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Abstract

Background

To evaluate the prognostic value of chemotherapy-induced neutropenia (CIN) in epithelial ovarian carcinoma (EOC) treated with primary surgery followed by platinum-based chemotherapy.

Methods

The records of primary EOC treated between Jan 1^st 2002 and Dec 31^st 2016 were reviewed according to the including and excluding criteria. CIN was defined as absolute neutrophil count (ANC) after chemotherapy <2.0 × 10⁹/L. Patients with CIN were further divided into mild and severe CIN (ANC <1.0 × 10⁹/L), early-onset and late-onset (>3 cycles) CIN. Clinical characteristic was compared by chi-square test. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan–Meier analysis, univariate and multivariate Cox regression models.

Results

Among 735 EOC patients enrolled, no significant differences of the prognosis were found between patients with and without CIN, early and late CIN, mild and severe CIN. However, Kaplan–Meier curve (65 vs 42 months for CIN vs non-CIN, P = .007) and Cox regression analysis (HR 1.499, 95% CI 1.142-1.966; P = .004) both revealed that CIN was significantly related with better OS in advanced EOC patients, but not for PFS. So, subgroup analysis was further conducted and date suggested that CIN was an independent predictor of better survival in advanced EOC with suboptimal surgery (PFS: 18 vs 14 months, P = .013, HR 1.526, 95% CI 1.072-2.171, P = .019; OS: 37 vs 27 months, P = .013, HR 1.455, 95% CI 1.004-2.108; P = .048).

Conclusions

CIN might be used as an independent prognostic indicator of advanced EOC, especially for those patients with suboptimal surgery.

Keywords

chemotherapy-induced neutropenia platinum-based chemotherapy epithelial ovarian carcinoma prognostic factor cancer survival

Introduction

Epithelial ovarian carcinoma (EOC) is the most lethal of the gynecologic malignancies.^1,2 Comprehensive staging surgery or cytoreductive surgery followed by platinum-based chemotherapy remains the standard treatment for patients with EOC.^3,4 Despite the improvements in chemotherapeutic regimens, the 5-year survival rate for EOC is still only 30-39%.⁵ In addition, chemotherapy is always accompanied by various side effects. Among them, neutropenia is the most common adverse effect following chemotherapy.^6,7 Previous studies have reported that chemotherapy-induced neutropenia (CIN) may be used for prediction of favorable prognosis in various cancers.^8-17 For instance, Jang et al. reported that the onset timing of CIN was an independent prognostic factor for progression-free survival and overall survival in patients with stage IV non-small cell lung cancer.¹⁸ However, the significance of CIN in the prognosis of EOC is still controversial. Tewari and Rocconi et al. reported severe CIN had better prognoses compared with non-severe CIN in patients with primary advanced ovarian and peritoneal cancer.^7,19 In contrast, Kim et al. demonstrated that CIN and the prognosis of EOC had no relevance.²⁰ Therefore, the aim of the present study was to evaluate the prognostic value of CIN in EOC treated with primary surgery followed by platinum-based chemotherapy.

Materials and Methods

Study Design

This was a retrospective cohort study, and the study has de-identified all patient details to protect patient data confidentiality. The reporting of this study conforms to REMARK guidelines.²¹ The flow diagram was shown in supplementary figure S1. EOC patients at Women’s hospital, Zhejiang University School of Medicine, who met the following including criteria, were enrolled: 1) histological confirmed EOC; 2) patients underwent primary surgery including comprehensive staging surgery and cytoreductive surgery, followed by platinum-based chemotherapy (≥3 cycles); 3) available follow-up data of blood routine test, recurrence and death; 4) absolute neutrophil count (ANC) over 2.0 ×10⁹/L before first chemotherapy; 5) normal bone marrow function; 6) normally functioning liver and kidney; 7) Karnofsky performance status (KPS) ≥70 before treatment; 8) without targeted therapy or bio-therapy; and 9) without chemotherapy or radiotherapy within 1 year before treatment. The exclusion criteria were 1) lost follow-up; 2) second malignancies or multiple primary malignancies; and 3) colony stimulating factor (CSF) was used before CIN first appearance. The study was approved by the Ethical Committee of women’s hospital, Zhejiang University School of Medicine (IRB-20200236-R) on Aug 22^st 2020. Owing to the retrospective character and the difficulty of recalling all enrolled patients, informed consent was specifically waived by the ethics committee. FIGO stage I and II EOC was defined as early stage, while FIGO stage III and IV EOC was defined as advanced stage. Early stage EOC received comprehensive staging surgery, and advanced stage EOC underwent cytoreductive surgery. Type I EOC includes low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, malignant Brenner tumor, and clear cell carcinoma. Type II EOC includes high-grade serous carcinoma (moderately and poorly differentiated), malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma.²² Optimal and suboptimal surgery are defined as postoperative residual tumor after primary surgery <1 cm and ≥1 cm. Carboplatin (AUC = 5-6)/cisplatin (75 mg/m²)/nedaplatin (100 mg/m²) and paclitaxel (175 mg/m²) were administered intravenously at least 3 times with a gap of 3 weeks.

