Eighty patients were recruited to PDL and PDG groups equally. Table 1 shows the comparison of demographic and clinical characteristics of breast cancer patients treated by PDG or PDL. The mean age of PDG and PDL groups were 47.8 ± 9.04 and 43.7 ± 9.23, respectively. There was no significant difference between two groups in terms of age, BMI, tumor size, excised LN, involved LN, Ki-67 index, education, marital, employment, ER, PR, and HER2 status.
Table 1
Demographic and clinical characteristics of patients in two study groups
Variable
|
PDG
|
PDL
|
P-value
|
|
Mean ± SD
|
Mean ± SD
|
|
Age, year
|
47.8 ± 9.04
|
43.7 ± 9.23
|
0.05
|
BMI, kg/m2
|
27.8 ± 4.88
|
26.6 ± 4.06
|
0.261
|
Tumor size, cm
|
3.0 ± 1.1
|
3.1 ± 0.9
|
0.744
|
Excised LN, n
|
7.9 ± 4.6
|
8.7 ± 6.1
|
0.566
|
Involved LN, n
|
2.1 ± 2.7
|
2.1 ± 2.6
|
0.958
|
Ki-67, %
|
36.0 ± 23.2
|
34.6 ± 26.5
|
0.819
|
|
No (%)
|
No (%)
|
|
Age
|
|
|
0.116
|
< 50
|
24 (60)
|
30 (75)
|
|
≥ 50
|
16 (40)
|
10 (25)
|
|
Education status
|
|
|
0.362
|
Illiterate / Elementary
|
16 (42.1)
|
19 (48.7)
|
|
Diploma / Academic
|
22 (57.9)
|
20 (51.3)
|
|
Marital status
|
|
|
0.387
|
Married
|
33 (82.5)
|
33 (87.5)
|
|
Single / Divorce / Widow
|
7 (17.5)
|
5 (12.5)
|
|
Employment status
|
|
|
0.293
|
Housewife
|
30 (75.5)
|
33 (82.5)
|
|
Employed
|
10 (25)
|
7 (17.5)
|
|
ER
|
|
|
0.150
|
Negative
|
11 (28.2)
|
6 (15.8)
|
|
Positive
|
28 (71.8)
|
32 (84.2)
|
|
PR
|
|
|
0.061
|
Negative
|
19 (48.7)
|
11 (28.9)
|
|
Positive
|
20 (51.3)
|
27 (71.1)
|
|
HER2
|
|
|
0.587
|
Negative
|
31 (79.5)
|
30 (78.9)
|
|
Positive
|
8 (20.5)
|
8 (21.1)
|
|
Outcome measurements were achieved at the start point, 7th and 15th days in each course of chemotherapy. The distribution of hematologic variables in eight courses of chemotherapy in both groups of study has been demonstrated in Table 2.
Table 2
Changes of hematologic variables during eight courses of chemotherapy in two groups
Time
|
variable
|
PDG
Mean ± SD
|
PDL
Mean ± SD
|
Time
|
variable
|
PDG
Mean ± SD
|
PDL
Mean ± SD
|
Start of study
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte ANC
|
9068.42 ± 1433.59
12.75 ± 1.04
298972.22 ± 130889.81
74.5 ± 6.62
24.97 ± 6.38
6659 ± 1263
|
8361.58 ± 1992.03
12.98 ± 1.2
281910.53 ± 104249.08
75.37 ± 6.09
22.92 ± 6.92
6388 ± 1682
|
5th course (7th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
2593.42 ± 538.79
11.78 ± .93
104027.78 ± 12112.53
50.53 ± 6.55
47.79 ± 9.516
1312 ± 360
|
2455.52 ± 688.89
11.93 ± .79
100473.68 ± 29235.82
52.63 ± 5.54
46.55 ± 6.41
1299 ± 406
|
1st course (7th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
3623.68 ± 1272.46
12.56 ± 1.01
141722.22 ± 77288.18
46.5 ± 6.19
52.97 ± 6.57
1662 ± 737
|
5997 ± 12404
12.8 ± 1.01
136584 ± 32865
47.6 ± 6.3
51.3 ± 6.6
2896 ± 6062
|
5th course (15th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
5339.47 ± 1450.54
11.68 ± .96
153888.89 ± 21372.58
88.24 ± 6.32
11.63 ± 6.41
4681 ± 1328
|
5121.08 ± 1699.03
11.89 ± .76
158657.89 ± 42731.9
88.58 ± 4.18
10.87 ± 3.4
4554 ± 1597
|
1st course (15th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
5618.42 ± 1216.74
12.52 ± .95
182694.44 ± 35740.19
85.18 ± 5.4
14.45 ± 4.75
4655 ± 1292
|
5827.63 ± 1127.22
12.76 ± 1.107
