3.1 Patient Characteristics
Of the 140 total patients, 52 had superficial AEG and 88 had advanced AEG (Table 1) Positivity for H. pylori was 13.6% in superficial AEG and 29.8% in advanced AEG. This infections rate was lower than expected for same age group because the predicted prevalence (with 95% CI) among those born in 1950 is 59.1% (58.2%–60.0%) [16]. Superficial AEG tumors had a high proportion of the GE subclassification, and advanced AEG tumors had a high proportion of EG. Barrett esophagus was found in 60% of those with superficial AEG and in 33% of those with advanced AEG. The number of patients with long-segment Barrett esophagus was low for both types. Multiple cancers were found in the stomachs of five patients with superficial AEG. Synchronous cancer was found in five cases of superfi-cial AEG and six of advanced AEG. Adjuvant (postoperative) chemotherapy was given to about half of the patients with advanced cancer. Preoperative (neoadjuvant) chemoradiotherapy has recently been introduced.
Table1 Clinical characteristics of the patients
Characteristic
|
Superficial (n = 52)
|
Advanced (n = 88)
|
Age (years)
|
68.5 (33–84)
|
64.5 (34–87)
|
Gender
|
|
|
Male
|
45 (87%)
|
76 (86%)
|
Female
|
7 (13%)
|
12 (14%)
|
H. pylori positive (%)
|
13.60%
|
29.80%
|
Tumor size (mm)
|
23.9 (5-80)
|
62.3 (19-114)
|
Tumor location
|
|
|
EG
|
15 (29%)
|
44 (50%)
|
E=G
|
6 (11%)
|
15 (17%)
|
GE
|
31 (60%)
|
29 (33%)
|
Barrett's esophagus
|
|
|
(+)
|
31 (60%)
|
29 (33%)
|
(–)
|
21 (40%)
|
59 (67%)
|
Length of Barrett's esophagus (mm)
|
14.8 (0–80)
|
27.8 (5–60)
|
Long-segment Barrett's esophagus
|
7 (14%)
|
11 (13%)
|
Short-segment Barrett's esophagus)
|
24 (46%)
|
18 (20%)
|
Macroscopic type
|
|
|
0-Ip
|
13
|
|
0-Is
|
4
|
|
0-IIa
|
19
|
|
0-IIb
|
1
|
|
0-IIc
|
14
|
|
0-III
|
1
|
|
1
|
|
9
|
2
|
|
25
|
3
|
|
50
|
4
|
|
1
|
5
|
|
3
|
Clinical stage (UICC-AJCC 8th)
|
|
|
I
|
47
|
0
|
IIA
|
4
|
0
|
IIB
|
0
|
8
|
III
|
0
|
79
|
IVA
|
1
|
0
|
IVB
|
0
|
1
|
Multiple cancer
|
|
|
Esophagus
|
0
|
1
|
Stomach
|
5
|
1
|
Synchronous cancer
|
|
|
Liver
|
0
|
2
|
Lung
|
1
|
1
|
Malignant lymphoma
|
1
|
0
|
Rectum
|
1
|
1
|
GIST
|
1
|
1
|
Prostate
|
0
|
1
|
Hypopharynx
|
1
|
0
|
Adjuvant therapy
|
|
|
Neoadjuvant chemotherapy
|
0
|
2 (2%)
|
Neoadjuvant chemoradiotherapy
|
0
|
15 (17%)
|
Postoperative chemotherapy
|
1 (2%)
|
45 (51%)
|
Surgical approach
|
|
|
Operation
|
29
|
88
|
ESD or EMR
|
23
|
0
|
Abbreviations:
AJCC: American Joint Committee on Cancer
UICC: Union for International Cancer Control
GIST: Gastrointestinal Stromal Tumor
EMR: endoscopic mucosal resection
ESD: endoscopic submucosal dissection
3.2 Pathological findings and surgical Procedures
Of the 52 patients with superficial AEG, 29 patients (56%) underwent surgery, 23 patients (54%) underwent ESD or EMR. In the 52 patients with superficial AEG, the depth of invasion was T1a in 15/23 of the patients with superficial AEG treated with ESD or EMR. Most of the surgical cases were T1b. Of the 29 patients who underwent surgery for superficial AEG, 5 had lymph node metastasis; the depth of invasion was sm2 in 4 patients and sm3 in 1 patient who had upper thoracic and lower thoracic lymph node metastases. Five patients in whom the tumor invaded to the submucosa received chemoradiotherapy or surgery as additional treatment. In superficial AEG, lymphatic vessel invasion was more common than vascular invasion. The proportion with undifferentiated histological type was higher in patients with advanced cancer than in those with superficial cancer. Most patients (90% with superficial AEG and 70% with advanced AEG) underwent lower esophagectomy + proximal gastrectomy. The surgical approach was transhiatal in 69% of those with superficial AEG and left thoracotomy in 56% of those with advanced AEG. Re-construction was performed with gastric tube in 55% of patients with superficial AEG and in 73% of patients with advanced AEG. Double-tract reconstruction was performed in 45% of cases of superficial AEG (Table2).
