Hematological parameters during concurrent chemoradiotherapy as potential prognosticators in patients with stage IIB cervical cancer

Abstract

We hypothesized that hemoglobin levels, absolute neutrophil count, and absolute lymphocyte count were associated with radiotherapy response and cancer progression and that they might reflect tumor repopulation during concurrent chemoradiotherapy. This study aimed to investigate these hematological parameters as prognosticators of cervical cancer. We analyzed 105 stage IIB cervical cancer patients treated with concurrent chemoradiotherapy, using log-rank tests and multivariate analyses. Hazard ratios were calculated weekly to evaluate changes in hemoglobin, absolute neutrophil count, and absolute lymphocyte count that were associated with disease-specific survival. Patients were categorized into the high hematological risk (patients with low hemoglobin plus high absolute neutrophil count and/or low absolute lymphocyte count) and the low hematological risk (others) groups according to the median cutoff values. During the second week of concurrent chemoradiotherapy, hematological factors were significantly associated with survival. In multivariate analysis, hematological risk was independently associated with disease-specific survival and progression-free survival. The 5-year disease-specific survival and progression-free survival rates in the high hematological risk group were significantly lower compared with those in the low hematological risk group (81.6% vs 92.6%, p = 0.0297; 73.7% vs 89.3%, p = 0.0163, respectively). During the second week of concurrent chemoradiotherapy, the hematological parameters could predict treatment outcome in stage IIB cervical cancer.

Keywords

Cervical cancer chemoradiotherapy hemoglobin neutrophil lymphocyte

Introduction

Radioresistance due to tumor repopulation during fractionated radiotherapy (RT) could lead to treatment failure.^1,2 Thus, the degree of tumor activity and RT sensitivity at repopulation onset time might be critical for predicting treatment outcomes. Therefore, for patients with cervical cancer, it would be beneficial to establish treatment strategies to mitigate repopulation during concurrent chemoradiotherapy (CCRT), which begins at the third week after RT initiation.³ However, to predict the effect of tumor repopulation and radioresistance on survival, specific markers of CCRT treatment response are needed.

Cancer-mediated induction of inflammatory and immunosuppressive factors, leading to an increase in absolute neutrophil count (ANC) and a decrease in absolute lymphocyte count (ALC), has been associated with prognosis in advanced cancers.^4–8 In addition, the neutrophil-to-lymphocyte ratio (NLR) is a prognosticator in various cancers including cervical cancer.⁹ Furthermore, in patients with cervical cancer undergoing RT, hemoglobin (Hb) levels reflected treatment outcome considering tumor hypoxia and neovascularization.^8,10–12 Therefore, we hypothesized that hematological parameters such as Hb levels, ANC, and ALC might reflect tumor activity or treatment response during CCRT and, therefore, might be useful prognostic factors in patients undergoing CCRT. In this study, we evaluated the usefulness of these hematological parameters as prognosticators of disease-specific survival (DSS) and progression-free survival (PFS) in patients with stage IIB cervical cancer undergoing pelvic CCRT.

Materials and methods

Study population

This study was approved by the Institutional Review Board. The need for informed consent was waived because of the retrospective nature of the study. All procedures involving human subjects were conducted in accordance with the principles of the Declaration of Helsinki. A total of 105 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical cancer, who underwent weekly cisplatin-based CCRT at our hospital between 2001 and 2014, were included in this study. Two patients who had Grave’s disease and chronic hepatitis B virus before treatment were excluded from this analysis because hematological parameters might be influenced by autoimmune disease or acute/chronic infection. Before undergoing CCRT, all patients underwent biopsy to determine tumor histology, physical examination, complete blood count, and imaging studies, including chest radiography, pelvic magnetic resonance imaging (MRI), and/or positron emission tomography–computed tomography. If patients showed bladder or rectal invasion on MRI, cystoscopy or sigmoidoscopy was performed; such patients were excluded from this study. All patients underwent a combination of external beam RT (EBRT) and high-dose-rate intracavitary brachytherapy (HDR BT). Cisplatin was administered weekly at 40–70 mg/m² for 4–6 weeks concurrent with RT. Patients were followed up every 3 months for the first year and every 6 months thereafter. The median follow-up period was 58 months (range = 15–136 months). During follow-up, progression was evaluated using a physical examination, Pap smear, and imaging, including computed tomography, MRI, and/or positron emission tomography–computed tomography. Patients showing progressive disease underwent chemotherapy, RT, or conservative care. Endpoints of this study included DSS and PFS.

