Prognosis and adjuvant chemotherapy for patients with malignant peritoneal cytology in early-stage non-endometrioid endometrial cancer

doi:10.21203/rs.3.rs-3214955/v1

Download PDF

Research Article

Prognosis and adjuvant chemotherapy for patients with malignant peritoneal cytology in early-stage non-endometrioid endometrial cancer

https://doi.org/10.21203/rs.3.rs-3214955/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Objective

To investigate the influence of malignant peritoneal cytology (MPC) on the prognosis of early-stage patients with endometrial clear cell carcinoma(CCC) and serous carcinoma(SC), and the value of chemotherapy in their treatment.

Methods

A retrospective observational cohort study was conducted by querying the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from 2010 to 2019. Women with early-stage CCC and SC with available peritoneal cytology results were enrolled. Propensity score matching(PSM) and propensity score inverse probability of treatment weighting (IPTW) was used to balance the measured covariates in each sub-cohort.

Results

A total of 3,616 eligible patients were included, and 368 patients had MPC (10.2%). Women with MPC were more likely to receive postoperative chemotherapy (OR 2.033;95%CI 1.589–2.602). In PSM model, MPC had worse overall survival(OS) and cancer-specific survival (CSS) (All,p < 0.001). The 5-year OS rates were 56.5% for women with MPC and 74.4% for those with negative peritoneal cytology, and the 5-year CSS rates were 60.8% versus 80.0%(All, p < 0.0001). In the subgroup analyses, MPC was associated with decreased OS and CSS in serous, clear cell histology group, and stage IA cases(All,p < 0.001), but not for stage IB or stage II disease. In multivariate analysis, chemotherapy improved the prognosis of patients with MPC(OS:p = 0.005; CSS:p = 0.010). Additionally, in stage IA subgroup, chemotherapy improved survival outcomes in patients with MPC(OS:P = 0.025; CSS:P = 0.038), in NPC patients, however, chemotherapy was a good prognostic factor for OS (P = 0.001) but not for CSS(P = 0.300).

Conclusion

MPC was a prognostic factor for decreased survival in early-stage endometrial CCC and SC, and those with MPC could further benefit from chemotherapy.

Clear cell endometrial cancer

Serous endometrial cancer

Peritoneal cytology

Survival outcomes

Endometrial cancer (EC) is one of most common gynecological cancers, with 66,200 estimated new cases in the United States in 2023(1). Traditionally, EC is classified as endometrioid and non-endometrioid cancer, and the latter account for about 20% of EC characterized by a higher rate of extra-uterine spread and worse prognosis(2). Of note, clear cell cancer and serous cancer are the major non-endometrioid endometrial cancer, together accounting for about 75% of non-endometrioid cancer(2–4).

Endometrial cancer is commonly diagnosed at an early stage. The standard surgical treatment approach for patients with apparent early-stage disease is hysterectomy, salpingo-oophorectomy, and additional lymphadenectomy, which allows primary tumor removal and identification of major prognostic factors (e.g., myometrial invasion, lymph vascular space invasion) for tailoring postoperative adjuvant therapy(5). The presence of tumor cells seen in the peritoneal cytologic specimen at hysterectomy, known as malignant peritoneal cytology, is another possible risk factor considered as an indication of adjuvant therapy. In the National Comprehensive Cancer Network® (NCCN®) guidelines, noninvasive stage IA CCC and SC are stratified according to peritoneal cytology results for tailored adjuvant treatment strategies(6).

Malignant peritoneal cytology can be seen in approximately 5% of early-stage endometrial cancer, and the incidence seems higher in the non-endometrioid histological type(7–9). Multiple studies have suggested that malignant peritoneal cytology is an adverse prognostic factor for survival outcome in early-stage EC, but studies specifically evaluating early-stage non-endometrioid types are limited due to its rarity(2, 7–13).

The objective of this study was to examine the association between malignant peritoneal cytology and survival in women with early-stage endometrial clear cell carcinoma and serous carcinoma, and to explore whether malignant peritoneal cytology may be used as an indication to guide the use of chemotherapy in early-stage CCC and SC.

2.1 Data Source

The Surveillance, Epidemiology, and End Results (SEER) database, a population-based cancer registry established by the National Cancer Institute (NCI), was searched for the analysis(14). Patient identification, data accumulation and entry, and rigorous quality control for the database are managed by registered trained personnel(15). We obtained the information of patients diagnosed between 2010 and 2019 from the SEER∗ Stat version 8.4.0.1 (https://seer.cancer.gov/seerstat/).

2.2 Study Population

The International Classification of Diseases for Oncology, Third Edition (ICD-O-3) morphology codes “8310/3: Clear cell adenocarcinoma, NOS; 8441/3: Serous cystadenocarcinoma, NOS; 8460/3: Papillary serous cystadenocarcinoma; 8461/3: Serous surface papillary carcinoma” was used to identify endometrial clear cell carcinoma (CCC) and serous carcinoma (SC) from patients with histologically confirmed primary endometrial cancer (ICD-O-3, C54.1). The American Joint Committee on Cancer staging classification schema was used for defining T stage. We gathered the following information: age at diagnosis, race, marital status, peritoneal cytology, tumor differentiation, stage, tumor size, hysterectomy type, para-aortic lymphadenectomy, pelvic lymphadenectomy, chemotherapy, radiotherapy, and survival data.

