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Purpose: Local recurrence remains the main cause of death in stage III-IV nonmetastatic head and neck cancer (HNC), with relapse-prone regions within high 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET)-signal gross tumor volume. We investigated if dose escalation within this subvolume combined with a 3-phase treatment adaptation could increase local (LC) and regional (RC) control at equal or minimized radiation-induced toxicity, by comparing adaptive 18 F-FDG-PET voxel intensity-based dose painting by numbers (A-DPBN) with nonadaptive standard intensity modulated radiation therapy (S-IMRT)., Methods and Materials: This 2-center randomized controlled phase 2 trial assigned (1:1) patients to receive A-DPBN or S-IMRT (+/-chemotherapy). Eligibility: nonmetastatic HNC of oral cavity, oro-/hypopharynx, or larynx, needing radio(chemo)therapy; T1-4N0-3 (exception: T1-2N0 glottic); KPS ≥ 70; ≥18 years; and informed consent., Primary Outcomes: 1-year LC and RC. The dose prescription for A-DPBN was intercurrently adapted in 2 steps to an absolute dose-volume limit (≤1.75 cm 3 can receive >84 Gy and normalized isoeffective dose >96 Gy) as a safety measure during the study course after 4/7 A-DPBN patients developed ≥G3 mucosal ulcers., Results: Ninety-five patients were randomized (A-DPBN, 47; S-IMRT, 48). Median follow-up was 31 months (IQR, 14-48 months); 29 patients died (17 of cancer progression). A-DPBN resulted in superior LC compared with S-IMRT, with 1- and 2-year LC of 91% and 88% versus 78% and 75%, respectively (hazard ratio, 3.13; 95% CI, 1.13-8.71; P = .021). RC and overall survival were comparable between arms, as was overall grade (G) ≥3 late toxicity (36% vs 20%; P = .1). More ≥G3 late mucosal ulcers were observed in active smokers (29% vs 3%; P = .005) and alcohol users (33% vs 13%; P = .02), independent of treatment arm. Similarly, in the A-DPBN arm, significantly more patients who smoked at diagnosis developed ≥G3 (46% vs 12%; P = .005) and ≥G4 (29% vs 8%; P = .048) mucosal ulcers. One arterial blowout occurred after a G5 mucosal toxicity., Conclusions: A-DPBN resulted in superior 1- and 2-year LC for HNC compared with S-IMRT. This supports further exploration in multicenter phase 3 trials. It will, however, be challenging to recruit a substantial patient sample for such trials, as concerns have arisen regarding the association of late mucosal ulcers when escalating the dose in continuing smokers., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Improved outcome is reported after surgery or external beam radiation therapy (EBRT) plus androgen deprivation therapy (ADT) for patients with lymph node (LN) positive (N1) prostate cancer (PC). Surgical series have shown that pathologic (p)N1 PC does not behave the same in all patients. The aim of this study was to perform a matched-case analysis to compare the outcome of pN1 and pN0 PC after high-dose EBRT plus ADT., Methods and Materials: Radiation therapy up to 80 Gy was delivered to the prostate with a minimal dose of 45 Gy to the pelvis for pN1 patients. After matching, Kaplan-Meier statistics were used to compare the 5-year biochemical and clinical relapse-free survival (bRFS and cRFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Acute and late rectal and urinary toxicity was evaluated., Results: Sixty-nine pN1 PC patients were matched 1:1 with pN0 PC patients. The median follow-up time was 60 months. The 5-year bRFS and cRFS for pN1 versus pN0 PC patients were 65% ± 7% versus 79% ± 5% (P=.08) and 70% ± 6% versus 83% ± 5% (P=.04) respectively. No significant difference was found in bRFS or cRFS rates between low volume pN1 (≤2 positive LNs) and pN0 patients. The 5-year PCSS and OS were comparable between pN1 and pN0 PC patients: PCSS: 92% ± 4% versus 93% ± 3% (P=.66); OS: 82% ± 5% versus 80% ± 5% (P=.58). Severe toxicity was rare for both groups, although pN1 patients experienced significantly more acute grade 2 rectal toxicity., Conclusion: Primary EBRT plus 2 to 3 years of ADT is a legitimate treatment option for pN1 PC patients, especially those with ≤2 positive LNs, and this with bRFS and cRFS rates comparable to those in pN0 PC patients. For pN1 PC patients with >2 positive LNs, bRFS and cRFS are worse than in pN0 patients, but even in this subgroup, long-term disease control is obtained., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to determine the effects of atlas selection based on different morphometric parameters, on the accuracy of automatic brachial plexus (BP) segmentation for radiation therapy planning. The segmentation accuracy was measured by comparing all of the generated automatic segmentations with anatomically validated gold standard atlases developed using cadavers., Methods and Materials: Twelve cadaver computed tomography (CT) atlases (3 males, 9 females; mean age: 73 years) were included in the study. One atlas was selected to serve as a patient, and the other 11 atlases were registered separately onto this "patient" using deformable image registration. This procedure was repeated for every atlas as a patient. Next, the Dice and Jaccard similarity indices and inclusion index were calculated for every registered BP with the original gold standard BP. In parallel, differences in several morphometric parameters that may influence the BP segmentation accuracy were measured for the different atlases. Specific brachial plexus-related CT-visible bony points were used to define the morphometric parameters. Subsequently, correlations between the similarity indices and morphometric parameters were calculated., Results: A clear negative correlation between difference in protraction-retraction distance and the similarity indices was observed (mean Pearson correlation coefficient = -0.546). All of the other investigated Pearson correlation coefficients were weak., Conclusions: Differences in the shoulder protraction-retraction position between the atlas and the patient during planning CT influence the BP autosegmentation accuracy. A greater difference in the protraction-retraction distance between the atlas and the patient reduces the accuracy of the BP automatic segmentation result., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To assess the accuracy of contour deformation and feasibility of dose summation applying deformable image coregistration in adaptive dose painting by numbers (DPBN) for head and neck cancer., Methods and Materials: Data of 12 head-and-neck-cancer patients treated