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Management and prognostic significance hypercalcemia in renal cell carcinoma
SCIENTIFIC ARTICLES
MANAGEMENT
AND PROGNOSTIC
HYPERCALCEMIA
SIGNIFIC:\\(
IN RENAL CELL CARCTKW
1“f 11.‘ 1
STUART A. CHASAN, M.D. L. RALPH POTHEL ROBERT
P HUBEN,
M.D.
From the Department of Urologic Oncology, Roswell Park Memorial Institute, Buffalo, New York
ABSTRACT-A retrospective study was conducted to evaluate the prognostic significance of hypercalcemia associated with renal cell carcinoma and the efficacy of different treatment modalities. Twenty-seven of 160 (16.8 %) patients with renal cell carcinoma werefound to have tumor-induced hypercalcemia: 24 had Stage IV disease, 1 Stage III disease, and 2 Stage I disease. There was no evidence of bone metastasis in 13 of 27 (48 %) patients. A total of 89 episodes of acute hypercalcemia were treated: 36 episodes resulted in a complete response ([CR] calcium levels returning to normal), 24 partial response ([PR] ca 1cium decrease >l mg/dL, but above normal) and 29 negligible response ([NR] ca 1cium decrease
Hypercalcemia associated with renal cell carcinoma is a problem the urologist must occasionally face. This condition can be quite perplexing to manage. Many times the urologist has limited experience with the types of agents available, their indications for use, and their effectiveness in treating hypercalcemia of renal cell carcinoma. Furthermore, one wonders how aggressive the treatment should be since many regard this condition as indicative of a rapidly declining status. In view of these questions, a retrospective study was undertaken to evaluate the prognostic significance of renal cell carcinoma-associated hypercalcemia and the efficacy of different treatment modalities.
UROI,OC~
I
MARCH
1989
/
VOLUME
XxX111,
NUMBER
Material and Methods The records of 160 patients with renal cell carcinoma seen at Roswell Park Memorial Institute (RPMI) over the past eight years were reviewed. Twenty-seven of these patients were found to have tumor-related hypercalcemia. Data were collected with respect to the stage of the disease at the initial diagnosis of hypercalcemia, evidence of bony metastasis at the initial diagnosis of hypercalcemia, and duration of survival between the onset of hypercalcemia and death. Furthermore, the response rates to each agent used to control the hypercalcemic episode were reviewed.
3
167
Response rates to treatment modalities for hypercalcemia of renal cell carcinoma*
TABLE I.
Agent Hydration Furosemide (Lasix) Mithramycin Mithramycin and furosemide Prednisone and furosemide Indocin and furosemide
Total Response
(??)
13
4 (31)
7 (54)
2 (15)
25 10
7 (28) 7 (70)
10 (40) 2 (20)
8 (32) 1 (10)
20
12 (60)
7 (35)
1
7
3 (43)
2 (28.5)
2 (28.5)
5
Other agents Oral or IV phosphates and furosemide, calcitonin and 6 furosemide Nephrectomy 3
(5)
5
1 2
2 1
3 0
*Complete response (CR)-serum normal (8.6-10.5 mg/dL). serum calcium greater than ble response (NR)-decrease
calcium level returning to Partial response (PR)-decreases in 1 mg/dL but above normal. Negligiin serum calcium less than 1 mg/dL.
