levoleucovorin and doxifluridine

Topics: Administration, Oral; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials as Topic; Combined Modality Therapy; Deoxycytidine; Female; Floxuridine; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Recurrence, Local; Neoplasms; Tegafur; Time Factors; Uracil

The standard beneficial chemotherapy proven for patients with advanced pancreatic cancer is a regimen containing gemcitabine. In the pregemcitabine era, 5-fluorouracil (5-FU) was the standard agent. Oral 5-FU can be added to gemcitabine to improve the efficacy of chemotherapy and to provide better patient convenience. The possibility to improve efficacy of gemcitabine by fixed dose rate infusion (FDRI) was proposed in addition to combining it with 5-FU. We tried a new chemotherapy combining FDRI of gemcitabine with doxifluridine and leucovorin. Eligibility criteria were pathologically proven, chemotherapy-naïve, and metastatic or nonoperable advanced pancreatic cancer. Gemcitabine 1,000 mg/m(2) was infused over 100 min (days 1, 8 and 15). Doxifluridine 200 mg/m(2) t.i.d. and leucovorin 15 mg b.i.d. were given orally (days 1-21). Chemotherapy was repeated every 28 days until a patient had received 6 cycles or progression was found. Twenty-nine patients were enrolled from October 2002 to December 2004. A total of 78 cycles were given at a mean of 2.7 cycles per patient. Response could be evaluated in 26 patients. Responses were partial remission in 4/26 patients (15.4%), stable disease in 8/26 (30.8%) and progression in 14/26 (53.8%). All patients progressed except for 2 in partial remission and 2 in stable disease. Toxicities could be assessed in 23 patients. Maximal hematological toxicities greater than grade 2 were leucopenia in 3 patients (11.5%), neutropenia in 2 (7.7%), anemia in 2 (7.7%), thrombocytopenia in 1 (3.8%) and febrile neutropenia in 3 (11.5%). Maximal nonhematological grade 3 or 4 toxicities were asthenia in 1 patient (3.8%), anorexia in 1 (3.8%), vomiting in 1 (3.8%), diarrhea in 2 (7.7%), allergic reaction in 1 (3.8%), hand-foot syndrome in 1 (3.8%) and hyperbilirubinemia in 1 (3.8%). All 29 patients were dead on last follow-up. Median progression-free survival was 3.91 months in 26 evaluable patients and median overall survival was 5.59 months in all patients. Combination chemotherapy including FDRI of gemcitabine seems minimally active for patients with advanced, nonoperable pancreatic cancer. Further research to improve effectiveness of chemotherapy for advanced pancreatic cancer is mandatory.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Female; Floxuridine; Follow-Up Studies; Gemcitabine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Remission Induction; Survival Analysis; Treatment Outcome

This phase II study was designed to evaluate the efficacy and toxicities of oral doxifluridine plus leucovorin as a randomized trial with those of intravenous 5-fluorouracil (5-FU) plus leucovorin in previously untreated metastatic colorectal cancer (CRC). Patients with metastatic CRC were randomized in either group A (oral doxifluridine 1,000 mg/m /d plus leucovorin 30 mg/d on days 1 to 7 and 15 to 21 of each cycle), or group B (intravenous 5-FU 400 mg/m /d plus leucovorin 20 mg/m /d on days 1-5 of each cycle), with the cycles repeated every 4 weeks. Between July 1998 and May 2000, 77 patients were enrolled (38 in group A and 39 in group B). Response rates were 23.7% (95% CI, 11-42%) in group A, and 15.4% (95% CI, 0-25%) in group B on an intent-to-treat analysis. The median response durations of the two groups were similar with 5.6 months in group A and 5.5 months in group B. Progression-free survival and overall survival were 5.4 months and 14.9 months in group A; 4.7 months and 19.5 months in group B. Toxicities in both groups were generally mild and reversible. This study shows that a combination of oral doxifluridine plus leucovorin can be active and safe as a first-line treatment for patients with metastatic CRC.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Floxuridine; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis

To assess the relationship between systemic exposure to capecitabine metabolites and parameters of efficacy and safety in patients with advanced or metastatic colorectal cancer from two phase III studies.. Concentration-effect analyses were based on data from 481 patients (248 males, 193 females; age range 27-86 years) in two phase III studies. Plasma concentration-time data for 5'-deoxy-5-fluorouridine (5'-DFUR), 5-fluorouracil (5-FU) and alpha-fluoro-beta-alanine (FBAL) were obtained from sparse blood samples collected within the time windows 0.5-1.5 h, 1.5-3.0 h, and 3.0-5.0 h after capecitabine administration (1250 mg m(-2)) on the first day of cycles 2 (day 22) and 4 (day 64), respectively. Systemic exposure based on plasma concentrations of capecitabine and its metabolites was determined using individual parameter estimates derived from a population pharmacokinetic model constructed for this purpose in NONMEM. Logistic regression analysis was conducted for selected safety parameters (all treatment-related grade 3-4 adverse events, treatment-related grade 3-4 diarrhoea, grade 3 hand-foot syndrome (HFS) and grade 3-4 hyperbilirubinaemia) and for tumour response. Cox regression analysis was used for the analysis of time-to-event data (time to disease progression and duration of survival).. Statistically significant relationships between covariates and PK parameters were found as follows. A doubling of alkaline phosphatase activity was associated with a 11% decrease in 5-FU clearance and a 12% increase in its AUC. A 50% decrease in creatinine clearance was associated with a 35% decrease in FBAL clearance, a 53% increase in its AUC, a 24% decrease in its volume of distribution, and a 41% increase in its Cmax. A 30% increase in body surface was associated with a 24% increase in the volume of distribution of FBAL and a 19% decrease in its Cmax. There was a broad overlap in systemic drug exposure between patients regardless of the occurrence of treatment-related grade 3-4 adverse events or response to treatment, leading to weak relationships between systemic exposure to capecitabine metabolites and the safety and efficacy parameters. Of 42 concentration-effect relationships investigated, only five achieved statistical significance. Thus, we obtained a positive association between the AUC of FBAL and grade 3-4 diarrhoea (P = 0.035), a positive association between the AUC of 5-FU and grade 3-4 hyperbilirubinaemia (P = 0.025), a negative association between the Cmax of FBAL and grade 3-4 hyperbilirubinaemia (P = 0.014), a negative association between the AUC of 5-FU (in plasma) and time to disease progression (hazard ratio (HR) = 1.626, P = 0.0056), and a positive association between the Cmax of 5'-DFUR and survival (HR = 0.938, P = 0.0048). Additionally, there were inconsistencies when concentration-effect relationships were compared across the two studies.. Systemic exposure to capecitabine and its metabolites in plasma is poorly predictive of safety and efficacy. The present results have no clinical implications for the use of capecitabine and argue against the value of therapeutic drug monitoring for dosage adjustment.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; beta-Alanine; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Floxuridine; Fluorouracil; Humans; Leucovorin; Male; Middle Aged

There is no consensus about the role of preoperative radiotherapy (RT) and chemotherapy (CT) in patients with resectable cancer of the distal rectum. This study analyzed the local clinical and pathologic response in patients receiving preoperative RT/CT for rectal cancer.. Thirty-two consecutive patients with a palpable adenocarcinoma of the rectum received preoperative RT (45 Gy in 25 fractions over 5 weeks) plus continuous chemotherapy with doxifluridine and leucovorin or 5-fluorouracil by continuous intravenous infusion during RT. Surgery was performed 8 weeks later. The Wilcoxon and chi(2) tests were used for data analysis.. Twelve patients had mild gastrointestinal toxicity, only one of whom required interruption of therapy. The tumor shrank to 57.8% of its original size, and at the echoendoscopy (u) there was a 58.7% decrease of the maximum diameter (P <.001). Downstaging from uT3 and uT2 to

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Floxuridine; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Rectal Neoplasms; Treatment Outcome

Preoperative radiation treatment with concomitant intravenous infusion of 5-fluorouracil (5-FU) is known to be effective in shrinking and downstaging of tumors. However, chemotherapy has often been limited by its toxicity and poor patient compliance. Oral 5-FU is known to have several advantages over conventional intravenous 5-FU infusion such as lower toxicity and higher quality of life without compromising the efficacy of the treatment. The aim of this study was to compare intravenous 5-FU with oral doxifluridine with respect to tumor response, toxicity and quality of life.. Twenty-eight patients with rectal cancer, staged as over T3N1 or T4 by transrectal ultrasonography between July 1997 and December 1998, were included in this study. Intravenous 5-FU (450 mg/m2) and leucovorin (20 mg/m2) were given for five consecutive days during the first and fifth weeks of radiation therapy (50.4 Gy) (n = 14). Oral doxifluridine (700 mg/m2/day) and leucovorin (20 mg/m2) were given daily during radiation treatment (n = 14). Quality of life was scored according to 22 activity items (good, >77; fair, >58; poor, <57). Surgical resection was performed 4 weeks after completion of concurrent chemoradiation treatment. Tumor response was classified into CR (complete remission), PR (partial response; 50% diminution of tumor volume or downstaging ) and NR (no response).. Tumor response was CR 3/14 (21.4%), PR 7/14 (50%) and NR 4/14 (28.6%) in the IV arm versus CR 2/14 (14.2%), PR 6/14 (42.9%) and NR 6/14 (42.9%) in the Oral arm (p = 0.16, 0.23, 0.24), respectively. The quality of life was poor (36.4% versus 33.3%), fair and good (63.6% versus 66.7%) between the IV arm and Oral arm, respectively. Gastrointestinal toxicity was 2/14 (14.3%) in the IV arm versus 5/14 (35.7%) in the Oral arm, respectively. Stomatitis was only observed in the IV arm (1/14, 7.1%). Hematological toxicity was 3/14 (21.4%) in the IV arm versus 4/14 (28.5%) in the Oral arm, respectively. Systemic recurrence during the follow-up periods were 1/14 (7.1%) in the IV arm and 2/14 (14.3%) in the Oral arm, respectively (p = 0.307). One local recurrence was observed in the Oral arm.. Even though the results were not entirely reliable owing to the small number of patients enrolled, oral doxifluridine-based chemotherapy as preoperative chemoradiation for advanced rectal cancer did not show any significant advantages over intravenous infusion.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Combined Modality Therapy; Female; Floxuridine; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Prospective Studies; Quality of Life; Rectal Neoplasms

