International Trial Shows Aspirin Protects Against Colorectal Cancer

A daily dose of aspirin can prevent the occurrence of cancer in people with a genetic predisposition towards Lynch syndrome, a condition which accounts for around five percent of all colon cancers, a scientist told the audience at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany.

Professor John Burn, from the Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK, said that he believed that he and his colleagues might have uncovered a simple way of controlling cancer stem cells, which are essential to the formation of malignant tumors.

The clinical trial, which involved 1071 carriers of the Lynch syndrome mutation in 42 centers worldwide, randomized participants to a daily dose of 600mg aspirin and/or 30g Novelose®, a resistant starch that escapes digestion in the small intestine. “Although there were many reports that aspirin might have a beneficial effect in a range of cancers,” said Prof Burn, “they were from case control and epidemiological studies. We decided that the only way to achieve conclusive proof was to undertake a randomized trial in a high risk population.”

Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is a rare type type of inherited cancer of the digestive tract that increases a patient’s risk of cancer, particularly the colon and rectum. People with Lynch syndrome have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, upper urinary tract, brain, skin, and prostate. Women carriers also have a high risk of developing endometrial and ovarian cancers.

These patients tend to develop cancer quickly, so the scientists expected to see answers at an early stage. The first results were disappointing, however; at an average of 29 months after randomization the scientists saw no evidence of the benefits of aspirin in the high-risk population studied.

“Our original design allowed for long term post trial follow-up,” noted Prof Burn. “We have managed to track down most of those who completed the trial – around 75% of the original consent cohort – with information extending up to 10 years from randomization. We found that, around four years after randomization, there was a divergence in the incidence of cancers between the aspirin and placebo groups. To date, there have been only six colon cancers in the aspirin group as opposed to 16 who took placebo. There is also a reduction in endometrial cancer. This is a statistically significant result and we are delighted – all the more so because we stopped giving the aspirin after four years, yet the effect is continuing, and is directly correlated with the duration of aspirin use on the trial.”

Although scientists believe that diet is a major factor in the prevention of colorectal cancers, there are no randomized trial data which can prove it, since running proper, controlled trials of diet is extremely difficult. However, there is a strong inverse relationship between colon cancer and how much starch people eat. Resistant starch, after escaping digestion in the upper gut, is fermented in the colon and forms short chain fatty acids, which are powerful anti-cancer agents.

“Our very large colon probably evolved to capture such nutrients from our forefathers’ diets,” explained Prof Burn. “Because we were giving starch as well as aspirin we would also have expected to see a decrease in cancers in the placebo group. However, there could be a number of reasons for this result – perhaps patients didn’t take the starch every day, or that it simply wasn’t resistant enough.”

There were minor problems due to aspirin side effects; out of over 1000 people, 11 in the aspirin group had notable gastro-intestinal bleeds or ulcers as opposed to nine in the placebo group. But this was counter-balanced by fewer strokes and heart attacks in the aspirin group.

The mechanism by which aspirin protects against cancer has yet to be elucidated, but the scientists believe that cancer stem cells are involved. “We do not think that the mechanisms discussed to date are likely to provide an explanation,” said Prof Burn. “For example, the inflammatory enzyme COX2(Cyclooxygenase-2), a protein that acts as an enzyme and specifically catalyzes the production of certain chemical messengers called prostaglandins, is over-expressed in early cancer, but our results suggest an effect that predates the cancer, and may even predate the adenoma which precedes it. We believe that aspirin may have an effect on the survival of aberrant stem cells in the colon. These cancer stem cells are normally resistant to chemotherapy, but if a stem cell mutates but does not reveal its potential until an adenoma is formed, and if aspirin reduced the chances of such cells surviving, this would explain our results.”

The team intends to undertake a further study to see whether a smaller dose of aspirin would have the same beneficial effect or not. “We are planning to ask people with Lynch syndrome to agree to ‘toss a coin’ and take, say, either one or two aspirin tablets per day. Then we can see whether the people on the lower dose have the same protection, with fewer side effects. The problem is that, to have a significant result, this will need about 10 times as many people as we needed for our first trial, but the good news is that everyone gets treated,” said Prof Burn.

