CN103394167B - A kind of Forecasting Methodology of the tumour radiotherapy complication based on biological effect dosage - Google Patents

Abstract

The invention provides a kind of Forecasting Methodology of the tumour radiotherapy complication based on biological effect dosage, the method uses for reference the concept of biological effect dosage BED, improvement is made to traditional Normal Tissue Complication probability NTCP model, introduces α/β factor pair model and carry out fractionated dose correction; Then, the dose-volume parameter that after retrospective analysis one group of patient accepts radiotherapy, certain organ is irradiated and the Follow-up results that this organ that the rear clinical observation for the treatment of obtains develops complications, utilize the NTCP model after improving, synchronous matching is carried out to model parameter and the α/β factor; Finally, the NTCP model parameter that matching is obtained and the α/β factor, the NTCP model after improving is substituted into the dose-volume information that will accept radiocurable one group of this organ of patient, calculate the probit that this organ of this group patient develops complications, thus realize to this group tumor patient after the different fractionated dose of acceptance is irradiated, the probability that this organ develops complications is predicted.

Description

A kind of Forecasting Methodology of the tumour radiotherapy complication based on biological effect dosage

Technical field

The present invention relates to a kind of radiotherapy clinical complication Predicting Technique, specifically a kind of Forecasting Methodology of the tumour radiotherapy complication based on biological effect dosage.

Background technology

The object of tumour radiotherapy is by improving target area (tumor) dosage and reducing target area normal surrounding tissue (jeopardizing organ) radiation injury, improve the Partial controll rate of tumor, thus improve further cancer patient survival rate, improve life in patients.But, tumor invasion position is usually located in patient body, inherently through some normal structure while ray penetrates human body, and the lateral scattering of x-ray too increases the dosage of target area normal surrounding tissue raying, even if the most accurate radiotherapy technology also cannot be avoided irradiating the mistake of target area normal surrounding tissue at present.And organ in human body is comparatively responsive to x-ray radiation, the organ of certain volume is subject to the irradiation of doses, will show the impaired of organ dysfunction, thus makes human body show complication.

Dose fractionation pattern in tumour radiotherapy:

According to the Biological characteristics of tumor cell, radiotherapy, in implementation process, according to the difference of fractionated dose, is divided into conventional fractionation, large segmentation and hyperfractionated Three models, wherein

Conventional fractionation refers to that fractionation of radiation dosage is 2.0Gy, once a day, is adopt maximum dose fractionation patterns;

Large segmentation refers to that fractionation of radiation dosage is greater than 2.0Gy, and irradiate interval and be more than or equal to one day, biological effect dosage is higher, damages comparatively conventional fractionation larger to tumor normal surrounding tissue;

Hyperfractionated refers to that fractionation of radiation dosage is less than 2.0Gy, and every day irradiates twice, and interval is greater than 6 hours, and biological effect dosage is lower, compared with conventional fractionation, can protect tumor normal surrounding tissue better.

For different patients, according to position, the pathology, by stages difference of tumor, will adopt different fractionated dose therapeutic schemes, the degree of impairment of the tumor surrounding normal organ thus caused is also by different.

Irradiation complication:

Some acute irradiation complication, acute lung injury as caused in radiotherapy in lung cancer process appears at patient and accepts in the process of radiotherapy, the treatment progress of patient may be delayed thus, more serious may affect radiocurable smooth enforcement, threaten patient vitals, thus reduce TCP, reduce survival; Some in late period irradiation complication, the bladder late lesions as caused in carcinoma of prostate Patients During Radiotherapy appeared in the time of 3 months after accepting radiotherapy to 5 years, reduced the life quality of patient, for patient brings more misery.

