Robust control for convection suppression in a fluid layer: The effects of boundary properties, actuator lag, and major parameter uncertainties.

The robustness of control is a requirement to maintain a fluid layer at conductive equilibrium heated to a highly supercritical condition. Robustness determines how much uncertainties, or design parameter mismatches, can be tolerated. Both linear stability analysis and three-dimensional fully nonlinear simulations are used for the study of the linear quadratic Gaussian (LQG) controller. The parameter mismatches from the nominal conditions are introduced into the plant model, while the LQG compensator assumes nominal conditions. The mismatches arise from boundary properties, actuator lag, sensor level uncertainty, and wall thickness, as well as from the major parameters such as Prandtl number, Rayleigh number, wave number, and truncation number in the reduced-order model. The results suggest that the LQG compensator action can preserve closed-loop stability at over ten times the critical Rayleigh number, provided that the mismatches in the sensor level and wall thickness are small. Mismatches in the Prandtl number and wall material properties have little impact. Mismatches in Rayleigh number and wave number are relatively benign compared with the sensor and thickness parameters. Techniques for measuring the plant output temperature at multiple levels with sufficient accuracy may be an implementation challenge.

Phase I-phase II trial of N-phosphonacetyl-L-aspartic acid given by intravenous infusion and 5-fluorouracil given by bolus injection.

A phase I clinical trial of N-phosphonacetyl-L-aspartic acid (PALA) and 5-fluorouracil (FUra) was performed on 30 patients. PALA was given as a 15-minute iv infusion once daily for 5 days, and FUra was given as a bolus injection on days 2, 3, 4, and 5. Cycles of treatment were repeated every 3 weeks. Dose-limiting toxicity was manifested by stomatitis and diarrhea. Skin rash was observed also but was not dose limiting. No consistent hematopoietic or renal toxicity was observed. Seventeen patients with disseminated metastatic melanoma and measurable disease were evaluated for response. One partial response was seen; however, the response was associated with significant toxicity, and the treatment could not be repeated. Stable disease was observed in 3 patients with melanoma, 1 patient with colon carcinoma, and 1 patient with ovarian carcinoma. Our findings suggest that the clinical activity of PALA and FUra given according to the above schedule for melanoma is less than 25% (P less than 0.05). Pharmacokinetic studies of FUra revealed no consistent effect of PALA pretreatment on FUra disappearance in plasma. The mean FUra elimination half-line in plasma was 7.11 +/- 0.84 minutes (SEM), which is no different from that reported for FUra alone. The recommended doses on this schedule for phase II studies are 1,000 mg PALA/m2/day iv daily for 5 days and 200 mg FUra/m2/day iv on days 2, 3, 4, and 5.

Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin.

BACKGROUND: Although doxorubicin is an anticancer agent with a wide spectrum of activity, therapy with this anthracycline must often be discontinued at a time of benefit to the patient because of the drug's cumulative cardiotoxicity. ICRF-187 (ADR-529, dexrazoxane) is a bisdioxopiperazine compound that protects against cardiac toxicity induced by doxorubicin. PURPOSE: Our objectives in this study were to determine the maximum tolerated dose of ADR-529 (which uses a different vehicle than ICRF-187) when given with a fixed doxorubicin dose and to determine whether ADR-529 alters doxorubicin pharmacokinetics. METHODS: Twenty-five patients were treated with doxorubicin (60 mg/m2) preceded by administration of ADR-529 in escalating dosages (i.e., 60, 300, 600, 750, and 900 mg/m2) to groups of three to nine patients. ADR-529 was administered over a 15-minute period beginning 30 minutes before doxorubicin treatment; the protocol was repeated every 3 weeks. Blood was sampled frequently for drug levels, which were determined by high-pressure liquid chromatography with fluorescence (doxorubicin) and electrochemical detection (ADR-529). RESULTS: Dose-limiting neutropenia occurred in four of six previously treated patients at an ADR-529 dose of 600 mg/m2; the dose ratio of ADR-529 to doxorubicin was 10:1. For three additional patients with better Eastern Cooperative Oncology Group performance status and a maximum of one prior chemotherapy regimen, 600 mg/m2 was tolerated, but grade 3 or 4 neutropenia occurred in four of six patients who received an ADR-529 dose of 900 mg/m2 and in three of four patients at a dose of 750 mg/m2. Doxorubicin's estimated terminal half-life was 39.5 +/- 18.3 (mean +/- SD) hours; the area under the curve for plasma concentration of drug x time (AUC) was 1.74 +/- 0.40 (micrograms/microL) x hour. Total-body clearance was 598 +/- 142 microL/m2 per minute (N = 20), and it did not vary with ADR-529 dose. Estimated distribution and elimination phase half-lives for plasma ADR-529 were 0.46 +/- 0.30 hours and 4.16 +/- 2.94 hours, respectively. Total-body clearance was 111 +/- 87 microL/m2 per minute (N = 18); AUC was linear (r2 = .92), and the clearance rate was constant (r2 = .18) from 60 to 900 mg/m2. CONCLUSIONS: Myelotoxicity was dose limiting for ADR-529 at 600-750 mg/m2 when given with a fixed dose of doxorubicin at 60 mg/m2 (dose ratios of ADR-529 to doxorubicin ranged from 10:1 to 12.5:1). When used in combination, ADR-529 did not perturb doxorubicin's distribution, metabolism, or excretion; therefore, other mechanisms of cardioprotection must be involved. IMPLICATIONS: We recommend that an ADR-529 dose of 600 mg/m2 be given with single-agent doxorubicin at a dose of 60 mg/m2 in future studies.

Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols.

The plasma pharmacokinetics of Adriamycin and adriamycinol following a 15-min infusion of 75 mg/sq m of Adriamycin were studied in ten patients previously untreated with Adriamycin. The disappearance kinetics of Adriamycin could adequately be described by a biexponential equation with an initial half-life of 8-min and a terminal half-life of 30 hr. The major drug exposure (area under the concentration-time curve) occurs during the terminal phase where drug concentrations are generally less than 10(-7) M (0.05 micrograms/ml). An improvement in the high-performance liquid chromatography sensitivity facilitated the determination of the terminal phase. The plasma kinetics of adriamycinol, the major and only known active metabolite of Adriamycin, show a rapid initial increase in plasma concentration followed by a slow decline which parallels that of Adriamycin during the terminal phase. The relative drug exposure of adriamycinol to Adriamycin was approximately 50%. The relationship between the measured plasma drug levels and free drug available for distribution into tissues was studied by comparing the plasma binding characteristics of Adriamycin and adriamycinol. A constant 20 to 25% of the total plasma concentrations of both Adriamycin and adriamycinol was freely diffusible over the whole range of observed concentrations, 20 nM to 2 microM. Thus, the free drug exposure (area under the concentration-time curve) of tumor and host tissues in vivo can be determined from these plasma measurements, since the free drug exposures in plasma and in extracellular fluid are equivalent. These results can also serve as a guide for the design of clinically relevant in vitro studies of Adriamycin and adriamycinol. The pharmacokinetic parameters determined in this study have been used to simulate plasma concentration-time courses for a variety of Adriamycin treatment schedules. Alternatives are suggested which reduce peak plasma Adriamycin concentration while antitumor area under the concentration-time curve is maintained.

Phase I and pharmacological studies of 5-fluorouracil administered intraperitoneally.

A Phase I study was conducted of 5-fluorouracil administered i.p. in a 2-liter volume of 1.5% Inpersol. The drug was administered via Tenckhoff peritoneal dialysis catheters to ten patients with tumors confined to the i.p. space. Dialysis concentrations ranged from 5 micro M to mM. Complications of the dialysis procedure alone included mild abdominal discomfort and 2 cases of gram-negative bacterial peritonitis, both easily controlled with antibiotics. 5-Fluorouracil caused the same pattern of toxicity as when administered by other routes. There was no local or central nervous system toxicity. Dose-limiting toxicity included pancytopenia and mucositis at a dialysis concentration of 4.5 to 5 mM administered for eight consecutive 4-hr exchanges. There were two documented responses in eight evaluable patients. 5-Fluorouracil concentrations were measured by high-pressure liquid chromatography. Peritoneal fluid concentrations decline in a first-order fashion with a half-life of 1.6 hr. The mean permeability area product was 14 ml/min. A mean of 82% of drug was absorbed in 4 hr. Plasma levels rise over the first 30 to 45 min and decline in a nonlinear fashion. Plasma levels are substantially lower than are peritoneal fluid levels. Mean 4-hr peritoneal fluid concentration was 298 times the simultaneously measured plasma levels. Total body clearance ranged from 0.9 to 15 liters/min and declined with increasing dialysate concentration. We conclude the i.p. route is a relatively safe way to deliver high concentrations and large amounts of drug to the i.p. cavity with a significant pharmacological advantage over conventional routes of administration.