Table 2 Pathological findings and surgical treatment of patients
Parameters
|
Superficial, ESD/EMR (n = 23)
|
Superficial, operated (n = 29)
|
Advanced, operated (n = 88)
|
Depth of tumor invasion
|
|
|
|
T1a
|
|
|
|
m1
|
1
|
0
|
|
m2
|
5
|
1
|
|
m3
|
9
|
6
|
|
T1b
|
|
|
|
sm1
|
7
|
5
|
|
sm2
|
1
|
11
|
|
sm3
|
0
|
6
|
|
T2
|
|
|
15
|
T3
|
|
|
66
|
T4
|
|
|
7
|
Degree of lymph node metastasis
|
|
|
|
N0
|
23
|
24
|
29
|
N1
|
0
|
4 (all patients were sm2)
|
16
|
N2
|
0
|
1 (sm3)
|
18
|
N3
|
0
|
0
|
25
|
Pathological stage (UICC-AJCC 8th)
|
|
|
|
Stage IA
|
15
|
7
|
|
Stage IB
|
8
|
17
|
|
Stage IIA
|
|
|
|
Stage IIB
|
|
4
|
|
Stage IIIA
|
|
|
|
Stage IIIB
|
|
|
|
Stage IVA
|
|
1
|
|
Stage IVB
|
|
|
|
Lymphatic invasion
|
|
|
|
ly0
|
19
|
15
|
7
|
ly1
|
3
|
8
|
33
|
ly2
|
0
|
4
|
28
|
ly3
|
1
|
2
|
20
|
Venous invasion
|
|
|
|
v0
|
22
|
25
|
28
|
v1
|
0
|
4
|
38
|
v2
|
1
|
0
|
16
|
v3
|
0
|
0
|
6
|
Histological grade
|
|
|
|
Differentiated-type carcinoma
|
22
|
24 (83%)
|
55 (63%)
|
Undifferentiated-type carcinoma
|
1
|
5 (17%)
|
33 (37%)
|
Type of surgery
|
|
|
|
Total gastrectomy
|
|
0 (0%)
|
6 (7%)
|
Lower esophagectomy + proximal gastrectomy
|
|
26 (90%)
|
62 (70%)
|
Subtotal esophagectomy
|
|
3 (10%)
|
20 (23%)
|
ESD or EMR
|
23
|
|
|
Approach
|
|
|
|
Right thoracotomy
|
|
2 (7%)
|
20 (23%)
|
Left thoracotomy
|
|
7 (24%)
|
49 (56%)
|
Trans-hiatal
|
|
20 (69%)
|
19 (21%)
|
Reconstruction
|
|
|
|
Gastric tube
|
|
16 (55%)
|
64 (73%)
|
Jejunum
|
|
0 (0%)
|
0 (0%)
|
Double tract
|
|
13 (45%)
|
14 (16%)
|
Roux-Y
|
|
0 (0%)
|
6 (7%)
|
Colon
|
|
0 (0%)
|
4 (4%)
|
Abbreviations: EMR—endoscopic mucosal resection, ESD—endoscopic submucosal dissection.
3.3 Lymph Node Metastasis
The calculated index for each nodal station in patients with advanced AEG was in stations 1, 2, 3, 7, 11 and 110 for 3-year survival and in stations 1, 2, 3 and 7 for 5-year survival (Table 3). We did not calculate the index for cervical, paraaortic lymph nodes and paraesophageal nodes at the esophageal hiatus of the diaphragm because only a few patients underwent dissection of these stations. The location of affected lymph nodes varied with the extent of esophageal involvement as well as with cancer stage (Table 4).
