System for heating a body organ

IS 2 256 267 T3

DESCRIPTION

System for heating the prostate gland.

Background of the invention

1. Field of the invention

The present invention relates generally to a system for delivering focused energy to a body selectively using one or multiple energy applicators to treat visible tumors and microscopic benign and malignant cells in hyperthermic prostate tissue. The system according to the invention can be used to treat healthy tissue containing undetected microscopic pathologically altered cells (neoplasia) which are high in water content to prevent the appearance or recurrence of cancerous, precancerous or benign prostatic lesions. Furthermore, the described system can be used to prevent the growth of tumors within the prostate, as well as to prevent the spread of cancer cells outside the prostate.

Description of the prior art

To treat hyperthermic prostate tumors, a considerable portion of the prostate gland must be heated without affecting healthy prostate tissues or surrounding tissues including the urethral and rectal walls of a patient. In the United States, approximately 200,000 cases of prostate cancer are detected per year as well as 375,000 cases of benign prostatic hyperplasia, called BPH, (enlarged prostate gland). BPH is a non-cancerous enlargement (tumor) of the prostate gland that occurs in almost all men with age, particularly after the age of 50 years. In the case of BPH, the enlargement of the prostate implies the excessive growth of tissue that eventually obstructs the exit of the bladder, creating difficulties when urinating. In the case of prostate cancer, eventually the cancer will rupture the capsule of the prostate gland, leading to the spread of the cancer to the bones and vital organs of the body. Although some of the signs of BPH and prostate cancer are the same, having BPH does not increase your chances of getting prostate cancer. However, a patient who has BPH may have undetected prostate cancer at the same time or may develop prostate cancer in the future.

As is known in the art, the use of heat to treat prostate tumors can be effective in a number of ways; however, in most cases, heat treatment should be able to warm a significant volume of the prostate gland without overheating the urethral and rectal walls. In radiation therapy, the entire prostate and surrounding tissues are irradiated with X-rays to kill all microscopic cancer cells. During heating, large volumes of the prostate can destroy many or all of the microscopic carcinoma cells in the prostate, known methods of heating tumors can destroy healthy tissue in the prostate and, more damagingly, the urethral and rectal walls of the prostate. a patient.

The prostate gland has muscle-like electrical properties (TS England and NA Sharples, Nature, Vol. 163, March 26, 1949, pp. 487-488) and is known to have a high water content, on the order of 80% ( FA Duck, Physical Properties of Tissue, A Comprehensive Reference Book, Academic Press, New York, p. 321, 1990). Tumor tissue, in general, tends to have 10-20% more water content than normal tissue (Foster and Schepps, Journal of Microwave Power, vol. 16, number 2, pp. 107-119, 1991). Thus, prostate tumors can have a water content of the order of about 90%. Therefore, selective microwave heating of the prostate would be the best method of treating cancer or benign cells.

It is known that microwave energy can heat high water content tumor tissues more rapidly compared to heating normal tissues with lower water content. Tumor tissue tends to be poorly irrigated so that blood flow frequently decreases at therapeutic temperatures allowing rapid heating, whereas in normal tissues blood flow frequently increases protecting normal healthy tissue from heat damage. Many clinical studies have established that hyperthermia (elevated temperature) induced by absorption of electromagnetic energy in the microwave band considerably improves the effect of radiation therapy in the treatment of malignant tumors in the human body (Valdagni et al., International Journal of Radiation Oncology Biology Physics, Vol. 28, pp. 163169, 1993; Overgaard et al., International Journal of Hyperthermia, Vol. 12, No. 1, pp. 3-20, 1996; Vernon et al., International Journal of Radiation Oncology Biology Physics, Vol. 35, pp. 731-744, 1996). Radioresistant cells, such as S-phase cells, can be directly killed by elevated temperature (Hall, Radiobiology for the Radiologist, 4^to edition, JB Lippincott Company, Philadelphia, pp. 262-263, 1994; Perez and Brady, Principles and Practice of Radiation Oncology, Second Edition, JB Lippincott Company, Philadelphia, pp. 396-397, 1994). Hyperthermia treatments with microwave radiation devices are generally administered in several treatment sessions, in which the malignant tumor is heated to approximately 43 ° C for approximately 60 minutes. The amount of time to kill tumor cells is known to decrease by a factor of two for every degree of temperature rise above about 43 ° C (Sapareto et al., International Journal of Radiation Oncology Biology Physics, Vol. 10, pp. 787-800, 1984). Thus, a heat treatment only for 60 minutes at 43 ° C can be reduced to only about 15 minutes at 45 ° C, which is often called an equivalent dose (t₄₃or_C equivalent minutes).

IS 2 256 267 T3

During non-invasive microwave applicator treatments, it has proven difficult to adequately heat semi-deep tumors, while preventing surrounding healthy surface tissues from suffering pain or damage due to unwanted hot spots. Specific absorption rate (SAR) in tissue is a common parameter used to characterize tissue heating. The SAR is proportional to the temperature increase in a given time interval by the specific heat of the tissue, and for microwave energy the SAR is also proportional to the electric field squared by the electrical conductivity of the tissue. The units of absolute SAR are watts per kilogram.

The first published report describing a non-adaptive phase network for deep tissue hyperthermia was a desk study (von Hippel et al., Massachusetts Institute of Technology, Laboratory for Insulation Research, Technical Report 13, AD-769 843, pp. 16- 19, 1973). US Patent No. 3,895,639 to Rodler describes two-channel and four-channel non-adaptive phase lattice hyperthermia circuits. Similarly, a non-adaptive phase lattice hyperthermia system was described in US Patent No. 4,589,423 to Turner.

Bassen et al., Radio Science, Vol. 12, No. 6 (5), Nov-Dec 1977, pp. 15-25, show that an electric field probe can be used to measure electric field configuration in tissue, and in particular, show several examples where the measured electric field has a focal peak in central tissue. This document also describes a concept for real-time measurements of the electric field in living specimens. However, Bassen and others did not develop the concept of measuring an electric field using real time with an electric probe to adaptively focus a grating in phase.

The most difficult aspect of implementing hyperthermia in deep prostate tissues, with microwave energy, is producing sufficient heating for a predetermined depth while protecting the urethral and rectal walls and surrounding organs from burns. Adaptive microwave phase networks with non-invasive multiple applicators can be used with invasive and non-invasive electric field probes to produce an adaptively focused beam to tumor position with adaptive nulls formed in healthy tissues as described in US Pat. Nos. 5,251,645, 5,441,532, 5,540,737, and 5,810,888 to Fenn. Ideally, a focused beam of microwave radiation is focused on the tumor with minimal energy delivered to surrounding healthy tissue. To monitor microwave power during treatment, a temperature sensing feedback probe is introduced into the tumor (Samaras et al., Proceedings of the 2nd International Symposium, Essen, Germany, June 2-4, 1977, Urban & Schwarzenberg, Baltimore, 1978, pp. 131-133); however, it is often difficult to accurately place the probe in the tumor. Additional difficulty occurs in administering hyperthermia to carcinoma spread throughout the prostate gland, due to a lack of a well-defined desired position of the temperature sensing feedback probe. In other situations, it is desirable not to simply introduce probes (temperature or E-field) into the prostate tissue to reduce the risk of infection or spread of cancer cells as the probe passes through the tumor region.

Several articles have been written on the use of dual intracavitary coherent phase network microwave applicators (transurethral and transrectal) for the treatment of prostate cancer (A. Surowiec et al., Hyperthermic Oncology 1992, Vol. 1, Summary Papers, Proceedings of the 6th International Congress on Hyperthermic Oncology, April 27-May 1, 1992 (Arizona Board of Regents), p. 268 (abstract); MM Yeh et al., Hyperthermic Oncology 1992, Vol. 1, Summary Papers, Proceedings of the 6th International Congress on Hyperthermic Oncology, April 27-May 1, 1992 (Arizona Board of Regents), p. 269 ​​(abstract); and JC Camart, Hyperthermic Oncology 1996, Vol. 2, Proceedings of the 7th International Congress on Hyperthermic Oncology, Rome, Italy, April 9-13, 1996, pp. 598-600). In addition, US Patent No. 5,007,437 to Sterzer describes the use of non-coherent transurethral and transrectal applicators for BPH treatments.

