Clinical implication of genetic intratumor heterogeneity for targeted therapy in head and neck cancer.

BACKGROUND: Genomic profiling is increasingly used both in therapeutic decision-making and as inclusion criteria for trials testing targeted therapies. However, the mutational landscape may vary across different areas of a tumor and intratumor heterogeneity will challenge treatments or clinical decisions based on single tumor biopsies. The purpose of this study was to assess the clinical relevance of genetic intratumor heterogeneity in head and neck squamous cell carcinomas (HNSCC) using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). MATERIALS AND METHODS: This prospective study included 33 whole tumor specimens from 28 patients with primary or recurrent HNSCC referred for surgery. Three tumor blocks were selected from central, semi-peripheral, and peripheral positions, mimicking biopsies in three different locations. Genetic analysis of somatic copy number alterations (SCNAs) was performed on the three biopsies using Oncoscan, focusing on 45 preselected HNSCC genes of interest. Clinical relevance was assessed using the ESCAT score to investigate whether and how treatment decisions would change based on the three biopsies from the same tumor. RESULTS: The SCNAs identified among 45 preselected genes within the three tumor biopsies derived from the same tumor revealed distinct variations. The detected discrepancies could potentially influence treatment approaches or clinical decisions in 36% of the patients if only one tumor biopsy was used. Recurrent tumors exhibited significantly higher variation in SCNAs than primary tumors (p = .024). No significant correlation between tumor size and heterogeneity (p = .7) was observed. CONCLUSION: In 36% of patients diagnosed with HNSCC, clinically significant intratumor heterogeneity was observed which may have implications for patient management. This finding substantiates the need for future studies that specifically investigate the clinical implications associated with intratumor heterogeneity.

A national repository of complete radiotherapy plans: design, Results, and experiences.

BACKGROUND: Previously, many radiotherapy (RT) trials were based on a few selected dose measures. Many research questions, however, rely on access to the complete dose information. To support such access, a national RT plan database was created. The system focuses on data security, ease of use, and re-use of data. This article reports on the development and structure, and the functionality and experience of this national database. METHODS AND MATERIALS: A system based on the DICOM-RT standard, DcmCollab, was implemented with direct connections to all Danish RT centres. Data is segregated into any number of collaboration projects. User access to the system is provided through a web interface. The database has a finely defined access permission model to support legal requirements. RESULTS: Currently, data for more than 14,000 patients have been submitted to the system, and more than 50 research projects are registered. The system is used for data collection, trial quality assurance, and audit data set generation.Users reported that the process of submitting data, waiting for it to be processed, and then manually attaching it to a project was resource intensive. This was accommodated with the introduction of triggering features, eliminating much of the need for users to manage data manually. Many other features, including structure name mapping, RT plan viewer, and the Audit Tool were developed based on user input. CONCLUSION: The DcmCollab system has provided an efficient means to collect and access complete datasets for multi-centre RT research. This stands in contrast with previous methods of collecting RT data in multi-centre settings, where only singular data points were manually reported. To accommodate the evolving legal environment, DcmCollab has been defined as a 'data processor', meaning that it is a tool for other research projects to use rather than a research project in and of itself.

Feasibility of Using Wearables for Home Monitoring during Radiotherapy for Head and Neck Cancer-Results from the OncoWatch 1.0 Study.

Background: Consumer wearables allow objective health data monitoring, e.g., of physical activity and heart rate, which might change over a cancer treatment course. Patients with head and neck cancer (HNC) receiving radiotherapy (RT) with curative intent typically experience side effects such as pain, decreased appetite, and dehydration, which may lead to hospitalizations. Therefore, health data monitoring could be important to understand a patient's condition outside the hospital. The OncoWatch 1.0 study investigated the feasibility of using smartwatches for patients with HNC receiving RT. Methods: This study was a prospective, single-cohort feasibility study. The inclusion criteria were patients ≥ 18 years of age who planned to receive curatively intended radiotherapy for HNC. Consenting patients were asked to wear a smartwatch during RT and until two weeks after the end of RT. The primary endpoint was adherence. The secondary endpoints were data acquisition and variations in heart rate and physical activity. Results: Ten patients were included, with a median age of 62 years and eight males. The adherence rate for wearing the watch >12 h/d over the study period was 31%. The data acquisition rate was 61%. Conclusions: Although the primary endpoint was not reached, new knowledge has been established, including the secure data setup and key points that need to be addressed in future studies.

