Methods, systems, and associated implantable devices for dynamic monitoring of physiological and biological properties of tumors

• US 6,402,689 B1
• Filed: 09/29/1999
• Issued: 06/11/2002
• Est. Priority Date: 09/30/1998
• Status: Expired due to Term

• Current Assignee: SNC Holdings Corp., North Carolina State University (University of North Carolina System)
• Original Assignee: Sicel Technologies, Inc., North Carolina State University (University of North Carolina System)
• Inventors: Kim, Chang-Soo, Mueller, Jeffrey, Scarantino, Charles W., Hall, Leslie C., Nagle, H. Troy
• Primary Examiner(s): Shaver, Kevin
• Assistant Examiner(s): Astorino, Michael C
• Application Number:
  US09/407,359
• Time in Patent Office: 986 Days
• Field of Search: 600/300-301, 600/326-327, 600/309, 600/361-365, 600/407, 600/436, 600/476, 600/1-7, 128/903, 128/904, 128/920-925, 424/9.1, 424/422, 424/423
• US Class Current: 600/300
• CPC Class Codes: A61B 2562/028 Microscale sensors, e.g. electromechanical sensors [MEMS]
• CPC Class Codes: A61B 2562/085 combined with means for recording calibration data
• CPC Class Codes: A61B 5/0031 Implanted circuitry
• CPC Class Codes: A61B 5/14539 for measuring pH
• CPC Class Codes: A61B 5/1473 invasive, e.g. introduced into the body by a catheter A61B5/1482 takes precedence
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: A61B 5/1495 Calibrating or testing of in-vivo probes
• CPC Class Codes: A61B 5/417 the bone marrow
• CPC Class Codes: A61B 6/507 for determination of haemodynamic parameters, e.g. perfusion CT
• CPC Class Codes: A61N 5/1048 Monitoring, verifying, controlling systems and methods
• CPC Class Codes: A61N 5/1071 for verifying the dose delivered by the treatment plan
• CPC Class Codes: G16H 20/40 relating to mechanical, radiation or invasive therapies, e.g. surgery, laser therapy, dialysis or acupuncture
• CPC Class Codes: G16H 40/67 for remote operation
• CPC Class Codes: Y10S 128/903 Radio telemetry
• CPC Class Codes: Y10S 128/904 Telephone telemetry
• CPC Class Codes: Y10S 128/92 Computer assisted medical diagnostics

Abstract

Methods of monitoring and evaluating the status of a tumor undergoing treatment includes monitoring in vivo at least one physiological parameter associated with a tumor in a subject undergoing treatment, transmitting data from an in situ located sensor to a receiver external of the subject, analyzing the transmitted data, repeating the monitoring and transmitting steps at sequential points in time and evaluating a treatment strategy. The method provides dynamic tracking of the monitored parameters over time. The method can also include identifying in a substantially real time manner when conditions are favorable for treatment and when conditions are unfavorable for treatment and can verify or quantify how much of a known drug dose or radiation dose was actually received at the tumor. The method can include remote transmission from a non-clinical site to allow oversight of the tumor'"'"'s condition even during non-active treatment periods (in between active treatments). The disclosure also includes monitoring systems with in situ in vivo biocompatible sensors and telemetry based operations and related computer program products.

Claims

1. A method of monitoring and evaluating the status of a tumor undergoing treatment, comprising the steps of:

(a) monitoring in vivo at least one physiological parameter associated with a tumor in a subject undergoing treatment with an in situ sensor unit;

(b) transmitting data associated with the at least one monitored physiological parameter from the in situ positioned sensor unit to a receiver located external to the subject;

(c) analyzing the transmitted data to determine a condition of the tumor;

(d) repeating steps (a), (b), and (c) periodically at a plurality of sequential points in time; and

(e) evaluating a tumor treatment strategy comprising at least one of;

identifying a favorable or unfavorable tumor treatment time for administration of at least one of a radiation, drug, and chemical therapy;

evaluating the efficacy of at least one of therapeutic radiation, drug, and chemical treatment on the tumor;

determining the amount of radiation delivered in vivo to the tumor site;

monitoring radiolabeled drug uptake at the tumor site; and

analyzing the transmitted data to monitor the influence of at least one of a thermal, chemical, or radiation therapy on the tumor based on data transferred before, during and after the therapy.

