5FU Continuous Infusion Research Articles

Activity of oxaliplatin and 5-fluorouracil/folinic acid (FOLFOX2) in elderly patients with simultaneous advanced colon (ACC) and Hormone refractory prostate cancer (HRPC)

8241 Background. There is a likelihood of simultaneous colon and HRPC given the increased actual incidence of both cancers in elderly patients. HRPC has a high prevalence of epigenetic mismatch repair deficiency where oxaliplatin, unlike other alkylators, maintains activity. FOLFOX2 has been show active in HRPC (Droz JP, Ann Oncol 2003). We describe two cases of simultaneous advanced tumors treated with FOLFOX2. Methods. Two chemo-naïve patients with synchronous pathologically documented ACC and HRPC received the FOLFOX2 combination every 2 weeks (85 mg/m2 oxaliplatin with 400 mg/m2 bolus 5FU and 100 mg/m2 folinic acid day 1 followed by 2200 mg/m2 48h continuous infusion 5FU). Tumor response was evaluated clinically by ultrasound, CT-Scan and CEA. PSA was also used to assess the response of prostate cancer. Results. Two patients (pts) (PS 1; age:72 and 74) with measurable liver metastasis (colon cancer), non measurable but symptomatic bone metastasis (prostate cancer), and elevated baseline PSA values (12.5 and 255 ng/ml) were evaluable for toxicity and response. Pt 1 had 8 cycles and PT 2, 6 cycles; Grade 2 anemia, nausea, and weight loss were reported in both pts. Grade 3 asthenia was reported in one pt after 4 cycles. No peripheral neuropathy was reported. FOLFOX2 induced objective responses (60% and 70% tumor regression that lasted 8+ and 6 months) in colon cancer liver metastasis. Responses were associated with >50% sustained decrease in CEA levels in both pts. Chemotherapy was associated with pain relief and significant reductions of PSA values (90% decrease in one pt and normalization in the other). Duration of biological PSA responses was 3 months for one pt with partial PSA response and sustained for 8+ months in the pt with complete PSA response. Conclusion. Our clinical experience suggests that front-line FOLFOX2 chemotherapy is safe and active to control tumor progression of synchronous advanced colon and hormone-refractory prostate cancers in elderly males. No significant financial relationships to disclose.

Small-field radiotherapy in combination with concomitant chemotherapy for locally advanced pancreatic carcinoma.

To evaluate the effectiveness of small-field radiotherapy in combination with concomitant 5-fluorouracil (5FU) or cisplatin for locally advanced pancreatic carcinoma. From November 1993 to January 1999, 53 patients underwent continuous 5FU infusion at 200mg/m2 (27 patients) or a 30-min cisplatin infusion at 5mg/m2/day (26 patients) just prior to each irradiation. The radiation field was limited to cover the primary and the paraaortic regions at celiac and supramesenteric axis levels. A total dose of 50.4Gy in 28 sessions was given in 5.6 weeks. Median and 1-year survival rates were 10.2 months and 35.2%, respectively. Local failure occurred in 19 patients (36%) and liver metastases in 16 patients (30%). All local recurrences occurred only within the radiation field. Median survival rates were comparable to other studies. Because local failure occurred only within the radiation field, the use of relatively small-field radiotherapy may be justified in the treatment of locally advanced pancreatic carcinoma in addition to concurrent administration of either 5FU or cisplatin.

頭頚部癌に対するＭＴＸ‐５ＦＵ‐ＣＢＤＣＡ療法の経験

Combination chemotherapy including 5FU and carboplatin (CBDCA) with methotrexate (MTX) and leucovorin (LV) as biochemical modulation was performed on patients with head and neck cancer. A total of 32 patients were treated in the order of MTX, continuous 5FU infusion and LV injection, CBDCA. 24 of the 32 patients were concurrently treated with radiation therapy. Treatment-associated toxicity was significant, including mucositis, myelosuppression and body weight losses, but they were within acceptable limits. The 5-year survival rates calculated using Kaplan-Meyer methods were 41.3%.

Adénocarcinomes du bas œsophage et du cardia: quelle chimiothérapie ou chimioradiothérapie dans le traitement des récidives et des métastases?