185578.95 ± 32961.59
84.66 ± 5.54
15 ± 5.57
4891 ± 1054
|
6th course (7th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
3515.79 ± 701.65
11.6 ± 1.03
118111.11 ± 22193.66
51.66 ± 6.84
47.55 ± 7.03
1809 ± 460
|
3531.58 ± 889.23
11.85 ± .71
116078.95 ± 17653.4
52.6 ± 6.82
46.95 ± 7.17
1879 ± 755
|
2nd course (7th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
2786.84 ± 850.17
12.36 ± 1.03
109055.55 ± 19608.95
47.71 ± 6.21
51.23 ± 6.09
1324 ± 476
|
3553.16 ± 3202.25
12.44 ± 1.06
117118.42 ± 20749.29
50.52 ± 8.98
48.21 ± 10.82
1819 ± 1891
|
6th course (15th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
7200 ± 1567.23
11.58 ± .9
173972.22 ± 19983.54
88.73 ± 5.23
11.13 ± 5.2
6371 ± 1558
|
7056.58 ± 1948.95
11.76 ± .72
171236.84 ± 37220.62
88.37 ± 3.97
11.63 ± 3.97
6244 ± 1792
|
2nd course (15th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
5405.52 ± 5803.10
12.25 ± .96
152444.44 ± 12622.98
86.73 ± 5.75
14.02 ± 8.14
4550 ± 4351
|
4693.42 ± 831.65
12.4 ± 1.18
160131.58 ± 20145.64
86.34 ± 4.39
12.89 ± 3.67
4009 ± 808
|
7th course (7th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
5722.37 ± 7130.64
11.52 ± .88
124611.11 ± 15331.16
52.87 ± 5.5
46.34 ± 5.82
3086 ± 4284
|
4190.79 ± 757.38
11.69 ± .73
122815.79 ± 16204.53
68.34 ± 98.78
46.18 ± 8.47
2923 ± 4491
|
3rd course (7th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
2610.52 ± 1345.12
12.14 ± .93
97802.78 ± 14290.07
47.4 ± 6.9
51.97 ± 6.52
1215 ± 582
|
2660.52 ± 1277.09
15.23 ± 17.99
103476.31 ± 132901.69
51.18 ± 4.57
47.55 ± 5.25
1359 ± 636
|
7th course (15th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
11797.37 ± 14999.43
11.48 ± .95
183500 ± 21285.14
89.44 ± 4.85
9.05 ± 3.38
10515 ± 13354
|
8007.9 ± 2431.03
11.63 ± .76
181289.47 ± 31302.28
90.63 ± 3.83
10.64 ± 10.17
7273 ± 2273
|
3rd course (15th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
3961.31 ± 668.86
12.06 ± .92
142861.11 ± 14204.93
87.1 ± 5.05
12.81 ± 5.11
1864 ± 431
|
3993.68 ± 717.65
15.14 ± 17.99
145589.47 ± 27305.87
87.87 ± 4.47
12 ± 4.6
2010 ± 450
|
8th course (7th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
5396.05 ± 1612.13
11.15 ± 1.91
128583.33 ± 20230.63
53.55 ± 6.03
45.39 ± 8.08
2924 ± 1057
|
5010.53 ± 945.41
11.51 ± .81
127594.74 ± 17224.53
52.21 ± 7.29
46.63 ± 7.65
2624 ± 648
|
4th course (7th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
2284.47 ± 1369.58
11.92 ± .92
90383.33 ± 28554.37
49.1 ± 10.91
50.29 ± 10.68
1148 ± 881
|
1976.58 ± 380.76
12.07 ± .84
92842.1 ± 11083.29
50.26 ± 4.92
47.68 ± 6.63
3711 ± 968
|
8th course (15th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
13300 ± 6704.21
11.52 ± 1.24
193444.44 ± 26144.04
88.94 ± 7.64
10.68 ± 7.39
11861 ± 6426
|
13448.68 ± 17942.84
11.41 ± .87
194526.31 ± 41315.36
90.05 ± 4.77
9.71 ± 4.79
12133 ± 16165
|
4th course (15th day)
|
WBC
Hgb
Platelet
Neutrophil
Lymphocyte
ANC
|
4213.15 ± 4968.81
11.61 ± 1.95
131355.55 ± 27377.83
86.52 ± 7.29
13.34 ± 7.21
3563 ± 3892
|
3415.79 ± 789.98
11.98 ± .78
134000 ± 27496.44
86.79 ± 4.89
13.08 ± 4.74
996 ± 222
|
|
|
|
|
Figure 2 shows the changes in ANC values during eight courses of chemotherapy in PDG and PDL groups. Similar trends of ANC values are notifiable between two groups.
