5-Fluorouracil and methotrexate administered simultaneously as a continuous infusion. A phase I study

Infusion delivery systems have been evaluated for administration of many individual chemotherapeutic agents including 5-fluorouracil (5-FU) and methotrexate (MTX). This study combined the two drugs as an admixture, and in a Phase I trial design established a useful dose schedule for each of the component drugs. 5-FU at a fixed dose rate of 300 mg/M2/day was delivered with methotrexate (MTX) at four different dose rates (0.75, 1.0, 1.5, or 2.0 mg/M2/day, respectively). The drug solution was delivered via a subclavian venous access with a portable infusion pump in an ambulatory setting. Twenty-nine patients received a total of 38 courses of the two-drug infusion: 21 courses were delivered with the two agents admixed constantly throughout treatment (Schedule A) and 17 were administered the treatment with 5-FU delivered continuously and MTX added to the 5-FU for alternate 14-day cycles (Schedule B). For the former schedule, dose-rate-limiting toxicity was related to MTX and included stomatitis developing at days 8 to 14 (median, day 8) with the higher dose rates (1.5-2.0 mg/M2/day) and thrombocytopenia developing at days 11 to 56 (median, day 14) at the lowest dose rates (1.0 mg/M2/day). For Schedule B, dose-rate-limiting toxicity was similarly due to the MTX with thrombocytopenia and/or chemical hepatitis developing in six of seven courses of MTX at 1.0 mg/M2/day and in five of ten courses delivered at 0.75 mg/M2/day. On Schedule B the MTX-associated toxicities were reversed when the MTX administration was interrupted and in the face of continued 5-FU infusion. A reasonable dose rate and schedule for continuous infusion of 5-FU combined with MTX is: 5-FU 300 mg/M2/day X 28 days and MTX 0.75 mg/M2/day for days 1 to 14, with cycles administered consecutively each 28 days.     

Cyclophosphamide, methotrexate, and 5-fluorouracil in a three-drug admixture. Phase I trial of 14-day continuous ambulatory infusion

The compatibility and stability at room temperature for up to 7 days of a three-drug admixture of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) was established permitting the practical delivery of the combination as an infusion in an ambulatory setting. Fourteen patients received 20 courses of CMF administered on a continuous infusion schedule for 14 days of a 28-day cycle. The dose rates were fixed for 5-FU (300 mg/M2/day) and methotrexate (0.75 mg/M2/day). The cyclophosphamide dose was escalated from 25 to 50, 75, and 100 mg/M2/d. Leukopenia and thrombocytopenia were observed in two of five patients receiving the maximal dose of cyclophosphamide. No other toxicities were observed including alopecia, stomatitis or liver function abnormalities. This Phase I trial suggests that the cumulative doses of cyclophosphamide, methotrexate, and 5-FU are comparable to the maximum doses delivered as single agent infusions. Furthermore, when the infusion CMF is compared to the "standard" bolus schedule for CMF, the infusion schedule delivers 116%, 8%, and 350% of the respective three component drugs (cyclophosphamide, methotrexate, and 5-FU).     

Combined 5-fluorouracil and floxuridine administered as a 14-day infusion. A phase I study

5-Fluorouracil (5-FU) and floxuridine (FUdR) were admixed in a single solution and administered via a central venous catheter on a continuous infusion schedule for 14 days. The Phase I trial design developed for admixture combinations was employed with starting doses for 5-FU at 250 mg/m2/day and for FUdR at 0.075 mg/kg/day. Twenty patients and 28 courses were studied. Dose rate limiting toxicity was pseudoregional enteritis with or without stomatitis experienced by five of ten of the courses administered at the highest dose rates of the admixture components. The simultaneous delivery of the two agents results in a modest compromise of the cumulative dose delivered for FUdR. Previous Phase I studies of single agent 5-FU and FUdR had demonstrated that the optimal dose rates for the individual agents in a 14-day continuous 24-hour infusion schedule is 350 mg/m2/d and 0.125 mg/Kg/day, respectively. The maximum dose rate of 5-FU at 350 mg/m2/day for 14 days is not restricted even with the addition of FUdR at up to 0.1 mg/kg/day. The optimal dose rates for Phase II trails should be as follows: 5-FU, 350 mg/m2/day; and FUdR, 0.1 mg/kg/day.     