Irradiation complication is carried out to feasibility and the meaning thereof of prediction:

Prepare to accept radiocurable patient to each example, all need to carry out CT scan to it before enforcement treatment, and be sent to radiotherapy planning system by scanning the faultage image obtained, after carrying out three-dimensional reconstruction, carry out radiotherapy plan again.Tumour radiotherapy physics teacher is to the design process of radiotherapy planning, be the incident direction of the x-ray of clinac injection when being treated by simulated emission, ray energy, irradiation field open the parameters such as wild shape, simulation radiation dose is each organ and the distribution situation in organizing in human body, and carries out qualitative assessment by the exposure dosage of dose-volume histogram to each organ around tumor.Tumour radiotherapy physics teacher by quality assurance equipment, detects the analog result of dose distribution, ensure analog result and human body is actual accept to irradiate after the actual dose distribution results that obtains consistent.Like this, just before patient accepts actual therapeutic, qualitative assessment accurately can be carried out to the radiation dose that patient will accept, and on this basis, the probability developed complications for normal structure is predicted.

In this case, tumor radiotherapy section doctor according to predicting the outcome, before enforcement treatment, can adjust Radiation treatment plans, targetedly the damage of prophylaxis of tumours normal surrounding tissue, thus reducing or avoid the generation of irradiation complication in time.

The effect of Normal Tissue Complication forecast model:

Normal Tissue Complication probability (NTCP) model is based upon dose-volume to close the mathematical model fastened, adjustment model parameter can be passed through, the probability that irradiation complication appears in different normal organ after accepting certain exposure dose is described, radiotherapy toxic reaction is predicted, also can carry out the quantification contrast of biological effect according to this to different therapeutic schemes.

Burman is in the complication probability model of application Lyman in 1991 proposition, on the basis of each organ clinical tolerance dosage provided at Emami, by the method for curve fitting and observation, give 27 kinds of normal organs occur corresponding to 29 kinds of irradiation complications NTCP model parameter (TD when accepting full volumetric uniform irradiation ₅₀(1), n, m) and be widely used in clinical practice.In recent years, lot of documents is also had to report correlational study Radiation treatment plans being carried out to quantitative evaluation and compares by NTCP model.

Biological effect dosage

" biological dose " and " physical dosage " in radiation therapy process is two different concepts.According to International Atomic energy committee IAEA No. 30 Report Definition, " biological dose " refers to the measurement to organism rdaiation response degree.Therefore, multidigit researcher is had to propose scaling module physical dosage being converted to biological dose, but only have the model of only a few to have practical value, its neutral line-secondary Linear-Quadrac, L-Q model is a kind ofly widely used in most the mathematical model of radiobiological studies and clinical radiotherapy, it draws from cell survival curve direct derivation, and therefore it is not a pure empirical equation.The biological effect dosage BiologicalEffectiveDose derived by L-Q model, BED, a kind of exactly method according to dose fractionation pattern difference, physical dosage being converted to biological dose.At present, this method is widely used in the conversion to physical dosage and biological dose in clinical position.

The deficiency that prior art exists:

The deficiency that prior art exists in actual use is, traditional NTCP model can only carry out complication prediction for the patient accepting identical fractionated dose in prediction prediction group, it is a kind of complication predictive mode of physically based deformation dosage, when all predicted patients accept be routine dose segmentation time, think that physical dosage is equal to biological dose, conventional model form can be directly adopted to predict, but, if there are some patients like this in predicted PATIENT POPULATION, they will accept unconventional dose fractionation and irradiate, the biological effect being different from routine dose segmentation brought thus, just cannot be embodied, namely traditional NTCP model cannot be predicted respectively to two parts patient (and clinical experience and statistical data all confirm, different fractionated dose scheme will affect the appearance of irradiation complication to some extent), therefore, this limitation makes the predictive ability of traditional NTCP model significantly reduce, the scope of application is restricted.

For making explanations to this feature better, now lift an example to illustrate: as shown in Figure 2, Fig. 2 (a) and (b) respectively show and accept routine dose segmentation (blueness, ArmA, 35 times × 2.0Gy/ time) and accept Hypofractionation (redness, ArmB, 28 times × 2.5Gy/ time) the integration and differentiation DVH of two routine patient's bladder exposure dosage scheme.Because two routine patients receive identical total prescribed dose (70Gy), therefore, the difference that may show complication after two routine patient's bladders accept irradiation cannot be found out from figure.But clinical experience and statistical result showed, accept the patient of Hypofractionation, its probability developed complications is greater than the patient accepting conventional fractionation, and difference has significance.In this case, the accumulation DVH being subject to irradiating total amount based on patient's organ completely due to traditional NTCP model schemes, do not consider that different fractionated dose scheme is on the impact of complication, therefore, for the probability that above-mentioned two routine patients develop complications, the same predicting the outcome will be provided, and this result does not conform to the actual conditions.

