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Introduction: This work presents a method to treat stereotactic body radiation therapy (SBRT) for pancreatic cancer on a magnetic resonance-guided linear accelerator (MR-linac) using daily adaptation, real-time motion monitoring, and abdominal compression. Methods: The motion management and treatment planning process involves a magnetic resonance imaging (MRI) simulation with cine and 3D images, a computed tomography (CT) simulation with a breath-hold CT and a 4DCT, pre-treatment verification and planning MRI, and intrafraction MRI cine images. Results: The results from 26 patients were included in this work. Our motion management process results in consistent motion analysis on the CT simulation, MRI simulation, and each treatment fraction. The liver dome was found to be an overestimate of tumor superior/inferior (SI) motion for most patients. Adding compression reduced SI liver dome motion by 6.2 mm on average. Clinical outcomes are similar to those observed in the literature. Conclusions: In this work, we demonstrate how pancreatic SBRT can be successfully treated on an MR-linac using abdominal compression. This allows for an increased duty cycle compared to gating and/or breath-hold techniques.
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Purpose: The purpose of this work was to investigate the use of a segmentation approach that could potentially improve the speed and reproducibility of contouring during magnetic resonance-guided adaptive radiation therapy. Methods and Materials: The segmentation algorithm was based on a hybrid deep neural network and graph optimization approach that also allows rapid user intervention (Deep layered optimal graph image segmentation of multiple objects and surfaces [LOGISMOS] + just enough interaction [JEI]). A total of 115 magnetic resonance-data sets were used for training and quantitative assessment. Expert segmentations were used as the independent standard for the prostate, seminal vesicles, bladder, rectum, and femoral heads for all 115 data sets. In addition, 3 independent radiation oncologists contoured the prostate, seminal vesicles, and rectum for a subset of patients such that the interobserver variability could be quantified. Consensus contours were then generated from these independent contours using a simultaneous truth and performance level estimation approach, and the deviation of Deep LOGISMOS + JEI contours to the consensus contours was evaluated and compared with the interobserver variability. Results: The absolute accuracy of Deep LOGISMOS + JEI generated contours was evaluated using median absolute surface-to-surface distance which ranged from a minimum of 0.20 mm for the bladder to a maximum of 0.93 mm for the prostate compared with the independent standard across all data sets. The median relative surface-to-surface distance was less than 0.17 mm for all organs, indicating that the Deep LOGISMOS + JEI algorithm did not exhibit a systematic under- or oversegmentation. Interobserver variability testing yielded a mean absolute surface-to-surface distance of 0.93, 1.04, and 0.81 mm for the prostate, seminal vesicles, and rectum, respectively. In comparison, the deviation of Deep LOGISMOS + JEI from consensus simultaneous truth and performance level estimation contours was 0.57, 0.64, and 0.55 mm for the same organs. On average, the Deep LOGISMOS algorithm took less than 26 seconds for contour segmentation. Conclusions: Deep LOGISMOS + JEI segmentation efficiently generated clinically acceptable prostate and normal tissue contours, potentially limiting the need for time intensive manual contouring with each fraction.
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Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.
The use of high doses of radiation delivered directly to tumors (stereotactic body radiation therapy [SBRT]) may improve survival compared with lower doses of radiation in patients with pancreatic cancer, but it may increase side effects. Rucosopasem, an investigational new drug being developed, can potentially improve the ability of SBRT to treat tumors without decreasing safety. In a previous study, median overall survival was improved when patients were treated with SBRT plus avasopasem, a drug that works the same way as rucosopasem. GRECO-2 is a clinical trial of rucosopasem used in combination with SBRT for treatment of localized pancreatic cancer. Patients will be randomly selected to receive either rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT treatment. The main result being studied is overall survival. Additional results include amount of time before tumors start to grow, how often patients get tumors surgically removed, best overall response and long-term safety. Clinical Trial Registration: NCT04698915 (ClinicalTrials.gov).
