Treatment of advanced colorectal cancer with 5-fluorouracil and interferon-α: An overview of clinical trials

Raderer, Markus; Scheithauer, Werner

doi:10.1016/0959-8049(95)00078-x

Cited by 31 publications

(22 citation statements)

References 31 publications

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“…Owing to this, various anti-cancer therapies were designed to target disease-specific mechanisms that are absent in normal cells. Such strategies include (i) inhibition of a specific oncoprotein, such as targeting the oncogenic fusion proteins Bcr–Abl and PML–RARA with Gleevec and all trans retinoic acid (ATRA) with arsenic trioxide respectively or (ii) activation of a specific immune response against cancerous cells demonstrated by the use of interferon alpha alone or in combination with other anti-cancer drugs including 5-fluorouracil and cytarabine (Raderer and Scheithauer, 1995; Guilhot et al, 1997; Druker et al, 2001; Kreitman et al, 2001; Tallman et al, 2002; Goldman and Melo, 2003; O’Brien et al, 2003; Sawyers, 2004; Kreitman, 2006; Ferrantini et al, 2007; Chin and Gray, 2008; Sellers, 2011). Many of these drugs are currently being used in the clinic and have established positive impact on patient survival.…”

Section: Cancer Tale: Its Treatment and Relapsementioning

confidence: 99%

Mechanisms and insights into drug resistance in cancer

Zahreddine¹,

Borden²

2013

Front. Pharmacol.

559

420

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Cancer drug resistance continues to be a major impediment in medical oncology. Clinically, resistance can arise prior to or as a result of cancer therapy. In this review, we discuss different mechanisms adapted by cancerous cells to resist treatment, including alteration in drug transport and metabolism, mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. Making the problem even more challenging, some of these resistance pathways lead to multidrug resistance, generating an even more difficult clinical problem to overcome. We provide examples of these mechanisms and some insights into how understanding these processes can influence the next generation of cancer therapies.

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Section: Cancer Tale: Its Treatment and Relapsementioning

confidence: 99%

Mechanisms and insights into drug resistance in cancer

Zahreddine¹,

Borden²

2013

Front. Pharmacol.

559

420

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“…IFN is a modulator that has been used to increase the cytotoxicity of 5-FU. In in vitro studies using colon cancer cell lines, IFN enhanced the metabolism of 5-FU to its active metabolite [13][14][15]. Several routes of 5-FU administration have been studied, not only intravenous but also intraportal and intra- peritoneal administration [3,5,7].…”

Section: Discussionmentioning

confidence: 99%

Effect of Early versus Delayed Postoperative Injection of 5-Fluorouracil plus Interferon-Alpha on Colonic Healing

Kanellos

Odisseos²,

Kazantzidou³

et al. 1998

Eur Surg Res

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The purpose of this study was to determine whether delayed, postoperative, intraperitoneal treatment with 5-fluorouracil (5-FU) plus interferon-α-2a (IFN) has adverse effects on colonic healing, as does early treatment. Seventy male Wistar rats underwent colonic anastomoses. The rats were randomized to one of four groups. Early intraperitoneal injection was given to groups 1 and 2 which was repeated once daily for the first 3 postoperative days. Treatment was delayed in groups 3 and 4, from the 4th to the 7th postoperative day. A 0.9% NaCl solution was injected in the rats of control groups 1 and 3. In groups 2 and 4, we infused 5-FU (20 mg/kg/day) and IFN (45,000 IU/kg/day). All the animals were sacrificed on the 8th postoperative day. The anastomotic rupture rate was significantly higher in the rats of group 2 compared to control group 1 (p < 0.05), while there were no differences between groups 3 and 4 (p > 0.05). Abscess formation and adhesions were more frequent in group 2 compared to control group 1, while no differences were observed between groups 3 and 4. Anastomotic bursting pressure was statistically significantly lower in the rats of group 2 compared to group 1 (p < 0.05); no differences were noticed between groups 3 and 4 (p > 0.05). Simultaneous histologic evaluation showed a more profound inflammatory reaction and delayed anastomotic healing in group 2 compared to control group 1; there were, however, no differences between groups 3 and 4. In conclusion, the immediate, postoperative, intraperitoneal injection of 5-FU plus IFN impairs colonic healing while delayed treatment (starting on the 4th postoperative day) has no adverse effects on wound healing.

