Hyperthermia as a treatment modality in benign prostatic hyperplasia

HYPERTHERMIA AS A TREATMENT MODALITY IN BENIGN PROSTATIC HYPERPLASIA HAIM MATZKIN,

M.D.

From the Department of Urology, Tel-Aviv Sourasky Medical Center. Sackler Faculty of Medicine, Tel-Aviv University Tel-Aviv, Israel

To review the current status of hyperthermia (heating the prostate up to 45°C) as a treatment modality for benign prostatic hyperplasia (BPH). Methods. Hyperthermia versus thermotherapy is defined, the techniques and equipment are presented, and the current English literature regarding safety and efficacy is reviewed. Results. Both transrectal and transurethral heat applications are very safe procedures. Most studies evaluating the efficacy have been nonrandomized and uncontrolled. The 50-70 percent symptom improvement rate should be compared with the natural history of the disease and the considerable placebo effect. The few controlled studies produced contradictory results. Conclusions. At the present time, hyperthermia has not been shown, in scientifically well-designed studies, to be a treatment modality with measurable and durable outcome in BPH.

ABSTRACT-Objective.

The concept of therapeutic heat application to the prostate is not entirely new. It is based on sporadic reports of spontaneous cure of various tumors following high systemic fever in the 19th century. Modern heat therapy to the prostate, utilizing far high er t emperatures, originated in Israel. The research was pioneered by Yerushalmi 4~ al.’ in 1982. for USC:in cancer of the prostate. Several years later. the same group endeavored to treat benign prostatic obstruction by microwave therapy designed to produce localized hyperthermia.’ In less than a decade this treatment modality underwent intense technical evolvement and clinical trials. However, that this is still an investigational tool in many countries emanates from the fact that urologists and others in the field of hyperthermia did not initially study the effect of heat on the prostate. It is only lately that research has concentrated on the mechanism of action in benign prostate hypertrophy (BPH). The sensitivity of tumor tissue to heat is well known. It is partly due to the increased sensitivity of malignant cells to heat, as opposed to normal cells, and to the local neovascular supply enabling heat accumulation in malignant tumors versus heat dissipation in normal tissues. By analogy to tumorous tissue, it was suggested that BPH would show similar response to heat.2 However, this was

never proven, and, in fact there are no grounds for the supposition that BPH tissue should be more susceptible to heat than normal tissue. HYPERTHERMIA AND ‘THERMOTFIERAPY The rapid technologic advances ha\rc brought along some misconceptions and misnomers.’ t Two different heat applications are currently recognized and clinically available: “Hyperthermia” is heat therapy in which the temperature within tht prostate does not exceed 45°C; “thermotherapy” is the technique in which the temperature within the prostate always exceeds 45°C and uses urethral cooling. 3.5’ The distinction is warranted, since different mechanisms of action may be responsible for the clinical efficacy. With hyperthermia, cellular infiltration may occur, but cell death has rarely been reported,’ and any long-term impact has not been detected under the microscope. Following thermotherapy, the prostate in both, animals and in man shows permanent necrotic changes.’ x.9 HEATING

TECHNIQUES

AND DEVICES

Over the past ten years, a variety of both transrectal and transurethral hyperthermia machines that deliver a multitude of radinfrcquencies to the gland have been developed. ‘The transrectal machines have a cooling system for the rectal

TABLE

I.

Characteristics of different hyperthermia devices

Company

Blocian (Israel] Technomatlx (Belgium) Bruker (Germany) BSD (USA] Dlrex (Israel)

Machine

Name

Prostathermer Primus Prostcare

BSD-300 Thermex II

Route

Rectal Rectal Rectal Transurethral Transurethral

Cooling

Rectal Rectal Rectal No No

mucosa, whereas the transurethral machines do not. Currently, there are some five to seven machines on the market (Table I). The present article will only briefly mention some of the prototypes. As already mentioned, there are two routes to administer heat in hyperthermia. The rectal cavity allows easy access to the prostate with minimal patient discomfort and was the first to be used, thus providing the longest experience and the most comprehensive clinical data. The Prostathermer (Biodan, Israel) heats through a transrectal applicator with a cooling system for the rectal wall and a urethral catheter with a receiving antenna and thermocouples to monitor temperature. 3 6,‘o,” The Primus machine (Technomatix, Belgium) consists of a similar heat source and rectal cooling system, but temperature is not directly measured in the urethra but entirely computed by the machine. The manufacturer claims better patient compliance because there is no need for a urethrally positioned catheter. It would seem that in a treatment based solely on a narrow spectrum of heat (42-45”C), if the actual temperature is not measured, the treatment is unrealistic and thus, unacceptable. However, the clinical efficacy of the two devices has been shown to be similar.12 The transrectal approach is relatively inefficient, because a significant proportion of the microwave power is lost in heating the water used to cool the rectal wall. The microwaves have to penetrate tissues with different densities and reflection may occur at interfaces. The correct placement of the probe may also be difficult at times. Contrariwise, a heating probe inserted transurethrally may be accurately positioned and the heat delivered from the antenna may indeed be transmitted to the center (periurethral, transitional gland) of the prostate. 13-15The Thermex II machine (Direx, Israel) uses a heating electrode mounted on a modified Foley catheter and the temperature is sensed by the thermocouples.‘h There are no generally accepted treatment protocols that define therapy time and frequency of sessions. Most transrectal devices base their treatment 18

