ESOPHAGEAL CANCER
Epidemiology
Overall, esophageal cancer contributes to 1% of all cancers diagnosed in the United States. Its prevalence in other geographical locations varies and higher incidences are seen in Asia, Africa, and Iran. However, the collective incidence continues to rise[1], and most of this increase is due to the increasing incidence of adenocarcinoma (AC). Today the incidence of SCC and AC are almost equal in the United States, where as of the 1960’s, 90% of esophageal cancers were squamous cell (SCC). With this shift in histological type, there is also a shift in demographics. Both AC and SCC are seen more commonly in men, but SCC has a high prevalence in urban populations and in African-Americans, while AC is predominately a disease in Caucasians. Despite the evolving epidemiology of esophageal cancer and the development of new treatments there has been little change in survival. The five year survival for both AC and SCC remains approximately 14%[2].
Risk factors
Due to the demographic variability and the recent rise in AC incidence, much emphasis has been placed on studying risk factors for esophageal cancer. Currently smoking is a known risk factor in both SCC and AC and alcohol consumption is primarily a risk factor for SCC[3-5]. Dietary factors that have been more closely associated with SCC include foods with N-nitroso compounds, betel nut chewing, and hot foods and beverages. The development of SCC is also seen in patients with achalasia of the esophagus, with Plummer-Vinson syndrome, and with the autosomal dominate disease, tylosis. AC, on the other hand, has been closely link with the severe gastroesophageal reflux disease and Barrett’s esophagus, the development of a columnar epithelium-lined esophagus[6-8]. Obesity, with a body mass index greater than 30, has also been shown to increase the risk of AC of the esophagus[9].
Clinical presentation
The most common complaints from patients with esophageal cancer are dysphagia and weight loss. Ninety percent of patients have difficulty swallowing solid food and subsequent changes in their diets lead to the loss of weight. Unfortunately the lumen obstruction that causes dysphagia is a sign of advanced disease. Patients with esophageal cancer often point to a specific trouble area in the neck or chest, unlike other dysphagia where there is generalized slowing of esophageal motility. Other less common symptoms include recurrent pneumonias secondary to aspiration, emesis of unprocessed food, hoarseness with recurrent laryngeal nerve invasion, or melena.
The physical exam unfortunately provides minimal additional information. Aside from weight loss, the physical findings are scarce except in metastatic disease where the liver may be enlarged or supraclavicular or cervical nodes may be palpable. Laboratory values may demonstrate a low hematocrit secondary to bleeding, and most patients have elevated blood urea nitrogen and serum creatinine levels because of dehydration. Markers of nutrition, namely albumin, may also be low. Liver function tests should also be evaluated for metastatic disease.
Diagnostic modalities
Prognosis and treatment planning for esophageal cancer are dependent on the ability to make a diagnosis and establish a clinical stage. A barium swallow study is often done and is an appropriate modality for patient screening, especially in male patients over 50 years of age complaining of dysphagia. It provides cancer suspicion and tumor localization for later endoscopy. Esophagoscopy, however, is necessary for making a diagnosis. It allows for direct visualization and evaluation of Barrett’s esophagus and tumors, and can provide a tissue diagnosis with a biopsy. Single biopsies of suspicious lesions in this setting are 93% accurate. The accuracy can improve to 100% with the addition of multiple biopsies (seven) and brushings[10]. An ultrasound probe combined with conventional endoscopy (endoscopic ultrasound) provides the most accurate estimate of disease stage by the tumor-node-metastasis criteria established by the American Joint Committee on Cancer. Ultrasound does so by evaluating the five layers of the esophageal wall with 85% accuracy and by detecting abnormal mediastinal lymph node metastasis with approximately 80% accuracy. EUS guided fine needle aspiration enhance this accuracy. EUS, however, is less accurate in accessing stage following the administration of preoperative chemoradiotherapy[11].
Metastatic disease is evaluated a number of ways. Computed tomography (CT) and positron emission tomography (PET) are both helpful in identifying distant metastasis. Bronchoscopy should also be performed in patients with upper and middle third tumors to exclude invasion into the trachea or bronchi. FNA of palpable supraclavicular or cervical nodes can provide additional valuable information about wide spread disease.
