Higher tumor cell density in patients with locally advanced rectal cancer receiving irinotecan-intensified neoadjuvant chemoradiotherapy was associated with improved survival outcomes compared with those treated with standard chemoradiotherapy, according to findings from a post-hoc analysis of the phase III ARISTOTLE trial that was published in eBioMedicine.
“While the original trial showed little benefit from adding irinotecan, by using artificial intelligence (AI) we found that we could distinguish patients who actually benefitted from those who did not. This demonstrates how AI can reveal tumor biology that is difficult to measure consistently by conventional means, and hopefully can be used to reveal additional insights that could lead to future treatments,” said lead author Zhuoyan Shen, PhD, a research fellow in the Department of Medical Physics and Biomedical Engineering at University College London (UCL).
Background and Study Methods
Researchers developed a computational approach to quantifying tumor cell density within epithelial and stromal regions of tumors, and to assess if a response to treatment differs by tumor cell density status among patients with locally advanced rectal cancer who were receiving neoadjuvant chemoradiotherapy. The team developed a free online tool, called Octopath, where clinicians can upload biopsy slides to be analyzed.
In the post-hoc analysis, patients with available digitized pretreatment biopsies came from the multicenter, open-label, randomized controlled phase III ARISTOTLE trial, which evaluated adding irinotecan to chemoradiotherapy as preoperative treatment for patients with locally advanced rectal cancer.
Tumor cell density was defined as the proportion of tumor cells in the tumor and stroma tissues. Tumor cell density was quantified with an AI framework that assessed digitized haematoxylin and eosin-stained whole-slide images.
Patients were stratified by low or high tumor cell density with a cut-off value of 0.5 (50% of tumor cells). Tumor cell density status was combined with the treatment arms to stratify response and survival.
Key Findings
Forty-five percent of the participants were considered tumor cell density–high.
A treatment–tumor cell density interaction was observed for disease-free survival (x2 = 6.88; P = .009) and overall survival (x2 = 10.61; P = .001), which was considered significant for both.
Among patients with high tumor cell density, the addition of irinotecan to capecitabine and radiotherapy was associated a prolonged disease-free survival (hazard ratio [HR] = 0.57; 95% confidence interval [CI] = 0.36–0.90; P = .014), overall survival (HR = 0.50; 95% CI = 0.30–0.84; P = .008), and higher pathological complete response rates of 23% vs 11% (odds ratio [OR] = 2.46; 95% CI = 1.01–5.98; P = .042 [P = .13 after adjustment for multiple testing]) vs standard capecitabine and radiotherapy.
In the low tumor cell density group, on the other hand, no significant difference was observed in disease-free survival between the treatment arms (HR = 1.29; 95% CI = 0.85–1.95; P = .22). Additionally, patients in the investigational treatment arm who had low tumor cell density showed a trend toward worse overall survival (HR = 1.55; 95% CI = 0.96–2.51; P = .07). No significant difference was noted in pathologic complete response rates either (14% vs 22%; OR = 0.60; 95% CI = 0.28–1.29; P = .19).
“Intensifying already taxing treatments puts additional strain on patients suffering from cancer. Clinicians need reliable ways to identify who is most likely to benefit before such treatments begin so potential side effects are avoided. Our findings show that doctors assisted by AI can pinpoint which patients will likely benefit from the more intensive treatment before it begins,” said senior author Maria A. Hawkins, MD, MCRP, FRCR, a consultant clinical oncologist and Professor of Radiation Oncology, Department of Medical Physics and Biomedical Engineering, UCL.
DISCLOSURES: Cancer Research UK Radiation Research Network - Project Seed Funding, Cancer Research UK ARISTOTLE sample collection grant, UK Research and Innovation Future Leadership Fellowship and the Radiation Research Unit at the Cancer Research UK City of London Centre Award. For full disclosures of the study authors, visit thelancet.com.
