Faculty Bibliography

We compiled a sampling of the treatment techniques of intensity-modulated total body irradiation, total marrow irradiation and total marrow and lymphoid irradiation utilized by several centers across North America and Europe. This manuscript does not serve as a consensus guideline, but rather is meant to serve as a convenient reference for centers that are considering starting an intensity-modulated program.

PURPOSE/OBJECTIVE:Acute radiation dermatitis (ARD) is common after radiation therapy for breast cancer, with data indicating that ARD may disproportionately affect Black or African American (AA) patients. We evaluated the effect of skin of color (SOC) on physician-reported ARD in patients treated with radiation therapy. METHODS AND MATERIALS/METHODS:We identified patients treated with whole breast or chest wall ± regional nodal irradiation or high tangents using 50 Gy in 25 fractions from 2015 to 2018. Baseline skin pigmentation was assessed using the Fitzpatrick scale (I = light/pale white to VI = black/very dark brown) with SOC defined as Fitzpatrick scale IV to VI. We evaluated associations among SOC, physician-reported ARD, late hyperpigmentation, and use of oral and topical treatments for RD using multivariable models. RESULTS:A total of 325 patients met eligibility, of which 40% had SOC (n = 129). On multivariable analysis, Black/AA race and chest wall irradiation had a lower odds of physician-reported grade 2 or 3 ARD (odds ratio [OR], 0.110; 95% confidence interval [CI], 0.030-0.397; P = .001; OR, 0.377; 95% CI, 0.161-0.883; P = .025), whereas skin bolus (OR, 8.029; 95% CI, 3.655-17.635; P = 0) and planning target volume D0.03cc (OR, 1.001; 95% CI, 1.000-1.001; P = .028) were associated with increased odds. On multivariable analysis, SOC (OR, 3.658; 95% CI, 1.236-10.830; P = .019) and skin bolus (OR, 26.786; 95% CI, 4.235-169.432; P = 0) were associated with increased odds of physician-reported late grade 2 or 3 hyperpigmentation. There was less frequent use of topical steroids to treat ARD and more frequent use of oral analgesics in SOC versus non-SOC patients (43% vs 63%, P < .001; 50% vs 38%, P = .05, respectively). CONCLUSIONS:Black/AA patients exhibited lower odds of physician-reported ARD. However, we found higher odds of late hyperpigmentation in SOC patients, independent of self-reported race. These findings suggest that ARD may be underdiagnosed in SOC when using the physician-rated scale despite this late evidence of radiation-induced skin toxicity.

PURPOSE/OBJECTIVE:The optimal local therapy of patients with nodal disease in supraclavicular (SCV), internal mammary nodes (IMN) and level III axilla is not well studied. We aimed to evaluate the outcomes of patients with breast cancer and advanced nodal disease that received a nodal boost. METHODS AND MATERIALS/METHODS:This retrospective study included 79 patients with advanced nodal disease who underwent adjuvant radiation with a nodal boost to the SCV, IMNs, and/or axilla. All patients had radiographic changes after systemic therapy concerning for gross nodal disease. Overall survival, disease-free survival (DFS), and local recurrence-free survival were estimated using the Kaplan-Meier method. RESULTS:All patients received an initial 50 Gy to the breast/chest wall and regional nodes, of whom 46.8% received an IMN boost, 38.0% axillary (ax)/SCV boost, and 15.2% both IMN and ax/SCV boost (IMN + ax/SCV). Most patients had hormone receptor positive (74.7%) and human epidermal growth factor receptor 2 negative disease (83.5%). In addition, 12.7% of patients had clinical (c) N2 disease, 21.5% cN3A disease, 51.9% cN3B disease, and 5.1% cN3C disease. Most patients received chemotherapy (97.5%). The median nodal boost dose was 10 Gy (range, 10-20 Gy), with 21.6% of IMN, 16.7% of