protocols on multiple one-hour sessions. The transurethral machines have a very attractive one session of two to three hours’ duration. However, it should be clearly stated that the length of time in transurethral hyperthermia is as empirical as the 6-10 one-hour sessions in the transrectal route. These may be of more marketing-strategy-related than of actual scientific significance, since there are no comparative randomized studies to evaluate the technical efficacy of the various protocols. When reviewing the impact and proper place of a new treatment regimen for any given condition, let alone treating symptomatic BPH, three basic questions have to be answered: How does the modality work? Is it safe? Is it effective? MECHANISM OF ACTION The early reports by Servadio et uI.~,~ suggested that up to 19 percent reduction in the cross-sectional area of the treated prostate occurred. Thus, they thought that hyperthermia works by reducing the bulk, the size of the gland, and therefore facilitating voiding. 3*17 It is quite clear now that this idea was erroneous. Such an effect would act by preferential destruction of the hyperplastic prostate. There is no evidence of any significant cell death occurring after hyperthermia, except for the report by Lauweryns et a1.7 on necrosis of the musculature of the prostatic parenchyma. Neither Strohmaier et al.‘* nor ourselves’0 have reported any changes in the size of the treated glands. Nor did we find any histologic changes in the glands of those patients who failed and underwent surgery. Likewise, Lindner et al.‘” did not find any changes in the serum prostate-specific antigen (PSA) following treatment, suggesting that no glandular cell death occurs after treatment. The contribution of Marian Devonec from Lyon, France, has been most helpful in our understanding of heat treatment in the prostate.9,20 According to his suggestion, heat treatment up to 45°C (hyperthermia) works by a nonheat-related mechanism, is reversible, and possibly includes ionic influx and efflux. Van Erps et ~1.” suggested that the main effect may be on the dynamic component of the obstruction, namely, altering the alpha receptor tonicity status. Although appealing, laboratory data are urgently needed to substantiate this assumption. Watson et al.,12 Nissenkorn et al.,” and Lauweryns et aI.,23 working with transurethral devices heating the gland to 45”-46”C, witnessed some periurethral necrosis, mainly small vessel necrosis. They suggest that some scarring and retraction follows transurethral hyperthermia and this may be the mechanism of

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symptom relied. Yet, we still require proof for the mechanism of action of this modality. SAFETY The safety question has been answered quite definitely after thousands of treated patients and many more treatment sessions. One can state quite confidently that hyperthermia is an extremely safe procedure. Lindner et al.lt published complications of 435 patients treated with transrectal hyperthermia, which is the largest series ever published. The overall complication rate was 6.6 percent and all complications were mild-e.g., transient hematuria, infected urine and epididymitis-and originated from the urethrally introduced catheter rather than from the heat treatment itself. With the current inclusion and exclusion criteria used by all institutes using hyperthermia as an alternative treatment in BPH, no major complications have been described. EFFICACY The most important question to the practicing urologist is the effectiveness of this modality. One has to bear in mind that evaluating any treatment modality in BPH is fraught with difficulties. The gland is composed of different tissues, epithelium and stroma. that have distinctive biologic behaviors. The disease is heterogeneous, causing in some cases acute urinary obstruction and in many others symptoms with a varying degree of severity. Add to this the large number of hyperthermia machines, the varying lengths of treatment time, the range of treatment sessions, and routes of delivery (transrectal or transurethral), and one ends with an almost impossible task to evaluate clinical data published on the subject. There are a number of articles in peer-reviewed journals with favorable results of either transrectaliJ’.l’.lh or transuretllral’3-‘j hyperthermia. Some of these articles report large numbers of treated patients. and several authors have reported subjective success rates greater than 75 percent.13-“,” These favorable results were obtained after transurethral hyperthermia. By contrast, Strohmaier c’t al.‘” treating 30 patients with transrectal hyperthermia, attained only a disappointing 7 percent success rate. Montorsi et al.,‘” reporting on a large series of 112 patients followed for a period of two years after transrectal hyperthermia, concluded that “although transrectal prostatic hyperthermia is a safe procedure, it does not resolve obstruction caused by BPH and should not be considered as a first-line treatment for symptomatic BPH.” We witnessed only intermediate re-