The authors analyzed the histological effect of preoperative chemotherapy for 62 advanced colorectal cancer patients using resected specimens. Thirty-one patients in the 5'-DFUR + LV group received 800 mg/day of 5'-DFUR and 30 mg/day of leucovorin for 10-14 days just before the operations. Thirty-one patients in the 5'-DFUR group received 5'-DFUR 800 mg/day during the same period. None of the patients in either group developed any side effects. The results of the histological examination showed the number of Grade 1a and 1b cases in the 5'-DFUR + LV group was 22 (66.7%) and 5 (15.2%), respectively, and in the 5'-DFUR group 21 (65.6%) and 5 (15.6%). In the 5'-DFUR + LV group, 3 lesions showed Grade 2 histological degeneration, while there were no such lesions in the 5'-DFUR group. However, our results did not demonstrate any statistical difference between the two groups (p = 0.25, U test).

Topics: Administration, Oral; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Administration Schedule; Female; Floxuridine; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Preoperative Care; Tablets

The use of oral chemotherapeutic agents in chemoradiotherapy provides several advantages. Doxifluridine, an oral 5-FU prodrug, has been shown to be effective in colorectal cancer. We attempted a Phase II trial of preoperative chemoradiotherapy with doxifluridine plus a low-dose oral leucovorin in unresectable primary rectal cancer patients. In this study, toxicity and efficacy were evaluated.. There were 23 patients with primary unresectable rectal cancer in this trial, 21 of whom were available for analysis. The patients were treated with oral doxifluridine (900 mg/day) plus oral leucovorin (30 mg/day) from days 1 to 35, and pelvic radiation of 45 Gy over 5 weeks. Surgical resection was performed 5-6 weeks after the treatment.. Acute toxicity involved thrombocytopenia, nausea/vomiting, diarrhea, and skin reaction. All were in Grade 1/2, except diarrhea, which was not only the most frequent (7 patients, 33.3%), but also the only toxicity of Grade 3 (2 patients). The clinical tumor response was shown in 5 patients (23.8%) as a complete response and 13 patients (61.9%) as a partial response. A complete resection with negative resection margin was done in 18 patients (85.7%), in 2 of whom a pathologic complete response was shown (9.5%). The overall downstaging rate in the T- and N-stage groupings was 71.4% (15 patients).. This study demonstrated the efficacy and low toxicity of chemoradiotherapy with doxifluridine. Currently, a Phase III randomized trial of chemoradiotherapy is ongoing at our institute to compare the therapeutic efficacy of oral 5-FU with respect to i.v. 5-FU in locally advanced and unresectable rectal cancer.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Diarrhea; Female; Floxuridine; Humans; Leucovorin; Male; Middle Aged; Preoperative Care; Radiotherapy; Rectal Neoplasms; Thrombocytopenia

