Patients’ characteristics
Our cohort included 393 chemotherapy naive patients with GCTs treated with first line chemotherapy (Flow diagram). Patients’ characteristics are summarized in Table 1. Median age of patients at time of enrollment was 31 years (ranging from 17 to 63 years). The majority of patients (68.2%) had non-seminomatous germ cell tumor (NSGCT). All patients received platinum-based chemotherapy. There were 128 (32.6%) without primary G-CSF prophylaxis and 265 patients (67.4%) who received primary prophylaxis. Forty patients (10.2%) received filgrastim and 225 (57.2%) patients received pegfilgrastim.
Table 1 Patients’ characteristics
|
N
|
%
|
All
|
393
|
100.0
|
Histology
|
|
seminoma
|
87
|
22.1
|
NSGCT
|
299
|
76.1
|
unknown
|
7
|
1.8
|
Primary tumor
|
|
Gonadal
|
351
|
89.3
|
Extragonadal
|
42
|
10.7
|
Retroperitoneum
|
26
|
6.6
|
Mediastinum
|
12
|
3.1
|
CNS
|
2
|
0.5
|
Unknown
|
2
|
0.5
|
Stage
|
|
I.A-B
|
39
|
9.9
|
I.S
|
22
|
5.6
|
II.A
|
31
|
7.9
|
II.B
|
48
|
12.2
|
II.C
|
47
|
12.0
|
III.A
|
49
|
12.5
|
III.B
|
50
|
12.7
|
III.C
|
107
|
27.2
|
IGCCCG Risk Group
|
|
I.A-B
|
39
|
9.9
|
Good
|
206
|
52.4
|
Intermediate
|
51
|
13.0
|
Poor
|
97
|
24.7
|
Treatment regimen
|
|
BEP
|
275
|
70.0
|
EP
|
56
|
14.2
|
Other regimen
|
62
|
15.8
|
Follow-up status
|
|
Alive
|
332
|
84.5
|
Exitus
|
61
|
15.5
|
NSGCT - nonseminomatous germ cell tumor. IGCCCG - International Germ Cell Cancer Collaborative Group, BEP – bleomycin, etoposide, cisplatin, EP – etoposide, cisplatin
FN events
During the study period, 71 patients (18.1%) suffered FN events. There were 42 patients (32.8%) without primary prophylaxis who suffered FN events. Out of these, 31 patients (24.2%) suffered only one FN episode, and 11 patients (8.6%) who suffered more than 1 episode. Out of 265 patients receiving prophylaxis, 29 patients (10.9%) suffered FN events, 25 patients (9.4%) suffered only one FN episode and 4 patients (1.5%) suffered more than one episode. The data are summarized in Table 2.
Table 2 FN episodes occurring in one patient
Number of FN episodes
|
No prophylaxis
|
G-CSF prophylaxis
|
P
|
1
|
31/128 (24.2%)
|
25/265 (9.4%)
|
0.0002
|
2
|
7/128 (5.5%)
|
3/265 (1.1%)
|
0.016
|
3
|
1/128 (0.8%)
|
1/265 (0.4%)
|
0.5459
|
4
|
3/128 (2.3%)
|
0/265 (0.0%)
|
0.034
|
any
|
42/128 (32.8%)
|
29/265 (10.9%)
|
0.0000001
|
FN – febrile neutropenia, G-CSF – granulocyte-colony stimulating factor
During the course of chemotherapy, 19 (4.8%) patients died. Out of these, eight patients suffered FN events, four patients received primary G-CSF prophylaxis, while four patients did not receive primary G-CSF prophylaxis. Patients on G-CSF prophylaxis had significantly longer time to FN compared to patients without prophylaxis (HR = 0.30, 95%CI 0.18 – 0.50, P = 0.00000001).
Association between FN prophylaxis and patients/tumor characteristics
The highest incidence of FN events (41.9%) was observed in patients receiving chemotherapy regimen other than bleomycin, etoposide, cisplatin (BEP) or etoposide, cisplatin (EP). Two regimens most frequently associated with FN development were paclitaxel, bleomycin, etoposide, cisplatin (T-BEP) (66.7%) and etoposide, iphosphamide, cisplatin (VIP) (50.0%). Very high incidence of FN was also observed in patients with poor risk according to the IGCCCG classification (38.1%) and in patients with extragonadal tumors (28.6%).
