Continuous infusion of high-dose 5-fluorouracil in combination with leucovorin and recombinant interferon-alpha-2b in patients with advanced colorectal cancer. A Multicenter Phase II study.

BACKGROUND: 5-Fluorouracil (5-FU), when combined with leucovorin (LV) or interferon-alpha (IFN-alpha), may result in improved response rates compared with 5-FU alone in patients with advanced colorectal cancer. The authors investigated the clinical efficacy of combining these three agents for patients in this group. METHODS: Forty-five patients were administered outpatient high-dose 5-FU, 60 mg/kg/48 hours (2400 mg/m2/48 hours) continuous intravenous infusion on days 1 and 2; LV, 90 mg orally every 6 hour, 8 times during 5FU infusion; and recombinant IFN-alpha-2b, 10 x 10(6) IU/dose subcutaneously on days 1, 3, and 5. Cycles were repeated weekly for 4 weeks and every 2 weeks thereafter. RESULTS: Forty-four patients were evaluable for response, and 11 patients (25%; 95% confidence interval, 12-38%) achieved a partial response with a median duration of 11 months. Median survival time for all patients was 11 months. Grade 3 and Grade 4 toxicities occurred in 21 patients (47%), which necessitated discontinuation of treatment in 2 patients (4%); permanent dose reductions were necessary in 11 patients (24%). The addition of IFN-alpha produced more 5-FU-related toxicity compared with a previous study in which the same dosage and schedule of 5-FU plus LV was used. CONCLUSIONS: The efficacy of 5-FU continuous infusion combined with LV and IFN-alpha does not appear to differ significantly from earlier reports on treatment using 5-FU plus LV or 5-FU plus IFN-alpha for patients with colorectal cancer. However, this schedule of 5-FU combined with LV and IFN-alpha produces less toxicity compared with previous trials using bolus 5-FU plus IFN-alpha.

Postprandial gallbladder motility and plasma cholecystokinin at regular time intervals after injection of octreotide in acromegalics on long-term treatment.

The increased risk of gallstone formation in acromegalics treated with the somatostatin analog octreotide has been related to an impaired gallbladder emptying. To determine the duration of these inhibitory effects, meal-stimulated gallbladder motility, plasma cholecystokinin (CCK), and pancreatic polypeptide (PP) were measured in five acromegalics treated for 6-32 months with 200-300 micrograms octreotide daily. Meal tests were performed 45 min, 8 hr and two weeks after the last 100-micrograms subcutaneous dose. Results were compared with those in normal subjects. Integrated postprandial gallbladder contraction (-125 +/- 194 cm3/120 min) and integrated PP secretion (-0.1 +/- 0.2 nmol/liter/120 min) were completely suppressed in the 45-min study, but significantly improved (P < 0.05) when measured 8 hr (1376 +/- 322 cm3/120 min and 3.0 +/- 1.0 nmol/liter/120 min) and two weeks (1437 +/- 263 cm3/120 min and 10.6 +/- 1.6 nmol/liter/120 min) after the last dose of octreotide. The integrated gallbladder contraction in acromegalics at 8 hr was comparable to that at two weeks and to that in normal subjects, but the integrated PP response at 8 hr was significantly smaller (P < 0.05 vs two weeks and vs normals). Integrated plasma CCK secretion at 45 min (0.13 +/- 0.06 nmol/liter/120 min) was not statistically significantly different from the response at 8 hr (0.15 +/- 0.02 nmol/liter/120 min) and from that in normal subjects, but it was significantly increased at two weeks after cessation of octreotide (P < 0.05 vs 45 min and 8 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

Aseptic bone necrosis in patients on glucocorticoid replacement therapy.

The incidence of aseptic bone necrosis in 167 patients on glucocorticoid replacement therapy in our hospital was found to be 2.4% (4 patients). The diagnosis was made 16 months to five years after initiation of the therapy. A review of eight other cases reported in the literature is presented. The incidence of aseptic bone necrosis in patients on glucocorticoid replacement therapy seems much higher than might be expected. It is suggested that the dose of glucocorticoid substitution therapy be established individually at the lowest acceptable level.

