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Background: Evaluation of delivered dose to the dominant intraprostatic lesion (DIL) for moderately hypofractionated radiotherapy of prostate cancer by cone beam computed tomography (CBCT)-based dose accumulation and target coverage analysis.Methods: Twenty-three patients with localized prostate cancer treated with moderately hypofractionated prostate radiotherapy with simultaneous integrated boost (SIB) between December 2016 and February 2020 were retrospectively analyzed. Included patients were required to have an identifiable DIL on bi-parametric planning magnetic resonance imaging (MRI). After import into the RayStation treatment planning system and application of a step-wise density override, the fractional doses were computed on each CBCT and were consecutively mapped onto the planning CT via a deformation vector field derived from deformable image registration. Fractional doses were accumulated for all CBCTs and interpolated for missing CBCTs, resulting in the delivered dose for PTVDIL, PTVBoost, PTV, and the organs at risk. The location of the index lesions was recorded according to the sector map of the Prostate Imaging Reporting and Data System (PIRADS) Version 2.1. Target coverage of the index lesions was evaluated and stratified for location.Results: In total, 338 CBCTs were available for analysis. Dose accumulation target coverage of PTVDIL, PTVBoost, and PTV was excellent and no cases of underdosage in DMean, D95%, D02%, and D98% could be detected. Delivered rectum DMean did not significantly differ from the planned dose. Bladder mean DMean was higher than planned with 19.4 ± 7.4 Gy versus 18.8 ± 7.5 Gy, p < 0.001. The penile bulb showed a decreased delivered mean DMean with 29.1 ± 14.0 Gy versus 29.8 ± 14.4 Gy, p < 0.001. Dorsal DILs, defined as DILs in the posterior medial peripheral zone of the prostate, showed a significantly lower delivered dose with a mean DMean difference of 2.2 Gy (95% CI 1.3-3.1 Gy, p < 0.001) compared to ventral lesions.Conclusions: CBCT-based dose accumulation showed an adequate delivered dose to the dominant intraprostatic lesion and organs at risk within planning limits. Cautious evaluation of the target coverage for index lesions adjacent to the rectum is warranted to avoid underdosage. [ABSTRACT FROM AUTHOR]

Purpose: To compare radiotherapy plans between an O‐ring and a conventional C‐arm linac for hypofractionated high‐dose prostate radiotherapy in terms of plan quality, dose distribution, and quality assurance in a multi‐vendor environment. Methods: Twenty prostate cancer treatment plans were irradiated on the O‐ring Varian Halcyon linac and were re‐optimized for the C‐arm Elekta Synergy Agility linac. Dose‐volume histogram metrics for target coverage and organ at risk dose, quality assurance, and monitor units were retrospectively compared. Patient‐specific quality assurance with ion chamber measurements, gamma index analysis, and portal dosimetry was performed using the Varian Portal Dosimetry system and the ArcCHECK® phantom (Sun Nuclear Corporation). Prostate‐only radiotherapy was delivered with simultaneous integrated boost (SIB) volumetric modulated arc therapy (VMAT) in 20 fractions of 2.5/3.0 Gy each. Results: For both linacs, target coverage was excellent and plan quality comparable. Homogeneity in PTVBoost was high for Synergy as well as Halcyon with a mean homogeneity index of 0.07 ± 0.01 and 0.05 ± 0.01, respectively. Mean dose for the organs at risk rectum and bladder differed not significantly between the linacs but were higher for the femoral heads and penile bulb for Halcyon. Quality assurance showed no significant differences in terms of ArcCHECK gamma pass rates. Median pass rate for 3%/2 mm was 99.3% (96.7 to 99.8%) for Synergy and 99.8% (95.6 to 100%) for Halcyon. Agreement between calculated and measured dose was high with a median deviation of −0.6% (−1.7 to 0.8%) for Synergy and 0.2% (−0.6 to 2.3%) for Halcyon. Monitor units were higher for the Halcyon by approximately 20% (p < 0.001). Conclusion: Hypofractionated high‐dose prostate cancer SIB VMAT on the Halcyon system is feasible with comparable plan quality in reference to a standard C‐arm Elekta Synergy linac. [ABSTRACT FROM AUTHOR]

Background: In head and neck cancer little is known about the kinetics of osteopontin (OPN) expression after tumor resection. In this study we evaluated the time course of OPN plasma levels before and after surgery.Methods: Between 2011 and 2013 41 consecutive head and neck cancer patients were enrolled in a prospective study (group A). At different time points plasma samples were collected: T0) before, T1) 1 day, T2) 1 week and T3) 4 weeks after surgery. Osteopontin and TGFβ1 plasma concentrations were measured with a commercial ELISA system. Data were compared to 131 head and neck cancer patients treated with primary (n = 42) or postoperative radiotherapy (n = 89; group B1 and B2).Results: A significant OPN increase was seen as early as 1 day after surgery (T0 to T1, p < 0.01). OPN levels decreased to base line 3-4 weeks after surgery. OPN values were correlated with postoperative TGFβ1 expression suggesting a relation to wound healing. Survival analysis showed a significant benefit for patients with lower OPN levels both in the primary and postoperative radiotherapy group (B1: 33 vs 11.5 months, p = 0.017, B2: median not reached vs 33.4, p = 0.031). TGFβ1 was also of prognostic significance in group B1 (33.0 vs 10.7 months, p = 0.003).Conclusions: Patients with head and neck cancer showed an increase in osteopontin plasma levels directly after surgery. Four weeks later OPN concentration decreased to pre-surgery levels. This long lasting increase was presumably associated to wound healing. Both pretherapeutic osteopontin and TGFβ1 had prognostic impact. [ABSTRACT FROM AUTHOR]

