Introduction

A recent global estimate has revealed that gastric cancer is the third leading cause of cancer-related death and the fifth most common cancer diagnosed worldwide [1]. Peritoneal dissemination is the most common and most lethal type of gastric cancer metastasis [2, 3]. Patients with peritoneal dissemination of gastric cancer frequently have symptoms such as abdominal pain, nausea/vomiting, and weight loss [4], and they are often unable to eat due to malignant bowel obstruction (MBO). Thus, peritoneal dissemination significantly impairs patient quality of life (QOL).

Palliative surgery such as small intestine/colon bypass and ileostomy/colostomy has been performed for MBO. However, it can be challenging to determine whether palliative surgery should be performed, because various factors, such as age, performance status (PS), nutritional status, and postoperative morbidity and mortality, affect outcomes. Furthermore, the efficacy of palliative surgery has not been fully verified with regard to the safety or improvement in postoperative QOL and oral intake.

QOL improvement is crucial, because patients with MBO have a short life expectancy. Ideally, palliative surgery reduces painful symptoms and allows QOL to be maintained for as long as possible without shortening survival. Although several studies on palliative surgery for MBO from peritoneal carcinomatosis have been published, many of them are retrospective [5,6,7].

Therefore, we prospectively investigated the impact of palliative surgery for gastric MBO on improvements in QOL and oral intake in a prospective multicenter observational study (UMIN000023495).

Patients and methods

This study was a multicenter observational trial. The study protocol was approved by the institutional review boards (IRBs) of each of the 14 participating Japanese hospitals before study initiation.

The primary endpoint was change in QOL assessed at 14 days, 1 month, and 3 months following palliative surgery compared with preoperative QOL. Secondary endpoints were postoperative improvement in oral intake and surgical complications.

Eligibility criteria

The eligibility criteria were as follows: histologically proven gastric adenocarcinoma presenting with bowel obstruction due to peritoneal dissemination diagnosed clinically, endoscopically, or radiographically; extremely poor or no oral intake requiring parenteral nutrition; age ≥ 20 years; surgical fitness without severe cardiac or pulmonary dysfunction, massive ascites, pleural effusion or edema; Eastern Cooperative Oncology Group (ECOG) PS score 0–2; adequate organ function within 14 days before enrollment, defined as a leukocyte count ≥ 3000/mm3, hemoglobin level ≥ 8.0 g/dL with or without transfusion, platelet count ≥ 100,000/mm3, total bilirubin level ≤ 3.0 mg/dL, and serum creatinine concentration ≤ 2.0 mg/dL; and provision of written informed consent.

Patients were excluded if they met any of the following criteria: active bleeding or perforation necessitating urgent surgery; active symptomatic coexisting cancer (synchronous coexisting cancer or recurrence of metachronous cancer); clinically suspected brain metastasis or carcinomatous meningitis; presence of disseminated intravascular coagulation; and severe psychiatric disorder.

Surgical procedures

Within 14 days of enrollment, patients underwent palliative surgery involving either small intestine/colon resection or small intestine/colon bypass for bowel stenosis. Ileostomy/colostomy and catheter ileostomy were allowed, but placement of an endoscopic stent was not. Selection of treatment was left to the discretion of the surgeon.

Assessments of quality of life and oral intake

After registration, patients completed baseline QOL surveys. Follow-up QOL surveys were conducted in all surviving patients at 14 days, 1 month, and 3 months after palliative surgery. Questionnaires were administered by research assistants via personal interviews with inpatients. Questionnaires were mailed from the data center to outpatients, who returned completed surveys.

QOL was assessed by questionnaire using the Euro QoL Five Dimensions (EQ-5D™; Euro QoL Group, Rotterdam, The Netherlands) [8,9,10] and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire gastric cancer module (QLQ-STO22) [11, 12]. The EQ-5D™ is a non-specific self-classifier with five questions (concerning mobility, self-care, daily activities, pain/discomfort, and mood); index scores ranging from − 0.111 to 1.000 were calculated based on UK preference weights [9], with high scores representing good health status. The QLQ-STO22 consists of 22 validated questions that evaluate five multi-item symptom scales (dysphagia, eating restrictions, pain, reflux, and anxiety) and four single-item symptoms scales (dry mouth, body image, hair loss, and loss of taste). Scoring was performed according to the EORTC QLQ-C30 Scoring Manual; scores ranging from 0 to 100 were calculated when at least half of the items were completed by the patient. A lower score indicates better QOL, with a score of 0 representing no symptoms.

