Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside

Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-l-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m² given on day 1, followed 24 h later by MMPR 150 mg/m², and escalating doses of 5-FU from 1625 to 2600 mg/m² by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m². Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m², MMPR 150 mg/m², and 5-FU 2300 mg/m² by continuous infusion over 24 h.     

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.     

Phase I study of phosphonacetyl-l-aspartate, 5-fluorouracil,and leucovorin in patients with advanced cancer

Low-dose phosphonacetyl-l-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 M suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 M. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m² PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m² admixed with 50 mg/m² leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m². Dose modification resulted in a mean dose intensity of 2,300 mg/m² at both the 2,600- and 2,300-mg/m² dose levels. The 2,300-mg/m² dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (C_ss) of 5-FU in 23 patients. The mean C_ss increased with dose from 0.738 to 1.03 g/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean C_ss (1.10±0.19) than those with grade O or I toxicity (0.835±0.25,P<0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU C_ss values. These results confirm the contribution of leucovorin to the toxicity of the 5-FU/leucovorin combination and suggest that interpatient differences in folate pharmacology may contribute to the therapeutic index of the 5-FU/leucovorin combination.Supported in part by NCI CA06927, NCI CA38053, and an appropriation from the Commonwealth of Pennsylvania     

A phase I trial of combination therapy with continuous-infusion PALA and continuous-infusion 5-FU

Summary Thirty-four patients were treated with N-(phosphonacetyl)-l-aspartate (PALA) at a dose of 850 mg/m²/dayx5 by continuous intravenous infusion (days 1–5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300–630 mg/m²/dayx5 by continuous intravenous infusion (days 2–6). Dose-limiting oral mucositis occurred at a 5-FU dose of 560 mg/m²/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and superficial venous phlebitis. Myelosuppression was rare. One partial response was observed in a patient with metastatic colorectal carcinoma. Plasma PALA levels were monitored in seven patients. Steady-state levels were achieved by the 2nd day of drug infusion and ranged between 10 and 20 g/ml.     

A phase II trial of PALA+dipyridamole in patients with advanced soft-tissue sarcoma

Summary A total of 21 patients with advanced soft tissue sarcoma enrolled in a phase II trial of 3.5 g/m² N-phosphonacetyl-l-aspartate (PALA) given intravenously every 3 weeks plus 50 mg/m² dipyridamole (Persantine) given orally every 6 h. Dipyridamole administration was initiated 1 week before the first dose of PALA. Peak and trough plasma concentrations of dipyridamole were measured before and after the first dose of PALA in 14 patients. In all, 19 patients were evaluable for therapeutic response. One subject experienced partial regression of a pulmonary metastasis; no other major response was observed. Diarrhea was the most prominent toxicity; in one patient it was life-threatening and was associated with a severe rash. On the day preceding PALA administration, the median peak plasma concentration of dipyridamole was 2,208 ng/ml and the median trough value was 904 ng/ml. Similar values were obtained on the day of PALA administration. Although the levels achieved were similar to those required to modulate the activity of PALA in preclinical systems, the therapeutic results obtained in the present study were not superior to those reported for PALA alone in previously treated patients with soft-tissue sarcoma.Supported by Boehringer Ingelheim, Inc., and NCI grant CA 47 179     

Phase II clinical trial of 5-fluorouracil, trimetrexate, and leucovorin (NFL) in patients with advanced pancreatic cancer

Background. Advanced pancreatic cancer has limited treatment options. 5-fluorouracil (5-FU) is frequently used in the treatment of pancreatic cancer. Preclinical studies suggest synergism between trimetrexate (TMTX), 5-FU, and leucovorin (NFL). Aim. We conducted a phase II trial to evaluate the activity and safety of NFL in pancreatic cancer. Method. Eligible patients (n=21) with untreated advanced pancreatic cancer were treated with 110 mg/m² intravenous (IV) THTX on day 1 and 200 mg/m² IV leucovorin prior to 500 mg/m² IV 5-FU on day 2. Oral leucovorin (15 mg every 6 h for seven doses) started intravenous 24 h later. Results. Treatment was administered for 6 wk followed by a 2-wk rest period. Response was evaluated every 8 wk. All patients were evaluable for response and toxicity. Most patients (80%) had distant metastases. Forty-five cycles of chemotherapy were administered. The most common serious toxicities were Grade 3 diarrhea (23.8%) and nausea and vomiting (14.2%). The response rate was 4.1% (95% CI, 0–23%), median survival was 6.8 mo, and 1-yr survival was 19%. Conclusion. Treatment with NFL is well-tolerated in patients with advanced pancreatic cancer. The median survival and 1-yr survival in these patients with poor prognosis compares favorably with other treatment options.     