Data Collection

The records of EOC received primary surgery and chemotherapy between Jan 1^st 2002 and Dec 31^st 2016 were retrieved. The variables were acquired by electronic medical record system and telephone interview, including age, ascites, pathological stage, tumor residual, tumor classification (type I and type II), pathological type, CA125 level, time to start chemotherapy, chemotherapy resistance, blood tests, recurrence and survival information. Progression-free survival (PFS) and overall survival (OS) were defined as the primary study endpoints. PFS was defined as the time from the first surgery to disease progression, and OS represented the time duration between primary surgery and death or the date of latest follow-up. The latest follow-up date was December 31, 2019.

Assessment of CIN

Routine blood counts were taken routinely at the day before chemotherapy and every 3 days after chemotherapy during each cycle of chemotherapy. CIN grading based on absolute neutrophil count (ANC) were classified into 4 levels according to ruling of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Grade 1: 1.5 × 10⁹ ≤ ANC <2.0 × 10⁹/L, Grade 2: 1.0 × 10⁹ ≤ ANC <1.5 × 10⁹/L, Grade 3: .5 × 10⁹ ≤ ANC <1.0 × 10⁹/L and Grade 4: ANC <.5 × 10⁹/L, ANC ≥2.0 × 10⁹/L represents CIN absent. Grade 1 and 2 were defined as mild CIN, while grade 3 and 4 were severe CIN. Depending on the onset timing of CIN, patients were further divided into early-onset (≤3 cycles) and late-onset (>3 cycles) groups. Besides, mild CIN was further divided into early-onset mild CIN and late-onset mild CIN according to the onset time of CIN and severe CIN was classified in the same way as mild CIN.

Statistical Analysis

Clinical features were compared by chi-square test and Fisher’s exact test. PFS and OS were calculated by the Kaplan–Meier curves and compared by means of the log-rank test. Univariate and multivariate Cox proportional hazards regression models were applied for analyzing the prognostic factors of EOC. SPSS 26.0 statistical software was used for all the statistical analyses and an alpha level <.05 was considered statistically significant.

Results

The Clinical-Pathological Characteristics and Prognosis in EOC Patients

A total of 735 EOC patients were included in the present analysis. The median follow-up time was 66.5 months (range 8-216 months). The median age of the patients was 51 (16-79) years. Among 735 patients, 570 (77.5%) experienced CIN, including 405 (79.0%) early-onset and 165 (29.0%) late-onset, 237 (41.6%) mild and 333 (58.4%) severe CIN, 661 (90%) treated with carboplatin, 49 (6.6%) with cisplatin, and 25 (3.4%) with Nedaplatin. Less ascites, early stage, postoperative residual tumor smaller than 1 cm, type I ovarian carcinoma, non-serous carcinoma, lower preoperative CA125 level and chemotherapy sensitivity were significantly correlated with better prognosis of EOC, no matter in all 735 patients or in 661 patients treated by carboplatin (Table 1 and Supplementary Table S1). However, there was no significant difference for the prognosis between the patients with and without CIN, early and late CIN, mild and severe CIN (all P > .05) (Table 1 and Supplementary Table S1).