Purpose: Advance directives (AD) are becoming increasingly widespread. We examine the prevalence of AD and the factors associated with AD in tumor patients during radiotherapy. Methods: A standardized questionnaire was handed out to all tumor patients on 9 random days with an interval of at least 12 weeks. The data were analyzed in a bivariate and multivariate way. Results: Of 1,208 questionnaires, 658 were completed and returned (54.5%). Of respondents, 23.6% had already signed an AD, 53.3% thought they were likely to sign an AD, 9.0% did not want to sign an AD, and 4.9% were not familiar with advance directives. Patients who have signed an AD and those who are likely to sign one think that ADs facilitate the physician's decision-making process (97.7% cf. 94.5%) and that they ease the burden on relatives (98.5% cf. 98.8%). Regardless of an AD having been signed, every second respondent was of the opinion that AD facilitates consultations rather than serving as a directive (55.1% cf. 57.3%). Patients likely to sign an AD are significantly younger compared to those unlikely to do so and have suffered from their tumor disease for a shorter period of time. Conclusions: Of advance directives is widely accepted among the tumor patients surveyed. Advanced directives are not exclusively seen as instruments for surrogate decision making, but also as mediums to improve communication. Training of physicians and additional offers for patients could increase the actual number of ADs and perhaps improve physicians and relatives understanding of patients needs and wishes. [ABSTRACT FROM AUTHOR]

Purpose: Single or few arc intensity-modulated arc therapy (IMAT) is intended to be a time saving irradiation method, potentially replacing classical intensity-modulated radiotherapy (IMRT). The aim of this work was to evaluate the quality of different IMAT methods with the potential of fast delivery, which also has the possibility of adapting to the daily shape of the target volume. Methods: A planning study was performed. Novel double and triple IMAT techniques based on the geometrical analysis of the target organ at risk geometry (2-step IMAT) were evaluated. They were compared to step and shoot IMRT reference plans generated using direct machine parameter optimization (DMPO®). Volumetric arc (VMAT) plans from commercial preclinical software (SMARTARC®) were used as an additional benchmark to classify the quality of the novel techniques. Four cases with concave planning target volumes (PTV) with one dominating organ at risk (OAR), viz., the PTV/OAR combination of the ESTRO Quasimodo phantom, breast/lung, spine metastasis/spinal cord, and prostate/rectum, were used for the study. The composite objective value (COV) and other parameters representing the plan quality were studied. Results: The novel 2-step IMAT techniques with geometry based segment definition were as good as or better than DMPO® and were superior to the SMARTARC® VMAT techniques. For the spine metastasis, the quality measured by the COV differed only by 3%, whereas the COV of the 2-step IMAT for the other three cases decreased by a factor of 1.4-2.4 with respect to the reference plans. Conclusions: Rotational techniques based on geometrical analysis of the optimization problem (2-step IMAT) provide similar or better plan quality than DMPO® or the research version of SMARTARC® VMAT variants. The results justify pursuing the goal of fast IMAT adaptation based on 2-step IMAT techniques. [ABSTRACT FROM AUTHOR]

Background: To introduce a novel method of patient positioning for high precision intracranial radiotherapy. Methods: An infrared(IR)-array, reproducibly attached to the patient via a vacuum-mouthpiece(vMP) and connected to the table via a 6 degree-of-freedom(DoF) mechanical arm serves as positioning and fixation system. After IR-based manual prepositioning to rough treatment position and fixation of the mechanical arm, a cone-beam CT(CBCT) is performed. A robotic 6 DoF treatment couch (HexaPOD™) then automatically corrects all remaining translations and rotations. This absolute position of infrared markers at the first fraction acts as reference for the following fractions where patients are manually prepositioned to within ± 2 mm and ± 2° of this IR reference position prior to final HexaPOD-based correction; consequently CBCT imaging is only required once at the first treatment fraction. The preclinical feasibility and attainable repositioning accuracy of this method was evaluated on a phantom and human volunteers as was the clinical efficacy on 7 pilot study patients. Results: Phantom and volunteer manual IR-based prepositioning to within ± 2 mm and ± 2° in 6DoF was possible within a mean(± SD) of 90 ± 31 and 56 ± 22 seconds respectively. Mean phantom translational and rotational precision after 6 DoF corrections by the HexaPOD was 0.2 ± 0.2 mm and 0.7 ± 0.8° respectively. For the actual patient collective, the mean 3D vector for inter-treatment repositioning accuracy (n = 102) was 1.6 ± 0.8 mm while intra-fraction movement (n = 110) was 0.6 ± 0.4 mm. Conclusions: This novel semi-automatic 6DoF IR-based system has been shown to compare favourably with existing non-invasive intracranial repeat fixation systems with respect to handling, reproducibility and, more importantly, intrafraction rigidity. Some advantages are full cranial positioning flexibility for single and fractionated IGRT treatments and possibly increased patient comfort. [ABSTRACT FROM AUTHOR]

