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Advanced hepatocellular carcinoma (HCC) is the most frequent liver cancer. Immunotherapy has been explored in this disease in order to improve survival outcomes. Nowadays, scientific research is focusing especially on immune checkpoint inhibitors, in particular anti-PD1, anti-PD-L1 and anti-CTLA4 monoclonal antibodies (mAbs), as single-agent or in combination with other immunotherapy agents, target therapies, anti-vascular endothelial growth factor (VEGF) and other agents targeting specific molecular pathways. Other immunotherapy strategies have been assessed or are under investigation in advanced HCC, namely cytokines, adoptive cell therapy, oncolytic virus, cancer vaccines. Each treatment presents specific efficacy and toxicity profiles, strictly related to their mechanism of action and to advanced HCC tumour microenvironment (TME). The aim of this review is to outline the state-of-the-art of immunotherapy in advanced HCC treatment, highlighting data on already investigated treatment strategies, safety and toxicity (including HBV/HCV-related HCC), and ongoing clinical trials focusing on new promising therapeutic weapons.

Background and aim: The aim of our retrospective study is to evaluate the prognostic significance of aspirin in patients with advanced HCC treated with sorafenib. Methods: 304 patients with HCC,consecutively treated with sorafenib from May 2007 to September 2018, were included in the clinical study. Of Them 93 patients token aspirin. Progression-free survival (PFS)and overall survival (OS)were estimated with the Kaplan–Meier method and compared with the log-rank test. Results: The concomitant use of sorafenib and aspirin was associated with a median OS of 18.3 months compared to 8.8 months of patients who did not receive aspirin (HR 0.57; P < 0.0001). The concomitant use of sorafenib and aspirin was associated with a median PFS of 7.3 months compared to 3.0 months of patients who did not receive aspirin (HR 0.61; P = 0.0003). In the multivariate analysis, the use of aspirin maintained an independent prognostic value for OS(HR 0.61; P = 0.0013). In second line the concomitant use of regorafenib and aspirin was associated with a median OS of 16.9 months compared to 8.0 months of patients who did not receive aspirin (HR 0.30; P = 0.02). Conclusion: Globally, our data seem to suggest that aspirin use may improve the clinical outcome of patients with advanced hepatocellular carcinoma receiving sorafenib and regorafenib.

Introduction: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated and the role of antidiabetic medications such as metformin has also been investigated. The objective of this study was to examine the association between insulin use and overall survival (OS) in patients with advanced PDAC and DM2. Methods: We retrospectively collected data from 164 patients, including an exploratory cohort of 96 patients from Medical Oncology Unit, University Hospital and University of Cagliari, Italy, and a validation cohort of 68 patients from Medical Oncology of Modena University Hospital. Patients had metastatic disease and received a first-line gemcitabine-based chemotherapy and, subsequently, a second-line fluoropyrimidines-based chemotherapy. We performed univariate analysis to evaluate correlation between long-term diabetes and overall survival. Then we performed multivariate analysis, adjusting for sex, metastatic sites, Eastern Cooperative Oncology Group Performance Status, Ca19.9 levels, N/L ratio, and lactate dehydrogenase levels at diagnosis, to confirm the independence of the variable. Results: In the exploratory cohort, DM2 was significantly associated with higher median OS at univariate analysis (16 vs 10 months; p = 0.004). This result was confirmed by validation cohort (11 months vs 6 months; p = 0.01). In multivariate analysis, insulin-treated patients compared with non diabetic patients showed a significantly increased survival of 4.6 months ( p = 0.03). Conclusions: Patients with insulin-treated metastatic PDAC showed better OS than non diabetic patients, as demonstrated by both cohorts. The correlation between OS and insulin-treated DM2 should be investigated further through a prospective clinical trial.