Subject(s)
Adenocarcinoma , Pancreatic Neoplasms , Radiosurgery , Humans , Clinical Trials, Phase II as Topic , Dose Fractionation, Radiation , Multicenter Studies as Topic , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/radiotherapy , Pancreatic Neoplasms/drug therapy , Radiosurgery/adverse effects , Randomized Controlled Trials as TopicABSTRACT
PURPOSE: The goal of this study was to commission the use of a magnetic resonance linear accelerator (MR-linac; Unity) for imaging of gynecologic high-dose-rate (HDR) brachytherapy. This included optimizing imaging protocols and workflow development. METHODS AND MATERIALS: T1-weighted and T2-weighted HDR imaging protocols were optimized on the Unity for HDR gynecologic imaging and treatment planning. Phantom measurements using these protocols were performed to determine geometric distortion and to assess reconstruction accuracy of the applicator compared with the ground truth computed tomography image. A treatment plan was created within the treatment planning system that was then delivered to a phantom. New workflows were developed which were tested with a full dry run with a healthy volunteer including patient transfer, anesthesia considerations, and data transfer. Validation of the workflow was completed on 1 patient who received imaging on both the Unity magnetic resonance imaging (MRI) and on a dedicated 3 Tesla MRI simulator. RESULTS: Imaging analysis results were favorable with MR-linac images with a maximum distortion of 0.96 mm and a 1.36-mm over a 350-mm diameter spherical volume on the T1- and T2-weighted images, respectively, and the maximum effect of the applicator was 0.36 ppm of the main magnetic field. Reconstruction uncertainties of the Venezia applicator's tandem and 2 lunar-ovoids on the MR-linac images were within the 2-mm tolerance of the International Commission on Radiation Units and Measurements Report 89. Treatment planning and delivery was performed on the MR-HDR quality assurance phantom without issue. Dry run and healthy volunteer imaging showed adequate performance of both vital monitoring and HDR equipment. For the patient for which both the Unity MRI and 3 Tesla images were acquired, 95.78% and 95.80% of the high risk clinical target volume received 100% of the dose, respectively. Both plans were considered clinically acceptable. CONCLUSIONS: Unity MR-linac images were successfully used in gynecologic HDR brachytherapy treatment planning, and a usable workflow was established.
Subject(s)
Brachytherapy , Humans , Female , Brachytherapy/methods , Magnetic Resonance Imaging/methods , Phantoms, Imaging , Tomography, X-Ray Computed/methods , Workflow , Radiotherapy Planning, Computer-Assisted/methodsABSTRACT
The intracellular redox-active labile iron pool (LIP) is weakly chelated and available for integration into the iron metalloproteins that are involved in diverse cellular processes, including cancer cell-specific metabolic oxidative stress. Abnormal iron metabolism and elevated LIP levels are linked to the poor survival of lung cancer patients, yet the underlying mechanisms remain unclear. Depletion of the LIP in non-small-cell lung cancer cell lines using the doxycycline-inducible overexpression of the ferritin heavy chain (Ft-H) (H1299 and H292), or treatment with deferoxamine (DFO) (H1299 and A549), inhibited cell growth and decreased clonogenic survival. The Ft-H overexpression-induced inhibition of H1299 and H292 cell growth was also accompanied by a significant delay in transit through the S-phase. In addition, both Ft-H overexpression and DFO in H1299 resulted in increased single- and double-strand DNA breaks, supporting the involvement of replication stress in the response to LIP depletion. The Ft-H and DFO treatment also sensitized H1299 to VE-821, an inhibitor of ataxia telangiectasis and Rad2-related (ATR) kinase, highlighting the potential of LIP depletion, combined with DNA damage response modifiers, to alter lung cancer cell responses. In contrast, only DFO treatment effectively reduced the LIP, clonogenic survival, cell growth, and sensitivity to VE-821 in A549 non-small-cell lung cancer cells. Importantly, the Ft-H and DFO sensitized both H1299 and A549 to chemoradiation in vitro, and Ft-H overexpression increased the efficacy of chemoradiation in vivo in H1299. These results support the hypothesis that the depletion of the LIP can induce genomic instability, cell death, and potentiate therapeutic responses to chemoradiation in NSCLC.
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Diffuse intrinsic pontine gliomas (DIPG) are an aggressive type of pediatric brain tumor with a very high mortality rate. Surgery has a limited role given the tumor's location. Palliative radiation therapy alleviates symptoms and prolongs survival, but median survival remains less than 1 year. There is no clear role for chemotherapy in DIPGs as trials adding chemotherapy to palliative radiation therapy have failed to improve survival compared to radiation alone. Thus, there is a critical need to identify tissue-specific radiosensitizers to improve clinical outcomes for patients with DIPGs. Pharmacologic (high dose) ascorbate (P-AscH-) is a promising anticancer therapy that sensitizes human tumors, including adult high-grade gliomas, to radiation by acting selectively as a generator of hydrogen peroxide (H2O2) in cancer cells. In this study we demonstrate that in contrast to adult glioma models, P-AscH- does not radiosensitize DIPG. DIPG cells were sensitive to bolus of H2O2 but have faster H2O2 removal rates than GBM models which are radiosensitized by P-AscH-. These data support the hypothesis that P-AscH- does not enhance DIPG radiosensitivity, likely due to a robust capacity to detoxify and remove hydroperoxides.
