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Treatment strategy and prognostic factors for Krukenberg tumors of gastric origin: report of a 10-year single-center experience from China

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Oncotarget. 2017; 8:82558-82570. https://doi.org/10.18632/oncotarget.19759

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Pengfei Yu _, Ling Huang, Guoping Cheng, Litao Yang, Gaiguo Dai, Jieer Ying and Yian Du

Abstract

Pengfei Yu1, Ling Huang1, Guoping Cheng2, Litao Yang1, Gaiguo Dai1, Jieer Ying3 and Yian Du1

1Department of Abdominal Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, China

2Department of Pathology, Zhejiang Cancer Hospital, Hangzhou 310022, China

3Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China

Correspondence to:

Pengfei Yu, email: [email protected]

Yian Du, email: [email protected]

Keywords: Krukenberg tumors, gastric cancer, metastasectomy, chemotherapy, prognosis

Abbreviations: OS: overall survival; HIPEC: hyperthermic intraperitoneal chemotherapy; ER: estrogen receptor; PR: progesterone receptor; IHC: immunohistochemistry

Received: May 16, 2017     Accepted: June 30, 2017     Published: August 01, 2017

ABSTRACT

Background: Gastric cancer patient with ovarian metastasis is common in clinical practice, but it is still uncertain whether surgical resection of ovarian metastasis could improve the outcome. This study aimed to explore the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone in the treatment of Krukenberg tumors arising from gastric cancer and to identify prognostic factors.

Results: A total of 152 patients were identified, including 93 patients with synchronous ovarian metastasis and 59 patients with metachronous ovarian metastasis. Overall survival (OS) was significantly better in metastasectomy group relative to the non-metastasectomy group for patients with synchronous ovarian metastasis (19.0 months vs. 11.8 months; P < 0.001) and those with metachronous ovarian metastasis (24.6 months vs. 14.3 months; P = 0.02), respectively. Metastasectomy (hazard ration [HR] 0.486; 95% confidence interval [CI] 0.323–0.729; P < 0.001), peritoneal carcinomatosis (HR 1.934; 95% CI 1.230–3.049; P = 0.004), and expression status of ER-β (HR 0.404; 95% CI 0.251–0.648; P < 0.001) and PR (HR 0.496; 95% CI 0.301–0.817; P < 0.001) were independent predictors of OS.

Methods: All patients who were diagnosed with gastric cancer and ovarian metastases between January 2005 and December 2014 were included in the current study. Patients were subdivided according to treatment modality: the metastasectomy group (metastasectomy plus chemotherapy) and the non-metastasectomy group (chemotherapy alone). The clinicopathological features and the treatment records were reviewed in detail and their association with survival were analyzed.

Conclusion: Metastasectomy plus chemotherapy was associated with survival benefits in patients with Krukenberg tumors from gastric cancer. Metastasectomy, peritoneal carcinomatosis, and expression status of ER-β and PR were independent prognostic factors for survival.


INTRODUCTION

Gastric cancer is one of the most common cancers worldwide, and the incidence is particularly high in Asian countries, including China [1]. Metastasis and recurrence are the major causes for poor prognosis in gastric cancer. Ovarian metastasis (Krukenberg tumor) is usually seen in female patients, including synchronous metastasis, and metachronous metastasis after curative resection of gastric cancer [2]. The reported incidence of ovarian metastasis or Krukenberg tumor is approximately 0.3% to 6.7%, however, some autopsy studies have reported incidence rates of 33% to 41% [3, 4]. Ovarian metastasis is associated with poor prognosis, and is one of the most important causes of treatment failure for gastric cancer in female patients [5]. Although systemic chemotherapy can provide symptom palliation and prolonged survival in patients with ovarian metastasis, the efficiency and survival time remain disappointing [2, 6]. Several studies have explored the utility of metastasectomy for Krukenberg tumors in patients with gastric cancer [7, 8] However, the role of ovarian metastasectomy is still under debate and is likely to benefit only a specific subset of patients [9]. So far, the optimal treatment strategy for Krukenberg tumors from gastric cancer had not been clearly established. This study was conducted to determine associations between metastasectomy of Krukenberg tumors, clinicopathological features, and survival outcome, and consequently provide optimal treatment strategy for these patients.

