Prognostic impact of Creatine Kinase (CK)-MB to total-CK ratio following curative resection of stage I-III colorectal cancer

doi:10.21203/rs.3.rs-2975036/v1

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Prognostic impact of Creatine Kinase (CK)-MB to total-CK ratio following curative resection of stage I-III colorectal cancer

https://doi.org/10.21203/rs.3.rs-2975036/v1

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Objectives:

The purpose of this study was to evaluate the prognostic significance of Creatine Kinase (CK)-MB to total-CK ratio (CK-MB/CK) in patients with stage I-III colorectal cancer (CRC) after radical resection.

Methods:

This study was a single-center retrospective cohort analysis. Subjects were stage I-III CRC patients hospitalized in Sichuan Cancer Hospital from January 2017 to May 2021, who underwent curative resection. The overall survival (OS), disease-free survival rate (DFS), and recurrence were analyzed between two groups according to the serum CK-MB/CK levels after surgery, as follows: patients with postoperative CK-MB/CK greater than 1 (CK-MB/CK > 1) classified as the elevated group, and patients without postoperative CK-MB/CK greater than 1 (CK-MB/CK ≤ 1) classified as the normal group. Cox regression analyses, Kaplan-Meier method, and receiver-operating characteristic (ROC) curve were performed.

Results:

CK-MB/CK > 1 was the strongest independent prognostic factor for OS, DFS, and recurrence. Compared to the normal group (n = 1177), the elevated group (n = 95) had worse OS (HR, 5.64; 95% CI, 2.533–12.536; p < 0.0001), worse DFS (HR, 8.34; 95% CI, 5.205–13.366; p < 0.0001), and higher recurrence rate (HR, 9.44; 95% CI, 6.014–14.828; p < 0.0001). Serum CK-MB/CK levels in patients with hepatic metastasis after surgery were significantly higher than those in patients without hepatic metastasis (median 0.35 and 0.09, respectively; Mann-Whitney p = 0.000). For the diagnosis of hepatic metastases after surgery, the ROC area under the curve (AUC) of CK-MB/CK was 0.720 [95% confidence interval (CI) 0.695–0.745; p < 0.001], CA19-9 was 0.723 (95% CI 0.692–0.753; p < 0.001), and CA242 was 0.687 (95% CI 0.661–0.713; p < 0.001). When CK-MB/CK > 1.01, the specificity was 94.84% and the negative predictive value (NPV) was 96.7%. Combined CK-MB/CK and CA19-9, the AUC value increased from 0.720 to 0.799 (p = 0.0362), with a sensitivity of 77.46% and a specificity of 97.25%.

Conclusions:

In stage I-III CRC patients with radical resection, patients with postoperative CK-MB/CK > 1 had a worse prognosis, a shorter survival time, and a higher risk of recurrence. CK-MB/CK might be a new biomarker for the diagnosis of hepatic metastasis in CRC patients after surgery, with high specificity and NPV.

Colorectal cancer

Prognosis

Biomarkers

Creatine Kinase

Hepatic metastasis

Colorectal cancer (CRC) is one of the most lethal malignancies worldwide. According to global cancer estimates, CRC ranks third in incidence but second in mortality[1]. In China, the incidence and mortality have both increased in the most recent decade[1], and the 1-year, 3-year, and 5-year survival rates were 0.79, 0.72, and 0.62 respectively[2]. Currently, radical resection is one of the main treatments for this disease. However, post-surgery, 30% of stage II and 50–60% of stage III patients develop recurrence or metastases within 5 years[3, 4]. Up to 50% of patients with the initially localized disease will develop metastases[5]. For this reason, recurrence and metastases after surgery remain the leading cause of treatment failure and cancer-related death[4, 6]. It is urgent to explore effective postoperative surveillance biomarkers to reduce the huge economic burden on society of this disease.

Creatine kinase (CK) is a central controller of cellular energy homeostasis, widely presented in body tissues. It reversibly catalyzes the formation of creatine phosphate and adenosine diphosphate from creatine and adenosine triphosphate, playing an important role in tissues with high energy demands[7]. CK has three major isoenzymes: CK-MM, CK-MB, and CK-BB[8]. In addition, Mitochondrial creatine kinase (MtCK) and macro-CK were also reported as different forms of CK in vivo[9, 10]. CK-MB is mainly used for the diagnosis of myocardial injury[11, 12]. When myocardial cells are damaged, serum CK-MB activity levels increase. For the determination of CK-MB, the immunoinhibition method is utilized most commonly. However, the detection of CK-MB activity by immunosuppressive assays might be affected by the presence of CK isoenzymes in the serum[13]. When CK-BB[14] or macro-CK[7, 15] is presented in the serum of tumor patients, even without myocardial injury, detected by the immunoinhibition method, abnormal results of increased CK-MB activity could occur[14, 16]. When a large number of CK-BB and macro-CK exist, there may even be an abnormal situation with CK-MB to total CK ratio (CK-MB/CK) exceeding 1[17]. The most common malignant tumor with CK-MB/CK greater than 1(CK-MB/CK > 1) was CRC[13, 18]. In our hospital, the phenomenon of CK-MB/CK > 1 measured by the immunosuppression method in CRC patients was also frequently observed. These patients did not show evidence of myocardial injury. It is speculated that other potential pathological factors may lead to the elevated expression of CK-BB and macro-CK in the serum of tumor patients. However, their role in tumors is not fully understood. Earlier studies had shown that macro-CK detected in the serum of patients with hepatocellular carcinoma[7, 19] and breast cancer[20] had prognostic significance. These findings suggest that CK-BB or macro-CK activity might be a potential biomarker in cancer patients[21, 22]. The CK-MB/CK is an easily available indicator and could be clinically utilized as a primary screening tool for cancer[13]. Given the emerging link between increased CK-MB activity detected by the immunosuppressive method in cancer patients and their poor prognosis[8], serum CK-MB/CK might ultimately serve as a prognostic marker, an issue that deserves further investigation. At present, no studies have reported the role of abnormally elevated CK-MB activity in the prognosis of patients with CRC. Therefore, this study is the first to explore the role of CK-MB/CK in postoperative patients with CRC.

