Bladder cancer (BC) is one of the most common cancers in the urinary system, and its incidence ranks eleventh in the global incidence of malignant tumors (1). 70% to 80% of patients with BC are diagnosed with non-muscle invasive bladder cancer (NMIBC) (2). The standard treatment for NMIBC is getting the transurethral resection of bladder tumor (TURBT) with postoperative intravesical chemotherapy or Bacillus Calmette-Guerin (BCG) infusion, and then undergoing a second surgery when it is necessary. However, the recurrence rate of NMIBC after surgery has remained high. Chemohyperthermia (CHT) is a new method for postoperative perfusion, which increases the absorption of chemotherapy drugs in the bladder wall by locally heating the bladder to improve its efficacy. Many studies have shown that its efficacy in NMIBC is better than intravesical chemotherapy and it is certainly safe. Using biomarkers to predict the prognosis of NMIBC can benefit the treatment of NMIBC and reduce its recurrence and progression.

Lymphocytes are involved in cytotoxic cell death and inhibit tumor cell proliferation and metastasis. Platelets are involved in different stages of tumor angiogenesis, including proliferation, migration, extracellular matrix degradation, and adhesion of endothelial cells. Platelet-to-lymphocyte ratio (PLR) has been shown to be significantly associated with cancer-specific survival (CSS) and overall survival (OS) in urothelial carcinoma patients who underwent total cystectomy (3). Mean platelet volume (MPV), a known biomarker of pro-inflammatory and prothrombotic states, is considered an inflammatory marker of cardiovascular, rheumatic, and digestive diseases. There are few studies on MPV to lymphocyte ratio (MVPLR) for tumor prognosis. In addition, there is little research on the relationship between the systemic immune-inflammatory index (SII) and the prognosis of NMIBC patients. But SII has a good prognostic value for patients with hepatocellular carcinoma and renal clear cell carcinoma.

The purpose of this study was to investigate whether PLR, MPVLR, and SII have prognostic value in NMIBC treated with conventional intravesical instillation or intravesical CHT. Will they play different prognostic roles due to different ways of perfusion?

A total of 222 cases were enrolled in this study, which consisted of 149 patients in the GEM group and 73 patients in the CHT group. The median follow-up time was 42 months (interquartile range:17-48 months). 69 cases in the GEM group had tumor recurrence and 19 of them progressed to MIBC or got metastasis, 3 of them died of cancer. while 19 cases in the CHT group recurred and 2 progressed, none of them died of cancer.

There have been nearly 20 years of research on intravesical CHT. Most of the studies have shown that the efficacy of intravesical CHT for NMIBC is better than traditional intravesical chemotherapy. In the research of Arends et al., 190 NMIBC patients were randomized in that controlled, open-label, multicentre trial for 1-yr CHT and 1-yr BCG immunotherapy. They found that the 24-mo RFS in the PP analysis was 81.8% in the CHT group compared with 64.8% in the BCG group (p=0.02) and turned out that CHT is a safe and effective treatment option in patients with intermediate- and high-risk papillary NMIBC (6). Our retrospective cohort study figured out a similar result that CHT can reduce the recurrence rate of NMIBC and also prevent tumor progression.

The complex connection between tumor cells and the body’s immune system influences tumor initiation and progression (7, 8). Neutrophilia can induce DNA damage by secreting reactive oxygen species, stimulating cancer cell proliferation, and promoting new blood vessels around cancer tissues (9). Studies have shown that neutrophils migrate to peritumoral tissues to participate in the induction of hypoxia and the release of vascular endothelial growth factor (VEGF) to promote tumor growth (10, 11). The progression of hypoxic necrosis within the tumor also further induces an innate immune response, resulting in an overall rise in neutrophil counts (12, 13). The increasing evidence suggests that the causal relationship between local immune responses and systemic inflammation in many malignancies is not an accident (14). Lymphocytes are considered as a basal anti-tumor defense line (15). Sharma et al. revealed that a greater number of CD8 + infiltrating lymphocytes improves the prognosis of patients with MIBC (16). Furthermore, advanced bladder cancer is associated with unstable host defense and a decreased number of lymphocytes (17). Cancer microenvironment cells stimulate monocytes and neutrophils to secrete, inter alia, interleukin 6 (IL-6), VEGF, and transforming growth factor β (TGF-β), causing general immunosuppression by inducing apoptosis of lymphocytes and a decrease in lymphopoiesis (18–21).

