Normal Tissue Dose Research Articles

Combined proton–photon treatment for breast cancer

Objective. Proton therapy remains a limited resource due to gantry size and its cost. Recently, a new design without a gantry has been suggested. It may enable combined proton–photon therapy (CPPT) in conventional bunkers and allow the widespread use of protons. In this work, we explore this concept for breast cancer. Methods. The treatment room consists of a LINAC for intensity modulated radiation therapy (IMRT), a fixed proton beamline (FBL) with beam scanning and a motorized couch for treatments in lying positions with accurate patient setup. Thereby, proton and photon beams are delivered in the same fraction. Treatment planning is performed by simultaneously optimizing IMRT and IMPT plans based on the cumulative dose. The concept is investigated for three breast cancers where the goal is to minimize mean dose to the heart and lung while delivering 40.05 Gy in 15 fractions to the PTV with a SIB of 48 Gy to the tumor bed. The probabilistic approach is applied to mitigate the sensitivity to range uncertainties. Results. CPPT is particularly advantageous for irradiating concave target volumes that wrap around a curved chest wall. There, protons may deliver dose to the peripheral and medial parts of the target volume including lymph nodes. Thereby, the mean dose in normal tissues is reduced compared to single-modality IMRT. However, tangential photon beams may treat parts of the target volume near the interface to the lung. To ensure target coverage for range undershoot in an IMPT plan, proton beams have to deliberately overshoot into the lung tissue—a problem that can be mitigated via the photon component which ensures plan conformity and robustness. Conclusion. CPPT using an FBL may represent a realistic approach to make protons available to more patients. In addition, CPPT may generally improve treatment quality compared to both single-modality proton and photon treatments.

Mathematical Modeling of Uniform and Nonuniform Malignian and Normal Tissues Irradiation. Mathematical Analysis of the Tumour Grid Irradiation

Purpose: On base created mathematical model (MM) modified Veybull distribution, intended for NTCP calculation, depending on irradiated volume V and uniform irradiation dose D, to develop the MM, which allows to realize transition from nonuniform dose in tissue to the equivalent, uniform identical dose. To research the hypothesis, under what condition lumpy sharing dose in system tumors+normal tissues will be more efficient, than uniform dose.
 Material and Methods: Lumpy sharing dose are described as a differential histogram dose-volume (DDVH). The MM for calculation transition lumpy distribution of the absence of the beam complication probability (ACPr) in tissue is designed. It was used for MM conclusion, which allows to calculate transition values of the Adequate Dose (AD) of the uniform irradiation tissues, which use brings about ACPr in tissues. 
 Results: On base of the suggestions and proved affirmation MMs are received, which allow for lumpy distribution of local NTCP values, presented as a DHDV, to calculate transition values ACPr, as well as select from it MM for reduction of the lumpy sharing dose. On base created MM question was explored, in what case tumors and normal tissue through a grid irradiation will be more effective than uniform irradiation.
 Conclusion: The transition from lumpy sharing doses in tissues to equivalent uniform dose present the significant interest for the RT planning efficiency. Their study is necessary, where the radiation of biosubjects is influenced.

Next Evolutions in Particle Therapy: Spot-Scanning Hadron Arc (SHArc) Therapy

To develop and evaluate spot-scanning hadron arc (SHArc) therapy, the first arc delivery technique for both light and heavy ions, in different clinical scenarios.Robust treatment planning and biological optimization procedures were developed within a GPU-accelerated dose engine and treatment planning system, establishing a dedicated energy/spot/angle selection protocol for robust SHArc delivery. Initial tests were performed for three clinical particle beams (protons, helium, and carbon ions) on water-equivalent cylindrical phantoms for simple targets and clinical-like scenarios with an organ-at-risk (OAR) in proximity of the target to compare SHArc against reference conventional techniques using single and multi-field configurations. SHArc patient treatments were surveyed in various sites (head, H&N, thorax and pelvic region). Dosimetric and biological features were calculated and evaluated applying the modified microdosimetric kinetic model. To determine impact of LET variations within the tumor volume, a model for hypoxia-induced radio-resistance was developed and applied for particle therapy to investigate impact on effective dose.SHArc plans exhibited similar target coverage with unique treatment attributes and distributions compared to conventional planning, with carbon ions demonstrating the greatest potential for tumor control and normal tissue sparing among the arc techniques. All SHArc plans exhibited a low-dose bath outside the target volume with a reduced maximum dose in normal tissues compared to single and multi-field plans. Moreover, favorable LET distributions were possible with the SHArc approach with substantial increases in LETmax and volume containing high-LET components. Moreover, reductions of high-LET regions in normal tissues and OARs were observed compared to static treatment beam delivery.The first arc treatment delivery technique using helium and carbon ion beams is proposed. Evidence suggests that through arc delivery of high-LET particle beams, SHArc therapy may offer uniquely valuable clinical advantages both dosimetrical and biological. Robust SHArc treatments could potentially improve tumor control by overcoming tumor microenvironment resistance factors such as hypoxia induced radio-resistance, and reduce toxicity in critical structures by minimizing high-LET components.