In this retrospective study, we analyzed whether 1272 patients with stage I-III CRC had abnormal CK-MB/CK > 1 after surgery, and the prognostic value of CK-MB/CK > 1 in survival, recurrence, and metastasis.

Study population and design

The study population comprised colorectal cancer patients who were hospitalized in the Sichuan Cancer Hospital between January 2017 and May 2021. The inclusion and exclusion criteria were as follows:

Inclusion criteria: (1) patients with colon cancer or rectal cancer diagnosed by histopathology; (2) patients with stages I-III as determined by the tumor-node-metastasis (TNM) stages established by the American Joint Committee on Cancer (AJCC); (3) patients with completed resection of the primary tumor; (4) patients with postoperative follow-up data; (5) patients with available postoperative serum CK-MB and total CK measurements.

Exclusion criteria: (1) patients with a history of other malignancies; (2) patients with an unknown pathological stage; (3) patients classified as Tis by histopathology; (4) patients with stage IV; (5) patients with myocardial injury caused by different reasons, including cardiovascular complications[23], COVID-19 infection[24], myocardial injury after noncardiac surgery [25], etc. Based on clinical manifestations and laboratory evidence, such as chest pain, electrocardiogram examination, cardiac troponin, myoglobin, and brain natriuretic peptide, etc.[26]; (6) patients with uncompleted data.

Finally, a total of 1272 patients were enrolled in the retrospective study. We extracted necessary data from medical records, such as demographics, clinical data, laboratory results, histological findings, follow-up, elapse time to either local or distant recurrence, the short and long term outcome as well as survival, etc. Follow-up data included prognosis, mortality status, and recurrence after the surgery. Overall Survival (OS) was calculated from the date of surgery registration until death or the end of the study. Disease-free survival (DFS) refers to the time from surgical operation to the date of tumor recurrence, metastasis, or the appearance of tumor-related diseases.

Patients were divided into the following two groups according to the presence of CK-MB/CK greater than 1 at postoperative follow-up: postoperative CK-MB/CK > 1 (the elevated group), and postoperative CK-MB/CK ≤ 1 (the normal group). OS, DFS, and recurrence were investigated in each group. The Institutional Review Board (IRB) of the Sichuan Cancer Hospital approved this retrospective study (IRB code:SCCHEC-02-2022-017).

Serum analyses

Serum total CK and CK-MB concentrations were measured by Mindray BS-2000M automatic biochemical analyzer (Mindray Bio-Medical Electronics Corporation, Shenzhen, Guangdong, China), using the phosphocreatine substrate method and the immunosuppression method, respectively. The reference range of CK-MB was set at ≤ 25 U/L. The reference range of total CK was 24 ~ 194 U/L for males and 24 ~ 170U/L for females. The results of CK-MB and total CK must be measured with the same serum on the same day. In the case of several measurements showing CK-MB/CK > 1, the first value was considered. We took the first test result because through it we were able to identify patients' health status earlier after surgery. The serum carbohydrate antigen 50 (CA50) and carbohydrate antigen 242 (CA242) concentrations were measured by the Mindray CL-6000i chemiluminescence analyzer (Mindray Bio‐Medical Electronics Corporation, Shenzhen, Guangdong, China). The serum carbohydrate antigen 724 (CA72-4), carbohydrate antigen 199 (CA19-9), and Carcinoembryonic antigen (CEA) concentrations were detected using the Roche e411 electrochemiluminescence analyzer (Roche Diagnostics, Mannheim, Germany). The reference range of CEA was set at ≤ 5 ng/ml, CA50 was set at ≤ 25 U/ml, CA19-9 was set at ≤ 37 U/ml, CA242 was set at ≤ 20 U/ml, CA72-4 was set at ≤ 6.9 U/ml.

Statistical analysis

Using the Kolmogorov–Smirnov test to determine normally distributed. The normally distributed data were depicted as the mean and standard deviation, and the non-normal distributed data were shown as the median and interquartile range. Pearson's Chi-square test and the Kruskal-Wallis test were performed for categorical variables and continuous variables, respectively. The Kaplan-Meier method was used to estimate OS, DFS, and recurrence. The median follow-up time was calculated by the Reverse Kaplan-Meier method, which considered the weight of the study object with the outcome event, and the results were more accurate. Differences in survival were assessed with the log-rank test. Cox regression analysis was used to estimate the independent effect of covariates on recurrence and death as measured by adjusted hazard ratio (HR) with a 95% confidence interval (CI). Variables that were statistically significant in the univariate Cox regression were included in the multivariate analysis. Multivariable Cox regression models were subsequently fitted to evaluate factors independently associated with recurrence and death.