Background: The dose distribution to the rectum, delineated as solid organ, rectal wall and rectal surface, in 3D conformal (3D-CRT) and intensity-modulated radiotherapy treatment (IMRT) planning for localized prostate cancer was evaluated. Materials and methods: In a retrospective planning study 3-field, 4-field and IMRT treatment plans were analyzed for ten patients with localized prostate cancer. The dose to the rectum was evaluated based on dose-volume histograms of 1) the entire rectal volume (DVH) 2) manually delineated rectal wall (DWH) 3) rectal wall with 3 mm wall thickness (DWH3) 4) and the rectal surface (DSH). The influence of the rectal filling and of the seminal vesicles' anatomy on these dose parameters was investigated. A literature review of the dose-volume relationship for late rectal toxicity was conducted. Results: In 3D-CRT (3-field and 4-field) the dose parameters differed most in the mid-dose region: the DWH showed significantly lower doses to the rectum (8.7% ± 4.2%) compared to the DWH3 and the DSH. In IMRT the differences between dose parameters were larger in comparison with 3D-CRT. Differences were statistically significant between DVH and all other dose parameters and between DWH and DSH. Mean doses were increased by 23.6% ± 8.7% in the DSH compared to the DVH in the mid-dose region. Furthermore, both the rectal filling and the anatomy of the seminal vesicles influenced the relationship between the dose parameters: a significant correlation of the difference between DVH and DWH and the rectal volume was seen in IMRT treatment. Discussion: The method of delineating the rectum significantly influenced the dose representation in the dose-volume histogram. This effect was pronounced in IMRT treatment planning compared to 3D-CRT. For integration of dose-volume parameters from the literature into clinical practice these results have to be considered. [ABSTRACT FROM AUTHOR]

An investigation of the effect of tumor volume and total dose on local control following primary radiotherapy for nasopharyngeal carcinoma was carried out in order to estimate the radiation dose necessary to control a specific tumor volume. Between 1983 and 1996 a total of 104 patients underwent radiation therapy for nasopharyngeal carcinoma at the Department of Radiation Oncology of the University of Wuerzburg. Total doses of between 8 and 80 Gy (5 fractions per week) were administered. Complete CT-data on primary tumor size, total tumor dose (calculated by 3D- or quasi 3D-CT-based radiation planning computer) and on local control status in the follow-up period were available for 63 patients. Lymph node metastases were present in 38 of these patients and they were also entered into the study. Thus this study is based on a total of 101 tumor regions. A Poisson probability-based model was used for calculating the dose-response relationship. Assuming a correlation between tumor volume and the total dose necessary to obtain local control, the individual tumor volumes were rescaled to a 1 ml volume by introducing a volume-dependent modification factor for the applied dose, in order to eliminate the influence of different individual tumor volumes. All dose values given are based on a fractionation scheme of 2 Gy single dose, 5 fractions per week. Nineteen tumors and 11 lymph nodes were considered locally uncontrolled or recurrent. Without dose-volume modification, a weak dose-response correlation was found and a typical shallow dose-response curve was calculated with a 50% response dose (RD50) of 60.2 Gy and a normalized dose-response gradient (γ50) of 3.2±0.62. After dose-volume modification and rescaling to a 1 ml tumor volume, a steep dose-response curve with an RD50 of 40.9 Gy and γ50 of 8.2. was found. Tumor volume is a very important factor influencing local control in nasopharyngeal carcinoma. The rescaling procedure to a reference volume of 1 ml used in this study revealed a very steep dose-response relationship. This result suggests that the clinically observed smooth dose-response relationships may be explained by interindividual tumor volume heterogeneity. The additional dose necessary to control a tumor of the double volume is close to 5 Gy. With a total dose of 72 Gy (5×2 Gy/week), tumor volumes larger than 64 ml are unlikely to be controlled. [ABSTRACT FROM AUTHOR]

