Visually guided inspiration breath-hold facilitated with nasal high flow therapy in locally advanced lung cancer.

BACKGROUND AND PURPOSE: Reducing breathing motion in radiotherapy (RT) is an attractive strategy to reduce margins and better spare normal tissues. The objective of this prospective study (NCT03729661) was to investigate the feasibility of irradiation of non-small cell lung cancer (NSCLC) with visually guided moderate deep inspiration breath-hold (IBH) using nasal high-flow therapy (NHFT). MATERIAL AND METHODS: Locally advanced NSCLC patients undergoing photon RT were given NHFT with heated humidified air (flow: 40 L/min with 80% oxygen) through a nasal cannula. IBH was monitored by optical surface tracking (OST) with visual feedback. At a training session, patients had to hold their breath as long as possible, without and with NHFT. For the daily cone beam CT (CBCT) and RT treatment in IBH, patients were instructed to keep their BH as long as it felt comfortable. OST was used to analyze stability and reproducibility of the BH, and CBCT to analyze daily tumor position. Subjective tolerance was measured with a questionnaire at 3 time points. RESULTS: Of 10 included patients, 9 were treated with RT. Seven (78%) completed the treatment with NHFT as planned. At the training session, the mean BH length without NHFT was 39 s (range 15-86 s), and with NHFT 78 s (range 29-223 s) (p = .005). NHFT prolonged the BH duration by a mean factor of 2.1 (range 1.1-3.9s). The mean overall stability and reproducibility were within 1 mm. Subjective tolerance was very good with the majority of patients having no or minor discomfort caused by the devices. The mean inter-fraction tumor position variability was 1.8 mm (-1.1-8.1 mm;SD 2.4 mm). CONCLUSION: NHFT for RT treatment of NSCLC in BH is feasible, well tolerated and significantly increases the breath-hold duration. Visually guided BH with OST is stable and reproducible. We therefore consider this an attractive patient-friendly approach to treat lung cancer patients with RT in BH.

The potential of an optical surface tracking system in non-coplanar single isocenter treatments of multiple brain metastases.

To evaluate the accuracy of a commercial optical surface tracking (OST) system and to demonstrate how it can be implemented to monitor patient positioning during non-coplanar single isocenter stereotactic treatments of brain metastases. A 3-camera OST system was used (Catalyst HD™, C-RAD) on a TruebeamSTx with a 6DoF couch. The setup accuracy and agreement between the OST system, and CBCT and kV-MV imaging at couch angles 0° and 270°, respectively, were examined. Film measurements at 3 depths in the Rando-Alderson phantom were performed using a single isocenter non-coplanar VMAT plan containing 4 brain lesions. Setup of the phantom was performed with CBCT at couch 0° and subsequently monitored by OST at other couch angles. Setup data for 7 volunteers were collected to evaluate the accuracy and reproducibility of the OST system at couch angles 0°, 45°, 90°, 315°, and 270°. These results were also correlated to the couch rotation offsets obtained by a Winston-Lutz (WL) test. The Rando-Alderson phantom, as well as volunteers, were fixated using open face masks (Orfit). For repeated tests with the Rando-Alderson phantom, deviations between rotational and translational isocenter corrections for CBCT and OST systems are always within 0.2° (pitch, roll, yaw), and 0.1mm and 0.5mm (longitudinal, lateral, vertical) for couch positions 0° and 270°, respectively. Dose deviations between the film and TPS doses in the center of the 4 lesions were -1.2%, -0.1%, -0.0%, and -1.9%. Local gamma evaluation criteria of 2%/2 mm and 3%/1 mm yielded pass rates of 99.2%, 99.2%, 98.6%, 89.9% and 98.8%, 97.5%, 81.7%, 78.1% for the 4 lesions. Regarding the volunteers, the mean translational and rotational isocenter shift values were (0.24 ± 0.09) mm and (0.15 ± 0.07) degrees. Largest isocenter shifts were found for couch angles 45˚ and 90˚, confirmed by WL couch rotation offsets. Patient monitoring during non-coplanar VMAT treatments of brain metastases is feasible with submillimeter accuracy.

