Impact of ovarian metastatectomy on survival outcome of colorectal cancer patients with ovarian metastasis: a retrospective study

DOI: https://doi.org/10.21203/rs.2.24117/v1

Abstract

Background Ovarian metastasis from colorectal cancer (CRC) is rare and lacks standard treatment. The benefit of metastatectomy remains to be elucidated. This study was conducted to assess the impact of metastatectomy on survival outcome and explore prognostic factors in ovarian metastatic CRC patients. Results Information of ovarian metastatic CRC patients between January 2008 and December 2017 were collected retrospectively from database of West China Hospital, Sichuan University. Totally, 68 female patients from a cohort of 2170 metastatic CRC cases were eligible. The median age at diagnosis was 46.5 years old. The median DSS was 25.0 months (95% confidence interval (CI): 21.0-29.0 months). Kaplan-Meier analysis and log-rank test showed that complete resection of ovarian metastases (median DSS: 33.0 months) could significantly prolong patients’ survival time, comparing with palliative and no resection (median DSS: 20.0 months and 22.0 months, respectively), regardless of systemic chemotherapy (P<0.05). Multivariate analysis demonstrated regional lymph nodes metastasis of primary tumor (hazard ratio (HR): 3.438, 95%CI: 1.094-10.810, P=0.035), primary tumor resection (HR: 6.436, 95%CI: 1.770-23.399, P=0.005), differentiation grade (HR: 0.272, 95%CI: 0.107-0.693, P=0.006), complete resection of ovarian metastases (versus palliative resection: HR: 17.091, 95%CI: 3.040-96.099, P=0.001; versus no resection: HR: 9.519, 95%CI: 1.581-57.320, P=0.014), and systemic chemotherapy (HR: 3.059, 95%CI: 1.089-8.595 P=0.034) were independent prognostic factors. Conclusions Complete resection of ovarian metastases could independently predict favorable survival in ovarian metastatic CRC, while palliative resection could not improve patients’ prognosis compared with no resection.

1. Background

Ovarian metastasis is relatively rare in colorectal cancer (CRC) female patients, with an incidence of about 0.8–7.4% []. Metastatic ovarian tumors from CRC commonly manifest as cyst-solidary masses on imaging examination, which are indistinguishable from primary ovarian cancer []. It is reported that about 4%-29% CRC patients with ovarian metastases are initially misdiagnosed and receive surgery as primary ovarian malignancies [-]. Pathological diagnosis of CRC ovarian metastasis generally needs assistance of immunohistochemistry, which is characterized as cytokeratin 7 (CK7) - /CK20+ / caudal-type homeobox transcription factor-2 (CDX2) + /carbohydrate antigen 125 (CA125) -/paired box gene 8 (PAX8)- [1,,].

In recent years, despite rapid progress in treatment strategies of advanced CRC, ovarian metastasis from CRC has poor prognosis. Studies have demonstrated primary resistance of ovarian metastases to systemic chemotherapy, with an objective response rate (ORR) less than 20%, which is much worse than that of metastases in other organs [,]. Although some retrospective studies with small sizes have indicated survival benefit of ovarian metastasectomy, the role of surgery for ovarian metastases still remains unclear []. The poor prognosis of ovarian metastasis may contribute to easy misdiagnosis and lack of standard treatment. In this study, we summarized clinicopathological characteristics, survival outcome and prognostic factors of ovarian metastatic CRC patients in a single institution during a 10-year period.

2. Results

2.1 Patient characteristics

Patients’ clinical characteristics were summarized in Table 1. In total, 68 patients newly diagnosed with ovarian metastatic CRC were identified from a cohort of 2170 female patients with metastatic CRC, including 54.4% premenopausal patients. Hence, the incidence of ovarian metastases in female metastatic CRC was 3.1%. The median age at diagnosis of ovarian metastasis was 46.5 years old. The median time from primary cancer diagnosis to ovarian metastasis detection was 4.5 months. And the median largest diameter of ovarian lesions was 8.0 cm. There were 32 (47.1%) cases presented with synchronous ovarian metastasis, while 36 (52.9%) with metachronous metastasis. Twelve (17.6%) patients had metastases confined in the ovaries, whereas the left 56 (82.4%) patients presented with extraovarian metastases in liver, lung, peritoneum, bone, and et al. when diagnosed with ovarian metastatic CRC. More than half of the patients (52.9%) had ascites and 41.2% had peritoneal metastasis. As to treatment approach, 42.6% of all cases underwent complete resection of ovarian metastases, 41.2% cases received palliative resection, and the left 16.2% patients did not undergo ovarian metastatectomy. Most patients (70.6%) received systemic chemotherapy after diagnosis of ovarian metastasis. In the group of no resection, all the patients received systemic chemotherapy, while in the groups of complete and palliative resection, 55.2% and 75% patients received chemotherapy, respectively.

