Does transurethral microwave thermotherapy have a different effect on prostate cancer than on benign or hyperplastic tissue?

ADULT UROLOGY

DOES TRANSURETHRAL MICROWAVE THERMOTHERAPY HAVE A DIFFERENT EFFECT ON PROSTATE CANCER THAN ON BENIGN OR HYPERPLASTIC TISSUE? ANIS A. KHAIR, ANNA PACELLI, KENNETH A. ICZKOWSKI, LIANG CHENG, FEDERICO A. CORICA, THAYNE R. LARSON, ALBERTO CORICA, AND DAVID G. BOSTWICK

ABSTRACT Objectives. Transurethral microwave thermotherapy is useful for the treatment of benign prostatic hyperplasia, but its effect on cancer is not documented. We analyzed the pathologic changes occurring after microwave thermotherapy in whole mount radical prostatectomy specimens from patients with cancer. Methods. Nine patients scheduled for radical prostatectomy for clinically localized prostate cancer were treated with transurethral microwave thermotherapy (Urologix Targis System). Patients ranged in age from 64 to 72 years (mean 68). Seven patients underwent prostatectomy 4 to 90 hours after thermotherapy, and 2 other patients underwent prostatectomy 12 months after thermotherapy. Whole mount totally embedded prostates were mapped for necrosis and cancer, and the volume of each was measured by the grid method. Results. Pathologic stages were T2a (n 5 4), T2b (n 5 4), and T3b (n 5 1). The prostates from patients who underwent radical prostatectomy within 4 to 90 hours of thermotherapy had a mean prostate weight of 47.4 g (range 19.5 to 70.3). Each consistently showed hemorrhagic necrosis and tissue devitalization without significant inflammation. Necrosis involved contiguous areas of benign epithelium, stroma, and cancer without skip areas. The mean volume of necrosis was 8.8 cc (range 1.4 to 17.8), and the mean percentage of the prostate involved by necrosis was 22% (range 3% to 39%). The necrosis was symmetric around the urethra in 6 of 7 cases. Urethral dilation was observed in 3 patients, and the mean maximum radial distance of necrotic tissue was 1.4 cm (range 0.6 to 1.8). Necrotic change was noted in 80% to 100% of the volume of cancer in 4 cases, 40% to 60% in 2 cases, and 5% in 1 case. The prostates from the 2 patients who underwent radical prostatectomy 12 months after thermotherapy had a mean weight of 88 g (55 and 121 g, respectively). Each showed periurethral fibrosis, nonspecific chronic inflammation, and squamous metaplasia of the urothelium. The mean volume of necrosis remaining was 0.2 cc. The mean percentage of the prostate involved by necrosis 1 year after thermotherapy was less than 1%. There was some reabsorption of dead tissue. The mean maximum radial distance of the necrotic tissue was 0.4 cm (0.2 and 0.7 cm, respectively). The prostatic urethra had viable and partially denuded urothelium in all cases. Conclusions. Microwave thermotherapy is clinically useful for ablation of benign prostate and cancer contiguous to the urethra, resulting in hemorrhagic necrosis with minimal damage to the urethra. There was no apparent differential morphologic sensitivity of benign prostatic tissue, hyperplastic tissue, or cancer to thermotherapy. UROLOGY 54: 67–72, 1999. © 1999, Elsevier Science Inc.

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rostate cancer is the second leading cause of cancer death in American men, with an estimated 179,300 new diagnoses and 37,000 deaths

