Clinical Target Volume Margin Research Articles

Correlation of microscopic tumor extension with tumor microenvironment in esophageal cancer patients.

In the era of image-guided adaptive radiotherapy, definition of the clinical target volume (CTV) is achallenge in various solid tumors, including esophageal cancer (EC). Many tumor microenvironmental factors, e.g., tumor cell proliferation or cancer stem cells, are hypothesized to be involved in microscopic tumor extension (MTE). Therefore, this study assessed the expression of FAK, ILK, CD44, HIF-1α, and Ki67 in EC patients after neoadjuvant radiochemotherapy followed by tumor resection (NRCHT+R) and correlated these markers with the MTE. Formalin-fixed paraffin-embedded tumor resection specimens of ten EC patients were analyzed using multiplex immunofluorescence staining. Since gold fiducial markers had been endoscopically implanted at the proximal and distal tumor borders prior to NRCHT+R, correlation of the markers with the MTE was feasible. In tumor resection specimens of EC patients, the overall percentages of FAK+, CD44+, HIF-1α+, and Ki67+ cells were higher in tumor nests than in the tumor stroma, with the outcome for Ki67+ cells reaching statistical significance (p < 0.001). Conversely, expression of ILK+ cells was higher in tumor stroma, albeit not statistically significantly. In three patients, MTE beyond the fiducial markers was found, reaching up to 31 mm. Our findings indicate that the overall expression of FAK, HIF-1α, Ki67, and CD44 was higher in tumor nests, whereas that of ILK was higher in tumor stroma. Differences in the TME between patients with residual tumor cells in the original CTV compared to those without were not found. Thus, there is insufficient evidence that the TME influences the required CTV margin on an individual patient basis. BO-EK-148042017 and BO-EK-177042022 on 20.06.2022, DRKS00011886, https://drks.de/search/de/trial/DRKS00011886 .

Comparison of different target volume delineation strategies based on recurrence patterns in adjuvant radiotherapy for glioblastoma.

Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) recommendations are commonly used guidelines for adjuvant radiotherapy in glioblastoma. In our institutional protocol, we delineate T2-FLAIR alterations as gross target volume (GTV) with reduced clinical target volume (CTV) margins. We aimed to present our oncologic outcomes and compare the recurrence patterns and planning parameters with EORTC and RTOG delineation strategies. Eighty-one patients who received CRT between 2014 and 2021 were evaluated retrospectively. EORTC and RTOG delineations performed on the simulation computed tomography and recurrence patterns and planning parameters were compared between delineation strategies. Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM, Armonk, NY, USA) was utilized for statistical analyses. Median overall survival and progression-free survival were 21 months and 11 months, respectively. At a median 18 month follow-up, of the 48 patients for whom recurrence pattern analysis was performed, recurrence was encompassed by only our institutional protocol's CTV in 13 (27%) of them. For the remaining 35 (73%) patients, recurrence was encompassed by all separate CTVs. In addition to the 100% rate of in-field recurrence, the smallest CTV and lower OAR doses were obtained by our protocol. The current study provides promising results for including the T2-FLAIR alterations to the GTV with smaller CTV margins with impressive survival outcomes without any marginal recurrence. The fact that our protocol did not result in larger irradiated brain volume is further encouraging in terms of toxicity.

RADT-25. IMPACT OF 18F-DOPA PET ON RADIATION TREATMENT PLANNING FROM PHASE II STUDY OF SHORT COURSE HYPOFRACTIONATED PROTON BEAM THERAPY FOR ELDERLY PATIENTS WITH GLIOBLASTOMA

Abstract PURPOSE 18F-DOPA is sensitive/specific for identifying areas of biologically aggressive disease for glioblastoma. We report the impact of 18F-DOPA on radiation treatment planning from a phase II study. METHODS Gross target volume (GTV) was defined by the boolean of high-risk PET (tumor/normal brain SUV &amp;gt; 2.0) and MRI T1 contrast enhancement (MRI-CE) including surgical cavity. The clinical target volume (CTV) included the GTV with 1cm margin. Using proton beam therapy, GTV ≤ 65 cc was treated with 25 (CTV), 30 (MRI-CE), and 35 (PET) GyE over 5 fractions with a simultaneous integrated boost. GTV &amp;gt; 65 cc received 30 (CTV), 35 (MRI-CE), and 40 (PET) GyE over 10 fractions. Radiation field design was compared to traditional 1.5cm CTV margin on MRI-CE. RESULTS Between May 2019 and October 2021, 39 patients were treated. The median MRI-CE tumor diameter was 5.2cm. The median PET volume was 7.9cc (range 0–64.9cc). The median MRI-CE volume was 35.1cc (range 8.6–114cc). High-risk PET was contained within: MRI-CE 18/39 (46%), MRI-CE + T2W FLAIR 13/39 (33%), MRI-CE + T2W FLAIR + outside GTV 4/39 (10%), outside GTV 2/39 (5%) and no uptake 2/39 (5%). Utilizing this planning technique, there was a 26% volume reduction in CTV to traditional 1.5 cm margin on MRI-CE. PET imaging in treatment planning allowed inclusion of high-risk disease that would have been excluded on traditional CTV in 23% of cases (range 1.6-33.8cc). PET was more predictive [HR 1.03 (95% CI 1.01, 1.05) p = 0.002] than MRI [HR 1.01 (95% CI 1.00, 1.03) p = 0.02] for death with each cc increasing risk of death by 3.1%. CONCLUSIONS The incorporation of 18F-DOPA in treatment planning yields a more targeted approach with reductions in both normal brain treated and risk of geographic miss compared to traditional CTV margins.