Patients were also asked to explain oral intake status at baseline, 14 days, 1 month, and 3 months after palliative surgery, based on the Gastric Outlet Obstruction Scoring System (GOOSS): 0, no oral intake; 1, liquids only; 2, soft solids; and 3, low-residue or full diet [13, 14].

Evaluation of operative morbidity and mortality

Surgical and non-surgical complications were diagnosed clinically, radiographically, or endoscopically, and evaluated according to the Clavien–Dindo classification [15, 16]. Reoperation details and duration of hospital stay after palliative surgery until hospital discharge were recorded. Postoperative death from any cause within 30 days of surgery and hospital death during the same hospital stay were also recorded.

Statistical analysis

The primary endpoint was change of EQ-5D™ index score from baseline at each postoperative time point evaluated by paired t-test. Changes of EQ-5D™ scores were characterized at each assessment after baseline as improved or deteriorated if the score changed by ≥ 0.05 points or ≤ − 0.05, and stable between -0.05 and 0.05 points. QLQ-STO22 score at each assessment point was compared with baseline value by paired t-test.

All statistical analyses were conducted using SAS® statistical software version 9.4 (SAS Institute, Cary, North Carolina, USA), and P < 0.05 was considered statistically significant. The planned sample size was 100 patients to enable detection of a measured EQ-5D™ QOL difference of 0.3 standard deviations after palliative surgery compared with before surgery, with a two-sided α of 5% and 80% statistical power. The trial was prematurely stopped at 74 patients, due to insufficient accrual.

Results

Patients

Between April 2013 and March 2018, 74 patients from 14 institutions were registered into this study. All the patients were confirmed to have peritoneal dissemination at laparotomy. Of these, 11 (9 patients able to eat soft solids and 2 patients with PS of 3) were ineligible leaving 63 patients in the analysis. Among these 63 patients, disseminated metastasis to the middle and lower abdominal peritoneum was observed in 57 patients while its spread was confined to the upper abdominal peritoneum in 6 patients. Patient characteristics are summarized in Table 1. Thirty-five patients were men. The median age and BMI were 65 (30–81) years and 17.9 (13.1–28.9) kg/m2, respectively. Half of the patients had an ECOG PS of 1, and 23 patients (37%) had a PS of 2. More than half of the patients had ascites before surgery. Types of surgery are shown in Table 1. Small bowel/colonic bypass was performed in 33 patients, ileostomy/colostomy in 28 patients, and exploratory laparotomy in 3 patients. One patient underwent both small bowel/colonic bypass and ileostomy/colostomy.

Table 1 Patient characteristics
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QOL changes

Sixty-two patients (98%) responded to the baseline QOL questionnaire. The response rate to the QOL questionnaire was 97% (61 patients) at 14 days, 89% (56 patients) at 1 month, and 71% (45 patients) at 3 months. Forty-five patients (71%) completed QOL questionnaires at all follow-up points (Fig. 1a).

Fig. 1
figure 1

Changes in EuroQoL Five Dimensions (EQ-5D™) scores after palliative surgery in all patients (a), in 45 patients who completed QoL questionnaires at all points (b), in 40 patients with baseline performance status (PS) of 0–1 (c), and in 23 patients with baseline PS of 2 (d). The index scores range from − 0.1 to 1.0, with high scores representing good status

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The primary endpoint, a measured QOL difference of 0.3 standard deviations after palliative surgery compared with before surgery, was not met. The mean baseline EQ-5D™ score of all patients was 0.6. The mean score of 0.7 at 3 months after surgery did not represent a significant improvement (Fig. 1a). In 45 patients who completed the QOL questionnaires at all points, the mean scores remained consistent with baseline scores (Fig. 1b). When dividing the patients into 2 categories, PS0/1 and PS2, the mean scores of 0.7 and 0.6 remained consistent with baseline scores, respectively (Fig. 1c, d).

