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Background: KRAS wild-type mutational status is necessary but not sufficient to get benefit from epidermal growth factor receptor inhibition. Predictive markers are currently being evaluated. In this study, we investigated early hypomagnesemia as a predictor of efficacy and outcome in terms of time to progression (TtP) and overall survival (OS) in a cohort of patients affected by advanced colorectal adenocarcinoma KRAS wild-type cetuximab-treated. Patients and methods: One hundred and forty-three patients affected by stage IV colorectal adenocarcinoma KRAS wild type receiving cetuximab + irinotecan (CTX+IRI) as third-line anticancer treatment and resistant to oxaliplatin- and irinotecan-based chemotherapy were retrospectively included. Magnesium plasma levels were measured before the first day and 7, 14, 21 and 28 days after CTX+IRI infusion. Results: The median magnesium basal value showed a statistically significant decrease after the start of CTX+IRI treatment (at 28 days, P 50% compared with the basal level had a higher tumor response rate (55.8% versus 16.7%, P < 0.0001), a longer TtP (6.3 versus 3.6, P < 0.0001) and a longer median OS (11.0 versus 8.1, P = 0.002). Conclusions: We have shown that early hypomagnesemia could be a predictor of efficacy and outcome in those patients. Magnesium circulating level is an easy and inexpensive biomarker to routinely be detected in patients treated with cetuximab.

Objective: We designed this trial to investigate if modifications in levels of circulating vascular endothelial growth factor (VEGF) may be related to clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. Methods: A total of 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab plus weekly irinotecan. VEGF circulating levels were assessed at the following time points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. Results: Basal VEGF median levels were significantly decreased just 1 day after the first anticancer infusion (p = 0.016) and reached the highest statistical significance 92 days after the first infusion (p

The proven antiangiogenic activity of zoledronic acid, a third-generation bisphosphonate widely used in bone metastatic cancer patients, led us to investigate if the vascular endothelial growth factor (VEGF)-related zoledronic acid modifications are correlated with survival advantages in advanced breast cancer patients. Forty-two consecutive breast cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg zoledronic acid before anticancer chemotherapy. The patients were prospectively evaluated for circulating levels of VEGF and interferon-gamma (IFN-gamma) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. Afterward, clinical outcome was prospectively monitored. The basal serum VEGF median levels were significantly decreased at each time point, but the major reduction was recorded 21 days after the infusion. In particular, 25 patients of 42 (59.5%) experienced a reduction of at least 25% in the VEGF circulating levels. In contrast, no statistically significant modifications of the IFN-gamma serum levels were recorded. We stratified patients on the basis of this VEGF reduction 21 days after the infusion. No differences in patient features were recorded between those with or without the VEGF reduction. The analysis of survival showed that patients with a reduction in the VEGF circulating levels had a longer time to first skeletal-related event (p = 0.0002), time to bone progression disease (p = 0.0024), and time to performance status worsening (p = 0.0352) than those without the VEGF reduction. No statistically significant differences were recorded in terms of overall survival and time to visceral progression. This study confirms that zoledronic acid could have an in vivo antiangiogenic property and that the VEGF modifications may represent a surrogate marker able to predict time to first skeletal-related event, time to bone progression disease, and time to worsening of performance status.

