Circulating Markers of Systemic Inflammation, Measured After Completion of Neoadjuvant Therapy, Associate With Response in Locally Advanced Rectal Cancer.

Background: The extent of neoadjuvant therapy response, prior to surgery, is an important prognosticator in locally advanced rectal cancer. A spectrum of response exists, with a dearth of reliable measurements. The host response to treatment remains unexplored. Within operable colorectal cancer, circulating markers of elevated systemic inflammation associate with poor survival. Studies have suggested that elevated pre-neoadjuvant inflammatory markers, including the modified Glasgow prognostic score and the neutrophil:lymphocyte ratio, associate with poorer response.

Objective: This study aimed to comprehensively evaluate hematological markers of inflammation pre- and post-neoadjuvant therapy.

Design: Longitudinal cohort study.

Settings: Single health board from a prospectively maintained regional cancer database.

Patients: Consecutive locally advanced rectal cancer patients who underwent curative-intent neoadjuvant therapy between; June 2016-July 2021.

Main Outcome Measures: Elevated markers of the systemic inflammatory response pre- and post-neoadjuvant therapy.

Results: A total of 278 patients (67.3% male, median age 65) were identified. A complete response (clinical or pathological complete response) was achieved in 27.34%, and good tumor regression was achieved in 37.05% (tumor regression grading 0-1). No pre-neoadjuvant marker associated with response or regression. Multivariate analysis of post-neoadjuvant variables revealed an elevated modified Glasgow prognostic score (OR 2.8, 95% CI: 1.22-6.41, p = 0.015), and an elevated carcinoembryonic-antigen (OR 4.09, 95% CI: 1.6-10.44, p = 0.003) independently associated with incomplete response. An elevated post-neoadjuvant modified Glasgow prognostic score (OR 2.14, 95% CI: 1.08-4.23, p = 0.029) also independently associated with poor tumor regression on multivariate analysis.

Limitations: Retrospective design. Slight variation in the timing of post-neoadjuvant blood tests.

Conclusions: We report that post-neoadjuvant modified Glasgow prognostic score associated with poorer response and regression, potentially indicating that radiation resistance is associated with the development of a protumor inflammatory environment. Further work is required to define the local intratumoral processes associated with response and their inter-relationship with systemic parameters. Ultimately, there may be a rationale for testing anti-inflammatory strategies in combination with radiotherapy as an option for optimizing treatment response. See Video Abstract.