ax/SCV, and 16.7% of IMN + ax/SCV receiving 14 to 20 Gy. With a median follow up of 30 months, the 3-year local recurrence-free survival, DFS, and overall survival rates were 94.5%, 86.3%, and 93.8%, respectively. Crude rates of failure were 13.9% (10.1% distant failure [DF] alone; 3.8% DF + locoregional failure [LRF]). Rates of failure by boost group were 13.3% for ax/SCV (10.0% DF alone; 3.3% DF + LRF), 5.4% for IMN (2.7% DF alone, 2.7% DF + LRF), and 41.7% for IMN + ax/SCV (33.3% DF, 8.3% DF + LRF). There were no LRFs without DFs. The median time to failure was 22.8 months (interquartile range, 18-34 months). Clinical tumor size and IMN + ax/SCV versus IMN or ax/SCV alone was associated with worse DFS (hazard ratio [HR]: 9.78; 95% confidence interval [CI], 2.07-46.2; P = .004 and HR: 9.49; 95% CI, 2.67-33.7; P = .001, respectively). On multivariate analysis, IMN + ax/SCV versus IMN or ax/SCV alone retained significance (HR: 4.80; 95% CI, 1.27-18.13; P = .02). CONCLUSIONS:In this population of patients with locally advanced breast cancer, the majority of failures were distant with no isolated LRFs. Failures were the highest in the IMN + ax/SCV group (∼40%). Further treatment escalation is necessary for these patients.

Purpose/Objective(s): Radiation dermatitis (RD) is common after RT for breast cancer with data indicating potentially worse RD in African American (AA) patients (pts). Current measures of RD, such as the CTCAE, do not include hyperpigmentation, which may disproportionately affect how RD is classified and treated in pts with skin of color (SOC). We aim to characterize RD in SOC and identify factors, including baseline skin pigmentation (BSP) that predict RD. Materials/Methods: Pts treated with whole breast (WB) or chest wall (CW) with regional nodal RT or high tangents with 50 Gy in 25 fractions from 2015-2018 were identified. Three dermatologists independently classified BSP using photographs from CT simulation based on the Fitzpatrick scale ([FS], range=I-VI; I=light/pale white to VI=black/ very dark brown). SOC was defined as FS IV-VI. Pt characteristics were investigated for association with interventions to treat RD, clinician-graded acute RD, and late skin toxicity (NCI CTCAE scale) with Chi-squared and logistic regression analyses.
Result(s): 325 pts met eligibility criteria (58 African American [AA], 42 Asian, 151 Caucasian, 77 other). 40% (n=129) had SOC, 60% underwent CW RT, 40% WB RT and 82% had systemic therapy. Pts with SOC were more likely to be Hispanic (14% vs 8% p=0.007), AA (43% vs 1%, p<0.001) and have greater mean BMI (28.0 vs 26.5, p=0.02). Acute grade 2/3 RD was lower in SOC (FS I 60%, FS II 63%, FS III 52%, FS IV 64%, FS V 40%, FS VI 41%; p=0.049). Increased BSP (OR 0.83; p=0.01) and AA pts (OR: 0.22; p<0.001) had lower odds of acute grade 2/3 RD, whereas bolus and dosimetric parameters such as increased PTV volume had increased odds. On multivariable analysis (MVA), AA pts and bolus remained significant (OR: 0.14, p=0.01; OR: 6.63 p<0.001, respectively). Topical steroid use to treat RD was less frequent and oral analgesic use was more frequent in SOC (43% vs 63%, p<0.001; 50% vs 38%, p=0.05, respectively). Pts with increased BSP (OR 0.73, p<0.001), AA race (OR 0.19, p<0.001) and greater BMI had lower use of topical interventions whereas any boost phase, bolus, IMN RT and increased PTV volume had greater use. On MVA, AA pts (OR 0.27, p=0.04), boost (OR 2.04, p=0.033), IMN RT (OR 2.73, p=0.003) and PTV V105% (OR=1.002, p=0.03) retained significance. Late grade 2/3 hyperpigmentation was greater in SOC (16% vs 3%, p=0.01). Increased BSP (OR 2.14, p=0.001), AA pts (OR 8.18, p=0.02), bolus and CW boost had greater odds of grade 2/3 hyperpigmentation. On MVA, increased BSP (OR: 3.76, p=0.03) and bolus (OR: 14.1, p=0.01) retained significance.