Constant infusion schedule for adriamycin: a phase I-II clinical trial of a 30-day schedule by ambulatory pump delivery system

Eighteen patients received a continuous intravenous infusion of adriamycin for 14-60 days in a phase I study in which the dose rates were escalated from 2 mg/sq m/day to 5 mg/sq m/day to establish the optimal dose to be delivered over a 30-day period. The drug was delivered via a tunneled subclavian catheter by a portable infusion pump (Cormed model ML-6) primed to provide a volume of diluted drug of 10 cc/day. Leukopenia and stomatitis were observed at 4 mg/sq m/day doses or greater in 50% of courses. At doses less than 4 mg/sq m/day, only 3/17 courses (18%) were associated with stomatitis. Partial alopecia developed in all patients, but less than 50% of scalp hair was affected. The cumulative dose of continuous infusion adriamycin at 30 days is comparable to the dose delivered by standard bolus intermittent schedules (60-90 mg/sq m g 21 days), but the adverse drug effects are eliminated or substantially reduced. Cardiac toxicity was assessed in selected patients treated to 450 mg/sq m or greater by cardiac biopsy and/or gated pool studies. No histopathologic lesions were noted in 3 patients receiving 450 mg/sq m or greater. The recommended daily dose rate of adriamycin in this protracted infusion regimen is 3 mg/sq m/day. The phase II study of this schedule and dose rate in 38 additional patients (a total of 52 evaluable patients) demonstrated objective responses in 1/9 soft tissue sarcoma, 1/3 mesothelioma, 1/3 hepatoma, and 2/13 breast cancer. Phase III studies of the protracted continuous infusion schedule for adriamycin are indicated in that clinical activity is demonstrated at a substantial reduction in toxicity. Pharmacologic studies expanding the existing data base are also necessary.     

Continuous 5-fluorouracil infusion and pulse methotrexate/leucovorin for colorectal adenocarcinoma. A report of excessive toxicity

Thirteen patients with metastatic colorectal adenocarcinoma underwent treatment with continuous ambulatory 5-fluorouracil (5-FU) infusion 300 mg/m2/day and intermittent bolus methotrexate (MTX) (200 mg/m2) with calcium leucovorin (LCV) 10 mg/m2 orally every 6 h X four to eight doses given 24 h after MTX. Although MTX administration was planned every 14 days, the average time between treatments exceeded 19 days (range 14-42) because of excessive toxicity. All patients experienced toxicity at some time in their treatment course, requiring interruption of 5-FU infusion in 12 of 13 patients. Significant toxicities included stomatitis (13 of 13 patients), hand-foot syndrome (8 of 13 patients), and diarrhea (3 of 13 patients). Toxicity did not appear to be minimized by attenuation of MTX and/or 5-FU dosage or by increasing the dose and/or duration of LCV. At this dosage schedule the addition of MTX/LCV to 5-FU infusion results in excessive and unacceptable toxicity and does not appear to improve treatment results.     

Infusional carboplatin. Phase I studies of 5-day and 14-day infusions

Twenty-two courses of carboplatin (Paraplatin; Bristol-Meyers, Evansville, IN) (CBDCA) were administered to 15 patients with advanced cancer on a continuous 24-hour per day infusion schedule for either 5 days or 14 days. The objective of the trial was to establish the optimal dose rate and cumulative dose for this treatment schedule. The dose-limiting toxicity was myelosuppression, with leukopenia and thrombocytopenia observed. The optimal dose rate for the 5-day infusion was 75 mg/m2/d or a total cumulative dose of 375 mg/m2/d. The optimal dose rate for the 14-day infusion was 25 mg/m2/d or a total cumulative dose of 350 mg/m2/d. The times to nadir levels of leukocyte and platelet counts were 34 days and 25 days, respectively, with a median time to recovery of 14 days and 7 days, respectively, in patients with Grade 3 or greater marrow suppression. The pattern of hematologic toxicity with infusional CBDCA is comparable to that seen with bolus schedules. There is, therefore, no clinical advantage of the infusional schedule for CBDCA in terms of toxicity and the dose delivered per cycle, and the dose intensity is slightly less than with a bolus schedule. If there is a therapeutic advantage for the infusional schedule, a prospective comparative trial against the standard bolus schedule will be required to establish it. Bolus and infusional schedules for CBDCA are associated with a delayed pattern of thrombocytopenia and prolonged leukopenia, necessitating 5 or more weeks between treatment cycles.     