The 5-HT3 receptor antagonist ondansetron re-establishes control in refractory emesis induced by non-cisplatin chemotherapy.

The efficacy and safety of two dose schedules of the 5-HT3 antagonist ondansetron (Zofran) were studied in 35 patients (group A: 19 patients, group B: 16 patients) previously refractory to standard antiemetics after non-cisplatin-based chemotherapy (greater than 5 emetic episodes). The maintenance of the antiemetic efficacy of ondansetron was further studied in 28 patients (13 A, 15 B) in respectively 36 and 48 retreatment courses. Ondansetron was administered as an 8 mg loading dose (A: 4 mg i.v. + 4 mg orally; B: 8 mg i.v.), followed by oral treatment for 5 days (A: 6-hourly; B: 8 mg 8-hourly). In the first treatment cycle acute emesis was completely controlled in 53% of the patients in group A and in 50% of the patients in group B. Delayed emesis was absent in 75% and 38% of the patients in group A and B respectively. In a second treatment cycle acute antiemetic control was achieved in 54% and 53% of the patients in group A and B respectively. Over the third and fourth subsequent treatments, complete control occurred in 56% and 38% of the patients in group A, and in 46% and 56% of the patients in group B respectively. Delayed emesis did not occur over the following courses in 62%, 89% and 75% of the patients on regimen A, in 57%, 60% and 63% of the patients on regimen B. The observed adverse effects were headache (37%) and constipation (42%). No extrapyramidal reactions were seen. Ondansetron is able to re-establish an acceptable antiemetic control in previously refractory patients on non-cisplatin-based chemotherapy, without major toxicity. This efficacy is maintained over the three following retreatment courses.

Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind, crossover study.

OBJECTIVE: To compare the efficacy and side effects of ondansetron with those of high-dose metoclopramide in treating acute and delayed cisplatin-induced nausea and vomiting. DESIGN: Randomized, double-blind, crossover trial. SETTING: Conducted at two university hospitals, a cancer institute, and six community hospitals. PATIENTS: Of 125 patients, 95 were evaluable for the acute phase and 79 for the delayed phase. Major reasons for not being evaluable were no second course (14 patients), protocol violation (5 patients), and change in cisplatin dose (3 patients) for the acute phase, and rescue medication on day 1 (7 patients), protocol violation (3 patients), and inadequate data (4 patients) for the delayed phase. INTERVENTIONS: All patients received cisplatin, 50 to 100 mg/m2 body surface area (median, 75 mg/m2); none had previously received chemotherapy. Thirty minutes before the cisplatin administration, ondansetron was given intravenously over 15 minutes, at a loading dose of 8 mg followed by a continuous infusion of 1 mg/h for 24 hours. Metoclopramide was given at a loading dose of 3 mg/kg body weight, followed by a continuous infusion for 8 hours (4 mg/kg). For the delayed phase (days 2 through 6), the first oral dose was given as soon as the infusion was completed; the oral dose consisted of either metoclopramide, 20 mg three times daily, or ondansetron, 8 mg three times daily for another 5 days. MEASUREMENTS AND MAIN RESULTS: In the acute phase, a major or complete response was seen in 72% of the ondansetron-treated and 41% of the metoclopramide-treated patients (P less than 0.001). Nausea was significantly better controlled among the ondansetron-treated patients (P = 0.04). In the delayed phase, no statistically significant difference was seen between ondansetron- and metoclopramide-treated patients. Nausea was significantly better controlled with metoclopramide (P = 0.016). CONCLUSIONS: Ondansetron is significantly more effective than metoclopramide in preventing acute nausea and vomiting. In the delayed phase, the results of both drugs were disappointing, although metoclopramide's effect on delayed nausea was superior. Patients preferred ondansetron.

