Anemic Patients With Myelodysplastic Syndromes Gain Long-Term Benefits From Erythropoietin and Myeloid Growth Factor Hormones

Myelodysplastic Syndromes (MDS), a group of blood disorders that can lead to acute myeloid leukemia (AML) in some patients, often cause severe anemia (when the body lacks a sufficient number of functional red blood cells). While certain treatments can help manage the symptoms of anemia, some studies have suggested that they may lead to complications.

Now a new study demonstrates that MDS patients with anemia may benefit from treatment with an erythropoietin (EPO)-based regimen plus supportive care without added complications as compared with those receiving supportive care alone. The study will appear in the September 17 issue of Blood, the official journal of the American Society of Hematology.

The phase III prospective, randomized trial, conducted by research teams of the Eastern Cooperative Oncology Group, was designed to evaluate the efficacy and safety of EPO with or without myeloid growth factor treatment (G-CSF, or granulocyte colony-stimulating factor) and supportive care (SC) with red blood cell transfusions for patients with early-stage MDS (n=53), in comparison to supportive care alone (n=57).

For the study, the researchers followed MDS treatment and dosing guidelines recommended by the National Comprehensive Cancer Network, which include managing anemia with erythropoiesis-stimulating agents (ESAs) such as EPO. EPO is a drug that imitates the action of the hormone erythropoietin, which stimulates the body to produce more red blood cells. Generally, therapy with G-CSF interacts with EPO treatment synergistically to improve erythroid (red blood cell) responses, especially in MDS patients that do not respond to EPO alone.

"EPO is a recommended treatment for MDS, but the combination with G-CSF and supportive care required comparative studies in this patient population," according to lead study author Peter Greenberg, MD, Professor of Medicine, Stanford University Cancer Center. "Our goal was to manage anemia while not increasing the risk of transformation to leukemia, and we undertook this study to understand if this combination might be successfully utilized in these patients."

The results of the study proved successful for this group of patients with lower-risk MDS and anemia. After the first course of therapy, 36 percent of patients in the EPO arm responded to treatment, compared with only 9.6 percent in the SC alone arm. After subsequent courses, 47 percent responded in the EPO arm. Researchers then followed both patient groups for a median of 5.8 years to determine their long-term response to treatment. Responders to EPO experienced increased survival in comparison to the non-responders (5.5 vs. 2.3 years) and significantly improved physical, emotional, and functional well-being, reduced fatigue, and improved overall quality of life.

The research team otherwise found no statistically significant differences in overall survival of patients between the EPO and SC arms (3.1 vs. 2.6 years) or the incidence of transformation to AML (7.5 vs. 10.5 percent of patients, respectively), suggesting long-term safety of the EPO treatment regimen.

The study results also indicated that the combination of EPO plus G-CSF was beneficial for patients who either did not respond initially to EPO or who experienced a delayed response. Furthermore, higher doses of EPO seemed to prove valuable for a proportion of patients who initially failed to respond. Importantly, the outcomes suggested long-term tolerance to the treatment combination, with a low overall incidence of adverse events. Specifically, the researchers found no significant treatment-related increase in incidence of either cardiovascular or thrombotic (clotting) events or transformation to AML in the patients who received EPO alone or with G-CSF, as compared with those in the SC arm.

Recently, the FDA has issued alerts regarding the use of ESAs, noting increased mortality, possible tumor promotion, and thromboembolic events that have been observed in some studies of non-MDS patients receiving ESAs. However, other studies of patients with solid tumors receiving chemotherapy did not demonstrate an adverse effect of ESAs on survival.

"We believe the data suggest that the negative effects of cytokines, like ESAs, demonstrated in some studies of other diseases may relate to biologic and clinical features or the specific treatments associated with the differing disorders studied," said Dr. Greenberg. "Findings from this study demonstrate the relative safety and efficacy of EPO plus G-CSF for treating anemic lower-risk MDS patients and may be considered as part of future treatment recommendations for the use of this class of therapies."

For Aditional Information

• Treatment of myelodysplastic syndromes patients with erythropoietin
  with or without granulocyte colony-stimulating factor: results of a
  prospective randomized phase III trial by the Eastern Cooperative
  Oncology Group (E1996), Blood First Edition Paper, prepublished online
  June 29, 2009
• American Society of Hematology/American Society of Clinical Oncology
  2007 Clinical Practice Guideline Update on the Use of Epoetin and
  Darbepoetin
• ASH Model Policy on Indications for ESA Treatment for Patients with MDS

Mutations in EGF Gene Associated with Increased Esophageal Cancer Risk

Researchers have identified specific mutations in the epidermal growth factor (EGF) gene that are associated with increased esophageal cancer risk in people with gastroesophageal reflux disease (GERD). This is the first study to examine EGF mutations as predictors of esophageal cancer risk in patients with GERD.

