Chemotherapy predictors and a time-dependent chemotherapy effect in metastatic esophageal cancer

Table 1 Baseline characteristics of all patients with advanced esophageal cancer who received or did not receive chemotherapy

Variable	All patients (n = 29182)	Chemotherapy received (n = 21911)	No chemo received (n = 7271)
Age
Median (IQR)	64 (56-73)	63 (55-71)	69 (59-79)
Gender
Female	5126 (17.57)	3569 (16.29)	1557 (21.41)
Male	24056 (82.43)	18342 (83.71)	5714 (78.59)
Race
Black	2878 (9.95)	1936 (8.9)	942 (13.12)
Other	1669 (5.77)	1245 (5.72)	424 (5.9)
White	24389 (84.29)	18574 (85.38)	5815 (80.98)
Insurance type
Medicaid	2415 (8.44)	1752 (8.14)	663 (9.36)
Medicare	13412 (46.87)	9263 (43.02)	4149 (58.58)
Not insured	1404 (4.91)	959 (4.45)	445 (6.28)
Other government	459 (1.6)	323 (1.5)	136 (1.92)
Private	10923 (38.17)	9233 (42.88)	1690 (23.86)
Income quartiles for place of residence
Less than $30000	3918 (13.99)	2687 (12.79)	1231 (17.61)
$30000-$34999	5362 (19.15)	3942 (18.77)	1420 (20.31)
$35000-$45999	8066 (28.81)	6081 (28.95)	1985 (28.39)
$46000+	10652 (38.05)	8297 (39.5)	2355 (33.69)
Treatment site
Academic	12955 (45.07)	9856 (45.75)	3099 (43.05)
Non-academic	15786 (54.93)	11686 (54.25)	4100 (56.95)
Geographic location in United States
Midwest	8278 (28.8)	6388 (29.65)	1890 (26.25)
Northeast	6772 (23.56)	5178 (24.04)	1594 (22.14)
South	9509 (33.09)	6977 (32.39)	2532 (35.17)
West	4182 (14.55)	2999 (13.92)	1183 (16.43)
Residence area type
Metro	22465 (80.15)	16883 (80.25)	5582 (79.88)
Rural	641 (2.29)	467 (2.22)	174 (2.49)
Urban	4921 (17.56)	3689 (17.53)	1232 (17.63)
Number of comorbidities1
0	22009 (75.42)	17017 (77.66)	4992 (68.66)
1	5401 (18.51)	3789 (17.29)	1612 (22.17)
≥ 2	1772 (6.07)	1105 (5.04)	667 (9.17)
Year of diagnosis
2004-2009	15715 (53.85)	11588 (52.89)	4127 (56.76)
2010-2014	13467 (46.15)	10323 (47.11)	3144 (43.24)
Grade2
1	633 (2.77)	475 (2.73)	158 (2.89)
2	7926 (34.65)	6099 (35.02)	1827 (33.46)
3	13849 (60.54)	10497 (60.28)	3352 (61.38)
4	467 (2.04)	343 (1.97)	124 (2.27)
AJCC T stage
T0	51 (0.32)	31 (0.24)	20 (0.58)
T1	2624 (16.26)	1889 (14.86)	735 (21.45)
T2	1751 (10.85)	1442 (11.35)	309 (9.02)
T3	7128 (44.18)	6105 (48.04)	1023 (29.86)
T4	4570 (28.33)	3233 (25.44)	1337 (39.03)
pIS	10 (0.06)	8 (0.06)	2 (0.06)
AJCC N stage
Negative	4983 (22.23)	3562 (20.36)	1421 (28.86)
Positive	17435 (77.77)	13933 (79.64)	3502 (71.14)

¹Per Charlson/Deyo[11].

²Grade 1, well-differentiated; grade 2, moderately differentiated; grade 3, poorly differentiated; grade 4, undifferentiated.

Data are presented as number of patients (column %) or median (interquartile range). AJCC: American Joint Committee on Cancer.

