Development of Patient Motion Tracking System during Radiation Therapy

Tumor hypoxia is an important mechanism of radioresistance in hypofractionated radiotherapy and must be considered in the treatment planning process

Optimizing the Radiotherapy of Lung Cancer.

The efficacy of the conventional 2D technique of radiation treatment planning and delivery Is limited by toxicity of normal tissue surrounding the target, such that the radiation dose that can be safely delivered to the prostate by external beam radiotherapy cannot exceed 70-72 Gy. Recent technological advances In radiation treatment planning and delivery have allowed higher doses of radiation (>72 Gy) to be safely delivered to the prostate with corresponding Improved outcomes. Over the past decades, high-energy (≥4MV) linear accelerators have gradually replaced Cobalt machines In external-beam radiation therapy delivery. 2D radiation therapy treatment systems have changed to 3D conformal radiation therapy and Intensity-modulated radiation therapy computed tomography-based systems, allowing tighter tumor margins and decreasing normal tissue toxicities. By switching to computed tomography-based planning, 3D-conformal radiation therapy provides better relative conformality of dose than conventional external beam irradiation therapy. Intensity-modulated radiation therapy has further refined dose conformality by spreading the low-dose region to a larger volume. Parallel with the development and implementation of 3D-conformal radiation therapy and intensity-modulated radiation therapy, improved precision of both target definition and treatment verification can be accomplished by Image guidance systems to correct for interfraction and Intrafraction movement of the prostate In real time. However, the potential long-term risks of larger volumes of normal tissues receiving low doses of radiation In Intensity-modulated radiation therapy are unknown. Particle beam radiation therapy (PBRT) offers unique dose distributions and characteristics with higher relative biological effect and linear energy transfer. PBRT Is believed to be more effective In controlling slowly proliferating tumors such as prostate carcinoma. However, the availability of PBRT Is limited and the development of economically operable particle beam radiation therapy facilities In the USA Is still In progress. Finally, the addition of hormonal therapy to radiation therapy has been shown to Improve outcome In selected patients. Androgen deprivation causes cytoreduction of the prostate cancer (smaller volume treated to high doses), better local control and disease-free survival. Long-term adjuvant androgen deprivation has also been shown to Improve overall survival, especially In more advanced tumors.

Correlation of Integral Dose, White Blood Cell Counts, and Radiation Therapy Techniques for Head and Neck Cancer Patients Under Radiation Therapy

：Objective To evaluatethe value of MR spectroscopy (MRS) in the differential diagnosis between recurrence andradiation encephalopathy after radiotherapy for nasopharyngeal carcinoma (NPC). MethodsMuhi-voxel proton MRS was performed on 50 patients with NPC, who were suspected ofintracalvarium tumor recurrence or radiation encephalopathy after radiotherapy byconventional MRI,including 44 males and 6 females. Among the 50 patients, 26 cases werefinally diagnosised as basicranial tumor recurrence and 24 cases as radiationencephalopathy by clinical and MRI follow-up. The following metabolites, such as Cho, NAA,Cr, lactate and lipid, were analyzed comparatively between basicranial tumor recurrenceand radiation encephalopathy(RE), and between the lesions and the relative normal braintissue. Wilcoxon's rank sum test was used to analyze the data. Results The median ofCho/Cr, Cho/NAA,LI/Cr in tumor recurrence group were 2. 22, 2. 13, and 1.77, respectively,and 1.40, 1.31, and 0. 57,respectively, in RE group. The difference of Cho/Cr, Cho/NAA,and LL/Cr between the two groups were statistically significant (P 0. 05). In the 14 cases whose normal brain tissue were compared with the recurrenttumor tissue in tumor recurrence group, the median of Cr, NAA, LL, Cho/Cr, Cho/NAA, LL/Crof recurrent tumor tissue and normal brain tissue were 1023.00, 1930.00, 2090.00, 3.76, 2.13, 3.39 and 2370.00, 3012.00, 1680.00, 1.64, 1.17, 0.75,The difference of Cr, NAA, LL,Cho/Cr, Cho/NAA, LL/Cr between the normal tissue and recurrent tumor tissue weresignificant (P <0.05). LL, Cho/Cr, Cho/NAA, LL/Cr of recurrent tumors were higher thanthose of the normal brain tissue,while NAA and Cr of recurrent tumors were lower thanthose of the normal brain tissue. In the 12 cases whose normal brain tissue were comparedwith the RE tissue in RE group, the median of Cho, Cr, NAA, LL, Cho/Cr, IX,/Cr of REtissue and normal brain tissue were 390.00, 217.50, 427.50, 39.00, 1.30, 0.40 and 680.00,360.00, 610.00, 30.00, 1.54, 0. 09. The difference of above-mentioned parameters betweenRE tissue and normal tissue were significant. Cho, Cr, NAA, Cho/Cr of RE were lower thanthose of normal tissue (P <0. 05) ,while LL and LL/Cr of RE were higher than those ofnormal tissue (P < 0. 05). Conclusion The changes of the metabolites in recurrentlesions and RE lesions were different on MRS. Parameters such as Cho/Cr, Cho/NAA andLL/Cr, which were higher in recurrent lesions than those of RE, were valuable for thedifferential diagnosis between basicranial tumor recurrence and radiation encephalopathyafter radiotherapy for NPC.

