Radiotherapy Fractionation Research Articles

Applicability of Gene Expression in Saliva as an Alternative to Blood for Biodosimetry and Prediction of Radiation-induced Health Effects.

As the great majority of gene expression (GE) biodosimetry studies have been performed using blood as the preferred source of tissue, searching for simple and less-invasive sampling methods is important when considering biodosimetry approaches. Knowing that whole saliva contains an ultrafiltrate of blood and white blood cells, it is expected that the findings in blood can also be found in saliva. This human invivo study aims to examine radiation-induced GE changes in saliva for biodosimetry purposes and to predict radiation-induced disease, which is yet poorly characterized. Furthermore, we examined whether transcriptional biomarkers in blood can also be found equivalently in saliva. Saliva and blood samples were collected in parallel from radiotherapy (RT) treated patients who suffered from head and neck cancer (n = 8) undergoing fractioned partial-body irradiations (1.8 Gy/fraction and 50-70 Gy total dose). Samples were taken 12-24 h before first irradiation and ideally 24 and 48 h, as well as 5 weeks after radiotherapy onset. Due to the low quality and quantity of isolated RNA samples from one patient, they had to be excluded from further analysis, leaving a total of 24 saliva and 24 blood samples from 7 patients eligible for analysis. Using qRT-PCR, 18S rRNA and 16S rRNA (the ratio being a surrogate for the relative human RNA/bacterial burden), four housekeeping genes and nine mRNAs previously identified as radiation responsive in blood-based studies were detected. Significant GE associations with absorbed dose were found for five genes and after the 2nd radiotherapy fraction, shown by, e.g., the increase of CDKN1A (2.0 fold, P = 0.017) and FDXR (1.9 fold increased, P = 0.002). After the 25th radiotherapy fraction, however, all four genes (FDXR, DDB2, POU2AF1, WNT3) predicting ARS (acute radiation syndrome) severity, as well as further genes (including CCNG1 [median-fold change (FC) = 0.3, P = 0.013], and GADD45A (median-FC = 0.3, P = 0.031)) appeared significantly downregulated (FC = 0.3, P = 0.01-0.03). A significant association of CCNG1, POU2AF1, HPRT1, and WNT3 (P = 0.006-0.04) with acute or late radiotoxicity could be shown before the onset of these clinical outcomes. In an established set of four genes predicting acute health effects in blood, the response in saliva samples was similar to the expected up- (FDXR, DDB2) or downregulation (POU2AF1, WNT3) in blood for up to 71% of the measurements. Comparing GE responses (PHPT1, CCNG1, CDKN1A, GADD45A, SESN1) in saliva and blood samples, there was a significant linear association between saliva and blood response of CDKN1A (R2 = 0.60, P = 0.0004). However, the GE pattern of other genes differed between saliva and blood. In summary, the current human invivo study, (I) reveals significant radiation-induced GE associations of five transcriptional biomarkers in salivary samples, (II) suggests genes predicting diverse clinical outcomes such as acute and late radiotoxicity as well as ARS severity, and (III) supports the view that blood-based GE response can be reflected in saliva samples, indicating that saliva is a "mirror of the body" for certain but not all genes and, thus, studies for each gene of interest in blood are required for saliva.

Utility of 30-day mortality as a quality metric for palliative radiation treatment: A population-based analysis from Queensland, Australia.

