Paul Didden

Introduction

The incidence of cancers of the upper gastrointestinal tract is rising [1]. Unfortunately, these cancers are frequently diagnosed at an advanced, incurable stage. In case of incurable disease one should aim for optimal palliative care. Dysphagia and vomiting are the most common symptoms to palliate in malignant diseases of the upper gastrointestinal (GI) tract. Obstruction of the esophagus results in dysphagia, while vomiting is the most pronounced symptom in case of strictures in the distal stomach or duodenum. Both result in anorexia, weight loss and weakness, and are associated with a reduced quality of life. Ideally, palliative therapy for GI strictures should be well tolerable and result in a rapid and long-term relief of obstructive symptoms, without the risk of adverse events. Endoscopically inserted self-expandable metal stents (SEMS) play an important role in the palliative management of malignant upper GI obstruction [2]. SEMS are easy to insert and are highly effective in improving obstructive symptoms [3, 4]. Unfortunately, SEMS therapy is also associated with disadvantages, such as SEMS related adverse events including recurrent obstruction [3, 4]. This thesis aims to increase our insights of the efficacy and adverse events of SEMS therapy.

SEMS for malignant esophageal obstruction

In Chapter 2 we describe a general overview of the current knowledge on SEMS in esophageal disease. Various types of esophageal SEMS are currently available worldwide [5]. Although the basic principle of all SEMS is more or less the same, differences exist in construction, material, shape, diameter and other features [6]. Although a substantial number of studies on SEMS have been published in the last decennia, most knowledge is derived from uncontrolled trials evaluating technical feasibility and efficacy of one particular SEMS. For malignant dysphagia, the number of randomized trials on clinical outcome is limited. In general, all SEMS are effective in providing rapid relief of malignant dysphagia. The radial expansion of all SEMS is sufficient to restore luminal patency on the short term. However, on the long-term recurrent obstruction due to SEMS dysfunction may occur [7]. In Chapter 3 we report the results of a retrospective analysis of 1011 patients who underwent esophageal SEMS placement for malignant esophageal disease over a time span of more than two decades. Despite the introduction of new types of SEMS, the incidence of re-obstruction has not improved over the years. Overall recurrent obstruction remained unchanged over time at approximately 30%. Significant tumor in- and overgrowth was the most common cause for recurrent obstruction, occurring in 13.7%, followed by migration in 11.4%, food occlusion in 7.1% and other causes in 1.2% of patients. Migration rate increased over time and was associated with a fully covered (FC) SEMS design (HR 1.65, 95% CI 1.10-2.49, p=0.02) and smaller (up to 20 mm) diameter SEMSs (HR 4.30, 95% CI 1.05-17.72, p=0.04). That FC SEMS are associated with an increased migration risk was also demonstrated in a retrospective study [8]. In our study, we have shown that occurrence of tumor growth was almost decreased by half for FC SEMS (HR 0.60, 95% CI 0.40-0.90, p=0.01). Importantly, this beneficial effect seems to outweigh the drawback of migration, as the risk of all-cause recurrent obstruction was diminished for a FC SEMS (HR 0.77, 95% CI 0.61-0.98, p=0.03). This is relevant information and favors the use FC SEMS in malignant esophageal disease. However, our results should be interpreted with some caution due to the retrospective nature of our study. In addition, information on the specific location of tumor growth, either in- or overgrowth, was unavailable. A previous randomized trial demonstrated that partially covered SEMS are superior to uncovered SEMS with less obstructive ingrowth [9]. In order to clarify whether extending the covering to the whole SEMS length is truly beneficial, we conducted a randomized controlled trial comparing a PC with a FC SEMS of which results are reported in Chapter 4. Ninety-eight patients with malignant dysphagia were included in this study. Recurrent obstruction was the primary outcome measure and patients were followed until death, second SEMS insertion or SEMS removal. The strength of this study was that both SEMS were identical in design with the exception of the length of covering. The PC SEMS was designed with a silicone covering attached on the inner side of the body of the stent, leaving both flares uncovered. In contrast, the covering of the FC SEMS extends over the entire length of the stent, including both flares. The Wallflex PC and FC SEMS (Boston Scientific) were used for the purpose of this study, which is a relatively new type of esophageal SEMS. We found that the overall rate of recurrent obstruction was similar between both SEMS (FC SEMS 18%, PC SEMS 22%, p=0.65). Thus, the length of covering doesn’t seem to matter for this specific brand of SEMS. Both the PC and FC SEMS (Wallflex, Boston Scientific) can be considered for palliative treatment of malignant esophageal obstruction. It is evident that extension of the covering is beneficial to reduce ingrowth through the meshes. However, potential disadvantages, such as tissue overgrowth and migration ought to be minimized for FC SEMS to be more favorable than PC SEMS. Tissue overgrowth over the edge of the flare can be caused by malignant tumor growth or benign reactive tissue hyperproliferation. Although malignant tumor overgrowth may happen when a SEMS too short in length is placed, it is usually related to rapid progression of the disease, independent of the type of SEMS. In contrast, benign reactive tissue growth only develops in the presence of a SEMS [10]. Although the exact pathogenesis still remains to be elucidated, it is a known fact that a hyperproliferative tissue reaction may occur when a foreign body is present. The severity is probably dependent on the type of material, as well as contact-surface, -force and –duration. At present, the optimal construction and design to prevent reactive tissue formation is unknown. Recently, more insight has gained in the radial and axial force patterns of the available esophageal SEMS [11]. A high axial force pattern could be one of the factors that plays a role in the occurrence of tissue overgrowth. In such case one side of the flare presses firmly in the esophageal wall which may result in more tissue reaction. Therefore, we believe that SEMS with a low axial force profile with flares more in line with the contour of the esophageal wall, are more favorable. For the same reasons, larger diameter flares may only increase tissue reaction and may not be preferred. The Wallflex SEMS used in our randomized trial has a relatively high axial force and is designed in a dog-bone shape. Both features may cause this SEMS to be more prone to tissue overgrowth. Indeed, we noticed several cases of overgrowth in the FC Wallflex SEMS group in which the flare was pressed in the esophageal wall. It should be mentioned that the data to support these considerations is limited and more studies are needed for better understanding.

