Doxifluridine and leucovorin: an oral treatment combination in advanced colorectal cancer.

PURPOSE: This study was designed to test the activity and feasibility of an all-oral regimen of levo-leucovorin and doxifluridine (dFUR) in the treatment of advanced colorectal cancer and to establish whether the pharmacokinetics of dFUR and fluorouracil (FU) are affected by demographic and/or biologic parameters. MATERIALS AND METHODS: One hundred eight patients with histologically proven colorectal cancer received orally administered levo-leucovorin 25 mg followed 2 hours later by dFUR 1,200 mg/m2 on days 1 to 5, with the cycle being repeated every 10 days. RESULTS: Among 62 previously untreated patients, two complete responses (CRs) and 18 partial responses (PRs) were observed (overall response rate, 32%; 95% confidence interval, 21% to 45%). The median response duration was 4 months (range, 2 to 13) and the median survival time, 14 months. Among 46 pretreated patients, there were three CRs and three PRs (response rate, 13%; 95% confidence interval, 5% to 26%). In this group of patients, the median response duration was 4 months (range, 1 to 12) and the median survival time, 12 months. No toxic deaths were observed. The only World Health Organization (WHO) grade 3 to 4 side effect was diarrhea (32 patients). CONCLUSION: This regimen is active in previously untreated colorectal cancer patients and combines good compliance with safety. Limited but definite efficacy was also detected in the patients previously treated with FU, which suggests incomplete cross-resistance between the two drugs. The pharmacokinetic results suggest that the conversion rate of dFUR to FU increases between days 1 and 5, but that FU levels remain low in comparison to those measured after classical FU therapy. Under the experimental conditions used in this study, the interpatient variability of pharmacokinetic parameters remains largely unexplained by the tested variables.

Nitrendipine does not impair long-term glucose control in hypertensive noninsulin-dependent diabetic patients.

The subjects, 15 noninsulin-dependent diabetic hypertensive patients (mean age, 61 years) and 15 nondiabetic hypertensive patients (mean age, 60 years), received placebo for four weeks and then 20 to 40 mg of nitrendipine once daily for 24 weeks. At the end of the placebo period their blood pressures were greater than or equal to 160 mmHg systolic or greater than or equal to 95 mmHg diastolic. Blood pressures declined significantly during treatment in both patient groups; after 24 weeks, 13 of 15 diabetic patients and 12 of 15 nondiabetic patients were normotensive (diastolic blood pressure less than 90 mmHg). Meanwhile, heart rate, indices of glycemic control (serum glucose, hemoglobin A1c, fructosamine, and C-peptide levels), and serum lipids (cholesterol, high-density cholesterol, triglycerides, apolipoprotein A1 and B levels) did not change. It is concluded that nitrendipine does not impair glucose or lipid metabolism in diabetic hypertensive patients.

Remarkable antitumor activity of 5'-deoxy-5-fluorouridine in human colorectal tumor xenografts.

5'-Deoxy-5-fluorouridine (doxifluridine) is a prodrug of 5-fluorouracil (5FU) selectively activated by tumor cells. Since in clinical studies the side effects of doxifluridine differed after intravenous (i.v.) or oral administration, and oral route was the most promising in preclinical studies with murine models, in this study the drug was tested orally against a panel of human colorectal tumor xenografts with varying degrees of sensitivity to 5FU. Doxifluridine efficacy was comparable to that of 5FU when it was delivered according to a weekly schedule, but it was statistically higher when it was delivered more frequently. Impressive tumor inhibition (between 90 and 97%) was achieved in 4 out of 5 tumor lines after treatments delivered twice a week or daily 5 times a week. No difference in 5FU activity was observed between weekly and biweekly treatments, or between oral and i.v. injections. Moreover, in one tumor line in which different dosages of doxifluridine were investigated, a marked antitumor effect was obtained with a wide range of tolerated doses (4000-8000 mg/kg). Overall, these data indicated that doxifluridine is well tolerated when given orally and frequently. Using an adequate schedule, the prodrug has a better therapeutic efficacy against a variety of human colon cancer models than 5FU.