Table 1
Characteristics and univariate disease specific survival analysis of patients with ovarian metastatic CRC
Variables
Number of patients (%)
mDSS (95%CI)
P
Age
       
 
≤ 46.5 years old
33(48.5)
27.0(22.5–31.5)
0.185
 
> 46.5 years old
35(51.5)
23.0(19.2–26.8)
 
Menopausal status
       
 
Premenopausal
37(54.4)
31.0(24.4–37.6)
0.039
 
Postmenopausal
31(45.6)
21.0(13.1–28.9)
 
CEA level
       
 
≤ULN
19(27.9)
48.0(23.7–72.3)
0.003
 
>ULN
49(72.1)
22.0(19.7–24.3)
 
Primary tumor location
       
 
Rectum
16(23.5)
29.0(17.1–41.0)
0.515
 
Colon
52(76.5)
25.0(21.0–29.0)
 
T stage of primary tumor*
       
 
T2 + T3
35(51.5)
26.0(23.1–28.9)
0.784
 
T4
33(48.5)
23.0(13.7–32.3)
 
N stage of primary tumor*
       
 
Negative
14(20.6)
31.0(22.2–39.8)
0.350
 
Positive
54(79.4)
25.0(20.2–29.8)
 
Primary tumor resection
       
 
Yes
62(91.2)
27.0(21.8–32.2)
0.002
 
No
6(8.8)
10.0(0.0–28.0)
 
Histological type of primary tumor
       
 
Adenocarcinoma
47(69.1)
25.0(19.8–30.2)
0.147
 
Mucinous adenocarcinoma + signet-ring cell carcinoma
21(30.9)
29.0(16.8–41.2)
 
Differentiation grade of primary tumor
       
 
Well differentiated
38(55.9)
25.0(18.0–32.0)
0.894
 
Poorly differentiated
30(44.1)
26.0(20.4–31.6)
 
Synchronous metastasis
       
 
Yes
32(47.1)
22.0(18.4–25.6)
0.193
 
No
36(52.9)
29.0(18.4–39.6)
 
Bilateral or unilateral metastasis
       
 
Bilateral
27(39.7)
21.0(18.9–23.1)
0.114
 
Unilateral
41(60.3)
26.0(20.8–31.2)
 
Combined with metastases outside ovaries
       
 
Yes
56(82.4)
23.0(17.8–28.2)
0.022
 
No
12(17.6)
40.0(35.8-NA)
 
Ascites
       
 
Yes
36(52.9)
25.0(19.2–30.8)
0.755
 
No
32(47.1)
25.0(16.5–33.5)
 
Peritoneal metastasis
       
 
Yes
28(41.2)
20.0(9.4–30.6)
0.032
 
No
40(58.8)
31.0(23.8–38.2)
 
Liver metastasis
       
 
Yes
19(27.9)
21.0(12.1–29.9)
0.007
 
No
49(72.1)
29.0(21.6–36.4)
 
Lung metastasis
       
 
Yes
12(82.4)
23.0(20.0–26.0)
0.158
 
No
56(17.6)
27.0(18.2–35.8)
 
The largest diameter of ovarian metastasis
       
 
≤ 8.0 cm
36(52.9)
29.0(17.7–40.3)
0.645
 
> 8.0 cm
32(47.1)
25.0(22.3–27.7)
 
Surgery of ovarian metastasis
       
 
Complete resection
29(42.6)
33.0(21.4–44.6)
0.002
 
Palliative resection
28(41.2)
20.0(13.1–26.9)
 
 
No resection (chemotherapy only)
11(16.2)
22.0(19.5–24.5)
 
Systemic chemotherapy
       
 
Yes
48(70.6)
27.0(20.8–33.2)
0.204
 
No
20(29.4)
23.0(9.1–36.9)
 
Total
 
68(100)
25.0(21.0–29.0)
-
Note: *In patients without primary tumor resection, the reported T and N stage were clinically evaluated based on imaging techniques. Abbreviations: CRC, colorectal cancer; mDSS, median disease specific survival; CEA, carcinoembryonic antigen; ULN, upper limit of normal

