Immune response induced in small-cell lung cancer by maintenance therapy with interferon gamma.

BACKGROUND: Chemotherapy, with or without radiotherapy, results in a 30%-40% complete response rate in small-cell lung cancer (SCLC), but approximately 90% of patients who have complete remission die within 2 years after relapse with chemoresistant disease. Randomized clinical studies of maintenance chemotherapy after complete response have failed to demonstrate survival advantage. However, studies have shown that the human cytokine interferon gamma (IFN-gamma) induces immune response in humans, including T-cell activation and expression of class II major histocompatibility complex (HLA-DR) and receptor for the Fc portion of immunoglobulin on monocytes. It has also been demonstrated that recombinant IFN-gamma (rIFN-gamma) induces immunomodulation and has antiproliferative activity. PURPOSE: In vivo effects of rIFN-gamma treatment were characterized by flow cytometric analysis of peripheral blood mononuclear cells in patients with SCLC who received rIFN-gamma as maintenance treatment. METHODS: After induction chemotherapy and radiotherapy, 100 patients who achieved a complete remission were randomly assigned to receive rIFN-gamma at a dose of 0.2 mg (4 x 10(6) units) once a day, subcutaneously, for 6 months, or observation only. In 31 patients, peripheral mononuclear cells were obtained prior to the study and at weeks 4, 8, and 12 for serial monitoring of immune response. By flow cytometric analysis, we identified the lymphocyte and monocyte populations using characteristic differences in electronic volume and right-angle scatter. In these populations, we determined the mean fluorescence channel after staining for CD14 (antigen expressed on monocytes), CD3 (antigen expressed on T lymphocytes), and HLA-DR (HLA class II expressed by monocytes and activated lymphocytes). To determine the number of Fc receptors per cell, an Fc receptor assay was performed using the monocyte cell line U937 as a standard. RESULTS: At weeks 4, 8, and 12, expression of HLA-DR and Fc receptors on monocytes in patients who received rIFN-gamma was significantly higher than that in untreated patients, and the difference was statistically significant. The number of Fc receptors per monocyte consistently increased during the rIFN-gamma treatment and reached a fivefold elevation at week 12. There was no statistically significant difference in lymphocyte surface antigen expression between the treated and untreated groups. CONCLUSION: The dose of rIFN-gamma used in this study resulted in immune stimulation in patients with SCLC who had complete remission after induction therapy. The in vivo immunomodulatory activity of rIFN-gamma in such patients is characterized by a strong monocyte activation but no significant alteration in T-cell activation.

Prophylactic cranial irradiation in complete responders with small-cell lung cancer: analysis of the Mayo Clinic and North Central Cancer Treatment Group data bases.

PURPOSE: To determine whether prophylactic cranial irradiation (PCI) has an impact on brain failure and survival in patients with small-cell lung cancer (SCLC) who have achieved a complete response to chemotherapy with or without thoracic radiation therapy (TRT). METHODS: Between 1975 and 1990, the Mayo Clinic and North Central Cancer Treatment Group entered 1,617 patients on 15 phase II and III SCLC protocols of chemotherapy with or without TRT and PCI. RESULTS: Of 772 patients with limited disease, 457 (59%) achieved a complete response, compared with 200 of 845 patients (24%) with extensive disease. With follow-up durations of 2 to 17 years (median, 4), the median survival time and 2-, 5-, and 10-year survival rates for the 457 completely responding limited-disease (LD-CR) patients were 19.6 months, 41%, 17%, and 5%, compared with 13.9 months, 26%, 8%, and 5%, respectively, for the 200 completely responding extensive disease (ED-CR) patients (P = .0001). Multiple prognostic factors, including whether the patient did or did not receive PCI (30 to 38 Gy in 2- to 3.6-Gy fractions) were analyzed. In both univariate and multivariate analyses, PCI was not associated with improved (or worsened) survival. The brain relapse rate was 37% for LD-CR patients who did not receive PCI versus 9% for those who did (P = .0001). In ED-CR patients, the brain relapse rate was 31% without PCI and 8% with (P = .009). Essentially all patients who developed brain relapse died within 2 years, with a median survival time of 3.7 months following relapse. Severe, life-threatening, or fatal CNS toxicity occurred in approximately 3% of patients who received PCI. CONCLUSION: The use of PCI remains controversial outside the setting of a clinical trial.

Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer.

PURPOSE: We evaluated the effect of recombinant interferon gamma (rIFN-gamma) on survival and toxicity in small-cell lung cancer (SCLC) patients in complete remission (CR). PATIENTS AND METHODS: One hundred patients in CR following treatment with six cycles of combination chemotherapy, thoracic radiotherapy (TRT), and prophylactic cranial irradiation (PCI) were studied. All patients had been enrolled onto a cooperative group trial (North Central Cancer Treatment Group [NCCTG] 86-20-51). Patients received observation only or rIFN-gamma at a dose of 4 x 10(6) U subcutaneously per day for 6 months. RESULTS: Six patients (12%) did not comply with rIFN-gamma treatment. Substantial nonhematologic toxicities consisting of chills, myalgia, lethargy, and alteration of mood-personality were observed. No patient experienced life-threatening or fatal toxicity. The median times to progression for rIFN-gamma treatment or observation were 6.9 and 8.1 months (P = .54). The median survival times were 13.3 and 18.8 months, respectively (P = .43). Approximately 70% of all patients relapsed within 2 years. CONCLUSION: Time to progression and survival were inferior in patients treated with rIFN-gamma compared with randomized control subjects, although this difference was not statistically significant. These data indicate that rIFN-gamma treatment is not associated with a 33% improvement in survival (P = .04). Because of the high rate of relapse, SCLC patients in CR are an ideal group in which to evaluate novel and minimally toxic agents.

Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer.

PURPOSE: Hydrazine sulfate, an agent that appears to inhibit gluconeogenesis, has been studied in cancer patients for approximately 20 years. There was a recent resurgence of interest in this drug when subset analysis of a small placebo-controlled, double-blind, clinical trial reported improved survival among non-small-cell lung cancer patients with a good performance status who were randomized to receive this drug along with standard chemotherapy. PATIENTS AND METHODS: Patients on this trial had newly diagnosed, unresectable non-small-cell lung cancer and were treated with cisplatin and etoposide. In addition, they were randomized to receive hydrazine sulfate or placebo in a double-blind manner. RESULTS: A total of 243 patients were randomized. Response rates were similar in the two treatment arms. There were trends for worse time to progression and survival in the hydrazine sulfate arm. No significant differences were noted in the two study arms with regard to toxicity or quality of life (QL). CONCLUSION: This trial failed to demonstrate any benefit for patients who received hydrazine sulfate.

Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial.

PURPOSE: The combination of etoposide (E) and cisplatin (P) is an accepted standard therapy for small-cell lung cancer (SCLC); however, the optimal sequencing and administration schedule has not been defined. This study was designed to evaluate different sequencing and administration schedules of E and P in the treatment of SCLC. PATIENTS AND METHODS: Five hundred fifty-two eligible patients with limited-(LD) and extensive-stage (ED) SCLC were randomized to receive one of the following regimens: arm A, P 30 mg/m2 by intravenous (IV) bolus followed by E 130 mg/m2 bolus; arm B, E 130 mg/m2 bolus followed by P 30 mg/m2 bolus; arm C, E 130 mg/m2 by 24-hour infusion and P 30 mg/m2 bolus at the end of each 24-hour infusion of E; arm D, E 130 mg/m2 by 24-hour infusion and P 45 mg/m2 by 24-hour infusion on day 2 and 3 only. Two 3-day induction cycles of IV EP were administered 4 weeks apart. Subsequent therapy was the same for all arms, consisting of four cycles of cyclophosphamide, doxorubicin, and vincristine (CAV) at 4-week intervals. Consolidative thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) were administered to responders. RESULTS: The overall response rate (84%) was similar in all treatment arms. Treatment arm A was associated with the best complete response (CR) rate (52%), the most favorable median survival time (MST) of 15 months, and a 26% 2-year survival rate. Patients with LD on arm A had a MST of 20 months and a 42% 2-year survival rate. Multivariate analysis indicated that extent of disease, performance status, arm of therapy, and sex were significant independent factors influencing survival. Toxicity of the four regimens was similar, except for greater thrombocytopenia on arm D. CONCLUSION: The bolus administration of EP with E following P for the first two cycles of chemotherapy was the most effective regimen, with especially encouraging survival for LD patients.

Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: a North Central Cancer Treatment Group study.

PURPOSE: Megestrol acetate has been reported to improve appetite and quality of life and to decrease nausea and vomiting in patients with cancer anorexia/cachexia. The present trial was formulated to evaluate the impact of megestrol acetate on quality of life, toxicity, response, and survival in individuals with extensive-stage small-cell lung cancer who received concomitant chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive megestrol acetate 800 mg/d orally or placebo. In addition, all patients were scheduled to receive a maximum of four cycles of cisplatin and etoposide chemotherapy. Quality of life was self-assessed at entry onto study, with every cycle of chemotherapy, and 4 months thereafter with a linear visual analog scale. Toxicity was evaluated by patient questionnaire and investigator reports. RESULTS: A total of 243 eligible patients were randomized. Those who received megestrol acetate had increased nonfluid weight gain (P = .004) and significantly less nausea (P = .0002) and vomiting (P = .02). Significant thromboembolic phenomena occurred more often in patients who received megestrol acetate versus placebo (9% v 2%, P = .01). Patients who received megestrol acetate had more edema (30% v 20%, P = .002), an inferior response rate to chemotherapy (68% v 80%, P = .03), and a trend for inferior survival duration (median, 8.2 v 10.0 months, P = .49). These findings may have been influenced by a poorer quality of life of the megestrol acetate group at study initiation. There were no significant changes in quality of life scores over time between either of the study arms. CONCLUSION: Megestrol acetate cannot be routinely recommended for all patients with small-cell lung cancer at the time of chemotherapy initiation. Rather, its therapeutic ratio may be more favorable for patients with problematic cancer anorexia/cachexia.

Significance of neuron-specific enolase levels before and during therapy for small cell lung cancer.

The level of serum neuron-specific enolase (NSE) has been implicated as a prognostic factor for patients with small cell lung cancer (SCLC). A prospective evaluation was undertaken to assess the prognostic significance of pretreatment NSE and treatment-induced minimum NSE values in patients with SCLC. Patients from two Phase III North Central Cancer Treatment Group trials [one for patients with extensive stage SCLC and one for patients with limited stage SCLC] were asked to enter this laboratory correlational trial. Both trials included treatment with four to six cycles of etoposide and cisplatin, and 121 patients (71 extensive stage SCLC and 50 limited stage SCLC) were entered into the present study of NSE. Pretreatment NSE values and treatment-induced minimum NSE values were independent predictors of time to progression and survival in multivariate analysis. Hazard rate modeling allowed the formulation of specific relationships of NSE to time to progression and survival. Pretreatment NSE levels inversely correlated with time to progression and survival in these patients with SCLC. Pretreatment NSE accounted for 28% of the variance in survival. Both pretreatment NSE and treatment-induced minimum NSE were independent prognostic predictors of time to progression and survival.

Systemic candidiasis in cancer patients.