Table 3 Calculated index for each nodal station in advanced AEG
Lymph node station
|
Incidence of lymph node metastasis (%)
|
3-year survival rate of patients with metastatic nodes (%)
|
IEBLD of 3 years
|
5-year survival rate of patients with metastatic nodes (%)
|
IEBLD of 5 years
|
1
|
32/88 (36%)
|
32
|
11.64
|
15
|
5.45
|
2
|
32/88 (36%)
|
30
|
10.91
|
15
|
5.45
|
3
|
31/88 (11%)
|
39
|
13.7
|
17
|
5.99
|
4sa
|
3/28 (11%)
|
0
|
0
|
0
|
0
|
4sb
|
0/13 (0%)
|
0
|
0
|
0
|
0
|
4d
|
0/9 (0%)
|
0
|
0
|
0
|
0
|
5
|
1/10 (10%)
|
23
|
2.3
|
23
|
2.3
|
6
|
0/4(0%)
|
0
|
0
|
0
|
0
|
7
|
36/8(41%)
|
30
|
12.27
|
13
|
5.32
|
8a
|
6/38 (16%)
|
20
|
3.16
|
0
|
0
|
9
|
5/36 (14%)
|
20
|
2.78
|
0
|
0
|
10
|
0/9 (0%)
|
0
|
0
|
0
|
0
|
11
|
5/34 (15%)
|
52
|
7.65
|
27
|
3.97
|
12
|
3/8 (38%)
|
32
|
12
|
0
|
0
|
16
|
3/6 (50%)
|
0
|
0
|
0
|
0
|
20
|
3/7 (16%)
|
50
|
21.4
|
50
|
21.4
|
101R
|
1/3 (33%)
|
0
|
0
|
0
|
0
|
101L
|
0/3 (0%)
|
0
|
0
|
0
|
0
|
104R
|
0/1 (0%)
|
0
|
0
|
0
|
0
|
104L
|
0/2 (0%)
|
0
|
0
|
0
|
0
|
105
|
2/13 (15%)
|
0
|
0
|
0
|
0
|
106rR
|
2/16 (13%)
|
0
|
0
|
0
|
0
|
106rL
|
2/16 (13%)
|
0
|
0
|
0
|
0
|
106P
|
1/3 (33%)
|
0
|
0
|
0
|
0
|
106tbR
|
0/3 (0%)
|
0
|
0
|
0
|
0
|
106tbL
|
0/11 (0%)
|
0
|
0
|
0
|
0
|
107
|
1/17 (6%)
|
0
|
0
|
0
|
0
|
108
|
3/30 (10%)
|
0
|
0
|
0
|
0
|
109R
|
1/12 (8%)
|
0
|
0
|
0
|
0
|
109L
|
1/17 (6%)
|
0
|
0
|
0
|
0
|
110
|
13/70 (19%)
|
32
|
5.94
|
0
|
0
|
111
|
5/32 (17%)
|
0
|
0
|
0
|
0
|
112
|
4/35 (11%)
|
25
|
2.86
|
25
|
2.86
|
Abbreviation: IEBLD: Index of Estimated Benefit from Lymph node Dissection
Table4 Relationship between esophageal involvement and metastatic lymph node
Location of lymph node
|
|
Cervical
|
Upper
|
Middle
|
Lower
|
Abdominal
|
0–19 mm
|
|
|
|
|
|
Superficial(n=25)
|
0
|
0
|
0
|
0
|
4
|
Advanced (n=22)
|
0
|
0
|
0
|
2
|
12
|
20–39 mm
|
|
|
|
|
|
Superficial (n = 3)
|
0
|
1
|
1
|
0
|
1
|
Advanced (n=37)
|
1
|
0
|
0
|
5
|
24
|
40 mm <
|
|
|
|
|
|
Superficial (n = 1)
|
0
|
0
|
0
|
0
|
0
|
Advanced (n = 29)
|
0
|
2
|
5
|
9
|
16
|
Abbreviation:
Cervical: Cervical lymph nodes (101, 104)
Upper: Upper thoracic lymph nodes (105, 106)
Middle: Middle thoracic lymph bodes (107,108,109)
Lower: Lower thoracic lymph bodes (110, 111, 112)
Abdominal: Abdominal lymph nodes (1, 2, 3, 7, 8 ,9, 10, 11, 12, 16, 20)
3.4 Survival
The median follow-up was 1476 days (range 125–4549). The 5-year overall survival rates were 88% for patients treated with ESD, 78% for those with superficial AEG who under-went surgery, and 24% for those with advanced AEG (p = 0.011; Fig. 1). Only two patients with superficial AEG experienced lymph node metastasis after surgery, but 13 patients with advanced AEG had metastases to thoracic lymph nodes and 12 had metastases to abdominal lymph nodes after surgery. Despite of lymph node dissection, twenty-five patients experienced lymph node metastasis after operation in advanced AEG and there were many disseminations in advanced AEG (Table5).
