Glasgow prognostic score is a prognosis predictor for patients with endometrial cancer

European Journal of Obstetrics & Gynecology and Reproductive Biology 210 (2017) 355–359

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Glasgow prognostic score is a prognosis predictor for patients with endometrial cancer$ Masayuki Saijo, Keiichiro Nakamura* , Hisashi Masuyama, Naoyuki Ida, Tomoko Haruma, Tomoyuki Kusumoto, Noriko Seki, Yuji Hiramatsu Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan

A R T I C L E I N F O

A B S T R A C T

Article history: Received 18 June 2016 Received in revised form 15 January 2017 Accepted 16 January 2017 Available online xxx

Objective: This study investigated whether the inflammation-based Glasgow prognostic score (GPS) predicted the prognosis of patients with endometrial cancer (EC) in terms of progression-free survival (PFS) and overall survival (OS). Study design: Pretreatment GPS was examined to determine the correlations with recurrence and survival in 431 patients with EC. Statistical analyses were performed using the Mann–Whitney U test. PFS and OS were analyzed using the Kaplan–Meier method. Cox’s proportional hazard regression was used for univariate and multivariate analyses. Results: Median PFS and OS were 49.7 and 52.7 months, respectively. The follow-up range was 1 to 140 months. Kaplan–Meier analysis revealed that patients with EC cancer and high GPS (GPS 2) had a shorter PFS and OS than those with lower GPS (GPS 0 + 1) (PFS: P < 0.001; OS; P < 0.001). On multivariate analysis, GPS (GPS 2) was an independent predictor of both recurrence (P < 0.001) and survival (P < 0.001) for all cases of EC. Conclusion: GPS can be useful as an indicator of poor prognosis in patients with EC. © 2017 Elsevier B.V. All rights reserved.

Keywords: Endometrial cancer Glasgow prognostic score Poor prognosis

1. Introduction Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with an estimated 60,050 new cases diagnosed so far in 2016 [1]. In Japan, EC is currently the second most common gynecologic malignancy in women, with an estimated incidence in 2014 of 9673 new cases [2]. The overall survival (OS) rate of patients with EC is expected to be high because most patients have early-stage disease at the time of diagnosis [3,4]. However, the 5-year OS rate is around 80% for patients at any stage. Known prognostic factors for EC include stage, histology, myometrial invasion, cervical involvement and lymph node metastasis [5–9], but these parameters are not sufficient to accurately predict the prognosis of EC. A new approach for the

$ Condensation: Glasgow prognostic score is a prognosis predictor for patients with endometrial cancer. * Corresponding author at: Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 25-1 Shikata-cho, Kika-ku, Okayama 700-8558, Japan. E-mail address: [email protected] (K. Nakamura).

http://dx.doi.org/10.1016/j.ejogrb.2017.01.024 0301-2115/© 2017 Elsevier B.V. All rights reserved.

pretreatment assessment of patients with EC is pivotal in improving outcomes. Although serum CA125 levels have become a valuable tumor marker for the diagnosis of epithelial ovarian cancer and the detection of recurrence after primary treatment [10], its role as a useful tumor marker in EC is controversial. Several studies have reported that serum CA125 levels are important for the preoperative diagnosis and prediction of disease recurrence [11], and that their elevation is correlated with advanced-stage EC [12,13]. Inflammatory markers are important prognostic factors for survival in various cancer types. C-reactive protein (CRP) and albumin play prominent roles in tumor-related inflammation [14– 16]. The Glasgow prognostic score (GPS) is based on the combination of CRP and albumin levels. Reportedly, inflammation-based prognostic scores, such as the GPS, are associated with survival in various cancers, including ovarian, lung, breast, esophagus, stomach, pancreas, kidney and colorectal cancers [17–24]. Thus far, GPS has not been shown to be a predictive factor for patients with EC. In this study, we investigated the correlation between pretreatment GPS and the prognosis of patients with EC.