2. A method according to claim 1, wherein the at least one monitored physiological parameter includes the temperature proximate the tumor site and at least one of the pH at the tumor site, the level of oxygenation at the tumor site, cell proliferation at the tumor site, and the amount of radiation exposure at the tumor site, and wherein said transmitting and analyzing steps are repeated sufficiently to track variation in the at least one of the monitored parameters and thereby assess the behavior of the tumor over time.

3. A method according to claim 1, wherein said monitoring step monitors a plurality of tumor physiological parameters, and wherein said analyzing step defines a plurality of predetermined test conditions, wherein at least one test condition associated with identifying a favorable treatment time and at least one test condition associated with identifying an unfavorable treatment time, and wherein said method further comprises the step of alerting a clinician as to when the transmitted data satisfies one of said test conditions which identifies when a favorable unfavorable treatment window for delivering a subsequent active treatment to the tumor is identified.

4. A method according to claim 3, wherein said favorable treatment test condition includes test criteria corresponding to the identification of a tumor susceptibility or vulnerability phase.

5. A method according to claim 2, wherein said transmitting step comprises transmitting data from a non-clinical site of a patient to a remote clinical site thereby allowing remote dynamic monitoring of the at least one physiological parameter.

6. A method according to claim 1, wherein steps (a) and (b) are repeated temporally proximate to an active treatment delivery of at least one of a radiation therapy and a chemotherapy to provide real-time information regarding the tumor and the appropriateness of proceeding with the active treatment at that time.

7. A method according to claim 1, wherein steps (a) and (b) are repeated during an active therapeutic cytotoxic chemical treatment delivery to provide real-time information to a physician to allow therapeutic treatment decisions based on the substantially real time monitored tumor parameters.

8. A method according to claim 1, wherein a therapeutic oncology treatment protocol is adjusted based on tumor information provided by the monitored in vivo physiological parameter of the tumor particular to the subject.

9. A method according to claim 1, wherein said repeating step is carried out at least once every 24 hours.

10. A method according to claim 1, wherein the repeating step is carried out at varying time intervals responsive to the progression or stage of treatment and responsive to detected relative changes in the monitored parameters.

11. A method according to claim 1, further comprising electronically storing a series of temporally related data measurements to dynamically monitor the variation in the at least one monitored physiological parameter overtime.

12. A method according to claim 1, wherein the tumor is one of carcinoma and scarcoma.

13. A method according to claim 1, wherein the tumor is a solid mass.

14. A method according to claim 1, further comprising the step of positioning at least one sensor unit configured to monitor a plurality of physiological parameters into a subject such that it is positioned in in situ in vivo contact with a target tumor, wherein the positioned sensor unit has a service life of at least about 4-10 weeks.

15. A method according to claim 1, wherein said monitoring step is performed by a sensor unit with a plurality of sensor elements positioned in situ, and wherein said sensor unit is positioned in the subject by at least one of implanting and injecting the sensor unit such that at least one of the sensor elements contacts the tumor.

16. A method according to claim 14, wherein said positioning step comprises injecting multiple discrete dependent sensor units into the subject such that they contact the target tumor and further comprises implanting a satellite sensor unit in wireless electrical communication with said dependent sensor units into the subject such that the satellite sensor is positioned proximate to said dependent sensor units.

17. A method according to claim 1, wherein said evaluating step includes at least one of determining the efficacy of the treatment and identifying a subsequent active favorable treatment window.

18. A method according to claim 17, wherein the subject has multiple tumors, and wherein said method further comprises positioning a first sensor unit in situ to contact a first tumor and positioning a second sensor unit in situ proximate to a second tumor different from the first tumor.

19. A method according to claim 15, wherein at least one of said sensor elements is configured to monitor the toxic effects of treatment on normal cell tissue proximate to the tumor.

20. A method according to claim 1, said method further comprising the step of monitoring at least one parameter associated with normal cells proximate to the tumor.

21. A method according to claim 20, wherein said normal cell monitoring parameter is pH and wherein said at least one monitored tumor parameter is pH.

22. A method according to claim 21, wherein said analyzing step compares the normal cell pH with the tumor pH and wherein said evaluating step includes reviewing the relative difference between the two pH parameters to establish a treatment strategy.

23. A method according to claim 1, wherein said monitoring step monitors a plurality of different tumor physiological parameters.