Iron is vital to living cells, playing a key role in cellular respiration, DNA synthesis, and various metabolic functions. Importantly, cancer cells have a higher dependency on iron compared to normal cells to support their rapid growth and survival. Due to this fact, tumors are more vulnerable to ferroptosis, an iron-dependent form of regulated cell death. Radiation therapy (RT), a standard treatment for many cancer patients, is known to induce ferroptosis. Ultra-high dose rate FLASH RT offers an improved therapeutic window by minimizing damage to normal tissues while preserving tumor control. However, the precise biological mechanisms behind the protective effects of FLASH RT on normal tissues remain unclear. In this study, we propose that variations in lipid peroxidation and ferroptosis, driven by intrinsic differences in iron levels between normal and cancerous tissues, contribute to this effect. Our findings show that FLASH RT increases lipid peroxidation and induces ferroptosis in tumor cells but does not significantly elevate lipid peroxidation and ferroptosis in normal tissues compared to conventional RT. To determine whether raising iron levels in normal tissues could abrogate the protective effects of FLASH, mice were fed a high-iron diet before RT. A high-iron diet before and after RT reversed the protective effect of FLASH, resulting in increased intestinal damage and lipid peroxidation. This suggests that baseline iron levels and iron-driven lipid peroxidation are critical factors in mediating the protective outcomes of FLASH RT. Overall, our study sheds light on the role of iron in modulating RT responses and provides new mechanistic insights into how FLASH RT influences normal and cancerous tissues.

Radiotherapy (RT) is a central component of standard treatment for many cancer patients. RT alone or in multimodal treatment strategies has a documented contribution to enhanced local control and overall survival of cancer patients, and cancer cure. Clinical RT aims at maximizing tumor control, while minimizing the risk for RT-induced adverse late effects. However, acute and late toxicities of IR in normal tissues are still important biological barriers to successful RT: While curative RT may not be tolerable, sub-optimal tolerable RT doses will lead to fatal outcomes by local recurrence or metastatic disease, even when accepting adverse normal tissue effects that decrease the quality of life of irradiated cancer patients. Technical improvements in treatment planning and the increasing use of particle therapy have allowed for a more accurate delivery of IR to the tumor volume and have thereby helped to improve the safety profile of RT for many solid tumors. With these technical and physical strategies reaching their natural limits, current research for improving the therapeutic gain of RT focuses on innovative biological concepts that either selectively limit the adverse effects of RT in normal tissues without protecting the tumor or specifically increase the radiosensitivity of the tumor tissue without enhancing the risk of normal tissue complications. The biology-based optimization of RT requires the identification of biological factors that are linked to differential radiosensitivity of normal or tumor tissues, and are amenable to therapeutic targeting. Extracellular adenosine is an endogenous mediator critical to the maintenance of homeostasis in various tissues. Adenosine is either released from stressed or injured cells or generated from extracellular adenine nucleotides by the concerted action of the ectoenzymes ectoapyrase (CD39) and 5′ ectonucleotidase (NT5E, CD73) that catabolize ATP to adenosine. Recent work revealed a role of the immunoregulatory CD73/adenosine system in radiation-induced fibrotic disease in normal tissues suggesting a potential use as novel therapeutic target for normal tissue protection. The present review summarizes relevant findings on the pathologic roles of CD73 and adenosine in radiation-induced fibrosis in different organs (lung, skin, gut, and kidney) that have been obtained in preclinical models and proposes a refined model of radiation-induced normal tissue toxicity including the disease-promoting effects of radiation-induced activation of CD73/adenosine signaling in the irradiated tissue environment. However, expression and activity of the CD73/adenosine system in the tumor environment has also been linked to increased tumor growth and tumor immune escape, at least in preclinical models. Therefore, we will discuss the use of pharmacologic inhibition of CD73/adenosine-signaling as a promising strategy for improving the therapeutic gain of RT by targeting both, malignant tumor growth and adverse late effects of RT with a focus on fibrotic disease. The consideration of the therapeutic window is particularly important in view of the increasing use of RT in combination with various molecularly targeted agents and immunotherapy to enhance the tumor radiation response, as such combinations may result in increased or novel toxicities, as well as the increasing number of cancer survivors.