Adenocarcinomas of esophagus and cardia represent in France approximately 20 to 40% of the esophagus cancers. They have a high risk to develop lymph nodes metastases and liver metastases. Currently, only 50 to 70% of patients may benefit from surgical curative resection at diagnosis, but more than 50% of them will recur. The standard of treatment of these metastatic adenocarcinomas is chemotherapy. Three large randomized comparative studies, between chemotherapy and supportive care, showed that chemotherapy significantly extends the median of survival (from 3–4 months to 10–12 months) and improves the quality of life. Currently, the combination of epirubicin-cisplatin-continuous 5FU (ECF) is the most effective regimen but it is difficult to administer and tolerate because of the long continuous 5FU infusion. In France, the most commonly used combination regimen still associates 5FU and cisplatin. New drugs (such as docetaxel, CPT11, oxaliplatin) used alone or in combination, especially with 5U, are very promising. Radio-chemotherapy is the preferred treatment for locoregional recurrences, because it improves dyphagia and enables to obtain complete tumor responses. Current results from concomitant radio-chemotherapy studies for esophagus cancer, based on 5FU alone, 5FU-cisplatin or 5FU-mitomycin, given as preoperative treatment or as exclusive treatment, support to use radio-chemotherapy for the treatment of loco-regional recurrences after surgical resection. Nevertheless, the optimal radio-chemotherapy schedule still remain to be defined (dose, duration, splitting of radiotherapy, choice of anticancer drugs).

Thymidine phosphorylase (TP) activation: convenience through innovation.

The management of patients with metastatic colorectal cancer most commonly involves treatment with 5-fluorouracil (5-FU), administered with or without leucovorin (LV) as an i.v. bolus or protracted infusion. Protracted infusion schedules have demonstrated superior efficacy compared with bolus regimens [1], but are associated with greater inconvenience and cost. Complications can also arise from the use of indwelling catheters [2]. The oral fluoropyrimidines have been developed to avoid some of these problems. Among the most promising of the oral agents is capecitabine (Xeloda ® ), a novel fluoropyrimidine carbamate that mimics continuous-infusion 5FU. Capecitabine is metabolized to 5-FU via a three-step enzymatic cascade, the third step of which is mediated by thymidine phosphorylase (TP). TP, also known as plateletderived endothelial cell growth factor, is correlated with poor prognosis, fast malignant growth, aggressive invasion potential, and anti-apoptotic properties. Preclinical studies have shown that TP is significantly more active in tumor tissue than in adjacent healthy tissue [3]. Capecitabine exploits the higher intratumoral concentrations of TP to achieve tumor-selective generation of 5-FU, resulting in increased concentrations of 5-FU in the tumor [4]. This tumor selectivity potentially reduces systemic exposure to 5-FU, improving efficacy and enhancing tolerability. Capecitabine has demonstrated considerable singleagent activity as first-line treatment for metastatic colorectal cancer. Data from two large, randomized, phase III clinical trials demonstrated that capecitabine results in a significantly superior tumor response rate compared with i.v. 5-FU/LV (Mayo Clinic regimen) and equivalent time to disease progression and overall survival [5]. Capecitabine also demonstrated an improved safety profile compared with i.v. 5-FU/LV. On the basis of these trials, capecitabine has recently been approved in Europe, the U.S., Canada, and numerous other countries for the first-line treatment of

The oral fluorinated pyrimidines.

The fluorinated pyrimidines have played a major role in the treatment of many common tumors since 5-fluorouracil (5FU) was first introduced. Studies of the cellular and clinical pharmacology of 5FU have led to an improved understanding of the mechanisms of action of this agent. This knowledge has allowed the optimal and rational development of fluoropyrimidine therapy, with significant therapeutic advances in recent years. Efforts to improve the therapeutic index of 5FU have included alteration of schedule, and the addition of biochemical modulators such as folinic acid. Although protracted continuous infusion of 5FU has led to better response rates and decreased toxicity, the administration of 5FU by protracted infusion is not only costly, but also inconvenient to the patient. Furthermore it is often associated with infectious and thrombotic complications related to the required indwelling intravenous catheter. Protracted oral administration is a rational route for administering 5FU, being preferred by the patient and the pharmaco-economist. The unpredictable and low oral bioavailability of 5FU initially discouraged this form of treatment. This problem has now been overcome by the new generation of oral fluoropyrimidines. Two main strategies have been pursued: 1) The administration of an inactive prodrug of 5FU, which is absorbed intact, and subsequently converted to 5FU. Capecitabine is converted to 5FU by a 3 step enzymatic process. 2) The administration of 5FU with an inhibitor of dihydropyrimidine dehydrogenase (DPD) to minimise the erratic absorption and variable clearance of 5FU: the preparations UFT, S1, and ethinyluracil/5FU contain an oral fluoropyrimidine co-administered orally with inhibitors of this enzyme. The development and characteristics of these agents are discussed.