The spouse of T. R. Larson holds stock in Urologix, Inc. From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Urology, Mayo Clinic, Scottsdale, Arizona; and Universidad Nacional de Cuyo, Mendoza, Argentina Reprint requests: 0 Bostwick Laboratories, 6722 Patterson Avenue, Richmond, VA 23226 Submitted: October 26, 1998, accepted (with revisions): January 13, 1999 © 1999, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

in 1998.1 Surgery and radiation therapy are the mainstays of treatment for localized and advanced prostate cancer. Although these treatments are beneficial, they carry significant morbidity and complications.2 Microwave thermotherapy is a minimally invasive procedure that ablates human prostatic tissue.3,4 Microwave hyperthermia was used successfully on dog and human prostates,5 although human clinical trials for benign prostatic hyperplasia did not start until this decade.4 To our knowledge, the effect of thermotherapy 0090-4295/99/$20.00 PII S0090-4295(99)00038-2 67

on prostate cancer has not been studied. The degree to which the tumor burden can be reduced by microwave thermotherapy is an important consideration for the development of minimally invasive surgery. Furthermore, the acute and long-term urethral and periurethral pathologic changes due to microwave thermotherapy for benign hyperplasia have not been described. In this report, we evaluate specimens from patients with cancer and benign prostatic hyperplasia who have undergone prostatectomy after thermotherapy. MATERIAL AND METHODS PATIENTS Patients were included in the study according to a protocol approved by the Institutional Review Board for benign prostatic hyperplasia.6 Seven patients were from Universidad Nacional de Cuyo, Mendoza, Argentina, and 2 patients were from Mayo Clinic, Scottsdale, Arizona. All had biopsy-proven clinically localized prostatic adenocarcinoma. Clinical evaluation included history, family history, digital rectal examination, pre-thermotherapy prostatic-specific antigen (PSA) concentration, urodynamic studies, and transrectal ultrasound. The postoperative PSA concentration was determined within 120 days of radical prostatectomy. Five patients received androgen deprivation therapy within 14 months before thermotherapy that included leuprolide and bicalutamide.

MICROWAVE THERMAL TREATMENT Nine patients scheduled for radical prostatectomy underwent thermotherapy before surgery using a transurethral microwave antenna by Urologix Targis System (Minneapolis, Minn). The thermal catheter contained a 2.8 or 3.5-cm-long microwave antenna located within the prostatic urethra just distal to a urethral catheter-positioning balloon. In addition, the catheter contained a fiberoptic temperature sensor and circulating water along its periphery to maintain the urethral temperature at 45°C or higher. The catheter was attached to a control box that contained the microwave power generator (915 MHz), the coolant system, and a control and data acquisition system.7 Before thermotherapy, each patient was given benzodiazepine every 12 hours the day before the procedure and an opiate analgesic perioperatively. After completion of the procedure, patients were given analgesics every 12 hours as needed. Each patient underwent one session of thermotherapy for 1 hour. The urethral temperature during thermotherapy was 45°C or higher, as previously described,8 and the intraprostatic energy varied from 35 to 45 W. The coolant temperature was in the range of 8.5 to 8.9°C. The water coolant flowed at a rate of 120 mL/min. The temperature of tissue surrounding the prostate was monitored by an endorectal inflatable balloon containing five heat sensors aligned along the length of the prostate. The temperature remained below 41.5°C at all sites. In the 7 patients who underwent radical prostatectomy within 4 to 90 hours after thermotherapy, a catheter was kept in the urethra until prostatectomy and was replaced at surgery. In the 2 patients who underwent radical prostatectomy 12 months after thermotherapy, the catheter was removed within 3 days of treatment.

PATHOLOGIC SPECIMENS Seven patients underwent radical prostatectomy 4 to 90 hours (mean 24.8) after thermotherapy. Two patients under68

FIGURE 1. Representative section of a whole mount specimen of prostate showing thermotherapy-induced necrosis (dots) involving prostate cancer (gray) (case 5) 17 hours after thermotherapy. © Mayo Foundation, used with permission.

