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Background Bevacizumab, a monoclonal antibody (mAb) targeting vascular endothelial growth factor (VEGF), has produced promising results when combined with chemotherapy in the treatment of advanced colorectal cancer (CRC). The aim of the present study was to define the immunological profile of metastatic CRC patients at baseline and following chemotherapy with either irinotecan/5-fluorouracil/leucovorin (IFL) alone or IFL in combination with.bevacizumab (B-IFL). Methods Peripheral blood mononuclear cells (PBMCs) obtained from healthy donors (HD) (n = 20) and patients (n = 40) were tested for T-cell proliferation in the autologous mixed lymphocyte reaction (auto-MLR), and cytokine production following stimulation with anti-CD3 mAb. Results,PBMCs obtained from CRC patients prior to treatment exhibited lower auto-MLR responses and low production of IL-2, IFN-γ, IL-12 and IL-18 cytokines, whereas IL-4 and IL-10 cytokines were increased as compared to HD (p < 0.001, for all parameters) following in vitro stimulation with anti-CD3 mAb. During treatment, and in particular in week 12 of evaluation, IL-2 (p < 0.001 for both IFL and B-IFL groups), IFN-γ (p < 0.001 for IFL and p = 0.001 for B-IFL), IL-12 (p < 0.001 for both IFL and B-IFL) and IL-18 (p < 0.001 for both IFL and B-IFL) production, as well as auto-MLR responses increased (p < 0.001 for both IFL and B-IFL), whereas IL-4 (p < 0.001 for IFL and p = 0.001 for B-IFL) and IL-10 [p < 0.001 for IFL and p = 0.067 (non-significant) for B-IFL] production decreased over baseline in the two treatment groups, yet their respective values never reached those of HD. Moreover, IL-2, IFN-γ production, and auto-MLR were higher in the B-IFL over the IFL treatment group (p < 0.001, p < 0.04, p < 0.001, respectively). Conclusion Our study demonstrates that the abnormal immune parameters observed in metastatic CRC patients at presentation can substantially improve during treatment with either IFL or B-IFL. The immune parameters examined can provide a sensitive and valuable tool for monitoring immune function in CRC patients, and could be applied as surrogate markers predicting treatment-related outcome.

The feasibility of the docetaxel-ifosfamide combination, as well as the definition of maximum tolerated doses (MTD) in a previous phase I study, led us to continue evaluating the regimen in an extended phase II study in patients with HER2-non-overexpressing, anthracycline pre-treated advanced breast cancer. Patients with histologically confirmed metastatic breast cancer failing prior anthracycline-based chemotherapy were treated with docetaxel 100 mg/m2 over 1 h on day 1 followed by ifosfamide 5 g/m2 divided over days 1 and 2 (2.5 g/m2/day over 1 h), and recycled every 21 days with prophylactic granulocyte-colony stimulating factor (G-CSF) administration from day 3-until a neutrophil count >10,000/microl. Between March 1999 and June 2002, 71 patients with a median age of 55 years (range, 28-72) and performance status (World Health Organization; WHO) of 1 (range, 0-2) were treated; all were assessable for toxicity and 70 patients for response. Clinical response rates (RRs), on an intention-to-treat basis were: 41/71 [58%; 95% CI, 46.5-69.5%]; 7 complete remissions (CRs), 34 partial remissions (PRs), 15 stable disease (SD) and 15 progressive disease (PD). The median response duration was 7.5 months (2-28 months), median time-to-progression (TTP) 6 months (0.1-30 months), and median overall survival (OS) 12 months (0.1-36 months). Grade 3/4 toxicities included; neutropenia in 63% of patients-with 52% developing grade 4 neutropenia (>or=7 days) and in 11% of these febrile neutropenia (FN), while no grade 3/4 thrombocytopenia was observed. Other toxicities included; peripheral neuropathy grade 2 only in 7%, grade 1/2 reversible central nervous system (CNS) toxicity in 11%, no renal toxicity, grade 2 myalgias in 7%, grade 3 diarrhea in 4%, skin/nail toxicity in 11%, and grade 1/2 fluid retention in 28% of patients. The present report has demonstrated encouraging activity of the docetaxel-ifosfamide combination in anthracycline-pretreated, HER2-negative advanced breast cancer. Therefore, future randomized phase III studies versus single-agent docetaxel or currently established combinations of the latter with other agents in this setting with established clinical activity, such as capecitabine or gemcitabine, will be warranted.

