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.

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.

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.

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.

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.

The TRENDY multi-center randomized trial on hepatocellular carcinoma - Trial QA including automated treatment planning and benchmark-case results.

BACKGROUND AND PURPOSE: The TRENDY trial is an international multi-center phase-II study, randomizing hepatocellular carcinoma (HCC) patients between transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT) with a target dose of 48-54 Gy in six fractions. The radiotherapy quality assurance (QA) program, including prospective plan feedback based on automated treatment planning, is described and results are reported. MATERIALS AND METHODS: Scans of a single patient were used as a benchmark case. Contours submitted by nine participating centers were compared with reference contours. The subsequent planning round was based on a single set of contours. A total of 20 plans from participating centers, including 12 from the benchmark case, 5 from a clinical pilot and 3 from the first study patients, were compared to automatically generated VMAT plans. RESULTS: For the submitted liver contours, Dice Similarity Coefficients (DSC) with the reference delineation ranged from 0.925 to 0.954. For the GTV, the DSC varied between 0.721 and 0.876. For the 12 plans on the benchmark case, healthy liver normal-tissue complication probabilities (NTCPs) ranged from 0.2% to 22.2% with little correlation between NCTP and PTV-D95% (R2 < 0.3). Four protocol deviations were detected in the set of 20 treatment plans. Comparison with co-planar autoVMAT QA plans revealed these were due to too high target dose and suboptimal planning. Overall, autoVMAT resulted in an average liver NTCP reduction of 2.2 percent point (range: 16.2 percent point to -1.8 percent point, p = 0.03), and lower doses to the healthy liver (p < 0.01) and gastrointestinal organs at risk (p < 0.001). CONCLUSIONS: Delineation variation resulted in feedback to participating centers. Automated treatment planning can play an important role in clinical trials for prospective plan QA as suboptimal plans were detected.

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.

Dual-energy CT quantitative imaging: a comparison study between twin-beam and dual-source CT scanners.

PURPOSE: To assess image quality and to quantify the accuracy of relative electron densities (ρe ) and effective atomic numbers (Zeff ) for three dual-energy computed tomography (DECT) scanners: a novel single-source split-filter (i.e., twin-beam) and two dual-source scanners. METHODS: Measurements were made with a second generation dual-source scanner at 80/140Sn kVp, a third-generation twin-beam single-source scanner at 120 kVp with gold (Au) and tin (Sn) filters, and a third-generation dual-source scanner at 90/150Sn kVp. Three phantoms with tissue inserts were scanned and used for calibration and validation of parameterized methods to extract ρe and Zeff , whereas iodine and calcium inserts were used to quantify Contrast-to-Noise-Ratio (CNR). Spatial resolution in tomographic images was also tested. RESULTS: The third-generation scanners have an image resolution of 6.2, ~0.5 lp/cm higher than the second generation scanner. The twin-beam scanner has low imaging contrast for iodine materials due to its limited spectral separation. The parameterization methods resulted in calibrations with low fit residuals for the dual-source scanners, yielding values of ρe and Zeff close to the reference values (errors within 1.2% for ρe and 6.2% for Zeff for a dose of 20 mGy, excluding lung substitute tissues). The twin-beam scanner presented overall higher errors (within 3.2% for ρe and 28% for Zeff , also excluding lung inserts) and also larger variations for uniform inserts. CONCLUSIONS: Spatial resolution is similar for the three scanners. The twin-beam is able to derive ρe and Zeff , but with inferior accuracy compared to both dual-source scanners.

The NCS code of practice for the quality assurance and control for volumetric modulated arc therapy.

In 2010, the NCS (Netherlands Commission on Radiation Dosimetry) installed a subcommittee to develop guidelines for quality assurance and control for volumetric modulated arc therapy (VMAT) treatments. The report (published in 2015) has been written by Dutch medical physicists and has therefore, inevitably, a Dutch focus. This paper is a condensed version of these guidelines, the full report in English is freely available from the NCS website www.radiationdosimetry.org. After describing the transition from IMRT to VMAT, the paper addresses machine quality assurance (QA) and treatment planning system (TPS) commissioning for VMAT. The final section discusses patient specific QA issues such as the use of class solutions, measurement devices and dose evaluation methods.

