Transurethral microwave thermotherapy.
Benign prostatic hypertrophy (BPH), or the benign enlargement of the prostate gland, affects most males as they age. It is estimated that 40 percent of men in their 50s, and as many as 70 percent of men in their 60s, will suffer prostatic enlargement.|1~ The incidence of BPH and the ever aging population impose an increasing demand on US health care. Over 400,000 men undergo transurethral surgery (TURP) each year in the US, with an estimated annual expenditure of $4 B.|2~ The necessity for anesthesia, hospitalization, post-operative catheterization, surgical mortality, surgical morbidity and failure rate have led to a search for safer but equally effective treatments.|3,4,5~
Since the mid 19th century, many ingenious methods of heating the prostate have been advocated for the relief of urinary obstruction and the symptoms of BPH. Attempts were consistently frustrated by technological limitations of delivering sufficient heat to the prostate without unwanted tissue damage.
In 1989, a flexible transurethral microwave applicator operating at 915 MHz was used.|6~ Some interesting clinical results were obtained, but no histological change in the adenoma itself could be shown.|7~ All of these human trials with microwave heating were conducted using the principles of hyperthermia, which is tissue heating in the range of 42 to 44|degrees~C, but all had the limiting factor of pain as soon as the urethral temperature reached 45|degrees~C or hotter. This pain limited the use of higher power and higher temperatures. Therefore, modifications of microwave heating were sought to obtain a way to achieve higher temperatures in the prostate without pain.
Transurethral microwave thermography (TUMT) is the unique process of delivering sufficient microwave heating to destroy prostatic tissue without unnecessary damage. TUMT combines the principles of microwave radiative heating and conductive cooling to destroy tissue deep within the prostate while preserving bladder neck, urethral mucosa (urethral skin) and distal urinary sphincter.
Physics of Microwaves
Microwaves comprise the 300 to 30,000 MHz range of the electro-magnetic spectrum. The entire spectrum of electromagnetic waves, including X-rays, visible light and infrared, can interact with biological matter, but the mechanisms of interactions are not the same over the entire frequency range. The microwave interaction results mainly in heating of biological tissue.
Microwaves propagating through living tissue heat because energy is transferred via electromagnetic field oscillation of free charges (electrons and ions) and by polarization of small molecules (mainly |H.sub.2~O). The resulting molecular kinetic energy raises the temperature of the tissue.
This microwave propagation follows the simple physical laws of all electromagnetic wave forms. For example, the speed c of the waves in the body is equal to the frequency F times the wavelength |lambda~ or c = F|lambda~. The speed depends upon the relative dielectric constant of the medium through which it passes (|lambda~|infinity~F/|square root of~||epsilon~.sub.r~) where ||epsilon~.sub.r~ = the relative dielectric constant. Thus, a 915 MHz microwave beam has a wavelength of 33 cm in air but 4.7 cm in muscle.|8~
The wavelength of microwaves will change within tissue, mostly as a result of varying water content. Penetration will be greater in fat, which has low water content, than in muscle, which has high water content. The higher the frequency, the less the penetration. Even for a given frequency, penetration varies with the temperature of the tissue.|9~
In microwave heating, the amount and rate of energy transfer is determined by the dielectric parameters of the tissue. The dielectric properties of materials measure the interaction of the material with the microwaves. In microwave heating, the dielectric parameters of the tissue determine the amount of energy coupling from the field, the degree of penetration and the rate and mechanism of energy dissipation.
The waves are further refracted, reflected and dispersed when encountering tissue inhomogeneities. Furthermore, tissue temperatures in a microwave field depend not only on the energy extracted but also on thermal conduction and convection (i.e. tissue perfusion). Therefore, studies in live animals are essential.
Proper studies in animals require an accurate thermometry system. Metallic electrodes absorb and distort the microwave field. Therefore, fiber-optic thermometry was chosen. Fiber optics do not cause any perturbation of the microwave field, nor do they reflect the microwaves. Safety is insured because they are thermally stable, inert, biocompatible and electrically nonconductive. Figure 1 is a schematic diagram of the fiber-optic principle.
