Very high-energy electron therapy as light-particle alternative to transmission proton FLASH therapy - An evaluation of dosimetric performances.

PURPOSE: Clinical translation of FLASH-radiotherapy (RT) to deep-seated tumours is still a technological challenge. One proposed solution consists of using ultra-high dose rate transmission proton (TP) beams of about 200-250 MeV to irradiate the tumour with the flat entrance of the proton depth-dose profile. This work evaluates the dosimetric performance of very high-energy electron (VHEE)-based RT (50-250 MeV) as a potential alternative to TP-based RT for the clinical transfer of the FLASH effect. METHODS: Basic physics characteristics of VHEE and TP beams were compared utilizing Monte Carlo simulations in water. A VHEE-enabled research treatment planning system was used to evaluate the plan quality achievable with VHEE beams of different energies, compared to 250 MeV TP beams for a glioblastoma, an oesophagus, and a prostate cancer case. RESULTS: Like TP, VHEE above 100 MeV can treat targets with roughly flat (within ± 20 %) depth-dose distributions. The achievable dosimetric target conformity and adjacent organs-at-risk (OAR) sparing is consequently driven for both modalities by their lateral beam penumbrae. Electron beams of 400[500] MeV match the penumbra of 200[250] MeV TP beams and penumbra is increased for lower electron energies. For the investigated patient cases, VHEE plans with energies of 150 MeV and above achieved a dosimetric plan quality comparable to that of 250 MeV TP plans. For the glioblastoma and the oesophagus case, although having a decreased conformity, even 100 MeV VHEE plans provided a similar target coverage and OAR sparing compared to TP. CONCLUSIONS: VHEE-based FLASH-RT using sufficiently high beam energies may provide a lighter-particle alternative to TP-based FLASH-RT with comparable dosimetric plan quality.

Assessment of hyperspectral imaging and CycleGAN-simulated narrowband techniques to detect early esophageal cancer.

The clinical signs and symptoms of esophageal cancer (EC) are often not discernible until the intermediate or advanced phases. The detection of EC in advanced stages significantly decreases the survival rate to below 20%. This study conducts a comparative analysis of the efficacy of several imaging techniques, including white light image (WLI), narrowband imaging (NBI), cycle-consistent adversarial network simulated narrowband image (CNBI), and hyperspectral imaging simulated narrowband image (HNBI), in the early detection of esophageal cancer (EC). In conjunction with Kaohsiung Armed Forces General Hospital, a dataset consisting of 1000 EC pictures was used, including 500 images captured using WLI and 500 images captured using NBI. The CycleGAN model was used to generate the CNBI dataset. Additionally, a novel method for HSI imaging was created with the objective of generating HNBI pictures. The evaluation of the efficacy of these four picture types in early detection of EC was conducted using three indicators: CIEDE2000, entropy, and the structural similarity index measure (SSIM). Results of the CIEDE2000, entropy, and SSIM analyses suggest that using CycleGAN to generate CNBI images and HSI model for creating HNBI images is superior in detecting early esophageal cancer compared to the use of conventional WLI and NBI techniques.

Robustness assessment of clinical adaptive proton and photon radiotherapy for oesophageal cancer in the model-based approach.

PURPOSE: In the Netherlands, oesophageal cancer (EC) patients are selected for intensity modulated proton therapy (IMPT) using the expected normal tissue complication probability reduction (ΔNTCP) when treating with IMPT compared to volumetric modulated arc therapy (VMAT). In this study, we evaluate the robustness of the first EC patients treated with IMPT in our clinic in terms of target and organs-at-risk (OAR) dose with corresponding NTCP, as compared to VMAT. MATERIALS AND METHODS: For 20 consecutive EC patients, clinical IMPT and VMAT plans were created on the average planning 4DCT. Both plans were robustly evaluated on weekly repeated 4DCTs and if target coverage degraded, replanning was performed. Target coverage was evaluated for complete treatment trajectories with and without replanning. The planned and accumulated mean lung dose (MLD) and mean heart dose (MHD) were additionally evaluated and translated into NTCP. RESULTS: Replanning in the clinic was performed more often for IMPT (15x) than would have been needed for VMAT (8x) (p = 0.11). Both adaptive treatments would have resulted in adequate accumulated target dose coverage. Replanning in the first week of treatment had most clinical impact, as anatomical changes resulting in insufficient accumulated target coverage were already observed at this stage. No differences were found in MLD between the planned dose and the accumulated dose. Accumulated MHD differed from the planned dose (p < 0.001), but since these differences were similar for VMAT and IMPT (1.0 and 1.5 Gy, respectively), the ΔNTCP remained unchanged. CONCLUSION: Following an adaptive clinical workflow, adequate target dose coverage and stable OAR doses with corresponding NTCPs was assured for both IMPT and VMAT.

