Endoscopic Stenting for Malignant Dysphagia with Esophageal Cancer

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1		Ryu Ishihara	--	2232	2023-06-26 12:15:00	\|
2	format correct	Catherine Yang	Meta information modification	2232	2023-06-27 03:08:57	\|

This entry is adapted from the peer-reviewed paper 10.3390/curroncol30070447

Malignant dysphagia is a common problem in patients with esophageal cancer. Endoscopic stenting can resolve dysphagia caused by malignant stricture; however, controversy exists regarding the use of esophageal stenting for the treatment of malignant stricture, including whether stenting or radiotherapy is superior, whether stenting before or after radiotherapy is safe, whether stenting before or after chemotherapy is safe, and whether low-radial-force stents are safer than conventional stents.

esophageal cancer malignant dysphagia radial force stent

1. Introduction

Esophageal cancer is the sixth most common cause of cancer-related mortality, with 455,800 new cases and 400,200 deaths worldwide in 2012 ^[1]. This cancer has a poor prognosis with an overall 5-year survival rate of <20% ^[2]. The two pathological types of esophageal cancer are esophageal adenocarcinoma and esophageal squamous cell carcinoma. Esophageal squamous cell carcinoma is the predominant type of esophageal cancer in South America, Africa, and Asia. Conversely, esophageal adenocarcinoma is increasing in frequency and is the predominant type of esophageal cancer in the United States and Europe ^[1]. Various treatments, including surgery, chemotherapy, radiotherapy (RT), and endoscopic therapy, are indicated as curative treatments for esophageal cancer. Although esophagectomy has been the mainstay of curative treatment for esophageal cancer, substantial proportions of patients are unsuitable for esophagectomy at presentation because of tumor growth into the lungs, bronchi, or aorta; extensive lymph node metastases; or distant metastases to the liver or lungs. In addition, severe comorbidities or a poor performance status prevents treatment by esophagectomy. Chemoradiotherapy (CRT) is another curative treatment option for esophageal cancer; however, the outcome of this treatment for patients with inoperable cancer is unfavorable. Thus, the treatment outcome of esophageal cancer remains poor ^[2], highlighting the importance of care for patients with incurable cancers.

Most patients with incurable cancers will require various palliative treatments. These patients frequently present with cancer-related complications that increase in number and severity as the disease advances, causing pain, malnutrition, a deteriorated performance status, and a deterioration in the quality of life (QoL) ^[1]. Dysphagia secondary to local tumor extension is one of the most frequent symptoms among patients with incurable and advanced esophageal cancer ^[3].

Multiple palliative treatment modalities are available for patients with dysphagia due to local tumor extension, including a bypass operation, gastrostomy, palliative RT, and esophageal stenting ^[4]. The optimal knowledge and use of the various treatment approaches for patients with unresectable and metastatic esophageal cancer will contribute to achieving the best possible outcomes in individual patients. Patients with incurable esophageal cancer require palliative treatment, which should be the safest, most effective treatment available and should also be cost-effective. In addition, the palliative treatment that is selected should be based on the location and physical features of the tumor, the age and general condition of the patient, the tumor spread, and the predicted survival interval. Endoscopic stenting is characterized by a prompt improvement in dysphagia and is an important treatment option for this condition. However, controversy exists regarding the use of esophageal stenting for the treatment of malignant stricture, including whether stenting or RT is superior, whether stenting before or after RT is safe, whether stenting before or after chemotherapy is safe, and whether low-radial-force stents are safer than conventional stents.

2. Stenting and Radiation for Palliation of Malignant Dysphagia

RT and CRT for dysphagia relief in the palliative setting were compared in a randomized trial including 220 patients ^[5]. This study showed no difference in the median survival time between the CRT group (6.9 months) and RT group (6.7 months). CRT showed a slightly better improvement in dysphagia than RT (45% vs. 35%, respectively; p = 0.13); however, the difference was not statistically significant. The incidence of grade 3 and 4 adverse events was significantly higher in the CRT group than in the RT group (36% vs. 16%, respectively; p = 0.0017). Palliative CRT showed a modest, but not statistically significant, increase in dysphagia relief compared with RT, with a cost of increased toxicity. This study concluded that RT alone should be considered a safe and well-tolerated treatment for malignant dysphagia in the palliative setting. Because CRT is considered to be superior to RT in many situations, further studies are required to confirm the efficacy of CRT for the palliation of malignant dysphagia.