RESULTS

Patient characteristics

The median follow-up duration for all patients was 37.2 (range 2.5–71) months; median age at treatment onset was 43.4 (range 18–65) years, and mean size of metastatic ovarian tumors was 8.13 (range 2–20) cm.

Clinicopathologic characteristics of gastric cancer with synchronous or metachronous ovarian metastasis are listed in Tables 1 and 2, respectively. Of these, tumor location, differentiation, ascites, ER and PR expression, tumor markers, and TNM stage were similar for both groups of either synchronous or metachronous ovarian metastasis.

Table 1: Clinical characteristics of 93 patients with synchronous Krukenberg tumors

Variable

Metastasectomy plus chemotherapy
(n = 49)

Chemotherapy alone
(n = 44)

P-value

Median age

43.1 (26–65)

40.9 (18–61)

0.290

Tumor size (cm)

8.70 (2–20)

7.33 (2.2–18)

0.119

ECOG performance status

 0-1

47

40

0.326

 2

2

4

Laterality

 Bilateral

33

31

0.747

 UnilateraI

16

13

Peritoneal metastasis

 No

35

37

0.145

 Yes

14

7

Signet-ring cells

 Positive

36

29

0.427

 Negative

13

15

Differentiation

 Well and moderately

8

4

0.299

 Poorly

41

40

Ascites

 No

20

11

0.106

 Yes

29

33

ER

 Positive

22

14

0.196

 Negative

27

30

PR

 Positive

16

8

0.111

 Negative

33

36

Serum CEA (ng/mL)

 Normal

40

36

0.982

 >5

9

8

Serum CA19-9 (U/mL)

 Normal

33

26

0.409

 >39

16

18

Serum CA125 (U/mL)

 Normal

20

14

0.368

 >35

29

30

Table 2: Clinical characteristics of 59 patients with metachronous Krukenberg tumors

Variable

Metastasectomy plus chemotherapy
(n = 40)

Chemotherapy alone
(n = 19)

P-value

Median age

46.9 (31–62)

42.7 (20–60)

0.128

Tumor size (cm)

8.78 (4.3–20)

7.73 (4.5–16.7)

0.261

ECOG performance status

 0-1

39

17

0.190

 2

1

2

Laterality

 Bilateral

32

16

0.700

 UnilateraI

8

3

Peritoneal metastasis

 No

29

15

0.595

 Yes

11

4

Signet-ring cells

 Positive

31

16

0.550

 Negative

9

3

Differentiation

 Well and moderately

6

4

0.563

 Poorly

34

15

AJCC stage

 I–II

5

1

0.390

 III–IV

35

18

Ascites

 No

9

5

0.748

 Yes

31

14

ER

 Positive

17

8

0.977

 Negative

23

11

PR

 Positive

13

6

 Negative

27

13

0.944

Serum CEA (ng/mL)

 Normal

33

16

0.870

 >5

7

3

Serum CA19-9 (U/mL)

 Normal

31

13

0.454

 >39

9

6

Serum CA125 (U/mL)

 Normal

21

7

0.260

 >35

19

12

Treatment outcome and prognostic factors

The median OS of patients with synchronous ovarian metastasis was 15.6 months (95% confidence interval [CI], 13.9 to 17.3 months). The median OS of metastasectomy group and non-metastasectomy group was 19.0 months (95% CI,16.6 to 21.5 months) and 11.8 months (95% CI, 10.1 to 13.5months), respectively. For patients with metachronous ovarian metastasis, median OS was 21.7 (95% CI 17.6–25.9) months. The median OS of metastasectomy group and non-metastasectomy group was 24.6months (95% CI,19.3 to 30.0 months) and 14.3 months (95% CI, 10.8 to 17.8months), respectively. Therefore, patients in the metastasectomy group had a significantly better OS than patients in the non-metastasectomy group (synchronous ovarian metastasis: P < 0.001, Figure 1; metachronous ovarian metastasis: P = 0.02, Figure 2).