Palliative radiotherapy (PRT) is frequently used to treat symptoms of advanced cancer, however benefits are questionable when life expectancy is limited. The 30-day mortality rate after PRT is a potential quality indicator, and results from a recent meta-analysis suggest a benchmark of 16% as an upper limit. In this population-based study from Queensland, Australia, we examined 30-day mortality rates following PRT and factors associated with decreased life expectancy. Retrospective population data from Queensland Oncology Repository was used. Study population data included 22,501 patients diagnosed with an invasive cancer who died from any cause between 2008 and 2017 and had received PRT. Thirty-day mortality rates were determined from the date of last PRT fraction to date of death. Cox proportional hazards models were used to identify factors independently associated with risk of death within 30 days of PRT. Overall 30-day mortality after PRT was 22.2% with decreasing trend in more recent years (P = 0.001). Male (HR = 1.20, 95% CI = 1.13-1.27); receiving 5 or less radiotherapy fractions (HR = 2.97, 95% CI = 2.74-3.22 and HR = 2.17, 95% CI = 2.03-2.32, respectively) and receiving PRT in a private compared to public facility (HR = 1.61, 95% CI = 1.51-1.71) was associated with decreased survival. The 30-day mortality rate in Queensland following PRT is higher than expected and there is scope to reduce unnecessarily protracted treatment schedules. We encourage other Australian and New Zealand centres to examine and report their own 30-day mortality rate following PRT and would support collaboration for 30-day mortality to become a national and international quality metric for radiation oncology centres.

Cancer-specific dose and fractionation schedules in stereotactic body radiotherapy for oligometastatic disease: An interim analysis of the EORTC-ESTRO E2-RADIatE OligoCare study

Background and introductionOptimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation. Materials and methodsAnalysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/β of 10 Gy for all primaries, and cancer-specific α/β of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC). ResultsOf the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3–5) and median dose per fraction was 9.7 (IQR, 7.7–12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions. ConclusionThis real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503).

A Randomised Phase II Trial to Evaluate the Feasibility of Radiotherapy Dose Escalation, Facilitated by Intensity-Modulated Arc Radiotherapy Techniques, in High-Risk Neuroblastoma

BACKGROUND AND PURPOSEFor high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. MATERIALS AND METHODSChildren with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. RESULTSBetween 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0–36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7–35.9 Gy). CONCLUSIONIMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial.

TGF-β3 increases the severity of radiation-induced oral mucositis and salivary gland fibrosis in a mouse model

Purpose Toxicities from head and neck (H&N) radiotherapy (RT) may affect patient quality of life and can be dose-limiting. Proteins from the transforming growth factor beta (TGF-β) family are key players in the fibrotic response. While TGF-β1 is known to be pro-fibrotic, TGF-β3 has mainly been considered anti-fibrotic. Moreover, TGF-β3 has been shown to act protective against acute toxicities after radio- and chemotherapy. In the present study, we investigated the effect of TGF-β3 treatment during fractionated H&N RT in a mouse model. Materials and methods 30 C57BL/6J mice were assigned to three treatment groups. The RT + TGF-β3 group received local fractionated H&N RT with 66 Gy over five days, combined with TGF-β3-injections at 24-hour intervals. Animals in the RT reference group received identical RT without TGF-β3 treatment. The non-irradiated control group was sham-irradiated according to the same RT schedule. In the follow-up period, body weight and symptoms of oral mucositis and lip dermatitis were monitored. Saliva was sampled at five time points. The experiment was terminated 105 d after the first RT fraction. Submandibular and sublingual glands were preserved, sectioned, and stained with Masson’s trichrome to visualize collagen. Results A subset of mice in the RT + TGF-β3 group displayed increased severity of oral mucositis and increased weight loss, resulting in a significant increase in mortality. Collagen content was significantly increased in the submandibular and sublingual glands for the surviving RT + TGF-β3 mice, compared with non-irradiated controls. In the RT reference group, collagen content was significantly increased in the submandibular gland only. Both RT groups displayed lower saliva production after treatment compared to controls. TGF-β3 treatment did not impact saliva production. Conclusions When repeatedly administered during fractionated RT at the current dose, TGF-β3 treatment increased acute H&N radiation toxicities and increased mortality. Furthermore, TGF-β3 treatment may increase the severity of radiation-induced salivary gland fibrosis.

213 Radiotherapy fraction delivery time does not affect survival outcomes in patients with oropharynx cancer, unselected for chronotype

213 Radiotherapy fraction delivery time does not affect survival outcomes in patients with oropharynx cancer, unselected for chronotype

Neoadjuvant Short- Vs. Long-Course Radiation for Locally Advanced Rectal Cancer: How to Choose.