Palliative RT and esophageal stenting are the most frequently used therapies for dysphagia due to incurable esophageal cancer, and their relative effectiveness was evaluated in two studies ^[6]^[7]. Brachytherapy and stenting were compared in a randomized study including 209 patients ^[6]. The median survival was not significantly different between the two groups (p = 0.23). The dysphagia score improved more rapidly after stent placement than after brachytherapy. However, at 30 days after treatment, the improvement in the dysphagia score no longer differed significantly between the stenting and brachytherapy groups. After 30 days, the dysphagia score was better after brachytherapy than after stenting, although this difference became smaller after about 350 days. Brachytherapy had fewer complications than stenting (5% vs. 13%, respectively), which was mainly due to a decreased incidence of late hemorrhage. Brachytherapy also had better health-related QoL scores than brachytherapy.

These studies show that palliative RT is associated with a lower risk of adverse events and improved pain control. Based on these studies, palliative RT is recommended for the treatment of patients with cStage IVB esophageal cancer presenting with obstruction in the recently published Japanese guidelines. Notably, however, stenting should be offered to patients with a short life expectancy because of its rapid efficacy for dysphagia.

3. Stenting and Gastrostomy for Palliation of Malignant Dysphagia

In patients who have a history of RT or cannot tolerate RT, stenting and gastrostomy are the major treatment options. The outcomes of these two procedures were compared in a retrospective study including 568 patients ^[8]. In this study, the main analyses were conducted in 188 patients using propensity score matching. Although there was no significant difference in the body weight change or occurrence of procedure-related adverse events between the two groups, the gastrostomy group showed slightly better survival after adjustment by multivariate analysis (hazard ratio, 0.69; 95% confidence interval (CI), 0.50–0.95). The advantages of stenting are the rapid relief of dysphagia and satisfaction derived from the ability to eat, whereas the disadvantages are adverse events such as chest pain, migration, mediastinitis, perforation, and bleeding. The advantages of gastrostomy are a stable nutritional status and the safety of the procedure, whereas the disadvantages are dissatisfaction with the inability to eat and esophageal-obstruction-related symptoms such as the reflux of saliva. These treatment characteristics should be taken into consideration when a strategy is selected. The author’s recommendation depends largely on the patient’s preference; stenting is recommended for those who wish to eat despite the risks of stenting.

4. Stent Type and Efficacy

Recurrent obstructions are caused by tumor ingrowth or overgrowth, stent migration, or food impaction in the stent. Partially covering the stent with a membrane has been shown to be superior to using uncovered stents, with a reduced rate of tumor ingrowth through the mesh of the stent ^[9]. However, the proximal and distal flares of a partially covered stent are not covered and still have the potential for ingrowth. Fully covered stents may overcome the limitation of tumor ingrowth, but the risk of migration may be increased.

During the last decade, three randomized trials were conducted to compare the effectiveness and risk of different types of stents ^[10]^[11]^[12], and two of these studies evaluated the effectiveness of fully covered stents ^[10]^[11]. Didden et al. ^[10] compared recurrent obstruction, adverse events, and health-related QoL between fully covered and partially covered stents in 98 patients. Recurrent obstruction after stent placement was similar between the two types of stents: 19% for fully covered stents and 22% for partially covered stents (p = 0.65). The frequency of adverse events was also similar between the two groups, with major adverse events occurring in 38% and 47% of patients with fully covered and partially covered stents, respectively (p = 0.34). No significant differences were seen in health-related QoL or migration. Stent removal was required in 4 of 97 patients. The reasons for self-expandable metallic stent removal were intolerable pain (n = 2), symptomatic tracheal compression (n = 1), and insufficient symptom relief (n = 1).

A stent may lead to acid reflux when it is placed across the gastroesophageal junction. A stent with an anti-reflux valve was designed to prevent acid reflux through the stent. The third of the three above-mentioned randomized studies ^[12] evaluated the efficacy and safety of this stent in 60 patients. The dysphagia scores, gastroesophageal reflux disease (GERD) symptom scores, and frequency of aspiration pneumonia were not different between stents with and without an anti-reflux valve during the follow-up period. The GERD symptom scores were similar between the two stents, implying either that the valve was not effective or that proton pump inhibitor therapy could have masked the symptoms of GERD.

In addition to the stent covering and the anti-reflux valve, the axial and radial forces of the stent are major determinants of the stent’s properties ^[13]. The radial force is the force that stents exert as they resist compression by the pressure of the esophageal wall; it is also the force that stents exert on the lumen as they expand to their original nominal diameter. The axial force is the force exerted on the luminal wall when the stent is in a curved position. The radial and axial forces of various stents were evaluated using an in vitro testing model ^[13].

