Background: Unpredictable and severe diarrhea (NCI grade ≧3) remains a life-threatening adverse event in patients treated with irinotecan (CPT-11). The aim of this study was to evaluate the efficacy and safety of orally administered budesonide for prevention of CPT-11-induced delayed diarrhea in patients with advanced colorectal cancer. Patients and Methods: A total of 56 patients with advanced colorectal cancer receiving CPT-11 therapy (125 mg/m2 once weekly) were enrolled in this multicenter trial. Patients were randomly treated with 3 mg budesonide orally 3 times daily versus placebo. Detailed assessment of diarrhea by monitoring stool frequency, stool consistency and loperamide rescue medication was made by keeping a diary. Results: Diarrhea, defined as number of stools >4 occurring on a single day during the study period, could be prevented in 58.3% of the budesonide-treated patients compared to 38.5% of the patients under placebo. Patients in the budesonide group had less episodes (0.7 vs. 2.2 episodes) and a considerably shorter total duration of diarrhea (1.8 vs. 4.2 days) episodes than patients in the placebo group. Loperamide use was more frequent in the placebo than in the budesonide arm (55.6 vs. 41.7%). Also, exposure to rescue medication of loperamide was higher for placebo (36.2 capsules) than for budesonide (24.9 capsules). A superior prevention of diarrhea was observed for budesonide compared to placebo in the first cycle (14 vs. 10; p = 0.257), with more failures observed in the placebo group (16 vs. 10). Conclusion: This double-blind randomized trial failed to show that budesonide has a significant benefit in preventing CPT-11-induced diarrhea. While a trend exists, further trials are warranted.
The aim of the study was to test whether fractionated (weekly) idarubicin administration to multiply pretreated leukemia patients is effective and tolerable for outpatient treatment, and whether idarubicin alone can overcome P-glycoprotein (P-gp)-related resistance. P-gp was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. P-gp. expression was characterized as a percentage of P-gp-positive blasts. Additionally, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test in combination with or without verapamil and expressed as the R123 accumulation ratio. Fractionated idarubicin (12 mg/m2/week) was given to 36 acute myelogenous leukemia (AML) patients, 12 acute lymphoblastic leukemia (ALL) patients, and eight chronic myelogenous leukemia (CML) patients in blast crisis. Furthermore, 11 AML and four ALL patients were treated with fractionated daunorubicin at a dose of 50 mg/m2/week. All patients had been pretreated with drugs inducing P-gp-related resistance including daunorubicin and/or doxorubicin or vindesine (CML patients). Of 71 pretreated patients, 51 (72%) had a P-gp value between 25 and 98%. Six of these patients with increased P-gp expression had a nonpumping P-gp; four of them were CD34 positive. Of 51 patients with increased P-gp expression, 30 (59%) were CD34 positive. With regard to idarubicin monotherapy, overall response was 33/56 (59%) patients, and 23/33 (70%) responding patients showed a P-gp expression between 25 and 95%. All idarubicin-responding patients with high P-gp expression before treatment showed a clear reduction of P-gp-positive blasts. No patients with P-gp expression between 34 and 85% treated with fractionated daunorubicin showed response or reduction of P-gp-positive blasts in bone marrow. This study demonstrates that P-gp-related resistance can be overcome in multiply pretreated leukemia patients with idarubicin alone, and that the protocol used here is tolerable for outpatient treatment.
