Endoscopic Diagnosis and Treatment of Upper Gastrointestinal Tumors

• Introduction
• Innovations in Endoscopic Diagnosis
• Innovations in Endoscopic Therapy
• Endoscopic Mucosal Resection and Other Endoscopic Interventions
• Esophagus
• Stomach
• Duodenum
• Palliative Treatment
• Other Issues
• References

Introduction

This year’s Digestive Disease Week (DDW) saw the presentation of more than 70 studies focusing on endoscopic diagnosis and treatment of precancerous conditions and tumors in the upper gastrointestinal tract. For reasons of space, only a handful of these are discussed in detail in this review [1] [2] [3] [4] [5] [6] [7] [8] [9]; the remaining are summarized in tabular form or simply mentioned in the text. The selection process was facilitated by the fact that the majority of studies were single-arm and retrospective - prospective or comparative studies, quite apart from randomized trials, were notable exceptions. Endoscopic diagnosis and treatment of Barrett’s esophagus were covered in a separate DDW report [10].

Innovations in Endoscopic Diagnosis

Research in this field focused on Barrett’s esophagus, with only a few studies on other topics being presented. Among the other topics, the microvascular pattern of the gastric mucosa appears to attract most attention. The idea is that local changes in the size, shape, and distribution of capillaries may be predictive of the histology. The examination technique involves magnification endoscopy, either alone or in combination with the use of a modified light source (narrow-band imaging [NBI] endoscopy), or with spraying the mucosa with epinephrine solution (pharmacoendoscopy). There is still only preliminary experience in this area, but the findings appear to be encouraging.

Yao et al. prospectively evaluated 161 flat reddened gastric lesions, corresponding either to cancer (n = 38) or gastritis (n = 123) on histology, for the presence of various predefined abnormalities in microvascular pattern, as observed on magnification endoscopy [1]. One of the features evaluated, namely the ”proliferation of microvessels irregular both in shape and distribution”, was present in 97.4 % of cancers (95 % CI, 92.3 - 100 %) and in only 0.8 % of gastritis lesions (95 % CI, 0 - 2.4 %). The sensitivity and specificity for cancer detection based on this feature were 97.4 % and 99.2 %, respectively. The study included only well-differentiated cancers, because - as shown in a previous work by the same group - early undifferentiated cancers are usually pale and produce a nonspecific image on magnifying endoscopy [11]. Another small study (including 13 patients) suggested that abnormalities in the microvasculature may be enhanced by spraying the surface of the lesion with epinephrine solution followed by indigo carmine dye. This appears to work, but only in the elevated type of early gastric cancer and not in the depressed lesions [12].

NBI endoscopy involves using light with modified spectral features to enhance details of the microcapillary and mucosal pattern on magnification endoscopy. Again, the ultimate goal is to predict the histology without obtaining a biopsy. Sharma et al. compared the findings on NBI endoscopy with the histology results in 54 patients with normal mucosa or with various degrees of chronic gastritis [2]. In normal mucosa and mild chronic gastritis, the capillaries had a normal size, shape, and distribution, whereas this pattern was clearly altered in the patients with severe chronic gastritis and intestinal metaplasia, who showed irregularity and decreased density of the small vessels. The sensitivity and specificity of the normal NBI pattern for detecting normal mucosa/mild gastritis were 97.8 % and 100 %, respectively.

NBI endoscopy may also improve the ability to detect early-stage pharyngeal cancer: 34 tumors confined to the epithelium or mucosa were detected in 18 (high-risk?) patients, mostly in the piriform sinuses [3]. Unfortunately, the abstract lacks some very important information: how many patients had to be examined to detect this number of tumors, and how many of the tumors were also visible on conventional endoscopy.

Other studies dealing with innovations in endoscopic diagnosis [13] [14] [15] [16] are summarized in Table [1].

Innovations in Endoscopic Therapy

Technical innovations presented this year include: a cutting holmium mucosectomy laser [17]; a diathermy-based device for the removal of mucosal or submucosal strips of a predetermined depth [18]; a balloon-based bipolar radiofrequency electrode for the circumferential ablation of esophageal mucosa [19] [20] [21]; various suturing devices [22] [23] [24]; and finally, a system for creating submucosal dissection using pressurized gas [25]. In addition, a computer-assisted endoscopic robot system heralds a new - hopefully not endoscopist-less - era in therapeutic endoscopy [26]. Experience with most of these innovative devices is limited to animal experiments.

