Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.

Effect of interferon therapy on the natural history of hepatitis C virus-related cirrhosis and hepatocellular carcinoma.

In patients with chronic hepatitis C who have a sustained virologic response to IFN therapy, there is a dramatic effect on the natural history of the disease, with ALT levels becoming normal, histologic activity improving or disappearing, and the progression of fibrosis slowing. A sustained virologic response 6 months after the end of treatment is predictive of a sustained remission 4 years later. From these results, a long-term survival benefit is expected from IFN treatment in patients with an intermediate or rapid rate of fibrosis. For patients with chronic hepatitis C who do not experience a sustained eradication of virus, there is evidence that IFN treatment significantly reduces the viral load and serum ALT level, improves histologic activity, and blocks fibrosis progression, in comparison with the natural history of this disease. Therefore, patients who still have a detectable level of HCV RNA should no longer be considered nonresponders to IFN therapy. Although the number of randomized trials is [figure: see text] small, cumulative data suggest that IFN therapy can reduce the incidence of and the mortality from hepatocellular carcinoma in patients with cirrhosis.

Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome.

AIM: To update previous overviews of placebo-controlled double-blind trials assessing the efficacy and tolerance of smooth muscle relaxants in irritable bowel syndrome. METHODS AND TRIALS: A total of 23 randomized clinical trials were selected for meta-analyses of their efficacy and tolerance. Six drugs were analysed: cimetropium bromide (five trials), hyoscine butyl bromide (three trials), mebeverine (five trials), otilium bromide (four trials), pinaverium bromide (two trials) and trimebutine (four trials). The total number of patients included was 1888, of which 945 received an active drug and 943 a placebo. RESULTS: The mean percentage of patients with global improvement was 38% in the placebo group (n=925) and 56% in the myorelaxant group (n=927), in favour of myorelaxants with a mean odds ratio of 2.13, P < 0.001 (95% CI: 1.77--2.58) and a mean risk difference of 22% P < 0.001 (95% CI: 13--32%). The percentage of patients with pain improvement was 41% in the placebo group (n=568) and 53% in the myorelaxant group (n=567): odds ratio 1.65, P < 0.001 (95% CI: 1.30--2.10) and risk difference 18%, P < 0.001 (95% CI: 7--28%). There was no significant difference for adverse events. CONCLUSION: Myorelaxants are superior to placebo in the management of irritable bowel syndrome.

Interferon for acute hepatitis C.

BACKGROUND: Acute hepatitis C virus (HCV) infection progresses to chronicity in the majority of patients. In order to prevent the progression to chronic disease, several studies have assessed interferon in patients with acute hepatitis C. OBJECTIVES: The aim of this review was to assess the efficacy of interferon in acute HCV infection. SEARCH STRATEGY: We searched MEDLINE, the Cochrane Controlled Trials Register, and the abstracts of the American Association for the Study of Liver Diseases (June 2001). We also contacted pharmaceutical companies to obtain unpublished trials. SELECTION CRITERIA: Randomised clinical trials comparing interferon with placebo or no treatment, and published as an article, abstract, or letter were selected. No language limitations were used. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. The following endpoints were analysed: normalization of alanine aminotransferase (ALT) activity at the end of treatment (biochemical ETR); sustained ALT normalization at the end follow-up (biochemical SR); disappearance of serum HCV RNA by polymerase chain reaction assay at the end of treatment (virologic ETR) and at the end of follow-up (virologic SR). Histologic data and adverse events were also recorded. Assessment of drug efficacy used the methods of Peto and Der Simonian and Laird. MAIN RESULTS: Six randomised trials involving 206 patients with acute hepatitis C met the inclusion criteria. Four trials assessing interferon alfa-2b in 141 patients, all with transfusion-acquired acute hepatitis C, were included. They demonstrated no significant heterogeneity in the outcomes assessed. When compared with no treatment, interferon alfa-2b was associated with an increase in the rates of virologic ETR and SR by 45% (95% CI 31-59%, P < 0.00001) and 29% (95% CI 14-44%, P = 0.0002), respectively. The virologic ETR was 42% (95% CI: 30-56%) in the interferon alfa-2b group versus 4% (95% CI 0-13%, P < 0.00001) in the control group. At the end of follow-up, a virologic SR was seen in 32% (95% CI 21-46%) of interferon-treated patients versus only 4% (95% CI 0-13%, P = 0.00007) of controls. The tolerability of therapy, or the impact of interferon alfa-2b on hepatic histology, was not reported. Two trials assessed interferon beta in a total 65 patients. The efficacy of interferon beta could not be assessed, however, due to heterogeneity of these trials. REVIEWER'S CONCLUSIONS: Interferon alfa is effective in improving biochemical outcomes and achieving sustained virologic clearance in patients with transfusion-acquired acute hepatitis C. The effect on long-term clinical outcomes could not be assessed due to limitations in the current data.

