We compared the predictive and prognostic values of leukocyte differential counts, systemic inflammatory (SIR) markers and cancer antigen 125 (CA-125) levels, and identified the most useful marker in patients with ovarian clear cell carcinoma (OCCC).
The study included 109 patients with OCCC who did not have any inflammatory conditions except endometriosis, and underwent primary debulking surgery between 1997 and 2012. Leukocyte differential counts (neutrophil, lymphocyte, monocyte, eosinophil, basophil, and platelet), SIR markers including neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), and platelet to lymphocyte ratio (PLR), and CA-125 levels were estimated to select potential markers for clinical outcomes.
Among potential markers (neutrophil, monocyte, platelet, NLR, MLR, PLR, and CA-125 levels) selected by stepwise comparison, CA-125 levels were best at predicting advanced stage disease, suboptimal debulking and platinum-resistance (cut-off values, ≥ 46.5, ≥ 11.45, and ≥ 66.4 U/mL; accuracies, 69.4%, 78.7%, and 68.5%) while PLR ≥ 205.4 predicted non-complete response (CR; accuracy, 71.6%) most accurately. Moreover, PLR < 205.4 was an independent factor for the reduced risk of non-CR (adjusted odds ratio, 0.17; 95% confidence interval [CI], 0.04 to 0.69), and NLR < 2.8 was a favorable factor for improved progression-free survival (PFS; adjusted hazard ratio, 0.49; 95% CI, 0.25 to 0.99) despite lack of a marker for overall survival among the potential markers.
CA-125 levels may be the most useful marker for predicting advanced-stage disease. Suboptimal debulking and platinum-resistance, and PLR and NLR may be most effective to predict non-CR and PFS in patients with OCCC.
Ovarian clear cell carcinoma (OCCC) is the fourth most common of histologic types of epithelial ovarian cancer (EOC). OCCC prognosis is similar to other histologic types in early-stage disease but it has the worst prognosis in advanced stage disease [
However, the prognostic value of CA-125 levels is less clear in OCCC. A limited number of studies found that CA-125 levels were lower in OCCC than in other histologic types, and did not reflect clinical outcomes of patients with OCCC [
We collected clinico-pathologic data from a database of EOC registered from Seoul National University Hospital and Seoul National University Bundang Hospital between February 1997 and December 2012. The Institutional Review Board at our institution approved the current study, and the informed consent requirement was waived because the current study was conducted by a retrospective medical record review.
We included only patients with OCCC who underwent primary debulking surgery. Leukocyte differential counts including neutrophil, lymphocyte, monocyte, platelet, basophil, and eosinophil, SIR markers such as NLR, MLR, and PLR, CA-125 levels were measured within one week before staging laparotomy. However, patients with any inflammatory conditions or other malignancies that could affect the results of laboratory tests were excluded, except endometriosis proved by biopsy. Clinico-pathologic data collected included age, International Federation of Gynecology and Obstetrics (FIGO) stage, endometriosis, extent of debulking surgery, regimen and cycles of adjuvant chemotherapy, leukocyte differential counts, SIR markers, CA-125 levels, tumor response, platinum-resistance, progression-free survival (PFS), and overall survival (OS).
Leukocyte differential counts were estimated 1 week prior to surgery (SYSMEX XE-2100, TOA Medical Electronics, Kobe, Japan), and CA-125 levels were measured at the same time using a radioimmunoassay kit (Fujirebio Diagnostics, Malvern, PA). Optimal debulking was defined as a residual tumor ≤ 1 cm in a maximal diameter, and complete response (CR) was defined as the disappearance of all tumor burdens for at least 4 weeks with normalization of CA-125 levels. PFS was calculated as the time elapsed from the date of completion of primary treatment to the date of clinically proven recurrence, and platinum-resistance was defined as PFS less than 6 months. OS was defined as the length of time from the date of surgery to the date of cancer-related death or the end of study.
We compared leukocyte differential counts, SIR markers and CA-125 levels based on clinico-pathologic characteristics using Student’s t test and Mann-Whitney U test in patients with OCCC, and selected potential markers associated with the clinico-pathologic characteristics among them. We calculated the best cut-off values of potential markers based on the receiver operating characteristic (ROC) curve, and assessed the sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and accuracy to identify the best marker for predicting clinical outcomes.
