Surgical resection and neoadjuvant therapy in patients with gastric cancer and ovarian metastasis: A real-world study

Abstract

BACKGROUND

Regarding when to treat gastric cancer and ovarian metastasis (GCOM) and whether to have metastatic resection surgery, there is presently debate on a global scale. The purpose of this research is to examine, in real-world patients with GCOM, the survival rates and efficacy of metastatic vs non-metastasized resection.

AIM

To investigate the survival time and efficacy of metastatic surgery and neoadjuvant therapy in patients with GCOM.

METHODS

This study retrospectively analyzed the data of 41 GCOM patients admitted to Zhejiang Provincial People’s Hospital from June 2009 to July 2023. The diagnosis of all patients was confirmed by pathology. The primary study endpoints included overall survival (OS), ovarian survival, OS after surgery (OSAS), disease-free survival (DFS), differences in efficacy.

RESULTS

This study had 41 patients in total. The surgical group (n = 27) exhibited significantly longer median OS (mOS) and median overall months (mOM) compared to the nonoperative group (n = 14) (mOS: 23.0 vs 6.9 months, P = 0.015; mOM: 18.3 vs 3.8 months, P = 0.001). However, there were no significant differences observed in mOS, mOM, median OSAS (mOSAS), and median DFS (mDFS) between patients in the surgical resection plus neoadjuvant therapy group (n = 11) and those who surgical resection without neoadjuvant therapy group (n = 16) (mOS: 26.1 months vs 21.8 months, P = 0.189; mOM: 19.8 vs 15.2 months, P = 0.424; mOSAS: 13.9 vs 8.7 months, P = 0.661, mDFS: 5.1 vs 8.2 months, P = 0.589).

CONCLUSION

Compared to the non-surgical group, the surgical group’s survival duration and efficacy are noticeably longer. The efficacy and survival time of the direct surgery group and the neoadjuvant therapy group did not differ significantly.

Key Words: Gastric cancer; Prognosis; Ovarian metastasis; Neoadjuvant therapy; Surgery

Core Tip: This study found that patients with gastric cancer ovarian metastases (GCOM) who underwent metastatic resection had significantly longer survival and a significantly better prognosis than patients with GCOM who did not undergo surgery. It also found that patients with GCOM who underwent surgery did or did not receive neoadjuvant therapy. There were no statistically significant differences in prognosis or survival time. Finally, a group of patients who would benefit from metastatic resection was screened.

INTRODUCTION

Among all malignant tumors, gastric cancer (GC) is the third most deadly cancer and the fifth most frequent cancer worldwide[1]. However, most patients are discovered in the middle or late stages, when cancer cells have spread, due to the lack of early signs, which places a great psychological burden on both patients and society[2,3]. The overexpression of PRX5 enhances carcinogenicity by promoting the growth and invasiveness of GC cells[4,5]. Through implantation, lymphatic, and blood channels, stomach cancer can spread to the ovaries and develop into the so-called Krukenberg tumor (KT)[6,7]. Depending on the subtype of GC, premenopausal and postmenopausal women are more likely to experience synchronous and metachronous metastases to the ovaries[8]. The research report states that the diagnostic incidence of ovarian metastasis (OM) in GC ranges from 0.3% to 6.7%, although autopsy reveal a range of metastasis rates of 33% to 41%[9]. With a median survival duration of just 7-14 months, a study has demonstrated that the prognosis of GCOM is worse than that of OM from other gastrointestinal origins[8,10]. Furthermore, when stomach cancer spreads to the ovaries, it frequently results in local consequences such ascites and intestinal obstruction, which have a substantial negative impact on the patient’s quality of life in addition to their overall health[11]. As a result, OM not only makes treating stomach cancer more difficult, but it also contributes significantly to treatment failure in female patients with the disease[6].

