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[Adriamycin, cyclophosphamide, and 5-fluorouracil in the treatment of metastasizing breast cancer (author's transl)].

In a prospective study eleven patients with metastasizing breast cancer were treated with 5-fluorouracil, adriamycin, and cyclophosphamide )FAC). Complete remission occurred in three patients, with two of them still in remission four and thirteen months later. Partial remission (50% decrease in tumour size for more than four weeks) was achieved in five cases, with three of them still in remission. Time for remission induction was one to three months. The mean duration of complete remissions is not yet reached after thirteen months- that of partial remissions was 6.5 months. Two patients showed stable disease for four and more than eleven months, respectively. Only in one case progressive disease was noticed. Mean survival time from the start of therapy was 7.5 months for all patients. For complete and partial responders mean survival is not yet reached after eighteen months. With one exception therapy was given on an outpatient basis. Experimental and clinical data on therapeutic synergism of adriamycin, cyclophosphamide, and 5-fluorouracil show no advantage of the three-drug combination over the combination of adriamycin and cylophosphamide alone.

Breast Neoplasms↗

Subacute leucoencephalopathy induced by carmofur, a 5-fluorouracil derivative.

Three cases of leucoencephalopathy induced by carmofur (1-hexylcarbamoyl-5-fluorouracil), an antineoplastic derivative of 5-fluorouracil are reported and the literature is reviewed. Initial symptoms were unsteady gait and dementia developing several weeks or months after carmofur had been started. Symptoms increased gradually even after stopping the drug. Severe encephalopathy with confusion, delirium or coma appeared frequently. Symptoms were usually reversible but death occasionally occurred. The EEG showed marked slowing. Computed tomography of the brains of severely intoxicated patients showed marked hypodensity of the entire cerebral white matter. Carmofur must be discontinued immediately if any psychomotor symptoms develop.

Aged↗

Phase II study of weekly mitoxantrone, 5-fluorouracil, and leucovorin in metastatic breast cancer.

A phase II study to test the toxicity and the efficacy of a weekly combination of Mitoxantrone, 5-Fluorouracil and L-Leucovorin (MFL) was carried out in 43 patients with metastatic breast cancer. Chemotherapy consisted of mitoxantrone 4 mg/m2, 5-fluorouracil 375 mg/m2, and L-leucovorin 100 mg/m2 on day 1, weekly. Patient characteristics were: median age 53 years (range 36-65); estrogen receptor (ER) status was known in 26 patients and of these 15 (57.7%) patients were ER-positive and 11 (42.3%) ER-negative. Of the 43 patients, 25 (58.1%) and 18 (41.9%) patients had received prior adjuvant chemotherapy and prior adjuvant endocrine treatment, respectively. MFL was administered to 22 (51.1%) patients as first line chemotherapy for advanced disease, while 21 (48.9%) patients had received 1 to 2 cytotoxic regimens for metastatic disease. The dominant sites of metastases were: soft tissue in 11 (25.5%) patients, bone in 8 (18.6%) patients and viscera in 24 (55.9%). All patients were assessable for toxicity: only 8 patients experienced WHO grade 3 leukopenia. Thrombocytopenia, diarrhea, stomatitis, and nausea/vomiting were negligible. Anemia and alopecia were not observed. Thirty-nine patients were assessable for response: overall response rate was 28.2% (complete response 7.7% and partial response 20.5%). Median duration of response was 12 months (range 6-34). Patients with no prior anthracyclines had a 42.1% response rate compared to 15% in patients who had received anthracyclines. Median overall survival of the 43 patients was 6 months (range 1-34). Weekly MFL is a well-tolerated and a moderately effective regimen for the treatment of metastatic breast cancer.

Adult↗

Ifosfamide, methotrexate, and 5-fluorouracil: effective combination in resistant breast cancer.