Table 2 Univariate and multivariable analyses of factors associated with receipt of chemotherapy vs no chemotherapy in advanced esophageal cancer patients

Variable		Univariate		Multivariable1
	n	Odds ratio (95%CI)	P value	Odds ratio (95%CI)	P value
Age	29182	0.96 (0.95-0.96)	< 0.001	0.95 (0.94-0.96)	< 0.001
Gender
Female	5126	0.71 (0.67-0.76)	< 0.001	0.86 (0.76-0.98)	0.019
Male	24056	1 (reference)		1 (reference)
Race (combined)
Black	2878	0.64 (0.59-0.70)	< 0.001	0.79 (0.67-0.93)	0.005
Other	1669	0.92 (0.82-1.03)	0.148	1.12 (0.89-1.40)	0.322
White	24389	1 (reference)		1 (reference)
Insurance type
Medicaid	2415	0.48 (0.44-0.54)	< 0.001	0.52 (0.43-0.64)	< 0.001
Medicare	13412	0.41 (0.38-0.44)	< 0.001	0.84 (0.73-0.97)	0.017
Other government	459	0.43 (0.35-0.53)	< 0.001	0.74 (0.50-1.09)	0.123
Not insured	1404	0.39 (0.35-0.45)	< 0.001	0.41 (0.33-0.52)	< 0.001
Private	10923	1 (reference)		1 (reference)
Income quartiles for place of residence
Less than $30000	3918	1 (reference)		1 (reference)
$30000-$34999	5362	1.27 (1.16-1.39)	< 0.001	1.12 (0.95-1.33)	0.172
$35000-$45999	8066	1.40 (1.29-1.53)	< 0.001	1.31 (1.12-1.54)	0.001
$46000+	10652	1.61 (1.49-1.75)	< 0.001	1.49 (1.27-1.75)	< 0.001
Treatment site
Academic	12955	1.12 (1.06-1.18)	< 0.001	Dropped out of the model
Non-academic	15786	1 (reference)
Geographic location in United States
Northeast	6772	1.28 (1.17-1.40)	< 0.001	1.45 (1.22-1.72)	< 0.001
Midwest	8278	1.33 (1.23-1.45)	< 0.001	1.43 (1.22-1.68)	< 0.001
South	9509	1.09 (1.00-1.18)	0.044	1.22 (1.04-1.43)	0.015
West	4182	1 (reference)		1 (reference)
Residence area type
Metro	22465	1.13 (0.94-1.34)	0.185	Dropped out of the model
Urban	4921	1.12 (0.93-1.34)	0.248
Rural	641	1 (reference)
Number of comorbidities2
1	5401	0.69 (0.65-0.74)	< 0.001	0.79 (0.70-0.90)	< 0.001
≥ 2	1772	0.49 (0.44-0.54)	< 0.001	0.61 (0.50-0.74)	< 0.001
0	22009	1 (reference)		1 (reference)
Year of diagnosis
2010-2014	13467	1.17 (1.11-1.23)	< 0.001	1.29 (1.17-1.43)	< 0.001
2004-2009	15715	1 (reference)		1 (reference)
Grade3
1	633	1 (reference)		1 (reference)
2	7926	1.11 (0.92-1.34)	0.273	1.08 (0.78-1.48)	0.648
3	13849	1.04 (0.87-1.25)	0.664	0.96 (0.70-1.31)	0.786
4	467	0.92 (0.70-1.21)	0.550	0.69 (0.44-1.08)	0.105
AJCC T stage
pIS	10	1.65 (0.35-7.80)	0.525	20075.87 (0.00-NA)	0.948
T0	51	0.64 (0.36-1.13)	0.123	0.63 (0.29-1.40)	0.261
T1	2624	1.06 (0.96-1.18)	0.262	1.10 (0.96-1.27)	0.181
T2	1751	1.93 (1.68-2.22)	< 0.001	1.87 (1.56-2.25)	< 0.001
T3	7128	2.47 (2.25-2.71)	< 0.001	2.29 (2.03-2.59)	< 0.001
T4	4570	1 (reference)		1 (reference)
AJCC N stage
Positive	17435	1.59 (1.48-1.71)	< 0.001	1.35 (1.20-1.52)	< 0.001
Negative	4983	1 (reference)		1 (reference)

¹10799 complete observations were used in the multivariable model.

²Per Charlson/Deyo[11].

³Grade 1, well-differentiated; grade 2, moderately differentiated; grade 3, poorly differentiated; grade 4, undifferentiated.

AJCC: American Joint Committee on Cancer; CI: Confidence interval; NA: Not available.

