Clinical features, treatment and prognosis analysis of distant metastatic esophageal cancer

doi:10.21203/rs.3.rs-4666614/v1

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Clinical features, treatment and prognosis analysis of distant metastatic esophageal cancer

https://doi.org/10.21203/rs.3.rs-4666614/v1

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Backgrounds

: Esophageal cancer (EC) is one of the most common malignant tumors in China. EC is characterized by poor clinical prognosis, with many patients being diagnosed at advanced stages. This study utilized data from the the Surveillance, Epidemiology, and End Results (SEER) database. The clinical features, treatment and prognostic factors of patients with distant metastatic esophageal cancer were screened and analyzed, a nomogram was drawn to construct a prognostic model.

Methods

Eligible patients with distant metastatic esophageal cancer diagnosed from January 2004 to December 2015 were extracted from SEER database. Propensity score matching(PSM)was used to eliminate baseline differences between groups. The data were divided into training cohort (1116 cases) and validation cohort (426 cases) by using R software and random sampling function at the ratio of 7: 3. The baseline table was plotted using x2 or Fisher's exact test. Kaplan-Meier curve, log rank test and Cox regression were used for survival analysis. C index and AUC were used to evaluate the performance of prognosis model. Calibration curve was used to evaluate the calibration of the model. Using the data of the validation cohort, external validation is used to create prediction model.

Results

After applying the inclusion and exclusion criteria and PSM, a total of 1,542 cases diagnosed between 2004 and 2015 were included in the study. Before and after PSM, we analyzed Kaplan-Meier survival of patients with metastatic esophageal cancer with different treatment methods. The results showed that radiotherapy, chemotherapy or surgical treatment brought significant survival benefits to patients with metastatic esophageal cancer(P < 0.05). Univariate and Multivariate regression analysis showed that T-stage, M-stage, primary site, surgery, chemotherapy and radiotherapy were independent prognostic factors affecting the prognosis of distant metastatic oesophageal cancer (P < 0.05). Evaluating the predictive ability of nomogram, the C index of the training cohort was 0.69(95%CI:0.67–0.71), and the C index of the validation cohort was 0.659 (95% CI:0.627–0.693). The AUC values for the training and validation cohort for the 1-year OS ranged from 0.50 to 0.70, and the AUC for the rest of the training and validation cohort ranged from 0.70 to 0.90, which suggests that the model is moderately discriminating. The calibration curves of 1 year, 2 years and 3 years in the two groups are very close to the 45°reference line, suggesting that the models exhibit a good degree of calibration. The C-index, AUC and calibration curves suggest that the models have good discriminating and calibration.

Conclusion

The results reveal that T stage, M stage, primary tumor site, surgery, chemotherapy and radiotherapy play an important role in influencing the treatment effect and prognosis of patients. The nomogram prediction model based on the above independent risk factors shows good discriminating and calibration.

Biological sciences/Cancer/Cancer models

Health sciences/Oncology/Cancer

Biological sciences/Cancer

Health sciences/Diseases

Health sciences/Oncology

Distant metastatic oesophageal cancer

PSM

SEER database

Prediction model

Esophageal cancer is the seventh most common malignant tumor in the world, ranking sixth among all cancer-related causes of death^[1]. Esophageal cancer was found to be the fourth leading cause of cancer deaths in Chinese men over the age of 45 in the National Cancer Center Registry in 2016^[2]. China is a new case of esophageal cancer, accounting for more than half of the global esophageal cancer cases^[3].The main histological subtype of esophageal cancer is squamous cell carcinoma^[2]. In 2020, the number of new cases of esophageal cancer will reach 604,000 and the number of deaths will reach 544,000^[1]. The prognosis of esophageal cancer is extremely poor, and the 5-year survival rate is about 20%. Esophageal cancer is usually diagnosed in the late stage, mainly due to the lack of early clinical symptoms. With the continuous progress of comprehensive treatment of esophageal cancer, the prognosis of esophageal cancer has improved by means of endoscopic treatment, surgical techniques, radiotherapy, chemotherapy, immunotherapy and targeted therapy. Identifying, exploring and intervening all potential risk factors may reduce the incidence of esophageal cancer. The risk factors of esophageal cancer include gastroesophageal reflux disease, obesity, smoking, drinking hot tea and alcohol, eating pickled vegetables, low fruit intake, hot food, drinks, malnutrition and low social and economic status^{[4, 5]}. Studies have shown that Barrett's esophagus is also an important risk factor for esophageal cancer. The risk factors of esophageal squamous cell carcinoma and adenocarcinoma are still different^[4]. Therefore, identifying risk factors and establishing a prediction models can benefit patients. It can also help clinicians to make more appropriate medical decisions for patients.