The changing face of chemotherapy in colorectal cancer.

Cytotoxic chemotherapy for colorectal cancer has undergone a period of dramatic development over the course of the last 5 years. Four distinct classes of drug with activity in this disease are now available, and the current challenge is to establish the best way to use these agents, either in sequence or in combination, for the benefit of patients. This review aims to summarize the data relating to the newer agents and to propose directions for future research. DRUGS TARGETING THYMIDYLATE SYNTHASE 5-fluorouracil (5-FU) has established single-agent activity in advanced colorectal cancer. Its main intracellular target is thymidylate synthase, which is inhibited by the active metabolite of 5-FU, 5-fluorodeoxyuridine monophosphate (FdUMP) (Figure 1). The lack of alternative agents until recent years has fuelled extensive research into the biochemical modulation of 5-FU and alternative methods of delivery, primarily based on continuous infusion of the drug. Many individual clinical trials have demonstrated enhanced response rates when 5-FU is co-administered with folinic acid (calcium leucovorin). However a significant survival benefit has been more difficult to establish. Indeed a meta-analysis of nine trials showed no survival advantage for folinic acidmodulated 5-FU over 5-FU alone (Advanced Colorectal Cancer Meta-Analysis Project, 1992). Similarly, continuous infusion of 5FU using a variety of different schedules also enhances response rates over bolus delivery. A meta-analysis of seven randomized trials addressing this question showed a small but statistically significant improvement in median survival for 5-FU infusion over 5-FU bolus (12.1 vs 11.3 months, P = 0.039). Haematological toxicity was also significantly less common with 5-FU infusion, underlining the improved therapeutic ratio provided by this approach (Meta-analysis Group In Cancer, 1998). Drawing on the experience gained with 5-FU infusion, two new avenues of drug development have been explored. The direct thymidylate synthase (TS) inhibitors are a group of rationally designed molecules that compete with folinic acid for binding to TS (Figure 1). Intracellular polyglutamation of some of these compounds leads to their retention within the cell, and hence prolonged inhibition of TS. Raltitrexed, the lead agent in this class, has been the subject of extensive clinical evaluation. Its efficacy at the established dose of 3 mg m −2

Prospective trial of preoperative concomitant boost radiotherapy with continuous infusion 5-fluorouracil for locally advanced rectal cancer

Rationale: To evaluate the response to a concomitant boost given during standard chemoradiation for locally advanced rectal cancer. Methods and Materials: Concomitant boost radiotherapy was administered preoperatively to 45 patients with locally advanced rectal cancer in a prospective trial. Treatment consisted of 45 Gy to the pelvis with 18 mV photons at 1.8 Gy/fraction using a 3-field belly board technique with continuous infusion 5FU chemotherapy (300mg/m 2) 5 days per week. The boost was given during the last week of therapy with a 6-hour inter-fraction interval to the tumor plus a 2–3 cm margin. The boost dose equaled 7.5 Gy/5 fractions (1.5 Gy/fraction); a total dose of 52.5 Gy/5 weeks was given to the primary tumor. Pretreatment tumor stage, determined by endorectal ultrasound and CT scan, included 29 with T3N0 [64%], 11 T3N1, 1 T3Nx, 2 T4N0, 1 T4N3, and 1 with TxN1 disease. Mean distance from the anal verge was 5 cm (range 0–13 cm). Median age was 55 years (range 33–77 years). The population consisted of 34 males and 11 females. Median time of follow-up is 8 months (range 1–24 months). Results: Sphincter preservation (SP) has been accomplished in 33 of 42 (79%) patients resected to date. Three patients did not undergo resection because of the development of metastatic disease in the interim between the completion of chemoradiation (CTX/XRT) and preoperative evaluation. The surgical procedures included proctectomy and coloanal anastomosis ( n = 16), low anterior resection ( n = 13), transanal resection ( n = 4). Tumor down-staging was pathologically confirmed in 36 of the 42 (86%) resected patients, and 13 (31%) achieved a pathologic CR. Among the 28 tumors (67%) located <6 cm from the anal verge, SP was accomplished in 21 cases (75%). Although perioperative morbidity was higher, toxicity rates during CTX/XRT were comparable to that seen with conventional fractionation. Compared to our contemporary experience with conventional CTX/XRT (45Gy; 1.8 Gy per fraction), improvements were seen in SP (79% vs. 59%; p = 0.02), SP for tumors <6 cm from the anal verge (75% vs. 42%; p = 0.003), and down-staging (86% vs. 62%; p = 0.003). Conclusion: The SP rate with concomitant boost radiation has been highly favorable with rates of response which are higher than those previously reported for chemoradiation without administration of a boost. Further evaluation of this radiotherapeutic strategy appears warranted.

