Prognostic Nomograms based on Homogeneous and Heterogeneous Associated Factors for Predicting the Overall Survival of Colorectal Cancer Patients with Distant Metastases

DOI: https://doi.org/10.21203/rs.3.rs-600814/v1

Abstract

Background: To identify the heterogeneous and homogeneous prognostic factors associated with distant metastases in colorectal cancer (CRC) patients and then construct nomograms to predict prognosis.

Methods: CRC patients registered in the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2016 were included. Cox regression was used to analyse homogeneous and heterogeneous prognostic factors, and Kaplan-Meier analysis was used to estimate overall survival (OS). Predictive nomograms were constructed, and their performance was evaluated with C-indexes and calibration curves.

Results: A total of 34933 patients with distant metastases were included. The median survival time of patients with liver metastases, lung metastases, bone metastases, and brain metastases were 12.00 months (95% CI: 11.71-12.29 months), 10.00 months (95% CI: 9.57-10.43 months), 5.00 months (95% CI: 4.47-5.53 months), and 3.00 months (95% CI: 2.31-3.70 months), respectively. Older age and no surgery were identified as homogeneous prognostic factors of the four types of metastases. Male sex, black race, unmarried status, uninsured status, primary CRC site, poor differentiation/grade, advanced N stage, T stage, high carcinoembryonic antigen (CEA) level and metastatic organ were heterogeneously associated with the prognosis of patients with distant metastases. The calibration curves and C-indexes exhibited good performance for predicting the OS of patients with distant metastases.

Conclusion: CRC patients with distant metastases exhibited homogeneous and heterogeneous prognostic factors, all of which were associated with poor survival. The nomograms showed good accuracy and can be used as tools for clinicians to predict the prognosis of CRC patients with distant metastases.

Background

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide [1]. Approximately 20% of patients with CRC have distant metastases at initial diagnosis [2], and these patients have a lower 1-year and 5-year cancer-specific survival rate than patients without distant metastases [35]. However, due to the heterogeneity of metastatic patterns, CRC patients with specific organ metastases experience different prognoses; for instance, CRC patients with brain metastases have worse 5-year survival than those with liver metastases (0.4% vs. 16.9%) [6, 7]. The early detection of prognostic factors for CRC with distant metastases may help predict the probability of survival. However, the survival of CRC patients with distant metastases and the prognostic factors for their specific organ metastases are still unclear.

To our knowledge, some studies have investigated the prognostic factors of distant metastases in CRC, but majority of them have focused on patients who have already received treatments [810]. In addition, only a few studies described models to predict the survival of CRC patients with distant metastases [11, 12], and the results remain controversial due to the limited sample size. Moreover, homogeneous and heterogeneous prognostic risk factors for CRC patients with specific organ metastases have not yet been explored.

Therefore, this study aimed to characterize the differences in prognostic factors based on a large population cohort of CRC patients with distant metastases. Furthermore, a nomogram was developed to predict the prognosis of CRC patients with specific organ metastases and provide a reference tool for clinicians to guide individualized treatment for CRC patients.

Methods

Population

In the present study, CRC patient data were acquired from the US National Cancer Institute (NCI) open public database, the Surveillance, Epidemiology, and End Results (SEER) database. This study included CRC patients diagnosed between 2010 and 2016. Patients were excluded if they were diagnosed at autopsy or via a death certificate, if the follow-up was unspecified, if the site of the primary tumour was not in the colorectal region, or if information on distant metastases was unavailable. This study used SEER*Stat version 8.3.5 (https://seer.cancer.gov/seerstat/) (Information Management Service, Inc. Calverton, MD, USA) to generate the patient list.

Statistical analysis

Quantitative data are presented as the mean ± standard deviation (SD), and categorical data are described as the number and percentage (N, %). Univariable and multivariable Cox regression analyses were conducted to identify potentially associated prognostic factors. Based on the results of the Cox regression analysis, the intersection of the prognostic factors for the four types of metastases was used to identify homogenous or heterogeneous factors. The Kaplan-Meier method was used to estimate overall survival (OS). Based on the results of the multivariable Cox regression analysis, predictive nomograms for liver, lung, bone, and brain metastases were formulated. C-indexes and calibration curves were used to evaluate their distinguishing and predictive abilities. Statistically significant levels were two-tailed and set at p < 0.05. Statistical analyses were conducted with the IBM Statistical Package for the Social Sciences (SPSS) version 23.0 software package for Windows (SPSS, Inc., Chicago, IL, USA). The nomogram was plotted using the “rms”, “Hmisc”, and “survival” packages in R version 3.4.1 (R Foundation for Statistical Computing, Vienna, Austria; www.r-project.org).

