e13009 Background: Epidermal growth factor (EGF) plays an important role in carcinogenesis. An adenine (A) to guanine (G) single nucleotide polymorphism at position 61 in the 5'-untranslated region (5'-UTR) of the EGF gene has been found to be associated with levels of EGF production and contribute to the risk of glioma. However, published data are contradictory. EGF +61G/A polymorphism may contribute to the risk of glioma in different ethnic group. Patients with glioma and GG genotype have been reported to have a risk of poorer otucome than patients with AA genotype. Purpose of this study is to investigate the potential role of this polymorphism in cancer progression and its role as predictive marker of outcome in glioma caucasian patients. Methods: EGF 61A/G polymorphism (rs4444903) was analyzed in glioma patients and was determined by means of Polymerase Chain Reaction and Direct Sequencing method (GenBank reference sequence-accession no. AC005509) from blood samples. Association of this genetic polymorphism with clinical and pathological data of patients was evaluated. Results: We investigated EGF +61G/A polymorphism in 24 glioma patients . EGF +61G allele has been found in 67% of glioma patients (25% G/G genotype and 42% A/G genotype). In astrocytomas, EGF +61G allele represents a 83% frequency; in glioblastomas and in oligodendrogliomas, EGF +61G allele frequency represents respectively 71% and 50%. In WHO IV gliomas, the EGF +61G allele represents a 63% frequency, (27% G/G and 36% A/G ), in WHO III gliomas a 77% frequency (33% G/G and 44% A/G ) and in WHO II gliomas a 50% frequency (100% A/G ). Median PFS of glioblastoma patients was 9 months. 83% of glioblastoma patients with a relapsing disease showed the G/G and A/G genotype. No difference was detected in the others histotypes. Conclusions: Our data conferm previous studies which reported G allele as a risk factor for glioma in Caucasian. G/A and G/G genotypes seem to be more rappresentative in high grade gliomas . Despite limited number of patients, our study supports the predictive role of EGF 61 A/G polymorphism in GBM. Additional large studies are warranted to confirm the role of EGF polymorphism as indipendent prognostic factor in glioma.

Aims and background. Advanced chemorefractory epithelial thymic tumors are still a challenge in clinical oncology A therapeutic approach targeting a key molecular pathway could be the ideal solution in a neoplasm that can overexpress epidermal growth factor receptor (EGFR) in the epithelial component.Methods. A patient with metastatic heavily pretreated thymic carcinoma was evaluated for EGFR expression in the primary tumor.Results. Strong EGFR expression was revealed by immunohistochemistry. The patient received erlotinib therapy but had obtained no response after four months of treatment.Conclusion. This preliminary experience suggests that erlotinib may not be a useful therapeutic choice in advanced pretreated thymic carcinomas.

Objective: Fatigue is a multidimensional symptom that is described in terms of perceived energy, mental capacity, and psychological status: it can impair daily functioning and lead to negative effects on quality of life. It is one of the most common side effects of chemotherapy and radiotherapy. In recent studies, L-carnitine (LC) supplementation has been demonstrated to be able to improve fatigue symptoms in patients with cancer.Methods: In the present study we tested the efficacy and safety of LC supplementation in a population of patients who had advanced cancer and developed fatigue, high blood levels of reactive oxygen species, or both. As outcome measures we evaluated fatigue and quality of life in relation to oxidative stress, nutritional status, and laboratory variables, mainly levels of reactive oxygen species, glutathione peroxidase, and proinflammatory cytokines. From March to July 2004, 12 patients who had advanced tumors (50% at stage IV) at different sites were enrolled (male-to-female ratio 2: 10, mean age 60 y, range 42-73). Patients were only slightly anemic (hemoglobin 10.9 g/dL) and hemoglobin levels did not change after treatment. LC was administered orally at 6 g/d for 4 wk. All patients underwent antineoplastic treatment during LC supplementation.Results: Fatigue, as measured by the Multidimensional Fatigue Symptom Inventory-Short Form, decreased significantly, particularly for the General and Physical scales, and for quality of life in each subscale of quality of life in relation to oxidative stress. Nutritional variables (lean body mass and appetite) increased significantly after LC supplementation. Levels of reactive oxygen species decreased and glutathione peroxidase increased but not significantly. Proinflammatory cytokines did not change significantly.Conclusion: Improvement of symptoms with respect to fatigue and quality of life in relation to oxidative stress may be explained mainly by an increase in lean body mass, which may be considered the most important nutritional or functional parameter in assessing the cachectic state of patients. In this view, fatigue with related symptoms can well be considered an important constituent of cancer-related anorexia cachexia syndrome. (c) 2006 Elsevier Inc. All rights reserved.

