The association between sites of distant metastases and overall

survival in cervical cancer

Ce Wang, Zhenyi Xu, Jiali Song, Yuhong Lu, Meng Wang, Yan Hou*

Department of Epidemiology and Biostatistics, School of Public Health, Harbin

Medical University, Harbin, 150086, China;

*Corresponding author: Yan Hou, Department of Epidemiology and Biostatistics,

School of Public Health, Harbin Medical University, Harbin, 150086, China;

telephone: 86-451-87502645; Fax number: 86-451-87202885; Email:

houyan@ems.hrbmu.edu.cn;

Abstract

Background: To assess the association between patterns of distant metastases and overall

survival in metastatic cervical cancer and identify prognostic factors for site-specific distant

metastases.

Method: A total of 1123 cervical cancer patients with pathologically confirmed between 2010 and

2015 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database.

Independent prognostic factors for overall survival were identified by univariate and multivariate

Cox proportional hazard models. Survival time were estimated using the Kaplan-Meier method

and compared between groups using the log-rank test.

Results: The most common distant sites were lymph node followed by lung, bone, liver and brain.

The site of distant metastases was an independent prognostic factor for overall survival. We found

that cervical cancer patients with liver or bone metastasis have the worst prognosis followed by

lung metastasis and distant lymph node metastasis. We also found the number of distant

metastases was an independent prognostic factor. Compared to single metastatic site, patients with

multiple metastatic sites had poorer survival. Besides, surgery, radiotherapy and chemotherapy

were found to associate with prognosis for distant lymph node metastasis; Chemotherapy for

distant lung metastasis; Radiotherapy and chemotherapy for distant liver metastases; Radiotherapy

and chemotherapy for distant bone metastasis.

Conclusions：The site of distant metastasis and the number of distant metastases can affect

overall survival in metastatic cervical cancer. Special treatment and management should be given

patients with specific distant metastatic sites.

Keyword: Cervical cancer; Distant metastases; Overall survival

1.Introduction

Cervical cancer is one of the most common types of gynecological malignancies around, in

many developing countries it is the most common cause of cancer death and years of life lost

owing to cancer and nearly 90% of cervical cancer deaths occurred in developing countries[1]. In

2018 worldwide, this disease ranks as the fourth most frequently diagnosed cancer and the fourth

leading cause of cancer death in women [2]. Though more advances in the treatment methods have

been improved in less developed countries and these treatment methods have resulted in better

control of the cervical cancer and longer patient survival, these improved results have been

accompanied by a higher incidence of distant metastases of cervical cancer[3]. And the prognosis

of patients with metastatic cervical cancer is poor with a median survival of 8-13 months[4].

In cervical cancer, common sites of distant metastasis include lymph ,liver, lung and bone,

while brain metastasis may also occur in patients with cervical cancer with an incidence rate

between 0.4 to 1.2% [5-10].Most studies have focused on single distant metastatic sites for

survival of cervical cancer, while few studies focus on survival differences of cervical cancer with

different metastatic sites[6, 7, 11]. Furthermore, it has been reported cervical cancer with different

distant metastasis may have different survival without statistical comparison[3]. Cervical cancer

patients with different distant metastasis will experience different clinical manifestations including

pain, anorexia cachexia, and psychological problems and have different survival

time[12].Therefore, understanding the patterns of distant metastasis in cervical cancer is important

to improve treatment and management for patients.

In this paper, the primary objective of this study was to investigate the relationship between

site-specific patterns of distant metastases and overall survival of metastatic cervical cancer. The

secondary objective was to explore the relationship between the number of distant metastases and

overall survival and to identify the prognostic factors for organ-specific distant metastases.

