Prognostic significance of platelet–lymphocyte ratio in patients receiving first-line tyrosine kinase inhibitors for metastatic renal cell cancer

Guidelines for the treatment of mRCC are rapidly evolving to incorporate the recently approved molecular-targeted therapies. Many mRCC patients have a poor prognosis, and TKIs have extremely changed their prospects. Prognostic factors can help clinicians determine the most appropriate use of TKIs by selecting the patients most likely to benefit from them (Noronha et al. 2016). Although numerous studies have attempted to determine which clinical factors might be predictors of PFS and OS, the results were inconsistent (Heng et al. 2009; Raungkaewmanee et al. 2012). In this study, we analyzed data obtained from 63 mRCC patients receiving first-line TKI with the aim of performing prognostic evaluations and promoting optimal surveillance strategies. Many studies have proved that a poor ECOG PS remains one of the most significant prognostic factors for various malignancies, such as GI cancer, lung cancer, ovarian cancer and mRCC (Zimmermann et al. 2010). Patients with a worse ECOG PS and limited functional capacity tend to tolerate cancer treatments with more difficulty. These patients have less favorable outcomes than patients with a better PS. This has been further strengthened by similar conclusions obtained from this study. However, one of the challenges when using PS as a prognostic measure is that it is subjective and may not be reproducible (Laird et al. 2013), as it is difficult to determine it accurately in the busy clinical setting, relying heavily on patient-reported information. In 1999, the Memorial Sloan-Kettering Cancer Center (MSKCC) reported for the first time that hemoglobin level lower than the normal limit, corrected calcium level higher than the normal limit, Karnofsky performance status lower than 80% and less than 1 year interval from diagnosis to treatment were independent predictors of short survival (Motzer et al. 1999; Cetin et al. 2014). This study defined pretreatment clinical features that were prognostic of survival in previously untreated mRCC patients who subsequently received cytokine therapy, such as IFN-α. Heng et al. (2009) also reported that lower hemoglobin level and higher serum corrected calcium, poor PS, and less than 1 year interval from initial diagnosis to initiation of therapy were independent predictive factors of poor survival. However, our study showed that hemoglobin and calcium levels were not significantly associated with the prognosis outcome of mRCC patients. Vickers et al. (2013) suggested that the number of brain metastases is also a prognostic factor of OS. Our study also found that the presence of brain metastases is associated with poor OS, while no significant correlation with PFS was observed. Kroeger et al. (2015) reported that the presence of lymph node metastases below the diaphragm is associated with poor survival in mRCC patients treated with targeted therapies. Our results are consistent with theirs concerning OS, but not PFS. The prognostic role of previous nephrectomy has recently been reported in patients with mRCC treated with target therapy (Choueiri et al. 2011; de Groot et al. 2016). Our results suggest that previous nephrectomy was not a significant prognostic factor for mRCC patients. All these differences may be due to the small number of analyzed mRCC patients and the characteristics of the study group, thus, further studies are needed.

Since Lu et al. (2006) suggested that tumors might form as a consequence of chronic inflammation, many studies have confirmed that inflammation is crucial for the development and progression of cancer. Therefore, inflammation markers have been regarded as significant for tumor progression and as risk factors for tumor recurrence. It has been recently suggested that systemic inflammation-based scores such as GPS (including albumin and CRP values), NLR, and PLR might be significant predictors of OS and PFS of cancer patients (de Vivar Chevez et al. 2014; Feng et al. 2014; Raungkaewmanee et al. 2012; Hu et al. 2015; Song et al. 2016; Nakano et al. 2014; Templeton et al. 2014a, b; Keskin et al. 2014). Over the last decade, it has become clear that these parameters are consistently associated with poor outcome, regardless of the tumor stage. Several studies suggested that inflammation is the key component of the tumor microenvironment, and that it has a significant role in carcinogenesis and disease progression (Balkwill and Mantovani 2012). Recent studies have tried to shed new light on molecular and cellular pathways linking inflammation and cancer (Porta et al. 2009). Despite the fact that RCC is an immunogenic tumor, there is little evidence that immune cells and inflammatory pathways can enhance the tumor’s growth and immune escape. However, recent studies are beginning to uncover the mechanisms of immune escape in RCC, and the role of inflammatory immune cells and cytokines is this process (Gunduz et al. 2015; de Vivar Chevez et al. 2014). Tumor-associated neutrophils (TANs) have a significant role in the malignant setting, as they may act as potent antitumor effector cells. However, increasing clinical evidence shows that TANs correlate with poor prognosis. As the tumor microenvironment controls neutrophil recruitment, TANs help tumor progression (Uribe-Querol and Rosales 2015). Reduction of lymphocyte infiltration in cancer-adjacent tissues tends to lead to the proliferation and metastasis of tumor cells (Whiteside 2014). Platelets can also lead to a higher level of cancer-related coagulation (Falanga et al. 2013). It is possible that active systemic inflammation induces a poor local immune response to a tumor, leading to lymph node spread and metastasis. Therefore, the ratios of platelets, neutrophils, and lymphocytes might be important prognostic factors in various cancers. Raungkaewmanee et al. (2012) studied the predictive value of PLR and NLR on the outcome of epithelial ovarian cancer patients. They reported that higher pretreatment PLR led to shorter PFS and OS, and that PLR was a better prognostic predictor of survival than NLR. However, Chrom et al. (2016) showed that only NLR ≥ 4 was significantly associated with shorter survival, while PLR ≥ 200 tended to associate with poor survival. Moreover, recent study revealed that high NLR at baseline and high NLR after targeted therapy was associated with shorter PFS and OS in mRCC (Templeton et al. 2016). However, this study investigated the effect of NLR on PFS and OS without other prognostic factors. Although our study included relative small patients, we evaluated the effect of PLR on PFS and OS in mRCC in addition to NLR and other prognostic factors. The data obtained in this study are not entirely in accordance with available literature data. We found that ECOG PS ≥ 2, brain metastases, multiple metastases, high NLR (>3.6), and high PLR (>150) were predictors of shorter PFS and poor OS when performing a Kaplan–Meier analysis. However, only the presence of brain metastases and a high PLR (>150) were found to be significant prognostic factors in terms of PFS and OS when performing the multivariable analysis. Our study has several limitations. First, it was a retrospective uncontrolled study regarding a single center’s experience with a relatively uncommon disease, thus, the number of analyzed patients was quite small. Second, the follow-up period might not have been long enough, so a further randomized clinical study involving more mRCC patients is needed. Third, the NLR and PLR cutoff values have not been previously established and were selected from the ROC curves. Fourth, we did not assess underlying disorders and other variables (e.g., diabetes mellitus, hypertension, body mass index, smoking, diet, nutrition) of the patients. Finally, our findings were expressed in terms of PFS and OS, rather than cancer specific survival. However, an inflammation-based prognostic score is a simple, convenient, and easily determined parameter that clinicians can use for assessing the prognosis of mRCC patients.