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Background: The prognosis of patients with advanced non-small-cell-lung cancer (NSCLC) is dismal.In these patients, the survival, clinical benefits, and toxicity of a multidrug regimen, based on combination of biotherapeutical agents and cyclophosphamide was determined.Methods: Patients with a diagnosis of advanced (stage ⅢB or stage Ⅳ) Non-Small Cell Lung Cancer (NSCLC) received a daily combination of somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide.The first group of patients had no previous surgery or chemoradiotherapy.The second group of patients had progression after prior standard chemotherapy.All the patients had a low Performance Status (PS ≥3d 2), according to the Eastern Cooperative Oncology Group (ECOG).Results: In the first group, twentyeight (28) patients were enrolled.The median age was 64 years (range, 35-74).The PS was 2 and 3 in 78.6% and 21.4% of patients, respectively.The median overall survival (intent-to-treat analysis) was 12.9 months (range, 1.5-33.5 months), The overall survival rates at 1 and 2 years were 51.2% and 21.1%, respectively.The side-effects were very mild, mostly consisting of diarrhoea, nausea/vomiting, and drowsiness of grade 1-2.Most patients experienced an improvement of both respiratory (cough and dyspnoea) and general (pain, fatigue, and insomnia) symptoms.In the second group, twenty-three (23) patients were enrolled.The median age was 59 years (range, 42-75).The PS was 2 and 3 in 73.9% and 26.1% of patients, respectively.The median overall survival (intent-to-treat analysis) was 95 days (range, 19-214).The side-effects were mild, mostly consisting of diarrhea, nausea and vomiting, and drowsiness of Grade 1-2.Therc was an improvement in both respiratory and general symptoms, which was more evident in patients surviving more than 95 days.Conclusions: chemotherapy-naive patients with advanced NSCLC and low PS may benefit from a combination of somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide, in terms of survival and quality of life, with very low side-effects.Also in heavily pretreated patients with latc-stage lung adenocarcinoma and poor PS, the same combination treatment is well tolerated and can improve disease-related symptoms.