Impact of radiotherapy protocol adherence in NSCLC patients treated with concurrent chemoradiation: RTQA results of the PET-Plan trial.

INTRODUCTION: The success of intensification and personalisation of the curative treatment of non-small cell lung cancer (NSCLC) is strongly associated with the precision in radiotherapy. Here, we evaluate the impact of radiotherapy protocol adherence in a prospective multicentre trial. METHODS: In the open-label, randomised, controlled PET-Plan trial, patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume delineation informed by 1F-FDG PET and CT plus elective nodal irradiation (arm A) or target volumes informed by PET alone (arm B) and received iso-toxically dose-escalated concurrent chemoradiation. The prospectively organised quality assurance program (RTQA) included individual case review by predefined criteria. For evaluation, protocol adherence was scored as per protocol (pP), with minor (miD), intermediate (inD) and major (maD) deviations. In order to exclude biases through patients who discontinued treatment, patients who received ≥60 Gy were additionally analysed. RESULTS: Between 05/2009-11/2016, 205 patients were randomized, 204 patients started treatment according to protocol of which 31 (15%) patients had maD. Patients with maD had an inferior overall survival (OS) (HR 2.9, 95% CI 1.8-4.4, p < 0.0001) and a higher risk of loco-regional progression (HR 5.7, 95% CI 2.7-11.1, p < 0.0001). These results were significant also in the subgroup of patients receiving ≥ 60 Gy. Patients with maD concerning normal tissue delineation and/or dose constraints had a worse OS (p = 0.006) although no higher incidence of grade ≥ 3 toxicities. CONCLUSIONS: Non-adherence to the radiotherapy protocol was associated with an inferior OS and loco-regional control. These results underline the importance of RTQA.

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer-A Secondary Analysis of the PET Plan Trial.

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m2 (day 1, 22) and vinorelbin 15 mg/m2 (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m2 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1-5, 29-33) and vinorelbin 12.5 mg/m2 (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician's discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 (p = 0.015, p = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, p = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias.

Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. METHODS: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333. FINDINGS: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13). INTERPRETATION: 18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours. FUNDING: German Cancer Aid (Deutsche Krebshilfe).

Improved inter-observer agreement of an expert review panel in an oncology treatment trial--Insights from a structured interventional process.

PURPOSE: Oncologic imaging is a key for successful cancer treatment. While the quality assurance (QA) of image acquisition protocols has already been focussed, QA of reading and reporting offers still room for improvement. The latter was addressed in the context of a prospective multicentre trial on fluoro-deoxyglucose (FDG)-positron-emission tomography (PET)/CT-based chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: An expert panel was prospectively installed performing blinded reviews of mediastinal NSCLC involvement in FDG-PET/CT. Due to a high initial reporting inter-observer disagreement, the independent data monitoring committee (IDMC) triggered an interventional harmonisation process, which overall involved 11 experts uttering 6855 blinded diagnostic statements. After assessing the baseline inter-observer agreement (IOA) of a blinded re-review (phase 1), a discussion process led to improved reading criteria (phase 2). Those underwent a validation study (phase 3) and were then implemented into the study routine. After 2 months (phase 4) and 1 year (phase 5), the IOA was reassessed. RESULTS: The initial overall IOA was moderate (kappa 0.52 CT; 0.53 PET). After improvement of reading criteria, the kappa values improved substantially (kappa 0.61 CT; 0.66 PET), which was retained until the late reassessment (kappa 0.71 CT; 0.67 PET). Subjective uncertainty was highly predictive for low IOA. CONCLUSION: The IOA of an expert panel was significantly improved by a structured interventional harmonisation process which could be a model for future clinical trials. Furthermore, the low IOA in reporting nodal involvement in NSCLC may bear consequences for individual patient care.

Accuracy of parathyroid imaging: a comparison of planar scintigraphy, SPECT, SPECT-CT, and C-11 methionine PET for the detection of parathyroid adenomas and glandular hyperplasia.

