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.     

A phase II study of 5-fluorouracil, leucovorin and cisplatin (FLP) for metastatic gastric cancer

The modulation of 5-fluorouracil (5-FU) with folinic acid (leucovorin, LV) is more efficacious than 5-FU alone in the treatment of metastatic colorectal cancer, and the combination of 5-FU with cisplatin is currently one of the most active regimens in advanced gastric cancer. A phase II study was therefore conducted to test the efficacy and toxicity of the combination of 5-FU, LV and cisplatin (FLP) in metastatic gastric cancer. 28 patients entered the study. Metastatic sites were observed in the liver (in 21 patients), the peritoneum (in 8), the lymph nodes (in 7) or the bones (in 1) and a local recurrence was noted in 4 cases. The performance status (using World Health Organisation criteria) was 0 for 13 patients and 1 or 2 for the others. Cycles of treatment were administered every 28 days and consisted of LV 200 mg/m2/day for 5 days followed by 5-FU 400 mg/m2/day for 5 days with cisplatin 100 mg/m2 on day 2. The response rate for the 27 evaluable patients was 51.8% (95% confidence interval (CI), 33-70.6%). There were four complete responses (14.8%) and 10 partial responses (37%). Median survival was 11 months and 4 patients were alive at 2 years. Both response rate and survival were better for patients with a good performance status. The overall toxicity was very low, except for 1 patient who died of dehydration and cardiac failure. In conclusion, the FLP protocol was effective and well tolerated in patients with metastatic gastric cancer.     

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.     

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.     

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.     

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.     

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.     

Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group

PURPOSE: To compare raltitrexed (Tomudex; Zeneca Pharmaceuticals Ltd, Macclesfield, United Kingdom) a direct, specific thymidylate synthase (TS) inhibitor with fluorouracil (5-FU) plus high-dose leucovorin (LV) as first-line treatment for advanced colorectal cancer (ACC). PATIENTS AND METHODS: A total of 495 patients were randomized to raltitrexed (3 mg/m2) once every 3 weeks or 5-FU (400 mg/m2) plus LV (200 mg/m2) daily for 5 days every 4 weeks. RESULTS: The randomized groups were well balanced demographically. With a minimum 17-month follow-up, median survival was comparable between groups (10.9 months raltitrexed v 12.3 months 5-FU/LV; hazards ratio, 1.15; 95% confidence interval [CI], 0.93 to 1.42; P=.197), although time to progression was statistically significantly shorter in the raltitrexed group. Overall objective responses were comparable (19% raltitrexed v 18% 5-FU/LV), with more than 50% of patients in each group having stable disease. Significantly less World Health Organization (WHO) grade 3 and 4 stomatitis (2% v 16%, P < .001) and a reduced incidence of leukopenia (6% v 13%) and diarrhea (10% v 19%) occurred in the raltitrexed group (particularly at cycle 1 ). This resulted in fewer dose reductions at cycle 2 (4% raltitrexed v 28% 5-FU/LV) and early quality-of-life (QoL) benefits for raltitrexed patients. Reversible, clinically insignificant increases in transaminases were reported in 13% of raltitrexed patients. Palliative benefits of weight gain, improved performance status, and reduced disease-related symptoms were evident in both groups. CONCLUSION: Raltitrexed is confirmed as an effective option in the first-line palliative management of ACC, with comparable efficacy to and tolerability advantages (in terms of reduced incidence of stomatitis, diarrhea, and leukopenia) over 5-FU/LV. Raltitrexed has the added convenience of an every 3 weeks dosing schedule.     

