Dose-intense capecitabine, oxaliplatin and bevacizumab as first line treatment for metastatic, unresectable colorectal cancer: a multi-centre phase II study

Colorectal cancer (CRC) is the second most incident solid tumour and the second leading cause of cancer-related death worldwide with over 1.2 million new cancer cases and 608,700 deaths estimated to have occurred in 2008 [1]. Due to an increasing incidence in developing countries as well as an aging population structure, the burden of colorectal cancer will continue to rise despite reductions in mortality in western countries [2]. With the use of chemotherapy and targeted agents for stage 4 disease, median overall survival has increased from 6 months with supportive care alone to over 20 months. The monoclonal antibody against vascular endothelial growth factor, bevacizumab (Avastin, Roche), improved progression-free and over-all survival when combined with IFL chemotherapy [3], and increased progression-free survival with a non-statistically significant increase in overall survival when combined with oxaliplatin based chemotherapy [4] and has been widely adapted as a standard component of first line therapy.

Capecitabine is an oral pro-drug of 5-fluorouracil, which in combination with Oxaliplatin (CapOx) has similar efficacy to the reference regimen FOLFOX-4, and obviates the need for a central venous access device and so is more convenient. Studies comparing CapOx in combination with bevacizumab have demonstrated similar PFS and overall survival to FOLFOX4-Bevacizumab [4, 5]. However up to 20% of patients receiving CapOx experienced grade 3/4 diarrhoea [5‐8] hence toxicity improvements in this schedule that maintain or improve efficacy are required.

The standard CapOx regimen is given on a 21-day cycle, with oxaliplatin 130 mg/m²iv on Day 1 and capecitabine 1000 mg/m² PO BD on days 1–14. Mathematical modelling as well as pre-clinical studies in breast cancer mouse xenografts have indicated that a dose-dense regimen of 7 days treatment with capecitabine followed by 7 days rest may result in a higher maximum tolerated dose being achieved [9]. Other groups have investigated the use of dose-dense capecitabine with oxaliplatin [10], adopting a two-weekly cycle with oxaliplatin 85 mg/m² on Day 1, and a 7 day administration of capecitabine. In a dose escalation study using this 7/7 schedule, a maximum tolerated dose of capecitabine was reached at 1750 mg/m² PO BDd1-7. The effective daily dose of capecitabine in a 21 day schedule is 1333 mg/m²/day, whereas in the 14 day schedule using 1750 mg/m² the daily dose received of capecitabine is 1750/m²/day – a 30% increase in total capecitabine delivered.

In the follow-on phase II trial [11] 89 patients were randomised to receive either dose-intense CapOx or a standard 21 day regimen. Those allocated to the dose intense arm had a significantly longer median progression-free survival time than those in the control arm (10.5 v 6.0 months; HR 2.15: 95% CI 1.43 to 4.35; p = 0.0013). In addition, there were comparable rates of haematological and non-haematological toxicities, and only 12% Grade 3/4 diarrhoea observed in the dose-dense arm.

Given that the addition of bevacizumab to chemotherapy appears to improve PFS, and that dose-dense chemotherapy may improve efficacy, we considered that dose-intense CapOx with bevacizumab warranted exploration. We undertook a phase II study to determine the feasibility and safety of a dose-intense capecitabine and oxaliplatin schedule with bevacizumab for patients with previously untreated advanced colorectal cancer.

This national, multicentre, open-label, single arm, phase II clinical trial had the primary objective of determining the feasibility and safety of a dose-dense Capecitabine-Oxaliplatin-Bevacizumab regimen. Feasibility was determined by dose delivery, measured by the proportion of patients who received at least 75% of the planned dose for the first two cycles. Safety was measured according to Common Toxicity Criteria for Adverse Events v3.0. Secondary end-points included radiologic response rate, progression free survival and overall survival. The trial was approved by the Multi-Region Ethics Committee (MEC/06/04/041). The study was registered as ISRCTN41540878.

Combination chemotherapy with capecitabine is a convenient alternative to infusional regimens with preserved efficacy, and dose-intense chemotherapy may result in greater dose delivery and enhanced efficacy over 21 day schedules. At the time of study inception, we were not aware of any published reports of a dose-intense capecitabine-oxaliplatin schedule combined with bevacizumab.

