Patient and treatment characteristics
Patient and treatment characteristics between the two groups are shown in Table 1. A total of 175 patients (72 in the S-1 group and 103 in the DP group) were eventually included in this study. The baseline patient and tumor characteristics (location, tumor length, and clinical stage) were well balanced between groups. The median age was 64 years (range 47–74 years) in the S-1 group and 62 years (range 49–74 years) in the DP group. Among all of these patients, tumor invasion to adjacent organs was seen in 80 patients (45.7%) and lymph node metastasis in 125 patients (71.4%).
Table 1
Baseline clinical characteristics
Patient characteristic
|
DP group
(n = 103)
|
S-1 group
(n = 72)
|
p value
|
Age (median, year)
|
62
|
64
|
0.647
|
< 60
|
48 (46.6%)
|
31 (43.1%)
|
|
≥ 60
|
55 (53.4%)
|
41 (56.9%)
|
|
Gender
|
|
|
0.873
|
Male
|
65 (63.1%)
|
47 (65.3%)
|
|
Female
|
38 (36.9%)
|
25 (34.7%)
|
|
KPS
|
|
|
0.756
|
90
|
43 (41.7%)
|
28 (38.9%)
|
|
≥ 70
|
60 (58.3%)
|
44 (61.1%)
|
|
Tumor location
|
|
|
0.394
|
Upper third
|
28 (27.2%)
|
16 (22.2%)
|
|
Middle third
|
60 (58.3%)
|
40 (55.6%)
|
|
Lower third
|
15 (14.5%)
|
16 (22.2%)
|
|
Primary tumor length (cm)
|
|
|
0.759
|
< 5
|
56 (54.4%)
|
41 (56.9%)
|
|
≥ 5
|
47 (45.6%)
|
31 (43.1%)
|
|
Smoking
|
|
|
0.273
|
Nonsmoker
|
43 (41.7%)
|
24 (33.3%)
|
|
Smoker
|
60 (58.3%)
|
48 (66.7%)
|
|
Drinking
|
|
|
0.358
|
No
|
49 (47.6%)
|
29 (40.3%)
|
|
Yes
|
54 (52.4%)
|
43 (59.7%)
|
|
Differentiation
|
|
|
0.838
|
Well
|
14 (13.6%)
|
8 (11.1%)
|
|
Moderate
|
59 (57.3%)
|
44 (61.1%)
|
|
Poor
|
30 (29.1%)
|
20 (27.7%)
|
|
Clinical T stage
|
|
|
1.000
|
No invasion to adjacent organs
|
56 (54.4%)
|
39 (54.2%)
|
|
Invasion to adjacent organs
|
47 (45.6%)
|
33 (45.8%)
|
|
Clinical N stage
|
|
|
0.867
|
N0
|
30 (29.1%)
|
20 (27.8%)
|
|
N1
|
73 (70.9%)
|
52 (72.2%)
|
|
Reason for no surgery
|
|
|
0.924
|
Patient refusal
|
8 (7.7%)
|
6 (8.3%)
|
|
Surgical contraindication
|
15 (14.6%)
|
9 (12.5%)
|
|
Unresectable disease
|
65 (63.1%)
|
44 (61.1%)
|
|
Unknown
|
15 (14.6%)
|
13 (18.1%)
|
|
Radiation dose (Gy)
|
|
|
0.698
|
50
|
34 (33.0%)
|
23 (31.9%)
|
|
50.4
|
46 (44.7%)
|
29 (40.3%)
|
|
> 50.4
|
23 (22.3%)
|
20 (27.8%)
|
|
Radiotherapy techniques
|
|
|
0.410
|
3D-CRT
|
30 (29.1%)
|
26 (36.1%)
|
|
IMRT
|
73 (70.9%)
|
46 (63.9%)
|
|
Consolidation chemotherapy
|
|
|
0.537
|
Yes
|
61 (59.2%)
|
39 (54.2%)
|
|
No
|
42 (40.8%)
|
33 (45.8%)
|
|
Abbreviations: KPS: Karnofsky performance status, 3D-CRT: three-dimensional conformal radiotherapy, IMRT: intensity modulated radiotherapy. |
Of the treatment characteristics, most patients received a radiation dose of 50-50.4 Gy in both groups, and the difference was not significant between the two groups (p = 0.698). Sixty-two patients (86.1%) in the S-1 group completed the planned 2 cycles of S-1 based concurrent chemotherapy, while 73 patients (70.9%) in the DP group completed the all cycles of concurrent chemotherapy (p = 0.027). Planned RT was completed in 68 patients (94.4%) in S-1 group, and 94 patients (91.3%) in the DP group. In the S-1 group, 39 patients (54.2%) received 2 additional cycles of consolidation chemotherapy after CCRT, as did 61 patients (59.2%) in the DP group (p = 0.537).
