Esophageal Carcinoma

Upper G.I. cancer cancers originating in the esophagus or esophagogastric junction, constitute a major global health problem with an estimated 604,000 new cases anf more than 544,000 deaths in 2020.

Esophageal cancer is the seventh, most frequently, diagnosed cancer, and the sixth leading cause of cancer related death in the world.

The global incidence of esophageal and esophagogastric junction cancers have wide geographic variations with a 60 fold difference between high and low incidence areas.

The highest incidence (esophageal cancer belt), spans from northern Iran, through central Asia, and into northern China.

Other areas of high incidence include southern and eastern Africa and northern France.

Esophageal cancer is one of the least recently diagnosed cancers in North America: 20th, most frequently diagnosed cancer and 11th leading cause of cancer deaths in the US.

In 2020 there was an estimated 544,000 deaths globally from esophageal cancer, which is one of every 18 cancer related deaths.

Among the cancers with the most rapidly increasing incidence in the western world.

Eighth most common cancer worldwide, with an estimated 456,000 new cases in 2012, with an estimated 400,000 deaths.

Five years survival is 10-15% among all patients but increases to 40% among patients who undergo curative surgery.

Rare in young people.

Annual incidence of esophageal cancer is approximately 5 per 100,000.

It is estimated that in 2023 21,560 cases will be diagnosed and approximately 15,120 will die.

Progressive decline in incidence of squamous cell carcinoma, while adenocarcinomas have shown a fivefold increase.

Adenocarcinoma of the esophagus has increased in incidence by 350% since 1970.

Squamous cell carcinoma is the most common histologic type worldwide in high incidence areas such as east Asia, and adenocarcinoma is the dominant is histologies type in the west.

Increased incidence due to adenocarcinomas ,secondary to multiple factors, including obesity.

The newest studies report patients with adenocarcinoma vs. squamous cell carcinoma is in a ratio of 4:1 to 5:1.

Adenocarcinoma of the esophagus is more likely to localize at or higher than the tracheal bifurcation, compared with squamous cell carcinomas and has a proclivity for early lymphatic spread, and is associated with a poorer prognosis.

Adenocarcinoma of the esophagus is most common in North America and western Europe, while squamous cell carcinoma, is most common in eastern Europe and Asia.

Higher body mass index is the strongest risk factor for adenocarcinoma of the esophagus.

Combined use of alcohol and tobacco synergistically increases the risk.

In the U.S. and Europe 90% of cases are related to tobacco smoking and alcohol consumption.

Simultaneous smoking and alcohol drinking increases the risk 12 fold and 19 fold in man and women, respectively.

The presence of ever smoking or consuming alcohol accounts for approximately 57% and 72% of esophageal squamous cell cancers of the esophagus in men and women, respectively.

Increasing in incidence with age, peaking in the seventh and eighth decades of life.

Adenocarcinoma is 3-4 times as common in men as in women.

The sex distribution and squamous cell carcinoma of the esophagus is more equal.

Esophageal adenocarcinoma usually affects the lower esophagus, while esophageal squamous cell carcinoma, is more likely to loclizev at or higher than the tracheal bifurcation.

Incidence related to widest variations, with a 60 fold difference between low and high regions.

High prevalence areas include Asia, eastern and southern Africa and northern France.

P13K/PTEN/AKT/mTOR signaling associated with disease progression and prognosis.

P13K/PTEN/AKT/mTOR signaling pathway correlates with chemo resistance.

Squamous cell type-occur typically in the mid-upper esophagus and are more common in black patients.

Squamous cell is most common in endemic areas and adenocarcinoma is most common in non endemic areas.

Squamous cell cancer of the esophagus incidence has steadily declined.

Squamous cell carcinoma of the esophagus treated with chemoradiation, the added benefit of surgical resection is controversial.

Squamous cell carcinoma of the esophagus treated with chemoradiotherapy is associated with a 25% overall survival rate at five years.

Overall cure rate  for esophageal cancer is low and approximately 20%.

