Challenging the indiscriminate use of temozolomide in pediatric high-grade gliomas: A review of past, current, and emerging therapies.

Pediatric high-grade gliomas (pHGG) constitute 8% to 12% of primary brain tumors in childhood. The most widely utilized treatment encompasses surgical resection followed by focal radiotherapy and temozolomide. However, experiences over past decades have not demonstrated improved outcomes. pHGG have been classified into different molecular subgroups defined by mutations in histone 3, IDH gene, MAPK pathway, and others, thereby providing a rationale for various targeted therapies. Additionally, immunotherapy and drug repurposing have also become attractive adjunctive treatments. This review focuses on past, present, and emerging treatments for pHGG integrating molecular research with the mainstream pediatric drug development in Europe and the United States to sketch a way forward in the development of novel therapeutic approaches. The implementation of randomized clinical trials with adaptive designs, underpinned by a robust biological rationale, and harnessing collaboration between the pharmaceutical industry, academia, regulators and patients/parents organizations will be essential to improve the outcomes for these children.

Patient-specific dosimetry for intracavitary 32P-chromic phosphate colloid therapy of cystic brain tumours.

PURPOSE: (32)P-chromic phosphate colloid treatments of astrocytoma and craniopharyngioma cystic brain tumours in paediatric patients are conventionally based on a sphere model under the assumption of uniform uptake. The aims of this study were to determine the distribution of the absorbed dose delivered by (32)P on a patient-specific basis and to evaluate the accuracy with which this can be predicted from a pretherapy administration of (99m)Tc-Sn colloid. METHODS: Three patients were treated with (32)P-chromic phosphate colloid following (99m)Tc-Sn colloid administrations. Convolution dosimetry was performed using pretherapy and posttherapy sequential SPECT imaging, and verified with EGSnrc Monte Carlo radiation transport simulations. Mean absorbed doses to the cyst wall and dose-volume histograms were also calculated and compared with those obtained by the sphere model approach. RESULTS: Highly nonuniform uptake distributions of both the (99m)Tc and (32)P colloids were observed and characterized by dose-volume histograms to the cyst wall. Mean absorbed doses delivered to the cyst wall, obtained with the convolution method, were on average 21 % (SD 18 %) and 50 % (SD 30 %) lower than those predicted by the (99m)Tc distribution and the uniform assumption of the sphere model, respectively. CONCLUSION: Absorbed doses delivered to the cyst wall by (32)P are more accurately predicted from image-based patient-specific convolution dosimetry than from simple sphere models. These results indicate the necessity to perform personalized treatment planning and verification for intracavitary irradiation of cystic brain tumours treated with radiocolloids. Patient-specific dosimetry can be used to guide the frequency and levels of repeated administrations and would facilitate data collection and comparison to support the multicentre trials necessary to progress this therapy.

Whole-body dosimetry for individualized treatment planning of 131I-MIBG radionuclide therapy for neuroblastoma.

UNLABELLED: The aims of this study were to examine the relationship between whole-body absorbed dose and hematologic toxicity and to assess the most accurate method of delivering a prescribed whole-body absorbed dose in (131)I-metaiodobenzylguanidine ((131)I-MIBG) therapy for neuroblastoma. METHODS: A total of 20 children (1-12 y), 5 adolescents (13-17 y), and 1 adult (20 y) with stage 3 or 4 neuroblastoma were treated to a prescribed whole-body absorbed dose, which in most cases was 2 Gy. Forty-eight administrations of (131)I-MIBG were given to the 26 patients, ranging in activity from 1,759 to 32,871 MBq. For 30 administrations, sufficient data were available to assess the effect of whole-body absorbed dose on hematologic toxicity. Comparisons were made between the accuracy with which a whole-body absorbed dose could be predicted using a pretherapy tracer study and the patient's most recent previous therapy. The whole-body absorbed dose that would have been delivered if the administered activity was fixed (7,400 MBq) or determined using a weight-based formula (444 MBq.kg(-1)) was also estimated. RESULTS: The mean whole-body absorbed dose for patients with grade 4 Common Terminology Criteria for Adverse Events (CTCAE) neutropenia after therapy was significantly higher than for those with grade 1 CTCAE neutropenia (1.63 vs. 0.90 Gy; P = 0.05). There was no correlation between administered activity and hematologic toxicity. Absorbed whole-body doses predicted from previous therapies were within +/-10% for 70% of the cases. Fixed-activity administrations gave the largest range in whole-body absorbed dose (0.30-3.11 Gy). CONCLUSION: The results indicate that even in a highly heterogeneous and heavily pretreated patient population, a whole-body absorbed dose can be prescribed accurately and is a more accurate predictor of hematologic toxicity than is administered activity. Therefore, a whole-body absorbed dose can be used to deliver accurate and reproducible (131)I-MIBG therapy on a patient-specific basis.