2.2 Survival analyses for different groups

In total, the median DSS after diagnosed with ovarian metastasis was 25.0 months (95% confidence interval (CI) = 21.0–29.0 months). Univariate survival analysis results were listed in Table 1. In this study, we classified surgical methods of ovarian metastases into three groups, i.e. no resection (chemotherapy only), palliative resection (R1 and R2 resection) and complete resection (R0 resection). Applying Kaplan-Meier method, we found that ‘complete resection group’ showed significantly longer DSS than that of the other two groups (‘complete resection group’ vs. ‘palliative resection group’: 33.0 vs. 20.0 months, P = 0.000; ‘complete resection group’ vs. ‘no resection group’: 33.0 vs. 22.0 months, P = 0.026, Fig. 1), while median DSS of ‘palliative resection group’ was similar to that of ‘no resection group’ (20.0 vs. 22.0 months, P = 0.630, Fig. 1). These results suggested that complete resection of metastatic ovaries predict better survival in CRC patients.

Stratified analysis revealed that in patients without systemic chemotherapy, the median DSS of complete resection group was significantly longer than that of palliative resection group (26.0 vs. 11.0 months, P = 0.001, Table 2, Fig. 2A). In patients receiving systemic chemotherapy, complete resection also prolonged patients’ survival time (vs. palliative resection: 69.0 vs. 21.0 months, P = 0.002; vs. no resection: 69.0 vs. 22.0 months, P = 0.007), while palliative resection could not improve survival outcome compared with no resection (21.0 vs. 22.0 months, P = 0.993, Table 2, Fig. 2B).

Table 2
Survival comparison for patients receiving different methods of ovarian metastatectomy stratified by chemotherapy
Chemotherapy
Surgery of ovarian metastasis
Number of patients
mDSS (95%CI)
Complete resection
Palliative resection
No resection
P
P
P
No
Complete resection
13
26.0(16.9–35.1)
-
0.001
-
Palliative resection
7
11.0(5.9–16.1)
0.001
-
-
Yes
Complete resection
16
69.0(0.0-140.3)
-
0.002
0.007
Palliative resection
21
21.0(18.0–24.0)
0.002
-
0.993
No resection
11
22.0(19.5–24.5)
0.007
0.993
-
Abbreviations: mDSS, median disease specific survival; CI, confidence interval

2.3 Prognostic factors associated with survival

Using multivariate Cox proportional hazard regression analysis, we determined the associations between survival and multiple variables such as age, menopausal status, the levels of CEA, primary tumor location, T and N stage of primary tumor, histological type, differentiation grade, primary tumor resection, ascites, synchronous metastasis, bilateral metastasis, size of ovarian metastases, peritoneal metastasis, liver metastasis, lung metastasis, surgical methods of ovarian metastases and systemic chemotherapy, et al. The results demonstrated that regional lymph nodes metastasis of primary tumor (hazard ratio (HR): 3.438, 95%CI: 1.094–10.810, P = 0.035), primary tumor resection (HR: 6.436, 95%CI: 1.770-23.399, P = 0.005), differentiation grade (HR: 0.272, 95%CI: 0.107–0.693, P = 0.006), complete resection of ovarian metastases (versus palliative resection: HR: 17.091, 95%CI: 3.040-96.099, P = 0.001; versus no resection: HR: 9.519, 95%CI: 1.581–57.320, P = 0.014), and systemic chemotherapy (HR: 3.059, 95%CI: 1.089–8.595 P = 0.034) were independent factors for predicting survival outcome (Table 3).

Table 3
Multivariate COX regression analysis of ovarian metastatic CRC patients
Variables
HR (95%CI)
P
Age
     
 
> 46.5 years old
1(Reference)
0.398
 
≤ 46.5 years old
0.490(0.094–2.560)
 
Menopausal status
     
 
Postmenopausal
1(Reference)
0.825
 
Premenopausal
0.817(0.137–4.891)
 
CEA level
     
 
>ULN
1(Reference)
0.251
 
≤ULN
0.523(0.173–1.582)
 
Primary tumor location
     
 
Rectum
1(Reference)
0.881
 
Colon
0.960(0.567–1.628)
 
T stage of primary tumor*
     
 
T2 + T3
1(Reference)
0.050
 
T4
2.374(1.000-5.634)
 
N stage of primary tumor*
     
 
Negative
1(Reference)
0.035
 
Positive
3.438(1.094–10.810)
 
