FORMULARY FORUM
GALLIUM NITRATE Thomas E. Hughes and Lea Ann Hansen
To evaluate the therapeutic role of gallium nitrate in the treatment of hypercalcemia associated with malignancy and related disease states. OBJECTIVE:
A literature search of English-language studies involving gallium nitrate for the period I %6-1991 using MEDLINE and the bibliographies of relevant articles.
DATA SOURCES:
Because of the limited number of studies, all clinical trials were reviewed, with particular emphasis on Phase ill comparative trials. Related investigative studies on the pharmacology, pharmacokinetics, and toxicity of gallium nitrate were also reviewed.
S11JDY SELECI10N:
DATA EXTRACTION: Two appraisers independently abstracted data from available clinical trials and evaluated trial quality. RESULTS OF DATA SYNTHESIS: Two Phase ill comparative trials evaluating gallium nitrate in the treatment of hypercalcemia of malignancy have been completed. Gallium nitrate was shown to be superior to both calcitonin and etidronate disodium, based on the comparative percentage of patients achieving normocalcemia and the subsequent duration of normocalcemia. Both trials employed similar methodology. Positive therapeutic effects of gallium nitrate have also been demonstrated in small, noncomparative trials for hypercalcemia associated with parathyroid carcinoma, Paget's disease of bone, and osteolytic bone metastases. CONCLUSIONS: Gallium nitrate is effective in the treatment of hypercalcemia associated with malignancy and is appropriate for formulary addition. In certain clinical situations, it may be clearly advantageous over such agents as calcitonin, plicamycin, and etidronate. Further investigation is needed to define the limitations of nephrotoxicity and the therapeutic potential for other indications. Further comparative clinical trials of gallium nitrate versus bisphosphonates and plicamycin could also help define its relative clinical benefit.
AnnPharmacother 1992;26:354-62. HYPERCALCEMIA may be a clinical manifestation of many disease states, including malignancy, endocrine disorders (e.g., primary hyperparathyroidism), granulomatous dis-
THOMAS E. HUGHES, Pharm.D., is a Clinical Pharmacist, Oncology, University of Virginia Health Sciences Center. Medical Center Box 274-11, Charlottesville. VA 22908; and LEA ANN HANSEN, Phann.D.• is an Assistant Professor. School of Pharmacy, Medical College of Virginia / Virginia Commonwealth University. Richmond, VA. Reprints: Thomas E. Hughes. Pharm.D. Gallium nitrate (Ganite), Fujisawa.
This article is approved for continuing education credit
354 •
The Annals ofPharmacotherapy •
eases (e.g., tuberculosis, sarcoidosis), and Paget's disease of bone. Hypercalcemia may also be a manifestation of drug toxicity, such as with vitamins A or 0 or be part of the adverse effect profile of certain agents, including sodium bicarbonate, calcium carbonate (milk-alkali syndrome), thiazide diuretics, or lithium. However, most cases of hypercalcemia (>90 percent) are related to either primary hyperparathyroidism or malignancy. Primary hyperparathyroidism is the leading cause of hypercalcemia overall (especially among outpatients because of its insidious onset) and accounts for 250 new cases per million per year. Primary hyperparathyroidism may be a result of parathyroid adenomas (accounting for 80-85 percent of cases), parathyroid hyperplasia (15 percent of cases), or parathyroid carcinoma.r-' Malignancy is the most common cause of hypercalcemia among hospitalized patients because of the rapid onset of symptoms or serendipitous detection. It accounts for 150 new cases per million persons per year. Hypercalcemia occurs in 10 -20 percent of patients with cancer and is more commonly associated with lung and breast carcinomas as well as multiple myeloma. Hypercalcemia of malignancy usually occurs secondary to increased bone resorption, which may be a result of either local bone metastases (local osteolytic hypercalcemia) or humoral effects. Local bone metastases may occur with solid tumors, such as breast cancer (50 percent of all cancer patients with hypercalcemia) or with hematologic malignancies, most notably multiple myeloma." Humoral hypercalcemia of malignancy occurs as a result of the ectopic secretion by tumor cells of humoral factors, such as parathyroid hormone-related protein (PTH-rP) and transforming growth factor alpha (TGFa). The PTH-rP produces similar effects on renal tubular functions as parathyroid hormone (PTH) by binding to and activating the PTH receptor. These effects include increased nephrogenous cyclic adenosine monophosphate (cAMP) production, inhibition of renal tubular phosphate reabsorption, and enhanced renal tubular calcium reabsorption. TGFa has biologic properties similar to epidermal growth factor, a known stimulator of osteoclastic bone resorption. Additionally, certain cytokines, such as tumor necrosis factor and interleukin I, may playa role in humoral hypercalcemia of malignancy.' Solid tumors in this category include squamous cell, transitional cell, bladder, renal, or ovarian cancers.'?
