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Gallium Nitrate for Acute Treatment of Cancer-Related Hypercalcemia: Clinicopharmacological and Dose Response Analysis1

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Gallium Nitrate for Acute Treatment of Cancer-Related Hypercalcemia: Clinicopharmacological and Dose Response Analysis1 [CANCER RESEARCH 46, 4208-4212, August 1986) Gallium Nitrate for Acute Treatment of Cancer-related Hypercalcemia: Clinicopharmacological and Dose Response Analysis1 Raymond P. Warrell, Jr.,2 Anastasia Skelos, Nancy W. Alcock, and Richard S. Bockman Developmental Chemotherapy [R. P. W., A. S.], Renal/Physiology ¡N.W. A.], and Endocrine ¡R.S. B.J Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Nm York, New York 10021 ABSTRACT This study extends our original observations to evaluate dose- response in patients with cancer-related hypercalcemia and to Current treatment of cancer-related hypercalcemia is limited by agents assess plasma gallium levels achieved after administration by of limited effectiveness or excessive toxicity. Gallium nitrate is a new i.v. infusion. drug which both inhibits bone résorptionand increases calcium content of bone. We have now treated 39 episodes of hypercalcemia with gallium nitrate administered as a continuous i.v. infusion for 5-7 days at 3 daily dose levels (100 and 200 mg/m2, and 50 mg/m2 by brief infusion followed MATERIALS AND METHODS by 150 mg/m2). Nadir calcium values were significantly lower (9.2 ±1.5 Patient Eligibility. Patients were eligible for treatment with gallium mg/dl) for patients who received the highest dose relative to patients who received the lowest dose (10.5 ±1.6 mg/dl, /' < 0.001). While the actual nitrate after they had been hospitalized and aggressively treated for hypercalcemia for at least 48 h. Treatment included hydration with i.v. percentage of patients who achieved normocalcemia was higher at the normal saline and furosemide-induced diuresis. Phosphates and corti- highest dose relative to the lowest dose (86 versus 60%), this difference costeroids p.o. were allowed if the dose was stable or decreasing. was not statistically significant. Mean serum concentration of inorganic Cytotoxic chemotherapy, radiation, and mithramycin were not allowed phosphorous declined significantly for all patients from 2.9 ±0.86 mg/ dl at base line to 1.8 ±0.66 mg/dl (/' < 0.001). Pharmacokinetic studies within 7 days preceding entry nor at any time during the study. Other study requirements included: total serum calcium >12.0 mg/dl after suggested that a threshold plasma gallium concentration of approximately rehydration and furosemide-induced diuresis; serum creatinine <3.0 I /Ji4ml must be attained to achieve acute normalization of elevated serum mg/dl; maintenance of urinary output >2000 ml/day. There was no calcium levels. Steady-state plasma gallium levels were attained after 48 restriction upon histológica!cancer diagnosis. All but one patient (with h; there was no evidence of drug accumulation in plasma after 2 days. non-small cell lung cancer) had previously received chemotherapy and/ Kffects on serum creatinine concentration were negligible, and there were or radiation, and all had developed progression of the underlying no other toxic reactions. These data confirm preclinical experiments disease. which suggested that inhibition of bone résorptionbygallium nitrate is Gallium Nitrate Treatment. The prescribed dose of gallium nitrate dependent upon the dose and duration of drug exposure. We conclude was diluted in 1000 ml of 5% dextrose solution and infused i.v. over that gallium nitrate is effective treatment for cancer-related hypercal 24 h using an infusion pump (IVAC, Inc., San Diego, CA). Patients cemia. The drug is now being evaluated against standard treatment in a were treated at one of three dose levels: 100 mg/m2/day for 5 days; 200 randomized, double-blind trial. mg/m2/day for 5-7 days; and 50 mg/m2 by 4-h infusion on Day 1 followed by 150 mg/m2/day for 5 days. This study was designed INTRODUCTION specifically to assess the ability of gallium nitrate to achieve acute normalization of elevated serum calcium levels. Maintenance of nor Cancer-related hypercalcemia is a substantial problem in the mocalcemia was not an objective, although patients could be retreated clinical management of patients with cancer. Almost one-half with subsequent infusions of gallium nitrate for recurrent episodes of of women with metastatic breast cancer eventually develop hypercalemia. hypercalcemia at some point (1). The particular mechanisms Pharmacokinetic Study. Approximately 10 ml of blood were drawn into heparinized glass tubes at base line and at specified times during which accelerate bone résorptionare controversial (2). How the drug infusion. Whole blood was centrifugea at 180 x g to separate ever, osteolysis ultimately causes excessive release of skeletal plasma from RBC. The plasma was