In addition to microwave applicators aimed at irradiating the prostate with microwave energy, WO93 / 08876 describes means for establishing the initial energy power delivered to the applicators, means for monitoring the temperatures of the walls of the adjacent urethra and rectum. to the prostate and means for regulating the relative energy power delivered to the applicators during treatment based on the monitored temperatures of the urethral and rectal walls.

However, the known prior art is directed to the use of transurethral and transrectal applicators to treat solid tumor masses. None of the known procedures refers to treating a microscopic disease and avoiding the appearance of solid tumor masses such as those that occur in cancer and BPH.

Prostate cancer

The current standard of care for treating prostate cancer includes nerve-sparing radical prostatectomy in which the entire prostate gland is surgically removed, and brachytherapy in which low-dose radiation seeds are permanently implanted into the prostate gland that radiate effectively for 6 to 9 months or high dose radiation seeds are temporarily implanted in the prostate for about 2 days, combined with external beam radiation therapy to capture microscopic cancer cells that may have or could penetrate the prostate capsule. Side effects of surgery include incontinence and impotence. The cancer recurrence rate after surgery can be up to about

IS 2 256 267 T3

35% at 5 years, and approximately 60% at 10 years, particularly when the level of prostate specific antigen (explained below) is greater than 10. Radiation therapy has short-term side effects such as skin reactions, fatigue and sickness. Additional long-term side effects of radiation therapy to the prostate include urinary incontinence (loss of bladder control) and impotence, as well as damage to surrounding organs.

Hormone therapy is also used to complement prostate cancer treatments by preventing the growth of cancer cells. Male hormones, such as testosterone, promote the growth of cancer cells and, in contrast, female hormones or estrogens inhibit growth. Side effects of estrogen therapy include nausea and vomiting, flushing, fluid retention, weight gain, headache, and gynecomastia (increased breast tissue) in men.

Fundamentally, the problem with current prostate treatments is the inability to control the microscopic capsular penetration of the prostate gland, which spreads cancer to vital organs. Men with microscopic capsular penetration of cancer cells are not cured by radical prostatectomy. These microscopic cells can spread away from the prostate gland to vital organs through the lymphatic system or by blood vessels through the prostate capsule.

Prostate cancer can be detected using the well-known serum prostate-specific antigen (PSA) test (MK Brawer, "Prostate-Specific Antigen: Current Status," CA A Cancer Journal for Clinicians, Vol. 49, pp. 264-281, 1999, and JE Oesterling, “Prostate Specific Antigen: A Critical Assessment of the Most Useful Tumor Marker for Adenocarcinoma of the Prostate,” The Journal of Urology, Vol. 145, pp. 907-923, May 1991 ). The prostate lumen contains the highest concentration of PSA in the human body. PSA is an enzyme produced in all types of prostate tissue (normal, benign hyperplastic, and malignant). In particular, PSA is a serine protease that is only produced by the epithelial cells that line the acini and ducts of the prostate gland; none of the other cellular components of the prostate, including stromal and vascular elements, produce PSA. Researchers have verified that PSA is produced in epithelial cells of BPH tissue, primary cancer of prostate tissue, and metastatic cancer of prostate tissue. The serum PSA test detects a considerable number of prostate cancers and the destruction of prostate tumors leads to reduced levels of PSA, since the body stops producing PSA when the tumors are removed. Currently, a PSA level of 4.0 ng / ml or higher is used to decide whether a patient should undergo biopsy to attempt to verify the presence of carcinoma in the prostate. Thus, patients with a PSA level below 4.0 ng / ml are not currently biopsied even though they experience the signs and symptoms of prostate cancer which may include: frequent urination, especially at night, inability to urinate, problems on initiating or withholding urination, a weak or interrupted flow of urine, and frequent pain or stiffness in the lower back, hip, or upper thigh.

In addition to the PSA level, the Gleason Classification is used to histologically classify prostate adenocarcinoma (GK Zagars et al., International Journal of Radiation Oncology Biology Physics, Vol. 31, No. 2, pp. 237-245, 1995), Grade 1 being the least malignant and the slowest growing. Gleason Grade 3 is the most common grade when diagnosed. Gleason Grades 4, 5 and above (up to 10) are considered highly aggressive, fast-growing carcinomas.

The results of the biopsy and staging are used to predict the behavior of the cancer and the likelihood of its spread. Stage 1 tumors are small and cannot be felt on rectal exam. Stage 2 or higher refers to prostates in which the tumor can be felt. Stage 3 cancers have spread beyond the limits of the prostate. In Stage 4, which can be determined by imaging studies such as bone scans, CT scans, or MRI scans, the cancer has spread to nearby lymph glands, the bones, to another location in the body. As is known in the medical field, the earlier cancer is found, the greater the chance of surviving it. If detection is not possible before stage 2, the next best medical option would be to safely treat apparently healthy tissue. Thus, healthy tissue must be treated since cancer, in general, cannot be detected until it has reached stage 2 or a later stage.

There are four types of ductal carcinomas of the prostate: transitional cell carcinoma, intraductal adenocarcinoma, mixed ductal carcinoma, and endometrioid carcinoma. Transitional and mixed cell ductal carcinomas are aggressive cancers that require complete removal of the prostate and bladder if discovered while the tumor is still confined to the prostate. Complete removal of the prostate and bladder is also the medically accepted treatment for endometrioid carcinoma. Intraductal adenocarcinomas are treated with radical prostatectomy. Thus, a system is needed to treat and prevent the growth and spread of cancer that does not require surgical prostatectomy.

Benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is primarily described as an enlargement of the prostate gland that exerts pressure on the urethra, leading to obstruction of urine flow, and is a common condition in middle-aged and older men. About 50% of people over 65 will have BPH symptoms that will significantly affect their quality of life. The American Urological Association (AUA) Symptom Index was developed to help categorize the symptoms of BPH. The AUA score has the following ranges:

ES 2 256 267 T3 from 0 to 7 points: BPH symptoms are considered mild; 8 to 19 points: BPH symptoms are considered moderate; and 20 to 35 points: BPH symptoms are considered severe. However, many BPH patients do not seek treatment until their AUA rating is approximately 12.

Several treatments for BPH have been developed in the last two decades, each with advantages and disadvantages. The main types of BPH treatment systems are: 1) Transurethral resection of the prostate (TURP), 2) Transurethral electrovaporization of the prostate (DVT), 3) Medications, 4) Interstitial laser coagulation, 5) RF needle ablation , and 6) Microwave thermotherapy of the prostate. Other treatment techniques, including transurethral incision of the prostate, prostate stents, and balloon dilation, have been explored but are used to a lesser extent.

The success and practicability of BPH treatment can be measured in terms of 1) efficacy, 2) durability, 3) level of pain (during and after the procedure), 4) recovery period, 5) complexity of the procedure, 6) cost of the procedure, and 7) collateral effects. The efficacy of BPH treatments is commonly quantified using the AUA Symptom Index (SI) and peak urine flow rate. The normal urine flow rate is approximately 16 ml / s. Other optional tests such as residual urine volume and pressure flow are sometimes used to judge efficacy. Durability is the length of time that the treatment is effective. The level of pain refers primarily to the need for general anesthesia or local anesthesia. The recovery period is measured in terms of the number of days of hospitalization and rest at home. The complexity of the procedure is a function of the duration of the procedure, the training of the person administering the procedure (a urologist or technician), the type of anesthesia required, and the length of time required for Foley characterization after treatment. The cost of the procedure is strongly influenced by the duration and complexity of the procedure, especially if hospital support is required.

Until about 1990, the main treatment ("Golden Rule") for BPH was transurethral resection of the prostate (TURP) performed by urologists. TURP is expensive, requires a long recovery time, and has several significant side effects, which have suggested a search for better treatment techniques. A summary of the methods of treating BPH, including surgery, medicine and laser, RF, and microwave applications are described below.