Interfractional dose accumulation for MR-guided liver SBRT: Variation among algorithms is highly patient- and fraction-dependent.

BACKGROUND AND PURPOSE: Daily plan adaptations could take the dose delivered in previous fractions into account. Due to high dose delivered per fraction, low number of fractions, steep dose gradients, and large interfractional organ deformations, this might be particularly important for liver SBRT. This study investigates inter-algorithm variation of interfractional dose accumulation for MR-guided liver SBRT. MATERIALS AND METHODS: We assessed 27 consecutive MR-guided liver SBRT treatments of 67.5 Gy in three (n = 15) or 50 Gy in five fractions (n = 12), both prescribed to the GTV. We calculated fraction doses on daily patient anatomy, warped these doses to the simulation MRI using seven different algorithms, and accumulated the warped doses. Thus, we obtained differences in planned doses and warped or accumulated doses for each algorithm. This enabled us to calculate the inter-algorithm variations in warped doses per fraction and in accumulated doses per treatment course. RESULTS: The four intensity-based algorithms were more consistent with planned PTV dose than affine or contour-based algorithms. The mean (range) variation of the dose difference for PTV D95% due to dose warping by these intensity-based algorithms was 10.4 percentage points (0.3 to 43.7) between fractions and 8.6 (0.3 to 24.9) between accumulated treatment doses. As seen by these ranges, the variation was very dependent on the patient and the fraction being analyzed. Nevertheless, no correlations between patient or plan characteristics on the one hand and inter-algorithm dose warping variation on the other hand was found. CONCLUSION: Inter-algorithm dose accumulation variation is highly patient- and fraction-dependent for MR-guided liver SBRT. We advise against trusting a single algorithm for dose accumulation in liver SBRT.

Patterns of relapse and long-term outcome in patients treated with a curative intent for advanced Hodgkin lymphoma.

BACKGROUND: Consolidation radiotherapy for advanced Hodgkin lymphoma (AHL) is controversial. Precise knowledge of the most likely relapse location is crucial for radiotherapy planning. We performed detailed patterns of relapse analyses and evaluated if initial bulky disease, initial 18F-fluoro-deoxy-glucose (FDG)-avidity and/or a residual mass on computed tomography (CT)-scan after chemotherapy are sites with a high risk of relapse. This information could provide guidance for optimal use of radiotherapy in AHL. MATERIAL AND METHODS: We included 133 patients treated with curatively intended chemotherapy for AHL. 23 patients received consolidation radiotherapy. For relapsed patients, imaging from diagnosis, response evaluation, relapse, and any radiotherapy planning, were retrieved and co-registered to determine the exact site(s) of relapse relative to initial site(s), residual mass(es) and to any irradiated volumes. Size and FDG-avidity of initial sites with later relapse, and residual CT-abnormalities after chemotherapy in these sites were registered. Survival analyses were done using the Kaplan-Meier method. RESULTS: Nine (6.8%) patients relapsed, eight in initially involved sites. One relapse was in an initially irradiated site (as well as other sites). Initial bulky disease, high initial FDG-uptake, and/or residual masses on CT-scan after chemotherapy did not predict sites with a high risk of relapse. Overall survival was 79.6% (95% CI, 72.7-86.5%) and 70.6% (95% CI, 62.4-78.8%) at 5 and 10 years, respectively. Time to progression analysis showed 91.8% (95% CI, 86.9-96.7%) and 90.7% (95% CI, 85.4-96.0%) without progression at 5 and 10 years, respectively. CONCLUSION: Current treatment strategies for AHL provide excellent disease control. Neither initial bulk, high initial FDG-uptake, nor a residual CT-abnormality post-chemotherapy seem to indicate sites with a high risk of relapse.

Accuracy and consistency of intensity-based deformable image registration in 4DCT for tumor motion estimation in liver radiotherapy planning.