Treatments and measurements

Whole pelvis EBRT—consisting of 45 Gy administered as 1.8 Gy per day in 25 fractions—was delivered using 10–15 MV photons in four fields. For 30 of 79 patients, patients with a maximum tumor size ⩾4 cm, partial hyperfractionations, including 18 Gy (or 15 Gy) delivered in 12 fractions (or 10 fractions), twice daily during the third week, were administered to reduce overall treatment time (OTT) and the time to completion of CCRT including HDR BT.¹³ The conventional whole-pelvis EBRT dose regimen was 45 Gy in 25 fractions; however, some patients underwent treatment with a modified regimen (45.6 Gy in 27 fractions or 45 Gy in 27 fractions). Boost irradiations of 5.4–10 Gy in three to five fractions were administered to the parametrium and pelvic lymph nodes (LN) following whole-pelvis EBRT. In 91 patients, central shielding using a midline block (MLB) was performed after administration of 36–52.4 Gy, depending on the reduction in tumor size as estimated by a physical examination with or without pelvic MRI. The EBRT dose delivered to the central pelvis was defined as the central pelvic dose (CPD). The inferior and superior borders of the 4-cm MLB were from the lower radiation field and tandem insertion site, respectively. Two-dimensional HDR BT (iridium 192 (¹⁹²Ir), Microselectron, Nucletron) was performed biweekly after patients underwent pelvic EBRT for 3–6 weeks. For HDR BT, 5–30 Gy in one to seven fractions (4–7 Gy per fraction) were administered to point A, as recommended by the International Commission on Radiation Units report 38. Point A was modified by 1 or 1.5 cm in patients with a small uterus. For two-dimensional HDR BT simulation planning, equivalent doses were planned for the bladder and rectal points (α/β ratio = 3) at <80 Gy and 70 Gy, in 2-Gy fractions, respectively. Total dose (TD) was defined as the sum of EBRT EQD2 (equivalent dose in 2-Gy fractions using an α/β ratio of 10) at the central pelvis and HDR BT EQD2 at point A. The HDR BT ratio was the ratio of the HDR BT dose to the TD.

Baseline Hb, ANC, and ALC were acquired before the start of CCRT and every week thereafter for 4 weeks. Nine patients underwent transfusion of packed red blood cells due to baseline Hb ⩽8 g/dL while two patients underwent transfusions due to Hb during pelvic CCRT ⩽8 g/dL.

From baseline to the fourth week, we calculated the hazard ratios (HRs) associated with weekly changes in Hb, ANC, and ALC to determine the most relevant time point for associations with DSS. The median values for each factor were used as cutoff values to stratify patients into the high hematological risk (HHR) and low hematological risk (LHR) groups. HHR was defined as a low Hb plus high ANC and/or low ALC. LHR was defined as a high Hb with high ANC and/or low ALC, or a high/low Hb plus both low ANC and high ALC.

Statistical analyses

We compared treatment outcomes, TD, CPD, and the HDR BT ratio between the HHR and LHR groups. Univariate analyses were performed for age, pathology, tumor size, pelvic LN status, OTT, TD, CPD, HDR BT ratio, and hematological risk. CPD and HDR BT ratio were grouped according to the median values. Age and variables having p values <0.1 in the univariate analysis were included in the multivariate analysis. In addition, variables and treatment results between the groups were compared according to the median HDR BT ratio (below and above the median value).

All analyses were performed using R software version 3.2.3 (R foundation for Statistical Computing, https://www.r-project.org/). We used the templot2 function of the rms package to plot correlations between HRs and hematological parameters. Fisher’s exact test or the χ² test was used to compare categorical variables between the groups. The Mann–Whitney U test was used to compare continuous data between the groups. Survival differences between the groups were compared using the Kaplan–Meier method and log-rank test. The enter method of the Cox proportional hazards model was used for multivariate analysis. The p value <0.05 was considered statistically significant.

Results

Patient characteristics

Patient characteristics and all hematological values from baseline to the end of treatment are shown in Table 1. All hematological variables tended to decrease as CCRT progressed. The degree of decline from baseline was the lowest for Hb and the highest for ALC. Figure 1 displays a strong association between DSS and the hematological parameters during the second week of CCRT.

Table 1.

Patient characteristics.