Conclusion(s): We found less clinician-graded acute RD in SOC and AA pts, less frequent use of topical interventions but more oral analgesic use. We also found higher rates of late pigmentation change with increased BSP independent of race. These findings suggest that RD may be under-diagnosed in SOC. This study confirms the necessity for objective measures of RD that account for variability in BSP to accurately classify the severity of radiation skin toxicity in SOC and treat accordingly.
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We present the case of a 56-year-old female with a diagnosis of acute T-cell lymphoblastic leukemia who received myeloablative conditioning for bone marrow transplant with total body irradiation (TBI) using volumetric modulated arc therapy (VMAT) to the upper body and anterior-posterior/posterior-anterior (AP/PA) open fields to the lower body followed by hematopoietic stem cell transplant. Her clinical course was complicated by high-grade pulmonary toxic effects 55 days after treatment that resulted in death. We discuss the case, planning considerations by radiation oncologists and radiation physicists, and the multidisciplinary medical management of this patient.

PURPOSE/OBJECTIVE(S): TBI is a backbone of many conditioning regimens for hematopoietic stem cell transplants but can lead to both acute and late toxicity including radiation-induced interstitial pneumonitis. The incidence of idiopathic pneumonia syndrome (IPS) after TBI-based myeloablative conditioning regimens ranges from 7% to 35%. The purpose of this study is to implement image guided volumetrically modulated technique (VMAT) for TBI with the goal of lung sparing and improved target coverage. MATERIALS/METHODS: Nine patients have been treated using image-guided VMAT based TBI at our institution as part of a single-arm phase 2 clinical trial for patients undergoing myeloablative conditioning regimens. The trial was approved by our internal review board (IRB) in September 2020 and aims to accrue 15 patients within one year. All patients enrolled in the trial have signed informed consent. The primary endpoints of the study are the following dosimetric constraints: V100% >= 90%, D98% >= 85% of Rx dose for the planning target volume (PTV), and a mean lung dose < 9 Gy. PTV is defined as the body contour cropped 5 mm from the surface and excluding lungs and kidneys but extended 3 mm into these organs. Additional secondary dosimetric endpoints include mean dose to each individual kidney < 11 Gy, and maximum dose to 2cc of the entire body < 130% of Rx dose. Clinical endpoints include the occurrence of IPS in the first 100 days after transplant, occurrence of acute graft versus host disease (GVHD), transplant related mortality or mortality in the first 100 days following transplant.
RESULT(S): Patients were treated to 12 Gy in 8 BID fractions (n=6) or 13.2 Gy in 8 BID fractions (n=3) over four consecutive days. All patients were able to complete treatment to the prescribed dose as planned. All patient plans met dosimetric constraints of the study. The median PTV V100% was 93.2% of Rx dose (Max: 95.6%, Min: 92.1%), the median PTV D98% was 90.2% of Rx dose (Max: 94.3%, Min: 88.3%), and the median lung dose mean was 7.63 Gy (Max: 7.94 Gy, Min: 7.29 Gy). In addition, individual kidney mean doses were < 11 Gy, and body maximum dose (D2cc) was < 130% of Rx dose for all patients. At this time, only one patient (12 Gy treatment) has reached the 100 day post-transplant follow-up with the following findings: no relapse on bone marrow biopsy, no pneumonitis, resolved acute GVHD overall grade 1 (skin: 1, GI: 0, Liver: 0), resolved dermatitis (grade 1), resolved vomiting (grade 2), ongoing diarrhea and nausea (grade 1, previously grade 2).
CONCLUSION(S): Our initial results indicate that primary and secondary dosimetric endpoints were achievable for all protocol patients treated thus far. As the trial progresses, secondary clinical endpoints at 100 day follow-up will be analyzed to evaluate occurrence of IPS, survival, and treatment related toxicities.