Studies were performed in the canine model at the experimental surgical laboratory of UFR Alexis Carrel, Lyon, France. Initially, 915 MHz and 2450 MHz were investigated because of their historical use, but quickly 1296 MHz was chosen because it appeared to be the optimum frequency for its penetration and spatial temperature distribution, as shown in Figure 2.
In the canine model, the cytotoxic thermal threshold for BPH tissue is |113|degrees~.sup.+~F (|is less than~ 45|degrees~C) maintained for 30 minutes. No irreversible thermal mediated injury can be demonstrated in areas of the prostate where temperatures are below 113|degrees~F (|is less than~ 45|degrees~C). The sharp delineation of cell death at the outer boundary further supports the absolute nature of the threshold.
Not all cells die within the treated area. The cytotoxic thermal threshold varies with cell type. While capillaries are thrombosed, larger vessels are preserved because flowing blood cools the vessel wall. As a result, an abscess does not ensue. No tissue sloughing occurs because the urethral mucosa is preserved through use of conductive catheter cooling.
Conductive cooling has been combined with microwave radiative heating so that cytotoxic prostatic temperatures can be achieved safely. The urethral cooling changes the thermal spatial distribution, allowing high cytotoxic temperatures of 113 to 130|degrees~F (45 to 55|degrees~C) to be achieved within the prostate without rectal damage, as shown in Figure 3.|10~
The urethral cooling not only allows the unique high temperatures (|is less than~ 113|degrees~F) to be safely achieved, but also preserves the urethral mucosa and minimizes pain. The thermal pain threshold is 113|degrees~F (45|degrees~C) and the urethral mucosa is very nociceptive. The threshold temperature of 113|degrees~F for pain and cell death is teleologically consistent. Pain is a protective mechanism and should warn at the level of potential injury. The BPH tissue itself has limited nociception and this region can be comfortably heated well above 113|degrees~F provided that the urethral mucosa is kept well below 113|degrees~F.
Urinary obstruction from BPH is not from the urethral mucosa but urethral compression from the periurethral BPH tissue, as shown in Figure 4a. Destroying urethral mucosa alone does not relieve urinary obstruction. TUMT relieves urinary obstruction because the BPH tissue is heated to 113 to 130|degrees~F, while the thermally nociceptive urethral mucosa is kept at |is less than or equal to~ 112|degrees~F (|is less than or equal to~ 44.5|degrees~C) by conductive cooling, shown in Figure 4b. Additionally, the conductive cooling preserves the urethral mucosa, avoiding the painful healing period of forming new urethral skin and other problems associated with urethral skin disruption.|11~
The transurethral route of energy administration was chosen for TUMT because benign prostatic hyperplasia develops only in a limited region around the proximal urethral segment of prostate. The transurethral route allows easy matching of the energy field to the adjacent hyperplasia. Even though benign prostatic hyperplasia growth vary, the thermal field will conform to the hyperplasia since the urethra and the flexible urethral antenna system are displaced by the underlying benign prostatic hyperplasia.
After adequate bench, canine and preclinical human studies, a commercial system, Prostatron|TM~, shown in Figure 5, was developed.|12~ This is an investigational device limited by federal law to investigational use only. The Prostatron is a computer-driven system designed to treat disorders of the prostate by raising the obstructing tissue temperature to therapeutic levels (45 to 50|degrees~C). This is achieved via transurethrally generated microwaves.
The depth of penetration is dependent on the frequency and the predominant type of targeted tissues. 1296 MHz has been selected to optimize the depth and the shape of the transurethral heating while carefully preserving the surrounding tissue and organs.
The treatment applicator containing the microwave antenna also includes a system to cool the urethral wall during heating. The combination of strong cooling with radiative heating at high power using the 1296 MHz frequency achieves a steep gradient of temperature in the gland. While the periurethral and perirectal temperatures do not exceed 45|degrees~C and 42.5|degrees~C, respectively, the benign prostatic hyperplasia zone of the prostate can purposely be heated and subsequently destroyed (at temperatures as high as 60|degrees~C) in total safety. Other components include a 100 W power oscillator, a urethral cooling system, a fiber-optic temperature monitoring system and a control console.