The SARS-CoV-2 pandemic and covid-19 diffusion are an international public health emergency.1 Cancer patients are particularly exposed to infections and their potential complications.2 In this context, the usual clinical decision-making process in radiation therapy is being consistently revised.3 There is an urgent need to share expertise and offer emergency guidance. It is crucial to minimise contacts and to reduce the complexity of radiation treatments where possible to optimise the workforce, keeping intact the effectiveness of the interventions.4 Radiation and systemic therapy modifications should be implemented depending on local circumstances.5 A general guiding principle should include approaches where clinical equivalence supported by trials testing de-escalation strategies is present even without level 1–2 evidence (box 1, bullet points 1).3 Patients with cancer have an intrinsic degree of frailty and therefore are prone to covid-19 complications. Age and comorbidities have been reported as independent risk factors for poor outcome during covid-19 infection and, of note, more than half of cancer patients are elderly and have significant comorbidities (box 1, bullet points 2).6 Hence, an appropriate evaluation of the risk-benefit of radiation therapy treatments is cogent. Urgent cases and non-deferrable treatments (ie, active tumours, spinal cord compression, life threatening bleeding) should be initiated or continued, provided there is full compliance with the safety regulations of local authorities for both patients and staff members. In non-urgent cases, irradiation can be postponed to an extent, depending on the clinical setting and the possibility to offer patients bridging systemic therapies. Whenever radiation therapy is indicated, dose prescription, fractionation and delivery techniques should be adapted, reduced in duration, and optimised (box 1, bullet points 3 and 4). A timely example of precision medicine application is non-metastatic breast cancer radiation …

Clinical Factors Predicting Pathologic Response after Preoperative Concurrent Chemoradiation for Rectal Cancer

A Retrospective Analysis of Factors Affecting Treatment Outcome and Patient Experience in Elderly Head and Neck Cancer Patients: The Odette Cancer Centre Experience

Individualized altered fractionation as a more effective radiotherapy for non-small cell lung cancer.

