Obesity Linked with Esophageal and Gastric Cardia Adenocarcinoma

A combined analysis of previously published studies suggests a link between high body mass index and adenocarcinoma of the esophagus and, possibly, of the gastric cardia. These results were published in the journal Cancer Epidemiology Biomarkers & Prevention.

The esophagus is a tube that connects the back of the throat to the stomach. Most cancers of the upper two thirds of the esophagus arise from squamous cells and are called squamous cell or epidermoid cancers. Cancers of the lower esophagus most often arise from columnar epithelium and are called adenocarcinomas. Over the past two decades, there has been a dramatic increase in the incidence of esophageal adenocarcinomas.

Cancer of the stomach is called gastric cancer. Gastric adenocarcinoma is the most common type of stomach cancer. It arises from the cells that line the surface of the stomach. An important risk factor for gastric cancer is infection with the bacterium Helicobacter Pylori (H. pylori).

Cancers that develops in different parts of the stomach may be linked with different causal factors. Cancer of the gastric cardia refers to cancer that develops in the upper part of the stomach near the esophagus. Cancer in other parts of the stomach is noncardia gastric cancer. Over the last few decades, the frequency of gastric cardia cancer has increased, while the frequency of noncardia gastric cancer has decreased.

Obesity has been thought to play a role in the development of esophageal adenocarcinoma, but previous studies have produced inconsistent results. To summarize the available information, researchers conducted a combined analysis of 14 previously published studies. These studies included cases of both esophageal adenocarcinoma and gastric cardia adenocarcinoma.

High body mass index (BMI greater than 25) was linked with a roughly two-fold increased risk of developing esophageal adenocarcinoma.
Risk of esophageal adenocarcinoma increased with increasing BMI (obese individuals had a greater risk than overweight but nonobese individuals).
High BMI was linked with a 50% increased risk of gastric cardia adenocarcinoma.
The researchers conclude that there does appear to be a link between high body mass index and risk of developing esophageal adenocarcinoma and, possibly, gastric cardia adenocarcinoma.

Reference: Kubo A and Corley DA. Body Mass Index and Adenocarcinoma of the Esophagus or Gastric Cardia: A Systematic Review and Meta-analysis. Cancer Epidemiology Biomarkers & Prevention. 2006;15:872-878.

Epoetin May Improve Survival in Patients with Esophageal Cancer

According to an article recently published in the International Journal of Radiation Oncology Biology, and Physics, the use of epoetin alfa to prevent or reduce anemia is associated with improved survival for patients with stage III esophageal cancer who are treated with chemotherapy and radiation therapy.

The esophagus is a muscular tube that carries food from the mouth to the stomach. Patients with stage III esophageal cancer have cancer that invades through the wall of the esophagus and has spread to the lymph nodes and/or invaded adjacent structures; many esophageal cancer patients are diagnosed at this stage of disease. Stage III cancer may also be referred to as locally advanced.

Anemia is a common adverse effect caused by some chemotherapy regimens, radiation therapy, and sometimes by the cancer itself. It is characterized by low levels of circulating red blood cells, which are responsible for delivering oxygen to tissues throughout the body.

Common symptoms of anemia are severe fatigue, shortness of breath, diminished activity levels, and a reduced overall feeling of well-being.

Severe anemia often requires treatment with blood transfusions, which have associated risks of infection, rejection, and increased medical costs. Furthermore, severe anemia may cause a delay in cancer treatment, resulting in suboptimal chances of a cure or optimal long-term survival.

Treatment of anemia with medications that stimulate the production of red blood cells (erythropoietic treatment) has been shown to have several benefits in cancer patients, including increased quality of life and decreased need for blood transfusions. These medications include Aranesp® (darbepoetin alfa) and Procrit® (epoetin alfa).

Researchers from Germany recently provided follow-up data of a study that evaluated the effects of epoetin alfa and outcomes of patients with stage III esophageal cancer. This study included 96 patients who were treated with chemotherapy (5-fluorouracil and Platinol® [cisplatin]) and radiation therapy followed by surgery. A total of 42 patients received epoetin alfa to maintain hemoglobin levels of 12-14 g/dL; 54 patients did not receive epoetin alfa (control group).