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.

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.

In vivo quantification of hypoxic and metabolic status of NSCLC tumors using [18F]HX4 and [18F]FDG-PET/CT imaging.

PURPOSE: Increased tumor metabolism and hypoxia are related to poor prognosis in solid tumors, including non-small cell lung cancer (NSCLC). PET imaging is a noninvasive technique that is frequently used to visualize and quantify tumor metabolism and hypoxia. The aim of this study was to perform an extensive comparison of tumor metabolism using 2[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET and hypoxia using HX4-PET imaging. EXPERIMENTAL DESIGN: FDG- and HX4-PET/CT images of 25 patients with NSCLC were coregistered. At a global tumor level, HX4 and FDG parameters were extracted from the gross tumor volume (GTV). The HX4 high-fraction (HX4-HF) and HX4 high-volume (HX4-HV) were defined using a tumor-to-blood ratio > 1.4. For FDG high-fraction (FDG-HF) and FDG high-volume (FDG-HV), a standardized uptake value (SUV) > 50% of SUVmax was used. We evaluated the spatial correlation between HX4 and FDG uptake within the tumor, to quantify the (mis)match between volumes with a high FDG and high HX4 uptake. RESULTS: At a tumor level, significant correlations were observed between FDG and HX4 parameters. For the primary GTV, the HX4-HF was three times smaller compared with the FDG-HF. In 53% of the primary lesions, less than 1 cm(3) of the HX4-HV was outside the FDG-HV; for 37%, this volume was 1.9 to 12 cm(3). Remarkably, a distinct uptake pattern was observed in 11%, with large hypoxic volumes localized outside the FDG-HV. CONCLUSION: Hypoxic tumor volumes are smaller than metabolic active volumes. Approximately half of the lesions showed a good spatial correlation between the PET tracers. In the other cases, a (partial) mismatch was observed. The addition of HX4-PET imaging has the potential to individualize patient treatment.

Hypoxia imaging with [¹8F]HX4 PET in NSCLC patients: defining optimal imaging parameters.

BACKGROUND AND PURPOSE: [(18)F]HX4 is a promising hypoxia PET-tracer. Uptake, spatio-temporal stability and optimal acquisition parameters for [(18)F]HX4 PET imaging were evaluated in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: [(18)F]HX4 PET/CT images of 15 NSCLC patients were acquired 2h and 4h after injection (p.i.). Maximum standardized-uptake-value (SUV(max)), tumor-to-blood-ratio (TBR(max)), hypoxic fraction (HF) and contrast-to-noise-ratio (CNR) were determined for all lesions. To evaluate spatio-temporal stability, DICE-similarity and Pearson correlation coefficients were calculated. Optimal acquisition-duration was assessed by comparing 30, 20, 10 and 5 min acquisitions. RESULTS: Considerable uptake (TBR >1.4) was observed in 18/25 target lesions. TBR(max) increased significantly from 2 h (1.6 ± 0.3) to 4 h p.i. (2.0 ± 0.6). Uptake patterns at 2 h and 4 h p.i. showed a strong correlation (R=0.77 ± 0.10) with a DICE similarity coefficient of 0.69 ± 0.08 for the 30% highest uptake volume. Reducing acquisition-time resulted in significant changes in SUV(max) and CNR. TBR(max) and HF were only affected for scan-times of 5 min. CONCLUSIONS: The majority of NSCLC lesions showed considerable [(18)F]HX4 uptake. The heterogeneous uptake pattern was stable between 2 h and 4 h p.i. [(18)F]HX4 PET imaging at 4 h p.i. is superior to 2 h p.i. to reach highest contrast. Acquisition time may be reduced to 10 min without significant effects on TBR(max) and HF.