Dosimetric accuracy of dynamic couch rotation during volumetric modulated arc therapy (DCR-VMAT) for primary brain tumours.

Radiotherapy treatment plans using dynamic couch rotation during volumetric modulated arc therapy (DCR-VMAT) reduce the dose to organs at risk (OARs) compared to coplanar VMAT, while maintaining the dose to the planning target volume (PTV). This paper seeks to validate this finding with measurements. DCR-VMAT treatment plans were produced for five patients with primary brain tumours and delivered using a commercial linear accelerator (linac). Dosimetric accuracy was assessed using point dose and radiochromic film measurements. Linac-recorded mechanical errors were assessed by extracting deviations from log files for multi-leaf collimator (MLC), couch, and gantry positions every 20 ms. Dose distributions, reconstructed from every fifth log file sample, were calculated and used to determine deviations from the treatment plans. Median (range) treatment delivery times were 125 s (123-133 s) for DCR-VMAT, compared to 78 s (64-130 s) for coplanar VMAT. Absolute point doses were 0.8% (0.6%-1.7%) higher than prediction. For coronal and sagittal films, respectively, 99.2% (96.7%-100%) and 98.1% (92.9%-99.0%) of pixels above a 20% low dose threshold reported gamma <1 for 3% and 3 mm criteria. Log file analysis showed similar gantry rotation root-mean-square error (RMSE) for VMAT and DCR-VMAT. Couch rotation RMSE for DCR-VMAT was 0.091° (0.086-0.102°). For delivered dose reconstructions, 100% of pixels above a 5% low dose threshold reported gamma <1 for 2% and 2 mm criteria in all cases. DCR-VMAT, for the primary brain tumour cases studied, can be delivered accurately using a commercial linac.

Optimization of equipment and methodology for whole body activity retention measurements in children undergoing targeted radionuclide therapy.

Accurate measurements of whole-body activity retention of patients during radionuclide therapy are essential for two reasons: First, they enable the correct radiation protection advice to be given and second, they permit the accurate determination of the absorbed whole-body dose delivered during therapy. This, in turn, allows treatment planning to be carried out for future radionuclide therapy on an individual patient basis, and also enables the investigation of the potential correlation of absorbed dose with treatment outcome in groups of patients. There are significant difficulties associated with taking whole-body retention measurements of children, especially when they are very young and/or unwell. It is essential to carry these out in a way that minimises disturbance to the child while still providing good quality data. To accomplish this, we have aimed to optimize the following aspects of the procedure: (i) the environment in which the measurements are performed; (ii) the equipment--which includes the recent installation of a specially designed whole-body activity monitoring system for these patients; and (iii) the methodology for calculating the absorbed dose. These improvements have allowed large numbers of accurate and reproducible whole-body measurements to be collected following patient administrations. This has enabled the identification of more phases of radionuclide excretion during therapy than had previously been observed. These data have been used for radiation protection advice and treatment planning. Two (2) patients were given multiple radionuclide treatments and we were able to compare the whole-body doses delivered.

Dosimetry for fractionated (131)I-mIBG therapies in patients with primary resistant high-risk neuroblastoma: preliminary results.

This paper describes the development of a protocol for SPECT-based tumor dosimetry for (131)I-mIBG therapy patients with high-risk neuroblastoma. The treatment aims to deliver a whole-body dose of 4 Gy in two fractions. Whole-body retention measurements taken during the first fraction are used to guide the second therapy administration. The tumor dose from 3 patients was assessed by acquiring a minimum of three SPECT scans. Dead-time and triple-energy window scatter corrections were applied. The images were reconstructed using filtered backprojection with a Chang attenuation correction, and a phantom-based calibration factor was used to convert to activity. A monoexponential fit was made to the data, and instantaneous uptake was assumed. Tumor absorbed-dose ratios were used to analyze intrapatient variations, and absolute tumor dosimetry was used to assess interpatient variation. The whole-body dose administered ranged from (3.7 +/- 0.1) Gy to (3.9 +/- 0.3) Gy. This method is more accurate than a weight-based administration method. Despite this, a variation in absorbed tumor dose of 10-103 Gy was observed. All repeat doses were in the same order of magnitude, although 2 patients received a lower tumor dose per MBq from the second therapy owing to a shorter biological half-life. The tumor dosimetry protocol was simple to apply and reproducible, but the errors in image quantitation needed to be evaluated.

