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Clinical Trials |
Imperial Cancer Research Fund Medical Oncology Unit, and Department of Urology, Churchill Hospital, Oxford OX3 7LJ, United Kingdom [J. P. B., K. J. O., D. J. P., M. S., N. D., C. H., J. W., K. M., J. C., K. S., T. S. G., D. C. T., A. L. H.]; Haemostasis, Thrombosis and Vascular Biology Laboratory, University Department of Medicine, City Hospital, Birmingham, B18 7QH, United Kingdom [A. B.]; and Finsen Laboratory, Righospitalet, DK-2100, Copenhagen, Denmark [R. S.]
Renal cell carcinoma (RCC) is an angiogenic tumor resistant to standard
cytotoxic chemotherapeutic agents. Although often responsive to
immunomodulatory agents including interleukin 2 and IFN-
, the
overall results in randomized Phase III studies are disappointing with
only modest improvements in overall survival. This Phase II study
evaluated the efficacy and tolerability of razoxane, an antiangiogenic
topoisomerase II inhibitor, in 40 patients (32 men, 8 women; age:
range, 31–76 years; median, 58 years) with inoperable RCC. Twenty
patients received razoxane 125 mg p.o., twice a day for 5
days each week for 8 weeks (one cycle). This was repeated in patients
with stable disease (StD), but was discontinued after 16 weeks
if there was no evidence of an objective response. Because minimal
toxicity was seen, subsequent patients (n = 20)
were treated until progressive disease (PD) was documented. Of 38
evaluable patients, 11 (29%) had StD for a minimum of 4 months, and
the remainder had PD. Median overall survival was 7.3 months. Duration
of survival was significantly better in patients with StD compared with
those with PD (P = 0.003). The effect of treatment
on six potential surrogate serum/plasma (vascular endothelial growth
factor (VEGF), basic fibroblast growth factor (bFGF), urokinase
plasminogen activator soluble receptor (uPAsr), E-selectin, vascular
cell adhesion molecule-1 (VCAM-1) and von Willebrand’s factor (vWF)
and two urinary (VEGF and bFGF) markers of angiogenesis was evaluated
before and after 1 cycle of treatment. Pretreatment serum VEGF and
E-selectin levels above the median value were associated with a poor
prognosis. Serum VCAM-1 levels and urinary VEGF levels rose
significantly after one cycle in patients with PD but not in those with
StD. Serum VEGF, bFGF, VCAM-1 and vWF, plasma uPAsr and urinary bFGF
levels were significantly higher in PD patients compared with StD
patients before and/or after 1 cycle of treatment. In conclusion,
razoxane is an antiangiogenic agent that has minimal toxicity and that
requires further evaluation in combination with other active agents in
the treatment of RCC. Surrogate serum and urinary markers of
angiogenesis may have a role to play in predicting disease response and
overall survival in RCC.
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