Patient characteristics
We retrospectively reviewed the clinical data of 184 patients with cervical cancer undergoing CCRT in our institution between October 2018 to March 2021. All patients received pelvic radiotherapy with an image-guided VMAT technique. All patients were treated with platinum-based chemotherapy; 42 (22.8%) received TP, 111 (60.3%) received weekly cisplatin, and 31 (16.9%) received weekly carboplatin. All patients received at least one cycle of concurrent chemotherapy (with a median of 2 cycles, range from 1 to 6 cycles). Basic clinical characteristics of the patients are available in Table 1.
Table 1. Basic clinical characteristics of the patients.
Patients (n)
|
|
184
|
Age (years)
|
Median, Mean (Range, SD)
|
54, 53.3 (31–81, 10.3)
|
BMI (㎏/㎡)
|
Median, Mean (Range, SD)
|
22.59, 23.1 (16.2–33.8, 3.3)
|
Duration of EBRT (days)
|
Median, Mean (Range, SD)
|
37, 38 (29–52, 3.9)
|
RT dose to pelvis (Gy)
|
Median, Mean (Range, SD)
|
45, 47.4(45–50.4, 2.6)
|
Cycles of chemotherapy
|
Median, Mean (Range, SD)
|
2, 2.9(1–6, 1.5)
|
Clinical stage FIGO2018 (n, %)
|
IB–IIB
IIIA–IVB
|
98(53.3)
86(46.7)
|
Histology, n (%)
|
Squamous carcinoma
Adenocarcinoma
|
166(90.2)
18(9.8)
|
Differentiation degree, n (%)
|
High–moderate
Lower / Unknown
|
85(46.2)
99(53.8)
|
PTV dose-pelvis
(n, %)
|
45 Gy
48.6Gy–50.4 Gy
|
99 (53.8)
85(46.2)
|
Chemotherapy regimen (n, %)
|
TP
Carboplatin
Cisplatin
|
42(22.8)
31(16.9)
111(60.3)
|
Abbreviation: BMI, body mass index; EBRT, pelvic external-beam radiotherapy; SD, standard deviation; RT, radiation therapy; TP, paclitaxel + cisplatin.
Dosimetric parameters of the pelvic bone
Descriptive statistical analysis of the dosimetric parameters was performed, and their mean values, median values, maximum, minimum, 25th percentile, 75th percentile, and standard deviations were recorded. Table 2 details the dosimetric parameters for the total pelvic bone marrow.
Table 2. Descriptive statistics of dosimetric parameters of the total pelvic bones.
Parameter
|
|
Mean
|
Median
|
Min-max
|
Q1–Q3
|
SD
|
TPB
|
Volume (cm³)
V10 (10%)
V20 (20%)
V30 (30%)
V40 (40%)
V50 (50%)
|
1189
90.39
71.53
45.41
23.32
5.14
|
1165
90.00
70.74
45.00
23.00
3.00
|
886–2219
49.00–100.00
27.23–92.90
14.00–68.00
6.00–46.00
0.00–26.00
|
1070–1266
88.00–94.00
66.95–76.89
39.00–51.00
18.00–27.00
0.00–10.00
|
177.6
5.780
7.977
8.832
6.617
5.422
|
Abbreviation: V10, V20, V30, V40, V50=volume receiving 10,20, 30, 40, 50 Gy; TPB, the total pelvic bones; Max, maximum; Min, minimum; Q1, 25th percentile; Q3, 75th percentile; SD, standard deviation.
Hematological baselines and nadirs
Compared with the hematological baselines, all the blood cell counts were decreased to various degrees throughout the study period(P<0.001). The median of WBC, ANC, HGB, AMC, and PLT counts at the nadirs were 1.99×109/L (Q1–Q3, 1.62–2.37), 1.21×109/L (Q1–Q3, 0.91–1.51), 90.00g/L (Q1–Q3, 80–103), 0.21×109/L (Q1–Q3, 0.14–0.28), and 104.00 109/L (Q1–Q3, 78.25–131.00), respectively. The WBC, ANC, HGB, AMC and PLT counts decreased by 64.72% , 64.86% , 16.00% , 50.00%, 53.44% ,respectively. (Figure 2).
Hematologic toxicity
At baseline, 26 patients (14.13%) had Grade 1 leukopenia, 11 patients(5.98%) had Grade 1 neutropenia, and 2 patients(1.09%) had Grade 1 thrombocytopenia. Moreover, anemia was more common at baseline, compared to other Hematologic toxicity. At baseline, 50 patients(27.17%) had Grade 1, 20 patients(10.89%) had Grade 2, and 7 patients(3.08%) had Grade 3 anemia. The percentage of Grade 3 or Grade 4 leukopenia, neutropenia, thrombocytopenia, and anemia during concurrent chemoradiotherapy was 52.17%, 30.43%, 6.52%, and 22.83%, respectively. Overall, 111 patients(60.33%) did experience any Grade 3+ hematologic toxicity.
Detailed data are given in Table 3.
Table 3. Hematological toxicity Graded according to hematological nadirs and baselines.