within a Phase I trial on adaptive (18)F-FDG positron emission tomography (PET)-guided DPBN were used. Each patient had two DPBN treatment plans: the initial plan was based on a pretreatment PET/CT scan; the second adapted plan was based on a PET/CT scan acquired after 8 fractions. The median prescription dose to the dose-painted volume was 30 Gy for both DPBN plans. To obtain deformed contours and dose distributions, pretreatment CT was deformed to per-treatment CT using deformable image coregistration. Deformed contours of regions of interest (ROI(def)) were visually inspected and, if necessary, adjusted (ROI(def_ad)) and both compared with manually redrawn ROIs (ROI(m)) using Jaccard (JI) and overlap indices (OI). Dose summation was done on the ROI(m), ROI(def_ad), or their unions with the ROI(def)., Results: Almost all deformed ROIs were adjusted. The largest adjustment was made in patients with substantially regressing tumors: ROI(def) = 11.8 ± 10.9 cm(3) vs. ROI(def_ad) = 5.9 ± 7.8 cm(3) vs. ROI(m) = 7.7 ± 7.2 cm(3) (p = 0.57). The swallowing structures were the most frequently adjusted ROIs with the lowest indices for the upper esophageal sphincter: JI = 0.3 (ROI(def)) and 0.4 (ROI(def_ad)); OI = 0.5 (both ROIs). The mandible needed the least adjustment with the highest indices: JI = 0.8 (both ROIs), OI = 0.9 (ROI(def)), and 1.0 (ROI(def_ad)). Summed doses differed non-significantly. There was a trend of higher doses in the targets and lower doses in the spinal cord when doses were summed on unions., Conclusion: Visual inspection and adjustment were necessary for most ROIs. Fast automatic ROI propagation followed by user-driven adjustment appears to be more efficient than labor-intensive de novo drawing. Dose summation using deformable image coregistration was feasible. Biological uncertainties of dose summation strategies warrant further investigation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The use of gold fiducial markers (GFMs) for prostate positioning in high-dose radiotherapy is gaining interest. The purpose of this study was to compare five GFMs regarding feasibility of ultrasound-based implantation in the prostate and intraprostatic lesion (IPL); toxicity; visibility on transabdominal ultrasound (TU) and cone-beam CT (CBCT); reliability of automatic, soft tissue, and GFM-based CBCT patient positioning by comparing manual and automatic fusion CBCT., Methods and Materials: Twenty-five patients were included. Pain and toxicity were scored after implantation and high-dose radiotherapy. Fisher exact test was used to evaluate the correlation of patients' characteristics and prostatitis. Positioning was evaluated on TU and kilovoltage CBCT images. CBCT fusion was performed automatically (Elekta XVI technology, release 3.5.1 b27, based on grey values) and manually on soft tissue and GFMs. Pearson correlation statistics and Bland-Altman evaluation were used. Five GFMs were compared., Results: Twenty percent of the patients developed prostatitis despite antibiotic prophylaxis. Cigarette smoking was significantly correlated with prostatitis. The visualization of all GFMs on TU was disappointing. Consequently we cannot recommend the use of these GFMs for TU-based prostate positioning. For all GFMs, there was only fair to poor linear correlation between automatic and manual CBCT images, indicating that even when GFMs are used, an operator evaluation is imperative. However, when GFMs were analyzed individually, a moderate to very strong correlation between automatic and manual positioning was found for larger GFMs in all directions., Conclusion: The incidence of prostatitis in our series was high. Further research is imperative to define the ideal preparation protocol preimplantation and to select patients. Automatic fusion is more reliable with larger GFMs at the cost of more scatter. The stability of all GFMs was proven., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To report late ocular (primary endpoint) and other toxicity, disease control, and survival (secondary endpoints) after intensity-modulated radiotherapy (IMRT) for sinonasal tumors., Methods and Materials: Between 1998 and 2009, 130 patients with nonmetastatic sinonasal tumors were treated with IMRT at Ghent University Hospital. Prescription doses were 70 Gy (n = 117) and 60-66 Gy (n = 13) at 2 Gy per fraction over 6-7 weeks. Most patients had adenocarcinoma (n = 82) and squamous cell carcinoma (n = 23). One hundred and one (101) patients were treated postoperatively. Of 17 patients with recurrent tumors, 9 were reirradiated. T-stages were T1-2 (n = 39), T3 (n = 21), T4a (n = 38), and T4b (n = 22). Esthesioneuroblastoma was staged as Kadish A, B, and C in 1, 3, and 6 cases, respectively., Results: Median follow-up was 52, range 15-121 months. There was no radiation-induced blindness in 86 patients available for late toxicity assessment (≥6 month follow-up). We observed late Grade 3 tearing in 10 patients, which reduced to Grade 1-2 in 5 patients and Grade 3 visual impairment because of radiation-induced ipsilateral retinopathy and neovascular glaucoma in 1 patient. There was no severe dry eye syndrome. The worst grade of late ocular toxicity was Grade 3 (n = 11), Grade 2 (n = 31), Grade 1 (n = 33), and Grade 0 (n = 11). Brain necrosis and osteoradionecrosis occurred in 6 and 1 patients, respectively. Actuarial 5-year local control and overall survival were 59% and 52%, respectively. On multivariate analysis local control was negatively affected by cribriform plate and brain invasion (p = 0.044 and 0.029, respectively) and absence of surgery (p = 0.009); overall survival was negatively affected by cribriform plate and orbit invasion (p = 0.04 and <0.001, respectively) and absence of surgery (p = 0.001)., Conclusions: IMRT for sinonasal tumors allowed delivering high doses to targets at minimized ocular toxicity, while maintaining disease control and survival. Avoidance of severe dry eye syndrome and radiation-induced blindness suggests IMRT as a standard treatment for sinonasal tumors., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The objective of this study was to compare setup precision, respiration-related breast movement and treatment time between prone and supine positions for whole-breast irradiation., Methods and Materials: Ten patients with early-stage breast carcinoma after breast-conserving surgery were treated with prone and supine whole breast-irradiation in a daily alternating schedule. Setup precision was monitored using cone-beam computed