Weekly therapy with folinic acid (FA) and high-dose 5-fluorouracil (5-FU) 24-hour infusion in pretreated patients with metastatic colorectal carcinoma: A multicenter study by the Association of Medical Oncology of the German Cancer Society (AIO)

BACKGROUND: No effective salvage therapy is known for patients with metastaticcolorectal carcinoma progressive after chemotherapy with 5-fluorouracil(5-FU)/folinic acid (FA) or 5-FU/alpha interferon (IFN) combinations.The aim of the study was to test whether weekly FA/high-dose5-FU is an effective therapy in pretreated patients with progressivemetastatic colorectal carcinoma. PATIENTS AND METHODS: Between January and December 1992, 57 patients with metastaticcolorectal carcinoma were treated with weekly infusions of high-dose5-fluorouracil (5-FU) (2600 mg/m² as 24-hour infusion) and folinicacid (FA) (500 mg/m² as 1-hour infusion prior to 5-FU). Allpatients were pretreated with chemotherapy, most of them withregimens containing 5-FU i.v. bolus/FA or 5-FU/alfa interferon(IFN), and all had documented progressive disease at the timeof entering the study. In patients with partial remission (PR)or stable disease (SD) with improvement of their clinical condition,therapy was continued until progressive disease (PD) was documented.In all other patients therapy was stopped after one course (6infusions). RESULTS: 5/57 patients (9%) achieved PR, 32/57 (56%) SD, in 19/57 (33%)disease was progressive and one toxic death occured. 26/32 patients(81%) with SD or PR after the first chemotherapy again obtainedSD or PR on high-dose 5-FU/FA but only 8/18 (44%) of those withPD after first chemotherapy did so. The median duration of SD/PRwas 3 months and the median survival for all patients 8 months(range 3–17+). Apart from one toxic death, toxicity consistingfor the most part of mucositis (n = 24), nausea (n = 23), diarrhoea(n – 18) and hand-foot syndrome (n = 12) was moderate. CONCLUSION: Pretreated patients with metastatic colorectal carcinoma, notablythose with a primary PR or SD, can probably benefit from weeklyhigh-dose 5-FU/FA. metastatic colorectal carcinoma, high-dose 5-FU/FA     

Neoadjuvant treatment with weekly high-dose 5-Fluorouracil as 24-hour infusion,folinic acid and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer

PURPOSE: To evaluate the efficacy and safety of neoadjuvant treatment comprising weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion, folinic acid (FA) and biweekly oxaliplatin (L-OHP), followed by metastatic resection in patients with primarily resectable liver metastases of colorectal cancer (CRC). PATIENTS AND METHODS: 20 patients with primarily resectable liver metastases of CRC were enrolled in a prospective phase II study. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m(2) L-OHP in the form of a 2-hour intravenous infusion and 500 mg/m(2) FA as a 1- to 2-hour intravenous infusion, followed by 2,600 mg/m(2 ) 5-FU administered as a 24-hour intravenous infusion once weekly. A single treatment cycle comprised one infusion per week during a period of 6 weeks followed by a 2-week rest. Two cycles were administered, with a third being added when the treatment was well tolerated. Thereafter, curative resection of the liver metastases was attempted, and the patients were followed up. RESULTS: After neoadjuvant therapy, 2 of the original 20 patients showed complete remission (CR; 10%) and 18 patients partial remission (PR; 90%). As the main symptom of toxicity, diarrhea (CTC toxicity grade 3-4) was observed in 6 patients (30%), followed by vomiting in 3 patients (15%). The curative resectability rate was 80% (16 of 20). In 9 of 18 patients (50%) undergoing surgical intervention, mild postoperative complications, mainly wound healing disturbances (n = 5), occurred. No postoperative mortality was observed. Over a median follow-up of 23 months (12-38) 6 of 16 curatively resected patients developed distant metastases and 1 patient a local pelvic recurrence. The 2-year disease-free survival rate was 52% and the 2-year cancer-related survival rate 80%. CONCLUSION: The neoadjuvant treatment with weekly high-dose 5-FU in the form of a 24-hour infusion combined with FA and L-OHP is very effective and well tolerated. Surgical morbidity does not appear to be increased by the neoadjuvant treatment.     

Phase II study of a weekly 24-hour infusion with 5-fluorouracil and simultaneous sodium-folinic acid in the first-line treatment of metastatic colorectal cancer.

