# Preoperative PET/CT18F-FDG Standardized Uptake by Lymph Nodes as a Significant Prognostic Factor in Patients with Colorectal Cancer

Authors: Ruohua Chen; Yining Wang; Xiang Zhou; Gang Huang; Jianjun Liu
Journal: Contrast Media & Molecular Imaging
 (2018)

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## Abstract

Purpose. We evaluated the prognostic value of preoperative 18F-FDG uptake by suspected lymph nodes (LNs) using 18F-FDG PET/CT in colorectal cancer patients. Methods. Patients with CRC underwent 18F-FDG PET/CT before radical surgery. We used Cox proportional hazards regression to examine the relationship between recurrence and the 18F-FDG maximum standardized uptake value (SUVmax) in the suspected LNs (SUVLN) on 18F-FDG PET/CT. Results. Clinical data, treatment modalities, and results from 90 CR C patients were reviewed. The median follow-up was 19 months (range 3 to 72 months). Receiver operating characteristic analysis identified SUVLN 1.15 was the optimal cut-off value for predicting recurrence. SUVLN correlated with tumour size (P=0.045), lymph node metastasis (P=0.03), and recurrence (P<0.0001). Univariate analysis showed significant associations between recurrence and SUVLN (P=0.017), and tumour grade (P=0.013). Multivariate analysis identified SUVLN (P<0.0001), and tumour grade (P=0.005) as independent risk factors for recurrence. Patients with SUVLN ≤ 1.15 and SUVLN > 0.15 differed significantly in terms of recurrence (P<0.0001). Conclusion. Preoperative SUVLN measured by 18F-FDG PET/CT was significantly associated with recurrence and had significant prognostic value for recurrence-free survival in patients with colorectal cancer.


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## Body

## 1. Introduction

Colorectal cancer (CRC) is one of the most common malignant tumours worldwide [1, 2]. Surgery and chemotherapy are the main two strategies for its treatment. However, treatment outcomes for CRC remain unsatisfactory, because of recurrence and metastasis, particularly in patients with advanced CRC [3–6]. The TNM classification has been widely used to estimate prognosis and to decide on treatment of malignant tumours [7]. Lymph node (LN) metastasis is one of the most important prognostic factors in CRC because the survival rate among CRC patients with lymph node metastasis was significantly lower the rate among those without lymph node metastasis [8–11]. Traditional imaging methods play an important role in detecting lymph node metastases of malignant tumours [12, 13]. However, these methods only reflect the size, density, and morphology of the lymph nodes; the biologic activity and aggressiveness of lymph nodes cannot be determined by traditional imaging methods. Thus, alternative imaging methods that better reflect the biologic behaviour of lymph nodes in CRC are of great importance.Fluorine 18 (18F) fluorodeoxyglucose (FDG)–combined positron emission tomography (PET) and computed tomography (CT) (PET/CT) is based on the abnormally high rate of glucose metabolism found in cancer cells. It is widely used in diagnostic imaging of many malignant tumours [14–16]. Although previous studies showed that 18F-FDG PET had relatively low sensitivity in the assessment of nodal status in early-stage CRC, it showed better performance than conventional imaging methods, including CT [17, 18]. 18F-FDG PET/CT was recommended as a routine procedure in the management of CRC. However, most studies have focused on the relationship between the metabolic activity of the primary tumour and prognosis in CRC [19–21]. The metabolic activity of lymph nodes, measured as 18F-FDG uptake, possibly better reflecting the biologic behaviour or aggressiveness in CRC, has been rarely evaluated. We hypothesized that the metabolic activity of lymph nodes in patients with CRC may reflect the biologic behaviour or aggressiveness of the primary tumour and may have prognostic importance.We investigated the relationship between18F-FDG uptake by lymph nodes and clinicopathological characteristics in patients with CRC, and evaluated the significance of 18F-FDG uptake by lymph nodes for predicting recurrence in CRC patients.