Assessment and validation of the internal gross tumour volume of gastroesophageal junction cancer during simultaneous integrated boost radiotherapy.

BACKGROUND: Respiratory motion may introduce errors during radiotherapy. This study aims to assess and validate internal gross tumour volume (IGTV) margins in proximal and distal borders of gastroesophageal junction (GEJ) tumours during simultaneous integrated boost radiotherapy. METHODS: We enrolled 10 patients in group A and 9 patients in group B. For all patients, two markers were placed at the upper and lower borders of the tumour before treatment. In group A, within the simulation and every 5 fractions of radiotherapy, we used 4-dimensional computed tomography (4DCT) to record the intrafractional displacement of the proximal and distal markers. By fusing the average image of each repeated 4DCT with the simulation image based on the lumbar vertebra, the interfractional displacement could be obtained. We calculated the IGTV margin in the proximal and distal borders of the GEJ tumour. In group B, by referring to the simulation images and cone-beam computed tomography (CBCT) images, the range of tumour displacement in proximal and distal borders of GEJ tumour was estimated. We calculated the proportion of marker displacement range in group B lay within the IGTV margin calculated based on the data obtained in group A to estimate the accuracy of the IGTV margin. RESULTS: The intrafractional displacement in the cranial-caudal (CC) direction was significantly larger than that in the anterior-posterior (AP) and left-right (LR) directions for both the proximal and distal markers of the tumour. The interfractional displacement in the AP and LR directions was larger than that in the CC direction (p = 0.001, p = 0.017) based on the distal marker. The IGTV margins in the LR, AP and CC directions were 9 mm, 8.5 mm and 12.1 mm for the proximal marker and 15.8 mm, 12.7 mm and 11.5 mm for the distal marker, respectively. In group B, the proportions of markers that located within the IGTV margin in the LR, AP and CC directions were 96.5%, 91.3% and 96.5% for the proximal marker and 100%, 96.5%, 93.1% for the distal marker, respectively. CONCLUSIONS: Our study proposed individualized IGTV margins for proximal and distal borders of GEJ tumours during neoadjuvant radiotherapy. The IGTV margin determined in this study was acceptable. This margin could be a reference in clinical practice.

Incremental value of endoscopic brush cytology in response assessment after chemo-irradiation for Esophageal cancer.

BACKGROUND: Response assessment after chemo-radiotherapy (CTRT) in locally advanced esophageal cancer is usually performed using a PET-CT scan, an upper GI endoscopy (UGIE) and histological correlation with biopsy or cytology. We aim to study the incremental value of brush cytology in addition to PET-CT for response assessment. MATERIALS AND METHODS: In this retrospective analysis, 40 patients with Stage II- IV carcinoma esophagus treated with radical intent between June 2015 and August 2019 were included. Patients were treated with either upfront concurrent CTRT or neo-adjuvant chemotherapy followed by CTRT. All patients underwent PET-CT and UGIE for initial staging and response assessment on follow-up. Patients with esophageal stricture (disease related or treatment induced) had brush cytology done during UGIE. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of brush cytology were calculated considering serial clinical follow-up as gold standard. RESULTS: Twenty-three male (57.5%) and 17 (42.5%) female patients with median age of 57 years (range: 27 - 79 years) were analyzed. Concurrent CTRT was delivered in 52.5%; 75% patients were treated with intensity-modulated radiotherapy (IMRT); median RT dose was 63 Gy (range- 41.4 to 64 Gy). At a median follow-up of 16 months (range 6- 54 months), 20 patients (55.5%) were clinically controlled, 9 (25%) had local recurrence, 5 (13.8%) had loco-regional recurrence and 2 had distant metastasis. Considering clinical follow-up as the gold standard, sensitivity, PPV and NPV of PET-CT combined with brush cytology improved compared to PET-CT alone and was found to be 75%, 90%, 85.7% and 81.8% respectively. CONCLUSION: We found that brush cytology on endoscopy is a simple tool with high specificity which adds value to the findings of response assessment PET-CT scan and thereby can increase the confidence of the treating oncologist in making clinical decisions.

Multimodal assessment of acute cardiac toxicity induced by thoracic radiotherapy in cancer patients. Study protocol.

