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.

Novel Cancer Drug Test May Results in Safer and More Effective Clinical Trials

A group of scientists from Hamburg may have taken a big step towards more effective cancer drug development. Dr Ilona Schonn, Director of Cell Culture Research at Indivumed GmbH, a company specialized in the analysis and procurement of highly standardized tissue samples and data of tumor patients, told the audience at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that they had developed a preclinical drug test platform that would enable researchers to analyze tumor tissue for individual patient drug responses on the molecular level.

To date most tests for drug metabolism and toxicity testing have used tissue slices of normal organs like liver, kidney and lung. The new test was created specifically for oncology drug testing and uses tumor tissues from colorectal and lung cancer patients.

A major problem of drug development at present is the inability to extrapolate response in preclinical cell models to patients. “Approximately 90% of clinical trials fail because the drugs used are too ineffective or too toxic,” explained Dr Schonn. “Not only does this result in unacceptably high costs for drug development, but it also exposes patients to risks from toxicity or simply wastes their time in testing a substance which proves to be ineffective.”

The problem arises from the fact that patients respond individually to drugs. In addition, each tumor consists of a variety of different cancer cells that interact in different ways with the framework of individual non-tumor cells, resulting in highly variable growth behavior and response to drugs. Dr Schonn and her team set out to try to develop a drug test that would eliminate these problems and provide an accurate model of individual patient response.

“Based on freshly cultivated intact tissue from surgically treated cancer patients we are now able to analyze numerous tumors from different patients, to identify differences in drug response between those patients, and to understand variations of response in cell subtypes within one tumor,” said Dr Schonn.

The new test allows scientists to translate findings from commonly used cell lines to a preclinical model which is as close as possible to using the same drug in the clinical setting, thus enabling a better estimate of the number of patients who are likely to respond to the treatment. It also helps to identify biomarkers that can predict drug response for patients entering a clinical trial, allowing researchers to include only those patients whose participation will provide a significant answer to the question being asked.

“Together with all the clinical patient data and several analytical test systems such as signaling pathway analysis, we have been able to characterize individual tumors in more detail. This will improve the understanding of drug effects and treatments, a step forward towards the goal of individualized cancer therapy,” she said. “The test is of particular interest to pharmaceutical companies because it allows the analysis of samples from meaningful number of patients with different tumors in a short period of time, and can, therefore, accelerate progression of a potential new treatment to clinical trials.”

In addition, it can help gain more knowledge about the mode of action of a new compound in patients, and identify optimal disease areas, for example tumors with particular mutations or over-expression of target receptors, and dosage.

To date the test has only been validated in colon, non-small cell lung (NSCLC), and breast cancer tumors but there is no reason to think that it would not be equally accurate in other solid tumor types, the scientists say.

“Because the test allows us to maintain the complex environment of the primary cancer tumor, we believe that it holds out great promise for the quick and effective elucidation of response to anticancer drugs,” said Dr Schonn. “We hope to be able to apply it to a growing number of drugs emerging from the labs of pharmaceutical companies to help to shorten development time and to make clinical trials both more efficient and safer for patients.”

The test can analyze numerous tumors from different patients, identify the patients’ diverse reactions to the test compounds and elucidate their varying effects on cell subtypes within the same tumor. Says Prof Dr Hartmut Juhl, CEO and founder of Indivumed. “In the long run, our test paves the way to personalized medicine, because it helps to understand and to embrace the individual reactions of the patients to a certain therapy.”

For more information:

• Abstract no: 1013, Basic Science/Translational Research poster discussion, Wednesday 17.00 – 18.00 hrs CEST (Hall 14.2)

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

Bevacizumab study does not meet primary endpoint, but results suggest future trials may hold promise for early-stage colon cancer treatment

Adding bevacizumab to standard adjuvant chemotherapy does not improve disease-free survival for early-stage colon cancer. This is the primary conclusion from the complete results from the first, randomized phase III trial of bevacizumab (Avastin, Roche) in early-stage colon cancer, known as NSABP C-08, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement between Genentech and NCI, and will be presented on Sunday, May 31, during the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) being held from May 27 – June 2, 2009 in Orlando, Florida.

NSABP C-08 was the first study to report results on the use of bevacizumab as an adjuvant treatment. Bevacizumab targets the vascular endothelial growth factor (VEGF) receptor, a key driver of tumor angiogenesis – an essential process in the development and maintenance of blood vessels which is required for a tumor to grow and to spread (metastasize) to other parts of the body.

