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Dosimetric parameters and absolute monocyte count can predict the prognosis of acute hematologic toxicity in cervical cancer patients undergoing concurrent chemotherapy and volumetric-modulatedarctherapy

Dosimetric parameters and absolute monocyte count can predict the prognosis of acute hematologic... Purpose: To explore clinical and dosimetric predictors of acute hematologic toxicity (HT ) in cervical cancer patients treated with concurrent chemotherapy and volumetric-modulated arc therapy ( VMAT ). Methods and materials: We retrospectively reviewed the clinical data of 184 cervical cancer patients who had con- current chemotherapy and VMAT. Hematological parameters were collected during the treatment period. The total pelvic bone ( TPB) was delineated retrospectively for dose-volume calculations. To compare the differences between two groups, the normality test findings were used to run a paired-samples t-test or Wilcoxon signed-rank test. Pear - son’s correlation analysis or Spearman’s correlation was used to testing the correlation between the two variables. Binary logistic regression analysis was used to analyze associations between HT and possible risk factors. The receiver operating characteristic curve(ROC) was used to evaluate the best cut-off point for dosimetric planning constraints. Results: The nadir of absolute monocyte count (AMC) was found to be positively correlated with the nadir of abso- lute white blood cells ( WBC) count (r = 0.5378, 95% CI 0.4227–0.6357, P < 0.0001) and the nadir of absolute neutrophil count(ANC) (r = 0.5000, 95% CI 0.3794–0.6039, P < 0.0001). The AMC decreased and increased before the ANC and WBC. In multivariate logistic regression analysis, the chemotherapy regimens and the TPB_V20 were independent risk factors for developing grade ≥ 3 HT. The optimal TPB_V20 cut-off value identified by ROC curves and the Youden test was 71% (AUC = 0.788; 95% CI 0.722–0.845; P value < 0.001). Conclusions: The changing trend of AMC can be used as an effective predictor for the timing and severity of the ANC/WBC nadirs and prophylactic G-CSF administration. Maintain TPB_V20 < 71% and selecting single-agent cis- platin or carboplatin could significantly reduce grade ≥ 3 HT in cervical cancer patients undergoing concurrent chemoradiotherapy. *Correspondence: xiangxiaoyong16@163.com; lee_ak@163.com Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xiang et al. Radiation Oncology (2022) 17:48 Page 2 of 11 Keywords: Bone marrow, Acute hematological toxicity, Cervical cancer, Volumetric-modulated arc therapy, Absolute monocyte count Introduction reduce the incidence of severe HT [8, 9]. Therefore, the Cervical cancer is one of the most prevalent malignan- aim of this study was to explore the clinical and dosimet- cies of the reproductive system in women, accounting ric predictors of HT in cervical cancer patients treated for ~ 340,000 annual mortalities, according to the global with CCRT in our institution. We also examined the pre- cancer statistics released in 2020 [1]. Radical surgery is dictive value of AMC for acute leukopenia/neutropenia. the first treatment strategy for early-stage cervical cancer. However, for patients with high-risk surgical-pathologi- Materials and methods cal factors, such as pelvic lymph node-positive, positive Patients resection margins, and parametrial infiltration, or locally We retrospectively reviewed the clinical data of 184 advanced cervical cancer, concurrent platinum-based cervical cancer patients who had CCRT at our institu- chemoradiotherapy remains one of the main therapeutic tion between October 2018 and March 2021. All eligible options [2]. Previous studies have suggested that concur- patients had either newly diagnosed or recurrent cervi- rent chemoradiotherapy (CCRT) improves treatment cal cancer that was confirmed using biopsy, and they had efficacy while increasing adverse reactions, with hema - either radical or postoperative pelvic radiotherapy with tological toxicity (HT) being one of the main adverse concurrent weekly platinum-based chemotherapy. The effects during CCRT and follow-up [3, 4]. pelvic radiotherapy was administered using an image- Patients with grade three or higher HT are more likely guided VMAT technique. Patients who had previously to develop life-threatening infections or febrile neutro- received pelvic radiotherapy or CCRT with extended penia, which may necessitate reducing CCRT  doses or field pelvic para-aortic irradiation, as well as those with terminating  it  entirely,  affecting therapeutic  efficacy [5]. incomplete data, were excluded from this study. Except Therefore, in addition to reducing the severity and inci - for anemia, patients with grade ≥ 2 HT in the last two dence of HT, improving pretreatment evaluation of leu- weeks before the CCRT, and patients with established kopenia and neutropenic risk may help ensure that most bone marrow metastases, were also excluded. During the patients continue to receive the optimal dose intensity chemoradiotherapy period, the patients were assessed for chemoradiotherapy, boosting their chance to meet their HT at least once a week using complete blood counts. All treatment goals. patients in this study signed informed consent forms. In  cancer  patients, approximately 34.5% of the active bone marrow is located in the pelvis bones, 16.6% in the Concurrent chemotherapy lumbar vertebrae, and 4.5% in the proximal femur [6]. All chemotherapy regimens were platinum-based. The Because of the high radiosensitivity of hematopoietic regimens included TP (135–175  mg/m paclitaxel, D1; stem cells, the pelvic bone is a potential organ at risk, 50–70 mg/m cisplatin, D2-4; 21 day repeat, 1–2 cycles), especially in cervical cancer patients undergoing CCRT. weekly cisplatin (40  mg/m , D1, 5–6 cycles), and weekly Furthermore,  we found that the absolute monocyte carboplatin (AUC 2, D1, 5–6 cycles). Chemotherapy regi- count (AMC) decreased and increased before the abso- mens differed because the patient, their family, and phy - lute neutrophil count (ANC)/absolute white  blood  cells sicians decidec on the specific regimen, with cisplatin as (WBC)  count, and that there  was  a  clear  correla- the preferred agent. Before each cycle of chemotherapy, tion  between the nadir of AMC and the severity of all patients underwent routine hematological examina- neutropenia/leukopenia. tion, including hematology, blood chemistry, renal func- Currently, cervical cancer is being treated with tion, and liver function. The next cycle of chemotherapy advanced  treatment techniques, including intensity- was administered if patients tolerated the previous cycle. modulated radiation therapy (IMRT), helical tomogra- phy radiotherapy (TOMO), or volumetric-modulated arc Volumetric‑modulated arc therapy therapy (VMAT) regimens. A recent dosimetric study Typically, the patient was simulated in the prone position. found that using VMAT with os coxae and lumbosacral If necessary, the patient was immobilized was performed spine as separate dose-volume constraints in patients in the supine position. A contrast-enhanced CT-based with cervical cancer can minimize CCRT-associated HT simulation was performed with a slice thickness of 5 mm [7]. However, there is no unified standard for limiting the when patients were moderately filling the bladder and optimal dosimetric parameters of pelvic bones marrow to emptying the rectum. The CT scan covered the area from Xiang  et al. Radiation Oncology (2022) 17:48 Page 3 of 11 Fig. 1 Typical images showing contours for the total pelvic bone ( TPB) [9] the lower edge of the T10 vertebrae to the 5  cm below considered insignificant. In the final week of external the ischial tuberosity. The clinical target area  (CTV) beam radiotherapy, patients