01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Concurrent chemoradiotherapy with or without cetuximab for stage II to IVb nasopharyngeal carcinoma: a case–control study
- Zeitschrift:
- BMC Cancer > Ausgabe 1/2017
Background
Methods
Pretreatment assessments
Concurrent chemotherapy and cetuximab
Radiotherapy
Outcome and follow-up
Statistical analysis
Results
Patient characteristics and treatment compliance
CCRT with cetuximab group (
n = 62)
|
CCRT group (
n = 124)
|
P value
|
|
---|---|---|---|
Age, years
|
1
|
||
Mean
|
46.32 (25–64)
|
46.05 (28–66)
|
|
Sex
|
1
|
||
Male
|
50 (80.6%)
|
100 (80.6%)
|
|
Female
|
12 (19.4%)
|
24 (19.4%)
|
|
Pathological type
|
1
|
||
WHO type II
|
3 (4.8%)
|
4 (3.2%)
|
|
WHO type III
|
59 (95.2%)
|
120 (96.8%)
|
|
T category
|
1
|
||
T2
|
14 (22.6%)
|
28 (22.6%)
|
|
T3
|
41 (66.1%)
|
82 (66.1%)
|
|
T4
|
7 (11.3%)
|
14 (11.3%)
|
|
N category
|
1
|
||
N0
|
6 (9.7%)
|
12 (9.7%)
|
|
N1
|
25 (40.3%)
|
50 (40.3%)
|
|
N2
|
28 (45.2%)
|
56 (45.2%)
|
|
N3
|
3 (4.8%)
|
6 (4.8%)
|
|
Disease stage
|
1
|
||
II
|
5 (8.1%)
|
10 (8.1%)
|
|
III
|
47 (75.8%)
|
94 (75.8%)
|
|
IVA
|
7 (11.3%)
|
14 (11.3%)
|
|
IVB
|
3 (4.8%)
|
6 (4.8%)
|
|
RT technique
|
1
|
||
2DRT
|
10 (16.1%)
|
20 (16.1%)
|
|
IMRT
|
52 (83.9%)
|
104 (83.9%
|
|
Cisplatin delivery
|
0.144
|
||
Every 3 weeks(80–100 mg/m
2)
|
39 (62.9%)
|
64 (51.6%)
|
|
Weekly (30–40 mg/m
2)
|
23 (37.1%)
|
60 (48.4%)
|
|
EBV DNA level
|
1
|
||
< 4000 copies
|
35 (56.5%)
|
70 (56.5%)
|
|
≥ 4000 copies
|
27 (43.5%)
|
54 (43.5%)
|
|
VCA-IgA
|
1
|
||
< 1:80
|
15 (24.2%)
|
30 (24.2%)
|
|
≥ 1:80
|
47 (75.8%)
|
94 (75.8%)
|
|
EA-IgA
|
0.148
|
||
< 1:10
|
24 (38.7%)
|
35 (28.2%)
|
|
≥ 1:10
|
38 (61.3%)
|
89 (71.8%)
|
|
ECOG
|
1
|
||
0
|
1 (1.6%)
|
2 (1.6%)
|
|
1
|
61 (98.4%)
|
122 (98.4%)
|
|
LDH,U/L
|
0.666
|
||
< 245
|
61 (98.4%)
|
120 (96.8%)
|
|
≥ 245
|
1 (1.6%)
|
4 (3.2%)
|
|
CRP,g/ml
|
0.286
|
||
< 3.00
|
49 (79.0%)
|
89 (71.8%)
|
|
≥ 3.00
|
13 (21.0%)
|
35 (28.2%)
|
|
Body mass index, kg/m
2
|
1
|
||
< 18.5
|
3 (4.8%)
|
5 (4.0%)
|
|
≥ 18.5
|
59 (95.2%)
|
119 (96.0%)
|
|
Smoking
|
0.46
|
||
Yes
|
20 (32.2%)
|
59 (47.6%)
|
|
No
|
42 (67.7%)
|
65 (52.4%)
|
|
Family history of cancer
|
0.02
|
||
Yes
|
13 (21.0%)
|
11 (8.9%)
|
|
No
|
49 (79.0%)
|
113 (91.1%)
|
Toxicities
Toxic effects, No. (%)
|
P value*
|
||||
CCRT alone (
n = 124)
|
CCRT + cetuximab(
n = 62)
|
||||
Grade 1
|
Grade 2
|
Grade 1
|
Grade 2
|
Grade 1–2
