Colorectal cancer (CRC) is the first most common and leading cause of gastrointestinal cancers (GI) worldwide, whose incidence and mortality rates accounted for 10% and 9.4%, respectively (1). Based on the statistics from International Researches Agency of Cancer (IRAC), the incidence and mortality of CRC would increase 40.1% and 43.4% by 2040 worldwide, respectively (2). Approximately 20% of CRC patients have initially diagnosed with metastases, mostly depositing in regional lymph nodes, liver, lung, and peritoneum (3). And the overall survival rate of patients is closely associated with stage at presentation; the 5-year survival rate drops drastically decreases from stage I (93%) to stage IV (8%) (4). Therefore, the precise staging of the CRC is essential for prognosis and effective therapy. The curative surgery has been remained as the “workhorse” at the early stage of cancers, and part of patients only with isolated liver metastasis (5). Nowadays, the standard of care regimens tends to be multidisciplinary, consisting of surgery, 5-fluorouracil-based chemotherapy, radiotherapy, targeted therapies, and PD-1/PD-L1 blockade biotherapy (5). Accurate pre- and postoperative staging are pivotal to tailor treatment avenues, which unequivocally improving the survival and quality of life. Variety of imaging techniques have been introduced for this purpose, with varying degree of success.

In the routine clinical practice, colonoscopy continues to be the preferred method for the diagnosis of colon cancer, because it allows tissue biopsies (6). In addition, a number of non-invasive imaging modalities, including as morphologic imaging such as computed tomography (CT), magnetic resonance imaging (MRI), and metabolic imaging such as positron emission tomography (PET), are presently used for staging colon cancer (7–9). Conventional imaging modalities, CT or MRI, are only based on the modifications of morphology of lesions, which could be invalid for cases mainly with metabolic changes. And serial elevated serum carcinoembryonic antigen (CEA) is usually coupled with false positives and false negatives (10). Recent studies showed that the combined-imaging modality is preferable for the detection and characterization of different malignant lesions including colorectum when compared with traditional imaging techniques (11). PET with flourine-18 fluorodeoxyglucose (¹⁸F-FDG PET/CT, hereafter refers as PET/CT) not only provides alternations of morphology, but also glycolytic metabolism changes based on glucose uptake, which increasing early diagnostic efficacy and visualize active tumor tissue (12). As for the molecular imaging, PET/CT represents a valuable ally for staging, therapeutic monitoring, and restaging for CRC patients (13, 14). However, the false positives were usually occurred when infection, inflammation, and other non-neoplastic conditions (15). Despite these drawbacks, PET/CT is irreplaceable in its ability to assess the abnormal metabolic activity precedes morphological change and to identify small sized malignant tumors in morphologically normal structures. This review attempts to discuss the role of PET/CT in the treatment of patients with CRC, which could pave the way for early accurate diagnosis and even individualized therapeutic strategies.

Tumor-Node-Metastasis (TNM) staging system (AJCC) has provided the universal framework for optimal management of CRC patients since 1959 (16). The curative surgery is the mainstay of treatment based on accurate preoperative staging by the combination of T, N, and M indicators ( Figure 1 ). Although the conventional imaging has served as the standard modality for this staging, PET/CT has been shown superior to evaluate the primary tumor, regional lymph nodes, and distant metastasis. Here we attempt to review and summarize the pros and cons of PET/CT in preoperative staging of CRC patients.

The developments of targeted therapies were renewed and have flourished in the past two decades (34). Recent applications of such treatments in CRC have been exemplified by the approval of oral kinase inhibitors or monoclonal antibodies, e.g., anti-angiogenesis (VEGF) and targeting epidermal growth factor receptor (EGFR). However, given only part of patients respond to these targeted therapies, it has been highly recommended to early stratify patients in order to reduce unnecessary toxicity and economic burden. Generally, the anatomic imaging modalities based on RECIST criteria, CT or MRI, have been utilized to monitor the response of cytoreductive or cytotoxic chemotherapy, while shows inappropriate for evaluating the cytostatic effect by the above-mentioned targeted therapy (35, 36). It is a common knowledge that the alternations of glucose metabolism within tumor precede the morphological changes by several weeks (37). Within this framework, we review the most widely accepted PET tracer and the only licensed biomarker, ¹⁸F-FDG (38), for assessing the responses to targeted therapies for patients with CRC.

Vascular endothelial growth factor (VEGF) targeted therapy disrupts tumor vasculature as well as inhibits angiogenesis, which have been exemplified by the first approved bevacizumab (Avastin) for metastatic colon cancer (mCRC) (39, 40). The semi-quantitative analysis of ¹⁸F-FDG uptake compared to normal liver was demonstrated to be instrumental for pathologic response prediction to bevacizumab in mCRC (41). Because of the quantitative trait of PET, quantitative measurement for early treatment response shows more attraction. Standardized uptake value (SUV) is the widely accepted quantitative metric for assessing treatment response in clinical PET/CT utility ( Figure 2 ) (42). For example, the reduction of maximum SUV (SUVmax) more than 50% showed predictive value for early response to Bevacizumab in mCRC patients, with the larger the decline, the greater the efficacy (43). And the relative decrease of SUVmax more than 15% presented highly predictive for non-responders detection after one cycle of Sorafenib combined with capecitabine in mCRC patients (44).

