Hepatoid adenocarcinoma of the peritoneal cavity: Prolonged survival after debulking surgery and 5-fluorouracil,leucovorin and oxaliplatin (FOLFOX) therapy

Hepatoid adenocarcinoma is an alpha-fetoprotein producing adenocarcinoma arising in numerous extra-hepatic organs. The diagnosis may be difficult because of the varied presentation but immunohistochemistries help make the diagnosis. The prognosis is often poor but in this report, we present a young female with hepatoid carcinoma who is doing well more than three years after her diagnosis.Key Words: Hepatoid adenocarcinoma, peritoneal adenocarcinoma, FOLFOX     

Chemoradiation using 5-fluorouracil (5-FU) and nedaplatin (NDP) for gynecological malignancy--the relation between hemotoxicity and sequence of 5-FU and NDP

We compared sequence-dependent schedules of 5-fluorouracil (5-FU) and nedaplatin (NDP) for hemotoxicity in genecological malignancy (GM). The safety of schedules using 5-FU before/after NDP combined radiotherapy in 8 patients with GM was evaluated. They received either 5-FU 700 mg/m2 i.v. continuous infusion on days (D) 1-4 + NDP 100 mg/m2 i.v. bolus on D1 (group A: 5 pts), or NDP on D4, 5-FU on D1-4 (group B: pts). In group A, 4 patients received a reduced dose of NDP because of less than 60 ml/min of creatinine clearance. In group A, WBC (2 pts), hemoglobin (3 pts), and platelet (1 pts) were grade 3 or higher. In group B, grade 3 or higher in hemotoxicity was not seen. A higher percentage of hemotoxicity was seen in group A compared with group B.     

In-vivo 19F-MRS study of 5-fluorouracil (5-FU) metabolism on tumors

5-Fluorouracil (5-FU) metabolism on tumors was studied by in-vivo 19F-MRS (magnetic resonance spectroscopy). In this study, two kinds of tumors were used, i.e., Yoshida sarcoma implanted subcutaneously to the abdomen of rats and drug-induced tumors in the rats livers. Sequential 19F spectra were obtained just after 150 mg/kg 5-FU injected intravenously. In Yoshida sarcoma, the accumulation of 5-FU was observed and disappearance of 5-FU was slower compared to the normal tissue. However, synthesis of fluoronucleotides (Fnct) could not be detected. In drug-induced liver tumors, the peak of fluoro-beta-alanine (FBAL) was observed. Disappearance of 5-FU and catabolism to FBAL in the liver tumors group were slower compared to the normal liver. Synthesis of Fnct did not increase in the liver tumor group. The results in the liver tumor group are considered to be the confined result of the hepatocytes and tumors cells. It was considered that the delayed catabolism to FBAL in the liver tumor group showed metabolic dysfunction of the liver. Also the synthesis of Fnct in tumors could not be detected by in-vivo 19F-MRS. 19F-MRS method could not detect Fnct in tumors in-vivo. However, the accumulation of 5-FU could be assessed by this method. It is expected that the evaluation of 5-FU pooling in tumors could be used for the index of chemotherapeutic effect.     

Suramin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in metastatic colorectal cancer patients resistant to 5-FU+LV-based chemotherapy

AIMS AND BACKGROUND: Suramin has been shown to be of interest as a potential new anticancer agent because of its capacity to inhibit the binding of several growth factors to their receptors and to inhibit the growth of cancer cells in vitro. Since multi-autocrine loops involving growth factors which are antagonized by suramin have been demonstrated in colorectal cancer, we previously evaluated the activity of suramin in patients with advanced colorectal cancer. Interestingly, in this study three patients who had received 5-FU+LV after suramin, although heavily pretreated with fluoropyrimidines, obtained an objective response. This observation was intriguing as it might have been that suramin had changed the biology of the tumor, making it sensitive to 5-FU+LV. We therefore conducted the present study to investigate the possibility that suramin might overcome the resistance to 5-FU+LV. METHODS AND STUDY DESIGN: Only colorectal cancer patients with metastatic and progressive disease during 5-FU+LV-based chemotherapy were eligible for this study. Suramin was administered for eight weeks at doses determined by means of a computer-assisted dosing algorithm that used Bayesian pharmacokinetics to maintain suramin plasma concentrations of 200-250 microg/ml. 5-FU was administered weekly at a dosis of 450 mg/m2 halfway through a two-hour infusion of I-LV 250 mg/m2 starting one week after the initiation of suramin for a maximum of 26 weeks. RESULTS: Treatment was relatively well tolerated, but no objective responses were observed after the accrual of 13 patients in the first stage of the trial. Consequently, the trial was interrupted according to the initial two-stage sampling design. CONCLUSIONS: The present study does not support the hypothesis that suramin might overcome resistance to 5-FU+LV and its use in colorectal cancer is not recommended.     