BACKGROUND: Today, cancer ranks as one of the leading causes of death. Despite the large number of novel available therapies, radiotherapy (RT) remains as the most effective non-surgical method to cure cancer patients. In fact, approximately 50% of all cancer patients receive some type of RT and among these 60% receive RT-treatment with a curative intent. However, as occurs with any other oncological therapy, RT treated patients may experience toxicity side effects that range from moderate to severe. Among these, cardiotoxicity represents a significant threat for premature death. Current methods evaluate cardiotoxic damage based on volumetric changes in the Left Ventricle Ejected Fraction (LVEF). Indeed, a 10% drop in LVEF is commonly used as indicator of cardiotoxicity. More recently, a number of novel techniques have been developed that significantly improve specificity and sensitivity of heart's volumetric changes and early detection of cardiotoxicity even in asymptomatic patients. Among these, the Strain by Speckle Tracking (SST) is a technique based on echocardiographic analysis that accurately evaluates myocardial deformation during the cardiac cycle (ventricular and atrial function). Studies also suggest that Magnetic Resonance Imaging (MRI) is a high-resolution technique that enables a better visualization of acute cardiac damage. METHODOLOGY: This protocol will evaluate changes in SST and MRI in cancer patients that received thoracic RT. Concomitantly, we will assess changes in serum biomarkers of cardiac damage in these patients, including: high-sensitivity cardiac Troponin-T (hscTnT), N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) and Circulating Endothelial Cells (CECs), a marker of endothelial dysfunction and vascular damage. DISCUSSION: The presented protocol is to our knowledge the first to prospectively and with a multimodal approach, study serological and image biomarkers off early cardiac damage due to radiotherapy. With a practical clinical approach we will seek early changes that could potentially be in the future be linked to clinical mayor events with consequences for cancer survivors.

An in-silico assessment of the dosimetric benefits of MR-guided radiotherapy for esophageal cancer patients.

PURPOSE: To assess the dosimetric benefits of online MR-guided radiotherapy (MRgRT) for esophageal cancer patients and to assess how these benefits could be translated into a local boosting strategy to improve future outcomes. METHODS: Twenty-nine patients were in-silico treated with both a MRgRT regimen and a conventional image guided radiotherapy (IGRT) regimen using dose warping techniques. Here, the inter and intrafractional changes that occur over the course of treatment (as derived from 5 MRI scans that were acquired weekly during treatment) were incorporated to assess the total accumulated dose for each regimen. RESULTS: A significant reduction in dose to the organs-at-risk (OARs) was observed for all dose-volume-histogram (DVH) parameters for the MRgRT regimen without concessions to target coverage compared to the IGRT regimen. The mean lung dose was reduced by 28%, from 7.9 to 5.7 Gy respectively and V20Gy of the lungs was reduced by 55% (6.3-2.8%). A reduction of 24% was seen in mean heart dose (14.8-11.2 Gy), while the V25Gy of the heart was decreased by 53% (14.3-6.7%) and the V40Gy of the heart was decreased by 69% (3.9-1.2%). In addition, MRgRT dose escalation regimens with a boost up to 66% of the prescription dose to the primary tumor yielded approximately the same dose levels to the OARs as from the conventional IGRT regimen. CONCLUSION: This study revealed that MRgRT for esophageal cancer has the potential to significantly reduce the dose to heart and lungs. In addition, online high precision targeting of the primary tumor opens new perspectives for local boosting strategies to improve outcome of the local management of this disease.

Assessment of a diaphragm override strategy for robustly optimized proton therapy planning for esophageal cancer patients.

PURPOSE: To ensure target coverage in the treatment of esophageal cancer, a density override to the region of diaphragm motion can be applied in the optimization process. Here, we evaluate the benefit of this approach during robust optimization for intensity modulated proton therapy (IMPT) planning. MATERIALS AND METHODS: For 10 esophageal cancer patients, two robustly optimized IMPT plans were created either using (WDO) or not using (NDO) a diaphragm density override of 1.05 g/cm3 during plan optimization. The override was applied to the excursion of the diaphragm between exhale and inhale. Initial robustness evaluation was performed for plan acceptance (setup errors of 8 mm, range errors of ±3%), and subsequently, on all weekly repeated 4DCTs (setup errors of 2 mm, range errors of ±3%). Target coverage and hotspots were analyzed on the resulting voxel-wise minimum (Vwmin ) and voxel-wise maximum (Vwmax ) dose distributions. RESULTS: The nominal dose distributions were similar for both WDO and NDO plans. However, visual inspection of the Vwmax of the WDO plans showed hotspots behind the right diaphragm override region. For one patient, target coverage and hotspots improved by applying the diaphragm override. We found no differences in target coverage in the weekly evaluations between the two approaches. CONCLUSION: The diaphragm override approach did not result in a clinical benefit in terms of planning and interfractional robustness. Therefore, we do not see added value in employing this approach as a default option during robust optimization for IMPT planning in esophageal cancer.

Palliative radiotherapy combined with stent insertion to reduce recurrent dysphagia in oesophageal cancer patients: the ROCS RCT.

