Scandinavian Journal of Urology and Nephrology
ISSN: 0036-5599 (Print) 1651-2065 (Online) Journal homepage: http://www.tandfonline.com/loi/isju19
Advanced Cancer of the Prostate Combined with Hypercalcaemia Arne M. Olsson & Gösta Jönsson To cite this article: Arne M. Olsson & Gösta Jönsson (1977) Advanced Cancer of the Prostate Combined with Hypercalcaemia, Scandinavian Journal of Urology and Nephrology, 11:3, 293-296, DOI: 10.3109/00365597709179968 To link to this article: http://dx.doi.org/10.3109/00365597709179968
Published online: 15 Feb 2010.
Submit your article to this journal
Article views: 1
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=isju19 Download by: [Monash University Library]
Date: 10 April 2016, At: 18:14
Scand J Urol Nephrol 11: 293-296, 1977
ADVANCED CANCER OF THE PROSTATE COMBINED WITH HYPERCALCAEMIA Arne M. Olsson and Gosta Jonsson From the Department of Urology, University Hospital of Lund, Lund, Sweden
(Submitted for publication October 14, 1976)
Downloaded by [Monash University Library] at 18:14 10 April 2016
Absfract. Despite the high frequency of skeletal meta-
stases from cancer of the prostate, hypercalcaemia is extremely uncommon in this condition. In two patients with advanced, poorly differentiated metastasizing cancer a fairly uniform clinical picture developed, with anaemia, leukocytosis, increased serum creatinine, thrombocytopenia, elevated alkaline and acid phosphatase levels and symptoms secondary to hypercalcaemia. The development of more effective agents against cancer of the prostate will probably afford longer palliation, but evidently at a risk of severe metabolic disturbances in the preterminal state.
According to Kessinger, Lemon & Foley (1972) hypercalcaemia is more often a manifestation of malignancy than of any other disease, including hyperparathyroidism. In their opinion, hypercalcaemia is most commonly a sign of skeletal metastases, though such metastases are absent in up to one in five patients with hypercalcaemia. Most forms of cancer follow a special pattern when metastasizing. The cause of this phenomenon in largely unknown. Cancer of the prostate often spreads to bone. Of these metastases 80% are osteoblastic, only a few are lytic and the rest are of mixed type (Bontoux, Massias, Sultan & Coste, 1964; Jorgens 1965). Despite the high incidence of skeletal metastases, hypercalcaemia in patients with such spread of prostatic cancer is extremely uncommon (Kessinger et al.). To our knowledge only one case has previously been reported. This patient, a 66-year-old diabetic, had pure osteolytic metastases and terminally appearing hypercalcaemia (Sors, Bousser, Chomette & Decroix, 1968). Even when the calcium level in the blood is normal, the metabolism of calcium is often disturbed when bone metastases are established. The osteo-
blastic metastases of prostatic cancer produce in most cases a positive calcium balance, as reflected in severe hypocalciuria. Osteolytic metastases, on the other hand, induce a clear negative balance with hypercalciuria. Treatment of the cancer with orchidectomy or oestrogens may cause, in addition to altered nitrogen balance, pronounced retention of calcium with hypocalciuria (Loeper & Loeper, 1946; Schilling, Laszlo, Bellin & Gottesman, 1950; Spencer, Eisinger & Laszlo, 1960; Spencer & Lewin, 1963; Beckett, 1969). The mineral metabolism in patients with prostatic carcinoma and extensive osteoblastic metastases differs greatly from that in patients with metastizing carcinoma of the breast, lung or thyroid. The outstanding differentiating feature is the skeletal affinity for calcium in patients with bone metastases from carcinoma of the prostate. A favourable response to oestrogen therapy is characterized by markedly lessened urinary excretion of calcium and relief of bone pain (Spencer et al.). Oestrogens have been shown to inhibit mobilization of calcium from the bones and probably also to increase the deposition of calcium. The mechanism is considered to be decreased sensitivity of the skeleton to parathyroid hormone following oestrogen treatment (Rasmussen & Bordier, 1974; Spencer et al.). We have recently treated two patients who when first seen had low-grade prostatic carcinoma with elevated levels of prostatic acid phosphatases. One of them also had a positive cervical lymph-node biopsy. Both responded favourably to estramustine phosphate (Estracyt@,Leo, Sweden) with normalization of the acid phosphatases. Bone metastases appeared, however, after 10 and 48 months, respectively. Within six months thereafter both patients Scnnd J Urol Nmhrol I I
294
A . M . Olsson and G. Jiinsson
showed a fairly similar clinical picture of anaemia, leukocytosis, raised serum creatinine readings, thrombocytopenia, greatly increased acid and alkaline phosphatases and symptoms secondary to h ypercalcaemia.
