EORTC PET response criteria are more influenced by reconstruction inconsistencies than PERCIST but both benefit from the EARL harmonization program.

BACKGROUND: This study evaluates the consistency of PET evaluation response criteria in solid tumours (PERCIST) and European Organisation for Research and Treatment of Cancer (EORTC) classification across different reconstruction algorithms and whether aligning standardized uptake values (SUVs) to the European Association of Nuclear Medicine acquisition (EANM)/EARL standards provides more consistent response classification. MATERIALS AND METHODS: Baseline (PET1) and response assessment (PET2) scans in 61 patients with non-small cell lung cancer were acquired in protocols compliant with the EANM guidelines and were reconstructed with point-spread function (PSF) or PSF + time-of-flight (TOF) reconstruction for optimal tumour detection and with a standardized ordered subset expectation maximization (OSEM) reconstruction known to fulfil EANM harmonizing standards. Patients were recruited in three centres. Following reconstruction, EQ.PET, a proprietary software solution was applied to the PSF ± TOF data (PSF ± TOF.EQ) to harmonize SUVs to the EANM standards. The impact of differing reconstructions on PERCIST and EORTC classification was evaluated using standardized uptake values corrected for lean body mass (SUL). RESULTS: Using OSEMPET1/OSEMPET2 (standard scenario), responders displayed a reduction of -57.5% ± 23.4 and -63.9% ± 22.4 for SULmax and SULpeak, respectively, while progressing tumours had an increase of +63.4% ± 26.5 and +60.7% ± 19.6 for SULmax and SULpeak respectively. The use of PSF ± TOF reconstruction impacted the classification of tumour response. For example, taking the OSEMPET1/PSF ± TOFPET2 scenario reduced the apparent reduction in SUL in responding tumours (-39.7% ± 31.3 and -55.5% ± 26.3 for SULmax and SULpeak, respectively) but increased the apparent increase in SUL in progressing tumours (+130.0% ± 50.7 and +91.1% ± 39.6 for SULmax and SULpeak, respectively). Consequently, variation in reconstruction methodology (PSF ± TOFPET1/OSEMPET2 or OSEM PET1/PSF ± TOFPET2) led, respectively, to 11/61 (18.0%) and 10/61 (16.4%) PERCIST classification discordances and to 17/61 (28.9%) and 19/61 (31.1%) EORTC classification discordances. An agreement was better for these scenarios with application of the propriety filter, with kappa values of 1.00 and 0.95 compared to 0.75 and 0.77 for PERCIST and kappa values of 0.93 and 0.95 compared to 0.61 and 0.55 for EORTC, respectively. CONCLUSION: PERCIST classification is less sensitive to reconstruction algorithm-dependent variability than EORTC classification but harmonizing SULs within the EARL program is equally effective with either.

Does PET SUV Harmonization Affect PERCIST Response Classification?