There currently is no agreement regarding the appropriate treatment of elderly patients with advanced breast carcinoma (ABC). Doxifluridine (5-dFUR), a prodrug of 5-fluorouracil, has been found to be effective in this entity, but its use is limited by neurotoxicity and cardiotoxicity that are not observed when the oral formulation is used. The objective of this Phase II trial was to evaluate the effectiveness and tolerability of oral 5-dFUR, biomodulated with levoleucovorin (1-leucovorin), in elderly patients (age > 70 years) with ABC.. 5-dFUR was administered orally at 600 mg/m2 twice daily for 4 consecutive days every 12 days, and oral 1-leucovorin was administered as 25 mg 2 hours before each 5-dFUR administration. Response was assessed every five cycles according to the World Health Organization criteria. In the presence of response or stable disease, the patients were treated for a maximum of 15 cycles.. Seventy-three eligible patients were enrolled, 27 of whom had been pretreated with chemotherapy and/or hormonotherapy; all were assessable for response and toxicity after a median follow-up of 15 months. The objective response rate was 26% (95% confidence interval, 17.4-45.4). Regression predominantly occurred in the presence of soft tissue involvement (skin, lymph nodes, and breast). The median time to response was 2 months (range, 1-2 months) and the median response duration was 7 months (range, 2-17+ months). The median survival was 24 months (range, 2-42+ months). The treatment was very well tolerated, and the side effects were manageable and always reversible.. The results of the current study show that 5-dFUR plus 1-leucovorin, both given orally, are associated with excellent patient compliance. Although the results are suboptimal in terms of an objective response, this characteristic could allow 5-dFUR to be used in elderly patients considered unsuitable for "aggressive" chemotherapy.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Female; Floxuridine; Fluorouracil; Humans; Leucovorin; Methotrexate; Neoplasm Staging

We conducted a multicentric phase II study on advanced colorectal cancer to determine the efficacy and toxicity of oral treatment with leucovorin (LV) plus doxifluridine (5'DFUR), a novel fluoropyrimidine derivative with proven antitumor activity in different experimental models. Thirty-six outpatients with measurable disease entered the trial and received orally LV 20 mg in the morning and in the afternoon, and 2 h later 5'-DFUR 500 mg/m2 every 2 days for 3 months. Thirty-four evaluable patients underwent a total of 408 weeks of treatment. The response rate was 35%, with two complete remissions and 10 partial responses. The median survival of patients who responded to treatment (responders) was 17.1 months (range 4-32), which was significantly longer (p<0.001) than the 6.5 months (range 2-11) of the patients who did not respond (non-responders). Therefore, after 4-8 weeks of treatment, 14 patients (41%) had an improvement in their performance status and/or stabilization of pain. General toxicity was usually mild, myelo and gastrointestinal toxicity were moderate, and there was no evidence of relevant neurological toxicity. These results show that a home therapy with oral LV-5'DFUR is a safe and effective treatment regimen for metastatic colorectal carcinoma.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Floxuridine; Humans; Italy; Leucovorin; Male; Middle Aged; Treatment Outcome

Doxifluridine (5-dFUR) is a fluoropyrimidine derivative, which is preferentially converted to 5-fluorouracil (5-FU) within tumour tissues. Although the activity of 5-FU in metastatic colorectal cancer is well recognised, resistance to this agent is frequently observed and remains its major limitation. The aim of this phase II study was to evaluate the activity of oral and i.v. 5-dFUR in metastatic or locally advanced colorectal cancer patients, who had been previously treated with a 5-FU containing regimen in either an adjuvant or metastatic setting. We treated 48 patients who, on the basis of tumour progression during, or within 8 weeks of the discontinuation of 5-FU therapy, were considered 5-FU resistant, 14 of the patients received 5-dFUR 3000 mg/m2 as a 1-h i.v. infusion, combined with L-leucovorin 25 mg/dose on days 1-5, every 3 weeks; the remaining 34 received oral 5-dFUR 1200 mg/m2 for 5 days followed by 5 days off. Oral L-leucovorin 25 mg/dose was administered 2 h before 5-dFUR. On the basis of WHO criteria, 4/14 (29%, 95% CI 4-51) partial responses were noted in the i.v. treated patients, and 4/34 (12%, 95% CI 1-23) in those treated orally. The radiological examinations documenting the response were a CT scan in 4 cases, ultrasound in 2 and NMR in 2. The median response duration was 6 months (range 3-11+), whereas the median time to treatment failure was 4 months (range 2-17). The responses were achieved in cases previously treated with a median of 9250 mg/m2 (range 5500-18,650) of 5-FU. No CTC-NC1 grade 4 toxicity was observed, although grade 3 diarrhoea occurred in 5 of the orally treated and in 3 of the intravenously treated patients. This is the first report documenting the efficacy of 5-dFUR in patients resistant to 5-FU therapy, and suggests that there is an absence of complete cross-resistance between these two fluoropyrimidines.

