WO2008062000A1

WO2008062000A1 - System and method for predicting and/or adjusting control parameters of interstitial photodynamic light therapy

Info

Publication number: WO2008062000A1
Application number: PCT/EP2007/062602
Authority: WO
Inventors: Johannes Swartling; Ann Johansson; Johan Axelsson
Original assignee: Spectracure Ab
Priority date: 2006-11-20
Filing date: 2007-11-20
Publication date: 2008-05-29

Abstract

A method and system for controlling and adjusting the treatment parameters in a photodynamic light therapy (PDT) in a subject are disclosed. More particularly, a method for controlling the treatment parameters in interstitial tumor photodynamic light therapy is described which uses a calibration procedure based on information from measured parameters and treatment outcome from prior treatments. Thus optimal treatment conditions are predicted and may be continuously updated during ongoing therapy.

Description

System and method for predicting and/or adjusting control parameters of interstitial photodynamic light therapy

Field of the Invention This invention pertains in general to the field of photodynamic light therapy (PDT) and related systems, devices, computer program products and methods. More particularly the invention relates to such a computer program product and/or method for controlling and adjusting light therapy parameters in such a PDT system comprising a calibration device or procedure, respectively. Even more particularly, the invention refers to interstitial tumor PDT.

Background of the Invention

Photodynamic therapy (PDT) is a cancer treatment modality that has shown promising results in terms of selectivity and efficacy; see e.g. Dougherty TJ, et. al . : Photodynamic therapy, Journal of the National Cancer Institute 1998; 90: 889-905.

PDT in the context of the present application relies on the use of a photosensitizer agent being activated by light in the presence of oxygen, leading to the production of toxic singlet oxygen radicals. Tissue destruction results from apoptosis, necrosis and vascular damage caused by these toxic singlet oxygen radicals, see e.g. Noodt BB, et. al . : Apoptosis and necrosis induced with light and 5- aminolaevulinic acid-derived protoporphyrin IX, British Journal of Cancer 1996; 74: 22-29. A limited penetration in the tissue of the activating light is a general issue of PDT. Only tumors less than about 5 mm in thickness may be treated by surface irradiation. In order to treat thicker and/or deeper lying tumors, interstitial PDT may be utilized. In interstitial PDT, for instance light-conducting optical fibers are brought into the tumor using, e.g., a syringe needle, in the lumen of which a fiber has been placed, which is for instance described in PCT/SE2006/050120 of the same applicant as the present application, and which is incorporated herein by reference in its entirety for all purposes. Other way of delivering light interstitially for PDT are for instance permanently or temporary implanted probes that for instance comprise miniaturized light sources or ends of optical fibers arranged in arrays.

In unpublished international application PCT/EP2007/058477 of the same applicant as the present application, which is incorporated by reference herein for all purposes, a method and system for controlling and adjusting light in interstitial photodynamic light therapy (IPDT) in a subject are disclosed. A calculation method for determination of status of tissue during the IPDT treatment is disclosed. This status is used in a feedback loop to control the continued IPDT treatment. Methods are disclosed that constitute pre-treatment and realtime dosimetry modules for IPDT including monitoring of light attenuation during the treatment procedure and updating individual fiber irradiation times to take into account any variation in tissue light transmission. The system comprises a control device that is arranged to restrict delivery of therapeutic light treatment at least temporary in dependence of at least one attribute of one of photodynamic treatment parameters. In comparison to no treatment feedback, a significant undertreatment of the patient as well as damage to healthy organs at risk are avoided.

The present application describes further improvements of the system and/or method of PCT/EP2007/058477, providing increased efficacy of a PDT or an IPDT therapy.

Summary of the Invention

Accordingly, embodiments of the present invention preferably seeks to mitigate, alleviate or eliminate one or more deficiencies, disadvantages or issues in the art, such as the above-identified, singly or in any combination by providing a system, a method, and a computer program product, according to the appended patent claims.

According to a first aspect of the invention, a system is provided, for adjusting photodynamic therapy on tissue in a body. The system comprises a calibration device for predicting control parameters of the photodynamic light therapy.

According to a second aspect of the invention, a computer program is provided, for processing by a computer, for adjusting interstitial photodynamic therapy on tissue in a body, the computer program comprising a calibration code segment for predicting control parameters of the photodynamic light therapy.

According to another aspect of the invention, a method is provided, for adjusting photodynamic therapy on tissue in a body, the system comprising a calibration step for predicting control parameters of the photodynamic light therapy.

Further embodiments of the invention are defined in the dependent claims, wherein features for the second and subsequent aspects of the invention are as for the first aspect mutatis mutandis.

One objective of the present invention may be to provide increased efficacy of an IPDT therapy by enhancing the accuracy of the dosimetry thereof.