24. A method according to claim 23, wherein said plurality of different tumor physiological parameters comprises pH, oxygenation, temperature, and quantification of the amount of radiation therein.

25. A method according to claim 23, wherein said monitoring step comprises detecting a period of increased cell proliferation and an increased level of oxygenation.

26. A method according to claim 15, wherein said multiple sensors have an extended clinically useful life of about at least 4-6 weeks.

27. A method according to claim 23, wherein said monitoring step monitors at least two of temperature proximate the tumor site, oxygenation level proximate the tumor site, delivered radiation proximate the tumor site, and pH level proximate the tumor site, and wherein said analyzing step predetermined test criteria evaluates the presence of at least one of an elevated oxygenation level, an elevated radiation level, and a decreased pH level.

28. A method according to claim 1, wherein said evaluating step comprises the steps of tracking the results of the monitored data over a period of time and comparing the transmitted data against a predictive model to determine when a planned therapeutic tumor treatment indicates an adjustment is desired based on deviation of the tumor'"'"'s response to the delivered therapy as measured against a population norm.

29. A method according to claim 1, wherein said predetermined test criteria includes absolute and relative test conditions.

30. A method according to claim 1, wherein said analyzing step identifies the amount of time elapsed from the time of the last active radiation or chemotherapy treatment.

31. A method according to claim 2, wherein said analyzing step tracks a dynamic history of at least two of the monitored parameters over time.

32. A method according to claim 20, further comprising administering one of a cytotoxic agent and radiation to the subject, and assessing the toxic effects on normal cell tissue proximate to the target tumor site.

33. A method according to claim 1, said method further comprising establishing a known active treatment date and known active treatment dose, wherein said monitoring step monitors the amount of treatment dose received at the tumor, and wherein said analyzing step compares the received dose with the known dose and identifies a discrepancy from the delivered dose to the measured dose to thereby confirm the efficacy of a targeted treatment dose.

34. A method according to claim 15, wherein said sensor unit includes sensor electronics, and wherein said method further comprises the step of adjusting the transmitted data to account for deviations in the data attributed to the sensor unit'"'"'s exposure to at least one of radiation and temperature.

35. A method according to claim 3, wherein the predetermined test criteria identifies the presence of a clustering of test conditions including the presence of an elevated oxygenation level and a period of cell proliferation measured corresponding to an elevated radiation level at the tumor.

36. A method according to claim 1, wherein said evaluating step includes adjusting a chemical or radiation treatment dose, delaying or advancing the next active treatment delivery of one of a chemical, radiation, and thermal therapy, or altering a selected treatment therapy type of one of chemical, radiation, or thermal to a different one.

37. A method according to claim 3, wherein said method further comprises automatically scheduling an active treatment session or evaluation appointment at a clinic.

38. A method according to claim 1, wherein said monitoring step is carried out remotely over at least one of a telephone line, fiber optic line, cable line, a computer modem, an internet hook-up, and other wireless communication mode.

39. A method according to claim 1, wherein said monitoring step is carried out via at least one sensor unit having a plurality of in situ sensor elements having a service life of at least about 4-10 weeks, and wherein said method further comprises the step of locally transmitting data associated with the at least one monitored physiological parameter representative of a physiological condition associated with the tumor thereby providing substantially real-time information regarding the condition of the tumor.

40. A method according to claim 39, wherein said local transmitting step is performed before an active therapy session to determine the suitability of delivering an active treatment.

41. A method according to claim 39, wherein said local transmitting step is performed during an active radiation, chemical, or thermal therapy session to control at least one of the amount, rate, or length of an active treatment session.

42. A tumor monitoring system for identifying enhanced active cancer treatment windows, comprising:

at least one implantable sensor unit comprising a plurality of sensor elements and associated sensor electronics, wherein a plurality of said plurality of sensor elements are configured for in vivo in situ contact with a cancerous tumor in a subject undergoing treatment for cancer, and wherein said sensor elements are configured to detect a plurality of different parameters associated with the tumor and wirelessly transmit data associated with the detected parameters, wherein said plurality of different parameters includes at least two of the amount of radiation exposure at the tumor site, extracellular pH of the tumor, pH of normal tissue, tumor cell oxygenation, tumor cell proliferation and temperature;

a remote receiver in wireless communication with said at least one sensor, said receiver configured to receive the transmitted data, wherein said receiver is spatially separate from said at least one sensor and positioned external to the subject; and

a processor having computer readable program code for analyzing the transmitted data to identify the presence or absence of a favorable cancer treatment condition.

