Hyperreactio luteinalis in a normal pregnancy: sonographic and MRI findings

We investigated the efficacy of combination chemo-therapy using 5-fluorouracil (5-FU), cisplatin (CDDP), and dipyridamole (DP), which is based on the concept of double biochemical modulation. Twenty-eight patients with advanced gastric cancer were treated with the simultaneous continuous intravenous (i.v.) infusion of 5-FU (800 mg/m2/day) and DP (4 mg/kg/day), and i.v. infusion of CDDP (20 mg/m2/day) for 5 days. The cycles were repeated every 4 weeks. Twelve patients (43%) had a partial response (PR), while stable disease (NC) occurred in 13 patients (46%), and progression (PD) in 3 patients (11%). An improved performance status was observed in 20 patients (71%). The carcinoembryonic antigen (CEA) level was markedly decreased in 75% of the CEA-positive patients. Toxicity was acceptable. The mean steady state plasma concentration of total DP was 6.40.5 microM, which thus seemed adequate to potentiate the cytotoxicity of 5-FU. The treatment regimen described herein thus appears to be effective, safe and well tolerated by patients with advanced gastric cancer.     

Cardiovascular disease prevention in eastern Europe

A phase II trial was conducted to evaluate the efficacy and toxicity of a modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) (with leucovorin (LV) rescue) as first-line chemotherapy in patients with locally advanced (inoperable) or metastatic gastric carcinoma. From July 1993 through August 1996, 36 patients with advanced gastric carcinoma received a regimen that consisted of: MTX 200 mg/m2 diluted in 250 ml normal saline by intravenous infusion over 20 minutes at hour 0; 5-FU 1,200 mg/m2 intravenous push injection at hour 20. Beginning 24 hours after MTX administration all patients received LV 15 mg/m2 intramuscularly every 6 hours for six doses. Cycles were repeated every 15 days. One patient was not assessable for response. Objective regression was observed in 15 of 37 patients (43%; 95% confidence interval, 26%-60%). One patient (3%) achieved complete response and 14 (40%) achieved partial response. No change was recorded in 14 patients (40%) and progressive disease was noted in six patients (17%). The median time to treatment failure was 7 months and the median survival was 12 months. Toxicity was within acceptable limits but one therapy-related death resulting from severe leukopenia occurred. The dose-limiting toxicity was mucositis. Five episodes of grade 3 or 4 stomatitis were observed and caused dosage modifications of MTX and 5-FU. Biochemical modulation of 5-FU by MTX appears as an attractive modality in patients with advanced gastric cancer. Further investigation both in experimental and clinical fields is needed to clearly define its role and to design the best modulatory strategy.     

Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma

BACKGROUND: Previous trials in patients with colorectal carcinoma have indicated that enhancement of 5-fluorouracil (5-FU) by leucovorin (LV) can result in an improved response rate and increased survival. METHODS: Phase II trials were performed with patients who had either gastric or papcreatic adenocarcinoma with inetastases. Forty-one gastric carcinoma patients and 31 pancreatic carcinoma patients with measurable disease were treated with 5-FU, 425 mg/m2 intraveneosly (i.v.) on Days 1-5 plus LV, 20 mg/m2 i.v., on Days 1-5, reported at 4 and 8 weeks, and then every 5 weeks thereafter. RESULTS: The patients with metastatic gastric carcinoma had a median survival of 4.8 months. There was a 22% objective response rate, including a 4.9% complete response rate and a 17.1% partial response rate. Among the 31 patients with pancreatic carcinoma, there was a median survival of 5.7 months. No patients in this group showed a response. CONCLUSIONS: The response rate for patients with metastatic gastric adenocarcinoma was modest and this regimen may provide temporary palliation for some patients. However, 5-FU and LV treatment is ineffective against metastatic pancreatic carcinoma.     