The thermotherapy procedure is applied transurethrally using a 20|degrees~C treatment applicator delivery system containing the microwave antenna and a cooling system. An inflatable Foley-type balloon at the extremity of the treatment applicator retains it at the bladder level during treatment.
Temperature sensors are used for the real time control of the urethral and rectal mucosa temperatures. These sensors are made of noninterfering fiber optics, a key aspect when total patient safety must be ensured at this high level of temperature. The generator and cooling unit are microprocessor controlled by a custom software program in response to temperatures of the rectal and urethral thermosensors to achieve preset parameters.
Patients in the US are now being treated under an FDA investigational study criteria at five sites. Strict criteria include urinary flow measurement, postvoid residual, urinary symptomatology and absence of prior prostatic treatment.|13,14~
The minimum workup necessary for safe TUMT appears to consist of the patient's history and a physical examination that includes a test of urine to exclude infection and prostate ultrasound tests. Most urologists perform more comprehensive evaluations of patients prior to prostatic surgery, and similar evaluations consistent with their individual preference should be done prior to any alternative therapy of BPH.
Treatment has been well described and basically consists of a single, one hour office session.|13~ Patients experience some discomfort, but if they are informed of probable treatment and post-treatment discomfort, they are less anxious and more cooperative. The patients will feel some pelvic warmth, the urge to urinate and occasional bladder spasms with passage of urine around the catheter during treatment.
After the special Foley-type urethral antenna or microwave applicator is inserted, the correct position is confirmed by transrectal ultrasound. A permanent record of the ultrasound picture confirming correct placement is suggested to reduce potential legal liability. Rectal and oral temperatures are measured with a standard thermometer. The rectal probe designed for controlling the temperature of the rectal wall is inserted.
During treatment, the anal plug and urethral catheter are checked for displacement and treatment is commenced after three minutes of temperature equilibration. The initial phase of treatment consists of urethral cooling until the cooling temperature of 20|degrees~C is achieved, at which point the power emission is activated. Power begins at 15 W and increases in 5 W increments every three minutes until either the rectal thermal sensor registers 42.5|degrees~C or a maximum of 60 W is reached. If the temperature measured by the rectal thermal sensors reaches 42.5|degrees~C, microwave emission is stopped until the rectal temperature falls below 42|degrees~C and then resumes at 5 W below the previous power level.
Once the rectal temperature reaches 42.5|degrees~C, or the maximum power output of 60 W is obtained, or after 20 minutes of treatment, the urethral cooling is reduced, allowing the urethral temperature to reach 44.5|degrees~C to treat the adenomatous tissue near the urethra adequately. Excessive urethral cooling could preserve a compressive ring of adenomatous tissue. If the temperature in the urethra exceeds 44.5|degrees~C, power is interrupted, urethral coolant temperature is lowered 1|degrees~C, and treatment resumes when urethral temperature falls below 44|degrees~C.
The complex program continuously monitors the urethral and rectal temperatures, and while the temperature achieved at these areas is limited, intraprostatic temperature easily is in the range of 45 to 55|degrees~C (113 to 130|degrees~F) during the one-hour treatment. The software modulates the treatment to obtain the desired intraprostatic temperatures and minimal operator intervention is usually required. However, the operator can interrupt power, increase urethral cooling, and restart microwave emission at 5 W below the previous level if desired.
The treatment antenna is removed and the patients are asked to stay in the office until they void successfully. Most post-treatment urinary retention occurs immediately. For those in urinary retention, a small urethral catheter is carefully inserted with a leg bag and usually the catheter can be removed in three days.
Postoperative patients are instructed to take over-the-counter anti-inflammatory agents to minimize any discomfort as well as post-treatment edema. Oral antibiotics are given for three days to prevent subsequent infection.