1992 March, Volume 26
Morbidity associated with hypercalcemia may be significant as patients can present with symptomatology (depending on the degree and acuteness of hypercalcemia) that includes generalized fatigue; weakness; nausea and vomiting; constipation; polyuria and polydypsia; and mental status alterations, such as confusion and lethargy. If untreated, hypercalcemia of malignancy can progress to profound renal dysfunction or acute renal failure, stupor and coma, cardiac arrhythmias, and eventually death.'? The medical management of hypercalcemia may play an important palliative role in patients with advanced cancer and hypercalcemia by alleviating the symptomatology described above," Common treatment measures for acute hypercalcemia include hydration and NaCI 0.9% diuresis and administration of loop diuretics (after adequate volume expansion), calcitonin, corticosteroids, plicamycin, and bisphosphonates (e.g., etidronate disodium). Gallium nitrate has been approved by the Food and Drug Administration for the treatment of hypercalcemia associated with malignancy and provides a new therapeutic option for this metabolic complication.
Pharmacology Gallium nitrate is a hydrated nitrate salt of the group rna element, gallium. Initially investigated as an antineoplastic agent, gallium nitrate was found to cause hypocalcemia in a significant number of patients, particularly when administered as a prolonged intravenous infusion.v' This induced hypocalcemia was shown not to result from increased urinary calcium excretion.?" Subsequent laboratory investigations demonstrated that gallium is a potent inhibitor of bone resorption," Gallium's effects on bone minerals include a decrease in the solubility of hydroxyapatite and an increase in the growth of existing hydroxyapatite crystallite, with an increase in calcium/phosphate content. Animal studies using atomic absorption spectroscopy and X-ray fluorescence microscopy have demonstrated that gallium nitrate is incorporated into the bone matrix, preferentially localizing to metabolically active regions of bone.v" Gallium's effects on bone are not apparently caused by cytotoxic actions, because no change in bone-cell morphology has been observed. Gallium has also been demonstrated to increase the bone content of osteocalcin (a bone-specific protein) and to increase bone-collagen synthesis.' Experiments with a bone resorption assay indicate that gallium may inhibit bone resorption by directly inhibiting osteoclast function, an effect that does not appear to be influenced by PTH.ll
Chemistry Gallium nitrate is available in a parenteral solution containing the active drug in anhydrous form plus sodium citrate dihydrate and sodium hydroxide for pH adjustment to 6.0 -7.0. It is commercially available in 500-mg vials (25 mg/mL concentration). The drug is stable at room temperature (15-30 "C), is not light sensitive, and has a two-year expiration date from the date of manufacture. Gallium nitrate has a peak stability at a pH of 6.0 -7.0. Once diluted in the suggested diluent (0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP), the manufacturer states that the product is stable for 48 hours at room temperature or for seven days if refrigerated (2- 8 °C).12 Other
investigators have determined that gallium nitrate at concentrations of 0.22- 0.6 mg/mL in either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, is stable for 14 days at room temperature or refrigerated at 5 °C in polyvinyl chloride containers.P Gallium nitrate is compatible with certain concentrations of potassium chloride and magnesium sulfate."