• Recommendations for risk-mitigation pandemic scenario: • Do not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. • Postponement or interruption of radiotherapy of COVID-19 positive patients is generally recommended Severe pandemic scenario characterized by reduced resources: • Factors for patient triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic. For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk–benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC. In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided. This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Purpose: Most radiobiological models for prediction of tumor control probability (TCP) do not account for the fact that many events could remain unobserved because of censoring. We therefore evaluated a set of TCP models that take into account this censoring.Methods and Materials: We applied 2 fundamental Bayesian cure rate models to a sample of 770 pulmonary metastasis treated with stereotactic body radiation therapy at German, Austrian, and Swiss institutions: (1) the model developed by Chen, Ibrahim and Sinha (the CIS99 model); and (2) a mixture model similar to the classic model of Berkson and Gage (the BG model). In the CIS99 model the number of clonogens surviving the radiation treatment follows a Poisson distribution, whereas in the BG model only 1 dominant recurrence-competent tissue mass may remain. The dose delivered to the isocenter, tumor size and location, sex, age, and pretreatment chemotherapy were used as covariates for regression.Results: Mean follow-up time was 15.5 months (range: 0.1-125). Tumor recurrence occurred in 11.6% of the metastases. Delivered dose, female sex, peripheral tumor location and having received no chemotherapy before RT were associated with higher TCP in all models. Parameter estimates of the CIS99 were consistent with the classical Cox proportional hazards model. The dose required to achieve 90% tumor control after 15.5 months was 146 (range: 114-188) Gy10 in the CIS99 and 133 (range: 101-164) Gy10 in the BG model; however, the BG model predicted lower tumor control at long (≳20 months) follow-up times and gave a suboptimal fit to the data compared to the CIS99 model.Conclusions: Biologically motivated cure rate models allow adding the time component into TCP modeling without being restricted to the follow-up period which is the case for the Cox model. In practice, application of such models to the clinical setting could allow for adaption of treatment doses depending on whether local control should be achieved in the short or longer term. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT ) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). Materials and methods: This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1–8) and median single fraction dose was 12.5Gy (2.9–33Gy); dose was prescribed to the median 65% PTV encompassing isodose (60–100%). Assuming an α/β-value of 10Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). Results: There was strong evidence for a dose–response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT ) at 11Gy (68% CI 8–14Gy) or 22Gy (14–42Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p =0.07, BF=2.1 and p =0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose–response relationships than PTV encompassing doses (BFs>20). Conclusion: Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate long-term quality-of-life (QoL) after neoadjuvant short-course radiotherapy (SC-RT) and long-course radiochemotherapy (LC-RCHT) for locally advanced rectal cancer. Methods: Between 1999 and 2008, 225 patients were treated with curative intent for locally advanced rectal cancer using neoadjuvant SC-RT (n =108) or LC-RCHT (n =117). SC-RT delivered 10×2.9Gy twice daily with immediate surgery. LC-RCHT delivered 28×1.8Gy concomitant with 5-FU based chemotherapy and delayed surgery. A cross-sectional QoL analysis was performed in disease-free patients using the EORTC-QLQ-C30 and EORTC-QLQ-CR29 questionnaires. Results: After a median follow-up of 67months, 133 patients were disease-free of which 120 (90%) returned the QoL questionnaires. Patients in the LC-RCHT cohort had a higher rate of uT4, uN+ and low tumor location. No difference in QoL was observed between SC-RT and LC-RCHT except an improved physical functioning in the LC-RCHT group (p =0.04). Comparing our total patient cohort with the general German population showed no difference in global health status but decreased QoL in several functional and bowel symptom scores. Conclusions: The finding of comparable long-term QoL after SC-RT and LC-RCHT adds to our knowledge of equivalent oncological outcome and may be useful in the decision making process between the two neoadjuvant approaches. [Copyright &y& Elsevier]

Abstract: HIF-1α regulated genes are mainly responsible for tumour resistance to radiation- and chemo-therapy. Among these genes, carbonic anhydrase isoform IX (CA9) is highly over expressed in many types of cancer especially in high grade brain cancer like Glioblastoma (GBM). Inhibition of the enzymatic activity by application of specific chemical CA9 inhibitor sulphonamides (CAI) like Acetazolamide (Aza.), the new sulfonamide derivative carbonic anhydrase inhibitor (SU.D2) or indirect inhibitors like the HIF-1α inhibitor Chetomin or molecular inhibitors like CA9-siRNA are leading to an inhibition of the functional role of CA9 during tumorigenesis. Human GBM cells were treated with in vitro hypoxia (1, 6, or 24h at 0.1%, O2). Aza. application was at a range between 250 and 8000nM and the HIF-1α inhibitor Chetomin at a concentration range of 150–500nM. Cell culture plates were incubated for 24h under hypoxia (0.1% O2). Further, CA9-siRNA constructs were transiently transfected into GBM cells exposed to extreme hypoxic aeration conditions. CA9 protein expression level was detectable in a cell-type specific manner under normoxic conditions. Whereas U87-MG exhibited a strong aerobic expression, U251 and U373 displayed moderate and GaMG very weak normoxic CA9 protein bands. Aza. as well as SU.D2 displayed inhibitory characteristics to hypoxia induced CA9 expression in the four GBM cell lines for 24h of hypoxia (0.1% O2) at concentrations between 3500 and 8000nM, on both the protein and mRNA level. Parallel experiments using CA9-siRNA confirmed these results. Application of 150–500nM of the glycolysis inhibitor Chetomin under similar oxygenation conditions led to a sharply reduced expression of both CA IX protein and CA9 mRNA levels, indicating a clear glucose availability involvement for the hypoxic HIF-1α and CA9 expression in GBM cells. Hypoxia significantly influences the behaviour of human tumour cells by activation of genes involved in the adaptation to hypoxic stress. The main objective in malignant GBM therapy is either to eradicate the tumour or to convert it into a controlled, quiescent chronic disease. Aza., SU.D2, Chetomin or CA9-siRNA possesses functional CA9 inhibitory characteristics when applied against human cancers with hypoxic regions like GBM. They may be used as alternative or in conjunction with other direct inhibitors possessing similar functionality, thereby rendering them as potential optimal tools for the development of an optimized therapy in human brain cancer treatment. [Copyright &y& Elsevier]