There were 61 FN events (20.4%) in patients with NSGCTs and 10 events (11.5%) occurred in patients with seminoma. While there was a significantly lower FN incidence in patients with NSGCT receiving prophylaxis when compared to patients without prophylaxis, the difference in incidences in patients with seminoma was not statistically significant (11.9% vs 36.2%; P < 0.0001; 9.2% vs 18.2%; P = 0.26) (Figure 2).
We observed 59 FN events (16.8%) in patients with gonadal tumors and 12 events were recorded (28.6%) in patients with extragonadal tumors (Figure 3). For both primary tumor locations, there was a significantly lower incidence of FN events in patients receiving prophylaxis.
There were 22 (10.7%) FN events in patients with good risk according to IGCCCG classification, 10 events (19.6%) occurred in patients with intermediate risk and 37 events (38.1%) were observed in patients with poor risk (Figure 4). There was a significantly lower incidence of FN events in patients receiving prophylaxis with good risk and poor risk. There was a trend to lower incidence in patients receiving G-CSF prophylaxis with intermediate risk. These data are summarized in Table 3.
FN events occurred in 40 patients (14.5%) receiving BEP, 20 patients (66.7%) receiving T-BEP, 5 patients (8.9%) receiving EP, 4 patients (50.0%) treated with VIP regimen and 2 patients (22.2%) treated with paclitaxel, iphosphamide, cisplatin (TIP) regimen (Table 4).
Table 3 FN events
|
Overall incidence
|
No prophylaxis
|
G-CSF prophylaxis
|
P
|
|
N
|
%
|
N
|
%
|
N
|
%
|
|
All FN events
|
71/393
|
18.1
|
42/128
|
32.8
|
29/265
|
10.9
|
0.0000001
|
Histology
|
|
|
|
|
|
|
|
Seminoma
|
10/87
|
11.5
|
4/22
|
18.2
|
6/65
|
9.2
|
0.2552
|
NSGCT
|
61/299
|
20.4
|
38/105
|
36.2
|
23/194
|
11.9
|
0.0000006
|
Primary tumor location
|
|
|
|
|
|
|
|
Gonadal
|
59/351
|
16.8
|
32/109
|
29.4
|
27/242
|
11.1
|
0.00002
|
Extragonadal
|
12/42
|
28.6
|
10/19
|
52.6
|
2/23
|
9.1
|
0.0017
|
IGCCCG risk group
|
|
|
|
|
|
|
|
Stage IA/B
|
2/39
|
5.1
|
0/12
|
0.0
|
2/27
|
7.4
|
0.3330
|
Good
|
22/206
|
10.7
|
12/55
|
21.8
|
10/151
|
6.6
|
0.0017
|
Intermediate
|
10/51
|
19.6
|
5/14
|
35.7
|
5/37
|
13.5
|
0.0747
|
Poor
|
37/97
|
38.1
|
25/47
|
53.2
|
12/50
|
24.0
|
0.0031
|
Chemotherapy regimen
|
|
|
|
|
|
|
|
BEP
|
40/275
|
14.5
|
16/71
|
22.5
|
24/204
|
11.8
|
0.0266
|
EP
|
5/56
|
8.9
|
3/23
|
13.0
|
2/33
|
6.1
|
0.3673
|
Other
|
26/62
|
41.9
|
23/34
|
67.6
|
3/28
|
10.7
|
0.000006
|
FN – febrile neutropenia, G-CSF – granulocyte-colony stimulating factor, NSGCT – nonseminomatous germ cell tumor, IGCCCG – International Germ Cell Cancer Collaborative Group, BEP – bleomycin, etoposide, cisplatin, EP – etoposide, cisplatin
Table 4 FN events incidence based on chemotherapy regimen
Regimen
|
FN
|
No prophylaxis
|
G-CSF prophylaxis
|
BEP
|
40/275 (14.55%)
|
16/71 (22.54%)
|
24/204 (11.76%)
|
EP
|
5/56 (8.93%)
|
3/23 (13.04%)
|
2/33 (6.06%)
|
T-BEP
|
