Phase II Evaluation of 5-Fluorouracil plus Folonic Acid and Alpha 2b-lnterferon in Metastatic Colorectal Cancer

Abstract

Biochemical modulation of 5-fluorouracil (5-FU) by folinic acid (FA) increases the response rate in patients with metastatic colorectal cancer compared to 5-FU alone. Phase II trials also demonstrated increased efficacy when interferon was added to 5-FU. In two consecutive trials, 76 patients were treated on days 1-5 with FA 200 mg/m² plus interferon 5 × 10⁶ U/m² and 5-FU 350 mg/m² as intravenous bolus injection (n = 33, regimen A) or 5-FU 500 mg/m² as 2-hour infusion (n = 43, regimen B), repeated every 3 weeks with individual 5-FU dose escalation in steps of 50 (regimen A) or 100 mg/m² (regimen B). In regimen A 5-FU dose reduction to 300 mg/m² due to toxicity was necessary in 49% of the patients; in regimen B a 5-FU dose of 600 mg/m² or above was tolerated by 70% of the patients. Dose-limiting toxicity was severe mucositis and/or diarrhea. Objective responses were observed in 5 of 33 patients (15%) in regimen A (3-28%, 95% confidence interval) and 7 of 41 patients (17%) in regimen B (5-29%, 95% confidence interval). Median time to progression was 4.7 and 4.8 months, and median survival 9.9 and 11.4 months for regimens A and B, respectively. Prolonged 5-FU administration over 2 h allows the administration of a higher 5-FU dose compared to bolus injection with no apparent improvement in antineoplastic efficacy. The addition of interferon to the combination of 5-FU plus FA in this dose and schedule does not seem to improve the response rate but appears to increase treatment toxicity.

Antisense Oligodeoxynucleotide Directed against c-myb Has Anticancer Activity and Potentiates the Antiproliferative Effect of Conventional Anticancer Drugs Acting by Different Mechanisms in Human Colorectal Cancer Cells

“…Specifically, we investigated whether the inhibition of a growth-promoting gene such as c-myb affected the antineoplastic activity of chemotherapeutic drugs such as taxol, 5-FU, vinblastine and doxorubicin used in the treatment of several solid human malignancies including colon carcinoma [12][13][14][15][16]. It has been postulated that the c-myb gene is involved in the pathogenesis of colon carcinoma [34], suggesting that the ability to selectively downregulate this expression by use of antisense ODNs might have therapeutic potential.…”

“…Therefore, the aim of this study was to evaluate the efficacy of the combination of oncogene-targeted antisense ODNs with chemotherapeutic drugs on human colorectal cancer cell lines in vitro. Specifically we investigated whether the inhibition of the growth-promoting gene c-myb affects the antineoplastic activity of chemotherapeutic drugs of different mechanisms of action as taxol, 5-fluorouracil (5-FU), doxorubicin and vinblastine which have been used in the treatment of several solid human malignancies including colon carcinoma [12][13][14][15][16].…”

Continuous sensing of IFNα by hepatic endothelial cells shapes a vascular antimetastatic barrier

“…Accordingly, there is growing recognition that the use of perioperative immunotherapies in CRC patients undergoing surgical resection may represent a unique treatment window to prevent metastatic colonization and control minimal residual disease (Badia-Ramentol et al , 2021; Bakos et al , 2018; Horowitz et al , 2015). In this context, interferon-alpha (IFNα), a pleiotropic cytokine with multiple antitumor effects such as the direct inhibition of cancer cell growth and angiogenesis (Indraccolo, 2010), the sustained upregulation of major histocompatibility complexes (Gessani et al , 2014) and the induction of innate and adaptive antitumor immune responses (Aichele et al , 2006; Curtsinger et al , 2007; Fuertes et al , 2013), has been used as adjuvant immunotherapy in various solid cancers such as renal cell carcinoma (Flanigan et al , 2001), melanoma (Lens & Dawes, 2002) and colorectal cancer (Kohne et al , 1997; Link et al , 2005). Unfortunately, systemic administration of IFNα has shown limited clinical efficacy, likely due to its short plasma half-life (∼1 hour) (Bocci, 1994) and the use of high and pulsed doses, which often resulted in systemic side effects (Weber et al , 2015).…”

Continuous sensing of IFNα by hepatic endothelial cells shapes a vascular antimetastatic barrier

“…Accordingly, there is growing recognition that the use of perioperative immunotherapies in CRC patients undergoing surgical resection may represent a unique treatment window to prevent metastatic colonization and control minimal residual disease ( Badia-Ramentol et al, 2021 ; Bakos et al, 2018 ; Horowitz et al, 2015 ). In this context, interferon-alpha (IFNα), a pleiotropic cytokine with multiple antitumor effects such as the direct inhibition of cancer cell growth and angiogenesis ( Indraccolo, 2010 ), the sustained upregulation of major histocompatibility complexes ( Gessani et al, 2014 ) and the induction of innate and adaptive antitumor immune responses ( Aichele et al, 2006 ; Curtsinger et al, 2007 ; Fuertes et al, 2013 ), has been used as adjuvant immunotherapy in various solid cancers such as renal cell carcinoma ( Flanigan et al, 2001 ), melanoma ( Lens and Dawes, 2002 ) and colorectal cancer ( Köhne et al, 1997 ; Link et al, 2005 ). Unfortunately, systemic administration of IFNα has shown limited clinical efficacy, likely due to its short plasma half-life (~1 hr) ( Bocci, 1994 ) and the use of high and pulsed doses, which often resulted in systemic side effects ( Weber et al, 2015 ).…”