PURPOSE: To compare the accuracy of planar scintigraphy, single photon emission computed tomography (SPECT), SPECT-CT, and positron emission tomography (PET) with C-11 methionine for the pre-operative detection of parathyroid adenomas. MATERIALS AND METHODS: We retrospectively evaluated the pre-operative studies of 60 patients with primary (n=56) and secondary (n=4) hyperparathyroidism. In 25/60 patients (Group 1), only planar scans were obtained, and additional SPECT and SPECT-CT were carried out in 35/60 patients (Group 2). PET or PET-CT with C-11 methionine was conducted in 8/60 patients (Group 3). RESULTS: The results of the planar scans (Group 1) were true positive in 19/25 patients and false negative in 6/25 patients (sensitivity per patient, 76%). Histopathology confirmed 27 adenomas and two hyperplasia. Planar imaging identified 20/29 of these pathologies, whereas 9/29 were missed (sensitivity per adenoma, 69%). SPECT (Group 2) results were true positive in 34/35 patients and false negative in only one case (sensitivity per patient, 97%). On a lesion-based analysis, 38 adenomas were identified, and two were missed (sensitivity per adenoma, 95%). The sensitivities of SPECT and SPECT-CT were equal; however, SPECT-CT provided superior topographic information. C-11 methionine PET (Group 3) results were true positive in all eight patients. In one case, surgery confirmed two ipsilateral adenomas, only one of which was identified by PET (sensitivity per patient, 100%; per adenoma, 88.9%). CONCLUSION: SPECT is superior to planar imaging. SPECT-CT has identical sensitivity compared to SPECT alone, but it provides additional topographic information. The sensitivity of PET appears to be even higher compared to SPECT. In the case of negative scintigraphic findings and proven hyperparathyroidism, additional C-11 methionine PET or PET-CT is recommended.

Phase II trial of a trimodality regimen for stage III non-small-cell lung cancer using chemotherapy as induction treatment with concurrent hyperfractionated chemoradiation with carboplatin and paclitaxel followed by subsequent resection: a single-center study.

PURPOSE We started a phase II trial of induction chemotherapy and concurrent hyperfractionated chemoradiotherapy followed by either surgery or boost chemoradiotherapy in patients with advanced, stage III disease. The purpose is to achieve better survival in the surgery group with minimum morbidity and mortality. PATIENTS AND METHODS Patients treated from 1998 to 2002 with neoadjuvant chemoradiotherapy and surgical resection for stage III NSCLC were analyzed. The treatment consisted of four cycles of induction chemotherapy with carboplatin/paclitaxel followed by chemoradiotherapy with a reduced dose of carboplatin/paclitaxel and accelerated hyperfractionated radiotherapy with 1.5 Gy twice daily up to 45 Gy. After restaging, operable patients underwent thoracotomy. Inoperable patients received chemoradiotherapy up to 63 Gy. Study end points included resectability, pathologic response, and survival. Results One hundred twenty patients were enrolled; 25% patients had stage IIIA, 73% had stage IIIB, and 2% stage IV. After treatment, 47.5% had downstaging, 29.2% had stable disease, and 23.3% had progressive disease. Thirty patients (25%) were not eligible for operation because of progressive disease, stable disease, and/or functional deterioration with one treatment-related death. The 30-day mortality was 5% in patients who underwent operation. The 5-year survival rate for 120 patients was 21.7%, and it was 43.1% in patients with complete resection. In postoperative patients with stage N0 disease, 5-year survival was 53.3%; if stage N2 or N3 disease was still present, 5-year survival was 33.3%. CONCLUSION Staging and treatment with chemoradiotherapy and complete resection performed in experienced centers achieve acceptable morbidity and mortality.

Hypoxia-imaging with (18)F-Misonidazole and PET: changes of kinetics during radiotherapy of head-and-neck cancer.

BACKGROUND AND PURPOSE: PET with (18)F-Misonidazole (FMISO-PET) is a non-invasive method for measuring tumor hypoxia. We analysed changes of FMISO-uptake during radiotherapy and their impact on patient outcome. MATERIALS AND METHODS: Fourteen patients with HNC underwent repeated FMISO-PET prior to radiotherapy and after 30Gy. Dynamic and static PET-scans (2+4h p.i.) were acquired. FMISO-uptake was quantified by calculating standard uptake values (SUV) and tumor-muscle-ratios (TMR). Kinetic curve types representing tissue hypoxia were defined. Change of curve type was correlated with patient outcome. RESULTS: The mean SUV 4h p.i. and the TMR decreased significantly during radiotherapy. SUV decreased clearly in 12/14 patients, and increased in 2 patients. TMR decreased in 11 patients, and increased in 3 patients. Prior to radiotherapy, three different shapes of kinetic curve types indicative for the degree of hypoxia could be defined in 12/14 patients: (1) accumulation type (severe hypoxia (n=8)), (2) intermediate type (intermediate degree of hypoxia (n=3)), and (3) wash-out type (low degree of hypoxia (n=1)). Curve type changed towards a lower degree of hypoxia at 30Gy in all but 3 patients. In three patients curve type remained unchanged. CONCLUSIONS: The changes in tumor FMISO-uptake during radiotherapy indicate radio-induced reoxygenation.