2.Materials and Methods

2.1 Materials

We identified cervical cancer cases from the SEER program of the National Cancer Institute

(http://seer.cancer.gov/). Inclusion criterion is that all patients who were pathologically confirmed

with cervical cancer from the SEER database from 2010 to 2015. Exclusion criteria are as follows:

unknown surgery or radiotherapy or distant metastatic sites. The original SEER database contains

11080 cervical cancer patients diagnosed from 2010 to 2015. Finally, a total of 1123 cervical

cancer patients were included in this study.

Variables were analyzed in the dataset included age, race, rumor grade, marital status,

histological subtype, treatments, stage, tumor size, sites of distant metastases, and the number of

distant metastatic sites. In our study, in these variables except treatments and sites of distant

metastases, all cervical patients with unknown information were classified ‘others’; Besides,

‘married’ is recorded as married and unmarried but having domestic partner; single is recorded as

‘single’; separated, divorced and widowed were classified as “others”. Except squamous cell

neoplasm and adenomas and adenocarcinomas, other histology types were recorded as “other”.

2.2Method

Categorical measurements are described as count and percentage. Independent predictors for

overall survival were identified by univariate and multivariate Cox proportional hazard models.

Variables that were statistically significant in the univariate Cox analysis were fitted in the

multivariate Cox proportional hazard model. Survival time were estimated using the Kaplan-Meier

method and compared between groups using the log-rank test. Hazard ratios (HR) and 95%

confidence intervals (CI) were estimated using the Cox proportional hazards model. A p-value of

<0.05 was considered as statistically significant. All statistical analyses are performed in R version

3.3.3 (http://www .r-project.org/).

3.Result

3.1Patient Characteristics

A total of 1123 cervical cancer patients between 2010 and 2015 were involved in this study.

The demographic and clinicial characteristics of patients in the cohorts were listed in Table 1. In

addition, detailed demographic and clinical characteristics by metastatic sites and the number of

metastatic sites for study patients were described in Table S1 and Table S2, respectively.

3.2. Distribution of distant metastatic sites

The detailed distributions of distant metastatic site were shown in Table2. The most common

sites for metastasis were distant lymph node (426,37.9%) followed by lung (277,24.7%), bone

(7,0.6%), liver (91,8.1%) and brain (7,0.6%). Patients with one distant metastatic site account for

80.1%, followed by two sites 15.1%, three sites 4.7%, four sites 0.3%.

3.3 Treatment

Overall, most of patients underwent chemotherapy (779,69.4%) or radiotherapy alone (722,

64.3%), while a small number of patients received surgery (133,11.8%), while 185 patients

(16.5%) never received any treatment. And 773 patients (68.9%) received two treatments, 51.2%

of patients receiving radiotherapy and chemotherapy,10.2% of patients receiving chemotherapy

and surgery, 7.5% of patients receiving radiotherapy and surgery. Only 77 patients (6.9%)

received radiotherapy, chemotherapy and surgery.

3.4. The impact of site-specific distant metastases on overall survival

The median survival times for patients with a single site of distant metastasis were 20, 6, 8, 9

and 8 months for patients with lymph, liver, lung, brain and bone, respectively (p<0.001;Figure 1).

And the median survival time for patients with single site of distant metastasis and multiple sites

were 12 and 5 months, respectively (p<0.001; Figure 2).

The univariate Cox analysis of only one site of distant metastases were listed in Table 3, and

the results manifested that age, race, grade, histology, treatments, tumor size, stage, metastatic

sites were statistically significant and associated with overall survival. And for the entire cohort,

the results of the univariate analysis were also listed in Table 3 demonstrated race, grade,

histology, treatment, stage, number of sites of metastases were statistically significant and

associated with overall survival.