Impact of clinical target volume margin reduction in glioblastoma patients treated with concurrent chemoradiation.

Glioblastoma (GBM) is widely treated using large radiotherapy margins, resulting in substantial irradiation of the surrounding cerebral structures. In this context, the question arises whether these margins could be safely reduced. In 2018, clinical target volume (CTV) expansion was reduced in our institution from 20 to 15 mm around the gross target volume (GTV) (ie, the contrast-enhancing tumor/cavity). We sought to retrospectively analyze the impact of this reduction. All adult patients with GBM treated between January 2015 and December 2020 with concurrent chemoradiation (60Gy/2Gy or 59.4Gy/1.8Gy) were analyzed. Patients treated using a 20 (CTV20, n = 57) or 15 mm (CTV15, n = 56) CTV margin were compared for target volumes, dose parameters to the surrounding organs, pattern of recurrence, and survival outcome. Mean GTV was similar in both groups (ie, CTV20: 39.7cm3; CTV15: 37.8cm3; P = .71). Mean CTV and PTV were reduced from 238.9cm3 to 176.7cm3 (P = .001) and from 292.6cm3 to 217.0cm3 (P < .001), for CTV20 and CTV15, respectively. As a result, average brain mean dose (Dmean) was reduced from 25.2Gy to 21.0Gy (P = .002). Significantly lower values were also observed for left hippocampus Dmean, brainstem D0.03cc, cochleas Dmean, and pituitary Dmean. Pattern of recurrence was similar, as well as patient outcome, ie, median progression-free survival was 8.0 and 7.0 months (P = .80), and median overall survival was 11.0 and 14.0 months (P = .61) for CTV20 and CTV15, respectively. In GBM patients treated with chemoradiation, reducing the CTV margin from 20 to 15 mm appears to be safe and offers the potential for less treatment toxicity.

Evaluating the geometric and dosimetric impact of applying anisotropic CTV to PTV margins in image-guided post-prostatectomy radiation therapy.

Guidelines for clinical target volume (CTV) to planning target volume (PTV) margins in post-prostatectomy radiation therapy (PPRT) are varied and often not clearly defined. Assessment of appropriateness of margins is commonly measured on prevalence of geographic miss. Cone-beam CT (CBCT) images (n = 92) for 10 PPRT patients were incorporated to provide on-treatment information on the appropriateness of six different CTV expansion margins in terms of geographic miss and change in dose-volume statistics for CTV, rectum and bladder. Uniform margins included 10 mm, 5 mm, 10 mm + 5 mm posteriorly and 5 mm + 3 mm posteriorly. In addition, two anisotropic margins were evaluated by separating the superior and inferior portions of the CTV before expansion. Treatment plans were created for each PTV retrospectively. The frequency of geographic miss was the smallest for the large uniform expansions but resulted in the highest organ-at-risk (OAR) doses. Geographic miss in the smaller uniform and anisotropic PTVs was more prevalent but commonly to a small volume < 1% of CTV. When averaged over all CBCT fractions, V95% dose for all CTV margins remained > 99%. The anisotropic expansions generated smaller irradiated target volumes and consequently saw up to 7.3% reduction in bladder dose when compared with similar uniform expansion margins. Supplementing the incidence of geographic miss with dosimetric information on target coverage and OAR doses provides more informed assessment of the appropriateness of different CTV expansion margins. Our study extends the evaluation of anisotropic margins for PPRT.

High-dose planned adaptive helical tomotherapy for cutaneous angiosarcoma of the scalp.