BACKGROUND: Most patients with oesophageal cancer present with incurable disease. For those with advanced disease, the mean survival is 3-5 months. Treatment emphasis is therefore on effective palliation, with the majority of patients requiring intervention for dysphagia. Insertion of a self-expanding metal stent provides rapid relief but dysphagia may recur within 3 months owing to tumour progression. Evidence reviews have called for trials of interventions combined with stenting to better maintain the ability to swallow. OBJECTIVES: The Radiotherapy after Oesophageal Cancer Stenting (ROCS) study examined the effectiveness of palliative radiotherapy, combined with insertion of a stent, in maintaining the ability to swallow. The trial also examined the impact that the ability to swallow had on quality of life, bleeding events, survival and cost-effectiveness. DESIGN: A pragmatic, multicentre, randomised controlled trial with follow-up every 4 weeks for 12 months. An embedded qualitative study examined trial experiences in a participant subgroup. SETTING: Participants were recruited in secondary care, with all planned follow-up at home. PARTICIPANTS: Patients who were referred for stent insertion as the primary management of dysphagia related to incurable oesophageal cancer. INTERVENTIONS: Following stent insertion, the external beam radiotherapy arm received palliative oesophageal radiotherapy at a dose of 20 Gy in five fractions or 30 Gy in 10 fractions. MAIN OUTCOME MEASURES: The primary outcome was the difference in the proportion of participants with recurrent dysphagia, or death, at 12 weeks. Recurrent dysphagia was defined as deterioration of ≥ 11 points on the dysphagia scale of the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire oesophago-gastric module questionnaire. Secondary outcomes included quality of life, bleeding risk and survival. RESULTS: The study recruited 220 patients: 112 were randomised to the usual-care arm and 108 were randomised to the external beam radiotherapy arm. There was no evidence that radiotherapy reduced recurrence of dysphagia at 12 weeks (48.6% in the usual-care arm compared with 45.3% in the external beam radiotherapy arm; adjusted odds ratio 0.82, 95% confidence interval 0.40 to 1.68; p = 0.587) and it was less cost-effective than stent insertion alone. There was no difference in median survival or key quality-of-life outcomes. There were fewer bleeding events in the external beam radiotherapy arm. Exploration of patient experience prompted changes to trial processes. Participants in both trial arms experienced difficulty in managing the physical and psychosocial aspects of eating restriction and uncertainties of living with advanced oesophageal cancer. LIMITATIONS: Change in timing of the primary outcome to 12 weeks may affect the ability to detect a true intervention effect. However, consistency of results across sensitivity analyses is robust, including secondary analysis of dysphagia deterioration-free survival. CONCLUSIONS: Widely accessible palliative external beam radiotherapy in combination with stent insertion does not reduce the risk of dysphagia recurrence at 12 weeks, does not have an impact on survival and is less cost-effective than inserting a stent alone. Reductions in bleeding events should be considered in the context of patient-described trade-offs of fatigue and burdens of attending hospital. Trial design elements including at-home data capture, regular multicentre nurse meetings and qualitative enquiry improved recruitment/data capture, and should be considered for future studies. FUTURE WORK: Further studies are required to identify interventions that improve stent efficacy and to address the multidimensional challenges of eating and nutrition in this patient population. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12376468 and Clinicaltrials.gov NCT01915693. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 31. See the NIHR Journals Library website for further project information.

Most people are diagnosed with oesophageal (gullet) cancer when it is already at an advanced stage. Losing the ability to swallow food and even fluids is very common when patients are approaching the last months of life. Placing a flexible metal tube, or stent, in the gullet opens it up and improves the ability to swallow quickly. Unfortunately this can fail after around 3 months because the cancer grows and presses on the stent. We designed this trial to see if giving a small dose of radiotherapy alongside insertion of the stent would allow more people to remain swallowing well after 3 months. This could then improve their quality of life and reduce hospitalisation towards the end of life. It may also reduce bleeding from the gullet, as well as other symptoms. We recruited 220 people across the UK, randomly assigning them to have the stent as usual or the stent and a low dose of radiotherapy. We collected a lot of information from the participants at home on how the cancer, the stent and the radiotherapy affected their ability to swallow and their quality of life. Overall, the study showed that the radiotherapy did not improve the ability to swallow 3 months following stent insertion and was less cost-effective than stent insertion alone. It seemed to reduce the risk of bleeding from the tumour itself, but patients found that radiotherapy made them tired and attending extra hospital visits could be troublesome. We also learned that, even after a stent was inserted, patients still struggled with food and needed more support with managing daily life with the stent. The trial results are important. They show that, to answer questions such as these, studies should use different ways of assessing what works, particularly focusing on patients' and families' viewpoints. The results will guide doctors to not routinely give radiotherapy in this situation. The results also suggest that, after the insertion of a stent, patients need extra help in managing their diet, their worries about the stent and their worries about the future.