The results of multivariate Cox analysis for the patients with only one site of distant

metastases indicated that the site of distant metastases was an independent prognostic factor for

overall survival (Table 4). Using liver metastasis as reference, lung metastasis (HR, 0.58 (95%CI,

0.44-0.76)) and distant lymph node (HR, 0.4 (95%CI, 0.3-0.52)) are both associated with better

overall survival. Using distant lymph node as reference, liver metastasis (HR, 2.52 (95%CI, 1.92-

3.31)), lung metastasis (HR, 1.46 (95%CI, 1.19-1.78)) and bone metastasis (HR, 1.98 (95%CI,

1.5-2.6)) are all associated with poor overall survival; Using bone metastasis as reference, distant

lymph node (HR, 0.51 (95%CI, 0.38-0.67)) and lung metastasis (HR, 0.74 (95%CI, 0.56-0.98))

are both associated with better overall survival. (Table S3).

And multivariate Cox analysis for the entire cohort revealed that the number of distant

metastatic sites was an independent prognostic factor for overall survival (Table 4). Compared to

single metastatic site, patients with multiple metastatic sites had poorer survival (HR, 1.95

(95%CI, 1.65-2.32)).

3.5 Prognostic factors for site-specific distant metastases

Taking into account the sample size of the patient with different distant metastases, we

identified prognostic factors that were associated with overall survival for the patients with distant

metastases except brain.

For patients with distant lymph node metastasis only, univariate Cox regression analysis and

multivariate Cox analysis indict that surgery, radiotherapy and chemotherapy were associated with

overall survival time (Table S4). The corresponding survival curves were shown in Fig.S1. For

patients with lung metastasis only, univariate Cox regression analysis and multivariate Cox

analysis indict that chemotherapy, stage and size were associated with overall survival time (Table

S5). The corresponding survival curves were shown in Fig.S2. For patients with liver metastasis

only, univariate Cox regression analysis and multivariate Cox analysis indict that histology,

radiotherapy and chemotherapy were associated with overall survival time (Table S6). The

corresponding survival curves were shown in Fig.S3. For patients with bone metastasis only,

univariate Cox regression analysis and multivariate Cox analysis indict that race, radiotherapy and

chemotherapy were associated with overall survival time (Table S7). The corresponding survival

curves were shown in Fig.S4.

Discussion

In this study, we explored the relationship between metastatic patterns and overall survival in

cervical cancer, which is important for treatment decisions. We found that the site of distant

metastases was an independent prognostic factor for overall survival among cervical cancer

patients. And, we also found that the number of distant metastatic sites was an independent

prognostic factor for overall survival among cervical cancer patients. Besides, we also identified

independent prognostic factor for cervical cancer patients with lymph node metastases only, lung

metastases, liver metastases only and bone metastases only, respectively.

We found that distant lymph node, lung, liver and bone metastases were the most common,

while brain metastasis is relatively rare in patients in our data. This distribution of distant

metastases in this study is similar with previous studies[13-15]. And most studies focus on effect

of cervical patients with one site of distant metastases. For example, Liu et al and Yan et al found

that patients with lymph node metastasis have longer survival than patients without lymph node

metastases [16, 17].Duangmaniv et al concluded that survival after diagnosis of bone metastasis

was longer in patients who had pelvic bone metastasis compared with ones who had extrapelvic

bone metastasis or both[15]. However, these studies only focused on one distant metastasis in

cervical cancer patients. In our study, we explored the survival differences of cervical cancer with

five different metastatic sites and explored prognostic factors for organ-specific distant metastasis.

We found that liver metastasis in cervical cancer patients is associated with poor overall survival

compared to lung and lymph node metastasis while lymph node metastasis in cervical cancer

patients is associated with better overall survival compared lung, liver and bone metastasis. In Fig

B, we found that brain metastasis may be related with poor survival compared to lymph node

metastasis. We speculated that there is no statistically significant difference between the two

metastatic sites due to the number of patients with brain metastasis is small. Furthermore, to our

knowledge, there were no studies comparing the number of metastatic site effecting on survival in

cervical cancer, and we found that the number of distant metastatic sites is also associated with

overall survival and patients with more than one metastatic site had poor survival compared with

only one metastatic site.