Some embodiments thus provide for IPDT with increased robustness. Some embodiments provide for instance for a compensation for differences between patients, differences within patients, differences between apparatuses, etc. In some embodiments this is provided by means of a procedure or method for allowing a target light dose to be individualized. In some embodiments this individualization of a target light dose is even adjusted during ongoing IPDT treatment in order to provide a more effective treatment. The individualized target light dose is in some embodiments determined based on measurement data acquired prior to and during the therapy. In some embodiments the basis of such a procedure is that treatment related data from previously performed IPDT treatments is collected and stored in a database. The treatment related data stored in the database is in some embodiments provided for statistical analysis, whereby correlations between treatment parameters are determined. Treatment parameters include for instance the delivered light dose, measured parameters, a treatment outcome, side effects, etc. In an embodiment the method comprises determining a unique treatment parameter, such as a unique, individualized target light dose, for each specific combination of treatment parameters, measured parameters and treatment outcome. This unique treatment parameter, such as the unique, individualized target, may be chosen based on different criteria. In some embodiment, it may for instance be chosen to be optimal or close to optimal in the sense that it gives the best or close to the best treatment outcome. Alternatively or in addition, a severity of side effects may be the unique treatment parameter or a secondary unique treatment parameter taken in to consideration with the first unique treatment parameter.

It should be emphasized that the term "comprises/comprising" when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

Brief Description of the Drawings

These and other aspects, features and advantages of which embodiments of the invention are capable of will be apparent and elucidated from the following description of embodiments of the present invention, reference being made to the accompanying drawings, in which Figure 1 is a schematic drawing of an interstitial PDT apparatus;

Figure 2 is a graph showing a normalized light transmission between patient fibers as a function of the delivered energy, wherein this measurement relates to the fluence rate distribution in the tissue;

Figure 3a is a graph showing raw spectrum from a diagnostic measurement using a 635-nm diode laser as a light source. Spectral intervals λ_∑ and λ_π indicate regions used for studying the light transmission at 635 nm and the photosensitizer fluorescence signals, respectively;

Figure 3b is a graph showing an average of the normalized light transmission between neighboring patient fibers as a function of the delivered light dose (D_L) from one patient. Signals within area T_x are averaged to constitute a measure of final light transmission;

Figure 3c is a graph showing an average of the normalized PpIX fluorescence as measured between neighboring patient fibers as a function of the delivered light dose (D_L) from one patient, wherein in Figure 3b and Figure 3c error bars denote ±1 standard deviation;

Figure 4a is a graph showing an average change in total hemoglobin content;

Figure 4b is a graph showing an average change in tissue oxygen saturation level;

Fig. 5 is a schematic illustration of an example of data sets A, B and C, wherein in this example only the delivered dose is shown as a treatment parameter, and measureables for treatment efficacy and side effects are not specified;

Fig. 6 is a schematic illustration of a correlation between the data sets of Fig. 5, wherein this illustration is an example for illustration purposes only and does not represent data from a real case; Fig. 7 is a schematic illustration of using a calibration procedure to determine a target light dose from measured parameters, wherein the calibration procedure is such that for these particular measured parameters the determined target light dose corresponds to a favorable treatment outcome, wherein also this Figure shown an example for illustration purposes only and does not represent data from a real case;

Fig. 8 is a flow chart illustrating a PDT procedure 800 with an initial factory calibration 801, and a subsequent procedure comprising a PDT treatment session 802; Fig. 9 is a schematic illustration of a delivered dose as a function of time in contrast to systems that have a fixed dose 903 to be achieved during the PDT treatment;

Fig. 10 is a schematic illustration of delivered dose as function of time, wherein it is illustrated how some embodiments of the present invention provide for an intermediate adjustment during a treatment 1003, i.e. the light dose to be delivered to the patient is adopted to therapy progress both with regard to temporal and spatial aspects within the tumor.

Description of embodiments

Specific embodiments of the invention will now be described with reference to the accompanying drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The terminology used in the detailed description of the embodiments illustrated in the accompanying drawings is not intended to be limiting of the invention. In the drawings, like numbers refer to like elements .

The following description focuses on embodiments of the present invention applicable to a PDT system and method, and in particular to an interstitial PDT system and method, with reference to an example of a practical embodiment of treatment of prostate cancer. However, it will be appreciated that the invention is not limited to this application but may be applied to PDT or IPDT treatment of many other organs, including for example liver, oesophagus, pancreas, breast, brain, lung, trachea, eye, urinary tract, brain stem, spinal marrow, bone marrow, kidneys, stomach, intestines, pancreas, gall bladder, etc. The method may in embodiments be based on previously acquired measurement data organized in a database. The method comprises determining a unique target light dose (or other key treatment parameters) for each specific combination of treatment parameters (of these, of particular interest is the delivered dose) , measured parameters and treatment outcome. This unique dose is optimal or close to optimal in the sense that it gives the best or close to the best treatment outcome.

A PDT treatment session is generally describable by parameters in three groups, i.e. Treatment parameters 510 (denoted data set A) , Measured parameters 520 (denoted data set B) and Treatment outcome 530 (denoted data set C) , as illustrated in the schematic illustration 500 in Fig. 5. Consider each of these data sets, consisting of one or several of the individual parameters for each parameter group or any combination of the parameters within each group. Moreover, the data in sets A, B and C may represent data points from essentially every point in the tissue to be treated. Thus the data sets may be large, which make processing thereof a computational challenge. Each dataset may comprise one or more parameters or groups of parameters, which each may lie within a certain range, as illustrated by the letters and arrows in Fig. 5, namely H (High), L (Low), S (Severe), N (None).