The results of the NSABP C-08 trial have found that adding bevacizumab to standard adjuvant chemotherapy did not improve disease-free survival (the time that patients are free of tumor recurrence) in early-stage colon cancer

The current study enrolled 2,710 patients who were randomized to receive six months of standard adjuvant chemotherapy or six months of adjuvant chemotherapy combined with bevacizumab plus an additional six months of bevacizumab after the chemotherapy had ended.

All patients in the study had stage II or stage III disease and first had surgery to remove their tumors. After a median follow-up of three years, the investigators found that 77.4 percent of patients in the experimental group (bevacizumab) were alive and free of disease, compared with 75.5 percent of patients in the control group, a difference that was not statistically significant. There were no unexpected side effects in either arm and the toxicities from bevacizumab were well tolerated.

“One interesting effect was that during the year that patients were receiving bevacizumab we saw a benefit in disease-free survival (DFS) that subsequently diminished when follow-up was completed,” said Norman Wolmark, MD, chairman of the Department of Human Oncology at Allegheny General Hospital and the study’s lead author. Patients receiving bevacizumab treatment had a 40 percent lower risk of cancer returning, however, this initial improvement over chemotherapy alone gradually diminished over time.

Commenting on the trial, Walmark continued “Our overall conclusion is that bevacizumab was not effective as an adjuvant treatment for early-stage colon cancer, but the transient benefit we saw in patients who received bevacizumab illustrates that we have more to learn about how this reagent works, and we need to design more clinical trials to determine how it can be used most effectively.”

No new safety signals for bevacizumab were observed in the study and careful review of the data did not provide evidence that cancer returns faster or more aggressively after bevacizumab therapy was stopped.

“These results are encouraging and suggest that Avastin may have an important role in early cancer treatment. We are committed to the ongoing program of Avastin in early-stage cancers and believe that these results could help us optimize the use of Avastin for the benefit of patients,’’ noted William M. Burns, CEO of the pharmaceutical division of Roche, a leader in research-focused healthcare.

Study Results
The NSABP C-08, a two-arm randomized prospective multi-center Phase III study evaluated the use of bevacizumab plus chemotherapy (mFolfox6 + bevacizumab/mFF6+B) for the treatment of Stage II or III adenocarcinoma immediately following surgery (adjuvant therapy) compared to chemotherapy alone (mFolfox6/mFF6). The study showed the addition of one year of bevacizumab to chemotherapy did not result in a statistically significant improvement in overall disease-free survival (DFS). However, during the year of bevacizumab treatment there was an early and significant improvement in disease-free survival that diminished over the course of the study.

Disease-Free Survival was measured from the date of randomization to the date of any type of cancer recurrence or death from any cause. Patients enrolled in the study were randomized after surgery to receive either FOLFOX chemotherapy alone for six months or FOLFOX in combination with bevacizumab (intravenously every two weeks) for six months, followed by an additional six months of bevacizumab monotherapy. Patients continue to be followed for overall survival, a secondary endpoint of the study.

Overall in the study, there was 12 percent improvement in DFS that was not statistically significant (hazard ratio=0.89, p=0.15; risk reduction 11 percent). In the first year of the study, while patients received bevacizumab in addition to a standard six-months of adjuvant chemotherapy, disease-free survival improved by 67 percent compared to chemotherapy alone (hazard ratio=0.60; risk reduction of 40 percent). However, this early improvement in DFS began to diminish after the first year, and overall DFS was not improved.

NSABP C-08 included a comprehensive safety analysis that showed no new or unexpected safety events related to bevacizumab in the study. Specific severe (Grade 3 or greater) adverse events (AEs) that occurred with increased frequency in patients who received bevacizumab versus chemotherapy alone were: hypertension (12 percent vs. 1.8 percent), pain (11.1 percent vs. 6.3 percent), proteinuria (2.7 percent vs. 0.8 percent) and wound-healing complications (1.7 percent vs. 0.3 percent).

Other trials and standard of care
Bevacizumab is currently approved for metastatic colorectal, breast, and lung cancers and other trials are ongoing to evaluate it as an adjuvant treatment for a variety of solid tumors. Therapy with bevacizumab is the standard of care in advanced colon cancer treatment which will be further confirmed throughout the ASCO meeting with 53 efficacy and safety data presentations including more than 6,000 patients.

In addition to early-stage colon cancer, bevacizumab is being studied as an adjuvant treatment in other early-stage diseases: HER2-negative breast cancer, HER2-positive breast cancer, and non-squamous, non-small cell lung cancer. Approximately 26,000 people are expected to participate in bevacizumab based adjuvant studies, making the bevacizumab development program one of the most comprehensive undertakings in cancer research since chemotherapy. The Avastin (bevacizumab) development program includes more than 450 clinical trials worldwide in approximately 30 different tumor types.