went radical prostatectomy 12 months after thermotherapy. All 9 patients underwent bilateral pelvic lymphadenectomy. Lymph nodes were evaluated by frozen section at the time of surgery. Each prostate was weighed, measured in three dimensions, and inked. The apex and the base were amputated at a thickness of 4 to 5 mm and serially sectioned at 3 mm. The remaining prostate was serially sectioned at 4 to 5-mm intervals by a knife perpendicular to the long axis of the gland from the apex of the prostate to the tip of the seminal vesicles. Whole mount sections were prepared and stained routinely with hematoxylin and eosin. Each prostate was mapped for necrosis and cancer by four authors (D.G.B., A.P., K.A.I., and L.C.) (Fig. 1). We considered cells with intact cell membranes and no nuclear dissolution as viable. The maximum radial distance from the urethra to the viable-necrotic tissue border was measured. The volume of necrosis was measured by the grid method.9 The prostate volume in the 7 patients who underwent radical prostatectomy 4 to 90 hours after thermotherapy was determined by transrectal ultrasound. In the 2 patients who underwent prostatectomy 12 months after thermotherapy, volume was calculated using a previously established method.10

RESULTS Patients ranged in age from 64 to 72 years (mean 68). The mean preoperative PSA was 9.8 ng/mL (range 4.3 to 20.2) (Table I). Gleason scores varied from 5 to 8 (mean 6.5). Pathologic stages were pT2a (4 patients), pT2b (4 patients), and pT3b (1 patient); none had lymph node involvement or distant metastasis. Prostatoseminovesiculectomy specimens had a mean weight of 56.6 g (range 19.5 to 121.0) and volume of 53.4 mm3 (range 20.5 to 124.7) (Table II). In the 7 patients undergoing prostatectomy 4 to 90 hours after thermotherapy, microscopic findings included coagulative necrosis, stromal hemorrhage, platelet-fibrin thrombi, and edema with mild to moderate acute and chronic inflammation. Variable amounts of tissue repair were present, including granulation tissue and fibroblast proliferation. Extraprostatic tissue was invariably normal. The prostatic urethra was dilated in 3 patients (Table II), and the urothelium showed partial denudation. Necrosis was UROLOGY 54 (1), 1999

TABLE I. Clinical findings in 9 patients with cancer treated with transurethral microwave thermotherapy and radical prostatectomy

Case No.

Age (yr)

PreTransurethral Microwave Thermotherapy PSA (ng/mL)

1 2 3 4 5 6 7 8 9

65 64 69 64 69 72 68 67 69

8.2 8.2 20.2 7.7 4.3 8.8 5.1 16.3 8.4

PostTransurethral Microwave Thermotherapy PSA (ng/mL) 0.08 0.80 0.01 0.16 0.60 0.98 0.98 11.2 9.0

Gleason Score of Cancer on Biopsy Specimens

Androgen Deprivation Therapy

Duration of Hormonal Therapy (mo)

1 1 1 1 1 1 1 1 1

None Yes Yes None Yes Yes Yes None None

None 2 14 None 1 4 5 None None

2 3 3 3 3 3 3 3 3

3 3 3 4 4 4 3 4 2

Interval from Transurethral Microwave Thermotherapy to Radical Prostatectomy 4 15 15 16 17 17 90 12 12

hr hr hr hr hr hr hr mo mo

KEY: No. 5 number; PSA 5 prostate-specific antigen.

semicircular and symmetrical around both sides of urethra, involving mainly the transition zone. A sharp (0.5-mm) line of demarcation separated necrotic and viable tissue. The area of necrosis and hemorrhage had a mean volume of 8.8 cc (range 1.4 to 17.8) and involved a mean 22% (range 3% to 39%) of prostate volume. The mean maximum radial distance of necrotic tissue measured from the urethra was 1.4 cm (range 0.6 to 1.8) (Fig. 2). Microscopically, necrosis involved stroma, non-neoplastic acini, and cancer acini. Non-neoplastic acini showed detachment and sloughing in all 7 cases (Fig. 3), cystic dilation in 2 cases, and focal squamous metaplasia in 1 case. Cancer acini showed varying degrees of change, including acinar detachment and intra-acinar epithelial sloughing (Fig. 4). Often, only shadows of acinar lumens could be recognized. In areas of necrosis, the cancer cells had deeply eosinophilic cytoplasm, nuclear karyolysis, and pyknosis. The amount of ablated cancer depended heavily on the prostate size, total cancer volume, and percentage of cancer volume located in the transition zone. Outside of the area of necrosis, cancer was present in 6 of 7 cases, including 1 case with seminal vesicle invasion. In the 5 of these 7 patients who were receiving preoperative androgen deprivation therapy, intact cancer showed typical nuclear pyknosis and cytoplasmic vacuolization. In the 2 patients whose prostates were removed 12 months after thermotherapy, the mean volume of necrosis was 0.2 cc. The mean maximum radial distance of necrosis was 0.45 cm (0.2 and 0.7 cm, respectively) (Fig. 2). The mean percentage of prostate involved by necrosis was less than 1%. The necrotic zone consisted only of periurethral fibrosis with no residual cancer. The urethra was dilated, with partial urothelial denudation and urethritis glandularis. Outside the necrotic zone, tumor was still evident in both cases. UROLOGY 54 (1), 1999

