High-dose Volume Research Articles

Relationship between radiation dose and cerebral microbleed formation in dogs with intracranial tumors.

Cerebral microbleeds (CMBs) are a possible sequela in human brain tumor patients treated with radiation therapy (RT). No such association is reported in dogs. To investigate whether CMBs occur in dogs after radiotherapy, and if there is an association between number and dose, and an increase over time. Thirty-four client-owned dogs irradiated for primary intracranial neoplasia. ≥2 magnetic resonance imaging (MRI) scans including susceptibility-weighted imaging (SWI) were required. Retrospective, observational, single-center study. Cerebral microbleeds identified on 3 T SWI were counted within the entire brain, and within low- (<20 Gy), intermediate- (20-30 Gy), and high- (>30 Gy) dose regions. A generalized linear mixed-effects model was used to analyze the relationship between the CMBs count and the predictor variables (irradiation dose, time after treatment). Median follow-up time was 12.6 months (range, 1.8-37.6 months). Eighty-three MR scans were performed. In 4/15 dogs (27%, 95% CI, 10%-52%) CMBs were present at baseline. ≥1 CMBs after RT were identified in 21/34 dogs (62%, 95% CI, 45%-77%). With each month, the number of CMBs increased by 14% (95% CI, 11%-16%; P < .001). The odds of developing CMBs in the high-dose region are 4.7 times (95% CI, 3.9-5.6; P < .001) greater compared with the low-dose region. RT is 1 possible cause of CMBs formation in dogs. Cerebral microbleeds are most likely to occur in the peritumoral high-dose volume, to be chronic, and to increase in number over time. Their clinical relevance remains unknown.

Comparison of 3D-printed multichannel non–co-planar vaginal applicators and single-channel vaginal applicators for brachytherapy with positive or close surgical margins in cervical cancer

OBJECTIVEThis study was conducted to compare the differences between 3D-printed multichannel non-coplanar vaginal applicators and single-channel vaginal applicators in cervical cancer patients with positive or close surgical margins. METHODSBetween January 2015 and June 2023, 104 cervical cancer patients who underwent radical surgery with positive or close surgical margins were enrolled to receive concurrent intensity-modulated chemoradiotherapy combined with 3D-printed multichannel non-coplanar vaginal applicators (3D-printed group, 41 patients) or single-channel vaginal applicators (single-channel group, 63 patients) guided brachytherapy. The dosimetric parameters, 5-year local control (LC), progression-free survival (PFS), overall survival (OS) of two groups were retrospectively analyzed. RESULTSThe high-risk clinical target volume (D90, D100) and high-dose volume fraction (V150) in 3D-printed group were significantly higher than those in single-channel group (p<0.05), and the homogeneity index (HI) and conformal index (COIN) were equally better in 3D-printed group. In 3D-printed group, the D2cc, D1cc, and D0.1cc of the bladder and rectum were significantly lower than those of the single-channel group (p<0.05). The 3D-printed group had significantly superior 5-year LC (70.0% vs. 51.3%, P=0.041) and PFS (63.0% vs. 44.2%, P=0.045), but OS were not significantly different between treatment groups (75.4% vs. 59.7%, P=0.112). The incidence of radiation enteritis and cystitis was lower in the 3D-printed group than in the single-channel group, but no statistical difference was noted. CONCLUSIONSThe 3D-printed multichannel non-coplanar vaginal insertion applicators shows the advantage of target dose, improve the LC and PFS in patients with positive or close surgical margins after cervical cancer surgery. Thus, the popularization of this method and its application may be of value.

Simultaneous dose and dose rate optimization via dose modifying factor modeling for FLASH effective dose.

Although the FLASH radiotherapy (FLASH) can improve the sparing of organs-at-risk (OAR) via the FLASH effect, it is generally a tradeoff between the physical dose coverage and the biological FLASH coverage, for which the concept of FLASH effective dose (FED) is needed to quantify the net improvement of FLASH, compared to the conventional radiotherapy (CONV). This work will develop the first-of-its-kind treatment planning method called simultaneous dose and dose rate optimization via dose modifying factor modeling (SDDRO-DMF) for proton FLASH that directly optimizes FED. SDDRO-DMF models and optimizes FED using FLASH dose modifying factor (DMF) models, which can be classified into two categories: (1) the phenomenological model of the FLASH effect, such as the FLASH effectiveness model (FEM); (2) the mechanistic model of the FLASH radiobiology, such as the radiolytic oxygen depletion (ROD) model. The general framework of SDDRO-DMF will be developed, with specific DMF models using FEM and ROD, as a demonstration of general applicability of SDDRO-DMF for proton FLASH via transmission beams (TB) or Bragg peaks (BP) with single-field or multi-field irradiation. The FLASH dose rate is modeled as pencil beam scanning dose rate. The solution algorithm for solving the inverse optimization problem of SDDRO-DMF is based on iterative convex relaxation method. SDDRO-DMF is validated in comparison with IMPT and a state-of-the-art method called SDDRO, with demonstrated efficacy and improvement for reducing the high dose and the high-dose volume for OAR in terms of FED. For example, in a SBRT lung case of the dose-limiting factor that the max dose of brachial plexus should be no more than 26Gy, only SDDRO-DMF met this max dose constraint; moreover, SDDRO-DMF completely eliminated the high-dose (V70%) volume to zero for CTV10mm (a high-dose region as a 10mm ring expansion of CTV). We have proposed a new proton FLASH optimization method called SDDRO-DMF that directly optimizes FED using phenomenological or mechanistic models of DMF, and have demonstrated the efficacy of SDDO-DMF in reducing the high-dose volume or/and the high-dose value for OAR, compared to IMPT and a state-of-the-art method SDDRO.