CTV-to-PTV margin assessment for esophageal cancer radiotherapy based on an accumulated dose analysis.

PURPOSE: This study aimed to assess the smallest clinical target volume (CTV) to planned target volume (PTV) margins for esophageal cancer radiotherapy using daily online registration to the bony anatomy that yield full dosimetric coverage over the course of treatment. METHODS: 29 esophageal cancer patients underwent six T2-weighted MRI scans at weekly intervals. An online bone-match image-guided radiotherapy treatment of five fractions was simulated for each patient. Multiple conformal treatment plans with increasing margins around the CTV were created for each patient. Then, the dose was warped to obtain an accumulated dose per simulated fraction. Full target coverage by 95% of the prescribed dose was assessed as a function of margin expansion in six directions. If target coverage in a single direction was accomplished, then the respective margin remained fixed for the subsequent dose plans. Margins in uncovered directions were increased in a new dose plan until full target coverage was achieved. RESULTS: The smallest set of CTV-to-PTV margins that yielded full dosimetric CTV coverage was 8 mm in posterior and right direction, 9 mm in anterior and cranial direction and 10 mm in left and caudal direction for 27 out of 29 patients. In two patients the curvature of the esophagus considerably changed between fractions, which required a 17 and 23 mm margin in right direction. CONCLUSION: Accumulated dose analysis revealed that CTV-to-PTV treatment margins of 8, 9 and 10 mm in posterior & right, anterior & cranial and left & caudal direction, respectively, are sufficient to account for interfraction tumor variations over the course of treatment when applying a daily online bone match. However, two patients with extreme esophageal interfraction motion were insufficiently covered with these margins and were identified as patients requiring replanning to achieve full target coverage.

Impact of Radiation on Cardiovascular Outcomes in Older Resectable Esophageal Cancer Patients With Medicare.

OBJECTIVES: Preoperative radiotherapy improves outcomes for operable esophageal cancer patients, though the proximity of the heart to the esophagus puts patients at risk of radiation-induced cardiovascular disease. This study characterizes the impact of radiotherapy and different radiation techniques on cardiovascular morbidity among a cohort of esophageal cancer patients. MATERIALS AND METHODS: We identified 1125 patients aged 65 and older diagnosed between 2000 and 2011 with esophageal cancer who received surgery alone, or surgery preceded by either preoperative chemotherapy or preoperative chemoradiation from the Surveillance Epidemiology and End Results (SEER)-Medicare database. We used Medicare claims to identify severe perioperative and late cardiovascular events. Multivariable logistic regression and Fine-Gray models were used to determine the effect of presurgery treatment on the risk of perioperative and late cardiovascular disease. RESULTS: Preoperative chemotherapy or chemoradiation did not significantly increase the risk of perioperative cardiovascular complications compared with surgery alone. Patients treated with preoperative chemoradiation had a 36% increased risk of having a late cardiovascular event compared with patients treated with surgery alone (subdistribution hazard ratio [SDHR]: 1.36; P=0.035). There was no significant increase in late cardiovascular events among patients treated with preoperative chemotherapy (SDHR: 1.18; P=0.40). Among patients treated with preoperative chemoradiation, those receiving intensity modulated radiotherapy had a 68% decreased risk of having a late cardiovascular event compared with patients receiving conventional radiation (SDHR: 0.32; P=0.007). CONCLUSIONS: This study demonstrates an increased risk of cardiovascular complications among operative esophageal cancer patients treated with preoperative chemoradiation, though these risks might be reduced with more cardioprotective radiation techniques such as intensity modulated radiotherapy.

Dose reduction in HDR brachytherapy of esophageal cancer using gold and gold alloy plaques: a Monte Carlo study.

In this work, the use of gold and gold alloy plaques is proposed for the first time, to reduce the dose to healthy organs in brachytherapy with Ir-192 sources. For dose simulations in tumour and healthy tissue, the MCNPX Monte Carlo code was used. The radiation source implemented in those simulations was benchmarked with well-known TG-43 criteria of dose rate constant, air-kerma strength, radial dose function, and 2D anisotropy function. For various arrangements of iridium sources and plaques of gold and gold alloy of various thicknesses, the dose distributions in an esophagus tumour and in surrounding healthy organs were simulated. The results showed that while the dose to the tumour is not much affected by the presence of gold plaques with a thickness of 3.5 mm in an optimized 192Ir sources' configuration, a relative reduction in average organ dose of 64%, 65%, 73%, 67%, and 35% was observed, for esophagus, thyroid, heart, stomach, and liver, respectively. Moreover, it was found that a gold plaque leads to smaller doses to healthy organs than a gold alloy plaque. It is concluded that gold plaques can be used to improve the treatment of esophageal cancer by HDR brachytherapy and to protect surrounding non-target organs.

