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.

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.

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.

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.

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.

What is the degree of innovation routinely implemented in Dutch radiotherapy centres? A multicentre cross-sectional study.

OBJECTIVE: To study the implementation of innovation activities in Dutch radiotherapy (RT) centres in a broad sense (product, technological, market and organizational innovations). METHODS: A descriptive cross-sectional study was conducted in 15 Dutch RT centres. A list of innovations implemented from 2011 to 2013 was drawn up for each centre using semi-structured interviews. These innovations were classified into innovation categories according to previously defined innovation indicators. Where applicable, each innovation was rated by each centre on the effort required to implement it and on its expected effects, to get an impression of how far reaching and radical the innovations were and to be able to compare the number of innovations between centres. RESULTS: The participating RT centres in the Netherlands implemented 12 innovations per year on average (range 5-25); this number was not significantly different for academic (n = 13) or non-academic centres (n = 10). Several centres were dealing with the same innovations at the same time. The average required effort and expected output did not differ significantly between product, technological and organizational innovation or between academic and non-academic centres. CONCLUSION: The number of innovations observed per centre varied across a large range, with a large overlap in terms of the type of innovations that were implemented. Registering innovations using the innovation indicators applied in our study would make it possible to improve collaboration between centres, e.g. with common training modules, to avoid duplication of work. Advances in knowledge: This study is the first of its kind investigating innovation implementation in RT in a broad sense.

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.

The influence of gastric filling instructions on dose delivery in patients with oesophageal cancer: A prospective study.

PURPOSE: To evaluate whether adaptive radiotherapy for unaccounted stomach changes in patients with adenocarcinoma of the gastroesophageal junction (GEJ) is necessary and whether dose differences could be prevented by giving patients food and fluid instructions before treatment simulation and radiotherapy. MATERIAL AND METHODS: Twenty patients were randomly assigned into two groups: patients with and without instructions about restricting food and fluid intake prior to radiotherapy simulation and treatment. Redelineation and offline recalculation of dose distributions based on cone-beam computed tomography (n=100) were performed. Dose-volume parameters were analysed for the clinical target volume extending into the stomach. RESULTS: Four patients who did not receive instructions had a geometric miss (0.7-12 cm(3)) in only one fraction. With instructions, 3 out of 10 patients had a geometric miss (0.1-1.9 cm(3)) in one (n=2) or two (n=1) fractions. The V95% was reduced by more than 5% for one patient, but this underdosage was in an in-air region without further clinical importance. CONCLUSIONS: Giving patients food and fluid instructions for the treatment of GEJ cancer offers no clinical benefit. Using a planning target volume margin of 1cm implies that there is no need for adaptive radiotherapy for GEJ tumours.

High dose rate and flattening filter free irradiation can be safely implemented in clinical practice.

PURPOSE: We hypothesize that flattening filter free (FFF) high dose rate irradiation will decrease cell survival in normal and cancer cells with more pronounced effects in DNA repair deficient cells. Additionally, we hypothesize that removal of the flattening filter will result in an enhanced relative biological effectiveness independent of the dose rate. MATERIALS AND METHODS: Clonogenic survival was assessed after exposure to dose rates of 4 or 24 Gy/min (FFF 10 megavolt [MV] photon beam) using a Varian TrueBeam accelerator. Additionally, cells were exposed to 4 Gy/min with or without flattening filter. Relative biological effectiveness estimations were performed comparing the different beam photon spectra. RESULTS: Cell survival in tumor and normal cell lines was not influenced by high dose rate irradiation. The intrinsic radiation sensitivity of DNA repair deficient cells was not affected by high dose rate compared to normal dose rate. Furthermore, the relative biological effectiveness was not significantly different from unity in any of the cell lines for both FFF and conventional flattened beam exposures. CONCLUSIONS: High dose rate irradiation did not affect long-term survival and DNA repair for cell lines of different tissues. This suggests that high dose rate does not influence treatment outcome or treatment toxicity and could be safely implemented in clinical routine.

Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long-term survival of patients with stage III NSCLC: a prospective population-based study.

BACKGROUND: Individualised, isotoxic, accelerated radiotherapy (INDAR) allows the delivery of high biological radiation doses, but the long-term survival associated with this approach is unknown. METHODS: Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included. RESULTS: Patients (1002) with stage III NSCLC were diagnosed, of which 938 had T4 and/or N2-N3 disease. Patients treated with curative intent were staged with FDG-PET scans and a contrast-enhanced CT or an MRI of the brain. There were no shifts over time in the patient or tumour characteristics at diagnosis. The number of stage III NSCLC patients remained stable over time, but the proportion treated with palliative intent decreased from 47% in 2002 to 37% in 2008, and the percentage treated with chemo-radiation (RT) increased from 24.6% in 2002 to 47.8% in 2008 (p<0.001). The proportion of surgical patients remained below 5%. Sequential chemotherapy and conventional RT resulted in a median and a 5-year survival of 17.5 months and 8.4%, respectively, whereas with sequential chemotherapy and INDAR this was 23.6 months and 31%, respectively (p<0.001). Concurrent chemotherapy and INDAR was associated with a median and 2-year survival that was not reached and 66.7%, respectively (p=0.004). CONCLUSIONS: The proportion of patients treated with a curative intention with chemo-RT has increased markedly over time of observation. INDAR is associated with longer survival when compared to standard dose RT alone given with or without chemotherapy.

