PROSTATIC

CARCINOMA

Treatment of Liver Metastases with Intravenous Diethylstilbestrol Diphosphate E. JACOBO,

M.D.

R. H. FLOCKS, D. A. CULP,

M.D.

M.D.

From the Department Iowa City, Iowa

of Urology, University of Iowa Hospitals,

ABSTRACT - A patient with Stage B adenocarcinoma of prostate treated with radical prostatectomy and interstitial radioactive gold presented ten years later with liver metastases without evidence of local recurrence. This patient was treated only with massive doses of intravenous diethylstilbestrol diphosphate, with regression of metastases and marked decline of the acid and alkaline phosphatase levels.

Although intravenous diethylstilbestrol diphosphate (Stilphostrol) has now been used in the treatment of prostatic adenocarcinoma for over twenty years and has been found effective for relief of bone pain over short periods of time, the chemotherapeutic and direct cytostatic action has remained in doubt during this time. The exact mode of action of the compound has been poorly understood. Reports in 1952 by Flocks et al. 1 and Druckrey and Raabe2 demonstrated the objective and subjective improvement of patients with metastatic carcinoma of the prostate, initiating in this fashion the use of this substance in larger series of patients and showing at the same time the relatively low toxicity and minimal side effects of the drug. More recent series by Hawtrey et a1.3 showed objective improvement with the use of diethylstilbestrol diphosphate in cases of paraplegia secondary to epidural metastatic involvement from carcinoma of the prostate. The following clinical abstract is presented of a patient with metastatic adenocarcinoma of the prostate to the liver treated only with diethylstilbestrol diphosphate and the therapeutic response obtained.

UROLOGY

/ SEPTEMBER1975

/ VOLUMEVI,

NUMBER3

Case Report A seventy-year-old male Caucasian was seen in 1964 with a Stage B adenocarcinoma of the prostate treated with perineal radical prostatectomy and instillation of radioactive gold to the prostatic pedicle. He was followed initially at six-month intervals and then later on a yearly basis with no evidence of metastatic involvement or local recurrence on clinical grounds, bone surveys, and alkaline and acid phosphatases. In March, 1974, the patient presented with malaise, a weight loss of 20 Kg. in a short period of time, acid phosphatase of 17.3 units (normal up to 0.7 units), and an alkaline phosphatase of 675 (normal up to 85 mu. per milliliter). The liver was enlarged and nodular. Elevated bilirubins and liver enzymes were present. A liver scan revealed filling defects consistent with spaceoccupying lesions (Fig. l), and the bone scan revealed increased uptake on the midthoracic and midlumbar spine areas without evidence of local recurrence on rectal examination. Bone survey of these areas did not show evidence of blastic or lytic lesions. The patient was treated initially with intravenous diethylstilbestrol diphosphate, 1 Gm. in 250

351

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A

r i.

=

I

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FIGURE 1. Liver scans (A) showing area of decreased uptake suggestive of space-occupying lesions initially, and (B) one year later showi&adequate uptake.

cc. of 5 per cent dextrose and water, daily for a period of eleven days with rapid decrease of the acid and alkaline phosphatases to 4.5 units and 240 mu. per milliliter, respectively, improvement of his general condition, and progressive decrease in the siae of the liver and the nodules. Since then, this patient has continued to be treated with diethylstilbestrol diphosphate every six weeks for seven days at the same daily dose, and the acid phosphatase remains in the range of 1.2 units with the alkaline phosphatase being 90 mu. per milliliter (Fig. 2). Repeat liver scan showed no evidence of progression of the lesion. He is active, and his body weight has returned to a normal range.

20- -STILPH. 1816145,2IO86-

Comment Although in this case we have no tissue diagnosis of the liver lesions, on clinical grounds and based on the elevation and subsequent decrease of the acid and alkaline phosphatases, liver scans, and objective improvement, we made the diagnosis of metastatic adenocarcinoma of the prostate to the liver. Interestingly, this patient never showed evidence of local recurrence and did show evidence of metastatic disease ten years after the radical perineal prostatectomy. From a chemical standpoint, it is postulated that diethylstilbestrol diphosphate is rapidly hydrolyzed by the prostatic phosphatase with the local liberation of stilbestrol; the acid phosphatase activity in the malignant tissue splits off the phosphatase groups from the stilbestrol diphosphate, a portion of the compound enters the cancer cells, and this leads to deposition of a relatively insolu-

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II days 77777

42-

FIGURE 2. Acid and alkaline phosphatase activities during ten years of follow-up showing a sharp rise at time of metastatic involvement and subsequent decline with diethylstilbestrol diphosphate therapy.

ble diethylstilbestrol which in local concentrations is thought to have a direct cytotoxic effect.4 It is also postulated that the phosphorylation reduces the side effects allowing the use of large intravenous dosage.

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Experimental data utilizing diethylstilbestrol diphosphate labeled with i4C suggested the high concentration of this material primarily in the liver and the kidney and a small concentration in the prostate itself. In our particular case, the fact that the metastatic lesions were present in the liver and the selectivity of this estrogenic compound toward the liver might have influenced the satisfactory chemotherapeutic response. Currently, Hawtrey,5 with the use of electronmicroscopy studies, showed that with the administration of intravenous diethylstilbestrol diphosphate there is swelling of the mitochondria cristae and disruption of the rough endoplasmic reticulum. Over twenty years of clinical experience has shown that diethylstilbestrol diphosphate is a good adjuvant for hormonal therapy of carcinoma of the prostate when employed initially with in-

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termittent use at intervals of every eight weeks. Currently, one year later, the patient has remained free of exacerbations from metastatic disease. Iowa City, Iowa 52242 (DR. CULP) References 1. FLOCKS, R. H., MARBERGER, H., BEGLEY, B. J., and PRENDERGAST, L. J. : Prostatic carcinoma: treatment of advanced cases with intravenous diethylstilbestrol diphosphate, J. Urol. 74: 4 (1955). 2. DRUCKREY, H., and RAABE, S. : Organs Pezifische Chemotherapie des Krebs (Prostata Karzinom), Klin Wschr. 30: 882 (1952). 3. HAWTREY, C. E., &al.: Paraplegia and paraparesis due to prostatic cancer, Urology 4: 4 (1974). 4. FERGUSSON, J. D.: Endocrine control therapy in prostatic cancer, Br. J. Urol. 30: 397 (1958). 5. HAWTREY, C. E.: Personal communication, 1975.

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Prostatic carcinoma: treatment of liver metastases with intravenous diethylstilbestrol diphosphate.

A patient with Stage B adenocarcinoma of prostate treated with radical prostatectomy and interstitial radioactive gold presented ten years later with ...
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