3-Dimensional target coverage assessment for MRI guided esophageal cancer radiotherapy.

PURPOSE: This study aimed to quantify the coverage probability for esophageal cancer radiotherapy as a function of a preset margin for online MR-guided and (CB)CT-guided radiotherapy. METHODS: Thirty esophageal cancer patients underwent six T2-weighted MRI scans, 1 prior to treatment and 5 during neoadjuvant chemoradiotherapy at weekly intervals. Gross tumor volume (GTV) and clinical target volume (CTV) were delineated on each individual scan. Follow-up scans were rigidly aligned to the bony anatomy and to the clinical target volume itself, mimicking two online set-up correction strategies: a conventional CBCT-guided set-up and a MR-guided set-up, respectively. Geometric coverage probability of the propagated CTVs was assessed for both set-up strategies by expanding the reference CTV with an isotropic margin varying from 0 mm to 15 mm with an increment of 1 mm. RESULTS: A margin of 10 mm could resolve the interfractional changes for 118 out of the 132 (89%) analyzed fractions when applying a bone-match registration, whereas the CTV was adequately covered in 123 (93%) fractions when the registration was directly performed at the CTV itself (soft-tissue registration). Closer analyses revealed that target coverage violation predominantly occurred for distal tumors near the junction and into the cardia. CONCLUSION: Online MR-guided soft-tissue registration protocols exhibited modest improvements of the geometric target coverage probability as compared to online CBCT-guided bone match protocols. Therefore, highly conformal target irradiation using online MR-guidance can only be achieved by implementing on-table adaptive workflows where new treatment plans are daily generated based on the anatomy of the day.

Diffusion-weighted MRI with ADC mapping for response prediction and assessment of oesophageal cancer: A systematic review.

PURPOSE: The aim was to perform a systematic review on the value of diffusion-weighted MRI (DW-MRI) with apparent diffusion coefficient (ADC) mapping in the prediction and assessment of response to chemo- and/or radiotherapy in oesophageal cancer. MATERIALS AND METHODS: A systematic search was performed on Pubmed, Embase, Medline and Cochrane databases. Studies that evaluated the ADC for response evaluation before, during or after chemo- and/or radiotherapy were included. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to assess the quality of the included studies. RESULTS: Fourteen studies, comprising 516 patients, in which the response to treatment in oesophageal cancer was evaluated on ADC maps were included. Acquisition parameter settings for DW-MRI and ROI placement varied substantially. The reference standard was RECIST or endoscopic assessment in eight non-surgery studies and histopathology after surgery in six studies. A high pre-treatment ADC significantly correlated with good response in three out of 12 studies; conversely, one study reported a significantly higher pre-treatment ADC in poor responders. In five out of eight studies good responders showed a significantly larger relative increase in ADC two weeks after the onset of treatment (range 23-59%) than poor responders (range 1.5-17%). After chemo- and/or radiotherapy ADC results varied considerably, amongst others due to large variation in the interval between completion of therapy and DW-MRI. CONCLUSION: DW-MRI for response evaluation to chemo- and/or radiotherapy in oesophageal cancer shows variable methods and results. A large relative ADC increase after two weeks of treatment seems most predictive for good response.

Harnessing radiation to improve immunotherapy: better with particles?

The combination of radiotherapy and immunotherapy is one of the most promising strategies for cancer treatment. Recent clinical results support the pre-clinical experiments pointing to a benefit for the combined treatment in metastatic patients. Charged particle therapy (using protons or heavier ions) is considered one of the most advanced radiotherapy techniques, but its cost remains higher than conventional X-ray therapy. The most important question to be addressed to justify a more widespread use of particle therapy is whether they can be more effective than X-rays in combination with immunotherapy. Protons and heavy ions have physical advantages compared to X-rays that lead to a reduced damage to the immune cells, that are required for an effective immune response. Moreover, densely ionizing radiation may have biological advantages, due to different cell death pathways and release of cytokine mediators of inflammation. We will discuss results in esophageal cancer patients showing that charged particles can reduce the damage to blood lymphocytes compared to X-rays, and preliminary in vitro studies pointing to an increased release of immune-stimulating cytokines after heavy ion exposure. Pre-clinical and clinical studies are ongoing to test these hypotheses.

External beam patient dose verification based on the integral quality monitor (IQM®) output signals.