The results of this study were presented during the sixth annual Gastrointestinal Cancers Symposium , which is co-sponsored by the American Gastroenterological Association (AGA) Institute , the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO) and the Society of Surgical Oncology (SSO), being held in San Francisco, CA (January 15 – 17, 2009).

‘We’ve known for some time that GERD is a risk factor for esophageal cancer, but our findings are the first to identify specific genetic markers that are linked with increased cancer risk in patients with GERD,’ said Winson Y. Cheung, MD, a clinical research fellow working with the University of Toronto and the Harvard School of Public Health, and the lead author of the study.

‘While our findings will need to be validated in larger and more diverse patient groups, this is a first step in the right direction toward developing a test to identify which patients are at highest risk of esophageal cancer and would benefit from more aggressive screening. And because GERD is a common condition, the ability to single out patients at high risk of cancer could lead to better outcomes and significant cost savings.’

Incidence and cause of GERD
Gastroesophageal reflux disease (GERD), also referred to as heartburn, is reflux and regurgitation of the contents of the stomach into the esophagus. The disease is quite common, can affect everyone, from newborn infants to adults, and is often frequent and severe enough to impact daily life. In the United States it is estimated that nearly 60 million people experience symptoms at least once a month. Over 60% of the elderly have frequent GERD, and over 14 million Americans have GERD so frequently and severely that they experience symptoms every single day.

In general, the presence of gastroesophageal reflux implies lower esophageal sphincter (LES) incompetence. Located at the very bottom of the esophagus, where the esophagus joins the top of the stomach, the esophageal sphincter is a ‘high pressure zone’ between the esophagus and stomach. After swallowing, food moves down the esophagus by esophageal contraction. Then esophageal sphincter relaxes to allow food to pass into the stomach, and then closes again to prevent reflux of the stomach content, including food and digestive juices, back into the esophagus. Another important contributor to GERD is the failure of the antireflux barrier (ARB) and its primary component, the gastroesophageal valve (GEV).

Although the lower esophageal sphincter plays a major role in the occurrence of GERD, researchers recently started to focus more on the gastroesophageal valve as the largest contributor to the anti-reflux barrier. In healthy individuals, the Angle of His, the angle at which the esophagus enters the stomach, is intact creating a valve that prevents duodenal bile, enzymes, and stomach acid from traveling back into the esophagus where it can cause burning and inflammation of the sensitive esophageal tissue. In gastroesophageal reflux disease, the ‘valve’ is damaged, weakened or absent. This causes the acidic digestive juices from the stomach to flow back (or reflux) into the esophagus. This often creates a burning pain in the center of the chest that starts in the upper abdomen and sometimes spreads into the neck.

There are a number of factors contributing to the development of GIRD. These may include weight gain, fatty foods, caffeinated or carbonated beverages, alcohol, tobacco smoking, and drugs, including anticholinergics, antihistamines, tricyclic antidepressants, Ca channel blockers, progesterone, and nitrates.

Complications
In severe or chronic GERD, regurgitation occurs regularly, spilling acid, bile, and other stomach contents not only into the esophagus but also into the lungs, mouth, pharynx and even the nose. This can lead to a variety of complications including esophagitis, anemia, esophageal stricture, peptic esophageal ulcer, and Barrett's esophagus, a condition that develops in the lining of the lower esophagus.

Uncontrolled regurgitation has also been associated with a number of atypical symptoms, including a chronic sore throat, cough, laryngitis, dental erosions, discomfort in the ears and nose, recurrent bronchitis, asthma like symptoms and sleep disturbance. Cell damage of the lower part of the esophagus has been linked to the development of esophageal adenocarcinoma.

Given the number of symptoms and the potential for severe complications, GERD has a significant impact on quality of life and, in extreme cases, life expectancy.
Treatment may include a combination of lifestyle changes (including weight loss), over the counter medications (OTC), and prescription drug regimens, and, in more severe cases, surgery.

Esophageal Cancer
According to the American Cancer Society, about 30 percent of esophageal cancers can be traced to GERD. In 2008, more than 16,000 cases of esophageal cancer were diagnosed. This disease is 3 to 4 times more common among men than among women and about 50% more common among African Americans than among caucasians. Nevertheless, if detected early, the disease is generally curable.