Phase II study of oral doxifluridine in elderly patients with advanced non-small-cell lung cancer.

Elderly patients with advanced non-small-cell lung cancer (NSCLC) are usually excluded from most clinical trials because of the toxicity associated with chemotherapy. About 50% of the new cases of lung cancer occur in patients older than 65 years. Doxifluridine is a fluoropyrimidine derivate which can be administered orally with very low toxicities. This phase II study evaluates the toxicity and activity of a home therapy with oral doxifluridine in elderly advanced NSCLC patients. Thirty-three advanced NSCLC patients, aged 70 years or more, entered the study; median ECOG performance status was 1 (0-2) and 22 patients (66.6%) had metastatic disease. Doxifluridine was given orally in three divided doses, for a total daily dose of 2,250 mg, for 4 consecutive days every week. The treatment was well tolerated; five patients (15%) experienced a grade 3 diarrhea which required doxifluridine dose reduction to 1,500 mg daily. Thirty-one patients are evaluable for response; four partial responses (12.9%) have been observed (95% confidence limit interval 3.6-29.8%); 17 patients (54.8%) had a stabilization of the disease. This study demonstrates that a home therapy with oral doxifluridine in elderly NSCLC patients is feasible and well tolerated and should encourage further studies.

A pilot safety study of capecitabine, a new oral fluoropyrimidine, in patients with advanced neoplastic disease.

5-fluorouracil (5-FU) is still one of the most prescribed cytostatic drugs, but gastrointestinal toxicity limits its use. Capecitabine, an orally administered prodrug of 5-FU, is activated by a cascade of three enzymes, resulting in the preferential release of 5-FU at the tumor site; it was developed in an attempt to avoid the problem of gastrointestinal toxicity of fluoropyrimidines. The aim of the present study was to investigate the safety profile of capecitabine at the daily oral dose of 502 mg/m2, given in two divided doses 12 hr apart for at least 10 days of treatment. In conformity with Italian law, 11 patients (8 females and 3 males) with advanced or metastatic pretreated solid tumors (4 colon-rectum, 3 breast, 2 stomach, 1 ovary, 1 lung) were enrolled. Treatment duration ranged from 1.5 to 14 days. Ten of the 11 patients received the planned 10 days of treatment. One patient was discontinued on the second treatment day when he presented with symptoms of intracranial hypertension with multiple brain metastases documented by CT scan. Toxicity consisted of 1 case of mild edema; no adverse events characteristic of fluoropyrimidines were recorded. No abnormalities in hematologic, renal, hepatic or electrolyte values were seen. In conclusion, capecitabine, given at this dose and for a relatively short period, proved to be well tolerated. Further investigation is recommended to define the promising antitumor efficacy documented in many human xenograft models in mice.

A phase I safety study of doxifluridine and interferon-alpha-2a in patients with advanced neoplastic disease.

AIMS AND BACKGROUND: Doxifluridine (RO 21-9738, 5'-dFUR) is a fluoropyrimidine derivative with proven antitumor activity in different experimental models. On the basis of experimental evidence, several clinical trials have been carried out to define the optimal 5'-dFUR dose and route of administration. In general, the maximum monthly dose of 5'-dFUR was 36-38 g. According to these clinical data, we explored the feasibility of a combination of 5'-dFUR and interferon-alpha-2a (IFN-alpha-2a). The aim of the protocol was to confirm the maximum tolerated dose (MTD) of the drug in combination with a settled dose of IFN alpha 2a. METHODS: An open-label phase I study with intravenous 5'-dFUR was carried out in 12 patients with a histologically proven diagnosis of advanced gastrointestinal or breast cancer refractory to previous conventional hormone-chemotherapy. Escalating doses of 5'-dFUR were administered as a 2-h intravenous infusion, once a week for at least 4 weeks in groups of 3 patients. IFN-alpha-2a was administered as an intramuscular injection of 3 MU 3 times a week for 4 consecutive weeks. Physical and laboratory parameters were assessed at baseline and then weekly until the end of treatment. RESULTS: The treatment with 5'-dFUR was stopped at 5 g/m2, since this level corresponded to the maximum monthly dosage reported in the literature (36-38 g). No severe toxicity was recorded up to this drug level. CONCLUSIONS: The combination of 5'-dFUR plus IFN-alpha-2a was well tolerated at the level of 5 g/m2. Although the MTD was not reached, it can be stated that the dosage administered in this study could be explored in a larger trial.