Downloaded by [Monash University Library] at 18:14 10 April 2016
CASE REPORTS Case I A 49-year-old man sought advice for haematuria and swelling of the left arm in April, 1973. Poorly differentiated cancer of the prostate with metastases to the left supraclavicular lymph nodes was diagnosed. The acid phosphatase readings were elevated, but roentgenologic examination showed no skeletal metastases. He was initially treated with estramustine phosphate (Estracyt") intravenously for three weeks and thereafter by the peroral route. After two months' treatment he was free from symptoms, the lymph-node metastases were no longer palpable and the acid phosphatase level had normalized. The administration of estramustine phosphate was continued. In January, 1974 the patient complained of pain in the back. The acid phosphatase reading had again been raised for about a month. Osteosclerotic bone metastases were now roentgenologically seen in the spine and pelvis. T w o months later he was admitted to the department of surgery with haematemesis. The serum creatinine was increased and leukocytosis was present. On April I , 1974 the serum calcium was seen for the first time to be increased. Several readings above 3.50 mmol/l were noted. The leukocyte count was now 2 0 ~ 1 0 ~ and / 1 the serum creatinine 200 pmol/l. The thrombocyte count was slightly subnormal. He was treated with 160 mg furosemide and 6 mg betamethasone daily and 100 mg testosterone proprionate every other day. At first his condition deteriorated until he was confined to bed by weakness, nausea and vomiting and frequent hallucinations. But within a week after this medication was begun the serum calcium normalized. Recovery proceeded but the patient remained in hospital for another month because of thrombocytopenia. H e was discharged in the beginning of May and was prescribed 300 mg Estracyt"x3 daily, 40 mg furosemidex2 and 0.5 mg betamethasonex3 daily. He was able to resume outdoor activities and, apart from impotence. was asymptomatic. In June and July there was roentgenologic progression of osteosclerotic and osteolytic metastases. Pulmonary lesions also appeared. On August I he was rehospitalized, now in poor condition with haematemesis and melaena. He was anaemic. His leukocyte count was 1 7 ~ 1 and 0~ thrombocytes 54X IO'/l. The serum calcium was 4.2 mmol and the serum creatinine 170 pmol/l. Ten days later he was able to leave hospital, but was soon readmitted. He died on August 21, 1974. The post-mortem examination showed extensive metastases to the skeleton, the para-aortic, paratracheal and hilar lymph nodes bilaterally. Metastases were seen also in lymph nodes around the coeliac artery and in the mesentery. Metastasis had further occurred to the adrena l ~ .the pericardium and retroperitoneally around the
ureters. Microscopy of specimens from the kidneys showed scattered calcifications in the tubules, but no other renal lesions. Case 2 A 48-year-old farmer presented in May, 1970 with frequency of micturition and weak stream. Moderately well differentiated cancer of the prostate with elevation of the acid phosphatase levels was diagnosed. An arteriovenous shunt was established and twice weekly intravenous administration of estramustine phosphate (Estracyt") was begun in August of that year. The skeleton. lungs and kidneys were roentgenologically normal. though skeletal scintigram was not performed. Because of practical problems concerning the injections, his medication was changed after three months to polyestradiolphosphate (Estradurin", Leo, Sweden). 