Proton Therapy for Adult Craniopharyngioma

Proton therapy (PT) is being increasingly used for craniopharyngioma. Most series focus on pediatric population. Real therapeutic gain of PT in adults has yet to be demonstrated. We evaluated the outcomes of all adult craniopharyngioma patients treated at our institution using PT to report outcomes for disease control, tumor response and treatment-related toxicity.We reviewed medical records from 93 histological proven adult craniopharyngioma patients treated with PT at our institution from December 2006 to November 2018. Endpoints were overall survival, disease control and toxicity. The median age at PT was 36.5 years (18-82). Ninety patients were treated after at least one tumor resection prior PT (20 patients as adjuvant treatment after incomplete surgery, 70 for recurrent disease) and 3 as exclusive PT. Patients received double-scattered conformal proton therapy to a mean dose of 54 GyRBE in 1.8 GyRBE/fraction (range 52.2-54 GyRBE). Toxicity was collected according CTCAE v5.With median clinical and radiographic follow-up of 37 and 31 months, respectively, the 3-year local control and overall survival rates were 100% and 93.5%, respectively. At last follow up, 16 patients remained in complete remission, 47 in partial remission, 24 with stable disease and 6 patients had a local relapse. Six patients required treatment replanning due to tumor changes during radiotherapy. There were two acute grade 3 toxicity events (one visual field decline and one headache). Two late grade 2 side-effects occurred (one visual field decline and one visual acuity deterioration) and one grade 3 neurocognitive dysfunction following radiotherapy. One patient with pre-existing visual field declines experienced grade 4 visual loss five months after PT and after receiving bevacizumab.Fractionated PT appears as an effective and safe treatment for adult craniopharyngioma compared to IMRT and 3DRT. Although the integral dose in normal tissues decreases drastically, the benefit of PT remains uncertain in adult patients. Prospective quality-of-life and neurocognitive studies are needed to better define late toxicity. Only prospective trials in adult population should define the role of RT in terms of techniques, prescribed doses, fractionation and sparing of organs at risk.N. Scher: None. G. Bentahila: None. A. Beddok: None. C. Alapetite: None. S. Helfre: None. S. Bolle: None. H. Mammar: None. R. Dendale: None. V. Calugaru: None. L. Feuvret: None.

Non-Coplanar vs. Coplanar Intensity-Modulated Radiation Therapy (IMRT) for Protection of Lip and Buccal Mucosa

In this study, by comparing the coplanar and non-coplanar intensity-modulated radiation therapy (IMRT) treatment planning in treating tongue cancer, the significance of non-coplanar fields in the protection of lip and buccal mucosa was determined, and a reasonable solution was selected.48 tongue cancer patients treated from June 2019 to Feb 2021 were selected and divided into coplanar field group and non-coplanar field group randomly: the former one used divided nine fields on average while the latter one adopted seven fields meanly with two other fields which needed to turn the bed 270 degrees for making the angle of radiation ray tangent to the region of mucous membrane. The mucosal dose limit changed from 15 Gy to 45 Gy for comparison of the two treatment plans. The evaluating indicators including conformal index (CI), homogeneity index (HI), D5, D50, D98 of the target volume. The dose of normal tissues and organs including spine, throat, bilateral parotid gland, pharyngeal constrictor and oral mucosa (lip, upper and lower buccal mucosa) were calculated under different mucosal dose limit. The clinical manifestations of lip and buccal mucositis of 48 cases were recorded and graded by NCI-CTCAE 4.0. Corresponding statistical analysis were performed.The difference of CI, HI, D98, D50 and D5 between two groups in the target volume has the tendency to become smaller when the mucosal dose limit is less than 30 Gy, with significant statistical difference (P < 0.05). When the limit exceeds 30 Gy, there are still statistical differences in other indicators except CI (P < 0.05). In terms of normal tissue, a certain gap of doses on normal tissues between two groups exists when the mucosal limit is lower than 20 Gy, with significant statistical difference (P < 0.05). When the limit exceeds 20 Gy, there was no statistical difference. There are statistical differences (P < 0.05) in D98, D50, D5, CI and HI of the target area between the two groups when the mucosal function setting is less than 30 Gy. When the mucosal function setting exceeds 30 Gy, there is no statistical difference in CI, but there were still statistical differences in others (P < 0.05). In normal tissue, there is statistical difference (P < 0.05) between two treatment plans when mucosal function setting is smaller than 20 Gy; if it exceeds, there is no statistical difference. The patients of non-coplanar group showed better results in terms of the radiation-related toxicity of lip and cheek membrane: the incidence rate and classification of severity were much lower. Patients usually developed lip and buccal mucositis after the fourth week during the radiotherapy, and symptoms of most cases were classified mild. 21 cases ranked grade I while the remaining 3 ranked grade II.Compared with coplanar field, non-coplanar field radiotherapy can effectively reduce the exposure dose of lip and buccal mucosa. The application of non-coplanar treatment plan has good clinical significance and deserves to be promoted.

