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Experiences with P-32 in Treatment of Metastatic Carcinoma of Prostate: a Preliminary Report
THE JOURNAL OF UROLOGY
Vol. 85, No. 3 March, 1961 Copyright @ 1961 by The Williams & Wilkins Co.
Printed in U.S.A.
EXPERIENCES WITH P-32 IN TREATMENT OF METASTATIC CARCINOMA OF PROSTATE: A PRELIMINARY REPORT ROBERT L. PARSONS From the Department of Urology, Orange Memorial Hospital, Orlando, Fla.
The purpose of this preliminary report is to acquaint the reader with a method of treating symptomatic bony metastatic carcinoma of the prostate and to describe the initial gratifying results. Since World War II atomic piles have made a wide variety of isotopes readily available for treatment of urologic tumors. Phosphorus, because of its presence in the nucleoproteins, 1 a basic constituent of protoplasm, is a logical element in the production of artificial radioisotopes. Embryonic and neoplastic tissue has been reported to have a greater uptake of P-32 than normal tissue. 2 •3 This factor of differential uptake between the faster growing neoplastic tissue and normal tissue is one of the reasons why P-32 can be aimed, so to speak, at metastatic carcinoma of the prostate. This affinity alone does not produce enough difference in uptake to spare surrounding normal tissue when cancerocidal doses of radioisotopes are administered. In 1950 Hertz 4 applied Albright's 5 findings concerning bone metabolism and found that the uptake of phosphorus in new bone formation was increased fifteen to twenty times by the administration of male hormones. It is not positively known if this androgenic factor causes a direct Read at annual meeting of Southeastern Section of American Urological Association, Inc., Jacksonville, Fla., March 13-17, 1960. NOTE BY EDITOR. This paper received the award of the Southeastern Section as a prize essay. 1 Holmes, B. E. and Mee, L. K.: Incorporation of methionine S-35 into proteins of Jensen rat sarcoma cells after irradiation of the tumor. Brit. J. Radiol., 25: 273-278, 1952. 2 Kenney, J. M., Morenelia, L. B. and Woodard, H. Q.: Tracer studies with radioactive phosphorus in malignant neoplastic disease. Radiology, 37: 683-687, 1941. 3 Shahon, D. B.: Radioactive phosphorus (P32) : Studies in transplanted carcinoma; incorporation of P-32 measured by surface activity in Walker carcinoma and normal tissues of albino rats. Cancer, 12: 862-865, 1959. 4 Hertz, S.: The modifying effects of steroid therapy on human neoplastic tissue as judged by radioactive phosphorus (P-32 studies). Abstract in J. Clin. Investig., 29: 821, 1950. 5 Albright, F. and Reifenstein, E.: Parathyroid Glands and Metabolic Bone Disease. Baltimore: Williams and Wilkins, 1948.
increase in the cell uptake of P-32 or if the increase is due to the incorporation of the phosphorus into the newly formed bone salts. 6 P-32 is available in two forms--oral and parenteral. Solutions are shipped with a stated assay for use at a given time. In this series the daily dosage (oral) vials were used. P-32 is an intense beta emitter with a half life of 14.3 days and has a maximum range of penetration in tissue of 7 mm. 7 Due to the limited penetration of beta particles, direct measurement of P-32 is impossible in deep seated lesions. However, these high energy electrons in tissue produce low energy gamma waves. Fourtunately these waves may be detected with a Geiger counter at the skin over concentrated "pools" of P-32 as in "activated" osteoblastic lesions. 8 1Vhat criteria are used in the selection of patients suitable for treatment with P-32? The basic features are roentgenographic demonstrable lesions, preferably osteoblastic in nature, in a patient whose pain does not respond to the usually accepted treatment with estrogens, narcotics, and steroids. The estimated prognosis for life expectancy should arbitrarily exceed three months. The method of treatment used in this series is as follows: 1) Discontinue estrogenic hormones. 2) Wean the patient from steroids if he has been on them. 3) Administer 100 mg. testosterone intranrnscularly each day for a total of 17 days. Start the injections 5 days before, continue 7 days during, and 5 days after the administration of P-32. 4) On the sixth day of testosterone administration, prescribe 1.8 millicuries of P-32 by mouth and each day following, for a total of 7 days. 6 Wildermuth, 0., Parker, V., Archanbean, J. 0. and Chahbazian, C.: The management of diffuse metastasis from carcinoma of prostate. To be published. 7 Sodium radio-phosphate (P-32): A brochure issued by Abbott Radio-Pharmaceutical Laboratories, Oak Ridge, Tenn. 8 Harding, P. C.: Radiologist, Orange Memorial Hospital, Orlando, Fla. Personal communication.