Risk factors for thrombotic events in giant cell arteritis and polymyalgia rheumatica

BACKGROUND: FOLFOX2, a bimonthly regimen of high-dose leucovorin (LV), 48-hour continuous infusion of 5-fluorouracil (5-FU) (LV-5-FU) and oxaliplatin (100 mg/m2) produced a high response rate (46%; 95% confidence interval (95% CI): 31%-60%) in 5-FU pre-treated patients with metastatic colorectal cancer. In this phase II study, pre-treated patients were given a lower dose of oxaliplatin to reduce the toxic effects of the regimen. PATIENTS AND METHODS: Thirty patients with advanced colorectal adenocarcinoma and progression while receiving bimonthly LV-5-FU (LV: 500 mg/m2, 5-FU: 1.5-2 g/m2/22 hours, days 1-2, every two weeks), were given the same LV-5-FU schedule with the addition of oxaliplatin (85 mg/m2) every two weeks (FOLFOX3). RESULTS: The main toxic effects were peripheral neuropathy (90%) with four severe sensitive neuropathies (WHO grade 2: 13%). The response rate was 20% (95% CI: 8%-39%). Median progression-free survival was 26 weeks, median survival was 57 weeks from the start of FOLFOX3 and median duration of the response was 37 weeks. CONCLUSIONS: Results obtained with FOLFOX3 confirmed the synergy between oxaliplatin and 5-FU in 5-FU-resistant metastatic colorectal cancer. However, the response rate seems to be lower than that obtained with FOLFOX2. Further studies to determine the best oxaliplatin dose intensity are in progress.     

Combination chemotherapy of continuous infusion 5-fluorouracil and daily low-dose cisplatin in advanced gastrointestinal and lung adenocarcinoma

Continuous intravenous infusion (c.v.i.) of 5-fluorouracil (5-FU) plus daily low-dose cisplatin (CDDP) was evaluated in 45 patients with advanced and recurrent unresected colorectal, lung, gastric and pancreatic adenocarcinoma. 5-FU was given at a dose of 320 mg/m2/day, c.v.i. for 4 weeks, and CDDP between 3.5 to 7 mg/m2/day, infused for one hour five times a week for 4 weeks. Patients received 1 to 3 cycles of treatment (average 1.5 cycle). Pancreatic cancer cases needed longer treatment periods (2.25 cycles). The response rate of colorectal cancer cases was 57.7% (15/26), pancreas cancer 40%, gastric cancer 62.5%, and lung cancer 66.7%. The overall response rate was 57.8%. No severe side effects occurred in any of these cases. These data indicate that this combination 5-FU + daily low-dose CDDP chemotherapy is effective in the treatment of advanced gastrointestinal and lung adenocarcinoma.     

Two cases of advanced gastric cancer effectively treated with chemotherapy of 5-fluorouracil, cisplatin and cytarabine

We reported two cases of advanced gastric cancer effectively treated with chemotherapy of 5-fluorouracil (5-FU), cisplatin (CDDP) and cytarabine (Ara-C), 5-FU (300-350 mg/body) was given by continuous intravenous infusion. Ara-C (20-40 mg/body) by continuous infusion and CDDP (15-20 mg/body) were added intravenously for 3-6 days. For case 1, epirubicin (30 mg/body) was also given on the first day of each therapy course. Case 1 was a 62-year-old female who had gastric cancer with liver metastasis, ovarian metastasis and peritonitis carcinomatosa. After 3 courses of the chemotherapy, reduction of ovarian metastasis greater than 75% was observed. The value of CA125 decreased from 6,800 U/ml to 527 U/ml and ascites disappeared. Case 2 was a 54-year-old male who had type 3 advanced gastric cancer with multiple liver metastases. He received 6 courses of the therapy. Both primary and metastatic tumors showed over 50% reduction in tumor size. These suggested that this combination therapy was effective for inoperable advanced gastric cancers.     