Within and between groups' variation of blood counts was analyzed during start point, 7th and 15th days in each course of chemotherapy. (Table 3) The results showed that in PDL and PGL groups, all of the hematologic components (WBC, Hgb, Plt, Neut, Lymph and ANC) had significant changes during each course of chemotherapy. Decreasing the hematologic component and increasing after GCF injection in each course is the prominent pattern of data variations. But in the fifth course of PDL injection, Hgb showed no significant change (P = 0.095).
Table 3
Comparing within and between groups blood counts measured at the start point, 7th and 15th days in each course of chemotherapy
Courses
|
|
PDL Group (Median)
|
p-value*
|
PGL Group (Median)
|
p-value*
|
p-value**
|
D0
|
D7
|
D15
|
D0
|
D7
|
D15
|
1
|
WBC
|
8900
|
4100
|
5850
|
< 0.001
|
9550
|
3850
|
5750
|
< 0.001
|
0.295
|
Hb
|
13.20
|
13.00
|
13.00
|
< 0.001
|
12.80
|
12.35
|
12.25
|
< 0.001
|
0.159
|
Plt
|
280000
|
124000
|
173000
|
< 0.001
|
248500
|
124000
|
168000
|
< 0.001
|
0.416
|
Neut
|
75
|
50
|
85
|
< 0.001
|
70
|
50
|
85
|
< 0.001
|
0.312
|
Lymph
|
25
|
50
|
15
|
< 0.001
|
27
|
50
|
15
|
< 0.001
|
0.130
|
ANC
|
6545
|
2050
|
5025
|
< 0.001
|
6830
|
1660
|
4600
|
< 0.001
|
0.327
|
2
|
WBC
|
5850
|
3100
|
4400
|
< 0.001
|
5750
|
3000
|
4500
|
< 0.001
|
0.866
|
Hb
|
13.00
|
13.00
|
12.90
|
< 0.001
|
12.25
|
12.20
|
12.20
|
< 0.001
|
0.307
|
Plt
|
173000
|
111000
|
156000
|
< 0.001
|
168000
|
107000
|
156000
|
< 0.001
|
0.468
|
Neut
|
85
|
50
|
85
|
< 0.001
|
85
|
50
|
86
|
< 0.001
|
0.504
|
Lymph
|
15
|
50
|
13
|
< 0.001
|
15
|
50
|
14
|
< 0.001
|
0.243
|
ANC
|
5025
|
1575
|
3838
|
< 0.001
|
4600
|
1400
|
3895
|
< 0.001
|
0.950
|
3
|
WBC
|
4400
|
2450
|
3950
|
< 0.001
|
4500
|
2500
|
3950
|
< 0.001
|
0.820
|
Hb
|
12.90
|
12.90
|
12.30
|
< 0.001
|
12.20
|
12.00
|
12.00
|
< 0.001
|
0.107
|
Plt
|
156000
|
101000
|
139000
|
< 0.001
|
156000
|
100000
|
146000
|
< 0.001
|
0.302
|
Neut
|
85
|
50
|
90
|
< 0.001
|
86
|
50
|
90
|
< 0.001
|
0.023
|
Lymph
|
15
|
50
|
10
|
< 0.001
|
14
|
50
|
10
|
< 0.001
|
0.006
|
ANC
|
3838
|
1305
|
1975
|
< 0.001
|
3895
|
1200
|
1900
|
< 0.001
|
0.229
|
4
|
WBC
|
3950
|
1900
|
3100
|
< 0.001
|
3950
|
2100
|
3400
|
< 0.001
|
0.443
|
Hb
|
12.30
|
12.05
|
12.05
|
< 0.001
|
12.00
|
12.00
|
12.00
|
< 0.001
|
0.473
|
Plt
|
139000
|
92500
|
128500
|
< 0.001
|
146000
|
98000
|
132000
|
< 0.001
|
0.969
|
Neut
|
90
|
50
|
90
|
< 0.001
