Association of Physical Activity and Derived Neutrophilto-Lymphocyte Ratio with Outcome in Patients with Recurrent and/or Metastatic Squamous Cell Carcinoma of Head and Neck Treated with Immunotherapy

Research Article

Austin J Cancer Clin Res. 2021; 8(1): 1086.

Association of Physical Activity and Derived Neutrophilto-Lymphocyte Ratio with Outcome in Patients with Recurrent and/or Metastatic Squamous Cell Carcinoma of Head and Neck Treated with Immunotherapy

Pesantez D1*, Basté N1, Oberoi HK1, Castillo P2, Berenguer J3, Vilaseca I4,5 and Grau JJ1,5

1Department of Medical Oncology, Hospital Clinic of Barcelona, Spain

2Department of Pathology, Hospital Clinic of Barcelona, Spain

3Department of Neuroradiology, Hospital Clinic of Barcelona, Spain

4Department of Otolaryngology, Hospital Clinic of Barcelona, Spain

5University of Barcelona, Agusti Pi Sunyer Biomedical Research Institute (IDIBAPS), Spain

*Corresponding author: David Pesántez, Department of Medical Oncology, Hospital Clínic de Barcelona, C/ Villarroel, 170, 08036, Barcelona, Barcelona, Spain

Received: January 25, 2021; Accepted: February 27, 2021; Published: March 06, 2021


Regular Physical Activity (PA) improves the outcomes of patients with cancer mainly by enhancing the immune system. The relationship of PA and the derived Neutrophil-to-Lymphocyte Ratio (dNLR) with the evolution of 31 consecutive patients with Recurrent and/or Metastatic Squamous Cell Carcinoma of Head and Neck (R/M SCCHN) treated with immunotherapy was determined in this retrospective study.

Seventeen patients (55%) performed PA and 14 (45%) did not. The time to progression and Overall Survival (OS) was significantly better in the first compared to the second group (p=0.002 and 0.0019, respectively). In patients with a dNLR less than 3.5 the survival was significantly longer than in patients with a higher dNLR (p=0.004).

Our results suggest that there is an association between PA and improved outcomes in R/M SCCHN patients treated with immunotherapy and that the dNLR is a predictive marker of good response to treatment.

Keywords: Head and neck cancer; Physical activity; Immunotherapy; Derived neu-trophil-to-Lymphocyte ratio


Head and neck cancer is a significant global health problem, accounting for over 650,000 cases and 330,000 deaths annually [1]. Patients are usually diagnosed with locoregional disease and the mainstream treatment is surgery and/or chemoradiotherapy. Despite receiving aggressive treatment, more than 50% of patients relapse with inoperable locally advanced or distant disease. Since 2008, standard treatment in patients with R/M SCCHN has been chemotherapy based on a platinum compound combined with 5-flurouracil and cetuximab [2]. Recently, nivolumab and pembrolizumab have proven to have benefits in terms of survival in patients with platinum refractory diseases [3,4]. Durvalumab and durvalumab + tremelimumab have also shown clinical benefits in patients with R/M SCCHN and low or no PD-L1 tumour cell expression, with few differences being observed between the two. A phase 3 study on the use of these drugs is currently ongoing [5].

It has been suggested that regular PA following the diagnosis of certain solid tumours may improve treatment outcomes, reducing disease progression and mortality [6]. In-deed, several studies have suggested that regular PA can modify the tumoral microenvironment by changing the distribution of immune cells, thereby achieving better anti-tumor response [7].

Mice models of SCCHN have shown a reduced number and activity of natural killer cells following inhibition with TGF-beta-1 [8]. Additionally, lower lymphocyte counts have been found in patients with SCCHN compared to healthy controls [9], and it has been proposed that a peripheral proinflammatory state is associated with poor response in cancer patients [10,11]. In this context, the utility of the derived neutrophil-to-lymphocyte ratio (dNLR) has been explored and confirmed as a prognostic and predictive factor in relation to immunotherapy, mostly in melanoma and non-small cell lung cancer [12-14], and this biomarker has become widely available in routine clinical practice because it is inexpensive and easy to obtain.

We hypothesised that daily PA, defined as aerobic walking outdoors for 1 hour a day, could modify the balance between the innate and adaptive immune system, towards the latter, increasing response to immunotherapy in patients with R/M SCCHN. However, many patients refuse to go outside because of facial cosmetic problems or discomfort due to tracheostomy and so, are not benefiting from the possible positive effect of PA and immunotherapy treatment [3]. Therefore, the objective of this study was to establish a potential correlation between clinical and biological factors (such as PA and the dNLR) and response to immunotherapy, time-to-progression and OS in patients with R/M SCCHN.



The inclusion criteria were pathologically confirmed R/M SCCHN of the oral cavity, pharynx or larynx not amenable to curative treatment; having received anti-PD-1 or anti-PD-L1 either in routine practice or within a clinical trial; having a performance-status score of ≤2; and the absence of physical or mental limitations to perform the minimum PA required.

Treatment and assessments

Nivolumab was administered at a dose of 240mg every 2 weeks until disease progression or unacceptable toxicity. Other anti-PD-L1 or anti-PD1 drugs (durvalumab, 10mg/k or avelumab, 10mg/k) were administered according to a clinical trial protocol until disease progression or unacceptable toxicity. All patients were invited to perform daily PA consisting in walking outdoors for at least 1 hour/ day prior to initiation and during treatment with immunotherapy. Compliance with PA was registered in the medical records for further analysis. According to what the patients referred, they were assigned to Group A (correctly carried at least a 75% out the recommended PA) or Group B (they carried less than a 75% of the recommended PA). No quantitative method to define the PA was used.

All patients underwent medical examination and a complete blood test, including cell counts and serum chemistry, before each treatment infusion as a part of routine clinical practice.

The dNLR was defined as an Absolute Neutrophil Count (ANC)/ (White Blood Cells (WBC) - ANC) [10]. The dNLR was determined in all patients regardless of their PA. Tumour assessment was carried out at baseline, at week 12 and every 12 weeks thereafter, and clinical response was classified according to immune-related response criteria (iRecist) [15].

OS was defined as the time from treatment initiation to death (event) or last control of the patient. Progression-Free Survival (PFS) was defined as the time from treatment initiation to disease progression or death whichever occurred first.

Statistical analysis

Analyses of efficacy followed the intention-to-treat principle. We used descriptive statistics to define patient characteristics and used parametric and nonparametric tests to establish differences. Based on previous retrospective studies, the cut-off point for the dNLR was established at 3.5. For the univariate analysis of OS and diseasefree survival, and response duration or PFS, we used Kaplan-Meier survival curves compared with the log rank test.


Thirty-one consecutive patients treated with Immune-Checkpoint Inhibitors (ICI) were included between May 2016 and July 2017. Treatment consisted in the administration of nivolumab (n=21), durvalumab (n=9) or avelumab (n=1). The basal characteristics of the patients studied are shown in (Table 1).