Results

Demographic and clinical characteristics

A total of 34933 patients with distant metastases and 31288 patients with liver metastases, 10598 patients with lung metastases, 2553 patients with bone metastases, and 587 patients with brain metastases were included in this study. The detailed workflow for patient selection is shown in Fig. 1. The mean age of all 34933 CRC patients with distant metastases was 64.19 ± 14.13 years (range 14 to 108), 55.2% of patients (N = 19273) were male, and 44.8% of patients (N = 15660) were female. Most of the patients were white (75.1%, N = 26234), followed by black (15.5%, N = 5400). Forty-eight percent (N = 16944) of patients were married, and 77.7% (N = 27152) were insured. Regarding the primary tumour sites, most were localized in the left colon (35.70%, N = 12470) and right colon (35.17%, N = 12285), followed by the rectum (20.31%, N = 7098). A total of 30.38% (N = 10612) of patients were initially diagnosed with a stage T3 tumour, and 47.23% (N = 16498) were diagnosed with a grade II tumour. Detailed demographic and clinical characteristics are shown in Table 1.

 

Table 1

Patient characteristics and 1-, 3-, and 5-year overall survival rates for colorectal cancer with distant metastases

Subject characteristics

CRC patients with distant metastases (N = 34933)

N

%

1-year (%)

3-year (%)

5-year (%)

Age(years)

         

≤ 50

5936

17.0

69.4

28.9

15.1

51–60

8382

24.0

60.4

24.9

12.2

61–70

9035

25.9

52.1

25.8

10.2

71–80

6460

18.5

38.1

12.3

6.1

81–90

4269

12.2

20.8

4.2

2.1

≥ 91

851

2.4

8.7

1.6

0

Sex

         

Female

15660

44.8

47.1

18.5

9.7

Male

19273

55.2

51.4

19.2

9.3

Race

         

White

26234

75.1

49.6

19.5

9.9

Black

5400

15.5

46.7

14.7

6.8

Othersa

3205

9.2

52.9

20.7

10.4

Unknown

94

0.3

66.7

40.0

26.7

Marital status

         

Married

16944

48.5

56.2

23.0

11.8

Unmarriedb

16189

46.3

42.5

14.7

7.0

Unknown

1800

5.2

48.7

18.7

10.2

Insurance status

         

Insured

27152

77.7

50.4

20.0

10.2

Any medic aid

6045

17.3

45.4

14.3

6.4

Uninsured

1736

5.0

48.7

17.9

8.5

Site

         

Right coon

12285

35.2

43.3

14.3

7.4

Left colon

12470

35.7

57.4

24.6

12.4

Rectum

7098

20.3

58.4

22.9

11.1

Unknown

3080

8.8

21.5

5.1

2.7

Histological grade

         

Grade I

1420

4.1

60.8

27.5

14.6

Grade II

16498

47.2

63.4

26.2

13.5

Grade III

5496

15.7

41.6

13.7

6.5

Grade IV

1037

3.0

38.3

13.6

5.9

Unknown

10482

30.0

31.2

9.3

4.3

Lymphatic metastasis

         

N0

11445

32.8

45.8

18.2

10.1

N1

11055

31.6

57.0

24.0

12.1

N2

7034

20.1

58.5

21.3

9.6

Unknown

5399

15.5

29.8

7.0

2.9

T stage

         

T1

3267

9.4

42.8

12.4

5.1

T2

735

2.1

66.9

37.0

25.1

T3

10612

30.4

67.2

31.3

16.9

T4

7962

22.8

51.3

18.0

8.2

Unknown

12357

35.4

32.9

8.5

3.5

CEA

         

Negative

3499

10.0

64.1

33.6

21.3

Positive

20199

57.8

51.7

17.4

7.9

Unknown

11235

32.2

42.8

16.9

8.7

Surg(pri)

         

