Fluorouracil and recombinant alfa-2a-interferon: an active regimen against advanced colorectal carcinoma.

Summary The combination of 5-fluorouracil (5-FU) and interferon-alpha (IFN-a) has reported activity in the treatment of advanced colorectal carcinoma. Laboratory studies of IFN-n suggest that this agent may offer theoretical advantages over IFN-a in combination with 5-FU. A total of 27 patients with advanced or recurrent colorectal carcinoma were treated in a non-randomized open phase 11 study with a combination of 5-fluorouracil (750 mg m-1 daily for 5 days as a continuous intravenous (i.v.) infusion followed, from day 15, by i.v. bolus 750 mg m-2 every 7 days) and recombinant interferon-f [r-hlFN-P-1 a; 9 MIU (total dose) by subcutaneous injection from day 1 on every Monday, Wednesday and Friday throughout the treatment period]. Toxicity was less than that seen with this schedule of 5-FU in combination with IFN-a. Among 21 evaluable patients, four objective responses were seen. Recombinant human interferon-beta-1 a in combination with 5-FU is an acceptable regimen in terms of toxicity. However, the study did not demonstrate a superior response rate when compared with previous reports of treatment with 5-FU alone or in combination with IFN-a.Keywords: interferon-beta; 5-fluorouracil; chemotherapy; colorectal carcinoma Five year survival from carcinoma of the colon and rectum is less than 40%. Although 5-fluorouracil has been the mainstay of palliative systemic therapy for advanced colorectal carcinoma for over 30 years, it is not curative in patients with metastatic disease. This agent gives objective responses in less than 25% of patients when used as a single agent, and there has been much interest in the potential for modulating its effects. Several studies indicate that 5-FU and IFN-a act in synergy to inhibit the growth of tumour cell lines in vitro (Wadler and Schwartz, 1990), and in some clinical studies this combination results in response rates (35-62%) higher than that predicted for 5-FU alone (Pazdur et al, 1990; Wadler and Wiernick, 1990;Wadler et al, 1991). However, this activity has not been confirmed in other trials (Corfu-A Study Group, 1995;Hill et al, 1995) Although IFN-,B has only 30% homology with interferon-a (de Grado et al, 1982), it binds with greater affinity to certain subclasses of interferon receptors (Ruzicka et al, 1987). In laboratory studies, r-hIFN-P-la exhibits greater antiproliferative activity than IFN-a against some tumour cell lines (Borden et al, 1982) and, against colorectal carcinoma cell lines, it demonstrates both direct antiproliferative activity and synergy in combination with 5-FU (Wong et al, 1989;Kase et al, 1993 (Lillis et al, 1987;Triozzi et al, 1987). This is similar to the single-agent activity of IFN-a, which has been reported to produce three responses among 66 patients (Kemeny and Younes, 1992). There is, therefore, a significant rationale for the testing of IFN-P in combination with 5-FU in this patient group.A phase II study examining the combination of r-hIFN-p-1a and 5-FU was designed modelled on the 5-FU/IFN-a regimen of Wadler et al (1990). In phase ...

Section: Discussionsupporting

confidence: 72%

A phase II study of recombinant interferon-β (r-hIFN-β 1a) in combination with 5-fluorouracil (5-FU) in the treatment of patients with advanced colorectal carcinoma

Joffe

Perren²,

Bradley³

et al. 1997

“…Although some recent studies of combined systemic 5 fluorouracil and folinic acid or interferon show promising results (O'Connell, 1989;Kerr, 1989;Wadler et al, 1989), conventional systemic chemotherapy has been associated with poor response rates. Attention has therefore turned to regional chemotherapy.…”

mentioning

confidence: 99%

Angiotensin II as a potential method of targeting cytotoxic-loaded microspheres in patients with colorectal liver metastases

Goldberg

Thomson²,

Bradnam³

et al. 1991

Summary Regional chemotherapy is commonly used to treat patients with colorectal liver metastases. However, improvement in survival has still not been demonstrated. Cytotoxic loaded albumin microspheres for arterial administration have been described as a means of improving the therapeutic index, but their distribution depends upon the prevailing pattern of arterial blood-flow at the time of injection. In this study, the ability of the vasoactive drug angiotensin II to target arterially injected microspheres to colorectal liver metastases is assessed in nine patients using scintigraphic planar and tomographic imaging.The median tumour: normal ratio in nine patients with colorectal liver metastases was 3.4:1 before the administration of angiotensin II. The corresponding ratio after administration of angiotensin II was 7.3:1. The median improvement factor was 1.8 (P <0.05).The data suggest that worthwhile tumour targeting can be achieved with angiotensin II in patients with colorectal liver metastases.Post-mortem studies have shown that up to 70% of patients dying after a potentially curative resection for colorectal cancer, die with liver metastases. The prognosis of patients with colorectal liver metastases is generally poor, survival being in the range of 3 to 9 months (Woods, 1984;Nielsen et al., 1971).Surgical resection of colorectal hepatic metastases may be effective in patients with limited disease (Bradpiece et al., 1987), but may not be feasible in the majority of patients where multiple tumours are present. Although some recent studies of combined systemic 5 fluorouracil and folinic acid or interferon show promising results (O'Connell, 1989;Kerr, 1989;Wadler et al., 1989), conventional systemic chemotherapy has been associated with poor response rates. Attention has therefore turned to regional chemotherapy.It is known that established colorectal liver metastases receive their blood supply from the hepatic artery and the administration of anti-cancer drugs via an indwelling hepatic arterial catheter is now widely practised (Ridge et al., 1987). Unfortunately, although the tumour response rates may increase when chemotherapeutic agents are administered intraarterially rather than systemically (Berger, 1981) a significant increase in survival among treated patients has not been demonstrated by randomised controlled trial (Malik & Wrigley, 1988).Novel chemotherapeutic drug delivery systems including cytotoxic loaded or radioactive microspheres for administration by the arterial route, have been developed. We have previously described cytotoxic loaded albumin microspheres (diameter 20-40IAm) which are trapped in the liver when injected into the hepatic artery (McArdle et al., 1988;Willmott et al., 1985), the drug being released as the microsphere degrades. However intra-arterial injection of such particles results in their unselective distribution throughout the liver, microsphere concentration within different regions of the organ being dependent upon the prevailing distribution of arterial blood-flow. How...

“…Interferon alfa as an immunomodulatory cytokine had been shown to increase the cytotoxic activity of 5-FU in human cancer cell lines (Wadler et al, 1990). Several clinical trials confirmed an increased responsiveness by addition of IFN to 5-FU in the treatment of metastatic colon cancer (Wadler et al, 1989(Wadler et al, , 1991. According to these promising data, the second aim of the present study was to examine the efficacy of IFN plus 5-FU as adjuvant therapy for stage III colon cancer in a 2 Â 2 factorial study design.…”

mentioning

confidence: 88%

A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer

Schippinger

Jagoditsch²,

Sorré³

et al. 2005

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 Â 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135 -1.856, P ¼ 0.0028; HR 1.506, 95% CI 1.150 -1.973, P ¼ 0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.