LAUSR

Colorectal cancer was the third-most commonly diagnosed malignancy in Australia in 2013. It is estimated to become the secondmost common cancer in 2017 with an expected increase with age for both males and females. The management of locally advanced rectal cancer (≥T3 and/or those with clinical or pathological evidence for lymph node metastasis) represents an ongoing challenge in clinical oncology where multimodal treatment approaches are recommended, and over the last three decades significant evolutions in treatment have occurred. Historically, surgical treatment alone for locally advanced rectal cancer was associated with high rates of local and distal recurrence of up to 50%. Evolution of surgical technique with total mesorectal excision (TME) which mandates sharp dissection of the mesorectal fascia has significantly reduced local recurrence rates. Incorporation of radiation therapy in the management of locally advanced rectal cancer resulted in further reduction in the locoregional recurrence even with TME, as shown in the Dutch TME trial with 10year local recurrence rate of 5% versus 11% (P < 0.0001), although without an effect on 10-year overall survival. In 1990, post-operative 5-fluorouracil (5-FU)-based chemoradiotherapy and additional post-operative adjuvant chemotherapy were recommended as the standard of care for patients with stages II and III rectal cancer. Recently, the German rectal cancer study group demonstrated that preoperative chemoradiation therapy was superior to post-operative therapy in terms of acute and late toxicity, tumour downstaging, sphincter preservation and local control with 10-year local failure rate of only 7%. Based on this level I evidence, most oncologists now advocate preoperative chemoradiotherapy. Meta-analyses have also confirmed lower rates of local failure and higher rates of disease-free survival, as well as overall survival in patients who achieve a pathological complete response after neoadjuvant chemoradiotherapy. Achieving complete pathological response is particularly desirable in patients with threatened circumferential margin. With the aim of increasing the sensitivity to radiation therapy, fluoropyrimidines including 5-FU and the oral agent capecitabine are the most commonly used chemotherapeutic agents for preoperative chemoradiotherapy. A number of trials in the late 2000s have compared capecitabine with continuous infusion of 5-FU, and these showed that the response to capecitabine was not inferior to that achieved by 5-FU. Capecitabine is often preferred for its convenience and safety profile, but the complete pathological response rate obtained with capecitabine is only around 10–20%. In the current issue of the journal, Jootun et al. reviewed the rate of complete pathological response of oral capecitabine (42 patients) compared with infusional 5-FU (341 patients) undergoing neoadjuvant chemoradiotherapy for rectal cancer. The complete pathological response was numerically higher in the infusional 5-FU group (20% versus 9.5%) compared with the capecitabine group but the difference was not statistically significant. The authors acknowledge the possibility of failure to show significance due to the small numbers, and the likely selection bias of the oncologists to infusional therapy in more advanced cases. Nonetheless, the paper highlights the need for larger randomized trials to show noninferiority with capecitabine. Although local recurrence rates are much reduced after preoperative chemoradiotherapy, adjuvant therapy does not impact on overall survival. For locally advanced cases where the circumferential margin is threatened according to magnetic resonance imaging, adding more active chemotherapy and/or biological agents to 5-FU-based chemoradiotherapy therefore became an attractive strategy. Early phase I–II trials integrated oxaliplatin or irinotecan to 5-FU/capecitabine-based chemoradiotherapy and suggested higher complete pathological response rates when compared historically with preoperative 5-FU chemoradiotherapy alone. However, acute toxicity was increased in the combination groups. Results from five phase III trials with the addition of oxaliplatin to 5-FU (STAR-01, ACCORD 12, NSABP-R04, German AIO-4 and PETACC-6) did not confirm a significant improvement of early end points such as complete pathological response rate. More importantly, the local recurrence rate, disease-free survival and the overall survival were not significantly different with or without the addition of oxaliplatin. The addition of cetuximab (anti-epidermal growth factor receptor agent) with capecitabine and irinotecan also failed to show any substantial clinical benefit. It is clear that many questions remain unanswered; several treatment strategies are being validated including neoadjuvant chemotherapy alone, induction and consolidation chemotherapy before or after 5-FU chemoradiation and the use of different targeted agents as antiangiogenic agents in combination with chemoradiotherapy.