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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.

BackgroundBone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) as disease-related survival improves. There are few data on the natural history of bone disease in RCC.Patients and methodsData on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 398 deceased RCC patients (286 male, 112 female) with evidence of bone metastasis were statistically analyzed.ResultsMedian time to bone metastasis was 25 months for patients without bone metastasis at diagnosis. Median time to diagnosis of bone metastasis by MSKCC risk was 24 months for good, 5 months for intermediate, and 0 months for poor risk. Median number of SREs/patient was one, and 71% of patients experienced at least one SRE. Median times to first, second, and third SRE were 2, 5, and 12 months, respectively. Median survival was 12 months after bone metastasis diagnosis and 10 months after first SRE. Among 181 patients who received zoledronic acid (ZOL), median time to first SRE was significantly prolonged versus control (n = 186) (3 months vs 1 month for control; PConclusionsRCC patients with bone metastasis are at continuous risk of SREs, and in this survey ZOL effectively reduced this risk.

Bisphosphonates (Bps) are a class of drugs approved for treatment of bone metastases. There are two classes, the Nitrogenous-containing and non-Nitrogenous-containing Bps. They act on osteoclasts, inhibiting malignant osteolysis which causes skeletal-related events. These events are defined as pathological fractures, spinal cord compression, bone pain requiring palliative radiotherapy, orthopaedic surgery (such as vertebroplasty, kyphoplasty, and cementoplasty) and malignant hypercalcemia (HCM). In this chapter we will describe the mechanism of action of Bps and the major preclinical and clinical studies which evaluated the efficacy of these agents for the treatment of bone metastases from solid tumors. We will also describe the clinical data on the adjuvant role of Bps in breast and prostate cancer.

PurposeTo evaluate bone density changes at the level of normal bone and bone metastases after zoledronic acid (ZA) treatment in oncologic patients.Materials and methodsWe retrospectively evaluated 72 consecutive adult patients with histologically confirmed solid tumors with at least 1 newly diagnosed bone metastatic lesion. Bone metastases were diagnosed by bone scans and confirmed with computed tomography (CT). Patients received intravenous ZA, 4mg, by 15-min infusion every 28 day through a peripheral or a central venous access and were monitored for at least 3 months and a maximum of 24 months. Bone density was determined at the level of bone metastases and at the level of normal trabecular and cortical bone using a ROI-based approach.ResultsA significant increase was demonstrated at the level of normal trabecular bone of the calvarium and the femoral neck. No significant increase of density was observed at the level of the normal cortical bone. Bone metastases showed a significant increase in CT density as compared to baseline up to 24 months after zoledronic acid.ConclusionWe have found that long term treatment with ZA increases trabecular bone density in oncologic patients whereas normal cortical bone changes are not detectable.

Background Data are limited regarding bone metastases from colorectal cancer (CRC). The objective of this study was to survey the natural history of bone metastasis in CRC. Patients and methods This retrospective, multicenter, observational study of 264 patients with CRC involving bone examined cancer treatments, bone metastases characteristics, skeletal-related event (SRE) type and frequency, zoledronic acid therapy, and disease outcomes. Results Most patients with bone metastases had pathologic T3/4 disease at CRC diagnosis. The spine was the most common site involved (65%), followed by hip/pelvis (34%), long bones (26%), and other sites (17%). Median time from CRC diagnosis to bone metastases was 11.00 months; median time to first SRE thereafter was 2.00 months. Radiation and pathologic fractures affected 45% and 10% of patients, respectively; 32% of patients had no reported SREs. Patients survived for a median of 7.00 months after bone metastases diagnosis; SREs did not significantly affect survival. Subgroup analyses revealed that zoledronic acid significantly prolonged median time to first SRE (2.00 months versus 1.00 month, respectively, P = 0.009) and produced a trend toward improved overall survival versus no zoledronic acid. Conclusion This study illustrates the burden of bone metastases from CRC and supports the use of zoledronic acid in this setting.

Background: This phase II trial was conducted to determine the activity and safety of the combination of fixed-dose rate (FDR) gemcitabine and capecitabine in metastatic biliary tract cancer (BTC) patients. Methods: Patients with unresectable BTC who had pathologically confirmed adenocarcinoma, no prior chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status ≤1 and measurable disease were enrolled. Treatment consisted of FDR gemcitabine at 800 mg/m2 on days 1 and 8 every 21 days with capecitabine administered orally b.i.d. in equal doses (650 mg/m2 b.i.d.) for 14 days (28 doses). Results: Between May 2005 and February 2009, 30 patients were enrolled. The median age was 67 years (45–76) and there were 14 males. Thirty patients were evaluable for response and toxicity. A total of 221 cycles were administered (median 7, range 2–16). One patient achieved complete response and 7 patients achieved partial response, giving an overall response rate of 26.7% in the intention-to-treat population. Twelve patients (40.0%) had stable disease. The median progression-free survival was 6.33 months. The median overall survival was 10.8 months. Grade 3/4 neutropenia and thrombocytopenia were noted in 13 and 7% of the patients, respectively. Grade 2/3 nonhematologic toxicities were asthenia (54% of patients), diarrhea (17%), stomatitis (23%) and hand-foot syndrome (7%). There was no treatment-related death. The drugs taken were skipped at least once in 45% of the patients and the dose was reduced in 26% of them. Conclusions: The combination of FDR gemcitabine and capecitabine in this 3-week cycle is safe and seems to have a good activity in advanced biliary cancer.