Topics: Administration, Oral; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Floxuridine; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Tomography, X-Ray Computed

Doxifluridine (5-dFUR) is a fluoropyrimidine derivative that has been shown to be active on a variety of solid tumors. The clinical use of intravenous (i.v.) 5-dFUR as a bolus injection or short term infusion has been limited because of its unpredictable severe neurotoxicity. Unlike fluorouracil (5-FU), 5-dFUR is effective when administered orally.. This randomized, parallel-group, Phase II trial of two schedules of 5-dFUR was conducted between April 1993 and September 1994. A total of 130 previously untreated patients with locally advanced or metastatic colorectal carcinoma were randomized to receive oral levo-leucovorin (1-leucovorin) 25 mg/dose followed by oral 5-dFUR 750 mg/m2 twice daily for 4 days every 12 days (arm A) or i.v. 1-leucovorin 25 mg/dose followed by i.v. 5-dFUR 3000 mg/m2 for 5 days every 21 days (arm B).. The two treatment arms were well balanced in terms of age, sex, and disease extension. Metastases were present in more than 90% of the total population, with the liver being the most common site. A median of 7 oral courses (range, 1-15) and 5 intravenous courses (range, 1-9) were administered. Intent-to-treat analysis rate of the randomized patients revealed a response rate of 15% (95% confidence interval [CI], 7-26) in arm A and 41% (95% CI, 29-54) in arm B. However, 7 cases in arm A and 12 in arm B were inadequately treated, and the response rates, according to standard analysis, were respectively 17% (95% CI, 8-28) and 51% (95% CI, 37-65). The median time to treatment failure was 4 months (range, 1-23) and 7 months (range, 1-9), respectively, for the two groups; median survival was 11 months (range, 1-24) in both groups. National Cancer Institute Grade 3 and 4 diarrhea were observed in 25% of the orally treated patients and in 18% of those receiving i.v. treatment. Stomatitis was reported mainly in arm B (15%). Mild and moderate neurotoxicity was observed in 6% of the patients in both arms; no severe neurotoxicity was reported.. 5-dFUR with l-leucovorin, administered either orally or intravenously, produces response rates that are similar to those offered by the regimens containing 5-FU that are usually used to treat advanced colorectal carcinoma. This study documents the good tolerance of the i.v. schedule administered as a 1-hour infusion; furthermore, oral administration seems to be promising and feasible as a home treatment.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antidotes; Antineoplastic Agents; Colorectal Neoplasms; Female; Floxuridine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Survival Rate

This study was designed to test the activity and feasibility of an all-oral regimen of levo-leucovorin and doxifluridine (dFUR) in the treatment of advanced colorectal cancer and to establish whether the pharmacokinetics of dFUR and fluorouracil (FU) are affected by demographic and/or biologic parameters.. One hundred eight patients with histologically proven colorectal cancer received orally administered levo-leucovorin 25 mg followed 2 hours later by dFUR 1,200 mg/m2 on days 1 to 5, with the cycle being repeated every 10 days.. Among 62 previously untreated patients, two complete responses (CRs) and 18 partial responses (PRs) were observed (overall response rate, 32%; 95% confidence interval, 21% to 45%). The median response duration was 4 months (range, 2 to 13) and the median survival time, 14 months. Among 46 pretreated patients, there were three CRs and three PRs (response rate, 13%; 95% confidence interval, 5% to 26%). In this group of patients, the median response duration was 4 months (range, 1 to 12) and the median survival time, 12 months. No toxic deaths were observed. The only World Health Organization (WHO) grade 3 to 4 side effect was diarrhea (32 patients).. This regimen is active in previously untreated colorectal cancer patients and combines good compliance with safety. Limited but definite efficacy was also detected in the patients previously treated with FU, which suggests incomplete cross-resistance between the two drugs. The pharmacokinetic results suggest that the conversion rate of dFUR to FU increases between days 1 and 5, but that FU levels remain low in comparison to those measured after classical FU therapy. Under the experimental conditions used in this study, the interpatient variability of pharmacokinetic parameters remains largely unexplained by the tested variables.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Floxuridine; Gastrointestinal Diseases; Humans; Leucovorin; Male; Middle Aged; Survival Rate; Treatment Outcome

Seventy-five patients with gastrointestinal cancer were entered in this study. The number of eligible cases were 38 in the group treated with sequential methotrexate (MTX)/5-fluorouracil (5-FU) with 5'-deoxy-5-fluorouridine (5'-DFUR) (group A) and 34 in the group without 5'-DFUR (group B). The treatment schedules were as follows: MTX/100 mg/m2 was given intravenously (i.v.) followed by 5-FU 600 mg/m2 i.v. 2 hours later and leucovorin 15 mg/body i.v. 8 and 20 hours later. This cycle was repeated once a week. In group A, 5'-DFUR 1,200 mg/body/day was given orally 5 consecutive days per week. Three of 35 cases in group A showed PR, while no case showed PR in group B. Median survival time was 5.0 months in group A and 5.3 months in group B, respectively. Gastrointestinal toxicity was commonly observed, and diarrhea was more frequent in group A (p < 0.05).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Quality of Life; Survival Analysis