Two hundred thirty-five fungal infections occurred in patients with malignant diseases over a four-year period. One hundred eighty-eight were due to Candida species and Torulopsis glabrata and are reviewed herein. The frequency was highest in patients with acute leukemia (11.9 per 100 registrations) with a frequency of 0.8 per 100 registrations in all cancer patients at this institution. Three or more predisposing factors were present in more than 50 percent of the cases; antecedent myelosuppression, chemotherapy, and antibiotic therapy were most common. Blood cultures were positive in only 35 percent of patients with disseminated candidiasis. Twenty-nine of 55 patients (53 percent) had candidemia without identifiable organ infection recovered. Eleven were given no systemic antifungal therapy and recurrence of infection was documented in two patients. Only six (4.5 percent) of 133 patients with proved deep organ infections recovered. Respiratory failure was the clinical cause of death in 62 percent of patients. Clinical features, cultures, and serologic tests were usually of no assistance in establishing the diagnosis early in the course of the infection.

Phase II trial of topotecan for the treatment of mesothelioma.

The North Central Cancer Treatment Group designed a phase II trial to assess the efficacy and toxicity of topotecan in patients with unresectable malignant pleural mesothelioma. Twenty-two previously untreated patients with unresectable pleural mesothelioma and good performance status (Eastern Cooperative Oncology Group performance status 0, 1, or 2) were enrolled on this trial from October 1993 through July 1994. Nineteen men and three women, median age 66 years (range, 44-78 years), were treated with topotecan 1.5 mg/m2 intravenously over 30 minutes daily for 5 days at 3-week intervals until toxicity, progression of disease, or a patient decided to discontinue treatment. There were seven patients with measurable disease and 15 with evaluable disease; all were assessable for response and toxicity. A total of 113 cycles of treatment were given, for a median of three cycles (range, 1-26 cycles). Myelosuppression was the most frequent toxicity. Eighteen of 21 patients (86%) experienced grade 3 or 4 neutropenia during the initial treatment cycle. The median neutrophil nadir was 0.5 x 10(3)/microl (range, 0.1-1.6 x 10(3)/microl), and the median platelet nadir was 127 x 10(3)/microl (range, 18-460 x 10(3)/microl). Other toxicities more than grade 2 included malaise (two patients), and anorexia, infection, fever, pulmonary, and cardiac in one patient each. There were no objective responses, and 18 patients had stable disease for a median of 74 days. The median survival for all patients was 230 days, with 23% alive at 1 year. Topotecan as administered in this trial is reasonably well tolerated; however, the response rate was insufficient to warrant additional study in pleural mesothelioma.

Growth of malignant histiocytic cells induced by phorbol myristate acetate.

Cells from the spleen of a patient with malignant histiocytosis were cultured in methyl cellulose with and without 100 ng/mL of phorbol myristate acetate (PMA). Colony growth occurred only with PMA; comparing surface marker studies of the cells before and after culture, it was evident that proliferation had occurred among the histiocytic cells as well as the lymphocytes. After exposure to PMA in organ culture for ten days, the histiocytes appeared to be differentiated and showed evidence of continuing phagocytosis by electron microscopy. This suggests that PMA is a mitogen for the histiocytes in this condition and maintains differentiation of the cells.

Lymphoid colony growth with phorbol myristate acetate and lymphocyte-conditioned media in chronic lymphocytic leukemia and malignant lymphomas.

Cell preparations from 49 cases of lymphoid malignancy were cultured to determine optimal culture conditions (in semisolid media). Colony growth was obtained in the majority of cases (73%) using the combination of phorbol myristate acetate (PMA) and lymphocyte-conditioned medium (L-CM). Cell surface marker studies of plated cells in 36 cases identified 31 to be B-cell type, 1 to be T-cell type, and 4 null-cell type. The morphology and markers of harvested cells were similar to plated cells, suggesting proliferation of neoplastic cells predominantly. A relationship was found between the degree of colony growth and the clinical course of the disease in lymphomas but not in chronic lymphocytic leukemia (CLL). The use of PMA in combination with other mitogens deserves further investigation as a colony growth stimulator in hemopoietic malignancies.