Pre- and posttreatment PET comparative scans should ideally be obtained with identical acquisition and processing, but this is often impractical. The degree to which differing protocols affect PERCIST classification is unclear. This study evaluates the consistency of PERCIST classification across different reconstruction algorithms and whether a proprietary software tool can harmonize SUV estimation sufficiently to provide consistent response classification. METHODS: Eighty-six patients with non-small cell lung cancer, colorectal liver metastases, or metastatic melanoma who were scanned for therapy monitoring purposes were prospectively recruited in this multicenter trial. Pre- and posttreatment PET scans were acquired in protocols compliant with the Society of Nuclear Medicine and Molecular Imaging and the European Association of Nuclear Medicine (EANM) acquisition guidelines and were reconstructed with a point spread function (PSF) or PSF + time-of-flight (TOF) for optimal tumor detection and also with standardized ordered-subset expectation maximization (OSEM) known to fulfill EANM harmonizing standards. After reconstruction, a proprietary software solution was applied to the PSF ± TOF data (PSF ± TOF.EQ) to harmonize SUVs with the OSEM values. The impact of differing reconstructions on PERCIST classification was evaluated. RESULTS: For the OSEMPET1/OSEMPET2 (OSEM reconstruction for pre- and posttherapeutic PET, respectively) scenario, which was taken as the reference standard, the change in SUL was -41% ± 25 and +56% ± 62 in the groups of tumors showing a decrease and an increase in 18F-FDG uptake, respectively. The use of PSF reconstruction affected classification of tumor response. For example, taking the PSF ± TOFPET1/OSEMPET2 scenario increased the apparent reduction in SUL in responding tumors (-48% ± 22) but reduced the apparent increase in SUL in progressing tumors (+37% ± 43), as compared with the OSEMPET1/OSEMPET2 scenario. As a result, variation in reconstruction methodology (PSF ± TOFPET1/OSEMPET2 or OSEM PET1/PSF ± TOFPET2) led to 13 of 86 (15%) and 17 of 86 (20%) PERCIST classification discordances, respectively. Agreement was better for these scenarios with application of the propriety filter, with κ values of 1 and 0.95 compared with 0.79 and 0.72, respectively. CONCLUSION: Reconstruction algorithm-dependent variability in PERCIST classification is a significant issue but can be overcome by harmonizing SULs using a proprietary software tool.

Applying Advanced Imaging Techniques to a Murine Model of Orthotopic Osteosarcoma.

INTRODUCTION: Reliable animal models are required to evaluate novel treatments for osteosarcoma. In this study, the aim was to implement advanced imaging techniques in a murine model of orthotopic osteosarcoma to improve disease modeling and the assessment of primary and metastatic disease. MATERIALS AND METHODS: Intra-tibial injection of luciferase-tagged OPGR80 murine osteosarcoma cells was performed in Balb/c nude mice. Treatment agent [pigment epithelium-derived factor (PEDF)] was delivered to the peritoneal cavity. Primary tumors and metastases were evaluated by in vivo bioluminescent assays, micro-computed tomography, [(18)F]-Fluoride-PET and [(18)F]-FDG-PET. RESULTS: [(18)F]-Fluoride-PET was more sensitive than [(18)F]-FDG-PET for detecting early disease. Both [(18)F]-Fluoride-PET and [(18)F]-FDG-PET showed progressive disease in the model, with fourfold and twofold increases in standardized uptake value (p < 0.05) by the study endpoint, respectively. In vivo bioluminescent assay showed that systemically delivered PEDF inhibited growth of primary osteosarcoma. DISCUSSION: Application of [(18)F]-Fluoride-PET and [(18)F]-FDG-PET to an established murine model of orthotopic osteosarcoma has improved the assessment of disease. The use of targeted imaging should prove beneficial for the evaluation of new approaches to osteosarcoma therapy.

STatistically Assigned Response Criteria in Solid Tumors (STARCIST).