More than 500,000 patients have been treated with bevacizumab so far. A comprehensive clinical program with more than 450 clinical trials is investigating the use of bevacizumab in various tumor types (including colorectal, breast, lung, brain, gastric, ovarian, prostate and others) and different settings (advanced or early stage disease).

Mode of Action
The precise mode of action of bevacizumab helps control tumor growth and metastases with only a limited impact on side effects of chemotherapy.

The drug has proven survival benefits across multiple tumor types and is approved in Europe for the treatment of the advanced stages of four common types of cancer, including colorectal cancer, breast cancer, lung cancer and kidney cancer. These types of cancer collectively cause nearly 3 million deaths each year in the US alone.

In the US, bevacizumab was the first anti-angiogenesis therapy approved by the FDA and is now approved for the treatment of four tumor types: breast, colorectal, glioblastoma, and non-small cell lung cancer (NSCLC).

For further information:

• American Society for Clinical Oncology
• Wolmark, G. Yothers, M. J. O’Connell, S. Sharif, J. N. et al. A phase III trial comparing mFolfox6 to mFolfox6 + bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08 N. Plenary presentation, Sunday, May 31, 3:15 PM EDT, Level 2, West Hall D2. Plenary Session, Lead Author: Norman Wolmark, MD, Allegheny General Hospital Pittsburgh, Pa. Abstract No# LBA4

Other, related, abstracts

• A quantitative multigene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in four large studies and results of the independent, prospectively designed QUASAR validation study.
  Meeting:2009 ASCO Annual Meeting Abstract No: 4000 First Author: D. KerrCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40993-SAKK 60/00 trial).
  Meeting:2009 ASCO Annual Meeting Abstract No: 4001 First Author: S. TejparCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)
• Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60-00 trial.
  Meeting:2009 ASCO Annual Meeting Abstract No: 4002 First Author: A. D. RothCategory:Gastrointestinal (Colorectal) Cancer - Colorectal Cancer (including liver metastases)

Folfox Background information:

• Wikipedia (Definition)
• Cancer Research UK
• NCI – National cancer Institute

Colorectal Cancer:

• Medical Oncology (at Boomja.com)
• Goldberg RM, Therapy for Metastatic Colorectal Cancer The Oncologist Vol. 11, No. 9, 981-987, October 2006

Pharmaceutical information:

• EMEA - European Public Assessment Report (bevacizumab)
• Highlights of Prescribing Information USA (bevacizumab)
  

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

Tumor Mutation Predicts Effectiveness of Treatment for Colorectal Cancer

Routine screening of patients with metastatic colorectal cancer (mCRC) for mutations of KRAS, a gene that encodes one of the proteins in the epidermal growth factor receptor (EGFR) signaling pathway, before initiating treatment with EGFr-inhibitors, will cut costs by providing treatment only to those patients who will benefit from the treatment and by helping those who will not benefit avoid unnecessary side effects.

This conclusion is based on an analysis of data presented during the sixth annual Gastrointestinal Cancers Symposium being held in San Francisco, California (January 15-17, 2009) by Dr.Veena Shankaran, MD, and his team from Northwestern University Feinberg School of Medicine, in Chicago, Illinois. These results demonstrate that savings can be realized by customizing therapy in any Gastrointestinal (GI) malignancy using a molecular tests.

European and US incidence
Gastrointestinal (GI) cancers include cancers of the esophagus, stomach, small intestine, colon, rectum, anus, pancreas and liver. More than 270,000 people are diagnosed with Gastrointestinal cancers in the United States every year and more than 135,000 people die from them annually.

In Europe, approximately 370,000 people develop colorectal cancer every year, accounting for 13% of the total cancer burden and an estimated 200,000 deaths. Around a quarter of CRC patients present with metastatic disease and for these patients survival rates areas low as 5%. Approximately 60-65% of mCRC patients have KRAS wild-type tumors.

Carcinogenesis
The epidermal growth factor receptor plays an important role in carcinogenesis and tumor progression of colorectal cancer (CRC), a multi-step process involving the accumulation of molecular alterations in a number of genes and pathways of proliferative cells of the colon.
These molecular alterations lead to a loss of coordination between the processes of cellular proliferation and differentiation . Researchers have observed aberrations in the EGFR signaling pathway in a number of cancers including mCRC. Therefore, the EGFR has now evolved as a relevant target in the treatment of mCRC.

