The stomach is host to a variety of benign and malignant conditions that may present acutely, as in the case of a bleeding or a perforated peptic ulcer, or indolently, as is often the case with gastric cancer.
Peptic ulcer disease is among the most common benign conditions, and its natural course has evolved significantly over the years. While antrectomies, vagotomies, and other acid-reducing procedures were common several decades ago, the introduction of acid-suppressing medications and the discovery (and eradication) of Helicobacter pylori have virtually eliminated such operations.1,2,3,4 Nonetheless, gastric and duodenal perforations due to complicated peptic ulcer disease remain a frequent cause for presentation to the emergency room and account for nearly 10% of hospital admissions related to peptic ulcer disease.1 As critical care and supportive treatments have improved, nonoperative approaches can be considered in subsets of patients with high operative risk due to medical comorbidities, or whose perforations appear to be self-contained.5 Similarly, the availability of acid-suppressing medications and therapies eradicating H. pylori have made less radical and less invasive surgical approaches, such as laparoscopic primary and/or omental patch repair, more common.
Acute upper GI hemorrhage is the most common presentation of peptic ulcer disease, although it may represent other etiologies, including Mallory–Weiss tears or varices. A certain proportion of patients will have self-limited episodes of bleeding, but ongoing bleeding requires upper GI endoscopy. There are a number of advanced endoscopic techniques to stop active bleeding, including cauterization, injection sclerotherapy with epinephrine, and clip application.6 As these techniques have evolved, so has the debate as to which endoscopic therapies are most effective, which we will examine in the chapter that follows. Surgical intervention is now reserved for the rare circumstances in which the patient is in shock or in which endoscopic therapies have failed.
Esophageal and gastric varices are a manifestation of an underlying disease process, most commonly cirrhosis. Spontaneous bleeding occurs at a rate of 5–15% per year,7 and studies have shown that variceal size and degree of decompensated cirrhosis (as graded by Child’s score) are strong predictors of bleeding.8 Gastric varices are associated with higher rates of bleeding and are commonly due to splenic vein thrombosis.7 Endoscopy is recommended for screening and monitoring of patients who are likely to develop bleeding varices,7 and endoscopic ligation can be undertaken to either eradicate them or, at a minimum, to reduce their bleeding risk. Prophylactic treatment is often considered for those patients at the highest risk of bleeding.
Gastric adenocarcinoma is the most common malignancy of the stomach, and without endoscopic screening most patients in Western countries present with advanced disease. As a result, the average 5-year survival rate for patients undergoing surgery is less than 30%.9 Comparatively, the incidence of gastric cancer is much higher in the East,10 and routine endoscopic screening programs result in a much higher proportion of gastric cancers diagnosed at an early, curable stage.11 Much of the evolution in the treatment of gastric cancer in the West has come about in the last 15–20 years, with a number of pioneering trials demonstrating improved survival rates with the use of multimodality therapy for adenocarcinomas of the distal esophagus, gastroesophageal (GE) junction, and stomach. Furthermore, there has been a great deal of debate about the optimal surgical management of gastric cancer, including the appropriate extent of gastric resection (subtotal vs. total gastrectomy) and of regional lymph node dissection (D1 vs. D2 lymphadenectomy). We will review several of these important trials in this chapter.
As the practice of surgery has become more focused on minimally invasive techniques, surgery on the stomach has followed the same trend. Laparoscopic and endoscopic procedures are becoming more common, although open surgery continues to be the predominant mode for oncologic resections. As this balance changes, the debate regarding adequate lymph node dissection will undoubtedly be a key point of consideration. Underlying these issues are differences in the approach to gastric cancer and treatment outcomes between Eastern and Western centers, led by the possibility that the etiology of gastric cancer, and even the underlying biology of the disease, may be different between East and West. The extent of these differences and their clinical implications have yet to be effectively demonstrated and remain an area in need of further investigation.
Extended lymph-node dissection for gastric cancer.
Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ, Welvaart K, Songun I, Meyer S, Plukker JT, Van Elk P, Obertop H, Gouma DJ, van Lanschot JJ, Taat CW, de Graaf PW, von Meyenfeldt MF, Tilanus H, Dutch Gastric Cancer Group
NEJM. 1999;340(12):908–914.Takeaway Point: Extended D2 lymph node dissection for gastric cancer results in higher morbidity and mortality and does not result in improved survival or locoregional tumor control when compared with D1 dissection.
Commentary: Eastern centers with high volumes of gastric cancer have long emphasized extensive lymph node dissections for adequate disease staging and improved locoregional tumor control. However, Western centers have not been able to replicate the same advantages with an extensive lymph node dissection. This multicenter trial was among the first large-scale efforts to investigate the use of D2 lymph node dissection in a Western population, and this publication serves as a report of long-term survival data at 5 years. Initial data from the Dutch study, published in 1995, demonstrated higher complication and mortality rates among the D2 group, despite active observation by master surgeons.12 Patients underwent splenectomy and distal pancreatectomy as a routine part of their resection, and this was postulated to be the major cause of the increased morbidity of the procedure. The group concluded that splenectomy should not be an essential part of the procedure, and they could not recommend a D2 lymph node dissection as a routine procedure during the resection of gastric cancer. The MRC and Italian trials (see b and m, below) did not necessitate resection of the spleen and distal pancreas in their protocols. While some patients in the MRC trial did undergo this more aggressive resection, allowing for subset comparison, the Italian trial carried out only pancreas-preserving resections. These three trials represent a progressive tailoring of the D2 dissection technique for safe application among Western populations.
Introduction: D2 lymph node dissection has been performed with very low morbidity and has been shown to improve disease staging and lead to better locoregional tumor control in patients with gastric cancer in the East. However, the safety and the potential benefit of D2 lymph node dissection have not been demonstrated in a Western population.
Objectives: To examine the safety and long-term outcomes of D1 versus D2 lymph node dissection in patients undergoing surgery for gastric cancer.
Trial Design: Multicenter randomized controlled trial.
Inclusion Criteria: Age <85 years with histologically proven gastric cancer and no evidence of metastatic disease.
Exclusion Criteria: Prior gastric resection, other malignant disease.
Intervention: Resection with D1 lymph node dissection or D2 lymph node dissection, including splenectomy and distal pancreatectomy.
Primary Endpoint: Survival.
Secondary Endpoint: Risk of relapse.
Sample Size: 996 patients enrolled from August 1989 to July 1993 from 80 Dutch hospitals, with 380 in the D1 group and 331 in the D2 group.
Statistical Analysis: Kaplan–Meier survival curves with log-rank testing.
Baseline Data: Median age 66 years; 57% male. No difference in T stage, extent of resection, rate of R0 resection, or lymph node involvement between the groups. Median follow-up time was 72 months.
Outcomes: In-hospital mortality occurred in 47 patients overall (7%). There was an overall complication rate of 25% with D1 dissection and 43% with D2 dissection (p <0.001), with in-hospital mortality at 4% and 10% for D1 and D2 groups, respectively (p 0.004). There was no difference in 5-year survival (45% and 47% for D1 and D2 dissections, HR = 1.0). Recurrence occurred in 43% versus 37% of the patients in the D1 and D2 groups, respectively (HR 0.84).
Conclusion: The group could not recommend D2 dissection because of the higher morbidity and mortality of the procedure and no significant advantage in 5-year survival or locoregional control.
Limitations: Despite direct observation, there was a high noncompliance rate, resulting in inadequate dissection among 36% of the D1 group and 51% of the patients in the D2 group. The authors suggested that this rate was inflated as a result of poor separation of lymph nodes from the specimen, but it nevertheless remains quite significant.
Patient survival after D1 and D2 resections for gastric cancer: Long-term results of the MRC randomized surgical trial.
Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V, Sydes M, Fayers P, Surgical Co-operative Group
Br J Cancer. 1999;79(9–10):1522–1530.Takeaway Point: Extended D2 lymph node dissection does not provide improved survival among patients with gastric cancer and is highly morbid, due to pancreaticosplenic resection.
Commentary: This article was the culmination of long-term data from the Medical Research Council (MRC) trial, an early prospective study to look at the effects of D2 resection on outcomes for gastric cancer in Western centers, and an attempt to replicate its advantages as espoused by Eastern centers. Although they could not show any survival difference, the authors postulated that much of the early mortality in the D2 group may have been due to resection of the pancreas and spleen, once considered essential to achieve adequate lymph node clearance but no longer mandated according to the Japanese Gastric Cancer Association. Although a subset analysis of patients who did not undergo pancreaticosplenectomy showed improved survival among the D2 group, this could not be definitively attributed to the dissection. The authors recommend against removal of the spleen or pancreas unless tumor involvement necessitated it, thereby limiting the mortality of these resections. This conclusion, along with results from the Dutch trial (see a, above) set the stage for the newer Italian trial discussed next. Presenting the case that the increased morbidity of the D2 dissection may be countered by elimination of the pancreaticosplenectomy portion of the procedure, this trial also left open the possibility of improved survival among this subset.
Introduction: While an extended D2 lymph node dissection is the standard of care for gastric cancer in Eastern centers, early use by Western surgeons was associated with higher in-hospital morbidity and mortality, particularly related to the splenectomy and distal pancreatectomy.
Objectives: To examine the long-term outcomes of D1 versus D2 lymph node dissection for gastric cancer.
Trial Design: Multicenter randomized controlled trial.
Inclusion Criteria: Histologically proven gastric cancer, TNM stage I–III.
Exclusion Criteria: Age <20 years, prior gastric resection, other malignancy, comorbidity that would preclude D2 dissection.
Intervention: Randomization to D1 or D2 dissection that included pancreaticosplenectomy in patients without antral tumors.
Primary Endpoint: Overall survival.
Secondary Endpoints: Recurrence-free survival.
Sample Size: 400 patients from 80 centers primarily in the United Kingdom, enrolled between August 1989 and July 1993, were randomized into equal groups of 200 to undergo D1 or D2 dissection.
Statistical Analysis: Survival was calculated using Kaplan–Meier curves with log-rank testing and Cox proportional-hazards models, intention-to-treat analysis.
Baseline Data: The cohort was 67% male, with 75% over the age of 60 and 40% over age 70.
Outcomes: Overall survival by intention to treat was equivalent in the two groups, at 35% and 33% for D1 and D2 groups, respectively (p 0.63). Recurrence-free survival was not significantly different. The spleen and pancreas were both resected in 56% of the D2 group and only 4% of the D1 group. Although significantly more lymph nodes were sampled in the D2 arm (median of 17 compared to 13 in the D1 arm), only 46 patients met the strict criteria of more than 26 lymph nodes considered adequate by the Japanese definition. When looking only at patients without pancreaticosplenectomy, those in the D2 arm had an improved survival compared to the D1 group, but they also had a higher proportion of antral tumors. In subgroup analyses, the D2 group with pancreaticosplenectomy had the poorest survival, and the D2 group with preservation of the pancreas and spleen had the best overall survival.
Conclusion: There is no long-term survival difference between patients undergoing D1 and D2 lymph node dissection. Pancreaticosplenic resection drastically increases mortality and may obscure any survival advantage of the D2 dissection, and should therefore not be a part of the resection unless these organs are directly involved by tumor.
Limitations: Although it was clear that pancreaticosplenectomy caused higher mortality rates, improved survival for D2 dissection without it could be proved only on subset analysis. Multivariate analysis controlled for a number of confounding factors, but it is unclear whether the subgroup analysis was adequately powered. The majority of patients in the D2 group fell short of the strict definition by both lymph node group and number.