tomography (CBCT) imaging. Respiration-related breast movement in the vertical direction was assessed by magnetic sensors. The time needed for patient setup and for the CBCT procedure, the beam time, and the length of the whole treatment slot were also recorded., Results: Random and systematic errors were not significantly different between positions in individual patients for each of the three axes (left-right, longitudinal, and vertical). Respiration-related movement was smaller in prone position, but about 80% of observations showed amplitudes <1 mm in both positions. Treatment slots were longer in prone position (21.2 ± 2.5 min) than in supine position (19.4 ± 0.8 min; p = 0.044)., Conclusion: Comparison of setup precision between prone and supine position in the same patient showed no significant differences in random and systematic errors. Respiratory movement was smaller in prone position. The longer treatment slots in prone position can probably be attributed to the higher repositioning need., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The present study aims to assess the interobserver agreement of prostate bed delineation after radical prostatectomy using CT alone as proposed by the European Organization for Research and Treatment of Cancer (EORTC) guidelines., Methods and Materials: Six observers delineated the postoperative prostate bed (PB) and the original seminal vesicle position or remnants (SV) of 10 patients according to the EORTC guidelines. Contours were then compared for agreement between observers (the apparent volume overlap and generalized kappa statistics). Standard deviations were also calculated to measure the variability of the position of the outer margins., Results: The mean volume of 100% agreement (±1 standard deviation, SD) was only 5.0 (±3.3) ml for the PB and 0.9 (±1.5) ml for the SV, whereas the mean union of all contours (±1 SD) was 41.1 (±11.8) ml and 25.3 (±13.4) ml, respectively. The mean overall agreement corrected for chance was moderate for both the PB (mean kappa, 0.49; range, 0.35-0.62) and SV (mean kappa, 0.42; range, 0.22-0.59). The overall SD of the outer margins of the PB ranged from 4.6 to 7.0 mm, Conclusion: The delineation of the postprostatectomy bed using CT shows only a moderate observer agreement when following the EORTC guidelines., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To investigate the feasibility of adaptive intensity-modulated radiation therapy (IMRT) using dose painting by numbers (DPBN) for head-and-neck cancer., Methods and Materials: Each patient's treatment used three separate treatment plans: fractions 1-10 used a DPBN ([(18)-F]fluoro-2-deoxy-D-glucose positron emission tomography [(18)F-FDG-PET]) voxel intensity-based IMRT plan based on a pretreatment (18)F-FDG-PET/computed tomography (CT) scan; fractions 11-20 used a DPBN plan based on a (18)F-FDG-PET/CT scan acquired after the eighth fraction; and fractions 21-32 used a conventional (uniform dose) IMRT plan. In a Phase I trial, two dose prescription levels were tested: a median dose of 80.9 Gy to the high-dose clinical target volume (CTV(high&#95;dose)) (dose level I) and a median dose of 85.9 Gy to the gross tumor volume (GTV) (dose level II). Between February 2007 and August 2009, 7 patients at dose level I and 14 patients at dose level II were enrolled., Results: All patients finished treatment without a break, and no Grade 4 acute toxicity was observed. Treatment adaptation (i.e., plans based on the second (18)F-FDG-PET/CT scan) reduced the volumes for the GTV (41%, p = 0.01), CTV(high&#95;dose) (18%, p = 0.01), high-dose planning target volume (14%, p = 0.02), and parotids (9-12%, p < 0.05). Because the GTV was much smaller than the CTV(high&#95;dose) and target adaptation, further dose escalation at dose level II resulted in less severe toxicity than that observed at dose level I., Conclusion: To our knowledge, this represents the first clinical study that combines adaptive treatments with dose painting by numbers. Treatment as described above is feasible., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The aim of the present study was to compare intensity-modulated radiotherapy (IMRT) with volumetric arc therapy (VMAT), in the treatment of prostate cancer with maximal dose escalation to the intraprostatic lesion (IPL), without violating the organ-at-risk constraints. Additionally, the use of 6-MV photons was compared with 18-MV photons for all techniques., Methods and Materials: A total of 12 consecutive prostate cancer patients with an IPL on magnetic resonance imaging were selected for the present study. Plans were made for three IMRT field setups (three, five, and seven fields) and one VMAT field setup (single arc). First, optimal plans were created for every technique using biologic and physical planning aims. Next, an additional escalation to the IPL was planned as high as possible without violating the planning aims of the first step., Results: No interaction between the technique and photon energy (p=.928) occurred. No differences were found between the 6- and 18-MV photon beams, except for a reduction in the number of monitor units needed for 18 MV (p<.05). All techniques, except for three-field IMRT, allowed for dose escalation to a median dose of ≥93±6 Gy (mean±standard deviation) to the IPL. VMAT was superior to IMRT for rectal volumes receiving 20-50 Gy (p<.05)., Conclusion: VMAT allowed for dose escalation to the IPL with better sparing of the rectum than static three-, five-, and seven-field IMRT setups. High-energy photons had no advantage over low-energy photons., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the regional relapse rate in the elective neck using intensity-modulated radiotherapy (IMRT) for head-and-neck cancer., Methods and Materials: We retrospectively analyzed the data from 285 patients treated with IMRT between 2000 and 2008. The median dose prescription to the primary tumor and involved lymph nodes was 69 Gy in 32 fractions. The elective neck was treated simultaneously according to Protocol 1 (multiple dose prescription levels of 56-69 Gy; 2-Gy normalized isoeffective dose, 51-70 Gy; 222 patients) or Protocol 2 (one dose prescription level of 56 Gy; 2-Gy normalized isoeffective dose, 51 Gy; 63 patients). Primary surgery or lymph node dissection was performed before IMRT in 72 (25%) and 157 (55%) patients, respectively. Also, 92 patients (32%) received concomitant chemotherapy. The median follow-up of living patients was 27.4 months (range, 0.3-99)., Results: Regional, local, and distant relapse were observed in 16 (5.6%), 35 (12.3%), and 47 (16.5%) patients, respectively. The 2- and 5-year rate of regional relapse was 7% and 10%, respectively, with a trend favoring Protocol 2 (p = 0.06). Seven isolated regional relapses were detected at a median follow-up of 7.3 months in patients treated with Protocol 1 and none in those treated with Protocol 2. Percutaneous gastrostomy was required more frequently in patients who received Protocol 1 (p = 0.079)., Conclusion: Isolated regional relapse is rare after IMRT for head-and-neck cancer. Elective neck node doses >51 Gy for a 2-Gy normalized isoeffective dose do not seem to improve regional control., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To report on the interfraction total positioning error of the postoperative prostate bed and to quantify its components (bony misalignment [BM] and prostate bed motion [PBM]) using daily kilovoltage cone-beam computed tomography (CBCT). The role of an adaptive radiotherapy schedule (ART) was investigated., Methods and Materials: A total of 547 daily CBCT images from 15 consecutive patients who had been treated with prostate bed radiotherapy were retrospectively analyzed. The positioning error was measured by rigid co-registration of the daily CBCT with pretreatment CT planning scan. The total positioning error was quantified by co-registration of the CBCT with the CT planning scan to match the anterior rectal wall. Automatic bony pelvis co-registration was performed to separate BM and PBM. The ART was determined by the average total positioning error from the first 5 CBCT images., Results: The systematic error for the total positioning error in the left-right, superoinferior, and anteroposterior direction was 2.69, 2.00, and 2.65 mm with a random error of 1.99, 1.49, and 2.25 mm, resulting in a planning target volume margin of 8, 6, and 8 mm, respectively. ART reduced the margin by 54%, 44%, and 40%, respectively. Systematic errors in the left-right, superoinferior, and anteroposterior direction for BM was 2.66, 1.83, and 2.60 mm and for PBM was 0.44, 0.92, and 2.50 mm with a random error of 1.88, 1.24, and 1.77 mm for BM and 0.99, 1.38, and 2.32 mm for PBM, respectively., Conclusion: Without treatment verifications, 6-8-mm planning target volume margins are required because of PBM and BM. The anteroposterior PBM was significant. An ART protocol can reduce these planning target volume margins., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to develop a rapid and reproducible technique for prone positioning and to compare dose-volume indices in prone and supine positions., Methods and Materials: Eighteen patients underwent computed tomography imaging for radiotherapy planning in prone and supine position. Experience was gained in the first eight patients, which lead to modifications of the Horizon prone breast board (Civco Medical Solutions, Orange City, Iowa, USA) and the patient setup technique. A unilateral breast holder (U-BH) was developed (Van de Velde, Schellebelle, Belgium) to retract the contralateral breast away from the treated breast. The technique was then applied to an additional 10 patients. The setup precision was evaluated using daily cone-beam CT., Results: Modifications to the breast board were made to secure a prone-lateral rather then a pure prone position. We evolved from a classical setup using laser marks on the patients' body to a direct breast setup using marks on the breast only. The setup precision of the direct positioning procedure with the modified breast board and the U-BH is comparable to supine setup data in the literature. Dose-volume indices for heart and lung show significantly better results for prone than for supine position, and dose homogeneity within the treated breast did not differ according to the treatment position., Conclusions: The setup precision of our prone-lateral positioning technique is comparable to supine data in literature. Our data show the advantage of prone radiotherapy to spare the lung and heart. Further research is necessary to reduce the duration of prone setup., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Purpose: To determine the planning results and acute toxicity after hypofractionated intensity-modulated arc radiotherapy and androgen deprivation for lymph node metastasized (Stage N1) prostate cancer., Methods and Materials: A total of 31 patients with Stage T1-T4N1M0 prostate cancer were treated with intensity-modulated arc radiotherapy and 3 years of androgen deprivation as primary treatment. The clinical target volume (CTV(p)) was the prostate and seminal vesicles. Elective lymph node areas ((e)) were delineated and expanded by 2 mm to create the CTV(e). The planning target volumes (PTV(p) and PTV(e)) were created using a three-dimensional expansion of the CTV(p) and CTV(e), respectively, of 7 mm. A median dose of 69.3 Gy and 50 Gy was prescribed to the PTV(p) and PTV(e) respectively, to be delivered in 25 fractions. Upper and lower gastrointestinal toxicity was scored using the Radiation Therapy Oncology Group toxicity and radiotherapy-induced lower intestinal toxicity scoring system. Genitourinary toxicity was scored using a combined Radiation Therapy Oncology Group, LENT-SOMA (late effects normal tissue-subjective, objective, management, analytic), and Common Toxicity Criteria toxicity scoring system., Results: The median follow-up time was 3 months. The mean prescription dose to the CTV(p) and PTV(p) was 70.4 Gy and 68.6 Gy, respectively. The minimal dose to the CTV(e) and PTV(e) was 49.0 Gy and 47.0 Gy, respectively. No acute Grade 2 or greater gastrointestinal toxicity occurred. Fourteen patients developed acute Grade 2 lower gastrointestinal toxicity. Acute Grade 3 and 2 genitourinary toxicity developed in 2 and 14 patients, respectively., Conclusion: The results of our study have shown that hypofractionated intensity-modulated arc radiotherapy as primary therapy for N1 prostate cancer is feasible with low toxicity.

Purpose: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer., Methods and Materials: A Phase I clinical trial was designed to escalate the dose limited to the [(18)-F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was applied for the remaining 22 fractions of 2.16 Gy., Results: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p = n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted (18)F-FDG-PET-delineated region., Conclusions: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.

