Radiobiological Parameters Research Articles

Modelling a new approach for radio-ablation after resection of breast ductal carcinoma in-situ based on the BAT-90 medical device

The majority of local recurrences, after conservative surgery of breast cancer, occurs in the same anatomical area where the tumour was originally located. For the treatment of ductal carcinoma in situ (DCIS), a new medical device, named BAT-90, (BetaGlue Technologies SpA) has been proposed. BAT-90 is based on the administration of 90Y β-emitting microspheres, embedded in a bio-compatible matrix. In this work, the Geant4 simulation toolkit is used to simulate BAT-90 as a homogenous cylindrical 90Y layer placed in the middle of a bulk material. The activity needed to deliver a 20 Gy isodose at a given distance z from the BAT-90 layer is calculated for different device thicknesses, tumour bed sizes and for water and adipose bulk materials. A radiobiological analysis has been performed using both the Poisson and logistic Tumour Control Probability (TCP) models. A range of radiobiological parameters (α and β), target sizes, and densities of tumour cells were considered. Increasing α values, TCP increases too, while, for a fixed α value, TCP decreases as a function of clonogenic cell density. The models predict very solid results in case of limited tumour burden while the activity/dose ratio could be further optimized in case of larger tumour beds.

Dosimetric and radiobiological evaluation of treatment plan for cervical cancer high-dose-rate intracavitary brachytherapy.

PurposeThe purpose of the study was to consider and calculate dosimetric parameters during treatment planning to improve radiobiological outcomes for cervical cancer patients treated with high-dose-rate (HDR) intracavitary brachytherapy (ICBT).Material and methodsIn the present study, dose volume histograms (DVH) of 30 cervical cancer patients treated with HDR brachytherapy using computer tomography (CT)-based planning were analyzed. High-risk clinical target volume (HR-CTV) was contoured as the main target volume for all the patients, with an assumption that there was no presence of gross tumor at the time of brachytherapy. Values of target coverage volumes (100%, 150%, and 200%) were obtained from DVH, which was used to calculate different quality indices (QIs), including coverage index (CI), dose homogeneity index (DHI), overdose volume index (ODI), and dose non-uniformity ratio (DNR). Values of these QIs were further used to calculate tumor control probability (TCP). Statistical correlation between all QIs with TCP was established. Also, normal tissue complication probabilities for bladder (NTCP_B) and rectum (NTCP_R) were calculated.ResultsThe mean values of the various calculated parameters, including CI, DHI, ODI, DNR, TCP, NTCP_B and NTCP_R were 0.92 ±0.07, 0.26 ±0.10, 0.50 ±0.10, 0.74 ±0.10, 0.92 ±0.07, 0.08 ±0.25, and 0.36 ±0.27, respectively. Pearson’s product moment correlation coefficient between CI, DHI, ODI, and DNR with regards to TCP was +0.85, –0.85, +0.84, and +0.85, respectively.ConclusionsThe correlation between dosimetric and radiobiological parameters was found statistically significant, which shows the influence of dosimetric parameters on the radiobiological outcome. Therefore, these parameters should be considered during the treatment planning to improve the radiobiological outcome.

A Systematic Approach to Optimise the Number of Beams for Intensity Modulated Radiotherapy in Pituitary Adenoma using Radiobiological Parameters

Introduction: The number of beams used in a Radiotherapy (RT) plan effects the overall quality of the plan and hence the treatment. The inclusion of radiobiological concepts in finding the optimum number of beams for a particular planning technique has the potential to provide a step ahead of the routine clinical practice where clinical decisions are more dependent on the physical dose parameters. Aim: To optimise the number of beams for Intensity Modulated Radiotherapy (IMRT) plan based on Tumour Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) biological parameters. Materials and Methods: This retrospective study was done on 30 patients with pituitary macro-adenoma who underwent radiotherapy with a prescribed dose of 50.4 Gy in 28 fractions in Delhi State Cancer Institutes, Delhi, India from December 2012 to August 2018. The study data was collected and analysed between June 2018 and April 2020. These patients were treated with step and shoot IMRT technique on ONCORTM Expression linear accelerator (Siemens Healthineers, USA). But, the number of beams used to deliver IMRT plans were different as decided by the medical physicist and hence planner dependent rather than the disease. Being a centrally located disease, a symmetric beam arrangement was adopted for IMRT planning. For dosimetric comparison, three IMRT plans with five, seven, and nine equispaced beams were generated in Monaco treatment planning system for each patient and thus, a total of 90 IMRT plans were created and evaluated. For fair comparison, same IMRT planning parameters were utilized in all three plans of each patient. Monte Carlo (MC) dose calculation algorithm was used for all the plans. Resulting Cumulative Dose Volume Histograms (CDVHs) were exported to MATLAB, where these cDVHs were processed as per Niemierko’s radiobiological model to calculate the values of TCP and NTCP based on the Equivalent Uniform Dose (EUD). After this, the analysis of variance, ANOVA test was conducted over the resulting values of EUD, TCP, and NTCP to assess the difference of quality among plans having different beam arrangements at 0.05 level of significance. Results: The mean tumour control probability (TCP) for IMRT plans with seven and nine beams were found to be 89.0±0.8% and 89.1±0.9% respectively for planning target volume (PTV). These values were not significantly different from each other. However, the mean TCP value for IMRT plans with five beams was found to be 88.4±1.1% for PTV. Further, this TCP value was proved to be significantly lower as compared to IMRT plans with seven and nine beams with a p-value of 0.008 and 0.004 respectively. On the other hand, the mean Normal Tissue Complication Probability (NTCP) was assessed to be less than 1% for all critical organs irrespective of the beam arrangement, indicating almost no probability of radiation induced toxicity in any of the organ. Conclusion: This study concludes that the plan efficiency can be improved by using optimum number of beams for IMRT planning of pituitary adenoma.

