Interferon-alpha does not improve the antineoplastic efficacy of high-dose infusional 5-fluorouracil plus folinic acid in advanced colorectal cancer

Purpose: A pilot study was performed to evaluate the tolerance and efficacy of a hepatic arterial infusion (HAI) of 5-fluorouracil (5-FU) and folinic acid (FA) in patients with unresectable liver metastases from colorectal carcinoma. Patients and Methods: In 11 patients, 135 applications of high-dose HAI of 5-FU/FA were administered. All patients had been intra-arterially pretreated, and 2 of them had received an additional intravenous therapy. The chemotherapy regimen consisted of a weekly HAI of FA 500 mg/m² over 1 h, immediately followed by HAI of 5-FU over 24 h. Four patients received a 5-FU starting dose of 2,000 mg/m² and 7 patients of 2,400 mg/m². One course consisted of 12 weekly applications interrupted by 1 week after 6 applications and 4 weeks after 12 applications. Results: The applied regimen caused only mild side effects. Nausea and vomiting were the most frequently side effects with 36 episodes out of 135 applications (WHO grade ≥3: 2 episodes). Diarrhea was a minor problem occurring with 8 episodes (WHO grade ≥3: 1 episode). There was no evidence of myelosuppression, hand-foot syndrome, neurotoxicity, and biliary sclerosis. A partial remission was observed in 3 patients, and a disease stabilization in 2 patients while the disease progressed in 6 patients under high-dose HAI of 5-FU/FA. Conclusion: The present pilot study demonstrates that the weekly high-dose HAI of 5-FU/FA is well tolerated and associated with very mild toxicity. Because of the encouraging response rate in patients, whose disease progressed under the conventional intra-arterial therapy either with 5-FU/FA or 5-fluorodeoxyuridine, this regimen seems to be an effective second-line treatment and should be evaluated in nonpretreated patients in a phase II study.

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“…Similar results could be confirmed by other reports [14,15]. Due to its very mild toxicity, this intravenous regimen is well tolerated.…”

Section: Introductionsupporting

confidence: 91%

A Pilot Study on Intensive Weekly 24-Hour Intra-Arterial Infusion with 5-Fluorouracil and Folinic Acid for Colorectal Liver Metastases

Lorenz

Staib-Sebler²,

Gog³

et al. 1997

Oncology

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“…The response rate seen with 5-FU-IFN-β is consistent with results from the only published study to use 5-FU with IFN-β in chemotherapy-naive patients with advanced colorectal cancer (35%; Wadler et al, 1995) and from randomized studies of 5-FU with IFN-α that used the same 5-FU schedule (Corfu-A Study Group, 1995;Hill et al, 1995;Dufour et al, 1996;Greco et al, 1996;Jäger et al, 1996): these studies reported response rates between 21% and 30%. Randomized trials of 5-FU with leucovorin, using different 5-FU schedules, reported similar rates (18-39%; Piedbois et al, 1992;Corfu-A Study Group, 1995;Köhne et al, 1995;Leichman et al, 1995;Jäger et al, 1996).…”

Section: Discussionmentioning

confidence: 91%

A randomized phase II trial of 5-fluorouracil, with or without human interferon-β, for advanced colorectal cancer

et al. 1999

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Colorectal cancer has an annual incidence of 53 cases per 100 000 in the USA and Europe, representing 15% of all malignant tumors (Beard et al, 1995; Netherlands Cancer Registry, 1989). Approximately 30% of patients present with advanced disease, and about 60% of these cases are no longer amenable to surgery. The prognosis for these patients is poor.The fluorinated pyrimidine 5-fluorouracil (5-FU) has been the principal treatment for advanced colorectal cancer for the past 4 decades (Heidelberger et al, 1957). Therapy with 5-FU leads to objective response in only 8-20% of patients, with few complete responses and minimal improvement in survival (Carter, 1976;Leichman et al, 1995;Moertel, 1982). Dosage of 5-FU is limited by the occurrence of mucosal and neutropenic toxicities (Moertel, 1975).Various modulating agents have been used in an attempt to synergistically enhance 5-FU's cytotoxicity. Results have so far been disappointing. Improved response rates have been reported with the combination of 5-FU and leucovorin, but responses were mainly partial rather than complete and most were of short duration. Two randomized studies observed significantly increased survival time for 5-FU with leucovorin (Ehrlichman et al, 1988;Poon et al, 1989), but a meta-analysis and two other randomized studies failed to confirm improvement over 5-FU monotherapy (Piedbois et al, 1992;Leichman et al, 1995;O'Dwyer et al, 1996). Early clinical trials reported encouraging results with the combination of 5-FU and interferon alpha (IFN-α), including tumor response rates as high as 35-63% and median survival times of up to 18 months. However, the cost was a high level of toxicity: in particular, fever, constitutional symptoms and myelosuppression (Wadler et al, 1989;Kemeny et al, 1990;Pazdur et al, 1990). Unfortunately, no improvements in response rate or survival time have been observed in further randomized trials of 5-FU with IFN-α versus 5-FU monotherapy (Hill et al, 1995;Greco et al, 1996) or 5-FU with leucovorin (Corfu-A Study Group, 1995).The interferons are a well-recognized group of naturally occurring proteins with antiviral, immunomodulatory and antiproliferative properties. Based on antigenic specificity, physico-chemical properties and cellular origin, they are classified as type I or type II. The type I interferons, IFN-α and IFN-β, are produced by leucocytes and fibroblasts respectively. IFN-β has a 30% level of amino acid homology with IFN-α (Taniguchi et al, 1980), and binds to the type I interferon receptor with higher affinity than IFN-α (Ruzicka et al, 1987). There is evidence for a receptorassociated protein specifically involved with IFN-β's signalling pathway and not IFN-α's (Platanias et al, 1994). Although the mechanisms of the interferons' anti-tumor activity and 5-FU modulation remain poorly understood, preclinical data suggest a theoretical benefit for IFN-β over IFN-α in the treatment of colorectal cancer. Antiproliferative activity against some tumor cell lines in vitro appears greater for IFN-β than IFN-α (Bo...

