LANGEREIS, Geert (AE Eindhoven, NL-5656, NL)
VAN BRUGGEN, Michel, P., B. (AE Eindhoven, NL-5656, NL)
IORDANOV, Ventzeslav, P. (AE Eindhoven, NL-5656, NL)
KRIJNSEN, Hendrika, C. (AE Eindhoven, NL-5656, NL)
LANGEREIS, Geert (AE Eindhoven, NL-5656, NL)
VAN BRUGGEN, Michel, P., B. (AE Eindhoven, NL-5656, NL)
IORDANOV, Ventzeslav, P. (AE Eindhoven, NL-5656, NL)
CLAIMS:
1. A device for medical treatment decision support and/or monitoring the status of a patient comprising a) a first measuring means, which measures at least one first body parameter at the ipsilateral side of a tumor for at least >1 measuring cycle, b) a second measuring means which measures at least one second body parameter at the contralateral side of a tumor for at least >1 measuring cycle, c) a comparison means to compare the data of the first and second measuring means and/or the fitting curves derived from the first and second measuring means.
2. The device according to claim 1, wherein the at least one first and/or second body parameter includes body temperature, core body temperature, skin surface temperature, activity (body or brain), heart rate, melatonin level, triacylglycerol level, Cortisol level, blood pressure and interstitial fluid pressure.
3. The device according to claim 1 or 2, wherein the number and nature of the second body parameter(s) are identical to the first body parameter (s).
4. The device according to any one of the claims 1 or 3, whereby the length of the measuring cycle(s) is from >7 h to < 48 h.
5. The device according to any one of the claims 1 to 4, wherein the device comprises a fitting means which generates at least one first fitting curve from the data of the first measuring means to determine the acrophase, amplitude, mesor and/or period and/or a fitting means which generates at least one second fitting curve from the data of the second measuring means to determine the acrophase, amplitude, mesor and/or period.
6. The device according to any one of the claims 1 to 5 wherein the device comprises a normalizing means for normalizing the data from the comparison means in order to normalize either the first and/or second body parameter data and/or the difference of the first and second fitting curve and/or data.
7. The device according to any one of the claims 1 to 6 wherein the comparison means includes a prediction means which predicts the peak(s) in the difference between the data of the first and second measuring means and/or the fitting curves derived from the first and second measuring means especially for determining an optimal and/or suboptimal time for drug treatment and/or other medical treatment steps.
8. The device according to any one of the claims 1 to 7 wherein the device comprises a drug administering device which comprises a drug release means, which starts a drug release program based upon the comparison means.
9. A method for the controlled release of drugs and/or monitoring the status of a patient, the method comprising the steps of a) measuring at least one first body parameter of the patient for at least one first body parameter at the ipsilateral side of a tumor for at least >1 measuring cycle, b) measuring at least one second body parameter of the patient for at least one second body parameter at the contralateral side of a tumor for at least >1 measuring cycle, c) comparing the data out of the first and second body parameters in order to optionally start a drug release program and/or determine an optimal and/or suboptimal time for drug treatment and/or other medical treatment steps.
10. A system incorporating a device according to any one of the claims 1 to 8 or using the method of claim 9 and being used in one or more of the following applications: - medical devices for the administering of drugs, for hyperthermia and for radiotherapy, medical devices for treatment of chronic diseases. |
A DEVICE FOR MEDICAL TREATMENT DECISION SUPPORT AND/OR MONITORING THE STATUS OF A PATIENT
This invention is in the field of devices for the analysis of a patient as well as devices for therapeutic administration, especially for cancer treatment, more especially for breast cancer treatment. The concept of homeostasis stipulates that there is constancy of the endogenous compounds in blood. This is a most powerful construct in biology, and has influenced not only the teaching and understanding of medical science but also the practice of clinical medicine. According to this concept, the risk of the occurrence and exacerbation of disease is independent of the time of day, day of month, and month of year, as is the response of patients to diagnostic tests and medications. However, most biological functions and processes are anything but constant; Findings from the field of biologic rhythm study (chronobiology) challenge the concept of homeostasis, as well as many of the assumptions and procedures of clinical medicine.
