"Primer shot" fractionation with an early treatment break is theoretically superior to consecutive weekday fractionation schemes for early-stage non-small cell lung cancer.

PURPOSE: Radiotherapy is traditionally given in equally spaced weekday fractions. We hypothesize that heterogeneous interfraction intervals can increase radiosensitivity via reoxygenation. Through modeling, we investigate whether this minimizes local failures and toxicity for early-stage non-small cell lung cancer (NSCLC). METHODS: Previously, a tumor dose-response model based on resource competition and cell-cycle-dependent radiosensitivity accurately predicted local failure rates for early-stage NSCLC cohorts. Here, the model mathematically determined non-uniform inter-fraction intervals minimizing local failures at similar normal tissue toxicity risk, i.e., iso-BED3 (iso-NTCP) for fractionation schemes 18Gyx3, 12Gyx4, 10Gyx5, 7.5Gyx8, 5Gyx12, 4Gyx15. Next, we used these optimized schedules to reduce toxicity risk (BED3) while maintaining stable local failures (TCP). RESULTS: Optimal schedules consistently favored a "primer shot" fraction followed by a 2-week break, allowing tumor reoxygenation. Increasing or decreasing the assumed baseline hypoxia extended or shortened this optimal break by up to one week. Fraction sizes of 7.5 Gy and up required a single primer shot, while smaller fractions needed one or two extra fractions for full reoxygenation. The optimized schedules, versus consecutive weekday fractionation, predicted absolute LF reductions of 4.6%-7.4%, except for the already optimal LF rate seen for 18Gyx3. Primer shot schedules could also reduce BED3 at iso-TCP with the biggest improvements for the shortest schedules (94.6Gy reduction for 18Gyx3). CONCLUSION: A validated simulation model clearly supports non-standard "primer shot" fractionation, reducing the impact of hypoxia-induced radioresistance. A limitation of this study is that primer-shot fractionation is outside prior clinical experience and therefore will require clinical studies for definitive testing.

Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are increasingly used to treat advanced cancers. Despite data indicating exaggerated radiation toxicities in patients with autoimmune disease, the safety of thoracic radiotherapy in patients with prior ICI-associated immune-related adverse events (irAEs) is undefined. PATIENTS AND METHODS: Patients treated from 2014 to 2020 with ICIs were queried for receipt of corticosteroids and radiotherapy. Patients who received thoracic radiation after symptomatic irAEs were assessed for ≥grade 2 radiation pneumonitis (RP). Characteristics predictive of RP were assessed using logistic regression and response relationships were modeled. RESULTS: Among 496 assessed patients, 41 with irAE history subsequently treated with thoracic radiotherapy were analyzed. Most irAEs were grade 2 (n = 21) and 3 (n = 19). Median time from irAE onset to radiotherapy was 8.1 months. Most patients received stereotactic body radiation therapy (n = 20) or hypofractionated radiotherapy (n = 18). In total, 25 patients (61%) developed ≥grade 2 RP at a median of 4 months from radiotherapy and 11 months from onset of irAEs. Three months from RP onset, 16 of 24 (67%) assessable patients had persistent symptoms. Among patients with prior ICI pneumonitis (n = 6), five patients (83%) developed ≥grade 2 RP (grade 2, n = 3; grade ≥3, n = 2). The mean lung radiation dose (MLD) predicted for RP (odds ratio: 1.60, P = 0.00002). The relationship between MLD and RP was strong (area under the receiver-operating characteristic curve: 0.85) and showed an exaggerated dose-response. Among patients with an MLD >5 Gy (n = 26), 21 patients (81%) developed ≥grade 2 RP. CONCLUSION: This is the first study assessing the toxicity of radiotherapy among patients with prior irAEs from ICIs. Patients with prior irAEs were found to be at very high risk for clinically significant and persistent RP from thoracic radiotherapy. Careful consideration should be given to the possibility of an increased risk of RP, and close monitoring is recommended in these patients.

Toward personalized dose-prescription in locally advanced non-small cell lung cancer: Validation of published normal tissue complication probability models.