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.

PET-based treatment response evaluation in rectal cancer: prediction and validation.

PURPOSE: To develop a positron emission tomography (PET)-based response prediction model to differentiate pathological responders from nonresponders. The predictive strength of the model was validated in a second patient group, treated and imaged identical to the patients on which the predictive model was based. METHODS AND MATERIALS: Fifty-one rectal cancer patients were prospectively included in this study. All patients underwent fluorodeoxyglucose (FDG) PET-computed tomography (CT) imaging both before the start of chemoradiotherapy (CRT) and after 2 weeks of treatment. Preoperative treatment with CRT was followed by a total mesorectal excision. From the resected specimen, the tumor regression grade (TRG) was scored according to the Mandard criteria. From one patient group (n = 30), the metabolic treatment response was correlated with the pathological treatment response, resulting in a receiver operating characteristic (ROC) curve based cutoff value for the reduction of maximum standardized uptake value (SUV(max)) within the tumor to differentiate pathological responders (TRG 1-2) from nonresponders (TRG 3-5). The applicability of the selected cutoff value for new patients was validated in a second patient group (n = 21). RESULTS: When correlating the metabolic and pathological treatment response for the first patient group using ROC curve analysis (area under the curve = 0.98), a cutoff value of 48% SUV(max) reduction was selected to differentiate pathological responders from nonresponders (specificity of 100%, sensitivity of 64%). Applying this cutoff value to the second patient group resulted in a specificity and sensitivity of, respectively, 93% and 83%, with only one of the pathological nonresponders being false positively predicted as pathological responding. CONCLUSIONS: For rectal cancer, an accurate PET-based prediction of the pathological treatment response is feasible already after 2 weeks of CRT. The presented predictive model could be used to select patients to be considered for less invasive surgical interventions or even a "wait and see" policy. Also, based on the predicted response, early modifications of the treatment protocol are possible, which might result in an improved clinical outcome.

Repeated positron emission tomography-computed tomography and perfusion-computed tomography imaging in rectal cancer: fluorodeoxyglucose uptake corresponds with tumor perfusion.

PURPOSE: The purpose of this study was to analyze both the intratumoral fluorodeoxyglucose (FDG) uptake and perfusion within rectal tumors before and after hypofractionated radiotherapy. METHODS AND MATERIALS: Rectal cancer patients, referred for preoperative hypofractionated radiotherapy (RT), underwent FDG-positron emission tomography (PET)-computed tomography (CT) and perfusion-CT (pCT) imaging before the start of hypofractionated RT and at the day of the last RT fraction. The pCT-images were analyzed using the extended Kety model, quantifying tumor perfusion with the pharmacokinetic parameters K(trans), v(e), and v(p). The mean and maximum FDG uptake based on the standardized uptake value (SUV) and transfer constant (K(trans)) within the tumor were correlated. Also, the tumor was subdivided into eight subregions and for each subregion the mean and maximum SUVs and K(trans) values were assessed and correlated. Furthermore, the mean FDG uptake in voxels presenting with the lowest 25% of perfusion was compared with the FDG uptake in the voxels with the 25% highest perfusion. RESULTS: The mean and maximum K(trans) values were positively correlated with the corresponding SUVs (ρ = 0.596, p = 0.001 and ρ = 0.779, p < 0.001). Also, positive correlations were found for K(trans) values and SUVs within the subregions (mean, ρ = 0.413, p < 0.001; and max, ρ = 0.540, p < 0.001). The mean FDG uptake in the 25% highest-perfused tumor regions was significantly higher compared with the 25% lowest-perfused regions (10.6% ± 5.1%, p = 0.017). During hypofractionated radiotherapy, stable mean (p = 0.379) and maximum (p = 0.280) FDG uptake levels were found, whereas the mean (p = 0.040) and maximum (p = 0.003) K(trans) values were found to significantly increase. CONCLUSION: Highly perfused rectal tumors presented with higher FDG-uptake levels compared with relatively low perfused tumors. Also, intratumor regions with a high FDG uptake demonstrated with higher levels of perfusion than regions with a relatively low FDG-uptake. Early after hypofractionated RT, stable FDG uptake levels were found, whereas tumor perfusion was found to significantly increase.