|
90
|
50
|
90
|
< 0.001
|
0.317
|
Lymph
|
10
|
50
|
11
|
< 0.001
|
10
|
50
|
10
|
< 0.001
|
0.143
|
ANC
|
1975
|
955
|
2738
|
< 0.001
|
1900
|
1020
|
2872
|
< 0.001
|
0.548
|
5
|
WBC
|
3100
|
2500
|
4500
|
< 0.001
|
3400
|
2500
|
4900
|
< 0.001
|
0.341
|
Hb
|
12.05
|
12.00
|
12.00
|
0.095
|
12.00
|
12.00
|
11.50
|
< 0.001
|
0.237
|
Plt
|
128500
|
100000
|
151000
|
< 0.001
|
132000
|
102000
|
159000
|
< 0.001
|
0.974
|
Neut
|
90
|
50
|
90
|
< 0.001
|
90
|
50
|
90
|
< 0.001
|
0.413
|
Lymph
|
11
|
50
|
10
|
< 0.001
|
10
|
50
|
10
|
< 0.001
|
0.590
|
ANC
|
2738
|
1350
|
3895
|
< 0.001
|
2872
|
1250
|
4410
|
< 0.001
|
0.289
|
6
|
WBC
|
4500
|
3200
|
6750
|
< 0.001
|
4900
|
3450
|
6800
|
< 0.001
|
0.581
|
Hb
|
12.00
|
12.00
|
12.00
|
0.001
|
11.50
|
11.40
|
11.30
|
< 0.001
|
0.206
|
Plt
|
151000
|
111500
|
159500
|
< 0.001
|
159000
|
110000
|
174000
|
< 0.001
|
0.919
|
Neut
|
90
|
50
|
90
|
< 0.001
|
90
|
50
|
90
|
< 0.001
|
0.663
|
Lymph
|
10
|
50
|
10
|
< 0.001
|
10
|
50
|
10
|
< 0.001
|
0.743
|
ANC
|
3895
|
1725
|
5948
|
< 0.001
|
4410
|
1900
|
6120
|
< 0.001
|
0.543
|
7
|
WBC
|
6750
|
4200
|
8400
|
< 0.001
|
6800
|
4600
|
9100
|
< 0.001
|
0.050
|
Hb
|
12.00
|
11.90
|
11.50
|
< 0.001
|
11.30
|
11.30
|
11.30
|
0.002
|
0.342
|
Plt
|
159500
|
121000
|
170500
|
< 0.001
|
174000
|
124000
|
186000
|
< 0.001
|
0.559
|
Neut
|
90
|
50
|
90
|
< 0.001
|
90
|
50
|
90
|
< 0.001
|
0.306
|
Lymph
|
10
|
50
|
10
|
< 0.001
|
10
|
50
|
10
|
< 0.001
|
0.898
|
ANC
|
5948
|
2100
|
7560
|
< 0.001
|
6120
|
2300
|
8330
|
< 0.001
|
0.146
|
8
|
WBC
|
8400
|
4950
|
10000
|
< 0.001
|
9100
|
5100
|
10550
|
< 0.001
|
0.395
|
Hb
|
11.50
|
11.35
|
11.35
|
< 0.001
|
11.30
|
11.25
|
11.25
|
< 0.001
|
0.528
|
Plt
|
170500
|
124000
|
186500
|
< 0.001
|
186000
|
124000
|
194500
|
< 0.001
|
0.637
|
Neut
|
90
|
50
|
90
|
< 0.001
|
90
|
50
|
90
|
< 0.001
|
0.781
|
Lymph
|
10
|
50
|
10
|
< 0.001
|
10
|
50
|
10
|
< 0.001
|
0.838
|
ANC
|
7560
|
2525
|
9000
|
< 0.001
|
8330
|
2575
|
9601
|
< 0.001
|
0.434
|
p-value*: Repeated measurements within groups (Friedman test) |
p-value**: Repeated measurements Between groups (GEE analysis) |
Applying GEE analysis showed no significant difference between the trend of hematologic values during the most courses of chemotherapy. There were two exceptions in the third course of chemotherapy regarding Neutrophil count ( p = 0.023) and Lymphocyte count (p = 0.006) with lower fluctuations in the PDL group.