At two years 67% of patients treated with epoetin alfa did not experience cancer progression at or near the site of origin compared with only 15% of the control group.
Overall survival at two years was 32% for those treated with epoetin alfa compared with only 8% in the control group.
The researchers concluded that use of epoetin alfa in patients with esophageal cancer undergoing chemotherapy and radiation therapy was associated with a reduced risk of cancer progression near the site of cancer origin, as well as improved overall survival. Further study is necessary to confirm these findings.

Patients with esophageal cancer who are to undergo treatment with chemotherapy and radiation therapy may wish to speak with their physician regarding their individual risks and benefits of treatment with epoetin alfa or Aranesp®.

Reference: Rades D, Tribius S, Yekebas EF, et al. Epoetin alfa improves survival after chemoradiation for stage III esophageal cancer: Final results of a prospective observational study. International Journal of Radiation Oncology Biology Physics. 2006;65:459-465.

Esophagitis Increases Risk of Esophageal Cancer

According to an early online publication in the American Journal of Gastroenterology, individuals with esophagitis have a significantly increased risk of developing esophageal cancer.

The esophagus is a muscular tube that carries food from the mouth to the stomach. Esophagitis refers to inflammation, irritation, or swelling of the esophagus. Esophagitis is most often caused by gastroesophageal reflux disease (GERD), a condition in which acids from the stomach enter back into the esophagus; however, it may also be caused from excessive vomiting, surgery, certain medications, or infections of the esophagus that most commonly occur in individuals with compromised immune systems.

Once cancer of the esophagus has spread from its site of origin, cure rates are not favorable. Individuals who are identified as having a high risk of developing esophageal cancer may be screened frequently. This allows disease to be detected and treated in its earliest stages, when it is most curable. There are two main types of esophageal cancer: adenocarcinoma and squamous cell carcinoma; the distinction refers to the type of cell within the esophagus where the cancer originated.

Researchers from Denmark recently conducted a clinical study to evaluate a possible association between esophagitis and the risk of esophageal cancer. This study included data from patients with previously diagnosed esophagitis from five population-based databases in Denmark from 1974 to 2002.

11,129 patients were previously diagnosed with esophagitis.
The risk of esophageal cancer (adenocarcinoma) was increased five-fold among patients with esophagitis compared to those without esophagitis.
The majority of esophageal cancers (adenocarcinoma) occurred in patients with Barrett’s esophagus (condition in which the lining of the esophagus is damaged—often caused by GERD).
The researchers concluded that a diagnosis of esophagitis appears to significantly increase the risk of developing esophageal cancer. Patients with esophagitis should speak with their physician regarding the risks and benefits of specific screening measures for esophageal cancer.

Reference: Lassen A, Hallas J, Muckadell, O. Esophagitis: Incidence and Risk of Esophageal Adenocarcioma-A Population-Based Cohort Study. American Journal of Gastroenterology. Early online publication April 28, 2006. DOI: 10.1111/j.1572-0241.2006.00550.x.

Selected Subsets of Patients with Esophageal Cancer Respond to Iressa®

Among patients with advanced esophageal cancer, treatment with Iressa® (gefitinib) produced better results in women, in patients with high expression of the epidermal growth factor receptor (EGFR), and in patients with squamous cell cancer. These results were published in the Journal of Clinical Oncology.

The esophagus is a multi-layered, hollow tube that connects the throat and stomach. Most cancers of the upper two thirds of the esophagus arise from squamous cells and are called squamous cell or epidermoid cancers. Cancers of the lower esophagus most often arise from columnar epithelium and are called adenocarcinomas.

In the recent past, squamous cell cancers made up more than 80% of all esophageal cancers. Over the past two decades, there has been a dramatic increase in the incidence of adenocarcinomas. Most of the adenocarcinomas of the lower esophagus are thought to arise in the setting of Barrett’s esophagus.

Current treatments for esophageal cancer include surgery, radiation, chemotherapy, or a combination of these options. Because survival after treatment for advanced esophageal cancer remains poor, researchers continue to evaluate new treatments.