Metastatic squamous cell carcinoma accounts for 90% of cases of metastatic esophageal cancer in Asia, Africa, and France, while adenocarcinoma represent 62% of cases in the United States.

Metastatic esophageal cancer is a fatal disease with a median overall survival ranging from 10-12 months.

In a randomized trial of 172 patients with squamous cell carcinoma of the esophagus treated with chemoradiation compared to another group treated with chemo- radiation followed by surgical resection: the surgical group had a significant improvement in local control at two years of 64% vs. 41%, the median survival was similar, 16.4 months in the surgery armC. and 14.9 months and the chemooradiation alone arm (Stahl M).

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.

Squamous cell cancer of the esophagus now accounts for fewer than 30% of all cases in the U.S.

In a review of surgical outcomes in almost 84,000 patients with esophageal squamous cell cancer in 1980: exploration was performed in 58% of the patients, 39% uncerwent resection and 30% died during or soon after surgery, 9% survived two years, and 4% survived five years.

Risk for squamous cell carcinoma of the esophagus drops substantially with smoking cessation.

Patients with squamous cell cancer of the esophagus often have a history of head and neck and lung cancers.

Expected overall survival for locally advanced ormetastatic disease is 8-12 months.

5-year survival rate of 10% with a median survival time of approximately 12 months with locoregional therapy.

5-year survival for resected patients is 20-40%.

Staging with ultrasound, CT scans of the chest and abdomen and PET-CT scan should be performed to assess the respectability of the lesion.

Staging is guided by the tumor-node-metastasis system (TNM).

Staging by endoscopic ultrasound with fine needle aspiration is the most accurate modality in the initial tumor and node staging of esophageal cancer.

In prospective trial examining the feasibility of thoracoscopy/laparoscopy in staging esophageal cancer it was found that noninvasive imaging using CT, MRI and EUS staged 50%, 40%, and 30% of patients incorrectly, respectively.

CT scans and PET scans are the most useful to detect metastatic disease.

A CT scan of the chest and abdomen are usually performed once a diagnosis is made, both to evaluate the region of the primary tumor and to search for distant metastatic disease.

Endoscopic ultrasound is considered the local regional modality of choice for T. and N. staging.

PET scans are more sensitive than CT in identifying metastatic disease in esophageal cancer.

When a tumor penetrates all the way through the wall of the esophagus(T3) or use node positive, it is considered to be advanced disease.

EUS (endoscopic ultrasound) for T. staging ranges from 61% to 76% and four N staging from 64 1/2% to 89%, compared to post surgical pathological staging.

EUS can accurately stratified patients into early(T0-2 or NO) or advanced(T3-4 or N1) disease categories in the 83% of patients, providing information that is highly predictive of treatment outcome and patient survival.

EUS changes patient management in about one third of cases, with 84% moving towards nonsurgical and palliative treatment after identification of advanced disease.

To avoid over staging it is essential that EUS guided needle biopsies of suspicious lymph nodes be performed because of up to 80% of N0 pathology staged tumors may be over staged as N1 by EUS alone.

Esophageal resections include lymph node dissections using standard or extended technique.

In an evaluation of the Surveillance Epidemiology and End Results database of 29,69 patients cancer free survival significantly longer in patients with 11 or more lymph nodes examined (Groth).

Randomized trials and meta- analyses show a survival benefit for preoperative chemoradiation.

Addition of neoadjuvant chemo radiation has improved treatment results when compared to surgery alone, and is presently the preferred treatment for potentially curable disease (Tepper JE et al).

Radiation Therapy Oncology Group (RTOG) trial 85-10 randomized patients between radiation alone, were radiation plus chemotherapy, and after a minimum follow-up of five years. The median survival was 9.3 months in the radiation alone on vs. 14.1 months in the combined treatment group, with a five-year survival rate at 26% for the combination treatment group compared to 0% for those treated with radiation alone (Herskovic A).

Surgical resection considered for fit patients with localized resectable disease with thoracic esophageal lesions 5 cm or more from the cricopharyngeus and intraabdominal esophagus or gastroesophageal junction cancers.