Studies have shown that concurrent chemoradiotherapy(CCRT) is the first choice for unresectable locally advanced esophageal cancer^[6]. At present, 5- fluorouracil or capecitabine combined with oxaliplatin or cisplatin is commonly used to treat locally advanced or metastatic esophageal squamous cell carcinoma^[7]. One study found that definitive radiotherapy improved overall survival (OS) in newly diagnosed metastatic esophageal cancer^[8]. Short-term radiotherapy is used to relieve dysphagia, malnutrition and chronic bleeding in esophageal cancer^[9]. Comprehensive treatment is very important for the relief of esophageal cancer. Endoscopic therapy and surgical intervention for early tumors. Chemotherapy, targeted drug therapy and immunotherapy are used for the treatment of unresectable locally advanced or advanced patients. Currently there are fewer drugs for targeted therapy of esophageal cancer, mostly targeting human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and inositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR)^[10].It is reported that adoptive T cell transfer technology is also used for distant metastatic esophageal cancer^[11]. Of course, it also needs a lot of clinical trial data to verify. Clinical trials such as KEYNOTE-590, CheckMate648, KEYNOTE-811 and ATTRACTION-3 all show that immunotherapy can improve the prognosis of advanced esophageal cancer patients.

Preference score matching (PSM) is a statistical method to reduce data bias and the influence of confounding variables in observation and research. PSM is often used to balance baseline characteristics and eliminate the bias between the treatment population and the control population. The SEER database is a large tumor database established by the National Cancer Institute. It is a public database commonly used clinically for surveillance and research in the field of cancer. Nomogram are widely used for cancer prognosis.

In recent years, there are few prognostic models for patients with metastatic esophageal cancer. Metastatic esophageal cancer is not clear in this field at present. The prognosis model has been constructed, which has a good prediction effect on patients with metastatic esophageal cancer and also has certain clinical references.

Patients and selection criteria

Patients with distant metastatic esophageal cancer from January 2004 to December 2015 were selected from SEER database. The database (Incidence-SEER Research Plus Data,18 Registries, Nov 2020 Sub2000-2018 varying)includes radiotherapy and chemotherapy information.

Patients with metastatic esophageal cancer were identified based on the following inclusion criteria: From January, 2004 to December, 2015, patients with esophageal cancer, AJCC 6th edition, M1 stage,; Patients must have complete survival time data; The effectiveness of follow-up must be guaranteed; Esophageal cancer was diagnosed by pathology.The exclusion criteria: Patients with missing or insufficient information such as staging, survival rate, follow-up time or cause of death; The treatment is not clear; The patient has not only one primary malignant tumor; The patients diagnosed only by autopsy results or death certificates.

Ethical approval

is not required as all data in the SEER database is available through a public method.

Study variables

Collect the following patient information includes: age, race, sex, primary site, histological type, degree of differentiation, TNM stage, radiotherapy, chemotherapy, surgery, survival time, survival status and so on. The end point of our research is OS. OS was defined as the time from the start of diagnosis to the time of death from any cause or the time of last follow-up cutoff.

Construction of the nomogram

After screening the data from the SEER database to meet the inclusion and exclusion criteria, baseline differences were eliminated by the PSM, and then the matched data were randomly divided into a training cohort and a validation cohort in a 7:3 ratio using the R software, and plotted a baseline table for each variable. Kaplan-Meier method was used to draw the survival curves of radiotherapy group and chemotherapy group. The log rank test was used to compare the differences between OS. Univariate cox regression model was used to analyze the prognostic factors of metastatic esophageal cancer (P < 0.05), The variables with p < 0.05 were analyzed by multivariate cox regression. The risk ratio (HR) and the corresponding 95% confidence interval (95%CI) are calculated. The index of independent risk factors for metastatic esophageal cancer was obtained(P<0.05).Based on these independent prognostic factors, we use R software to construct nomogram, which can predict the probability of OS in patients with metastatic esophageal cancer for 1 year, 2 years and 3 years.

Discrimination and calibration of the nomogram

C index and calibration curve are often used to evaluate the performance and accuracy of nomograms. The discrimination degree of prediction model is the degree of evaluating the ability of model to predict events. The degree of discrimination can reflect the prediction ability of constructing this prediction model. It can be evaluated by C index, ROC curve and AUC. In the ROC curve, the abscissa is specificity and the ordinate is sensitivity. C index and AUC of 0.5 indicate that the model has no predictive ability. The range of 0.50 ~ 0.70 indicates that the discrimination of the prediction model is low. A range of 0.70 ~ 0.90 indicates that the prediction discrimination is moderate. More than 0.90 indicates that the prediction model has high discrimination.

