Development and Validation of Prognostic Survival Nomograms for Patients with Anal Canal Cancer: A SEER-Based Study

Figures & data

Figure 1 Flow diagram for the selection of patients with anal canal cancer from the SEER database between 2004 and 2015.

Abbreviations: SEM, squamous epithelial-derived malignancy; AEM, adeno epithelial-derived malignancy.

Table 1 Demographic and Clinical Data of the Patients with Anal Canal Cancer

Characteristics		Train Cohort	Validation Cohort	P-value
		n=1720(%)	n=738(%)
Gender	Male	594(34.5)	246(33.3)	0.565
	Female	1126(65.5)	492(66.7)
Age (years)	Range	26–104	22–97	0.954
	Median	59	59
	Mean	60.3±12.1	60.2±12.3
Race	White	1487(86.5)	642(87.0)	0.579
	Black	184(10.7)	71(9.6)
	Other/NA	49(2.8)	25(3.4)
Marital status	Married	750(43.6)	338(45.8)	0.315
	Non-married	970(56.4)	400(54.2)
Tumor size (cm)	Range	0.1–88.8	0.1–15.0	0.525
	Median	3.1	3.3
	Mean	3.9±3.3	3.8±2.3
Grade	Well, I	211(12.3)	84(11.4)	0.795
	Moderately, II	784(45.6)	352(47.7)
	Poorly, III	691(40.2)	288(39.0)
	Anaplastic, IV	34(2.0)	14(1.9)
Histological type	SEM	1529(88.9)	664(90.0)	0.505
	AEM	110(6.4)	47(6.4)
	Other	81(4.7)	27(3.6)
AJCC stage	I	366(21.3)	167(22.6)	0.277
	II	694(40.3)	319(43.2)
	III A	208(12.1)	88(11.9)
	III B	353(20.5)	125(16.9)
	IV	99(5.8)	39 (5.3)
T stage	T1	440(25.6)	194(26.3)	0.957
	T2	857(49.8)	362(49.1)
	T3	286(16.6)	126(17.1)
	T4	137(8.0)	56(7.6)
N stage	N0	1137(66.1)	522(70.7)	0.127
	N1	204(11.9)	77(10.4)
	N2	236(13.7)	92(12.5)
	N3	143(8.3)	47(6.4)
M stage	M0	1621(94.2)	699(94.7)	0.642
	M1	99(5.8)	39(5.3)
SEER stage	Localized	846(49.2)	383(51.9)	0.445
	Regional	682(39.7)	274(37.1)
	Distant	192(11.2)	81(11.0)
Surgery	No Surgery	1027(59.7)	456(61.8)	0.443
	Local Resection	576(33.5)	228(30.9)
	Radical Resection	117(6.8)	54(7.3)
Chemotherapy	Yes	1458(84.8)	620(84.0)	0.634
	No/NA	262(15.2)	118(16.0)
Radiotherapy	Yes	1496(87.0)	648(87.8)	0.573
	No/NA	224(13.0)	90(12.2)
Survival Months	Range	1–155	1–155	0.174
	Median	42	40
	Mean	53.8±40.5	51.4±39.8

Abbreviations: SEM, squamous epithelial-derived malignancy; AEM, adeno epithelial-derived malignancy; SEER, surveillance, epidemiology, and end results; AJCC, American Joint Committee on Cancer.