Determining the optimum tumor control probability model in radiotherapy of glioblastoma multiforme using magnetic resonance imaging data pre- and post- radiation therapy

Background:Glioblastoma multiforme (GBM) is the most common and malignant brain tumor. The current standard of care is surgery followed by radiation therapy (RT). Radiotherapy treatment plan evaluation relies on radiobiological models for accurate estimation of tumor control probability (TCP). This study aimed to assess the impact of obtained magnetic resonance imaging (MRI) data before and 12 weeks after RT to achieve the optimum TCP model to improve dose prescriptions in radiation therapy of GBM.Materials and Methods::In this quasi-experimental study, MR images and its relevant data from 30 patients consisting of 9 females and 21 males (mean age of 46.3 ± 15.8 years) diagnosed with GBM, whose referred for radiotherapy were selected. The data of age, gender, tumor size, volume, and signal intensity using analysis of MRI data pre- and postradiotherapy were used for calculating TCP. TCP was calculated from three common radiobiological models including Poisson, linear quadratic, and equivalent uniform dose. The impact of some radiobiological parameters on final TCP in all patients planned with three-dimensional conformal radiation therapy was obtained.Results:A statistically significant difference was found among TCP in Poisson model compared to the other two models (P < 0.001). Changes in tumor volume and size after treatment were statistically significant (P < 0.05). Different combinations of radiobiological parameters (α/β and SF2 in all models) observed were meaningful (P < 0.05).Conclusion:The results showed that among TCP radiobiological models, the optimum is the Poisson. The results also identified the importance of TCP radiobiological models in order to improve radiotherapy dose prescriptions.

A Practical Workflow to Calculate 3D BED Composite Plan Using Organ-Specific Radiobiological Parameters

Biological effective dose (BED) distribution calculation is desirable for combining multiple treatments based on image sets at different times and/or with different fractionations, e.g., re-irradiation. In addition, the composite BED plan needs to be converted back to a physical dose plan in a common fractionation for plan evaluation and/or comparison. The purpose of this work is to develop a practical workflow to composite 3D BED plan and to convert it back to a physical dose plan.The workflow was developed using contouring software. The organ-specific radiobiological parameters (e.g., α/β, γ/α and dt) for different organs at risk (OAR) were obtained by fitting available clinical dose volume constraint data using a linear-quadratic-linear (LQ-L) model and were stored in the software. The BEDs in each voxel for two separate treatments were calculated using the LQ-L model for each OAR. By contour-based deformable image registration (DIR) algorithm in the software, the two images were registered to obtain a 3D composite BED. Using the rearranged LQ-L model in the software extension, the physical dose was calculated for a given fractionation scheme voxel by voxel from the 3D composite BED.The contouring software workflow along with the organ-specific BED parameters was implemented and successfully tested with two head and neck cancer re-irradiation cases. Case I was initially treated with 36 Gy in 6 fractions in 2017 and was re-irradiated with 35 Gy in 5 fractions in 2020. The case II had the first treatment of 70 Gy in 35 fractions in 2008 and the second treatment with 40 Gy in 5 fractions in 2020. The composite BED distributions calculated by the contouring software workflow were converted back to physical dose distributions with 2 Gy per fraction. The total physical doses received by the OARs after second treatments were all within acceptable clinical dose limits, consistent with the fact that no radiation related toxicity was reported for both patients. The obtained organ-specific parameters and the calculation results for these two cases are tabulated below.A practical workflow along with organ-specific radiobiological parameters was developed to generate BED composite plan and to convert it back into physical dose distribution. This study provides an additional tool to evaluate overall dose for each OAR in re-irradiation or iso-toxic adaptive radiation therapy.