Migration is another drawback of FC SEMS and has been described in up to 35% in observational studies, usually occurring downwards [12-18]. We found a relatively low FC SEMS migration in our randomized study, corresponding to previous reports on the Wallflex SEMS with rates of approximately 10% [16, 17]. This might be related to the effective anti-migration features of this particular SEMS, including a dog-bone shape and a covering overlying the inner side of the metal framework. Several other endoscopic techniques have been investigated to resist dislocation. Larger-diameter SEMS have been associated with less migration, but might be more prone to major complications, such as fistula [7, 19, 20]. Other integrated features include larger diameter flares, outer struts, rings or flaps [12-14, 18]. It is hard to say whether these techniques are truly beneficial in preventing dislocation, since controlled trials are lacking. An alternative approach is the application of anchoring devices, such as over-the-scope clips and sutures, to fixate the SEMS to the esophageal wall [21-23].

SEMS-related adverse events, other than SEMS dysfunction, are frequently encountered. Adverse events after SEMS placement are often hazardous for patients and can sometimes be fatal. In Chapter 3 the frequency of adverse events after 1011 palliative SEMS insertions is described over a 23 year period. This study demonstrates that the overall incidence of adverse events is considerable, almost 50%, including 20.6% major adverse events. Major complications include perforation, hemorrhage, pneumonia, fistula, fever and pressure necrosis. We noticed that the incidence of major complications has declined up to 2009, mainly due to a lower occurrence of perforation and hemorrhage. Omitting pre-SEMS dilation has probably contributed to a reduced perforation incidence. In addition, hemorrhage was associated with distal tumors and over time a shift was noted towards more proximal tumors being stented. After 2009, however, the rate of major complications increased. Not new SEMS related features, but enhanced patient vulnerability seems to be responsible. The use of prior chemoradiotherapy has intensified after 2009 and this was recognized as the only significant risk factor for major complications (HR 1.83 [95% CI 1.19-2.81]. The effect of chemo- and radiotherapy prior to SEMS placement has been a matter of debate. Although some studies have denied an association with the occurrence of adverse events [19, 24-26], our results are in line with more recent data showing a higher risk in pretreated patients [27-30]. In our analysis a significant association was seen in patients who have undergone both chemo- and radiotherapy, indicating that these patients are more prone to SEMS related complications. This also suggests a cumulative toxic effect of both treatment modalities as the association did not hold for either treatment alone. Especially pulmonary infections were more commonly seen after chemoradiotherapy. Possible mechanism include pulmonary toxicity leading to diminished respiratory tract cleaning and immunosuppressive status [31]. The negative influence of previous chemoradiotherapy is also illustrated in Chapter 5. Here we describe the outcome of 13 patients who underwent palliative SEMS placement for malignant dysphagia after definitive chemoradiotherapy. In recent years, definitive chemoradiotherapy has become a curative alternative in patients both with an irresectable locally advanced (T4) carcinoma as well as in patients who are unfit for surgery due to co-morbidity [32-34]. In this series, major adverse events were frequently encountered, occurring in 7 out of 13 patients (54%). The majority of these events were related to pulmonary infections or tracheal- or aortic-fistula. It seems that especially tumors invading surrounding structures (T4) are at risk for esophago-respiratory or –aortic fistula. This is probably caused by continuous stent pressure on a vulnerable esophageal wall due to radiation-induced ischaemic changes. It is known that the toxicity of radiotherapy is dose-dependent and we presume that the relatively high external radiotherapy dose of 50.4 Gy induces an even more deleterious effect. The relation between previous radiotherapy and stent-related esophago-respiratory fistula has also been demonstrated in a recent case-control study [27]. In this study, also a trend towards a dose-dependent relation was reported. However, statistical significance was not reached, probably due to a relatively small number of subjects with fistula.