Phase II study of weekly 24-hour intra-arterial high-dose infusion of 5-fluorouracil and folinic acid for liver metastases from colorectal carcinomas

Background:A multicenter phase II trial was initiated inorder to evaluate the weekly, high-dose 24-hour infusion of5-fluorouracil (5-FU) plus folinic acid (FA) in patients with unresectablecolorectal cancer hepatic metastases. Patients and methods:A weekly hepatic arterial infusion (HAI) ofFA 500 mg/m² followed by a 24-hour infusion of 5-FU 2,600mg/m² (later reduced to 2,200 mg/m²) was given via asurgically implanted intra-arterial port system. One treatment cycle consistedof six weekly applications followed by a two-week rest period. Toxicity wasassessed according to the WHO criteria. Chemotherapy was continued untildisease progression or complete response occured. Results:A total of 50 patients (40 chemonaive, 10 pretreated)entered this trial. An objective tumor response occurred in 28 patients(56%), while 13 patients (26%) had stable disease. The medianprogression free survival was 12 months, and the median survival 22.3 months.Due to a high rate of gastrointestinal side-effects in the initial phase ofthe trial, the dosage of 5-FU was reduced to 2,200 mg/m² for allsubsequent patients. Diarrhea and nausea led to a dose reduction in 40%of applications and 24% of patients, respectively. One patient died ofcardiac insufficiency unrelated to chemotherapy before responseevaluation. Conclusions:This HAI approach using high-dose 5-FU was relativelywell tolerated when 2,200 mg/m² instead of 2,600 mg/m²was used. The activity of this regimen is promising and warrants furtherevaluation and modification.     

A phase I, II study of high-dose 5-fluorouracil and high-dose leucovorin with low-dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies

Twenty-eight patients with refractory advanced malignancies were treated with a 24-hour infusion of 5-fluorouracil (5-FU), leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable to assess toxicity and antitumor activity. The PALA was administered as an intravenous bolus over 15 minutes at a fixed dose (250 mg/m2) 24 hours before the start of the 5-FU and leucovorin infusions. Initially the dose of 5-FU was 750 mg/m2; this was increased incrementally to 2600 mg/m2. The LV was administered in a fixed dose of 500 mg/m2 concurrently with the 5-FU over a 24-hour period. This regimen was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among the dose-limiting toxicities. Others were hand-foot syndrome, hair loss of the scalp and eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. The maximum tolerated dose of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated with 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose reductions, but most received 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients were treated previously. Eight patients had a partial response; five of these were treated previously. A complete response was observed in one patient with pancreatic carcinoma, previously untreated. The overall response rate for patients treated with 2100 or 2600 mg/m2 of 5-FU was nine of 18 patients (50%). Three of four previously untreated patients with pancreatic cancer responded to this treatment (two responded partially, and one had a complete response). One of three heavily pretreated patients with non-small cell lung cancer had a partial response as did a patient with breast cancer. Four of ten patients with colorectal cancer responded to the treatment (four partial responses), of whom three had been treated previously.     

High-dose 5-fluorouracil and leucovorin as second-line chemotherapy in patients with platinum-resistant epithelial ovarian cancer

A total of 14 patients with platinum-resistant advanced epithelial ovarian cancer were treated with a continuous infusion of high-dose 5-fluorouracil (5-FU, 1200 mg/m² per day) for 2 consecutive days weekly for 4 weeks and, thereafter, every 2 weeks in combination with a push injection of folinic acid (20 mg/m²) given just before 5-FU and after 24 h. No objective response was documented, and only five patients showed stable disease. The median survival was 6.5 months. There was minimal toxicity. This schedule of 5-FU in combination with folinic acid is not effective as second-line chemotherapy in advanced ovarian cancer.     