The purpose of this study was to investigate the feasibility and effectiveness of high-dose planned adaptive intensity-modulated radiation therapy (IMRT) with helical tomotherapy (HT) for cutaneous angiosarcoma (cAS) of the scalp. This retrospective cross-sectional included atotal of 12consecutive patients with cAS of the scalp who underwent high-dose planned adaptive IMRT with HT. Prescribed doses were 72.5-74 Gy in 35-37 fractions for the gross tumor volume plus a1-2 mm margin (PTV1), 58-60 Gy in 29-30 fractions for the clinical target volume plus a2-3 mm margin (PTV2), and 46 Gy in 23fractions for the clinical target volume plus a5-15 mm margin (PTV3) over periods of 7.5, 6and 4.5weeks, respectively. The estimated 1‑year and 2‑year overall survival rate were 65.6% and 27.3%, respectively, and the local progression-free survival at 2years was 74.1%. All local recurrences were either in or marginal to the PTV2 or PTV3. No local recurrence was observed in the PTV1. All patients tolerated the treatment without grade3 or higher adverse events during the radiotherapy period. No late adverse events were observed during the follow-up period. Planned adaptive high-dose IMRT with HT has the potential to improve local control rate without increasing adverse events.

Proton therapy and limited surgery for paediatric and adolescent patients with craniopharyngioma (RT2CR): a single-arm, phase 2 study.

Compared with photon therapy, proton therapy reduces exposure of normal brain tissue in patients with craniopharyngioma, which might reduce cognitive deficits associated with radiotherapy. Because there are known physical differences between the two methods of radiotherapy, we aimed to estimate progression-free survival and overall survival distributions for paediatric and adolescent patients with craniopharyngioma treated with limited surgery and proton therapy, while monitoring for excessive CNS toxicity. In this single-arm, phase 2 study, patients with craniopharyngioma at St Jude Children's Research Hospital (Memphis TN, USA) and University of Florida Health Proton Therapy Institute (Jacksonville, FL, USA) were recruited. Patients were eligible if they were aged 0-21 years at the time of enrolment and had not been treated with previous radiotherapeutic or intracystic therapies. Eligible patients were treated using passively scattered proton beams, 54 Gy (relative biological effect), and a 0·5 cm clinical target volume margin. Surgical treatment was individualised before proton therapy and included no surgery, single procedures with catheter and Ommaya reservoir placement through a burr hole or craniotomy, endoscopic resection, trans-sphenoidal resection, craniotomy, or multiple procedure types. After completing treatment, patients were evaluated clinically and by neuroimaging for tumour progression and evidence of necrosis, vasculopathy, permanent neurological deficits, vision loss, and endocrinopathy. Neurocognitive tests were administered at baseline and once a year for 5 years. Outcomes were compared with a historical cohort treated with surgery and photon therapy. The coprimary endpoints were progression-free survival and overall survival. Progression was defined as an increase in tumour dimensions on successive imaging evaluations more than 2 years after treatment. Survival and safety were also assessed in all patients who received photon therapy and limited surgery. This study is registered with ClinicalTrials.gov, NCT01419067. Between Aug 22, 2011, and Jan 19, 2016, 94 patients were enrolled and treated with surgery and proton therapy, of whom 49 (52%) were female, 45 (48%) were male, 62 (66%) were White, 16 (17%) were Black, two (2%) were Asian, and 14 (15%) were other races, and median age was 9·39 years (IQR 6·39-13·38) at the time of radiotherapy. As of data cutoff (Feb 2, 2022), median follow-up was 7·52 years (IQR 6·28-8·53) for patients who did not have progression and 7·62 years (IQR 6·48-8·54) for the full cohort of 94 patients. 3-year progression-free survival was 96·8% (95% CI 90·4-99·0; p=0·89), with progression occurring in three of 94 patients. No deaths occurred at 3 years, such that overall survival was 100%. At 5 years, necrosis had occurred in two (2%) of 94 patients, severe vasculopathy in four (4%), and permanent neurological conditions in three (3%); decline in vision from normal to abnormal occurred in four (7%) of 54 patients with normal vision at baseline. The most common grade 3-4 adverse events were headache (six [6%] of 94 patients), seizure (five [5%]), and vascular disorders (six [6%]). No deaths occurred as of data cutoff. Proton therapy did not improve survival outcomes in paediatric and adolescent patients with craniopharyngioma compared with a historical cohort, and severe complication rates were similar. However, cognitive outcomes with proton therapy were improved over photon therapy. Children and adolescents treated for craniopharyngioma using limited surgery and post-operative proton therapy have a high rate of tumour control and low rate of severe complications. The outcomes achieved with this treatment represent a new benchmark to which other regimens can be compared. American Lebanese Syrian Associated Charities, American Cancer Society, the US National Cancer Institute, and Research to Prevent Blindness.

Assessment of Setup Errors in Gynecological Malignancies Treated With Radiotherapy Using Onboard Imaging.