Thymidylate synthase (TS) protein expression in advanced colon cancer: correlation with the site of metastasis and the clinical response to leucovorin-modulated bolus 5-fluorouracil (5FU)

Recently, we have demonstrated that thymidylate synthase (TS) protein expression predicts for the clinical response to a regimen of infusional 5-fluorouracil (5FU) in advanced colorectal cancer patients. Previous studies by other groups that showed a correlation between TS gene expression and response to the fluoropyrimidine also involved infusional regimens. Considering the putatively different mechanism of action of bolus compared with continuous infusion of 5FU, the aim of the present study was to test whether the correlation between TS expression and the clinical response to 5FU is valid for bolus regimens. A secondary aim was to compare TS levels between liver metastases and abdominal recurrences from colon cancer, because these sites have a distinctly different responsiveness to 5FU chemotherapy. The study population consisted of 41 patients (25 males and 16 females; median age, 60 years) with unresectable metastatic or recurrent colon cancer, homogeneously treated with 5FU (420 mg/m2 i.v., days 1-5) and leucovorin (20 mg/m2 i.v., days 1-5); cycles were repeated every 28 days. Twenty-seven patients (66%) showed high levels of TS expression as defined by TS scores equal to 3 and 4. The proportion of cases with high levels of TS expression was significantly higher in abdominal recurrences (18 of 22, 82%) compared with liver metastases (9 of 19, 47%; P = 0.02). Intratumoral TS protein expression was inversely correlated with response to chemotherapy (response rate: 7 of 14, 50%, versus 0 of 27 in patients with low and high levels of TS expression, respectively; P = 0.0001). These results confirm that the level of TS protein expression predicts for response to 5FU, even with a bolus schedule. The higher TS levels observed in abdominal compared with liver metastases may account for their different responsiveness to 5FU chemotherapy. Immunohistochemical quantitation of TS protein levels may thus allow us to change the therapeutic approach to advanced colorectal cancer from a general to an individual treatment strategy at a time when new non TS-targeted drugs have become available for this disease.

No circadian variation of dihydropyrimidine dehydrogenase, uridine phosphorylase, beta-alanine, and 5-fluorouracil during continuous infusion of 5-fluorouracil.

Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases and it catalyses the reduction of thymine and uracil to 5,6-dihydrothymine and 5,6-dihydrouracil, respectively. In mammals, the degradation of uracil by DPD is the only pathway leading to the biosynthesis of β-alanine. Furthermore, DPD is also responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5FU), thereby limiting the efficacy of the therapy. 5FU is one of the few drugs that shows some antitumour activity against various otherwise untreatable tumours including carcinomas of the gastrointestinal tract, breast, ovary and skin. Furthermore, 5FU is one of the few drugs for which a limited clinical effect has been shown when applied as a single agent during the treatment of advanced colorectal cancer. In order to exert its cyto-toxic effect against cancer, 5FU must first be anabolised to the nucleotide level. 5FU can be converted into FUMP by a sequential, two-step reaction consisting of the initial addition of a ribose by uridine phosphorylase (UP) to yield 5-fluorouridine (5FUrd), followed by phos-phorylation to FUMP by uridine kinase. The direct conversion of 5FU to FUMP is catalyzed by orotate phosphoribosyl transferase (OPRT) which transfers the ribose-phosphate moiety from phosphoribosyl pyrophosphate (PRPP) to 5FU. Although the cytotoxic effects of 5FU are probably directly mediated by the anabolic pathways, the catabolic route plays a significant role since more than 80% of the administered 5FU is catabolised by DPD. It has been reported that the bioavailability, efficacy as well as host-toxicity of 5FU follows a circadian rhythm in rodents1 and cancer patients2. In the present study, we investigated whether a circadian variation could be observed of the activity of DPD, UP and the plasma concentration of β-alanine and 5FU in patients treated with continuous infusion of 5FU.

