Publications by authors named "Guy Storme"

127 Publications

First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies.

Int J Radiat Oncol Biol Phys 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiation Oncology, City of Hope Medical Center, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models.

Methods And Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry.

Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI.

Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.001DOI Listing
June 2021

Breast cancer preoperative FDG-PET, overall survival prognostic separation compared with the lymph node ratio.

Breast Cancer 2021 Jul 10;28(4):956-968. Epub 2021 Mar 10.

Universitair Ziekenhuis Brussel, 1090, Brussels, Belgium.

Purpose: To evaluate the overall survival prognostic value of preoperative F-fluorodeoxyglucose positron emission tomography (PET) in breast cancer, as compared with the lymph node ratio (LNR).

Methods: Data were abstracted at a median follow-up 14.7 years from a retrospective cohort of 104 patients who underwent PET imaging before curative surgery. PET-Axillary|Sternal was classified as PET-positive if hypermetabolism was visualized in ipsilateral nodal axillary and/or sternal region, else as PET-negative. The differences of 15 years restricted mean survival time ∆ according to PET and LNR were computed from Kaplan-Meier overall survival. The effect of PET and other patients' characteristics was analyzed through rankit normalization, which provides with Cox regression the Royston-Sauerbrei D measure of separation to compare the characteristics (0 indicating no prognostic value). Multivariate analysis of the normalized characteristics used stepwise selection with the Akaike information criterion.

Results: In Kaplan-Meier analysis, LNR > 0.20 versus ≤ 0.20 showed ∆ = 3.4 years, P = 0.003. PET-Axillary|Sternal positivity versus PET-negative showed a ∆ = 2.6 years, P = 0.008. In Cox univariate analyses, LNR appeared as topmost prognostic separator, D = 1.50, P < 0.001. PET ranked below but was also highly significant, D = 1.02, P = 0.009. In multivariate analyses, LNR and PET-Axillary|Sternal were colinear and mutually exclusive. PET-Axillary|Sternal improved as prognosticator in a model excluding lymph nodes, yielding a normalized hazard ratio of 2.44, P = 0.062.

Conclusion: Pathological lymph node assessment remains the gold standard of prognosis. However, PET appears as a valuable surrogate in univariate analysis at 15-year follow-up. There was a trend towards significance in multivariate analysis that warrants further investigation.
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http://dx.doi.org/10.1007/s12282-021-01234-zDOI Listing
July 2021

Two-Level Factorial Pre-TomoBreast Pilot Study of Tomotherapy and Conventional Radiotherapy in Breast Cancer: Post Hoc Utility of a Mean Absolute Dose Deviation Penalty Score.

Technol Cancer Res Treat 2020 Jan-Dec;19:1533033820947759

University Hospital of Martinique, Site Clarac, Martinique, France.

Background: A 2-level factorial pilot study was conducted in 2007 just before starting a randomized clinical trial comparing tomotherapy and conventional radiotherapy (CR) to reduce cardiac and pulmonary adverse effects in breast cancer, considering tumor laterality (left/right), target volume (with/without nodal irradiation), surgery (tumorectomy/mastectomy), and patient position (prone/supine). The study was revisited using a penalty score based on the recently developed mean absolute dose deviation (MADD).

Methods: Eight patients with a unique combination of laterality, nodal coverage, and surgery underwent dual tomotherapy and CR treatment planning in both prone and supine positions, providing 32 distinct combinations. The penalty score was applied using the weighted sum of the MADDs. The Lenth method for unreplicated 2-level factorial design was used in the analysis.

Results: The Lenth analysis identified nodal irradiation as the active main effect penalizing the dosimetry by 1.14 Gy (P = 0.001). Other significant effects were left laterality (0.94 Gy), mastectomy (0.61 Gy), and interactions between left mastectomy (0.89 Gy) and prone mastectomy (0.71 Gy), with P-values between 0.005 and 0.05. Tomotherapy provided a small reduction in penalty (reduction of 0.54 Gy) through interaction with nodal irradiation (P = 0.080). Some effects approached significance with P-values > 0.05 and ≤ 0.10 for interactions of prone × mastectomy × left (0.60 Gy), nodal irradiation × mastectomy (0.59 Gy), and prone × left (0.55 Gy) and the main effect prone (0.52 Gy).

Conclusions: The historical dosimetric analysis previously revealed the feasibility of tomotherapy, but a conclusion could not be made. The MADD-based score is promising, and a new analysis highlights the impact of factors and hierarchy of priorities that need to be addressed if major gains are to be attained.
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http://dx.doi.org/10.1177/1533033820947759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502852PMC
September 2020

Is there any benefit to particles over photon radiotherapy?

Ecancermedicalscience 2019 9;13:982. Epub 2019 Dec 9.

Department of Radiotherapy, University Hospital Brussels, Vrije Universiteit Brussel, 1050 Brussel, Belgium.

Particle, essentially, proton radiotherapy (RT) could provide some benefits over photon RT, especially in reducing the side effects of RT. We performed a systematic review to identify the performed randomised clinical trials (RCTs) and ongoing RCTs comparing particle RT with photon therapy. So far, there are no results available from phase 3 RCTs comparing particle RT with photon therapy. Furthermore, the results on side effects comparing proton and carbon ion beam RT with photon RT do vary. The introduction of new techniques in photon RT, such as image-guided RT (IGRT), intensity-modulated RT (IMRT), volumetric arc therapy (VMAT) and stereotactic body RT (SBRT) was already effective in reducing side effects. At present, the lack of evidence limits the indications for proton and carbon ion beam RTs and makes the particle RT still experimental.
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http://dx.doi.org/10.3332/ecancer.2019.982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974365PMC
December 2019

Axillary Lymph Node Involvement in Breast Cancer: A Random Walk Model of Tumor Burden.