Purpose: To test the efficacy and safety of an integrated treatment based on a pharmaconutritional support, antioxidants, and drugs, all given orally, in a population of advanced cancer patients with cancer-related anorexia/cachexia and oxidative stress.Patients and Methods: An open early-phase II study was designed according to the Simon two-stage design. The integrated treatment consisted of diet with high polyphenols content (400 mg), antioxidant treatment (300 mg/d alpha-lipoic acid + 2.7 g/d carbocysteine lysine salt + 400 mg/d vitamin E + 30,000 IU/d vitamin A + 500 mg/d vitamin C), and pharmaconutritional support enriched with 2 cans per day (n-3)-PUFA (eicosapentaenoic acid and docosahexaenoic acid), 500 mg/d medroxyprogesterone acetate, and 200 mg/d selective cyclooxygenase-2 inhibitor celecoxib. The treatment duration was 4 months. The following variables were evaluated: (a) clinical (Eastern Cooperative Oncology Group performance status); W nutritional [lean body mass (LBM), appetite, and resting energy expenditure]; (c) laboratory [proinflammatory cytokines and leptin, reactive oxygen species (ROS) and antioxidant enzymes]; W quality of life (European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5D, and MFSI-SF).Results: From July 2002 to January 2005, 44 patients were enrolled. Of these, 39 completed the treatment and were assessable. Body weight increased significantly from baseline as did LBM and appetite. There was an important decrease of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha, and a negative relationship worthy of note was only found between LBM and IL-6 changes. As for quality of life evaluation, there was a marked improvement in the European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5DVAs, and multidimensional fatigue symptom inventory-short form scores. At the end of the study, 22 of the 39 patients were "responders" or "high responders." The minimum required was 21; therefore, the treatment was effective and more importantly was shown to be safe.Conclusion: The efficacy and safety of the treatment have been shown by the study; therefore, a randomized phase III study is warranted.

8103 Background: CACS/OS play a key role in the progression and outcome of cancer. The conventional treatment based on progestagens shows limited efficacy. An important role may be played by a pharmaco-nutritional support containing EPA. Patients and Methods: A phase II non randomized study has been designed to evaluate the efficacy and tolerability of an innovative approach consisting of: diet with high polyphenols content (400 mg), oral pharmaco-nutritional support enriched with n-3 PUFA (EPA, DHA) 2 cans (237 ml each)/day, medroxyprogesterone acetate 500 mg/day, antioxidant treatment (alpha lipoic acid 300 mg/day + carbocysteine lysine salt 2.7 g/day + vitamin E 400 mg/day + vitamin A 30000 IU/day + vitamin C 500 mg/day), selective COX-2 inhibitor Celecoxib 200 mg/day. The treatment is administered for 16 weeks. The planned accrual is 40 patients. The 1) clinical (stage and ECOG PS), 2) nutritional (Lean Body Mass, LBM, appetite (VAS), resting energy expenditure), 3) laboratory (serum proinflammatory cytokines, CRP and leptin and blood levels of reactive oxygen species (ROS) and antioxidant enzymes) and 4) quality of life (EORTC QLQ-C30, EQ-5D and EQ-5Dvas) parameters have been evaluated. Results: 29 patients have been enrolled (16 head and neck, 4 breast; all stage IV). 22 patients are evaluable: 13 patients after 4 months, 17 after 2 months and 22 after 1 month of treatment. As for LBM a mean increase of 1.3 kg (+5.7%) after 1 month (p=ns), 1.4 kg (+5.0%) (p=0.042) after 2 months and 4.4 kg (+17.6%) (p=0.044) after 4 months have been recorded. TNFalpha and IL-6 decreased significantly after 2 months (p=0.029, p<0.0001) and 4 months (p=0.026, p=0.006, respectively). ROS decreased significantly after 1 month(p=0.020), 2 months (p=0.022) and 4 months (p=0.022). The QL evaluation showed a mean increase (improved QL) of 14.9% by EORTC QLQ-C30 and 17.3% by EQ-5Dvas after 1 month. Appetite increased of 22.4% after 1 month. Conclusions: At the interim analysis on the first 22 patients the treatment appears effective for the main parameters studied, safe and achieving an optimal compliance by patients. No significant financial relationships to disclose.