Purpose: In rectal cancer, combined radiotherapy and chemotherapy, either pre- or postoperatively, is an accepted treatment. Late small bowel (SB) toxicity is a feared side effect and limits radiation-dose escalation in a volume-dependent way. A planning strategy for intensity- modulated arc therapy (IMAT) was developed, and IMAT was clinically implemented with the aim to reduce the volume of SB irradiated at high doses and thus reduce SB toxicity. We report on the treatment plans of the first 7 patients, on the comparison of IMAT with conventional 3D planning (3D), and on the feasibility of IMAT delivery., Methods and Materials: Seven patients, who were referred to our department for preoperative (n = 4) or postoperative (n = 3) radiotherapy for rectal cancer, gave written consent for IMAT treatment. All patients had a planning CT in prone position. The delineation of the clinical target volume was done after fusion of CT and MRI, with the help of a radiologist. For the IMAT plan, arcs were generated using an anatomy-based segmentation tool. The optimization of the arcs was done by weight optimization (WO) and leaf position optimization (LPO), both of which were adapted for IMAT purposes. The 3D plans used one posterior and two lateral wedged beams, of which the outlines were shaped to the beam's-eye view projection of the planning target volume (PTV). Beam WO was done by constrained matrix inversion. For dose-volume histogram analysis, all plans were normalized to 45 Gy as median PTV dose. Polymer gel dosimetry (PGD) on a humanoid phantom was used for the validation of the total chain (planning to delivery). IMAT treatments were delivered by an Elekta SliPlus linear accelerator using prototype software with the same interlock class as in clinical mode., Results: The IMAT plan resulted in 3 to 6 arcs, with a mean delivery time of 6.3 min and a mean of 456 monitor units (MU) for a 180 cGy fraction. The minimal dose in the PTV was not significantly different between 3D and IMAT plans. Inhomogeneity was highest for the IMAT plans (14.1%) and lowest for the 3D plans (9.9%). Mean dose to the SB was significantly lower for the IMAT plans (12.4 Gy) than for the 3D plans (17.0 Gy). The volume of SB receiving less than any dose level was lower for the IMAT plans than for 3D plans. Integral dose was lower in the IMAT plans than for the 3D plans (respectively 244 J and 262 J to deliver 45 Gy). Differences between the PGD measured dose and the calculated dose were as small for IMAT as for 3D treatments., Conclusion: IMAT plans are deliverable within a 5-10-minute time slot, and result in a lower dose to the SB than 3D plans, without creating significant underdosages in the PTV. PGD showed that IMAT delivery is as accurate as 3D delivery.

Purpose: Whole abdominopelvic radiation therapy (WAPRT) is a treatment option in the palliation of patients with relapsed ovarian cancer. With conventional techniques, kidneys and liver are the dose- and homogeneity-limiting organs. We developed a planning strategy for intensity-modulated arc therapy (IMAT) and report on the treatment plans of the first 5 treated patients., Methods and Materials: Five consecutive patients with histologically proven relapsed ovarian cancer were sent to our department for WAPRT. The target volumes and organs at risk (OAR) were delineated on 0.5-cm-thick CT slices. The clinical target volume (CTV) was defined as the total peritoneal cavity. CTV and kidneys were expanded with 0.5 cm. In a preset range of 8 degrees interspaced gantry angles, machine states were generated with an anatomy-based segmentation tool. Machine states of the same class were stratified in arcs. The optimization of IMAT was done in several steps, using a biophysical objective function. These steps included weight optimization of machine states, leaf position optimization adapted to meet the maximal leaf speed constraint, and planner-interactive optimization of the start and stop angles. The final control points (machine states plus associated cumulative monitor unit counts) were calculated using a collapsed cone convolution/superposition algorithm. For comparison, two conventional plans (CONV) were made, one with two fields (CONV2), and one with four fields (CONV4). In these CONV plans, dose to the kidneys was limited by cerrobend blocks. The IMAT and the CONV plans were normalized to a median dose of 33 Gy to the planning target volume (PTV). Monomer/polymer gel dosimetry was used to assess the dosimetric accuracy of the IMAT planning and delivery method., Results: The median volume of the PTV was 8306 cc. The mean treatment delivery time over 4 patients was 13.8 min. A mean of 444 monitor units was needed for a fraction dose of 150 cGy. The fraction of the PTV volume receiving more than 90% of the prescribed dose (V(90)) was 9% higher for the IMAT plan than for the CONV4 plan (89.9% vs. 82.5%). Outside a build-up region of 0.8 cm and 1 cm away from both kidneys, the inhomogeneity in the PTV was 15.1% for the IMAT plans and 24.9% for the CONV4 plans (for CONV2 plans, this was 34.9%). The median dose to the kidneys in the IMAT plans was lower for all patients. The 95th percentile dose for the kidneys was significantly higher for the IMAT plans than for the CONV4 and CONV2 plans (28.2 Gy vs. 22.2 Gy and 22.6 Gy for left kidney, respectively). No relevant differences were found for liver. The gel-measured dose was within clinical planning constraints., Conclusion: IMAT was shown to be deliverable in an acceptable time slot and to produce dose distributions that are more homogeneous than those obtained with a CONV plan, with at least equal sparing of the OARs.

