[en] Standardized uptake values (SUV) are commonly used for quantification of whole-body [¹⁸F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies. Changes in SUV following therapy, however, only provide a proper measure of response in case of homogeneous FDG uptake in the tumour. The purpose of this study was therefore to implement and characterize a method that enables quantification of heterogeneity in tumour FDG uptake. Cumulative SUV-volume histograms (CSH), describing % of total tumour volume above % threshold of maximum SUV (SUV_max), were calculated. The area under a CSH curve (AUC) is a quantitative index of tumour uptake heterogeneity, with lower AUC corresponding to higher degrees of heterogeneity. Simulations of homogeneous and heterogeneous responses were performed to assess the value of AUC-CSH for measuring uptake and/or response heterogeneity. In addition, partial volume correction and image denoising was applied prior to calculating AUC-CSH. Finally, the method was applied to a number of human FDG scans. Partial volume correction and noise reduction improved CSH curves. Both simulations and clinical examples showed that AUC-CSH values corresponded with level of tumour heterogeneity and/or heterogeneity in response. In contrast, this correspondence was not seen with SUV_max alone. The results indicate that the main advantage of AUC-CSH above other measures, such as 1/COV (coefficient of variation), is the possibility to measure or normalize AUC-CSH in different ways. AUC-CSH might be used as a quantitative index of heterogeneity in tracer uptake. In response monitoring studies it can be used to address heterogeneity in response. (orig.)

[en] Purpose: Erlotinib has shown activity in patients with brain metastases from non-small-cell lung cancer. The present dose-escalation Phase I trial evaluated the toxicity of whole brain radiotherapy (WBRT) with concurrent and maintenance erlotinib in this patient group. Methods and Materials: Erlotinib (Cohort 1, 100 mg/d; Cohort 2, 150 mg/d) was started 1 week before, and continued during, WBRT (30 Gy in 10 fractions). Maintenance erlotinib (150 mg/d) was continued until unacceptable toxicity or disease progression. Results: A total of 11 patients completed WBRT, 4 in Cohort 1 and 7 in Cohort 2. The median duration of erlotinib treatment was 83 days. No treatment-related neurotoxicity was observed. No treatment-related Grade 3 or greater toxicity occurred in Cohort 1. In Cohort 2, 1 patient developed a Grade 3 acneiform rash and 1 patient had Grade 3 fatigue. Two patients in Cohort 2 developed erlotinib-related interstitial lung disease, contributing to death during maintenance therapy. The median overall survival and interval to progression was 133 and 141 days, respectively. Six patients developed extracranial progression; only 1 patient had intracranial progression. In 7 patients with follow-up neuroimaging at 3 months, 5 had a partial response and 2 had stable disease. Conclusion: WBRT with concurrent erlotinib is well tolerated in patients with brain metastases from non-small-cell lung cancer. The suggestion of a high intracranial disease control rate warrants additional study.

[en] Purpose: High local control rates can be achieved using stereotactic radiotherapy in Stage I non-small-cell lung cancer (NSCLC), but reports have suggested that toxicity may be of concern. We evaluated early clinical outcomes of 'risk-adapted' fractionation schemes in patients treated in a single institution. Methods and Materials: Of 206 patients with Stage I NSCLC, 81% were unfit to undergo surgery and the rest refused surgery. Pathologic confirmation of malignancy was obtained in 31% of patients. All other patients had new or growing 18F-fluorodeoxyglucose positron emission tomography positive lesions with radiologic characteristics of malignancy. Planning four-dimensional computed tomography scans were performed and fractionation schemes used (3 x 20 Gy, 5 x 12 Gy, and 8 x 7.5 Gy) were determined by T stage and risk of normal tissue toxicity. Results: Median overall survival was 34 months, with 1- and 2-year survivals of 81% and 64%, respectively. Disease-free survival (DFS) at 1 and 2 years was 83% and 68%, respectively, and DFS correlated with T stage (p = 0.002). Local failure was observed in 7 patients (3%). The crude regional failure rate was 9%; isolated regional recurrence was observed in 4%. The distant progression-free survival at 1 and 2 years was 85% and 77%, respectively. SRT was well tolerated and severe late toxicity was observed in less than 3% of patients. Conclusions: SRT is well tolerated in patients with extensive comorbidity with high local control rates and minimal toxicity. Early outcomes are not inferior to those reported for conventional radiotherapy. In view of patient convenience, such risk-adapted SRT schedules should be considered treatment of choice in patients presenting with medically inoperable Stage I NSCLC