Patients were divided into three groups: those with improved QOL scores, those with stable QOL scores, and those with deteriorated QOL scores or those who died or had no data available. As patients who did not return questionnaires were likely to have been in the poorest condition, they were included in the deteriorated QOL score group. The proportion of patients with deteriorated QOL scores compared with before surgery was 35% at 14 days after surgery, 48% at 1 month, and 51% at 3 months (Fig. 2a). This chronological increase in the proportion of patients with deteriorated QOL scores was constant regardless of baseline PS (Fig. 2b, c).

Fig. 2
figure 2

Number of patients with improved or stable EuroQoL Five Dimensions (EQ-5D™) scores after palliative surgery, compared with the number of patients whose scores deteriorated, or who died or had no data available, in all patients (a), in 40 patients with PS of 0–1 (b), and in 23 patients with PS of 2 (c). The EQ-5D™ scores at each postoperative assessment were considered to have improved or deteriorated if the score changed by ≥ 0.05 points, and stable if it changed by < 0.05 points

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Gastric-specific symptoms such as dysphagia, eating restrictions, reflux, pain, anxiety, and dry mouth assessed by QLQ-STO22 were significantly improved after surgery at most assessment points. In contrast, taste was not improved at any assessment point (Fig. 3).

Fig. 3
figure 3

Changes in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire gastric cancer module (EORTC QLQ-STO22) scores: a dysphagia, b eating restrictions, c reflux, d pain, e anxiety, f dry mouth, g taste. Scores range from 0 to 100, with low scores representing a lower symptom burden

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Improvement in oral intake

Changes in oral intake based on GOOSS at baseline, 2 weeks, 1 month, and 3 months after palliative surgery are shown in Fig. 4. Although no patient could eat solid food at baseline, more than half of patients were able to eat solid food 14 days after surgery, and this situation was maintained for 3 months, with 36 patients (57%) able to eat soft solids, low-residue foods, or solid food (Fig. 4a). Improved oral intake of GOOSS 2/3 was achieved in more than half of patients regardless of baseline PS (Fig. 4b, c).

Fig. 4
figure 4

Changes in oral intake after palliative surgery based on the Gastric Outlet Obstruction Scoring System (0, no oral intake; 1, liquids only; 2, soft solids; 3, low-residue foods or full diet), in all patients (a), in 40 patients with PS of 0–1 (b), and in 23 patients with PS of 2 (c)

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Operative morbidity and mortality

Postoperative complications were observed in 28 patients (44%), including Clavien–Dindo grade III or higher complications in 10 patients (16%) (Table 2). Reoperation was necessary in two patients (3.2%), in one for tumor bleeding 5 days after surgery and in the other for ileus 14 days after surgery. A total of 8 patients (13%) died during hospitalization, 2 (3.2%) of whom died within 30 days of surgery. All deaths were considered to reflect disease progression rather than postoperative complications, with brain metastasis and cancerous disseminated intravascular coagulation in one each and multiple organ failure in 6 patients. The median hospital stay was 24 (range, 8–83) days.

Table 2 Operative morbidity and mortality
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Discussion

Palliative surgery for MBO associated with peritoneal dissemination of gastric cancer can alleviate various obstructive symptoms, but its effectiveness has not been fully verified. The decision to perform palliative surgery is influenced by prognosis, PS, surgeon experience, and patient expectations and attitudes. It is not yet clear what factors determine the optimal treatment strategy for MBO. When considering palliative surgery for MBO, traditional surgical outcome measures such as morbidity, mortality, and survival are not sufficient due to the patients’ short remaining life expectancy. It is necessary to evaluate the effect of palliative surgery on improvements in QOL and oral intake. Improving QOL in patients who are unable to eat is expected to lead to longer survival if chemotherapy can be performed [17,18,19,20]. Few prospective studies examining the improvements in QOL and oral intake in this patient population have been performed, with most of the palliative surgical literature focusing on esophageal, colorectal, pancreatic, biliary, and ovarian cancers [5, 21]. This prospective study presented two quantitative validated QOL measures (EQ-5D and QLQ-STO22) and two objective measures (postoperative improvement in oral intake and safety of palliative surgery). Our findings are easy for surgeons and patients to understand and must be useful for decision-making.

The purpose of this study was not to compare small intestine/colon bypass with ileostomy/colostomy, as the degree of peritoneal dissemination differs between patients who have undergone small intestine/colon bypass and those who have undergone ileostomy/colostomy. Instead, we evaluated the improvements in QOL and oral intake in all patients who underwent palliative surgery. Endoscopic stenting was not allowed in this study, because we assumed most patients had multisite intestinal stenosis due to peritoneal dissemination of gastric cancer.