The primary aim of the present study was to examine the relationship of changes in hemoglobin levels following recombinant human erythropoietin (rHuEPO) treatment to changes in cognitive functioning studied by Mini Mental State Examination (MMSE) in elderly cancer patients undergoing chemotherapy treatment. The secondary aim was that to assess the relationship of changes in hemoglobin levels following rHuEPO treatment to changes in functions studied by Comprehensive Geriatic Assessment (CGA), such as Activity of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Geriatric Depression Scale (GDS) and the Mini Nutritional Assessment (MNA). To this end, hemoglobin levels and cognitive functioning were evaluated in a sample of cancer patients prior to the start of chemotherapy treatment and again after 4, 8 and 12 weeks of treatment with chemotherapy plus rHuEPO. Ten elderly patients (mean age 71.4 years) were enrolled. At baseline, enrolled patients had a mean Hb value of 10.3g/dl. After 4 weeks of rHuEPO treatment, Hb values increased significantly (p<0.0001), with a mean increase of 1.2g/dl (range: 0.2–2.1). Remarkably, 8 out of 10 (80%) showed an increase of Hb levels ≥1g/dl in comparison to baseline and therefore were considered responders. At baseline, four patients (40%) showed a moderate cognitive impairment, whilst six patients (60%) showed a normal cognitive function. After 4 weeks of rHuEPO treatment nine patients (90%) showed a significant improvement of cognitive functions in comparison to baseline (p<0.005): eight of them were responders also to rHuEPO in terms of correction of anemia. The Spearman's rank correlation test showed a statistical significant correlation between Hb increase and increase in cognitive functioning assessed by MMSE after 4 weeks (p=0.049), 8 weeks (p=0.044) and 12 weeks (p=0.031) of rHuEPO treatment. Therefore, the findings of this study provide support for the hypothesis that significant increases in hemoglobin over the course of chemotherapy supplemented with rHuEPO administration would be accompanied by significant improvement in cognitive performance over the same interval.

Evidence of haemostatic activation has been demonstrated in cancer patients.The role of chemotherapy as a risk factor for venous thrombosis has been reported during therapy for breast cancer (tamoxifen) and for Multiple Myeloma (thalidomide).Among the markers of thrombin activation, D-dimer test has been found increased after chemotherapy for breast and lung cancer (Weitz et al., Thromb Haemost 2002; 88: 213(220).However, the type of cancer and the regimen of chemotherapy give a different risk of thrombosis.Therefore, no definitive conclusions are present on the role of markers of thrombin activation for identifying patients, on chemotherapy, at high risk of thrombosis.In an ongoing clinical trial, we assessed D-dimer levels in patients on chemotherapy for cancer of the colon.Materials and methods: Consecutive patients receiving adjunctive chemotherapy for colon neoplasm were considered eligible.D-dimer test was tested at the beginning and at the end of any cycle of chemotherapy.Standard chemotherapy consists in Campto (CPT11) 180 mg/mq, and Fluororacile (400 and 600 mg/mq) for 2 days.D-dimer was furnished by Dade Behring (D-dimer PLUS, turbidimetric methods, normal value <192 m L).D-dimer variation before and after chemotherapy was assessed by Wilcoxon test.Objective test for deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were performed in symptomatic patients during the follow-up.Results: At the interim analysis, 26 patients were evaluated; D-dimer levels did not vary between the beginning and the end of chemotherapy (1 st cycle P = 0.8, 2 nd cycle P = 0.9, 3 rd cycle 0.67, 4 th cycle 0.79).One patient only (3.4%) developed symptomatic DVT of the upper limb; he had a central venous line.The last determination of D-dimer level was 1298 m L. Conclusion: At the present, our study does not confirm a significant increase of D-dimer levels in patients on chemotherapy for cancer of the colon.