who accepted radical radio- included the entire cervix, uterus, partial vaginal, vesico- therapy usually started receiving four to five fractions of vaginal and rectovaginal spaces, gross tumor, parametria, 3D image-guided high dose rate brachytherapy (intra- and regional lymph nodes. Lymph node metastasis was cavitary or interstitial or a combination of both; one to diagnosed using imaging test results (such as MRI, CT, two fractions per week). We aimed for cumulative EBRT and PET-CT) or pathological biopsy. The planning target and brachytherapy doses of > 85 Gy (EQD2) for HR-CTV volume (PTV) included the CTV and a uniform three- D90. dimensional expansion of 5 mm. All the patients in this study underwent pelvic volu- Bone marrow delineation metric-modulated arc therapy. The pelvic radiation dose All bone marrow contours were retrospectively delin- was 45–50.4  Gy in 1.8  Gy daily fractions, and the dose eated manually according to Mell et  al. [9]. To ensure delivered to the affected lymph nodes was 58.8–60.2  Gy repeatability and limit inter-observer variations, all the in 2.1–2.15  Gy daily fractions. The following organs at external contours of the bones within the PTV cover- risk (OARs) were delineated for dose-volume calcula- age (defined as from the centrum 2  cm above the upper tions: bladder, spinal cord, femoral heads, rectum, small boundary of PTV to the ischial tuberosities) were ret- intestine, sigmoid colon, and bowel bag. The pelvic bone rospectively delineated as a proxy for the bone marrow marrow was not included in the OARs but was deline- rather than the low-density areas within the bones by a ated retrospectively for dose-volume calculations. Cone- single radiation oncologist and subsequently reviewed by beam computed tomography was used to minimize the another senior radiation oncologist. The contour of the daily setup error. Vaginal brachytherapy was depend- total pelvic bone (TPB) is shown in Fig. 1. ent on the specific circumstances of the patient, and the Dose-volume histograms (DVHs) corresponding to dose to pelvic bone marrow from brachytherapy was the delivered VMAT plan were used to assess the dose Xiang et al. Radiation Oncology (2022) 17:48 Page 4 of 11 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 (kg/m ) 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 98 (53.3) IIIA–IVB 86 (46.7) Histology, n (%) Squamous carcinoma 166 (90.2) Adenocarcinoma 18 (9.8) Differentiation degree, n (%) High–moderate 85 (46.2) Lower / Unknown 99 (53.8) PTV dose-pelvis 45 Gy 99 (53.8) (n, %) 48.6 Gy–50.4 Gy 85 (46.2) Chemotherapy regimen (n, %) TP 42 (22.8) Carboplatin 31 (16.9) Cisplatin 111 (60.3) BMI, body mass index; EBRT, pelvic external-beam radiotherapy; SD, standard deviation; RT, radiation therapy; TP, paclitaxel + cisplatin volumes (V10, V20, V30, V40, and V50, respectively) Shapiro–Wilk test was used to determine the normal- received by the TPB. ity of data distribution. Data with to normal distribution were expressed as mean ± standard deviation, whereas Hematologic toxicity the rest were expressed as the median and interquar- All patients agreed to a routine blood examination before tile range (IQR). Categorical data were assessed and receiving external irradiation or platinum-based chemo- described as frequencies and percentages. To compare therapy. Blood routine tests should be taken at least once the differences between two groups, the normality test a week during the period of CCRT and within two weeks findings were used to run a paired-samples t-test or Wil - after completing external radiation therapy. However, the coxon signed-rank test. Pearson’s correlation analysis or frequency of routine blood examination can be increased Spearman’s correlation was used to testing the correla- if necessary. The day of CCRT initiation was defined as tion between the two variables, with P < 0.05 considered day 0 (D0), while the first day after CCRT initiation was significant. Possible risk factors for grade ≥ 3 HT were defined as day 1 (D1). The days were calculated from D0, analyzed using binary logistic regression analysis, and when AMC, ANC, PLT, WBC, and HGB were at their variable with P values < 0.05 in the binary logistic regres- minimal level. Using a similar approach, the days from sion analysis were entered into the multiple logistic the D1 were calculated when AMC, ANC, and WBC regression analysis. The receiver operating characteris - increased from the nadir to ≥ normal value for the first tic (ROC) curve was used to evaluate the area under the time. ROC curve (AUC), best cut-off point, specificities, and The HT was graded according to the Common Ter - sensitivities. Statistical significance was considered when minology Criteria for Adverse Events (CTCAE) v5.0. P < 0.05. Whether the patients were treated with granulocyte- monocyte colony-stimulating factors, red cell transfu- Results sion, or platelet transfusion was based on the clinical Patient characteristics judgment of the attending physicians. Generally, the cri- In this study, 184 cervical cancer patients received pelvic teria were as follows: absolute neutrophil counts < 1000/ radiotherapy using an image-guided VMAT technique. 3 3 mm or absolute WBC count < 2000/mm , haemoglo- Furthermore, the patients were treated with platinum- bin < 60 g/L, and PLT < 20 × 109/L. based chemotherapy, with 42 (22.8%) receiving TP, 111 (60.3%) receiving weekly cisplatin, and 31 (16.9%) receiv- Statistical analysis ing weekly carboplatin. Every patient received at least Data analysis was performed using SPSS (IBM SPSS one cycle of concurrent chemotherapy (with a median of 23.0, SPSS Inc). Descriptive statistics were generated two cycles, range from one to six cycles). The basic clini - for relevant clinical and dosimetric parameters. The cal characteristics of the patients are shown in Table 1. Xiang  et al. Radiation Oncology (2022) 17:48 Page 5 of 11 Table 2 Descriptive statistics of dosimetric parameters of the total pelvic bones Parameter Mean Median Min–max Q1–Q3 SD TPBVolume (cm ) 1189 1165 886–2219 1070–1266 177.6 V10 (10%) 90.39 90.00 49.00–100.00 88.00–94.00 5.780 V20 (20%) 71.53 70.74 27.23–92.90 66.95–76.89 7.977 V30 (30%) 45.41 45.00 14.00–68.00 39.00–51.00 8.832 V40 (40%) 23.32 23.00 6.00–46.00 18.00–27.00 6.617 V50 (50%) 5.14 3.00 0.00–26.00 0.00–10.00 5.422 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 Fig. 2 Descriptive statistics of hematological baselines and nadirs Dosimetric parameters of the pelvic bone 0.91–1.51), 90.00  g/L (Q1–Q3, 80–103), 0.21 × 10 /L The dosimetric parameters were subjected to a descrip - (Q1–Q3, 0.14–0.28), and 104.00 10 /L (Q1–Q3, 78.25– tive statistical analysis, and their mean values, median 131.00), respectively. The WBC, ANC, HGB, AMC, and values, maximum, minimum, 25th percentile, 75th per- PLT counts decreased by 64.72%, 64.86%, 16.00%, 50.00%, centile, and standard deviations were recorded. Table  2 and 53.44%, respectively (Fig. 2). shows the dosimetric parameters for the total pelvic bone marrow. Hematologic toxicity At baseline, 26 patients (14.13%) had grade 1 leukopenia, Hematological baselines and nadirs 11 patients (5.98%) had grade 1 neutropenia, and two Compared to the hematological baselines, all patients (1.09%) had grade 1 thrombocytopenia. Moreo- blood  cell  counts declined to varying  degrees through- ver, anemia was more prevalent at baseline than other out  the  study  period (P < 0.001). The median of WBC, HT. At baseline, 50 patients (27.17%) had grade 1, 20 ANC, HGB, AMC, and PLT counts at the nadirs were patients (10.89%) had grade 2, and seven patients (3.08%) 9 9 1.99 × 10 /L (Q1–Q3, 1.62–2.37), 1.21 × 10 /L (Q1–Q3, had grade 3 anemia. The percentages of grade 3 or grade Xiang et al. Radiation Oncology (2022) 17:48 Page 6 of 11 Table 3 Hematological toxicity graded according to hematological nadirs and baselines Hematologic toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 (n, %) (n, %) (n, %) (n, %) (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) Fig. 3 The changing tendency and correlation between AMC and ANC/WBC 4 leukopenia, neutropenia, thrombocytopenia, and ane- 24–42 days) for the HGB. When compared to the WBC mia during CCRT were 52.17%, 30.43%, 6.52%, and and ANC, the AMC was the first to decreased to the 22.83%, respectively. Fifty-six (30.4%) patients received nadir (median = five days, Q1–Q3 = 0  to  11  days , colony-stimulating factors, four (2.2%) received platelet P < 0.001, Fig .  