Treatment-related toxicities and mortality
Acute treatment-related toxicities are shown in Table 2. The incidence of grade 3–4 adverse events were significantly lower in the S-1 group than in the DP group (22.2% versus 45.6%, p = 0.002). In the S-1 group, 13 patients (18.1%) experienced a grade 3 toxicity and 3 (4.1%) a grade 4 toxicity. However, in the DP group, 31 patients (30.1%) experienced a grade 3 toxicity and 16 (15.5%) a grade 4 toxicity. In terms of hematological toxicities, grade 3–4 leukopenia and neutropenia were more frequently observed in the DP group than in the S-1 group (leukopenia: 34.0% versus 12.5%, p = 0.001, neutropenia: 29.1% versus 9.7%, p = 0.002). There were no statistical differences in the incidence of grade 3–4 non-hematological toxicities during CCRT between the two groups, with the exception of nausea/vomiting (9.7% versus 1.4%, p = 0.028), which was more frequent in the DP group. There were 2 treatment-related deaths in the DP group. One patient died due to aspiration pneumonia. The other patient died due to trachea-esophageal fistula. No treatment-related death was observed in the S-1 group.
Table 2
Treatment-related toxicities during CCRT
Toxicities
|
DP group
(n = 103)
|
S-1 group
(n = 72)
|
p value
|
Overall toxicity ≥ 3
|
47 (45.6%)
|
16 (22.2%)
|
0.002
|
Grade 3
|
31 (30.1%)
|
13 (18.1%)
|
0.079
|
Grade 4
|
16 (15.5%)
|
3 (4.1%)
|
0.024
|
Hematological toxicities ≥ 3
|
|
|
|
Anemia
|
7 (6.8%)
|
4 (5.6%)
|
0.767
|
Leukopenia
|
35 (34.0%)
|
9 (12.5%)
|
0.001
|
Neutropenia
|
30 (29.1%)
|
7 (9.7%)
|
0.002
|
Thrombocytopenia
|
6 (5.8%)
|
2 (2.8%)
|
0.473
|
Non-hematological toxicities ≥ 3
|
|
|
|
Esophagitis
|
24 (23.3%)
|
12 (16.7%)
|
0.344
|
Nausea/vomiting
|
10 (9.7%)
|
1 (1.4%)
|
0.028
|
Mucositis
|
4 (3.9%)
|
3 (4.1%)
|
1.000
|
Fatigue
|
9 (8.7%)
|
5 (6.9%)
|
0.781
|
Pneumonitis
|
5 (4.9%)
|
3 (4.1%)
|
1.000
|
Next, we further investigated the adverse effects in elderly patients. A total of 96 patients were older than 60 years (41 patients in the S-1 group and 55 in the DP group). In the S-1 group, the rate of ≥ grade 3 adverse effects was 24.3% (10/41) for patients ≥ 60 years and 19.4% (6/31) for those < 60 years (p = 0.776). However, in the DP group, the rate of ≥ grade 3 adverse effects was 58.1% (32/55) for patients ≥ 60 years, which was significantly higher (31.3%, 15/48) than those < 60 years (p = 0.01).
Response to treatment
Tumor response is shown in Table 3. Of the 72 patients in the S-1 group, CR and PR were achieved in 18 patients (25.0%) and 31 patients (43.1%), respectively. In the DP group, 29 patients (28.2%) had a CR and 47 patients (45.6%) had a PR. The ORR was similar in the S-1 group and the DP group (68.1% versus 73.8%, p = 0.497).
Table 3
Tumor response after treatment
Response
|
DP group
n = 103
|
S-1 group
n = 72
|
p value
|
CR
|
29 (28.2%)
|
18 (25.0%)
|
|
PR
|
47 (45.6%)
|
31 (43.1%)
|
|
SD
|
25 (24.3%)
|
21 (29.1%)
|
|
PD
|
2 (1.9%)
|
2 (2.8%)
|
|
ORR
|
76 (73.8%)
|
49 (68.1%)
|
0.497
|
Abbreviations: CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease, ORR: objective response rate. |
Follow up and survival
During the follow-up period, 57 patients (79.2%) in the S-1 group had disease progression, including 15 patients in primary tumor, 25 in regional lymph node, and 17 in distant metastasis. For patients in the DP group, disease progression was observed in 75 patients (72.8%). The initial sites of tumor progression were detailed as follows: primary tumor in 19 patients, regional lymph node in 35 patients, and distant metastasis in 21 patients. The 1- and 3-year PFS rates were 65.3% and 25.0%, respectively in the S-1 group, and 72.8% and 33.0%, respectively in the DP group. PFS was longer in the DP group than that in the S-1 group but without significant differences (Fig. 1A, p = 0.275). Of note, 42.1% (24/57) and 32.0% (24/75) of patients who had disease progression received targeted therapy or PD-1 inhibitor in the S-1 and DP group.
The median follow-up time was 19 months (range: 1–66 months). As of May 31, 2020, 55 patients (76.4%) in the S-1 group and 73 patients (70.9%) in the DP group had died or were followed for more than 3 years. The median OS was not reached in both groups. The 1- and 3-year survival rates were 72.2% and 34.7%, respectively in S-1 group, and 75.7% and 38.8%, respectively in DP group. As shown in Fig. 1B, OS was not significantly different between the two groups (p = 0.422).
Because there were more patients in the DP group who did not complete the all cycles of concurrent chemotherapy than in the S-1 group, we further investigated the role on survival. As shown in Fig. 1C-D, patients in the DP group who completed the planned concurrent chemotherapy had longer PFS (p = 0.011) and OS (p = 0.016) than those who did not.