According to earlier research, individuals who have radical surgery typically have far longer survival times[12]. The metastatic lesion resection group’s median survival time was 17.0 months [95% confidence interval (CI): 10.0-24.0 months] in the Cheong et al[12] data, which was substantially longer than the non-resection group’s 3.0 months (95%CI: 2.0-4.0 months) (P < 0.001); according to Ma et al[13], patients with concurrent KT who underwent metastasis resection had a median survival time of 14.0 months (95%CI: 12.109-15.891 months); this was significantly longer than the non-metastasis resection group’s median survival time of 8.0 months (95%CI: 6.939-9.061 months) (P = 0.001); Patients with metachronous KT who underwent metastasis resection had a median survival time of 14.0 months (95%CI: 8.524-19.476 months), compared to 8.0 months (95%CI: 4.966-11.034 months) for the non-metastasis resection group (P = 0.018). As a result, compared to the non-metastasis resection group, the overall survival (OS) of the metastasis resection group was noticeably longer[14]. On the other hand, a study by Brieau et al[14] indicates that chemotherapy, as opposed to surgery, may increase the survival time of patients with GCOM. There has also been data in recent years supporting the superiority of chemotherapy plus metastatic resection over palliative treatment alone[15]. According to a study by Cho et al[16], patients with GC who had a KT and underwent metastatic resection along with chemotherapy had an improved OS than patients who just received palliative treatment (19.0 months vs 9.0 months; P = 0.002). According to Yada et al[17], there is only a 19% 5-year survival rate following resection of metastatic ovarian tumors. Tumor resection should be considered as a second cell depletion treatment option for non-gynecological organ malignancies[18]. As a result, a contentious and urgent subject in contemporary clinical research is if surgical resection can improve patient survival.

Treatment options for GCOM now include chemotherapy, metastatic excision, immunotherapy, and intraperitoneal heating, according to some specialists[19-21]. However, there is no clear consensus on the treatment modality and timing of GCOM. In order to provide a useful foundation for future clinical practice, this study primarily examined GCOM. It also examined the clinical importance of metastasis resection surgery and non-surgical treatment, as well as prognostic factors affecting patient survival rate.

MATERIALS AND METHODS

Materials

We conducted a retrospective analysis of 41 GCOM patients admitted to Zhejiang Provincial People’s Hospital from June 2009 to July 2023. Of them, 27 patients underwent surgery (neoadjuvant therapy was administered to 11 patients prior to surgical resection, and surgical resection was performed immediately on 16 patients), while 14 patients did not undergo surgical resection at any point during the disease. In keeping with the recommendations of the American Joint Committee on Cancer, clinical patient staging was carried out. The Zhejiang Provincial People’s Hospital ethics committee accepted the study, and all operations were carried out in compliance with the Declaration of Helsinki and the institutional and national human experimentation committees’ ethical requirements.

Treatment options

Within the resection group, 11 patients underwent direct surgical resection, while 16 patients underwent neoadjuvant therapy first. All patients in the resection group underwent the following surgical procedures: Total ovariectomy and bilateral salpingo oophorectomy (n = 4), bilateral salpingo oophorectomy (n = 21), and unilateral salpingo oophorectomy (n = 2), based on the pathological report of the section and the clinical suspicion of ovarian involvement.

Treatment evaluations

Patients’ response to therapy was assessed using computed tomography and magnetic resonance imaging, in accordance with the revised response evaluation criteria for solid tumors (version 1.1).

Statistical analysis

Utilizing an examination of the receiver operating characteristic curve, the critical value of the index was determined. The Youden index[22] was utilized to ascertain the ideal cut-off value. Using the following formula, the maximum value for the Youden index was determined: Sensitivity - (1-specificity). The OS is described as the time interval between the start of surgery and the last follow-up or death. For patients undergoing surgery, disease-free survival (DFS) refers to the time interval between the end of surgery and when the disease does not progress or recurs.

The OS, OM, OS after surgery (OSAS), and DFS were analyzed using the Kaplan-Meier technique. The Cox proportional regression model was employed to examine the patients’ prognosis and survival rate. Utilizing univariate Cox proportional hazards models, significant independent variables linked to the length of survival following surgical intervention were found. Variables having P values less than 0.05 in univariate analysis were included in the multivariate model. IBM SPSS statistics software version 23.0 (IBM Corp, grouponkny, NY, United States) was used for all statistical analyses.

RESULTS

Analysis of curative effect and survival of surgical treatment

Clinical factors of patients: The study included 41 patients with GCOM, of whom 27 underwent surgical resection and 14 did not. Baseline characteristics of patients with GCOM who underwent surgical resection and those who did not undergo surgical resection (Table 1), the cut-off values for tumor markers carbohydrate antigen 125 (CA125), CA199, carcinoembryonic antigen (CEA), and metastasis were all derived from the receiver operating characteristic curve (Supplementary Figure 1).

Table 1 Baseline characteristics of patients in the surgical and non-surgical group.