Impact of joint peer review with a specialist radiologist in head and neck cancer radiotherapy planning.

e18059 Background: Head and neck oncology is heavily dependent on interpretation of radiology. This raises the question whether input from radiology should be formally scheduled as part of the radiotherapy contouring processes. Our aim was to assess the impact of this practice through qualitative and quantitative analysis. Methods: H &amp; N patients treated with radiotherapy between May-2022 and August-2023 were reviewed by a specialist HN radiologist. Incidence of changes in T, N, M and TNM-stage, change as defined by The RCR guidance: 'major' (change in gross tumour volume and/or high-dose clinical target volume, dose/fractionation) or 'minor' (change in intermediate or elective dose clinical target volumes or organs at risk), was recorded. We evaluated whether any of these changes were time dependent (Time interval between MDT to RT Peer Review). Other clinical variables: age, gender, primary diagnosis, tumour site, significant incidental findings, post-operative pTNM, post-operative disease status in adjuvant setting on planning imaging (NIRADS), need for additional imaging. We also recorded number of scans reviewed per patient, types of imaging studies reviewed, time taken for review and number of radiologist PA’s required. Retrospective analysis of a prospective database was performed. Results: 410 patients (252-definitive, 137-adjuvant, 21-palliative) were reviewed of which 51.5%-oropharynx followed by 26.8%-Larynx &amp; Hypopharynx. Mean age was 66.14 yrs (SD 11.46) and M:F was 4:1. Baseline and Therapy planning imaging was reviewed for 100% patients of which baseline included: MR (91.7%), CT (96.1%), US (34.1%), PETCT (31%) and therapy planning (62%-CECT, 19%-MR&amp;CT, 15%-CT, 4%-PETCT). In all patients (n=410), T/N/M/TNM-stage percentage upstage was 27/36.8/8.3/42.2% and in definitive cohort (n=252), it was 41.7/56.7/7.1/59.5%. Reviewing RT-planning Imaging in adjuvant cohort (n=137), 76.6% were NIRADS-1, 11.7% NIRADS-3/4/loco-regional disease and 11.7% distant metastasis. T/N/M/TNM-stage upstage was time dependent and the mean time interval between MDT to RT was higher in upstaged patients (p &lt;0.001). Overall percentage change in treatment plan: no/minor/major/palliative was 40.5/33.9/17.3/8.3% and in definitive cohort 30.2/42.1/20.6/7.1%. Change in plan was not dependent on mean time interval between MDT to RT. Average 10 patients (4 imaging studies/patient) were reviewed by radiologist in 1PA (time to review and peer review meeting time). Conclusions: Routine head and neck radiologist input in radiotherapy peer review is feasible and resulted in a number of major and minor changes to treatment. Inputs not only eased the contouring for oncologists but also lead to updating of current disease stage just prior to treatment. Overall, our results suggest that this is a practice changing step in the radiotherapy workflow which has a direct impact on patient management.

Exclusion of non-Involved uterus from the target volume (EXIT-trial): An individualized treatment for locally advanced cervical cancer using modern radiotherapy and imaging techniques followed by completion surgery