Ifosfamide has definite efficacy in many malignant tumours, including breast cancer. In the present study we substituted cyclophosphamide with ifosfamide in the combination CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) regimen in 25 patients with breast cancer whose disease was refractory to CMF or who had relapsed after previous response. Ifosfamide was given in an i.v. infusion at a dose of 1.2 g/m2 daily for 5 days, together with mesna as a uroprotector (at 20% of the ifosfamide dose). Methotrexate was given at a dose of 40 mg/m2 and 5-fluorouracil was given at 600 mg/m2, both by i.v. push. Courses were repeated every 21 days. The 24 evaluable patients received 3-12 courses (average, 5 courses); results included a complete remission in 3 patients (12.5%) and a partial remission in 3 (12.5%). Among the remaining patients, improvement was seen in 4 (16.6%); stable disease, in 7; and progressive disease, in 7 (29.2%). The complete responses lasted for 11+, 13+, and 15+ months, and partial remissions, for 2, 6, and 9 months. The responses were detected in soft-tissue as well as visceral lesions, but not in bony lesions. The responders remain under follow-up. This study shows the efficacy of ifosfamide-containing chemotherapy in breast cancer. As toxicities were tolerable, higher doses of ifosfamide could safely be used in these patients. Use of this combination as first-line therapy in breast cancer could be considered for a future study.

Adult↗

Weekly 5-fluorouracil and high-dose folinic acid in combination with epidoxorubicin as first-line therapy in advanced breast cancer: a phase II study.

A total of 25 patients with advanced breast cancer were treated weekly with i.v. 5-fluorouracil at 350 mg/m2, folinic acid at 500 mg/m2, and epidoxorubicin at 35 mg/m2 as first-line chemotherapy for a maximum of 18 cycles. In all, 24 patients were evaluable for response. Overall, 1 patient achieved a complete response and 11 patients showed a partial response, for an objective response rate of 50%; the median duration of response was 18.3+ months and median survival amounted to 18.8+ months. Side effects were generally mild, with grade II leukopenia occurring in 10 patients and grade III leukopenia, in 1 patient. Other toxicity included nausea and vomiting (82%), diarrhea (48%), stomatitis (48%), and alopecia (92%), all of which were mainly restricted to WHO grades I and II. Our results suggest that leucovorin modulation of 5-fluorouracil can safely be incorporated into combination chemotherapy with epidoxorubicin on the investigated schedule. The observed response rate appears comparable with that obtained with other first-line regimens.

Adult↗

Effect of gastrectomy on the pharmacokinetics of tegafur, uracil, and 5-fluorouracil after oral administration of a 1:4 tegafur and uracil combination.

The effects of gastrectomy on the pharmacokinetics of UFT, a combined oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil at a molar ratio of 1:4, were examined in 26 patients with macroscopic Stage I gastric cancer. In all, 200 mg UFT (in terms of tegafur) was given to 17 patients who underwent partial gastrectomy (9 cases of Billroth I reconstruction, 8 cases of Billroth II reconstruction) and to 9 patients who underwent total gastrectomy with modified Roux-en-Y reconstruction. Before the operation, the area under the curve (AUC) for tegafur, uracil, and 5-fluorouracil (5-FU) was 79.28 +/- 26.88, 4.41 +/- 1.78, and 0.51 +/- 0.20 micrograms h ml-1, respectively. Partial (Billroth I and II) and total gastrectomy did not alter the AUC of tegafur, and partial gastrectomy using the Billroth I and II methods decreased the AUCs of uracil and 5-FU during the first 2 weeks postoperation. However, plasma levels of uracil and 5-FU reverted to preoperative values at 3 months postsurgery. Our findings show that when UFT is prescribed for patients treated in the early postoperative period following partial gastrectomy for cancer, dose increases and the timing of administration should be given close attention.

Administration, Oral↗

A phase II study of 5-fluorouracil plus folinic acid in malignant gliomas in adults.