Etoposide admixed with cisplatin. Phase I clinical investigation of 72-hour infusion

The compatibility of etoposide (VP-16-213) and cisplatin (CDDP) in an admixture solution was established by High Pressure Liquid Chromatography (HPLC) studies in vitro at room temperature. A Phase I dual-dose escalation study of the admixture was subsequently carried out utilizing a 24-hour continuous infusion schedule administered for 3 consecutive days and repeated at 3 to 4 week intervals. Twenty-seven patients received a total of 42 treatment courses. The daily dose rates for VP-16-213 were 50, 75, and 100 mg/m2/day. Cisplatin was delivered at 20, 30, and 40 mg/m2/day for each dose level of VP-16-213. Dose-rate limiting toxicity was observed first at the VP-16 dose of 50 mg/m2/day and CDDP at 30 mg/m2/day. At 100 mg/m2/day for VP-16-213, six of 17 courses were associated with life-threatening leukopenia and four of six patients died with sepsis. All but one of the patients developing severe or life-threatening leukopenia had associated acute renal failure with serum creatinine levels greater than 2 mg/dl. The optimal dose rate of delivery for VP-16 and CDDP administered as a 72-hour infusion admixture is 75 mg/m2/day and 30 mg/m2/day, respectively.     

Effects of a combination chemotherapy "VEMA" consisting of vincristine, cyclophosphamide, methotrexate and ACNU in the treatment of small cell bronchogenic carcinoma

A combination chemotherapy "VEMA" consisting of vincristine (VCR), cyclophosphamide (Endoxan, EX), methotrexate (MTX) and nimustine (ACNU) has been carried out for the treatment of small cell bronchogenic carcinoma since September, 1978. "VEMA" regimen consists of VCR 1.3 mg/m2 iv push on day 1, EX 500 mg/m2 iv infusion on day 1 and 2, MTX 28 mg/m2 iv push on day 1, 2 and 3, and ACNU 67 mg/m2 iv push on day 3. This dose schedule was repeated every 3 to 4 weeks. The regimen was given to 14 patients and 12 patients were evaluable. In the 12 evaluable cases, 2 case of complete response (CR), 7 cases of partial response (PR) and 2 cases of effusion effective were obtained. Response rate of CR + PR was 90%. Response rate including CR, PR and effusion effective was 91.7%. The major clinical toxicity of "VEMA" therapy was bone marrow suppression. Other side effects were anorexia, nausea, vomiting, alopecia and stomatitis: etc; however, these side effects were not life threatening to terminate "VEMA" therapy. In conclusion, "VEMA" regimen is a new potent combination chemotherapy in the treatment of small cell bronchogenic carcinoma.     

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphon-acetyl)-L-aspartate (PALA) is inactive in advanced pancreatic carcinoma

Purpose: To evaluate the effect of biochemical modulation by PALA and methotrexate on the therapeutic activity of 5-fluorouracil (5-FU) in patients with advanced pancreatic adenocarcinoma.Patients and methods: The treatment protocol consisted of phosphonacetyl-L-aspartate (PALA) 250 mg/m² i.v. 15-minute infusion followed by methotrexate 200 mg/m² i.v. 30-minute infusion on day 1 and 5-FU 600 mg/m² i.v. push on day 2. Folinic acid was given at 15 mg/m² p.o. every six hours for eight doses, starting 24 hours after methotrexate infusion. Cycles were repeated every two weeks.Results: Thirty patients with advanced chemotherapy-naive pancreatic cancer were included; 26 had measurable disease. Median age 56 years (27–72); median PS 1 (0–2). One PR (3.9%) was achieved; nine patients had stable disease. Median time to progression was 91 days. Median survival was 177 days and one year survival was 13.3% (4 of 30 patients). Treatment was well tolerated; diarrhea WHO grade 2 or 3 occurred in six patients; stomatitis WHO grade 2 and 3 in nine patients.Conclusions: Modulation of 5-FU by PALA and MTX given in this dose and schedule appears to be ineffective in patients with advanced pancreatic adenocarcinoma.     