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sults, with improvement in both suhjcctive and objective parameters, in 25 percent 01. the treated men.‘” The longest follow-up (5.5 years) was recently reported by Braf and coworkers,jO with positive results observed among 212 transrectally treated patients in this noncontrolled study. However, none of these studies was randomized or controlled in any sense. The variability in the natural history of BPH, along with the known placebo effect, makes it difficult, if not impossible, to evaluate the impact of hyperthermia in the clinical setup. Only a few studies have been conducted in a randomized, controlled fashion. Theoretically, they should provide us with the answer to the proper role of this modality. Zerbib et (11.” performed a well-controlled study of 68 patients randomized to either transrectal hyperthermla or sham therapy. They showed a certain, persistent improvement in both subjective and objective parameters in the treated arm. However, it should he noted that the objective parameters in that report were less favorably affected than the subjective ones. At the end of the treatment, the maximal flow rate reached was still lower than the normal range. Contrariwise, Fabricius et al.” conducted a similar placebo-controlled study with transrectal hyperthermia in 50 patients. Their results were much less impressive and, indeed, there was no objective evidence of success. In summary, even the few well-controlled studies have produced inconsistent results. More phase III studies are definitely needed to prove the efficacy of hyperthermia in BPH. COMPARATIVE.

STUDIES

Only a small number of investigators have published comparative studies in hyperthermia. Stawarz et ~1.~~ published a prospectlvc study in which they compared the clinical outcome in 22 and 14 patients treated with transrectal and transurethral hyperthermia, respecl.ivcly. The subjective response rate was far better in the transurethrally treated patients: 79 percent versus only 41 percent in the transrectal hyperthermia group. In a similar design, but in a larger number of patients, Watson et al.” compared more than 20 patients in each study arm. The comparison was made between the Prostathermer. the Primus, both heating through the rectum, and the Thermex II, heating through the urethra. Uroflowmetrv improved in all three groups to within a range of 1.6-3.3 mUsec. Residual urine volume also decreased significantly in all groups. A similar trend was observed in the decrease in the Boyarski symptom score.

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CONCLUSIONS Hyperthermia is a palliative and not a curative treatment. Some have indicated that the relief of irritative symptoms is more pronounced. Thus, no comparisons should be made to the clinical outcome of transurethral prostatectomy. Phase III randomized trials of hyperthermia should be undertaken and compared with other symptomatic treatments, such as a-adrenergic blockers. If hyperthermia is shown to be superior in repeated clinical trials, then other issues, such as patient acceptability and cost-benefit ratios, should also be determined before any conclusions regarding the role of hyperthermia in BPH can be established. While all this information is still being gathered, hyperthermia should in the interim be considered as a therapeutic tool still under investigation. REFERENCES 1. Yerushalmi A. Servadio C, Leib Z, Fishelovitz Y, Rokowsky E, and Stein JA: Local hyperthermia for treatment of carcinoma of the prostate: a preliminary report. Prostate 3: 623-630, 1982. 2. Yerushalmi A, Fishelovitz Y, Singer D, Rciner 1, Ariell) J, Abramovici Y, Catsenelson R. Levy E, and Shani A: Localized deep microwave hyperthermia in the treatment of poor operative risk patients with benign prostatic hyperplasia. J Urol 133: 873-876, 1985. 3. Servadio C. Lelb Z, and Lev A: Diseases of prostate treatment by local microwave hyperthermia. Urology 30: 97-99, 1987. 4. Servadio C, Braf Z, Siegel Y, Leib Z, Saranga R, and Lindner A: Local thermotherapy of the benign prostate: a lyear follow-up. Eur Urol 18: 169-173. 1990. 5. P&mutter AP: Prostatic heat treatments. Semen Urol 10: 169-179. 1992. 6. Servadio C, Leib Z, and Lev A: Further observations on the use of local hyperthermla for the treatment of diseases of the prostate in man. Eur Urol 12: 38-40, 1986. 7. Lauweryns J, Baert L, Vandenhove J, and Petrovich Z: Histopathology of prostatic tissue after transurcthral hyperthermia. Int J Hyperthermia 7: 221-230, 1991. 8. Blute ML, Tomera KM, Hellerstein DK, Atkinson EJ, Patterson DE, and Segura JW: Transurethral microwave thermotherapy for prostatism: early Mayo Foundation experience. Mayo Clin Proc 67: 417-421, 1992. 9. Devonec M, Berger N, and Perrm P: Transurethral microwave heating of the prostate-or from hyperthermia to thermotherapy. J Endourol 5: 129-135, 1091. 10. Saranga R. Matzkin H, and Braf Z: Local microwave hyperthermia in the treatment of benign prostatic hypertrophy. Br J Urol 65: 349-353, 1990. 11. Braf ZF, Matzkin H, Lindner A, Saranga R, Siegel Y, Leib Z, and Servadio C: Four year follow-up of patients with benign prostatic hyperplasia (BPH) treated with transrectal deep hyperthermia (Abstr). J Urol 145: 363A, 1991. 12. Watson GM, Perlmutter AP, Shah TK. and Barnes DG: Heat treatment for severe symptomatic prostatic outflow obstrucnon. World J Urol 9: 7-11. 1991. 13. Baert L, Willemcn P. Amcye E and Petrovich Z: Treatment response with transurethral microwave hypcrthermia in different forms of benign prostatic hyperplasia: a preliminar) report. Prostate 18: 315-320, 1991.