A phase I-II study of oral doxifluridine plus radiotherapy in radiosensitive tumors of the pelvic region.

AIMS AND BACKGROUND: Fluoropyrimidines have shown synergic effects in combination with radiotherapy in several tumor types. Doxifluridine is a novel 5-fluorouracil (5-FU) prodrug which is transformed into 5-FU in neoplastic tissue. This would imply enhancement of radiotherapy by 5-FU in neoplastic tissue, where the drug is concentrated higher than in surrounding healthy tissues. METHODS: A phase I-II study was carried out on 10 patients with radiosensitive tumors of the pelvic area (4 uterine carcinomas). Escalating doses of oral doxifluridine were administered in combination with standard radiotherapy to assess the efficacy and toxicity profile of the combined treatment. The 9 evaluable patients (3 groups of 3 patients each) received oral doxifluridine, at daily doses of 500, 750, or 1000 mg, for 6 consecutive weeks in combination with a standard (1.8-2.0 Gy) dose of radiotherapy. Assessment of physical and laboratory parameters was made at baseline, then weekly up to the end of the treatment and at follow-up. RESULTS: At the final evaluation, one patient with a diagnosis of uterine carcinoma showed a complete response that lasted 10 weeks. One patient had a partial response, and 7 patients had no change. The most frequent adverse events were gastrointestinal: 27 episodes of mild to moderate nausea/vomiting and diarrhea. Three patients complained of severe diarrhea of 5-7 days duration: all patients spontaneously recovered. There were no significant changes in laboratory or clinical parameters, and no serious toxicity requiring reduction or interruption of the radiotherapy. CONCLUSIONS: The maximum tolerated dose of oral doxifluridine in combination with standard radiotherpay was assessed at 1000 mg/patient/day (equivalent to 36-38 g monthly, previously reported as mTD in phase I studies).

Pharmacokinetics of oral doxifluridine in patients with colorectal cancer.

AIMS AND BACKGROUND: Doxifluridine is a new fluoropyrimidine that has excellent absorption by the gastrointestinal tract when given orally. The aim of the study was to determine the disposition of doxifluridine and fluorouracil when the former is given orally for 5 days and to assess whether their pharmacokinetics are influenced by demographic or biologic parameters. METHODS AND STUDY DESIGN: Twenty colorectal cancer patients received levo-leucovorin, 25 mg orally on days 1-5, followed 2 hrs later by doxifluridine, 1200 mg/m2; the cycle was repeated every 10 days. Doxifluridine and fluorouracil levels were measured by reverse-phase high-performance liquid chromatography during the first cycle of therapy. The lowest dose given over the first 24 hrs was 1750 mg and the highest was 2500 mg. RESULTS: The distribution of doxifluridine parameters remained the same between days 1 and 5, with an AUC that ranged between 72.2 and 74.5 mmol h/l and a C max that remained in a narrow band of 67.1 to 68.3 mmol/l. In contrast, the variability of fluorouracil parameters increased from day 1 to day 5, with an AUC of respectively 5.46 and 7.52 mmol h/l and a C max that increased from 5.81 on day 1 to 7.34 mmol/l on day 5. A significant correlation between the AUC of doxifluridine and fluorouracil was found on day 1 and on day 5 (P < 0.001). None of the demographic or biologic parameters considered was significantly related to pharmacokinetic parameters. Fluorouracil levels remained low in comparison with levels measured after classical fluorouracil therapy, although detectable for a longer time. CONCLUSIONS: A large interpatient pharmacokinetic variability was observed without any significant correlation with the clinical parameters studied.