Dysregulations of EGFR pathway have been extensively involved in carcinogenesis of CRC, such as metastasis, proliferation, and resistant to apoptosis (45–47). The cetuximab-based regimens targeting EGFR signaling cascade is clinically utilized as the third-line therapy for mCRC patients without KRAS mutation (48). The PET Response Criteria in Solid Tumors (PERECIST) criterion was proposed for assessing the early therapy response by the relative change of SULpeak, i.e., peak SUV normalized to lean body mass (SUL) in a spherical 1 cm³ volume of interest (VOI) (49). Although treatment response using PERECIST predicted survival parameters (PFS & OS) at the end of cetuximab-based therapy (4 week) for mCRC, the innovative principle based on any eligible VOI more than 2 could ahead of this schedule after one week (50). And the early metabolic response based on the reduction of SUVmax more than 20%, fitted with EORTC criteria (51), could serve as the surrogate parameter for early clinical response under cetuximab in CRC patients (52). All cases reviewed here are summarized in Table 2 .

Therefore, detection of non-responders at early treatment stage could spare patients from the exposure of unnecessary toxicity and heavy economic burden.

Most of CRC patients diagnosed at advanced staged would be suffered from recurrences, including liver, lung, and peritoneum metastases (21, 53). And serum markers and imaging modalities are utilized as the main examinations for those detection. Despite ceCT remains the clinical guideline recommendation, PET/CT is suggested in the workup of recurrent CRC patients with metachronous metastases, or elevated serial CEA but negative conventional imaging modalities and optical colonoscopy. Besides, PET/CT also presents the unique strengths for those kinds of scenarios.

Distinction of recurrent lesions from postoperative scar tissues is the important superiority of PET/CT. FDG uptake within recurrences could significantly reduce false positives and false negatives as well (54). The sensitivity and specificity of serum surrogate marker CEA has been demonstrated elevated when combined with PET/CT. One of the retrospective studies including 112 patients showed the early detection of recurrent CRC was 71% compared with 55% of CT when CEA level greater than 13 ng/mL (55). Actually, the level of CEA less than 5 ng/mL also presented excellent performance by PET/CT (56). Besides, the diagnostic accuracy of PET/CT for recurrent cases with elevated CEA was moderate (65-75%) in the case of negative findings by conventional imaging modalities (57). Moreover, with the aim of assess the impact of PET/CT in tailoring management in CRC patients with proven or suspected recurrence, and further to evaluate the impact of different management on the prognosis of patients. Scott et al. reported that PET/CT modified the therapeutic strategies of 65.6% CRC patients with symptomatic or residual lesions suggestive of recurrence. And the treatment maneuvers of 43.9% patients with resectable metastatic deposits in lung or liver have also been changed. Besides, the additional lesions of those patients showed progressive disease in 60.5% and 65.9% in the above-mentioned two groups of patients compared with conventional imaging techniques (36.2% & 39.2%), which indicated the value of PET/CT regarding the stratification of patients into curative or palliative avenues (58). In addition, there are also plenty of studies demonstrated that the outstanding performance for recurrent lesions by PET/CT in comparison with CT or MRI, which was generally accounted for the combination with functional imaging (59–61).

Effective and precise pre- and postoperative staging is essential for the best and individualized management of CRC patients, especially for those with metastatic lesions. Nowadays, the conventional imaging modalities are still the mainstay for staging processes, while insensitivity to the monitor the treatment response of targeted therapy. Given that the single trait of morphological imaging techniques, the additional function of metabolic evaluation by PET/CT shows particular advantages, including early detection for tumors, sensitivity to the treatment response to cytostatic drugs, and evaluation numerous body regions in a single process. This makes PET/CT particularly helpful in the staging of patients to exclude the presence of distant metastases as well as in the restaging. However, more research is required to standardize the ideal PET/CT timing in relation to the chosen therapy (immunotherapy or chemotherapy). And there is still a dearth of information regarding the diagnostic potency of PET/CT in the evaluation of CRC. Given that anatomic imaging techniques are superior to detect small lesions because of the high resolution, the combined molecular and morphological imaging PET/CT would broaden its clinical utility. In conclusion, PET/CT adds value to the diagnosis of metastatic lesions and may aid patients with CRC in selecting more appropriate treatment modalities.

YS, XM, and JJZ formulated the design of this study; YS and XM wrote the manuscript; MW and CL revised the draft; JYZ drew the illustrations and figures; ZX assessed the histopathology of CRC. All authors contributed to the article and approved the submitted version.