160 g per month and ethinyl-estradiol 1 mg daily. Another change was made in May, 1971. now to Estracyt by mouth. and this treatment was maintained. Follow-up examination now showed the patient to be symptom-free and with normal acid phosphatase. Roentgenologically the bladder showed a diminished prostatic impression, which accorded with considerable palpatory regression of the tumour. For the next three years the patient was in good health. apart from diminished libido, though he was embarrassed by gynaecomastia. During this time the acid phosphatase was normal, a s were roentgenograms of the skeleton, kidneys and lungs. Progression of the primary tumour was noted early in 1974 and at examination on April 25 the acid phosphatase reading was slightly elevated. T w o weeks later he was admitted to the department of urology for problems relating to micturition. The skeleton. kidneys and lungs were still roentgenologically normal, and also a skeletal scintigram. After local radiotherapy (5000 rad) t o the prostate the symptoms subsided. Aching pain in the right hip and the spine developed in August. Increased levels of alkaline and acid phosphatases were found on October 10. but laboratory tests otherwise were normal. During this month the patient attended the department of surgery several times because of abdominal pain and vomiting. On one Occasion the serum amylase was found to he increased. but the serum calcium was normal. On November 27 he was admitted as a surgical emergency with abdominal pain. Two days later the serum calcium was 3.9 mmol/l and similar values were observed on the following days. Furosemide in a dose of 8OL120 mg per day was ineffective and on December 3 he received an infusion of calcitonin. On the following day the serum calcium was 2 . 8 mmol/l. Examination of the sternal marrow showed numerous malignant cells. He was transferred to the department of urology. In addition to increased serum calcium. the thrombocyte count was < l 0 0 X lo9 and the serum creatinine about 400 pmol/l. Basic treatment of the hypercalcaemia consisted of 5 mg betamethasone and 80-190 mg furosemide daily. One week later the daily urinary output had increased to 7 liters and the serum calcium and creatinine levels were lowered. At the beginning of January. 197.5 the
Advanced cancer of the prostate and hyperculcuernia thromhocyte count had fallen to 10x109 and petechiae appeared on the mucosa and the skin. For the last two months of his life he received parenteral nutrition. Progressive deterioration was associated with epigastric pain, vomiting and hypoalhuminaemic oedema and he died on February 3, 1975. Autopsy showed prostatic carcinoma with extensive metastases to the skeleton, liver and para-aortic lymph nodes.
Downloaded by [Monash University Library] at 18:14 10 April 2016
DISCUSSION Both these patients were relatively young when prostatic cancer with initially increased prostatic acid phosphatase was detected. In Case 1 histologically confirmed distant metastases had already appeared. Both patients reacted favourably to Estracyt@. They survived for 18 and 55 months, respectively, after the diagnosis was made. When the tumour became therapy-resistant, elevated acid phosphatase readings were the first objective sign of tumour progression. Skeletal metastases appeared later. The clinical course was chronologically different, though the presentation was similar. In addition to hypercalcaemia, both patients became anaemic with leukocytosis and thrombocytopenia and increased serum creatinine and acid and alkaline phosphatases. Extensive metastases were found at autopsy. This can explain the altered blood counts and the elevated acid phosphatase readings, but scarcely the increased serum creatinine. The histologic observations indicated that the patients had renal changes of the type usually seen in hypercalcaemic states, such as hyperparathyroidism. Many theories have been advanced concerning the origin of the hypercalcaemia seen in malignancies without skeletal metastases. They include production by the tumour of a parathyroidor vitamin D-like hormone, of a parathyroidstimulating substance o r of factors activating prostaglandins or osteoblasts (Munson. Tashjian & Levine, 1965: Raisz. 1973; Powell. Singer, Murray, Minkin & Potts, 1973; Benson, Riggs. Pickard & Arnaud, 1974: Brewer, 1974; Tashjian. 1974). In the two cases here presented, however, extensive, partly lytic skeletal metastases were, in our opinion. the cause of the hypercalcaemia. Treatment with furosemide and betamethasone was highly effective, and the infusion of calcitonin in Case 2 WBS probably unnecessary.