Transurethral resection of the prostate (TURP)

The "Golden Rule" of BPH treatments involves a surgical procedure in which a rigid transurethral instrument with an electrosurgical loop is used to remove part of the enlarged prostate tissue (primarily the central area of ​​the prostate) with RF energy. In practice, 90% of surgical procedures for BPH involve TURP, due to its excellent efficacy (85% or more), long-term durability (10-15 years) for 90% of patients. In the United States, around 200,000 TURPs are carried out annually. TURP has several drawbacks: it is a very painful procedure and requires 2-4 days of hospitalization and 2-4 weeks of recovery at home. The TURP procedure takes about an hour and requires general anesthesia. The procedure must be performed by a urologist. A Foley catheter is required for approximately 23 days after treatment. Some of the main possible side effects of TURP include impotence, incontinence, high blood loss, and retrograde ejaculation.

Open prostatectomy

Open prostatectomy is used primarily in patients with very large prostates with excellent results: efficacy is greater than 95% and durability is the same as TURP (10-15 years). With any surgical procedure, the pain level is very high and general anesthesia is required. Approximately 7 to 10 days of hospitalization are required with another 3-5 weeks to stay home. The procedure takes a few hours and must be performed by a urologist. After treatment, a Foley catheter should be used for 2-4 days to drain the bladder. An open prostatectomy costs about twice as much as a TURP, and has serious side effects and potential complications including high blood loss, impotence, and incontinence.

Transurethral electrovaporization of the prostate (DVT)

Basically a modification of TURP, transurethral electrovaporization of the prostate employs a slotted electrosurgical ball electrode to canalize the urethra blocked by prostate tissue. The DVT procedure is safer and has minimal side effects compared to TURP. The efficiency is excellent (85%), but it is still a very painful procedure that requires 2-4 days of hospitalization and 1-2 weeks at home. A urologist performs this 60-minute procedure and the patient is under general anesthesia. A Foley catheter should be used for 2-4 days after this procedure. The cost of the procedure is slightly less than TURP. There is less blood loss than with TURP, but the potential side effects of impotence, incontinence, and retrograde ejaculation remain.

Transurethral Incision of the Prostate (TUIP)

In a relatively new procedure for patients with small prostates, the transurethral incision of the prostate provides an efficacy of approximately 80%. However, tUip is not effective in large prostates.

IS 2 256 267 T3

In this procedure, a minimal amount of prostate tissue is removed: a simple incision is made along the entire length of the prostate. The TUIP procedure allows the bladder neck to be opened, allowing free urinary flow. The durability is expected to be close to TURP, but clinical research is still ongoing. This procedure is moderately painful and requires only a day or two of hospitalization, or for some patients it is a non-hospital procedure. Generally, 4 to 7 days of rest at home are needed after the procedure. A urologist should perform this 60-minute surgical procedure and a Foley catheter should be used for 2 to 4 days. The cost of TUIP is approximately the same as that of TURP. There is less blood loss with this procedure compared to TURP, but the potential side effects of impotence, incontinence, and retrograde ejaculation remain.

Balloon dilation

For patients with small prostates, balloon dilation can be used within the prostatic urethra to somewhat alleviate the symptoms of BPH. The efficiency is only about 60% and the durability is only 1 to 5 years. This procedure is less expensive than TURP and is usually performed without hospitalization with several days of rest at home. The procedure is carried out under local anesthesia by a urologist in approximately 30 minutes. A Foley catheter is required for approximately 2-4 days. There may be some bleeding in this procedure and there are the possible side effects of infection and impotence. The procedure does not work well for large prostates.

Stents

For very sick patients with small prostates, stents can be used with good effectiveness to improve the symptoms of BPH. Durability is not a major problem since these patients are generally very sick with other diseases. This procedure is moderately painful and requires only local anesthesia, is performed in approximately 30 minutes by a urologist, and is performed without hospitalization with approximately 45 days of rest at home. The cost of this procedure is less than that of TURP. Some of the potential side effects are irritation, infection, and debris on the stent.

Medicines

Two categories of drugs are used when treating BPH. One category uses an alpha blocker (Hytrin or Cardura) to relax the muscles around the prostate to allow better urinary flow. The other type of medicine is a reductase inhibitor (Proscar) which actually contracts the prostate gland.

Hytrin, for example, is very effective (74%) and offers some immediate relief from BPH symptoms; however, it takes 2-3 weeks for full effectiveness to be reached. Clinical data indicates that this drug has a shelf life of at least 3 to 5 years and is simply prescribed by a general practitioner. The cost is less than TURP depending on the number of years of treatment. There may be some serious side effects such as fainting, chest pain, irregular heartbeat, and dyspnea.

Proscar works well on large prostates, but is ineffective on small prostates. The full effectiveness of the drug takes approximately 3 to 6 months, and the durability is estimated to be at least 3 to 5 years. This medicine is prescribed by a general practitioner and should be taken for at least 12 months. The cost of the drug is less than TURP. Some of the known side effects are impotence, swollen lips, decreased ejaculation volume, and skin rash.

Interstitial laser coagulation

Here, a surgical laser interstitial coagulation device delivers laser energy radially along the length of a custom designed light diffuser. The diffuser produces an ellipsoidal configuration of thermal damage, applying the laser energy omnidirectional and uniformly, to maximize the volume of tissue treated in the prostate. This is a moderately painful surgical procedure, requiring one to two days in the hospital and then 1 to 2 weeks at home. This 30-minute procedure must be performed by a urologist, with the option of general or local anesthesia depending on the patient's condition. A serious drawback of this procedure is the long time required of 1 to 2 weeks in which a Foley catheter must be used to drain the bladder of urine. The cost of the procedure is less than TURP. This treatment has many potential side effects including impotence, incontinence, blood loss, and retrograde ejaculation.

RF needle ablation (transurethral needle ablation)

This system uses two high-energy RF needles (approximately 0.47 MHz) that are inserted through the urethra into the prostate, to remove the prostate tissue in a few minutes. More than 10,000 patients worldwide have been treated with this system, which provides good to very good efficacy. There is only limited durability data to 12 months for this system, so long-term efficacy is unknown. The procedure is moderately painful (local anesthesia is required) and is performed without hospitalization with 1-2 weeks recovery at home. The procedure is usually performed by a urologist in about 30 minutes. Approximately 40% of patients require a Foley catheter for approximately 2 to 3 days. The cost of the procedure is

ES 2 256 267 T3 lower than TURP. The main side effects of this procedure are irritating urination, erectile dysfunction, and retrograde ejaculation.

In view of the known treatments for BPH, which require expensive, painful surgery, or medications that have potentially dangerous side effects, a system of treating benign prostatic hyperplasia (BPH) that is not painful is needed; can be done without hospitalization; and the patient quickly returns to normal functions. Furthermore, a method is needed that can safely treat the prostate gland with focused energy before a considerable number of microscopic tumor cells form in the prostate.

Summary of the invention

The above problems associated with the known treatments are solved with the system according to the invention. The system according to the invention safely heats precancerous, cancerous, pre-benign and benign states of the prostate by heating the prostate gland with focused or concentrated energy, such as microwave energy, delivered by non-coherent or coherent phase network applicators in the urethra and the rectum, or with interstitial applicators placed inside the prostate. In a non-coherent network, separate microwave oscillators can move the applicators and there is no common phase relationship. In a coherent phase network (in-phase network), a single microwave oscillator can move multiple applicators with a common phase relationship.

Applicant's method is to treat the prostate gland with focused energy, such as microwave energy, before a considerable number of microscopic tumor cells are formed in the prostate gland. As described above, all past uses of heat therapy were used for the treatment of established prostate cancers with moderate to high PSA levels (greater than 4.0 ng / ml) or for the treatment of moderate to high titers. severe AUA symptom index for BPH. The preferred embodiment of this invention is for prevention or early detection, or before medical intervention is required.

The preferred system includes coherent adaptive phase network and means for monitoring urethral and rectal wall temperatures, two microwave applicators in at least the urethra or rectum, means for regulating the microwave power to be delivered to the prostate based on at monitored urethral and rectal wall temperatures, means for monitoring the dose of microwave energy delivered to the prostate being treated, and means for automatically completing the treatment when the microwave applicators have delivered a desired total dose of microwave energy.