Pain is one of the most devastating symptoms in incurable patients. In our 23-year retrospective analysis (Chapter 3) we noticed that postprocedural pain seems to be more frequently encountered over the years. The rate increased from approximately 25% to almost 50% in the 2 most recent time periods (2010-2017). Whether this observed increase is related to under-reporting in the past is uncertain, but pain has never been the primary focus of interest in past studies evaluating outcome after SEMS insertion. In Chapter 6 we describe a two-week prospective evaluation of pain experience in 65 patients with malignant esophageal disease. We noticed that two-thirds of patients develop significant pain after SEMS placement with a concomitant increase of analgesic use, including opiates. Although the severity of pain seems to decline after the first day, more than 30% of patients were still in need of opiates after the two weeks. Our results outline the importance of proper pro-active pain management, especially shortly after SEMS placement. Information and instructions should be provided to every patient undergoing palliative SEMS treatment. In addition, health care providers should be easily accessible to prescribe analgesics if needed. Pain probably has a multifactorial etiology, including patient- and SEMS-characteristics. In this study we were unable to identify risk factors for the development of significant pain, most probably due to a small cohort size. Remarkably, we observed a relatively high rate of severe pain after SEMS placement in our randomized trial comparing PC versus FC SEMSs (Chapter 4). Almost 20% of patients experienced retrosternal pain and in the majority hospital admission and opiates were required. The Wallflex SEMS was used in this study and similar findings on this particular SEMS have been reported in previous studies [16, 35]. This SEMS has a dog-bone shape and exerts a high axial force. These particular features could be of potential influence on for pain development after SEMS deployment and deserve further investigation.

SEMS for malignant gastric outlet obstruction

Multiple types of duodenal SEMS are available worldwide. Although the basic principle is similar, differences exist in construction, material and deployment system. In Chapter 7 we describe the clinical outcome of a new duodenal uncovered SEMS (Evolution SEMS, Cook Medical) in a large prospective cohort of 108 patients with malignant gastric or duodenal strictures. This SEMS is made from nitinol providing flexibility, has flared ends as anti-migration feature, and a small cell size to withstand ingrowth. In addition, the deployment system includes a recapture mechanism to facilitate correct positioning. Successful technical deployment of the SEMS was achieved in 99.1%. Clinical success after 14 days with a relief of obstructive symptoms and/or improvement of oral intake was experienced in 85% of patients. A gradual decline in SEMS patency was seen over time with SEMS dysfunction occurring in 17% of patients. In most patients occlusion was caused by tumor ingrowth through the meshes of the SEMS and most cases were successfully managed with an additional SEMS. The only other SEMS-related adverse event was gastrointestinal hemorrhage occurring in 3.7%. The clinical results from this study are in accordance with earlier studies, indicating that this SEMS is generally safe and effective for malignant outlet obstruction [4, 36-38]. However, this study does not prove its superiority over other SEMS available. Considering the published results of duodenal stenting of the last two decades, it becomes clear that an improvement in SEMS performance is hard to achieve. One can assume that not only SEMS-related factors but also certain patient and tumor characteristics are involved in the pathogenesis of SEMS dysfunction. The knowledge on the influence of patient-related factors on SEMS dysfunction is limited. Only a few studies are available, of which the results are difficult to interpret and to compare [39-43]. Most reports lack uniformity with heterogeneity in the study population and the use of different sets of variables. In our prospective cohort study (Chapter 7) we could not identify any patient- or disease related factors associated with stent dysfunction. However, only a few variables were considered for analysis. Some studies have suggested that rapid progression and an advanced stage of disease may put patients at a higher risk of SEMS dysfunction. SEMS overgrowth was found to be associated with presence of bile duct stenosis and liver metastasis [43], while on the other hand palliative chemotherapy and a longer time to disease progression improve stent patency [39, 41, 42].