Randomized phase II noncomparative trial of oral and intravenous doxifluridine plus levo-leucovorin in untreated patients with advanced colorectal carcinoma.

BACKGROUND: Doxifluridine (5-dFUR) is a fluoropyrimidine derivative that has been shown to be active on a variety of solid tumors. The clinical use of intravenous (i.v.) 5-dFUR as a bolus injection or short term infusion has been limited because of its unpredictable severe neurotoxicity. Unlike fluorouracil (5-FU), 5-dFUR is effective when administered orally. METHODS: This randomized, parallel-group, Phase II trial of two schedules of 5-dFUR was conducted between April 1993 and September 1994. A total of 130 previously untreated patients with locally advanced or metastatic colorectal carcinoma were randomized to receive oral levo-leucovorin (1-leucovorin) 25 mg/dose followed by oral 5-dFUR 750 mg/m2 twice daily for 4 days every 12 days (arm A) or i.v. 1-leucovorin 25 mg/dose followed by i.v. 5-dFUR 3000 mg/m2 for 5 days every 21 days (arm B). RESULTS: The two treatment arms were well balanced in terms of age, sex, and disease extension. Metastases were present in more than 90% of the total population, with the liver being the most common site. A median of 7 oral courses (range, 1-15) and 5 intravenous courses (range, 1-9) were administered. Intent-to-treat analysis rate of the randomized patients revealed a response rate of 15% (95% confidence interval [CI], 7-26) in arm A and 41% (95% CI, 29-54) in arm B. However, 7 cases in arm A and 12 in arm B were inadequately treated, and the response rates, according to standard analysis, were respectively 17% (95% CI, 8-28) and 51% (95% CI, 37-65). The median time to treatment failure was 4 months (range, 1-23) and 7 months (range, 1-9), respectively, for the two groups; median survival was 11 months (range, 1-24) in both groups. National Cancer Institute Grade 3 and 4 diarrhea were observed in 25% of the orally treated patients and in 18% of those receiving i.v. treatment. Stomatitis was reported mainly in arm B (15%). Mild and moderate neurotoxicity was observed in 6% of the patients in both arms; no severe neurotoxicity was reported. CONCLUSIONS: 5-dFUR with l-leucovorin, administered either orally or intravenously, produces response rates that are similar to those offered by the regimens containing 5-FU that are usually used to treat advanced colorectal carcinoma. This study documents the good tolerance of the i.v. schedule administered as a 1-hour infusion; furthermore, oral administration seems to be promising and feasible as a home treatment.

Antihypertensive efficacy and effects of nitrendipine on cardiac and renal hemodynamics in mild to moderate hypertensive patients: randomized controlled trial versus hydrochlorothiazide.

In this study antihypertensive efficacy, safety, and the effects of short-term nitrendipine administration on central and renal hemodynamics were evaluated in mild to moderate hypertensives. Our final goal was to ascertain whether the reduction in blood pressure induced by nitrendipine treatment was associated with maintained renal function. After a run-in period with placebo, 26 hypertensives without cardiac or renal disease were randomly assigned to a double-blind 8-week controlled trial with nitrendipine (N) 20 mg once a day (13 pts) or hydrochlorothiazide (HCT) 25 mg once a day (13 pts). Renal hemodynamic measurements included effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) by radionuclide study using I-131 hippuran and Tc-99m, according to the methods described by Schlegel and Gates, respectively. Effective renal blood flow [ERBF = ERPF/(1-Ht)], filtration fraction (FF = GFR/ERPF), and renal vascular resistance (RVR = MBP x 80/ERBF) were also calculated. Other hemodynamic measurements included cardiac index (CI), left ventricular (LV) ejection fraction (EF), and total peripheral resistance (TPR) measured by the first-pass radionuclide angiography technique. At the end of N or HCT administration significant decreases (p less than 0.001) in SBP, DBP, and MBP vs. baseline values were observed in both hypertensive groups. In the N group a significant decrease (p less than 0.01) in TPR and RVR, and significant increases (p less than 0.05) in CI, ERPF, and ERBF were observed. In the HCT group a significant decrease (p less than 0.05) in RVR was found without significant changes in other hemodynamic parameters. No important side effects were observed with either therapy. In conclusion, nitrendipine was effective in reducting blood pressure in mild to moderate hypertensive patients and exerted favorable effects on cardiac and renal function.