Table 2 ICD-O-3 Code

ICD-O-3 Code	Hist/Behav	n
8010/3	Carcinoma, NOS	8
8020/3	Carcinoma, undifferentiated, NOS	1
8041/3	Small cell carcinoma, NOS	10
8045/3	Combined small cell carcinoma	1
8051/3	Verrucous carcinoma, NOS	7
8052/3	Papillary squamous cell carcinoma	3
8070/3	Squamous cell carcinoma, NOS	1715
8071/3	Squamous cell carcinoma, keratinizing, NOS	224
8072/3	Squamous cell carcinoma, large cell, nonkeratinizing, NOS	92
8073/3	Squamous cell carcinoma, small cell, nonkeratinizing	1
8074/3	Squamous cell carcinoma, spindle cell	2
8076/3	Squamous cell carcinoma, micro-invasive	1
8083/3	Basaloid squamous cell carcinoma	151
8094/3	Basosquamous carcinoma	4
8120/3	Transitional cell carcinoma, NOS	1
8123/3	Basaloid carcinoma	21
8124/3	Cloacogenic carcinoma	30
8140/3	Adenocarcinoma, NOS	108
8210/3	Adenocarcinoma in adenomatous polyp	7
8215/3	Adenocarcinoma of anal glands	3
8246/3	Neuroendocrine carcinoma, NOS	10
8255/3	Adenocarcinoma with mixed subtypes	5
8261/3	Adenocarcinoma in villous adenoma	4
8263/3	Adenocarcinoma in tubulovillous adenoma	7
8430/3	Mucoepidermoid carcinoma	2
8480/3	Mucinous adenocarcinoma	18
8481/3	Mucin-producing adenocarcinoma	5
8490/3	Signet ring cell carcinoma	4
8542/3	Paget disease, extramammary (except Paget disease of bone)	3
8560/3	Adenosquamous carcinoma	8
8574/3	Adenocarcinoma with neuroendocrine differentiation	2

Table 3 Survival Analyses of Overall Survival for Anal Canal Cancer Patients

Characteristics	Univariate Analysis		Multivariate Analysis
	HR (95% CI)	P-value	HR (95% CI)	P-value
Gender
Male	Reference		Reference
Female	0.629(0.533–0.742)	<0.001	0.565(0.475–0.671)	<0.001
Age (years)
≤76	Reference		Reference
>76	2.805(2.285–3.445)	<0.001	3.040(2.444–3.780)	<0.001
Race
White	Reference		Reference
Black	1.524(1.206–1.927)	<0.001	-	0.106
Other	1.128(0.713–1.784)	0.608	-	0.907
Marital status
Married	Reference		Reference
Non-married	1.451(1.223–1.721)	<0.001	1.219(1.023–1.454)	0.027
Tumor size (cm)
<2.8	Reference		Reference
2.8–6.2	1.720(1.415–2.091)	<0.001	1.389(1.071–1.802)	0.013
>6.2	3.126(2.406–4.061)	<0.001	2.038(1.482–2.803)	<0.001
Grade
I	Reference		Reference
II	1.108(0.839–1.464)	0.470	1.186(0.891–1.581)	0.243
III	1.304(0.987–1.723)	0.062	1.418(1.060–1.898)	0.019
IV	2.113(1.250–3.571)	0.005	2.287(1.298–4.029)	0.004
Histological type
SEM	Reference		Reference
AEM	1.899(1.439–2.506)	<0.001	1.531(1.145–2.047)	0.004
Other	1.921(1.423–2.593)	<0.001	1.698(1.224–2.356)	0.002
AJCC stage
I	Reference		Reference
II	1.790(1.374–2.332)	<0.001	1.317(0.931–1.865)	0.120
III A	1.991(1.434–2.765)	<0.001	1.233(0.781–1.946)	0.370
III B	2.758(2.077–3.663)	<0.001	1.666(1.092–2.542)	0.018
IV	7.051(5.057–9.830)	<0.001	2.761 (1.567–4.866)	<0.001
T stage
T1	Reference		Reference
T2	1.572(1.253–1.973)	<0.001	-	0.279
T3	2.469(1.898–3.212)	<0.001	-	0.901
T4	2.689(1.962–3.686)	<0.001	-	0.702
N stage
N0	Reference		Reference
N1	1.521(1.188–1.947)	0.001	-	0.174
N2	1.681(1.336–2.115)	<0.001	-	0.200
N3	2.322(1.790–3.013)	<0.001	-	0.396
M stage
M0	Reference		Reference
M1	3.904(3.028–5.033)	<0.001	-	>0.05
SEER stage
Localized	Reference		Reference
Regional	1.629(1.356–1.957)	<0.001	1.405(1.083–1.824)	0.011
Distant	3.711(2.946–4.675)	<0.001	2.223(1.441–3.428)	<0.001
Surgery
No surgery	Reference		Reference
Local resection	0.752(0.624–0.906)	0.003	-	0.946
Radical resection	1.639(1.253–2.144)	<0.001	-	0.847
Chemotherapy
Yes	Reference		Reference
No/NA	1.485(1.207–1.825)	<0.001	1.783(1.429–2.226)	<0.001
Radiotherapy
Yes	Reference		Reference
No/NA	1.488(1.195–1.853)	<0.001	-	0.504