Phased versus midventilation attenuation-corrected respiration-correlated PET for patients with non-small cell lung cancer.

UNLABELLED: Respiration-correlated PET (RCPET) can reduce motion artifacts, but image quality generally decreases. The use of phase-by-phase attenuation correction (PAC) for RCPET using respiration-correlated CT (RCCT) requires large computational resources, and tumor positions will not always match correctly because of different binning methods for CT and PET. In this study, we investigated whether PAC for RCPET can be replaced by midventilation attenuation correction (MidV-AC) for a group of lung cancer patients. METHODS: RCPET/CT scans of 19 non-small cell lung cancer patients were performed. List-mode PET and CT data were binned and reconstructed into 8 phases. Two AC methods for RCPET were applied. First, the corresponding 8 RCCT phases were used for PAC. Then MidV-AC was used. Analyses were performed in terms of standardized uptake values (SUVs), volume recovery, contrast, and signal-to-noise ratio (SNR). RESULTS: Average differences between PAC and MidV-AC for mean and maximum SUV were 1.0% and 0.9% (P = 0.007 and P = 0.002), respectively, whereas SNR, contrast, and volume did not differ significantly (P >or= 0.2). Large motion amplitudes and irregular breathing revealed larger differences between phase 1 and MidV-AC values. CONCLUSION: Differences in SUV, volume, SNR, and contrast between PAC as available in currently used clinical software and MidV-AC for RCPET are small. MidV-AC provides an excellent surrogate for PAC for most lung cancer patients encountered in clinical practice.

Identification of residual metabolic-active areas within individual NSCLC tumours using a pre-radiotherapy (18)Fluorodeoxyglucose-PET-CT scan.

BACKGROUND AND PURPOSE: Non-small cell lung cancer (NSCLC) tumours are mostly heterogeneous. We hypothesized that areas within the tumour with a high pre-radiation (18)F-deoxyglucose (FDG) uptake, could identify residual metabolic-active areas, ultimately enabling selective-boosting of tumour sub-volumes. MATERIAL AND METHODS: Fifty-five patients with inoperable stage I-III NSCLC treated with chemo-radiation or with radiotherapy alone were included. For each patient one pre-radiotherapy and one post-radiotherapy FDG-PET-CT scans were available. Twenty-two patients showing persistent FDG uptake in the primary tumour after radiotherapy were analyzed. Overlap fractions (OFs) were calculated between standardized uptake value (SUV) threshold-based auto-delineations on the pre- and post-radiotherapy scan. RESULTS: Patients with residual metabolic-active areas within the tumour had a significantly worse survival compared to individuals with a complete metabolic response (p=0.002). The residual metabolic-active areas within the tumour largely corresponded (OF>70%) with the 50%SUV high FDG uptake area of the pre-radiotherapy scan. The hotspot within the residual area (90%SUV) was completely within the GTV (OF=100%), and had a high overlap with the pre-radiotherapy 50%SUV threshold (OF>84%). CONCLUSIONS: The location of residual metabolic-active areas within the primary tumour after therapy corresponded with the original high FDG uptake areas pre-radiotherapy. Therefore, a single pre-treatment FDG-PET-CT scan allows for the identification of residual metabolic-active areas.

Tumor delineation based on time-activity curve differences assessed with dynamic fluorodeoxyglucose positron emission tomography-computed tomography in rectal cancer patients.

PURPOSE: To develop an unsupervised tumor delineation method based on time-activity curve (TAC) shape differences between tumor tissue and healthy tissue and to compare the resulting contour with the two tumor contouring methods mostly used nowadays. METHODS AND MATERIALS: Dynamic positron emission tomography-computed tomography (PET-CT) acquisition was performed for 60 min starting directly after fluorodeoxyglucose (FDG) injection. After acquisition and reconstruction, the data were filtered to attenuate noise. Correction for tissue motion during acquisition was applied. For tumor delineation, the TAC slope values were k-means clustered into two clusters. The resulting tumor contour (Contour I) was compared with a contour manually drawn by the radiation oncologist (Contour II) and a contour generated using a threshold of the maximum standardized uptake value (SUV; Contour III). RESULTS: The tumor volumes of Contours II and III were significantly larger than the tumor volumes of Contour I, with both Contours II and III containing many voxels showing flat TACs at low activities. However, in some cases, Contour II did not cover all voxels showing upward TACs. CONCLUSION: Both automated SUV contouring and manual tumor delineation possibly incorrectly assign healthy tissue, showing flat TACs, as being malignant. On the other hand, in some cases the manually drawn tumor contours do not cover all voxels showing steep upward TACs, suspected to be malignant. Further research should be conducted to validate the possible superiority of tumor delineation based on dynamic PET analysis.

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.

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.