|
|
Neutropenia
|
34 (27.4%)
|
49 (39.5%)
|
16 (25.8%)
|
18 (29.0%)
|
0.107
|
Leucopenia
|
36 (29.0%)
|
24 (19.4%)
|
17 (27.4%)
|
13 (21.0%)
|
1
|
Anemia
|
44 (35.5%)
|
23 (18.5%)
|
3 (4.8%)
|
5 (8.1%)
|
< 0.001
|
Thrombocytopenia
|
19 (15.3%)
|
10 (8.1%)
|
5 (8.1%)
|
3 (4.8%)
|
0.091
|
AST increased
|
17 (13.7%)
|
3 (2.4%)
|
9 (14.5%)
|
1 (1.6%)
|
1
|
ALT increased
|
22 (17.7%)
|
11 (8.9%)
|
31 (50.0%)
|
4 (6.5%)
|
< 0.001
|
BUN
|
9 (7.3%)
|
1 (0.8%)
|
2 (3.2%)
|
1 (1.6%)
|
0.549
|
CRE
|
13 (10.5%)
|
0
|
2 (3.2%)
|
0
|
0.087
|
Mucositis
|
36 (29.0%)
|
54 (43.5%)
|
9 (14.5%)
|
21 (33.9%)
|
0.001
|
Dermatitis
|
73 (58.9%)
|
26 (21.0%)
|
28 (45.2%)
|
23 (37.1%)
|
0.694
|
Vomiting
|
47 (37.9%)
|
17 (13.7%)
|
35 (56.5%)
|
11 (17.7%)
|
0.003
|
Weight loss
|
42 (36.8%)
|
56 (49.1%)
|
14 (23.7%)
|
39 (66.1%)
|
0.298
|
Acneiform rash
|
0 (0.0%)
|
0 (0.0%)
|
31 (50.0%)
|
15 (24.2%)
|
-
|
Toxic effects, No. (%)
|
P value*
|
||||
CCRT alone (
n = 124)
|
CCRT + cetuximab(
n = 62)
|
||||
Grade 3
|
Grade 4
|
Grade 3
|
Grade 4
|
||
Neutropenia
|
18 (14.5%)
|
1 (0.8%)
|
8 (12.9)
|
0 (0.0%)
|
0.097
|
Leucopenia
|
8 (6.5%)
|
1 (0.8%)
|
4 (6.5%)
|
0 (0.0%)
|
1
|
Anemia
|
2 (1.6%)
|
0 (0.0%)
|
2 (3.2%)
|
0 (0.0%)
|
0.602
|
Thrombocytopenia
|
4 (3.2%)
|
1 (0.8%)
|
1 (1.6%)
|
0 (0.0%)
|
0.665
|
AST increased
|
0
|
0
|
0
|
0
|
-
|
ALT increased
|
2 (1.6%)
|
0
|
1 (1.6%)
|
0
|
1
|
Renal impairment
|
0
|
0
|
0
|
0
|
-
|
BUN
|
0
|
0
|
0
|
0
|
-
|
CRE
|
0
|
0
|
0
|
0
|
-
|
Mucositis
|
29 (23.4%)
|
0 (0.0%)
|
29 (46.8%)
|
3 (4.8%)
|
< 0.001
|
Dermatitis
|
5 (4.0%)
|
0 (0.0%)
|
3 (4.8%)
|
0 (0.0%)
|
1
|
Vomiting
|
2 (1.6%)
|
0 (0.0%)
|
2 (3.2%)
|
1 (1.6%)
|
0.335
|
Weight loss
|
0
|
-
a
|
2 (3.2%)
|
-
a
|
0.110
|
Late toxicity
|
Cetuximab + CCRT
(
n = 62)
|
CCRT
(
n = 124)
|
P
|
---|---|---|---|
Xerostomia*
|
11 (17.7%)
|
27 (21.8%)
|
0.52
|
Hearing loss*
|
13 (21.0%)
|
23 (18.5%)
|
0.694
|
Skin dystrophy
|
3 (4.8%)
|
5 (4.0%)
|
1
|
Neck fibrosis
|
6 (9.7%)
|
17 (13.7%)
|
0.431
|
Trismus
|
2 (3.2%)
|
11 (8.9%)
|
0.263
|
Radiation encephalopathy
|
1 (1.6%)
|
9 (7.3%)
|
0.108
|
Cranial nerve palsy
|
7 (11.3%)
|
9 (7.3%)
|
0.364
|
*Grade 2–4 toxicities
|
Survival
CCRT plus cetuximab group (%)
|
CCRT group (%)
|
Hazard ratio
a
|
P value
|
|
---|---|---|---|---|
N = 62
|
N = 124
|
(95% CI)
|
||
Overall survival
|
||||
Deaths
|
6
|
11
|
_
|
|
Rate at 5 years
|
89.7%
|
90.7%
|
0.705
|
0.386
|
(81.9–97.5)
