Esophageal Cancer: New Ideas About Risk and Management

An Expert Interview With Jaffer A. Ajani, MD

Shira Berman; Jaffer A. Ajani, MD


November 04, 2011

Editor's note:

Esophageal cancer is one of the less common cancers in the United States, but its incidence is on the rise. Chronic gastroesophageal reflux disease (GERD) is a known risk factor for the development of esophageal injury and Barrett esophagus, which, in turn predisposes patients to the development of esophageal cancer.[1]

Recently published findings have reopened discussion on the risk factors for this cancer. Two studies published in 2010 reported conflicting data on whether long-term bisphosphonate use might increase the risk of esophageal cancer,[2,3] prompting a formal review of the issue by the US Food and Drug Administration (FDA). Separately, another study suggested that all patients with long-standing GERD, even those whose symptoms are well controlled, are at increased risk for esophageal cancer.[4] More recently, 2 large studies reported that the risk for esophageal cancer among patients with Barrett esophagus was much lower than previously thought,[5,6]raising further questions about the etiology of this uncommon cancer.

Research into the molecular mechanisms behind disease development led to the approval in 2010 of trastuzumab for patients with HER2-positive metastatic esophageal cancer,[7] and studies of additional targeted therapies are underway.[8]

In an interview with Medscape, Jaffer A. Ajani, MD, Professor of Gastrointestinal Medical Oncology at the MD Anderson Cancer Center in Houston, Texas, discussed how these and other issues are influencing research into the pathogenesis of esophageal cancer, and how practicing clinicians should optimally approach patients with this disease.

Medscape: Studies published in the past 2 years have raised questions about whether patients taking bisphosphonates long term or those with longstanding, well-controlled GERD are at increased risk for esophageal cancer.[2,3,4]

What might these data suggest about screening for this cancer in patients who have either longstanding disorders that might predispose them to esophagitis or who are taking medications that might increase their risk for esophagitis?

Jaffer A. Ajani, MD: The questions raised about bisphosphonates fits in with the general notion about the links between injury to the esophagus and esophageal cancer.

Bisphosphonates have a crystalline structure and typically reside in the mucosa for a long time, not getting absorbed, potentially resulting in esophagitis.[9] In fact, there are cases in which crystals of bisphosphonates have been found in biopsy specimens.[10] Patients who are taking this drug chronically could therefore show locally enduring effects because of the nature of this chemical.

[Ed: FDA advises physicians to instruct patients to carefully follow the dosing instructions for taking oral bisphosphonates to minimize the risk for esophagitis. Patients should be instructed to take the medication on an empty stomach, to swallow each tablet with a full glass of water, and not to lie down or eat any food for at least 30-60 minutes after dosing.]

Also, there was a very interesting report showing that bisphosphonates can suppress the Arf retinoblastoma protein.[11] The retinoblastoma gene is a tumor suppressor gene; if you block it, then you can allow tumor formation.

So there may be 2 mechanisms -- physical injury to the surface of the mucosa and inactivation of a tumor suppressor gene -- that could result in tumor formation.

In the British study that showed an increased incidence of esophageal cancer, the incidence rose from 1 case per 1000 people in the general population to 2 cases per 1000 people in patients taking bisphosphonates for 5 years.[3] It's not a high risk, but patients who will be taking the drugs for a prolonged period should probably be monitored for symptoms, and then undergo an endoscopy if the symptoms warrant further attention.

This link between injury to the esophagus and cancer has also been explored in regions where the incidence of esophageal cancer is high. In Iran, for example, silica is more common in the diet, and it is thought that crystals may be getting caught in the esophagus or the mucosal surfaces, resulting in caustic, physical injury to the esophagus.[12] Also, there are communities in Brazil, Iran, and also the eastern part of Germany, where people drink liquids at very high temperatures -- essentially burning the esophagus as the liquids are poured toward the back of the throat.[13]

For these patients, where the risk for injury is known to be high, perhaps the level of surveillance should be high as well, but there are not enough data to establish specific screening guidelines.

In the Western world, the increase in obesity is leading to an increased incidence of GERD.[14] In particular, in patients with truncal obesity, which is the most common form of increase in body mass index, fat cells produce inflammatory cytokines, which are known to result in inflammation in the gastrointestinal tract. This process is thought to account for the increase in the incidence of cancers of gastrointestinal tract, including the esophagus.[15]

We know that the squamous surface of the esophagus is not meant to withstand acid. But when you lose the function of the gastroesophageal sphincter and biliary and acidic material refluxes, the esophagus forms Barrett mucosa, which is similar to the mucosa of the stomach or intestines and can withstand the regurgitated acid.

In most people, the development of Barrett esophagus is good, because it protects the natural squamous surface of the esophagus. However, in this chronic process of reflux, the injury just continues. In a small percentage of patients, the Barrett mucosa is transformed into cancer.