Phase II study of biochemical modulation of fluorouracil by low-dose PALA in patients with colorectal cancer

Higher response rates in colorectal cancer have been observed with regimens that increase the cytotoxicity of fluorouracil (5-FU) by altering the biochemical milieu at its site(s) of action. Phosphonacetyl-L-aspartate (PALA), which inhibits aspartate transcarbamylase and depletes uridine nucleotide pools in vitro and in vivo, selectively potentiates the antitumor activity of 5-FU in preclinical models. In a phase I/II study in patients with advanced colorectal cancer, PALA 250 mg/m2 was given on day 1, followed 24 hours later by 5-FU 2,600 mg/m2 by 24-hour infusion repeated weekly. Through the use of subcutaneous ports and portable infusion pumps, all patients were treated outside the hospital setting. Thirty-nine patients without prior chemotherapy received 884 courses of treatment. The primary site was colon in 31, rectum in eight. Toxicity was generally mild to moderate except among four patients who were escalated to 5-FU 3,250 mg/m2: two developed severe gastrointestinal toxicity and myelosuppression. Among the remaining 35 patients, gastrointestinal and neurologic toxicities predominated, but usually did not develop until the third or fourth month of treatment. Two patients were inevaluable for response. Among the 37 evaluable patients there were three complete and 13 partial remissions for a total response rate of 43% (95% confidence interval [Cl], 27% to 59%). The median duration of response was 5 months (range, 1.5 to 15 months). The projected mean survival is in excess of 17 months. This high response rate is comparable to the best results obtained with other means of modulation of 5-FU. Demonstration of a survival benefit will require larger phase III studies.     

Combination chemotherapy of cisplatin and 5-fluorouracil for advanced colorectal adenocarcinoma

Summary A total of 24 patients with advanced colorectal adenocarcinoma were entered into a phase I–II study of 5-fluorouracil (5-FU) and cisplatin, 21 of whom had previously received 5-FU. The starting dose of cisplatin was 20 mg/m² diluted in 1000 cc normal saline, given over 20 h daily for 5 days, together with 600 mg/m² 5-FU diluted in 1000cc fluid, given simultaneously over 20 h daily for 5 days. This regiment was given every 4 weeks. The dose-limiting toxicity was renal and cumulative. All 24 patients were evaluable for toxicity. Of 12 patients on the abovementioned starting dose, 8 underwent a cisplatin dose reduction to 15 mg/m² due to a progressive decrease in creatinine clearance following the second or third course of treatment. Of 12 patients who started cisplatin at 15 mg/m² and 5-FU at 600 mg/m², 11 were maintained at this dose. A WBC nadir count of<2000/mm³ was seen in four patients. Thrombocytopenia occurred in three patients who received 15 mg/m² cisplatin and 600 mg/m² 5-FU. In all, 21 of the 24 patients had objectively measurable disease and were also evaluable for response as follows: 1 complete response, 2 partial responses, 1 case of stable disease, and 17 patients with progressive disease.     

Metastatic carcinoid and islet cell tumours of the pancreas: A phase II trial of the efficacy of combination chemotherapy with 5-fluorouracil,doxorubicin and cisplatin

A phase II trial of chemotherapy in carcinoid and islet cell pancreatic tumours has been conducted with the FAP protocol: 5-fluorouracil 400 mg/m² per day (5-FU) for 3 days, 50 mg/m² doxorubicin on day 2, and 90 mg/m² cisplatin on day 2, repeated every 4 weeks. 24 patients, 20 non-pretreated and 4 pretreated, were included. For non-pretreated patients we observed 1 complete response and 2 partial responses. The response rate was 15% (95% confidence interval 0–31%). No response was observed in the pretreated patients. The toxicity was mainly digestive and haematological with 7 patients experiencing vomiting grade 3 and 3 patients with leucopenia grade 3. We conclude that the FAP protocol is of poor efficiency in endocrine tumours.     

Five-day continuous infusion of 5-fluorouracil and pulsed folinic acid in patients with metastatic colorectal carcinoma: An effective second-line regimen

Objective: A previous phase I trial in 14 pretreated patients with progressive advanced colorectal cancer demonstrated 750 mg/m² to be the maximum tolerable dose of 5-fluorouracil (5-FU) administered as a 5-day continuous infusion modulated by short infusions of 100 mg/m² folinic acid twice daily. The dose-limiting toxicities were hand-foot syndrome and severe mucositis. A response rate of 21% and 50% stable disease could be achieved. In order to determine the effectiveness and tolerability, we initiated a multicenter phase II trial applying a 650 mg/m² recommended dose of 5-FU and 100 mg/m² folinic acid twice daily every three weeks.Patients and methods: From January 1994 to July 1996, 88 advanced and progressive colorectal cancer patients either previously treated with a bolus schedule of 5-FU and folinic acid (34 patients) or without (54 patients) previous chemotherapy were included in this trial.Results: In the group of previously treated patients, therapy led to 6% (2 of 34 patients) remissions while stable disease could be observed in 68% (23 of 34 patients) of the patients. The median survival time was 14 months. The main toxicity was mucositis grade 3 in 15% of the previously treated patients and 10% in the nonpretreated patients. In the population of nonpretreated patients, the overall response rate was 15% (eight of 54 patients) and stable disease could be induced in 67% (36 of 54 patients). The median survival time was 13.7 months.Conclusion: This regimen is an active second-line therapy in advanced colorectal cancer with minimal toxicity, thus preserving the quality of life during palliative chemotherapy. Antitumor activity in previously untreated patients does not seem superior to that obtained with weekly regimens applying 24- or 48-hour continuous infusions of 5-FU and folinic acid.     