BACKGROUND: Several reproducibility studies have established good test-retest reliability of FDG-PET in various oncology settings. However, these studies are based on relatively short inter-scan periods of 1-3 days while, in contrast, response assessments based on FDG-PET in early phase drug trials are typically made over an interval of 2-3 weeks during the first treatment cycle. With focus on longer, on-treatment scan intervals, we develop a data-driven approach to calculate baseline-specific cutoff values to determine patient-level changes in glucose uptake that are unlikely to be explained by random variability. Our method takes into account the statistical nature of natural fluctuations in SUV as well as potential bias effects. METHODS: To assess variability in SUV over clinically relevant scan intervals for clinical trials, we analyzed baseline and follow-up FDG-PET scans with a median scan interval of 21 days from 53 advanced stage cancer patients enrolled in a Phase 1 trial. The 53 patients received a sub-pharmacologic drug dose and the trial data is treated as a 'test-retest' data set. A simulation-based tool is presented which takes as input baseline lesion SUVmax values, the variance of spurious changes in SUVmax between scans, the desired Type I error rate, and outputs lesion and patient based cut-off values. Bias corrections are included to account for variations in tracer uptake time. RESULTS: In the training data, changes in SUVmax follow an approximately zero-mean Gaussian distribution with constant variance across levels of the baseline measurements. Because of constant variance, the coefficient of variation is a decreasing function of the magnitude of baseline SUVmax. This finding is consistent with published results, but our data shows greater variability. Application of our method to NSCLC patients treated with erlotinib produces results distinct from those based on the EORTC criteria. Based on data presented here as well as previous repeatability studies, the proposed method has greater statistical power to detect a significant %-decrease on SUVmax compared to published criteria relying on symmetric thresholds. CONCLUSIONS: Defining patient-specific, baseline dependent cut-off values based on the (null) distribution of naturally occurring fluctuations in glucose uptake enable identification of statistically significant changes in SUVmax. For lower baseline values, the produced cutoff values are notably asymmetric with relatively large changes (e.g. >50 %) required for statistical significance. For use with prospectively defined endpoints, the developed method enables the use of one-armed trials to detect pharmacodynamic drug effects based on FDG-PET. The clinical importance of changes in SUVmax is likely to remain dependent on both tumor biology and the type of treatment.

Bifunctional (64)Cu-labelled macrobicyclic cage amine isothiocyanates for immuno-positron emission tomography.

New macrobicyclic cage amine or "sarcophagine" (sar) bifunctional chelators have been synthesised that form copper complexes of exceptional in vivo stability and incorporate isothiocyanate (-NCS) functional groups for conjugation to an antibody. The chelators were synthesised from the methyl-capped complex [Mg(II)(CH3)(NH2)sar](2+). Coordination of Mg(II) within the cavity of the cage amine ligand protects the secondary amine atoms from reacting with the -NCS functional groups. Two different [Mg(II)(NCS-sar)](2+) derivatives were conjugated to the HER2/neu-targeting antibody trastuzumab and the progress of the reaction monitored by electrospray mass spectrometry. The Mg(II) ion was removed from the immunoconjugates under mild conditions (0.1 M citrate buffer, pH 6). Labelling of the (CH3)(p-NCS-Ph)sar-trastuzumab conjugate with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (∼5 min) and easily performed at room temperature with high radiochemical purity (>95%). Biodistribution and PET imaging studies in vivo showed that (64)Cu-labelled (CH3)(p-NCS-Ph)sar-trastuzumab maintained high stability under physiological conditions with high and selective uptake in a HER2-positive cancer cell line. The stability of the copper complex and the 12.7 h half-life of the radioisotope allows clear visualisation of tumours out to 48 h.

Effect of PET/CT on management of patients with non-small cell lung cancer: results of a prospective study with 5-year survival data.

UNLABELLED: We investigated the incremental management impact and prognostic value of staging with (18)F-FDG PET/CT in patients with non-small cell lung cancer (NSCLC) being considered for potentially curative therapies. METHODS: Information on 168 consecutive patients with NSCLC being considered for surgery or definitive radiotherapy with curative intent before PET/CT was entered into a prospective database. The pre-PET/CT management plan, based on conventional imaging (conventional CT, appropriately supplemented by bone scintigraphy or other modalities), was defined prospectively by referring clinicians before PET/CT results became available. After PET/CT, actual clinical management was recorded, and patients were followed up until 5 y or death. The appropriateness of PET/CT management plans was assessed by biopsy when available, clinical follow-up, and survival analysis. RESULTS: Stage was discordant on PET/CT and conventional imaging in 50.6% of patients (41.1% upstaged, 9.5% downstaged), with high management impact (change in treatment modality or curative intent) in 42.3% of patients. Both conventional imaging stage and PET/CT stage were strongly predictive of overall survival (OS) but there were greater differences between hazard rates and separations in the OS curves for stage groupings determined using PET/CT. OS was also strongly predicted by PET/CT-directed choice of therapy (P < 0.0001). CONCLUSION: PET/CT frequently affects patient management and strongly predicts OS in NSCLC, supporting the appropriateness of such changes.