Abbreviations: SEM, squamous epithelial-derived malignancy; AEM, adeno epithelial-derived malignancy; SEER, surveillance, epidemiology, and end results; AJCC, American Joint Committee on Cancer.

Table 4 Survival Analyses of Cancer-Specific Survival for Anal Canal Cancer Patients

Characteristics	Univariate Analysis		Multivariate Analysis
	HR (95% CI)	P-value	HR (95% CI)	P-value
Gender
Male	Reference		Reference
Female	0.545(0.447–0.665)	<0.001	0.499(0.406–0.614)	<0.001
Age (years)
≤76	Reference		Reference
>76	1.934 (1.468–2.548)	<0.001	2.500(1.877–3.331)	<0.001
Race
White	Reference		Reference
Black	1.792(1.369–2.345)	<0.001	1.410(1.069–1.859)	0.015
Other	1.363(0.812–2.288)	0.242	1.233(0.729–2.088)	0.435
Marital status
Married	Reference		Reference
Non-married	1.280(1.044–1.568)	0.017	-	0.615
Tumor size (cm)
<2.8	Reference		Reference
2.8–6.2	1.792(1.404–2.286)	<0.001	1.723(1.138–2.608)	0.010
>6.2	3.812(2.806–5.180)	<0.001	2.644(1.560–4.480)	<0.001
Grade
I	Reference		Reference
II	1.184(0.831–1.685)	0.350	1.238(0.861–1.779)	0.249
III	1.531(1.079–2.173)	0.017	1.625(1.128–2.341)	0.009
IV	2.454(1.307–4.608)	0.005	2.479(1.245–4.939)	0.010
Histological type
SEM	Reference		Reference
AEM	2.072 (1.501–2.859)	<0.001	1.649(1.171–2.322)	0.004
Other	2.213(1.560–3.138)	<0.001	1.904(1.295–2.800)	0.001
AJCC stage
I	Reference		Reference
II	1.914(1.344–2.727)	<0.001	2.444(1.385–4.314)	0.002
III A	2.608(1.726–3.940)	<0.001	2.384 (1.267–4.486)	0.007
III B	3.514(2.439–5.065)	<0.001	3.093(1.690–5.661)	<0.001
IV	11.002(7.389–16.383)	<0.001	4.998(2.247–11.117)	<0.001
T stage
T1	Reference		Reference
T2	1.533(1.152–2.039)	0.003	-	0.043
T3	2.991(2.184–4.096)	<0.001	-	0.868
T4	3.106(2.135–4.519)	<0.001	-	0.929
N stage
N0	Reference		Reference
N1	1.898(1.425–2.528)	<0.001	-	0.225
N2	1.993(1.520–2.613)	<0.001	-	0.327
N3	2.979(2.218–4.000)	<0.001	-	0.394
M stage
M0	Reference		Reference
M1	5.262(4.014–6.897)	<0.001	-	>0.05
SEER stage
Localized	Reference		Reference
Regional	2.058 (1.631–2.598)	<0.001	1.514(1.085–2.114)	0.015
Distant	5.421(4.133–7.111)	<0.001	2.717(1.402–5.264)	0.003
Surgery
No surgery	Reference		Reference
Local resection	0.676(0.535–0.853)	0.001	-	0.766
Radical resection	1.938(1.436–2.615)	<0.001	-	0.330
Chemotherapy
Yes	Reference		-
No/NA	1.262(0.972–1.639)	0.081	-	-
Radiotherapy
Yes	Reference		Reference
No/NA	1.508(1.159–1.962)	0.002	1.664(1.250–2.214)	<0.001

Abbreviations: SEM, squamous epithelial-derived malignancy; AEM, adeno epithelial-derived malignancy; SEER, surveillance, epidemiology, and end results; AJCC, American Joint Committee on Cancer.

