IMMUNOENDOCRINE THERAPY WITH LOW-DOSE SUBCUTANEOUS INTERLEUKIN-2 PLUSMELATONIN OF LOCALLY ADVANCED OR METASTATIC ENDOCRINE TUMORS

Recent evidence has shown that endocrine tumors are under an endocrine and an immune regulation, and that biotherapies with interferon or th e long-acting somatostatin analog octreotide may be effective in the c ontrol of tumor growth and clinical symptomatology. Within the biother apies of tumors, interleukin-2 (IL-2) has appeared to play an essentia l role in the antitumor immune response. Despite its important antitum or role, very few studies have been carried out to investigate the pos sible use of IL-2 in the treatment of advanced endocrine tumors. Its p otential toxicity would represent the main limiting factor for the cli nical experiments with IL-2. Our previous studies have shown that the pineal hormone melatonin (MLT) may amplify the antitumor activity of I L-2, either through immunomodulating mechanisms or through a direct cy tostatic activity by inhibiting tumor growth factor production. On thi s basis, we have performed a phase II pilot study with low-dose IL-2 p lus MLT in 14 patients with untreatable endocrine tumors because of di sseminated disease, lack of response to previous standard biotherapies or chemotherapies, or tumors for whom no effective therapy is availab le. Thyroid cancers, carcinoid and endodrine pancreatic tumors were th e most frequent neoplasms. IL-2 was given at 3 million IU/day s.c. at 8 p.m. for 6 days/week for 4 weeks, corresponding to one cycle. MLT wa s given orally at 40 mg/day at 8 p.m. every day. In nonprogressed pati ents, a second cycle was given after a 21-day rest period. Patients we re considered as evaluable when they received at least one complete cy cle, and 12 patients were fully evaluable. According to WHO criteria, a partial response was achieved in 3/12 (25%) patients (carcinoid tumo r: 1; neuroendocrine lung tumor: 1; pancreatic islet cell tumor: 1). A nother patient with gastrinoma had a more than 50% reduction of tumor markers. Toxicity was low in all patients. This preliminary study sugg ests that low-dose IL-2 immunotherapy in association with the pineal h ormone MLT may constitute a new well-tolerated and potentially active therapy of untreatable advanced endocrine tumors.