Women with stage I-II (T1/N0/M0, T2/N0/M0) endometrial cancer with histologic confirmation who had available data on survival time and peritoneal cytology results from 2010 to 2019 were included. Exclusion criteria included non-CCC and non-SC, and no hysterectomy or unknown surgery type.

2.3 Outcome Measure

Overall survival (OS) and cancer-specific survival (CSS) were assessed for outcome analysis. OS was considered as the time from diagnosis to death for any cause or to the last contact. CSS was defined as the time from diagnosis to death due to endometrial carcinoma. Women who had no survival event at the last follow-up were censored.

2.4 Statistical analyses

The first step of the analysis was to identify the independent characteristics associated with malignant peritoneal cytology. Differences in the baseline characteristics were assessed with chi-square test for univariable analysis. All the significant covariates with a p-value < 0.05 on univariable analysis were entered in the

binary logistic regression model, and effect size was expressed with an adjusted odds ratio (OR) and corresponding 95% confidence interval (CI). Hosmer-Lemeshow test was used to assess the goodness-of-fit in the final model, and a P > 0.05 was interpreted as a good-fit model.

The second step of the analysis was to evaluate the survival effect of malignant peritoneal cytology in stage I-II endometrial CCC and SC. The propensity score was calculated based on the covariates age at diagnosis, race, marital status, tumor differentiation, stage, tumor size, hysterectomy type, para-aortic lymphadenectomy, pelvic lymphadenectomy, chemotherapy, radiotherapy to reduce the imbalance between the malignant and negative peritoneal cytology groups. Malignant peritoneal cytology cases were matched to negative peritoneal cytology group in a 1:4 ratio and a caliper width of 0.05 standard deviation (SD) was specified. Survival analysis was assessed with the Kaplan–Meier method, and the results were compared with the log-rank test. The Kaplan-Meier method was used to plot survival curves, and a Cox proportional hazard regression model was fitted to estimate hazard ratio (HR) with 95% confidence interval (CI) for malignant peritoneal cytology.

Lastly, cox regression analyses were employed to identify whether adjuvant chemotherapy improved the outcome of endometrial CCC/SC patients with malignant peritoneal cytology by reporting the hazard ratios (HR) and 95% CI.

In addition, we conducted multiple subgroup analyses to enhance the validity of this study. First, the effect of peritoneal cytology results on survival outcome was examined, stratified by histology (clear cell versus serous), and stage (stage IA, stage IB, stage II). Second, the effect of chemotherapy on the prognosis of women with stage IA was examined based on peritoneal cytology results (malignant versus negative). Propensity score inverse probability of treatment weighting (IPTW) was used to balance the measured covariates in each subcohort(16). The Kaplan-Meier method was used to plot survival curves, and the survival analysis results were compared with the log-rank test.

Statistical analyses were all performed with SPSS (version26.0, IBM Corporation, USA) and R software (version 4.2.1; http://www.R-project.org/). A two-sided p value < 0.05 was considered statistically significant.

3.1 Patient population

A total of 3,616 patients were eligible for incidence analysis (Fig. 1). Of those, malignant peritoneal cytology was reported in 368 (10.2%) women and the remaining 3,248 (89.8%) women had negative peritoneal cytology. Majority of women were 60–69 years (43.5%), white (71.1%), and married (50.3%). In terms of histopathology, most of patients were serous carcinoma (84.2%), poor differentiated or undifferentiated (67.7%), and IA stage (71.2%). Simple hysterectomy was performed in 90.7% of patients. Pelvic and para-aortic lymphadenectomy were performed in 88.9% and 55.9% cases, respectively. 47.6% of the included patients received radiotherapy, and more than half of patients received chemotherapy (60.6%).

3.2 Factors associated with malignant peritoneal cytology

In the univariable and multivariable analysis (Table 1), race, marital status, and postoperative adjuvant chemotherapy were the factors associated with peritoneal cytology results (all p < 0.05). Blacks were more likely to have negative peritoneal cytology than whites (OR 0.565; 95%CI 0.406–0.787). Women in the malignant peritoneal cytology were more likely to receive postoperative adjuvant chemotherapy (OR 2.033; 95%CI 1.589–2.602).