## 2. Materials and Methods

### 2.1. Study Population

We included 90 patients (56 men and 34 women; age range, 43–87 y) with colorectal cancer. All had undergone18F-FDG PET/CT before radical resection between 2011 and 2017. Patients were included when they met the following criteria: they had been treated by radical resection of colorectal cancer with lymphadenectomy; the diagnosis of colorectal cancer had been confirmed by histopathologic examination; complete case records, including data on age, sex, tumour location, tumour size, T-stage, lymph node metastasis, lymphovascular invasion, tumour grade, and adjuvant treatment, were available. The study was approved by the institutional review board of the Shanghai Jiaotong University–affiliated Ren Ji Hospital and was in accordance with the 2013 revision of the Declaration of Helsinki. Informed consent was waived in this study.


### 2.2.18F-FDG PET/CT

18F-FDG PET/CT was performed using a whole-body scanner (Biograph mCT; Siemens Medical Systems). All patients received an intravenous 3.7 MBq/kg injection of 18F-FDG after having fasted for at least 6 h and rested for 1 h. The mean uptake time was 50 ± 6 min. Blood glucose levels were measured and were found to be less than 140 mg/dL at the time 18F-FDG was administered. The CT component of the scan was performed without contrast administration at 120 kV, 140 mA, and a section thickness of 5.0 mm to match the thickness of the PET images. PET image datasets were reconstructed iteratively, with the CT data applied for attenuation correction.


### 2.3. Image Analysis

For quantitative analysis, irregular regions of interest were placed over the most intense area of18F-FDG uptake. SUVmax was calculated as (maximum pixel value with the decay-corrected region-of-interest activity (MBq/mL))/(injected dose (MBq)/body weight (kg)). SUVLN was defined as the maximum standardized uptake value of suspected lymph nodes. As for the SUVLN, a single lymph node with the most avid FDG uptake was chosen for analysis and blood pool activity was used as the representative value of SUVLN, if there were no visible lymph nodes on CT scan and there was no avid 18F-FDG uptake on PET [22]. The PET/CT images were evaluated by two experienced nuclear medicine physicians.


### 2.4. Lymph Node Dissection and Histologic Evaluation

All patients were treated with radical surgery and lymphadenectomy, according to tumour location. Primary tumour and each lymph node were sliced and stained with haematoxylin and eosin and examined microscopically by a pathologist. The numbers of lymph nodes retrieved in each area and the presence or absence of metastases were recorded.


### 2.5. Clinical Endpoints and Follow-Up

After surgical resection, all patients underwent clinical follow-up that included diagnostic imaging methods and blood tests after surgical resection. During follow-up, clinical assessment, including serum CEA, CA199, and CA724 levels, was performed every 2–3 months. Enteroscopy, contrast-enhanced CT, or MRI scans were performed every 6–8 months. Median follow-up was 19 months (range, 3–72 months). In addition,18F-FDG PET/CT was performed if the clinical assessment or studies performed during follow-up showed an abnormal finding. Recurrent tumour and distant metastasis were diagnosed based on either a positive biopsy or unequivocal clinical or radiographic evidence of progression. The time to recurrence was defined as the time from the date of surgery to the date of recurrence.


### 2.6. Statistical Analysis

The relationship between the clinicopathological characteristics and recurrence were analysed by theχ2 test, the unpaired two-tailed test and the Mann–Whitney U test, where applicable. The Kaplan–Meier method with the log-rank test was used to explore the relationship between SUVLN and recurrence. The Cox proportional hazard model was used to evaluate prognostic variables. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values for predicting recurrence. The receiver operating characteristic curve was used to assess the optimal threshold of SUVLN with which to predict recurrence. Pearson correlation coefficient was used to measure the correlations between SUVLN and clinicopathological characteristics. The data are represented as mean ± standard deviation. P<0.05 was indicated significant difference. All statistical analyses were performed with SPSS software (SPSS, version 13.0; SPSS, Chicago, Ill).


## 2.1. Study Population

We included 90 patients (56 men and 34 women; age range, 43–87 y) with colorectal cancer. All had undergone18F-FDG PET/CT before radical resection between 2011 and 2017. Patients were included when they met the following criteria: they had been treated by radical resection of colorectal cancer with lymphadenectomy; the diagnosis of colorectal cancer had been confirmed by histopathologic examination; complete case records, including data on age, sex, tumour location, tumour size, T-stage, lymph node metastasis, lymphovascular invasion, tumour grade, and adjuvant treatment, were available. The study was approved by the institutional review board of the Shanghai Jiaotong University–affiliated Ren Ji Hospital and was in accordance with the 2013 revision of the Declaration of Helsinki. Informed consent was waived in this study.