43. A tumor monitoring system according to claim 42, further comprising computer readable program code means for reviewing and adjusting the received transmitted data to correct for variations in the signal data attributed to environmental exposure of the sensor unit or sensors elements held in the subject.

44. A tumor monitoring system according to claim 42, wherein, in position, said plurality of sensor elements are configured to reside at different locations on and within the tumor, and wherein at least one of said plurality of sensor elements is configured to contact normal tissue cells proximate to the tumor.

45. A tumor monitoring system according to claim 42, wherein said remote unit is configured to be worn by the subject, and wherein said remote receiver further comprises a remote interface to allow a user to transmit data from a physically remote non-clinical site to a central processing unit at a clinical site during a non-emission cancer treatment period.

46. A tumor monitoring system according to claim 42, wherein said sensor unit is configured as a cylindrically shaped body having opposing first and second ends, and wherein said sensor unit includes an inductively coupled power source, wherein said sensor is sized to have a length which is less than about 0.5 inches (1.27 cm) and is configured to be injectable via a trochar into the subject such that at least one of said first and second ends contacts a tumor within a mammalian body, and wherein said at least one sensor unit has an implanted service life of at least about 4-10 weeks.

47. A tumor monitoring system according to claim 42, wherein said sensor unit comprises operating electronics positioned within a first body portion and a plurality of flexible arms extending outwardly therefrom, each of said arms having distal portions containing at least one sensor element thereon and having at least one signal path between said operating electronics in said first body portion to each of said sensor elements in each of said arms.

48. A tumor monitoring system according to claim 42, wherein said sensor unit includes an inductively coupled power source, and wherein at least one of said arms includes a plurality of sensor elements.

49. A tumor monitoring system according to claim 42, wherein said arms are configured with an anchor portion to positionally attach to a desired portion of the tumor.

50. A tumor monitoring system according to claim 42, wherein said sensor elements include at least one pH sensor element, at least one oxygen sensor element, at least one temperature sensor element, and at least one radiation sensor element.

51. A tumor monitoring system according to claim 42, wherein said at least one sensor unit comprises a plurality of sensor elements is configured as an implantable satellite sensor unit and an associated plurality of injectable discrete dependent sensor units, wherein each of said discrete dependent sensor units have at least one sensor element thereon, and wherein said plurality of discrete dependent sensor units are in wireless communication with said satellite sensor unit.

52. A tumor monitoring system according to claim 42, wherein said at least one sensor unit is a plurality of sensor units, and wherein each sensor unit includes a unique identifier to allow transmitted data to be correlated to the appropriate in situ sensor unit position.

53. A tumor monitoring system according to claim 42, wherein said remote receiver is portable and wearable by the patient so as to be held proximate thereto.

54. A computer program product for monitoring and analyzing the condition of a tumor in a patient undergoing cancer treatment, the computer program product comprising:

a computer readable storage medium having computer readable program code means embodied in said medium, said computer-readable program code means comprising;

computer readable program code means for commencing a first wireless data transmission from an in situ wireless sensor with at least one sensor element positioned in a subject proximate to a tumor site undergoing treatment for cancer, the data transmission including data corresponding to the output of the at least one sensor element;

computer readable program code means for commencing a second wireless data transmission from the in situ sensor temporally separate from the first wireless data transmission;

computer readable program code means for tracking variation between the first and second data transmissions to provide a dynamic behavioral model of the tumor'"'"'s response to the treatment;

computer readable program code for analyzing the transmitted data to identify at least one favorable cancer treatment opportunity;

computer readable program code means for evaluating at least one of (a) the amount of radiation exposure delivered to the tumor site from a cancer radiation treatment session, (b) cell proliferation associated with the tumor, (c) the response of normal tissue proximate the tumor site to the cancer treatment;

(d) the value of at least one physiological or biological parameter of the tumor to evaluate efficacy of a cytotoxic or targeted drug or chemical treatment or to confirm delivery of the cytotoxic or targeted drug or chemical treatment to the tumor site, (e) a variation in the value of a physiological or biological parameter of the tumor from a predictive model, (f) the presence of an unfavorable cancer treatment period, and (g) the value of at least one physiological or biological parameter of the tumor to identify a receptiveness for a particular cancer therapy type.

