A phase II study of 5-fluorouracil, leucovorin and cisplatin (FLP) for metastatic gastric cancer

The modulation of 5-fluorouracil (5-FU) with folinic acid (leucovorin, LV) is more efficacious than 5-FU alone in the treatment of metastatic colorectal cancer, and the combination of 5-FU with cisplatin is currently one of the most active regimens in advanced gastric cancer. A phase II study was therefore conducted to test the efficacy and toxicity of the combination of 5-FU, LV and cisplatin (FLP) in metastatic gastric cancer. 28 patients entered the study. Metastatic sites were observed in the liver (in 21 patients), the peritoneum (in 8), the lymph nodes (in 7) or the bones (in 1) and a local recurrence was noted in 4 cases. The performance status (using World Health Organisation criteria) was 0 for 13 patients and 1 or 2 for the others. Cycles of treatment were administered every 28 days and consisted of LV 200 mg/m2/day for 5 days followed by 5-FU 400 mg/m2/day for 5 days with cisplatin 100 mg/m2 on day 2. The response rate for the 27 evaluable patients was 51.8% (95% confidence interval (CI), 33-70.6%). There were four complete responses (14.8%) and 10 partial responses (37%). Median survival was 11 months and 4 patients were alive at 2 years. Both response rate and survival were better for patients with a good performance status. The overall toxicity was very low, except for 1 patient who died of dehydration and cardiac failure. In conclusion, the FLP protocol was effective and well tolerated in patients with metastatic gastric cancer.     

Phase II trial of Oral UFT and leucovorin in advanced gastric carcinoma

The action of some phosphonium betains on cholinesterases from different biological sources has been studied. It has been shown, that all studied betains are reversible inhibitors of cholinesterase hydrolysis of acetyltiocholine. Inhibiting action of these compounds on acetylcholinesterases is about ten times weaker that of the majority of known phosphonium salts, while their action on butyrylcholinesterases has no peculiarities. There were found certain differences for each betain compounds in their action on cholinesterases from different biological sources. These results may be used for detail classification of cholinesterases and allow to extend knowledge in comparative enzymology.     

Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma

BACKGROUND: This study was designed to evaluate the efficacy and toxicity of the combination of 5-fluorouracil, interferon-alpha, and interleukin-2 for patients with metastatic renal cell carcinoma. METHODS: Previously untreated patients with a Zubrod performance status of < or =2; adequate cardiac, pulmonary, and renal function; and absence of brain metastases were eligible. One course of therapy was 28 days. 5-fluorouracil was administered at a dose of 600 mg/m2/day as a continuous infusions on Days 1-5. Interleukin-2 also was administered as a continuous infusion on Days 1-5 at a dose of 2 million Roche U/m2/day. Interferon-alpha was given as a daily subcutaneous injection of 4 million U/m2/day. RESULTS: Fifty-five patients were enrolled in the trial and 52 were evaluable for response. All patients experienced fever and flu-like symptoms. Grade 3 or 4 nonhematologic toxic effects included hypertension (48%), dermatitis (12%), stomatitis (11%), and altered mental status (9%). There was one toxic death. Four complete responses and 12 partial responses were observed for a total response rate of 31% (95% confidence interval, 18-46%). The survival of responding patients was significantly better than that of nonresponding patients. The improvement in survival was even more significant when comparing patients with at least stable disease with those who progressed through treatment. CONCLUSIONS: The three-drug combination described in this study demonstrates activity. However, it appears to be more toxic than other regimens with similar response rates and cannot be recommended for standard practice. Changing the interleukin-2 route to subcutaneous administration may permit more continuous administration with less toxic effects.     

A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma

BACKGROUND: Unresectable adenocarcinoma of the biliary tree are associated with a very poor prognosis. 5-fluorouracil (5-FU) combination regimens have produced objective response rates in approximately 10-20% of patients. Leucovorin increases the selective cytotoxicity of 5-FU. There also are encouraging reports of carboplatin in combination with 5-FU in other gastrointestinal tract malignancies. METHODS: Fourteen consecutive eligible patients were treated with a combination of carboplatin, 300 mg/m2, intravenously (i.v.) on Day 1 only and 5-FU, 400 mg/m2, i.v. with leucovorin, 25 mg/m2, i.v. on Days 1-4. All patients were required to have a histologically confirmed diagnosis and measurable disease. Patients were evaluated for response, survival, and toxicity. RESULTS: A total of 48 cycles of therapy were delivered. The median survival was 5 months. One patient achieved complete remission and two others partial remission, for a total response rate of 21.4%. Four additional patients had stable disease for a median duration of 4 months. The therapy was well tolerated, with moderate myelosuppression as the main dose-limiting toxicity. CONCLUSIONS: The current combination regimen of leucovorin-modulated 5-FU with carboplatin is well tolerated with appropriate supportive care, produces significant objective responses in 21% of patients with biliary tree carcinoma, and should be considered for the treatment of this disease.     

Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.     

A phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer

PURPOSE: This multicenter phase II study was designed to assess the efficacy of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients with histologically proven metastatic colorectal cancer, and at least one bidimensionally measurable lesion, aged 18-70, with performance status < or = 2, normal baseline biological values and no prior chemotherapy (or only adjuvant chemotherapy completed > or = 6 months before study entry) were selected. Treatment was irinotecan 350 mg/m2, i.v., day 1, alternating with leucovorin 20 mg/m2 i.v. and 5-FU 425 mg/m2, i.v. daily for five consecutive days, day 22-26 (Mayo Clinic regimen). One alternating cycle was to be performed every six weeks. Patients were evaluated for efficacy every alternating cycle. Treatment was administered until five alternating cycles, disease progression, unacceptable toxicity or patient refusal. RESULTS: Thirty-three patients (28 chemotherapy-na?ve and five with prior adjuvant treatment completed > 1 year prior to accrual) were enrolled. The objective response rate (RR) was 30% (95% CI: 16-49; 10 patients/33; nine partial response and one complete response). All responses were reviewed by an independent external review committee. An additional 49% of patients had stable disease. The median survival was 16 months, the one year survival amounted to 58% and the median progression free survival was 7.2 months. Relative dose intensity was nearly 90% for both drugs. Grade 3-4 diarrhea and neutropenia were the most frequent severe toxic events, seen in 24% and 64% of patients, respectively. CONCLUSIONS: The alternating schedule of CPT-11 350 mg/m2 with five days bolus of 5-FU and low dose LV is an active and feasible regimen as front-line therapy for metastatic CRC. It is well tolerated, without evidence of overlapping toxicity. The response rate appears promising with regard to that expected with either single agent. This regimen warrants further assessment in randomized trials.     

A phase II trial of weekly infusional 5-fluorouracil in combination with low-dose leucovorin in patients with advanced colorectal cancer

We examined 59 breast cancers for p53 and bcl-2 protein expression by immunohistochemistry. The results were correlated with Ki-67 immunostaining. p53-negativity was noted in 40 cases and the remaining 19 tumours were p53-positive. Thirty-six tumours showed strong expression of bcl-2 and in 23 no staining for this protein was observed. We found statistically significant reverse correlation between expression of p53 and bcl-2 in majority of carcinomas: 31 cases were bcl-2 positive and p53-negative, and 14 tumours were bcl-2-negative and p53-positive. Six carcinomas showed no nuclear staining for Ki-67 and in the remaining 53 the percent of cancer cells positive for Ki-67 ranged from 1 to 60 (mean: 14.6). In these 53 cases we found that bcl-2-positive tumours were characterized by lower proliferation than bcl-2-negative tumours, the mean value of Ki-67 immunostaining being 10.7% and 23.0%, respectively. p53-negative tumours showed lower proliferation than p53-positive tumours: mean Ki-67 index was 10.2% and 23.9%, respectively. We conclude that immunohistochemically detected p53 and bcl-2 proteins show a significant inverse relationship in majority of breast carcinomas and their expression correlates with tumour proliferation (Ki-67 immunostaining).     

Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced pancreatic carcinoma: a University of Chicago phase II consortium study

BACKGROUND/OBJECTIVES: Uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) has broad anti-tumor activity for cancers arising from the gastrointestinal tract. However, there are no published data regarding the efficacy of leucovorin-modulated UFT in patients with pancreatic cancer. The objective of this trial was to determine the activity and evaluate the toxicity of UFT plus oral calcium leucovorin in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Fourteen patients with advanced measurable adenocarcinoma of the pancreas were enrolled onto the trial. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided doses every eight hours for 28 days repeated every 35 days. Objective tumor response was evaluated after two courses of therapy. RESULTS: Fourteen patients were evaluable for response and toxicity. No objective responses were seen. The median (range) time to progression and survival were 14 (1.6-37), and 15 (1.9-62) weeks, respectively. Toxicity was mild with severe (grade 3 or 4) hyperbilirubinemia, pain, diarrhea, transaminitis, venous thrombus, weakness, renal failure, confusion, and edema/ascites seen in three (21%), one (7%), two (14%), one (7%), one (7%), one (7%), one (7%), one (7%), and two (14%) patients, respectively. CONCLUSION: In the 14 patients evaluable, UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate anti-tumor activity against advanced pancreatic adenocarcinoma; however, this oral regimen was well tolerated and devoid of neutropenia, significant oral mucositis or diarrhea.     

Continuous venous infusion 5-fluorouracil and interferon-alpha in pancreatic carcinoma

Blood flow via an aberrant internal carotid artery within the tympanic cavity is a rare pathogenic embryonic variation causing pulsatile tintinus and a vascularized tympanum. CT-scan provides the diagnosis. MRI and 3D time-of-flight MRA appear ideal for exploring aberrant flow both for diagnostic purposes and to establish the vascular morphology.     

Phase II study of 5-fluorouracil and adriamycin in transitional cell carcinoma of the urinary tract

A prospective study was carried out to determine the effectiveness and tolerance of the combination of 5-fluorouracil (600 mg/m2) and Adriamycin (50 mg/m2) given iv every 3 weeks to patients with disseminated transitional cell carcinoma of the urinary tract. Twenty-one of 23 patients entered in the study were evaluable for both response and toxicity. Two patients had complete responses and six had partial responses (greater than or equal to 50% reduction), yielding an overall response rate (complete plus partial) of 38%. Leukopenia (72.7%) and thrombocytopenia (54.5%) were common. Toxicity was life-threatening in one patient. Other common side effects were alopecia, nausea and vomiting, and a generalized feeling of weakness. Responders had a median survival time of 29 weeks compared to a median survival time of 9 weeks for nonresponders.     

Phase II trial of edatrexate in patients with metastatic colorectal cancer

Edatrexate is an analog of methotrexate which in vitro demonstrated activity against human colon cancer xenografts grown in nude mice. In a phase II trial, 12 patients with metastatic colorectal cancer and no prior chemotherapy were treated with Edatrexate 80 mg/m2/week for an initial period of 8 weeks. No objective responses were observed. Edatrexate is inactive against colon cancer at the dose and schedule used in this trial.     

5-Fluorouracil, epirubicin, and mitomycin C versus 5-fluorouracil, epirubicin, mitomycin C, and leucovorin in advanced gastric carcinoma. A randomized trial

Leucovorin (LV) enhances the activity of 5-fluorouracil (5FU). Based on these data, we performed a randomized trial with 5FU, epirubicin (EPI), mitomycin C(MMC) with/ without LV in advanced gastric cancer (AGC). The purpose of our study was to investigate if the addition of LV improved the response rate of the combination 5FU EPI, MMC (FEM) over FEM. From January 1988 until April 1994, 88 patients with recurrent or metastatic AGC were randomly received 5FU, EPI, MMC with (group A) or without (group B) LV. Between the two arms of the study no difference was noticed in sex, performance status, primary site of tumor, and lymph node metastases. Therapy included group A (5FU 600 mg/m2/day, i.v. bolus, on days 1, 8, 29, 36, and EPI 45 mg/m2/day, i.v. bolus, on days 1 and 29, MMC 10 mg/m2/day, i.v. bolus, on day 1) and group B (the same as group A plus LV 200 mg/m2/day by 2 h intravenous infusion with 5FU intravenous push at midinfusion). No significant difference in response rate was noticed between the two treatment arms; there were two (5%) patients with complete response in group A, and five (12%) in A and 11 (26%) partial responders in group B (p < 0.1). A significantly higher number of patients achieving stable disease was observed in group B; 19 (44%) in comparison to group A 10 (24%) (p < 0.048). There were more patients with progressive disease in group A 25 (59%) than in group B 12 (28%) (p < 0.003) (Table 2). No difference was noted in mean duration of response: group A, 15.8 (6-31) weeks; and group B, 17.6 (6-28) weeks. The mean time to progression was for group A [11.4 (6-35) weeks] and for group B [17.6 (8-33) weeks]. Mean survival was for group A [27.4 (12-59) weeks] and for group B [30.6 (17-53) weeks], for 50% of patients. Causes of death were, for group A, 40 patients from disease progression and two sudden deaths; for group B, causes of death were for 41 patients disease progression and two sudden deaths. There were two patients in group A and one in group B that were not evaluable because they abandoned therapy after the first cycle. Toxicity was increased in group B; anemia, nausea and vomiting, and alopecia (p < 0.055) were more severe in group B, but not statistically different when compared to group A. Neutropenia, thrombocytopenia, mucositis, and fatigue of any grade were significantly more common and severe in group B. Significant dose reductions due to toxicity were required more commonly in group B. We conclude that the response rate was increased in the schedule with the addition of LV, at the cost of increased toxicity and with no difference in survival. A randomized trial comparing FEM-LV with new generation regimens would determine whether the addition of LV qualifies FAM equally active with these.     