Purpose: To describe the theoretical basis, the algorithm, and implementation of a tool that optimizes segment shapes and weights for step-and-shoot intensity-modulated radiation therapy delivered by multileaf collimators., Methods and Materials: The tool, called SOWAT (Segment Outline and Weight Adapting Tool) is applied to a set of segments, segment weights, and corresponding dose distribution, computed by an external dose computation engine. SOWAT evaluates the effects of changing the position of each collimating leaf of each segment on an objective function, as follows. Changing a leaf position causes a change in the segment-specific dose matrix, which is calculated by a fast dose computation algorithm. A weighted sum of all segment-specific dose matrices provides the dose distribution and allows computation of the value of the objective function. Only leaf position changes that comply with the multileaf collimator constraints are evaluated. Leaf position changes that tend to decrease the value of the objective function are retained. After several possible positions have been evaluated for all collimating leaves of all segments, an external dose engine recomputes the dose distribution, based on the adapted leaf positions and weights. The plan is evaluated. If the plan is accepted, a segment sequencer is used to make the prescription files for the treatment machine. Otherwise, the user can restart SOWAT using the new set of segments, segment weights, and corresponding dose distribution. The implementation was illustrated using two example cases. The first example is a T1N0M0 supraglottic cancer case that was distributed as a multicenter planning exercise by investigators from Rotterdam, The Netherlands. The exercise involved a two-phase plan. Phase 1 involved the delivery of 46 Gy to a concave-shaped planning target volume (PTV) consisting of the primary tumor volume and the elective lymph nodal regions II-IV on both sides of the neck. Phase 2 involved a boost of 24 Gy to the primary tumor region only. SOWAT was applied to the Phase 1 plan. Parotid sparing was a planning goal. The second implementation example is an ethmoid sinus cancer case, planned with the intent of bilateral visus sparing. The median PTV prescription dose was 70 Gy with a maximum dose constraint to the optic pathway structures of 60 Gy., Results: The initial set of segments, segment weights, and corresponding dose distribution were obtained, respectively, by an anatomy-based segmentation tool, a segment weight optimization tool, and a differential scatter-air ratio dose computation algorithm as external dose engine. For the supraglottic case, this resulted in a plan that proved to be comparable to the plans obtained at the other institutes by forward or inverse planning techniques. After using SOWAT, the minimum PTV dose and PTV dose homogeneity increased; the maximum dose to the spinal cord decreased from 38 Gy to 32 Gy. The left parotid mean dose decreased from 22 Gy to 19 Gy and the right parotid mean dose from 20 to 18 Gy. For the ethmoid sinus case, the target homogeneity increased by leaf position optimization, together with a better sparing of the optical tracts., Conclusions: By using SOWAT, the plans improved with respect to all plan evaluation end points. Compliance with the multileaf collimator constraints is guaranteed. The treatment delivery time remains almost unchanged, because no additional segments are created.

Purpose: In segmental intensity-modulated radiation therapy (IMRT), the beam fluences result from superposition of unmodulated beamlets (segments). In the inverse planning approach, segments are a result of ''clipping'' intensity maps. At Ghent University Hospital, segments are created by an anatomy-based segmentation tool (ABST). The objective of this report is to describe ABST., Methods and Materials: For each beam direction, ABST generates segments by a multistep procedure. During the initial steps, beam's eye view (BEV) projections of the planning target volumes (PTVs) and organs at risk (OARs) are generated. These projections are used to make a segmentation grid with negative values across the expanded OAR projections and positive values elsewhere inside the expanded PTV projections. Outside these regions, grid values are set to zero. Subsequent steps transform the positive values of the segmentation grid to increase with decreasing distance to the OAR projections and to increase with longer pathlengths measured along rays from their entrance point through the skin contours to their respective grid point. The final steps involve selection of iso-value lines of the segmentation grid as segment outlines which are transformed to leaf and jaw positions of a multileaf collimator (MLC). Segment shape approximations, if imposed by MLC constraints, are done in a way that minimizes overlap between the expanded OAR projections and the segment aperture., Results: The ABST procedure takes about 3 s/segment on a Compaq Alpha XP900 workstation. In IMRT planning problems with little complexity, such as laryngeal (example shown) or thyroid cancer, plans that are in accordance with the clinical protocol can be generated by weighting the segments generated by ABST without further optimization of their shapes. For complex IMRT plans such as paranasal sinus cancer (not shown), ABST generates a start assembly of segments from which the shapes and weights are further optimized., Conclusions: ABST is a fast procedure to generate a set of segments for IMRT planning. The plan is finalized by assigning weights to the segments or by direct optimization of segment shapes and weights. ABST allows us to avoid the step of translating optimized intensity maps to sequences of segments.

Purpose: To develop a protocol for the irradiation of ethmoid sinus cancer, with the aim of sparing binocular vision; of developing a strategy of intensity-modulated radiation therapy (IMRT) planning that produces dose distributions that (1) are consistent with the protocol prescriptions and (2) are deliverable by static segmental IMRT techniques within a 15-minute time slot; of fine tuning the implementation strategy to a class solution approach that is sufficiently automated and efficient, allowing routine clinical application; of reporting on the early clinical implementation involving 11 patients between February 1999 and July 2000. patients and methods: Eleven consecutive T1-4N0M0 ethmoid sinus cancer patients were enrolled in the study. For Patients 1-8, a first protocol was implemented, defining a planning target volume prescription dose of 60 to 66 Gy in 30-33 fractions and a maximum dose (Dmax) of 50 Gy to optic pathway structures and spinal cord and limit of 60 Gy to brainstem. For Patients 9-11, an adapted (now considered mature) protocol was implemented, defining a (planning target volume) prescription dose of 70 Gy in 35 fractions and a Dmax to optic pathway structures and brainstem of 60 Gy and to spinal cord of 50 Gy., Results: The class solution-directed strategy developed during this study reduced the protocol translation process from a few days to about 2 hours of planner time. The mature class solution involved the use of 7 beam incidences (20-37 segments), which could be delivered within a 15-minute time slot. Acute side effects were limited and mild. None of the patients developed dry eye syndrome or other visual disturbances. The follow-up period is too short for detection of retinopathy or optic nerve and chiasm toxicity., Conclusion: Conventional radiotherapy of ethmoid sinus tumors is associated with serious morbidity, including blindness. We hypothesize that IMRT has the potential to save binocular vision. The dose to the optic pathway structures can be reduced selectively by IMRT. Further enrollment of patients and longer follow-up will show whether the level of reduction tested by the clinical protocol is sufficient to save binocular vision. An adaptive strategy of IMRT planning was too inefficient for routine clinical practice. A class solution-directed strategy improved efficiency by eliminating human trial and error during the IMRT planning process.