Many biological functions wax and wane in cycles that repeat on a daily, monthly or annual basis. Such patterns do not reflect simply an organism's passive response to environmental changes, such as daily cycles of light and darkness. Rather, they reflect the organism's biological rhythms, that is, its ability to keep track of time and to direct changes in function accordingly.
Especially in the field o f cancer treatment the concept o f taking into account circadian fluctuations and/or circadian circles has become more prominent in recent times.
In 1992 it was discovered by Hori et al, Circadian variation of tumor blood flow in rat subcutaneous tumors and its alteration by angiotensin II-induced hypertension, Cancer Research, Vol. 52, pp. 912-916 (1992) that circadian fluctuations exist in tissue blood flow of rat tumors. In 1995 it was found that the time during which tumor tissue blood flow increases coincides with the time during
which tumor growth becomes more rapid.
This supports the idea that there may be an optimal time at which the anti-cancer drugs have highest treatment efficacy. Commonly used anti-cancer drugs effects are believed to be highest when cancer cells are actively dividing, something that in most concepts in the field corresponds with highest tumor blood flow.
However, in prior art, e.g. in Simpson, H. W., Sir James Young Simpson memorial lecture 1995, J R Coll Surg Edinb, Vol. 41, pp. 359-370 (1996) rhythms were measured by a daily measurement of a body parameter (e.g. temperature) at a constant time during the day, e.g. 8 o'clock in the evening. This once-a-day measurement provides a snap-shot of the rhythm of a tumor, only providing information on the infradian rhythm where ultradian rhythms may also be present. The ultradian rhythms are not properly identified when only 1 measurement (or a series of measurements in a short time interval) is being performed every 24h.
It is therefore an object of the present invention to provide a device for the analysis and / or drug administration, especially in cancer treatment, which is adapted to take into account the rhythm of a patient.
This object is achieved by a device according to claim 1 of the present invention. Accordingly, a device for medical treatment decision support and/or monitoring the status of a patient is provided, comprising a) a first measuring means, which measures at least one first body parameter at the ipsilateral side of a tumor for at least >1 measuring cycle, b) a second measuring means which measures at least one second body parameter at the contralateral side of a tumor for at least >1 measuring cycle, c) a comparison means to compare the data of the first and second measuring means and/or the fitting curves of derived from the first and second measuring means.
The term "ipsilateral" and/or "ipsilateral side" especially means and/or includes on orrelatingto the same side (of the body), i.e. nearorat thediseased or cancerous tissue.
The term "contralateral" and/or "contralateral side" especially means and/or includes on or related to the side opposite to the injured / diseased / cancerous tissue.
By doing so, at least one of the following advantages is achieved for most of the applications within the present invention:
For a wide range of applications within the present invention, no initial longer term measurements are needed that have to be analysed before the therapy can start. This allows a wide range of applications within the present invention to speed-up the process of therapy providing an earlier start, which is desired in fast-growing and advanced stage tumors
For a wide range of applications within the present invention, fewer side effects can be noticed.
For a wide range of applications within the present invention the therapeutic dose (such as radiation, drugs...) may be increased to increase treatment, efficacy.
For a wide range of applications within the present invention, also a higher efficacy of treatment can be achieved.
For a wide range of applications within the present invention, a better efficiency is noticed in a case of a temporary refusal of the therapy by the patient. In the mean time, rhythm may have changed, which is taken into account by the present invention. - For a wide range of applications within the present invention, more information on the actual status of the tumor side and thus on the tumor doubling time / growth rate of the tumor (stage) can be gathered.
For a wide range of applications within the present invention, more information on the effectiveness of the therapy at the tumor side is feasible, which may lead to a more effective treatment, which results in a change in
amplitude of the rhythm and the acrophase.
For a wide range of applications within the present invention, the invention allows the observation of desynchronization. This observation of desynchronization would be lost in studies relying solely on cosinor treat- ment restricted to the fit of a single period assumed to be equal to 24 hrs.
For a wide range of applications within the present invention, the invention allows better treatment especially for fast growing tumors (tumor doubling times are short, metabolic heat production is high). For a wide range of applications within the present invention, also a higher efficacy of treatment can be achieved.
For a wide range of applications within the present invention, the invention allows estimation of rhythms other than 24 hrs.