We investigate the accuracy of intensity-based deformable image registration (DIR) for tumor localization in liver stereotactic body radiotherapy (SBRT). We included 4DCT scans to capture the breathing motion of eight patients receiving SBRT for liver metastases within a retrospective clinical study. Each patient had three fiducial markers implanted. The liver and the tumor were delineated in the mid-ventilation phase, and their positions in the other phases were estimated with deformable image registration. We tested referenced and sequential registrations strategies. The fiducial markers were the gold standard to evaluate registration accuracy. The registration errors related to measured versus estimated fiducial markers showed a mean value less than 1.6mm. The positions of some fiducial markers appeared not stable on the 4DCT throughout the respiratory phases. Markers' center of mass tends to be a more reliable measurement. Distance errors of tumor location based on registration versus markers center of mass were less than 2mm. There were no statistically significant differences between the reference and the sequential registration, i.e., consistency and errors were comparable to resolution errors. We demonstrated that intensity-based DIR is accurate up to resolution level for locating the tumor in the liver during breathing motion.

Risk of Bacterial, Viral, and Fungal Infections in Patients With Solid Malignant Tumors Treated With Curative Intent Radiation Therapy.

Purpose: The incidence, etiology, and association of infections with radiation therapy (RT)-induced lymphopenia in patients with solid tumors is not well elucidated. Methods and Materials: We identified possible, probable, and definite infections caused by bacteria, fungi, and viruses, combining data on medication, microbiology, and diagnoses. Definite infections had either a diagnosis or a positive microbiological isolation. We analyzed the incidence and adjusted incidence-rate ratio of infections in the year after the start of RT among patients who received RT plus chemotherapy and RT monotherapy, by type of infection and according to the degree of RT-induced lymphopenia. Results: A total of 4450 of 6334 (70.3%) patients experienced 11264 infections overall; 1424 (22.5%) patients developed 2104 definite infections in the first year after RT. Infections were more frequent among patients who received RT plus chemotherapy (2590 of 3469; incidence: 16.5 [95% confidence interval {CI}, 16.1-17.0], per 100 patient-years) compared with patients who received RT monotherapy (1860 of 2865; incidence: 12.7 [95% CI, 12.3-13.2]). The incidence of infection was highest in the first 3 months overall (28.2 vs 18.0 in patients who received RT plus chemotherapy compared with those who received RT monotherapy) and for definite infections (4.7 vs 3.8). The proportion of specific bacterial infections were similar among patients who received RT plus chemotherapy versus those who received RT monotherapy. Urinary tract infections were the most frequent (51.2% vs 56.2%), followed by pneumonias (24.1% vs 22.4%). Viral and fungal infections were more frequent among patients who received RT plus chemotherapy, but they were uncommon. In multivariable analyses, patients who received RT plus chemotherapy with a lymphopenia grade of 1-2 or ≥3 versus no lymphopenia at end of RT had an increased risk of bacterial infections 0 to 3 months after RT (incidence rate ratio, 1.45 [95% CI, 1.06-1.97] and 1.71 [95% CI, 1.26-2.34], respectively). Limiting to definite bacterial infections, the incidence rate ratio for lymphopenia grade ≥3 versus no lymphopenia was 2.66 (95% CI, 1.40-5.03). Conclusions: The incidence of bacterial infections 0 to 3 months after RT plus chemotherapy for solid tumors was high, especially among patients with RT-induced lymphopenia grade 1-2 and ≥3.

Radiation-Induced Toxicity Risks in Photon Versus Proton Therapy for Synchronous Bilateral Breast Cancer.

Purpose: This study compares photon and proton therapy plans for patients with synchronous bilateral early breast cancer and estimates risks of early and late radiation-induced toxicities. Materials and Methods: Twenty-four patients with synchronous bilateral early breast cancer receiving adjuvant radiation therapy using photons, 3-dimensional conformal radiation therapy or volumetric modulated arc therapy, were included and competing pencil beam scanning proton therapy plans were created. Risks of dermatitis, pneumonitis, acute esophageal toxicity, lung and breast fibrosis, hypothyroidism, secondary lung and esophageal cancer and coronary artery events were estimated using published dose-response relationships and normal tissue complication probability (NTCP) models. Results: The primary clinical target volume V95% and/or nodal clinical target volume V90% were less than 95% in 17 photon therapy plans and none of the proton plans. Median NTCP of radiation dermatitis ≥ grade 2 was 18.3% (range, 5.4-41.7) with photon therapy and 58.4% (range, 31.4-69.7) with proton therapy. Median excess absolute risk (EAR) of secondary lung cancer at age 80 for current and former smokers was 4.8% (range, 0.0-17.0) using photons and 2.7% (range, 0.0-13.6) using protons. Median EAR of coronary event at age 80, assuming all patients have preexisting cardiac risk factors, was 1.0% (range, 0.0-5.6) with photons and 0.2% (range, 0.0-1.3) with protons. Conclusion: Proton therapy plans improved target coverage and reduced risk of coronary artery event and secondary lung cancer while increasing the risk of radiation dermatitis.

