‘Astounding’ increase in esophageal adenocarcinoma largely unexplained
Which is the better approach in esophageal adenocarcinoma: Preoperative chemotherapy or combined chemoradiation?
Not long ago, esophageal adenocarcinoma was an extremely rare cancer.
During the past 40 years, however, incidence has increased dramatically worldwide — particularly in the United States and other Western countries.
Data from the SEER database show esophageal adenocarcinoma rates increased from 1.01 per 100,000 person-years from 1975 to 1979 to 5.69 per 100,000 person-years from 2000 to 2004.
During that time, the number of cases rose 463% among white men and 335% among white women.
That makes the disease, which most frequently develops where the esophagus meets the stomach, the fastest-growing cancer in the United States, according to the NCI.
“Esophageal adenocarcinoma is replacing distal gastric cancer as the most common malignancy of the upper [gastrointestinal] tract,” said David H. Ilson, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center’s Gastrointestinal Oncology Service and a professor of medicine at Weill Cornell Medical College.
Despite the alarming increase in incidence, researchers have had some success in their fight against this often fatal disease.
“Incremental progress is being made with the advent of molecularly targeted agents such as trastuzumab, as well as demonstration of a survival benefit for preoperative strategies encompassing chemotherapy and radiotherapy followed by surgery,” Ilson said.
HemOnc Today spoke with clinicians about the factors that contributed to the increased incidence of esophageal adenocarcinoma, trends in diagnosis and treatment, and new insights into risk factors for this malignancy.
The start of an epidemic
A global epidemic of esophageal adenocarcinoma started sometime around 1950, according to Swedish researchers.
Source: Photo courtesy of Gustaf Edgren, MD, PhD, reprinted with permission.
Gustaf Edgren, MD, PhD, and colleagues collected data on 117,946 cases of esophageal adenocarcinoma from population-based cancer registries in Australia, Europe, North America and Asia.
Results of their analysis, published earlier this year in Gut, revealed a dramatic increase in age-adjusted incidence. The average increase per year varied from 3.5% in Scotland to 8.1% in Hawaii. Generally, men and women shared a similar proportional increase. However, incidence was three to six times higher in men.
“Esophageal adenocarcinoma is still a comparatively rare cancer in most countries,” Edgren, an associate professor of epidemiology at the Karolinska Institutet in Stockholm, told HemOnc Today. “However, the rate of increase has been truly dramatic in many Western countries. Given that we now see evidence of increasing rates in many developing countries, it is slowly becoming more important.”
Australian researchers uncovered a similar trend.
Aaron P. Thrift, BAppSc (Hons), of the Cancer Control Laboratory at Queensland Institute of Medical Research, and colleagues used data from cancer registries in Australia, the United States and Sweden to assess incidence trends for esophageal and gastric cardia tumors. Their results, published online in July in the Annals of Oncology, showed esophageal adenocarcinoma continues to increase at a statistically significant rate in Australia and the United States, although the rate of increase has started to plateau.
Questions remain about what triggered the rising incidence of esophageal adenocarcinoma.
Edgren and colleagues suggested it was caused by some exposure that was introduced around 1950, although they were unable to determine a precise cause.
“While changes in the exposure prevalence to known major risk factors and mis- or reclassification of other malignancies in the esophagus and proximal part of the stomach have likely contributed to an increasing incidence of esophageal adenocarcinoma, they are unlikely to explain neither the abrupt change nor the astounding rate of increase,” the researchers wrote. “Therefore, it seems reasonable to hypothesize that effects of a strong, highly prevalent and yet unidentified causal factor … are superimposed on the effects of known risk factors.”
The explanation likely is multifaceted, said Ilson, HemOnc Today’s gastrointestinal cancers section editor.
“There appear to be a number of potential factors, but no one knows for sure,” he said. “Part of it is an overall shift in the epidemiology of the disease. We used to see a lot more distal gastric cancers … now distal gastric cancers are disappearing and we’re seeing a shift in the disease to the distal esophagus-[gastroesophageal] junction.”
