This study was conducted to validate the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone for treatment of Krukenberg tumors from gastric cancer and to identify prognostic factors for survival.
Clinical data from 216 patients with Krukenberg tumors from gastric cancer were collected. Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy and arm B, chemotherapy alone.
Overall survival (OS) was significantly increased in arm A relative to arm B for patients initially diagnosed with stage IV gastric cancer (18.0 months vs. 8.0 months; p < 0.001) and those with recurrent Krukenberg tumors (19.0 months vs. 9.0 months; p=0.002), respectively. Metastasectomy (hazard ratio [HR], 0.458; 95% confidence interval [CI], 0.287 to 0.732; p=0.001), signet-ring cell pathology (HR, 1.583; 95% CI, 1.057 to 2.371; p=0.026), and peritoneal carcinomatosis (HR, 3.081; 95% CI, 1.610 to 5.895; p=0.001) were significant prognostic factors for survival.
Metastasectomy plus chemotherapy offers superior OS when compared to palliative chemotherapy alone in gastric cancer with Krukenberg tumor. Prolonged survival applies to all patients, regardless of gastric cancer stage. Metastasectomy, signet-ring cell pathology, and peritoneal carcinomatosis were prognostic factors for survival. Future prospective randomized trials are needed to confirm the optimal treatment strategy for Krukenberg tumors from gastric cancer.
Gastric cancer is the second leading cause of cancer-related death worldwide. In Western countries, the incidence of gastric cancer has been decreasing, whereas it remains a main cause of cancer-related death in Korea. Gastric cancer infrequently metastasizes to the ovary, a hormone-related organ. The incidence of ovarian metastasis or Krukenberg tumor after curative resection of gastric cancer is approximately 0.3%-6.7% [
Krukenberg tumor is associated with poor prognosis in gastric cancer [
Although systemic chemotherapy is the optimal treatment strategy for recurrent or metastatic gastric cancer, it has not provided significant survival benefits. Therefore, several treatment strategies have been investigated to improve overall survival (OS) in metastatic gastric cancer patients with oligometastases or limited metastasis. Several local treatments including metastasectomy, radiofrequency ablation, and stereotactic body radiation therapy have shown impressive results [
Of 27,103 patients who were diagnosed with gastric cancer between March 2004 and February 2012 at Yonsei University Medical Center, 9,217 (34%) were women. Among female gastric cancer patients, 216 with Krukenberg tumor detected by abdominal-pelvis computed tomography (CT) or gynecologic ultrasonography were included in this study and reviewed retrospectively (Severance Hospital, n=172; Gangnam Severance Hospital, n=44). Patient information was obtained from outpatient clinical or admission records and information regarding patient survival was obtained from the Korean National Statistics Registry Database. The protocols were approved by the Yonsei University Health System Institutional Review Board.
In general, curative surgery plays an important role in gastric cancer without distant metastasis. Therefore, for data analysis, patients were divided into two groups according to initial gastric cancer stage: stage I-III and stage IV. Patients received surgery or palliative chemotherapy according to the initial disease stage. Patients suspected of having Krukenberg tumor underwent imaging studies to confirm disease resectability. However, 87% of patients (93/107) who underwent oophorectomy had disease that already extended beyond the ovary, in which case oophorectomy was performed for palliative symptom control. The residual disease state of each patient was documented as 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). R0 resection was achieved in only 38% (41/107) of patients who underwent oophorectomy.
Overall, 125 patients were initially diagnosed with stage IV gastric cancer and 91 with recurrent Krukenberg tumor after they underwent curative resection of gastric cancer. Among the patients initially diagnosed with stage IV gastric cancer, Krukenberg tumors were detected synchronously and metachronously in 84 patients and 41 patients, respectively.
To compare OS, patients with initial stage IV gastric cancer (n=125) were divided into two arms according to treatment modality. Arm A1 comprised 49 patients who received both chemotherapy and metastasectomy for Krukenberg tumor. Arm B1 comprised 76 patients who received chemotherapy alone. Patients with recurrent Krukenberg tumor (n=91) were assigned to arm A2 or arm B2. Arm A2 comprised 58 patients who received chemotherapy and metastasectomy for recurrent Krukenberg tumor, and arm B2 comprised 33 patients who received chemotherapy alone. In arms A1 and B1, OS was defined as the time from the date of pathologic diagnosis of gastric cancer to the date of death or last follow-up. In arms A2 and B2, OS was defined as the time from the date of Krukenberg tumor diagnosis by imaging to the date of death or last follow-up.