Pretreatment factors	N = 105	Treatment factors	N = 105
Age (years)		OTT (weeks)
>65	40 (38.1%)	>8	39 (37.1%)
⩽65	65 (61.9%)	⩽8	66 (62.9%)
Pathology		Total dose (EQD2, Gy)
SCC	99 (94.3%)	>70	50 (47.6%)
Adeno subtype	6 (5.7%)	⩽70	55 (52.4%)
Tumor size (cm)		Central pelvis dose (EQD2, Gy)
>5	41 (39%)	>40.7	52 (49.5%)
⩽5	64 (61%)	⩽40.7	53 (50.5%)
Pelvic lymph node		HDR BT ratio
Involved	72 (68.6%)	>0.434	52 (49.5%)
Not involved	33 (31.4%)	⩽0.434	53 (50.5%)
Hematological factors	N	Median	Range
Hb (g/dL)
Baseline	105	11.8	3.9–14.8
First week	103	11.4	8.4–13.7
Second week	104	11.1	6.7–13.8
Third week	102	11	5.9–13.5
Fourth week	104	10.5	8.0–12.8
ANC (cells/µL)
Baseline	104	4476	2024–14,588
First week	95	4081	1524–12,892
Second week	98	3764	1716–10,301
Third week	101	3221	1307–9960
Fourth week	103	2617	746–9957
ALC (cells/µL)
Baseline	104	1233	252–2859
First week	95	773	347–1795
Second week	98	500	251–1170
Third week	101	336	90–826
Fourth week	103	280	121–660
NLR	104	3.59	1.03–30.3

OTT: overall treatment time; SCC: squamous cell carcinoma; EQD2: equivalent dose in 2-Gy fractions using an α/β ratio of 10; HDR BT ratio: the ratio of high-dose-rate intracavitary brachytherapy dose to total dose; Hb: hemoglobin; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; NLR: neutrophil-to-lymphocyte ratio before treatment.

Figure 1.

The hazard ratios of disease-specific survival according to changes in hemoglobin, absolute neutrophil count, and absolute lymphocyte count from baseline to the fourth week since the start of concurrent chemoradiotherapy.

Treatment outcomes

The 5-year DSS and 5-year PFS rates in all patients were 86.7% and 81.8%, respectively. In all, 20 of 105 patients had progression, 14 of whom died due to the disease (Table 2). Cervical recurrence without distant metastasis occurred in three patients. Progression of residual cervical tumor plus distant metastasis occurred in four patients. A total of 13 patients had distant metastasis without local progression. Metastatic sites included the para-aortic LN (eight cases), lungs (eight cases), bone (three cases), peritoneum (three cases), liver (two cases), brain (one case), adrenal glands (one case), supraclavicular LN (one case), and muscle (one case). In all, 12 of 20 patients who had disease progression underwent more than three cycles of chemotherapy (cisplatin plus paclitaxel), whereas the remaining eight could not tolerate chemotherapy or were treated conservatively.

Table 2.

Comparison between the hematological risk groups according to hemoglobin, absolute neutrophil count, and absolute lymphocyte count at the second week since the start of concurrent chemoradiotherapy.

	HHR	LHR
ANC and ALC second week (cells/µL)	ANC > 3764 and/or ALC ⩽ 500	ANC > 3764 and/or ALC ⩽ 500	Both ANC ⩽ 3764 and ALC > 500		HHR versus LHR
Hb second week (g/dL)	⩽11.1	>11.1	⩽11.1	>11.1
	n = 46	n = 39	n = 5	n = 8	p
Disease-specific death^a	10	3	0	0	0.043
Progression^b	13	5	0	0	0.034
Central pelvis dose (EQD2, Gy)	43.3 ± 7.0	41.6 ± 6.0			0.188
Total dose (EQD2, Gy)	70.6 ± 4.1	71.4 ± 5.5			0.459
HDR BT ratio	0.386 ± 0.1	0.417 ± 0.08			0.081
5-year disease-specific survival	81.6%	92.6%			0.0297
5-year progression-free survival	73.7%	89.3%			0.0163

EQD2: equivalent dose in 2-Gy fractions using an α/β ratio of 10; HDR BT ratio: the ratio of high-dose-rate intracavitary brachytherapy dose to total dose; Hb: hemoglobin; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; HHR: high hematological risk; LHR: low hematological risk.

a,b

The seven patients who did not have data available for Hb, ANC, or ALC during the second week of concurrent chemoradiotherapy included two patients who showed disease progressions and one patient who died.