Iressa is an anticancer agent that selectively blocks the epidermal growth factor receptor (EGFR). EGFR is a protein involved in the growth and replication of a cell. In some cancers, the EGFR may not be working properly; this leads to excessive replication of the cancer cell. Iressa is taken orally and binds to a portion of EGFR to inhibit cancer cell growth.

To evaluate response to Iressa among patients with advanced esophageal cancer, researchers in The Netherlands conducted a phase II clinical trial. The study enrolled 36 patients with advanced esophageal cancer who had relapsed after chemotherapy. Patients received 500 mg per day of Iressa and were evaluated for response every eight weeks.

One patient experienced a partial reduction in detectable cancer.
10 patients (28%) had cancer that remained stable.
17 patients (47%) had cancer that got worse.
8 patients (22%) could not be evaluated.
Median overall survival time was 164 days.
Response to treatment (either improvement or stabilization of cancer) was more common among women, among patients with squamous cell cancer, and among patients with high tumor EGFR expression.
The most common side effects of treatment were diarrhea and rash.
The researchers conclude that overall, Iressa produces modest treatment effects in patients with advanced esophageal cancer. Response to treatment was better, however, among women, patients with high EGFR expression, and patients with squamous cell cancer.

Patients with advanced esophageal cancer may wish to talk with their doctor about the risks and benefits of participating in clinical trial to explore new therapeutic approaches. Two sources of information regarding ongoing clinical trials include the National Cancer Institute (www.cancer.gov) and www.cancerconsultants.com.

Reference:Janmaat ML, Gallegos-Ruiz M, Rodriguez JA et al. Predictive Factors for Outcomes in a Phase II Study of Gefitinib in Second-Line Treatment of Advanced Esophageal Cancer Patients. Journal of Clinical Oncology. 2006;24:1612-1619.

Advexin® Promising for Inoperable, Refractory Esophageal Cancer

According to a press release by Introgen Therapeutics, Inc., the vaccine Advexin® appears promising as single-agent therapy in patients with inoperable esophageal that has stopped responding to standard therapies.

The esophagus is a multi-layered, hollow tube that connects the throat and stomach, allowing transportation of food and fluids. The prognosis for esophageal cancer depends on four factors:

The stage (extent of spread) when disease is diagnosed
The size of the tumor
The sites to which the cancer has spread
The patient’s general health
Current treatments include surgery, radiation, chemotherapy, or a combination of these options.

Cancer that has stopped responding to standard therapies is referred to as refractory cancer. Treatment options for patients with refractory esophageal cancer remain limited, and long-term outcomes are not favorable. Researchers continue to evaluate novel treatment strategies in order to improve survival for patients with this disease.

The p53 gene is found in most cells; some of its activity suppresses the growth of cancer cells. However, in many cancers, the p53 gene is mutated so that it does not stop the growth of the cancer cells. In such cases, researchers have been evaluating ways to “activate” the normal actions of the p53 genes in patients with cancer.

Advexin is a vaccine that is injected directly into the sites of cancer. The vaccine delivers a functioning p53 gene into these cancerous areas. To produce Advexin, the p53 gene is inserted into a common virus (adenovirus) that has been rendered unable to produce illness in humans. Once injected into the patient, the virus inserts itself into the DNA of the cancer cells; the p53 gene can then begin its normal function of inhibiting excessive growth or spread of the cancer cells.

Researchers from Japan recently conducted a small clinical trial to evaluate Advexin for the treatment of refractory esophageal cancer. This trial included 10 patients who were not eligible for surgery and had stopped responding to standard therapies. Patients were treated with Advexin as a single agent.

Advexin produced promising results:

60% of patients experienced disease stabilization for more than one year.
One patient remained alive and progression-free for nearly 4 years following treatment with Advexin.
One patient who was not able to swallow upon entering the trial was able to swallow liquids and meals after two injections of Advexin.
Advexin was well tolerated.
The researchers concluded that Advexin provides long-lasting anticancer responses while being well tolerated in patients with refractory, inoperable esophageal cancer. Advexin is still in the clinical trials processes and is not yet approved by the U.S. Food and Drug Administration (FDA).

