Leukocytosis and neutrophilia as independent prognostic immunological biomarkers for clinical outcome in the CAO/ARO/AIO‐04 randomized phase 3 rectal cancer trial

Abstract

Peripheral blood leukocytosis and neutrophilia reflect cancer inflammation and have been proposed as prognostic immunological biomarkers in various malignancies. However, previous studies were limited by their retrospective nature and small patient numbers. Baseline peripheral blood leukocytes, neutrophils, hemoglobin, platelets, lactate dehydrogenase and carcinoembryonic antigen (CEA) were correlated with clinicopathologic characteristics, and clinical outcome in 1236 patients with rectal cancer treated with 5‐FU‐based preoperative chemoradiotherapy (CRT) alone or with oxaliplatin followed by surgery and adjuvant chemotherapy within the CAO/ARO/AIO‐04 randomized phase 3 trial. Multivariable analyses were performed using Cox regression models. After a median follow‐up of 50 months, baseline leukocytosis remained an independent adverse prognostic factor for disease‐free survival (DFS; HR 1.457; 95% CI 1.163–1.825; p = 0.001), distant metastasis (HR 1.696; 95% CI 1.266–2.273; p < 0.001) and overall survival (OS; HR 1.716; 95% CI 1.264–2.329; p = 0.001) in multivariable analysis. Similar significant findings were observed for neutrophilia and high CEA levels. Conversely, treatment‐induced leukopenia correlated with favorable DFS (p = 0.037), distant metastasis (p = 0.028) and OS (p = 0.012). Intriguingly, addition of oxaliplatin to 5‐FU CRT resulted in a significant DFS improvement only in patients with neutrophilia and leukocytosis (p = 0.028 and p = 0.002). Our findings have important clinical implications and provide high‐level evidence on the adverse prognostic role of leukocytes and neutrophils, and the impact of chemotherapy in the context of these biomarkers. These data could help guide patient stratification and should be further validated within prospective studies.

Neutrophil-to-Lymphocyte Ratio in Rectal Cancer—Novel Biomarker of Tumor Immunogenicity During Radiotherapy or Confounding Variable?

“…Liu et al found an association between absolute number of systemic lymphocytes and pathologic response; furthermore, they showed that a higher peripheral lymphocyte count was associated with a higher infiltration of CD4+ and CD8+ cells into the tumor [18]. Likewise, an effective local or systemic treatment of tumors leads to a decline of systemic inflammatory markers, so that a link between tumor mass and the degree of systemic inflammatory response, which our data emphasize, seems reasonable [19,29,30,31,32]. The knowledge of this association is important for the interpretation of the study results and the design of translational studies that investigate the underlying mechanisms.…”

The clinical value and usage of inflammatory and nutritional markers in survival prediction for gastric cancer patients with neoadjuvant chemotherapy and D2 lymphadenectomy

“…Until now, only few studies concerned the issues about how were the inflammatory markers changed, and what were the impacts of the changes on the prognosis. According to the study [22] related to rectal cancer, the treatment-induced leukopenia correlated with a favorable OS; however, when it came to Lym, there was contradictory result reported [23]. Another study [24] related to gastric cancer revealed that the NACT had different effects on Lym depending on the subgroups.…”

Neutrophil-Lymphocyte Ratio and Circulating Tumor Cells Counts Predict Prognosis in Gastrointestinal Cancer Patients

“…Neutrophils are major inflammatory constituents of TME, which can facilitate the growth and development of tumor by different mechanisms (24,25). Diefenhardt et al (26) found that leukocytosis and neutrophilia tended to predict the poor clinical outcome. Meanwhile, the variation of lymphocytes often related to virus infection, as the center of immune response.…”