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PURPOSE/OBJECTIVE:Radiomics modeling is an exciting avenue for enhancing clinical decision making and personalized treatment. Radiation oncology patients often undergo routine imaging for position verification, particularly using LINAC-mounted cone beam computed tomography (CBCT). The wealth of imaging data collected in modern radiation therapy presents an ideal use case for radiomics modeling. Despite this, texture feature (TF) calculation can be limited by concerns over feature stability and reproducibility; in theory, this issue is compounded by the relatively poor image quality of CBCT, as well as variation of acquisition and reconstruction parameters. METHODS:In this study, we developed and validated a novel three-dimensional (3D) printed phantom for evaluating CBCT-based TF reliability. The phantom has a cylindrical shape (22 cm diameter and 25.5 cm height) with five inner inserts designed to hold custom-printed rods (1 cm diameter and 10-20 cm height) of various materials, infill shapes, and densities. TF reproducibility was evaluated across and within three LINACs from a single vendor using sets of three consecutive CBCT taken with the head, thorax, and pelvis clinical imaging protocols. PyRadiomics was used to extract a standard set of TFs from regions of interest centered on each rod. Two-way mixed effects absolute agreement intra-class correlation coefficient (ICC) was used to evaluate TF reproducibility, with features showing ICC values above 0.9 considered robust if their Bonferroni-corrected p-value was below 0.05. RESULTS:A total of 63, 87, and 83 features exhibited test-retest reliability for the head, thorax, and pelvis imaging protocols respectively. When assessing stability between discreet imaging sessions on the same LINAC, these numbers were reduced to 5, 63, and 70 features, respectively. The thorax and pelvis protocols maintained a rich candidate feature space in inter-LINAC analysis with 61 and 65 features, respectively, exceeding the ICC criteria. Crucially, no features were deemed reproducible when compared between protocols. CONCLUSIONS:We have developed a 3D phantom for consistent evaluation of TF stability and reproducibility. For LINACs from a single vendor, our study found a substantial number of features available for robust radiomics modeling from CBCT imaging. However, some features showed variations across LINACs. Studies involving CBCT-based radiomics must preselect features prior to their use in clinical-based models.

Purpose: To investigate the effect of patient positioning in Volumetric Modulated Arc Therapy (VMAT) for Total Body Irradiation (TBI) given the use of multiple isocenters, by simulating offsets in patient positioning and evaluating changes to planned dose distributions.
Method(s): VMAT treatment plans for seven TBI patients treated as part of a prospective stage II clinical trial were evaluated. Plan uncertainties were calculated by introducing 5mm and 10mm translational shifts to the plans' isocenters in the lateral (x), vertical (y), and longitudinal (z) directions. Dose distributions were then re-calculated in the treatment planning system (Eclipse), in order to evaluate dosimetric robustness to one global imaging shift at treatment. Differences in target volume (PTV) coverage and doses to organs at risk were evaluated based on four parameters: lung mean dose, PTV-V100%, PTV-D98%, and kidney mean doses.
Result(s): Lung mean dose increased an average of 8.2cGy, 4.4cGy, and 3.3cGy when shifted 5mm in the x, y, z directions (respectively) across seven patients; 33.2CGy, 18.5cGy, 18.3cGy for 10mm shifts in x, y, z. Target coverage V100% decreased an average of 0.3%, 0.03%, 0.1% for 5mm shifts, and 1.1%, 0.8%, 0.4% for 10mm shifts in x, y, z. D98% decreased 0.9%, 0.3%, 0.3% when shifted 5mm; 3.5%, 2.1%, 1.0% when shifted 10mm in x, y, z. Mean dose to the left kidney increased 6.6cGy, 9.7cGy, 2.8cGy for 5mm, and 28.1cGy, 32.7cGy, 18.0cGy for 10mm shifts in x, y, z. Right kidney mean dose increased 11.9cGy, 8.9cGy, 3.1cGy for 5mm, and 36.5, 30.5, 19.8cGy for 10mm.