Cureus 2019 Nov 27;11(11):e6249. Epub 2019 Nov 27.

Oncology, Comprehensive Cancer Center, Ohio State University, Columbus, USA.

We reinvestigate the relationship between axillary lymph node involvement in breast cancer and the overall risk of death. Patients were women from the Surveillance, Epidemiology, and End Results (SEER) program, aged between 50 and 65 years, presenting a first primary T1-T2 (tumor size ≤5 cm), node-positive, non-metastasized unilateral breast carcinoma, diagnosed from 1988 to 1997, treated with mastectomy without radiotherapy. Hazard ratios (HRs) were computed at each percentage of involved nodes using the proportional hazards model, adjusting for the patient's demographic and tumor characteristics. The pattern of the hazard ratios was examined using serial correlations. Significance testing used the "portmanteau" test. Based on 4,387 records available for analysis, the relation between adjusted mortality and axillary lymph node involvement was modeled as H - H = μ + a, where t is the percentage of involved nodes, H is the mortality hazard ratio at the percentage t, μ is a constant, and a is white noise. The constant μ was estimated at 0.020, corresponding to a 2% increment in the mortality hazard ratio per 1% increase in the percentage of positive nodes. The model was considered acceptable by the "portmanteau" test (P=0.205). We conclude that the effect of the tumor burden might be expressed as a random walk difference model, relating the mortality hazard ratio with the percentage of involved nodes. We will use the model to explore how treatments affect the course of the disease.
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http://dx.doi.org/10.7759/cureus.6249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935340PMC
November 2019

Multi-institutional evaluation of MVCT guided patient registration and dosimetric precision in total marrow irradiation: A global health initiative by the international consortium of total marrow irradiation.

Radiother Oncol 2019 12 14;141:275-282. Epub 2019 Aug 14.

Department of Radiation Oncology, Beckman Research Institute, City of Hope, Duarte, USA. Electronic address:

Purpose: Total marrow irradiation (TMI) is a highly conformal treatment of the human skeleton structure requiring a high degree of precision and accuracy for treatment delivery. Although many centers worldwide initiated clinical studies using TMI, currently there is no standard for pretreatment patient setup. To this end, the accuracy of different patient setups was measured using pretreatment imaging. Their impact on dose delivery was assessed for multiple institutions.

Methods And Materials: Whole body imaging (WBI) or partial body imaging (PBI) was performed using pretreatment megavoltage computed tomography (MVCT) in a helical Tomotherapy machine. Rigid registration of MVCT and planning kilovoltage computed tomography images were performed to measure setup error and its effect on dose distribution. The entire skeleton was considered the planning target volume (PTV) with five sub regions: head/neck (HN), spine, shoulder and clavicle (SC), and one avoidance structure, the lungs. Sixty-eight total patients (>300 images) across six institutions were analyzed.

Results: Patient setup techniques differed between centers, creating variations in dose delivery. Registration accuracy varied by anatomical region and by imaging technique, with the lowest to the highest degree of pretreatment rigid shifts in the following order: spine, pelvis, HN, SC, and lungs. Mean fractional dose was affected in regions of high registration mismatch, in particular the lungs.

Conclusions: MVCT imaging and whole body patient immobilization was essential for assessing treatment setup, allowing for the complete analysis of 3D dose distribution in the PTV and lungs (or avoidance structures).
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http://dx.doi.org/10.1016/j.radonc.2019.07.010DOI Listing
December 2019

Early assessment of dosimetric and biological differences of total marrow irradiation versus total body irradiation in rodents.

Radiother Oncol 2017 09 1;124(3):468-474. Epub 2017 Aug 1.

Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, USA.

Purpose: To develop a murine total marrow irradiation (TMI) model in comparison with the total body irradiation (TBI) model.

Materials And Methods: Myeloablative TMI and TBI were administered in mice using a custom jig, and the dosimetric differences between TBI and TMI were evaluated. The early effects of TBI/TMI on bone marrow (BM) and organs were evaluated using histology, FDG-PET, and cytokine production. TMI and TBI with and without cyclophosphamide (Cy) were evaluated for donor cell engraftment and tissue damage early after allogeneic hematopoietic cell transplantation (HCT). Stromal derived factor-1 (SDF-1) expression was evaluated.

Results: TMI resulted in similar dose exposure to bone and 50% reduction in dose to bystander organs. BM histology was similar between the groups. In the non-HCT model, TMI mice had significantly less acute intestinal and lung injury compared to TBI. In the HCT model, recipients of TMI had significantly less acute intestinal injury and spleen GVHD, but increased early donor cell engraftment and BM:organ SDF-1 ratio compared to TBI recipients.

Conclusions: The expected BM damage was similar in both models, but the damage to other normal tissues was reduced by TMI. However, BM engraftment was improved in the TMI group compared to TBI, which may be due to enhanced production of SDF-1 in BM relative to other organs after TMI.
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http://dx.doi.org/10.1016/j.radonc.2017.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624834PMC
September 2017

Combination therapeutics of Nilotinib and radiation in acute lymphoblastic leukemia as an effective method against drug-resistance.

PLoS Comput Biol 2017 Jul 6;13(7):e1005482. Epub 2017 Jul 6.

Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota, United States of America.

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is characterized by a very poor prognosis and a high likelihood of acquired chemo-resistance. Although tyrosine kinase inhibitor (TKI) therapy has improved clinical outcome, most ALL patients relapse following treatment with TKI due to the development of resistance. We developed an in vitro model of Nilotinib-resistant Ph+ leukemia cells to investigate whether low dose radiation (LDR) in combination with TKI therapy overcome chemo-resistance. Additionally, we developed a mathematical model, parameterized by cell viability experiments under Nilotinib treatment and LDR, to explain the cellular response to combination therapy. The addition of LDR significantly reduced drug resistance both in vitro and in computational model. Decreased expression level of phosphorylated AKT suggests that the combination treatment plays an important role in overcoming resistance through the AKT pathway. Model-predicted cellular responses to the combined therapy provide good agreement with experimental results. Augmentation of LDR and Nilotinib therapy seems to be beneficial to control Ph+ leukemia resistance and the quantitative model can determine optimal dosing schedule to enhance the effectiveness of the combination therapy.
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http://dx.doi.org/10.1371/journal.pcbi.1005482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500007PMC
July 2017

Auranofin radiosensitizes tumor cells through targeting thioredoxin reductase and resulting overproduction of reactive oxygen species.

