Palliative interventions for patients with advanced gastric cancer: a systematic review

Introduction

Background and rationale

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related death worldwide (1,2). In Western countries, the majority of patients with gastric cancer are diagnosed with advanced disease at the time of initial presentation (1,3). Advanced gastric cancer (AGC) is defined as T1b to T4 disease, invading the submucosa, muscularis propria, subserosa, perforating serosa, or invading adjacent structures, without distant metastasis (4). For the purposes of this review, AGC includes unresectable locally advanced, locally recurrent, and metastatic disease. AGC has a poor prognosis overall and is associated with significant morbidity and mortality (5). Patients with AGC may suffer from a variety of distressing symptoms, which typically occur late in disease progression. The most common symptoms include nausea, vomiting, anorexia, weight loss, dyspepsia, abdominal pain, and bleeding (3,5,6).

According to the World Health Organization (WHO), palliative care is “an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual” (7). The treatment of AGC should be influenced by palliative care principles, which aim to relieve symptoms, improve quality of life (QoL), and aid patients with informed decision-making and advanced care planning (5). Treatment is multimodal and should include an interprofessional team, comprised of surgical, medical, and radiation oncologists, gastroenterologists, palliative care specialists, nurses, and allied care providers (8). Throughout this review, we will refer to interventions as ‘palliative interventions’ including surgery, endoscopy, chemotherapy, radiation therapy, systemic therapy, and supportive care interventions, if they are delivered with the goal of addressing the physical, psychosocial, and spiritual needs of the patient. It should be noted that the decision to pursue a palliative intervention is made by the patient in conjunction with the interprofessional care team, based on a multitude of factors, including the extent of disease, the symptom burden, and importantly, the patient’s goals of care.

Despite palliative care being a relatively well-defined field of study, palliative interventions in gastric cancer are not well characterized and there is significant heterogeneity in the literature defining palliative interventions (6). Previous work has highlighted the need to focus on outcome measures relevant to symptom management and QoL (6). Despite this, most of the research on AGC remains survival-oriented with a focus on outcomes related to survival benefit with a disregard of the patient experience. It is therefore important that health care providers and researchers share common priorities in order to provide individualized and comprehensive care plans for patients with AGC. We present the following article in accordance with the PRISMA reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-22-102/rc).

Objectives

The primary objective of this systematic review was to explore the published literature on palliative interventions for AGC. The secondary objective was to characterize updates in the literature on palliative interventions, specifically focused on the management of common symptoms, QoL, and the psychosocial and spiritual needs of patients with AGC.

Methods

Eligibility criteria

We included English language studies published between January 1, 2010 and August 18, 2022, that investigated palliative interventions for AGC. Palliative interventions were defined as surgery, endoscopy, chemotherapy, radiation therapy, targeted therapy, and supportive care interventions, delivered with the goal of addressing the physical, psychosocial, and spiritual needs of the patient. AGC was defined as T1b to T4 disease, including unresectable locally advanced, locally recurrent, and metastatic cancer.

Inclusion and exclusion criteria

We included primary literature in the form of clinical trials, cohort studies, case-control studies, and case series. We excluded studies according to the following exclusion criteria: (I) unpublished research (i.e., conference abstracts only), (II) secondary literature (i.e., review articles), (III) studies not focused on patients with AGC, (IV) studies with outcome measures that were not associated with the relief of symptoms or improvement in QoL, (V) case reports and/or studies with less than ten patients, (VI) studies on mixed cancer types, with either less than 50% gastric cancer patients or an undefined patient population. Studies with less than 10 patients and those with <50% of cases with AGC were excluded as we felt that the findings from such studies would not be generalizable. A summary of the search strategy is outlined in Table 1.

Information source, selection process, and search strategy

An informationist from Welch Medical Library at Johns Hopkins University developed and conducted the literature searches with team input. We searched PubMed, Embase, and Cochrane Library to identify studies published within our timeframe of interest. We developed our search strategies using a combination of controlled vocabulary and keywords to define the concepts of gastric cancer and palliative care interventions. References from included studies and review articles were hand-searched to identify any additional relevant studies for analysis. The PubMed search is outlined in Table S1.

