Gastroesophageal reflux disease is a risk factor for what is now the more common type of esophageal cancer, adenocarcinoma. Immunotherapy is coming on strong as a treatment.
Esophageal cancer accounts for a disproportionate share of cancer deaths in the U.S. relative to the number of new cases that occur each year. According to the American Cancer Society’s 2023 statistical report, 21,560 new cases will be diagnosed in this year and 16,120 people are expected to die from the disease. Esophageal cancer ranks 17th among cancers in incidence (new cases) in the U.S. but is the 11th leading cause of cancer death, according to the National Cancer Institute (NCI). Worldwide, it ranks higher: It is the sixth leading cause of cancer-related deaths and the eighth most common cancer.
However, the direction of some overall U.S. trends in esophageal cancer have been favorable. The incidence and death rates have been declining for about a decade for reasons that entirely aren’t clear, and the five-year survival rate has been increasing, partly because treatments have improved.
Types and risk factors
The esophagus is a hollow 10- to 12-inch-long muscular tube that connects the back of the throat to the stomach. It is situated behind the trachea (windpipe) and in front of the spine. Esophageal cancer starts in the inner lining of the tube and spreads outward through the multiple layers of tissue that make up the esophagus.
There are two main types of esophageal cancer: squamous cell carcinoma, which forms in the thin, flat squamous cells that line the inside of the esophagus, and adenocarcinoma, which forms in glandular tissue.
Squamous cell carcinoma used to comprise most of the diagnosed esophageal cancers in the U.S., but over the past three decades, the adenocarcinoma type has become more common than the squamous cell type. Smoking and drinking alcohol are risk factors for squamous cell carcinoma. Gastroesophageal reflux disease (GERD), especially severe cases, is associated with an increased risk of developing adenocarcinoma. Squamous cell carcinoma and adenocarcinoma have traded places partly because smoking rates have decreased. There is also a theory that as Helicobacter pylori infection of the stomach has decreased, esophageal adenocarcinoma has increased because H. pylori infection lowers gastric acid secretion. Mark Richard Dylewski, M.D., chief of thoracic surgery at Miami Cancer Institute, part of Baptist Health South Florida, notes that a lot of people who develop GERD don’t get treated because the symptoms are mild or come and go.
The treatment for esophageal cancer depends on the stage at which it is diagnosed, and the staging is complex. There are five stages (0-4), and many stages are divided further into two or three substages. Moreover, squamous cell carcinoma and adenocarcinoma are staged separately, and recurrent cases are put in a separate category when it comes to treatment.
If diagnosed at an early stage, esophageal cancer can be treated by surgery alone, according to the NCI. The surgery may involve removing part of the esophagus, shaping part of the stomach into a tube-like structure and connecting it to what remains of the esophagus.
But often, esophageal cancer is diagnosed at a later stage, so resection alone is not adequate treatment, especially with such a wide array of therapies now available
Federico Steiner, M.D., a thoracic surgeon for the Atlantic Health System in Morristown, New Jersey, says that treatment of esophageal cancer usually involves “trimodality therapy,” which includes chemotherapy, radiation and surgery. “A multidisciplinary approach is used in most cases because esophageal cancer is usually diagnosed in an advanced stage,” says Steiner.
Treatment has become more precise, Steiner notes. “By analyzing a small portion of the tumor, clinicians can profile the genetic makeup of the tumor and identify unique characteristics,” Steiner says. “From there, the clinician can use this information to determine what the best form of treatment will be, which may include targeted therapy. This is leading to a higher rate of positive treatment outcomes for patients with esophageal (cancer), as well as other cancers.”
David Zeltsman, M.D., chief of thoracic surgery and director of minimally invasive thoracic surgery at Northwell Health in New Hyde Park, New York, says the problem with esophageal cancer is that it’s so deadly. The hope, he says, is that a “normal” treatment of some kind — whether targeted therapy or immunotherapy — can make a difference. “The fields are really ... evolving, and I personally think that nanotechnology will have a much greater presentation in this field,” he says.
Immunotherapy coming on strong
Conventional chemotherapy agents such as oxaliplatin continue to be an important part of esophageal cancer treatment. Many studies have shown that chemoradiation — chemotherapy in combination with radiation — results in better outcomes than chemotherapy alone. Sometimes people are treated with chemoradiation before surgery. If surgery is not possible, chemoradiation can be “definitive treatment” without surgery.
In recent years, however, treatment options have expanded, and now an increasing number of immunotherapy drugs are being used to treat esophageal cancer. Immunotherapy agents latch on to immune system cells, often T cells, or to cancer cells themselves, in a way that makes the cancer cells newly “visible” to the immune system and therefore vulnerable to its attacks.
“The difficulty with using the immune system to fight cancer is that the immune system, if operating properly, should not attack normal cells,” explains Steiner. “Cancer often uses specific areas of the cell to make it appear ‘normal’ and (mask itself) from the immune system so it doesn’t get destroyed.
Immunotherapy drugs that have been approved for late-stage esophageal cancer include Keytruda (pembrolizumab), Opdivo (nivo-
lumab) and Yervoy (ipilimumab).
Drugmakers and cancer researchers have conducted many clinical trials aimed at figuring out how immunotherapies might be combined with chemotherapy and other treatments — including other immunotherapies — to produce the best outcomes. A prominent example is the Checkmate 648 trial, the results of which were published early last year in the New England Journal of Medicine. They showed that treatment with Opdivo and chemotherapy or Opdivo and Yervoy resulted in longer overall survival than treatment with just chemotherapy in patients with advanced esophageal cancer of the squamous cell carcinoma type.
Biomarker testing can provide important clues as to whether a patient will derive benefit from immunotherapy drugs. A meta-analysis published in JAMA Oncology in December 2022 showed a lack of survival benefit from immuno-therapy agents such as Opdivo compared chemotherapy in patients with cancers that had a low percentage of cells expressing programmed death ligand-1. “In the past,” says Dylewski “we as oncologists used to pick a drug off the shelf that was known to be responsive to the particular tumor we were treating. We would give it to the patient and do a repeat CT/PET scan many months later to determine if the drug worked. Many times, this process didn’t work because we weren’t giving the best drug for that particular type of tumor.”
Steiner says that most patients who are diagnosed with esophageal cancer present with symptoms such as weight loss and difficulty swallowing as a result of advanced disease. But the NCI notes some of the problems with screening: “Based on solid evidence, screening would result in uncommon, but serious (adverse) effects associated with endoscopy, which may include perforation, cardiopulmonary events and aspiration, and bleeding requiring hospitalization.”
Steiner notes that at Atlantic Health System, high-risk patients with risk factors such as obesity, GERD, and tobacco and alcohol use may undergo evaluation with endoscopy to help detect presence of cancer before symptoms develop. “For patients, being aware and having knowledge alongside credible information (are) key when consulting with a doctor around the right form of treatment,” Steiner says.
Keith Loria is a freelance writer in the Washington, D.C., area.
Peter Wehrwein is managing editor of Managed Healthcare Executive®.