Circadian variation of dihydropyrimidine dehydrogenase (DPD), uridine phosphorylase (UP), β-alanine and 5-fluorouracil (5FU) during continuous infusion of 5FU

Circadian variation of dihydropyrimidine dehydrogenase (DPD), uridine phosphorylase (UP), β-alanine and 5-fluorouracil (5FU) during continuous infusion of 5FU

Role of first-line palliative chemotherapy in metastatic colorectal cancer

The prognosis of metastatic colorectal cancer remains poor. The 5-year survival rate is indeed 0 to 7%. The median survival duration is 8 months in patients without disease-related symptoms, and 6 months in patients with disease-related symptoms. The true benefit of palliative chemotherapy to increase the overall survival, and the symptom-free survival, has been largely discussed. In patients with disease-related symptoms, combinations of 5 fluoro-uracil (5-FU) and a biomodulator (leucovorin or methotrexate) have demonstrated a benefit on overall survival. In patients with asymptomatic disease, the advantage of systematic chemotherapy is more debatable. Two randomized studies have recently demonstrated that early chemotherapy yielded increased overall survival, disease-free symptom survival, and quality of life. Consequently, in patients with metastatic colorectal cancer, palliative chemotherapy must be performed even at early stages, before the onset of disease-related symptoms. Several regimens can be used as first line chemotherapy. In patients with good general status, and patients in whom a further resection of metastatic tumors could be possible, intensive regimens seem to be more appropriate. In the other patients, 5-FU-based regimens or raltitrexed can be proposed. Generally, the "standard" first line regimen seems to currently be LV5FU2 (bolus and continuous infusion of 5FU and leucovorin).

Modulation of 5-fluorouracil with folinic acid in advanced colorectal cancers. Groupe d'étude et de recherche sur les cancers de l'ovaire et digestifs (GERCOD)

The rational of leucovorin modulation of 5-fluorouracil and the clinical results in colorectal cancer are reviewed with special emphasis on the monthly schedule of low dose leucovorin and 5FU bolus for 5 consecutive days (NCCTG-Mayo Clinic regimen) and the bimonthly schedule of high-dose leucovorin and 5FU bolus plus continuous infusion for two consecutive days (LV5FU2) which is now considered as a new standard.

702 Randomized phase III trial comparing 5FU bolus and low dose leucovorin versus 5FU bolus plus continuous 5FU infusion and high dose LV in metastatic colorectal cancer

Monthly 5 day course of 5FU bolus infusion with low dose Leucovorin (FUFOL 1d) has the best therapeutic index for 5FU modulation in metastatic colorectal cancer. Delivering 5FU protracted continuous infusion has also a better index than 5FU bolus. The bi-monthly combination of 5FU bolus followed by 5FU continuous infusion and high dose (LV 5FU2) has show a good efficacy with low toxicity in several phase II studies. The current study compares FUFOLId and LV 5FU2. From March 1991 until April 1994, 437 patients (pts), stratified according to performance status, presence of measurable disease, and synchroneous or metachroneous disease, were randomized to (A) FUFOLld: IV bolus 5FU 425 mg/m2 d1-5 with folinic acid 20 mg/m2 IV d1-5 q 4 wk or (B) LV 5FU2: folinic acid 200 mg/m2 2-hour infusion followed by IV bolus 5FU 400 mg/m2 and 22-hour infusion FU 600 mg/m2 d1-2 q 2 wk. Therapy was continued until disease progression and second-line chemotherapy including 5FU continuous infusion was allowed in both arms. Response rate (306 evaluable pts), progressionfree survival (PFS) and overall survival (OS) are as follows: Treatment Pts Response Pts PFS (wk) OS (wk) FUFOL1d 147 17% 218 22.8 57.2 LVSFU2 159 34% 219 29.5 61.4 P = 0.002 P = 0.008 P = 0.006 41 pts (21.5%) experienced grade 3–4 toxicities in arm A versus 18 pts (9.2%) in arm B, P = 0.0004. grade 3–4 toxicities (%) were in arm A: neutrophils 7.9 platelets 1, nausea 2.6, diarrhea 4.7, mucositis 9.9, alopecia I, skin 0.5 and in arm B: neutrophils 2, platelets 0.5, nausea 3.1, mucositis 1.5, alopecia 0.5, skin 0.5. Treatment was stopped in one patient in arm A and 3 in arm B who experienced angina pectoris. We conclude that the bi-monthly combination of 5FU bolus and continuous infusion with high-dose folinic acid is more active and less toxic than monthly 5 day course of bolus 5FU with low dose Leucovorin.