Renal toxicity with cumulative doses of cis-diamminedichloroplatinum-II in pediatric patients with osteosarcoma. Effect on creatinine clearance and methotrexate excretion

Sequential corrected creatinine clearance (CCC) evaluations were obtained in 30 patients treated with intra-arterial and/or intravenous cis-diamminedichloroplatinum-II (CDP). The dose was 150 mg/M2 administered with mannitol diuresis at 2 to 3 weekly intervals. Four hundred fifty-three courses were administered (range, 6-18) over 18 months. Patients also were treated with 283 courses of high-dose methotrexate (MTX) and citrovorum factor "rescue" which were interposed between treatments. Deleterious effects of cumulative courses of CDP manifested as progressive reductions in CCC and delayed excretion of serum MTX. Severe MTX toxicity was aborted by augmenting the fluid intake and prolonging citrovorum factor rescue when elevated levels of serum MTX were detected. The first indication of renal induced CDP toxicity occurred with a cumulative dose of 450 mg/M2. At the termination of treatment (cumulative CDP dose over 1050 mg/M2) renal impairment still was present.     

Methotrexate plus L-asparaginase. An active combination for children with acute nonlymphocytic leukemia

Forty-one children with refractory acute nonlymphocytic leukemia (ANLL) were treated from March 1975 to February 1979 with a schedule-dependent combination of methotrexate (MTX) and L-asparaginase. Intravenous (IV) MTX was followed 24 hours later by IV L-asparaginase (10,000 units [U]/m2). The MTX dose was started at 60 to 100 mg/m2 and was escalated by 20 to 40 mg/m2 as tolerated. This sequence was repeated every 7 to 10 days. Eight patients (20%) achieved a complete remission (CR) and six others had a partial response (PR), with clearance of blasts from the peripheral blood and reduction of bone marrow blasts to less than 25% of nucleated marrow cells. Responding patients received a median maximum MTX dose of 120 mg/m2 (range, 60 to 220 mg/m2). The median number of courses required to achieve a CR was 6 (range, 2 to 13 courses). Toxicity consisted of allergic reactions to L-asparaginase (n = 12), stomatitis (n = 6), minimal elevation of hepatic enzymes (n = 2), and hyperglycemia (n = 1). Treatment was given on an outpatient basis in 95% of all courses. The data indicate that this combination therapy has antileukemic activity and is relatively nontoxic in childhood ANLL.     

Final results of a phase I and pharmacokinetic study of γ-methylene-10-deazaaminopterin (MDAM) administered intravenously daily for five consecutive days in patients with solid tumors

Purpose To determine the maximum tolerated dose (MTD) of -methylene-10-deazaaminopterin (MDAM), a unique antifolate structurally similar to methotrexate (MTX), in the treatment of patients with solid tumors and to characterize toxicity and pharmacokinetic profiles of MDAM administered intravenously for five consecutive days repeated every 21 days.Methods A group of 18 patients with treatment-refractory colorectal cancer (CRC) were given MDAM at increasing dose levels from 80 to 300 mg/m² per day intravenously for 5 days every 3 weeks.Results A total of 18 patients were entered into the study. Grade 2 or less nausea, vomiting, diarrhea, anorexia and fatigue were observed at doses 160 mg/m² per day. Both patients enrolled at 300 mg/m² per day experienced grade 3 stomatitis and one patient had grade 4 granulocytopenia. At 270 mg/m² per day, grade 3 stomatitis (n=2), thrombocytopenia (n=1) and hyperbilirubinemia (n=1) were observed. All toxicities were relatively brief in duration and reversible. Leucovorin rescue was not required. Of 17 evaluable patients, no complete or partial responses were observed, and 3 patients demonstrated stable disease. Pharmacokinetic analyses were performed in 16 of the 18 patients receiving MDAM at doses of 80, 160, 240, 270 and 300 mg/m². Normalized clearance of MDAM was approximately 1.5 times that reported for MTX (125 vs 80 ml/min per m²) in adults.Conclusion MDAM is a novel antifolate with potential pharmacokinetic and safety advantages over MTX. Based on the results of this phase I study, stomatitis emerged as the dose-limiting toxicity and the recommended starting dose for phase II trials using this schedule and route of administration is 240 mg/m² per day.     