BACKGROUND: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. METHODS: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. RESULTS: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-β, which require further research. CONCLUSION: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients. ispartof: CANCERS vol:12 issue:5 ispartof: location:Switzerland status: published

Cancer-related anemia (CRA) is a common sign occurring in more than 30% of cancer patients at diagnosis before the initiation of antineoplastic therapy. CRA has a relevant influence on survival, disease progression, treatment efficacy, and the patients’ quality of life. It is more often detected in patients with advanced stage disease, where it represents a specific symptom of the neoplastic disease, as a consequence of chronic inflammation. In fact, CRA is characterized by biological and hematologic features that resemble those described in anemia associated to chronic inflammatory disease. Proinflammatory cytokine, mainly IL-6, which are released by both tumor and immune cells, play a pivotal action in CRA etiopathogenesis: they promote alterations in erythroid progenitor proliferation, erythropoietin (EPO) production, survival of circulating erythrocytes, iron balance, redox status, and energy metabolism, all of which can lead to anemia. The discovery of hepcidin allowed a greater knowledge of the relationships between immune cells, iron metabolism, and anemia in chronic inflammatory diseases. Additionally, chronic inflammation influences a compromised nutritional status, which in turn might induce or contribute to CRA. In the present review we examine the multifactorial pathogenesis of CRA discussing the main and novel mechanisms by which immune, nutritional, and metabolic components affect its onset and severity. Moreover, we analyze the status of the art and the perspective for the treatment of CRA. Notably, despite the high incidence and clinical relevance of CRA, controlled clinical studies testing the most appropriate treatment for CRA are scarce, and its management in clinical practice remains challenging. The present review may be useful to indicate the development of an effective approach based on a detailed assessment of all factors potentially involved in the pathogenesis of CRA. This mechanism-based approach is essential for clinicians to plan a safe, targeted, and successful therapy, thereby promoting a relevant amelioration of patients’ quality of life.

Background Preclinical and clinical data support that p53 might modulate the EGFR activity and as a consequence it might influence response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. In our study we evaluated the role of p53 expression in RAS/BRAF wild type (WT) metastatic colorectal (mCRC) patients (pts) receiving irinotecan-cetuximab by using a validation cohort. Methods p53 immunohistochemical expression was retrospectively analysed in tumour samples of RAS/BRAF WT mCRC pts treated with second-third line irinotecan-cetuximab. Our aim was to evaluate the correlation between p53 expression and OS, PFS and RR. Statistical analysis was performed with the MedCalc package. Survival distribution was assessed by the Kaplan-Meyer method and comparison of survival curves was performed with log-rank test. Results Globally 120 RAS/BRAF WT mCRC pts were included in our analysis, 88 in the exploratory cohort and 32 in the validation cohort. 36/88 and 14/32 pts had p53 normal expression, whereas 52/88 and 18/32 showed p53 overexpression. In the exploratory cohort, RR was 61.1% in pts with p53 normal expression versus (vs) 3.8% in pts overexpressing p53 (p Conclusions In our study p53 normal expression was associated with better outcome in RAS/BRAF WT mCRC pts receiving irinotecan-cetuximab, as confirmed by the validation cohort. Further prospective studies are needed to validate the role of p53 in these pts and to investigate its cross-talk with EGFR. Legal entity responsible for the study Mario Scartozzi. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

e15663 Background: For over ten years the most stimulating results in systemic therapy for advanced HCC derived from the use of sorafenib (S). But in the last two years several drugs, in particular other multikinase inhibitors like lenvatinib (L), regorafenib (R), cabozantinib (C), proved to be effective both as an alternative or a sequential therapy to sorafenib. In this widened and rapidly increased scenario, without any head-to-head trial, clinicians struggle to define the best drug and the best treatment sequence. Aim of the first part of this project is to evaluate the activity of different treatment sequences in HCC cell lines to pave the way to a future clinical trial investigating their efficacy. Methods: Compounds of S, R, L and C were dissolved in DMSO and aliquoted. HepG2 cell line, obtained from ECACC (Salisbury, UK), was seeded at the density of 3 x 104 cells/ml. After 24 h of incubation, compounds or vehicle (DMSO) were added. Treatments were performed in single administration and six replicates were carried out for each dose. At 48h post-treatment, cells were fixed and stained with acid solution. The absorbance was measured at 520 nm using an ELISA reader (BioTek Instruments, USA). The assay was also performed with the sequences of: S-R, S-C, L-R, L-C (first line treatments for 48h followed by the second compound for 48h). Higher doses than the minimum inhibiting one were tested. Results: S showed superior activity than L as first line compound. In the sequence assay S-C and S-R seems to have the best results in terms of cell viability. After L the best compound appears to be R. See table. Conclusions: Our results showed relevant variations in cell viability with different drug sequences. Already planned analyses in the RISE-HEP project in vivo and in humans are mandatory to confirm which sequence would have the highest efficacy.[Table: see text]