20/30 (66.67%)
|
19/28 (67.86%)
|
1/2 (50.00%)
|
GETUG 13
|
0/11 (0.00%)
|
0/0 (0.00%)
|
0/11 (0.00%)
|
TIP
|
2/9 (22.22%)
|
0/0 (0.00%)
|
2/9 (22.22%)
|
VIP
|
4/8 (50.00%)
|
4/6 (66.67%)
|
0/2 (0.00%)
|
cDDP
|
0/1 (0.00%)
|
0/0 (0.00%)
|
0/1 (0.00%)
|
etoposide + CBDCA
|
0/1 (0.00%)
|
0/0 (0.00%)
|
0/1 (0.00%)
|
BEP/CBDCA
|
0/1 (0.00%)
|
0/0 (0.00%)
|
0/1 (0.00%)
|
CHOP, EP
|
0/1 (0.00%)
|
0/0 (0.00%)
|
0/1 (0.00%)
|
FN – febrile neutropenia, G-CSF – granulocyte-colony stimulating factor, BEP – bleomycin, etoposide, cisplatin, EP – etoposide, cisplatin, T-BEP – paclitaxel, bleomycin, etoposide, cisplatin, GETUG 13 – dose dense regimen [32], TIP – paclitaxel, iphosphamide, cisplatin, VIP – etoposide, iphosphamide, cisplatin, CDDP – cisplatin, CBDCA – carboplatin, BEP/CBDCA – bleomycin, etoposide, carboplatin, CHOP – cyclophosphamide, doxorubicin, vincristine, prednisone
Patients receiving G-CSF prophylaxis had significantly longer OS when compared to patients without prophylaxis (HR = 0.44, 95% CI 0.26-0.75; P = 0.0009) (Figure 5). The results are summarized in Table 6. Patients with gonadal GCT and patients with NSGCT histology receiving G-CSF prophylaxis had significantly longer survival compared to patients without prophylaxis. (HR = 0.43, 95% CI 0.23 – 0.81; P = 0.0032, HR = 0.43, 95% CI 0.25 – 0.75; P = 0.0012 respectively) (Figure 6). Patients receiving G-CSF prophylaxis with EP chemotherapy regimen had significantly longer OS when compared to patients without prophylaxis. (HR = 0.11, 95% CI 0.02 – 0.50; P = 0.0119). We have also observed a trend to longer OS in patients receiving G-CSF prophylaxis with BEP chemotherapy regimen when compared to patients without prophylaxis (HR = 0.52, 95% CI 0.23 – 1.18; P = 0.0762). We have also observed longer OS in good risk patients receiving prophylaxis (HR = 0.28, 95% CI 0.04 – 1.92; P = 0.1390).
Table 6 Overall survival
|
G-CSF prophylaxis
|
N
|
HR
|
lower 95% CI
|
upper 95% CI
|
P
|
All patients
|
1/0
|
128/265
|
0.44
|
0.26
|
0.75
|
0.0009
|
IGCCCG risk group
|
|
|
|
|
|
|
Stage IA/B
|
1/0
|
27/12
|
0
|
0
|
0
|
0
|
Good
|
1/0
|
151/55
|
0.28
|
0.04
|
1.92
|
0.1390
|
Intermediate
|
1/0
|
37/14
|
0.85
|
0.07
|
10.11
|
0.8968
|
Poor
|
1/0
|
50/47
|
0.70
|
0.40
|
1.21
|
0.1986
|
Chemotherapy regimen
|
|
|
|
|
|
|
BEP
|
1/0
|
204/71
|
0.52
|
0.23
|
1.19
|
0.0762
|
EP
|
1/0
|
33/23
|
0.11
|
0.02
|
0.50
|
0.0119
|
Other
|
1/0
|
28/34
|
1.03
|
0.47
|
2.27
|
0.9454
|
Tumor histology
|
|
|
|
|
|
|
Seminoma
|
1/0
|
65/22
|
0
|
0
|
0
|
0
|
NSGCT
|
1/0
|
194/105
|
0.43
|
0.25
|
0.75
|
0.0012
|
Primary tumor location
|
|
|
|
|
|
|
Gonadal
|
1/0
|
242/109
|
0.43
|
0.23
|
0.81
|
0.0032
|
Extragonadal
|
1/0
|
23/19
|
0.62
|
0.21
|
1.76
|
0.3570
|
G-CSF – granulocyte-colony stimulating factor, IGCCCG – International Germ Cell Cancer Collaborative Group, BEP – bleomycin, etoposide, cisplatin, EP – etoposide, cisplatin, NSGCT – nonseminomatous germ cell tumor