29s
Corticosteroids are considered to be especially effective against the hypercalcaemia of malignancy by acting directly on the tumour, decreasing hormone production and also altering hormone metabolism (Pearson, 1964). Although oestrogens undoubtedly alter calcium metabolism, hypercalcaemia has not been observed in this department either among the conventionally oestrogen-treated patients with prostatic carcinoma or among the more than 200 who have received Estracyt@some of them for more than five years. E s t r a c y P is more effective when given as initial therapy (Nilsson & Jonsson, 1976), and consequently it should be the treatment of choice in poorly differentiated or advanced prostatic carcinoma. The advent of EstracytO has augmented the therapeutic arsenal against prostatic carcinoma with a very effective weapon, and we may anticipate that many more patients with advanced disease will obtain much longer palliation. The terminal stage of the disease, however, can probably be delayed only with increasing risk of clinical phenomena of the type presented by our two patients.
REFERENCES Beckett, V. L. 1969. Hypercalcemia associated with estrogen administration in patients with breast carcinoma. Cancer 24, 610. Benson, R. C., Riggs, B. L., Pickard, B. M. & Arnaud, C. D. 1974. Radioimmunoassay of parathyroid hormone in hypercalcemic patients with malignant disease. Am J M e d 5 6 , 821. Brewer, H. B. 1974. Osteoclastic bone resorption and the hypercalcemia of cancer. N Engl J M r d 291, 1081. Bontoux, D., Massias, P., Sultan, Y . & Coste. F. 1964. A propos des metastases osteolytiques d u cancer de la prostate. Revue Rhum 31. 604. Jacobsen, E. & Nilsson. T. 1975. Remarkable response of estrogen resistant prostatic carcinoma to Estracyt. OIJUSC
Mrd 20, 20.
Jorgens, J . 196.5. The radiographic characteristics of carcinoma of the prostate. Surx CIin North A m 42, 1427. Kessinger, A , , Lemon, H. M . & Foley, J . F. 1972. Hypercalcemia of malignancy. Geriofric.s27, 97. Loeper, J. & Loeper, J . 1946. Le metabolisme du calcium au cour des cancers du sein et de la prostate avec metastases osseuses. Lr ProgrPs ML.d 74, 70. Munson, P. L., Tashjian, A. H., Jr & Levine, L. 1965. Evidence for parathyroid hormone in nonparathyroid tumors associated with hypercalcemia. Cancer Res 25, 1062.
Nilsson, T. & Jonsson, G. 1976. Primary treatment of prostatic carcinoma with estramustine phosphate. Preliminary report. J Urol115. 168. S C( m l J U r o l Nrplirril I I
296
A . M . Olssan und G. Jiinsson
Downloaded by [Monash University Library] at 18:14 10 April 2016
Pearson. 0. H . 1964. Disturbances of calcium metabolism in the cancer patient. Proc Nutl Cancer C o n f 5 , 445. Powell, D., Singer, F. R., Murray, T. M., Minkin, C. & Potts, J. T., Jr. 1973. Nonparathyroid humoral hypercalcemia in patients with neoplastic diseases. N Engl J Med 289, 176. Raisz, L. G. 1973. Prostaglandins and the hypercalcemia of cancer. N Engl J Med 289, 214. Rasmussen, H . & Bordier, Ph. 1974. The physiological and cellular basis of metabolic bone disease. Williams & Wilkins, Baltimore. Schilling, A , , Laszlo, D., Bellin, J. & Gottesman, E. D. 1950. The effect of diethylstilbestrol on the calcium, phosphorus and nitrogen metabolism of prostatic carcinoma. J CIin Invest 29, 918.
Sors, Ch., Bousser, M. G.. Chomette, G. & Decroix, G . 1968. Syndrome hypercalcemique terminal au cows de metastases osteo-lytiques d’un cancer de la prostate. Bull et Mem de lu Soc Med des Hfip 119 , 43 1. Spencer, H . , Eisinger, R. & Laszlo, D. 1960. Metabolic and radioactive tracer studies in carcinoma of the prostate. A m J Med 29, 282. Spencer, H. & Lewin, I . 1963. Derangements of calcium metabolism in patients with neoplastic bone involvement. J Chronic Dis 16, 713. Tashjian, A . H . , Jr. 1974. Tumor humors and the hypercalcemias of cancer. N Engl J Med 290, 905.
