As the range of treatments expands, patients with esophageal cancer can advocate for the care that’s best for them.
David Smalley, 59, hopes he’ll be used to his new normal before April and the beginning of this year’s Major League Baseball season. Smalley, a freelance television production specialist for the Baltimore Orioles and Washington, D.C.-area sports teams, underwent an esophagectomy on Nov. 30, 2018, almost a year after he first experienced symptoms of what turned out to be esophageal cancer.
“It was the week before Thanksgiving, November 2017, that I had my first incidence of clogging when swallowing,” Smalley says. In his business, he often worked long hours and ate dinner late, so he attributed the clogging to eating too fast and chose not to seek immediate medical help.
But after six months of increasingly painful swallowing, in June 2018, Smalley decided to heed the advice of his gastroenterologist to undergo a colonoscopy and endoscopy, procedures that use instruments to view the inside of the colon and esophagus.
“The gastroenterologist said the colonoscopy was clean as a whistle, but when he showed me pictures from my esophagus, I could tell by the look on his face that some- thing was wrong,” Smalley recalls.
Biopsies of his esophagus taken during the procedure revealed that Smalley, who does not drink or smoke but did suffer from gastrointestinal reflux disease, or GERD, had esophageal cancer.
An Uncommon Cancer
Esophageal cancers can occur in either the upper part of the esophagus, called the upper esophageal sphincter, or the lower part, which connects with the stomach; disease there is called gastroesophageal junction cancer.
Esophageal cancers are divided into two main types. Squamous cell carcinoma, which accounts for about 25% of esophageal cancers, occurs in the cells lining the length of the esophagus and is usually diagnosed in the upper region. The more common esophageal adenocarcinoma starts in the mucus-forming gland cells and usually occurs in the lower third of the organ.
“Historically, squamous cell carcinoma was more common, as it is a histology associated with chronic alcohol abuse and cigarettes,” says Dr. Ronan J. Kelly, director of the Charles A. Sammons Cancer Center at Baylor Scott & White Health in Dallas and an adjunct associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore. “As we have seen a decrease in the incidence of smoking, the rates of esophageal squamous cell carcinoma are decreasing rapidly and reports of adenocarcinoma, associated with lifestyle factors like obesity and chronic gastro- esophageal reflux disease, are increasing dramatically.”
The American Cancer Society estimates that esophageal cancer makes up about 1% of all cancers diagnosed in the United States. It is estimated that, in 2019, there will be about 17,500 new esophageal cancer cases diagnosed and 16,000 esophageal cancer deaths.
Factors that increase a person’s risk of esophageal cancer include heavy tobacco or alcohol use, older age — the median age at diagnosis is 68 — or having a precancerous condition called Barrett’s esophagus. Additionally, more men than women receive a diagnosis of esophageal cancer. Infection with human papillomavirus is also a risk factor.
More than half of cases diagnosed will be caught in either the localized stage, in which disease is confined to the esophagus, or the regional stage, in which disease has spread only to lymph nodes in the same region of the body as the tumor. Four in 10 people receive a diagnosis of meta- static disease, which means it has spread to other organs.
“Esophageal cancer still has one of the worst prognoses compared with other cancers,” Kelly says, adding that patients who have metastatic disease face the poorest health outcomes.
Of course, that means that chances for survival are best if the disease is caught early, according to Dr. Manish A. Shah, chief of the solid tumor service and director of the gastrointestinal oncology program at NewYork- Presbyterian/Weill Cornell Medicine Medical Center.
One of the most commons signs and symptoms of esophageal cancer is painful or difficult swallowing, according to Shah. Other commons signs include weight loss, pain behind the breastbone, hoarseness and cough, indigestion or a lump under the skin. “However, there are a number of patients who do not have any of these issues, yet can still develop esophageal adenocarcinoma,” Kelly says.
An Atypical Case
Dana Deighton was just 43 when she received a diagnosis of esophageal cancer in 2012. A marketing professional and mother of three, she was part of a very active family that enjoyed sports and outdoor activities.
Deighton’s attention turned to her health in 2012 when she began to experience a variety of odd symptoms that were attributed to a suspected but unconfirmed case of the autoimmune disease lupus. After successfully treating those symptoms for about six months, Deighton noticed a new set of issues. “It began as stomach pain that was nonspecific, and I thought maybe it was irritable bowel syndrome,” Deighton recalls. “Then the stomach pain began to migrate to my back, and I wasn’t able to even sit at a table comfortably for a long time.”
As the pain grew worse, Deighton explored possible food intolerances, such as a gluten allergy, but had no success in relieving her symptoms. “During yet another trip to my general practitioner, I happened to throw my hands up in a type of frustration and felt a big lump on my neck, about the size of a large grape,” she says. “That is when I knew something was not right.”
