PET for treatment monitoring during a course of therapy should only be done in a clinical trial or as part of a prospective registry.

Positron emission tomography in non-small-cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use.

PURPOSE: To prospectively evaluate the use of positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) to predict response to chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC scheduled to undergo platinum-based chemotherapy were eligible for this study. Patients were studied by FDG-PET before and after the first cycle of therapy. Based on previous studies, a reduction of tumor FDG uptake by more than 20% as assessed by standardized uptake values (SUV) was used as a criterion for a metabolic response. Furthermore, changes in tumor SUVs were compared with changes in FDG net-influx constants (Ki) and tumor/muscle ratios (t/m). RESULTS: Fifty-seven patients were included in the study. There was a close correlation between metabolic response and best response to therapy according to Response Evaluation Criteria in Solid Tumors (P <.0001; sensitivity and specificity for prediction of best response, 95% and 74%, respectively). Median time to progression and overall survival were significantly longer for metabolic responders than for metabolic nonresponders (163 v 54 days and 252 days v 151 days, respectively). Similar results were obtained when Ki was used to assess tumor glucose use, whereas changes in t/m showed considerable overlap between responding and nonresponding tumors. CONCLUSION: In NSCLC, reduction of metabolic activity after one cycle of chemotherapy is closely correlated with final outcome of therapy. Using metabolic response as an end point may shorten the duration of phase II studies evaluating new cytotoxic drugs and may decrease the morbidity and costs of therapy in nonresponding patients.