This study identified NLR as a significant factor for predicting tumor recurrence and progression, and inclusion of preoperative NLR enhanced the accuracy of the CUETO model to predict progression in patients with NMIBC.
In the early stages, NMIBC is not life-threatening, but it will recur in more than half of patients and progress from 10–20% to MIBC [13]. Although numerous efforts have been made to predict and prevent tumor recurrence and progression, the exact characteristics of NMIBC are unknown due to its heterogeneity [14].
The European Organization for Research and Treatment of Cancer (EORTC) has developed a simple scoring system that uses information such as tumor size and number, prior recurrence rate, stage, and concomitant CIS and WHO grade based on data of 2596 patients with NMIBC, to predict the risk of relapse and progression[15]. The CUETO scoring model was created to compensate for the EORTC with low rates of BCG treatment, using information from 1062 patients who received BCG treatment [7]. Compared to EORTC, where most of the 78% patients received intravesical chemotherapy, all patients in the CUETO study received BCG instillation, and 15% of them received mitomycin C.
Intravesical instillation of BCG is a standard treatment for CIS and an adjuvant option for T1 and higher-grade Ta bladder tumors after TUR [16]. The CUETO model is thought to be more suitable for patients treated with BCG. In this study, as with the CUETO study, we included patients who completed 6 BCG instillations. However, compared with the CUETO scoring model, only female gender, concomitant CIS, multiplicity (> 3), and prior recurrence status were significant factors for predicting tumor recurrence (all P < 0.05). About tumor progression, only concomitant CIS and prior recurrence status were significant factors (all P < 0.05). A Kaplan–Meier curve analysis demonstrated that the CUETO score was associated with RFS (P < 0.05), but not with PFS (P = 0.423). We therefore decided to add the NLR ratio to the CUETO scoring model if inclusion of an NLR would enhance the predictability of CUETO scoring.
Preoperative NLR has proven to be a useful marker and a high NLR has been linked to higher tumor stages and adverse oncologic outcomes in numerous cancers, including not only the gastrointestinal cancer but genitourinary tract cancer, such as urothelial carcinoma of the bladder [17–20]. Although the pathophysiology is not understood clearly, relative neutrophilia may increase inflammatory markers that include proangiogenic factors, growth factors, proteases, and antiapoptotic markers, which facilitate tumor growth and progression [21]. In addition, lymphocytopenia may destroy cell-mediated immune responses and therefore worsen prognoses [22]. In bladder tumors, several previous studies have evaluated the predictive value of NLRs; most focused on MIBC and were conducted mainly on patients who underwent radical cystectomy [23–26]. In 2014, Viers et al. evaluated 899 patients who underwent radical cystectomy without neo-adjuvant chemotherapy and who had a preoperative NLR. An elevated preoperative NLR (> 2.7) was associated with a significantly higher risk of a locally advanced disease as well as subsequent disease recurrence and cancer-specific and all-cause mortality. In 2012, Can et al. demonstrated that among 80 NMIBC patients and 102 patients with MIBC, an NLR > 2.57 was a predictor of invasive urothelial carcinoma. According to a 2014 study by Potretzke et al., among 102 consecutive patients undergoing radical cystectomy, NLR was significantly related to pathologic tumor staging and to upstaging of non-organ confined disease ( ≧ pT3). Similarly, Krane et al. reported that, among 68 consecutive cases of radical cystectomy for MIBC, an NLR > 2.5 was associated with poor overall and cancer-specific survival, suggesting that such patients may benefit from neo-adjuvant chemotherapy.
