Optimizing radiation therapy treatments by exploring tumour ecosystem dynamics in-silico

In this contribution, we propose a system-level compartmental population dynamics model of tumour cells that interact with the patient (innate) immune system under the impact of radiation therapy (RT). The resulting in silico - model enables us to analyse the system-level impact of radiation on the tumour ecosystem. The Tumour Control Probability (TCP) was calculated for varying conditions concerning therapy fractionation schemes, radio-sensitivity of tumour sub-clones, tumour population doubling time, repair speed and immunological elimination parameters. The simulations exhibit a therapeutic benefit when applying the initial 3 fractions in an interval of 2 days instead of daily delivered fractions. This effect disappears for fast-growing tumours and in the case of incomplete repair. The results suggest some optimisation potential for combined hyperthermia-radiotherapy. Regarding the sensitivity of the proposed model, cellular repair of radiation-induced damages is a key factor for tumour control. In contrast to this, the radio-sensitivity of immune cells does not influence the TCP as long as the radio-sensitivity is higher than those for tumour cells. The influence of the tumour sub-clone structure is small (if no competition is included). This work demonstrates the usefulness of in silico – modelling for identifying optimisation potentials

Modelling the impact of treatment uncertainties in radiotherapy

Uncertainties are inevitably part of the radiotherapy process. Uncertainty in the dose deposited in the tumour exists due to organ motion, patient positioning errors, fluctuations in machine output, delineation of regions of interest, the modality of imaging used, and treatment planning algorithm assumptions among others; there is uncertainty in the dose required to eradicate a tumour due to interpatient variations in patient-specific variables such as their sensitivity to radiation; and there is uncertainty in the dose-volume restraints that limit dose to normal tissue. This thesis involves three major streams of research including investigation of the actual dose delivered to target and normal tissue, the effect of dose uncertainty on radiobiological indices, and techniques to display the dose uncertainty in a treatment planning system. All of the analyses are performed with the dose distribution from a four-field box treatment using 6 MV photons. The treatment fields include uniform margins between the clinical target volume and planning target volume of 0.5 cm, 1.0 cm, and 1.5 cm. The major work is preceded by a thorough literature review on the size of setup and organ motion errors for various organs and setup techniques used in radiotherapy. A Monte Carlo (MC) code was written to simulate both the treatment planning and delivery phases of the radiotherapy treatment. Using MC, the mean and the variation in treatment dose are calculated for both an individual patient and across a population of patients. In particular, the possible discrepancy in tumour position located from a single CT scan and the magnitude of reduction in dose variation following multiple CT scans is investigated. A novel convolution kernel to include multiple pretreatment CT scans in the calculation of mean treatment dose is derived. Variations in dose deposited to prostate and rectal wall are assessed for each of the margins and for various magnitudes of systematic and random error, and penumbra gradients. The linear quadratic model is used to calculate prostate Tumour Control Probability (TCP) incorporating an actual (modelled) delivered prostate dose. The Kallman s-model is used to calculate the normal tissue complication probability (NTCP), incorporating actual (modelled) fraction dose in the deforming rectal wall. The impact of each treatment uncertainty on the variation in the radiobiological index is calculated for the margin sizes.Thesis (Ph.D.)--Department of Physics and Mathematical Physics, 2002

Preclinical animal research on therapy dosimetry with dual isotopes

Preclinical research into radionuclide therapies based on radiation dosimetry will enable the use of any LET-equivalent radionuclide. Radiation dose and dose rate have significant influence on dose effects in the tumour depending on its radiation sensitivity, possibilities for repair of sublethal damage, and repopulation during or after the therapy. Models for radiation response of preclinical tumour models after peptide receptor radionuclide therapy based on the linear quadratic model are presented. The accuracy of the radiation dose is very important for observation of dose-effects. Uncertainties in the radiation dose estimation arise from incomplete assay of the kinetics, low accuracy in volume measurements and absorbed dose S-values for stylized models instead of the actual animal geometry. Normal dose uncertainties in the order of 20% might easily make the difference between seeing a dose-effect or missing it altogether. This is true for the theoretical case of a homogeneous tumour type behaving in vivo in the same way as its cells do in vitro. Heterogeneity of tumours induces variations in clonogenic cell density, radiation sensitivity, repopulation capacity and repair kinetics. The influence of these aspects are analysed within the linear quadratic model for tumour response to radionuclide therapy. Preclinical tumour models tend to be less heterogenic than the clinical conditions they should represent. The results of various preclinical radionuclide therapy experiments for peptide receptor radionuclide therapy are compared to the outcome of theoretical models and the influence of increased heterogeneity is analysed when the results of preclinical research is transferred to the clinic. When the radiation dose and radiobiology of the tumour response is known well enough it may be possible to leave the current phenomenological approach in preclinical radionuclide therapy and start basing these experiments on radiation dose. Then the use of a gamma ray-emitting radionuclides for a chemically comparable beta-particle-emitting paired isotope for therapy evaluation would be feasible