Non-coplanar trajectories to improve organ at risk sparing in volumetric modulated arc therapy for primary brain tumors.

BACKGROUND AND PURPOSE: To evaluate non-coplanar volumetric modulated arc radiotherapy (VMAT) trajectories for organ at risk (OAR) sparing in primary brain tumor radiotherapy. MATERIALS AND METHODS: Fifteen patients were planned using coplanar VMAT and compared against non-coplanar VMAT plans for three trajectory optimization techniques. A geometric heuristic technique (GH) combined beam scoring and Dijkstra's algorithm to minimize the importance-weighted sum of OAR volumes irradiated. Fluence optimization was used to perform a local search around coplanar and GH trajectories, producing fluence-based local search (FBLS) and FBLS+GH trajectories respectively. RESULTS: GH, FBLS, and FBLS+GH trajectories reduced doses to the contralateral globe, optic nerve, hippocampus, temporal lobe, and cochlea. However, FBLS increased dose to the ipsilateral lens, optic nerve and globe. Compared to GH, FBLS+GH increased dose to the ipsilateral temporal lobe and hippocampus, contralateral optics, and the brainstem and body. GH and FBLS+GH trajectories reduced bilateral hippocampi normal tissue complication probability (p=0.028 and p=0.043, respectively). All techniques reduced PTV conformity; GH and FBLS+GH trajectories reduced homogeneity but less so for FBLS+GH. CONCLUSIONS: The geometric heuristic technique best spared OARs and reduced normal tissue complication probability, however incorporating fluence information into non-coplanar trajectory optimization maintained PTV homogeneity.

Feasibility of dosimetry-based high-dose 131I-meta-iodobenzylguanidine with topotecan as a radiosensitizer in children with metastatic neuroblastoma.

INTRODUCTION: (131)I-meta iodobenzylguanidine ((131)I-mIBG) therapy is established palliation for relapsed neuroblastoma. The topoisomerase-1 inhibitor, topotecan, has direct activity against neuroblastoma and acts as a radiation sensitiser. These 2 treatments are synergistic in laboratory studies. Theoretically, the benefit of (131)I-mIBG treatment could be enhanced by dose escalation and combination with topotecan. Haematological support would be necessary to overcome the myelosuppression, which is the dose-limiting toxicity. AIMS: Firstly, one aim of this study was to establish whether in vivo dosimetry could be used to guide the delivery of a precise total whole-body radiation-absorbed dose of 4 Gy accurately from 2 (131)I-mIBG treatments. Secondly, the other aim of this study was to determine whether it is feasible to combine this treatment with the topotecan in children with metastatic neuroblastoma. MATERIAL AND METHODS: An activity of (131)I-mIBG (12 mCi/kg, 444 MBq/kg), estimated to give a whole-body absorbed-radiation dose of approximately 2 Gy, was administered on day 1, with topotecan 0.7 mg/m(2) administered daily from days 1-5. In vivo dosimetry was used to calculate a 2nd activity of (131)I-mIBG, to be given on day 15 which would give a total whole-body dose of 4 Gy. A further 5 doses of topotecan were given from days 15-19. The myeloablative effect of this regimen was circumvented by peripheral blood stem cell or bone marrow support. RESULTS: Eight children with relapsed stage IV neuroblastoma were treated. The treatment was delivered according to protocol in all patients. There were no unanticipated side-effects. Satisfactory haematological reconstitution occurred in all patients. The measured total whole-body radiation-absorbed dose ranged from 3.7 Gy to 4.7 Gy (mean, 4.2 Gy). CONCLUSIONS: In vivo dosimetry allows for a specified total whole-body radiation dose to be delivered accurately. This schedule of intensification of (131)I-mIBG therapy by dose escalation and radiosensitization with topotecan with a haemopoietic autograft is safe and practicable. This approach should now be tested for efficacy in a phase II clinical trial.