New emerging data suggest that bisphosphonates may exert antitumor properties. Preclinical studies have demonstrated that zoledronic acid (ZA) can induce direct and indirect antitumor activities such as inhibition of angiogenesis, invasion and adhesion of tumor cells, and overall tumor progression, stimulation of adoptive and innate immunity and emerging evidence suggests that the use of these agents may prevent the development of skeletal and extra skeletal metastases. This review will critically describe the new growing evidence of antitumor activity exerted by bisphosphonates in cancer patients, both in metastatic disease and in the adjuvant setting. The effects of bisphosphonates on survival in metastatic cancer patients will be described and evidence from retrospective analyses and prospective studies will be critically reported. The early evidence from prospective analyses of survival impact by ZA in the adjuvant setting in breast cancer will be discussed together with the recently published results of the ABCSG-12 study. A new "era" for bisphosphonates in the oncological setting is opening. The clinical data that will be reported in this review represent the first step in a path that will conduct us to explore new horizons in the field of adjuvant and metastatic cancer therapies.

e15530 Background: The aims of this phase II trial are to determine the activity and the safety of the new combination modality with Gemcitabine fixed dose rate (FDR) infusion and Capecitabine in patients with advanced pancreatic cancer. Methods: Patients with unresectable pancreatic cancer who had pathologically confirmed adenocarcinoma, no prior chemotherapy, ECOG PS < 2 and measurable disease were enrolled. Gemcitabine (800 mg/mq IV infused in 80 minutes on days 1 and 8) and Capecitabine (650 mg/mq orally twice daily for 14 days) were administered and repeated every 21 days. Results: 47 patients were enrolled between January 2004 and October 2008. Median age was 66 (range: 37–79), 18 female and 29 male. A total of 299 cycles were administered, median cycles for patient were 6 (range: 1–17). CR was observed in one patient (2.1 %) and 10 patients achieved PR (21.3 %) giving an overall response rate of 23.4 % in intention-to-treat population. 22 pts (46.8 %) had stable disease obtaining an overall tumour control of 70.2 %. The median time to progression was 5.2 months (95 % CI, 2.4–7.6); the median overall survival was 8.4 months (95 % CI, 5.5–20). Grade 3–4 neutropenia was observed in 29.8 % of subjects, thrombocytopenia in 6.4 %. Grade 1–2 non-hematological toxicities were asthenia (61.7 %), diarrhea (29.8%), stomatitis (29.8 %) and hand foot syndrome (2.1 %). There were no treatment-related deaths. Gemcitabine was skipped at least once/reduced in 51/10.6 % of the patients, respectively. Capecitabine was skipped at least once/reduced in 16/8 % of the patients, respectively. Conclusions: The combination of FDR Gemcitabine and Capecitabine with this modality of infusion is feaseble, safe and seems to be active. No significant financial relationships to disclose.

Bisphosphonate (BPs) therapy has become a standard of care for patients with malignant bone disease. In addition, preclinical and preliminary clinical data suggest that BPs exert their direct or indirect antitumoral effects on cancer growth factor release, on cancer cell adhesion, invasion and viability, on cancer angiogenesis and on cancer cell apoptosis. Here, after a brief analysis on clinical indications, on the last generation amino-bisphosphonates (N-BP) and on biochemical pathways as molecular targets of BPs, we will discuss the molecular mechanisms of these antitumor effects. Recent evidence suggests that part of the antitumor activity of bisphosphonates may be attributed to an antiangiogenic effect. For this reason, we will analyse all the in vitro and in vivo preclinical reports and the first clinical evidence of anti-angiogenic activity exerted by this class of drugs. Several patents have been reported in the review, considering the recents activities observed for these drugs. Taking together all the major results obtained in the described studies, it is possible to affirm that BPs, particularly zoledronic acid and pamidronate, could potentially represent a very powerful tool for angiogenesis inhibition leading to a better control of cancer growth and progression. The translation into the clinical setting of the preclinical evidence of an antiangiogenic power of these drugs is becoming an imperative need and should represent the objective of future clinical trials.

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.

