Comparative tolerability of drug therapies for hypercalcaemia of malignancy

The bisphosphonates are the treatment of choice in hypercalcaemia of malign ancy. However, plicamycin (mithramycin) an calcitonin treatment may still b e of value should bisphophonate treatment fail, and gallium nitrate has rec ently been introduced as an alternative therapy. We analysed the tolerabili ty 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 greater than or equal to 10 patients. Although bisphosphonat es are generally well tolerated, elevation of serum creatinine level, nause a/vomiting and fever have been reported following their application. Patien ts receiving etidronate (n = 268) or clodronate (n = 127) more frequently e xperienced creatinine elevation (8 and 5%, respectively) than did patients receiving pamidronate (n = 424; 2%), aledronate (n = 79; 0%), or ibandronat e (n = 203; <1%). The difference in the frequency of reported creatinine le vel elevations reached statistical significance only for etidronate (z-test : p < 0.001 versus pamidronate; p < 0.02 versus alendronate; p < 0.001 vers us ibandronate). With regard to the frequency of creatinine level elevation s, clodronate treatment did not differ significantly from treatment with pa midronate, alendronate and ibandronate. An exception among the bisphosphona tes is tiludronate, which has been reported on s a treatment of hypercalcae mia in only 1 study (n = 19) resulting in 1 case of lethal and 1 case of ma nageable acute renal failure. Nausea and vomiting are rare adverse effects of bisphosphonate treatment but seem to be mote frequent with first generat ion 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 assoc iated with an acute phase reaction leading to reported fever in 16% of pami dronate, 20% of aledronate, and 11% of ibandronate-treated patients. The most frequently reported adverse effects of treatment with the cytostat ic drug plicamycin were hepatotoxicity (26%), nausea/vomiting (23%), and se rum creatinine level elevation (5%). Furthermore, plicamycin application wa s-associated with bone marrow suppression and a bleeding tendency due to ab normalities in multiple clotting factors and platelet dysfunction. The use of calcitonin is limited more by the short duration of its therapeutic effe ct than by toxicities (most frequent: nausea/vomiting in 16% of treated cas es). The few publications on gallium nitrate in the treatment of hypercalca emia of malignancy characterise it as an efficient drug, which is, however, associated with a higher frequency of renal toxicity (10%) and of nausea a nd vomiting (14%) than are the bisphosphonates.