A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer.

PURPOSE: To assess the effect of gemcitabine in patients with metastatic pancreas cancer that had progressed despite prior treatment with 5-FU. PATIENTS AND METHODS: Seventy-four patients were enrolled in this multicenter trial. Alleviation of cancer-related symptoms was the primary endpoint. Sixty-three patients completed a pain stabilization period and were treated with gemcitabine. Clinical Benefit Response was defined as a > or = 50% reduction in pain intensity, > or = 50% reduction in daily analgesic consumption, or > or = 20 point improvement in KPS that was sustained for > or = 4 consecutive weeks. RESULTS: Seventeen of 63 pts (27.0%) attained a Clinical Benefit Response (95% CI: 16.0%-38.0%). The median duration of Clinical Benefit Response was 14 weeks (range: 4-69 weeks). Median survival for patients treated with gemcitabine was 3.85 months (range: 0.3-18.0+ months). Therapy was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. CONCLUSION: Systematic assessment of subjective outcomes can be used to evaluate the clinical impact of new therapies for pancreas cancer, a highly symptomatic disease. Our findings suggest that gemcitabine is a useful palliative agent in patients with 5-FU-refractory pancreas cancer.

Phase II trial of gemcitabine in patients with advanced gastric cancer.

BACKGROUND: Approximately 22,000 new cases of gastric cancer are diagnosed each year in the United States, most of which are advanced disease and thus are not curable by surgery. Chemotherapy has had little impact on patient survival. Consequently, the evaluation of new agents is needed. Gemcitabine, a cytosine arabinoside analogue, was evaluated in a Phase II trial to assess its efficacy in previously untreated patients with advanced gastric cancer. METHODS: Patients were treated with weekly gemcitabine, 800 mg/m2, for 3 consecutive weeks, followed by a 1-week rest period. Eighteen patients were enrolled. Fifteen patients were evaluable for response; 2 patients refused therapy before the completion of one cycle of treatment, and one patient was found to have nonmeasurable disease. RESULTS: No major objective responses were seen. Two minor responses occurred. One patient with a minor response was removed from the study at his request after ten cycles of treatment. The other patient remains on the study with stable disease at more than 17 months. Toxicities on this study were mild. Median leukocyte count and platelet nadirs were 5.0 (range, 2.2-51.0) and 234,000/microliters (range, 59,000-554,000/microliters), respectively. CONCLUSION: Gemcitabine at this dose and schedule has no significant antitumor activity in gastric cancer.

Phase II trial of gemcitabine (2,2'-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas.

Gemcitabine is a novel nucleoside analog which demonstrated a broad spectrum of preclinical activity in solid tumor models, and responses in patients with pancreas cancer during phase I evaluation. Patients with measurable adenocarcinoma of the pancreas who had received no previous chemotherapy were eligible for this multicenter phase II clinical trial. Gemcitabine 800 mg/m2 was administered intravenously weekly for 3 consecutive weeks, followed by one week rest, every 4 weeks. Forty-four patients entered the trial; 35 had at least 2 cycles of therapy. Partial response was observed in 5 patients (11%, estimated 95% confidence interval 2-20%), with a median duration of 13 months. All responding patients had stabilization or improvement in performance status. Fourteen patients had stable disease of 4 or more months. The median WBC nadir was 3.8 x 10(3)/microliters (range 1.6-9.3) and the median absolute neutrophil (ANC) nadir was 2.0 x 10(3)/microliters (range 0.4-7.2). Thrombocytopenia - 100.0 x 10(3)/microliters was observed in 15 patients; the median platelet nadir was 123.0 (range 30.0-245.0). All patients experienced a mild to moderate flu-like syndrome. In addition, one patient had a mild hemolytic-uremic syndrome which appeared related to gemcitabine therapy. Gemicitabine demonstrated marginal activity in this resistant neoplasm, without excessive toxicity. Further evaluation, including the use of more intense dosing and/or combination therapy, is warranted.

Successful renal transplantation for Epstein syndrome.