Introduction Radiotherapy plays a vital role in the management of gynecological malignancies. However, maintaining patient position poses a challenge during daily radiotherapy treatment of these patients. This study identifies and calculates setup errors in interfraction radiotherapy and optimum clinical target volume-planning target volume (CTV-PTV) margins in patients with gynecological malignancies. Material and methods A total of 38 patients with gynecological malignancies were included in the study. They were treated with a dose of 50 Gy in 25 fractions for five weeks, followed by brachytherapy. All patients were immobilized using a 4-point thermoplastic cast. Anteroposterior and lateral images were taken thrice weekly for five weeks. Setup verification was done using kilovoltage images obtained using Varian On-board Imager (Varian Medical System, Inc., Palo Alto, CA). Manual matching was done utilizing bony landmarks such as the widest portion of the pelvic brim, anterior border of S1 vertebrae, and pubic symphysis in the X, Y, and Z axes, respectively. Results A total of 1140 images were taken. The individual systematic errors ranged from -0.24 to 0.17 cm (LR), -0.15 to 0.19 cm (AP) and -0.36 to 0.29 cm (CC) while the individual random errors ranged from 0.04 to 0.36 cm (LR), 0.06 to 0.33 cm (AP) and 0.10 to 0.29 cm (CC). The calculated CTV-PTV margins in LR, AP and CC directions were 0.17, 0.18, and 0.25 cm (ICRU-62); 0.28, 0.31 and 0.47 cm in LR, AP and CC directions (Stroom's), and 0.32, 0.36 and 0.55 cm (Van Herk) respectively. Conclusion Based on this study, the calculated CTV-PTV margin is 6 mm in gynecological malignancies, and the present protocol of 7 mm of PTV margin is optimum.

Comparison of Online-Onboard Adaptive Intensity-Modulated Radiation Therapy or Volumetric-Modulated Arc Radiotherapy With Image-Guided Radiotherapy for Patients With Gynecologic Tumors in Dependence on Fractionation and the Planning Target Volume Margin

Patients with newly diagnosed locally advanced cervical carcinomas or recurrences after surgery undergoing radiochemotherapy whose tumor is unsuited for a brachytherapy boost need high-dose percutaneous radiotherapy with small margins to compensate for clinical target volume deformations and set-up errors. Cone-beam computed tomography-based online adaptive radiotherapy (ART) has the potential to reduce planning target volume (PTV) margins below 5 mm for these tumors. To compare online ART technologies with image-guided radiotherapy (IGRT) for gynecologic tumors. This comparative effectiveness study comprised all 7 consecutive patients with gynecologic tumors who were treated with ART with artificial intelligence segmentation from January to May 2022 at the West German Cancer Center. All adapted treatment plans were reviewed for the new scenario of organs at risk and target volume. Dose distributions of adapted and scheduled plans optimized on the initial planning computed tomography scan were compared. Online ART for gynecologic tumors. Target dose coverage with ART compared with IGRT for PTV margins of 5 mm or less in terms of the generalized equivalent uniform dose (gEUD) without increasing the gEUD for the organs at risk (bladder and rectum). The first 10 treatment series among 7 patients (mean [SD] age, 65.7 [16.5] years) with gynecologic tumors from a prospective observational trial performed with ART were compared with IGRT. For a clinical PTV margin of 5 mm, IGRT was associated with a median gEUD decrease in the interfractional clinical target volume of -1.5% (90% CI, -31.8% to 2.9%) for all fractions in comparison with the planned dose distribution. Online ART was associated with a decrease of -0.02% (90% CI, -3.2% to 1.5%), which was less than the decrease with IGRT (P < .001). This was not associated with an increase in the gEUD for the bladder or rectum. For a PTV margin of 0 mm, the median gEUD deviation with IGRT was -13.1% (90% CI, -47.9% to 1.6%) compared with 0.1% (90% CI, -2.3% to 6.6%) with ART (P < .001). The benefit associated with ART was larger for a PTV margin of 0 mm than of 5 mm (P = .004) due to spreading of the cold spot at the clinical target volume margin from fraction to fraction with a median SD of 2.4 cm (90% CI, 1.9-3.4 cm) for all patients. This study suggests that ART is associated with an improvement in the percentage deviation of gEUD for the interfractional clinical target volume compared with IGRT. As the gain of ART depends on fractionation and PTV margin, a strategy is proposed here to switch from IGRT to ART, if the delivered gEUD distribution becomes unfavorable in comparison with the expected distribution during the course of treatment.

An Integrated Monte Carlo Model for Heterogeneous Glioblastoma Treated with Boron Neutron Capture Therapy.