Evaluation on dosimetric plan quality and treatment delivery time of dynamic jaw mode in TomoTherapy® for left-side breast cancer patients

Abstract Background: Few studies claimed that dynamic jaw (DJ) mode in Helical TomoTherapy® (HT) could improve the cranio-caudal dose distribution without prolonging the treatment time in treating different types of cancer. Also, studies suggested that DJ with a wider 5 cm field width (FW) could replace fixed jaws (FJ) with 2.5 cm FW to reduce the delivery time with the sustainable plan quality. Yet, the study on breast cancer with supraclavicular fossa (SCF) nodal involvement using DJ mode in HT is limited. This study aims to evaluate the DJ mode retrospectively by comparing their dosimetric quality with normal tissue complication probability (NTCP) of organs at risk and treatment delivery time with FJ mode on treating left-side breast with SCF nodal involvement. Materials and methods: All post-mastectomy patients, who had been irradiated for left-side breast with SCF nodal involvement were selected retrospectively in this study. With the same dose constraint and prescription as the treated DJ2.5 plan, two extra plans using DJ mode with 5 cm FW(DJ5.0) and FJ mode with 2.5 cm FW (FJ2.5) were computed for plan comparison. Results: No statistical significance was found in all the parameters of PTV and OARs, except for V20 of whole lung. DJ5.0 received V20 in ipsilateral left lung than FJ2.5 and DJ2.5. However, the average delivery time of DJ5.0 was significantly lower than that of DJ2.5 and FJ2.5 by almost 40%. Conclusions: No statistical significance was found in those dosimetric and radiobiological parameters among three modes while the delivery time has greatly reduced by using DJ5.0. A shorter treatment time can minimise intra-fractional error and better the patient’s experience during treatment.

Radiobiological modeling of radiation-induced acute rectal mucositis: A single-institutional study of cervical carcinoma.

This study aimed to estimate the fitting parameters of sigmoidal dose-response (SDR) curve of radiation-induced acute rectal mucositis in pelvic cancer patients treated with Intensity Modulated Radiation Therapy (IMRT) for the calculation of normal tissue complication probability (NTCP). Thirty cervical cancer patients were enrolled to model the SDR curve for rectal mucositis. The patients were evaluated weekly for acute radiation-induced (ARI) rectal mucositis toxicity and their scoring was performed as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The radiobiological parameters, namely n, m, TD50, and γ50 were calculated from the fitted SDR curve obtained from the clinical data of cervical cancer patients. ARI toxicity for rectal mucosa in carcinoma of cervical cancer patients was calculated for the endpoint rectal mucositis. The n, m, TD50, and γ50 parameters from the SDR curve of Grade 1 and Grade 2 rectal mucositis were found to be 0.328, 0.047, 25.44 ± 1.21 (confidence interval [CI]: 95%), and 8.36 and 0.13, 0.07, 38.06 ± 2.94 (CI: 95%), and 5.15, respectively. This study presents the fitting parameters for NTCP calculation of Grade 1 and Grade 2 ARI rectal toxicity for the endpoint of rectal mucositis. The provided nomograms of volume versus complication and dose versus complication for different grades of rectal mucositis help radiation oncologists to decide the limiting dose to reduce the acute toxicities.

Radiobiological modeling of radiation-induced acute mucosal toxicity (oral mucositis and pharyngeal mucositis): A single-institutional study of head-and-neck carcinoma.