Conclusion(s): Though small in relation to total dose, the largest increase in mean lung dose and decrease in coverage was seen with lateral shifts as compared to vertical or longitudinal shifts. These results support the use of an approach with preferential alignment to the chest region (lung-sparing), as long as residual imaging alignment outside the chest is kept below 10mm. Jose Teruel has received honorarium from Varian Medical Systems

Purpose: Multi-isocentric treatment delivery for CSI and TBI poses specific challenges for treatment delivery. We have developed a software tool to streamline all aspects of delivery for therapists and physicists at the machine, as well as to inform attending physicians of setup variability and image residuals at different locations.
Method(s): Our institution delivers VMAT-based CSI and TBI with up to 3 and 7 isocenters, respectively. A software tool was developed to assist with treatment delivery including initial patient setup, patient imaging, automatic calculation of the optimal global shift based on each isocenter's ideal shift, and automatic calculation of each isocenter's couch coordinates. Initial treatment couch coordinates are queried via the Eclipse scripting API. The global shift was calculated prioritizing the head isocenter for CSI treatments and the chest isocenter for TBI treatments by first maximizing residual tolerance at any other location prior to accepting any residual deviation at these locations. Maximum residuals tolerance was determined based on target margins, plan uncertainty and as per physician instructions. Delivery parameters are reported to a document uploaded to ARIA via API.
Result(s): The developed tool was employed for 11 cases. The software tool replaced the need for plan shift comments or instructions for therapists. In particular, its use eliminated the need to provide isocenter shifts to therapists by directly providing final couch parameters for treatment, greatly reducing the risk of delivery errors. The software effectively informed the therapists if any expected tolerance was surpassed, triggering a patient setup evaluation.
Conclusion(s): The described software tool is a core component to our multi-isocenter treatment programs and has streamlined delivery of these complex techniques that would otherwise require complicated instructions, including multiple shifts and on-the-fly calculations of optimal image alignment based on multiple imaging locations. This has substantially reduced the possibility of delivery errors

Purpose: Patients receiving myeloablative total body irradiation (TBI) doses >= 12Gy are at risk of developing interstitial pneumonitis. At our institution, TBI transitioned from extended distance opposed Laterals to image-guided VMAT, in an effort to improve coverage while sparing lungs and kidneys. This work presents a dosimetric comparison between 3D Laterals and VMAT.
Method(s): Nine patients were treated with VMAT as part of an ongoing phase II single-arm clinical trial. VMAT patients were CT-simulated supine, with thermoplastic masks for head/neck, chest/abdomen/pelvis and feet. VMAT planning (12Gy (n=6) or 13.2Gy (n=3) in 8-BID fractions) utilizes 6MV multi-isocentric arcs and AP/PA beams to treat the upper and lower body, respectively. Ten 3D Lateral patients were CT-simulated supine with arms positioned/immobilized for lung shielding, with rice compensation between legs/feet. Laterals plan (12Gy in 8-BID fractions) uses 15MV, beam spoiler, head compensation, and subfields to maintain coverage and mean-lungs dose <10.5Gy. Target (Body-5mm, extending 3mm into lungs and kidneys for VMAT; Body-2cm for Laterals) coverage was evaluated at V100%, and D98% (percentage of Rx). Absolute dose to lungs and kidneys were reportedResults: Median Target V100% and D98% for VMAT was 93.2% (Range: 95.6% to 92.1%) and 90.2% (94.3% to 88.3%), whereas for Laterals V100% and D98% was 57.3% (66.5% to 46.3%) and 80.6% (75.5% to 84%). The median Lung mean dose was 7.6Gy (7.3Gy to 7.9Gy) for VMAT. The median mean dose to kidney was 10.4Gy (10.1Gy to 10.7Gy) for VMAT, and 12.5Gy (11.9Gy to 13.5Gy) for Laterals.
Conclusion(s): We have established a VMAT-TBI program for patients requiring myeloablative irradiation. Improvement in target coverage is demonstrated by V100% and D98%, while reducing the mean dose to the lungs significantly from 10.5Gy to 8Gy