Compliance with PET acquisition protocols for therapeutic monitoring of erlotinib therapy in an international trial for patients with non-small cell lung cancer.

PURPOSE: The Response Evaluation Criteria in Solid Tumors (RECIST) are widely used but have recognized limitations. Molecular imaging assessments, including changes in (18)F-deoxyglucose (FDG) or (18)F-deoxythymidine (FLT) uptake by positron emission tomography (PET), may provide earlier, more robust evaluation of treatment efficacy. METHODS: A prospective trial evaluated on-treatment changes in FDG and FLT PET imaging among patients with relapsed or recurrent non-small cell lung cancer treated with erlotinib to assess the relationship between PET-evaluated response and clinical outcomes. We describe an audit of compliance with the study imaging charter, to establish the feasibility of achieving methodological consistency in a multicentre setting. RESULTS: Patients underwent PET scans at baseline and approximately day 14 and day 56 of treatment (n = 73, 66 and 51 studies, and n = 73, 63 and 50 studies for FDG PET and FLT PET, respectively). Blood glucose levels were within the target range for all FDG PET scans. Charter-specified uptake times were achieved in 86% (63/73) and 89% (65/73) of baseline FDG and FLT scans, respectively. On-treatment scans were less consistent: 72% (84/117) and 68% (77/113), respectively, achieved the target of ±5 min of baseline uptake time. However, 96% (112/117) and 94% (106/113) of FDG and FLT PET studies, respectively, were within ±15 min. Bland-Altman analysis of intra-individual hepatic average standardized uptake value (SUV(ave)), to assess reproducibility, showed only a small difference in physiological uptake (-0.006 ± 0.224 in 118 follow-up FDG scans and 0.09 ± 0.81 in 111 follow-up FLT scans). CONCLUSION: It is possible to achieve high reproducibility of scan acquisition methodology, provided that strict imaging compliance guidelines are mandated in the study protocol.

Distribution of proliferating bone marrow in adult cancer patients determined using FLT-PET imaging.

PURPOSE: Given that proliferating hematopoietic stem cells are especially radiosensitive, the bone marrow is a potential organ at risk, particularly with the use of concurrent chemotherapy and radiotherapy. Existing data on bone marrow distribution have been determined from the weight and visual appearance of the marrow in cadavers. 18F-fluoro-L-deoxythymidine concentrates in bone marrow, and we used its intensity on positron emission tomography imaging to quantify the location of the proliferating bone marrow. METHODS AND MATERIALS: The 18F-fluoro-L-deoxythymidine positron emission/computed tomography scans performed at the Peter MacCallum Cancer Centre between 2006 and 2009 on adult cancer patients were analyzed. At a minimum, the scans included the mid-skull through the proximal femurs. A software program developed at our institution was used to calculate the percentage of administered activity in 11 separately defined bony regions. RESULTS: The study population consisted of 13 patients, 6 of whom were men. Their median age was 61 years. Of the 13 patients, 9 had lung cancer, 2 had colon cancer, and 1 each had melanoma and leiomyosarcoma; 6 had received previous, but not recent, chemotherapy. The mean percentage of proliferating bone marrow by anatomic site was 2.9%±2.1% at the skull, 1.9%±1.2% at the proximal humeri, 2.9%±1.3% at the sternum, 8.8%±4.7% at the ribs and clavicles, 3.8%±0.9% at the scapulas, 4.3%±1.6% at the cervical spine, 19.9%±2.6% at the thoracic spine, 16.6%±2.2% at the lumbar spine, 9.2%±2.3% at the sacrum, 25.3%±4.9% at the pelvis, and 4.5%±2.5% at the proximal femurs. CONCLUSION: Our modern estimates of bone marrow distribution in actual cancer patients using molecular imaging of the proliferating marrow provide updated data for optimizing normal tissue sparing during external beam radiotherapy planning.