Patient compliance with follow-up QOL surveys was good at about 90% until 1 month after surgery, but dropped to about 70% at 3 months after surgery. In this study, patients with poor prognoses were targeted, and we thought that the compliance rate decreased 3 months after surgery due to death or deterioration of general condition. Another study that prospectively investigated QOL in patients with malignant gastric outlet obstruction reported that the compliance rate was 55% 1 month after palliative intervention and 21% at 3 months. The authors concluded that QOL studies are difficult to complete in this population due to severity of disease and short life expectancy [22].

Although this study was a QOL survey in patients with severe prognoses, it provided important insights into the significance of palliative surgery for MBO associated with peritoneal dissemination. QOL after palliative surgery did not improve, but baseline QOL was maintained for at least 3 months. However, it should be noted that QOL seems to be maintained if no patients report experiencing worsened conditions and/or information about patients with decreased QOL is lost. When considering the 45 patients who completed the QOL questionnaires at all points, their QOL was really maintained for 3 months after palliative surgery but not improved. We also compared the proportion of patients with improved or stable EQ-5D™ scores with the proportion of those with deteriorated scores or who had died or had no data available at each time point. The proportion of patients who could have experienced deterioration in QOL at 14 days after surgery was 35%, and the percentages were 48% at 1 month and 51% at 3 months. A greater percentage of patients came to be classified as deteriorated over time. The effect of palliative surgery on gastric-specific symptoms was more pronounced for dysphagia and eating restrictions than for other symptoms. As a whole, QOL gradually declined.

On the other hand, all patients were unable to eat solid food before palliative surgery. However, 57% of patients came to eat low-residue or solid food 3 months after surgery, which is in accordance with the dietary resumption rate of 45–75% reported previously [6]. In this respect, palliative surgery was considered beneficial.

The efficacy of palliative surgery could be severely impaired by postoperative complications. Palliative surgery is reserved for patients with poor prognoses, so their mortality and morbidity rates are expected to be lower. Overall morbidity rate of 44% and Clavien–Dindo (CD) grade III or higher complication rate of 16% observed in this study is acceptable, compared with the overall and ≥ CD III morbidity rates of 58% and 30%, respectively, demonstrated in the previous study [7] which evaluated the outcomes of palliative surgery for MBO caused by peritoneal carcinomatosis from a variety of primary cancers. Two patients (3.2%) underwent reoperation in our study, which is within the reported reoperation rates of 2–15% [6]. Although 13% of the patients in this study (8 of 64) died during hospitalization, they all died from disease progression rather than postoperative complications. Similarly, in the previous study [7], more than 16% of patients died in hospital or in a hospice directly following discharge. The 30-day postoperative mortality rate of 3.2% observed in this study is acceptable, considering the comparable mortality rate of 1.9% of palliative surgery for malignant gastric outlet obstruction [23] and much higher rate of 26.4% or more associated with palliative surgery for MBO from peritoneal carcinomatosis [7].

The present study has some limitations. First, the planned sample size was not achieved because this study had many intrinsic difficulties in patient accrual in view of its strict eligibility criteria, patient preferences, and biases of individual clinicians, which may have led to the low annual inclusion rate at each institution, restricting the statistical power to support conclusions. A screening log is not available, irrespective of the willingness to perform a case survey of the eligible patients, who were successfully enrolled, declined enrollment, and did not receive any explanation of this study, which might raise the doubts of the highly selective nature of the enrolled patients. Second, death and worsening of patients’ general condition affected the response rates of QOL surveys. However, this limitation is inherent in all QOL studies involving patients with a short life expectancy. Third, similarly, the QOL follow-up period was limited for 3 months after palliative surgery. Finally, there was no information available about patients who received palliative treatments such as endoscopic stenting or medical management only, making it difficult to evaluate our palliative surgery with other palliative modalities.

In conclusion, to the best of our knowledge, this is the first multicenter prospective observational study of palliative surgery on postoperative QOL in patients with poor oral intake due to peritoneal dissemination of gastric cancer. Palliative surgery did not improve QOL while improving solid food intake with an acceptable postoperative morbidity and mortality rate for at least the first 3 months after surgery. The results of this study should help facilitate decision-making for physicians, patients, and carers.