Oncotarget 2017 May;8(22):35728-35742

Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

Auranofin (AF) is an anti-arthritic drug considered for combined chemotherapy due to its ability to impair the redox homeostasis in tumor cells. In this study, we asked whether AF may in addition radiosensitize tumor cells by targeting thioredoxin reductase (TrxR), a critical enzyme in the antioxidant defense system operating through the reductive protein thioredoxin. Our principal findings in murine 4T1 and EMT6 tumor cells are that AF at 3-10 μM is a potent radiosensitizer in vitro, and that at least two mechanisms are involved in TrxR-mediated radiosensitization. The first one is linked to an oxidative stress, as scavenging of reactive oxygen species (ROS) by N-acetyl cysteine counteracted radiosensitization. We also observed a decrease in mitochondrial oxygen consumption with spared oxygen acting as a radiosensitizer under hypoxic conditions. Overall, radiosensitization was accompanied by ROS overproduction, mitochondrial dysfunction, DNA damage and apoptosis, a common mechanism underlying both cytotoxic and antitumor effects of AF. In tumor-bearing mice, a simultaneous disruption of the thioredoxin and glutathione systems by the combination of AF and buthionine sulfoximine was shown to significantly improve tumor radioresponse. In conclusion, our findings illuminate TrxR in cancer cells as an exploitable radiobiological target and warrant further validation of AF in combination with radiotherapy.
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http://dx.doi.org/10.18632/oncotarget.16113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482612PMC
May 2017

The cost of cancer care is not related to its outcomes.

Ecancermedicalscience 2016 28;10:687. Epub 2016 Oct 28.

Department of Radiation Oncology, UZ Brussel, Belgium.

Solid tumours make up 90% of all proliferative diseases and the main action for cure remains surgery, removing the visible tumour as well as the surrounding tissue. Radiotherapy is an added value for eliminating local microscopic as well as regional disease. Systemic treatment has a small impact on the outcome but has a cost, which is as much as all the other actions such as diagnostic tools and treatments.
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http://dx.doi.org/10.3332/ecancer.2016.687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130330PMC
October 2016

Evaluation of Functional Marrow Irradiation Based on Skeletal Marrow Composition Obtained Using Dual-Energy Computed Tomography.

Int J Radiat Oncol Biol Phys 2016 11 6;96(3):679-87. Epub 2016 Jul 6.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota; Department of Radiation Oncology, Beckman Research Institute, City of Hope, Duarte, California. Electronic address:

Purpose: To develop an imaging method to characterize and map marrow composition in the entire skeletal system, and to simulate differential targeted marrow irradiation based on marrow composition.

Methods And Materials: Whole-body dual energy computed tomography (DECT) images of cadavers and leukemia patients were acquired, segmented to separate bone marrow components, namely, bone, red marrow (RM), and yellow marrow (YM). DECT-derived marrow fat fraction was validated using histology of lumbar vertebrae obtained from cadavers. The fractions of RM (RMF = RM/total marrow) and YMF were calculated in each skeletal region to assess the correlation of marrow composition with sites and ages. Treatment planning was simulated to target irradiation differentially at a higher dose (18 Gy) to either RM or YM and a lower dose (12 Gy) to the rest of the skeleton.

Results: A significant correlation between fat fractions obtained from DECT and cadaver histology samples was observed (r=0.861, P<.0001, Pearson). The RMF decreased in the head, neck, and chest was significantly inversely correlated with age but did not show any significant age-related changes in the abdomen and pelvis regions. Conformity of radiation to targets (RM, YM) was significantly dependent on skeletal sites. The radiation exposure was significantly reduced (P<.05, t test) to organs at risk (OARs) in RM and YM irradiation compared with standard total marrow irradiation (TMI).

Conclusions: Whole-body DECT offers a new imaging technique to visualize and measure skeletal-wide marrow composition. The DECT-based treatment planning offers volumetric and site-specific precise radiation dosimetry of RM and YM, which varies with aging. Our proposed method could be used as a functional compartment of TMI for further targeted radiation to specific bone marrow environment, dose escalation, reduction of doses to OARs, or a combination of these factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081224PMC
http://dx.doi.org/10.1016/j.ijrobp.2016.06.2459DOI Listing
November 2016

Mild Lung Restriction in Breast Cancer Patients After Hypofractionated and Conventional Radiation Therapy: A 3-Year Follow-Up.

Int J Radiat Oncol Biol Phys 2016 Jul 6;95(3):937-945. Epub 2016 Feb 6.

Respiratory Division, University Hospital UZ Brussel, Brussels, Belgium.

Purpose: To assess the effect of radiation therapy on lung function over the course of 3 years.

Methods And Materials: Evolution of restrictive and obstructive lung function parameters was investigated in 108 breast cancer participants in a randomized, controlled trial comparing conventional radiation therapy (CR) and hypofractionated tomotherapy (TT) (age at inclusion ranging 32-81 years). Spirometry, plethysmography, and hemoglobin-corrected diffusing capacity were assessed at baseline and after 3 months and 1, 2, and 3 years. Natural aging was accounted for by considering all lung function parameters in terms of percent predicted values using the most recent reference values for women aged up to 80 years.