Interferon for interferon naive patients with chronic hepatitis C.

BACKGROUND: A previous meta-analysis of interferon therapy in naive patients with chronic hepatitis C has documented its efficacy in achieving virologic clearance, and improving liver biochemistry and histology; however, since its publication additional trials have been reported. OBJECTIVES: To evaluate the response to interferon in interferon naive patients with chronic hepatitis C. The effect of treatment dose and duration, and the response in patients with cirrhosis and those with normal aminotransferases was also investigated. SEARCH STRATEGY: The Cochrane Controlled Trials Register (Cochrane Library Issue 1, 1999), MEDLINE (January 1966 to December 1999), and reference lists were searched, and pharmaceutical companies were contacted for unpublished trials. SELECTION CRITERIA: Randomised clinical trials comparing interferon with placebo, no treatment, or different regimens of interferon were selected. Abstracts were excluded. DATA COLLECTION AND ANALYSIS: The primary outcome measure was sustained disappearance of serum HCV RNA (virologic sustained response (SR)). Biochemical and end of treatment responses, liver histology, and adverse events were also recorded. Assessment of drug efficacy used the methods of Peto and Der Simonian and Laird. MAIN RESULTS: Fifty-four trials enrolling 6545 patients were included. Compared with no treatment, interferon 3 MU thrice weekly for 12 months increased the probability of a virologic SR (Peto odds ratio (OR) 4.60; 95% confidence interval (CI) 1.53 to 13.85). At this dosage and duration of therapy, the rate of virologic SR was 17% (95% CI 10 to 28%) in interferon-treated patients versus 3% (95% CI 1 to 10%) in controls. A dose of 6 MU was more effective than 3 MU thrice weekly (OR for 12 months treatment, 2.21; 95% CI 1.10 to 4.45), as were durations of 12 months or greater versus six months (OR 1.87; 95% CI 1.30 to 2.67). Adverse events were more common with higher doses and prolonged durations of treatment. Compared with no therapy, interferon increased the probability of histologic improvement (OR 9.22; 95% CI 5.69 to 14.94). The response to interferon in cirrhotic patients (virologic SR, 17%; 95% CI 11 to 26%) was similar to that in non-cirrhotic patients. However, interferon was no more effective than control in patients with normal aminotransferases. REVIEWER'S CONCLUSIONS: Interferon is effective in achieving viral clearance and improving liver biochemistry and histology in interferon naive patients with chronic hepatitis C. Higher doses and prolonged durations are more effective, but associated with more frequent adverse events. Interferon is associated with similar benefits in patients with cirrhosis, but the efficacy in patients with normal aminotransferases is unproven.

[Late-occurrence hemolytic anemia after mitral valve bioprosthesis. 2 cases]. / Anémie hémolytique survenant tardivement après bioprothèse mitrale. Deux observations.

The authors report the cases of two patients admitted to hospital for investigation of haemolytic anaemia. Both had undergone, 10 and 12 years previously, mitral valve replacement with a Ionescu-Shiley bioprosthesis. In both cases, in the absence of signs of cardiac failure, Doppler echocardiography showed mitral regurgitation. The association of haemolytic anaemia and dysfunction of the bioprosthesis led to redux valve replacement and correction of the anaemia. Haemolytic anaemia was the presenting sign of bioprosthetic valve dysfunction requiring replacement of the prosthesis. This complication is common with mechanical valve prostheses but much more rare in bioprosthetic valves.

[Treatment of acute chemically induced diarrhea by inhibition of enkephalinase. Results of a pilot study]. / Traitement de la diarrhée aiguë chimio-induite par inhibition de l'enképhalinase. Résultats d'une étude pilote.

BACKGROUND AND OBJECTIVES: Acute chemotherapy-induced diarrhoea may require reducing or even stopping subsequent therapy. Antidiarrhoeal drug efficiency has not been extensively studied and the effects of the new antisecretory compound acetorphan--a potent enkephalinase inhibitor active in acute diarrhoea--are unknown. The aim of this study was to investigate the possible effects of acetorphan on 5 FU-induced diarrhoea in man. MATERIAL AND METHODS: Fifteen patients reporting acute diarrhoea following chemotherapy were included in this study. They presented with metastatic colo-rectal cancer (n = 14) or pancreatic carcinoma (n = 1) and were treated, once weekly, by an 8-hour IV infusion of folinic acid 200 mg/m2 and 5 FU 1,800 to 3,000 mg/m2. In each patient, number and consistency of stools were assessed every day during the week following chemotherapy, once without (control period) and once with acetorphan p.o. 300 mg/d/7d. RESULTS: During the control period, 3 out of 15 patients did not have significant diarrhoea, but 2 out of 3 patients had abdominal pain which was relieved by acetorphan without appearance of constipation. Twelve out of 15 patients presented with diarrhoea (> 3 stools/day for > 2 days: WHO grades 2 and 3); with acetorphan, the number of stools per day was reduced in all cases from 6.3 (range: 3-10.6) to 4.9 (range: 2.6-8.9) (P < 0.002), and the number of days with liquid stools dropped from 4.7 (range: 2-7) to 2.4 (range: 0-7) (P < 0.02). In addition, during treatment with acetorphan, there was a close positive linear relationship between the percent reduction in the number of stools and the number of stools during control period up to a 8 stools/day level (8 patients) above which efficiency decreased (4 patients). CONCLUSION: These results suggest the efficacy of acetorphan on chemotherapy-induced diarrhoea and urgent need for a randomized controlled trial.