FIGURE 2. Three-dimensional diagram of the prostate showing extent of necrosis in 9 patients after microwave thermotherapy. © Mayo Foundation, used with permission.

In 3 of 9 cases, up to 20% of cancer cells in the necrotic zone were viable; these cases had some acini, with viable cells next to necrotic cells. The proportion of cancer ablated was 80% to 100% in 4 cases, 40% to 60% in 2 cases, and 5% in 1 case (Table II). Of 9 patients, 8 had Stage T2a and T2b and Gleason score between 2 1 3 and 3 1 4, and the percentage of cancer ablated was 80% to 100%. One patient had Stage T3b and Gleason score 4 1 3, and the percentage of cancer ablated was 5% (Tables I and II). COMMENT We analyzed the effect of microwave thermotherapy on prostate cancer and found that there was a variable degree of destruction that depended on the amount and anatomic location of cancer 69

FIGURE 3. (A) Benign prostatic tissue with coagulation necrosis involving the stroma and the acinar epithelium. Original magnification 3160. (B) Higher power image showing sloughing of the acinar epithelium. Original magnification 3400.

within the prostate and the prostate size. About 80% of prostate cancers originate in the peripheral zone, an area that is usually beyond the reach of microwave energy, so only in a few cases is most or all of the cancer destroyed. Extension of microwave energy deep into the peripheral zone increases the risk of destruction of extraprostatic tissue, including nerves and vessels. In our 9 patients, the urothelium and the extraprostatic tissue were not damaged by thermotherapy. The urethral dilation seen after thermotherapy is likely due to reabsorption of hemorrhagic necrosis. Transurethral microwave thermotherapy is currently approved for treatment of bladder outlet obstruction due to benign prostatic hyperplasia. The heat produced by the microwave antenna is deposited in and restricted to the prostate.11,12 The advantages of the procedure are its simplicity, safety, lack of anesthesia, and completion in a single 1-hour session in an outpatient setting.13 Urethral 70

FIGURE 4. Prostatic adenocarcinoma. (A, B) Thermotherapy effects on prostate cancer showing necrosis, glandular detachment, and nuclear pyknosis. (C) Area of viable prostate cancer not affected by thermotherapy.

trauma is reportedly less than that caused by operative intervention.8,14 Transurethral microwave thermotherapy is efficient in producing significant improvement in peak urinary flow rates15,16 and Madsen symptom score.17 Thermotherapy does UROLOGY 54 (1), 1999

90 60 90 5 40 100 80 NA NA Present Present Present Present Present Absent Present Present Present 20 5 0 0 10 0 0 No cancer noted No cancer noted Absent Absent Present Present Absent Present Absent Present Present 1.5 1.7 1.2 0.6 1.3 1.6 1.8 0.2 0.7 22 24 17 3 41 10 39 ,1 ,1 12.6 10.4 3.4 1.4 8.5 7.7 17.8 0.2 0.2 56.8 44.2 20.5 50.0 20.6 78.5 45.5 40.5 124.7 59.1 47.4 24.5 51.4 19.5 70.3 60 55 121 3.5 3.2 2.5 4.0 2.5 4.5 3.5 3.0 5.0 3 3 3 3 3 3 3 3 3 3.5 4.5 3.0 4.5 3.0 4.5 4.5 3.0 4.3 3 3 3 3 3 3 3 3 3 4.5 5.0 4.0 5.5 4.0 5.0 5.5 4.5 5.8 1 2 3 4 5 6 7 8 9

KEY: No. 5 number; NA 5 not available since no viable or necrotic cancer is present in the necrotic zone.

