METHOD FOR ESTIMATING THE TOXICITY LEVEL OF RADIOTHERAPY TREATMENT ON A PATIENT
By integrating dosimetric data with radiosensitivity analysis of patient cells, the method enhances the precision of radiotherapy toxicity prediction, addressing variability and uncertainty in existing methods.
Patent Information
- Application Number
- FR2021002157
- Authority / Receiving Office
- FR · FR
- Patent Type
- Patents
- Current Assignee / Owner
- Filing Date
- 2021-03-05
- Publication Date
- 2025-04-18
- Estimated Expiration
- 2041-03-05
AI Technical Summary
Existing methods for predicting radiotherapy toxicity in patients show significant variability and uncertainty, leading to either premature treatment cessation or excessive risk, as they fail to provide personalized and reliable estimates of a patient's ability to tolerate ionizing radiation doses.
A method combining dosimetric data analysis from treatment planning systems with in vitro radiosensitivity analysis of patient-derived fibroblasts or lymphocytes, using ATM phosphorylation levels, to predict toxicity levels through logistic regression models.
Provides a more accurate and reliable prediction of radiotherapy toxicity, reducing uncertainty and ensuring appropriate treatment continuation or cessation based on individual patient radiosensitivity and treatment planning data.
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Abstract
Description
Title of the invention: METHOD FOR ESTIMATING THE TOXICITY LEVEL OF A TREATMENT BY RADIOTHERAPY ON A PATIENT Scope of the invention
[0001] The present invention relates to the field of oncology and more particularly to the evaluation of the risk factors of radiotherapy treatment on a patient suffering, for example, from cancer in the head or neck area, in order to determine whether he is able to withstand further irradiation without major toxicological or even lethal risk.
[0002] Radiotherapy (RT) is one of the most frequently used and effective treatments for cancer. As with all cancer treatments, the therapeutic benefit of radiotherapy is weighed against the potential adverse effects (or toxicity) in normal tissues. Therefore, accurate scoring and reporting of radiotherapy adverse effects are crucial for improving the quality of RT and for researching treatment efficacy.
[0003] The total dose of ionizing radiation delivered to the tumor is a major factor in locoregional control. An increase in this dose to tumor volumes is most often correlated with an increase in the dose to healthy tissues.
[0004] Approximately 1 to 15% of patients treated with radiotherapy for cancer experience a tissue reaction (such as dermatitis or proctitis) that can jeopardize the success of the treatment, as it may lead the physician to decide to discontinue radiotherapy before the end of the planned protocol. Furthermore, this tissue reaction is an indicator of the patient's particularly high sensitivity to ionizing radiation. Thus, radiotherapy, even when interrupted at the onset of the first visible tissue signs, can increase post-treatment morbidity and even mortality, not only because the cancer it was intended to treat could not be completely eradicated due to the premature cessation of treatment, but also because of the collateral damage to healthy tissues induced by the radiation itself.
[0005] External beam radiotherapy planning must therefore take into account dose constraints to organs at risk. Delivering the highest possible dose generates more toxicity, both early and late.
[0006] This toxicity must be recorded prospectively by practitioners.
[0007] Recording and scoring must be done in a simple, reproducible and sensitive manner in order to obtain an accurate and appropriate assessment for each organ and the The "CTCAE" (Common Terminology Criteria for Adverse Events) classification system, developed by the National Cancer Institute, is a recognized indicator to guide radiation oncologists in determining the appropriateness of further radiation therapy. It uses a scale of 1 to 5 grades, corresponding, in ascending order, to the terms Mild, Moderate, Severe, Life-threatening, and Death.
[0008] To objectify the appropriate criterion for a patient, it is necessary to have reliable analysis tools, in order to avoid foregoing further irradiation for a patient who could tolerate it, and foregoing further irradiation for a patient for whom it would lead to fatal consequences.