Fig. 6 illustrates in a schematic illustration 600 a possible relationship between the three parameter groups A, B and C. The example shows a relatively high target light dose 511, a moderate fluence rate distribution 521, a low tissue blood perfusion 522, and a high oxygenation 523, as well as a high treatment efficacy rating 531 and a very low side effect rating 532. However the relationship shown in Fig. 6 shall not be seen as a specific practical relationship rather as an example. Variation of the relationship estimate is expected as a relationship is determined individually for essentially every point in the tissue to be treated. The specific relationship, for a given treatment session and point in the tissue, may also reflect non-obvious circumstances. Sources of such circumstances may comprise background noise which fluctuates by definition, thus affecting the relationship estimate .

The treatment parameters (data set A) are those parameters administrated in order to give treatment. According to conventional dose metrics, a certain, predetermined, light dose 511 is delivered to each point in the tumor. Hitherto this light dose was pre-determined and fixed. For instance according to a system and methods disclosed in unpublished international application PCT/EP2007/058477 of the same applicant as the present invention, such a light dose is delivered in a feedback controlled manner, taking into consideration progress of the therapeutic procedure performed. However, known PDT systems do not take into consideration if this pre- determined total light dose may has to be adjusted to specific circumstances, for instance related to the apparatus used, inter patient differences, intra patient differences, treatment progress, etc. or an arbitrary combination thereof. The measured parameters 520 (data set B) are typically response parameters due to the treatment performed or to be performed. In PDT related parameters, the measured parameters comprise parameters that are monitored during and/or after the treatment itself, such as fluence rate distribution 521, photosensitizer concentration and distribution, tissue blood content, tissue blood perfusion 522, oxygenation 523, necrosis of tissue, tissue temperature, to mention a few. Suitable measurement methods for these parameters are for instance in detail described in unpublished international application PCT/EP2007/058477. With reference to Fig. 9 a schematic illustration is given of a delivered dose as a function of time in contrast to systems that have a fixed dose 903 to be achieved during the PDT treatment. However, the total dose to be delivered is pre-determined and fixed according to these systems , such as disclosed in PCT/EP2007/058477.

Finally, treatment outcome 530 (data set C) , may for instance comprise a treatment efficacy rating 531 and/or a side effect rating 532. In an example it may be desired to have a high treatment efficacy rating in combination with a low side effect rating. However, in practice this may not always be obtainable, and in another example it may be acceptable to have a lower treatment efficacy rating and a higher side effect rating, for instance when a patient has an advanced form of cancer, where side effects are acceptable when weight against the potential success of therapy allowing survival of the patient.

Information data elements related to treatment outcome may be acquired from data from various sources: e.g., in vitro studies of cell cultures or tissues; animal model studies; studies on human patients; collection of data from routine clinical PDT treatment of patients. Conventional data for evaluation of treatment efficacy include monitoring of biochemical substances in the body that relate to the disease, such as prostate-specific antigene (PSA) for prostate cancer; cell-death determined by microscopic evaluation (for in vitro studies) , histopathological examination of biopsies or excised tissue or blood samples, changes in the tissue determined by radiological diagnostic methods or any other imaging modality e.g. MR, CT or Ultrasound. These treatment effect parameters mentioned above have an additional long-term relevance as effects may be further pronounced with time. Information related to treatment outcome may also comprise data on side effects. Side effects may be overtreatment of healthy tissue evaluated by any of the methods outlined above, any disturbance of the normal bodily functions of patients, any discomfort, illness or fatality that arise as a consequence of the treatment. The side effects may be further distinct with time whereby follow-ups and additional adjustments of the data base in effort to eliminate of these potential occurrences. One or more inherent relationships between these interlinked parameter groups represented by data sets A, B and C, each comprising specific information data elements, may in embodiments be determined by statistical analysis using a multivariate approach. Thus efficacy of the therapy may be increased by enhancing the accuracy of the treatment parameters, e.g. of a PDT light dose. Inter patient differences and intra patient differences may thus be compensated for, as the multivariate based analysis provides a robust and reliable arrangement to predict treatment parameters in a photodynamic therapy system or method, comprising IPDT.

The procedure for multivariate calibration, e.g. using the above described data sets A, B and C, may be performed using methods known in the art. For instance these methods be comprised in the non-limited list of Linear or non-linear regression methods; Principal component analysis; Independent component analysis; Partial least-squares calibration; Artificial neural networks, etc. Fig. 10 is a schematic illustration of delivered dose as function of time, wherein it is illustrated how some embodiments of the present invention provide for an intermediate adjustment during a treatment 1003, i.e. the light dose to be delivered to the patient is adopted to therapy progress both with regard to temporal and spatial aspects within the tumor.

For the sake of completeness, it is mentioned that multivariate analysis is known and is used to analyze several parameters at the same time. For instance in US2005/0222501 it is disclosed a multivariate analysis method for classifying cell surfaces and also to determine blood glucose in a non-invasive way using skin auto- fluorescence spectra. In EP0595506, multivariate analysis has been used to detect cancerous or precancerous malignancies in tissue. Images of cell nuclei are used in the analysis. A number of other documents also exists, e.g. WO85/01348, where multivariate analysis has been used to analyze a couple of analytes in a biological sample.

However, none of the previous applications of multivariate based analysis has been used to predict treatment parameters in a photodynamic therapy system or method. Due to the complex nature of the relationships between the groups A, B and C, the calibration procedure may in practical implementations not always result in optimal treatment parameters for every position in the tissue to be treated or under treatment. However, the multivariate calibration procedure ensures that the determined treatment parameters will be optimal or close to optimal in a global sense, restricted only by the accuracy of the input parameters.

