In the phase III ARISTOTLE trial, adding irinotecan to preoperative capecitabine-based chemoradiotherapy did not improve disease-free survival in patients with locally advanced rectal cancer, and was also associated with substantially more severe toxicity. The findings were reported by Sebag-Montefiore et al in The Lancet Oncology.
Study Details
The multicenter, open-label, randomized phase III trial was conducted at 75 hospitals in the United Kingdom. Eligible patients were aged 18 years or older and had MRI-defined, locally advanced rectal cancer threatening or involving the surgical resection margin, without confirmed metastatic disease.
Patients were randomly assigned 1:1 to receive preoperative pelvic radiotherapy at 45 Gy in 25 daily fractions over 5 weeks with either capecitabine alone or capecitabine plus weekly intravenous irinotecan during weeks 1 through 4. The primary endpoint was disease-free survival.
A total of 589 patients were randomly assigned, and 564 were included in the modified intention-to-treat analysis: 280 in the irinotecan group and 284 in the standard-of-care group. The median age was 61 years, 66% of patients were male, and most had MRI-defined T3 or T4 tumors.
Patients receiving irinotecan were less likely to complete the planned treatment: 75% received the full 45-Gy radiotherapy dose vs 89% in the standard-of-care group, and 68% vs 89%, respectively, received at least 90% of the planned capecitabine dose.
Key Findings
After a median follow-up of 78 months, irinotecan was not associated with a significant improvement in disease-free survival. At 3 years, disease-free survival was 68% with irinotecan and 67% with standard-of-care treatment (hazard ratio [HR] = 0.91, P = .54).
Overall survival was also similar between groups, at 88% with irinotecan and 83% with standard-of-care treatment at 3 years (HR = 0.97, P = .86). There were 88 deaths in the irinotecan group and 92 in the standard-of-care group, with rectal cancer being the most common cause of death in both groups.
Pathologic complete response was also similar between groups, occurring in 19% of patients who underwent surgery in the irinotecan group and 17% in the standard-of-care group (P = .56).
Severe toxicity was substantially more common with irinotecan. Grade 3 to 5 adverse events occurred in 78% of patients in the irinotecan group compared with 52% in the standard-of-care group (P < .0001). Grade 3 to 5 gastrointestinal events occurred in 21% vs 12%, including diarrhea in 14% vs 4%. Hematologic abnormalities, including decreased lymphocyte and neutrophil counts, were also more common with irinotecan.
Five treatment-related adverse events resulted in death: three in the irinotecan group and two in the standard-of-care group. In the irinotecan group, two patients died following thromboembolic events and one from multiorgan failure with sepsis. In the standard-of-care group, one patient died following cardiac arrest and one from febrile neutropenia with acidosis.
The investigators said the findings do not support the addition of concurrent irinotecan to capecitabine-based chemoradiotherapy in this setting.
“In conclusion, the ARISTOTLE trial shows no evidence of a benefit from the addition of irinotecan to standard chemoradiotherapy in either short-term or long-term oncological outcomes,” they wrote.
David Sebag-Montefiore, FRCR, of the Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom, is a corresponding author of the article in The Lancet Oncology.
DISCLOSURE: The study was funded by Cancer Research UK. For full disclosures of the study authors, visit thelancet.com.
