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Adjuvant fluorouracil, epirubicin and cyclophosphamide in early breast cancer: is it cost-effective?

Adjuvant chemotherapy (ACT) in breast cancer exposes patients to morbidity, but improves survival. The FEC (fluorouracil, epirubicin, cyclophosphamide) regimen has taken over the prior role of CMF (cyclophosphamide, methotrexate, fluorouracil). In this model, efficacy, tolerability and quality of life (QoL) data from the literature were incorporated with Norwegian practice and cost data in a cost-effectiveness approach. The FEC efficacy was calculated 3-7% superior CMF. There was no difference in quality of life. An 80-100% dose intensity range was employed, one Euro was calculated NOK 8.78 and a 3% discount rate was used. The total cost of FEC employing the friction cost method on production loss, including amount spent on drugs, administration and travelling ranged between 3,278-3,850 Euros (human capital approach 12,143-12,715 Euros). Money spent on drugs alone constituted 15-48%, depending on method chosen. A cost-effectiveness analysis revealed a cost per life year (LY) saved replacing FEC by CMF of 3,575-15,125 Euros. Adjuvant FEC is cost effective in Norway.

Antineoplastic Combined Chemotherapy Protocols↗

Paclitaxel, cisplatin and 5-fluorouracil in recurrent squamous cell carcinoma of the head and neck: a phase II trial from an Italian cooperative group.

The aim of this multicenter trial was to test the feasibility and the activity of a three-drug combination where paclitaxel is added to cisplatin and 5-fluorouracil. Patients with metastatic or relapsed SCC-HN unsuitable for further loco-regional radical treatment, not previously treated with chemotherapy, were eligible to receive paclitaxel 160 mg/m2 (3-hr infusion) day 1, CDDP 25 mg/m2/day and 5-FU 250 mg/m2/day bolus on days 1, 2, 3 every three weeks up to a maximum of five courses. Fourty-seven patients were enrolled by five Institutions in Italy. Main grade III-IV toxicities were: neutropenia (48%), thrombocytopenia (6%), anemia (4%), diarrhea (2%), mucositis (2%). Six patients had a complete response (13.3%) and eight a partial response (17.8%). Median progression free survival and overall survival are 4.1 and 7.9 months. One-year progression free survival and overall survival are 16% and 29%. This three-drug regimen has an excellent safety profile. The activity in the palliation of recurrent SCC-HN, however, does not appear to be improved in comparison with cisplatin and 5-fluorouracil or cisplatin and paclitaxel regimens. Recent studies indicate a more promising role of taxanes including triplets in the induction therapy of previously untreated patients.

Adult↗

Concurrent chemoradiotherapy with pirarubicin and 5-fluorouracil for resectable oral and maxillary carcinoma.

OBJECTIVE: We present the response rate and adverse effects of our regimen of concurrent chemoradiotherapy with pirarubicin (THP) and 5-fluorouracil (5-FU) for oral and maxillary carcinoma. PATIENTS AND METHODS: Fifteen patients with oral (10 cases) or maxillary (5 cases) squamous cell carcinoma who underwent our concurrent chemoradiotherapy with the combination of intraarterial pirarubicin, intravenous continuous 5-fluorouracil, and radiation between March 2001 and February 2003 in our department were entered in this study. THP (5 mg/day) was infused into the lingual or maxillary artery one hour before radiation on days 1-5 and 8-12, while intravenous 5-FU (150 mg/m2/day) was instilled continuously on days 1-5, 8-12, 15-19, and 22-26 in accordance with the radiation schedule (2 Gy/day). Consequently, total doses of THP, 5-FU, and radiation were 50 mg, 3000 mg/m2 and 40 Gy, respectively. After the treatment series, response rate and adverse effects were evaluated. RESULTS: Response rate achieved 100% (12 cases exhibited a complete response and the remaining 3 a partial response). Notably, all 10 patients with oral carcinoma exhibited complete response. The main adverse effects were leucopenia (6/15) and mucositis (6/15), both of which were acceptable. CONCLUSIONS: This concurrent chemoradiotherapy is very useful for oral and maxillary carcinoma as a preoperative modality with remarkably high response rate and acceptable adverse events.

