In vivo effects of zoledronic acid on peripheral gammadelta T lymphocytes in early breast cancer patients.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: A significant decrease of the different gammadelta T cell subsets was observed: Naïve (CD3+/Vdelta2+/CD45RA+/CD27+) after 180 days (P < 0.01); Central Memory (CD3+/Vdelta2+/CD45RA-CD27+) after 28 (P < 0.05), 90 (P < 0.01) and 180 days (P < 0.01); and Effector Memory (CD3+/Vdelta2+/CD45RA-/CD27-) after 56 (P < 0.01) and 90 (P < 0.05) 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. CONCLUSION: 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.

Early magnesium reduction in advanced colorectal cancer patients treated with cetuximab plus irinotecan as predictive factor of efficacy and outcome.

INTRODUCTION: Magnesium plays a role in a large number of cellular metabolic reactions. Cetuximab is able to induce hypomagnesemia by interfering with magnesium (Mg(2+)) transport in the kidney. We designed this trial to investigate if Mg(2+) 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 Mg(2+) 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 Mg(2+) 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 Mg(2+) 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 Mg(2+) group. The median time to progression was 6.0 versus 3.6 months in the reduced Mg(2+) group and in that without reduction, respectively (P < 0.0001). Overall survival was longer in patients with Mg(2+) reduction than in those without (10.7 versus 8.9 months). CONCLUSIONS: Our results confirm that cetuximab treatment may induce a reduction of Mg(2+) circulating levels and offer the first evidence that Mg(2+) reduction may represent a new predictive factor of efficacy in advanced colorectal cancer patients treated with cetuximab plus irinotecan.

Survey on learning needs and preferred sources of information to meet these needs in Italian oncology patients receiving chemotherapy.

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.

Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients.

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.

Circulating VEGF reduction, response and outcome in advanced colorectal cancer patients treated with cetuximab plus irinotecan.

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 < 0.0001). A total of 22 patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusion with respect to the basal time point. For patients with at least a 50% reduction in VEGF levels, the response rate was 45.5% compared with 8.7% in the nonreduced VEGF group (p = 0.014). The median time to progression was 6 months in the reduced VEGF group versus 3.9 months in the other patients (p < 0.0001). In addition, overall survival was longer in patients with VEGF reduction (11.0 months) than in patients without (9.6 months; p = 0.01). CONCLUSION: These data represent the first evidence that suggests a role of VEGF reduction in the prediction of efficacy of treatment with cetuximab plus weekly irinotecan in heavily pretreated advanced colorectal cancer patients.

Meeting information needs on cancer-related fatigue: an exploration of views held by Italian patients and nurses.

BACKGROUND: 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. MATERIALS AND METHODS: 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. MAIN RESULTS: 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. CONCLUSION: 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.

Continuous infusion of oxaliplatin plus chronomodulated capecitabine in 5-fluorouracil- and irinotecan-resistant advanced colorectal cancer patients.

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.

Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients.

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.

Fever after zoledronic acid administration is due to increase in TNF-alpha and IL-6.

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 p < 0.001) 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.

Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: This study confirms that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels.

S-adenosylmethionine (AdoMet) supplementation for treatment of chemotherapy-induced liver injury.

BACKGROUND: Liver toxicity can be observed during treatment with most chemotherapic agents, and represents one of the principal causes of dose reduction or chemotherapy delays. S-Adenosylmethionine (AdoMet) plays a critical role in the synthesis of polyamines and provides cysteine for the production of glutathione (GSH), the major endogenous hepatoprotective agent. Our study was aimed at assessing the protective effect of AdoMet supplementation in cancer chemotherapy-induced liver toxicity. PATIENTS AND METHODS: Fifty cancer patients who developed, for the first time, anticancer chemotherapy-induced liver toxicity were studied. Enrolled patients received oral AdoMet supplementation. RESULTS: AST, ALT and LDH levels recorded at the moment of the recognition of liver toxicity were significantly reduced after one week of AdoMet therapy (respectively p: 0.009, 0.0005 and 0.012). AST, ALT and LDH decrease was confirmed after two weeks of treatment. Furthermore, the effect on these enzyme levels persisted in the following chemotherapy courses, permitting our patients to perform the scheduled chemotherapy courses with a minimal number of dose reductions or administration delays. The efficacy of AdoMet supplementation was not influenced by the presence of liver metastases, and no appreciable side-effects were recognized. CONCLUSION: The results of our study clearly demonstrate a protective effect of AdoMet in cancer chemotherapy-induced liver toxicity. Further large phase III studies are required to assess the real clinical benefit associated with AdoMet supplementation.