Pharmacokinetics and Pharmacodynamics When administered as a bolus dose (short infusion of 15-150 min), gallium has been shown to have a volume of distribution of 1.27 ± 0.24 L/kg. 14 It primarily undergoes renal elimination without any prior metabolism in the liver or kidney.12,l4-16 After a single parenteral bolus dose of 500-900 mg/m', 65 percent of the drug was recovered in the urine within the first 24 hours. IS Other investigators found that with bolus doses of 300 - 600 mg/m' in patients with normal renal function, the mean cumulative 24 -hour urinary excretion was 35 percent. Elimination appears to be biphasic with an initial distribution half-life (at l l2) of approximately 1.25 hours and an elimination half-life (~tl/2) of approximately 24 hours. I4-16 The terminal ~tl/2 appears to be dependent on the method of administration. A prolonged intravenous infusion of gallium nitrate has a ~tl/2 of 72-115 hours, compared with a ~tl/2 of 24 hours with bolus administration. This may be attributable to reversible binding and slow release from a deep tissue compartment, such as bone." The clearance of gallium nitrate is reported to be 0.15 Lh-kg (range 0.12-0.20 Lh-kg) when infused at 200 mg/m'-d for five to seven days." When administered as a bolus dose of 300-600 mg/m', other investigators have reported a mean clearance of 0.039 L/h-kg. 14 Steady-state drug concentrations are achieved in 24 - 48 hours when infused at a dose of 200 mg/m-« d. The range of steady-state plasma concentrations at 200 mg/m--d is reported to be 1000-2399 ng/mL (2.4-5.7 J.U110l/L).12·16 Renal clearance is not affected by hydration or mannitol diuresis; however, these interventions have been shown to decrease gallium nitrate-induced nephrotoxicity by decreasing the concentration of gallium in the urine and renal tubules.7.ls In a Phase II, dose-response analysis study, investigators noted that clinical response may correlate with plasma gallium concentrations. Of five patients who had blood sampling at the study's lowest dose level (100 mg/m--d for five days), only one patient did not achieve normocalcemia; this patient had consistently lower plasma gallium concentrations during the treatment period compared with the other four patients. In addition, of 12 infusions fully evaluable with pharmacokinetic analysis, 11 resulted in normocalcemia and were associated with a plasma gallium concentration ~20 ng/mL (2.2 umol/l.) at 72 hours. The authors postulated that a threshold plasma gallium concentration of 1000 ng/mL (2.4 umol/l.) must be achieved in order to obtain normocalcemia." Gallium nitrate's effect on serum calcium occurs within 24 - 48 hours of initiating therapy." In clinical trials, patients who respond to therapy usually reached normocalcemia within four to seven days of initiating therapy.,,16,17 In a relatively small proportion of patients who have not received other concurrent calcium-lowering or antineoplastic therapy, the duration of normocalcemia is reported to be six to eight dayS.12,16-18
The Annals ofPharmacotherapy
•
1992 March, Volume 26 •
355
Clinical Studies HYPERCALCEMIA OF MALIGNANCY
Phase I and II Studies. The initial clinical pilot study of gallium nitrate for hypercalcemia of malignancy was performed by Warrell et al. in ten patients hospitalized with advanced cancer and hypercalcemia. Patients were treated with aggressive NaCl 0.9% hydration, furosemide diuresis, and oral phosphates for the first 48 hours of hospitalization. Each patient included in the study at the end of this time period had serum calcium concentrations ~ 12.0 mg/dL (3.0 mmol/L, corrected for serum albumin), a serum creatinine concentration ~2.0 mg/dL (180 umol/L), and maintained a urine output volume ~2000 mL/d. Gallium nitrate 200 mg/m--d was administered as a continuous intravenous infusion for five to seven days. The types of cancer in the study group included breast cancer (3 patients), lung cancer (2), lymphoma (2), head and neck cancer (2), and cancer of the penis (1). In all patients, total serum calcium was either reduced to normal or the patient became hypocalcemic with gallium nitrate therapy. The onset of response was, with one exception, within the first 48 hours of treatment. Duration of normocalcemia was difficult to accurately measure because many patients later received cytotoxic chemotherapy. However, the mean duration of normocalcemia was estimated to be ten days (range 6-19+). Both of the patients who received a seven- day infusion of gallium nitrate developed hypocalcemia «7.0 mg/dL [1.75 mmol/l.l), and required parenteral calcium supplements." In a subsequent Phase II, dose-response analysis study, Warrell et al. investigated three dose levels of gallium nitrate for hypercalcemia associated with malignancy, including 100 mg/m-vd for five days, 200 mg/m--d for five to seven days, and 50 mg/m' by a four-hour infusion on day 1 followed by 150 mg/mt-d for five days. Entry criteria were similar to those of the pilot