frozen in plastic tubes at 0"( ' until calcium into the circulation which overwhelms renal excretory analyzed. Gallium concentration was measured by flameless atomic capability. Serum calcium increases with consequential morbid absorptiometry using a method with minor modifications which we ity such as nausea, dehydration, stupor, and coma. have previously described (10). Plasma gallium levels were also deter Conventionally, it has been assumed that cancer-related cal mined in 4 normocalcemic patients who received gallium nitrate (200 cium can best be controlled by achieving control of the under mg/m2/day) for 7 days as part of a study of patients with bone lying malignant disease. However, new drugs have been discov métastases(11).Pharmacokinetic data from these patients are reported ered which are potent inhibitors of bone résorptionand which in this study. Patient Monitoring. The following tests were performed prior to have no direct antitumor activity. Such agents include the biphosphonates (3-5), WR-2721 (6), and gallium nitrate (7-9). entry into the study: total serum calcium; serum albumin; serum inor ganic phosphorous; 12 channel automated biochemical profile; blood In a pilot study, we found that gallium nitrate was effective urea nitrogen; and creatinine. The presence or absence of bone involve treatment for cancer-related hypercalcemia (7). This agent di ment by tumor was assessed by skeletal scintigraphy or roentgenograms. rectly inhibits calcium release from bone (8). Unlike mithra- Total serum calcium, blood urea nitrogen, and creatinine concentra mycin, these effects are achieved without causing toxicity to tions were measured daily during the drug infusion and for several days bone cells (9). thereafter (along with inorganic serum phosphorous concentration) to determine the duration of normocalcemia and any potential drug- Received 1/10/86; revised 4/1/86; accepted 4/18/86. related toxicity. Total serum calcium was adjusted for serum albumin The costs of publication of this article were defrayed in part by the payment concentration using the formula: corrected calcium (mg/dl) = measured of page charges. This article must therefore be hereby marked advertisement in calcium (mg/dl) - serum albumin (g/dl) -I-4.0 (12). Patients were also accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Presented in part at the Annual Meeting of the American Society for Clinical monitored for any other evidence of antitumor effects. Investigation, Washington, DC. April 30, 1983. and the American Society of Data Analysis and Report. As with any agent, the effects of concom- Clinical Oncology, Los Angeles, CA, May 5. 1986. 2Supported in part by Grant CA-37768 from the National Cancer Institute, itantly administered therapy are potentially confounding factors in the N1H. To whom requests for reprints should be addressed, at 1275 York Avenue, analysis of response and toxicity. In this paper, these parameters are New York, NY 10021. specifically defined. Concomitant administration of p.o. phosphorous 4208 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1986 American Association for Cancer Research. GALLIUM NITRATE IN HYPERCALCEMIA or corticosteroids was allowed only if the dose was stable or decreasing. Table 1 Hypocalcémieresponseto gallium nitrate Introduction of hypocalcémiemedication(s), cytotoxic chemotherapy, See text for definition of normocalcemic duration. or radiation (even if localized) was a protocol violation which made serum that treatment course inevaluable for response. The duration of nor- calcium"Initial14.216.116.613.614.815.215.014.014.213.615.713.214.718.714.415.315.612.513.214.312.314.6±calcemic mocalcemia was defined as that period after normalization of serum Histológica! duration duration Bone calcium up to the day of recurrent hypercalcemia, hospital discharge diagnosisDose: (days)557S67555557555575557555555555555555555Total(days)métastases6921 without follow-up determinations of serum calcium, or (most com mg/m2/dayBreastBreastLymphomaHead200 monly) the administration of other antitumor or hypocalcémietreat ment (including p.o. phosphorous or corticosteroids). In view of these factors, the reported durations of normocalcemia may understate the +96+14+1486+57+81+5+83+824+3+41283+2+1+6+67NoYesNoNoYesNoYesNoYesYesYesYesYesYesYesNoYesNoYesYesYesYesNoYesYesYesNoYesNoNoNoNoYesYesYesYesYesNoNo hypocalcémieeffect of gallium nitrate in many patients. Similarly, the neckBreastLymphomaLungPenisHeadand evaluation for potential drug-related toxicity (particularly effects on serum creatinine and phosphorous) includes data obtained up to the day of recurrent hypercalcemia, administration of chemotherapeutic or hypocalcémiemedications, or a maximal period of 2 wk after complet neckLungLungLungLungBladderHeadand ing the drug infusion if none of these conditions applied. Data are presented as median values or
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