Next, we investigated the best prognostic factors among the potential markers for tumor response and survival in the patients. To this end, we performed logistic regression and Cox’s proportional hazard analyses, and calculated odds ratio (OR), hazard ratio (HR) and 95% confidence interval (CI). Statistical analyses were performed with SPSS ver. 19.0 (SPSS Inc., Chicago, IL). We rejected null hypotheses of no difference if p-values were less than 0.05, or, equivalently, if the 95% CIs of risk point estimates excluded 1.
One hundred and nine patients with OCCC were included, and
When we compared leukocyte differential counts, SIR markers and CA-125 levels based on clinico-pathologic characteristics, neutrophila, monocytosis, thrombocytosis, elevated NLR, PLR, and CA-125 levels were associated with advanced-stage disease, non-CR, and platinum-resistance. Thrombocytosis, elevated NLR, PLR, and CA-125 levels were associated with suboptimal debulking, and elevated MLR was associated with non-CR and platinum-resistance (
To determine the best prognostic factors among the potential markers, we performed logistic regression analyses, which showed that optimal debulking (adjusted OR, 0.02; 95% CI, 0.01 to 0.12) and PLR < 205.4 (adjusted OR, 0.17; 95% CI, 0.04 to 0.69) were independent factors associated with the reduced risk of non-CR (
SIR involves secondary changes in the levels of circulating leukocytes, which show neutrophilia, monocytosis, lymphocytopenia and thrombocytosis [
In the current study, CA-125 levels were best for predicting advanced-stage disease, suboptimal debulking and platinum-resistance in patients with OCCC. Although most leukocyte differential counts and SIR markers were statistically significant for predicting advanced-stage disease, suboptimal debulking and platinum-resistance, we found that CA-125 levels had the highest SN, SP, PPV, NPV, and accuracy. Specific leukocyte differential counts (neutrophil, monocyte, and platelet), and SIR markers (NLR, MLR, and PLR) increase proportionally with a growing burden of inflammation such as cancer, whereas CA-125 levels are relatively low in early-stage OCCC in comparison with other histologic types of EOC because of the apparent initial smaller volume of disease as well as fundamental differences in the biology of malignancy [
Furthermore, PLR was the most significant to predict tumor response after primary treatment among the potential markers. Platelets interact with tumor cells, and to contain factors contributing to tumor growth, invasion and angiogenesis [
Last, NLR was the most important prognostic factor for PFS despite there being no marker related to OS among the potential markers. Many studies reports that a higher neutrophil count or a lower lymphocyte predicts poorer survival in EOC [
Whether the potential markers can be applied to predict clinical outcomes in patients with OCCC is controversial. Although recent meta-analyses emphasized the importance of SIR markers to predict prognosis of solid tumors, research that interprets their usefulness in EOC when compared with other malignancies is lacking [
Although the current study has some limitations such as a retrospective design and unassessed possible confounders affecting SIR (e.g., smoking or oral contraceptive use) [
Conflict of interest relevant to this article was not reported.
This research was supported by grants (No. 04-2012-0890; 03-2012-0170) from the Seoul National University Hospital research fund, and the Priority Research Centers Program (No. 2009-0093820), Basic Science Research Program (No. 2011-0025394), and BK21 plus program (No. 5256-20140100) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology. Moreover, it was also supported by a grant of the Korean Health Technology R&D Project, Ministry of Health of Welfare (HI14C2404).
The receiver operating characteristic curves to determine the best cut-off values of leukocyte differential counts including neutrophil, monocyte and platelet, neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR), and cancer antigen 125 (CA-125) levels for predicting International Federation of Gynecology and Obstetrics (FIGO) stage III-IV disease (A), suboptimal debulking (B), platinum-resistance (C), and non-complete response (D) in 109 patients with ovarian clear cell carcinoma.
Clinico-pathologic characteristics of 109 patients with ovarian clear cell carcinoma
Characteristic | No. of patients (%) |
---|---|
Age (yr) | |
< 54 | 57 (52.3) |
≥ 54 | 52 (47.7) |
FIGO stage | |
I-II | 68 (62.4) |
III-IV | 41 (37.5) |
Histology | |
Pure | 101 (92.6) |
Mixed | 8 (7.4) |
Endometriosis | |
No | 62 (56.9) |
Yes | 47 (43.1) |
Optimal debulking | |
No | 95 (87.2) |
Yes | 14 (12.8) |
Regimen of chemotherapy | |
No | 6 (5.5) |
Non-taxane and platinum | 17 (15.6) |
Taxane and platinum | 86 (78.9) |
Cycles of chemotherapy | |
≤ 6 | 93 (85.3) |
6-9 | 16 (14.7) |
Platinum-resistance | |
No | 89 (81.7) |
Yes | 20 (18.3) |
Tumor response | |
Non-CR | 20 (18.3) |
CR | 89 (81.7) |
FIGO, International Federation of Gynecology and Obstetrics; CR, complete response.