Kaplan&#x2013;Meier analysis of overall survival in patients with or without metastasectomy of synchronous Krukenberg tumors.

Figure 1: Kaplan–Meier analysis of overall survival in patients with or without metastasectomy of synchronous Krukenberg tumors.

Kaplan&#x2013;Meier analysis of overall survival in patients with or without metastasectomy of metachronous Krukenberg tumors.

Figure 2: Kaplan–Meier analysis of overall survival in patients with or without metastasectomy of metachronous Krukenberg tumors.

Based on univariate analysis, metastasectomy, peritoneal carcinomatosis, signet ring cell, ascites, expression of ER-β and PR, and serum levels of CA19-9 (>37 U/mL) were prognostic factors associated with survival. After adjusting covariates on multivariate analysis, metastasectomy (hazard ration [HR] 0.486; 95% CI 0.323–0.729; P < 0.001), presence of peritoneal carcinomatosis (HR 1.934; 95% CI 1.230–3.049; P = 0.004), ER-β positivity (HR 0.404; 95% CI 0.251–0.648; P < 0.001), and PR positivity (HR 0.496; 95% CI 0.301–0.817; P < 0.001) were independent predictors of OS (Table 3).

Table 3: Univariate and multivariate analysis of overall survival

Variable

Univariate

Multivariate

HR (95% CI)

P-value

HR (95% CI)

P-value

Age (≥50 years)

0.712 (0.445–1.139)

0.156

-

-

Size of tumor (<5 cm)

0.736 (0.491–1.104)

0.139

-

-

Bilateral ovarian metastases

0.775 (0.515–1.165)

0.220

-

-

Metastasectomy

0.467 (0.318–0.685)

<0.001

0.486 (0.323–0.729)

<0.001

Peritoneal carcinomatosis

2.359 (1.585–3.512)

<0.001

1.934 (1.230–3.049)

0.004

Signet-ring cells

1.871 (1.272–2.751)

0.001

1.183 (0.778–1.802)

0.430

Ascites

1.968 (1.269–3.051)

0.002

1.450 (0.914–2.294)

0.114

Gastrectomy

0.761 (0.520–1.114)

0.160

-

-

ER positive

0.254 (0.166–0.389)

<0.001

0.404 (0.251–0.648)

<0.001

PR positive

0.376 (0.238–0.596)

<0.001

0.496 (0.301–0.817)

<0.001

CA125

1.427 (0.939–2.170)

0.096

-

-

CEA

1.369 (0.873–2.146)

0.171

-

-

CA199

1.628 (1.108–2.393)

0.013

1.447 (0.963–2.179)

0.075

Additionally, 63.3% (57/90) of the patients had R0 resection. Median OS was 30.5 (95% CI 25.1–35.9) months in the R0 resection group and 12.2 (95% CI 10.4–14.0) months in the non-R0 resection groups. Survival was superior in the R0 resection group as compared to the non-R0 resection groups (P < 0.001; Figure 3).

Kaplan&#x2013;Meier analysis of overall survival in patients with or without R0 resection.

Figure 3: Kaplan–Meier analysis of overall survival in patients with or without R0 resection.

Correlation between expression of sex hormone receptors, clinicopathologic factors, and survival

The positive rate of ER-β and PR was 44.7% and 31.6%.However, ER-α showed no positivity in any gastric cancer tissue sample.

The positive/negative expression profiles of representative sex hormone receptors are shown in Figures 4 and 5. Uni- and multivariate analyses showed a positive correlation between expression of ER-β and PR and better survival. The average OS in ER-β-positive and -negative patients was 24.4 (95% CI 21.5–27.4) months and 12.6 (95% CI 10.8–14.4) months, respectively (P < 0.001; Figure 6). Average OS in PR-positive and -negative patients was 23.7 (95% CI 20.2–27.3) months and 15.4 (95% CI 13.2–17.5) months, respectively (P < 0.001; Figure 7). These results indicate that expression of ER-β or PR are favorably associated with better prognosis in patients with ovarian metastases from a primary gastric cancer.

A representative image of negative (4-1) or positive (4-2) ER-&#x03B2; expression.