Fourteen patients with malignant gliomas were entered on a phase II study of 5-fluorouracil 300-370 mg/m2 plus folinic acid 200 mg/m2 x 5 days q4 weeks. To be eligible, patients could not have received more than 1 prior chemotherapy regimen. A single patient with a recurrent oligodendroglioma responded. Toxicity (predominantly stomatitis, diarrhea, and granulocytopenia) was tolerable and was similar to that seen in studies of 5-fluorouracil plus folinic acid in other tumor types. This regimen has minimal activity in recurrent malignant gliomas.

Adult↗

Cytokine production in whole blood cell cultures of patients undergoing therapy with biological response modifiers or 5-fluorouracil.

We have measured the levels of interferon gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), IL-1 beta, and IL-2 in the whole blood cell culture supernatants of 43 tumor patients undergoing a treatment with biological response modifiers or a conventional therapy with 5-fluorouracil and leucovorin. In the blood cell cultures of the 16 patients who received 5-fluorouracil and leucovorin IFN gamma levels decreased (P < or = 0.01) and TNF alpha levels rose (P < or = 0.05) during each therapy cycle. However, in the blood samples a declining number of total leukocytes and lymphocytes was measured (P < or = 0.05). Progressive disease could be correlated to a tendency towards lower IFN gamma levels in the pretherapeutic cultures of these patients. The second group analyzed consisted of 8 patients receiving a low-dose IL-1 beta therapy. In this group we found either an unchanged or an augmented IFN gamma production of the blood cells during treatment. In the group of 13 patients receiving low-dose recombinant IL-2 (< or = 4.5 x 10(6) IU m-2 day-1) significantly increasing IFN gamma levels were seen in the blood cell cultures during the therapy (P < or = 0.05), although total leukocyte counts decreased. In this group, 4 had stable disease for at least 2 months and 9 patients had tumor progression under therapy. In the cultures of the latter a tendency towards lower IFN gamma values was found. Finally, the cytokine production in the blood cell cultures of 6 patients receiving a combination therapy of IFN alpha and high-dose IL-2 was studied. During this therapy a dramatically reduced production not only of IFN gamma but also of all other measured cytokines was found. In this group all patients had tumor progression under therapy. It is concluded that the measurements of cytokine production in a reproducible whole blood culture system may be useful for monitoring immunological therapies and may help us to find out which doses of biological response modifiers have enhancing or suppressive effects on the functions of the immune cells.

Adult↗

[Intraductal chemotherapy of bile duct cancer with 5-fluorouracil].

The prognosis of bile duct cancer is still poor. Curative surgical therapy is possible in only 10%-20% of cases. Palliative effects of chemotherapy and radiation are small. Newer palliative techniques like iridium 192 wire radiation or hepatic artery infusion of chemotherapeutic agents seem to be more effective. Another new form of palliative local chemotherapy, intrabiliary application of 5-fluorouracil, is described. A 67-year-old woman with an adenocarcinoma of the left and common hepatic ducts received symptomatic therapy by an external biliary drainage for 20 months. In the following 3 weeks the amount of drained bile diminished and finally stopped, while icterus occurred. Catheter cholangiography showed a right catheter position, the known obstruction of the common hepatic duct and the left bile duct, and a diffuse right-sided peripheral bile duct occlusion, regarded as multifocal tumor spreading. Intraductal application of 5-fluorouracil via the PTCD tube, 125-375 mg twice a week, effected a rising bile secretion after a few days, to a final volume of 1,000 ml/day. An X-ray control 34 days after start of the therapy showed a nearly complete reopening of the formerly occluded peripheral bile duct system and a filiform reopening of the common hepatic duct with sufficient flowing off into the common bile duct and the duodenum. Certain side effects of this therapy were not noticed. After successful reopening of malignant bile tract occlusion, other palliative therapeutic techniques like internal bile drainage or iridium 192 wire radiation can be applied.

Adenocarcinoma↗

Prednimustine in combination with methotrexate and 5-fluorouracil in advanced breast cancer: a phase I-II study.