Clinical Results in BPH Open Study: Mayo Clinic Jacksonville
Urinary voiding symptoms are greatly improved after TUMT and continue to improve with time. The overall mean symptomatic improvement by the Madsen score is equal to that after standard surgery. Unlike surgery,|15~ all individual symptom scores are improved, including terminal dribbling. The results of 30 patients are shown in Figure 6.
The most bothersome complaint of nocturnal voiding decreased from an average of 3.3 to only 1.5 by three months. The range of nocturnal voiding dropped from one to eight voids per night to zero to three voids per night, reflecting remarkable improvement in all patients with significant nocturnal voiding.
Twenty-two patients were treated in urinary retention. Twenty out of 22 were able to void after a single TUMT session.|16~ After treatment, at least six weeks are necessary to allow tissue resorption and reorganization.
Future Directions Prostatitis-TUMT
Another disease of the prostate that TUMT may be used for is prostatitis. Drs. Sorenson and McGarragle at the International Prostate Center, Windsor, Canada, treated nine patients, age 39 to 72, with irritated prostates or nonbacterial prostatitis. These patients were treated using the standard antenna and software protocol. The mean symptom score dropped from 26 pretreatment to 5.2 in three months. The only nonresponder did have psychological problems and this may have explained his failure to improve. While this series is small, it must be noted that these patients exhausted standard therapy and their urologists without significant improvement.
The recent interest with hyperthermia in the 1970s was because of the spontaneous regression of malignancy noticed after febrile episodes.|17~ In addition, in-vivo and in-vitro studies have confirmed the greater thermal sensitivity of cancer cells as opposed to normal tissue.|18~
However, cell survival after treatment is an exponential curve. It is not likely that every single cancer cell will die after a single treatment and the nonuniformity of an in-vivo microwave field might not adequately treat all cancer cells.
Still, there are theoretical features that make thermal treatment attractive. Cell survival after either radiation or thermal treatment is influenced by the position in the cell cycle at the time of exposure. Generally speaking, cells are significantly more radioresistant in the late S phase,|19,20~ but also are extremely sensitive to thermal cytotoxic treatment.
Additionally, hypoxic cells are known to be radioresistant but oxygen concentrations appear to have no modification of the thermal cytotoxic survival curve. This mirror image makes the addition of microwave therapy to radiation therapy potentially attractive. Further understanding of the thermal sensitivity of prostate cancer and the thermokinetics of the prostate are needed before microwave thermal treatment can be given with intent to cure prostate cancer.
Heat is a physical agent and its biological effects are related to the intensity, duration and manner of application. Microwave heating has been used for other diseases, and with a combination of conductive cooling, transurethral microwave thermotherapy (TUMT) has been developed for prostate diseases.
TUMT has unique treatment goals, thermokinetics, histological and biological effects with advantageous therapeutic outcomes for symptomatic BPH. TUMT should be clearly distinguished from other thermal techniques, such as transurethral or transrectal hyperthermia, transurethral laser incision of the prostate and high energy focussed ultrasound.
Other prostatic diseases in which TUMT has potential clinical utility include nonbacterial prostatitis and prostatic carcinoma. Definitive treatment with curative intent for prostatic carcinoma may be possible with TUMT alone or more probably in combination with radiation therapy. With a better understanding of microwave effects on biological tissue, improvements in transurethral microwave thermotherapy will be inevitable. Potential uses of microwave energy for other diseases and organs will be possible.
1. S.J. Berry, "The Development of Human Prostatic Hyperplasia With Age," J. Urol., 1984, pp. 132-474.
2. P. Cotton, "Case for Prostate Therapy Reigns Despite More Treatment Options," JAMA, Vol. 266, 1991, p. 459.
3. J. McLoughlin and G. Williams, "Alternatives to Prostatectomy," Brit. J. Urol., Vol. 65, 1990, p. 313.
4. W.P. Stephenson, C.C. Chute, H.A. Guess, S. Schwartz and M. Lieber, "Incidence and Outcome of Surgery for Benign Prostatic Hyperplasia Among Residents of Rochester, Minnesota: 1980-1987," Urology Suppl., Vol. 38, 1991, p. 32.