Anemia occurs in more than 30% of patients with epithelial ovarian cancer before any surgery. High levels of proinflammatory cytokines and increased oxidative stress may contribute to the development of cancer-related anemia. We assessed a population of previously untreated patients with advanced epithelial ovarian cancer to evaluate whether there was a correlation between hemoglobin (Hb) and parameters of inflammation and oxidative stress, stage of disease, and performance status (PS). In 91 patients with epithelial ovarian cancer and 95 healthy women matched for age, weight, and height, levels of Hb, C-reactive protein (CRP), fibrinogen (Fbg), proinflammatory cytokines, leptin, reactive oxygen species (ROS), and antioxidant enzymes were assessed at diagnosis before treatment. The correlations between Hb, parameters of inflammation and oxidative stress, stage, and PS were evaluated. Hb levels were lower in patients with advanced epithelial ovarian cancer than in control subjects and inversely related to stage and PS. Hb negatively correlated with CRP, Fbg, interleukin 1beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNFalpha), and ROS, and positively correlated with leptin and glutathione peroxidase (GPx). Multivariate regression analysis showed that stage and IL-6 were independent factors determining Hb values. This evidence suggests that anemia in epithelial ovarian cancer is common and its presence is related to stage of disease and markers of inflammation.

1402 Cancer Anorexia/Cachexia Syndrome (CACS) and Oxidative Stress (OS) play a key role in the progression and outcome of cancer. The conventional nutritional approach through enteral/parenteral nutrition has been demonstrated to be ineffective. Synthetic progestagens are to date the only approved drugs, although their use is limited because of significant side effects. An important role may be played by a pharmaco-nutritional support containing EPA, which is able to decrease proinflammatory cytokines and PIF. Patients and Methods: Our previously published studies and clinical experience have prompted us to develop an innovative approach consisting of: diet with high polyphenols content (400 mg), oral pharmaco-nutritional support enriched with n-3 PUFA (EPA, DHA) 2 cans (237 ml each)/day, medroxyprogesterone acetate 500 mg/day, antioxidant treatment with alpha lipoic acid 300 mg/day + carbocysteine lysine salt 2.7 g/day + vitamin E 400 mg/day + vitamin A 30000 IU/day + vitamin C 500 mg/day, selective COX-2 inhibitor Celecoxib 200 mg/day. The treatment is administered for 16 weeks. The following parameters have been evaluated: 1) clinical (stage and ECOG PS); 2) nutritional (Lean Body Mass, LBM, appetite and resting energy expenditure); 3) laboratory parameters (serum levels of proinflammatory cytokines, CRP and leptin and blood levels of reactive oxygen species (ROS) and antioxidant enzymes); 4) quality of life (EORTC QLQ- C30, EQ-5D and EQ-5D vas). A phase II non randomized study has been designed to enroll 40 patients with advanced cancer at different sites with symptoms of CACS/OS. Results: To date 20 patients have been enrolled (12 head and neck, 4 breast, 1 ovarian, 1 lung, 1 stomach and 1 pancreatic cancer; all stage IV). 18 patients are currently evaluable. Ten patients have been evaluated after 4 months of treatment, 13 after 2 months and 18 after 1 month. As for LBM a mean increase of 1.1 kgs (+5.3 %) after 1 month (p=n.s.), 2.3 kgs (+10.1%) (p=0.05) after 2 months and 3.0 kgs (+14.6%) (p=0.036) after 4 months have been recorded. As for proinflammatory cytokines: TNFalpha decreased significantly after 1 month (p=0.015), 2 months (p=0.004) and 4 months (p=0.026) of treatment; IL-6 decreased significantly after 2 months (p=0.001) and 4 months (p=0.006) of treatment. As for ROS, a significant decrease after 2 months (p=0.025) and 4 months (p=0.046) of treatment has been recorded. The evaluation of QL showed a mean percent increase (improved QL) of 28% by EORTC QLQ-C30 and 16.6% by EQ-5Dvas after 1 month of treatment. Conclusions: At the interim analysis on the first 20 patients enrolled the treatment appears to be effective for the main parameters studied, safe and to achieve an optimal compliance by patients. The study is in progress until the accrual will be completed. Work supported by Special Program for Experimental Research, Prevention and Medical Education funded by Regione Autonoma Sardegna, Italy, 2002.