55. A computer program product according to claim 54, wherein said computer readable program code means for evaluating includes computer program code means for evaluating the efficacy of the cancer treatment by comparing the value of at least one predetermined physiological or biological parameter to a corresponding predetermined value established for each of the at least one physiological or biological parameters.

56. A computer program product according to claim 54, wherein said computer readable program code means for evaluating includes computer program code means for evaluating the efficacy of the cancer treatment by comparing the value of at least one predetermined physiological or biological parameter to a corresponding relative change in the monitored at least one physiological or biological parameters, over time.

57. A computer program product according to claim 54, further comprising computer readable program code means for commencing ongoing periodic data transmissions over a predetermined time period, the predetermined time period including time away from a clinical treatment site, and computer readable program code means for analyzing the periodic data transmissions to identify a favorable active cancer treatment opportunity.

58. A computer program product according to claim 54, further comprising computer readable program code means for initiating a subsequent data transmission temporally proximate to a planned treatment time to thereby provide real time information for therapeutic decisions regarding the condition of the tumor in a manner which can estimate the likelihood of success of a planned treatment strategy.

59. A computer program product according to claim 58, further comprising computer readable program code means for initiating a subsequent data transmission during an active treatment session to thereby provide real time information for therapeutic decisions regarding the treatment session itself.

60. A computer program product according to claim 59, further comprising a computer readable program code means for controlling the delivery of the treatment itself corresponding to a change in the one or more monitored physiological parameters during the treatment session.

61. A computer program product according to claim 54, further comprising computer readable program code means for remotely directing the transmission of data from a non-clinical site to a clinical or data processing site remote from the non-clinical site for offsite evaluation.

62. A computer program product according to claim 57, wherein said ongoing periodic data transmissions monitors the at least one physiological parameter at least at sequential semi-continuous time intervals, and wherein said computer program product comprises computer readable program code means for storing the semi-continuously monitored data transmissions and then subsequently transmitting the stored data transmissions as a bulk update to a clinical site.

63. A computer program product according to claim 54, wherein said computer program code means evaluates a plurality of said items (a) through (e).

64. A computer program product according to claim 63, wherein said computer program code means evaluates at least three of said items (a) through (e).

65. A computer program product according to claim 64, wherein said computer program code means evaluates all of said items (a) through (e).

66. A computer program product according to claim 63, wherein said computer readable program code means for evaluating the value of at least one physiological or biological parameter of the tumor to evaluate efficacy of a cytotoxic or drug or chemical treatment or to confirm delivery of the cytotoxic or drug or chemical treatment to the tumor site comprises comparing the pH of the subject'"'"'s normal tissue to the extracellular pH of the tumor tissue.

67. A computer program product according to claim 63, wherein said computer readable program code means for evaluating the value of at least one physiological or biological parameter of the tumor to evaluate efficacy of a Cytotoxic or drug or chemical treatment or to confirm delivery of the cytotoxic or drug or chemical treatment to the tumor site comprises comparing the extracellular pH of the subject'"'"'s cancerous tumor tissue to a predetermined value before delivery of an active cancer treatment.

68. A computer program product according to claim 63, wherein said computer readable program code means for evaluating the amount of radiation exposure delivered to the tumor site during a cancer radiation treatment session confirms that the radiation level received at the tumor site is between about 3000-6000 cG.

69. A computer program product according to claim 63, wherein said computer readable program code means for evaluating a variation in the value of a physiological or biological parameter of the tumor from a predictive model compares the physiological or biological values of the tumor to a statistical model of values at corresponding periods of time into comparative treatment regiments.

70. A computer program product according to claim 63, wherein said computer readable program code means for evaluating the value of at least one physiological or biological parameter of the tumor identifies an unfavorable cancer treatment period associated with when the tumor is hypoxic.

71. A computer program product according to claim 63, wherein said computer readable program code means for evaluating the value of at least one physiological or biological parameter of the tumor identifies a favorable cancer treatment period associated with when the tumor is in an active cell proliferation phase.

72. A computer program product according to claim 63, wherein said computer readable program code means for evaluating the value of at least one physiological or biological parameter of the tumor to identify a receptiveness for a particular cancer therapy type identifies the extracellular pH level of the tumor for assessing which drug to administer to the patient.