6 7 8 7 7 7 7 5 5 5 5 5 5 5 5 5 5 5 3 3 4 3 3 4 3 2 2 1 1 1 1 1 1 1 1 1 3 4 4 4 4 3 4 3 3

Urethral Dilation Gleason Score Pathologic Stage (TNM) Prostate Volume (cc) Case No.

Prostate Dimensions (cm)

Prostate Weight (g)

T2a T2b T2a T3b T2b T2a T2a T2b T2b

Estimated Total Cancer Ablated (%) Viable Cancer Outside Necrotic Zone Viable Cancer Cells in Necrotic Zone (%) Maximum Radial Distance of Necrosis (cm) Prostate Involved by Necrosis (%) Volume of Necrosis/ Hemorrhage (cc)

TABLE II. Histologic findings in 9 patients with cancer treated with transurethral microwave thermotherapy and radical prostatectomy

UROLOGY 54 (1), 1999

not have the morbidity or the short- and long-term complications of operative intervention. It does not cause retrograde ejaculation and minimizes the risk of post-treatment erectile dysfunction. The incidence of sexual dysfunction after transurethral microwave thermotherapy is low, so this form of therapy is attractive for young men in whom sexual function and antegrade ejaculation are important.18 It may be useful to treat patients with benign prostatic hyperplasia who are poor surgical candidates or who fear operative intervention and its complications.19,20 Our results indicate that microwave thermotherapy may also be of value for palliation of local symptoms or treatment of select patients with prostatic adenocarcinoma, particularly those with predominantly periurethral or transition zone cancer. The prostatectomy specimens of the 2 patients who underwent thermotherapy 12 months before surgery contained residual or recurrent cancer that was identical to that in their pretreatment biopsies. There was no significant change in Gleason scores with therapy in either case. The malignant acini were infiltrative, and many cells displayed nuclear enlargement and prominent nucleoli. There was prominent periurethral fibrosis, indicating resolved thermal injury. In contrast, immediately after thermotherapy (within 90 hours), the cancer often showed varying degrees of thermotherapyinduced changes, including acinar detachment and intra-acinar epithelial sloughing. The benign prostate showed necrosis, stromal hemorrhage, and granulation tissue. These findings suggest that thermotherapy induces long-term ablation of normal prostatic tissue in the periurethral region. The effect of thermotherapy on the peripheral zone tissue, including prostate cancer, was limited, because it did not reach this area. Future studies should be directed at the feasibility of thermotherapy for the treatment of prostate cancer. Our study is limited by the variable use of androgen deprivation therapy before thermotherapy (5 of 9 patients). We also had a limited number of patients, and the range of intervals between thermotherapy and radical prostatectomy was narrow. CONCLUSIONS Transurethral microwave thermotherapy is effective in destroying benign prostatic tissue, hyperplastic tissue, and cancer. It ablates periurethral parenchyma with minimal damage to the urethra, and benign tissue and cancer are uniformly affected by thermotherapy. Where there was cancer, it was destroyed by thermotherapy. There is no morphologically identifiable differential tissue sensitivity or resistance to thermal destruction in cancer when compared with normal or 71

