Methods of palliation of esophageal and gastric cancer

Surg Oncol Clin N Am 11 (2002) 459–483

Methods of palliation of esophageal and gastric cancer Carla L. Nash, MD, Hans Gerdes, MD* Gastroenterology-Nutrition Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

Esophageal and gastric malignancies are common cancers worldwide. In the United States, the incidence for esophageal cancer is 4/100,000 and for gastric cancer it is 5/100,000 [1]. Unfortunately, more than 50% are diagnosed with regional or metastatic involvement, precluding curative treatment. Consequently, the management goal of patients with esophageal or gastric malignancies is often to palliate symptoms. Progression of esophageal cancer may lead to dysphagia or tracheoesophageal fistula (TEF) and aspiration, and, in gastric cancer, gastrointestinal bleeding and nausea with emesis caused by gastric outlet obstruction may be present. Pain and malnutrition may be present in both cancers. This article focuses on the medical, endoscopic, and surgical options in managing the palliation of patients with advanced esophageal and gastric cancer. Because of the concise nature of this article, the pharmacologic management of pain will not be discussed. Esophageal cancer Esophageal cancer accounts for 1% of all malignancies in the United States. Progressive tumor growth occurs through the esophageal wall, resulting in decreased lumen patency. Dysphagia develops in up to 90% of patients, usually when the lumen is compromised by more than 50% [2]. Typically, difficulty with swallowing begins with solid foods and progresses to include liquids and even the patient’s own saliva. A dysphagia scoring system (Table 1) has been devised to indicate severity of symptoms and to compare the efficacy of treatment strategies objectively [3]. Because of decreased oral intake from dysphagia and anorexia, weight loss is found in approximately 55% of esophageal cancer patients. Pain occurs in 16%,

* E-mail address: [email protected] (H. Gerdes). 1055-3207/02/$ - see front matter Ó 2002, Elsevier Science (USA). All rights reserved. PII: S 1 0 5 5 - 3 2 0 7 ( 0 2 ) 0 0 0 1 0 - 8

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Table 1 Grading of dysphagia Grade

Symptom

0 1 2 3 4

No dysphagia Dysphagia for normal solids Dysphagia for soft solids Dysphagia for solids and liquids Unable to swallow saliva

From Mellow MH, Pinkas H. Endoscopic laser therapy for malignancies affecting the esophagus and gastroesophageal junction. Arch Intern Med 1985;145:1443–6; with permission.

likely because of tumor infiltration of surrounding structures or because of esophageal dilation proximal to the obstruction site [4]. TEFs may occur in 1% to 13% [4] of patients and is characterized by a cough precipitated by food ingestion, often leading to aspiration pneumonia [5]. Bleeding, either acute or chronic, is present in approximately 5% of patients [4]. The palliative management of esophageal cancer is not influenced directly by the histologic type of cancer (predominantly squamous cell or adenocarcinoma), but rather by the location and bulk of the tumor. Because squamous cell carcinoma is more likely to affect the upper to middle portion of the esophagus, where TEFs and aspiration may be more common. Adenocarcinoma is predominant in the distal esophagus. Because of the anatomy of the esophagus and surrounding structures, these differences may make certain palliation methods more or less appropriate. Chemoradiation Esophageal cancer is generally not responsive to chemotherapy alone. Objective tumor response with fluorouracil is 15% to 25%, which increases to 30% to 60% when combined with cisplatin [6,7]. Only two publications (from the same group) have compared the use of fluorouracil and cisplatin after palliative resection versus no treatment, and they found no difference in survival, degree of dysphagia, or duration of autologous oral feeding [8,9]. Major complications in the chemotherapy group involved neurologic, renal, and hematologic toxicities and were responsible for four deaths. Documentation of the effects of chemotherapy alone on reducing dysphagia is scarce. One study of patients with metastatic or unresectable esophageal cancer undergoing treatment with etoposide and cisplatin reported a relief in dysphagia for 89% of patients [10]. A recent study of irinotecan and cisplatin showed an improvement or resolution of dysphagia in 90% of 20 patients who had no other treatment for dysphagia. The improvement was noted after one cycle of chemotherapy and lasted for 1 to 5 months. Of the entire group undergoing treatment, chemotherapy side effects were few: only 9% with life-threatening neutropenia and 11% with diarrhea causing hospitalization, and no treatment–related deaths were reported [11].