Subject(s)
Antineoplastic Agents , Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Child , Adult , Humans , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/pathology , Brain Stem Neoplasms/radiotherapy , Brain Stem Neoplasms/pathology , Peroxides/therapeutic use , Hydrogen Peroxide/pharmacology , Hydrogen Peroxide/therapeutic use , Glioma/radiotherapy , Glioma/pathology , Antineoplastic Agents/therapeutic useABSTRACT
Purpose: This study assesses the impact of intra-fraction motion and PTV margin size on target coverage for patients undergoing radiation treatment of pelvic oligometastases. Dosimetric sparing of the bowel as a function of the PTV margin is also evaluated. Materials and methods: Seven patients with pelvic oligometastases previously treated on our MR-linac (35 Gy in 5 fractions) were included in this study. Retrospective adaptive plans were created for each fraction on the daily MRI datasets using PTV margins of 5 mm, 3 mm, and 2 mm. Dosimetric constraint violations and GTV coverage were measured as a function of PTV margin size. The impact of intra-fraction motion on GTV coverage was assessed by tracking the GTV position on the cine MR images acquired during treatment delivery and creating an intra-fraction dose distribution for each IMRT beam. The intra-fraction dose was accumulated for each fraction to determine the total dose delivered to the target for each PTV size. Results: All OAR constraints were achieved in 85.7%, 94.3%, and 100.0% of fractions when using 5 mm, 3 mm, and 2 mm PTV margins while scaling to 95% PTV coverage. Compared to plans with a 5 mm PTV margin, there was a 27.4 ± 12.3% (4.0 ± 2.2 Gy) and an 18.5 ± 7.3% (2.7 ± 1.4 Gy) reduction in the bowel D0.5cc dose for 2 mm and 3 mm PTV margins, respectively. The target dose (GTV V35 Gy) was on average 100.0 ± 0.1% (99.6 - 100%), 99.6 ± 1.0% (97.2 - 100%), and 99.0 ± 1.4% (95.0 - 100%), among all fractions for the 5 mm, 3 mm, and 2 mm PTV margins on the adaptive plans when accounting for intra-fraction motion, respectively. Conclusion: A 2 mm PTV margin achieved a minimum of 95% GTV coverage while reducing the dose to the bowel for all patients.
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A highly sensitive, circulating tumor cell (CTC)-based liquid biopsy was used to monitor gastrointestinal cancer patients during treatment to determine if CTC abundance was predictive of disease recurrence. The approach used a combination of biomimetic cell rolling on recombinant E-selectin and dendrimer-mediated multivalent immunocapture at the nanoscale to purify CTCs from peripheral blood mononuclear cells. Due to the exceptionally high numbers of CTCs captured, a machine learning algorithm approach was developed to efficiently and reliably quantify abundance of immunocytochemically-labeled cells. A convolutional neural network and logistic regression model achieved 82.9% true-positive identification of CTCs with a false positive rate below 0.1% on a validation set. The approach was then used to quantify CTC abundance in peripheral blood samples from 27 subjects before, during, and following treatments. Samples drawn from the patients either prior to receiving radiotherapy or early in chemotherapy had a median 50 CTC ml-1 whole blood (range 0.6-541.6). We found that the CTC counts drawn 3 months post treatment were predictive of disease progression (p = .045). This approach to quantifying CTC abundance may be a clinically impactful in the timely determination of gastrointestinal cancer progression or response to treatment.