Receiver operating characteristic (ROC) curves were used to assess the performance of biomarkers by MedCalc 12.7 (MedCalc Software, Ostend, Belgium). Optimal cut-off points were determined based on ROC curves. The biomarker combinations were based on a scoring system that attributed one point for each marker with a value above the cut-off point. And the area under the ROC curve (AUC), sensitivity, specificity, positive predictive value (PPV), negative predictive value(NPV), and positive and negative likelihood ratio was calculated.

A two-sided P-value of less than 0.05 was considered statistically significant, and 95% CI was calculated. All statistical analyses were performed with the IBM SPSS Statistics Program, version 24, or Python version 3.6.8 (Python Project).

Subjects

From January 2017 to May 2021, 4965 CRC patients were treated in our hospital. 3693 patients who didn’t meet the inclusion and exclusion criteria were excluded, including 1789 patients without completed resection of the primary tumor or postoperative follow-up, 728 patients without postoperative serum CK-MB/CK results, 245 patients with a history of other malignancies, 357 patients with an unknown pathological stage, 4 patients classified as Tis, 393 patients with stage IV, 45 patients with myocardial injury, and 132 patients with uncompleted data. Finally, 1272 patients with stage I-III were included in the analysis. Among them, 95 patients were classified in the elevated group, and 1177 patients were classified in the normal group. The study design and flowchart were described in Figure 1. Since the first patient was included, we counted the number and proportion of patients included each year. The results showed that 71.86% of patients were included in 2017-2019 (Supplementary Table 1). The median follow-up time of our study population was 32.6 months (95%CI, 30.964-34.236) ( Supplementary Table 2).

Table 1 summarizes the clinical and laboratory variables of CRC patients in the elevated and normal groups. Overall, clinical features were well-balanced between the two groups. There were no significant differences in age, gender, or primary site of cancer. Besides, other variables indicating disease severity, such as TNM stage(AJCC 8th), tumor differentiation, depth of tumor, or regional lymph nodes were not significantly different between the two groups. In terms of treatment, there was no significant difference between the two groups in neoadjuvant therapy, while postoperative adjuvant chemotherapy showed a significant difference (P = 0.003). However, several variables differed significantly, such as survival status, postoperative recurrence, distant metastasis, CEA, CA50, CA19-9, CA242, CA72-4, CK-MB, and serum total-CK levels. Patients with CK-MB/CK>1 in the elevated group had a higher percentage of outliers in serum CEA, CA50, CA19-9, CA242, CA72-4, and CK-MB (all P < 0.000). What’s more, they also had a higher proportion of dead (42.1% vs. 7.8%), postoperative recurrence(65.3% vs. 9.7%), and postoperative distant metastasis (98.4% vs. 91.2%) than patients in the normal group(Table 1).

Table 1 Clinicopathologic characteristics of patients with normal (⩽1) and elevated (>1) postoperative serum CK-MB/CK concentrations.