Monoclonal antibodies
Monoclonal antibodies (MoAb), including cetuximab (Erbitux®, ImClone Systems Incorporated, Branchburg, NJ 08876, Bristol-Myers Squibb Company, Princeton, NJ 08543 and Merck KGaA, Darmstadt, Germany), a human antibody against the epidermal growth factor receptor and panitumumab (Vectibix®, Amgen Inc, One Amgen Center Drive, Thousand Oaks, Ca 91320-1799), a fully human IgG2 monoclonal antibody that is highly selective for the epidermal growth factor receptor, inhibit EGFR activity. However, not all colorectal tumors respond, and not all patients benefit from these therapies. Recent discoveries have shown that the KRAS gene, when mutated, confers resistance to cetuximab and panitumumab by circumventing EGFR’s role in the signaling pathway.

In March 2008, the Journal of Clinical Oncology published results from an analysis of the first randomized, controlled clinical trial which showed that mCRC patients with mutated KRAS tumors do not respond to panitumumab monotherapy. Conversely, patients with wild-type KRAS tumors treated with panitumumab had a better response rate and a prolonged progression-free survival (PFS). Compared to best supportive care (BSC) alone, this therapy also had an impact on quality of life (QoL) and disease-related symptoms.

The Role of KRAS
Over twenty year of study has shown that the KRAS gene plays a central role in tumor development, regulating downstream proteins that are involved in proliferation, survival, metastasis and angiogenesis. It serves as a mediator between extracellular ligand binding and intracellular transduction of signals from the EGFR to the nucleus. Researcher identified the presence of activating KRAS mutations as a potent predictor of resistance to EGFR-directed monoclonal antibodies.

Anti-epidermal growth factor receptor (EGFr) therapies work by blocking the activation of EGFr, thereby inhibiting downstream events that lead to cancer cell signaling. However, in patients with tumors harboring a mutated or activated KRAS, the KRAS protein is always turned 'on' regardless of whether EGFr has been activated or therapeutically inhibited. Thus, in patients with mutated KRAS, signaling continues despite anti-EGFr therapy. Mutated KRAS is detected in approximately 40% of CRC tumors.

Long term evidence
Although activating mutations in KRAS correlates with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker had not yet been established in randomized trials. A number of clinical trials have now demonstrated that patients can benefit from the addition of cetuximab to FOLFOX or FOLFIRI regime in the first-line treatment of metastatic CRC (mCRC). However, subsequent correlative analyses of these trials have also shown that this benefit is limited to patients whose tumors have wild type KRAS status by PCR-based testing.

Cetuximab
A study by the Central European Cooperative Oncology Group (CECOG), the CECOG/CORE1.2.001 study, a randomized Phase II trial investigating the influence of KRAS status on the efficacy of cetuximab in combination with FOLFOX or FOLFIRI in the first-line treatment of 117 mCRC patients, provided a response rate (RR) of 53% in patients with KRAS wild-type tumors versus 36% in those with mutant tumors. The study also showed a trend towards improved overall survival (OS) in patients with KRAS wild-type tumors – 24.4 months for patients with KRAS wild-type tumors vs. 16.7 months for patients with KRAS mutant tumors (p=0.057).

‘It is really exciting to see such a consistent efficacy profile for cetuximab in patient populations defined by KRAS mutational status,' commented Prof. Thomas Brodowicz, MD from the University Hospital of Vienna, Austria, lead investigator of the CECOG/CORE1.2.001 study. 'This further highlights the absolute necessity to define mCRC according to the KRAS status of the tumor in order to determine the most effective treatment strategy and to provide patients with the best possible outcomes.’

The results of the CECOG/CORE1.2.001 study support the pivotal cetuximab trials – the randomized Phase III study CRYSTAL, also presented at this meeting, and OPUS recently published in the Journal of Clinical Oncology. Patients receiving cetuximab in the CRYSTAL and OPUS trials who had KRAS wild-type tumors showed similar response rates to those in the CECOG/CORE1.2.001 study, at 59%2 and 61%,3 respectively.

Panitumumab
To further independently evaluate the association of KRAS status seen in a biomarker analysis of a Phase III, randomized, controlled clinical trial (the so-called ‘408’ study) that investigated the treatment effect of panitumumab monotherapy plus Best Supportive Care (BSC) versus BSC alone in patients with mCRC, additional retrospective analyses of all other studies of panitumumab monotherapy in mCRC were performed.

‘These data are consistent with 30 years of biology which indicate that KRAS is a clinically relevant oncogene,’ said Dr Sean Harper, MD., chief medical officer and head of Global Development at Amgen. ‘We believe the data from our panitumumab monotherapy trial indicates that the benefit-risk profile of panitumumab is improved by restricting use to those patients with mCRC whose tumors have wild-type KRAS genes.’