[Clinical application of (18)F-FDG PET/CT to staging and treatment effectiveness monitoring of nasopharyngeal carcinoma].

BACKGROUND & OBJECTIVE: Fluorine-18 fluorodeoxyglucose ((18)F-FDG) PET/CT could increase the accuracy of diagnosis, staging, and treatment effectiveness monitoring of many malignant diseases, such as lung cancer and esophageal cancer. This study was to evaluate the clinical application of (18)F-FDG PET/CT to the staging, restaging, and treatment effectiveness monitoring of nasopharyngeal carcinoma (NPC). METHODS: The reports of whole body (18)F-FDG PET/CT scans, performed from Feb. 2002 to Dec. 2005 on 43 NPC patients (26 men and 17 women with median age of 52 years) in Peter MacCallum Cancer Center, were reviewed. The final diagnoses were made according to medical records, pathologic reports and follow-up information. The accuracy, specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of (18)F-FDG PET/CT, CT and MRI were calculated and analyzed. RESULTS: The accuracy, specificity, sensitivity, PPV, and NPV of (18)F-FDG PET/CT were 95.3%, 100.0%, 85.7%, 93.8%, and 100.0%, respectively; those of CT and MRI were 65.5%, 79.4%, 64.7%, 81.8%, and 57.9%, respectively. The results of (18)F-FDG PET/CT led to changes in the medical management of 2 staged patients, and 7 restaged patients and 5 patients in monitoring group. (18)F-FDG PET/CT scan affected the therapy plan of 3 restaged patients and 11 patients in monitoring group. Two cases of second primary malignancies(1 case of thyroid carcinoma and 1 case of low grade gastric carcinoma) were detected by (18)F-FDG PET/CT scan. CONCLUSION: (18)F-FDG PET/CT is better than conventional imaging in N and M staging and treatment effectiveness monitoring of NPC.

How do oncologists deal with incidental abnormalities on whole-body fluorine-18 fluorodeoxyglucose PET/CT?

BACKGROUND: Combined positron emission tomography (PET)/computed tomography (CT) using fluorine-18 fluorodeoxyglucose (FDG) is an exciting technique for cancer evaluation, but false-positive results are a recognized limitation. The aim of the study was to evaluate how oncologists deal with focal extrathyroidal FDG abnormalities considered by imaging specialists to be unrelated to the referral indication. METHODS: PET scan reports from a 12-month period from August 2002 to July 2003 in 1727 consecutive patients (mean age, 63 years) were reviewed. Incidental, nonphysiologic FDG abnormalities were classified based on the report conclusion. The frequency with which such abnormalities were investigated by oncologists and the final diagnosis were compared with the imaging diagnosis with a minimum potential follow-up of 2 years (mean, 27.5 months). RESULTS: Incidental FDG abnormalities were reported in 199 (12%) of 1727 patients, including 181 with adequate follow-up. Of 59 cases with a suspected second malignancy, 34 (58%) were actively investigated, with 14 confirmed, 7 unexpected metastatic sites, and 10 other active pathologies. Only 1 further cancer was subsequently detected in the 25 (42%) patients not actively investigated. Conversely, of 122 sites presumed to be benign, only 10 (8%) were actively investigated. Only 2 were proven to relate to malignancy. CONCLUSIONS: Although incidental abnormalities were common, most were benign and appropriately categorized by experienced readers. For actively investigated extrathyroidal abnormalities, a neoplastic basis was confirmed in over 60% of cases. Conversely, for cases deemed most likely benign by the PET/CT report or after review of readily available clinical information by the referring oncologist, the rate of malignancy was less than 2%.

Clinical experience with the first combined positron emission tomography/computed tomography scanner in Australia.