Leukocyte differential counts, systemic inflammatory response markers, and CA-125 levels based on clinico-pathologic characteristics of 109 patients with ovarian clear cell carcinoma
Characteristic | Leukocyte differential counts |
SIR markers |
CA-125 (U/mL) | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Neutrophil (cell/μL) | Lymphocyte (cell/μL) | Monocyte (cell/μL) | Eosinophil (cell/μL) | Basophil (cell/μL) | Platelet (×103/μL) | NLR | MLR | PLR | ||
Age (yr) | ||||||||||
< 54 | 4,481±1,863 | 1,691±713 | 396±189 | 27±17 | 109±107 | 308±100 | 3.1+1.7 | 0.3±0.1 | 206.4±103.7 | 163.1±436.7 |
≥ 55 | 4,355±1,729 | 1,715±532 | 381±151 | 26±16 | 133±106 | 318±95 | 2.9±1.7 | 0.2±0.1 | 204±93 | 412.9±1,270.8 |
FIGO stage | ||||||||||
I-II | 4,019±1,403 |
1,787±718 | 359±152 |
24±16 | 130±109 | 287±75 |
2.6±1.4 |
0.2±0.1 |
181.3±80.4 |
110.8±378.2 |
III-IV | 5,100±2,162 | 1,561±422 | 440±193 | 27±16 | 102±104 | 355±115 | 3.5±1.9 | 0.3±0.2 | 245.7±112.8 | 565.4±1,412.8 |
Histology | ||||||||||
Pure | 4,473±1,820 | 1,722±642 | 386±174 | 26±17 | 115±98 | 315±99 | 3.0±1.7 | 0.2±0.1 | 204.9±98.6 | 279.7±961.8 |
Mixed | 3,724±1,275 | 1,449±426 | 439±141 | 18±8 | 182±191 | 274±49 | 3.0±2.1 | 0.3±0.2 | 210.1±102.2 | 329.1±648.3 |
Endometriosis | ||||||||||
No | 4,573±1,930 | 1,685±710 | 398±184 | 24±16 | 107±103 | 316±97 | 3.2±1.8 | 0.3±0.2 | 209.2±88.6 | 411±1212 |
Yes | 4,214±1,586 | 1,725±513 | 376±154 | 26±17 | 137±111 | 307±99 | 2.7±1.4 | 0.2±0.1 | 199.8±111.1 | 117.8±298.9 |
Optimal debulking | ||||||||||
Yes | 4,207±1,494 | 1,710±661 | 381±159 | 25±16 | 127±112 | 297±83 |
2.8±1.6 |
0.3±0.1 | 196±93 |
166.3±439.8 |
No | 5,890±2,831 | 1,653±387 | 448±243 | 30±19 | 72±34 | 419±120 | 3.8±2.3 | 0.3±0.2 | 270±114 | 1,069.8±2,263.3 |
Tumor response | ||||||||||
Non-CR | 5,644±2,419 |
1,502±354 | 476±221 |
26±17 | 91±54 | 401±118 |
3.9±1.8 |
0.3±0.1 |
283.7±111.3 |
781.1±1,931.5 |
CR | 4,142±1,500 | 1,748±673 | 370±154 | 25±16 | 126±115 | 292±79 | 2.8±1.6 | 0.2±0.1 | 187.3±86.2 | 170.3±449.4 |
Platinum-resistance | ||||||||||
Yes | 5,352±1,827 |
1,552±473 | 461±180 |
24±16 | 124±119 | 363±114 |
3.7±1.8 |
0.3±0.2 |
259.2±120.9 |
720.7±1,925.7 |
No | 4,209±1,727 | 1,737±661 | 373±167 | 25±16 | 119±105 | 301±90 | 2.8±1.6 | 0.2±0.1 | 192.9±88.7 | 184±471.9 |
CA-125, cancer antigen 125; SIR, systemic inflammatory response; NLR, neutrophil to lymphocyte ratio; MLR, monocyte to lymphocyte ratio; PLR, platelet to lymphocyte ratio; FIGO, International Federation of Gynecology and Obstetrics; CR, complete response.
p < 0.05.