Objectives: The aim of the study was to define the feasibility and efficacy of Xelox (capecitabine and oxaliplatin) administered through a new and original schedule in advanced pretreated colorectal cancer (CRC) patients. Methods: 36 metastatic CRC patients resistant at least to a previous 5-fluorouracil- and irinotecan-based chemotherapy line were included in the study. Treatment: Oxaliplatin 70 mg/m2 as continuous infusion for 12 h (8.00 a.m. to 8.00 p.m.) on days 1, 8 plus chronomodulated capecitabine 1,750 mg/m2/day per os (8.00 a.m. 25% of total dose; 6.00 p.m. 25% of total dose; 11.00 p.m. 50% of total dose), on days 1–14 every 21 days. 16 (44.4%) patients had previously received only 1 chemotherapy line for metastatic disease and 20 patients (55.6%) 2 chemotherapy lines. Moreover, 12 patients (33.3%) progressed after a first or second line of oxaliplatin-based regimen as well. Results: Most frequent related G3–4 adverse reactions were diarrhea (11.6%), nausea/vomiting (8.3%), neuropathy (8.3%), mucositis (8.3%), asthenia (16.7%) and hand-foot syndrome (5.5%). G3–4 anemia, leucopenia and liver toxicities were not observed. The overall response rate was 30.6% (11/36 patients). Disease stabilization was observed in 13 patients (36.1%) and progression in 12 patients (34.3%). Between the 12 oxaliplatin-resistant patients, the overall response rate was 25% (3 patients); 6 patients (54.5%) obtained a stable disease, and only 3 patients (25%) progressed. The median overall survival was 11.3 months (95% confidence interval 7.0–15.7 months), the median response duration 2.8 months (95% confidence interval 1.2–5.6 months) and the median time to progression 6.7 months (95% confidence interval 5.7–6.3 months). The 1-year survival rate was 53.8%. Conclusions: The high overall tumor growth control, the remarkable median time to progression and overall survival and the good safety profile are of particular interest for patients with heavy pretreated metastatic CRC.

Amino-bisphosphonates are potent activators of human gammadelta T cells. The aim of our study was to evaluate the immunomodulating properties of a single-dose of zoledronic acid (ZA) on gammadelta T cells in a select group of disease-free breast cancer patients with osteopenia.Blood samples were obtained, from 23 patients, before and 7, 28, 56, 90 and 180 days after a single-dose (4 mg) of ZA and analyzed by flow cyometry.A significant decrease of the different gammadelta T cell subsets was observed: Naïve (CD3+/Vdelta2+/CD45RA+/CD27+) after 180 days (P0.01); Central Memory (CD3+/Vdelta2+/CD45RA-CD27+) after 28 (P0.05), 90 (P0.01) and 180 days (P0.01); and Effector Memory (CD3+/Vdelta2+/CD45RA-/CD27-) after 56 (P0.01) and 90 (P0.05) days. Based on the observed gammadelta T cells kinetics patients could be divided in two groups: "responders" that showed a significant decrease in total numbers of gammadelta T cells and "non-responders" that showed no significant change. However, in vitro phosphoantigen stimulation of patients cells did not show significant differences in terms of IFN-gamma response by Vdelta2 T cells.We describe for the first time a long-lasting activation of effector subsets of gammadelta T cells in disease-free breast cancer patients after a single-dose of ZA. Our results highlight the need to further investigate the clinical significance of the immunomodulating properties of N-BPs.

Introduction: Magnesium plays a role in a large number of cellular metabolic reactions. Cetuximab is able to induce hypomagnesemia by interfering with magnesium (Mg2+) transport in the kidney. We designed this trial to investigate if Mg2+ serum level modifications may be related with clinical response and outcome in advanced colorectal cancer patients during treatment with cetuximab plus irinotecan. Experimental Design: Sixty-eight heavily pretreated metastatic colorectal cancer patients were evaluated for Mg2+ serum levels at the following time points: before; 6 hours; and 1, 7, 14, 21, 50, and 92 days after the start of treatment. Results: Basal Mg2+ median levels were significantly decreased just 7 days after the first anticancer infusion and progressively decreased from the 7th day onward, reaching the highest significance at the last time point (P < 0.0001). Twenty-five patients showed a reduction in median Mg2+ circulating levels of at least 20% within the 3rd week after the first infusion. Patients with this reduction showed a response rate of 64.0% versus 25.6% in the nonreduced Mg2+ group. The median time to progression was 6.0 versus 3.6 months in the reduced Mg2+ group and in that without reduction, respectively (P < 0.0001). Overall survival was longer in patients with Mg2+ reduction than in those without (10.7 versus 8.9 months). Conclusions: Our results confirm that cetuximab treatment may induce a reduction of Mg2+ circulating levels and offer the first evidence that Mg2+ reduction may represent a new predictive factor of efficacy in advanced colorectal cancer patients treated with cetuximab plus irinotecan.