Aged↗

A phase II study of doxorubicin, cisplatin, and 5-fluorouracil in patients with advanced adenocarcinoma of the stomach or esophagus.

BACKGROUND: The combination of epirubicin, cisplatin, and infusional 5-fluorouracil (ECF) currently represents a standard and effective regimen for the treatment of advanced gastroesophageal cancer. The use of doxorubicin as an alternative to epirubicin in the ECF regimen has not been evaluated. METHODS: Thirty-two patients with metastatic adenocarcinoma of the stomach, gastroesophageal junction, or esophagus were treated with cisplatin 60 mg/m2 and doxorubicin 30 mg/m2 repeated every 21 days, in combination with infusional 5-fluorouracil 200 mg/m2/day (ACF). RESULTS: Major objective responses were observed in 28 percent of patients (46 percent previously untreated; 13 percent previously treated), with one complete response. The median progression-free survival was 4.0 months, and the median overall survival was 5.8 months (9.3 months previously untreated; 4.5 months previously treated). The major (Grade 3-4) toxicities were neutropenia (34 percent), anorexia (31 percent), nausea (28 percent), diarrhea (19 percent), and stomatitis (16 percent). CONCLUSION: In comparison with historical data taken from published trials of ECF, the ACF regimen appears similar in efficacy when differences in prior treatment status are taken into account. However, ACF appears to be associated with a higher incidence of major toxicities. Our findings therefore support the continued use of epirubicin rather than doxorubicin in combination chemotherapy regimens for advanced gastroesophageal cancer.

Adenocarcinoma↗

Peroral IMUNOR, a low-molecular-weight immunomodulator prepared from disintegrated and ultrafiltered leukocytes, enhances recovery from myelosuppression induced by cisplatin or 5-fluorouracil.

A single dose of IMUNOR, a low-molecular-weight immunodulator prepared from disintegrated and ultrafiltered pig leukocytes, was found to enhance recovery of murine pool of hemopoietic progenitor cells for granulocytes and macrophages damaged by a single injection of cytotoxic drugs 5-fluorouracil or cisplatin. The best results were obtained after the treatment with IMUNOR on days 3 or 4 after the injection of 5-fluorouracil or cisplatin. These results together with previous findings obtained in our laboratory suggest that IMUNOR has the potential to become a part of treatment schemes in oncological practice aimed at alleviation of myelosuppression evoked by cytotoxic anti-tumor therapy.

Animals↗

Chronic cutaneous lupus flare induced by systemic 5-fluorouracil.

5-Fluorouracil is an antineoplastic antimetabolite responsible for a variety of cutaneous reactions. We report a case of chronic cutaneous lupus flare related to systemic 5-fluorouracil administration for breast cancer in a patient with documented history of chronic cutaneous lupus.

Adenocarcinoma↗

Postoperative chemoendocrine therapy for women with node-positive stage II breast cancer with combined cyclophosphamide, tamoxifen, and 1-hexylcarbamoyl-5-fluorouracil.

OBJECTIVE: To find out whether the addition of 1-hexylcarbamoyl-5-fluorouracil to a postoperative regimen of oral cyclophosphamide and tamoxifen improved the prognosis of carcinoma of the breast. DESIGN: Randomised controlled clinical trial. SETTING: 127 Institutions in Japan. SUBJECTS: 785 Patients with stage II carcinoma (palpable axillary nodes) who had total mastectomy and axillary clearance. INTERVENTIONS: The control group were given oral cyclophosphamide 50 mg/day and tamoxifen 20 mg/day for 2 years; the experimental group were given these drugs plus 1-hexylcarbamoyl-5-fluorouracil 300 mg/day for 2 years. RESULTS: There was no survival advantage (and more toxicity) in the experimental group, except in a subgroup with 1-3 axillary nodes involved. CONCLUSION: The advantage of triple chemotherapy in the subgroup must be substantiated by a new randomised trial confined to patients with 1-3 axillary nodes involved.

Administration, Oral↗

Cardiotoxicity during chemotherapy treatment with 5-fluorouracil and cisplatin.