Incoherent or non-adaptive phase lattice hyperthermia treatment systems can be used to heat semi-deep and deep tissue, depending on the frequency of radiation. Due to the dielectric heating of high water content tissue such as prostate tumor, it is possible to safely heat prostate tumors with non-coherent networks or networks in non-adaptive phase.

Furthermore, the system according to the invention has application in situations where there is no well-defined position where to place the temperature feedback sensor, or where it is desirable to avoid the introduction of a temperature probe into the prostate tissue. In the case of a single applicator, an E field probe (or E field sensors) is not needed and thus an invasive probe is not required in the preferred system according to the invention. The system of the invention can destroy all precancerous or cancerous prostate cells or benign lesions with heat generated by the focused energy thereby preventing further progression of the cancer cells or benign lesions.

Furthermore, the system according to the invention can be used to enhance radiation therapy or for targeted drug delivery and / or targeted delivery of gene therapy with or without heat-sensitive liposomes as described in US Patent No. 5,810,888 to Fenn .

The system according to the invention can be used to destroy precancerous, cancerous, prebenign and benign cells in the prostate while preserving normal prostate tissue. Thus, the system according to the invention achieves a thermal prostatectomy and prevents damage to healthy tissue.

The temperature of the urethral and rectal walls can be measured by temperature probe sensors positioned away from the transurethral and transrectal applicators to obtain the true temperature of the urethral and rectal walls. Alternatively, tissue temperatures can be monitored by external means, including infrared, laser, ultrasound, electrical impedance tomography, magnetic resonance imaging, and radiometric techniques as is known in the art.

Alternatively, a temperature probe could be inserted at an appropriate depth into the prostate tissue to monitor its temperature. As explained below, the introduction of a temperature probe is not a preferred embodiment.

In an embodiment with two or more energy applicators, an invasive E-field probe, inserted into the prostate, may or may not be used to measure the microwave power delivered to the tissue to be treated to determine the duration of the focused energy treatment. In a preferred embodiment, the invasive E-field probe can be used to focus applied energy onto the E-field probe introduced into the prostate.

IS 2 256 267 T3

As an alternative embodiment, for a phase coherent network, two E-field sensors can be placed in the prostatic urethra and rectum non-interstitially and used to bypass the E-field in the urethra and rectum and effectively focus radiation from microwave in prostate tissue. In addition, the microwave phase for the transurethral and transrectal applicators can be adjusted so that microwave energy is scanned through an area of ​​the prostate.

The system according to the invention can be achieved with or without compression of the prostate. A patient's prostate could be compressed by expanding at least one urethral balloon or rectal balloon. The focused energy and compression of the prostate provides preferential heating of high water content prostate carcinoma and benign cells in the prostate compared to the surrounding normal prostate tissues of lower water content and the tissue surrounding the prostate.

To consistently focus energy, such as microwave energy, into the prostate, the patient's prostate can be compressed by a urethral and rectal balloon and means are used to determine where to focus the energy on the patient's prostate. The means for determining where to focus the energy can be a single electric field probe, inserted in the central portion of the prostate, or two non-interstitial electric field sensors in the urethral and rectal walls. The probe or sensors receive signals that can be used to measure a feedback signal to adjust the phase of energy delivered to the applicators located in the urethra and rectum.

The main advantages offered by the treatment according to the system of the invention over the known treatments are listed below:

1. Prevention and destruction of prostate tumors (including cancerous and benign);

2. Immediate relief of any BPH symptoms that may exist;

3. Long-term durability;

Four. Only a low level of pain may be experienced;

5. Procedure without hospitalization;

6. Local anesthesia;

7. Foley catheter is not required; Y

8. There are no significant side effects or complications.

A biological stent can form in the prostatic urethra due to the combination of the compression dilation balloon and microwave heat (microwave urethroplasty) as evidenced by clinical tests performed by the assignee, Celsion Corporation, during 1999. As a result, one of the major shortcomings of known BPH treatments, namely the need for a Foley catheter for several days, is no longer needed, and a patient can experience immediate relief from BPH symptoms.

As described below, the system of Applicant's invention involves means for monitoring the dose of energy delivered to the prostate being treated and means for completing the treatment based on the total dose of energy that has been received. Preferably, microwave energy is chosen as the type of prostate energy being treated. That is, conventional temperature feedback measurements of the thermal dose of the tumor can be substituted for the total microwave energy delivered to the phase coherent or non-coherent network microwave applicators and then to the treated area. Accordingly, with the present invention, instead of temperature feedback measurements, which require the introduction of a temperature feedback probe into the prostate and its inherent problems, the microwave energy dose is used as a feedback to determine the required duration of treatment. In this application the term “microwave energy dose” (in Joules or watt-seconds) is similar to the dose used in radiation therapy, namely the absorbed radiation dose (Rad) which is a unit of the absorbed dose radiation defined as deposition of 100 ergs of energy per gram of tissue.

Thus, the present system for selectively heating cancerous and benign conditions of the prostate avoids the risk of diffusion of cancer cells since the temperature probe is not introduced into the treated area (tumor bed) of the prostate. Elimination of an inserted temperature probe reduces the risk of infection in a patient as a result of the insertion of the probe. Likewise, the microwave field applied to a tumor would not be subjected to scattering or other disturbance produced by a temperature probe, especially a metal probe. Plus, you save the time and costs associated with introducing the temperature probe.

The system of the invention can also be used to treat healthy prostate tissue or high water microscopic pre-cancer or prebenign cells not detected in apparently healthy prostate tissue to prevent the occurrence or recurrence of prostate cancer conditions. Thus, the system according to the invention would be capable of destroying or excising microscopic precancerous or prebenign cells in the major prostate gland.

ES 2 256 267 T3 water content (eg 90%) than the prostate gland (eg 80%) prior to detection. This would be an early treatment that could prevent the cancer from growing in the prostate and spreading from the prostate, or the enlargement of the prostate gland. In the case of apparently healthy tissue, the prostate tissue would be irradiated with focused microwave energy to microscopic high water content cells which are known to form lesions without damaging healthy lower water content prostate tissue.

If transurethral and transrectal applicators are used and expanded by respective balloons, a preferred system is achieved having means for compressing and immobilizing the prostate to reduce the depth of penetration into the tissue and to reduce blood flow to the prostate.

In an alternative system, the prostate is compressed with a single transurethral balloon, which immobilizes prostate tissue, reduces blood flow, and reduces the depth of penetration required for microwave radiation. The compression balloon is made of a microwave transparent plastic material such as latex. Placement of an E-field feedback probe in the prostate can be accomplished with an ultrasound transducer or other image guidance. Another reduction in blood flow can be achieved, in a preferred method, by injecting a local anesthetic lidocaine with epinephrine or antiangiogenesis drug into the prostate.

Two microwave applicators (as described in US Patent No. 5,007,437 to Sterzer) can be placed transurethrally and transrectally. A phased network can be achieved with a multiple number of applicators greater than or equal to two. In a preferred embodiment, coherent 915 MHz microwave power is supplied to the two transurethral and transrectal applicators, at a predetermined power level, while the phase shifters on each channel are regulated to maximize and focus microwave energy to the probe sensor. field E. Cooling with water within catheters and balloons allows the urethral and rectal walls to be cooled. Additional interstitial applicators can be inserted into the prostate to supplement the heating produced by the transurethral and transrectal applicators.

During hyperthermia treatment, the microwave power level delivered to each of the applicators can be adjusted manually or automatically to avoid high temperatures that could cause burns or blisters on the urethral or rectal walls. Additionally, the amount of prostate compression, if used, is regulated as needed during treatment to provide patient comfort. Each time the compression of the prostate is regulated, the microwave / in-phase energy network is refocused so that the E-field probe sensor receives maximum power. The total microwave energy, from the beginning of the treatment, delivered to the microwave applicators is verified during the treatment. Treatment is terminated when a desired amount of total microwave energy is delivered to the microwave applicators, indicating that the lesion cells are significantly destroyed (i.e., thermal reduction in size) or completely destroyed (i.e., prostatectomy thermal).

To determine the effectiveness of the treatment, the prostate tissue can be represented and examined with X-rays, ultrasound, and magnetic resonance imaging before and after the administration of the full dose of microwave energy, as well as with pathological results of needle biopsy. of the prostate tissues.