Early non-cancer mortality risk prediction after curative-intent radiotherapy or chemoradiotherapy for head and neck squamous cell carcinoma.

BACKGROUND: In patients with head and neck squamous cell carcinoma (HNSCC), curative-intent radiotherapy (RT) and chemoradiotherapy (CRT) are associated with substantial acute morbidity and 5-10% of patients die within 180 days of treatment initiation. Most of these early deaths occur without HNSCC recurrence or progression and may therefore be preventable to some extent. We developed a prediction tool to estimate the risk of non-HNSCC mortality occurring within the first 180 days followingRT/CRT initiation. METHODS: Patients with HNSCC treated with RT/CRT, including postoperative RT/CRT, at Rigshospitalet or Herlev Hospitals between 2010-2017 were identified in the Danish Head and Neck Cancer Group (DAHANCA) database. Predictor variables included age, stage, performance status, tumor subsite including p16 status, comorbidity, postoperative status, smoking and pre-treatment albumin levels. The 180-day non-HNSCCmortality risk was estimated by combining cause-specific Cox regression models. RESULTS: We included 2209 patients. The 180-day non-HNSCCmortality rate was 4.4% and almostone third (31.6%) of non-HNSCCdeathswere caused by pneumonia.After internal model validation, the area under the receiver operating curve was 0.74 (95% CI: 0.66-0.81) and calibration was good for risk predictions ranging from 0% to 20%. CONCLUSION: We developed a prediction tool to estimate the 180-day non-HNSCC mortality risk. This tool can be used to select high-risk patients for supportive interventions aiming to improve survival rates, and is availablefor interactive use at https://emriskpred.shinyapps.io/EMNED_App/.

Patient-reported outcome during radiotherapy for head and neck cancer: the use of different PRO questionnaires.

PURPOSE: Head and neck cancer (HNC) patients are typically treated with radiotherapy (RT), which might lead to side effects and deterioration of quality of life (QoL). Studies in other cancers indicate that systematic use of patient-reported outcome (PRO) can be a tool to increase awareness of patients' symptoms and improve QoL. Multiple PRO questionnaires have been developed and validated for HNC, complicating the interpretation of results from scientific studies. In this exploratory study, symptom scores from four essential symptoms present in four different HNC-specific PRO questionnaires were evaluated. METHODS: Four HNC-specific PRO questionnaires (EORTC QLQ-H&N35, FACT-H&N, MDASI-HN, and PRO-CTCAE) for patients undergoing radiotherapy were completed by eligible HNC patients up to ten times during and after RT. Four essential symptoms (pain, dysphagia, hoarseness, and dry mouth) were present in all questionnaires. The symptom scores for these symptoms were aligned and evaluated. RESULTS: Twelve patients were included and completed a total of 328 PRO questionnaires out of 420. Similarity between symptom score for the four symptoms was found, when the symptom scores were aligned. The symptom scores increased during RT and decreased afterwards for all four symptoms and in all four questionnaires. CONCLUSION: Four HNC-specific PRO questionnaires are found similar in reflecting symptom scores over time concerning four important HNC symptoms (pain, dysphagia, hoarseness, and dry mouth). PRO can contribute with targetable information about symptoms, and PRO questionnaires might be a valuable add on to clinical practice enabling a varied picture of patients' symptoms during radiotherapy.

RootPainter3D: Interactive-machine-learning enables rapid and accurate contouring for radiotherapy.