ISSN: 0036-5599 (Print) 1651-2065 (Online) Journal homepage: http://www.tandfonline.com/loi/isju19
Advanced Cancer of the Prostate Combined with Hypercalcaemia Arne M. Olsson & Gösta Jönsson To cite this article: Arne M. Olsson & Gösta Jönsson (1977) Advanced Cancer of the Prostate Combined with Hypercalcaemia, Scandinavian Journal of Urology and Nephrology, 11:3, 293-296, DOI: 10.3109/00365597709179968 To link to this article: http://dx.doi.org/10.3109/00365597709179968
Published online: 15 Feb 2010.
Submit your article to this journal
Article views: 1
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=isju19 Download by: [Monash University Library]
Date: 10 April 2016, At: 18:14
Scand J Urol Nephrol 11: 293-296, 1977
ADVANCED CANCER OF THE PROSTATE COMBINED WITH HYPERCALCAEMIA Arne M. Olsson and Gosta Jonsson From the Department of Urology, University Hospital of Lund, Lund, Sweden
(Submitted for publication October 14, 1976)
Downloaded by [Monash University Library] at 18:14 10 April 2016
Absfract. Despite the high frequency of skeletal meta-
stases from cancer of the prostate, hypercalcaemia is extremely uncommon in this condition. In two patients with advanced, poorly differentiated metastasizing cancer a fairly uniform clinical picture developed, with anaemia, leukocytosis, increased serum creatinine, thrombocytopenia, elevated alkaline and acid phosphatase levels and symptoms secondary to hypercalcaemia. The development of more effective agents against cancer of the prostate will probably afford longer palliation, but evidently at a risk of severe metabolic disturbances in the preterminal state.
According to Kessinger, Lemon & Foley (1972) hypercalcaemia is more often a manifestation of malignancy than of any other disease, including hyperparathyroidism. In their opinion, hypercalcaemia is most commonly a sign of skeletal metastases, though such metastases are absent in up to one in five patients with hypercalcaemia. Most forms of cancer follow a special pattern when metastasizing. The cause of this phenomenon in largely unknown. Cancer of the prostate often spreads to bone. Of these metastases 80% are osteoblastic, only a few are lytic and the rest are of mixed type (Bontoux, Massias, Sultan & Coste, 1964; Jorgens 1965). Despite the high incidence of skeletal metastases, hypercalcaemia in patients with such spread of prostatic cancer is extremely uncommon (Kessinger et al.). To our knowledge only one case has previously been reported. This patient, a 66-year-old diabetic, had pure osteolytic metastases and terminally appearing hypercalcaemia (Sors, Bousser, Chomette & Decroix, 1968). Even when the calcium level in the blood is normal, the metabolism of calcium is often disturbed when bone metastases are established. The osteo-
blastic metastases of prostatic cancer produce in most cases a positive calcium balance, as reflected in severe hypocalciuria. Osteolytic metastases, on the other hand, induce a clear negative balance with hypercalciuria. Treatment of the cancer with orchidectomy or oestrogens may cause, in addition to altered nitrogen balance, pronounced retention of calcium with hypocalciuria (Loeper & Loeper, 1946; Schilling, Laszlo, Bellin & Gottesman, 1950; Spencer, Eisinger & Laszlo, 1960; Spencer & Lewin, 1963; Beckett, 1969). The mineral metabolism in patients with prostatic carcinoma and extensive osteoblastic metastases differs greatly from that in patients with metastizing carcinoma of the breast, lung or thyroid. The outstanding differentiating feature is the skeletal affinity for calcium in patients with bone metastases from carcinoma of the prostate. A favourable response to oestrogen therapy is characterized by markedly lessened urinary excretion of calcium and relief of bone pain (Spencer et al.). Oestrogens have been shown to inhibit mobilization of calcium from the bones and probably also to increase the deposition of calcium. The mechanism is considered to be decreased sensitivity of the skeleton to parathyroid hormone following oestrogen treatment (Rasmussen & Bordier, 1974; Spencer et al.). We have recently treated two patients who when first seen had low-grade prostatic carcinoma with elevated levels of prostatic acid phosphatases. One of them also had a positive cervical lymph-node biopsy. Both responded favourably to estramustine phosphate (Estracyt@,Leo, Sweden) with normalization of the acid phosphatases. Bone metastases appeared, however, after 10 and 48 months, respectively. Within six months thereafter both patients Scnnd J Urol Nmhrol I I
294
A . M . Olsson and G. Jiinsson
showed a fairly similar clinical picture of anaemia, leukocytosis, raised serum creatinine readings, thrombocytopenia, greatly increased acid and alkaline phosphatases and symptoms secondary to h ypercalcaemia.