BACKGROUND: A weekly continuous 24-hour infusion therapy with 5-fluorouracil (5-FU) and calcium - folinic acid (CA-FA) was shown to be an effective first-line treatment in advanced metastatic colorectal cancer. Sodium - folinic acid (S-FA) is a new formulation which, in contrast to CA-FA allows the simultaneous i.v. administration in combination with 5-FU in one pump. PATIENTS AND METHODS: From 1997 to 1998, 51 patients [median age 60 (range 24-77) years; 38 male, 13 female] with metastatic colorectal cancer were recruited in 5 centers to receive weekly 24-hour infusions of 5-FU (2,600 mg/m(2)) and S-FA (500 mg/m(2)) dissolved in one pump for 6 weeks as first-line treatment. The treatment cycle was repeated after a 2-week rest period. RESULTS: 1,178 administrations (median 24, range 3-54) were performed during the study. Out of 51 patients (median follow-up 20.2 months), 2 (3.9%) achieved complete remission (CR), 17 (33.3%) partial remission (PR), and 21 (41.2%) no change (NC). Progressive disease (PD) was observed in 11/51 (21.6%) patients, including 6 patients who did not complete the first cycle. Median time to tumor progression (TTP) was 8.5 months (95% CI: 5.8-11.3). 32/51 (62.7%) patients survived for more than 1 year, the median survival was reached at 16.5 months (95%CI: 10.2-22.8). Among major toxicities, NCICTC grade III/IV diarrhea occurred in 13/51 (25.4%), grade III hand-foot syndrome in 6/51 (11.7%) patients. Grade III/IV stomatitis was observed in 4/51 (7.8%), cardiac toxicity occurred in 2/51 patients (3.9%). CONCLUSION: Similar to conventional 24-hour 5-FU + CA-FA treatment, the combination with S-FA induced 37.2% objective responses with moderate toxicity. However, TTP seems favorable and the administration of S-FA is convenient, while saving costs and time for the patient in outpatient units.     

Weekly regimen of 5-FU vs 5-FU + intermediate dose folinic acid in the treatment of advanced colorectal cancer.

Sixty-four patients with advanced colorectal cancer were randomized to receive 5-fluorouracil (5-FU) at the dose of 600 mg/sm weekly or the same regimen of 5-FU administered halfway through a 1 hour i.v. infusion of folinic acid (FA) at the dose of 200 mg/sm. A partial remission (PR) was obtained in 1/30 patients (3%) treated with 5-FU and in 9/34 patients (26%) treated with 5-FU + FA (P = 0.028). The objective response was accompanied by an improvement in subjective status and general conditions. The median duration of PR in 5-FU + FA arm was 10 months (range: 6-17). The median time to progression was 5 and 6 months in patients treated with 5FU and 5FU + FA, respectively (not a statistically significant difference). There were no cases of grade 4 toxicity. A higher, but not statistically significant, incidence and intensity of diarrhoea was observed in the 5-FU + FA arm. However, 14 patients on 5-FU + FA as opposed to 3 on 5-FU had to stop the treatment temporarily because of side-effects (P = 0.011). Median survival was higher with 5-FU + FA treatment (10 vs 7 months), but the difference is not statistically significant. This study confirms that the addition of an intermediate dose of FA enhances the cytotoxicity of 5-FU. Although its clinical advantage was limited, this weekly 5-FU + FA regimen appears useful in the treatment of advanced colo-rectal cancer on a outpatient basis.     

Palliative second-line treatment with weekly high-dose 5-fluorouracil as 24-hour infusion and folinic acid (AIO) plus oxaliplatin after pre-treatment with the AIO-regimen in colorectal cancer (CRC)