Glioblastomas (GBMs) are notorious for their aggressive features, e.g., intrinsic radioresistance, extensive heterogeneity, hypoxia, and highly infiltrative behaviours. The prognosis has remained poor despite recent advances in systemic and modern X-ray radiotherapy. Boron neutron capture therapy (BNCT) represents an alternative radiotherapy technique for GBM. Previously, a Geant4 BNCT modelling framework was developed for a simplified model of GBM. The current work expands on the previous model by applying a more realistic in silico GBM model with heterogeneous radiosensitivity and anisotropic microscopic extensions (ME). Each cell within the GBM model was assigned an α/β value associated with different GBM cell lines and a 10B concentration. Dosimetry matrices corresponding to various MEs were calculated and combined to evaluate cell survival fractions (SF) using clinical target volume (CTV) margins of 2.0 & 2.5 cm. SFs for the BNCT simulation were compared with external X-ray radiotherapy (EBRT) SFs. The SFs within the beam region decreased by more than two times compared to EBRT. It was demonstrated that BNCT results in markedly reduced SFs for both CTV margins compared to EBRT. However, the SF reduction as a result of the CTV margin extension using BNCT was significantly lower than using X-ray EBRT for one MEP distribution, while it remained similar for the other two MEP models. Although the efficiency of BNCT in terms of cell kill is superior to EBRT, the extension of the CTV margin by 0.5 cm may not increase the BNCT treatment outcome significantly.

Patterns of Progression in Patients With Newly Diagnosed Glioblastoma Treated With 5-mm Margins in a Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With Concurrent and Adjuvant Temozolomide

In patients with newly diagnosed glioblastoma (GBM), tumor margins of at least 20 mm are the standard of care. We sought to determine the pattern of tumor progression in patients treated with 5-fraction stereotactic radiosurgery with 5-mm margins. Thirty adult patients with newly diagnosed GBM were treated with 5-fraction stereotactic radiosurgery in escalated doses from 25 to 40 Gy with a 5-mm total treatment margin. Progression was scored as "in-field" if the recurrent tumor was within or contiguous with the 5-mm margin, "marginal" if between 5 and 20 mm, and "distant" if entirely occurring greater than 20 mm. As geometric patterns of progression do not reflect the biologic dose received, we calculated the minimum equi-effective dose in 2 Gy (EQD2) per day at the site of tumor recurrence. Progression was "dosimetrically in-field" if covered by a minimum EQD2 per day of 48 Gy10. From 2010 to 2016, 27 patients had progressed. Progression was in-field in 17 (63%), marginal in 3 (11%), and distant in 7 (26%) patients. In the 3 patients with marginal progression, the minimum EQD2 to recurrent tumor were 48 Gy10, 56 Gy10 (both considered dosimetrically in-field), and 7 Gy10 (ie, dosimetrically out-of-field). Median overall survival was 12.1 months for in-field (95% confidence interval [CI], 8.9-17.6), 15.1 months (95% CI, 10.1 to not achieved) for marginal, and 21.4 months (95% CI, 11.2-33.5) for distant progression. Patients with radiation necrosis were less likely to have in-field progression (1 of 7; 14%) compared with those without radiation necrosis (16 of 20; 80%; P=.003); those with necrosis had a median overall survival of 27.2 months (95% CI, 11.2-48.3) compared with 11.7 months (95% CI, 8.9-17.6) for patients with no necrosis (P=.077). In patients with newly diagnosed GBM treated with a 5-mm clinical target volume margin, 3 patients (11%) had marginal progression within 5 to 20 mm; only 1 patient (4%) may have dosimetrically benefitted from conventional 20-mm margins. Radiation necrosis was associated with in-field tumor control.

Voluntary deep inspiration breath-hold with volumetric modulated arc therapy in pediatric patients with mediastinal Hodgkin lymphoma.

Background: Deep inspiration breath-hold (DIBH) has been established to decrease normal tissue radiation dose in breast cancer. Methods: Forty-nine patients had two CT scans during DIBH or free breathing. Chest-wall position, setup verification and breath-hold monitoring were performed. Cone-beam CT and a surface image system were used for verification. Results: A total of 1617 breath-holds were analyzed in 401 fractions. The mean time bit was 6.01min. The mean breaths-holds per fraction was 4.96. The median for intra-breath hold variability was 3mm. No patient stopped treatment for intolerance. Clinical target volume margins were calculated as 0.36, 0.36and 0.32 for the three translational positions. The mean saved volume was 26.3%. Conclusion: Voluntary DIBHis feasible, tolerableand easy to apply for children with Hodgkin lymphoma involving the mediastinum.