[en] Background and purpose: Multiple primary lung cancers (MPLC) are not an uncommon presentation. Current guidelines recommend a curative approach when early-stage MPLC is diagnosed as favorable outcomes have been reported after surgery. We studied outcomes following stereotactic ablative radiotherapy (SABR). Materials and methods: Following review of imaging and pathology at a multi-disciplinary tumor board, a total of 62 patients were referred for SABR with a diagnosis of synchronous MPLC. SABR was performed for both lesions in 56 patients, while another 6 underwent SABR for only one lesion and surgery for the other lesion. A total dose of 54–60 Gy was delivered in 3–8 fractions. Results: Median follow-up was 44 months (95% CI: 29–59). Overall survival of all patients was 31 months (95% CI: 17–44), with an actuarial 2-year survival of 56%. No grade 4 or 5 post-SABR toxicity was observed. Local control rates calculated per lesion, were 84% at 2 years, and 78% at 3 years. The two-year actuarial regional control rate was 87%. Conclusions: SABR for synchronous MPLC achieves a lesion control rate of 84% after 2 years, with limited toxicity. SABR should be considered when patients with lung cancer present with a synchronous second lesion and no nodal involvement

[en] Imaging with positron emission tomography (PET) using ¹⁸F-2-fluoro-2-deoxy-D-glucose (FDG) plays an increasingly important role for response assessment in oncology. Several methods for quantifying FDG PET results exist. The goal of this study was to analyse and compare various semi-quantitative measures for response assessment with full kinetic analysis, specifically in assessment of novel therapies. Baseline and response dynamic FDG studies from two different longitudinal studies (study A: seven subjects with lung cancer and study B: six subjects with gastrointestinal cancer) with targeted therapies were reviewed. Quantification of tumour uptake included full kinetic methods, i.e. nonlinear regression (NLR) and Patlak analyses, and simplified measures such as the simplified kinetic method (SKM) and standardized uptake value (SUV). An image-derived input function was used for NLR and Patlak analysis. There were 18 and 9 lesions defined for two response monitoring studies (A and B). In all cases there was excellent correlation between Patlak- and NLR-derived response (R ² > 0.96). Percentage changes seen with SUV were significantly different from those seen with Patlak for both studies (p < 0.05). After correcting SUV for plasma glucose, SUV and Patlak responses became similar for study A, but large differences remained for study B. Further analysis revealed that differences in responses amongst methods in study B were primarily due to changes in the arterial input functions. Use of simplified methods for assessment of drug efficacy or treatment response may provide different results than those seen with full kinetic analysis. (orig.)