Subject(s)
Biosensing Techniques , Gastrointestinal Neoplasms , Neoplastic Cells, Circulating , Humans , Neoplastic Cells, Circulating/pathology , Leukocytes, Mononuclear , Biomarkers , Nanotechnology , Biomarkers, TumorABSTRACT
PURPOSE: Ataxia telangiectasia mutated kinase (ATM) inhibitors are potent radiosensitizers that regulate DNA damage responses and redox metabolism, but they have not been translated clinically because of the potential for excess normal tissue toxicity. Pharmacologic ascorbate (P-AscH-; intravenous administration achieving mM plasma concentrations) selectively enhances H2O2-induced oxidative stress and radiosensitization in tumors while acting as an antioxidant and mitigating radiation damage in normal tissues including the bowel. We hypothesized that P-AscH- could enhance the therapeutic index of ATM inhibitor-based chemoradiation by simultaneously enhancing the intended effects of ATM inhibitors in tumors and mitigating off-target effects in adjacent normal tissues. METHODS AND MATERIALS: Clonogenic survival was assessed in human (human colon tumor [HCT]116, SW480, HT29) and murine (CT26, MC38) colorectal tumor lines and normal cells (human umbilical vein endothelial cell, FHs74) after radiation ± DNA repair inhibitors ± P-AscH-. Tumor growth delay was assessed in mice with HCT116 or MC38 tumors after fractionated radiation (5 Gy × 3) ± the ATM inhibitor KU60019 ± P-AscH-. Intestinal injury, oxidative damage, and transforming growth factor ß immunoreactivity were quantified using immunohistochemistry after whole abdominal radiation (10 Gy) ± KU60019 ± P-AscH-. Cell cycle distribution and ATM subcellular localization were assessed using flow cytometry and immunohistochemistry. The role of intracellular H2O2 fluxes was assessed using a stably expressed doxycycline-inducible catalase transgene. RESULTS: KU60019 with P-AscH- enhanced radiosensitization in colorectal cancer models in vitro and in vivo by H2O2-dependent oxidative damage to proteins and enhanced DNA damage, abrogation of the postradiation G2 cell cycle checkpoint, and inhibition of ATM nuclear localization. In contrast, concurrent P-AscH- markedly reduced intestinal toxicity and oxidative damage with KU60019. CONCLUSIONS: We provide evidence that redox modulating drugs, such as P-AscH-, may facilitate the clinical translation of ATM inhibitors by enhancing tumor radiosensitization while simultaneously protecting normal tissues.
Subject(s)
Ataxia Telangiectasia , Pancreatic Neoplasms , Humans , Animals , Mice , Ascorbic Acid/pharmacology , Ascorbic Acid/therapeutic use , Hydrogen Peroxide , Cell Line, Tumor , Pancreatic Neoplasms/pathology , Oxidation-Reduction , Therapeutic Index , Ataxia Telangiectasia Mutated Proteins/metabolism , DNA Damage , Cell Cycle Proteins/metabolismABSTRACT
MR-guided adaptive radiotherapy (MRgART) provides opportunities to benefit patients through enhanced use of advanced imaging during treatment for many patients with various cancer treatment sites. This novel technology presents many new challenges which vary based on anatomic treatment location, technique, and potential changes of both tumor and normal tissue during treatment. When introducing new treatment sites, considerations regarding appropriate patient selection, treatment planning, immobilization, and plan-adaption criteria must be thoroughly explored to ensure adequate treatments are performed. This paper presents an institution's experience in developing a MRgART program for a 1.5T MR-linac for the first 234 patients. The paper suggests practical treatment workflows and considerations for treating with MRgART at different anatomical sites, including imaging guidelines, patient immobilization, adaptive workflows, and utilization of bolus.
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PURPOSE: The cohort of patients with locally advanced prostate cancer (PC) and positive surgical margin(s) at radical prostatectomy (RP) who would benefit from salvage or adjuvant treatment is unclear. This study examines the risk of prostate-specific antigen (PSA) relapse in a large population of men with PC after margin-positive RP. METHODS AND MATERIALS: Using a multi-institutional database, patients with clinically localized PC who underwent RP between 2002 and 2010 with recorded follow-up PSA were retrospectively selected. Patients were excluded for pathologic seminal vesicle or lymph node involvement, metastatic disease, pre-RP PSA ≥ 30, or adjuvant (nonsalvage) radiation therapy or hormone therapy. The primary endpoint was biochemical relapse free survival (bRFS), where PSA failure was defined as PSA > 0.10 ng/mL and rising, or at salvage intervention. The Kaplan-Meier method was employed for bRFS estimates; recursive partitioning analysis using cumulative or single maximal margin extent (ME) and Gleason grade (GG) at RP was applied to identify variables associated with bRFS. RESULTS: At median follow-up of 105 months, 210 patients with positive margins at RP were eligible for analysis, and 89 had experienced PSA relapse. Median age was 61 years (range, 43-76), and median pre-RP PSA 5.8 ng/mL (1.6-26.0). Recursive partitioning analysis yielded 5 discrete risk groups, with the lowest risk group (GG1, ≤ 2 mm ME) demonstrating a bRFS of 92% at 8 years compared with the highest risk group (GG3-5, ≥ 3 mm ME) of 11%. CONCLUSIONS: This retrospective study suggests that it may be possible to risk-stratify patients undergoing margin-positive RP using commonly acquired clinical and pathologic variables. Patients with low-grade tumors and minimally involved margins have a very low recurrence risk and may be able to forego postprostatectomy radiation. Meanwhile, those with higher grade and greater involvement could benefit from adjuvant or early salvage radiation therapy.