Surgical treatment
There are a number of different surgical approaches for treating early esophageal cancer. For the most part these procedures have similar perioperative mortality rates, approximately 4%[12,13]; however variations are seen in the types of complications that result from each given procedure. Choosing the best treatment strategy for an individual patient is therefore based on a number of different features of a specific lesion and on the preference and discretion of the surgeon. Important things to consider include the tumor location, the extent of lymphadenectomy necessary, and the use of neoadjuvant therapy. Resectable tumors of the middle and distal third of the esophagus are treated with a total esophagectomy. The two most common approaches are the transhiatal esophagectomy and the Ivor Lewis transthoracic esophagectomy. The primary differences between these approaches are the incision sites, the exposure provided by the incision, and the anastomotic site.
The transhiatal esophagectomy uses a midline laparotomy and a left neck incision. The laparotomy allows for blunt dissection of the thoracic esophagus and dissection and mobilization of the often conduit stomach. A cervical anastomosis is carried out through the left neck incision. The Ivor Lewis esophagectomy requires a midline laparotomy with a right thoracotomy. This allows for complete lymph node sampling under direct visualization and a high right sided intrathoracic anastomosis. A variation in this approach is a left thoracoabdominal incision (one incision), but some feel a high anastomosis in the left chest can present additional technical challenges. Another variation is a triincisional esophagectomy using a right posterolateral thoracotomy followed by a laparotomy and a left neck incision. Although the perioperative mortalities and the long term survivals are similar when comparing these different approaches, the anastomotic leak rate has been shown to be higher with the transhiatal approach, while respiratory and cardiovascular complications are more prevalent following the Ivor-Lewis approach[12-14]. However, cervical anastomoses provide a lower incidence of post-operative reflux, and anastomotic leaks are more easily controlled in the neck with lower associated mortalities.
The benefit provided from an extended, or three field, lymphadenectomy (mediastinal, abdominal, and cervical lymph nodes), through a transthoracic approach, remains controversial. A recently published prospective randomized trial from the Netherlands suggested a trend toward improved survival for 220 patients undergoing esophagectomies with extended lymphadenectomy for lower esophageal adenocarcinomas. Patients were randomly selected for either a transhiatal approach or a transthoracic approach with an extended lymphadenectomy. The overall 4.7 year survival rates were 29% and 39%, respectively[15], however, this was not a statistically significant difference. Currently in the United States this three field lymphadenectomy is not standard of care, although adequate lymph node sampling remains necessary for proper staging and prognosis.
Chemotherapy and radiation therapy
A survival advantage with chemoradiotherapy for esophageal cancer is still a matter of controversy. Currently neoadjuvant therapy seems to have a role in managing marginally resectable tumors and tumors with known lymph node involvement. Unpublished data from a trial in London, the MRC Adjuvant Gastric Infusional Chemotherapy Trial (MAGIC), presented at the American Society of Clinical Oncology this year, did show a statistically significant advantage in perioperative chemotherapy versus surgery alone in resectability, progression-free survival and overall survival for lower esophageal cancer[16]. Though this trial grouped esophageal and gastric Ge junction together, it is one of only a handful of studies to demonstate a significant survival advantage for neoadjuvant therapy, even though multiple trials have demonstrated the ability to downstage tumors and achieve a complete resection with clear margins. Though the evidence is sparse, neoadjuvant chemoradiation has become the norm for patients with T3 or N1 disease on pre-operative evaluation. Definitive chemoradiotherapy is used alone in patients with unresectable tumors and post-operative chemoradiotherapy has shown modest survival benefits in small retrospective trials only[17,18] and is not generally recommended.
