Characterization and radiosensitivity of HPV-related oropharyngeal squamous cell carcinoma patient-derived xenografts.

Background: Oropharyngeal squamous cell carcinomas (OPSCC) are rising rapidly in incidence due to Human Papillomavirus (HPV) and/or tobacco smoking. Prognosis is better for patients with HPV-positive disease, but may also be influenced by tobacco smoking and other factors. There is a need to individualize treatment to minimize morbidity and improve prognosis. Patient-derived xenografts (PDX) is an emerging pre-clinical research model that may more accurately reflect the human disease, and is an attractive platform to study disease biology and develop treatments and biomarkers. In this study we describe the establishment of PDX models, compare PDX tumors to the human original, and assess the suitability of this model for radiotherapy research and biomarker development. Material and methods: Tumor biopsies from 34 patients with previously untreated OPSCC were implanted in immunodeficient mice, giving rise to 12 squamous cell carcinoma PDX models (7 HPV+, 5 HPV-). Primary and PDX tumors were characterized extensively, examining histology, immunohistochemistry, cancer gene sequencing and gene expression analysis. Radiosensitivity was assessed in vivo in a growth delay assay. Results: Established PDX models maintained histological and immunohistochemical characteristics as well as HPV-status of the primary tumor. Important cancer driver gene mutations, e.g., in TP53, PIK3CA and others, were preserved. Gene expression related to cancer stem cell markers and gene expression subtype were preserved, while gene expression related to hypoxia and immune response differed. Radiosensitivity studies showed high concordance with clinical observations. Conclusion: PDX from OPSCC preserves important molecular characteristics of the human primary tumor. Radiosensitivity were in accordance with clinically observed treatment response. The PDX model is a clinically relevant surrogate model of head and neck cancer. Perspectives include increased understanding of disease biology, which could lead to development of novel treatments and biomarkers.

DBCG hypo trial validation of radiotherapy parameters from a national data bank versus manual reporting.

INTRODUCTION: The current study evaluates the data quality achievable using a national data bank for reporting radiotherapy parameters relative to the classical manual reporting method of selected parameters. METHODS: The data comparison is based on 1522 Danish patients of the DBCG hypo trial with data stored in the Danish national radiotherapy data bank. In line with standard DBCG trial practice selected parameters were also reported manually to the DBCG database. Categorical variables are compared using contingency tables, and comparison of continuous parameters is presented in scatter plots. RESULTS: For categorical variables 25 differences between the data bank and manual values were located. Of these 23 were related to mistakes in the manual reported value whilst the remaining two were a wrong classification in the data bank. The wrong classification in the data bank was related to lack of dose information, since the two patients had been treated with an electron boost based on a manual calculation, thus data was not exported to the data bank, and this was not detected prior to comparison with the manual data. For a few database fields in the manual data an ambiguity of the parameter definition of the specific field is seen in the data. This was not the case for the data bank, which extract all data consistently. CONCLUSIONS: In terms of data quality the data bank is superior to manually reported values. However, there is a need to allocate resources for checking the validity of the available data as well as ensuring that all relevant data is present. The data bank contains more detailed information, and thus facilitates research related to the actual dose distribution in the patients.

Setup error and motion during deep inspiration breath-hold breast radiotherapy measured with continuous portal imaging.

BACKGROUND: The position and residual motion of the chest wall of breast cancer patients during treatment in deep inspiration breath-hold (DIBH) were investigated. MATERIAL AND METHODS: The study included 58 left-sided breast cancer patients treated with DIBH three-dimensional (3D) conformal radiotherapy in 15 or 25 fractions. The DIBH levels were monitored using an external marker block placed on the chest, either shifted 5 cm to the right at the level of the xiphoid process (Group 1, 27 consecutive patients) or placed medially on the inferior part of the sternum (Group 2, 31 consecutive patients). At every third treatment fraction, continuous portal images were acquired. The time-resolved chest wall position during treatment was compared with the planned position to determine the inter-fraction setup errors and the intra-fraction motion of the chest wall. RESULTS: The DIBH compliance was 95% during both recruitment periods. A tendency of smaller inter-fraction setup errors and intra-fraction motion was observed for group 2 (medial marker block position). However, apart from a significantly reduced inter-field random shift (σ = 1.7 mm vs. σ = 0.9 mm, p = 0.005), no statistically significant differences between the groups were found. In a combined analysis, the group mean inter-fraction setup error was M = - 0.1 mm, with random and systematic errors of σ = 1.7 mm and Σ = 1.4 mm. The group mean inter-field shift was M = 0.0 (σ = 1.3 mm and Σ = 1.1 mm) and the group mean standard deviation of the intra-field motion was 0.5 mm. The absolute setup error had a maximum of 16.3 mm, exceeding 5 mm in 2.2% of the imaged fields. CONCLUSION: Compared to free breathing treatments, the primary benefit of the DIBH technique was the separation of the heart from the target rather than more accurate targeting. Despite a small gating window, occasional large errors in the chest wall position were observed for some patients, illustrating limitations of the external marker block as surrogate in a broad patient population.