Table 1

Patient demographics per peritoneal cytology status (N = 3616).
Characteristics	Total = 3,616 (n,%)	Negative ,n = 3,248 (n,%)	Malignant ,n = 368 (n,%)	P-value	Adjusted OR (95% CI)	P-value
Age (year)				0.103
<50	26(0.7)	20(0.6)	6(1.6)
50–59	484(13.4)	427(13.1)	57(15.5)
60–69	1572(43.5)	1419(43.7)	153(41.6)
70–79	1146((31.7)	1038(32.0)	108(29.3)
≥ 80	388(10.7)	344(10.6)	44(12.0)
Race				0.028
White	2572(71.1)	2287(70.4)	285(77.4)		1
Black	672(18.6)	625(19.2)	47(12.8)		0.565(0.406–0.787)	0.001
Asian or Pacific Islander	333(9.2)	299(9.2)	34(9.2)		0.888(0.608–1.296)	0.537
American Indian/Alaska Native	22(0.6)	21(0.6)	1(0.3)		0.417(0.055–3.142)	0.396
Unknown	17(0.5)	16(0.5)	1(0.3)		0.513(0.067–3.922)	0.520
Marital status				0.015
Married	1819(50.3)	1617(49.8)	202(54.9)		1
Divorced	404(11.2)	380(11.7)	24(6.5)		0.537(0.346–0.835)	0.006
Separated	50(1.4)	43(1.3)	7(1.9)		1.502(0.660–3.422)	0.332
Single (never married)	511(14.1)	454(14.0)	57(15.5)		1.156(0.838–1.595)	0.376
Unmarried or Domestic Partner	12(0.3)	9(0.3)	3(0.8)		2.353(0.626–8.848)	0.205
Widowed	640(17.7)	578(17.8)	62(16.8)		0.988(0.728–1.340)	0.937
Unknown	180(5.0)	167(5.1)	13(3.5)		0.661(0.368–1.188)	0.166
Histology type				0.332
Clear cell carcinoma	572(15.8)	521(16.0)	51(13.9)
Serous carcinoma	3044(84.2)	2727(84.0)	317(86.1)
Tumor differentiation				0.255
Well differentiated	65(1.8)	60(1.8)	5(1.4)
Moderately differentiated	109(3.0)	92(2.8)	17(4.6)
Poorly differentiated or undifferentiated	2448(67.7)	2200(67.7)	248(67.4)
Unknown	994(27.5)	896(27.6)	98(26.6)
Stage				0.122
IA	2575(71.2)	2330(71.7)	245(66.6)
IB	538(14.9)	477(14.7)	61(16.6)
I NOS	97(2.7)	88(2.7)	9(2.4)
II	406(11.2)	353(10.9)	53(14.4)
Tumor size (cm)				0.196
≤ 2.0	899(24.9)	823(25.3)	76(20.7)
2.1−4.0	1011(28.0)	908(28.0)	103(28.0)
4.1−6.0	552(15.3)	483(14.9)	69(18.8)
6.1−8.0	166(4.6)	146(4.5)	20(5.4)
>8	98(2.7)	86(2.6)	12(3.3)
Unknown	890(24.6)	802(24.7)	88(23.9)
Hysterectomy type				0.599
Simple	3279(90.7)	2952(90.9)	327(88.9)
Supracervical	22(0.6)	20(0.6)	2(0.5)
Modified/radical	181(5.0)	159(4.9)	22(6.0)
NOS	134(3.7)	117(3.6)	17(4.6)
Para-aortic lymphadenectomy				0.919
No	1431(39.6)	1289(39.7)	142(38.6)
Yes	2022(55.9)	1813(55.8)	209(56.8)
Unknown	163(4.5)	146(4.5)	17(4.6)
Pelvic lymphadenectomy				0.290
No	348(9.6)	305(9.4)	43(11.7)
Yes	3213(88.9)	2895(89.1)	318(86.4)
Unknown	55(1.5)	48(1.5)	7(1.9)
Radiotherapy				0.272
Radioactive implants (includes brachytherapy) or radioisotopes	1216(33.6)	1088(33.5)	128(34.8)
Beam radiation	332(9.2)	295(9.1)	37(10.1)
Combination of beam with implants or isotopes	164(4.5)	151(4.6)	13(3.5)
Radiation,NOS	10(0.3)	9(0.3)	1(0.3)
No	93(2.6)	90(2.8)	3(0.8)
Unknown	1801(49.8)	1615(49.7)	186(50.5)
Chemotherapy				< 0.001
No/Unknown	1426(39.4)	1331(41.0)	95(25.8)		1
Yes	2190(60.6)	1917(59.0)	273(74.2)		2.033(1.589–2.602)	< 0.001
Abbreviations: NOS, not otherwise significant. Bold values indicate significance at p < 0.05.

3.3 Survival effect of malignant peritoneal cytology

All of the 12 measured covariates were well-balanced after propensity score matching (PSM) (Table S1). In the PSM model, 365 women with malignant peritoneal cytology were compared with 1406 women with negative peritoneal cytology for survival outcome analysis. The cox proportional hazard regression model showed that malignant peritoneal cytology was an independent risk prognostic factor for overall survival (OS) (Univariate: HR 2.028; 95%CI 1.650–2.492; p < 0.001. Multivariate: HR 2.200; 95%CI 1.781–2.718; p < 0.001). A similar association was observed for cancer-specific survival (CSS) (Univariate: HR 2.453; 95%CI 1.945–3.094; p < 0.001. Multivariate: HR 2.704; 95%CI 2.130–3.432; p < 0.001) (Table S2). The 5-year OS rates were 56.5% for women with malignant peritoneal cytology and 74.4% for those with negative peritoneal cytology (p < 0.0001) (Fig. 2A), and the 5-year CSS rates were 60.8% versus 80.0% (p < 0.0001) (Fig. 2B).

