Combined prognostic value of the SUVmax derived from FDG-PET and the lymphocyte-monocyte ratio in patients with stage IIIB-IV non-small cell lung cancer receiving chemotherapy

Globally, lung cancer has 5-year survival rates as low as 15% [1]. Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, accounting for 85% of all cases [1]. Owing to lack of early symptoms, close to 70% of patients are already in late stage when they are initially diagnosed with NSCLC, and most of them have lost the opportunity for surgical therapy [2]. For advanced stage IIIB and IV NSCLC, the front line therapy remains platinum-based doublet chemotherapy [3]. However, the response rate to chemotherapy and the survival in advanced NSCLC are not ideal [4]. In order to develop appropriate treatment guidelines and balance therapeutic toxicity in individual patients, precise prediction of chemotherapy sensitivity and prognosis is crucial. The anatomical range of the tumor, which is expressed by the tumor, node, metastasis (TNM) classification, is recognized as the most powerful prognostic factor for lung cancer [5]. However, TNM staging is only an anatomical description of the tumor and is not enough to develop treatment programs and evaluate prognosis. In the future, the most promising will be the composite prognostic model for NSCLC based on biological characteristics in conjunction TNM staging [6].

Reprogramming energy metabolism is one of the biological hallmarks in cancer [7]. Indeed, significantly elevated glucose uptake and utilization have been observed in various types of tumors [7]. ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT), which can noninvasively quantify glucose uptake that precedes anatomic changes, has been widely applied in NSCLC diagnosis, staging, response evaluation and survival prediction [8]. Maximum standardized uptake value (SUVmax) is a commonly used parameter for quantifying FDG uptake and has been reported to have a strong prognostic value for NSCLC [9‐13]. The common conclusion of these studies is that higher values of SUVmax could predict a high risk of disease recurrence or death. However, this conclusion is still controversial since some studies also demonstrated that SUVmax cannot provide reliable prognostic information for NSCLC patients [14, 15]. Therefore, the prognostic role of SUVmax in NSCLC needs further validation.

Tumor-promoting inflammation is another recognized biological hallmark of cancer [7]. Accumulating evidence has demonstrated that the cancer-related inflammation response can enhance tumor progression by facilitating angiogenesis, invasion, and metastasis [16‐18]. Hematological markers of systemic inflammation include the lymphocyte-monocyte ratio (LMR), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), all of which are prognostic markers for a range of solid tumors, including NSCLC [19‐26]. However, the optimal hematological markers for predicting clinical outcomes in NSCLC have yet to be defined [22‐26].

The combined evaluation of FDG uptake of primary tumor and systemic inflammatory response may provide complementary information and may be highly effective at predicting outcomes in advanced NSCLC patients. Hence, we combined the two factors to explore their integrated predictive value for treatment response and survival in stage IIIB-IV NSCLC patients.

Our retrospective study revealed that pre-treatment SUVmax and LMR were independent factors for predicting treatment response and prognosis in stage IIIB-IV NSCLC patients receiving chemotherapy. More importantly, an innovative scoring system based on SUVmax and LMR was constructed that can serve as an accurate and effective tool for predicting chemotherapeutic response and prognosis.

SUVmax is one of the most important parameters derived from PET that can accurately measure the metabolic activity of tumors and provide valuable prognostic information. Although the cellular and molecular mechanisms are not well known, some studies have reported that SUVmax is closely associated with biological factors that influence cancer proliferation and progression in NSCLC, such as Ki-67 [27, 28] and VEGF [28]. A large prospective study by Vesselle et al. [27] investigated the correlation between Ki-67 expression and tumor FDG uptake in 178 patients with NSCLC. The results showed that SUVmax was positively correlated with Ki-67 scores in tumor tissue, and it is well known that the overexpression of Ki-67 in tumors indicates active proliferative activity and aggressive biological behaviour. In another study on NSCLC, Takenaka et al. [28] assessed the relationship between SUVmax and intratumoral expression of VEGF and demonstrated that SUVmax was significantly higher in patients with high expression of VEGF, which plays an important role in tumor angiogenesis, invasion, and metastasis. Above studies revealed that SUVmax could reflect tumor proliferation and angiogenesis, which is related to prognosis. In NSCLC, many studies have demonstrated the prognostic significance of SUVmax [10, 29]. A meta-analysis by Berghmans et al. [29] encompassing 13 studies highlighted tumor SUVmax values as a prognostic factor of NSCLC. In another retrospective study of 315 NSCLC patients, Cerfolio et al. [10] found that patients with SUVmax ≥10 were more likely to have cancer recurrence and shorter survival compared with those of patients with low SUVmax. More importantly, they also concluded that SUVmax was a more powerful independent prognostic factor than TNM stage [10]. Consistent with these findings, we also observed that high SUVmax values (> 11.6) of primary tumor is independently associated with poor PFS and OS. In addition, we also demonstrated that a high SUVmax was a significant predictive marker of poor chemotherapeutic response. The mechanism may be related to the overexpression of p53 in tumor cells, as a previous study confirmed the positive correlation between SUVmax and p53 expression [30], and p53 overexpression has been proved to be significantly correlated with chemotherapy resistance in lung cancer [31]. This may be an underlying mechanism to explain why the high SUVmax is associated with poor chemotherapeutic effects.

