Modern clinical research: How rapid learning health care and cohort multiple randomised clinical trials complement traditional evidence based medicine.

BACKGROUND: Trials are vital in informing routine clinical care; however, current designs have major deficiencies. An overview of the various challenges that face modern clinical research and the methods that can be exploited to solve these challenges, in the context of personalised cancer treatment in the 21st century is provided. AIM: The purpose of this manuscript, without intending to be comprehensive, is to spark thought whilst presenting and discussing two important and complementary alternatives to traditional evidence-based medicine, specifically rapid learning health care and cohort multiple randomised controlled trial design. Rapid learning health care is an approach that proposes to extract and apply knowledge from routine clinical care data rather than exclusively depending on clinical trial evidence, (please watch the animation: http://youtu.be/ZDJFOxpwqEA). The cohort multiple randomised controlled trial design is a pragmatic method which has been proposed to help overcome the weaknesses of conventional randomised trials, taking advantage of the standardised follow-up approaches more and more used in routine patient care. This approach is particularly useful when the new intervention is a priori attractive for the patient (i.e. proton therapy, patient decision aids or expensive medications), when the outcomes are easily collected, and when there is no need of a placebo arm. DISCUSSION: Truly personalised cancer treatment is the goal in modern radiotherapy. However, personalised cancer treatment is also an immense challenge. The vast variety of both cancer patients and treatment options makes it extremely difficult to determine which decisions are optimal for the individual patient. Nevertheless, rapid learning health care and cohort multiple randomised controlled trial design are two approaches (among others) that can help meet this challenge.

Experimental comparison of cylindrical and plane parallel ionization chambers for reference dosimetry in continuous and pulsed scanned proton beams.

Objective. In this experimental work we compared the determination of absorbed dose to water using four ionization chambers (ICs), a PTW-34045 Advanced Markus, a PTW-34001 Roos, an IBA-PPC05 and a PTW-30012 Farmer, irradiated under the same conditions in one continuous- and in two pulsed-scanned proton beams.Approach. The ICs were positioned at 2 cm depth in a water phantom in four square-field single-energy scanned-proton beams with nominal energies between 80 and 220 MeV and in the middle of 10 × 10 × 10 cm3dose cubes centered at 10 cm or 12.5 cm depth in water. The water-equivalent thickness (WET) of the entrance window and the effective point of measurement was considered when positioning the plane parallel (PP) ICs and the cylindrical ICs, respectively. To reduce uncertainties, all ICs were calibrated at the same primary standards laboratory. We used the beam quality (kQ) correction factors for the ICs under investigation from IAEA TRS-398, the newly calculated Monte Carlo (MC) values and the anticipated IAEA TRS-398 updated recommendations.Main results. Dose differences among the four ICs ranged between 1.5% and 3.7% using both the TRS-398 and the newly recommendedkQvalues. The spread among the chambers is reduced with the newlykQvalues. The largest differences were observed between the rest of the ICs and the IBA-PPC05 IC, obtaining lower dose with the IBA-PPC05.Significance. We provide experimental data comparing different types of chambers in different proton beam qualities. The observed dose differences between the ICs appear to be related to inconsistencies in the determination of thekQvalues. For PP ICs, MC studies account for the physical thickness of the entrance window rather than the WET. The additional energy loss that the wall material invokes is not negligible for the IBA-PPC05 and might partially explain the lowkQvalues determined for this IC. To resolve this inconsistency and to benchmark MC values,kQvalues measured using calorimetry are needed.

Quality assurance of scanned proton beams at different gantry angles using an ionization chamber array in a rotational phantom.