Purpose: On the basis of stimulating data on animals reporting that weekly regimens of zoledronic acid (ZA) were effective in reducing skeletal tumor burden, we designed a study on humans to investigate the potential antiangiogenic role of a weekly low-dose therapy with ZA in patients with malignancies. Experimental Design: Twenty-six consecutive patients with advanced solid cancer and bone metastases received 1 mg of ZA every week for four times (days 1, 7, 14, and 21) followed by 4 mg of ZA with a standard 28-day schedule repeated thrice (days 28, 56, and 84). Patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) just before the beginning of drug infusion (0) and again at 7, 14, 21, 28, 56, and 84 days after the first ZA infusion. Results: The median VEGF basal value showed an early statistically significant (P = 0.038) decrease 7 days after the first 1-mg infusion of ZA. This effect on VEGF-circulating levels persisted also after the following 1-mg infusions at 14 (P = 0.002), 21 (P = 0.001), and 28 days (P = 0.008). Interestingly, the decrease of VEGF-circulating levels persisted also at each programmed time point during the second phase of the study (ZA 4 mg every 4 weeks). No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after each ZA infusion. Conclusions: In the present study, we report that a repeated low-dose therapy with ZA is able to induce an early significant and long-lasting decrease of VEGF levels in cancer patients.

Summary Cancer patient education can be especially important in topics like side effects of chemotherapy. Information needs of oncology patients are scarcely investigated in Italy. This study aimed to identify the learning needs, the amount of information desired and the preferred methods of information delivery of Italian cancer patients receiving chemotherapy. A total of 111 cancer patients completed a questionnaire developed for this study, which was assessed for validity and reliability. Respondents ranked the following priority information: illness, recovery, treatments, chemotherapy side effects and trajectory of illness. The great majority wanted to receive as much information as possible about all these topics. Most patients showed their wish to be informed along with their relatives, but only a few wanted relatives to be informed before them. The preferred method for receiving information about side effects of chemotherapy was oral conversation, followed by written information. Patients preferred receiving information from the oncologist, followed by the oncology nurse and the general practitioner. Most respondents preferred to be informed before receiving the first cycle of chemotherapy. Results are consistent with the existing literature with regard to information priorities, quantity of information desired and preferred methods of information. In contrast with a non-disclosure dominant culture, Italian cancer patients manifest their wish to be informed a great deal and personally about their condition. In order to meet cancer patients’ information needs, health professionals’ education and practice should be improved.

Background: Capecitabine and gemcitabine given as fixed dose rate (FDR) has not been demonstrated to be well tolerated in phase I previous studies. The goals of this phase I study were to determine the maximum-tolerated dose of this combination and to describe the dose-limiting toxic effects (DLT) and the safety profile of this way of administration. Patients and methods: Patients with advanced solid tumors were eligible for this study. Capecitabine was administered orally at a dose of 650 mg/m2 bis in die (b.i.d.) for 14 consecutive days. Gemcitabine was administered at FDR of 10 mg/m2 per min in escalating durations of infusion on days 1 and 8. The cycles were repeated every 21 days. Results: All 20 patients enrolled into the study were assessable for toxicity. Only one out of the first six patients treated at FDR gemcitabine dose of 800 mg/m2 met protocol-specified DLT criteria (grade 4 neutropenia lasting ≥7 days) during the first two cycles. At these doses the majority of cycles of therapy were, however, delivered without dose reduction or delay. Another similar episode of DLT was observed at the same dose step among the following eight included patients. The dose of FDR gemcitabine 800 mg/m2 in 80 min on days 1 and 8 plus capecitabine 650 mg/m2 b.i.d., for 14 consecutive days followed by 1 week of rest is recommended for further study. Conclusion: The combination of FDR gemcitabine plus capecitabine can be administered with acceptable toxicity. The evidence of antitumor activity deserves further investigation in phase II combination chemotherapy studies.