Accuracy and potential improvements of surface-guided breast cancer radiotherapy in deep inspiration breath-hold with daily image-guidance.

Objective.Radiotherapy of left-sided breast cancer in deep inspiration breath-hold (DIBH) reduces the heart dose. Surface guided radiotherapy (SGRT) can guide the DIBH, but the accuracy is subject to variations in the chest wall position relative to the patient surface.Approach.In this study, ten left-sided breast cancer patients received DIBH radiotherapy with tangential fields in 15-18 fractions. After initial SGRT setup in free breathing an orthogonal MV/kV image pair was acquired during SGRT-guided breath-hold. The couch was corrected to align the chest wall during another breath-hold, and a new SGRT reference surface was acquired for the gating. The chest wall position error during treatment was determined from continuous cine MV images in the imager direction perpendicular to the cranio-caudal direction. A treatment error budget was made with individual contributions from the online registration of the setup MV image, the difference in breath-hold level between setup imaging and SGRT reference surface acquisition, the SGRT level during treatment, and intra-fraction shifts of the chest wall relative to the SGRT reference surface. In addition to the original setup protocol (Scenario A), SGRT was also simulated with better integration of image-guidance by capturing either the new reference surface (Scenario B) or the SGRT positional signal (Scenario C) simultaneously with the setup MV image, and accounting for the image-guided couch correction by shifting the SGRT reference surface digitally.Main results.In general, the external SGRT signal correlated well with the internal chest wall position error (correlation coefficient >0.7 for 75% of field deliveries), but external-to-internal target position offsets above 2 mm occasionally occurred (13% of fractions). The PTV margin required to account for the treatment error was 3.5 mm (Scenario A), 3.4 mm (B), and 3.1 mm (C).Significance. Further integration of SGRT with image-guidance may improve treatment accuracy and workflow although the current study did not show large accuracy improvements of scenario B and C compared to scenario A.

Fully automated detection of heart irradiation in cine MV images acquired during breast cancer radiotherapy.

PURPOSE: To develop robust automated detection of heart irradiation in continuous portal images (cine MV images) of tangential breast cancer treatments. METHODS: Cine MV images of 302 tangential field deliveries were recorded for ten left-sided breast cancer patients receiving deep-inspiration breath-hold radiotherapy. An algorithm for fully automated heart edge detection in cine MV images was developed and tested for all images. The algorithm first enhances the heart edge contrast greatly by exploiting that pixels on the heart edge change their intensity cyclically, and highly correlated, at 1-3 Hz due to heartbeat. The algorithm then detects the heart edge in the enhanced image and calculates the exposed heart area within the field aperture. RESULTS: The algorithm correctly identified the heart edge in all cine MV series with heart exposure (169 of 302 field deliveries). With conservative selection criteria the algorithm on average identified 70 heart edge pixels in the heart-including field deliveries (range: 10-230) without false positives. With less strict criteria 106 heart edge pixels were identified on average (range: 13-262) with 0.6% being false positives. The heart edge bordering the lung was segmented highly reliably even a few millimeters outside the field edge. For six patients with frequent heart irradiation, the exposed heart area showed large interfraction variations and smaller intrafraction variations. CONCLUSIONS: Automated heart edge detection in cine MV images was proposed, developed and shown to be highly efficient for heart exposure detection in tangential breast fields. It may allow unsupervised surveillance of heart exposure at all tangential breast cancer treatments in a clinic.

Analysis of cardiac substructure dose in a large, multi-centre danish breast cancer cohort (the DBCG HYPO trial): Trends and predictive modelling.