Yes

15634

44.8

66.4

31.0

16.8

None

19190

54.9

35.5

8.5

3.1

Unknown

109

0.3

36.8

14.7

10.5

Abbreviations: CEA = carcinoembryonic antigen; Surg(pri) = surgical treatments of primary site.
a Includes American Indian/Alaska Native and Asian or Pacific Islander
b Includes single, separated, widowed, and divorced
c Sites were unclear

Survival Outcomes In Patients With Distant Metastases

The 1-, 3-, and 5-year OS rates were 49.5%, 18.9%, and 9.5% for all patients, respectively. The mean survival time was 20.94 months. The 1-, 3-, and 5-year OS rates rapidly decreased with increasing age. However, the 1-, 3-, and 5-year OS rates in patients who underwent surgery at the primary site were much higher than those in patients who did not (p < 0.001). The detailed data of the patients’ 1-, 3-, and 5-year OS rates are listed in Table 1, and the median survival times are listed in Table 2.

Table 2

Multivariable Cox regression for analyzing the prognosis factors for colorectal cancer with distant metastases.

Subject characteristics

No. of CRC patients with distant metastases

Survival median, months

Univariate

Multivariate

HR (95% CI)

P-value

HR (95% CI)

P-value

Age (years)

           

≤ 50

5936

22.00(21.25–22.75)

1(Reference)

1.00

1(Reference)

1.00

51–60

8382

18.00(17.39–18.61)

1.20(1.15–1.25)

<0.001

1.15(1.10–1.20)

<0.001

61–70

9035

14.00(13.42–14.58)

1.44(1.38–1.5)

<0.001

1.38(1.32–1.44)

<0.001

71–80

6460

7.00(6.55–7.45)

2.02(1.93–2.1)

<0.001

1.93(1.85–2.01)

<0.001

81–90

4269

3.00(2.78–3.22)

3.25(3.1–3.4)

<0.001

2.79(2.66–2.93)

<0.001

≥ 91

851

1.00(0.74–1.26)

5.00(4.63–5.4)

<0.001

3.62(3.34–3.92)

<0.001

Sex

           

Female

15660

11.00(10.59–11.41)

1(Reference)

1.00

1(Reference)

1.00

Male

19273

13.00(12.62–13.38)

0.93(0.91–0.96)

<0.001

1.07(1.04–1.1)

<0.001

Race

           

White

26234

12.00(11.67–12.33)

1(Reference)

1.00

1(Reference)

1.00

Black

5400

11.00(10.38–11.62)

1.12(1.08–1.16)

<0.001

1.10(1.07–1.14)

<0.001

Othersa

3205

14.00(12.91–15.09)

0.91(0.88–0.96)

<0.001

0.97(0.92–1.01)

0.133

Unknown

94

25.00(13.41–36.59)

0.58(0.42–0.79)

0.001

0.57(0.41–0.78)

0.001

Marital status

           

Married

16189

16.00(15.55–16.45)

1(Reference)

1.00

1(Reference)

1.00

Unmarriedb

16944

9.00(8.64–9.36)

1.37(1.34–1.41)

<0.001

1.20(1.17–1.23)

<0.001

Unknown

1800

12.00(10.6–13.4)

1.18(1.11–1.25)

<0.001

1.09(1.03–1.15)

0.005

Insurance status

           

Insured

27152

13.00(12.67–13.33)

1(Reference)

1.00

1(Reference)

1.00

Any medic aid

1736

11.00(10.44–11.56)

1.15(1.11–1.19)

<0.001

1.24(1.19–1.28)

<0.001

Uninsured

6045

12.00(10.68–13.32)

1.05(0.99–1.11)

0.082

1.30(1.23–1.38)

<0.001

Site

           

Right colon

12285

10.00(9.61–10.39)

1(Reference)

1.00

1(Reference)

1.00

Left colon

12470

17.00(16.45–17.55)

0.71(0.69–0.73)

<0.001

0.78(0.76–0.80)

<0.001

Rectum

7098

17.00(16.3–17.7)

0.71(0.68–0.73)

<0.001

0.66(0.63–0.68)

<0.001

Unknown

3080

2.00(1.74–2.26)

1.79(1.71–1.86)

<0.001

1.13(1.08–1.19)

<0.001

Histological grade

           

Grade I

1420

19.00(17.03–20.97)

1(Reference)

1.00

1(Reference)

1.00

Grade II

16498

20.00(19.54–20.46)

0.99(0.93–1.06)

0.821

1.10(1.03–1.18)