14. Baert 0, Ameye E Willemen P, Vandcnhove J, Lauwcryns J. Astrahan M, and Petrovich Z: Transurethral mcrowave hyperthermia for benign prostatic hyperplasia: prcliminary clinIca and pathological results. J Urol 144: 1383-1387.1990. 15. Sapozink MD, Boyd SD, Astrahan MA. Jozsef G. and Petrovich Z: Transurethral hyperthermia for benign prostatic hyperplasia: preliminary clinical results. J Urol 143: 944-950, 1990. 16. van den Bossche M, Noel JC, and Schulman CC: Transurethral hyperthermia for benign prostatic hypertrophl: World J Urol 9: 2-6, 1991. 17. Leib Z, Lev A, and Servadio C: Transrectai ultrasound in local hyperthermia to the benign prostate. World J Urol 9: 15-18.1991. 18. Strohmaier WL, Bichler KH. Fluchtcr SH, and Wilbert DM: Local microwave hyperthermia of benign prostatic hyperplasia. J Urol 144: Y 13-917. 1990. 19. Lindner A, Siegel Yl, and Korczak D: Serum prostate specific antigen levels during hyperthermia treatment of bcnign prostatic hyperplasia. J Urol 14: 1388-1389, 1990. 20. Devonec M, Fendler JP, Nasser M, Joubert P, and Perrin P: The clinical response to transurethral microwave thermotherapy is dose-dependent: from thermocoagulation to thermoablation. J Urol 149: 249A, 1993. 21. Van Erps PM. Dourcy B, and Denis LJ: Transrectal hyperthermia in benign prostatic hyperplasla (Abstr. 203). J Ural 145: 263A, 1991. 22. Nissenkorn I, Saba K, Meshorer 1. and Meshorer A: Temperature mapping and histology of the canine prostate during transurethral hyperthermia of the prostate usmg Thermex-11 (Abstr. 736). J Urol 145: 3Y6A, 199 1. 23. Lauweryns J, Baert L, Vandtnhove J, and Petrovich Z: Histopathology of prostatic tissue after transurethral hyperthermia. lnt J Hyperthermia 7: 221-230, 1YY I. 24. Lindner A, Siegel YI, Saranga R, Korczak D, Matzkm H, and Braf Z: Complications m hyperthermia treatment of benign prostatic hyperplasia. J Urol 144: 1390-1392, 1990. 25. Lindner A, Braf Z, Lev A, Golomb J. Leib Z, Siegel Y, and Servadio C: Local hyperthermia of the prostate gland for the treatment of benign prostatic hypertrophy and urinary rctention. Br J Ural 65: 201-203. 1940. 26. Servadio C, Lindner A. Lev A, Leib Z, Siegel Y. and Braf Z: Further observations on the effect of local hyperthermia on benign enlargement of the prostate. World J Urol 6: 204-208, 1989. 27. Stawarz 8, Szmiggielski 5, Ogrodnik J, Astrahan M, and Petrovich Z: A comparison of transurethral and transrectal microwave hyperthermia in poor surgical risk benign prostatic hyperplasia patients. J Urol 146: 353-357, 1991 28. Strohmaier WL, Bichler KH, Bockmg A, and Fluchtcr H: Histological effects of local microwave hyperthermia in prostatic cancer. Int J Hyperthermia 7: 27-33, 1991. 29. Montorsi E Guazzoni G, Colombo R, DaPozzo L, and Rigatti P: Transrectal prostatic hyperthermia does not relieve bladder outlet obstruction due to BPH: a long term follow-up study. J Urol 14: 306A, 1992. 30. Braf Z, Lindner A, and Servadio C: 51/; year follow-up of patients with benign prostatic hyperplasia treated with transrectal deep hyperthermia. J Urol 149: 25lA, lY93. 31. Zerbib M, Steg A, Conquy S, Martinache PR, Flam TA, and Debre B: Localized hyperthermla versus sham procedure in obstructive bemgn hyperplasia of the prostate: a prospective randomized study. J Urol 147: 1048-1052, 1992. 32. Fabricius PG, Schafer J. Schmeller N, and Cahussy C: Efficacy of transrectal hyperthermia for benign prostatic hyperplasia (Abstr. 602). J Urol 145: 363A, 1991