Worldwide, cervical cancer is the second most common cancer and third lethal cause of malignancy among women [1]. Radiotherapy (RT) with or without concurrent chemotherapy is regarded as the standard therapy for locally advanced cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage IB2 and above) [2]. However, markedly different responses to RT are seen among patients with similar FIGO stages. After RT, the cervical mass in some patients markedly decreased disappeared. However, in other patients, the mass either did not shrink or increase in bulk suggesting resistance to RT. Thus, factors that can predict treatment response after RT are highly desired.

A number of studies [3, 4, 5] have reported that peripheral blood inflammation indicators are related to the treatment outcome and survival for a variety tumors including gastric, prostate, and non-small cell lung cancer. The peripheral blood inflammation indicators include the systemic immune-inflammation index (SII), neutrophil/lymphocyte ratio (NLR), tumor-related leukocytosis (TRL), platelet/lymphocyte ratio (PLR) and monocyte/lymphocyte ratio (MLR). As for locally advanced cervical cancer, there were reports that overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with higher SII or higher NLR, revealing a negative impact of high SII or high NLR on prognosis [6, 7]. Takai et al. [8] reported that a low NLR demonstrated significant association with a complete response (CR) to RT alone or concurrent chemoradiation therapy (CCRT) at every stage of cervical cancer, indicting a positive impact of low NLR on treatment outcome after RT. There are two main defects in this study. First is that the therapeutic response to RT was assessed by computed tomography (CT). Although magnetic resonance imaging (MRI) is superior to CT in evaluating morphological characteristics of cervical cancer as well as pelvic lymph node status. An appropriate correlation has been seen between preoperative MRI and post-operative pathological results [9]. The MRI findings, including stage, tumor diameter, vaginal involvement, and uterine body involvement have been confirmed as important prognostic factors for cervical cancer patients [10, 11]. Second, except for NLR, the correlation between other peripheral blood inflammation indicators and treatment outcome after RT in cervical cancer patients has not been evaluated. Thus, further research on peripheral blood inflammation indicators predicting treatment outcome in cervical cancer patients after RT is warranted.

In our study, we retrospectively evaluated the value of peripheral blood inflammation indicators, including SII, NLR, TRL, PLR and MLR, in predicting the treatment response in cervical cancer patients referred for RT. Treatment response was assessed by MRI in our study on account of the superiority of MRI over CT. The purpose of our observations was to establish the personalized choice of therapeutic strategies for cervical cancer patients.

Response to treatment is often used as a surrogate for prognosis or survival in cervical cancer patients treated with RT. However, it is critical to be able to discriminate between responders and non-responders using clinical information prior to treatment. Recently, cancer-related inflammation has been recognized as a prognostic biomarker as well as an indicator for treatment response. Systemic inflammation, which is reflected by peripheral leukocytes, lymphocytes, neutrophils, monocytes and platelets are proved to play a major role in cancer progression and development [13]. A variety of studies have reported that peripheral blood inflammation indicators are related to the treatment outcome of a number of tumors including rectal adenocarcinomas, gastric cancer, and non-small cell lung cancer. For example, in a study conducted by Sun et al. [14], 100 patients with rectal mucinous adenocarcinomas (MACs) undergoing neoadjuvant chemoradiotherapy (NCRT) and curative resection were included. Inflammation-based indexes such as SII, NLR, PLR, and prognostic nutritional index (PNI) were calculated. Logistic regression analysis showed that smaller tumor size, lower pre-treatment NLR level and PLR level, higher pre-treatment PNI level were independent predictors of good response to NCRT. In another study conducted by Graziano et al. [15], 373 patients affected by breast cancer and candidates to neoadjuvant chemotherapy (NACT) were investigated, in order to reveal a possible relationship between pathological complete response (pCR) and two peripheral indicators of immunity, including NLR and PLR. The results showed NLR and PLR were not significantly associated with pCR if analyzed separately. However, when analyzed together, patients with a NLR${}^{\text{low}}$/PLR${}^{\text{low}}$ profile achieved a significantly higher rate of pCR compared to those with NLR${}^{\text{high}}$ and/or PLR${}^{\text{high}}$. This study indicated low levels of both NLR and PLR may thus suggest a status of immune system activation that may predict pCR in breast cancer patients treated with NACT.

The present study demonstrated that treatment responses (CR, PR, SD) were significantly different between different groups of peripheral blood inflammation indicators, including SII, NLR, PLR and MLR. Our study revealed that TRL-negative and lower PLR were significant predictive factors of a better response to RT, which is consistent with previous reports. The TRL and PLR are proved prognostic factors influenced by the immune environment to the host, which are associated with the systemic inflammatory response.

