A Phase II Study of Gefitinib, 5-Fluorouracil, Leucovorin, and Oxaliplatin in Previously Untreated Patients with Metastatic Colorectal Cancer

Abstract

Purpose: We investigated the gefitinib, 5-fluorouracil (5-FU), leucovorin and oxaliplatin (IFOX) regimen as first-line therapy in patients with metastatic colorectal cancer. Experimental Design: Eligible patients had stage IV colorectal adenocarcinoma, and had not received prior chemotherapy for metastatic disease. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin, leucovorin, and 5-FU (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg orally daily throughout the 14-day cycle. Results: Forty-five patients were enrolled and were assessable for toxicity. Forty-three patients were assessable for response.Thirty-one of the 43 patients (72%) had either a complete or partial response by the Response Evaluation Criteria in Solid Tumors. Median overall survival was 20.5 months. Median time to progression was 9.3 months. Commonly encountered grade 3 or 4 toxicities included diarrhea in 67% of patients and neutropenia in 60%. Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients. Conclusions: IFOX is an active first-line regimen in patients with metastatic colorectal adenocarcinoma, showing higher response rates but also increased toxicities compared with FOLFOX-4 alone in a similar patient population.Over the last 10 years, incremental gains in response rates and the median survival for patients with metastatic colorectal cancer have been achieved with the introduction of active new chemotherapeutic and biologically targeted agents. Combinations of irinotecan or oxaliplatin with 5-fluorouracil (5-FU) and leucovorin for first-line therapy of metastatic colorectal cancer have shown improved response rates and median survival times over 5-FU and leucovorin alone (1, 2). In addition, infusional 5-FU has replaced bolus 5-FU as a platform for combination chemotherapy based on decreased toxicity and improved efficacy (3,4). In the initial study investigating the combination of oxaliplatin, 5-FU, and leucovorin (FOLFOX-4) for first-line therapy of metastatic colorectal cancer, there was a 50% objective response rate compared with 22% with infusional 5-FU/leucovorin alone (2). The FOLFOX-4 regimen was also associated with a longer time to progression (9.0 months versus 6.2 months) and a trend toward improved overall survival. Although a direct comparison of FOLFOX-4 and irinotecan, 5-FU, and leucovorin in previously untreated patients showed that FOLFOX-4 was superior, a subsequent comparison of FOL-FOX-6 and folinic acid, 5-FU, and irinotecan showed no significant difference in efficacy (5, 6). This confirmed that both irinotecan and oxaliplatin are active agents against colorectal cancer, and selection of an appropriate regimen could focus on their different toxicity profiles.The effort to further improve the efficacy and tolerability of treatment for metastatic colorectal cancer has led to the discovery of new agents targeting cell-signaling molecules such as epidermal growth factor receptor (EGFR). EGFR expression has been shown in 60% to 80% of ...

Inclusion of targeted therapies in the standard of care for metastatic colorectal cancer patients in a German cancer center: the more the better?!

“…First-line treatment included a backbone of an irinotecan-fluoropyrimidin or oxaliplatin-fluoropyrimidin-based CTX with the addition of a VEGF (bevacizumab), EGFR (cetuximab, panitumumab), or RTK (sunitinib, sorafenib, imatinib, gefitinib) inhibitor when appropriate, as described before (Awada et al 2011;Blesa and Pulido 2010;Cutsem et al 2007;Fisher et al 2008;Hurwitz et al 2004;Kelley et al 2013;Kindler et al 2005;Peeters et al 2010;Qvortrup et al 2010;Samalin et al 2014;Tournigand et al 2004). As a second-line treatment backbone CTX was continued in a crossover design, while VEGF, EGFR, or RTK inhibition was either discontinued or switched over (see Fig.…”

Gefitinib, Fluorouracil, Oxaliplatin, and Leucovorin (IFOX) Regimen for Colorectal Cancer

“…[20][21][22][23][24] The studies reviewed reported grade 3 nausea or vomiting in 18% to 27% of patients. 13,16 Prophylactic antiemetic therapy with a steroid and serotonin antagonist is recommended. [21][22][23][24] One group suggests that addition of a neurokinin (NK 1 ) antagonist may be appropriate in some patients.…”

“…Serum bilirubin (1) Less than or equal to 1.5 mg/dL. 13 (2) Less than or equal to 1.5 times ULN. 16 b. ALT/ AST less than or equal to 2.5 times the ULN 13,16 or less than or equal to 5 times the ULN if liver metastases were present.…”

“…13 (2) Less than or equal to 1.5 times ULN. 16 b. ALT/ AST less than or equal to 2.5 times the ULN 13,16 or less than or equal to 5 times the ULN if liver metastases were present. 16 In clinical practice, a pretreatment ANC of 1,000 cells/mcL and platelets of 75,000 cells/mcL are usually considered acceptable.…”

Treatment in advanced colorectal cancer: what, when and how?

“…Several phase II studies found little additional benefit of EGFR TKI on a conventional chemotherapy platform (Hofheinz et al, 2006;Chau et al, 2007;Gelibter et al, Zampino et al, 2007;Cascinu et al, 2008;Fisher et al, 2008;Stebbing et al, 2008). More importantly, excessive toxicities were encountered in a number of these studies, especially with irinotecan combinations.…”