Results: In the patients with negligible history of respiratory disease or smoking (n=77), the greatest rate of functional decline was observed during the initial 3 months, this acute decrease being more marked in the CR versus the TT arm. During the remainder of the 3-year follow-up period, values (in terms of percent predicted) were maintained (diffusing capacity) or continued to decline at a slower rate (forced vital capacity). However, the average decline of the restrictive lung function parameters over a 3-year period did not exceed 9% predicted in either the TT or the CR arm. Obstructive lung function parameters remained unaffected throughout. Including also the 31 patients with a history of respiratory disease or more than 10 pack-years showed a very similar restrictive pattern.

Conclusions: In women with breast cancer, both conventional radiation therapy and hypofractionated tomotherapy induce small but consistent restrictive lung patterns over the course of a 3-year period, irrespective of baseline respiratory status or smoking history. The fastest rate of lung function decline generally occurred in the first 3 months.
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http://dx.doi.org/10.1016/j.ijrobp.2016.02.008DOI Listing
July 2016

Motion management during SBRT for oligometastatic cancer: Results of a prospective phase II trial.

Radiother Oncol 2016 06 11;119(3):519-24. Epub 2016 May 11.

Department of Radiotherapy, UZ Brussel, Vrije Universiteit Brussel, Belgium. Electronic address:

Purpose: To optimize the local control of stereotactic body radiotherapy (SBRT) using the Vero-SBRT system and respiratory motion management in patients with oligometastatic cancer.

Materials And Methods: Patients with five or less metastases were eligible. In metastases with significant motion, a fiducial was implanted for Vero dynamic tracking. For other metastases an internal target volume (ITV) was defined to encompass the respiratory tumor trajectory. A dose of 50Gy in 10 fractions was prescribed on the 80% isodose line.

Results: We treated 87 metastases in 44 patients, with colorectal cancer as the most common primary origin (65.9%). Metastatic sites were mainly lung (n=62) and liver (n=17). Twenty-seven metastases were treated with dynamic tracking, the remaining 60 using the ITV-concept. Three patients (7%) experienced grade ⩾3 toxicity. After a median follow-up of 12months, the overall one-year local control (LC) amounted to 89% (95% CI 77-95%), with corresponding values of 90% and 88% for the metastases irradiated with the ITV-approach and dynamic tracking, respectively. Median progression-free survival reached 6.5months, one-year overall survival 95%.

Conclusions: SBRT with proper respiratory motion management resulted in a high LC and an acceptable toxicity profile in oligometastatic cancer patients.
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http://dx.doi.org/10.1016/j.radonc.2016.04.020DOI Listing
June 2016

Myeloid-derived suppressor cells reveal radioprotective properties through arginase-induced l-arginine depletion.

Radiother Oncol 2016 05 10;119(2):291-9. Epub 2016 Feb 10.

Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address:

Background And Purpose: High arginase-1 (Arg) expression by myeloid-derived suppressor cells (MDSC) is known to inhibit antitumor T-cell responses through depletion of l-arginine. We have previously shown that nitric oxide (NO), an immune mediator produced from l-arginine, is a potent radiosensitizer of hypoxic tumor cells. This study therefore examines whether Arg(+) overexpressing MDSC may confer radioresistance through depleting the substrate for NO synthesis.

Material And Methods: MDSC and Arg expression were studied in preclinical mouse CT26 and 4T1 tumor models and further validated in rectal cancer patients in comparison with healthy donors. The radioprotective effect of MDSC was analyzed in hypoxic tumor cells with regard to l-arginine depletion.

Results: In both mouse tumors and cancer patients, MDSC expansion was associated with Arg activation causing accelerated l-arginine consumption. l-Arginine depletion in turn profoundly suppressed the capacity of classically activated macrophages to synthesize NO resulting in impaired tumor cell radiosensitivity. In advanced cT3-4 rectal cancer, circulating neutrophils revealed Arg overexpression approaching that in MDSC, therefore mounting a protumor compartment wherein Arg(+) neutrophils increased from 17% to over 90%.

Conclusions: Protumor Arg(+) MDSC reveal a unique ability to radioprotect tumor cells through l-arginine depletion, a common mechanism behind both T-cell and macrophage inhibition.
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http://dx.doi.org/10.1016/j.radonc.2016.01.014DOI Listing
May 2016

Marrow damage and hematopoietic recovery following allogeneic bone marrow transplantation for acute leukemias: Effect of radiation dose and conditioning regimen.

Radiother Oncol 2016 Jan 30;118(1):65-71. Epub 2015 Nov 30.

Dept. of Therapeutic Radiology, University of Minnesota, Minneapolis, USA; Masonic Cancer Center, University of Minnesota, Minneapolis, USA. Electronic address:

Background And Purpose: Total body irradiation (TBI) is a common component of hematopoietic cell transplantation (HCT) conditioning regimens. Preclinical studies suggest prolonged bone marrow (BM) injury after TBI could contribute to impaired engraftment and poor hematopoietic function.

Materials And Methods: We studied the longitudinal changes in the marrow environment in patients receiving allogeneic HCT with myeloablative (MA, n=42) and reduced intensity (RIC, n=56) doses of TBI from 2003-2013, including BM cellularity, histologic features of injury and repair, hematologic and immunologic recovery.

Results: Following MA conditioning, a 30% decrease in the marrow cellularity persisted at 1 year post-transplant (p=0.03). RIC HCT marrow cellularity transiently decreased but returned to baseline by 6 months even though the RIC group received mostly umbilical cord blood (UCB) grafts (82%, vs. 17% in the MA cohort, p<0.01). There was no evidence of persistent marrow vascular damage or inflammation. Recipients of more intensive conditioning did not show more persistent cytopenias with the exception of a tendency for minimal thrombocytopenia. Immune recovery was similar between MA and RIC.

