Colorectal cancer (CRC) is the second most commonly diagnosed cancer in Australia, with 14300 new cases and 4047 deaths (2,191 males; 1,856 females)  recorded in 2007. It is projected that 19000 new cases of CRC will be diagnosed, in Australia, in 2020 . Approximately 25% of patients present with metastatic CRC (mCRC) at initial diagnosis and another 25% will develop subsequent metastases . Treatment outcomes have improved significantly in the last decade as a result of the introduction of new systemic treatments and the expanded use of hepatic metastatectomy; with median survivals now well in excess of two years .
For the majority of patients diagnosed with mCRC palliative chemotherapy is the most appropriate treatment option in order to achieve the goals of prolonging survival and improving quality of life (QoL). The backbone of first- and second-line palliative chemotherapy for mCRC consists of a fluoropyrimidine (infusional 5-FU or oral capecitabine) based therapy in various combinations and schedules. Combination chemotherapy with fluoropyrimidine/oxaliplatin (FOLFOX or XELOX) or 5-FU/LV/irinotecan (FOLFIRI) provides higher response rates, longer progression-free survival (PFS) and better overall survival (OS) than a fluoropyrimidine alone. Both FOLFOX/XELOX and FOLFIRI have similar efficacy regardless of the sequence used but have different toxicity profiles . Favorable survival has been shown to correlate with the percentage of patients receiving all active chemotherapeutic agents, emphasizing the importance of exposure to all active drugs during treatment .
The use of bevacizumab in combination with fluoropyrimidine-containing chemotherapy is a well-established first-line and second-line treatment for patients with mCRC [7–13]. Despite this, a number of data gaps remain to be addressed, notably, the need for reproducible, validated, inexpensive and easy to administer prognostic biomarkers to aid in treatment selection. The optimal treatment duration and the role of bevacizumab in certain patient subgroups, specifically those considered at particular risk of bevacizumab-mediated toxicity, also require further investigation.
An increasing proportion of patients with mCRC at first presentation are treated with systemic chemobiologic therapy without pre-emptive resection of the primary tumour. Limited data currently exist to guide treatment decisions in this setting and uncertainty exists around the risk/benefit of bevacizumab-based treatment in patients with a primary in situ tumour [14–16]. Although the recent NSABP C-10 trial contributed important data regarding bevacizumab use in the setting of an asymptomatic colonic primary tumour , similar studies have not yet been undertaken in patients with a minimally symptomatic primary colon cancer or those with an in situ primary rectal cancer. It is therefore necessary to further study the safety and effectiveness of bevacizumab in the setting of an in situ primary rectal lesion.
A wealth of preclinical models support the notion that vascular endothelial growth factor (VEGF) is continually expressed throughout the lifecycle of the tumour and that sensitivity to anti-VEGF therapy remains even after disease progression . The continuation of bevacizumab after disease progression on bevacizumab-based first-line treatment (bevacizumab beyond progression or BBP) is common practice in countries such as the United States . Multivariate analyses from two large observational cohort studies (BRiTE and ARIES registries) [19, 20] suggest that BBP is an independent predictor of prolonged survival in mCRC. Although the use of BBP has been addressed in a recently published, randomized phase III trial (ML18147) , this study was not open in Australia and did not collect data on QoL.
Biomarkers play an increasingly important role in both cancer research and clinical practice. They can be used to assess prognosis and to predict how individual patients will respond to specific treatments [22, 23]. Despite concerted international research efforts, there has not yet been a validated and easy to administer biomarker to predict treatment outcomes for patients treated with bevacizumab. A broad range of blood- and tumour tissue-based markers have been explored during the development phase of bevacizumab (preclinical > 10,000; clinical > 100) with most of the existing data focused on VEGF pathway markers, including tumour VEGF expression , or oncogene mutations such as K-Ras [25, 26]. Relatively little attention has been paid to the role of biomarkers associated with the tumour microenvironment and host factors such as the inflammatory response. Both the tumour microenvironment and the inflammatory response are considered key aspects of cancer biology and tumourigenesis  and are important regulators of angiogenesis. Infiltration of small tumours by inflammatory cells that produce proangiogenic ligands makes a contribution to the angiogenic switch that drives tumour growth. Tumour development and progression induced by an inflammatory response is thought to be mediated by pro-inflammatory cytokines stimulating pathways especially those mediated by the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the Signal transducer and activator of transcription 3 (STAT3) . Given the established link between systemic inflammation and tumour angiogenesis the potentially valuable role of inflammatory markers as predictive or prognostic tools in the setting of bevacizumab is of interest. The use of blood-based inflammatory markers such as neutrophil/lymphocyte ratio (NLR) as prognostic/predictive biomarkers in patients receiving bevacizumab-based chemotherapy has not yet been evaluated.
Elevated NLR (> 5) has been shown to be predictive of diminished survival in patients with liver-only colorectal metastases receiving neo-adjuvant chemotherapy prior to hepatic metastectomy . Patients in whom NLR normalised after chemotherapy had significantly improved 1-, 3- and 5-year survival which was similar to patients with NLR ≤ 5 at baseline . More recently, a study by Chua et al. demonstrated an elevated NLR, pre-treatment, in patients with unresectable mCRC, in approximately 30% of patients. In this patient cohort, who underwent first-line combination chemotherapy, NLR was found to be an independent predictor of clinical benefit, progression and survival. The NLR was statistically significantly associated with overall survival (P < 0.0001). Patients with NLR ≤ 5 had median overall survival of 19.1 months (95% CI 15.3–22.8) compared with patients with NLR > 5 (11.3 months; 95% CI 8.3–14.3). In addition, normalization of the NLR after one cycle of chemotherapy was associated with improved progression free survival.
The primary objective of this study (NCT01588990; ML25753) is to validate and quantify the prognostic value of the host inflammatory response as assessed by the NLR on Progression Free Survival. Secondary objectives include firstly, investigating the relationship further in light of other clinical and biological markers; secondly, providing clinically relevant information regarding the safety, effectiveness and QoL outcomes prior to, and after, progression. Patients will be treated with bevacizumab in combination with standard chemotherapy regimens in a generalized, community-based population of mCRC patients. The study has started recruitment in 16 centres around Australia.