Background and purposeChemoradiotherapy followed by brachytherapy is the standard of care for locally advanced cervical cancer (LACC). In this study, we postulate that omitting an iconographical unaffected uterus (+12 mm distance from the tumour) from the treatment volume is safe and that no tumour will be found in the non-targeted uterus (NTU) leading to reduction of high-dose volumes of surrounding organs at risk (OARs) Material and MethodsIn this single-arm phase 2 study, two sets of target volumes were delineated: one standard-volume (whole uterus) and an EXIT-volume (exclusion of non-tumour-bearing parts of the uterus with a minimum 12 mm margin from the tumour). All patients underwent chemoradiotherapy targeting the EXIT-volume, followed by completion hysterectomy. In 15 patients, a plan comparison between two treatment plans (PTV vs PTV_EXIT) was performed. The primary endpoint was the pathological absence of tumour involvement in the non-targeted uterus (NTU). Secondary endpoints included dosimetric impact of target volume reduction on OARs, acute and chronic toxicity, overall survival (OS), locoregional recurrence-free survival (LRFS), and progression-free survival (PFS). ResultsIn all 21 (FIGO stage I: 2; II: 14;III: 3; IV: 2) patients the NTU was pathologically negative. Ssignificant reductions in Dmean in bladder, sigmoid and rectum; V15Gy in sigmoid and rectum, V30Gy in bladder, sigmoid and rectum; V40Gy and V45Gy in bladder, bowel bag, sigmoid and rectum; V50Gy in rectum were achieved. Median follow-up was 54 months (range 7–79 months). Acute toxicity was mainly grade 2 and 5 % grade 3 urinary. The 3y- OS, PFS and LRFS were respectively 76,2%, 64,9% and 81 %. ConclusionMRI-based exclusion of the non-tumour-bearing parts of the uterus at a minimum distance of 12 mm from the tumour out of the target volume in LACC can be done without risk of residual disease in the NTU, leading to a significant reduction of the volume of surrounding OARS treated to high doses.

Personalizing dental screening and prevention protocols in dentulous patients with oropharyngeal cancer undergoing radiotherapy: A retrospective cohort study

ObjectivesPatients with head and neck cancer are routinely screened for dental foci prior to radiotherapy (RT) to prevent post- RT tooth extractions associated with an increased risk of osteoradionecrosis. We evaluated the risk factors for post-RT tooth extraction to personalise dental screening and prevention protocols prior to RT. Materials and methodsThis retrospective cohort study included dentulous patients diagnosed with oropharyngeal cancer who had undergone radiation therapy at doses 60–70 Gy and achieved a disease-free survival of ≥ 1 year (N = 174). Risk factors were assessed using Cox regression models. ResultsThe cumulative incidence of post-RT tooth extraction was 30.7 % at 5 years. Main indications for extraction (n = 62) were radiation caries (n = 20) and periodontal disease (n = 27). Risk factors associated (p < 0.05) with radiation caries-related extractions included active smoking, alcohol abuse, poor oral hygiene, parotid gland irradiation, and mandibular irradiation. A high-dose volume in the mandible was associated with periodontal disease events. ConclusionPost-RT extractions due to radiation caries were influenced by lifestyle factors and RT dose in the mandible and parotid glands. Periodontal disease-related extractions were primarily associated with the mandibular dose. During dental screening these post-RT risk factors should be taken into account to prevent osteoradionecrosis.

Treatment planning for patients with low rectal cancer in a multicenter prospective organ preservation study

BackgroundNon-surgical management of rectal cancer relies on (chemo)radiotherapy as the definitive treatment modality. This study reports and evaluates the clinical high dose radiotherapy treatment plans delivered to patients with low resectable rectal cancer in a Danish multicenter trial. MethodsThe Danish prospective multicenter phase II Watchful Waiting 2 trial (NCT02438839) investigated definitive chemoradiation for non-surgical management of low rectal cancer. Three Danish centers participated in the trial and committed to protocol-specified treatment planning and delivery requirements. The protocol specified a dose of 50.4 Gy in 28 fractions to the elective volume (CTV-/PTV-E) and a concomitant boost of 62 Gy in 28 fractions to the primary target volume (CTV-/PTV-T). ResultsThe trial included 108 patients, of which 106 treatment plans were available for retrospective analysis. Dose coverage planning goals for the main target structures were fulfilled for 94% of the treatment plans. However, large intercenter differences in doses to organs-at-risk (OARs) were seen, especially for the intestines. Five patients had a V60Gy>10 cm3 for the intestines and two patients for the bladder. ConclusionPrescribed planning goals for target coverage were fulfilled for 94% of the treatment plans, however analysis of OAR doses and volumes indicated intercenter variations. Dose escalation to 62 Gy (as a concomitant boost to the primary tumor) introduced no substantial high dose volumes (>60 Gy) to the bladder and intestines. The treatment planning goals may be used for future prospective evaluation of highdose radiotherapy for organ preservation for low rectal cancer.

A Beam Angle Selection Method to Improve Plan Robustness Against Position Error in Intensity-Modulated Radiotherapy for Left-Sided Breast Cancer.