In an alternative embodiment of the invention, the single invasive E-field probe is replaced by two E-field sensors placed in the urethra and rectum and the coherent array is phase focused minimizing (nullifying) the individual or combined power received by the two sensors, providing a completely non-invasive treatment. In a preferred embodiment, the two E-field sensors are contained with catheters attached to the outer surface of a compression balloon that provides pressure contact to the urethral and rectal walls. Algorithms are used in conjunction with the feedback signals detected by the E-field sensors to bypass areas on the urethral and rectal walls thereby focusing the applied energy on an internal site. After completion of the nullification algorithm, the E-field sensors can be removed and the temperature sensors inserted to measure the temperatures of the urethral and rectal walls.

Such totally non-interstitial hyperthermia treatment where E-field sensors and temperature sensors monitor the urethral and rectal walls, would provide an effective method of destroying benign and cancerous lesions in the prostate. In an embodiment with non-coherent applicators, an E-field focusing probe and phase shifters are not required to heat the tissue. With non-coherent energy, only the power radiated by the applicator is additive and no phase shift is used.

Although the preferred embodiment is described with reference to adaptive microwave phase lattice technology, Applicant's system can be achieved by focusing energy, in general, to heat and ablate an area of ​​tissue. The focused energy can include electromagnetic waves, ultrasound waves, or radio frequency waves. That is, the system of Applicant's invention includes energy that can be focused to heat and excise an area of ​​tissue. This energy, such as microwave or ultrasound energy, can be coherent or non-coherent.

In another embodiment of the invention with a coherent phase lattice, the boundary of an area of ​​tissue to be treated in a body (for example, prostate) is calculated, an E-field probe can be inserted into the body, or at least two E-field sensors within the urethra and rectum; and applies energy using applicators to the area to be treated. In this embodiment, the focus of the energy would shift so that the focus scans the area to be treated. That is, there is no longer a fixed focus point since the relative phase of the applied energy would be adjusted so that the focus moves within the area to be treated thereby obtaining a heating geometric shape.

IS 2 256 267 T3

A fixed focus point is determined by the appropriate algorithm. Then, for example, the relative phase of the applicators to obtain this fixed focus point is adjusted 30 ° to one side and then 30 ° to the other to "scan" a larger heated / treated area. Depending on the size of the area to be treated, the scan can be focused between 180 ° and 90 ° or 60 ° or 120 °.

Other objects and advantages will be apparent from a consideration of the description and the drawings.

Brief description of the drawings

The invention is better understood by reading the following detailed description with reference to the accompanying figures, in which like reference numerals refer to like elements throughout, and in which:

Figure 1 shows the microwave thermotherapy system according to a preferred embodiment of the invention for heating the prostate under compression from coherent transurethral and transrectal applicators.

And figure 2 shows the microwave thermotherapy system according to a preferred embodiment of the invention for heating the prostate under compression of non-coherent transurethral and transrectal applicators.

Detailed description of the preferred embodiment

Description of the prostate gland and its microwave properties

The prostate gland 220 is part of the male reproductive system and is a solid walnut-shaped organ that surrounds the first part of the urethra 205 immediately below the bladder 202 and in front of the rectum 210. Prostate cancer arises from the glands of the prostate and the most common form of prostate cancer is called adenocarcinoma, which means cancer of the glands. Most prostate cancers develop within the lower portion of the prostate (sometimes called the peripheral zone involving about 70% of the glandular prostate) closest to the rectum, and this is the region that needs a significant amount treatment. Although a digital rectal exam is useful to detect hardened areas or lumps in the prostate gland; however, it is not very useful in detecting microscopic prostate disease. The use of a transrectal applicator (in addition to a transurethral applicator) to reach this portion of the prostate is essential for a complete treatment of the prostate. The central area of ​​the prostate (closest to the bladder) is relatively immune to BPH and prostate cancer diseases. HPB arises mainly in the transition zone located between the central zone and the peripheral zone.

As explained above, the current medical procedure does not biopsy a tumor until a PSA of 4.0 ng / ml is reached. The data in Table 1 indicate that there is only about a 15% chance of detecting cancer by needle biopsy when the pSa is less than 4 ng / ml. Although the probability of detecting cancer is very low, the actual probability of microscopic cancer cells in the prostate is significant (25% or more) (FH Schroder et al., The Journal of Urology, Vol. 163, No. 3, p. 806 (abstract), March 2000) (Eschenbach et al., CA Cancer J. Clinicians, Vol. 47, pp. 261-264, 1997). Thus, thermotherapy treatment of the prostate is probably ensured, even if the PSA level is in the range of 0 to 4 ng / ml. Thermotherapy treatment of the prostate for PSA levels below 4 ng / ml is intended to kill microscopic prostate cancer cells and prevent PSA from rising above 4 ng / ml.

TABLE 1

Probability of detecting cancer in initial biopsy for different levels of PSA

<td>PSA level</td><td>Probability of detecting cancer in initial biopsy</td>

<td>2 ng / ml</td><td> 1%</td>

<td>2-4 ng / ml</td><td> 15%</td>

<td>4-10 ng / ml</td><td> 25%</td>

<td>&gt; 10 ng / ml</td><td> &gt; 50%</td>

Microwave radiation in the industrial, scientific, medical (ISM) band 902 to 928 MHz is commonly used in commercial clinical hyperthermia systems, and is the primary frequency band considered here. The prostate is known to be high water content tissue and therefore similar to muscle tissue that is well characterized. For normal prostate tissue at 915 MHz, the mean dielectric constant is 50 and the mean conductivity is 1.3 S / m. The calculated loss due to attenuation of a plane wave at 915 MHz propagating through prostate tissue is approximately 3 dB per cm. Prostatic intraepithelial neoplasia, also called atypical hyperplasia and intraductal dysplasia, are pre-cancers and are associated with the development of adenocarcinoma of the prostate. Neoplastic cells are assumed to be of higher water content than surrounding normal prostate cells and are

ES 2 256 267 T3 heat faster than normal healthy prostate cells. Normal ductal tissue in the prostate is assumed to be in the range of low to medium water content.

The safety of using radio frequency electromagnetic fields (microwaves) to treat cancer has been questioned. A general study recently concluded that there is no association between the incidence or promotion of cancer and exposure to radio frequency electromagnetic fields in the frequency range 3 KHz to 300 GHz (LN Heynick, Radiofrequency Electromagnetic Fields (RFEMF) and Cancer: A Comprehensive Review of the Literature Pertinent to Air Force Operations, AFRL-HE-BR-TR-1999-0145, United States Air Force Research Laboratory, Directed Energy Bioeffects Division, June 1999) . Thus, based on this report, Applicants observed that there is significant evidence that microwave prostate treatment can safely heat an apparently healthy prostate gland containing microscopic cancer cells in such a way that no new cancer would form as a result. microwave treatment.

System for heating prostate tissues

Figure 1 shows a preferred system for heating carcinomas and benign tumor cells in prostate tissues, using an adaptive energy phase lattice hyperthermia system, preferably microwave, with E field and temperature feedback. To reliably heat deep tissues to energy frequencies, the body (lobes of the prostate 220) must be surrounded by two or more energy applicators 110,111 (within the urethra 205 and rectum 210, respectively) controlled by a network algorithm in adaptive phase. The energy applicators 110, 111 may be coherent microwave applicators. The black circle, indicated as focus 190, represents a central tumor or healthy tissue of the prostate 226 to be treated.

Focus 190 may represent cancerous conditions of the prostate including one of adenocarcinoma, carcinosarcoma, rhabdomyosarcoma, chondrosarcoma, and osteosarcoma, or precancerous conditions including prostatic intraepithelial neoplasia, and benign lesions of the prostate including benign prostatic hyperplasia. Furthermore, the system according to the invention can apparently treat healthy tissue to prevent the appearance or reappearance of cancerous or benign conditions.