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“…A recently published study failed to demonstrate a difference in survival for weekly HD-FU compared with the Mayo Clinic regimen [9, 10]. Although the difference in PFS between the HD-FU and the LV5FU2 arms was not statistically significant at 4.9 and 5.4 months, respectively, these better results were obtained with less toxicity than in the HD-FU arm: grade 3–4 neutropenia was observed in 11% of the patients in the HD-FU arm versus 3 and 4% in the LV5FU2 and ldLV5FU2 arms, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…In France, the so-called ‘de Gramont’ schedule combining bolus and 48-hour infusional 5FU has resulted in better response rates and progression-free survival (PFS) compared with bolus 5FU alone [8]. A large randomised EORTC (European Organisation of Research and Therapy against Cancer) trial recently showed that high-dose 5FU given as a weekly 24-hour infusion was better tolerated than bolus 5FU + leucovorin (LV) without any major advantage in terms of efficacy [9, 10]. This regimen has totally replaced bolus 5FU in routine practice in Germany.…”

Section: Introductionmentioning

confidence: 99%

Randomised Trial Comparing Three Different Schedules of Infusional 5FU and Raltitrexed Alone as First-Line Therapy in Metastatic Colorectal Cancer

et al. 2006

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LV5FU2 with high-dose leucovorin (LV), weekly infusional 5-fluorouracil (5FU) (AIO schedule) and raltitrexed have been demonstrated to be active agents in first-line treatment of colorectal cancer. We performed a 4-arm randomised trial to compare (1) a low-dose intravenous bolus of LV (20 mg/m²), followed by an intravenous bolus of 5FU (400 mg/m²), followed by a 22-hour continuous infusion of 5FU (600 mg/m²) on day 1 and day 2/2 weeks (ldLV5FU2 arm), (2) a weekly continuous infusion of high-dose 5FU (2.6 g/m²/week) for 6 weeks followed by a rest week (HD-FU arm) and (3) raltitrexed (Tomudex® arm; 3 mg/m²/3 weeks) to standard LV5FU2. From 1997 to 2001, 294 patients were included. The 4 arms were well balanced for sex ratio, age, WHO performance status, the primary tumour site and prior adjuvant chemotherapy. Treatment was stopped due to low accrual. Two toxicity-related deaths were observed in the Tomudex arm. The treatments gave rise to different rates of grade 3–4 neutropenia (3, 4, 11 and 14% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively, p = 0.028), leucopenia and vomiting. At least one episode of grade 3–4 toxicity was observed in 27, 25, 38 and 47% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.016). An objective response was observed in 28, 21, 22 and 10% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.04). Progression-free survival (PFS) of the patients in the Tomudex arm was statistically lower compared to that of patients treated with LV5FU2 or ldLV5FU2 (combined group; p = 0.013, log rank test). In conclusion, Tomudex is more toxic and yields shorter PFS than infusional 5FU. Despite the early closure of the study and the lack of power of the comparison, it seems that ldLV5FU2 could be considered as an active, easier and less expensive option for the treatment of metastatic colorectal cancer compared to classic LV5FU2 or weekly HD-FU.

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Interferon-alpha does not improve the antineoplastic efficacy of high-dose infusional 5-fluorouracil plus folinic acid in advanced colorectal cancer

Cited by 28 publications

References 12 publications

A Pilot Study on Intensive Weekly 24-Hour Intra-Arterial Infusion with 5-Fluorouracil and Folinic Acid for Colorectal Liver Metastases

A Pilot Study on Intensive Weekly 24-Hour Intra-Arterial Infusion with 5-Fluorouracil and Folinic Acid for Colorectal Liver Metastases

A randomized phase II trial of 5-fluorouracil, with or without human interferon-β, for advanced colorectal cancer

Randomised Trial Comparing Three Different Schedules of Infusional 5FU and Raltitrexed Alone as First-Line Therapy in Metastatic Colorectal Cancer

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