Cryotherapy in advanced prostatic cancer

CRYOTHERAPY PROSTATIC EROL

0.

IN ADVANCED

CANCER*

GURSEL,

M.D.

MYRON

S. ROBERTS,

M.D.

RALPH

J. VEENEMA,

M.D.

From the Columbia-Presbyterian Medical Center and Francis Delafield Hospital, New York, New York

ABSTRACT-In 39 patients with metastatic cancer of the prostate and with pain refractory to orchiectomy and estrogens at the site of metustases, sequential cryotherapy to the prostate was utilized in an attempt to palliate the pain. An excellent result was achieved in 20 patients. The response lasted from six weeks to three years after cryotherapy. Possible mechanisms for this response are discussed. Early use of cryotherapy is suggested to obtain maximum immunologic response in patients with prostatic cancer.

Extensive investigations into cancer immunology suggest that host immunity may be a significant factor in resistance to neoplasia. Augmentation of this response, “immunotherapy,” has recently been added to the therapeutic management of cancer. The immunologic reactivity of the host may be increased by freezing the tissues. Freezing of the rabbit prostatic complex produces antibodies against rabbit-prostate cells as shown by increased hemagglutination titers.’ This “cryoimmunothermic” response may be increased by the repeated, sequential freezing of the prostate, the booster phenomenon.” The presence of tissue-specific antigens in the prostate of man3 the occurrence of the booster phenomenon after freezing the rabbit prostatic complex, and the regression of metastases of prostatic cancer following repeated cryosurgery in men4,” were the basis for cryotherapy (freezing) in an attempt to palliate refractory pain at the site of metastases in patients with advanced prostatic cancer. Presented at the 70th Annual Meeting ofthe New York Section of the American Urological Association Inc., Montreal, Canada, October 22 to 25, 1972. *This work has been supported in part by National Institutes of Health Training Grant No. TIAM 5451; Cryosurgery Fund No. 7694; Urology Neoplasm Research Gift No. 9890.

392

Materials

and Methods

Thirty-nine patients, ages ranging from fortyeight to seventy-nine, with metastatic prostatic cancer were admitted to the study. The presence of bone metastases was proved by skeletal survey in 38 patients and by Strontium-85 bone scan in 1 patient. The indication for cryotherapy was intractable pain at the site of metastases in 37 patients, prostatic obstruction in 1, and hematuria due to involvement of the prostatic urethra in 1 patient. All patients were poor surgical risks due to cardiopulmonary conditions, dehydration, anemia, or cachexia. However, none had pulmonary metastases. Previous and present treatment modalities given to these patients for prostatic cancer are shown in Figure 1. Prior to cryotherapy, the presence of prostatic cancer was confirmed either by perineal cup biopsy or by transurethral resection of the prostate. They were evaluated prior to treatment with intravenous pyelography, voiding cystourethrography or retrograde urethrography, roentgenograms of the chest and skeletal system, and by isotopic bone scanning. Immunoelectrophoresis of serum protein9 and measurement of circulating tumor-associated antigens7 were done in addition to complete blood count, blood urea nitrogen, serum proteins, albumin/globulin ratio,