Synchronous hepatocellular carcinoma or metastatic hepatic tumor with primary gastric cancer

BACKGROUND/AIMS: When a solitary hepatic tumor occurs synchronously with gastric cancer, it is usually presumed to be metastatic. However, this may not be true in a place like Taiwan, where hepatocellular carcinoma (HCC) is prevalent. This study was conducted to examine the clinicopathological factors of both conditions. METHODOLOGY: A retrospective analysis of 14 patients who underwent a synchronous hepatectomy in combination with radical gastrectomy over the past 15 years was performed. RESULTS: Seven patients had metastatic gastric cancer, and seven had concomitant gastric and hepatic cancer. Serosal invasion and lymph node metastasis were the major features in the patients with metastatic gastric cancer. Early gastric cancer was found in three of the patients with the coexisting primary cancers. No patient with solitary metastatic cancer survived more than one year, but long-term survival of more than two years was achieved in two patients with the two forms of cancer. CONCLUSIONS: Double cancer of the stomach and liver should be kept in mind in patients with gastric cancer concomitant with a solitary hepatic tumor, in order to provide optimal treatment.     

Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05

BACKGROUND: National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 showed a benefit from leucovorin (LV)-modulated 5-fluorouracil (5-FU) adjuvant therapy (5-FU + LV) in patients with Dukes' stage B or C carcinoma of the colon. Preclinical and clinical phase I/II data suggested that interferon alfa-2a (IFN) enhanced the efficacy of 5-FU therapy. Accordingly, in NSABP protocol C-05, the addition of recombinant IFN to 5-FU + LV adjuvant therapy was evaluated. METHODS: Data are presented for 2176 patients with Dukes' stage B or C cancer entered onto protocol C-05 during the period from October 1991 through February 1994. Individuals with an Eastern Cooperative Oncology Group performance status of 0-2 (ranges from fully active to ambulatory and capable of self-care but unable to work), a life expectancy of at least 10 years, and curative resection were stratified by sex, disease stage, and number of involved lymph nodes and were randomly assigned to receive either 5-FU + LV or 5-FU + LV + IFN; the mean time on the study as of June 30, 1997, was 54 months. All statistical tests were two-sided. RESULTS: There was no statistically significant difference in either disease-free survival (5-FU + LV, 69%; 5-FU + LV + IFN, 70%) or overall survival (5-FU + LV, 80%; 5-FU + LV + IFN, 81%) at 4 years of follow-up. Toxic effects of grade 3 or higher were observed in 61.8% of subjects in the group treated with 5-FU + LV and in 72.1% of subjects in the group treated with 5-FU + LV + IFN; fewer patients in the latter group completed protocol-mandated 5-FU + LV therapy than in the former group (77.1% versus 88.5%). CONCLUSION: The addition of IFN to 5-FU + LV adjuvant therapy confers no statistically significant benefit, but it does increase toxicity.     

Determination of leucovorin and 5-fluorouracil in plasma by high-performance liquid chromatography

A method was developed for the determination of (6R)- and (6S)-leucovorin and 5-fluorouracil in plasma. As leucovorin diastereoisomers cannot be separated on a classical reversed-phase column, it was necessary to use a chiral stationary phase. The method presented is based on the same principle as the method described by Wainer and Stiffin [J. Chromatogr., 424 (1988) 158], i.e., coupling of a bovine serum albumin phase to an achiral stationary phase. Before the chromatography, the drug was isolated from the plasma matrix by solid-phase extraction. For 5-fluorouracil, chromatography was performed on a classical RP-18 column after extraction from the plasma by liquid-liquid extraction. Both methods were validated and applied to the analysis of patients' samples.     

