Search

Simple Summary: From a scientific perspective, we are beginning to comprehend the evolution of cancer better, but much remains unknown. The quantity of medications has grown significantly during the past few decades; however, most solid tumor outcomes have not been much affected. Circumstances impact genes that are key players in cancer development. Maybe we should concede that the story of cancer never ends. Despite our increasing understanding of the biology and evolution of the cancer process, it is indisputable that the natural process of cancer creation has become increasingly difficult to cure, as more mutations are found with age. It is significantly more difficult to challenge the curative method when there is heterogeneity within the tumor, as it hampers clinical and genetic categorization. With advances in diagnostic technologies and screening leading to progressive tumor shrinkage, it becomes more difficult over time to evaluate the effects of treatment on overall survival. New treatments are often authorized based on early evidence, such as tumor response; disease-free, progression-free, meta-static-free, and event-free survival; and, less frequently, based on clinical endpoints, such as overall survival or quality of life, when standard guidelines are not available to approve pharmaceuticals. These clearances usually happen quite rapidly. Although approval takes longer, relative survival demonstrates the genuine worth of a novel medication. Pressure is being applied by pharmaceutical companies and patient groups to approve "new" treatments based on one of the above-listed measures, with results that are frequently insignificantly beneficial and frequently have no impact on quality of life. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper states that although numerous new drugs are available for breast cancer, no population benefit is shown from the year 2000 on. It urges the oncological community to revise the "drug approach strategy" in daily practice and pay more attention to early detection and prevention. Background: Breast cancer treatment has seen tremendous progress since the early 1980s, with the first findings of new chemotherapy and hormone therapies. Screening started in the same period. Methods: A review of population data (SEER and the literature) shows an increase in recurrence-free survival until 2000 and it stagnates afterwards. Results: Over the period 1980-2000, the 15% survival gain was presented by pharma as a contribution of new molecules. The contribution of screening during that same period was not implemented by them, although screening has been accepted as a routine procedure in the States since the 1980s and everywhere else since 2000. Conclusions: Interpretation of breast cancer outcome has largely focused on drugs, whereas other factors, such as screening, prevention, biologics, and genetics, were largely neglected. More attention should now be paid to examining the strategy based on realistic global data. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: A cohort of 123 women with stage I-II breast cancer enrolled in a prospective clinical trial of adjuvant radiotherapy who were followed for over 10 years. Year 2020 was associated with excess mortality. The number of deaths (n = 5) in that single year represented a third of all deaths (n = 15) in the full decade before. There was in that year a significant increase in lung-heart toxicity and a significant decline in lung-heart function as measured by left ventricular ejection fraction, forced vital capacity and carbon-monoxide diffusing capacity. We investigated lung-heart toxicity and mortality in 123 women with stage I-II breast cancer enrolled in 2007–2011 in a prospective trial of adjuvant radiotherapy (TomoBreast). We were concerned whether the COVID-19 pandemic affected the outcomes. All patients were analyzed as a single cohort. Lung-heart status was reverse-scored as freedom from adverse-events (fAE) on a 1–5 scale. Left ventricular ejection fraction (LVEF) and pulmonary function tests were untransformed. Statistical analyses applied least-square regression to calendar-year aggregated data. The significance of outliers was determined using the Dixon and the Grubbs corrected tests. At 12.0 years median follow-up, 103 patients remained alive; 10-years overall survival was 87.8%. In 2007–2019, 15 patients died, of whom 11 were cancer-related deaths. In 2020, five patients died, none of whom from cancer. fAE and lung-heart function declined gradually over a decade through 2019, but deteriorated markedly in 2020: fAE dipped significantly from 4.6–4.6 to 4.3–4.2; LVEF dipped to 58.4% versus the expected 60.3% (PDixon = 0.021, PGrubbs = 0.054); forced vital capacity dipped to 2.4 L vs. 2.6 L (PDixon = 0.043, PGrubbs = 0.181); carbon-monoxide diffusing capacity dipped to 12.6 mL/min/mmHg vs. 15.2 (PDixon = 0.008, PGrubbs = 0.006). In conclusion, excess non-cancer mortality was observed in 2020. Deaths in that year totaled one-third of the deaths in the previous decade, and revealed observable lung-heart deterioration. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies in patients with breast cancer have shown acute radiation therapy-induced reductions of pulmonary diffusing capacity, essentially owing to lung volume restriction. We aimed to assess the long-term effect of 2 radiation therapy regimens, which differed in terms of radiation technique and dose fractionation, on lung function.Methods and Materials: From a randomized controlled trial comparing conventional 3-dimensional conformal radiation therapy (CR) and hypofractionated tomotherapy (TT), 84 patients with breast cancer (age at inclusion 54 ± 10 [standard deviation] years) could be assessed at baseline, after 3 months, and after 1, 2, 3, and 10 years. Measurements included forced vital capacity, total lung capacity (TLC), and diffusing capacity (TLco).Results: Radiation therapy-induced lung function changes over 10 years (Δ) were similar for both treatment arms, and in a patient subgroup with negligible history of respiratory disease or smoking (n = 57) these averaged: Δ forced vital capacity = -13 (± 9) percent predicted; ΔTLco = -14 (± 12) percent predicted; and ΔTLC = -11 (± 9) percent predicted. The only significant correlation was between V20 (lung volume exposed to dose exceeding 20 Gy) and ΔTLco (rho = -0.36; P = .007). In this subgroup, as well as in the entire patient cohort, the incurred pulmonary restriction in terms of TLC and TLco showed a greater decline at 3 months for CR versus TT. However, at 10 years, no significant difference could be detected between CR and TT (P = .9 for TLC and P = .2 for TLco in the entire patient cohort). Of the patients with normal TLC and TLco at baseline (ie, above lower limits of normal), respectively 94% and 96% were still normal 10 years later.Conclusions: In women with breast cancer, conventional 3-dimensional conformal radiation therapy and hypofractionated tomotherapy induce similar restrictive lung patterns during the course of a 10-year period, despite some treatment-dependent differences in the first 3 months. The large majority of women with normal lung function at baseline maintained a normal lung function status 10 years after radiation therapy, irrespective of treatment arm. [ABSTRACT FROM AUTHOR]