Lack of effect of cyclophosphamide on the immunogenicity of a melanoma antigen vaccine.

Melanoma antigen vaccines are a conceptually attractive approach to prevent or delay disease recurrence in patients with surgically resected malignant melanoma. However, the immunogenicity of current vaccines is relatively low. Cyclophosphamide, when given in low doses prior to antigen exposure, is an immunomodulator which has been shown to enhance both humoral and cellular antitumor responses in animals and humans. We conducted a prospective, randomized, clinical trial to study whether pretreatment with cyclophosphamide augments the immunogenicity of a polyvalent, allogeneic, melanoma antigen vaccine in patients with melanoma and low tumor burden. Forty-five patients with resected stage II melanoma (regional metastases) were randomly allocated to treatment with melanoma vaccine or melanoma vaccine plus cyclophosphamide. All patients received the same dose and schedule of vaccine immunizations; those randomized to cyclophosphamide received 300 mg/m2 i.v. 3 days prior to each vaccine immunization. Cellular immune responses were evaluated by delayed-type hypersensitivity (DTH) skin reactivity to a test dose of vaccine at baseline (prior to treatment) and following the fourth immunization. Humoral immune responses were measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiographic analysis of indirect immunoprecipitates of patients' sera at the same time points. Twenty-four patients were randomized to cyclophosphamide pretreatment and 21 to vaccine alone; 22 and 18 patients were evaluable in each group, respectively. Differences were statistically nonsignificant with respect to either cellular (DTH) or humoral (antibody) responses between the two groups. DTH responses were induced in 16 of 22 (73%) and 15 of 18 (83%) patients treated with cyclophosphamide plus vaccine and vaccine alone, respectively. The mean posttreatment augmentation in DTH response in the cyclophosphamide group was 9.5 mm, compared with 9.9 mm in the vaccine-only group. Eight of 12 (66%) cyclophosphamide-pretreated patients and 9 of 12 (75%) vaccine-only patients produced increased titers of antimelanoma antibodies following treatment. No differences were observed between the groups in disease-free or overall survival. In summary, low-dose cyclophosphamide pretreatment failed to augment the immunogenicity of a polyvalent, allogeneic, melanoma vaccine in patients with completely resected early-stage melanoma.

Portal levels and hepatic clearance of 5-fluorouracil after intraperitoneal administration in humans.

Intrahepatic tumor is a major problem in clinical oncology. While direct intravascular infusions provide high local drug concentrations and variable rates of tumor response, they are limited by technical considerations and complications. In this study, we have tested whether high portal venous and hepatic arterial concentrations of 5-fluorouracil (5-FUra) can be achieved by administering drug via peritoneal dialysis. Four patients with metastatic colon carcinoma had a Tenckhoff catheter surgically implanted. During dialysis therapy with 4 mM 5-FUra, simultaneous samples of peritoneal fluid and of portal venous, hepatic venous, and peripheral venous, and arterial blood were obtained, and 5-FUra concentrations were determined. Mean peak portal vein drug concentrations were 60 microM and exceeded the measured concentrations in the other vessels. Total drug exposures as measured by concentration x time (mM x min) during Exchange 1 were: portal, 3.8 +/- 0.65; hepatic vein, 0.97 +/- 0.44; peripheral vein, 0.90 +/- 0.32; and arterial, 1.1 +/- 0.26. During Exchange 7, total drug exposures were: portal, 6.3 +/- 1.4; hepatic vein, 2.5 +/- 1.3; peripheral vein, 2.3 +/- 1.1; and arterial, 2.7 +/- .85. The fraction of i.p. drug that exited the peritoneal cavity through the portal venous system ranged from 0.29 to 1.0. This variation resulted in part from uncertainty in estimating portal blood flow and gastrointestinal drug elimination. Calculated hepatic extraction was 67% (range, 0.23 to 0.89). Extrahepatic metabolism was demonstrated. Measured 5-FUra concentrations compared favorably to values predicted by a pharmacokinetic model for 5-FUra. Dialysis therapy (i.p.) with 5-FUra provides a means of achieving high drug concentrations for treating both i.p. and intrahepatic tumor. Further clinical testing of this route of administration is warranted.