GASTRIC CANCER
Epidemiology
Gastric cancer is one of the most common cancers worldwide. In the United States alone, 21 860 patients have been diagnosed with gastric cancer this year, and 11 550 are expected to die as a result of this diagnosis[2]. Interestingly, its prevalence varies significantly with geographic location and in Japan, Korea, and parts of South and Central America, gastric cancer is up to 10 times more common than in the United States. Males are affected more often than females, and African Americans, Hispanics and Native Americans more than Caucasians. As our understanding of gastric cancer evolves, the epidemiology of the disease does as well. Since the 1930’s there has been a 75% decrease in the overall incidence of gastric cancer in the United States[2], even without the implementation of routine screening modalities, like in Japan where the high incidence makes screening a cost effective modality. Simultaneous to the decreasing overall incidence is an increasing incidence of proximal gastric cancers and cancers of the gastroesophageal (GE) junction, escalating at a rate higher than that of nearly all other types of cancer. Proximal tumors are known to be more aggressive than distal tumors and have a worse prognosis for stage[20]. This shift to a more aggressive disease pattern and the inability to detect cancer at an early stage has limited our ability to make much progress in gastric cancer survival in the last 2 decades. The 5-year survival rate in the United States remains less than 30%[2].
The majority (95%) of gastric cancers are adenocarcinomas. Other tumors such as gastrointestinal stromal tumors, squamous cell carcinomas, gastric lymphoma, and carcinoid contribute to the other 5% of cancers. However the focus of this article will be on gastric adenocarcinomas.
Risk factors
Because of the geographic distribution and the recent shift in tumor anatomic location, much attention has been focused on determining risk factors associated with gastric cancer. Regional diets in particular have been under scrutiny to help shed light on causes of the disease. Studies comparing different foods have noted that western style breakfasts, diets high in antioxidants, and diets low in salt are shown to be inversely proportional to the incidence of gastric cancer[21]. With the discovery of the bacteria Helicobacter pylori’s (H pylori) role in ulcer disease, the role of H pylori in the development of gastric cancer has been examined as well. H pylori infection has now been show to increase the risk of body and antrum gastric cancers up to 6-fold[22,23]. In a prospective randomized control trial from China by Wong et al, there was a statistically significant decrease over 7.5 years in the incidence of gastric cancer in patients that received treatment for H pylori compared to those that did not receive treatment[24]. The same treatment, however, did not alter the incidence of gastric cancer in patients with premalignant lesions. There has also been an increase in the incidence of gastric cancer in patients with H pylori infection when the infection leads to gastric mucosal atrophy and pepsinogen 1 production compared to infected patients without this histological change[25].
A number of medical conditions have also been associated with gastric cancer development. The presence of adenomatous polyps increases the incidence of gastric cancers up to 20%, with greatest risk to patients with multiple polyps and polyps over 2 cm in diameter[26]. The same risk has not been seen in patients with hyperplastic polyps, which account for approximately 80% of diagnosed polyps. Chronic gastritis, pernicious anemia, intestinal metaplasia, acid hypersecretion conditions, Barrett’s esophagus, and previous gastric surgeries have also been shown to influence the incidence of gastric cancer. Genetic risk factors for gastric caner include patients with hereditary non-polyposis colon cancer and familial polyposis coli. Cigarette smoking has also been linked with gastric cancer[27].
Clinical presentation
The vague clinical presentation of gastric cancer is the leading reason patients do not get diagnosed until the disease has progressed. Symptoms are nonspecific and are often not present. The most common complaint is epigastric pain, seen in 70% of early gastric cancers[20]. The pain is characterized as constant, nonradiating, and relieved sometimes with food ingestion or antacids. Less than 50% of patients with early cancers will complain of weight loss as a result of dietary changes secondary to the other symptoms. Other less common complaints include dysphagia, in patients with proximal cancers, and nausea and vomiting from gastric outlet obstruction in patients with distal tumors, anorexia, and melena.
The physical exam, unfortunately provides minimal additional information in early disease. Advanced disease may reveal a palpable epigastric mass, an enlarged liver, ascites, a periumbilical nodule or Sister Mary Joseph’s node, left supraclavicular adenopathy or Virchow’s node. An ovarian enlargement on pelvic exam (Krunkenberg tumor), or mass in the cul-de-sac on rectal exam (Blumer’s shelf) may also be present. Elevation of serum alkaline phosphatase and anemia can be seen on laboratory values, but are not specific. Tumor markers are not yet a routinely used. Guaiac positive stools are seen in one third of patients.