SN, SP, PPV, NPV, and accuracy of leukocyte differential counts, systemic inflammatory response markers, CA-125 levels by the receiver operating characteristic curve
Characteristic | Cut-off value | AUC | SN (%) | SP (%) | PPV (%) | NPV (%) | Accuracy (%) | p-value |
---|---|---|---|---|---|---|---|---|
FIGO stage III-IV disease | ||||||||
Neutrophil (cell/μL) | ≥ 4,370 | 0.66 | 60.5 | 59.4 | 46.9 | 71.7 | 59.8 | < 0.01 |
Monocyte (cell/μL) | ≥ 389 | 0.65 | 65.8 | 64.6 | 52.1 | 76.4 | 65 | 0.01 |
Platelet (×103/μL) | ≥ 300 | 0.70 | 60.5 | 57.8 | 46 | 71.2 | 58.8 | < 0.01 |
NLR | ≥ 2.4 | 0.65 | 60.5 | 56.3 | 45.1 | 70.6 | 57.8 | 0.01 |
MLR | ≥ 0.2 | 0.64 | 60.5 | 60 | 46.9 | 72.2 | 60.2 | 0.02 |
PLR | ≥ 178.3 | 0.68 | 60.5 | 57.8 | 46 | 71.2 | 58.8 | < 0.01 |
CA-125 (U/mL) | ≥ 46.5 | 0.78 | 73.2 | 67.2 | 57.7 | 80.4 | 69.4 | < 0.01 |
Suboptimal debulking | ||||||||
Neutrophil (cell/μL) | ≥ 4,254 | 0.69 | 61.5 | 50.6 | 15.4 | 90 | 51.9 | 0.03 |
Monocyte (cell/μL) | ≥ 354 | 0.54 | 61.5 | 43.3 | 13.6 | 88.6 | 45.6 | 0.65 |
Platelet (×103/μL) | ≥ 295 | 0.80 | 76.9 | 51.7 | 18.9 | 93.9 | 54.9 | < 0.01 |
NLR | ≥ 2.4 | 0.64 | 61.5 | 50.6 | 15.4 | 90 | 52 | 0.11 |
MLR | ≥ 0.2 | 0.56 | 61.5 | 54.4 | 16.3 | 90.7 | 55.3 | 0.49 |
PLR | ≥ 205.4 | 0.72 | 69.2 | 67.4 | 23.7 | 93.8 | 67.6 | 0.01 |
CA-125 (U/mL) | ≥ 114.5 | 0.87 | 78.6 | 78.7 | 35.5 | 96.1 | 78.7 | < 0.01 |
Non-CR | ||||||||
Neutrophil (cell/μL) | ≥ 4,428 | 0.71 | 68.4 | 62.7 | 29.5 | 89.7 | 63.7 | < 0.01 |
Monocyte (cell/μL) | ≥ 394 | 0.67 | 63.2 | 63.1 | 27.9 | 88.3 | 66 | 0.03 |
Platelet (×103/μL) | ≥ 297 | 0.77 | 73.7 | 54.2 | 26.9 | 90 | 57.8 | < 0.01 |
NLR | ≥ 2.7 | 0.71 | 73.7 | 65.1 | 32.6 | 91.5 | 66.7 | < 0.01 |
MLR | ≥ 0.3 | 0.69 | 68.4 | 63.1 | 29.5 | 89.8 | 64.1 | < 0.01 |
PLR | ≥ 205.4 | 0.78 | 73.7 | 71.1 | 36.8 | 92.2 | 71.6 | < 0.01 |
CA-125 (U/mL) | ≥ 66.9 | 0.76 | 70 | 69.3 | 34.1 | 69.3 | 69.4 | < 0.01 |
Platinum-resistance | ||||||||
Neutrophil (cell/μL) | ≥ 4,436 | 0.70 | 63.2 | 62.7 | 27.9 | 88.1 | 62.7 | < 0.01 |
Monocyte (cell/μL) | ≥ 394 | 0.65 | 63.2 | 63.1 | 27.9 | 88.3 | 63.1 | 0.04 |
Platelet (×103/μL) | ≥ 297 | 0.67 | 63.2 | 51.8 | 23.1 | 86 | 53.9 | 0.02 |
NLR | ≥ 2.8 | 0.69 | 68.4 | 65.1 | 31 | 90 | 65.7 | < 0.01 |
MLR | ≥ 0.3 | 0.66 | 63.2 | 61.9 | 27.3 | 88.1 | 62.1 | 0.03 |
PLR | ≥ 178.3 | 0.67 | 68.4 | 55.4 | 26 | 88.5 | 57.8 | 0.02 |
CA-125 (U/mL) | ≥ 66.4 | 0.73 | 70 | 68.2 | 33.3 | 90.9 | 68.5 | < 0.01 |
SN, sensitivity; SP, specificity; PPV, positive predictive value; NPV, negative predictive value; AUC, area under curve; FIGO, International Federation of Gynecology and Obstetrics; NLR, neutrophil to lymphocyte ratio; MLR, monocyte to lymphocyte ratio; PLR, platelet to lymphocyte ratio; CA-125, cancer antigen 125.