We report a dosimetric study in whole breast irradiation (WBI) of plan robustness evaluation against position error with two radiation techniques: tangential intensity-modulated radiotherapy (T-IMRT) and multi-angle IMRT (M-IMRT). Ten left-sided patients underwent WBI were selected. The dosimetric characteristics, biological evaluation and plan robustness were evaluated. The plan robustness quantification was performed by calculating the dose differences (Δ) of the original plan and perturbed plans, which were recalculated by introducing a 3-, 5-, and 10-mm shift in 18 directions. M-IMRT showed better sparing of high-dose volume of organs at risk (OARs), but performed a larger low-dose irradiation volume of normal tissue. The greater shift worsened plan robustness. For a 10-mm perturbation, greater dose differences were observed in T-IMRT plans in nearly all directions, with higher ΔD98%, ΔD95%, and ΔDmean of CTV Boost and CTV. A 10-mm shift in inferior (I) direction induced CTV Boost in T-IMRT plans a 1.1 (ΔD98%), 1.1 (ΔD95%), and 1.7 (ΔDmean) times dose differences greater than dose differences in M-IMRT plans. For CTV Boost, shifts in the right (R) and I directions generated greater dose differences in T-IMRT plans, while shifts in left (L) and superior (S) directions generated larger dose differences in M-IMRT plans. For CTV, T-IMRT plans showed higher sensitivity to a shift in the R direction. M-IMRT plans showed higher sensitivity to shifts in L, S, and I directions. For OARs, negligible dose differences were found in V20 of the lungs and heart. Greater ΔDmax of the left anterior descending artery (LAD) was seen in M-IMRT plans. We proposed a plan robustness evaluation method to determine the beam angle against position uncertainty accompanied by optimal dose distribution and OAR sparing.

Abscopal effect in metastatic breast cancer treated with stereotactic body radiotherapy in the absence of immunotherapy.

In this study, we aimed to assess the abscopal effect (AE) after CyberKnife stereotactic body radiotherapy (SBRT) in metastatic breast cancer patients without immunotherapy. We reviewed breast cancer patients who received SBRT with a fraction size of ≥ 6 Gy for metastatic lesions between July 2008 and December 2021. We selected patients who had at least one measurable extracranial lesion in addition to SBRT target lesions and were not treated with immunotherapy. A total of 40 SBRT cases from 34 patients were included in the analysis. The AE was defined as occurring before the overall progression of the disease, regardless of the use of systemic treatment. The median follow-up duration was 16.4 months. Among 40 SBRT cases, the AE was observed in 10 (25.0%) with a median interval of 2.1 months. Of these lesions, 70.0% did not progress for one year. In multivariate logistic regression analysis, no change in systemic treatment after SBRT was significantly associated with an increase in the AE (odds ratio [OR] = 1.428, 95% confidence interval [CI] = 1.108 - 1.841, p = 0.009). A post-SBRT neutrophil-to-lymphocyte ratio (NLR) of < 2 marginally increased the AE (OR = 1.275, 95% CI = 0.998 - 1.629, p = 0.060). However, a high SBRT dose and large planning target volume did not (p = 0.858 and 0.152, respectively) in univariate analysis. One out of four patients experienced the AE after SBRT in the absence of immunotherapy. The AE could occur more frequently when systemic treatment remains unchanged, and patients have a low NLR after SBRT.

Dose planning study of proton versus photon radiotherapy for head and neck squamous cell carcinoma of unknown primary in the primary and recurrent setting

Background Patients with head and neck squamous cell carcinoma of unknown primary (HNCUP) are often treated with extensive radiotherapy (RT). Frequently, the bilateral nodal clinical target volume (nCTV) and the volumes of suspected mucosal primary sites (mCTV) of the pharynx and larynx is irradiated. This treatment is effective but toxic. New data suggest that omission of the contralateral nCTV and mCTV, results in few recurrences. The present study explores photon versus proton therapy, in the primary and recurrent setting. Material and methods An analysis of twelve patients previously treated for HNCUP was performed. A fictitious recurrence was defined in patients treated for unilateral disease. Independently a volumetric arc photon plan and an intensity-modulated proton plan was made for all cases and scenarios. Results Compared to the standard bilateral treatment this study shows that limiting the target to unilateral nCTV leads to a significant decrease in dysphagia of 18% and 17% and xerostomia of 4.0% and 5% for photon and protons, respectively. Comparing photon RT directly to proton RT shows a small and often insignificant gain, using protons for both bilateral and unilateral targets. Focusing on re-irradiation, benefits from using protons in both the primary setting and at re-irradiation were limited. However, using protons for re-irradiation only leads to a decrease in the tissue volume receiving a specific dose outside the target overlapping region, e.g., V90Gymean was 31, 25, and 22 cm3 for photons-photons, photons-protons, and protons-protons, respectively. For V100Gy of the ipsilateral carotid artery, no differences were observed. Conclusion Omitting contralateral nCTV irradiation and mCTV irradiation will significantly reduce toxicity. The accumulated high dose volumes can be minimised using protons for re-irradiation. However, the use of protons for primary treatment provides limited benefit in most patients.

