INT. J . HYPERTHERMIA,
1991, VOL. 7,
NO.
1, 27-33
Histological effects of local microwave hyperthermia in prostatic cancer W. L. STROHMAIER-tt, K.-H. BICHLERT, A. BOCKINGP and ST. H. FLUCHTER~ ?Department of Urology, University of Tubingen, FRG §Department of Pathology, RWTH Aachen, FRG
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
(Received 10 March I989;jnal version received 2 April 1990; accepted 6 April 1990) Recent investigationshave shown that hyperthermia can reduce the volume of the prostate and improve local symptoms in patients with carcinoma of the prostate. Histological examinations of the effect of hyperthermia on prostatic cancer tissue, however, have not been performed systematically until now. Thus, we initiated a study to investigate the effects of heat on prostatic cancer as a prerequisite for further clinical trials on hyperthermia as treatment for prostatic cancer. Twenty patients with untreated prostatic cancer underwent local hypthermia (915 MHz), each receiving four sessions of 60 min each. The intraprostatic temperature was 42-43 "C. Histological specimens of the prostate were taken before the treatment and 1-2 weeks after the last hyperthermia session. Hyperthermia produced hyperaemic alterations of the prostatic stroma and a diffuse oedema with interstitial lymphoplasmacellular infiltration. Definite signs of tumour cell necrosis, however, could not be seen in any of the patients. Hence the shrinkage of prostatic tumours described earlier cannot be explained by histologically proven tumour cell destruction. Thus hyperthermia is not adequate as a single treatment for prostatic cancer. Hyperthermia may, however, be useful as part of integrated therapy regimens together with cytostatic or hormonal agents and radiotherapy because of hyperaemic, chemo- and radiosensitizing effects. Key words: Prostatic cancer, histology, hyperthermia.
1. Introduction Several investigations have demonstrated the efficacy of hyperthermia in different malignant tumours. For a long time hyperthermia of the prostate was problematic because of the anatomical situation of this organ. Difficulties with thermometry in particular prevented a systematic application of hyperthermia in prostatic cancer. Some years ago Yerushalmi et al. (1982) and Servadio and Leib (1984) first reported on hyperthermia treatment in prostatic cancer patients, These results were promising: hyperthermia induced a shrinkage of the prostatic tumour volume, urinary flow rate and residual urine were improved and local complaints could be mitigated. Szmigielski et al. (1988) described a response rate of 50% in patients with advanced carcinoma of the prostate after local prostatic hyperthermia. In two patients a disappearance of bone metastases was noted. The functioning of hyperthermia in prostatic cancer, however, has not been elucidated so far. Histological examinations on the effect of hyperthermia on prostatic cancer tissue in particular have not been performed systematically. To investigate these effects the following study was performed.
2. Materials and methods Twenty patients with newly diagnosed prostatic cancer (adenocarcinoma) of different stages (T 2-4, N 0-2, M 0-1, G 1-3, UICC classification 1987, Table 1) were treated with local (transrectal) hyperthermia prior to conventional cancer therapy. The diagnosis $Address correspondence to: Dr med. W. L. Strohmaier, Department of Urology, University of Tubingen, Calwerstr. 7, D-7400 Tiibingen, FRG. 0256-6736191 $3.00 01991 Taylor & Francij Ltd