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This work presents a comprehensive commissioning and workflow development process of a real-time, ultrasound (US) image-guided treatment planning system (TPS), a stepper and a US unit. To adequately benchmark the system, commissioning tasks were separated into (1) US imaging, (2) stepper mechanical, and (3) treatment planning aspects. Quality assurance US imaging measurements were performed following the AAPM TG-128 and GEC-ESTRO recommendations and consisted of benchmarking the spatial resolution, accuracy, and low-contrast detectability. Mechanical tests were first used to benchmark the electronic encoders within the stepper and were later expanded to evaluate the needle free length calculation accuracy. Needle reconstruction accuracy was rigorously evaluated at the treatment planning level. The calibration length of each probe was redundantly checked between the calculated and measured needle free length, which was found to be within 1 mm for a variety of scenarios. Needle placement relative to a reference fiducial and coincidence of imaging coordinate origins were verified to within 1 mm in both sagittal and transverse imaging planes. The source strength was also calibrated within the interstitial needle and was found to be 1.14% lower than when measured in a plastic needle. Dose calculations in the TPS and secondary dose calculation software were benchmarked against manual TG-43 calculations. Calculations among the three calculation methods agreed within 1% for all calculated points. Source positioning and dummy coincidence was tested following the recommendations of the TG-40 report. Finally, the development of the clinical workflow, checklists, and planning objectives are discussed and included within this report. The commissioning of real-time, US-guided HDR prostate systems requires careful consideration among several facets including the image quality, dosimetric, and mechanical accuracy. The TPS relies on each of these components to develop and administer a treatment plan, and as such, should be carefully examined.
Subject(s)
Brachytherapy , Humans , Male , Prostate/diagnostic imaging , Radiotherapy Dosage , Radiotherapy Planning, Computer-Assisted , Ultrasonography , Ultrasonography, InterventionalABSTRACT
BACKGROUND: Approximately 40% of patients with esophageal cancer present with metastatic disease. Survival with palliative treatment is poor, and the benefit of aggressive focal therapies is unclear. This study aimed to identify a subset of patients with metastatic esophageal cancer with favorable outcomes after curative doses of radiation therapy, esophagectomy, or both. METHODS: Between 2004 and 2015, the study investigators found 28,101 patients with metastatic esophageal cancer in the National Cancer Database and identified those who underwent chemotherapy and definitive radiation therapy with or without surgery over the study period. The study compared the estimated median overall survival (OS) of all patients with metastatic esophageal cancer with the estimated median OS of patients with metastatic esophageal cancer who underwent radiation therapy with or without surgery. Multivariable analysis was used to examine clinical and pathologic factors associated with OS. RESULTS: At a median follow-up of 11.1 months, 3219 patients with a median age of 64 years and a radiation dose of 50.4 Gy were identified. Only 202 (6.2%) patients undergoing definitive-dose radiation therapy underwent esophagectomy, with a median age of 60 years. The median OS durations for all patients, for patients treated with radiation, and for patients treated with radiation therapy in combination with esophagectomy were 6.6, 11.5, and 30.2 months, respectively. Among patients undergoing surgery, median OS after surgery was 23.7 months. Patients with lung, liver, or bone metastases were less likely to undergo esophagectomy. On multivariable analysis, esophagectomy and low tumor grade were associated with higher OS, whereas liver and bone metastases at diagnosis were associated with worse OS. CONCLUSIONS: This analysis suggests that select subsets of patients with primarily nonvisceral, nonosseous metastatic esophageal cancer have favorable survival and may potentially benefit from aggressive local therapies.