In the preferred embodiment, an E field feedback probe 175 can be inserted at an appropriate depth into the prostate tissue 220 to be treated. The introduction of the E 175 field feedback probe can be accomplished under the guidance of an ultrasound transducer. The means for establishing the initial phase of energy supplied to each applicator 110, 111 includes field feedback signals E 450 from the field probe E 175 and a computer 250 with an appropriate algorithm to focus the energy radiation to the field probe. E entered 175. Preferably, the E 175 field probe is used with an adaptive phase lattice fast acceleration gradient search algorithm, as described in U.S. Patent No. 5,810,888 to Fenn, to direct energy radiation to the site. of the tumor 190.

Furthermore, the system according to the invention includes means for setting the initial energy or microwave power supplied to each energy applicator, and means for monitoring the temperatures of the walls of the urethra and rectum adjacent to the prostate to be treated in order to ensure that the walls do not overheat. The means for monitoring the urethral and rectal walls may include temperature feedback sensors 410 that are inserted non-interstitially against the urethral and rectal walls (215, 216) to monitor the temperatures of the walls of the urethra and rectum adjacent to the prostate tissue. Temperature feedback sensors 410 send feedback temperature signals 400 to computer 250 where signals 400 are used to regulate the relative level of microwave power to be delivered to applicators 110, 111 to heat the tumor or tissue in focus. 190.

Preferably, the design of the transurethral and transrectal energy applicators, which are preferably microwave applicators, is according to US Patent No. 5,007,437 to Sterzer. The transrectal applicator, in particular, may use a reflector or a phased array to direct microwave energy preferentially toward the prostate. The applicators can be non-invasive applicators such as waveguides, monopole or dipole antennas, or interstitial applicators such as monopole or dipole antennas. In a preferred embodiment, the applicators can be coherently moved as an in-phase network. In addition, multiple applicators can be used surrounding the prostate that can move non-coherently in a multi-frequency network to selectively heat the prostate tissue.

Preferably, the body or prostate 220 is compressed between two compression balloons 112, 113, which surround the transurethral and transrectal applicators 110, 111, respectively. Compression balloons 112, 113 can be inflated with distilled or deionized water. Alternatively, compression balloons 112, 113 can be inflated pneumatically or by other known means for inflating balloons. The compression balloons 112, 113 are made of a material such as latex that is microwave transparent. In addition to immobilizing the prostate tissue and fixing the positions of the applicators, compression of the prostate has several potential advantages for hyperthermia treatments. The use of compression of the prostate results in less depth of penetration needed to achieve deep microwave heating and reduce blood flow, which also improves the ability to heat the tissue.

Compression of the prostate from the inside and outside of the prostate further moves the surface of the prostate gland away from the radiators of microwave applicators, helping to reduce surface hot spots. In

In a preferred embodiment, the applicator would have a fluid-filled cavity that would improve the coupling of the microwave energy of the applicator to the tissue to be treated. Cooling the fluid, such as distilled or deionized water, within the transurethral and transrectal applicators or applicator balloons during hyperthermia treatments helps prevent the possibility of developing hot spots in the urethra 205 and rectum 210, thereby protecting the urethral and rectal walls against overheating.

Prior to adaptive phase lattice hyperthermia treatment, the prostate is compressed between compression balloons 112, 113 and a single invasive field feedback probe E 175 is inserted into the central tissue site (focus 190) in the prostate, parallel to the polarization of the microwave applicators 110, 111. The microwave applicators 110, 111 are monopole or dipole antenna radiators of straight or helical shape. The E field probe 175 is used to check the width of the E focal field when the phase shifters are adjusted for maximum feedback signal using an adaptive phase grating gradient search algorithm. Non-invasive temperature sensors 410 monitor the urethral and rectal wall temperatures at positions 184, 185, respectively, and these signals are individually transmitted to the computer as feedback temperature signals 400.

The tips of the temperature sensors 410 can be attached to the exterior of the transurethral and transrectal compression balloons 112, 113 provided the tips are thermally insulated. By mounting a thin pad (not shown) between the temperature probe and the outer surface of the balloon, thermal insulation from the effects of the cooling fluid contained with the compression balloons can be achieved. The dual applicator adaptive phase array of the invention in conjunction with the E-field feedback probe allows the phase shifters to be regulated so that a concentrated E-field can be generated allowing targeted heating of tissue at the appropriate depth.

Preferably, the temperature sensors 410 are not interstitially inserted through the holes in the urethra 205 and rectum 210 so that the sensors 410 are in pressure contact with the respective urethral and rectal wall. Thus, as depicted in FIG. 1, two temperature feedback probe sensors 410 are located in urethra 205 and rectum 210, respectively, and produce temperature feedback signals 400. Two water-cooled microwave catheters 300, 301 with microwave applicators 110, 111, respectively, are placed in urethra 205 and rectum 210. The transurethral catheter 300 contains a Foley balloon 118 that is inflated with air in the bladder 202 to fix the microwave applicator 110 in the correct position relative to the desired area of ​​the prostate.

For coherent treatments, an oscillator 105 splits at node 107 and feeds phase shifters 120. Oscillator 105 in a preferred method is a microwave power source at approximately 915 MHz. Phase control signal 125 controls the phase of the signal microwave in the range of 0 to 360 electrical degrees. The microwave signal from each phase shifter 120 is fed to microwave power amplifiers 130. The resulting microwave signal is controlled by a computer generated control signal 135, which sets the initial level of microwave power delivered to each microwave applicator. Microwave signals 150 in the form of coherent microwave power at 915 MHz are supplied by microwave power amplifier 130 to the two applicators 110, 111, while phase shifters 120 on each channel are regulated to maximize and focus microwave energy. to field probe sensor E 175 so that microwave power is maximized at focus position 190. Treatment then begins.

In another embodiment, the means for monitoring the temperature of the prostate is a temperature probe that is inserted at an appropriate depth into the prostate tissue. In this case, after focusing the means for establishing the initial relative energy phase supplied to each applicator to the field probe E 175, the field probe E can be removed and the temperature probe 176 can be inserted into its place at an appropriate depth in the prostate tissue.

In another embodiment contemplated by the invention, second temperature monitoring means are provided, in addition to non-interstitial temperature sensors in pressure contact with the walls of the urethra and rectum. The second temperature monitoring means is the invasive temperature probe 176 which is inserted into the prostate tissue at the same point from which the field probe E 175 was removed.

The system according to the invention allows the destruction of all prostate carcinomas, precancerous cells, and benign lesions treated when the total dose of microwave energy desired has been delivered to the microwave applicators while avoiding the damage produced in the normal tissue. of the prostate.

For non-coherent treatments, as depicted in Figure 2, separate oscillators 105, preferably operating at 915 MHz, power the two microwave power amplifiers 130 which are computer controlled and supply microwave power to the two applicators 110, 111 .

During the hyperthermia treatment, the microwave signals 150 and the power level supplied to each of the applicators is measured as a power feedback signal 500, which is sent to a microprocessor or computer 250 such as a PC. The power control signal from the power amplifiers 130 is regulated manually or automatically to control the temperatures of the urethra and rectum, as well as the equivalent thermal dose delivered to the prostate tissue. The 410 sensors measure the temperatures of the urethral and rectal walls and the signal of

ES 2 256 267 T3 power control 135 is regulated based on the detected temperature to avoid high temperatures that could cause burns or blisters. The amount of compression performed by compression balloons 112, 113 is adjusted as necessary during treatment to provide patient comfort. Each time the compression of the prostate is regulated, for consistent treatments, the phase shifters 120 are readjusted / refocused so that the E field probe 175 receives maximum power.

According to the system according to the invention, means for monitoring the microwave energy supplied to the microwave applicators 110, 111 monitor the energy / power administered during the treatment and when the microwave applicators 110, 111 have supplied the prostate with microwave energy desired total, the means of terminating the treatment interrupts the radiation of energy to the applicators. That is, the system according to the invention automatically cuts off the energy delivered to the prostate, thereby terminating the hyperthermia treatment when a total dose of desired microwave energy has been delivered to the prostate 220. In a preferred embodiment, the total dose of microwave energy produces a total equivalent thermal dose in prostate tumors, which is approximately between 60 minutes and 400 minutes relative to 43 degrees Celsius. The total microwave energy, since the beginning of the treatment, supplied to the microwave applicators is calculated in the computer 250 and can be displayed on the computer monitor 260 during the treatment.

