Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy.

I.V. fluid therapy does not result in the extracellular volume distribution expected from Starling's original model of semi-permeable capillaries subject to hydrostatic and oncotic pressure gradients within the extracellular fluid. Fluid therapy to support the circulation relies on applying a physiological paradigm that better explains clinical and research observations. The revised Starling equation based on recent research considers the contributions of the endothelial glycocalyx layer (EGL), the endothelial basement membrane, and the extracellular matrix. The characteristics of capillaries in various tissues are reviewed and some clinical corollaries considered. The oncotic pressure difference across the EGL opposes, but does not reverse, the filtration rate (the 'no absorption' rule) and is an important feature of the revised paradigm and highlights the limitations of attempting to prevent or treat oedema by transfusing colloids. Filtered fluid returns to the circulation as lymph. The EGL excludes larger molecules and occupies a substantial volume of the intravascular space and therefore requires a new interpretation of dilution studies of blood volume and the speculation that protection or restoration of the EGL might be an important therapeutic goal. An explanation for the phenomenon of context sensitivity of fluid volume kinetics is offered, and the proposal that crystalloid resuscitation from low capillary pressures is rational. Any potential advantage of plasma or plasma substitutes over crystalloids for volume expansion only manifests itself at higher capillary pressures.

Effect of very high-dose thymidine infusions on leukemia and lymphoma patients.

The physiological pyrimidine nucleoside thymidine (dThd) is cytotoxic to normal and neoplastic cells in culture that are exposed to concentrations in excess of 1 mM for prolonged periods. In order to explore the antileukemic potential of the compound, we have treated six patients with relapsed leukemia or lymphoma with marrow and blood involvement, by prolonged infusions of dThd, at dosages of 90 to 240 g/sq m/day for 14 to 29 days. Mean plasma dThd concentration ranged from 3.8 to 5.5 mM. Cerebrospinal fluid levels were measured on three occasions and ranged from 2 to 23.5% of simultaneous plasma levels. Diarrhea was dose limiting in one patient. The other side effects included nausea and vomiting in all patients, hepatotoxicity in two patients, electrolyte imbalance in one, progression of a pericardial effusion to tamponade in one, and mild central nervous system toxicity in five. In all cases, this therapy produced bone marrow aplasia. One patient with acute lymphoblastic leukemia, refractory to prior treatment, achieved a complete remission which lasted for 16 weeks. Another patient with lymphoblastic lymphoma had a greater than 50% reduction in his mediastinal mass which lasted for less than 1 month. At multiple points during therapy, the bone marrow S-phase fraction was measured by flow cytometry and autoradiography. In five patients, the proportion of cells in S phase increased during the first few days of the infusion but then returned to base line, concomitant with an overall reduction in the number of bone marrow blasts. Cytoreduction was evaluated by the technique of W. Hiddemann, B. D. Clarkson, T. Buchener, M. R. Melamed, and M. Andreeff (Blood, 59: 216-225, 1982). The magnitude of tumor cell kill ranged from 0.7 to 3.6 logs of blasts/cu mm of bone marrow. The data demonstrate that dThd is able to induce a complete remission in a patient with acute leukemia previously refractory to treatment. However, because of the very large drug quantities, fluid volumes, and the prolonged course required to produce the necessary tumor cell kill, this treatment approach is too impractical to be used extensively.

Phase I and pharmacological studies of pentamethylmelamine administered by 24-hour intravenous infusion.