PURPOSE: To implement a single set-up monthly QA procedure for 9 different beam parameters at different gantry angles and evaluate its clinical implementation over a 12 month period. METHODS: We developed a QA procedure using an array detector (PTW Octavius 1500XDR) embedded in a rotational unit (PTW Octavius 4D) at our proton facility. With a single set-up we can monitor field central axis position, field symmetry, field size, flatness, penumbrae, output, spot size, spot position and range at different gantry angles (AAPM TG 224). The set-up is irradiated with homogenous 2D fields with dynamic aperture and spot patterns at five gantry angles. A modular top is used to check the range consistency. Absolute γ analysis were performed to compare measured dose distributions to calculated dose. All other parameters are directly extracted from the measurements. Additionally, the sensitivity of the set-up to small changes in beam parameters were compared to the Lynx detector (IBA). RESULTS: Over a 12 month period, output, symmetry, and flatness were within ± 2 %; FWHM, spot positions, penumbra widths, and central axis fields were within ± 1 mm. Range differences were all within 1/2 of the energy spacing (±0.6 MeV) relative to baseline. Most (2 %, 2 mm) γ-analysis showed agreement scores higher than 90 %. The sensitivity is comparable to the Lynx detector and measurement time is reduced by 40 %. CONCLUSION: The time-efficient monthly QA procedure that we developed can accurately be used to measure a large range of beam parameters at different gantry angles, within the TG 224 AAPM recommendations.

Joint EURADOS WG9-WG11 rem-counter intercomparison in a Mevion S250i proton therapy facility with Hyperscan pulsed synchrocyclotron.

Objective Proton therapy is gaining popularity because of the improved dose delivery over conventional radiation therapy. The secondary dose to healthy tissues is dominated by secondary neutrons. Commercial rem-counters are valuable instruments for the on-line assessment of neutron ambient dose equivalent (H*(10)). In general, however, a priori knowledge of the type of facility and of the radiation field is required for the proper choice of any survey meter. The novel Mevion S250i Hyperscan synchrocyclotron mounts the accelerator directly on the gantry. It provides a scanned 227 MeV proton beam, delivered in pulses with a pulse width of 10 µs at 750 Hz frequency, which is afterwards degraded in energy by a range shifter modulator system. This environment is particularly challenging for commercial rem-counters; therefore, we tested the reliability of some of the most widespread rem-counters to understand their limits in the Mevion S250i stray neutron field. Approach This work, promoted by the European Radiation Dosimetry Group (EURADOS), describes a rem-counter intercomparison at the Maastro Proton Therapy centre in the Netherlands, which houses the novel Mevion S250i Hyperscan system. Several rem-counters were employed in the intercomparison (LUPIN, LINUS, WENDI-II, LB6411, NM2B-458, NM2B-495Pb), which included simulation of a patient treatment protocol employing a water tank phantom. The outcomes of the experiment were compared with models and data from the literature. Main results We found that only the LUPIN allowed for a correct assessment of H*(10) within a 20% uncertainty. All other rem-counters underestimated the reference H*(10) by factors from 2 to more than 10, depending on the detector model and on the neutron dose per pulse. In pulsed fields, the neutron dose per pulse is a fundamental parameter, while the average neutron dose rate is a secondary quantity. An average 150-200 µSv/GyRBE neutron H*(10) at various positions around the phantom and at distances between 186 cm and 300 cm from it was measured per unit therapeutic dose delivered to the target. Significance Our results are partially in line with results obtained at similar Mevion facilities employing passive energy modulation. Comparisons with facilities employing active energy modulation confirmed that the neutron H*(10) can increase up to more than a factor of 10 when passive energy modulation is employed. The challenging environment of the Mevion stray neutron field requires the use of specific rem-counters sensitive to high-energy neutrons (up to a few hundred MeV) and specifically designed to withstand pulsed neutron fields.

EURADOS REM-COUNTER INTERCOMPARISON AT MAASTRO PROTON THERAPY CENTRE: COMPARISON WITH LITERATURE DATA.

The Maastro Proton Therapy Centre is the first European facility housing the Mevion S250i Hyperscan synchrocyclotron. The proximity of the accelerator to the patient, the presence of an active pencil beam delivery system downstream of a passive energy degrader and the pulsed structure of the beam make the Mevion stray neutron field unique amongst proton therapy facilities. This paper reviews the results of a rem-counter intercomparison experiment promoted by the European Radiation Dosimetry Group at Maastro and compares them with those at other proton therapy facilities. The Maastro neutron H*(10) in the room (100-200 µSv/Gy at about 2 m from the isocentre) is in line with accelerators using purely passive or wobbling beam delivery modalities, even though Maastro shows a dose gradient peaked near the accelerator. Unlike synchrotron- and cyclotron-based facilities, the pulsed beam at Maastro requires the employment of rem-counters specifically designed to withstand pulsed neutron fields.