Calibration degree, also called fitting degree, which can be evaluated by calibration curve to evaluate the degree of accurate risk estimation by the model. The higher the overlap of the model prediction curve with the diagonal standard line, this indicates a better calibration of the model.

Case inclusion and exclusion process

The inclusion and exclusion criteria of the study cases are shown in Fig. 1. We selected patient cases from the SEER database between January 2004 and December 2015, and these patients were diagnosed with esophageal cancer in a total of 10,792 cases. Patients with esophageal cancer with M1 distant metastases were subsequently included. After that, we excluded patients with missing race (3 cases); patients with missing marital status (77 cases); patient cases with missing grading (388 cases); patient cases with missing tumor size (2,165 cases); patients with incomplete information on TNM staging (6,002 cases); and patients diagnosed only by autopsy results or death certificates (89 cases), which left 2,068 patients. These patients were treated with radiotherapy in 1087 cases, and there were

981 patients who did not receive radiotherapy.

Baseline characteristics

Table 1 shows the clinical baseline characteristics of all patients with metastatic esophageal cancer. From the analysis of the table, it can be seen that the number of patients in the radiotherapy group was 1,087 and the number of patients in the non-radiotherapy group was 981, and the number of patients receiving radiotherapy in metastatic esophageal cancer accounted for 52.6% of the total number of patients. Prior to the use of PSM, it was possible to observe some differences in the distribution of some variables between the two groups, which included marital status, chemotherapy treatment, tumor location, surgical treatment, and degree of differentiation. The proportion of unmarried patients who received radiotherapy increased relative to those who did not receive radiotherapy; patients who received radiotherapy were more likely to receive chemotherapy and surgery; patients with upper and mid-stage esophageal cancer were more likely to receive radiotherapy; and receipt of radiotherapy was increased in patients with lower levels of differentiation; of these, there were no statistically significant differences in the variables of gender, age, ethnicity, and histology on whether or not they received radiotherapy. By matching using the PSM method, we categorized patients into a group that did not receive radiotherapy and a group that received radiotherapy, each including 771 patients. By analyzing the baseline characteristics of the two groups, we can observe that there is no statistically significant difference in the data of patients who received radiotherapy or not after matching by PSM method, and the data after balancing for the same variable satisfy P > 0.05, which indicates that PSM has well balanced the baseline characteristics between the group that received radiotherapy and the group that did not receive radiotherapy. With this method, we eliminated the interference of confounding factors on the study results during the research process and improved the reliability of the study results.

Table 1

Clinical characteristics before and after PSM according to radiotherapy or not
Variables	Before matching		P^a value	After matching		P value
Variables	Non-radiotherapy N = 981(%)	Radiotherapy N = 1087 (%)	P^a value	Non- radiotherapy N = 771(%)	Radiotherapy N = 771(%)	P value
Sex			0.684			1.000
Male	811(82.7%)	907(83.4%)		644(83.5%)	644(83.5%)
Female	170(17.3%)	180(16.6%)		127(16.5%)	127(16.5%)
Age			0.407			0.758
<65 years	539(54.9%)	618(56.9%)		435(56.4%)	442(57.3%)
≥ 65 years	442(45.1%)	469(43.1%)		336(43.6%)	329(42.7%)
Race			0.128			0.545
White	810(82.6%)	868(79.9%)		642(83.3%)	632(82.0%)
Unwhite	171(17.4%)	219(20.1%)		129(16.7%)	139(18.0%)
Marriage			0.005			0.918
Married	458(46.7%)	440(40.5%)		429(55.6%)	432(56.0%)
Unmarried	523(53.3%)	647(59.5%)		342(44.4%)	339(44.0%)
Chemotherapy			<0.001			0.169
None	429(43.7%)	229(21.1%)		252(32.7%)	226(29.3%)
Yes	552(56.3%)	858(78.9%)		519(67.3%)	545(70.7%)
Primary site			<0.001			0.667
Cervical/upper	36(3.7%)	65(6.0%)		31(4.0%)	30(3.9%)
Thoracic/middle	170(17.3%)	207(19.0%)		142(18.4%)	137(17.8%)
Abdominal/lower	699(71.3%)	768(70.7%)		558(72.4%)	561(72.8%)
Overlapping	76(7.7%)	47(4.3%)		40(5.2%)	43(5.6%)
Histology			0.102			1.000
Adenocarcinoma	652(66.5%)	684(62.9%)		516(66.9%)	516(66.9%)
Non-adenocarcinoma	329(33.5%)	403(37.1%)		255(33.1%)	255(33.1%)
Surgery			<0.001			0.498
None	928(94.6%)	977(89.9%)		726(94.2%)	733(95.1%)
Yes	53(5.4%)	110(10.1%)		45(5.8%)	38(4.9%)
Grade			0.002			0.710
I + II	336(34.3%)	447(41.1%)		280(36.3%)	272(35.3%)
III + IV	645(65.7%)	640(58.9%)		491(63.7%)	499(64.7%)
T Stage			0.950			0.817
T1	284(29.0%)	244(22.4%)		217(28.1%)	197(25.6%)
T2	50(5.1%)	70(6.4%)		37(4.8%)	47(6.1%)
T3	208(21.2%)	361(33.2%)		176(22.8%)	214(27.8%)
T4	253(25.8%)	254(23.4%)		206(26.7%)	193(25.0%)
Tx	186(19.0%)	158(14.5%)		135(17.5%)	120(15.6%)
N Stage			0.076			0.652
N0	268(27.3%)	288(26.5%)		211(27.4%)	206(26.7%)
N1	600(61.2%)	731(67.2%)		489(63.4%)	509(66.0%)
Nx	113(11.5%)	68(6.3%)		71(9.2%)	56(7.3%)
M Stage			<0.001			0.190
M1a	44(4.5%)	150(13.8%)		43(5.6%)	31(4.0%)
M1b	937(95.5%)	937(86.2%)		728(94.4%)	740(96.0%)
Vital status			0.189			0.488
Alive	20(2.0%)	32(2.9%)		15(1.9%)	19(2.5%)
Death	961(98.0%)	1055(97.1%)		756(98.1%)	752(97.5%)