High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.     

Protracted infusional 5-fluorouracil (5-FU) with bolus mitomycin in 5-FU-resistant colorectal cancer

Background:MF (protracted infusion 5-fluorouracil (5-FU), 300mg/m²/24 hours plus bolus mitomycin, 7 mg/m² every 6weeks, maximum 4 doses), was recently shown in a randomised trial to besuperior to protracted 5-FU alone, as first-line chemotherapy for metastaticcolorectal cancer (Ross et al. Ann Oncol 1997; 8: 995–1001 [5]). We haveexamined the same regimen in patients with 5-FU-resistant disease. Patients and methods:MF was given to 24 patients with metastaticcolorectal cancer, median age 63 years. Two had progressed within four monthsof adjuvant 5-FU; the rest had already received palliative 5-FU, withprogression during (11 patients), within four months (5 patients) or afterfour months of completion (6 patients). The prior 5-FU regimens were bolus5-FU/FA (8 patients); 48 hour bolus + infusion 5-FU/FA (18 patients) orprotracted 5-FU alone (3 patients). Five patients had received more than oneprior 5-FU regimen. Results:Three patients, 12.5%, achieved WHO partialresponse; seven others had minor response or stable disease (SD or better =42%, 95% confidence interval (95% CI):22%–64%). Median failure-free survival (FFS) was 15 weeks;median overall survival was 9.0 months. No grade 3 or 4 drug toxicityoccurred, but dose reduction and/or interruption for persistent grade 2toxicity was required in eight patients (33%). Three patients(12.5%) had venous line problems (2 thrombosis; 1 dislodged). Therewere no toxic deaths. 12 patients (50%) went on to receive third-linetherapy after MF, including irinotecan or oxaliplatin. Conclusions:MF is a low-cost, well-tolerated regimen insecond-line treatment of metastatic colorectal cancer. The response rate andFFS obtained in this small group are similar to those reported for singleagent irinotecan. Half our patients obtained a useful period of control withMF before moving on to further treatment with new agents such as irinotecanand oxaliplatin.     

Phase I trial of 5-fluorouracil,leucovorin, and cisplatin in combination

Summary The ongoing evaluation of combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin in several tumors prompted a phase I clinical trial of cisplatin with 5-FU modulated by leucovorin. A total of 26 patients were treated with varying doses of 5-FU by continuous i.v. infusion for 5 days; 200 mg/m² leucovorin was given by daily bolus injection for 5 days; and 20 mg/m² cisplatin was infused over 2 h on each day of treatment. Courses were repeated every 21–28 days. The starting dose of 5-FU was 300 mg/m². Poor-risk patients (extensive prior radiation, performance status of 2 or worse) did not tolerate the initial dose; the maximum tolerated dose of 5-FU in this group was 200 mg/m² daily. Good-risk patients tolerated 300 mg/m², but a majority had excessive toxicity at higher doses. The dose-limiting toxicity was gastrointestinal (mucositis/diarrhea) and/or myelosuppression; additional side effects included were nausea and vomiting (grade 2) and ataxia (one patient). Among 13 patients with colorectal cancer, 4 partial responses were observed. The marked reduction in the tolerable dose of 5-FU occasioned by the addition of modulating doses of leucovorin is noteworthy. The response observed support further investigation of this regimen in phase II trials.     

