High-Dose 5-Fluorouracil / Folinic Acid in Combination with Three-Weekly Mitomycin C in the Treatment of Advanced Gastric Cancer. A Phase II Study

Abstract

Background: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus MMC. Patients and Methods: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m² preceded by 2-hour FA 500 mg/m² for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m² was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients’ characteristics were: male/female ratio 20/13; median age 57 (27–75) years; median WHO status 1 (0–2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7–11.8 months). Results: 32 patients were evaluable for response – complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7–11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4–10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). Conclusions: High-dose 5-FU/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur.

Capecitabine in combination with mitomycin C in patients with gastrointestinal cancer: results of an extended multicentre phase-I trial

“…This regimen may be considered for patients with colorectal cancer after pretreatment with 5-FU, irinotecan and oxaliplatin, but it is also likely to be a valuable, cost-saving and convenient treatment option even in earlier stages of colorectal cancer chemotherapy. Our results in gastric cancer patients, together with our earlier reported experience with infusional 5-FU/ mitomycin C combination therapy in this type of cancer (Hartmann et al, 2003;Hofheinz et al, 2002), suggest that the capecitabine/mitomycin C regimen could be considered as an alternative regimen for patients not suitable for cisplatin-based therapy.…”

“…Hofheinz et al, 2004. Mitomycin (10 mg m À2 ) added every third week to weekly infusional high-dose 5-FU/FA yielded a response rate of 54%, and an overall survival of 10.2 months in patients with advanced gastric cancer (Hofheinz et al, 2002). In a randomised study comparing ECF (three-weekly epirubicin and cisplatin with protracted venous infusional (PVI) 5-FU 200 mg m À2 daily) to MCF (mitomycin 7 mg m À2 every 6 weeks and three-weekly cisplatin with PVI-5-FU 300 mg m À2 daily) in patients with advanced oesophagogastric cancer, both regimens resulted in equivalent response rates and survival (Ross et al, 2002), thus confirming the efficacy of combined infusional 5-FU and mitomycin C. In patients with either colorectal or pancreatic cancer, PVI-5-FU plus MMC resulted in a superior response rate (and an improved TTP in colorectal cancer) compared with PVI-5-FU alone (Ross et al, 1997.…”

Pegylated liposomal doxorubicin in combination with mitomycin C, infusional 5-fluorouracil and sodium folinic acid. A phase-I-study in patients with upper gastrointestinal cancer

“…In gastric cancer, MMC (10 mg m À2 ) added every third week to weekly infusional 5-FU/FA yielded a response rate of 54%, and a median overall survival of 10.2 months (Hofheinz et al, 2002). Ross et al (2002) reported the results of a randomised study comparing ECF (3-weekly epirubicin and cisplatin in combination with protracted venous infusional (PVI) 5-FU 200 mg m À2 daily) to MCF (MMC 7 mg m À2 every 6 weeks and 3-weekly cisplatin with PVI-5-FU 300 mg m À2 daily).…”

“…The phase I study presented here was designed to evaluate the safety and tolerability of escalating doses of Caelyx in combination with weekly infusional 5-FU/ sodium FA and 4-weekly bolus MMC. 5-Fluorouracil and MMC were planned for use at 75% of the doses administered in our former studies (Hofheinz et al, 2002;Hartmann et al, 2003) and the Caelyx dose was escalated. Four-weekly Caelyx 20 mg m À2 can safely be combined with weekly infusional 5-FU/sodium FA and 4-weekly MMC.…”

“…When combined with infusional 5-FU, objective remission rates up to 54% in gastric cancer patients have been observed (Hofheinz et al, 2002;Hartmann et al, 2003). In colorectal and pancreatic cancer, protracted infusional 5-FU plus MMC resulted in a superior response rate in comparison with 5-FU alone, and in an improved failure-free survival in colorectal cancer (Ross et al, 1997;Maisey et al, 2002).…”