Comparison of hematological parameters between the high- and low-risk groups

Comparisons of hematological parameters measured 2 weeks after CCRT initiation for the HHR and LHR groups are shown in Table 2. Patients in the HHR group had poorer DSS and PFS compared with those in the LHR group (p = 0.043 (DSS) and 0.034 (PFS)). The CPD was higher in the HHR group than in the LHR group (p = 0.188). The HDR BT ratio was lower in the HHR group than in the LHR group (p = 0.081).

Comparisons of survival rates between the high- and low-risk groups

The 5-year DSS and PFS rates were significantly lower in the HHR group than in the LHR group (Table 2; DSS: p = 0.0297; PFS: p = 0.0163).

Multivariate analyses of parameters associated with survival

Multivariate analyses of parameters associated with survival are shown in Table 3. HHR was independently associated with DSS and PFS (DSS: HR p = 0.043, adjusted HR (AHR) p = 0.07; PFS: HR p = 0.024, AHR p = 0.065). A high HDR BT ratio (>0.434) was independently associated with DSS and PFS (DSS: AHR p = 0.053 and PFS: AHR p = 0.058).

Table 3.

Univariate and multivariate analyses for disease-specific survival and progression-free survival.

Factors	Disease-specific survival				Progression-free survival
Factors	HR (95% CI)	p	AHR (95% CI)	p	HR (95% CI)	p	AHR (95% CI)	p
Age >65 years	2.76 (0.95–8.02)	0.062	2.37 (0.75–7.47)	0.14	1.62 (0.66–3.99)	0.294	1.35 (0.5–3.64)	0.507
Adeno subtype	3.19 (0.7–14.36)	0.13			1.43 (0.41–4.99)	0.578
Tumor size >5 cm	0.9 (0.3–2.7)	0.858			1.33 (0.55–3.21)	0.526
Pelvic LN (+)	0.93 (0.29–2.97)	0.9			0.96 (0.37–2.51)	0.939
OTT >8 weeks	0.89 (0.28–2.87)	0.845			0.79 (0.3–2.06)	0.628
TD >70 EQD2	1.83 (0.63–5.3)	0.226			2.39 (0.95–6)	0.064	1.88 (0.67–5.27)	0.227
CPD >40.7 EQD2	1.51 (0.52–4.45)	0.45			1.85 (0.74–4.58)	0.186
NLR >3.59	1.45 (0.47–4.43)	0.518			0.95 (0.38–2.39)	0.909
HDR BT ratio >0.434	0.17 (0.08–0.9)	0.033	0.26 (0.07–1.02)	0.053	0.26 (0.13–0.9)	0.01	0.31 (0.09–1.04)	0.058
HHR	3.78 (1.04–13.76)	0.043	3.31 (0.91–12.1)	0.07	3.3 (1.17–9.25)	0.024	2.68 (0.94–7.6)	0.065

HR: hazard ratio; AHR: adjusted HR; LN: lymph node; OTT: overall treatment time; EQD2: equivalent dose in 2-Gy fractions using an α/β ratio of 10; TD: total dose; CPD: central pelvic dose; NLR: neutrophil-to-lymphocyte ratio before treatment; HDR BT ratio: the ratio of high-dose-rate intracavitary brachytherapy dose to total dose; HHR: high hematological risk; CI: confidence interval.

Analysis of a combination of hematological risk and HDR BT ratio on survival

Differences between the LHR and HHR groups according to the HDR BT ratio are shown in Table 4 and Figure 2. In the HHR group, those with a HDR BT ratio ⩽0.434 had significantly poorer 5-year DSS and 5-year PFS rates compared to those with a HDR BT ratio >0.434 (DSS p = 0.005; PFS p = 0.003). By contrast, in the LHR group, there were no differences in survival rates according to the HDR BT ratio (DSS p = 0.879; PFS p = 0.972).

Table 4.

Comparisons between the hematological risk groups depending on the high-dose-rate intracavitary brachytherapy dose to total dose ratio.