Cervical meningoceles and myelocystoceles: a unifying hypothesis

We initiated a pilot study of adjuvant hepatic arterial infusion chemotherapy (AHAIC) using 5-fluorouracil (5-FU) and leucovorin. Hepatic arterial infusion ports were placed in 15 consecutive patients undergoing curative resection of colorectal liver metastases. The chemotherapy regimen consisted of a weekly infusion of 5-FU (12 mg m 2 per day) and leucovorin (200 mg m 2 per day) for 12 months. The mean follow-up was 22 months (range 3-62 months, SD 21-37 months). There were no clinical or biological complications related to chemotherapy, except for sharp epigastric burns in four patients immediately after 5-FU infusions. Catheter irreversible occlusions led to early cessation of the treatment in three patients. Four of the 15 evaluable patients developed recurrent disease. The site of relapse was the liver in two patients and extra-hepatic sites in the two remaining patients. Three of these four patients died of their recurrent disease. These results suggest that 5-FU and leucovorin can be combined for AHAIC in a long duration regimen with a very low rate of side-effects. This protocol could be safely employed in a prospective randomized study in combination with 5-FU systemic infusions.     

A case of left main bronchus obstruction due to recurrent esophageal cancer successfully treated by Nd-YAG laser followed by radiotherapy, low-dose CDDP and continuous infusion of 5-FU

A 63-year-old female patient with obstruction of left main bronchus due to recurrent esophageal cancer was treated by emergency Nd-YAG laser therapy under bronchoscopy. Severe dyspnea subsided dramatically and she was the given radiotherapy with a total dose of 50 Gy (2 Gy/f and 25 f/5 wks). Concurrent chemotherapy was performed at the 3rd week of radiation therapy. In this chemotherapy of CDDP plus 5-FU, CDDP (10 mg/day) was given for 5 days by intravenous and 5-FU (500 mg/day) for 5 days by continuous infusion the same week. By this treatment, a partial response (PR) was obtained, and the patient returned to normal life. But after 4 months, she had a recurrent lesion at the same place, and underwent only palliative laser therapy. Nd-YAG laser therapy for obstructive lesion of trachea due to recurrent cancer is the most useful one, but some subsequent treatment is required.     

Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer

PURPOSE: This study had two major goals: (1) to assess the effectiveness of a regimen of fluorouracil (5-FU) plus levamisole plus leucovorin as postoperative surgical adjuvant therapy for patients with high-risk colon cancer, and (2) to evaluate 6 months versus 12 months of chemotherapy. PATIENTS AND METHODS: Patients with poor-prognosis stage II or III colon cancer were randomly assigned to receive adjuvant chemotherapy with either intensive-course 5-FU and leucovorin combined with levamisole, or a standard regimen of 5-FU plus levamisole. Patients were also randomly assigned to receive either 12 months or 6 months of chemotherapy, which resulted in four treatment groups. RESULTS: Eight hundred ninety-one of 915 patients entered (97.4%) were eligible. The median follow-up duration is 5.1 years for patients still alive. There was a difference among the four treatment groups with respect to patient survival, and a significant duration-by-regimen interaction was observed. Specifically, standard 5-FU plus levamisole was inferior to 5-FU plus leucovorin plus levamisole when treatment was given for 6 months (5-year survival rate, 60% v 70%; P < .01). CONCLUSION: There was no significant improvement in patient survival when chemotherapy was given for 12 months compared with 6 months. When chemotherapy was given for 6 months, standard 5-FU plus levamisole was associated with inferior patient survival compared with intensive-course 5-FU plus leucovorin plus levamisole. These data suggest that 5-FU plus levamisole for 6 months should not be used in clinical practice, whereas 6 months of treatment with 5-FU plus leucovorin plus levamisole is effective.     

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.     

The role of lipogenesis in the development of obesity and diabetes in Israeli sand rats (Psammomys obesus)