Malignant peritoneal cytology was a prognostic risk factor observed for the sub-cohorts of patients with CCC histology(OS: P < 0.001; CSS: P < 0.001)(Fig. 3A;3B), SC histology (OS:P < 0.001; CSS: P < 0.001) (Fig. 3C;3D), and stage IA(OS: P < 0.001; CSS: P < 0.001) (Fig. 3E;3F). In contrast, peritoneal cytology was not associated with prognosis in the stage IB (OS: P = 0.366; CSS: P = 0.131) (Figure S1 A;B) and stage II (OS: P = 0.215; CSS: P = 0.100) (Figure S1 C;D) subgroups.

3.4 Significance of adjuvant chemotherapy in patients based on peritoneal cytology results

The association between adjuvant chemotherapy and survival was examined among women with malignant peritoneal cytology (Table 2). According the multivariate cox regression analysis, after controlling for confounding factors, adjuvant chemotherapy as an independent prognostic factor could improve the survival of patients with malignant peritoneal cytology (OS: HR 0.557, 95%CI 0.370–0.839, p = 0.005; CSS: HR 0.553, 95%CI 0.354–0.866, p = 0.010).

Table 2

Univariate and Multivariate cox regression analysis of patients with malignant peritoneal cytology.(n = 368)
Clinical variables	OS				CSS
	Univariate analysis		Multivariate analysis		Univariate analysis		Multivariate analysis
	HR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value
Age (year)
<50	Ref				Ref
50–59	2.337(0.311–17.564)	0.410			1.931(0.254–14.691)	0.525
60–69	2.428(0.335–17.613)	0.380			2.112(0.290−15.369)	0.460
70–79	3.633(0.500−26.383)	0.202			2.959(0.406–21.594)	0.285
≥ 80	6.101(0.829–44.918)	0.076			5.280(0.713–39.113)	0.103
Race
White	Ref		Ref		Ref		Ref
Black	1.525(0.970–2.398)	0.068	1.396(0.846–2.302)	0.192	1.318(0.784–2.215)	0.195	1.247(0.706–2.201)	0.447
Asian or Pacific Islander	0.973(0.491–1.925)	0.936	1.121(0.553–2.271)	0.752	1.003(0.486–2.071)	0.448	1.153(0.542–2.452)	0.711
American Indian/Alaska Native	46.980(5.860−376.665)	< 0.001	38.512(4.550−325.987)	0.001	91.188(10.163−818.194)	< 0.001	78.844(8.219−756.378)	< 0.001
Unknown	-	-	-	-	-	-	-	-
Marital status
Married	Ref		Ref		Ref		Ref
Divorced	1.110(0.533–2.311)	0.781	1.069(0.495–2.309)	0.865	1.109(0.506–2.430)	0.796	1.015(0.434–2.376)	0.972
Separated	1.840(0.577–5.864)	0.303	1.464(0.446–4.804)	0.529	1.398(0.341–5.734)	0.642	1.187(0.281–5.018)	0.816
Single (never married)	1.042(0.620–1.753)	0.875	1.152(0.674–1.967)	0.605	0.938(0.524–1.680)	0.829	1.110(0.610–2.021)	0.733
Unmarried or Domestic Partner	-	-	-	-	-	-	-	-
Widowed	2.334(1.538–3.542)	< 0.001	1.830(1.164–2.877)	0.009	2.223(1.408–3.509)	0.001	1.836(1.118–3.014)	0.016
Unknown	0.942(0.380–2.338)	0.898	1.228(0.421–3.578)	0.707	01.087(0.436–2.710)	0.858	1.671(0.623–4.480)	0.308
Histology type
Clear cell carcinoma	Ref				Ref
Serous carcinoma	0.688(0.439–1.078)	0.102			0.751(0.454–1.243)	0.265
Tumor differentiation
Well differentiated	Ref				Ref
Moderately differentiated	1.777(0.218–14.465)	0.591			1.229(0.143–10.533)	0.851
Poorly differentiated or undifferentiated	1.432(0.200−10.279)	0.721			1.172(0.163–8.427)	0.875
Unknown	1.166(0.159–8.580)	0.880			1.018(0.138–7.522)	0.986
Stage
IA	Ref		Ref		Ref		Ref
IB	0.841(0.499–1.417)	0.514	0.925(0.539–1.587)	0.777	0.796(0.449–1.411)	0.435	0.934(0.514–1.698)	0.823
I NOS	2.188(0.886–5.405)	0.090	1.269(0.480–3.358)	0.631	2.002(0.730–5.486)	0.177	1.074(0.365–3.159)	0.897
II	1.994(1.313–3.029)	0.001	2.390(1.496–3.818)	< 0.001	1.851(1.166–2.939)	0.009	2.283(1.371–3.801)	0.002
Tumor size (cm)
≤ 2.0	Ref				Ref
2.1−4.0	0.838(0.521–1.350)	0.468			0.916(0.546–1.537)	0.739
4.1−6.0	0.869(0.505–1.496)	0.613			0.773(0.414–1.441)	0.418
6.1−8.0	1.577(0.774–3.210)	0.210			1.737(0.813–3.709)	0.154
>8	1.111(0.464–2.658)	0.813			1.132(0.434–2.948)	0.800
Unknown	0.786(0.476–1.301)	0.349			0.871(0.505−1.500)	0.618
Hysterectomy type
Simple	Ref				Ref		Ref
Supracervical	0.856(0.119–6.133)	0.877			-	-	-	-
Modified/radical	0.393(0.145–1.064)	0.066			0.230(0.057–0.932)	0.040	0.240(0.055–1.051)	0.058
NOS	1.107(0.487–2.514)	0.809			1.284(0.563–2.928)	0.552	1.206(0.499–2.918)	0.677
Para-aortic lymphadenectomy
No	Ref		Ref		Ref		Ref
Yes	0.575(0.408–0.811)	0.002	0.796(0.525–1.207)	0.284	0.659(0.453–0.960)	0.030	0.925(0.581–1.471)	0.741
Unknown	0.569(0.178–1.819)	0.342	1.086(0.143–8.258)	0.937	0.499(0.121–2.057)	0.336	1.424(0.183–11.080)	0.736
Pelvic lymphadenectomy
No	Ref		Ref		Ref		Ref
Yes	0.504(0.326–0.780)	0.002	0.658(0.391–1.107)	0.115	0.482(0.303–0.769)	0.002	0.569(0.322–1.008)	0.053
Unknown	0.380(0.090–1.609)	0.189	0.323(0.023–4.564)	0.403	0.220(0.030–1.640)	0.140	0.244(0.012–4.961)	0.358
Radiotherapy
Radioactive implants (includes brachytherapy) or radioisotopes	Ref		Ref		Ref		Ref
Beam radiation	1.424(0.774–2.623)	0.256	1.126(0.597–2.122)	0.714	1.402(0.729–2.696)	0.312	1.080(0.544–2.146)	0.825
Combination of beam with implants or isotopes	1.887(0.735–4.845)	0.187	1.501(0.552–4.083)	0.426	1.686(0.591–4.806)	0.329	1.234(0.395–3.851)	0.718
Radiation,NOS	-	-	-	-	-	-	-	-
No	2.771(0.664–11.565)	0.162	2.568(0.585–11.266)	0.211	3.123(0.744–13.107)	0.120	2.778(0.618–12.478)	0.183
Unknown	1.945(1.295–2.921)	0.001	1.502(0.950–2.376)	0.082	1.822(1.176–2.823)	0.007	1.413(0.860–2.323)	0.173
Chemotherapy
No/unknown	Ref		Ref		Ref		Ref
Yes	0.411(0.291–0.581)	< 0.001	0.557(0.370–0.839)	0.005	0.423(0.290–0.618)	< 0.001	0.553(0.354–0.866)	0.010
Abbreviations: NOS, not otherwise significant. OS,overall survival.CSS,specific cancer survival. Bold values indicate significance at p < 0.05.