Interferon instillation for malignant pleural effusions.

BACKGROUND: Malignant pleural effusions can be managed in various ways including instillation of antineoplastic agents. Instillations of alfa interferon-2b (IFN-alpha 2b) have been utilized with success in various loco-regional malignancies suggesting a possible role in management of pleural effusions. This trial was designed to evaluate the tolerability and efficacy of intrapleural IFN-alpha 2b instillations in this situation. PATIENTS AND METHODS: Twenty-three patients with cytologically proven malignant pleural effusions were given IFN-alpha 2b 50 x 10(6) units in 50 ml normal saline (NS) by intrapleural instillation after partial or complete clearance of effusions by percutaneous aspiration or chest tube drainage. For persistent or recurrent effusions, instillations were repeated with dose escalation to 75 x 10(6) units. Patients were assessed and monitored by regular clinical examinations, chest radiographs, biochemical and hematological parameters and assays of lymphocyte subpopulations until relapse or death in each case. RESULTS: Fourteen of 20 evaluable patients (70%) had responses lasting for a median of 6 months; there were 8 complete responses (CR) and 6 partial responses (PR). In 6 CR patients the effusions did not recur after the first instillation. In 2 of 6 other patients, the second instillation was successful in inducing CR. Intrapleural instillation of IFN-alpha 2b was well tolerated, no grade 4 toxicities were encountered. There were no significant effects on any of the studied parameters at the initial dose level; however, grade 3 neutropenia occurred with the escalated dose. The most common toxicity was flu-like syndrome, after 70% of the instillations. CONCLUSIONS: Intrapleural instillation of IFN-alpha 2b produced an encouraging response rate without significant toxicities. This approach may warrant additional phase II or phase III comparative clinical studies.

Pharmacokinetics of ketoconazole in patients with neoplastic diseases.

Twenty-seven patients with advanced malignancies were given 200 mg of ketoconazole orally every 6 or 12 h. Blood samples were collected during these intervals and after the last dose to determine plasma concentrations and half-lives. The mean plasma concentrations measured after the initial dose were 1.7 +/- 1.1 microgram/ml at 2 h, 0.9 +/- 0.2 microgram/ml at 6 h, and 0.7 +/- 0.4 microgram/ml at 8 h. Plasma concentrations rose significantly in patients on the every-6-h schedule. Concentrations were more variable in patients on the every-12-h schedule, and changes in mean plasma concentrations after 7 and 14 days were not significant. Half-lives ranged from 1.3 to 11.6 h in individual patients. The mean half-life for all patients studied was 3.7 +/- 0.6 h on day 1. The calculated area under the curve was 12.0 +/- 4.7 micrograms-h/ml on day 1; it increased after 7 and 14 days of administration (every-6-h schedule), suggesting plasma binding or wide drug distribution or both. Saturation of storage compartments is also suggested. Less than 1% of the administered dose was recoverable as active drug from the urine over 6 h.

Age-related prognostic factor analysis in non-Hodgkin's lymphoma.

BACKGROUND: Age is known to have an important influence on survival in non-Hodgkin's lymphoma (NHL). This observation and the relationship of age to other prognostic factors are of interest in designing treatment programs for these patients. This study was conducted to investigate the relationship of age to other known prognostic variables and survival in NHL. PATIENTS AND METHODS: Data on clinical features, treatment, response, survival and cause of death from 547 patients with NHL diagnosed between 1980 and 1989 were collected and analyzed by age group. Multivariate analysis of prognostic factors and a survival comparison to an age and sex matched control population were performed. RESULTS: Survival curves for 5-year age groups up to and including age 60-64 years were similar, after which a major effect of age upon survival was apparent. When groups aged < 65 years and > and = 65 years were compared, there were similar proportions of most known prognostic factors, except for a higher proportion with increased lactate dehydrogenase (LDH) levels and extranodal disease in older patients. When analyzed by age group, older patients had a lower response rate to initial therapy and salvage treatments. In younger patients, several recognized prognostic variables were found to lack significance. CONCLUSIONS: Prognostic variables differ between younger and older patients with NHL. Age, histology, LDH elevation and gender are less important in younger patients; only bulky disease is more important than in older patients. A lower response rate, poor response to salvage therapy and excess mortality, often due to concurrent diseases, were apparent in older patients. Age is a significant prognostic factor only in patients age > and = 65 years.