W. L. Strohmaier et al.
28
Table 1. Staging and grading in 20 patients with histologically proven prostatic cancer treated by local microwave hyperthermia (UICC classification 1987) Non-metastatic (n= 8) Metastatic (n= 12) T2
T3
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
T4
T2
G2
(n=l)
(n=2) (n=l
T3
(n=4)
(n=l)
T4
G2 G3 G3
G1
(n=l)
G2 G2 G2 G2
(n=3) (n=6) (n=l)
was established by transperineal punch biopsy and histological examination of the specimens. For staging of the tumoars transrectal ultrasound, abdominal/pelvic computed tomography (CT) and nuclear bone scans were performed. Informed consent to hyperthermia treatment and biopsies was obtained from all patients. Patients underwent four hyperthermia sessions of 60 min each. Sessions were given twice a week. Anaesthesia or seda.tion was not required. The intraprostatic temperature of 42-43°C was reached within the first 10 min of the treatment. For hyperthermia treatments the Prostathermer (Biodan Medical Systems Ltd, Rehovot, Israel) was used. This equipment consists of a 915 M:Hz power source (maximum energy 100 W) connected to a special applicator. The applicator, containing a skirt-type quarter wavelength dipole antenna, was inserted into the rectum and directed towards the prostate. A radiofrequency locator part integrated into the urethral catheter allows for exact alignment of the applicator opposite to the prostate. A special clamp attached to the applicator allows for a constant position of the applicator during the treatment. Temperature in the prostatic urethra was monitored using a special balloon catheter containing three copper-constantan thermocouples. The interval between the balloon and the first thermocouple was 2 cm, corresponding to the distance between bladder neck and prostatic urethra. The catheter was inserted after urethral instillation of a lubricant containing lidocain 2 % (Instillagel, Farco Pharma Cologne, FRG) the balloon being positioned at the bladder neck and thus the temperature probes within the prostatic urethra (Figure 1). Animal experiments with dogs using the same equipment have shown that temperature measurements within the prostatic urethra are representative for the whole prostate as the prostatic urethra is in the ventral third of the prostate (Leib et al. 1986). In this study temperatures were measured in the prostatic urethra and at three different sites in the prostatic gland. The antenna’s in vivo heat profiles showed that a volume of 20-60 cm3 could homogeneously be heated to the desired temperature. The histological examination of the canine prostates revealed no differences in hyperthermic effects between different areas of the prostate. Heat mapping phantom and animal experiments with an applicator of the same properties have also demonstrated suitability for sufficient heating of the prostate (Mendecki et al. 1980). Special devices for cooling the rectal wall (water circulation) and for controlling the temperature in the rectum (copper--constantan thermocouples) were included. Cooling the rectal wall shifts the peak temperature towards the prostate, thus preventing damage of the rectal wall (Servadio and Leih 1984, Lindner et ul. 1987, Bichler 1988, Bichler ef ul. 1988, Strohmaier et al. 1988). The thermal equivalent dose (TED) is calculated by the Prostathermer for each treatment based on the assumptions of Sapareto and Dewey (1984). For example, a TED of 1800 is equivalent to heating at 43°C for 30 min. Profiles of the power delivered by the generator and the temperatures of the rectum and the prostatic urethra were registered continuously during the treatment. Following treatmt:nt a print-out of these profiles may be obtained (Figure 2).
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
Hyperthermia in prostatic cancer
29
Figure 1 . Position of the applicator (A) and the thermocouples in the prostatic urethra (P) and the rectum (R) during the treatment.
To study the effects of local hyperthermia on prostatic cancer tissue, histological specimens were taken by punch biopsy before the treatment. One to 2 weeks after the last hyperthermia session histological specimens were obtained by radical prostatectomy in patients with non-metastatic T2-T3 tumours. The remaining patients underwent punch biopsy or, in case of subvesical obstruction, transurethral resection. Tissue specimens were fixed in formalin, embedded in paraffin and sections stained with haematoxylin and eosin (H&E).
3. Results The same histological effects of hyperthermia could be detected in each patient. The prostatic stroma showed a distinct oedema and a diffuse lymphoplasmacellular infiltration as an indication of interstitial inflammation (Figure 3). Near the capsule in particular, hyperaemic capillary blood vessels and bleeding into the interstitium could be found (Figure 4).In the centre of the prostatic glands macrophages laden with haemosiderin were observed as signs of previous bleeding (Figure 5). Furthermore, damaged blood vessels showed a swelling of the wall. In some patients groups of necrotic prostatic glands were seen. The cytoplasm of some tumour cells demonstrated a slight vacuolization, which was, however, also found before hyperthermia. Definite signs of tumour cell necrosis could not be observed in any of the patients (Figure 6). There was no difference between the histological appearance regarding tumour size, location within the prostate or tumour grade. As could best be evaluated from the radical prostatectomy specimens in which the whole organ could be examined, hyperthermia effects were the same in the whole prostate regardless of the distance from the microwave applicator. The mean thermal equivalent dose (TED) was 1868 &610 equivalent seconds at 43°C per hyperthermia session (range 925-2730). As the patients underwent four sessions the
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
30
.'U L. Strohmaier
T
I
N
E
et al.