A Phase I study of pentamethylmelamine (PMM) was conducted, administering the drug as a 24-hr i.v. infusion once weekly for 3 weeks. Doses ranged from 80 to 3000 mg/sq m/week. Twenty-six evaluable patients received a total of 30 courses of PMM. The median performance status of the patients was 60% (range, 40 to 90%), and the median age was 58 years (range, 43 to 72 years). The highest tolerated dose was 2000 mb/sq m/week. Nausea and vomiting were the dose-limiting toxicities; myelosuppression was neither consistent nor severe. One objective response lasting 10 months was noted in a patient with renal cancer. Pharmacokinetic studies using [ring-14C]PMM demonstrated a postinfusion half-life of 14C of approximately 12 hr, with the majority of the radiolabel excreted in the urine. PMM was introduced as a parenteral form of hexamethylmelamine. The present schedule does not permit administration of PMM in a dose greater than the tolerated dose of hexamethylmelamine and does not appear to offer an advantage over the p.o. use of the parent compound.

Biochemical, pharmacological, and phase I clinical evaluation of pseudoisocytidine.

Pseudoisocytidine (psi ICyd) is a C-nucleoside with enhanced stability and resistance to enzymatic deamination when compared to 5-azacytidine and 1-beta-D-arabinofuranosylcytosine. Elimination kinetics in plasma using [14C]psi ICyd showed a beta-phase for t1/2 for 14C of 2 hr and a beta-phase t1/2 of unchanged psi ICyd of 1.5 hr. Net recovery of radioactivity in urine over 24 hr varied between 40 and 80% of the administered dose; 50 to 90% was unchanged drug and the rest was pseudouridine. Human leukemic cells in vitro deaminated psi ICyd very slowly, formed appreciable quantities of pseudoisocytidine triphosphate, and incorporated small amounts into RNA and DNA. Clinical trials were done using a daily i.v. injection for 5 consecutive days. Hematological or intestine toxicities were not seen, nor was depression of white blood cell count observed in leukemic patients. Hepatic toxicity proved to be dose limiting; this was characterized by an early phase with elevation of prothrombin time and aspartate aminotransferase. A later phase with cirrhosis was observed in two patients. Autopsy showed massive hepatic necrosis in patients dying of acute toxicity and micronodular cirrhosis in one patient dying with the chronic form.

Combination chemotherapy with cis-diamminedichloroplatinum and vinblastine in advanced non-small cell lung cancer.

Twenty-seven patients (25 males and 2 females) with histologically confirmed, unresectable, or metastatic non-small cell lung cancer were entered on a combination chemotherapy protocol including cisplatinum and vinblastine sulfate (DDP)(VLB). Patients had to have measurable disease as defined by the presence of two clearly measurable perpendicular diameters, be untreated with either chemotherapy or radiation therapy, and give informed consent to be eligible for study entry. The median age was 57 yr and the median performance status was 70 (Karnofsky scale); 10 patients had epidermoid carcinoma, 9 adenocarcinoma, 4 large cell carcinoma, and 4 undifferentiated carcinoma. All patients had intrathoracic disease, 12 also had extrathoracic lymph node involvement, 8 bone involvement, 2 liver metastasis, and 2 central nervous system metastasis prior to beginning chemotherapy; 9 patients had involvement of one site, 12 of two sites, 5 of three sites, and 1 of four sites. Cisplatinum was given as a short intravenous infusion of 120 mg/m2 on days 1 and 28, and then every 6 wk. Vinblastine was administered as an intravenous injection of 8 mg/m2 on days 1, 14, and 28, and then every 3 wk. Patients were evaluated prior to each course of cisplatinum. If progression occurred, therapy was discontinued. If stabilization or response was noted, then therapy was continued until intolerable toxicity or progression supervened. Every patient entered is considered evaluable for toxicity and response. There were no complete remissions; 14 patients achieved a partial response, 3 had a minimal response, 5 had stabilization of their disease, 1 had disease progression, and 4 are considered to have had drug deaths. Responses were seen after the first cisplatinum course in 13 patients and after the second in 1. Toxicities seen were universal nausea and vomiting; elevation of creatinine occurred in 6 patients, ranging from 2.1 to 14.6 mg/dl, and was clinically significant in 2 patients. Myelosuppression, with a leukocyte nadir of less than 3.0 X 10(9)l in 10 cases and platelet nadir of less than 100.0 X 10(9)l was seen in 5 cases and partial hearing deficit occurred in 2 patients. Median survival was 22 wk for the whole group (24 wk for the whole group if the 4 early drug deaths are excluded). Median survival was 26 wk for responding patients and 13 wk for nonresponding patients (remains the same if the early deaths are excluded from the latter group).(ABSTRACT TRUNCATED AT 400 WORDS)