Figure 4: A representative image of negative (4-1) or positive (4-2) ER-β expression.

A representative image of negative (5-1) or positive (5-2) PR expression.

Figure 5: A representative image of negative (5-1) or positive (5-2) PR expression.

Survival curves of patients with positive or negative expression of ER-&#x03B2;.

Figure 6: Survival curves of patients with positive or negative expression of ER-β.

Survival curves of patients with positive or negative expression of PR.

Figure 7: Survival curves of patients with positive or negative expression of PR.

Furthermore, we evaluated the relationship between the expression of ER-β, PR, and clinicopathologic factors, and found negative expression of ER-β to be significantly associated with peritoneal metastasis, signet-ring cells, and ascites; negative expression of PR was significantly associated with laterality as well as peritoneal metastasis [Table 4]. On multivariate analysis, peritoneal metastasis was significantly associated with negative expression of ER-β and PR. In addition, laterality was also significantly associated with negative expression of PR.

Table 4: Correlation between ER-β and PR expressions and clinicopathologic characteristics.

ER-β

PR

(+)

(-)

P

(+)

(-)

P

Age (years)

 ≥50

16

22

0.706

16

22

0.107

 <50

52

62

32

82

Tumor size (cm)

 ≥5

48

58

0.837

38

68

0.086

 <5

20

26

10

36

Laterality

 Bilateral

50

57

0.446

41

67

0.008

 UnilateraI

18

27

7

37

Peritoneal metastasis

 No

57

44

<0.001

40

61

0.003

 Yes

11

40

8

43

Signet-ring cells

 Positive

26

46

0.042

21

51

0.544

 Negative

42

38

27

53

Ascites

 No

30

23

0.031

19

34

0.407

 Yes

38

61

29

70

Ovarian metastases

 Synchronous

41

52

0.839

28

65

0.624

 Metachronous

27

32

20

39

Serum CEA (ng/mL)

 Normal

58

61

0.059

38

81

0.859

 >5

10

23

10

23

Serum CA19-9 (U/mL)

 Normal

43

53

0.986

31

65

0.805

 >39

25

31

17

39

Serum CA125 (U/mL)

 Normal

27

25

0.199

14

38

0.373

 >35

41

59

34

66

Chemotherapy regimens and toxicity

Paclitaxel and S-1 were the most frequently used chemotherapeutic drugs. Median chemotherapy duration was longer in the metachronous group (4.5 cycles, range 3–8 cycles) as compared to the synchronous group (3.7 cycles, range 1–7 cycles) although the difference was not statistically significant (P > 0.05). Drug-related adverse events and grade 3 or 4 toxicity occurred in 67.1% (102/152) and 37.5% (57/152) of patients, respectively. The most common grade 3 or 4 hematological toxic effects were leucopenia/neutropenia(26.3%) and thrombocytopenia(7.9%); the most common grade 3 or 4 nonhematological toxic effects were elevated serum aspartate aminotransferase levels (4.6%) and rash (2.6%).

Postoperative complications

Fifteen patients (16.9%) developed postoperative complications, including anastomotic leakage (n = 5), abdominal abscesses (n = 4), delayed gastric emptying (n = 4), pneumonia (n = 2), and bleeding (n = 1).Most of these patients were conservatively managed with a successful outcome, but reoperation was necessary in one patient due to intra-abdominal bleeding.

DISCUSSION

Cancers of the gastrointestinal tract are most likely to generate ovarian metastases in female patients and this is one of the most important causes of treatment failure [11]. The prognosis of patients with gastric cancer and metastasis to the ovaries has been reported to be poorer, as compared with prognosis in other primary gastrointestinal tumors [12]. In the past, chemotherapy was the main treatment for gastric cancer with ovarian metastasis, but the efficiency was disappointing, with a median survival time of 7 to 11 months [13]. Some retrospective study reports in recent years indicated that metastasectomy of Krukenberg tumors could improve prognosis of these patients [7, 8, 9]. However, an optimal therapeutic strategy for Krukenberg tumors from gastric cancer has not been fully established.