Pressure on the esophageal wall is mainly determined by the stent radial force. A higher radial force may better stabilize the stent position; however, the strong compression may also cause adverse events such as perforation and bleeding. Two recent studies from Japan showed a reduced risk of adverse events in patients treated with low-radial-force stents ^[14]^[15]. Iwagami et al. ^[15] compared 51 procedures performed with low-radial-force stents and 56 procedures performed with high-radial-force stents. Severe adverse events occurred more frequently in procedures performed with high- than low-radial-force stents (14% (8/56) vs. 2% (1/51), respectively; p = 0.03). In patients who had undergone prior RT, severe adverse events were also more frequent in procedures performed with high- than low-radial-force stents (36% (4/11) vs. 0% (0/13), respectively; p = 0.03). There was no significant difference in re-obstruction or migration between procedures performed with low- and high-radial-force stents (p = 0.59 and p = 1, respectively). A low-radial-force stent may reduce the risk of severe adverse events after stenting without compromising its efficacy, which may be a preferred option for patients with malignant dysphagia, especially after RT.

While stents provide immediate and efficient palliation of dysphagia, the recurrence of dysphagia after stenting leads to a worsening QoL and requires further intervention, such as re-stenting. Although RT takes a longer time to relieve the symptoms of dysphagia caused by esophageal cancer, it usually allows for oral intake and is associated with fewer treatment-related adverse events. The combination of stents and radiation appears to be a viable and effective palliative therapy for patients with malignant dysphagia. However, there is concern regarding an increased incidence of adverse events. Brachytherapy delivers radiation precisely inside the esophageal cancer tissue, thus sparing surrounding normal organs, such as the aorta and lungs. The placement of ¹²⁵I brachytherapy seeds on the esophageal stent can alleviate dysphagia and prevent tumor extension into the stent lumen. Stents loaded with ¹²⁵I seeds have been developed to combine the immediate relief of dysphagia by stenting with the long-term effects of radiation ^[16]^[17]. In such stents, an ¹²⁵I radioactive seed is preloaded in the sheath and attached to the outer surface of the stent prior to stent insertion.

In a single-center randomized controlled trial ^[16], 27 patients in the irradiation stent group and 26 patients in the stent-alone group showed significantly better dysphagia grades in the first month after stenting than before stenting. However, the irradiation stent group showed better dysphagia grades than the stent-alone group after 2 months. The median and mean survival times were significantly better in the irradiation stent group than in the stent-alone group (p < 0.001). This study suggests that esophageal stents loaded with ¹²⁵I seeds offer advantages over conventional coated stents in terms of a reduced duration of dysphagia and prolonged survival. A multicenter randomized controlled trial ^[17] was conducted to confirm the efficacy of stents loaded with ¹²⁵I seeds. In that study, 160 patients were randomly allocated to receive either a stent loaded with ¹²⁵I seeds or a conventional stent. The median overall survival was better in the irradiation stent group than in the stent-alone group (177 vs. 147 days, respectively; p = 0.0046). The mean dysphagia score in the irradiation stent group remained significantly better than that in the stent-alone group from 1 month after stent insertion until the final follow-up. The main treatment-related complication was severe chest pain in 23% of patients in the irradiation stent group and 20% of patients in the stent-alone group.

The incorporation of drugs and stents has resulted in a new type of stent called a drug-eluting stent ^[18]^[19]. Drug-eluting stents allow for the sustained release of therapeutic agents while simultaneously providing the stent function. Controlled drug elution is often achieved using a drug-impregnated polymer membrane or coating that acts as a drug reservoir for sustained drug release ^[20]. Several approaches and drug–polymer combinations have been employed to create drug-eluting stents that deliver chemotherapy drugs, including 5-fluorouracil, paclitaxel, and docetaxel, for the treatment of esophageal cancer ^[21]^[22].

A paclitaxel or 5-fluorouracil stent was prepared by covering a nitinol stent with a bilayer polymer film consisting of a layer of 50% paclitaxel or 5-fluorouracil and a layer of a drug-free backing ^[23]. The in vivo evaluation of their performance in a porcine model revealed localized drug accumulation in the esophageal lumen relative to other organs, although stent migration was noted as a limitation. Although the drug-eluting stent is a promising device to realize rapid dysphagia relief, with long-term dysphagia relief provided by chemotherapy, clinical studies are needed to confirm its efficacy.

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Ryu Ishihara

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