[0009] It is therefore desirable to have a predictive testing method to determine the maximum cumulative dose that a given patient can receive without risk. This question arises primarily in radiotherapy in the context of high ionizing doses. State of the art
[0010] In the prior art, several solutions are known for the evaluation by biodosimetry of the radiation dose received by an individual who has been subjected to ionizing radiation, based on the characterization of markers in a biological sample taken from the patient.
[0011] French patent FR3067467 describes a method for characterizing the radiosensitivity of a cell sample from an individual to ionizing radiation, said cell sample having been obtained from cells taken from said individual. The radiosensitivity is determined from the amount of phosphorylated ATM protein pATM in the basal state t0, without irradiation of said cell sample.
[0012] European patent EP3108253B1 describes a method for predicting the cellular radiosensitivity of a cell sample obtained from cells taken from a patient in a non-irradiated or slightly irradiated area, wherein:
[0013] - the said cells taken are amplified, these amplified cells constituting " the cell sample";
[0014] - the average number of nuclear foci is determined on said cell sample obtained with the pH2AX marker and their evolution over time;
[0015] - the total dose not to be exceeded (TDNPD), expressed in Gray, is determined by a processing of these measures.
[0016] The article Surucu M, Shah KK, Roeske JC, Choi M, Small W Jr, Emami B. Adaptive radiotherapy for head and neck cancer. Treatment Technol Cancer Res. 2017; 16 (2): 218-223. doi: 10.1177 / 1533034616662165, which presents results validating the importance of adaptive replanning for the This reduced dose to normal tissues while improving target volume coverage for patients undergoing repeat CT scans during head and neck radiotherapy. Without replanning, the dose to some organs of radiation (OARs) would have exceeded their respective tolerance thresholds. Disadvantages of prior art
[0017] Prior art solutions based on the quantification of biomarkers were not totally satisfactory and significant variations were observed from one patient to another, resulting in predictions that were too favorable in some cases, which could lead to unfortunate consequences for some patients, and too pessimistic in other cases, which deprived the patient of further radiotherapy treatment which would have reduced the cancer cells.
[0018] The object of the invention is to provide a higher-quality risk factor estimate, personalized for each patient, with a lower margin of uncertainty. Solution provided by the invention
[0019] In order to address these drawbacks, the present invention relates to a method for estimating the toxicity level of radiotherapy treatment on a patient, comprising a step of characterizing the radiosensitivity of a cell sample to ionizing radiation, said cell sample having been obtained from cells taken from said patient, to determine a first radiosensitivity factor by biological analysis,
[0020] characterized in that - it also includes a step of analyzing dosimetric data from data obtained from treatment planning, in order to determine a second treatment factor, - the level of toxicity being determined by a combination of said first radiosensitivity factor and second treatment factor.
[0021] For the purposes of this patent, "biological analysis" shall mean all molecular / genetic or other biological analyses performed on a biological sample from the patient to determine a radiosensitivity factor.
[0022] According to a first variant, the determination of the radiosensitivity factor is carried out on fibroblasts from a connective tissue sample of said patient.
[0023] According to a second variant, the determination of the radiosensitivity factor is carried out on fibroblasts from a skin sample of said patient.
[0024] According to a third variant, the determination of the radiosensitivity factor is carried out on lymphoblasts / lymphocytes from a blood sample of the patient.
[0025] Advantageously, the determination of the radiosensitivity factor is carried out by determining the total fractions of the cell sample of said sample of the quantity of phosphorylated ATM pATM protein in the basal state.