study" and included patients who had been hospitalized for longer than 48 hours and aggressively treated with NaCl 0.9% hydration and furosemide diuresis. If patients after this time period had a serum calcium concentration> 12.0 mg/dL (3 mmol/L, adjusted for serum albumin), a serum creatinine ~3.0 mg/dL (270 umol/L), and maintained a urine output >2000 mL/d, they were included in the study. Patients were excluded if they had received plicamycin or cytotoxic chemotherapy within seven days of entry into the study. There were no exclusions based on the cancer diagnosis or histology. Patients could receive oral phosphates and corticosteroids during treatment if the doses were stable or decreasing. The amount of fluid intake was consistent both before and during therapy and did not differ significantly among the dose levels. The duration of normocalcemia was defmed as the duration from the onset of normocalcemia up to the day of recurrent hypercalcemia, hospital discharge without follow-up, or the administration of other antineoplastic or hypocalcemic treatment." Thirty-nine of 45 treatment courses in 31 patients (of 36 total) were considered evaluable for hypocalcemic response. Six treatment courses were not evaluable because of early withdrawal secondary to clinical deterioration that was not drug related (4 patients) and two protocol violations. Fifteen patients received the lowest dosage (100 mg/mt-d for five days). Clinical diagnosis in this group included breast cancer (5 patients); lung cancer (2); head and 356 •
The Annals ofPharmacotherapy
•
neck cancer (2); and one case each of lymphoma, myeloma, and carcinomas of the kidney, ovary, pancreas, and anus. Nine of the 15 patients had bone metastases. The 2oo-mg/m2 ed dosage was administered to 21 patients; however, 10 of these patients were from the initial pilot study," Patient diagnosis included breast cancer (6 patients), lung cancer (6), head and neck cancer (4), lymphoma (2), and one case each of penile cancer, bladder cancer, and sarcoma. Fourteen of the 21 patients had bone metastases. The percentage of patients who achieved normocalcemia was higher at the 200 mg/m' dose (86 percent) versus that in the low-dose group (100 mg/m-) (60 percent). However, this difference was not statistically significant. The high-dose group did have a lower mean serum calcium nadir compared with the low-dose group (9.2 mg/dL [2.3 mmol/L] vs. 10.5 mg/dL [2.6 mmol/L], respectively; p
GALLIUM NITRATE Thomas E. Hughes and Lea Ann Hansen
To evaluate the therapeutic role of gallium nitrate in the treatment of hypercalcemia associated with malignancy and related disease states. OBJECTIVE:
A literature search of English-language studies involving gallium nitrate for the period I %6-1991 using MEDLINE and the bibliographies of relevant articles.
DATA SOURCES:
Because of the limited number of studies, all clinical trials were reviewed, with particular emphasis on Phase ill comparative trials. Related investigative studies on the pharmacology, pharmacokinetics, and toxicity of gallium nitrate were also reviewed.
S11JDY SELECI10N:
DATA EXTRACTION: Two appraisers independently abstracted data from available clinical trials and evaluated trial quality. RESULTS OF DATA SYNTHESIS: Two Phase ill comparative trials evaluating gallium nitrate in the treatment of hypercalcemia of malignancy have been completed. Gallium nitrate was shown to be superior to both calcitonin and etidronate disodium, based on the comparative percentage of patients achieving normocalcemia and the subsequent duration of normocalcemia. Both trials employed similar methodology. Positive therapeutic effects of gallium nitrate have also been demonstrated in small, noncomparative trials for hypercalcemia associated with parathyroid carcinoma, Paget's disease of bone, and osteolytic bone metastases. CONCLUSIONS: Gallium nitrate is effective in the treatment of hypercalcemia associated with malignancy and is appropriate for formulary addition. In certain clinical situations, it may be clearly advantageous over such agents as calcitonin, plicamycin, and etidronate. Further investigation is needed to define the limitations of nephrotoxicity and the therapeutic potential for other indications. Further comparative clinical trials of gallium nitrate versus bisphosphonates and plicamycin could also help define its relative clinical benefit.
AnnPharmacother 1992;26:354-62. HYPERCALCEMIA may be a clinical manifestation of many disease states, including malignancy, endocrine disorders (e.g., primary hyperparathyroidism), granulomatous dis-
THOMAS E. HUGHES, Pharm.D., is a Clinical Pharmacist, Oncology, University of Virginia Health Sciences Center. Medical Center Box 274-11, Charlottesville. VA 22908; and LEA ANN HANSEN, Phann.D.• is an Assistant Professor. School of Pharmacy, Medical College of Virginia / Virginia Commonwealth University. Richmond, VA. Reprints: Thomas E. Hughes. Pharm.D. Gallium nitrate (Ganite), Fujisawa.