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2. Materials and methods 2.1. Study population In this retrospective study, we reviewed the medical records of 431 patients with EC who were treated at the Department of Obstetrics and Gynecology of Okayama University Hospital between January 2002 and December 2015. From the medical records, we extracted clinical and pathological data regarding pretreatment albumin, C-reactive protein (CRP), serum CA125, surgical International Federation of Gynecology and Obstetrics (FIGO) stage, histology, maximum tumor size, myometrial invasion, cervical invasion, lymphovascular space (LVS) involvement, peritoneal cytology, ovarian metastasis, lymph node metastasis, date of progression, date of last follow-up visit, and patient status at last visit. All patients were treated according to the Japan Society of Gynecologic Oncology clinical guidelines. Adjuvant chemotherapy was administered depending on risk factors (FIGO stage and histology), patient preference, and physician discretion. Chemotherapy consisted of paclitaxel (175 mg/m2 infused over 3 h) and carboplatin (dose to achieve an area under the concentration-time curve of 5) for 3 to 6 cycles. All of the patients underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy with or without pelvic and/or para-aortic lymphadenectomy. Pelvic lymph node dissection included the right and left common iliac nodes, external and internal iliac nodes, as well as suprainguinal, obturator, sacral and parametrial nodal chains. Para-aortic lymph node dissection included the nodes located from the bifurcation of the aorta to the level of the renal vein. 2.2. Laboratory data collection The serum albumin, CRP and CA125 levels of all subjects were recorded within 1 week before their treatments. Serum CA125 level was measured by electrochemiluminescence immunoassay (Modular Analysis E170, Roche Diagnostics, Tokyo, Japan). The cutoff value for the CA125 level was 35.0 U/ml. Levels of serum albumin and CRP were measured using latex nephelometry (LT Auto Wako, Osaka, Japan). The GPS was estimated as described previously [18]. Briefly, the high GPS group included patients with GPS 2: CRP levels >1.0 mg/dL and hypoalbuminemia (<3.5 g/dL). The low GPS group included patients with abnormal level of only one of these parameters (GPS 1) or no abnormalities (GPS 0).

involvement, peritoneal cytology, ovarian metastasis, lymph node metastasis, and CA125 are shown in Table 1. We examined pretreatment GPS in patients with EC. P retreatment GPS was GPS 0 (CRP  1.0 mg/dL and albumin 3.5 g/dL) in 376 patients (87.2%), GPS 1 in 38 patients (8.8%) (CRP > 1.0 mg/dL and albumin 3.5 g/dL; 34 patients (7.9%), CRP 1.0 mg/dL and albumin <3.5 g/dL; 4 patients (0.9%)), and GPS 2 (CRP >1.0 mg/dL and albumin <3.5 g/dL) in 17 patients (4.0%) (Fig. 1A). We investigated whether pretreatment clinical characteristics were correlated with GPS and found that GPS was significantly associated with FIGO stage (P = 0.001), myometrial invasion (P = 0.016), cervical invasion (P = 0.003), LVS involvement (P = 0.004), lymph node metastasis (P = 0.015), and CA125 level (P < 0.001) of patients with EC (Mann–Whitney U test, P < 0.05; Table 2). Patients had follow-up examinations approximately every 1 to 2 months for first 6 months, every 3 months for next 2 years, and every 6 months thereafter. For all patients, median PFS and OS were 49.7 and 52.7 months, respectively. The follow-up range was Table 1 Patient and tumor characteristics. Baseline characteristics

All patients

Age at diagnosis, y

Mean,58.0; range, 23–88 Numbers

(%)

Stage I II III IV

309 36 51 35

71.7 8.3 11.8 8.2

Histology Endometrioid adenocarcinoma G1 Endometrioid adenocarcinoma G2 Endometrioid adenocarcinoma G3 Clear cell carcinoma Serous adenocarinoma Mixed type carcinoma Carcinosarcoma Other carcinoma