There are several risk factors for esophageal adenocarcinoma. Many of them are on the rise and may help explain why incidence of the disease has increased so rapidly.
Chronic acid reflux is at the top of the list, said Anthony Infantolino, MD, AGAF, FACG, FACP, the director of the Jefferson Barrett’s Esophagus Treatment Center at Thomas Jefferson University Hospital in Philadelphia.
After years of being bathed in acid reflux, esophageal tissue cells change and start to resemble the cells of the stomach and small intestine. This condition is known as Barrett’s esophagus.
“Chronic acid reflux seems to be the major precursor for the development of Barrett’s esophagus,” Infantolino said.
Subsequent genetic alternations to the tissue — probably changes in tumor suppressor genes such as p53, p16 and cyclin D1, according to Infantolino — allow cell hyperproliferation. This leads to dysplasia and, in some patients, cancer.
However, Barrett’s esophagus progresses to cancer only rarely, Infantolino said. Among patients with mild Barrett’s esophagus without dysplasia, only about 0.5% will develop adenocarcinoma.
Obesity and diet
Secondary factors — many of which lead to increased reflux — play a role in the development of esophageal adenocarcinoma. Obesity may influence disease development, with a higher risk assigned to patients with abdominal obesity.
In a study published in Gut in September, O’Doherty and colleagues assessed data on 218,854 AARP members who participated in the NIH-AARP Diet and Health Study from 1995 to 1996. The study participants answered one questionnaire that asked about demographics, diet and health behavior, and a second questionnaire that asked for waist and hip measurements. The results revealed a link between BMI of 35 kg/m2 or greater and a risk for esophageal adenocarcinoma and gastric cardia carcinoma.
Another risk factor is diet, particularly one low in fruit and vegetable consumption.
“There is good epidemiologic evidence to suggest that [this type of diet] is tied with increased risk of esophageal adenocarcinoma,” said Andrew H. Ko, MD, an associate professor in the division of hematology/oncology at the University of California, San Francisco, and a HemOnc Today Editorial Board member.
Studies of tobacco use and alcohol consumption have not consistently shown an association with esophageal adenocarcinoma, Ko said.
Although there is no one-size-fits-all patient, he noted that the typical patient with esophageal cancer may be “a middle-aged to older Caucasian male, perhaps slightly overweight with a history of heartburn, oftentimes working in a high-stress type of job.”
H. pylori rates on the decline
The decreasing rates of Helicobacter pylori infection also have been considered a factor in the increasing incidence of esophageal adenocarcinoma, Ilson said.
H. pylori is a spiral-shaped bacterium that resides in the stomachs of about two-thirds of the world’s population, according to the NCI.
“As we get better food preservation and refrigeration and have less salting of foods, Helicobacter is disappearing,” Ilson said. “Helicobacter was a major cause of gastric cancer over the last century. It’s a leading worldwide cause of gastric cancer.
“As a consequence, some have speculated that because Helicobacter infection is related to atrophic gastritis and overall reduced gastric acid output,” Ilson said. “Paradoxically, getting rid of Helicobacter from our population may actually be increasing population-wide risk of reflux problems, which could contribute to the adenocarcinoma incidence.”
Oral bisphosphonate use also has been implicated as a secondary risk factor.
“If people don’t take oral bisphosphonates correctly — that is, they’re not remaining in an upright position for at least 30 minutes after taking them — this can cause chronic irritation to the esophagus,” Ko said. “Mechanistically, that makes sense.”
The influence of oral bisphosphonate use is controversial, said Tanios S. Bekaii-Saab, MD, medical director of gastrointestinal oncology and associate professor of medicine and pharmacology at The Ohio State University — James Cancer Hospital.
Tanios S. Bekaii-Saab
“It could be caustic,” said Saab, who also is a HemOnc Today Editorial Board member. “It probably induces an injury to the esophagus and the [gastroesophageal] junction.”
Some of the more recent literature does not support the theory, however. Researchers from the United Kingdom, who examined general practice research data on about 42,000 patients, failed to find a link between oral bisphosphonates and esophageal or gastric cancers, Saab said.