3A and B). The time it took for AMC to transfusion, and seventeen (9.2%) received packed RBC increase from the nadir to ≥ normal value for the first transfusion. Overall, 111 patients (60.33%) did experience time was less than for WBC (median = four days, Q1– any grade 3+ HT. Further information is given in Table 3. Q3 = 0  to  11  days , P < 0.001) and ANC (median = three days, Q1–Q3 = 0  to  10  days , P < 0.001, Fig .  3C and D). The changing trend of blood cell counts We also assessed the relationship between variables The  median  time  to  the  nadir was 26  days (Q1– using the Spearman rank correlation test. The nadir Q3, 19–34  days) for  the  WBC and ANC, 20  days of AMC was found to be positively correlated with (Q1–Q3, 8  to  –29  days) for  the  AMC, 29  days (Q1– the nadir of WBC (r = 0.5378, 95% CI 0.4227–0.6357, Q3, 20–39  days) for  the  PLT, and 35  days (Q1–Q3, Xiang  et al. Radiation Oncology (2022) 17:48 Page 7 of 11 Table 4 Univariate logistic regression analysis of factors that the changing tendency of AMC had certain predic- associated with the development of any grade ≥ 3 hematologic tive value to the changing trend of WBC and ANC. toxicity Predictors of hematologic toxicity Parameter Odds ratio 95% CI P value The univariate and multiple binary logistic regression Age (years) 1.000 0.972–1.029 0.991 analyses were performed to identify any grade ≥ 3 HT BMI (kg/m ) 0.982 0.898–1.074 0.982 predictors. In univariable binary logistic regression anal- Duration of EBRT (days) 1.069 0.987–1.158 0.102 ysis, the chemotherapy regimen and the total pelvic bone Clinical stage (FIGO2018) 1.759 0.964–3.208 0.066 (TPB_V10, TPB_V20, TPB_V30, TPB_V40, and TPB_ Histology 0.559 0.232–1.345 0.194 V50) were associated with any grade ≥ 3 HT (Table 4). Differentiation degree 0.789 0.431–1.445 0.443 Subsequently, multivariate analysis was performed using PTV dose-pelvis 1.696 0.930–3.094 0.085 all the significant factors in the univariate analysis. The Cycles of chemotherapy 1.056 0.861–1.295 0.600 results demonstrated that the chemotherapy  regimens Volume (cm ) 1.002 1.000–1.004 0.053 and TPB_V20 were independent factors. Patients who Chemotherapy regimen received the TP chemotherapy regimen were more likely TP 0.027* to develop grade ≥ 3 HT than those who received cisplatin Carboplatin 0.257 0.094–0.701 0.008* or carboplatin (76.2% vs. 58.6% vs. 45.2%). Furthermore, Cisplatin 0.442 0.198–0.987 0.046* patients with increased TPB_V20 were more likely to TPB_V10 1.197 1.109–1.292 < 0.001* develop grade ≥ 3 HT (OR 1.154; SE 0.69; P = 0.034; 95% TPB_V20 1.176 1.109–1.248 < 0.001* CI 1.008–1.321). Hosmer–Lemeshow test indicated that TPB_V30 1.102 1.057–1.149 < 0.001* the models fitted well (χ = 8.412, P value = 3.94 > 0.05). TPB_V40 1.114 1.055–1.177 < 0.001* The detailed results are shown in Fig. 4 . TPB_V50 1.142 1.069–1.221 < 0.001* The ROC curve for grade ≥ 3 HT versus TPB_V20 was BMI, body mass index; EBRT, pelvic external-beam radiotherapy; TPB_V10, TPB_ analyzed to determine the optimal thresholds for dosi- V20, TPB_V30, TPB_V40, TPB_V50 = the total pelvic bones of volume receiving metric planning. The optimal TPB_V20 cut-off value 10,20, 30, 40, 50 Gy; TP, paclitaxel + cisplatin. Bold indicates the significant values determined by ROC curves and the Youden test was (*P < 0.05) 71% (AUC = 0.788; 95% CI, 0.722–0.845; P value < 0.001, Fig.  5). Patients who received TPB_V20 ≥ 71% were P < 0.0001) and the nadir of ANC (r = 0.5000, 95% more likely to develop grade ≥ 3 HT (84.1% vs. 38.5%, CI 0.3794–0.6039, P < 0.0001) (Fig . 3E and F). P < 0.001). The specificity and sensitivity for this thresh - All of the preceding analyses indicate that AMC old were 78.1% and 71.2%, respectively. The positive decreased and increased before the ANC and WBC, and and negative predictive values for TPB_V20 ≥ 71% were Fig. 4 The results of multivariate binary logistic regression analysis for any grade ≥ 3 HT in patients Xiang et al. Radiation Oncology (2022) 17:48 Page 8 of 11 in high-risk patients [9]. However, treatment time and cost will be high in patients with grade ≥ 3 neutropenia/ leukopenia despite the use of G-CSF. In the current clini- cal practice, risk assessment, control, and prevention of life-threatening infection or febrile neutropenia, are not standardized. Therefore, minimizing HT is critical when adopting more intense chemotherapy regimens for cervi- cal cancer, and HT research should be strengthened. Previous research has found statistically strong correla- tions between AMC and ANC during chemotherapy [13– 18]. Kondo  et al. showed that AMC < 150/microl after six to eight days of advanced lung cancer chemotherapy could be a predictor of grade 3 or higher neutropenia at three- or four-week intervals [13]. Subsequently, Oshita F et al. compared a group of 60 patients with unresectable lung cancer who were randomly assigned to prophylac- tic G-CSF administration when monocytopenia appeared (group A) or G-CSF administration when neutropenia (< 1,000/microl) or leukopenia (< 2000/microl) appeared Fig. 5 Receiver operating characteristic (ROC) curves for any after chemotherapy (group B) [14]. Their results indicated grade ≥ 3 hematologic toxicity as a function of TPB_V20 that prophylactic G-CSF administration can considerably shorten the duration (1.4 ± 1.7  days vs. 2.9 ± 1.9  days, P = 0.004) and frequency (48% vs. 83%, P = 0.002) of 83.1% (95% CI 77.3%–87.7%) and 64.1% (95% CI 56.7%– grade 3 neutropenia [14]. Furthermore, in another study 70.8%), respectively. of 75 patients with advanced lung cancer undergoing chemotherapy, the number of days that elapsed between Discussion the first day of chemotherapy and the median AMC nadir Acute hematological toxicity (HT) is prevalent in cervical was shorter than that for AMC nadir (6 days vs. 12 days, cancer patients who receive CCRT, especially grade ≥ 3 P < 0.001); AMC at the nadir of 100/μL predicted an ANC HT, which may result in lower CCRT  doses or termina- at the nadir of < 1000/μL with a sensitivity of 83% and a tion  of  CCRT  altogether, affecting  therapeutic  efficacy specificity of 56% [15]. Similar results were reported in [5]. To our knowledge, this is the first report to explore another study, which found that the changing trend of the predictive value of AMC in cervical cancer patients AMC was the same as that of ANC. The initial decrease / undergoing  CCRT. We observed the AMC trend corre- reaching the nadir / final increase days of AMC were sig - sponded to the WBC/ANC during CCRT. The decrease nificantly less than those of ANC [16]. Two more studies and increase of AMC occurred before the ANC/WBC, found a correlation between ANC and AMC in patients and there was a significant correlation between the nadir receiving chemotherapy [17, 18]. of AMC and the severity of neutropenia/leukopenia. Fur- In this retrospective  study, we  evaluated the relation- thermore, the findings in this study revealed quantifiable ship between AMC and ANC/WBC, as well as the prog- evidence of an association between TPB_V20 and acute nostic value of AMC for acute leukopenia/neutropenia grade ≥ 3 HT. in cervical cancer