A 46-year-old male patient underwent sigmoidectomy with D2 lymph node dissection and partial resection of the bladder for advanced colon cancer in January 2000. The lesion was judged to be pT2, pN0, sP0, sH0, sM0 and Stage II, and the patient was treated on a regular schedule as an outpatient. Fourteen months after the first operation, liver metastases (S4, S5) were found and partial resections of the liver were performed. However, a recurrence had often been detected in the residual liver for five years afterwards. Liver resections had been repeated for four times before radiofrequency ablation was performed in January 2005. The patient received adjuvant chemotherapy with 5'-DFUR, 5-FU/l-LV (RPMI method), and TS-1. In January 2006, obstructive jaundice due to tumor growth occurred and a self-expandable metallic stent was placed in the narrowed portion of the intrahepatic bile duct. The patient is,currently undergoing FOLFOX4 and FOLFIRI regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Catheter Ablation; Chemotherapy, Adjuvant; Colon, Sigmoid; Combined Modality Therapy; Floxuridine; Fluorouracil; Hepatectomy; Humans; Jaundice, Obstructive; Leucovorin; Liver Neoplasms; Lymph Node Excision; Male; Middle Aged; Sigmoid Neoplasms; Stents; Tegafur

A 66-year-old man underwent a curative operation for cecal cancer on the 30th of November, 1998. Since his CEA level rose in January 2001, computed tomography (CT) revealed a tumor in the abdomen. He underwent a resection of this tumor and disseminated tumors that were diagnosed during the operation. He received systemic chemotherapy (5'-DFUR 600 mg 3x everyday, CPT-11 80 mg/body div every 2 weeks), but the CEA level rose again in August 2003. He was diagnosed with spleen metastasis and underwent splenectomy. The tumor disseminated in the left diaphragm was also resected. After that, he received systemic chemotherapy (5-FU 500 mg/body/week div, levofolinate calcium 250 mg/body/week i.v.) as an outpatient. Peritoneal carcinomatosis from colorectal cancer with distant metastasis, in general, has no indication for an operation. However, if dissemination is located after a sufficient observation period, its resection may be recommended.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoembryonic Antigen; Cecal Neoplasms; Combined Modality Therapy; Floxuridine; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neoplasm Seeding; Peritoneal Neoplasms; Reoperation

A 71-year-old man underwent low anterior resection for rectal cancer. Two years after the surgery, liver metastasis and local recurrence were found on the CT scan. The first-line treatment was systemic chemotherapy (CPT-11 and 5'-DFUR). Effect was satisfactory for local recurrence, but a new liver tumor was found on the CT scan. The second-line treatment was a hepatic arterial infusion (5-FU) and systemic chemotherapy (UFT). After 4 courses, the liver metastasis was reduced, but after 5 courses, the liver tumors had enlarged. The third-line treatment was a hepatic arterial infusion (5-FU + levofolinate) and systemic chemotherapy (UFT). After 5 courses, the liver tumor disappeared, and no other recurrence was found on the CT scan.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Administration Schedule; Drug Combinations; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Rectal Neoplasms; Tegafur; Uracil

A left radical mastectomy was performed on a 53-year-old woman, diagnosed with left inflammatory breast cancer, after local arterial chemotherapy with cyclophosphamide (CPA), doxorubicin and 5-fluorouracil (5-FU). Adjuvant therapy was added with irradiation and ECF. Four months after the operation, a red eruption was detected on the left upper chest wall. The lesion was diagnosed by skin biopsy as a recurrent breast cancer with carcinoma erysipeloides. Tumor marker levels suggested the recurrent cancer was ECF resistant, so we changed the chemotherapy regime to a single dose of TXT. Although tumor marker levels and the skin eruptions improved at the beginning of the therapy, pleuritis carcinomatosa was found. We changed the regime again to a continuous dose of 5'-DFUR and LV for day 1 to 7. With this regime the clinical symptoms improved, and 2 courses of this modified FL therapy were carried out. After the therapy, the tumor seemed resistant to this modified FL therapy. Therefore, we tried a sequential therapy with TXT and the modified FL, which induced an improvement in clinical symptoms. Two years later, the patient died from the breast cancer. Therefore, we conclude that the sequential therapy may be beneficial in managing untreatable carcinoma erysipeloides of recurrent breast cancer.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Cyclophosphamide; Docetaxel; Doxorubicin; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Humans; Injections, Intra-Arterial; Leucovorin; Mastectomy; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Skin Neoplasms; Taxoids