[en] Background: Approximately two-thirds of patients with early-stage non-small-cell lung cancer (NSCLC) in The Netherlands currently undergo surgical resection. As an increasing number of fit patients have elected to undergo stereotactic ablative radiotherapy (SABR) in recent years, we studied outcomes after SABR in patients with potentially operable stage I NSCLC. Methods and Materials: In an institutional prospective database collected since 2003, 25% of lung SABR cases (n = 177 patients) were found to be potentially operable when the following patients were excluded: those with (1) synchronous lung tumors or other malignancy, (2) prior high-dose radiotherapy/pneumonectomy, (3) chronic obstructive pulmonary disease with a severity score of 3-4 according to the Global initiative for Obstructive Lung Disease classification. (4) a performance score of ≥3, and (5) other comorbidity precluding surgery. Study patients included 101 males and 76 females, with a median age of 76 years old, 60% of whom were staged as T1 and 40% of whom were T2. Median Charlson comorbidity score was 2 (range, 0–5). A SABR dose of 60 Gy was delivered using a risk-adapted scheme in 3, 5, or 8 fractions, depending on tumor size and location. Follow-up chest computed tomography scans were obtained at 3, 6, and 12 months and yearly thereafter. Results: Median follow-up was 31.5 months; and median overall survival (OS) was 61.5 months, with 1- and 3-year survival rates of 94.7% and 84.7%, respectively. OS rates at 3 years in patients with (n = 59) and without (n = 118) histological diagnosis did not differ significantly (96% versus 81%, respectively, p = 0.39). Post-SABR 30-day mortality was 0%, while predicted 30-day mortality for a lobectomy, derived using the Thoracoscore predictive model (Falcoz PE et al. J Thorac Cardiovasc Surg 2007;133:325–332), would have been 2.6%. Local control rates at 1 and 3 years were 98% and 93%, respectively. Regional and distant failure rates at 3 years were each 9.7%. Toxicity was mild, with grade ≥3 radiation pneumonitis and rib fractures in 2% and 3%, respectively. Conclusions: Patients with potentially operable disease who underwent primary SABR had a median OS that exceeded 5 years. This finding supports ongoing randomized clinical trials comparing surgery and SABR in cases of operable stage I NSCLC.

[en] We investigated the feasibility of serial dynamic contrast-enhanced computed tomography (DCE-CT) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) receiving anti-angiogenic (sorafenib) and anti-EGFR (erlotinib) treatment, and correlated tumour blood flow (BF) with treatment outcome. DCE-CTs were performed at baseline and 3 and 6 weeks after starting treatment. Tumour BF, calculated with the maximum slope method, and percentage change were measured in 23 patients (14 male; median age 59 years). Tumour BF was compared at baseline and weeks 3 and 6; the relation with RECIST/Crabb response and progression-free survival (PFS) was assessed. Mean tumour perfusion decreased from 39.2 ml/100 g/min at baseline to 15.1 ml/100 g/min at week 3 (p < 0.001) and 9.4 ml/100 g/min at week 6 (p < 0.001). Tumour perfusion was lower in RECIST and Crabb responders versus non-responders at week 3 (4.2 versus 17.7 ml/100 g/min, p = 0.03) and week 6 (0 versus 13.4 ml/100 g/min, p = 0.04). Patients with a decrease larger than the median at week 6 tended to have a longer PFS (7.1 versus 5.7 months, p = 0.06). Serial DCE-CTs are feasible in patients with NSCLC and demonstrated a significant decrease in tumour BF following sorafenib/erlotinib therapy. Early changes in tumour BF correlated with objective response and showed a trend towards longer PFS. (orig.)

[en] Solitary pulmonary nodule (SPN, intraparenchymal lung mass <3 cm) is often a diagnostic challenge. This study was performed to evaluate the diagnostic accuracy of¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET) in radiologically indeterminate SPN ≤10 mm on spiral CT. Between August 1997 and March 2001, we identified all patients with radiologically indeterminate SPNs ≤10 mm who were referred for FDG PET imaging at the VU University Medical Centre. All PET scans were retrospectively reviewed by an experienced nuclear medicine physician. PET was considered positive in cases with at least moderately enhanced focal uptake, and otherwise as negative. Lesions were considered benign on the basis of histology, no growth during 1.5 years or disappearance within at least 6 months. Thirty-five patients with 36 SPNs ≤10 mm in diameter at clinical presentation were identified (one patient had two metachronous lesions). In 13 of 14 malignant nodules and in two of 22 benign nodules, diagnosis was confirmed by histology. Prevalence of malignancy was 39%. PET imaging correctly identified 30 of 36 small lesions. One lesion proved to be false negative on PET (CT: 10 mm), and in five lesions, PET scans proved to be false positive. Specificity was 77% (17/22; 95% CI: 0.55-0.92), sensitivity 93% (13/14; 95% CI: 0.66-1.0), positive predictive value 72% (13/18; 95% CI: 0.46-0.90) and negative predictive value 94% (17/18; 95% CI: 0.73-1.0). This retrospective study suggests that FDG PET imaging could be a useful tool in differentiating benign from malignant SPNs ≤10 mm in diameter at clinical presentation. Such results may help in the design of larger prospective trials with structured clinical work-up. (orig.)

