Salivary gland 18F-FDG-PET/CT uptake patterns in Sjögren's syndrome and giant cell arteritis patients.

OBJECTIVES: Wide variety in salivary gland 18F-FDG-uptake is observed in the general population. A general consensus about the usefulness of 18F-FDG-PET/CT to detect salivary gland inflammatory conditions, such as in primary Sjögren's syndrome (pSS), is not yet clear. This study aimed to investigate whether there are differences in uptake of 18F-FDG in salivary glands among two autoimmune groups [pSS, giant cell arteritis (GCA)] and a non-autoimmune group (lung cancer). METHODS: PSS patients aged ≥50 years who underwent 18F-FDG-PET/CT were included and age-matched with GCA patients and a non-autoimmune control group (lung cancer patients). Scans were visually evaluated and quantitative analysis was performed by measuring standardised uptake values (SUV) within salivary glands and lacrimal glands. For GCA patients, arteries in the vicinity of the parotid and submandibular gland were assessed for positivity. RESULTS: PSS patients did not show increased 18F-FDG-uptake in the parotid or submandibular gland, compared to the other two groups. For the tubarial gland, significantly higher SUVmax was found in the pSS patient group. Interestingly, GCA patients had significantly higher SUVmax in the submandibular gland than the other two groups. Visual 18F-FDG-positivity of cranial arteries related to the parotid and submandibular glands was associated with significantly higher SUVmax in salivary glands of GCA patients. CONCLUSIONS: Although 18F-FDG-uptake was not increased in parotid and submandibular glands of pSS patients, increased 18F-FDG-uptake in tubarial glands of pSS patients might indicate a role for these glands in pSS. Furthermore, parotid and submandibular glands may be affected by local vasculitis in GCA.

Randomised phase 3 study of adjuvant chemotherapy with or without nadroparin in patients with completely resected non-small-cell lung cancer: the NVALT-8 study.

BACKGROUND: Retrospective studies suggest that low molecular weight heparin may delay the development of metastasis in patients with resected NSCLC. METHODS: Multicentre phase 3 study with patients with completely resected NSCLC who were randomised after surgery to receive chemotherapy with or without nadroparin. The main exclusion criteria were R1/2 and wedge/segmental resection. FDG-PET was required. The primary endpoint was recurrence-free survival (RFS). RESULTS: Among 235 registered patients, 202 were randomised (nadroparin: n = 100; control n = 102). Slow accrual enabled a decrease in the number of patients needed from 600 to 202, providing 80% power to compare RFS with 94 events (α = 0.05; 2-sided). There were no differences in bleeding events between the two groups. The median RFS was 65.2 months (95% CI, 36-NA) in the nadroparin arm and 37.7 months (95% CI, 22.7-NA) in the control arm (HR 0.77 (95% CI, 0.53-1.13, P = 0.19). FDG-PET SUVmax ≥10 predicted a greater likelihood of recurrence in the first year (HR 0.48, 95% CI 0.22-0.9, P = 0.05). CONCLUSIONS: Adjuvant nadroparin did not improve RFS in patients with resected NSCLC. In this study, a high SUVmax predicted a greater likelihood of recurrence in the first year. CLINICAL TRIAL REGISTRATION: Netherlands Trial registry: NTR1250/1217.

External validation of NTCP-models for radiation pneumonitis in lung cancer patients treated with chemoradiotherapy.

PURPOSE: Normal tissue complication probability (NTCP) models can be used to estimate the risk of radiation pneumonitis (RP). The aim of this study was to externally validate the most frequently used prediction models for RP, i.e., the QUANTEC and APPELT models, in a large cohort of lung cancer patients treated with IMRT or VMAT. [1-2] METHODS AND MATERIALS: This prospective cohort study, included lung cancer patients treated between 2013 and 2018. A closed testing procedure was performed to test the need for model updating. To improve model performance, modification or removal of variables was considered. Performance measures included tests for goodness of fit, discrimination, and calibration. RESULTS: In this cohort of 612 patients, the incidence of RP ≥ grade 2 was 14.5%. For the QUANTEC-model, recalibration was recommended which resulted in a revised intercept and adjusted regression coefficient (from 0.126 to 0.224) of the mean lung dose (MLD),. The APPELT-model needed revision including model updating with modification and elimination of variables. After revision, the New RP-model included the following predictors (and regression coefficients): MLD (B = 0.250), age (B = 0.049, and smoking status (B = 0.902). The discrimination of the updated APPELT-model was higher compared to the recalibrated QUANTEC-model (AUC: 0.79 vs. 0.73). CONCLUSIONS: This study demonstrated that both the QUANTEC- and APPELT-model needed revision. Next to changes of the intercept and regression coefficients, the APPELT model improved further by model updating and performed better than the recalibrated QUANTEC model. This New RP-model is widely applicable containing non-tumour site specific variables, which can easily be collected.