|
(85.4–96.0)
|
(0.318–1.560)
|
||
Progression-free survival
|
||||
Progression
|
13
|
19
|
_
|
|
Rate at 5 years
|
77.6%
|
84.5%
|
0.607
|
0.115
|
(66.6–88.5)
|
(78.0–91.0)
|
(0.324–1.137)
|
||
Locoregional relapse-free survival
|
||||
Locoregional relapses
|
3
|
7
|
_
|
|
Rate at 5 years
|
95.0%
|
94.0%
|
0.803
|
0.695
|
(89.5–100)
|
(89.7–98.3)
|
(0.269–2.403)
|
||
Distant metastasis-free survival
|
||||
Distant metastases
|
10
|
12
|
_
|
|
Rate at 5 years
|
82.0%
|
90.3%
|
0.489
|
0.068
|
(71.8–92.2)
|
(85.0–95.6)
|
(0.223–1.072)
|
HR (95% CI)
|
P value
|
|
---|---|---|
Overall survival
|
||
Cetuximab (yes vs. no)
|
1.457 (0.639 ~ 3.322)
|
0.371
|
Smoking history (yes vs. no)
|
1.217 (0.537 ~ 2.757)
|
0.638
|
Disease stage (IV vs. II–III)
|
5.052 (2.194 ~ 11.631)
|
< 0.001
|
EBVDNA (≥ vs. < 4000 copies)
|
2.072 (0.878 ~ 4.893)
|
0.096
|
BMI (≥vs. < 23 kg/m
2)
|
0.84 (0.373 ~ 1.893)
|
0.674
|
CRP (≤ vs. >3.0 g/ml)
|
0.736 (0.267 ~ 2.027)
|
0.553
|
VCA-IgA (< vs. ≥ 1:80)
|
0.877 (0.209 ~ 3.687)
|
0.858
|
EA-IgA (< vs. ≥ 1:10)
|
0.894 (0.24 ~ 3.326)
|
0.867
|
Family history of cancer (yes vs. no)
|
0.953 (0.271 ~ 3.346)
|
0.94
|
Progression-free survival
|
||
Cetuximab (yes vs. no)
|
1.85 (0.956 ~ 3.58)
|
0.068
|
Smoking history (yes vs. no)
|
0.917 (0.47 ~ 1.79)
|
0.8
|
Disease stage (IV vs. II–III)
|
3.747 (1.823 ~ 7.704)
|
< 0.001
|
EBVDNA (≥ vs. < 4000 copies)
|
1.127 (0.571 ~ 2.222)
|
0.731
|
BMI (≥vs. < 23 kg/m
2)
|
0.802 (0.424 ~ 1.517)
|
0.497
|
CRP (≤ vs. >3.0 g/ml)
|
1.315 (0.644 ~ 2.688)
|
0.452
|
VCA-IgA (< vs. ≥ 1:80)
|
1.087 (0.376 ~ 3.143)
|
0.877
|
EA-IgA (< vs. ≥ 1:10)
|
0.712 (0.268 ~ 1.892)
|
0.496
|
Family history of cancer (yes vs. no)
|
0.678 (0.233 ~ 1.97)
|
0.302
|
Discussion
Conclusion
Acknowledgements
Funding
Availability of data and materials
Ethics approval and consent to participate
Consent for publication
Competing interests
Publisher’s Note
Appendix 1
Cycles
|
Cetuximab + CCRT
(
n = 62)
|
CCRT
(
n = 124)
|
---|---|---|
Triweekly regimen
|
||
1
|
1 (1.6%)
|
0 (0.0%)
|
2
|
28 (45.2%)
|
50 (40.3%)
|
3
|
10 (16.1%)
|
14 (11.3%)
|
Weekly regimen
|
||
4
|
1 (1.6%)
|
4 (3.2%)
|
5
|
4 (6.5%)
|
16 (12.9%)
|
6
|
16 (25.8%)
|
31 (25%)
|
7
|
2 (3.2%)
|
9 (7.3%)
|
Appendix 2
Years
|
Authors
|
Trial or research
|
Research design
|
Primary endpoint
|
RT/CRT Vs. RT/CRT + cetuximab
|
P value
|
Cancer
|
---|---|---|---|---|---|---|---|
2006
|
Bonner JA et al.