This article is approved for continuing education credit
354 •
The Annals ofPharmacotherapy •
eases (e.g., tuberculosis, sarcoidosis), and Paget's disease of bone. Hypercalcemia may also be a manifestation of drug toxicity, such as with vitamins A or 0 or be part of the adverse effect profile of certain agents, including sodium bicarbonate, calcium carbonate (milk-alkali syndrome), thiazide diuretics, or lithium. However, most cases of hypercalcemia (>90 percent) are related to either primary hyperparathyroidism or malignancy. Primary hyperparathyroidism is the leading cause of hypercalcemia overall (especially among outpatients because of its insidious onset) and accounts for 250 new cases per million per year. Primary hyperparathyroidism may be a result of parathyroid adenomas (accounting for 80-85 percent of cases), parathyroid hyperplasia (15 percent of cases), or parathyroid carcinoma.r-' Malignancy is the most common cause of hypercalcemia among hospitalized patients because of the rapid onset of symptoms or serendipitous detection. It accounts for 150 new cases per million persons per year. Hypercalcemia occurs in 10 -20 percent of patients with cancer and is more commonly associated with lung and breast carcinomas as well as multiple myeloma. Hypercalcemia of malignancy usually occurs secondary to increased bone resorption, which may be a result of either local bone metastases (local osteolytic hypercalcemia) or humoral effects. Local bone metastases may occur with solid tumors, such as breast cancer (50 percent of all cancer patients with hypercalcemia) or with hematologic malignancies, most notably multiple myeloma." Humoral hypercalcemia of malignancy occurs as a result of the ectopic secretion by tumor cells of humoral factors, such as parathyroid hormone-related protein (PTH-rP) and transforming growth factor alpha (TGFa). The PTH-rP produces similar effects on renal tubular functions as parathyroid hormone (PTH) by binding to and activating the PTH receptor. These effects include increased nephrogenous cyclic adenosine monophosphate (cAMP) production, inhibition of renal tubular phosphate reabsorption, and enhanced renal tubular calcium reabsorption. TGFa has biologic properties similar to epidermal growth factor, a known stimulator of osteoclastic bone resorption. Additionally, certain cytokines, such as tumor necrosis factor and interleukin I, may playa role in humoral hypercalcemia of malignancy.' Solid tumors in this category include squamous cell, transitional cell, bladder, renal, or ovarian cancers.'?
1992 March, Volume 26
Morbidity associated with hypercalcemia may be significant as patients can present with symptomatology (depending on the degree and acuteness of hypercalcemia) that includes generalized fatigue; weakness; nausea and vomiting; constipation; polyuria and polydypsia; and mental status alterations, such as confusion and lethargy. If untreated, hypercalcemia of malignancy can progress to profound renal dysfunction or acute renal failure, stupor and coma, cardiac arrhythmias, and eventually death.'? The medical management of hypercalcemia may play an important palliative role in patients with advanced cancer and hypercalcemia by alleviating the symptomatology described above," Common treatment measures for acute hypercalcemia include hydration and NaCI 0.9% diuresis and administration of loop diuretics (after adequate volume expansion), calcitonin, corticosteroids, plicamycin, and bisphosphonates (e.g., etidronate disodium). Gallium nitrate has been approved by the Food and Drug Administration for the treatment of hypercalcemia associated with malignancy and provides a new therapeutic option for this metabolic complication.