Downloaded by [Monash University Library] at 18:14 10 April 2016
CASE REPORTS Case I A 49-year-old man sought advice for haematuria and swelling of the left arm in April, 1973. Poorly differentiated cancer of the prostate with metastases to the left supraclavicular lymph nodes was diagnosed. The acid phosphatase readings were elevated, but roentgenologic examination showed no skeletal metastases. He was initially treated with estramustine phosphate (Estracyt") intravenously for three weeks and thereafter by the peroral route. After two months' treatment he was free from symptoms, the lymph-node metastases were no longer palpable and the acid phosphatase level had normalized. The administration of estramustine phosphate was continued. In January, 1974 the patient complained of pain in the back. The acid phosphatase reading had again been raised for about a month. Osteosclerotic bone metastases were now roentgenologically seen in the spine and pelvis. T w o months later he was admitted to the department of surgery with haematemesis. The serum creatinine was increased and leukocytosis was present. On April I , 1974 the serum calcium was seen for the first time to be increased. Several readings above 3.50 mmol/l were noted. The leukocyte count was now 2 0 ~ 1 0 ~ and / 1 the serum creatinine 200 pmol/l. The thrombocyte count was slightly subnormal. He was treated with 160 mg furosemide and 6 mg betamethasone daily and 100 mg testosterone proprionate every other day. At first his condition deteriorated until he was confined to bed by weakness, nausea and vomiting and frequent hallucinations. But within a week after this medication was begun the serum calcium normalized. Recovery proceeded but the patient remained in hospital for another month because of thrombocytopenia. H e was discharged in the beginning of May and was prescribed 300 mg Estracyt"x3 daily, 40 mg furosemidex2 and 0.5 mg betamethasonex3 daily. He was able to resume outdoor activities and, apart from impotence. was asymptomatic. In June and July there was roentgenologic progression of osteosclerotic and osteolytic metastases. Pulmonary lesions also appeared. On August I he was rehospitalized, now in poor condition with haematemesis and melaena. He was anaemic. His leukocyte count was 1 7 ~ 1 and 0~ thrombocytes 54X IO'/l. The serum calcium was 4.2 mmol and the serum creatinine 170 pmol/l. Ten days later he was able to leave hospital, but was soon readmitted. He died on August 21, 1974. The post-mortem examination showed extensive metastases to the skeleton, the para-aortic, paratracheal and hilar lymph nodes bilaterally. Metastases were seen also in lymph nodes around the coeliac artery and in the mesentery. Metastasis had further occurred to the adrena l ~ .the pericardium and retroperitoneally around the
ureters. Microscopy of specimens from the kidneys showed scattered calcifications in the tubules, but no other renal lesions. Case 2 A 48-year-old farmer presented in May, 1970 with frequency of micturition and weak stream. Moderately well differentiated cancer of the prostate with elevation of the acid phosphatase levels was diagnosed. An arteriovenous shunt was established and twice weekly intravenous administration of estramustine phosphate (Estracyt") was begun in August of that year. The skeleton. lungs and kidneys were roentgenologically normal. though skeletal scintigram was not performed. Because of practical problems concerning the injections, his medication was changed after three months to polyestradiolphosphate (Estradurin", Leo, Sweden). 