It may allow better timing of therapy even within the general operating hours of a hospital. The term "measuring cycle" means and/or includes especially that a body parameter of the patient is measured, which is known and/or believed to behave in a cyclic and/or periodic manner, e.g. the body temperature.
According to an embodiment of the present invention, the at least one first body parameter includes body temperature, core body temperature, skin surface temperature, activity (body or brain), heart rate, melatonin level, triacylglycerol level, Cortisol level, blood pressure, interstitial fluid pressure.
According to an embodiment of the present invention, the length of the measuring cycle(s) is from >7 h to < 48 h. This has been shown to be sufficient in practice for a wide range of applications within the present invention. According to an embodiment of the present invention, the length of the measuring cycle(s) is from >8 h to < 30 h.
According to an embodiment of the present invention, the number and nature of the second body parameter(s) are identical to the first body parameter(s). According to an embodiment of the present invention the number
and/or nature of the second body parameter(s) differ to those of to the first body parameter(s).
In the latter case, it is especially preferred for a wide range of applications to use normalized data and/or data derived from fitting curves as will be described later on.
According to an embodiment of the present invention, the device comprises a fitting means which generates at least one first fitting curve from the data of the first measuring means to determine the acrophase, amplitude, mesor and/or period and/or a fitting means which generates at least one second fitting curve from the data of the second measuring means to determine the acrophase, amplitude, mesor and/or period.
Such a fitting has been shown in practice to enhance the predictability of the behavior of the first and/or second body parameters for a wide range of applications within the present invention, which may help to increase the performance of the device according to the invention.
According to an embodiment of the present invention, the device comprises a normalizing means for normalizing the data from the comparison means in order to normalize either the first and/or second body parameter data and/or the difference of the first and second fitting curve and/or data. The term "normalizing" means includes especially that from the data derived from the circadian curve, the normalizing curve is calculated by the equation:
Z = (X-mean(X))/standard deviation *100% with X (also written as X 1 ) being the body parameter and mean(X) being the mathematical average of X 1 over a defined period. It should be noticed that usually X may have both positive and negative values.
The normalizing data obtained from the method used here are in % on a normalized scale; however it goes without saying that this is merely for the sake of better understanding and any person skilled in the art may easily transform the data to any given scale known in the field.
It has been shown in a range of applications that such a normalizing step may be of use for the reason that the normalization of the difference between ipsilateral and contralateral side may be of value to provide changes in normalized data that may be used to start and/or stop a therapy, either drug therapy, hyperthermia or radiotherapy.
According to an embodiment of the present invention, the comparison means includes a prediction means which predicts the peak(s) in the difference between the data of the first and second measuring means and/or the fitting curves derived from the first and second measuring means especially for determining an optimal and/or suboptimal time for drug treatment and/or other medical treatment steps.
According to an embodiment of the present invention, the device comprises a drug administering device which comprises a drug release means, which starts a drug release program based upon the comparison means. According to an embodiment of the present invention, the device comprises a radiotherapy device, which starts a radiotherapy program based upon the comparison means.
According to an embodiment of the present invention, the device comprises a hyperthermia device, which starts a hyperthermia program based upon the comparison means.
The term "based upon the comparison means" means and/or includes especially that upon the data derived from the comparison means certain start and/or stop signals are issued upon which a drug release and/or radiotherapy program is started and/or halted. According to an embodiment of the present invention, the drug release program includes a delay of >0 and <24 hours prior to the release of drugs.
According to an embodiment of the present invention, the device comprises a drug administering device which is chosen from transdermal patches, epills, implants, minipumps, port-a-caths, or drug administering and/or releasing implants.
It should be noted that according to an embodiment of the present invention, the measuring, selection and/or curve generation and/or normalizing means are included in the drug administering and/or radiotherapy device, whereas according to another embodiment of the present invention, they are separate. In the latter case, according to an embodiment of the present invention, the data and/or a start signal are transferred to the drug administering device and/or radiotherapy device in order to start the drug release program when needed.