Table 3 Univariate and multivariable analysis of patient and disease factors on overall survival in advanced esophageal cancer

Variable	Univariate		Multivariable1
	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value
Chemotherapy
Chemotherapy received vs not received
If 0 < time ≤ 10 mo2	-	< 0.001	-	< 0.001
If time > 10 mo	0.95 (0.88-1.03)	0.204	0.98 (0.86-1.11)	0.699
Age	1.01 (1.01-1.01)	< 0.001	1.01 (1.00-1.01)	< 0.001
Gender
Female	0.99 (0.96-1.02)	0.420	0.90 (0.86-0.95)	< 0.001
Male	1 (reference)		1 (reference)
Race (combined)
Black	1.09 (1.05-1.14)	< 0.001	1.02 (0.96-1.09)	0.457
Other	0.86 (0.82-0.91)	< 0.001	0.87 (0.80-0.95)	0.002
White	1 (reference)		1 (reference)
Insurance type
Medicaid	1.28 (1.22-1.34)	< 0.001	1.21 (1.13-1.31)	< 0.001
Medicare	1.30 (1.26-1.33)	< 0.001	1.04 (0.99-1.10)	0.119
Other government	1.15 (1.04-1.26)	0.006	0.95 (0.82-1.10)	0.493
Not insured	1.37 (1.29-1.45)	< 0.001	1.20 (1.09-1.31)	< 0.001
Private	1 (reference)		1 (reference)
Income quartiles for place of residence
$30000-$34999	0.94 (0.90-0.98)	0.007	Dropped out of the model
$35000-$45999	0.93 (0.90-0.97)	< 0.001
$46000+	0.87 (0.83-0.90)	< 0.001
Less than $30000	1 (reference)
Treatment site
Academic	0.87 (0.85-0.89)	< 0.001	0.91 (0.87-0.94)	< 0.001
Non-academic	1 (reference)		1 (reference)
Geographic location in United States
Northeast	0.92 (0.89-0.96)	< 0.001	0.96 (0.90-1.02)	0.180
Midwest	1.02 (0.98-1.06)	0.340	1.07 (1.01-1.14)	0.032
South	1.03 (0.99-1.07)	0.142	1.05 (0.99-1.11)	0.138
West	1 (reference)		1 (reference)
Residence area type
Metro	0.93 (0.86-1.01)	0.086	Dropped out of the model
Urban	0.95 (0.87-1.03)	0.193
Rural	1 (Reference)
Number of comorbidities
1	1.20 (1.17-1.24)	< 0.001	1.09 (1.04-1.14)	< 0.001
≥ 2	1.45 (1.37-1.52)	< 0.001	1.16 (1.07-1.26)	< 0.001
0	1 (reference)		1 (reference)
Year of diagnosis
2010-2014	0.99 (0.96-1.01)	0.286	Dropped out of the model
2004-2009	1 (Reference)
Grade
2	1.08 (1.00-1.18)	0.065	1.06 (0.95-1.20)	0.297
3	1.30 (1.20-1.41)	< 0.001	1.28 (1.14-1.44)	< 0.001
4	1.30 (1.15-1.48)	< 0.001	1.21 (1.02-1.45)	0.032
1	1 (reference)		1 (reference)
AJCC T stage
pIS	0.57 (0.30-1.09)	0.090	1.11 (0.46-2.66)	0.821
T0	0.94 (0.69-1.26)	0.665	0.86 (0.59-1.25)	0.424
T1	0.88 (0.84-0.93)	< 0.001	0.89 (0.84-0.95)	< 0.001
T2	0.66 (0.62-0.69)	< 0.001	0.69 (0.65-0.74)	< 0.001
T3	0.65 (0.63-0.68)	< 0.001	0.73 (0.70-0.76)	< 0.001
T4	1 (reference)		1 (reference)
AJCC N stage
Positive	0.94 (0.91-0.97)	< 0.001	Dropped out of the model
Negative	1 (reference)

¹12370 observations were used in the multivariable model.

²As chemotherapy effect is not constant over time up to 10 mo, it was modeled with a time-dependent coefficient and the unadjusted hazard ratio for chemotherapy versus no chemotherapy is exp [-2.34 + 0.998 × log(time)] and adjusted hazard ratio is exp [-2.30 + 0.966 × log(time)].

AJCC: American Joint Committee on Cancer; CI: Confidence interval.