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

Abstract

Mitomycin C (MMC) in combination with infusional 5-fluorouracil (FU) plus folinic acid (FA) is an effective treatment for metastatic gastrointestinal cancer. Anthracyclines are commonly used in the treatment of upper gastrointestinal cancer. The aim of this study was to determine the maximum tolerated dose of liposomal, pegylated doxorubicin (Caelyx) in combination with infusional 5-FU/sodium FA and MMC. Escalating doses of Caelyx (15 -25 -30 -35 mg m À2 corresponding to dose levels I -IV) were applied on days 1 and 29, given to fixed doses of 24-h 5-FU (2000 mg m À2 ) and sodium FA (500 mg m À2 , mixed with 5-FU in one pump) weekly for 6 weeks, and MMC 7 mg m À2 on days 8 and 36. At least three patients were treated at each dose level. A total of 25 patients are evaluable. No dose-limiting toxicity (DLT) was observed on level I (n ¼ 3). On level II, DLT occurred in three out of five patients (mucositis and leucopenia). Owing to the early DLTs at this dose, we added a 20 mg m À2 Caelyx dose level (Ia). In total, 17 patients were treated at this dose level. Among these, only two patients experienced DLT in cycle one and 37 complete cycles have been administered in association with a low toxicity profile. The median dose intensity was 100% for each drug during the first course and no treatment delay exceeding 7 days was required. The recommended dose of 4-weekly Caelyx in combination with weekly 24-h 5-FU/sodium FA and 4-weekly MMC is 20 mg m À2 . Preliminary antitumour activity has been observed in patients with pretreated pancreatic cancer and in untreated gastric cancer.

Major innovations and clinical applications of disodium-levofolinate: a review of available preclinical and clinical data

“…16 In the last few years, the infusion of Na-Lv with 5-FU has been largely tested in association with other chemotherapeutic and molecular-target agents, showing efficacy and safety profile overlapping with those observed with Ca-FA. 17–24…”

“…In several recent trials, 5-FU and Na-Lv were tested in various associations with other drugs in colon, oesophageal, gastric and breast cancer with data of safety concordant with those reported in the studies mentioned above. 17–24 None of these trials described the occurrence of catheter occlusion or damage. 11,15–24…”

“…14 The availability of Na-Lv had offered also the opportunity to re-test the administration of the original schedule proposed by Ardalan 6 in clinical trials, obtaining favourable results and toxicity overlapping to that previously reported for combination of 5-FU and Ca-FA. 10,11,15–24…”

Infusional 5-Fluorouracil and Mitomycin C: An Effective Regimen in the Treatment of Advanced Gastric Cancer

“…Current efforts focus on the optimisation of the AIO plus MMC regimen by using capecitabine instead of infusional 5-FU [23], or adding further cytostatic drugs, e.g. pegylated liposomal doxorubicin [24]. Meanwhile, new active agents against gastric cancer (e.g.…”

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

“…Combination treatment with mitomycin C and bolus 5-FU/FA is both active and well tolerated in patients with advanced gastric cancer (Hartung et al, 2000). The addition of mitomycin to infusional 5-FU is also effective and well tolerated as first-or second-line therapy in patients with gastrointestinal tumours (Hartmann et al, 2003. Hofheinz et al, 2004.…”