Survival analyses

In order to further demonstrate the therapeutic effects of radiotherapy, chemotherapy and surgery in patients with distant metastatic esophageal cancer, we grouped the patients according to whether they received radiotherapy, chemotherapy or not, or surgery or not, and then we performed Kaplan-Meier survival analysis of metastatic esophageal cancer patients before and after PSM, and the specific results are detailed in Figure.2. Figure 2A showed that the survival graph of metastatic esophageal cancer patients before PSM, and there was a significant improvement in the chemotherapy group OS compared with no chemotherapy ([HR] 0.324, 95% CI: 0.294 ~ 0.358, p < 0.0001). Figure 2B shows the survival graph after PSM in patients with metastatic esophageal cancer, and there was a significant improvement in OS in the chemotherapy group compared with no chemotherapy ([HR]0.369,95%CI:0.330 ~ 0.413, p < 0.0001). Figure 2C shows the survival graph of metastatic esophageal cancer patients before PSM, and there was a significant improvement in OS in the radiotherapy group compared with the no-radiotherapy group ([HR]0.681,95%CI:0.624 ~ 0.744, p < 0.0001). Figure 2D shows the survival graph of metastatic esophageal cancer patients before PSM, and there was a significant improvement in OS in the radiotherapy group compared with no radiotherapy ([HR] 0.879, 95% CI: 0.795 ~ 0.973, p = 0.0084). Figure 2E shows the survival graph of metastatic esophageal cancer patients before PSM, and there was a significant improvement in OS in the surgical group compared with the non-surgical group ([HR] 0.455, 95% CI: 0.383 ~ 0.540, p < 0.0001). Figure 2F shows the survival graph after PSM in patients with metastatic esophageal cancer, and there was a significant improvement in OS in the surgical group compared with the non-surgical group ([HR]0.482,95%CI:0.379 ~ 0.612, p < 0.0001). According to the results of our study, patients who had been treated with radiotherapy, chemotherapy, and surgery demonstrated longer survival than those who did not receive these treatment modalities, regardless of whether or not a propensity score matching process was performed.

Comparison of clinical case data between training and validation cohort

After eliminating baseline differences by the PSM method described above, a total of 1542 eligible patients were included, and we randomly divided the 1542 patients into training cohort and a validation cohort according to the ratio of 7:3, in which 1116 patients were in the training cohort and 426 patients were in the validation cohort. Among them, the case data of patients in the overall, training cohort, and validation cohort are shown in Table 2.

