A national study to assess outcomes of definitive chemoradiation regimens in proximal esophageal cancer

Figures & data

Table 1. Baseline characteristics of 200 consecutive patients with proximal esophageal cancer treated with definitive chemoradiation (2004–2014).

	Cis-low-dose RT	Cis-high-dose RT	CP-low-dose RT	CP-high-dose RT	^ap Value
	N = 54 (26%)	N = 39 (19.5%)	N = 95 (47.5%)	N = 12 (6%)
Age at diagnosis					.02
Median, years (range)	62 (35–77)	61 (30–81)	66 (49–85)	62 (44–76)
≥70 years	6 (11%)	6 (15%)	31 (33%)	3 (25%)
Gender					.27
Male	38 (70%)	22 (56%)	59 (62%)	10 (83%)
WHO performance status					.55
0	21 (39%)	12 (31%)	28 (29%)	4 (33%)
1	30 (56%)	20 (51%)	50 (53%)	8 (67%)
2–3	2 (4%)	2 (5%)	8 (8%)	0
Unknown	1 (2%)	5 (13%)	9 (10%)	0
Comorbidity					.27
Any	30 (56%)	18 (46%)	61 (64%)	7 (58%)
Cardiovascular	13 (24%)	11 (28%)	31 (33%)	6 (50%)
Pulmonary	4 (7%)	6 (15%)	7 (7%)	0
Previous malignancy	12 (22%)	1 (3%)	23 (24%)	1 (8%)
None	24 (44%)	21 (54%)	34 (36%)	5 (42%)
Tumor differentiation grade					.04
G1	3 (6%)	2 (5%)	4 (4%)	0
G2	9 (17%)	12 (31%)	33 (35%)	4 (33%)
G3	19 (35%)	11 (28%)	14 (15%)	0
Gx	23 (43%)	14 (36%)	44 (46%)	8 (67%)
Clinical T stage					.20
T1-3	31 (57%)	22 (56%)	63 (66%)	6 (50%)
T4	19 (35%)	9 (23%)	26 (27%)	5 (42%)
Tx	4 (7%)	8 (21%)	6 (6%)	1 (8%)
Clinical N stage					.47
N0	17 (31%)	10 (26%)	27 (28%)	6 (50%)
N+	35 (65%)	27 (69%)	67 (71%)	6 (50%)
Nx	2 (4%)	2 (5%)	1 (1%)	0
Tumor location					.03
Cervical (<18 cm)	15 (28%)	21 (54%)	27 (28%)	4 (33%)
Upper thoracic (18–24 cm)	39 (72%)	18 (46%)	68 (72%)	8 (67%)
GTV, cm^3					.11
Median (range)	34.9 (2.4–190.5)	39.5 (10.3–130.8)	31.5 (6.8–142.0)	55.2 (29.0–106.0)
Unknown	16 (30%)	11 (28%)	9 (10%)	3 (25%)
Radiation dose parameters
Median total radiation dose applied, Gy (range)	50.4 (23.4–50.4)	70.0 (12.0–70.0)	50.4 (37.8–50.4)	61.6 (54–70.0)	<.001
Median fraction dose, Gy (range)	1.8 (1.8–2.0)	2.0 (1.8–2.8)	1.8 (1.8–2.5)	2.0 (1.8–2.2)
Median number of applied fractions (range)	27 (13–28)	35 (6–35)	28 (20–28)	30 (28–35)
CRT completed as planned					.24
Yes	44 (82%)	23 (59%)	68 (72%)	10 (83%)
No	7 (13%)	14 (36%)	20 (21%)	2 (17%)
Unknown	3 (6%)	2 (5%)	7 (7%)	0
RT completed as planned					.24
Yes	53 (98%)	34 (87%)	89 (94%)	11 (92%)
No	1 (2%)	5 (13%)	5 (5%)	1 (8%)
Unknown	0	0	1 (1%)	0
Chemotherapy completed as planned					.61
Yes	44 (82%)	25 (64%)	69 (73%)	10 (83%)
No	7 (13%)	11 (28%)	19 (20%)	2 (17%)
Unknown	3 (6%)	3 (8%)	7 (7%)	0

Percentages may not add up to 100 because of rounding.

^a Continuous variables are calculated with the ANOVA-test or Kruskal–Wallis test. Categorical variables are calculated with the Chi-squared test or Fisher exact test where needed.

Cis-low-dose RT: cisplatin-based chemotherapy with low-dose RT; CRT: chemoradiation; Cis-high-dose RT: cisplatin-based chemotherapy with high-dose RT; CP-low-dose RT: carboplatin/paclitaxel with low-dose RT; CP-high-dose RT: carboplatin/paclitaxel with high-dose RT; GTV: gross tumor volume as delineated on the CT scan used for radiation treatment planning; CRT: chemoradiation; RT: radiotherapy.