All statistical analyses were performed using IBM SPSS ver. 20.0 (IBM Co., Armonk, NY). For continuous variables, two-tailed Student t tests were used to compare the demographic and clinical characteristics between patient arms. For discrete variables, a chi-square test was used. Survival rates and 95% confidence intervals (CIs) were calculated using the Kaplan-Meier method. The influence of the covariates on survival length between treatment arms was assessed using the log-rank test. A p-value of < 0.05 was considered significant. Significant variables in the univariate analysis were entered into multivariate analysis using the Cox proportional hazards model.
The median follow-up duration for all patients was 30.0 months until the OS data cutoff date (June 30, 2013), at which time 90% of the patients had discontinued treatment. The median age of patients at Krukenberg tumor diagnosis was 43.4 years (range, 21 to 78 years) and the average size of metastatic ovarian tumors was 6.8 cm (range, 1.5 to 24 cm).
The clinical characteristics of patients with initial stage IV gastric cancer (n=125) are listed in
The clinical characteristics of patients with recurrent Krukenberg tumor of gastric origin (n=91) are listed in
The median OS of patients with initial stage IV gastric cancer was 12.0 months (95% CI, 9.7 to 14.3 months). The median OS of arm A1 and arm B1 was 18.0 months (95% CI, 15.2 to 20.8 months) and 8.0 months (95% CI, 6.6 to 9.4 months), respectively. Therefore, patients in the chemotherapy plus metastasectomy arm had a significantly better OS than patients in the chemotherapy arm (p < 0.001) (
The median OS of patients with recurrent Krukenberg tumors was 15.0 months (95% CI, 12.7 to 17.3 months). The median OS time of arm A2 and arm B2 was 19.0 months (95% CI, 14.4 to 23.6 months) and 9.0 months (95% CI, 6.2 to 11.8 months), respectively. Patients in the chemotherapy plus metastasectomy arm had a significantly better OS than patients in the chemotherapy alone arm (p=0.002) (
Upon univariate analysis of all patients, metastasectomy, signet-ring cell pathology, presence of peritoneal carcinomatosis, gastrectomy, and elevated serum levels of carcinoembryonic antigen (CEA; >5 ng/mL), CA 19-9 (>24 U/mL), and CA-125 (>35 U/mL) were prognostic factors associated with survival. After adjusting for covariates in multivariate analysis, metastasectomy (hazard ratio [HR], 0.458; 95% CI, 0.287 to 0.732; p=0.001), signet-ring cell pathology (HR, 1.583; 95% CI, 1.057 to 2.371; p=0.026), and presence of peritoneal carcinomatosis (HR, 3.081; 95% CI, 1.610 to 5.895; p=0.001) were independent predictors of OS (
It was difficult to statistically analyze survival differences between patients in whom metastasis was limited to the ovary and those who have metastasis beyond the ovary because only 8% of patients showed metastasis limited to the ovary. Most of these patients were alive at the time of the study. A few patients who showed metastasis to other sites were subjected to additional surgery with oophorectomy, such as total hysterectomy and bowel resection.
As shown in
Oophorectomy was found to still be beneficial when other unresectable metastasis were present, for both metastatic and recurrent disease. Analysis of all cases except single ovarian metastasis revealed that the median OS time of arm A1 and arm B1 was 16.0 months (95% CI, 13.7 to 18.3 months) and 8.0 months (95% CI, 6.6 to 9.4 months; p < 0.001), respectively. Additionally, the median OS time of arm A2 and arm B2 was 16.0 months (95% CI, 12.5 to 19.5 months) and 8.0 months (95% CI, 5.8 to 10.2 months; p=0.039), respectively.
The frequencies and response rates of chemotherapy regimens initially used after ovarian metastasis diagnosis were also analyzed (
Most patients diagnosed with Krukenberg tumor of gastric origin have poor prognosis. Many studies have shown that the median survival after Krukenberg tumor diagnosis is 7-11 months [
Our study showed that patients with Krukenberg tumor of gastric origin who underwent both chemotherapy plus metastasectomy had longer OS than those who underwent chemotherapy alone, regardless of stage. The difference in OS was actually underestimated because the OS in arms A2 and B2 was determined from the date of recurrent Krukenberg tumor diagnosis and not the date of the initial gastric cancer diagnosis. Despite the small proportion of R0 resections, a prolonged OS was observed in the chemotherapy plus metastasectomy arm. In our study, one patient in arm A1 survived more than 9 years after the initial diagnosis of gastric cancer, while one patient in arm A2 survived more than 7.5 years after resection of metachronous Krukenberg tumor.