Data collection process

Search results from each database were imported into Covidence systematic review software (9) to remove duplicate records and facilitate screening. Two reviewers (KK and OM) independently screened all titles and abstracts. Conflicts were discussed by the two reviewers until agreement was achieved. Two reviewers (KK and OM) conducted the full-text review and independently extracted and verified data points to be included in the manuscript.

Data items and synthesis method

We identified and abstracted the following data points from all included studies: number of participants, study design, and treatment modality (Table 2). Based on the data abstraction, we created a concept map, generated the included tables, and synthesized the conclusions from the selected articles. Meta-analysis was not performed given the heterogeneity of the included interventions.

Quality assessment

As recommended by Ma et al. (10) we included various validated quality assessment tools for our quality assessment, including the NIH Quality Assessment Tool for Case Series Studies to assess case series studies (11), the Critical Appraisal Skills Programme worksheets to assess cohort and case control studies (12), the ROBINS-I tool to assess non-randomized clinical trials (13), and the Cochrane Risk of Bias Tool for Randomized Controlled Trials (14) to assess randomized controlled trials. Using the assessment tools outlined above, we assigned overall quality ratings of high, moderate, low, or very low based on the study design and risk for bias.

Results

Our search results are reported in accordance with the PRISMA 2020 statement (15) (Figure 1). We identified 10,361 studies from our systematic database search, including 3,631 PubMed, 6,209 EMBASE, and 521 Cochrane Library records, in addition to 3 studies identified through manual review. We identified 2,918 duplicates, which were removed before screening. We screened a total of 7,446 studies by title and abstract review, of which 7,292 studies were excluded. We sought retrieval of 154 studies. Fifteen studies were not able to be retrieved in full text and were therefore excluded; no attempt was made to contact authors directly. We assessed 139 studies for eligibility through full-text review, of which 73 were studies excluded. We included 66 studies in our review.

Figure 1 PRISMA diagram.

In total, 66 full-text publications met our inclusion criteria and were included for final review. Twenty-three studies addressed the palliative management of bleeding in AGC, with radiation therapy being the most studied modality for bleeding control. Twenty-two studies addressed the management of obstructive symptoms in AGC including nausea, vomiting, anorexia, and dyspepsia, secondary to obstruction. Interventions aimed to ameliorate both proximal [gastroesophageal junction (GEJ)] and distal (gastric outlet) obstruction were included. Five publications assessed modalities to reduce the burden of symptomatic intraabdominal ascites, including hyperthermic intraperitoneal chemotherapy (HIPEC) and systemic chemotherapeutics. A total of 15 studies assessed QoL in a spectrum of patient populations, including those receiving chemotherapy, radiotherapy, supplemental nutrition, and procedural interventions, including surgery. Only five of these studies used QoL as a primary outcome, while ten studies reported QoL as a secondary outcome. Only one study evaluated specialty palliative care consultation for patients with AGC, and no studies outlined the prevalence or practices of advanced care planning for this patient population.

Bleeding

Symptom description

Bleeding caused by AGC occurs due to uncontrolled tumor growth, which can result in anemia and numerous related symptoms. Patients may experience hematemesis or have melanotic stools. Bleeding and anemia contribute to the related symptoms of fatigue, weakness, and shortness of breath. Uncontrolled bleeding can cause severe symptoms, including dizziness, light-headedness, and syncope, secondary to hypotension. Without hemostasis, uncontrolled bleeding can be life-threatening.

Treatment modalities

Described treatment modalities for bleeding in AGC include radiation, surgical or endoscopic interventions including the application of topical hemostatic agents, transcatheter arterial embolization (TAE), and chemotherapy (see Table 3 and Figure 2).

Figure 2 Published methods of addressing bleeding for patients with AGC, 2010–2022. AGC, advanced gastric cancer.

Radiation

All but one of the published studies regarding the use of radiation therapy for the management of bleeding secondary to AGC was a retrospective case series or case-control study, with only one non-randomized clinical trial intervention studied (16-22,24-26,28-31,39). The most common treatment regimen was 30 Gy in 10 fractions ranging from a single 8 Gy fraction dose to 42 Gy over 20 fractions. Some studies, but not all, reported biologically equivalent doses (BEDs). Most studies assessed post-intervention success by the absence of re-bleeding within a defined time period, though some authors reported the need for post-procedural transfusion or changes in the post-procedural hemoglobin levels as a surrogate for reduction in tumor bleeding. The range of response rates to the varying doses of radiation was 50–89.5%. In contrast, Kawamoto et al. focused solely on symptoms as a primary outcome and demonstrated that shortness of breath, pain, and distress improved after radiotherapy (30). At least two studies reported on the use of repeat radiotherapy doses in an attempt to control re-bleeding (19,31). In one of these studies (31), two patients were re-irradiated for hemostasis, and, unfortunately, gastrointestinal perforation occurred in both patients.