PURPOSE: To identify published normal tissue complication probability (NTCP) models suitable for patient-specific dose-prescription in locally advanced non-small cell lung cancer (LA-NSCLC) through in-house validation. MATERIAL AND METHODS: From eight previously published candidate NTCP models (≥grade 2 acute esophagitis and radiation pneumonitis; AE2, RP2), patient-specific dose-responses were calculated using model variables and fractionation-corrected doses for 241 LA-NSCLC patients treated with chemo-IMRT to 50-80 Gy@1.8-2.0 Gy between 2004 and 2014 (AE2/RP2 rate: 50%/12%). A model was judged final if it significantly predicted AE2 or RP2 (p ≤ 0.05), was discriminative and well calibrated (AUC > 0.60; Hosmer-Lemeshow test pHL > 0.05), which were assessed as the median over 1000 bootstrap samples. RESULTS: Models for AE2 had superior discrimination to RP2 models (AUC = 0.63-0.65 vs. 0.51-0.65). The final AE2 model included mean esophageal dose and concurrent chemotherapy (AUC = 0.65; p < 0.0001). The final RP2 model was a slightly adjusted version of the RP2 model with the best discrimination, and included age, mean lung dose, and pulmonary comorbidity (AUC = 0.73; p < 0.0001). CONCLUSION: Of the eight investigated and published NTCP models, one model successfully described AE2 and one slightly adjusted model successfully described RP2 in the independent cohort. Estimates from these two NTCP models will, therefore, be considered internally when prescribing patient-specific doses in LA-NSCLC patients.

A study of respiration-correlated cone-beam CT scans to correct target positioning errors in radiotherapy of thoracic cancer.

PURPOSE: There is increasingly widespread usage of cone-beam CT (CBCT) for guiding radiation treatment in advanced-stage lung tumors, but difficulties associated with daily CBCT in conventionally fractionated treatments include imaging dose to the patient, increased workload and longer treatment times. Respiration-correlated cone-beam CT (RC-CBCT) can improve localization accuracy in mobile lung tumors, but further increases the time and workload for conventionally fractionated treatments. This study investigates whether RC-CBCT-guided correction of systematic tumor deviations in standard fractionated lung tumor radiation treatments is more effective than 2D image-based correction of skeletal deviations alone. A second study goal compares respiration-correlated vs respiration-averaged images for determining tumor deviations. METHODS: Eleven stage II-IV nonsmall cell lung cancer patients are enrolled in an IRB-approved prospective off-line protocol using RC-CBCT guidance to correct for systematic errors in GTV position. Patients receive a respiration-correlated planning CT (RCCT) at simulation, daily kilovoltage RC-CBCT scans during the first week of treatment and weekly scans thereafter. Four types of correction methods are compared: (1) systematic error in gross tumor volume (GTV) position, (2) systematic error in skeletal anatomy, (3) daily skeletal corrections, and (4) weekly skeletal corrections. The comparison is in terms of weighted average of the residual GTV deviations measured from the RC-CBCT scans and representing the estimated residual deviation over the treatment course. In the second study goal, GTV deviations computed from matching RCCT and RC-CBCT are compared to deviations computed from matching respiration-averaged images consisting of a CBCT reconstructed using all projections and an average-intensity-projection CT computed from the RCCT. RESULTS: Of the eleven patients in the GTV-based systematic correction protocol, two required no correction, seven required a single correction, one required two corrections, and one required three corrections. Mean residual GTV deviation (3D distance) following GTV-based systematic correction (mean ± 1 standard deviation 4.8 ± 1.5 mm) is significantly lower than for systematic skeletal-based (6.5 ± 2.9 mm, p = 0.015), and weekly skeletal-based correction (7.2 ± 3.0 mm, p = 0.001), but is not significantly lower than daily skeletal-based correction (5.4 ± 2.6 mm, p = 0.34). In two cases, first-day CBCT images reveal tumor changes-one showing tumor growth, the other showing large tumor displacement-that are not readily observed in radiographs. Differences in computed GTV deviations between respiration-correlated and respiration-averaged images are 0.2 ± 1.8 mm in the superior-inferior direction and are of similar magnitude in the other directions. CONCLUSIONS: An off-line protocol to correct GTV-based systematic error in locally advanced lung tumor cases can be effective at reducing tumor deviations, although the findings need confirmation with larger patient statistics. In some cases, a single cone-beam CT can be useful for assessing tumor changes early in treatment, if more than a few days elapse between simulation and the start of treatment. Tumor deviations measured with respiration-averaged CT and CBCT images are consistent with those measured with respiration-correlated images; the respiration-averaged method is more easily implemented in the clinic.