Some studies have reported the survival benefit of metastasectomy for Krukenberg tumor; however, most of these included a small number of patients (approximately 50 patients) and Krukenberg tumors of different origins, including gastric, colon, and breast cancers [
In the present study, the prognostic factors associated with survival in patients with Krukenberg tumor of gastric origin were analyzed. Metastasectomy, signet-ring cell pathology, and peritoneal carcinomatosis were identified as significant prognostic factors. Several studies have also shown that metastasectomy is a prognostic factor for better OS in patients with Krukenberg tumors [
Published studies of the role of chemotherapy in the treatment of Krukenberg tumors have included only small patient numbers or case reports. In the present study, response rates to chemotherapy regimens were analyzed in 111 patients diagnosed with Krukenberg tumor, and response rates ranged from 12% to 26%. In most of our cases, Krukenberg tumor was diagnosed during later stages of gastric cancer progression. Therefore, at the time of Krukenberg tumor diagnosis, patients have already received standard first-line chemotherapy for advanced or metastatic gastric cancer.
In our experience, ovarian metastases show less chemotherapy responsiveness than other sites of metastasis. Early detection of ovarian metastases is important to successful treatment. In the present study, serum CEA, CA 19-9, and CA-125 level were not useful predictors of Krukenberg tumor. Despite continual efforts to develop a practical biomarker that can predict relapse or metastasis of ovary metastasis with gastric cancer, no clinical tests have been established [
Clinical heterogeneity is most likely due to the diverse molecular profile of gastric cancer. Thus, identifying diversity in the molecular profile of gastric cancer that governs the clinical behavior of tumors could lead to new and more effective clinical strategies. Recent studies of gastric cancer have identified genes that differ according to histologic factors and age, as well as those useful for gastric cancer prognosis prediction [
It should be noted that several factors may have affected the decision of surgery for treatment of the patients evaluated in the present study, including the extent of metastasis, possibility of curative surgery, surgeon’s opinion, etc. Additionally, the difference in the chemotherapy regimen between arm A and arm B may have influenced patient survival or toxicity.
CT was used to identify patients who would benefit from the curative resection of Krukenberg tumors. Although imaging modalities, including CT scanning, have been developed to detect intraperitoneal metastasis, CT has been shown to only have a 50% accuracy for detecting intraperitoneal metastatic cancers [
In conclusion, we demonstrated that metastasectomy was associated with longer survival in patients with Krukenberg tumors in gastric cancer. Therefore, metastasectomy should be performed in stage IV gastric cancer patients diagnosed synchronously or metachronously with Krukenberg tumor. Our data also suggest that metastasectomy plus chemotherapy may play a role in the treatment of Krukenberg tumors of gastric origin. Furthermore, we found that metastasectomy, signet ring cells, and peritoneal carcinomatosis were prognostic factors for Krukenberg tumors. Future prospective randomized trials are needed to confirm our findings and will be important in establishing standard treatment guidelines for patients with Krukenberg tumor in metastatic gastric cancer.
Conflict of interest relevant to this article was not reported.
This research was supported by a CMB-Yuhan research grant from the Yonsei University College of Medicine (6-2013-0065) and the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (No. 2010-0024248).
Kaplan-Meier overall survival based on treatment arm in initial stage IV gastric cancer. Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy; arm B, chemotherapy alone.
Kaplan-Meier overall survival based on treatment arm with recurred Krukenberg tumor. Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy; arm B, chemotherapy alone.
Kaplan-Meier overall survival based on curative resection of Krukenberg tumor in stomach cancer. The residual disease state of each patient was documented as 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).