patients undergoing CCRT. The results Multiple studies have established that prolonging the revealed that AMC decreased and increased before ANC treatment time has a negative impact on disease-specific and WBC, and that the changing tendency of AMC had survival in cervical cancer patients who have undergone certain predictive  value to the changing trend of WBC CCRT [10–12]. However, treatment time was mainly and ANC. The nadir of AMC was also found to be posi - prolonged due to the acute HT, especially in patients tively correlated with the nadir of WBC/ANC. Dur- with grade ≥ 3 neutropenia/leukopenia. These patients ing hematopoiesis, both neutrophils and monocytes are more likely to develop life-threatening infections or are differentiated from the granulocyte–macrophage febrile neutropenia, which could lead to a reduction in colony-forming cells, providing a good explanation for CCRT doses or termination of CCRT  altogether, affect - a positive correlation between AMC and ANC nadirs ing  the  therapeutic  efficacy. According to the ASCO during CCRT. Therefore, based on the findings of previ - recommendation, granulocyte colony-stimulating fac- ous research and this study, the increase or decrease in tor (G-CSF) can be used to prevent febrile neutropenia AMC can be used as an effective predictor for the timing Xiang  et al. Radiation Oncology (2022) 17:48 Page 9 of 11 and severity of the ANC/WBC nadirs and prophylactic into three subsites: lumbosacral spine, lower pelvis, and G-CSF administration. ilium, and the importance of these particular regions Additionally, all the blood  cell  counts of patients were was stated [8, 21, 25]. However, in our study, all exter- reduced to varying degrees during the CCRT. The WBC, nal contours of the bones within the PTV coverage were ANC, HGB, AMC, and PLT counts decreased by 64.72%, delineated as a proxy for the TPB to ensure repeatability 64.86%, 16.00%, 50.00%, and 53.44%, respectively. The and to avoid multiple collinearities in the multivariate percentage of patients with grade 3 or grade 4 neutrope- analysis. Our results are consistent with previous stud- nia, leukopenia, thrombocytopenia, and anemia during ies, which found that patients with bigger volumes of TPB CCRT was 52.17%, 30.43%, 6.52%, and 22.83%, respec- who received low-dose radiation had higher rates of HT tively. Overall, 111 patients (60.33%) experienced grade (grade ≥ 3) [20, 28]. Patients who received TPB_V20 ≥ 71% 3+ HT. We found that white blood cell and neutrophil were more likely to develop grade ≥ 3 HT (84.1% vs. 38.5%, counts declined significantly in most patients during P < 0.001), with specificity and sensitivity threshold of CCRT. The current treatment option for stage IB-IVA 78.1% and 71.2%, respectively. The association with the cervical cancer is weekly cisplatin with radiotherapy. low-dose dosimetric parameter (TPB_V20) was consistent However, different results were obtained in various stud - with the known radiosensitivity of bone marrow. ies. For example, according to a meta-analysis by Petrelli This study has several limitations. First, this was a F et al., platinum-based doublet chemotherapy combined single-center retrospective study with a small number with concurrent radiotherapy can improve the overall of patients, which may have resulted in selection bias. survival and disease-free survival compared to weekly Furthermore, the dosage and duration of G-CSF treat- cisplatin with radiotherapy. Nonetheless, severe HT was ment differed with the conditions of patients, which may largely underreported in the reviewed publications [19]. have affected on the changing trend of AMC, ANC, and In our study, weekly cisplatin and weekly carboplatin WBC. Finally, we contoured the external contours of the were considerably more effective than the TP regimen in bones as opposed to the actual proliferating active bone. reducing ≥ 3 HT (58.6% vs. 45.2% vs. 76.2%). Therefore, Despite the aforementioned limitations, the present it is critical to identify the optimum chemotherapy regi- study highlights the prognostic efficacy of dosimetric mens for individual patients in order to reduce the chem- parameters and AMC for HT in cervical cancer patients otherapy-related HT. undergoing CCRT. Several studies had analyzed the relationship between pelvic dosimetry parameters and HT in patients under- Conclusion going pelvic radiotherapy with respect to radiation doses. The changing trend of AMC can be used as an effective For example, Mell et  al. analyzed 37 cervical cancer predictor for the timing and severity of the ANC/WBC patients who received CCRT and found that the risk of nadirs and prophylactic G-CSF administration. Fur- developing grade 2 or higher leukopenia and neutropenia thermore, according to the multivariate logistic regres- increased by a factor (odds ratio) of 2.09 if the TPB_V10 sion analysis, the chemotherapy  regimen and TPB_V20 exceeds 90% [9]. According to Rose et  al., HT increases were independent  risk factors for the development of as the total pelvic bone volume irradiated increases, grade ≥ 3 HT. Maintaining TPB_V20 < 71% and selecting and efforts to keep TPB_V10 < 95% and TPB_V20 < 76% single-agent cisplatin or carboplatin could significantly may help avoid grade 3+ leukopenia [20]. Additionally, a reduce grade ≥ 3 HT in cervical cancer patients under- recent study demonstrated that lower pelvis (V5 > 95% or going CCRT. However, the predictive value of dosimet- V20 > 45%), TPB_V20 ≥ 65%, and the mean dose of iliac ric parameters and AMC for acute HT requires further crests > 31  Gy were most significantly correlated with investigations. grade 4 HT [8]. Wan et  al. demonstrated that lumbosa- cral spine V40 was most significantly correlated with grade ≥ 2 HT in rectal cancer patients, and they recom- Abbreviations VMAT: Volumetric-modulated arc therapy; CCRT : Concurrent chemoradio- mended dose constraints to the lumbosacral spine to be therapy; HT: Hematological toxicity; AMC: Absolute monocyte count; ANC: V40 < 60% [21]. Franco et  al. found that a higher TPB_ Absolute neutrophil count; WBC: White blood cells; IMRT: Intensity-modulated V20 was associated with lower WBC nadir in anal can- radiation therapy; TOMO: Helical tomography radiotherapy; 3D-CRT : Conven- tional three-dimensional conformal radiotherapy; OARs: Organs at risk; TPB: cer patients, and that patients with lumbosacral spine Total pelvic bones; Q1: 25Th percentile; Q3: 75Th percentile; SD: Standard V40 < 41% may reduce grade 3 + HT. In summary, no deviation; G-CSF: Granulocyte colony-stimulating factor. optimal bone marrow dose/volume constraints standard Acknowledgements has been proposed until now. Not applicable. In several studies, the external contour of all the pelvis bones was delineated as TPB. The TPB was then divided Xiang et al. Radiation Oncology (2022) 17:48 Page 10 of 11 Authors’ contributions modulated radiation therapy for patients with cervical cancer? Front NL and XX was responsible for the primary concept and the design of the Oncol. 2020. https:// doi. org/ 10. 3389/ fonc. 2020. 554241. study; XX, ZD, and QZ performed the data capture and analysis; XX, ZD, and 8. Kumar T, Schernberg A, Busato F, et al. Correlation between pelvic bone NL drafted the manuscript; All the external contours of the bones were deline- marrow radiation dose and acute hematological toxicity in cervical can- ated by XX and subsequently reviewed by NL; LF, CQ, DC, and JL provided cer patients treated with concurrent chemoradiation. 2019;11:6285–6297. study materials or patients; All authors revised the manuscript. All authors https:// doi. org/ 10. 2147/ CMAR. S1959 89. have read and approved the final manuscript. 9. Mell LK, Kochanski JD, Roeske JC, et al. Dosimetric predictors of acute hematologic toxicity in cervical cancer patients treated with concurrent Funding cisplatin and intensity-modulated pelvic radiotherapy. Int J Radiat Oncol Supported by the Sanming Project of Medicine in Shenzhen (No. Biol Phys. 2006;66(5):1356–65. https:// doi. org/ 10. 1016/j. ijrobp. 2006. 03. SZSM201612063) and the Shenzhen Key Medical Discipline Construction Fund 018. (No.SZXK013). 10. Lin SM, Ku HY, Chang TC, et al. 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Dosimetric parameters and absolute monocyte count can predict the prognosis of acute hematologic toxicity in cervical cancer patients undergoing concurrent chemotherapy and volumetric-modulatedarctherapy