226 96 43 4 24 6 27 5

52.3 22.2 10 0.9 5.8 1.3 6.4 1.1

Tumor maximum size 4 cm >4 cm

308 123

71.5 28.5

Myometrial invasion 1/2 >1/2

292 139

67.8 32.2

Cervical invasion Absent Present

361 70

83.8 16.2

LVS involvement Absent Present

357 74

82.8 17.2

Peritoneal cytology Absent Present

359 72

83.3 16.7

Ovarian metastasis Absent Present

399 32

92.6 7.4

Lymph node metastasis Absent Present

378 53

87.7 12.3

CA125 35.0U/ml >35.0 U/ml

292 139

67.8 32.2

2.3. Statistical analysis Statistical analyses were performed using the Mann–Whitney U test for comparisons with controls. Progression-free survival (PFS) and OS of the groups were analyzed using the Kaplan–Meier method. Differences between the recurrence and survival curves were examined using the log-rank test. We performed univariate and multivariate analyses using Cox’s proportional hazards model to determine which factors predicted PFS and OS after adjusting for effects of known prognostic factors. Analyses were performed using SPSS software version 20.0 (SPSS Inc., Chicago, IL, USA). A P < 0.05 was considered statistically significant. 3. Results Patients were aged between 23 and 88 (mean: 58.0) years. Their mean pretreatment values were as follows: CRP, 0.1 (range: 0– 15.23) mg/dl; albumin, 4.2 (2.1–5.2) g/dl; and CA125, 21.0 (3.5– 1690.0) U/ml. Data on patients’ FIGO stage, histology, maximum tumor size, myometrial invasion, cervical invasion, LVS

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Fig. 1. A. Glasgow prognostic score (GPS) at pretreatment of 431 patients with endometrial cancer. Patients with elevated C-reactive protein (CRP) levels (>1.0 mg/dL) and hypoalbuminemia (<3.5 g/dL) were allocated a score of 2, only one of these biochemical abnormalities were allocated a score of 1. Patients with neither of these abnormalities were allocated a score of 0. B. Kaplan–Meier curves for progression-free survival (PFS) and overall survival (OS) rates of 431 patients with ovarian cancer according to their Glasgow prognostic score (GPS) at pretreatment. GPS score 0 (n = 376); GPS 1 (n = 38); GPS 2 (n = 17).

1–140 months for both OS and PFS. At the time of the last followup, 362 patients were alive with no evidence of disease (84.0%), 42 patients had died of the disease (9.6%), and 27 patients were alive with disease (6.4%). Fig. 1B shows the PFS and OS curves for the 431 patients with EC, according to their pretreatment GPS. The Kaplan– Meier analysis showed that the PFS and OS for patients with EC and high GPS (GPS 2) were shorter than for patients with EC that had lower GPS (GPS 0 + 1) (PFS and OS: P < 0.001 and P < 0.001) (Fig. 1B). The correlations between clinical factors of patients with EC and PFS and OS were assessed by univariate and multivariate analyses (Table 3). In univariate analysis of PFS and OS, FIGO stage, histology, maximum tumor size, myometrial invasion, cervical invasion, LVS involvement, peritoneal cytology, ovarian metastasis, lymph node metastasis and CA125 (P < 0.001 for all) were significantly associated with both PFS and OS of patients with EC. Furthermore, GPS 1 and GPS 2 were significantly associated with both PFS and OS of patients with EC (PFS; P = 0.003, and P < 0.001, OS; P = 0.046, and P < 0.001). In multivariate analysis, FIGO stage (P < 0.001), histology (P = 0.001) and GPS 2 (P < 0.001) were significantly associated with the PFS of patients with EC. Furthermore, FIGO stage (P = 0.001), histology (P < 0.001), ovarian metastasis (P = 0.037) and GPS 2 (P < 0.001) were significantly associated with the OS of patients with EC. However, the multivariate analysis indicated that GPS 1 were not independent prognostic factors for either PFS or OS with EC. In particular, the multivariate analysis indicated that GPS 2 is an independent predictor of both recurrence and survival in patients with EC.