Randomized Phase III Trial of Erlotinib versus Docetaxel in Patients with Advanced Squamous Cell Non-Small Cell Lung Cancer Failing First-Line Platinum-Based Doublet Chemotherapy Stratified by VeriStrat Good versus VeriStrat Poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial.

INTRODUCTION: Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial. METHODS: EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second-line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC. RESULTS: A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events. CONCLUSIONS: The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study).

An instrument dedicated for modelling of pulmonary radiotherapy.

BACKGROUND AND PURPOSE: Radiotherapy plays a pivotal role in lung cancer treatment. Selection of patients for new (radio)therapeutic options aiming at improving outcomes requires reliable and validated prediction models. We present the implementation of a prospective platform for evaluation and development of lung radiotherapy (proPED-LUNG) as an instrument enabling multidimensional predictive modelling. MATERIALS AND METHODS: ProPED-LUNG was designed to comprise relevant baseline and follow up data of patients receiving pulmonary radiotherapy with curative intent. Patient characteristics, diagnostic and staging information, treatment parameters including full dose-volume-histograms, tumour control, survival, and toxicity are scored. Besides physician-rated data, a range of patient-rated data regarding symptoms and health-related quality-of-life are collected. RESULTS: After 18 months of accrual, 315 patients have been included (accrual rate, 18 per month). Of the first hundred patients included, 70 received conformal (chemo)radiotherapy and 30 underwent stereotactic radiotherapy. Compliance at 3 and 6 months follow-up was 96-100% for patient-rated, and 81-94% for physician-rated assessments. For data collection, 0.4 FTE were allocated in a 183 FTE department (0.2%). CONCLUSIONS: ProPED-LUNG is feasible with high compliance rates and yields a large amount of high quality prospective disease-related, treatment-related, patient- and physician-rated data which can be used to evaluate new developments in pulmonary radiotherapy.

PET for the evaluation of pleural thickening observed on CT.

UNLABELLED: Early discrimination between benign and malignant pleural diseases is vital for the treatment and prognosis of a patient. Imaging is traditionally performed with CT or MRI, with an accuracy of 50%-75%. PET has proven to be superior as a diagnostic tool in several malignancies. In this prospective study, PET results in patients with pleural abnormalities on CT were compared with histologic results. METHODS: Eligible patients had pleural thickening on CT and were medically fit for surgical diagnostic procedures. All patients underwent PET. Qualitative assessment led to a PET score of 1 (definitely normal), 2 (probably normal), 3 (probably abnormal), or 4 (definitely abnormal). PET scores of 1 or 2 indicated a negative PET finding, whereas PET scores of 3 or 4 indicated a positive PET finding. Pathologic verification techniques included thoracocentesis, thoracoscopy, or open pleural biopsy at thoracotomy. RESULTS: Thirty-two patients were enrolled, 19 with malignant and 13 with benign pleural disease. PET was true positive in 18 and true negative in 12 patients, with an accuracy and negative predictive value of 94% and 92%, respectively. PET was false negative in a patient with a slowly growing malignant solitary fibrous tumor and false positive in a patient with infectious pleuritis. Median standardized uptake values calculated for 7 patients with malignant and benign pleural diseases were 6.28 and 1.69, respectively. Patients with a PET score of 1 or 2 survived significantly longer than patients with a PET score of 3 or 4. CONCLUSION: Qualitative assessment of pleural thickening with PET accurately discriminates between malignant and benign pleural thickening, with a high accuracy and negative predictive value.

Comparison of (11)C-choline and (18)F-FDG PET in primary diagnosis and staging of patients with thoracic cancer.