TAE

Two studies retrospectively analyzed the use of TAE for bleeding secondary to AGC (32,33). In both studies, all patients with positive angiograms underwent selective embolization, and those with negative angiography underwent empirical embolization. Both studies report technical and clinical success rates. Park et al. noted a clinical success rate of 65%, and found that the median interval between TAE and re-bleeding was 16 days (32). Cho et al. had a higher clinical success rate of 72.4%, though the primary endpoint was measured 14 days after embolization (33).

Endoscopy

Two studies reported on endoscopic interventions for patients with AGC (34,40). Kim et al. focused on assessing success rates for each intervention type, which included electrocoagulation and clipping, or combination therapy, where more than one technique was required to achieve hemostasis (34). Contrarily, Koh et al. (35) characterized the differences in the gastric lesions themselves as predictive factors for the success of hemostatic therapeutic interventions. Both studies reported the Forrest Classification to describe the stigmata of recent hemorrhage (40).

Chemotherapy

A single study by Biswas et al. reported the efficacy of chronomodulated treatments of epirubicin and oxaliplatin every 3-week, for a total of six cycles (36). Chronomodulation refers to the practice of administering anticancer drugs at specific times of the day to exploit the circadian variation in drug response. To assess response to treatment, the team formulated a scoring system to quantify upper gastrointestinal bleeding, termed the “average episodes per-week” score, or AEP score, which was defined as the total number hematemesis episodes experienced in the last 6 weeks divided by six. Hemoglobin levels and the number of required transfusions over the treatment period were used to quantify the severity of the blood loss. At 12-week follow-up, the authors identified a significant decrease in average episodes of hematemesis per week, from 2.7 episodes of hematemesis per week to 1.5 for the entire cohort.

Medication

The only study that assessed the use of medication in the management of bleeding secondary to inoperable gastric cancer was a prospective double-blind, randomized, placebo-controlled trial, which studied the effects of proton pump inhibitor (PPI) treatment on the prevention of tumor bleeding (37). For this study, 127 patients with inoperable gastric cancer were randomly assigned to receive oral Lansoprazole (30 mg) or placebo daily. The authors found that during the median follow-up of 6.4 months, tumor bleeding rates were 7.8% in the Lansoprazole group compared to 9.5% in the placebo group however this difference was not statistically significant. The authors concluded that Lansoprazole did not significantly reduce the incidence of tumor bleeding, and recommended that future studies focus on the effects of PPI therapy on tumor bleeding during the earlier phases of chemotherapy.

Comparative outcomes

One retrospective analysis assessed the treatment outcomes of patients with AGC who underwent palliative surgery or palliative radiotherapy for bleeding (38) (see Table 2 and Figure 2). Of the 48 patients, 23 underwent palliative surgery (69.6% total gastrectomy, 26.1% distal gastrectomy), and 25 received palliative radiation therapy (median dose of 39 Gy). Post-operative complications (Clavien-Dindo grade II or higher) were reported in 26.1% of patients receiving surgery. For the radiation group, re-bleeding was noted in 40% of patients within 30 days of completing radiotherapy, and no severe adverse events were observed. Chemotherapy was introduced in 91.3% of patients having received palliative surgery, and 68% of patients having received palliative radiation. Overall, the authors recommended consideration of palliative surgery for chemo-naïve patients in good general condition, and radiation therapy for patients in poor general condition or those who have already received chemotherapy.

Obstruction

Symptom description

The symptoms of obstruction secondary to AGC include nausea, vomiting, weight loss, early satiety, dehydration, malnutrition, epigastric pain, and occasionally jaundice or ureteral obstruction. Obstruction can be secondary to obstruction at the GEJ, presenting with symptoms of dysphagia, or gastric outlet obstruction (GOO), leading to nausea and vomiting.