Phase I clinical trial of 9,10-anthracene dicarboxaldehyde (Bisantrene) administered in a five-day schedule.

Bisantrene is a substituted anthracene derivative which preclinically demonstrated a spectrum of activity similar to that of doxorubicin but without associated cardiotoxicity. A Phase I evaluation of the drug has been performed using daily i.v. administrations for 5 days. Sixty courses of treatment were administered to 23 patients at doses from 2.5 to 90 mg/sq m/day. Courses were repeated at 4-week intervals. Dose-limiting toxicities were leukopenia and local cutaneous reactions. The leukopenia was dose related, noncumulative, and of brief duration. Local reactions occurred in 14 of 37 courses administered at doses greater than 60 mg/sq m and in 13 patients resulted in clinical cellulitis of the infused extremity. Gastrointestinal side effects were mild. No alopecia or cardiotoxicity was observed. Two mixed responses were obtained in patients with hypernephromas. Using a daily schedule for 5 days, approximately 40% more drug can be delivered per course than by single-day i.v. administration. However, with this schedule, local cutaneous reactions may prove additionally dose limiting. Phase II studies of Bisantrene in a daily i.v. schedule for 5 days are planned at a dose of 80 mg/sq m/day to be repeated every 4 weeks.

Phase I trial of escalating dose doxorubicin administered concurrently with alpha 2-interferon.

The clinical use of alpha 2-interferon and doxorubicin is based on in vitro and preclinical in vivo observations of synergistic antitumor efficacy. To test this combination a Phase I clinical and pharmacokinetic study of the concurrent use of alpha 2-interferon and doxorubicin was initiated in patients with malignant solid tumors. Each 5-wk treatment cycle consisted of 3 wk of drug administration and 2 wk of rest. The alpha 2-interferon was administered s.c. at a constant dose of 10 million IU/m2 on Mondays, Wednesdays, and Fridays in all patients while the doxorubicin was administered weekly beginning with a dose of 5 mg/m2 and escalated to the maximum tolerated dose of 25 mg/m2. At least three evaluable patients were entered at each dose level, and no dose escalations were allowed within patients. The dose-limiting toxicities were granulocytopenia and thrombocytopenia. Hepatic enzyme elevations and systemic symptoms due to interferon occurred at all dose levels. None was severe or dose limiting, and all were reversible. These toxicity data suggest that the hepatotoxic effects of interferon do not enhance doxorubicin toxicity when given by this dose and schedule. Doxorubicin plasma levels were measured at each dose level. The recommended dose of doxorubicin is 25 mg/m2 per wk when administered with 10 million IU/m2 of interferon in this schedule. This schedule allows for the administration of a greater total dose of doxorubicin than has been achieved when given every 3 wk with the same dose and schedule of alpha 2-interferon in a parallel study.

A reassessment of the role of second-look laparotomy in advanced ovarian cancer.

Thirty-nine patients with stage III and IV epithelial ovarian cancer who underwent second-look laparotomy (SLL) at New York University Medical Center and 11 eligible patients who did not undergo reexploration were retrospectively studied with follow-up from 24 to 105 months after diagnosis. Sixteen patients (41%) were found to have macroscopic disease, six (15%) microscopic tumor, and 17 (44%) no disease at SLL. Five of 22 patients who received further therapy based on positive SLL findings have remained without clinical evidence of disease 17 to 65 months after SLL. Nine of 17 patients with negative SLL, in whom treatment was stopped, recurred 8 to 52 months after SLL, five in extraperitoneal sites only. Five of 11 patients not undergoing SLL recurred 16 to 39 months after diagnosis, four intraperitoneally. There was no significant difference in survival between the second-look and no second-look groups for the period of study. Clinical trials are needed to determine if SLL influences longer-term survival and if continued treatment is indicated in a high-risk subgroup despite negative SLL. The value of SLL is limited by the efficacy of second line therapy. The role of routine SLL outside an investigational setting is questioned.

