Patient characteristics and treatment
Characteristics of the 118 patients are summarized in Table 1. Median age was 65 years (range, 26-85 years) and males were predominant (78%). Nearly all patients were at PS 0 or 1. Most patients were in the normal range for BMI (64%). Primary tumor site was the oral cavity in 57 cases (48%), hypopharynx in 31 (26%), oropharynx in 11 (9%), larynx in 9 (8%), and other in 10 (8%). Further, 71% had a history of smoking and 75% had a history of drinking. As for tumor stage, both patients with early and advanced diseases were included, although no patients had distant metastases. Patients who underwent salvage surgery after definitive treatment accounted for 23%, including postoperative recurrence in 14% and post-irradiation recurrence in 16%. Ten percent had a history of chemotherapy.
Table 1
Patient characteristics at baseline.
|
|
N = 118
|
(%)
|
Sex
|
|
|
|
|
Male
|
92
|
(78)
|
|
Female
|
26
|
(22)
|
Age [26-85 (median 65)]
|
|
|
|
< 65 years
|
57
|
(48)
|
|
≥ 65 years
|
61
|
(52)
|
ECOG performance status
|
|
|
|
0
|
86
|
(73)
|
|
1
|
31
|
(26)
|
|
≥ 2
|
1
|
(1)
|
BMI [16-31.6 (median 21.2)]
|
|
|
|
< 18.5
|
20
|
(17)
|
|
≥ 18.5, < 25
|
75
|
(64)
|
|
≥ 25
|
23
|
(19)
|
Primary tumor site
|
|
|
|
Oral cavity
|
57
|
(48)
|
|
Hypopharynx
|
31
|
(26)
|
|
Oropharynx
|
11
|
(9)
|
|
p16-positive
|
3
|
(3)
|
|
Larynx
|
9
|
(8)
|
|
External auditory canal
|
3
|
(3)
|
|
Paranasal sinus
|
2
|
(2)
|
|
Cervical esophagus
|
2
|
(2)
|
|
Unknown
|
3
|
(3)
|
Histology
|
|
|
|
Squamous cell carcinoma
|
118
|
(100)
|
Smoking
|
|
|
|
Ever
|
84
|
(71)
|
|
Never
|
34
|
(29)
|
Alcohol
|
|
|
|
Ever
|
89
|
(75)
|
|
Never
|
29
|
(25)
|
T category
|
|
|
|
1
|
2
|
(2)
|
|
2
|
35
|
(30)
|
|
3
|
45
|
(38)
|
|
4
|
3
|
(3)
|
|
4a
|
20
|
(17)
|
|
0 a
|
13
|
(11)
|
N category
|
|
|
|
0
|
45
|
(38)
|
|
1
|
23
|
(19)
|
|
2a
|
3
|
(3)
|
|
2b
|
24
|
(20)
|
|
2c
|
5
|
(4)
|
|
3b
|
18
|
(15)
|
M category
|
|
|
|
0
|
118
|
(100)
|
Salvage surgery
|
|
|
|
Yes
|
27
|
(23)
|
|
No
|
91
|
(77)
|
Previous surgery
|
|
|
|
Yes
|
16
|
(14)
|
|
No
|
102
|
(86)
|
Previous radiotherapy
|
|
|
|
Yes
|
19
|
(16)
|
|
No
|
99
|
(84)
|
Previous chemotherapy
|
|
|
Yes
|
12
|
(10)
|
|
Previous use of S-1
|
4
|
(3)
|
|
No
|
106
|
(90)
|
Institution
|
|
|
|
IUHW
|
75
|
(64)
|
|
Kitasato University
|
43
|
(36)
|
a T staging of recurrent cases with no primary lesion was defined as T0.
ECOG Eastern Cooperative Oncology Group, IUWH International University of Health and Welfare Mita Hospital, BMI Body mass index
|
Details of S-1 administration are summarized in Table 2. Median administration period was 14 days (range, 7-28 days), with 7-13 days in 26 cases (22%), 14-20 days in 81 (predominant; 69%), and 21-28 days in 11 (9%). Median period from the end of administration to surgery was 13 days (range, 5-35 days), with 5-13 days in 64 cases (predominant; 54%), 14-20 days in 33 (28%), and 21-35 days in 21 (18%). Hence, patients typically underwent surgery about one week after taking S-1 for two weeks. Administration dose was reduced by one step in 34 cases (29%), and administration was discontinued due to adverse events (AEs) in 6 cases (5%).