Radioiodine therapy (RITh) is an effective mode of treatment of different types of hyperthyroidism (immunogenic, IH; nonimmunogenic, NIH). The aim of this study was to evaluate the risk of thyroid storm after RITh. For this purpose a systematic determination of thyroid hormones (TT3, TT4) 5 and if possible 12 days after RITh was performed in 416 patients with borderline or overt hyperthyroidism. Additional antithyroid medication after RITh was necessary in 20 patients. Among the remaining 396 patients 48% had been pretreated with antithyroid drugs because of more severe clinical symptoms. This medication was canceled 10 to 5 days before RITh in all cases. After RITh the mean TT3 and TT4 levels of the subgroups, with and without antithyroid premedication, decreased nearly in parallel course. The whole group of 396 patients presented a significant decrease in TT3 levels with a mean from 1.9 to 1.4 ng/ml. In 18 cases (5%) an increase in TT3 level (greater than or equal to 0.5 ng/ml) was detected without requiring antithyroid therapy. No case of thyroid storm was observed in the entire patient group. TT3 decrease appeared to be more pronounced in patients with higher pretreatment levels. TT4 showed a significant decrease only in case of elevated levels. Post-therapeutic hormone levels were not dependent on the etiology of hyperthyroidism (IH, NIH). The decrease of TT3 levels in the IH group was more pronounced after application of 150 Gy compared with 60 Gy. The additional medication with propranolol (greater than or equal to 60 mg/day) enforced the TT3 decrease. Accompanying glucocorticoid medication had no influence on the hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Insulin is a growth stimulating hormone for several malignant tumors. In experimental breast cancer, diabetes induction with alloxan, strep-tozotocin or diazoxide leads to remission and intensifies the effect of an ovariectomy and of antiestrogen treatment. Clinically, in one of nine breast cancer patients, a partial remission of dermal metastases of seven months duration was achieved following a tamoxifen-induced remission by additional treatment with 200 mg diazoxide daily. In two other breast cancer patients, diazoxide led to stable disease of four (monotherapy) and eight months duration. Increased insulin levels can enhance the effect of simultaneous cytostatic therapy in a number of experimental systems. Initial clinical trials of combined therapy with methotrexate (MTX)/5-fluorouracil (5FU) and glucose/insulin indicate an increased cytostatic effect of this combination in some patients with breast cancer and in two patients with colon cancer, who were both pretreated with the same MTX/5FU regimen without glucose/insulin. In a case treated with high dose methotrexate therapy, the decrease of serum MTX-levels was slightly accelerated during and markedly delayed after the end of the glucose/ insulin-infusion.
Background: The biochemical rationale for the use of folinic acid (FA) and interferon (IFN) to modulate and thereby enhance the antitumor activity of 5-fluorouracil (5-FU) in vitro has been well established. Based on randomized trials comparing 5-FU alone and 5-FU and FA, the combination has been recommended as standard treatment in patients with advanced colorectal carcinoma. Recently, phase II trials demonstrated higher response rates for 5-FU and IFN than those anticipated for 5-FU alone. The present investigation was therefore undertaken to compare efficacy, toxicity, and quality of life of IFN and FA as modulators of 5-FU in a multicenter randomized trial. Patients and Methods: 129 patients with advanced and measurable colorectal carcinoma previously unexposed to chemotherapy or cytokines were randomly assigned to treatment with either 5-FU administered at a dose of 600 mg/m2 as an i.v. 2-hour infusion and FA at a dose of 200 mg/m2 given by bolus weekly or 5-FU (in the same dose and schedule) and IFN α-2b at a dose of 5 million IU three times a week. We used the 52-item EORTC QLQ Core 30 questionnaire including a diagnosis-specific module to assess the patients’ quality of life before and during chemotherapy.c Results: The treatment arms were well balanced for prognostic criteria including performance status, age, metastatic sites and size. Median time to disease progression was 134 days in patients treated with 5-FU and FA and 105 days in those receiving 5-FU and IFN α-2b. Median survival was 255 days for patients in the 5-FU+FA arm and 185 days in the 5-FU+IFN ot-2b arm (p = 0.06). An analysis of the toxicities experienced by the patients of the two treatment groups showed significantly more flu-like syndrome (p = 0.004) in patients treated with 5-FU+IFN α-2b. Mucositis grade 3 or 4 did not occur and diarrhea was found in only 1% and 3%. Nausea and vomiting were reported in 9% and 8%, respectively. There was no drug-related death. The compliance with the EORTC QL assessment was high (92%) and the data received of high quality. Serial assessment of the qualitiy of life revealed a trend towards a higher quality of life in the 5-FU and FA group with regard to most items. Conclusions: The results of this interim analysis suggest that there is a trend towards an improved survival and better quality of life for FA as modulator of 5-FU so far. Moreover, we have shown that the EORTC QL questionnaire is a feasible instrument for measuring the quality of life in prospective randomized trials in patients with palliative cancer therapy.
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