Parameter	Total	Normal group	Elevated group	P value
Parameter	n=1272	n=1177	n=95
Age (years)	1272	62.0(53.0-70.0)	58.2±13.1	0.087
≤ 60	576(45.3)	525(44.6)	51(53.7)
＞60	696(54.7)	652(55.4)	44(46.3)
Gender	1272			0.805
Male	725(57.0)	672(57.1)	53(55.8)
Female	547(43.0)	505(42.9)	42(44.2)
Primary site	1272			0.101
Colon	554(43.6)	505(42.9)	49(51.6)
Rectum	718(56.4)	672(57.1)	46(48.4)
Differentiation	1028	949	79	0.937
Well	157(12.3)	136(11.6)	21(22.1)
Moderate	696(54.7)	660(56.1)	36(37.9)
Poor	175(13.8)	153(13.0)	22(23.2)
Not available	244(19.2)	228(19.4)	16(16.8)
TNM stage(AJCC 8th)	1272			0.258
I	195(15.3)	179(15.2)	16(16.8)
II	450(35.4)	427(36.3)	23(24.2)
III	627(49.3)	571(48.5)	56(58.9)
Depth of tumor	1272			0.085
T1	58(4.6)	53(4.5)	5(5.3)
T2	182(14.3)	171(14.5)	11(11.6)
T3	650(51.1)	611(51.9)	39(41.1)
T4	382(30.0)	342(29.1)	40(42.1)
Regional lymph nodes	1272			0.120
N0	645(50.7)	606(51.5)	39(41.1)
N1	436(34.3)	395(33.6)	41(43.2)
N2	191(15.0)	176(15.0)	15(15.8)
Neoadjuvant therapy	1272			0.307
Yes	332(26.1)	303(25.7)	29(30.5)
No	940(73.9)	874(74.3)	66(69.5)
Adjuvant chemotherapy	1272			0.003
Yes	828(65.1)	753(64.0)	75(78.9)
No	444(34.9)	424(36.0)	20(21.1)
Dead	1272			0.000
Yes	132(10.4)	92(7.8)	40(42.1)
No	1140(89.6)	1085(92.2)	55(57.9)
Recurrence	1272			0.000
Yes	176(13.8)	114(9.7)	62(65.3)
No	1096(86.2)	1063(90.3)	33(34.7)
Site of recurrence	176	114	62
Distant	165(93.75)	104(91.2)	61(98.4)	0.000
Local	11(6.25)	10(8.8)	1(1.6)	0.837
CEA	1272			0.000
normal	781(61.4)	766(65.1)	15(15.8)
elevated	491(38.6)	411(34.9)	80(84.2)
CA50	849	782	67	0.000
normal	743(58.4)	718(61.0)	25(26.3)
elevated	106(8.3)	64(5.4)	42(44.2)
Not available	423(33.3)	395(33.6)	28(29.5)
CA19-9	871	790	81	0.000
normal	726(57.1)	696(59.1)	30(31.6)
elevated	145(11.4)	94(8.0)	51(53.7)
Not available	401(31.5)	387(32.9)	14(14.7)
CA242	1270	1176	94	0.000
normal	1077(84.7)	1037(88.1)	40(42.1)
elevated	193(15.2)	139(11.8)	54(56.8)
Not available	2(0.2)	1(0.1)	1(1.1)
CA72-4	851	784	67	0.000
normal	595(46.8)	574(48.8)	21(22.1)
elevated	256(20.1)	210(17.8)	46(48.4)
Not available	421(33.1)	393(33.4)	28(29.5)
CK-MB (U/L)	1272	10.8(8.2-14.5)	98.0(45.8-212.4)	0.000
CK (U/L)	1272	117.0(68.0-223.0)	69.0(39.0-146.0)	0.000

Data were shown as median (interquartile ranges), mean±standard deviation, number (percentage); P values from the Mann-Whitney test, Pearson's chi-square test, or Fisher's exact test, where appropriate. AJCC: American Joint Committee on Cancer, CEA: carcinoembryonic antigen, CA: carbohydrate antigen, CK-MB: creatine kinase myocardial band, CK: creatine kinase.

What’s more, we compared the correlation between CK-MB/CK and other biomarkers, including CEA, CA50, CA19-9, CA242, and CA72-4. The results showed that serum expression levels of CK-MB/CK were significantly positively correlated with these biomarkers, whether in the total study population or subgroups of different stages, genders, and age ranges(≤60 or＞60 years old) (Supplementary Table 3).

Univariable and multivariable Cox regression analyses of prognostic factors for overall survival, disease-free survival, and recurrence.

Postoperative CK-MB/CK>1 (defined as elevated CK-MB/CK) was found to be the strongest prognostic factor for OS, DFS, and recurrence (Table 2). In the univariate analysis, age (＞60 years, P = 0.044), primary site (rectum, P = 0.002), tumor differentiation (low, P < 0.0001), regional lymph nodes (N1 or N2, P < 0.0001), TNM stage (stage III, P = 0.006), postoperative CEA (elevated, P < 0.0001), postoperative CA50 (elevated, P < 0.0001), postoperative CA19-9 (elevated, P < 0.0001), postoperative CA242 (elevated, P < 0.0001), postoperative CA72-4 (elevated, P = 0.001), and CK-MB/CK (elevated, P < 0.0001) were significantly associated with worse OS. After adjusting for the above clinicopathologic parameters, postoperative CA19-9 (elevated, P = 0.046), postoperative CA242 (elevated, P = 0.024), and elevated CK-MB/CK (HR, 5.64; 95% CI, 2.533– 12.536; p < 0.0001) were ultimately identified as independent prognostic makers for worse OS in the multivariate analysis. In terms of DFS, CK-MB/CK>1 remained an independent predictor in the multivariate analysis (HR, 8.34; 95% CI, 5.205– 13.366; p < 0.0001), along with the primary site and CA242. In terms of recurrence, CK-MB/CK>1 also remained an independent predictor in the multivariate analysis (HR, 9.44; 95% CI, 6.014– 14.828; p < 0.0001), along with the age, primary site, CA19-9, and CA242 (Table 2).

Table 2 Univariable and multivariable cox regression analyses of prognostic factors for overall survival, disease-free survival, and recurrence.