As an alternative embodiment, means are provided to monitor the level of microwave power supplied to the E field probe 175 to determine when the treatment should be terminated. According to this embodiment, the total microwave energy calculated from the field feedback signal E 450 received by the field probe E 175 is used to control the duration of treatment. This E 450 field feedback signal can be useful for coherent and non-coherent treatments. To determine the effectiveness of the treatment, the prostate tissue is represented with X-rays and magnetic resonance imaging before and after the full dose of microwave energy is administered, as well as the pathological results of the needle biopsy of the prostate tissues.

For consistent treatments, the single invasive E-field probe 175 can be replaced with two non-invasive E-field sensors at fixed positions 186, 187 within the urethra and rectum, respectively. The E-field sensors are inserted into the natural foramina of the urethra 205 and rectum 210 and set in a position that is suitable for heating the tumor or healthy tissue. E-field sensors can be attached to the urethral and rectal walls at positions 186, 187, but they do not have to be in contact with the urethral and rectal walls. An ultrasound, X-ray or other known E field monitoring device can verify the proper positions of the E field sensors. The total power measured by the two non-invasive E-field sensors is minimized (as in U.S. Patent No. 5,810,888) by regulating the 120 microwave phase shifters, to create an E-field focused on the central portion of the prostate, or the prostate area to be treated.

With this embodiment, there is no risk of infection from an inserted probe, no risk of skin scarring from a procedure that requires cutting the skin and inserting a probe, and there is no risk of spreading cancer cells when a probe is not used. field E entered. E-field sensors are simply attached within the urethra and rectum and thus do not penetrate the tumor bed, thereby reducing the possibility of inadvertently seeding viable cancer cells during a surgical procedure, thus reducing local recurrences of cancer in surrounding tissues. . Likewise, since the temperature and field sensors E can be placed in the urethra 205 and rectum 210 according to this method, the present invention would work well when no single zone has been defined in the prostate such as in treating disease. microscopic view of the prostate.

Preferably, each channel (on node 107 side) of the in-phase network contains an electronically variable microwave power amplifier 130 (0 to 100 W), an electronically variable phase shifter 120 (0 to 360 degrees), and water-cooled microwaves 110, 111.

Although the preferred embodiment describes microwave energy at about 915 MHz, the frequency of the microwave energy can be between 100 MHz and 10 GHz. The frequency of the microwave energy could be selected from the range of 902 MHz and 928 MHz. In fact, lower energy frequencies can be used to remove or avoid cancerous tissue.

In a preferred embodiment, the initial microwave power supplied to each applicator is between 0 and 70 watts, preferably between 20 and 60 watts. During the entire tissue treatment, the microwave power delivered to each applicator can be adjusted in the range of 0-150 watts to deliver the desired dose of microwave energy and avoid overheating of the urethra and rectum. In addition, the relative microwave power delivered to the two microwave applicators is regulated between -180 degrees and 180 degrees before and during treatment to create a focused field in the prostate tissue. Typically, more microwave power is required for non-coherent applicator treatments than for coherent applicator treatments.

In a preferred embodiment, a 0.9 mm outer diameter (OD) E-field invasive coaxial monopole probe (rG-034 semi-rigid), with the center conductor extended 1 cm, can be used as the E 175 field probe to measure the amplitude of the electric field directed to the tissue and to provide the feedback signal 450 used to determine the relative phase needed for the electronic phase shifters prior to treatment. Coaxial feed monopole probes of this type have been used to make accurate measurements of linearly polarized electric fields in compressed breast phantoms (Fenn et al., International Symposium on Electromagnetic Compatibility, May 17-19, 1994, pp. 566-569) . This linearly polarized E-field probe is inserted into a Teflon catheter

ES 2 256 267 T3 of 1.6 mm OD. Thermocouple probes (Physitemp Instruments, Inc., Type T copper-constantan, enclosed within a 0.6 mm OD Teflon shell) can be used to measure the local temperature in the tumor during treatment. These temperature probes have a response time of 100 ms with an accuracy of 0.1 ° C. Fiber optic temperature probes can also be used.

The E 175 field probe is used with the adaptive phase lattice fast acceleration gradient search algorithm, as described in U.S. Patent No. 5,810,888 to Fenn, to direct microwave radiation to the tumor site . The temperature detected by the invasive temperature probe 175 in the tumor could be used as a real-time feedback signal during treatment. This feedback signal 450 could be used to control the microwave output power level of variable power amplifiers, which establish and maintain the focal temperature at the tumor site in the range of 43 to 46 ° C. The power and phase supplied to the two channels of the in-phase network are adaptively regulated using digital to analog converters under computer control.

The total dose of microwave energy can be used to estimate the required heating time. That is, Applicants observed that a non-interstitial equivalent temperature sensing means could replace interstitial temperature probes, and that the total dose of microwave energy could be reliably used to control the duration of treatment. Compressing the prostate, as mentioned above, reduces blood flow, which likely eliminates the effects of blood flow on the microwave energy required for treatment, and can reduce the microwave energy variation that can be expected in treatments. by microwave.

According to a preferred embodiment, the total microwave energy supplied to the waveguide applicators to determine the completion of the treatment is between 25 kilojoules and 250 kilojoules. The total dose amount of microwave energy that would destroy all cancerous or precancerous tissue would be approximately 175 kilojoules. But, under certain conditions, the required dose of microwave energy can be as low as 25 kilojoules.

As recognized by the applicants, compression of a body that results in less thickness may require a lower dose of microwave energy (compared to compression that results in greater thickness) for effective treatments by preventing or destroying cancerous lesions, precancerous or benign. It is important to select an appropriate starting level of microwave power (P₁, P₂) supplied to each applicator as well as the appropriate microwave phase between the two applicators to focus the energy to the area to be treated.

During hyperthermia treatment, urethral and rectal wall temperatures should be monitored so that they do not rise significantly above approximately 41 degrees Celsius for more than several minutes. The equivalent thermal dose for the urethral and rectal wall sensors can be calculated (Sapareto et al., International Journal of Radiation Oncology Biology Physics, Vol. 10, pp. 787-800, 1984) and can be used as a feedback signal. Typically, it is necessary to avoid administering more than an equivalent thermal dose of a few minutes. The prevention of high urethral and rectal temperatures according to the invention is carried out by regulating the individual potencies (P₁, P₂) supplied to applicators during treatment by manual or automatic computer control.

Doppler ultrasound can be used to measure blood flow in tumors and surrounding prostate tissue, before and during treatment to plan and adjust the dose of microwave energy. For example, less energy doses are required when the tumor's blood flow rate is reduced, which can occur when the prostate is compressed and / or the tumor is heated to therapeutic temperatures. Alternatively, the water content and dielectric parameters of prostate tumor tissue from needle biopsies could be measured and used to determine, prior to treatment, the required dose of microwave energy. For example, higher water content and higher electrical conductivity in the tumor would reduce the amount of microwave energy dose required. In addition to the above variables, the size of the tumor impacts the dose of microwave energy required. Larger tumors are more difficult to heat than smaller tumors and require a larger dose of microwave energy. An initial treatment planning session involving a low dose of microwave energy administration can be performed to assess the heartability of the tumor, followed by a full treatment at the required full microwave energy dose.

Simplified theory of microwave radiation

Microwave energy from hyperthermia applicators, in the near field of a body, is radiated as a spherical wave with the electric field amplitude varying, in part, as the inverse of the radial distance r from the applicator. Furthermore, the amplitude decays as an exponential function of the product of the attenuation constant α of the body tissue and the distance d traveled (or depth) within the body as indicated in Figure 1. The electric field phase varies linearly with the distance as the product of the phase propagation constant β and the distance d. For the sake of simplicity, dual opposing applicators are discussed here on the assumption that the radiation from the applicator is approached by a plane wave. Mathematically, the plane wave electric field versus depth in the tissue is given by E (d) = E₀ exp (-ad) expt-i / 'd), where E₀ is the surface electric field (generally represented by an amplitude and phase angle), and i is the imaginary number (Field and Hand, An Introduction to the Practical Aspects of Clinical Hyperthermia, Taylor &amp; Francis, New York p. 263, 1990) .