BACKGROUND: The Integral Quality Monitor (IQM®) can essentially measure the integral fluence through a segment and provide real-time information about the accuracy of radiation delivery based on comparisons of measured segment signals and pre-calculated reference values. However, the present IQM chamber cannot calculate the dose in the patient. AIM: This study aims to make use of IQM field output signals to calculate the number of monitor units (MUs) delivered through an arbitrary treatment field in order to convert Monte Carlo (MC)-generated dose distributions in a patient model into absolute dose. METHODS: XiO and Monaco treatment planning systems (TPSs) were used to define treatment beam portals for cervix and esophagus conformal radiotherapy as well as prostate intensity-modulated radiotherapy for the translation of patient and beam setup information from DICOM to DOSXYZnrc. The planned beams were simulated in a patient model built from actual patient CT images and each simulated integral field/segment was weighted with its MUs before summation to get the total dose in the plan. The segment beam weights (MUs) were calculated as the ratio of the open-field IQM measured signal and the calculated signal per MU extracted from chamber sensitivity maps. These are the actual MUs delivered not just MUs set. The beam weighting method was evaluated by comparing weighted MC doses with original planned doses using profile and isodose comparisons, dose difference maps, γ analysis and dose-volume histogram (DVH) data. RESULTS: γ pass rates of up to 98% were found, except for the esophagus plan where the γ pass rate was below 45%. DVH comparisons showed good agreement for most organs, with the largest differences observed in low-density lung. However, these discrepancies can result from differences in dose calculation algorithms or differences in MUs used for dose weighting planned by the TPS and MUs calculated using IQM field output signals. To test this, a 4-field box DOSXYZnrc MC simulation weighted with planned (XiO) MUs was compared with the same simulation weighted with IQM-based MUs. Dose differences of up to 5% were found on the isocentre slice. For XiO versus MC, up to 7% dose differences were found, indicating additional error due to limitations of XiO's superposition algorithm. Dose differences between MC Monaco and MC EGSnrc were less than 3%. CONCLUSIONS: The most valuable comparison was MC versus MC as it eliminated algorithm discrepancies and evaluated dose differences precisely according to beam weighting. For XiO TPS, care must be taken as dose differences may also arise due to limitations in XiO's planning software, not merely due to differences in MUs. Overall, the IQM was successfully used to compute beam dose weights to accurately reconstruct the patient dose using unweighted MC beams. Our technique can be used for pre-treatment QA provided each segment output is known and an accurate linac source model is available.

Comparison of the dose on specific 3DCT images and the accumulated dose for cardiac structures in esophageal tumors radiotherapy: whether specific 3DCT images can be used for dose assessment?

BACKGROUND: Cardiac activity could impact the accuracy of dose assessment for the heart, pericardium and left ventricular myocardium (LVM). The purpose of this study was to explore whether it is possible to perform dose assessment by contouring the cardiac structures on specific three-dimensional computed tomography (3DCT) images to reduce the impact of cardiac activity. METHODS: Electrocardiograph-gated 4DCT (ECG-gated 4DCT) images of 22 patients in breath-hold were collected. MIM Maestro 6.8.2 (MIM) was used to reconstruct specific 3DCT images to obtain the Maximal intensity projection (MIP) image, Average intensity projection (AIP) image and Minimum intensity projection (Min-IP) image. The heart, pericardium and LVM were contoured in 20 phases of 4DCT images (0, 5%... 95%) and the MIP, AIP and Min-IP images. Then, a radiotherapy plan was designed at the 0% phase of the 4DCT images, and the dose was transplanted to all phases of 4DCT to acquire the dose on all phases, the accumulated dose of all phases was calculated using MIM. The dose on MIP, AIP and Min-IP images were also obtained by deformable registration of the dose. The mean dose (Dmean), V5, V10, V20, V30 and V40 for the heart, pericardium and LVM in MIP, AIP and Min-IP images were compared with the corresponding parameters after dose accumulation. RESULTS: The mean values of the difference between the Dmean in the MIP image and the Dmean after accumulation for the heart, pericardium and LVM were all less than 1.50 Gy, and the dose difference for the pericardium and LVM was not statistically significant (p > 0.05). For dose-volume parameters, there was no statistically significant difference between V5, V10, and V20 of the heart and pericardium in MIP, AIP, and Min-IP images and those after accumulation (p > 0.05). For the LVM, only in the MIP image, the differences of V5, V10, V20, V30 and V40 were not significant compared to those after dose accumulation (p > 0.05). CONCLUSIONS: There was a smallest difference for the dosimetry parameters of cardiac structures on MIP image compared to corresponding parameters after dose accumulation. Therefore, it is recommended to use the MIP image for the delineation and dose assessment of cardiac structures in clinical practice.

Comparison  of  efficacy, safety, and costs between neoadjuvant hypofractionated radiotherapy and conventionally fractionated radiotherapy for esophageal carcinoma.