[0026] According to one example of implementation, said toxicity level is determined by fitting two-variable logistic regression models, comprising:
[0027] (a) the result of the pATM test on blood lymphocytes and
[0028] (b) prediction from dosimetric models based on data dosimetric treatment planning for toxicities of grade >3 or grade >2
[0029] Detailed description of a non-limiting example of an embodiment of the invention
[0030] The present invention will be better understood upon reading the following description illustrated by the accompanying drawings relating to a non-limiting example of an embodiment where: - [Fig. 1] [Fig. 1] represents the results on the development of mucosal inflammation in patients with a CTCAE radiosensitivity grade greater than or equal to 2 - [Fig. 2] [Fig. 2] represents the results on development inflammation of the mucous membranes in patients with CTCAE grade radiosensitivity greater than or equal to 3 - [Fig. 3] [Fig. 3] represents the results on dysphagia in patients exhibiting a CTCAE grade radiosensitivity greater than or equal to 2 - [Fig. 4] [Fig. 4] represents the results on dysphagia in patients exhibiting a radiosensitivity of CTCAE grade greater than or equal to 3 - [Fig. 5] [Fig. 5] represents the results on acute toxicity and toxicity late on patients. General principle
[0031] The invention aims to provide a radiation oncologist with an objective and reliable indicator representing a patient's ability to tolerate further irradiation in the context of radiotherapy. This indicator is determined based on the results of two treatments: - a dosimetric analysis of the treatment planning system (TPS) established to prepare a radiotherapy treatment plan to establish a treatment factor - an in vitro radiosensitivity analysis performed on a biological sample from the patient, to establish a radiosensitivity factor.
[0032] These two factors are combined to establish a predictive indicator of the level of toxicological risk in the "CTCAE" (Common Terminology Criteria for Adverse Events) reference framework. Determination of the treatment factor
[0033] The treatment factor is determined from data available in the treatment planning system (TPS), extracted from the software used to prepare the radiotherapy treatment plan for a given patient. The TPS has become an indispensable tool in modern radiotherapy. Based on the medical prescription, the images and anatomical volumes retrieved by the medical physics team to prepare the treatment plan, it allows for the implementation of the most appropriate treatment beam geometry (beam energy; number, shape, and incidence of fields; intensity modulation or not, etc.). Often, several trials are performed. The dose calculation is carried out using an algorithm that models energy deposition in matter, according to the interaction laws of the particles involved. It allows:
[0034] • 3D visualization of the patient's anatomical images (multi-modality: MRI, scanner and PET). "The possible registration of 2 or more independent sets of images.
[0035] “The delineation of target and at-risk volumes.
[0036] “The creation of a treatment ballistics (positioning of beams, choice of their energy, shape, etc).
[0037] • Calculating the dose in 3D in the patient, using algorithms that model the energy deposition of particles involved in tissues.
[0038] • Quantitative visualization of dose deposition in organs in the form dose-volume histogram (DVH). The precise operation of this software requires significant configuration.
[0039] "Calculating the dose to the patient from CT images requires knowing the conversion curve of Hounsfield Units (HU, information contained in the CT images) into relative electron density (information directly related to tissue composition). This curve is measured for a given CT scan and voltage in a 'phantom' containing inserts of different electron densities to cover all electron densities available in the human body. The calculations performed by the TPS take into account the properties of the accelerator: dose rate, energy, beam homogeneity and symmetry, filtration, collimation accessories, etc., are all elements for which a precise description must be provided to the TPS. This parameterization is directly linked to the acceptance testing step of a treatment machine described elsewhere."
[0040] Once configured for the available accelerators, the TPS allows for treatment planning. Using volumetric images of the patient and the volumes to be treated, as well as the OARs delineated by the radiation oncologist, the dosimetrist programs treatment beams with the correct parameters: energy, dimensions, orientation, dynamic filter, etc., in order to obtain the best possible dose distribution for the treatment. The dose calculation relies on algorithms capable of simulating the interaction of photons and electrons in tissues, for example by the Monte Carlo simulation code.