0.005

Grade III

5496

9.00(8.52–9.48)

1.62(1.51–1.74)

<0.001

1.72(1.6–1.85)

<0.001

Grade IV

1037

8.00(6.99–9.01)

1.68(1.53–1.85)

<0.001

1.92(1.74–2.11)

<0.001

Unknown

10482

5.00(4.73–5.27)

2.15(2.01–2.3)

<0.001

1.40(1.3–1.5)

<0.001

Lymphatic metastasis

           

N0

11445

10.00(9.51–10.49)

1(Reference)

1.00

1(Reference)

1.00

N1

11055

16.00(15.41–16.59)

0.78(0.76–0.81)

<0.001

1.06(1.03–1.10)

<0.001

N2

7034

17.00(16.38–17.62)

0.80(0.77–0.83)

<0.001

1.36(1.30–1.42)

<0.001

Unknown

5399

5.00(4.66–5.34)

1.56(1.5–1.62)

<0.001

1.13(1.09–1.18)

<0.001

T stage

           

T1

3267

9.00(8.27–9.73)

1(Reference)

1.00

1(Reference)

1.00

T2

735

24.00(20.78–27.22)

0.47(0.43–0.52)

<0.001

0.74(0.67–0.83)

<0.001

T3

10612

22.00(21.35–22.65)

0.53(0.51–0.56)

<0.001

0.81(0.77–0.85)

<0.001

T4

7962

13.00(12.47–13.53)

0.80(0.77–0.84)

<0.001

1.08(1.03–1.14)

0.002

Unknown

12357

5.00(4.72–5.28)

1.28(1.22–1.33)

<0.001

1.03(0.98–1.07)

0.246

CEA

           

Negative

3499

22.00(20.68–23.32)

1(Reference)

1.00

1(Reference)

1.00

Positive

20199

13.00(12.65–13.35)

1.56(1.49–1.63)

<0.001

1.38(1.32–1.45)

<0.001

Unknown

11235

9.00(8.55–9.45)

1.78(1.7–1.87)

<0.001

1.45(1.38–1.52)

<0.001

Surg(pri)

           

Yes

15634

22.00(21.47–22.53)

1(Reference)

1.00

1(Reference)

1.00

None

19190

7.00(6.76–7.24)

2.27(2.21–2.33)

<0.001

2.17(2.09–2.26)

<0.001

Unknown

109

7.00(2.87–11.13)

1.81(1.45–2.25)

<0.001

1.53(1.23–1.91)

<0.001

Abbreviations: CEA = carcinoembryonic antigen, NA = not available, Surg(pri) = surgical treatments of primary site.
a Includes American Indian/Alaska Native and Asian or Pacific Islander.
b Includes single, separated, widowed, and divorced.

The median survival times of patients with liver metastases, lung metastases, bone metastases, and brain metastases were 12.00 months (95% CI: 11.71–12.29 months), 10.00 months (95% CI: 9.57–10.43 months), 5.00 months (95% CI: 4.47–5.53 months), and 3.00 months (95% CI: 2.31–3.70 months), respectively, with a significant difference (p < 0.001) (Fig. 2). The 1-year survival rate was highest for patients with liver metastases (49.1%), followed by those with lung metastases (44.2%), bone metastases (29.3%), and brain metastases (26.0%). The 3-year survival rates for patients with liver metastasis and lung metastases were 18.4% and 13.5%, respectively, which were higher than those for patients with bone metastases (7.0%) and brain metastases (5.1%). The 5-year survival rates for patients with liver metastases (9.2%), lung metastases (5.2%), bone metastases (3.0%), and brain metastases (3.6%) were all poor and lower than 10%. Details on the 1-, 3-, and 5-year OS rates of CRC patients with liver metastases, lung metastases, bone metastases and brain metastases are listed in Tables S1-S4.

Prognostic Factors In Crc Patients With Distant Metastases

Age, sex, race, marital status, insurance status, primary tumour site, histological grade, lymphatic metastasis, T stage, carcinoembryonic antigen (CEA) level and surgical treatment at the primary site were correlated with the prognosis of patients with distant metastases in the univariate analysis. The results of the multivariable model indicated that older age, male sex, black race, unmarried status, uninsured status, poor histological grade, stage T4/T1, high CEA level and no surgical treatment all showed positive associations with the prognosis of patients with metastases (see Table 2). The associated prognostic factors and their HRs with 95% CIs according to the different sites of metastases are presented in Tables S5-S8.