Trigger-Based Adaptive Planning to Reduce Bowel Dose in Patients Receiving Radiotherapy for Anal Cancer

<h3>Purpose/Objective(s)</h3> Standard of care for locally advanced anal carcinoma is definitive chemoradiation with IMRT. Currently, target and organ-at-risk (OAR) volumes are created using a pre-treatment CT-simulation scan. However, during the course of radiotherapy, there is often change in the size and/or position of the tumor and surrounding normal structures. Therefore, we hypothesize that the implementation of an adaptive radiation therapy treatment protocol in anal cancer may reduce radiation dose to critical surrounding normal structures, such as the bowel, through the use of anatomy-adapted replanning. <h3>Materials/Methods</h3> Retrospective daily adaptive CTs were created for 4 patients (54 Gy, 30 fraction VMAT) in an oncology imaging informatics system using the Adaptive Calculation and Tracking for Offline Plan Review (ACTOR) toolkit. Each adaptive CT was created by deformable image registration (dir) of the planning CT to the daily CBCT. The structure sets from the planning CT were deformed onto each adaptive CT and ultimately corrected and revised by two qualified radiation oncologists. The adaptive CTs were transferred to a treatment planning system for recalculation. The original treatment plan was recalculated on each fraction adaptive CT to establish the real dose received during treatment. A two-sample t-test was used to compare the average real dose received dosimetric values to the values obtained on trigger-based adaptive planning. <h3>Results</h3> Using dose prescriptions for target volumes and normal tissue dose constraints as defined in RTOG 0529 (Kachnic et al 2013), normal bowel dose metrics, including bowel V45 < 20cc, were tracked as possible triggers for adaptation. Using bowel V45 > 20cc as trigger 1, there was a significant reduction in bowel V45 for each patient (table), with an average reduction in bowel V45 of 86.7% (<i>P</i> = 0.0001) across all patients. Adapting only the 5 fractions with the highest values for bowel V45 (trigger 2), we also found a significant reduction for each patient (table), with an average reduction of 20.8 % (<i>P</i> = 0.0011) across all patients. <h3>Conclusion</h3> Our study demonstrated that triggered adaptive re-planning using bowel V45 > 20cc could likely achieve reductions in normal tissue dose. Adaptive planning during radiation treatment of anal cancer may therefore be beneficial for reduction of treatment-related GI toxicity. These results can help inform a future randomized trial of adaptive therapy vs. standard planning.

Consideration of Margin in SRS/SRT Plans for Brain Metastases Treatment With Volumetric Modulated Radiotherapy

It is well known that when treating brain metastases tumors local control depends not only on the amount of dose delivered but also on the margin to the clinical target volume in SRS/SRT treatment. The margin is commonly thought to be contributed from uncertainties of planning/treatment delivery, such as setup, imaging and target contouring, etc. It is defined as the margin expanding clinical target volume (CTV) to plan target volume (PTV). This margin, however, is the intended planning margin (PM) of clinicians. When considering contribution to the local control/toxicities from margin, it should be the delivery margin (DM), which is defined as the volume between CTV and the isodose surface at the minimum dose to PTV. The DM is contributed both from the high dose region outside of PTV and from the PM. The former has been ignored in current clinical practice though it is also a crucial part to affect the local control and treatment toxicities since this part is the high dose region in normal tissue but low dose region for the target.To access the contribution from the high dose region outside of PTV, two indexes were proposed: the modified conformity index (mCI) and modified Paddick confirmity index (mPCI). mCI = Vmin/PTV = CI + Vextra/PTV, where Vmin is the volume of brain tissue received the minimum dose to PTV or more and Vextra is the volume of brain tissue received the dose between the minimum dose to PTV and the prescribed dose. mPCI = TV2min/(PTV*Vmin), where TVmin is the target volume that is covered by the minimum dose to PTV. This retrospective study evaluated the DM with mCI, mPCI, V12 Gy, etc. for volumetric modulated radiotherapy (VMAT) planning techniques in 50 clinically treated brain metastasis cases.After implementing a set of planning techniques conformity has largely improved in the retrospective plans. Comparing the clinically treated plans with the retrospective study plans, the average CI and mCI were decreased by (6.5 ± 4.1)% and (28.1 ± 5.7)%, and the PCI and mPCI have been increased by (8.9 ± 2.9)% and (17.2 ± 2.8)% respectively (all data is expressed as ± std). The V12 (normal tissue volume irradiated within 12 Gy) was reduced by more than 35%. Comparison of historic data from 3D conformal, Dynamic conform arc and VMAT was made, and it showed that the typical CI decreased about 36% from the pioneer modality of SRS/SRT (1.67 ± 0.07) to the latest modality, VMAT (1.07 ± 0.05). This indicates that the more conformal is treatment plan the smaller the DM margin.Proposed mCI and mPCI to evaluate the DM in SRS/SRT plans for BM treatment with VMAT. Implementation of a set of planning techniques in VMAT largely improved the conformity of the VMAT plans. Comparison of CI from the progress of treatment modalities showed that the DM has been reduced 36% and its clinical impact on local control/toxicity is unknown.D. Wang: None. A.S. DeNittis: None.