Postprandial exocrine pancreatic function during long-term treatment with the somatostatin analogue SMS 201-995 in acromegalic patients.

Long-term treatment with the somatostatin analogue SMS 201-995 (SMS) might impair exocrine pancreatic function, secretion of cholecystokinin (CCK) and pancreatic polypeptide (PP), and pancreatic size. In five acromegalics on chronic treatment with SMS, we investigated postprandial 6-h urinary excretion of p-aminobenzoic acid (PABA) and p-aminosalicylic acid (PAS) after s.c. injection of 100 micrograms SMS or placebo and after ingestion of 2 mmol nBT-PABA and 2 mmol PAS. In the acromegalics, urinary PABA/PAS ratio (reflecting exocrine pancreatic function) after SMS was similar to that after placebo (P greater than 0.10) and higher than in healthy volunteers (n = 8, P = 0.05). The initial inhibition of plasma CCK secretion by SMS was cancelled during the 3rd h after the meal, whereas PP release remained completely abolished. Pancreatic size as measured by ultrasonography, was not reduced in seven acromegalics compared with 14 healthy volunteers. It is concluded that despite a blunted release of the trophic hormone CCK, long-term treatment with SMS 201-995 neither induces an abnormally small pancreas nor deterioration of postprandial exocrine pancreatic function in patients with acromegaly.

Hypothyroidism and goiter in a patient during treatment with interleukin-2.

The development of transient hypothyroidism and goiter in a patient with a metastasized malignant melanoma during treatment with recombinant interleukin-2 (rIL-2) and dacarbazine is reported. Signs of autoimmune thyroiditis became apparent 2 weeks after the start of treatment and disappeared after treatment stopped. It is likely that rIL-2 was responsible by interfering with preexisting autoimmune thyroid disease. The possible mechanisms are discussed here. Patients with positive antithyroid microsomal antibody titers are prime candidates for rIL-2-induced thyroiditis.

Lack of antibody formation during long-term subcutaneous treatment with the somatostatin analogue octreotide in acromegaly.

Serum samples from 13 patients with active acromegaly on long-term sc treatment with octreotide (SMS 201-995, 1-36 months, mean daily dose 285 micrograms) were taken 12 h after the injection of their regular evening doses. Octreotide assay was performed using 125I-Tyr-SMS and a polyclonal rabbit anti-serum. For assessment of antibody formation both serum coated charcoal adsorption (adsorption of free octreotide) and polyethylene glycol precipitation (precipitation of IgG complexes) were used. The mean binding percentage in the patients proved to be similar to that of 5 healthy volunteers (p greater than 0.10). No specific binding was detected, whatever method used. No correlation was found between the binding percentages and octreotide serum levels, duration of octreotide treatment or daily octreotide dose (p greater than 0.10). These results strongly suggest that clinically relevant endogenous antibody formation is not a frequent event during long-term sc treatment of acromegalic patients with octreotide.

Pancreatic exocrine and gallbladder function during long-term treatment with octreotide (SMS 201-995).

Since octreotide (SMS 201-995, Sandostatin; Sandoz Pharmaceuticals) is a potent inhibitor of pancreatic exocrine secretion and gallbladder contraction, long-term treatment with this drug may theoretically result in impaired pancreatic function and gallstones. However, we observed excellent pancreatic exocrine function--as assessed by the PABA/PAS test--in acromegalics who received octreotide treatment for more than 6 months. Plasma cholecystokinin showed a significant, although blunted, postprandial response, which exceeded the threshold for gallbladder contraction in healthy controls. Remarkably, postprandial gallbladder contraction was completely abolished for at least 2 h during octreotide treatment. In contrast to other studies, none of 16 acromegalic patients on long-term octreotide treatment developed gallstones. Although the incidence of gallstones in patients on long-term octreotide treatment may be increased, the risk seems to be variable.