Objectives: To evaluate the efficacy and safety of weekly administration of gemcitabine treatment in chemotherapy-naive patients with advanced biliary tract and gallbladder cancer. Patients and methods: Gemcitabine at a dose of 800 mg/m2 was administered weekly as a 30-min infusion to patients with previously operated, histologically confirmed, metastatic, or unresectable locally advanced cholangiocarcinoma. Treatment was continued until unacceptable toxicity or disease progression. Results: A total of 30 patients (median age 66 years; range 54–72 years) were included in the study. A median of 14 (range, 4–33) weekly doses was administered. Out of 30 patients evaluable for response, nine partial responses were observed (30.0%), while a further 11 patients demonstrated stable disease (36.7%). The median time to disease progression was 7 months (range, 5–34). Overall response rate was superior in patients with cancer of the gallbladder (ORR=35.7%) compared with those patients with biliary duct cancer (ORR=27.3%). This correlated to a significantly longer time to progression of 6.4 months (95% confidence interval (CI), 5.6–7.1 months) versus 3.6 months (95% CI, 2.9–4.3 months; p=0.03) and a significantly better overall survival of 17.1 months (95% CI, 15.8–18.5 months) versus 11.4 months (95% CI, 10.2–12.6 months, p=0.021). Toxicities were generally mild with only one case of grade 3 neutropenia. There were no cases of febrile neutropenia and no treatment-related deaths. Conclusions: Weekly administration of gemcitabine provides a safe, well-tolerated, and effective treatment for chemotherapy naive patients with advanced cholangiocarcinoma, particularly with a gallbladder origin.

Study objectives: The present study was conducted to evaluate the efficacy and safety of the combination of Oxaliplatin, Leucovorin and 5-FU as second line therapy, following relapse to Gemcitabine, in patients with advanced adenocarcinoma of the pancreas. Patients and methods: Patients with advanced pancreatic cancer previously treated with Gemcitabine were included in the study. All patients had histologically or cytologically confirmed adenocarcinoma of the pancreas that was unresectable, locally advanced or metastatic. Treatment consisted of Oxaliplatin 50 mg/m2 (2-hour iv infusion), followed by Leucovorin 50 mg/m2 (i.v. bolus) and 500 mg/m2 5-FU (1-hour iv infusion), administered weekly, until unacceptable toxicity or disease progression. Objective tumour response and toxicity were evaluated according to World Health Organisation (WHO) criteria. Results: A total of 30 patients, 20 men and 10 women, median age 63 years (range 52–71 years) and Karnofsky Performance Status (PS) of ≥50 entered the study. The majority of patients (96%) had locally advanced disease. A total of 380 doses of chemotherapy were delivered, a median of 12 doses per patient. Partial responses were observed in 7 patients (PR 23.3%), stable disease in 9 (SD 30.0%), while 14 patients progressed (PD 46.7%). Improved PS was observed in 18 (42.8%) patients. Patients that had responded to first-line Gemcitabine treatment were found more likely to respond or stabilize their disease with second-line treatment. The median duration of response was 22 weeks, and median overall survival was 25 weeks, Grade 3/4 toxicity expressed per chemotherapy dose included leukopenia 16%, anemia 3.2%, thrombocytopenia 3.2%, diarrhea 14.2%, fatigue 16.1% and neurotoxicity 4.2%. Eight patients (27%) suffered a febrile neutropenic event managed successfully with oral antibiotic home therapy, while 17 patients required G-CSF support. There were no treatment related deaths. Conclusions: The combination of Oxaliplatin, Leucovorin and 5-FU was tolerated with manageable toxicity, offering encouraging activity as second-line treatment of patients with advanced or metastatic pancreatic adenocarcinoma, previously treated with Gemcitabine. Additional studies are warranted with this regimen in Gemcitabine relapsed pancreatic cancer patients.

Purpose: To evaluate efficacy of Raltitrexed, a specificthymidilate synthase inhibitor, in patients with advancedcolorectal cancer (ACC) failing multiple prior chemotherapyregimens (e.g. 5-FU+LV, CPT-11, etc). Methods: 20 patients with ACC; 13 males/7 females,median age 64 (range: 53–69), median Karnovsky PS: 80 (70–90), and sites of metastases; liver: 16, lung: 6, lymph nodes:9, peritoneal: 8 and a life expectancy of at least 3 months,were entered in the present pilot study of Raltitrexedadministration. All patients had progressed after priorchemotherapy with 5-FU+LV and subsequently CPT-11, and somehad received further infusional 5-FU. Raltitrexed wasadministered at a dose of 3 mg/m2 i.v. every 21 days. Results: 3 patients obtained stable disease (SID), 15%,with tumor marker decline (CEA, CA-19.9). Time-to-progressionwas 4.8 months (2.2–7) and survival 7.4 months (6.0–7.8).Toxicity was in general not severe and consisted mainly ofmyelosuppression; neutropenia (WHO) grade 2: 45% and grade 3:22%, and anemia grade 1–2: 40%. Conclusion: Response to treatment with Raltitrexed islimited in patients with ACC failing multiple priorchemotherapy regimens, however, a limited percentage ofpatients with SD derived clinical benefit.