[en] Positron emission tomography (PET) using ¹⁸F-3'-deoxy-3'-fluorothymidine ([¹⁸F]FLT) allows noninvasive monitoring of tumour proliferation. For serial imaging in individual patients, good reproducibility is essential. The purpose of the present study was to evaluate the reproducibility of quantitative [¹⁸F]FLT measurements. Nine patients with non-small-cell lung cancer (NSCLC) and six with head-and-neck cancer (HNC) underwent [¹⁸F]FLT PET twice within 7 days prior to therapy. The maximum pixel value (SUV_max) and a threshold defined volume (SUV_41%) were defined for all delineated lesions. The plasma to tumour transfer constant (K_i) was estimated using both Patlak graphical analysis and nonlinear regression (NLR). NLR was also used to estimate k₃, which, at least in theory, selectively reflects thymidine kinase 1 activity. The level of agreement between test and retest values was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. All primary tumours and >90% of clinically suspected locoregional metastases could be delineated. In total, 24 lesions were defined. NLR-derived K_i, Patlak-derived K_i, SUV_41% and SUV_max showed excellent reproducibility with ICCs of 0.92, 0.95, 0.98 and 0.93, and SDs of 16%, 12%, 7% and 11%, respectively. Reproducibility was poor for k₃ with an ICC of 0.43 and SD of 38%. Quantitative [¹⁸F]FLT measurements are reproducible in both NSCLC and HNC patients. When monitoring response in individual patients, changes of more than 15% in SUV_41%, 20-25% in SUV_max and Patlak-derived K_i, and 32% in NLR3k-derived K_i are likely to represent treatment effects. (orig.)

[en] Docetaxel is an important chemotherapeutic agent used for the treatment of several cancer types. As radiolabelled anticancer agents provide a potential means for personalized treatment planning, docetaxel was labelled with the positron emitter ¹¹C. Non-invasive measurements of [¹¹C]docetaxel uptake in organs and tumours may provide additional information on pharmacokinetics and pharmacodynamics of the drug docetaxel. The purpose of the present study was to determine the biodistribution and radiation absorbed dose of [¹¹C]docetaxel in humans. Biodistribution of [¹¹C]docetaxel was measured in seven patients (five men and two women) with solid tumours using PET/CT. Venous blood samples were collected to measure activity in blood and plasma. Regions of interest (ROI) for various source organs were defined on PET (high [¹¹C]docetaxel uptake) or CT (low [¹¹C]docetaxel uptake). ROI data were used to generate time-activity curves and to calculate percentage injected dose and residence times. Radiation absorbed doses were calculated according to the MIRD method using OLINDA/EXM 1.0 software. Gall bladder and liver demonstrated high [¹¹C]docetaxel uptake, whilst uptake in brain and normal lung was low. The percentage injected dose at 1 h in the liver was 47 ± 9%. [¹¹C]docetaxel was rapidly cleared from plasma and no radiolabelled metabolites were detected. [¹¹C]docetaxel uptake in tumours was moderate and highly variable between tumours. The effective dose of [¹¹C]docetaxel was 4.7 μSv/MBq. As uptake in normal lung is low, [¹¹C]docetaxel may be a promising tracer for tumours in the thoracic region. (orig.)