Patients with refractory esophageal cancer may wish to speak with their physician regarding their individual risks and benefits of participating in a clinical trial further evaluating Advexin or other novel promising treatment approaches. Two sources of information regarding ongoing clinical trials include the National Cancer Institute (www.cancer.gov) and www.cancerconsultants.com.

Reference: Introgen Therapeutics, Inc. Phase I/II Clinical Data Demonstrate Safety and Antitumor Activity of Introgen's ADVEXIN(R) in Patients With Advanced Esophageal Cancer.

FDA Advisory Committee Concludes Cervical Cancer Vaccine is Safe and Effective

A U.S. Food and Drug Administration (FDA) Advisory Committee has concluded that Gardasil®, an investigational cervical cancer vaccine, appears to be safe and effective. This information was published in a press release by Merck & Co.

Human papillomavirus (HPV) is a sexually transmitted infection that is the primary cause of cervical cancer. Different types of HPV are classified as “low-risk” or “high-risk” based on how likely they are to cause cervical cancer.

While several types of HPV have been linked with cervical cancer, HPV types 16 and 18 are thought to account for roughly 70% of all cervical cancer cases. High-risk types of HPV also contribute to the development of precancerous changes to the cervix known as cervical intraepithelial neoplasia (CIN). High-grade CIN (CIN2 and CIN3) can progress to cancer if not treated.

Gardasil is an investigational vaccine that protects against infection with HPV types 16 and 18, as well as two types of HPV linked with genital warts (HPV types 6 and 11). Gardasil is not intended to treat HPV in individuals who are already infected.

An application for approval of Gardasil was submitted to the FDA by Merck & Co in December 2005. The FDA expects to complete its review of the application by June 8, 2006. As part of this process, information about the safety and efficacy of the vaccine was reviewed by one of the FDA’s advisory committees.

Based on review of evidence from phase II and phase III clinical trials, the advisory committee agreed on the following points:

Gardasil appears to be safe and effective against HPV 16- and HPV 18-related cervical cancer, as well as precancerous changes to the cervix, vulva, and vagina.
Gardasil appears to be safe and effective against other conditions related to HPV types 6, 11, 16, or 18, including genital warts.
The FDA will consider the committee’s conclusions when making its final decision about approval of the vaccine.

The President of Merck Research Laboratories notes. “If approved, Gardasil will be the first and only vaccine to prevent cervical cancer and other HPV-related diseases.”

Reference: Merck & Co. Research and Development News. FDA Advisory Committee Votes Unanimously that Clinical Data Support the Efficacy and Safety of GARDASIL®, Merck’s Investigational Cervical Cancer Vaccine. May 18, 2006.

Phase II Trial of HPV Therapeutic Vaccine Produces Promising Results

According to a press release from Transgene, an experimental human papillomavirus (HPV) therapeutic vaccine resulted in the disappearance of high-grade precancerous changes to the cervix in nine out of 18 vaccinated women.

Human papillomavirus (HPV) is a sexually transmitted infection that is the primary cause of cervical cancer. Different types of HPV are classified as “low-risk” or “high-risk” based on how likely they are to cause cervical cancer.

While several types of HPV have been linked with cervical cancer, HPV types 16 and 18 are thought to account for roughly 70% of all cervical cancer cases. High-risk types of HPV also contribute to the development of precancerous changes to the cervix known as cervical intraepithelial neoplasia (CIN). High-grade CIN (CIN2 and CIN3) can progress to cancer if not treated.

The link between HPV and cervical cancer opened important avenues of research. These included the development of tests to identify women infected with high-risk types of HPV, as well as work on HPV vaccines.

The HPV vaccines under development fall into two broad categories: preventive and therapeutic. Preventive vaccines are designed to prevent infection with the virus, whereas therapeutic vaccines would treat the infection, the precancerous changes, or the cancer in individuals who are already infected.

Prevention of infection is the ultimate goal, but treatment of existing infections and cervical abnormalities would benefit the many women who are infected currently.