Influence of the jaw tracking technique on the dose calculation accuracy of small field VMAT plans.

PURPOSE: The aim of this study was to evaluate experimentally the accuracy of the dose calculation algorithm AcurosXB in small field highly modulated Volumetric Modulated Arc Therapy (VMAT). METHOD: The 1000SRS detector array inserted in the rotational Octavius 4D phantom (PTW) was used for 3D dose verification of VMAT treatments characterized by small to very small targets. Clinical treatment plans (n = 28) were recalculated on the phantom CT data set in the Eclipse TPS. All measurements were done on a Varian TrueBeamSTx, which can provide the jaw tracking technique (JTT). The effect of disabling the JTT, thereby fixing the jaws at static field size of 3 × 3 cm2 and applying the MLC to shape the smallest apertures, was investigated for static fields between 0.5 × 0.5-3 × 3 cm2 and for seven VMAT patients with small brain metastases. The dose calculation accuracy has been evaluated by comparing the measured and calculated dose outputs and dose distributions. The dosimetric agreement has been presented by a local gamma evaluation criterion of 2%/2 mm. RESULTS: Regarding the clinical plans, the mean ± SD of the volumetric gamma evaluation scores considering the dose levels for evaluation of 10%, 50%, 80% and 95% are (96.0 ± 6.9)%, (95.2 ± 6.8)%, (86.7 ± 14.8)% and (56.3 ± 42.3)% respectively. For the smallest field VMAT treatments, discrepancies between calculated and measured doses up to 16% are obtained. The difference between the 1000SRS central chamber measurements compared to the calculated dose outputs for static fields 3 × 3, 2 × 2, 1 × 1 and 0.5 × 0.5 cm2 collimated with MLC whereby jaws are fixed at 3 × 3 cm2 and for static fields shaped with the collimator jaws only (MLC retracted), is on average respectively, 0.2%, 0.8%, 6.8%, 5.7% (6 MV) and 0.1%, 1.3%, 11.7%, 21.6% (10 MV). For the seven brain mets patients was found that the smaller the target volumes, the higher the improvement in agreement between measured and calculated doses after disabling the JTT. CONCLUSION: Fixing the jaws at 3 × 3 cm2 and using the MLC with high positional accuracy to shape the smallest apertures in contrast to the JTT is currently found to be the most accurate treatment technique.

Evaluation of tumour hypoxia during radiotherapy using [18F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer.

BACKGROUND AND PURPOSE: Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [18F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence. MATERIAL AND METHODS: [18F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [18F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed. RESULTS: At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7 ± 19.8 % (baseline) to 3.6 ± 10.0 % (during treatment; P < 0.001). Only two patients had a HV > 1 cm3 during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased. CONCLUSIONS: [18F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia.

Quantification of CT-assessed radiation-induced lung damage in lung cancer patients treated with or without chemotherapy and cetuximab.

BACKGROUND AND PURPOSE: Prediction models for radiation-induced lung damage (RILD) are still unsatisfactory, with clinical toxicity endpoints that are difficult to quantify objectively. We therefore evaluated RILD more objectively, quantitatively and on a continuous scale measuring the lung tissue density changes per voxel. MATERIAL AND METHODS: Patients treated with radiotherapy (RT) alone, sequential and concurrent chemo-RT with and without the addition of cetuximab were studied. Follow-up computed tomography (CT) scans were co-registered using deformable registration to baseline CT scans. CT density changes were correlated to the RT dose delivered in every part of the lungs. RESULTS: One hundred and seventeen lung cancer patients were included. Mean dose to tumor was 60 Gy (range 45-79.2 Gy). Dose response curves showed a linear increase in the dose region between 0 and 65 Gy having a slope (based on coefficients of the multilevel model) expressed as a lung density increase per dose of 0.86 (95% CI 0.73-0.99), 1.31 (95% CI 1.19-1.43), 1.39 (95% CI 1.28-1.50) and 2.07 (95% CI 1.93-2.21) for patients treated only with RT (N=19), sequential chemo-RT (N=30), concurrent chemo-RT (N=49), and concurrent chemo-RT with cetuximab (N=19), respectively. CONCLUSIONS: CT density changes allow quantitative assessment of lung damage after fractionated RT, giving complementary information to standard used clinical endpoints. Patients receiving cetuximab showed a significantly larger dose response compared with other treatments.

