According to the GLOBOCAN 2020 reports, colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related deaths worldwide (1). The outcome of patients with CRC has greatly improved with the advancement of multimodality treatment. However, the prognosis remains poor for patients at late stages (clinical stages III and IV) since these patients present tumor metastasis and poor response to treatment (2, 3). Unfortunately, many patients with CRC are diagnosed at the advanced stage. Therefore, the early detection and prediction of CRC is still a challenge for physicians (4). Currently, the most commonly used indicator in predicting the survival of patients is the tumor-node-metastasis (TNM) stage. Besides, some gene mutations or endogenous proteins are also reported to be associated with the prognosis of patients with CRC, such as KRAS mutation and the Ki-67 index (5, 6). Moreover, the non-invasive imaging biomarkers of cellular proliferation represent a great promising prospect for precision medicine in CRC (7).

To date, ¹⁸F-flurodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) computed tomography (CT) has been used for the diagnosis, monitoring treatment response, surveillance of local recurrence, and prognosis for CRC (8, 9). ¹⁸F-FDG PET is a qualitative and quantitative method used to evaluate tumor development (10–12). The standardized uptake value (SUV) is one of the important semi-quantitative parameters, which is used to assess the degree of ¹⁸F-FDG accumulation. Previously, several studies reported that the maximum SUV (SUVmax) was associated with the lymph node metastasis of CRC, and served as a potential predictor of survival in patients with CRC, indicating its promising value (13, 14). Furthermore, studies suggested that the SUVmax was greatly increased in patients with KRAS mutations, which is particularly crucial to the therapeutic strategy (15).

Despite several studies showing the association between the SUVmax and KRAS mutation and prognostic value in CRC, inconsistent results have been found in some studies (16, 17). Generally, the causes of the disparity in the results can be explained by the small sample size. Besides, Ki-67 was described to be correlated with the proliferative capacity, invasive potential, and prognosis of CRC in two studies (18, 19). However, the number of the patients was small, and the results still need to be further validated. Therefore, this study aimed to explore the role of the SUVmax of ¹⁸F-FDG PET/CT in CRC by analyzing the association of the SUVmax with the clinical features of CRC, KRAS mutation, and the Ki-67 index. We also performed a meta-analysis by combining data from previous studies to confirm our results and explored the prognostic value of the SUVmax in patients with CRC.

As one of the important parameters of ¹⁸F-FDG PET/CT, the SUVmax is able to measure the activity of tissue metabolism, which is strongly correlated with cell division and proliferation (49). Thus, the SUVmax is considered to sensitively predict the biological behavior of tumors that is influenced by various clinical factors (50). At present, the SUVmax has been widely applied to assess the malignant lesions from benign ones and could act as a critical indicator to predict the prognosis of patients with cancers. Using the data from our center, the present study found that the SUVmax was associated with the location of tumors and was remarkably increased in colon cancer compared with that in rectal cancer, which is similar to the findings of previous reports (35, 44). We also found that the SUVmax was associated with nerve invasion of CRC, which was not reported previously. However, the results did not show an association between the SUVmax and TNM and clinical stages of CRC. Moreover, no significant association was found between the SUVmax and KRAS mutation and the Ki-67 index. We conducted a meta-analysis due to the small sample size of the present study, by combining the previous published studies in order to achieve a robustness of results. In the meta-analysis, we found that the SUVmax was associated with the KRAS mutation status but not with OS or DFS of patients with CRC. The meta-analysis results also confirmed that there was no association between the SUVmax and Ki-67 index in patients with CRC. Considering the increasing application of ¹⁸F-FDG PET/CT in the clinical setting, our results provided important information for helping to make appropriate treatment strategy for the patients.