Results of an independent dosimetry audit for scanned proton beam therapy facilities.

PURPOSE: An independent dosimetry audit based on end-to-end testing of the entire chain of radiation therapy delivery is highly recommended to ensure consistent treatments among proton therapy centers. This study presents an auditing methodology developed by the MedAustron Ion Beam Therapy Center (Austria) in collaboration with the National Physical Laboratory (UK) and audit results for five scanned proton beam therapy facilities in Europe. METHODS: The audit procedure used a homogeneous and an anthropomorphic head phantom. The phantoms were loaded either with an ionization chamber or with alanine pellets and radiochromic films. Homogeneously planned doses of 10Gy were delivered to a box-like target volume in the homogeneous phantom and to two clinical scenarios with increasing complexity in the head phantom. RESULTS: For all tests the mean of the local differences of the absolute dose to water determined with the alanine pellets compared to the predicted dose from the treatment planning system installed at the audited institution was determined. The mean value taken over all tests performed was -0.1±1.0%. The measurements carried out with the ionization chamber were consistent with the dose determined by the alanine pellets with a mean deviation of -0.5±0.6%. CONCLUSION: The developed dosimetry audit method was successfully applied at five proton centers including various "turn-key" Cyclotron solutions by IBA, Varian and Mevion. This independent audit with extension to other tumour sites and use of the correspondent anthropomorphic phantoms may be proposed as part of a credentialing procedure for future clinical trials in proton beam therapy.

Beam commissioning of the first compact proton therapy system with spot scanning and dynamic field collimation.

OBJECTIVES: To describe the measurements and to present the results of the beam commissioning and the beam model validation of a compact, gantry-mounted, spot scanning proton accelerator system with dynamic layer-by-layer field collimation. METHODS: We performed measurements of depth dose distributions in water, spot and scanned field size in air at different positions from the isocenter plane, spot position over the 20 × 20 cm2 scanned area, beam monitor calibration in terms of absorbed dose to water and specific field collimation measurements at different gantry angles to commission the system. To validate the beam model in the treatment planning system (TPS), we measured spot profiles in water at different depths, absolute dose in water of single energy layers of different field sizes and inversely optimised spread-out Bragg peaks (SOBP) under normal and oblique beam incidence, field size and penumbra in water of SOBPs, and patient treatment specific quality assurance in homogeneous and heterogeneous phantoms. RESULTS: Energy range, spot size, spot position and dose output were consistent at all gantry angles with 0.3 mm, 0.4 mm, 0.6 mm and 0.5% maximum deviations, respectively. Uncollimated spot size (one sigma) in air with an air-gap of 10 cm ranged from 4.1 to 16.4 mm covering a range from 32.2 to 1.9 cm in water, respectively. Absolute dose measurements were within 3% when comparing TPS and experimental data. Gamma pass rates >98% and >96% at 3%/3 mm were obtained when performing 2D dose measurements in homogeneous and in heterogeneous media, respectively. Leaf position was within ±1 mm at all gantry angles and nozzle positions. CONCLUSIONS: Beam characterisation and machine commissioning results, and the exhaustive end-to-end tests performed to assess the proper functionality of the system, confirm that it is safe and accurate to treat patients. ADVANCES IN KNOWLEDGE: This is the first paper addressing the beam commissioning and the beam validation of a compact, gantry-mounted, pencil beam scanning proton accelerator system with dynamic layer-by-layer multileaf collimation.

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.

Individualized radical radiotherapy of non-small-cell lung cancer based on normal tissue dose constraints: a feasibility study.