Table 1.

The Relationship Between Clinical-Pathological Characteristics and Prognosis of all EOC Patients (n = 735).

Variables		n	No recurrence	Recurrence	P	n	Survival	Death	P
Age (year)	<51	352	175 (51.8%)	177 (44.6%)	.052	345	216 (51.7%)	129 (42.0%)	.010
Age (year)	≥51	383	163 (48.2%)	220 (55.4%)	.052	380	202 (48.3%)	178 (58.0%)	.010
Ascites (ml)	≤50	343	205 (60.7%)	138 (34.8%)	.000	341	240 (57.4%)	101 (32.9%)	.000
Ascites (ml)	>50	392	133 (39.3%)	259 (65.2%)	.000	384	178 (42.6%)	206 (67.1%)	.000
Pathological grade	Early stage	282	234 (69.2%)	48 (12.1%)	.000	280	251 (60.0%)	29 (9.4%)	.000
Pathological grade	Advanced stage	453	104 (30.8%)	349 (87.9%)	.000	445	167 (40.0%)	278 (90.6%)	.000
Tumor residual (cm)	<1	583	324 (95.9%)	259 (65.2%)	.000	575	390 (93.3%)	185 (60.3%)	.000
Tumor residual (cm)	≥1	152	14 (4.1%)	138 (34.8%)	.000	150	28 (6.7%)	122 (39.7%)	.000
Surgical outcomes	Optimal	301	90 (86.5%)	211 (60.5%)	.000	295	139 (83.2%)	156 (56.1%)	.000
Surgical outcomes	Suboptimal	152	14 (13.5%)	138 (39.5%)	.000	150	28 (16.8%)	122 (43.9%)	.000
Tumor classification	Type I	167	127 (37.6%)	40 (10.1%)	.000	164	133 (31.8%)	31 (10.1%)	.000
Tumor classification	Type II	568	211 (62.4%)	357 (89.9%)	.000	561	285 (68.2%)	276 (89.9%)	.000
Pathological type	Serous	473	163 (48.2%)	310 (78.1%)	.000	466	234 (56.0%)	232 (75.6%)	.000
Pathological type	Non-serous	262	175 (51.8%)	87 (21.9%)	.000	259	184 (44.0%)	75 (24.4%)	.000
CA125 level (U/ml)	≤35	104	83 (27.1%)	21 (5.6%)	.000	103	88 (23.0%)	15 (5.2%)	.000
CA125 level (U/ml)	>35	574	223 (72.9%)	351 (94.4%)	.000	566	295 (77.0%)	271 (94.8%)	.000
Interval from surgery to first chemotherapy (day)	≤14	614	271 (80.2%)	343 (86.4%)	.023	605	340 (81.3%)	265 (86.3%)	.075
Interval from surgery to first chemotherapy (day)	>14	121	67 (19.8%)	54 (13.6%)	.023	120	78 (18.7%)	42 (13.7%)	.075
Drug resistance	No	614	338 (100%)	276 (69.5%)	.000	602	410 (98.1%)	195 (63.5%)	.000
Drug resistance	Yes	121	0 (.0%)	121 (30.5%)	.000	123	8 (1.9%)	112 (36.5%)	.000
CIN onset	No	165	78 (23.1%)	87 (21.9%)	.707	164	88 (21.1%)	76 (24.8%)	.239
CIN onset	Yes	570	260 (76.9%)	310 (78.1%)	.707	561	330 (78.9%)	231 (75.2%)	.239
Severity of CIN	Mild	237	113 (43.5%)	124 (40.0%)	.404	235	136 (41.2%)	99 (42.9%)	.698
Severity of CIN	Severe	333	147 (56.5%)	186 (60.0%)	.404	326	194 (58.8%)	132 (57.1%)	.698
Timing of CIN	Early-onset	405	188 (72.3%)	217 (70.0%)	.545	398	239 (72.4%)	159 (68.8%)	.356
Timing of CIN	Late-onset	165	72 (27.7%)	93 (30.0%)	.545	163	91 (27.6%)	72 (31.2%)	.356
Timing of mild CIN	Early-onset mild	155	76 (67.3%)	79 (63.7%)	.566	153	94 (69.1%)	59 (59.6%)	.131
Timing of mild CIN	Late-onset mild	82	37 (32.7%)	45 (36.3%)	.566	82	42 (30.9%)	40 (40.4%)	.131
Timing of severe CIN	Early-onset severe	250	112 (76.2%)	138 (74.2%)	.676	245	145 (74.7%)	100 (75.8%)	.835
Timing of severe CIN	Late-onset severe	83	35 (23.8%)	48 (25.8%)	.676	81	49 (25.3%)	32 (24.2%)	.835