554 Demonstrated efficiency of 5fluorouracil (5FU) continuous infusion (CI) and cisplatin (P) in patients with advanced biliary tract carcinoma

Little is known about the efficiency of chemotherapy in advanced biliary tract carcinoma. Accordingly, we conducted a phase II study of combined 5FU CI and P in this disease. 28 patients (pts) (13 M/15 F) were included. Median age: 57 years. ECOG performance status: grade (g) 0;1: 79%, g 2: 18%, g 3: 3%. More than 10% weight loss: 36% Primary tumor: gallbladder: 11, Vater ampulla: 5, cholangiocarcinoma: 5, bile ducts: 7. 25 patients had metastases, 2 had local recurrences of their tumor and 1 a nodulary intrahepatic non resectable form. Sites of the metastases: liver: 12 pts, abdominal lymph nodes: 6 pts, lung: 6 pts, peritoneum: 6 pts, mediastinal lymph nodes: 1 pt. Treatment schedule: 5FU CI: 1g/m² × 5 days, P: 100mg/m² day 2 repeated every 4 weeks. <h3>Results</h3> Median number of cycles: 4. 25 pts are evaluable for the tumor response (1 too early, 2 non evaluable), no complete response, partial response (PR): 8, objective response rate=29% (CI: 12–46%). Minor response: 2, stabilisation: 10, progressive disease: 6. Toxicity was tolerable: g 3 vomiting: 21% of the pts, g 3 mucositis: 4%. Some pts experienced haematological toxicity: g 3 granulocytopenia: 18%, g 4: 4%; no g 3–4 thrombocytopenia. Other toxicities: g 1–2 renal: 3 pts; g 1 neuropathy: 1 pt. No toxic death. Median survival was 10 months and 1-year actuarial survival 33%. We conclude that this regimen is tolerable and active in patients with advanced biliary tract cancer.

385 Pilot study of continuous infusion 5FU and bolus doxocubicin and cyclophosphamide for breast cancer

The therapeutic index of 5FU is improved with continuous iv infusion (ci) compared with bolus administration. We have combined 18 weeks ci5FU with 6 courses of bolus doxorubicin (50 mg/m 2 ) and cyclophos-phamide (600 mg/m 2 ) q3/52, aiming to develop a regimen for neoad-juvant treatment of breast cancer. 25 patients hâve been treated 6 large operable tumours, 5 locally advanced disease, and 13 metastatic disease. 5FU mg/m 2 /day Patients treated Neutropaenia Mucositis grade 3 grade 4 grade 2 grade 3 100 6 4 1 4 0 l50 4 1 2 3 0 200 14 5 7 7 2 The 3rd dose level produced tolerable toxicity. WHO grade 3−4 neutropaenia was frequent but short-lived in the majority. Mucositis required 5FU dose reduction in 2 patients. Two patients had neutropaenic sepsis and one died of unresolving pneumonia. Grade 2 piantar palmar skin toxicity occurred in 5 patients and grade 2 diarrhea in 2. Hickman line-associated proximal vein thrombosis occurred in 4 patients despite prophylactic warfarin (1−3 mg/d). The response rate in 20 evaluable patients was 5 CR, 9 PR, 3 SD, 2 PD. Patient accrual will continue to further define the response rate in neoadjuvant patients.