4. Comments It has been reported that the prognosis of patients with EC depends on tumor stage, histology, myometrial invasion, cervical involvement and lymph node metastasis [5–9]. Inflammatorybased scores, such as GPS, are important prognostic factors in various cancers. However, to the best of our knowledge, this study is the first to evaluate whether high pretreatment GPS is useful in predicting poor prognosis in patients with EC. In patients with cancer, CRP levels may increase owing to the production of inflammation-related cytokines such as vascular endothelial growth factor and interleukin (IL)-6 [25,26]. Further, hypoalbuminemia is often observed in patients with advanced cancer, and it is usually considered a marker for malnutrition and cachexia. Low albumin concentration is related to the increased expression of proinflammatory cytokines, such as IL-1, IL-6, and tumor necrosis factor, which modulate albumin production [27,28]. Thus, the GPS, which is based on a combination of CRP and albumin levels, may reflect both the presence of a systemic inflammatory response and progressive nutritional decline in cancer patients. We investigated whether clinical characteristics were correlated with GPS, and found that the pretreatment GPS of patients with EC was significantly associated with FIGO stage, myometrial invasion, cervical invasion, LVS involvement, lymph node metastasis, and CA125 levels. This study investigated whether the inflammatory markers comprising the GPS predicted PFS and OS of patients with EC. The PFS and OS of patients with EC that had a high GPS (GPS 2) were significantly shorter than the PFS and OS of those with a low GPS. Moreover, multivariate analysis of our study population with EC

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Table 2 Associations of GPS with clinical factors on ovarian cancer. Variable

Numbers of GPS 0

Numbers of GPS 1

Numbers of GPS 2

Stage I–II III–IV

317 59

24 14

4 13

Histology Type I Type II

298 78

19 19

5 12

Tumor maximum size 4 cm >4 cm

282 94

20 18

6 11

Myometrial invasion 1/2 >1/2

268 108

20 18

4 13

Cervical invasion Absent Present

322 54

31 7

8 9

LVS involvement Absent Present

304 72

27 11

6 11

Peritoneal cytology Absent Present

317 59

30 8

12 5

Ovarian metastasis Absent Present

354 22

33 5

12 5

Lymph node metastasis Absent Present

341 35

29 9

8 9

CA125 35.0U/ml >35.0 U/ml

269 107

21 17

2 15

p-value 0.001*

0.095

0.161

0.016*

0.003*

0.004*

0.43

0.145

0.015*

<0.001*

Abbreviations: GPS, Glasgow prognostic score. * p < 0.05.

Table 3 Prognostic factors for progression-free survival and overall survival with endometrial cancer selected by Cox’s univariate and multivariate analysis. Univariate analysis

Multivariate analysis

Hazard ratio

95% CI

p-value

Hazard ratio

95% CI

p-value

Progression free survival Stage (Stage III–IV) Grade (Type II) Tumor size (>4 cm) Myometrial invasion Cervical invasion LVS involvement Peritoneal cytology Ovarian metastasis Lymph node metastasis CA125 (>35.0 U/ml) GPS (1) GPS (2)

10.12 6.31 3.122 4.278 2.685 5.195 3.09 4.073 7.601 3.369 2.53 14.696

6.188–16.549 3.864–10.303 1.952–4.993 2.632–6.954 1.620–4.451 3.247–8.312 1.894–5.040 2.300–7.214 4.701–12.290 2.095–5.418 1.358–4.713 7.963–27.123

<0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* 0.003* <0.001*

5.287 2.68 1.157 1.276 0.842 1.406 1.554 0.509 0.908 1.269 1.847 5.17

2.470–11.318 1.534–4.68 0.667–2.008 0.697–2.338 0.468–1.515 0.797–2.481 0.898–2.690 0.256–1.013 0.455–1.810 0.727–2.215 0.919–3.714 2.311–11.565