Purpose: Recent initial findings suggest that radiation therapy improves blood perfusion and cellular chemotherapy uptake in mice with leukemia. However, the ability of radiation therapy to influence drug accumulation in the extracellular bone marrow tissue is unknown, due in part to a lack of methodology. This study developed longitudinal quantitative multiphoton microscopy (L-QMPM) to characterize the bone marrow vasculature (BMV) and drug accumulation in the extracellular bone marrow tissue before and after radiation therapy in mice bearing leukemia.Methods and Materials: We developed a longitudinal window implant for L-QMPM imaging of the calvarium BMV before, 2 days after, and 5 days after total body irradiation (TBI). Live time-lapsed images of a fluorescent drug surrogate were used to obtain measurements, including tissue wash-in slope (WIStissue) to measure extracellular drug accumulation. We performed L-QMPM imaging on healthy C57BL/6 (WT) mice, as well as mice bearing acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).Results: Implants had no effects on calvarium dose, and parameters for wild-type untreated mice were stable during imaging. We observed decreased vessel diameter, vessel blood flow, and WIStissue with the onset of AML and ALL. Two to 10 Gy TBI increased WIStissue and vessel diameter 2 days after radiation therapy in all 3 groups of mice and increased single-vessel blood flow in mice bearing ALL and AML. Increased WIStissue was observed 5 days after 10 Gy TBI or 4 Gy split-dose TBI (2 treatments of 2 Gy spaced 3 days apart).Conclusions: L-QMPM provides stable functional assessments of the BMV. Nonmyeloablative and myeloablative TBI increases extracellular drug accumulation in the leukemic bone marrow 2 to 5 days posttreatment, likely through improved blood perfusion and drug exchange from the BMV to the extravascular tissue. Our data show that neo-adjuvant TBI at doses from 2 Gy to 10 Gy conditions the BMV to improve drug transport to the bone marrow. [ABSTRACT FROM AUTHOR]

Background: Long-term prospective patient-reported outcomes (PRO) after breast cancer adjuvant radiotherapy is scarce. TomoBreast compared conventional radiotherapy (CR) with tomotherapy (TT), on the hypothesis that TT might reduce lung-heart toxicity.Methods: Among 123 women consenting to participate, 64 were randomized to CR, 59 to TT. CR delivered 50 Gy in 25 fractions/5 weeks to breast/chest wall and regional nodes if node-positive, with a sequential boost (16 Gy/8 fractions/1.6 weeks) after lumpectomy. TT delivered 42 Gy/15 fractions/3 weeks to breast/chest wall and regional nodes if node-positive, 51 Gy simultaneous-integrated-boost in patients with lumpectomy. PRO were assessed using the European Organization for Research and Treatment of Cancer questionnaire QLQ-C30. PRO scores were converted into a symptom-free scale, 100 indicating a fully symptom-free score, 0 indicating total loss of freedom from symptom. Changes of PRO over time were analyzed using the linear mixed-effect model. Survival analysis computed time to > 10% PRO-deterioration. A post-hoc cardiorespiratory outcome was defined as deterioration in any of dyspnea, fatigue, physical functioning, or pain.Results: At 10.4 years median follow-up, patients returned on average 9 questionnaires/patient, providing a total of 1139 PRO records. Item completeness was 96.6%. Missingness did not differ between the randomization arms. The PRO at baseline were below the nominal 100% symptom-free score, notably the mean fatigue-free score was 64.8% vs. 69.6%, pain-free was 75.4% vs. 75.3%, and dyspnea-free was 84.8% vs. 88.5%, in the TT vs. CR arm, respectively, although the differences were not significant. By mixed-effect modeling on early ≤2 years assessment, all three scores deteriorated, significantly for fatigue, P ≤ 0.01, without effect of randomization arm. By modeling on late assessment beyond 2 years, TT versus CR was not significantly associated with changes of fatigue-free or pain-free scores but was associated with a significant 8.9% improvement of freedom from dyspnea, P = 0.035. By survival analysis of the time to PRO deterioration, TT improved 10-year survival free of cardiorespiratory deterioration from 66.9% with CR to 84.5% with TT, P = 0.029.Conclusion: Modern radiation therapy can significantly improve long-term PRO.Trial Registration: Trial registration number ClinicalTrials.gov NCT00459628 , April 12, 2007 prospectively. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Progress in radiotherapy is guided by the need to realize improved dose distributions, i.e. the ability to reduce the treatment volume toward the target volume and still ensuring coverage of that target volume in all dimensions. Poor ability to control the tumour’s location limits the accuracy with which radiation can be delivered to tumour-bearing tissue. Image-guided radiation therapy (IGRT) aims at in-room imaging guiding the radiation delivery based on instant knowledge of the target location and changes in tumour volume during treatment. Advancements are usually not to be attributed to a single event, but rather a combination of many small improvements that together enable a superior result. Image-guidance is an important link in the treatment chain and as such a major factor in this synergetic process. A historic review shows that many of the so-called new developments are not so new at all, but did not make it into mainstream radiotherapy practice at that time. Recent developments in improved IT infrastructures, novel irradiation techniques, and better knowledge of functional and morphologic information may have created the need and optimal environment to revive the interest in IGRT. [Copyright &y& Elsevier]

