Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma.

BACKGROUND: Pancreatic carcinoma is considered among the most chemoresistant of human malignancies. The most commonly used cytotoxic single agents, 5-fluorouracil and 2'-deoxy-2',2'-difluorocytidine (gemcitabine), have objective response rates of less than 10% in large studies. Hypothesizing noncross resistance and a synergistic interaction between gemcitabine and cisplatin, early clinical studies have demonstrated significant activity with this combination in patients with several types of malignant disease. A Phase II study was undertaken to determine the efficacy of gemcitabine in combination with cisplatin in patients with locally advanced and metastatic pancreatic carcinoma based on these considerations. METHODS: The eligibility criteria included histologically confirmed, locally advanced, unresectable or metastatic exocrine carcinoma of the pancreas with no prior gemcitabine therapy; prior adjuvant therapy was allowed provided the last day of therapy was at least 6 months prior to starting treatment; clinically measurable or evaluable disease; a Southwest Oncology Group scale performance status of 0-2; a life expectancy of > 12 weeks; and adequate bone marrow, hepatic, and renal function. A total of 42 patients, 4 patients with locally advanced, unresectable disease and 38 patients with metastatic disease, were treated and received a total of 211 cycles of therapy between May 1997 to March 1999. The median age of patients was 61.5 years. The patients were treated in the outpatient setting with a combination of gemcitabine 1,000 mg/M(2) intravenously over 30 minutes administered on Days 1, 8, and 15 of each cycle and cisplatin 50 mg/M(2) intravenously administered after gemcitabine infusion on Days 1 and 15 with adequate prehydration accompanied by adequate urinary output. Cycles were repeated every 28 days. Response and toxicity were assessed according to World Health Organization and standard criteria. RESULTS: The complete and partial response rate among all 42 registered patients was 11 of 42 patients (26%; 95% confidence interval, 0.14-0.42). Stabilization of disease was seen in 15 patients (38%). Two additional patients with metastatic disease who achieved major responses to chemotherapy were rendered free of disease surgically, achieving a complete response status. The median overall survival was 7.1 months (95% confidence interval [CI], 6.3-9.1 months), with 64% of patients alive at 6 months and 19% of patients alive at 12 months. The median time to disease progression was 5.4 months (range, 0.9-20.8 months). Major toxicities were neutropenia and thrombocytopenia, with one episode of neutropenic fever. CONCLUSIONS: The combination of gemcitabine and cisplatin appeared to have significantly greater activity than single-agent gemcitabine in this Phase II study, with tolerable toxicity. The antitumor activity of this combination needs to be confirmed in multi-institutional or comparative trials.

A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer.

Current chemotherapy for patients with advanced colorectal cancer is relatively ineffective and may be associated with significant toxicity. Bryostatin 1 (bryo 1) influences cell proliferation, intracellular metabolism and signaling, differentiation, and apoptosis in human cancer cell lines via modulation of protein kinase C (PKC) activity. This trial investigates the efficacy and toxicity of bryo 1 as a novel therapeutic agent for patients with advanced colorectal cancer who have had previous 5-fluorouracil therapy. The primary end point was tumor response to bryo 1. Toxicity was also assessed. Twenty-eight patients with advanced colorectal cancer were enrolled. The mean age was 59 years (range, 38-76), with 16 men and 12 women, and good minority representation (11 African-Americans). The first 10 patients initially received 25 microg/m2 of bryo 1 weekly as a 24-h infusion for 3 weeks of every 4-week cycle, with dose escalation to 35 microg/m2 starting with the second cycle. The remaining patients were started at 35 microg/m2 and escalated to 40 microg/m2, if toxicity was minimal. Twenty-five patients were evaluable for objective tumor response, and complete data on toxicity were collected on 26 patients. No partial or complete tumor responses were observed. All 25 patients had disease progression within four cycles. Myalgia was the most common toxicity. Myelosuppression was not seen. bryo 1 as a weekly 24-h continuous infusion lacks single-agent antitumor activity in advanced colorectal cancer. Toxicity differs from that of traditional chemotherapeutic drugs.

Cisplatin, cytarabine, caffeine, and continuously infused 5-fluorouracil (PACE) in the treatment of advanced pancreatic carcinoma: a phase II study.

Encouraging results using cisplatin, cytarabine, and caffeine for the treatment of pancreatic carcinoma prompted a phase II study using these agents and adding continuous intravenous infusion (CI) 5-fluorouracil (5-FU) (PACE). Patients with advanced pancreatic adenocarcinoma who had not received prior cytotoxic therapy were eligible. Treatment consisted of the following: on day 1, the administration of cisplatin 100 mg/m2 IV, cytarabine 2 g/m2 IV every 12 hours x 2 doses, and caffeine 400 mg/m2 subcutaneously after each cytarabine dose; and on days 3 to 21, 5-FU 250 mg/m2/day given by CI. Cycles were repeated every 28 days. Thirty eligible patients were entered in the study. The median number of cycles received was three. Grade IV neutropenia and thrombocytopenia occurred in 53% and 27% of patients, respectively. Among 30 treated patients, complete remission (CR) was seen in 2 patients and partial remission (PR) in 3 patients, for an overall response rate of 16.7% (95% confidence interval 6.8-32.4%). The median survival was 5.0 months (range: 0.3-32.4 months) and 16.7% and 10% of patients were alive at 1 and 2 years. respectively. Changes in the serum level of CA 19-9 provided an early marker of response which translated in differences in survival. Those with increasing or decreasing/stable levels of CA 19-9 after the first cycle of therapy had median survivals of 1.7 and 8.3 months, respectively (p = 0.0002). Although PACE chemotherapy produced durable responses in pancreatic cancer, the toxicity was substantial. A modification of this regimen with newer, less toxic drugs may provide better results and reduced toxicity. Also, the monitoring of the serum CA 19-9 level may provide a means to assess response and predict survival.