[0041] The processing factor calculated from the data from the TPS software consists, for example: - the cumulative dose (in Gy) over the entire radiotherapy treatment received by a healthy organ in the vicinity of the tumor area - the maximum dose (in Gy) received by a healthy organ near the tumor area during a radiotherapy session - the distribution of doses to healthy organs in the vicinity of the tumor area - and more generally any dosimetric indicator representative of the radiotreatment of the patient in question. Determination of the radiosensitivity factor
[0042] The second factor, designated as the radiosensitivity factor, is determined by a known method of biochemical analysis of a sample from the patient in question to quantify a marker or a combination of markers, in particular proteins of the kinase family such as ATM and ATR.
[0043] It is known that the question of tissue sensitivity to ionizing radiation is linked to DNA damage repair mechanisms. Indeed, at the cellular level, ionizing radiation can break certain types of chemical bonds by generating free radicals (particularly through peroxidation) and other reactive species that cause DNA damage. DNA damage from endogenous or exogenous aggressions (such as ionizing radiation and free radicals) can lead to different types of DNA damage, depending in particular on the energy deposited: base damage, single-strand breaks, and double-strand breaks (DSBs). Unrepaired DSBs are associated with cell death, toxicity, and more specifically, radiosensitivity. Poorly repaired DSBs are associated with genomic instability, mutagenic phenomena, and a predisposition to cancer.The body has repair systems specific to each type of DNA damage. Regarding DSBs, mammals have two main repair methods: suture repair (ligation of strands) and recombination repair (insertion of a homologous or non-homologous strand).
[0044] It is also known that the sensitivity of tissues to ionizing radiation varies greatly from one organ to another and from one individual to another. Even apart from certain rare cases of extreme radiosensitivity, the genetic origin of which seems to be proven, radiosensitivity is generally thought to stem from a genetic predisposition: it is therefore specific to an individual.
[0045] By way of non-limiting example, the determination of the radiosensitivity factor is carried out using a sample of healthy tissue, preferably fibroblasts or lymphoblasts / lymphocytes. The former are preferably taken from the connective tissue or skin of an individual, and the latter from blood. This sample can be obtained by biopsy or blood sampling.
[0046] Example of a protocol for determining the radiosensitivity factor
[0047] The determination of the radiosensitivity factor can be carried out with a kit for characterizing the radiosensitivity of a cell sample from an individual to ionizing radiation. This kit includes:
[0048] a) means for extracting the total fractions from the cell sample, i.e. reagents such as a lysis buffer known to those skilled in the art,
[0049] b) means for determining said fractions of said cell sample the amount of phosphorylated pATM protein ATM in the basal state, such as a plate coated with a specific anti-pATM antibody for performing an ELISA test.
[0050] The operator takes a cellular sample from the patient, such as a blood sample containing lymphoblasts or lymphocytes. The analysis protocol is, for example, one of those described in patent FR3067467B1.
[0051] Combination of treatment and radiosensitivity factors
[0052] Combined radiosensitivity factor-treatment factor mathematical models have been developed by fitting two-variable logistic regression models, including:
[0053] (a) the result of the pATM test on blood lymphocytes (using the dichotomous classification previously determined of patients as radiosensitive vs radioresistant, with a binary variable, YES = radiosensitive, NO = radioresistant) and
[0054] (b) prediction from dosimetric models based on data dosimetric treatment planning for grade >3 or grade >2 toxicities.
[0055] Such dosimetric models are proposed in the following articles: • Orlandi, E., Lacovelli, NA, Rancati, T., Cicchetti, A., Bossi, P., Pignoli, E., et al. Multivariable model for predicting acute oral mucositis during combined IMRT and chemotherapy for locally advanced nasopharyngeal cancer patients. Oral Oncol 2018, 86, 266-272. • Cavallo, A., Rancati, T., Cicchetti, A., lacovelli, NA, Palorini, F., Fallai, C. et al. Development of multivariable models for acute toxicities in nasopharyngeal cancer radiotherapy (original English title “Development of multivariable models for acute toxicities in nasopharyngeal cancer radiotherapy Radiother”) Oncol 2017, 123, S858-S859.