BACKGROUND: We compared the efficacy, safety, and costs of hypofractionated radiotherapy (HFRT) and conventional fractionated radiotherapy (CFRT) for the neoadjuvant treatment of esophageal cancer. MATERIALS AND METHODS: Overall, 110 patients with esophageal cancer treated with neoadjuvant chemoradiotherapy from October 2002 to July 2017 were retrospectively included and divided into a HFRT group (42 patients received 30 Gray [Gy]/10 fractions for 2 weeks) and a CFRT group [68 patients received 40 Gy/20 fractions for 4 weeks]. Concurrent chemotherapy comprised cisplatin combined with either 5-FU or taxane. Surgery was performed 3-8 weeks after radiotherapy. We compared the outcomes, adverse events, and costs between the two groups. RESULTS: Pathological downstaging was achieved in 78.6% of the HFRT group and 83.8% of the CFRT group (P = 0.612). Compared with the CFRT group, the HFRT group had similar pathological complete response (pCR) (33.3% vs 35.3%; P = 0.834), median overall survival (OS) (40.8 months vs 44.9 months; P = 0.772) and progression free survival (32.7 months vs 35.4 months; P = 0.785). The perioperative complication rates were also similar between the groups, but the treatment time and costs were significantly reduced in the HFRT group (P < 0.05). Finally, multivariate analysis identified cN0 stage, pathological downstaging and pCR as independent predictors of better OS. CONCLUSION: Preoperative HFRT is effective and safe for esophageal cancer. Moreover, it is similar to CFRT in terms of overall survival and toxicity and is cost effective and less time consuming.

Quantitative Multiparametric MRI May Augment the Response to Radiotherapy in Mid-Treatment Assessment of Patients with Esophageal Carcinoma.

OBJECTIVE: The purpose of this study was to assess the mid-treatment response to radiotherapy (RT) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI) in patients with esophageal cancer (EC). METHODS: 42 patients with squamous EC were prepared for DCE-MRI and DWI scans both before treatment (NRT) and after the fifth radiotherapy (5th RT). The patients were classified into two groups (complete response [CR] and partial response [PR]) according to tumor regression after treatment. The quantitative parameters of DCE-MRI (Ktrans, Kep, Ve, and ADC) were measured. A receiver operating characteristic curve (ROC) was used to detect the efficiency of the above parameters. RESULTS: After 1 month of RT, 29 patients were classified as CR and 11 patients were classified as PR. In the NRT group, the p values of Ktrans, Kep, Ve, and ADC were 0.004, 0.078, 0.0008, and <0.0001, respectively. After the 5th RT, the p values of the above parameters were <0.001, 0.005, 0.108, and 0.365, respectively. In the NRT group, the areas under the ROC curves of Ktrans, Ve, and ADC were 0.790, 0.617, and 0.737; the sensitivity values were 89.3, 92.5, and 90.0%; the specificity values were 69.4, 27.5, and 50.0%. In the 5th RT group, the areas under the ROC curves of Ktrans and Kep were 0.816 and 0.804; the sensitivity values were 71.2 and 95.0%; the specificity values were 81.6 and 50.0%. CONCLUSION: DCE-MRI combined with DWI is effective in the early prediction of radiotherapeutic response of EC after the 5th RT other than after the traditional final treatment.

Commissioning of the Mobius3D independent dose verification system for TomoTherapy.

In radiation therapy, a secondary independent dose verification is an important component of a quality control system. Mobius3D calculates three-dimensional (3D) patient dose using reference beam data and a collapsed cone convolution algorithm and analyzes dose-volume histogram automatically. There are currently no published data on commissioning and determining tolerance levels of Mobius3D for TomoTherapy. To verify the calculation accuracy and adjust the parameters of this system, we compared the measured dose using an ion chamber and film in a phantom with the dose calculated using Mobius3D for nine helical intensity-modulated radiation therapy plans, each with three nominal field widths. We also compared 126 treatment plans used in our institution to treat prostate, head-and-neck, and esophagus tumors based on dose calculations by treatment planning system for given dose indices and 3D gamma passing rates with those produced by Mobius3D. On the basis of these results, we showed that the action and tolerance levels at the average dose for the planning target volume (PTV) at each treatment site are at µ ± 2σ and µ ± 3σ, respectively. After adjusting parameters, the dose difference ratio on average was -0.2 ± 0.6% using ion chamber and gamma passing rate with the criteria of 3% and 3 mm on average was 98.8 ± 1.4% using film. We also established action and tolerance levels for the PTV at the prostate, head-and-neck, esophagus, and for the organ at risk at all treatment sites. Mobius3D calculations thus provide an accurate secondary dose verification system that can be commissioned easily and immediately after installation. Before clinical use, the Mobius3D system needs to be commissioned using the treatment plans for patients treated in each institution to determine the calculational accuracy and establish tolerances for each treatment site and dose index.