Additionally, in stage IA patients with malignant peritoneal cytology, adjuvant chemotherapy could improve the survival outcomes (OS: P = 0.025; CSS: P = 0.038) (Fig. 4A;B). Of note, in stage IA patients with negative peritoneal cytology, chemotherapy was a good prognostic factor for OS (P = 0.001) but not for CSS (P = 0.300) (Fig. 4C;D).

Our study found that malignant peritoneal cytology was significantly correlated with shorter OS and CSS in early-stage endometrial clear cell carcinoma and serous carcinoma. Moreover, the survival effect of adjuvant chemotherapy may differ depending on peritoneal cytology status for early-stage endometrial clear cell carcinoma and serous carcinoma.

In our study, malignant peritoneal cytology was seen in 10.2% of stage I-II ECCC and SC, compared to 6.0–10.9% which has been reported in prior studies(7, 17–21). This prevalence is far higher than in early-stage endometrioid endometrial cancer, where malignant peritoneal cytology is reported to be around 5%(8, 10, 11). One possible mechanism of malignant peritoneal cytology is the retrograde spread of tumor cells via the fallopian tubes. A study of 4489 EC patients, including 686 SC patients and 172 CCC patients, revealed that tubal ligation is associated with decreased risk of peritoneal tumor metastasis (GOG-210)(22). The risk reduction is much more significant in SC group than endometroid histology (SC: OR 0.28, 95% CI 0.11–0.68; Low-grade endometroid: OR 1.27, 95% CI 0.41–3.89). In the CCC group, although no statistically significant conclusions can be drawn due to the small number of CCC patients, CCC patients with tubal ligation tend to have a lower risk of peritoneal tumor metastasis (OR 0.27, 95% CI 0.00-2.24). Non-endometrioid EC is more likely to have trans-tubal spread, which may explain the higher incidence of malignant peritoneal cytology in SC and CCC than endometrioid tumors. Based on a SEER study(7), the increased risk of malignant peritoneal cytology is associated with diagnosis at an older age (> 78 years old), serous histology, and larger tumor size (4.1-6.0cm vs. <2cm) in stage I non-endometrioid EC. Our study, however, failed to find an association between the above factors and malignant peritoneal cytology, which is consistent with several studies targeted SC/CCC histology (21, 23).