SU-E-T-595: Comparison of Volumetric Modulated Arc Therapy (VMAT) and Static Intensity Modulated Radiotherapy (IMRT) for Malignant Pleural Mesothelioma in Patients with Intact Lungs/Post Pleurectomy.

PURPOSE: This planning study compares VMAT and static gantry, sliding window IMRT for malignant pleural mesothelioma for post pleurectomy. METHODS: We compared plans for a left sided (L) and a right sided case (R). Plans used clinically approved planning target volumes (PTVs) and critical organ contours. IMRT plans employed 7-8 6 MV photon beam directions over a 215° range centered on the ipsilateral lung. VMAT plans used 4 partial arcs within the same range and energy. Prescription dose per fraction was 1.8 Gy; case L went to 50.4 Gy, case R to 46.8 Gy. Planning objectives were: Lyman model NTCP for both lungs < 25%; contralateral lung, mean dose < 8 Gy; heart, V30 Gy < 50%, mean < 30 Gy; Each Kidney, V18 Gy < 33%; liver_not_GTV, mean < 30 Gy, V30 Gy < 50%; stomach not PTV, mean < 30 Gy; cord maximum < 45 Gy; bowel maximum < 55 Gy, D05 < 45 Gy; PTV D95 = 94%, V95 = 94%, D05 = 115%. Dose calculation was done with the AAA algorithm. RESULTS: VMAT and IMRT both met the dosimetric constraints. The VMAT MU were 887 (L)_and 896 (R) and for IMRT were 1691 (L) and 2409 (R). IMRT required 14-16 fields (wide-field splitting). The delivery times were 8 minutes (VMAT) and 20 minutes (IMRT). For coverage and plan homogeneity parameters within 1.5% - 2%, VMAT better spared organs at risk. CONCLUSIONS: Both VMAT and IMRT are feasible techniques for the treatment of malignant pleural mesothelioma with intact lungs, with less MU and a shorter delivery time for VMAT. Additional cases must be planned to test generality of our preliminary results.

SU-E-J-67: A Potential New Technique to Measure Respiratory Tidal Volume Using Optical Surface Imaging: A Geometric and Deformable Phantom Study.

PURPOSE: To develop a new method for accurate measurement of dynamic respiratory tidal volume, we investigate the feasibility of measuring torso volume change using optical surface imaging (OSI). METHODS: Based on a validated volume conservation theory, the tidal volume is equal to the volume change of the torso during quiet respiration (Li et al, PMB, 54:1693, 2009). A clinical OSI system was employed to acquire surface images of seven geometric phantoms and two 'deformable' torso phantoms. The mesh surface images were converted into contours for volume calculation using a treatment planning system. For geometric phantoms, their volumes under the incomplete surface images were calculated with aid of their symmetry. The results were compared with theoretical calculation and water containment experiments. For deformable torso phantoms, we created volume-controlled deformation stages by placing deformable PlayDoh (DPD) materials on top of rigid Rando/Thorax phantoms, mimicking respiration-induced torso surface elevation and volume change. The volume difference under the surfaces with and without the DPD padding was calculated with aid of a common posterior line to enclose the region of interest. Three different volumes of DPD padding (>500cc) were mounted on the torso phantoms and CT scanned for volume measurements. RESULTS: For geometric phantoms, the OSI measured volume had accuracy (±1s) of 0.0%±1.6% (vs. geometric volume calculation) and 0.6%±3.8% (vs. water containment experiment). For deformable torso phantoms, the volume change was measured using OSI with an accuracy of 1.5%±2.5% against the measured volume using CT imaging. Linear regression showed a one-to-one relationship between the OSI volumes and CT volumes with a slope of 1.003 (r2=0.999). CONCLUSIONS: The optical surface imaging system can accurately measure the volume of geometric phantoms and the volume change of deformable torso phantoms. The accuracy is about 3% against standard volume measurement methods. Further study on human subjects is under investigation. Memorial Sloan-Kettering Cancer Center has a reserach agreement with Vision RT, Inc.

