Gastroesophageal junction adenocarcinoma

Increasing in incidence.

Incidence increasing by 5-10% per year since the 1980’s, making it the fastest growing malignancy compared to other common malignancies.

Has increased particularly in Caucasian male population with more than a 400% increase in incidence since the late 1990’s.

Estimated 1.5 million new cases in 2018.

It represents the fifth most common cancer worldwide in the third leading cause of cancer related death.

Less common in the US than in Asia.

GE cancers in 2021 accounted for 26,000 deaths in the US.

Gastroesophageal cancers make up 80% of esophageal cancers.

Occur most commonly in middle-aged white males.

Divided into adenocarcinomas and squamous cell carcinomas.

Associated with obesity, high fat intake, tobacco use, GERD, hiatus hernia, esophagitis, and use of drugs that relax the lower esophageal sphincter.

Ot is less common in the US than in Asia.

Accounted for more than 26,000 deaths in the US in 2021.

About 1/3 of tumors are characterized by chromosomal instability and aberrant activation of HER1-4.

27% of patients undergoing curative resection have disseminated tumor cells in the bone marrow.

5-year survival with resection 10-15%.

70-80% have inoperable disease at the time of diagnosis.

For resectable disease chemotherapy followed by surgery associated with a median survival of 4.5 years versus 1.8 years for surgery alone, and a 5 year survival of 39% vs. 16%, respectively (Tepper).

Median overall survival is not over 12 months in most trials, for patients with advanced disease.

In  the 15 to 20% of patients with human epidermal growth factor receptor 2 over expression, median survival is improved by the addition of trastuzumab to the combination chemotherapy regimen.

For unresectable locally advanced or metastatic GEJ adenocarcinoma systemic chemotherapy improves survival and quality of life.

The median overall survival in gastroesophageal adenocarcinomas is less than a year except for 15 to 20% of patients with HER2 over expression in whom median survival is improved by the addition of trastusumab to the chemotherapy.

Standard regimens in the first line treatment consisted of a fluorpyrimidine with platinum agents with either an anthracycline or a taxane.

Trimodality therapy is the standard of care for patients with resectable esophagogastric junction disease (Tepper).

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 a anabiotic that binds to VEGFR2.

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.

PD-1 inhibitors have efficacy.

Pembrolizumab approved for patients with recurrent, locally advanced or metastatic gastric or gastrointestinal junction adenocarcinoma, whose tumors express programmed cell death ligand PD-L1.

In the KEYNOTE-062 study of 763 patients with PD-L1-positive advanced gastric or GEJ cancers randomized to one of three arms: pembrolizumab alone for up to 35 cycles, pembrolizumab for up to 35 cycles plus chemotherapy, or placebo plus chemotherapy.

Pembrolizumab alone was not inferior compared to chemotherapy, with median overall survival rates of 10.5 and 11.1 months, respectively.

Lesions with MSI-high have a higher response to pembrolizumab with or without chemotherapy/

Overall survival appeared to be prolonged in patients with high levels of PD-L1 expression,.

The median survival in that subgroup was 17.4 months for those receiving pembrolizumab, and just 10.8 months for chemotherapy.

Looking at the overall study population, pembrolizumab plus chemotherapy did not improve survival versus chemotherapy alone, reporting median overall survivals of 12.5 and 11.1 months, respectively.

Subgroup analysis suggested that Asian patients derived particular benefit from pembrolizumab as compared to chemotherapy.

Trifluridine/tipracil approved for the treatment of adults with metastatic gastric or gastroesophageal junction (GEJ).

FOLFIRINOX regimen with or without trastuzumab  is associated with improved overall response rate and progression free survival in patients with a advanced gastroesophageal adenocarcinoma in the first setting (Park H).
In patients with HER2 positive metastatic gastroesophagealcancer pembrolizumab combined with trastuzumab has significant activity.
Among patients with resected esophageal gastroesophageal junction cancer who receive neoadjuvant chemo radiotherapy, disease free survival was significantly longer among those are received nivolumab therapy than among those who receive placebo.

The phase 3 KEYNOTE-590 trial, pembrolizumab was approved for use in patients with metastatic or locally advanced esophageal or gastroesophageal junction carcinoma, when used in combination with platinum and fluoropyrimidine-based chemotherapy.


Tumors eligible for treatment need to have an epicenter 1 to 5 cm above the GEJ.


Pembrolizumab plus chemotherapy demonstrated significant improvements in the dual primary end points of overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with locally advanced unresectable or metastatic esophageal and GEJ cancer, regardless of PD-L1 expression status and tumor histology.

Treatment with perioperative capecitabine, o I platinum, and pembrolizumab, have encouraging activity and acceptable toxicity in patients with gastric and gastroesophageal junction adenocarcinoma.

Randomized, placebo-controlled trial enrolled 749 patients with metastatic or locally advanced esophageal or GEJ carcinoma who could not have surgical resection or definitive chemoradiation, with PD-L1 status.


Statistically significant improvement in median OS was observed with the experimental regimen at 12.4 months versus 9.8 months with chemotherapy


The median PFS also saw a significant boost with the pembrolizumab combination, at 6.3 months and 5.8 months, respectively.


The most common adverse events: nausea, constipation, diarrhea, vomiting, stomatitis, fatigue/asthenia, decreased appetite, and weight loss, all occurring in more than 20% of the trial population.


Patients receiving pembrolizumab for this indication are recommended for 200 mg every 3 weeks or 400 mg every 6 weeks.

Nivolumab in combination with chemotherapy for advanced or metastatic esophageal adenocarcinoma has been approved.

The addition of immune therapy to chemotherapy in the front line setting is significantly improved outcomes in patients with metastatic GE Junction adenocarcinoma.

PD-L1 expression more than any other variable identifies the varying degrees of benefit from immune checkpoint inhibitor containing therapy versus standard of care.

Second line treatment for metastatic gastric/GEJ adenocarcinoma is paclitaxel and ramucirumab.

Subsequent lines of therapy include trifluridine and tripiraci.

HER2 positive gastroesophageal adenocarcinoma is usually treated with trastusumab plus chemotherapy.

Pembrolizumab added to chemotherapy and  Trastusumab  showed significant improvement in overall response rate (74.4%) compared with the placebo group of chemotherapy and trastusumab with placebo in HER2 positive cancers.

Other agents beyond first line HER2 positive gastric/GEJ adenocarcinoma therapies include trastuzumab deruxtecan.





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