UROLOGY

/ MAY 1973 / VOl,UME I, NUMBER 5

4

PRESENT THERAPY

NO. I:fS

I

-

~~~~

RESPONSE

EXCELLENT1 MODERATE

1 POOR I

ORCH. + DES. t CORTISONE

I

ORCH. + DES. + ERT (Prorl)

MODERATE

‘ALIVE

ORCH. + DES. tERT. (met]

AT

I

1

-

q;mFt\SP,ONSE

) 12

mos

ORCH . + DES. + ERT. (port ) t CORT.

6

0:

1

3

oi-

0

PRESENT

FIGURE 2. pain.

ORCW.t DES. + ERT. (prod t mot )

Response

of 29 patients

to palliatiorb oj

intravenous diazepam (Valium) was found to be sufficient for analgesia, since the freezing was not a painful procedure. Pain was usually elicited by prostatic palpation during the procedure.

ORCH (alone) DES (olonr) THERAPY

TOOTAL

Results

FIGURE 1. Previous treatment und sults in advanced prostatic cancer.

cryotherapy

re-

and electrophoresis of serum proteins. Urinalysis and urine cultures were routinely performed. These parameters were again measured after cryotherapy. Cryotherapy of the prostate was performed by introducing an LR-10 prostatic cryoprobe (no. 24 French) and positioning the probe by rectal palpation.x A CR-4 cryogenic unit* with liquid nitrogen as the freezing agent was used in this study. During the freezing period, the temperature of the probe was kept at 160°C. Temperatures at the prostatic capsule were not monitored during the study. Initially a single freeze was used (once in 3 patients, twice in 2 patients, and three times in I5 patients). Later a double freeze, consisting of two 5-minute periods interrupted by a 5-minute thaw, was used (once in 16 patients, and twice in 2 patients) to produce a greater degree of cryonecrosis in the prostate. In 30 patients with prostatic obstruction, cryotherapy was performed immediately following partial transurethal resection prostatectomy where not more than 15 Gm. of prostatic tissue were resected to minimize the slough formation and to shorten the postcryocatheterization period. In 6 patients with no prostatic obstruction, cryotherapy was performed following perineal cup biopsy of the prostate. In 3 patients cryotherapy alone was done. Epidural anesthesia was routinely used in patients treated by transurethral resection prostatectomy and cryotherapy. Otherwise, IO mg. of

Palliation of pain at the site of metastases was evaluated in 35 patients. Their responses were classified into 3 groups: (1) An excellent response was observed in 20 patients as demonstrated by the disappearance or decrease of bone pain with reduction of dosage in medication for pain. This response was also associated with an increased sense of well being, better appetite, and better mobility of the patient. (2) A moderately good response was observed in 9 patients. Although it was associated with a decrease in bone pain, there was no change in the demand for medication to alleviate pain. (3) No palliation was achieved in the remaining 6 patients (Fig. 2). Changes in serum acid phosphatase levels

The preoperative levels of serum acid phosphatase were closely related to the degree of palliative response observed after cryotherapy. Six patients with a poor response to cryotherapy had increased serum acid phosphatase levels prior to cryotherapy. On the other hand, postcryotherapy serum acid phosphatase levels were not related to the clinical response (Table I). TABLE I. Pre- und Postoperntive serum ucid phosphatase levels and response to cryotherapy Serum Acid Phosphatase Preoperative Increase stable Postoperative Decrease

Stable

* Mannfwtured by Frigitronics, Shelton, Connecticut.

ITROLKY

PERIOD3

EXCELLENT

ORCH. + DES.

NO

(fmos

Response

/ MAY

1973 / VOLUME

1,NUMBER

5

Increase

Response-, Number of 1 Excellent \/loderate Patients

Poor

24 13

12 10

6 3

6 0

8 21 6

5 11 4

2 6 1

1 4 1

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In patients with an excellent response to cryotherapy, similar percentages of decreased serum acid phosphatase were found. Changes in the serum alkaline phosphatase, serum protein, and gamma globulin fractions were not found to be related to the palliative effects of cryotherapy.

I

RESPONSE

L

SERUM TAA I

BEFORE

LEVEL AFTER

1

EXCELLENT

4 Eflects Renal function. Seven patients had hydronephrosis prior to cryotherapy. In 3 patients no changes in hydronephrosis were observed. In 1 patient hydronephrosis was further increased. No follow up was available on the remaining 3 patients. In one patient who had normal results on preoperative intravenous pyelogram, hydronephrosis developed following cryotherapy. Blood urea nitrogen was elevated in 7 patients prior to cryotherapy; it returned to normal levels in 3, remained unchanged in 1, and was further increased in 3 patients. One patient with normal preoperative blood urea nitrogen following the development of vesicorectal fistula had gradually increased levels of blood urea nitrogen. He refused colostomy and finally died of uremia. Znfection in urinary tract. In 6 of 16 patients with urinary tract infection before cryotherapy, infection was eradicated after cryotherapy. However, in 4 patients with negative preoperative urine cultures, infection of the urinary tract developed. Gram-negative sepsis was diagnosed in 4 patients two weeks to six months after cryotherapy, respectively. Three of the 4 patients recovered and 1 died. Urination. The urethral catheter was removed four to ten days postoperative in 33 of 35 patients. One patient had a nephrostomy, and the other had a suprapubic cystostomy. Voiding pattern was evaluated by taking a careful history, by determining residual urine, and by the voiding cystourethrogram. Three patients had stress urinary incontinence lasting three weeks after cryotherapy. Slough retention complicated with total urinary incontinence was noted in 1 patient. Size of prostate: Rectal examination revealed no remarkable changes in the size of the prostate in these patients. A few patients were found to have decreased prostatic impressions on postvoiding cystograms following intravenous pyelograms. However, the combination of transurethral resection prostatectomy with cryotherapy made it difficult to evaluate prostatic size by radiologic means. Bone metastases. Changes in bone metastases were evaluated in 35 patients. No changes were