A complete response (CR) was defined as a calcium level returning to our normal laboratory range (8.6-10.5 mg/dL), a partial response (PR) as a decrease in serum calcium greater than 1 mg/dL but above normal, and a neglible response (NR) was defined as a decrease in serum calcium less than 1 mg/dL. The total number of CRs, PRs, and NRs for each agent was recorded. The agents used primarily to manage the hypercalcemic episodes in this series were hydration (0.45 NS or 0.09 NS at 100-200 cc/hr), furosemide (40-160 mg IV in divided doses), mithramycin (15-25 p/kg), prednisone (30-60 mg/day in divided doses) and indomethacin (50 mg po tid). Intravenous calcitonin and oral phosphates were also used in a small number of patients. Results Twenty-seven of 160 patients (16.8%) with renal cell carcinoma were found to have tumorrelated hypercalcemia. There was no evidence of bone metastasis in 13 of 27 (48%) patients. A total of 89 episodes of hypercalcemia were documented. Thirty-six episodes had CR, 24 episodes had PR, and 29 episodes had NR to treatment modalities used. Twenty-four of 27 patients had Stage IV disease, 1 had Stage III disease, and 2 had Stage I disease. One patient with localized disease and 2 patients with metastatic disease underwent a
168
nephrectomy at the time of their hypercalcemic presentation. Of the 2 patients with metastatic disease, 1 had a PR and the other had a CR. The 1 patient with localized disease had CR to nephrectomy. The response rates of these agents by themselves and in combination were the following: mithramycin had the highest response rate. Seven of 10 hypercalcemic episodes (70%) had a CR to mithramycin and 12 of 20 episodes (60%) had a CR to furosemide and mithramytin. Furosemide or hydration had moderately effective response rates. Four of 13 (31%) hypercalcemic episodes had a CR to hydration and 7 of 25 (28 %) had CR to furosemide. Prednisone had an effective response rate. Three of 7 (43%) hypercalcemic episodes had CR to furosemide and prednisone. Indomethacin produced NR in 5 hypercalcemic episodes. The response rates to intravenous phosphates, oral phosphates, and calcitonin were low but this was a limited experience (Table I). The survival following the diagnosis of hypercalcemia of 24 patients with Stage IV disease was 5-239 days with an average survival of 87.3 days. The survival of Stage IV patients who had an initial calcium level of 13 or greater was 5-203 days with an average survival of 84.9 days. Stage IV patients with an initial calcium level less than 13 survived 8-239 days with an average of 89.2 days. Comment Renal cell carcinoma accounts for approximately 3 percent of patients with hypercalcemia of malignancy. 1,2 Hypercalcemia occurs in approximately 3-13 percent of patients with renal cell carcinoma.3-5 In our experience, most of our patients with hypercalcemia of renal cell carcinoma presented with advanced disease. We assume this fact accounts for our higher incidence (16.8 % ) of hypercalcemia of renal cell carcinoma than reported in other studies. Several local and systemic agents have been proposed as the mediators responsible for producing hypercalcemia of renal cell carcinoma. These include parathyroid hormone (PTH), PTH-like factor, prostaglandins, osteoclastic activating factor, and 1,25-dihydroxy vitamin D.6mgIn the past, it was assumed that bony destruction secondary to metastatic disease was largely responsible for renal cell carcinoma-associated hypercalcemia. This theory has been refuted by substantial evidence that systemic mediators are responsible for hypercalcemia of
UROLOGY
/ MARCH 1989 / VOLUME XxX111, NUMBER 3
weeks.1.14 Side effects of mithramycin include hepatotoxicity, thrombocytopenia, and nephrotoxicity. 1 l4 We have found mithramycin alone or used with furosemide to be effective in controlling hypercalcemia, with a 60-70 percent CR rate. Other authors have had similar success. Their effective rates have varied from 80-100 percent.‘.15 Glucocorticoids may reduce hypercalcemia in malignancy by inhibiting tumor growth which may prevent the production of hypercalcemic mediators or may increase urinary calcium excretion. l6 Cushing syndrome may occur with the use of steroids. The recommended glucocorticoid dose of prednisone is 30-100 mg per day or its equivalent. l6 Response rates in the literature have varied from O-90 percent. 1~1*5.17 l8 Our responses with prednisone in 7 hypercalcemic episodes were 3 CR, 2 PR, and 2 NR. Most studies have shown little success with the use of indomethacin for treating hypercalcemia of malignancy. ].I9 Our data, too, have shown little response with the use of this drug alone. If the drug is used, a dose of 150 mg po per day is recommended.’ Other modalities that may be used for the management of malignancy-associated hypercalcemia are oral and intravenous phosphates, calcitonin, diphosphonates, and dialysis. We have had little or no experience with these modalities. Oral phosphates are drugs commonly used to control chronic hypercalcemia of malignancy. Their mechanism is to inhibit bone resorption, to decrease calcium absorption by forming calcium phosphate salts in the gut, and to prevent the conversion of 25-hydroxy vitamin D to 1,25dihydroxy vitamin D.’ The major side effects of phosphates are nausea and diarrhea. They also can cause soft tissue calcification and nephrocalcinosis. l.ly The usual dose of oral phosphates is l-3 g elemental phosphorus per day in divided doses. Their efficacy has been reported as high as 70 percent. 1 Intravenous phosphates are usually not recommended because they can frequently cause significant extraskeletal calcification.“j Also, a number of deaths have been reported with the use of this drug.lfi Calcitonin is a hormone produced by the thyroid gland that acts to inhibit bone resorption directly.] Calcitonin alone or with steroids has been shown to be effective for treating hypercalcemia of malignancy, especially hematologic malignancies.’ Response rates as high as 7080 percent have been reported.‘-‘” ADP
renal cell carcinomaafi y Furthermore, in the literature and in our study there are documented cases of renal cell carcinoma with hypercalcemia without bone metastasis.‘O Our series showed 13 of 27 patients had no evidence of bony lesions. There are a number of modalities available to treat renal cell carcinoma-associated hypercalcemia. General management should begin with stopping any drugs that might increase the serum calcium level, such as vitamin D, thiazides and absorbable antacids. Placing patients on a calcium restricted diet is unnecessary, since the source of the hypercalcemia is from bone. “.‘2 Agents that have been used to treat hypercalcemia of renal ceil carcinoma are hydration, loop diuretics, mithramycin, steroids, phosphates, diphosphonates, calcitonin, and indomethacin. Hydration is usually the initial agent used to treat acute hypercalcemia. Patients that present with acute hypercalcemia are usually severely dehydrated from vomiting, nausea, and polyuria. Aggressive hydration will serve to correct volume contraction. Normal saline is the fluid of choice since saline diuresis will promote calcium excretion by the kidneys.” Hypokalemia, hypomagnesemia, hypernatremia, and volume overload can occur with saline hydraelectrolytes should be monition, ‘I Therefore, tored closely. In patients who have a history of congestive heart failure or renal failure, vigorous fluid administration should be used cautiously. Loop diuretics (furosemide and ethacrynic acid) reduce calcium levels by stimulating a sodium diuresis which causes increased calcium excretion. lD As with hydration, electrolyte imbalance can occur. Potassium, sodium, and magnesium should be monitored carefully. The use of loop diuretics in the management of hypercalcemia is controversial. Effective response rates with furosemide have been reported.]:’ Howsever, opponents to loop diuretics argue their effect is secondary to hydration that is usually given with diuretics.’ We have had moderate success with furosemide, with 28 percent CR and 40 percent PR to such treatment. Mithramycin is a cytotoxic substance that inhibits RNA synthesis and bone resorption.‘.14 It can be used to manage both acute and chronic hypercalcemia. The standard dose is 15-25 pg/ effect is kg body weight. ’ l4 The hvpocalcemic usually seen within twenty-four to forty-eight hours and may last from a few days to several
UROI.OCY
I/ hlARCH
1989
I) \‘OI,UME XXXIII,
NUMBER
3
169
