Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5-fluorouracil induced diarrhea and failure of loperamide treatment.

BACKGROUND: Diarrhea is one of the most disturbing effects of chemotherapy, affecting quality of life on the one hand and limiting applicable doses on the other. Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are associated with an elevated risk of developing severe diarrhea. Standard therapy consists of high-dose loperamide, but is associated with frequent failure. Other therapeutic regimens are still experimental. Endoscopic examination of a patient with severe loperamide-resistant diarrhea after CPT-11 chemotherapy revealed an inflammation of the ileo-coecal region. Oral therapy with the topical corticosteroid budesonide was immediately effective. This led to a phase I study of budesonide in CPT-11- and 5-FU-induced and loperamide-refractory diarrhea. PATIENTS AND METHODS: Fourteen patients with CPT-11- and seven patients with 5-FU-induced grade 3-4 (NCI/WHO) diarrhea and loperamide failure were enrolled in this study. All patients had metastatic colorectal cancer. RESULTS: In 86% of the CPT-11- and 57% of the 5-FU-treated patients with grade 3-4 diarrhea and loperamide failure, treatment with budesonide resulted in a reduction of diarrhea severity by at least two grades. CONCLUSIONS: The orally administered topical active steroid budesonide is highly effective in the therapy of loperamide-refractory chemotherapy (CPT-11 or 5-FU)-induced diarrhea.

High-dose infusional 5-fluorouracil combination therapy of metastatic gastric and colorectal cancer.

To improve the therapeutic ratio of palliative chemotherapy in patients with metastatic colorectal and gastric cancer 5-fluorouracil (5-FU) was administered as weekly high-dose 24-hour continuous infusion in combination with leucovorin (LV) and interferon-alpha-2b (IFN) as biomodulating agents: Chemotherapy consisted of a weekly schedule of 500 mg/m2 leucovorin as a 2-hour infusion, followed by a 24-hour continuous infusion of 2500 mg/m2 5-FU. IFN was administered subcutaneously at a dose of 3 mio I.E. three times a week. In patients with gastric carcinoma, etoposide (VP) 100 mg/m2 as 30-minute bolus infusion was added. Eighty-five patients (colorectal: 55 points, gastric: 30 points) are evaluable for response, toxicity, and survival analysis. Colorectal: CP+PR: 19/55 (34.5%), NC: 25/55 (45.5%), PD: 11/55 (20.0%). Median duration of remission in months (90% confidence interval): 5.2 (3.1 to 9.2), median survival since the start of salvage chemotherapy: 13.9 months (12.3 to 20.1), from initial diagnosis of metastasis: 30.2 months (26.3 to 44.5). Gastric: CR: 8/30 (26.7%), PR: 14/30 (46.6), NC: 5/30 (16.7), PD: 3/30 (10.0%). Median duration of remission in months (90% confidence interval): 6.75 (1.5 to 16.2), median survival since start of chemotherapy: 15.1 months (90% confidence interval 11.8 to 20.3 months). Hematologic toxicity: hemoglobin: I: 20.0%, II: 10.0%, leukocytes: I: 13.3%, II: 33.3%, III: 16.6%, platelets: I: 10.0% and III: 3.3%. Hematologic toxicity was moderate to negligible, peripheral toxicity consisted mainly of tolerable stomatitis and diarrhea. Dose and schedule intensified weekly 5-FU combination therapy in metastatic colorectal and gastric cancer is highly active in terms of response and median survival time. Chemotherapy pretreated patients with colorectal cancer seem to have a substantial survival benefit with this salvage protocol.

Ambulatory high-dose 5-day continuous-infusion ifosfamide combination chemotherapy in advanced solid tumors: a feasibility study.

The oxazaphosphorine analog ifosfamide (IFO) has demonstrated an increased therapeutic index in a variety of solid tumors and hematologic malignancies compared with its parent compound cyclophosphamide. A fractionated dose schedule over 5 days as continuous infusion in combination with the uroprotective agent sodium-2-mercapto-ethane-sulfonate (mesna) is considered to provide an improved therapeutic/toxic ratio. Stability data of IFO demonstrate long-term stability for use in disposable infusion pumps as outpatient treatment. In all, 52 patients with various malignancies were entered in a feasibility study to receive outpatient continuous infusion of IFO. All patients were required to have a subcutaneous venous port system implanted. The following drug combinations were used: IFO as single agent, IFO/mitoxantrone, IFO/carboplatinum/etoposide, IFO/etoposide/MTX, IFO/epirubicin. Mitoxantrone and epirubicin were given as continuous infusion together with IFO. Starting dose of IFO was between 1.6-2.0 g/m2/day x 5 and was increased in absence of major hematologic or peripheral toxicity. Mesna was given in combination with IFO as continuous infusion at a dose of 50% of that calculated for IFO. No renal, bladder or central nervous system toxicity was observed. In 247 courses of outpatient continuous ifosfamide infusion only few technical complications due to improper handling were documented.

Chemotherapy of advanced and relapsed squamous cell cancer of the head and neck with split-dose cisplatinum (DDP), 5-fluorouracil (Fura) and leucovorin (CF).

58 patients with locally advanced or relapsed squamous cell head and neck cancer were treated on 5 consecutive days with DDP 20 mg/m2/d IV-push, followed by CF 100 mg/m2/d IV-bolus and Fura 400 mg/m2/d IV-push 60 minutes later. Treatment was recycled on day 22(-29), according to toxicity. CF was added to the widely used DDP/Fura combination, because recent studies showed enhancement of Fura-activity by CF. 45/58 patients had no prior therapy and 13/58 pts were relapsed after chemotherapy and/or radiation therapy. All patients were evaluable for toxicity and response. After 3 courses of induction chemotherapy 23/45 pts in the previously untreated group had a complete response (CR); 20/45 a partial response (PR), 2/45 were restaged as no change (CR + PR: 95%). Induction chemotherapy was followed by radical surgery and postoperative radiation therapy. In the pretreated group 4/13 pts had a complete response; 6/13 a partial response; no change in 3/13 pts. Median duration of remission (MDR) has not been reached in the primarily untreated group, whereas in pretreated patients the MDR was 3.8 months (range 2.3 - 11.7 months). Hematologic and gastrointestinal toxicity was substantial but manageable and therapy was performed on an outpatient basis. The combination of DDP, CF and Fura has high activity in untreated and pretreated head and neck cancer patients. The obtained results are comparable to the widely used DDP/Fura continuous infusion regimen.