(Recombinant
Human Granulocyte Colony Stimulating Factor Injection)
as an adjuvant drug in tumor chemotherapy
Summary
96 pathologically diagnosed malignant tumor patients,
including lung cancer, malignant lymphoma, breast cancer
and ovary cancer, underwent 2 courses of chemotherapy with
identical chemotherapeutic regimen according to tumor type.
In one of the 2 courses, Jilifen was added as treatment
group. Cross-over self-controlled method was used in comparing
the dynamic changes of ANC between the 2 groups. The results
demonstrated that: Jilifen reduce the severity of ANC decrease
after chemotherapy, shortened the duration of neutropenia,
promoted the recovery of ANC without obvious adverse or
toxic reaction, therefore could act as a valuable adjuvant
drug in tumor chemotherapy.
Key
words: Jilifen granulocyte colony-stimulating factor
tumor chemotherapy
Introduction
Jilifen(recombinant
human granulocyte colony-stimulating factor injection),
produced by Hangzhou Jiuyuan Gene Engineering Co., Ltd.,
is a drug pruduced by DNA recombinant technique. The
active protein of Jilifen contains 175 amino acids, expressed
and secreted by E. Coli whose plasmid was inserted with
a human granulocyte colony stimulating factor gene. It exhibited
the activity of stimulating the formation of granulocyte
colonies.
It was demonstrated in preclinical cell culture and animal
experiments that recombinant human granulocyte colony stimulating
factor had the action of promoting growth, proliferation
and differentiation of granulocyte.
The
clinical study performed by J. Craford in US had demonstrated
that rhG-CSF could promote the recovery of neutrophil
after a variety of chemotherapeutic regimens effectively
and safely. Among the study there were 211 small cell lung
cancer cases who received treatment of CAE regimen(CTX 1000mg/m2
d1, ADR 50mg/m2 d1, VP-16 120mg/m2
d1-3, 21 days as a course, 6 courses in total), and a randomized,
double-blinded, placebo-control test was performed simultaneously
to comparing the recovery of neutrophil after the administration
of rhG-CSF or placebo. The results showed that in rhG-CSF
group, the incidence of neutrophil count <0.5'109/L
was significantly lower than that of control group. In the
entire courses the lasting time of ANC<0.5'109/L in rhG-CSF group and control
group was 1 day and 6 days respectively; With administration
of rhG-CSF, the incidence of fever and intravenous antibiotic
use resulted from neutropenia and hospitalization decreased
obviously, those differences were all statistically significant.
The domestically performed clinical trials of imported homologous
products gave similar results.
Aimed at investigating the clinical value of rhG-CSF produced
by Hangzhou Jiuyuan Gene Engineering Co., Ltd., under the
permission of the Phamaceutical Bureau of the Ministry of
Health in P. R. China, with the 2nd affiliated
hospital of Zhongshan Medical University as leading unit,
in cooperation with the affiliated Tumor Hospital of Chinese
Medical Science Institute, affiliated Tumor Hospital of
Shanghai Medical University and the Tumor Hospital of Jiangsu
province, the phase II clinical study of Jilifen was performed
between Dec. 1995 to May 1996. Patients with lung cancer,
breast cancer, ovary cancer and malignant lymphoma were
treated by corresponding standard chemo-therapeutic regimens,
with or without administration of Jilifen, using cross-over
self-controlled method, the major objective of the study
was to evaluate the impact of Jilifen on neutrophils in
patients undergone chemotherapy.
Patients
and method
1.
Drug: Jilifen
was produced by Hangzhou Jiuyuan Gene Engineering Co., Ltd.
It was a colorless and clear liquid. Batch number were 950504
and 950508, 300ug/1.2ml/ampoule.
2. Patients: Pathologically diagnosed cancer patients,
with good performance status (ECOG grade 0-2), peripheral
ANC³2.0'109/L,
PLT³100'109/L³, with no abnormality of
hepatic or renal function, BUN£7.1mmol/L, serum creatinine£176.8mmol/L.
3.
Treatment: Patients enrolled were treated with selected
chemotherapeutic regimens(see table 1), each case received
2 courses of chemotherapy with identical regimen. All patients
were divided into group A and B randomly. For group A, Jilifen
was added in the 1st course(defined as treatment
course) of chemotherapy and ommited at the 2nd
course as control, while in group B, Jilifen was used in
the 2nd course only.
4.