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Most of the data about the palliative effect of chemoradiation therapy (CRT) must be extrapolated from studies where the primary outcome has been measured in patient survival. Few studies have reported on the palliation of dysphagia with CRT. Coia et al [12] treated 90 patients with esophageal cancer, 33 of whom had stage III or IV disease, with 50 Gy over 6 to 7 weeks plus infusional fluorouracil and bolus mitomycin C. Of the stage III and IV patients, 77% were dysphagia free at the end of treatment, and 60% remained dysphagia free until death, with a median duration of response of 5 months. Other studies document a 60% durable improvement in dysphagia after treatment with radiotherapy and 5-FU/cisplatin [13], bleomycin/cisplatin [14], and carboplatin/5-FU [15]. Unfortunately, CRT does not immediately relieve symptoms of pain or dysphagia. The treatment often requires a hospital stay and may lead to complications, such as esophagitis, bone marrow toxicity, infection, and fistulization in 20% to 30% of patients [16,17]. In addition, dysphagia may be worsened by edema. Post-treatment stricture formation, which occurs in 10% to 50% [6,16], may require repeated endoscopic dilation [18] with a subsequent higher risk of perforation. Coia et al reported a severe acute toxicity rate in 12% of patients and late toxicity in 3% of patients [12]. Therefore, CRT should only be offered if the patient has locoregional disease, a good functional status, and a life expectancy that is in the order of many months. Radiation therapy alone, in the form of external beam treatment (EBT) and/or brachytherapy, has been used to palliate esophageal cancer. Squamous cell carcinoma appears to be more responsive than adenocarcinoma [18]. One hundred thirty-three patients from the University of South California received 55 Gy: 34% achieved good palliation of dysphagia lasting 6 months and 18% achieved moderate palliation [17]. Other groups also noted improvement in dysphagia in about approximately 65% to 70% of patients receiving radiation therapy alone [19,20]. Another study of 110 esophageal cancer patients undergoing EBT found that the duration of response related to radiation dose. Patients receiving more than 45 Gy had a median palliation of symptoms of 52 weeks, whereas those receiving less than 45 Gy lasted an average of 27 weeks [21]. Generally, 50 to 60 Gy given over 5 weeks improved dysphagia in 40% to 80% of patients. Because of edema, however, a transient worsening of dysphagia may be noted over the first 5 to 7 days, and improvement occurs slowly over the following weeks. Up to 20% of patients are unable to tolerate a full treatment course [20]. Duration of response may be sustained, and median survival is 5 to 10 months. Approximately 20% to 30% of patients develop esophagitis or fistulas, and 30% to 50% may develop strictures secondary to benign fibrosis or persistent carcinoma [17,22,23]. The use of brachytherapy may relieve symptoms of esophageal cancer and may be better tolerated by patients than EBT. Treatment consists of one to three fractions of 7.5 to 20 Gy radiation. Three small series have reported intraluminal therapy with (low dose) cesium-137 [24–26] and (high dose)

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iridium-192 [24] brachytherapy. All three series report efficacy rates of 70% to 90% with a more rapid onset than with EBT. Esophagitis is the primary complication, occurring in 30% to 40%; although serious complications, such as TEF and stricturing, may also occur [17]. Duration of effect is 4 to 5 months, usually with retreatment offered. This form of radiation treatment is recommended for patients who are unable to tolerate a full external beam course. Combination EBT and brachytherapy had only a marginally increased effect in relieving dysphagia: 48% had good palliation results and 28% had more moderate effects [17]. Endoscopic therapy Endoscopic management of malignant dysphagia and TEF has advanced significantly in the last 15 years, with the improvement of prostheses and the use of ablative therapies. Options may include dilation, the use of expandable metal stents, or ablation therapies, such as electrocautery, neodymium: yttrium aluminum garnet (Nd:YAG) laser and photodynamic therapy. Recently, combination therapies, typically with ablation and stenting either with or without CRT, have been investigated. Dilation Dilation of esophageal obstruction from tumor bulk may be accomplished by several mechanical means, including the use of mercury weighted rubber bougies, wire-guided polyvinyl tubes, or hydrostatic dilating balloons. Although the detailed practice of dilation is beyond the scope of this article, the general principles of sequential graded manipulations are practiced. No large controlled trials have documented the efficacy or complication rate of dilation of malignant strictures. A retrospective review of 39 patients undergoing dilation as part of a palliative management strategy documented an efficacy of 90% in relieving dysphagia, with one perforation and two minor complications of fever and chest pain [27]. A prospective analysis of 41 patients who underwent 128 total dilations established an approximate 5% perforation risk. Although improvement in dysphagia was noted, patients required repeated dilation approximately every 4 weeks [28]. Generally, the risk of perforation is thought to be higher when dilating malignant strictures in comparison with benign strictures [29]. Theoretically, the radial force of the dilating balloon is thought to be safer than the longitudinal force of bougies; however, this has not been compared in dilations of malignant strictures. Many groups have found that wire-guided polyvinyl tube dilation is more effective than balloon dilation, although this has not been studied [28,29]. Furthermore, although effective in alleviating dysphagia, the duration of response is only a few days to weeks [18,28]. The advent of expandable metal stents has allowed most centers to no longer use dilation as the sole modality to treat malignant dysphagia.