160 g per month and ethinyl-estradiol 1 mg daily. Another change was made in May, 1971. now to Estracyt by mouth. and this treatment was maintained. Follow-up examination now showed the patient to be symptom-free and with normal acid phosphatase. Roentgenologically the bladder showed a diminished prostatic impression, which accorded with considerable palpatory regression of the tumour. For the next three years the patient was in good health. apart from diminished libido, though he was embarrassed by gynaecomastia. During this time the acid phosphatase was normal, a s were roentgenograms of the skeleton, kidneys and lungs. Progression of the primary tumour was noted early in 1974 and at examination on April 25 the acid phosphatase reading was slightly elevated. T w o weeks later he was admitted to the department of urology for problems relating to micturition. The skeleton. kidneys and lungs were still roentgenologically normal, and also a skeletal scintigram. After local radiotherapy (5000 rad) t o the prostate the symptoms subsided. Aching pain in the right hip and the spine developed in August. Increased levels of alkaline and acid phosphatases were found on October 10. but laboratory tests otherwise were normal. During this month the patient attended the department of surgery several times because of abdominal pain and vomiting. On one Occasion the serum amylase was found to he increased. but the serum calcium was normal. On November 27 he was admitted as a surgical emergency with abdominal pain. Two days later the serum calcium was 3.9 mmol/l and similar values were observed on the following days. Furosemide in a dose of 8OL120 mg per day was ineffective and on December 3 he received an infusion of calcitonin. On the following day the serum calcium was 2 . 8 mmol/l. Examination of the sternal marrow showed numerous malignant cells. He was transferred to the department of urology. In addition to increased serum calcium. the thrombocyte count was < l 0 0 X lo9 and the serum creatinine about 400 pmol/l. Basic treatment of the hypercalcaemia consisted of 5 mg betamethasone and 80-190 mg furosemide daily. One week later the daily urinary output had increased to 7 liters and the serum calcium and creatinine levels were lowered. At the beginning of January. 197.5 the
Advanced cancer of the prostate and hyperculcuernia thromhocyte count had fallen to 10x109 and petechiae appeared on the mucosa and the skin. For the last two months of his life he received parenteral nutrition. Progressive deterioration was associated with epigastric pain, vomiting and hypoalhuminaemic oedema and he died on February 3, 1975. Autopsy showed prostatic carcinoma with extensive metastases to the skeleton, liver and para-aortic lymph nodes.
Downloaded by [Monash University Library] at 18:14 10 April 2016
DISCUSSION Both these patients were relatively young when prostatic cancer with initially increased prostatic acid phosphatase was detected. In Case 1 histologically confirmed distant metastases had already appeared. Both patients reacted favourably to Estracyt@. They survived for 18 and 55 months, respectively, after the diagnosis was made. When the tumour became therapy-resistant, elevated acid phosphatase readings were the first objective sign of tumour progression. Skeletal metastases appeared later. The clinical course was chronologically different, though the presentation was similar. In addition to hypercalcaemia, both patients became anaemic with leukocytosis and thrombocytopenia and increased serum creatinine and acid and alkaline phosphatases. Extensive metastases were found at autopsy. This can explain the altered blood counts and the elevated acid phosphatase readings, but scarcely the increased serum creatinine. The histologic observations indicated that the patients had renal changes of the type usually seen in hypercalcaemic states, such as hyperparathyroidism. Many theories have been advanced concerning the origin of the hypercalcaemia seen in malignancies without skeletal metastases. They include production by the tumour of a parathyroidor vitamin D-like hormone, of a parathyroidstimulating substance o r of factors activating prostaglandins or osteoblasts (Munson. Tashjian & Levine, 1965: Raisz. 1973; Powell. Singer, Murray, Minkin & Potts, 1973; Benson, Riggs. Pickard & Arnaud, 1974: Brewer, 1974; Tashjian. 1974). In the two cases here presented, however, extensive, partly lytic skeletal metastases were, in our opinion. the cause of the hypercalcaemia. Treatment with furosemide and betamethasone was highly effective, and the infusion of calcitonin in Case 2 WBS probably unnecessary.