Very few studies have investigated the prognostic factors for organ specific distant metastasis

for cervical cancer. From Table S4 results, we concluded that surgery, radiotherapy and

chemotherapy can improve the prognosis of cervical cancer with distant lymph node metastasis

only. The previous studies reported that chemoradiotherapy is efficient for improving prognosis

patients with distant lymph node metastasis only though there is an increased risk of hematologic

toxicity and surgery may be feasible with low complication rates[18-20].From Fig A and Table

S3, the prognosis of distant lymph node metastasis was the best among the five distant metastatic

sites and these patients should receive these treatments without delay. For the patients with lung

metastasis only, chemotherapy and tumor size and stage were associated with overall patients.

Compared to the patients with distant lymph node metastasis for treatment, chemotherapy is

indispensable for lung metastasis. Furthermore, those patients who were tumor size≥4cm with

stage III/IV should be given special treatments and management. The previous study concluded

appropriate chemotherapy can prolong the survival of patients with lung metastasis from uterine

carcinoma which is consistent with our study [21]. And some studies thought that surgery is a

good choice for improving survival of patients [22, 23], while we found that surgery is not

associated with survival in multivariate analysis results.

For the patients with liver metastasis only, radiotherapy, chemotherapy, histology were

associated with overall survival. And radiotherapy and chemotherapy were important for

improving survival of patients with liver metastasis only. In addition, we found that patients with

adenocarcinoma had shorter survival than patients with squamous cell carcinoma. So the patients

with adenocarcinoma should be given special treatment except radiotherapy and chemotherapy.

For the patients with bone metastasis only, we found that race, radiotherapy, chemotherapy and

stage were associated with overall survival, however, the patients who were black with stage

III/IV had shorter survival. And the previous studies concluded that chemotherapy and

radiotherapy were crucial for survival of cervical cancer with bone metastasis [12, 24, 25].

Notably, although surgery was an independent prognostic factor in patients with distant

lymph node metastasis only, it was not an independent prognostic factor in patients with lung

metastasis only, liver metastasis only and bone metastasis only, which indicated that surgery was

not mandatory for cervical cancer patients with these metastasis. Even though surgery can

improve overall survival with distant lymph node metastasis only, there is no information on

whether surgery for distant lymph nodes in the current data. Besides, we also did not know

whether the metastasis occurred before or after surgery, which prevents us from identifying more

accurate prognostic information.

We have to acknowledge that this study has some limitations. First, there is some inevitable

bias because of the study being a retrospective study. Secondly, the variables we have are limited

from the SEER program. For example, we can not get detailed information on time of metastases.

Thirdly, the number of patients with brain metastasis is so small that we can not identify

independent prognostic factors in patients with brain metastasis only. Besides, if the number of

patients with brain metastasis was small, the conclusion that there was no significant difference on

survival between patients with brain metastasis and lymph node metastasis was not reliable.

Fourth, we did not conduct stratified analyses metastatic site, because the number of patients with

some metastatic sites such as liver, bone and brain.

Though there are limitations in our study, our study still conclude that the site of distant

metastasis is an independent prognostic factor for overall survival in patients with metastatic

cervical cancer. Cervical cancer patients with distant lymph node metastasis have best overall

survival in these metastatic sites while patients with liver metastasis and bone have poorest overall

survival. Besides, we speculate that patients with brain metastasis are associated with poor overall

survival compared to distant lymph node metastasis. Furthermore, we found the number of distant

metastatic sites is an independent prognostic factor for overall survival. Furthermore, treatment

methods are different for with cervical patients with different site distant metastases.

Funding support

This work was funded by National Natural Science Foundation of China under Grant number

81773550 and 81573256.

Conflict of interest statement

The authors have no conflicts of interests to declare.