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Stents Before 1990, mechanical methods to maintain relief from malignant dysphagia were in the form of plastic intubation devices or stents. These devices are inserted under endoscopic or surgical guidance to keep the esophagus open. Unfortunately, many problems are associated with these prostheses. Because of the fixed external diameters, dilation of the tumor to approximately 18 mm is required to place the stent, thus putting patients at high risk for perforation. Furthermore, the fixed internal diameter of 10 to 12 mm is relatively small and is often ineffective in fully relieving dysphagia. In addition, the plastic stents are difficult to insert or remove and may cause pain. Overall risks include perforation (8% to 12%), hemorrhage (2% to 5%), and fistula (1% to 3%). Mortality related to the procedure is estimated at 2% to 10% [6]. Since 1990, self-expandable metal stents (SEMS) have all but replaced the plastic variety. They are technically easier to insert, have fewer procedural risks, and are more effective in relieving dysphagia. These come in a variety of sizes and with different delivery systems. In general, the SEMS are placed in the esophageal lumen at the region of tumor bulk and are then deployed by a spring-loaded or self-expanding system under fluoroscopic and endoscopic guidance. The procedure can be done under conscious sedation, and only minimal dilation of the tumor to admit the delivery device (7 to 11 mm) is required. The radial expansive force of the stent maintains lumen patency. The SEMS have a large luminal diameter (16 to 23 mm), which ensures effective relief of dysphagia. Typically, the tumor bulk holds the stent in place, and a mild tissue inflammatory reaction occurs. Complications (which occur in approximately 10% of patients) include major complications, such as perforation and bleeding, and minor complications, such as pain and stent migration [30]. Acid reflux may be a problem in stents placed across the gastroesophageal junction (GEJ), but a specially designed stent is now available that reduces reflux [31]. In addition, recurrent dysphagia caused by food impaction or tumor ingrowth may occur. Several studies have compared plastic stents with the SEMS [30,32–36]. Of the prospective trials, insertion success of both types was 90% to 100% [30,34,35] and resulted in a similar improvement in dysphagia scores from pretreatment levels of three to post-treatment scores of one [32,35]. Karnofsky performance scores improved from approximately 45 to 65, which was also similar between groups [32]. Although thirty-day mortality was not statistically different, it tended to be higher in the plastic stent groups [32,34,35]. Overall, complications were lower in the SEMS groups (range: 0% to 16%) versus those of the plastic stent groups (21% to 47%) [32,34,35]. Although similar among both groups, recurrence of dysphagia was mainly caused by stent migration in the plastic prosthesis groups and by tumor overgrowth or ingrowth in the SEMS groups [32,34,35]. In retrospective reviews, similar results were seen with high success rates of insertion and dysphagia improvement in both plastic and SEMS groups, as well as

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fewer complications in the SEMS groups [30,33,36]. Only one retrospective analysis showed a higher complication rate in the SEMS group [36]. Although there are several types of SEMS currently used, the most common are the Wallstent, Gianturco Z-stent, and Ultraflex varieties, which are compared in Table 2. A recent prospective, randomized trial comparing these stents showed equal efficacy in relieving dysphagia 4 weeks after insertion [37]. Aside from placement issues, the most common problems are stent migration (1% to 15%) and tumor ingrowth (10% to 15%) [6,30]. Most varieties of stents available today are coated and designed to reduce the degree of tumor ingrowth [38]. This feature comes at the cost of increased migration. The presence of barbs on the stents has been used to reduce migration; however, they may cause mucosal injury and may make the stent difficult or impossible to remove. Migration can also be reduced by minimizing dilation to a size just large enough to allow the endoscopic placement of the stent delivery system and by choosing a stent size approximately 4 cm longer than the region occluded by the tumor. The stent is ideally inserted to maintain a 1- to 2-cm margin proximally and distally to the region of tumor bulk [16]. The covered coating of most stents consists of silicone or polyurethane. Should tumor ingrowth or overgrowth occur, several studies have shown that additional therapy with another stent (a stent within a stent) [39,40], or a variety of ablation methods including Nd:YAG laser [32,41], argon plasma coagulation (APC) [42,43], and photodynamic therapy [44,45] is possible, albeit at risk of damage to the original stent [46]. SEMS are relatively easy to use and place, even outside of expert centers [16]. Technical success in insertion is 95% and results in improvement of dysphagia in 85% to 100% of cases [6,30]. In a national survey of gastroenterologists in the United States, 75% of the respondents had inserted fewer than four stents, yet complication rates were similar to other reported rates in the literature [47]. Individualized consideration is necessary. Two prior studies have documented the poor outcome of SEMS used in patients with prior chemotherapy or radiation therapy [34,48]. SEMS placed near the GEJ are more susceptible to migration because of the angulated nature of the distal esophagus and may potentiate acid reflux. Stents placed near the cricopharyngeus are often problematic because of pain, migration, and a persistent globus sensation. Occasionally, tumors are completely obstructing and Table 2 Self-expanding metallic stents