Phase I clinical and pharmacologic trial of trimetrexate in combination with 5-fluorouracil

Summary Based on the synergy of sequential methotrexate (MTX) and 5-fluorouracil (5-FU) in vitro and in vivo and the superior antitumor activity of trimetrexate (TMTX) compared with MTX in preclinical models, we carried out a phase I trial of TMTX and 5-FU (fixed dose, 400 mg/m² per day), both given as 10-min i.v. infusions daily x5 days, every 28 days. The TMTX dose was escalated from 3.0 to 14.0 mg/m² per day. In all, 92 evaluable courses were given to 34 patients, half of whom were heavily pretreated with radiation or cytotoxics. Myelosuppression and mucositis were the dose-limiting toxicities but were not different in heavily or minimally pretreated patients; there were five episodes of moderate to severe mucositis. Rash, fatigue, and diarrhea were mild toxicities. Plasma TMTX elimination was biexponential, with a mean t._1/2 of 0.23 h and a t._1/2 of 16.7 h. The area under the plasma TMTX concentration versus time curve increased linearly with dose, suggesting first-order elimination. Total plasma TMTX clearance (mean±SD) was 14.3±5.9 ml/min per m². Renal clearance accounted for approximately 7% of total clearance, indicating biotransformation as the major route of elimination. TMTX was highly protein-bound (97%). Thus, TMTX can be given with 5-FU (400 mg/m²) on a daily x 5-day bolus schedule at the 12 mg/m² per day dose level, which was the recommended dose of TMTX as a single agent for phase II studies using the 5-day bolus schedule.     

Capecitabine: fixed daily dose and continuous (noncyclic) dosing schedule

Background: Oral fluoropyrimidines are presumed to emulate a parenteral continuous low-dose infusion delivery of the drug and the commonly used schedule is a 14 day on, 7 day off cycle at a total daily dose of 2500 mg/m² dose. There is a substantial incidence of diarrhea and hand/foot syndrome with this dose schedule. Objective: To retrospectively analyze a clinical experience with a fixed-unit daily dose of capecitabine employed continuously (open ended without cycling) as a single agent, in combination with other agents, or combined with radiation to determine the drug tolerability with regard to stomatitis, diarrhea, and hand/foot syndrome, compared with the “standard” dose schedule. Method: Fifty patients received 58 courses of continuous fixed daily dose capecitabine as a single agent (19 courses), combination with weekly irinotecan (15 courses); combined with 24-hour 5-fluorouracil (5-FU) infusion weekly (5 courses), combined with radiation (3 courses), or with other chemotherapy (16 courses). A fixed divided daily dose of 1500 or 2000 mg was administered for an open-ended period of time designed to deliver 10 weeks of continuous administration. Incidence and time to adverse event (toxicity) was determined for each course. Results: Capecitabine was administered continuously for 4 weeks to 8 months with a median of 3 months. Seven of 50 patients (14%) experienced grade 2 or 3 toxicity; hand/foot syndrome, 4 (8%); stomatitis plus diarrhea (grade 2), 1%; and diarrhea alone, 3 (6%). Four of the 7 patients developing toxicity received concomitant weekly 24-hour 5-FU and 3 patients received concomitant CPT 11 (1), doxil (1), or taxane (1). None of the patients on single-agent capecitabine (19) developed toxicity of any grade. The total daily dose of capecitabine was 830 to 1250 mg/m². The maximum dose intensity of the continuous fixed-dose schedule is 8750 mg/m²/week compared with 11,666 mg/m²/week for the standard dose and schedule (2500 mg/m²/day for 14 days every 21 days). Conclusion: Capecitabine administered as a continuous daily fixed dose has a low toxicity profile and can be administered in conjunction with other therapies relatively easily. This schedule provides for convenience and simplicity, and therapeutic effects are demonstrated even at low doses. The dose intensity of the noncycling continuous regimen is approximately 20% less than the standard cycling 2 weeks on every 21-day schedule.     