The encouraging results in immunotherapy for melanoma also led the way for translational and clinical research about immune-related mechanisms possibly relevant for gastrointestinal tumours. It is in fact now evident that the immune checkpoint modulation and in particular cell-mediated immune-response through programmed cell death-1 (PD-1) and the cytotoxic T-lymphocyte antigen-4 (CTLA4) receptors along with the regulatory T cells activity all have a relevant role in gastrointestinal cancers as well. This review aims to explore the state of the art of immunotherapy for gastrointestinal tumours, deepening recent scientific evidence regarding anti PD-1/PDL-1 and anti CTLA4 monoclonal antibodies, peptide based vaccine, DNA based vaccine, and pulsed dendritic cells, either alone or in combination with other antineoplastic medical therapy and locoregional treatments. Considering the non-negligible toxicity profile deriving from such a treatment approach, predictive biomarkers of response to immunotherapy in gastrointestinal cancer are also urgently needed in order to better select the patients’ group with the highest likelihood of benefit.

Obesity is considered the most important risk and prognostic factor for estrogen-dependent breast cancer in postmenopausal women. Adipokines, in particular leptin, are at the center of the etiopathogenetic mechanisms by which obesity and related metabolic disorders influence breast cancer risk and its prognosis. The present prospective observational study aims to investigate the relationship between body mass index (BMI), serum levels of leptin and proinflammatory cytokines, and breast cancer prognostic factors. In the study, 98 postmenopausal and 82 premenopausal patients with ER-positive breast cancer participated. During the same study period, 221 control subjects were simultaneously recruited. Women underwent baseline measurements pre-operatively, before any surgical and systemic treatments. Pathologic characteristics of tumors were abstracted from pathology reports. Leptin and proinflammatory cytokines were assayed in stored fasting blood specimens. In postmenopausal breast cancer patients, BMI, leptin, and interleukin-6 significantly correlated with pathological tumor classification (pT) and TNM stage. Multivariate regression analysis showed that BMI and leptin, but not interleukin-6, were independent predictive variables of pT and TNM stage. Our results seem to suggest a twofold role of leptin in the etiopathogenesis of postmenopausal estrogen-positive breast cancer. Indeed, leptin reflects the total amount of fat mass, which correlates to aromatase activity and subsequent estrogens levels. Further studies are warranted to clarify the role of leptin and interleukin-6 in breast carcinogenesis and identify new therapeutic options, beyond the use of aromatase inhibitors, acting selectively on adipokine-driven pathways.

TPS215 Background: It's known that composition of intestinal flora can influence the development of inflammatory gastrointestinal diseases, even though the association of inflammation with specific intestinal microbes is still unknown, because the inflammation and its treatment can change the composition of microbiote. Some bacterial species are essential to maintain the mucosal physiological tolerance, although species such as Bacteroides, Clostridium and Faecalibacterium can induce the up-regulation of T-cells and stimulate the production of anti-inflammatory cytokines. Innovative therapies such as anti-CTLA-4 antibody and inhibitors of the PD-1 receptor are particularly involved in the up-regulation of lymphocyte system: among their side effects, the most relevant are those immune-mediated such as hypophysitis, thyroiditis and colitis. In particular this last one usually occurs within 16weeks from the start of treatment: about one third of patients develop intestinal inflammation of any grade as a result of immune system dysregulation. So, the high incidence of colitis in patients treated with immunotherapy offers the possibility to characterize the intestinal microbiote before the development of immune-mediated inflammation. In addition, our curiosity has been oriented to the response to immunotherapy and the HLA class expressed by our patients: which any better predictor of response to immunological treatment than this one? Methods: Our is a single-center study of clinical and biological parameters prospectively stratified. Specifically, we collect from patients eligible for immunotherapy a blood sample to analyze HLA class and an other one to analyze serum cytokines levels, inflammatory indices and a sample of fecal material at baseline and at least after 3 administrations of treatment: actually we enrolled 34 out of 40 planned patients; we suppose to complete the enrollment in 2 months. According to preliminary data published in literature, we expect to find an alteration of intestinal microbiote in metastatic patients treated with immunotherapy. Once we'll identify it, we want to assess whether there is any correlation with the patient's clinical outcome.