The data showed the relative effect of panitumumab versus best supportive care (BSC) was significantly greater in patients with non-mutated versus mutated KRAS (HR = 0.45 vs. HR = 0.99). Median PFS in patients without the mutation treated with panitumumab plus BSC was 12.3 weeks versus 7.3 weeks, respectively. When the analysis standardized the time to tumor assessment, the median PFS was 16 weeks versus 8 weeks, respectively (HR= 0.49 vs. 1.07). Some of these data were presented for the first time at the European Cancer Conference (ECCO) in September 2007, but a pooled analysis from data including more than 700 patients was presented at the European Society of Medical Oncology (ESMO) in 2008.

Additional endpoints of this analysis examined overall survival by KRAS status and treatment. When the treatment arms were combined (non-mutated vs. mutated) overall survival was longer in patients with non-mutated compared with mutated KRAS (HR = 0.67). No differences in overall survival were observed between panitumumab and BSC in either KRAS subgroup, potentially due to a high rate of crossover from BSC to panitumumab after progression, and similar efficacy of panitumumab in these patients.

In exploratory analyses, colorectal cancer symptoms and
health-related quality of life (HRQoL) outcomes were compared between panitumumab and BSC treated patients using a validated instrument such as the Functional Assessment of Cancer Therapy-colorectal symptom index and HRQoL using the EQ-5D index, and the EORTC-QLQ-C30 Global Health Status. In patients with tumors carrying non-mutated KRAS genes, the analysis demonstrated that in panitumumab treated patients clinically meaningful inferior symptom control and QoL scores could be excluded compared to BSC, and that in fact, a clinically meaningful difference in favor of

Panitumumab was observed at most time points. In contrast, a clinically significant worsening of symptom control and QoL scores could not be excluded in patients with mutated KRAS tumors treated with panitumumab compared to best supportive care (BSC). The United States (U.S.) prescribing information states that the effectiveness of panitumumab as a single agent is based on progression-free survival. However, there is no currently data available that demonstrates an improvement in disease-related symptoms or increased survival with panitumumab.

In the panitumumab-treated group, patients with non-mutated KRAS had on average double the number of panitumumab infusions as patients with mutated KRAS (10.0 vs. 4.9). Additionally, 20 percent of the KRAS evaluable patients had a treatment-related grade 3 adverse event (12 percent mutated vs. 25 percent non-mutated).

New recommendations and opinions
In November 2008 the National Comprehensive Cancer Network (NCCN) announced, updates to their Guidelines on Colon and Rectal Cancers that included the recommendation that a determination of the KRAS gene status of either the primary tumor or a site of metastasis should be part of the pre-treatment work-up for patients diagnosed with metastatic colorectal cancer. Further, the guidelines recommended that EGFr inhibitors, including panitumumab, should only be used in patients with tumors characterized by the wild-type KRAS gene. These updates were prompted by a systematic review of the relevant literature.

Based on similar evidence, the American Society of Clinical Oncology (ASCO), last week released its first Provisional Clinical Opinion (PCO), reflecting the expert consensus based on clinical evidence on the use of KRAS gene mutation testing in patients with metastatic colorectal cancer. Provisional Clinical Opinions are intended to assist physicians in clinical decision-making and identify questions and settings for further research.

To help guide treatment with the anti-EFGR monoclonal antibodies (MoAb), such as cetuximab and panitumumab, the authors of this Provisional Clinical Opinion recommend that all patients with metastatic colorectal cancer who are candidates for anti-EFGR therapy have their tumors tested for KRAS gene mutations. If a patient has a mutated form of the KRAS gene, it recommends against the use of anti-EFGR antibody therapy, based on recent studies indicating this treatment is only effective in patients with the normal (wild-type) form of the KRAS gene. It is estimated that 40 percent of colon cancer patients have the KRAS mutation.

Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with MoAbs directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy.

Five randomized controlled trials of cetuximab or panitumumab have evaluated outcomes for patients with metastatic colorectal carcinoma in relation to KRAS mutational status as no mutation detected (wild type) or abnormal (mutated). Another five single-arm studies have retrospectively evaluated tumor response according to KRAS status.

Researchers analyzed tumors from 587 patients with metastatic colorectal cancer for a mutated KRAS gene to determine which patients will benefit the most from treatment with a combination of chemotherapy and cetuximab. The KRAS gene is involved in the growth of cancer cells. About 30% to 45% of colorectal cancers have a KRAS mutation, which has been shown in previous studies to predict whether patients will benefit from treatment with drugs that block the epidermal growth factor receptor (EGFR), such as cetuximab.