Manufacturer Component Dynamics Lumen diameter Delivery system diameter

Ultraflex

Gianturco-Z

Wallstent

Microvasive/Boston Scientific Inc. Nickel titanium Flexible, least wall force 17–22 mm 24F

Wilson-Cook

Schneider

Stainless steel Less shortening 18–22 mm 24–31F

Elgiloy Greater wall force 16–20 mm 18F

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therefore dilation is necessary. One group has shown that dilation of the malignant tumor to the point of being able to successfully insert the stent, approximately 10 mm, is reasonably safe [49]. Although cost remains an issue for many endoscopic centers, several studies have shown that the use of SEMS in malignant esophageal obstruction is more cost effective than plastic stents despite the higher initial cost [32,50]. Ablation Although tumor ablation to treat malignant dysphagia has been available for decades, recent developments have expanded the spectrum of options. Injection therapy. Although injection of sclerosing agents to precipitate tumor necrosis has been used in the past, it has never gained widespread acceptance despite its ease of administration and low cost. Injection of alcohol, sodium morrhuate, polidocanol, and fluorouracil has been described; however, generally the degree of tissue necrosis is less predictable than that from the newer thermal ablation techniques described below. Because of the range of tumor texture, dosimetry of the sclerosing agent may be difficult to achieve. The effect of reducing dysphagia may be delayed, and repeat treatments are often required every few weeks [18]. In the largest series reported, 36 patients were treated with alcohol injection in 0.5 to 1.0 mL aliquots. Dysphagia significantly improved with a mean duration effect of 5 weeks. Side effects included mediastinitis in one patient and TEF in two others [51]. BICAP therapy. BICAP thermal ablation is a form of bipolar electrocoagulation delivered to esophageal tumors under fluoroscopic guidance through an olive-shaped probe ranging from 6 to 15 mm in diameter. The electrocautery is administered under medium energy (approximately 50 W) in a 360° field, which delivers a treatment burn 1 to 2 mm deep. Post-treatment effects include eschar formation and tumor friability. Repeat treatment is usually done 48 hours after necrotic tissue debridement. Although treatment is usually effective in restoring luminal patency and reducing dysphagia, the duration of effect is only about 2 months [52–54]. Side effects consist of chest pain, fever, leukocytosis, and occasionally mucosal edema, which may temporarily worsen dysphagia. Major complications include perforation, delayed hemorrhage, stricture, and TEF [52–54]. Similar to injection therapy, BICAP electrocautery has not been used extensively. It requires dilation to admit the probe and therefore is associated with higher perforation rates. In addition, the thermal energy is dispersed in 360°, so in noncircumferential tumors normal tissue will also be treated. Therefore, BICAP is mainly restricted to treating circumferential exophytic tumors. Nd:YAG laser therapy. Endoluminal therapy with the Nd:YAG laser is a thermal ablation technique that coagulates protein and vaporizes tissue to restore luminal patency. It may also be used for hemostasis of chronically

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bleeding tumors [18]. The Nd:YAG laser energy is delivered through the endoscope via a quartz fiber. Coaxial air or carbon dioxide gas flows between the quartz fiber and the plastic sheath to cool the fiber tip. The laser beam is aimed at the tumor tissue approximately 1 to 2 cm from the tissue, and energy is delivered in short pulses of 1 to 2 seconds. Moderate energy of 40 to 50 W is used to obtain protein coagulation and blood vessel constriction for hemostasis. Higher energy at 90 to 96 W is used for vaporization of tissue to relieve dysphagia. Original descriptions of the use of Nd:YAG laser recommended an antegrade approach to treatment [55]. Generally, if the tumor is passable with the endoscope, retrograde treatment is preferred to minimize the risk of perforation and, when compared to the antegrade approach, results in fewer treatment sessions to achieve relief of dysphagia [56,57]. As with the BICAP electrocautery, repeat treatment is recommended 48 hours later, at the time of maximal necrosis, to permit debridement of necrotic tissue. Ideal lesions to be treated with Nd:YAG laser include short exophytic tumors. Although midesophageal locations are technically the easiest to treat, proximal or GEJ tumors may be treated with some effort and with less than optimal results. Unfortunately, submucosal or extrinsic tumors causing malignant dysphagia are not amenable to this treatment. Nd:YAG laser treatment relieves dysphagia in 69% to 93% of cases [57– 62]. In addition, Nd:YAG laser therapy is one of the few types of invasive palliative treatments that has undergone quality of life assessment. Barr et al [63] reported that quality of life and dysphagia improved after treatment. Duration of response is between 1 and 3 months, and multiple treatments may be needed for recurrent symptoms. Nd:YAG therapy with external beam radiation or brachytherapy increases the duration of effect [64], but may also increase the complication rate [64–66]. Overall, risk of complication is approximately 4%. Minor complications include chest pain, transient fever, worsening dysphagia caused by edema, and leukocytosis. Major complications include bleeding, perforation, TEF, pneumomediastinum/pneumoperitoneum, and stricture [33,52,59]. Photodynamic therapy. Photodynamic therapy (PDT) is a nonthermal ablation technique that uses a photosensitizing agent incorporated by tumor cells to induce cell necrosis after exposure to light. A hematoporphyrin sensitizing agent (porfimer sodium) is given intravenously 48 hours before planned treatment. This agent selectively accumulates in tumor cells more so than in normal cells, and is activated by illumination with monochromic light from a tunable dye laser delivered through a thin endoscopically positioned light diffuser. Activation of the sensitizing agent initiates a cascade of events resulting in tumor necrosis. The depth of injury is approximately 2 to 3 mm and, because it is not limited to bulky tumors, infiltrating or flat lesions may be amenable to PDT. Typically, two treatments are completed 48 hours apart. The response rate is approximately 60% to 90% [67,68]. Acute complications may include chest pain and odynophagia, nausea,