BACKGROUND AND AIMS: The aim of this work was to evaluate the efficacy and safety of second-line treatment with weekly high-dose 5-Fluorouracil (5-FU) as a 24-hour infusion (24-h inf.) and folinic acid (FA) (AIO-regimen) plus Oxaliplatin (L-OHP) after pre-treatment with the AIO regimen, focusing in particular on the efficacy of palliative first- and second-line treatment in colorectal carcinoma (CRC). PATIENTS AND METHODS: Patients with non-resectable distant CRC metastases were enrolled in a prospective phase II study for palliative second-line treatment after previous palliative first-line treatment in accordance with the AIO regimen. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m2 L-OHP in the form of a 2-hour intravenous (i.v.) infusion and 500 mg/m2 FA as a 1 to 2-hour i.v. infusion, followed by 2,600 mg/m2 5-FU administered as a 24-h inf. i.v. once weekly. A single treatment cycle comprised 6 weekly infusions followed by 2 weeks of rest. RESULTS: During second-line treatment, a total of 26 patients received 340 chemotherapy applications. As the main symptom of toxicity, diarrhoea (NCI-CTC toxicity grade 3+4) presented in 5 patients (19%; 95% CI: 4-34), followed by nausea (CTC grade 3) in one patient (4%; 95% CI: 0-11). Twenty-three patients were evaluable for treatment response. The remission data can be summarised as follows: Complete remission (CR): n=1 (4%; 95% CI: 0-13); partial remission (PR): n=3 (13%; 95% CI: 0-27); stable disease (SD): n=11 (48%; 95% CI: 27-68) and progressive disease (PD): n=8 (35%; 95% CI: 15-54). The median progression-free survival (PFS) rate (n=26) was 3.3 months (range 0-11.5), the median survival time counted from the start of second-line treatment (n=26) 11.6 months (range 2.1-33.0) and the median survival time counted from the start of first-line treatment (n=26) 19.9 months (range 7.7-49.8). CONCLUSION: Palliative second-line treatment according to the AIO regimen plus L-OHP is feasible in an outpatient setting and well tolerated by the patients. Tumour control (CR + PR + SD) was achieved in 65% of the patients, the median survival time being 11.6 months. The AIO regimen followed by the 'AIO regimen plus L-OHP' therapy sequence led to a promising median survival time of 19.9 months (range 7.7-49.8).     

Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction.

BACKGROUND: Patients with hepatic or renal dysfunction are often treated with 5-fluorouracil (5-FU), but there are few data to confirm the safety of this practice. PATIENTS AND METHODS: Patients with solid tumors were eligible if they were able to fit into one of three organ dysfunction cohorts: I, creatinine >1.5 but < or =3.0 mg/dl and normal bilirubin; II, bilirubin >1.5 but <5.0 mg/dl with normal creatinine; or III, bilirubin > or =5.0 mg/dl with normal creatinine. 5-FU doses were escalated separately within each of the three cohorts. Leucovorin (LV) dosage was fixed at 500 mg/m(2). 5-FU was given as a 24-h infusion at 1000, 1800 or 2600 mg/m(2), and plasma concentrations were measured every 3 h during the first two infusions for each patient. RESULTS: Sixty-four patients were treated. Toxicities did not appear to be related to organ dysfunction cohort. A weekly dose of of 5-FU 2600 mg/m(2) produced dose-limiting toxicity (DLT) in six of 20 evaluable patients.These DLTs included grade 3 fatigue (n = 3), grade 2 neutropenia precluding weekly dosing (n = 1), grade 3 thrombocytopenia (n = 1) and grade 3 mental status changes (n = 1). There was no relationship between serum bilirubin or serum creatinine and 5-FU clearance. CONCLUSIONS: Patients with elevated bilirubin may be safely started on a weekly regimen of 5-FU 2600 mg/m(2) with leucovorin 500 mg/m(2) as a 24-h continuous infusion.     

Cetuximab and irinotecan/5-fluorouracil/folinic acid is a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma.

BACKGROUND: To investigate the safety/tolerability of the EGFR-antibody cetuximab when added to irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) for first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Twenty-one patients with untreated, metastatic, EGFR-expressing CRC received cetuximab 400 mg/m(2) as an initial dose, and thereafter 250 mg/m(2) weekly. In addition, patients received infusional 5-FU (24 h) in two dose levels (1500 mg/m(2), low 5-FU group, n = 6 or 2000 mg/m(2), high 5-FU group, n = 15), plus FA at 500 mg/m(2) and irinotecan at 80 mg/m(2), weekly x6 q50d. RESULTS: Twenty patients were assessable for tolerability after the first cycle. There were no dose limiting toxicities (DLTs) in the low 5-FU group and three DLTs (20%) in the high 5-FU group (two patients with diarrhea grade 3 and one patient with diarrhea grade 4). In the low 5-FU group all six patients received >80% of the planned dose. In the high 5-FU group, seven of 14 patients (50%) received < or =80% of the planned chemotherapy dose during the first cycle due to dosage reductions whilst treatment delays occurred in 10/14 patients. During the whole study period, the common grade 3/4 adverse events were acne-like rash (38%) and diarrhea (29%). Chemotherapy did not affect the pharmacokinetics of cetuximab determined at weeks 1 and 4. Fourteen patients (67%, 95% CI 47% to 87%) had a confirmed response, and six (29%) had stable disease. Median time to progression was 9.9 months [lower 95% confidence limit (CL) 7.9, upper 95% CL not reached]. Median survival time was 33 months (lower CL 20, upper CL not reached). Four patients received secondary surgery with curative intent, and a fifth was potentially eligible for surgery but declined. CONCLUSIONS: Addition of cetuximab to weekly infusional 5-FU/FA plus irinotecan is safe and first data suggest a promising activity. The 5-FU dose of 1500 mg/m(2) is recommended for further studies.     