For more information:

• Abstract no: 6000, Gastro-intestinal malignancies, colorectal cancer session, Monday 11.00 hrs CEST (Hall 2)

Also read these PubMed abstracts:

• Hua A, Mackenzie GG, Rigas B. The differential cell signaling effects of two positional isomers of the anticancer NO-donating aspirin. Int J Oncol. 2009 Oct;35(4):837-44.
• Barry EL, Sansbury LB, Grau MV, Ali IU, Tsang S, et al. Cyclooxygenase-2 Polymorphisms, Aspirin Treatment, and Risk for Colorectal Adenoma Recurrence--Data from a Randomized Clinical Trial. Cancer Epidemiol Biomarkers Prev. 2009 Sep 15. [Epub ahead of print]
• Lang DL. Aspirin as Colorectal Cancer Adjuvant Therapy. Gastroenterology. 2009 Aug 22. [Epub ahead of print]
• Neugut AI. Aspirin as adjuvant therapy for colorectal cancer: a promising new twist for an old drug. JAMA. 2009 Aug 12;302(6):688-9
• Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, et al. Aspirin dose and duration of use and risk of colorectal cancer in men. Gastroenterology. 2008 Jan;134(1):21-8. Epub 2007 Sep 26.

Bevacizumab Data Gives Hope to Colorectal Cancer Patients with Liver Metastases

New data from several studies presented at the joint multidisciplinary meeting of ECCO 15 (European CanCer Organisation) and ESMO 34 (European Society for Medical Oncology) in Berlin, Germany, confirm unique benefits of bevacizumab (Avastin®, Roche, Basel, Switzerland), an antibody that specifically binds and blocks VEGF (vascular endothelial growth factor), and capecitabine (Xeloda®, Roche, Basel, Swizerland), a highly effective targeted oral chemotherapy offering patients a survival advantage when taken on its own or in combination with other anticancer drugs, in treatment of colon cancer.

Colorectal cancer is the second most common cause of death from cancer across all tumor types in Europe and is the third most commonly reported cancer in the world.

Bevacizumab in combination with chemotherapy led to shrinkage or disappearance (overall response rate) of liver metastases (disease that has spread to the liver) in 78% of patients with advanced colorectal cancer. As a result, one third (33%) of patients who were initially unable to undergo surgery were eligible to undergo a potentially lifesaving surgery. Complete surgical removal of the metastases was achieved in 56% of all bevacizumab-treated patients.

II BOXER study
The multicentre phase II BOXER study, a single arm phase II study, investigated the efficacy and safety of bevacizumab in combination with oral capecitabine and intravenous oxaliplatin (NO16968 XELOX trial, an open-label, randomised, phase III study of oral capecitabine in combination with intravenous oxaliplatin versus 5-fluorouracil/leucovorin (5-FU/LV) as adjuvant therapy for patients with stage III colon cancer who have undergone surgery) in patients considered unsuitable for upfront resection (surgical removal) of their liver metastases.

Response rates in this trial were measured by RECIST criteria. Secondary objectives of BOXER trial included complete resection rate, safety and feasibility of the regimen, PFS and overall survival.

“The data from BOXER shows that bevacizumab in combination with standard chemotherapy has the ability to shrink metastatic lesions which might allow surgical removal and therefore offer a potential for cure for patients with advanced disease,” explained Professor David Cunningham, Head of the Gastrointestinal Unit at the Royal Marsden Hospital, UK.

First BEAT
Data from the large, observational First BEAT phase IV trial assessing the safety and efficacy of bevacizumab in almost 2,000 previously untreated patients with mCRC in combination with a variety of standard chemotherapies, showed that bevacizumab -based treatment delivers the same benefits to all patients including those aged above 65 years who represent the majority of people with advanced colorectal cancer. This is an important finding as older patients are often under-represented in clinical trials. The study results showed that the time patients lived without their disease advancing (PFS) was similar across age groups – 10.8 months for those below 65 years, 11.2 months for those between 65 and 74 years and 10 months for those 75 years and older.