Imaging of tumour hypoxia and metabolism in patients with head and neck squamous cell carcinoma.

BACKGROUND: Tumour hypoxia and a high tumour metabolism increase radioresistance in patients with head and neck squamous cell carcinoma (HNSCC). The aim of this study was to evaluate the correlation between hypoxia ([(18)F]HX4 PET) and glucose metabolism ([(18)F]FDG PET) molecular imaging. MATERIAL AND METHODS: [(18)F]HX4 and [(18)F]FDG PET/CT images of 20 HNSCC patients were acquired prior to (chemo)radiotherapy, in an immobilisation mask, with a median time interval of seven days (NCT01347281). Gross tumour volumes of the primary lesions (GTVprim) and pathological lymph nodes (GTVln) were included in the analysis. [(18)F]FDG PET/CT images were rigidly registered to the [(18)F]HX4 PET/CT images. The maximum and mean standardised uptake values (SUVmax, SUVmean) within both GTVs were determined. In addition, the overlap was compared between the [(18)F]HX4 high volume ([(18)F]HX4 HV) with a tumour-to-muscle ratio > 1.4 and the [(18)F]FDG high volume ([(18)F]FDG HV) with an SUV > 50% of the SUVmax. We report the mean ± standard deviation. RESULTS: PET/CT scans including 20 GTVprim and 12 GTVln were analysed. There was a significant correlation between several [(18)F]FDG and [(18)F]HX4 parameters, the most pronounced being the correlation between [(18)F]FDG HV and [(18)F]HX4 HV (R = 0.93, p < 0.001). The fraction of the GTVprim with a high HX4 uptake (9 ± 10%) was on average smaller than the FDG high fraction (51 ± 26%; p < 0.001). In 65% (13/20) of the patients, the GTVprim was hypoxic. In four of these patients the [(18)F]HX4 HV was located within the [(18)F]FDG HV, whereas for the remaining nine GTVprim a partial mismatch was observed. In these nine tumours 25 ± 21% (range 5-64%) of the HX4 HV was located outside the FDG HV. CONCLUSIONS: There is a correlation between [(18)F]HX4 and [(18)F]FDG uptake parameters on a global tumour level. In the majority of lesions a partial mismatch between the [(18)F]HX4 and [(18)F]FDG high uptake volumes was observed, therefore [(18)F]FDG PET imaging cannot be used as a surrogate for hypoxia. [(18)F]HX4 PET provides complementary information to [(18)F]FDG PET imaging.

Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging.

Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [(18)F]HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [(18)F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 ± 0.926 and optimal imaging properties 4 h after injection. [(18)F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [(18)F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [(18)F]HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P < 0.001) in [(18)F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [(18)F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.

First clinical results of adaptive radiotherapy based on 3D portal dosimetry for lung cancer patients with atelectasis treated with volumetric-modulated arc therapy (VMAT).