Our study demonstrated that malignant peritoneal cytology was a poor prognostic factor for stage I -II ECCC and SC histology, which was in line with the results of previous studies, but our study specifically targeted SC and CCC groups and the sample size was larger(2, 7, 12, 21, 23). A big-data SEER analysis reported by Matsuo K, et al. revealed that malignant peritoneal cytology was associated with a nearly two-fold increase in all-cause mortality risk compared to negative peritoneal cytology (5-year rates, 63.4% versus 80.2%, HR 2.18, 95% CI 1.78–2.66) in stage I non-endometrioid EC(7). In an analysis of a large cohort of stage I SC/CCC patients with long-term follow-up, Jeans EB, et al. demonstrated any recurrence was worse for tumors of at least 3.5 cm (HR 3.8, 95%CI 1.3–11.7, p = 0.02) and patients with positive/suspicious cytology (HR 4.4, 95%CI 1.5 to 12.4, p ≤ 0.01), and multivariate modeling showed worse any recurrence with positive/suspicious cytology after adjusting for the effect of age(2). A recent study of 101 patients with stage I SC and CCC showed that patients with malignant cytology had a higher likelihood of peritoneal recurrence and a shorter time to relapse (13 vs. 38 months, p = 0.022), as compared to patients with negative cytology(21). A retrospective study of 148 patients diagnosed with uterine serous carcinoma reported malignant peritoneal cytology had a statistically significant effect on OS (HR: 2.09, 95% CI 1.19–3.68) and on CSS (HR: 2.02, 95% CI 1.06–3.82), but the study included stage III SC patients (23). A study enrolling patients with stage I-II uterine serous carcinoma without adjuvant therapy demonstrated malignant peritoneal cytology was significant prognosticators (DFS: HR 4.24; 95% CI 1.56–11.50; p = 0.005; OS: HR 4.96; 95% CI 1.34–18.30; p = 0.017)(12).

Our study explored the prognostic value of malignant peritoneal cytology in not only early-stage non-endometrioid EC patients but also in various subgroups stratified based on stage and histological type. In the subgroup analyses, malignant peritoneal cytology was associated with decreased OS and CSS in serous, clear cell histology group, and stage IA disease, but not for stage IB or stage II disease, which was consistent with the big-data results reported by Matsuo K, et al(7). The previous retrospective study on 68 cases with USC without adjuvant therapy also showed that malignant peritoneal cytology had significant worse prognostic impact on OS (p = 0.0012) and DFS (p = 0.0001) in stage IA disease (n = 42), but not in stage IB (n = 7) (OS: p = 0.722; DFS: p = 0.911) and II (n = 19) (OS: p = 0.48; DFS : p = 0.85)(12). Yang J, et al, however, reported that the detrimental effects of malignant cytology on survival were more prominent in patients with stage IB disease. Notably, the limited number of patients with malignant peritoneal cytology may result in a few underpowered analyses in the study reported by Yang J, et al(21).

Adjuvant therapy for early-stage endometrial clear cell carcinoma and serous carcinoma is highly individualized, and the role of chemotherapy remains controversial. Previous studies have shown that chemotherapy could improve the prognosis of patients with stage I SC and CCC(19, 21). These study, however, did not consider peritoneal cytology as a stratification factor to explore the role of chemotherapy. In our study, patients with malignant peritoneal cytology tended to receive adjuvant chemotherapy, and subgroup analysis found that malignant peritoneal cytology was an adverse prognostic factor in SC/CCC patients with stage IA, so we further explored whether adjuvant chemotherapy could improve the prognosis of patients with malignant peritoneal cytology in stage IA. We found that in stage IA patients with malignant peritoneal cytology, those who received chemotherapy had longer OS (p = 0.025) and CSS (p = 0.038), and for those with negative peritoneal cytology, chemotherapy improved OS (p = 0.001) but not CSS (p = 0.300). Therefore, we believed that SC and CCC patients with stage IA and malignant peritoneal cytology could be considered for chemotherapy. Our finding was in accordance with the NCCN recommendation. According to the 2023 NCCN guideline, noninvasive stage IA CCC and SC are stratified according to peritoneal cytology results for tailored adjuvant therapy strategies, and systemic therapy and vaginal brachytherapy is recommended if positive washings(6). Additionally, for patients with invasive stage IA, systemic therapy could be considered regardless of peritoneal cytology(6).