Figure 2 Nomogram predicting 1-, 3- and 5-year overall survival (OS) and cancer-specific (CSS) survival rate of patients with anal canal cancer. (A) Nomogram to predict 1-, 3- and 5-year OS for patients with anal canal cancer; (B) Nomogram to predict 1-, 3- and 5-year CSS for patients with anal canal cancer.

Abbreviations: AJCC, American Joint Committee on Cancer; SEER, surveillance, epidemiology, and end results; OS, overall survival; CSS, cancer-specific survival; SEM, squamous epithelial-derived malignancy; AEM, adeno epithelial-derived malignancy.

Figure 3 Time-dependent ROC curves. (A) Time-dependent ROC curves of the OS nomogram reveal that the AUCs in the training cohort are 0.767, 0.728 and 0.768 for predicting 1-, 3- and 5-year OS, respectively; (B) Time-dependent ROC curves of the CSS nomogram in the training cohort reveal that the AUCs are 0.780, 0.744 and 0.768 for predicting 1-, 3- and 5-year CSS, respectively; (C) Time-dependent ROC curves of the OS nomogram reveal that the AUCs in the validation cohort are 0.757, 0.757 and 0.738 for predicting 1-, 3- and 5-year OS, respectively; (D) Time-dependent ROC curves of the CSS nomogram in the validation cohort reveal that the AUCs are 0.743, 0.754 and 0.729 for predicting 1-, 3- and 5-year CSS, respectively.

Abbreviations: ROC, receiver operating characteristic; AUC, area under the curve; OS, overall survival; CSS, cancer-specific survival.

Figure 4 Calibration curves in the training cohort. (A–C) Calibration curves of the nomogram for predicting 1-, 3- and 5-year OS; (D–F) Calibration curves of the nomogram for predicting 1-, 3- and 5-year CSS.

Abbreviations: OS, overall survival; CSS, cancer-specific survival.

Figure 5 Calibration curves in the validation cohort. (A–C) Calibration curves of the nomogram for predicting 1-, 3- and 5-year OS; (D–F) calibration curves of the nomogram for predicting 1-, 3- and 5-year CSS.

Abbreviations: OS, overall survival; CSS, cancer-specific survival.

Figure 6 DCA curves of the nomogram, AJCC stage and SEER staging system. (A) DCA curves for OS in the training cohort; (B) DCA curves for CSS in the training cohort; (C) DCA curves for OS in the validation cohort; (D) DCA curves for CSS in the validation cohort.

Abbreviations: DCA, decision curve analysis; AJCC, American Joint Committee on Cancer; SEER, Surveillance, epidemiology, and end results; OS, overall survival; CSS, cancer-specific survival.

Figure 7 Kaplan–Meier curves survival curves for the high- and low-risk groups. (A) Kaplan–Meier curve for OS in the training cohort; (B) Kaplan–Meier curve for CSS in the training cohort; (C) Kaplan–Meier curve for OS in the validation cohort; (D) Kaplan–Meier curve for CSS in the validation cohort.

Abbreviations: OS, overall survival; CSS, cancer-specific survival.

Table 5 Comparison of AJCC Stage and Tumor Size Between Local Resection Group and Radical Resection Group

Characteristics		Local Resection N (%)	Radical Resection N (%)	P-value
Tumor size (cm)
	<2.8	454(50.8)	37(20.0)	<0.001
	2.8–5.4	281(31.5)	78(42.2)
	>5.4	158(17.7)	70(37.8)
AJCC stage
	I/II	714(80.0)	92(49.7)	<0.001
	III/IV	179(20.0)	93(50.3)

Abbreviation: AJCC, American Joint Committee on Cancer.