UNLABELLED: Atelectasis in lung cancer patients can change rapidly during a treatment course, which may displace the tumor/healthy tissues, or change tissue densities locally. This may result in differences between the planned and the actually delivered dose. With complex delivery techniques treatment verification is essential and inter-fractional adaptation may be necessary. We present the first clinical results of treatment adaptation based on an in-house developed three-dimensional (3D) portal dose measurement (PDM) system. MATERIAL AND METHODS: A method was developed for 3D PDM combined with cone beam computed tomography (kV-CBCT) imaging. Lung cancer patients are monitored routinely with this imaging technique. During treatment, the first three fractions are analyzed with 3D PDM and weekly thereafter. The reconstructed measured dose is compared to the planned dose using dose-volume histograms and a γ evaluation. Patients having |γ|> 1 in more than 5% of the (primary tumor or organ at risk) volume were subjected to further analysis. In this study we show the PDM dose changes for five patients. RESULTS: We detected relevant dose changes induced by changes in atelectasis in the presented cases. Two patients received two treatment adaptations after being detected with PDM confirmed by visual inspection of the kV-CBCTs, and in two other patients the radiation treatment plan was adapted once. In one case no dose delivery change was detected with PDM. CONCLUSION: The first clinical patients show that 3D PDM combined with kV-CBCT is a valuable quality assurance tool for detecting anatomical alterations and their dosimetric consequences during the course of radiotherapy. In our clinic, 3D PDM is fully automated for ease and speed of the procedure, and for minimization of human error. The technique is able to flag patients with suspected dose discrepancies for potential adaptation of the treatment plan.

A traffic light protocol workflow for image-guided adaptive radiotherapy in lung cancer patients.

BACKGROUND AND PURPOSE: Image-guided radiotherapy using cone beam-CT (CBCT) images is used to evaluate patient anatomy and positioning before radiotherapy. In this study we analyzed and optimized a traffic light protocol (TLP) used in lung cancer patients to identify patients requiring treatment adaptation. MATERIALS AND METHODS: First, CBCT review requests of 243 lung cancer patients were retrospectively analyzed and divided into 6 pre-defined categories. Frequencies and follow-up actions were scored. Based on these results, the TLP was optimized and evaluated in the same way on 230 patients treated in 2018. RESULTS: In the retrospective study, a total of 543 CBCT review requests were created during treatment in 193/243 patients due to changed anatomy of lung (24%), change of tumor volume (24%), review of match (18%), shift of the mediastinum (15%), shift of tumor (15%) and other (4%). The majority of requests (474, 87%) did not require further action. In 6% an adjustment of the match criteria sufficed; in 7% treatment plan adaptation was required. Plan adaptation was frequently seen in the categories changed anatomy of lung, change of tumor volume and shift of tumor outside the PTV. Shift of mediastinum outside PRV and shift of GTV outside CTV (but inside PTV) never required plan adaptation and were omitted to optimize the TLP, which reduced the CBCT review requests by 23%. CONCLUSIONS: The original TLP selected patients that required a treatment adaptation, but with a high false positive rate. The optimized TLP reduced the amount of CBCT review requests, while still correctly identifying patients requiring adaptation.

Positron emission tomography guided dose painting by numbers of lung cancer: Alanine dosimetry in an anthropomorphic phantom.

BACKGROUND AND PURPOSE: Dose painting by numbers (DPBN) require a high degree of dose modulation to fulfill the image-based voxel wise dose prescription. The aim of this study was to assess the dosimetric accuracy of 18F-fluoro-2-deoxy-glucose positron emission tomography(18F-FDG-PET)-based DPBN in an anthropomorphic lung phantom using alanine dosimetry. MATERIALS AND METHODS: A linear dose prescription based on 18F-FDG-PET image intensities within the gross tumor volume (GTV) of a lung cancer patient was employed. One DPBN scheme with low dose modulation (Scheme A; minimum/maximum fraction dose to the GTV 2.92/4.26 Gy) and one with a high modulation (Scheme B; 2.81/4.52 Gy) were generated. The plans were transferred to a computed tomograpy (CT) scan of a thorax phantom based on CT images of the patient. Using volumetric modulated arc therapy (VMAT), DPBN was delivered to the phantom with embedded alanine dosimeters. A plan was also delivered to an intentionally misaligned phantom. Absorbed doses at various points in the phantom were measured by alanine dosimetry. RESULTS: A pointwise comparison between GTV doses from prescription, treatment plan calculation and VMAT delivery showed high correspondence, with a mean and maximum dose difference of <0.1 Gy and 0.3 Gy, respectively. No difference was found in dosimetric accuracy between scheme A and B. The misalignment caused deviations up to 1 Gy between prescription and delivery. CONCLUSION: DPBN can be delivered with high accuracy, showing that the treatment may be applied correctly from a dosimetric perspective. Still, misalignment may cause considerable dosimetric erros, indicating the need for patient immobilization and monitoring.