i i n
minute;)
3gure 2 . Profiles of the power delivered by the generator and the temperatures of the rectum and the prostatic urethra as reconied during a hyperthermia treatment of a patient with prostatic cancer.
Figure 3. Oedema of' the stroma of the prostate with lymphoplasmacellular infiltration indicating interslitial inflammation (arrows). H&E, X 98.
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
Hyperthermia in prostatic cancer
Figure 4. Capillary blood vessels with distinct hyperemia after hyperthermia (arrows). H&E,
31
X 130.
mean of equivalent minutes at 43°C was 125*40 for the whole treatment. There was no correlation between TED and intensity of histological alterations caused by hyperthermia. 4. Discussion Our investigations showed that local microwave hyperthermia does not cause any significant tumour necrosis in prostatic cancer. From specimens taken from patients
Figure 5. Macrophages laden with haemosiderin (arrows) inside prostatic glands as residuals of previous bleeding. H&E, X 130.
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
W. L. Strohmaier et al.
t:ipiure 6
Vital prostatic cancer cells without definite signs of turnour cell necrosis after hyperthernmia treatment. H&E, ~ 9 8 .
undergoing radical prostatectomy one can conclude that this is not due to the prostate failing to he heated equally throughout: the whole organ showed the same alterations as oedema. tiyperaemia, haemorrhage and inflammation. Exactly the same findings were reported in dogs with normal prostates using the same equipment and temperatures (Leib et al. 1986). In this study temperature measurements taken in the prostatic urethra and at three different points in the prostatic gland itself showed no significant differences, this being another indication that measurements in the prostatic urethra are representative. This indicates that shrinkage of prostatic cancer mass after local hyperthermia described in earlier studies (Servadio and L,eib 1984, Servadio er al. 1986, Szmigielski et al. 1988) cannot be explained by histologically proven tumour cell destruction. This is supported by the fact that the shrinkage of the prostate can also be found after hyperthermia treatment in benign hyperplasia of the pros,tate (Servadio et al. 1986). Thus hyperthermia must not be regarded as a monotherapy for carcinoma of the prostate. On the other hand hyperthermia induces a distinct hyperaemia of the prostate. This may be helpful in increasing the concentration of cytostatic or hormonal agents in the target tissue. In a small number of patients with recurrent rectal cancer the combination of intraarterial chemotherapy with hypetihermia seems to be superior to intra-arterial chemotherapy alone (Estes et al. 1986). Furthermore one has to consider the chemosensitizing effect of hyperthermia, as could be demonstrated in several experimental and clinical studies for different tumours (Nagaoka et al. 1987, Starace et al. 1987, Shang Wang et al. 1987). Thus it seems logical also to develop integrated treatment modalities with hyperthermia for the therapy of prostatic cancer. Studies on local hyperthermia combined with cytostatic microsphere carcinoma infusion (CMCI), as used for bladder cancer (Fluchter et LIL. 1988) and liver tumours (Akuta et al. 1987) are in progress.