(amino-hydroxy-prophylidine diphosphonate) and ClzMDP (dichloromethylene diphosphonate) are diphosphonates that inhibit bone resorption. lg Currently, they are investigational drugs. 1g,2oHowever, clinical trials have shown effective response rates with these drugs.19320 For patients who present with acute hypercalcemia and severe renal failure, dialysis may be employed. Peritoneal or hemodialysis will cause a rapid reduction in serum calcium.16 A few cases of surgical management of renal cell carcinoma-associated hypercalcemia have been reported in the literature. Goldberg et aL21 reported many cases of renal cell-associated hypercalcemia which had effective responses to excision of their tumor7 One case of renal cell carcinoma-associated hypercalcemia which was effectively managed by surgical debulking of metastatic lesions has been reported. 22 Our series also has shown success in controlling renal cell carcinoma-associated hypercalcemia via surgery. One of our patients with Stage IV renal cell carcinoma and 1 patient with localized disease had a complete response to nephrectomy. In summary, mithramycin was the most effective agent in controlling renal cell carcinoma-associated hypercalcemia in the present series. Prednisone seems to be effective, but our experience was limited. Furosemide and/or hydration were moderately effective. We would recommend patients who present with renal cell carcinoma-associated hypercalcemia be managed initially with furosemide and/or hydration. Prednisone may also be used as an initial or supplementary agent. If these agents are unsuccessful, mithramycin should be employed. Excision of the primary tumor or metastatic lesions may be considered occasionally in selected patients if all medical treatment modalities fail and performance status is otherwise good. Surprisingly, the degree of calcium elevation did not show a significant correlation with survival. Although hypercalcemia is a dire prognostic sign, effective management may be associated with moderately prolonged survival (average survival of about 3 months in the present series, with occasional survivals of 7 to 8 months). In view of the fact that there are effective treatment modalities for renal cell car-
170
cinoma-associated hypercalcemia and that hydistressing percalcemia may produce symptoms, aggressive treatment of this condition may improve the patient’s quality of life, as well as survival. Buffalo,
666 Elm Street New York 14263 (DR. HUBEN)
References 1. Mundy GR, and Martin TJ: The hypercalcemia of malignancy-pathogenesis and management, Metabolism 31: 1247 (1982). 2. Smith R: Hypercalcemia presentation, Br J Hosp Med 3: 174 (1984). 3. Lockich JJ, and Harrison JH: Renal cell carcinoma: natural history and chemotherapeutic experience, J Ural 114: 371 (1975). 4. Skinner DG, et ~2: Diagnosis and management of renal cell carcinoma, Cancer 28: 1165 (1971). 5. Warren MM, Utz DC, and Kelalis PP: Concurrence of hypernephroma and hypercalcemia, Ann Surg 174: 863 (1971). 6. Altaffer LF, and Chenault OW: Paraneoplastic endocrinopathies associated with renal tumors, J Urol 122: 573 (1979). 7. Lubensky JD, and Gangai MP: The hypercalcemia of genitourinary malignancy, J Urol 121: 259 (1979). 8. Mundy GR: Pathogenesis of hypercalcemia of malignancy, Clin Endocrinol 23: 705 (1985). 9. Sufrin G, Golio A, and Murphy G: Serologic markers, paraneoplastic syndromes and ectopic hormone production in renal adenocarcinoma, in deKernion JB, and Pavane-Macaluso M (Eds): International Perspectives in Urology-Tumors of the Kidney, Baltimore, Williams & Wilkins, 1986, vol 13, pp 1-71. 10. Plimpton CH, and Gellhorn A: Hypercalcemia in malignant disease without evidence of bone destruction, Am J Med 21: 750 (1956). 11. Buescu A, Dimich AB, and Myers WP: Cancer hypercalcemia-a pragmatic approach, Clin Bull 5: 91 (1975). 12. Chopra D, and Clerkin EP: Hypercalcemia and malignant disease, Med Clin North Am 59: 441 (1975). 13. Suki WN, et al: Acute treatment of hypercalcemia with furosemide, N Engl J Med 283: 836 (1970). 14. Deftos LJ, and Neer R: Medical management of the hypercalcemia of malignancy, Ann Rev Med 25: 323 (1974). 15. Kimura S, et al: A retrospective evaluation of the medical treatment of malignancy-associated hypercalcemia, Jpn J Cancer Res 77: 85 (1986). 16. Walser M: Treatment of hypercalcemias, Mod Treat 7: 662 (1970). 17. Ashkar FS, Miller R, and Katimis RB: Effect of corticosteroids of hypercalcemia of malignant disease, Lancet 1: 41 (1971). 18. Thalassinos NC. and Ioulin GF: Failure of corticosteroid therapy to correct the hypercalcemia of malignant disease, Lancet 2: 537 (1970). 19. Stewart AF: Therapy of malignancy-associated hypercalcemia: 1983, Am J Med 74: 475 (1983). 20. Fetchick DA, and Mundy GR: Hypercalcemia of malignancy. Diagnosis and therapy, Comp Ther 12: 27 (1986). containing a 21. Goldberg MF, et al: Renal adenocarcinoma parathyroid hormone-like substance and associated with marked hypercalcemia, Am J Med 36: 805 (1964). 22. Goldberg RS, Pilcher DB, and Yates JW: The aggressive surgical management of hypercalcemia due to ectopic parathormone production, Cancer 45: 2652 (1980).
UROLOGY
I MARCH
1989
/ VOLUME
XXXIII.