Distinct B-cell clonal bands in Helicobacter pylori gastritis with lymphoid hyperplasia.

Helicobacter pylori (Hp)-associated gastritis is a risk factor for gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Clonal B-cell populations are present in both reactive and neoplastic MALT tissue, thus limiting their usefulness in the evaluation of gastric lymphoid infiltrates in endoscopic biopsy specimens. The aim of this study was to identify the presence of clonal B-cell populations in Hp-gastritis with MALT and to assess their usefulness in distinguishing reactive from malignant infiltrates. Routinely fixed paraffin-embedded blocks from 20 patients with Hp-gastritis with lymphoid hyperplasia were analysed for B-cell clonality by a semi-nested polymerase chain reaction (PCR) using FRIII/LJH and FRIII/VLJH primers for amplification of the VDJ region of the immunoglobulin heavy chain gene. The histopathological findings were evaluated according to a previously published scoring system. Immunohistochemistry was performed by the labelled streptavidin-biotin technique using the following primary antibodies: CD45, CD45RO, CD3, CD20, and cytokeratin. The histopathological findings were diagnostic of Hp-chronic active gastritis (grade 2, n=17; grade 3, n=3). Scattered intraepithelial B-cells were present in all cases and non-destructive lymphoepithelial lesions in one grade 3 case. Amplifiable DNA was obtained from all samples. Clonal bands were observed in ten (7/17 grade 2 and 3/3 grade 3 lesions) and polyclonal smears in ten cases (all grade 2). The clonal bands were often (n=6) associated with a background polyclonal smear and were not reproducible from deeper sections (n=10) or another paraffin block (n=1), while the clonal bands in control low-grade MALT lymphomas were not associated with a background smear and were reproducible from deeper sections. None of the patients has developed lymphoma to date (follow-up 21-44 months). In conclusion, B-cell clonal bands are common in H. pylori-gastritis with lymphoid hyperplasia. The irreproducibility of these bands is a useful feature in favouring a reactive process.

Establishment of cell lines derived from chronic lymphocytic leukaemic cells by transfection with myc and ras.

Seventy-one samples from 37 cases of chronic lymphocytic leukaemia (CLL) were transfected with human c-myc and/or N-ras. In only three cases did the CLL cells further transform and four cell lines were established following transfection with myc plus ras. Surface marker profiles and immunoglobulin gene rearrangement studies confirm that all cell lines have arisen from the original CLL cells. The cell lines are EBNA positive but negative for EBV latent membrane protein (LMP). Karyotyping of the cell lines is as follows: SA4, 46,XY; SA4-2, 45,XY, 20; RK4, 48,XY,+ 5,+ 12; EHC4, 47,XY, t(14;18)(q32;q21), + 12. Although the majority of CLL cells appear resistant to transformation in vitro with myc and ras with the methods used, it does occur in a small percentage (about 8%). There appeared to be no correlation between the ability to transform in vitro and clinical behaviour.

Non-Hodgkin's lymphoma in Saskatchewan. A review of 10 years' experience.

