Esophageal Cancer Updates

Epidemiology EAC vs SCC Esophageal adenocarcinoma (EAC) has become the predominant type of esophageal cancer in the US GERD and obesity are the main risk factors Barrett’s esophagus (BE) is the precursor lesion Esophageal squamous-cell carcinoma (SCC) remains the predominant esophageal cancer in Asia, Africa, and South America and among African Americans in the US. Alcohol and tobacco use are the main risk factors Squamous dysplasia is the precursor lesion

Epidemiology EAC vs SCC Gender differences Adenocarcinoma M:F = 3-4:1 Squamous cell carcinoma M:F = 1:1 Alcohol Not a definite risk factor EAC SCC is 3-5X more among people who consume alcohol (three or more drinks daily) risk increases synergistically with tobacco smoking High intake red meats, fats, and processed foods is associated with an increased risk of EAC and SCC High intake of fiber, fresh fruit, and vegetables is associated with a lower risk Obesity increases risk of EAC approximately 2.5 X

Increasing Incidence

BE and EAC Risk Non dysplastic - 0.12-0.4 % annual risk Low grade dysplasia – 1% High grade dysplasia – 5% 80 - 90% of cases of EAC are diagnosed in patients without known h/o Barrett’s esophagus Obesity increases risk approximately 2.5 X Barrett’s (non dysplastic) annual risk is 0.12-0.4 %

Squamous dysplasia and SCC Risk of SCC Mild dysplasia – 3X increase Moderate dyplasia – 10X increase Severe dysplasia – 30X increase

BE Screening Endoscopic screening BE is detected in 6-12% of patients with prolonged GERD symptoms most frequently white men >50 yo Endoscopic surveillance every 3 years is recommended for patients non-dysplastic BE No direct evidence from randomized trials Observational studies - compared to symptomatic patients, those with EAC detected during endoscopic surveillance for BE are more likely to: have early-stage cancer receive curative therapy survive longer

BE Therapy Radiofrequency ablation (RFA) of Barrett’s esophagus lesions with low-grade or high-grade dysplasia resolution of metaplasia 77% of cases resolution of dysplasia in 86% of cases lower risk of progression and fewer cancers.5

EAC Prevention Observational cohort studies in BE patients Significant association between PPI and a decreased risk of high-grade dysplasia and adenocarcinoma in patients with Barrett’s esophagus No reduction in the risk of EAC among patients with GERD or Barrett’s esophagus after anti-reflux surgery although limitations of these studies included selection bias and limited adjustment for possible confounders.63 Surgery is not recommended for the sole purpose of cancer prevention

SCC Prevention Observational studies show a 40-50% reduction in the risk of EAC and SCC with aspirin or (NSAID) treatment RCT study of PPI and aspirin on clinical outcomes in BE is ongoing However, one randomized trial of daily celecoxib treatment did not show a reduction in cancer risk among patients with Bar- rett’s esophagus and low-grade or high-grade dys- plasia

Staging

Staging Endoscopic ultrasonography- 70 to 80% accuracy in assessment of tumor and lymph node status staging in patients with no obvious regional or distant spread seen on imaging of the chest and abdomen Adding FNA improves LN staging Adding EMR offers improved staging as well as an opportunity for cure. PET scanning identifies occult distant metastases, which are most common in the supraclavicular and retroperitoneal lymph nodes Establishes a more advanced stage in 10 to 20% of cases

Endoscopic Mucosal Resection EMR - treating Barrett’s esophagus with high-grade dysplasia or adenocarcinoma that is limited to the epithelial portion of the mucosa (category T1a) small non-circumferential tumors (<2 cm in diameter) usually supplemented by RFA of the remaining BE lesions the risk of lymph-node mets is correlated with the depth of tumor invasion; Near zero for BE with high-grade dysplasia 1 to 2% among patients with stage I tumors No randomized trials comparing endoscopic with surgical therapy observational studies suggest that cure and survival rates are equivalent Endoscopic therapy should be considered as first-line therapy for patients with stage 0 or I EAC In patients with category T1b tumors that have penetrated the muscularis mucosae and entered the submucosa risk of lymph-node spread as high as 20%, radical esophagectomy is preferred