Sequential biochemical modulation of fluorouracil with folinic acid, N-phosphonacetyl-L-aspartic acid, and interferon alfa-2a in advanced colorectal cancer.

PURPOSE: Several agents have been evaluated for their effect as biochemical modulators of fluorouracil (5-FU) in the treatment of metastatic colorectal carcinoma. In this study, we used folinic acid (FA), N-phosphonacetyl-L-aspartic acid (PALA), and recombinant interferon alfa-2a (IFNalpha-2a) in a sequential order to assess the efficacy of this approach in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Forty-four patients with metastatic colorectal carcinoma were enrolled onto the study. The treatment course consisted of three cycles: (cycle 1) FA 20 mg/m(2) followed by 5-FU 425 mg/m(2) on days 1 to 5; (cycle 2) PALA 250 mg/m(2) on days 29, 36, 43, and 50 and 5-FU 2,600 mg/m(2) as a 24-hour infusion on days 30, 37, 44, and 51; and (cycle 3) IFNalpha-2a 9 million units (MU) three times a week for 5 weeks beginning on day 57, with a continuous infusion of 5-FU 750 mg/m(2) on days 57 to 61, and then weekly bolus of 5-FU 750 mg/m(2)/wk on days 71, 78, and 85. Response was determined after cycle 3. RESULTS: All patients had a Zubrod performance status >/= 2, measurable disease, and had received no prior chemotherapy for their metastatic disease. A total of 212 cycles were given. Thirty-six patients were assessable for response. No complete responses were seen. Seven patients had a partial response, eight had stable disease, and 15 had progressive disease. The median duration of response was 25 weeks, and the median survival was 53 weeks. Grade 3 and 4 toxic effects included granulocytopenia, stomatitis, diarrhea, rash, nausea, and fatigue. CONCLUSION: This trial provided no evidence that sequential biochemical modulation of 5-FU in patients with metastatic colorectal carcinoma had any therapeutic advantage over conventional treatment regimens of 5-FU plus FA.     

A simplified regimen of weekly high dose 5-fluorouracil and leucovorin as a 24-hour infusion in patients with advanced colorectal carcinoma

BACKGROUND: Reports of in vitro experiments in colorectal carcinoma cells suggest that prolonged cellular exposure to 5-fluorouracil (5-FU) combined with relatively low concentrations of leucovorin (LV) provides optimal enhancement of 5-FU efficacy. In this study, a simplified regimen of weekly 24-hour infusion of high dose 5-FU combined with a relatively low dose of LV was used to treat patients with advanced colorectal carcinoma. METHODS: Thirty-six patients with advanced colorectal carcinoma received 5-FU, 2600 mg/m2, admixed with LV, 100 mg/m2, in a portable infusion pump administered intravenously over a 24-hour period. High dose 5-FU/LV was delivered once a week for 5 consecutive weeks followed by a 1-week recovery period. All patients were assessable for toxicity and response. RESULTS: Two complete responses and 15 partial responses were observed (response rate of 47.2%; 95% confidence interval, 30.1-64.4%). The median response duration was 9.6 months. The median survival and time to progression were 11.9 months and 7.1 months, respectively. The toxicity was mild and acceptable. The major dose-limiting factors were hand-foot syndrome and fatigue. CONCLUSIONS: This simplified regimen of weekly 24-hour continuous infusion of high dose 5-FU/LV is an effective regimen in the treatment of patients with advanced colorectal carcinoma. Further study of the pharmacokinetics of combination therapy with 5-FU and LV as used in this regimen and its correlation with response and toxicity is warranted.     