The present invention also relates to a method for the controlled release of drugs and/or monitoring the status of a patient, the method comprising the steps of a) measuring at least one first body parameter of the patient for at least one first body parameter at the ipsilateral side of a tumor for at least >1 measuring cycle, b) measuring at least one second body parameter of the patient for at least one second body parameter at the contralateral side of a tumor for at least
>1 measuring cycle, c) comparing the data out of the first and second body parameters in order to optionally start a drug release program and/or determine an optimal and/or suboptimal time for drug treatment and/or other medical treatment steps.
The invention furthermore relates to the use of a device for medical treatment and/or monitoring the status of a patient for the diagnosis and/or treatment of cancer, especially breast cancer.
It has been shown for a wide range of applications that a device according to the present invention may therefore take a greater account for these rhythms and therefore may be of use for the diagnosis and/or treatment of cancer, especially breast cancer.
A device according to the present invention may be of use in a broad variety of systems and/or applications, among them one or more of the following: - medical devices for the administering of drugs, for hyperthermia and
for radiotherapy, medical devices for treatment of chronic diseases. The aforementioned components, as well as the claimed components and the components to be used in accordance with the invention in the described embodiments, are not subject to any special exceptions with respect to their size, shape, material selection and technical concept, so that the selection criteria known in the pertinent field can be applied without limitations.
Additional details, features, characteristics and advantages of the object of the invention are disclosed in the dependent claims, the figures and the following description of the respective figures, tables and examples.
Fig. 1 shows a diagram of temperature plotted against time of the ipsilateral side of a tumor;
Fig. 2 shows a diagram of temperature plotted against time of the contralateral side of a tumor;
Fig. 3 shows a diagram of the difference in temperatures of the diagrams of Figs. 1 and 2, and Fig. 4 shows a diagram of the difference in normalized temperatures of the diagrams of Figs. 1 and 2.
The invention will furthermore be better understood with the following examples for some applications in which a device according to the present invention may be of use, but which are merely to be understood as exemplarily and not limiting for the present invention. Figs. 1 and 2 refer to the measurement of superficial temperature
(ipsilateral and contralateral) of a tumor, whereby the temperature was measured over a period of 194 hrs by the hour.
The exact data are shown in Table I:
Table I: time ipsilateral contralateral difference
(hrs.) temperature temperature
0 34.06208 32.45 1.612078
1 33.95013 32.13934 1.810791
2 33.83232 31.90096 1.931358
3 33.72829 31.75111 1.977182
4 33.65687 31.7 1.956868
5 33.63384 31.75111 1.882726
6 33.67008 31.90096 1.769116
7 33.77019 32.13934 1.63085
8 33.9318 32.45 1.481801
9 34.14563 32.81177 1.333857
10 34.3963 33.2 1.196299
11 34.66383 33.58823 1.075597
12 34.92561 33.95 0.975607
13 35.15873 34.26066 0.898066
14 35.3423 34.49904 0.843263
15 35.45965 34.64889 0.810758
16 35.5 34.7 0.8
17 35.45965 34.64889 0.810758
18 35.3423 34.49904 0.843263
19 35.15873 34.26066 0.898066
20 34.92561 33.95 0.975607
21 34.66383 33.58823 1.075597
22 34.3963 33.2 1.196299
23 34.14563 32.81177 1.333857
24 33.9318 32.45 1.481801
25 33.77019 32.13934 1.63085
26 33.67008 31.90096 1.769116