Managing teenage/young adult (TYA) brain tumors: a UK perspective.

Tumors of the CNS are among the commonest malignancies occurring in teenage/young adult patients (i.e., those aged between 15 and 24 years). The treatment of this patient population is challenging. Adolescence and young adulthood are a turbulent period of life, with physical, emotional, social and cognitive changes. Best practice advocates their treatment in dedicated teenage/young adult units, with multidisciplinary team input and access to clinical trials. Treatment of CNS malignancies is dependent upon histological subtype and staging, with varying combinations of surgery, radiotherapy and chemotherapy used. Clinical trials directly targeted at this patient population are rare; treatments are based on pediatric protocols as studies have demonstrated improved outcomes in patients (with other malignancies) treated as such. Scope for improvement lies in minimizing patient risk of recurrence and long-term sequelae of treatment. Molecular characterization of tumors may provide further information.

Stereotactically guided conformal radiotherapy for progressive low-grade gliomas of childhood.

PURPOSE: To describe the rationale, technique, and early results of stereotactically guided conformal radiotherapy (SCRT) in the treatment of progressive or inoperable low-grade gliomas (LGGs) of childhood. METHODS AND MATERIALS: Between September 1994 and May 1999, 14 children (median age 6 years, range 5-16) with LGG were treated with SCRT at the Royal Marsden NHS Trust. Tumors were located at the optic chiasm (n = 9), third ventricle (n = 2), hypothalamus, craniocervical junction, and pineal region (each n = 1). Four patients received chemotherapy before SCRT. Immobilization was in a Gill-Thomas-Cosman frame (n = 12) and subsequently in a specially designed pediatric version of the frame (n = 2). Stereotactic coordinates and the tumor were defined by CT scanning with a fiducial system and MRI fusion. The median tumor volume was 19.5 cm(3) (range 7.5-180). The planning target volume was defined as the area of enhancing tumor plus a 5-10-mm margin. The treatment technique consisted of 4 isocentric, noncoplanar, conformal, fixed fields. Treatment was delivered in 30-33 daily fractions to a total dose of 50-55 Gy. RESULTS: SCRT was well tolerated, with transient hair loss the only acute toxicity. The median follow-up was 33 months (range 2-53). At 6 months after SCRT, 4 of 12 children with neurologic deficits improved and 5 remained stable. Twelve children were available for MRI evaluation. Two had a complete response, 6 a partial response, and 4 stable disease. One child with optic chiasm glioma had local progression at 25 months, and 1 developed diffuse leptomeningeal disease without local progression at 27 months. The 3-year local progression-free survival and overall survival rate after SCRT was 87% and 100%, respectively, compared with 89% and 98% for an historic control treated with conventional RT. New endocrine deficiencies were noted in 2 children after a follow-up of 20 and 23 months. CONCLUSION: SCRT is a feasible, high-precision technique of RT for children with LGGs for whom RT is considered appropriate. The local control and acute toxicity of SCRT are comparable to a historic control of patients with conventionally delivered RT. The frequency of delayed hypothalamic-pituitary axis dysfunction reflects tumor location adjacent to the hypothalamus and pituitary. Additional follow-up is required to demonstrate that SCRT contributes to a reduction in treatment-related late toxicity, while maintaining the local control achieved with conventionally delivered RT in children with progressive LGGs.

Commissioning and implementation of a stereotactic conformal radiotherapy technique using a general-purpose planning system.