Purpose: A hybrid between step-and-shoot and dynamic operation, called interrupted dynamic sequences, was investigated for prostate intensity-modulated radiotherapy (IMRT) delivered by a multisegment close-in technique. The new delivery mode was compared to the step-and-shoot mode concerning dose distribution., Methods and Materials: Segments suitable for dynamic transition were selected using a system of segment classes. Transitions were only allowed between two segments of the same class, keeping intended sharp in-field dose gradients unchanged. Delivery was performed by an Elekta SLiplus (Crawley, UK) linear accelerator equipped with a dynamic multileaf collimator (MLC). Because no modeling of the dose during the transitions is made, accurate dose measurements were performed. Dose profiles were measured using a linear ion chamber array (LA48, PTW-Freiburg). The suitability of this detector for measurements in sharp dose gradients was investigated first. In addition, field flatness was examined for segments with a low monitor unit (MU) count. Uncertainties in dose output were investigated using an ionization chamber (30001, PTW-Freiburg)., Results: Because linear array measured penumbrae are only slightly broader (< or = 0.4 mm for MLC collimated field) than those obtained using a diamond detector, the array is a good device for profile measurements. Uncertainties related with the use of low MU beam segments are very small (< 1% for segments of minimum 3 MU), giving no contra-evidence for the step-and-shoot mode. Interrupted dynamic sequences are shown to introduce only small dosimetric differences as compared to the step-and-shoot delivery., Conclusion: Both delivery modes, step-and-shoot and interrupted dynamic sequences, result in similar dose distributions for the forward planned prostate class solution.

Purpose: To evaluate whether intensity modulated radiotherapy (IMRT) by static segmented beams allows the dose to the main portion of the prostate target to escalate while keeping the maximal dose at the anterior rectal wall at 72 Gy. The value of such IMRT plans was analyzed by comparison with non-IMRT plans using the same beam incidences., Methods and Materials: We performed a planning study on the CT data of 32 consecutive patients with localized adenocarcinoma of the prostate. Three fields in the transverse plane with gantry angles of 0 degrees, 116 degrees, and 244 degrees were isocentered at the center of gravity of the target volume (prostate and seminal vesicles). The geometry of the beams was determined by beam's eye view autocontouring of the target volume with a margin of 1.5 cm. In study 1, the beam weights were determined by a human planner (3D-man) or by computer optimization using a biological objective function with (3D-optim-lim) or without (3D-optim-unlim) a physical term to limit target dose inhomogeneity. In study 2, the 3 beam incidences mentioned above were used and in-field uniform segments were added to allow IMRT. Plans with (IMRT-lim) or without (IMRT-unlim) constraints on target dose inhomogeneity were compared. In the IMRT-lim plan, target dose inhomogeneity was constrained between 15% and 20%. After optimization, plans in both studies were normalized to a maximal rectal dose of 72 Gy. Biological (tumor control probability [TCP], normal tissue complication probability [NTCP]) and physical indices for tumor control and normal tissue complication probabilities were computed, as well as the probability of the uncomplicated local control (P+)., Results: The IMRT-lim plan was superior to all other plans concerning TCP (p < 0.0001). The IMRT-unlim plan had the worst TCP. Within the 3D plans, the 3D-optim-unlim had the best TCP, which was significantly different from the 3D-optim-lim plan (p = 0.0003). For rectal NTCP, both IMRT plans were superior to all other plans (p < 0.0001). The IMRT-unlim plan was significantly better than the IMRT-lim plan (p < 0.0001). Again, 3D-optim-unlim was superior to the other 3D plans (p < 0. 0007). Physical endpoints for target showed the mean minimal target dose to be the lowest in the IMRT-unlim plan, caused by a large target dose inhomogeneity (TDI). Medial target dose, 90th percentile, and maximal target dose were significantly higher in both IMRT plans. Physical endpoints for the rectum showed the IMRT-unlim plan to be superior compared to all other plans. There was a strong correlation between the 65th percentile (Rp65) and rectal NTCP (correlation coefficient > or =89%). For bladder, maximal bladder dose was significantly higher in the IMRT-unlim plan compared to all other plans (p < or = 0.0001).P+ was significantly higher in both IMRT-plans than in all other plans. The 3D-optim-unlim plan was significantly better than the two other 3D plans (p < 0.0001)., Conclusion: IMRT significantly increases the ratio of TCP over NTCP of the rectum in the treatment of prostate cancer. However, constraints for TDI are needed, because a high degree of TDI reduced minimal target dose. IMRT improved uncomplicated local control probability. In our department, IMRT by static segmented beams is planned and delivered in a cost-effective way. IMRT-lim has replaced non-modulated conformal radiotherapy as the standard treatment for prostate cancer.

Purpose: To evaluate the effects of beam weight optimization for 3D conformal radiotherapy plans, with or without beam intensity modulation, in Stage III non-small cell lung cancer (NSCLC)., Methods and Materials: Ten patients with Stage III NSCLC were planned using a conventional 3D technique and a technique involving noncoplanar beam intensity modulation (BIM). Two planning target volumes (PTVs) were defined: PTV1 included macroscopic tumor volume and PTV2 included macroscopic and microscopic tumor volume. Virtual simulation defined the beam shapes and incidences as well as the wedge orientations (3D) and segment outlines (BIM). Weights of wedged beams, unwedged beams, and segments were determined by human trial and error for the 3D-plans (3D-manual), by a standard weight table (SWT) for the BIM-plans (BIM-SWT) and by optimization (3D-optimized and BIM-optimized) using an objective function with a biological and a physical component. The resulting non-optimized and optimized dose distributions were compared, using physical endpoints, after normalizing the median dose of PTV1 to 80 Gy., Results: Optimization improved dose homogeneity at the target for 3D- and BIM-plans and the minimum dose at PTV1. The minimum dose at PTV2 was decreased by optimization especially in 3D-plans. After optimization, the dose-volume histograms (DVHs) of lung and heart were shifted to lower doses for 80-90% of the organ volume. Since lung is the dose-limiting organ in Stage III NSCLC, an increased minimum dose at PTV1 together with a decreased dose at the main lung volume suggests an improved therapeutic ratio. Optimization allows 10% dose escalation for 3D-plans and 20% for BIM-plans at isotoxicity levels of lung and spinal cord. Upon dose escalation, esophagus may become the dose-limiting structure when PTV1 extends close to the esophagus., Conclusions: Optimization using a biophysical objective function allowed an increase of the therapeutic ratio of radiotherapy planning for Stage III NSCLC.