Forty-seven patients with advanced breast cancer were treated with a combination of prednimustine (P), methotrexate (M), 5-fluorouracil (F), and tamoxifen (TAM). Twenty-six patients received P, 80 mg/m2 day 1-5 (series I) and 21 patients received P, 100 mg/m2 day 1-5 (series II). Both series of patients received M, 40 mg/m2 day 1 and 8 and F, 600 mg/m2 day 1 and 8 with a cycle duration of 4 weeks. All patients received TAM 20 mg twice daily. As concerns the haematologic toxicity, WBC were depressed significantly more often than platelet counts, and during the first 3 cycles 70% of the patients had a WBC nadir corresponding to toxicity grade II or more. No signs of cumulative haematologic toxicity were observed. Nausea and vomiting were registered in 40 out of 47 patients but in 35 of these only of grade I-II. Only one patient developed alopecia requiring a wig. The response to treatment could be evaluated in 28 patients, 21 of whom experienced response (CR or PR) of a median duration of 13 months. In conclusion, it seems that prednimustine can be safely used in combination with methotrexate and 5-fluorouracil. The frequency of alopecia is definitely lower than with CMF. Whether this relates also to subjective side effects will require a randomized study, as will a final conclusion concerning the efficacy compared to that of CMF.

Aged↗

Cisplatin and 5-fluorouracil in refractory breast cancer patients: a phase II study.

24 patients with a median of 3 prior chemotherapy regimens were treated in our department with cisplatin 20 mg/m2 (with pre- and posthydration) and 5-fluorouracil 200 mg/m2 i.v. on day 1-5, every three weeks. 23 patients are evaluable; one had early death. 4 patients (17%) achieved a partial response, 8 had stable disease, and 11 progressed. Toxicity observed was moderate and no renal toxicity was noted. This study therefore shows tolerable toxicity but limited usefulness of adding cisplatin to 5-fluorouracil according to this schedule in these highly pretreated patients.

Adult↗

Bolus vs. continuous hepatic arterial infusion of cisplatin plus intravenous 5-fluorouracil chemotherapy for unresectable colorectal metastases.

UNLABELLED: A multicenter, randomized Phase 2 study that compared patients, affected by colorectal liver metastases, who received intrahepatic arterial infusion with two different schedules of cisplatin, bolus vs. continuous infusion, and systemic 5-fluorouracil. PURPOSE: The aim of this study was to validate results of a previous Phase 2 trial on bolus cisplatin intrahepatic arterial infusion, which reported a 47 percent response rate and a 32 percent 4-year survival rate for Gennari's Stage 2 patients, with a high rate of neurologic, gastrointestinal, and hematologic toxicity. METHODS: One hundred nine patients were randomized in a Phase 2 study to receive cisplatin intrahepatic arterial infusion (24 mg/m2/day, 1-->5, bolus vs. continuous infusion) and systemic intravenous 5-fluorouracil (250, 375, or 500 mg/m2/day, 1-->5; escalating doses, respectively, at cycles I, II, III, and VI). To avoid neurotoxicity a maximum of six cycles was administered. RESULTS: Preliminary results for the 78 evaluable patients are similar to those of the previous study: response rate 46 percent and at a median follow-up of 16.5 months, the overall survival was 16.5 months, with 45 percent of the patients who received more than 3 cycles alive at 3 years. Toxicity, evaluable in 99 patients, showed a decreased incidence of neurotoxicity and a tolerable gastrointestinal and hematologic toxicity, lower in the cisplatin continuous infusion arm. CONCLUSION: This study clearly shows that cisplatin intrahepatic arterial infusion is able to provide a good palliative effect with a tolerable toxicity.

Antineoplastic Combined Chemotherapy Protocols↗

Effect of 5-fluorouracil and leucovorin on the integrity of colonic anastomoses in the rat.