Table 2
Details of the administration of S-1.
|
|
N = 118
|
(%)
|
Period of administration of S-1 [7-28 (median 14)] (days)
|
|
|
|
7-13
|
26
|
(22)
|
|
14-20
|
81
|
(69)
|
|
21-28
|
11
|
(9)
|
Period from the end of S-1 to surgery [5-35 (median 13)] (days)
|
|
|
|
5-13
|
64
|
(54)
|
|
14-20
|
33
|
(28)
|
|
21-35
|
21
|
(18)
|
Administered dose of S-1
|
|
|
|
Standard
|
84
|
(71)
|
|
1-step reduction
|
34
|
(29)
|
Discontinuation of administration
|
|
|
|
Yes
|
6
|
(5)
|
|
No
|
112
|
(95)
|
Characteristics of resected tumors
Resected tumors are characterized in Table 3. Maximum tumor diameter could be measured in 108 cases with a median of 27.5 mm (range, 0-90 mm) after formalin fixation. In 2 cases, the tumor had completely disappeared pathologically. Surgical margin was negative in 114 of 118 cases (97%). Differentiation was well, moderate, and poor in 37%, 52%, and 11%, respectively, in 98 cases. Positive rates of vascular invasion, lymphatic invasion, and perineural invasion were 51%, 38%, and 29%, respectively, in 101 cases.
Table 3
Characteristics of resected tumors.
|
|
N
|
(%)
|
Maximum diameter (mm) (N = 108)
|
0 – 90 (median 27.5)
|
|
|
Surgical margin (N = 118)
|
|
|
|
Positive
|
4
|
(3)
|
|
Negative
|
114
|
(97)
|
Differentiation (N = 98)
|
|
|
|
Well
|
36
|
(37)
|
|
Moderate
|
51
|
(52)
|
|
Poor
|
11
|
(11)
|
Vascular invasion (N = 101)
|
|
|
|
Positive
|
52
|
(51)
|
|
Negative
|
49
|
(49)
|
Lymphatic invasion (N = 101)
|
|
|
|
Positive
|
38
|
(38)
|
|
Negative
|
63
|
(62)
|
Perineural invasion (N = 101)
|
|
|
|
Positive
|
29
|
(29)
|
|
Negative
|
72
|
(71)
|
Safety (Adverse events)
AEs of the 118 patients during the study period are summarized in Table 4. For all grades, 125 AEs were detected in 71 patients (60%). Anemia was the most common AE (31%). No grade 4 or 5 AE were reported while grade 3 AEs were detected in 3 patients (3%), comprising one each of anemia, anorexia, and hypokalemia. Among these, 2 patients who developed grade 3 anemia or hypokalemia had the same AE of grade 2 before S-1 administration, respectively. S-1 was discontinued in 3 patients due to grade 2 maculopapular rash, grade 2 diarrhea plus grade 3 anorexia, and grade 2 watering of the eyes due to dacryocystitis. The median duration of administration for these 6 discontinued cases was 10 days (range, 7-14 days). Surgery was postponed in 3 patients, including 2 patients postponed for 6 and 7 days due to grade 1 fever, and 1 patients postponed for 12 days due to influenza of the patient's family. There was no cancellation of surgery due to AEs.
Table 4
Summary of adverse events (N=118).