Pharmacology Gallium nitrate is a hydrated nitrate salt of the group rna element, gallium. Initially investigated as an antineoplastic agent, gallium nitrate was found to cause hypocalcemia in a significant number of patients, particularly when administered as a prolonged intravenous infusion.v' This induced hypocalcemia was shown not to result from increased urinary calcium excretion.?" Subsequent laboratory investigations demonstrated that gallium is a potent inhibitor of bone resorption," Gallium's effects on bone minerals include a decrease in the solubility of hydroxyapatite and an increase in the growth of existing hydroxyapatite crystallite, with an increase in calcium/phosphate content. Animal studies using atomic absorption spectroscopy and X-ray fluorescence microscopy have demonstrated that gallium nitrate is incorporated into the bone matrix, preferentially localizing to metabolically active regions of bone.v" Gallium's effects on bone are not apparently caused by cytotoxic actions, because no change in bone-cell morphology has been observed. Gallium has also been demonstrated to increase the bone content of osteocalcin (a bone-specific protein) and to increase bone-collagen synthesis.' Experiments with a bone resorption assay indicate that gallium may inhibit bone resorption by directly inhibiting osteoclast function, an effect that does not appear to be influenced by PTH.ll
Chemistry Gallium nitrate is available in a parenteral solution containing the active drug in anhydrous form plus sodium citrate dihydrate and sodium hydroxide for pH adjustment to 6.0 -7.0. It is commercially available in 500-mg vials (25 mg/mL concentration). The drug is stable at room temperature (15-30 "C), is not light sensitive, and has a two-year expiration date from the date of manufacture. Gallium nitrate has a peak stability at a pH of 6.0 -7.0. Once diluted in the suggested diluent (0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP), the manufacturer states that the product is stable for 48 hours at room temperature or for seven days if refrigerated (2- 8 °C).12 Other
investigators have determined that gallium nitrate at concentrations of 0.22- 0.6 mg/mL in either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, is stable for 14 days at room temperature or refrigerated at 5 °C in polyvinyl chloride containers.P Gallium nitrate is compatible with certain concentrations of potassium chloride and magnesium sulfate."
Pharmacokinetics and Pharmacodynamics When administered as a bolus dose (short infusion of 15-150 min), gallium has been shown to have a volume of distribution of 1.27 ± 0.24 L/kg. 14 It primarily undergoes renal elimination without any prior metabolism in the liver or kidney.12,l4-16 After a single parenteral bolus dose of 500-900 mg/m', 65 percent of the drug was recovered in the urine within the first 24 hours. IS Other investigators found that with bolus doses of 300 - 600 mg/m' in patients with normal renal function, the mean cumulative 24 -hour urinary excretion was 35 percent. Elimination appears to be biphasic with an initial distribution half-life (at l l2) of approximately 1.25 hours and an elimination half-life (~tl/2) of approximately 24 hours. I4-16 The terminal ~tl/2 appears to be dependent on the method of administration. A prolonged intravenous infusion of gallium nitrate has a ~tl/2 of 72-115 hours, compared with a ~tl/2 of 24 hours with bolus administration. This may be attributable to reversible binding and slow release from a deep tissue compartment, such as bone." The clearance of gallium nitrate is reported to be 0.15 Lh-kg (range 0.12-0.20 Lh-kg) when infused at 200 mg/m'-d for five to seven days." When administered as a bolus dose of 300-600 mg/m', other investigators have reported a mean clearance of 0.039 L/h-kg. 14 Steady-state drug concentrations are achieved in 24 - 48 hours when infused at a dose of 200 mg/m-« d. The range of steady-state plasma concentrations at 200 mg/m--d is reported to be 1000-2399 ng/mL (2.4-5.7 J.U110l/L).12·16 Renal clearance is not affected by hydration or mannitol diuresis; however, these interventions have been shown to decrease gallium nitrate-induced nephrotoxicity by decreasing the concentration of gallium in the urine and renal tubules.7.ls In a Phase II, dose-response analysis study, investigators noted that clinical response may correlate with plasma gallium concentrations. Of five patients who had blood sampling at the study's lowest dose level (100 mg/m--d for five days), only one patient did not achieve normocalcemia; this patient had consistently lower plasma gallium concentrations during the treatment period compared with the other four patients. In addition, of 12 infusions fully evaluable with pharmacokinetic analysis, 11 resulted in normocalcemia and were associated with a plasma gallium concentration ~20 ng/mL (2.2 umol/l.) at 72 hours. The authors postulated that a threshold plasma gallium concentration of 1000 ng/mL (2.4 umol/l.) must be achieved in order to obtain normocalcemia." Gallium nitrate's effect on serum calcium occurs within 24 - 48 hours of initiating therapy." In clinical trials, patients who respond to therapy usually reached normocalcemia within four to seven days of initiating therapy.,,16,17 In a relatively small proportion of patients who have not received other concurrent calcium-lowering or antineoplastic therapy, the duration of normocalcemia is reported to be six to eight dayS.12,16-18