Comparison of 5-fluorouracil anabolite levels after intravenous bolus and continuous infusion

The levels of 5-fluorouracil (5FU) and its anabolites in the serum, bile, pancreatic juice, liver, pancreas, and skeletal muscle of dogs were compared after single bolus administration and after continuous infusion. Six dogs had a bolus of 5FU (15 mg/kg) and were studied for 120 min. Five dogs had a continuous infusion of 5FU (30 mg/kg) and were studied for 24 h. After the bolus infusion, serum 5FU levels were initially high and then declined, whereas anabolite levels gradually increased over 45 min. Within 2 h, anabolite levels exceeded 5FU levels in tissues but were undetectable in bile and pancreatic juice. During the continuous infusion, anabolite levels in serum increased more rapidly than 5FU levels and remained significantly higher for 24 h. Anabolite levels also exceeded 5FU levels in bile, pancreatic juice, pancreas, and muscle but not in the liver. Continuous infusion of 5FU produced higher levels of the anabolites than did bolus infusion and maintained constant levels throughout the infusion period.

A CASE OF BORRMANN 3 TYPE GASTRIC CANCER WITH REMARKABLY EFFECTIVE PREOPERATIVE CHEMOTHERAPY

A 68-year-old woman was successfully diagnosed as having a poorly defferentiated gastoric cancer of Borrmann 3 type preoperatively. The patient received preoperative chemotherapy with continuous infusion of 5FU 300 mg/m2/day from day 1 to 17, totally 6800mg/body and iv drip of CDDP 15 mg/m2/day from day 1 to 2, totally 50 mg/body; followed by total gastrectomy D3, splenectomy, and cholecystectomy (Stage IIIb). Histophathological examination of the primary tumor revealed that only a few cancer cell nests (por) remained in the mucosal layer. In all of the lymph nodes which were preoperatively suspected to be metastatic lesions, cancer nests have been completely destroyed. This case was judged to be in stage I a after chemotherapy, indicating a down staging.

Fluorouracil: biochemistry and pharmacology.

Fluorouracil (5FU) is still considered the most active antineoplastic agent in the treatment of advanced colorectal cancer. The drug needs to be converted to the nucleotide level in order to exert its effect. It can be incorporated into RNA leading to interference with the maturation of nuclear RNA. However, its conversion to 5-fluoro-2'deoxy-5' monophosphate (FdUMP) leading to inhibition of thymidylate synthase (TS) and subsequently of DNA synthesis, is considered to be its main mechanism of action. In the presence of a folate cofactor a covalent ternary complex is formed, the stability of which is the main determinant of the action of 5FU. Resistance against 5FU can be mainly attributed to aberrations in its metabolism or to alterations of TS, eg, gene amplification, altered kinetics in respect to nucleotides or folates. Biochemical modulation of 5FU metabolism can be applied to overcome resistance against 5FU. A variety of normal purines, pyrimidines, and other antimetabolites have been studied in this respect, but only some of them have been clinically successful. Delayed administration of uridine has recently been shown to "rescue" mice and patients from toxicity, while pretreatment with leucovorin is the most promising combination to enhance the therapeutic efficacy. 5FU is frequently administered in an intravenous (IV) injection, and shows a rapid distribution and a triphasic elimination. The nonlinearity of 5FU pharmacokinetics is related to saturation of its degradation. Continuous infusion of 5FU led to different kinetics. Regional administration, such as hepatic artery infusion, offers a way to achieve higher drug concentrations in liver metastases and is accompanied by lower systemic concentration. The current status of the biochemical and pharmacokinetic data is reviewed.

Continuous 5-Fluorouracil (5FU) Infusion in Carcinoma of the Pancreas: A Phase II Study

Sixteen patients with metastatic carcinoma of the pancreas were treated with continuous ambulatory 5-Fluorouracil (5FU) infusion (200-300 mg/m2/day) through a chronic indwelling central venous catheter. Twelve of sixteen patients (75%) had two or more sites of disease, and eleven of sixteen (69%) had liver metastases. Five patients had previous chemotherapy. partial remission, 3/16 (19%); stable disease, 8/16 (50%); and progressive disease, 5/16 (31%). Improvement in ECOG performance status was observed in 2/3 responding and 6/8 stable disease patients, respectively. Toxicities included hand-foot syndrome, mucositis, diarrhea, and cerebellar ataxia, which required treatment interruption in 9/16 patients (56%). No myelosuppression or catheter related problems were seen. The authors conclude that continuous infusion 5FU is a potentially efficacious palliative therapy in the management of carcinoma of the pancreas.