Correlation between Thyroid Radiation Dose and Thyroid Function after Adjuvant Hypofractionated Locoregional Radiotherapy in Breast Cancer Patients

Radiotherapy (RT) is used quite often among breast cancer patients, and because these patients now live longer than they used to, long-term treatment-related adverse effects, such as hypothyroidism, are becoming increasingly relevant. Radiation-induced hypothyroidism is a late side effect of radiation to the thyroid gland, which could develop months to years after radiotherapy. However, there is no sufficient data on hypothyroidism in patients with breast cancer who receive locoregional RT, which usually affects a portion of the thyroid gland. In this prospective study, we tried to correlate between the radiation dose received by the thyroid gland and the incidence of thyroid dysfunction in breast cancer patients treated with hypofractionated locoregional radiotherapy, as well as establishing potential planning objectives that could help in sparing the thyroid gland. Our study included 109 women who received 3-D conformal loco-regional breast radiotherapy, these patients had normal thyroid function prior to start of radiotherapy. Patients had follow-up thyroid function tests 6 months after finishing radiotherapy. Based on dose volume histograms (DVH), the percentages of the thyroid volume, and ipsilateral thyroid lobe, receiving 5, 10, 15, 20, 25, 30, 35, and 40 Gy (V5, V10, V15, V20, V25, V30, V35, and V40 respectively), in addition to the mean and maximum thyroid doses, were estimated. Follow-up assessment of thyroid function and statistical analysis unveiled incidence of radiotherapy induced hypothyroidism to be 8.3%. Possible risk factors included high maximum radiation dose and V40 to the thyroid gland and the ipsilateral thyroid lobe, as well as high mean dose and smaller volume of the ipsilateral thyroid lobe. The likelihood of hypothyroidism was significantly increased with V40 of >5% of the thyroid gland, and V40 of >11% of the ipsilateral thyroid lobe. Further study is recommended for larger populations and longer follow-up periods.

Dosimetric Analysis Using Automated Tools of Trigeminal Neuralgia Treatment with Stereotactic Radiosurgery

Symptoms from trigeminal neuralgia (TGN) can be significantly debilitating. For treatment of TGN with stereotactic radiosurgery (SRS), there is some data that suggests dose and location of treatment along the trigeminal nerve (TN) pathway may be associated with improved outcomes; however, recurrence rates are widely variable. Limited data exists to evaluate dosimetric parameters of SRS for TGN in relation to patient outcome. This study evaluated the hypothesis that specific characteristics of high dose volume coverage of the TN was associated with outcomes in the treatment of TGN with SRS. Patients who underwent a non-invasive stereotactic radiosurgery instrument for the treatment of TGN at a single institution from 2008-2020 were retrospectively reviewed. Patients were selected for treatment with SRS after consensus from neurosurgery and radiation oncology teams. Patient must have undergone MR FIESTA sequence imaging for treatment planning and had at least 3mo TGN follow up after SRS. Using commercially available software, an automated script was developed to extract detailed characteristics of isodose line structures (IDL) created from the delivered radiation treatment plan. Variables evaluated included voxel volume, mean/max of the HU signal, kurtosis/skewness (a measure of non-spheroidicity) of the IDL, and HU integral of the 140-195% IDL structures, all of which could serve as possible surrogates to the degree and shape of TN pathway dosimetric coverage. Patient reported pain was graded prior and post treatment using Barrow Neurologic Institute pain scale (BNI). Post SRS BNI score I-III was considered significant symptom improvement while BNI score IV-V was considered no benefit. Univariate and multivariable analysis was performed using the cox proportional hazard model. Of the 73 patients included, 52 (71%) were female and 21 (29%) were male, and median age at time of treatment was 73 years (60-79 years). Pretreatment BNI scores were BNI III in 9 (12%) patients, BNI IV in 42 (58%) patients, and BNI V in 22 (30%) patients. After SRS, 62 (85%) patients experienced significant symptom relief (BNI I-III). Median time to symptom relief was 2mo (IQR 1-4mo) with a median duration of 12mo (2-28mo). Median time to treatment failure was 12mo (IQR 2-28mo). On multivariable analysis evaluating IDL characteristics associated with achieving symptom relief, 195% IDL kurtosis was associated with increased likelihood of achieving symptom relief (HR 1.94, p<.001), while and 180% IDL voxel size was associated with reduced likelihood of achieving symptom relief (HR 0.99, p<.001). In the treatment of TGN with SRS, these initial results suggests that high dose IDL structure characteristics, specifically the size and shape features of the dose distributions, may be associated with likelihood of achieving symptom relief. Future directions include analysis of a richer set of dosimetric features in a larger cohort to further refine significant dosimetric parameters for treatment planning.