Acknowledgement We thank Mr Martin Bauschert for excellent technical assistance
Hyperthermia in prostatic cancer
33
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
References AKUTA,K., HIRAOKA,M., Jo, S . , MA, F., NISHIMURA, Y., TAKAHASHI, M., ABE, M., MALMQVIST, M., LINDBOM, L. O., and LINDBLOM, R., 1987, Regional hyperthermia combined with blockade of the hepatic arterial blood flow by degradable starch microspheres in pigs. International Journal of Radiation Oncology, Biology, Physics, 13, 239-242. BICHLER, K. -H., 1988, Local hyperthermia for treatment of diseases of the prostate. Abstract, 26th World Congress of the International College of Surgeons, Milan, 3-9 July. W . L., FLUCHTER,S . H., and LEV, A . , 1988, BICHLER,K . - H . , STROHMAIER, Mikrowellenhyperthermie bei chronischer Prostatitis und Prostatopathie. Niere Blase Prostata, 13, 6-10. ESTES,N. C., MORPHIS,J. G., HORNBACK, N. B., and JEWELL,W. R., 1986, Intraarterial chemotherapy and hyperthermia for pain control in patients with recurrent rectal cancer. American Journal of Surgery, 152, 597-600. FLUCHTER, S . H., BICHLER,K. -H., LABERKE, H. G., and WILBERT,D. M., 1988, Neoadjuvant local treatment of locoregional advanced bladder cancer. Regional Cancer Treatment, 1,50-54. LEIB,Z., ROTHEM,A,, LEV, A., and SERVADIO, C., 1986, Histopathological observations in the canine prostate treated by local microwave hyperthermia. 7he Prostate, 7, 93-102. J., SIEGEL,Y., and LEV, A , , 1987, Local hyperthermia of the prostate LINDNER, A,, GOLOMB, gland for the treatment of benign prostatic hypertrophy and urinary retention. British Journal of Urology, 60, 567-571. MENDECKI, J., FRIEDENTHAL, E., BOTSTEIN, C., PAGLIONE, R., and STERZER, F., 1980, Microwave applicators for localized hyperthermia of cancer of the prostate. International Journal of Radiation Oncology, Biology, Physics, 6 , 1583-1588. NAGAOKA, S . , KAWAWSAKI, S . , KARINO,Y., HIRAKI, Y ., and NAKANISHI, T . , 1987, In vivo effects of hyperthermia on the cellular uptake of adriamycin. Journal of Radiation Research, 28, 262-267. SAPARETO, S. A,, and DEWEY,W. C., 1984, Thermal dose determination in cancer therapy. International Journal of Radiation Oncology, Biology, Physics, 6, 1583- 1588. SERVADIO, C., and LEIB,Z . , 1984, Hyperthermia in the treatment of prostate cancer. Zhe Prostate, 5, 205-21 1 . SERVADIO, C., LEIB,Z., and LEV,A , , 1986, Further observations on the use of local hyperthermia for the treatment of diseases of the prostate. European Urology, 12, 38-40. SHANG WANG,B., LUMANGLAS, A. L., SILVA,J., RUSZALA-MALLON, V . , and DURR,F . E., 1987, Effect of hyperthermia on the sensitivity of human colon carcinoma cells to mitoxantrone. Cancer Treatment Reports, 71, 83 1-836. STARACE, G., BADAROCCO, G., BERTUZZI,A , , GANDOLFI, A,, GRECO,C . , TOTARO.M. D., VITELLI,R., and ZUPI, G., 1987, Kinetic and survival response of the M14 cell line to lonidamine associated with adriamycin or hyperthermia. Journal of Cancer Research and Clinical Oncology, 113, 451-458. STROHMAIER, W. L., BICHLER, K. H., KIEFER,M . , and LEV,A,, 1988, Mikrowellenhyperthermie bei chronischer Prostatitis bzw . Prostatopathie-Vorlaufige Ergebnisse. Verhandlungsberichte. Deutsche Gesellschafr f i r Urologie, 39, 527-529. SZMIGIELSKI, S . , ZIELINSKI,H., STAWARZ,B., GIL, J . , SOBCZYNSKI, J., SOKOLSKA, G., JELJASZEWICZ, J., and PULVERER, G., 1988, Local microwave hyperthermia in treatment of advanced prostatic adenocarcinoma. ffrological Research, 16, 1-7. YERUSHALMI, A,, SERVADIO, C., LEIB, Z., FISHELOVITZ, Y., ROKOWSKY, E., and STEIN,J. A., 1982, Local hyperthermia for treatment of carcinoma of the prostate: a preliminary report. The Prostate, 3, 623-630.