Successful cadaveric renal transplantation was accomplished in a patient with Epstein syndrome, a triad of macrothrombocytopenia, partial high-frequency hearing loss, and nephritis, which often progresses to complete renal failure. The success of the transplant demonstrates that the macrothrombocytopenia which occurs in this syndrome is not a contraindication to aggressive management of end-stage renal disease.

Pyridoxal phosphate as an antisickling agent in vitro.

Although pyridoxal phosphate is known to inhibit gelation of purified hemoglobin S, antisickling activity has never been demonstrated for intact erythrocytes. We incubated washed erythrocytes at 37 degrees C either in buffer alone, or with added pyridoxal phosphate or pyridoxal, washed these cells, suspended them in untreated buffer, and compared the percent modified hemoglobin, the oxygen affinity, and the extent of sickling under hypoxia. Pyridoxal phosphate modified intracellular hemoglobin more slowly than pyridoxal. Pyridoxal phosphate lowered the oxygen affinity of normal cells, but had no effect on oxygen binding by sickle cells. Pyridoxal increased the oxygen affinity of normal and sickle erythrocytes equally. Pyridoxal phosphate significantly inhibited sickling of sickle or sickle trait erythrocytes (P less than 0.001). Inhibition of sickling by pyridoxal phosphate was largely independent of oxygen binding; whereas inhibition of sickling by pyridoxal was almost entirely dependent on increased oxygen binding. Although pyridoxal phosphate and pyridoxal both inhibit sickling by modification of hemoglobin S, they differ in the kinetics of whole cell modification, the effect on oxygen affinity of intact cells, and the mechanism of action of the antisickling activity.

Modification of intracellular hemoglobin with pyridoxal and pyridoxal 5'-phosphate.

The aldehyde forms of vitamin B6, pyridoxal and pyridoxal 5'-phosphate (PLP) have aroused interest as antisickling agents because of their ability to modify hemoglobin (Hb) and their low toxicity. To study their rate of formation and stability inside red cells, pyridoxal-Hb and PLP-Hb were measured in lysates from treated normal and sickle erythrocytes using isocratic high pressure liquid chromatography on Bio-Rex 70. The validity of this assay was confirmed by isoelectric focussing, fluorescence scans of reduced globin, and treatment of cells with pyridoxal 14C. Optimal conditions were described for treatment of whole blood with pyridoxal and washed erythrocytes with PLP. Although there was competition between 2,3-DPG and PLP, but not pyridoxal, for binding to Hb, depletion of 2,3-DPG prior to treatment was unnecessary. No special requirements were noted for the anticoagulants or buffers used. Sickle erythrocytes formed PLP-Hb more rapidly than normal erythrocytes, but pyridoxal-Hb appeared at the same rate in both types of erythrocytes. During incubation of treated erythrocytes in untreated plasma, the stability of pyridoxal-Hb varied inversely with the hematocrit, but PLP-Hb was stable at all hematocrits tested. The absence of hemolysis during a 4 day incubation of treated normal red cells implies that treatment with pyridoxal or PLP did not severely impair red cell metabolism.

Inhibition of erythrocyte sickling in vitro by pyridoxal.

To test the antisickling activity of pyridoxal, we compared the oxygen affinity and the percent sickling at low PO2 of untreated erythrocytes with values for cells from the same blood sample incubated with pyridoxal, glyceraldehyde, or pyridoxine. Pyridoxal increased oxygen affinity much more than glyceraldehyde. 20 mM pyridoxal and glyceraldehyde had equivalent antisickling activity. At PO2 levels above 20 mm Hg, both agents reduced sickling to less than 2%. In samples examined by electron microscopy, pyridoxal reduced the percent sickled cells and the percent cells that contain hemoglobin S fibers by the same amount (from 74 to 3%). Pyridoxine had no effect on oxygen affinity or sockling. Pyridoxal reacts with intracellular hemoglobin to increase oxygen affinity, which inhibits hemoglobin S polymerization and sickling.