Genta's first drug, Ganite, is approved to treat cancer-related hypercalcemia
When it comes to calcium, the human body typically exerts unusually tight regulatory control over this essential electrolyte, since it is required for cell membrane functions, neuromuscular activities, endocrine and exocrine secretion, coagulation, and cardiac contractions. To keep serum calcium levels stable, within rather narrow limits, requires regulation by a rather complex system that involves parathyroid hormone, vitamin D, and calcitonin. Since these hormones usually work together quite nicely in a concerted fashion to maintain calcium homeostasis, we rarely give a second thought to the activities of calcium in our bodies.
Yet, for some people, disruptions in calcium balance are problematic. In fact, hypercalcemia (serum calcium > 10.5 mg/dl) is a potential complication for those with malignancies. Up to 50% of patients with advanced cancers of the lung, breast, ovaries, kidneys, or bladder, as well as patients with multiple myeloma and T-cell lymphomas, experience life-threatening elevations of serum calcium levels. This occurs because of increased calcium resorption from bone. Calcium resorption occurs, in part, because of cancer metastases involving the skeletal system, but also as a result of hormonal factors produced by tumors that elevate serum calcium levels.
The spectrum of signs and symptoms associated with hypercalcemia is quite broad and may include anorexia, nausea, vomiting, constipation, dehydration, renal insufficiency, and impaired mental status. Timothy Tyler, Pharm.D., director of pharmacy services at the Comprehensive Cancer Center at Desert Regional Medical Center in Palm Springs, Calif., said, "Patients with serum calcium levels between 12 and 15 mg/dl may present with altered mentation or agitation." If untreated, the situation may progress to coma, malignant ventricular arrhythmias, and death.
Typically, the first step in treating patients with hypercalcemia is correction of fluid abnormalities, but a subset of patients are resistant to hydration. These patients may benefit from gallium nitrate, Ganite, the first drug from Genta; it's a compound approved to treat cancer-related hypercalcemia resistant to hydration.
Gallium nitrate was originally developed as a cancer chemotherapeutic agent. However, subsequent studies demonstrated that the drug markedly reduces calcium loss from bone. In clinical trials, gallium nitrate stabilized serum calcium levels by inhibiting bone resorption. "The precise mechanism of action has not been determined," said Genta spokeswoman Joy Schmitt, but a number of cellular processes are affected, including inhibition of matrix metalloproteinase activity.
In clinical trials, gallium nitrate was administered to patients with hypercalcemia via continuous infusion at a dosage of 200 mg/m2 per day for five days, and the drug was compared with 8 IU/kg calcitonin given four times per day for five days. Normal serum calcium levels were achieved in 75% of patients in the gallium nitrate arm of the study compared with 27% of those receiving calcitonin.
In studies to date, gallium nitrate is reportedly well tolerated, but its use is contraindicated in those with severely impaired kidney function (serum creatinine > 2.5 mg/dl). Concurrent use of other nephrotoxic drugs may increase the risk of developing renal insufficiency. According to package labeling, "It is strongly recommended that serum creatinine be monitored during Ganite therapy." Additionally, in clinical trials, some other metabolic adverse effects were noted, including mild-to-moderate hypophosphatemia in 79% of patients, a decreased serum bicarbonate level in 40%-50% of patients, and mild-to-moderate hypocalcemia in 38% of patients.
When asked about the role of gallium nitrate in cancer patients, Tyler said that at his institution, pamidronate (Aredia, Novartis) and zoledronic acid (Zometa, Novartis) are used to treat hypercalcemia. However, he added, "Ganite is another agent, and it's never a bad thing to have another agent to choose from." There is little doubt that future head-to-head studies between bisphosphonates and gallium nitrate will be of interest, to compare the efficacy among all the possible options available for patients with hypercalcemia associated with malignancy.
Kelly Karpa. Bad to the bone?
Oct. 20, 2003;147:HSE5.