Adding cetuximab to chemoradiotherapy for localized esophageal cancer is associated with the shorter median survival compared with no cetuximab, 22.1 months versus 25.4 months.

Adding cetuximab to concurrent chemoradiation does not improve overall survival (Suntharalingam M).

Chemoradiation alone curative in 25% of patients (Radiation Therapy Oncology Group 8501).

Recurrence is unlikely in patients who survive 3 years or longer after undergoing induction chemoradiotherapy and esophagectomy.

Postoperative chemoradiation prolongs survival in patients with lymph node positive, resected esophageal carcinoma.

At diagnosis nearly half of patients have disease that extends beyond the locoregional confines of the primary lesion.

Fewer than 60% of patients with locoregional involvement can undergo a curative resection, with 70-80% of resected specimens harboring metastases in the regional lymph nodes.

Likelihood of nodal metastases depends on the depth to which the tumor invades the esophageal wall.

When a tumor is limited to the submucosa only about 19% of patients will have lymph nodes metastases.

Local recurrence after standard resection techniques are in the range of 20-60%.

Patients with thoracic esophagus involvement have a poor prognosis because most patients present with a locally advanced tumor.

Half of patients are unresectable or have metastases at the time of diagnosis.

Five or more metastatic nodes can be considered as an indicator of systemic disease with a high likelihood of distant organ metastases.

Significant risk for esophageal cancer following lye ingestion.

Adjuvant chemotherapy has not increased treatment outcome in surgically treated patients.

Endoscopic ultrasound superior to CT scans for staging with respect to locoregional disease.

Endoscopic ultrasound has a greater than 85% accuracy in determination of T stage and greater than 75% accuracy for determining N staging in patients who undergo surgical exploration and resection without preoperative treatment.

Endoscopic ultrasound can image as a five-layered structure and the tumor depth of invasion is correlated to the level wall layer abnormality.

Endoscopic ultrasound is not reliable for restaging after chemoradiation therapy is given.

Endoscopic ultrasound useful in detecting recurrent submucosal disease at the esophageal-gastric anastomosis after esophagogastrectomy with a sensitivity of 95% and specificity of 80%.

Adjuvant chemotherapy has not increased treatment outcome in surgically treated patients.

The addition of systemic chemotherapy to chemo radiation preoperatively or postoperatively has minimal or no benefit.

At surgery, most patients still have persistent disease, in particular, node positive disease that often recur within the first year after surgery.

The implementation of biomarker testing, especially analysis of HER2 status, microsattelite instability, status, and expression of programed death ligand-1 has a significant impact on clinical practice and patient care.

Targeted therapies include transtuzumab, nivolumab,ipilimumab  and pembrolizumab.

In chemo refractory squamous cell carcinoma of the esophagus treated with nivolumab had a 17% response rate with an overall survival at 10.8 months (Kudo T).

Compared with esophageal stenting, radiation is associated with decreased risk of adverse effects, greater pain relief and equivalent relief of moderate to severe dysphasia overtime.

KEYNOTE-180 Study demonstrated Pembrolizumab has modest activity in patients heavily pre-treated metastatic esophageal cancer.

Nivolumab is associated with significant improvement in overall survival versus chemotherapy in previously treated patients with the best esophageal squamous cell carcinoma.

Nivolumab (Opdivo) is approved for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine-and platinum-based chemotherapy.

First line treatment of advanced esophageal squamous cell carcinoma with either nivolumab plus chemotherapy  or  nivolumab plus ipilimumab resulted in significant overall survival benefit and durable responses compared with chemotherapy alone.

Tislelizumab-jsgr (Tevimbra) is approved for single-agent use in adult patients with unresectable or metastatic esophageal squamous cell carcinoma following prior systemic chemotherapy that did not include a PD-1/PD-L1 inhibitor.

The addition of tislelizumab to chemotherapy led to a median overall survival (OS) of 17.2 months vs 10.6 months with placebo plus chemotherapy.


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