PURPOSE: Local recurrence is a major problem after (chemo-)radiation for non-small-cell lung cancer. We hypothesized that for each individual patient, the highest therapeutic ratio could be achieved by increasing total tumor dose (TTD) to the limits of normal tissues, delivered within 5 weeks. We report first results of a prospective feasibility trial. METHODS AND MATERIALS: Twenty-eight patients with medically inoperable or locally advanced non-small-cell lung cancer, World Health Organization performance score of 0-1, and reasonable lung function (forced expiratory volume in 1 second > 50%) were analyzed. All patients underwent irradiation using an individualized prescribed TTD based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8-Gy fractions twice daily. No concurrent chemoradiation was administered. Toxicity was scored using the Common Terminology Criteria for Adverse Events criteria. An (18)F-fluoro-2-deoxy-glucose-positron emission tomography-computed tomography scan was performed to evaluate (metabolic) response 3 months after treatment. RESULTS: Mean delivered dose was 63.0 +/- 9.8 Gy. The TTD was most often limited by the mean lung dose (32.1%) or spinal cord (28.6%). Acute toxicity generally was mild; only 1 patient experienced Grade 3 cough and 1 patient experienced Grade 3 dysphagia. One patient (3.6%) died of pneumonitis. For late toxicity, 2 patients (7.7%) had Grade 3 cough or dyspnea; none had severe dysphagia. Complete metabolic response was obtained in 44% (11 of 26 patients). With a median follow-up of 13 months, median overall survival was 19.6 months, with a 1-year survival rate of 57.1%. CONCLUSIONS: Individualized maximal tolerable dose irradiation based on normal tissue dose constraints is feasible, and initial results are promising.

Radiation dose prescription for non-small-cell lung cancer according to normal tissue dose constraints: an in silico clinical trial.

PURPOSE: Local tumor recurrence remains a major problem in patients with inoperable non-small-cell lung cancer undergoing radiotherapy. We investigated the theoretical gain in the estimated tumor control probability (TCP) using an individualized maximal tolerable dose (MTD) prescription, for both conventional and accelerated fractionation schemes. METHODS AND MATERIALS: For 64 non-small-cell lung cancer patients, five treatment plans were compared, dependent on the normal tissue dose constraints for the lung and spinal cord. The first two used a classic fractionation (2 Gy/d, 5 d/wk) to a total dose of 60 Gy (QD(classic)) or determined by the individualized MTD (QD(MTD)). The third scheme assumed a hypofractionated schedule of 2.75-Gy fractions (QD(hypofr)). The fourth and fifth assumed hyperfractionation and acceleration (1.8 Gy twice daily, either BID(classic) or BID(MTD)). The TCPs for the groups of patients were estimated. RESULTS: The mean biologic equivalent dose in 2-Gy fractions for tumor, corrected for accelerated repopulation was significantly greater for the BID(MTD) scheme (62.1 Gy) than for any other scheme (QD(classic), 47.5 Gy; QD(MTD), 52.0 Gy; QD(hypofr), 56.9 Gy; and BID(classic), 56.9 Gy; p < 0.001). Although both dose-escalation (QD(MTD)) and hypofractionation (QD(hypofr)) resulted in an increase in the mean estimated TCP of 5.6% (p < 0.001) and 14.6% (p < 0.001), respectively, compared with QD(classic), the combination of escalation and acceleration (BID(MTD)) improved the mean estimated TCP by 26.4% (p < 0.001). CONCLUSION: The results of this planning study showed a large gain in the estimated TCP using an MTD scheme with 1.8-Gy fractions BID compared with other fractionation schedules. Clinical studies implementing this concept are ongoing.

Stability of 18F-deoxyglucose uptake locations within tumor during radiotherapy for NSCLC: a prospective study.

PURPOSE: Because individual tumors are heterogeneous, including for (18)F-deoxyglucose (FDG) uptake and, most likely, for radioresistance, selective boosting of high FDG uptake zones within the tumor has been suggested. To do this, it is critical to know whether the location of these high FDG uptake patterns within the tumor remain stable during radiotherapy (RT). METHODS AND MATERIALS: Twenty-three patients with Stage I-III non-small-cell lung cancer underwent repeated FDG positron emission tomography computed tomography scans before radical RT (Day 0) and at Days 7 and 14 of RT. On all scans, the high and low FDG uptake regions were autodelineated using several standardized uptake value thresholds, varying from 34% to 80% of the maximal standardized uptake value. The volumes and overlap fractions of these delineations were calculated to demonstrate the stability of the high FDG uptake regions during RT. RESULTS: The mean overlap fraction of the 34% uptake zones at Day 0 with Days 7 and 14 was 82.8% +/- 8.1% and 84.3% +/- 7.6%, respectively. The mean overlap fraction of the high uptake zones (60%) was 72.3% +/- 15.0% and 71.3% +/- 19.7% at Day 0 with Days 7 and 14, respectively. The volumes of the thresholds varied markedly (e.g., at Day 0, the volume of the 60% zone was 16.8 +/- 20.3 cm(3)). In contrast, although the location of the high FDG uptake patterns within the tumor during RT remained stable, the delineated volumes varied markedly. CONCLUSION: The location of the low and high FDG uptake areas within the tumor remained stable during RT. This knowledge may enable selective boosting of high FDG uptake areas within the tumor.