Multivariate analyses of the hominid ulna from Klasies River mouth

BACKGROUND: The combination of 5-fluorouracil (5-FU) and cisplatin has shown great activity in many different types of tumour with an in vitro synergistic effect between 5-FU and cisplatin. A phase II study of 5-FU plus cisplatin was performed in 25 previously untreated patients with inoperable locally advanced or metastatic biliary tract carcinoma. PATIENTS AND METHODS: Twenty-five patients, 10 of them men and 15 women with a median age of 58, were entered into the study. The chemotherapy regimen consisted of 5-FU: 1 g/m2/day in continuous intravenous (i.v.) infusion for five consecutive days, and cisplatin: 100 mg/m2/day on day 2 in a one-hour infusion with standard hyperhydration. Twenty-two patients had metastatic tumours and three had locally advanced disease. RESULTS: Of the 25 patients entered into the study, 24 were evaluable for response and 25 for toxicity. Nausea and vomiting was the main toxic side effect in 19 patients. Severe, WHO grade 3-4 thrombocytopenia or neutropenia were observed in three and seven patients, respectively. There were no toxic deaths. Of 25 patients, six had partial remissions (overall response 24%, 95% confidence interval 7%-41%). For three patients, tumour reduction permitted local radiotherapy and one of these patients with initially advanced disease is still alive six years after the beginning of treatment. CONCLUSIONS: This study, one of the largest phase II trials performed in this disease, shows interesting activity of the combination of 5-FU and cisplatin in advanced biliary tract carcinoma.     

Etoposide, epirubicin and cisplatin (EEP) combination in metastatic cancers of the cardia and the stomach. Groupe de recherche en cancérologie du Nord (GRECNO)

This study was aimed to confirm the therapeutic activity of the combination of etoposide, doxorubicin and cisplatin which has shown some clinical efficiency as first line therapy in advanced gastric cancer. Seventeen patients with metastatic gastric cancer were treated with etoposide (120 mg/m2, i.v., on day 5, 6 and 7), epirubicin (20 mg/m2, i.v., on day 1 and 7) and cisplatin (40 mg/m2, i.v., on day 2 and 8), q 4 weeks. In 16 patients evaluable for response, three (19%) obtained a partial response lasting from 93 to 360 days. Fifteen patients were evaluable for toxicity. Main toxicities > grade 2 included anemia (2/15), neutropenia (5/15), alopecia (8/15), fatigue (3/15), diarrhea (2/15), vomiting (2/15). Twenty nine per cent of severe toxic events were documented all along 52 cycles. Therefore we failed to confirm that this regimen could be of clinical efficiency in advanced gastric cancer as regards the benefits/toxicity ratio.     

A phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer

PURPOSE: This multicenter phase II study was designed to assess the efficacy of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients with histologically proven metastatic colorectal cancer, and at least one bidimensionally measurable lesion, aged 18-70, with performance status < or = 2, normal baseline biological values and no prior chemotherapy (or only adjuvant chemotherapy completed > or = 6 months before study entry) were selected. Treatment was irinotecan 350 mg/m2, i.v., day 1, alternating with leucovorin 20 mg/m2 i.v. and 5-FU 425 mg/m2, i.v. daily for five consecutive days, day 22-26 (Mayo Clinic regimen). One alternating cycle was to be performed every six weeks. Patients were evaluated for efficacy every alternating cycle. Treatment was administered until five alternating cycles, disease progression, unacceptable toxicity or patient refusal. RESULTS: Thirty-three patients (28 chemotherapy-na?ve and five with prior adjuvant treatment completed > 1 year prior to accrual) were enrolled. The objective response rate (RR) was 30% (95% CI: 16-49; 10 patients/33; nine partial response and one complete response). All responses were reviewed by an independent external review committee. An additional 49% of patients had stable disease. The median survival was 16 months, the one year survival amounted to 58% and the median progression free survival was 7.2 months. Relative dose intensity was nearly 90% for both drugs. Grade 3-4 diarrhea and neutropenia were the most frequent severe toxic events, seen in 24% and 64% of patients, respectively. CONCLUSIONS: The alternating schedule of CPT-11 350 mg/m2 with five days bolus of 5-FU and low dose LV is an active and feasible regimen as front-line therapy for metastatic CRC. It is well tolerated, without evidence of overlapping toxicity. The response rate appears promising with regard to that expected with either single agent. This regimen warrants further assessment in randomized trials.     