Lu et al. retrospectively reviewed a series of 85 patients diagnosed with advanced gastric cancer together with Krukenberg tumor between 2000 and 2010, and reported a median survival time of 14.1 months in the resection group as compared to 8 months in the nonresection group [7]. In another paper, Cho et al. reported that OS differed significantly between patients undergoing metastasectomy plus chemotherapy and those undergoing chemotherapy alone (18.0 months vs. 8.0 months in patients with stage IV gastric cancer; 19.0 months vs. 9.0 months in patients with recurrent Krukenberg tumors).Nevertheless, the imbalance between the two groups should cast some doubts on the significance of the findings [8].

In the present study, we retrospectively analyzed outcomes of 152 patients with synchronous and metachronous ovarian metastasis. Metastasectomy, relative to non-metastasectomy treatment, resulted in significantly better OS in patients with synchronous (19.0 months vs. 13.5 months; P < 0.001) and metachronous (24.6 months vs. 14.3 months; P = 0.02) ovarian metastasis. The present series included a large study sample, with similar clinicopathologic characteristics for both study groups. Our results are in accordance with those reported in the earlier literature, therefore, we can conclude that metastasectomy should be recommended in patients with ovarian metastasis.

Analysis of prognostic factors can, moreover, facilitate identification of patients most likely to benefit from treatment. Metastasectomy, peritoneal carcinomatosis, and expression of ER-β and PR were independent predictors of OS. Krukenberg tumors are often associated with different degrees of peritoneal metastasis, which frequently induces ascites, intestinal obstruction, or hydronephrosis and seriously impair patient quality of life [14]. There is currently no standard treatment for ovarian metastasis when it presents with peritoneal metastases from gastric cancer, however, cytoreductive surgery in combination with chemotherapy could offer a survival advantage for these patients [15, 16]. In our study, limited peritoneal metastases were resected in a metastasectomy, and this was followed by systemic chemotherapy. Subgroup analysis showed that the survival of the R0 resection group was superior to that of the non-R0 resection group. Therefore, surgical resection without gross residual disease may improve prognosis in patients with Krukenberg tumors. Chemotherapy is another main treatment for these patients, and improves quality of life and OS [17]. Several chemotherapeutic agents are effective against Krukenberg tumors with peritoneal metastasis, including fluoropyrimidine, platinum, taxanes, and epirubicin, either alone or in combination [18, 19]. A European study reported encouraging results from the use of hyperthermic intraperitoneal chemotherapy (HIPEC) [5], but these need to be validated in future research.

Some studies have reported a correlation between expression of sex hormone receptors and the incidence and progression of gastric cancer [20]. It has been suggested that sex hormones play critical protective roles in female patients with gastric cancer [21, 22]. Recently, a meta-analysis suggested that longer exposure to the effects of estrogen may potentially decrease the risk of gastric cancer [23]. However, the presence and role of sex hormone receptors in Krukenberg tumors were undetermined. We evaluated the expression of ER-a, ER-β, and PR in gastric cancer specimens, and found that only ER-β and PR were detected. Our data showed that positive expression of ER-β or PR were favorably associated with better prognosis of gastric cancer patients with ovarian metastases. From our results and those reported in the related literature, ER and PR play an important role in the etiopathogenesis of Krukenberg tumors. However, some issues remain to be resolved. It is unclear whether targeted therapy of sex hormone receptors can lower the incidence of ovarian metastasis from ER- or PR-positive gastric cancer. Moreover, the possibility of ER or PR expression being used as a reliable indicator of prophylactic ovariectomy is worth exploring. Thus, future studies investigating the significance of ER or PR expression in carcinogenesis and tumor progression of gastric cancer and Krukenberg tumor are necessary.

Our study had certain limitations because it was a retrospective analysis, and several confounding factors may have influenced our findings. However, the fact that it reports results from a large series of patients and presents the first evaluation of the role of sex hormone receptors in Krukenberg tumors from gastric cancer. The results are expected to provide useful information for formulating treatment strategies for those patients.