The purpose of this paper is to report on commissioning and clinical implementation of a customized system for pediatric stereotactic conformal radiotherapy (SCRT). The system is based on the Pinnacle treatment-planning system and its interfaces with other equipment: (1) Beam models were optimized for our compact blocking system and a new LINAC. (2) Three CT-to-density conversion tables were evaluated, one using tabulated data for a commercial phantom, the second including additional points from the manufacturer's data for the inserts in an in-house phantom, and the third using measured densities for the in-house phantom materials combined with tabulated data for the commercial phantom. (3) Blocks were transferred to a computerized block cutter using in-house software that extracted the block shape from the export file and custom-fitted the additional necessary shapes. (4) In the absence of a DICOM RT Image link, a method based on screen data capture was used to export digitally reconstructed radiographs (DRRs) to two portal imaging systems for treatment verification. Lens shielding by multileaf collimation in the anterior-posterior isocenter verification field was investigated. (1) Computed dose distributions using the beam models agreed with measurements well within published acceptability criteria. A difference of up to 1.0 mm was measured between the beam's eye views of aperture blocks and computed 50% isodose contours for a 2 x 2 x 2 mm dose calculation grid. (2) The third table, which included measured densities, improved the accuracy of the calculated isocenter dose by up to 0.5% in typical patient SCRT treatments and up to 1.0% in a phantom with 5-cm diameter inhomogeneity inserts. (3) The block export and customization process was shown to introduce no additional uncertainty. A 1-mm block production uncertainty was measured using film dosimetry on six blocks. (4) The DRR transfer method did not introduce uncertainty into the process. Verification field shielding reduced lens dose by 12 to 15 times. In conclusion, this customized system for planning and verification of pediatric SCRT provides a high level of precision as well as reasonable practical efficiency.

Use of volumetric-modulated arc therapy for treatment of Hodgkin lymphoma.

To evaluate volumetric-modulated arc therapy (VMAT) for treatment of Hodgkin lymphoma (HL) in patients where conventional radiotherapy was not deliverable. A planning computed tomography (CT) scan was acquired for a twelve-year-old boy with Stage IIIB nodular sclerosing HL postchemotherapy with positive positron emission tomography scan. VMAT was used for Phase 1 (19.8Gy in 11 fractions) and Phase 2 (10.8Gy in 6 fractions) treatment plans. Single anticlockwise arc plans were constructed using SmartArc (Philips Radiation Oncology Systems, Fitchburg, WI) with control points spaced at 4°. The inverse-planning objectives were to uniformly irradiate the planning target volume (PTV) with the prescription dose while keeping the volume of lung receiving greater than 20Gy (V20Gy) to less than 30% and minimize the dose to the other adjacent organs at risk (OAR). Pretreatment verification was conducted and the treatment delivery was on an MLCi Synergy linear accelerator (Elekta Ltd, Crawley, UK). The planning results were retrospectively confirmed in a further 4 patients using a single PTV with a prescribed dose of 19.8Gy in 11 fractions. Acceptable dose coverage and homogeneity were achieved for both Phase 1 and 2 plans while keeping the lung V20Gy at 22.5% for the composite plan. The beam-on times for Phase 1 and Phase 2 plans were 109 and 200 seconds, respectively, and the total monitor units were 337.2MU and 292.5MU, respectively. The percentage of measured dose points within 3% and 3mm for Phase 1 and Phase 2 were 92% and 98%, respectively. Both plans were delivered successfully. The retrospective planning study showed that VMAT improved PTV dose uniformity and reduced the irradiated volume of heart and lung, although the volume of lung irradiated to low doses increased. Two-phased VMAT offers an attractive option for large volume sites, such as HL, giving a high level of target coverage and significant OAR sparing together with efficient delivery.

Helical volumetric modulated arc therapy for treatment of craniospinal axis.

PURPOSE: Volumetric modulated arc therapy (VMAT) can be used with multiple isocenters to provide an effective treatment of the craniospinal axis. Additional efficiency can be achieved by simultaneously applying linear couch motion to generate a helical arc trajectory. This study investigated the treatment planning and delivery of helical VMAT for treatment of the craniospinal axis. METHODS AND MATERIALS: VMAT plans were retrospectively created for 5 patients. The first plan consisted of multiple separate arcs. A second plan consisted of a single helical arc with a pitch of 10 cm. Three additional plans consisted of multiple helical arcs with the beam rotating alternately clockwise and counterclockwise to avoid the need for the gantry to pass through 180°. The three plans had a pitch of 5, 10, and 15 cm. For 1 of the patients, three possible plans with alternate gantry motion and a pitch of 10 cm were delivered helically, and the dose was verified. RESULTS: Relative to the plan with separate arcs, the continuous helical plan produced a mean objective value of 104.0% ± 14.8% (standard deviation), and the alternating helical plans produced an objective value of 118.9% ± 9.8%, 102.3% ± 13.5%, and 101.5% ± 15.8% for a pitch of 5 cm, 10 cm, and 15 cm, respectively (with lower values representing better plans). For the delivered plans, taking a mean of 17 min 51 s to deliver, a mean of 97.1% of the measurements were within 4% and 4 mm of the planned dose. CONCLUSIONS: A continuous helical VMAT plan provides comparable dose quality to a plan with separate VMAT arcs. Comparable quality is also produced by an alternating helical plan, provided the pitch is chosen appropriately. Alternating helical plans have been delivered and verified successfully. Alternating helical delivery offers the ultimate delivery efficiency for intensity-modulated radiotherapy for the craniospinal axis.