Subject(s)
Esophageal Neoplasms/therapy , Esophagectomy/methods , Neoplasm Staging , Chemoradiotherapy/methods , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/secondary , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Retrospective StudiesABSTRACT
Purpose: This study aimed to investigate the feasibility of stereotactic body radiation therapy (SBRT) as salvage therapy for locally recurrent esophageal cancer. We hypothesized that SBRT would provide durable treated tumor control with minimal associated toxicity in patients with progressive disease after definitive radiation, chemotherapy, and surgical resection. Methods: This single-institution retrospective study assessed outcomes in patients who received SBRT for locoregional failure of esophageal cancer after initial curative-intent treatment. Only patients who had received neoadjuvant chemoradiation (≥41.4 Gy) for esophageal cancer were selected. Subsequent surgical resection was optional but institutional follow-up by an oncologist was required. The primary endpoints of this study were gastrointestinal and constitutional toxicity, scored with the Common Terminology Criteria for Adverse Events v5.0. A secondary outcome, treated-tumor control, was assessed with RECIST v1.1. Results: Nine patients (11 locoregional recurrences) treated with SBRT were reviewed, with a median follow-up time of 10.5 months. Most patients initially presented with T3 (88.9%), N1 (55.6%), moderately differentiated (66.7%) adenocarcinoma (88.9%), and had received a median 50.4 Gy delivered over 28 fractions with concurrent carboplatin/paclitaxel chemotherapy followed by surgical resection. Median time to recurrence was 16.3 months. Median total dose delivered by SBRT was 27.5 Gy (delivered in five fractions). Two patients experienced acute grade 1 fatigue and vomiting. No patient experienced grade 3 or higher toxicity. One patient experienced failure in the SBRT treatment field at 5.8 months after treatment and six patients developed distant failure. The median progression-free survival time for SBRT-treated tumors was 5.0 months, and median overall survival time was 12.9 months. Conclusions: This single-institution study demonstrated the feasibility of SBRT for locoregional recurrence of esophageal cancer with minimal treatment-related toxicity and high rates of treated tumor control. Prospective studies identifying ideal salvage SBRT candidates for locoregional failure as well as validating its safety are needed.
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PURPOSE: The majority of colorectal cancers are resistant to cancer immune checkpoint inhibitors. Ionizing radiation (IR) and several radiosensitizers, including PARP inhibitors, can enhance responsiveness to immune checkpoint inhibitors by potentially complementary mechanisms of action. We assessed the ability of radiation and PARP inhibition to induce proimmunogenic changes in tumor cells and enhance their in vivo responsiveness to anti-PD-1 antibodies. METHODS AND MATERIALS: We performed a candidate drug screen and used flow cytometry to assess effects of the PARP inhibitor veliparib on IR-mediated changes in MHC-1 antigen presentation and surface localization of immune-modulating proteins including PD-L1 and calreticulin in colorectal cancer tumor models. Reverse transcription polymerase chain reaction was used to assess the effects of veliparib and radiation on the expression of proinflammatory and immunosuppressive cytokines. The ability of concurrent PARP inhibition and subablative doses of radiation therapy to enhance in vivo responsiveness to anti-PD-1 antibodies was assessed using unilateral flank-tumor models with or without T-cell depletion. RESULTS: Veliparib was a potent radiosensitizer in both cell lines. Radiation increased surface localization of MHC-1 and PD-L1 in a dose-dependent manner, and veliparib pretreatment significantly enhanced these effects with high (8 Gy) but not with lower radiation doses. Enhancement of MHC-1 and PD-L1 surface localization by IR and IR+ veliparib remained significant 1, 3, and 7 days after treatment. IR significantly increased delayed tumoral expression of proinflammatory cytokines interferon-Ƴ and CXCL10 but had no significant effect on the expression of IL-6 or TGF-ß. Concurrent administration of veliparib and subablative radiation therapy (8 Gy × 2) significantly prolonged anti-PD-1-mediated in vivo tumor growth delay and survival in both tumor models. Moreover, these effects were more pronounced in the microsatellite instability-mutated MC38 tumor model. Enhancement of anti-PD-1 mediated tumor growth delay with veliparib and IR was attenuated by CD8+ T-cell depletion. CONCLUSIONS: We provide preclinical evidence for a novel therapeutic strategy to enhance responsiveness of colorectal tumors to immune checkpoint inhibitors.