Utilizing Log Files For Treatment Planning And Delivery Qa In Radiotherapy

Purpose: Monte Carlo-based log file quality assurance (LF-MC QA) is investigated as an alternative method to phantom-based patient-specific quality assurance in radiotherapy (e.g. ArcCHECK QA (AC QA)). Methods: First, the shortcomings of AC QA were investigated. The sensitivity dependence of ArcCHECK diodes on dose rate (in-field) and energy (primarily out-of-field) was quantified. LF-MC QA was then analyzed on the phantom geometry. Planned (‘Plan’) and LF-reconstructed CS and MC doses were compared with each other and AC measurement via statistical (mean ± StdDev(σ)) and gamma analyses to isolate dosimetric uncertainties and quantify the relative accuracies of AC QA and LF-MC QA. LF-MC QA was then analyzed on the patient geometry. Calculation algorithm dependent (Plan-MC vs Plan-CS) and delivery error (LF-MC vs Plan-MC) dependent dosimetric discrepancies were isolated. Dose discrepancies were evaluated using PTV Dmean, D99, and D1 as well as tumor control probability (TCP). Dose discrepancy due to calculation algorithm was further assessed as a function of heterogeneity and beam modulation complexity (MU/Rx). LF QA results were compared to clinical AC QA results. Various LF-MC QA pass/fail protocols were assessed. Results: Calculation and ArcCHECK measurement differed up to 1.5% in-field due to variations in dose rate and up to 5% out-of-field due to energy effects. On the ArcCHECK geometry, phantom-dependent, calculation algorithm-dependent (MC vs. CS), and delivery error-dependent dose uncertainties were 0.8±1.2%, 0.2±1.1%, and 0.1±0.9% respectively. On the patient anatomy, percent differences in [PTV Dmean, D99, D1] were [-0.1±0.1%, 0.0±0.2%, -0.2±0.2%] for machine delivery error, [-3.4±1.9%, -4.6±2.8%, -1.2±2.8%] for dose calculation difference, and [0.5±2.0%, 0.2±1.2%, 2.6±4.1%] due to limited VMAT beam sampling. Drop in TCP due to calculation difference (MC-CS) was -3.1±1.8% [min -5.7%]. 41% of PTV D99 dose calculation difference was due to beam complexity. Heterogeneity effects were negligible for H&N. For lung, 18% of dose calculation difference on PTV Dmean was due to heterogeneity Conclusions: ArcCHECK QA was consistently incapable of catching clinically relevant dose discrepancies as calculated on the patient anatomy using LF-MC QA

Towards Adaptive Radiotherapy through Development of Treatment Response Prediction

Despite modern treatment advances, overall survival (OS) remains poor for many cancers such as liver and brain. Cancer is a fundamentally heterogeneous and adaptable disease and therefore personalized adaptive treatment strategies may be a key towards improving OS. Radiotherapy, a commonly used cancer treatment technique which employs ionizing radiation to kill tumours, holds promise for delivering adaptive treatment. However, effective adaptation requires the ability to assess and predict tumour treatment response. Therefore development of treatment response prediction tools represents a critical first step towards improving patient outcomes via treatment adaptation. The overall goal of this thesis is to develop treatment response prediction methods with a view towards guiding adaptive radiotherapy. First, we investigated the relationship between radiation dose and local tumour control among patients with primary and metastatic colorectal liver tumours. We established and compared their dose-response relationships and found that 84 Gy and 95 Gy of radiation could provide 90% probabilities of 6-month local control for the primary and metastatic groups respectively. Tumour control most often cannot be improved simply through escalating the dose to the entire tumour due to increased risk of side effects. However, it may be possible to safely increase the dose to tumour sub-volumes. Therefore, the second and third contributions of this thesis involve development of image-based treatment response prediction methods which are needed to identify tumour sub-volumes where additional radiation should be deposited to improve tumour control. Our second contribution involved augmenting a voxel-based method known as parametric response mapping (PRM) to account for image registration error (IRE). The augmented PRM helped to quantify and visualize IRE-related variability. In our third contribution, we further generalized PRM to permit collective analysis of multi-parametric image data. The proposed method was applied to multi-parametric imaging from a patient cohort with glioblastoma and was found to predict OS ≥ 18 months (median OS) with a sensitivity and specificity of 90% and 78% respectively. In summary, these contributions provided some of the response assessment groundwork needed to guide adaptive RT. Image-based dose response relationships via the augmented and multi-parametric response maps will facilitate personalization and guidance of adaptive radiotherapy

A double masked randomised 4-week, placebo-controlled study in the USA, Thailand and Taiwan to compare the efficacy of oral valganciclovir and topical 2% ganciclovir in the treatment of cytomegalovirus anterior uveitis: study protocol.

