27 Advanced Esophageal Cancer
Sheeva K. Parbhu and Douglas G. Adler
Esophageal cancer is the eighth most common cancer worldwide, with over 95% of cases made up of squamous cell carcinoma or adenocarcinoma. 1 , 2 Patients often present with complaints of rapidly progressing dysphagia, commonly associated with weight loss and fatigue. 3 Unfortunately, only a minority of patients have localized disease at the time of presentation, which limits subsequent treatment modalities. 4
27.2 Diagnosis and Classification
While initial radiologic studies may prompt further investigation, endoscopy is necessary to establish a diagnosis. Advantages of an endoscopic examination include the ability to obtain diagnostic biopsies, as well as to more fully examine smaller lesions. 5 Single biopsies of suspicious lesions are 93% accurate, with an improvement in accuracy approaching 100% with the addition of multiple biopsies and, less commonly, brushings. 6 Endoscopic ultrasonography (EUS) is initially used for staging purposes because it is more accurate than computed tomography (CT) or positron emission tomography (PET) for evaluating tumor depth and invasion. 7 Once the diagnosis and initial staging have been made, patients often undergo CT or PET examinations to identify distant metastases. 8
Advanced esophageal cancer, defined for our purposes as unresectable disease, corresponds with a primary tumor classification of T4b (▶Table 27.1) (▶Fig. 27.1; Video 27.1). This classification correlates with tumors which invade adjacent structures including the aorta, vertebral body, or trachea 9 (▶Fig. 27.2). Advanced disease includes not only patients with T4b tumor burden, but also patients who are deemed unresectable due to medical comorbidities which preclude surgery, and patients with distant metastases. In these cases, treatment is focused on control rather than cure of disease. While prolonged progression-free survival is possible for a few patients, most therapies center around symptom palliation and quality of life improvement.
27.2.1 Malignant Dysphagia
As previously mentioned, esophageal cancer is often diagnosed at an incurable stage, with an overall 5-year survival rate as low as 20%. 10 For these patients with advanced disease, malnutrition, dysphagia, and weight loss negatively impact the quality of life. In fact, up to 80 to 90% of patients experience dysphagia during the course of their disease. 11 In these cases, relief of dysphagia allowing for oral nutrition, hydration, and medication delivery becomes the primary palliative goal.
Endoscopic treatment options include dilation, placement of stents, cryotherapy ablation, and bypass of the obstruction via enteral feeding. While mechanical dilation (via balloon or bougie) can be performed, it almost never provides sustained relief of symptoms and cannot be recommended. In addition, repeated dilations of malignant stenosis can be associated with a high perforation rate. 12 Techniques such a photodynamic therapy (PDT) or laser ablation have been extensively described in the literature but are rarely used in the current era.
The first stents used to relieve malignant dysphagia were made of rigid plastic and were associated with poor patient tolerance and a high complication rate. These are no longer in use. In the 1990s, self-expanding metal stents (SEMS) were developed and have emerged as a cornerstone of palliative therapy for patients with malignant dysphagia (▶Fig. 27.3). 13 , 14 Because these stents are constrained and have a small diameter before placement, aggressive dilation of the esophagus (and related complications) is usually avoided. 15 In the hands of experienced endoscopists, modern stents can be successfully placed in more than 90% of cases. 16 The technical aspects of placing esophageal stents and how to pick stent type and length are based on individual operator experience and can vary widely.
Partially Covered Stents
Partially covered SEMS (PCSEMS) along with uncovered SEMS were the first nonplastic stents to be used for patients with incurable esophageal malignancy. While uncovered esophageal stents are no longer available in the United States, PC stents are still widely used, usually in patients in whom no surgery is planned. They have sections of uncovered bare metal at both the proximal and distal ends of the stent, which allows the stent to embed into the esophageal wall, preventing migration. 17
PC stents were first compared to plastic stents in a randomized-controlled fashion by Knyrim et al. Forty-two patients were studied, and both stents were found to provide similar improvement in dysphagia symptoms. The PC stents, however, were found to be associated with fewer stent migrations, fewer complications, and shorter hospitalizations, and were therefore thought to be superior. 14 These stents are susceptible to tumor ingrowth through the stent interstices (▶Fig. 27.4).
Davies et al retrospectively studied 87 patients who had a plastic stent or a PCSEMS placed to palliate dysphagia in inoperable esophageal carcinoma. Similar to the prior study, they found that while both stents successfully relieved dysphagia, the PC stent was associated with a lower perforation rate and a reduced length of hospital stay. 18 An even larger retrospective study subsequently followed 153 patients who had had either a plastic or a PC stent. Stent placement was successful in over 90% of cases, and dysphagia was successfully treated without recurrence in more than 70% of patients in both groups. Differences were again highlighted in the rate of complications associated with the plastic stents (22%) compared to the PC stents (9%). 19 All of these studies helped usher in the era of SEMS.
PC stents have the drawbacks of not being removable due to tumor and/or tissue ingrowth of the uncovered portions. This complication can be treated with a fully covered (FC) stent placed inside the PC stent, or with ablative techniques such as argon plasma coagulation (APC) or cryotherapy. 20 Newer stent-design developments have included silicone covers attached to the inside to minimize ingrowth, “fish-scale coating” to reduce migration, and a “dog-bone” shape of the stent allowing it to better attach to the esophageal wall. One prospective trial using a newer design described improvement in patients’ dysphagia scores (▶Table 27.2) from 3 (able to tolerate liquids only) to 1 (ability to eat all liquids and some solid foods). 21 Importantly, no study has been able to describe a survival advantage with either modality, highlighting the palliative nature of this intervention.