27 33.63384 31.75111 1.882726
28 33.65687 31.7 1.956868
29 33.72829 31.75111 1.977182
30 33.83232 31.90096 1.931358
31 33.95013 32.13934 1.810791
32 34.06208 32.45 1.612078
33 34.14995 32.81177 1.338183
34 34.19908 33.2 0.999083
35 34.2 33.58823 0.611771
36 34.14954 33.95 0.199536
37 34.0512 34.26066 -0.20946
38 33.91479 34.49904 -0.58425
39 33.75531 34.64889 -0.89358
40 33.5913 34.7 -1.1087
41 33.44272 34.64889 -1.20616
42 33.3287 34.49904 -1.17034
43 33.26531 34.26066 -0.99535
44 33.26371 33.95 -0.68629
45 33.32876 33.58823 -0.25947
46 33.45832 33.2 0.258316
47 33.64333 32.81177 0.831557
48 33.86861 32.45 1.418615
49 34.11436 32.13934 1.975021
50 34.35812 31.90096 2.457154
51 34.57709 31.75111 2.825974
52 34.75048 31.7 3.050485
53 34.8617 31.75111 3.110584
54 34.9 31.90096 2.999038
55 34.8617 32.13934 2.722356
56 34.75048 32.45 2.300485
57 34.57709 32.81177 1.765314
58 34.35812 33.2 1.158116
59 34.11436 33.58823 0.526133
60 33.86861 33.95 -0.08139
61 33.64333 34.26066 -0.61733
62 33.45832 34.49904 -1.04072
63 33.32876 34.64889 -1.32013
64 33.26371 34.7 -1.43629
65 33.26531 34.64889 -1.38358
66 33.3287 34.49904 -1.17034
67 33.44272 34.26066 -0.81794
68 33.5913 33.95 -0.3587
69 33.75531 33.58823 0.167083
70 33.91479 33.2 0.714786
71 34.0512 32.81177 1.239426
72 34.14954 32.45 1.699536
73 34.2 32.13934 2.06066
74 34.19908 31.90096 2.298122
75 34.14995 31.75111 2.398843
76 34.06208 31.7 2.362078
77 33.95013 31.75111 2.19902
78 33.83232 31.90096 1.931358
79 33.72829 32.13934 1.588953
80 33.65687 32.45 1.206868
81 33.63384 32.81177 0.822065
82 33.67008 33.2 0.470078
83 33.77019 33.58823 0.181961
84 33.9318 33.95 -0.0182
85 34.14563 34.26066 -0.11503
86 34.3963 34.49904 -0.10274
87 34.66383 34.64889 0.014936
88 34.92561 34.7 0.225607
89 35.15873 34.64889 0.509837
90 35.3423 34.49904 0.843263
91 35.45965 34.26066 1.198986
92 35.5 33.95 1.55
93 35.45965 33.58823 1.871418
94 35.3423 33.2 2.142301
95 35.15873 32.81177 2.346954
96 34.92561 32.45 2.475607
97 34.66383 32.13934 2.524485
98 34.3963 31.90096 2.495337
99 34.14563 31.75111 2.394517
100 33.9318 31.7 2.231801
101 33.77019 31.75111 2.019079
102 33.67008 31.90096 1.769116
103 33.63384 32.13934 1.494497
104 33.65687 32.45 1.206868
105 33.72829 32.81177 0.916521
106 33.83232 33.2 0.63232
107 33.95013 33.58823 0.361902
108 34.06208 33.95 0.112078
109 34.14995 34.26066 -0.11071
110 34.19908 34.49904 -0.29995
111 34.2 34.64889 -0.44889
112 34.14954 34.7 -0.55046
113 34.0512 34.64889 -0.59769
114 33.91479 34.49904 -0.58425
115 33.75531 34.26066 -0.50535
116 33.5913 33.95 -0.3587
117 33.44272 33.58823 -0.1455
118 33.3287 33.2 0.128699
119 33.26531 32.81177 0.453538
120 33.26371 32.45 0.813709
121 33.32876 32.13934 1.189416
122 33.45832 31.90096 1.557354
123 33.64333 31.75111 1.892218
124 33.86861 31.7 2.168615
125 34.11436 31.75111 2.36325
126 34.35812 31.90096 2.457154
127 34.57709 32.13934 2.437746
128 34.75048 32.45 2.300485
129 34.8617 32.81177 2.049924
130 34.9 33.2 1.7
131 34.8617 33.58823 1.273467
132 34.75048 33.95 0.800485
133 34.57709 34.26066 0.316426
134 34.35812 34.49904 -0.14092
135 34.11436 34.64889 -0.53453
136 33.86861 34.7 -0.83139
137 33.64333 34.64889 -1.00556
138 33.45832 34.49904 -1.04072
139 33.32876 34.26066 -0.9319
140 33.26371 33.95 -0.68629
141 33.26531 33.58823 -0.32292
142 33.3287 33.2 0.128699
143 33.44272 32.81177 0.630953
144 33.5913 32.45 1.141303
145 33.75531 32.13934 1.615971
146 33.91479 31.90096 2.013824
147 34.0512 31.75111 2.300086
148 34.14954 31.7 2.449536
149 34.2 31.75111 2.448889
150 34.19908 31.90096 2.298122
151 34.14995 32.13934 2.010614
152 34.06208 32.45 1.612078
153 33.95013 32.81177 1.138359
154 33.83232 33.2 0.63232
155 33.72829 33.58823 0.140064
156 33.65687 33.95 -0.29313
157 33.63384 34.26066 -0.62682