Combination chemotherapy of cis-diamminedichloroplatinum (CDDP) and 5-fluorouracil (5-FU) in gastrointestinal tumors

Twenty-five patients with gastrointestinal tumors (stomach 13, colon 8, pancreas 2, liver 2) were treated with a combination chemotherapy regimen consisting of CDDP (30 mg/m2/day d 1, 2) and 5-FU (500 mg/m2/day d 1-3), repeated every 3 or 4 weeks. The patients comprised 14 males and 11 females with a median age of 50 years (range 24-69), and a median performance status of 80% (range 40-100%). Thirteen patients had had prior chemotherapy. Partial response was observed in 2 patients (colon and liver), which lasted for 2 months each, respectively. No objective response was observed in 11 patients evaluable for gastric cancer. Non-hematological toxicities were nausea (92%), vomiting (56%), proteinuria (17%), transient elevation of BUN (8%), and hepatotoxicity (11%). Leukopenia and thrombocytopenia were observed in 71% and 25%, respectively. However, these toxicities were mild to moderate, and generally well tolerated.     

Preoperative treatment with 5-fluorouracil (5-FU) in gastric and colorectal cancer

Preoperative chemotherapy with 5-FU was carried out on patients with gastric and colorectal cancer. 5-FU was given at a dose of 500 mg daily with a drip infusion for 7 days (Group A), with a one-shot intravenous infusion daily (Group B) and orally for 7 days (Group C). Histological effects were evaluated, using the criteria proposed by Ohboshi. In group A for gastric cancer and in group C for colon cancer, the histological response was stronger at the edge of the cancer than at its surface. In group C for gastric cancer and in group A for colon cancer, the histological response was more remarkable at the surface of the cancer than at its edge. The histological effects on metastatic lymph nodes in gastric cancer were the same as for the cancer nests in groups A and C. 5-FU used as a drip infusion or orally was more effective on metastatic lymph nodes of gastric cancer than on metastatic lymph nodes of colon cancer. 5-FU was detected at a high concentration in tumor tissues of gastric cancer in group A, Grade II response being obtained in 3 of 7 patients. Changes in regional lymph nodes, plasma and other organs in cases of combined resection were not obtained with regard to either the concentration of 5-FU or the histological findings for all three groups.     

Etoposide,leucovorin (LV) and 5-fluorouracil (5-FU) in 5-FU+LV pre-treated patients with advanced colorectal cancer

In the present study, we evaluated the efficacy and safety of the weekly combination of etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer (ACC), previously treated with weekly LV+5-FU. Etoposide was administered at 3 different dose levels (DLs), in 3 groups of 20 patients each (total: 60); DL-I: etoposide 80 mg/m2, DL-II: etoposide 120 mg/m2, and DL-III: etoposide 180 mg/m2, in 45 min i.v. infusion, and followed in all levels by LV 100 mg/m2 i.v. over 1 hour and 5-FU 500 mg/m2 i.v. bolus. Treatment was administered weekly until disease progression or unacceptable toxicity. No patients at DL-I responded, while 2 patients at DL-II and 3 at DL-III had a partial response (PR). Stable disease (SD) rates were as follows; at DL-I: 2, DL-II: 8 and DL-III: 9. More patients in DL-I progressed (n = 19) compared to DL-II (n=10) and DL-II (n = 8) (p < 0.0007). Time to progression was for DL-I, -II, -III: 17, 15, and 14 weeks, respectively. Median survival was DL-I, -II, -III: 30, 30, and 32.5 weeks, respectively. Toxicity consisted mainly of neutropenia, diarrhea and mucositis at all DLs, and was significantly more severe in DL-III. No difference was noted in responses between DL-II and DL-III. The authors conclude that the combination of etoposide with LV+5-FU has limited activity when administered after failure of weekly LV+5-FU in patients with ACC and should not be recommended for further evaluation.     

