Front-line Bevacizumab in combination with Oxaliplatin, Leucovorin and 5-Fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study.(Research article)(Drug overview)(Clinical report)

Authors: Christos Emmanouilides [1]; Georgia Sfakiotaki [2]; Nikolaos Androulakis [2]; Kostas Kalbakis [2]; Charalambos Christophylakis [3]; Antonia Kalykaki [2]; Lambros Vamvakas [2]; Athanasios Kotsakis [2]; Sofia Agelaki [2]; Eleni Diamandidou [1]; Nikolaos Touroutoglou [1]; Adam Chatzidakis [4]; Vassilis Georgoulias [2]; Dimitris Mavroudis [2]; John Souglakos (corresponding author) [2]

Background

Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide [1] accounting for 8% of all malignant tumors in adults [2]. Despite that macroscopically curative surgical resection is possible in 70-80% of patients at diagnosis, almost half of them will develop local or/and metastatic recurrence and will die of the disease.

Although, historically, chemotherapy was used for palliation of symptoms, during the last few years the median overall survival of patients with advanced CRC has been substantially increased from 12 months to about 21-22 months when all of the available chemotherapeutic agents are administered [3]. Therefore treatment of metastatic colorectal cancer (mCRC) has changed considerably in the recent years. Combinations of 5-fluorouracil/Leucovorin (5-FU/LV) containing both bolus (Roswell Park) and infusional administration (De Gramont schedule) combined with a second active drug, either irinotecan [4] or oxaliplatin are accepted as the mainstay of first-line treatment, while the choice of a particular drug to combine with 5FU does not influence overall survival[5].

The advent of targeted therapy further expanded treatment options for patients with mCRC. In particular, inhibition of angiogenesis by blocking Vascular Endothelial Growth Factor (VEGF) using the monoclonal antibody bevacizumab led to further improvement in the outcome of patients with mCRC. Indeed, randomized studies demonstrated that the addition of bevacizumab to either 5FU/LV [6, 7, 8], or to an Irinotecan-5FU/LV combination (IFL) [9] as first-line treatment of mCRC was associated with improved objective response rate, time to tumor progression and overall survival.

During the last years, the IFL regimen (weekly irinotecan and IV push administration of 5FU and LV) no longer represents the gold standard of front line treatment of mCRC and it was replaced by the combinations of irinotecan or oxaliplatin with the infusional 5-FU regimens (FOLFIRI and FOLFOX, respectively) [10, 11]. A recent study (E3200) [12] demonstrated that the addition of bevacizumab improved the activity of second-line oxaliplatin-containing combination in patients with mCRC. However in this study the effect of the combination on survival and response rate was modest, reflecting the more advanced stage of the disease in such patients.

Since there was no information concerning the efficacy and tolerance of the combination of FOLFOX4 plus bevacizumab as front line treatment of patients with mCRC, the Gastrointestinal (GI) Working Group of the Hellenic Oncology Research Group (HORG) decided to conduct this multicenter phase II study.

Methods

Eligibility criteria

Chemotherapy na�ve patients, aged [greater than or equal to] 18 years with histologically documented mCRC were enrolled; other eligibility criteria included: patients who had received prior adjuvant 5-FU-based chemotherapy were eligible if they had remained free of disease for at least 6 months after the completion of adjuvant therapy; performance status (ECOG) 0-2; at least one bidimensionally measurable lesion of [greater than or equal to] 2 cm; a life expectancy of at least 3 months; adequate hematologic parameters (absolute neutrophil count [greater than or equal to] 1.5 x 10

9 /L and platelets [greater than or equal to] 100 x 109 /L); creatinine and total bilirubin [less than or equal to] 1.25 times the upper limit of normal; aspartate and alanine aminotransferases [less than or equal to] 3.0 times the upper limit of normal; absence of active infection or malnutrition (loss of more than 10% of body weight); absence of a second primary tumor other than non-melanoma skin cancer or in situ cervical carcinoma; patients receiving palliative radiotherapy had to have measurable metastatic disease outside the irradiation fields.

Patients with operable metastatic disease, clinically significant cardiovascular disease or major surgery within one month prior to study registration were excluded from the study. Other exclusion criteria included: pregnancy or lactation, regular use of aspirin (more than 325 mg per day) or other …