Irinotecan and chronomodulated infusion of 5-fluorouracil and folinic acid in the treatment of patients with advanced colorectal carcinoma: a phase I study

BACKGROUND: Irinotecan (CPT-11) is an active drug in the treatment of patients with advanced colorectal carcinoma. The infusion of 5-fluorouracil (5-FU) according to circadian rhythms was used previously to decrease toxicity and to increase its therapeutic efficacy. The objective of this study was to establish the maximum tolerated dose (MTD) of CPT-11 together with a chronomodulated infusion of 5-FU and the l-form of folinic acid (FA). Secondary end points were the assessment of activity and quality of life (QoL). METHODS: Twenty-six patients with advanced colorectal carcinoma who had received previous treatment with 5-FU were entered on this Phase I study. At least three patients were recruited at each dose level. The CPT-11 starting dose was 175 mg/m(2) on Day 1 with an increase of 50 mg/m2 per dose level. A daily administration of chronomodulated 5-FU (900 mg/m2; peak delivery rate at 04:00) and FA (175 mg/m2; peak delivery rate at 04:00) for 5 days every 3 weeks was given with CPT-11. After the first three patients, the 5-FU dose was reduced to 700 mg/m2 per day due to toxicity. No intrapatient dose escalation was allowed. RESULTS: One hundred sixty-one courses were delivered. Dose-limiting toxicity was observed during the first course in seven patients (27%). Four patients developed neutropenia, with one patient reporting febrile neutropenia, two patients reporting severe stomatitis, and six patients reporting severe diarrhea. CPT-11 MTD was reached at 350 mg/m2 when a toxic death was observed with a recommended dose of 325 mg/m2. Six partial responses were observed (23%). The median duration of response and the progression free and overall survival rates were 199 days, 175 days, and 359 days, respectively. QoL was not affected by the treatment. CONCLUSIONS: The recommended dose for Phase II trials is 325 mg/m2 CPT-11 on Day 1, which is similar to the dose given as a single agent, together with a 5-day chronomodulated infusion of 700 mg/m2 5-FU and 175 mg/m2 FA. Intensification of this schedule every 2 weeks should be achievable.     

Phase I trial of 5-fluorouracil and dipyridamole administered by seventy-two-hour concurrent continuous infusion

Forty-seven patients with advanced malignancies were treated with a concurrent 72-h continuous infusion of 5-fluorouracil (FUra) and dipyridamole. The FUra dose was escalated over the dose range of 185 to 3600 mg/m2/day for 3 days. Dipyridamole was administered in a fixed dose of 7.7 mg/kg/day for 3 days. A total of 155 courses of therapy were completed of which there were 31 paired courses of the combination and FUra alone, at the same dose of FUra and in the same patient. This was for purposes of analysis of pharmacokinetics and modulation of FUra toxicity by dipyridamole. Stomatitis was the dose-limiting toxicity experienced by patients entered into this trial. Myelosuppression was not a serious problem. Increasing FUra plasma concentration was associated with greater leukopenia and stomatitis. Dipyridamole did not appear to modulate the systemic toxicity of FUra. The pharmacokinetics of FUra were altered by the concurrent administration of dipyridamole. Dipyridamole promoted the total body clearance of FUra which resulted in lower mean steady-state FUra plasma concentrations when compared with courses of FUra alone administered at the same dose level. These differences were statistically significant over the course of the trial. For courses of the combination, FUra exhibited linear pharmacokinetics over the dose range studied. Total body clearance of FUra declined slightly at the higher dose levels, but the differences were not significant. For courses of FUra alone, total body clearance was significantly decreased above the dose level of 2300 mg/m2/day. At the maximal tolerated dose of FUra, 2300 mg/m2/day x3, mean steady-state FUra plasma concentration and total body clearance were 6.6 microM and 122 liters/h/m2, respectively, for courses of the combination. The corresponding pharmacokinetic parameters were 7.4 microM and 103 liters/h/m2 for courses when FUra was given alone. Further evaluation of the utility of this regimen and basis of these pharmacokinetic observations appear warranted.     

A phase I clinical trial of combined fluoropyrimidines with leucovorin in a 14-day infusion. Demonstration of biochemical modulation

Two consecutive Phase I trials of continuous infusion 5-fluorouracil (5-FU) or floxuridine (5-FUdR) admixed with leucovorin (LCV) were performed and involved 19 and 24 patients, respectively. The studies were carried out to identify the optimal dose rate of delivery for the two admixtures (5-FU + LCV and 5-FUdR + LCV) administered for 14 days, and to determine if biochemical modulation could be identified. The optimal dose rates for 5-FU plus LCV were 200 mg/m2/d and 5 mg/m2/d, respectively. The optimal dose rates for 5-FUdR plus LCV were 0.075 mg/kg/d and 5 mg/m2/d, respectively. The dose rate limiting toxicity for 5-FU plus LCV was stomatitis and for 5-FUdR plus LCV it was diarrhea. LCV administered as an admixture with either 5-FU or 5-FUdR on an infusion schedule decreases the optimally tolerated dose rates for these two agents to 83% and 60%, respectively. This is achieved with low-dose LCV infusions.     