## 2.2.18F-FDG PET/CT

18F-FDG PET/CT was performed using a whole-body scanner (Biograph mCT; Siemens Medical Systems). All patients received an intravenous 3.7 MBq/kg injection of 18F-FDG after having fasted for at least 6 h and rested for 1 h. The mean uptake time was 50 ± 6 min. Blood glucose levels were measured and were found to be less than 140 mg/dL at the time 18F-FDG was administered. The CT component of the scan was performed without contrast administration at 120 kV, 140 mA, and a section thickness of 5.0 mm to match the thickness of the PET images. PET image datasets were reconstructed iteratively, with the CT data applied for attenuation correction.


## 2.3. Image Analysis

For quantitative analysis, irregular regions of interest were placed over the most intense area of18F-FDG uptake. SUVmax was calculated as (maximum pixel value with the decay-corrected region-of-interest activity (MBq/mL))/(injected dose (MBq)/body weight (kg)). SUVLN was defined as the maximum standardized uptake value of suspected lymph nodes. As for the SUVLN, a single lymph node with the most avid FDG uptake was chosen for analysis and blood pool activity was used as the representative value of SUVLN, if there were no visible lymph nodes on CT scan and there was no avid 18F-FDG uptake on PET [22]. The PET/CT images were evaluated by two experienced nuclear medicine physicians.


## 2.4. Lymph Node Dissection and Histologic Evaluation

All patients were treated with radical surgery and lymphadenectomy, according to tumour location. Primary tumour and each lymph node were sliced and stained with haematoxylin and eosin and examined microscopically by a pathologist. The numbers of lymph nodes retrieved in each area and the presence or absence of metastases were recorded.


## 2.5. Clinical Endpoints and Follow-Up

After surgical resection, all patients underwent clinical follow-up that included diagnostic imaging methods and blood tests after surgical resection. During follow-up, clinical assessment, including serum CEA, CA199, and CA724 levels, was performed every 2–3 months. Enteroscopy, contrast-enhanced CT, or MRI scans were performed every 6–8 months. Median follow-up was 19 months (range, 3–72 months). In addition,18F-FDG PET/CT was performed if the clinical assessment or studies performed during follow-up showed an abnormal finding. Recurrent tumour and distant metastasis were diagnosed based on either a positive biopsy or unequivocal clinical or radiographic evidence of progression. The time to recurrence was defined as the time from the date of surgery to the date of recurrence.


## 2.6. Statistical Analysis

The relationship between the clinicopathological characteristics and recurrence were analysed by theχ2 test, the unpaired two-tailed test and the Mann–Whitney U test, where applicable. The Kaplan–Meier method with the log-rank test was used to explore the relationship between SUVLN and recurrence. The Cox proportional hazard model was used to evaluate prognostic variables. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values for predicting recurrence. The receiver operating characteristic curve was used to assess the optimal threshold of SUVLN with which to predict recurrence. Pearson correlation coefficient was used to measure the correlations between SUVLN and clinicopathological characteristics. The data are represented as mean ± standard deviation. P<0.05 was indicated significant difference. All statistical analyses were performed with SPSS software (SPSS, version 13.0; SPSS, Chicago, Ill).