In order to optimize the therapeutic index of combining etoposide, epirubicin, cisplatin, 5-fluorouracil (5-FU), leucovorin (EEPFL) chemotherapy in the treatment of advanced gastric cancer, a trial of a novel schedule of weekly administration was conducted. Weekly EEPFL treatment consisted of a concomitant boost of etoposide 40 mg m(-2) i.v. over 30 min, epirubicin 10 mg m(-2) i.v. over 5 min to a backbone regimen, weekly PFL chemotherapy with cisplatin 25 mg m(-2), 5-FU 2200 mg m(-2), leucovorin 120 mg m(-2) given simultaneously by 24-h i.v. infusion. Response, survival and toxicity were evaluated. Forty-two patients were studied. Median age was 69 (range 31-84) years. Twenty-six per cent of patients showed complete response and 45% partial response. The overall response rate was 71% (95% confidence interval 58-84%). For a total of 507 weekly EEPFL cycles delivered, the incidence of grade 4 leucopenia was 1% of cycles. One patient died of neutropenia septicaemia. There was no other grade 4 toxicity. Grade 3 and 2 leucopenia occurred in 7% and 14% of cycles. The incidence of grade 3 and 2 mucositis was 1% and 3% of cycles. Grade 3 and 2 diarrhoea occurred in 0.4% and 1.6% of cycles. Overall median survival was 10 months (range 3-41+ months). Weekly EEPFL chemotherapy is an effective regimen with tolerable toxicities in the treatment of advanced gastric cancer. A randomized controlled clinical trial to formally assess the efficacy and benefit of EEPFL chemotherapy is under way.     

Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05

BACKGROUND: National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 showed a benefit from leucovorin (LV)-modulated 5-fluorouracil (5-FU) adjuvant therapy (5-FU + LV) in patients with Dukes' stage B or C carcinoma of the colon. Preclinical and clinical phase I/II data suggested that interferon alfa-2a (IFN) enhanced the efficacy of 5-FU therapy. Accordingly, in NSABP protocol C-05, the addition of recombinant IFN to 5-FU + LV adjuvant therapy was evaluated. METHODS: Data are presented for 2176 patients with Dukes' stage B or C cancer entered onto protocol C-05 during the period from October 1991 through February 1994. Individuals with an Eastern Cooperative Oncology Group performance status of 0-2 (ranges from fully active to ambulatory and capable of self-care but unable to work), a life expectancy of at least 10 years, and curative resection were stratified by sex, disease stage, and number of involved lymph nodes and were randomly assigned to receive either 5-FU + LV or 5-FU + LV + IFN; the mean time on the study as of June 30, 1997, was 54 months. All statistical tests were two-sided. RESULTS: There was no statistically significant difference in either disease-free survival (5-FU + LV, 69%; 5-FU + LV + IFN, 70%) or overall survival (5-FU + LV, 80%; 5-FU + LV + IFN, 81%) at 4 years of follow-up. Toxic effects of grade 3 or higher were observed in 61.8% of subjects in the group treated with 5-FU + LV and in 72.1% of subjects in the group treated with 5-FU + LV + IFN; fewer patients in the latter group completed protocol-mandated 5-FU + LV therapy than in the former group (77.1% versus 88.5%). CONCLUSION: The addition of IFN to 5-FU + LV adjuvant therapy confers no statistically significant benefit, but it does increase toxicity.     

Hepatic arterial infusion chemotherapy (HAI) for advanced hepatocellular carcinoma inefficacious with transcatheter arterial embolization (TAE)

For 6 patients with advanced hepatocellular carcinoma (HCC) in whom TAE was inefficacious, we tried hepatic arterial infusion chemotherapy. 5-FU 500 mg/day + CDDP 10 mg/day was administered during 5 days. The AFP level was decreased for 4 patients, and 2 patients showed a partial response in CT image. These 2 patients have been alive over 22 and 18 months, respectively. These results suggest that 5-FU + CDDP HAI might be a useful treatment of HCC inefficacious with TAE.     

Evaluation of enzyme-linked immunosorbent assay for the diagnosis of Helicobacter pylori infection in children from different age groups with and without duodenal ulcer