1991, VOL. 7,
NO.
1, 27-33
Histological effects of local microwave hyperthermia in prostatic cancer W. L. STROHMAIER-tt, K.-H. BICHLERT, A. BOCKINGP and ST. H. FLUCHTER~ ?Department of Urology, University of Tubingen, FRG §Department of Pathology, RWTH Aachen, FRG
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
(Received 10 March I989;jnal version received 2 April 1990; accepted 6 April 1990) Recent investigationshave shown that hyperthermia can reduce the volume of the prostate and improve local symptoms in patients with carcinoma of the prostate. Histological examinations of the effect of hyperthermia on prostatic cancer tissue, however, have not been performed systematically until now. Thus, we initiated a study to investigate the effects of heat on prostatic cancer as a prerequisite for further clinical trials on hyperthermia as treatment for prostatic cancer. Twenty patients with untreated prostatic cancer underwent local hypthermia (915 MHz), each receiving four sessions of 60 min each. The intraprostatic temperature was 42-43 "C. Histological specimens of the prostate were taken before the treatment and 1-2 weeks after the last hyperthermia session. Hyperthermia produced hyperaemic alterations of the prostatic stroma and a diffuse oedema with interstitial lymphoplasmacellular infiltration. Definite signs of tumour cell necrosis, however, could not be seen in any of the patients. Hence the shrinkage of prostatic tumours described earlier cannot be explained by histologically proven tumour cell destruction. Thus hyperthermia is not adequate as a single treatment for prostatic cancer. Hyperthermia may, however, be useful as part of integrated therapy regimens together with cytostatic or hormonal agents and radiotherapy because of hyperaemic, chemo- and radiosensitizing effects. Key words: Prostatic cancer, histology, hyperthermia.
1. Introduction Several investigations have demonstrated the efficacy of hyperthermia in different malignant tumours. For a long time hyperthermia of the prostate was problematic because of the anatomical situation of this organ. Difficulties with thermometry in particular prevented a systematic application of hyperthermia in prostatic cancer. Some years ago Yerushalmi et al. (1982) and Servadio and Leib (1984) first reported on hyperthermia treatment in prostatic cancer patients, These results were promising: hyperthermia induced a shrinkage of the prostatic tumour volume, urinary flow rate and residual urine were improved and local complaints could be mitigated. Szmigielski et al. (1988) described a response rate of 50% in patients with advanced carcinoma of the prostate after local prostatic hyperthermia. In two patients a disappearance of bone metastases was noted. The functioning of hyperthermia in prostatic cancer, however, has not been elucidated so far. Histological examinations on the effect of hyperthermia on prostatic cancer tissue in particular have not been performed systematically. To investigate these effects the following study was performed.
2. Materials and methods Twenty patients with newly diagnosed prostatic cancer (adenocarcinoma) of different stages (T 2-4, N 0-2, M 0-1, G 1-3, UICC classification 1987, Table 1) were treated with local (transrectal) hyperthermia prior to conventional cancer therapy. The diagnosis $Address correspondence to: Dr med. W. L. Strohmaier, Department of Urology, University of Tubingen, Calwerstr. 7, D-7400 Tiibingen, FRG. 0256-6736191 $3.00 01991 Taylor & Francij Ltd