Summary of the invention

The object of the invention is the deficiency overcoming prior art existence, a kind of method for there is irradiation complication after different fractionated dose program prediction treatment patients is provided.

Method of the present invention realizes in the following manner, utilize " biological effect dosage " BiologicalEffectiveDose, BED concept, to traditional Normal Tissue Complication probability NormalTissueComplicationProbability, NTCP model makes improvement, introduces α/β factor pair model and carries out fractionated dose correction; Then, the dose-volume parameter that after retrospective analysis one group of patient accepts radiotherapy, certain organ is irradiated and the Follow-up results that this organ that the rear clinical observation for the treatment of obtains develops complications, utilize the NTCP model after improving, synchronous matching is carried out to model parameter and the α/β factor; Finally, the NTCP model parameter that matching is obtained and the α/β factor, the NTCP model after improving is substituted into the dose-volume information that will accept radiocurable one group of this organ of patient, calculate the probit that this organ of this group patient develops complications, thus realize to this group tumor patient after the different fractionated dose of acceptance is irradiated, the probability that this organ develops complications is predicted.Concrete steps are as follows:

(1) traditional NTCP model is improved

1) biological dose conversion: to the maximal dose described in traditional NTCP model and each volume element volumebin corresponding dosage unit dosebin, according to bioequivalence dosage BiologicalEffectiveDose, the concept of BED carries out biological dose conversion, and formula is

$D_i^{\′}=D_i\·\left(\frac{\frac{\mathrm{\α}}{\mathrm{\β}}+\frac{D_i}{N_{fr}}}{\frac{\mathrm{\α}}{\mathrm{\β}}+2}\right)$ (formula 1)

Wherein, D _ithe maximal dose irradiated for patient i organ or the dosage of a dosage unit, α/β is used to the factor of carrying out fractionated dose correction, N _frthat patient i connects subject point of number of times, D _i' be through formula 1 change after obtain and D _ithe biological dose of equivalence.

(2) matching is carried out to NTCP model parameter and the α/β factor after improvement

1) dose distribution is obtained: derive from radiotherapy planning system and describe the dose-volume histogram that human body organ accepts radiation dose, and this figure is converted to differential form by integrated form, dosage unit corresponding to each volume element of this organ is obtained, i.e. its radiation dose received (unit: Gy) with this;

2) estimated parameter value: need maximum likelihood estimate be adopted to the matching of model parameter.For each the routine patient i from retrospective analysis group, its NTCP value can be expressed as the form of model parameter, α/β Summing Factor differential post dose, volume element function, that is:

NTCP _i=F (parameters, α/β, d _i, v _i) (formula 2)

Then for being used for the retrospective analysis group patient data of fitted model parameters, its log-likelihood function L is expressed as

$L(Parameters,\mathrm{\α}/\mathrm{\β},d_i,v_i)=\underset{i}{\Σ}(log{\left({\mathrm{NTCP}}_i\right)}^{Ri}+log{\left(1-{\mathrm{NTCP}}_i\right)}^{1-Ri})$ (formula 3)

Wherein, for patient i, if there is radiation complication in clinical observation, then R _i=1 otherwise R _i=0.Then, utilize optimization tool, make likelihood function L get maximum, namely matching obtains describing the model parameter value and α/β factor values that this organ develops complications.

(3) complication is predicted

1) each routine patient radiocurable is accepted to the preparation from prediction prediction group and design radiotherapy treatment planning, and according to described method above, by the dose distribution of radiotherapy planning system simulation organ, and derive with differential form the radiation dose that each volume element of this organ receives;

2) the dose-volume factor (i.e. volume element and corresponding dosage unit) of each routine this organ of patient in prediction prediction group simulation obtained, and NTCP model parameter value and α/β factor values after the improvement that obtains of matching above, substitute into the NTCP model after improving in the lump, calculate the NTCP value of each routine patient of this group, namely obtain the probit that irradiation complication appears in each routine patient, realize the prediction to complication.