Treatment modalities

Described treatment modalities for the management of obstruction secondary to AGC include endoscopic stenting and surgical interventions, including incomplete or partial tumor resection (R1 or R2), gastrojejunostomy, partial stomach-partitioning gastrojejunostomy, small intestine or colonic bypass, and ileostomy or colostomy creation (Table 4). Of note, studies were identified on the topic of endoscopic ultrasound-guided gastrojejunostomy but were not included as they did not meet our inclusion criteria. No studies described percutaneous endoscopic gastrostomy tube placement in AGC.

Stenting

Five studies described palliative endoscopic stenting for patients with AGC, including covered and uncovered endoscopically placed self-expandable metal stents (SEMS) of both custom and standard designs (see Table 5 and Figure 3) (41-45). All studies assessed outcomes after placement of an endoscopic SEMS. Most of the studies assessed stent patency and clinical success using the Gastric Outlet Obstruction Scoring System (GOOSS) (63,64). The GOOSS assigns a scores for no oral intake, liquids only, soft solids, and low-residues or full diet, and currently is the most widely used scoring system to quantify the clinical improvement of patients treated for malignant GOO (64,65). Clinical success was achieved in 82–95% of patients undergoing endoscopic stenting. Kim et al. demonstrated that the technical and clinical success rates of endoscopic stenting were worse for patients with obstruction at the GEJ (technical success rate of 97.6%, clinical success rate of 83.3%), compared to GOO (technical success rate of 98.5%, clinical success rate of 88.8%) (45). Overall, the mean stent patency ranged from 86–158 days (43,45). Endo et al. reported that 72% of patients in their series were able to receive chemotherapeutics after stenting (41).

Figure 3 Design of studies addressing treatments for obstruction secondary to AGC, 2010–2022. AGC, advanced gastric cancer.

Surgery

Three studies evaluated surgical interventions for patients with AGC (46-48). One study assessed gastric partitioning with gastrojejunostomy in patients presenting with both obstruction and/or bleeding. The authors noted early oral tolerance and an average hospital stay of 13 days (46). In a second study, the target population was comprised of patients with histologically proven gastric adenocarcinoma who presented with bowel obstruction due to peritoneal dissemination. Surgical intervention in this study consisted of a combination of segmental enterectomy, segmental colectomy, ileostomy, and colostomy, depending on the specific clinical scenario (47). In this group of patients, symptoms showed statistically significant improvement from baseline, with 67% of patients able to eat solid food 2 weeks after surgery and 57% of patients able to tolerate oral intake for 3 months. The final study that evaluated surgical interventions for AGC was a retrospective case series study of patients who presented with obstruction caused by primary unresectable or incurable recurrent gastric cancer. The patients in this study underwent either surgical gastrojejunostomy, small bowel or colonic bypass, intestinal resection, or ostomy creation. The authors found that 64% of patients demonstrated a QoL improvement as defined by oral intake improvement, hospital discharge, and ability to start chemotherapy.

Stent after surgery

Two retrospective studies evaluated the efficacy of endoscopic stenting in patients with AGC who had previously undergone curative-intent partial or total gastrectomy (49,50). The clinical success rate in this group was 90–95%, with a complication rate of 25–44%.

Comparative outcomes

A total of 12 publications assessed comparative outcomes for patients with AGC, including stenting versus surgery, surgery versus surgery, or surgery versus no surgery (see Table 4 and Figure 3) (51-62).

Stent versus surgery

Eight studies examined outcomes between stenting versus surgery, including endoscopic placement of SEMS versus stomach-partitioning gastrojejunostomy, partial gastrectomy with Roux-en-Y gastrojejunostomy, and gastrojejunostomy alone. Taken together, the studies demonstrated a faster return to oral intake with fewer complications and shorter index hospitalizations for patients undergoing stenting compared to surgical intervention however, the median symptom-free interval and median patency rate was longest in those undergoing palliative resection (54). Patients undergoing surgical intervention had complications, including delayed gastric emptying, pulmonary embolism, bleeding requiring reoperation, and wound infection. The rate of late adverse events was significantly higher in the stenting group (56).