The combination of radiotherapy and fluorouracil (5-FU) in patients with locally unresectable pancreatic carcinoma has led to a significant increase in survival in comparison with radiotherapy alone. Doxifluridine (5-DFUR) is an orally active fluoropyrimidine, and its cytotoxic metabolite (5-FU) may concentrate in areas of high tumor vascularization. This trial was carried out with the aims of improving locoregional control and making lesions resectable in patients with unresectable pancreatic cancer.. 5-DFUR was given at a dose of 500 mg/m2 b.i.d. by way of mouth for 4 days every other week for a total of four courses, with leucovorin 25 mg b.i.d. orally being given 2 hours before each 5-DFUR administration. External beam RT was administered at a dose of 1000 cGy per week for 3 weeks, followed by a 2-week break and then by 1000 cGy per week for a further 2 weeks (a total dose of 5000 cGy). The patients were restaged 4 weeks after the end of treatment and explored for resection in cases of partial response (PR).. A total of 32 patients were treated between 1992 and 1997. Ab initio unresectability was shown by laparotomy (16 cases) or computed tomography (16 cases), and was due to vascular invasion in 27 patients, massive regional nodal metastases in nine, and both in four. The median age was 63 years (range 36-71); performance status (PS) (ECOG): 0-1 = 28 and PS 2 = 4. All the patients had measurable disease and were evaluable for response. There were seven PR (22%), 10 SD (31%), and 15 PD (47%). All of the responders underwent surgical exploration, and radical resection was possible in 5. Three of these patients are still disease-free with a follow-up of 18, 27, and 65 months; the other two cases relapsed 11 and 14 months after surgery. The median survival time was 9 months for the entire group, and 1-year survival rate was 31%. The treatment was never stopped because of toxicity. There were no CTC-NCI grade 3 or 4 toxic events; grade 1-2 diarrhea was observed in 10 cases.. This preoperative regimen was feasible and led to a successful surgical resection in 16% of otherwise inoperable cases. The median survival was comparable with the results obtained after 5-FU infusion plus radiotherapy. The resectability rate, and the benefit in terms of survival in the resected patients, make these results worthy of confirmation by larger studies.

Topics: Adult; Aged; Antidotes; Antineoplastic Agents; Combined Modality Therapy; Disease Progression; Feasibility Studies; Female; Floxuridine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Pancreatectomy; Pancreatic Neoplasms; Survival Rate

Combination chemotherapy with FUra and LV has been reported as a useful treatment for patients suffering from colon carcinoma. Usually, both FUra and LV are administered by intravenous infusion, but not orally. UFT, an anti-neoplastic agent consisting of FT and uracil, is widely used for oral administration in Japan. Using human tumor xenografts of 10 cell lines, we evaluated the efficacy of UFT combined with l-LV, which is the active form of LV, by oral administration. Combined treatment of UFT with l-LV was more effective than UFT alone on the growth suppression of colon carcinoma (KM 20 C, Col-1) and mammary carcinoma (H-31, MX-1). When 1.85 mg/kg (5.55 mg/m2) of LV was given to tumor bearing mice, the antitumor activity of UFT was augmented and at a dose of 5.56 mg/kg (16.7 mg/m2) of LV, it was significantly augmented. Among various 5-FU derivatives, such as UFT, 5'-DFUR or FUra, combined treatment using UFT with l-LV was the most effective by oral administration. l-LV did not improve the anti-tumor efficacy or toxicity of 5'-DFUR. l-LV seemed to augment the anti-tumor activity of FUra, but not significantly. These results suggest that combination chemotherapy of UFT with LV is a promising approach for the clinical treatment of human colon cancer.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Floxuridine; Humans; Leucovorin; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Tegafur; Transplantation, Heterologous; Uracil

Topics: Adult; Aged; Antidotes; Antineoplastic Agents; Biliary Tract Neoplasms; Drug Therapy, Combination; Female; Floxuridine; Humans; Leucovorin; Male; Middle Aged

