Phase II clinical study of modified FOLFOX7 (intermittent oxaliplatin administration) plus bevacizumab in patients with unresectable metastatic colorectal cancer—CRAFT study

Abstract

SummaryPurpose Continuous treatment with FOLFOX therapy is associated with peripheral nerve toxicity, and to improve this inconvenient side effect various methods of administration are being investigated. A regimen of intermittent oxaliplatin administration by continuous infusion therapy, i.e., modified FOLFOX7 (mFOLFOX7) + bevacizumab, was designed with the goal of alleviating severe peripheral nerve disorders and hematological toxicity. A phase II clinical study was conducted to evaluate the efficacy and safety of this regimen. Methods Previously untreated patients were assigned to mFOLFOX7 (oxaliplatin 85 mg/m2, levofolinate [l-LV] 200 mg/m2, 5-fluorouracil [5-FU] 2400 mg/m2) + bevacizumab (5 mg/kg) administered every 2 weeks for 8 cycles, maintenance without oxaliplatin for 8 cycles, and reintroduction of mFOLFOX7 + bevacizumab for 8 cycles or until disease progression. Progression free survival (PFS) following the first dose (PFS 1) and following reintroduction of oxaliplatin (PFS 2) were used as indices for assessing the efficacy of intermittent administration. Results Fifty-two patients were enrolled, with median age of 64 years (range, 36–74). Median PFS 1 was 11.8 months (95 % confidence interval [CI], 9.5 to 13.7), median time to treatment failure was 10.3 months (95 % CI, 5.6 to 12.1), percentage of patients with neutropenia of grade 3 or higher was 7.8 %, and percentage with peripheral nerve disorders was 3.9 %. Response rate was 50 %, and 84.4 % of patients who started modified simplified LV5FU2 + bevacizumab were reintroduced to oxaliplatin. Conclusion By excluding 5-FU bolus administration and administering bevacizumab continuously the mFOLFOX7 + bevacizumab regimen with preplanned withdrawal of oxaliplatin showed high tolerability and prevented severe peripheral neuropathy and neutropenia without reducing efficacy.

Retrospective comparison of the efficacy and the toxicity of standard and modified FOLFIRINOX regimens in patients with metastatic pancreatic adenocarcinoma

“…This is similar to what has been reported in prospective (13,14) and retrospective studies of modified FOLFIRINOX in pancreatic cancer (16,19,20). In colorectal cancer, the omission of bolus 5-Fluorouracil has shown to improve the toxicity profile while maintaining treatment activity (21,22). Even in anatomical borderline pancreatic adenocarcinoma, a setting in which optimization of response is pursued in order to achieve R0 resections, FOLFIRINOX has been recently employed without bolus 5-Fluorouracil (23).…”

The efficacy and safety of CapeOX plus bevacizumab therapy followed by capecitabine plus bevacizumab maintenance therapy in patients with metastatic colorectal cancer: a multi-center, single-arm, phase II study (CCOG-0902)

“…In the CAIRO3 trial, a large randomized trial evaluating maintenance treatment with capecitabin plus bevacizumab, the reintroduction rate of oxaliplatin was 47% in patients receiving the maintenance therapy [14]. The overall reintroduction rates were reported 40–50% in several other studies testing intermittent use of oxaliplatin [8, 9, 11–13]. In our study, oxaliplatin was reintroduced in 55.8% of the whole cohort, and 64.4% of patients who received maintenance therapy could tolerate reintroduction, achieving a 28% objective response and 83% disease control during the reintroduction phase.…”

Evaluation of Cumulative Effects of Chemotherapy and Bevacizumab (Avastin�) in Oncological Patients with Periodontal Disease

“…Taking into account the secondary effects of oxaliplatin which manifest through neutropenia, neuropathy and thrombocytopenia [19], in combination with bevacizumab which has more secondary effects, it is possible that the general effect on the body is a cumulative one. The values of the percentages quoted in literature vary for each secondary effect in part: neutropenia between 7.8% -16.3%, neuropathy between 3.9% -18.4% and thrombocytopenia (6.1%) [20].…”