Cancer-related anorexia/cachexia syndrome (CACS) is a multifactorial syndrome characterised by tissue wasting, particularly lean body mass (LBM), metabolic alterations, fatigue, anorexia and reduced food intake. In April 2005 we started a phase III randomised study to establish the most effective and safest treatment for CACS addressing as primary endpoints: LBM, resting energy expenditure (REE), total daily physical activity, interleukin (IL)-6 and tumour necrosis factor (TNF)-α levels, and fatigue. According to the statistical design the sample size was 475 patients (95 per arm). Eligibility criteria: histologically confirmed tumours of any site; weight loss −5% in the last 3 months and/or abnormal laboratory values; life expectancy >4 months. Patients were treated with either antineoplastic therapy or supportive care. All patients received as basic oral treatment polyphenols plus alpha lipoic acid plus carbocysteine plus vitamins A, C and E. Patients were then randomised to one of the following 5 arms: (1) medroxyprogesterone acetate (MPA)/megestrol acetate (MA); (2) pharmaconutritional support containing eicosapentaenoic acid (EPA); (3) l-carnitine; (4) thalidomide; and (5) a combination of all the above agents. Treatment duration was 4 months. Interim analyses were planned after every 100 randomised patients. In September 2008, 280 patients were randomised and 240 were evaluable: M/F 167/113, mean age 62 years (range 30-84), 96% stage IV. A first interim analysis on 125 patients showed a worsening of LBM, REE and fatigue in arm 2 in comparison to the others and therefore it was withdrawn from the study. A second interim analysis after the enrolment of 204 patients showed that arm 1 was clearly significantly less effective than the others for primary efficacy endpoints, therefore it was withdrawn from the study. Statistical analysis in September 2008 showed a significant improvement of LBM (by dual X-ray energy absorptiometry), REE and fatigue in arm 5, a decrease of IL-6 in arms 3 and 5, and a decrease of TNF-α in arms 3 and 4. As for toxicity, 1 patient discontinued MPA because of deep vein thrombosis and 1 patient discontinued L-carnitine because of severe diarrhoea. In conclusion, the interim results seem to suggest that the most effective treatment for cancer patients with CACS/oxidative stress (OS) should be the combination regimen. The study is in progress.

The progression of the neoplastic disease is characterized by specific alterations of energy metabolism and by symptoms like fatigue, anorexia, nausea, anaemia, immunodepression and poor performance status (PS). The main cause of these symptoms and metabolic abnormalities is the chronic action of proinflammatory cytokines released both by tumour and immune cells. The present study aimed to assess the relationship between markers of inflammation (C-Reactive Protein, Fibrinogen, proinflammatory cytokines) and energy metabolic status (BMI, leptin, oxidative stress) according to clinical parameters in 104 ovarian cancer patients at different stage and, moreover, to evaluate prospectively the changes of these parameters in accordance to tumour response in a subgroup of 70 advanced stage ovarian cancer patients. Advanced stage and poor PS were associated to high-grade inflammation and impaired energy metabolism. Among inflammatory mediators, interleukin (IL)-6 had a central role as predictive factor of leptin, reactive oxygen species and glutathione peroxidase. In turn, leptin considered the key marker of the nutritional status and energy metabolism, was independently determined from stage and IL-6, not only from BMI. Moreover, the evaluation of the changes of these parameters during the course of the neoplastic disease in the subgroup of advanced ovarian cancer patients clearly unveils the central role of IL-6 and leptin as early markers of the metabolic alterations and symptoms associated to disease progression in advanced stage ovarian cancer. Their assessment should be included in monitoring disease outcome, especially when cancer is no longer curable and quality of life becomes the primary endpoint.