This study aimed to estimate the fitting parameters of sigmoidal dose-response (SDR) curve of radiation-induced acute oral and pharyngeal mucositis in head-and-neck (H and N) cancer patients treated with Intensity Modulated Radiation Therapy (IMRT) for the calculation of normal tissue complication probability (NTCP). Thirty H-and-N cancer patients were enrolled to model the SDR curve for oral and pharyngeal mucositis. The patients were evaluated weekly for acute radiation-induced (ARI) oral and pharyngeal mucositis toxicity, and their scoring was performed as per the common terminology criteria adverse events version 5.0. The radiobiological parameters, namely n, m, TD50, and γ50 were calculated from the fitted SDR curve obtained from the clinical data of H-and-N cancer patients. ARI toxicity for oral and pharyngeal mucosa in carcinoma of H-and-N cancer patients was calculated for the endpoint oral mucositis and pharyngeal mucositis. The n, m, TD50, and γ50 parameters from the SDR curve of Grade 1 and Grade 2 oral mucositis were found to be [0.10, 0.32, 12.35 ± 3.90 (confidence interval [CI] 95%) and 1.26] and [0.06, 0.33, 20.70 ± 6.95 (CI 95%) and 1.19] respectively. Similarly for pharyngeal mucositis, n, m, TD50, and γ50 parameters for Grade 1 and Grade 2 were found to be [0.07, 0.34, 15.93 ± 5.48 (CI. 95%) and 1.16 ] and [0.04, 0.25, 39.02 ± 9.98(CI. 95%) and 1.56] respectively. This study presents the fitting parameters for NTCP calculation of Grade 1 and Grade 2 ARI toxicity for the endpoint of oral and pharyngeal mucositis. The provided nomograms of volume versus complication and dose versus complication for different grades of oral mucositis and pharyngeal mucositis help radiation oncologists to decide the limiting dose to reduce the acute toxicities.

Assessment of radiation sensitivity of unresectable intrahepatic cholangiocarcinoma in a series of patients submitted to radioembolization with yttrium-90 resin microspheres

Radioembolization is a valuable therapeutic option in patients with unresectable intrahepatic cholangiocarcinoma. The essential implementation of the absorbed dose calculation methods should take into account also the specific tumor radiosensitivity, expressed by the α parameter. Purpose of this study was to retrospectively calculate it in a series of patients with unresectable intrahepatic cholangiocarcinoma submitted to radioembolization. Twenty-one therapeutic procedures in 15 patients were analysed. Tumor absorbed doses were calculated processing the post-therapeutic 90Y-PET/CT images and the pre-treatment contrast-enhanced CT scans. Tumor absorbed dose and pre- and post-treatment tumor volumes were used to calculate α and α3D parameters (dividing targeted liver in n voxels of the same volume with specific voxel absorbed dose). A tumor volume reduction was observed after treatment. The median of tumor average absorbed dose was 93 Gy (95% CI 81–119) and its correlation with the residual tumor mass was statistically significant. The median of α and α3D parameters was 0.005 Gy−1 (95% CI 0.004–0.008) and 0.007 Gy−1 (95% CI 0.005–0.015), respectively. Multivariate analysis showed tumor volume and tumor absorbed dose as significant predictors of the time to tumor progression. The knowledge of radiobiological parameters gives the possibility to decide the administered activity in order to improve the outcome of the treatment.

Heuristic estimation of the α/β ratio for a cohort of Mexican patients with prostate cancer treated with external radiotherapy techniques.

The aim of the study was to Estimate and compare the radiobiological ratio α/β with the heuristic method for a cohort of Mexican patients with prostate cancer (PCa) who were treated with external radiotherapy (RT) techniques at three Hospital Institutions in Mexico City. With the Kaplan-Meier technique and the Cox proportional hazards model, the biochemical relapse-free survival (bRFS) is determined and characterized for cohorts of Mexican patients with PCa who received treatment with external RT. Using these clinical outcomes, the radiobiological parameter α/β is determined using the heuristic methodology of Pedicini et. al. The α/β is calculated from the survival curves for different treatment schemes implemented at three distinct hospitals. The Pedicini's techniques allow to determine the parameters α/β, k and N 0 when treatments are not radiobiologically equivalent, therefore, are built up of a set of curved pairs for the biologically effective dose (BED) versus the ratio α/β, where the ratio is given by the intersection for each pair of curves. Six different values of α/β were found: the first α/β = 2.46 Gy, the second α/β = 3.30 Gy, the third for α/β = 3.25 Gy, the fourth α/β = 3.24 Gy, the fifth α/β = 3.38 Gy and the last α/β = 4.08 Gy. These values can be explained as follows: a) The bRFS of the schemes presents a statistical variation; b) The absorbed doses given to the patient present uncertainties on the physical dosimetry that are not on the modeling; c) Finally, in the model for the bRFS of Eq. (3), there are parameters that have to be considered, such as: the number of clonogenic tumor cells N 0 , the overall treatment time (OTT), the kick-off time for tumor repopulation T k and the repopulation doubling time. Therefore, the mean value to α/β for all schemes has an average value of 3.29 (± 0.52) Gy. The value of is determined from cohorts of Mexican patients with PC a treated with external radiotherapy using the time-dependent LQ model, which is a higher value with respect to the "dogma" value of α/β 1.5 Gy obtained with the LQ model without temporal dependence. Therefore, there is a possibility of optimizing treatments radiobiologically and improving the results of bRFS in Mexican patients with PCa treated with external radiotherapy.