Excellent effect of the present invention is: use method of the present invention to predict the probability that radiotherapy causes tumor surrounding normal organ to develop complications, can before patient accepts actual therapeutic, for the PATIENT POPULATION that will accept various dose splitting scheme and carry out treating, the prediction of distinguishing individuation is provided, embody the significant difference that various dose splitting scheme shows producing irradiation complication, for radiotherapy department doctor provides assessment tool easily and effectively, what is more important, in clinical practice, effectively reduce the probability developed complications after patient accepts radiotherapy, improve the life quality of patient, and improve survival to a certain extent.

The present invention predicts that carcinoma of prostate radiotherapy causes predicting the outcome of bladder complication in late period and the contrast with traditional method prediction effect thereof, as shown in the table.

Accompanying drawing explanation

Fig. 1. be radiotherapy complication Forecasting Methodology flow chart;

Fig. 2 is that the patient after accepting the treatment of various dose Fractionation regimen has identical dose distribution map;

Fig. 3 is that after being corrected by the inventive method, the integration and differentiation DVH of corresponding diagram 2 schemes.

Detailed description of the invention

Below in conjunction with accompanying drawing, method of the present invention is described in further detail.

(1) traditional NTCP model is improved

1) certain normal organ is after its certain volume receives certain radiation dose, and the probability (NTCP) that may show complication is as follows:

${\mathrm{NTCP}}_i=\frac{1}{\sqrt{2\mathrm{\π}}}\underset{-\mathrm{\∞}}{\overset{t}{\∫}}\exp (-\frac{t^2}{2})dt$ (formula 4)

Wherein,

$t=(D_{{\max }_i}-{\mathrm{TD}}_{{50}_i}(v\left)\right)/(m\·{\mathrm{TD}}_{{50}_i}(v\left)\right)$ (formula 5)

${\mathrm{TD}}_{{50}_i}\left(v\right)={\mathrm{TD}}_{50}\left(1\right)\·V_{{\mathrm{eff}}_i}^{-n}$ (formula 6)

$V_{{\mathrm{eff}}_i}=\underset{ij}{\Σ}{v}_{ij}{d}_{ij}^{1/n}$ (formula 7)

V in formula 7 _ijand d _ijthe irradiated volume element of organ and the corresponding dosage unit of patient i respectively, TD ₅₀(1), n and m is three parameters of NTCP model;

2) for the maximal dose in formula 5 with each the dosage unit d in formula 7 _ij, utilize formula 1 to change respectively, physical dosage be converted to biological dose, obtain accordingly and d' _ij;

3) use and d' _ijdistinguish in replacement formula 5 and formula 7 and d _ij, complete the improvement to traditional NTCP model, on the basis of original three parameters, introduce the different fractionated dose of α/β factor pair and correct, thus make traditional NTCP model can carry out complication prediction for the PATIENT POPULATION accepting different fractionated dose.

(2) matching is carried out to NTCP model parameter and the α/β factor after improvement

For the situation that a certain normal organ develops complications, choose one group there is same area tumor and accepted radiocurable patient, collect each this organ of routine patient and be subject to the situation that the dose-volume information (DVH) of radiation and this organ develop complications on certain follow up time point;

1) for each routine patient i of this group, its NTCP value can be expressed as the form of model parameter, α/β Summing Factor differential post dose, volume element function, that is:

NTCP _i=F (parameters, α/β, d _i, v _i) (formula 2)

Then for being used for the retrospective analysis group patient data of fitted model parameters, its log-likelihood function L is expressed as

$L(Parameters,\mathrm{\α}/\mathrm{\β},d_i,v_i)=\underset{i}{\Σ}(log{\left({\mathrm{NTCP}}_i\right)}^{Ri}+log{\left(1-{\mathrm{NTCP}}_i\right)}^{1-Ri})$ (formula 3)

Wherein, for patient i, if there is radiation complication in clinical observation, then R _i=1 otherwise R _i=0;