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Table1 clinical Characteristics of the 1123 cervical cancer patients

variable N(%)

Age

x<65 350 (31.2)

x≥65 773 (68.8)

Race

Asian 59 ( 5.3)

Black 186 (16.6)

White 861 (76.7)

Other 17 ( 1.5)

Grade

G1/G2 253 (22.5)

G3/G4 513 (45.7)

Other 357 (31.8)

Marry

Single 327 (29.1)

Married 401 (35.7)

Other 395 (35.2)

Histology

Squamous cell

neoplams 736 (65.5)

Adenomas and

adenocarcinomas 174 (15.5)

Other 213 (18.9)

Surgery

Yes 133 (11.8)

No 990 (88.2)

Radiotherapy

Yes 722 (64.3)

No 401 (35.7)

Chemotherapy

Yes 779 (69.4)

No 344 (30.1)

Size

x<4 89 ( 7.9)

x≥4 548 (48.8)

other 486 (43.3)

Stage

Early(stage I/II) 199 (17.7)

Late(stage III/IV) 93 ( 8.3)

Other 831 (74.0)

Table2 Patterns of distant metastases for the 1123 cervical cancer patients

Site of distant metastasis N (%)

One site of distant metastasis

Distant lymph node 426 (37.9)

Liver 91 ( 8.1)

Lung 277 (24.7)

Brain 7 ( 0.6)

Bone 99 ( 8.8)

Two sites of distant metastasis

Distant lymph node + liver 0

Distant lymph node + lung 4 ( 0.4)

Distant lymph node + brain 0

Distant lymph node + bone 3 ( 0.3)

Liver + lung 52( 4.6)

Liver + brain 1 ( 0.1)

Liver + bone 30 ( 2.7)

Lung + brain 13 ( 1.2)

Lung + bone 54 ( 4.8)

Brain + bone 11 ( 1.0)

Three sites of distant metastasis

Distant lymph node + liver + lung 1 ( 0.1)

Distant lymph node + liver + brain 0

Distant lymph node + liver + bone 1 ( 0.1)

Distant lymph node + lung + brain 0

Distant lymph node + lung + bone 1 ( 0.1)

Distant lymph node + brain + bone 0

Liver + lung + brain 3 ( 0.3)

Liver + lung + bone 36 ( 3.2)

Liver + brain + bone 2 ( 0.2)

Lung + brain + bone 8 ( 0.7)

Four sites of distant metastasis

Distant lymph node + liver + lung+ brain 0

Distant lymph node + liver + lung + bone 0

Distant lymph node + liver + brain+ bone 0

Liver + lung + brain + bone 3 ( 0.3)

Table 3 Univariate Cox regression analysis of prognostic factors for overall survival in cervical cancer