Hematologic toxicity
|
Grade 0
(n, %)
|
Grade 1
(n, %)
|
Grade 2
(n, %)
|
Grade 3
(n, %)
|
Grade 4
(n, %)
|
Baselines
|
Leukopenia
|
158(85.87)
|
26(14.13)
|
0(0)
|
0(0)
|
0(0)
|
Neutropenia
|
173(94.02)
|
11(5.98)
|
0(0)
|
0(0)
|
0(0)
|
Thrombocytopenia
|
182(98.91)
|
2(1.09)
|
0(0)
|
0(0)
|
0(0)
|
Anemia
|
107(58.15)
|
50(27.17)
|
20(10.89)
|
7(3.80)
|
0(0)
|
Nadirs
|
Leukopenia
|
0(0)
|
9(4.89)
|
79(42.93)
|
88(47.83)
|
8(4.35)
|
Neutropenia
|
9(4.89)
|
41(22.28)
|
78(42.39)
|
46(25.00)
|
10(5.43)
|
Thrombocytopenia
|
100(53.8)
|
45(24.46)
|
27(14.67)
|
11(5.98)
|
1(0.54)
|
Anemia
|
17(9.24)
|
62(33.70)
|
63(34.24)
|
29(15.76)
|
13(7.07)
|
The changing trend of blood cell counts
The median time to the nadir was 26 days (Q1–Q3, 19 to 34 days) for the WBC and ANC, 20 days (Q1–Q3, 8 to 29 days) for the AMC, 29 days (Q1–Q3, 20 to 39 days) for the PLT, 35 days (Q1–Q3, 24 to 42 days) for the HGB. Compared with the WBC and ANC, the AMC was decreased to the nadir first (median = 5 days, Q1–Q3 = 0 to 11 days,P<0.001). (Figure 3. A and Figure 3. B). The time for AMC to increase from the nadir to ≥ normal value for the first time was less than that for WBC (median = 4 days, Q1–Q3 = 0 to 11 days,P<0.001) and ANC (median = 3 days, Q1–Q3 = 0 to 10 days,P<0.001). (Figure 3. C and Figure 3. D ). We also assessed the correlations between variables by the Spearman rank correlation test. We obtained that the nadir of AMC was positively correlated with the nadir of WBC (r=0.5378, 95%CI = 0.4227 to 0.6357, P<0.0001) and the nadir of ANC (r=0.5000,95%CI = 0.3794 to 0.6039, P<0.0001). (Figure 3. E and Figure 3. F ).
All analyses above indicate that the decrease and increase of AMC usually occurred before the ANC and WBC,and the changing tendency of AMC had some predictive value to the changing trend of WBC and ANC.
Predictors of hematologic toxicity
Theunivariate and multiple binary logistic regression analyses were performed to identify any Grade ≥3 HT predictors. The chemotherapy regimen and the total pelvic bone(TPB_V10, TPB_V20, TPB_V30, TPB_V40, and TPB_V50) were in univariable binary logistic regression analysis associated with any Grade ≥3 HT (Table 4).
Table 4 Univariate logistic regression analysis of factors associated with the development of any Grade ≥3 hematologic toxicity.
Parameter
|
Odds ratio
|
95% CI
|
P-value
|
Age (years)
|
1.000
|
0.972–1.029
|
0.991
|
BMI (㎏/㎡)
|
0.982
|
0.898–1.074
|
0.982
|
Duration of EBRT (days)
|
1.069
|
0.987–1.158
|
0.102
|
Clinical stage (FIGO2018)
|
1.759
|
0.964–3.208
|
0.066
|
Histology
|
0.559
|
0.232–1.345
|
0.194
|
Differentiation degree
|
0.789
|
0.431–1.445
|
0.443
|
PTV dose-pelvis
|
1.696
|
0.930–3.094
|
0.085
|
Cycles of chemotherapy
|
1.056
|
0.861–1.295
|
0.600
|
Volume (cm³)
|
1.002
|
1.000–1.004
|
0.053
|
Chemotherapy regimen
|
TP
|
|
|
0.027*
|
Carboplatin
|
0.257
|
0.094–0.701
|
0.008*
|
Cisplatin
|
0.442
|
0.198–0.987
|
0.046*
|
TPB_V10
|
1.197
|
1.109–1.292
|
<0.001*
|
TPB_V20
|
1.176
|
1.109–1.248
|
<0.001*
|
TPB_V30
|
1.102
|
1.057–1.149
|
<0.001*
|
TPB_V40
|
1.114
|
1.055–1.177
|
<0.001*
|
TPB_V50
|
1.142
|
1.069–1.221
|
<0.001*
|
Abbreviation: BMI, body mass index; EBRT, pelvic external-beam radiotherapy; TPB_V10, TPB_V20, TPB_V30, TPB_V40, TPB_V50=the total pelvic bones of volume receiving 10 ,20, 30, 40, 50 Gy; TP, paclitaxel + cisplatin. Bold indicates the significant values (*p < 0.05).
Subsequently, multivariate analysis was performed with all the significant factors in the univariate analysis. Results of this multivariate analysis demonstrated that the chemotherapy regimens and TPB_V20 were independent factors. Patients who received TP chemotherapy regimen were more likely to develop Grade ≥3 HT than those who received cisplatin or carboplatin (76.2% vs. 58.6% vs. 45.2% ). We also observed that the patient with increased TPB_V20 were more likely to develop Grade ≥3 HT (OR 1.154; SE 0.69; p = 0.034; 95 % CI 1.008–1.321). Hosmer-Lemeshow test indicated that the models fitted well (χ2 = 8.412, p-value = 3.94>0.05). Detailed results are given in Figure 4.
The ROC curve for Grade ≥3 hematologic toxicity versus TPB_V20 was analyzed to determine the optimal thresholds for dosimetric planning. The optimal TPB_V20 cut-off value identified by ROC curves followed by Youden test was 71% (AUC = 0.788; 95%CI, 0.722–0.845; p-value<0.001). Figure 5. Patients who received TPB_V20 ≥71 % were more likely to develop Grade ≥3 HT (84.1% vs. 38.5%, p < 0.001). The specificity and sensitivity for this threshold were 78.1% and 71.2%, respectively. The positive and negative predictive values for TPB_V20≥71% were 83.1% (95% CI, 77.3%–87.7%) and 64.1% (95% CI,56.7%–70.8%), respectively, with a relative risk of 3.86 (95% CI,2.66–5.6).