The multivariate analysis based calibration procedure may in some embodiments be arranged to feed a PDT treatment control system in order to adequately regulate treatment parameters used for PDT treatment or any other desirable treatment therapy. In some embodiments the multivariate calibration process calculates the desired value, to be distributed to a therapy treatment parameter delivery control system, based on the relationships between the described groups A, B and C above. The therapy treatment parameter delivery control system may for instance be arranged to control the light dose to be delivered, such as described in unpublished international application

PCT/EP2007/058477 of the same applicant as the present application . Now turning to Fig. 8, a flow chart is shown that illustrates a PDT procedure 800 with an initial factory calibration 801, and a subsequent procedure comprising a PDT treatment session 802, which will be elucidated in more detail below.

A treatment session 802 of method 800 typically follows subsequent to an initialization step 801 comprising initial calibration of a PDT system, e.g. by means of a factory calibration. Based on the data sets A, B and C, comprised in a database 810, perhaps together with treatment specific ordinations defined by a physician and in some embodiments patient related information, a calibration procedure 811, e.g. a multivariate calibration procedure as described above, is carried out. The object of the multivariate calibration is to determine correlations between A, B and C.

In a particular example, the object is to determine the combinations of data in A and B that correlate positively with high treatment efficacy in C, and, at the same time, preferably correlate negatively with a high degree of side effects. However, depending on the specific situation and circumstances, other approaches may be taken into consideration. For example, based on a type of tumor, e.g. malign or benign, a weight factor for a target treatment outcome may be adjusted for a desired ratio between treatment efficacy and side effects. More side effects, to a certain level, may for instance be tolerated when treating a malign tumor in contrast to treating a benign tumor. Some embodiments of the method provide for this type of alterations, wherein the multivariate calculations in the calibration procedure adjust the treatment parameters' initial settings accordingly. A schematic picture of one possible correlation is shown in Fig. 6. The picture in Fig. 6 may for example represent a correlation for one position or sub-region in the tissue. Thus, the calibration is used to determine optimal or close to optimal treatment parameters that are provided when starting a treatment session 802 of a subject. This is illustrated in Fig. 8 by a step 812 that comprises providing of calibration model data files. It may be noteworthy that the calibration model itself is determined by the treatment system itself, i.e. how it is physically constructed and which treatment parameters may be provided with target values for an actual therapeutic treatment session 802. The calibration procedure 801 provides data files for this given calibration model in order to provide an as efficient treatment from the outset of a therapy session .

Thus, after the initial factory calibration is performed in step 801, the system is prepared for the actual treatment session 802. The treatment session 802 starts with a set of calibration model data that is delivered to a step of calibration look-up 821 whereupon the therapeutic treatment session procedure of the PDT system may start.

Initially the calibration look-up is overridden as initial levels for the treatment parameters are provided by the factory calibration 801. Initially, the PDT system commences the treatment with the settings delivered by the treatment control system. As treatment progresses, the calibration look-up 821 comprises appropriate treatment parameters 822 based on input data resulting from the ongoing treatment.

The up-to date treatment parameters are provided to a treatment control system for delivery of continued therapy in step 823. Continued therapy is performed by the PDT performing system.

A succeeding control 824 checks if adequate treatment is performed, e.g. after a predetermined total treatment time. If so the procedure ends at step 830, or may branch to further subsequent methods not described in more detail herein . If the treatment is not finished a new set of realtime measurements, data set B, are recorded 820. This may be done with the same system as used by treatment delivery, e.g. by switching into a temporary diagnosis mode. With this new set of measured parameters the treatment session is adopted to changes of the patient's organs and alike within a treatment session. The calibration look-up 821 is updated based on a re-calibration 710 derived from the updated values of measurement, as e.g. described with reference to Fig. 7. Hence, treatment parameters are adjusted to the new circumstances and the up-to date treatment parameters are in turn again provided to the treatment control system for delivery of continued therapy in step 823. Continued therapy is performed by the PDT performing system, as described above, until a stop criterion allows proceeding to step 830.

In some embodiments, sequential or parallel monitoring of real-time measurements 820 in respect to the treatment control system may be performed. These embodiments provide for adapting the dose to be delivered in accordance to a patient and the specific treatment session. Traditional systems, as described with reference to Fig. 9, ensure delivery of a pre-defined light dose 903 not taking into account changing conditions during treatment. These changing conditions may be time dependent and/or vary within a tissue as to natural variations of for example blood vessel and/or nerve path positions, which could render either an overtreatment with possible severe undesired effects, or an undertreatment implying a non sufficient effect of the treatment. By adapting the delivered dose, such patient variabilities are overcome and an adequate desired outcome of the therapy is provided.

A principle of a PDT-system configured with the prediction calibration ability described above with reference to Fig. 8, is shown Fig. 10. The delivered dose

1003 is predictively adapted during treatment to counteract the variabilities by adopting a treatment parameter, such as the illustrated dose level during a treatment session.

In embodiments with sequential monitoring the treatment is set on hold for a period of time, while measurement parameters are recorded and evaluated.

Measurements are recorded 820 which correspond to the same types of measurements that were used to create data set B. A calibration look-up is used to select the optimal treatment parameters 711 for the particular measurements, as is depicted in the illustration 700 showing an example in Fig. 7. This procedure is similar to the initial calibration but instead of using patient population data, data from the specific patients is used. Thereby the treatment session is adjusted to the specific circumstances for this patient and session. After the calculation lookup, the procedure is continued as described above.