Impact of MGMT Promoter Methylation Status on Tumor Dynamics during Weekly Adaptive Radiotherapy for Glioblastoma

<h3>Purpose/Objective(s)</h3> Adaptive MRI-guided radiotherapy (RT) on a 1.5T MR-Linac using a reduced clinical target volume (CTV) of 5mm instead of the 15mm standard for glioblastoma (GBM) is currently being evaluated on the UNITED clinical trial (NCT04726397). We present a preliminary comparison of morphological changes during a course of adaptive RT with concurrent temozolomide between tumors with MGMT promotor methylation (MGMT-m) and those that are MGMT promoter unmethylated (MGMT-um). <h3>Materials/Methods</h3> The first 30 patients with GBM (all IDH wildtype) enrolled on the UNITED trial were analyzed. RT consisted of 60 Gy in 30 fractions (n=12) or 40 Gy in 15 fractions (n=18) (Fx). Expansions on the gross tumor volume (GTV) consisted of a 5 mm CTV with the provision to include FLAIR hyperintense areas at-risk and a 3 mm planning target volume (PTV). A pre-treatment reference plan was developed from a standard planning MRI (FxRef) followed by weekly on-line fully adaptive re-planning at Fx1, Fx6, Fx11, etc., based on a gadolinium contrast-enhanced MRI acquired on the MR-Linac. Remaining fractions were image-guided by pre-beam-on onboard non-contrast MRI, to ensure stability of the treatment volumes. The GTV and CTV were quantified by their absolute volumes, volumes relative to the FxRef and the maximum linear distance from the edges of the reference contour at FxRef to the weekly adapted contours (migration distance, d_mig). MGMT promoter methylation status was explored as a fixed effect in a linear mixed statistical model. <h3>Results</h3> The median changes in GTV relative to FxRef at Fx1, Fx6, Fx11, Fx16, Fx21, and Fx25 in MGMT-um tumors (n=12) were 10.3%, 9.2%, 10.6%, 14.5%, 18.0% and 17.3%, respectively, while for MGMT-m (n=18) were 3.4%, 0.0%, -8.6%, -11.3%, -11.3% and -5.6% (p=0.021). A similar significant trend was observed with the CTV. With a median time interval of 6 days (range, 1-18 days) between FxRef and Fx1, the GTV increased by over 10% in 58% of MGMT-um tumors compared to only 33% of MGMT-m tumors. MGMT-um tumors had significantly larger maximum d_mig compared to tumors with MGMT-m, with a median d_mig of 9.6 mm vs. 5.8 mm, respectively (p=0.018). The maximum GTV migration distance was greater than 5, 10 and 15 mm in 83%, 50% and 17% of MGMT-um tumors but only 56%, 11% and 0% for MGMT-m tumors, respectively. <h3>Conclusion</h3> MGMT-um GBM exhibited significant changes in morphology and migration distance between the time of treatment planning to the first treatment fraction, as well as throughout a course of RT. In this population, our results support a greater frequency of imaging and plan adaptation when applying personalized reduced CTV margins.

Radiation Therapy Techniques in the Management of Locally-Advanced, High-Grade, Soft-Tissue-Sarcoma

<h3>Purpose/Objective(s)</h3> Assess which prognostic factors affect local recurrence (LR) rates and wound complications of locally-advanced, high-grade, soft-tissue-sarcoma (STS). <h3>Materials/Methods</h3> Retrospective analysis was performed on patients 2005 to 2018, with high-grade STS of extremity or trunk, >5cm, histology specific, with central pathology review. Wide-excision was performed in 100 patients along with radiation, whose radiation fields and dose plans were available for review, of which 31 also received Ifosfamide-Doxorubicin, with a minimum follow-up of 1-year. Multi-variable-analysis (MVA) of prognostic factors were calculated to see which variables affected LR, and nonhealing wound rates. <h3>Results</h3> Median follow-up was 5.8 years. Univariate analysis revealed that trunk location, proximal, distal, and radial clinical-target-volume (CTV) margins of 1.5cm had higher rates of LR vs ≥2cm or presence of fascial boundary. MVA of these prognostic factors revealed that trunk location (p=0.048), and radial CTV of 1.5cm (p=0.006) independently predicted for higher LR, as 10 of 15 LR were at the edge of the radial margin. Bolus did not affect LR. The odds ratio for nonhealing wounds at 3 months were higher for T2a disease, larger tumor size, proximal CTV ≥2cm, wider field size, use of chemotherapy, and bolus technique. <h3>Conclusion</h3> Proximal/distal CTV margins of 3cm seem adequate, but high-grade STS ≥ 5cm may benefit from increased radial CTV margins of 2-2.5cm in the absence of a fascial boundary, although larger CTV may increase nonhealing wound rates. Bolus techniques lead to higher wound complications in T2a-b STS, and should be avoided.