A recent retrospective study revealed that chemotherapy did not improve RFS or OS in type II ECs (SC: n = 22, CCC: n = 12) with stage IA and malignant peritoneal cytology. Although the results were not statistically significant, it could be found that the 5-year relapse-free survival rate and 5-year overall survival rate in the chemotherapy group were higher than those in the non-chemotherapy group (RFS:85.2% vs. 66.7%, p = 0.11; OS: 91.9% vs. 77.8%, p = 0.15), so it may be better to treat them with adjuvant chemotherapy(24). An observational retrospective study of 16,851 stage I-II ECs including 973 serous carcinomas and 190 clear cell carcinomas revealed that adjuvant chemotherapy was associated with increased overall survival in early-stage EC patients with malignant peritoneal cytology (HR 0.62, 95%CI 0.40–0.95, P = 0.03). However, studies have not fully discussed which histologic subtype of early-stage patients with malignant peritoneal cytology may be able to experience increased survival with adjuvant chemotherapy(9). A study, involving stage I SC and CCC patients who had received adjuvant vaginal cuff brachytherapy and/or chemotherapy, reported that positive/suspicious cytology were at increased risk for relapse and worse survival, and should be considered for additional upfront adjuvant treatments, such as platinum-based chemotherapy(2). However, the role of chemotherapy has not been individually investigated in stage IA patients in this analysis(2). For early-stage non-endometrioid endometrial cancer with negative peritoneal cytology, Matsuo K, et al. stated that women who received chemotherapy-based postoperative therapy had higher 5-year OS rates compared to those received whole pelvic irradiation (79.6% for chemotherapy ± brachytherapy, 77.4% for chemotherapy with whole pelvic irradiation, and 56.9% for whole pelvic irradiation, P < 0.001)(7). However, a study reported by Tate K, et al. revealed that patients with stage IA or IB USC showing negative peritoneal cytology might have an extremely favorable prognosis (5-year DFS rate:88.8%; 5-year OS rate:93.6%) and did not need any adjuvant therapies(12). More clinical studies are needed to investigate the significance of adjuvant chemotherapy in patients with stage IA non-endometrioid endometrial cancer with negative peritoneal cytology.

Strengths of the current study include: this was a population-based analysis with the large sample size for endometrial clear cell carcinoma and serous carcinoma; the long follow-up period; several subgroup analyses with stage and histologic type as stratification factors enhanced the interpretation of the study results; the analytic approach with propensity score matching and propensity score inverse probability of treatment weighting enriched the statistical rigor.

Additionally, our study does have several limitations. Predominantly, it was a retrospective study with inherent unmeasured bias. For example, details of surgical-pathological factors such as lympho-vascular space invasion, and omental biopsy were not available in the SEER Program, but may be associated with the incidence of malignant peritoneal cytology as well as the oncologic outcomes. Second, the accuracy of malignant cytology results was unknown due to the lack of central pathology review in the study. Third, as this study only examined the U.S. population, whether our findings are generalizable to other study populations needs to be further examined. Fourth, per the SEER Program definition, cases with no and unknown status are grouped together in chemotherapy, and details of chemotherapy (regimen and cycle) were not available.

In conclusion, the current study clearly showed that malignant peritoneal cytology was identified as an adverse prognostic factor in analyses of all early-stage endometrial clear cell carcinoma and serous carcinoma as well as in CCC histology type, SC histology type, and stage IA subgroup analyses. Based on the results of the present study, stage IA SC/CCC patients with malignant peritoneal cytology could further benefit from chemotherapy. Of note, peritoneal cytology results should not be taken in isolation to guide adjuvant therapy, and it should also be considered in combination with other risk factors for survival outcomes. Further prospective clinical trials are necessary to evaluate the efficacy of adjuvant therapy in stage IA SC/CCC groups.

Ethics approval and consent to participate: Not applicable

Consent for publication: Not applicable

Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests

Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Authors' contributions: Xinyue Tang: Proiect development, Data collection, Manuscript writing. Na Li: Data collection. Yuanjing Hu: Project development. All the authors have reviewed the final draft of the manuscript and approved it for publication.