Two additional parameters may be used in some embodiments to control the progress of the therapy session: the time during which the treatment is performed and the time period during which real-time measurement are recorded and calibration look-up is performed, i.e. during which the treatment is off. For the latter period the tissue may be flushed with more oxygen and sensitizer to even render the therapy session more effective. In embodiments with parallel monitoring, the treatment parameters are adjusted continuously in real-time throughout the treatment session. Real-time measurements in the patient may be continuously performed, which correspond to the same types of measurements that were used to create the initial data set B. The calibration look-up is used to select the optimal treatment parameters for the particular measurements, as is depicted in the example in Fig. 7. This procedure is similar to the initial calibration but instead of using patient population data, data from the specific patients is used. Thereby the session may be adjusted to the specific circumstances for a specific patient and treatment session. During the treatment, a check on delivered dose is performed continuously. If the check in step 824 is positive, the treatment procedure is aborted and the process jumps to step 830.

The different setting, the initial settings and those during the treatment procedure, are stored for later calculation and further adjustment of the data base comprising the patient population data. In this effort complementing resources may be used, such as imaging modalities, e.g. MR, CT, Ultrasound, as well as long-term results. The data base comprising the patient population data is thus continuously updated and further improved to provide an optimal prediction.

The contents of the database may also be updated regularly, e.g. during a service of the PDT system. This update may be done automatically or initiated manually, either in defined intervals or continuously, e.g. via a suitable communication interface.

In addition, or alternatively, the contents of the database in a PDT system may be uploaded to a global knowledge database in which data from a plurality of PDT systems is stored. In this way, a certain type of PDT system may be dynamically updated with data based on real treatment data from other PDT systems of the same type. This iterative optimization provides even further optimized prediction of PDT treatment parameters on a long-term basis .

In addition, as an optional step prior to the calibration procedure, pre-processing of the input data may be performed to enhance the accuracy in the calibration model. The purpose of pre-processing is to normalize the data by incorporating underlying mechanisms that affect data sampling, or, transform the data into a form which is a closer estimator of the actual physical property of interest for the therapy.

For example, the physical property of direct importance for PDT is not the fluorescence of the sensitizer itself, but rather the spatial distribution of the concentration of the sensitizer in the tissue. Therefore, fluorescence data, as obtained from measurements, may in an embodiment be processed using a model that estimates the distribution of sensitizer concentration. In addition to the recorded fluorescence measurements, the three-dimensional geometry of the tissues for treatment are considered in the calculations, as well as the positions of the light sources and detectors, and the optical properties of the tissue itself. This data may for instance at least partly be provided from an imaging modality, such as Ultrasound, MR or CT.

On the other hand, it is also in some embodiments possible to feed all these parameters into the calibration procedure without performing the pre-processing and let the calibration model from that initial data calculate the significant relationships. Such an approach is envisaged to work well in cases of linear relationships, but may fail in cases where the parameter dependencies are non-linear, such as in the example of the relationship between fluorescence and concentration. Thus, for non-linear data the preprocessing approach generally further improves the results of the final calibration.

A schematically illustrated setup of an interstitial photodynamic therapy apparatus suitable for implementing embodiments of the present invention is shown in Figure 1. The apparatus 100 allows for therapeutic light delivery and treatment monitoring via optical fibers 105. While in treatment mode, light from the therapeutic light unit 102 is guided into the distribution module 104 and directed into the patient fibers. Intermittently, the therapeutic irradiation is interrupted in order to perform measurement sequences, during which light from each of the diagnostic light sources is successively coupled into each of the optical fibers. The term "diagnostic" is here used to describe the status of the progression of the treatment and does not refer to diagnosis of the patient's status. The PDT delivery system may differ from system 100 and be any PDT system suitable for implementing embodiments of the present invention. For instance, a system by the same applicant disclosed in unpublished international application PCT/EP2007/058477 of the same applicant as the present application, which is incorporated by reference herein for all purposes, discloses such a PDT system.

Another example of a system that may be useful for implementing embodiments of the present invention is for instance described in Swedish patent SE 503408 of the same proprietor as the applicant of the present application, which is incorporated by reference herein in its entirety. Here, several fibers have been used to ascertain that all tumor cells are subjected to a sufficient dose of radiation so that a toxic singlet state is obtained. A plurality of fibers are used for treatment as well as for measurement of the light flux which reaches a given fiber in the penetration through the tissue from the other fibers. Another example of a PDT system suitable for implementing embodiments of the present invention is disclosed in WO04100789 of the same applicant as the applicant of the present application, which hereby is incorporated by reference herein in its entirety. WO04100789 discloses a PDT system using optical switches. Yet another PDT system at least partly suitable for implementing embodiments of the present invention is disclosed in WO04101069 of the same applicant as the applicant of the present application, which hereby is incorporated by reference herein in its entirety. WO04101069 discloses a PDT system using translatory switches .

A further PDT system suitable for implementing embodiments of the present invention is disclosed in WO04100761 of the same applicant as the applicant of the present application, which hereby is incorporated by reference herein in its entirety. WO04100761 discloses a PDT system using purely mechanical and purely non- mechanical switching solutions in a synergetic way.