PURPOSE: This study was designed to determine the effects of 5-fluorouracil and leucovorin on the healing of colonic anastomoses and assess the safety of conducting a colonic resection and anastomosis during and shortly after a course of this chemotherapy in a rat model. METHODS: Fifty-six male Wistar rats, weighing 200 to 250 gm, were divided into four groups, each consisting of 14 animals. Animals in Group I (control group) underwent colon resection and primary anastomosis. Animals in Group II received 10 mg/kg intravenous 5-fluorouracil and 10 mg/kg leucovorin once a week for four weeks and then underwent the same operation. Animals in Groups III and IV received the same drug dosage for six weeks and were operated at different intervals: Group III at one week and Group IV at two weeks after completion of chemotherapy. Within each group, one-half of the animals were sacrificed on the third postoperative day and one-half on the seventh postoperative day, and anastomotic bursting pressure measurements were performed. RESULTS: At three and seven days, mean bursting pressure of the anastomoses were determined: 98 mmHg and 180.7 mmHg in Group I, 95 and 197.8 in Group II, 85.7 and 189.2 in Group III, and 98.6 and 179.2 in Group IV, respectively. There was no significant difference in bursting pressure between treated animals and controls by the third postoperative day or by the seventh day. The burst occurred at the anastomosis in all specimens tested on the third postoperative day and in the bowel wall adjacent to the anastomosis in all specimens tested on the seventh postoperative day. CONCLUSION: This study demonstrates that the above regimen of chemotherapy has no effect on the healing of colonic anastomoses and that surgery can be performed safely during and shortly after this regimen of chemotherapy.

Anastomosis, Surgical↗

Intraoperative electron and external beam irradiation with or without 5-fluorouracil and maximum surgical resection for previously unirradiated, locally recurrent colorectal cancer.

PURPOSE/OBJECTIVE: 1) Disease control and survival will be evaluated for treatment regimens containing intraoperative electron irradiation (IOERT) for locally recurrent, previously unirradiated colorectal cancers. 2) Various prognostic factors will be evaluated to determine whether they have an impact on disease control or survival. MATERIALS AND METHODS: From April 1981 through August 1995, 123 patients with previously unirradiated locally recurrent colorectal cancers received IOERT at our institution, usually as a supplement to external beam irradiation (EBRT) and maximum resection. All received EBRT with or without concomitant 5-fluorouracil-based chemotherapy. Forty-five Gy in 25 fractions was given to the tumor or tumor bed plus 3-cm to 5-cm margins in 121 of 123 patients and a boost of 5.4 to 9 Gy in 3 to 5 fractions to the tumor plus 2-cm margins. Maximum resection was performed before or after EBRT. IOERT doses ranged from 10 to 20 Gy in 119 of 123 patients, with dose dependent on resection margins (130 fields in 123 patients). Maintenance chemotherapy was given to only two patients. RESULTS: Disease relapse and survival were evaluated. Central failure (within the IOERT field) was documented in 13 of 123 patients (11 percent) with a five-year actuarial rate of 26 percent. Local relapse (in EBRT field) occurred in 24 patients (20 percent); five-year rate was 37 percent. Distant metastases occurred in 66 patients (54 percent); five-year rate was 72 percent. Median survival was 28 months, with overall survival at two, three, and five years of 62, 39, and 20 percent, respectively. Tolerance data suggest a relationship between IOERT dose and incidence of Grade 2 or 3 neuropathy (< or = 12.5 Gy, 2 of 29 or 7 percent; > or = 15 Gy, 19 of 101 or 19 percent; P = 0.12). Survival and disease control were analyzed as a function of potential prognostic factors. None of the prognostic factors had a significant impact on disease control or survival. Although there was a trend for reduction in local relapse rates with gross total vs. partial resection, this neither achieved statistical significance nor translated into improved survival. Patients with gross residual disease after maximum resection had three-year and five-year survival rates of 36 and 18 percent, respectively, which paralleled results for patients with gross total resection at 41 and 24 percent, respectively. CONCLUSION: Encouraging trends for improved local control with or without survival exist in separate locally recurrent colorectal IOERT analyses from our institution and other institutions. Therefore, continued evaluation of IOERT approaches seems warranted. Disease control within the IOERT and external fields is decreased when the surgeon is unable to accomplish a gross total resection. Therefore, it is reasonable to consistently add 5-fluorouracil or other dose modifiers during EBRT and to evaluate the use of dose modifiers in conjunction with IOERT (sensitizers and hyperthermia). In view of high systemic failure rates of > 50 percent in patients with locally recurrent disease, more routine use of systemic therapy is indicated as a component of IOERT-containing treatment regimens (use existent chemotherapy and/or develop effective immunotherapy and gene transfer therapy). Even with locally recurrent lesions, the aggressive multimodality approaches including IOERT have resulted in improved local control and long-term survival rates of 20 percent vs. an expected 5 percent with conventional techniques.