W. L. Strohmaier et al.
28
Table 1. Staging and grading in 20 patients with histologically proven prostatic cancer treated by local microwave hyperthermia (UICC classification 1987) Non-metastatic (n= 8) Metastatic (n= 12) T2
T3
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
T4
T2
G2
(n=l)
(n=2) (n=l
T3
(n=4)
(n=l)
T4
G2 G3 G3
G1
(n=l)
G2 G2 G2 G2
(n=3) (n=6) (n=l)
was established by transperineal punch biopsy and histological examination of the specimens. For staging of the tumoars transrectal ultrasound, abdominal/pelvic computed tomography (CT) and nuclear bone scans were performed. Informed consent to hyperthermia treatment and biopsies was obtained from all patients. Patients underwent four hyperthermia sessions of 60 min each. Sessions were given twice a week. Anaesthesia or seda.tion was not required. The intraprostatic temperature of 42-43°C was reached within the first 10 min of the treatment. For hyperthermia treatments the Prostathermer (Biodan Medical Systems Ltd, Rehovot, Israel) was used. This equipment consists of a 915 M:Hz power source (maximum energy 100 W) connected to a special applicator. The applicator, containing a skirt-type quarter wavelength dipole antenna, was inserted into the rectum and directed towards the prostate. A radiofrequency locator part integrated into the urethral catheter allows for exact alignment of the applicator opposite to the prostate. A special clamp attached to the applicator allows for a constant position of the applicator during the treatment. Temperature in the prostatic urethra was monitored using a special balloon catheter containing three copper-constantan thermocouples. The interval between the balloon and the first thermocouple was 2 cm, corresponding to the distance between bladder neck and prostatic urethra. The catheter was inserted after urethral instillation of a lubricant containing lidocain 2 % (Instillagel, Farco Pharma Cologne, FRG) the balloon being positioned at the bladder neck and thus the temperature probes within the prostatic urethra (Figure 1). Animal experiments with dogs using the same equipment have shown that temperature measurements within the prostatic urethra are representative for the whole prostate as the prostatic urethra is in the ventral third of the prostate (Leib et al. 1986). In this study temperatures were measured in the prostatic urethra and at three different sites in the prostatic gland. The antenna’s in vivo heat profiles showed that a volume of 20-60 cm3 could homogeneously be heated to the desired temperature. The histological examination of the canine prostates revealed no differences in hyperthermic effects between different areas of the prostate. Heat mapping phantom and animal experiments with an applicator of the same properties have also demonstrated suitability for sufficient heating of the prostate (Mendecki et al. 1980). Special devices for cooling the rectal wall (water circulation) and for controlling the temperature in the rectum (copper--constantan thermocouples) were included. Cooling the rectal wall shifts the peak temperature towards the prostate, thus preventing damage of the rectal wall (Servadio and Leih 1984, Lindner et ul. 1987, Bichler 1988, Bichler ef ul. 1988, Strohmaier et al. 1988). The thermal equivalent dose (TED) is calculated by the Prostathermer for each treatment based on the assumptions of Sapareto and Dewey (1984). For example, a TED of 1800 is equivalent to heating at 43°C for 30 min. Profiles of the power delivered by the generator and the temperatures of the rectum and the prostatic urethra were registered continuously during the treatment. Following treatmt:nt a print-out of these profiles may be obtained (Figure 2).
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
Hyperthermia in prostatic cancer
29
Figure 1 . Position of the applicator (A) and the thermocouples in the prostatic urethra (P) and the rectum (R) during the treatment.
To study the effects of local hyperthermia on prostatic cancer tissue, histological specimens were taken by punch biopsy before the treatment. One to 2 weeks after the last hyperthermia session histological specimens were obtained by radical prostatectomy in patients with non-metastatic T2-T3 tumours. The remaining patients underwent punch biopsy or, in case of subvesical obstruction, transurethral resection. Tissue specimens were fixed in formalin, embedded in paraffin and sections stained with haematoxylin and eosin (H&E).