|
NCT00004227
|
RT(
n = 213) Vs. RT + cetuximab(
n = 211)
|
LR control (2 yr)
|
41% Vs. 50%
|
0.005
|
HNSCC
|
2014
|
K. Kian Ang et al.
|
RTOG 0522 Phase III
|
CRT(
n = 444) Vs. CRT + cetuximab(
n = 447)
|
PFS (3 yr)
|
61.2% Vs. 58.9%
|
0.76
|
HNSCC
|
2016
|
Xin Wu et al.
|
A retrospective matched case–control study
|
TPF + CRT(
n = 56) Vs. TPF + RT + cetuximab(
n = 56)
|
OS (5 yr)
|
79.3% Vs. 79.5%
|
0.797
|
NPC
|
2015
|
T. Xu et al.
|
NCT01614938 Phase II
|
CRT(
n = 23) Vs. RT + cetuximab(
n = 21)
|
DFS (3 yr)
|
78.3% Vs. 85.7%
|
0.547
|
NPC
|
Appendix 3
Toxic effects received weekly cisplatin, No. (%)
|
p value*
|
|||||
CCRT +Cetuximab(
n = 23)
|
CCRT alone(
n = 60)
|
|||||
All Grades
|
Grade3 ~ 4
|
All Grades
|
Grade3 ~ 4
|
All Grades
|
Grade3 ~ 4
|
|
Leucopenia
|
14
|
4
|
49
|
11
|
0.047
|
1
|
Neutropenia
|
13
|
2
|
32
|
5
|
0.794
|
1
|
Anaemia
|
4
|
1
|
36
|
1
|
0.001
|
0.48
|
Thrombocytopenia
|
3
|
1
|
20
|
3
|
0.065
|
1
|
AST increased
|
3
|
0
|
10
|
0
|
0.945
|
—
|
ALT increased
|
15
|
1
|
17
|
1
|
0.002
|
0.48
|
BUN
|
0
|
0
|
4
|
0
|
0.486
|
—
|
CRE
|
0
|
0
|
0
|
0
|
—
|
—
|
Mucositis
|
23
|
7
|
58
|
13
|
0.931
|
0.403
|
Dermatitis
|
17
|
1
|
50
|
4
|
0.507
|
1
|
Vomiting
|
17
|
2
|
24
|
0
|
0.006
|
0.074
|
Weight loss
|
20
|
1
|
54
|
0
|
0.996
|
0.277
|
Toxic effects received triweekly cisplatin, No. (%)
|
p value*
|
|||||
CCRT +Cetuximab(
n = 39)
|
CCRT alone(
n = 64)
|
|||||
All Grades
|
Grade3 ~ 4
|
All Grades
|
Grade3 ~ 4
|
All Grades
|
Grade3 ~ 4
|
|
Leucopenia
|
28
|
4
|
54
|
8
|
0.124
|
0.978
|
Neutropenia
|
21
|
2
|
37
|
4
|
0.694
|
1
|
Anaemia
|
6
|
1
|
33
|
1
|
< 0.001
|
1
|
Thrombocytopenia
|
6
|
0
|
14
|
2
|
0.419
|
0.525
|
AST increased
|
7
|
0
|
10
|
0
|
0.758
|
—
|
ALT increased
|
21
|
0
|
18
|
1
|
0.009
|
1
|
BUN
|
3
|
0
|
6
|
0
|
1
|
—
|
CRE
|
2
|
0
|
13
|
0
|
0.034
|
—
|
Mucositis
|
39
|
25
|
61
|
16
|
0.442
|
< 0.001
|
Dermatitis
|
37
|
2
|
54
|
1
|
0.196
|
0.66
|
Vomiting
|
32
|
1
|
42
|
2
|
0.072
|
1
|
Weight loss
|
37
|
1
|
51
|
0
|
0.034
|
0.379
|
Appendix 4
OR(95% CI)
|
P value
|
||
---|---|---|---|
Acute toxicities
|
|||
Cetuximab (yes vs. no)
|
3.011
|
(1.533–5.915)
|
0.001
|
RT technique (IMRT vs. 2D–RT)
|
8.326
|
(2.688–25.788)
|
<0.001
|
Late toxicities
|
|||
Age
|
0.917
|
(0.863–0.975)
|
0.006
|
RT technique (IMRT vs. 2D–RT)
|
0.367
|
(0.133–1.016)
|
0.054
|