Testing results in considerable savings
Shankaran and his team calculated the cost savings by creating an economic model derived from publicly available lab and drug-cost information and the 2008 estimated incidence of mCRC from the American Cancer Society. Clinical data were drawn from a recent, 2007, study by Van Cutsem and colleagues published in the
Journal of Clinical Oncology investigated the effectiveness of cetuximab in combination with standard FOLFIRI compared with FOLFIRI alone in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing mCRC. The model used by Shankaran did not include the necessary additional costs associated with clinic appointments, infusion visits, and managing toxicity.

Based on the available data, there are an estimated 29,762 new cases of mCRC annually. The costs for screening is estimated to cost $13 million ($452.00/patient). Using the average wholesale price of cetuximab ($4,032.00/loading dose and $2,880.00/weekly dose for a patient of average height/weight) and assuming an average of 24 doses per patient, as seen in the analysis of the CRYSTAL trial, the first study to compare chemotherapy alone with chemotherapy plus cetuximab as the primary treatment for patients with metastatic colorectal cancer, drug cost per patient were estimated to cost $71,120.00.

According to Shankaran, data from studies indicate that the prevalence of KRAS mutations ranges from 35.6% to 42.3% in all patients with metastatic colorectal cancer. An even higher percentage has been recorded in several trials, suggestion KRAS mutations in up to 46% of all patients. Approximately 59% of patients whose tumors did not have a KRAS mutation and who received cetuximab and chemotherapy had a reduction in tumor size, compared with 43% of patients who received only chemotherapy. Patients with tumors with a mutated KRAS gene did not receive any benefit when cetuximab was added to chemotherapy.

With the assumption that patients with mutated KRAS (35.6% of all patients) would not receive cetuximab, theoretical drug cost savings would be $753 million; considering the cost of KRAS testing, net savings would be $740 million.

Benefit for patients
Commenting on the importance of these studies, Jennifer C. Obel, M.D., a gastrointestinal cancers specialist and attending physician at NorthShore University HealthSystem in Illinois, said ‘These studies address a pressing question in cancer care – how can we identify those patients who will benefit from treatment and differentiate them from those who will not?’

Because patients with colorectal cancer who carry KRAS mutations have been shown not to respond to treatment with EGFr-inhibitors, upfront KRAS testing to limit cetuximab therapy to patients with wild-type KRAS tumors can result in drug cost savings if patients with metastatic colorectal cancer undergoes first-line therapy with a cetuximab-containing regimen.

Dr Obel also said ‘In an era when the cost of cancer care continues to increase, the ability to tailor treatment to each patient’s disease could lead to improved outcomes and fewer side effects for patients, and significant cost savings.’

Personalized medicine
‘This study helps us to identify which patients are most likely to benefit from adding cetuximab to treatment,’ said lead author Eric Van Cutsem, MD, PhD, Professor at the University Hospital Gasthuisberg in Leuven, Belgium. ‘KRAS testing in all people with colorectal cancer immediately after diagnosis could help doctors find the best treatment strategies for the individual patient.’

‘Based on available data, we believe that focusing panitumumab treatment on patients with wild-type KRAS tumors will avoid unnecessary adverse events in patients who are unlikely to benefit, maximize response rates and PFS in patients with wild-type KRAS genes, and redirect patients with a mutated KRAS gene to alternative therapies,' Sean Harper explained. 'We are thrilled to be taking a step forward in advancing the field of personalized medicine by being one of the first to realize the clinical potential of the KRAS gene in guiding treatment of advanced colorectal cancer patients.’

‘Personalized medicine is the next frontier in cancer care. Basing cancer treatment on the unique genetic characteristics of the tumor or the individual with cancer will improve patient outcomes and help avoid unnecessary costs and side effects for patients who are unlikely to benefit,’ said Richard L. Schilsky, MD, ASCO president and Professor of Medicine at the University of Chicago Medical Center. ‘Using KRAS testing to guide colorectal cancer treatment is a prime example of where cancer care is heading.’

Emphasizing the importance and the benefits for individual patients, Dr. Wolfgang Wein, MD Executive Vice President, Oncology, Merck Serono, concluded ‘This can help physicians help in the treatment decision-making process. Tailoring treatment for mCRC is now a reality. Through a simple diagnostic test, patients can be provided with a treatment that is most likely to succeed in their tumor type.’

For more information, read:

• Shankaran V, Bentrem DJ, Mulcahy MF, et al. Economic implications of Kras testing in metastatic colorectal cancer (mCRC).2009 Gastrointestinal Cancers Symposium (GICS). Abstract 298. Presented January 17, 2009. General Poster Session E (Poster Presentation).