Conclusions: These findings suggest that TBI associated with MA conditioning leads to prolonged reductions in marrow cellularity, but does not show additional histological evidence of long-term injury, which is further supported by similar peripheral counts and immunologic recovery.
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http://dx.doi.org/10.1016/j.radonc.2015.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764403PMC
January 2016

Feasibility of markerless tumor tracking by sequential dual-energy fluoroscopy on a clinical tumor tracking system.

Radiother Oncol 2015 Dec 3;117(3):487-90. Epub 2015 Sep 3.

Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Belgium.

A novel approach to dual-energy imaging for markerless tumor tracking was proposed consisting of sequential dual-energy fluoroscopy, omitting the need for fast-switching kV generators. The implementation of this approach on a clinical tumor tracking system and its efficacy is shown feasible through optimization of the imaging parameters.
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http://dx.doi.org/10.1016/j.radonc.2015.08.021DOI Listing
December 2015

A comparison of two clinical correlation models used for real-time tumor tracking of semi-periodic motion: A focus on geometrical accuracy in lung and liver cancer patients.

Radiother Oncol 2015 Jun 14;115(3):419-24. Epub 2015 May 14.

Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Belgium.

Purpose: A head-to-head comparison of two clinical correlation models with a focus on geometrical accuracy for internal tumor motion estimation during real-time tumor tracking (RTTT).

Methods And Materials: Both the CyberKnife (CK) and the Vero systems perform RTTT with a correlation model that is able to describe hysteresis in the breathing motion. The CK dual-quadratic (DQ) model consists of two polynomial functions describing the trajectory of the tumor for inhale and exhale breathing motion, respectively. The Vero model is based on a two-dimensional (2D) function depending on position and speed of the external breathing signal to describe a closed-loop tumor trajectory. In this study, 20 s of internal motion data, using an 11 Hz (on average) full fluoroscopy (FF) sequence, was used for training of the CK and Vero models. Further, a subsampled set of 15 internal tumor positions (15p) equally spread over the different phases of the breathing motion was used for separate training of the CK DQ model. Also a linear model was trained using 15p and FF tumor motion data. Fifteen liver and lung cancer patients, treated on the Vero system with RTTT, were retrospectively evaluated comparing the CK FF, CK 15p and Vero FF models using an in-house developed simulator. The distance between estimated target position and the tumor position localized by X-ray imaging was measured in the beams-eye view (BEV) to calculate the 95th percentile BEV modeling errors (ME(95,BEV)). Additionally, the percentage of ME(95,BEV) smaller than 5 mm (P(5mm)) was determined for all correlation models.

Results: In general, no significant difference (p>0.05, paired t-test) was found between the CK FF and Vero models. Based on patient-specific evaluation of the geometrical accuracy of the linear, CK DQ and Vero correlation models, no statistical necessity (p>0.05, two-way ANOVA) of including hysteresis in correlation models was proven, although during inhale breathing motion, the linear model resulted in a decreased P(5mm) with 5-6% compared to both the DQ CK and Vero models.

Conclusion: Dual-quadratic CyberKnife and 2D Vero correlation models were interchangeable in terms of geometrical accuracy with the CK linear ME(95,BEV)=4.1 mm, CK dual-quadratic ME(95,BEV)=3.9 mm and Vero ME(95,BEV)=3.7 mm, when modeled with FF sequence. CK DQ modeling based on 15p acquired in 20 s may lead to problems for internal motion estimation.
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http://dx.doi.org/10.1016/j.radonc.2015.05.004DOI Listing
June 2015

Stromal contribution to the colorectal cancer transcriptome.

Nat Genet 2015 Apr 23;47(4):312-9. Epub 2015 Feb 23.

1] Candiolo Cancer Institute, Fondazione Piemontese per l'Oncologia'Istituto di Ricovero e Cura a Carattere Scientifico (FRO-IRCCS), Candiolo, Italy. [2] Department of Oncology, University of Torino, Candiolo, Italy.

Recent studies identified a poor-prognosis stem/serrated/mesenchymal (SSM) transcriptional subtype of colorectal cancer (CRC). We noted that genes upregulated in this subtype are also prominently expressed by stromal cells, suggesting that SSM transcripts could derive from stromal rather than epithelial cancer cells. To test this hypothesis, we analyzed CRC expression data from patient-derived xenografts, where mouse stroma supports human cancer cells. Species-specific expression analysis showed that the mRNA levels of SSM genes were mostly due to stromal expression. Transcriptional signatures built to specifically report the abundance of cancer-associated fibroblasts (CAFs), leukocytes or endothelial cells all had significantly higher expression in human CRC samples of the SSM subtype. High expression of the CAF signature was associated with poor prognosis in untreated CRC, and joint high expression of the stromal signatures predicted resistance to radiotherapy in rectal cancer. These data show that the distinctive transcriptional and clinical features of the SSM subtype can be ascribed to its particularly abundant stromal component.
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http://dx.doi.org/10.1038/ng.3224DOI Listing
April 2015

Quality Assurance of a 50-kV Radiotherapy Unit Using EBT3 GafChromic Film: A Feasibility Study.

Technol Cancer Res Treat 2016 Feb 9;15(1):163-70. Epub 2015 Jan 9.

Department of Radiotherapy, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

Purpose: Radiochromic EBT3 film is gaining acceptance as a valuable dosimetry system for high-energy photon beams. The advantages of these films over other dosimetry systems are low spectral sensitivity and high spatial resolution. The aim of this study was to validate EBT3 film as a dosimeter for machine and treatment quality assurance (QA) of a 50-kV radiotherapy unit.

Methods And Materials: Absolute and relative doses were acquired using EBT3 GafChromic films and compared to a parallel-plate ionization chamber (IC), the standard IC for low-energy X-rays. EBT3 was also used to evaluate beam profiles and output factors. Two films above each other, mimicking the clinical situation of a dosimeter on top of the skin, were simultaneously irradiated to evaluate EBT3 as in vivo dosimeter. All films were irradiated for 3 minutes, which corresponds with a surface dose of 3.25 ± 0.07 Gy.