Variables	Surgical group (n = 27)	Non-surgical group (n = 14)	Total (n = 41)	P value
Median age (range)	55.07 ± 11.737	49.50 ± 14.821	53.17 ± 12.963	0.195
Number of metastatic sites	2.00 (1.00-3.00)	2.50 (2.00-3.25)	2.00 (1.00-3.00)	0.301
OM metastases foci size (cm)	6.00 (4.00-12.00)	5.90 (3.40-8.65)	6.00 (4.00-10.50)	0.403
Metastasis of stomach cancer to the ovaries (months)	0.00 (0.00-0.30)	0.00 (0.00-1.32)	0.00 (0.00-2.52)	0.419
Family history of cancer				0.179
Yes, n (%)	4 (14.8)	5 (35.7)	9 (22)
No, n (%)	23 (85.2)	9 (64.3)	32 (78)
ECOG PS 0-1				0.976
Yes, n (%)	25 (92.6)	13 (92.9)	38 (92.7)
No, n (%)	2 (7.4)	1 (7.1)	3 (7.3)
Primary lesion				0.03
Cut, n (%)	15 (55.6)	3 (21.4)	18 (43.9)
Uncut, n (%)	12 (44.4)	11 (78.6)	23 (56.1)
Oligotransfers				0.165
Yes, n (%)	9 (33.3)	2 (14.3)	11 (26.8)
No, n (%)	18 (66.7)	12 (85.7)	30 (73.2)
Ascites				0.149
Yes, n (%)	9 (33.3)	8 (57.1)	17 (41.5)
No, n (%)	18 (66.7)	6 (42.9)	24 (58.5)
Peritoneal metastases				0.428
Yes, n (%)	10 (37)	4 (28.6)	14 (34.1)
No, n (%)	17 (63)	10 (71.4)	27 (65.9)
CA125 > 26.1				0.883
Yes, n (%)	18 (66.7)	9 (64.3)	27 (65.9)
No, n (%)	9 (33.3)	5 (35.7)	14 (34.1)
CA199 > 7.3				0.758
Yes, n (%)	20 (74.1)	11 (78.6)	31 (75.6)
No, n (%)	7 (25.9)	3 (21.4)	10 (24.4)
CEA > 0.95				0.694
Yes, n (%)	24 (88.9)	13 (92.9)	37 (90.2)
No, n (%)	3 (11.1)	1 (7.1)	4 (9.8)
CA125				0.596
Normal, n (%)	14 (51.9)	6 (42.9)	20 (48.8)
Abnormal, n (%)	13 (48.1)	8 (57.1)	21 (51.2)
CA199				0.091
Normal, n (%)	19 (70.4)	6 (42.9)	25 (61)
Abnormal, n (%)	8 (29.6)	8 (57.1)	16 (39)
CEA				0.913
Normal, n (%)	14 (51.9)	7 (50)	21 (51.2)
Abnormal, n (%)	13 (48.1)	7 (50)	20 (48.8)
Bilateral ovarian metastases				0.456
Yes, n (%)	16 (59.3)	10 (71.4)	26 (63.4)
No, n (%)	11 (40.7)	4 (28.6)	15 (36.6)
OM metastases foci size < 3.15				0.604
Yes, n (%)	4 (14.8)	3 (21.4)	7 (17.1)
No, n (%)	23 (85.2)	11 (78.6)	34 (82.9)
OM metastases foci size < 5				0.762
Yes, n (%)	12 (44.4)	5 (35.7)	17 (41.5)
No, n (%)	15 (55.6)	9 (64.3)	24 (58.5)

ECOG PS: Eastern Cooperative Oncology Group Performance Status; CA199: Carbohydrate antigen 199; CEA: Carcinoembryonic antigen; CA125: Carbohydrate antigen 125; OM: Ovarian metastasis.

Efficacy: The operation group’s and the non-operation group’s median OS (mOS) values were 23 months (95%CI: 14.97-31.03 months) vs 6.93 months (95%CI: 3.21-10.66 months), according to a Kaplan-Meier analysis, with a P < 0.05 result. The median overall months (mOM) values were 18.33 months (95%CI: 10.36-26.31 months) and 3.8 months (95%CI: 0-8.2 months), respectively, with a P < 0.05. Thus, in patients with GCOM, there were statistically significant differences in mOS and mOM following OM between the group without surgical resection and the group with surgical resection (Figure 1). A comparison was made between the surgical and non-surgical groups’ efficacy (P = 0.043). Therefore, there was a statistically significant difference in efficacy between the surgical resection group and the non-surgical resection group in GCOM patients (Supplementary Table 1).

Figure 1 Kaplan-Meier curves of patients who received surgical vs nonsurgical treatment. A: Overall survival of patients who underwent surgical resection vs nonsurgical resection; B: Ovarian metastasis after ovarian metastasis in patients who underwent surgical vs nonsurgical resection.