Interest in cancer-related fatigue has been growing over the last two decades and efforts have been dedicated to investigate this topic. However, research addressing the adequacy of educational resources for patients with this distressing and common symptom is lacking. Only one study has been undertaken and this explored Swiss and British patients’ views. The current study replicated and extended the study previously undertaken in the United Kingdom (UK) and Switzerland. It sought views on the adequacy of materials on cancer-related fatigue available to patients with cancer living in Italy, and to determine the educational preferences and needs of Italian patients with cancer-related fatigue. These were attained through conduct of two focus groups. One was undertaken with Italian patients and the other with a group of Italian nurses. Findings from this study supported patients’ desire for timely, accurate and individualised information. Barriers to effective fatigue education included the limited dialogue regarding fatigue initiated in clinical settings. It appeared that nurses and patients held different priorities in symptom management. Further, it was acknowledged that there was often insufficient time to inform patients adequately about fatigue. Participants considered written materials as helpful complements to oral information, thus supporting the provision of information in both forms. However, it was clear that fewer written resources concerning cancer-related fatigue were available in Italy compared to either in Switzerland or in the UK. The study supported the view within the current literature that whilst cancer-related fatigue is recognised as a frequent and disruptive symptom, patient education about this symptom and its management still needs to be enhanced. The resources available to educate patients about cancer-related fatigue should be improved and made more accessible to patients who experience it.

The most common adverse event typically associated with bisphosphonate therapy is transient fever. The aim of this study was to define the role of the main cytokines of the acute-phase reaction interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) involved in the pathogenesis of zoledronic acid-induced fever. Eighteen consecutive cancer patients with bone metastases were treated, for the first time, with a single dose of 4 mg zoledronic acid infusion. They were prospectively evaluated for circulating TNF-alpha, interferon-gamma (IFN-gamma), and IL-6 levels at different times, just before and 1, 2, 7, and 21 days after diphosphonate infusion. Clinical and standard laboratory parameters were recorded at the same time points. TNF-alpha circulating levels increased significantly 1 and 2 days after zoledronic acid infusion (respectively, p = 0.002 and p0.001) and then decreased to levels similar to the basal levels. IL-6 levels increased significantly 1 day after the infusion (p = 0.007), returning to values similar to the median basal values 2 days after zoledronic acid administration. Moreover, in patients who experienced fever, the TNF-alpha and IL-6 increases were higher than in patients without fever. No statistically significant differences in IFN-gamma were identified at different time points in patients with and without fever. Our results show that zoledronic acid induces transient TNF-alpha and IL-6 increases and that these increases are higher in patients who have developed fever, suggesting that these cytokines could be responsible for fever pathogenesis. The sharp reduction in serum calcium levels observed in patients with fever may be related to zoledronic acid pharmacokinetic modifications.

The commercial availability of zoledronic acid, a third generation bisphosphonate, prompted us to evaluate the modifications in angiogenic cytokines levels after a single i.v. infusion of this drug.Thirty consecutive cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg of zoledronic acid before any chemotherapy. The patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion.Basal serum VEGF median levels were significantly decreased at days 2 (-23%), 7 (-28%), and 21 (-34%) after zoledronic acid infusion (P = 0.0498, 0.0090, and 0.0011, respectively). Serum PDGF levels were significantly decreased by 25% 1 day after zoledronic acid infusion (P = 0.0032). This effect on circulating PDGF levels persisted for 2 days after bisphosphonate infusion (P = 0.0050). PDGF levels had returned to values similar to the median basal value at 7 and 21 days. Moreover, a linear regression model with variance analysis showed a significant positive correlation between basal VEGF and PDGF values but not at the following time points. No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after zoledronic acid single infusion.This study confirms that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels.

Background: Although bone marrow is a common site of micrometastases for non-small cell lung cancer (NSCLC), thrombocytopathia and hemorrhagic diathesis are rare causes of death. Case Report: A 57-year-old patient was admitted to the emergency room because of massive nosebleeding and hemoptysis. Routine blood analysis showed thrombocytopenia and prolonged bleeding time; results of functional platelet tests suggested concomitant thrombocytopathia. Routine chest X-ray revealed an 18 mm large spot in the right superior lobe. During the first hour of recovery the patient had another episode of nosebleeding. A bone marrow biopsy showed a wide infiltration with neoplastic cells. Histology was compatible with NSCLC. The clinical conditions and hematological parameters progressively deteriorated, and on the third day the patient died because of hypovolemic shock. Conclusion: This is a very rare clinical presentation of NSCLC characterized by massive bleeding due to thrombocytopenia and thrombocytopathia secondary to wide bone marrow infiltration.

