Treatment with bevacizumab and FOLFOXIRI in patients with advanced colorectal cancer: presentation of two novel trials (CHARTA and PERIMAX) and review of the literature

Abstract

BackgroundMore than half of patients with colorectal cancer will develop metastatic disease either evident at the time of initial diagnosis or during their course of disease. Besides multidisciplinary management further treatment intensification is warranted to improve the still limited prognosis.Methods/designIn these two multi-centre, randomized phase II trials, conducted in Germany, 380 patients with R0-resectable colorectal liver metastases (PERIMAX) and with unresectable, metastatic colorectal cancer (CHARTA) will be recruited. Patients previously untreated for metastatic disease with either synchronous or metachronous metastases are randomly assigned in a 1:1 ratio to resection of colorectal liver metastases followed by postoperative FOLFOX for 6 months or perioperative FOLFOXIRI and bevacizumab for 3 months pre- and postoperative and resection (PERIMAX), or to induction chemotherapy with FOLFOX and bevacizumab +/− irinotecan for a maximum of 6 months followed by maintenance treatment with fluoropyrimidine and bevacizumab. The primary objective of these trials is to evaluate the feasibility and efficacy of FOLFOXIRI and bevacizumab in metastatic colorectal cancer. Primary endpoint is failure free survival rate at 18 months in the PERIMAX trial and progression free survival rate at 9 months in CHARTA. Secondary objectives include efficacy, safety and tolerability.DiscussionThe CHARTA and PERIMAX trials are designed to evaluate the benefits and limitations of a highly active four-drug regimen in distinct treatment situations of metastatic CRC. Eligible patients are classified into resectable liver metastases to be randomized to perioperative treatment with FOLFOXIRI and bevacizumab or postoperative FOLFOX in the PERIMAX, or unresectable metastatic CRC to be randomized between FOLFOX and bevacizumab with or without irinotecan, stratified for clinical groups according to disease and patients’ characteristics in the CHARTA trial.Trial registrationClinical trial identifier CHARTA: NCT01321957, PERIMAX: NCT01540435

UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice

“…These combinations have become the standard treatment options for first-and second-line treatments of mCRC and have resulted in significantly improved response rates. Triplet chemotherapies (e.g., FOLFIRINOX or FOLFOXIRI) with or without bevacizumab are also possible treatment options for progressive diseases [66,67]. The dose of irinotecan used in these combinations is unchanged as compared to chemotherapy alone, although some authors recommend using colony-stimulating growth factors.…”

Evidence-Based Medicine in Daily Surgical Decision Making: A Survey-Based Comparison between the UK and Germany

“…laparoscopic cholecystectomy, continuously evolving surgical techniques, and natural orifice transluminal endoscopic surgery, single incision laparoscopic surgery or associating liver partition with portal vein ligation for staged hepatectomy in liver resection [24]); (iii) diseases with a lack of guidelines refer to standard treatments and classifications that exist without sufficient and convincing evidence from clinical trials (e.g. sigmoid diverticulitis, suture or stapling of loop ileostomy closure, clipping or sutures in thyroid surgery, immunosuppression in patients with renal impairment or hepatocellular carcinoma after liver transplantation [25,26,27,28,29,30,31,32,33]), and (iv) complex treatment decisions in interdisciplinary oncologic settings that still reveal clinical insecurity and need clarification with clinical trials (e.g. neoadjuvant and adjuvant therapy strategies in colorectal liver metastases), but also warrant an individualized and tailored therapy.…”

New Strategies to Enhance the Efficacy of Surgical Treatment for Colorectal Liver Metastasis

“…Moreover, it has been shown that bevacizumab, combined with FOLFOX or FOLFIRI, may also be active in chemorefractory and selected mCRC patients [89]. Currently, new trials (CHARTA and PERIMAX) are being conducted with bevacizumab plus FOLFIRI, designed to assess the benefits and limitations of a highly active four-drug regimen in mCRC [4]. In addition, it is also important to note that in patients with mCRC on a bevacizumab-containing regimen who show disease progression and hence need a change in the chemotherapy regimen, maintenance therapy with bevacizumab appears to be associated with significantly longer overall survival than the same regimen without bevacizumab [90]; this fact highlights the importance of bevacizumab therapy beyond disease progression in patients with mCRC, although this use is not currently recommended outside clinical trials.…”

“…In order to obtain the best results in a systemic disease such as metastatic CRC (mCRC), the optimal integration of medical treatment and surgery is essential. The introduction of several effective cytotoxic and targeting agents, in combination with surgical treatment, has extended survival [4]. In addition, promising emerging therapies -cancer stem cell (CSC)-targeted therapies, pathway inhibitors for CRC, induction of tumour cell differentiation, improving liver regeneration, and nanoparticle (NP)-guided tumour ablation, among others-may be found to be effective in achieving better control and even complete eradication of CRC-LM.…”