Diagnosis and treatment
Patients often are not diagnosed with esophageal adenocarcinoma until they schedule an appointment with their physician to complain about their symptoms, which may include pain when swallowing, pain in the chest or back, weight loss, heartburn or a lingering cough.
“Diagnosis is typically made by endoscopic evaluation for patients who have symptoms,” Ko said. “There’s not a population-wide screening tool akin to colonoscopy. In other parts of the world where stomach cancer is common, notably Japan, they do screen the population at large with upper endoscopy, but in the Western world, in the United States, this has not been shown to be a cost-effective strategy. Diagnostic evaluation is pursued based on symptoms.”
This is particularly problematic because of low survival rates. Five-year survival rates range from 37% for patients diagnosed with localized esophageal cancer to 18% for those diagnosed with regional disease and 3% for those diagnosed with distant disease, according to the NCI.
Treatment options depend on patient presentation, Saab said. Patients who have early, easily resectable disease and who are unlikely to benefit from chemotherapy and radiation will get surgery, such as endoscopic mucosal resection or ablation.
“These will be superficial, small tumors in the esophagus,” he said.
Patients who have larger tumors and regional lymph node involvement “seem to benefit the most from giving chemotherapy and radiation before surgery,” Saab said.
Still, some studies suggest those patients derive an equal benefit by undergoing surgery first, then receiving chemotherapy and radiation. Another option is to give patients chemotherapy before and after surgery without radiation, although that is not widely employed in the United States.
For patients with metastatic disease, treatment is confined to chemotherapy alone, with two or three drugs used in combination.
“We’re finding more and more that giving three drugs is relatively unnecessary, given the added toxicities and not much added benefit,” Saab said.
The most promising new drug treatment seems to be trastuzumab (Herceptin, Genentech) for HER-2–positive gastroesophageal (GE) junction or esophageal adenocarcinoma, Ilson said.
“Studies from GE junction cancers and gastric cancers show that in 20% of patients who are HER-2–positive, adding trastuzumab to front-line chemotherapy in metastatic disease improves response, time on chemotherapy, PFS and OS compared with chemotherapy alone,” Ilson said.
Other drugs have been screened in phase 3 trials, with varying results.
In one trial, panitumumab (Vectibix, Amgen) — an EGFR-targeted antibody — actually worsened outcomes compared with chemotherapy alone when used to treat advanced GE junction, esophageal and gastric adenocarcinomas.
“That has decreased the interest in looking at EGFR antibody-targeted drugs in the adenocarcinoma patients,” Ilson said.
In a global trial, the addition of bevacizumab (Avastin, Genentech) to chemotherapy for treatment of GE junction and gastric adenocarcinomas did not improve survival when compared with chemotherapy alone, Ilson said.
In the neoadjuvant setting, results from the CROSS Group showed that weekly carboplatin and paclitaxel combined with radiation followed by surgery improved outcomes in patients with esophageal or GE junction cancers.
“Many people feel that [this study] has established a new benchmark that chemoradiation with weekly carboplatin and paclitaxel and radiation followed by surgery is considered the new standard of care in this disease,” Ilson said.
For advanced disease, researchers are studying cetuximab (Erbitux, ImClone), another EGFR receptor-targeted antibody.
“Although, with the negative results for panitumumab, we’re concerned that cetuximab also may not improve outcome,” Ilson said.
There is considerable interest in c-Met–inhibiting drugs, both c-Met tyrosine kinase inhibitors and c-Met pathway antibodies that target the ligands, Ilson said. Other researchers are studying the effect of adding rilotumumab (Amgen), which targets hepatocyte growth factors, to first-line chemotherapy.
Other investigators are evaluating the potential role of trastuzumab emtansine (T-DM1, ImmunoGen/Genentech), which recently received priority review status from the FDA for treatment of HER-2–positive, unresectable locally advanced or metastatic breast cancer.
The SWOG cooperative group also has an ongoing clinical trial that is evaluating the ERCC1 biomarker, Ilson said.
No broad screening
There currently are no recommendations to screen the general population for esophageal adenocarcinoma because the risk for the disease is so low.