Acknowledgements: Not applicable

Authors' information (optional)Compliance with Ethical Standards :Not Applicable

Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: a cancer journal for clinicians. 2023;73(1):17-48.
Jeans EB, Breen WG, Mullikin TC, Looker BA, Mariani A, Keeney GL, et al. Adjuvant brachytherapy for FIGO stage I serous or clear cell endometrial cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2021;31(6):859-67.
Bogani G, Ray-Coquard I, Concin N, Ngoi NYL, Morice P, Enomoto T, et al. Clear cell carcinoma of the endometrium. Gynecologic oncology. 2022;164(3):658-66.
Bogani G, Ray-Coquard I, Concin N, Ngoi NYL, Morice P, Enomoto T, et al. Uterine serous carcinoma. Gynecologic oncology. 2021;162(1):226-34.
Oaknin A, Bosse TJ, Creutzberg CL, Giornelli G, Harter P, Joly F, et al. Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology. 2022;33(9):860-77.
Abu-Rustum. NR, Yashar. CM, Bradley. K, Brooks. R, Campos SM. NCCN Guidelines®Uterine Neoplasms.Version 1.2023.https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf.
Matsuo K, Nusbaum DJ, Matsuzaki S, Chang EJ, Roman LD, Wright JD, et al. Malignant peritoneal cytology and increased mortality risk in stage I non-endometrioid endometrial cancer. Gynecologic oncology. 2020;159(1):43-51.
Matsuo K, Yabuno A, Hom MS, Shida M, Kakuda M, Adachi S, et al. Significance of abnormal peritoneal cytology on survival of women with stage I-II endometrioid endometrial cancer. Gynecologic oncology. 2018;149(2):301-9.
Seagle BL, Alexander AL, Lantsman T, Shahabi S. Prognosis and treatment of positive peritoneal cytology in early endometrial cancer: matched cohort analyses from the National Cancer Database. American journal of obstetrics and gynecology. 2018;218(3):329.e1-.e15.
Takenaka M, Kamii M, Iida Y, Yanaihara N, Suzuki J, Takahashi K, et al. Re-thinking the prognostic significance of positive peritoneal cytology in endometrial cancer. Gynecologic oncology. 2021;161(1):135-42.
Matsuo K, Matsuzaki S, Nusbaum DJ, Machida H, Nagase Y, Grubbs BH, et al. Malignant peritoneal cytology and decreased survival of women with stage I endometrioid endometrial cancer. European journal of cancer (Oxford, England : 1990). 2020;133:33-46.
Tate K, Yoshida H, Ishikawa M, Uehara T, Ikeda SI, Hiraoka N, et al. Prognostic factors for patients with early-stage uterine serous carcinoma without adjuvant therapy. Journal of gynecologic oncology. 2018;29(3):e34.
Garg G, Gao F, Wright JD, Hagemann AR, Mutch DG, Powell MA. Positive peritoneal cytology is an independent risk-factor in early stage endometrial cancer. Gynecologic oncology. 2013;128(1):77-82.
Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER Research Plus Data, 17 Registries, Nov 2021 Sub (2000-2019) - Linked To County Attributes - Time Dependent (1990-2019) Income/Rurality, 1969-2020 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2022, based on the November 2021 submission.
National Cancer Registrars Association. http://www.ncra-usa.org/. Accessed 23 Jul 2020.
Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Statistics in medicine. 2015;34(28):3661-79.
Mysona DP, Tran LKH, Tran PMH, Gehrig PA, Van Le L, Ghamande S, et al. Clinical calculator predictive of chemotherapy benefit in stage 1A uterine papillary serous cancers. Gynecologic oncology. 2020;156(1):77-84.
Orellana TJ, Garrett AA, Soong TR, Rives T, Courtney-Brooks M, Taylor SE, et al. The role of adjuvant treatment for early-stage uterine clear cell carcinomas. Gynecologic oncology. 2023;170:77-83.
Qu XM, Velker VM, Leung E, Kwon JS, Elshaikh MA, Kong I, et al. The role of adjuvant therapy in stage IA serous and clear cell uterine cancer: A multi-institutional pooled analysis. Gynecologic oncology. 2018;149(2):283-90.
Ditto A, Leone Roberti Maggiore U, Lopez S, Martinelli F, Bogani G, Lo Vullo S, et al. Uterine serous carcinoma: role of surgery, risk factors and oncologic outcomes. Experience of a tertiary center. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2022;48(1):268-74.
Yang J, Yang J, Cao D, Wu M, Xiang Y. Prognostic Value of Peritoneal Cytology in Stage I Serous and Clear Cell Carcinoma of the Endometrium. Journal of clinical medicine. 2023;12(4).
Felix AS, Brinton LA, McMeekin DS, Creasman WT, Mutch D, Cohn DE, et al. Relationships of Tubal Ligation to Endometrial Carcinoma Stage and Mortality in the NRG Oncology/ Gynecologic Oncology Group 210 Trial. Journal of the National Cancer Institute. 2015;107(9).
Corey L, Fucinari J, Elshaikh M, Schultz D, Musallam R, Zaiem F, et al. Impact of positive cytology in uterine serous carcinoma: A reassessment. Gynecologic oncology reports. 2021;37:100830.
Kanno M, Yunokawa M, Nakabayashi M, Omi M, Ikki A, Mizusaki M, et al. Prognosis and adjuvant chemotherapy for patients with positive peritoneal cytology in stage IA endometrial cancer. Scientific reports. 2022;12(1):166.

No competing interests reported.

FigureS1.tif
Figure S1 Based on the adjuvant chemotherapy, overall survival (A) and cancer-specific survival (B) for stage IB patients; overall survival (C) and cancer-specific survival (D) for stage II patients.
TableS1andS2.docx
Table S1 Patient demographics per peritoneal cytology status after PSM (N=1771). PSM, propensity score matching; NOS, not otherwise significant. Table S2 Cox proportional hazard regression model after PSM.

Download PDF

Version 1

posted

You are reading this latest preprint version

Prognosis and adjuvant chemotherapy for patients with malignant peritoneal cytology in early-stage non-endometrioid endometrial cancer

Status:

Version 1

Abstract

Objective

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials and methods

2.1 Data Source

2.2 Study Population

2.3 Outcome Measure

2.4 Statistical analyses

3. Results

3.1 Patient population

3.2 Factors associated with malignant peritoneal cytology

3.3 Survival effect of malignant peritoneal cytology

3.4 Significance of adjuvant chemotherapy in patients based on peritoneal cytology results

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1