BACKGROUND AND PURPOSE: Radiotherapy for breast cancer can increase the risks of heart disease. Patient-specific risk assessment may be improved with the inclusion of doses to cardiac substructures. The purpose of this work was to use automatic segmentation to evaluate substructure doses and develop predictive models for these based on the dose to the whole heart. MATERIAL AND METHODS: Automatic segmentation was used to delineate cardiac substructures in a Danish breast cancer trial (DBCG HYPO) dataset comprising over 1500 Danish women treated between 2009 and 2014. Trends in contouring practices and cardiac doses over time were investigated, and models to predict substructure doses from whole heart dose parameters were fit to the data. RESULTS: Manual contouring consistency improved over the study period when compared with automatic segmentation; systematic differences between automatically and manually defined heart volume decreased from 106 cm3 to 12.0 cm3. Doses to the heart and cardiac substructures also decreased. Mean whole heart doses for left-sided treatments in 2009 and 2014 were 1.94±1.19 Gy and 1.29±0.69 Gy (average ± SD), respectively. Prediction of mean substructure doses is accurate, with R2 scores in the range 0.45-0.95 (average 0.77), depending on the particular structure. CONCLUSION: This study reports heart and cardiac substructure doses in a large breast cancer cohort. Predictive models generated in this work can be used to estimate mean cardiac substructure doses for datasets where patient imaging and dose distributions are not available, provided the tangential field techniques are consistent with those used in the trial.

A model for managing patient booking in a radiotherapy department with differentiated waiting times.

BACKGROUND: In Denmark, the waiting time from the ready-to-treat date to the first radiotherapy fraction is by national legislation guaranteed not to exceed 4 weeks. This guarantee has now been tightened for some specific diagnoses as it is required that e.g. intestinal and head and neck cancer patients have to be treated without unnecessary delays. Thus, patients with these tumour sites have to start radiotherapy treatment immediately after diagnosis, if it is their primary treatment modality. Previously, patients have been booked at the first empty time slot after their ready-to-treat date. Now, booking has to take the differentiated waiting times into account. To facilitate this, a model has been developed. It is used to manage the booking of patients, reserve accelerator capacity for patients with no waiting time and establish the waiting times for other patients. METHODS: The patients are divided into categories according to their waiting time guarantee and for each category a maximum waiting time is defined. The required daily accelerator capacity and average new starts rate for each waiting time category has been determined from the actual patient case-mix in the department. To account for variations in treatment capacity, a prospective daily accelerator capacity is set. Based on the prospective capacity, preparation times, maximum waiting times, and new starts rates, a maximum booking curve (MBC) and a lower limit curve (LLC) are derived. They show the daily maximum and minimum limits, respectively, for booking at future dates. RESULTS: The method is evaluated by a retrospective analysis of actual number of appointments booked compared to the MBC and LLC in situations of both excessive workload and ineffective use of capacity. CONCLUSION: The model represents a tool for effectively managing the capacity in a radiotherapy department with differentiated waiting times. It improves the transparency of the booking process and prospective waiting times can easily be derived on a daily basis.

Risk of second primary lung cancer in women after radiotherapy for breast cancer.

BACKGROUND: Several epidemiological studies have reported increased risks of second lung cancers after breast cancer irradiation. In this study we assessed the effects of the delivered radiation dose to the lung and the risk of second primary lung cancer. METHODS: We conducted a nested case-control study of second lung cancer in a population based cohort of 23,627 early breast cancer patients treated with post-operative radiotherapy from 1982 to 2007. The cohort included 151 cases diagnosed with second primary lung cancer and 443 controls. Individual dose-reconstructions were performed and the delivered dose to the center of the second lung tumor and the comparable location for the controls were estimated, based on the patient specific radiotherapy charts. RESULTS: The median age at breast cancer diagnosis was 54 years (range 34-74). The median time from breast cancer treatment to second lung cancer diagnosis was 12 years (range 1-26 years). 91% of the cases were categorized as ever smokers vs. 40% among the controls. For patients diagnosed with a second primary lung cancer five or more years after breast cancer treatment the rate of lung cancer increased linearly with 8.5% per Gray (95% confidence interval=3.1-23.3%; p<0.001). This rate was enhanced for ever smokers with an excess rate of 17.3% per Gray (95% CI=4.5-54%; p<0.005). CONCLUSIONS: Second lung cancer after radiotherapy for early breast cancer is associated with the delivered dose to the lung. Although the absolute risk is relative low, the growing number of long-time survivors after breast cancer treatment highlights the need for advances in normal tissue sparing radiation techniques.

[Postoperative radiotherapy treatment of early breast cancer]. / Postoperativ strålebehandling ved cancer mammae.

Postoperative radiotherapy (RT) is an important part of the multidisciplinary treatment of early breast cancer. Meta-analyses of large randomized trials of RT after lumpectomy and mastectomy have shown that RT reduces the risk of local recurrence with at least 70% and mortality after 15 years with 5%. The effect is most pronounced in patients with a high risk of local recurrence, but is independent of adjuvant systemic treatment. Late radiation effects, in particular cardiac mortality can now be avoided using modern treatment technique. However, there is a continuous need to find the overall balance between the risk and benefit of RT based on individual prognostic parameters and technical possibilities.