A phase Ib/II trial of granulocyte-macrophage-colony stimulating factor and interleukin-2 for renal cell carcinoma patients with pulmonary metastases- A case of fatal central nervous system thrombosis

BACKGROUND. Interleukin-2 (IL-2) and granulocyte-macrophage-colony stimulat ing factor (GM-CSF) are cytokines with nonoverlapping pleiotropic effects. in a prior Phase Ib study, this combination of agents exhibited antitumor e ffects in the lungs of four of eight patients with renal cell carcinoma and pulmonary metastases. We conducted this Phase Ib/II trial to determine the response rate of renal cell carcinoma patients with pulmonary metastases t reated with continuous infusion IL-2 plus GM-CSF. METHODS. Patients with renal cell carcinoma and pulmonary metastases were t reated with 1.5, 2.25, or 4.5 x 10(6) IU/m(2)/day 96-hour continuous infusi on IL-2 on Days 1-4, 8-11, and 15-18, and 1.25, 2.25, or 2.5 mu g/kg/day GM -CSF on Days 8-19. RESULTS. Sixteen patients were treated per protocol, 14 of whom could be ev aluated for disease progression. None of these 14 patients had >50% shrinka ge of either total tumor burden or pulmonary metastasis. One patient develo ped Grade 5 neurotoxicity. Autopsy revealed acute multifocal cerebral venou s thrombosis as well as acute subdural and subarachnoid hemorrhage. CONCLUSIONS. The combination of IL-2 and GM-CSF may be associated with mark ed morbidity and, as in one case in this study, mortality. No significant a ntitumor activity was appreciated. Thus, the combination of IL-2 and GM-CSF ; when administered at this dose and according to this schedule, does not a ppear to be active in renal cell carcinoma and is associated with significa nt toxicities. Further studies using this combination of agents should only be undertaken with extreme caution and particular attention to neurotoxici ty. Cancer 2000;88: 1892-901, (C) 2000 Americnn Cancer Society.