2) optimization tool is utilized, as genetic algorithm, simulated annealing and simplex algorithm etc., likelihood function L is made to get maximum, the i.e. globe optimum of likelihood function, each model parameter corresponded and the value of the α/β factor are exactly that this organ of description of obtaining of matching develops complications the model parameter value of probability and α/β factor values;

(3) complication is predicted

1) for each the routine patient in prediction prediction group formulates radiotherapy planning, and therefrom derive radiation dose-volume information that organ to be predicted is subject in radiotherapy planning, and integrated form is converted to differential form, namely obtains the dosage unit that each volume element of this organ is corresponding;

2) for each the routine patient in prediction prediction group, by the volume element that obtains in previous step and dosage unit, with the NTCP model parameter that matching obtains for this organ injury, substitute in the lump in the NTCP model after improving and calculate, obtain the NTCP value for each routine patient, namely obtain the probit that irradiation complication appears in each routine patient, realize the prediction to complication.

Inventive method accuracy and feasibility checking

For verifying effectiveness and the accuracy of Forecasting Methodology provided by the present invention, now enumerating the situation that one group of tumor radiotherapy patient actually observed in clinical position develops complications, and predicting by the method.

Enter group 192 example and accept radiocurable patients with prostate cancer, all patients all receives the irradiation of 70Gy prescribed dose, wherein, 89 routine patients (ArmA) receive the conventional fractionation irradiation that fractionated dose is 2.0Gy/ time, and 103 routine patients (ArmB) receive the large fractionated irradiation that fractionated dose is 2.5Gy/ time.We follow up a case by regular visits to and have recorded patient and to accept after radiotherapy the 3rd year, and occur the situation of bladder late lesions, wherein: ArmA has 8 routine patients to develop complications, ArmB has 21 routine patients to develop complications.Here, whether develop complications, weigh with the LENT/SOMA standard that international radiotherapy tissue proposes, think and occur that the patient being more than or equal to LENT/SOMA secondary complication symptom enters complication performance group, otherwise enter complication not performance group.Details is as follows:

ArmA: enter group 89 example, prescribed dose 2.0Gy/ time × 35 times=70Gy, 5 times/week, treat after 3 years and have 8 routine patients to develop complications, complication is 8.99%;

ArmB: enter group 103 example, prescribed dose 2.5Gy/ time × 28 times=70Gy, 4 times/week, treat after 3 years and have 21 routine patients to develop complications, complication is 20.39%.

Because ArmA and ArmB two groups of patients receive identical radiation prescribed dose (70Gy), therefore, if do not consider the impact that dose fractionation pattern is brought, two groups of patients occur that the probability of irradiation complication should be identical, but observed result but has sizable difference (8.99%vs.20.39%), this just requires that we are when carrying out complication prediction to analogue, the NTCP forecast model after using the present invention to improve and prediction flow process thereof.

NTCP model after we utilize traditional NTCP model and the present invention to improve, done prediction respectively to above-mentioned situation, result is as shown in table 1.

For calculating parameter, two kinds of Forecasting Methodologies, in fit procedure, obtain similar NTCP model parameter value (i.e. TD ₅₀(1), n, m value), and the difference of two groups is just, tradition NTCP model does not use the α/β factor to carry out fractionated dose correction, and method provided by the invention is improved traditional NTCP model, introduces the α/β factor and participates in forecasting process.

Can see from predicting the outcome of table 1, traditional NTCP model predicting the outcome for ArmA and ArmB, all about 15.1%, and overall complication probability when ArmA and ArmB patient is mixed into one group of patient by this result just, namely

(formula 8)

This result masks different fractionated dose scheme to the appreciable impact producing complication after radiotherapy and bring, and employ the present invention improve after NTCP model and correlation predictive flow process after, sets forth 8.93% and 20.45% predict the outcome to ArmA and ArmB, the actual sickness rate of the complication with observable 8.99% and 20.39% is very close.