High-dose cisplatin and vinblastine infusion with or without radiation therapy in patients with advanced non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) patients with locally advanced or metastatic measurable disease were given a combination of cisplatin, 200 mg/m2 divided in five daily doses, and simultaneously, vinblastine, 7.5 mg/m2 as a continuous intravenous (IV) infusion over five days. Five courses of chemotherapy were planned. Afterwards or on progression, patients were randomized to receive maximally tolerated radiation to all sites of disease v observation only. Forty males and seven females were entered. Median age was 60 years (range, 37 to 74), median Karnofsky performance status was 70 (range, 30 to 90). Five patients had previous brain radiation therapy for metastatic disease, all others were previously untreated. Side effects in the 87 courses of chemotherapy administered included leukopenia (WBC less than 1,000/microL following nine courses) and thrombocytopenia (platelets less than 20,000/microL following four courses). Ten patients became septic, nine of them while leukopenic. Elevations of serum creatinine followed eight courses; in all cases the level was less than 3.0 mg/dL. Nausea and vomiting were mild to moderate. Five patients experienced mild hypoacusis and six had sensory polyneuropathy. The deaths of three patients were considered drug-related. The response rate was 28%. The median survival for the group was 22 weeks, 63.2 weeks for responders and 17.9 weeks for nonresponders. Twenty-six patients received radiation therapy, 16 randomized to this arm as planned, ten to palliate symptoms. Median survival of all irradiated patients was 24.8 weeks. Seven responders to chemotherapy were randomized to receive radiotherapy; their median survival was 25 weeks. In six responders randomized not to receive radiation, the median survival was 77.8 weeks (P greater than .3). Among nonresponding patients, the median survival of those radiated was 22.2 weeks, while that of nonradiated patients was 11 weeks. This regimen is cumbersome and toxic. It has offered no major survival benefits, or improvement in response rates, therefore, we do not recommend it for the standard treatment of NSCLC.

The effects of oral pentoxifylline on interleukin-2 toxicity in patients with metastatic renal cell carcinoma.

Interleukin-2 (IL-2) mediates the regression of metastatic renal cell carcinoma, but clinical application has been limited by associated toxicities. Preclinical studies show that pentoxifylline (PTXF), a methylxanthine derivative, inhibits IL-2 toxicity while preserving anti-tumour efficacy. This study was designed to determine whether oral PTXF would alter IL-2-induced toxicities. Patients with disseminated renal cell carcinoma were treated with continuous infusion of 18 x 10(6) IU/m2/24 h for 4 days followed by 3 days without treatment, for 4 consecutive weeks. After a 2-week interval, the 4-week treatment cycle was repeated. All patients concomitantly received oral PTXF (2000 mg/24 h) in five divided doses. Despite the co-administration of PTXF, all patients demonstrated a spectrum and severity of toxicities consistent with previous reports of continuous infusion of IL-2 alone. There was considerably more nausea and vomiting associated with the administration of PTXF which improved on withdrawal of PTXF. Oral PTXF in IL-2 therapy did not show any substantiated benefit. Indeed, patients suffered more severe nausea and vomiting than if they had received IL-2 alone, resulting in the early termination of the trial.

Comparison of different treatment strategies for diffuse large-cell lymphomas: a decision analysis.