Optimal gating compared to 3D and 4D PET reconstruction for characterization of lung tumours.

PURPOSE: We investigated the added value of a new respiratory amplitude-based PET reconstruction method called optimal gating (OG) with the aim of providing accurate image quantification in lung cancer. METHODS: FDG-PET imaging was performed in 26 lung cancer patients during free breathing using a 24-min list-mode acquisition on a PET/CT scanner. The data were reconstructed using three methods: standard 3D PET, respiratory-correlated 4D PET using a phase-binning algorithm, and OG. These datasets were compared in terms of the maximum SUV (SUVmax) in the primary tumour (main endpoint), noise characteristics, and volumes using thresholded regions of SUV 2.5 and 40% of the SUVmax. RESULTS: SUVmax values from the 4D method (13.7 ± 5.6) and the OG method (14.1 ± 6.5) were higher (4.9 ± 4.8%, p < 0.001 and 6.9 ± 8.8%, p < 0.001, respectively) than that from the 3D method (13.1 ± 5.4). SUVmax did not differ between the 4D and OG methods (2.0 ± 8.4%, p = NS). Absolute and relative threshold volumes did not differ between methods, except for the 40% SUVmax volume in which the value from the 3D method was lower than that from the 4D method (-5.3 ± 7.1%, p = 0.007). The OG method exhibited less noise than the 4D method. Variations in volumes and SUVmax of up to 40% and 27%, respectively, of the individual gates of the 4D method were also observed. CONCLUSION: The maximum SUVs from the OG and 4D methods were comparable and significantly higher than that from the 3D method, yet the OG method was visibly less noisy than the 4D method. Based on the better quantification of the maximum and the less noisy appearance, we conclude that OG PET is a better alternative to both 3D PET, which suffers from breathing averaging, and the noisy images of a 4D PET.

Operation and calibration of the novel PTW 1600SRS detector for the verification of single isocenter stereotactic radiosurgery treatments of multiple small brain metastases.

OBJECTIVES: The aim of this work was to evaluate the operation of the 1600SRS detector and to develop a calibration procedure for verifying the dose delivered by a single isocenter stereotactic radiosurgery (SRS) treatment of small multiple brain metastases (BM). METHODS: 14 clinical treatment cases were selected with the number of BM ranging from 2 to 11. The dosimetric agreement was investigated between the calculated and the measured dose by an OCTAVIUS 1600SRS array detector in an OCTAVIUS 4D phantom equipped with dedicated SRS top. The cross-calibration procedure deviated from the manufacturer's as it applied field sizes and dose rates corresponding to the volumetric modulated arc therapy segments in each plan. RESULTS: Measurements with a plan specific cross-calibration showed mean ± standard deviation (SD) agreement scores for cut-off values 50%, 80%, 95%, of 98.6 ± 1.7%, 96.5 ± 4.6%, 97.3 ± 4.4% for the 6 MV plans respectively, and 98.6 ± 1.5%, 96.6 ± 4.0% 96.4 ± 6.3%, for the 6 MV flattening filter free (FFF) plans respectively. Using the default calibration procedure instead of the plan specific calibration could lead to a combined systematic dose offset of 4.1% for our treatment plans. CONCLUSION: The 1600SRS detector array with the 4D phantom offers an accurate solution to perform routine quality assurance measurements of single isocenter SRS treatments of multiple BM. This work points out the necessity of an adapted cross-calibration procedure. ADVANCES IN KNOWLEDGE: A dedicated calibration procedure enables accurate dosimetry with the 1600SRS detector for small field single isocenter SRS treatment of multiple brain metastases for a large amount of BM.