Evaluation of hepatic arterial infusion chemotherapy with levofolinate (l-LV) and 5-fluorouracil (5-FU) for multiple liver metastases from colorectal cancer

We evaluated the effect of hepatic arterial infusion chemotherapy with levofolinate (l-LV) and 5-fluorouracil (5-FU) for multiple liver metastases from colorectal cancer. All patients received drugs on an outpatient basis every six weeks, followed by no medication for two weeks. In this regimen levofolinate (200 mg/m2) was administered for two hours and 5-fluorouracil (500 mg/m2) was administered for thirty minutes as a bolus. A complete response was obtained in five patients and a partial response in five patients; the overall response rate was 40%. All patients could receive this therapy on an outpatient basis because no patient had side effects of Grade 3 or over. It is suggested that our protocol may be useful for improvement of outcome.     

Oral administration of 5-fluorouracil (5-FU) with intravesical chemotherapy as prophylaxis against recurrence of superficial bladder tumors

The oral administration of 5-FU together with the intravesical instillation of carboquone and cytosine arabinoside was attempted in cases of superficial bladder tumor for the purpose of prophylaxis against postoperative recurrence. The recurrence rate in 25 patients treated by this intravesical chemotherapy and oral 5-FU administration was 9.1% after one year, 14.0% after two years and 27.8% at three to five years. The recurrence rate in 13 patients with intravesical chemotherapy alone was 8.7% after one year, 31.5% after two years and 58.9% at three to four years. The recurrence rate in six patients with oral 5-FU administration alone was 18.2% after one year, 41.6% after two years and 100% after three years. These results suggest that oral administration of 5-FU in combination with intravesical chemotherapy is useful as prophylaxis against recurrence of superficial bladder tumors.     

Phase I study of combination chemotherapy with 5-fluorouracil (5-FU) and nedaplatin (NDP): adverse effects and eecommended dose of NDP administered after 5-FU

When nedaplatin (NDP) was used as a single agent in the phase I study, the dose-limiting toxicity (DLT) was thrombocytopenia and the recommended dose (RD) was 100 mg/m2. However, the DLT, maximum tolerated dose (MTD) and RD of NDP used in combination with 5-fluorouracil remained unknown. Therefore, we performed this study to assess the DLT and RD of NDP administered after 5-fluorouracil (5-FU). In this study, 5-FU was administered to 38 patients at a fixed dose (700 mg/m2/d on days 1-5) and NDP administered on day 6 at an initial dose of 80 mg/m2, which was subsequently increased to 100, 120, 130, 140, 150, and 160 mg/m2. The DLT of NDP was leukopenia and its MTD and RD were 160 and 150 mg/m2, respectively. Concerning impairment of renal function, only two patients had a grade I increase in serum creatinine. There were 19 responders (50%, 19/38) achieving partial response or complete response in the evaluation of antitumor effect. The result of this study is notable in that administration of 5-FU before NDP allows the dose of NDP to be substantially increased.     

A multicenter randomized study comparing 5-fluorouracil continuous infusion (ci) plus 1-hexylcarbamoyl-5-fluorouracil and 5-FU ci alone in colorectal cancer

To verify the effectiveness of oral 1-hexylcarbamoyl-5-fluorouracil (HCFU) in improving the surgical cure rate in advanced colorectal cancer, a multicenter randomized comparative study was conducted. A total of 429 patients who had had curative resection for stage II and III colorectal cancer were randomly assigned to a study group receiving a 14-day course of 5-FU continuous infusion (320 mg/m2/day) followed by oral HCFU for a year (300 mg/day), or to the control group receiving a 14-day course of 5-FU continuous infusion alone. In terms of background factors, no significant differences were found between the 214 patients in the study group and the 215 in the control group. Adverse reactions during the treatment were more frequently seen in the study group. But with few exceptions, the toxicities were mild and the compliance was acceptable. The 5-year overall survival rate of the study group was similar to that of the control group. The 5-year disease-free survival rate of the study group was better than that of the control group in the patients with colon cancer (hazard ratio=1.87; 95% confidence interval 1.03-3.38; p=0.037). However, this benefit was not seen in the patients with rectal cancer. A significant improvement in the disease-free survival rate was demonstrated through the addition of HCFU to 5-FU continuous infusion for the patients with colon cancer. The usefulness of oral fluoropyrimidine as an adjuvant for curative surgery for colon cancer was further warranted.     