• WBI institutions have lower overall setup error compared with PBI. • MVCT WBI ensures accurate assessment of 3D regional and global dose variations. • Variation is greatest in DVH of skeletal target at 90% and the lung at 10% isodose. • Dose planning (avoidance vs targeting) has significant impact on lung dose coverage. 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. 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. 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. 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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Organization of European Cancer Institutes (OECI) has the mission to facilitate the development of European comprehensive cancer centres by integrating care and prevention with research and education. Core issues are to deliver a complete multidisciplinary care of high quality and stimulate translational cancer research. The goal is to innovate the cancer care. The increasing problem of critical mass will be solved by networking comprehensive cancer centres containing quality assured harmonized infrastructures. This will give Europe a new potential to extend the cancer research to areas not possible to cover by single centres. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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 50 Gy 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 12 months, 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 6.5 months, 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 50 Gy in 10 fractions, without specific respiratory motion management and PTV-margins of 10–10–12 mm 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 >75 Gy. [ABSTRACT FROM AUTHOR]

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 (ME 95 ), incidences of full geometrical coverage of the CTV by a 5 mm extended PTV ( P 5mm ) 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 ME 95 and P 5mm 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 ME 95,3D (from 4.1 mm to 3.4 mm) and an increased 5th percentile P 5mm (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. [ABSTRACT FROM AUTHOR]

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 5.0 mm was applied for treatment planning of RTTT. From patient data on residual geometric uncertainties, a CTV–PTV margin of 3.2 mm was calculated. Reduction of the GTV–PTV margin below 5.0 mm 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. [ABSTRACT FROM AUTHOR]

Abstract: 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⩾9cm2 vs 89% for CSA<9cm2, 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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 54months. Methods and materials: A total of 108 patients were treated preoperatively with IMRT–IGRT, delivering a dose of 46Gy in fractions of 2Gy. 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 55.2Gy. 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. [Copyright &y& Elsevier]

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 Tomo Therapy, and static Tomo Direct. 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 PTV boost (P = 0.04). The dose to the organs at risk (OAR) was not influenced by SIB compared to sequential boost. Helical Tomo Therapy 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 Tomo Therapy and the conventional technique delivered acceptable dosimetry. SIB seems a safe alternative and can be implemented in clinical routine. [ABSTRACT FROM AUTHOR]

Abstract: 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 3.40mm (lung B) based on EPID fluoroscopy and good agreement with XR-log file data by an E90 of 3.13, 1.92 and 3.33mm, respectively, during beam on. Conclusion: Dual-modality verification was successfully implemented, offering the possibility of detailed reporting on RTTT performance. [Copyright &y& Elsevier]

Purpose: To report potential dose heterogeneity leading to underdosing at different skeletal sites in total marrow irradiation (TMI) with helical tomotherapy due to the thread effect and provide possible solutions to reduce this effect. Methods and Materials: Nine cases were divided into 2 groups based on patient size, defined as maximum left-to-right arm distance (mLRD): small mLRD (≤47 cm) and large mLRD (>47 cm). TMI treatment planning was conducted by varying the pitch and modulation factor while a jaw size (5 cm) was kept fixed. Ripple amplitude, defined as the peak-to-trough dose relative to the average dose due to the thread effect, and the dose–volume histogram (DVH) parameters for 9 cases with various mLRD was analyzed in different skeletal regions at off-axis (eg, bones of the arm or femur), at the central axis (eg, vertebrae), and planning target volume (PTV), defined as the entire skeleton plus 1-cm margin. Results: Average ripple amplitude for a pitch of 0.430, known as one of the magic pitches that reduce thread effect, was 9.2% at 20 cm off-axis. No significant differences in DVH parameters of PTV, vertebrae, or femur were observed between small and large mLRD groups for a pitch of ≤0.287. Conversely, in the bones of the arm, average differences in the volume receiving 95% and 107% dose (V95 and V107, respectively) between large and small mLRD groups were 4.2% (P=.016) and 16% (P=.016), respectively. Strong correlations were found between mLRD and ripple amplitude (rs=.965), mLRD and V95 (rs=−.742), and mLRD and V107 (rs=.870) of bones of the arm. Conclusions: Thread effect significantly influences DVH parameters in the bones of the arm for large mLRD patients. By implementing a favorable pitch value and adjusting arm position, peripheral dose heterogeneity could be reduced. [Copyright &y& Elsevier]