The integration of PET-CT scans from different hospitals into radiotherapy treatment planning.

PURPOSE: To integrate PET-CT scans from different hospitals into radiotherapy treatment planning. METHODS AND MATERIALS: A cylindrical phantom with spheres of different diameters was scanned on three different Siemens Biograph PET-CT scanners in three hospitals. The spheres and cylinder were filled with 18F-FDG such that different sphere-to-background (S/B) ratios were obtained. Scans were analyzed using dedicated software for automated delineation based on standardized uptake value (SUV) and using different reconstruction parameters. RESULTS: SUV thresholding curves for different S/B ratios were obtained for the different scanners. Differences in SUV auto-contouring thresholds were found to be significant for PET-CT simulators from different radiotherapy and nuclear medicine departments. A change in PET reconstruction parameters showed a significant effect on the results. CONCLUSION: Synchronization of PET-CT imaging protocols between cooperating hospitals is important for reliable determination of SUV auto-contouring thresholds. Whenever this goal has been achieved automated SUV delineation based on a S/B ratio using PET-CT images from different institutions can reliably be performed using individually determined threshold curves.

Correlation of intra-tumour heterogeneity on 18F-FDG PET with pathologic features in non-small cell lung cancer: a feasibility study.

We evaluated the feasibility to correlate intra-tumour heterogeneity as visualized on 18F-FDG PET with histology for NSCLC. For this purpose we used an ex-vivo model. The procedure was feasible in all operated patients. We have shown that this method is suitable for correlating intra-tumour heterogeneity in tracer uptake with histology.

18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: a planning study.

BACKGROUND AND PURPOSE: To investigate the influence of selective irradiation of 18FDG-PET positive mediastinal nodes on radiation fields and normal tissue exposure in limited disease small cell lung cancer (LD-SCLC). MATERIAL AND METHODS: Twenty-one patients with LD-SCLC, of whom both CT and PET images were available, were studied. For each patient, two three-dimensional conformal treatment plans were made with selective irradiation of involved lymph nodes, based on CT and on PET, respectively. Changes in treatment plans as well as dosimetric factors associated with lung and esophageal toxicity were analyzed and compared. RESULTS: FDG-PET information changed the treatment field in 5 patients (24%). In 3 patients, this was due to a decrease and in 2 patients to an increase in the number of involved nodal areas. However, there were no significant differences in gross tumor volume (GTV), lung, and esophageal parameters between CT- and PET-based plans. CONCLUSIONS: Incorporating FDG-PET information in radiotherapy planning for patients with LD-SCLC changed the treatment plan in 24% of patients compared to CT. Both increases and decreases of the GTV were observed, theoretically leading to the avoidance of geographical miss or a decrease of radiation exposure of normal tissues, respectively. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation, is ongoing in our department.

PET-CT-based auto-contouring in non-small-cell lung cancer correlates with pathology and reduces interobserver variability in the delineation of the primary tumor and involved nodal volumes.