Risk of Subsequent Neoplasms in Childhood Cancer Survivors After Radiation Therapy: A PENTEC Comprehensive Review

A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors. A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated. The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P < .0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs. This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors.

Assessment of Minimum Dose as a Strong Predictor of Local Failure after Spine SBRT

Stereotactic body radiation therapy (SBRT) has demonstrated robust clinical benefits in carefully selected patients, improving local control and even overall survival (OS). Even so, a wide range of dose-fractionation schemes are used in clinical practice. We seek to assess a large database to determine clinical and dosimetric predictors of local failure after spine SBRT. From a large institutional database, spine SBRT treatments with subsequent imaging follow-up to assess local control were identified. Patients were treated with a simultaneous integrated boost technique using 1 or 3 fractions, generally delivering 20-24 Gy in 1 fraction to the high dose volume and 16 Gy to the low dose volume (or 30-36 Gy and 24 Gy for 3 fraction treatments). Exclusions included: lack of imaging follow-up, proton therapy, and benign primary histologies. Statistical analyses included Cox proportional hazards analyses and the robust log-rank statistic for cut-point analysis. The cumulative incidence of local failure with death as a competing risk was considered as the primary endpoint. A total of 522 eligible spine SBRT treatments (68% single fraction) were identified in 377 unique patients. Patients had a median OS of 43.7 months (95% confidence interval: 34.3-54.4). The cumulative incidence of local failure was 19.3% (15.3-23.2) at 1 year and 25.6% (21.1-29.9) at 2 years. Univariate analysis identified that the minimum dose (normalized for the prescription dose) was a strong predictor of local failure (p = 0.0093). Among patients treated with a single fraction, statistical significance was maintained (p = 0.024). No other dosimetric factors were predictive of local failure. In a cut point analysis, the log-rank statistic was maximized at 15.8 Gy minimum dose for single-fraction treatment (HR = 0.51, 95% CI: 0.34 - 0.75, p = 0.0009). Cumulative incidence of local failure was 15.1% (9.8-20.2) vs. 24.7% (17.2-31.5) at 1 year using this cut-off. Comparable local control was demonstrated with a minimum dose of 14 Gy (HR = 0.57, 95%: 0.37 - 0.87, p = 0.009), with reduced local control with lower minimum doses. Among a range of clinical factors assessed, only epidural and soft tissue involvement were predictive of local failure (HR = 1.80 and 1.98, respectively). Multivariable analyses incorporating soft tissue involvement, epidural extension, and multilevel disease confirmed the 15.8 Gy cutoff for single fraction cases (HR = 0.58, 95% CI: 0.38-0.88, p = 0.011). Spine SBRT offers favorable local control using a range of dose-fractionation schemes; however, minimum dose has a strong association with local control, unlike any other dosimetric factors tested. Furthermore, statistical significance was maintained even when considering epidural extension and potential limitations from dose to the spinal cord. Our data suggests that the minimum dose should be prioritized during treatment planning, ideally to at least 14 - 15.8 Gy for single fraction.

A convolution-superposition fluence model for the Siemens HD120 multi leaf collimator with application to a 3D VMAT dose engine

Purpose. To construct a fast-calculating fluence modelfor the Siemens HD120 multi leaf collimator (MLC) using convolution-superposition techniques, and to develop a 3D VMAT dose engine using this fluence model. This work offers analternative to time-consuming open-source Monte Carlo simulations for thosedeveloping in-house dose-calculating software for research or clinical needs.Methods. EPID-acquired images of sweeping-window and sweeping-checker field profiles were used to commission transmission, 2 Dinterleaf leakage, and tongue-and-groove maps specific to the HD120 MLC. These maps, along with a 2D head-scattermodel were incorporated into a convolution-superposition algorithm to provide a fluence model for the HD120 MLC. This fluence model was used to develop a 3D VMAT dose engine, where 3D pre-computed 6MV dose kernels (EGSnrc) and a 3D fluence curvature-correction map were incorporatedto calculate 3D VMAT doses in a 22 cm diameter cylindrical phantom. Four VMAT patient plans witha large range of PTV sizes (36 cc to 604 cc) were chosen to test the fluence model and dose engine. Results. Excellent agreement was observed between the simulated commissioning fields and measured EPID-responses. 2D 2%/2 mm gamma analysis yielded a 98.9% pass rate for 1 cm, 2 cm, and 4 cm sweeping-window fields. 2D 2%/2mm gamma analysis for outer/inner MLC leaves yielded 89.1%/77.0% and 95.2%/91.1% pass rates from 1 cm and 2 cm sweeping-checker fields. Mean 3%/3 mm gamma analysis showed excellent agreement between our dose engine and Eclipse (Acuros) regardless of PTV size: 98.7% pass rate, with 95.1% pass rate in the high-dose volume. Fluence calculation times were13.6 seconds per dynamic MLC field and 1.4 minutes/arc for 3D VMAT dose on a standard PC. Conclusions. A fast-calculating convolution-superposition fluence model has been commissioned for the Siemens HD120 MLC and incorporatedinto a 3D VMAT dose engine. This work can be used to facilitate the development of fast in-house dose-calculating software.

