Courses Of 5-fluorouracil Research Articles

The Effects of Perioperative Fluorouracil Administration on Convalescence and Wound Healing

Administration of chemotherapy is delayed by most clinicians until complete recovery from surgery because it is generally feared that cytotoxic drugs impair wound healing, reduce resistance against infection, and may hinder the recovery process. However, clinical experience is lacking. This clinical study examines the effect of perioperative administration of fluorouracil on the healing of wounds and intestinal anastomoses and the recovery process in general. Forty patients with advanced gastrointestinal tract cancers entered the study. Intravenous bolus administration of 0.5 g of fluorouracil was started during surgery. The patients underwent a variety of abdominal operations for palliation or cure. A total of 22 gastric and enteric anastomoses were performed. One half gram of fluorouracil diluted in 150 mL of 5% glucose solution was given intravenously over one hour daily for ten days postoperatively. The patients were carefully evaluated for any alteration in the postoperative recovery. Thirty-eight of the 40 patients received the full course of fluorouracil. Twenty-one patients had an uneventful postoperative course. Eighteen had mild to moderate respiratory and cardiovascular complications unrelated to fluorouracil administration. One patient died of pulmonary emboli 16 days after abdominoperineal resection. Surgical wounds healed without complications in 37 patients. One case of wound disruption occurred after sigmoidectomy. Two patients developed wound infections that healed secondarily. All 22 patients with anastomoses recovered without any evidence of leakage. Colostomies and gastrostomies functioned as anticipated. Side effects attributed to fluorouracil appeared in seven of the patients; in only two of the patients were complications life-threatening, involving bone marrow depression. All patients recovered after discontinuation of fluorouracil therapy and with supportive treatment. On the whole, the course of recovery of this group was no different than expected from patients with advanced malignant neoplasms who were undergoing extensive surgery. Based on this study, it seems that fluorouracil administration during and immediately after surgery has no deleterious effect on wound healing and recovery.

Topical fluorouracil. II. Postoperative administration in an animal model of glaucoma filtering surgery.

Unilateral posterior lip sclerectomies were performed in ten owl monkeys. Five milligrams of fluorouracil was injected subconjunctivally in each operated eye immediately after surgery. Three drops (approximately 2.4 mg/drop) of fluorouracil were instilled ten minutes apart in each operated eye twice daily on postoperative days 1 through 7 and once daily on postoperative days 8 through 15, 17, 19, and 21. One monkey died on the seventh postoperative day; its death could not be attributed to systemic fluorouracil toxicity. All of the operated eyes had filtering blebs after the full course of fluorouracil, but seven also had corneal epithelial defects. By the seventh postoperative week, two of the operated eyes manifested moderately severe corneal opacification. Ten weeks postoperatively, the electroretinographic a- and b-wave amplitudes averaged 17% and 12% less, respectively, in the seven operated eyes without clinically significant corneal opacification than in the unoperated fellow eyes. Only two eyes had blebs after the 12th postoperative week. Histopathologic examination was performed on five eyes, of which only two revealed patent sclerostomies. Although topical fluorouracil appears to delay bleb scarring, the corneal findings suggest that it may be more toxic than subconjunctival fluorouracil.

Randomized Study of Adjuvant Chemotherapy for Head and Neck Cancer

The ability of surgery and radiotherapy to control advanced squamous cell carcinoma of the head and neck has reached its maximal potential. We initiated a randomized, prospective, stratified study of adjuvant chemotherapy. Patients with stage II disease of the pyriform sinus and stage II and IV disease of the oral cavity, larynx, hypopharynx, oropharynx, nasopharynx, and paranasal sinuses were eligible. Patients were randomized to receive either standard therapy alone or two courses of 5-fluorouracil (B-CMF) chemotherapy prior to and two courses after the completion of standard therapy. Standard therapy consisted of preoperative irradiation followed by radical surgery. Of 133 patients with advanced disease, 83 were included in the study--43 in the chemotherapy group and 40 in the control group. Rates of residual and recurrent disease, as well as distant metastases, were similar for the two groups. The survival rates of patients without persistent disease at the end of treatment showed no significant difference for the two groups. The study has been discontinued because statistical analysis indicated that the addition of more patients would not materially increase the statistical significance of the study.