This risk of progression to esophageal cancer is actually quite low. In a recent study of more than 8500 patients with Barrett esophagus who were followed for 7 years, cancer developed in only 0.2%, which is about half of what was previously thought.[6]

The problem is that a number of studies have shown that severity and chronicity of GERD increases the risk of both Barrett esophagus and of transformation to cancer.[16] Standard antacid medications, such as the proton-pump inhibitors that are available over the counter, have no effect on the mechanics of reflux. They can reduce the level of acid production, but obviously not 100%, and they have no effect on the production of bile, which has been shown to cause dysplasia in preclinical models.[17]

Medscape: So patients with longstanding GERD are still potentially at risk for esophageal cancer, even if they are technically well controlled.

Dr. Ajani: Correct. The big dilemma is whom to observe and how often. One can develop a model in which we can select out a population at highest risk and say that these individuals should be followed more closely, but there are no national guidelines yet that fully address this issue.

In addition to looking at clinical signs and symptoms, researchers are also looking at genetic characteristics, such as whether genetic abnormalities in DNA repair or inflammation might predispose patients to dysplasia.

It might be a 2-hit theory: if you have a genetic susceptibility and you are exposed to chronic inflammation/injury, cancer is more likely to develop.

Medscape: That's a good lead-in to our next topic: in patients with metastatic disease, there has been a lot of work on trying to molecularly characterize the tumor to identify targets for therapy.

For example, trastuzumab is approved for patients in this setting, and testing for HER2 overexpression is a standard part of the workup.[1] There are a lot of other therapies being explored, including those targeting vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). How do you see this area of research developing?

Dr. Ajani: Two different approaches have been implemented. The trastuzumab study was enriched for a population of patients whose tumors were known to express HER2, and it proved to be a good strategy.[18]

But for the anti-angiogenic agents and for the EGFR inhibitors, the current trials are not enriched for patients with the target receptors. I think that is unfortunate because we know that there are subsets within each tumor type that are likely to benefit from certain drugs and trials typically don't have the power to detect benefits in small fractions of patients.

For example, the AVAGAST trial did not show a survival benefit with the addition of bevacizumab to chemotherapy in patients with advanced gastric cancer.[18] However, a biomarker presented at the European Multidisciplinary Cancer Congress in Stockholm[19] showed that patients with high levels of VEGF-A, which is the molecule that cancer makes to attract endothelial cells to form blood vessels, tend to benefit more from bevacizumab than those who do not.

The original results also showed that Asians enrolled in the trial tended not to benefit from bevacizumab but non-Asians did, and the biomarker analysis showed that the Asians did not have high levels of VEGF-A.

I think future trials should really focus on biomarker discovery validation, and then treat the enriched population. One emerging pathway where an enriched population could be studied is c-Met.[20] More effort should be put into figuring out which patients are more likely to benefit, similar to what has been done in lung cancer in identifying key mutations.[21]

To do this type of research, we're going to need to ask patients to give some extra tissue. Because it's voluntary and because a lot of patients will refuse, we need to urge the population at large to be open to donating tissue and blood. The future of research is in these patient samples.

Medscape: This idea of a collaborative effort leads to our final topic -- the multidisciplinary team approach. You chaired the panel for the National Comprehensive Cancer Network (NCCN) guidelines on the management of patients with esophageal cancer,[1] and included a section describing the need for a multidisciplinary team approach, especially for patients with localized esophageal cancer. Why is this so important?

Dr. Ajani: This is a real challenge for all physicians treating these patients. Traditionally, a "multidisciplinary approach" meant that a patient was seen by physicians in all of the different specialties one by one. Sometimes they talked with each other and sometimes they read each other's notes, but they mostly came to treatment decisions independently.

For example, the patient starts at her primary care physician's office, is referred to a gastroenterologist, who then refers her to a surgeon. The surgeon operates on the patient, but may or may not contact a medical oncologist or a radiation oncologist about follow-up care.

What my colleagues and I advocate is a true multidisciplinary evaluation, with all of the different treating physicians talking with each other before any treatment is started. All of the specialists would have access to all of the patient's data and could review and discuss staging and treatment decisions, together with other experts who, although not in treating, could offer opinions and advice. If everyone comes together to form a consensus decision, the patient is going to benefit a lot more.

It's going to take some time to implement this, but the NCCN principles provide some guideline as to what should be done. We need to change the way we work together in order provide the most benefit to every patient.

Medscape: In the community where we know that this type of collaboration is often a challenge, how likely is it that this actually can be implemented?

Dr. Ajani: It probably cannot be. Patients with less common and more complex cancers such as gastric and esophageal cancers should be referred to major treatment centers. Community practices often lack the surgical and radiation sophistication, and although medical oncologists might be familiar with the drugs, they're likely not very familiar with the disease.

This isn't surprising; there is literature demonstrating that morbidity and mortality are lower from surgical complications in high-volume centers, and even for high-volume surgeons independent of the center.[22,23]

In England, there are specialized centers for heart transplants and pediatric surgeries, and they are starting to do it for esophageal cancer. I think it will also happen for gastric surgery. In Canada, if you have Barrett esophagus and it requires endoscopic mucosal resection, you cannot get reimbursed at your own institution, you have to refer the patient to a specialized center.

In the United States, it will probably take many, many years for this to happen. It has not been seen as a necessity, and, for a lot of cancers, it might not be. But for complex and less common cancers, it is something that we should move toward.


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