Zoledronic Acid Delays the Onset of Skeletal-Related
Events and Progression of Skeletal Disease in
Patients with Advanced Renal Cell Carcinoma
Allan Lipton, M.D.1
Ming Zheng, Ph.D.2
John Seaman, Pharm.D.2
1Department of Medicine, Milton S. Hershey Med-
ical Center, Hershey, Pennsylvania.
Hanover, New Jersey.
The authors gratefully acknowledge the participa-
tion of investigators from Argentina, Australia,
Austria, Belgium, Brazil, Canada, France, Ger-
many, Italy, New Zealand, Poland, Switzerland, the
United Kingdom, and the United States.
Allan Lipton has 200 shares of Norvartis stock in a
retirement account and has received honoraria
from Novartis Pharmaceuticals Corporation
Ming Zheng and John Seaman are both employed
by Novartis Pharmaceuticals Corporation
Address for reprints: Allan Lipton, M.D., Depart-
ment of Medicine, Milton S. Hershey Medical Cen-
ter, P.O. Box 850 H-46, Hershey, PA 17033; Fax:
(717) 531-5076; E-mail: firstname.lastname@example.org
Received April 11, 2003; accepted May 13, 2003.
BACKGROUND. The objective of this study was to assess the efficacy and safety of
zoledronic acid in patients with bone metastases secondary to renal cell carcinoma
METHODS. A retrospective subset analysis of patients with RCC enrolled in a
multicenter, randomized, placebo-controlled study of zoledronic acid was per-
formed. Patients were randomized to receive zoledronic acid (4 or 8 mg as a
15-minute infusion) or placebo with concomitant antineoplastic therapy every 3
weeks for 9 months. The primary efficacy analysis was the proportion of patients
with one or more skeletal-related events (SREs), which were defined as pathologic
fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary
analyses included time to first SRE, skeletal morbidity rate (events per year),
disease progression, and multiple event analysis.
RESULTS. In this subset of 74 patients with RCC, zoledronic acid (4 mg) was found
to significantly reduce the proportion of patients with an SRE (37% vs. 74% for
placebo; P ? 0.015). Similarly, zoledronic acid significantly reduced the mean
skeletal morbidity rate (2.68 vs. 3.38 for placebo; P ? 0.014) and extended the time
to the first event (median not reached vs. 72 days for placebo; P ? 0.006). A
multiple event analysis demonstrated that the risk of developing an SRE was
reduced by 61% compared with placebo (hazard ratio of 0.394; P ? 0.008). The
median time to progression of bone lesions was significantly longer for patients
who were treated with zoledronic acid (P ? 0.014 vs. placebo). Zoledronic acid
appeared to be well tolerated; the most common adverse events in all treatment
groups included bone pain, nausea, anemia, and emesis.
CONCLUSIONS. Zoledronic acid (4 mg as a 15-minute infusion) demonstrated
significant clinical benefit in patients with bone metastases from RCC, suggesting
that further investigation of zoledronic acid in this patient population is warranted.
Cancer 2003;98:962–9. © 2003 American Cancer Society.
KEYWORDS: bisphosphonate, bone, renal cell carcinoma (RCC), neoplasm metasta-
over the last 2 decades,1and it has been estimated that bone metas-
tases will develop in approximately 30% of patients with RCC.2Bone
metastases cause considerable skeletal morbidity, including bone
pain, pathologic fractures, spinal cord compression, and hypercalce-
mia of malignancy (HCM).3It has been reported that approximately
81% of patients with RCC and bone metastasis require radiotherapy,
42% experience a long-bone fracture, and 29% require orthopedic
surgery or develop HCM at some point during the course of their
keletal involvement is common in patients with renal cell carci-
noma (RCC). The incidence of RCC has been increasing steadily
© 2003 American Cancer Society
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Zoledronic Acid for Renal Cell Carcinoma/Lipton et al.969