OBJECTIVE Cancer-related anorexia/cachexia syndrome and oxidative stress play a key role in the progression and outcome of neoplastic disease. PATIENTS AND METHODS On the basis of our previously published studies and clinical experience, we have developed an innovative approach consisting of diet with high polyphenol content (400 mg), p.o. pharmaconutritional support enriched with n - 3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) 2 cans (237 mL each) per day, medroxiprogesterone acetate 500 mg/d, antioxidant treatment with alpha-lipoic acid 300 mg/d plus carbocysteine lysine salt 2.7 g/d plus vitamin E 400 mg/d plus vitamin A 30,000 IU/d plus vitamin C 500 mg/d, and selective cyclooxygenase-2 inhibitor Celecoxib 200 mg/d. The treatment is administered for 16 weeks. The following variables are evaluated: (a) clinical variables (stage and Eastern Cooperative Oncology Group performance status); (b) nutritional variables (lean body mass, appetite, and resting energy expenditure); (c) laboratory variables (serum levels of proinflammatory cytokines, C-reactive protein, and leptin and blood levels of reactive oxygen species and antioxidant enzymes); and (d) quality of life variables (European Organization for Research and Treatment of Cancer QLQ-C30, EQ-5Dindex, and EQ-5DVAS). A phase II nonrandomized study has been designed to enroll 40 patients with advanced cancer at different sites with symptoms of cancer-related anorexia/cachexia syndrome and oxidative stress. RESULTS As of January 2004, 28 patients have been enrolled: 25 patients were evaluable and 14 of them have completed the treatment (20 patients have completed 2 months of treatment). As for clinical response, five patients improved, three patients remained unchanged, and six patients worsened. The Eastern Cooperative Oncology Group performance status (grade) 1 remained unchanged. As for nutritional/functional variables, the lean body mass increased significantly at 2 and 4 months. As for laboratory variables, reactive oxygen species decreased significantly and proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha decreased significantly. As for quality of life, it comprehensively improved after treatment. CONCLUSIONS The treatment has been shown to be effective for clinical response, increase of lean body mass, decrease of reactive oxygen species and proinflammatory cytokines, and improvement of quality of life. The treatment has been shown to be safe with good compliance of patients. The study is in progress (14 further patients will be included).