The Impact of Radiotherapy Protocol Adherence on the Treatment Outcome in Patients With Locally Advanced NSCLC Treated With Concurrent Chemoradiation: Results From the Radiotherapy Quality Assurance of the International Randomized PET-Plan Trial

The success of intensification and personalization of the curative treatment of non-small cell lung cancer (NSCLC) is strongly associated with the precision in radiotherapy (RT) treatment, which must therefore follow high standards. Herein we evaluate the impact of RT protocol adherence in the prospective international multicenter trial on curative treatment of NSCLC.In the open-label, randomized, controlled PET-Plan trial, patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume delineation informed by ¹⁸F-FDG PET and CT plus elective nodal irradiation (Arm A) or target volumes informed by PET alone (Arm B) and received iso-toxically dose-escalated concurrent chemoradiation. The prospectively organized quality assurance program (RTQA) included individual case review by predefined criteria. 24 items (arm A) and 20 items (arm B) were scored as per protocol (pP), minor (miD), intermediate (inD) and major (maD) deviation by a multicenter panel of radiation oncologists and medical physicists.Between 05/2009 and 11/2016, 205 patients were randomized, (one patient was excluded after randomization), 173 were treated per-RT protocol and 31 (15%) patients had maD. Patients with maD had an inferior overall survival (OS) (HR 2.9, 95% CI 1.8-4.4, P < .0001) as well as a higher risk of loco-regional progression (HR 5.7, 95% CI 2.7-11.1, P < .0001). Especially, patients with maD concerning normal tissue delineation and/or dose constraints had a worse OS (HR 3.6, 95% CI 1.5-7.3, P = 0.006) although there was no impact on the incidence of toxicities. Adjusting for the UICC stadium and the gross tumor volume as prognostic factors, the effects remained similar.Non-adherence to the RT protocol was associated with an inferior OS and loco-regional control. These results underline the importance of RTQA.

Proton reirradiation for recurrent or new primary breast cancer in the setting of prior breast irradiation

Background and purposeLate local recurrences and second primary breast cancers are increasingly common. Proton beam therapy (PBT) reirradiation (reRT) may allow safer delivery of a second definitive radiotherapy (RT) course. We analyzed outcomes of patients with recurrent or new primary breast cancer who underwent reRT. Materials and methodsIn an IRB-approved retrospective study, patient/tumor characteristics, treatment parameters, outcomes, and toxicities were collected for all consecutive patients with recurrent or new primary non-metastatic breast cancer previously treated with breast or chest wall RT who underwent PBT reRT. ResultsForty-six patients received reRT using uniform (70%) or pencil beam (30%) scanning PBT. Median first RT, reRT, and cumulative doses were 60 Gy (range 45–66 Gy), 50.4 Gy(RBE) (40–66.6 Gy(RBE)), and 110 Gy(RBE) (96.6–169.4 Gy(RBE)), respectively. Median follow-up was 21 months. There were no local or regional recurrences; 17% developed distant recurrence. Two-year DMFS and OS were 92.0% and 93.6%, respectively. Nine of 13 (69.2%) patients who underwent implant or flap reconstruction developed capsular contracture, 3 (23.1%) requiring surgical intervention. One (7.7%) patient developed grade 3 breast pain requiring mastectomy after breast conserving surgery. No acute or late grade 4–5 toxicities were seen. Increased body mass index (BMI) was protective of grade ≥ 2 acute toxicity (OR = 0.84, 95%CI = 0.70–1.00). ConclusionIn the largest series to date of PBT reRT for breast cancer recurrence or new primary after prior definitive breast or chest wall RT, excellent locoregional control and few high-grade toxicities were encountered. PBT reRT may provide a relatively safe and highly effective salvage option. Additional patients and follow-up are needed to correlate composite normal tissue doses with toxicities and assess long-term outcomes.

Predicting the Clinical Gains Associated With Further Reduction of Normal Tissue Dose Constraints in Oropharynx Cancer Radiotherapy

<h3>Purpose/Objective(s)</h3> Toxicity mitigation is a salient focus in the treatment of HPV-associated oropharyngeal cancer. As the standard of care evolves, toxicity mitigation can be facilitated by adopting more stringent normal tissue constraints. We hypothesize that further reduction in currently accepted constraints leads to reductions in normal tissue complication probabilities (NTCP) without compromising disease outcomes. <h3>Materials/Methods</h3> This was a retrospective, single-institution study of patients with oropharynx cancer treated with adjuvant volumetric modulated arc therapy to standard doses (60-66 Gy) and volumes (i.e., bilateral neck) from 2015-2018. Doses delivered to organs at risk were compared to recommended dose acceptance criteria from a recent, cooperative trial of RT to 60 Gy (NRG HN002). We applied validated, published NTCP models for xerostomia, dysphagia, dysgeusia, oral mucositis and esophagitis relevant to oropharyngeal cancer. <h3>Results</h3> 92 patients were identified. Median follow-up was 2.2 years. The doses achieved and corresponding estimates of NTCP are shown in Table 1, as compared to a nationally recognized standard (NRG HN002). Notable NTCP reductions were observed for salivary flow, dysphagia, dysgeusia, mucositis, and esophagitis. The use of more stringent constraints did not impact disease outcome, with only a total of 3 patients having experienced locoregional recurrence (1 local, 2 regional), for an overall locoregional control of 96.7%. <h3>Conclusion</h3> Improved normal tissue sparing compared to current dose constraint standards is achievable with contemporary RT planning techniques. These improved constraints may lead to decreased toxicity, while preserving excellent disease outcomes. Our constraints can easily be adopted as standard of care and used in conjunction with other efforts to mitigate toxicity.

