Neoplasia-related and treatment-induced lymphopenia: impact on the outcome of chemoradiotherapy in laryngeal cancer

Abstract

Introduction

The role of the immune system in the efficacy of radiotherapy (RT) has been well established. We examined the role of neoplasia-related and treatment-induced lymphopenia in the outcome of RT or chemoradiotherapy (CRT) in squamous cell laryngeal cancer.

Materials and Methods

We retrospectively analyzed a series of 135 laryngeal carcinomas treated with radical or postoperative RT/CRT. Six lymphocyte-related variables were defined and examined: i. lymphocyte counts (LCs) before a brief course of induction chemotherapy, ii. pre-RT LCs, iii. post-RT LCs, iv. pre-RT neutrophil/lymphocyte ratio (N/L), v. pre-RT monocyte/lymphocyte ratio (M/L), and vi. pre-RT platelet/lymphocyte ratio (Pt/L).

Results

RT and CRT resulted in a significant decrease of LCs at the end of therapy, and this was significantly more prominent in patients treated with radical intent and neck irradiation (median LC nadir 810/μl vs. 1250/μl; p = .0003). Induction chemotherapy did not intensify the lymphotoxic effect of RT. LCs lower than the 33^rd percentile before RT (<1718/μl) and after RT (<720/μl) were significantly linked to poor locoregional progression-free survival (LRFS; p = .02 and p = .08, respectively) and disease-specific overall survival (OS; p = .02 and p = .03, respectively). This was also confirmed multivariate analysis (LRFS: p = .006/HR = 2.41 and p = .08/HR = 1.76, respectively; OS: p = .001/HR = 3.06 and p = .02/HR = 2.07, respectively). High pre-RT N/L, M/L, and Pt/L ratios were also of ominous prognostic relevance.

Conclusions

Both neoplasia-related and RT-induced lymphopenia define the outcome of RT in terms of locoregional failure, incidence of metastasis, and, finally, disease-specific survival of patients with laryngeal cancer. Restoration of pre-RT lymphopenia and protection of peripheral lymphocytes during RT emerge as critical issues that demand therapeutic interventions to maximize the efficacy of RT/CRT in patients with laryngeal cancer.

Keywords:

• Laryngeal cancer
• lymphopenia
• radiotherapy
• chemotherapy
• prognosis

Ethical approval

The study has been approved by the local Ethics and Research Committee (SD7/26-2-04, SD36/34/28-9-06, and ES1/23-01-19). The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent to enter the trial was obtained from all patients before therapy. Patients’ consent included permission to publish anonymously their clinical and laboratory data for research and educational purposes.

Authors’ contributions

All authors contributed to the study’s conception and design. MIK supervised the study and was responsible for the treatment of patients. IMK and AGG were responsible for the material preparation and data collection. IMK performed analysis and first draft preparation. AG supervised the study and was responsible for diagnosing patients. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data reported in the study are available in patients’ files kept in the Department of Radiotherapy/Oncology of the Democritus University of Thrace.

Additional information

Funding

The study did not receive any financial support.

Notes on contributors

Ioannis M. Koukourakis

Ioannis M. Koukourakis, MD, is a Radiation Oncology resident at Aretaieion University Hospital and a PhD candidate at the National and Kapodistrian University of Athens. His research interests focus on the interactions between radiotherapy and the immune system.

Anastasia G. Gkegka

Anastasia G. Gkegka, MD is Pathology resident at the Department of Pathology and at the Medical School, Democritus University of Thrace, and a PhD candidate. Her research interests focus on the immune response in head and neck cancer.

Alexandra Giatromanolaki

Professor Alexandra Giatromanolaki is head of the Department of Pathology and the Tumor Immunology Unit at the Medical School, Democritus University of Thrace. Her research focuses on translational studies for developing tumor biomarkers related to prognosis and response to cytotoxic therapy and immunotherapy. Her published research is available at https://pubmed.ncbi.nlm.nih.gov/?term=Giatromanolaki+A

Michael I. Koukourakis

Professor Michael I. Koukourakis is Head of the Department of Radiotherapy/Oncology at the Medical School, Democritus University of Thrace, and Head of the Molecular Radiobiology Unit. His research interests focus on tumor resistance to radiotherapy, hypoxia, tumor metabolism, and immune response. His published research is available at https://pubmed.ncbi.nlm.nih.gov/?term=koukourakis+M