Comparative tolerability of drug therapies for hypercalcaemia of malignancy

The bisphosphonates are the treatment of choice in hypercalcaemia of malignancy. However, plicamycin (mithramycin) an calcitonin treatment may still be of value should bisphophonate treatment fail, and gallium nitrate has recently been introduced as an alternative therapy. We analysed the tolerability of different treatments based on articles identified in a Medline search covering the period 1979 through September 1998. Articles were included if they met two criteria: (i) quantitative assessment of adverse effects; (ii) inclusion of > or = 10 patients. Although bisphosphonates are generally well tolerated, elevation of serum creatinine level, nausea/vomiting and fever have been reported following their application. Patients receiving etidronate (n = 268) or clodronate (n = 127) more frequently experienced creatinine elevation (8 and 5%, respectively) than did patients receiving pamidronate (n = 424; 2%), aledronate (n = 79; 0%), or ibandronate (n = 203; <1%). The difference in the frequency of reported creatinine level elevations reached statistical significance only for etidronate (z-test: p < 0.001 versus pamidronate; p < 0.02 versus alendronate; p < 0.001 versus ibandronate). With regard to the frequency of creatinine level elevations, clodronate treatment did not differ significantly from treatment with pamidronate, alendronate and ibandronate. An exception among the bisphosphonates is tiludronate, which has been reported on s a treatment of hypercalcaemia in only 1 study (n = 19) resulting in 1 case of lethal and 1 case of manageable acute renal failure. Nausea and vomiting are rare adverse effects of bisphosphonate treatment but seem to be more frequent with first generation drugs: etidronate (8%) and clodronate (7%) versus pamidronate (2%) [p < 0.001 and 0.009, respectively] and versus ibandronate (<1%) [p< 0.002 and 0.02, respectively]. Bisphosphonates containing a nitrogen atom were associated with an acute phase reaction leading to reported fever in 16% of pamidronate, 20% of aledronate, and 11% of ibandronate-treated patients. The most frequently reported adverse effects of treatment with the cytostatic drug plicamycin were hepatotoxicity (26%), nausea/vomiting (23%), and serum creatinine level elevation (5%). Furthermore. plicamycin application was associated with bone marrow suppression and a bleeding tendency due to abnormalities in multiple clotting factors and platelet dysfunction. The use of calcitonin is limited more by the short duration of its therapeutic effect than by toxicities (most frequent: nausea/vomiting in 16% of treated cases). The few publications on gallium nitrate in the treatment of hypercalcaemia of malignancy characterise it as an efficient drug, which is, however, associated with a higher frequency of renal toxicity (10%) and of nausea and vomiting (14%) than are the bisphosphonates.