The feasibility of a dose painting procedure to treat prostate cancer based on mpMR images and hierarchical clustering

BackgroundWe aimed to assess the feasibility of a dose painting (DP) procedure, known as simultaneous integrated boost intensity modulated radiation Therapy (SIB-IMRT), for treating prostate cancer with dominant intraprostatic lesions (DILs) based on multi-parametric magnetic resonance (mpMR) images and hierarchical clustering with a machine learning technique.MethodsThe mpMR images of 120 patients were used to create hierarchical clustering and draw a dendrogram. Three clusters were selected for performing agglomerative clustering. Then, the DIL acquired from the mpMR images of 20 patients were categorized into three groups to have them treated with a DP procedure being composed of three planning target volumes (PTVs) determined as PTV1, PTV2, and PTV3 in treatment plans. The DP procedure was carried out on the patients wherein a total dose of 80, 85 and 91 Gy were delivered to the PTV1, PTV2, and PTV3, respectively. Dosimetric and radiobiologic parameters [Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP)] of the DP procedure were compared with those of the conventional IMRT and Three-Dimensional Conformal Radiation Therapy (3DCRT) procedures carried out on another group of 20 patients. A post-treatment follow-up was also made four months after the radiotherapy procedures.ResultsAll the dosimetric variables and the NTCPs of the organs at risks (OARs) revealed no significant difference between the DP and IMRT procedures. Regarding the TCP of three investigated PTVs, significant differences were observed between the DP versus IMRT and also DP versus 3DCRT procedures. At post-treatment follow-up, the DIL volumes and apparent diffusion coefficient (ADC) values in the DP group differed significantly (p-value < 0.001) from those of the IMRT. However, the whole prostate ADC and prostate-specific antigen (PSA) indicated no significant difference (p-value > 0.05) between the DP versus IMRT.ConclusionsThe results of this comprehensive clinical trial illustrated the feasibility of our DP procedure for treating prostate cancer based on mpMR images validated with acquired patients’ dosimetric and radiobiologic assessment and their follow-ups. This study confirms significant potential of the proposed DP procedure as a promising treatment planning to achieve effective dose escalation and treatment for prostate cancer.Trial registration: IRCT20181006041257N1; Iranian Registry of Clinical Trials, Registered: 23 October 2019, https://en.irct.ir/trial/34305.

Detailed dosimetry calculation for in-vitro experiments and its impact on clinical BNCT.

Boron Neutron Capture Therapy (BNCT) is a form of hadrontherapy based on the selective damage caused by the products of neutron capture in 10B to tumour cells. BNCT dosimetry strongly depends on the parameters of the dose calculation models derived from radiobiological experiments. This works aims at determining an adequate dosimetry for in-vitro experiments involving irradiation of monolayer-cultured cells with photons and BNCT and assessing its impact on clinical settings. M&M: Dose calculations for rat osteosarcoma UMR-106 and human metastatic melanoma Mel-J cell survival experiments were performed using MCNP, transporting uncharged particles for KERMA determinations, and secondary particles (electrons, protons, 14C, 4He and 7Li) to compute absorbed dose in cultures. Dose-survival curves were modified according to the dose correction factors determined from computational studies. New radiobiological parameters of the photon isoeffective dose models for osteosarcoma and metastatic melanoma tumours were obtained. Dosimetry implications considering cutaneous melanoma patients treated in Argentina with BNCT were assessed and discussed. KERMA values for the monolayer-cultured cells overestimate absorbed doses of radiation components of interest in BNCT. Detailed dose calculations for the osteosarcoma irradiation increased the relative biological effectiveness factor RBE1% of the neutron component in more than 30%. The analysis based on melanoma cases reveals that the use of survival curves based on KERMA leads to an underestimation of the tumour doses delivered to patients. Considering detailed dose calculation for in-vitro experiments significantly impact on the prediction of the tumor control in patients. Therefore, proposed methods are clinically relevant.

Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) in Mono and Dual-isocentric Techniques of Breast Cancer Radiation Therapy

Background: Nowadays, radiation therapy plays an important role in the treatment of breast cancer. The important point is the optimal control of the tumor along with the protection of organs at risk. This study aims to investigate and compare the radiobiological factors of the tumor and organs at risk in two different radiation therapy techniques of breast cancer.Methods: Ten left-sided breast cancer patients with breast-conservative surgery were selected for this study. Three-dimensional treatment planning was performed using CT scan images of the patients using PCRT 3D software. Two different tangential external beam techniques were compared: first, dual-isocentric technique (DIT) with two isocentre, one on the breast tissue, and the other one on the supraclavicular lymph nodes and second, a mono-isocentric technique (MIT) with one isocentre at the intersection of the tangential and the supraclavicular field. The total prescribed dose was 5000 cGy per 25 fractions. Dose-volume histograms (DVHs), Tumor control probability (TCP), and normal tissue complication probability (NTCP) curves were used to compare the dosimetric and radiobiological parameters of the tissues in the prementioned techniques. Results: The results showed that the maximum doses in planning target volume (PTV) with mean values of 109% and 110% in the SI and DIT were not significantly different in both techniques and that they were indeed at the optimum level based on the RTOG 1005 protocol. The dose homogeneity index in MMIT was more than that in DIT, while the conformity index and the mean TCP did not show a significant difference in the two techniques. Furthermore, minimum, mean, and maximum dose in the lung and the probability of pneumonitis decreased in MIT. On the other hand, the maximum dose, the dose of 33%, 66%, and 100% of the heart, and the probability of pericarditis in MIT were lower than the figure in DIT. Conclusion: Due to the absence of hot spots at the intersection of tangential and supraclavicular fields and the reduction of mechanical movements of the coach and collimator in MIT, the superiority of this method was confirmed.

Patient-Derived Nasopharyngeal Cancer Organoids for Disease Modeling and Radiation Dose Optimization.

Effective radiation treatment (RT) for recurrent nasopharyngeal cancers (NPC), featuring an intrinsic hypoxic sub-volume, remains a clinical challenge. Lack of disease‐specific in-vitro models of NPC, together with difficulties in establishing patient derived xenograft (PDX) models, have further hindered development of personalized therapeutic options. Herein, we established two NPC organoid lines from recurrent NPC PDX models and further characterized and compared these models with original patient tumors using RNA sequencing analysis. Organoids were cultured in hypoxic conditions to examine the effects of hypoxia and radioresistance. These models were then utilized to determine the radiobiological parameters, such as α/β ratio and oxygen enhancement ratio (OER), characteristic to radiosensitive normoxic and radioresistant hypoxic NPC, using simple dose-survival data analytic tools. The results were further validated in-vitro and in-vivo, to determine the optimal boost dose and fractionation regimen required to achieve effective NPC tumor regression. Despite the differences in tumor microenvironment due to the lack of human stroma, RNA sequencing analysis revealed good correlation of NPC PDX and organoid models with patient tumors. Additionally, the established models also mimicked inter-tumoral heterogeneity. Hypoxic NPC organoids were highly radioresistant and had high α/β ratio compared to its normoxic counterparts. In-vitro and in-vivo fractionation studies showed that hypoxic NPC was less sensitive to RT fractionation scheme and required a large bolus dose or 1.4 times of the fractionated dose that was effective against normoxic cells in order to compensate for oxygen deficiency. This study is the first direct experimental evidence to predict optimal RT boost dose required to cause sufficient damage to recurrent hypoxic NPC tumor cells, which can be further used to develop dose-painting algorithms in clinical practice.

Photon beam energy dependent single-arc volumetric modulated arc optimization.

The purpose of this work was to present a new single-arc mixed photon (6&18MV) VMAT (SAMP) optimization framework that concurrently optimizes for two photon energies with corresponding partial arc lengths. Owing to simultaneous optimization of energy dependent intensity maps and corresponding arc locations, the proposed model poses nonlinearity. Unique relaxation constraints based on McCormick approximations were introduced for linearization. Energy dependent intensity maps were then decomposed to generate apertures. Feasibility of the proposed framework was tested on a sample of ten prostate cancer cases with lateral separation ranging from 34 cm (case no.1) to 52cm (case no.6). The SAMP plans were compared against single energy (6MV) VMAT (SE) plans through dose volume histograms (DVHs) and radiobiological parameters including normal tissue complication probability (NTCP) and equivalent uniform dose (EUD). The contribution of higher energy photon beam optimized by the algorithm demonstrated an increase for cases with a lateral separation >40cm. SAMP-VMAT notably improved bladder and rectum sparing in large size cases. Compared to single energy, SAMP-VMAT plans reduced bladder and rectum NTCP in cases with large lateral separation. With the exception of one case, SAMP-VMAT either improved or maintained femoral heads compared to SE-VMAT. SAMP-VMAT reduced the nontarget tissue integral dose in all ten cases. A single-arc VMAT optimization framework comprising mixed photon energy partial arcs was presented. Overall results underline the feasibility and potential of the proposed approach for improving OAR sparing in large size patients without compromising the target homogeneity and coverage.

