Pitot, Henry C.

PURPOSE: To compare the pharmacokinetics of continuous venous infusion (CVI) fluorouracil (5-FU) with that of oral eniluracil/5-FU and to describe toxicities and clinical activity of prolonged oral administration of eniluracil/5-FU. PATIENTS AND METHODS: A randomized, open-label, cross-over study compared CVI 5-FU to an oral 5-FU/eniluracil combination. Seventeen patients (arm A) were randomly assigned to receive eniluracil/5-FU combination tablets (10:1 mg/m 2 BID for 7 days) during the first study period, followed by 5-FU (300 mg/m 2 CVI for 7 days) during period 2, with a 14-day washout between periods. Sixteen patients (arm B) received treatment in the opposite sequence. In period 3, all patients received eniluracil/5-FU tablets BID for 28 days. Plasma levels of 5-FU during CVI and oral administration were analyzed in periods 1 and 2. Dihydropyrimidine dehydrogenase (DPD) activity was determined by measuring plasma uracil, urinary α–fluoro-β-alanine, and peripheral-blood mononuclear cell (PBMC) DPD activity. RESULTS: There were no grade 3 or 4 toxicities in either arm. Partial responses were observed in three patients. Another three patients had stable disease for ≥ 3 months. Eniluracil and 5-FU pharmacokinetics were similar to those observed in previous studies and were unaffected by administration sequence. The mean ± SD steady-state plasma concentration (C P ) and area under the curve (AUC) 144-168h for CVI 5-FU (104 ± 45 ng/mL and 2,350 ± 826 ng·h/mL, respectively) were three-fold greater than those for oral 5-FU (38.1 ± 7.7 ng/mL and 722 ± 182 ng·h/mL, respectively [P < .00001]). Individual 5-FU concentrations during CVI were highly variable, whereas those after eniluracil/5-FU were very reproducible. DPD activity in PBMCs before each study period was normal. CONCLUSION: Both CVI 5-FU and oral eniluracil/5-FU were well tolerated, with moderate activity in these heavily pretreated patients. However, 5-FU steady-state C P and AUCs achieved with oral eniluracil/5-FU were significantly less than with CVI 5-FU.

259 Background: Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are produced by bladder cancer cell lines in vitro and expressed in human tumor tissues. Preclinical studies have also shown that bladder cancer cell lines express VEGF receptor 1 and 2 on their surface membrane. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and antitumor activity in several preclinical models. A two-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib administered to patients with metastatic, urothelial carcinoma. Methods: Patients with one prior systemic therapy for recurrent, metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally daily for 4 week cycle. Results: Nineteen patients were enrolled. Median age was 66 years, with > 89% of patients presenting poorly differentiated bladder cancer. Adverse event data is available on 18 patients. No grade 4 or 5 events have been experienced. Nine patients have experienced 11 grade 3 adverse events of which 7 were deemed at least possibly related to treatment. Most common toxicities were anemia, thrombocytopenia, leucopenia and fatigue. For stage 1, none of the first 16 evaluable patients were deemed success (CR or PR) by the RECIST criteria during the first four 4-week cycles of treatment. Median progression- free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore, the trial was recommended to be permanently closed. Correlative studies including measurement of VEGF levels in archived tissues and blood are pending. Conclusions: Pazopanib did not show activity in urothelial carcinoma patients. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. [Table: see text]