Clinical reevaluation of continuous intravenous infusion of 5-fluorouracil--plasma concentrations and clinical dose by continuous intravenous and 60-min infusions

Daily and intermittent continuous intravenous infusions [by gravity drip, (IVG) or infusion pump, (IVP)] and intermittent short-time intravenous drip infusion of 5-FU were carried out on advanced cancer patients. The MTD and dose-limiting toxicity were investigated in relation to the plasma concentrations of 5-FU determined by HPLC. Responses in eleven patients receiving IVG administration daily at 8-21 mg/kg/day were NC, but those given 5-FU alone showed no adverse reactions. Plasma concentrations were too low to be determined. In 9 patients receiving IVG or IVP administration weekly at 60 mg/kg for 24 hr, 1 of the 5 evaluable patients showed reduced hepatic metastatic lesions. One of 4 patients receiving IVP administration weekly at 120 mg/kg for 48 hr showed a disappearance of metastatic lesions in the skeletal muscle, but bone marrow suppression was observed as dose-limiting toxicity. Pharmacokinetics were more stable in IVP than in IVG with less individual difference in the plasma concentrations. Among the outpatients receiving short-time iv, IVG administration once or twice a week, 2 patients given weekly administrations at 20 mg/kg for 60 min showed slight adverse reactions. In 6 patients given high-dose administrations, bone marrow suppression was observed. When pharmacokinetics in the patients given 5-FU for 60 min were compared between the IVG and IVP groups, there were individual differences in plasma concentrations, but the differences were not significant. It was concluded from above results that the following practical dose schedules would be recommendable: 60 mg/kg for 24hr/week by IVP for inpatients and 20 mg/kg for 60 min/week by IVG for outpatients.     

Influence of oxaliplatin on 5-fluorouracil plasma clearance and clinical consequences

The influence of oxaliplatin (OXA) on 5-fluorouracil (5-FU) plasma clearance was investigated. PATIENTS AND METHODS: A group of 29 patients with advanced colorectal cancer refractory to prior weekly 8-h 5-FU infusion plus bolus folinic acid (FA), received the same combination plus OXA at 130 mg/m(2) every 3 weeks, OXA plus 5-FU plus FA on day 1, and 5-FU plus FA on days 8 and 15. Steady-state 5-FU concentrations in plasma were measured weekly and 5-FU clearance was calculated. Both before and after the addition of OXA, the 5-FU dose was individually adjusted according to the pharmacokinetic follow-up (target steady-state plasma concentrations 2.5-3 mg/l). RESULTS AND DISCUSSION: A total of 122 OXA-containing infusions and 338 5-FU plus FA infusions were given and the median number of infusions per patient was 4 (2-9) and 10 (5-28), respectively. 5-FU plasma clearance was significantly decreased on days 8 and 15 when compared with the value on day 1 and with the values before OXA introduction using a direct paired comparison (2.36 and 2.31 l/min, respectively, vs 3.12 and 3.05 l/min; P<10(-5)). Of 25 evaluable patients, 6 had an objective response after the introduction of OXA (24% objective response rate, 95% confidence interval 9.4-45%). CONCLUSION: OXA reduces 5-FU plasma clearance for 15 days. This may be a factor in the synergy between the two drugs. It is not linked to dihydropyrimidine dehydrogenase inhibition. Implications for drug schedules in clinical practice are discussed.     

High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study

BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur.     

Second-line treatment of advanced colorectal cancer with a weekly simultaneous 24-hour infusion of 5-fluorouracil and sodium-folinate: a multicentre phase II trial