Table 2

Demographics and clinicopathological characteristics of patients with esophageal carcinoma
Characteristics	All patients(n = 1542)		Training cohort (N = 1116)		Validation cohort (N = 426)		P value
	Number	%	Number	%	Number	%
Sex							0.857
Male	1288	83.5	931	83.4	357	83.8
Female	254	16.5	185	16.6	69	16.2
Race							0.885
White	1274	82.6	923	82.7	351	82.4
Unwhite	268	17.4	193	17.3	75	17.6
Age							0.588
<65 years	877	56.9	630	56.5	247	58.0
≥65 years	665	43.1	486	43.5	179	42.0
Marriage							0.658
Married	861	55.8	627	56.2	234	54.9
Unmarried	681	44.2	489	43.8	192	45.1
Chemotherapy							0.534
None	478	31.0	351	31.5	127	29.8
Yes	1064	69.0	765	68.5	299	70.2
Radiotherapy							0.733
None	771	50	561	50.3	210	49.3
Yes	771	50	555	49.7	216	50.7
Histology							0.619
Adenocarcinoma	1032	66.9	751	67.3	281	66.0
Non- adenocarcinoma	510	33.1	365	32.7	145	34.0
Primary site							0.058
Cervical/upper	61	4.0	40	3.6	21	4.9
Thoracic/middle	279	18.1	201	18.0	78	18.3
Abdominal/lower	1119	72.6	805	72.1	314	73.7
Overlapping	83	5.4	70	6.3	13	3.1
Surgery							0.626
None	1459	94.6	1054	94.4	405	95.1
Yes	83	5.4	62	5.6	21	4.9
Grade							0.859
I + II	552	35.8	401	35.9	151	35.4
III + IV	990	64.2	715	64.1	275	64.6
T Stage							0.620
T1	414	26.8	295	26.4	119	27.9
T2	84	5.4	66	5.9	18	4.2
T3	390	25.3	285	25.5	105	24.6
T4	399	25.9	291	26.1	108	25.4
Tx	255	16.5	179	16.0	76	17.8
N Stage							0.684
N0	417	27.0	299	26.8	118	27.7
N1	998	64.7	721	64.6	277	65.0
Nx	127	8.2	96	8.6	31	7.3
M Stage							0.496
M1a	74	4.8	51	4.6	23	5.4
M1b	1468	95.2	1065	95.4	403	94.6
Vital status							0.814
Alive	34	2.2	24	2.2	10	2.3
Death	1508	97.8	1092	97.8	416	97.7

Of the 1542 patients with distant metastatic esophageal cancer, gender included 1288 male patients (83.5%) and 254 female patients (16.5%). Among races, there were 1274 cases of Caucasians, accounting for up to 82.6%, and 268 cases of non-Caucasians, accounting for 17.4%. Age < 65 years had 877 patients (56.9%) and age ≥ 65 years had 665 patients (43.1%). In marriage there were 861 patients (55.8%) who were married and 681 patients (44.2%) who were other (single, divorced, separated, widowed). Of chemotherapy there were 1064 patients (69.0%) who received chemotherapy and 478 patients (31.0%) who did not receive chemotherapy. The number of patients who received radiotherapy and those who did not was 771 cases, accounting for 50%, and the histologic types were adenocarcinoma in 1032 cases, accounting for 66.9%, and non-adenocarcinoma in 510 cases, accounting for 33.1%. The tumor location was located in the upper esophageal cancer in 61 cases, accounting for 4.0%, in the middle esophageal cancer in 279 cases, accounting for 18.1%, in the lower esophageal cancer in 1,119 patients, accounting for 72.6%, and in the other patients in 83 cases, accounting for 5.4%. In surgical treatment, there were 1459 patients without surgery, accounting for 94.6%, and 83 patients with surgery, accounting for 5.4%. There were a total of 990 patients in grade III + IV tumor differentiation, accounting for 64.2%, and a total of 552 patients in grade I + II, accounting for 35.8%.There were 414 patients in T1 stage in T staging, accounting for 26.8%, 84 patients in T2 stage, accounting for 5.4%, 390 patients in T3 stage, accounting for 25.3%, 399 patients in T4 stage, accounting for 25.9%, 255 patients in Tx stage, accounting for 16.5%, and 417 patients in lymph node stage N0, accounting for 27.0%, 998 patients in N1, accounting for 64.7%, and 127 patients in Nx, accounting for 8.2%. Among distant metastases, there were 74 patients with M1a (4.8%) and 1,468 patients with M1b (95.2%). A total of 1,508 (97.8%) of the 1,542 patients died and 34 (2.2%) survived.

After statistical tests, it was found that there was no statistically significant difference between the training and validation cohort on the baseline balance (p > 0.05), and the differences in the various study indicators were not statistically significant, see Table 2. After plotting the OS survival curves for the training and validation cohort, it was found that there was also no statistically significant difference between the two groups (p = 0.77), and the detailed data are shown in Fig. 3.

Independent prognostic factors in the training cohort

The results of univariate and multivariate Cox regression analysis are shown in Table 3. Univariate Cox regression analysis was performed on all variables to explore the effects of different factors on the prognosis of metastatic esophageal cancer, and the results showed that "race, age, marriage, chemotherapy, radiotherapy, histological grading, tumor site, surgery, T stage, N stage, and M stage" were the prognostic factors affecting the OS of metastatic esophageal cancer (P<0.05). and in the multifactorial Cox risk proportional regression model, chemotherapy, radiotherapy, tumor site, surgery, T stage, and M stage were independent prognostic factors affecting OS in metastatic esophageal cancer (Table 3).