“Overall, we see about 17,000 Americans a year with esophageal cancer, and about two-thirds of those patients have adenocarcinoma,” Ilson said. “So, we’re talking about 10,000 to 11,000 cases, which are about 5% of the incidence of prostate and breast cancer. The yield of screening in the general population is obviously going to be low because of the rarity of the disease.”
Patients with known Barrett’s esophagus should be screened. According to the standard guidelines published by the American College of Gastroenterology, patients with nondysplastic Barrett’s esophagus — those who just have an altered esophageal lining — should have a repeat endoscopy and multiple biopsies, Infantolino said. The biopsies are performed every 1 cm to 2 cm in a four-quadrant fashion.
If the second set of biopsies — performed a year after the first set — do not reveal any dysplasia, then the patient should be screened every 3 years, he said.
The question of which patients to screen for Barrett’s remains unanswered, Infantolino said.
A novel prediction model eventually may help identify the best candidates. Australian researchers compared data from two groups: 285 patients with known nondysplastic Barrett’s esophagus and 313 patients who had esophageal inflammatory changes without Barrett’s esophagus.
Results showed predictive factors included age, sex, smoking status, BMI, highest level of education and frequency of use of acid-suppressing medications.
“If you have a smart person who is obese, a smoker, male, a frequent user of anti-acids [and] over 50, that is like a poster child for a potential Barrett’s esophagus patient,” Infantolino said. “You should strongly consider suggesting that that patient have at least one baseline endoscopy to see if they have Barrett’s esophagus.”
Early detection of Barrett’s
Biomarkers also may help detect Barrett’s esophagus, potentially offering a more sensitive and accurate monitoring approach that would require only two or three random biopsies vs. the traditional four-quadrant biopsies.
In findings presented at the 2012 ASCO Gastrointestinal Cancers Symposium, researchers reported that they had identified three optical biomarkers — nuclear optical path length, intra-nuclear uniformity and entropy — that can differentiate patients with nondysplastic Barrett’s esophagus from patients with esophageal adenocarcinoma and high-grade dysplasia.
Further, a prediction model that combined all three biomarkers distinguished patients with Barrett’s esophagus and esophageal adenocarcinoma/high-grade dysplasia from patients with intestinal metaplasia. This research is still in its infancy and requires validation.
“It’s still a work in progress,” Ilson said. “We know that Barrett’s esophagus is a neoplasm, it is clonal [and] it does acquire genetic mutations. Right now, there are no validated biomarkers. There have been some studies looking at potential biomarkers and gene polymorphisms, but nothing is ready for prime time and nothing has been validated in larger clinical studies.”
There is no known factor that will prevent esophageal adenocarcinoma. Surveillance may be able to catch the disease in its earliest stages. Although lifestyle risk factors can be controlled, there is no proven pharmacologic intervention that can be globally recommended, Ko said.
Some unproven factors may hold promise, however.
For example, researchers previously did not believe that proton pump inhibitors were effective against this type of cancer.
“Now it seems that if you have patients on proton pump inhibitors with Barrett’s esophagus, there is less of a transition to dysplasia and cancer,” Ilson said. “There may be some reduction in the risk of progression of Barrett’s to dysplasia with antacids. Patients with Barrett’s should be on antacid therapy.”
Aspirin — which has been shown to reduce risk for gastric adenocarcinoma — also may be a promising preventive agent in esophageal adenocarcinoma.
In the United Kingdom-based Aspirin Esomeprazole Chemoprevention Trial, researchers randomly assigned nearly 4,000 patients with Barrett’s esophagus to aspirin or placebo to assess whether aspirin will influence the disease’s natural history.
The findings could be significant.
“An aspirin a day is better than an apple,” Saab said. “An aspirin a day really keeps the doctor away — at least we think.” – by Colleen Owens
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NCI. SEER Stat Fact Sheets: Esophagus. Available at: seer.cancer.gov/statfacts/html/esoph.html#prevalence. Accessed Nov. 14, 2012.