Deighton underwent an ultrasound and biopsy of the lymph node, but tests came back nondefinitive. Continued diagnostic tests looking for ovarian cancer, then lung cancer, then colorectal cancer eventually revealed a tumor in her lower esophagus that had already begun to spread.
“All the leading doctors up and down the East Coast said, ‘You don’t have much time. We would recommend palliative care so you can enjoy your time with your family,’” Deighton says. “I knew they were basing this prognosis on all the other cases they treat — men who are over 65 and had smoked or drank, or had an unhealthy lifestyle.”
Because she did not fit the mold of a typical patient with esophageal cancer, Deighton was determined to find treatment that was right for her.
Standard of Cancer
Surgery — called esophagectomy — is traditionally among the most common treatments for patients who have localized or regional esophageal cancer. Surgery alone is typically used only in patients with early-stage disease, according to Shah. During an esophagectomy, the surgeon removes the diseased part of the esophagus and connects the remaining healthy parts to the stomach.
For patients with locally advanced disease or those who may not qualify for surgery, treatment will start with a combination of chemotherapy and radiation therapy. New study findings show that coupling chemotherapy with prehabilitation — nutritional and psychosocial support and exercise — can shorten patients’ hospital stays and frequency and boost their nutritional status.
“Standard treatment for the last several years has been combination chemotherapy with a platinum agent like Taxol (paclitaxel) combined with carboplatin plus radiation,” Shah says. Prior to his surgery, Smalley received this regimen, a strategy called neoadjuvant chemotherapy, which is given in an attempt to shrink the tumor before it is surgically removed.
Other chemotherapy combinations can be used depending on the patient’s age, health and history of previous drug regimens, as well as the location of the tumor. Eventually, doctors may be able to test patients to assess whether chemoradiotherapy is likely to eliminate most or all of the cancer so that surgery can be avoided. Possible methods are being investigated in clinical trials, such as one in China involving locally advanced disease; researchers will look for resistance biomarkers in tissue and blood samples and through positron emission tomography, or PET scans. Another predictive measure recently tested found that patients whose tumors have poorly differentiated cells, which tend to be faster-growing and more aggressive, are most likely to experience cancer recurrences after chemoradiation and surgery appeared to eradicate their cancer. This could help doctors tailor treatment and surveil- lance to individuals.
Smalley was given chemotherapy treatments combined with external-beam radiation, which comes from a machine outside the body and focuses on the cancer. Certain patients with more advanced esophageal cancer may undergo internal radiation therapy, or brachytherapy, which involves placing radioactive material inside the esophagus for a period of time. This procedure is mainly for symptom relief.
In Deighton’s case, all her physicians agreed on one thing: Starting systemic chemotherapy was critical. Although standard of care for metastatic cases is usually a chemo- therapy regimen known as FOLFOX (leucovorin, fluorouracil and oxaliplatin), an insurance hiccup denied coverage of the pump required for the delivery of one of those medications. Knowing she was not going home without some sort of treatment, her doctor switched to EOX (epirubicin, oxaliplatin and capecitabine). That regimen is no longer typically used to treat esophageal cancer, but it didn’t require a pump, according to Dr. David H. Ilson, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.
“This was a blessing for me, because the regimen was really effective and resulted in residual resolution in some of my distant metastases,” Deighton says.
Patients like Deighton are often given chemotherapy alone for their metastatic disease. Radiation therapy may be added to relieve symptoms associated with the disease, such as pain or difficulty swallowing. Deighton did not have these problems, but after completing her chemotherapy, she was determined to pursue radiation therapy with curative intent. She found a few written cases in which radiologists suggested that this could further resolve the cancer, and she discussed the idea with several physicians. Just one was willing to try it.
“My physician recognized my health, instead of just my cancer, and that I may be able to handle some outside-of-the- box treatment ideas,” Deighton says. “The trust he cultivated was very powerful, yet never reckless or without a strong dose of what could be a disappointing and uncomfortable reality.”
Her outside-the-box radiation resulted in further resolution and was followed by a high-risk esophagectomy, an unusual treatment for a patient with stage 4 disease.
“It was dangerous, and every day I know how lucky I am,” Deighton says.
In recent years, several targeted treatments have also been approved for esophageal cancer. “Targeted treatments are reserved for stage 4 metastatic disease,” Ilson explains.
Patients with advanced disease should be tested for the status of their HER2 protein, which drives cancer; 10% to 30% of gastroesophageal adenocarcinomas express too much of this protein. The drug Herceptin (trastuzumab) an antibody against HER2, targets and disables the protein and is approved for gastroesophageal junction cancers. The disease can also be treated with any of five biosimilars that are nearly identical to Herceptin, including Kanjinti (trastuzumab-anns), which was approved in June.