Factors	High hematological risk			Low hematological risk
	HDR BT ratio ⩽ 0.434	HDR BT ratio > 0.434	p	HDR BT ratio ⩽ 0.434	HDR BT ratio > 0.434	p
	N = 27	N = 19	p	N = 21	N = 31	p
Age (years)			0.153			0.047
>65	14 (51.9%)	5 (26.3%)		12 (57.1%)	8 (25.8%)
⩽65	13 (48.1%)	14 (73.7%)		9 (42.9%)	23 (74.2%)
TD (EQD2)			0.397			0.674
>70	16 (59.3%)	8 (42.1%)		11 (52.4%)	13 (41.9%)
⩽70	11 (40.7%)	11 (57.9%)		10 (47.6%)	18 (58.1%)
CPD (EQD2)			<0.001			0.001
>40.7	23 (85.2%)	1 (5.3%)		17 (81%)	9 (29%)
⩽40.7	4 (14.8%)	18 (94.7%)		4 (19%)	22 (71%)
Progression			0.01			1
Yes	12 (44.4%)	1 (5.3%)		2 (9.5%)	3 (9.7%)
No	15 (55.6%)	18 (94.7%)		19 (90.5%)	28 (90.3%)
LP			0.632			1
Yes	2 (7.4%)	0 (0%)		0 (0%)	0 (0%)
No	25 (92.6%)	19 (100%)		21 (100%)	31 (100%)
DM			0.094			1
Yes	8 (29.6%)	1 (5.3%)		1 (4.8%)	2 (6.5%)
No	19 (70.4%)	18 (94.7%)		20 (95.2%)	29 (93.5%)
LP + DM			0.632			1
Yes	2 (7.4%)	0 (0%)		1 (4.8%)	1 (3.2%)
No	25 (92.6%)	19 (100%)		20 (95.2%)	30 (96.8%)
DSD			0.056			1
Yes	9 (33.3%)	1 (5.3%)		1 (4.8%)	2 (6.5%)
No	18 (66.7%)	18 (94.7%)		20 (95.2%)	29 (93.5%)
5-year DSS	70.9%	94.7%	0.005	91.7%	92.4%	0.879
5-year PFS	59.3%	94.7%	0.003	86.6%	90.2%	0.972

HDR BT ratio: the ratio of high-dose-rate intracavitary brachytherapy dose to total dose; EQD2: equivalent dose in 2-Gy fractions using an α/β ratio of 10; TD: total dose; CPD: central pelvic dose; LP: local progression; DM: distant metastasis; DSD: disease-specific death; DSS: disease-specific survival; PFS: progression-free survival.

Figure 2.

Kaplan–Meier plots for (a) disease-specific survival and (b) progression-free survival according to the hematological risk and HDR BT ratio.

Discussion

In this study, the hematological values 2 weeks after CCRT initiation were most reflective of survival outcomes. In addition, patients in the HHR group, according to Hb levels, ANC, and ALC at that time, had significantly poorer survival compared to those in the LHR group. Furthermore, the risk was especially pronounced in those with a low HDR BT ratio, whereas, conversely, the HDR BT ratio did not affect outcome in those in the LHR group.

Hematological risk grouping intended to reflect Hb, ANC, and ALC second week during CCRT synthetically. They were divided into two groups of low and high according to their median value without consideration of the sensitivity and specificity due to the following reasons. First, median cut was more general and robust method than determining cutoff from receiver operation characteristics curve. Second, median cut was favorable to secure proper numbers for HHR group, which otherwise would have had too small of a sample size for analysis of the three factors.

Previous studies have reported that Hb during RT for cervical cancer was associated with treatment outcome,^10,14 and that this might be due to hypoxia and neovascularization because of decreased Hb levels.^11,12 This theory would support the consistent correlation between low Hb levels and poor survival in this study. In particular, low Hb levels during the second treatment week caused an abrupt increase in the HR, implying that preventing tumor cell activity at this point might be paramount for better disease control. In this study, increases in ANC were most apparent at week 2, and a high ANC from week 2 onward was associated with an increased mortality risk. Previous preclinical and clinical studies have shown that cancer activation could be related to an increase in the ANC.^15,16 Severe lymphopenia is commonly observed in advanced cancers;⁷ therefore, similarity between ANC and ALC levels might be expected. However, ALC was not similar to ANC in the third and fourth weeks. This might be because ALC was rapidly reduced by CCRT because lymphocytes are more sensitive to regional-fractionated RT compared with neutrophils.¹⁷ These data suggest that tumor progression during the second week of CCRT might be associated with tumor repopulation and treatment outcome. This would be concordant with the results of previous studies that showed rapid proliferation of cervical cancer occurring 19 days after RT treatment initiation.³ In this study, the slightly shorter repopulation time (14 days) might be due to the inclusion of chemotherapy in CCRT, which might also affect tumor repopulation.¹⁸