A phase II trial of weekly high dose continuous infusion 5-fluorouracil plus oral leucovorin in patients with advanced colorectal cancer

Background. In a previous Phase II trial, the authors showed that a weekly continuous infusion of 5-fluorouracil (5-FU) at a dose of 3.5 g/m² for 48 hours is an active treatment for advanced colorectal cancer. The overall response rate was 38.5%, and the median survival was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. To study the modulation of this weekly, high dose, continuous infusion 5-FU with oral leucovorin, a new Phase II trial was planned. Methods. From December 1991 to July 1992, 43 previously untreated patients with measurable advanced colorectal cancer were included in a multicenter study. They received on an outpatient basis 5-FU at a weekly dose of 3 g/m² by continuous infusion for 48 hours until progression or toxicity. Oral leucovorin (60 mg every 6 hours) also was given during the infusion of 5-FU. Results. Patients received a median dose intensity of 5-FU of 2.2 g/m²/week (range, 0.76-3 g/m²/week). One complete response and 11 partial responses were observed. The overall response rate was 29% (95% confidence interval [CI], 16–45%). Median time to progression was 7 months, and the median survival was 15 months. World Health Organization Grades 3 and 4 diarrhea were observed in 19 (45%) and 6 (14%) patients, respectively. Grade 3 mucositis also was observed in 10 (24%) patients, and Grade 4 mucositis was observed in 1. Grade 3 nausea and vomiting were reported in seven (17%) patients. Grade 3 hand–foot syndrome was detected in only two (2.5%) patients. No leukopenia or thrombocytopenia was observed. Conclusions. Oral leucovorin modulation of a weekly 48-hour infusion of 5-FU at a dose of 3 g/m² of leucovorin is a toxic regimen, always requiring dose reduction, with diarrhea and mucositis as the main limiting toxicities. Its antitumor activity does not seem superior to that observed with a weekly 48-hour infusion of 5-FU alone at a dose of 3.5 g/m². Cancer 1995; 76:559–63.     

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer

Purpose

To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer.

Methods

Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m², respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m² to the MTD.

Results

A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m². All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12–66%) in 13 chemotherapy-naïve patients.

Conclusions

A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m² of docetaxel, 30 mg/m² of cisplatin and 1,500 mg/m² of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial.     

A phase II multi-institutional trial of low-dose N-(phosphonacetyl)-L-aspartate and high-dose 5-fluorouracil as a short-term infusion in the treatment of adenocarcinoma of the pancreas. A Southwest Oncology Group study

Adenocarcinoma of the pancreas is a highly lethal malignancy and chemotherapy has had little impact on the natural history of this disease. PALA, used to potentiate 5-fluorouracil (5-FU), has been shown to have synergy in vivo and in vitro. Twenty-seven patients were treated with an intravenous push dose of PALA (250 mg/m2) followed 24 hours later with a 24-hour infusion of 5-FU (2600 mg/m2). This regimen was repeated weekly. There was one partial response of 21 eligible patients with an estimated response rate of 5%. Toxicity was severe with one toxic death and four patients experiencing Grade 4 toxicity. 5-Fluorouracil and PALA, given in the schedule described, do not appear to be effective against adenocarcinoma of the pancreas.     

N-(phosphonacetyl)-l-aspartate and calcium leucovorin modulation of fluorouracil administered by constant rate and circadian pattern of infusion over 72 hours in metastatic gastrointestinal adenocarcinoma

Background:We have reported thatN-(phosphonacetyl)-l-aspartic acid (PALA) 1266 mg/m² cansafely be given 24 hours prior to the start of a 72-hour infusion offluorouracil (FUra) and leucovorin (LV) at doses of 2000 and 500mg/m²/day. Since inhibition of aspartate carbamoyltransferase(ACTase) activity was evident 4 hours post PALA, we wished to evaluatePALA given 1 hour prior to FUra. Further, we studied the toxicity andpharmacokinetics with FUra given by either fixed-or variable-rateinfusion. Patients and methods:Twenty-seven patientswith gastrointestinal tract adenocarcinomas were treated with PALA 1266mg/m²/15 min followed by a 72-hour infusion of FUra and LV (1750 & 500 mg/m²/day) given by fixed- orvariable-rate (peak at 4:00 A.M.). Results:Clinicaltoxicity was similar in two consecutive cycles in 17 patients receivingfixed- and variable-rate infusion at the same FUra dose. Overall, grade3 stomatitis and hand-foot syndrome occurred in 12% and 4%patients receiving fixed- and in 16% and 10.5% of patientsreceiving variable-rate infusions. Six of 24 evaluable patients(25%) had a partial response. The profile of FUra plasma levels(Cp) over a 24-hour period during fixed- and variable-rate infusionswere strikingly different, but the average Cp and area under theconcentration-time curves were comparable. ACTase activity wassignificantly decreased at 4 and 24 hours after PALA(12% and 18% of baseline;P < 0.001), but enzyme activity had recovered to40% by 72 hours. Conclusions:This regimen wasactive and well tolerated with similar toxicities with FUra given byeither fixed- or variable rate infusion. PALA 1266 mg/m²significantly inhibited ACTase activity for at least 24 hours.