Numerous studies have investigated the relationship between TRL and outcomes in cancer patients [16, 17], suggesting an association between TRL and resistance to RT. Cho et al. [18] retrospectively studied 2456 cervical cancer patients who received RT or CCRT, in order to evaluate the predictive values of TRL for treatment outcome. Their results indicated that compared with TRL-negative patients, TRL-positive patients showed a significantly lower percentage of CR, as well as had larger tumor size, advanced clinical stage and more frequent lymph node metastases. In contrast with TRL-negative patients, OS and locoregional failure-free survival (LFFS) were significantly shorter in TRL-positive patients, revealing a poor response to radiation therapy in TRL-positive patients. A study of cervical cancer patients by Mabuchi et al. [19] revealed that TRL-positive was significantly associated with larger tumors, higer tumor stage, and lower overall survival (OS). The study further indicated that granulocyte colony-stimulating factor (G-CSF) may be an underlying cause of the rapidly developing and radioresistant character of TRL-positive patients with cervical cancer.

Although the primary role of platelets is considered to be wound healing, hemostasis and thrombosis, studies have focused on the function of platelets in cancer ogenesis, tumor biology and inflammation. Elevation of platelet count has been proved to be related to tumor aggressiveness and decreased survival in colon, pancreatic, and lung cancer [20, 21]. In a study conducted by Wang et al. [22], 120 patients with unresectable gastric cancer were assessed. The results demonstrated a close association between low baseline PLR and increased response to chemotherapy, suggesting that PLR may be a candidate blood biomarker in order to distinguish responders from non-responders. Other studies have suggested the important role of serum PLR in inflammation within the tumor microenvironment [23]. Platelets may mediate the tumor microenvironment via dense granules, lysosomes, or $\alpha$-granules [24, 25].

Treatment response was assessed by MRI, which is a major strength of this study. In a previous study conducted by Takai et al. [8], the therapeutic response to RT was assessed mainly by CT. MRI has been shown to be superior to physical examination or CT at evaluating morphological characteristics of cervical cancer. With better soft tissue contrast, MRI can accurately measure the size, invasion, and possible metastatic disease in cervical cancer patients [26]. MRI is a better follow-up imaging modality for detection of residual lesions or local recurrence of cervical cancer following RT. Small residual lesions or local recurrence, which is difficult to identify by CT due to poor soft tissue contrast, can be visible on an MRI [27]. Therefore, treatment response was assessed by MRI in our study, so as to make the results more accurate and reliable. Accurate evaluation of treatment response makes it possible to better formulate the need for further local or systematic treatments.

We acknowledge several limitations of our study. The major limitation is that this is a retrospective study in a single center, with a relatively small population and short follow-up duration. Consequently, a larger research population with longer follow-up time is needed to support our findings. Currently, we are planning prospective studies in order to evaluate the utility of finding predictive factors in patients with other cancers, such as colorectal, lung or nasopharyngeal carcinoma.

The present study demonstrated that treatment response was significantly different between different groups of peripheral blood inflammation indicators, including SII, NLR, PLR and MLR. Multivariate logistic regression revealed that TRL-negative and lower PLR patients responded better to radiation therapy than patients with TRL-positive or higher PLR, suggesting radiosensitivity with TRL-negative or lower PLR tumors. Furthermore, our study emphasizes the importance of MRI for follow-up of cervical cancer patients. The result of present study may provide important information for the prediction of treatment response in cervical cancer patients referred for RT. We believe the application of this information obtained prior to treatment would be advantageous and meaningful for choosing an optimal therapeutic approach in order to avoid the higher probability of treatment failure and unfavorable prognosis.

The data of this study are available from the corresponding author upon request.

CL—extraction and drafting of the manuscript; KW and XS—designment and revision, statistical analysis; ZX—collecting clinical data of patients; GY and JL—Evaluating the patient’s MRI images. All authors read and approved the final manuscript.

The ethic code of this research is: [2021]079, approved by the university of Hong Kong-Shenzhen hospital’s Ethics Committee. Written informed consents were obtained from all participants.

The authors would like to thank Dr. Chaoxia Lv from department of obstetrics and gynecology, the university of Hong Kong-Shenzhen hospital, for the kind help provided.

This project is supported by Shenzhen Science and Technology Program [No. JCYJ20210324114600002], and High Level-Hospital Program, Health Commission of Guangdong Province, China [HKUSZH201901017].

The authors declare no conflict of interest.