Proton Reirradiation for Recurrent or New Primary Breast Cancer in the Setting of Prior Breast Irradiation

Local breast cancer recurrences and new primary breast cancers are an increasingly common clinical challenge without clear treatment guidelines. To date, photon reirradiation (reRT) has not been widely adopted due to concerns for toxicities. Proton beam therapy (PBT) can optimize normal tissue sparing and may allow for safer delivery of a second definitive radiotherapy (RT) course. We hypothesize salvage PBT reRT can be safely delivered, and we present clinical outcomes and toxicities of patients with recurrent or new primary non-metastatic breast cancer who received prior RT and PBT reRT.In an IRB-approved retrospective study, all consecutive patients with recurrent or new primary non-metastatic breast cancer treated with breast or chest wall (CW) RT and PBT reRT from a single institution were identified. Patient and tumor characteristics, treatment parameters, clinical outcomes and toxicities were collected. Distant metastasis-free survival (DMFS) and overall survival (OS) were defined from PBT reRT start to date of distant recurrence, death or last follow-up and estimated using Kaplan-Meier methodology.Forty-six consecutive patients were assessed. Eight patients (17.4%) were reirradiated to an intact breast, 13 (28.3%) to CW without reconstruction, 20 (43.5%) to CW with reconstruction, and 5 (10.9%) to regional lymph nodes (LN) alone. PBT reRT was delivered with uniform (70%) or pencil beam (30%) scanning PBT. Median first course dose was 60Gy (45-66Gy); median PBT reRT dose was 50.4Gy (RBE) (40-66.6Gy); median cumulative dose was 108.9Gy2, a/b = 3(RBE) (95.0-168.8 Gy2, a/b = 3 (RBE)). When regional LN were retreated, median first course dose was 50.4 Gy (48.6-66.6Gy) and median PBT reRT dose was 50 Gy2, a/b = 3 (46.7-66.0Gy2, a/b = 3). Four patients had significant brachial plexus overlap with cumulative doses up to 99.0 Gy. At a median follow-up of 21 months, there were no local or regional recurrences; 8 patients (17%) developed distant recurrence, of whom three died. Estimated 3-year DMFS and OS were 60% and 88%, respectively. Grade 3 acute toxicities were limited exclusively to RT dermatitis (30.4%). Grade 3 late toxicities occurred in 4 patients (8.7%) (3 capsular contracture requiring surgical intervention, 1 breast pain requiring mastectomy). Two patients developed rib fracture. No cases of neuropathies, skin ulceration or other acute or late grade ≥3 toxicities occurred.In the largest series to date of PBT reRT for breast cancer recurrence or new primary after prior definitive breast or CW RT, PBT reRT provided excellent locoregional control with a low rate of high-grade toxicities limited to target tissue not amenable to sparing from full reRT dose. These data are encouraging and suggest PBT reRT may provide patients with a relatively safe and highly effective salvage option. Longer follow-up and additional patients are needed to correlate composite normal tissue doses with toxicities and assess long-term outcomes.

Tangential VMAT vs. 3D-Conformal Radiotherapy for Left-Sided Whole Breast and Regional Lymph Node Irradiation

<h3>Purpose/Objective(s)</h3> Whole breast and regional nodal irradiation presents a challenge in balancing the need for target coverage with avoidance of normal tissues. The novel technique termed tangential VMAT (tVMAT) utilizes beam angles tangential to the curvature of the chest wall without beams entering perpendicular to the chest wall in the direction of thoracic organs. In this study tVMAT was compared to standard 3D-conformal radiotherapy (3DCRT) in a dosimetric analysis. To our knowledge this is the first study to assess tVMAT in left-sided breast cancer patients requiring regional nodal irradiation. <h3>Materials/Methods</h3> Ten patients with left-sided breast cancer previously treated with adjuvant RT to the breast, axillary, and supraclavicular nodal regions were selected for this study. For each patient two plans were created: 1) a standard dual-isocenter three-field 3DCRT plan (two tangents and a supraclavicular field) using field-in-field dose modulation and 2) a tVMAT plan. Each tVMAT plan utilized a single isocenter for two partial arcs with angles selected to keep the central axis of the beams tangential to the curvature of the chest wall at all points. The prescription for both techniques was 5000 cGy in 25 fractions to the breast, axillary levels I-III, and supraclavicular target volumes with a goal coverage of 95% of the breast and nodal target volumes receiving at least 95% of the prescription dose. Normal tissue dose constraints were adapted from NSABP B51. Plans were created using a treatment planning system and differences in mean values for dosimetric endpoints were assessed for statistical significance using a Student's t-test (α = 0.05). <h3>Results</h3> Compared to 3DCRT plans, tVMAT provided more uniform coverage to the breast and regional lymph nodes (mean conformity index was 1.38 for tVMAT versus 2.42 for 3DCRT, <i>P</i> < 0.01) and the max point dose for tVMAT was lower on average (112.8% for tVMAT versus 121.5% for 3DCRT, <i>P</i> < 0.001). Both plans met the breast target coverage goals, however coverage to the lymph nodes was superior for tVMAT (mean coverage to 95% of the axillary plus supraclavicular target volumes was ≥ 99.0% of the prescribed dose for tVMAT versus ≥ 94.8% for 3DCRT, <i>P</i> < 0.001). Cold spots within the breast and nodal target volumes were on average lower for 3DCRT (952 cGy for 3DCRT versus 2760 cGy for tVMAT, <i>P</i> < 0.001). OAR sparing was improved with tVMAT, with a lower average V20_Gy for the left lung (16.5% for tVMAT versus 24.6% for 3DCRT, <i>P</i> < 0.01), and lower mean heart dose (168 cGy for tVMAT versus 200 cGy for 3DCRT, <i>P</i> = 0.03). <h3>Conclusion</h3> Tangential VMAT is a promising technique for the treatment of intact breast and regional lymph nodes and may provide better target coverage and OAR sparing compared to conventional 3D-conformal techniques. The use of a single isocenter for tVMAT could yield a simplified setup and more accurate treatment delivery, ideally with the use of deep inspiration breath hold or respiratory gating.