The prognostic factors associated with CRC with metastases at different organs were homogeneous and heterogeneous. Both older age and no surgery at the primary site showed positive associations with the prognosis of CRC patients with distant metastases. Male sex, black race, unmarried status, uninsured status, poor histological grade, lymphatic metastasis, stage T4/T1, high CEA level, and metastatic organ showed positive associations with the prognosis of CRC patients with liver metastases. Unmarried status, uninsured status, poor histological grade, lymphatic metastasis, high CEA level, and metastatic organ showed positive associations with the prognosis of CRC patients with lung metastases. Unmarried status, poor histological grade, lymphatic metastasis, and metastatic organ showed positive associations with the prognosis of CRC patients with bone metastases, and high CEA level showed a positive association with the OS of CRC patients with brain metastases (see Fig. 3).

Performance Of The Prognostic And Predictive Nomogram

All significant variables associated with the prognosis of CRC patients with distant metastases were incorporated into the nomogram for predicting the 1-, 3-, and 5-year OS rates of CRC patients with liver metastases, lung metastases, bone metastases, and brain metastases (Fig. 4(A-D)). The C-indexes for the prediction of the OS of patients with liver metastases, lung metastases, bone metastases, and brain metastases were 74.4% (95% CI, 74.2–74.8%), 77.6% (95% CI, 77.1–78.1%), 83.6% (95% CI, 82.8–84.4%), and 85.3% (95% CI, 83.6–87.1%), respectively. The calibration curves revealed good agreement between the predicted and observed survival probabilities of CRC patients with liver metastases (Fig. 5A1–A3), lung metastases (Fig. 5B1–B3), bone metastases (Fig. 5C1–C3), and brain metastases (Fig. 5D1–D3).

Discussion

Recently, majority of studies on the prognosis of CRC patients with distant metastases have shown different results. The results of our study were not entirely consistent with those of some previous studies [5, 1318, 12]. The 5-year survival rates for CRC patients with liver metastases and lung metastases were 16.9% [7] and 8.0% [12], respectively, which were higher than those found in our study. Compared to CRC patients with liver or lung metastases, the prognosis of CRC patients with brain or bone metastases was worse, with a 5-year survival rate of < 5%. Previous studies reported that the median survival time for CRC patients with bone metastases ranged from 5.0 to 7 months [16, 13, 19], consistent with our results. However, we found that the median survival time for patients with brain metastases was only three months, which was worse than that reported (from 4.2 to 7 months) [14, 16, 20, 21]. Overall, the OS rates for patients with distant metastases were poor, and the prognosis of CRC patients with brain metastases was the worst, followed by those with bone metastases, lung metastases and liver metastases. This finding is similar to that of a previous study [3].

The present study showed that different sites of metastasis exhibited homogeneity and heterogeneity regarding the prognostic factors associated with distant metastases from CRC. To our knowledge, a previous study has not reported these homogeneous prognostic factors (older age, no surgery at the primary site) for the prognosis of CRC patients with distant metastases. This finding will help clinicians tailor targeted preventive treatment strategies, thereby further improving patient survival. Previous studies have mostly focused on the prognosis of CRC patients, and whether age is an independent factor remains controversial. Some studies reported that young patients with CRC had a worse prognosis than older patients [2224]. Some studies reported the opposite results [25, 26], and another study demonstrated that age was not associated with the prognosis of CRC [27]. This controversy may be due to the limited sample sizes. Our study, based on a large population cohort, showed that older age was a prognostic factor for the four types of metastases. Thus, compared with older patients, younger patients have a better prognosis, consistent with previous reports [28, 29]. This finding is presumably due to their better physiological reserve and lower incidence of comorbidities. The present study also demonstrated that surgery at the primary site showed a positive association with the four types of metastases (liver, lung, bone, and brain). Many studies on different samples all showed that surgical resection may improve survival. Therefore, when CRC patients are initially diagnosed with distant metastases, surgery at both the primary site and distant lesions may be an appropriate and effective treatment. However, this potential treatment approach still needs to be confirmed through more research.