Norton-Simon mathematical and pre-clinical models of capecitabine administration in breast cancer mouse xenografts have indicated that a 7 day treatment schedule followed by a seven day rest (7/7 schedule) may result in a higher maximum tolerated dose of capecitabine being achieved, with lower toxicity [9]. A phase 1 trial of capecitabine monotherapy in breast cancer found this 7/7 schedule was well tolerated with 1/21 patients experiencing grade 3 diarrhoea [14]. A subsequent phase 2 study of fixed-dose capecitabine 2000 mg/PO/BD 7/7 combined with bevacizumab 10 mg/kg q14d had activity and reported 0% grade 3/4 diarrhoea [15]. A randomised phase 2 study containing 89 patients compared standard CapOx (Cap1000 mg/m2/BD d1-14 q21d; Ox130 mg/m2 d1 q21d) with dose intense CapOx (Cap 1750 mg/m2/BD d1-7, Ox85 mg/m2/d1; q14d) and reported a higher confirmed radiological response rate (54.5% v 42.2%) and longer PFS (10.5 v 6.0 months, p = 0.0013) favouring the dose intense schedule. Grade 3/4 diarrhoea rates were reported as 9 and 12% for the standard and dose intense arms respectively [11]. Reported rates of grade 3/4 diarrhoea of have been reported with three weekly CapOx-B regimens [16]. This contrasts with the results of a randomised phase 3 study, published following the completion of our study, of 435 patients of patients with advanced colorectal cancer, comparing 21 day Capecitabine with Oxaliplatin (Capecitabine 850 mg/m2/BD d1-14 q21d; Oxaliplatin 130 mg/m2 IV d1 q21d) to a 14 day schedule with increased dose capecitabine (Cap 1500 mg/m2/BD d1-7 q14d,Oxaliplatin 85 mg/m2 IV d1 q14d). This study showed the dose-intense regimen had a non-significantly shorter PFS compared to the standard regimen (8.4 months v 9.7 months; hazard ratio [HR] = 0.84; 95% CI = 0.62-1.13). Patients in the dose intense group experienced higher rates of grade 3/4 diarrhoea (29% vs 24%), hand-foot syndrome (12% vs 8%), and treatment discontinuation rates (40% vs 20%) [17]. A summary of studies of dose-intense regimens is described in Table 5.

Our study tested a dose of Capecitabine at the upper range of doses previously tested, with the addition of bevacizumab. Our observed rate of 23% G3/4 diarrhoea is comparable to other studies of Capecitabine-based doublets. Indeed our overall grade 3/4 adverse event rate of 74% is comparable to the 80% grade 3/4 adverse event rate for FOLFOX4/CapOx-Bev arms seen in the NO16966 study [6]. However the 3 deaths represented unacceptably high toxicity, and we observed more perforations than seen in the NO16966 study. The overwhelming diarrhoea that resulted in the death of one patient happened after 7 days of therapy, suggesting that there may have been underlying DPD deficiency, and this death may not have been attributable to the dose-intense schedule. One of the deaths was from tumour site perforation that was deemed treatment-related. In the BEAT study, a phase 4 study of bevacizumab 5 mg/kg (biweekly regimens) or 7.5 mg/kg (3-weekly regimens) in combination with FOLFOX, CapOx (18% of patients), FOLFIRI or 5-FU, tumour site perforation occurred in 3 of 223 patients with unresected colorectal cancers, indicating that this is a rare event [18]. The rates of perforation in our study were higher than seen in other studies. This may be either a chance finding or due to an interaction with this schedule. With these events our study could not demonstrate safety of the dose-intense CapOx-Bev regimen.

The response rate in the C1750 group was similar to other 5-FU-Oxaliplatin-Bevacizmab regimens and may have been higher if confirmatory scans were completed at 4 weeks instead of 8. The response rate was lower at the reduced dose of capecitabine, however the study was not powered to compare the response rate between dose levels. The median PFS and OS of seen in our study are similar to other reported regimens. Our data are similar to the phase III trial published recently [17], with lower response rates than in the initial phase II studies, suggesting difficulty translating studies in more selected small groups of patients to the more general phase 3 population, even when performance status was relatively good. It is also noted that the eligible patients did not have resectable disease and were at the worse end of the spectrum for metastatic/recurrent disease.

The cluster of adverse events, particularly perforation and toxic death reminiscent of DPD deficiency may have been due to chance occurrence or may have been due to the toxicity of a dose intense regimen. A phase one design with a smaller population may not have detected these events, whereas a larger, randomised study may have balanced events between arms (if the adverse events are due to chance). These factors are limitations of a single-arm phase 2 design study.

The primary endpoint of the study was safety and feasibility as measured by the proportion of patients who received at least 75% of the planned dose for the first two cycles. Whilst this was achieved for 80% of participants, the toxicity over the course of treatment was too great. Despite preclinical modelling and two other studies of similar dose-intense regimens showing possible enhanced efficacy with acceptable toxicity, we could not demonstrate this with our regimen. We conclude that dose intense CapOx-Bev should not be used outside of clinical studies.