Prognostic Role of the CIN in Subgroup Analysis

Due to the significantly different prognosis between early and advanced stage EOC, we further performed subgroup analysis according to tumor stage. As shown in Figure 1, in advanced EOC, Kaplan–Meier analysis confirmed that the OS in the CIN group and the early-onset mild group were significantly longer than non-CIN group (65 vs 42 months, P = .007) and late-onset mild group (68 vs 47 months, P = .039) separately, but not for PFS. Univariate analysis demonstrated similar results in advanced EOC. But there was no characteristic other than age associated with PFS and OS in early stage EOC (Table 2). Further multivariate analysis verified that CIN was an independent prognostic factor for better OS in advanced EOC (HR 1.499, 95% CI 1.142-1.966; P = .004). In addition, multivariate analysis also demonstrated that ascites and suboptimal surgery were independent prognostic factors for poorer survival in patients with advanced EOC, except ascites for PFS (Table 3).

Figure 1.

CIN onset and early-onset mild CIN are associated with better OS in patients of advanced EOC. (A) Kaplan–Meier curves for PFS depending on CIN occurrence. (B) Kaplan–Meier curves for OS depending on CIN occurrence. (C) Kaplan–Meier curves for PFS depending on timing of mild CIN. (D) Kaplan–Meier curves for OS depending on timing of mild CIN.

Table 2.

Univariate Cox Regression Analysis of Factors Related to Survival in Early and Advanced of all EOC Patients (n = 735).

Variables	Early stage				Advanced stage
	PFS		OS		PFS		OS
	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
Age (year) (≥51 vs < 51)	.579 (.321-1.047)	.070	.333 (.139-.799)	.014	1.099 (.888-1.358)	.386	.936 (.736-1.190)	.590
ascites (ml) (≤50 vs > 50)	.794 (.402-1.567)	.506	.650 (.244-1.734)	.389	1.421 (1.124-1.796)	.003	1.607 (1.231-2.096)	.000
Surgical outcomes (optimal vs Suboptimal)	—		—		1.950 (1.568-2.426)	.000	2.173 (1.708-2.765)	.000
Tumor classification (type I vs type II)	1.345 (.744-2.429)	.327	1.258 (.583-2.833)	.534	1.033 (.649-1.643)	.892	.935 (.564-1.553)	.796
Pathological type (serous vs non-serous)	1.011 (.549-1.862)	.971	.606 (.242-1.519)	.285	1.183 (.888-1.577)	.252	.907 (.669-1.231)	.531
CA125 (U/ml) (≥35 vs < 35)	1.220 (.644-2.309)	.542	.954 (.417-2.183)	.911	1.955 (.871-4.386)	.104	1.419 (.631-3.190)	.397
Interval from surgery to first chemotherapy (day) (≤14 vs > 14)	.560 (.221-1.418)	.221	.984 (.337-2.873)	.977	.886 (.653-1.202)	.437	.939 (.664-1.329)	.723
Non-CIN vs CIN	.680 (.316-1.460)	.322	.419 (.125-1.402)	.158	1.100 (.854-1.418)	.461	1.442 (1.100-1.891)	.008
Mild CIN vs severe CIN	1.204 (.625-2.322)	.579	.838 (.363-1.933)	.678	.942 (.738-1.204)	.635	.893 (.675-1.182)	.429
Early-onset CIN vs late-onset CIN	.795 (.375-1.685)	.550	.706 (.260-1.916)	.494	1.158 (.893-1.503)	.268	1.211 (.901-1.628)	.205
Early-onset mild CIN vs late-onset mild CIN	.871 (.298-2.550)	.802	1.018 (.298-3.481)	.977	1.346 (.907-1.999)	.140	1.564 (1.016-2.407)	.042
Early-onset severe CIN vs late-onset severe CIN	.763 (.258-2.256)	.625	.349 (.045-2.727)	.315	1.022 (.720-1.451)	.903	.966 (.634-1.473)	.873

Table 3.