Penetration kinetics of 5-fluorouracil into pancreatic fluid in post-pancreatoduodenectomy patients

Our aim was to investigate the pharmacokinetic behavior of 5-fluorouracil (5-FU) in pancreatic fluid and to evaluate its penetration characteristics in post-pancreatoduodenectomy patients. After completing the external drainage of the pancreatic duct during pancreatoduodenectomy surgery, eight patients were administered 1.0 g 5-FU i.v. by a 5 min infusion after the eighth day post-surgery on average. Blood and pancreatic fluid were collected, and the 5-FU concentrations were determined by HPLC assay. Their pharmacokinetic parameters were obtained by PCNONLIN and statistical analysis was performed. The Cmax was 20.03 +/- 18.25 mg/l in pancreatic fluid with a Tmax of 15.6 +/- 9.5 min following i.v. administration and 49.69 +/- 20.75 mg/l in plasma. 5-FU in plasma and pancreatic fluid were all in conformity with a non-linear model with a K(m) of 1098.08 +/- 1426.57 and 11.08 +/- 6.38 mg/l, respectively. The concentrations in pancreatic fluid were similar to that observed in plasma with an average penetration index up to 1.01 +/- 0.49. It is suggested therefore that 5-FU is capable of penetrating from blood into the pancreas as evidenced by the observed pancreatic concentrations.     

Treatment of advanced gastric cancer with oral etoposide, leucovorin and tegafur: experience with an oral modification of the etoposide, leucovorin and 5-fluorouracil (ELF) regimen

Recent data have suggested enhanced therapeutic activity with prolonged administration of both etoposide as well as fluoropyrimidines in the treatment of gastrointestinal malignancies. Based on this rationale, we investigated the clinical effectiveness and tolerance of an oral modification of the widely applied etoposide, leucovorin and 5-fluorouracil (ELF) regimen in patients with advanced gastric cancer. 32 patients with advanced gastric cancer were treated with oral etoposide (100 mg), leucovorin (3 x 100 mg), and tegafur (3 x 200 mg) over 14-21 days for a maximum of six cycles. Objective response was seen in only 5 patients (16%), stable disease was documented in 7 (22%), while the remaining patients progressed during therapy. The median time to progression was 2.8 months (range 0.7-12 months) and median overall survival was 6 months (range 1-18+ months). Due to grade 3 nausea/emesis, 8 patients discontinued treatment prematurely, while 12 patients experienced anorexia and progressive weight loss. Haematological toxicity was modest, with 4 patients developing asymptomatic grade 3-4 granulocytopenia. We conclude that this oral combination regimen cannot be recommended for the treatment of advanced gastric cancer.     

Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer

Melatonin production in the chick pineal gland is high at night and low during the day. This rhythm reflects circadian changes in the activity of serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AA-NAT; EC 2.3.1.87), the penultimate enzyme in melatonin synthesis. In contrast to the external regulation of pineal rhythms in mammals by the suprachiasmatic nucleus, rhythmic changes in AA-NAT activity in cultured chick pineal cells are controlled by an oscillator located in the pineal cells themselves. Here we present evidence that the chick pineal clock generates a rhythm in the abundance of AA-NAT mRNA in cultured cells that parallels the rhythm in AA-NAT activity. In contrast, elevating cAMP by forskolin treatment markedly increases AA-NAT activity without producing strong changes in AA-NAT mRNA levels, and lowering cAMP by norepinephrine treatment decreases enzyme activity without markedly decreasing mRNA. These results suggest that clock-controlled changes in AA-NAT activity occur primarily through changes at the mRNA level, whereas cAMP-controlled changes occur primarily through changes at the protein level. Related studies indicate that the clock-dependent nocturnal increase in AA-NAT mRNA requires gene expression but not de novo protein synthesis, and that AA-NAT mRNA levels are suppressed at all times of the day by a rapidly turning over protein. Further analysis of the regulation of chick pineal AA-NAT mRNA is likely to enhance our understanding of the molecular basis of vertebrate circadian rhythms.