Subtotal versus total gastrectomy for gastric cancer: Five-year survival rates in a multicenter randomized Italian trial.
Bozzetti F, Marubini E, Bonfanti G, Miceli R, Piano C, Gennari L, Italian Gastrointestinal Tumor Study Group
Ann Surg. 1999;230(2):170–178.Takeaway Point: Subtotal gastrectomy does not show a decreased survival when compared to total gastrectomy and should be the preferred resection in patients with distal tumors where adequate margins can be obtained.
Commentary: While subtotal gastrectomy (SG) and total gastrectomy (TG) were both in use for resection of antral gastric tumors, there was a concern among proponents of TG that a subtotal resection resulted in poorer long-term outcomes. This trial provides evidence of equal survival between the two techniques and put forth the argument for preferentially performing SG in order to decrease rates of postoperative complications as well as long-term nutritional difficulties.
Introduction: Distal gastric tumors of the body and antrum have been cured with subtotal gastric resection or total gastrectomy. Total gastrectomy (TG) has a higher potential for complications and long-term nutritional difficulties among patients. There is concern, however, that subtotal gastrectomy (SG) may yield poorer long-term disease control.
Objectives: To examine survival outcomes with subtotal versus total gastrectomy for gastric cancer.
Trial Design: Multicenter randomized controlled trial.
Inclusion Criteria: Age >75 years with cancer of the distal stomach.
Exclusion Criteria: Previous gastric resection, other malignancy, previous chemotherapy, metastatic disease.
Intervention: Randomized to SG or TG.
Primary Endpoint: Mortality.
Secondary Endpoint: None.
Sample Size: 618 patients from 28 Italian centers between April 1982 and December 1993. The SG group contained 315 patients, and the TG group contained 303 patients.
Statistical Analysis: Kaplan–Meier survival with Cox proportional-hazards regression modeling.
Baseline Data: The cohort was 58% male, 86% between stages T1b and T3, and 22% with tumors larger than 5 cm. Extension of resection to other structures outside of the stomach occurred in 18%. Splenectomy was performed significantly more often in the TG group (18% vs. 5%), but there were no other differences between the two groups.
Outcomes: Overall survival for patients undergoing SG was 36%, compared to 39% for those undergoing TG. The adjusted hazard ratio for survival was 1.01 between the groups. When analyzing for other prognostic factors, patients with tumors isolated to the antrum had worse prognosis than did those in the body of the stomach. As expected, other factors that decreased survival included T3 or T4 disease and involvement of the spleen or other extragastric structures.
Conclusion: Subtotal gastrectomy has long-term survival outcomes similar to those of total gastrectomy and should be considered in all patients with anatomically eligible tumors.
Limitations: Although the authors suggested decreased operative and long-term complications with subtotal gastrectomy as compared to total gastrectomy, they did not seek to analyze these factors in this study. The total gastrectomy group had significantly more patients undergoing splenectomy.
Eradication of Helicobacter pylori prevents recurrence of ulcer after simple closure of duodenal ulcer perforation: Randomized controlled trial.
Ng EK, Lam YH, Sung JJ, Yung MY, To KF, Chan AC, Lee DW, Law BK, Lau JY, Ling TK, Lau WY, Chung SC
Ann Surg. 2000;231(2):153–158.Takeaway Point: H. pylori eradication results in lower peptic ulcer recurrence rates among high-risk patients.
Commentary: This single-center study examined H. pylori as a risk factor for peptic ulcer recurrence in patients who previously presented with an episode of perforation and documented H. pylori infection. A simple patch repair, as is commonly performed for perforated peptic ulcer, carries a high risk of recurrent symptomatic disease. Participants in this trial were randomized to either a proton pump inhibitor (PPI) alone or H. pylori eradication therapy along with a PPI. Although both groups were documented as having experienced complete healing of their initial ulceration, those with eradication of their infection had a much lower rate of ulcer recurrence at one-year follow up. This article forms part of the literature that supports symptomatic peptic ulcer disease as an indication for treatment of H. pylori infection with antibiotic eradication therapy.13,14
Introduction: Uncomplicated peptic ulcer disease is treated with H. pylori eradication; however, perforated duodenal ulcers represent advanced disease with a high risk of ulcer relapse. It is unclear whether eradication of the bacteria prevents the need for additional acid suppression surgery.