Cardiotoxicity of 5-fluorouracil and cisplatin chemotherapy for esophageal, head and neck and gastric carcinoma was studied. Before treatment all patients had a cardiac evaluation and during treatment serial electrocardiographic (ECG) recordings were performed. In the pre-treatment evaluation signs of cardiovascular disease were found in 31(38.75%) patients. During treatment cardiotoxicity was observed in 12(15%) patients. The incidence of cardiotoxicity was not higher in patients with signs of cardiovascular disease than in those without in the pre-treatment evaluation. The most common signs of cardiotoxicity were chest pain, ST-T wave changes and arrhythmia. This study suggests that patients on 5-fluorouracil and cisplatin treatment should be under close supervision and that the treatment should be discontinued if chest pain and/or arrhythmias are observed.

Arrhythmias, Cardiac↗

Second-line chemotherapy of advanced colorectal cancer with sequential high-dose methotrexate and 5-fluorouracil.

Twenty-five patients with pretreated advanced colorectal carcinoma were subjected to second-line chemotherapy with sequential high-dose methotrexate and 5-fluorouracil. In 20 evaluable patients 2 (10%) partial responses, 12 (60%) stable disease and 6 (30%) progressions were observed. Partial responses were maintained for 3 and 4 months respectively; stable disease had a median duration of 4 months. The overall median survival after progression was 7 months. From our results sequential high-dose methotrexate and 5-fluorouracil cannot be recommended as second-line chemotherapy in advanced colorectal cancer.

Adult↗

Fluorouracil, high-dose folinic acid, low-dose alpha-2b interferon and dipyridamole in the treatment of advanced colorectal cancer. A pilot study.

Twenty-six patients with advanced colorectal cancer were treated with a combination based on multimodal biochemical modulation of 5-fluorouracil by means of high dose folinic acid, low-dose alpha-2b interferon and dipyridamole. The overall response rate was 42% (95% confidence intervals = 23%. 61%) with four complete remissions (15%). The median duration of response was 9 months and the median survival for responders was 15 months (all patients = 12 months). Toxic side effects included oral mucositis (grade III-IV = 38%) and a generally mild flu-like syndrome. This regimen seems active and safe enough to be compared with the combination of fluorouracil and high-dose folinic acid.

Adult↗

Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics.

Even though 5-fluorouracil (FU) is one of the oldest anticancer drugs, its use in cancer chemotherapy continues to increase. Fluorouracil is a pro-drug that requires intracellular activation to exert its effects. This makes it difficult to associate blood drug concentration with cell toxicity directly, although data from the literature show the existence of such a relationship. The relationship between FU pharmacokinetics and patient response has been explored extensively and reports attest a link between systemic drug exposure and response and survival. This has led to the concept of maximal tolerated exposure, and strategies to achieve this rely on pharmacokinetic follow-up and individual dose adjustment. More than 80% of the administered FU dose is eliminated by catabolism through dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme. Dihydropyrimidine dehydrogenase activity is found in most tissues but is highest in the liver. Peripheral blood mononuclear cells (PBMC) are used to monitor clinically DPD activity. A significant, but weak correlation between PBMC and liver DPD activity has been observed. The relationship between PBMC-DPD activity and FU systemic clearance is weak (r2 = 0.10); thus, simply determining PBMC-DPD is not sufficient to predict accurately FU clearance. Population pharmacokinetic analysis identified patient co-variables that influence FU clearance; drug kinetics is significantly reduced by increased age, high serum alkaline phosphatase, length of drug infusion, and low PBMC-DPD. Autoregulation of FU metabolism also is suggested; inhibition of DPD activity was observed after FU administration in both colorectal cancer patients and an animal model. Circadian rhythmicity in DPD activity is suggested from both human and animal investigations. In patients receiving protracted low dose 5-FU infusion, the circadian rhythm in FU plasma concentration peaks at 11:00h and is lowest at 23:00h, on average. The inverse relationship observed between the circadian profile of FU plasma concentration and PBMC-DP activity in these same patients suggests a link between DPD activity and FU pharmacokinetics. The impact of the biological time of drug administration was also studied with short venous infusions; clearance was 70% greater at 13:00h than at 01:00h. Similarly, peak drug concentration occurred in the first half of the night in patients receiving constant rate 5-FU infusion for 2-5d. Several studies describe wide interindividual variation in the timing of the peak and trough of the 24h rhythm in DPD activity. The rational for FU chronomodulated therapy has been the circadian rhythm in host drug tolerance, which is greatest during the night time when the proliferation of normal target tissue is least. A randomized study of chronomodulated FU therapy with maximal delivery rate at 04:00h was shown clearly to be significantly more effective and less toxic than control flat FU therapy. Future research must focus on easy-to-obtain markers of specific rhythms to individualize the chronomodulated FU delivery.