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fever, leukocytosis, and pleural effusion in 5% to 20% of patients [68–71], and long-term effects may include stricture formation (15%) and TEF (5% to 30%) [69]. Sun sensitivity persists for 4 to 6 weeks, and sunscreens (designed for ultraviolet light protection) are not effective because the photosensitizing agent responds to visible light. As a result, patients must avoid sunlight exposure to skin and eyes for 4 to 6 weeks. Approximately 10% to 20% of patients will develop problems related to the photosensitivity [68,69,71]. One prohibitive problem with PDT is the cost of equipment and the photosensitizing agent. Generally, porfimer sodium is given at a dose of 2 mg/kg. A 75-mg dose can cost in excess of $2000. Similarly, the cost of the dye laser is more than $100,000, thus limiting access to only a few institutions in most states. APC. APC is a noncontact monopolar electrocautery form of treatment that delivers electrically ionized conductive argon gas through an endoscopic catheter. The argon gas causes a plasma arc to tissue, which results in coagulation and desiccation to a depth of 2 to 3 mm. Like Nd:YAG laser therapy, APC is somewhat tedious to deliver, but has shown good success albeit for a limited period. Multiple sessions may be needed. The largest study noted recanalization in 58% of subjects, with an additional 26% needing two treatments. Failure was noted in 16%, and perforation occurred in 8%. Two thirds of patients required retreatment every 3 to 4 weeks, with a mean number of six treatments. One third of patients eventually received SEMS [72]. APC should be reserved for small lesions or vascular lesions, since it effectively treats hemorrhagic lesions. The variety of endoscopic modalities available may make it difficult to decide the most appropriate option. Table 3 offers a summary comparison of the individual palliative options. Several studies have compared ablative therapies against each other and against SEMS. The only comparative study with alcohol injection therapy compared this modality with Nd:YAG laser therapy. No difference in survival was noted between the two groups; however, the laser group experienced less pain. The duration of effect was similar between groups (approximately 1 month) [73]. In a prospective randomized trial comparing polidocanol injection with Nd:YAG laser therapy, dysphagia was relieved in 81% and 88%, respectively; a nonsignificant difference [74]. In a nonrandomized comparison of Nd:YAG laser with BICAP electrocautery in 28 patients with malignant dysphagia, 86% had improvement of their dysphagia. Complications of pain, edema and strictures were more common in the Nd:YAG laser group [53]. A randomized comparison of Nd:YAG laser with brachytherapy showed similar improvement in dysphagia and performance status. More minor complications were noted in the brachytherapy group (ie, dysphagia, pain, fever, bleeding); one perforation was noted in the Nd:YAG group [75]. Several trials have compared Nd:YAG laser therapy with PDT. Although similar efficacy was noted in both treatments, PDT had a longer duration of

100%

90%

40%–80%

70%–90%

90%

85%–100%

Surgery

Chemotherapy

External beam radiotherapy

Brachytherapy

Dilation

SEMS

Efficacy

5–6 mon

0.5–1 mon

3–7 mon

3–10 mon

1–5 mon

Indefinite

Duration of effect

Table 3 Summary comparison of methods of palliation for malignant dysphagia

5%–15%

5%–10%

10%–40%

10%–40%

10%

35%

Complication rate

Migration Tumor ingrowth Bleeding Perforation Pain Reflux

Perforation Fever Chest pain

Esophagitis TEF Stricture

Dysphagia Stricture TEF Esophagitis

Neurologic toxicity Diarrhea Renal toxicity Marrow toxicity

Anastomotic leak Cardiopulmonary Stricture Sepsis

Complications

Not generally used in isolation

Good functional status Unable to tolerate radiotherapy

Good functional status

Good functional status Not used in isolation

Ideal for

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60%–70%

85%

85%

PDT

APC

Electrocautery

2 mon

1 mon

1–3 mon

1–3 mon

1%–3%

10%

10%–30%

2%–4%

Pain Fever Leukocytosis

Perforation

Chest pain Nausea/emesis Fever Stricture TEF

Chest pain Fever Dysphagia Leukocytosis Bleeding Perforation

Circumferential exophytic tumors

Small vascular tumors

Infiltrating lesions Flat lesions

Short exophytic tumors Midesophageal location

Data presented include a general range derived from references given. Abbreviations: SEMS, selfexpanding metallic stent; Nd:YAG, neodymium: yttrium aluminum garnet; PDT, photodynamic therapy; APC, argon plasma coagulation; TEF, tracheoesophogeal fistula.