There are more than 20 drug combinations in use for the treatment of diffuse large-cell non-Hodgkin's lymphoma (NHL). New treatments have been developed without prior comparison in clinical trials. The authors devised a Markov-process model to compare the efficacy of a first-generation combination chemotherapy regimen (CHOP) with that of a third-generation regimen (MACOP-B) using currently available data. For a typical 57-year-old male patient, life expectancy with MACOP-B was 12.1 years, compared with 8.3 years with CHOP. The remission rate after initial treatment and the functional status after the first remission is achieved were the most important determinants of life expectancy. It was still possible for CHOP to become better strategy provided that the initial remission rate with MACOP-B were lower than 50% or that functional status after remission was achieved were less than 66%. The analysis suggests that the most effective therapeutic regimen for diffuse large-cell lymphoma must not only result in a high remission rate but also cause minimal late sequelae. These two parameters were incorporated into the nomogram, which can serve as a basis for comparison of the efficacy of any chemotherapeutic regimen in non-Hodgkin's lymphoma.

A phase II trial of chlorambucil in non-small cell lung cancer.

A Phase II trial of high-dose chlorambucil at 108 mg/m2 was undertaken in non-small cell lung cancer. No complete or partial objective responses were observed, and significant toxicity, including nausea, vomiting, and seizures, was noted. Chlorambucil at this dose and schedule of administration is not recommended for the treatment of non-small cell lung cancer.

Residual mediastinal mass after treatment of Hodgkin's disease: a decision analysis.

A residual mediastinal mass after completion of initial treatment for Hodgkin's disease is a frequent clinical problem. Investigators have suggested three possible approaches to this important problem: 1) observation, 2) additional diagnostic tests with subsequent action based upon test results, or 3) immediate treatment for high-risk patients. The method of decision analysis was applied to determine the optimal management for residual mediastinal abnormalities following treatment of Hodgkin's disease with combined modalities of MOPP chemotherapy and radiation therapy. The three parameters of the importance for making the best decision were: 1) the probability that the mass is truly active disease, 2) the salvage success rate using MOPP or ABVD treatment and 3) the specificity of the gallium scan. The analysis favored the gallium imaging strategy as an initial management choice when the probability was greater than 3% that the residual mass represented active disease and the specificity of gallium imaging was greater than 56%. This strategy proved to be the most cost effective, as well. Additional chemotherapy was favored only when there was a greater than 99% probability that the mass represented active disease. A nomogram has been constructed combining all three parameters of importance for graphically determining the best decision.

Phase I evaluation of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) by a weekly iv dose schedule.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (AMSA), a derivative of acridine, was evaluated in patients with advanced malignant neoplasms in a phase I clinical trial. The drug was administered in an iv infusion on a weekly x 4 schedule. Seventy-four courses of AMSA were administered to 34 patients over a dose range of 20-90 mg/m2. Dose-limiting toxicity, which was solely hematologic, was observed at 90 mg/m2. Objective antitumor effects were observed in two of 22 evaluable patients: a partial remission in a patient with abdominal desmoid fibrosarcomas and a minor regression in a patient with adenocarcinoma of the colon. A dose of 70-90 mg/m2 would be suitable for trials of AMSA on a weekly basis.

Complications of implantable chemotherapy pump. A case of pump inversion.

Regional chemotherapy with the use of implantable pumps is becoming more frequent. The authors report here a case of the pump inverting in the subcutaneous pocket. Speculation on diagnosis, correction, and prevention are discussed.

Responsiveness of metastatic basal-cell carcinoma to chemotherapy. A case report.

Basal cell carcinoma normally causes major morbidity only by direct extension of the tumor into adjacent tissues. Occasionally the tumor will metastasize to distant sites such as the lungs, the bones, regional lymph nodes, and the abdominal viscera. Over 100 cases of this disseminated disease are reported in the literature. Once a tumor has metastasized beyond the regional lymph nodes it is uniformly fatal. This article reports a case of basal cell carcinoma, metastatic to the lung, which was successfully treated with cisplatin. Three other cases treated similarly are reviewed, and the prospects for treatment of advanced basal cell carcinomas with chemotherapy are discussed.

