The Prostate 1: 279-286 (1980)

Cryotherapy of Prostate Cancer Stefan Loening, Charles Hawtrey, William Bonney, Ambati Narayana, and David A. Culp

Department of Urology, University Hospitals and Clinics, University of lowa, lowa City, Iowa

Cryosurgical destruction of primary adenocarcinoma of the prostate was performed via perineal route in 215 patients during a 12-year period. The average age of the patients was 66 years. The stage of the disease varied from stage B to D. In 74% of the patients, no clinical evidence of tumor was found in the prostatic fossa following cryosurgery. Few patients needed transurethral surgery and none needed repeated transurethral resections for obstructive symptoms. This experience suggests that local destruction of prostatic carcinoma can be achieved with little morbidity and mortality. Herein we discuss the method of cryosurgery, stage and histology of tumor, survival, local recurrence, and complications.

Key words: cryotherapy, prostate cancer

INTRODUCTION

Cryosurgery appears to be another modality of treatment for local destruction of carcinoma. In 1966 Gonder and Soanes introduced the use of transurethral cryosurgery. Primarily, the procedure was used for patients with benign disease [ 1 I. They subsequently published their experience, utilizing the transurethral cryoprobe in 50 prostatic carcinoma patients for local prostatic destruction [2]. Since the bulk of prostatic cancer in large lesions cannot be destroyed transurethrally and the transurethral application of the cryoprobe is a blind procedure, Flocks introduced cryosurgery via the perineal route [3]. With this approach, it was hoped to prevent complications from local prostatic cancer and obviate the need for repeated transurethral resections for obstructive symptoms. The treatment also allowed the permanent destruction of small lesions. Additionally, modification of distant metastases by immunological means was considered a possible beneficial side effect.

MATERIALS AND METHODS

prostate have been treated by cryosurgery via the open perineal route at the University of Iowa from April 1968, to January 1979. The patients ranged in age from 41 to 81 years. The mean age was 66 years at diagnosis of prostatic carcinoma. Most patients presented with symptoms of bladder neck obstruction

Two hundred fifteen patients with histologically proven carcinoma of the

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280 Loening et al

(133, or 62%). Some patients were identified on routine physical examination (43, or 20%), and others had symptoms of bone pain or other evidence of distant metastases (26, or 12.1%).

Stage and Grade Initial assessment of the size and extent of the prostatic cancer followed

the classification of Whitmore and modifications by Prout and Jewett [4, 5 , 61. In addition to routine blood and urine tests, further preoperative evaluations to stage the patients were used and are listed in Table I. Lymphangiography and pelvic node dissection or biopsy were carried out in selected cases. A review of our findings has been reported previously [7]. Using these parameters, there were 4 (1.8%) patients with stage A, 18 (8.4%) with B, and 77 (35.8%) with stage C lesions. One hundred sixteen (54.0%) patients had stage D disease. Where available, histological grade of the primary was determined as follows: Well-differentiated -42/ 190 (22.1'3'0); moderately well-differentiated- 80/190 (42.1%); and poorly differentiated-68/190 (35.8%) (Table 11).

Surgical Technique

are exposed via the classic perineal approach as previously described [3, 8-10]. Under general or spinal anesthesia, the patient is positioned in exaggerated lithotomy position so the pubic arch parallels the operation table. An O'Connor shield is sutured to the anal margin to permit operative rectal palpation and a Lowsley retractor is placed per urethra. A U-shaped curvilinear incision is made around the lateral and superficial margins of the rectum, extending into the ischiorectal fat. Both ischiorectal fossae are developed by blunt finger dissection, the transverse tendon is divided, and index and middle fingers are used to retract the anal sphincter and rectum posteriorly and caudally as scissors are used in incising the superficial transverse perineal muscles. The prominent bulge of the bulbocavernosus muscle is noted anteriorly and

The posterior surface of the prostate, bladder base, and seminal vesicles

TABLE I. Preoperative Evaluation

1. Physical and rectal examination 2. Acid and alkaline phosphatase 3. KUB,IVP 4. Bone scan or survey 5. (Lyrnphangiograrn) 6. (Pelvic lyrnphadenectomy) 7. (Lymph node biopsy) 8. Prostatic biopsy