BACKGROUND: Myocardial ischemia induced by 5-fluorouracil (5-FU) is a relatively rare, but potentially serious, occurrence. Some case reports have indicated that recurrent ischemia may be prevented if 5-FU is resumed after pretreatment with antianginal therapy. METHODS: A 54-year old woman was diagnosed with stage IIA squamous cell carcinoma of the anus. Treatment with concurrent radiation and chemotherapy (mitomycin-C and 5-FU) was initiated with curative intent. RESULTS: The patient had no evidence of underlying coronary artery disease based on history, physical examination or ECG. Approximately 48 h after initiation of 5-FU infusion the patient developed anginal pain associated with ECG changes compatible with ischemia. After resolution of ischemia and ruling out of myocardial infarction, coronary arteriography demonstrated normal coronary arteries. In an attempt to prevent myocardial ischemia, calcium channel blocker and nitrate therapy was started, but anginal pain with ECG change recurred when 5-FU was resumed. This necessitated selection of an alternative chemotherapy regimen. CONCLUSIONS: Even in the presence of normal coronary arteries, antianginal therapy may not preclude the occurrence of potentially serious 5-FU induced myocardial ischemia. For patients who experience 5-FU-induced myocardial ischemia, development of alternative chemotherapy regimens should be considered.     

Abnormalities of CD45 isoform expression in HIV infection

Systemic chemotherapy with 5-fluorouracil (5-FU) has been the mainstay of treatment for patients with metastatic colorectal carcinoma. Administering the drug in a continuous low-dose schedule has produced better result than bolus therapy. Resistance to short-pulse treatment can also be overcome by prolonged exposure. Recent studies suggest the feasibility of biomodulation of 5-FU with recombinant interferon (rIFN alpha-2a) with improved response. Sixteen patients were treated with continuous 5-FU 250 mg/m2 and rIFN alpha-2a 10 x 10(6) u thrice weekly for a maximum of 24 weeks. Five of them had received bolus 5-FU previously. Nine (82%) of the chemonaive group and 1 (20%) previously treated patient had partial response. The median duration of response was 7 months. Grade II to III mucositis were seen in 44% of the patients and 2 patients developed neurological complications. Although the overall response appeared encouraging, the incidence of toxicity was high. In the absence of further phase III studies, rIFN alpha-2a biomodulation of 5-FU cannot be regarded as standard treatment for patients with metastatic colorectal carcinoma.     

High expression of thymidylate synthase is associated with the drug resistance of gastric carcinoma to high dose 5-fluorouracil-based systemic chemotherapy

BACKGROUND: In the past 4 years, the weekly 24-hour infusion of high dose 5-fluorouracil (5-FU) and leucovorin in the treatment of patients with advanced gastric carcinoma has been prospectively studied at the authors' institution. This has enabled them to explore the possibility that the level of expression of thymidylate synthase (TS), the target enzyme of 5-FU, is related to the drug sensitivity of gastric carcinoma to 5-FU-based chemotherapy. METHODS: To be eligible for this study, patients were required to have received high dose 5-FU and leucovorin chemotherapy (weekly 24-hour infusions of 5-FU, 2,600 mg/m2, and leucovorin, 300 mg/m2) and to have had adequate prechemotherapy gastric carcinoma tissues for immunohistochemical study. TS106 monoclonal antibody was used to detect the expression of TS. A visual scoring system, which ranged from 0 to 3+, was adopted by 2 independent pathologists to semiquantitate the intensity of TS expression. RESULTS: Between 1993 and 1996, a total of 30 patients, 18 men and 12 women, with a median age of 61.5 years, were enrolled. Of these patients, 16 (53.3%) and 14 (46.7%) had high and low expression of TS, respectively. Two of the 16 patients (12.5%) with high expression of TS and 13 of the 14 patients (92.9%) with low expression of TS responded to chemotherapy (P < 0.001, chi-square test). The median overall survival was 10 months for patients with low TS expression and 4 months for patients with high TS expression (P < 0.01, log rank test). CONCLUSIONS: The data from this study suggest that the expression of TS, as determined by immunohistochemistry, is a relatively reliable indicator of whether 5-FU should be used in the treatment of patients with gastric carcinoma.     

Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients

PURPOSE: This prospective phase II study was designed to test the activity and toxicity of a regimen of fluorouracil (5-FU) and cisplatin (CDDP) in combination with radiation therapy in the treatment of epidermoid cancer of the anal canal. PATIENTS AND METHODS: Thirty-five consecutive patients with untreated epidermoid cancer of the anal canal were candidates for chemoradiation therapy (CRT). Staging of cancer was as follows: T1, 26%; T2, 60%; T3, 14%; and N1, 2,3, 26%. No patient had distant metastases. The treatment protocol consisted of two to three cycles of chemotherapy starting on days 1 and 21 and concurrent radiotherapy at a daily dose of 1.8 Gy up to a total dose of 36 to 38 Gy in 4 weeks, delivered to the anal region, perineum, middle and lower pelvis, and inguinal and external iliac nodes. Radiotherapy was then delivered to the anoperineal region and metastatic inguinal nodes to a total dose of 18 to 24 Gy in 10 fractions. Chemotherapy consisted of 24-hour intravenous (IV) infusion of 5-FU 750 mg/m2 on days 1 to 4 and CDDP 100 mg/m2 by 60-minute IV infusion on day 1. RESULTS: All patients received two cycles of chemotherapy; the second was delayed in three patients because of leukopenia that was evident in 11 (31%). In eight patients, a third cycle was added. They all experienced nausea or vomiting; one patient showed signs of cardiotoxicity and one developed proctitis, dermatitis, and diarrhea (grade 3). Complete regression (CR) was assessed in 33 patients (94%); nine patients with metastatic lymph nodes also had CR. Two patients had a partial response (PR); both underwent abdominoperineal resection, which was not curative in one. Two patients (6%) had a local recurrence; in one, this was associated with hepatic metastases. One of these patients underwent surgery and is alive after about 4 years, while the other is undergoing chemotherapy. After a median follow-up duration of 37 months, 94% of patients are alive without evidence of disease and 86% are colostomy-free. CONCLUSION: This regimen is well tolerated; its toxicity does not exceed that observed with the combination of 5-FU and mitomycin (MMC). Compared with our previous experience based on the classic CRT (5-FU, MMC, and radiation), the objective response rate observed with this new combination was similar. However, the local recurrence rate, observed in patients treated with the new regimen, was lower (6% v 24%). According to more recent data from the literature, primary CRT is the elective indication in epidermoid cancer of the anus and replacement of MMC with CDDP seems an effective and logical evolution.     

Comparison of 5-fluoro-2'-deoxyuridine with 5-fluorouracil and their role in the treatment of colorectal cancer

Despite more than 30 years of intensive studies on new drugs against advanced colorectal cancer, the fluoropyrimidines remain the drugs of choice for systemic treatment and for hepatic artery infusion (HAI). This overview describes new developments in advanced colorectal cancer chemotherapy, providing a rationale for more effective use of the fluoropyrimidines, with biochemical modulation, scheduling or by revealing biochemical mechanisms of action that correlate with antitumour activity. In human colorectal cancer cell lines and various animal tumour model systems 5-fluoro-2'-deoxyuridine (FdUrd) is more effective than 5-fluorouracil (5-FU). Comparably, FdUrd's modulation by leucovorin (LV) is more potent than 5-FU. In animal studies it is shown that intermittent high-bolus administration of FdUrd generates better antitumour activity, compared with equal toxic doses or any other schedule of 5-FU. These effects are related to prolonged-thymidylate synthase (TS) inhibition and the prevention of TS induction, rather than RNA incorporation. Preclinical studies with modulators such as N-phosphonacetyl-L-aspartate (PALA), WR-2721, mitomycin C and platinum derivatives provide a rationale for clinical use in the future. The first choice systemic chemotherapy of patients with advanced colorectal cancer remains 5-FU combined with LV. Some improvement in therapeutic efficacy has been achieved with locoregional HAI. In randomised studies HAI FdUrd improves the quality of life and survival as compared with optimal systemic therapy. Chronomodulation decreases toxicity, allowing dose intensification, while modulators such as LV or dexamethasone increase survival of patients treated with HAI FdUrd to 86% after 1 year. In conclusion, the clinical use of FdUrd has not been fully explored. Intermittent high-dose FdUrd, chronomodulation together with the use of modulators or drugs focused on prolonged TS inhibition, should be studied in large randomised studies.