PURPOSE: Organ-at-risk contouring is still a bottleneck in radiotherapy, with many deep learning methods falling short of promised results when evaluated on clinical data. We investigate the accuracy and time-savings resulting from the use of an interactive-machine-learning method for an organ-at-risk contouring task. METHODS: We implement an open-source interactive-machine-learning software application that facilitates corrective-annotation for deep-learning generated contours on X-ray CT images. A trained-physician contoured 933 hearts using our software by delineating the first image, starting model training, and then correcting the model predictions for all subsequent images. These corrections were added into the training data, which was used for continuously training the assisting model. From the 933 hearts, the same physician also contoured the first 10 and last 10 in Eclipse (Varian) to enable comparison in terms of accuracy and duration. RESULTS: We find strong agreement with manual delineations, with a dice score of 0.95. The annotations created using corrective-annotation also take less time to create as more images are annotated, resulting in substantial time savings compared to manual methods. After 923 images had been delineated, hearts took 2 min and 2 s to delineate on average, which includes time to evaluate the initial model prediction and assign the needed corrections, compared to 7 min and 1 s when delineating manually. CONCLUSIONS: Our experiment demonstrates that interactive-machine-learning with corrective-annotation provides a fast and accessible way for non computer-scientists to train deep-learning models to segment their own structures of interest as part of routine clinical workflows.

FDG-PET/CT identified distant metastases and synchronous cancer in squamous cell carcinoma of the head and neck: the impact of smoking and P16-s.

PURPOSE: Whole-body FDG-PET-CT is widely used at diagnosis of squamous cell carcinoma of the head and neck (SCCHN) but may identify suspicious lesions outside the neck that require investigation. This study evaluated the impact of smoking and P16-status on the incidence of malignant disease outside the head and neck region in newly diagnosed patients with SCCHN. METHODS: All PET-positive foci outside the head-neck area were registered in 1069 patients planned for postoperative or curative intent radiotherapy with whole-body FDG-PET/CT from 2006 to 2012. All patient files were retrospectively investigated and clinical parameters, tobacco use, HPV (P16)-status and subsequent malignant disease registered. RESULTS: Malignancy outside the neck was diagnosed in 9% of smokers, 2% of never-smokers, and 5% of patients with P16-positive oropharyngeal squamous cell carcinoma (OPSCC). Clinically suspicious PET-positive foci outside the head-neck were malignant in 55% of smokers, 34% of never-smokers, and in 38% of P16-pos OPSCC. All but two patients with cancer occurring outside the head and neck region were smokers. CONCLUSION: Malignancy outside the neck at diagnosis was more frequent in smokers compared to non-smokers or P16-pos OPSCC. A high proportion of clinically suspicious PET-positive foci were non-malignant.

Toward PET/MRI as one-stop shop for radiotherapy planning in cervical cancer patients.

BACKGROUND: Radiotherapy (RT) planning for cervical cancer patients entails the acquisition of both Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Further, molecular imaging by Positron Emission Tomography (PET) could contribute to target volume delineation as well as treatment response monitoring. The objective of this study was to investigate the feasibility of a PET/MRI-only RT planning workflow of patients with cervical cancer. This includes attenuation correction (AC) of MRI hardware and dedicated positioning equipment as well as evaluating MRI-derived synthetic CT (sCT) of the pelvic region for positioning verification and dose calculation to enable a PET/MRI-only setup. MATERIAL AND METHODS: 16 patients underwent PET/MRI using a dedicated RT setup after the routine CT (or PET/CT), including eight pilot patients and eight cervical cancer patients who were subsequently referred for RT. Data from 18 patients with gynecological cancer were added for training a deep convolutional neural network to generate sCT from Dixon MRI. The mean absolute difference between the dose distributions calculated on sCT and a reference CT was measured in the RT target volume and organs at risk. PET AC by sCT and a reference CT were compared in the tumor volume. RESULTS: All patients completed the examination. sCT was inferred for each patient in less than 5 s. The dosimetric analysis of the sCT-based dose planning showed a mean absolute error (MAE) of 0.17 ± 0.12 Gy inside the planning target volumes (PTV). PET images reconstructed with sCT and CT had no significant difference in quantification for all patients. CONCLUSIONS: These results suggest that multiparametric PET/MRI can be successfully integrated as a one-stop-shop in the RT workflow of patients with cervical cancer.

A framework for voxel-based assessment of biological effect after proton radiotherapy in pediatric brain cancer patients using multi-modal imaging.