## 3. Results

### 3.1. Patient Characteristics

The clinicopathological characteristics of the 90 enrolled patients are shown in Table1. The median duration of follow-up was 19 months (range, 3–72). There were 44 (48.9%) patients with colon disease and 46 (51.1%) patients with rectal disease. Seventy-one (78.9%) were well- or moderately-differentiated and 19 (21.1%) were poorly-differentiated. The median tumour size was 4.67 cm (range, 1.2–12.0). There were 27 patients (30%) with lymph node metastasis and 12 patients (13.3%) with lymphovascular invasion. Nineteen patients (21.1%) suffered recurrence.Table 1
Characteristics of 90 patients with CRR who underwent PET/CT before radical operation.
Characteristics
Patients
%
Age, median (range)
66 (43–87)
Sex
Male
56
62.2
Female
34
37.8
Tumour location
Colon
44
48.9
Rectum
46
51.1
Mean tumour size, cm (range)
4.67 (1.2–12.0)
T stage
T1/2
17
18.9
T3
47
52.2
T4
26
28.9
Lymph node metastasis
No
63
70
Yes
27
30
Lymphovascular invasion
No
78
86.7
Yes
12
13.3
Tumour grade
Well/moderate
71
78.9
Poor
19
21.1
Adjuvant treatment
No
31
34.4
Yes
59
65.6
SUV
Tumor
, median (range)
20.01 (6.3–55.4)
SUV
LN
, median (range)
2.51 (0.4–16.9)
Recurrence
No
71
78.9
Yes
19
21.1Among the 19 patients with recurrence, 17 (89.5%) experienced recurrence within the first two years. The most frequent site of recurrence was distant metastasis (n=9, 47.4%), followed by locoregional recurrence (n=6, 31.6%), and peritoneal recurrence (n=4, 21.0%). The most common site of distant metastasis was liver (n=4), followed by the lung (n=3), distant lymph node (n=1), and bone (n=1).


### 3.2. Differences between Nonrecurrent and Recurrent Patients

Table2 depicts the patient characteristics and 18F-FDG PET/CT imaging grouped by CRC patients with or without recurrence. No significant differences between these groups were found in terms of age, sex, tumour location, tumour size, lymph node metastasis, lymphovascular invasion, adjuvant treatment, or SUVTumour. However, a significant difference in SUVLN, T-stage, and tumour grade was found between these groups.Table 2
Patient characteristics according to cancer recurrence.
Characteristics
Total (n=90)
No recurrence (n=71)
Recurrence (n=19)
P
Age
66.41 ± 10.27
65.05 ± 11.34
0.618
Sex
Male
56
46
10
0.332
Female
34
25
9
Tumour location
Colon
44
32
12
0.161
Rectum
46
39
7
Tumour size
4.57 ± 1.92
5.04 ± 2.56
0.382
T stage
T1/2
17
16
1
0.023
T3
47
39
8
T4
26
14
12
Lymph node metastasis
No
63
51
12
0.464
Yes
27
20
7
Lymphovascular invasion
No
78
64
14
0.120
Yes
12
7
5
Tumour grade
Well/moderate
71
61
10
0.004
Poor
19
10
9
Adjuvant treatment
No
31
27
4
0.167
Yes
59
44
15
SUV
Tumor
20.52 ± 10.77
18.11 ± 9.75
0.409
SUV
LN
2.22 ± 0.32
3.58 ± 0.87
0.015Table3 summarizes the relationship between SUVLN and site of recurrence in 19 patients with recurrence. In the 19 patients with recurrence, the Kruskal–Wallis test showed that there were no significant differences in SUVLN between nine patients with distant metastasis (median, 3.42; range, 0.7–10.2), four patients with peritoneal recurrence (median, 3.0; range, 2.0–4.0), and six patients with locoregional recurrence (median, 3.59; range, 0.7–15.2; P=0.841).Table 3
The relationship between SUVLN and site of recurrence.
Recurrence site
Number of patients (%)
SUVLN, median (range)
P
Distant metastasis
9
3.42 (0.7–10.2)
0.841
Peritoneal recurrence
4
3.0 (2.0–4.0)
Locoregional recurrence
6
3.59 (0.7–15.2)


### 3.3. Measurement of SUVLN Cut-Off Value

ROC analysis identified a cut-off value of 1.15 as significant for SUVLN (area under the curve 0.683;P=0.015; 95% CI 0.562–0.803; Figure 1). The sensitivity and specificity at this value were 84.2% and 59.2%, respectively. Based on the ROC curve analysis, the patients could be divided into two groups: SUVLN ≤ 1.15 vs. SUVLN > 1.15.Figure 1
ROC curve analysis of recurrence prediction according to the18F-FDG uptake of lymph node in 90 patients with CRC. The area under the curve was 0.683 (95%CI 0.562–0.803, P=0.015), and 1.15 was determined as the best SUVLN cut-off value for predicting recurrence. With an SUVLN of 1.15 as the threshold, sensitivity and specificity in the prediction of recurrence were 84.2% and 59.2%, respectively.