342
METASTATIC CARCINOMA OF PROSTATE
5) Upon completion of the administration of P-32, give iron, J3 complex, and liver extract prophylac:tically to maintain an adequate hemogram. DiGalcium phosphate is also given as an adjunGt to the reossification of the destroyed osteoblastic lesions. The foregoing medications are continued for one to two rn.onths following tRrmination of P-32 therapy. 6) Fourteen days after completion of P-32 administration, estrogen therapy is resumed and continued indefinitely. The blood picture is checked every third day during P-32 administration, and at least once every 2 weeks for the following 6 weeks. In this series practically no depression of the usually radiosensitive hematopoietit: tissue 11·as noted. It is felt that this is possibly due to the relative lack of P-32 available to bone marrow as compared to the P-32 taken up in the phosphorus hungry, hormone primed, osteoid material. · The six step program of administration is much the same as that used by :\Iaxfield, 9 who reported some of the original clinical work utilizing P-32 in metastatic bone lesions from carcinoma of the breast and prostate. Five patients with proven carcinoma of the prostate previously treated 1Yith estrogens, castration, and narcotics, and 11011" resistant, 1Yere selected for study.* Ead1 patient had roentgenographic evidence of bony metastasis (fig. 1) and all but one had increased serum acid and alkaline phosphatase. The first patient (C. B. H.) was suspected of having carcinoma of the prostate when a rib biopsy was reported as adenocarcinoma. Subsequent urologic work-up confirmed this suspicion. Following orchiectomy the patient was discharged on estrogen and steroid therapy. Two months later he was readmitted because of his general lack of response to therapy. vVhen it was decided to administer P-32 he was in a critical conditon, semicomatose, and practically terminaL He expired shortly before the completion of the scheduled P-32 therapy. The second patient (C. E. H.) had one injection of testosterone preliminary to the administration of P-32. The following clay he began to vomit coffee ground 9 Maxfield, J. G. S., Jr., Maxfield, J. G. S. and Maxfield, W. S.: Use of radioactive phosphorus and testosterone in metastatic bone lesions from breast and prostate. South Med. J., 51: 320-327
1958.
'
* These 5 patients were from the private prac-
tice of Drs. Louis M. Orr, James L. Campbell and Miles W. Thomley.
Fm. 1. Patient J. E. C. X-ray shows osteoblastic metastasis typical of patients in this series material. His severe leg and back pains grew more intense. The vomiting persisted ancl he complained of chest pain, went into shock ancl expired. A postmortem examination was not obtained in either of these patients. It 1rns felt that the demise of these 2 patients 11·as a result of their disease processes, and not from P-32 therapy. Three subsequent patients (J. E. 0. G., R. L. P.) completed the fully prescribed course of P-32. At the time of admission all required regular closes of narcotics and each had been reduced to a minimum of activity because oi debilitating pain. No improvement was noted with male hormones alone in contrast to the relief reported by Brendler, Chase and Scott_IO Actually, it was felt that male hormones greatly intensified the pain. Slight improvement was evident two to three clays after P-32 11•as started,. but one to two weeks after the completion of P-32: marked improvement 11·as noted in each patient At the encl of 1 month all 3 patients were free of of pain.None took any form of analgesics and each reported improvement in appetite, weight gain, and a sense of well being. One patient, a pilot boat captain, who had not worked for 2 years, requested permission to resume his old job. Another patient climbed freely on and off the x-ray table 10 Brendler, H., Chase, W. H. and Scott, W. W . Prostatic cancer: Further investigation of hormonal relationships. Arch. Surg., 61: 440-443, 1950.
344
ROBERT L. PARSONS
in dramatic contrast to the assistance needed 011 arising from bed in the hospital prior to therapy. There are questions unanswered concerning the use of P-32 which, if answered, may make further use of this drug more refined. Would a low phosphorus diet be beneficial? Is the dosage schedule the most effective? How often and how much P-32 can be administered? Does P-32 act equally well on osteolytic as well as osteoblastic lesions? Is P-32 indicated for nonsymptomatic patients with roentgenographic evidence of metastases?
SUMMARY
The purpose of this preliminary report is to acquaint the reader with a method of treating symptomatic bony metastatic carcinoma of the prostate and to list the initial satisfying results. No definite conclusion as to the duration and quality of the results has been suggested. It is felt, however, that P-32 will earn a commanding position in the fight against metastatic carcinoma of the prostate. 1300 Orange Ave., Orlando, Fla.