Another PDT system at least partly suitable for implementing embodiments of the present invention is disclosed in WO03041575 of the same applicant as the applicant of the present application, which hereby is incorporated by reference herein in its entirety. WO03041575 discloses a PDT system using rotating switches. The PDT system disclosed in EP 1470837 of Tulip, which hereby is incorporated by reference herein in its entirety, is also suitable for implementing embodiments of the present invention.

Nagypal et. al in US006146410A discloses a switched photodynamic therapy device which is capable of adaptively incorporate intra-patient tissue variations and tissue changes due to ongoing treatment session. The control system incorporates a module to check sensor readings in respect to predefined healthy tissue values stored pre- treatment. With the outcome from the control system the light source is controlled attempting to obtain a predetermined spectral pattern. However, the sensor readings are checked with the pre-defined healthy tissue values, no efficiency parameter is provided determining the outcome of the particular treatment session. A possible system with additional adaptations disclosed in EP 1470837 of Tulip et. al . discloses a switched photodynamic therapy apparatus and method. Moreover, the system US2006/0063995A1 of Yodh et .al. discloses a diagnostic apparatus configuration and method for screening and determining deep tissue characteristics by combining diffusion correlation spectroscopy and diffuse reflection spectroscopy, is also suitable for implementing embodiments of the present invention.

All the aforementioned PDT delivery system and the therapy delivered by means of these systems may be considerably improved by implementing embodiments of the present invention in these systems. In some embodiments of the apparatus and method, the measurement sequences may be performed prior to commencing therapeutic light delivery and at varying time intervals during the entire treatment and thereby give information on the temporal profile of the PDT parameters, such as the fluence rate, the sensitizer level and the tissue oxygenation, which in turn are used for the above described calibration purposes in the multivariate analysis to provide a reliable and robust prediction of treatment. In some embodiments of the apparatus these measurements of PDT parameters may also be performed in realtime, simultaneously with the therapeutic light delivery to the extent that such PDT parameter measurements are feasible without the therapeutic light interfering with the diagnostic measurements of the PDT parameters.

An example of a measured temporal profile of the light transmission between patient fibers is shown in Figure 2. The curve 210 is normalized to its initial value. The measurement was acquired with a source-detector separation of approximately 7 mm. The fibers were placed in opposite quadrants of the target volume so that the detected light had probed the center of the lesion. The measurement illustrates the typical behavior of increased attenuation of the tissue as the light delivery progresses. Thus, this measurement relates to the fluence rate distribution in the tissue.

An example of a typical spectrum 310 recorded when a diode laser emitting at 635 nm was used as the diagnostic light source is shown in the graph 300 in Figure 3a. Light transmission curves 330 as a function of delivered light dose are presented in the graph 320 in Figure 3b, similar to Figure 2.

A photobleaching curve 350 for a typical sensitizer agent, namely protoporphyrin IX, is shown in the graph 340 in Figure 3c, where the average of the normalized fluorescence signal, as detected between neighboring patient fibers in one patient, is plotted as a function of the delivered light dose. Data from the treatments indicate rapid initial photobleaching, followed by a slowly decaying fluorescence level. It should be noted that other photosensitizers may exhibit other photobleaching characteristics, and the method according to certain embodiments of the invention is not limited to the described sensitizer, protoporphyrin IX.

Figure 4 shows the change in average tissue blood volume and oxygenation status 420 evaluated by spectral analysis of the absorption properties of oxygen-saturated and non-oxygen-saturated hemoglobin in the near-infrared wavelength region. Referring to Figure 4a, graph 400, it can be seen that the blood volume increases during the treatment, while the oxygen saturation decreases when referring to Figure 4b, graph 420.

In conclusion, a method and system is presented that constitute a realtime dosimetry calibration module for IPDT. The target value for at least one treatment parameter may be initially reliably be predicted and subsequently be dynamically adapted during an ongoing IPDT treatment. In addition to that, a monitoring of light attenuation during the treatment procedure and updating individual fiber irradiation times may be performed during the treatment. Thus, the delivered light dose may be adjusted to take into account patient-specific and treatment-induced variations in tissue light transmission during the treatment itself. Finally, by continuously monitoring the tissue light transmission and updating irradiation times during a treatment session, an undertreatment, which otherwise is evident for the case of no treatment feedback, is avoided.

The present invention has been described above with reference to specific embodiments. However, other embodiments than the above described are equally possible within the scope of the invention. Different method steps than those described above, performing the method by hardware or software, may be provided within the scope of the invention. The different features and steps of the invention may be combined in other combinations than those described. The scope of the invention is only limited by the appended patent claims.

Claims

1. A system for adjusting photodynamic therapy on tissue in a body, said system comprising: a calibration device for predicting control parameters of said photodynamic light therapy.

2. The system according to claim 1, wherein said calibration device is arranged to conjointly evaluate at least one photodynamic treatment parameter of said interstitial photodynamic therapy and at least one treatment outcome parameter of said therapy; and a device for modifying characteristics of said treatment parameter of said interstitial photodynamic therapy in response to the evaluation of said photodynamic treatment parameter and treatment outcome parameter by said calibration device.

3. The system according to claim 1, wherein said calibration device is arranged to adapt said delivery of therapeutic light treatment to therapy progress at least temporary in dependence of at least one attribute of one of said photodynamic treatment parameters.