Variable	OS						DFS						Recurrence
	Univariate analysis			Multivariate analysis			Univariate analysis			Multivariate analysis			Univariate analysis			Multivariate analysis
	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Gender
male	1.00						1.00						1.00
female	0.82	0.58-1.17	0.270				0.81	0.63-1.05	0.109				0.87	0.64-1.17	0.358
Age(years)
≤60	1.00			1.00			1.00						1.00			1.00
＞60	1.44	1.01-2.04	0.044	1.36	0.74-2.50	0.320	0.85	0.66-1.09	0.202				0.62	0.46-0.84	0.002	0.62	0.46-0.86	0.004
Primary site
Colon	1.00			1.00			1.00			1.00			1.00			1.00
Rectum	1.83	1.26-2.66	0.002	1.56	0.78-3.10	0.205	2.64	1.97-3.56	0.000	2.97	1.97-4.47	0.000	2.65	1.87-3.76	0.000	4.89	3.24-7.38	0.000
Differentiation
low	1.00			1.00			1.00			1.00			1.00
medium	0.29	0.18-0.48	0.000	0.56	0.28-1.12	0.098	0.48	0.33-0.69	0.000	0.60	0.39-0.92	0.020	0.61	0.40-0.95	0.028
high	0.53	0.29-0.97	0.038	0.62	0.25-1.56	0.311	0.61	0.38-0.97	0.037	0.65	0.36-1.15	0.135	0.84	0.49-1.43	0.515
T
T1	1.00						1.00						1.00
T2	1.09	0.36-3.30	0.885				1.08	0.49-2.37	0.851				1.14	0.46-2.81	0.779
T3	1.43	0.52-3.92	0.492				1.44	0.71-2.95	0.316				1.36	0.60-3.11	0.466
T4	1.82	0.66-5.03	0.249				1.51	0.73-3.13	0.264				1.47	0.63-3.40	0.369
N
N0	1.00			1.00			1.00			1.00			1.00			1.00
N1	2.24	1.48-3.38	0.000	0.56	0.24-1.31	0.179	2.08	1.56-2.77	0.000	1.34	0.90-1.98	0.149	1.96	1.41-2.74	0.000	1.29	0.89-1.87	0.173
N2	3.96	2.55-6.16	0.000	0.90	0.37-2.16	0.805	2.67	1.91-3.74	0.000	1.25	0.77-2.01	0.370	2.09	1.39-3.16	0.000	1.28	0.81-2.00	0.288
Stage
I	1.00						1.00						1.00
II	0.72	0.37-1.38	0.315				0.76	0.49-1.20	0.238				0.74	0.45-1.23	0.248
III	2.19	1.25-3.85	0.006				1.87	1.26-2.78	0.002				1.63	1.04-2.56	0.032
CEA
normal	1.00			1.00			1.00			1.00			1.00			1.00
elevated	3.74	2.60-5.39	0.000	2.08	0.98-4.39	0.057	2.70	2.09-3.48	0.000	0.99	0.67-1.47	0.963	2.81	2.07-3.80	0.000	1.08	0.74-1.58	0.696
CA50
normal	1.00			1.00			1.00			1.00			1.00			1.00
elevated	4.49	2.88-7.00	0.000	1.25	0.31-5.0	0.751	3.78	2.75-5.19	0.000	1.67	0.67-4.16	0.274	4.16	2.94-5.88	0.000	1.35	0.62-2.97	0.453
CA19-9
normal	1.00			1.00			1.00			1.00			1.00			1.00
elevated	4.43	2.90-6.78	0.000	4.24	1.03-17.52	0.046	3.55	2.64-4.78	0.000	2.43	0.99-5.92	0.052	3.82	2.76-5.28	0.000	3.08	1.44-6.57	0.004
CA242
normal	1.00			1.00			1.00			1.00			1.00			1.00
elevated	3.63	2.52-5.22	0.000	0.30	0.11-0.86	0.024	2.74	2.06-3.65	0.000	0.38	0.20-0.70	0.002	2.94	2.11-4.10	0.000	0.41	0.23-0.73	0.003
CA72-4
normal	1.00			1.00			1.00			1.00			1.00			1.00
elevated	2.13	1.39-3.28	0.001	1.67	0.89-3.13	0.110	1.72	1.29-2.30	0.000	1.25	0.87-1.80	0.229	1.94	1.41-2.67	0.000	1.39	0.98-1.96	0.064
CK-MB/CK
normal	1.00			1.00			1.00			1.00			1.00			1.00
elevated	6.91	4.76-10.03	0.000	5.64	2.53-12.54	0.000	8.13	6.10-10.84	0.000	8.34	5.21-13.37	0.000	12.22	8.93-16.72	0.000	9.44	6.01-14.83	0.000

P values from Mann-Whitney U test. Abbreviations: OS, overall survival; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; CK-MB, creatine kinase myocardial band; CK, creatine kinase.

The impact of postoperative CK-MB/CK on long-term outcomes after the curative reaction

Patients with postoperative CK-MB/CK>1 showed impaired OS compared with patients with postoperative CK-MB/CK≤1 (38.055 months vs. 54.218 months; HR, 6.857, 95% CI, 3.336–14.090; P < 0.0001). Survival rates at 3 years in the CK-MB/CK≤1 and CK-MB/CK＞1 groups were 90.6% and 54.4%, respectively. On the other hand, patients with postoperative CK-MB/CK>1 had significantly shorter DFS (23.378 months vs. 48.937 months; HR, 7.844, 95% CI, 4.261– 14.440; P < 0.0001) than patients with CK-MB/CK≤1. What's more, patients with CK-MB/CK>1 had significantly shorter recurrence (24.568 months vs. 51.752 months; HR, 11.64, 95% CI, 5.691– 23.800; P < 0.0001) than patients with CK-MB/CK≤1 (Figure 2).