Background: The α/β ratio for prostate cancer is postulated being in the range of 0.8 to 2.2 Gy, giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation. To do so, we carried out a randomized trial comparing hypofractionated and conventionally fractionated image-guided intensity modulated radiotherapy (IG-IMRT) in high-risk prostate cancer. Here, we report on acute toxicity and quality of life (QOL) for the first 124 randomized patients.Methods: The trial compares 76 Gy in 38 fractions (5 fractions/week) (Arm 1) to 63 Gy in 20 fractions (4 fractions/week) (Arm 2) (IG-IMRT). Prophylactic pelvic lymph node irradiation with 46 Gy in 23 fractions sequentially (Arm 1) and 44 Gy in 20 fractions simultaneously (Arm 2) was applied. All patients had long term androgen deprivation therapy (ADT) started before RT. Both physician-rated acute toxicity and patient-reported QOL using EPIC questionnaire are described.Results: There were no differences in overall maximum acute gastrointestinal (GI) or genitourinary (GU) toxicity. Compared to conventional fractionation (Arm 1), GI and GU toxicity both developed significantly earlier but also disappeared earlier in the Arm 2, reaching significant differences from Arm 1 at week 8 and 9. In multivariate analyses, only parameter shown to be related to increased acute Grade ≥1 GU toxicity was the study Arm 2 (p = 0.049). There were no statistically significant differences of mean EPIC scores in any domain and sub-scales. The clinically relevant decrease (CRD) in EPIC urinary domain was significantly higher in Arm 2 at month 1 with a faster recovery at month 3 as compared to Arm 1.Conclusions: Hypofractionation at 3.15 Gy per fraction to 63 Gy within 5 weeks was well tolerated. The GI and GU physician-rated acute toxicity both developed earlier but recovered faster using hypofractionation. There was a correlation between acute toxicity and bowel and urinary QOL outcomes. Longer follow-up is needed to determine the significance of these associations with late toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Our previous studies showed that intrafraction motion needs to be corrected for in frameless radiosurgery. This study was designed to evaluate if verification images can correct for mechanical inaccuracy and intrafraction motion. With proper immobilization and verification images on a regular basis during treatment, mechanical (table-) inaccuracies and intrafraction motion can be corrected for and the absence of PTV-margins warranted. [Copyright &y& Elsevier]

Purpose: To determine whether host hepatocytes may reverse hypoxic radioresistance through nitric oxide (NO)-induced oxygen sparing, in a model relevant to colorectal cancer (CRC) liver metastases. Methods and Materials: Hepatocytes and a panel of CRC cells were incubated in a tissue-mimetic coculture system with diffusion-limited oxygenation, and oxygen levels were monitored by an oxygen-sensing fluorescence probe. To activate endogenous NO production, cocultures were exposed to a cytokine mixture, and the expression of inducible nitric oxide synthase was analyzed by reverse transcription–polymerase chain reaction, Western blotting, and NO/nitrite production. The mitochondrial targets of NO were examined by enzymatic activity. To assess hypoxic radioresponse, cocultures were irradiated and reseeded for colonies. Results: Resting hepatocytes consumed 10-40 times more oxygen than mouse CT26 and human DLD-1, HT29, HCT116, and SW480 CRC cells, and thus seemed to be the major effectors of hypoxic conditioning. As a result, hepatocytes caused uniform radioprotection of tumor cells at a 1:1 ratio. Conversely, NO-producing hepatocytes radiosensitized all CRC cell lines more than 1.5-fold, similar to the effect of selective mitochondrial inhibitors. The radiosensitizing effect was associated with a respiratory self-arrest of hepatocytes at the level of aconitase and complex II, which resulted in profound reoxygenation of tumor cells through oxygen sparing. Nitric oxide–producing hepatocytes were at least 10 times more active than NO-producing macrophages to reverse hypoxia-induced radioresistance. Conclusions: Hepatocytes were the major determinants of the hypoxic microenvironment and radioresponse of CRC cells in our model of metabolic hypoxia. We provide evidence that reoxygenation and radiosensitization of hypoxic CRC cells can be achieved through oxygen sparing induced by endogenous NO production in host hepatocytes. [Copyright &y& Elsevier]

Purpose: This study evaluated the ability of helical tomotherapy to spare the function of the parotid glands in patients with head-and-neck cancer by analyzing dose–volume histograms, salivary gland scintigraphy, and quality of life assessment. Methods and Materials: Data from 76 consecutive patients treated with helical tomotherapy (Hi-Art Tomotherapy) at the University Hospital Brussel were analyzed. During planning, priority was given to planning target volume (PTV) coverage: ≥95% of the dose must be delivered to ≥95% of the PTV. Elective nodal regions received 54 Gy (1.8 Gy/fraction). A dose of 70.5 Gy (2.35 Gy/fraction) was prescribed to the primary tumor and pathologic lymph nodes (simultaneous integrated boost scheme). Objective scoring of salivary excretion was performed by salivary gland scintigraphy. Subjective scoring of salivary gland function was evaluated by the European Organization for Research and Treatment of Cancer quality of life questionnaires Quality of Life Questionnaire—C30 (QLQ-C30) and Quality of Life Questionnaire—Head and Neck 35 (H&N35). Results: Analysis of dose–volume histograms (DVHs) showed excellent coverage of the PTV. The volume of PTV receiving 95% of the prescribed dose (V95%) was 99.4 (range, 96.3–99.9). DVH analysis of parotid gland showed a median value of the mean parotid dose of 32.1 Gy (range, 17.5–70.3 Gy). The median parotid volume receiving a dose <26 Gy was 51.2%. Quality of life evaluation demonstrated an initial deterioration of almost all scales and items in QLQ-C30 and QLQ-H&N35. Most items improved in time, and some reached baseline values 18 months after treatment. Conclusion: DVH analysis, scintigraphic evaluation of parotid function, and quality of life assessment of our patient group showed that helical tomotherapy makes it possible to preserve parotid gland function without compromising disease control. We recommend mean parotid doses of <34 Gy and doses <26 Gy to a maximum 47% of the parotid volume as planning goals. Intensity-modulated radiotherapy should be considered as standard treatment in patients with head-and-neck cancer. [Copyright &y& Elsevier]