The benefits from medical treatment in colorectal cancer are limited. Fluorouracil remains the only recognized drug, and how to treat unresponsive patients is still debated. To evaluate the role of folinic acid (FA) in circumvence resistance in colorectal cancer, 28 patients pretreated with fluoropyrimidine were candidated to receive one of the following schedules: fluorouracil (600 mg/m2) associated with FA (500 mg/m2) weekly for 6 weeks (Regimen A: 21 cases), or fluorouracil (370 mg/m2) plus FA (200 mg/m2) daily for 5 days every 4 weeks (Regimen B: 7 cases). Fourteen patients were pretreated with doxifluridine, a new fluoropyrimidine derivative with a peculiar mechanism of action, and the remaining 14 patients with fluorouracil. All but 2 patients were unresponsive to first-line treatments. When the treatment began, the median age of the patients was 60 years (range, 30-68). The performance status (ECOG) was 0/1 in 25 of them, and the primary tumor was in the colon and rectum in 19 and 9 patients, respectively. Sites of disease were liver (64%), lung (35%), local recurrence (10%) and peritoneum (10%). A median of 3 cycles (range, 1-7) was delivered, and no objective response was observed in the group of patients pretreated with doxifluridine or in the group pretreated with fluorouracil. In 5 cases a significant decrease in baseline CEA values was observed. Therapy was well tolerated, and no grade 4 toxicity was encountered. Severe toxicity was limited and included diarrhea (7 patients), stomatitis (1 patient) and nausea/vomiting (1 patient). High-dose FA has no role in reversing resistance to fluoropyrimidine, and other mechanisms of refractoriness are surely involved. FA should be associated with fluoropyrimidine as first-line therapy together with other biochemical modulators. Further rescue therapies need to be developed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Resistance; Female; Floxuridine; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

Folinic acid (leucovorin, [LV]) can potentiate the growth inhibitory effects of fluorouracil (5-FU) in vitro and in vivo. LV is a precursor for 5,10-methylene-tetrahydrofolate (CH2-THF). Sufficient levels of CH2-THF enhance the inhibition of the enzyme thymidylate synthase by the 5-FU metabolite FdUMP. This study describes the effects of 5-FU and LV in two murine (C26-10, C38-1) and two human (WiDr, HT-29) colon carcinoma cell lines and in two murine tumors (Colon 26 and Colon 38). In vitro, only C38-1 was more sensitive for the combination of LV/5-FU compared with 5-FU alone. This effect was not dose or schedule dependent. l-LV, a purified stereo-isomere of LV, is thought to be the biological active form. Tests with this compound in vitro did not show a better effect than the mixture of d- and l-LV. In vivo, dl-LV could potentiate 5-FU antitumor effect in two murine colon tumors (Colon 26, Colon 38). This effect was clearly schedule dependent. dl-LV administered 1 hour before and together with 5-FU was much better than only simultaneous or posttreatment, but there was no dose dependency, while like in vitro l-LV effect was comparable to dl-LV. TdR was used to study the role of TS inhibition in the growth inhibitory effect of 5-FU with and without LV. TdR can reverse growth inhibition caused by TS inhibition due to 5-FU. In vitro, a partial reversal of growth inhibition of 5-FU and 5-FU/LV was observed, but in vivo there was no reversal. In vivo, TdR combinations led to high toxicity. Measurements of TS amounts in cells and tumors showed that those of human origin had much lower TS than the murine. C38-1 and Colon 38 with low TS were more sensitive to 5-FU than Colon 26 with higher TS amounts. TS inhibition was studied in the two murine colon tumors at several time points after weekly 5-FU or LV and 5-FU administration. LV did not increase the extent or retention of TS inhibition due to 5-FU during the first week. After three courses of treatment a fourfold increase of TS levels was seen in Colon 26 after 5-FU therapy. This resulted in a less effective TS inhibition after this treatment. Tumors treated with 5-FU and LV also showed an increase of TS, but to a lower extent, while the effect on TS inhibition remained the same.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Colonic Neoplasms; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Leucovorin; Mice; Mice, Inbred BALB C; Thymidine; Thymidylate Synthase; Tumor Cells, Cultured; Uridine Monophosphate

We reported 2 patients treated with Methotrexate (MTX)-Fluorouracil (5-FU) sequential therapy combined with Doxifluridine (5'-DFUR). The method of administration was as follows: MTX 60 mg was given intravenously (iv) followed by 5-FU 600 mg iv 2 hours later in colon cancer and 5 hours later in gastric cancer. Leucovorin 20 mg was administered 3 times every 6 hours beginning 6 hours after 5-FU infusion. This cycle was repeated once a week for 5 weeks. 5'-DFUR 1,200 mg was given orally daily and continued after MTX.5-FU therapy. Patient 1 was a 60-yr-old female with recurrent colon cancer developed four years after sigmoidectomy. She was referred to our hospital for further examinations of elevated serum carcinoembryonic antigen (CEA). The enlarged intraabdominal lymph nodes due to recurrence were demonstrated on computer tomography and the chemotherapy was performed as described above. The swelling of lymph nodes showed marked reduction in size and CEA value was normalized. Patient 2 was a 59-yr-old man with advanced gastric cancer accompanied by giant liver metastasis. Both primary and metastatic lesion responded favorably to this regimen. There was no remarkable side effect in either patient. These results suggest that this method is worth performing in further clinical trials for cancer patients.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Colonic Neoplasms; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Remission Induction; Stomach Neoplasms