Dose-finding study of 5'-deoxy-5-fluorouridine in combination with fixed doses of cisplatin and L-folinic acid for the treatment of advanced or recurrent squamous cell carcinoma of the head and neck.

In order to assess the maximum tolerated dose of 5'-deoxy-5-fluorouridine (5dFUR) combined with a cisplatin (20 mg/m2 i.v.) and L-folinic acid (100 mg/m2 i.v.), 5-day schedule 19 consecutive chemotherapy-naive patients affected by advanced or recurrent carcinoma of the head and neck were entered in this phase I trial. Doses of 5dFUR were escalated from a starting level of 2,000 mg/m2/day up to 3,000 and 5,000 mg/m2/day. At the latter step the dose-limiting acute toxicities were stomatitis and diarrhea, which were of WHO grade 3-4 and occurred in 3 and 1 out of 4 evaluated patients, respectively. Other grade 3 acute toxicities were leukopenia, anemia, renal impairment, and neurologic symptoms, observed in 1 patient each. Furthermore, one possibly treatment-related death was registered among patients entered in the highest dose level. Eleven out of 19 patients (58%; 95% CI:34-80%) showed a complete (2 cases) or partial (9 cases) response to this treatment, regardless of the 5dFUR dosage employed. From our results we may define the maximum tolerated dose of 5dFUR to be associated with cisplatin and L-folin acid used in this trial as 3,000 mg/m2/day x 5 days. Assessment of the real activity of this combination chemotherapy deserves further studies.

Oral doxifluridine plus levoleucovorin in elderly patients with advanced breast cancer.

BACKGROUND: There currently is no agreement regarding the appropriate treatment of elderly patients with advanced breast carcinoma (ABC). Doxifluridine (5-dFUR), a prodrug of 5-fluorouracil, has been found to be effective in this entity, but its use is limited by neurotoxicity and cardiotoxicity that are not observed when the oral formulation is used. The objective of this Phase II trial was to evaluate the effectiveness and tolerability of oral 5-dFUR, biomodulated with levoleucovorin (1-leucovorin), in elderly patients (age > 70 years) with ABC. METHODS: 5-dFUR was administered orally at 600 mg/m2 twice daily for 4 consecutive days every 12 days, and oral 1-leucovorin was administered as 25 mg 2 hours before each 5-dFUR administration. Response was assessed every five cycles according to the World Health Organization criteria. In the presence of response or stable disease, the patients were treated for a maximum of 15 cycles. RESULTS: Seventy-three eligible patients were enrolled, 27 of whom had been pretreated with chemotherapy and/or hormonotherapy; all were assessable for response and toxicity after a median follow-up of 15 months. The objective response rate was 26% (95% confidence interval, 17.4-45.4). Regression predominantly occurred in the presence of soft tissue involvement (skin, lymph nodes, and breast). The median time to response was 2 months (range, 1-2 months) and the median response duration was 7 months (range, 2-17+ months). The median survival was 24 months (range, 2-42+ months). The treatment was very well tolerated, and the side effects were manageable and always reversible. CONCLUSIONS: The results of the current study show that 5-dFUR plus 1-leucovorin, both given orally, are associated with excellent patient compliance. Although the results are suboptimal in terms of an objective response, this characteristic could allow 5-dFUR to be used in elderly patients considered unsuitable for "aggressive" chemotherapy.