Purpose: To evaluate the accuracy of real-time couch tracking for prostate cancer. Methods and Materials: Intrafractional motion trajectories of 15 prostate cancer patients were the basis for this phantom study; prostate motion had been monitored with the Calypso System. An industrial robot moved a phantom along these trajectories, motion was detected via an infrared camera system, and the robotic HexaPOD couch was used for real-time counter-steering. Residual phantom motion during real-time tracking was measured with the infrared camera system. Film dosimetry was performed during delivery of 3-dimensional conformal radiation therapy (3D-CRT), step-and-shoot intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT). Results: Motion of the prostate was largest in the anterior–posterior direction, with systematic (∑) and random (σ) errors of 2.3 mm and 2.9 mm, respectively; the prostate was outside a threshold of 5 mm (3D vector) for 25.0%±19.8% of treatment time. Real-time tracking reduced prostate motion to ∑=0.01 mm and σ = 0.55 mm in the anterior–posterior direction; the prostate remained within a 1-mm and 5-mm threshold for 93.9%±4.6% and 99.7%±0.4% of the time, respectively. Without real-time tracking, pass rates based on a γ index of 2%/2 mm in film dosimetry ranged between 66% and 72% for 3D-CRT, IMRT, and VMAT, on average. Real-time tracking increased pass rates to minimum 98% on average for 3D-CRT, IMRT, and VMAT. Conclusions: Real-time couch tracking resulted in submillimeter accuracy for prostate cancer, which transferred into high dosimetric accuracy independently of whether 3D-CRT, IMRT, or VMAT was used. [ABSTRACT FROM AUTHOR]

Purpose: The recognition of the true prevalence of cardiac toxicity after mediastinal radiotherapy requires very long follow-up and a precise diagnostic procedure. Cardiac magnetic resonance imaging (MRI) permits excellent quantification of cardiac function and identification of localized myocardial defects and has now been applied to a group of 20-year Hodgkin''s disease survivors. Methods and materials: Of 143 patients treated with anterior mediastinal radiotherapy (cobalt-60, median prescribed dose 40 Gy) for Hodgkin''s disease between 1978 and 1985, all 53 survivors were invited for cardiac MRI. Of those, 36 patients (68%) presented for MRI, and in 31 patients (58%) MRI could be performed 20–28 years (median, 24) after radiotherapy. The following sequences were acquired on a 1.5-T MRI: transversal T1-weighted TSE and T2-weighted half-fourier acquisition single-shot turbo-spin-echo sequences, a steady-state free precession (SSFP) cine sequence in the short heart axis and in the four-chamber view, SSFP perfusion sequences under rest and adenosine stress, and a SSFP inversion recovery sequence for late enhancement. The MRI findings were correlated with previously reconstructed doses to cardiac structures. Results: Clinical characteristics and reconstructed doses were not significantly different between survivors undergoing and not undergoing MRI. Pathologic findings were reduced left ventricular function (ejection fraction <55%) in 7 (23%) patients, hemodynamically relevant valvular dysfunction in 13 (42%), late myocardial enhancement in 9 (29%), and any perfusion deficit in 21 (68%). An association of regional pathologic changes and reconstructed dose to cardiac structures could not be established. Conclusions: In 20-year survivors of Hodgkin''s disease, cardiac MRI detects pathologic findings in approximately 70% of patients. Cardiac MRI has a potential role in cardiac imaging of Hodgkin''s disease patients after mediastinal radiotherapy. [Copyright &y& Elsevier]

