A randomized phase II study to compare oxaliplatin plus 5-fluorouracil and leucovorin (FOLFOX4) versus oxaliplatin plus raltitrexed (TOMOX) as first-line chemotherapy for advanced colorectal cancer

Abstract

IntroductionThe aim of this study was to compare TOMOX versus FOLFOX4 as first-line treatment of advanced colorectal cancer (CRC).Materials and methods191 chemotherapy-naïve patients were randomized to receive TOMOX or FOLFOX4. Patients were evaluated every 3 months and chemotherapy was continued until disease progression or unacceptable toxicity. Overall response rate was the primary endpoint.Results183 patients were included in the intent-to-treat analysis (92 TOMOX and 91 FOLFOX4). Overall response rate was 45.6 and 36.3 % (p = 0.003) for TOMOX and FOLFOX4, respectively. No statistically significant differences were observed in overall survival (15.6 and 17.2 months; p = 0.475); progression-free survival (7.7 and 8.7 months; p = 0.292), and response duration (6.4 and 7.6 months; p = 0.372) for TOMOX and FOLFOX4, respectively. Grades 3 and 4 neutropenia (p < 0.0001) and leukopenia (p = 0.028) were more common with the FOLFOX4 regimen, while hepatic disorders and asthenia were higher in TOMOX group (p = ns). There were two treatment-related deaths in the FOLFOX4 arm and one in the TOMOX arm. Quality of life analysis based on the SF-36 revealed differences between the two regimens for physical and mental composite scores after 6 weeks, and for body pain and emotional role functioning after 6 and 12 weeks; all of these favored the FOLFOX4 arm (p ≤ 0.05).ConclusionsTOMOX and FOLFOX4 seem to have similar efficacy and are well tolerated in the first-line treatment for advanced CRC with different profiles of toxicity. The convenient TOMOX regimen may offer an alternative to fluoropyrimidine-based regimens.

A systematic review of raltitrexed-based first-line chemotherapy in advanced colorectal cancer

“…Martoni et al [11] Gravalos et al [5] Feliu et al Chiara et al [8] Cascinu et al [3] Carnaghi et al [ The referent regimens were FOLFIRI and FOLFOX in the study by Tournigand et al However, in both trials, a high proportion of patients switched to second-line irinotecan-based chemotherapy; this likely could have made the median OS longer compared with that observed in our series. In the trials included in our series, the rate of post-treatment therapies prescribed after raltitrexed failure reported by authors ranged from 50 to 60%, which was largely inferior to modern first-line trials where biological agents have been introduced.…”

“…The results in the outcome of this pooled analysis appear similar even if slightly inferior to conventional FOLFOX and FOLFIRI regimens. In the headto-head comparison presented in the study by Gravalos et al [5], TOMOX was found to be noninferior to FOLFOX. In two randomized studies carried out by Goldberg and Tournigand, upfront FOLFOX4 was associated with RRs of 44 and 56%, a median PFS of 8 months, and a median OS of ∼ 20 months [16,17].…”

“…On the basis of the predefined eligibility criteria, we selected 12 studies [3][4][5][7][8][9][10][11][12][13][14][15] that fulfilled the qualitative and quantitative requirements of the systematic analysis. A total of 735 patients were enrolled across the selected trials (range, 37-94).…”

“…In 2012, TOMOX was compared with the standard FOLFOX with better RR for TOMOX schedule (45 vs. 36%). The OS and progression-free survival (PFS) were similar [5]. Raltitrexed was also associated with a potentially lower risk of cardiotoxicity in patients with cardiac disease or in those who experienced a cardiac event with 5-FU [6].…”

“…Aparicio et al [7] Carnaghi et al [4] Cascinu et al [3] Chiara et al [8] Feliu et al [10] Feliu et al [9] TOMIRI Feliu et al [9] TOMOX Gravalos et al [5] Martoni et al [11] Neri et al [12] Santini et al [13] Seitz et al [15] Scheithauer et al [14] 0 required, unlike fluoropyrimidines [1]. In addition, results reported at the American Society of Clinical Oncology meeting in 2000 suggest that the prophylactic use of the 5-HT3 antagonist ondansetron reduces the severity of nausea and diarrhea, preventing dehydration, and the use of dexamethasone reduces the incidence of fever and fatigue [23].…”