Hematologic parameters’ changes during 8 courses of chemotherapy, were compared between two groups by Generalized Estimation Equation analysis. The comparison of the WBC (p = 0.527), Hgb (p = 0.075), Platelet (p = 0.819), Neutrophil (p = 0.575), Lymphocyte (p = 705) and ANC (p = 0.675) changes during eight courses of treatment identified no statistically significant difference between two study groups.
Since the probability of neutropenia frequency fluctuates during treatment, the changes in blood parameters were compared between the first four courses of chemotherapy with the second four courses. In the PDG group, the mean value of WBC, Plt, and ANC in the first half of treatment were 6281, 153171, and 3358 and in the second half of 6280, 151064 and 5220, respectively. P-Value of WBC, Plt and ANC the mean difference between two halves was < 0.001, o.543 and < 0.001. In the PDL group, the mean value of WBC, Plt, and ANC in the first half of the treatment were 4446, 154095 and 3249 and in the second half of 6820, 152298 and 5575, respectively. P-Value of the WBC, Plt and ANC mean difference between two halves was < 0.001, o.651 and < 0.001.
Results showed that WBC (p = 0.439), Hgb (p = 0.052), Platelet (p = 0.7), Neutrophil (p = 0.324), Lymphocyte (p = 0.463) and ANC (p = 0.571) changes during two halves of treatment were not statistically significant between the two study groups.
The comparison of side effects between the two groups is shown in Table 4. There was no side effect in 50% of patients of the PDL group compared to 12.5% in the PDG group. The most common side effects in the PDG group were musculoskeletal pain with a relative frequency of 47.5% compared to 15% in PDL groups. Headache (30%), injection site reaction (25%), leukocytosis (20%), and bone pain (17.5%) were other common side effects in the PDG group.
Table 4
Comparison of very common side effects between two groups
Side effect
|
PDG
N (%)
|
PDL
N (%)
|
Total
N (%)
|
No
|
5 (12.5)
|
20 (50%)
|
25 (31.25)
|
Headache
|
24 (30)
|
10 (25)
|
34 (42.5)
|
Bone pain
|
7 (17.5)
|
3 (7.5)
|
10 (12.5)
|
Nausea
|
3 (7.5)
|
4 (10)
|
7 (8.75)
|
Musculoskeletal pain
|
19 (47.5)
|
6 (15)
|
25 (31.25)
|
Fever
|
-
|
1 (2.5)
|
1 (1.25)
|
Injection site reaction
|
10 (25)
|
1 (2.5)
|
11 (13.75)
|
Leukocytosis
|
8 (20)
|
4 (10)
|
12 (15)
|
Non cardiac chest pain
|
1 (2.5)
|
-
|
1 (1.25)
|
Anaphylaxis
|
1 (2.5)
|
-
|
1 (1.25)
|
Three patients were excluded from the study. In the PDL group, two patients were excluded from the study because of fever and neutropenia. The first patient received PDL in two courses of chemotherapy. In the third course, ANC on the 7th day of injection decreased to 490. In the second case of this group, an ANC of 750 was recorded at the end of the third course of chemotherapy. Both patients received antibiotics out patiently, and PDL was not continued. In PDG group one patient was hospitalized because of fever and neutropenia after one course of injection. Her ANC on first course of chemotherapy decreased from 5440 to 70 during 15 days of injection. She had oral mucositis and high grade of fever. After three days of antibiotic therapy in hospital, she was recovered.