Surgery versus surgery

Four studies examined outcomes between two types of surgical interventions (59-62). One study assessed outcomes following open versus laparoscopic gastrojejunostomy (59). The open group had a higher rate of postoperative delayed gastric emptying compared to the laparoscopic group. The median time to resumption of oral intake was 4 days after open surgery compared to 2 days after laparoscopic surgery (59). A separate study analyzed outcomes following non-curative intent gastrectomy versus gastrojejunostomy; in patients undergoing non-curative intent gastrectomy versus gastrojejunostomy, there was improvement in the GOOSS score in most of the patients with acceptable patency rates at the end of 90 days (60). The final study investigated gastric partitioning with gastrojejunostomy or Roux-en-Y versus gastrojejunostomy (61). In this study, oral tolerance of soft solids and low-residue or full diet were achieved by 93.3% of patients who had undergone gastric partitioning compared to 75.9% of patients who had undergone gastrojejunostomy (61). There were no differences in postoperative complications or surgical mortality between groups. Finally, one study examined differences between gastrectomy, exploration without resection, and no surgery (62). The authors showed that a R2 gastrectomy improved abdominal pain in 44% of patients and improved symptoms of nausea and vomiting in 40% of patients. This was significantly better than exploration without resection however the procedure was associated with more postoperative complications.

Ascites

Symptom description

Intraabdominal ascites causes a fullness or a tense feeling in the abdomen, depending on severity. Malignant and non-malignant ascites have similar symptom profiles, however, malignant ascites is often recalcitrant to interventions and reaccumulates quickly. In this section, ascites was graded by symptom experience (66), and by computed tomography (CT) as either none (undetectable by CT scanning), mild (localized in only the upper abdominal space or pelvis), moderate (neither mild nor massive), or massive (ascites filled the abdomen and pelvis) (67).

Treatment modalities

Two treatment modalities were used to address symptoms of malignant ascites for patients with AGC including HIPEC and intravenous chemotherapy alone (see Table 6 and Figure 4).

Figure 4 Published modalities to address symptomatic ascites for patients with AGC, 2010–2022. AGC, advanced gastric cancer; HIPEC, hyperthermic intraperitoneal chemotherapy.

HIPEC for ascites

Three studies assessed HIPEC for the treatment of ascites in AGC and each study administered the HIPEC differently (66,68,69). Yarema et al. administered HIPEC intraoperatively following aggressive cytoreduction and found that 20% of patients required post-operative paracentesis compared to 100% of patients in the control subgroup (66). Zhao et al. (68) administered whole-body hyperthermia without cytoreduction in conjunction with intraperitoneal chemo-perfusion over two treatments and demonstrated a complete and partial remission rate of ascites of 70.6% in the intervention group compared to 33.3% in the control group. Finally, Zhang et al. administered HIPEC 48 hours postoperatively, for a total of 4 times on alternate days, and found that the objective remission rate of ascites in the study group was significantly higher than that in the control group (69).

Chemotherapy for ascites

Two studies evaluated the use of fluorouracil-based chemotherapy in the treatment of ascites for AGC (67,70). In these studies, improvement in ascites occurred in 27-39% of all patients who presented with ascites.

Comparative outcomes

There were no published studies regarding comparative outcomes for the treatment of ascites secondary to AGC during the timeframe of 2010–2022.

QoL

Description

Studies in this group evaluated QoL in a spectrum of patient populations, including those receiving chemotherapy, radiotherapy, supplemental nutrition, and procedural interventions including surgery. Several different QoL metrics were used to characterize symptoms, the overall impact of AGC, and its related interventions (see Table 7).

Treatment modalities

A total of 15 studies assess varying aspects of QoL. Five studies focused on QoL while receiving systemic therapies (71-75), three studies assessed QoL after surgical interventions (76-78), one study examined QoL after percutaneous liver ablation (79), two studies considered QoL during radiation treatments (80,81), two studies assessed QoL with nutritional interventions (82,83), two studies evaluated QoL in the last 6 months of life with or without the support of hospice services (84,85), and the last study examined the effects of low-frequency rotary magnetic fields on patients with symptomatic AGC (see Table 8 and Figure 5) (86). All studies were quantitative, as the only study reporting on the qualitative experiences of patients with gastric cancer did not specify that the patients in that study had AGC (87).

Figure 5 Published QoL assessments for different patient populations with AGC, 2010–2022. QoL, quality of life; AGC, advanced gastric cancer; XRT, radiotherapy.