In addition, circulating tumor cells (CTCs) are shielded from natural killer cell cytolysis by platelets, which enclose the tumor cells in a thrombus (22). tumor cells stimulate platelets through specific mechanisms to promote a persistent adhesion between them and tumor cells, which increased platelet numbers, led to hypercoagulation, and raised thrombosis risks in cancer patients. Some of the chemicals that platelets emit have the ability to increase the proliferation and development of tumor cells (23, 24). Moreover, Platelets with elevated MPV have strong reactivity and aggregation ability, so MPV is also considered a surrogate marker of platelet activation. Activated platelets can recruit neutrophils and monocytes and release Chemokines like p-selectin, VEGF, and IL-8, which play a role in promoting hemostasis, vascular remodeling, and inflammation (25, 26). Therefore, we believed that MPV should be related to tumor occurrence, progression, and other tumor behaviors.

The suggested NLR reflects the dynamic balance of the host’s inflammatory response and anti-tumor effect and is based on the neutrophil count and lymphocyte count. The probability of locally progressed disease, future disease recurrence, cancer-specific, and all-cause mortality is dramatically enhanced in patients having RC when their preoperative NLR is elevated (27). NLR≧2.41 may be employed as a standalone predictor of postoperative cancer recurrence in patients with NMIBC, according to Mano et al. (28). Considering that there have been many reports of NLR correlation with NMIBC, we chose other 3 indices that few studies have evaluated a particular outcome in patients with NMIBC: PLR, SII, and MPVLR.

PLR is the ratio of platelets to lymphocytes. Jiwei Huang et al. found that the Preoperative PLR value can be used as a negative independent prognostic factor for survival outcomes in patients with localized upper tract urothelial carcinoma (29). However, no study has investigated the prognostic role of PLR for patients with NMIBC. By using the ROC curve and the approximately identical index, our study found the best cut-off value for PLR: 93.075 in the GEM group and 183.863 in the CHT group. In both the GEM group and the CHT group, the RFS rate of the high PRL group was substantially lower than that of the low PLR group (p<0.05). High PLR appeared to be an independent risk factor for postoperative recurrence in the GEM group and was associated with postoperative recurrence in both groups, according to Cox single and multivariate analyses. We noticed that the cut-off value of the CHT group was different from that of the GEM group. We considered the reason may be that patients from the two hospitals may differ in a local environment, lifestyle, patient inflammatory state and then caused this bias.

A recently proposed prognostic indicator is the Systemic Immune Inflammation Index (SII), which incorporates neutrophil count, lymphocyte count, and platelet count. Patients with liver cancer, lung cancer, and kidney cancer have been proven to have a bad prognosis when this indication is uncommon (30, 31). Based on a study, SII is substantially linked to poorer survival outcomes and unfavorable pathological features in BC patients (32). Lower SII was also seemed as a vital independent predictor of response to intravesical BCG immunotherapy and revealed a preferable prognosis in NMIBC patients (33). Similarly, our study showed the result that NMIBC patients with lower SII had a lower risk of tumor recurrence in both the GEM group and the CHT group, although it could not be used as an independent risk factor for tumor recurrence in NMIBC patients treated with intravesical GEM chemotherapy, nor those treated with intravesical CHT. Additionally, compared to the research above, our study’s cut-off value for SII was somewhat different. Given the patients’ health conditions, the varying tumor tolerance levels of various geographic and racial groupings, and the fact that only two facilities were engaged in this retrospective analysis, there may be some discrepancies resulting in a selectivity bias.