Purpose: To evaluate if the use of inhomogeneous target-dose distributions, obtained by 3D conformal radiotherapy plans with or without beam intensity modulation, offers the possibility to decrease indices of toxicity to normal tissues and/or increase indices of tumor control stage III non-small cell lung cancer (NSCLC)., Methods and Materials: Ten patients with stage III NSCLC were planned using a conventional 3D technique and a technique involving noncoplanar beam intensity modulation (BIM). Two planning target volumes (PTVs) were defined: PTV1 included macroscopic tumor volume and PTV2 included macroscopic and microscopic tumor volume. Virtual simulation defined the beam shapes and incidences as well as the wedge orientations (3D) and segment outlines (BIM). Weights of wedged beams, unwedged beams, and segments were determined by optimization using an objective function with a biological and a physical component. The biological component included tumor control probability (TCP) for PTV1 (TCP1), PTV2 (TCP2), and normal tissue complication probability (NTCP) for lung, spinal cord, and heart. The physical component included the maximum and minimum dose as well as the standard deviation of the dose at PTV1. The most inhomogeneous target-dose distributions were obtained by using only the biological component of the objective function (biological optimization). By enabling the physical component in addition to the biological component, PTV1 inhomogeneity was reduced (biophysical optimization). As indices for toxicity to normal tissues, NTCP-values as well as maximum doses or dose levels to relevant fractions of the organ's volume were used. As indices for tumor control, TCP-values as well as minimum doses to the PTVs were used., Results: When optimization was performed with the biophysical as compared to the biological objective function, the PTV1 inhomogeneity decreased from 13 (8-23)% to 4 (2-9)% for the 3D-(p = 0.00009) and from 44 (33-56)% to 20 (9-34)% for the BIM plans (p < 0. 00001). Minimum PTV1 doses (expressed as the lowest voxel-dose) were similar for both objective functions. The mean and maximum target doses were significantly higher with biological optimization for 3D as well as for BIM (all p values < 0.001). Tumor control probability (estimated by TCP1 x TCP2) was 4.7% (3D) and 6.2% (BIM) higher for biological optimization (p = 0.01 and p = 0.00002 respectively). NTCP(lung) as well as the percentage of lung volume exceeding 20 Gy was higher with the use of the biophysical objective function. NTCP(heart) was also higher with the use of the biophysical objective function. The percentage of heart volume exceeding 40 Gy tended to be higher but the difference was not significant. For spinal cord, the maximum dose as well as NTCP(cord) were similar for 3D plans (D(max): p = 0.04; NTCP: p = 0.2) but were significantly lower for BIM (D(max): p = 0.002; NTCP: p = 0.008) if the biophysical objective function was used., Conclusions: When using conventional 3D techniques, inhomogeneous dose distributions offer the potential to further increase the probability of uncomplicated local control. When using techniques as BIM that would lead to large escalation of the median and maximum target doses, it seems indicated to limit target-dose inhomogeneity to avoid dose levels that are so high that the safety becomes questionable.

Purpose: We developed a semiautomatic class solution to irradiate centrally located Stage III non-small cell lung cancer (NSCLC), involving a beam intensity modulation technique and optimization using a biophysical cost function., Methods and Materials: Treatment for 10 patients with Stage III NSCLC was planned, using a conventional three- or four-beam three-dimensional (3D) technique and two techniques involving, respectively, seven (BIM1) and five (BIM2) noncoplanar beam incidences with intensity modulation. Two planning target volumes were defined: PTV1 included macroscopic tumor volume and PTV2 included macroscopic and microscopic disease. Beams were divided into beam parts (segments) and their outlines were defined during virtual simulation. Optimization using a biophysical cost function determined beam weights, segment weights, and wedge angles. Biological end points included tumor control probability of both target volumes (TCP1 and TCP2) and normal tissue complication probability (NTCP) of heart, lung, and spinal cord. The resulting uncomplicated local control probability (UCLP) was calculated. Physical end points included dose at PTV1 expressed as a dose minimum and dose maximum. Target-dose inhomogeneity was constrained in all plans., Results: Concerning tumor evaluation, TCP1 was 74% (range 54-89%) for the 3D plan, 78.0% (range 62-94%) for BIM1, and 86.0% (range 59-93%) for BIM2. TCP1*TCP2 was, respectively, 67.0% (range 39-81%), 73.0% (range 56-94%), and 81.0% (range 54-93%). Minimum doses to PTV1 were 85, 80, and 88 Gy with the three respective techniques, while dose maxima were 89, 101, and 100 Gy. NTCPs of lung were 45.0% (range 11-75%) for 3D, 19.5% (range 8-59%) for BIM1, and 24.5% (range 3-61%) for BIM2. NTCPs of heart and spinal cord were comparable for all techniques. ULCPs were 37.0% (range 9-73%), 52.5% (range 22-86%), and 60.0% (range 20-85%), respectively. Applying physical limits to ensure clinical safety, minimum doses at PTV1 were recalculated. These were 72, 71, and 74 Gy for 3D, BIM1, and BIM2, respectively., Conclusion: The BIM2 plan is a candidate class solution for dose escalation studies in centrally located Stage III NSCLC.