Although the vaccines that are farthest along in development (Gardasil™ and Cervarix™) are both preventive vaccines, research into therapeutic vaccines continues. In order to assess the safety and effectiveness of an experimental HPV therapeutic vaccine, researchers in France conducted a phase II clinical trial among 21 women with HPV 16-related CIN2 or CIN3. The women ranged in age from 25 to 44. Rather than undergoing immediate surgery, the women were vaccinated with an experimental vaccine known as TG4001 and were observed by colposcopy (a magnified examination of the cervix) every two months.

At the end of six months of follow-up, information was available for 18 women:

Nine out of 18 women (50%) had no CIN2 or CIN3.
Nine out of 18 women (50%) had no evidence of the HPV proteins known as E6 and E7. These proteins are thought to play a role in HPV-related cancers.
There were no serious side effects of vaccination.
The researchers conclude that use of this experimental vaccine allowed 50% of women with HPV 16-related CIN2 or CIN3 to avoid surgery.

Reference: Transgene. Press Release. Transgene Announces Positive Phase II Results for its HPV Therapeutic Vaccine in Precancerous Cervical Lesions. April 25, 2006.

Addition of Radiation Therapy Following Surgery Reduces Recurrences in Early Cervical Cancer

According to an article published in the International Journal of Radiation Oncology, Biology, and Physics, the addition of radiation to the pelvis following surgery for the treatment of stage IB cervical cancer reduces recurrences and improves progression-free survival compared to surgery alone.

The American Cancer Society estimates that there will be 10,370 new cases of cervical cancer in the U.S. in 2005. Fortunately, the number of deaths resulting from cervical cancer has declined dramatically over the years; this is credited to widespread use of a screening test called the Pap smear. Currently, over half of patients with cervical cancer are diagnosed when the cancer is still confined to the cervix (stage I).

Stage IB cervical cancer refers to cancer that has not spread from the cervix. However, the cancer may have invaded some tissue layers of the cervix. The cancer may also be referred to as “bulky” if it measures greater than 4 centimeters in diameter.

Stage IB cervical cancer may be treated with surgery alone, surgery plus radiation therapy, or even chemotherapy. Researchers continue to evaluate the optimal treatment for stage IB cervical cancer; side effects of treatment are weighed in relation to overall outcomes.

Researchers from multiple institutions in the U.S. recently conducted a phase III clinical trial to directly compare surgery to surgery plus radiation therapy in the treatment of 277 patients with stage IB cervical cancer.

The addition of radiation therapy improved outcomes:

The addition of radiation therapy reduced the risk of a cancer recurrence by 46%.
The risk of cancer progression or death was reduced by 42% with the addition of radiation therapy.
The researchers concluded that the addition of radiation therapy following radical surgery significantly improves outcomes among women with stage IB cervical cancer compared with surgery alone. However, radiation therapy is also associated with side effects, so it is important for all women diagnosed with cervical cancer to discuss their individual risks and benefits of radiation therapy with their physician.

Reference: Rotman M, Sedlis A, Piedmonte M, et al. A Phase III Randomized Trial of Postoperative Pelvic Irradiation in Stage IB Cervical Carcinoma with Poor Prognostic Features: Follow-Up of a Gynecologic Oncology Group Study. International Journal of Radiation Oncology,Biology and Physics. 2006; 65: 169-176.

Telephone Intervention Improves Screening Rates

According to a study published in the Annals of Internal Medicine, a telephone support intervention improved the rates of screening for breast, cervical, and colorectal cancer among low-income women.

Screening for early detection of cancer has improved survival for many types of cancer, including breast, cervical, and colorectal. Cervical and colorectal screening also offers the benefit of detecting precancerous changes. Treating these precancerous changes may prevent the development of cancer.

In spite of the known benefits of cancer screening, many women are not screened at the recommended intervals or are not screened at all. This is a particular problem among low-income women who may experience many barriers to care. Researchers are therefore interested in identifying ways to decrease disparities in receipt of cancer screening.

In order to evaluate the effect of telephone support on screening rates for three types of cancer—breast, cervical, and colorectal—researchers conducted a randomized trial among women who received care at community and migrant health centers in New York City.