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“…Based upon preclinical results, a number of phase II studies employing the association of IFN a and 5FU were conducted with response rates ranging from 26% to 43%, a ®gure that diered considerably from Wadler's ®rst enthusiastic report (Fornasiero et al 1990;Huberman et al 1990;Kemeny and Younes 1992;Raderer and Scheithauer 1995;Wadler et al 1991;Weh et al 1992). Con®rmation by phase III randomized trials became mandatory at this point.…”

Section: Discussionmentioning

confidence: 99%

5-Fluorouracil plus interferon α-2a compared to 5-fluorouracil alone in the treatment of advanced colon carcinoma: A multicentric randomized study

Palmeri

Meli

Danova

et al. 1998

Journal of Cancer Research and Clinical Oncology

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Biochemical modulation is one of the most interesting fields in cancer chemotherapy. Interferon-alpha (IFNalpha) is a cytokine that is able to influence the pharmacodynamics of 5-fluorouracil (5FU) through a number of mechanisms. With the aim of confirming some data emerging from the literature, we initiated a multicentric randomized study comparing the combination of 5FU and IFNalpha-2a with 5FU alone in the treatment of advanced or metastatic colon cancer. A group of 205 colon cancer patients (104 in the 5FU arm and 101 in the 5FU + IFNapha-2a arm) were included in the final intention-to-treat analysis. Rectal cancers were not considered eligible. All patients had measurable disease, were aged 75 years or less, had a Karnofsky index of at least 60 and had good bone marrow, renal, liver and cardiac functions. No previous chemo-immunotherapy was allowed. The treatment was 750 mg/m2 5FU (4 h i.v. infusion) on days 1 5 and then i.v. bolus weekly, starting from day 12, with or without IFNalpha-2a given s.c. three times weekly (starting dose 3 x 10(6) IU rising to 9 x 10(6) IU, if tolerated). Patients were treated until progression or, if responsive, for a maximum of 48 weeks and then observed for a period of 2 years. The primary end-point of the study was objective clinical response (OR); secondary parameters were time to progression, overall survival, and time to death after progression. WHO criteria were used for both clinical response and toxicity measurements. Dose reduction was planned a priori in the event of significant toxicity due to 5FU, IFNalpha-2a or both. Association between primary and secondary end-points and treatment was studied by univariate and multivariate analysis. Altogether, 47 patients achieved a documented response. A 25% OR was observed in the combination arm while a 21% OR was seen in the 5FU arm; this difference is not statistically significant (P = 0.6). Patients with a small tumour burden (below 5 cm2) showed a higher probability of response in both arms. Patients in the experimental arm had a higher but not statistically significant cumulative progression-free probability. Median survival was 47.1 weeks overall, while it was 43.7 and 48.5 weeks in the control and experimental arms, respectively. The combination was clearly more toxic than 5FU alone, leukopenia being the most frequent side-effect in the experimental arm and nausea and vomiting in the control arm. In conclusion these results are quite disappointing and 5FU + IFNalpha-2a can not be considered a standard treatment for advanced colon cancer.

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Treatment of advanced colorectal cancer with 5-fluorouracil and interferon-α: An overview of clinical trials

Cited by 31 publications

References 31 publications

Mechanisms and insights into drug resistance in cancer

Mechanisms and insights into drug resistance in cancer

Effect of Early versus Delayed Postoperative Injection of 5-Fluorouracil plus Interferon-Alpha on Colonic Healing

5-Fluorouracil plus interferon α-2a compared to 5-fluorouracil alone in the treatment of advanced colon carcinoma: A multicentric randomized study

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