NUMBER
3
MANAGEMENT
AND PROGNOSTIC
HYPERCALCEMIA
SIGNIFIC:\\(
IN RENAL CELL CARCTKW
1“f 11.‘ 1
STUART A. CHASAN, M.D. L. RALPH POTHEL ROBERT
P HUBEN,
M.D.
From the Department of Urologic Oncology, Roswell Park Memorial Institute, Buffalo, New York
ABSTRACT-A retrospective study was conducted to evaluate the prognostic significance of hypercalcemia associated with renal cell carcinoma and the efficacy of different treatment modalities. Twenty-seven of 160 (16.8 %) patients with renal cell carcinoma werefound to have tumor-induced hypercalcemia: 24 had Stage IV disease, 1 Stage III disease, and 2 Stage I disease. There was no evidence of bone metastasis in 13 of 27 (48 %) patients. A total of 89 episodes of acute hypercalcemia were treated: 36 episodes resulted in a complete response ([CR] calcium levels returning to normal), 24 partial response ([PR] ca 1cium decrease >l mg/dL, but above normal) and 29 negligible response ([NR] ca 1cium decrease
Hypercalcemia associated with renal cell carcinoma is a problem the urologist must occasionally face. This condition can be quite perplexing to manage. Many times the urologist has limited experience with the types of agents available, their indications for use, and their effectiveness in treating hypercalcemia of renal cell carcinoma. Furthermore, one wonders how aggressive the treatment should be since many regard this condition as indicative of a rapidly declining status. In view of these questions, a retrospective study was undertaken to evaluate the prognostic significance of renal cell carcinoma-associated hypercalcemia and the efficacy of different treatment modalities.
UROI,OC~
I
MARCH
1989
/
VOLUME
XxX111,
NUMBER
Material and Methods The records of 160 patients with renal cell carcinoma seen at Roswell Park Memorial Institute (RPMI) over the past eight years were reviewed. Twenty-seven of these patients were found to have tumor-related hypercalcemia. Data were collected with respect to the stage of the disease at the initial diagnosis of hypercalcemia, evidence of bony metastasis at the initial diagnosis of hypercalcemia, and duration of survival between the onset of hypercalcemia and death. Furthermore, the response rates to each agent used to control the hypercalcemic episode were reviewed.
3
167
Response rates to treatment modalities for hypercalcemia of renal cell carcinoma*
TABLE I.
Agent Hydration Furosemide (Lasix) Mithramycin Mithramycin and furosemide Prednisone and furosemide Indocin and furosemide
Total Response
(??)
13
4 (31)
7 (54)
2 (15)
25 10
7 (28) 7 (70)
10 (40) 2 (20)
8 (32) 1 (10)
20
12 (60)
7 (35)
1
7
3 (43)
2 (28.5)
2 (28.5)
5
Other agents Oral or IV phosphates and furosemide, calcitonin and 6 furosemide Nephrectomy 3
(5)
5
1 2
2 1
3 0
*Complete response (CR)-serum normal (8.6-10.5 mg/dL). serum calcium greater than ble response (NR)-decrease
calcium level returning to Partial response (PR)-decreases in 1 mg/dL but above normal. Negligiin serum calcium less than 1 mg/dL.