Development and evaluation of multiple isocentric volumetric modulated arc therapy technique for craniospinal axis radiotherapy planning.

PURPOSE: To develop and compare a volumetric modulated arc therapy (VMAT) technique with conventional radiotherapy for craniospinal irradiation with respect to improved dose conformity and homogeneity in the planning target volume (PTV) and to reduced dose to organs at risk (OAR). METHODS AND MATERIALS: Conventional craniospinal axis radiotherapy plans of 5 patients were acquired. The median (range) length of the PTV was 58.9 (48.1-83.7) cm. The 6-MV VMAT plans were inversely planned with one isocenter near the base of the brain and the minimum number of isocenters required for the specified lengths of spine. The plans were optimized with high weighting for PTV coverage and low weighting for OAR sparing. Conformity and heterogeneity indices, dose-volume histograms, mean doses, and non-PTV integral doses from the two plans (prescription dose 23.4 Gy in 13 fractions) were compared. RESULTS: The median (range) conformity index of VMAT was 1.22 (1.09-1.45), compared with 1.69 (1.44-2.67) for conventional plans (p = 0.04). The median (range) heterogeneity index was also lower for VMAT compared with conventional plans: 1.04 (1.03-1.07) vs. 1.12 (1.09-1.19), respectively (p = 0.04). A significant reduction of mean and maximum doses was observed in the heart, thyroid, esophagus, optic nerves, and eyes with VMAT when compared with conventional plans. A decrease in body V(10Gy) was observed, but for 4 of 5 patients non-PTV integral dose was increased with VMAT when compared with the conventional plans. CONCLUSIONS: A VMAT technique to treat the craniospinal axis significantly reduces OAR dose, potentially leading to lower late organ toxicity. However, this is achieved at the expense of increased low-dose volumes, which is inherent to the technique, carrying a potentially increased risk of secondary malignancies.

Comparison of conventional radiotherapy and intensity-modulated radiotherapy for post-operative radiotherapy for primary extremity soft tissue sarcoma.

INTRODUCTION: Doses in conventional radiotherapy for extremity soft tissue sarcoma (STS) potentially exceed normal tissue tolerances. This study compares 3D-conformal radiotherapy (3D-CRT) with intensity-modulated radiotherapy (IMRT) in optimising target volume coverage and minimising integral dose to organs-at-risk (OAR). METHODS AND MATERIALS: Ten patients undergoing post-operative radiotherapy for extremity STS were assessed. PTV(1) was defined as tumour bed plus 5cm superiorly/inferiorly and 3cm circumferentially, PTV(2) was defined as 2cm isotropically. OAR were defined as whole femur, neurovascular bundle, tissue corridor and normal tissue outside PTV(1). For each patient 2-phase 3D-CRT was compared to 2/3 field (2/3f) and 4/5 field (4/5f) IMRT with simultaneous integrated boost (SIB). The primary planning objective was to minimise femur and skin corridor dose. Volumetric analysis and conformity and heterogeneity indices were used for plan comparison. RESULTS: A planning protocol containing dose/volume constraints for target and OAR was defined. 4/5f IMRT showed greatest conformity and homogeneity. IMRT resulted in significantly lower femur V45 using 2/3f (p=0.01) and 4/5f (p=0.0009) than 3D-CRT. 4/5f IMRT resulted in significantly lower normal tissue V55 (p=0.004) and maximum dose (p=0.04) than 3D-CRT. CONCLUSIONS: A reproducible set of planning guidelines and dose-volume constraints for 3D-CRT and IMRT planning for extremity sarcomas was devised. 4/5f IMRT with SIB resulted in better target coverage and significantly decreased OAR dose. Further evaluation of this technique within a clinical trial is recommended to demonstrate that the technical benefit of the more complex technique translates into patient-derived benefit by reducing late toxicity.