Figure 1. Kaplan–Meier curves for overall survival by treatment, intention-to-treat analysis. Cis/low: cisplatin and low-dose radiotherapy; Cis/high: cisplatin and high-dose radiotherapy; CP/low: carboplatin/paclitaxel and low-dose radiotherapy; CP/high: carboplatin/paclitaxel and high-dose radiotherapy.

Table 2. Univariable and multivariable comparison of overall survival by four definitive chemoradiation regimens, and propensity score adjusted for overall survival.

	Univariable		Multivariable		Propensity score weighted
	HR (95% CI)	p Value	HR (95% CI)	p Value	HR (95% CI)	p Value
Definitive chemoradiation regimen
Cis-low-dose RT	Ref		Ref		Ref
Cis-high-dose RT	1.05 (0.65–1.71)	.84	1.05 (0.62–1.79)	.86	1.00 (0.57–1.78)	.99
CP-low-dose RT	1.03 (0.69–1.55)	.88	1.02 (0.67–1.56)	.93	1.03 (0.68–1.57)	.87
CP-high-dose RT	1.33 (0.66–2.68)	.43	1.32 (0.64–2.72)	.45	1.65 (0.83–3.25)	.15
Age at diagnosis	1.00 (0.98–1.02)	.93	—		NA
Gender
Male	Ref		Ref		NA
Female	0.78 (0.55–1.11)	.17	0.65 (0.44–0.97)	.04	NA
WHO performance status
0	Ref		Ref		NA
1	1.16 (0.80–1.68)	.44	1.22 (0.83–1.80)	.32	NA
2–3	1.94 (0.97–3.87)	.06	2.56 (1.18–5.60)	.02	NA
Unknown	1.13 (0.57–2.25)	.73	1.57 (0.76–3.28)	.23	NA
Comorbidity
No comorbidity	Ref				NA
Comorbidity	1.04 (0.74–1.45)	.83	—		NA
cT stage
T1–3	Ref		Ref		NA
T4	1.44 (0.99–2.09)	.06	1.35 (0.90–2.03)	.15	NA
Tx	1.54 (0.89–2.67)	.13	1.85 (1.03–3.34)	.04	NA
cN stage
N0	Ref		Ref		NA
N+	1.32 (0.92–1.91)	.14	1.69 (1.13–2.53)	.01	NA
Nx	1.00 (0.24–4.15)	1.00	0.88 (0.21–3.78)	.87	NA
Tumor location
Cervical (<18 cm)	Ref		Ref		NA
Upper thoracic (18–24 cm)	0.66 (0.47–0.94)	.02	0.60 (0.42–0.86)	.006	NA
Tumor length
≤5 cm	Ref		—		NA
>5 cm	1.16 (0.74–1.80)	.52	—		NA
Obstruction or unknown	1.37 (0.93–2.01)	.11	—		NA

Cis-low-dose RT: cisplatin-based chemotherapy with low-dose RT; Cis-high-dose RT: cisplatin-based chemotherapy with high-dose RT; CP-low-dose RT: carboplatin/paclitaxel with low-dose RT; CP-high-dose RT: carboplatin/paclitaxel with high-dose RT; NA: not applicable. Bold font indicates significant prognostic factors of overall survival.

Table 3. Adverse events, No. (%).