158 33.67008 34.49904 -0.82896
159 33.77019 34.64889 -0.8787
160 33.9318 34.7 -0.7682
161 34.14563 34.64889 -0.50326
162 34.3963 34.49904 -0.10274
163 34.66383 34.26066 0.403165
164 34.92561 33.95 0.975607
165 35.15873 33.58823 1.570497
166 35.3423 33.2 2.142301
167 35.45965 32.81177 2.647875
168 35.5 32.45 3.05
169 35.45965 32.13934 3.320307
170 35.3423 31.90096 3.441339
171 35.15873 31.75111 3.407615
172 34.92561 31.7 3.225607
173 34.66383 31.75111 2.912714
174 34.3963 31.90096 2.495337
175 34.14563 32.13934 2.006289
176 33.9318 32.45 1.481801
177 33.77019 32.81177 0.958419
178 33.67008 33.2 0.470078
179 33.63384 33.58823 0.045608
180 33.65687 33.95 -0.29313
181 33.72829 34.26066 -0.53237
182 33.83232 34.49904 -0.66672
183 33.95013 34.64889 -0.69876
184 34.06208 34.7 -0.63792
185 34.14995 34.64889 -0.49893
186 34.19908 34.49904 -0.29995
187 34.2 34.26066 -0.06066
188 34.14954 33.95 0.199536
189 34.0512 33.58823 0.462969
190 33.91479 33.2 0.714786
191 33.75531 32.81177 0.94354
192 33.5913 32.45 1.141303
193 33.44272 32.13934 1.303385
194 33.3287 31.90096 1.427737
As can be seen in Fig. 2, the contralateral side follows a regular pattern with a 24-hour circadian period.
However, the data for the ipsilateral side (Fig. 1 ) are more complex; however an ultradian rhythm of 19 hours can be observed.
Fig. 3 shows a diagram of the difference in temperatures of the diagrams of Figs. 1 and 2. From this diagram can be clearly seen that there are two main peaks at 53hrs and 170 hrs, together with several peaks at 3, 29, 75, 97, 126 and 149 hrs. Fig. 4 shows a diagram of the difference in normalized temperatures of the diagrams of Figs. 1 and 2 using a normalizing procedure as described above. The peaks here are - of course - identical with those of Fig. 3. Such a normalized curve may help to further increase the capability of the device for medical treatment decision support, e.g. in that certain drug or therapy programs are started when the curve rises above a certain threshold or by taking into account the steepness of the normalized curve.
A possible medical treatment would best be started at these peaks; depending on the treatment (and on the drug and/or radiotherapy dosis which needs to be applied) one could consider to only use the main peaks or also apply a drug
and/or a radio dosis at one or more of the other peaks as well.
It should be noticed that the optimum times as indicated by Fig. 3 (and in accordance with the present invention) differ greatly from most of the peaks of Fig. 1. Actually the first maximum in skin temperature at the ipsilateral side occurs at the same time as the peak on the contralateral side, which indicates that both tissues do show cell division (cancer and healthy cells) and at which high-dose therapy may have to be avoided to avoid serious side effects even though the tumor cells are dividing. By applying the present invention, one is able to take this into account. The particular combinations of elements and features in the above detailed embodiments are exemplary only; the interchanging and substitution of these teachings with other teachings in this and the patents/applications incorporated by reference are also expressly contemplated. As those skilled in the art will recognize, variations, modifications, and other implementations of what is described herein can occur to those of ordinary skill in the art without departing from the spirit and the scope of the invention as claimed. Accordingly, the above description is given by way of example only and is not intended to be limiting. The invention's scope is defined in the following claims and the equivalents thereto. Furthermore, reference signs used in the description and claims do not limit the scope of the invention as claimed.