Accumulating evidence has demonstrated that systemic inflammation plays a key role in tumorigenesis, progression and metastasis [17]. LMR, one of the simple markers of systemic inflammatory response, has been shown to correlate with clinical outcomes of NSCLC [25, 26]. In a retrospective assessment of 107 patients with advanced lung squamous cell carcinoma who received chemotherapy, Minami et al. showed that a low LMR (< 2.07) could independently predict a poor OS, while NLR could not [25]. In terms of short-term efficacy, their results showed that the high LMR group exhibited a higher response rate to chemotherapy than did the low LMR group (25). Lin et al. also reported that high LMR values (> 4.56) were predictive of a longer PFS and OS in 370 metastatic NSCLC patients receiving chemotherapy [26]. Our data were consistent with these findings, as a low pre-treatment LMR (≤3.73) was a significant predictor of unfavourable chemotherapeutic responses and a poor PFS and OS. The exact mechanisms of these associations currently remain unclear, but there are some hypotheses on this issue. On the one hand, it is well known that lymphocytes, especially cytotoxic T lymphocytes, play a critical role in the antitumor immune response by inducing cytotoxic cell death and suppressing tumor cell proliferation and invasion [32]. A previous study has demonstrated that a low lymphocyte count was associated with a poor DFS in NSCLC patients [33]. On the other hand, circulating monocytes can differentiate into tumor-associated macrophages (TAMs) in the tumor microenvironment, and growing evidence suggests that TAMs promote cancer initiation, progression and metastasis by inducing mutagenesis, stimulating angiogenesis, and suppressing anti-tumor immunity [16‐18]. All the above theories suggested that the LMR can reflect the balance between the anti-tumor immunity of the lymphatic system and the unfavourable tumor-promoting effects of monocytes. A low LMR indicates a relatively decreased lymphocyte count and an increased monocyte count, so it may predict a poor clinical outcome.

To summarize, SUVmax represents the local metabolic status of primary tumor, and LMR reflects the host’s systemic inflammatory response. The comprehensive evaluation of these two factors may be more accurate and effective at predicting the chemotherapeutic response and prognosis. Interestingly, we demonstrated a weak but significant negative correlation between SUVmax and LMR in this study. A similar correlation between SUVmax and hematological parameters was observed in colorectal cancer [34], NSCLC [35] and breast cancer [36]. In a study of colorectal cancer, Xu et al. [34] demonstrated that SUVmax was significantly correlated with LMR and NLR. In addition, in other studies on NSCLC and breast cancer, Jeong et al. [35] and Fujii et al. [36] also demonstrated the correlation between SUVmax and NLR. The results of previous studies may offer some explanations for this correlation. One potential opinion was that inflammatory cells infiltrating the tumor microenvironment, such as neutrophils and macrophages, also consumed FDG, resulting in increased FDG uptake throughout the tumor [37]. Another possible explanation may be related to inflammation-induced angiogenesis. Inflammation promotes hypoxia in the tumor microenvironment and induces angiogenesis by stimulating VEGF secretion [38]. Then, the uptake of FDG will increase significantly during tumor angiogenesis [39]. These analyses shed new insight into the relationship between tumor metabolic activity and the host’s inflammatory response process. Therefore, in present study, we established a scoring system based on the SUVmax and LMR, and demonstrated its value to predict PFS and OS, highlighting its prognostic potential. Patients with baseline SUVmax ≤11.6 along with LMR > 3.73 (score 0) exhibited the longest PFS and OS of the three groups, whereas patients with both pre-treatment SUVmax > 11.6 and LMR ≤3.73 (score 2) showed the worst treatment outcome, with significantly poorer OS and PFS. Another highlight of this study was the association between the SUV_LMR score and first-line chemotherapeutic response. Patients with a score of 0 had the highest ORR among the subgroups, while patients with a score of 2 had the worst ORR. The SUV_LMR score therefore has the potential to predict treatment response and prognosis and may be helpful in selecting appropriate treatment strategies for advanced patients. Patients with a score of 0 appeared to be more sensitive to chemotherapy, so the current platinum-based doublet chemotherapy may be the optimal strategy for them; thus, for these patients, chemotherapy should be implemented as soon as possible. However, for patients with a score of 2, they seemed to be relatively insensitive to chemotherapy, and their prognosis was extremely poor. Therefore, alternative strategies should be considered for these patients, such as molecularly targeted therapies and immunotherapies.

Some study limitations should be discussed. The study was retrospective and from a single centre, and the number of patients was small. Secondly, selection criteria were limited to stage IIIB-IV NSCLC, and the prognostic impact of the SUV_LMR scores may be differ in those at early disease stages. Finally, the predictive performance of the SUV_LMR score needs further validation in larger prospective studies containing more samples.

Pre-treatment SUVmax and LMR were independent predictive factors of clinical tumor response and prognosis in stage IIIB-IV NSCLC patients who were treated with first-line chemotherapy. More importantly, the SUV_LMR score, which is based on primary tumor metabolic activity and the systemic inflammatory response, provides a promising tool to predict chemosensitivity, recurrence and survival of advanced NSCLC.