Results: A fifth-order polynomial function was found to be the best fit for the calibration curves. Good agreement between IC and EBT3 was found for absolute (0.92% for green and red color channels) and relative (1.2% and 1.0% for green and red color channels, respectively) dosimetry. Output factors for IC and EBT3 were comparable within 2.04% and 1.02% for the green and red color channels, respectively. Flatness and symmetry at the surface were within 2%. By applying film as in vivo dosimeter, an absorption of 4.70% needs to be taken into account with respect to the surface dose.

Conclusion: EBT3 GafChromic film is a feasible and valuable QA and dosimetry tool for a 50-kV radiotherapy unit. EBT3 can be used for absolute and relative dosimetry, measurement of output factors and beam profiles. In vivo patient-specific QA can also be performed if one corrects for the dose absorption of the film.
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http://dx.doi.org/10.1177/1533034614565910DOI Listing
February 2016

Analysis of the targeting uncertainty of a stereotactic frameless radiosurgery technique for arteriovenous malformation.

Radiother Oncol 2014 Dec 29;113(3):371-3. Epub 2014 Oct 29.

Department of Radiotherapy, UZ Brussel, Vrije Universiteit Brussel, Belgium.

In order to target arteriovenous malformations (AVM) in a frameless approach, registration of two-dimensional (2D) digital-subtracted-angiographs (DSA) with three-dimensional (3D) computed tomography (CT) is required. Targeting accuracy and delineation of a frameless 2D-DSA and 3D-CT image registration tool based on bony anatomy of the skull was evaluated. This frameless approach assures accurate target localization and can be used in a clinical setting.
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http://dx.doi.org/10.1016/j.radonc.2014.10.003DOI Listing
December 2014

Improving the intra-fraction update efficiency of a correlation model used for internal motion estimation during real-time tumor tracking for SBRT patients: fast update or no update?

Radiother Oncol 2014 Sep 24;112(3):352-9. Epub 2014 Oct 24.

Department Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Belgium.

Background And Purpose: For tumor tracking, a correlation model is used to estimate internal tumor position based on external surrogate motion. When patients experience an internal/external surrogate drift, an update of the correlation model is required to continue tumor tracking. In this study, the accuracy of the internal tumor position estimation for both the clinical available update at discrete points in time (rebuild) and an in-house developed non-clinical online update approach was investigated.

Methods: A dynamic phantom with superimposed baseline drifts and 14 SBRT patients, treated with real-time tumor tracking (RTTT) on the Vero system, were retrospectively simulated for three update scenarios, respectively no update, clinical rebuild and 0.5 Hz automated online update of the correlation model. By comparing the target positions based on 0.5 Hz verification X-ray images with the estimated internal tumor positions regarding all three update scenarios, 95th percentile modeling errors (ME95), incidences of full geometrical coverage of the CTV by a 5 mm extended PTV (P₅mm) and population-based PTV margins were calculated. Further, the treatment time reduction was estimated when switching from the clinical rebuild approach to the online correlation model update.

Results: For dynamic phantom motion with baseline drifts up to 0.4 mm/min, a 0.5 Hz intra-fraction update showed a similar accuracy in terms of ME95 and P5 mm compared to clinical rebuild. For SBRT patients treated on Vero with RTTT, accuracy was improved by 0.5 Hz online update compared to the clinical rebuild protocol, yielding smaller PTV margins (from 3.2 mm to 2.7 mm), reduced ME95,3D (from 4.1 mm to 3.4 mm) and an increased 5th percentile P5 mm (from 90.7% to 96.1%) for the entire patient group. Further, 80% of treatment sessions were reduced in time with on average 5.5 ± 4.1(1 SD)min.

Conclusion: With a fast (0.5 Hz) automated online update of the correlation model, an efficient RTTT workflow with improved geometrical accuracy was obtained.
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http://dx.doi.org/10.1016/j.radonc.2014.09.007DOI Listing
September 2014

Multi-institutional feasibility study of a fast patient localization method in total marrow irradiation with helical tomotherapy: a global health initiative by the international consortium of total marrow irradiation.

Int J Radiat Oncol Biol Phys 2015 Jan 30;91(1):30-8. Epub 2014 Oct 30.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: To develop, characterize, and implement a fast patient localization method for total marrow irradiation.

Methods And Materials: Topographic images were acquired using megavoltage computed tomography (MVCT) detector data by delivering static orthogonal beams while the couch traversed through the gantry. Geometric and detector response corrections were performed to generate a megavoltage topogram (MVtopo). We also generated kilovoltage topograms (kVtopo) from the projection data of 3-dimensional CT images to reproduce the same geometry as helical tomotherapy. The MVtopo imaging dose and the optimal image acquisition parameters were investigated. A multi-institutional phantom study was performed to verify the image registration uncertainty. Forty-five MVtopo images were acquired and analyzed with in-house image registration software.

Results: The smallest jaw size (front and backup jaws of 0) provided the best image contrast and longitudinal resolution. Couch velocity did not affect the image quality or geometric accuracy. The MVtopo dose was less than the MVCT dose. The image registration uncertainty from the multi-institutional study was within 2.8 mm. In patient localization, the differences in calculated couch shift between the registration with MVtopo-kVtopo and MVCT-kVCT images in lateral, cranial-caudal, and vertical directions were 2.2 ± 1.7 mm, 2.6 ± 1.4 mm, and 2.7 ± 1.1 mm, respectively. The imaging time in MVtopo acquisition at the couch speed of 3 cm/s was <1 minute, compared with ≥15 minutes in MVCT for all patients.