Over the past decades, the treatment of locally advanced rectal cancer has evolved dramatically due to improvements in diagnostic imaging, surgical technique, and the addition of radiotherapy and/or chemotherapy. Fractionation of neoadjuvant radiotherapy with or without concurrent chemotherapy remains the subject of discussion and the question multiple recent trials have aimed to answer. In light of recent data and concern for locoregional recurrence, our institution favors long-course chemoradiation in most cases, especially in low-lying primaries, threatened circumferential resection margin, consideration of non-operative management, or if the surgeon has concerns for resectability. Exceptions would include cases of oligometastatic disease planned for metastasectomy in which curative-intent treatment was pursued or if additional factors required a reduction in treatment time.

A 15-Year Single-Institution Retrospective Study of Primary Pancreatic Cancer Treated with Non-Ablative Palliative Radiotherapy.

We studied the use of palliative radiotherapy (RT) among patients with primary, non-curable, locally advanced pancreatic cancer. In this subset of patients, with very poor survival, various palliative RT dose fractionation schemes are used; but, in the absence of a guideline, practice patterns vary, and dose choice is mainly based on the physician's intuition. We divided the patients into three groups, according to the dose fractionation schedules received: low (A), intermediate (B), and high (C) dose groups, to study the potential differences in outcome between the different dose prescriptions. Cohort: n = 184. Median age: 69 years. Male: n = 105 (57%), female: n = 79 (43%). Stage IV: n = 117 (64%). T4: n = 127 (69%). Tumor location: head: n = 109 (59%), body: n = 37 (20%), tail: n = 25 (14%), neck: n = 11 (6%), and uncinate: n = 2 (1%). Prior systemic therapy: n = 66 (36%). Most common dose fractionations received: 20 Gy in five fractions n = 67 (36%), 30 Gy in 10 fractions n = 49 (27%), and 8 Gy in one fraction n = 23 (13%). Group A: n = 33 (18%), median overall survival (OS) 19 days (95% CI 4-33). Group B: n = 84 (46%), median OS 52 days (95% CI 43-60). Group C: n = 67 (36%), median OS 126 days (95% CI 77-174). Median days to in-field progression: Group A 59 days (range 7-109), Group B 96 days (range 19-173), and Group C 97 days (range 13-475). To our knowledge, this is the largest reported retrospective cohort of patients receiving non-ablative palliative RT to treat their primary pancreatic tumors. Most patients had metastatic disease, T4 tumors of the pancreatic head and had not received prior systemic therapy. A significant survival benefit was seen favoring the high dose/longer RT fractionation group, presumably due to appropriate patient selection rather than an RT effect. Despite the relatively short median overall survival, one fifth of the patients were found to experience an in-field progression following RT.

A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial

BC2001 showed combining chemotherapy (5-FU+mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). invasive loco-regional control (ILRC); secondary overall survival. Hypoxia affected overall survival (HR=1.30; 95% CI 0.99-1.70; p=0.062): more uncertainty for ILRC (HR=1.29; 95% CI 0.82-2.03; p=0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n=90, HR 1.69; 95% CI 0.99-2.89 p=0.057) but not conventional (n=207, HR 0.70; 95% CI 0.28-1.80, p=0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n=51; HR 14.2; 95% CI 1.7-119; p=0.015) but not conventional (n=24, HR 1.04; 95% CI 0.07-15.5, p=0.978) radiotherapy. Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. Cancer Research UK, NIHR, MRC.

PPARα Agonism Enhances Immune Response to Radiotherapy While Dietary Oleic Acid Results in Counteraction.

Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show that altered fatty acid (FA) metabolism correlates with outcome. We hypothesized that pharmacologic and dietary modulation of FA catabolism will affect therapeutic efficacy. We performed in vivo and in vitro experiments using PPARα agonism with fenofibrate (FF) or high oleic acid diets (OAD) with radiotherapy, generating metabolomic, proteomic, stable isotope tracing, extracellular flux analysis, and flow-cytometric data to investigate these alterations. FF improved antitumor efficacy of high dose per fraction radiotherapy in HNC murine models, whereas the OAD reversed this effect. FF-treated mice on the control diet had evidence of increased FA catabolism. Stable isotope tracing showed less glycolytic utilization by ex vivo CD8+ T cells. Improved efficacy correlated with intratumoral alterations in eicosanoid metabolism and downregulated mTOR and CD36. Metabolic intervention with increased FA catabolism improves the efficacy of HNC therapy and enhances antitumoral immune response.