After completing her surgery, Deighton’s physicians wanted to continue to fight her disease by treating her with Herceptin. Similar to many chemotherapies, Herceptin is given by infusion once every three weeks, usually in combination with chemotherapy.
If treatment with Herceptin is not successful or patients do not have HER2-positive disease, the next targeted agent to consider is Cyramza (ramucirumab), which targets the VEGF protein, according to Ilson. This protein tells the body to make new blood vessels, which can feed tumors and help them grow. “There are some data that ramucirumab can be given alone, but that is less effective than when it is combined with a chemotherapy like paclitaxel,” Ilson says.
Additional cellular signaling pathways that may help drive this cancer type — PARP, EGFR, PIK3CA and FGFR — are being studied and could lead to new targeted drugs for esophageal cancer. Signaling pathways orchestrate the activities of cells, and glitches in communication along them can give rise to cancer or other diseases.
A third precision approach involves a type of immunotherapy called immune checkpoint inhibition. Immunotherapy attempts to use a person’s own immune system to fight their cancer. The only Food and Drug Administration (FDA)-approved immunotherapy for gastroesophageal junction cancers is Keytruda (pembrolizumab), which targets the protein PD-1. “It is approved for gastroesophageal junction or gastric cancers, but the National Comprehensive Cancer Network guidelines typically apply the same criteria for those cancers to esophageal cancers,” Ilson explains.
Keytruda can be used in patients whose disease has progressed or recurred on multiple prior lines of chemo- therapy or whose cancer is positive for the protein PD-1 or for PD-L1, a molecule that binds to it. Overexpression of PD-L1 is estimated to occur in 40% of esophageal squamous cell carcinomas and 18% of adenocarcinomas. In addition, Keytruda can be used to treat cancer that is microsatellite instability (MSI)-high, meaning it has trouble repairing its own DNA when damaged. However, Ilson says, less than 1% of patients with esophageal cancer have MSI-high disease, as Deighton does.
Prior to Keytruda’s FDA approval in 2017 and after treatment with Herceptin, Deighton’s disease began to spread again. Her oncologists began off-label treatment with another PD-1-targeting immunotherapy, Opdivo (nivolumab). “I have been on it about three years now, and my doctors tell me I am one of the furthest out with gastroesophageal junction cancer who continues to do well,” Deighton says.
Opdivo is not approved for esophageal cancer, but recently released data from a phase 3 clinical trial showed that, compared with chemotherapy, it extended the lives of patients with advanced or recurrent esophageal cancer, regardless of PD-L1 status.
Smalley also underwent treatment with Opdivo in combination with his neoadjuvant chemotherapy and radiation as part of a clinical trial at Johns Hopkins.
“Immune checkpoint inhibitors are being looked at in earlier lines of treatment for metastatic disease and in combination with preoperative treatment, but only in the context of clinical trials,” Ilson says.
Before his esophagectomy, Smalley’s surgeon warned him that during recovery, he would feel like he had been hit by National Football League defenseman Ray Lewis. “What he didn’t tell me was how many times Ray Lewis was going to hit me,” Smalley jokes.
After surgery, he spent two days in the intensive care unit and about 10 days in the hospital.
Recently, Smalley’s first follow-up showed that he is clear of disease, and his esophagus has healed enough so his feeding tube can be removed. Although he is still adjusting, he is hopeful that he will get back to work soon.
Deighton, who is more than five years out from her stage 4 diagnosis with no evidence of disease, has beaten the odds and had more time to adjust to life after cancer. Her experience led her to a career as a project manager for the company Inspire, a social network for health, which aims to accelerate medical progress through a world of connected patients.
Both Smalley and Deighton credit their successful outcomes to many of the more recent advances in esopha- geal cancer treatment and to their own willingness and drive to find physicians that fit their needs.
As part of her knowledge gathering, Deighton researched patient advocacy groups like the Esophageal Cancer Action Network, of which she is now a board member. “You have to advocate for yourself,” she says. “You have to have a relationship with your doctor, read and gain knowledge, have (an) in-depth conversation and ask questions.”
The future remains uncertain but hopeful for Smalley and Deighton, and both are eager to generate greater awareness about esophageal cancer.
“Who knew that something like heartburn could cause cancer? I certainly didn’t,” Smalley says. “I’m hopeful that my treatment will help me, but when I was diagnosed, I knew I wanted to do more to help others, like participate in the clinical trial and raise awareness to help other people learn about esophageal cancer.”