Adverse events
|
Any grade (N)
|
(%)
|
Grade 3 (N)
|
(%)
|
Anemia
|
37
|
(31)
|
1
|
(1)
|
Creatinine increased
|
9
|
(8)
|
0
|
(0)
|
Hyperkalemia
|
9
|
(8)
|
0
|
(0)
|
Hypoalbuminemia
|
8
|
(7)
|
0
|
(0)
|
Platelet count decreased
|
7
|
(6)
|
0
|
(0)
|
Chronic kidney disease
|
5
|
(4)
|
0
|
(0)
|
Rash maculopapular
|
5
|
(4)
|
0
|
(0)
|
Serum amylase increased
|
5
|
(4)
|
0
|
(0)
|
Anorexia
|
3
|
(3)
|
1
|
(1)
|
ALT increased
|
3
|
(3)
|
0
|
(0)
|
AST increased
|
3
|
(3)
|
0
|
(0)
|
CPK increased
|
3
|
(3)
|
0
|
(0)
|
Diarrhea
|
3
|
(3)
|
0
|
(0)
|
Fever
|
3
|
(3)
|
0
|
(0)
|
Hyponatremia
|
3
|
(3)
|
0
|
(0)
|
Hyperglycemia
|
2
|
(2)
|
0
|
(0)
|
Hypokalemia
|
2
|
(2)
|
1
|
(1)
|
Malaise
|
2
|
(2)
|
0
|
(0)
|
Nausea
|
2
|
(2)
|
0
|
(0)
|
Watering eyes
|
2
|
(2)
|
0
|
(0)
|
ALP increased
|
1
|
(1)
|
0
|
(0)
|
Dizziness
|
1
|
(1)
|
0
|
(0)
|
Epistaxis
|
1
|
(1)
|
0
|
(0)
|
Hypercalcemia
|
1
|
(1)
|
0
|
(0)
|
Hyperuricemia
|
1
|
(1)
|
0
|
(0)
|
Neutrophil count decreased
|
1
|
(1)
|
0
|
(0)
|
Pharyngitis
|
1
|
(1)
|
0
|
(0)
|
Pruritus
|
1
|
(1)
|
0
|
(0)
|
WBC decreased
|
1
|
(1)
|
0
|
(0)
|
Total
|
125
|
|
3
|
|
|
(71 patients)
|
(60)
|
(3 patients)
|
(3)
|
ALT Alanine aminotransferase, AST Aspartate aminotransferase, CPK Creatine phosphokinase, ALP Alkaline phosphatase, WBC White blood cell
|
Efficacy (Tumor response)
Tumor response to preoperative S-1 therapy is summarized in Table 5. In the 35 cases that could be image-evaluated, median diameter of the primary site was 32 mm (range, 10-72 mm) and median rate of change in diameter after administration of S-1 was -10% (range, -70-+50%). Thirty-one cases (89%) were evaluated as effective (≥ 0% decrease) and 4 (11%) as non-effective (> 0% increase). Further, in the 27 cases that could be image-evaluated, median diameter of the metastatic lymph node was 21 mm (range, 11-73 mm) and median rate of change in diameter was ±0% (range, -42-+38%). Twenty-three cases (85%) were evaluated as effective and 4 (15%) as non-effective.
Table 5
Tumor response to preoperative S-1 therapy.
|
Primary site
|
Metastatic lymph node
|
|
N=35
|
N=27
|
Maximum diameter (mm)
|
10 - 72
|
(median 32)
|
11 - 73
|
(median 21)
|
Rate of change after S-1 therapy (%)
|
-70 - +50
|
(median -10)
|
-42 - +38
|
(median ±0)
|
Tumor response
|
N
|
(%)
|
N
|
(%)
|
Effective (≥ 0% decrease)
|
31
|
(89)
|
23
|
(85)
|
Non-effective (> 0% increase)
|
4
|
(11)
|
4
|
(15)
|
Figure 1 shows a representative case with S-1 therapy before surgery.
Factors affecting the efficacy and the safety of S-1 therapy
Background factors and details of S-1 administration were not significantly associated with tumor non-growth or the occurrence of grade 3 AEs with S-1 therapy (Supplemental table 1, 2). Regarding pathological features, although no association was seen with the degree of differentiation, efficacy rate was higher in cases without vascular (100% vs 76%), lymphatic (92% vs 75%) or perineural invasion (92% vs 78%) than in cases with these invasions (Table 6).
Table 6
Analysis of the characteristics of resected tumors on efficacy.
|
|
Effective a
|
Non-effective a
|
p-value
|
Differentiation
|
Well (N= 13)
|
11 (85)
|
2 (15)
|
1
|
|
Moderate (N= 17)
|
15 (88)
|
2 (12)
|
|
|
Poor (N= 2)
|
2 (100)
|
0 (0)
|
|
Vascular invasion
|
Positive (N= 17)
|
13 (76)
|
4 (24)
|
0.103
|
|
Negative (N= 17)
|
17 (100)
|
0 (0)
|
|
Lymphatic invasion
|
Positive (N= 8)
|
6 (75)
|
2 (25)
|
0.229
|
|
Negative (N= 26)
|
24 (92)
|
2 (8)
|
|
Perineural invasion
|
Positive (N= 9)
|
7 (78)
|
2 (22)
|
0.281
|
|
Negative (N= 25)
|
23 (92)
|
2 (8)
|
|
a Evaluation of the primary lesion.
|