Laser interstitial thermal therapy as a radiation-sparing approach for central nervous system tumors in children with cancer predisposition syndromes: report of a child with Li-Fraumeni syndrome. Illustrative case.

Ionizing radiation and alkylating chemotherapies increase secondary malignancy risk in patients with cancer predisposition syndromes (CPSs), such as Li-Fraumeni syndrome. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has not been associated with mutagenic risks. We describe the case of a child with LFS and a history of treated choroid plexus carcinoma (CPC) who developed a second primary glial tumor that was safely treated with magnetic resonance imaging (MRI)-guided LITT. A 4-year-old male with left parietal World Health Organization grade III CPC associated with a TP53 germline mutation was evaluated. The patient underwent neoadjuvant platinum-based chemotherapy before near-total resection, followed by 131I-8H9 immunotherapy and 30 fractions of 54-Gy proton radiotherapy. He remained without evidence of disease for 2 years before developing a slow-growing mass adjacent to the left frontal ventricular horn. Stereotactic biopsy revealed a glial neoplasm. Given the nonsuperficial location and focality of the lesion, MRI-guided LITT was performed for ablative therapy. There were no complications, and 2 years of surveillance revealed continued retraction of the ablated tumor focus and no subsequent disease. Alternatives to mutagenic therapies for brain tumors should be explored for patients with CPS. LITT paired with imaging surveillance is a logical strategy to ensure durable outcomes and mitigate treatment-related secondary neoplasms.

LET Dependence of 8-Hydroxy-2'-deoxyguanosine (8-OHdG) Generation in Mammalian Cells under Air-Saturated and Hypoxic Conditions: A Possible Experimental Approach to the Mechanism of the Decreasing Oxygen Effect in the High-LET Region.

One of the most distinguished features in biological effects of heavy ions would be the decrease of oxygen effect in the high-LET region. This feature has been referred to as the radiobiological basis for the control of hypoxic fraction in cancer radiotherapy. However, mechanisms to explain this phenomenon have not been fully understood. One of the explanations was given by the oxygen in the track hypothesis, which proposes that oxygen is produced along ion tracks even in the hypoxic irradiation condition. In the present study, we designed an experimental approach to support this hypothesis by using 8-hydroxy-2'-deoxyguanosine (8-OHdG) as DNA damage requiring oxygen to produce. The LET dependence of 8-OHdG under hypoxic condition revealed that with increasing LET 8-OHdG yield seems to increase, despite that the yield of OH radical, which is also required for the production of 8-OHdG, decreases in the high-LET region. This result is consistent with the explanation that the local generation of oxygen along ion tracks contributes to the increase of 8-OHdG yield.

A prospective study of changes in bone health in adult cancer patients treated with pelvic radiotherapy.

Cancer is a major health problem in today's world. Many patients of pelvic malignancies need treatment by radiation therapy. Post-treatment morbidity due to loss of bone health is less commonly studied. Our study aims at studying the impact of pelvic radiation therapy on bone health including bone mineral density and blood parameters and time of maximum change in Indian patients after pelvic radiotherapy. Patients suffering from histologically confirmed pelvic malignancies were included. Patients having metastasis, primary bone tumor or uncontrolled co-morbid conditions were excluded. Patients were treated with concomitant chemoradiation using conventional fractionation of external beam radiotherapy followed by brachytherapy where indicated. T score and Z score of bone mineral density, serum alkaline phosphatase, vitamin D3, phosphorus and calcium were measured before radiation therapy and 6 weeks, three months, and six months after completion of radiation therapy. A p-value ≤ 0.05 was considered statistically significant. We found that there was a significant decrease in mean Z score and a significant rise of mean serum alkaline phosphatase at three months post radiation therapy. This was associated with an insignificant changes of mean T score, vitamin D3, phosphorus and calcium after radiation therapy. No pelvic insufficiency fractures were detected. In Indian patients, alkaline phosphatase rises, and Z score falls significantly after radiation therapy at three months after treatment. This suggests maximum bone turnover at three months after treatment. Pharmacological intervention, when necessary, may be considered by careful monitoring of patients by this time.