Table 5 Locations of recurrence
Parameters
|
Superficial, ESD/EMR (n = 23)
|
Superficial, operated (n = 29)
|
Advanced, operated (n = 88)
|
Lymph node
|
|
|
|
Cervical
|
0
|
0
|
0
|
Mediastinal
|
0
|
0
|
13
|
Abdominal
|
1
|
1
|
12
|
Dissemination
|
1
|
1
|
18
|
Liver
|
1
|
2
|
14
|
Lung
|
0
|
1
|
4
|
Bone
|
0
|
0
|
4
|
Brain
|
0
|
0
|
3
|
Others
|
0
|
0
|
2
|
3.5 Neoadjuvant Chemoradiotherapy
There were no differences in survival between patients who received postoperative adjuvant therapy with S-1 for advanced AEG and those who received surgery alone (p = 0.5192; Fig.2). We selected new neoadjuvant therapy for the following reasons. 1. The effect of the S-1 as a postoperative adjuvant therapy was insufficient (Figure 2). 2. It seems that radiation therapy was more effective because there was dissemination after operation as a pattern of recurrence (Table 5). 3. The nab-paclitaxel was reported in a gastric cancer preclinical model with subcutaneous and peritoneal xenografts, comparing with paclitaxel [17-19]. We have started a Phase I trial of nab-paclitaxel combined with radiotherapy for advanced AEG (registration number UMIN000024088) to compare the efficacy of low-dose nab-paclitaxel with the current standard dose (260 mg/m2) of nab-paclitaxel as first- or second-line chemotherapy for advanced AEG. The radiotherapy targets lymph node stations 110, 1, 2, 3, 7 and 11. Enrollment of patients was started at level 1, and the three patients at this starting dose level experienced no dose limiting toxicity (DLT). Enrollment at level 2 was started in accordance with the specified procedure for progression to the next level. At level 2, one of three enrolled patients experienced treatment-related adverse events corresponding to DLT. These treatment-related adverse events were grade 1 peripheral neuropathy. Enrollment at level 3 was started in accordance with the specified procedure for progression to the next level. These treatment-related adverse events were grade 3 peripheral neuropathy and grade 4 Febrile neutropenia. An additional three patients were enrolled at level 2, but none experienced treatment-related adverse events corresponding to DLT, thus leading to the recommended dose was level 2 (Fig.3).
In this study 14 patients have performed nab-paclitaxel combined with radiotherapy as neoadjuvant therapy for advanced AEG. Tumor grade after treatment for evaluation of therapeutic effectiveness would be achieving a grade> 1b was considered evidence of effectiveness. When therapeutic efficacy was evaluated, 13 patients in 14 were at Grade 1b or higher (table.6), but there were no differences in OS between the group that received neoadjuvant chemoradiotherapy and the group that received preoperative chemotherapy with S-1 (p = 0.5908; Fig.4), because the patients who received neoadjuvant chemoradiotherapy was too much small numbers. Because of the nature of a phase I trial and the small number of patients enrolled, it is not appropriate to draw meaningful conclusions concerning overall response rate (ORR) or survival.
Table 6 The result of nab-paclitaxel combined with radiotherapy for advanced AEG
Patients
|
Age
|
Gender
|
Stage
|
Dose
|
RT(Gy)
|
Response
|
Evaluation therapeutic effectiveness
|
1.
|
51
|
Male
|
IIB
|
120
|
39.6
|
PR
|
1b
|
2.
|
55
|
Male
|
IIB
|
120
|
39.6
|
PR
|
2
|
3.
|
76
|
Male
|
IIB
|
120
|
39.6
|
PR
|
2
|
4.
|
56
|
Male
|
IIB
|
150
|
39.6
|
PR
|
2
|
5.
|
49
|
Male
|
III
|
150
|
39.6
|
PR
|
1b
|
6.
|
45
|
Male
|
III
|
150
|
39.6
|
PR
|
2
|
7.
|
64
|
Male
|
III
|
180
|
39.6
|
PR
|
2
|
8.
|
45
|
Male
|
IVA
|
180
|
39.6
|
PR
|
1b
|
9.
|
64
|
Male
|
III
|
180
|
39.6
|
PR
|
2
|
10.
|
59
|
Male
|
IVA
|
150
|
39.6
|
PR
|
1b
|
11.
|
65
|
Male
|
III
|
150
|
39.6
|
SD
|
1a
|
12.
|
63
|
Male
|
III
|
150
|
39.6
|
PR
|
1b
|
13.
|
47
|
Male
|
III
|
150
|
39.6
|
PR
|
2
|
14.
|
48
|
Male
|
III
|
150
|
39.6
|
CR
|
3
|