The present review aimed at discussing the impact, pathogenesis and therapeutic approaches of muscle wasting, which is a major clinical feature of cancer-related cachexia syndrome. The pathogenesis of muscle wasting in cancer cachexia lies in a discrepancy between anabolic and catabolic pathways mediated by chronic inflammation. Effective interventions specifically aimed at hampering muscle loss and enhancing muscle function are still lacking. Promising agents include anti-inflammatory, orexigenic and anabolic drugs, alongside with nutritional supplements that influence the STAT3 and PI3K/Akt/mTOR pathways involved in muscle wasting. Personalized physical activity combined with pharmacological and nutritional support hold promise. A greater understanding of the pathogenetic processes of cancer cachexia-related muscle wasting will enable the development of an early and effective targeted mechanism-based multimodal approach.

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.

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.

e17540 Background: The Neutrophil-to-Lymphocytes ratio (NLR) represents a potential prognostic and predictive marker in a different tumor types. The purpose of our study was to investigate the prognostic value of the pretreatment inflammatory marker NLR in patients with head and neck squamous cell carcinoma (HNSCC). Methods: Pretreatment NLR were retrospectively investigated for correlation with overall survival (OS). Kaplan-Meier statistic and long rang test were used. Univariate analysis for categorical and descriptive variables were performed. Results: Thirty-nine patients, from local to advanced stage disease, were included in our analysis. At a median follow up of 9.44 months (2.04 – 30.3), of the total patients 30.7% died and 41.9% had progression of disease. The median PFS was 4.6 months (2.9 – 27.2) and the median OS (mOS) was 18.9 months. Following ROC curve analysis the optimum cut-off value of NLR was 3.93 (p = 0.017). Patient with NLR > 3.92 had a mOS of 11.9 months, whereas the mOS for NLR ≤ 3.92 was 30.3 months (Log-rank p = 0.189). The 1 year Kaplan-Meier estimates of OS for NLR ≤ 3.92 vs. >3.92 was 72% vs. 45% respectively (Log-rank p = 0.243). According to COX univariate analysis, the risk of death increases of 7.7% each unitary rise of NLR mean value (p = 0.3407). Conclusions: In our limited case series NLR was not significantly associated with clinical outcome. Therefore, multicenter studied are needed to determine an optimal NLR cutoff value. [Table: see text]

The aim of this study was to assess the impact of three different psychological interventions on the quality of life (QL) of elderly cancer patients with symptoms of anxiety and/or depression. Seventy-four patients were enrolled in the study. All were aged over 65 and had solid tumours or haematological malignancies, generally in advanced stages (III-IV). The cancer treatment was administered for a mean duration of 5 months and the mean number of chemotherapy cycles was 4. After stratification for the main prognostic factors, patients were randomly assigned to one of three groups: Group A, psychopharmacological treatment; Group B, treatment A plus social support carried out by volunteers and Group C, treatment as Group B plus structured psychotherapy. The planned duration of intervention was the same as that of the medical treatment. Patients who did not complete the planned chemotherapy nevertheless received all the planned psychological intervention. The evaluation of patients' QL was assessed using either uni- or multi-dimensional instruments to explore functional status and physical symptoms as well as psychological status at subsequent times during treatment (i.e., pre-treatment, mid-treatment and at the end of treatment). The present study shows that the combination of psychopharmacological treatment with either social support for patients and their relatives carried out by volunteers (SSV), or SSV plus structured psychotherapy (SSV + SP), yielded the best results in terms of QL in the long-term treatment of elderly patients with advanced cancer. According to the analysis these two ‘integrated’ approaches proved to be almost equally effective.