TABLE 11. Pathologic Grading

Well differentiated Moderately differentiated Poorly differentiated

21.1% 421 190 42.1% 801 190 35.8% 68/190

Cryotherapy of Prostate Cancer 281

retracted with a Young bulb retractor as the central tendon is incised. Dissection is carried superiorly and laterally, perforating the endopelvic fascia just caudal to the genitourinary diaphragm. The previously placed curved Lowsley prostatic retractor then lies medial to the dissecting finger and the open wings of the instrument are palpable through the prostatic mass and the bladder neck.

Following this maneuver the levator ani muscles are visible coursing laterally around the apex of the prostate and the urethra. The dissecting scissors are directed laterally under the levators, which are then incised. Denonvillier's fascia is incised sharply or with electrodissection. Gentle bimanual palpation identifies the apex of the rectal fold as it courses over the prostate. Using downward traction, the rectal muscle fibers are incised over the prostate. Since most patients with stage C and D carcinoma have extensive local neoplastic tissue, infiltration of the rectal muscular coat may be encountered. It may be necessary, then, to cut through tumor tissue with the high-frequency current.

After isolating the seminal vesicles in the operative field with the lateral prostatic vascular lymphatic pedicle, a small incision is made obliquely along the lateral margin of each seminal vesicle and the pointed cryoprobe is inserted into the enveloping perivesicle fascia and freezing commenced on both sides with the Linde CE, unit. The probe's temperature is reduced to - 180" to -190°C. Application of the liquid nitrogen trocal probe varied from 2 to 5 minutes, obtaining complete freeze of the seminal vesicles and portions of the ductus deferens. Following cryodestruction of the seminal vesicles, the prostatic base is frozen usually at extended intervals of 3-5 minutes to ensure confluence of the ice ball with the seminal vesicle segments. The probe is thrust into the interstices of the gland and directed initially laterally and then medially and anteriorly, assuring adequate anterior commissure freezing. The ice ball progresses across the prostatic base before migrating toward the apex. The freezing process can be repeated to assure adequate tissue destruction. The probe may be used on one lateral lobe alternating with the contralateral lobe to assure interdigitation of each ice ball by an interval thawing of 5-10 minutes.

ready removal. The wound is closed in layers about a Penrose drain and an indwelling urethral catheter left in situ for 2 weeks.

RESULTS

surgery within a month or less of their diagnosis of prostatic cancer. The remainder were treated later, ranging up to 10 years prior to institution of cryosurgery. The mean duration between diagnosis and cryosurgery was 9.3 months. The standard deviation was 20.5 months, reflecting this rather wide fluctuation between diagnosis and treatment (Table 111). One hundred thirty-eight (64.2%) patients had no therapy, and 77 (35.8%) had some form of therapy prior to their cryotherapy . Hormonal therapy, including estrogens and orchiectomy, was selected with or without transurethral resection of the prostate. Approximately 12% (26) of the patients had had a previous

At the termination of the freezing, the probe is rewarmed to facilitate its

Of the 215 patients treated with cryosurgery, 121 (56.3%) had their

282 Loening et a1

orchiectomy. Because of large local lesions, bilateral orchiectomy was combined with cryosurgery in 107 (49.8%) of the patients. The remaining 82 patients (38.1%) were not treated initially with orchiectomy.

Complications

Major complications of concern include urethrorectal and urethrocutaneous fistulae. Three urethrorectal fistulae occurred, representing 1.4% of the total patient population. Two fistulae were closed primarily, and one patient required temporary colostomy diversion. Twenty-three (10.7%) urethroperineal-cutaneous fistulae were encountered and closed spontaneously on urethral catheter drainage. Since the surgeon awaits complete cessation of urinary leakage before removing the catheter, patients were left on catheter drainage from 1 week to 3 months with a mean duration of 23 days.

Bladder neck obstruction requiring transurethral resection of the prostate occurred in 15 (7%) instances. Sixteen (7.4%) patients encountered stress-incontinence immediately postoperatively, but in only one instance was the incontinence total.