Epidemiologic evidence in humans suggests a role for selenium in reducing cancer incidence and mortality. The aim of the present study was that to assess the ability of selenium dioxide (SeO2) to enhance the lymphocyte progression through the cell cycle in patients with advanced (stage IV) cancer. Ten patients (mean age 51.9 years, range: 32-74; M/F ratio: 3/7) with tumors at different sites were included in the study. The addition into culture of SeO2 1.5 microM enhanced significantly the progression into S phase of PBMCs isolated from cancer patients, whilst no significant effect was observed on PBMCs isolated from controls. ROS levels were significantly higher, whereas GPx activity was significantly lower in cancer patients than controls. Serum levels of IL-6 and TNFalpha were significantly higher in cancer patients than controls. Our results show the ability of selenium to induce a progression of PBMCs from cancer patients into the cell cycle, which is an essential prerequisite for the physiological functioning of the immune system and thus positively influence the immune status of advanced cancer patients. The mechanism of action of selenium could be to downregulate the production and release of proinflammatory cytokines, which have a role in cancer progression and particularly in the onset of cachexia.

The purpose of the study was to assess response rate, clinical outcome, organ/function preservation and toxicity in head and neck cancer patients treated with induction chemotherapy followed by concomitant chemoradiotherapy and, when necessary, limited surgery. The study was a phase II non-randomized trial. Induction chemotherapy consisted of 6 weekly doses of carboplatin at AUC of 2 and docetaxel 30 mg/m(2) (1 h) followed by 5 cycles of docetaxel 25 mg/m(2)/day 1, 5-FU 600 mg/m(2) c.i. days 1-5, hydroxyurea 500 mg orally every 12 h for 11 and concomitant twice daily radiation therapy at 150 cGy/fraction given every other week per 5 cycles (TFHX), for a total radiation dose of 75 Gy. 13 cis-retinoic acid was administered for chemoprevention and systematic prophylaxis of mucositis with systemic amifostine and local GM-CSF was administered to all patients during TFHX. Conservative surgical resection was reserved to patients with no optimal response (PR > or =70%), whereas radical surgery was performed as salvage treatment. Thirteen patients (mean age 54.9 years, range 44-62; 12/13 site oropharynx, all stage IV) were enrolled: 31% of patients had ECOG performance status (PS) 0 and 69% had PS 1. Response to induction chemotherapy was analyzed in 12 patients: 2/12 (16.7%) achieved a partial response (PR) for an overall response (ORR) of 16.7%, 10/12 (83.3%) achieved stable disease (SD). TFHX was administered to 7 patients: 2 patients (28.6%) had complete remission (CR), 1 patient (14.3%) had PR for an ORR of 42.9%, 3 patients (42.8%) had SD and 1 patient (14.3%) had PD. At the completion of TFHX, 1 patient underwent local therapy. The toxicity was mild and consisted in: grade 3/4 neutropenia (7.7%), anemia (23.1%), diarrhea (15.4%), mucositis (7.7%), neurotoxicity (7.7%) during induction chemotherapy. During TFHX only 42.8% of grade 3/4 mucositis was observed. All patients spared organ/function. In conclusion, this regimen has been found feasible for its acceptable toxicity, particularly mucositis. However, the overall response rate and the data on survival were not satisfactory.