QoL during systemic therapy

Systemic therapies in this group of reviews spans first-line to last-line chemotherapeutic options, oral fluoropyrimidines, S-1, and tyrosine-kinase inhibitors (i.e., apatinib). Investigators found that patients taking these agents showed no deterioration in global health status and had improved social functioning scores. Small changes were observed in physical functioning, pain, dyspnea, insomnia, appetite loss, constipation, reflux symptoms, dry mouth, taste, body image, and hair loss, cognitive functioning, and global health status, as well as the ability to carry out social roles (such as parenting, being a spouse, etc.). Social functioning, emotional functioning, and global health status/QoL showed improvements that gained statistical significance. Patients on fourth-line treatments demonstrated insufficient oral intake as compared to patients on first-, second-, and third-line treatments, reflecting more severe/progressive disease in this population of patients.

QoL after surgery

Additional QoL outcomes after surgery are discussed above in the obstruction section, however, from a global perspective, for patients undergoing surgical intervention in the absence of symptomatic obstruction, overall QoL was not as drastically improved. Two of the three studies showed insignificant differences in QoL (76,78), and one study documented an average 8.6 months of symptom relief after surgical intervention (77).

QoL after ablation

One study assessed QoL after percutaneous liver ablation for metastatic gastric cancer. The mean scores for physical well-being and functional well-being increased while the scores for social and emotional well-being remained unchanged. The total QoL score was statistically significant. Most patients experienced minor limitations after the procedure, including pain at the percutaneous puncture site, fever, transient liver damage, and pleural effusion, which all recovered spontaneously or as a result of timely supportive treatment.

QoL during radiation therapy

One retrospective study reported general QoL improvements after the completion of palliative-intent radiation (81). The study showed symptomatic improvement in 90.5% of patients.

QoL with nutritional intervention

Two studies addressed nutritional interventions for patients with AGC, namely intravenous iron administration and supplemental home parenteral nutrition (82,83). Patients receiving intravenous iron demonstrated improved QoL with physical well-being, emotional well-being, and anemia-specific QoL. The study of home parental nutrition revealed that QoL scores were maintained and statistically equivalent to those in the control group.

QoL in the last 6 months of life

One study was a descriptive study of symptom for patients with AGC. The authors found that tiredness and lack of appetite were the two most intrusive symptoms for this patient population. The overall rates of moderate-to-severe symptom scores increased as patients neared death, with a prevalence of moderate-to-severe scores 50% or greater for all symptoms except nausea in the final month of life.

Other

A final study assessed the effects of low-frequency rotary magnetic fields on AGC and demonstrated improved abdominal pain, nausea, vomiting, and weight loss (86).

Comparative outcomes

Two studies in this category were comparative studies. The first, discussed above, evaluated standard of care versus single dose of intravenous iron before chemotherapy, and found that the group randomized to intravenous iron showed improvements in physical well-being, emotional well-being, and anemia-specific QoL (82). A final study assessed QoL for patients with and without hospice support services (85).

QoL with or without the support of hospice services

In this study, the intervention group (patients receiving hospice support services) had higher reported improvements in the domains of physiological function, psychological function, emotional function, social function, and mental health compared to the control group.

Palliative care consultation and advanced care planning

Only one study assessed outcomes for patients with AGC who had received palliative care consultation (88). This study was a prospective, multicenter study, randomized trial of patients who received either standard cancer care or standard cancer care plus early palliative care specialty consultation and was of moderate quality. The primary outcome was a change in QoL, as measured by the Functional Assessment of Cancer Therapy-Gastric questionnaire 12 weeks after randomization. The results demonstrated a slight, but not statistically significant, benefit of early palliative care. No studies were published on advanced care planning specific to the AGC patient population.

Quality of included studies and risk for bias

Of the total 66 included studies, eight were rated high quality, 38 were rated moderate quality, and 20 studies were rated low or very low quality, indicating a high likelihood of bias. Most studies answered a specific study question, clearly described the patient population and the intervention studied, and used validated outcomes measures that were applied consistently. However, the large majority of studies included were retrospective in nature and had small sample sizes (often N<50). Not all studies accounted for possible confounders in their design and statistical analysis.