29s
Corticosteroids are considered to be especially effective against the hypercalcaemia of malignancy by acting directly on the tumour, decreasing hormone production and also altering hormone metabolism (Pearson, 1964). Although oestrogens undoubtedly alter calcium metabolism, hypercalcaemia has not been observed in this department either among the conventionally oestrogen-treated patients with prostatic carcinoma or among the more than 200 who have received Estracyt@some of them for more than five years. E s t r a c y P is more effective when given as initial therapy (Nilsson & Jonsson, 1976), and consequently it should be the treatment of choice in poorly differentiated or advanced prostatic carcinoma. The advent of EstracytO has augmented the therapeutic arsenal against prostatic carcinoma with a very effective weapon, and we may anticipate that many more patients with advanced disease will obtain much longer palliation. The terminal stage of the disease, however, can probably be delayed only with increasing risk of clinical phenomena of the type presented by our two patients.
REFERENCES Beckett, V. L. 1969. Hypercalcemia associated with estrogen administration in patients with breast carcinoma. Cancer 24, 610. Benson, R. C., Riggs, B. L., Pickard, B. M. & Arnaud, C. D. 1974. Radioimmunoassay of parathyroid hormone in hypercalcemic patients with malignant disease. Am J M e d 5 6 , 821. Brewer, H. B. 1974. Osteoclastic bone resorption and the hypercalcemia of cancer. N Engl J M r d 291, 1081. Bontoux, D., Massias, P., Sultan, Y . & Coste. F. 1964. A propos des metastases osteolytiques d u cancer de la prostate. Revue Rhum 31. 604. Jacobsen, E. & Nilsson. T. 1975. Remarkable response of estrogen resistant prostatic carcinoma to Estracyt. OIJUSC
Mrd 20, 20.
Jorgens, J . 196.5. The radiographic characteristics of carcinoma of the prostate. Surx CIin North A m 42, 1427. Kessinger, A , , Lemon, H. M . & Foley, J . F. 1972. Hypercalcemia of malignancy. Geriofric.s27, 97. Loeper, J. & Loeper, J . 1946. Le metabolisme du calcium au cour des cancers du sein et de la prostate avec metastases osseuses. Lr ProgrPs ML.d 74, 70. Munson, P. L., Tashjian, A. H., Jr & Levine, L. 1965. Evidence for parathyroid hormone in nonparathyroid tumors associated with hypercalcemia. Cancer Res 25, 1062.
Nilsson, T. & Jonsson, G. 1976. Primary treatment of prostatic carcinoma with estramustine phosphate. Preliminary report. J Urol115. 168. S C( m l J U r o l Nrplirril I I
296
A . M . Olssan und G. Jiinsson
Downloaded by [Monash University Library] at 18:14 10 April 2016
Pearson. 0. H . 1964. Disturbances of calcium metabolism in the cancer patient. Proc Nutl Cancer C o n f 5 , 445. Powell, D., Singer, F. R., Murray, T. M., Minkin, C. & Potts, J. T., Jr. 1973. Nonparathyroid humoral hypercalcemia in patients with neoplastic diseases. N Engl J Med 289, 176. Raisz, L. G. 1973. Prostaglandins and the hypercalcemia of cancer. N Engl J Med 289, 214. Rasmussen, H . & Bordier, Ph. 1974. The physiological and cellular basis of metabolic bone disease. Williams & Wilkins, Baltimore. Schilling, A , , Laszlo, D., Bellin, J. & Gottesman, E. D. 1950. The effect of diethylstilbestrol on the calcium, phosphorus and nitrogen metabolism of prostatic carcinoma. J CIin Invest 29, 918.
Sors, Ch., Bousser, M. G.. Chomette, G. & Decroix, G . 1968. Syndrome hypercalcemique terminal au cows de metastases osteo-lytiques d’un cancer de la prostate. Bull et Mem de lu Soc Med des Hfip 119 , 43 1. Spencer, H . , Eisinger, R. & Laszlo, D. 1960. Metabolic and radioactive tracer studies in carcinoma of the prostate. A m J Med 29, 282. Spencer, H. & Lewin, I . 1963. Derangements of calcium metabolism in patients with neoplastic bone involvement. J Chronic Dis 16, 713. Tashjian, A . H . , Jr. 1974. Tumor humors and the hypercalcemias of cancer. N Engl J Med 290, 905.