MPVLR is the ratio of mean platelet volume (MPV) to lymphocytes. So far MPVLR has been widely studied in cardiovascular disease, and inflammatory response, but few in tumor prognosis. A recent study proved that high MPVLR (≥3.61) was independently associated with higher long-term overall mortality in nonmetastatic ccRCC patients (34). Our study was the first to investigate whether MPVLR was associated with the recurrence of patients with NMIBC. Did MPVLR play different predictive roles between conventional intravesical chemotherapy and intravesical CHT? It turned out that high MPVLR (≥6.377) was independently associated with lower recurrence-free survival in NMIBC patients treated with intravesical GEM chemotherapy. However, in NMIBC patients treated with intravesical CHT, MPVLR had no predictive value for tumor recurrence. We considered the reason for this phenomenon may be that intravesical CHT could stop tumor recurrence by influencing the effect of mean platelet volume on tumor growth through certain mechanisms so that MPVLR could no longer predict the postoperative recurrence in these patients. But more research needs to be done to prove the possibility of these unknown mechanisms.

Furthermore, the results of Cox regression analysis in this study suggested that postoperative recurrence in patients with NMIBC treated with intravesical GEM chemotherapy was related to gender, preoperative age, tumor pathological grade, and tumor pathological grade was an independent risk factor. In the NMIBC patients treated with intravesical CHT, postoperative recurrence was associated with tumor size, amount of tumors, and tumor pathological stage when tumor pathological stage was an independent risk factor. However, we did not use any prognostic scoring model because of the limit of this retrospective study and the lack of other clinical data.

Novel emerging tools such as circulating cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), Whole exome sequencing (WES), and next-generation sequencing (NGS) based strategies represent an attractive platform for diagnosis, longitudinal monitoring, and prognosis prediction to specifically guide the treatment strategy within different settings (35). However, DNA sequencing tools are time-consuming and expensive. Gene mutation will also bring difficulties to their clinical use. Compared with these tools, although the inflammation, immuno-nutrition-based and other blood-related markers also have limits in clinical use because of the lack of reproducibility and prospective studies, they are easy to get and economical. As long as a scoring system can be built to help reduce bias, these biomarkers will play a key role in evaluating tumor prognosis in the future. Besides the predictive values, our study confirms that intravesical CHT could stop tumor recurrence by influencing the effect of mean platelet volume on tumor growth through certain mechanisms, which needs more research to explore.

This research had several restrictions. Because it was a retrospective cohort analysis, this study was unable to gather and assess data on how PLR, SII, and MPVLR variations affected clinical outcomes throughout a follow-up period. Selection bias was unavoidable as a result of the study’s small sample size and dependence on just two centers. Due to the scarcity of data, we were unable to incorporate some possible confounders in our study, including smoking history, concurrent inflammation, medications consumed, and genetic variables. The EORTC scoring model was developed based on patients receiving several different perfusion regimens and was used to predict recurrence and prognosis in NMIBC patients (internally validated c-index for recurrence and progression, 0.66 and 0.75, respectively) (36). Afterwards, a CUETO score model was developed to predict the prognosis of patients treated with BCG perfusion (the c-index of recurrence and progression were 0.636 and 0.687, respectively) (37). However, there has no such scoring model to predict the prognosis of NMIBC patients treated with intravesical CHT. Therefore, we need to expand the sample size and conduct prospective studies to form a scoring model for them in the future.

Our study demonstrated that elevated PLR, SII, and MPVLR have a certain predictive effect on the postoperative recurrence of patients with NMIBC who were treated with intravesical GEM chemotherapy, of which PLR and MPVLR were two independent risk factors. While PLR and SII, without MPVLR, were associated with postoperative recurrence of patients with NMIBC who were treated with intravesical CHT, which indicated that intravesical CHT could possibly inhibit tumor recurrence in NMIBC patients by influencing the effect of mean platelet volume on tumor cells. Based on the results of our retrospective cohort study, we recommend exploring this relationship and determining the optimal cut-off values of PLR, SII, and MPVLR for patients with NMIBC treated with conventional intravesical chemotherapy or intravesical CHT using other well-designed datasets.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Medical Ethics Committee of Lanzhou University Second Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

CW did the data collection and manuscript writing. WJ and XM did the data collection. ZD did the manuscript correcting and formed the final manuscript. All authors contributed to the article and approved the submitted version.