5. J.E. Wennberg, M. Roos, L. Sola, A. Schior and R. Jaffey, "Use of Claims Data Systems to Evaluate Health Care Outcomes, Mortality and Reoperation Following Prostatectomy," JAMA, Vol. 257, 1989, p. 933.
6. M.A. Astrahand, M.D. Sapozink, D. Cohen, G.L. Luxton, T.D. Kampp, S. Boyd and Z. Petrovich, "Microwave Applicator for Transurethral Hyperthermia of Benign Prostatic Hyperplasia," International J. Hypertherm., Vol. 5, 1989, p. 283.
7. M.D. Sapozink, S.D. Boyd, M.A. Astrahand, G. Jozsef and Z. Petrovich, "Transurethral Hyperthermia for Benign Prostatic Hyperplasia: Preliminary Clinical Results," J. Urol., Vol. 143, 1990, pp. 944-950.
8. J.W. Hunt, "Application of Microwave, Ultrasound and Radio Frequency Heating," Monograph 61, 3rd International Symposium: Cancer Therapy, Hyperthermia, Drugs, and Radiation.
9. Ohlsoon, et al., J. Microwave Power, 1974.
10. M. Devonec, M. Cathaud, P. Mouriquand, J.H. Maquet, H. Oukheira, N. Berger and P. Perrin, "Effects of Transurethral Heating on the Canine Prostate," Proceedings of the 7th World Congress on Endourology and ESWL, Kyoto, Nov. 1989, p. 73.
11. W.K. Mebust and C. Damico, "Prostatic Desiccation: A Preliminary Report of Laboratory and Clinical Experience," J. Urol., Vol. 108, 1972, p. 601.
12. M. Devonec, S. Carter and P. Perrin, "Prostatic Hyperthermia -- A New System," in Proceedings of the BAUS., St. Helier, Jersey, 1989, p. 98.
13. K.M. Tomera, D.K. Hellerstein, S.P. Petrou and R.G. Ferrigni, "Preliminary Results of TUMT for Prostatism," Annual Meeting of the RSNA (abs 773), Chicago, Dec. 1991.
14. M. Blute, K.M. Tomera, D.K. Hellerstein, D.E. Patterson and J.W. Segura, "Early Results of TUMT for Benign Prostatic Obstruction: Mayo Foundation Experience," Mayo Clinic Proc., Vol. 67, 1992, pp. 417-421.
15. R.C. Bruskewitz and M.M. Christensen, "Critical Evaluation of Transurethral Resection and Incision of the Prostate," Prostate Suppl., Vol. 3, 1990, pp. 27-38.
16. R. Cauweleart, O. Castillo, C.A. Aquirre, G. Azocar and F. Medina, "Transurethral Thermotherapy for the Treatment of the Prostate Gland Adenoma," European Urology, In Press.
17. W. Busch, "Uber den Einfluss Weichen Hefigere Erysipelen Zuweilen auf Organisierte Neubildungen Ausuken Verhandle, Rheinisch-Westfael," Akad Wiss Nat Lng Wirtschaftswiss Vortr, Vol. 23, 1866, p. 28.
18. R.A. Lambert, "Demonstration of the Greater Sensitivity to Heat of Sarcoma Cells as Compared with Actively Proliferating Cancer Tissue Cells," JAMA, Vol. 59, 1912, p. 2147.
19. S.B. Field, "Hyperthermia in the Treatment of Cancer," Phys. Med. Biol., Vol. 32, 1986, pp. 789-811.
20. L.E. Gerweck and B. Richards, "Influence of Variable Oxygen Concentrations on the Response of Cells to Heat or X Irradiation," Radiation Res., Vol. 85, 1981, pp. 314-320.
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|Author:||Tomera, Kevin M.; Hellerstein, Daniel K.|
|Date:||Nov 1, 1992|
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