The Annals ofPharmacotherapy
•
1992 March, Volume 26 •
355
Clinical Studies HYPERCALCEMIA OF MALIGNANCY
Phase I and II Studies. The initial clinical pilot study of gallium nitrate for hypercalcemia of malignancy was performed by Warrell et al. in ten patients hospitalized with advanced cancer and hypercalcemia. Patients were treated with aggressive NaCl 0.9% hydration, furosemide diuresis, and oral phosphates for the first 48 hours of hospitalization. Each patient included in the study at the end of this time period had serum calcium concentrations ~ 12.0 mg/dL (3.0 mmol/L, corrected for serum albumin), a serum creatinine concentration ~2.0 mg/dL (180 umol/L), and maintained a urine output volume ~2000 mL/d. Gallium nitrate 200 mg/m--d was administered as a continuous intravenous infusion for five to seven days. The types of cancer in the study group included breast cancer (3 patients), lung cancer (2), lymphoma (2), head and neck cancer (2), and cancer of the penis (1). In all patients, total serum calcium was either reduced to normal or the patient became hypocalcemic with gallium nitrate therapy. The onset of response was, with one exception, within the first 48 hours of treatment. Duration of normocalcemia was difficult to accurately measure because many patients later received cytotoxic chemotherapy. However, the mean duration of normocalcemia was estimated to be ten days (range 6-19+). Both of the patients who received a seven- day infusion of gallium nitrate developed hypocalcemia «7.0 mg/dL [1.75 mmol/l.l), and required parenteral calcium supplements." In a subsequent Phase II, dose-response analysis study, Warrell et al. investigated three dose levels of gallium nitrate for hypercalcemia associated with malignancy, including 100 mg/m-vd for five days, 200 mg/m--d for five to seven days, and 50 mg/m' by a four-hour infusion on day 1 followed by 150 mg/mt-d for five days. Entry criteria were similar to those of the pilot study" and included patients who had been hospitalized for longer than 48 hours and aggressively treated with NaCl 0.9% hydration and furosemide diuresis. If patients after this time period had a serum calcium concentration> 12.0 mg/dL (3 mmol/L, adjusted for serum albumin), a serum creatinine ~3.0 mg/dL (270 umol/L), and maintained a urine output >2000 mL/d, they were included in the study. Patients were excluded if they had received plicamycin or cytotoxic chemotherapy within seven days of entry into the study. There were no exclusions based on the cancer diagnosis or histology. Patients could receive oral phosphates and corticosteroids during treatment if the doses were stable or decreasing. The amount of fluid intake was consistent both before and during therapy and did not differ significantly among the dose levels. The duration of normocalcemia was defmed as the duration from the onset of normocalcemia up to the day of recurrent hypercalcemia, hospital discharge without follow-up, or the administration of other antineoplastic or hypocalcemic treatment." Thirty-nine of 45 treatment courses in 31 patients (of 36 total) were considered evaluable for hypocalcemic response. Six treatment courses were not evaluable because of early withdrawal secondary to clinical deterioration that was not drug related (4 patients) and two protocol violations. Fifteen patients received the lowest dosage (100 mg/mt-d for five days). Clinical diagnosis in this group included breast cancer (5 patients); lung cancer (2); head and 356 •
The Annals ofPharmacotherapy
•
neck cancer (2); and one case each of lymphoma, myeloma, and carcinomas of the kidney, ovary, pancreas, and anus. Nine of the 15 patients had bone metastases. The 2oo-mg/m2 ed dosage was administered to 21 patients; however, 10 of these patients were from the initial pilot study," Patient diagnosis included breast cancer (6 patients), lung cancer (6), head and neck cancer (4), lymphoma (2), and one case each of penile cancer, bladder cancer, and sarcoma. Fourteen of the 21 patients had bone metastases. The percentage of patients who achieved normocalcemia was higher at the 200 mg/m' dose (86 percent) versus that in the low-dose group (100 mg/m-) (60 percent). However, this difference was not statistically significant. The high-dose group did have a lower mean serum calcium nadir compared with the low-dose group (9.2 mg/dL [2.3 mmol/L] vs. 10.5 mg/dL [2.6 mmol/L], respectively; p