A complete response (CR) was defined as a calcium level returning to our normal laboratory range (8.6-10.5 mg/dL), a partial response (PR) as a decrease in serum calcium greater than 1 mg/dL but above normal, and a neglible response (NR) was defined as a decrease in serum calcium less than 1 mg/dL. The total number of CRs, PRs, and NRs for each agent was recorded. The agents used primarily to manage the hypercalcemic episodes in this series were hydration (0.45 NS or 0.09 NS at 100-200 cc/hr), furosemide (40-160 mg IV in divided doses), mithramycin (15-25 p/kg), prednisone (30-60 mg/day in divided doses) and indomethacin (50 mg po tid). Intravenous calcitonin and oral phosphates were also used in a small number of patients. Results Twenty-seven of 160 patients (16.8%) with renal cell carcinoma were found to have tumorrelated hypercalcemia. There was no evidence of bone metastasis in 13 of 27 (48%) patients. A total of 89 episodes of hypercalcemia were documented. Thirty-six episodes had CR, 24 episodes had PR, and 29 episodes had NR to treatment modalities used. Twenty-four of 27 patients had Stage IV disease, 1 had Stage III disease, and 2 had Stage I disease. One patient with localized disease and 2 patients with metastatic disease underwent a
168
nephrectomy at the time of their hypercalcemic presentation. Of the 2 patients with metastatic disease, 1 had a PR and the other had a CR. The 1 patient with localized disease had CR to nephrectomy. The response rates of these agents by themselves and in combination were the following: mithramycin had the highest response rate. Seven of 10 hypercalcemic episodes (70%) had a CR to mithramycin and 12 of 20 episodes (60%) had a CR to furosemide and mithramytin. Furosemide or hydration had moderately effective response rates. Four of 13 (31%) hypercalcemic episodes had a CR to hydration and 7 of 25 (28 %) had CR to furosemide. Prednisone had an effective response rate. Three of 7 (43%) hypercalcemic episodes had CR to furosemide and prednisone. Indomethacin produced NR in 5 hypercalcemic episodes. The response rates to intravenous phosphates, oral phosphates, and calcitonin were low but this was a limited experience (Table I). The survival following the diagnosis of hypercalcemia of 24 patients with Stage IV disease was 5-239 days with an average survival of 87.3 days. The survival of Stage IV patients who had an initial calcium level of 13 or greater was 5-203 days with an average survival of 84.9 days. Stage IV patients with an initial calcium level less than 13 survived 8-239 days with an average of 89.2 days. Comment Renal cell carcinoma accounts for approximately 3 percent of patients with hypercalcemia of malignancy. 1,2 Hypercalcemia occurs in approximately 3-13 percent of patients with renal cell carcinoma.3-5 In our experience, most of our patients with hypercalcemia of renal cell carcinoma presented with advanced disease. We assume this fact accounts for our higher incidence (16.8 % ) of hypercalcemia of renal cell carcinoma than reported in other studies. Several local and systemic agents have been proposed as the mediators responsible for producing hypercalcemia of renal cell carcinoma. These include parathyroid hormone (PTH), PTH-like factor, prostaglandins, osteoclastic activating factor, and 1,25-dihydroxy vitamin D.6mgIn the past, it was assumed that bony destruction secondary to metastatic disease was largely responsible for renal cell carcinoma-associated hypercalcemia. This theory has been refuted by substantial evidence that systemic mediators are responsible for hypercalcemia of
UROLOGY
/ MARCH 1989 / VOLUME XxX111, NUMBER 3
weeks.1.14 Side effects of mithramycin include hepatotoxicity, thrombocytopenia, and nephrotoxicity. 1 l4 We have found mithramycin alone or used with furosemide to be effective in controlling hypercalcemia, with a 60-70 percent CR rate. Other authors have had similar success. Their effective rates have varied from 80-100 percent.‘.15 Glucocorticoids may reduce hypercalcemia in malignancy by inhibiting tumor growth which may prevent the production of hypercalcemic mediators or may increase urinary calcium excretion. l6 Cushing syndrome may occur with the use of steroids. The recommended glucocorticoid dose of prednisone is 30-100 mg per day or its equivalent. l6 Response rates in the literature have varied from O-90 percent. 1~1*5.17 l8 Our responses with prednisone in 7 hypercalcemic episodes were 3 CR, 2 PR, and 2 NR. Most studies have shown little success with the use of indomethacin for treating hypercalcemia of malignancy. ].I9 Our data, too, have shown little response with the use of this drug alone. If the drug is used, a dose of 150 mg po per day is recommended.’ Other modalities that may be used for the management of malignancy-associated hypercalcemia are oral and intravenous phosphates, calcitonin, diphosphonates, and dialysis. We have had little or no experience with these modalities. Oral phosphates are drugs commonly used to control chronic hypercalcemia of malignancy. Their mechanism is to inhibit bone resorption, to decrease calcium absorption by forming calcium phosphate salts in the gut, and to prevent the conversion of 25-hydroxy vitamin D to 1,25dihydroxy vitamin D.’ The major side effects of phosphates are nausea and diarrhea. They also can cause soft tissue calcification and nephrocalcinosis. l.ly The usual dose of oral phosphates is l-3 g elemental phosphorus per day in divided doses. Their efficacy has been reported as high as 70 percent. 1 Intravenous phosphates are usually not recommended because they can frequently cause significant extraskeletal calcification.“j Also, a number of deaths have been reported with the use of this drug.lfi Calcitonin is a hormone produced by the thyroid gland that acts to inhibit bone resorption directly.] Calcitonin alone or with steroids has been shown to be effective for treating hypercalcemia of malignancy, especially hematologic malignancies.’ Response rates as high as 7080 percent have been reported.‘-‘” ADP
renal cell carcinomaafi y Furthermore, in the literature and in our study there are documented cases of renal cell carcinoma with hypercalcemia without bone metastasis.‘O Our series showed 13 of 27 patients had no evidence of bony lesions. There are a number of modalities available to treat renal cell carcinoma-associated hypercalcemia. General management should begin with stopping any drugs that might increase the serum calcium level, such as vitamin D, thiazides and absorbable antacids. Placing patients on a calcium restricted diet is unnecessary, since the source of the hypercalcemia is from bone. “.‘2 Agents that have been used to treat hypercalcemia of renal ceil carcinoma are hydration, loop diuretics, mithramycin, steroids, phosphates, diphosphonates, calcitonin, and indomethacin. Hydration is usually the initial agent used to treat acute hypercalcemia. Patients that present with acute hypercalcemia are usually severely dehydrated from vomiting, nausea, and polyuria. Aggressive hydration will serve to correct volume contraction. Normal saline is the fluid of choice since saline diuresis will promote calcium excretion by the kidneys.” Hypokalemia, hypomagnesemia, hypernatremia, and volume overload can occur with saline hydraelectrolytes should be monition, ‘I Therefore, tored closely. In patients who have a history of congestive heart failure or renal failure, vigorous fluid administration should be used cautiously. Loop diuretics (furosemide and ethacrynic acid) reduce calcium levels by stimulating a sodium diuresis which causes increased calcium excretion. lD As with hydration, electrolyte imbalance can occur. Potassium, sodium, and magnesium should be monitored carefully. The use of loop diuretics in the management of hypercalcemia is controversial. Effective response rates with furosemide have been reported.]:’ Howsever, opponents to loop diuretics argue their effect is secondary to hydration that is usually given with diuretics.’ We have had moderate success with furosemide, with 28 percent CR and 40 percent PR to such treatment. Mithramycin is a cytotoxic substance that inhibits RNA synthesis and bone resorption.‘.14 It can be used to manage both acute and chronic hypercalcemia. The standard dose is 15-25 pg/ effect is kg body weight. ’ l4 The hvpocalcemic usually seen within twenty-four to forty-eight hours and may last from a few days to several
UROI.OCY
I/ hlARCH
1989
I) \‘OI,UME XXXIII,
NUMBER
3
169