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Abstract

Purpose: To explore clinical and dosimetric predictors of acute hematologic toxicity (HT ) in cervical cancer patients treated with concurrent chemotherapy and volumetric-modulated arc therapy ( VMAT ). Methods and materials: We retrospectively reviewed the clinical data of 184 cervical cancer patients who had con- current chemotherapy and VMAT. Hematological parameters were collected during the treatment period. The total pelvic bone ( TPB) was delineated retrospectively for dose-volume calculations. To compare the differences between two groups, the normality test findings were used to run a paired-samples t-test or Wilcoxon signed-rank test. Pear - son’s correlation analysis or Spearman’s correlation was used to testing the correlation between the two variables. Binary logistic regression analysis was used to analyze associations between HT and possible risk factors. The receiver operating characteristic curve(ROC) was used to evaluate the best cut-off point for dosimetric planning constraints. Results: The nadir of absolute monocyte count (AMC) was found to be positively correlated with the nadir of abso- lute white blood cells ( WBC) count (r = 0.5378, 95% CI 0.4227–0.6357, P < 0.0001) and the nadir of absolute neutrophil count(ANC) (r = 0.5000, 95% CI 0.3794–0.6039, P < 0.0001). The AMC decreased and increased before the ANC and WBC. In multivariate logistic regression analysis, the chemotherapy regimens and the TPB_V20 were independent risk factors for developing grade ≥ 3 HT. The optimal TPB_V20 cut-off value identified by ROC curves and the Youden test was 71% (AUC = 0.788; 95% CI 0.722–0.845; P value < 0.001). Conclusions: The changing trend of AMC can be used as an effective predictor for the timing and severity of the ANC/WBC nadirs and prophylactic G-CSF administration. Maintain TPB_V20 < 71% and selecting single-agent cis- platin or carboplatin could significantly reduce grade ≥ 3 HT in cervical cancer patients undergoing concurrent chemoradiotherapy. *Correspondence: xiangxiaoyong16@163.com; lee_ak@163.com Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xiang et al. Radiation Oncology (2022) 17:48 Page 2 of 11 Keywords: Bone marrow, Acute hematological toxicity, Cervical cancer, Volumetric-modulated arc therapy, Absolute monocyte count Introduction reduce the incidence of severe HT [8, 9]. Therefore, the Cervical cancer is one of the most prevalent malignan- aim of this study was to explore the clinical and dosimet- cies of the reproductive system in women, accounting ric predictors of HT in cervical cancer patients treated for ~ 340,000 annual mortalities, according to the global with CCRT in our institution. We also examined the pre- cancer statistics released in 2020 [1]. Radical surgery is dictive value of AMC for acute leukopenia/neutropenia. the first treatment strategy for early-stage cervical cancer. However, for patients with high-risk surgical-pathologi- Materials and methods cal factors, such as pelvic lymph node-positive, positive Patients resection margins, and parametrial infiltration, or locally We retrospectively reviewed the clinical data of 184 advanced cervical cancer, concurrent platinum-based cervical cancer patients who had CCRT at our institu- chemoradiotherapy remains one of the main therapeutic tion between October 2018 and March 2021. All eligible options [2]. Previous studies have suggested that concur- patients had either newly diagnosed or recurrent cervi- rent chemoradiotherapy (CCRT) improves treatment cal cancer that was confirmed using biopsy, and they had efficacy while increasing adverse reactions, with hema - either radical or postoperative pelvic radiotherapy with tological toxicity (HT) being one of the main adverse concurrent weekly platinum-based chemotherapy. The effects during CCRT and follow-up [3, 4]. pelvic radiotherapy was administered using an image- Patients with grade three or higher HT are more likely guided VMAT technique. Patients who had previously to develop life-threatening infections or febrile neutro- received pelvic radiotherapy or CCRT with extended penia, which may necessitate reducing CCRT  doses or field pelvic para-aortic irradiation, as well as those with terminating  it  entirely,  affecting therapeutic  efficacy [5]. incomplete data, were excluded from this study. Except Therefore, in addition to reducing the severity and inci - for anemia, patients with grade ≥ 2 HT in the last two dence of HT, improving pretreatment evaluation of leu- weeks before the CCRT, and patients with established kopenia and neutropenic risk may help ensure that most bone marrow metastases, were also excluded. During the patients continue to receive the optimal dose intensity chemoradiotherapy period, the patients were assessed for chemoradiotherapy, boosting their chance to meet their HT at least once a week using complete blood counts. All treatment goals. patients in this study signed informed consent forms. In  cancer  patients, approximately 34.5% of the active bone marrow is located in the pelvis bones, 16.6% in the Concurrent chemotherapy lumbar vertebrae, and 4.5% in the proximal femur [6]. All chemotherapy regimens were platinum-based. The Because of the high radiosensitivity of hematopoietic regimens included TP (135–175  mg/m paclitaxel, D1; stem cells, the pelvic bone is a potential organ at risk, 50–70 mg/m cisplatin, D2-4; 21 day repeat, 1–2 cycles), especially in cervical cancer patients undergoing CCRT. weekly cisplatin (40  mg/m , D1, 5–6 cycles), and weekly Furthermore,  we found that the absolute monocyte carboplatin (AUC 2, D1, 5–6 cycles). Chemotherapy regi- count (AMC) decreased and increased before the abso- mens differed because the patient, their family, and phy - lute neutrophil count (ANC)/absolute white  blood  cells sicians decidec on the specific regimen, with cisplatin as (WBC)  count, and that there  was  a  clear  correla- the preferred agent. Before each cycle of chemotherapy, tion  between the nadir of AMC and the severity of all patients underwent routine hematological examina- neutropenia/leukopenia. tion, including hematology, blood chemistry, renal func- Currently, cervical cancer is being treated with tion, and liver function. The next cycle of chemotherapy advanced  treatment techniques, including intensity- was administered if patients tolerated the previous cycle. modulated radiation therapy (IMRT), helical tomogra- phy radiotherapy (TOMO), or volumetric-modulated arc Volumetric‑modulated arc therapy therapy (VMAT) regimens. A recent dosimetric study Typically, the patient was simulated in the prone position. found that using VMAT with os coxae and lumbosacral If necessary, the patient was immobilized was performed spine as separate dose-volume constraints in patients in the supine position. A contrast-enhanced CT-based with cervical cancer can minimize CCRT-associated HT simulation was performed with a slice thickness of 5 mm [7]. However, there is no unified standard for limiting the when patients were moderately filling the bladder and optimal dosimetric parameters of pelvic bones marrow to emptying the rectum. The CT