70%–85%

Nd: YAG laser

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response [68,71] and was associated with an improved Karnofsky performance status [68]. PDT tended to be more effective for tumors located in the upper or lower third of the esophagus, for tumors larger than 10 cm in length, for tumors that had failed other forms of treatment [71], and in patients with high Karnofsky performance status [18]. More adverse effects, such as skin photosensitivity, nausea, fever and pleural effusions, were reported with PDT; however, the perforation rate was higher in the Nd:YAG group [71]. Ablation has been compared with SEMS placement. Gevers et al [33] conducted a retrospective review of patients treated with Nd:YAG laser with those treated with SEMS and plastic stents. The effect in relieving dysphagia of laser and SEMS treatment was 80%, compared with 66% for plastic stents (nonsignificant); however, complications were higher in either stent group compared with laser. Some studies have shown that Nd:YAG laser has a longer duration of effect with fewer complications [76] and even an increased survival [77]. Other studies have shown better effect with SEMS [78], with lower complication rates and fewer reinterventions [79]. Palliation for TEF The current article mainly focuses on the palliation of malignant dysphagia, which is the most common symptom in the natural history of progressive esophageal cancer. TEF may occur in approximately 10% of patients with advanced esophageal cancer, either secondary to the underlying cancer itself or secondary to a variety of treatments, including radiation therapy, SEMS, Nd:YAG laser, and PDT. TEF carries a dismal prognosis, with life expectancy measured only in weeks and an overall 30-day mortality of 46% despite treatment [5]. A variety of techniques have been used to correct TEF, including resection, bypass and exclusion surgery (cervical esophagostomy and gastrostomy with closure of the esophagus above and below the fistula), and chemoradiation therapy. Unfortunately, 30-day mortality rate remains high at 20% to 60% [5]. Early reports of plastic stent insertion for TEF treatment showed poor efficacy and high mortality [5]. The use of SEMS is a relatively new option with encouraging early results. A series of 11 patients with TEF had SEMS placed, with closure of 10 fistulae [80]. In another study of SEMS compared with plastic stent placement, dysphagia was equally treated; however, SEMS was 92% successful for fistula closure, as opposed to 77% success for the plastic stent group [81]. Raijman et al [82] has reported the largest series (101 patients) with TEF treated with SEMS. All but one patient had successful stent insertion, with 100% success in sealing fistulae and in reducing dysphagia. Although no procedural deaths were noted, the life-threatening hemorrhage rate was almost 8%. Other small case series report similar efficacies of 70% to 100% and complication rates of 15% to 30% [82–87]. Fig. 1 outlines a case report of a patient treated successfully with stent insertion. Surgical treatment is the only remaining option if the region of

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Fig. 1. Palliation of TEF in a patient with esophageal cancer. Esophagram (A) at the time of diagnosis showed barium extravasation from the esophagus to lung cavity (arrows). At endoscopy (B), the fistula (f) was easily located; the esophageal lumen (l) was prepared for stent insertion with a guidewire in place (arrows). A covered Gianturco Z-stent was used to seal the fistula and maintain patency of the lumen. (C) Proximal end of the stent after insertion. Postinsertion esophagram (D) visualized the stent (arrows) and confirmed adequate closure of the fistula, with residual barium (b) in the abscess cavity.

fistulization is not amenable to stenting, such as with very proximal fistulae, or if endoscopic treatment fails in relieving dysphagia. Surgery Because of the advanced stage of most esophageal cancers at presentation, a large proportion of resections for curative intent will be palliative