Effect of propylene glycol, Azone and n-decylmethyl sulphoxide on skin permeation kinetics of 5-fluorouracil

The effect of propylene glycol (PG), azone (LDA) and n-decylmethyl sulfoxide (LDB) on the permeation course of fluorouracil through the hairless mouse skin was studied. Steady-state fluxes and permeability coefficients were measured in buffer solutions and in systems containing the enhancing agents. The permeation rates of fluorouracil have been shown to be highly pH dependent in the pH range of 5–9, the rate decreases with an increase in pH. The solubility of fluorouracil in pure propylene glycol at equilibrium measured by the solubility method was found to be 2.2 mg · ml −1 at 25°C which is a relatively low value as compared to the solubility in water. The effect of various concentrations of propylene glycol in aqueous donor solutions on the drug permeation rate was examined at pH's 5.7 and 9.0. It was found that propylene glycol decreases the permeation flux when increasing concentrations are added to the aqueous pH 5.7 system; however, at pH 9, a strong enhancement effect was shown. PG was also found to decrease the drug reservoir in the hairless mouse skin e.g. 8.4 and 2.8 mg · (mg skin) −1 for buffer pH 9 and PG/aqueous solution pH 9 systems, respectively. The concentration dependent enhancement effects of azone and n-decylmethyl sulfoxide have been measured. Both have been found to be potent enhancing agents. However, at relatively low concentrations such as 5%, Azone induced a 50-fold and n-decylmethyl sulfoxide only a two-fold enhancement of the drug steady-state flux. At high concentrations as much as 40%, n-decylmethyl sulfoxide appears to be more effective than Azone. The fluxes measured with these systems were 0.21, 0.17 and 0.003 mg · cm −2 · h −1 for the n-decylmethyl sulphoxide, Azone and PG/H 2O systems, respectively.

Superior clinical response and survival rates with initial bolus of cisplatin and 120 hour infusion of 5-fluorouracil before definitive therapy for locally advanced head and neck cancer

One hundred ninety-one patients were treated by one of three cisplatin-containing multidrug protocols. The initial 77 patients received two courses of cisplatin and vincristine plus bleomycin. The next 26 patients received two courses of 5-fluorouracil and cisplatin, and the final 88 patients were placed on a three course 5-fluorouracil and cisplatin protocol. Overall response rates were similar for each of the three protocols. The complete response rate, however, was much better (54 percent) for three course 5-fluorouracil and cisplatin versus cisplatin vincristine, and bleomycin (29 percent) and two course 5-fluorouracil and cisplatin (19 percent). Survival curves were also better for the three course 5-fluorouracil and cisplatin segment of this nonrandomized pilot study.

Improved treatment of a brain-tumor model. Part 2: Sequential therapy with BCNU and 5-fluorouracil.

A combination chemotherapy regimen for brain tumors was developed, based on investigations of the survival of animals harboring the intracerebral 9L rat brain-tumor model and on analyses of their clonogenic tumor cells. Fischer 344 rats harboring 9L brain tumors were treated with 2-day courses of 5-fluorouracil (5-FU), in order to expose all cycling tumor cells to the drug during DNA synthesis and achieve maximum anti-tumor activity for this cell-cycle-specific anti-metabolite. Although a 74% cell kill was obtained for a total dose of 45 mg/kg or greater, animal life span was not increased over that of untreated tumor-bearing controls. However, when 5-FU (48 to 96 mg/kg total dose over 2 days) was administered after a single LD10 dose of BCNU (13.3 mg/kg), additive cell kill was suggested. In three large series, long-term animal survivors and occasional tumor cures were observed with this drug combination, a result never observed following BCNU alone. Schedule dependency was not apparent. A previously published protocol for treating recurrent malignant gliomas with sequential courses of BCNU and 5-FU was partially planned based upon these initial observations. Anti-tumor activity with the combination of drugs was superior to therapy with BCNU alone. Both animal and human studies confirm that, contrary to presently accepted oncological tenets, a chemotherapeutic agent that kills significant numbers of tumor cells but is clinically ineffective when given alone might, nevertheless, be useful in combination therapy regimens.