scan covered the area from Xiang  et al. Radiation Oncology (2022) 17:48 Page 3 of 11 Fig. 1 Typical images showing contours for the total pelvic bone ( TPB) [9] the lower edge of the T10 vertebrae to the 5  cm below considered insignificant. In the final week of external the ischial tuberosity. The clinical target area  (CTV) beam radiotherapy, patients who accepted radical radio- included the entire cervix, uterus, partial vaginal, vesico- therapy usually started receiving four to five fractions of vaginal and rectovaginal spaces, gross tumor, parametria, 3D image-guided high dose rate brachytherapy (intra- and regional lymph nodes. Lymph node metastasis was cavitary or interstitial or a combination of both; one to diagnosed using imaging test results (such as MRI, CT, two fractions per week). We aimed for cumulative EBRT and PET-CT) or pathological biopsy. The planning target and brachytherapy doses of > 85 Gy (EQD2) for HR-CTV volume (PTV) included the CTV and a uniform three- D90. dimensional expansion of 5 mm. All the patients in this study underwent pelvic volu- Bone marrow delineation metric-modulated arc therapy. The pelvic radiation dose All bone marrow contours were retrospectively delin- was 45–50.4  Gy in 1.8  Gy daily fractions, and the dose eated manually according to Mell et  al. [9]. To ensure delivered to the affected lymph nodes was 58.8–60.2  Gy repeatability and limit inter-observer variations, all the in 2.1–2.15  Gy daily fractions. The following organs at external contours of the bones within the PTV cover- risk (OARs) were delineated for dose-volume calcula- age (defined as from the centrum 2  cm above the upper tions: bladder, spinal cord, femoral heads, rectum, small boundary of PTV to the ischial tuberosities) were ret- intestine, sigmoid colon, and bowel bag. The pelvic bone rospectively delineated as a proxy for the bone marrow marrow was not included in the OARs but was deline- rather than the low-density areas within the bones by a ated retrospectively for dose-volume calculations. Cone- single radiation oncologist and subsequently reviewed by beam computed tomography was used to minimize the another senior radiation oncologist. The contour of the daily setup error. Vaginal brachytherapy was depend- total pelvic bone (TPB) is shown in Fig. 1. ent on the specific circumstances of the patient, and the Dose-volume histograms (DVHs) corresponding to dose to pelvic bone marrow from brachytherapy was the delivered VMAT plan were used to assess the dose Xiang et al. Radiation Oncology (2022) 17:48 Page 4 of 11 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 (kg/m ) 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 98 (53.3) IIIA–IVB 86 (46.7) Histology, n (%) Squamous carcinoma 166 (90.2) Adenocarcinoma 18 (9.8) Differentiation degree, n (%) High–moderate 85 (46.2) Lower / Unknown 99 (53.8) PTV dose-pelvis 45 Gy 99 (53.8) (n, %) 48.6 Gy–50.4 Gy 85 (46.2) Chemotherapy regimen (n, %) TP 42 (22.8) Carboplatin 31 (16.9) Cisplatin 111 (60.3) BMI, body mass index; EBRT, pelvic external-beam radiotherapy; SD, standard deviation; RT, radiation therapy; TP, paclitaxel + cisplatin volumes (V10, V20, V30, V40, and V50, respectively) Shapiro–Wilk test was used to determine the normal- received by the TPB. ity of data distribution. Data with to normal distribution were expressed as mean ± standard deviation, whereas Hematologic toxicity the rest were expressed as the median and interquar- All patients agreed to a routine blood examination before tile range (IQR). Categorical data were assessed and receiving external irradiation or platinum-based chemo- described as frequencies and percentages. To compare therapy. Blood routine tests should be taken at least once the differences between two groups, the normality test a week during the period of CCRT and within two weeks findings were used to run a paired-samples t-test or Wil - after completing external radiation therapy. However, the coxon signed-rank test. Pearson’s correlation analysis or frequency of routine blood examination can be increased Spearman’s correlation was used to testing the correla- if necessary. The day of CCRT initiation was defined as tion between the two variables, with P < 0.05 considered day 0 (D0), while the first day after CCRT initiation was significant. Possible risk factors for grade ≥ 3 HT were defined as day 1 (D1). The days were calculated from D0, analyzed using binary logistic regression analysis, and when AMC, ANC, PLT, WBC, and HGB were at their variable with P values < 0.05 in the binary logistic regres- minimal level. Using a similar approach, the days from sion analysis were entered into the multiple logistic the D1 were calculated when AMC, ANC, and WBC regression analysis. The receiver operating characteris - increased from the nadir to ≥ normal value for the first tic (ROC) curve was used to evaluate the area under the time. ROC curve (AUC), best cut-off point, specificities, and The HT was graded according to the Common Ter - sensitivities. Statistical significance was considered when minology Criteria for Adverse Events (CTCAE) v5.0. P < 0.05. Whether the patients were treated with granulocyte- monocyte colony-stimulating factors, red cell transfu- Results sion, or platelet transfusion was based on the clinical Patient characteristics judgment of the attending physicians. Generally, the cri- In this study, 184 cervical cancer patients received pelvic teria were as follows: absolute neutrophil counts < 1000/ radiotherapy using an image-guided VMAT technique. 3 3 mm or absolute WBC count < 2000/mm , haemoglo- Furthermore, the patients were treated with platinum- bin < 60 g/L, and PLT < 20 × 109/L. based chemotherapy, with 42 (22.8%) receiving TP, 111 (60.3%) receiving weekly cisplatin, and 31 (16.9%) receiv- Statistical analysis ing weekly carboplatin. Every patient received at least Data analysis was performed using SPSS (IBM SPSS one cycle of concurrent chemotherapy (with a median of 23.0, SPSS Inc). Descriptive statistics were generated two cycles, range from one to six cycles). The basic clini - for relevant clinical and dosimetric parameters. The cal characteristics of the patients are shown in Table 1. Xiang  et al. Radiation Oncology (2022) 17:48 Page 5 of 11 Table 2 Descriptive statistics of dosimetric parameters of the total pelvic bones Parameter Mean Median Min–max Q1–Q3 SD TPBVolume (cm ) 1189 1165 886–2219 1070–1266 177.6 V10 (10%) 90.39 90.00 49.00–100.00 88.00–94.00 5.780 V20 (20%) 71.53 70.74 27.23–92.90 66.95–76.89 7.977 V30 (30%) 45.41 45.00 14.00–68.00 39.00–51.00 8.832 V40 (40%) 23.32 23.00 6.00–46.00 18.00–27.00 6.617 V50 (50%) 5.14 3.00 0.00–26.00 0.00–10.00 5.422 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 Fig. 2 Descriptive statistics of hematological baselines and nadirs Dosimetric parameters of the pelvic bone 0.91–1.51), 90.00  g/L (Q1–Q3, 80–103), 0.21 × 10 /L The dosimetric parameters were subjected to a descrip - (Q1–Q3, 0.14–0.28), and 104.00 10 /L (Q1–Q3, 78.25– tive statistical analysis, and their mean values, median 131.00), respectively. The WBC, ANC, HGB, AMC, and values, maximum, minimum, 25th percentile, 75th per- PLT counts decreased by 64.72%, 64.86%, 16.00%, 50.00%, centile, and standard deviations were recorded. Table  2 and 53.44%, respectively (Fig. 2). shows the dosimetric parameters for the total pelvic bone marrow. Hematologic toxicity At baseline, 26 patients (14.13%) had grade 1 leukopenia, Hematological baselines and nadirs 11 patients (5.98%) had grade 1 neutropenia, and two Compared to the hematological baselines, all patients (1.09%) had grade 1 thrombocytopenia. Moreo- blood  cell  counts declined to varying  degrees through- ver, anemia was more prevalent at baseline than other out  the  study  period (P < 0.001). The median of WBC, HT. At baseline, 50 patients (27.17%) had grade 1, 20 ANC, HGB, AMC, and PLT counts at the nadirs were patients (10.89%) had grade 2, and seven patients (3.08%) 9 9 1.99 × 10 /L (Q1–Q3, 1.62–2.37), 1.21 × 10 /L (Q1–Q3, had grade 3 anemia. The percentages of grade 3 or grade Xiang et al. Radiation Oncology (2022) 17:48 Page 6 of 11 Table 3 Hematological toxicity graded according to hematological nadirs and baselines Hematologic toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 (n, %) (n, %) (n, %) (n, %) (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) Fig. 3 The changing tendency and correlation between AMC and ANC/WBC 4 leukopenia, neutropenia, thrombocytopenia, and ane- 24–42 days) for the HGB. When compared to the WBC mia during CCRT were 52.17%, 30.43%, 6.52%, and and ANC, the AMC was the first to decreased to the 22.83%, respectively. Fifty-six (30.4%) patients received nadir (median = five days, Q1–Q3 = 0  to  11  days , colony-stimulating factors, four (2.2%) received platelet P < 0.001, Fig .  