Table 3

Univariate and multivariate Cox proportional hazards regression analysis in esophageal cancer patients
Variables	HR Comparison	Univariate analysis		Multivariable analysis
		HR (95%CI)	P value	HR (95%CI)	P value
Sex	Male	.
	Female	1.091(0.931–1.279)	0.280
Race	White
	Unwhite	1.332(1.138–1.559)	<0.001
Age	<65 years
	≥ 65 years	1.170(1.038–1.318)	0.010
Marriage	Married
	Unmarried	0.817(0.725–0.921)	0.001
Chemotherapy	No vs Yes	0.338(0.295–0.386)	<0.001	0.308(0.266–0.357)	<0.001
Radiotherapy	No vs Yes	0.874(0.776–0.985)	0.027	0.835(0.740–0.942)	0.003^*
Histology	Adenocarcinoma
	Non-adenocarcinoma	1.274(1.121–1.447)	<0.001
Primary site	Overlapping
	Cervical/upper	0.884(0.596–1.312)	0.541	0.611(0.407–0.918)	0.018
	Thoracic/middle	0.997(0.757–1.313)	0.981	0.814 (0.612–1.082)	0.157
	Abdominal/lower	0.739(0.576–0.947)	0.017	0.788 (0.612–1.015)	0.065
Surgery	No vs Yes	0.465(0.353–0.614)	<0.001	0.446 (0.333–0.596)	<0.001
Grade	I + II
	III + IV	1.124(0.993–1.272)	0.066
T Stage	T1
	T2	0.770(0.587–1.010)	0.059	0.879(0.668–1.158)	0.360
	T3	0.814(0.690–0.960)	0.015	0.956(0.805–1.135)	0.607
	T4	1.183(1.004–1.394)	0.045	1.227 (1.038–1.451)	0.017
	Tx	1.216(1.008–1.467)	0.041	1.091(0.894–1.333)	0.391
N Stage	N0
	N1	0.959(0.837–1.099)	0.548
	Nx	1.490(1.182–1.879)	0.001
M Stage	M1a
	M1b	1.749(1.303–2.349)	<0.001	1.799(1.325–2.444)	<0.001

From the results of multifactorial Cox regression, we can learn that receiving chemotherapy was an independent prognostic factor for improving overall survival of metastatic esophageal cancer compared with not receiving chemotherapy (HR = 0.038,95% CI: 0.266–0.357, p < 0.001); receiving radiotherapy was also an independent prognostic factor for improving overall survival of metastatic esophageal cancer compared with not receiving radiotherapy (HR = 0.835,95% CI: 0.740–0.942, p = 0.003); receiving surgery was also an independent prognostic factor for improving OS in distant metastatic esophageal cancer compared to not receiving surgery (HR = 0.446,95% CI: 0.333–0.596, p < 0.001); and in the upper esophagus (HR = 0.611,95% CI: 0.407–0.918, p = 0.018) and lower esophagus (HR = 0.788,95%CI: 0.612–1.015, p = 0.065) had a poorer prognosis than patients with other tumor sites; patients with stage T4 (HR = 1.227,95%CI: 1.038–1.451, p = 0.017) had a poorer prognosis than patients with T1; patients with stage Nx (HR = 1.226,95% CI: 0.958–1.568, p = 0.105) patients had a worse prognosis than N0 patients; M1b stage (HR = 1.799,95% CI: 1.325–2.444, p < 0.001) patients had a worse prognosis than M1a stage patients. (Table 3)

Prognostic nomogram for OS

The statistically significant study variables obtained from the multifactorial Cox regression analysis above, such as the six independent risk factors of radiotherapy, T-stage, M-stage, surgery, chemotherapy, and tumor site, were plotted on a column-line graph (Fig. 4).The OS at 1 year, 2 years, and 3 years can be easily calculated, and the score value at the very top is the score obtained from the upwardly-directed vertical line made by each of the study variables below, and an individual risk score can be calculated by summing the scores obtained by all of them. The corresponding points were then found on the survival scale. The scores obtained can be summed to give a total score, an individual risk score is calculated, and the corresponding points are then found on the survival scale.