UNLABELLED: PET with (18)F-FDG is used for detection and staging of thoracic cancer; however, more specific PET radiopharmaceuticals would be welcome. (11)C-labeled choline (CHOL) is a new radiopharmaceutical potentially useful for tumor imaging, since it is incorporated into cell membranes as phosphatidylcholine. The aim of this study was to investigate whether (11)C-CHOL PET has advantages over (18)F-FDG PET in patients with thoracic cancer. METHODS: We evaluated 17 patients with thoracic cancer both with (11)C-CHOL PET and (18)F-FDG PET. After transmission scanning, (11)C-CHOL was injected intravenously, and whole-body scanning was started after 5 min. Immediately thereafter, (18)F-FDG was injected intravenously, followed after 90 min by interleaved attenuation-corrected whole-body scanning. Scans were performed from crown to femur. Visual and quantitative (standardized uptake value) analyses of (11)C-CHOL PET and (18)F-FDG PET were performed and compared with results of traditional staging and follow-up. RESULTS: The most prominent features of normal (11)C-CHOL distribution were high uptake in liver, renal cortex, and salivary glands. Except for some uptake in choroid plexus and pituitary gland, brain uptake was negligible. All primary thoracic tumors were detected with (11)C-CHOL PET and (18)F-FDG PET. Both (11)C-CHOL PET and (18)F-FDG PET correctly identified all 16 patients with lymph node involvement. However, in a lesion-to-lesion analysis, (11)C-CHOL PET detected only 29 of 43 metastatic lymph nodes, whereas (18)F-FDG PET detected 41 of 43. (11)C-CHOL PET detected fewer intrapulmonary and pleural metastases than (18)F-FDG PET (27/47 vs. 46/47). More brain metastases were detected with (11)C-CHOL PET (23/23) than with (18)F-FDG PET (3/23). For primary tumors, the median (range) standard uptake values of (11)C-CHOL and (18)F-FDG were 1.68 (0.98-3.22) and 4.22 (1.40-8.26), respectively (P = 0.001). CONCLUSION: (11)C-CHOL PET can be used to visualize thoracic cancers. Although detection of lymph node metastases with (11)C-CHOL PET was inferior compared with (18)F-FDG PET, the detection of brain metastases was superior.

Concurrent gemcitabine and 3D radiotherapy in patients with stage III unresectable non-small cell lung cancer.

BACKGROUND: Stage III unresectable non-small cell lung cancer (NSCLC) is preferably treated with concurrent schedules of chemoradiotherapy, but none is clearly superior Gemcitabine is a radiosensitizing cytotoxic drug that has been studied in phase 1 and 2 studies in this setting. The aim of this study was to describe outcome and toxicity of low-dose weekly gemcitabine combined with concurrent 3-dimensional conformal radiotherapy (3D-CRT). PATIENTS & METHODS: Treatment consisted of two cycles of a cisplatin and gemcitabine followed by weekly gemcitabine 300 mg/m2 during 5 weeks of 3D-CRT, 60 Gy in 5 weeks (hypofractionated-accelerated). Overall survival (OS), progression-free survival (PFS), and treatment related toxicity according to Common Toxicity Criteria of Adverse Events (CTCAE) version 3.0 were assessed. RESULTS: Between February 2002 and August 2008, 318 patients were treated. Median age was 64 years (range 36-86); 72% were male, WHO PS 0/1/2 was 44/53/3%. Median PFS was 15.5 months (95% confidence interval [CI], 12.9-18.1) and median OS was 24.6 months (95% CI., 21.0-28.1). Main toxicity (CTCAE grade ≥3) was dysphagia (12.6%), esophagitis (9.6%), followed by radiation pneumonitis (3.0%). There were five treatment related deaths (1.6%), two due to esophagitis and three due to radiation pneumonitis. CONCLUSION: Concurrent low-dose gemcitabine and 3D-CRT provides a comparable survival and toxicity profile to other available treatment schemes for unresectable stage III.

Common and rare EGFR and KRAS mutations in a Dutch non-small-cell lung cancer population and their clinical outcome.

INTRODUCTION: In randomly assigned studies with EGFR TKI only a minor proportion of patients with NSCLC have genetically profiled biopsies. Guidelines provide evidence to perform EGFR and KRAS mutation analysis in non-squamous NSCLC. We explored tumor biopsy quality offered for mutation testing, different mutations distribution, and outcome with EGFR TKI. PATIENT AND METHODS: Clinical data from 8 regional hospitals were studied for patient and tumor characteristics, treatment and overall survival. Biopsies sent to the central laboratory were evaluated for DNA quality and subsequently analyzed for mutations in exons 18-21 of EGFR and exon 2 of KRAS by bidirectional sequence analysis. RESULTS: Tumors from 442 subsequent patients were analyzed. For 74 patients (17%) tumors were unsuitable for mutation analysis. Thirty-eight patients (10.9%) had EGFR mutations with 79% known activating mutations. One hundred eight patients (30%) had functional KRAS mutations. The mutation spectrum was comparable to the Cosmic database. Following treatment in the first or second line with EGFR TKI median overall survival for patients with EGFR (n = 14), KRAS (n = 14) mutations and wild type EGFR/KRAS (n = 31) was not reached, 20 and 9 months, respectively. CONCLUSION: One out of every 6 tumor samples was inadequate for mutation analysis. Patients with EGFR activating mutations treated with EGFR-TKI have the longest survival.