[Gastric stromal tumor with osteoclast-like multinucleated giant cells during Lynch II syndrome]. / Tumeur stromale gastrique à cellules géantes multinucléées de type ostéoclastique au cours d'un syndrome de Lynch II.

We report an unusual case of gastric tumor: a stromal tumor with osteoclast-like giant cells. This type of cells has been described in epithelial tumors, especially in adenocarcinoma of the pancreas, lung, thyroid and breast. It has also been reported in smooth cell tumors such as uterine leiomyosarcoma and malignant fibrous histiocytoma. In our patient, this gastric stromal tumor with osteoclast-like giant cells was diagnosed in a man with adenocarcinoma of the colon in the context of a familial cancer syndrome. This is the first report of stromal tumor with osteoclast-like giant cells associated with Lynch syndrome.

[Complete remission of a mesenteric fibromatosis after taking sulindac]. / Régression complète d'une fibromatose mésentérique après prise de sulindac.

We report the case of a 22-year-old-man having a familial adenomatous polyposis coli treated by total colectomy with ileo-rectal anastomosis. Two years after the operation, an asymptomatic mesenteric fibromatosis appeared which was nonresectable due to mesenteric vessels infiltration. Nine years later, sulindac therapy was started for residual polyps in the rectal stump. This treatment was taken intermittently, during periods of 1 to 8 months, for 6 years. After 4 years of treatment, the tumor was no longer palpable. Four years after sulindac discontinuation, the patient was operated on for suspicion of intestinal adhesion. The mesenteric fibromatosis had completely disappeared and mesenteric vessels were free. This complete macroscopic regression of a desmoid tumor after sulindac therapy emphasizes again the interest of this treatment for mesenteric fibromatosis.

[Hepatic artery ligation for liver metastasis of a acinar cell carcinoma of the pancreas revealed by a nodular panniculitis]. / Ligature de l'artère hépatique pour métastases hépatiques d'un carcinome à cellules acineuses du pancréas révélé par une panniculite nodulaire.

We report the case of a 67-year-old-man presenting with pancreatic acinar cell carcinoma revealed by dermatological manifestations of cytosteatonecrosis and treated by hepatic artery ligation. The pancreatic etiology of these lesions was suspected due to hyperlipasemia, and was confirmed by abdominal computerized tomography showing a pancreatic tumor and multiple liver nodules, and by histological examination of one of these lesions. Because of symptomatic treatment failure, rapid impairment of patient's general condition, and by analogy with the treatment of hepatic metastases of neuroendocrine tumors, hepatic artery ligation was performed. Lipasemia decreased markedly and symptoms disappeared for 45 days. Hepatic artery obstruction may be used for emergency treatment of secreting liver metastases.

[Low-grade gastric MALT lymphoma and helicobacter heilmannii (Gastrospirillum hominis]. / Lymphome gastrique de bas grade du MALT et Helicobacter heilmannii (Gastrospirillum hominis).

We report the fourth case of low-grade gastric MALT lymphoma associated to Helicobacter heilmannii. This spiral organism may be present in the gastric mucosa of animals where it is non pathogenic while, in humans, its presence is always associated with chronic gastritis. In this case, Helicobacter heilmannii was observed in the absence of Helicobacter pylori. Regression of endoscopic and histological lesions after Helicobacter heilmannii eradication suggests its role in gastric lymphoma. This observation underlines the need for searching for Helicobacter heilmannii by careful histological examination, in the absence of Helicobacter pylori, and the importance of its eradication in the treatment of gastric lymphoma.

[Treatment and prevention of hepatitis C]. / Traitement et prévention de l'hépatite C.