Because esophageal cancer is usually diagnosed at a relatively late stage, it is one of the most deadly forms of gastrointestinal cancer. With a mortality rate exceeding 85%, most patients will eventually die of the disease. However, statistics from the American Cancer Society show that survival rates have been improving. During the early 1960s, only 4% of all white patients and 1% of all African-American patients survived at least 5 years after diagnosis. Today, about 18% of Caucasian, and 11% of African-American patients survive at least 5 years after diagnosis.

Early detection is the best prevention. But screening is invasive and expensive, and therefore not recommended for all patients with GERD. The American College of Gastroenterology therefore recommends periodic endoscopies only for patients with long-standing symptoms of reflux.

Genetics
Esophageal carcinogenesis involves multiple genetic alterations. In this study, Cheung and his team of researchers collected DNA samples from 309 patients being treated for esophageal adenocarcinoma (the most common type of esophageal cancer in North America) at Massachusetts General Hospital in Boston, and 275 healthy, matched controls. The investigators analyzed study participants’ genotypes and GERD history.

Baseline characteristics were comparable between cases and controls except that epidermal growth factor (EGF) variants (A/G or G/G) were more common (p=0.02) and GERD was more prevalent (p<0.001)epidermal growth factor (EGF) called G/G who experienced symptoms associated with GERD more than once a month, compared with those who had the A/A (normal, or wild-type) variant epidermal growth factor (EGF) without GERD, were at a 10-fold increased risk of esophageal cancer (OR 1.90; 95% CI, 1.2-3.0; p=0.007).

Stratified analyses revealed that this correlation between G/G genotype and esophageal cancer risk was evident only for the subset of patients with GERD. The researchers noted that the risk of esophageal cancer increased further among patients with the mutation who suffered from GERD more frequently, generally more than 1 time per week (OR 21.8; 95% CI, 5.1-94.0; p<0.001), p="0.007)or for more than 15 years (OR 22.4; 95% CI, 6.5-77.6; p<0.001).

The study showed a highly significant interaction between the G/G genotype and the presence of GERD (p=0.007).

Patients with GERD and the genetic variant called A/G had an intermediate increase in risk.

While researchers concluded that performing EGF genotyping for patients with severe or longstanding GERD can help to identify individuals at the greatest risk of esophageal adenocarcinoma, the results of this test are just one step that may lead to the development of new tests for finding esophageal cancer at an earlier, more curable stage.

Better understanding of the genetic predisposition may eventually lead to new therapies that repair the abnormal genetic changes in esophageal cancer cells.

For more information, read:

• W. Y. Cheung, WY Zhai R, Kulke M, et al. Epidermal growth factor (EGF) gene polymorphism, gastroesophageal reflux disease (GERD) and risk of esophageal adenocarcinoma (EA). 2009 Gastrointestinal Cancers Symposium General Session II: Cancers of the Esophagus and Stomach: Translational Research. Abstract 2. Translational research

Also read PubMed abstracts:

• Xu XC. Risk factors and gene expression in esophageal cancer. Methods Mol Biol. 2009;471:335-60.
• Kuwano H, Kato H, Miyazaki T et al. Genetic alterations in esophageal cancer. Surg Today. 2005;35(1):7-18.
• Feagins LA, Souza RF. Molecular targets for treatment of Barrett's esophagus. Dis Esophagus. 2005;18(2):75-86.
• Souza RF. Molecular and biologic basis of upper gastrointestinal malignancy -esophageal carcinoma. Surg Oncol Clin N Am. 2002 Apr;11(2):257-72, viii.

Also visit:

• American Gastroenterological Association (AGA)
• American Society of Clinical Oncology (ASCO)
• American Society for Radiation Oncology (ASTRO)
• Society of Surgical Oncology (SSO)
• European Society of Surgical Oncology (ESSO)
• Canadian Society for Surgical Oncology (CSSO)

Information for Healthcare Professionals:

• The Merck Manual: Esophageal Cancer.
• NCCN – National Comprehensive Cancer Network (Practice Guidelines).

For your patients:

• Cancer.Net Guide to Esophageal Cancer.
• Mayo Clinic: Esophageal Cancer.

Books to read:

• 100 Questions & Answers About Esophageal Cancer (100 Questions Series)
• Esophageal Cancer Medical Guide
• Esophageal Cancer: Principles and Practice
• Esophageal Cancer
• Esophageal Cancer Toolkit - Comprehensive Medical Encyclopedia with Treatment Options, Clinical Data, and Practical Information
• Esophageal Cancer - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References