A previous study has shown that some PET parameters, such as SUVmax, SUVmean, and MTV, can guide the differentiation of benign, premalignant, and malignant lesions with incidentally detected foci of colorectal uptake [32092771]. There was a study that showed that focal colorectal ¹⁸F-FDG uptake on PET/CT is associated with a high risk of advanced colorectal neoplasia and is affecting subsequent patient management (51). These results suggested that various histopathological degrees might affect the FDG uptake value. In addition to the most commonly used ¹⁸F-FDG, ⁶⁸Ga-fibroblast-activation-protein inhibitors (FAPIs) and ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA)-617 are two other radioisotopes used in PET/CT determination. Kratochwil et al. (52) evaluated ⁶⁸Ga-FAPI PET/CT uptake in 28 different kinds of cancer and showed that the highest average SUVmax was found in sarcoma, esophageal, breast, cholangiocarcinoma, and lung cancer. The lowest ⁶⁸Ga-FAPI uptake was observed in pheochromocytoma, renal cell, differentiated thyroid, adenoid cystic, and gastric cancer. Cuda et al. (53) performed ⁶⁸Ga-PSMA-11 PET/CT imaging on 10 patients with metastatic CRC to assess metastasis avidity, and they showed that none of the patients exhibited tumor avidity sufficient to be considered for ¹⁷⁷Lu-PSMA-617 PRRT. These results indicated that ⁶⁸Ga-PSMA-11 and ¹⁷⁷Lu-PSMA-617 PRRT might be an important alternative to the ¹⁸F-FDG.

In the present study, we analyzed the SUVmax data and clinical features data of 66 CRC patients, which included 60 colon cancers and six rectal cancers. A previous study has reported that SUVmax was associated with the lymph node metastasis and clinical stage of CRC (43). However, the results of the 66 CRC failed to show significant differences in the SUVmax regarding lymph metastasis and distant metastasis; after the data of rectal cancer were removed (only six cases), the differences in the SUVmax slightly increased in these two parameters. Therefore, the difference of SUVmax between colon and rectal cancers should be made cautiously.

The association of ¹⁸FDG accumulation with KRAS mutations in CRC was explored previously, but the results were inconsistent. The results of the 66 CRC suggested little association between the SUVmax and KRAS, which was consistent with what Kawada et al. (27) reported but in contrast to the results of Chen et al. (26). We speculated that the reasons might be that, in addition to the small sample size of each study, the doubtful locoregional disease, such as polyps, and precancerous lesions might affect the ¹⁸FDG accumulation. The common tumor biomarkers, including CEA, CA125, CA153, and CA199, have been used to evaluate the CRC development, treatment effect, or prognosis in clinical setting. Regarding the correlations between SUVmax and tumor biomarkers, Sokolović et al. (46) found that SUVmax was associated with CEA levels, but not associated with CA199. Our results failed to show significant correlation between SUVmax and CEA, CA125, CA153, or CA199 levels, which was partly consistent with previously reported data (46).

With respect to the Ki-67 index, we did not find a significant correlation with SUVmax, which was in agreement with previous reports (18, 38). Taken together, the results from the 66 CRC patients showed that SUVmax has little associations with the clinical features of CRC, KRAS mutation, tumor biomarkers, and Ki-67 index. However, considering the fewer cases in those studies, this association needs to be confirmed by a larger study or by adding more samples to improve the reliability of the results. In addition, due to the lack of survival data, the prognostic value of SUVmax still needs to be determined. Therefore, we subsequently performed a meta-analysis to further validate the clinical significance of SUVmax in CRC patients.

Since some of the epidemiological indicators, such as age and gender, were associated with the development of CRC, they could influence the association of SUVmax with the CRC. In our data, we did not observe differences between age and gender with the SUVmax, which were similar to the previous studies, demonstrating that these epidemiological indicators might not affect the association of SUVmax with the CRC.

A previous study has indicated that different differentiation of CRC was associated with the KRAS genes mutation (54); thus the differentiation of CRC might also lead to the difference in SUVmax in these cases. However, in our data, we showed no significant difference among the different differentiation of CRC, which was similar to the results of Lee et al. (44), but contrary to the Jiang et al. (43) report; these inconsistent results might be due to the small sample size or other reasons, suggesting that the exact impact of differentiation of CRC on the association with SUVmax still needs to be further validated in a larger cohort.

KRAS mutation occurs in approximately 40% of CRC patients, which is a crucial biomarker for the selection of patients who are suitable for the epidermal growth factor receptor therapy (55). Previously, several studies have indicated that the SUVmax was elevated in the mutated-type KRAS compared with the wild-type KRAS patients with CRC. For example, Chen et al. (19) analyzed the data from 121 patients with CRC and found that the SUVmax was significantly associated with the KRAS mutation status, and similar results were found in the report by Kawada et al. (18). However, inconsistent results were also reported in the study conducted by Krikelis et al. (11). Recently, a study conducted a meta-analysis using the data from nine studies with 804 patients, and the results observed low sensitivity and specificity of ¹⁸F-FDG for the prediction of KRAS mutation in patients with CRC. However, this meta-analysis did not specifically analyze the SUVmax or other parameters in PET/CT inspection, which reduced the reliability of the results. In the present study, we included studies with patients with CRC and the results demonstrated that the SUVmax in patients with mutated-type KRAS was significantly increased compared with those with wild type, suggesting that there is a significant association between the SUVmax and KRAS mutation.