The most common chemotherapy regimens combined with bevacizumab in First BEAT were FOLFOX, XELOX, FOLFIRI (oxaliplatin, fluorouracil and irinotecan) and capecitabine. The primary endpoint of First BEAT was safety and secondary objectives were PFS and overall survival.

NO16968 (XELOXA) study
Patients taking capecitabine with oxaliplatin immediately after surgery live disease free for longer compared to those treated with commonly used chemotherapy regimen. New results for capecitabine in early colon cancer were also presented at the ECCO 15 - ESMO 34 meeting. The pivotal NO16968 (XELOXA) study, the largest-ever study of patients with stage III colon cancer, showed that the three year disease-free survival (DFS) for patients receiving XELOX was 70.9%, superior to the 5-FU/LV arm (66.5%) (HR=0.80 (95% CI: 0.69-0.93), p=0.0045). The DFS result obtained with XELOX is similar to that shown in trials evaluating the use of FOLFOX in patients with stage III colon cancer.

"We know that XELOX helps keep patients free from recurrence of their cancer longer,’’ said Dr Dan Haller, Professor of Medicine, University of Pennsylvania. "These results now confirm that patients have an additional option for the treatment of stage III colon cancer. In these potentially curable patients, XELOX offers the additional benefit of an oral medication, Xeloda."

"Colorectal cancer sadly claims more than 600,000 lives each year, despite the treatment advances made in the last decade” said William M. Burns, CEO of Roche’s Pharmaceuticals. “Today’s announcements about Avastin and Xeloda are therefore very welcome news for patients and their families as they offer more options for fighting this disease and hope that some patients may even have the potential to be cured” he added.

Images courtesy American Society of Clinical oncology (ASCO) and Roche Pharmaceuticals.

Promising Results from two New Blood Tests may lead to Simple, Cost-effective Diagnosis of Gastrointestinal Cancers

Patients are often worried about invasive tests used to detect Gastrointestinal (GI) Cancer , like colonoscopies, and yet these tests have been the key to early cancer detection and prevention. But new more patient-friendly noninvasive test may soon be widely available.

Researchers today presented promising results from two new blood tests that can aid in the early identification of patients with gastrointestinal (GI) cancers. The results were presented at Europe’s largest cancer congress, ECCO 15 – ESMO 34, the comined 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology, in Berlin (Germany). The new blood tests will make GI cancer detection simpler, cost-effective, and more acceptable to patients than current methods, the researchers say.

The first study, presented by Joost Louwagie, PhD, Vice President at OncoMethylome Sciences (Liège, Belgium), showed data in which tumor markers for colorectal cancer were selected, the analytical performance of the test and the first results from a multi-centre feasibility study. “This test has potential to provide a better balance of performance, cost-effectiveness and patient compliance than other options currently available for colorectal cancer screening,” Louagie said.

The scientists collected blood before surgery from 193 patients known to have colorectal cancer, as well as from 688 controls undergoing colonoscopy for cancer screening. DNA was extracted from the blood plasma and tested for the presence of DNA methylation of specific genes. DNA methylation is involved in the regulation of protein expression, and methylation or silencing of key genes has been linked to the initiation and progression of tumors.

Based on studies conducted in colorectal tissues, methylated genes that were capable of discriminating accurately between cancerous and normal tissues were chosen. The scientists then evaluated the best-performing methylated genes in blood samples, with the ultimate goal of providing a sensitive, specific and patient-friendly option for colorectal cancer screening.

SYNE1 and FOXE1
Says Louwagie: “We optimized the methods of DNA extraction and methylation detection so that we could detect low levels of methylated genes in people with colorectal cancer. We were able to find a high frequency of two newly reported methylation genes, SYNE1 and FOXE1, in colorectal cancer patients. The same methylation genes occurred infrequently in non-cancerous individuals.”