Multivariate Cox Regression Analysis of Factors Related to Survival in Advanced of all EOC Patients (n = 735).

Variables		PFS		OS
Variables		HR (95% CI)	p	HR (95% CI)	p
Non-CIN vs CIN	Ascites (ml) (≤50 vs > 50)	1.273 (1.003-1.615)	.047	1.444 (1.102-1.890)	.008
	Surgical outcomes (optimal vs suboptimal)	1.867 (1.495-2.331)	.000	2.083 (1.631-2.659)	.000
	CIN onset (Non-CIN vs CIN)	—	—	1.499 (1.142-1.966)	.004
Mild early onset CIN vs mild advanced onset CIN	Ascites (ml) (≤50 vs > 50)	1.364 (.912-2.041)	.131	1.608 (1.020-2.535)	.041
	Surgical outcomes (optimal vs suboptimal)	1.885 (1.266-2.806)	.002	1.932 (1.246-2.996)	.003
	Early-onset mild CIN vs late-onset mild CIN	—	—	1.513 (.980-2.335)	.062

Next, we compared the prognosis between optimal surgery subgroup and suboptimal surgery group in advanced EOC. Kaplan–Meier curves revealed that the CIN group was related with better PFS (18 vs 14 months, P = .013) and OS (37 vs 27 months, P < .001) in suboptimal surgery EOC (Figure 2). Univariate Cox regression analysis also demonstrated that CIN group had a better prognosis in suboptimal surgery EOC. But no prognostic factor except ascites was associated with PFS and OS in optimal surgery EOC (Table 4). Further multivariate analyses showed that age <51 years (PFS: HR 1.526, 95% CI 1.072-2.171; P = .019; OS: HR 1.455, 95% CI 1.004-2.108; P = .048) and CIN (PFS: HR 1.669, 95% CI 1.139-2.447; P = .009; OS: HR 1.974, 95% CI 1.320-2.951; P = .001) were independent prognostic factors in patients of suboptimal surgery EOC (Table 5).

Figure 2.

CIN onset is associated with better PFS (A) and OS (B) in patients of suboptimal EOC.

Table 4.

Univariate Cox Regression Analysis of Factors Related to Survival in Optimal and Suboptimal of all EOC Patients (n = 735).

Variables	Optimal				Suboptimal
	PFS		OS		PFS		OS
	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
Age (year) (≥51 vs < 51)	1.079 (.822-1.416)	.584	.838 (.609-1.153)	.277	1.455 (1.026-2.063)	.035	1.393 (.964-2.014)	.078
Ascites (ml) (≤50 vs > 50)	1.315 (.988-1.748)	.06	1.441 (1.032-2.012)	.032	1.186 (.772-1.821)	.435	1.400 (.883-2.219)	.152
Tumor classification (type I vs type II)	.876 (.509-1.508)	.632	.867 (.469-1.603)	.649	1.337 (.543-3.291)	.527	.830 (.337-2.049)	.687
Pathological type (serous vs non-serous)	1.157 (.819-1.636)	.408	.859 (.590-1.251)	.429	1.032 (.834-1.278)	.769	.610 (.354-1.051)	.075
CA125 (U/ml) (≥35 vs < 35)	1.878 (.772-4.568)	.164	1.281 (.524-3.127)	.587	.492 (.068-3.553)	.482	.240 (.033-1.760)	.160
Interval from surgery to first chemotherapy (day) (≤14 vs > 14)	1.063 (.739-1.529)	.74	1.166 (.758-1.793)	.484	.664 (.374-1.179)	.162	.716 (.394-1.302)	.273
Non-CIN vs CIN	.856 (.604-1.213)	.382	1.116 (.762-1.634)	.572	1.589 (1.088-2.321)	.017	2.012 (1.358-2.980)	.000
Mild CIN vs severe CIN	1.028 (.754-1.402)	.859	.914 (.635-1.316)	.630	.791 (.530-1.181)	.252	.849 (.547-1.317)	.465
Early-onset CIN vs late-onset CIN	1.241 (.895-1.721)	.195	1.381 (.941-2.027)	.099	.964 (.627-1.482)	.867	.930 (.584-1.482)	.761
Early-onset mild CIN vs late-onset mild CIN	1.476 (.893-2.437)	.129	1.675 (.957-2.931)	.071	1.194 (.624-2.286)	.592	1.427 (.722-2.820)	.306
Early-onset severe CIN vs late-onset severe CIN	1.091 (.703-1.693)	.697	1.125 (.649-1.951)	.674	.806 (.450-1.445)	.470	.669 (.346-1.295)	.233