Conclusion: Whole-body MVtopo imaging could be an effective alternative to time-consuming MVCT for total marrow irradiation patient localization.
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http://dx.doi.org/10.1016/j.ijrobp.2014.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385424PMC
January 2015

Impact of inadequate respiratory motion management in SBRT for oligometastatic colorectal cancer.

Radiother Oncol 2014 Nov 28;113(2):235-9. Epub 2014 Nov 28.

Department of Radiotherapy, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Belgium.

Purpose: Stereotactic body radiotherapy (SBRT) in oligometastatic colorectal cancer (CRC) resulted in a disappointing 1-year local control rate of 54% in our experience. We aimed to determine the root cause(s).

Methods: 47 oligometastatic CRC patients were treated with SBRT by helical tomotherapy to a dose of 40 or 50Gy in 10 fractions, without specific respiratory motion management and PTV-margins of 10-10-12mm in all patients. The local recurrences (LRs) were delineated on diagnostic PET-CT scans and co-registered with initial planning CTs. LRs were classified as in-field or marginal with respect to the initial dose distribution, and predictors for LR were determined.

Results: Out of 105 irradiated metastases, LR modeling yielded 15 in-field and 15 marginal failures. Metastases in moving organs (liver and lung) exhibited a local control of 53% at 1-year (95% confidence interval (CI): 38-67%), compared to 79% for lymph nodes (95% CI: 32-95%). The first group exhibited a sixfold increased risk compared to the latter on multivariate analysis (p=0.01).

Conclusions: The nature and locations of LR indicated that dose prescription and methodology were both inadequate for liver and lung metastases. This study demonstrates the need for individual respiratory motion management and a biological effective dose of >75Gy.
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http://dx.doi.org/10.1016/j.radonc.2014.11.005DOI Listing
November 2014

Breast conserving treatment for breast cancer: dosimetric comparison of sequential versus simultaneous integrated photon boost.

Biomed Res Int 2014 4;2014:827475. Epub 2014 Aug 4.

Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090 Brussels, Belgium.

Background: Breast conserving surgery followed by whole breast irradiation is widely accepted as standard of care for early breast cancer. Addition of a boost dose to the initial tumor area further reduces local recurrences. We investigated the dosimetric benefits of a simultaneously integrated boost (SIB) compared to a sequential boost to hypofractionate the boost volume, while maintaining normofractionation on the breast.

Methods: For 10 patients 4 treatment plans were deployed, 1 with a sequential photon boost, and 3 with different SIB techniques: on a conventional linear accelerator, helical TomoTherapy, and static TomoDirect. Dosimetric comparison was performed.

Results: PTV-coverage was good in all techniques. Conformity was better with all SIB techniques compared to sequential boost (P = 0.0001). There was less dose spilling to the ipsilateral breast outside the PTVboost (P = 0.04). The dose to the organs at risk (OAR) was not influenced by SIB compared to sequential boost. Helical TomoTherapy showed a higher mean dose to the contralateral breast, but less than 5 Gy for each patient.

Conclusions: SIB showed less dose spilling within the breast and equal dose to OAR compared to sequential boost. Both helical TomoTherapy and the conventional technique delivered acceptable dosimetry. SIB seems a safe alternative and can be implemented in clinical routine.
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http://dx.doi.org/10.1155/2014/827475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137720PMC
May 2015

Treating patients with real-time tumor tracking using the Vero gimbaled linac system: implementation and first review.

Radiother Oncol 2014 Sep 18;112(3):343-51. Epub 2014 Jul 18.

Radiotherapy Department, UZ Brussel, Vrije Universiteit Brussel, Brussels; Vrije Universiteit Brussel, Medical Imaging and Physical Sciences Group, Faculty of Medicine and Pharmacy.

Purpose: To report on the first clinical application of a real-time tumor tracking (RTTT) solution based on the Vero SBRT gimbaled linac system for treatment of moving tumors.

Methods And Materials: A first group of 10 SBRT patients diagnosed with NSCLC or oligometastatic disease in lung or liver was treated with the RTTT technique. The PTV volumes and OAR exposure were benchmarked against the widely used ITV approach. Based on data acquired during execution of RTTT treatments, a first review was performed of the process.

Results: The 35% PTV volume reduction with RTTT of the studied single lesions SBRT irradiations of small target volumes is expected to result in a small (<1%) reduction of lung or liver NTCP. A GTV-PTV margin of 5.0mm was applied for treatment planning of RTTT. From patient data on residual geometric uncertainties, a CTV-PTV margin of 3.2mm was calculated. Reduction of the GTV-PTV margin below 5.0mm without better understanding of biological definition of tumor boundaries was discouraged. Total treatment times were reduced to 34.4 min on average.

Conclusion: A considerable PTV volume reduction was achieved applying RTTT and time efficiency for respiratory correlated SBRT was reestablished with Vero RTTT.
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http://dx.doi.org/10.1016/j.radonc.2014.05.017DOI Listing
September 2014

Impact of planning target volume margins and rectal distention on biochemical failure in image-guided radiotherapy of prostate cancer.

Radiother Oncol 2014 Apr 13;111(1):106-9. Epub 2014 Mar 13.

Department of Radiotherapy, UZ Brussel, Vrije Universiteit Brussel, Belgium.

Background And Purpose: A previous study in our department demonstrated the negative impact on freedom from biochemical failure (FFBF) of using too narrow planning target volume (PTV) margins during prostate image-guided radiotherapy (IGRT). Here, we investigated the impact of appropriate PTV margins and rectal distention on FFBF.

Methods And Materials: A total of 50 T1-T3N0M0 prostate cancer patients were treated with daily IGRT by implanted markers. In the first 25 patients, PTV margins were 3mm laterolateral, 5mm anterioposterior and 4mm craniocaudal. The subsequent 25 patients were treated with isotropic margins of 6mm. The rectal cross-sectional area (CSA) was determined on the planning CT. Median follow-up was 61months.

