A phase II study of subcutaneous low-dose interleukin-2 plus erythropoietin in metastatic renal cell carcinoma progressing on interleukin-2 alone.
OBJECTIVE
The activation of angiogenesis has been proven to suppress the anti-cancer immunity. The evidence of abnormally high pretreatment blood levels of vascular endothelial growth factor (VEGF), which is the main angiogenic factor, has appeared to predict resistance to IL-2 immunotherapy of metastatic renal cell carcinoma (RCC). Therefore, the control of VEGF secretion could influence the efficacy of IL-2. Recent data suggest that erythropoietin (EPO) may modulate VEGF secretion and IL-2 biological activity. On this basis, a study was planned with subcutaneous (s.c.) low-dose IL-2 plus EPO in metastatic RCC, which had progressed on IL-2 alone (6 million IU/day for 6 days/week for 4 weeks).


METHODS
Patients received IL-2 at the same dose as the previous cycle, plus EPO (10,000 3 times/week until the end of IL-2 therapy. Serum levels of VEGF were measured by enzyme immunoassay on venous blood samples collected at weekly intervals. The study included 12 evaluable metastatic RCC patients.


RESULTS
The treatment was well-tolerated and most patients referred a relief of IL-2-induced asthenia. A partial response (PR) and 4 stable diseases (SD) were achieved on IL-2 plus EPO, whereas the other 7 patients had a progressive disease (PD). Hemoglobin mean levels were significantly higher on IL-2 plus EPO than during the previous therapy with IL-2 alone in the same patients. In the same way, mean lymphocyte increase was higher on IL-2 plus EPO than on IL-2 alone, even though this difference was not significant. Finally, VEGF increase was significantly lower on IL-2 plus EPO than during IL-2 alone.


CONCLUSIONS
This preliminary study shows that the concomitant administration of EPO may allow a control of the neoplastic growth in advanced cancer patients progressing on IL-2 alone, reduce the subjective toxicity, prevent hemoglobin decrease and counteract IL-2-related VEGF increase.
Lissoni
P
P
Division of Radiation Oncology, San Gerardo Hospital, Monza, Milan, Italy.
Rovelli
F
F
Baiocco
N
N
Tangini
G
G
Fumagalli
L
L
D000368:Aged; D000740:Anemia / Q000188:drug therapy* / Q000209:etiology; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy*; D003864:Depression, Chemical; D018450:Disease Progression; D004357:Drug Synergism; D016228:Endothelial Growth Factors / Q000378:metabolism*; D004921:Erythropoietin / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D016879:Salvage Therapy; D012636:Secretory Rate / Q000187:drug effects; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D007155:Immunologic Factors; D007376:Interleukin-2; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004921:Erythropoietin