The study enrolled a total of 1413 women between the ages of 50 and 69. All were overdue for at least one type of cancer screening.

Half the women were assigned to receive the telephone support intervention, and half were assigned to receive usual care.

The telephone support intervention consisted of a series of telephone calls from a trained prevention care manager. The point of the telephone calls was to identify and address each woman’s barriers to screening. Over an 18-month period, women in the intervention group received an average of four telephone calls.

Over the study period, the rate of mammography increased from 58% to 68% among women in the intervention group and decreased from 60% to 58% among women in the usual care group.
The rate of Pap testing increased from 71% to 78% among women in the intervention group and did not change among women in the usual care group.
The rate of colorectal cancer screening increased from 39% to 63% among women in the intervention group and from 39% to 50% among women in the usual care group.
The proportion of women who were up-to-date for all three types of screening increased from 21% to 43% among women in the intervention group and from 22% to 30% among women in the usual care group.
The researchers conclude, “Telephone support can improve cancer screening rates among women who visit community and migrant health centers.” This may be a useful strategy for reducing existing disparities in receipt of recommended screening tests.

Reference: Dietrich AJ, Tobin JN, Cassells A et al. Telephone Care Management to Improve Cancer Screening Among Low-Income Women: A Randomized Controlled Trial. Annals of Internal Medicine. 2006;144:563-571.

HPV Test Identifies a Majority of Women with High-Grade CIN

An analysis of several previously published studies concludes that a test for high-risk types of human papillomavirus (HPV) identifies a large majority of women with high-grade cervical intraepithelial neoplasia (CIN). These results were published in the International Journal of Cancer.

Effective screening programs for cervical cancer have decreased the frequency of cervical cancer in the U.S. Screening can detect precancerous changes to the cervix, known as cervical intraepithelial neoplasia (CIN). The severity of CIN is classified on a scale of 1 to 3, with 3 being the most severe. Because the more severe types of CIN may progress to cervical cancer, removal of these lesions reduces the risk of cancer.

Cervical cancer screening has traditionally relied on the Pap test. During a Pap test, a sample of cells is removed from the cervix using a small wooden spatula or a brush. The cells are examined by a laboratory and results are then classified into five categories: normal; atypical squamous cells of undetermined significance (ASCUS); low-grade squamous intraepithelial lesions (LSIL); high-grade squamous intraepithelial lesions (HSIL); or cancer.

More recently, researchers have evaluated the role of HPV testing in cervical cancer screening. HPV is a sexually transmitted infection that is the primary cause of cervical cancer. Different types of HPV are classified as “low-risk” or “high-risk” based on how likely they are to cause cervical cancer. Screening women for high-risk types of HPV may identify women who are most likely to have precancerous changes to the cervix.

To compare the Pap test and the HPV test as cervical cancer screening tools, researchers assessed the results of several previously published studies. The studies were conducted in North American and Europe and enrolled more than 60,000 women.

The HPV test identified a higher proportion of the women with high-grade CIN (CIN 2 or CIN 3) than the Pap test. HPV testing identified 96% of these women and the Pap test identified 53%.
The ability of the HPV test to identify women with high-grade CIN did not vary by age. The ability of the Pap test to identify women with high-grade CIN was greatest in women over the age of 50.
The HPV test was less accurate than the Pap test at correctly classifying women without high-grade CIN. Among women without high-grade CIN, the HPV test correctly classified 91% of the women and the Pap test correctly classified 96% of the women.
Among women with a positive HPV test, 16% were found to have high-grade CIN. Among women with a positive Pap test, 20% were found to have high-grade CIN.
Although questions remain about the most appropriate use of HPV testing, the researchers suggest that a strategy of initial HPV testing, followed by a Pap test for those with positive HPV results, may improve the accuracy of cervical cancer screening.

Reference: Cuzick J, Clavel C, Petry K-U et al. Overview of the European and North American Studies on HPV Testing in Primary Cervical Cancer Screening. International Journal of Cancer. Early online publication April 3, 2006.