Results: The overall 5-year FFBF was 83%. A 6mm PTV margin was related to increased 5-year FFBF on univariate analysis (96% vs 74% with the tighter PTV margins, p=0.04). The 5-year FFBF of patients with a rectal distention on the planning CT was worse compared to those with limited rectal filling (75% for CSA⩾9cm(2) vs 89% for CSA<9cm(2), p=0.02), which remained significant on multivariate analysis (p=0.04).

Conclusion: This retrospective study illustrated the positive impact of PTV margin adaptation and addressed the importance of avoiding rectal distention at time of the planning CT.
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http://dx.doi.org/10.1016/j.radonc.2014.02.009DOI Listing
April 2014

Breast conserving treatment for breast cancer: dosimetric comparison of different non-invasive techniques for additional boost delivery.

Radiat Oncol 2014 Jan 27;9:36. Epub 2014 Jan 27.

UZ Brussel, Vrije Universiteit Brussel (VUB), Brussels, Belgium.

Background: Today it is unclear which technique for delivery of an additional boost after whole breast radiotherapy for breast conserved patients should be state of the art. We present a dosimetric comparison of different non-invasive treatment techniques for additional boost delivery.

Methods: For 10 different tumor bed localizations, 7 different non-invasive treatment plans were made. Dosimetric comparison of PTV-coverage and dose to organs at risk was performed.

Results: The Vero system achieved an excellent PTV-coverage and at the same time could minimize the dose to the organs at risk with an average near-maximum-dose (D2) to the heart of 0.9 Gy and the average volume of ipsilateral lung receiving 5 Gy (V5) of 1.5%. The TomoTherapy modalities delivered an average D2 to the heart of 0.9 Gy for the rotational and of 2.3 Gy for the static modality and an average V5 to the ipsilateral lung of 7.3% and 2.9% respectively. A rotational technique offers an adequate conformity at the cost of more low dose spread and a larger build-up area. In most cases a 2-field technique showed acceptable PTV-coverage, but a bad conformity. Electrons often delivered a worse PTV-coverage than photons, with the planning requirements achieved only in 2 patients and with an average D2 to the heart of 2.8 Gy and an average V5 to the ipsilateral lung of 5.8%.

Conclusions: We present advices which can be used as guidelines for the selection of the best individualized treatment.
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http://dx.doi.org/10.1186/1748-717X-9-36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907792PMC
January 2014

Preoperative intensity-modulated and image-guided radiotherapy with a simultaneous integrated boost in locally advanced rectal cancer: report on late toxicity and outcome.

Radiother Oncol 2014 Jan 12;110(1):155-9. Epub 2013 Nov 12.

Department of Radiotherapy, UZ Brussel, Vrije Universiteit Brussel, Belgium.

Background And Purpose: The addition of chemotherapy to preoperative radiotherapy has been established as the standard of care for patients with cT3-4 rectal cancer. As an alternative strategy, we explored intensity-modulated and image-guided radiotherapy (IMRT-IGRT) with a simultaneous integrated boost (SIB) in a prospective phase II study. Here, we report outcome and late toxicity after a median follow-up of 54 months.

Methods And Materials: A total of 108 patients were treated preoperatively with IMRT-IGRT, delivering a dose of 46 Gy in fractions of 2 Gy. Patients (n=57) displaying an anticipated circumferential resection margin (CRM) of less than 2mm based on magnetic resonance imaging received a SIB to the tumor up to a total dose of 55.2 Gy.

Results: The absolute incidence of grade ≥3 late gastrointestinal and urinary toxicity was 9% and 4%, respectively, with a 13% rate of any grade ≥3 late toxicity. The actuarial 5-year local control (LC), progression-free survival (PFS) and overall survival (OS) were 97%, 57%, and 68%. On multivariate analysis, R1 resection and pN2 disease were associated with significantly impaired OS.

Conclusions: The use of preoperative IMRT-IGRT with a SIB resulted in a high 5-year LC rate and non-negligible late toxicity.
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http://dx.doi.org/10.1016/j.radonc.2013.10.026DOI Listing
January 2014

A complementary dual-modality verification for tumor tracking on a gimbaled linac system.

Radiother Oncol 2013 Dec 14;109(3):469-74. Epub 2013 Nov 14.

Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Belgium. Electronic address:

Background And Purpose: For dynamic tracking of moving tumors, robust intra-fraction verification was required, to assure that tumor motion was properly managed during the course of radiotherapy. A dual-modality verification system, consisting of an on-board orthogonal kV and planar MV imaging device, was validated and applied retrospectively to patient data.

Methods And Materials: Real-time tumor tracking (RTTT) was managed by applying PAN and TILT angular corrections to the therapeutic beam using a gimbaled linac. In this study, orthogonal X-ray imaging and MV EPID fluoroscopy was acquired simultaneously. The tracking beam position was derived from respectively real-time gimbals log files and the detected field outline on EPID. For both imaging modalities, the moving target was localized by detection of an implanted fiducial. The dual-modality tracking verification was validated against a high-precision optical camera in phantom experiments and applied to clinical tracking data from a liver and two lung cancer patients.

Results: Both verification modalities showed a high accuracy (<0.3mm) during validation on phantom. Marker detection on EPID was influenced by low image contrast. For the clinical cases, gimbaled tracking showed a 90th percentile error (E90) of 3.45 (liver), 2.44 (lung A) and 3.40 mm (lung B) based on EPID fluoroscopy and good agreement with XR-log file data by an E90 of 3.13, 1.92 and 3.33 mm, respectively, during beam on.

Conclusion: Dual-modality verification was successfully implemented, offering the possibility of detailed reporting on RTTT performance.
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http://dx.doi.org/10.1016/j.radonc.2013.10.005DOI Listing
December 2013
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