A phase II study of razoxane, an antiangiogenic topoisomerase II inhibitor, in renal cell cancer with assessment of potential surrogate markers of angiogenesis

Renal cell carcinoma (RCC) is an angiogenic tumor resistant to standard cyt otoxic chemotherapeutic agents. Although often responsive to immunomodulato ry agents including interleukin 2 and IFN-alpha, the overall results in ran domized Phase III studies are disappointing with only modest improvements i n overall survival. This Phase II study evaluated the efficacy and tolerabi lity of razoxane, an antiangiogenic topoisomerase II inhibitor, in 40 patie nts (32 men, 8 women; age: range, 31-76 years; median, 58 years) with inope rable RCC, Twenty patients received razoxane 125 mg p.o., twice a day for 5 days each week for 8 weeks tone 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, subse quent patients (n = 20) were treated until progressive disease (PD) was doc umented. Of 38 evaluable patients, 11 (29%) had StD for a minimum of 4 mont hs, and the remainder had PD, Median overall survival was 7.3 months. Durat ion of survival was significantly better in patients with StD compared with those with PD (P = 0.003). The effect of treatment on six potential surrog ate serum/plasma (vascular endothelial growth factor (VEGF), basic fibrobla st growth factor (bFGF), urokinase plasminogen activator soluble receptor ( uPAsr), E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Will ebrand's factor (vWF) and two urinary (VEGF and bFGF) markers of angiogenes is was evaluated before and after 1 cycle of treatment. Pretreatment serum VEGF and E-selectin levels above the median value were associated with a po or prognosis. Serum VCAM-1 levels and urinary VEGF levels rose significantl y 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 significa ntly higher in PI) patients compared with StD patients before and/or after 1 cycle of treatment, In conclusion, razoxane is an antiangiogenic agent th at has minimal toxicity and that requires further evaluation in combination with other active agents in the treatment of RCC, Surrogate serum and urin ary markers of angiogenesis may have a role to play in predicting disease r esponse and overall survival in RCC.