In the elevated group, a total of 62 (65.26%) patients developed a recurrence of the disease after surgery. One patient developed local recurrence(1.1%), while the remaining 61 developed distant metastases namely: liver (n=32, 33.7%), lung (n=9, 9.5%), bone (n=6, 6.3%), and other sites (n=18, 18.9%). In the normal group, a total of 114(9.69%) patients had a recurrence or distant metastasis, including local recurrence(n=10, 0.8%), liver (n=30, 3.3%), lung (n=49, 4.2%), bone (n=13, 1.1%), and other sites(n=19, 1.6%) ( Table 3). What’s more, by correlation analysis, we found that CA19-9, CA242, and CK-MB/CK were correlated significantly with liver metastasis (Spearman’s Rho 0.208, P=0.000; Rho 0.149, P=0.000; Rho 0.175, P=0.000, respectively), but weakly correlated with lung metastasis(Table 4).

Table 3 The locoregional or systemic recurrence after operation in the elevated group and the normal group

	Normal group n=1177	Elevated group n=95	P value
Locoregional recurrence	10(0.8)	1(1.1)	0.576
Systemic recurrence
Hepatic	39(3.3)	32(33.7)	0.000
Pulmonary	49(4.2)	9(9.5)	0.034
Bone	13(1.1)	6(6.3)	0.002
Other*	19(1.6)	18(18.9)	0.000

*Other anatomic sites included the abdominal cavity, pelvic cavity, adnexa, ovary, uterus, and bladder.

Table 4 The correlation analysis of biomarkers and systemic recurrence after surgery.

Biomarkers		Hepatic	Pulmonary	Bone	Other*
CA19-9	Rho	0.208	0.022	0.030	0.049
	P	0.000	0.523	0.369	0.148
CA242	Rho	0.149	0.017	0.017	0.033
	P	0.000	0.548	0.551	0.241
CK-MB/CK	Rho	0.175	0.041	0.061	0.138
	P	0.000	0.147	0.030	0.000

Rho and P values from Spearman’s correlation test. *Other anatomic sites included the abdominal cavity, pelvic cavity, adnexa, ovary, uterus, and bladder. CK-MB/CK, creatine kinase myocardial band to total creatine kinase ratio.

Biomarkers in hepatic metastases versus non-hepatic metastases patients after surgery.

Among the 869 cancer patients who had the results of CA19-9, CA242, and CK-MB/CK, we compared the serum expression levels of those biomarkers between the hepatic metastases and non-hepatic metastases patients after surgery. The results showed that CA19-9, CA242, and CK-MB/CK all had significant differences between the two groups. Compared with the non-hepatic metastases patients, the hepatic metastases had higher CA19-9 (median 35.46 U/ml and 12.22 U/ml, respectively; Mann-Whitney P=0.000), CA242 (median 12.27 U/ml and 5.81 U/ml, respectively; Mann-Whitney P=0.000), and CK-MB/CK (median 0.35 and 0.09, respectively; Mann-Whitney P=0.000) (Table 5).

Table 5 The serum expression levels of biomarkers in the hepatic metastases and non-hepatic metastases patients after surgery.

Biomarkers	Hepatic metastases (n = 68)	Non-hepatic metastases (n = 801)	P value
CA19-9(U/ml)	35.46(14.69-226.50)	12.22(6.67-23.91)	0.000
CA242(U/ml)	12.27(4.40-85.91)	5.81(2.71-11.94)	0.000
CK-MB/CK	0.35(0.07-1.22)	0.09(0.05-0.18)	0.000

P values from Mann-Whitney U test. CA, carbohydrate antigen; CK-MB/CK, creatine kinase myocardial band to total creatine kinase ratio.

Performance of CK-MB/CK and other tumor markers to predict hepatic metastasis

To examine the potential predictability of serum CK-MB/CK for liver metastasis after colorectal cancer surgery, ROC were plotted to define the optimal cut-off values and to identify the sensitivity and specificity of CK-MB/CK, CA242, and CA19-9 for differentiating patients with hepatic metastases from those without hepatic metastases. The results showed that the AUC for serum CK-MB/CK was 0.720 [95% confidence interval (CI) 0.695-0.745; P<0.001], CA19-9 was 0.723 (95% CI 0.692-0.753; P<0.001), and CA242 was 0.687 (95% CI 0.661-0.713; P<0.001). Thus, CK-MB/CK had an AUC between that of CA242 and CA19-9. The optimal cut-off value for each marker was presented in Table 6. When CK-MB/CK>1.01, the specificity was 94.84% and the NPV was 96.7%. What’s more, we tested combinations including two and three of these markers. The results showed that only combined two markers, CK-MB/CK and CA19-9, for the diagnosis of hepatic metastases, the AUC value increased from 0.720 to 0.799(p = 0.0362), the sensitivity was increased to 77.46%, the specificity was increased to 97.25% (Table 6).

Table 6 Diagnosis ability of biomarkers to distinguish hepatic metastases and non-hepatic metastases after surgery.