Table 5.

Multivariate Cox Regression Analysis of Factors Related to Survival in Suboptimal of all EOC Patients (n = 735).

Variables	PFS		OS
Variables	HR (95% CI)	P	HR (95% CI)	P
Age (year) (≥51 vs < 51)	1.526 (1.072-2.171)	.019	1.455 (1.004-2.108)	.048
Pathological type (serous vs non-serous)	—		.721 (.414-1.256)	.249
CIN onset (Non-CIN vs CIN)	1.669 (1.139-2.447)	.009	1.974 (1.320-2.951)	.001

The similar results were obtained in 661 EOC patients treated with carboplatin, except that the OS of early-onset mild vs late-onset mild CIN was not statistically significant in patients with advanced ovarian cancer (Supplementary Table S2-S5 and Supplementary Figure S2-S3).

Discussion

Although our study showed no significant difference for the prognosis between EOC patients with and without CIN, early and late CIN, mild and severe CIN, further subgroup analysis revealed that the CIN group was significantly related with better PFS and OS in suboptimal surgery advanced EOC.

CIN is a common side effect caused by chemotherapy, which is manifested in the reduction of neutrophiles in peripheral blood.⁵ The prognostic role of CIN in multiple malignancies has been validated.^7-17,19 However, the association between CIN and the prognosis of EOC was conflicting in previous reports.^20,23 Therefore, we further evaluated the prognostic value of CIN in EOC in present study. Kim et al. found that CIN was not a predictor of improved PFS and OS among EOC patients treated with paclitaxel/carboplatin as first-line chemotherapy.²⁰ He et al. also reported that there was no correlation between severity of CIN and prognosis.²³ Consistent with previous results, our study also suggested that the prognosis has no significant differences between EOC patients with and without CIN, early and late CIN, mild and severe CIN. But He et al. found that patients with early-onset CIN showed improved median PFS (23 vs 9 months; P < .001) and OS (55 vs 24 months; P < .001) than non-early onset in 255 serous EOC patients.²³ The contradiction for the prognostic role of CIN onset time might contribute to the different pathological types and different sample size.

Considering the prognosis was varied in different status of EOC, further subgroup analysis would provide more precise results. Rocconi et al. validated that neutropenic patient showed improvement prognosis (PFS: 14 vs 6 months, P = .01, OS: 45 vs 29 months, P = .03) and chemotherapy sensitivity rates (69% vs 44%, P = .001) compared to non-neutropenic patients with primary EOC (stage II-IV).¹⁹ Additionally, when stratified by debulking status, neutropenia conferred a survival advantage in suboptimally debulked patients, but only demonstrated marginal improvements in optimally debulked patients.¹⁹ Tewari et al. performed a pooled analysis including 3447 patients with advanced (stage III/IV) ovarian and peritoneal carcinoma, and found that patients developed neutropenia survived significantly longer than patients who did not (OS: 47 vs 38 months; P = .04).⁷ Unfortunately, the chemotherapy in this study adopted multiple experimental triple regimens, which might affect the prognosis outcome. Similar to previous result, our study also revealed that CIN was an independent predictor of better PFS and OS in advanced EOC after suboptimal surgery, and OS in CIN group and early-onset mild group were significantly longer than non-CIN and late-onset mild group for advanced EOC. There was still no relevance between CIN and prognosis in early stage or optimal surgery EOC, which might due to their good prognosis.