Evaluation of novel AI-based extended field-of-view CT reconstructions.

PURPOSE: Modern computed tomography (CT) scanners have an extended field-of-view (eFoV) for reconstructing images up to the bore size, which is relevant for patients with higher BMI or non-isocentric positioning due to fixation devices. However, the accuracy of the image reconstruction in eFoV is not well known since truncated data are used. This study introduces a new deep learning-based algorithm for extended field-of-view reconstruction and evaluates the accuracy of the eFoV reconstruction focusing on aspects relevant for radiotherapy. METHODS: A life-size three-dimensional (3D) printed thorax phantom, based on a patient CT for which eFoV was necessary, was manufactured and used as reference. The phantom has holes allowing the placement of tissue mimicking inserts used to evaluate the Hounsfield unit (HU) accuracy. CT images of the phantom were acquired using different configurations aiming to evaluate geometric and HU accuracy in the eFoV. Image reconstruction was performed using a state-of-the-art reconstruction algorithm (HDFoV), commercially available, and the novel deep learning-based approach (HDeepFoV). Five patient cases were selected to evaluate the performance of both algorithms on patient data. There is no ground truth for patients so the reconstructions were qualitatively evaluated by five physicians and five medical physicists. RESULTS: The phantom geometry reconstructed with HDFoV showed boundary deviations from 1.0 to 2.5 cm depending on the volume of the phantom outside the regular scan field of view. HDeepFoV showed a superior performance regardless of the volume of the phantom within eFOV with a maximum boundary deviation below 1.0 cm. The maximum HU (absolute) difference for soft issue inserts is below 79 and 41 HU for HDFoV and HDeepFoV, respectively. HDeepFoV has a maximum deviation of -18 HU for an inhaled lung insert while HDFoV reached a 229 HU difference. The qualitative evaluation of patient cases shows that the novel deep learning approach produces images that look more realistic and have fewer artifacts. CONCLUSION: To be able to reconstruct images outside the sFoV of the CT scanner there is no alternative than to use some kind of extrapolated data. In our study, we proposed and investigated a new deep learning-based algorithm and compared it to a commercial solution for eFoV reconstruction. The deep learning-based algorithm showed superior performance in quantitative evaluations based on phantom data and in qualitative assessments of patient data.

The use of FDG-PET to target tumors by radiotherapy.

Fluorodeoxyglucose positron emission tomography (FDG-PET) plays an increasingly important role in radiotherapy, beyond staging and selection of patients. Especially for non-small cell lung cancer, FDG-PET has, in the majority of the patients, led to the safe decrease of radiotherapy volumes, enabling radiation dose escalation and, experimentally, redistribution of radiation doses within the tumor. In limited-disease small cell lung cancer, the role of FDG-PET is emerging. For primary brain tumors, PET based on amino acid tracers is currently the best choice, including high-grade glioma. This is especially true for low-grade gliomas, where most data are available for the use of (11)C-MET (methionine) in radiation treatment planning. For esophageal cancer, the main advantage of FDG-PET is the detection of otherwise unrecognized lymph node metastases. In Hodgkin's disease, FDG-PET is essential for involved-node irradiation and leads to decreased irradiation volumes while also decreasing geographic miss. FDG-PET's major role in the treatment of cervical cancer with radiation lies in the detection of para-aortic nodes that can be encompassed in radiation fields. Besides for staging purposes, FDG-PET is not recommended for routine radiotherapy delineation purposes. It should be emphasized that using PET is only safe when adhering to strictly standardized protocols.

PET imaging of hypoxia using [18F]HX4: a phase I trial.