Exploiting DNA repair pathways for tumor sensitization, mitigation of resistance, and normal tissue protection in radiotherapy.

More than half of cancer patients are treated with radiotherapy, which kills tumor cells by directly and indirectly inducing DNA damage, including cytotoxic DNA double-strand breaks (DSBs). Tumor cells respond to these threats by activating a complex signaling network termed the DNA damage response (DDR). The DDR arrests the cell cycle, upregulates DNA repair, and triggers apoptosis when damage is excessive. The DDR signaling and DNA repair pathways are fertile terrain for therapeutic intervention. This review highlights strategies to improve therapeutic gain by targeting DDR and DNA repair pathways to radiosensitize tumor cells, overcome intrinsic and acquired tumor radioresistance, and protect normal tissue. Many biological and environmental factors determine tumor and normal cell responses to ionizing radiation and genotoxic chemotherapeutics. These include cell type and cell cycle phase distribution; tissue/tumor microenvironment and oxygen levels; DNA damage load and quality; DNA repair capacity; and susceptibility to apoptosis or other active or passive cell death pathways. We provide an overview of radiobiological parameters associated with X-ray, proton, and carbon ion radiotherapy; DNA repair and DNA damage signaling pathways; and other factors that regulate tumor and normal cell responses to radiation. We then focus on recent studies exploiting DSB repair pathways to enhance radiotherapy therapeutic gain.

Myths, facts and scope of spinal cord tolerance dose revision in Intensity modulated SIB treatment of locally advanced head and neck cancer: A dosimetrical and radiobiological demonstration

PurposeTo explore the possibility of revising the spinal cord tolerance dose in Simultaneously Integrated Boost (SIB) intensity modulated treatment plan of locally advanced head and neck (H&N) cancer and assessment of achieved planning gain due to the revision. In SIB regimen, the Organ at Risk (OARs) tolerance dose is equally distributed throughout the treatment. Clinicians have usually considered the spinal cord tolerance to be the same as in conventional technique. However, in SIB fractionation regimen with intensity modulation treatment, the spinal cord may receive a physical dose of 45Gy, with much lesser dose per fraction than 2Gy per fraction. So when the dose of spinal cord is distributed throughout the treatment, the tolerance dose limit of physical dose can be considered higher than the usual conventional dose limits. In this study, an attempt has been made to explore the possibilities of dose escalation and treatment planning benefits while exploiting this “Window of Opportunity (WoO)” of increase in spinal cord and Planning Risk Volume (PRV) spinal cord tolerance dose. Material and methodsA total of 12 patients CT data set along with approved structure set of H&N cancer used for treatment planning in. Three independent SIB VMAT plans named as SPC, SPR and SPDE were generated for the 12 patients. First plan (SPC) was generated by considering standard spinal cord tissue constraint of maximum dose of 45Gy and PRV spinal cord maximum dose 50Gy as per QUANTEC summary and second plan (SPR) was generated considering spinal cord tissue constraint of maximum dose 52.50Gy and PRV spinal cord maximum dose 56.35Gy while optimization and dose calculation. The objectives for rest of the Organ at Risk (OAR) were kept same in both the plans during optimization and dose calculation. The SPC plan was copied for creation of third plan (SPDE) in which dose was escalated by increasing dose per fraction for target volumes such that dose to spinal cord reached a maximum dose of 52.50Gy and PRV spinal cord maximum dose of 56.35Gy. In this plan there have been changes to only dose per fraction, however dose optimization and dose calculation have not been performed. Radiobiological parameters TCP and NTCP were also calculated by using indigenously developed software. ResultsConsidering the increase of spinal cord tolerance dose as “window of opportunity”, a sufficient escalation in physical dose, Biological Effective Dose (BED) and Tumor Control Probability (TCP) was observed for all target volumes with acceptable level of NTCP values. ConclusionSufficient dose escalation and increased in TCP for target volumes or effective planning benefits can be achieved by revising the spinal cord tolerance dose in intensity modulated SIB treatment of locally advanced H&N cancers.