In this study, based on data from week 2, we considered that Hb enhanced RT through an improvement of ability to carry oxygen,¹¹ and ANC or ALC likely reflected the degree of tumor extent. Chemokines, such as granulocyte-colony stimulating factor or angiotensin II, secreted by tumor cells, increased neutrophil production from the bone marrow or spleen,⁴ while immunosuppressive factors, such as tumor growth factor β, interleukin-10, or reactive oxygen species, derived from the tumor or tumor microenvironment decreased lymphocyte production.⁵ In addition, the findings of this study are consistent with the information given in a review article, suggesting that radioresistance and recurrence occur through comprehensive interactions between hypoxia, inflammation, and immunomodulation in the tumor microenvironment after RT.⁸ Patients in the HHR group had higher mean CPD and inferior survival compared with patients in the LHR group. This suggests that Hb levels may play the most pertinent role in active tumor repopulation. In addition, the relative HDR BT dose determined survival within the HHR group, whereas in the LHR group, the relative HDR BT ratio did not affect survival. This suggested that increasing the relative HDR BT dose might compensate for uncontrolled tumor repopulation early during CCRT. In Japan, studies investigating the brachytherapy pattern and low-dose schedules have suggested that increasing the HDR BT ratio had a more significant clinical impact compared to dose escalation.^19–21 This study suggests that a TD of 70 EQD2 during HDR BT could suppress tumor repopulation and improve survival in patients with a HHR.

This study had a significant difference compared with past studies about Hb, ANC, and ALC in cervical cancer. Weekly changes in ANC and ALC during CCRT in this study were relevant to treatment response while the role of baseline ANC, ALC, and NLR in previous studies was to supplement staging by reflecting tumor extent.^6,7,9 That DSS was not associated with NLR as well as baseline ANC and ALC in these data based on a single stage supported this point. The prognostic impact of weekly change in Hb as CCRT progressed was not investigated in past studies, although it was well known that Hb during RT or CCRT was associated with prognosis in cervical cancer.^10,14 Our results suggested the second week was most relevant to treatment outcome among ANC, ALC, and Hb from baseline to fourth week. This difference implied that HHR patients achieve survival benefit through a few modifications of current treatment.

Decreasing OTT during CCRT had less of an effect on inhibiting tumor repopulation compared with decreasing OTT during RT alone;²² therefore, rather than shortening OTT, risk stratification during CCRT would be a better strategy for overcoming radioresistance. Two facts suggest that those with a HHR would benefit from HDR BT: (1) that patients in the HHR group had a poorer response compared with those in the LHR group and (2) that a high HDR BT ratio within the HHR group could improve treatment response. In contrast, those with a LHR, who did not show any additional benefit of increased HDR BT ratios, would be better treated using EBRT. In addition, a recent study showed that there were no survival benefits of anemia correction by blood transfusion in patients with cervical cancer undergoing RT or CCRT.²³ This would seem contradictory; however, this study suggests that overcoming anemia in the second week of treatment, which we believe represents the point of tumor repopulation initiation, might show a significant clinical benefit. Further studies are needed to evaluate this hypothesis.

This study has two limitations. First, there were no direct data to support an association between changes in hematological variables and tumor repopulation. Pelvic MRI at regular intervals during and after CCRT might be useful for direct correlations between these factors because that would allow us to estimate tumor control rate based on the change in tumor volume according to RT dose. Second, the subgroup analysis was conducted retrospectively in a small number of patients, and the statistical power of the analysis was not determined. Nevertheless, this is the first study to suggest and investigate an association between tumor proliferation during CCRT and clinical outcome according to hematological parameters.

In conclusion, monitoring Hb, ANC, and ALC during the second week of CCRT might reflect CCRT response and survival in patients with FIGO stage IIB cervical cancer. During the second week of CCRT, patients with a HHR had significantly poorer DSS and PFS compared to those with a LHR. These findings present a potential risk stratification protocol relevant to tumor repopulation that could facilitate better patient selection and treatment planning, such as the decision for HDR BT or EBRT. Future well-designed large prospective studies are warranted to validate these findings and determine the benefit of blood transfusion to treat anemia during CCRT.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Informed consent

The need for informed consent was waived because of the retrospective nature of the study.

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