Purpose: Shoulder/arm morbidity is a known complication of breast cancer surgery and radiotherapy (RT), but the consequences of choosing one RT technology over another for shoulder/arm morbidity are not clearly defined. In this work, we examine early breast cancer patients to compare the incidence of shoulder/arm morbidity, including breast cancer related lymphedema (BCRL) of the arm, between conventional RT and short-course, image-guided RT (IGRT) treatments. Methods: We randomized patients between post-surgery IGRT over 3 weeks and conventional RT over 5 to 7 weeks, as part of the TomoBreast trial (whose primary endpoint was to assess pulmonary and cardiac toxicities). BCRL and shoulder/arm mobility were assessed prior to and between one and three months following RT, using physical function assessment and common terminology criteria for adverse events. Intention to treat analyses used the matched-pairs t-test for continuous measurements and the chi-squared test for categorical data. Results: Analysis of the first 91 evaluable patients found that >80% experienced an increase in the adverse event score in at least one shoulder/arm mobility measurement, and 18% had BCRL symptoms. Arm volume on both sides increased significantly and significant impairment of movement occurred in both limbs. However, there was no significant difference in BCRL incidence or shoulder/arm mobility impairment between the treatment groups. Conclusion: One to three months after treatment, short-course IGRT had not increased shoulder/arm morbidity compared with conventional RT. Although confirmation requires a longer follow-up, the results support the use of a short-course schedule. The incidental finding that morbidity affected the contralateral limb warrants further investigation. [ABSTRACT FROM AUTHOR]

Purpose: The addition of concomitant chemotherapy to preoperative radiotherapy is considered the standard of care for patients with cT3–4 rectal cancer. The combined treatment modality increases the complete response rate and local control (LC), but has no impact on survival or the incidence of distant metastases. In addition, it is associated with considerable toxicity. As an alternative strategy, we explored prospectively, preoperative helical tomotherapy with a simultaneous integrated boost (SIB). Methods and Materials: A total of 108 patients were treated with intensity-modulated and image-guided radiotherapy using the Tomotherapy Hi-Art II system. A dose of 46 Gy, in daily fractions of 2 Gy, was delivered to the mesorectum and draining lymph nodes, without concomitant chemotherapy. Patients with an anticipated circumferential resection margin (CRM) of less than 2 mm, based on magnetic resonance imaging, received a SIB to the tumor up to a total dose of 55.2 Gy. Acute and late side effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Results: A total of 102 patients presented with cT3–4 tumors; 57 patients entered the boost group and 51 the no-boost group. One patient in the no-boost group developed a radio-hypersensitivity reaction, resulting in a complete tumor remission, a Grade 3 acute and Grade 5 late enteritis. No other Grade ≥3 acute toxicities occurred. With a median follow-up of 32 months, Grade ≥3 late gastrointestinal and urinary toxicity were observed in 6% and 4% of the patients, respectively. The actuarial 2-year LC, progression-free survival and overall survival were 98%, 79%, and 93%. Conclusions: Preoperative helical tomotherapy displays a favorable acute toxicity profile in patients with cT3–4 rectal cancer. A SIB can be safely administered in patients with a narrow CRM and resulted in a promising LC. [Copyright &y& Elsevier]

Purpose: Stereotactic radiosurgery using frame-based positioning is a well-established technique for the treatment of benign and malignant lesions. By contrast, a new trend toward frameless systems using image-guided positioning techniques is gaining mainstream acceptance. This study was designed to measure the detection and positioning accuracy of the ExacTrac/Novalis Body (ET/NB) for rotations and to compare the accuracy of the frameless with the frame-based radiosurgery technique. Methods and Materials: A program was developed in house to rotate reference computed tomography images. The angles measured by the system were compared with the known rotations. The accuracy of ET/NB was evaluated with a head phantom with seven lead beads inserted, mounted on a treatment couch equipped with a robotic tilt module, and was measured with a digital water level and portal films. Multiple hidden target tests (HTT) were performed to measure the overall accuracy of the different positioning techniques for radiosurgery (i.e., frameless and frame-based with relocatable mask or invasive ring, respectively). Results: The ET/NB system can detect rotational setup errors with an average accuracy of 0.09° (standard deviation [SD] 0.06°), 0.02° (SD 0.07°), and 0.06° (SD 0.14°) for longitudinal, lateral, and vertical rotations, respectively. The average positioning accuracy was 0.06° (SD 0.04°), 0.08° (SD 0.06°), and 0.08° (SD 0.07°) for longitudinal, lateral and vertical rotations, respectively. The results of the HTT showed an overall three-dimensional accuracy of 0.76 mm (SD 0.46 mm) for the frameless technique, 0.87 mm (SD 0.44 mm) for the relocatable mask, and 1.19 mm (SD 0.45 mm) for the frame-based technique. Conclusions: The study showed high detection accuracy and a subdegree positioning accuracy. On the basis of phantom studies, the frameless technique showed comparable accuracy to the frame-based approach. [ABSTRACT FROM AUTHOR]

Introduction: Shoulder/arm morbidity is a common complication of breast cancer surgery and radiotherapy (RT), but little is known about acute contralateral morbidity. Methods: Patients were 118 women enrolled in a RT trial. Arm volume and shoulder mobility were assessed before and 1-3 months after RT. Correlations and linear regression were used to analyze changes affecting ipsilateral and contralateral arms, and changes affecting relative interlimb differences (RID). Results: Changes affecting one limb correlated with changes affecting the other limb. Arm volume between the two limbs correlated (R = 0.57). Risk factors were weight increase and axillary dissection. Contralateral and ipsilateral loss of abduction strongly correlated (R = 0.78). Changes of combined RID exceeding 10% affected the ipsilateral limb in 25% of patients, and the contralateral limb in 18%. Aromatase inhibitor therapy was significantly associated with contralateral loss of abduction. Conclusions: High incidence of early contralateral arm morbidity warrants further investigations. [ABSTRACT FROM AUTHOR]