PURPOSE: To compare source-to-background ratio (SBR)-based PET-CT auto-delineation with pathology in non-small-cell lung cancer (NSCLC) and to investigate whether auto-delineation reduces the interobserver variability compared with manual PET-CT-based gross tumor volume (GTV) delineation. METHODS AND MATERIALS: Source-to-background ratio-based auto-delineation was compared with macroscopic tumor dimensions to assess its validity in 23 tumors. Thereafter, GTVs were delineated manually on 33 PET-CT scans by five observers for the primary tumor (GTV-1) and the involved lymph nodes (GTV-2). The delineation was repeated after 6 months with the auto-contour provided. This contour was edited by the observers. For comparison, the concordance index (CI) was calculated, defined as the ratio of intersection and the union of two volumes (A intersection B)/(A union or logical sum B). RESULTS: The maximal tumor diameter of the SBR-based auto-contour correlated strongly with the macroscopic diameter of primary tumors (correlation coefficient = 0.90) and was shown to be accurate for involved lymph nodes (sensitivity 67%, specificity 95%). The median auto-contour-based target volumes were smaller than those defined by manual delineation for GTV-1 (31.8 and 34.6 cm(3), respectively; p = 0.001) and GTV-2 (16.3 and 21.8 cm(3), respectively; p = 0.02). The auto-contour-based method showed higher CIs than the manual method for GTV-1 (0.74 and 0.70 cm(3), respectively; p < 0.001) and GTV-2 (0.60 and 0.51 cm(3), respectively; p = 0.11). CONCLUSION: Source-to-background ratio-based auto-delineation showed a good correlation with pathology, decreased the delineated volumes of the GTVs, and reduced the interobserver variability. Auto-contouring may further improve the quality of target delineation in NSCLC patients.

Time trends in the maximal uptake of FDG on PET scan during thoracic radiotherapy. A prospective study in locally advanced non-small cell lung cancer (NSCLC) patients.

BACKGROUND AND PURPOSE: 18F-fluoro-2-deoxy-glucose (FDG) uptake on PET scan is a prognostic factor for outcome in NSCLC. We investigated changes in FDG uptake during fractionated radiotherapy in relation to metabolic response with the ultimate aim to adapt treatment according to early response. METHODS AND MATERIALS: Twenty-three patients, medically inoperable or with advanced NSCLC, underwent four repeated PET-CT scans before, during and after radiotherapy. Changes in maximal standardized uptake value (SUVmax) were described. Patients were treated with accelerated radiotherapy with a total tumour-dose depending on normal tissue dose constraints. RESULTS: The most striking result was the large intra-individual heterogeneity in the evolution of SUVmax. For the total group a non-significant increase in the first week (p=0.05), and a decrease in the second week (p=0.02) and after radiotherapy (p<0.01) was observed. Different time trends were shown for responders (no change during radiotherapy) and non-responders (48% increase during first week, p=0.02 and 15% decrease in the second week, p=0.04). Non-responders had a higher SUVmax on all time points investigated. CONCLUSIONS: Time trends in SUVmax showed a large intra-individual heterogeneity and different patterns for metabolic responders and non-responders. These new findings may reflect intrinsic tumour characteristics and might finally be useful to adapt treatment.

Tumour delineation and cumulative dose computation in radiotherapy based on deformable registration of respiratory correlated CT images of lung cancer patients.

PURPOSE: To improve treatment planning in radiotherapy for non-small cell lung cancer by including Respiratory Correlated-Computed Tomography (RC-CT) information in tumour delineation and dose planning. METHODS AND MATERIALS: Dense displacement fields were computed using a combination of rigid and non-rigid registrations between RC-CT phases. These registrations have been performed independently between each phase of the respiratory cycle and a reference phase for 13 patients. A manual delineation in the reference frame was propagated to every other phase according to the deformation fields recovered from the inter-phase registrations. Resulting delineations were compared to two manual delineations drawn by two physicians at each phase. On the other hand, dose distributions computed for every phase were deformed towards the reference phase. These distributions were then added on the reference phase to estimate the total dose received by each voxel through the whole respiratory cycle. RESULTS: The overlap between the deformed and the manual delineations was not significantly different than the overlap between the delineations made by the two physicians for 11 out of 13 patients thus proving that the method accuracy is comparable to inter-observer variability. Calculation of the effective dose distributions showed that these were conserved after deformation. CONCLUSION: We developed a method to use RC-CT information into the radiation treatment planning, including semi-automatic segmentation of lung tumours on each phase of the respiratory cycle and a total received dose per voxel estimation.

Individualized early death and long-term survival prediction after stereotactic radiosurgery for brain metastases of non-small cell lung cancer: Two externally validated nomograms.