BACKGROUND AND PURPOSE: Noninvasive PET imaging of tumour hypoxia could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers. In this phase I trial, we aimed to determine the toxicity of [(18)F]HX4, a member of the 2-nitroimidazole family, at different dose levels. The secondary aim was to analyse image quality related to the HX4 dose and the timing of imaging. METHODS: Patients with a histologically proven solid cancer without curative treatment options were eligible for this study. A study design with two dose steps was used in which a single dose of a maximum of 222 MBq (step 1) or 444 MBq (step 2) [(18)F]HX4 was injected. Toxicity was scored on day 0 and on days 3 and 7 after injection, according to the CTCAE 3.0 scoring system. PET/CT images of the largest tumour site were acquired 30, 60 and 120 min after injection. RESULTS: Six patients with stage IV carcinoma were included, four with non-small-cell lung carcinoma, one with thymus carcinoma, and one with colon carcinoma. No toxicity was observed in any of the patients at either dose level. The median tumour to muscle ratio 120 min after injection was 1.40 (range 0.63-1.98). CONCLUSION: The findings of this study showed that [(18)F]HX4 PET imaging for the detection of hypoxia is not associated with any toxicity. Imaging was successful; however, future trials are needed to determine the optimal image parameters.

Dynamic contrast-enhanced CT in patients treated with sorafenib and erlotinib for non-small cell lung cancer: a new method of monitoring treatment?

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Acuros® dose verification of ultrasmall lung lesions with EBT-XD film in a homogeneous and heterogeneous anthropomorphic phantom setup.

PURPOSE: Modern type 'c' dose calculation algorithms like Acuros® can predict dose for lung tumors larger than approximately 4 cm3 with a relative uncertainty up to 5%. However, increasingly better tumor diagnostics are leading to the detection of very small early-stage lung tumors that can be treated with stereotactic body radiotherapy (SBRT) for inoperable patients. This raises the question whether dose algorithms like Acuros® can still accurately predict dose within 5% for challenging conditions involving small treatment fields. Current recommendations for Quality Assurance (QA) and dose verification in SBRT treatments are to use phantoms that are as realistic as possible to the clinical situation, although water-equivalent phantoms are still largely used for dose verification. In this work we aim to demonstrate that existing dose verification methods are inadequate for accurate dose verification in very small lung tumors treated with SBRT. METHOD: The homogeneous PTW Octavius4D phantom with the Octavius 1000 SRS detector ("Octavius4D phantom") and the heterogeneous CIRS Dynamic Thorax phantom ('CIRS phantom') were used for dose measurements. The CIRS phantom contained different lung-equivalent film-holding cylindrical phantom inserts ("film inserts") with water-equivalent spherical targets with diameters 0.5, 0.75, 1, 2, and 3 cm. Plans were calculated for 6 and 10 MV for each spherical target in the CIRS phantom, resulting in 14 treatment plans. The plans were delivered to both Octavius4D and CIRS phantom to compare measured dose in a commonly used homogeneous and more realistic heterogeneous phantom setup. In addition, treatment plans of seven clinical lung cancer patients with lung tumors below approximately 1.0 cm3 were irradiated in the heterogeneous CIRS phantom. The actual tumor size within the clinical treatment plans determined the choice of the spherical target size, such that both measurement geometry and clinical target volumes match as closely as possible. The Acuros® dose algorithm (version 15.5.11) was used for all dose calculations reporting dose-to-medium using a 0.1-cm-grid size. RESULTS: The measurement discrepancies in the homogeneous Octavius4D phantom for the fourteen treatment plans were within 1.5%. Dose discrepancies between measurement and treatment planning systems (TPS) for the heterogeneous CIRS phantom increased for both 6 and 10 MV with decreasing target diameters up to 23.7 ± 1.0% for 6 MV and 8.8 ± 1.1% for 10 MV for the smallest target of 0.5 cm in diameter with a 2-mm-CTV-PTV margin. For the seven clinical plans this trend of increasing dose difference with decreasing tumor size is less pronounced although the smallest tumors show the largest differences between measurement and TPS up to 16.6 ± 0.9%. CONCLUSION: Current verification methods using homogenous phantoms are not adequate for lung tumors with diameters below approximately 0.75 cm. The current Acuros® dose calculation algorithm underestimates dose in very small lung tumors. Dose verification of small lung tumors should be performed in an anthropomorphic lung phantom incorporating a water-equivalent target that matches clinical tumor size as closely as possible.