In order to the change brought after embodying α/β factor correction more intuitively, we carry out α/β factor correction to two routine patient's bladder exposure dose-volume histogram curves listed in Fig. 2, namely by after carrying out α/β factor correction to bladder maximum point dosage and each volume element matched doses unit, again delineate dose volume histogram, result as shown in Figure 3.Fig. 3 (a) and (b) distinguish the correspondence integration and differentiation DVH of Fig. 2 (a) and (b).As seen from Figure 3, originally two curves overlaped, after the different fractionated dose of α/β factor pair corrects, accept the high dose area of its bladder exposure dosage of patient (ArmB) that large fractionated dose irradiates to have moved right a segment distance, embody large segmentation fractionated dose and there is higher biological effect dosage, and many sections of documents show, drop on the change of Supravesical high dose area volume, by the appearance of appreciable impact bladder complication.Therefore, Fig. 3 explains well and accepts large fractionated irradiation patient bladder and to develop complications the higher reason of probability.

The known technology of those skilled in the art is except technical characteristic disclosed in description of the present invention.

Claims (1)

1. the Forecasting Methodology based on the tumour radiotherapy complication of biological effect dosage, towards the tumor patient that will accept the irradiation of different fractionated dose, before it accepts actual therapeutic, its complication probability produced may be caused to predict treatment, it is characterized in that, first, traditional Normal Tissue Complication probability NTCP model is improved, make it can predict for the PATIENT POPULATION of different fractionated dose; Then, utilize the treatment of one group of patient and the rear follow up data for the treatment of, synchronous matching is carried out to the NTCP model parameter after improvement and the α/β factor; Finally, utilize fitting result, predict accepting the probability that radiocurable one group of patient develops complications, concrete steps are as follows:

(1) biological dose conversion: to the maximal dose described in traditional NTCP model and each volume element volumebin corresponding dosage unit dosebin, carry out biological dose conversion according to the concept of bioequivalence dosage BED, conversion formula is

$D_i^{\′}=D_i\·\left(\frac{\frac{\mathrm{\α}}{\mathrm{\β}}+\frac{D_i}{N_{fr}}}{\frac{\mathrm{\α}}{\mathrm{\β}}+2}\right)$ (formula 1)

Wherein, D _ithe maximal dose irradiated for patient i organ or the dosage of a dosage unit, α/β is used to the factor of carrying out fractionated dose correction, N _frthat patient i connects subject point of number of times, D ' _ibe through formula 1 change after obtain and D _ithe biological dose of equivalence;

(2) matching is carried out to NTCP model parameter and the α/β factor after improvement

1) dose distribution is obtained: derive from radiotherapy planning system and describe the dose-volume histogram DVH that human body organ accepts radiation dose, and this figure is converted to differential form by integrated form, dosage unit corresponding to each volume element of this organ is obtained with this, its radiation dose received i.e., unit: Gy;

2) estimated parameter value: adopt maximum likelihood estimate to carry out matching to model parameter, for each the routine patient i from retrospective analysis group, its NTCP value can be expressed as the form of model parameter, α/β Summing Factor differential post dose, volume element function, that is:

NTCP _i=F (parameters, α/β, d _i, v _i) (formula 2)

Then for being used for the retrospective analysis group patient data of fitted model parameters, its log-likelihood function L is expressed as

$L\left(Parameters,\mathrm{\α}/\mathrm{\β},d_i,v_i\right)=\underset{i}{\Σ}\left(\log {\left({\mathrm{NTCP}}_i\right)}^{Ri}+\log {\left(1-{\mathrm{NTCP}}_i\right)}^{1-Ri}\right)$ (formula 3)

Wherein, for patient i, if there is radiation complication in clinical observation, then R _i=1 otherwise R _i=0;

Then, utilize optimization tool, make likelihood function L get maximum, namely matching obtains describing the model parameter value and α/β factor values that this organ develops complications;

(3) complication is predicted

1) each routine patient radiocurable is accepted to the preparation from prediction prediction group and design radiotherapy treatment planning, by the dose distribution of radiotherapy planning system simulation organ, and derive each volume element of this organ with differential form and simulate the radiation dose received;

2) the dose-volume factor of each routine this organ of patient in prediction prediction group simulation obtained, i.e. volume element and corresponding dosage unit, and NTCP model parameter value and α/β factor values after the improvement that obtains of matching above, substitute into the NTCP model after improving in the lump, calculate the NTCP value of each routine patient of this group, namely obtain the probit that irradiation complication appears in each routine patient, realize the prediction to complication.