	Cis-low-dose RT (N = 54)			Cis-high-dose RT (N = 39)			CP-low-dose RT (N = 95)			CP-high-dose RT (N = 12)
	Any grade^a	Grades 3–4	Grade 5	Any grade^a	Grades 3–4	Grade 5	Any grade^a	Grades 3–4	Grade 5	Any grade^a	Grades 3–4	Grade 5
Acute toxicity
Any	35 (65)	22 (41)	1 (2)	25 (64)	19 (49)	1 (3)	60 (63)	21 (22)	1 (1)	9 (75)	5 (42)	0
Dysphagia	22 (41)	12 (22)	0	17 (44)	11 (28)	0	30 (32)	8 (8)	0	7 (58)	4 (33)	0
Mucositis	12 (22)	3 (6)	0	5 (13)	0	0	16 (17)	5 (5)	0	2 (17)	0	0
Esophageal fistula	1 (2)	1 (2)	0	0	0	0	0	0	0	0	0	0
Esophageal perforation	1 (2)	1 (2)	0	0	0	0	0	0	0	0	0	0
Nausea	1 (2)	0	0	0	0	0	0	0	0	0	0	0
Vomiting	1 (2)	0	0	0	0	0	0	0	0	0	0	0
Diarrhea	1 (2)	0	0	0	0	0	0	0	0	0	0	0
Radiation dermatitis	11 (20)	1 (2)	0	4 (10)	0	0	13 (14)	1 (1)	0	4 (33)	0	0
Respiratory disorders	11 (20)	3 (6)	1 (2)	4 (10)	3 (8)	1 (3)	7 (7)	3 (3)	1 (1)	0	0	0
Cardiac disorders	2 (4)	1 (2)	0	0	0	0	1 (1)	0	0	0	0	0
Thromboembolic events	0	0	0	0	0	0	1 (1)	1 (1)	0	0	0	0
Anemia	2 (4)	2 (4)	0	2 (5)	1 (3)	0	1 (1)	0	0	0	0	0
Platelet count decreased	1 (2)	1 (2)	0	5 (13)	3 (8)	0	2 (2)	1 (1)	0	1 (8)	0	0
Neutrophil count decreased	5 (9)	3 (6)	0	1 (3)	1 (3)	0	2 (2)	0	0	1 (8)	0	0
Fever	2 (4)	1 (2)	0	1 (3)	0	0	4 (4)	2 (2)	0	2 (17)	1 (8)	0
Febrile neutropenia	0	0	0	0	0	0	3 (3)	3 (3)	0	0	0	0
Acute kidney injury	4 (7)	3 (6)	0	6 (15)	3 (8)	0	3 (3)	1 (1)	0	0	0	0
Hearing impaired	0	0	0	2 (5)	0	0	1 (1)	0	0	0	0	0
Neuropathy	0	0	0	0	0	0	0	0	0	0	0	0
Other	10 (19)	0	0	2 (5)	1 (3)	0	5 (5)	1 (1)	0	1 (8)	0	0
Late toxicity
Any	14 (26)	9 (17)	0	18 (46)	10 (26)	1 (3)	30 (32)	16 (17)	1 (1)	7 (58)	3 (25)	1 (8)
Dysphagia/esophageal stenosis	14 (26)	9 (17)	0	13 (33)	9 (23)	0	25 (26)	13 (14)	1 (1)	7 (58)	2 (17)	0
Esophageal fistula	0	0	0	1 (3)	1 (3)	0	2 (2)	2 (2)	0	1 (8)	0	1 (8)
Esophageal perforation	0	0	0	1 (3)	0	1 (3)	0	0	0	0	0	0
Tracheal obstruction	0	0	0	1 (3)	1 (3)	0	1 (1)	1 (1)	0	1 (8)	1 (8)	0
Other	3 (6)	0	0	4 (10)	1 (3)	0	7 (7)	2 (2)	0	1 (8)	1 (8)	0

Adverse event terms preprinted in the case report forms (all other adverse events were coded by preferred terms using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.). Cis-low-dose RT: cisplatin-based chemotherapy with low-dose RT; Cis-high-dose RT: cisplatin-based chemotherapy with high-dose RT; CP-low-dose RT: carboplatin/paclitaxel with low-dose RT; CP-high-dose RT: carboplatin/paclitaxel with high-dose RT.

a Any grade = grades 1–5 or unknown.

Table 4. Multivariable multilevel (patients within centers) analyses of grades 3–5 acute and late toxicity.

	Grades 3–5 acute tox			Grades 3–5 late tox
	N (%)	OR (95% CI)	p Value	N (%)	OR (95% CI)	p Value
Definitive chemoradiation regimen
Cis-low-dose RT	23 (43)	2.43 (0.83–7.08)	.10	9 (17)	0.87 (0.30–2.53)	.80
Cis-high-dose RT	20 (51)	3.78 (1.31–10.87)	.01	11 (28)	1.62 (0.58–4.53)	.36
CP-low-dose RT	22 (23)	Ref		17 (18)	Ref
CP-high-dose RT	5 (42)	2.41 (0.52–11.1)	.26	4 (33)	1.96 (0.48–8.03)	.35
Period
2004–2006	6 (21)	Ref		5 (19)	Ref
2007–2009	19 (35)	3.03 (0.89–10.35)	.08	15 (29)	1.78 (0.52–6.14)	.36
2010–2014	45 (39)	5.64 (1.66–19.16)	.01	21 (18)	1.06 (0.30–3.70)	.92
GTV (tertiles), cm^3
≤25	11 (23)	Ref		4 (9)	Ref
25-43	20 (40)	2.82 (0.99–8.08)	.05	14 (29)	3.87 (1.13–13.27)	.03
>43	22 (35)	1.77 (0.65–4.81)	.27	13 (22)	2.64 (0.76–9.12)	.13
Unknown	17 (44)	2.49 (0.73–8.45)	.14	10 (26)	3.83 (0.95–15.46)	.06

Cis-low-dose RT: cisplatin-based chemotherapy with low-dose RT; Cis-high-dose RT: cisplatin-based chemotherapy with high-dose RT; CP-low-dose RT: carboplatin/paclitaxel with low-dose RT; CP-high-dose RT: carboplatin/paclitaxel with high-dose RT. Bold font indicates significant prognostic factors of toxicity.