BACKGROUND: The incidence and treatment of non-Hodgkin's lymphoma (NHL) have changed in recent years. This study was intended to compare current features with a previous study (1966-1975) and assess the impact of these changes in our jurisdiction. METHODS: Clinical features and treatment of 547 patients with NHL registered at our center from January 1980 through December 1989 were reviewed, including reassessment of histologic type in each patient. Multivariate analysis of potential pretreatment prognostic factors was performed using the Cox proportional hazards model, and survival was analyzed in relation to treatment outcome. RESULTS: This review includes virtually all incident cases of NHL in a defined geographic area, representing an average annual incidence of 11.3/100,000 population. The male-to-female ratio was 1.1:1, median age was 65 years (range, 4-92 years). Median survival time (MST) of 482 patients with disease diagnosed antemortem was 4.8 years (95% confidence interval [CI], 3.7-6.1 years), 52% of whom have died. Thirty-nine percent of patients with disease classified by the International Working Formulation (IWF) had low-grade disease (MST, 103 months); 27% had intermediate disease (MST, 62 months), and 30% had high-grade disease (MST, 35 months). Sixteen percent of patients had associated neoplasms: 4 acute leukemias, 35 skin cancers, and 37 miscellaneous solid tumors. Results of radiation therapy (RT), chemotherapy (CT), and combined CT/RT were analyzed. Survival correlated strongly with responsiveness to treatment. Considering all patients treated with CT, anthracycline-containing CT was associated with the highest response rate, and survival time (more than 48 months) may have been affected by the addition of this agent. A survival advantage for patients with bulky Stage I and II disease treated with consolidative RT after CT is suggested, but not for more advanced stage disease. The proportional hazards model identified histologic type, disease stage, patient age, hemoglobin level, lactate dehydrogenase (LDH) level, bulky abdominal disease, and systemic "B" symptoms as significant independent prognostic factors influencing survival. CONCLUSIONS: The incidence of NHL has increased, and the survival of patients with high-grade disease has improved significantly since the previous study. A high incidence of other associated malignancies was demonstrated in this group of patients with NHL. Recognition of prognostic factors should permit a rational application of innovative treatments for patients in unfavorable prognostic categories.

Disposition of 5-fluorouracil during chronic hepatic arterial infusion to patients with carcinoma in the liver and effect on circulating platelets.

5-Fluorouracil was administered by continuous hepatic intra-arterial infusion to eight patients with the diagnosis of cancer of the gastrointestinal tract and hepatic metastases. Its elimination characteristics were investigated to see if they correlated with therapeutic effect or reduced clinical toxicity when the drug was given by this route. Urinary excretion of drug and metabolites was similar to findings after intravenous bolus doses. Disposition changes could not be correlated with therapeutic effect or clinical toxicity. A dose-related biphasic effect of 5-fluorouracil was found on circulating platelets. Doses greater than 6 mg kg-1 d-1 decreased the number of circulating platelets, while doses less than that resulted in an increase in circulating platelets. Further studies are required to determine the mechanism of the effect of 5-fluorouracil on platelets.

Pharmacokinetics of cefoperazone in patients with neoplastic disease.

The pharmacokinetics of cefoperazone, a new semisynthetic cephalosporin, were studied in 34 patients with neoplastic disease. This compound was administered in a variety of doses and schedules without observable toxicity in any patient. The mean peak serum concentration after a 15-min intravenous infusion of 2 g was 264 microgram/ml after the first dose; the serum half-life was 2.1 h. There was no significant change in half-life or serum concentrations after 4 or 7 days of therapy. The mean peak serum concentration after infusion of 1 g over 15 min was 133 microgram/ml, with a mean of 10.7 microgram/ml at 6 h. The serum half-life was 2 h. The mean peak serum concentration after infusion of 1 g over 0.5 h was 101 microgram/ml. When 8 g was subsequently administered daily by a continuous infusion schedule, levels were maintained at 80 microgram/ml. When the dose was increased to 16 g daily, serum concentrations were maintained at an average of 153 microgram/ml. Only 37% of cefoperazone was recovered in the urine in a 12-h period after the initial dose, suggesting the importance of other mechanisms of excretion; however, serum concentrations in one patient with renal insufficiency were significantly higher than serum concentrations in patients with normal renal function.