Microdosimetric measurements as a tool to assess potential in-field and out-of-field toxicity regions in proton therapy

Relative biological effectiveness (RBE) variations are thought to be one of the primary causes of unexpected normal-tissue toxicities during tumor treatments with charged particles. Unlike carbon therapy, where treatment planning is optimized on the basis of the RBE-weighted dose, a constant RBE value of 1.1 is currently used in proton therapy. Assuming a uniform value can lead to under- or over-dosage, not just to the tumor but also to surrounding normal tissue. RBE changes have been linked with dose/fraction, the biological endpoint and beam properties. Understanding radiation quality and the associated RBE can improve the prediction of normal-tissue toxicities.In this study, we exploited microdosimetry for characterizing radiation quality in proton therapy in-field, and off-beam at 20 (beam edge), 50 (close out-of-field) and 100 (far out-of-field) mm from the beam center. We measured the lineal energy y spectra in a water phantom irradiated with 152 MeV protons, from which beam quality as well as the physical dose could be obtained. Taking advantage of the linear quadratic model and a modified version of the microdosimetric kinetic model, the microdosimetric data were combined with radiobiological parameters (α and β) of human salivary gland tumor cells for assessing cell survival RBE and RBE-weighted dose.The results indicate that if a dose of 60 Gy is delivered to the peak, the beam edge receives up to 6 Gy while the close and far out-of-field regions receive doses on the order of 10−3 Gy and 10−4 Gy, respectively. The RBE estimate in-beam shows large variations, ranging from 1.0 ± 0.2 at the entrance channel to 2.51 ± 0.15 at the tail. The beam edge follows a similar trend but the RBE calculated at the Bragg peak depth is 2.27 ± 0.17, i.e. twice the RBE in-beam (1.05 ± 0.15). Out-of-field, the estimated RBE is always significantly higher than 1.1 and increases with increasing lateral distance, reaching the overall highest value of 3.4 ± 0.3 at a depth of 206 mm and a lateral distance of 10 mm. The combination of RBE and dose into the biological dose points to the beam edge and the end-of-range in-beam as the areas with the highest risk of potential toxicities.

Combined 3-O-acetylbetulin treatment and carbonic anhydrase IX inhibition results in additive effects on human breast cancer cells

Hypoxia plays a key role in tumor progression and resistance to radiotherapy. Expression of the transmembrane-tethered enzyme carbonic anhydrase IX (CA IX) is strongly induced by hypoxia. High CA IX expression levels correlate with poor prognosis in cancer patients. Previously, we showed that the downregulation of CA IX expression by siRNA interference and the inhibition of CA IX activity results in increased cytotoxicity, inhibition of migration and radiosensitization of hypoxic cancer cells. Betulinic acid (BA) is a natural compound derived from birch bark. It has shown promising anti-tumor effects due to its cancer cell specific cytotoxic properties. We have shown that BA inhibits the HIF-1α pathway, resulting in apoptosis, inhibition of migration and enhanced cytotoxicity of breast cancer cells. In this study, we investigate the effects of the novel betulin derivative 3-O-acetylbetulin (3-AC) and carbonic anhydrase inhibitors (CAI) octyl disulfamate (OCT) or 4-(3-[4-fluorophenyl]ureido)benzenesulfonamide (SLC-0111), on cellular and radiobiological parameters in MDA-MB-231 and MCF-7 cells. Treatment with 3-AC or OCT alone only caused moderate cytotoxicity, reduction in cell migration, ROS production and DNA damage. However, the combined treatment with 3-AC and CAI strongly enhanced radiosensitivity, increased cytotoxicity, inhibited cell motility and enhanced DNA damage. Our findings suggest that the combination of two bioactive drugs 3-AC and a CAI, such as OCT or SLC-0111, could be a promising therapeutic approach for targeting hypoxic tumor cells.

Evaluation of an Early Regression Index (ERITCP) as Predictor of Pathological Complete Response in Cervical Cancer: A Pilot-Study

Background: Recent studies have highlighted the potentialities of a radiobiological parameter, the early regression index (ERITCP), in the treatment response prediction for rectal cancer patients treated with chemoradiotherapy followed by surgery. The aim of this study is to evaluate the performance of this parameter in predicting pathological complete response (pCR) in the context of low field MR guided radiotherapy (MRgRT) for cervical cancer (CC). Methods: A total of 16 patients affected by CC were enrolled. All patients underwent a MRgRT treatment, with prescription of 50.6 Gy in 22 fractions. A daily MR acquisition was performed at simulation and on each treatment fraction. Gross tumor volume (GTV) was delineated on the MR images acquired at the following biological effective dose (BED) levels: 14, 28, 42, 54 and 62 Gy. The ERITCP was calculated at the different BED levels and its predictive performance was quantified in terms of receiver operating characteristic (ROC) curve. Results: pCR was observed in 11/16 cases. The highest discriminative power of ERITCP was reported when a BED value of 28 Gy is reached, obtaining an area under curve (AUC) of 0.84. Conclusion: This study confirmed ERITCP as a promising response biomarker also for CC, although further studies with larger cohort of patients are recommended.