Prognostic factors associated with the reduced risk of non-complete response after primary treatment in 109 patients with ovarian clear cell carcinoma
Factor | Univariate |
Multivariate |
||||
---|---|---|---|---|---|---|
OR | 95% CI | p-value | Adjusted OR | 95% CI | p-value | |
Age < 54 yr | 0.70 | 0.26-1.85 | 0.47 | - | - | - |
FIGO stage I-II disease | 0.07 | 0.02-0.24 | < 0.01 | - | - | - |
Pure OCCC | 0.65 | 0.12-3.49 | 0.62 | - | - | - |
Optimal debulking | 0.02 | 0.01-0.08 | < 0.01 | 0.02 | 0.01-0.12 | < 0.001 |
Taxane- and platinum-based chemotherapy | 0.61 | 0.16-2.29 | 0.46 | - | - | - |
> 6 cycles of chemotherapy | 0.42 | 0.13-1.40 | 0.16 | - | - | - |
PLR < 205.4 | 0.15 | 0.05-0.45 | < 0.01 | 0.17 | 0.04-0.69 | 0.01 |
CA-125 < 66.9 (U/mL) | 0.19 | 0.07-0.55 | < 0.01 | - | - | - |
OR, odds ratio; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; OCCC, ovarian clear cell carcinoma; PLR, platelet to lymphocyte ratio; CA-125, cancer antigen 125.
Prognostic factors related with improved progression-free and overall survivals in 109 patients with ovarian clear cell carcinoma
Factor | Univariate |
Multivariate |
||||
---|---|---|---|---|---|---|
HR | 95% CI | p-value | Adjusted HR | 95% CI | p-value | |
Progression-free survival | ||||||
Age < 54 yr | 1.14 | 0.60-2.17 | 0.68 | - | - | - |
FIGO stage I-II disease | 0.15 | 0.08-0.31 | < 0.01 | 0.18 | 0.08-0.41 | < 0.01 |
Pure OCCC | 0.56 | 0.20-1.59 | 0.28 | - | - | - |
Optimal debulking | 0.13 | 0.06-0.27 | < 0.01 | 0.37 | 0.16-0.84 | 0.02 |
Taxane- and platinum-based chemotherapy | 0.87 | 0.41-1.84 | 0.72 | 0.36 | 0.15-0.89 | 0.03 |
> 6 cycles of chemotherapy | 1.79 | 0.82-3.93 | 0.14 | - | - | - |
NLR < 2.8 | 0.34 | 0.18-0.67 | < 0.01 | 0.49 | 0.25-0.99 | 0.04 |
CA-125 < 68.5 (U/mL) | 0.29 | 0.15-0.57 | < 0.01 | - | - | - |
Overall survival | ||||||
Age < 54 yr | 2.00 | 0.85-4.69 | 0.11 | - | - | - |
FIGO stage I-II disease | 0.12 | 0.05-0.30 | < 0.01 | 0.08 | 0.03-0.22 | < 0.01 |
Pure OCCC | 0.53 | 0.16-1.78 | 0.30 | - | - | - |
Optimal debulking | 0.14 | 0.06-0.36 | < 0.01 | 0.26 | 0.09-0.75 | 0.01 |
Taxane- and platinum-based chemotherapy | 0.69 | 0.29-1.65 | 0.40 | - | - | - |
> 6 cycles of chemotherapy | 3.06 | 1.31-7.13 | 0.10 | - | - | - |
NLR < 2.8 | 0.29 | 0.13-0.68 | < 0.01 | - | - | - |
CA-125 < 68.5 (U/mL) | 0.26 | 0.11-0.59 | < 0.01 | - | - | - |
HR, hazard ratio; CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; OCCC, ovarian clear cell carcinoma; NLR, neutrophil to lymphocyte ratio; CA-125, cancer antigen 125.