Individualized accelerated isotoxic concurrent chemo-radiotherapy for stage III non-small cell lung cancer: 5-Year results of a prospective study.

BACKGROUND: Stage III non-small cell lung cancer (NSCLC) still has a poor prognosis. Prior studies with individualized, accelerated, isotoxic dose escalation (INDAR) with 3D-CRT showed promising results, especially in patients not treated with concurrent chemo-radiotherapy. We investigated if INDAR delivered with IMRT would improve the overall survival (OS) of stage III NSCLC patients treated with concurrent chemotherapy and radiotherapy. PATIENTS AND METHODS: Patients eligible for concurrent chemo-radiotherapy were entered in this prospective study. Radiotherapy was given to a dose of 45 Gy/30 fractions BID (1.5 Gy/fraction), followed by QD fractions of 2 Gy until a total dose determined by the normal tissue constraints. The primary endpoint was OS, secondary endpoints were loco-regional relapses and toxicity. RESULTS: From May 4, 2009 until April 26, 2012, 185 patients were included. The mean tumor dose was 66.0 ±â€¯12.8 Gy (36-73 Gy), delivered in a mean of 39.7 fractions in an overall treatment time of 38.2 days. The mean lung dose (MLD) was 17.3 Gy. The median OS was 19.8 months (95% CI 17.3-22.3) with a 5-year OS of 24.3%. Loco-regional failures as first site of recurrence occurred in 59/185 patients (31.8%). Isolated nodal failures (INF) were observed in 3/185 patients (1.6%). Dyspnea grade 3 was seen in 3.2% of patients and transient dysphagia grade 3 in 22%. CONCLUSIONS: INDAR with IMRT concurrently with chemotherapy did not lead to a sign of an improved OS in unselected stage III NSCLC patients.

Time trends in nodal volumes and motion during radiotherapy for patients with stage III non-small-cell lung cancer.

PURPOSE: Knowledge of changes in gross tumor volume (GTV) and of GTV motion during a course of radiotherapy is necessary for accurate treatment delivery. This study describes the time trends in nodal computed tomography (CT) volume and motion for patients with locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In a prospective clinical trial, 12 patients with a total of 22 positive nodes underwent a CT-positron emission tomography scan before treatment, as well as in the first and second week following start of radiotherapy. Volume changes could be measured for all nodes. For 21 nodes, the motion was measured on the basis of a respiration correlated CT (RCCT) scan. Repeated RCCT scans were available for 11 nodes to evaluate the change in motion. RESULTS: In 6 of 22 (27%) patients, the nodal volume increased >30%, whereas in 3 of 22 (14%) the volume decreased >30%. On average, the nodal volume did not change significantly (from 4.9 to 5.1 to 4.6 cm(3)). The average motion of the nodal areas was initially 5.6 +/- 2.8 mm. This motion decreased slightly during therapy but not statistically significant. However, large interpatient and internodal motion differences were observed. CONCLUSION: A large variability of changes in nodal volume between patients was observed. However, this had limited clinical impact because volumes and hence volume changes were small. The nodal motion did not change significantly during therapy. However, because of the large interpatient variability of nodal motion before treatment, internal margins for nodal areas should be calculated before radiotherapy using RCCT, such that the margins can be applied for individual patients. Repeated imaging of the nodes seems however to be of limited use because the observed individual changes in nodal volume and motion tend to fall within the commonly applied margins.