Setup margins based on the inter- and intrafractional setup error of left-sided breast cancer radiotherapy using deep inspiration breath-hold technique (DIBH) and surface guided radiotherapy (SGRT).

The use of volumetric modulated arc therapy (VMAT), simultaneous integrated boost (SIB), and hypofractionated regimen requires adequate patient setup accuracy to achieve an optimal outcome. The purpose of this study was to assess the setup accuracy of patients receiving left-sided breast cancer radiotherapy using deep inspiration breath-hold technique (DIBH) and surface guided radiotherapy (SGRT) and to calculate the corresponding setup margins. The patient setup accuracy between and within radiotherapy fractions was measured by comparing the 6DOF shifts made by the SGRT system AlignRT with the shifts made by kV-CBCT. Three hundred and three radiotherapy fractions of 23 left-sided breast cancer patients using DIBH and SGRT were used for the analysis. All patients received pre-treatment DIBH training and visual feedback during DIBH. An analysis of variance (ANOVA) was used to test patient setup differences for statistical significance. The corresponding setup margins were calculated using the van Herk's formula. The intrafractional patient setup accuracy was significantly better than the interfractional setup accuracy (p<0.001). The setup margin for the combined inter- and intrafractional setup error was 4, 6, and 4mm in the lateral, longitudinal, and vertical directions if based on SGRT alone. The intrafractional error contributed ≤1mm to the calculated setup margins. With SGRT, excellent intrafractional and acceptable interfractional patient setup accuracy can be achieved for the radiotherapy of left-sided breast cancer using DIBH and modern radiation techniques. This allows for reducing the frequency of kV-CBCTs, thereby saving treatment time and radiation exposure.

Predicting Radiotherapy Patient Outcomes with Real-Time Clinical Data Using Mathematical Modelling

Longitudinal tumour volume data from head-and-neck cancer patients show that tumours of comparable pre-treatment size and stage may respond very differently to the same radiotherapy fractionation protocol. Mathematical models are often proposed to predict treatment outcome in this context, and have the potential to guide clinical decision-making and inform personalised fractionation protocols. Hindering effective use of models in this context is the sparsity of clinical measurements juxtaposed with the model complexity required to produce the full range of possible patient responses. In this work, we present a compartment model of tumour volume and tumour composition, which, despite relative simplicity, is capable of producing a wide range of patient responses. We then develop novel statistical methodology and leverage a cohort of existing clinical data to produce a predictive model of both tumour volume progression and the associated level of uncertainty that evolves throughout a patient’s course of treatment. To capture inter-patient variability, all model parameters are patient specific, with a bootstrap particle filter-like Bayesian approach developed to model a set of training data as prior knowledge. We validate our approach against a subset of unseen data, and demonstrate both the predictive ability of our trained model and its limitations.

Understanding the impact of radiotherapy fractionation on overall survival in a large head and neck squamous cell carcinoma dataset: a comprehensive approach combining mechanistic and machine learning models.

