Correlation between hematological parameters and PET/CT metabolic parameters in patients with head and neck cancer

Radiotherapy (RT) is the standard of care for most patients with head and neck squamous cell carcinoma (HNSCC) treated definitively or adjuvantly. Besides the effects of RT through direct or indirect deoxyribonucleic acid damage, RT can also induce antitumor immune responses that contribute to indirect tumor cell killing [1, 2]. Several studies have demonstrated that tumor-infiltrating lymphocytes (TILs) are present in the tumor microenvironment in various malignant tumors [3‐5]. In oropharyngeal carcinoma, TILs can identify stage I human papillomavirus (HPV)-associated patients likely to be poor candidates for treatment de-escalation [6]. In non-small-cell lung carcinoma (NSCLC), studies have shown that the tumor microenvironment correlates with ¹⁸F-fluorodeoxyglucose (FDG) positron-emission tomography/computed tomography (PET/CT) metabolic parameters (MPs) [7]. The therapeutic potential of radioimmunotherapy in HNSCCs is as vast as the tumor microenvironment of HNSCCs is complex [8]. This field awaits results from ongoing clinical trials providing immunological and genomic analyses from radioimmunotherapy trials, hopefully revealing information on tumor behavior and therapeutic options [8]. The expression of programmed cell death ligand-1 (PD-L1) by tumor cells and TILs have been proposed as promising prognostic biomarkers for response to immunotherapy in HNSCCs [9, 10]. In NSCLCs, Wang et al. showed an association between FDG-PET/CT-MPs and immune cell expression in the tumor microenvironment [7]. This association suggests that PET/CT-MPs could be potential predictors for selecting immunotherapy candidates for treatment with anti-programmed cell death-1/PD-L1 antibodies [7, 11]. Systemic inflammation is also correlated with cancer prognosis. Many lines of evidence indicate that markers of systemic inflammation are independent prognostic factors for survival in many malignancies [5, 12‐17]. The neutrophil–lymphocyte ratio (NLR) is one such commonly used marker that has been reported as a prognostic factor [16‐18]. Since the correlation between systemic inflammation and tumor microenvironment has been described [7] and owing to the scarcity of retrospective data as well as relevant literature concerning interactions between the tumor microenvironment and MPs derived from FDG-PET/CT in HNSCC, we aimed to evaluate correlations between readily available markers of host inflammation with PET/CT-MPs in patients with nonmetastatic HNSCC before definitive treatment such as surgery followed by adjuvant radio(chemo)therapy or definitive radio(chemo)therapy alone. As described in other tumor entities, e.g., breast [19] and lung cancer [7], we hypothesized that NLR and platelet-to-lymphocyte-ratio (PLR) at baseline are positively correlated with PET/CT-MPs such as standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor.

A total of 189 patients were identified, of whom 118 patients (62%) were excluded. Of these, 105 were excluded because no pretreatment PET/CT was available. In 12 patients, the PET/CT scan was obtained after surgery. The remaining patient received induction chemotherapy before his PET/CT scan. Thus, a total of 71 patients with a pathologically proven diagnosis of oral cavity, oropharyngeal, hypopharyngeal, or laryngeal cancer were eligible and included for analysis. Eight patients underwent postoperative treatment, 6 of them being OCC patients having the standard of care treatment with primary surgery and adjuvant RT. The other 2 patients received a postoperative RT after an oncologic tonsillectomy could be performed. In 4 patients, due to the locally advanced stage and the inoperability of the primary tumor, it was not possible to distinguish between an oropharyngeal and an hypopharyngeal origin. Therefore we defined these primary tumors as multicompartmental. The median follow-up was 41 months (range 6–71 months). Patient and disease characteristics are presented in Table 1. The majority of patients were male (86%) and had good performance status (Karnofsky performance status > 70). Median NLR and PLR were 3.5 (IQR 2.1–4.7) and 195 (IQR 133–249), respectively.

In this retrospective analysis of 71 patients with HNSCC with a relatively long follow-up of 41 months treated with definitive or adjuvant radio(chemo)therapy after oncologic surgery, we found a statistically significant correlation between pretreatment PET/CT-MPs and hematological parameters (HPs; i.e., NLR and PLR). To our knowledge, the present study results are the first to show in patients with HNSCC that MTV and TLG correlate with pretreatment systemic inflammatory parameters, i.e., PLR. These findings align with the few other studies analyzing relationships between PET/CT-MPs and HPs in different tumor entities (Table 4). A positive correlation between HPs and PET/CT-MPs has previously been demonstrated in carcinomas of the rectum [21], esophagus [20], cervix [30], breast [19], and lung [7, 31]. In colorectal cancers, NLR was correlated with SUV, MTV, and TLG [21], except in the recurrent setting [32]. In esophageal carcinomas, NLR correlated with MTV but not with SUV [20]. In cervical carcinomas, a correlation was described between NLR and MTV with PLR and TLG [30]. In lymph node-positive breast carcinomas, a correlation between NLR and SUV and TLG of regional metastases in the axilla was shown [19]. Similarly, correlations between NLR, PLR, SUV, and MTV could also be demonstrated in small cell [31] and non-small cell [7] lung carcinomas.