A model of reoxygenation dynamics of head-and-neck tumors based on serial 18F-fluoromisonidazole positron emission tomography investigations.

PURPOSE: To develop a model for reoxygenation dynamic and its relationship to local control after radiotherapy (RT), based on repeated dynamic [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) examinations in head-and-neck cancer patients. METHODS AND MATERIALS: Ten head-and-neck cancer patients were examined with dynamic FMISO PET before RT with 70 Gy and after approximately 20 Gy. Two of these patients had two additional dynamic FMISO scans during treatment. Local recurrence was assessed by computed tomography-based follow-up 8-24 months after RT. Tumor-specific values for the level of FMISO retention R and the vascular perfusion efficiency P were determined with a kinetic compartment model. RESULTS: Individual R-P scattergrams before and during therapy were analyzed, and significant therapy-induced changes in the characteristic R-P patterns were observed. A tumor control probability model was derived that involves the tissue parameters R and P and estimates the time to reoxygenation. On the basis of this model, a malignancy value M was introduced and calibrated by a fit to the observed outcome data. Reoxygenation is reflected by the model as a progression to less-malignant tumor types (i.e., smaller values of M). In 4 of 6 patients with severe hypoxia, M had decreased after 20 Gy, whereas 2 patients showed increasing M. Four patients showed no hypoxia in the pretreatment scan. CONCLUSION: A tumor control probability model was developed based on repeated FMISO PET scans during RT. The model combines the local perfusion efficiency and the degree of hypoxia to estimate reoxygenation time. It constitutes a key for hypoxia image-guided dose escalation in RT.

Hypoxia dose painting by numbers: a planning study.

PURPOSE: To investigate the feasibility of different hypoxia dose painting strategies in head-and-neck radiotherapy; the potential benefit was limited by the stipulation of isotoxicity with respect to the conventional intensity-modulated radiotherapy (IMRT) treatment. METHODS AND MATERIALS: Thirteen head-and-neck cancer patients were included into the planning study. For each patient, three different treatment plans were created: a conventional IMRT plan, an additional uniform dose escalation (uniDE) of 10% to the fluorodeoxyglucose (FDG)-positive volume, and a plan in which dose painting by numbers (DPBN) was implemented. Dose painting by numbers was realized according to a map of dose-escalation factors calculated from dynamic [(18)F]-fluoromisonidazole (FMISO) positron emission tomography data. RESULTS: Both dose-escalation approaches were shown to be feasible under the constraint of limiting normal tissue doses to the level of conventional IMRT. For DPBN, the prescriptions could be fulfilled in larger regions of the target than for uniDE. Fluorodeoxyglucose-positive volumes had sizes up to 94 cm(3). In contrast, regions receiving comparable dose levels with DPBN presented volumes in the range of 0-2.7 cm(3). Overtreatment of the target was observed with uniDE in most of the cases, whereas some regions did not receive the required dose to overcome hypoxia-induced radiation insensitivity. Tumor control probability increased from 55.9% with conventional IMRT to 57.7% for the uniDE method in the patient group. For DPBN, a potential increase in tumor control probability from 55.9% to 70.2% was determined. Therefore, DPBN seems to result in higher benefits for the patients. CONCLUSION: Dose painting by numbers delivers the dose more effectively than an additional uniform boost to the FDG-positive area. If hypoxia could be adequately quantified with a simple imaging technique like FMISO positron emission tomography, DPBN in head-and-neck cancer could substantially increase tumor control.

18F-FDG PET for assessment of therapy response and preoperative re-evaluation after neoadjuvant radio-chemotherapy in stage III non-small cell lung cancer.