Relative importance of dose, body surface area, sex, and age for 5-fluorouracil clearance

The pharmacokinetics of 5-fluorouracil (FU) has been investigated in 26 cancer patients; 15 of these patients were pretreated with methotrexate (MTX). FU was given by a constant rate intravenous infusion within 10 min, at doses of 320-960 mg/m2. Total plasma clearance, beta-half-life, and steady-state distribution volume were determined with 43 treatments, based on plasma level measurements up to 90 min after the end of the infusion. Average clearance decreased from 1.3 l/min for 320 to 0.7 l/min for 960 mg FU/m2. Multiple linear regression calculations with dose, body surface area, sex, age, and MTX pretreatment as independent variable and clearance as dependent variable confirmed the dependency of clearance on dose and body surface area but also showed that, with equal FU dose per m2, clearance was higher in males than in females, on the average, by 0.22 l/min. There was also suggestive (although not significant) evidence of a (reducing) influence of age on FU clearance.     

Variability in the disposition of intraventricular methotrexate: a proposal for rational dosing

Despite the clinical experience with Ommaya reservoir-facilitated intraventricular methotrexate (MTX) therapy, established age-related dosage guidelines do not exist. In an attempt to design such a schedule, 49 courses of intra-Ommaya MTX (median dose, 6 mg) administered to 12 patients were studied. Using a fluorescence polarized immunoassay (TDx; Abbott, Dallas, TX), the median peak intraventricular CSF MTX concentration (CSF [MTX]) was 423 mumol/L. Median CSF [MTX] at 24 hours was 4.6 mumol/L, and at 48 hours was 1.05 mumol/L. Median MTX half-life (t1/2) was 5.7 hours. A CSF [MTX] greater than 1 mumol/L was maintained for 24 hours in all but one course and for 48 hours in half of the courses. No correlations were found between MTX dose, patient age, [MTX], t1/2 or prior therapy. Considerable intra- and interpatient variability was seen in MTX disposition, emphasizing the need to monitor [MTX] with each course. A schedule for intraventricular MTX with an initial dose of 6 mg and supplemental doses of 6, 4, or 2 mg at 24 and 48 hours according to serial measurements of intraventricular [MTX] should be initiated to provide a minimum CSF [MTX] of 1 mumol/L for 72 hours.     

Neoadjuvant PFL augmented by methotrexate and piritrexim followed by concomitant chemoradiotherapy for advanced head and neck cancer: a feasible and active approach.

To increase the complete remission (CR) rate achieved with two cycles of cisplatin, continuous infusion fluorouracil (5-FU) and oral leucovorin (PFL) we added two antifolate drugs, methotrexate (MTX) and the lipophilic piritrexim (PTX), to the combination (PFL-MP). Twenty-eight patients with previously untreated Stage IV squamous cell carcinoma of the head and neck received 2 cycles of cisplatin 100 mg/m2 on day 1 followed by a 5-day continuous infusion of 5-FU at 800 mg/m2/day and 100 mg of leucovorin administered orally every 4 hours. MTX was administered at 40 mg/m2 IV on day 15 and PTX at 75 mg orally twice daily on days 22 to 26, with cycle 2 starting on day 36. After 2 of the first 5 patients had tumor progression between days 15 and 35, the regimen was intensified to MTX 50 mg/m2, PTX 100 mg twice daily and a cycle duration of 28 days. Local therapy consisted of surgery and/or radiotherapy with concomitant 5-FU and hydroxyurea (FHX) administered every other week. Eleven patients (39%, 95% confidence intervals 21-57%) had a CR, 9 (32%) had a PR, and four patients had no response. Four patients were unevaluable for response to PFL-MP. Patients with poor performance status or N3 disease were less likely to achieve a CR. Mucositis following PFL was the dose-limiting toxicity. Local therapy included surgery in 15 patients and FHX chemoradiotherapy in 19 patients. The administration of FHX in this setting proved feasible and the regimen was given near the intended dose intensity in the majority of patients.(ABSTRACT TRUNCATED AT 250 WORDS)