Also read:

• F. Di Fiore, E. Van Cutsem, P. Laurent-Puig, et al.
  Role of KRAS mutation in predicting response, progression-free survival, and overall survival in irinotecan-refractory patients treated with cetuximab plus irinotecan for a metastatic colorectal cancer: Analysis of 281 individual data from published series. Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20 Supplement), 2008: 4035
• E. Van Cutsem, I. Lang, G. D'haens, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC)treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20 Supplement), 2008: 2
• Van Cutsem E, Peeters M, Siena S et al. Panitumumab significantly improves progression-free survival in patients with metastatic colorectal cancer. Ann Oncol 2006; 17 (Suppl 6): vi27 (Abstr O-027).
• Van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. J Clin Oncol (Meeting Abstracts) 2007 25: 4000.

For more information read PubMed abstracts:

• Heinemann V, Stintzing S, Kirchner T, Boeck S, Jung A. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat Rev. 2008 Dec 29. [Epub ahead of print]
• Weber J, McCormack PL. Panitumumab: in metastatic colorectal cancer with wild-type KRAS. BioDrugs. 2008;22(6):403-11.
• Amado RG, Wolf M, Peeters M, et al.
  Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008 Apr 1;26(10):1626-34. Epub 2008 Mar 3.
• Van Cutsem EJ, Oliveira J; ESMO Guidelines Working Group.
  Colon cancer: ESMO clinical recommendations for diagnosis, adjuvant treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii29-30.
• Van Cutsem EJ, Oliveira J; ESMO Guidelines Working Group. Advanced colorectal cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008 May;19 Suppl 2:ii33-4
• Van Cutsem E, Dicato M, Haustermans K, et al. The diagnosis and management of rectal cancer: expert discussion and recommendations derived from the 9th World Congress on Gastrointestinal Cancer, Barcelona, 2007. Ann Oncol. 2008 Jun;19 Suppl 6:vi1-8. Contact the author.
• Annemans L, Van Cutsem E, Humblet Y, et al.
  Cost-effectiveness of cetuximab in combination with irinotecan compared with current care in metastatic colorectal cancer after failure on irinotecan--a Belgian analysis. Acta Clin Belg. 2007 Nov-Dec;62(6):419-25
• Van Cutsem E, Peeters M, Siena S. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64
• Tappenden P, Jones R, Paisley S, Carroll C. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. Health Technol Assess. 2007 Mar;11(12):1-128, iii-iv
• Starling N, Tilden D, White J, Cunningham D. Cost-effectiveness analysis of cetuximab/irinotecan vs active/best supportive care for the treatment of metastatic colorectal cancer patients who have failed previous chemotherapy treatment.
Br J Cancer. 2007 Jan 29;96(2):206-12.

Also read:

• Full prescribing information (USA) Vectibix®
• Vectibix® website.
• Full prescribing information cetuximab.

Waste from Olive Grinding May Inhibit Colorectal Cancer

Researchers from the University of Granada and the University of Barcelona have shown that treatment with maslinic acid, a triterpenoid compound isolated from olive-skin pomace, results in a significant inhibition of cell proliferation and causes apoptotic death in colorectal cancer cells.

Triterpenoids, which also includes maslinic or crataegolic acid, are compounds present in a wide range of plants used in traditional medicine and known to have anti-carcinogenic properties. Low concentrations of maslinic acid, a pentacyclic terpene, can be found in plants with medicinal properties. However, the compound is present in high concentrations in the leaf and the olive skin wax extracted from alpeorujo, the crushed olive waste from olive grinding, or dry olive-pomace oil.

Based on the results of the study, the researchers feel that the compound has the capacity to inhibit or prevent cancer as well as regulating apoptosis or programmed death in human HT29 colon adenocarcinoma cell lines via the intrinsic mitochondrial pathway. Scientifics now suggest that this mechanism of action could be a useful new therapeutic strategy for the treatment of colorectal cancer as it allows controlling the hyperplasia and hypertrophy processes.

A novel compound
This study is the first to investigate the precise molecular mechanisms of the anti-carcinogenic and pro-apoptotic effects of maslinic acid against colorectal cancer. Chemopreventive agents of a natural origin, often a part of our daily diet, may provide a cheap, effective way of controlling such diseases such as colorectal cancer. A wide range of European studies in recent years has shown that triterpenoids hinder carcinogenesis by intervening in pathways such as carcinogen activation, DNA repair, cell cycle arrest, cell differentiation and the induction of apoptosis in cancer cells.