Our study belongs to the clinical trials in which the health-related quality of life (HQL) evaluation constitutes the primary endpoint. It was carried out with the aim of comparing the impact of three different types of psychological intervention, namely a psychopharmacological treatment alone, the same treatment plus social support carried out by volunteers (SSV) and a third treatment modality including “structured psychotherapy” (autogenous training), on improving the HQL of elderly cancer patients undergoing antineoplastic therapy with symptoms of anxiety and/or depression related to their disease. The eight questionnaires used for HQL evaluation were generally. self-rated and multidimensional but unidimensional models were also employed. Seventy-four patients aged over 65 years with either solid tumors in different sites or hematological malignancies, generally in advanced stages (III–IV), were enrolled in the study. Of these patients, 72 (42 men and 30 women, mean age 70.68 years, range 66–85) were evaluable. Our study high-lighted the usefulness of the pharmacological therapy (alprazolam + sulpiride) and of other specific ancillary treatments in reducing the incidence of the main HQL-related side-effects of antineoplastic therapy and the superiority of an “integrated” strategy, based both on psychopharmacology and psychosocial interventions, such as SSV with or without structured psychotherapy. The one-way analysis of variance carried out by us did not allow us to draw definitive conclusions about which of the two integrated treatments was to be considered the treatment of choice, as they proved to be almost equally effective.

e21009Background: Ipilimumab is an inhibitor of CTLA4 receptor of T lymphocytes that has been approved by FDA both as first and second line treatment for patients with metastatic melanoma. Despite ...

e15004Background: Regorafenib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with metastatic colorectal cancer failing fluoropyrimidine-based chemotherapy in comb...

We report the case of a 52-year-old woman with primary CD30+ anaplastic large-cell lymphoma of T cell phenotype with skin involvement, stage IVB, fulfilling almost all the clinical, histopathologic and immunophenotypic criteria for this disease, associated with adult-onset celiac disease. The diagnoses of malignancy and celiac disease were made during the same clinical episode. The clinical course of the patient has been extremely favorable and she is in complete remission, 15 months after finishing consolidation therapy.

Summary Background & aims A phase III, randomized non-inferiority study was carried out to compare a two-drug combination (including nutraceuticals, i.e. antioxidants) with carnitine + celecoxib ± megestrol acetate for the treatment of cancer-related anorexia/cachexia syndrome (CACS): the primary endpoints were increase of lean body mass (LBM) and improvement of total daily physical activity. Secondary endpoint was: increase of physical performance tested by grip strength and 6-min walk test. Methods Sixty eligible patients were randomly assigned to: arm 1, l-carnitine 4 g/day + Celecoxib 300 mg/day or arm 2, l-carnitine 4 g/day + celecoxib 300 mg/day + megestrol acetate 320 mg/day, all orally. All patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, carbocysteine 2.7 g/day, Vitamin E, A, C. Treatment duration was 4 months. Planned sample size was 60 patients. Results The results did not show a significant difference between treatment arms in both primary and secondary endpoints. Analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) increased significantly in both arms as well as physical performance assessed by 6MWT. Toxicity was quite negligible and comparable between arms. Conclusions The results of the present study showed a non-inferiority of arm 1 (two-drug combination) vs arm 2 (two-drug combination + megestrol acetate). Therefore, this simple, feasible, effective, safe, low cost with favorable cost-benefit profile, two-drug approach could be suggested in the clinical practice to implement CACS treatment.