Simulation study on potential accuracy gains from dual energy CT tissue segmentation for low-energy brachytherapy Monte Carlo dose calculations.

This work compares Monte Carlo (MC) dose calculations for (125)I and (103)Pd low-dose rate (LDR) brachytherapy sources performed in virtual phantoms containing a series of human soft tissues of interest for brachytherapy. The geometries are segmented (tissue type and density assignment) based on simulated single energy computed tomography (SECT) and dual energy (DECT) images, as well as the all-water TG-43 approach. Accuracy is evaluated by comparison to a reference MC dose calculation performed in the same phantoms, where each voxel's material properties are assigned with exactly known values. The objective is to assess potential dose calculation accuracy gains from DECT. A CT imaging simulation package, ImaSim, is used to generate CT images of calibration and dose calculation phantoms at 80, 120, and 140 kVp. From the high and low energy images electron density ρ(e) and atomic number Z are obtained using a DECT algorithm. Following a correction derived from scans of the calibration phantom, accuracy on Z and ρ(e) of ±1% is obtained for all soft tissues with atomic number Z ∊ [6,8] except lung. GEANT4 MC dose calculations based on DECT segmentation agreed with the reference within ±4% for (103)Pd, the most sensitive source to tissue misassignments. SECT segmentation with three tissue bins as well as the TG-43 approach showed inferior accuracy with errors of up to 20%. Using seven tissue bins in our SECT segmentation brought errors within ±10% for (103)Pd. In general (125)I dose calculations showed higher accuracy than (103)Pd. Simulated image noise was found to decrease DECT accuracy by 3-4%. Our findings suggest that DECT-based segmentation yields improved accuracy when compared to SECT segmentation with seven tissue bins in LDR brachytherapy dose calculation for the specific case of our non-anthropomorphic phantom. The validity of our conclusions for clinical geometry as well as the importance of image noise in the tissue segmentation procedure deserves further experimental investigation.

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.

Residual metabolic tumor activity after chemo-radiotherapy is mainly located in initially high FDG uptake areas in rectal cancer.

PURPOSE: Recent literature suggests that tumor cells and areas within tumors with a high initial FDG uptake might be more resistant to (chemo)radiotherapy ((C)RT). This study was undertaken to test this hypothesis in rectal cancer using rigid and non-rigid image registration. PATIENTS AND METHODS: Twenty-eight patients, diagnosed with locally advanced rectal cancer and referred for pre-operative treatment with CRT were included in this study. All patients underwent FDG-PET-CT imaging prior to and after CRT. Rigid and non-rigid image registration was performed to compensate organ deformations between the pre- and post-treatment PET-CT scans. The tumor was contoured on both PET-scans using SUV iso-contouring based on the SBR-method. The voxels with residual increased FDG uptake were studied and correlated to their pre-treatment FDG uptake level. Two SUV-volume-histograms were made based on the pre-treatment PET-data, one for the voxels within the pre-treatment tumor PET-based iso-contour and one for the voxels within the PET-based iso-contour of the residual tumor non-rigidly registered onto the pre-treatment scan. RESULTS: For the voxels with a pre-treatment FDG uptake of >50% of SUV(max), 70.6±5.6% of the voxels were still metabolic active in the residual tumor, whereas for voxels with an FDG uptake of <50% of SUV(max) only 51.1±6.7% were present in the metabolic active residual tumor. CONCLUSION: This study presents areas in rectal tumors with an initially high FDG uptake to be most likely to show residual disease after CRT. This could indicate a higher (C)RT-resistance for tumor regions with a high FDG uptake prior to treatment.