A pilot study of gamma-1b-interferon in combination with fluorouracil, leucovorin, and alpha-2a-interferon

The combination of IFN-alpha-2a (IFN-alpha) and IFN-gamma-1b (IFN-gamma) has been found to produce more than additive cytotoxicity with fluorouracil (5-FU) in HT 29 colon cancer cells due to enhanced DNA-directed effects. We therefore studied the combination of IFN-gamma with IFN-alpha, 5-FU, and leucovorin (LV) in a clinical trial. Fifty-three patients received an initial cycle of 5 million units (MU)/m2 IFN-alpha s.c. on days 1-7 with 500 mg/m2 LV and 370 mg/m2 5-FU i.v. on days 2-6. IFN-gamma was then added once tolerable doses of 5-FU and IFN-alpha were established for each patient. IFN-gamma was administered at one of six dose levels between 0.3-4.8 MU/m2 s.c. on days 1-7. This design permitted comparison of the clinical toxicity and pharmacokinetics of 5-FU in two consecutive cycles in an individual treated with the same doses of 5-FU/LV/IFN-alpha in the absence and presence of IFN-gamma. In 43 matched patient cycles, the addition of IFN-gamma did not seem to worsen gastrointestinal toxicity, and skin toxicity tended to be milder. 5-FU clearance was higher in 14 cycles with IFN-gamma compared to the patient's prior cycle with the same doses of 5-FU/LV/IFN-alpha: 798 +/- 309 versus 601 +/- 250 ml/min/m2 (mean +/- SD; P = 0.04). In these 28 cycles, the median 5-FU clearance was significantly lower in 11 cycles that were complicated by more severe diarrhea: 524 versus 798 ml/min/m2 (grade 2 versus 0-1; P = 0. 0032). Overall, 38% and 26% of patients had grade 3-4 diarrhea and mucositis. Dose reductions of IFN-gamma for chronic fatigue, malaise, or anorexia were ultimately required more frequently with >/=2.4 MU/m2 (P = 0.018), and the maximum tolerated dose of IFN-gamma was considered to be 1.2 MU/m2/ day. Objective responses were seen in 41% of 29 measurable colorectal cancer patients. Compared to our previous experience with 5-FU/LV/IFN-alpha, IFN-gamma and IFN-alpha appeared to have opposite effects on 5-FU clearance. These results suggest that any potential benefit of adding IFN-alpha to 5-FU/LV on this schedule may not depend solely on alterations in 5-FU clearance.     

Ischemia/reperfusion injury in flow-through venous flaps

This study was designed to test the activity and feasibility of 5'-deoxy-5-fluorouridine (5'-DFUR) and cisplatin combination therapy in the treatment of advanced gastric cancer. Nineteen patients with inoperable and/or metastatic gastric cancer, which was histologically proven, were orally administered 5'-DFUR 1,200 mg/m2 on days 1 to 4 and days 15-18 combined with 70 mg/m2 of cisplatin being repeated every 4 weeks. Five partial responses (PRs) were achieved. Seven patients had stable disease and 6 progressed on therapy. The overall response rate was 27.7% (95% confidence interval: 9.69% to 53.5%). The median survival duration of all 18 patients was 25 weeks (9-64). The majority of patients had WHO grade I/II toxicity, but there was no treatment-related death. These data support that the combinations of oral 5'-DFUR and cisplatin are well tolerable and have a moderate activity with low toxicity in the treatment of advanced gastric cancer.     

