Understanding Esophageal Cancer
From Paths of Progress 2016
by Elizabeth Dougherty
Collaborative Efforts Are Bringing New Therapies to This Rapidly Rising Disease
When oncologist Charles Fuchs, MD, MPH, started his career at Dana-Farber 30 years ago, he had little to offer his patients with esophageal cancer. Hope was scant, too; there was almost no research going on to understand the disease.
Things have changed. Research at Dana-Farber is uncovering the genetic changes that cause the cancer to form and grow. This work is beginning to pay off, with collaboration from Fuchs and other clinical specialists at the Center for Esophageal and Gastric Cancer at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). Not only is this research leading to the testing of new treatments for esophageal cancer, but also it is adding an investigative dimension to the center's already unique multispecialty care, provided by oncologists, radiologists, and a surgical team with expertise in minimally invasive techniques.
This all-hands-on-deck approach to finding new ways to treat esophageal cancer could not be more timely. Survival rates for this rare disease remain low, while the number of cases diagnosed each year is on the rise. Some forms, such as esophageal adenocarcinoma, have risen 600 percent over the last 30 years. "For a while, it was the most rapidly increasing cancer in the U.S.," says oncologist Peter Enzinger, MD, director of the Center for Esophageal and Gastric Cancer.
Esophageal cancer typically affects men over age 50, so numbers may be increasing as the population ages. Alcohol and smoking are also risk factors. Obesity, on the rise in the U.S., also increases the risk of the disease. The connection between obesity and esophageal cancer is clear statistically, but the mechanism isn't fully understood. Doctors speculate that added weight in the body increases pressure inside the abdomen, which could lead to more acid reflux, causing damage that raises the risk of cancer.
Esophageal cancer can be found early through an endoscopy, in which a doctor uses a scope to look inside the esophagus and stomach. But doctors don't routinely screen for the disease and patients often ignore warning signs, such as frequent heartburn, weight loss, or abdominal discomfort. As a result, the disease is diagnosed in many patients at an advanced stage, lowering their chances of survival. "People with persistent heartburn should get endoscopies, especially if they are age 50 or older," says Enzinger.
A Home Base for Patients
Because there are so few cases of esophageal cancer each year, oncologists in community hospitals rarely see enough patients to develop the depth of experience needed to treat them. With case numbers on the rise, the field needed a place where patients could find expert care. So, in 2014, DF/BWCC formed the Center for Esophageal and Gastric Cancer to bring together a core group of experts to develop the best practices for caring for these patients.
At a first visit to the center, a patient typically sees a surgeon, radiation oncologist, and medical oncologist, who review the case together and recommend a course of action.
"This is a disease where it's really important to involve all the specialties, because combining all three modes of treatment — surgery, radiation, and chemotherapy — leads to the best outcomes," says Enzinger.
A typical patient will begin with chemotherapy to treat any cancer that may have spread into the liver or lungs. During chemotherapy, radiation is applied to control the main tumor. Surgery follows to remove the cancer. For patients diagnosed early, the team also offers localized treatment that removes only the lining of the esophagus, so patients don't need more extensive surgery.
The center's team of thoracic surgeons have a spectrum of minimally invasive approaches, including robotically guided surgery. "There's never a gap in coverage; it's a comprehensive team effort," says thoracic surgeon Scott Swanson, MD, chief surgical officer of DF/BWCC and disease center leader of the Thoracic Oncology Program.
In the past, some patients were deemed too sick for esophageal surgery, which is often a critical part of treatment. But with minimally invasive techniques, surgery is now a safe option for a wider range of patients. Swanson and other surgeons in the center now routinely perform the procedure on elderly patients, and also operate with success on obese patients and those with advanced heart disease.
The procedure may involve removing all or part of the pipe that connects the throat to the stomach, yet patients typically spend less than a week in the hospital and leave with small incisions on the chest and abdomen.
"Most patients go home surprised at how well they feel," Swanson says. "Doing this surgery is a lot more rewarding now, because patients do so well."
The surgical team's expertise is one reason why the center's mortality rate for esophageal cancer was up to 10 times better than the national average, says Swanson.
Research Drives Advances in Care
Treatment advances in other cancers helped fuel the first steps toward better esophageal cancer drugs. For example, when newer chemotherapy drugs worked for other cancers, researchers tried them in esophageal to see if they'd work there, too. "That did move the needle in terms of improving patient outcomes," says Fuchs.
More recently, however, the field has become poised for more significant improvements. In cases of breast cancer that are HER2-positive, meaning the HER2 gene is overactive driving the tumor's growth, trastuzumab (Herceptin) is used to block that growth mechanism. For these patients, survival rates have improved substantially. It turns out that some forms of esophageal cancers are also HER2-positive, and trastuzumab also improves outcomes for this group of patients. Dana-Farber's Adam Bass, MD, co-director of the Cancer Genome Atlas project for esophageal cancer, is leading further genomic research.
"We're trying to drill down on the question of what esophageal cancer is," says Bass. "Understanding the landscape of genes that are amplified in these tumors will help point out new candidate therapeutics."
Bass and colleagues are sequencing the genomes of a large number of samples of esophageal cancers and looking for patterns of abnormal genetic activity. They recently found that a gene called PD-L2 is expressed in some esophageal tumors. PD-L2 is part of a cloaking mechanism many tumors use to hide from the immune system, which would otherwise attack the cancer cells.
In recent years, pharmaceutical companies have developed a "checkpoint inhibitor" drug called pembrolizumab (Keytruda) that deactivates the cloaking mechanism so that the immune system can find and attack the tumor. The development of pembrolizumab was based in no small part on the early investigations of Dana-Farber scientist Gordon Freeman, PhD, into the basic workings of the immune system and checkpoint proteins.
While these immunotherapy drugs were developed for more commonly studied cancers, such as melanoma, Enzinger and Fuchs are working with pharmaceutical partners to test pembrolizumab in esophageal cancer. Enzinger is leading a clinical trial at DF/BWCC for esophageal cancer that was slated to begin recruiting patients in early 2016. Fuchs is also leading a trial involving pembrolizumab for patients with gastric cancer.
The center is applying its all-hands-on-deck approach to these trials, as well, by involving surgeons in the investigative process. Patients will be biopsied before and after treatment with the drug so that Bass, Fuchs, and Enzinger can evaluate the drug's effects and learn more about the tumors in which it works best.
As promising as immunotherapy may be, Bass has also uncovered other possible options. In his laboratory, Bass grows tumor samples from patient biopsies in plastic dishes or animal models, turning them into models of the cancer. His team is working to make many copies of each model and then test an array of drugs and drug combinations against them to see which drugs work best in different circumstances.
"Patients want us to figure this out in the laboratory so that we can then bring the best ideas forward into clinical trials," Bass says.
For a long time, oncologists had little to offer patients with esophageal cancer. But now, through collaborative efforts at the center to both advance clinical care and move research forward, options are expanding rapidly.
"There's an opportunity to make radical improvements in this field," Enzinger says. "We're working hard to make that happen."
Learn more about esophageal and gastric cancer.
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