A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma

Abstract

Previous results suggest that GEM affects 5-fluorouracil (5-FU) metabolism and pharmacokinetics in cancer patients, while combined with oxaliplatin, levo-folinic acid, and 5-FU (GOLF regimen), at doses achievable in cancer patients, determines high cytotoxic and proapoptotic antitumour activity in colon cancer cells in vitro. On these bases we designed a phase I -II clinical trial testing the GOLF regimen in patients with metastatic colorectal carcinoma, who had received at least a prior line of chemotherapy. In total, 29 patients (20 males and nine females) enrolled in the study received every 2 weeks, gemcitabine (patients #1 -3 received 600 mg m À2 ; patients # 4 -6 received 850 mg m À2 ; while patients # 7 -29 received 1000 mg m À2 ) on the day 1, levo-folinic acid (100 mg m À2 ) on the days 1 and 2; 5-fluorouracil (400 mg m À2 ) in bolus injection, followed by a 22-h continuous infusion (800 mg m À2 ) on the days 1 and 2, and oxaliplatin (85 mg m À2 ), 6 h after the 5-FU bolus on day 2. The most frequent side effect was grade I -II haematological toxicity. In total, 28 patients were evaluable for response: three achieved a complete response, nine a partial response, 10 had a stable disease, and six progressed. The average time to progression and overall survival of the patients was, respectively, 7.26 and 22 months. Our GOLF combination is well tolerated and seems promising for the treatment of advanced colorectal cancer.

Dendritic Cell-Mediated Cross-Presentation of Antigens Derived from Colon Carcinoma Cells Exposed to a Highly Cytotoxic Multidrug Regimen with Gemcitabine, Oxaliplatin, 5-Fluorouracil, and Leucovorin, Elicits a Powerful Human Antigen-Specific CTL Response with Antitumor Activity in Vitro

“…These findings have been supported by the results of three recent clinical trials showing the powerful antitumor activity of the GOLF regimen in patients with metastatic colorectal and gastric cancer (Ref. 7 and manuscript submitted for publication).…”

“…1). The GOLF combination has also been tested in clinical trials in advanced colon cancer patients in whom it has been shown to have a good safety profile and highly significant antitumor activity (7).…”

Tumor Infiltration by T Lymphocytes Expressing Chemokine Receptor 7 (CCR7) Is Predictive of Favorable Outcome in Patients with Advanced Colorectal Carcinoma

“…On the basis of preclinical findings (5), we designed a novel therapeutic regimen that includes a sequential combination of 5-FU-based polychemotherapy (gemcitabine, oxaliplatin, levofolinic acid, and 5-FU; ref. 6), followed by the immune-adjuvant cytokine recombinant granulocyte macrophage colony-stimulating factor (rGM-CSF), and ultra low-dose metronomic human recombinant interleukin-2 (aldesleukine rIL-2). rGM-CSF was included in the aim to activate peripheral dendritic cells (DC) and rIL-2 to endure an antitumor antigen-specific T-cell-mediated immune response.…”

Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased raf-1 ubiquitin-dependent degradation

“…6 The GOLF combination has also been used in the treatment of advanced colon and gastric cancer patients and shown a good safety profile and highly significant anti-tumor activity. [15][16][17] The favorable anti-tumor activity of GOLF regimen could be explained by changes of the pharmacokinetics and pharmacodinamics of both 5-FU and OXA induced by GEM (refs. 8, 9 and unpublished results).…”