Four patients died in the postoperative period. Two patients had a pulmonary embolus, one patient developed acute renal failure, and one patient died from disseminated intravascular coagulation. Thus the total surgical mortality was four of 215, or 1.9%.

The immediate complications following cryosurgery are listed in Table IV.

TABLE 111. Pre-Op Time Interval

Mean interval 215 patients 9 months 121 patients I month

3 patients unknown

TABLE IV. Post-Op Complications (Immediate)

Urethro-rectal fistula Urethro-cutaneous fistula Bladder neck obstruction Epididymitis or orchitis Cerebrovascular accident Pulmonary embolus Renal insufficiency Renal insufficiency Dessminated intravascular coagulation Rupture renal pelvis Jaundice Perineal hematoma Gout Wound infection Incontinence Cardiac arrest

3 23 15 7 2

2a l a 1

l a I 1 1 1 3 1 1

“Died

Cryotherapy of Prostate Cancer 283

Three-Month Evaluation An initial assessment of all patients was carried out 3 months following

surgery (Table V). Five patients (2.3%) had bladder neck obstructive symptoms and required a transurethral resection of residual tissue. Of the 14 (6.5%) patients with urinary incontinence, 13 had mild stress-incontinence.

by the surgical procedure, led to problems with bowel control in seven patients. Two patients still had persistent perineal leakage at 3 months, which cleared with curettage and catheter drainage.

In addition to the complications as listed, three patients had developed in the interim neurologic deficits from strokes or bony metastases and one patient developed nausea and vomiting from his renal insufficiency.

Rectal examination after 3 months offered striking remarkable changes in the local prostatic lesion. In 161 of the 215 patients (74.8%) the prostatic fossa .was empty without clinical evidence of residual tumor. At 3 months, the remaining 22 patients (10.2%) had incomplete destruction of the local prostatic lesion. The rectal findings varied from a residual nodule or induration in a seminal vesicle to no discernible change in size. In 32 (14.9%) patients, no 3-month follow-up or rectal examination was listed. Residual lesions tended to increase in size on further follow-up examinations.

There was no significant change in the acid or alkaline phosphatase determinations.

The diagnosis was confirmed histologically in all cases and the results of histologic grading are shown in Table 11. A previous review by Peterson and Milleman of 154 patients revealed 37 patients who had a biopsy of the prostatic fossa following cryoprostatectomy [ 111. Biopsies were performed because a local recurrence was noted or tissue was obtained via a transurethral resection because of symptoms of bladder neck obstruction. Carcinoma was found in 25 of the 37 patients. Cancer was present in 90% of the patients with poorly differentiated tumors but in only 56% of the patients with well-differentiated cancers. Histologic grade correlated well with survival. Seventy-seven percent of patients with well differentiated neoplasms were surviving, whereas 20% with poorly differentiated neoplasms survived.

Patient Survival

1. The end results of absolute survival included 116 patients who were alive, 92 patients who were dead, and three patients lost to follow-up. Only three

Hemorrhoids or perineal irritation, in addition to probable damage caused

The actuarial survival curves related to clinical stage are shown in Figure

TABLE V. Post-Op 3 Months

No symptoms Bladder neck obstruction Bone pain Urinary incontinence Fecal incontinence Urethrocutaneous fistula

126 patients 58.6% 5 patients 2.3%

13 patients 6.0% 14 patients 6.5% 1 patients 2 patients

284 Loening et a1

patients died of causes not related to cancer of the prostate. Tables VI-VIII give further breakdown of patients in stage B, C, and D. The mean survival time for all patients was 33.4 months. There were only four patients with stage A disease; all of these patients are alive and doing well with no evidence for recurrent cancer.

DISCUSSION

Over the last 10 years, perineal cryoprostatectomy for the destruction of local prostatic cancer has been used by us effectively in all stages of adenocarcinoma of the prostate. With experience, we found these procedures mainly applicable for a selected group of patients who either have a large, surgically unresectable lesion or stage D disease where control of the local tumor is desired.