hyperplastic tissue. Thermotherapy may be palliative for debulking cancer and relieving obstruction caused by benign hyperplasia and cancer in select patients. ACKNOWLEDGMENT. To Ms. Roxann M. Neumann for help with photographs and coordinating data collection. REFERENCES 1. Landis SH, Murray T, Bolden S, et al: Cancer Statistics, 1999. CA Cancer J Clin 48: 8 –31, 1999. 2. Doll HA, Black NA, McPhearson K, et al: Mortality, morbidity and complications following transurethral resection of the prostate for benign prostatic hypertrophy. J Urol 147: 1566 –1573, 1992. 3. Devonec M, Berger N, and Perrin P: Transurethral microwave heating of prostate or, from hyperthermia to thermotherapy. J Endourol 5: 129 –135, 1991. 4. Schullman CC, and van den Bosche M: Hyperthermia and thermotherapy of benign prostatic hyperplasia: a critical review. Eur Urol 23(suppl): 53–59, 1993. 5. Bostwick DG, and Larson TR: Transurethral microwave thermal therapy: pathologic findings in the canine prostate. Prostate 26: 116 –122, 1995. 6. Sapozink MD, Boyd SD, Astrahan MA, et al: Transurethral hyperthermia for benign prostatic hyperplasia: preliminary clinical results. J Urol 143: 944 –950, 1990. 7. Larson TR, and Collins JM: An accurate technique for detailed prostatic interstitial temperature mapping in patients receiving microwave thermal treatment. J Endourol 9: 339 – 347, 1995. 8. Larson TR, Bostwick DG, and Corica A: Temperature correlated histopathological changes following microwave thermoablation of obstructive tissue in patients with benign prostatic hyperplasia. Urology 47: 463– 469, 1996. 9. Humphrey PA, and Vollmer TR: Intraglandular tumor extent and prognosis in prostatic carcinoma: application of a grid method to prostatectomy specimens. Hum Pathol 21: 799 – 804, 1990.

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10. Bostwick DG, and Eble JN: Urologic Surgical Pathology. Philadelphia, Mosby, 1997, p 354. 11. Baert L, Ameye F, Pike MC, et al: Transurethral hyperthermia for benign prostatic hyperplasia patients with retention. J Urol 147: 1558 –1561, 1992. 12. Larson TR, Collins JM, and Corica A: Detailed interstitial tissue mapping during treatment with a novel transurethral microwave thermoablation system in patients with benign prostatic hyperplasia. J Urol 159: 258 –264, 1998. 13. Nativ O, Mor Y, Leibovitch I, et al: Transurethral hyperthermia for relieving obstructive voiding symptoms in patients with hormone refractory prostate cancer. Isr J Med 33: 182–185, 1997. 14. Marteinson VT, and Due J: Transurethral microwave thermotherapy for uncomplicated benign prostatic hyperplasia. A prospective study with emphasis on symptomatic improvement and complication. Scand J Urol Nephrol 28: 83–89, 1994. 15. Bdesha AS, Bunce CJ, Kelleher JP, et al: Transurethral microwave treatment for benign prostate hypertrophy: a randomised clinical trial. BMJ 306: 1293–1296, 1993. 16. Larson TR, Blute ML, Bruskewitz RC, et al: A high efficiency microwave thermoablation for the treatment of benign prostatic hyperplasia: results of a randomized, sham controlled prospective double blind multicenter clinical trial. Urology 51: 731–742, 1998. 17. Blute ML, Tomera KM, Hellerstein DK, et al: Transurethral microwave thermotherapy for the management of benign prostatic hyperplasia: results of the United States Prostatron Cooperative Study. J Urol 150: 1591–1596, 1993. 18. Astrahan M, Imanaka K, Jozsef G, et al: Heating characteristics of a helical microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia. Int J Hypertherm 7: 141–155, 1991. 19. Stawarz B, Szmigielski S, Ogrodnik J, et al: A comparison of transurethral and transrectal microwave hyperthermia in poor surgical risk benign prostatic hyperplasia patients. J Urol 146: 353–357, 1991. 20. Astrahan M, Sapozink MD, Cohen D, et al: Microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia. Int J Hypertherm 5: 283–296, 1989.

UROLOGY 54 (1), 1999