EAC Management Guidelines

EAC Management Guidelines Locally advanced tumors, defined as category T3N1 Treatment includes esophagectomy. cure through definitive chemoradiotherapy alone has been reported, especially in patients with squamous-cell carcinoma, Esophagectomy alone is associated with a high rate of recurrence and low 5-year survival rates (5 to 34%). The main advance in treating patients who undergo esophagectomy has been the adoption of neoadjuvant treatment. Randomized, controlled trials have shown a survival benefit with neoadjuvant chemoradiotherapy or chemotherapy, as compared with esophagectomy alone, in both types of esophageal carcinoma.83-85 Radiation + carboplatin and paclitaxel or cisplatin and fluorouracil is becoming the standard treatment in the United States848586; neoadjuvant chemotherapy alone is the preferred approach in Europe Chemoradiation alone is not supported by evidence from randomized, controlled trials and should be restricted to pa-tients whose condition is declining or who are not healthy enough to undergo esophagectomy83. , There may be a small advantage to neoadjuvant chemoradiotherapy over chemotherapy alone. A meta-analysis showed a pooled hazard ratio for death from any cause of 0.78 neoadjuvant chemoradiotherapy and 0.87 for neoadjuvant chemotherapy,

CROSS Trial ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) T1N1M0 or T2–3N0–1M0 (TNM 6th ed) Weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin + paclitaxel with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery vs surgery alone. Primary endpoint = overall survival No adverse event data were collected

CROSS Trial 368 pts from 8 centers, the Netherlands (2004-2008) 178 surgery plus neoadjuvant chemoradiotherapy (162 completed) 188 surgery alone. Median follow-up for surviving patients of 84.1months SCC median survival 81.6 months neoadjuvant + surgery group 21.1months in the surgery alone group EAC Median survival 43.2months neoadjuvant + surgery group 27.1 months in the surgery alone group

Surgery Surgical outcomes appear to be better in high volume centers and with experienced surgeons, a benefit apparently related to the incidence and management of postoperative complications

Adjuvant therapy Resected specimen confirms the response to neoadjuvant therapy Patients with adenocarcinoma who have residual, node-positive, completely resected disease after neoadjuvant therapy have poor outcomes In EAC the benefit of adjuvant chemotherapy or chemoradiotherapy is unclear in these patients. In SCC adjuvant chemotherapy is used for node-positive patients, benefit has been shown in randomized trials in Japan

Palliation Obstructive symptoms related to unresectable disease can be palliated with endoscopic esophageal stenting or high-dose intraluminal brachytherapy RCT showed higher symptomatic relief, as well as less need for reintervention due to complications, with self-expanding metal stents than with locoregional treatment. Addition of high-dose brachytherapy to stenting may result in a prolonged survival

Palliation Palliative chemotherapy for the prolongation of survival unresectable, metastatic, or recurrent disease. cisplatin or oxaliplatin combined with either infusional fluorouracil or capecitabine achieves response rates of 35 to 45% and a few months of prolonged survival, especially among patients with squamous-cell carcinoma. The addition of a third drug may increase response rates by an additional 5 to 10 percentage points but is associated with higher toxicity. Under investigation docetaxel (which interferes with cell division by stabilizing micro- tubules)95 ramucirumab (which targets vascular endothelial growth factor receptor 2). trastuzumab, a biologic agent in which ERBB2 is amplified, confers a modest 2.7-month increase in overall survival and a 1.7-month increase in progression-free survival among patients with advanced esophageal adenocarcinomas

Prognosis EAC 5-year survival = 17% 39% in localized disease 4% with distant metastasis. Despite improving detection early-stage EAC 30% of cases are found with regional metastasis 40% of cases are found with distant metastasis EAC survival is slightly higher than the rate for patients with squamous-cell carcinoma (Fig. 1).

Summary EAC risk factors = GERD, obesity, and cigarette smoking SCC risk factors = cigarette smoking and alcohol consumption Endoscopic screening may identify BE esophagus which allows for surveillance for detection of dysplasia and early- stage EAC Endoscopic ablative therapy is efficacious for treatment of dysplasia and may have an important role in the treatment of Early stage EAC. Neoadjuvant chemoradiotherapy followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced esophageal cancer. 60 to 70% of patients with esophageal cancer have not been receiving guideline-concordant treatment. The management of esophageal cancer appears to be improved by discussion with a multidisciplinary tumor board H. pylori infection is associated with a reduced risk.