Visualisation and assessment of the protein synthesis rate of lung cancer using carbon-11 tyrosine and positron emission tomography.

This study evaluated the potential role of L-(1-(11)C)-tyrosine positron emission tomography (TYR PET) for visualisation and quantification of protein metabolism in lung cancer. Dynamic TYR PET scans of the thorax were performed in 17 patients with lung cancer. Protein synthesis rate (PSR in micromol/min x l) and standardised uptake value (SUV, corrected for body measurements) of tumour tissue and contralateral normal tissue were calculated before and after chemotherapy or radiotherapy. All tumours [11 non-small cell lung carcinomas (NSCLCs), five small cell lung carcinomas (SCLCs), and one pleural mesothelioma] were visualised as a hot spot. The median PSR in tumour tissue was higher than that in corresponding contralateral normal lung tissue before [1.88 micromol/min x l (range 1.10-3.42) vs 0.40 micromol/min x l (range 0.12-0.86); P=0.003] and after treatment [1.33 micromol/min x l (range 0.45-2.21) vs 0.28 micromol/min x l (range 0.18-0.51); P<0.02]. In contrast to PSR of normal lung tissue, PSR of tumour tissue decreased significantly after therapy (P=0.03). Before therapy, no significant difference in PSR between NSCLCs and SCLCs was observed, but after therapy the PSR differed significantly between the subgroups [1.69 micromol/min x l (range 0.63-2.78) for NSCLC vs 0.67 micromol/min x l (range 0.45-0.92) for SCLC; P=0.03], irrespective of the treatment modality. The median SUV of tumour tissue was higher than that in corresponding contralateral normal lung both before and after therapy. Only a weak correlation between PSR and SUV was found when the latter was corrected for body surface area or lean body mass. Carbon-11 labelled tyrosine appears to be a good tracer for visualising lung cancer. PSR of tumour tissue can be used to quantify reduction in the metabolic rate of the tumour. Future studies need to be performed to determine whether TYR PET will supply additional clinical information with treatment implications in patients with lung cancer.

Quantification of beta-adrenoceptor density in the human heart with (S)-[11C]CGP 12388 and a tracer kinetic model.

The aim of this study was to determine whether the beta-adrenoceptor receptor density (Bmax) and the ligand affinity (KD) of (S)-[11C]CGP 12388 for the beta-adrenoceptor receptor could be determined using full tracer kinetic modelling of the transport of the ligand and its interaction with the receptor. This approach minimises the a priori assumptions and may thus serve as a gold standard to validate other simplified methods. Dynamic positron emission tomography (PET) data were acquired in six healthy subjects during 60 min. Three different injection protocols were applied, each consisting of three injections with varying SAs: high specific activity (SA), low SA or unlabelled ligand only. Arterial blood samples were collected via a cannula in the radial artery. Time-activity data in myocardial tissue were obtained using regions of interest (ROIs) on short-axis planes. All data were analysed with a two-tissue compartment, six-parameter (K1, k2, k(on), k(off), Bmax, F(bv)) model that relies on explicit compartments for describing the kinetics of both labelled and unlabelled radioligand. Time-activity curves showed that unlabelled ligand could displace the radioligand from the receptor. This resulted in increased radioactivity levels in plasma. Modelling results yielded Bmax values of 9.74+/-1.80 nM and a KD of 0.58+/-0.22 nM, assuming a reaction volume of 0.15. In addition, parametric polar images of Bmax could be calculated. The protocol with injections of high SA, low SA, and unlabelled ligand, respectively, was found to be the most sensitive to parameter changes. We conclude that with tracer kinetic modelling of (S)-[11C]CGP 12388, the beta-adrenoceptor density in the human heart can accurately be obtained in vivo. This approach may thus serve as a gold standard.