21142 Introduction: Previous studies on the association between interleukin-1 (IL-1) genetic polymorphisms and the risk of gastric cancer have produced conflicting results. The purpose of this study was to examine the association between IL-1 genotype and gastric cancer by systematically reviewing the original studies. Materials and Methods: We searched the MEDLINE, CENTRAL, and PubMed databases (last research performed on July 2005) and reviewed cited references to identify relevant studies. Search key words were: gastric cancer (OR stomach cancer OR gastric adenocarcinoma OR stomach adenocarcinoma) and IL-1 (OR IL1). The literature review identified 23 titles that met the search criteria. Data from 15 articles that investigated the association between any of IL-1B-511 and IL-1B-31 polymorphisms and gastric cancer met the inclusion criteria, and they were included in the meta-analysis. Eight studies evaluated the role of IL-1B-511, four the role of IL- 1B-31 and three investigated both IL-1B-511 and IL-1B-31. Results: By pooling all the studies identified, our study shows that individuals IL-1B-31T carrier have got an increased risk developing gastric cancer (OR of 1.25; 95% CI 1.06–1.47) in particular in Caucasian sub-group (OR of 1.41; 95% CI 0.97–2.05). IL-1B-31CC genotype confers a decreased risk (OR of 0.80; 95% CI 0.68–0.95) especially in Caucasian population (OR of 0.71; 95% CI 0.49–1.03) compared to Asians (OR of 0.83; 95% CI 0.69–0.99). This association might be explained with the well-known near complete linkage disequilibrium between IL1B-511T and IL1B-31C polymorphism. Furthermore our results suggest a strong association between IL1B-511T polymorphism and gastric cancer risk only in Caucasians and not in Asians. Conclusions: In conclusion, although affected by the common bias of each epidemiologic studies, this pooled analysis suggests that IL1B-511T polymorphism is associated with an increased risk of developing gastric cancer in Caucasian population. No significant financial relationships to disclose.

3558 Purpose: Recent data have demonstrated in preclinical tumor models an antiangiogenic and antitumor activity of low weekly doses of ZA. As a consequence, the purpose of this study was to confirm these data, evaluating in cancer patients the modifications in angiogenic cytokines levels following repeated weekly low doses of ZA. Experimental Design: 26 consecutive cancer patients with bone metastases treated, for the first time, with four weekly doses of 1 mg of ZA followed by standard doses (4 mg every 28 days) were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) at different time points: just before and after 1, 7, 14, 21, 28, 56 and 84 days following the first disphosphonate infusion. Results: Basal serum VEGF median levels were significantly decreased just after 7 days (-29.7%) (with only one weekly infusion) (P=0.038), This significant decrease of circulating VEGF levels persisted 14(-33.2%), 21 (-39.4%), 28(-31.8%), 56(-33.6%) and 84(-27.9%) days after the first infusion (respectively, P=0.002, P=0.001, P=0.008, P=0.002, P=0.014). Conclusions: This study confirms, for the first time in humans, that weekly low doses of zoledronic acid could have antiangiogenic properties through a significant and long lasting decrease of VEGF serum levels. No significant financial relationships to disclose.

3562 Background: Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated clinically as progressive or stable disease. We designed this trial to investigate if Vascular Endothelial Growth Factor (VEGF) circulating levels modifications may be related with clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. Methods: 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab (initial dose of 400 mg per square meter, followed by weekly infusions of 250 mg per square meter) plus weekly irinotecan (90 mg per square meter). VEGF circulating levels were assessed at the following time-points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. Results: Basal serum VEGF median levels were significantly decreased just at the first day (after the first treatment infusion (P=0.016). The VEGF persisted at the following time points reaching the highest statistical significance 92 days after the first infusion (P No significant financial relationships to disclose.