Purpose: To evaluate the potential of adaptive radiotherapy (ART) for advanced-stage non–small cell lung cancer (NSCLC) in terms of lung sparing and dose escalation. Methods and Materials: In 13 patients with locally advanced NSCLC, weekly CT images were acquired during radio- (n = 1) or radiochemotherapy (n = 12) for simulation of ART. Three-dimensional (3D) conformal treatment plans were generated: conventionally fractionated doses of 66 Gy were prescribed to the planning target volume without elective lymph node irradiation (Plan_3D). Using a surface-based algorithm of deformable image registration, accumulated doses were calculated in the CT images acquired during the treatment course (Plan_4D). Field sizes were adapted to tumor shrinkage once in week 3 or 5 and twice in weeks 3 and 5. Results: A continuous tumor regression of 1.2% per day resulted in a residual gross tumor volume (GTV) of 49% ± 15% after six weeks of treatment. No systematic differences between Plan_3D and Plan_4D were observed regarding doses to the GTV, lung, and spinal cord. Plan adaptation to tumor shrinkage resulted in significantly decreased lung doses without compromising GTV coverage: single-plan adaptation in Week 3 or 5 and twice-plan adaptation in Weeks 3 and 5 reduced the mean lung dose by 5.0% ± 4.4%, 5.6% ± 2.9% and 7.9% ± 4.8%, respectively. This lung sparing with twice ART allowed an iso–mean lung dose escalation of the GTV dose from 66.8 Gy ± 0.8 Gy to 73.6 Gy ± 3.8 Gy. Conclusions: Adaptation of radiotherapy to continuous tumor shrinkage during the treatment course reduced doses to the lung, allowed significant dose escalation and has the potential of increased local control. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the feasibility and accuracy of a method for markerless tracking of lung tumors in electronic portal imaging device (EPID) movies and to analyze intra- and interfractional variations in tumor motion. Methods and Materials: EPID movies were acquired during stereotactic body radiotherapy (SBRT) given to 40 patients with 49 pulmonary targets and retrospectively analyzed. Tumor visibility and tracking accuracy were determined by three observers. Tumor motion of 30 targets was analyzed in detail via four-dimensional computed tomography (4DCT) and EPID in the superior-inferior direction for intra- and interfractional variations. Results: Tumor visibility was sufficient for markerless tracking in 47% of the EPID movies. Tumor size and visibility in the DRR were correlated with visibility in the EPID images. The difference between automatic and manual tracking was a maximum of 2 mm for 98.3% in the x direction and 89.4% in the y direction. Motion amplitudes in 4DCT images (range, 0.7-17.9 mm; median, 4.9 mm) were closely correlated with amplitudes in the EPID movies. Intrafractional and interfractional variability of tumor motion amplitude were of similar magnitude: 1 mm on average to a maximum of 4 mm. A change in moving average of more than ±1 mm, ±2 mm, and ±4 mm were observed in 47.1%, 17.1%, and 4.5% of treatment time for all trajectories, respectively. Mean tumor velocity was 3.4 mm/sec, to a maximum 61 mm/sec. Conclusions: Tracking of pulmonary tumors in EPID images without implanted markers was feasible in 47% of all treatment beams. 4DCT is representative of the evaluation of mean breathing motion on average, but larger deviations occurred in target motion between treatment planning and delivery effort a monitoring during delivery. [Copyright &y& Elsevier]

Abstract: Purpose: To correlate non-invasively acquired radiobiologically relevant magnetic resonance (MR) parameters with functional histology and tumor control doses (TCD50). Materials and methods: The MR parameters relative perfusion, re-oxygenation and lactate (Lac) concentration from eight human xenograft squamous tumor lines were compared with the histologically acquired pimonidazole hypoxic fraction, the perfused vessel area and TCD50. Results: Good spatial correlation in the parameter maps could be observed between the pimonidazole staining and tumor regions, which can be reoxygenated when breathing carbogen. A strong positive correlation (R =0.74) was found between whole tumor pimonidazole hypoxic fraction and re-oxygenation, as one would expect. A good correlation was also observed between Lac concentration and re-oxygenation (R =0.71) and between TCD50 and re-oxygenation (R =0.64), whereas Lac and TCD50 showed a moderate relation (R =0.44). The in vivo measurement of relative perfusion could be validated to reflect the perfused vessel area (R =0.63). No correlation was detected between perfusion and re-oxygenation or TCD50. Conclusions: Lac and re-oxygenation were shown to be pretreatment predictive markers independent from the pathophysiological changes induced during a fractionated course of radiotherapy. These parameters hold promise to be acquired non-invasively with results just a few minutes after measurement and to tailor radiotherapy to individual patterns of a tumor microenvironment. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate outcome of radiotherapy for locally recurrent cervical and endometrial cancer. Materials and methods: Nineteen patients were treated for a locally recurrent cervical (n =12) or endometrial (n =7) cancer median 26months after initial surgery (n =18) or radiotherapy (n =1). The whole pelvis was irradiated with 50Gy conventionally fractionated radiotherapy (n =16). Because of large size of the recurrent cancer (median 4.5cm) and peripheral location (n =12), stereotactic body radiotherapy (SBRT; median 3 fractions of 5Gy to 65%) was used for local dose escalation instead of (n =16) or combined with (n =3) vaginal brachytherapy. Results: After median follow-up of 22months, 3-year overall survival was 34% with systemic progression the leading cause of death (7/10). Median time to systemic progression was 16months. Three local recurrences resulted in a local control rate of 81% at 3years. No correlation between survival, systemic or local control and any patient or treatment characteristic was observed. The rate of late toxicity>grade II was 25% at 3years: two patients developed a grade IV intestino-vaginal fistula and one patient suffered from a grade IV small bowel ileus. Conclusion: Image-guided SBRT for local dose escalation resulted in high rates of local control but was associated with significant late toxicity. [Copyright &y& Elsevier]