Hepatitis C is a chronic disease with lethal complications and recent treatments have a strong efficacy. Ribavirin and alpha interferon combination allows obtaining a sustained viral response in 40% of patients who are theoretically protected against the progression to cirrhosis and its complications. In non responders prospective trials are in progress assessing the efficacy of stronger regimen or using sustain-release interferons. It is also possible that in non responders interferon reduces the progression of liver fibrosis permitting to reduce cirrhosis incidence and to wait for new drugs. Patients who need definitively a treatment are patients with fibrosis progression, patients with extrahepatic manifestations and those who can transmit the virus. Treatment of HCV should be systematically discussed in patients coinfected with HIV and HCV.

Effects of interferon therapy in "non responder" patients with chronic hepatitis C.

We reviewed the impact of interferon treatment on viral load, transaminase serum activity and histological features in patients with chronic hepatitis C in whom treatment did not result in a sustained virus eradication. As patients with cirrhosis are often called non responders, we also reviewed the impact of interferon on these end points as well as on hepatocellular carcinoma incidence and survival. This overview provides evidence that interferon in patients who have not cleared hepatitis C virus (HCV) significantly reduces viral load, serum ALT activity, improves histological activity and blocks progression of fibrosis compared to the natural history of the disease. Thus, patients who still have a positive HCV PCR should no longer be called non responders to interferon. Although the number of randomized trials is limited, there is also cumulative data suggesting that interferon could reduce the incidence of hepatocellular carcinoma incidence and mortality.

Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C in naive patients: 1999 update.

The aim of this study was to update our previous meta-analysis of interferon (IFN) in the treatment of hepatitis C and to analyse new factors, namely, HCV RNA end-point, patients with cirrhosis and patients with normal ALT. We use the Der Simonian and Laird method, with heterogeneity and sensitivity analyses. Seventy-six randomized control trials (RCTs) in naive patients were found but we focused our analysis on 59 RCTs with chronic hepatitis C (26 vs. controls and 33 comparing different regimens) and on seven RCTs in acute hepatitis. Interferon-alpha (IFN-alpha) at 3 MU thrice weekly (TIW) for 12 months exhibited 39% of virological end-of-treatment response (ETR) and 17% of virological sustained response (SR), respectively, vs. 1% and 3% in untreated controls (all P < 0.001). There was a significant dose effect (in favour of 6 vs. 3 MU TIW): the virological SR at 6 months were 35% in the 6 MU group (95% CI: 24-47) and 16% in the 3 MU group (95% CI: 8-27) and were at 12 months 43% in the 6 MU group (95%CI: 31-56) and 25% in the 3 MU group (95% CI: 16-37). There was a significant duration effect (12 vs. 6 months) upon the virological SR rate both at 3 and 6 MU: 3 MU provided 14% of virological SR (95% CI: 11-19) in the 12 months group vs. 7% (95% CI: 5-11) in the 6 months group and 6 MU provided 22% (95% CI: 17-29) and 16% (95% CI: 11-22) virological SR in the 12 and 6 months groups, respectively. Cirrhotic treated patients had 17% of virological SR (95 CI: 9-24%; P < 0.001) vs. 0% in controls and provided a 20% reduction rate (95 CI: -2% to -37%, P=0.03) in hepatocellular carcinoma incidence. In acute hepatitis C, a 3-month treatment with IFN-alpha showed significant efficacy vs. controls upon the virological SR rate (32% vs. 4%, P < 0.001). In conclusion, we confirm the dose and duration effect of IFN in chronic hepatitis C, and the efficacy of IFN-alpha in the treatment of acute hepatitis and in cirrhotic patients.

Is antiviral treatment (IFN alpha and/or ribavirin) justified in cirrhosis related to hepatitis C virus? Société Royale Belge de Gastro-entérologie.

AIM: To assess the benefit risk ratio of interferon and ribavirin in the treatment of patients with post hepatitis C cirrhosis we summarize the spontaneous over mortality of this disease, and made an overview of the randomized trials and of other controlled studies. RESULTS: In comparison to controls, patients with post hepatitis C cirrhosis have a 17 fold increase risk of dying from a liver disease that a control population, and a 6 fold increase from primary liver cancer. In France the hepatitis C epidemic which start in the sixties explains now the observed dramatic increase in mortality by primary liver cancer, both in men and women. Meta-analysis of randomized trials and controlled retrospective studies showed that interferon treatment is associated with a significant increase in ALT response at the end of the treatment, with a decrease in hepatocellular incidence as well as a decrease in mortality in comparison with controls. Very few data are published concerning ribavirin alone or in combination with interferon in patients with cirrhosis. Preliminary data suggest that this combination during 48 weeks permit to obtain in patients with compensated cirrhosis 20% of sustained virological response. The safety was acceptable but patients with low initial blood cells count must be carefully followed. In conclusion this overview clearly demonstrates a benefit-risk ratio in favor of treatment in patients with post hepatitis C cirrhosis by interferon.