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in nature. Surgical options for palliation specifically include resection or bypass. Usually, a transhiatal approach for resection is optimal to avoid the morbidity related to thoracotomy. Gastrointestinal continuity is restored by connecting the proximal esophagus to a tubularized gastric conduit or to a colonic interposition. Contraindications to resection include tumor involvement of the trachea, bronchi, or major blood vessels. Dysphagia is relieved in 70% to 80%, and median survival is 7 to 9 months. Operative mortality varies from 5% to 10% and is dependent on tumor extent and preoperative functional status. The postoperative complication rate is 40% to 50% [88,89]. For nonresectable cases, bypass is the only remaining surgical option. Although this palliates dysphagia in 25% to 70%, other symptoms, such as bleeding, pain, or TEF, may not be avoided. The mortality rates reported are higher at 11% to 35% [88,90–92], with an average survival time of 5 to 6 months [90,91]. Because of the reasonable alternative options provided with endoscopy, surgical treatment for palliation of dysphagia is rarely considered. As mentioned, surgical treatment of TEF may be necessary after the failure of endoscopic methods in the few patients who remain fit enough for surgery. Gastric cancer The rate of gastric cancer in the United States is 5/100,000 [1]. With the exception of gastric cardia cancer, the incidence rate in the United States has remained static. Like esophageal cancer, most patients present with advanced disease, and therefore palliation is the primary focus. Symptoms related to GEJ and cardia tumors are secondary to distal esophageal obstruction, and therefore palliation methods are similar to those described for esophageal cancer. For gastric cancers affecting the body and antrum of the stomach, progression of disease may lead to pain, nausea, and emesis caused by gastric outlet obstruction, or acute or chronic gastrointestinal bleeding. The following text will discuss palliative methods for gastric cancer restricted to the distal stomach. The authors will not discuss the palliative management of metastatic disease, such as bile duct obstruction or ascites, but rather will focus on controlling the disease that is causing gastric outlet obstruction and bleeding. Chemoradiation Although gastric cancer appears to be more responsive than esophageal cancer, the effect of palliative chemotherapy remains less than ideal. Multiple drugs, such as doxorubicin, cisplatin, 5-fluorouracil, and mitomycin C, have shown more than 20% response rates as single agents [93]. Newer agents, such as docetaxol and irinotecan, are being examined for their efficacy [94]. The success of palliative chemotherapy in gastric cancer relies, however, on a patient’s ability to eat and maintain nutrition balance through the course of treatment. Radiation alone has limited value

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in gastric cancer palliation [23]. Anecdotal experience exists for radiation therapy use to control hemorrhage or pain secondary to tumor invasion [95,96]. Endoscopic therapy Endoscopic treatment for gastric cancer may include therapies to control tumor bleeding and to establish patency of the gastroduodenum. Stents Although there is considerable experience with esophageal stent placement, gastroduodenal stenting has only recently been studied because of limitations in stent delivery systems. Several anatomic aspects make gastric stenting different than esophageal stenting. The acute angulation can make insertion difficult with the fairly rigid esophageal stent delivery systems [97]. This angulation is sometimes exacerbated by redundancy of the greater curve. One group has reported the use of an overtube to overcome these technical problems [98]. Recently, a new stent, the Enteral Wallstent (Microvasive Boston/Scientific, Natick, MA, USA) has been specifically designed for placement through the endoscope into the pylorus, duodenum, jejunum, or colon. Small case series have been published on gastroduodenal stenting to relieve obstruction [97,99–102]. Technical success of stent insertion ranges from 75% to 100%. Clinical response varies from 70% to 95% in terms of decreased dysphagia, nausea, and emesis. The primary complication is stent migration (up to 25% in some series), particularly with covered stents. Migration proximally usually requires the endoscopic removal of the stent, and stents that migrate distally are often passed uneventfully or result in small bowel obstruction, potentially requiring surgical management. Fig. 2 shows successful treatment of gastric outlet obstruction with the use of an endoscopically placed stent. As more experience becomes available and as more improvements are made in stent design, SEMS will become a reasonable nonsurgical option for gastric outlet obstruction. Ablation Nd:YAG laser therapy has shown a limited success in treating gastric outlet obstruction. One case series showed the successful use of Nd:YAG laser therapy to recanalize prepyloric obstruction caused by gastric cancer in two patients [103]. Other studies have been less encouraging. Suzuki et al [104] treated 52 patients with gastric cancer. For the 14 patients with antral cancer, only 14% had effective therapy with Nd:YAG laser. Two smaller trials have also noted an approximate 50% response rate of antral cancer to Nd:YAG laser [105,106]. Oguro et al [107] reported a national Japanese trial of 71 patients with antral cancer in which only 50% had successful recanalization with Nd:YAG laser. Furthermore, even when a large size lumen was established, symptoms often persisted, likely because of poor gastric motility.

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Fig. 2. Palliation of malignant pyloric stenosis in a patient with metastatic colon cancer causing gastric outlet obstruction. Endoscopy (A) revealed infiltration and obstruction of the pylorus (p). Computed tomography (CT) scan (B) showed large obstructing mass (m) with occlusion of the duodenum and dilated stomach (g). A good result is noted after an uncovered Enteric Wallstent is inserted across the pylorus, as shown in the endoscopic image (C), abdominal flat plate (D), and CT scan (E) images.

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Fig. 2 (continued )

APC has had only limited use for imminent gastric outlet obstruction. Akhtar et al reported effective palliation in two patients with gastric outlet obstruction [43]. To palliate gastrointestinal bleeding, Nd:YAG laser has been used with mixed results. In 18 patients with bleeding esophageal and gastric cancer, hemostasis with Nd:YAG laser was achieved in 94.5%. This effect was persistent for 77.8% of patients [104]. Oguro et al [107] noted successful hemostasis in 75% of 102 patients with upper gastrointestinal cancer bleeding. Other studies have been less optimistic. One study has shown, that the cessation of hemorrhage with Nd:YAG laser can be only temporary, with all six patients rebleeding within days [106].