SU-E-J-121: A New 4D Radiotherapy Planning Strategy Using Synthesized Tumor-Motion-Compensated Computed Tomography.

PURPOSE: To validate a four-dimensional radiotherapy (4DRT) planning based on a synthesized CT image compensating for tumor motion, accounting for tumor rotation, deformation and distortion due to motion artifacts, and producing realistic normal tissue density in motion-tracking beam eye view. METHODS: 4D computed tomography (4DCT) images of six patients with peripheral lung lesions in mid or lower lobs (motion range: 0.5-3.5cm and size: 1.5±2.0 cm3 ) were used. A customized program was used for simulating the patient anatomy with a motion-compensated tumor using 4DCT by aligning the tumor and averaging the 4DCT into a static 3.5DCT image. The gross tumor volume (GTV) was delineated semiautomatically using a threshold algorithm. Variation of GTV in each phase CT was assessed across all phases. 3DRT plans were generated using 3.5DCT and 4DCT and compared for validation. An integrated dose volume histogram (iDVH) from all phase plans and dose warping using deformable image registration (DIR) were used for evaluating 4D plans and comparing with 3.5D plans. RESULTS: The range of tumor volume variation over the mean within a breathing cycle was 87%±46%. The 3.5DCT produced an 'averaged' GTV, more reliable than that from any phase CT. The results show that the 3.5D plan is equivalent to the 4D plan, except for low dose area, using the iDVH evaluation. On average, the percentage difference for the areas under the DVH and iDVH is 4.3%±2.7%, while 2/3 of the difference results from low dose region blow D20%. Using DIR-based dose warping, PTV coverage varies due to DIR uncertainty for the small lesions. CONCLUSIONS: The 3.5D plan is equivalent to the 4D plan for peripheral lung lesions, yet requires much less clinical workload. The 3.5D plan accounts for tumor motion and tumor variation for a more reliable delineation, and for realistic normal tissue representation for motion tracking.

SU-E-J-119: Comparative Evaluation of Respiratory Motion-Corrected Cone-Beam CT Images Derived from Treatment-Day Vs. Simulation-Day Respiration-Correlated CT Scans.

PURPOSE: Respiration-induced motion artifacts in cone-beam CT (CBCT) can be corrected using a model of patient motion obtained from respiration-correlated CT (RCCT). This approach assumes that respiration-induced organ deformations at simulation, when RCCT scans are normally acquired, are still valid at treatment. The purpose of this study is to compare lung tumor image quality in motion-corrected CBCT images derived from treatment-day RCCT(tx) to simulation-day RCCT(sim) patient images. METHODS: In an IRB-approved study, lung cancer patients receive an RCCT at simulation, and an RCCT, gated CBCT and 1-minute CBCT at one treatment session. CBCT projections from the 1-minute scan are sorted according to breathing amplitude from an external monitor and reconstructed and warped to obtain a motion-corrected MC-CBCT at end expiration. Motion correction uses a model adapted from either RCCT(tx) or RCCT(sim), thus obtaining MC-CBCT(tx) and MC-CBCT(sim) images respectively. A gated CBCT, in which gantry rotation and projection acquisition occur within a gate at end expiration, serves as ground truth for comparison. Quality of MC-CBCT images is evaluated from tumor-to-background contrast ratio (TBCR) values measured by delineating the tumor and annular volume around it on the gated CBCT then transferring the contours and aligning them to each MC-CBCT. RESULTS: TBCR is found tobe lower in MC-CBCT(sim) images, relative to MC-CBCT(tx), in four out of five patients with mean 21% reduction in a range 9-39%. In the remaining case, where there was no change in TBCR, tumor motion observed in the RCCT was small (2mm). Tumor motion extent relative to diaphragm is observed to change between RCCT(tx) and RCCT(sim) scans. CONCLUSIONS: Preliminary results indicate that deformation patterns in lung do change between simulation and treatment. Such variations may reduce the validity of using simulation data for motion-corrected CBCT at treatment. The findings require confirmation with larger numbers of patients. NIH/NCI award R01 CA126993, research grant from Varian Medical Systems.

Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma.