Variable　 single distant metastases n=900 　 entire cohort n=1123

　 HR (95% CL) p-value 　 HR(95%CL) p-value

Age

x<65 reference reference

x≥65 1.22(1.02-1.45) 0.03 1.23(1.05-1.44) 0.01

race

White reference reference

Asian 0.95(0.66-1.37) 0.8 0.94(0.68-1.30) 0.71

Black 1.35(1.10-1.67) 0.005 1.34(1.11-1.61) 0.002

Other 0.62(0.23-1.49) 0.28 0.84(0.44-1.63) 0.61

Grade

G1/G2 reference reference

G3/G4 1.29(1.04-1.59) 0.02 1.41(161-1.70) <0.001

Other 1.44(1.15-1.80) 0.001 1.54(1.26-1.88) <0.002

Marry

Married reference reference

Single 1.11(0.90-1.37) 0.33 1.04(0.87-1.25) 0.65

Other 1.39(1.14-1.69) <0.001 1.31(1.11-1.54) 0.002

Histology

Squamous cell

neoplams reference reference

Adenomas and

adenocarcinomas 0.85(0.68-1.07)0.16

0.89(0.73-1.08) 0.24

Other 1.32(1.01-1.74) 0.04 1.47(1.16-1.86) 0.001

Surgery

No reference reference

Yes 0.41(0.32-0.55) <0.001 0.45(0.35-0.58) <0.001

Radiotherapy

No reference reference

Yes 0.51(0.43-0.60) <0.001 0.50(0.44-0.58) <0.001

Chemotherapy

No reference reference

Yes 0.29(0.24-0.34) <0.001 0.28(0.24-0.33) <0.001

Size

x<4 reference reference

x≥4 1.44(1.04-2.00) 0.03 1.32(0.99-1.75) 0.058

other 1.78(1.28-2.48) <0.001 1.75(1.31-2.32) <0.001

Stage

Early(stage I/II) reference reference

Late(stage III/IV) 2.24(1.58-3.18) <0.001 1.91(1.41-2.59) <0.001

Other 2.16(1.69-2.76) <0.001 1.94(0.52-2.39) <0.001

Metastatic sites

Liver reference NA NA

Lung 0.38(0.29-0.50) 0.03 NA NA

Bone 0.81(0.59-1.12) 0.20 NA NA

Brain 1.03(0.47-2.23) 0.94 NA NA

Distant lymph node 0.38(0.29-0.50) <0.001 NA NA

Number of sites of metastases

1 NA NA reference

>1 　 NA NA 　 2.36(1.99-2.79) <0.001

Table 4 Multivariate Cox regression analysis of prognostic factors for overall survival in cervical cancer

Variable　 single distant metastases n=900 　 the entire cohort n=1123

　 HR(95% CL) p-value 　 HR(95% CL) p-value

Age

x<65 reference reference

x≥65 0.98(0.81-1.19) 0.84 1.01(0.86-1.2) 0.87

race

White reference reference

Asian 0.73(0.5-1.06) 0.1 0.79(0.57-1.11) 0.17

Black 1.14(0.91-1.43) 0.23 1.15(0.95-1.39) 0.14

Other 0.66(0.27-1.62) 0.37 0.66(0.34-1.29) 0.22

Grade

G1/G2 reference reference

G3/G4 1.07(0.85-1.33) 0.58 1.27(1.04-1.55) 0.02

Other 1.1(0.87-1.39) 0.43 1.28(1.04-1.58) 0.02

Marry

Married reference reference

Single 0.96(0.77-1.2) 0.74 0.94(0.78-1.14) 0.54

Other 1.12(0.91-1.37) 0.30 1.01(0.85-1.2) 0.92

Histology

Squamous cell

neoplams reference reference

Adenomas and

adenocarcinomas 1.05(0.83-1.33) 0.66 1(0.82-1.22) 0.99

Other 1.42(1.07-1.88) 0.02 1.51(1.19-1.91) <0.001

Surgery

No reference reference

Yes 0.6(0.44-0.82) 0.001 0.6(0.45-0.78) <0.001

Radiotherapy

No reference reference

Yes 0.63(0.52-0.75) <0.001 0.66(0.56-0.77) <0.001

Chemotherapy

No reference reference

Yes 0.31(0.26-0.37) <0.001 0.32(0.27-0.38) <0.001

Size

x<4 reference reference

x≥4 1.75(1.25-2.45) 0.001 1.38(1.03-1.85) 0.03

other 1.65(1.17-2.33) 0.004 1.48(1.11-1.99) 0..01

Stage

Early(stage I/II) reference reference

Late(stage III/IV) 1.57(1.1-2.26) 0.01 1.3(0.95-1.78) 0.1

Other 1.59(1.23-2.06) <0.001 1.35(1.09-1.69) 0.007

Metastatic sites

Liver reference NA NA

Lung 0.58(0.44-0.76) <0.001 NA NA

Bone 0.78(0.56-1.09) 0.15 NA NA

Brain 0.62(0.28-1.37) 0.30 NA NA

Distant lymph node 0.4(0.3-0.52) <0.001 NA NA

Number of sites of metastases

1 NA NA reference

>1 　 NA NA 1.95(1.65-2.32) <0.001

Figure 1 Survival curves of different distant metastases

Figure 2 Survival curves of one site and multiple sites