PURPOSE: The aim of this study was to evaluate FDG-PET for assessment of therapy response and for prediction of patient outcome after neo-adjuvant radio-chemotherapy (NARCT) of advanced non-small cell lung cancer (NSCLC). METHODS: Seventy patients with histologically proven stage III NSCLC underwent FDG-PET investigations before and after NARCT. Changes in FDG uptake and PET findings after completion of NARCT were compared with (1) the histology of tumour samples obtained at surgery or repeat mediastinoscopy, and (2) treatment results in terms of achieved operability and long-term survival. RESULTS: The mean average FDG uptake of the primary tumours in the patient group decreased significantly during NARCT (p = 0.004). Sensitivity, specificity and overall accuracy of FDG-PET were 94.5%, 80% and 91%, respectively, for the detection of residual viable primary tumour, and 77%, 68% and 73%, respectively, for the presence of lymph node metastases. A negative PET scan or a reduction in the standardised uptake value (SUV) of more than 80% was the best predictive factor for a favourable outcome of further treatment. Progressive disease according to PET (new tumour manifestations or increasing SUV) was significantly correlated with an unfavourable outcome (p = 0.005). In this subgroup, survival of patients who underwent surgery was not significantly different from survival among those who did not undergo surgery, whereas for the whole patient group, complete tumour resection had a significant influence on outcome. CONCLUSION: FDG-PET is suitable to assess response to NARCT in patients with stage III NSCLC accurately. It was highly predictive for treatment outcome and patient survival. PET may be helpful in improving restaging after NARCT by allowing reliable assessment of residual tumour viability.

Added value of SPECT/CT in patients suspected of having bone infection: preliminary results.

AIM: We evaluated the contribution of SPECT/CT as an adjunct to combined three-phase bone scintigraphy (planar and SPECT) for diagnosing and localizing bone infection. Subsequently, the diagnostic performance of SPECT/CT was compared to visual fusion of SPECT with data of additional CT, X-ray, or MRI studies (SPECT + CT/X-ray/MRI). MATERIALS AND METHODS: Thirty-one patients suspected of bone infection, presenting pathological findings on triple-phase bone scintigraphy, underwent additional SPECT/CT. The SPECT/CT-technology combines the acquisition of SPECT and CT data with the same imaging device enabling perfect overlay of anatomical and functional images. (99m)Tc-DPD was used as radiopharmaceutical in all patients. For data analysis findings of bone scintigraphy (planar scans as well as SPECT) were categorized as positive, negative, or equivocal for the presence of osteomyelitis. In a second step, they were compared with SPECT/CT and SPECT + CT/X-ray/MRI with respect to localization and classification of lesions. Validation was achieved by surgery, biopsy, or by clinical follow up over at least 9 months including microbiological and radiological findings. RESULTS: Three-phase bone scan (incl. SPECT) correctly classified 7 lesions as positive and 11 lesions as negative for osteomyelitis. Six scans were interpreted false positive, two false negative, and five as equivocal. Rating the latter as positive for osteomyelitis, sensitivity of bone scan was (78%), specificity (50%). SPECT/CT was true positive in 7 patients, and true negative in 19. There were two false positive and two false negative findings, one scan was equivocal (sensitivity 78%, specificity 86%). Definition of anatomical localization of inflammatory foci was much easier by SPECT/CT due to better depiction of underlying anatomical details. SPECT + CT/X-ray/MRI yielded the highest sensitivity (100% compared to 78% of SPECT/CT), if equivocal findings (5/31 compared to 1/31 for SPECT/CT) are rated as true positive for osteomyelitis. Among radiological techniques, MRI (2 x FP) and CT (2 x FN) proved equal and expectedly superior to X-ray in delivering the correct diagnosis. CONCLUSION: SPECT/CT improves the diagnostic performance of three-phase bone scan for osteomyelitis by avoiding false positive or equivocal results. An additional benefit over visual fusion of SPECT with X-ray, CT, or MRI studies could not be confirmed in our study.

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.