In the present open non-randomized phase II study we looked for effectiveness, safety, tolerability and costs of locally applied GM-CSF in preventing or treating mucositis in patients receiving chemotherapy or chemoradiotherapy for head and neck cancer. In addition to clinical mucositis scoring system, the effects of treatment with GM-CSF were evaluated by its impact on patient quality of life and by laboratory immunological assays such as serum proinflammatory cytokines, IL-2 and leptin. The trial was designed to assess the effectiveness of local GM-CSF treatment in two different settings: i) prophylaxis of mucositis; ii) treatment of mucositis. Prophylaxis was chosen for chemoradiotherapy treatments of high mucosatoxic potential, while curative treatment was reserved for chemotherapy or chemoradiotherapy treatments of lesser potential of inducing mucositis. From January 1998 to December 2001, 68 patients entered the study. The great majority of patients of both groups had head and neck cancer, were stage IV, PS ECOG 0-1, were habitual smokers and were treated with chemotherapy and concomitant (or sequential) chemoradiotherapy. Forty-six patients were included in the 'prophylactic' setting and 22 patients in the 'curative' setting. The main findings of our study are: only 50% of patients included in the 'prophylactic' setting developed mucositis; the duration of oral mucositis from appearance until complete remission was significantly shorter in the 'prophylactic' than in the 'curative' setting; the mean grade of oral mucositis at baseline, on day 3 of therapy and on day 6 of therapy was significantly lower in the 'prophylactic' than in the 'curative' setting; 24 (55.82%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis at baseline compared to 25 (80.60%) patients in the 'curative' setting (p=0.048). Thirteen (30.23%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis on day 3 of therapy compared to 19 (61.29%) patients in the 'curative' setting (p=0.015); 'prophylactic' setting was able to shorten grade 3/4 oral mucositis to grade 0/1 more effectively than the 'curative' one on day 6 of therapy (p=0.05). The present clinical trial is to date by far the largest study assessing the effectiveness of topical GM-CSF and it is the first study comparing the efficacy of topical GM-CSF in the 'prophylactic' setting, i.e., with the aim to prevent the chemoradiotherapy-induced oral mucositis, with that in the 'curative' treatment, i.e., the therapy for established oral mucositis. The topical application of GM-CSF was demonstrated to be effective for oral mucositis induced by chemotherapy and chemoradiotherapy regimens. Moreover, the 'prophylactic' setting was demonstrated to be more effective than the 'curative' one.

We carried out an open, non-randomized phase II study including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response (complete response, CR, or partial response, PR) or stable disease (SD). The treatment consisted of administration of recombinant interleukin-2 (rIL-2) at a dose of 1.8 MIU subcutaneously three times/week (every other day) for the first 2 weeks of every month plus medroxyprogesterone acetate (MPA) 500 mg/day every other day plus antioxidant agents alpha-lipoic acid 300 mg/day and N-acetyl cysteine 1800 mg/day or carbocysteine lysine salt oral solution 2.7 g/day. The treatment was administered for 1 year except when progression of disease occurred. The primary study endpoints were to define clinical outcome, i.e. duration of response, survival (overall survival, OS and progression-free survival, PFS), the toxicity profile, and the evaluation of quality of life (QL). As secondary endpoints, we measured the changes of lymphocyte count, serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin, blood levels of reactive oxygen species (ROS) and antioxidant enzymes (glutathione peroxidase, GPx and superoxide dismertase, SOD). From July 1998 to June 2003, 42 patients were enrolled in the study (M/F ratio, 39/3; mean age, 62.5 years). Twenty (47.6%) patients were elderly (> 65 years). The majority of patients had either head and neck cancer or lung cancer, 88% had locally advanced or metastatic disease at diagnosis, and 76% had ECOG 0. Forty patients were previously treated with chemotherapy (27 also with radiotherapy), two with IL-2 and interfiron (IFN), one with endocrine therapy and one with only surgery. We obtained an objective response to maintenance treatment of 50%. Median duration of response was 19 months and median PFS was 33 months. Median duration of maintenance treatment was 12 months, median follow-up duration from diagnosis to June 2003 was 40 months, and median follow-up duration from study entry to June 2003 was 17 months. The median overall survival has not been reached. Toxicity was negligible. As for QL, a significant improvement of cognitive functions was observed, whereas all other functioning and symptom scales did not change significantly. As for laboratory parameters, absolute lymphocyte count increased significantly, IL-6, IL-1 beta, tumor necrosis factor-alpha, CRP, and fibrinogen decreased significantly whereas IL-2 and leptin increased significantly after treatment. ROS decreased significantly, whereas GPx increased significantly after treatment. Patients alive at study end showed a significant increase in absolute lymphocyte count, IL-2, leptin, and GPx and a significant decrease of proinflammatory cytokines, CRP, fibrinogen, and ROS, whereas patients who died before study end exhibited only a significant increase in absolute lymphocyte count, IL-2, and GPx and a significant decrease of ROS. Long-term combined maintenance therapy with rIL-2 + MPA + antioxidant agents is feasible, has a very low toxicity, and results in the improvement of clinical outcome, QL, and laboratory parameters.