Uniform versus non-uniform dose prescription for proton stereotactic body radiotherapy of liver tumors investigated by extensive motion-including treatment simulations

Compared to x-ray-based stereotactic body radiotherapy (SBRT) of liver cancer, proton SBRT may reduce the normal liver tissue dose. For an optimal trade-off between target and liver dose, a non-uniform dose prescription is often applied in x-ray SBRT, but lacks investigation for proton SBRT. Also, proton SBRT is prone to breathing-induced motion-uncertainties causing target mishit or dose alterations by interplay with the proton delivery. This study investigated non-uniform and uniform dose prescription in proton-based liver SBRT, including effects of rigid target motion observed during planning-4DCT and treatment. The study was based on 42 x-ray SBRT fractions delivered to 14 patients under electromagnetic motion-monitoring. For each patient, a non-uniform and uniform proton plan were made. The uniform plan was renormalized to be iso-toxic with the non-uniform plan using a NTCP model for radiation-induced liver disease. The motion data were used in treatment simulations to estimate the delivered target dose with rigid motion. Treatment simulations were performed with and without a repainting scheme designed to mitigate interplay effects. Including rigid motion, the achieved CTV mean dose after three fractions delivered without repainting was on average (±SD) 24.8 ± 8.4% higher and the D98% was 16.2 ± 11.3% higher for non-uniform plans than for uniform plans. The interplay-induced increase in D2% relative to the static plans was reduced from 3.2 ± 4.1% without repainting to −0.5 ± 1.7% with repainting for non-uniform plans and from 1.5 ± 2.0% to 0.1 ± 1.3% for uniform plans. Considerable differences were observed between estimated CTV doses based on 4DCT motion and intra-treatment motion. In conclusion, non-uniform dose prescription in proton SBRT may provide considerably higher tumor doses than uniform prescription for the same complication risk. Due to motion variability, target doses estimated from 4DCT motion may not accurately reflect the delivered dose. Future studies including modelling of deformations and associated range uncertainties are warranted to confirm the findings.

Joint Optimization of Photon-Carbon Ion Treatments for Glioblastoma.

Carbon ions are radiobiologically more effective than photons and are beneficial for treating radioresistant gross tumor volumes (GTV). However, owing to a reduced fractionation effect, they may be disadvantageous for treating infiltrative tumors, in which healthy tissue inside the clinical target volume (CTV) must be protected through fractionation. This work addresses the question: What is the ideal combined photon-carbon ion fluence distribution for treating infiltrative tumors given a specific fraction allocation between photons and carbon ions? We present a method to simultaneously optimize sequentially delivered intensity modulated photon (IMRT) and carbon ion (CIRT) treatments based on cumulative biological effect, incorporating both the variable relative biological effect of carbon ions and the fractionation effect within the linear quadratic model. The method is demonstrated for 6 glioblastoma patients in comparison with the current clinical standard of independently optimized CIRT-IMRT plans. Compared with the reference plan, joint optimization strategies yield inhomogeneous photon and carbon ion dose distributions that cumulatively deliver a homogeneous biological effect distribution. In the optimal distributions, the dose to CTV is mostly delivered by photons and carbon ions are restricted to the GTV with variations depending on tumor size and location. Improvements in conformity of high-dose regions are reflected by a mean EQD2 reduction of 3.29 ± 1.22 Gy in a dose fall-off margin around the CTV. Carbon ions may deliver higher doses to the center of the GTV, and photon contributions are increased at interfaces with CTV and critical structures. This results in a mean EQD2 reduction of 8.3 ± 2.28 Gy, in which the brain stem abuts the target volumes. We have developed a biophysical model to optimize combined photon-carbon ion treatments. For 6 glioblastoma patient cases, we show that our approach results in a more targeted application of carbon ions that (1) reduces dose in normal tissues within the target volume, which can only be protected through fractionation; and (2) boosts central target volume regions to reduce integral dose. Joint optimization of IMRT-CIRT treatments enable the exploration of a new spectrum of plans that can better address physical and radiobiological treatment planning challenges.