Endoscopic Mucosal Resection and Other Endoscopic Interventions

Esophagus

Adjuvant chemoradiotherapy after endoscopic mucosal resection (EMR) of squamous-cell carcinoma (SCC) - a novel concept developed to minimize the risk of metastatic spread of tumors invading the muscularis mucosae or upper submucosa - was evaluated in a prospective, nonrandomized study by Shimizu et al. [4]. Sixteen patients who underwent EMR and chemoradiotherapy were compared with 39 control individuals with similar cancer stages who were treated surgically. Despite a 10 - 20 % chance of having lymphatic spread at the baseline, none of the patients who received EMR plus chemoradiotherapy developed metastases or local recurrences after a median follow-up period of 43 months. The estimated 5-year overall survival rates in the EMR plus chemoradiotherapy group and surgical group were 100 % and 87.5 %, respectively (not significant). The study has already been published in full [27].

The potential role of chemoradiotherapy in patients with submucosal cancer treated with EMR is emphasized by the results reported by Pech et al. [5]. Their prospective study included 10 patients with submucosal SCC who were not fit for or did not accept surgery and were treated exclusively by EMR. Although the complete response rate in this subgroup after a mean follow-up period of 29.7 ± 14.3 months was 80 %, two cancer-related deaths occurred, and the estimated 5-year survival was nil (as compared with 90 % and 89 % for patients with in-situ and mucosal tumors, respectively). Other studies on EMR (or photodynamic therapy) in the esophagus are summarized in Table [2] [28] [29] [30] [31] [32].

Stomach

Complete (or curative) resection rates achieved in early gastric cancer and gastric adenoma patients varied between 72 % and 91 % [33] [34] [35] [36]; however, it remains unclear whether the term ”complete” has the same meaning in all studies and whether it always refers to microscopic or rather to macroscopic completeness. Data on the recurrence rate are scant, often incomplete (with the follow-up period not being specified) and difficult to interpret (with reporting of residual tumors mixed with true recurrences). The risk of recurrence after EMR for mucosal cancer may be as low as 1.8 % [33] or as high as 56 % (in material including both esophageal and gastric tumors) [37]. Incidentally, neither of these studies specified the follow-up period. Location in the upper part of the stomach and piecemeal resection were found to be significant risk factors for recurrence in a multivariate analysis (P = 0.002 and 0.042, respectively) [34].

EMR causes submucosal fibrosis, which means that if a repeat intervention for recurrent tumor is needed, it is much more difficult than at the first attempt. Yokoi et al. used an insulation-tipped needle-knife to overcome this problem [6]. En-bloc resection was achieved in 38 of 43 patients (88 %) and was curative ( = complete?) in 30 cases (70 %). This compared favorably with a 0 % en-bloc resection rate in 18 historical controls in whom conventional EMR was attempted for similar indications (P = < 0.0001). Neither local recurrence nor distant metastases were found in the curative resection group after a median follow-up period of 25 months (range 6 - 68). Perforations in three patients (9 %) were managed endoscopically [6].

Three retrospective studies focused specifically on the incidence of and risk factors for post-EMR bleeding [38] [39] [40]. The immediate and delayed bleeding rates reported ranged from 15 % to 31.8 % and from 8.1 % to 11 %, respectively. Major hemorrhage was much less common (3.5 % of patients treated, or only one in nine bleeding episodes) [39]. Data on the risk factors for bleeding identified in multivariate analyses carried out in two of the studies are given in Table [3] [38] [39]. The table also summarizes other abstracts on EMR in the stomach [6] [33] [34] [35] [36] [37] [40] [41] [42] [43] [44] [45] [46].

Duodenum

Five groups presented their experience on the endoscopic treatment of ampullary tumors or duodenal polyps (Table [4]) [47] [48] [49] [50] [51]. In addition, various strategies of screening and surveillance for duodenal polyps in patients with familial adenomatous polyposis were evaluated in a Markov-Monte Carlo decision model [52].

Palliative Treatment

Among numerous, usually single-arm, studies on the palliative treatment of malignant dysphagia, three randomized trials clearly stood out [7] [8] [9]. These were conducted in large groups of patients, and their results suggest that alternatives to self-expanding metal stent (SEMS) placement for palliative treatment of esophageal cancer do exist, and may in fact be a better option.