IntroductionCytomegalovirus (CMV) anterior uveitis is a recognised cause of anterior uveitis in immunocompetent patients and is preventable cause of vision loss. Ocular sequelae include corneal endothelial damage which can cause corneal oedema and failure, as well as glaucoma. Recurrences of inflammation are common and therefore patients are often exposed to long-term therapy. Oral therapy is available in the form of valganciclovir, although with the caveat of systemic side effects such as bone marrow suppression and renal failure necessitating regular interval laboratory monitoring. Recent reports have demonstrated that topical 2% ganciclovir solution may offer promising treatment outcomes in patients with CMV anterior uveitis with superior safety, cost-effectiveness and convenience profiles. An investigation into the relative equipoise of these therapies is warranted for these reasons.Methods and analysisThe Systemic and Topical Control of Cytomegalovirus Anterior uveitis: Treatment Outcomes (STACCATO) trial is designed as a multicentre, block randomised by site, double-masked, placebo-controlled trial comparing the efficacy of oral valganciclovir, 2% topical ganciclovir and placebo in treating PCR-proven CMV anterior uveitis. Participant clinical evaluation will occur at three study time points by a masked study ophthalmologist over a 28-day period to assess resolution of ocular inflammation (secondary outcome). A control group will provide additional information about the possible impact that the infected host's immune response may play in controlling local viral replication. The primary analysis is an analysis of covariance (three arms) correcting for baseline to compare quantitative CMV viral load in the anterior chamber (AC) aqueous fluid before and 7 days after treatment.Ethics and disseminationThe University of California San Francisco Committee on Human Research and the Khon Kaen University Institutional Review Board have given ethical approval. The results of this trial will be presented at local and international meetings and submitted for peer-reviewed journals for publication.Trial registration numberNCT03576898

New approaches to the management of adult acute lymphoblastic leukemia

Traditional treatment regimens for adult acute lymphoblastic leukemia, including allogeneic hematopoietic cell transplantation, result in an overall survival of about 40%, a figure hardly comparable with the extraordinary 80-90% cure rate currently reported in children. When translated to the adult setting, modern pediatric-type regimens improve the survival to about 60% in young adults. The addition of tyrosine kinase inhibitors for patients with Philadelphia chromosome positive disease and the measurement of minimal residual disease to guide risk stratification and post-remission approaches has led to further improvements in outcomes. Relapsed disease and treatment toxicity - sparing no patient but representing a major concern especially in the elderly - are the most critical current issues awaiting further therapeutic advancement. Recently, there has been considerable progress in understanding the disease biology, specifically the Philadelphia-like signature as well as other high-risk subgroups. In addition, there are several new agents that will undoubtedly contribute to further improvement in the current outcomes. The most promising agents are new the monoclonal antibodies, immunomodulators, and chimeric antigen receptor T cells and, to a lesser extent, several new drugs targeting key molecular pathways involved in leukemic cell growth and proliferation. This review examines the evidence supporting the increasing role of the new therapeutic tools and treatment options in different disease subgroups, including frontline and relapsed/refractory disease. It is now possible to define the best individual approach based on to the emerging concepts of precision medicine

Choline PET based dose-painting in prostate cancer - Modelling of dose effects

Background: Several randomized trials have documented the value of radiation dose escalation in patients with prostate cancer, especially in patients with intermediate risk profile. Up to now dose escalation is usually applied to the whole prostate. IMRT and related techniques currently allow for dose escalation in sub-volumes of the organ. However, the sensitivity of the imaging modality and the fact that small islands of cancer are often dispersed within the whole organ may limit these approaches with regard to a clear clinical benefit. In order to assess potential effects of a dose escalation in certain sub-volumes based on choline PET imaging a mathematical dose-response model was developed. Methods: Based on different assumptions for alpha/beta, gamma 50, sensitivity and specificity of choline PET, the influence of the whole prostate and simultaneous integrated boost (SIB) dose on tumor control probability (TCP) was calculated. Based on the given heterogeneity of all potential variables certain representative permutations of the parameters were chosen and, subsequently, the influence on TCP was assessed. Results: Using schedules with 74 Gy within the whole prostate and a SIB dose of 90 Gy the TCP increase ranged from 23.1% (high detection rate of choline PET, low whole prostate dose, high gamma 50/ASTRO definition for tumor control) to 1.4% TCP gain (low sensitivity of PET, high whole prostate dose, CN + 2 definition for tumor control) or even 0% in selected cases. The corresponding initial TCP values without integrated boost ranged from 67.3% to 100%. According to a large data set of intermediate-risk prostate cancer patients the resulting TCP gains ranged from 22.2% to 10.1% (ASTRO definition) or from 13.2% to 6.0% (CN + 2 definition). Discussion: Although a simplified mathematical model was employed, the presented model allows for an estimation in how far given schedules are relevant for clinical practice. However, the benefit of a SIB based on choline PET seems less than intuitively expected. Only under the assumption of high detection rates and low initial TCP values the TCP gain has been shown to be relevant. Conclusions: Based on the employed assumptions, specific dose escalation to choline PET positive areas within the prostate may increase the local control rates. Due to the lack of exact PET sensitivity and prostate alpha/beta parameter, no firm conclusions can be made. Small variations may completely abrogate the clinical benefit of a SIB based on choline PET imaging