IS 2 256 267 T3

Plane wave electromagnetic energy, at the microwave frequency of 915 MHz, is attenuated at a rate of approximately 3 dB per cm in tissue with high water content, such as prostate tissue. Thus, a single irradiating applicator has a significant fraction of its microwave energy absorbed by intervening superficial body tissue compared to the energy radiating from deep tissue, probably creating a hot spot in superficial tissue. Since surface cooling with air or water protects the tissue only to a maximum depth of approximately 0.25 to 0.5 cm, to avoid hot spots, a second phase-coherent applicator has to be inserted, which has the same radiation amplitude. microwave than the first applicator. The second phase coherent applicator can theoretically increase the power (and therefore energy) delivered to deep tissue by a factor of four compared to a single applicator (Field and Hand, p. 290, 1990).

The phase characteristics of electromagnetic radiation from two or more applicators (called an in-phase network) can have a pronounced effect on the delivery of power delivered to different tissues. The relative specific absorption rate (SAR) in homogeneous tissue is approximated by the square of the electric field amplitude IEI². SAR is proportional to the increase in temperature in a given time interval. A simplified case, homogeneous prostate tissue, in which microwave radiation is focused to a central location in the tissue, is described in detail below. As described in an article by Fenn et al., International Symposium on Electromagnetic Compatibility, Sendai, Japan, Vol. 10, No. 2, May 17-19, 1994, pp. 566-569, the effects of multiple reflections of microwave signals within the transparency can be ignored.

The wavelength in homogeneous normal prostate tissue (with an approximate dielectric constant 50 and electrical conductivity 1.3 S / m) is approximately 4.5 cm at 915 MHz, and the microwave loss is 3 dB / cm. The attenuation constant α is 0.34 radians / cm and the propagation constant β is 1.4 radians / cm (or 80 degrees / cm). (For a compressed prostate thickness of 2.25 cm, the electric field of a single applicator radiating on the left side is E₀ on the surface of the prostate, -i0.7E₀ (where i represents a 90 degree phase shift) at the center position (1.125 cm deep), and -0.5E₀ on the right surface. The combination of two phase coherent applicators gives an electric field value of 0.5E0 on both surfaces and -i1.4E0 at the central position (1.125 cm deep). Thus, for the compressed prostate, squaring the above coherent E fields to calculate SAR, there is a considerably lower SAR at the surface, approximately by a factor of 2.0 compared to the central sAr. The 180 degree phase shift experienced by the microwave field transmitted through 2.25 cm of prostate tissue, in part cancels or nullifies the field entering the 0 degree phase shift tissue. Due to destructive microwave interference away from the central focus, lower temperatures would be expected in the surface tissues of the prostate tissues. Lower SAR measurement and performance on opposing surfaces effectively focus microwave energy deep into the prostate. In cases where it is desirable to irradiate the prostatic tissues of the superficial or peripheral zone more strongly, the compression thickness can be greater than 2.25 cm so that the phase delay of the propagation wave is longer and the two waves are not canceled at the surface, or only one of the transurethral or transrectal applicators (especially the transrectal applicator) can be used to warm the prostate.

Repeat the above calculation, but now for non-coherent applicators, for a compressed prostate thickness of 2.25 cm, the electric field of a single applicator radiating on the left side is E0 at the surface of the prostate, -i0.7E₀ (where i represents a 90 degree phase shift) at the center position (1.125 cm deep), and -0.5E0 at the right surface. Combining two applicators non-coherently, squaring the individual E fields and adding them, gives a SAR value of 1.5E₀² on both surfaces and 0.98 E₀² in the center position (1.125 cm deep). Thus, for the compressed prostate, squaring the above non-coherent E fields to calculate SAR, there is a considerably higher SAR at the surface, approximately by a factor of 1.5 compared to the central SAR. For this reason, it is more difficult to heat deep prostate tissue with the non-coherent network compared to the coherent network. However, as mentioned above, for prostate cancer treatment, some prostate cancer cells may be near the rectum and inconsistent treatment may provide adequate warming.

The adaptive phase array system according to the preferred embodiment of the invention utilizes two microwave channels, fed by a common oscillator 105, containing two electronically adjustable phase shifters 120 to focus microwave energy to an E 175 field feedback probe. This The implementation of the adaptive phase network system of the invention has a considerable advantage over a non-adaptive phase network. A non-adaptive in-phase network with two channels could, in theory, produce a null, maximum, or intermediate value of the E field depending on whether the two waves are 180 degrees out of phase, fully in phase, or partially out of phase, respectively. That is, the microwave phase delivered to the microwave applicators, according to the preferred embodiment of the invention, can be adjusted between -180 degrees and 180 degrees before and during treatment to create a focused field in the prostate tissue.

The adaptive phase lattice according to the preferred embodiment of the invention automatically focuses the E field in the presence of all scattering structures in the tissue. Thus, the adaptive phased array according to the preferred embodiment of the invention should provide more reliable deep focused heating compared to manually adjusted or pretreatment scheduling controlled phase arrays as described in U.S. Patent No. 4,589,423 to Turner . Furthermore, the adaptive phase lattice system according to the preferred embodiment of the invention does not use an invasive temperature probe, which could scatter or alter the E field at the tumor site.

IS 2 256 267 T3

Calculation of microwave energy

Electric power consumption is commonly expressed in units of kilowatt hours. Mathematically, the expression for the microwave energy W delivered by an applicator is given by (Vitrogan, Elements of Electric and Magnetic Circuits, Rinehart Press, San Francisco, pp. 31-34, 1971):

W = AtZ P_t.

(1)

In the above equation, At represents the constant intervals (in seconds) in which the microwave power is measured and the sum Σ is in the entire treatment interval with the power (in watts) in the i-th interval denoted by P_t.

Microwave energy W has units of watt-seconds, which is also designated Joules. For example, in three consecutive 60 second intervals, if the microwave power is 30 watts, 50 watts, 60 watts, respectively, the total microwave energy delivered in 180 seconds is calculated as W = 60 (30 + 50 + 60) = 8,400 watt seconds = 8,400 Joules = 8.4 kJ.

To better understand the focused energy per unit time W '(where' denotes prime) deposited at a central position in homogeneous prostate tissue of varying thickness (denoted by D) by double opposing applicators, consider the following calculation for consistent treatments. Let P₁ And p₂ the power delivered to the two applicators, respectively. The electric field radiated by each applicator is proportional to the square root of the power supplied to the applicator. Assuming symmetry, the radiated fields are in phase at the central focused position of the two applicators. Assuming equal power of each applicator, that is, Pi = P₂ = P, and plane wave illumination, the focused energy per unit time at the center depth is expressed as

W '(D) = | E |² = 4P exp (-aD). (2)

Calculation of the equivalent thermal dose

The cumulative or total equivalent thermal dose relative to 43 degrees Celsius is calculated as a sum (Sapareto et al., International Journal of Radiation Oncology Biology Physics, Vol. 10, pp. 787-800, 1984):

t₄₃or_C equivalent minutes = At ​​Σ R^(43-T), (3) where Σ is the sum in a series of temperature measurements during the treatment, T is the series of temperature measurements (T₁, T₂, T₃, ...), At is the constant time interval (units of seconds and converted to minutes) between measurements, R is equal to 0.5 if T&gt; 43 ° C and R is equal to 0.25 if T &lt;43 ° C. Calculation of the equivalent thermal dose is useful in evaluating any possible heat damage to prostate tissues, urethra, and rectum. Equivalents

Although the hyperthermia system described herein refers to the treatment of prostate carcinomas and benign prostatic lesions, the invention is applicable to the treatment of other types of cancers such as breast, liver, lung and ovary. It is also understood that a greater or lesser number of network antenna applicators, or single antenna applicators such as transurethral or transrectal, can be used with similar results. Some of the methods and techniques described here are also applicable to the ultrasound hyperthermia system, in particular the use of energy doses for feedback control. The system according to the invention can be used to enhance radiation therapy or for targeted drug delivery and / or targeted delivery of genes using heat-sensitive liposomes or for targeted gene therapy. The invention is also applicable to non-medical hyperthermia systems, such as those used for industrial heating.