Fully Covered Stents
Complications of PC stents include tumor ingrowth, tumor overgrowth, and food impaction related to recurrent obstruction. Food impaction is a relatively rare event, whereas tumor ingrowth is more common (▶Fig. 27.5). In addition, these stents are generally not amenable to removal after placement. 20 FC self-expanding metal stents (FCSMES) have no uncovered region that can embed into tissue, and thus are more resistant to tumor ingrowth and overgrowth. Their FC design makes these stents completely removable if needed, and have been studied in patients undergoing adjuvant chemotherapy as well as those in whom treatment of dysphagia is the only goal. As they cannot embed in the surrounding tissue, the main drawback of FCSEMS is a much higher risk of migration.
In a retrospective study of 152 patients receiving either a FC-or PCSEMS, the FC version was found to be associated with less tumor ingrowth (53–100%) as well as less incidence of recurrent dysphagia due to stenosis of the stent (8 vs. 37%). The FC stents were also found to migrate more (10 vs. 0%). 22
Another retrospective study reported experience with 55 patients receiving FCSEMS for malignant dysphagia. These patients were also undergoing neoadjuvant therapy. In this cohort, the mean dysphagia score was improved significantly from baseline (1 vs. 2.4), and baseline body weight was able to be maintained. Thirty-one percent (17/55) patients also experienced migration of the stents, although none of these patients had adverse events related to migration or subsequent removal of the stent. 23
A newer design with a “dog-bone” shape and internal covering is the most common FCSEMS available today. This design was prospectively studied to evaluate relief of dysphagia while avoiding stent migration. In the 33 patients who received the stent, only 3 (10%) patients experienced stent migration that was associated with recurrent dysphagia. 24
Efficacy and Complications
While both FC- and PCSEMS are routinely used due to ease of insertion and technical success rates, various ranges of efficacy and complications have been reported in the literature. 13
In a prospective randomized trial comparing three different types of FCSEMS, 100 patients were treated with stents for malignant dysphagia. In 4-week follow-up, all patients had an improvement in dysphagia scores by at least 1 point, with no differences found between the three stents. 25 A similar study comparing two different FCSEMS also found an improvement in dysphagia both immediately after stenting and in follow-up at 1 month. 26 Studies that have included PCSEMS have shown similar rates of dysphagia relief. 21 , 22 In general, SEMS have been shown to improve dysphagia scores (on average) between 1 to 2 points and provide immediate symptom relief in over 90% of patients. 27 In regard to palliation of symptoms, no particular FC or PC stent has been shown to be clearly superior to others. The choice of a brand, type, and size of stent for an individual is left to the endoscopist and is usually based on anatomical conditions, goals of care, and operator preference.
Complication and reintervention rates are relatively high for this group of patients, likely due to their significant disease burden, the severity of their esophageal stenosis, and the lack of a perfect or ideal esophageal stent that treats dysphagia in a manner that is free of complications. Mean survival (related to disease progression) is just over 3 months in patients with advanced esophageal cancer, with patients usually succumbing to disseminated disease—patients generally do not die from primary esophageal symptoms or difficulties. 10
The most common early complications (occurring within 2–4 weeks of stent placement) include chest pain, nausea with or without vomiting, bleeding, gastroesophageal reflux disease (GERD), perforation, and stent migation. 10 These vary in frequency, with chest pain being relatively frequent (12–14%), and significant bleeding occurring less than 1% of the time in some studies. 28 , 29 GERD is very common in patients who undergo esophageal stent placement across the gastroesophageal junction (GEJ). While stents with antireflux valves are used in Europe, this technology is not yet widely available in the United States. Nausea, occasionally with vomiting, is frequently encountered in the first 24 to 72 hours and generally fades as the stent fully effaces over time.
Another common complication, stent migration, is clearly related to stent characteristics. It is commonly seen more than a week after successful stent placement, and is considered a “late” complication. Incidence of migration has been quoted as low as less than 10% (in PCSEMS) and as high as greater than 70% (in FCSEMS). 30 A more recent retrospective study of 133 patients found that stent migration occurred in 14.2% of patients with FC stents, compared to only 5.9% of patients with PC stents. 20 Strategies to help mitigate the risk of FCSEMS migration include placement of an over-the-scope clip or endoscopic sutures to anchor the stent in place. 17 , 31 Other risk factors associated with stent migration include placement across the GEJ (the most common site of placement), shrinkage of tumor mass with adjuvant chemotherapy or radiation, and overdilation of the esophagus before placing the stent. 13
Other late or delayed complications of stent placement include esophagorespiratory fistula formation, bleeding, tumor overgrowth, and tumor ingrowth. While covered stents are mostly resistant to tumor ingrowth (seen rarely when the coating of the stent breaks down), this complication is seen commonly in PC stents, in as many as 10 to 18% of patients. 32 Larger-diameter stents can reduce the risk of these complications, but may increase the risk of hemorrhage, perforation, and fistula formation when compared to smaller-diameter stents. 33