When testing a first set of 444 controls and 124 colorectal cancer patients, with plasma volumes ranging between 0.8 and 4.3 ml, the sensitivity and specificity for the combination of SYNE1 and FOXE1 was 58% and 90% respectively. Testing this marker combination in a second, independent group of 242 controls and 69 cases, the sensitivity (proportion of positives correctly identified) and specificity (proportion of negatives correctly identified) were 56% and 91% respectively (77% and 91% in the samples with at least 3.3 ml of plasma). The sensitivity for stage I and II disease was 41% and 80% respectively.

Colorectal cancer occurs in approximately one in every 17 people during their lifetime and is the second leading cause of cancer death in the United States and Europe; in these places a combined total of about 560,000 people develop the disease each year, and 250,000 die from it. Deaths can be reduced if the cancer is diagnosed at an early stage, when it is most treatable. Although there are already two effective screening methods, they both have drawbacks.

Colonoscopy, where the interior of the colon and rectum is examined using a tiny camera mounted on a flexible tube, is the most sensitive test currently available and has the benefit of allowing removal of pre-cancerous polyps. Colonoscopy, however, is invasive, expensive, requires bowel preparation and skilled practitioners, making it inaccessible or unacceptable for many patients.

Faecal occult blood testing (FOBT), where patients give stool samples to be analyzed, is less invasive, inexpensive and is used in national screening programs in some European countries. However, due to patients’ reluctance to handle stool samples, compliance for even the best-organized national screening programs is often less than 50%.

“Once validated in a prospective colorectal screening trial, the new methylation test could be used as a non-invasive screening option for patients who decline or do not have access to colonoscopy or do not wish to undertake the faecal occult blood test,” said Louwagie. “The blood sample can be taken by nurses or primary care doctors without the need for special equipment or training, leading to higher rates of patient compliance and the identification of patients needing the more expensive and diagnostic colonoscopy procedure. Giving such a blood sample could become part of the regular physical examination undertaken as part of a health insurance package in many countries.”

The scientists are currently enrolling people into a prospective colorectal screening study in several German colonoscopy centers. “We plan to complete enrollment of 7000 people by the end of 2009,” noted Louwagie “and are currently talking to several partners about distribution rights. This new test will not replace colonoscopy, but provide a way of screening a larger part of the population in a more patient-friendly and non-invasive manner so that more cancers are detected and treated successfully.”

Another test: S100A4 mRNA
In a different study, researchers from Germany said that they have developed another blood test that helps diagnose tumors in patients with colon, rectal, or gastric cancers. Professor Ulrike Stein, PhD, at ECRC Charité University of Medicine, and the Max-Delbrueck-Centre for Molecular Medicine, both based in Berlin (Germany), says that the test can also predict the likelihood of metastatic disease in patients after diagnosis of these cancers.

Stein and her team looked for the existence of an S100A4 transcript, by isolating RNA from blood plasma samples from patient with GI tumors. Genetic transcription takes place when the information carried in DNA is copied into an RNA molecule, and is the first stage in the expression of a protein. They collected daily blood samples from hospitalized and outpatients; 185 samples for colon cancer, 190 for rectal, and 91 for gastric cancer patients. They also analyzed the blood of 51 age-matched, tumor-free volunteers.

“We found that S100A4 mRNA was present at significantly higher levels in the group of cancer patients, no matter whether they had colorectal or gastric cancer, than in the tumor-free control group,” Stein explained. “And there were yet higher levels in the patients with metastases than in those where the disease had not yet metastasized. More importantly, prospective analysis of the data showed that follow-up patients who later developed metastases showed higher S100A4 levels at initial blood analysis than those whose disease did not metastasize. This means that in future we might be able to identify those patients who are likely to develop metastases.”

Because the new test could be useful in identifying tumors in patients showing no signs of disease, it could be an effective tool in population screening for GI cancers. This needs to be tested in a large prospective trial, the researchers say. The S100A4 transcript was already known to promote the increased metastatic capability of cancer cells, but the problem to date has been that tests to establish its existence in a tumor have been expensive and complicated.