Recent studies have confirmed the effects of whole-brain radiation therapy (RT) on the blood-brain-barrier and vasculature permeability. Optimal therapeutic targeting of cancer depends on ability to distinguish tumor from normal tissue. This study recruits nested model selection (NMS) and time-frequency analyses of the time-trace of contrast agent from dynamic-contrast-enhanced MRI information to characterize the acute (i.e., within hours) RT response of tumor and normal brain tissues in an animal model of brain tumors. Twenty immune-compromised-RNU rats were implanted orthotopically with human U251N glioma cells. Twenty-eight days after the brain implantation, two DCE-MRI studies were performed 24h apart. 20Gy stereotactic radiation was delivered 1-6.5h before the second MRI. NMS-based DCE-MRI analysis was performed to distinguish three different brain regions by model selection using a nested paradigm. Model 1 was characterized by non-leaky vasculature and considered as normal brain tissue. Model 2 was characterized by contrast agent (CA) movement predominantly in one direction, out of the vasculature, and was primarily associated with the tumor boundary. In contrast, Model 3 exhibited contrast agent movement in both directions, into and out of the vasculature, and corresponded to the tumor core. Time-traces of CA concentration from pre- and post-RT DCE-MRI data for the different models were analyzed using wavelet-based coherence and wavelet cross-spectrum phase analyses to characterize and rank the magnitude of RT-induced effects. Four distinct time-direction classes (in-phase/anti-phase with lead/lag time) were introduced to describe the impact of RT on CA concentration profiles, allowing for comparison of RT effects across different model-based zones of rat brains. The time-frequency analyses revealed both average lag and lead times between the pre- and post-RT CA concentration profiles for the three model regions. The average lag times were 2.882s (95% CI: 2.606-3.157) for Model 1, 1.546s (95% CI: 1.401-1.691) for Model 2, and 2.515s (95% CI: 2.319-2.711) for Model 3, all exhibiting anti-phase oscillation. The average lead times were 1.892s (95% CI: 1.757-2.028) for Model 1, 2.632s (95% CI: 2.366-2.898) for Model 2, and 2.160s (95% CI: 2.021-2.299) for Model 3, also with anti-phase oscillation. Results imply that compared to pre-RT, Model 1, 2, and 3 regions that correspond to normal tissue, periphery, and core of the tumor, show lag-time (2.882 [2.606 3.157]s), lead-time (2.632 [2.366 2.898] s), and lag-time (2.515 [2.319 2.711]s), in their post-RT time-trace of CA concentration, respectively. RT-induced lead/lag time changes were found to be more significant for the lower frequency components of the CA concentration profiles of all the three models. The analysis further revealed that Model 2 (tumor periphery) exhibited the most significant lead time, implying a shorter retainage-time of CA after radiation. Conversely, Model 1, normal tissue, showed the most pronounced lag-time, suggesting longer retainage-time of CA. This study demonstrates a novel approach to analyze the time-frequency information of DCE-MRI CA concentration profiles of the animal brain to detect acute changes in tumor and normal tissue physiology in response to RT that has clinical translatability and has potential to improve treatment planning and RT efficacy.

Radiotherapy (RT) is the primary treatment for nasopharyngeal carcinoma (NPC). However, it can cause implicit RT-induced injury by irradiating normal brain tissue. To date, there have been no detailed reports on the radiated exact location in the brain, the corresponding radiation dose, and their relationship. We analyzed 803 Chinese NPC patients treated with RT and used a CT brain template in a Montreal Neurological Institute (MNI) space to compare the group differences in RT dose distribution for different RT technologies (IMRT or VMAT). Brain regions that received high doses (>50 Gy) of radiation were mainly located in parts of the temporal and limbic lobes, where radioactive damage often occurs. Brain regions that accepted higher doses with IMRT were mainly located near the anterior region of the nasopharyngeal tumor, while brain regions that accepted higher doses with VMAT were mainly located near the posterior region of the tumor. No significant difference was detected between IMRT and VMAT for T1 stage patients. For T2 stage patients, differences were widely distributed, with VMAT showing a significant dose advantage in protecting the normal brain tissue. For T3 stage patients, VMAT showed an advantage in the superior temporal gyrus and limbic lobe, while IMRT showed an advantage in the posterior cerebellum. For T4 stage patients, VMAT showed a disadvantage in protecting the normal brain tissue. These results indicate that IMRT and VMAT have their own advantages in sparing different organs at risk (OARs) in the brain for different T stages of NPC patients treated with RT. Our approach for analyzing dosimetric characteristics in a standard MNI space for Chinese NPC patients provides greater convenience in toxicity and dosimetry analysis with superior localization accuracy. Using this method, we found interesting differences from previous reports: VMAT showed a disadvantage in protecting the normal brain tissue for T4 stage NPC patients.