Primary tumor resection
     
 
Yes
1(Reference)
0.005
 
No
6.436(1.770-23.399)
 
Histological type of primary tumor
     
 
Adenocarcinoma
1(Reference)
0.363
 
Mucinous adenocarcinoma + signet-ring cell carcinoma
1.522(0.616–3.765)
 
Differentiation grade of primary tumor
     
 
Poorly differentiated
1(Reference)
0.006
 
Well differentiated
0.272(0.107–0.693)
 
Synchronous metastasis
     
 
No
1(Reference)
0.102
 
Yes
2.478(0.836–7.343)
 
Bilateral or unilateral metastasis
     
 
Bilateral
1(Reference)
0.998
 
Unilateral
0.999(0.408–2.445)
 
Combined with metastases outside ovaries
     
 
Yes
1(Reference)
0.882
 
No
0.890(0.190–4.157)
 
Ascites
     
 
No
1(Reference)
0.147
 
Yes
1.859(0.803–4.303)
 
Peritoneal metastasis
     
 
No
1(Reference)
0.813
 
Yes
1.121(0.435–2.889)
 
Liver metastasis
     
 
Yes
1(Reference)
0.237
 
No
0.560(0.214–1.463)
 
Lung metastasis
     
 
Yes
1(Reference)
0.493
 
No
0.677(0.222–2.063)
 
The largest diameter of ovarian metastasis
     
 
> 8.0 cm
1(Reference)
0.375
 
≤ 8.0 cm
0.697(0.315–1.546)
 
Surgery of ovarian metastasis
     
 
Complete resection
1(Reference)
 
 
Palliative resection
17.091(3.040-96.099)
0.001
 
No resection (chemotherapy only)
9.519(1.581–57.320)
0.014
Systemic chemotherapy
     
 
Yes
1(Reference)
0.034
 
No
3.059(1.089–8.595)
 
Note: *In patients without primary tumor resection, the reported T and N stage were clinically evaluated based on imaging techniques. Abbreviations: CRC, colorectal cancer; mDSS, median disease specific survival; CEA, carcinoembryonic antigen; ULN, upper limit of normal; CI, confidence interval; HR, hazard ratio

3. Discussion

In current study, we found that in ovarian metastatic CRC, complete resection of ovarian metastases was an independent prognostic factor for favorable survival. Although palliative resection of ovaries could relieve symptoms such as abdominal distension and pain, it failed to improve DSS compared with no resection.

Previous studies have demonstrated ovarian metastases from CRC are resistant to systemic chemotherapy [6,9], which is possibly associated with specific gene mutations [,]. Goéré D. et al. [6] analyzed chemotherapy response in 23 patients with metastatic (ovarian and extraovarian) CRC, and found that ovarian metastases were less responsive to chemotherapy compared to other sites. The objective response rate (ORR) of ovarian metastases was 0% and disease control rate (DCR) was 13%, in contrast, ORR and DCR of measurable extraovarian metastases were respectively 35% and 65%. Another study of 33 patients conducted by Lee SJ. et al. [9] also indicated lower ORR of ovarian metastases compared with extraovarian metastases (18.2% vs. 33.3%, P < 0.001).

Considering resistance to chemotherapy of ovarian metastases, researchers tried to investigate the benefit of metastasectomy for survival. The retrospective study performed by Lee SJ. et al. [9] demonstrated that CRC patients with ovarian metastases received an oophorectomy before chemotherapy survived significantly longer than those without an oophorectomy (28.1 vs. 21.2 months, P = 0.015). Additionally, multivariate analysis indicated that no oophorectomy was an independent prognostic factor associated with poorer survival (RR = 1.954, 95%CI = 1.220–3.130, P = 0.005). This survival benefit of metastasectomy in ovarian metastatic CRC was confirmed by other retrospective studies too [-]. However, a study published in 2017 [] suggested that patients treated with surgery of ovarian metastases and chemotherapy did not have better survival compared with those treated with chemotherapy alone (23 vs. 28 months, P = 0.376). Furthermore, Jiang R. et al. [] analyzed the impact of residual disease on survival in metastatic ovarian cancer patients (mainly originated from gastric cancer and CRC) who underwent metastasectomy. They found that visible residual disease after metastasectomy independently predicted poorer survival (P < 0.01). Since the above studies were of small sizes and based on retrospective data, the role of metastasectomy in ovarian metastatic CRC still remains controversial. In our study, we found that complete resection of ovarian metastases could predict better survival (DSS = 33.0 months), while palliative and no resection of ovaries were factors of poorer prognosis (P < 0.05).