Table 1
chemotherapeutic regimens in phase II clinical trial of
Jilifen
|
Non-Hodgkin’s
lymphoma
(CHOP,32
cases)
|
CTX
|
750mg/M2
|
iv
|
D1
|
|
ADM
|
50mg/M2
|
iv
|
D1
|
|
VCR
|
1.4mg/M2
|
iv
|
D1
|
|
PRED
|
60mg/M2
|
iv
|
D1
|
|
Small cell
lung carcinoma (SCLC)
(CAV,2
cases)
|
CTX
|
750mg/M2
|
iv
|
D1
|
|
ADM
|
50mg/M2
|
iv
|
D1
|
|
VCR
|
1.4mg/M2
|
iv
|
D1
|
|
SCLC and
NSCLC
(CE,17
cases)
|
Carboplatin
|
350mg/M2
|
iv
|
D1
|
|
VP-16
|
120mg/M2
|
iv
|
D1,2,3
|
|
Non-small
cell lung carcinoma(NSCLC)
(MVP,17
cases)
|
MMC
|
6mg/M2
|
iv
|
D1
|
|
VDS
|
3mg/M2
|
iv
|
D1,D5
|
|
DDP
|
80mg/M2
|
iv
|
D1
|
|
NSCLC
(NVB+DDP,
3cases)
|
NVB
|
25mg/M2
|
iv
|
D1,D5
|
|
DDP
|
80mg/M2
|
iv
|
D1
|
|
Breast
carcinoma
(FAC,18
cases)
|
CTX
|
750mg/M2
|
iv
|
D1
|
|
ADM
|
50mg/M2
|
iv
|
D1
|
|
5-FU
|
750mg/M2
|
iv
|
D1
|
|
Ovary carcinoma
(CTX+Carbo,7
cases)
|
CTX
|
600mg/M2
|
iv
|
D1
|
|
Carbo
|
350mg/M2
|
iv
|
D1
|
4. Use of Jilifen: In chemotherapeutic course designed to add Jilifen,
all patients received Jilifen subcutaneously once daily,
at a dosage of 5mg/kg
body weight, and Jilifen was withdrawn till ANCs of patients
deceased to nadir and then recovered to more than 5.0'109/L or WBCs recovered to more
than 10.0'109/L.
5. Observation items:
1) Absolute neutrophil
count (ANC) of all cases (either use Jilifen or not) were
examined once every 2days, and the dynamic curve changes
of ANCs were ploted out. The decrease and recovery of ANC
in treatment and control group were compared, including
the severity and duration of neutropenia, and recovery rate.
2) Comparing the ANC
nadirs of treatment and control group.
3) Comparing the incidence
and lasting duration of ANC<2.0'109/L in treatment and control group.
4) Comparing the incidence
and time of chemotherapy delay due to neutropenia between
treatment and control group.
Results
According to the above standards, totally 102 cases were
enrolled in the study, 96 of which underwent the whole study,
6 cases were deleted for : treatment abrupt due to progress
of disease in 2 cases, 1 in control course and another in
treatment course; 4 cases were absent from the study before
it was ended.
Among
96 cases, there were 32 non-Hodgkin's lymphoma, 39 lung
cancer(including small and non-small cell lung cancer),
18 breast cancer and 7 ovary cancer cases(see table2), with
age ranged from 18 to 67, 52 males and 44 females, male/female
ratio 1.18:1.
Table
2 Tumor type and case number
|
Tmor
type
|
NHL
|
Lung cancer
|
Ovary cancer
|
Breast cancer
|
total
|
|
Case
number
|
32
|
39
|
7
|
18
|
96
|
1.
Dynamic changes of ANC before and after chemotherapy
of different tumors in treatment and control group (see
fig 1-7)
There were common points among the results indicated
by those curves:
1)
In the treatment group, ANC increased rapidly 24 hours after
subcutaneous injection of Jilifen, and reached the 1st
peak at 48-72 hours after injection, probably indicating
the effect of Jilifen in promoting the release of neutrophil
from bone marrow into peripheral blood; thereafter
ANC decreased gradually as the action of chemotherapy persisted;
then recovered to more than 10'109/L. In the control groups, ANC decreased continuously
after chemotherapy.
2)
ANC nadirs of the treatment groups were higher
than that of the control groups.
3)
The lasting duration of ANC<2.0'109/L
of control group were significantly longer than that of
treatment group.
2.
After chemotherapy, the lasting duration of
neutropenia, ANC nadir and delay of the next chemotherapeutic
course due to neutropenia(treatment and control group) were
shown in table 3 and 4.
Table
3 Lasting time of neutropenia, ANC nadir and delay
time of chemotherapy in different tumor types (Jilifen represents
treatment group)
|
Tumor type
|
Duration of neutopenia
(ANC<2.0'109/L)
|
ANC nadir(˜109/L)
|
Delay
of chemotherapy(day)
|
|
Jilifen
|
control
|
Jilifen
|
control
|
Jilifen
|
control
|
|
lung
cancer
(CE,17cases)
|
1.31
|
7.63
|
2.85
|
1.36
|
0.13
|
2.06
|
|
lung
cancer (MVP,17cases)
|
0.31
|
5.44
|
3.06
|
1.65
|
0
|
0
|
|
lung
cancer
(NVB+DDP, 3cases)
|
1.33
|
11.67
|
2.78
|
1.01
|
0
|
2.33
|
|
lung
cancer
(CAV,2cases)
|
2.50
|
7.00
|
1.80
|
0.90
|
0
|
0
|
|
Breast
cancer (FAC,18cases)
|
1.39
|
8.00
|
2.31
|
1.26
|
0.56
|
2.33
|
|
NHL(CHOP,32cases)
|
0.34
|
5.13
|
3.01
|
1.60
|
0
|
0.97
|
|
Ovary
cancer
(CTX+CARBO,7cases)
|
0.86
|
7.71
|
3.42
|
1.50
|
1.57
|
2.86
|
Table
4. Comparison of ANC related items between treatment and
control groups
|
Items
|
Jilifen
|
control
|
t value
|
P value
|
|
Lasting duratin of neutropenia(day)
|
0.81±1.51
|
6.57±4.94
|
10.87
|
P<0.001
|
|
ANC nadir('109/L)
|
2.85±1.64
|
1.46±0.71
|
7.575
|
P<0.001
|
|
Delay of chemotherapy(day)
|
0.24±1.32
|
1.40±3.02
|
3.905
|
P<0.001
|
Table 3 showed: lasting duration of neutropenia (ANC<2.0'109/L) in treatment group was 0.31-2.50 days,
which in control group was 5.13 to 11.67 days. ANC nadir
in treatment group was 1.80-3.42'109/L, while in control group as 0.90-1.65'109/L,
significantly lower than that of treatment group.