Bone marrow sparing in prostate cancer patients treated with Post-operative pelvic nodal radiotherapy – A proton versus photon comparison

PurposeExtending salvage radiotherapy to treat the pelvic lymph nodes (PLNRT) improves oncologic outcomes in prostate cancer (PCa). However, a larger treatment volume increases the extent of bone marrow (BM) exposure, which is associated with hematologic toxicity (HT). Given the potential long-term impact of BM dose in PCa, clinical studies on BM sparing (BMS) are warranted. Herein, we dosimetrically compared photon and proton plans for BMS. Materials and MethodsTreatment plans of 20 post-operative PCa patients treated with volumetric-modulated arc photon therapy (VMAT) PLNRT were retrospectively identified. Contours were added for the whole pelvis BM (WPBM) and BM sub-volumes: lumbar-sacral (LSBM), iliac (ILBM), and lower pelvis (LPBM). Three additional plans were created: VMAT_BMS, intensity-modulated proton therapy (IMPT), and IMPT_BMS. Normal tissue complication probabilities (NTCP) for grade >3 hematologic toxicity (HT3+) were calculated for the WPBM volumes. ResultsCompared to the original VMAT plan, mean doses to all BM sub-volumes were statistically significantly lower for VMAT_BMS, IMPT, and IMPT_BMS resulting in average NTCP percentages of 20.5 ± 5.9, 10.7 ± 4.2, 6.1 ± 2.0, and 2.5 ± 0.6, respectively. IMPT_BMS had significantly lower low dose metrics (V300cGy-V2000cGy) for WPBM and sub-volumes except for LPBM V2000cGy compared to VMAT_BMS and ILBM V20Gy compared to IMPT. In most cases, V4000cGy and V5000cGy within ILBM and LSBM were significantly higher for IMPT plans compared to VMAT plans. ConclusionsBMS plans are achievable with VMAT and IMPT without compromising target coverage or OARs constraints. IMPT plans were overall better at reducing mean and NTCP for HT3+ as well as low dose volumes to BM. However, IMPT had larger high dose volumes within LSBM and ILBM. Further studies are warranted to evaluate the clinical implications of these findings.

Dysphagia-optimised intensity-modulated radiotherapy versus standard intensity-modulated radiotherapy in patients with head and neck cancer (DARS): a phase 3, multicentre, randomised, controlled trial

Most newly diagnosed oropharyngeal and hypopharyngeal cancers are treated with chemoradiotherapy with curative intent but at the consequence of adverse effects on quality of life. We aimed to investigate if dysphagia-optimised intensity-modulated radiotherapy (DO-IMRT) reduced radiation dose to the dysphagia and aspiration related structures and improved swallowing function compared with standard IMRT. DARS was a parallel-group, phase 3, multicentre, randomised, controlled trial done in 22 radiotherapy centres in Ireland and the UK. Participants were aged 18 years and older, had T1-4, N0-3, M0 oropharyngeal or hypopharyngeal cancer, a WHO performance status of 0 or 1, and no pre-existing swallowing dysfunction. Participants were centrally randomly assigned (1:1) using a minimisation algorithm (balancing factors: centre, chemotherapy use, tumour type, American Joint Committee on Cancer tumour stage) to receive DO-IMRT or standard IMRT. Participants and speech language therapists were masked to treatment allocation. Radiotherapy was given in 30 fractions over 6 weeks. Dose was 65 Gy to primary and nodal tumour and 54 Gy to remaining pharyngeal subsite and nodal areas at risk of microscopic disease. For DO-IMRT, the volume of the superior and middle pharyngeal constrictor muscle or inferior pharyngeal constrictor muscle lying outside the high-dose target volume had a mandatory 50 Gy mean dose constraint. The primary endpoint was MD Anderson Dysphagia Inventory (MDADI) composite score 12 months after radiotherapy, analysed in the modified intention-to-treat population that included only patients who completed a 12-month assessment; safety was assessed in all randomly assigned patients who received at least one fraction of radiotherapy. The study is registered with the ISRCTN registry, ISRCTN25458988, and is complete. From June 24, 2016, to April 27, 2018, 118 patients were registered, 112 of whom were randomly assigned (56 to each treatment group). 22 (20%) participants were female and 90 (80%) were male; median age was 57 years (IQR 52-62). Median follow-up was 39·5 months (IQR 37·8-50·0). Patients in the DO-IMRT group had significantly higher MDADI composite scores at 12 months than patients in the standard IMRT group (mean score 77·7 [SD 16·1] vs 70·6 [17·3]; mean difference 7·2 [95% CI 0·4-13·9]; p=0·037). 25 serious adverse events (16 serious adverse events assessed as unrelated to study treatment [nine in the DO-IMRT group and seven in the standard IMRT group] and nine serious adverse reactions [two vs seven]) were reported in 23 patients. The most common grade 3-4 late adverse events were hearing impairment (nine [16%] of 55 in the DO-IMRT group vs seven [13%] of 55 in the standard IMRT group), dry mouth (three [5%] vs eight [15%]), and dysphagia (three [5%] vs eight [15%]). There were no treatment-related deaths. Our findings suggest that DO-IMRT improves patient-reported swallowing function compared with standard IMRT. DO-IMRT should be considered a new standard of care for patients receiving radiotherapy for pharyngeal cancers. Cancer Research UK.