First experiences of radiation treatment planning with PET/CT.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) is composed of modern CT and PET technology in one machine enabling examinations of patients in one session in the same position. Its value for modern radiation treatment planning is under investigation. METHODS: In 53 patients with head-and-neck (n = 11), non-small cell lung (n = 16), prostate (n = 14) and other cancers (n = 12), a PET/CT investigation was performed. During the diagnostic examination process an integrated scan under radiation treatment-planning conditions was included. Interpretation and delineation of macroscopic tumor were done in an interdisciplinary approach. Treatment changes occurred after critical interpretation of the PET/CT findings by the responsible radiotherapist. Analysis is descriptive with regard to changes in treatment intention, mode, radiation volumes and doses. RESULTS: Examinations were well tolerated. CT datasets in treatment position could be used for planning. Delineation of macroscopic tumor led to changes of the planning target volume after PET/CT 15 times, total dose was modified twelve times. PET/CT examinations led to changes of the general treatment mode in 19 cases. Using the separate CT and PET datasets, fusion in the planning software was easily performed in all patients due to the use of the same positioning and immobilization devices in PET/CT. CONCLUSION: Despite the low number of patients and an expected bias of selection, the first results are encouraging to perform more extended and detailed trials of this technology in radiotherapy planning. Whether PET/CT is superior to PET alone is part of ongoing investigations.

Kinetic analysis of dynamic 18F-fluoromisonidazole PET correlates with radiation treatment outcome in head-and-neck cancer.

BACKGROUND: Hypoxia compromises local control in patients with head-and-neck cancer (HNC). In order to determine the value of [18F]-fluoromisonidazole (Fmiso) with regard to tumor hypoxia, a patient study with dynamic Fmiso PET was performed. For a better understanding of tracer uptake and distribution, a kinetic model was developed to analyze dynamic Fmiso PET data. METHODS: For 15 HNC patients, dynamic Fmiso PET examinations were performed prior to radiotherapy (RT) treatment. The data was analyzed using a two compartment model, which allows the determination of characteristic hypoxia and perfusion values. For different parameters, such as patient age, tumor size and standardized uptake value, the correlation to treatment outcome was tested using the Wilcoxon-Mann-Whitney U-test. Statistical tests were also performed for hypoxia and perfusion parameters determined by the kinetic model and for two different metrics based on these parameters. RESULTS: The kinetic Fmiso analysis extracts local hypoxia and perfusion characteristics of a tumor tissue. These parameters are independent quantities. In this study, different types of characteristic hypoxia-perfusion patterns in tumors could be identified. The clinical verification of the results, obtained on the basis of the kinetic analysis, showed a high correlation of hypoxia-perfusion patterns and RT treatment outcome (p = 0.001) for this initial patient group. CONCLUSION: The presented study established, that Fmiso PET scans may benefit from dynamic acquisition and analysis by a kinetic model. The pattern of distribution of perfusion and hypoxia in the tissue is correlated to local control in HNC.

Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy.

UNLABELLED: In radiotherapy of head and neck cancer (HNC) and non-small cell lung cancer (NSCLC), hypoxia is known to be an important prognostic factor for long-term survival and local tumor control. The PET tracer (18)F-fluoromisonidazole (FMISO) allows noninvasive assessment of tumor hypoxia. This study analyzed whether FMISO PET could predict tumor recurrence after radiotherapy. METHODS: Forty patients with advanced HNC (n = 26) or NSCLC (n = 14) were studied before curative radiotherapy. Dynamic (0-15 min) and static PET scans were acquired up to 4 h after injection of 400 MBq of FMISO. Standardized uptake values (SUVs) and ratios to reference tissues (mediastinum or muscle) were calculated. In addition, time-activity curves up to 14 min after injection were classified visually. PET data were correlated with clinical follow-up data (presence or absence of local recurrence within 1 y), which were available for 21 patients. RESULTS: For HNC, patients with local recurrence could be separated from disease-free patients by SUV 4 h after injection (all recurrences had an SUV > 2). For NSCLC, no such correlation was observed. The tumor-to-muscle ratios (T/Mu) and tumor-to-mediastinum ratios (T/Me) at 4 h after injection correlated with the risk of relapse in both tumor entities: All patients with a T/Me greater than 2.0 (NSCLC, n = 5) or with a T/Mu greater than 1.6 (HNC, n = 5) presented with tumor recurrence, whereas only 3 of the remaining 11 patients experienced recurrence (27%). Qualitative analysis of time-activity curves for 37 patients revealed 3 curve types (rapid washout, n = 9; intermediate [delayed washout], n = 12; and accumulation, n = 16). Eighteen patients categorized by curve type could be followed up: In 5 of 6 patients with an accumulation curve, disease recurred locally within 1 y, compared with 5 of 8 patients with a delayed-washout curve and 0 of 4 with a rapid-washout curve. CONCLUSION: Our results indicate that outcome after radiotherapy can be predicted on the basis of kinetic behavior of FMISO in tumor tissue. An accumulation-type curve, high SUV, and high T/Mu and T/Me at 4 h after injection are highly suggestive of an incomplete response to treatment and might be used to select patients for intensified therapy protocols.