Intraperitoneal carboplatin: favorable results in women with minimal residual ovarian cancer after cisplatin therapy.

From August 1985 to November 1989 we conducted a trial of intraperitoneal (IP) carboplatin including a dose-escalation design in 25 women with advanced gynecologic malignancies. All had extensive prior therapy with cisplatin (median cumulative dose, 525 mg/m2). Carboplatin was administered IP in 2 L of 1.5% dextrose with a 4-hour dwell time every 4 weeks for six cycles at a starting dose of 200 mg/m2. Patients with reduced creatinine clearance (30 to 60 cc/min) were escalated more slowly than those with high (greater than 60 cc/min) clearance. Thrombocytopenia was dose-limiting and often more severe in patients with compromised renal function; there was no local drug toxicity. The median time of follow-up is 25 months. Complete responses (CRs) were documented in six of 23 assessable patients (26%) by repeat laparotomy, and an additional 11 patients (48%) had no disease evident by noninvasive restaging. Five of the CRs and six of the patients with no clinically evident disease have relapsed from 3 to 40 months after therapy. Six patients (26%) are alive and free of disease 8 to 47 (median, 20) months after therapy. IP carboplatin is effective against relapsed ovarian cancer, even after prior cisplatin therapy.

ICRF-187 permits longer treatment with doxorubicin in women with breast cancer.

PURPOSE: To test potential protection by ICRF-187 against cumulative doxorubicin-dose-related cardiac toxicity, we conducted a randomized clinical trial in 150 women with advanced breast cancer. PATIENTS AND METHODS: Patients received fluorouracil (5FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2 every 21 days intravenously (IV) (control regimen, 74 patients), or the same regimen preceded by ICRF-187 1,000 mg/m2 IV (experimental regimen, 76 patients). RESULTS: We previously reported that ICRF-187 in this dose and schedule provides cardiac protection and does not substantially alter the noncardiac toxicity or antitumor efficacy of the control regimen. In this updated analysis of the entire patient cohort, we provide additional support for these findings and demonstrate that patients in the ICRF-187 group received more cycles (median, 11) and higher cumulative doses (median, 500 mg/m2) of doxorubicin than patients in the control group (median, nine cycles, P less than .01; and 441 mg/m2, P less than .05). Twenty-six patients in the ICRF-187 group received doxorubicin doses of at least 700 mg/m2, and among them, 11 patients received 1,000 mg/m2 or more. Only three patients in the control group received doxorubicin doses of 700 mg/m2; the maximum dose administered to one patient in this group was 950 mg/m2. ICRF-187 cardiac protection was demonstrated by difference in incidence of clinical congestive heart failure (CHF; two patients in the ICRF-187 group v 20 in the control group; P less than .0001) and by differences in resting left ventricular ejection fraction (LVEF) determined by multigated radionuclide (MUGA) scan from baselines and that required patient removal from study (five patients in the ICRF-187 group had a decrease in LVEF to less than 0.45 or a decrease from the baseline LVEF of 0.20 or more v 32 in the control group; P less than .000001). Among the 30 patients who had an assessable endomyocardial biopsy at cumulative doxorubicin 450 mg/m2, none of 16 in the ICRF-187 group and six of 14 in the control group had a score of 2 (P less than .05). ICRF-187 cardiac protection was observed in patients with and without prior chest-wall radiation or other risk factors for developing doxorubicin cardiac toxicity. CONCLUSION: By protecting against cumulative doxorubicin-induced cardiac toxicity, ICRF-187 permits significantly greater doses of doxorubicin to be administered to patients with greater safety.

Evidence of the selective alteration of anthracycline activity due to modulation by ICRF-187 (ADR-529).