3A and B). The time it took for AMC to transfusion, and seventeen (9.2%) received packed RBC increase from the nadir to ≥ normal value for the first transfusion. Overall, 111 patients (60.33%) did experience time was less than for WBC (median = four days, Q1– any grade 3+ HT. Further information is given in Table 3. Q3 = 0  to  11  days , P < 0.001) and ANC (median = three days, Q1–Q3 = 0  to  10  days , P < 0.001, Fig .  3C and D). The changing trend of blood cell counts We also assessed the relationship between variables The  median  time  to  the  nadir was 26  days (Q1– using the Spearman rank correlation test. The nadir Q3, 19–34  days) for  the  WBC and ANC, 20  days of AMC was found to be positively correlated with (Q1–Q3, 8  to  –29  days) for  the  AMC, 29  days (Q1– the nadir of WBC (r = 0.5378, 95% CI 0.4227–0.6357, Q3, 20–39  days) for  the  PLT, and 35  days (Q1–Q3, Xiang  et al. Radiation Oncology (2022) 17:48 Page 7 of 11 Table 4 Univariate logistic regression analysis of factors that the changing tendency of AMC had certain predic- associated with the development of any grade ≥ 3 hematologic tive value to the changing trend of WBC and ANC. toxicity Predictors of hematologic toxicity Parameter Odds ratio 95% CI P value The univariate and multiple binary logistic regression Age (years) 1.000 0.972–1.029 0.991 analyses were performed to identify any grade ≥ 3 HT BMI (kg/m ) 0.982 0.898–1.074 0.982 predictors. In univariable binary logistic regression anal- Duration of EBRT (days) 1.069 0.987–1.158 0.102 ysis, the chemotherapy regimen and the total pelvic bone Clinical stage (FIGO2018) 1.759 0.964–3.208 0.066 (TPB_V10, TPB_V20, TPB_V30, TPB_V40, and TPB_ Histology 0.559 0.232–1.345 0.194 V50) were associated with any grade ≥ 3 HT (Table 4). Differentiation degree 0.789 0.431–1.445 0.443 Subsequently, multivariate analysis was performed using PTV dose-pelvis 1.696 0.930–3.094 0.085 all the significant factors in the univariate analysis. The Cycles of chemotherapy 1.056 0.861–1.295 0.600 results demonstrated that the chemotherapy  regimens Volume (cm ) 1.002 1.000–1.004 0.053 and TPB_V20 were independent factors. Patients who Chemotherapy regimen received the TP chemotherapy regimen were more likely TP 0.027* to develop grade ≥ 3 HT than those who received cisplatin Carboplatin 0.257 0.094–0.701 0.008* or carboplatin (76.2% vs. 58.6% vs. 45.2%). Furthermore, Cisplatin 0.442 0.198–0.987 0.046* patients with increased TPB_V20 were more likely to TPB_V10 1.197 1.109–1.292 < 0.001* develop grade ≥ 3 HT (OR 1.154; SE 0.69; P = 0.034; 95% TPB_V20 1.176 1.109–1.248 < 0.001* CI 1.008–1.321). Hosmer–Lemeshow test indicated that TPB_V30 1.102 1.057–1.149 < 0.001* the models fitted well (χ = 8.412, P value = 3.94 > 0.05). TPB_V40 1.114 1.055–1.177 < 0.001* The detailed results are shown in Fig. 4 . TPB_V50 1.142 1.069–1.221 < 0.001* The ROC curve for grade ≥ 3 HT versus TPB_V20 was BMI, body mass index; EBRT, pelvic external-beam radiotherapy; TPB_V10, TPB_ analyzed to determine the optimal thresholds for dosi- V20, TPB_V30, TPB_V40, TPB_V50 = the total pelvic bones of volume receiving metric planning. The optimal TPB_V20 cut-off value 10,20, 30, 40, 50 Gy; TP, paclitaxel + cisplatin. Bold indicates the significant values determined by ROC curves and the Youden test was (*P < 0.05) 71% (AUC = 0.788; 95% CI, 0.722–0.845; P value < 0.001, Fig.  5). Patients who received TPB_V20 ≥ 71% were P < 0.0001) and the nadir of ANC (r = 0.5000, 95% more likely to develop grade ≥ 3 HT (84.1% vs. 38.5%, CI 0.3794–0.6039, P < 0.0001) (Fig . 3E and F). P < 0.001). The specificity and sensitivity for this thresh - All of the preceding analyses indicate that AMC old were 78.1% and 71.2%, respectively. The positive decreased and increased before the ANC and WBC, and and negative predictive values for TPB_V20 ≥ 71% were Fig. 4 The results of multivariate binary logistic regression analysis for any grade ≥ 3 HT in patients Xiang et al. Radiation Oncology (2022) 17:48 Page 8 of 11 in high-risk patients [9]. However, treatment time and cost will be high in patients with grade ≥ 3 neutropenia/ leukopenia despite the use of G-CSF. In the current clini- cal practice, risk assessment, control, and prevention of life-threatening infection or febrile neutropenia, are not standardized. Therefore, minimizing HT is critical when adopting more intense chemotherapy regimens for cervi- cal cancer, and HT research should be strengthened. Previous research has found statistically strong correla- tions between AMC and ANC during chemotherapy [13– 18]. Kondo  et al. showed that AMC < 150/microl after six to eight days of advanced lung cancer chemotherapy could be a predictor of grade 3 or higher neutropenia at three- or four-week intervals [13]. Subsequently, Oshita F et al. compared a group of 60 patients with unresectable lung cancer who were randomly assigned to prophylac- tic G-CSF administration when monocytopenia appeared (group A) or G-CSF administration when neutropenia (< 1,000/microl) or leukopenia (< 2000/microl) appeared Fig. 5 Receiver operating characteristic (ROC) curves for any after chemotherapy (group B) [14]. Their results indicated grade ≥ 3 hematologic toxicity as a function of TPB_V20 that prophylactic G-CSF administration can considerably shorten the duration (1.4 ± 1.7  days vs. 2.9 ± 1.9  days, P = 0.004) and frequency (48% vs. 83%, P = 0.002) of 83.1% (95% CI 77.3%–87.7%) and 64.1% (95% CI 56.7%– grade 3 neutropenia [14]. Furthermore, in another study 70.8%), respectively. of 75 patients with advanced lung cancer undergoing chemotherapy, the number of days that elapsed between Discussion the first day of chemotherapy and the median AMC nadir Acute hematological toxicity (HT) is prevalent in cervical was shorter than that for AMC nadir (6 days vs. 12 days, cancer patients who receive CCRT, especially grade ≥ 3 P < 0.001); AMC at the nadir of 100/μL predicted an ANC HT, which may result in lower CCRT  doses or termina- at the nadir of < 1000/μL with a sensitivity of 83% and a tion  of  CCRT  altogether, affecting  therapeutic  efficacy specificity of 56% [15]. Similar results were reported in [5]. To our knowledge, this is the first report to explore another study, which found that the changing trend of the predictive value of AMC in cervical cancer patients AMC was the same as that of ANC. The initial decrease / undergoing  CCRT. We observed the AMC trend corre- reaching the nadir / final increase days of AMC were sig - sponded to the WBC/ANC during CCRT. The decrease nificantly less than those of ANC [16]. Two more studies and increase of AMC occurred before the ANC/WBC, found a correlation between ANC and AMC in patients and there was a significant correlation between the nadir receiving chemotherapy [17, 18]. of AMC and the