e17568 Background: Although numerous factors have been reported to increase RT/RTCT toxicity, identification of patients with high risk of toxicities is lacking. Methods: The monocentric NutriNeck study (NCT02900963) recruited all HNSCC patients between 2014 and 2018 treated by RT or RTCT. Patients fed by enteral nutrition before RT initiation were excluded. All clinical and biological, planned RT or RTCT parameters were collected at baseline. A daily monitoring of the weight and a weekly evaluation of clinical, biological and food intake during RT/RTCT were performed. A nutritional intervention by enteral feeding was systematically proposed in case of 2 kg weight loss under treatment. Complete treatment was defined as full planned RT doses without more than 3 days interruption, and full planned doses of cisplatin and cetuximab if indicated. Primary endpoint assessed factors associated with non-completion of the planned treatment. Secondary endpoint assessed factors associated with use of enteral nutrition during treatment. A p value &lt; 0.01 was considered significant. Results: Among the 249 HNSCC patients included, 118 (47%) were treated by RT and 131 (53%) by RTCT. 63 patients (25%) did not complete treatment: 3/118 (2.5%) in the RT group compared to 60/131 (45.8%) the RTCT group, p &lt; 0.0001. Median weight lost during treatment (7 vs 3.8 kg, p &lt; 0.0001) and grade 3 toxicities (53 vs 33%, p = 0.006) were more frequent in patients with incomplete RT/RTCT. Nutritional intervention was performed in 111 patients: 28 (23.7%) with RT and 83 (62.6%) with RTCT (p &lt; 0.0001). Week 4 was associated with the higher rate of enteral nutrition initiation in both RT and RTCT groups. Among RTCT group, weight loss during treatment (OR 1.2 for each kg, p &lt; 0.0001) and use of enteral feeding (OR 2.7, p = 0.005) were associated with incomplete treatment in multivariate analysis. Of note, 48 patients refused enteral nutrition while indicated, they had comparable grade 3 toxicities and weight loss during treatment compared to the 111 patients who accepted enteral nutrition. Conclusions: Incomplete treatment is overwhelmingly associated with RTCT rather than RT. Baseline clinical, biological features or treatment volume/dose are not associated with incomplete treatment. Enteral nutrition initiated during treatment is poorly efficient.

Robust approaches to quantify tumor heterogeneity are needed to provide early decision support for precise individualized therapy. To conduct a technical exploration of longitudinal changes in tumor heterogeneity patterns on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) and FDG positron emission tomography / computed tomography (PET/CT), and their association to radiation therapy (RT) response in cervical cancer. Prospective observational study with longitudinal MRI and PET/CT pre-RT, early-RT (2 weeks), and mid-RT (5 weeks). Twenty-one FIGO IB2 -IVA cervical cancer patients receiving definitive external beam RT and brachytherapy. 1.5T, precontrast axial T1 -weighted, axial and sagittal T2 -weighted, sagittal DWI (multi-b values), sagittal DCE MRI (<10 sec temporal resolution), postcontrast axial T1 -weighted. Response assessment 1 month after completion of treatment by a board-certified radiation oncologist from manually delineated tumor volume changes. Intensity histogram (IH) quantiles (DCE SI10% and DWI ADC10% , FDG-PET SUVmax ) and distribution moments (mean, variance, skewness, kurtosis) were extracted. Differences in IH features between timepoints and modalities were evaluated by Skillings-Mack tests with Holm's correction. Area under receiver-operating characteristic curve (AUC) and Mann-Whitney testing was performed to discriminate treatment response using IH features. Tumor IH means and quantiles varied significantly during RT (SUVmean : ↓28-47%, SUVmax : ↓30-59%, SImean : ↑8-30%, SI10% : ↑8-19%, ADCmean : ↑16%, P < 0.02 for each). Among IH heterogeneity features, FDG-PET SUVCoV (↓16-30%, P = 0.011) and DW-MRI ADCskewness decreased (P = 0.001). FDG-PET SUVCoV was higher than DCE-MRI SICoV and DW-MRI ADCCoV at baseline (P < 0.001) and 2 weeks (P = 0.010). FDG-PET SUVkurtosis was lower than DCE-MRI SIkurtosis and DW-MRI ADCkurtosis at baseline (P = 0.001). Some IH features appeared to associate with favorable tumor response, including large early RT changes in DW-MRI ADCskewness (AUC = 0.86). Preliminary findings show tumor heterogeneity was variable between patients, modalities, and timepoints. Radiomic assessment of changing tumor heterogeneity has the potential to personalize treatment and power outcome prediction. 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1388-1396.