Treating head and neck squamous cell carcinomas (HNSCC), especially human papillomavirus negative (HPV-) and locally advanced cases, remains difficult. Our previous analyses of radiotherapy-only HNSCC clinical trials data using mechanistically-motivated models of tumor repopulation and killing by radiotherapy predicted that hyperfractionation with twice-daily fractions, or hypofractionation involving increased doses/fraction and reduced treatment durations, both improve tumor control and reduce late normal tissue toxicity, compared with standard protocols using 35×2 Gy. Here we further investigated the validity of these conclusions by analyzing a large modern dataset on 3,346 HNSCC radiotherapy patients from the University Health Network in Toronto, Canada, where 42.5% of patients were also treated with chemotherapy. We used a two-step approach that combines mechanistic modeling concepts with state-of-the-art machine learning, beginning with Random Survival Forests (RSF) for an exploratory analysis and followed by Causal Survival Forests (CSF) for a focused causal analysis. The mechanistic concept of biologically effective dose (BED) was implemented for the standard dose-independent (DI) tumor repopulation model, our alternative dose-dependent (DD) repopulation model, and a simple model with no repopulation (BEDsimp). These BED variants were included in the RSF model, along with age, stage, HPV status and other relevant variables, to predict patient overall survival (OS) and cause-specific mortality (deaths from the index cancer, other cancers or other causes). Model interpretation using Shapley Additive Explanations (SHAP) values and correlation matrices showed that high values of BEDDD or BEDDI, but not BEDsimp, were associated with decreased patient mortality. Targeted causal inference analyses were then performed using CSF to estimate the causal effect of each BED variant on OS. They revealed that high BEDDD (>61.8 Gy) or BEDDI (>57.6 Gy), but not BEDsimp, increased patient restricted mean survival time (RMST) by 0.5-1.0 years and increased survival probability (SP) by 5-15% several years after treatment. In addition to population-level averages, CSF generated individual-level causal effect estimates for each patient, facilitating personalized medicine. These findings are generally consistent with those of our previous mechanistic modeling, implying the potential benefits of altered radiotherapy fractionation schemes (e.g. 25×2.4 Gy, 20×2.75 Gy, 18×3.0 Gy) which increase BEDDD and BEDDI and counteract tumor repopulation more effectively than standard fractionation. Such regimens may represent potentially useful hypofractionated options for treating HNSCC.

Improved effectiveness of X-PDT against human triple-negative breast cancer cells through the use of liposomes co-loaded with protoporphyrin IX and perfluorooctyl bromide.

In this study, we utilized X-ray-induced photodynamic therapy (X-PDT) against triple-negative breast cancer (TNBC) cells. To achieve this, we developed a liposome delivery system that co-loaded protoporphyrin IX (PPIX) and perfluorooctyl bromide (PFOB) in a rational manner. Low-dose X-ray at 2 Gy was employed to activate PPIX for the generation of reactive oxygen species (ROS), and the co-loading of PFOB provided additional oxygen to enhance ROS production. The resulting highly toxic ROS effectively induced cell death in TNBC. In vitro X-PDT effects, including intracellular ROS generation, cell viability, and apoptosis/necrosis assays in TNBC cells, were thoroughly investigated. Our results indicate that the nanocarriers effectively induced X-PDT effects with very low-dose radiation, making it feasible to damage cancer cells. This suggests the potential for the effective utilization of X-PDT in treating hypoxic cancers, including TNBC, with only a fraction of conventional radiotherapy.

Long-term treatment results of conventional and hypofractionation radiotherapy in postmastectomy cancer breast patients: A retrospective study from rural cancer center of Maharashtra, India.

This study aims to evaluate the long-term treatment outcome of conventional and hypofractionation radiotherapy in postmastectomy cancer breast patients. A total of 140 postmastectomy breast cancer patients were included in this retrospective study, who were treated from 2012 to 2014 with chemotherapy and various fractionation radiotherapy schedules. Radiotherapy treatment records for study group-I received radiotherapy 4256 cGy in 16 fractions over 3½ weeks, group-II patients received 4005 cGy in 15 fractions over 3 weeks, and conventional radiotherapy group-III received 5000 cGy in 25 fractions over 5 weeks. The median follow-up of patients from all groups was 60 months (range 9 to 111 months). There were 39 cases with disease failure, 13 (26%) in group I (42.56 Gy), 16 (40%) in group II (40.05 Gy), and 10 (20%) in group III (50 Gy). There were 4 locoregional recurrences (LRRs), two isolated, and 11 distant failures in group I, 3 LRRs (1 isolated LRR) and 15 distant failures in group II, and only one LRR and 9 distant failures in group III. The disease-free survival (DFS) were 74%, 60%, and 80%, respectively, in groups I, II, and III (P =0.044). The long-term results of this study show that hypofractionation radiotherapy in postmastectomy cases is well tolerated and acute and late side effects are also comparable to conventional fractionation. In our study, locoregional and distant failure seems slightly higher with hypofractionation schedules than in other studies, highlighting the need for more studies with long-term follow-up in postmastectomy patients.

