9576 Background: Cancer-related anorexia (CRA) and weight loss is a major clinical problem in up to seventy percent of patients with advanced disease. The use of megestrol acetate (MA) has resulted in weight gain in some CRA patients, but MA has had less effect on improving appetite and quality of life (QOL). Olanzapine (OLN) has been shown to be a safe and effective antiemetic in patients receiving chemotherapy and has been used successfully to treat chronic nausea and emesis. METHODS: Adult patients with advanced gastrointestinal or lung cancer (Stages III-IV) with 5% or more loss of pre-illness stable weight were randomized to receive MA (800 mg/day) or MA (800 mg/day) plus OLN (5 mg/day) for eight weeks. Patients were excluded if they had undergone major surgery, chemotherapy, or radiotherapy in the previous four weeks, had active dysphasia or GI tract obstruction, or were receiving systemic corticosteroids. Patients were assessed weekly using the M.D. Anderson Symptom Inventory (MDASI) with specific measurement of weight, appetite, nausea, and QOL measures. Eighty patients (median age 63, range 39 - 81, 36 females, Eastern Cooperative Oncology Group Performance Status ≤ 2) consented to the protocol and 76 were evaluable. RESULTS: Twenty-one of the 37 patients receiving MA experienced a 5% weight gain over the initial four week period; the weight gain was maintained for an additional four weeks. There was no significant change in appetite, nausea, or QOL measures at four weeks or eight weeks. Thirty-five of the 39 patients receiving MA plus OLN had a significant improvement (p<0.01) in weight, appetite, nausea, and QOL measures at four and eight weeks. There were no Grade III or IV treatment-related toxicities in patients receiving MA or the combination of MA plus OLN. CONCLUSIONS: The combination of OLN and MA appears to be an effective intervention for patients with CRA. No significant financial relationships to disclose.