Subject(s)
Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/radiotherapy , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerases/metabolism , Animals , Antigen Presentation/drug effects , Benzimidazoles/pharmacology , Benzimidazoles/therapeutic use , Cell Transformation, Neoplastic , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Combined Modality Therapy , Female , Humans , Male , Mice , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Radiation-Sensitizing Agents/pharmacology , Radiation-Sensitizing Agents/therapeutic use , Treatment OutcomeABSTRACT
PURPOSE: To assess the capability of an intracavitary 169 Yb-based helical multishield rotating shield brachytherapy (RSBT) delivery system to treat cervical cancer. The proposed RSBT delivery system contains a pair of 1.25 mm thick platinum partial shields with 45° and 180° emission angles, which travel in a helical pattern within the applicator. METHODS: A helically threaded tandem applicator with a 45° tandem curvature containing a helically threaded catheter was designed. A 0.6 mm diameter 169 Yb source with a length of 10.5 mm was simulated. A 37-patient treatment planning study, based on Monte Carlo dose calculations using MCNP5, was conducted with high-risk clinical target volumes (HR-CTVs) of 41.2-192.8 cm3 (average ± standard deviation of 79.9 ± 35.8 cm3 ). All patients were assumed to receive 25 fractions of 1.8 Gy of external beam radiation therapy (EBRT) before receiving 5 fractions of high-dose-rate brachytherapy (HDR-BT). For each patient, 192 Ir-based intracavitary (IC) HDR-BT, 192 Ir-based intracavitary/interstitial (IC/IS) HDR-BT using a hybrid applicator with eight IS needles, and 169 Yb-based RSBT plans were generated. RESULTS: For the IC, IC/IS, and RSBT treatment plans, 38%, 84%, and 86% of the plans, respectively, met the planning goal of an HR-CTV D90 (minimum dose to hottest 90%) of 85 GyEQD2 (α/ß = 10 Gy). Median (25th percentile, 75th percentile) treatment times for IC, IC/IS, and RSBT were 11.71 (6.62, 15.40) min, 68.00 (45.02, 80.02) min, and 25.30 (13.87, 35.39) min, respectively. 192 Ir activities ranging from 159.1-370 GBq (4.3-10 Ci) and 169 Yb activities ranging from 429.2-999 GBq (11.6-27 Ci) were used, which correspond to the same clinical ranges of dose rates at 1 cm off-source-axis in water. Extra needle insertion and planning time beyond that needed for intracavitary-only approaches was accounted for in the IC/IS treatment time calculations. CONCLUSION: 169 Yb-based RSBT for cervical cancer met the HR-CTV D90 goal of 85 Gy in a greater percentage of the patients considered than IC/IS (86% vs 84%, respectively) and can reduce overall treatment time relative to IC/IS. 169 Yb-based RSBT could be used to replace IC/IS in instances where IC/IS treatment is not available, especially in instances when HR-CTV volumes are ≥30 cm3 .
Subject(s)
Brachytherapy/instrumentation , Radiation Protection/instrumentation , Radioisotopes/therapeutic use , Rotation , Uterine Cervical Neoplasms/radiotherapy , Ytterbium/therapeutic use , Female , Humans , Radiotherapy Dosage , Radiotherapy Planning, Computer-AssistedABSTRACT
Nanotechnology has made remarkable contributions to clinical oncology. Nanotherapeutics and diagnostic tools have distinctive characteristics which allow them superior abilities to deliver therapeutics and imaging agents for radiation oncology. Compared to solid biopsies and imaging, the analysis of circulating tumor cells (CTCs) offers a more rapid, real-time, and less invasive method to monitor the dynamic molecular profiles of tumors. The potential of CTCs to be translated as a novel cancer biomarker has been demonstrated in numerous clinical studies. This review will discuss clinical applications of nanomaterials in radiation oncology and the implication of CTCs in cancer detection and monitoring.
Subject(s)
Biomarkers, Tumor/analysis , Nanotechnology/methods , Neoplasms/pathology , Neoplasms/radiotherapy , Neoplastic Cells, Circulating/pathology , Radiation Oncology/methods , HumansABSTRACT
PURPOSE: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH-) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH- to standard RT/TMZ therapy. PATIENTS AND METHODS: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH-) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH- phase). Eight P-AscH- dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH- doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH- was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03). RESULTS: Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable MGMT promoter methylation (n = 8), median PFS was 10 months and median OS was 23 months. CONCLUSIONS: P-AscH-/RT/TMZ is safe with promising clinical outcomes warranting further investigation.