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![Page 1: · Web viewThe 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](https://reader038.vdocuments.us/reader038/viewer/2022100609/5f0767597e708231d41cd060/html5/thumbnails/1.jpg)
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:
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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.
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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
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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.
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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,
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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
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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
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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
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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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11. Kim H, Lee KK, Heo MH, Kim JY. The prognostic factors influencing overall survival in uterine cervical cancer with brain metastasis. Korean J Intern Med. 2019; 34: 1324.12. Friedlander M, Grogan M. Guidelines for the treatment of recurrent and metastatic cervical cancer. Oncologist. 2002; 7: 342-7.13. Disibio G, French SW. Metastatic patterns of cancers: results from a large autopsy study. Arch Pathol Lab Med. 2008; 132: 931-9.14. Li H, Wu X, Cheng X. Advances in diagnosis and treatment of metastatic cervical cancer. J Gynecol Oncol. 2016; 27.15. Thanapprapasr D, Nartthanarung A, Likittanasombut P, Ayudhya NIN, Charakorn C, Udomsubpayakul U, et al. Bone metastasis in cervical cancer patients over a 10-year period. Int J Gynecol Cancer. 2010; 20: 373-8--8.16. Liu Y-M, Ni L-Q, Wang S-S, Lv Q-L, Chen W-J, Ying S-P. Outcome and prognostic factors in cervical cancer patients treated with surgery and concurrent chemoradiotherapy: a retrospective study. World J Surg Oncol. 2018; 16: 18.17. Yan D-D, Tang Q, Tu Y-Q, Chen J-H, Lv X-J. A comprehensive analysis of the factors of positive pelvic lymph nodes on survival of cervical cancer patients with 2018 FIGO stage IIIC1p. Cancer Manag Res. 2019; 11: 4223.18. Kim HS, Kim T, Lee ES, Kim HJ, Chung HH, Kim JW, et al. Impact of chemoradiation on prognosis in stage IVB cervical cancer with distant lymphatic metastasis. Cancer Res Treat. 2013; 45: 193.19. Smits RM, Zusterzeel PL, Bekkers RL. Pretreatment retroperitoneal para-aortic lymph node staging in advanced cervical cancer: a review. Int J Gynecol Cancer. 2014; 24: 973-83.20. Lee SH, Lee SH, Lee KC, Lee KB, Shin JW, Park CY, et al. Radiation therapy with chemotherapy for patients with cervical cancer and supraclavicular lymph node involvement. J Gynecol Oncol. 2012; 23: 159-67.21. Saijo N. Chemotherapy against pulmonary metastasis from uterine cervical carcinoma. Gan To Kagaku Ryoho. 1982; 9: 992-7.22. Bacalbasa N, Balescu I, Dima S, Popescu I. Hepatic resection for liver metastases from cervical cancer is safe and may have survival benefit. Anticancer Res. 2016; 36: 3023-7.23. Casaurrán GG, Adiego CS, Pascual RP, Mata NM, Barriuso MÁL, Aragoneses FG. Surgery of female genital tract tumour lung metastases. Arch Bronconeumol. 2011; 47: 134-7.24. McQuay H, Carroll D, Moore R. Radiotherapy for painful bone metastases: a systematic review. Clin Oncol. 1997; 9: 150-4.25. Koike Y, Takizawa K, Ogawa Y, Muto A, Yoshimatsu M, Yagihashi K, et al. Transcatheter arterial chemoembolization (TACE) or embolization (TAE) for symptomatic bone metastases as a palliative treatment. Cardiovasc Intervent Radiol. 2011; 34: 793-801.
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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)
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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)
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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
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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
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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
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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
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Figure 1 Survival curves of different distant metastases
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Figure 2 Survival curves of one site and multiple sites