Subgroup evaluation of survival and effectiveness in patients having surgical resection

The majority of patients (65.9%) in this study had surgical resection. Based on this, patients were further categorized and separated into groups to establish the appropriate time for surgical resection: Neoadjuvant treatment followed by surgical resection group and direct surgical resection group, in accordance with the surgical resection scheme.

Clinical characteristics of patients receiving direct surgery and neoadjuvant therapy: The baseline characteristics of patients with GCOM treated with neoadjuvant therapy followed by surgical resection and direct surgical resection (Supplementary Table 2). This study included 27 patients with GCOM, of whom 11 underwent neoadjuvant therapy followed by surgical resection and 16 underwent direct surgical resection.

Efficacy: The neoadjuvant therapy group and the direct surgery group had mOS values of 26.1 months (95%CI: 4.4-47.9 months) and 21.8 months (95%CI: 10.4-33.1 months), respectively, according to a Kaplan-Meier analysis, P = 0.189. The mOM values were 19.8 months (95%CI: 6.2-33.5 months) and 15.2 months (95%CI: 4.8-25.6 months), respectively, P = 0.424. The median OSAS (mOSAS) values were 13.9 months (95%CI: 1.9-26.0 months) and 8.7 months (95%CI: 6.9-10.5 months) and P = 0.661. The postoperative median DFS (mDFS) values were 5.1 months (95%CI: 3.4-6.8 months) and 8.2 months (95%CI: 7.4-9.1 months), respectively, P = 0.589. Thus, in patients with ovarian metastases from GC, there was no statistically significant difference in mOS, mOM, mOSAS, and mDFS between the neoadjuvant treatment group and the direct surgery group (Figure 2). Neoadjuvant treatment group and direct surgery group both showed significant improvements in efficacy (P = 0.194). Thus, in patients with GCOM, there was no statistically significant difference in the efficacy of the neoadjuvant therapy group and the immediate surgery group (Supplementary Table 3).

Figure 2 Kaplan-Meier curves of patients receiving neoadjuvant therapy vs direct surgery. A: Overall survival of patients treated with neoadjuvant therapy and direct surgery; B: Ovarian metastasis after ovarian metastasis in patients treated with neoadjuvant therapy and direct surgery; C: Postoperative overall survival in patients with neoadjuvant therapy and direct surgery; D: Postoperative disease-free survival in patients with neoadjuvant therapy and direct surgery.

Survival analysis of the neoadjuvant therapy group and the direct surgery group: The univariate Cox proportional hazards model for patients with GCOM in the neoadjuvant therapy group revealed the absence of any independent factors (Supplementary Tables 4 and 5). When patients with GCOM underwent direct surgical resection, ascites and age were independent significant factors for OS (Supplementary Table 6); in patients with GCOM undergoing direct surgical resection, ascites and age were independent significant factors for OM (Supplementary Table 7); in patients with GCOM undergoing direct surgical resection, ascites was an independent significant factor for DFS (Supplementary Table 8); in patients with GCOM undergoing direct surgical resection, ascites and CA125 > 26.1 were independent significant factors of OSAS (Supplementary Table 9).

Patients with GCOM were found to be older than 45 and to not have ascites, according to a Kaplan-Meier study. Patients without ascites who are over 45 years old can gain longer OM with direct surgical resection; patients without ascites can receive longer surgery times through direct surgical resection. Direct surgical resection can result in a prolonged OSAS for patients without ascites and CA125 > 26.1 (Figure 3).

Figure 3 Independent significant factors of medium and long-term survival based on direct surgical resection. A: Patients older than 45 years old had a longer overall survival (OS) than patients younger than 45 years old who underwent direct surgical resection (P = 0. 029); B: Patients without ascites had a longer overall OS than those with ascites who underwent direct surgical resection (P = 0.016); C: Patients older than 45 years old had longer OS after ovarian metastasis than those younger than 45 years old (P = 0.044); D: Patients without ascites had longer OS after ovarian metastasis than patients with ascites who underwent direct surgical resection (P = 0.006); E: Patients without ascites had longer postoperative disease-free survival than patients with ascites who underwent direct surgical resection (P = 0.004); F: Patients without ascites had longer postoperative OS than those with ascites who underwent direct surgical resection (P = 0.003); G: Patients with carbohydrate antigen 125 > 26.1 had a longer postoperative OS than those with carbohydrate antigen 125 < 26.1 who underwent direct surgical resection (P = 0.046). CA125: Carbohydrate antigen 125.

DISCUSSION

Treatment guidelines for GCOM are currently lacking worldwide agreement. This study found that surgical resection treatment was beneficial and prolonged patient survival compared to non-resection treatment. Similar to our findings, other studies have shown that metastasectomy extends a patient's survival time more than non-metastasectomy[13,14,23].