4. The system according to claim 1, wherein said calibration device is arranged to pre-process input data to enhance accuracy in a calibration model of said calibration device .

5. The system according to any of claims 1 to 4, wherein said calibration device is arranged to perform a multivariate analysis of said photodynamic treatment parameter .

6. The system according to any of claims 1 to 5, wherein said calibration system is arranged to provide initial treatment parameter settings prior to treatment, and wherein said calibration system is arranged to provide adjusted treatment parameter settings during said treatment .

7. The system according to any of claims 1 to 6, wherein said calibration device is arranged to adapt said delivery of therapeutic light treatment to therapy progress at least temporary without stopping it completely.

8. The system according to any of claims 1 to 7, wherein said calibration device is arranged to stop said delivery of therapeutic light treatment at least temporary.

9. The system according to any of the preceding claims, wherein said calibration device is arranged to provide compensation for differences between patients and/or differences within patients to be treated by said system.

10. The system according to any of the preceding claims, wherein said calibration device is configured to provide an individualized target light dose.

11. The system according to claim 10, wherein said calibration device is configured to adjust said individualized target light dose during an ongoing treatment session of said system.

12. The system according to any of the preceding claims 10 to 11, wherein said system comprises a unit providing measurement data acquired prior to and/or during said therapy.

13. The system according to any of the preceding claims, wherein said calibration device is configured to provide a statistical analysis of data from previously performed treatments that is provided from a database, wherein said calibration device is configured to provide a statistical analysis and to provide correlations between treatment parameters for providing a target value for a treatment parameter for said therapy.

14. The system according to claim 13, wherein said calibration device is configured to determine a unique treatment parameter, such as a unique, individualized target light dose, for a specific combination of treatment parameters, measured parameters and treatment outcome.

15. The system according to claim 14, wherein said calibration device is configured to chose said unique treatment parameter in relation to a desired treatment outcome.

16. The system according to any of the preceding claims, wherein said system is a system for interstitial photodynamic therapy.

17. The system according to any of the preceding claims, wherein said system comprises

(a) at least one light emitting source for therapy, said light emitting source for therapy being adapted to be inserted interstitially within said tissue site, said source having means for controlling said light dose;

(b) at least one light emitting source for diagnosis, said light emitting source for diagnosis being adapted to be inserted interstitially within said tissue site and being adapted to determine a tissue status or a sensitizer parameter;

(c) said calibration device is arranged to provide an initial set of at least one treatment parameter and a is based on a calibration method for controlling said light dose; (d) said system is configured to treat said subject with said light therapy based on said at least one treatment parameter;

(e) wherein said light emitting source for diagnosis is arranged to determine, directly or indirectly, at least one measured parameter related to said tissue status or sensitizer concentration;

(f) and wherein said calibration device is configured to calculate an updated set of said at least one treatment parameter from said measured parameter and said calibration method for providing an updated target light dose; and

(g) said system is arranged to repeat said treatment (d) , determination (e) and calculation (f) until a treatment target related to said tissue status or sensitizer concentration is reached.

18. The system according to claim 17 where said calibration device is a multivariate calibration device based on stored data related to the treatment outcome from prior treatments.

19. The system according to claim 18 wherein said stored data refers to treatments of prostate cancer.

20. The system according to claim 18 wherein said stored data refers to cell-death determined by microscopic evaluation .

21. The system according to claim 18 wherein said stored data refers to tissue necrosis determined by biopsy.

22. The system according to claim 18 wherein said stored data refers to tissue necrosis determined by radiological diagnostic methods.

23. The system according to claim 17 wherein said treatment parameter is the target light dose in substantially all positions in the tissue which is updated and the delivered light dose is calculated from said measured parameters .

24. The system according to claim 17 wherein said measured parameter is light fluence rate distribution.

25. The system according to claim 24, wherein calculating said light dose distribution comprises calculating the latter from said light fluence rate distribution and a initial light power multiplied by the time in which light is turned on in said light emitting source for therapy.

26. The system according to claim 17 wherein said at least one said measured parameter is tissue oxygenation.

27. The system according to claim 17 wherein said at least one said measured parameter is blood flow.

28. The system according to claim 17 wherein said at least one said measured parameter is a sensitizer concentration.

29. The system according to claim 17 wherein at least one said treatment parameter is a number of light sources in said tissue.

30. The system according to claim 17 or 23 wherein at least one said treatment parameter is a plurality of positions of said light sources for therapy in the tissue.

31. The system according to claim 17, 23 or 24 wherein said at least one treatment parameter is the power of each individual light source for therapy in the tissue.

32. The system according to claim 17 wherein said at least one treatment parameter is the irradiation time of each individual light source for therapy in the tissue.

33. The system according to claim 17 wherein at least one said treatment parameter is the light energy delivered by each individual light source for therapy in the tissue.

34. The system according to claim 17 wherein said at least one treatment parameter is the target light dose in substantially all positions in the tissue.

35. The system according to claim 17 wherein said at least one treatment parameter is a threshold light dose in substantially all positions in surrounding healthy tissue.

36. The system according to claim 17 wherein said tissue is a tumor tissue.

37. A computer program for processing by a computer, for adjusting interstitial photodynamic therapy on tissue in a body, the computer program comprising a calibration code segment for predicting control parameters of said photodynamic light therapy.