NCI. National Cancer Institute Fact Sheet: Helicobacter pylori and Cancer. Available at: www.cancer.gov/cancertopics/factsheet/Risk/h-pylori-cancer. Accessed Nov. 14, 2012.
O’Doherty MG. Gut. 2012;61:1261-1268.
Thrift AP. Ann Oncol. 2012;doi:10.1093/annonc/mds181.
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For more information:
Tanios S. Bekaii-Saab, MD, may be reached at 320 W. 10th Ave., Columbus, OH 43210; email: firstname.lastname@example.org.
Gustaf Edgren, MD, PhD, may be reached at Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden; email: email@example.com.
David H. Ilson, MD, PhD, can be reached at Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: firstname.lastname@example.org.
Anthony Infantolino, MD, AGAF, FACG, FACP, may be reached at Jefferson University Hospitals, 132 S. 10th St., 480 Main Building, Philadelphia, PA 19107.
Andrew H. Ko, MD, may be reached at UCSF Comprehensive Cancer Center, 1600 Divisadero St., 4th floor, Box 1705, San Francisco, CA 94115; email: email@example.com.
Neoadjuvant chemotherapy increases survival.
It is widely accepted that the management of high-risk patients with esophageal carcinoma (T3, node positive) requires a multimodality approach in the neoadjuvant setting. Although surgery is the primary curative modality for gastroesophageal junction cancers, long-term outcomes are not satisfactory with resection alone, even if microscopically complete (R0). This poor long-term outcome has prompted an evaluation of both neoadjuvant and adjuvant combined modality therapy.
The benefit of preoperative therapy is that it allows for response assessment with the primary tumor in place, has the potential for down-staging and enhancing R0 resections, enhances therapy tolerance and increases the chance for pathologic complete response. The two modalities used preoperatively are chemotherapy or chemoradiation. It is still up for debate which therapeutic sequence is best and which modality is superior.
When discussing neoadjuvant therapies for high-risk esophageal cancer, it is important to distinguish between to two common histologies: squamous and adenocarcinoma. Chemoradiation alone can be curative for the squamous esophageal cancer; therefore, there is no debate for the role of chemotherapy in the preoperative setting for this histological subtype.
The debate remains for esophageal adenocarcinoma. A number of trials inform us about the benefit of preoperative chemotherapy, but none are definitive. The American data are negative while the European trials are positive, demonstrating a survival benefit from 6% to 14%. A meta-analysis looked at the updated survival data of approximately 2,100 patients treated with neoadjuvant chemotherapy and demonstrated a survival benefit of 4% for squamous and 7% for adenocarcinoma (Thirion PG. Abstract #4512. Presented at: 2007 ASCO Annual Meeting; June 1-5, 2007; Chicago). Although this is not definitive, it demonstrates that neoadjuvant chemotherapy is feasible and increases survival, especially for adenocarcinoma.
The only trial that compared head-to-head neoadjuvant chemotherapy alone vs. chemoradiation failed to accrue and answer this important question. With the limited number of patients, the POET trial showed a better pathologic complete response with chemoradiation and suggested a trend toward increase survival (Stahl M. J Clin Oncol. 2009;27:851-856). Unfortunately, this is not definitive data and does not exclude neoadjuvant chemotherapy for cytoreduction, local control and distant control in the neoadjuvant setting.
To better define the superiority of one modality vs. the other, a meta-analysis that included trials with neoadjuvant chemotherapy vs. trials with neoadjuvant chemoradiation confirmed that OS for adenocarcinoma is approximately 7% for neoadjuvant chemotherapy but did not show superiority of chemoradiation (Sjoquist KM. Lancet Oncol. 2011;12:681-692).
In summary, the definitive data for chemotherapy is lacking. So far, we know that chemotherapy in the neoadjuvant setting is effective, increases survival, provides rapid dysphagia relief and controls micrometastatic disease, which is paramount in a tumor type with such a high relapse rate. The rationale for advocating for systemic therapy in the neoadjuvant setting is that only approximately 50% of the patients are fit for adjuvant chemotherapy. Controlling distant metastatic disease is paramount in impacting survival. The experience with clinical trials enrolling patients for perioperative multimodality therapy demonstrates that many of them do not recover enough to be able to sustain systemic chemotherapy. While timely resection is very important in treating esophageal cancer, probably the best approach is to give these patients an opportunity to receive systemic therapy while they can tolerate it. Incorporating chemotherapy, known as induction chemotherapy and chemoradiation in the neoadjuvant setting, is conceptually important and hopefully will prove a synergistic effect.