Laetrile-Induced Agranulocytosis

PROPONENTS of laetrile claim it is beneficial and safe. Opponents point to the lack of proof of its efficacy, the delay in seeking more effective therapy its use may entail, and the risk of death or illness from cyanide poisoning resulting from its use. We report the case of a patient in whom agranulocytosis developed, apparently due to laetrile. <h3>Report of a Case</h3> On May 10, 1980, a 61-year-old woman who had been treating herself with laetrile for five years was admitted to Greenwich (Conn) Hospital because of sudden onset of rigors with fever (temperature to 39.4 °C). She had had a simple right mastectomy with axillary lymph node dissection for infiltrating ductal carcinoma in 1966. In 1975 a second primary developed and she underwent a left modified radical mastectomy, followed by a course of fluorouracil. She received five doses of 500 mg intravenously during June and July 1975, but

Chemotherapy as an Adjuvant to Surgery for Colorectal Cancer

An adjuvant program of fluorouracil for patients undergoing "curative" resection for adenocarcinoma of the colon and rectum was initiated as a randomized clinical trial in January 1968. Patients were randomly assigned to an intraluminal fluorouracil or intraluminal control (saline) group and were so treated at the time of surgical resection if findings at operation indicated that all gross neoplastic disease could be resected. Those patients receiving intraluminal fluorouracil (30 mg/kg) received intravenous fluorouracil (10 mg/kg) on each of the first two postoperative days and five subsequent postoperative courses of oral fluorouracil (90 mg/kg) in each 18-day course over a one-year period. By July 1, 1975, there were 203 patients undergoing curative resection entered into the study. Survival and disease-free data, as of Dec 31, 1976, revealed no benefit from this adjuvant course of fluorouracil. These data support the need for continued randomized clinical trials of new and innovative adjuvant therapy compared with an untreated control group.

Fluorouracil as an Adjuvant to Colorectal Cancer Surgery; The Breakthrough That Never Was

To the Editor.— In an article published inThe Journal(235:2825, 1976) that was endorsed by an editorial, and Ross claimed significant improvement of five-year cure rate for patients with type B and C Dukes colorectal cancer through the use of fluorouracil as a surgical adjuvant.The Journaleditorial would appear to offer enthusiastic concurrence: Li and Ross show clearly the benefit from two postoperative courses of fluorouracil in patients with colorectal carcinoma, and One of the striking features... is the exceptionally short duration of treatment with fluorouracil necessary to achieve the impressive results. It is scarcely surprising that such outspoken claims made breakthrough headlines in the news media. These claims have no foundation in fact. and Ross have attempted to demonstrate the effectiveness of fluorouracil as a surgical adjuvant by comparing survivorship in patients so treated from 1965 to 1970 with survivorship in patients treated with

Time and vehicle studies of a safe and effective method for administration of 5-fluorouracil

Eighty-seven patients with histologically proven cancer were given a course of 5-fluorouracil to study the effect of time of infusion and of 5% glucose in regard to toxicity and antitumor effectiveness. The over-all response rate of 25% was unrelated to time of infusion or vehicle and compares favorably with that reported for more toxic methods of administration. Beneficial effect was not dependent upon the production of systemic drug toxicity; the data suggest that, when response is slow, a significant number of patients may be forced to discontinue the drug because of toxicity before sufficient time is allowed for response. The frequency and degree of toxicity encountered with 5-FU infusions was lower than that noted following courses of undiluted drug. Infusion of 5-FU in the regimen tested seems a safe and effective method of drug administration which can be used widely on an ambulatory basis.