BACKGROUND The carcinoid syndrome is a rare cause of acquired valvular heart disease. Although the typical echocardiographic features of carcinoid heart disease are well recognized, this large series provides new information about unusual manifestations of the disease as well as the role of Doppler echocardiography. METHODS AND RESULTS Between 1980 and 1989, 132 patients with carcinoid syndrome underwent echocardiographic study. The echocardiographic, Doppler, and clinical features of the 74 patients (56%) with echocardiographic evidence of carcinoid heart disease are described. Among these patients, 97% had shortened, thickened tricuspid leaflets. Tricuspid regurgitation was present in all 69 patients with carcinoid heart disease who underwent Doppler examination, and it was of moderate or severe degree in 62 patients (90%). Severe tricuspid regurgitation was characterized by a dagger-shaped Doppler spectral profile with an early peak pressure and rapid decline. The pressure half-time was prolonged (mean, 116 msec), which is consistent with associated tricuspid stenosis. The pulmonary valve appeared thickened, retracted, and immobile in 36 patients (49%) and was diminutive to the extent of not being visualized in an additional 29 patients (39%). Among the 47 patients who underwent Doppler evaluation of the pulmonary valve, regurgitation was present in 81%, and stenosis was present in 53%. Left-sided valvular involvement was present in five patients (7%), four of whom had patent foramen ovale or carcinoid tumor involving the lung. Previously undescribed myocardial metastases were present in three patients (4%) and were confirmed by biopsy in each case. Small pericardial effusions were present in 10 patients (14%). Patients with and without echocardiographic evidence of carcinoid heart disease did not differ with regard to sex, age, location of the primary tumor, duration of diagnosis, or duration of symptoms of carcinoid syndrome. However, the mean pretreatment level of urinary 5-hydroxyindoleacetic acid was higher in patients with carcinoid heart disease than in patients without carcinoid heart disease (270 versus 131 mg/24 hrs, p < 0.001). The symptom of dyspnea was more prevalent among patients with carcinoid heart disease than in patients without the disease (54% versus 27%, p = 0.003); as expected, heart murmurs were also noted more frequently in patients with disease (92% versus 43%, p < 0.0001). Treatment regimens and response to therapy were similar in the two groups. Survival of patients with echocardiographic evidence of carcinoid heart disease was reduced compared with those without cardiac involvement (p = 0.0003). ECG and chest roentgenographic findings in patients with carcinoid heart disease were nonspecific. CONCLUSIONS The broad spectrum of carcinoid heart disease is detailed in this large series. This includes not only right-sided valvular lesions but also left-sided involvement, pericardial effusion, and myocardial metastases.

Purpose Symptoms and complications of metastatic colorectal cancer (mCRC) differ by metastatic sites. There is a paucity of prospective survival data for patients with peritoneal carcinomatosis colorectal cancer (pcCRC). We characterized outcomes of patients with pcCRC enrolled onto two prospective randomized trials of chemotherapy and contrasted that with other manifestations of mCRC (non-pcCRC). Methods A total of 2,095 patients enrolled onto two prospective randomized trials were evaluated for overall survival (OS) and progression-free survival (PFS). A Cox proportional hazard model was used to assess the adjusted associations. Results The characteristics of the pcCRC group (n = 364) were similar to those of the non-pcCRC patients in median age (63 v 61 years, P = .23), sex (57% males v 61%, P = .23), and performance status (Eastern Cooperative Oncology Group performance status 0 or 1 94% v 96%, P = .06), but differed in frequency of liver (63% v 82%, P < .001) and lung metastases (27% v 34%, P = .01). Median OS (12.7 v 17.6 months, hazard ratio [HR] = 1.3; 95% CI, 1.2 to 1.5; P < .001) and PFS (5.8 v 7.2 months, HR = 1.2; 95% CI, 1.1 to 1.3; P = .001) were shorter for pcCRC versus non-pcCRC. The unfavorable prognostic influence of pcCRC remained after adjusting for age, PS, liver metastases, and other factors (OS: HR = 1.3, P < .001; PFS: HR = 1.1, P = .02). Infusional fluorouracil, leucovorin, and oxaliplatin was superior to irinotecan, leucovorin, and fluorouracil as a first-line treatment among pcCRC (HR for OS = 0.62, P = .005) and non-pcCRC patients (HR = 0.66, P < .001). Conclusion pcCRC is associated with a significantly shorter OS and PFS as compared with other manifestations of mCRC. Future trials for mCRC should consider stratifying on the basis of pcCRC status.