Gemcitabine and UFT plus oral calcium folinate: phase I study.

Gemcitabine (Gemzar) is a nucleoside analog increasingly used in the treatment of a variety of solid tumors. DNA synthesis is inhibited by gemcitabine by masked chain termination and via inhibition of ribonucleotide reductase. Synergy may exist between gemcitabine and other antimetabolites, including 5-fluorouracil. The varying patterns of dose-limiting toxicities to gemcitabine and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) permit their use in combination. The primary aim of this phase I study is to determine the maximum tolerated doses of gemcitabine and UFT plus oral calcium folinate in patients with a variety of solid tumors. Only eight patients have been recruited to date, with myelosuppression being the main toxicity observed.

The clinical significance of p21(WAF1/CIP-1) and p53 expression in pancreatic adenocarcinoma.

BACKGROUND: Wild-type p53 protein activates the WAF1/CIP-1 (p21) gene, leading to G1 arrest after DNA damage. The authors investigated the relation of p21 and p53 expression in pancreatic adenocarcinomas to disease stage, overall patient survival, and survival when chemotherapy or radiation therapy was given. METHODS: Paraffin embedded tissue sections of 75 ductal adenocarcinomas of the pancreas were immunostained for p53 and p21. Nuclear expression was scored as absent, focal (<10%), moderate (10-50%), or strong or diffuse (>50%). RESULTS: The median survival of patients whose pancreatic tumors expressed the p21 protein (43 of 75 cases, 57%) was better than that for patients whose tumors were p21 negative (32 of 75 cases, 43%) (median survival, 13.5 vs. 9.8 months, respectively; P = 0.23). No difference in survival was found with regard to p53 protein expression (43 of 75 cases, 57%); however, strong p53 expression was significantly associated with advanced disease stage (70% in Stage IV vs. 13-28% in lower stages). Expression of p21 correlated with earlier clinical stage. Stage specific comparisons showed a trend toward increased survival among p21 positive tumor patients diagnosed at clinical Stages I and III but not among those diagnosed at Stage IV. Adjuvant chemotherapy or radiation improved survival significantly if tumors expressed p21 or no p53. CONCLUSIONS: Expression of p21 is significantly associated with earlier clinical stage in pancreatic adenocarcinoma, perhaps accounting for the better survival observed in this patient group than among those whose tumors were p21 negative. Improved survival with either chemotherapy or radiation therapy was observed for patients whose tumors were p21 positive or p53 negative.

Relationship of family cancer history to the expression of p53, p21WAF-1, HER-2/neu, and K-ras mutation in pancreatic adenocarcinoma.

CONCLUSION: In our series of 81 cases, a history of family cancer was present in 52% of patients (42/81) with pancreatic cancer. Nine percent (7/81)had a family history of pancreatic cancer. Our studies suggest a possible relationship of family cancer history to the expression of p53 and p21WAF in pancreatic tumors, but show no relationship to the expression of HER-2/neu or to the prevalence of K-ras mutations. A lower incidence of p53 expression observed in patients with a family history of cancer suggests normal p53 protein is present in a majority of patients who develop pancreatic tumors related to other--as yet unidentified-inherited or familial risk factors. There was no significant difference in survival of pancreas cancer patients with and without a family history of cancer. However, survival in pancreas cancer patients may be influenced (improved) by p21WAF-1 expression. BACKGROUND: Pancreas cancer is the fifth leading cause of cancer deaths (27,800 deaths/yr) in the United States. Various risk factors, including cigarette smoking, high-fat diet, DDT exposure, chronic pancreatitis, and diabetes mellitus, have been associated with pancreatic carcinoma. A few studies have suggested a genetic predisposition or increased risk for pancreatic cancer within families, but the exact etiology is largely unknown. In a series of 81 patients with pancreatic carcinoma, we analyzed the status of K-ras gene mutations and the expression of P21WAF-1, p53, and HER-2/neu protein to identify possible molecular associations in pancreas cancer cases of these molecular markers to family histories of cancer and pancreas cancer. METHODS: Paraffin-embedded tissue sections from 81 cases of pancreatic adenocarcinoma were used for DNA extraction and immunohistochemical staining. K-ras mutation was studied by single-stranded conformation polymorphism (SSCP) and slot-blot allele-specific oligonucleotide (ASO) hybridization of PCR-amplified DNA product. Overexpression (aberrant expression) of p53, p21WAF-1, and HER-2/neu was documented by scoring nuclear localized p53, p21WAF-1 protein and cell membrane expression of HER-2/neu after immunostaining with gene product-specific monoclonal antibodies (MAbs). RESULTS: Forty-two (42) of 81 patients studied in this series had a history of cancer in their families (52%). Seven of those 42 had a history of pancreatic carcinoma (17% or 9% of total cases). The incidence of K-ras mutation and the expression of p21WAF-1 and HER-2/neu in patient groups with and without a family history of cancer was not statistically different (83 vs 74%, p = 0.416; 57 vs 41%, p = 0.184; and 83 vs 81%, p = 1.000, respectively). However, the incidence of p53 expression was significantly lower in patients with a family history of cancer (40 vs 72%, p = 0.007). There was no statistical difference in survival of patients with a family history of cancer in relation to either K-ras mutation, p53 expression, p21, or HER-2/neu expression. However, patients lacking a family history of cancer showed improved survival trends in relation to p21 expression (median survival of 16 vs 8 mo, p = 0.029).