A Phase II Study of Razoxane, an Antiangiogenic Topoisomerase II Inhibitor, in Renal Cell Cancer with Assessment of Potential Surrogate Markers of Angiogenesis

• Published in: Clinical cancer research Vol. 6; no. 12; pp. 4697 - 4704
• Main Authors: BRAYBROOKE, Jeremy P, O'BYRNE, Kenneth J, SMITH, Kenneth, STEPHENS, Ross, GANESAN, Trivadi S, TALBOT, Denis C, HARRIS, Adrian L, PROPPER, David J, BLANN, Andrew, SAUNDERS, Mark, DOBBS, Nicola, HAN, Cheng, WOODHULL, Jane, MITCHELL, Karen, CREW, Jeremy
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-12-2000
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biomarkers; Carcinoma, Renal Cell - blood; Carcinoma, Renal Cell - drug therapy; Chemotherapy; Disease-Free Survival; E-Selectin - blood; Endothelial Growth Factors - blood; Endothelial Growth Factors - urine; Female; Fibroblast Growth Factor 2 - blood; Fibroblast Growth Factor 2 - urine; Humans; Kidney Neoplasms - blood; Kidney Neoplasms - drug therapy; Lymphokines - blood; Lymphokines - urine; Male; Medical sciences; Middle Aged; Neovascularization, Pathologic; Pharmacology. Drug treatments; Razoxane - adverse effects; Razoxane - therapeutic use; Receptors, Cell Surface - blood; Receptors, Urokinase Plasminogen Activator; Time Factors; Topoisomerase II Inhibitors; Treatment Outcome; Vascular Cell Adhesion Molecule-1 - blood; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; von Willebrand Factor - biosynthesis; Antineoplastic agent; Carcinoma; Prognosis; Razoxane; Toxicity; Biological marker; Kidney; Blood plasma; Angiogenesis; Isomerases; Phase II trial; Serum; Antiangiogenic agent; Kidney disease; Human; DNA topoisomerase (ATP-hydrolysing); Urinary system disease; Enzyme; Treatment efficiency; Enzyme inhibitor; Malignant tumor; Survival; Chemotherapy; Treatment; Predictive factor
• ISSN: 1078-0432; 1557-3265

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-α, 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.