Purpose: To evaluate the outcomes after dose-escalated radiotherapy (RT) for spinal metastases and paraspinal tumors. Methods and Materials: A total of 14 patients, 12 with spinal metastases and a long life expectancy and 2 with paraspinal tumors, were treated for 16 lesions with intensity-modulated, image-guided RT. A median biologic effective dose of 74 Gy10 (range, 55–86) in a median of 20 fractions (range, 3–34) was prescribed to the target volume. The spinal canal was treated to 40 Gy in 20 fractions using a second intensity-modulated RT dose level in the case of epidural involvement. Results: After median follow-up of 17 months, one local recurrence was observed, for an actuarial local control rate of 88% after 2 years. Local control was associated with rapid and long-term pain relief. Of 11 patients treated for a solitary spinal metastasis, 6 developed systemic disease progression. The actuarial overall survival rate for metastatic patients was 85% and 63% after 1 and 2 years, respectively. Acute Grade 2-3 skin toxicity was seen in 2 patients with no late toxicity greater than Grade 2. No radiation-induced myelopathy was observed. Conclusion: Dose-escalated irradiation of spinal metastases was safe and resulted in excellent local control. Oligometastatic patients with a long life expectancy and epidural involvement are considered to benefit the most from fractionated RT. [Copyright &y& Elsevier]

Abstract: Background: The ability of a geometry-based method to expeditiously adapt a “2-Step” step and shoot IMRT plan was explored. Both changes of the geometry of target and organ at risk have to be balanced. A retrospective prostate planning study was performed to investigate the relative benefits of beam segment adaptation to the changes in target and organ at risk coverage. Methods: Four patients with six planning cases with extraordinarily large deformations of rectum and prostate were chosen for the study. A 9-field IMRT plan (A) using 2-Step IMRT segments was planned on an initial CT study. The plan had to fulfil all the requirements of a conventional high-quality step and shoot IMRT plan. To adapt to changes of the anatomy in a further CT data set, three approaches were considered: the original plan with optimized isocentre position (B), a newly optimized plan (C) and the original plan, adapted using the 2-Step IMRT optimization rules (D). DVH parameters were utilized for quantification of plan quality: D 99 for the CTV and the central planning target volume (PTV), D 95 for an outer PTV, V 95, V 80 and V 50 for rectum and bladder. Results: The adapted plan (D) achieved almost the same target coverage as the newly optimized plan (C). Target coverage for plan B was poor and for the organs at risk, the rectum V 80 was slightly increased. The volume with more than 95% of the target dose (V 95) was 1.5±1.5cm3 for the newly optimized plan (C), compared to 2.2±1.3cm3 for the original plan (A) and 7.2±4.8cm3 (B) on the first and the second CT, respectively. The adapted plan resulted in 4.3±2.1cm3 (D), an intermediate dose load to the rectum. All other parameters were comparable for the newly optimized and the adapted plan. Conclusions: The first results for adaptation of interfractional changes using the 2-Step IMRT algorithm are encouraging. The plans were superior to plans with optimized isocentre position and only marginally inferior to a newly optimized plan. [Copyright &y& Elsevier]

Abstract: Purpose: To compare step-and-shoot intensity-modulated radiotherapy (ss-IMRT) with volumetric-modulated arc therapy (VMAT) for complex-shaped target volumes with a simultaneous integrated boost (SIB). Materials and methods: This retrospective planning study was based on 20 patients composed of prostate cancer (n =5), postoperative (n =5) or primary (n =5) radiotherapy for pharyngeal cancer and for cancer of the paranasal sinuses (n =5); a SIB with two or three dose levels was planned in all patients. For each patient, one ss-IMRT plan with direct-machine-parameter optimization (DMPO) and VMAT plans with one to three arcs (SmartArc technique) were generated in the Pinnacle planning system. Results: Single arc VMAT improved target coverage and dose homogeneity in radiotherapy for prostate cancer. Two and three VMAT arcs were required to achieve equivalent results compared to ss-IMRT in postoperative and primary radiotherapy for pharyngeal cancer, respectively. In radiotherapy for cancer of the paranasal sinuses, multiarc VMAT resulted in increased spread of low doses to the lenses and decreased target coverage in the region between the orbits. Conclusions: The complexity of the target volume determined whether single arc VMAT was equivalent to ss-IMRT. Multiple arc VMAT improved results compared to single arc VMAT at cost of increased delivery times, increased monitor unites and increased spread of low doses. [Copyright &y& Elsevier]

Abstract: Purpose: To evaluate the potential of image-guidance, gating and real-time tumor tracking to improve accuracy in pulmonary stereotactic body radiotherapy (SBRT). Materials and methods: Safety margins for compensation of inter- and intra-fractional uncertainties of the target position were calculated based on SBRT treatments of 43 patients with pre- and post-treatment cone-beam CT imaging. Safety margins for compensation of breathing motion were evaluated for 17 pulmonary tumors using respiratory correlated CT, model-based segmentation of 4D-CT images and voxel-based dose accumulation; the target in the mid-ventilation position was the reference. Results: Because of large inter-fractional base-line shifts of the tumor, stereotactic patient positioning and image-guidance based on the bony anatomy required safety margins of 12mm and 9mm, respectively. Four-dimensional image-guidance targeting the tumor itself and intra-fractional tumor tracking reduced margins to <5mm and <3mm, respectively. Additional safety margins are required to compensate for breathing motion. A quadratic relationship between tumor motion and margins for motion compensation was observed: safety margins of 2.4mm and 6mm were calculated for compensation of 10mm and 20mm motion amplitudes in cranio–caudal direction, respectively. Conclusion: Four-dimensional image-guidance with pre-treatment verification of the target position and online correction of errors reduced safety margins most effectively in pulmonary SBRT. [Copyright &y& Elsevier]