INTRODUCTION: The exact dependence of biological effect on dose and linear energy transfer (LET) in human tissue when delivering proton therapy is unknown. In this study, we propose a framework for measuring this dependency using multi-modal image-based assays with deformable registrations within imaging sessions and across time. MATERIALS AND METHODS: 3T MRI scans were prospectively collected from 6 pediatric brain cancer patients before they underwent proton therapy treatment, and every 3 months for a year after treatment. Scans included T1-weighted with contrast enhancement (T1), T2-FLAIR (T2) and fractional anisotropy (FA) images. In addition, the planning CT, dose distributions and Monte Carlo-calculated LET distributions were collected. A multi-modal deformable image registration framework was used to create a dataset of dose, LET and imaging intensities at baseline and follow-up on a voxel-by-voxel basis. We modelled the biological effect of dose and LET from proton therapy using imaging changes over time as a surrogate for biological effect. We investigated various models to show the feasibility of the framework to model imaging changes. To account for interpatient and intrapatient variations, we used a nested generalized linear mixed regression model. The models were applied to predict imaging changes over time as a function of dose and LET for each modality. RESULTS: Using the nested models to predict imaging changes, we saw a decrease in the FA signal as a function of dose; however, the signal increased with increasing LET. Similarly, we saw an increase in T2 signal as a function of dose, but a decrease in signal with LET. We saw no changes in T1 voxel values as a function of either dose or LET. CONCLUSIONS: The imaging changes could successfully model biological effect as a function of dose and LET using our proposed framework. Due to the low number of patients, the imaging changes observed for FA and T2 scans were not marked enough to draw any firm conclusions.

Hematological toxicity in patients with solid malignant tumors treated with radiation - Temporal analysis, dose response and impact on survival.

PURPOSE: To describe the kinetics of the peripheral blood components after radiotherapy, to examine radiation exposure vs. End-of-Radiation-Therapy (EoRT) counts and to associate the EoRT lymphocyte count with death and cancer treatment failure. MATERIALS AND METHODS: Cohort study of patients who received curative intent radiotherapy for solid tumor diagnoses from 2009-2016 at Rigshospitalet, Copenhagen and had available 3D radiation exposure data. We illustrated peripheral blood count kinetics within 12 months before and after radiotherapy start and analyzed the impact of the irradiated body volume. We investigated overall survival and cancer treatment failure according to EoRT lymphopenia using Cox regression analyses. RESULTS: We analyzed 4055 patients with both pre-treatment and EoRT platelet counts and 2318 patients who also had neutrophil and lymphocyte counts. Only the lymphocyte decline after radiotherapy start was clinically relevant and remained low one year after radiotherapy. The higher the volume of the body exposed to radiation, the lower the EoRT blood counts. Female gender (p < 0.001), number of fractions (p = 0.010), dose-volume (p < 0.001) and concomitant use of chemotherapy, particularly the platinum compounds (p < 0.001) were independently associated with a lower EoRT lymphocyte count. Patients with head and neck cancer had the lowest EoRT lymphocyte count. Patients with lymphopenia had a higher risk of death in the year after radiotherapy, compared with patients with no lymphopenia. CONCLUSION: Radiation schemes with fewer fractions and radiation techniques allowing reduction of the volume of the body exposed to radiation could be expected to better preserve patients' immune function.

Intrafractional fiducial marker position variations in stereotactic liver radiotherapy during voluntary deep inspiration breath-hold.

OBJECTIVES: To evaluate intrafractional fiducial marker position variations during stereotactic body radiotherapy (SBRT) in patients treated for liver metastases in visually guided, voluntary deep inspiration breath-hold (DIBH). METHODS: 10 patients with implanted fiducial markers were studied. Respiratory coaching with visual guidance was used to ensure comfortable voluntary breath-holds for SBRT imaging and delivery. Three DIBH CTs were acquired for treatment planning. Pre- and post-treatment CBCTs were acquired for each of the three treatment fractions. Per-fraction marker position was evaluated on planar 2D kV images acquired during treatment fractions for 4 of the 10 patients. RESULTS: The median difference in marker position was 0.3 cm (range, 0.0-0.9 cm) between the three DIBH CTs and 0.3 cm (range, 0.1 to 1.4 cm) between pre- and post-treatment CBCTs. The maximum intrafractional variation in marker position in craniocaudal (CC) direction on planar kV images was 0.7 to 1.3 cm and up to 1.0 cm during a single DIBH. CONCLUSION: Difference in marker position of up to 1.0 cm was observed during a single DIBH despite use of narrow external gating window and visual feedback. Stability examination on pre-treatment DIBH CTs was not sufficient to guarantee per-fraction stability. Evaluation of differences in marker position on pre- and post-treatment CBCT did not always reveal the full magnitude of the intrafractional variation. ADVANCES IN KNOWLEDGE: To increase treatment accuracy, it is necessary to apply real-time monitoring of the tumour or a reliable internal surrogate when delivering liver SBRT in voluntary DIBH.