Vol. 85, No. 3 March, 1961 Copyright @ 1961 by The Williams & Wilkins Co.
Printed in U.S.A.
EXPERIENCES WITH P-32 IN TREATMENT OF METASTATIC CARCINOMA OF PROSTATE: A PRELIMINARY REPORT ROBERT L. PARSONS From the Department of Urology, Orange Memorial Hospital, Orlando, Fla.
The purpose of this preliminary report is to acquaint the reader with a method of treating symptomatic bony metastatic carcinoma of the prostate and to describe the initial gratifying results. Since World War II atomic piles have made a wide variety of isotopes readily available for treatment of urologic tumors. Phosphorus, because of its presence in the nucleoproteins, 1 a basic constituent of protoplasm, is a logical element in the production of artificial radioisotopes. Embryonic and neoplastic tissue has been reported to have a greater uptake of P-32 than normal tissue. 2 •3 This factor of differential uptake between the faster growing neoplastic tissue and normal tissue is one of the reasons why P-32 can be aimed, so to speak, at metastatic carcinoma of the prostate. This affinity alone does not produce enough difference in uptake to spare surrounding normal tissue when cancerocidal doses of radioisotopes are administered. In 1950 Hertz 4 applied Albright's 5 findings concerning bone metabolism and found that the uptake of phosphorus in new bone formation was increased fifteen to twenty times by the administration of male hormones. It is not positively known if this androgenic factor causes a direct Read at annual meeting of Southeastern Section of American Urological Association, Inc., Jacksonville, Fla., March 13-17, 1960. NOTE BY EDITOR. This paper received the award of the Southeastern Section as a prize essay. 1 Holmes, B. E. and Mee, L. K.: Incorporation of methionine S-35 into proteins of Jensen rat sarcoma cells after irradiation of the tumor. Brit. J. Radiol., 25: 273-278, 1952. 2 Kenney, J. M., Morenelia, L. B. and Woodard, H. Q.: Tracer studies with radioactive phosphorus in malignant neoplastic disease. Radiology, 37: 683-687, 1941. 3 Shahon, D. B.: Radioactive phosphorus (P32) : Studies in transplanted carcinoma; incorporation of P-32 measured by surface activity in Walker carcinoma and normal tissues of albino rats. Cancer, 12: 862-865, 1959. 4 Hertz, S.: The modifying effects of steroid therapy on human neoplastic tissue as judged by radioactive phosphorus (P-32 studies). Abstract in J. Clin. Investig., 29: 821, 1950. 5 Albright, F. and Reifenstein, E.: Parathyroid Glands and Metabolic Bone Disease. Baltimore: Williams and Wilkins, 1948.
increase in the cell uptake of P-32 or if the increase is due to the incorporation of the phosphorus into the newly formed bone salts. 6 P-32 is available in two forms--oral and parenteral. Solutions are shipped with a stated assay for use at a given time. In this series the daily dosage (oral) vials were used. P-32 is an intense beta emitter with a half life of 14.3 days and has a maximum range of penetration in tissue of 7 mm. 7 Due to the limited penetration of beta particles, direct measurement of P-32 is impossible in deep seated lesions. However, these high energy electrons in tissue produce low energy gamma waves. Fourtunately these waves may be detected with a Geiger counter at the skin over concentrated "pools" of P-32 as in "activated" osteoblastic lesions. 8 1Vhat criteria are used in the selection of patients suitable for treatment with P-32? The basic features are roentgenographic demonstrable lesions, preferably osteoblastic in nature, in a patient whose pain does not respond to the usually accepted treatment with estrogens, narcotics, and steroids. The estimated prognosis for life expectancy should arbitrarily exceed three months. The method of treatment used in this series is as follows: 1) Discontinue estrogenic hormones. 2) Wean the patient from steroids if he has been on them. 3) Administer 100 mg. testosterone intranrnscularly each day for a total of 17 days. Start the injections 5 days before, continue 7 days during, and 5 days after the administration of P-32. 4) On the sixth day of testosterone administration, prescribe 1.8 millicuries of P-32 by mouth and each day following, for a total of 7 days. 6 Wildermuth, 0., Parker, V., Archanbean, J. 0. and Chahbazian, C.: The management of diffuse metastasis from carcinoma of prostate. To be published. 7 Sodium radio-phosphate (P-32): A brochure issued by Abbott Radio-Pharmaceutical Laboratories, Oak Ridge, Tenn. 8 Harding, P. C.: Radiologist, Orange Memorial Hospital, Orlando, Fla. Personal communication.