Open perineal cryosurgery is well tolerated: it offers access to the primary lesion and the opportunity for its complete local destruction. Theoretically, the

TABLE VI. Perineal Cryosurgery (Stage B)

Average age Mean survival Orchiectomy Tumor grade 5 Dead: 1 Ca, 1 MI, 1 pulmonary embolus, 2 unknown Alive, no treatment

N = I8 69 41 months 7/18 W 5 , M 9, P 3, Unknown 1

13118

TABLE VII. Perineal Cryosurgery (Stage C)

N = 17 Average age 67.2 Mean survival 39 months Orchiectomy 59177 Tumor grade Patients available for > 12 months evaluation N = 69 Alive, no treatment 33169 Alive, on treatment 14169 Dead 22169

W 21, M 29, P 16, Unknown 1 I

TABLE VIII. Perineal Cryosurgery (Stage D)

Average age Mean survival Orchiectomy Tumor grade Patients available for > 12 months evaluation N = 84 Alive, no treatment Alive, on treatment Dead

N = 116 64.8 29.7 months 671116 W 16, M 42, P 49, Unknown 9

25184 21184 32/84

Cryotherapy of Prostate Cancer 285

freezing process could destroy the periprostatic neoplasm without resorting to extensive dissection and resultant incontinence. The ice ball progression can be controlled visually avoiding rectal spincteric and trigonal injury. Even antenor prostatic tissue can be reached by proper probe placement. Cryosurgery produces tissue death by intracellular dehydration and toxic electrolyte concentrations, crystallizations with secondary membrane rupture, denaturation of proteins, thermal shock, and vascular stasis [12, 131. Hansen and Wanstrup noted edema and necrosis for 1-10 weeks after transurethral cryosurgery [141. The degenerative phase usually changes to a reparative phase between 2 and 3 months after treatment.

Prolonged catheter drainage and curettage of the fistula tract, however, led to closure of the fistula in all patients, but necessitated prolonged hospitalization. In view of the older patient population and the extent of the prostatic cancer, the incidence of operative morbidity and mortality has been low. Because of the minimal risks, the procedure is applicable to cardiopulmonary-impaired patients and to older patients who might not be considered candidates for total prostatectomy .

It is felt that primary site ablation via cryoprostatectomy in patients with stage D disease avoids late urinary incontinence, decreases the incidence of repeated transurethral resection, and avoids late complication such as ureteral obstruction of bladder neck infiltration by the neoplasm. Additionally, modification of the distant metastases by immunological means were considered as possibly beneficial side effects. However, its possible role in stimulating an immunological response is further investigated [15-171.

In a recent review by Bonney et al, the cryosurgery patients had a probability of survival equal to that seen in the total prostatectomy patients of each stage [l8]. Following radical prostatectomy , Boxer reported 5-year survival rates for surgical stages A and B prostatic cancer of 82% 1193. For patients with stage C disease, the results of radical surgery as reported by

The principal complication has been a temporary urethrocutaneous fistula.

PERCENT I 0 0 ',,

\,STAGE c

0 12 24 36 48 60 72 84 96 108 120 MONTHS

Fig. 1. Actuarial survival curve - 215 cases CA of prostate - treated by cryosurgery.

286 Loening et al

Boxer was 67%. External radiation therapy resulted in 73% 5-year survival in patients with stage B disease and 46% survival in patients with stage C prostatic cancer 1201. Tumor failure rates, however, were much higher in patients with positive lymph nodes [21].

relationship has been observed to the volume of tumor and cure rates 1211. The larger the primary tumor at the time of surgery, the lower the long-term cure rates. In view of these considerations, radical surgery or high-dose external radiation therapy has limited benefits in patients with large local lesions or stage D, cancer. In these stages, perineal cryosurgical destruction affords the opportunity to control the local process, even in the high risk patient.

In addition to the bad prognostic sign of lymphatic involvement, a direct

CONCLUSION

In conclusion, we would like to say that cryosurgery of the prostatic carcinoma 1) is useful in local control of the tumor in all stages; 2) obviates further repeated transurethral resections for recurrent regrowth of tumor; and 3) is well tolerated and complications are minimal. Survival following cryosurgery appeared to be comparable to patients undergoing total prostatectomy .

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