Antimetabolites, Antineoplastic↗

A study on the preparation and anti-tumor efficacy of bovine serum albumin nanospheres containing 5-fluorouracil.

The therapeutic profile of many anti-cancer drugs has been improved by their modified distribution through a colloidal carrier system. Hence, bovine serum albumin nanospheres containing 5-fluorouracil were prepared by pH-coacervation methods. To select the most suitable cryoprotector for the formulated nanosphere system, a study on the effect of cryoprotectors in the prevention of particle agglomeration was done. Using glucose and mannitol at various concentrations during freeze drying, glucose at a concentration of 5% was observed to be relatively more effective in the prevention of particle agglomeration than the other cryoprotectors. The carrier capacity was determined through the drug-to-albumin ratio. The particle size of all the drug-loaded batches was analyzed before and after freeze drying. The batch of nanospheres with uniform size distribution, and highest drug loading, was used for other subsequent studies. The effect of surfactant in drug loading was estimated through various concentrations of sodium lauryl sulfate, and it was observed that the surfactant has no influence on drug loading at the selected concentrations. The batch of nanospheres with highest drug loading was evaluated for its in-vitro release, and the drug release was found to be in a bi-phasic pattern. To evaluate the efficacy of 5-fluorouracil-loaded nanospheres against cancer cells, an in vitro cytotoxicity study was carried out using HEp-2 cell lines. The nanosphere-bound drug was observed to produce a better cytotoxic effect than the free drug. The anti-tumor efficacy of drug-loaded nanosphere was investigated in DLA tumor-induced mice models, and the percentage tumor inhibition was relatively higher in animals treated with nanosphere-bound drug than with free drug.

Animals↗

Studies of hematopoietic stem cells spared by 5-fluorouracil.

Mouse marrow cells were exposed to 5-fluorouracil (FU) either in vivo or in vitro and the effects on the hematopoietic stem cell compartment were studied. The drug was highly toxic to bone marrow cells including the spleen colony-forming unit (CFU-S) population. The small population of stem cells surviving FU, however, caused a different pattern of spleen colony growth when injected into lethally irradiated mice. Whereas numbers of spleen colonies caused by normal marrow cells remained constant during an 8-14 d period after transplantation, spleen colonies derived from FU-treated marrow cells increased by as much as 100-fold during this time. This effect on stem cells was dose dependent both in vitro and in vivo. When FU was given in vivo, the day 14/day 8 ratio of colonies was greatest 1 d after injection and, over the next 7 d, returned to a near-normal value, that is, unity. A number of studies have shown that the stem cell compartment is heterogeneous with respect to self-replicative capacity and developmental potential. An age structure for the stem cell compartment has been proposed wherein cells with a short mitotic history are more likely to self-replicate than they are to differentiate; hence they are more primitive. 'Older' stem cells with a longer mitotic history are, according to the hypothesis, more likely to differentiate. 5-fluorouracil may be toxic to the older stem cells and selectively spare the more primitive subpopulation. Although the surviving cells may not themselves be able to form spleen colonies, they may give rise to an older cohort of cells more likely to differentiate and form spleen colonies. It is the requisite developmental maturation within the stem cell compartment that may be responsible for the delay in appearance of spleen colonies derived from FU-treated marrow. Our results support this explanation and identify the locus of at least part of this activity as the bone marrow. We found that the FU-treated marrow did not cause an increase in spleen colony numbers between 8 and 14 d in hosts with a long-standing marrow aplasia, due to the incorporation of 89Sr into bone. I propose that the delayed spleen colony appearance in normal hosts is the result of developmental maturation of the primitive stem cell compartment that survives FU and is responsible for spleen colonies arising around day 14. This maturation, at least initially, occurs in the marrow and leads to the replenishment of the more differentiated CFU-S subsets ablated by FU, which are normally responsible for spleen colonies appearing earlier after transplantation.