3. Results The same histological effects of hyperthermia could be detected in each patient. The prostatic stroma showed a distinct oedema and a diffuse lymphoplasmacellular infiltration as an indication of interstitial inflammation (Figure 3). Near the capsule in particular, hyperaemic capillary blood vessels and bleeding into the interstitium could be found (Figure 4).In the centre of the prostatic glands macrophages laden with haemosiderin were observed as signs of previous bleeding (Figure 5). Furthermore, damaged blood vessels showed a swelling of the wall. In some patients groups of necrotic prostatic glands were seen. The cytoplasm of some tumour cells demonstrated a slight vacuolization, which was, however, also found before hyperthermia. Definite signs of tumour cell necrosis could not be observed in any of the patients (Figure 6). There was no difference between the histological appearance regarding tumour size, location within the prostate or tumour grade. As could best be evaluated from the radical prostatectomy specimens in which the whole organ could be examined, hyperthermia effects were the same in the whole prostate regardless of the distance from the microwave applicator. The mean thermal equivalent dose (TED) was 1868 &610 equivalent seconds at 43°C per hyperthermia session (range 925-2730). As the patients underwent four sessions the
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
30
.'U L. Strohmaier
T
I
N
E
et al.
i i n
minute;)
3gure 2 . Profiles of the power delivered by the generator and the temperatures of the rectum and the prostatic urethra as reconied during a hyperthermia treatment of a patient with prostatic cancer.
Figure 3. Oedema of' the stroma of the prostate with lymphoplasmacellular infiltration indicating interslitial inflammation (arrows). H&E, X 98.
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
Hyperthermia in prostatic cancer
Figure 4. Capillary blood vessels with distinct hyperemia after hyperthermia (arrows). H&E,
31
X 130.
mean of equivalent minutes at 43°C was 125*40 for the whole treatment. There was no correlation between TED and intensity of histological alterations caused by hyperthermia. 4. Discussion Our investigations showed that local microwave hyperthermia does not cause any significant tumour necrosis in prostatic cancer. From specimens taken from patients
Figure 5. Macrophages laden with haemosiderin (arrows) inside prostatic glands as residuals of previous bleeding. H&E, X 130.
Int J Hyperthermia Downloaded from informahealthcare.com by Mcgill University on 02/16/15 For personal use only.
W. L. Strohmaier et al.
t:ipiure 6
Vital prostatic cancer cells without definite signs of turnour cell necrosis after hyperthernmia treatment. H&E, ~ 9 8 .
undergoing radical prostatectomy one can conclude that this is not due to the prostate failing to he heated equally throughout: the whole organ showed the same alterations as oedema. tiyperaemia, haemorrhage and inflammation. Exactly the same findings were reported in dogs with normal prostates using the same equipment and temperatures (Leib et al. 1986). In this study temperature measurements taken in the prostatic urethra and at three different points in the prostatic gland itself showed no significant differences, this being another indication that measurements in the prostatic urethra are representative. This indicates that shrinkage of prostatic cancer mass after local hyperthermia described in earlier studies (Servadio and L,eib 1984, Servadio er al. 1986, Szmigielski et al. 1988) cannot be explained by histologically proven tumour cell destruction. This is supported by the fact that the shrinkage of the prostate can also be found after hyperthermia treatment in benign hyperplasia of the pros,tate (Servadio et al. 1986). Thus hyperthermia must not be regarded as a monotherapy for carcinoma of the prostate. On the other hand hyperthermia induces a distinct hyperaemia of the prostate. This may be helpful in increasing the concentration of cytostatic or hormonal agents in the target tissue. In a small number of patients with recurrent rectal cancer the combination of intraarterial chemotherapy with hypetihermia seems to be superior to intra-arterial chemotherapy alone (Estes et al. 1986). Furthermore one has to consider the chemosensitizing effect of hyperthermia, as could be demonstrated in several experimental and clinical studies for different tumours (Nagaoka et al. 1987, Starace et al. 1987, Shang Wang et al. 1987). Thus it seems logical also to develop integrated treatment modalities with hyperthermia for the therapy of prostatic cancer. Studies on local hyperthermia combined with cytostatic microsphere carcinoma infusion (CMCI), as used for bladder cancer (Fluchter et LIL. 1988) and liver tumours (Akuta et al. 1987) are in progress.
Acknowledgement We thank Mr Martin Bauschert for excellent technical assistance
Hyperthermia in prostatic cancer
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