<0.001* 0.001* 0.604 0.429 0.566 0.24 0.115 0.054 0.783 0.402 0.085 <0.001*

Overall Survival Stage (Stage III–IV) Grade (Type II) Tumor size (>4 cm) Myometrial invasion Cervical invasion LVS involvement Peritoneal cytology Ovarian metastasis Lymph node metastasis CA125 (>35.0 U/ml) GPS (1) GPS (2)

14.916 10.474 3.442 5.058 3.823 5.697 3.53 4.623 9.747 4.743 2.28 19.003

7.506–29.642 5.262–20.848 1.887–6.278 2.670–9.581 2.072–7.054 3.124–10.389 1.915–6.506 2.329–9.176 5.318–17.864 2.528–8.897 1.013–5.130 10.934–40.362

<0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* <0.001* 0.046* <0.001*

5.772 4.894 1.377 0.925 1.152 1.303 1.893 0.387 1.08 1.203 1.847 5.984

1.948–14.901 2.069–9.486 0.648–2.638 0.3771.952 0.549–2.416 0.635–2.546 0.982–4.115 0.157–0.943 0.505–2.744 0.578–2.724 0.723–4.573 2.820–18.287

0.001* <0.001* 0.455 0.714 0.71 0.499 0.056 0.037* 0.705 0.566 0.204 <0.001*

Abbreviations: GPS, Glasgow prognostic score. * p < 0.05.

M. Saijo et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 210 (2017) 355–359

showed that high pretreatment GPS independently predicted shorter PFS and OS. Therefore, the calculation of GPS may be useful in evaluating the prognosis of patients with EC. We acknowledge that our study has some limitations. The number of patients was relatively small, and the duration of follow-up was relatively short. Further prospective studies with more patients and longer follow-up periods would provide more definitive data to clarify the significance of our findings. In conclusion, this report shows that high GPS can be a useful predictor of poor prognosis in patients with EC. Conflict of interest None declared. References [1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30. [2] Annual Report of Oncology Committee of Japan Society of Obstetrics and Gynecology, Tokyo, Japan 2016. [3] Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD, et al. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol 1991;40:55–65. [4] Aalders JG, Abeler V, Kolstad P. Recurrent adenocarcinoma of the endometrium: a clinical and histopathological study of 379 patients. Gynecol Oncol 1984;17:85–103. [5] Berman ML, Ballon SC, Lagasse LD, Watring WG. Prognosis and treatment of endometrial cancer. Am J Obstet Gynecol 1980;136:679–88. [6] Boronow RC, Morrow CP, Creasman WT, Disaia PJ, Silverberg SG, Miller A, et al. Surgical staging in endometrial cancer: clinical-pathologic findings of a prospective study. Obstet Gynecol 1984;63:825–32. [7] Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987;60:2035–41. [8] Gal D, Recio FO, Zamurovic D, Tancer ML. Lymphvascular space involvement – a prognostic indicator in endometrial adenocarcinoma. Gynecol Oncol 1991;42:142–5. [9] Larson DM, Connor GP, Broste SK, Krawisz BR, Johnson KK. Prognostic significance of gross myometrial invasion with endometrial cancer. Obstet Gynecol 1996;88:394–8. [10] Kim HS, Park NH, Chung HH, Kim JW, Song YS, Kang SB. Serum CA-125 level after 6 cycles of primary adjuvant chemotherapy is a useful prognostic factor for complete responders’ survival in patients with advanced epithelial ovarian cancer. Onkologie 2008;31:315–20. [11] Rose PG, Sommers RM, Reale FR, Hunter RE, Fournier L, Nelson BE. Serial serum CA 125 measurements for evaluation of recurrence in patients with endometrial carcinoma. Obstet Gynecol 1994;84:12–6.

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