The aim of the investigation was to study directly the IL-2 receptor (IL-2 R) and its subunits, p55 and p75 chains, either membrane-bound or soluble, on PBMC of patients with solid malignancies and, indirectly, the same patients’ PBMC ability to produce IL-2. Fifty-eight cancer patients, 29 men and 29 women, were studied: their mean age was 57.3 yr, range 35–79. Twenty-two healthy age-sex-matched subjects served as controls. The tumors were the most common and the most representative among human cancers, i.e., breast, lung, head and neck, digestive tract and liver, prostate and gynecologic cancers: they were generally in advanced stages and in 23 cases metastatic. The PBMC proliferative response to PHA, PHA plus IL-2, and IL-2 was evaluated along with the response to PHA in the presence of anti-p55, anti-p75 monoclonal antibodies, or both. Moreover, membrane-bound IL-2 R (p55 and p75 chains) on PHA-stimulated PBMC was detected, along with soluble IL-2 R in the serum and in the culture supernatants. The conclusions suggest that in solid malignancies: the membrane-bound IL-2 Rs, both p55 and p75 chains, are expressed normally, there is an high serum level of soluble IL-2 R, there is a normal release of soluble IL-2 R in culture, and there is an indirect evidence of a lack of IL-2 production. Therefore, no primary impairment of IL-2 R was found in solid tumors. Moreover, in our study we have found no difference in any parameter studied between patients with and patients without metastases.

Aim of the present phase II non-randomized study was to verify whether palonosetron might be able to prevent acute and especially delayed CINV for either HEC or MEC, starting from the second chemotherapy cycle, in patients who had failed to respond to a different antiemetic 5-HT(3) antagonist during the first cycle. Stratification factor was age65 years vs.or =65 years of patients included. Forty-seven cancer patients (23 elderly and 24 non-elderly) scheduled to receive HEC or MEC regimens who had experienced CINV grade 3-4 during the first chemotherapy course and for whom the same course of chemotherapy regimen was further scheduled were enrolled. Complete response (CR) and complete control (CC) rates for the acute, delayed and overall phases of CINV were not significantly different between elderly and non-elderly patients. Palonosetron was safe: only grade 1-2 toxicities were observed with a peak of 12.9% for asthenia with no significant difference between elderly and non-elderly patients. In conclusion, single dose palonosetron (250 microg) should be considered a safe and effective second generation 5-HT(3) antagonist in the prevention of nausea and vomiting induced by HEC or MEC, irrespective of patients' age.

Objectives To establish a correlation between a specific MGA category, an appropriate preventively established treatment and clinical outcome in a population of elderly cancer patients. The ultimate goal was to verify whether the appropriate treatment given to elderly cancer patients according to their MGA category could translate into a better clinical outcome assessed as clinical response and toxicity, i.e whether this process might achieve a clinically meaningful impact. Patients and methods We carried out a phase II open, prospective non-randomized study in 75 elderly cancer patients (lung, head and neck, colorectal, gynecologic and breast) hospitalized at the Department of Medical Oncology, University of Cagliari, Italy. All patients underwent MGA evaluation and were assigned to three different categories: fit, intermediate and frail. Thereafter, an appropriate preventively established treatment was administered and the clinical outcome was assessed. The clinical outcome after 3 month treatment was defined on the basis of objective clinical response and toxicity. The difference of clinical outcome in the MGA categories was assessed by ANOVA test. Moreover, the correlation between MGA category and the clinical outcome (clinical response and toxicity) was assessed by Spearman's correlation test. Results A better clinical response was observed in fit patients as compared both to intermediate and frail patients. Treatment toxicity was comparable in the different MGA categories. The correlation analysis between MGA category, clinical response to treatment and toxicity showed that there was a significant direct correlation with clinical response and no correlation with toxicity. Overall, the regression analysis showed that MGA was predictive of clinical outcome, in the sense that it is truly predictive for clinical response and no predictive for toxicity. Conclusion Our study demonstrates that the MGA, although time-consuming, is a useful and cost-benefit effective tool to appropriately select elderly cancer patients to be treated effectively in terms of a survival advantage and those who would benefit mainly in terms of improvement of quality of life. Moreover, the treatment preventively established for each MGA category was shown to be adequate and accomplished the most appropriate performances in terms of effectiveness and toxicity.

e13501 Background: OPN, a potential diagnostic biomarker and therapeutic target, is a multifunctional protein involved in the carcinogenesis, neoangiogenesis and metastasization in many solid neopl...