The multicenter study by Shenfine et al. randomly assigned 217 patients to treatment with SEMS or with ”conventional palliative treatment modalities”, which unfortunately are not specified. The patients were followed up until death [7]. Improvements in swallowing quality and early complication rates were similar in both study arms. The quality of life, however, was significantly poorer in the SEMS group (P = 0.018). In addition, a survival advantage was demonstrated in the conventional treatment group (mean survival 24.6 ± 2.2 vs. 20.1 ± 2.1 weeks); it is, however, not entirely clear whether this difference was statistically significant or not. The higher initial costs of SEMS were compensated for by less frequent late complications and re-interventions, as well as lower hospital attendance, in this group. As a result, both treatments turned out to be equally cost-effective (with low but comparable quality-adjusted life-year values). Subgroup analysis revealed that in the conventional treatment group, rigid intubation was associated with the poorest quality of swallowing, more late complications, a higher re-intervention rate, and less favorable survival. In the SEMS group, the large-diameter stents were associated with significantly more pain negatively affecting the quality of life. This led the authors to conclude that these treatments should no longer be recommended [7].

Homs et al. evaluated the quality of life in a group of 209 patients (both adenocarcinoma and SCC) who were randomly assigned to receive either single-dose brachytherapy (12 Gy) or a covered Ultraflex stent [8]. Using a set of disease-specific (dysphagia score, EORTC OES-23, visual analogue pain scale) and generic health-related quality-of-life scales (EORTC QLQ-C30, EuroQol), they showed that dysphagia improved more rapidly after stent placement, but long-term relief was better after brachytherapy. In addition, there was an overall significant difference in favor of brachytherapy on several functional scales (role, emotional, cognitive, and social functioning) [8]. The quality-of-life analysis presented this year is only one part of this very important study, and its full publication in The Lancet is awaited with great interest.

A new plastic self-expanding stent (Polyflex 18 × 23 mm) was compared with standard SEMS (Ultraflex 23 × 28 mm) in a randomized study by Conio et al., including 78 patients [9]. The extent of dysphagia relief at 7 days and 1 month was similar in both groups, as were the complication rates and profiles. A trend towards longer survival in the Polyflex group was not statistically significant. The authors emphasize the lower cost of the Polyflex stent.

The remaining studies on the palliative management of upper gastrointestinal tumors are summarized in Table [5] (malignant dysphagia, [53] [54] [55] [56] [57] [58]) and Table [6] (gastric outlet/duodenal obstruction, [59] [60] [61] [62] [63]).

Other Issues

A few studies addressed issues related to endoscopic screening [64] [65] [66], surveillance, and follow-up [67] [68] [69] [70] [71] [72].

A prospective multicenter study in France found that endoscopic screening (with Lugol staining) for esophageal SCC or dysplasia is justified in patients with head and neck or tracheobronchial cancer, but not in other risk groups, such as alcohol and tobacco addicts or patients with alcoholic pancreatitis or cirrhosis [64].

The results of a community-based screening program using balloon cytology followed by endoscopy in positive cases were reported by investigators from western Kenya. Among 5760 individuals screened in this high-risk area, 19 % had abnormal cytology, 10 % underwent endoscopy, and 1.3 % were diagnosed with squamous dysplasia. Half of the patients with abnormal cytology did not attend for endoscopy [65].

Among various gastric cancer screening strategies analyzed with a Markov decision model, endoscopy every 3 years was shown to be most cost-effective, at least as far as asymptomatic 50-year-old Japanese men are concerned. The incremental cost-effectiveness ratio, however, was relatively high ($ 61 000 per year of life gained in comparison with no screening) [66].

A retrospective analysis of a large endoscopic database by Liebovich and Sontag led the authors to conclude that endoscopic surveillance for gastric intestinal metaplasia is a noble but futile struggle to prevent cancer death [67]. The risk of developing adenocarcinoma of the stomach during a 13-year period covered by the database (with a mean follow-up period of 64.2 months) was virtually the same in patients with and without gastric intestinal metaplasia documented at the baseline endoscopy (two of 694 = 0.26 % vs. four of 1544 = 0.29 % respectively; not significant). All six patients with cancer were older than 72 years; three died of the cancer and one after surgery [67]. Similar negative conclusions can be drawn from two other retrospective studies specifically looking at the yield of endoscopic follow-up in patients after radical surgery for gastric cancer. Distant recurrences prevail in these patients, and situations in which endoscopy is the only method of detecting recurrence are rare. Furthermore, detecting an endoscopic recurrence only infrequently leads to treatment, quite apart from a cure [71] [72].

Two studies dealt with endoscopic treatment of submucosal tumours [73] [74].

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M. Polkowski, M. D.

Dept. of Gastroenterology · Medical Center for Postgraduate Education · Institute of Oncology

Roentgena 5 · 02-781 Warsaw · Poland

Fax: +48-22-6447601

eMail: polek@coi.waw.pl

References

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M. Polkowski, M. D.

Dept. of Gastroenterology · Medical Center for Postgraduate Education · Institute of Oncology

Roentgena 5 · 02-781 Warsaw · Poland

Fax: +48-22-6447601

eMail: polek@coi.waw.pl