Biomarkers	P	AUC (95% CI)	Cut-off	Sensitivity (%)	Specificity (%)	PLR	NLR	PPV (%)	NPV (%)
Individual biomarkers
CA19-9	<0.001	0.723(0.692-0.753)	>18.16	73.53	66.13	2.17	0.40	15.5	96.7
CA242	<0.001	0.687(0.661-0.713)	>11.72	53.52	79.07	2.56	0.59	13.1	96.6
CK-MB/CK	<0.001	0.720(0.695-0.745)	>0.35	53.52	90.59	5.69	0.51	25.2	97.1
			>1.01	45.07	94.84	8.73	0.58	34.0	96.7
Two biomarkers
CK-MB/CK+CA19-9	<0.001	0.799(0.776-0.821)	≥1positive	77.46	74.94	3.09	0.30	15.4	98.3
			=2positive	38.03	97.25	13.84	0.64	45.0	96.4
CK-MB/CK+CA242	<0.001	0.722(0.697-0.747)	≥1positive	60.56	76.94	2.63	0.51	13.4	97.1
			=2positive	38.03	97.00	12.69	0.64	42.9	96.4
CA19-9+CA242	<0.001	0.749(0.724-0.773)	≥1positive	76.06	71.19	2.64	0.34	13.5	98.1
			=2positive	47.89	85.26	3.25	0.61	16.1	96.5
Three biomarkers
CK-MB/CK+CA19-9+CA242	<0.001	0.785(0.762-0.808)	≥1positive	78.87	69.28	2.57	0.30	13.2	98.2
			=2positive	56.34	84.51	3.64	0.52	17.7	97.0
			=3positive	33.80	97.50	13.53	0.68	44.4	96.1

AUC, area under the curve; CI, confidence interval; PLR, positive likelihood ratio; NLR, negative likelihood ratio; PPV, positive predictive value; NPV, negative predictive value; CA, carbohydrate antigen; CK-MB/CK, creatine kinase myocardial band to total creatine kinase ratio.

The incidence rate of cancer has been increasing worldwide[27]. Thus, it is necessary to establish effective biomarkers to monitor cancer risk. However, novel tumor markers are usually cost-ineffective at the initial beginning, resulting in unpopular application in clinical laboratories. Hence, easily available biomarkers that help risk evaluation and diagnosis of cancer would be useful and applicable in clinical practice. The ratio of CK-MB and total CK(CK-MB/CK), based on the data of CK-MB activity and total CK activity that were commonly used in the evaluation of the myocardial injury[11], was a widely available indicator that could be applied to cancer in clinical laboratories. Many studies have shown that the higher CK-MB/CK ratio was specifically associated with certain malignancies[18], like CRC, lung cancer, pancreatic cancer[28], and hepatocellular carcinoma[13]. However, the specific relationship between a tumor and its pathogenesis is not clear. In this research institution, we observed that there were many measurements of CK-MB/CK > 1 in CRC patients, consistent with what Chang C C et al.[18] reported. Therefore, our study aims to explore the relationship between CK-MB/CK > 1 and CRC patients.

We compared the clinical data of patients with postoperative CK-MB/CK > 1 and those without postoperative CK-MB/CK > 1 after radical resection of colorectal cancer and tried to find the clinical features or laboratory-related test indicators associated with this difference. The results showed that there was no significant difference between the normal group and the elevated group in age, sex, primary cancer site, tumor differentiation, and TNM stage, which showed that the difference was not caused by the above factors. Interestingly, we observed a significant difference between the two groups in the proportion of postoperative survival status, recurrence, and metastasis. Research reports that regional lymph nodes were a significant prognosis factor of survival after surgery[29]. However, the differences in survival in our study were not caused by regional lymph nodes. We speculated that CK-MB/CK might be a potential new prognostic indicator for CRC patients after radical surgery. In addition, we also observed that the proportion of abnormal increase of tumor markers (CEA, CA50, CA19-9, CA242, and CA72-4) in the postoperative follow-up was significantly higher in the elevated group. CA72-4 were valuable indicators in predicting tumor recurrence survival in non-metastatic CRC patients undergoing surgery[30]. In radically operated CRC patients, a postoperatively elevated CEA or CA19-9 might indicate patients at high risk of relapse[31–34]. Thus, we speculated that CK-MB/CK might have synergistic effects with these tumor markers.

To explore the role of CK-MB/CK in postoperative follow-up, we further analyzed the role of CK-MB/CK in OS, DFS, and recurrence through univariate and multivariate Cox regression. The results showed that postoperative CK-MB/CK > 1 was the strongest independent prognostic factor for OS, DFS, and recurrence. The Kaplan-Meier results showed that patients with postoperative CK-MB/CK > 1 had worse OS and DFS, and were more prone to recurrence. After surgery, those patients had a worse prognosis, shorter survival time, and higher risk of recurrence and distant metastasis than those in the normal group. Therefore, we analyzed the specific situation of recurrence and metastasis in the elevated group and the normal group. No significant differences were found between the two groups in locoregional recurrence. However, there were significant differences in distant metastasis, such as liver metastasis, lung metastasis, and bone metastasis. Presumably, postoperative CK-MB/CK > 1 might be related to specific organs or tissues with distant metastasis. As the previous studies reported, it was possible to further distinguish tissue damage by measuring the activity of different CK subtypes[13]. Kovar FM et al.[13] also found that the CK-MB/CK ratio might reflect the extent of inner organ damage, which usually represented one of the major prognostic risk factors. Therefore, we further studied the relationship between CK-MB/CK and metastasis sites. Through correlation analysis, CA19-9, CA242, and CK-MB/CK were found to be significantly correlated with liver metastasis. However, the correlation with lung metastasis and bone metastasis were weak.

