Esophageal Adenocarcinoma

Adenocarcinoma of the esophagus will affect approximately 12,000 Americans per year.

Over the last 30 years has increased over 350%.

Predominant type of esophageal cancer in North America and Europe.

Incidence of esophageal adenocarcinoma has increased by a factor of six in the United States between 1975 and 2001.

Rising incidence and now makes up more than 50% of cases of esophageal carcinoma.

In 2007 adenocarcinomas accounted for 58% of wall esophageal cancers.

Increasing incidence contrasts with the stable or declining incidence of esophageal squamous cell carcinoma.

Annual incidence increased 2-17%, predominantly among men in the western world.

Diagnosed predominantly in white men, in whom the incidence has risen steeply.

More prevalent than squamous cell lesions of the esophagus in the U.S. and western Europe.

More common in Caucasians.

Six to eight times more common in men than women.

Incidence increases with age.

Strong male predominance, approaching greater than 77%.

Among the US males has the highest death rate among malignancies with increased mortality trends from 1990-2006 and is the fifth leading cause of cancer death in ages 40-79 years(Jemal A et al).

Caucasians affected 3-4 times greater than African-Americans.

Annual increased rate in white men of 4-10% since the 1970’s.

Adenocarcinoma of the esophagus incidence been rising at a more rapid rate than that of any other malignancy.

Adenocarcinoma of the esophagus incidence now 3 cases per 100,000 per year and for Caucasian males 5.9 cases per 100,000 per year.

Cases among African American women have decreased somewhat.

When newly diagnosed nearly 50% of patients have either metastatic or unresectable carcinoma.

Localized cancer amenable to local regional treatment in about 50% of patients for potential curative management.

5-year survival 13% for adenocarcinoma of the esophagus.

5-year survival for patients after curative resection is 20%.

With optimal local regional treatment of localized esophageal cancer only 17% this up on 5 years, 37% with localized disease, 19% and regional nodal involvement 3% with distant metastases (Brown L et al).

GERD and Barrett’s esophagus are the most important risk factors.

Esophageal adenocarcinoma odds of developing are increased by a factor of five for individuals with weekly GERD symptoms and by a factor of seven for persons with daily GERD symptoms, as compared with those with less frequent episodes.

Barrett’s esophagus is the only recognized pathologic precursor of esophageal adenocarcinoma.

Absolute risk of esophageal adenocarcinoma developing in a person 50 years old or older with GERD IS approximately .04% per year.

95% of patients with newly diagnosed adenocarcinoma of the esophagus do not have a previous diagnosis of Barrett’s esophagus.

Surveillance of Barrett’s esophagus only detects about 5% of esophageal adenocarcinomas.

Associated with high body mass, central obesity, smoking and diet.

Obesity contributes to the development of gastroesophageal reflux disease, a major underlying cause of esophageal adenocarcinoma.

GERD is associated with the development Barrett esophagus.

Patients with Barrett esophagus have a 30 to 60 times greater risk of developing adenocarcinoma of the esophagus than the general population.

Older age, male gender, long-standing GERD, hiatal hernia size, and the length of Barrett esophagus are strongly associated with higher grades of dysplasia, and an increased risk of esophageal adenocarcinoma.

Estimated up to 15% of patients may have a genetic predisposition and genes involved may affect macrophage function and inflammatory pathways (Orloff M et al).

Increased abdominal visceral fat is a risk factor for esophageal adenocarcinoma.

Elevated intra-abdominal pressure in obese patients may increase gastroesophageal reflux by disrupting the GE junction and lead to esophageal injury and development of Barrett’s esophagus, the precursor lesion for esophageal adenocarcinoma.

Abdominal adipose tissue is a metabolically active site, secreting inflammatory mediators, cytokines, insulin like growth factors and can cause a systemic inflammatory process and an insulin resistant state that is a fertile environment for carcinogenesis.

The risk of adenocarcinoma of the esophagus in patients with Barrett’s esophagus is approximately 0.4% per year (Murray L et al).

Almost half of the patients with adenocarcinoma of the esophagus have no previous symptoms of heartburn (Lagergen J).

GERD related inflammation and transforming growth factor beta (TGFB) pathway has been implicated in Barrett’s esophagus and esophageal adenocarcinoma.

Endoscopic screening of the esophagus does not result in a reduction of deaths from adenocarcinoma of the esophagus.

Not all cancers arise from preclinical Barrett’s esophagus.

Smoking and alcohol intake are moderate risk factors, and risk remains unchanged with smoking cessation.

In a large study of esophageal or gastric cardia adenocarcinomas 77% of patients had no findings of Barrett’s esophagus on the pathology specimen, and of patients with upper endoscopy more than 6 months before diagnosis only 38% had Barrett’s identified, indicating that fewer patients with esophageal adenocarcinoma have Barrett’s than previously thought.

Obesity among never smokers is independently associated with twofold worsening of disease specific survival, disease free survival, and overall survival after surgery for esophageal adenocarcinoma.

Curative resection with removal of the primary carcinoma and regional lymph nodes (RO resection) is possible in only 60%.

Treatment options for patients with local regional disease, stages I_III are perioperative chemotherapy, definitive chemoradiation, preoperative chemoradiation followed by esophagectomy and esophagectomy.

Perioperative chemotherapy with etoposide, cisplatin and 5-FU had a 36% 5 year survival rate compared to esophagectomy alone (Cunningham D et al).

Chemoradiation data is limited compared to data for squamous cell carcinoma of the esophagus, but chemotherapy with 5-FU and cisplatin and radiation had a greater than median survival compared with radiation alone (Herskovic A et al).

Conflicting results exists for the benefits of neoadjuvant chemoradiation in locally advanced esophageal cancer.

Up to 30% of patients with RO resection will have local recurrences.

If diagnosed after symptoms have developed <10% of patients survive > 5 years.

For patients with metastatic esophageal adenocarcinoma metastatic, the five-year survival is less than 3%.

The number of positive lymph nodes, the location of such lymph nodes and extracapsular involvement of the lymph nodes influences the survival of patients who undergo surgery without neoadjuvant chemoradiation therapy.

Preoperative chemoradiation provides a complete response rate of approximately 25-30% of patients with advanced disease.

Preoperative radiotherapy associated with a better 5 year overall survival than those who received postoperative RT, 33% vs 23% (Wojcieszynski A et al).

In the above study overall survival at 10 years favored preoperative RT 22% vs. 15%.

Patients with a single metastatic lymph node have a better prognosis than patients with multiple positive lymph nodes with a prognosis is similar to patients with negative lymph nodes.

Patients with T1 N0 esophageal cancer can be treated with surgery alone, while patients with T2 N1 disease should be treated with combined modality therapy.

Neoadjuvant chemoradiation downstages patients in a number of studies.

A direct correlation exists between the depth of tumor invasion and the presence of lymph nodes metastases.

About 80% of patients with T3 tumors will have positive lymph node involvement.

Ramucirumab an agent indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after fluoropyrimidine or platinum containing chemotherapy.

Ramucirumab is an anti-angiogenic therapy under the trade name Cyramza.

Ramucirumab overall survival as a single agent in patients who have failed previous chemotherapy is 5.2 months compared to placebo of 3.8 months, a 37% % increase in median overall survival.

The addition of immunotherapy to chemotherapy his lead to a statistical significance in clinical the meaning for improvement in antitumor activity in patients with advanced local or metastatic esophageal or gastroesophageal junction carcinoma.

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