Calibration and validation of the nomogram

The accuracy and discriminative power of the column line drawings of distant metastatic esophageal cancer could be evaluated based on C-index and AUC. In the prediction model, the C-index of OS in the training cohort was 0.690 (95% CI:0.672–0.709), and that of OS in the validation cohort was 0.659 (95% CI:0.627–0.693), and the AUCs of OS for metastatic esophageal cancer in the training cohort for 1 year, 2 years, and 3 years were 69%, 73%, and 77.3%, respectively. The AUCs of 1, 2, and 3 years for OS of metastatic esophageal cancer in the validation cohort were 69.4%, 73.4%, and 78.1%, respectively. In the constructed model, the AUC values of the area under the curve for 1-year OS in the training cohort and validation cohort were between 0.50 and 0.70, and the AUCs of the rest of the training and validation cohorts were between 0.70 and 0.90, which indicated that the model had a medium degree of differentiation, and, it could be observed that the AUC of the area under the curve might get bigger and bigger with the prolongation of the time, and that the predictive model was getting more and more reliable, and the prediction model was getting differentiation is getting stronger. The ROC curves for the 1-year, 2-year, and 3-year OS for the training and validation cohort are shown in Fig. 5. The calibration of the prediction model is assessed by the calibration curve, and the calibration curve is similar to the 45° diagonal line, which indicates that the calibration of the prediction model is good, and the calibration curves of the OS for 1, 2, and 3 years for the training and validation cohort are shown in Fig. 6.

Esophageal cancer remains an aggressive disease with a low survival rate^[12], with a low 5-year survival rate and distant metastases in 20–30% of patients with esophageal cancer at initial diagnosis^[13]. It is necessary to construct a prognostic model for metastatic esophageal cancer. Through univariate and multivariate Cox regression analysis, we found that radiotherapy, chemotherapy, surgery, tumor site, T-stage, and M-stage were independent risk factors affecting OS.

Some studies have indicated that metastatic esophageal cancer treated with surgery or radiotherapy can provide survival benefit for patients. Zhao et al. showed that the median survival of patients with M1a stage metastatic squamous esophageal cancer undergoing R0 esophagectomy after simultaneous radiotherapy could reach 36.9 months^[14]. Elk et al. found that after the use of a multimodal treatment approach including surgery in patients with extraintestinal metastases or liver metastases from esophageal cancer, recurrence occurred in about 64% of R0 resection patients, and 50% of the operated patients were still alive after a median follow-up of 22 months^[15]. This suggests that palliative resection or radiotherapy may be beneficial for survival. There are also some case reports suggesting that a combination of treatments such as surgery or radiotherapy treatment improves the overall survival of patients with metastatic esophageal cancer^[16–20]. The above studies are consistent with the findings of the present study.

Surgery is an option for earlier staging of esophageal cancer, and simultaneous radiochemotherapy is considered to be the preferred treatment option for locally advanced patients who are inoperable or unresectable. The results of a prospective phase II study showed that among patients with inoperable squamous esophageal cancer, those who received simultaneous radiotherapy with a chemotherapy regimen of cisplatin and doxorubicin had a more prolonged overall survival^[22].Seyedin et al. found that patients with non-visceral and non-osteosynovial metastatic esophageal cancer who underwent radical radiotherapy in combination with surgery had a higher median overall survival than those who were treated with radiotherapy alone^[23]. The results of the study conducted by David et al. showed that chemotherapy combined with radical radiotherapy improved the overall survival of patients even more^[8]. The results of the study in our SEER database also showed that radiotherapy improved the overall survival of patients with metastatic esophageal cancer.

This study also has some limitations; the phase III study KEYNOTE-590 evaluated the efficacy of pembrolizumab in combination with chemotherapy as a first-line treatment for patients with advanced esophageal cancer^[24].ORIENT-15, also a phase III trial, compared to placebo in the first-line treatment of patients with advanced or metastatic esophageal squamous cell carcinoma, sindelizumab in combination with cisplatin in combination with paclitaxel showed significant benefits in terms of overall survival and progression-free survival^[25]. In addition, similar benefits of sindilizumab in combination with cisplatin plus 5-fluorouracil showed significant potential^[25].The ESCORT-1st randomized clinical trial, a phase III trial designed to investigate the efficacy of chemotherapy combined with karelizumab treatment compared to placebo-combined chemotherapy in patients with advanced or metastatic esophageal squamous cell carcinoma, demonstrated that the chemotherapy-combined karelizumab treatment group significantly improved patients' overall survival and progression-free survival^[26]. A multicenter phase III trial, the JUPITER-06 study, demonstrated that teraplizumab in combination with paclitaxel plus cisplatin chemotherapy significantly improved overall and progression-free survival in patients with primary advanced esophageal squamous carcinoma^[27].Cetuximab targeting epidermal growth factor receptor (EGFR) and bevacizumab targeting vascular endothelial growth factor (VEGF) have been shown to significantly improve the prognosis of patients with esophageal cancer^{[28, 29]}. Pabolizumab (PD-L1 inhibitor) has been approved for the treatment of patients with PD-L1-positive or advanced esophageal squamous cell carcinoma (ESCC), showing significant efficacy ^[30].