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APC has also been used infrequently to treat gastric cancer hemorrhage. Of five patients treated, APC achieved complete cessation of hemorrhage in three patients and a partial response in two patients [43]. In general, APC treatment for upper gastrointestinal cancer bleeding is safe. Akhtar et al [43] reported only two perforations in more than 300 procedures, and the authors note that these occurred during the first 24 procedures. Surgery Surgical palliation of gastric cancer may include resection, bypass, or decompression. Many authors have suggested that some form of resection should be completed if possible (even if the extent of tumor is not curable) because of a higher survival rate [108–111]. The type of resection to choose is debatable, however. One study detailed 53 patients who received a total gastrectomy because of tumor location and extent. Mortality was 8%, with a median hospital stay of 13 days, and a median survival of 19 months. Quality of life after surgery was considered good in 60% of patients and moderate in 28% of patients [109]. Other studies have suggested that either total or partial gastrectomy has an acceptable rate of morbidity and mortality with good palliative results. Meijer et al [110] reported on 26 partial or total gastrectomies completed only for palliative intent. Fifty percent of patients reported good symptom relief, and another 27% reported moderate symptom relief. Bypass provides effective symptom relief in fewer patients (30% to 80%) [108,110], and, presumably because of the greater extent of disease, it carries a lower median survival of approximately 3.5 months. In general, gastric resection either by total or partial gastrectomy for selected patients appears to be a good palliative option. Gastrointestinal bleeding in patients with esophageal or gastric malignancies is usually caused by tumor extension into blood vessels or by tumor regression after chemoradiation. Bleeding may be unresponsive to endoscopic treatment because of the large caliber of vessels involved. Although some patients may still have limited disease amenable to surgical therapy, most are poor surgical candidates and are best treated endoscopically, with radiation therapy, or with arterial embolization [112]. Nutrition Nutritional support in patients with upper gastrointestinal cancer is often difficult to achieve for several reasons. Obstruction caused by the tumor may preclude oral ingestion, and odynophagia, TEF, and anorexia may compound the problem. Although the variety of palliative methods described above are often effective, failures do occur. Furthermore, many studies have shown that even when luminal patency is achieved, dysphagia persists because of functional difficulties with swallowing that may be related to tumor invasion of neuromuscular structures [16]. In addition, the anorexia

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associated with cancer often results in reduced nutritional intake despite a nonobstructed gastrointestinal tract. Options to enhance nutrition include total parental nutrition, which is costly and somewhat incongruous with palliative management, and enteral nutrition support through the use of percutaneous endoscopically placed tubes in the stomach (percutaneous endoscopic gastrostomy [PEG]) or the jejunum (percutaneous endoscopic jejunostomy [PEJ]). The specific details of insertion have been described elsewhere [113]. In addition to facilitating nutrition, PEGs and PEJs are also used to prevent aspiration caused by luminal esophageal or gastric obstruction. Two large studies have shown good long-term success of PEGs in supplying nutrition and preventing aspiration in patients with cancer [114,115]. In a study of patients with predominantly esophageal and gastric malignancies, percutaneous endoscopic enteral tubes were successfully placed in 86% of 129 patients. A low complication rate was noted, with only one case each of bleeding, perforation, and abscess requiring surgical intervention. The average duration of tube use was 110 days; discontinuation of tube use in 90% of patients was because of death or resumption of oral nutrition [114]. A separate report detailed 42 patients with head and neck cancer who were evaluated for percutaneous enteral feeding due to symptoms of severe dysphagia. Thirty six patients received PEGs, and three patients with prior gastrectomies received PEJs; three patients could not receive endoscopically placed tubes for technical reasons. Over a mean follow-up period of 4.5 months, there was only one case of aspiration. No procedural-related complications were reported, and three cases of localized cellulitis at the site of tube insertion were effectively treated with antibiotics [115]. It is evident from these studies that percutaneous endoscopically placed tubes for enteral nutrition are safe to insert and are effective in providing long-term nutrition for patients with dysphagia, gastric outlet obstruction, or recurrent aspiration. Conclusion Most patients presenting with esophageal and gastric malignancies are incurable at presentation. Palliation of symptoms caused by obstruction, bleeding, or fistulization is often the focus of management. Chemoradiation therapy has been disappointing to cure or improve survival, and few studies have shown success in relieving symptoms. Surgical options may be effective, but at a relatively high cost of morbidity and mortality given a rapidly progressive disease. Endoscopic methods to palliate obstruction or bleeding are mostly effective and have low risk. Experience and expanded technology in the last two decades has improved the palliation in esophageal and gastric cancer, with feasibility now at the community hospital level. Although these methods may be effective, efforts focused on early detection of upper gastrointestinal malignancy will make the most impact on these debilitating diseases.

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