There is no research that demonstrates how patients’ survival times differ between surgery and neoadjuvant therapy, despite some studies suggesting that the survival benefit of individuals receiving both surgery and chemotherapy is attributed to palliative chemotherapy alone[17]. Consequently, it is imperative to ascertain which approach is more effective in extending patients’ survival times: Direct surgical resection or neoadjuvant therapy followed by surgical resection. The P value between the direct surgery group and the neoadjuvant therapy group did not differ statistically, although. The neoadjuvant treatment group (mOS = 26.1 months, 95%CI: 4.4-47.9 months; mOM = 19.8 months, 95%CI: 6.2-33.5 months; mOSAS = 13.9 months, 95%CI: 1.8-26.0 months), and the direct surgery group (mOS = 21.8 months, 95%CI: 10.4-33.1 months; mOM = 15. 2 months, 95%CI: 4.8-25.6 months; mOSAS = 8.7 months, 95%CI: 6.9-10.5 months) compared with the neoadjuvant treatment group. This may be because there were fewer cases in the neoadjuvant treatment group. However, the research result is encouraging, and it is anticipated that more cases can be examined in the future.

To find predictors of survival time, all patients’ baseline characteristics were examined. Research indicates that patients with GCOM are more likely to survive if they have peritoneal cancer, metastatic resection, estrogen-receptor-β, and progesterone-receptor expression status[19,24,25]. This study demonstrated that ascites and age were independent predictors of longer OS and OM in patients with GC-related ovarian metastases who underwent direct surgical resection; ascites is an independent predictor of longer DFS in patients with GC-related ovarian metastases who underwent direct surgical resection; and ascites and CA125 were independent predictors of longer OSAS in patients with GCOM who underwent direct surgical resection. The prognosis of GC was discovered to be correlated with the expression of CA125 in human tissues and cells by Streppel et al[26]. Consistent with the findings of this investigation, researchers like Moro et al[27] showed that CEA and CA125 have clinical utility in the identification of GCOM. As a result, it demonstrated that not all patients were candidates for immediate surgical resection treatment, and additional clinic screening was still required.

Since GCOM typically results in peritoneal metastasis as well as additional complications like ascites and intestinal obstruction, which shorten patients’ survival times, ascites is one of the independent predictors of OS, according to the analysis of prognostic factors. The results of this study are consistent with those of Kitayama et al[28], who showed that oral S-1 treatment in combination with intravenous and intraperitoneal paclitaxel is promising for patients with advanced GC, severe peritoneal metastases, and malignant ascites. A dearth of pertinent studies has reported on the effects of prophylactic resection and no prophylactic resection on the survival of patients with GCOM. Previous research has found that surgical resection extended the survival time of patients[29], and prophylactic resection was beneficial to patients with ovarian tumors[30,31]. The study found no statistically significant difference in the P value of survival time between individuals who underwent preventive resection and those who did not. In comparison to prophylactic resection of GCOM, patients with mOS, mOM, mOSAS, and mDFS are better off. However, surgical resection is a traumatic treatment that may result in postoperative wound infection. Kaplan-Meier analysis revealed that prophylactic resection (mOS = 23.5 months; mOM = 23.5 months; mOSAS = 9.1 months; mDFS = 8.2 months), and non-prophylactic resection (mOS = 12.9 months; mOM = 9.9 months; mOSAS = 6.9 months; mDFS = 5.4 months). Patients’ survival times are impacted by postoperative hemorrhage, incision dehiscence, and other issues[32]. Since there are not many cases in our study, we’re hoping to explore more of them in depth.

However, this study still had several limitations because it was carried out in a single institution, only a small number of patients were engaged, and there were unequal numbers of patients in each group. The prophylactic resection and non-prophylactic resection groups could not be subjected to additional analysis due to insufficient sample size. Future random comparison and verification of multicenter clinical cases and huge samples is anticipated. Our findings, however, are positive and support surgical resection in patients with GCOM, while also identifying patients who might benefit better from direct surgical resection.

CONCLUSION

The survival rate of patients with GCOM treated with neoadjuvant therapy is not influenced by the patients’ physical condition. On the other hand, patients’ survival rates with GCOM treated with neoadjuvant therapy can be improved by surgical resection, but not by non-surgical resection. Thus, the survival duration can be increased by carefully choosing patients who will benefit from immediate surgical resection. The survival duration can be extended in patients who are above 45, have no ascites, a CA125 value greater than 26.1, and had direct surgical resection treatment.