Addition of irinotecan to chemoradiotherapy as preoperative treatment for locally advanced rectal cancer (ARISTOTLE): a multicentre, open-label, phase 3, randomised controlled trial

Background Locally advanced rectal cancer is routinely treated with neoadjuvant radiotherapy. Concomitant systemic anticancer therapy with standard fluoropyrimidines has not generally improved outcomes. Small studies reported high pathological complete response rates and acceptable toxicity using irinotecan and fluoropyrimidine chemoradiation. We aimed to explore the effect of the addition of concomitant irinotecan to standard-of-care chemoradiotherapy in patients with locally advanced rectal cancer. Methods ARISTOTLE is a multicentre, open-label, parallel-design, phase 3, randomised controlled trial conducted at 75 UK hospital sites treating patients with rectal cancer. Patients were eligible if they were aged at least 18 years with MRI-defined, locally advanced rectal cancer threatening or involving resection margins without metastases. Patients were randomly assigned (1:1) to preoperative radiotherapy 45 Gy in 25 daily fractions, combined with either oral capecitabine 900 mg/m2 alone twice daily on weekdays (standard-of-care group) or oral capecitabine 650 mg/m2 twice daily on weekdays plus intravenous irinotecan 60 mg/m2 once weekly in weeks 1–4 (irinotecan group). Randomisation was done centrally, with allocation concealed to investigators; masking of patients and treating clinicians was not feasible. Stratification was by radiotherapy centre, mesorectal fascia involvement, and presence or absence of equivocal metastatic disease. The primary endpoint was disease-free survival, with analysis done on a modified intention-to-treat basis (ie, all eligible patients who were randomly assigned to treatment). Safety analyses were conducted in all patients who started protocol treatment (as-treated population). For time-to-event endpoints, patients without an event were censored at the date they were last known to be alive; missing radiological and pathological response assessments were classified as non-response. The study is registered with EudraCT, 2008-005782-59, and is complete. Findings Between Oct 25, 2011, and July 5, 2018, 589 patients were randomly assigned to treatment; after exclusions, 564 were included in the modified intention-to-treat population (284 in the standard-of-care group and 280 in the irinotecan group). 370 (66%) patients were male, 194 (34%) were female, and median age was 61 years (IQR 54–68); ethnicity data were not collected. Staging in both groups was similar: 223 (79%) patients in the standard-of-care group and 212 (76%) in the irinotecan group had mrT3 tumours; 44 (15%) and 45 (16%) had mrT4 tumours, respectively. Patients in the irinotecan group were less likely to receive 45 Gy radiotherapy than in the standard-of-care group (208 [75%] of 276 vs 251 [89%] of 283) or at least 90% of the planned capecitabine dose (187 [68%] of 276 vs 253 [89%] of 283). With a median follow-up was 78 months (95% CI 75–86), 36-month disease-free survival was 68% (95% CI 63–73) in the irinotecan group versus 67% (61–72) in the standard-of-care group (hazard ratio 0·91 [95% CI 0·68–1·23]; p=0·54). Deaths occurred in 88 (31%) patients in the irinotecan group and 92 (32%) in the standard-of-care group; rectal cancer was the leading cause, occurring in 59 (67%) patients in the irinotecan group and 67 (73%) in the standard-of-care group. There were five deaths related to protocol treatment: three in the irinotecan group (two had a thromboembolic event and one had multiorgan failure plus sepsis) and two in the standard-of-care group (one cardiac arrest and one febrile neutropenia). Grade 3 or worse were more frequent in patients receiving irinotecan than those receiving standard of care (215 [78%] vs 148 [52%]), including haematological investigations (235 [85%] vs 109 [39%]) and gastrointestinal events (57 [21%] vs 35 [12%]), notably diarrhoea (38 [14%] vs ten [4%]), lymphocyte count decreased (181 [66%] vs 100 [35%]), and neutrophil count decreased (27 [10%] vs three [1%]). Interpretation For MRI-defined, high-risk, locally advanced rectal cancer, the addition of irinotecan to standard of care did not improve outcomes and should not be used in combination with radiotherapy plus capecitabine. Funding Cancer Research UK.