Overall, the limited number of studies published on this topic have mainly described a correlation between NLR and SUV and MTV, and less frequently between PLR and SUV. Interestingly, we found no correlation between NLR and SUV in our analyses. In contrast, the analysis of PLR with MTV and TLG shows a significant positive correlation, albeit not strong. The same results are provided by Sürücü et al., showing no correlation between NLR and SUV [20] in esophageal cancer. The investigators of this work attribute this to the relatively small cohort (n = 52) they analyzed. How the interaction of the tumor microenvironment and FDG-PET/CT could influence treatment decisions has also been evaluated. In NSCLCs, Wang et al. described a correlation between PD-L1-expression and PET/CT-MPs. This correlation between SUVmax and immune cell expression in the tumor microenvironment of NSCLC suggests that SUVmax on FDG-PET/CT could be predicting for immunotherapy receiving patient selection [7]. Several studies have demonstrated that TILs are present in the tumor microenvironment in various malignant tumors [3‐5]. In oropharyngeal carcinoma, TILs can identify stage I HPV-associated patients likely to be poor candidates for treatment de-escalation [6]. An interplay between systemic inflammatory parameters and tumor microenvironment has also been shown. In gastric cancer, systemic inflammation is associated with the density of CD4 + lymphocytes in the tumor microenvironment [33]. We investigated whether systemic inflammatory parameters correlate with PET/CT MPs to potentially provide indirect information about the tumor microenvironment with easily accessible blood tests in combination with PET/CT-MPs. Hitherto, such analyses have not been performed in HNSCC using FDG-PET/CT. We propose that such findings would be particularly prescient in oligometastatic disease. For example, it might be possible to identify lesions that respond less to immunotherapy. FDG-PET/CT, in combination with NLR and PLR, might identify candidate lesions amenable to stereotactic radiation. We note that histopathological analysis is not always available for several patients, either for local lesions, which are not easily biopsied due to their anatomical location, or for distant metastases.

Furthermore, primary tumor and nodal metastases show poor to fair agreement when comparing biopsy material and resection tissue [34]. Predictive biomarkers, such as the composite positive score developed by Roach et al. in 2017 [35], have the potential to surmount some of these challenges and have shown promise in NSCLC [34, 36, 37]. The idea of using HPs in combination with PET/CT-MPs in patients with oligometastatic disease as a clinically useful prognostic tool for therapy response of a metastasis that is difficult to access through biopsy holds potential, not only in NSCLC but also in HNSCC.

More is known about the relationship between systemic inflammatory parameters and outcomes. In multiple studies, retrospective analyses and meta-analyses have shown that baseline circulatory NLR is a strong predictor of survival outcomes after radio(chemo)therapy for patients with HNSCC [38‐42]. Cancer is a systemic disease whose course and prognosis is influenced by inflammatory reactions in the micromillieu, as a hallmark of cancer by tumor invasion and metastasis [12]. Two decades ago, Balkwill et al. reported that inflammatory cells and cytokines in the tumor could contribute to tumor growth, progression, and immunosuppression [43]. Since then, several HPs, such as platelets, neutrophils, lymphocytes, NLR, PLR, and MPV, have been studied in various malignant tumors for their effects on tumor pathology [44‐48]. In patients with HNSCC, numerous analyses have been performed concerning PET/CT-MPs regarding tumor control and prognosis, reporting MTV defined from pretreatment FDG-PET scans as the strongest predictor of patient outcome after radio(chemo)therapy [49]. The effect of pretreatment SUVmax and SUVmean on patient outcome seems to be a less important factor compared with MTV [49].

There is no clear answer on the relationship between systemic inflammatory parameters and outcome. A possible explanation is that distant (micro)metastases are already manifest at initial diagnosis, which cannot yet be detected by any imaging modality [50]. For clinical routine, it might be interesting to compute a score comprising PET/CT-MPs and HPs for the prediction of already existing but subclinical distant metastases, in order to adapt individual therapy concepts.

In addition to its retrospective design, this hypothesis-generating study has a number of limitations. Using our small cohort, we did not observe a correlation between NLR and PET/CT-MP. Studies with larger or pre-defined cohort sizes are required to further test these potential relationships, because of a substantial type II error risk due to our under-powered sample size. At the time patients in this study were examined, HPV status was not routinely acquired, and we are unable to assess the influence of HPV status on the parameters measured in this study. Furthermore, the effect of some PET/CT-MPs, in particular MTV, could be influenced by the tumor lesion's size, similar to the influence of tumor volume on the TNM stage [51, 52]. For example, the relationship with PLR could be a result of the platelets' contribution to tumor growth [53]. Moreover, we have only recorded PET/CT-MPs for the primary lesions, and other FDG-avid metastatic lesions should be considered by future studies, ideally of prospective design. Finally, although our historical patient collective (2007–2010) afforded a follow-up for clinical outcomes, the scanner type used does not represent the state of the art, where digital and long axial field-of-view PET/CT systems can show improved lesion quantification [54].

In patients with HNSCC treated with definitive radio(chemo)therapy or oncologic surgery followed by adjuvant RT, baseline PLR is correlated with MTV and TLG but not with SUV. NLR did not correlate with any PET/CT-MPs analyzed in our study. Confirmatory studies and further investigation concerning immunohistochemistry in HNSCC are needed, and a potential interaction between tumor microenvironment, host inflammation, and FDG-PET/CT measures warrants more detailed research, maybe yielding information on tumor behavior and decision-making in radioimmunotherapeutic or treatment deescalating options.