Modulation of 5-FU action by thymidine in murine and human tumors.

The biochemical basis of, and preclinical experience with, combined chemotherapy with thymidine and 5-FU are reviewed. Phase I trial and clinical pharmacologic evaluation of a monthly schedule of thymidine and 5-FU showed marked increase in the biologic activity of 5-FU. Both toxic and antitumor effects were observed. Myelosuppression was the dose-limiting side effect. The central nervous system toxicity of 5-FU appeared increased; gastrointestinal toxicity was not. The available data do not permit an assessment of whether the therapeutic index of 5-FU has been altered by combination with thymidine. The basis for the observed increase in potency of 5-FU appears to be a thymine-induced marked slowing in its catabolism that results in a prolonged plasma half-life for 5-FU and an increased cellular exposure to the drug.

Hepatic perfusion with FUdR utilizing an implantable system in patients with liver primary cancer or metastatic cancer confined to the liver.

Nineteen patients with colorectal adenocarcinoma, three with cholangiocarcinoma, two with hepatocellular carcinoma, and one with carcinoid were treated with hepatic artery infusion chemotherapy. An implantable pump system was used to deliver floxuridine (FUdR), starting at 400 mg for 2 weeks with 2 weeks of rest. Eleven of 15 (73%) measurable patients with colorectal carcinoma responded. Of 6 complete responses, 4 were documented by laparotomy, including 1 with cholangiocarcinoma. Toxicity included dyspepsia and elevated liver function tests in all patients, gastric ulcer in 2, cholecystitis in 2, and sclerosing cholangitis in 3. Overall median survival for the colon cancer patients has not been reached at 16 months. Regional disease was controlled in the majority of patients treated with this regimen with acceptable toxicity and good quality of life.

Tetrahydrouridine: Physiologic disposition and effect upon deamination of cytosine arabinoside in man.

[14C]-tetrahydrouridine (THU), a strong inhibitor of cytidine (CR) deaminase, was, after iv administration, rapidly and quantitatively cleared from the blood with a plasma half-life of about 1 hour. The main pathway of excretion was through the kidneys: most of a dose of 50 mg/kg was excreted within 12 hours and excretion was essentially complete within 48 hours. Oral administration of the same dose revealed absorption of about 10% from the gastrointestinal tract. THU at 10, 25, and 50 mg/kg given 15 minutes before [3H]-cytosine arabinoside (ara-C) at a dose of 0.003 mg/kg produced about a two fold increase in ara-C blood levels at all times measured from 5 minutes to 4 hours, with only slight increases in the half-life of ara-C. A dose-related effect of THU upon the deamination of ara-C was obvious only during the time from 15 minutes to 1 hour after the injection of 3H-ara-C. The inhibitory effect of THU upon CR deaminase was also reflected in a considerably increased ratio of ara-C/uracil arabinoside in the urine.

Physiologic disposition of cytosine arabinoside and its derivatives in man.

Enzymatic and clinical pharmacologic studies indicate that 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine (AAFC) is relatively resistant to enzymatic deamination and is not phosphorylated but slowly releases 1-beta-D-arabinofuranosyl-5-fluorocytosine. The latter is deaminated rapidly to 1-beta-D-arabinofuranosyl-5-fluorouracil. After iv injection of labeled cytosine arabinoside (Ara-C), 2,2'-anhydro-1-beta-D-arabinofuranosylcytosine, and AAFC into patients, radioactivity appears in substantial amounts and persists for a prolonged time in the saliva. AAFC slowly penetrates into the cerebrospinal fluid, reaches significant levels, and is retained there for a long time. Ara-C, due to rapid deamination in plasma, does not provide sustained levels of Ara-C in the cerebrospinal fluid. It is likely that this difference between AAFC and Ara-C is due to reduced polarity of the former compound.