Diagnostic modalities
A clear method for diagnosing and screening gastric cancer is important since its presentation often mimics other disease processes and there is a small window of time where the disease is potentially curable. Each different modality has its own strengths and weakness in diagnosing and staging the disease in order to plan the appropriate treatment. Although invasive and costly, endoscopy is currently the most specific and sensitive method for obtaining a definitive diagnosis besides laparotomy, and has replaced barium contrast radiographs due to its ability to biopsy. It allows for direct visualization of lesions and the opportunity to obtain tissue samples. Endoscopy with seven biopsies of the margin and base of gastric ulcers has a sensitivity of 98% for diagnosing gastric cancers of all stages[10], compared to barium studies with a sensitivity of only 14% in early gastric cancers[28]. Barium continues to have a major role in diagnosing of linitis plastica, a diffuse type gastric cancer which is difficult to appreciate with endoscopy. Brush biopsies are performed in areas at risk of bleeding.
Staging for gastric cancer is based on the evaluation of the tumor (T), regional lymph nodes (N), and metastasis (M), as outlined by the American Joint Committee on Cancer system, and is essential for treatment planning and prognosis. Computed tomography (CT) is heavily relied on as a non-invasive test gathering information regarding metastasis and is performed routinely in patients diagnosed with gastric cancer. Although CT often underestimates nodal involvement and overestimates the depth of invasion, it is useful in assessing for liver metastases and distant spread. Endoscopic ultrasound, on the other hand, is more useful in evaluating the depth of tumor invasion (77% accurate) and regional lymph nodes (69% accurate)[29], but has no role in distant metastatic evaluation. Laparoscopy is the most invasive form of staging, but also 23% more accurate than CT scan in diagnosing peritoneal metastasis, which then precludes curative resection[30]. It is therefore reserved for patients with good performance status and those in which accurate staging is necessary for further treatment planning. New data also suggests that positive cytological washings at the time of laparoscopy are the most predictive preoperative factor of death from gastric cancer[31].
Surgical treatment
Complete surgical resection of gastric cancer provides the only chance for a cure. To obtain this goal, a 6 cm surgical margin with pathologic margins free from microscopic invasion should be attempted in order to offer the lowest possible rate for local recurrence. The type of gastrectomy performed to achieve this goal, however, has changed over time and still remains controversial. It was once thought that a total gastrectomy, with resection of splenic and celiac lymph nodes, splenectomy, and distal pancreatectomy was necessary for all gastric adenocarcinomas. The high morbidity of this operation, without a survival advantage over total gastrectomies with varying levels of lymph node dissections and partial gastrectomies, has led to a change from this practice. By evaluating a number of factors, including the tumor location, stage, and histological type, variation in surgical plans have been entertained and put into practice.
In proximal adenocarcinomas of the stomach, total gastrectomy or esophagogastrectomy remains the operation of choice for most surgeons. When compared to a proximal subtotal gastrectomy, a Roux-en-Y reconstruction has a lower incidence of reflux esophagitis[32]. In addition, the most common site of nodal metastasis for proximal tumors is on the lesser curvature. These nodes may be left behind in a proximal subtotal gastrectomy. However, a proximal gastrectomy, with an adequate node dissection, has an equivalent survival to total gastrectomy, and is still advocated by some surgeons. For distal tumors a subtotal gastrectomy is the procedure of choice. It has been shown that there is no added survival benefit for patients with distal tumors undergoing total gastrectomy and the operative morbidity and mortality is greater for patients who undergo total gastrectomy[33]. In addition, other studies have demonstrated that the quality of life is better for patients following subtotal gastrectomy compared to total gastrectomy[34,35].