Metabolic imaging with fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is increasing rapidly worldwide because of superior accuracy compared with conventional non-invasive techniques used for evaluating cancer. Limited anatomical information from FDG-PET images alone dictates that complementary use with structural imaging is required to optimise benefit. Recently, combined positron emission tomography/computed tomography (PET/CT) scanners have overtaken standalone PET scanners as the most commonly purchased PET devices. We describe our experience of over 5500 scans performed since the first PET/CT scanner in Australia was commissioned at the Peter MacCallum Cancer Centre (PMCC), Melbourne, in January 2002. Clinical indications for PET/CT scans performed at PMCC largely reflect current Medicare reimbursement policy. Advantages of PET/CT include greater patient comfort and higher throughput, greater diagnostic certainty and accuracy, improved biopsy methods, and better treatment planning. We believe PET/CT will underpin more effective and efficient imaging paradigms for many common tumours, and lead to a decrease in imaging costs.

Evaluation of high-risk melanoma: comparison of [18F]FDG PET and high-dose 67Ga SPET.

Recently the potential of whole-body positron emission tomography scanning using 18F-fluorodeoxyglucose (FDG PET) has led to renewed interest in the use of functional imaging for the detection of occult metastatic melanoma. This study compared dedicated FDG PET with high-dose gallium-67 imaging incorporating whole-body scanning and comprehensive single-photon emission tomography (SPET) in 122 cases (121 patients) in which the two scans were performed <6 weeks apart. All patients were at high clinical risk of occult metastatic disease and 49 (40%) had abnormality suggestive of metastatic disease by at least one functional imaging technique. Discrepant scan findings were followed up to determine which technique more accurately reflected disease status. There were 23/122 (19%; 95% CI: 12%-26%) cases with discordant scan results in respect of either the presence of melanoma (11 cases) or the extent of disease (12 cases). PET correctly identified more disease than 67Ga SPET in 14 cases (including three incidental primary tumours) and was true negative in three further patients with abnormal 67Ga SPET. There were six patients with true positive 67Ga SPET in whom FDG PET was false negative (one small cutaneous deposit, one residual axillary node rated equivocal on FDG PET due to postoperative changes, one adrenal metastasis inseparable from renal activity on FDG PET and three cases in which sites missed on FDG PET were seen on 67Ga SPET. Thus, FDG PET provided incremental diagnostic information compared with 67Ga SPET in 17/23 patients, while 67Ga SPET provided incremental information compared with PET in 6/23 cases ( P=0.035). Based on Australian Medicare reimbursement levels, the net cost per patient with clinical management benefit of replacing 67Ga SPET with FDG PET was estimated to be less than EUR 1,750. These results suggest that FDG PET provides incremental and clinically important information in around 10% of patients at a low incremental cost which, combined with greater patient convenience and lower radiation dosimetry, make FDG PET the functional imaging technique of choice for evaluation of suspected metastatic melanoma.

Inadvertent 2-deoxy-2-[18F]fluoro-D-glucose lymphoscintigraphy: a potential pitfall characterized by hybrid PET-CT.

PURPOSE: To communicate an important pitfall in positron emission tomography (PET) oncologic staging using 2-deoxy-2-[18F]fluoro-D-glucose (FDG). PROCEDURE: A 60-year-old man with a right upper lobe bronchogenic carcinoma was injected with FDG through a cannula in his left cubital fossa, with a small amount of the dose extravasating. RESULTS: Images obtained one hour post-injection with a positron emission tomography-computerized tomography (PET-CT) scanner demonstrated linear FDG activity running with the left arm brachial vascular bundle and along collateral channels, and accumulation of FDG in a low left axillary lymph node of normal size and CT appearance. CONCLUSIONS: Following inadvertent extravasation, FDG appears to accumulate in regional lymph nodes in the same fashion as bone scanning agents or lymphoscintigraphy colloid. Physicians and technologists need to be aware of this important pitfall in order to avoid the false positive diagnosis of nodal metastases. The ability of PET to demonstrate lymphatics and lymph nodes indicates its possible future use in lymphoscintigraphy.