Background: TomoBreast is a unicenter, non-blinded randomized trial comparing conventional radiotherapy (CR) vs. hypofractionated Tomotherapy (TT) for post-operative treatment of breast cancer. The purpose of the trial is to compare whether TT can reduce heart and pulmonary toxicity. We evaluate early toxicities. Methods: The trial started inclusion in May 2007 and reached its recruitment in August 2011. Women with stage T1-3N0M0 or T1-2N1M0 breast cancer completely resected by tumorectomy (BCS) or by mastectomy (MA) who consented to participate were randomized, according to a prescribed computer-generated randomization schedule, between control arm of CR 25x2 Gy/5 weeks by tangential fields on breast/chest wall, plus supraclavicular-axillary field if node-positive, and sequential boost 8x2 Gy/2 weeks if BCS (cumulative dose 66 Gy/7 weeks), versus experimental TT arm of 15x2.8 Gy/3 weeks, including nodal areas if node-positive and simultaneous integrated boost of 0.6 Gy if BCS (cumulative dose 51 Gy/3 weeks). Outcomes evaluated were the pulmonary and heart function. Comparison of proportions used one-sided Fisher's exact test. Results: By May 2010, 70 patients were randomized and had more than 1 year of follow-up. Out of 69 evaluable cases, 32 were assigned to CR (21 BCS, 11 MA), 37 to TT (20 BCS, 17 MA). Skin toxicity of grade ≥1 at 2 years was 60% in CR, vs. 30% in TT arm. Heart function showed no significant difference for left ventricular ejection fraction at 2 years, CR 4.8% vs. TT 4.6%. Pulmonary function tests at 2 years showed grade ≥1 decline of FEV1 in 21% of CR, vs. 15% of TT and decline of DLco in 29% of CR, vs. 7% of TT (P = 0.05). Conclusions: There were no unexpected severe toxicities. Short course radiotherapy of the breast with simultaneous integrated boost over 3 weeks proved feasible without excess toxicities. Pulmonary tests showed a slight trend in favor of Tomotherapy, which will need confirmation with longer follow-up of patients. [ABSTRACT FROM AUTHOR]

Background: Health-related quality of life (HRQOL) assessment is a key component of clinical oncology trials.However, few breast cancer trials comparing adjuvant conventional radiotherapy (CR) and hypofractionatedtomotherapy (TT) have investigated HRQOL. We compared HRQOL in stage I-II breast cancer patients who were randomized to receive either CR or TT. Tomotherapy uses an integrated computed tomography scanner to improve treatment accuracy, aiming to reduce the adverse effects of radiotherapy.Methods: A total of 121 stage I–II breast cancer patients who had undergone breast conserving surgery (BCS) or mastectomy (MA) were randomly assigned to receive either CR or TT. CR patients received 25 × 2 Gy over 5 weeks,and BCS patients also received a sequential boost of 8 × 2 Gy over 2 weeks. TT patients received 15 × 2.8 Gy over 3weeks, and BCS patients also received a simultaneous integrated boost of 15 × 0.6 Gy over 3 weeks. Patients completed the EORTC QLQ-C30 and BR23 questionnaires. The mean score (± standard error) was calculated at baseline, the end of radiotherapy, and at 3 months and 1, 2, and 3 years post-radiotherapy. Data were analyzed by the 'intention-to-treat' principle.Results: On the last day of radiotherapy, patients in both treatment arms had decreased global health status and functioning scores; increased fatigue (clinically meaningful in both treatment arms), nausea and vomiting, and constipation; decreased arm symptoms; clinically meaningful increased breast symptoms in CR patients and systemic side effects in TT patients; and slightly decreased body image and future perspective.At 3 months post-radiotherapy, TT patients had a clinically significant increase in role- and social-functioning scores and a clinically significant decrease in fatigue. The post-radiotherapy physical-, cognitive- and emotional-functioning scores improved faster in TT patients than CR patients. TT patients also had a better long-term recovery from fatigue than CR patients. ANOVA with the Bonferroni correction did not show any significant differences between groups in HRQOL scores.Conclusions: TT patients had a better improvement in global health status and role- and cognitive-functioning,and a faster recovery from fatigue, than CR patients. These results suggest that a shorter fractionation schedule may reduce the adverse effects of treatment. [ABSTRACT FROM AUTHOR]

Background: Scapula alata (SA) is a known complication of breast surgery associated with palsy of the serratus anterior, but it is seldom mentioned. We evaluated the risk factors associated with SA and the relationship of SA with ipsilateral shoulder/arm morbidity in a series of patients enrolled in a trial of post-surgery radiotherapy (RT). Methods: The trial randomized women with completely resected stage I-II breast cancer to short-course image-guided RT, versus conventional RT. SA, arm volume and shoulder-arm mobility were measured prior to RT and at one to three months post-RT. Shoulder/arm morbidities were computed as a post-RT percentage change relative to pre-RT measurements. Results: Of 119 evaluable patients, 13 (= 10.9%) had pre-RT SA. Age younger than 50 years old, a body mass index less than 25 kg/m2, and axillary lymph node dissection were significant risk factors, with odds ratios of 4.8 (P=0.009), 6.1 (P = 0.016), and 6.1 (P = 0.005), respectively. Randomization group was not significant. At one to three months' post-RT, mean arm volume increased by 4.1% (P = 0.036) and abduction decreased by 8.6% (P = 0.046) among SA patients, but not among non-SA patients. SA resolved in eight, persisted in five, and appeared in one patient. Conclusion: The relationship of SA with lower body mass index suggests that SA might have been underestimated in overweight patients. Despite apparent resolution of SA in most patients, pre-RT SA portended an increased risk of shoulder/arm morbidity. We argue that SA warrants further investigation. Incidentally, the observation of SA occurring after RT in one patient represents the second case of post-RT SA reported in the literature. [ABSTRACT FROM AUTHOR]