BACKGROUND: A weekly continuous 24-h infusion therapy with 5-fluorouracil (5-FU) preceded by a 2-h infusion of calcium folinate (CA-FA) was shown to be an effective first- and secondline treatment in advanced metastatic colorectal cancer. Substitution of CA-FA by the new formulation sodium folinate (S-FA) allows the simultaneous i.v. administration of folinic acid with 5-FU in one pump. PATIENTS AND METHODS: From 1999 to 2001, 42 patients with metastatic colorectal cancer after pre-treatment with a 5-FU bolus regimen were recruited in 5 centres to receive weekly 24-h infusions of 5-FU (2,600 mg/m2) and S-FA (500 mg/m2) dissolved in one pump for 6 weeks as second-line treatment. The treatment cycle was repeated after a 2-week rest period. RESULTS: 106 6-week cycles (median 2, range 1-6 per patient) were administered during the study. The median followup was 22 months. Out of 42 patients, 1 (2%) achieved complete remission, 3 (7%) partial remission, and 31 (74%) no change. Median time to tumour progression was 5.7 months (95% CI: 4.1-6.5). The median survival was reached at 14.7 months (95% CI: 11.0-22.0). Among major toxicities, NCI-CTC grade III/IV diarrhoea occurred in 8/42 (19%), grade III hand-foot-syndrome in 5/42 (12%) and grade III/IV stomatitis in 3/42 (7%) patients. CONCLUSION: Similar to conventional 24-h 5-FU + CA-FA treatment, the combination with S-FA in second-line therapy induced 9% objective responses and stopped tumour progression in 74%. The simultaneous administration of both, S-FA and 5-FU over 24 h dissolved in one pump is convenient, safe and effective as second-line treatment for patients with colorectal cancer.     

Fluorouracil modulation in colorectal cancer: lack of improvement with N -phosphonoacetyl- l -aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule--an Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study.

PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P <.001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.     

Phase I chemotherapy study of biochemical modulation of folinic acid and fluorouracil by gemcitabine in patients with solid tumor malignancies.

PURPOSE: This phase I biochemical modulation study evaluated the maximum-tolerated dose (MTD), toxicity, and effectiveness of the combination of folinic acid (FA)/fluorouracil (5-FU) followed by escalated dose levels of gemcitabine (FFG) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were refractory to primary treatment and/or without effective treatment options. Twenty-eight patients received an intravenous (IV) infusion of FA 100 mg/m(2) over 1 hour and a 5-FU 450 mg/m(2) IV bolus in the middle of the FA infusion. After the FA infusion, gemcitabine was administered at a steady rate of infusion of 10 mg/m(2)/min over initially 30 minutes and with increases of an additional 15 minutes at each given level. One cycle consisted of six weekly treatments followed by a 2-week rest. RESULTS: The MTD of gemcitabine was established at 900 mg/m(2) given over 90 minutes. Eight patients of 21 with metastatic colorectal cancer achieved responses (one complete response; seven partial responses), for a response rate of 38%. Responses were seen across the gemcitabine doses of 300 to 900 mg/m(2). One patient had prior treatment with FA/5-FU for advanced disease. Patients with colorectal carcinoma had a median survival of 18 months, and the patient with lung carcinoma has been alive for 24+ months. CONCLUSION: The combination chemotherapy of FFG was well tolerated and may benefit patients with advanced colorectal carcinoma. A phase II evaluation in this patient population is in progress.     

A phase I study of weekly docetaxel, 24-hour infusion of high-dose fluorouracil/leucovorin and cisplatin in patients with advanced gastric cancer

OBJECTIVES: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of both docetaxel and 5-fluorouracil (5-FU) when administered weekly in a regimen of docetaxel, 5-FU/leucovorin and cisplatin (DFLP) for 2 consecutive weeks every 3 weeks. PATIENTS AND METHODS: A total of 31 patients with chemo-naive, advanced adenocarcinoma of the stomach were enrolled in the study. Cisplatin and leucovorin dosages were fixed throughout the study at 30 and 300 mg/m2, respectively. 5-FU dosage was fixed at 1,600 mg/m2 while docetaxel was evaluated at weekly 1-hour infusion dosages of 30, 40 and 50 mg/m2 to determine the MTD. Cisplatin, 5-FU and leucovorin were administered together as a 24-hour continuous infusion following docetaxel. Weekly 5-FU dosages of 1,600, 2,000 and 2,400 mg/m2 were then evaluated after setting the docetaxel dosage at the MTD. RESULTS: A total of 95 chemotherapy cycles were administered, with a median of three cycles per patient. The MTD of docetaxel was defined at 40 mg/m2. At a docetaxel dosage of 50 mg/m2 per week, the dose-limiting events of grade 4 febrile neutropenia and grade 3 hypomagnesemia occurred. With fixation of docetaxel to 40 mg/m2, the DLT for 5-FU was found at 2,400 mg/m2 per week. This incurred grade 4 neutropenia such that the MTD of 5-FU was defined at 2,000 mg/m2. Grade 3/4 neutropenia occurred in 14 patients (45%), with 2 patients developing febrile neutropenia. Grade 2 and 3 hypomagnesemia and hypokalemia occurred in 9 (41%) and 4 (18%) patients, respectively, of the first 22 patients treated with a 24-hour infusion of cisplatin and 5-FU/leucovorin immediately following docetaxel. Following a change in the cisplatin administration schedule to a 3-hour infusion after 5-FU/leucovorin infusion, no such complications were observed in 9 subsequently treated patients. Grade 2 diarrhea was recorded in 11 patients (35%). Grade 2/3 asthenia occurred in 9 patients (30%), which resolved after correction of electrolyte disorders. Twenty-six patients were assessable for response analysis. There were 2 (7.8%) complete and 14 (53.8%) partial responses, with the overall response rate being 61.5% (95% confidence interval, 41.5-81.6%). Responses were observed at all dose levels. CONCLUSION: Two consecutive weeks of DFLP infusions every 3 weeks appear to be an active regimen with a tolerable toxicity profile in advanced gastric cancer. For further phase II studies, the recommended dose for this combination is 40 mg/m2 of docetaxel and 2,000 mg/m2 of 5-FU per week.     