[0056] The evaluation of the predictive value of the combination of treatment factors and radiosensitivity is carried out by ROC curve analysis, determination of AUC (Area Under Curve) and evaluation of probabilities (Chi-square test). Results observed
[0057] Figures 1 to 5 show the correlation rate between predictive indicators and pathologies that actually appeared in a cohort of patients who underwent radiotherapy for head and neck cancer (HNC) observed in several clinical trials.
[0058] The predictive indicators were determined for the tests illustrated in Figures 1 to 4: a. Based on a dosimetric model (left column) b. From a radiosensitivity factor obtained based on the quantification of the phosphorylated ATM protein in lymphocytes (middle column) c. From a combination of a treatment factor and a combined radiosensitivity factor according to the invention (right column).
[0059] The predictive indicators were determined for the tests illustrated by [Fig.5]: a. From a radiosensitivity factor based on the quantification of phosphorylated ATM protein in lymphocytes (left column) b. From a combination of a treatment factor and a combined radiosensitivity factor according to the invention (right column).
[0060] 53 patients were considered to evaluate the predictive capacity of the RTD for Acute grade 3 (G3) toxicity was assessed. Patients were treated with postoperative radiotherapy and were prospectively evaluated for toxicity as determined by the CTCAE grade at baseline and weekly during radiotherapy. The actual pathological consequences were determined at least 6 months after the completion of radiotherapy.
[0061] 67 patients were included in the validation cohort. They were followed prospectively, the toxin score was assessed in the same manner as for the training cohort. These points were also subjected to delayed toxicological evaluation up to three years of follow-up. The trials in the validation population were conducted blinded.
[0062] The validation population analysis included the evaluation of the predictive value of the indicator determined according to the method of the invention.
[0063] The tests show that in all cases, the predictive quality of the indicator determined according to the invention is superior to the indicators known in the prior art.
Claims
Claims
1. - Method for estimating the toxicity level of a radiotherapy treatment on a patient comprising a step of characterizing the radiosensitivity of a cell sample to ionizing radiation, said cell sample having been obtained from cells taken from said patient, to determine a first radiosensitivity factor by biological analysis, characterized in that: - the determination of the radiosensitivity factor is carried out by determining the total fractions extracted from the lysed cell sample of said sample, to measure the quantity of phosphorylated ATM pATM protein in the basal state, - in that it further comprises a step of analyzing the dosimetric data from the data resulting from the treatment planning, to determine a second treatment factor,and - in that the toxicity level is determined by a combination of said first radiosensitivity factor and second treatment factor.,
2. - Method for estimating the level of toxicity of a radiotherapy treatment on a patient according to claim 1 characterized in that the determination of the radiosensitivity factor is carried out on fibroblasts originating from a sample of connective tissue from said patient.
3. - Method for estimating the level of toxicity of a radiotherapy treatment on a patient according to claim 1 characterized in that the determination of the radiosensitivity factor is carried out on fibroblasts originating from a sample of the skin of said patient.
4. - Method for estimating the level of toxicity of a radiotherapy treatment on a patient according to claim 1 characterized in that the determination of the radiosensitivity factor is carried out on lymphoblasts / lymphocytes from a blood sample of the patient.
5. - Method for estimating the toxicity level of a radiotherapy treatment on a patient according to claim 1 characterized in that the determination of the radiosensitivity factor is carried out by determination of the total fractions extracted from the lysed cell sample of said sample, to measure the quantity of phosphorylated ATM pATM protein in the basal state.
6. - Method for estimating the toxicity level of a radiotherapy treatment on a patient according to claim 1 characterized in that said toxicity level is determined by an adjustment of the two-variable logistic regression models, comprising: (a) the result of the pATM test on blood lymphocytes and (b) the prediction from dosimetric models based on treatment planning data, such as the cumulative dose received by a healthy organ, the maximum dose received during a radiotherapy session, or the distribution of doses on healthy organs, for toxicities of grade >3 or grade >2.