The present study demonstrated that the metastasectomy in combination with chemotherapy was associated with survival benefits in patients with synchronous or metachronous Krukenberg tumors from gastric cancer. Metastasectomy, peritoneal carcinomatosis, and ER-β and PR expression status were prognostic factors for survival. Well-designed prospective studies are needed to confirm these results, and will be important in developing optimal treatment strategies for Krukenberg tumors of gastric origin.

MATERIALS AND METHODS

Patients

From January 2005 to December 2014, 4381 female gastric cancer patients were admitted and treated at the Zhejiang Cancer Hospital. Among these patients, 152 with krukenberg tumor detected by the imaging studies or by pathological evaluation of the metastasectomy specimens were retrospectively reviewed. Patient demographics, radiological details, surgical data, pathological features, and survival were collected and analyzed. Outpatient records combined with telephone interviews were used for follow-up. All the patients suspected of having Krukenberg tumor underwent imaging studies to identify the extent of disease and resectability. The patients included in this study were initially regarded as having resectable diseases. Therefore, a resection was only performed in case of Krukenberg tumor without or with limited peritoneal dissemination. At the completion of surgery, the residual disease state of each patient was recorded according to the presence or absence of gross residual disease, which was classified as negative resection margins (R0), microscopic tumor infiltration (R1), and macroscopic residual tumor (R2).

Overall, 93 patients were initially diagnosed as synchronous metastasis and 59 as metachronous metastasis after they underwent curative resection of gastric cancer. Patients were divided into two groups according to treatment modality: the metastasectomy group( received both chemotherapy and metastasectomy for Krukenberg tumor) and the non-metastasectomy group(received chemotherapy alone). Overall survival (OS) of patients with synchronous ovarian metastasiswas defined as duration from the date of pathologic diagnosis of gastric cancer to the date of death or last follow-up. OS of patients with metachronous ovarian metastasis was defined as duration from the date of radiologic diagnosis of Krukenberg tumor to the date of death or last follow-up. For both groups, December 31, 2016 was the cutoff date for OS.

Detection of sex hormone receptors in gastric cancer specimens

The expression of estrogen receptor (ER)-α,ER-β, and progesterone receptor (PR) in gastric cancer, which may potentially be related to the ovarian metastasis, was detected by immunohistochemistry (IHC) using the Novolink Polymer Detection System as described previously [10]. The following primary antibodies were used: ER-α (ab37438, dilution 1:200; Abcam, Cambridge, UK), ER-β (ab288, dilution 1:100; Abcam), and PR (ab16661, dilution 1:100; Abcam). All specimens were independently evaluated by two pathologists who were blinded to study grouping. Samples where more than 10% of the tumor cells were stained were regarded as positive.

Ethics statement

The study was approved by the institutional ethics review board of Zhejiang Cancer Hospital. Written informed consent was obtained from all study participants. All study procedures were undertaken in accordance with the principles of the Declaration of Helsinki and relevant human research policies in China.

Statistical analysis

For continuous variables, two-tailed Student t-tests were used to compare demographic and clinical characteristics between the study groups. For discrete variables, a chi-square test was used. Kaplan–Meier analysis was used to calculate survival, and log-rank test was performed to compare OS between treatment groups. Independent prognostic factors were determined by multivariate analysis using the Cox proportional hazards model. All statistical analyses were conducted on SPSS 19.0 for Windows (IBM Corporation, Armonk, NY, USA). A P value less than 0.05 was considered indicative of statistical significance.

Author contributions

Pengfei Yu, Litao Yang, Gaiguo Dai, Jieer Ying, Yian Du: Concept and design of study; Ling Huang, Guoping Cheng,:analysis and interpretation of data; Pengfei Yu, Ling Huang and Yian Du, Drafting the article; Pengfei Yu and Yian Du :Final approval of the version to be published.

ACKNOWLEDGMENTS

We express our appreciation to Professor Ahmed O. Kaseb (Gastrointestinal Medical Oncology, M. D. Anderson Cancer Center) who has offered many valuable comments and suggestions.

CONFLICTS OF INTEREST

The authors declare no competing interests.

FUNDING

This study was supported by Natural Science Foundation of Zhejiang Province of China (No.LY14H160007) and “1022 Talent Plan” of Zhejiang Cancer Hospital.

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