Similar to esophageal cancer, the extent of lymph node dissection for curative surgery in gastric cancer remains controversial as well. Retrospective data from Japan has shown a survival benefit for patients with extensive lymph node dissection in stage II or stage III disease. The number of positive lymph nodes also predicts and influences survival when at least 15 lymph nodes, regardless of their position, are surgically biopsied[36,37]. However, extended lymph node dissections in the United States have been linked with increased operative mortality. Therefore numerous studies have looked specifically at this concept; the best way to limit operative mortality without leaving microscopic disease. The draining lymph nodes of the stomach are categorized into 16 stations. These stations are group into clusters referred to as D1, D2, and D3. D1 includes perigastric lymph nodes, D2 includes nodes along the hepatic, left gastric, celiac, and splenic arteries, and the splenic hilum, and D3 includes nodes within the porta hepatic and periaortic region. In the last 20 years, at least five prospective randomized trials have not show a statistically significant survival advantage of a D2 versus D1 lymphadenectomy or a D3 versus D2 lymphadenectomy, including trials from the Medical Research Council[38], the Dutch Gastric Cancer Group[39,40], and the Japan Clinical Oncology Group Study[41] in which 400, 711, and 523 patients were enrolled respectively. Criticism of these studies revolve around the inability of small sample sizes to adequately predict changes in the survival of patients with N2 disease since N2 patients only make up 30% of all the patients studied and only one-forth of these patients are predicted to survive following D2 dissections[42]. In addition, it was shown that surgeons varied in their compliance to dissection guidelines. Recent studies from the United States have demonstrated that in selected high volume centers operative mortality following D2 gastrectomies is no greater than that associated with the D1 resection[43]. Therefore, D2 resections have still been recommended by surgeons in the US who can perform the operation with low mortality. At minimum, a total of 15 lymph nodes must be removed at the time of gastrectomy to adequately stage patients[36] and this requirement has been adopted in the most recent AJCC staging handbook.
The role of laparoscopic surgery for gastric carcinoma is still in evolution. Currently there are a number of centers that successfully perform laparoscopic-assisted distal gastrectomies (LADG) and total gastrectomies, as well as hand-assisted gastrectomies with D1 lymph node dissections for early gastric cancer treatment. Even more recently laparoscopic techniques have expanded to include treatment of cancers infiltrating deep submucosal layers and treatment of advanced tumors with no known lymph node metastasis with LADG and D2 lymph node dissections[44]. Although in general the operative time for laparoscopic procedures exceeds open procedures, outcomes of the laparoscopic approach suggest a decrease in postoperative pain and operative blood loss, shorter hospital stays, earlier return of bowel function, and fewer cardiac and respiratory complications[44,45]. Authors have not reported a statistically significant difference in the number of nodes dissected or in the adequacy of surgical margins when compared to open procedures. However these studies are limited by a low number of patients enrolled and a lack of long term follow-up regarding patient survival and the recurrence rates of cancer.
Chemotherapy and radiation therapy
Complete surgical resection remains the only chance for cure in patients with gastric cancer, but approximately 80% of patients with adequate negative margins still have recurrences and most patients ultimately die from their disease[46]. Therefore there has been a strong push toward developing effective chemotherapy and radiation regimens to be used with surgical management and many trials have been attempted or are underway. The results from these treatment modalities to date have been modest with little or no effect on overall survival. However in 2001, Macdonald et al looked at the survival benefits of chemoradiotherapy in 556 patients following curative gastric resections[47]. Results showed a 36 mo median overall survival with postoperative chemoradiotherapy compared to a 27 mo median overall survival with surgery alone. This data has established the current standard of care for patients in the United States who have undergone potentially curative gastric resections[47]. The regimen includes a combination of 5-fluorouacil (5-FU) (425 mg/m2 of body-surface area per day) and leucovorin (20 mg/m2 per day) for five days, followed one month later with radiation (1.8 Gy/d and 45 Gy total) and modified doses of 5-FU and leucovorin, followed by 2 more 5 d cycles of 5-FU and leucovorin one month later. New data presented from the MAGIC trial in London also demonstrated a significant improvement in resectability, progression-free and overall survival in patients with gastric and gastroesophageal junction tumors given perioperative chemotherapy compared to surgery alone[16]. Other treatment options for unresectable tumors and for patients with distant metastasis are still being investigated in a number of ongoing clinical trials.
In summary, the epidemiology of both esophageal and gastric cancer has changed in the last few decades. Both the surgical management and chemoradiotherapy has evolved as well. Even with our advances in understanding these disease processes and with our improvement in treatment strategies, the overall 5 year survival rate remains exceedingly low and most patients die from their disease. This emphasizes the importance of continued research efforts into both esophageal and gastric cancer in order to continue to improve on what is known.