Study of pretreatment serum levels of HER-2/neu oncoprotein as a prognostic and predictive factor in patients with advanced nonsmall cell lung carcinoma.

BACKGROUND: HER-2/neu tissue overexpression is found in nearly 15% of patients with nonsmall cell lung carcinoma and is reported to affect prognosis adversely in surgical series. However, the prognostic role of serum HER-2/neu oncoprotein, particularly in patients with advanced lung carcinoma, remains unknown. This study was designed to assess the potential value of measuring serum levels of HER-2/neu oncoprotein in predicting response to treatment and survival in patients with locally advanced and metastatic nonsmall cell lung carcinoma. METHODS: Baseline serum HER-2/neu levels (fm/mL) were studied using an enzyme-linked immunosorbent assay method in 84 patients with newly diagnosed, advanced nonsmall cell lung carcinoma who underwent chemotherapy. RESULTS: The patients enrolled in the study included 76 males and 8 females, with a median age of 62 years (range, 36-73 years) and a median performance status of 1. Fifty patients (59.5%) had nonsquamous histology, and 34 patients (40.5%) had squamous cell carcinoma. Thirty-four patients (40.5%) had Stage III disease, and 50 patients (59.5%) had Stage IV disease. The mean baseline value of HER-2/neu in the whole series was 56.1 fm/mL (range, 13.0-103.8 fm/mL). HER2 immunohistochemistry on paraffin embedded tissue was performed in 18 patients. HER-2/neu tissue overexpression was found in only one patient, who also showed high serum levels (102 fm/mL). No correlation was observed between protein serum quantitation and gender, age, histology, stage, performance status, leukocyte count, or smoking. Nonresponding and responding patients exhibited similar oncoprotein levels (median, 57.6 fm/mL vs. 51.9 fm/mL, respectively). The overall survival rate was 42.5% at 1 year and 12% at 2 years, with a median survival duration of 10 months. At univariate analysis, high HER-2/neu serum levels were associated with an unfavorable survival outcome. Using a cut-off point for HER-2/neu of 73.0 fm/mL (corresponding to the 80th percentile of protein concentration), the survival of patients who had higher serum levels of HER-2/neu was significantly worse compared with patients who had lower serum levels (median, 7.1 months vs. 10.9 months; P = 0.004). Multivariate analysis confirmed the independent predictive value of serum HER-2/neu concentration as a negative prognostic factor (P = 0.02). CONCLUSIONS: High pretreatment levels of HER-2/neu oncoprotein are associated with an adverse prognostic impact on survival in patients with locally advanced or metastatic nonsmall cell lung carcinoma.

Oral doxifluridine in advanced hepatocellular carcinoma: A phase II study.

Hepatocellular carcinoma (HCC) remains one of the most common neoplasms in the world. Doxifluridine is an oral fluoropyrimidine derivative activated to 5-fluorouracil by uridine phosphorylase which is more expressed in malignant cells. Therefore, we conducted a phase II study to evaluate the activity of oral doxifluridine in patients with advanced hepatocellular carcinoma. Twenty-five advanced hepatocellular carcinoma patients entered the study; doxifluridine was given orally at the initial daily total dose of 2,250 mg for 4 consecutive days every week. All patients are evaluable for toxicity: these included mainly grade 1-2 (WHO) diarrhea, stomatitis, nausea and vomiting; 4 patients (16%) experienced grade 3-4 diarrhea. Twenty-four patients are evaluable for response and 1 complete and 3 partial responses have been observed (response rat 17%, 95% confidence interval: 5-37). Oral doxifluridine at the dose and schedule we used, although having only modest activity in advanced HCC, may represent an alternative to other frequently used chemotherapeutic agents, because of its favorable toxicity profile and its simple route of administration.