### 3.4. Prediction of Recurrence

Table4 summarizes the results of the Cox proportional hazard model of prognostic factors for recurrence-free survival. Optimal cut-off values were 4.25 cm for tumour size and 10.65 for SUVTumour, as determined by receiver operating characteristic curve analysis. Among clinicopathological characteristics and 18F-FDG PET/CT parameters, SUVLN (P=0.017), and tumour grade (P=0.013) were risk factors for recurrence at univariate regression analysis. T-stage showed marginal significance (P=0.054). Multivariate analysis showed that SUVLN (P<0.0001) and tumour grade (P=0.005) were the independent risk factors for recurrence. The patient group categorized by SUVLN showed a significant difference in PFS (log-rank test, P<0.0001) as shown in the Kaplan–Meier survival curves (Figure 2).Table 4
Regression analyses of prognostic factors for recurrence-free survival in patients with CRC.
Variable
Test for recurrence-free survival
Univariate analysis
Multivariate analysis
Hazard ratio
95% CI
P
Hazard ratio
95% CI
P
Age
>60 versus ≤60
0.657
0.262–1.647
0.371
Sex
Male versus female
0.463
0.187–1.149
0.097
Tumour location
Rectum versus colon
0.448
0.176–1.142
0.093
Tumour size
>4.25 versus ≤4.25
2.336
0.885–6.172
0.087
T Stage
3/4 versus 1/2
2.018
0.987–4.123
0.054
Lymph node metastasis
Yes versus No
1.182
0.463–3.021
0.727
Lymphovascular invasion
Yes versus No
2.396
0.842–6.815
0.101
Tumour grade
Poor versus well/Moderate
3.143
1.272–7.767
0.013
3.837
1.501–9.81
0.005
Adjuvant treatment
Yes versus No
1.803
0.596–5.449
0.296
SUVTumor
>10.65 versus ≤10.65
1.613
0.601–4.334
0.343
SUVLN
>1.15 versus ≤1.15
4.538
1.317–15.642
0.017
10.107
2.832–36.064
<0.0001Figure 2
The Kaplan–Meier survival graph of the recurrence-free survival of patients with CRC stratified according to SUVLN. There as a statistically significant difference in recurrence-free survival between patients with SUVLN > 1.15 (green line) and SUVLN ≤ 1.15 (blue line) (P<0.001, log-rank test).


### 3.5. Correlations between SUVLN and Clinicopathological Characteristics

Table5 depicts the correlation between SUVLN and clinicopathological characteristics in patients with CRC. There were significant correlations between SUVLN and tumour size (P=0.045), lymph node metastasis (P=0.03), and recurrence (P<0.0001).Table 5
Characteristics of patients categorized according to SUVLN.
Characteristics
Total (n=90)
SUVLN
P
≤1.15
>1.15
Age
67.33 ± 10.21
64.68 ± 10.68
0.234
Sex
Male
56
28
28
0.277
Female
34
21
13
Tumour location
Colon
44
21
23
0.211
Rectum
46
28
18
Tumour size
4.27 ± 1.87
5.14 ± 2.20
0.045
T stage
T1/2
17
12
5
0.307
T3
47
23
24
T4
26
14
12
Lymph node metastasis
No
63
39
24
0.03
Yes
27
10
17
Lymphovascular invasion
No
78
43
35
0.740
Yes
12
6
6
Tumour grade
Well/Moderate
71
40
31
0.486
Poor
19
9
19
Adjuvant treatment
No
31
19
12
0.345
Yes
59
30
29
SUV
Tumor
20.09 ± 10.40
19.91 ± 10.87
0.935
Recurrence
No
71
46
25
<0.0001
Yes
19
3
16