There were some limitations in this study, such as retrospective data, small sample size and single-center cohort. However, the large cohort and complete clinical information of our study confirmed the rarity of ovarian metastasis with an incidence of 3.1%, indicated the survival benefit of complete resection of ovarian matastases and concluded several prognostic factors such as regional lymph nodes metastasis of primary tumor, primary tumor resection, differentiation grade, surgical methods of ovarian metastases and systemic chemotherapy.

4. Conclusions

Our study suggested that limited ovarian metastases could be the candidates for surgery, which could help clinicians making individualized treatment strategies. Well-designed prospective trial is warranted to verify this viewpoint.

5. Patients And Methods

5.1 Patient selection

Female patients who were newly diagnosed with ovarian metastatic CRC between January 2008 and December 2017 were identified retrospectively from the database of Cancer Center at West China Hospital, Sichuan University. Patients’ information and treatment history were obtained through medical records. All patients were followed-up to July 31, 2018.

Data of the patients were collected including age at the time of diagnosis with ovarian metastasis, menopausal status, pretreatment serum carcinoembryonic antigen (CEA) level, primary tumor location, initial T and N stage of primary tumor, time interval between diagnosis of primary tumor and that of ovarian metastasis (metachronous vs. synchronous), size of ovarian metastases, combined metastases outside ovaries, ascites, surgical methods of ovarian metastases (no resection vs. palliative resection vs. complete resection), systemic chemotherapy and response evaluation. For patients received surgical resection of ovarian masses, pathological diagnoses were confirmed by immunohistochemistry staining of ovarian specimens (CK7-/ CK20+/ CDX2+ /CA125-/ PAX8-). In current study, the time interval between diagnosis of primary tumor and that of ovarian metastasis exceeding 3 months was defined as metachronous ovarian metastasis, otherwise as synchronous metastasis. Palliative resection of ovarian metastases meant microscopic or macroscopic residual disease in ovaries (R1 or R2 resection), while complete resection referred to no residual disease left in ovaries (R0 resection).

This study was approved by the West China Hospital, Sichuan University Ethic Committee for Clinical Investigation. And all methods were performed in accordance with the relevant guidelines and regulations.

5.2 Statistical analysis

Median disease specific survival (DSS) was estimated with Kaplan-Meier method, which was calculated from the date of diagnosis with ovarian metastasis to death (caused by cancer) or last follow-up time. Death caused by CRC was considered as endpoint event. Patients who were still alive at last follow-up time or who had died of other causes were censored. Log-rank test was used to compare survival time of different groups and a multivariate Cox proportional hazard regression model was established to determine the associations between survival time and other factors such as age, menopausal status, primary tumor location, ascites, surgical methods of metastases and systemic chemotherapy, et al. Statistical tests were two sided and P < 0.05 was considered statistically significant. SPSS Statistics 22.0 (IBM, Armonk, NY, USA) was applied to perform all the statistical analyses.

List Of Abbreviations

CRC, colorectal cancer; DSS, disease specific survival; OS, overall survival; CK7, cytokeratin 7; CDX2, caudal-type homeobox transcription factor-2; CA125, carbohydrate antigen 125; PAX8, paired box gene 8; CEA, carcinoembryonic antigen; CT, computed tomography; CI, confidence interval; HR, hazard ratio; ORR, objective response rate; DCR, disease control rate; RR, rate ratio; ULN, upper limit of normal

Declarations

7.1 Ethical approval and consent to participate

Written informed consent for the use of patient information in our study was obtained from all patients at the time of admission as a routine practice at West China Hospital, Sichuan University. And this study was approved by the West China Hospital, Sichuan University Ethic Committee for Clinical Investigation.

7.2 Consent for publication

Consent for publication of patient information was obtained from all patients at the time of admission as a routine practice at West China Hospital, Sichuan University.

7.3 Availability of data

The data used to support the findings of this study are available from the corresponding author upon request.

7.4 Competing interests

All of the authors declare no potential competing interests.

7.5 Funding

This work was supported by the National Key Development Plan for Precision Medicine Research (2017YFC0910004).

7.6 Author contributions statement

XL and MQ conceived of and designed this study. XL, HH and LR performed the analyses. LR, CF and YY prepared all tables and figures. XL wrote the main manuscript. All authors reviewed the manuscript and approved to the submission.

7.7 Acknowledgements

Not applicable.

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