Purpose: In routine practice, the tumor response in head-and-neck cancer (HNC) is assessed 3–4 months after radiotherapy (RT). We compared the results of fluorodeoxyglucose-positron emission tomography (FDG-PET) during (47 Gy) and 4 months after RT. Methods and Materials: In 40 patients with HNC, PET was performed before (PET1), at the end of Week 4 (47 Gy) (PET2), and 4 months after RT (PET3). Visual analysis classified patients as having a complete response (CR) or a non-CR (NCR). The sensitivity, specificity, accuracy, negative predictive value, and positive predictive value for PET2 and PET3 were determined. The 2-year overall survival (OS) rate for a CR and NCR was calculated for both response evaluation points. Results: After a median follow-up of 26 months, 10 patients had died, 6 had residual disease, and 24 remained disease free. The overall sensitivity, specificity, negative predictive value, positive predictive value, and accuracy of PET2 vs. PET3 for the detection of a CR was 28.6%, 81.8%, 31.0%, 80.0%, and 42.5% vs. 78.6%, 75.0%, 60.0%, 88.0%, and 77.5%, respectively. The 2-year OS rate determined at 47 Gy was 90.0% and 71.8% for a CR and NCR, respectively, and did not appear to be significantly different (p = .50). For the study, at 4 months, the OS was significantly better in the CR group (91.8%) than in the NCR group (49.9%; p = .0055). Conclusion: The high specificity and positive predictive value for the evaluation of tumor response with PET2 and PET3 might avoid unnecessary salvage surgery in patients with a CR. In contrast to PET3, the sensitivity of PET 2 was low, and the difference in OS between the CR and NCR groups was not significantly different. Therefore, the evaluation of the tumor response with FDG-PET at 4 months after RT completion cannot be replaced by FDG-PET during RT at 47 Gy. [ABSTRACT FROM AUTHOR]

Purpose: To assess the predictive or comparative value of volumetric changes, measured on daily megavoltage computed tomography during radiotherapy for lung cancer. Patients and Methods: We included 80 patients with locally advanced non–small-cell lung cancer treated with image-guided intensity-modulated radiotherapy. The radiotherapy was combined with concurrent chemotherapy, combined with induction chemotherapy, or given as primary treatment. Patients entered two parallel studies with moderately hypofractionated radiotherapy. Tumor volume contouring was done on the daily acquired images. A regression coefficient was derived from the volumetric changes on megavoltage computed tomography, and its predictive value was validated. Logarithmic or polynomial fits were applied to the intratreatment changes to compare the different treatment schedules radiobiologically. Results: Regardless of the treatment type, a high regression coefficient during radiotherapy predicted for a significantly prolonged cause-specific local progression free-survival (p = 0.05). Significant differences were found in the response during radiotherapy. The significant difference in volumetric treatment response between radiotherapy with concurrent chemotherapy and radiotherapy plus induction chemotherapy translated to a superior long-term local progression-free survival for concurrent chemotherapy (p = 0.03). An enhancement ratio of 1.3 was measured for the used platinum/taxane doublet in comparison with radiotherapy alone. Conclusion: Contouring on daily megavoltage computed tomography images during radiotherapy enabled us to predict the efficacy of a given treatment. The significant differences in volumetric response between treatment strategies makes it a possible tool for future schedule comparison. [ABSTRACT FROM AUTHOR]

Purpose: Validation of a prospective, risk-adapted strategy for early-stage non–small-cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT). Methods and Materials: Patients with a T1–3N0M0 (American Joint Committee on Cancer 6th edition) NSCLC were accrued. Using the Radiation Therapy Oncology Group definition, patients were treated to a total dose of 60,Gy in three fractions for peripherally located lesions and four fractions for centrally located lesions. The primary endpoint was toxicity, graded according to the Radiation Therapy Oncology Group acute and late morbidity scoring system, and the National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0. Secondary endpoints were local control and survival. Results: A total of 40 patients were included, 17 with a centrally located lesion. The lung toxicity-free survival estimate at 2 years was 74% and was related to the location (central vs. peripheral) and the size of the target volume. No dose volumetric parameters could predict the occurrence of lung toxicity. One patient died because of treatment-related toxicity. The 1-year and 2-year local progression-free survival estimates were 97% and 84%, respectively, and were related to stage (T1 vs. T2) related (p = 0.006). Local failure was not more frequent for patients treated in four fractions. The 1-year local progression-free survival estimate dropped below 80% for lesions with a diameter of more than 4 cm. Conclusion: The proposed risk-adapted strategy for both centrally and peripherally located lesions showed an acceptable toxicity profile while maintaining excellent local control rates. The correlation between local control and tumor diameter calls for the inclusion of tumor stage as a variable in future study design. [ABSTRACT FROM AUTHOR]