Comparative efficacy of palliative radiotherapy dose schedules in advanced bladder cancer-associated gross hematuria.

Gross hematuria (GH) in advanced/inoperable bladder cancer patients causes significant morbidity. Patients frequently need multiple transfusions. Hypofractionated radiotherapy (RT) has been shown to be effective in symptom palliation. In this study, we explore the efficacy of various fractionation regimens in these patients. This single institute retrospective analysis was conducted on 60 consecutive patients treated with palliative RT. Fractionation (single versus multiple) and biologically equivalent doses (BED; high ≥36 Gy versus low <36 Gy) were used to compare the efficacy of various fractionation regimens. The primary outcome was the difference in objective response rate (ORR) between various strata at 2, 4, 8 and 12 weeks. Major secondary outcomes were differences in ORR according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and tumour node metastases (TNM) stage, and the proportion of patients requiring re-transfusion(s) at 12 weeks. Data were analysed using SPSS 23. Overall ORR at 2, 4, 8 and 12 weeks was 86%, 77%, 67% and 55%, respectively. There was no statistically significant difference in response rates between single or multi-fraction, or high versus low BED groups (All p = >0.05). Moreover, ECOG PS (p = 0.11) or TNM stage (p = 0.58) also had no impact on the response rate at 12 weeks. Nearly one-third (31%) of patients required further transfusions at 12 weeks. RT is an effective modality to control GH. No difference in ORR was found between single fractions versus multiple fractions, or high versus low BED regimens. Single fraction RT can be offered to these patients considering low cost, patient convenience and minimal side effects.

Radiotherapy and blockade of immune checkpoints in treatment of cancer patients

Background. Immunotherapy, which aims to use immune defense mechanisms to fight cancer, is a new area of anticancer treatment. A major breakthrough in tumor immunotherapy was the discovery of immune checkpoint proteins, which act as powerful suppressors of the immune system. Humanized monoclonal antibodies, which target these proteins, have proven to be clinically effective in patients with different types of cancer. However, the majority of patients do not respond to checkpoint inhibitor therapy, which necessitates the use of combination strategies to overcome resistance to immunotherapy. In recent years, the combination of radiotherapy and immune checkpoint inhibitors has attracted considerable attention and has been widely studied in preclinical and clinical trials. Much attention is given to the optimization of combined treatment regimens. However, the optimal radiation dose, fractionation scheme, radiation volumes, and radiation sequence in checkpoint inhibitor treatment still remain unclear. Purpose – to analyze and summarize data from preclinical and clinical trials aimed at solving problems related to the choice of optimal doses, fractionation, radiation volume, and sequencing of checkpoint inhibitor immunotherapy and radiotherapy. Materials and methods. For data search, we used Cochrane library and databases (Pubmed, Scopus, Google Scholar). The results of the studies published over the period from 2008 to 2023 were analyzed. Results and discussion. The evidence of the rationality of combining radiotherapy and checkpoint inhibitors in the treatment of cancer patients is shown. The data on the effects of radiation dose and fractionation on antitumor immune responses were analyzed. The results of works that deal with the search for the optimal sequence of radiotherapy and immune checkpoint inhibitors and the selection of the irradiation volume necessary for the generation of an effective systemic antitumor immune response are considered. Conclusions. Combined treatment with radiation therapy and immune checkpoint inhibitors is a promising strategy for patients with metastatic tumors. Preclinical and clinical data indicate that different radiation regimens can cause different effects on antitumor immunity. Further studies of doses and fractionation regimens of radiation therapy, irradiation volume, and the optimal time for each component of combination therapy are needed to determine the conditions for maximizing the immune response. The obtained results will help optimize the combination treatment regimens and wider implementation of such treatment in clinical practice.