Little is known about the influence of specific SEMS features and the development of SEMS dysfunction for malignant gastric outlet obstruction. Several characteristics could be relevant, including length, diameter and shape of the SEMS, material and structure of the wires, size of the cells between the wires, axial and radial forces, and the presence of a covering. The difficulty is that it is almost impossible to evaluate the impact of each of these features separately. Clinical outcome of new SEMS designs are generally evaluated in single-arm prospective studies and the number of randomized trials is limited. To our knowledge, the covering of the SEMS is the only characteristic of which the effect has been assessed in comparative studies [44-46]. Overall SEMS patency seems similar, but patterns of dysfunction were different. While covered SEMS are able to prevent ingrowth, they are associated with migration more frequently. Various anti-migration features have been developed in order to prevent dislocation. In Chapter 8 we describe the clinical outcome of a newly developed covered duodenal SEMS with two distinct anti-migration features: a double flare shaped design and uncovered ends. It was hypothesized that these two features result in better adhesion of the SEMS to the enteral wall. Indeed, SEMS migration was seen in only 1 of 9 patients. However, the study was prematurely ended due to mechanical failure of the SEMS with broken struts occluding the lumen in three of the nine included patients. Due to the small patient group, the value of the applied anti-migration features still remains to be determined. The reason for SEMS failure and breakage of the struts is still unclear, but could be related to insufficient physical durability, strong peristaltic enteral movements, and/or acid corrosion. In contrast to the esophagus, the lumen in the distal stomach and especially the proximal duodenum run an angulated course and stents are subjected to forceful peristaltic contractions. It seems worthwhile to perform a new clinical trial using a covered SEMS with the same anti-migration features, but with a durable and flexible framework. Mechanical fixation of the SEMS to the enteral wall has been proposed as an alternative solution to prevent dislocation. In malignant gastric outlet obstruction only the experience of standard through-the-scope (TTS) clips has been described, showing promising results in a prospective series of 25 patients [47]. The disadvantage is that TTS clips only grasp small and superficial tissue, which will probably not provide long-lasting fixation. Using over-the-scope-clips or suturing devices could potentially be more beneficial. These techniques seem to provide better fixation of SEMS in esophageal disease, but have never been tried for duodenal SEMS [21-23].

Conclusions and future perspectives

SEMS placement is currently an established palliative treatment for malignant upper gastrointestinal strictures with an excellent ability to restore luminal patency. This thesis shows that, despite technical developments and increasing experience, recurrent obstruction and other SEMS-related adverse events after esophageal SEMS insertion are still a major concern. Although modifications of SEMS design over the past decades were intended to be beneficial, increasing treatment efficacy and reducing adverse events have shown to be challenging. We demonstrated that covered SEMS are superior over uncovered SEMS, mainly due to less ingrowth. However, we could not show a beneficial effect of fully covered esophageal SEMS compared to partially covered SEMS in malignant dysphagia. Recurrent obstruction was related to complications other than ingrowth, such as overgrowth and migration, for which further stent design refinements need to be developed. However, little is known about the clinical consequences of other distinctive SEMS modifications and further research is indicated. It must also be taken into account that the type of patients that receive a SEMS is changing. In particular, the observation that more patients have been exposed to chemo- and/or radiotherapy is relevant. Major complications are seen more often, especially when both chemo- and radiotherapy have been applied. This mainly concerns pulmonary infections and fistula formation, probably due to the chemoradiotherapy-related esophageal and pulmonary injury, and continuous pressure of the SEMS. SEMS with a low pressure profile and less flared shape seem better suited in these circumstances and we believe this hypothesis deserves further investigation. In this thesis we also highlight the importance of retrosternal pain after SEMS placement which occurs more often than previously assumed. Adequate instruction and pro-active pain management are recommended, especially in the first days.

Technical adjustments have also been applied with regards to SEMS for malignant gastric outlet obstruction. However, this has not led to a significant reduction of SEMS-related adverse events. Nevertheless, this thesis demonstrates good clinical efficacy and an acceptable safety profile of a new uncovered duodenal SEMS within a large study population. Prospective registration and publication of the application of new devices is recommended. This may reveal potential technical shortcomings at an early stage as was seen in a clinical evaluation of a new partially covered duodenal SEMS. In multiple patients broken struts were encountered, which prompted for discontinuation of the trial. Although duodenal SEMS covering seems to prevent ingrowth, the benefit of anti-migration features remains to be established.

Technology in the field of SEMS therapy is continuously evolving. Future innovations to suppress tumor or tissue growth include drug-eluting stents and stents with the ability to release photothermal energy [48, 49]. These more advanced developments are to be encouraged. However, our knowledge of the mechanistic behaviour of metal stents in relation to anatomy and clinical outcome is still not fully evolved and deserves continued investigation. Ideally, the effect of a single modification to a particular stent design should be established in preclinical testing before introduction in humans. The lack of access to representative animal or in vivo models is however challenging. Controlled trials on distinct SEMSs, preferably in a randomized fashion, should therefore be promoted. It is evident that combining efforts through multicenter collaborations is crucial in order to include a sufficient number of patients to provide strong scientifically sound recommendations. In addition, a more accurate assessment of the risk profile based on patient-related characteristics is needed. This should ultimately lead to individually based SEMS therapy to ensure an optimal clinical outcome.