The combination of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (I-OHP) was shown to be both more active against metastatic colorectal carcinoma and better tolerated if the drug delivery rate was chronomodulated according to circadian rhythms rather than constant. The aim of the present study was to define the feasibility and efficacy of XELOX administered through a new chronomodulated schedule in untreated advanced colorectal cancer (CRC) patients. Chemotherapy-naive patients with advanced CRC were considered eligible for the study accrual. Treatment: oxaliplatin 70 mg/m2 continuous infusion (c.i.) for 12 h (8:00 a.m. to 8:00 p.m.) days 1, 8 plus chronomodulated oral capecitabine 1,750 mg/m2/die (h 8:00 a.m. 25% of total dose; h 6:00 p.m. 25% of total dose; h 11:00 p.m. 50% of total dose), days 1–14 every 21 days. Forty-six patients were evaluated for safety and efficacy (male/female, 20/26). Median age was 64 years (range 28–77 years). Median Eastern Cooperative Oncology Group performance status (PS) was 0 (range 0–1). A total of 324 cycles have been administered: median per patient 6 (range 3–10 courses). Median number of metastatic sites was 1. Metastatic sites distribution was as follows: liver (65.2%), lung (34.8%), and nodes (32.6%). Median follow-up was 14 months (range 6.0–40.3 months). In an intent-to-treat efficacy analysis, objective response and stable disease were recorded in 27 (58.6%) and in 16 patients (34.9%), respectively. The median response duration was 8.0 months (95% CI; 5.03–10.96 months). The median time to progression (TTP) was 9.0 months (95% CI; 6.47–11.52 months). The overall survival (OS) was not reached, with a median value > 24 months (95% CI; 23.66–36.30 months). The grade 3 toxicities were diarrhea (8.7%), liver toxicity (13.1%), fatigue (8.7%), neurotoxicity (2.2%), neutropenia (8.7%), and thrombocytopenia (2.2%). This regimen resulted of particular interest for patients with untreated metastatic CRC.

Background Elderly patients have been often excluded from or underrepresented in the study populations of combination chemotherapy trials. The primary end point of this study was to determine the response rate and the toxicity of the weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) regimen in elderly patients with advanced gastric cancer. The secondary objective was to measure the time to disease progression and the survival time. Methods Chemotherapy-naive patients with advanced gastric cancer aged 70 or older were considered eligible for study entry. Patients received weekly oxaliplatin 40 mg/m2, fluorouracil 500 mg/m2 and folinic acid 250 mg/m2. All drugs were given intravenously on a day-1 schedule. Results A total of 42 elderly patients were enrolled. Median age was 73 years and all patients had metastatic disease. The response rate according to RECIST criteria was 45.2% (95% CIs: 30%–56%) with two complete responses, 17 partial responses, 13 stable diseases and 10 progressions, for an overall tumor rate control of 76.2% (32 patients). Toxicity was generally mild and only three patients discontinued treatment because of treatment related adverse events. The most common treatment-related grade 3/4 adverse events were fatigue (7.1%), diarrhoea (4.8%), mucositis (2.4%), neurotoxicity (2.4%) and neutropenia (4.8%). The median response duration was 5.3 months (95% CIs: 2.13 – 7.34), the median time to disease progression was 5.0 months (95% CIs: 3.75 – 6.25) and the median survival time was 9.0 months (95% CIs: 6.18 – 11.82). Conclusion OXALF represents an active and well-tolerated treatment modality for elderly patients with locally advanced and metastatic gastric cancer.

12016 Background: Combination of C and G has been demonstrated to be well tolerated, with apparent efficacy in patients with advanced cancers. To determine the toxicity of C plus Fixed Dose Rate (FDR) G in metastatic cancer patients, a phase I trial was conducted. Methods: This is an open-label, single-center, dose-escalating phase I study. C was administered orally according to the standard 21-day schedule: bid in equal doses (650 mg/m2 bid) for 14 days every 21 days. G was administered at a FDR of 10 mg/m2 per min in escalating durations of infusion on days 1 and 8 every 21 days. The doses of G explored were 600, 700, 800 mg/m2 infused at FDR in 60, 70 and 80 minutes, respectively. 15 pts (10 female, 5 male), aged 37–70 yr (median 66) with a variety of advanced solid tumors have been treated (11 peri-ampullary cancers, 3 colorectal cancers and 1 ovarian cancer). The FDR G dose was escalated when 3 patients in a cohort had completed two cycles of treatment without experiencing dose-limiting toxicities (DLT). The MTD was defined as the dose level at which no more than one of nine patients experienced a DLT. Results: No DLT occurred at doses of 600 and 700 mg/m2 in any of the 3 patients included at each level. At 800 mg/m2, 1 of 9 patients experienced DLT (neutropenia grade 4 with fever). The non-haematological toxicities have been generally mild or moderate in all patients (grade 2 stomatitis: 4 patients; grade 2 fatigue: 3 patients; grade 2 nausea/vomiting: 2 patients). 2 patients showed one episode of grade 4 neutropenia spontaneously regressed in 3 days. 2 patients showed one episode of grade 2 thrombocytopenia. The recommended dose for further studies is C bid in equal doses (650 mg/m2 bid) for 14 days (28 doses) plus FDR G at 800 mg/m2 infused in 80 minutes on days 1 and 8 every 21 days. Other patients with periampullary carcinoma are being evaluated at the same dose level, with an ongoing evaluation of cumulative (all cycles) toxicity and efficacy. In terms of response, we have observed 2 PR and 3 SD in the 6 pancreatic cancer patients evaluated for response after the first 3 cycles. Conclusions: C plus FDR G combination seems to be a feasible and safety approach which has demonstrated promising clinical activity. No significant financial relationships to disclose.