## 3.1. Patient Characteristics

The clinicopathological characteristics of the 90 enrolled patients are shown in Table1. The median duration of follow-up was 19 months (range, 3–72). There were 44 (48.9%) patients with colon disease and 46 (51.1%) patients with rectal disease. Seventy-one (78.9%) were well- or moderately-differentiated and 19 (21.1%) were poorly-differentiated. The median tumour size was 4.67 cm (range, 1.2–12.0). There were 27 patients (30%) with lymph node metastasis and 12 patients (13.3%) with lymphovascular invasion. Nineteen patients (21.1%) suffered recurrence.Table 1
Characteristics of 90 patients with CRR who underwent PET/CT before radical operation.
Characteristics
Patients
%
Age, median (range)
66 (43–87)
Sex
Male
56
62.2
Female
34
37.8
Tumour location
Colon
44
48.9
Rectum
46
51.1
Mean tumour size, cm (range)
4.67 (1.2–12.0)
T stage
T1/2
17
18.9
T3
47
52.2
T4
26
28.9
Lymph node metastasis
No
63
70
Yes
27
30
Lymphovascular invasion
No
78
86.7
Yes
12
13.3
Tumour grade
Well/moderate
71
78.9
Poor
19
21.1
Adjuvant treatment
No
31
34.4
Yes
59
65.6
SUV
Tumor
, median (range)
20.01 (6.3–55.4)
SUV
LN
, median (range)
2.51 (0.4–16.9)
Recurrence
No
71
78.9
Yes
19
21.1Among the 19 patients with recurrence, 17 (89.5%) experienced recurrence within the first two years. The most frequent site of recurrence was distant metastasis (n=9, 47.4%), followed by locoregional recurrence (n=6, 31.6%), and peritoneal recurrence (n=4, 21.0%). The most common site of distant metastasis was liver (n=4), followed by the lung (n=3), distant lymph node (n=1), and bone (n=1).


## 3.2. Differences between Nonrecurrent and Recurrent Patients

Table2 depicts the patient characteristics and 18F-FDG PET/CT imaging grouped by CRC patients with or without recurrence. No significant differences between these groups were found in terms of age, sex, tumour location, tumour size, lymph node metastasis, lymphovascular invasion, adjuvant treatment, or SUVTumour. However, a significant difference in SUVLN, T-stage, and tumour grade was found between these groups.Table 2
Patient characteristics according to cancer recurrence.
Characteristics
Total (n=90)
No recurrence (n=71)
Recurrence (n=19)
P
Age
66.41 ± 10.27
65.05 ± 11.34
0.618
Sex
Male
56
46
10
0.332
Female
34
25
9
Tumour location
Colon
44
32
12
0.161
Rectum
46
39
7
Tumour size
4.57 ± 1.92
5.04 ± 2.56
0.382
T stage
T1/2
17
16
1
0.023
T3
47
39
8
T4
26
14
12
Lymph node metastasis
No
63
51
12
0.464
Yes
27
20
7
Lymphovascular invasion
No
78
64
14
0.120
Yes
12
7
5
Tumour grade
Well/moderate
71
61
10
0.004
Poor
19
10
9
Adjuvant treatment
No
31
27
4
0.167
Yes
59
44
15
SUV
Tumor
20.52 ± 10.77
18.11 ± 9.75
0.409
SUV
LN
2.22 ± 0.32
3.58 ± 0.87
0.015Table3 summarizes the relationship between SUVLN and site of recurrence in 19 patients with recurrence. In the 19 patients with recurrence, the Kruskal–Wallis test showed that there were no significant differences in SUVLN between nine patients with distant metastasis (median, 3.42; range, 0.7–10.2), four patients with peritoneal recurrence (median, 3.0; range, 2.0–4.0), and six patients with locoregional recurrence (median, 3.59; range, 0.7–15.2; P=0.841).Table 3
The relationship between SUVLN and site of recurrence.
Recurrence site
Number of patients (%)
SUVLN, median (range)
P
Distant metastasis
9
3.42 (0.7–10.2)
0.841
Peritoneal recurrence
4
3.0 (2.0–4.0)
Locoregional recurrence
6
3.59 (0.7–15.2)


## 3.3. Measurement of SUVLN Cut-Off Value

ROC analysis identified a cut-off value of 1.15 as significant for SUVLN (area under the curve 0.683;P=0.015; 95% CI 0.562–0.803; Figure 1). The sensitivity and specificity at this value were 84.2% and 59.2%, respectively. Based on the ROC curve analysis, the patients could be divided into two groups: SUVLN ≤ 1.15 vs. SUVLN > 1.15.Figure 1
ROC curve analysis of recurrence prediction according to the18F-FDG uptake of lymph node in 90 patients with CRC. The area under the curve was 0.683 (95%CI 0.562–0.803, P=0.015), and 1.15 was determined as the best SUVLN cut-off value for predicting recurrence. With an SUVLN of 1.15 as the threshold, sensitivity and specificity in the prediction of recurrence were 84.2% and 59.2%, respectively.