Anthracyclines are powerful anticancer drugs whose use is limited by the development of chronic cardiotoxicity. The bisdioxopiperazine compound ICRF-187 (ADR-529) specifically abrogates this toxicity both in preclinical animal models and in humans. It does this without effecting either the acute toxicities or the anticancer activity. Therefore, with a specific antagonist, the mechanism of activity of the anthracyclines can be explored. This review discusses recent clinical trials and animal models addressing this issue and concludes by hypothesizing a mechanism of action.

Gain-scheduled controller for the suppression of convection at high Rayleigh number.

Recent studies in the feedback control of Rayleigh-Bénard convection indicate that one can sustain the no-motion state at a moderate supercritical Rayleigh number (Ra) using only proportional compensation. However, stabilization occurs at a much higher Rayleigh number using linear-quadratic-Gaussian (LQG) control synthesis. The restriction is that the convection model is linear. In this paper, we show that a comparable degree of stabilization is achievable for a fully nonlinear convection state. The process is demonstrated in two stages using a fully nonlinear, 3D Boussinseq model, compensated by a reduced-order LOQ controller and a gain-schedule table. In the first stage a fully-developed convective state is suppressed through the control action at a moderate supercritical Ra. After the residual convection decays to a sufficiently small amplitude, in the second stage, we increase the Ra by a large step and switch the compensator gains using the gain-schedule table. During this change the control action is in place. Our nonlinear simulation results suggest that the nonlinear system can be stabilized to the limit predicted by the linear analysis. The simulation shows that the large Ra jump induces a large transient temperature in the conductive component, which appears to have very small impact on the stabilization.

Nonlinear pharmacokinetic models for 5-fluorouracil in man: intravenous and intraperitoneal routes.

A two-compartment physiologic pharmacokinetic model has been developed for 5-fluorouracil (5FU). This model, which incorporates saturable whole body clearance, satisfactorily predicts disappearance kinetics after an intravenous bolus and steady-state levels during constant intravenous infusions. A half-saturating concentration (KM) of 15 microM was determined by comparison of model simulations with literature data. Both hepatic and extrahepatic elimination can be inferred for 5FU, but the exact anatomic or compartmental location of the clearance cannot be determined from the available clinical data. The effect of venous and arterial plasma sampling is discussed. This model has been extended to include intraperitoneal and oral administration of 5FU by the addition of peritoneal fluid and liver compartments.

The rationale behind intraperitoneal chemotherapy in gastrointestinal malignancies.

Local regional chemotherapy has yet to be proven superior to other methods of drug administration. While current studies are underway to assess the value of intraperitoneal chemotherapy in patients with gastrointestinal (GI) malignancies, many factors affect the success of such trials. Route of delivery and drug metabolism are all important. It is theorized that local exposure of liver with high concentrations of drug (even considering the limited efficacy of available agents) will result in improved tumor kill. In GI tumors, the putative route of spread is through the portal system to the liver. Intraperitoneal (IP) administration of drug offers an opportunity to deliver high concentrations of drug to local intraperitoneal surfaces, and, if there is sufficient hepatic extraction, IP administration also delivers a high concentration of drug to the liver. In a study of 5-fluorouracil (5-FU) in patients with metastatic colorectal carcinomas, high portal drug concentrations were achieved by this method of administration. It was concluded that IP therapy is an excellent method of delivering high concentrations of 5-FU and possibly other drugs to the hepatic parenchyma as well as to the intraperitoneal space. Since the effectiveness of such administration of still unclear, further clinical trials are indicated.

Intraperitoneal carboplatin: rationale and experience.

We conducted a phase I/II trial of intraperitoneal (IP) carboplatin in 27 patients with advanced gynecologic malignancies. This was based on the known activity of carboplatin in ovarian cancer and pharmacologic measurements that predict a favorable ratio of IP to plasma drug exposure when carboplatin is administered by the IP route. All patients had extensive prior therapy with cisplatin (mean dose, 554 mg/m2). Starting dose was 200 mg/m2, which was escalated to 500 mg/m2. Patients with compromised renal function (creatinine clearance 30 to 60 mL/min) had slower escalations than patients with creatinine clearances greater than 60 mL/min. Myelosuppression, especially thrombocytopenia, was the dose-limiting toxicity. In pretreated patients, we recommend a starting dose of 400 mg/m2. Patients with creatinine clearances of 30 to 60 mL/min should start at the lower dose of 200 mg/m2. This is in general agreement with the results of other trials of IP carboplatin. Measurements of IP carboplatin in preclinical studies predict less tissue penetration by carboplatin than the parent compound cisplatin. Nevertheless, in our series of heavily pretreated patients receiving IP carboplatin, eight patients remained free of disease progression for more than 2 years. Further trials of IP carboplatin are indicated.