Purpose: Morphologic imaging techniques perform poorly in assessing the response to preoperative radiotherapy (RT), mainly because of desmoplastic reactions. The aim of this study was to investigate the potential of sequential 18-fluoro-2-deoxy-d-glucose (18FDG-PET) in assessing the response of rectal cancer to neoadjuvant RT and to determine which parameters can be used as surrogate markers for histopathologic response. Methods and Materials: 18FDG-PET scans were acquired before and during the 5th week after the end of RT. Tracer uptake was assessed semiquantitatively using standardized uptake values (SUV). The percentage differences (%Δ) between pre- and post-RT scans in SUVmax, SUVmean, metabolic volume (MV), and total glycolytic volume (tGV) were calculated. Results: Forty-five consecutive patients with histologically confirmed rectal adenocarcinoma were enrolled. After neoadjuvant RT, 20 of the 45 patients were classified as histopathologic responders and 25 as non-responders. Intense 18F-FDG uptake was seen in all tumors before neoadjuvant RT (average SUVmax 12.9 ± 6.0). When patients were classified as histologic responders and nonresponders, significant differences in %ΔSUVmax (55.8% vs. 37.4%, p = 0.023) and %ΔSUVmean (40.1% vs. 21.0%, p = 0.001) were observed between the two groups. For %ΔMV and %ΔtGV, decreases were more prominent in responders but were not significantly different from those in nonresponders. As demonstrated by receiver operating characteristic analysis, %ΔSUVmean was a more powerful discriminator than was %ΔSUVmax. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for optimal threshold of %ΔSUVmean (24.5%) were 80%, 72%, 76%, 70%, and 82% respectively. Conclusion: Sequential 18FDG-PET allows assessment of the response to preoperative RT. Both %ΔSUVmean and %ΔSUVmax correlate with histopathologic response and can be used to evaluate and compare the effectiveness of different neoadjuvant treatment strategies. The maximum accuracy figures and the positive predictive value figures for both Δ%SUVmean and Δ%SUVmax are, however, too low to justify modification of the standard treatment protocol of an individual patient. [Copyright &y& Elsevier]

Abstract: Purpose: VERO is a novel platform for image guided stereotactic body radiotherapy. Orthogonal gimbals hold the linac-MLC assembly allowing real-time moving tumor tracking. This study determines the geometric accuracy of the tracking. Materials and methods: To determine the tracking error, an 1D moving phantom produced sinusoidal motion with frequencies up to 30 breaths per minute (bpm). Tumor trajectories of patients were reproduced using a 2D robot and pursued with the gimbals tracking system prototype. Using the moving beam light field and a digital-camera-based detection unit tracking errors, system lag and equivalence of pan/tilt performance were measured. Results: The system lag was 47.7ms for panning and 47.6ms for tilting. Applying system lag compensation, sinusoidal motion tracking was accurate, with a tracking error 90% percentile E 90% <0.82mm and similar performance for pan/tilt. Systematic tracking errors were below 0.14mm. The 2D tumor trajectories were tracked with an average E 90% of 0.54mm, and tracking error standard deviations of 0.20mm for pan and 0.22mm for tilt. Conclusions: In terms of dynamic behavior, the gimbaled linac of the VERO system showed to be an excellent approach for providing accurate real-time tumor tracking in radiation therapy. [Copyright &y& Elsevier]

Summary: Background: We did a randomised phase 3 trial assessing the benefit of addition of long-term androgen suppression with a luteinising-hormone-releasing hormone (LHRH) agonist to external irradiation in patients with prostate cancer with high metastatic risk. In this report, we present the 10-year results. Methods: For this open-label randomised trial, eligible patients were younger than 80 years and had newly diagnosed histologically proven T1–2 prostatic adenocarcinoma with WHO histological grade 3 or T3–4 prostatic adenocarcinoma of any histological grade, and a WHO performance status of 0–2. Patients were randomly assigned (1:1) to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. Treatment allocation was open label and used a minimisation algorithm with institution, clinical stage of the disease, results of pelvic-lymph-node dissection, and irradiation fields extension as minimisation factors. Patients were irradiated externally, once a day, 5 days a week, for 7 weeks to a total dose of 50 Gy to the whole pelvis, with an additional 20 Gy to the prostate and seminal vesicles. The LHRH agonist, goserelin acetate (3·6 mg subcutaneously every 4 weeks), was started on the first day of irradiation and continued for 3 years; cyproterone acetate (50 mg orally three times a day) was given for 1 month starting a week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analysis was by intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00849082. Findings: Between May 22, 1987, and Oct 31, 1995, 415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9·1 years (IQR 5·1–12·6). 10-year clinical disease-free survival was 22·7% (95% CI 16·3–29·7) in the radiotherapy-alone group and 47·7% (39·0–56·0) in the combined treatment group (hazard ratio [HR] 0·42, 95% CI 0·33–0·55, p<0·0001). 10-year overall survival was 39·8% (95% CI 31·9–47·5) in patients receiving radiotherapy alone and 58·1% (49·2–66·0) in those allocated combined treatment (HR 0·60, 95% CI 0·45–0·80, p=0·0004), and 10-year prostate-cancer mortality was 30·4% (95% CI 23·2–37·5) and 10·3% (5·1–15·4), respectively (HR 0·38, 95% CI 0·24–0·60, p<0·0001). No significant difference in cardiovascular mortality was noted between treatment groups both in patients who had cardiovascular problems at study entry (eight of 53 patients in the combined treatment group had a cardiovascular-related cause of death vs 11 of 63 in the radiotherapy group; p=0·60) and in those who did not (14 of 154 vs six of 145; p=0·25). Two fractures were reported in patients allocated combined treatment. Interpretation: In patients with prostate cancer with high metastatic risk, immediate androgen suppression with an LHRH agonist given during and for 3 years after external irradiation improves 10-year disease-free and overall survival without increasing late cardiovascular toxicity. Funding: AstraZeneca; Ligue Nationale Contre le Cancer (France), through the EORTC Charitable Trust. [Copyright &y& Elsevier]