## 3.4. Prediction of Recurrence

Table4 summarizes the results of the Cox proportional hazard model of prognostic factors for recurrence-free survival. Optimal cut-off values were 4.25 cm for tumour size and 10.65 for SUVTumour, as determined by receiver operating characteristic curve analysis. Among clinicopathological characteristics and 18F-FDG PET/CT parameters, SUVLN (P=0.017), and tumour grade (P=0.013) were risk factors for recurrence at univariate regression analysis. T-stage showed marginal significance (P=0.054). Multivariate analysis showed that SUVLN (P<0.0001) and tumour grade (P=0.005) were the independent risk factors for recurrence. The patient group categorized by SUVLN showed a significant difference in PFS (log-rank test, P<0.0001) as shown in the Kaplan–Meier survival curves (Figure 2).Table 4
Regression analyses of prognostic factors for recurrence-free survival in patients with CRC.
Variable
Test for recurrence-free survival
Univariate analysis
Multivariate analysis
Hazard ratio
95% CI
P
Hazard ratio
95% CI
P
Age
>60 versus ≤60
0.657
0.262–1.647
0.371
Sex
Male versus female
0.463
0.187–1.149
0.097
Tumour location
Rectum versus colon
0.448
0.176–1.142
0.093
Tumour size
>4.25 versus ≤4.25
2.336
0.885–6.172
0.087
T Stage
3/4 versus 1/2
2.018
0.987–4.123
0.054
Lymph node metastasis
Yes versus No
1.182
0.463–3.021
0.727
Lymphovascular invasion
Yes versus No
2.396
0.842–6.815
0.101
Tumour grade
Poor versus well/Moderate
3.143
1.272–7.767
0.013
3.837
1.501–9.81
0.005
Adjuvant treatment
Yes versus No
1.803
0.596–5.449
0.296
SUVTumor
>10.65 versus ≤10.65
1.613
0.601–4.334
0.343
SUVLN
>1.15 versus ≤1.15
4.538
1.317–15.642
0.017
10.107
2.832–36.064
<0.0001Figure 2
The Kaplan–Meier survival graph of the recurrence-free survival of patients with CRC stratified according to SUVLN. There as a statistically significant difference in recurrence-free survival between patients with SUVLN > 1.15 (green line) and SUVLN ≤ 1.15 (blue line) (P<0.001, log-rank test).


## 3.5. Correlations between SUVLN and Clinicopathological Characteristics

Table5 depicts the correlation between SUVLN and clinicopathological characteristics in patients with CRC. There were significant correlations between SUVLN and tumour size (P=0.045), lymph node metastasis (P=0.03), and recurrence (P<0.0001).Table 5
Characteristics of patients categorized according to SUVLN.
Characteristics
Total (n=90)
SUVLN
P
≤1.15
>1.15
Age
67.33 ± 10.21
64.68 ± 10.68
0.234
Sex
Male
56
28
28
0.277
Female
34
21
13
Tumour location
Colon
44
21
23
0.211
Rectum
46
28
18
Tumour size
4.27 ± 1.87
5.14 ± 2.20
0.045
T stage
T1/2
17
12
5
0.307
T3
47
23
24
T4
26
14
12
Lymph node metastasis
No
63
39
24
0.03
Yes
27
10
17
Lymphovascular invasion
No
78
43
35
0.740
Yes
12
6
6
Tumour grade
Well/Moderate
71
40
31
0.486
Poor
19
9
19
Adjuvant treatment
No
31
19
12
0.345
Yes
59
30
29
SUV
Tumor
20.09 ± 10.40
19.91 ± 10.87
0.935
Recurrence
No
71
46
25
<0.0001
Yes
19
3
16