394

3.6

MODERATE

6.7 4.0

3

25-19-11 4 I .8-4

POOR

3 I-

*ng/ml

FIGURE 3. Circulating and response

tumor-associated to cryotherapy in 10 patients.

antigens

observed in 29 patients. Five patients had further progression of metastases. Strontium-85 bone scan showed regression of bone metastases in 1 patient.” Circulating tumor-associated antigen. Circulating tumor-associated antigen levels were evaluated in 10 patients (Fig. 3). Excellent response was noted in 4 patients with normal preoperative tumor-associated antigen levels. One of these 4 patients had a transient increase in tumor-associated antigen, above-normal levels during the first two weeks after cryotherapy. However, it returned to zero four weeks after cryotherapy. In the remaining 6 patients with elevated preoperative tumor-associated antigen either moderate or poor responses were noted. Serum immunoglobulins. Changes in serum immunoglobulin levels after cryotherapy in 13 patients are shown in Figure 4. During the first postoperative week, increases in immunoglobulins G and M were correlated with the response to palliation of pain. In the poor-response group, no elevation of IgM was noted. At the fourth postoperative week, 2 of the 8 patients had elevated immlrnoglobulins G and M. No remarkable changes were noted in IgA after cryotherapy.

Complications Three patients died during the early postoperative period and two on the first postoperative day, one of cardiac arrest and the other of pulmonary emboli. One patient died in the

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/ MAY 1973

/ VOLUME

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RESPONSE

IEP

INCREASE

STABLE

OECREASE

Three patients who died more than six months after cryotherapy showed severe fibrosis with the absence of cancer cells in the prostate in spite of diffuse metastases.

Comment

FIGURE

4.

globulins

Effects of cryotherapy in 13 patients.

on serum immuno-

operating room of what appeared to be anaphylactic shock at the time of the second doublePostmortem studies revealed acute freeze. obstructive pulmonary disease associated with glottis edema. Stress urinary incontinence lasting three weeks was observed in 3 patients. One patient had slough retention complicated by total urinary incontinence and underwent permanent suprapubic cystostomy. Periurethral abscess developed in 2 patients. Perineal fistula developed in 1 patient who underwent permanent cystostomy; the other patient died of pulmonary embolus three weeks after cryotherapy and six hours after suprapubic cystostomy. One patient had a mild stricture at membranous urethra which responded to urethral dilatation. A rectovesical fistula developed in 1 patient. He refused colostomy and died of progressive uremia.

Follow-up

Studies

Two patients were lost to follow-up. At the present time, 10 patients are alive. In 8 of the 10 patients (three months to three years after cryotherapy, respectively), palliation of pain is still continuing. Twenty-seven patients have died during the period of study (3 postoperatively, 3 of cardiac arrest, 1 of uremia, 1 of Gramnegative sepsis, and 18 of carcinoma). Autopsies were done in 9 patients who died twenty-four hours to one-year postcryotherapy. In two patients who died on the first postoperative day, severe cryonecrosis was noted. In 4 patients who died six to eight weeks after, cryofibrosis with a decrease in cancer cells was found.

L~ROLO(:Y

/

MAY lH73 / \‘OLUME I, NUMBER 5

The possibility that immunologic factors might influence tumor growth and development was mentioned by Ehrlich as early as 1909. However, during the last decade substantial evidence has been brought forth in support of this phenomenon.” Earlier use of single sequential (two or three times) cryotherapy was mainly based on the observation of the booster phenomenon following the freezing of rabbit prostatic complex,’ on the regression of metastases of prostatic cancer >4d and on palliation of bone pain at the site of metastases.“’ Palliation of pain observed in some of our patients as early as twenty-four hours following cryotherapy needs to be explained. Placebo effect was certainly considered. However, in 2 patients sham procedures, such as insertion of cryoprobe and repeated rectal examination without freezing, failed to achieve palliation of bone pain at the site of metastases. The relationship between the preoperative elevated serum acid phosphatase levels and the palliative response is understandable. A poor response was noted in patients with elevated serum acid phosphatase, as expected. In the postoperative period, palliative response was not related to the serum acid phosphatase levels. This was explained by the size of the cryonecrosis produced with freezing. The effective mechanism of cryosurgery in the management of prostatic cancer is twofold.