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.     

Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study.

BACKGROUND: To identify the most effective of two combinations, irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) and irinotecan/cisplatin, in the treatment of advanced gastric cancer, for investigation in a phase III trial. PATIENTS AND METHODS: Patients were randomized to receive irinotecan [80 mg/m2 intravenously (i.v.)], FA (500 mg/m2 i.v.) and a 22-h infusion of 5-FU (2000 mg/m2 i.v.), weekly for 6 weeks with a 1-week rest, or irinotecan (200 mg/m2 i.v.) and cisplatin (60 mg/m2 i.v.), on day 1 for 3 weeks. RESULTS: A total of 115 patients were eligible for analysis in the per-protocol population. The overall response rate in the irinotecan/5-FU/FA arm (n=59) was 42.4%, with a complete response rate of 5.1%. Corresponding figures for the irinotecan/cisplatin arm (n=56) were 32.1% and 1.8%, respectively. The median time to progression was 6.5 months (irinotecan/5-FU/FA) and 4.2 months (irinotecan/cisplatin) (P < 0.0001), with median survival times of 10.7 and 6.9 months, respectively (P=0.0018). The major toxicity was grade 3/4 neutropenia, which was more pronounced with irinotecan/cisplatin than with irinotecan/5-FU/FA (65.7% versus 27%). Diarrhea was the main grade 3/4 non-hematological toxicity with both irinotecan/5-FU/FA (27.0%) and irinotecan/cisplatin (18.1%). CONCLUSIONS: Both combinations were active, with acceptable safety profiles. Irinotecan/5-FU/FA was selected as the most effective combination for investigation in a phase III trial in advanced gastric cancer.     

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.     

Mitomycin C plus infusional 5-fluorouracil in platinum-refractory gastric adenocarcinoma: an extended multicenter phase II study

OBJECTIVE: To assess the toxicity and activity of bolus mitomycin C (MMC) in combination with a 24-hour continuous infusion of 5-fluorouracil (5-FU) in gastric cancer patients who had received at least one prior chemotherapy regimen. PATIENTS AND METHODS: Patients were treated with MMC (10 mg/m(2)) on days 1 and 22, 5-FU (2.6 g/m(2)) as a 24-hour infusion, and folinic acid 500 mg/m(2) weekly for 6 weeks. RESULTS: Thirty-four patients with gastric cancer, 16 after failure of first-line chemotherapy and 18 after failure of at least two prior chemotherapies, were included. In the intent-to-treat analysis, 9 (26.5%) of the 34 patients had a partial response and 10 (29.4%) a disease stabilization (disease control rate 56%). The median time to progression was 3.3 months (CI95: 2.8-3.7), and the median overall survival was 7.2 months (CI95: 5.9-8.4). Grade III/IV thrombocytopenia occurred in 14.7% of patients (n = 5), while the most frequent nonhematological grade III/IV toxicities were mucositis and diarrhea, each affecting 9% of patients. CONCLUSIONS: As the tested regimen was generally safe and well tolerated by the patients, MMC plus infusional 5-FU/folinic acid may be a potential second-line regimen for patients with advanced gastric cancer.