38. The computer program according to claim 37, further comprising code segments for controlling and adjusting light therapy in a photodynamic treatment of a subject, in a system for providing interstitial photodynamic therapy on tissue in a body, said system comprising at least one optical fiber for delivering a therapeutic light to said tissue for interaction with a photosensitizer agent in said tissue, wherein said optical fiber is devised to be interstitially inserted into said tissue with a distal end region thereof; comprising a first code segment for evaluating at least one photodynamic treatment parameter of said interstitial photodynamic therapy at said distal end region of said optical fiber; a second code segment for modifying characteristics of said therapeutic light of said interstitial photodynamic therapy in response to the evaluation of said photodynamic treatment parameter; and a third code segment for restricting said delivery of therapeutic light treatment at least temporary in dependence of at least one attribute of one of said photodynamic treatment parameters.

39. The computer program of claim 38 enabling carrying out of a method according to claims 42 to 62.

40. The computer program of claim 38 or 39, stored on a computer-readable medium.

41. Use of a per se known apparatus for photodynamic treatment for performing the method according to claims 42 to 62.

42. A method for adjusting photodynamic therapy on tissue in a body, said system comprising a calibration step for predicting control parameters of said photodynamic light therapy.

43. The method according to claim 42 for controlling and adjusting a light therapy in a photodynamic treatment of a subject, in vivo or in vitro, comprising: (a) providing at least one light emitting source for therapy, said light emitting source for therapy being adapted to be inserted interstitially within said tissue site, said source having means for controlling said light dose; (b) providing at least one light emitting source for diagnosis, said light emitting source for diagnosis being adapted to be inserted interstitially within said tissue site and being adapted to determine a tissue status or a sensitizer parameter;

(c) providing an initial set of at least one treatment parameter and a calibration method for controlling said light dose;

(d) treating said subject with said light therapy based on said at least one treatment parameter;

(e) determining, directly or indirectly, at least one measured parameter related to said tissue status or sensitizer concentration determined by said light emitting source for diagnosis;

(f) calculating an updated set of said at least one treatment parameter from said measured parameter and said calibration method for providing an updated target light dose; and

(g) repeating steps (d) , (e) and (f) until a treatment target related to said tissue status or sensitizer concentration are reached.

44. The method according to claim 33 where said calibration method is a multivariate calibration method based on stored data related to the treatment outcome from prior treatments.

45. The method according to claim 44 wherein said stored data refers to treatments of prostate cancer.

46. The method according to claim 44 wherein said stored data refers to cell-death determined by microscopic evaluation.

47. The method according to claim 44 wherein said stored data refers to tissue necrosis determined by biopsy.

48. The method according to claim 44 wherein said stored data refers to tissue necrosis determined by radiological diagnostic methods.

49. The method according to claim 43 wherein the treatment parameter is the target light dose in substantially all positions in the tissue which is updated and the delivered light dose is calculated from said measured parameters .

50. The method according to claim 43 wherein said measured parameter is light fluence rate distribution.

51. The method according to claim 50, wherein calculating said light dose distribution comprises calculating the latter from said light fluence rate distribution and a initial light power multiplied by the time in which light is turned on in said light emitting source for therapy.

52. The method according to claim 43 wherein said at least one said measured parameter is tissue oxygenation.

53. The method according to claim 43 wherein said at least one said measured parameter is blood flow.

54. The method according to claim 43 wherein said at least one said measured parameter is a sensitizer concentration.

55. The method according to claim 43 wherein at least one said treatment parameter is a number of light sources in said tissue.

56. The method according to claim 43 or 49 wherein at least one said treatment parameter is a plurality of positions of said light sources for therapy in the tissue.

57. The method according to claim 43, 49 or 50 wherein said at least one treatment parameter is the power of each individual light source for therapy in the tissue.

58. The method according to claim 43 wherein said at least one treatment parameter is the irradiation time of each individual light source for therapy in the tissue.

59. The method according to claim 43 wherein at least one said treatment parameter is the light energy delivered by each individual light source for therapy in the tissue.

60. The method according to claim 43 wherein said at least one treatment parameter is the target light dose in substantially all positions in the tissue.

61. The method according to claim 43 wherein said at least one treatment parameter is a threshold light dose in substantially all positions in surrounding healthy tissue.

62. The method according to claim 43 wherein said tissue is a tumor tissue.

63. A method for controlling and adjusting light therapy in a photodynamic treatment of a subject, comprising: determining treatment parameters for at least one therapeutic light source by taking all therapeutic light sources in a volume of said tissue into account, wherein said determining said treatment parameters is performed prior to commencing therapeutic light emission and then repeated after each measurement sequence to provide updated treatment parameters that reflect the changes in tissue status that have occurred as a result of the treatment or other physiological processes.

64. A method for controlling and adjusting light in interstitial photodynamic light therapy (IPDT) in tissue in a subject, comprising reconstruction of a target geometry, optimization of source fiber positions within this geometry, reconstructing a target geometry of said tissue, optimizing positioning of source fiber positions within this geometry, using a calculation method for determination of status of said tissue during said IPDT, and using said status in a feedback loop to control continued IPDT treatment .

65. The method according to claim 64, comprising monitoring of light attenuation during said IPDT and updating individual fiber irradiation times to take into account any variation in tissue light transmission.

66. The method according to claim 64 or 65, comprising performing said method substantially in realtime .