Impact of Zoledronic Acid on Renal Function in Patients With Cancer ...

McDermott, Kloth, Wang, et al
Because these patients have advanced or metastatic cancer,
it is possible that the number <strong>of</strong> doses received may be a surrogate,
at least in part, for progression <strong>of</strong> disease and overall
deterioration in multiple systems. In licensing studies, the incidence
<strong>of</strong> renal deterioration appeared to be related to the time
on study, whether the patients were receiving zoledronic acid,
pamidronate, or placebo. 2,3,5,11 This relation was also reflected in
the analysis <strong>of</strong> our own patient population with renal deterioration,
in many <strong>of</strong> whom it was a preterminal event. Finally, age
is an accepted risk factor for the development <strong>of</strong> renal failure,
most likely due to the accumulation <strong>of</strong> comorbid illnesses. 17
On multivariate analysis, we did not find a significant relationship
between an elevated baseline serum creatinine level
and renal deterioration, as described in the package insert. 18 This
finding may be attributable to the fact that the degree <strong>of</strong> baseline
renal function impairment was not severe in these patients. In a
small pharmacokinetic study <strong>of</strong> 19 cancer patients stratified by
creatinine clearance, 19 dosage adjustment <strong>of</strong> zoledronic acid did
not appear to be necessary in patients with mild to moderate renal
impairment. Nonetheless, zoledronic acid is not recommended in
patients with serum creatinine levels > 3 mg/dL, and caution is
advisable in all patients with impaired renal function. 18
Using these risk factors, we have constructed a model that
can be used to predict the likelihood <strong>of</strong> an individual patient
developing renal deterioration with the use <strong>of</strong> zoledronic acid.
We chose a cut<strong>of</strong>f point <strong>of</strong> 10%, as it is similar to the previously
published incidence <strong>of</strong> renal deterioration with zoledronic
acid 2–5 and represents a level <strong>of</strong> risk above which clinicians may
wish to proceed more cautiously. The risk-factor pr<strong>of</strong>ile and the
accompanying model potentially could be used by physicians involved
in the treatment <strong>of</strong> patients with metastatic cancer when
calculating the risk-benefit ratio associated with zoledronic acid
therapy as an adjunct to other anticancer therapies.
It is important to note, however, that the review <strong>of</strong> the cases
in this series in which there was evidence <strong>of</strong> renal deterioration
demonstrated that the rise in creatinine level was <strong>of</strong>ten
mild and not clinically significant in the eyes <strong>of</strong> the treating
physician. In many instances, zoledronic acid therapy was continued
without sequelae. Moreover, in other patients, renal
deterioration was a preterminal event, with evidence <strong>of</strong> widely
progressive disease, a general deterioration in performance
status, and a switch to symptom-based care. This finding is
consistent with the fact that once bisphosphonate therapy is
begun for treatment <strong>of</strong> bone metastasis, it is <strong>of</strong>ten continued
until the decision is made to end active cancer therapy. Nonetheless,
there are patients in whom use <strong>of</strong> zoledronic acid will
induce a rise in serum creatinine level that may drop upon
discontinuation <strong>of</strong> the drug, and our model is unable to differentiate
between these differing patient types.
Conclusion
<strong>Zoledronic</strong> acid must be regarded as a potentially nephrotoxic
agent, similar to many other medications used in the
treatment <strong>of</strong> patients with cancer. However, the impact <strong>of</strong>
monitoring renal function before each dose <strong>of</strong> zoledronic
acid effectively negates the time advantage <strong>of</strong> the infusion,
as patients typically must wait for laboratory results before
commencing therapy. Regular monitoring <strong>of</strong> serum creatinine
levels in these patients represents good clinical practice;
there are many reasons why renal function might deteriorate
in patients with advanced disease. Based on the available
data, monitoring <strong>of</strong> serum creatinine levels before each dose
<strong>of</strong> zoledronic acid is given appears warranted in patients at
high risk for renal deterioration; however, compulsive creatinine
level monitoring is burdensome and expensive and may
not be necessary in all patients.
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