Visualization and comparison of CT dose distribution between axial and helical acquisitions.

It is challenging to assess the accuracy of volume CT Dose Index (CTDIvol ) when the axial scan modes corresponding to a helical scan protocol are not available. An alternative approach was proposed to directly measure using helical acquisitions and relatively small differences (<20%) from CTDIvol were observed. To visually demonstrate the 3D dose distribution for both axial and helical CT acquisitions and quantitively compare and CTDIvol . 3D dose distribution within the standard CTDI phantoms (16 and 32cm diameter) from a single CT projection, Dp (x,y,z) was first generated using Monte Carlo simulation (GEANT4) with 9×108 photons per combination of tube voltage (80-140kV), collimation width (1-8cm), and z-axis location of the central ray of the x-ray beam, with a spatial resolution of 1 mm3 . These dose distributions from one single projection were analytically ensembled to simulate 3D dose volumes DA (x,y,z) and DH (x,y,z) for axial and helical scans, respectively, with different helical pitches (0.3-2) and scan lengths (100-150mm). 2D planar dose distributions were obtained by integrating the inside 100mm of the dose volumes. CTDIvol and were calculated using the planar dose data at corresponding pencil chamber locations and the percentage differences (PD) were reported. High spatial resolution 3D CT dose volumes were generated and visualized. PDs between and CTDIvol had strong dependency on scan length and peripheral chamber locations, with subtle dependency on collimation width and pitch. PDs were mostly within the range of±3% for a scan length of 150mm with four peripheral chamber locations. With a scan length covering the entire phantom length, directly measured from helical scans can serve as an alternative to CTDIvol only if all four peripheral locations were measured.

Why subclinical involvement is prescribed the same high dose as gross tumor volume: A study on high-dose clinical target volume in intensity-modulated radiotherapy plan of nasopharyngeal carcinoma.

Most nasopharyngeal carcinoma (NPC) protocols define primary gross tumor volume (GTVnx) plus a range from 2 to 5 mm as the high-dose clinical target volume (hd-CTV). However, in China, hd-CTV is defined as GTVnx plus 0 mm. A total of 40 patients with newly diagnosed nonmetastatic NPC (T1-T4 ten cases each) treated with IMRT were consecutively enrolled. Real and virtual treatment plans were designed according to the definitions of hd-CTV recommended by China and Radiation Therapy Oncology Group (RTOG), respectively. The hd-CTV in China was significantly smaller than that of RTOG. Exposure doses to 5 mm subclinical involvement and OARs as well as NTCP in the China treatment plan were significantly lower than those of RTOG. It could be recommended to divide the hd-CTV into GTV and subclinical target volume and to prescribe different doses for the GTV and subclinical involvement in the IMRT plan of NPC.

Gross tumor volume margin and local control in p16-positive oropharynx cancer patients treated with intensity modulated proton therapy.

To determine if the extent of high-dose gross tumor volume (GTV) to clinical target volume (CTV) expansion is associated with local control in patients with p16-positive oropharynx cancer (p16+ OPC) treated with definitive intensity modulated proton therapy (IMPT). We performed a retrospective analysis of patients with p16+ OPC treated with IMPT at a single institution between 2016 and 2021. Patients with a pre-treatment PET-CT and restaging PET-CT within 4months following completion of IMPT were analyzed. Sixty patients were included for analysis with a median follow-up of 17 months. The median GTV to CTV expansion was 5 mm (IQR: 2 mm). Thirty-three percent of patients (20 of 60) did not have a GTV to CTV expansion. There was one local failure within the expansion group (3%). Excellent local control was achieved using IMPT for p16+ OPC independent of GTV expansion. IMPT with minimal target expansions represent a potential harm-minimization technique for p16-positive oropharynx cancer.