(amino-hydroxy-prophylidine diphosphonate) and ClzMDP (dichloromethylene diphosphonate) are diphosphonates that inhibit bone resorption. lg Currently, they are investigational drugs. 1g,2oHowever, clinical trials have shown effective response rates with these drugs.19320 For patients who present with acute hypercalcemia and severe renal failure, dialysis may be employed. Peritoneal or hemodialysis will cause a rapid reduction in serum calcium.16 A few cases of surgical management of renal cell carcinoma-associated hypercalcemia have been reported in the literature. Goldberg et aL21 reported many cases of renal cell-associated hypercalcemia which had effective responses to excision of their tumor7 One case of renal cell carcinoma-associated hypercalcemia which was effectively managed by surgical debulking of metastatic lesions has been reported. 22 Our series also has shown success in controlling renal cell carcinoma-associated hypercalcemia via surgery. One of our patients with Stage IV renal cell carcinoma and 1 patient with localized disease had a complete response to nephrectomy. In summary, mithramycin was the most effective agent in controlling renal cell carcinoma-associated hypercalcemia in the present series. Prednisone seems to be effective, but our experience was limited. Furosemide and/or hydration were moderately effective. We would recommend patients who present with renal cell carcinoma-associated hypercalcemia be managed initially with furosemide and/or hydration. Prednisone may also be used as an initial or supplementary agent. If these agents are unsuccessful, mithramycin should be employed. Excision of the primary tumor or metastatic lesions may be considered occasionally in selected patients if all medical treatment modalities fail and performance status is otherwise good. Surprisingly, the degree of calcium elevation did not show a significant correlation with survival. Although hypercalcemia is a dire prognostic sign, effective management may be associated with moderately prolonged survival (average survival of about 3 months in the present series, with occasional survivals of 7 to 8 months). In view of the fact that there are effective treatment modalities for renal cell car-
170
cinoma-associated hypercalcemia and that hydistressing percalcemia may produce symptoms, aggressive treatment of this condition may improve the patient’s quality of life, as well as survival. Buffalo,
666 Elm Street New York 14263 (DR. HUBEN)
References 1. Mundy GR, and Martin TJ: The hypercalcemia of malignancy-pathogenesis and management, Metabolism 31: 1247 (1982). 2. Smith R: Hypercalcemia presentation, Br J Hosp Med 3: 174 (1984). 3. Lockich JJ, and Harrison JH: Renal cell carcinoma: natural history and chemotherapeutic experience, J Ural 114: 371 (1975). 4. Skinner DG, et ~2: Diagnosis and management of renal cell carcinoma, Cancer 28: 1165 (1971). 5. Warren MM, Utz DC, and Kelalis PP: Concurrence of hypernephroma and hypercalcemia, Ann Surg 174: 863 (1971). 6. Altaffer LF, and Chenault OW: Paraneoplastic endocrinopathies associated with renal tumors, J Urol 122: 573 (1979). 7. Lubensky JD, and Gangai MP: The hypercalcemia of genitourinary malignancy, J Urol 121: 259 (1979). 8. Mundy GR: Pathogenesis of hypercalcemia of malignancy, Clin Endocrinol 23: 705 (1985). 9. Sufrin G, Golio A, and Murphy G: Serologic markers, paraneoplastic syndromes and ectopic hormone production in renal adenocarcinoma, in deKernion JB, and Pavane-Macaluso M (Eds): International Perspectives in Urology-Tumors of the Kidney, Baltimore, Williams & Wilkins, 1986, vol 13, pp 1-71. 10. Plimpton CH, and Gellhorn A: Hypercalcemia in malignant disease without evidence of bone destruction, Am J Med 21: 750 (1956). 11. Buescu A, Dimich AB, and Myers WP: Cancer hypercalcemia-a pragmatic approach, Clin Bull 5: 91 (1975). 12. Chopra D, and Clerkin EP: Hypercalcemia and malignant disease, Med Clin North Am 59: 441 (1975). 13. Suki WN, et al: Acute treatment of hypercalcemia with furosemide, N Engl J Med 283: 836 (1970). 14. Deftos LJ, and Neer R: Medical management of the hypercalcemia of malignancy, Ann Rev Med 25: 323 (1974). 15. Kimura S, et al: A retrospective evaluation of the medical treatment of malignancy-associated hypercalcemia, Jpn J Cancer Res 77: 85 (1986). 16. Walser M: Treatment of hypercalcemias, Mod Treat 7: 662 (1970). 17. Ashkar FS, Miller R, and Katimis RB: Effect of corticosteroids of hypercalcemia of malignant disease, Lancet 1: 41 (1971). 18. Thalassinos NC. and Ioulin GF: Failure of corticosteroid therapy to correct the hypercalcemia of malignant disease, Lancet 2: 537 (1970). 19. Stewart AF: Therapy of malignancy-associated hypercalcemia: 1983, Am J Med 74: 475 (1983). 20. Fetchick DA, and Mundy GR: Hypercalcemia of malignancy. Diagnosis and therapy, Comp Ther 12: 27 (1986). containing a 21. Goldberg MF, et al: Renal adenocarcinoma parathyroid hormone-like substance and associated with marked hypercalcemia, Am J Med 36: 805 (1964). 22. Goldberg RS, Pilcher DB, and Yates JW: The aggressive surgical management of hypercalcemia due to ectopic parathormone production, Cancer 45: 2652 (1980).
UROLOGY
I MARCH
1989
/ VOLUME
XXXIII.
NUMBER
3