title: A phase II study of razoxane, an antiangiogenic topoisomerase II inhibitor, in renal cell cancer with assessment of potential surrogate markers of angiogenesis.
abstract: 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-alpha, 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.
authors.affiliation: Department of Urology, Churchill Hospital, Oxford, United Kingdom.
authors.forename: J P
authors.initials: JP
authors.lastname: Braybrooke
authors.forename: K J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: D J
authors.initials: DJ
authors.lastname: Propper
authors.forename: A
authors.initials: A
authors.lastname: Blann
authors.forename: M
authors.initials: M
authors.lastname: Saunders
authors.forename: N
authors.initials: N
authors.lastname: Dobbs
authors.forename: C
authors.initials: C
authors.lastname: Han
authors.forename: J
authors.initials: J
authors.lastname: Woodhull
authors.forename: K
authors.initials: K
authors.lastname: Mitchell
authors.forename: J
authors.initials: J
authors.lastname: Crew
authors.forename: K
authors.initials: K
authors.lastname: Smith
authors.forename: R
authors.initials: R
authors.lastname: Stephens
authors.forename: T S
authors.initials: TS
authors.lastname: Ganesan
authors.forename: D C
authors.initials: DC
authors.lastname: Talbot
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy*; D018572:Disease-Free Survival; D019040:E-Selectin / Q000097:blood; D016228:Endothelial Growth Factors / Q000097:blood / Q000652:urine; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood / Q000652:urine; D006801:Humans; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy*; D008222:Lymphokines / Q000097:blood / Q000652:urine; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D011929:Razoxane / Q000009:adverse effects / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000097:blood; D055293:Receptors, Urokinase Plasminogen Activator; D013997:Time Factors; D059005:Topoisomerase II Inhibitors; D016896:Treatment Outcome; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D019040:E-Selectin; D016228:Endothelial Growth Factors; D008222:Lymphokines; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D059005:Topoisomerase II Inhibitors; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014841:von Willebrand Factor; D016222:Fibroblast Growth Factor 2; D011929:Razoxane