Human malignant gliomas are highly lethal neoplasms. Involved-field radiotherapy is the most important therapeutic measure. Most relapses originate from the close vicinity of the irradiated target field. Here, we report that sublethal doses of irradiation enhance the migration and invasiveness of human malignant glioma cells. This hitherto unknown biological effect of irradiation is p53 independent, involves enhanced alphavbeta3 integrin expression, an altered profile of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9) expression and activity, altered membrane type 1 MMP and tissue inhibitor of metalloproteinases-2 expression, and an altered BCL-2/BAX rheostat favoring resistance to apoptosis. BCL-2 gene transfer and irradiation cooperate to enhance migration and invasiveness in a synergistic manner. Sublethal irradiation of rat 9L glioma cells results in the formation of a greater number of tumor satellites in the rat brain in vivo concomitant with enhanced MMP-2 and reduced tissue inhibitor of metalloproteinases-2 expression. Collectively, these data suggest that the current concepts of involved-field radiotherapy for malignant glioma need to be reconsidered and that the pharmacological inhibition of migration and invasion during radiotherapy may represent a new therapeutic approach to improve the therapeutic efficacy of radiotherapy for malignant glioma.

Identification by suppression subtractive hybridization of p21 as a radio-inducible gene in human glioma cells.

BACKGROUND: Radio-gene therapy involves the delivery, to tumor cells, of a therapeutic transgene whose expression is controlled by irradiation. MATERIALS AND METHODS: Here, we sought to identify novel radio-inducible transcripts in U87MG human malignant glioma cells using suppression subtractive hybridization (SSH). RESULTS: Of 998 clones from a subtracted library of irradiated U87MG cells, 24 candidate clones were identified by dot blot and 3 clones were confirmed as having been induced by irradiation by Northern blot analysis. All three clones showed 99-100% homology to the cyclin-dependent kinase (cdk) inhibitor, p21(Waf/Cip1). A screening of 12 human malignant glioma cell lines revealed that irradiation increased p21 mRNA expression and p21 protein levels levels in all of the five cell lines retaining p53 wild-type activity in a p53 reporter assay, but in none of seven p53 reporter-negative cell lines. CONCLUSION: Irradiation induces p21 mRNA expression in a strictly p53-dependent manner and may only enhance the expression of a limited number of genes in glioma cells. We conclude that the identification of radio-inducible genomic sequences suitable for radio-gene therapy may turn out to be difficult.

"Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions".

Allograft inflammatory factor-1 (AIF-1) is a 17-kDa-peptide identified in rat cardiac allografts undergoing chronic rejection and in activated microglial cells in inflammatory autoimune disease of the CNS. We have investigated the expression of AIF-1 in 18 autopsy cases of human focal cerebral infarction. AIF-1-positive cells show the morphology of microglia and are CD68- but not GFAP-positive. The peptide is expressed at a low level in normal brain. In infarctions, activated microglial cells in the area of glial reaction show strongly enhanced cytoplasmic immunoreactivity. The density of AIF-1-expressing cells increases during the first three days post infarction and remains elevated until chronic cystic stages. The upregulation of AIF-1-immunoreactivity precedes the rise in expression of the S-100-protein MRP-8. We conclude that AIF-1 is a sensitive marker of human microglial activation not only in inflammation but also in non-inflammatory lesions of the CNS.

Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions.

Allograft inflammatory factor-1 (AIF-1) is a 17-kDa-peptide identified in rat cardiac allografts undergoing chronic rejection and in activated microglial cells in inflammatory autoimune disease of the CNS. We have investigated the expression of AIF-1 in 18 autopsy cases of human focal cerebral infarction. AIF-1-positive cells show the morphology of microglia and are CD68- but not GFAP-positive. The peptide is expressed at a low level in normal brain. In infarctions, activated microglial cells in the area of glial reaction show strongly enhanced cytoplasmic immunoreactivity. The density of AIF-1-expressing cells increases during the first three days post infarction and remains elevated until chronic cystic stages. The upregulation of AIF-1-immunoreactivity precedes the rise in expression of the S-100-protein MRP-8. We conclude that AIF-1 is a sensitive marker of human microglial activation not only in inflammation but also in non-inflammatory lesions of the CNS.