## 4. Discussion

The purpose of our study was to determine if preoperative metabolic activity in the lymph node as measured in terms of SUVmax on18F-FDG PET/CT had prognostic significance in patients with CRC. The preoperative evaluation of the metabolic activity of suspected LN by 18F-FDG PET/CT was found to be a highly accurate prognostic tool for predicting recurrence in colorectal cancer. To the best of our knowledge, this study was the first to investigate the prognostic value of preoperative SUVLN for recurrence risk in colorectal cancer treated with radical surgery.Several studies have evaluated18F-FDG PET in prognosis of patients with CRC. 18F-FDG uptake of tumour lesions was a significant prognostic factor for CRC patients who underwent curative surgical resection [19, 23]. In the present study, SUVTumour was not associated with recurrence in patients with CRC. This may be due to the small number of enrolled patients. The principle finding was that preoperative SUVLN measured on 18F-FDG PET/CT was the most significant factor for predicting recurrence in colorectal cancer. Though the TNM classification has been widely used in the clinical setting to estimate prognosis, and previous studies have demonstrated that lymph node metastasis was a well-known risk factor for disease-free survival and overall survival in patients with CRC [7–10], contrary to these prognostic factors, 18F-FDG PET was advantageous in providing prognostic information even before surgery. Although several studies have evaluated the relationship between the recurrence and the SUV of lymph node in patients with CRC pathologically confirmed node-positive disease [24, 25], our study showed that preoperative SUVLN measured on 18F-FDG PET/CT could predict the recurrence and it is not necessary to consider whether lymph node is positive.In our study, the Pearson correlation coefficient provided strong evidence that SUVLN was positively associated with lymph node metastasis, tumour size and recurrence. These results suggest that the metabolic activity of lymph node can be a useful functional marker of tumour aggressiveness. In this respect, the preoperative metabolic activity of suspected lymph node in patients with CRC, as measured by 18F-FDG PET/CT, may become a novel and promising functional biomarker for predicting recurrence before surgery.The size, density, and morphology of the lymph nodes in malignant patients with early-stage may not change significantly, and thus, in such patients CT or MRI may prove less accurate in detecting metastatic lymph nodes. Therefore, care is necessary in interpreting18F-FDG PET/CT results, especially when the lymph node size is small and the lymph node morphology is normal. False-negative findings are mainly due to the limited spatial resolution of 18F-FDG PET/CT. Therefore, preoperative metabolic activity of suspected lymph nodes in CRC patients measured by 18F-FDG PET/CT scan may be a novel biomarker for predicting recurrence. When the SUVLN in CRC patients increased, the recurrence risk increased significantly. This result emphasized the importance of the metabolic activity of lymph node and highlights the possibility that preoperative SUVLN could be a promising prognostic marker before radical surgery. More intensive attention should be paid to high SUVLN group patients. Although the clinical benefit of the intensive surveillance strategy was not evaluated, earlier detection of recurrence might influence decision-making for treatment and may affect prognosis. This strategy should be confirmed in further prospective studies.This study has several limitations. First, our study was in part limited by its retrospective design at a single institution with a small sample size. Further large prospective studies in different institutions are needed to validate the prognostic value of SUVLN in patients with CRC. Nevertheless, our study is noteworthy because it is the first study to show the importance and prognostic value of preoperative SUVLN in patients with CRC. Second, the area under the curve in the ROC analysis was 0.683, and the specificity using the cut-off of SUVLN was only 59.2%. Although the sensitivity was 84.2%, low specificity at the SUVLN cut-off value may be a problem in clinical practice. Third, we did not perform overall survival analysis because there were only six patients who were died during follow-up. Future large prospective studies are needed to investigate the relationship between SUVLN and overall survival in CRC patients.


## 5. Conclusion

In conclusion, we provide for the first time the importance of metabolic activity of lymph nodes, showing that preoperative SUVLN was an intuitive and simple method, significantly associated with recurrence in patients with CRC. Therefore, preoperative assessment of SUVLN may be a promising prognostic marker to identify patients with a high risk of recurrence of CRC.



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*Source: 5802109-2018-11-01.xml*