In contrast, the strategy of palliative chemotherapy combined with immunotherapy should be considered for those patients with distant metastatic disease ^[6]. For example, pembrolizumab combined with chemotherapy is used as first-line treatment for patients with advanced esophageal cancer. Immunotherapy is performed by activating one's own T-lymphocytes so that they recognize and kill tumor cells^[31]. There are nationally renowned large clinical trials of immunotherapy for esophageal cancer, such as the study in KEYNOTE-028 which showed that pembrolizumab PD-L1-positive patients with advanced esophageal cancer demonstrated manageable toxicity and continued to exhibit antitumor activity^[32].The study in CheckMate648 showed that in patients with advanced esophageal squamous cell carcinoma, either nabulizumab in combination with chemotherapy or na nabulizumab in combination with ibritumomab as first-line treatment regimens both demonstrated significant benefits and were able to significantly prolong overall survival^[33].ATTRACTION-3, a phase III clinical trial, demonstrated that nabulizumab was associated with a significantly higher overall survival in patients with advanced esophageal squamous cell carcinoma who had received prior therapy compared to chemotherapy and a favorable safety profile was associated^[34].

There are also some limitations in this study, First, the SEER database does not contain information such as immunotherapy, targeted therapy, clinical manifestations, basic diseases and surgical types. Second, although we consider chemotherapy in the nomogram, the specific scheme is unknown, different treatment schemes may lead to different results. In addition, we used SEER data mainly in America for validation and analysis, but did not use data from patients in other countries. Therefore, the reliability of the findings would be higher if data from domestic and foreign multicenter studies were integrated for external validation.

The strength of our study lies in the selection of a large sample of metastatic esophageal cancer patients and the adequate statistical analysis of a column line graph of distant metastatic esophageal cancer patients, which has a better predictive effect on the prognosis of the patients and also has some clinical reference value. Moreover, with the continuous progress of immunotherapy and targeted therapies, the prediction of survival of cancer patients with different treatment combinations may be more challenging. Therefore, more multicenter studies and prospective data collection with other potential variables are needed to improve this column line graph.

We developed and validated a column-line diagram based on the SEER database, which can assist clinicians in predicting patient prognosis and also provide a convenient and reliable individualized survival prediction tool for patients with distant metastatic esophageal cancer. Our study demonstrated that T-stage, M-stage, primary tumor site, surgery, chemotherapy, and radiotherapy were independent prognostic risk factors affecting the survival of patients with distant metastatic esophageal cancer. Meanwhile radiotherapy, chemotherapy as well as surgical treatment can prolong the survival time of patients with distant metastatic esophageal cancer, which can bring survival benefit to patients with distant metastatic esophageal cancer.

Conflict of Interest

The authors have declared that no competing interest exists.

Funding

This research was funded by grants from the National Natural Science Foundation of China (82203377, to Yanwei Lu; 82003236, to Haibo Zhang); Natural Science Foundation of Zhejiang Province (Grant number: LQ22H160036, to Yanwei Lu; LY24H160022 to Haibo Zhang). Zhejiang Health Science and Technology Project (2022KY537, to Yanwei Lu, 2022KY596, to Haibo Zhang)

Author Contribution

Shuang Li and Yanwei Lu wrote the main manuscript text,and Ruiqi Liu ,Luanluan Huang and Ding Nan prepared Figures 1-3. Xiaoyan Chen and Wenjie Xia prepared Figures 4-5.Xiaodong Liang and Haibo Zhang prepared Figures 6.All the authors reviewed the manuscript.

Acknowledgement

The authors thank all patients, especially the ability to have open access to the SEER database.

Data Availability

All data included in this study are available upon request by contact with the corresponding author.

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Clinical features, treatment and prognosis analysis of distant metastatic esophageal cancer

Status:

Version 1

Abstract

Backgrounds

Methods

Results

Conclusion

Figures

Introduction

Methods

Patients and selection criteria

Study variables

Construction of the nomogram

Discrimination and calibration of the nomogram

Results

Case inclusion and exclusion process

Baseline characteristics

Survival analyses

Comparison of clinical case data between training and validation cohort

Independent prognostic factors in the training cohort

Prognostic nomogram for OS

Calibration and validation of the nomogram

Discussion

Conclusions

Declarations

Conflict of Interest

Funding

Author Contribution

Acknowledgement

Data Availability

References

Additional Declarations

Status:

Version 1