INTRODUCTION: Commonly used clinical models for survival prediction after stereotactic radiosurgery (SRS) for brain metastases (BMs) are limited by the lack of individual risk scores and disproportionate prognostic groups. In this study, two nomograms were developed to overcome these limitations. METHODS: 495 patients with BMs of NSCLC treated with SRS for a limited number of BMs in four Dutch radiation oncology centers were identified and divided in a training cohort (n=214, patients treated in one hospital) and an external validation cohort n=281, patients treated in three other hospitals). Using the training cohort, nomograms were developed for prediction of early death (<3months) and long-term survival (>12months) with prognostic factors for survival. Accuracy of prediction was defined as the area under the curve (AUC) by receiver operating characteristics analysis for prediction of early death and long term survival. The accuracy of the nomograms was also tested in the external validation cohort. RESULTS: Prognostic factors for survival were: WHO performance status, presence of extracranial metastases, age, GTV largest BM, and gender. Number of brain metastases and primary tumor control were not prognostic factors for survival. In the external validation cohort, the nomogram predicted early death statistically significantly better (p<0.05) than the unfavorable groups of the RPA, DS-GPA, GGS, SIR, and Rades 2015 (AUC=0.70 versus range AUCs=0.51-0.60 respectively). With an AUC of 0.67, the other nomogram predicted 1year survival statistically significantly better (p<0.05) than the favorable groups of four models (range AUCs=0.57-0.61), except for the SIR (AUC=0.64, p=0.34). The models are available on www.predictcancer.org. CONCLUSION: The nomograms predicted early death and long-term survival more accurately than commonly used prognostic scores after SRS for a limited number of BMs of NSCLC. Moreover these nomograms enable individualized probability assessment and are easy into use in routine clinical practice.

The current status of FDG-PET in tumour volume definition in radiotherapy treatment planning.

Positron emission tomography (PET) scan, mainly using 18 F-fluoro-deoxyglucose (FDG) as a tracer, is currently widely accepted as a diagnostic tool in oncology. It may lead to a change in staging and therefore in treatment management. PET can also be used to define the target volume in radiation treatment planning and to evaluate treatment response. In this review, we focused on issues concerning the role of PET in target volume delineation, both for the primary tumour and regional lymph nodes. A literature search was performed using MEDLINE. Furthermore, the following questions were addressed: does PET allow accurate tumour delineation and does it improve the outcome of radiotherapy, in terms of reduced toxicity or a higher tumour control probability? Combined computer tomography (CT) and PET information seems to influence target volume delineation. Using (CT-) PET scan, interobserver variability is being reduced. Only few studies compared delineation based on PET with pathologic examination, showing a complex relation. Preliminary results concerning incorporation of PET information in to target volume delineation varies in different tumour sites. In the field of lung cancer, incorporation of PET seems to improve tumour coverage and spare normal tissues, which may lead to less toxicity or the possibility to escalate dose. In oesophageal cancer and in lymphoma, PET scan can be used to include PET positive lymph nodes in the target volume. In most other tumour sites not enough data are currently available to draw definitive conclusions about the role of PET in radiation treatment planning.

Intra-patient variability of tumor volume and tumor motion during conventionally fractionated radiotherapy for locally advanced non-small-cell lung cancer: a prospective clinical study.

PURPOSE: The aim of this study was to investigate the change in tumor volume, motion, and breathing frequency during a course of radiotherapy, for locally advanced non-small-cell lung cancer. METHODS AND MATERIALS: A total of 23 patients underwent computed tomography-positron emission tomography (CT-PET) and respiration correlated CT scans before treatment, which was repeated in the first and second weeks after the start of radiotherapy. Patients were treated with an accelerated fractionation schedule, 1.8 Gy twice a day, with a total tumor dose depending on preset dose constraints for the lungs and spinal cord. RESULTS: A striking heterogeneity of tumor volume changes was observed at all time points. In some patients the volume decreased >30% (3/23), whereas in others the volume increased >30% (4/24); but for the majority of patients (16/23), the tumor volume changed only slightly (<30%). No significant changes in average tumor motion or breathing frequencies were observed during treatment. Although a number of changes in individual tumor motion were seen, only in 1 patient would this have led to an increase of the internal margin >1 mm in 1 direction, 1 week after the start of treatment, and in 3 patients for 1 direction, 2 weeks after the start of the treatment. CONCLUSION: In this patients in this study, a large variability in changes in tumor volume was observed. This underscores the need for repeated imaging during the course of radiotherapy. However, the changes in tumor motion are small, which indicates that repeated respiration correlated CT does not appear to be necessary.