“,12 First is the production of cryonecrosis followed by fibrosis and then eradication of the local tumor growth in the early stages. Local eradication of cancer was observed in 3 patients who died of metastases but whose prostatic tissue beds showed that no cancer remained. This local effect could be augmented by the repeated freezing, and depending on these observations, we are at the present time evaluating cryotherapy in locally invasive (Stage III) prostatic cancer. Second is the antigen release from the cancerous tissues following cryonecrosis, as shown in some of our patients. Immunologic function of the host can be classified as humoral antibody formation and cellmediated response. The presence of decreased cell-mediated response in patients with cancer is shown.1”s14 We have utilized skin tests for

395

tuberculosis and Candida albicans in the first 10 patients treated with cryotherapy.13 All had negative skin test results which remained negative following cryotherapy. We have not, however, used the other antigenic substances or cross-reacting chemicals such as Repeated DNCB (dinitrochlorobenzene).z*4 blood studies in patients treated with cryotherapy failed to show lymphopenia which suggests an impaired cell-mediated response.15 Because of this impaired response, patients with neoplasia are not able to recognize foreign cells, including cancer cells. When antigen was released into the circulatory system, antibody formation would be triggered. Increased tumor-associated antigen release after cryotherapy has been shown in all patients with Stage III prostatic cancer. The level of tumor-associated antigen, however, never exceeded the normal levels of 2.5 ng. per ml. in these patients.r4 Whereas, in Stage IV cancer some patients responded to cryotherapy with a greater increase of tumor-associated antigen. This response (elevation of tumor-associated antigen levels) was followed by increases in IgM levels.16 Immunoglobulin M is known to be cytotoxic, and it appeared promptly after initial antigen exfollowing posure. The IgG level is increased repeated antigen exposure in a relatively delayed fashion.17 The capacity for antibody formation is well preserved in Stage III cancer, but it is relatively impaired in patients with Stage IV prostatic cancer.ls Our findings, therefore, suggest there is an immunothermic response following cryotherapy in patients with prostatic cancer. The preservation of the capacity to produce antibodies in Stage III prostatic cancer also suggests that earlier use of cryotherapy is indicated to obtain a maximum immunologic response.

New

620 West 168th York, New York

Street 10032

(DR. GURSEL)

396

References

1. SHULMAN, S., et al.: Urogenital 99 (1966).

tissues

and

Studies on organ specificity. autoantibodies, Immunology

XVI. 10:

2. ABLIN, R. J., WITEBSKY, E., JAGODZINSKI, A. B., and immunologic response as a SOANES, W. A.: Secondary consequence of the in situ freezing of rabbit male adrenal glands, Exper. Med. & Surg. 29: 72 (1971). properties of human 3. BARNES, G., et al.: Immunologic prostatic fluid, J, Lab. Clin. Med. 61: 578 (1963). 4. SOANES, W. A., ABLIN, R. J., and GONDER, M. J.: Remission of metastatic lesions following cryosurgery in prostatic cancer, J. Urol. 104: 154 (1970). 5. GURSEL, E., ROBERTS, M., and VEENEMA, R. J.: Regression of prostatic cancer following sequential cryotherapy to the prostate, ibid. 108: 928 (1972). 6. MANCINI, G., CARBONARA,A. O., and HEREMANS, J. F.: Immunochemical quantitation of antigens by single radial immunodiffision, Immunol. Chem. 2: 235 (1965). 7. LOGERFO, P., KRUPEY, J., and HANSEN, H. J.: Demonstration of an antigen common to several varieties of neoplasia, New England J, Med. 285: 138 (1971). 8. SOANES, W. A., GONDER, M. J., and SHULMAN, S.: Ap-

9.

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paratus and technique for cryosurgery of the prostate, J. Urol. 96: 508 (1966). and problems of immunoSMITH, R. J.: Possibilities logic intervention on cancer, New England J. Med. 287: 439 (1972). CURSEL, E.: Cryoimmunotherapy in disseminated prostatic carcinoma, presented at New York Section of American Urological Association, New York, March, 1970. NEEL, H. B., III, KETCHAM, A. S., and HAMMOND,W. G.: Requisites for successful cryogenic surgery of cancer, Arch. Surg. 102: 45 (1971). IDEM: Cryonecrosis of normal and tumor-bearing rat and liver potentiated by inflow occlusion, Cancer 28: 1211 (1971). PINSKY, C. M., et al.: Delayed hypersensitivity reactions on patients with cancer, Proc. Am. Assoc. Cancer

Res. 12: 100 (1971). 14. GURSEL, E. O., and VEENEMA, R. J.: Immunologic responses to cryotherapy in Stage III versus Stage IV prostate cancer, in preparation. 15. EILBER, F. R., and MORTON, D. L.: Impaired immuno-

logic reactivity and recurrence following cancer surgery, Cancer 25: 362 (1970). 16. GURSEL, E. O., and VEENEMA, R. J.: Effects of cryotherapy on circulating immunoglobulins in patients with prostate cancer, To be presented at Internat. Congress of Urology, ._. Amsterdam, Holland, July, 1973. 17. FAHEY, J. L.: Developments on fundamental research related to clinical uses of immunoglobulins. , .I. Immunoglobulins, National Academy of Sciences, Washington, D.C., 1970, p. 15. 18. GURSEL, E. O., MEGALLI, M. R., and VEENEMA, R. J.: Immunoglobulins in prostate cancer, in press.

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