Objectives: To determine whether eradication of H. pylori could lead to sustained ulcer remission in patients who underwent only simple repair for duodenal ulcer perforation.
Trial Design: Randomized controlled trial.
Inclusion Criteria: Patients with perforated duodenal ulcers requiring emergent omental patch repair who were proven to have H. pylori by positive biopsy culture or positive rapid urease test along with identification of helical organisms by Gram stain or histology.
Exclusion Criteria: Age <16 or >75 years, previous gastrectomy or vagotomy, pregnancy, use of antibiotics or acid suppressants within 4 weeks, actively undergoing treatment for another illness, or perforation larger than 1 cm not amenable to patch repair.
Intervention: Treatment with H. pylori eradication therapy (bismuth, tetracycline, metronidazole, and omeprazole) compared to treatment with just omeprazole.
Primary Endpoint: Healing of ulceration.
Secondary Endpoints: H. pylori eradication, recurrent ulceration.
Sample Size: 99 patients from a single center between September 1994 and January 1997, with 51 randomized to eradication therapy and 48 to omeprazole alone.
Statistical Analysis: χ2 test and Student’s t-test.
Baseline Data: Mean age among patients was 44 years, and 85% were male. Of the cohort, 20% underwent laparoscopic repair of their perforation. Baseline characteristics were similar between the two groups.
Outcomes: There was an initial dropout of 9 patients from both groups, leaving 44 patients in the treatment arm and 46 in the control arm. At initial follow-up endoscopy, 8 weeks from initiation of therapy, H. pylori had been eradicated in 84% of the treatment group and 17% of the control group. Ulcers had completely healed in 82% and 88% of patients in the therapy and control groups, respectively (p 0.58). The remaining patients’ ulcers did not heal despite continued omeprazole therapy, so they were deemed as having failed treatment and were excluded from further analysis. Among the 78 patients that followed up at 1 year, 18 had ulcer recurrence, 5% in the treatment group, and 38% in the omeprazole-only control group (p <0.01). On testing, patients were found to be H. pylori–positive in 1 of 2 recurrences in the treatment arm and 14 of 16 in the control arm.
Conclusion: There was no difference in the rates of ulcer healing between those receiving treatment for H. pylori and those receiving only omeprazole. Treatment for H. pylori decreased the recurrence of both occult and symptomatic peptic ulcer disease compared with omeprazole alone.
Limitations: Cross contamination of groups, with patients in the control group receiving antibiotic courses for other indications in the postoperative period that may have treated their H. pylori. Further, the treatment group did not all achieve eradication of their organism. The follow-up period of 1 year is relatively short for this disease process.
Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction.
Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA
NEJM. 2001;345(10):725–730.Takeaway Point: Postoperative chemoradiation after R0 resection for gastric cancer improves survival and reduces disease recurrence.
Commentary: This trial by the Southwest Oncology Group (SWOG) sought to establish a precedent for adjuvant therapy in the treatment of gastric cancer in order to improve on the high recurrence rates after surgical resection. The group compared patients who received only surgery (the standard of care at the time) with those undergoing postoperative chemoradiation therapy and found a survival advantage of 9 months and an increased recurrence-free survival of 17% with adjuvant therapy. This trial definitively established a role for adjuvant therapy in gastric cancer and resulted in a new standard of care, and it paved the way for further investigation into the routine use of chemotherapy and radiotherapy for this disease, including the MAGIC and CROSS trials discussed later in this chapter (see j and k below).
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