A phase II experience with neoadjuvant irinotecan (CPT-11), 5-fluorouracil (5-FU) and leucovorin (LV) for colorectal liver metastases

Background  

Chemotherapy may improve survival in patients undergoing resection of colorectal liver metastases (CLM). Neoadjuvant chemotherapy may help identify patients with occult extrahepatic disease (averting unnecessary metastasectomy), and it provides in vivo chemosensitivity data.     

Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells

The purpose of this study was to evaluate the use of 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), to enhance the antitumour activity of the fluoropyrimidines. In an in vitro study, CDHP did not influence cell proliferation by itself. However, CDHP did inhibit 5-fluorouracil (5-FU) degradation and enhanced 5-FU cytotoxicity in a concentration-dependent manner in two human tumour cell lines (MIAPaCa-2 and HuTu80) with relatively high basal DPD activity. CDHP exhibited a maximum effect at a molar ratio (CDHP:5-FU) of more than 0.2. However, CDHP did not have any effect on 5-FU cytotoxicity in the CAL27 tumour cell line, which has a relatively low basal DPD activity, even at concentrations where the DPD activity is almost completely inhibited. In an in vivo study, the maximal tolerable doses (MTD) of tegafur (FT) and a combination of FT and CDHP at a molar ratio of 1:0.4 (FT/CDHP) for nude mice were determined by oral administration for 14 consecutive days. After a single oral administration of either FT or FT/CDHP at the MTD, the 5-FU serum concentration-time profiles were almost the same for both treatment strategies. When nude mice bearing subcutaneous (s.c.) MIAPaCa-2 cells were treated with either FT or FT/CDHP at the MTD, the FT/CDHP treatment showed a significantly higher antitumour effect than the FT treatment (tumour growth inhibition: FT/CDHP, 51+/-12%; FT, 21+/-25%; P<0.05). However, the host-body weight suppression induced by FT/CDHP and FT was equivalent. These findings suggest that the combination of fluoropyrimidine and CDHP for the treatment of tumours with a high basal DPD elicits a greater antitumour effect than treatment with fluoropyrimidines alone and we suggest that CDHP inhibits the degradation of 5-FU in the tumour.     

Cardiopulmonary hemodynamics and pharmacokinetics after hepatic intraarterial infusion of 5-fluorouracil (5-FU)

Summary Reported 5-FU-induced cardiac side effects may be explained by drug-induced hemodynamic changes and/or by direct myocardial toxicity due to regional drug uptake. This question was studied in 11 animals given constant infusions and 6 animals given bolus 5-FU infusions into the hepatic artery. Six animals, which received normal saline infusion, served as controls. A second aim was to study possible pulmonary drug clearance. Aortic, pulmonary arterial, and coronary sinus plasma 5-FU concentrations were determined during constant and after the bolus infusions of 5-FU. The V5 ECG, aortic, pulmonary arterial, and right atrial pressures were recorded continuously, and cardiac output and coronary sinus blood flow were recorded intermittently in all animals. No significant alterations in hemodynamic variables were seen during constant infusion. After the bolus infusion, an increased arterio-mixed venous oxygen content difference was recorded. Pharmacokinetic data after 3-min infusions indicated pulmonary drug uptake and release; during constant infusions, the data indicated myocardial drug uptake. As there were no alterations in myocardial oxygen demand or supply or in systemic hemodynamics during this myocardial drug uptake, it is likely that the cardiotoxicity is related to the direct effects of the drug on cardiac myocytes.This study was supported in part by grants from Lions Foundation, Umeå and financial support from Roche, Stockholm, Sweden