Tumor cells and neutrophil in same patient was usually considered sharing similar pharmacokinetics to the chemotherapy, so CIN might reflect the drug sensitivity of tumor cells.¹⁶ The effect of chemotherapy depends on drug dose because of the narrow therapeutic window of cytotoxic drugs.²⁴ Insufficient dose leads to poor curative effect, and excessive dose leads to severe side effects including death.²⁵ But it is too expensive and unrealistic to measure drug plasma concentration in each patient. Therefore, compared with traditional dosing strategies, CIN might be one simple and reliable indicator for adjusting chemotherapy drug dose according to our findings. Moreover, previous studies have recognized that inflammation in tumor microenvironment plays crucial roles in tumor cell survival, proliferation, and migration.^26-29 Neutrophils enhance tumor angiogenesis by releasing proinflammatory cytokines and matrix metalloproteinase9 (MMP9). In addition, neutrophils restrain antitumor immune by releasing argininase 1 to inhibit T cell function.^30-34 Therefore, we deduced that CIN might improve survival through promoting anti-tumor immunological response and disrupting angiogenesis, although the intrinsic mechanisms are still needed to be further clarified.

In addition, previous research had showed that ascites plays an important role in the invasion and metastasis of tumor by producing cytokines and growth factors.³⁵ Colozza et al. also found that ascites was the only significant prognostic factor in patients with advanced EOC.³⁶ Consistent with previous results, our study also validated the prognostic role of ascites in advanced EOC. Furthermore, we found that age was an independent prognosis factor in suboptimal surgery EOC patients. Tewari et al. also validated that age (<50 years) was an independent favorable prognostic predictor in advanced EOC.⁷ We speculate that the favorable prognosis in younger patients may be due to the fewer complications and better chemotherapy tolerance.³⁷

Our study has several limitations. First, the sample size used in present study lacked calculation and justification due to the retrospective character. Second, platinum-based chemotherapy was used, so further study stratified by certain chemotherapy regimen would be needed. Nevertheless, present study was a relatively large sample reports to evaluate independently the relationship between CIN and the prognosis of EOC treated with platinum-based chemotherapy.

Conclusion

Taken all together, CIN was strongly associated with better prognosis in advanced EOC and suboptimal EOC, even though CIN showed no correlation with prognosis in all EOC patients. We believe that CIN might be potentially used as an easy and reliable indicator for favorable prognosis and adjusting chemotherapy dose in advanced EOC, especially with suboptimal surgery. Further large-scale prospective studies are warranted for confirming the role of CIN in EOC prognosis and clarifying its intrinsic regulatory mechanism.

Supplemental Material

Supplemental Material - Chemotherapy-Induced Neutropenia as a Prognostic Factor in Patients With Advanced Epithelial Ovarian Carcinoma

Supplemental Material for Chemotherapy-Induced Neutropenia as a Prognostic Factor in Patients With Advanced Epithelial Ovarian Carcinoma by Yaping Xu, MM, Mingjing Wei, BM, Xiaodong Cheng, MD, and Xiao Li, MD in Cancer Control.

Footnotes

Author Contributions

Yaping Xu and Mingjing Wei contributed to data curation and project administration. Yaping Xu contributed to formal analysis and methodology. Xiao Li contributed to conception and original draft. Xiao Li and Xiaodong Cheng contributed to supervision and reviewing the final manuscript.

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.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by Key research and development program of Zhejiang province (2019C03010) and Hangzhou Medical and health science and Technology Project (0020190447).

Ethics Approval

The study was approved by the Ethical Committee of women’s hospital, Zhejiang University School of Medicine (IRB-20200236-R).

Informed Consent

We have obtained the waiver of informed consent for our study.

ORCID iDs

Yaping Xu

Mingjing Wei

Xiao Li

Supplemental Material

Supplemental material for this article is available online.

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