342
METASTATIC CARCINOMA OF PROSTATE
5) Upon completion of the administration of P-32, give iron, J3 complex, and liver extract prophylac:tically to maintain an adequate hemogram. DiGalcium phosphate is also given as an adjunGt to the reossification of the destroyed osteoblastic lesions. The foregoing medications are continued for one to two rn.onths following tRrmination of P-32 therapy. 6) Fourteen days after completion of P-32 administration, estrogen therapy is resumed and continued indefinitely. The blood picture is checked every third day during P-32 administration, and at least once every 2 weeks for the following 6 weeks. In this series practically no depression of the usually radiosensitive hematopoietit: tissue 11·as noted. It is felt that this is possibly due to the relative lack of P-32 available to bone marrow as compared to the P-32 taken up in the phosphorus hungry, hormone primed, osteoid material. · The six step program of administration is much the same as that used by :\Iaxfield, 9 who reported some of the original clinical work utilizing P-32 in metastatic bone lesions from carcinoma of the breast and prostate. Five patients with proven carcinoma of the prostate previously treated 1Yith estrogens, castration, and narcotics, and 11011" resistant, 1Yere selected for study.* Ead1 patient had roentgenographic evidence of bony metastasis (fig. 1) and all but one had increased serum acid and alkaline phosphatase. The first patient (C. B. H.) was suspected of having carcinoma of the prostate when a rib biopsy was reported as adenocarcinoma. Subsequent urologic work-up confirmed this suspicion. Following orchiectomy the patient was discharged on estrogen and steroid therapy. Two months later he was readmitted because of his general lack of response to therapy. vVhen it was decided to administer P-32 he was in a critical conditon, semicomatose, and practically terminaL He expired shortly before the completion of the scheduled P-32 therapy. The second patient (C. E. H.) had one injection of testosterone preliminary to the administration of P-32. The following clay he began to vomit coffee ground 9 Maxfield, J. G. S., Jr., Maxfield, J. G. S. and Maxfield, W. S.: Use of radioactive phosphorus and testosterone in metastatic bone lesions from breast and prostate. South Med. J., 51: 320-327
1958.
'
* These 5 patients were from the private prac-
tice of Drs. Louis M. Orr, James L. Campbell and Miles W. Thomley.
Fm. 1. Patient J. E. C. X-ray shows osteoblastic metastasis typical of patients in this series material. His severe leg and back pains grew more intense. The vomiting persisted ancl he complained of chest pain, went into shock ancl expired. A postmortem examination was not obtained in either of these patients. It 1rns felt that the demise of these 2 patients 11·as a result of their disease processes, and not from P-32 therapy. Three subsequent patients (J. E. 0. G., R. L. P.) completed the fully prescribed course of P-32. At the time of admission all required regular closes of narcotics and each had been reduced to a minimum of activity because oi debilitating pain. No improvement was noted with male hormones alone in contrast to the relief reported by Brendler, Chase and Scott_IO Actually, it was felt that male hormones greatly intensified the pain. Slight improvement was evident two to three clays after P-32 11•as started,. but one to two weeks after the completion of P-32: marked improvement 11·as noted in each patient At the encl of 1 month all 3 patients were free of of pain.None took any form of analgesics and each reported improvement in appetite, weight gain, and a sense of well being. One patient, a pilot boat captain, who had not worked for 2 years, requested permission to resume his old job. Another patient climbed freely on and off the x-ray table 10 Brendler, H., Chase, W. H. and Scott, W. W . Prostatic cancer: Further investigation of hormonal relationships. Arch. Surg., 61: 440-443, 1950.
344
ROBERT L. PARSONS
in dramatic contrast to the assistance needed 011 arising from bed in the hospital prior to therapy. There are questions unanswered concerning the use of P-32 which, if answered, may make further use of this drug more refined. Would a low phosphorus diet be beneficial? Is the dosage schedule the most effective? How often and how much P-32 can be administered? Does P-32 act equally well on osteolytic as well as osteoblastic lesions? Is P-32 indicated for nonsymptomatic patients with roentgenographic evidence of metastases?
SUMMARY
The purpose of this preliminary report is to acquaint the reader with a method of treating symptomatic bony metastatic carcinoma of the prostate and to list the initial satisfying results. No definite conclusion as to the duration and quality of the results has been suggested. It is felt, however, that P-32 will earn a commanding position in the fight against metastatic carcinoma of the prostate. 1300 Orange Ave., Orlando, Fla.