Laser ablation (LA) is currently used in our institute as palliative treatment for endobronchial nonresectable or recurrent lung cancer. The objective of this study was to assess the impact of LA on the quality of life (QOL) in a large group of patients with endobronchial obstructions due to nonresectable or re-current lung cancer. Evaluation was based on Eastern Cooperative Oncology Group performance status (ECOG PS) for the "objective" assessment of QOL and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 version 1.0 (EORTC QLQ-C30(v1)) for the "subjective" assessment of QOL. From May 1994 to June 1997, 133 LAs were performed using neodymium: yttrium-aluminum garnet (Nd:YAG) laser at low power settings (30W) on 89 evaluable patients (Male/Female 78/11, mean age 63.5/62.8 years, range 42-82/47-73). The QOL was evaluated by ECOG PS and QLQ-C30(v1) at baseline (3 days before LA), t1 (7 days after LA), and t2 (1 month after LA). The objective tumor response was evaluated at t2. The objective tumor response to LA intervention was "excellent," ie, complete response (CR), in 33 (24.8%) patients and "fair," ie, partial response (PR), in 97 (72.9%) patients, with an overall response rate (ORR) of 97.7%. A highly significant decrease in high score (ECOG PS 3-4) was registered from baseline to t1 and from t1 to t2. However, at the same time a significant increase of low score (ECOG PS 0-2) was observed. The comparison of patient QOL assessment by QLQ-C30(v1) at different times during the study was also made; the functioning scales, the global QOL scale, and the symptom scales/items showed a highly significant improvement at t1 compared to baseline (P0.001), whereas only global QOL improved at t2 compared to t1. A comparison of baseline ECOG PS scale with QLQ-C30(v1) scale revealed a strong relationship between PS and the symptom "fatigue." Our study demonstrates that dramatic clinical improvement obtained by an effective though palliative treatment such as LA improves QOL based on both physician-rated (PS) and mostly self-rated (QLQ-C30(v1)) assessment.

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 (PRor =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.

An open, non-randomized phase II study was carried out including patients with advanced solid tumors who achieved an objective response or disease stabilization as a result of previous chemotherapy, to receive a maintenance treatment with recombinant interleukin-2 (rIL-2) plus medroxyprogesterone acetate (MPA) plus antioxidant agents alpha-lipoic acid (ALA) and N-acetyl cysteine (NAC). The first study endpoints were to define clinical outcome and toxicity as well as the evaluation of quality of life. As secondary endpoints we measured the changes of lymphocyte absolute count, the serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin after treatment. rIL-2 was administered at a dose of 1.8 MIU subcutaneously 3 times/week on alternate days for the first two weeks of every month and MPA was given orally at a dose of 500 mg/day at alternate days without interruption. ALA 300 mg/day orally and NAC 1800 mg/day orally were also administered continuously. Twenty-eight patients were enrolled in the study. The median duration of maintenance treatment was 10 months (6-30+). The response to maintenance treatment at September 15, 2001 was: CR 11 patients (39.3%); SD 2 patients (7.1%); PD 15 patients (53.6%). The median duration of response was 11 months (6-34+). The median follow-up duration was 11 months (6-34+). The median OS was not reached. The median PFS was 21.5 months (1-40+). The 1-year survival rate was 72.2%. At September 15, 2001, 16 patients were still surviving. No grade 3/4 toxicity and one grade 2 skin toxicity were observed. We found a significant increase of the absolute lymphocyte count and serum levels of IL-2 and a significant decrease of TNF alpha after treatment. The evaluation of patient subgroups showed the following: the patients alive at the end of study had a significant increase of lymphocyte count, IL-2 and leptin, and a significant decrease of IL-1 beta, IL-6 and TNF alpha, whereas the patients who had died had only a significant increase of lymphocyte count and IL-2. Among the patients alive, those in objective clinical response (CR + PR) + those in SD had a significant increase of lymphocyte count, IL-2 and leptin and a significant decrease of IL-1 beta, IL-6 and TNFalpha, whereas those with PD had no significant changes in any of the above values. We conclude that the combination of s.c. rIL-2 with oral MPA and anti-oxidant agents ALA and NAC in an intermittent schedule, repeated for a long-term period, is feasible, has a very low toxicity and results in the improvement of biological markers which are predictive for patient outcome.