Animals↗

The feasibility of classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF) for pre- and post-menopausal node-positive breast cancer patients in a Belgian multicentric trial: a study of consistency in relative dose intensity (RDI) and cumulative doses across institutions.

BACKGROUND: Classical cyclophosphamide, methotrexate, 5-fluorouracil (CMF) including oral cyclophosphamide is still considered an important adjuvant chemotherapy regimen in patients with early breast cancer (BC). Concern has been raised regarding the feasibility of this regimen, especially in postmenopausal patients. PATIENTS AND METHODS: 254 pre- and post-menopausal node-positive BC patients aged < or = 70 years received six cycles of CMF in the context of a Belgian multicentric phase III trial of adjuvant chemotherapy. CMF dose and schedule were as follows: cyclophosphamide 100 mg/m2 p.o. on days 1 to 14, methotrexate 40 mg/m2 intravenously (i.v.) on days 1 and 8, 5-fluorouracil 600 mg/ml i.v. on days 1 and 8; cycles q. 28 days. The relative dose intensity (RDI) was calculated as the ratio between the delivered DI and the planned DI. We also analysed the RDI in two subgroups of patients with age > or = 50 years or < 50 years. RESULTS: Overall, the percentage of patients ending the six cycles of the planned CMF regimen was 90%. The mean RDI achieved in the population of 254 patients was 90% (range 8% to 129%). The subgroup analysis of patients aged > or = 50 years and < 50 years showed that 81% and 76% of patients, respectively, received > or = 80% of the planned chemotherapy dose intensity (P = 0.33). No statistically significant difference was found between the percentage of patients who received a RDI < 80% and the participating institutions (P = 0.50). CONCLUSIONS: The classical CMF regimen was a feasible regimen in the context of a multicentric trial, in which academic institutions as well as community hospitals participated. No substantial differences in RDI and cumulative doses were found in relation to a patient's age and the participating institution.

Adult↗

Vinorelbine, methotrexate and fluorouracil (VMF) as first-line therapy in metastatic breast cancer: a randomized phase II trial.

BACKGROUND: The purpose of this study was to determine the best tolerated and efficacious dose of vinorelbine given once or twice in 3-week cycles in combination with methotrexate and fluorouracil (VMF). PATIENTS AND METHODS: Vinorelbine 40 mg/m(2) was given as follows: 20 mg/m(2) on days 1 and 8 (group 1); 30 mg/m(2) on day 1 and 10 mg/m(2) on day 8 (group 2); or 40 mg/m(2) on day 1 (not exeeding 60 mg/m(2)) (group 3). The methotrexate dose was 40 mg/m(2) on day 1 and the fluorouracil dose 600 mg/m(2) on days 1 and 8. Thirty patients with evaluable metastases were randomly allocated to the groups (first step). The second step was to exclude the worst tolerated regimen and then to expand the study to 60 patients. Thus, group 1 had 26 patients, group 2 had 24 patients and group 3 had 10 patients. RESULTS: World Health Organization (WHO) grade 3 hematological toxicity occurred in 23%, 36% and 50% of patients and grade 4 in 39%, 32% and 50% of patients in groups 1, 2 and 3, respectively; grade 3 infections were observed in 15%, 9% and 10% of patients in groups 1, 2 and 3, and grade 4 infections in 5% and 10% of patients in groups 2 and 3, respectively. Nonhematological toxicity included a mild to moderate neurotoxicity manifesting as constipation, abdominal colics and myalgia in the majority of patients. One patient in group 3 had serious convulsions after vinorelbine administration; she also developed neutropenic sepsis; all symptoms were reversible. No patient died from side-effects. The objective response rates were 50%, 55% and 44% for groups 1, 2 and 3, respectively. Median time to progression was 7, 10 and 8 months and median survival time was 26, 23 and 16 months in groups 1, 2 and 3, respectively. CONCLUSION: VMF regimens where the vinorelbine dose (40 mg/m(2)) is divided (20 + 20 mg/m(2) and 30 + 10 mg/m(2)) between days 1 and 8 of a 3-week cycle are equally well tolerated and the efficacy is comparable to other modern first line regimens used in the treatment of metastatic breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗

Paclitaxel, 5-fluorouracil and hydroxyurea concurrent with radiation in locally advanced nasopharyngeal carcinoma.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is the standard treatment for locally advanced nasopharyngeal carcinoma (NPC). We conducted a phase II trial using paclitaxel, 5-fluorouracil and hydroxyurea concurrent with radiation (TFHX). PATIENTS AND METHODS: Fifty-nine patients with locally advanced NPC were treated with CRT consisting of 4-day continuous infusions of paclitaxel (20 mg/m(2)/d) and 5-fluorouracil (600 mg/m(2)/d), and oral hydroxyurea 500 mg bid for nine doses, every 3 weeks concurrent with radiotherapy (RT). RT consisted of once daily 200cGy fractions 5 times per week to a total of 7000cGy. RESULTS: Complete response was seen in 86% and 71% of patients at 4 and 12 months after CRT. The median follow-up was 34 months. Twenty-three patients experienced relapse. Sixteen deaths occurred: 13 from progressive disease. Three-year overall survival and progression-free survival were 72% and 54% respectively, with locoregional and distant control rates of 83% and 64% at 3 years respectively. Grade 3 to 4 acute toxicities included oropharyngeal mucositis in 81% of patients treated, dermatitis in 63%, weight loss in 32%, and neutropenia in 22%. Neutropenic fever was seen in 14%. There were no treatment-related deaths from acute toxicity. CONCLUSIONS: TFHX is shown to be feasible in NPC. Non-cross resistant induction chemotherapy should be further studied with this regimen.

Adult↗

Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil.

Dihydropyrimidine dehydrogenase catalyzes the first step in pyrimidine degradation: the NADPH-dependent reduction of uracil and thymine to the corresponding 5,6-dihydropyrimidines. Its controlled inhibition has become an adjunct target for cancer therapy, since the enzyme is also responsible for the rapid breakdown of the chemotherapeutic drug 5-fluorouracil. The crystal structure of the homodimeric pig liver enzyme (2x 111 kDa) determined at 1.9 A resolution reveals a highly modular subunit organization, consisting of five domains with different folds. Dihydropyrimidine dehydrogenase contains two FAD, two FMN and eight [4Fe-4S] clusters, arranged in two electron transfer chains that pass the dimer interface twice. Two of the Fe-S clusters show a hitherto unobserved coordination involving a glutamine residue. The ternary complex of an inactive mutant of the enzyme with bound NADPH and 5-fluorouracil reveals the architecture of the substrate-binding sites and residues responsible for recognition and binding of the drug.

Amino Acid Sequence↗

Phase II study of the modified regimen of etoposide, leucovorin and 5-fluorouracil for patients with advanced gastric cancer.

BACKGROUND: The efficacy of the treatment of advanced gastric cancer is not very good. The response rate to the original etoposide--leucovorin--5-fluorouracil (ELF) treatment is 53% with tolerable side effects. Whether increasing the dose intensity by prolonging the duration of infusion with 5-fluorouracil (5-FU) and leucovorin (LV) from 3 to 5 days for advanced or metastatic gastric cancer patients would enhance the efficacy but not increase side effects is still unknown. METHODS: Thirty-six advanced or metastatic gastric cancer and chemotherapy-naïve patients with measurable or evaluable diseases were scheduled to receive intravenous etoposide 100 mg/m2/day on days 2-4, LV 300 mg/m2/day intravenously and 5-FU 500 mg/m2/day intravenously on days 1-5, every 4 weeks. All patients who received at least two courses of chemotherapy were evaluated for tumor response, survival and response duration and toxicity according to the WHO criteria. RESULTS: Thirteen patients showed a response, including five with complete response (CR). The overall response rate was 36% (95% confidence interval, CI, 20-52%) in the whole group and 46% (95% CI 28-66%) in the 28 patients with measurable disease. The median progression-free interval and overall median survival time were 5 and 7 months, respectively. The most frequent toxicity was alopecia (grade I/II 56.3%). The incidence of grade III or greater myelosuppression was 5.9%. No treatment-related death occurred. CONCLUSIONS: The efficacy of the modified ELF by increasing the dosages of 5-FU and LV is not superior to the results of the original regimen, yet it is a relatively safe and tolerable combination regimen for advanced gastric cancer.

Adult↗