Prospective randomized trial of intravenous v intraperitoneal 5-FU in patients with advanced primary colon or rectal cancer.

No new chemotherapy agents have been developed in the recent past that present hope for improving survival in patients with colon or rectal cancer. This study was undertaken to investigate a new route of administering an old drug, 5-fluorouracil (5-FU). When 5-FU is delivered by the intraperitoneal (IP) route the tolerable dose of drug was markedly increased without an increase in adverse side effects. The natural history of surgically treated disease was changed by reducing the incidence of peritoneal carcinomatosis, but time to relapse and survival was not improved. Intraperitoneal 5-FU may be recommended for investigation in patients with perforated colon cancer, peritoneal implants, or as one part of a multimodality treatment protocol for colorectal cancer. If 5-FU is given to patients with gastrointestinal malignancy, the IP route should be strongly considered.

Intraperitoneal chemotherapy: technical experience at five institutions.

With the rapid expansion of research programs examining intraperitoneal chemotherapy for ovarian cancer and other intraabdominal malignancies, there is a need for a reliable and safe access to the peritoneal cavity. The technical experience accumulated with either the Tenckhoff catheter or the Port-A-Cath in 288 patients treated at five institutions showed a low incidence of catheter-related peritonitis (5% and 8%, respectively), skin infection (6.6% and 0%), and bowel perforation following surgical implantation (3.5% and 1.3%). Postoperative leakage of intraabdominal fluid, bleeding, or ileus were uncommon and easily controlled. Drainage failure was the major problem with both systems; occurring in 45% of patients. Although both systems are workable, improved catheters for the administration of intraperitoneal chemotherapy are warranted.

Prospective evaluation of cardiotoxicity during a six-hour doxorubicin infusion regimen in women with adenocarcinoma of the breast.

In order to test the possible cardiac-sparing effect of doxorubicin administered by six-hour intravenous infusion and to prospectively evaluate the role of resting left ventricular ejection fraction in monitoring these patients, 33 women with advanced breast cancer were treated with combination chemotherapy containing 5-fluorouracil, cyclophosphamide, and doxorubicin. Doxorubicin was administered via a femoral catheter as a six-hour infusion. Cardiac function was monitored prior to therapy and at intervals during therapy by history and physical examination and by measurement of resting left ventricular ejection fraction with gated pool radionuclide angiography. Twenty-six responses were observed (complete response, seven [21 percent]; partial response, 19 [57 percent]). Systemic toxicity included alopecia, myelosuppression, and nausea and vomiting. There was a progressive fall in resting left ventricular ejection fraction during treatment from a median baseline value of 0.63. Mean fall from baseline left ventricular ejection fraction at a cumulative doxorubicin dose of 200 to 300 mg/m2 was 0.06 (p less than 0.005); at 301 to 449 mg/m2 it was 0.09 (p less than 0.0005); and at 450 mg/m2 or greater it was 0.15 (p less than 0.0005). Clinical congestive heart failure developed in three patients. Even though the decrease in left ventricular ejection fraction was often within the "normal range" (left ventricular ejection fraction 0.50 or greater), these changes were progressive and appeared to be part of a continuum of doxorubicin-induced myocardial damage. Steady-state infusion levels of doxorubicin in plasma ranged from 90 to 120 nM. They confirm the hypothesis that lower concentrations can be achieved by continuous infusion rather than by bolus infusion. In this study, however, administration of doxorubicin by six-hour infusion did not appear to have a major cardiac-sparing effect. Studies of anthracycline cardiac toxicity should include determination of baseline left ventricular ejection fraction and serial observations during therapy. Failure to include deteriorations in function above an arbitrary cutoff point or to make observations only at higher cumulative doses may underestimate drug-induced myocardial damage.