Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986.

PURPOSE: To demonstrate that adding irinotecan to a standard weekly schedule of high-dose, infusional fluorouracil (FU) and leucovorin (folinic acid [FA]) can prolong progression-free survival (PFS). PATIENTS AND METHODS: Four hundred thirty patients with measurable or assessable metastatic colorectal cancer were randomly assigned to receive either FA 500 mg/m(2) as a 2-hour infusion and FU 2.6 g/m(2) by intravenous 24-hour infusion, both administered weekly for 6 weeks, followed by a 2-week rest (Arbeitsgemeinschaft für Internistische Onkologie [AIO] arm, n = 216), or a similar schedule but with FU 2.3 or 2.0 g/m(2) preceded by irinotecan 80 mg/m(2) administered over 30 minutes (experimental group, n = 214). RESULTS: The median PFS time in the experimental group was 8.5 months (95% CI, 7.6 to 9.9 months) compared with 6.4 months (95% CI, 5.3 to 7.2 months) in the AIO arm (P < .0001). The median overall survival time was increased from 16.9 to 20.1 months (P = .2779). The objective response rate was 62.2% (95% CI, 55.0% to 69.5%) in the experimental group and 34.4% (95% CI, 27.5% to 41.3%) in the AIO arm (P < .0001). CONCLUSION: The addition of irinotecan to the standard AIO FU/FA regimen was associated with a highly significant improvement in PFS and response rate and was well tolerated. The results of this study confirm that irinotecan in combination with high-dose infusional FU/FA is a reference first-line treatment.

Randomized phase III study of high-dose fluorouracil given as a weekly 24-hour infusion with or without leucovorin versus bolus fluorouracil plus leucovorin in advanced colorectal cancer: European organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952.

PURPOSE: This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV. PATIENTS AND METHODS: A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m2 intravenously + LV 20 mg/m2 on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + LV)-all given weekly x6 followed by a 2-week rest period. Survival was the major study end point. RESULTS: With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P =.724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P =.029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms. CONCLUSION: Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.

Donor outcomes in right lobe adult living donor liver transplantation: single-center experience in Egypt.

INTRODUCTION AND OBJECTIVES: Living donor liver transplantation (LDLT) is an alternative source of organs for patients with end-stage liver disease (ESLD) in absence of deceased donor LT. In LDLT the greatest concern is donor safety. Our objective was to evaluate the outcome of donors after right lobe liver donation in a single LT center in Egypt. PATIENTS AND METHODS: Fifty LDL resections were performed from 2001 to 2004. The mean donor age was 29.2 +/- 6.4 years. Residual liver volume was 41.1 +/- 4.5%. Mean operative time was 560 +/- 62.2 minutes; mean ICU stay, less than 24 hours; mean hospital stay, 15.4 +/- 7.7 days; and mean follow-up period, 6 months. RESULTS: There was no mortality. The overall complication rate was 68% (34 donors). Major complications included intraoperative bleeding in one, biliary leak in two, and pneumonia in three donors. Minor complications included mild pleural effusion in 13 donors, transient ascites in 10, mild depression in 7, intra-abdominal collections in 3, and wound infections in 1 donor. Residual liver volume did not affect the complication rate. None required reoperation. Return to predonation activity occurred within 6 to 8 weeks. No liver impairment occurred during follow-up. CONCLUSION: Right lobe adult LDLT is a safe procedure with regard to donor outcome. Major complications occurred in only 10% of our series.

Clinical pharmacology of tamoxifen in patients with breast cancer: correlation with clinical data.

Blood tamoxifen levels were determined for patients with metastatic breast cancer following initial and chronic dosing at twice daily 10 mg/m2 or a 20 mg/m2 single dose. Median time to response was six weeks. Blood tamoxifen levels at that time were ten-fold greater than those obtained after an initial single dose; however, steady-state values were not achieved until 16 weeks of chronic dosing. On a loading dose schedule of 40 mg/m2 twice daily for seven days and 20 mg/m2 daily thereafter, blood levels greater than or equal to 10 mg/m2 twice daily steady-state values were reached in one week. Levels drawn at peak and trough times suggest that tamoxifen may be given on a once-daily basis. Tamoxifen half-life was 9-12 hours after the initial dose and seven days after chronic dosing.

Neoadjuvant chemotherapy plus conventional radiotherapy or accelerated hyperfractionation in stage III and IV nasopharyngeal carcinoma--a phase II study.

A prospective phase II trial was initiated in previously untreated patients with locally advanced nasopharyngeal carcinoma (NPC). The goal was to achieve improvement in locoregional control, disease-free interval and overall survival using induction chemotherapy and to compare conventional fractionation (CF) with an accelerated hyperfractionation (AHF) regimen. Fifty patients were treated (5 AJCC Stage III, 45 Stage IV) with induction chemotherapy consisting of two cycles of cisplatin and 5-fluorouracil. Patients were then randomized between CF and AHF therapy. A clinical response to induction chemotherapy was reported in 86% of patients prior to radiotherapy (44% complete response, 42% partial response). Patients with complete or major partial responses to induction chemotherapy had a significantly better 5-year overall survival (60%) and disease-free interval (59%) than those with no response or minor partial response (15% and 18% p = 0.009 and 0.0009). Acute radiation reactions were more pronounced in the AHF group (p = 0.0002), and the incidence of late normal tissue injury was more frequent (p = 0.08). At 5 years, the locoregional control rate was higher in the AHF arm (76%) than in the CF group (54%), but the difference was not significant (HR, 0.52; 95%, Cl, 0.15-2.83; p = 0.186). With a median follow-up period of 55 months (range 4-120), the 5-year disease-free interval and overall survival rates were more favorable in the AHF group than in the CF group, but the differences were not significant (59% and 54% vs. 34% and 36%, respectively, HR for disease-free interval = 0.71; 95% CI, 0.27-1.88; p=0.198 and HR for overall survival = 0.81; 95% CI, 0.37-1.78; p=0.433). The overall treatment failure rate was 48%. Locoregional failures occurred in 12 patients (24%) and the incidence of distant metastases reached 30%. Response to induction chemotherapy is strongly predictive for locoregional control, disease-free interval and overall survival. Accelerated hyperfractionation was associated with high incidence of acute and late toxicity without significant improvement in locoregional control rate. The optimal chemotherapy dose and sequencing with radiotherapy needs to be investigated in future studies. Distant metastases remain the main cause of treatment failure in NPC.

Chemotherapy in invasive carcinoma of the bladder. A review of phase II trials in Egypt.

Since 1976, a series of phase II studies with screening of various chemotherapeutic agents in invasive bladder cancer have been conducted at the National Cancer Institute, Cairo. Different drugs were screened, one by one, in groups of 20-25 patients with inoperable, metastatic, or recurrent carcinomas. Evaluation was done by clinical bimanual examination, radiography, sonography, cystoscopy, and urine cytology. In these trials bleomycin and doxorubicin were ineffective. Tenoposide, 5-fluorouracil, methotrexate, and cisplatin had minimal or moderate effect (response rates 4-16%). More pronounced effect was found for dibromodulcitol, cyclophosphamide, pentamethylmelamine, etoposide, hexamethylmelamine, ifosfamide, vindesine, vincristine, and epidoxorubicin (response rates 18-60%). Some complete responders remained in response for a period of 3-7 years. Drugs seemed to be more effective in metastatic than in local lesions.