New combination therapy with FTM [5-FU, pirarubicin (THP) and MMC] for treatment of inoperable advanced gastric cancer

Clinical usefulness of a new combination FTM therapy consisting of 5-FU, Pirarubicin (THP) and MMC for the treatment of advanced gastric cancers was investigated. 5-FU, THP or MMC was administered at a dose of 600 mg/m2 on day 1, 8, 22 and 29, 30 mg/m2 on days 1 and 22, and 10 mg/m2 on day one only of each course, respectively. Eighteen patients with inoperable advanced gastric cancer were treated with FTM. All drugs were investigated by intravenously by one shot. The tumor response rate was 50% [9 of 18 showed PR]. The survival rate was higher in responders than in nonresponders (18.1% vs 11.1%) (p < 0.05). Side effects in the gastrointestinal tract were minimal. Cardiotoxicity and nephrotoxicity were not detected, but myelosuppression was prominent in most cases. G-CSF was given in sixteen patients (88%), and platelet transfusion was performed in two patients (11%). New combination FTM therapy is an effective treatment regimen even for advanced inoperable gastric cancer.     

A phase I study of paclitaxel and 5-fluorouracil in advanced gastric cancer

This is a phase I study to determine the maximum tolerated dose (MTD) and toxicity of a combination of paclitaxel and 5-Fluorouracil (5-FU) in advanced gastric cancer patients. The patients, refractory to the PELF regimen (5-FU, leucovorin, cisplatin, epidoxorubicin), received weekly 5-FU at the fixed dose of 500 mg/m2, and escalating doses of paclitaxel every 3 weeks with a starting dose of 150 mg/m2 given as in 3-h infusion. The dose was escalated by 25 mg/m2 every 3 patients. Fifteen patients entered the study. The upper paclitaxel dose (225 mg/m2) was given to 6 patients. Up to this dose, no severe toxicity (grade 3-4) was recorded. Apart from alopecia, grade 1-2 leukopenia occurred in 5 patients and grade 1-2 neurotoxicity in 2 patients. All patients were evaluable for response (at least 2 cycles): 2 patients achieved an objective response (200 and 225 mg/m2). In 6 patients, treatment resulted in notable relief from symptoms. Out-patient paclitaxel given over 3 h and 5-FU may be combined safely for the treatment of patients with advanced gastric cancer. The recommended doses for phase II study are paclitaxel 225 mg/m2 and 5-FU 500 mg/m2.     

5-fluorouracil and low-dose leucovorin as surgical adjuvant therapy from viewpoint of long-term outcome

Biochemical modulation of 5-FU by leucovorin (LV) has been demonstrated to increase the therapeutic effect compared to single agent 5-FU in the treatment of patients (pts) with advanced colorectal cancer. The purpose of this study was to determine the effectiveness of the 5-FU + LV combination as adjuvant therapy following surgery in pts with Dukes' B, C colon cancer. Pts were entered in a stratified clinical trial comparing two different combination chemotherapeutic regimens to single agent 5-FU, given orally as a control. This report summarized the result of treatment in 61 pts who were 5-FU oral alone and 32 pts who were 5-FU (375 mg/m2) and low-dose LV (20 mg/m2) intravenously for 5 days with 5-FU oral intake. 5-FU with LV regimen was associated with an improved survival compared with the single agent 5-FU oral intake (p < 0.05). 5-FU with LV regimen resulted in less recurrence in liver and lung compared with single-agent 5-FU oral intake.     

Biventricular repair in neonates with hypoplastic left heart complex

PURPOSE: We previously developed an inpatient regimen that consisted of infusional fluorouracil (5-FU), epirubicin, and cisplatin (ECisF), with a response rate of 86% in advanced breast cancer. The current phase II 2:1 randomized study investigated whether cyclophosphamide can be substituted for cisplatin (ECycloF) to reduce toxicity and allow the regimen to be administered on an outpatient basis without loss of efficacy. PATIENTS AND METHODS: Ninety-six women (median age, 49 years; range, 28 to 73) with breast cancer (59 metastatic, 37 locally advanced) received continuous infusional 5-FU (200 mg/m2/d via Hickman line) and six cycles of epirubicin (60 mg/m2 every 21 days) with either cyclophosphamide 600 mg/m2 every 21 days (38 metastatic, 24 locally advanced) or cisplatin 60 mg/m2 every 21 days (21 metastatic, 13 locally advanced). There were no significant differences in patient characteristics between these groups. RESULTS: ECycloF was better tolerated than ECisF in terms of lethargy (P = .005), stomatitis (P = .008), plantar palmar erythema (P = .02), constipation (P < .001), thrombosis (P = .0014), and nausea and vomiting (P = .05). Although there was a trend toward more anemia and leukopenia with ECisF (P =. 1), there was no significant difference in the rates of infection. Efficacy was comparable in terms of overall response (69% v 68%), complete response (CR; 13% v 15%), and median progression-free survival (9 v 8 months). CONCLUSION: ECycloF is an outpatient regimen with a lower incidence of severe nonhematologic toxicity than inpatient ECisF; it has comparable efficacy and is considerably more economical.     

Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study

PURPOSE: A prospective randomized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy (CT) and radiotherapy (RT) in previously untreated patients with unresectable stage III/IV head and neck cancer. PATIENTS AND METHODS: Patients with locoregionally advanced head and neck cancer were treated either with RT alone (arm A) or simultaneous RT plus CT (RCT; arm B). RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily. During one course, from day 3 to 11, 23.4 Gy was delivered. In arm B, cisplatin (CDDP) 60 mg/m2, fluorouracil (5-FU) 350 mg/m2 by intravenous (i.v.) bolus, and leucovorin (LV) 50 mg/m2 by i.v. bolus were given on day 2, and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5. Treatment was repeated on days 22 and 44; a total RT dose of 70.2 Gy was administered. Treatment breaks were scheduled from days 12 to 21 and days 34 to 43. RESULTS: From 1989 to 1993, 298 patients were enrolled and 270 patients were assessable. Acute mucositis grade 3 or 4 was more frequent in arm B (38%) than in arm A (16%) (P < .001). Total treatment time was significantly longer in arm B than in arm A (P < .001) due to prolonged breaks. According to hematologic toxicity, scheduled drug doses were given in 74% of patients for the second course and 46% for the third course. The 3-year overall survival rate was 24% in arm A and 48% in arm B (P < .0003). The 3-year locoregional control rate was 17% in arm A and 36% in arm B (P < .004). Both arms showed similar distant failure patterns (arm A, 13 of 140; arm B, 12 of 130). Serious late side effects were not significantly different between treatment arms (arm A, 6.4%; arm B, 10%; not significant). CONCLUSION: Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients. Due to increased acute toxicity, more supportive care is demanded when CT is given simultaneously. Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen.     

Circadian chemotherapy in cancer patients

Continuous infusion of 5-FU at night was performed for four patients: three had liver metastasis (one with gastric cancer and two with rectal cancer) and one had local recurrence of rectal cancer. The chemotherapy schedule was 400 mg/m2/day 5-FU intraarterial or intravenous infusion from 6:00 p.m. to 6:00 a.m. for five days repeated every 3 weeks. There were one complete response, two partial responses and one with no change. It is expected that the chemotherapy of 5-FU at night will result in a high efficacy and lower toxicity.     

In vitro percutaneous penetration through hairless rat skin: influence of temperature, vehicle and penetration enhancers