severity of neutropenia/leukopenia. Fur- In this retrospective  study, we  evaluated the relation- thermore, the findings in this study revealed quantifiable ship between AMC and ANC/WBC, as well as the prog- evidence of an association between TPB_V20 and acute nostic value of AMC for acute leukopenia/neutropenia grade ≥ 3 HT. in cervical cancer patients undergoing CCRT. The results Multiple studies have established that prolonging the revealed that AMC decreased and increased before ANC treatment time has a negative impact on disease-specific and WBC, and that the changing tendency of AMC had survival in cervical cancer patients who have undergone certain predictive  value to the changing trend of WBC CCRT [10–12]. However, treatment time was mainly and ANC. The nadir of AMC was also found to be posi - prolonged due to the acute HT, especially in patients tively correlated with the nadir of WBC/ANC. Dur- with grade ≥ 3 neutropenia/leukopenia. These patients ing hematopoiesis, both neutrophils and monocytes are more likely to develop life-threatening infections or are differentiated from the granulocyte–macrophage febrile neutropenia, which could lead to a reduction in colony-forming cells, providing a good explanation for CCRT doses or termination of CCRT  altogether, affect - a positive correlation between AMC and ANC nadirs ing  the  therapeutic  efficacy. According to the ASCO during CCRT. Therefore, based on the findings of previ - recommendation, granulocyte colony-stimulating fac- ous research and this study, the increase or decrease in tor (G-CSF) can be used to prevent febrile neutropenia AMC can be used as an effective predictor for the timing Xiang  et al. Radiation Oncology (2022) 17:48 Page 9 of 11 and severity of the ANC/WBC nadirs and prophylactic into three subsites: lumbosacral spine, lower pelvis, and G-CSF administration. ilium, and the importance of these particular regions Additionally, all the blood  cell  counts of patients were was stated [8, 21, 25]. However, in our study, all exter- reduced to varying degrees during the CCRT. The WBC, nal contours of the bones within the PTV coverage were ANC, HGB, AMC, and PLT counts decreased by 64.72%, delineated as a proxy for the TPB to ensure repeatability 64.86%, 16.00%, 50.00%, and 53.44%, respectively. The and to avoid multiple collinearities in the multivariate percentage of patients with grade 3 or grade 4 neutrope- analysis. Our results are consistent with previous stud- nia, leukopenia, thrombocytopenia, and anemia during ies, which found that patients with bigger volumes of TPB CCRT was 52.17%, 30.43%, 6.52%, and 22.83%, respec- who received low-dose radiation had higher rates of HT tively. Overall, 111 patients (60.33%) experienced grade (grade ≥ 3) [20, 28]. Patients who received TPB_V20 ≥ 71% 3+ HT. We found that white blood cell and neutrophil were more likely to develop grade ≥ 3 HT (84.1% vs. 38.5%, counts declined significantly in most patients during P < 0.001), with specificity and sensitivity threshold of CCRT. The current treatment option for stage IB-IVA 78.1% and 71.2%, respectively. The association with the cervical cancer is weekly cisplatin with radiotherapy. low-dose dosimetric parameter (TPB_V20) was consistent However, different results were obtained in various stud - with the known radiosensitivity of bone marrow. ies. For example, according to a meta-analysis by Petrelli This study has several limitations. First, this was a F et al., platinum-based doublet chemotherapy combined single-center retrospective study with a small number with concurrent radiotherapy can improve the overall of patients, which may have resulted in selection bias. survival and disease-free survival compared to weekly Furthermore, the dosage and duration of G-CSF treat- cisplatin with radiotherapy. Nonetheless, severe HT was ment differed with the conditions of patients, which may largely underreported in the reviewed publications [19]. have affected on the changing trend of AMC, ANC, and In our study, weekly cisplatin and weekly carboplatin WBC. Finally, we contoured the external contours of the were considerably more effective than the TP regimen in bones as opposed to the actual proliferating active bone. reducing ≥ 3 HT (58.6% vs. 45.2% vs. 76.2%). Therefore, Despite the aforementioned limitations, the present it is critical to identify the optimum chemotherapy regi- study highlights the prognostic efficacy of dosimetric mens for individual patients in order to reduce the chem- parameters and AMC for HT in cervical cancer patients otherapy-related HT. undergoing CCRT. Several studies had analyzed the relationship between pelvic dosimetry parameters and HT in patients under- Conclusion going pelvic radiotherapy with respect to radiation doses. The changing trend of AMC can be used as an effective For example, Mell et  al. analyzed 37 cervical cancer predictor for the timing and severity of the ANC/WBC patients who received CCRT and found that the risk of nadirs and prophylactic G-CSF administration. Fur- developing grade 2 or higher leukopenia and neutropenia thermore, according to the multivariate logistic regres- increased by a factor (odds ratio) of 2.09 if the TPB_V10 sion analysis, the chemotherapy  regimen and TPB_V20 exceeds 90% [9]. According to Rose et  al., HT increases were independent  risk factors for the development of as the total pelvic bone volume irradiated increases, grade ≥ 3 HT. Maintaining TPB_V20 < 71% and selecting and efforts to keep TPB_V10 < 95% and TPB_V20 < 76% single-agent cisplatin or carboplatin could significantly may help avoid grade 3+ leukopenia [20]. Additionally, a reduce grade ≥ 3 HT in cervical cancer patients under- recent study demonstrated that lower pelvis (V5 > 95% or going CCRT. However, the predictive value of dosimet- V20 > 45%), TPB_V20 ≥ 65%, and the mean dose of iliac ric parameters and AMC for acute HT requires further crests > 31  Gy were most significantly correlated with investigations. grade 4 HT [8]. Wan et  al. demonstrated that lumbosa- cral spine V40 was most significantly correlated with grade ≥ 2 HT in rectal cancer patients, and they recom- Abbreviations VMAT: Volumetric-modulated arc therapy; CCRT : Concurrent chemoradio- mended dose constraints to the lumbosacral spine to be therapy; HT: Hematological toxicity; AMC: Absolute monocyte count; ANC: V40 < 60% [21]. Franco et  al. found that a higher TPB_ Absolute neutrophil count; WBC: White blood cells; IMRT: Intensity-modulated V20 was associated with lower WBC nadir in anal can- radiation therapy; TOMO: Helical tomography radiotherapy; 3D-CRT : Conven- tional three-dimensional conformal radiotherapy; OARs: Organs at risk; TPB: cer patients, and that patients with lumbosacral spine Total pelvic bones; Q1: 25Th percentile; Q3: 75Th percentile; SD: Standard V40 < 41% may reduce grade 3 + HT. In summary, no deviation; G-CSF: Granulocyte colony-stimulating factor. optimal bone marrow dose/volume constraints standard Acknowledgements has been proposed until now. Not applicable. In several studies, the external contour of all the pelvis bones was delineated as TPB. The TPB was then divided Xiang et al. Radiation Oncology (2022) 17:48 Page 10 of 11 Authors’ contributions modulated radiation therapy for patients with cervical cancer? Front NL and XX was responsible for the primary concept and the design of the Oncol. 2020. https:// doi. org/ 10. 3389/ fonc. 2020. 554241. study; XX, ZD, and QZ performed the data capture and analysis; XX, ZD, and 8. Kumar T, Schernberg A, Busato F, et al. 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Journal

Radiation OncologySpringer Journals

Published: Mar 5, 2022

Keywords: Bone marrow; Acute hematological toxicity; Cervical cancer; Volumetric-modulated arc therapy; Absolute monocyte count

References