Purpose: To evaluate outcome after image-guided stereotactic body radiotherapy (SBRT) for early-stage non–small-cell lung cancer (NSCLC) and pulmonary metastases. Methods and Materials: A total of 124 patients with 159 pulmonary lesions (metastases n = 118; NSCLC, n = 41; Stage IA, n = 13; Stage IB, n = 19; T3N0, n = 9) were treated with SBRT. Patients were treated with hypofractionated schemata (one to eight fractions of 6–26 Gy); biologic effective doses (BED) to the clinical target volume (CTV) were calculated based on four-dimensional (4D) dose calculation. The position of the pulmonary target was verified using volume imaging before all treatments. Results: With mean/median follow-up of 18/14 months, actuarial local control was 83% at 36 months with no difference between NSCLC and metastases. The dose to the CTV based on 4D dose calculation was closely correlated with local control: local control rates were 89% and 62% at 36 months for >100 Gy and <100 Gy BED (p = 0.0001), respectively. Actuarial freedom from regional and systemic progression was 34% at 36 months for primary NSCLC group; crude rate of regional failure was 15%. Three-year overall survival was 37% for primary NSCLC and 16% for metastases; no dose–response relationship for survival was observed. Exacerbation of comorbidities was the most frequent cause of death for primary NSCLC. Conclusions: Doses of >100 Gy BED to the CTV based on 4D dose calculation resulted in excellent local control rates. This cutoff dose is not specific to the treatment technique and protocol of our study and may serve as a general recommendation. [Copyright &y& Elsevier]

Abstract: Background and purpose: Detailed knowledge of quality of life (QoL) after permanent I-125 brachytherapy may aid in counselling patients with early-stage prostate cancer. Materials and methods: Seventy-four consecutive patients with low-risk prostate cancer were asked to complete the EORTC QLQ-C30 questionnaire with the prostate-specific PR25 module before implant, four weeks and one year after implant (response rates 97%, 88% and 89%, respectively). Implant characteristics were correlated with QoL scores. Results: Global QoL was stable from pre-treatment to one year after implant and similar to age-adjusted scores of healthy controls. Significant changes versus baseline in QLQ-C30 domains were worsened social function at four weeks, increased constipation at four weeks and at one year and improved emotional function at one year. PR25 urinary symptoms were significantly increased at four weeks and, despite some improvement, at one year; bowel symptoms were slightly increased. Both types of symptoms were most strongly related with pre-treatment symptom scores. Prostate-V150 was the only implant parameter significantly associated with both urinary and bowel symptoms at four weeks and one year. Conclusions: Limiting the high-dose subvolume in the prostate may be beneficial to reduce urinary and bowel symptoms but the major determinant of symptoms after I-125 implant is the baseline symptom level. [Copyright &y& Elsevier]

Purpose: To evaluate doses to the microscopic disease (MD) in adaptive radiotherapy (ART) for locally advanced non–small-cell lung cancer (NSCLC) and to model tumor control probability (TCP). Methods and Materials: In a retrospective planning study, three-dimensional conformal treatment plans for 13 patients with locally advanced NSCLC were adapted to shape and volume changes of the gross tumor volume (GTV) once or twice during conventionally fractionated radiotherapy with total doses of 66 Gy; doses in the ART plans were escalated using an iso-mean lung dose (MLD) approach compared to non-adapted treatment. Dose distributions to the volumes of suspect MD were simulated for a scenario with synchronous shrinkage of the MD and GTV and for a scenario of a stationary MD despite GTV shrinkage; simulations were performed using deformable image registration. TCP calculations considering doses to the GTV and MD were performed using three different models. Results: Coverage of the MD at 50 Gy was not compromised by ART. Coverage at 60 Gy in the scenario of a stationary MD was significantly reduced from 92% ± 10% to 73% ± 19% using ART; however, the coverage was restored by iso-MLD dose escalation. Dose distributions in the MD were sufficient to achieve a TCP >80% on average in all simulation experiments, with the clonogenic cell density the major factor influencing TCP. The combined TCP for the GTV and MD was 19.9% averaged over all patients and TCP models in non-adaptive treatment with 66 Gy. Iso-MLD dose escalation achieved by ART increased the overall TCP by absolute 6% (adapting plan once) and by 8.7% (adapting plan twice) on average. Absolute TCP values were significantly different between the TCP models; however, all TCP models suggested very similar TCP increase by using ART. Conclusions: Adaptation of radiotherapy to the shrinking GTV did not compromise dose coverage of volumes of suspect microscopic disease and has the potential to increase TCP by >40% compared with radiotherapy planning without ART. [ABSTRACT FROM AUTHOR]