Clinical characteristics of 125 patients with initial stage IV gastric cancer
Variable | Arm A1 |
Arm B1 |
p-value |
---|---|---|---|
Median age (yr) | 43.3 (26-69) | 42.1 (27-72) | 0.428 |
< 50 | 39 (80.0) | 64 (84.2) | 0.508 |
≥ 50 | 10 (20.4) | 12 (15.8) | - |
Laterality | 0.315 | ||
Bilateral | 37 (75.5) | 51 (67.0) | - |
Unilateral | 12 (24.5) | 25 (33.0) | - |
Krukenberg tumor size (cm) | 7.99 (3.4-19) | 5.76 (1.5-24) | 0.004 |
Pathologic differentiation | 0.236 | ||
WD-MD | 7 (14.3) | 6 ( 7.9) | - |
PD-SRC | 42 (85.7) | 69 (90.8) | - |
Chronology | 0.676 | ||
Synchronous | 34 (69.3) | 50 (65.8) | - |
Metachronous | 15 (30.6) | 26 (34.2) | - |
Metastasis site | |||
Peritoneum | 38 (77.6) | 66 (86.8) | 0.175 |
Liver | 6 (12.2) | 10 (13.2) | 0.881 |
Bone | 5 (10.2) | 11 (14.4) | 0.723 |
Lung | 2 (4.1) | 5 (6.6) | 0.704 |
Other | 23 (46.9) | 32 (42.1) | 0.699 |
Extent of disease | 0.028 | ||
Limited to the ovary | 7 (14.3) | 2 (2.6) | - |
Beyond the ovary | 42 (85.7) | 74 (97.4) | - |
R status | |||
R0 resection | 14 (28.6) | - | - |
R2 resection | 35 (71.4) | - | - |
Serum CEA (ng/mL) | 3.05 (0.01-36.3) | 5.80 (0.01-121) | 0.277 |
Normal | 41 (83.7) | 56 (73.7) | 0.083 |
> 5 | 4 (8.2) | 15 (19.7) | - |
Serum CA 19-9 (U/mL) | 96.64 (0.1-1,850) | 484.5 (0.1-12,100) | 0.067 |
Normal | 32 (65.3) | 30 (39.5) | 0.009 |
> 24 | 14 (28.6) | 37 (48.7) | - |
Serum CA-125 (U/mL) | 74.1 (5.5-244) | 187 (11-1,555) | 0.051 |
Normal | 14 (28.6) | 11 (14.5) | 0.159 |
> 35 | 14 (28.6) | 23 (30.3) | - |
Values are presented as median (range) or number (%). WD-MD, well differentiated adenocarcinoma and moderately differentiated adenocarcinoma; PD-SRC, poorly differentiated adenocarcinoma and signet ring cell carcinoma; CEA, carcinoembryonic antigen; CA, cancer antigen.
Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy; arm B, chemotherapy alone,
p-values from chi-square test except for Krukenberg tumor size, and median age at Krukenberg tumor diagnosis, which were determined by a two-tailed Student t test.
Clinical characteristics of 91 patients with recurrent Krukenberg tumor
Variable | Arm A2 |
Arm B2 |
p-value |
---|---|---|---|
Median age (yr) | 43.9 (21-78) | 45.9 (25-75) | 0.372 |
< 50 | 41 (70.7) | 18 (54.5) | 0.121 |
≥ 50 | 17 (29.3) | 15 (45.5) | - |
Relapse free survival (mo) | 24.3 (3-109) | 27.8 (4-91) | 0.435 |
Laterality | 0.022 | ||
Bilateral | 42 (72.4) | 16 (48.5) | - |
Unilateral | 16 (27.6) | 17 (51.5) | - |
Krukenberg tumor size (cm) | 7.39 (3-18) | 5.95 (1.9-15) | 0.068 |
Pathologic differentiation | 0.499 | ||
WD-MD | 6 (10.3) | 5 (15.2) | - |
PD-SRC | 52 (89.7) | 28 (84.8) | - |
AJCC stage | 0.824 | ||
I, II | 26 (44.8) | 14 (42.4) | - |
III | 32 (55.2) | 19 (57.6) | - |
Metastasis site | |||
Peritoneum | 45 (77.6) | 26 (78.8) | 0.894 |
Liver | 4 (6.9) | 4 (12.1) | 0.454 |
Bone | 6 (10.3) | 5 (15.2) | 0.519 |
Lung | 2 (3.4) | 0 (0) | 0.533 |
Other | 33 (56.9) | 13 (39.4) | 0.108 |
Extent of disease | 0.25 | ||
Limited to the ovary | 7 (12.1) | 1 (3.0) | - |
Beyond the ovary | 51 (87.9) | 32 (97.0) | - |
R status | |||
R0 resection | 27 (46.6) | - | - |
R2 resection | 31 (53.4) | - | - |
Serum CEA (ng/mL) | 2.79 (0.13-22.2) | 332 (0.65-10,410) | 0.319 |
Normal | 44 (75.9) | 24 (72.7) | 0.276 |
> 5 | 8 (13.8) | 8 (24.2) | - |
Serum CA 19-9 (U/mL) | 118.73 (0.1-2,270) | 1,702 (0.1-20,000) | 0.097 |
Normal | 38 (65.6) | 15 (45.5) | 0.035 |
> 24 | 14 (25.0) | 15 (45.5) | - |
Serum CA-125 (U/mL) | 36.4 (4-241) | 60.82 (5-227.8) | 0.117 |
Normal | 33 (56.9) | 10 (30.3) | 0.08 |
> 35 | 11 (19.0) | 9 (27.3) | - |
Values are presented as median (range) or number (%). WD-MD, well differentiated adenocarcinoma and moderately differentiated adenocarcinoma; PD-SRC, poorly differentiated adenocarcinoma and signet ring cell carcinoma; AJCC, American Joint Committee on Cancer; CEA, carcinoembryonic antigen; CA, cancer antigen.
Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy; arm B, chemotherapy alone,
p-values from chi-square test except for Krukenberg tumor size, median age at Krukenberg tumor diagnosis, and relapse free survival, which were determined by a two-tailed Student t test.
Univariate and multivariate analysis showing factors associated with overall survival in 216 patients
Variable | Univariate |
Multivariate |
||
---|---|---|---|---|
HR (95% CI) | p-value | HR (95% CI) | p-value | |
Metastasectomy | 0.404 (0.302-0.539) | < 0.001 | 0.458 (0.287-0.732) | 0.001 |
Age (≥ 50 yr) | 1.065 (0.769-1.477) | 0.704 | - | - |
Metachronous disease | 0.870 (0.587-1.289) | 0.487 | - | - |
Unilateral ovarian metastases | 1.097 (0.809-1.487) | 0.552 | - | - |
Size of Krukenberg tumor (< 5 cm) | 0.749 (0.547-1.024) | 0.070 | - | - |
Signet-ring cells | 0.642 (0.479-0.859) | 0.003 | 1.583 (1.057-2.371) | 0.026 |
Peritoneal carcinomatosis | 3.034 (1.990-4.625) | < 0.001 | 3.081 (1.610-5.895) | 0.001 |
Gastrectomy | 2.022 (1.507-2.712) | < 0.001 | 1.293 (0.787-2.124) | 0.311 |
Relapse free survival (≥ 12 mo) | 1.433 (0.958-2.144) | 0.080 | - | - |
CEA | 1.434 (1.061-1.938) | 0.052 | - | - |
CA 19-9 | 1.614 (1.193-2.182) | 0.002 | 0.683 (0.447-1.042) | 0.077 |
CA-125 | 2.091 (1.420-3.078) | < 0.001 | 0.653 (0.421-1.014) | 0.057 |
HR, hazard ratio; CI, confidence interval; CEA, carcinoembryonic antigen; CA, cancer antigen.
Frequencies and response rates of chemotherapy regimens initially used after ovarian metastasis diagnosis
Variable | Arm A1 |
Arm A2 |
Arm B1 |
Arm B2 |
Total |
|||||
---|---|---|---|---|---|---|---|---|---|---|
No. | RR (%) |
No. | RR (%) | No. | RR (%) | No. | RR (%) | No. | RR (%) | |
Platinum |
8 | 25 | 1 | 0 | 21 | 14 | 13 | 46 | 43 | 26 |
Irinotecan |
0 | 0 | 0 | 0 | 4 | 25 | 4 | 25 | 8 | 25 |
Taxane |
4 | 0 | 2 | 0 | 17 | 18 | 3 | 0 | 26 | 12 |
Total | 12 | 17 | 3 | 0 | 42 | 17 | 20 | 35 | 77 | 21 |
Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy; arm B, chemotherapy alone,
RR, response rate (comlete response or partial response patients/total patients),
Cisplatin+TS-1, cisplatin+capecitabine (XP), cisplatin+5-fluorouracil (5-FU) (FP), oxaliplatin+capecitabine (XELOX), oxaliplatin+5-FU/leucovorin (LV) (FOLFOX), oxaliplatin+TS-1 (SOX),
Irinotecan mono, irinotecan+TS-1, irinotecan+5-FU/LV (FOLFIRI),
Paclitaxel mono, paclitaxel+5-FU/LV, paclitaxel+TS-1, docetaxel mono, docetaxel+5-FU/LV, docetaxel+TS-1, docetaxel+capecitabine.