From February 1995 through October 1996, 25 patients with metastatic colorectal cancer showing a clinical resistance to 5-fluorouracil (5-FU) entered this study. Thirteen received oxaliplatin alone and 12 received it in combination with 5-FU. Oxaliplatin was administered at 130 mg/m2 over a 2-hour infusion every 3 weeks, alone or added either to 5-FU as a continuous infusion at 200 mg/m2 to 300 mg/m2 (six patients) or to a 5-FU bolus, 375 mg/m2, plus leucovorin, 100 mg/m2, daily for 5 days every 3 weeks (6 patients). Eighty-six of 98 administered cycles were evaluable for toxicity (47 for oxaliplatin plus 5-FU and 39 for oxaliplatin alone). Hematologic toxicity was mild, occurring as grade 2 leukopenia in 23% of the cycles of 5-FU and oxaliplatin and in 5% of the cycles of oxaliplatin alone. The most common toxicity was neurologic (grade 1 to 2 in 60%-6% of the cycles of the combination, respectively, and 68%-10% of oxaliplatin given alone) as hand-foot paresthesia or hypersensitivity to cold. No grade 4 toxicity was reported and only three patients in the 5-FU group developed grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 33% of the cycles when both drugs were given and in 15% when oxaliplatin was administered alone. The combination of oxaliplatin and 5-FU induced four partial remissions (33%; 95% confidence interval, 6%-60%), whereas eight patients of the whole group had stable disease. No response occurred when oxaliplatin was administered as a single agent. The results of this study confirm the antitumor activity of oxaliplatin when added to 5-FU in patients who have metastatic colorectal cancer previously refractory to 5-FU. The possible therapeutic synergy with 5-FU was not accompanied by increased toxicity.     

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)-L-aspartate in patients with advanced colorectal cancer. Results of a phase II study

Methotrexate (MTX) and N-phosphonacetyl-L-aspartate acid (PALA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU). A phase II study was initiated to evaluate the feasibility, toxicity and efficacy of PALA/MTX and 5-FU in patients with metastatic colorectal cancer. 26 patients received PALA 250 mg/m2 as an intravenous 15-min infusion plus MTX 200 mg/m2 as a 30-min intravenous (i.v.) infusion on day 1 and 5-FU 600 mg/m2 as i.v. push on day 2. Cycles were repeated every 14 days and the 5-FU dose was escalated in the individual patient in steps of 100 mg/m2 for the third, fifth and seventh cycle in the absence of toxicity. 7 patients had received prior 5-FU-based chemotherapy while 19 patients were chemotherapy naive. Objective responses occurred in 23% of patients (1 CR, 5 PR of which 2 were pretreated), no change in 13 patients (50%) and tumour progression (6 patients) or toxic death (one patient) in 27%. Responses lasted for a median of 7 months (range 6-9), the median time to progression was 4 months and median survival 13 months. Toxicity was mainly gastrointestinal with diarrhoea and mucositis, and severe or life threatening in only 3 patients. In 3 patients an increase in serum glucose levels occurred while being treated with PALA/MTX and 5-FU. 2 patients with insulin-dependent diabetes had a 33% increase in insulin requirement and 1 patient with dietary-controlled diabetes died due to a ketoacidotic coma. PALA/MTX/5-FU in this dose and schedule is active in patients with colorectal cancer. Hyperglycaemia may be a potential side-effect of PALA-containing regimens especially in patients with diabetes. Careful monitoring of serum glucose levels in these patients is indicated.     

Changes in folate status as determined by reduction in total plasma homocysteine levels during leucovorin modulation of 5-fluorouracil therapy in cancer patients

We measured plasma total homocysteine (tHcy) in 14 patients (13 patients with colorectal cancer and 1 patient with breast cancer) during their first treatment with 5-fluorouracil (5-FU) plus leucovorin [LV (5-FULV)]. Eight of these patients were investigated a second time after 3-10 cycles (median, 4 cycles) with 5-FULV. Each cycle consisted of two administrations of 5-FU (500 mg/m2) and LV (60 mg/m2) given 24 h apart. The first administration of 5-FULV on day 1 of the first cycle induced a rapid reduction of the tHcy level from 12.5 micromol/liter (10.4-15.1 micromol/liter; geometric mean with 95% confidence interval of the mean) to 9.1 micromol/liter (7.5-11.1 micromol/liter) in 24 h. tHcy remained stable at this level after the second administration of 5-FULV. In addition, the 5-FULV regimen caused a concurrent 4-fold increase in both serum and erythrocyte folate. The fifth cycle with 5-FULV had only marginal effects on the tHcy level. 5-FU without LV modulation had no effect on the plasma tHcy or folate status in eight breast cancer patients. Our data establish the reduction of tHcy as a responsive indicator of LV pharmacodynamics.