Long-Term Outcomes of Reduced High-Risk Clinical Target Volume Margin for Intensity-Modulated Radiotherapy in Locally Advanced Head and Neck Cancers

Long-Term Outcomes of Reduced High-Risk Clinical Target Volume Margin for Intensity-Modulated Radiotherapy in Locally Advanced Head and Neck Cancers

Pediatric Craniopharyngioma: The Effect of Visual Deficits and Hormone Deficiencies on Long-Term Cognitive Outcomes After Conformal Photon Radiation Therapy

Pediatric patients with craniopharyngioma risk cognitive deficits when treated with radiation therapy. We investigated cognitive outcomes after conformal photon radiation therapy (CRT) and the effect of visual deficits and hormone deficiencies. One hundred one pediatric patients were enrolled on a single institutional protocol beginning in 1998 (n=76) or followed a similar nonprotocol treatment plan (n=25). CRT (54 Gy) was administered using a 1.0- or 0.5-cm clinical target volume margin. Median age at CRT was 9.50 years (range, 3.20-17.63 years). Patients were followed for 10 years with assessment of hearing, vision, hormone deficiencies, and cognitive performance. Intellectual functioning (intelligence quotient) was significantly lower in children treated at a younger age and those who received higher doses to temporal lobes and hippocampi. Black race (-17.77 points, P=.002) and cerebrospinal fluid shunting (-11.52 points, P=.0068) were associated with lower baseline intelligence quotient. Reading scores were lower over time in models incorporating age, shunt, and dose to specific brain structures. Patients treated for growth hormone deficiency within 12 months of CRT had better intelligence and attention outcomes. Among patients with normal baseline vision, the 10-year cumulative incidence of change in visual acuity was 4.00% ± 2.82% and in visual field 10.42% ± 4.48%. Reading scores decreased after treatment (0.7873 points/y, P=.0451) in those with impaired baseline vision. Cognitive outcomes are selectively affected by dose to brain subvolumes, comorbidities of visual deficits, and treatment of endocrinopathy in pediatric craniopharyngioma. Improved treatment selection, normal tissue sparing methods of irradiation, and posttreatment management of endocrinopathy should be considered.

KS01.5.A Impact of reduced treatment volumes on pattern of tumor recurrence and radiation dose to normal brain parenchyma in glioblastoma

Abstract Background to analyze GBM recurrence pattern after standard chemoradiotherapy according to different target volume delineations. We hypothesized that reduced target volume margins may result in similar pattern of failure. Material and Methods 207 patients with GBM who recurred after standard chemoradiation were evaluated. According to the Advisory Committee for Radiation Oncology Practice (ACROP) committee of the European Organisation for Research and Treatment of Cancer (EORTC) target volume delineation guideline, the clinical target volume (CTV) used for treatment planning consisted of residual tumor and resection cavity plus 2-cm margin. MRI scans showing tumor recurrences were fused with the planning computed tomography (CT), and the patterns of failure were analyzed dosimetrically using dose-volume histograms. The recurrent lesions were defined as in-field, marginal, or distant if &amp;gt;80%, 20-80%, or &amp;lt;20% of the intersecting volume was included in the 95% isodose line. For each patient a theoretical plan consisting of a reduced CTV using 1-cm margin was created and patterns of failure evaluated. Results The median overall survival and progression-free survival were 15.3 months and 7.8 months, respectively, from the date of surgery. Recurrences were in-field in 180 patients, marginal in 5 patients, and distant in 22 patients. Analysis of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status showed different recurrence patterns of GBMs in patients with MGMT methylated compared with patients with MGMT unmethylated status. Recurrences occurred in-field and distant in 75.6% and 18.6% of methylated patients and in 91.8% and 6% of unmethylated patients, respectively (p=0.0046). Patterns of failure were similar between the different treatment plans. Reduced target volumes were associated with significantly lower doses of 20-50 Gy to normal brain and hippocampi (p=0.0001). Conclusion Most of patients treated with standard chemioradiotherapy have in-field recurrences; however, an increased risk of distant recurrences occurs in methylated tumors. The use of target delineation using 1-cm CTV margin is associated with smaller volumes of normal brain and hippocampi irradiated to high doses, without significant changes in the pattern of failure. The impact of different target delineation in terms of efficacy and risk of late radiation-induced toxicity should be assessed prospectively.

LOCL-16 IMPACT OF MGMT PROMOTER METHYLATION STATUS ON TUMOR DYNAMICS DURING WEEKLY ADAPTIVE RADIOTHERAPY FOR GLIOBLASTOMA