Selecting the patients who are chemotherapy sensitive upfront would tailor our therapy further. In the MUNICON trail, using PET-CT after two cycles of chemotherapy to assess response showed that the PET responders had a better survival with neoadjuvant chemotherapy and is a paradigm change in the management of esophageal cancer. Selecting the patients who benefit most from chemotherapy, defining the best sequence for neoadjuvant therapies and identifying superior combinations while lessening toxicity is the focus of research for this disease.
Angela Alistar, MD, is an assistant professor of medicine in the section of hematology and oncology at the Comprehensive Cancer Center at Wake Forest Baptist Health. Disclosure: Alistar reports no relevant financial disclosures.
Direct-aimed radiation therapy may be effective, but more data are needed.
It is human nature for clinicians to seek to optimize their modality — that is, to seek more aggressive and extensive surgery, larger radiation volumes and doses, and more intensive systemic agents and biologics. This often translates to a desire to initiate treatment with each modality early in the treatment course because there may be a lesser need to compromise in treatment intensity. Some clinicians have been disappointed in the outcomes with treatment intensification, even when limited to a single modality.
Induction chemotherapy is being tested in numerous solid tumors. The rationale is that chemotherapy intensity may be less likely to be compromised by combined modality toxicities; however, the direct treatment of the bulky tumor volume is more fully addressed only after a delay for local treatment whether surgery and/or radiation therapy.
A study published earlier this year showed that, in 16 randomized trials with 2,594 patients, induction chemotherapy before surgery was associated with improved survival (Xu XH. Asian Pac J Cancer Prev. 2012;13:103-110). There seems to be a benefit from induction chemotherapy; however, the more important question is, which is superior: preoperative chemotherapy or preoperative chemoradiotherapy? Further, in nonsurgical patients, does induction chemotherapy followed by combined chemoradiotherapy produce better outcomes than combined chemoradiotherapy?
It is important to remember that, even with the best therapy, approximately half of the patients succumb due to the persistence of local esophageal cancer.
In a study published last year, Hingorani and colleagues reviewed nine randomized trials that focused on preoperative radiochemotherapy (CRT) and eight that focused on preoperative chemotherapy as a single modality [Hingorani M. Clin Oncol (R Coll Radiol). 2011;23:696-705]. In their review, two trials demonstrated a survival benefit and seven demonstrated a trend without unexpected increased toxicity. There was a 15% to 49% pathologic complete response rate. Four meta-analyses had a CRT survival benefit that was as high as 13% at 2 years. The CT neoadjuvant studies had a pathological CR rate of less than 10%. Three of five of the meta-analysis were unable to demonstrate a survival benefit, and two were positive up to 7% at 2 years.
Kranzfelder and colleagues identified nine randomized trials of induction CRT vs. surgery alone (Kranzfelder M. Br J Surg. 2011;98:768-783). In eight trials, patients were randomly assigned to induction CT preoperatively. The HR for OS was 0.81 (0.7-0.95; P=.008), which compared favorably to a HR of 0.93 (0.81-1.08; P=.368) for single-modality induction therapy.
Oncological care is constantly being optimized, whether through new radiation, surgical techniques, or systemic treatment agents and strategies. My intuition that a direct-aimed tumor treatment such as radiation therapy adds to the improvement in outcome may need a large randomized trial to convince some of our colleagues. Such a trial could address many other additional questions, such as whether our diagnostic experience and tools could help predict and confirm pathologic responses, and utilize information regarding sites of failure to determine the direction for future improvements in the care of these critically ill patients.
Arnold M. Herskovic, MD, is a radiation oncologist with Rush University Medical Center in Chicago. Disclosure: Herskovic reports no relevant financial disclosures.