3.
In treatment group,chemotherapy delay were
0.13 days, 0.56 days and 1.57 days in CE regimen,FAC regimen
and ovary cancer patients respectively, and was 0 day in
the rest; while in control group, delay time were 0.97-2.86
days except 2 of the regimens in which it was 0 day.
4.
In the present study, Jilifen exhibited no
obvious adverse reaction.
Discussion
1.
In
the present study, it was demonstrated that adjuvant use
of Jilifen in chemotherapy could decrease the severity of
neutropenia and lasting duration of neutropenia after chemotherapy.
The result is in accordance with that reported by Crawford
in which the G-CSF injection was produced in U.S., and also
in accordance with the result of our previously performed
study for the G-CSF product GRAN (Generic name: Filgrastim)
produced by Kirin-Amgen company. U.S. researcher G. Bodey
had demonstrated that adjuvant use of G-CSF decreased the
incidence of infection, administration quantity of antibiotics,
time of hospitalization and mortality due to infection after
chemotherapy. In summary, Jilifen can be used as a valuable
adjuvant drug in tumor chemotherapy.
2.
In clinical chemotherapy, the next chemotherapeutic
course is frequently delayed due to inability of the prompt
recovery of homogram, hence affecting the anti-tumor treatment.
Jilifen promotes neutrophil recovery and helps to
ensure chemotherapeutic dose, thereby improving the effectiveness
of chemotherapy.
3.
Recent
study suggested that the anti-tumor effect of chemotherapy
could be improved if the dose intensify, i.e. the quantity
of chemotherapeutic drug administrated within a certain
time course, is increased. It is especially important to
the eradication of sensitive tumor. The clinical application
of Jilifen provides a higher possibility of high dose chemotherapy.
Fig1-7 Effect of Jilifen on ANC under different chemotherapeutic
regimens.(arrow represents the day of administration of
chemotherapeutic drugs)
Conclusion
1. Among 192 chemotherapeutic courses, in those Jilifen was used
as adjuvant drug, the mean lasting time of neutropenia
(ANC<2.0'109/L) was 0.31-2.50 days, while in control
courses that Jilifen was omitted, the mean lasting time
was 5.13-11.67 days.
2. In treatment group
(Jilifen group). ANC nadir after chemotherapy was 1.80-3.42'109/L,while
in control group it was 0.90-1.65'109/L, significantly lower than
that of treatment group.
3. In Jilifen groups,
24 hours after injection of Jilifen, ANC increased rapidly,
then decreased gradually after reached a peak, and usually
recovered to normal or a higher level at day 10-14; after
withdrawal of Jilifen, ANC decreased gradually, but still
maintaining at a normal level, generally did not result
in delay of chemotherapy. In patients underwent chemotherapy
without adjuvant use of Jilifen, ANC decreased gradually
and recovered to normal level 3-4 weeks later, in some of
these patients, chemotherapy had to be delayed due to neutropenia.
Therefore Jilifen helps ANC to recover much earlier.
4. Jilifen exhibited
similar effect in the treatment of different tumors, and
the results also in accordance with that obtained from the
studies of the homologous product GRAN(generic name: Filgrastim)
produced by Kirin-Amgen company performed in China and abroad.
5. In the present study,
Jilifen did not show any severe adverse or toxic reaction.
In summary, Jilifen promoted the recovery
of ANC of patients and decreased the severity and lasting
duration of neutropenia after chemotherapy, without severe
adverse or toxic reaction. Jilifen can therefore act as
a valuable adjuvant drug in tumor chemotherapy. Jilifen
probably can give support in increasing dose intensity of
chemotherapeutic drugs so as to improve the anti-tumor effect
of chemotherapy. The results suggested the safety and effectiveness
of Jilifen were similar to that of the imported homologous
product.
Head
institute:Tumor Hospital of Zhongshan Medical University
Documents organized by: Guan Zhongzheng, Zhang Li
Primary
documents kept in:
Internal medicine faculty, Tumor Hospital of Zhongshan
Medical University
Internal
medicine faculty, affiliate Tumor Hospital of Chinese Medical
Science Institute
Chemotherapy faculty, affiliated Tumor Hospital of Shanghai
Medical University
Tumor Hospital of Jiangsu province