Involved node radiation therapy in the combined modality treatment for early-stage Hodgkin lymphoma: Analysis of relapse location and long-term outcome.

BACKGROUND AND PURPOSE: Involved node radiation therapy (INRT) in the combined modality treatment for early-stage Hodgkin lymphoma (ESHL) has reduced the irradiated volume dramatically. Limiting the irradiated volume further based on initial disease bulk, 18F-fluoro-deoxy-glucose (FDG)-avidity, or residual computed tomography (CT) abnormality after chemotherapy seems attractive. In a cohort of patients treated with INRT a meticulous pattern-of-relapse analysis was performed to examine these options. MATERIAL AND METHODS: Patients treated for ESHL in our institution from 2005 to 2014 who achieved complete remission with chemotherapy were included. Patient characteristics, treatment details and clinical outcome were registered. For relapsed patients, rigid co-registration of the positron emission tomography/computed tomography-scans from the time of diagnosis and at relapse was done to visually assess the relapse location relative to initial involvement and, if irradiated, the irradiated volume. Size and maximum Standardized Uptake Value of the initial node(s) with later relapse, and residual CT abnormalities after chemotherapy in those locations were measured. RESULTS: We included 182 patients. Twelve (6.6%) patients relapsed, five in previously involved nodes (two irradiated, three not irradiated). Relapses did not occur preferentially in initially bulky disease, in lymph node(s) with the highest FDG-uptake, or in residual CT abnormalities after chemotherapy. CONCLUSIONS: Modern treatment with brief chemotherapy and limited radiotherapy provides excellent long-term disease control in ESHL. Neither bulk, high FDG-uptake, nor residual CT abnormality after chemotherapy could predict initially involved lymph nodes with a high risk of relapse.

Biological optimization for mediastinal lymphoma radiotherapy - a preliminary study.

Purpose: In current radiotherapy (RT) planning and delivery, population-based dose-volume constraints are used to limit the risk of toxicity from incidental irradiation of organs at risks (OARs). However, weighing tradeoffs between target coverage and doses to OARs (or prioritizing different OARs) in a quantitative way for each patient is challenging. We introduce a novel RT planning approach for patients with mediastinal Hodgkin lymphoma (HL) that aims to maximize overall outcome for each patient by optimizing on tumor control and mortality from late effects simultaneously.Material and Methods: We retrospectively analyzed 34 HL patients treated with conformal RT (3DCRT). We used published data to model recurrence and radiation-induced mortality from coronary heart disease and secondary lung and breast cancers. Patient-specific doses to the heart, lung, breast, and target were incorporated in the models as well as age, sex, and cardiac risk factors (CRFs). A preliminary plan of candidate beams was created for each patient in a commercial treatment planning system. From these candidate beams, outcome-optimized (O-OPT) plans for each patient were created with an in-house optimization code that minimized the individual risk of recurrence and mortality from late effects. O-OPT plans were compared to VMAT plans and clinical 3DCRT plans.Results: O-OPT plans generally had the lowest risk, followed by the clinical 3DCRT plans, then the VMAT plans with the highest risk with median (maximum) total risk values of 4.9 (11.1), 5.1 (17.7), and 7.6 (20.3)%, respectively (no CRFs). Compared to clinical 3DCRT plans, O-OPT planning reduced the total risk by at least 1% for 9/34 cases assuming no CRFs and 11/34 cases assuming presence of CRFs.Conclusions: We developed an individualized, outcome-optimized planning technique for HL. Some of the resulting plans were substantially different from clinical plans. The results varied depending on how risk models were defined or prioritized.