Regarding the Ki-67, it is mainly expressed in proliferating cells from the G1 to the M-phase of the cell cycle. Previous studies reported that a high expression of Ki-67 was an independent good prognostic indicator in CRC (56, 57). The SUVmax and Ki-67 index are the direct markers of cellular proliferation; therefore, several studies explored the association of the SUVmax with Ki-67, but the sample size of the studies was small, which would undermine the association between them; thus, more studies are warranted to further determine their correlation. In this study, no correlation was found between Ki-67 expression and KRAS mutation, which was in agreement with the study by Petrowsky et al. (58). Since our study and previous studies included a small number of CRC cases, we performed a meta-analysis by combining the currently available studies and the data of our study in order to achieve reliable results. The results showed that the SUVmax has no significant difference between high or low Ki-67 expression using 75% as cutoff. Thus, the current results suggest that there is no significant association between the SUVmax and Ki-67 index based on the current lines of evidence. We speculate that at least two reasons could explain the little association between these two indicators. First, the sample size was small, which could not achieve statistical power. Second, in our study and the included studies, the different cutoff of Ki-67 might have also affected the association of these two indicators.

Preoperative prediction of patient’s prognosis could provide numerous benefits to the treatment selection and improve the treatment effect and quality of the patients. As a non-invasive imaging modality, whether the parameter in PET/CT inspection has a high prognostic value for patients with CRC is one of the most crucial issues. There were inconsistent results with respect to the association of SUVmax with the survival of patients with CRC. In this study, we retrieved data on the SUVmax to predict the survival of patients with CRC and found that the SUVmax has little association, on both OS and DFS, even in the subgroup analysis that divided the patients according to different countries or follow-up time. Thus, the present study did not support the prognostic value of the SUVmax in patients with CRC. However, we also noted that this result was obtained from a meta-analysis; the exact relation of SUVmax with CRC patient’s survival, especially a particular subtype of the cancer, needs to be validated in a large CRC cohort.

Despite several meta-analysis studies exploring the role of ¹⁸F-FDG PET/CT in CRC, including the diagnosis of lymph node metastasis, KRAS mutation, and prognostic value (59–61), none analyzed the association of the SUVmax with KRAS mutation, the Ki-67 index, and their prognostic value. In addition, this study included available studies and incorporated the data from our center, which can achieve reliable results compared with previous studies. Nevertheless, some limitations should be noted. First, the present study was retrospective in nature, and some of the included studies in the meta-analysis were also retrospective, which could lead to selection bias. Second, compared with some previous reports (28–30), the number of patients from our center was relatively small, especially those with rectal cancer; thus, the robustness of our results might be undermined. Third, in the meta-analysis results, some factors across the studies were heterogeneous, including the follow-up time, treatment strategy, and staging; thus, the possibility of bias caused by disease profiles should be noted. Therefore, our results still need to be further validated using a large cohort with a prospective design.

By combining our data with previously published data, the present study demonstrated that the SUVmax of ¹⁸FDG-PET/CT is different in colon and rectal cancers and is associated with KRAS mutation but not with the Ki-67 index; there was no significant association between the SUVmax and survival of patients with CRC.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Institutional Review Board of Guangxi Medical University Cancer Hospital. The patients/participants provided their written informed consent to participate in this study.

Study concept and design: Y-XY and B-LH. Collection and assembly of data: Y-XY and M-ZX. Performed the experiment: Y-XY, X-QL, and M-ZX. Data analysis and interpretation: B-LH, J-LL, and M-ZX. Manuscript writing and review: All authors. All authors contributed to the article and approved the submitted version.

This study was partially supported by research funding from the National Natural Science Foundation (No. 81860417) and the Natural Science Foundation of Guangxi (No. 2018JJA140136).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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