To confirm the relationship between postoperative CK-MB/CK and liver metastasis, the 869 patients with CK-MB/CK, CA19-9, and CA242 detection results were analyzed separately. The serum expression levels of these biomarkers were compared between patients with liver metastasis and patients without liver metastasis after the operation. We found that patients with liver metastasis had higher levels of serum CK-MB/CK, CA19-9, and CA242. This was consistent with the previous research findings of Kovar FM et al.[13] and Chang C C et al.[18], that the CK-MB/CK ratio was markedly higher in liver metastasis than in non-liver metastasis. Furthermore, it was recently reported that higher CK-BB activity was associated with human liver metastasis[35], and serum MtCK activity increases in patients with liver cancer[7], which was partially compatible with and illustrates our results. But the underlined mechanism remained unknown and could be worth further research. Could this significant difference in expression level be used as an effective criterion to distinguish between postoperative liver metastasis and non-liver metastasis? Therefore, we further analyzed the ROC curve. The results showed that the AUC of CK-MB/CK was 0.720, that of CA19-9 was 0.723, and that of CA242 was 0.687. CA19-9 had the highest sensitivity and CK-MB/CK had the highest specificity. When CK-MB/CK > 1.01, the specificity was 94.84% and NPV was 96.7%. When we combined those biomarkers for diagnosis, we found that when only CK-MB/CK and CA19-9 were combined, the maximum AUC value was 0.799, the sensitivity was increased to 77.46%, and the specificity was increased to 97.25%.

There were several limitations in our study. All subjects were stage I-III patients without distant metastasis. In stage IV patients with distant metastasis, the prognostic value of CK-MB/CK needs further exploration. Additionally, our study didn’t rule out clinical conditions that could lead to high CK-MB to total CK ratios rather than neoplasms, including brain injury, skeletal muscle injury, poly traumatism [13], or severe shock syndrome because cancer patients usually had other complications. These comorbidities might also cause CK-MB/CK > 1. In addition, the abnormal CK-MB activity estimated by the immunosuppression method has not been further determined. It might be caused by an increase in specific CK isoenzyme subtypes, which would have a specific role in CRC and need to be further clarified.

In conclusion, our results demonstrated that postoperative CK-MB/CK was a potentially valuable prognostic marker after surgery in patients with stage I-III colorectal cancer. It could evaluate OS, DFS, and recurrence of patients after radical surgery. It might be useful to detect the serum CK-MB/CK in stage I-III CRC after surgery in judging the prognosis. The serum CK-MB/CK might be a new biomarker for the diagnosis of postoperative liver metastasis in CRC patients, with high specificity and NPV. Besides, CK-MB/CK used in combination with CA19-9, the sensitivity can also be significantly improved in diagnosing postoperative liver metastasis.

CK: Creatine Kinase

CK-MB: Creatine kinase myocardial band

CRC: Colorectal cancer

OS: Overall survival

DFS: Disease-free survival

CEA: Carcinoembryonic antigen

CA: Carbohydrate antigen

ROC: Receiver-operating characteristic

AUC: Area under the curve

NPV: Negative predictive value

PPV: Positive predictive value

PLR: Positive likelihood ratio

NLR: Negative likelihood ratio

HR: Hazard ratio

CI: Confidence interval

AJCC: American Joint Committee on Cancer

Acknowledgments

Thank Mr. Kundong Mo for his hard work in data collation and analysis. We gratefully acknowledge all the staff of the Cancer Follow-up Center and the Information Section for their hard work and diligence in collecting cancer information, without which this research could not have been done.

Funding: This work was supported by the Key R&D Project of Sichuan Provincial Department of Science and Technology (Grant numbers [2022ZYF1927]), the Youth of Sichuan Science and Technology Program (Grant numbers[2023NSFSC1896], and the Key R&D Project of Chengdu Science and Technology Bureau (Grant numbers [YF05-01792-SN]).

Competing Interests：The authors have no relevant financial or non-financial interests to disclose.

Author Contributions：All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Lubei Rao, Ying Yang, and Bo Ye. The first draft of the manuscript was written by Lubei Rao and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data Availability: The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics approval: The research related to human use has complied with all the relevant national regulations, institutional policies and follows the tenets of the Helsinki Declaration, and has been approved by the Institutional Ethics Committee of The Sichuan Cancer Hospital.

Consent to participate: The study was a retrospective analysis and doesn’t require the patient's informed consent.

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Prognostic impact of Creatine Kinase (CK)-MB to total-CK ratio following curative resection of stage I-III colorectal cancer

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Background

Patients and Methods

Study population and design

Serum analyses

Statistical analysis

Results

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Univariable and multivariable Cox regression analyses of prognostic factors for overall survival, disease-free survival, and recurrence.

The impact of postoperative CK-MB/CK on long-term outcomes after the curative reaction

Biomarkers in hepatic metastases versus non-hepatic metastases patients after surgery.

Performance of CK-MB/CK and other tumor markers to predict hepatic metastasis

Discussion

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