Evaluation of combined transmission and emission tomography for classification of skeletal lesions.

OBJECTIVE: This study assessed the benefit of transmission emission tomography (TET) for classification of skeletal lesions in patients with known malignant disease. SUBJECTS AND METHODS: The TET technology combines acquisition of SPECT and CT data using the same imaging device, thus allowing perfect overlay of anatomic and functional images. We performed TET in 47 patients with tumors who had a total of 104 focal lesions found on bone scintigraphy. Technetium-99m diphosphonate was used as the radiopharmaceutical in all patients. Findings of bone scintigraphy (planar and SPECT), SPECT + CT or radiography, and TET were compared with regard to the precise location and nature (benign vs malignant) of each lesion. Validation was achieved by radiologic follow-up on CT, MRI, or radiography, especially for the extremities, and using biopsy results in five patients. RESULTS: TET could classify 88 (85%) of 104 lesions compared with 37 (36%) of 104 on SPECT. When we counted inconclusive studies as positive for cancer, discrepant findings between SPECT and TET were obtained in 39 lesions. In 38 (97%) of these, TET was correct. Sensitivity for cancer detection was 98% for TET and 94% for SPECT (p = 0.63), and specificity was 81% for TET and 19% for SPECT (p < 0.0001). The highest diagnostic gain was in the spine, thoracic cage, skull, and pelvis. Small osteolytic lesions were missed because of the limited resolution of transmission images. SPECT + CT or radiography and TET were discordant in nine of 104 lesions. TET was false-negative in one lesion and false-positive in another, and SPECT + CT or radiography was false-positive in seven lesions. As a result, sensitivities of TET and SPECT + CT or radiography were nearly the same, but the specificity of TET was significantly higher (p = 0.015). CONCLUSION: TET improves the accuracy of bone scintigraphy by correctly classifying equivocal lesions, especially by identifying benign abnormalities in the axial skeleton and thus increasing the specificity of positive findings.

The value of SPET/CT in chronic osteomyelitis.

Immunoscintigraphy with technetium-99m labelled anti-granulocyte antibodies (AGA) is an equivalent technique to imaging with in vitro-labelled leucocytes, which is now considered state of the art in the diagnostic work-up of patients with suspected post-traumatic chronic osteomyelitis. In this study, we evaluated the use of a combined single-photon emission tomography/computed tomography (SPET/CT) device to improve detection and anatomical definition of inflammatory bone lesions. Twenty-seven patients with 29 sites of suspected bone infection underwent immunoscintigraphy with 750 MBq 99mTc-labelled AGA. Planar scans were acquired immediately, 4 h and 24 h after injection, and combined SPET/CT was performed using a dual-head multifunctional gamma camera equipped with a low-power X-ray system. Accumulation of AGA in inflammatory lesions was quantitated, comparing uptake at 4 and 24 h after injection. The validation was based on culture data derived from surgical or biopsy samples (20 lesions in 18 patients) or clinical follow-up without further therapy for more than 6 months (nine lesions). On a lesion-by-lesion basis 19 true positive, one false positive and nine true negative findings were obtained. SPET/CT correctly identified the location of all positive foci in the appendicular skeleton and that of a cold lesion in the axial skeleton. It also enabled differentiation between soft tissue infection, septic arthritis and osteomyelitis, as well as between cortical, corticomedullary and subperiosteal foci. Sensitivity was identical for SPET and SPET/CT (100%), whereas specificity was improved from 78% to 89% by the use of SPET/CT. Combined SPET/CT improves the accuracy of immunoscintigraphy by allowing correct differentiation between soft tissue infection and bone involvement. This technique may gain clinical relevance in the selection of patients for surgical therapy.

[18F]FLT PET for diagnosis and staging of thoracic tumours.

