Phase II Trial of 5-Fluorouracil/Leucovorin/Gemcitabine/Cisplatin as Second-Line Treatment in Patients with Metastatic or Recurrent Colorectal Carcinoma: A Cancer Therapeutics Research Group Study

Second-line treatment of relapsed or metastatic colorectal cancer (CRC) after failure of treatment with a fluoropyrimidine is composed of oxaliplatin in combination with a fluoropyrimidine or an irinotecan-containing regimen. Cisplatin and gemcitabine are synergistic in preclinical studies, as is 5-fluorouracil (5-FU) combined with either agent. Fixed-rate infusional gemcitabine is more effective than bolus administration in animal models. A 2-stage phase II trial was conducted to assess the efficacy (the primary endpoint was response rate) and safety of a regimen consisting of 5-FU 400 mg/m 2 as an intravenous bolus at the middle of a 60-minute infusion of leucovorin 100 mg/m 2, followed by gemcitabine 800 mg/m 2 over 80 minutes, and cisplatin 20 mg/m 2 over 15 minutes. Treatment was repeated weekly for 3 weeks followed by a 1-week rest. Patients with advanced CRC were eligible if they had experienced treatment failure with fluoropyrimidine-based therapy. Nineteen patients were enrolled. The median age was 60 years; 15 patients were men and 4 were women. Twelve patients had colon cancer and 7 had rectal cancer. Sites of metastasis were as follows: liver (n = 10), lung (n = 8), skin (n = 1), and non-regional lymph nodes (n = 1). All patients had an Eastern Cooperative Oncology Group performance status of 0/1. A total of 44 cycles of chemotherapy were delivered (median, 2 cycles; range, 1–5 cycles). One patient exhibited a partial response (5%), 8 had stable disease (42%), and 5 experienced disease progression (26%); another 5 patients were nonevaluable (26%). The median time to progression was 8 weeks and median survival was 36 weeks. Grade 3/4 toxicities were as follows: diarrhea (n = 1), dyspnea (n = 1), pneumonia (n = 1), neutropenia (n = 2), and thrombocytopenia (n = 1). Despite acceptable toxicity and a reasonable overall survival, the combination of 5-FU/leucovorin/gemcitabine/cisplatin does not seem to improve current standard therapy in the second-line treatment of patients with CRC in whom a first-line fluoropyrimidine-containing regimen has failed

Inhibition of Akt pathway phosphorylation as a mechanism in the pathogenesis of functional intestinal obstruction in carcinomatosis peritonei

BACKGROUND AND OBJECTIVES: The purpose of this study was to confirm our hypothesis that the development of functional intestinal obstruction in carcinomatosis peritonei (CP) is related to cytokine-mediated inhibition of the Akt pathway and to investigate the phenomenon of relative adrenal insufficiency in CP. METHODS: Human adrenocortical cells (NCI-H295R) were treated with serum derived from eight cancer patients who had intestinal obstruction and functional adrenal insufficiency. Serum from three normal healthy subjects and three who had CP but without intestinal obstruction or adrenal insufficiency were used as controls. The differential effects of serum on the treated cells were studied using Western blot analysis. Cortisol production of these treated cells was assayed with cortisol ELISA kits. RESULTS: Phosphorylation of Akt at Ser473 and Ser308 in cells was significantly reduced when treated with serum from patients with intestinal obstruction but not controls. Phosphorylation of PDK1 at Ser241, mTOR downstream targets like p70S6 at Thr421/Ser424 and Thr389, and lastly 4EBP-1 at Ser70 a downstream target of p70S6 was reduced by approximately 50%, 40%, and 70%, respectively. There was enhanced phosphorylation of eIF4E an initiating factor in protein translation in cells treated with patient serum compared to controls. Cortisol synthesis was stimulated upon treatment with patient serum but not with control serum. CONCLUSION: Inhibition of Akt phosphorylation is a mechanism that could play a major role in the development of intestinal obstruction in carcinomatosis peritonei. The identification of the mediating cytokines will lead to the development of cogent targeted therapeutic strategies

Phase II trial of gemcitabine in combination with cisplatin in inoperable or advanced hepatocellular carcinoma

Introduction: Advanced hepatocellular carcinoma (HCC) has a dismal prognosis and is notoriously chemo-resistant. We conducted a Phase II prospective study to evaluate the activity and tolerability of gemcitabine and cisplatin in chemo-naïve advanced hepatocellular carcinoma. The trial considered a “no further interest” response rate of 10% and a target response rate of 30%. Utilising a Simon’s minimax two-stage design with a type I error of 0.05 and power of 80%, 25 subjects would be required. Fifteen patients would be needed in stage 1 and if fewer than 2 responses were observed, the trial would be stopped and lack of efficacy claimed. Materials and Methods: Patients with advanced HCC, diagnosed based on histology or by World Health Organization (WHO) criteria, were administered gemcitabine 1000 mg/m2 and cisplatin 25 mg/ m2 on day 1 and day 8 of a 21-day schedule. Assessment of response based on computer tomography was performed after every 2 cycles of chemotherapy. Results: The trial was stopped early due to a lack of efficacy. A total of 15 patients were accrued. Twelve patients were hepatitis B positive and the other 3 patients were negative for both hepatitis B and C. Only 1 patient had a history of prior heavy alcohol use. Two patients had Child C liver cirrhosis, 5 patients had Child B cirrhosis, and the remaining 8 patients had Child A cirrhosis. This regime was well tolerated and there was only 1 patient who experienced grade IV toxicities. Only 5 of 15 patients experienced grade III toxicities (nausea and emesis, 1 patient; anemia, 1 patient; thrombocytopenia, 1 patient; and neutropaenia, 2 patients). Only 1 patient experienced a partial response to the combination of gemcitabine and cisplatin. A further 3 patients experienced stable disease and 11 patients progressed on chemotherapy. The median time to progression was 6 weeks. The progression-free curve showed a sharp descent in the initial part of the study, suggesting that many patients had disease progression after enrolment. The median overall survival was 18 weeks. Conclusion: The progression-free survival and overall survival in our study were extremely short. Based on the results of our phase 2 study, we are unable to recommend further studies utilising gemcitabine and cisplatin combination in patients with advanced HC

Clinical Benefit of Allogeneic Melanoma Cell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients

Purpose: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)–pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate. Experimental Design: DCs were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83- and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 × 106 cells per dose) at biweekly intervals. Results: Twenty patients received a total of 161 vaccinations. Treatment was well tolerated and quality of life measurements did not vary much across time. One patient experienced partial response [5%; 95% confidence interval (CI), 1-24%] and seven achieved stable disease (35%; 95% CI, 18-57%), one of whom also achieved late tumor regression, yielding a clinical benefit response rate of 40% (95% CI, 22-61%). Although overall median progression-free survival was 2.4 months (95% CI, 1.9-4.1 months), five patients (25%) experienced prolonged progression-free survival (>6 months), two of whom (10%) remain progression-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding patients that may correlate with vaccine activity and report a prevaccination protein signature distinguishing responders from nonresponders. Conclusion: This phase II vaccine study using mature, MCL-pulsed DCs has shown promising results and warrants further evaluation in a prospective randomized setting