A Comparison of Isotoxic Dose-escalated Radiotherapy in Lung Cancer with Moderate Deep Inspiration Breath Hold, Mid-ventilation and Internal Target Volume Techniques

AimsWith interest in normal tissue sparing and dose-escalated radiotherapy in the treatment of inoperable locally advanced non-small cell lung cancer, this study investigated the impact of motion-managed moderate deep inspiration breath hold (mDIBH) on normal tissue sparing and dose-escalation potential and compared this to planning with a four-dimensional motion-encompassing internal target volume or motion-compensating mid-ventilation approach. Materials and methodsTwenty-one patients underwent four-dimensional and mDIBH planning computed tomography scans. Internal and mid-ventilation target volumes were generated on the four-dimensional scan, with mDIBH target volumes generated on the mDIBH scan. Isotoxic target dose-escalation guidelines were used to generate six plans per patient: three with a target dose cap and three without. Target dose-escalation potential, normal tissue complication probability and differences in pre-specified dose-volume metrics were evaluated for the three motion-management techniques. ResultsThe mean total lung volume was significantly greater with mDIBH compared with four-dimensional scans. Lung dose (mean and V21 Gy) and mean heart dose were significantly reduced with mDIBH in comparison with four-dimensional-based approaches, and this translated to a significant reduction in heart and lung normal tissue complication probability with mDIBH. In 20/21 patients, the trial target prescription dose cap of 79.2 Gy was achievable with all motion-management techniques. ConclusionmDIBH aids lung and heart dose sparing in isotoxic dose-escalated radiotherapy compared with four-dimensional planning techniques. Given concerns about lung and cardiac toxicity, particularly in an era of consolidation immunotherapy, reduced normal tissue doses may be advantageous for treatment tolerance and outcome.

Consideration of the target area of radiotherapy for lung cancer with 4DPET

AbstractObjectiveThrough the study of 4‐dimensional (4D) positron emission tomography (PET)/computed tomography (CT) for lung tumor, the delineation of the lung tumor target area was analyzed, the accurate target area was received, and the radiation dose of normal tissue was compared .MethodsThe average 4DPET volume, 3DPET volume, average 4DCT volume, and 3DCT volume of 10 tumors were compared. Taking the relative difference between the average 4D volume and the 3D volume as the difference of the volumes, the influence of the tumor size and the range of motion for 4D volume and 3D volume were studied respectively, then the target areas were delineated respectively, and the radiation doses of the normal tissues associated with the respective target areas were compared after the intensity‐modulated radiation therapy plan was formulated.ResultsThe PET volumes of all tumors were smaller than those of CT, no matter 4D or 3D, from small to large, the volume sizes were 3DPET volume, average 4DPET volume, 3DCT volume and average 4DCT volume. The relative volume difference was related to the respiratory movement and the size of the tumors. The average 4DPET volume was 22.8% larger than the average 3DPET volume, and the volume ratio was 1.23. The volume of the average 4DCT was 15.4% larger than that of the average 3DCT, and the volume ratio was 1.16. The average volume of 4DCT was 59.5% larger than that of 4DPET. When the movement amplitude of the tumor was greater than 3 mm and less than 5 mm, the larger the tumor volume, the larger the volume ratio of the average 4DCT volume to the average 4DPET volume, with the maximum value being 1.54. When the tumor movement amplitude was greater than 5 mm, the ratio was about 1.4. When the volume of conventional 3DCT was larger than 5 cm3, the ratio of the average 4DCT volume to the average 4DPET volume was 1.9. The planning target area internal target volume (ITV)3DCT was much larger than that of ITV3DPET, intersected ITV4DCTave and ITV4DPETave, the dose V20 and V5 of normal lung tissue, and the dose V30 of heart were increased accordingly. Of these, the dose of lung and heart of ITV4DPETave was the lowest. The V20 and V5 of lung of ITV4DPETave was about 2% lower than ITV4DCTave.ConclusionTo delineate lung tumor targets at various positions, particular attention should be paid to the effect of breathing exercises on large movements and large volumes. The target volume seemed to be overestimated by 4DCT, and the average multiphased 4DPET volume was more accurate for delineating the target area while reducing the radiation dose of the lung.

Influence of target dose heterogeneity on dose sparing of normal tissue in peripheral lung tumor stereotactic body radiation therapy

ObjectiveTo evaluate the influence of target dose heterogeneity on normal tissue dose sparing for peripheral lung tumor stereotactic body radiation therapy (SBRT).MethodsBased on the volumetric-modulated arc therapy (VMAT) technique, three SBRT plans with homogeneous, moderate heterogeneous, and heterogeneous (HO, MHE, and HE) target doses were compared in 30 peripheral lung tumor patients. The prescription dose was 48 Gy in 4 fractions. Ten rings outside the PTV were created to limit normal tissue dosage and evaluate dose falloff.ResultsWhen MHE and HE plans were compared to HO plans, the conformity index of the PTV was increased by approximately 0.08. The median mean lung dose (MLD), V5, V10, V20 of whole lung, D2%, D1cc, D2cc of the rib, V30 of the rib, D2% and the maximum dose (Dmax) of the skin, and D2% and Dmax of most mediastinal organs at risk (OARs) and spinal cord were reduced by up to 4.51 Gy or 2.8%. Analogously, the median Dmax, D2% and mean dose of rings were reduced by 0.71 to 8.46 Gy; and the median R50% and D2cm were reduced by 2.1 to 2.3 and 7.4% to 8.0%, respectively. Between MHE and HE plans there was little to no difference in OARs dose and dose falloff beyond the target. Furthermore, the dose sparing of rib V30 and the mean dose of rings were negatively correlated with the rib and rings distance from tumor, respectively.ConclusionsFor peripheral lung tumor SBRT, target conformity, normal tissue dose, and dose falloff around the target could be improved by loosening or abandoning homogeneity. While there was negligible further dose benefit for the maximum target dose above 125% of the prescription, dose sparing of normal tissue derived from a heterogeneous target decreased as the distance from the tumor increased.