Adult↗

Intra-hepato-arterial infusions of cis-diamminedichloroplatinum (II) and 5-fluorouracil clinically effective for malignant liver tumors.

Four hepatocellular cancer patients and 11 metastatic liver cancer patients were treated with intra-hepato-arterial infusions of cis-diamminedichloroplatinum (II) plus 5-fluorouracil. Cis-diamminedichloroplatinum (II) (25-35 mg/m2) was given once a week, 5-fluorouracil (150-180 mg/m2) was infused daily. A partial response was obtained in 3 of 4 patients with primary cancer and in 5 of 9 evaluable metastatic cancer patients; the mean response durations were 27+ weeks in the former and 47+ weeks in the latter. However, severe bone marrow suppression occurred in 4 patients; 3 died of septicemia (2 cases) and massive intra-tracheal bleeding, respectively. This combined intra-hepato-arterial chemotherapy exerts a synergistic anticancer effect on malignant liver tumors, however, the related bone marrow suppression remains to be overcome.

Adult↗

Pseudomembranous colitis associated with chemotherapy with 5-fluorouracil.

Pseudomembranous colitis is frequently associated with antibiotics and more rarely with chemotherapeutic agents such as 5-fluorouracil. The objective of this study is to show that it is possible to confuse this infection with chemotherapy associated toxicity. We present a 54 year old woman who underwent surgery for colorectal cancer and in the first cycle of chemotherapy with 5-fluorouracil developed pseudomembranous colitis. We detected the toxin B of Clostridium difficile in stools and we began early antibiotic treatment. Thus, in patients with post chemotherapy neutropenia and diarrhoea that develop negatively, we have to rule out this infection.

Adenocarcinoma↗

[5-Fluorouracil-induced small bowel toxicity in a patient with colorectal cancer].

5-Fluorouracil-induced gastro-intestinal toxicity predominantly affects the upper and the lower gastro-intestinal tract. Although 5-fluorouracil (5-FU) can cause severe small-bowel toxicity, this has been reported only in 6 patients with colon carcinoma receiving 5-FU-based therapy. The presentation was extensive ulceration and inflammation of the small bowel with no involvement of the colon. We report another case of this toxicity, and discuss the diagnosis and mechanisms by which 5-FU can induce small-bowel toxicity.

Aged↗

Phase I clinical trial of cisplatin given i.v. with 5-fluorouracil and high-dose folinic acid.

We report the results of a phase I study of intravenously administered cisplatin, 5-fluorouracil and high-dose folinic acid. This trial was designed to exploit potential biochemical interactions between these three agents. The maximum tolerated doses were cisplatin, 75 mg/m2, day 1; 5-fluorouracil, 375 mg/m2, days 1-5 and leucovorin 500 mg/m2, days 1-5. The dose-limiting toxic effect of this regimen was myelosuppression. Mild non-hematologic toxic effects were also observed and included nausea, vomiting, stomatitis, and diarrhea. Phase II trial of this regimen are underway, however randomized studies will eventually be necessary to establish whether cisplatin contributes clinically significant activity to this regimen.

Adult↗