PURPOSEAdaptive MRI-guided radiotherapy (RT) on a 1.5T-MR-Linac using reduced clinical target volumes (CTV) of 5mm instead of the 15mm standard for glioblastoma (GBM) is currently being evaluated on the UNITED clinical trial (NCT04726397). We explored the morphological changes that occur during adaptive RT with concurrent temozolomide between tumors with MGMT promotor methylation (MGMT-m) vs. unmethylation (MGMT-um). METHODSThirty patients with IDH-wildtype GBMs were treated with 60Gy in 30 (n=12) or 40Gy in 15 fractions (n=18) (Fx). The CTV included a 5mm expansion on the gross tumor volume (GTV) +/- FLAIR hyperintense areas-at-risk and a 3mm planning target volume. Planning was performed on a pre-treatment reference MRI (FxRef) followed by weekly on-line adaptive re-planning at Fx1, Fx6, etc. acquired on the MR-Linac. Interim fractions were image-guided by pre-beam-on onboard MRI. The GTV/CTVs were quantified by their absolute volumes, volumes relative to the FxRef and the maximum linear distance from the edges of the reference contour to the weekly adapted contours (migration distance, dmig). MGMT promoter methylation status was explored as a fixed effect in a linear mixed statistical model. RESULTSWeekly median changes in GTV relative to FxRef in MGMT-um tumors (n=12) were 10.3%, 9.2%, 10.6%, 14.5%, 18.0% and 17.3%, respectively, while for MGMT-m (n=18) were 3.4%, 0.0%, -8.6%, -11.3%, -11.3% and -5.6% (p=0.021). Between FxRef and Fx1, the GTV increased by over 10% in 58% of MGMT-um tumors vs. 33% of MGMT-m tumors. Similar significant trends were observed with the CTVs. MGMT-um tumors had significantly larger dmig compared to tumors with MGMT-m (median 9.6mm vs. 5.8mm, respectively (p=0.018)). CONCLUSIONSMGMT-um GBM exhibited significant changes in morphology and migration distance between the time of treatment planning to the first treatment fraction, as well as throughout a course of RT. In this population, our results support a greater frequency of imaging and plan adaptation when applying personalized reduced CTV margins.

QOL-17. Neurocognitive outcomes after treatment for medulloblastoma with reduced primary site target volume margins

PURPOSE: Children treated for medulloblastoma (MB) undergo intensive multimodality treatment compromising surgery, irradiation, and chemotherapy, which is associated with a significant risk of neurocognitive deficits. Successive multicenter frontline treatment protocols have introduced reduced posterior fossa boost margins for cranial irradiation for sparing collateral tissue and preserving function. This study examines neurocognitive outcomes in the setting of reduced primary site target volume margins in children treated for MB. PATIENTS & METHODS: Prospective longitudinal neurocognitive data were collected from newly diagnosed patients with MB (n = 372, ages 3-21 years) enrolled on one of two sequential multicenter clinical protocols between 1996 and 2012. The treatment regimen included surgery, risk-adapted craniospinal irradiation with a posterior fossa boost with restricted clinical target volume (CTV) margins (2 cm and 1 cm), and dose-intensive chemotherapy. Comparative analysis of neurocognitive outcomes was performed using linear mixed-effects models. RESULTS: Intelligence quotient (IQ) scores were better preserved in average-risk patients who received treatment using a clinical target volume with a lesser margin of 1 cm (p < 0.0099). Findings were consistent with prior studies on measures of academics including reading performance, mathematical reasoning, and spelling across both risk groups regardless of CTV. CONCLUSION: This study presents compelling evidence in favor of restricted CTVs for preserving IQ without sacrificing treatment efficacy in average childhood MBs.

Limited surgery and conformal photon radiation therapy for pediatric craniopharyngioma: long-term results from the RT1 protocol.

Our aim was to estimate long-term disease control and complications after conformal radiation therapy (CRT) in children and adolescents with craniopharyngioma. Pediatric patients with craniopharyngioma (n = 101) were enrolled on or treated according to a phase II single institutional protocol from 1998. Surgery was individualized, and CRT (54Gy) was administered using a 1.0 cm or 0.5 cm clinical target volume margin. Patients were followed for 10 years by serial MR imaging and MR angiography and a battery of tests to measure the effects of treatment. Twenty patients had tumor progression. Twelve patients who had tumor progression died due to tumor (n = 6) or complications related to tumor or treatment (n = 6). With a median follow-up of 14.94 years for survivors, the 10 year estimates (±SE) of progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) were 78.84% ± 4.10%, 77.12% ± 4.19%, and 96.02% ± 1.95%, respectively. OS, EFS, and PFS were significantly associated with race, shunt status, and tumor volume. The 10 year cumulative incidence (±SE) of the secondary tumor (1.99% ± 1.40%), secondary malignant tumor (1.0% ± 1.0%), necrosis (1.98% ± 1.39%), vasculopathy (8.47% ± 2.90%), and permanent neurologic deficits (8.28% ± 3.37%) were estimated by competing risk analysis. Three patients required revascularization surgery. Salvage therapy was successful in 13 patients using surgery and radiosurgery. Limited surgery and CRT using photons results in excellent tumor control. Tumor control and the incidence and severity of complications are associated with host, tumor, and treatment factors.