When focusing on NMIBC, several trials [8, 17, 27, 28] evaluated the predictive value of the NLR. In 2015, Mano et al. revealed that an NLR > 2.41 was an independent predictor of disease progression and recurrence in 107 patients with NMIBC treated with TUR. According to Favilla et al.’s study in 2016, an NLR ≥ 3 was associated with worse disease recurrence (HR, 2.84; P < 0.01) in 178 patients with Ta or T1 bladder tumor who underwent TUR. The 5-year RFS was 49% and 62% in patients with an NLR ≥ 3 and < 3 (P < 0.01). A prospective study of Albayrak et al. in 2016 found that a higher NLR was associated with recurrence and progression of Ta or Ta bladder tumors, although, and in contrast with the finding of previous studies, a significant relationship with NLR was lost after correcting for age. Another prospective trial by Getzler et al. in 2018 demonstrated that an NLR > 2.5 was a significant predictor of disease recurrence and a worse RFS in 113 patients with NMIBC, particularly those treated with BCG. As with the studies described above, we found that an NLR > 2.29 was associated with higher tumor recurrence (HR, 2.451; 95% CI, 1.567–3.834; P < 0.001) and tumor progression (HR, 5.911; 95% CI, 1.579–22.126; P = 0.008) according to a multivariate Cox proportional hazards regression model. Kaplan–Meier curve analysis showed that an NLR > 2.29 showed significantly low RFS and PFS (P < 0.001 and < 0.002, respectively). However, the four studies mentioned above were not restricted to patients treated with BCG.
When narrowing the scope of predictive values of NLRs in all BCG treated patients, Racioppi et al. (2019) [29] evaluated whether an NLR ratio can predict the response to BCG in high-risk NMIBC patients. One hundred consecutive patients with newly diagnosed high-risk NMIBC were analyzed retrospectively. All received an induction course of intravesical immunotherapy with BCG followed by a maintenance course for at least a year. Forty-eight patients underwent radical cystectomy for high-grade recurrence or progression to muscle invasive disease (BCG non-responder group). The mean NLR was 2.61 ± 0.77 in the BCG responder group and 3.65 ± 1.16 in the BCG non-responder group (P = 0.01). The NLR was associated with both recurrence (P = 0.01) and progression (P = 0.01). A Kaplan–Meier analysis with a log-rank test showed statistically significant differences between the curves for an NLR < 3 and an NLR ≥ 3 (P < 0.05).
Based on the ability of the NLR to predict tumor recurrence and progression, we added the NLR to the CUETO scoring model. Using the CUETO scoring model alone, a significant association was observed with low RFS (P < 0.001), but not with PFS (P = 0.423) (Fig. 2). However, after combining the NLR (cut-off value 2.29) and CUETO scoring model (cut-off value 7), the resulting modified risk model showed that a high NLR and high CUETO score were significantly associated with both low RFS and PFS (P < 0.001 and P = 0.002, respectively) (Fig. 3). Other combined risk models have been shown to enhance the predictability of each risk model [8, 22]. Getzler et al. provided statistical evidence that an NLR > 2.5 may improve the predictive power of an EORTC score when the two are calculated together. In 2019, Aydin et al. evaluated the correlation between NLR and EORTC recurrence and progression scores. They reported that as the NLR increased, recurrence (P < 0.001) and progression (P = 0.034) scores increased significantly. Nevertheless, this study is the first to analyze the prognostic significance of the NLR and its synergic relation with the CUETO scoring model in patients with NMIBC after intravesical BCG instillation.
There were several limitations to be considered in this study. First, it was based on a retrospective analysis of the records of patients treated at a single institution with unavoidable selection biases. Small numbers and heterogeneous patients are also weak points. It should also be noted that in many previous studies, various NLR cut-off values were evaluated and utilized [30]. Each study’s results should be interpreted carefully. Because the idealized and generalized NLR have not yet been established, each study selected cut-off values with different sensitivities and specificities. Furthermore, the main limitation concerning NLRs is the volatile counts of neutrophils and lymphocytes. Although we excluded patients with hematologic malignances and acute or chronic infections, it is possible that individual chronic medications, herbs, or antibiotics affected the NLR value. A prospective study with a larger cohort is required to solidify the place of NLR in predicting disease recurrence and progression in patients with NMIBC.