The scientists now intend to look at the correlation of S100A4 transcript levels in blood and the survival of individual patients after a minimum of three years follow-up. “We are hoping that, by enabling the identification of those patients whose disease is likely to progress more quickly, we will be able to treat them in the future accordingly by tailoring therapy to their individual needs,” Stein said.

For more information:

• Gastrointestinal malignancies, colorectal cancer 1, Monday 12.45 and 13.00 hrs CEST (Hall 2) Abstract #12LBA (Louwagie) and 13LBA (Stein).

Also read these PubMed Abstracts:

• Mokarram P, Kumar K, Brim H, Naghibalhossaini F, Saberi-firoozi M, et al. Distinct high-profile methylated genes in colorectal cancer. PLoS One. 2009 Sep 11;4(9):e7012.
• Ikenaga N, Ohuchida K, Mizumoto K, Yu J, et al. S100A4 mRNA is a Diagnostic and Prognostic Marker in Pancreatic Carcinoma. J Gastrointest Surg. 2009 Aug 4. [Epub ahead of print]
• Ohuchida K, Mizumoto K, Miyasaka Y, Yu J, Cui L et al. Over-expression of S100A2 in pancreatic cancer correlates with progression and poor prognosis. J Pathol. 2007 Nov;213(3):275-82

Images courtesy American Society of Clinical oncology (ASCO)

CDC Awards Millions for Colorectal Cancer Screening Program

The Centers for Disease Control and Prevention (CDC) has awarded a total of $22 million to 26 states and tribal organizations to provide colorectal cancer screening services for low–income people aged 50–64 years, who are underinsured or uninsured. Colorectal cancer is the second leading cause of cancer deaths among men and women aged 50 and older in the United States.

The awards range from $358,283 to $1.1 million. The awardees are expected to begin screening patients for colorectal cancer within six months.

The states receiving five–year awards are: Alabama, Arizona, California, Colorado, Connecticut, Delaware, Florida, Iowa, Maine, Maryland, Massachusetts, Minnesota, Montana, Nebraska, New Hampshire, New Mexico, New York, Oregon, Pennsylvania, South Dakota, Utah, and Washington. The tribal organizations receiving awards are: Alaska Native Tribal Health Consortium, Arctic Slope Native Association, South Puget Intertribal Planning Agency, and Southcentral Foundation.

The funding will support screening and diagnostic follow–up care, data collection and tracking, public education and outreach, provider education, and an evaluation to measure the clinical outcomes, costs, and effectiveness of the program. The awardees can choose from among any of the recommended screenings for colorectal cancer – colonoscopy, sigmoidoscopy and stool testing.

“Colorectal cancer kills more people than any other cancer except lung cancer,” said CDC Director Thomas Frieden, M.D., M.P.H. “These colorectal cancer screening awards will save lives. We need to reach more adults aged 50 and over and others at high risk to prevent colorectal cancer.”

In 2005, more than 141,000 new cases of colorectal cancer were diagnosed and 53,000 people died from this disease. The number of new colorectal cancer cases could be reduced by as much as 90 percent if all precancerous polyps (abnormal growths in the colon or rectum), were identified using screening tests and removed before they become cancerous. However, only half of all U.S. adults aged 50 or older have been screened appropriately for colorectal cancer, and while screening rates are slowly increasing, disparities still exist. Screening rates remain higher for whites compared to all other races, for non–Hispanics compared to Hispanics, and for people with health insurance compared to those with no health insurance.

“Screening tests can detect colorectal cancer at its earliest stages, when it is most treatable,” said Laura Seeff, M.D., medical director of CDC′s colorectal cancer screening program. “This screening program has tremendous potential to address the disparities that exist in colorectal cancer screening and to save lives.”

The goals of CDC′s colorectal cancer screening program are to increase population–level screening among all persons aged 50 and older in the participating states and tribes, and to reduce health disparities in colorectal cancer screening, incidence and mortality.