The nucleoside analogue 3'-deoxy-3'-[18F]fluorothymidine (FLT) has been introduced for imaging of tumour cell proliferation by positron emission tomography (PET). This study evaluated the use of FLT in patients with thoracic tumours prior to treatment. Whole-body FLT PET was performed in 16 patients with 18 tumours [17 thoracic tumours (nine non-small cell lung cancers, five oesophageal carcinomas, two sarcomas, one Hodgkin's lymphoma) and one renal carcinoma] before treatment. Fluorine-18 fluorodeoxyglucose (FDG) PET was performed for comparison except in those patients with oesophageal carcinoma. For semi-quantitative analysis, the average and maximum standardised uptake values (avgSUV and maxSUV, respectively) (FLT, 114+/-20 min p.i.; FDG, 87+/-8 min p.i.; 50% isocontour region of interest) was calculated. All 17 thoracic tumours and 19/20 metastases revealed significant FLT accumulation, resulting in easy delineation from surrounding tissue. The additional small grade 1 renal carcinoma was not detected with either FLT or FDG. In most lung tumours (avgSUV 1.5-8.2) and metastases, FLT showed intense uptake. However, one of two spinal bone metastases was missed owing to the high physiological FLT uptake in the surrounding bone marrow. Oesophageal carcinoma primaries (avgSUV 2.7-10.0) and occasional metastases showed particularly favourable tumour/non-tumour contrast. Compared with FDG, tumour uptake of FLT was lower (avgSUV, P=0.0006; maxSUV, P=0.0001), with a significant linear correlation (avgSUV, r2=0.45; maxSUV, r2=0.49) between FLT and FDG. It is concluded that FLT PET accurately visualises thoracic tumour lesions. In the liver and the bone marrow, high physiological FLT uptake hampers detection of metastases. On the other hand, FLT may be favourable for imaging of brain metastases owing to the low physiological uptake.

Benefit of anatomical-functional image fusion in the diagnostic work-up of neuroendocrine neoplasms.

The aim of this prospective study was to evaluate anatomical-functional image fusion using the new technology of combined transmission and emission tomography (SPET/CT) in patients with neuroendocrine tumours (NET). Fifty-four patients with known or suspected NET prospectively underwent both tumour scintigraphy with (111)In-octreotide (n=43) or (123)I-MIBG (n=11) and contrast-enhanced high-end spiral CT. Scintigraphy was performed using a gamma camera (Millennium VG & Hawkeye, GE) with an integrated X-ray tube for combined transmission and emission tomography. SPET and high-end CT were interpreted blinded with regard to localisation and classification of lesions. Analysis of fused images (SPET/CT) was done on a lesion-by-lesion basis, followed by re-evaluation of SPET and high-end CT by consensus. The standard of reference for confirming the presence or absence of malignancy was either histopathology or clinical and imaging follow-up data. A total of 120 lesions were identified by CT and/or scintigraphy. This group included four patients with negative SPET but eight liver lesions on CT that were proven to be metastases. We excluded from the analysis two patients with no evidence of tumour on either modality, two lesions that lacked comparison with the standard of reference and two patients, each with two lesions, who were lost to follow-up. In 56 of the 114 evaluated lesions (49%), the results of SPET and CT were concordant; all lesions were interpreted as malignant. In 58 of 114 lesions (51%), consensus reading of fused images changed the image interpretation of 39 CT scans and 19 SPET studies: 31 lesions previously interpreted as equivocal (n=10) or benign (n=21) were re-classified as malignant and 27 lesions previously interpreted as equivocal (n=19) or malignant (n=8) were re-evaluated as benign. The highest accuracy (99%) in classifying NET lesions was achieved by combined analysis of SPET/CT ("hawkeye") and high-end CT. The specificity of SPET/CT was significantly higher than that of CT alone (P=0.0026) and slightly higher than that of SPET alone, but the accuracy of SPET/CT was inferior to that of side-by-side analysis of SPET and high-end CT (P=0.013) or visual correlation of SPET/CT and high-end CT (P<0.0001). Therapy was changed in 14 of 50 patients (28%) owing to the results of image fusion: in five patients tumour could be excluded, three patients were spared unnecessary surgery because of additional lesions indicating systemic tumour spread, in four patients the surgical approach was changed owing to precise tumour localisation and minimising of the surgical field, and in two patients medical and radiopeptide therapy was changed. Anatomical-functional image fusion allows for improved localisation and characterisation of NET with resultant alteration of the treatment approach in a substantial proportion of patients.