Prospects for daily online adaptive radiotherapy via ethos for prostate cancer patients without nodal involvement using unedited CBCT auto-segmentation.

Purpose Implementing new online adaptive radiation therapy technologies is challenging because extra clinical resources are required particularly expert contour review. Here, we provide the first assessment of Varian's Ethos™ adaptive platform for prostate cancer using no manual edits after auto‐segmentation to minimize this impact on clinical efficiency.MethodsTwenty‐five prostate patients previously treated at our clinic were re‐planned using an Ethos™ emulator. Clinical target volumes (CTV) included intact prostate and proximal seminal vesicles. The following clinical margins were used: 3 mm posterior, 5 mm left/right/anterior, and 7 mm superior/inferior. Adapted plans were calculated for 10 fractions per patient using Ethos's auto‐segmentation and auto‐planning workflow without manual contouring edits. Doses and auto‐segmented structures were exported to our clinical treatment planning system where contours were modified as needed for all 250 CTVs and organs‐at‐risk. Dose metrics from adapted plans were compared to unadapted plans to evaluate CTV and OAR dose changes.ResultsOverall 96% of fractions required auto‐segmentation edits, although corrections were generally minor (<10% of the volume for 70% of CTVs, 88% of bladders, and 90% of rectums). However, for one patient the auto‐segmented CTV failed to include the superior portion of prostate that extended into the bladder at all 10 fractions resulting in under‐contouring of the CTV by 31.3% ± 6.7%. For the 24 patients with minor auto‐segmentation corrections, adaptation improved CTV D98% by 2.9% ± 5.3%. For non‐adapted fractions where bladder or rectum V90% exceeded clinical thresholds, adaptation reduced them by 13.1% ± 1.0% and 6.5% ± 7.3%, respectively.Conclusion For most patients, Ethos's online adaptive radiation therapy workflow improved CTV D98% and reduced normal tissue dose when structures would otherwise exceed clinical thresholds, even without time‐consuming manual edits. However, for one in 25 patients, large contour edits were required and thus scrutiny of the daily auto‐segmentation is necessary and not all patients will be good candidates for adaptation.

Normal tissue tolerance amongst paediatric brain tumour patients- current evidence in proton radiotherapy.

Proton radiotherapy (PT) is used increasingly for paediatric brain cancer patients. However, as demonstrated here, the knowledge on normal tissue dose constraints, to minimize side-effects, for this cohort is limited. A search strategy was systematically conducted on MEDLINE® database. 65 papers were evaluated ranging from 2013 to 2021. Large variations in normal tissue tolerance and toxicity reporting across PT studies makes estimation of normal tissue dose constraints difficult, with the potential for significant late effects to go unmeasured. Mean dose delivered to the pituitary gland varies from 20 to 30 Gy across literature. Similarly, the hypothalamic dose delivery ranges from 20 to 54.6 Gy for paediatric patients. There is a significant lack of radiobiological data for paediatric brain cancer patients undergoing proton therapy, often using data from x-ray radiotherapy and adult populations. The way forward is through standardisation of reporting in order to validate relevant dose constraints.

Proton range uncertainty reduction benefits for skull base tumors in terms of normal tissue complication probability (NTCP) and healthy tissue doses.

Proton therapy allows for more conformal dose distributions and lower organ at risk and healthy tissue doses than conventional photon-based radiotherapy, but uncertainties in the proton range currently prevent proton therapy from making full use of these advantages. Numerous developments therefore aim to reduce such range uncertainties. In this work, we quantify the benefits of reductions in range uncertainty for treatments of skull base tumors. The study encompassed 10skull base patients with clival tumors. For every patient, six treatment plans robust to setup errors of 2mm and range errors from 0% to 5% were created. The determined metrics included the brainstem and optic chiasm normal tissue complication probability (NTCP) with the endpoints of necrosis and blindness, respectively, as well as the healthy tissue volume receiving at least 70% of the prescription dose. A range uncertainty reduction from the current level of 4% to a potentially achievable level of 1% reduced the probability of brainstem necrosis by up to 1.3 percentage points in the nominal scenario in which neither setup nor range errors occur and by up to 2.9 percentage points in the worst-case scenario. Such a range uncertainty reduction also reduced the optic chiasm NTCP with the endpoint of blindness by up to 0.9 percentage points in the nominal scenario and by up to 2.2 percentage points in the worst-case scenario. The decrease in the healthy tissue volume receiving at least 70% of the prescription dose ranged from -7.8 to 24.1cc in the nominal scenario and from -3.4 to 38.4cc in the worst-case scenario. The benefits quantified as part of this study serve as a guideline of the OAR and healthy tissue dose benefits that range monitoring techniques may be able to achieve. Benefits were observed between all levels of range uncertainty. Even smaller range uncertainty reductions may therefore be beneficial.