For more information:

• CDC's efforts to prevent colorectal cancer
• Screen for Life

New Test Helps Assess Colorectal Cancer Risk

A new assessment tool can help individuals calculate their risk for colorectal cancer, also known as cancer of the colon or rectum. The test designed by National Cancer Institute (NCI), the University of Utah, and the Kaiser Permanente Medical Care Program of Northern California is now available online.

With more than 108,000 new cases of colon cancer and more than 40,000 new cases of rectal cancer, colorectal cancer is the fourth most common cancer in men and women in the United States and the second leading cause of cancer-related deaths. The symptoms can remain undetected for many years and in most cases will develop quite slowly. However, as a result of better detection and treatment, the death rate from colorectal cancer has been dropping. Caught early, colorectal cancer is often curable.

The new assessment tool is designed for people 50 years of age and older and based on data collected from two large US population-based case control studies of colon and rectal cancer, data from 13 NCI Surveillance, Epidemiology and End Result Registries (SEER data), and the US national mortality rates.

How it works
The Colorectal Cancer Risk Assessment Tool uses the respondent’s answers about risk and preventive factors to calculate that person’s absolute risk for developing colorectal cancer for a specific time period. The online test is interactive, simple and straightforward and takes only 5-8 minutes to complete. After answering the questions, the tool will calculate an individual’s risk for colorectal cancer.

To validate the accuracy, the model was tested in a large population. The results show that the tool is accurate in predicting absolute risk. Because the majority of participants in the case-control studies were non-Hispanic white males and females, relative risks for other racial or ethnic groups could not be estimated. Researchers are in the process of updating the tool by using SEER rates for minority populations to allow the tool to produce more accurate results for men and women in these populations. When available, the expanded functionality will include additional ages and racial/ethnic groups.

The risk calculator will be updated periodically as new data or research become available. In addition, the tool may prove useful to researchers who are designing research intervention studies.

Man and Women
To help assess the risk for, the tool is gender specific. For men, the model included a cancer-negative sigmoidoscopy/colonoscopy in the last 10 years, polyp history in the last 10 years, a history of colorectal cancer in a first-degree relatives, use of aspirin and nonsteroidal anti-inflammatory drug (NSAID), cigarette smoking, body mass index (BMI), current leisure-time vigorous activity, and vegetable consumption.

For women, the model included sigmoidoscopy/colonoscopy, polyp history, a history of colorectal cancer in a first-degree relatives, aspirin and NSAID use, BMI, leisure-time vigorous activity, vegetable consumption, hormone-replacement therapy (HRT), and estrogen exposure on the basis of menopausal status.

Better Understanding
The tool is designed to assist health care providers in counseling their patients. A better understanding of the risk will help patients and their doctor make more informed choices about how to screen and which screening tests they should take to detect signs of cancer before symptoms appear.

Although the questionnaire is suitable for 'self-administrations', researchers stress that it’s important that patients talk with their primary health care provider about the results. Commenting of the test they claim ‘The test is designed to be used by health professionals and their patients. If patients are using the tool at home, we encourage them to discuss the results, and their individual risk of colorectal cancer with their healthcare provider.’

For more information:

• The new tool is now available online.
• SEER: Surveillance, Epidemiology, and End Results Colon & Rectum (statistics).

Also, read PubMed abstracts:

• Freedman AN, Slattery ML, Ballard-Barbash R, et al. A colorectal cancer risk prediction tool for white men and women without known susceptibility. J Clin Oncol. 2008 Dec 29. [Epub ahead of print].
• Park Y, Freedman AN, Gail MH, et al. Validation of a colorectal cancer risk prediction model among whites 50 years old and over. J Clin Oncol. 2008 Dec 29. [Epub ahead of print].

Patient information:

• National Cancer Institute: Understanding cancer risks
• NIH senior health: colorectal cancer
• MedlinePlus: colorectal cancer

Organizations to contact:

• Colon Cancer Alliance - USA
• Colon Cancer Concern (The Bowel Cancer Charity) - United Kingdom
• Europa Colon - Europe