In addition to these homogeneous factors, some other heterogeneous associated prognostic factors were also found. However, these heterogeneous factors are not completely consistent with those described in previous studies. For instance, both unmarried status and uninsured status showed positive associations with the prognosis of CRC patients with liver metastases, lung metastases and bone metastases. However, these factors have seldom been reported in other studies [12, 30]. One possible reason for the poor prognosis of unmarried or uninsured patients is the lack of mental or financial support from their family members. In addition, the primary site of CRC, a poor differentiation grade, lymphatic metastasis and the metastatic organ were found to be significantly associated with the development of the four types of distant metastases [31]. However, in the present study, these four factors were identified only as homogeneous factors of the prognosis of patients with three types of distant metastases (all except brain metastases). A previous study reported that the tumour site and extracranial metastases were significantly associated with the poor survival of CRC patients with brain metastases [14]. Whether these factors are associated with the prognosis of CRC patients with brain metastases is still controversial, and more studies are needed to confirm this hypothesis.

Additionally, CEA is a widely used biomarker for CRC, and routine monitoring of CEA levels is commonly used to monitor postoperative recurrence and distant metastases [3234]. A previous study reported that CEA can also be used to predict the prognosis of CRC patients with distant metastases [12, 35, 36]. However, this study showed that CRC patients with bone metastases did not tend to have a significantly poor prognosis when they had a high CEA level. For patients with bone metastases, whether CEA levels affect survival remains to be studied.

Although some studies have reported prognostic factors for metastatic CRC, the homogeneity and heterogeneity of the prognostic factors of the four types of metastases from CRC have not been comprehensively studied. The homogeneous and heterogeneous associated prognostic factors mentioned in our study may help clinicians guide individualized treatment for patients with metastatic CRC. Based on these prognostic factors, four predictive nomograms were constructed, and all were validated and showed good prediction performance. Similar to the model used to predict distant metastases previously constructed by our team [31], the prognostic and predictive model described herein is also a rapid and cost-effective tool. After screening using our model, patients with metastatic CRC could receive timely targeted therapy to improve their prognosis and avoid other unnecessary expenses.

However, this study still had several limitations. First, distant metastases can be divided into synchronous metastasis and metachronous metastasis. In this study, we investigated the prognostic factors of only synchronous metastasis. Therefore, the results may not be suitable for metachronous metastasis. Second, treatment factors such as chemotherapy and radiotherapy were not incorporated into our study because this information is not available in the SEER database. Last, all of the study participants were from the U.S., and prospective studies in other populations are encouraged.

Conclusion

This study demonstrated that the median survival times of CRC patients with liver metastases, lung metastases, bone metastases, and brain metastases were 12.00 months (95% CI: 11.71–12.29 months), 10.00 months (95% CI: 9.57–10.43 months), 5.00 months (95% CI: 4.47–5.53 months), and 3.00 months (95% CI: 2.31–3.70 months), respectively. Older age and no surgery at the primary site were identified as the homogeneous prognostic factors of the four patterns of metastases. The calibration curves and C-indexes exhibited good performance for predicting the OS of CRC patients with distant metastases. Four nomograms for predicting OS probabilities in CRC patients were established, and all nomograms showed good accuracy and can be used as tools for clinicians to predict the prognosis of CRC patients with distant metastases.

Abbreviations

CRC

colorectal cancer

SEER

Surveillance, Epidemiology, and End Results

NCI

National Cancer Institute

SD

standard deviation

ROC

receiver operating characteristics

AUC

area under the curve

SPSS

Statistical Package for the Social Sciences

CEA

carcinoembryonic antigen

Declarations

Ethics approval and consent to participate

The present study was exempt from the ethical review of the ethics board of the First Affiliated Hospital of Chongqing Medical University.

Consent for publication

Not applicable.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Conflict of interest:

The authors declare that they have no conflict of interest.

Funding:

This project was supported by Innovation Research group in Colleges and Universities Program of Chongqing Municipal Education Commission (No. CXQT20012) and Postgraduate Tutor Team Development Program of Chongqing Municipal Education Commission (No. dstd201807).

Authors' contributions

HW and WZ designed the study. HW and MZ collected the data. HW, XS and MZ analysed the data. KQ and WZ organized the manuscript. HW, XS and MZ reviewed the papers and revised the manuscript. All the authors read and approved the final manuscript. All authors contributed to data analyses and the drafting and revising of the paper and agree to be accountable for all aspects of the work.

Acknowledgments

None.

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