Discussion

This study reviewed the palliative interventions currently available for patients with AGC with a focus on symptom management and QoL in accordance with the WHO’s definition of a palliative approach (7). Palliative interventions for symptoms related to bleeding and obstruction were well characterized in the literature though the primary outcomes were almost exclusively focused on resolution of the acute bleeding. For instance, in the bleeding category, all studies except one exclusively defined success of the primary intervention as resolution of bleeding. Only one study included the broader symptom profile of shortness of breath, pain, and distress, and no studies assessed the psychosocial or emotional impact of bleeding. No studies assessed shared decision-making to help patients and providers consider outcomes and alternatives (i.e., radiation versus endoscopy versus surgical intervention versus hospice). No publications examined the inconvenience of daily radiation therapies or the impact it had on the patient’s overall QoL. Additionally, radiation and chemotherapy delivered for bleeding have physiologic side effects including fatigue, nausea, and vomiting and these side effects were unaccounted for in the present studies which predominantly categorize success as the discontinuation of hemorrhage.

Similar trends were identified in the publications outlining interventions for patients with obstructive symptoms. The primary outcome in nearly all studies was resumption of oral intake, length of hospital stay, and the need for re-intervention. Only one study evaluated global QoL domains, and no studies performed qualitative assessments of the patient’s experience with obstruction and any required interventions. As above, no studies assessed shared decision-making to help patients and providers consider outcomes and alternatives (i.e., endoscopic stenting versus surgical intervention versus hospice), and no publications examined the impact that obstruction had on patients’ psychosocial QoL. Similar patterns were found for studies examining ascites.

The various interventions that studied QoL as a primary or secondary outcome measure did tend to capture a broader picture of the patient’s overall QoL, including emotional and social functioning in addition to physical and cognitive functioning, global health status, pain, dyspnea, insomnia, appetite loss, constipation, reflux symptoms, dry mouth, taste, body image, and hair loss. However, each of these studies was quantitative, with a lack of rich descriptions of the patient experience. The majority of the QoL outcomes were secondary outcome measures and thusly not as well characterized as the lauded outcome measures of overall survival, technical success, and tumor response as measured by imaging, to name a few.

During the process of reviewing the literature, we identified studies examining the use of endoscopically placed topical hemostatic agents which prevent tumor bleeding by providing immediate hemostasis. Unfortunately, no studies of these agents were performed in populations comprising >50% AGC patients. We also noted papers that described endoscopic ultrasound-guided gastrojejunostomy, but unfortunately, none of the publications comprised of >50% AGC patients and thus had to be excluded.

Our work builds on a review by Mahar et al., published in 2012 (6). The authors argued that relief of symptoms should be the primary focus of palliative treatment. Despite improvements in specific areas over the last decade there is still significant work to be done to characterize the spectrum of symptoms associated with AGC and its treatment options. We agree with the authors that there continues to be a need for more prospectively designed studies in this area of research, and we believe that qualitative and mixed-methods studies are required to better characterize the patient experience. This information should be used to guide shared decision-making and allow for a more comprehensive and nuanced understanding of the risks, benefits, and alternatives associated with each palliative-focused intervention.

Limitations

Like all systematic reviews, our study has limitations including potentially missed publications despite a comprehensive search of multiple databases and citation searching with manual review.

Conclusions

This study reviewed the palliative interventions currently available for patients with AGC, with a focus on symptom management and QoL in accordance with the WHO’s definition of a palliative approach (7). Palliative interventions for symptoms related to bleeding and obstruction were well characterized in the literature, as were the interventions for the symptomatic burden of ascites, though to a lesser extent. There was a significant amount of heterogeneity in the studies that assessed QoL. Importantly, no studies were identified that described advanced care planning in this patient population. Prospective research with credible and comprehensive outcome measures related to symptom management and QoL as well as research exploring the psychosocial and spiritual domains of care in AGC is required.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Adam Yopp) for the series “Multimodal Management of Gastric and Gastroesophageal Cancers” published in Chinese Clinical Oncology. The article has undergone external peer review.

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-22-102/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-22-102/coif). The series “Multimodal Management of Gastric and Gastroesophageal Cancers” was commissioned by the editorial office without any funding or sponsorship. KK attended an industry-sponsored education event through the AHPBA (Americas hepatobiliary Association) in conjunction with his role as a clinical fellow in surgical oncology and hepatobiliary surgery in the United States. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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