Therapeutic use in HIV
In a number of previous but unrelated studies, researchers from the university of Granada have also shown that maslinic or crataegolic acid inhibits serine proteases or serine endopeptidases,
an enzyme used by HIV to release itself from the infected cell into the extracellular environment and, consequently, to spread the infection into the whole body. They determined that the use of maslinic acid can effective reduce, up to 80%, AIDS spreading in the body. Furthermore, maslinic acid is very active against opportunistic parasitic infections, including protozoa Cryptosporidium, a parasite commonly found in HIV-patients presenting with intestine infection and diarrhea.

The therapeutic effects of maslinic acid in the fight against AIDS are now simultaneously being studied by the researchers in Granada and by Professor Dr. Vallejo Nájera and his team at the Hospital Carlos III in Madrid, Spain.

Anti-inflammatory properties
While maslinic acid is only one of the compounds found in the leaf and the olive skin wax, researches have long observed the potential health and medical benefits of olive oil. Researchers from the Lipids and Atherosclerosis Unit at the Hospital Universitario Reina Sofía de Córdoba in Spain, carried out a study in order to determine the influence of the micronutrients of certain fats on cardiovascular diseases, diabetes or cancer. They also tried to discern if the consumption of these micronutrients could possibly modify the inflammatory process in healthy people.

Doctor Pablo Pérez Martínez, one of the researchers, studying these effects, said that ‘the main property of olive oil is its richness of antioxidants, which makes it a unique fat. Therefore, we must clarify which is the added value of its components, including maslinic acid, as that is the only way to establish that a healthy diet must contain olive oil as its main fat.’ Martínez believes that because ‘olive oil is… the main source of fats… in the Mediterranean diet, it provides [this diet] with high-nutritional-value micro-components.’ According to the researcher, such a diet reduces LDL-C, brings arterial pressure down, improves diabetes control and lessen effects from thrombosis.

For more information, read:

• Reyes-Zurita FJ, Rufino-Palomares EE, Lupiáñez JA, Cascante M. Maslinic acid, a natural triterpene from Olea europaea L., induces apoptosis in HT29 human colon-cancer cells via the mitochondrial apoptotic pathway. Cancer Lett. 2009 Jan 8;273(1):44-54. Epub 2008 Sep 14.

Also read PubMed abstracts:

• Parra A, Rivas F, Lopez PE, et al. Solution- and solid-phase synthesis and anti-HIV activity of maslinic acid derivatives containing amino acids and peptides. Bioorg Med Chem. 2008 Dec 25. [Epub ahead of print].
• Juan ME, Planas JM, Ruiz-Gutierrez V, et al. Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells. Br J Nutr. 2008 Jul;100(1):36-43. Epub 2008 Feb 26.
• Juan ME, Wenzel U, Ruiz-Gutierrez V, Daniel H, Planas JM. Olive fruit extracts inhibit proliferation and induce apoptosis in HT-29 human colon cancer cells. J Nutr. 2006 Oct;136(10):2553-7. Contact the authors.
• Juan ME, Wenzel U, Daniel H, Planas JM. Erythrodiol, a natural triterpenoid from olives, has antiproliferative and apoptotic activity in HT-29 human adenocarcinoma cells. Mol Nutr Food Res. 2008 May;52(5):595-9. Contact the authors.
• Reyes FJ, Centelles JJ, Lupiáñez JA, Cascante M. (2Alpha,3beta)-2,3-dihydroxyolean-12-en-28-oic acid, a new natural triterpene from Olea europea, induces caspase dependent apoptosis selectively in colon adenocarcinoma cells. FEBS Lett. 2006 Nov 27;580(27):6302-10. Epub 2006 Oct 27.
• Gamet-Payrastre L, Li P, Lumeau S, Cassar G, et al. Sulforaphane, a Naturally Occurring Isothiocyanate, Induces Cell Cycle Arrest and Apoptosis in HT29 Human Colon Cancer. Cells. Cancer Res. 2000 Mar 1;60(5):1426-33.

CT Colonography Offers One-Stop Screening for Cancer and Osteoporosis

New research reveals that computed tomography (CT) colonography, also known as virtual colonoscopy, has the potential to screen for two diseases at once—colorectal cancer and osteoporosis, both of which commonly affect adults over age 50. The results of this study were presented on Tuesday at the 94th Scientific Assembly and Annual Meeting (November 30 – December 5, 2008) of the Radiological Society of North America (RSNA).

"With CT colonography, in addition to screening for colorectal cancer, we were able to identify patients with osteoporosis," explained lead author Rizwan Aslam, M.B.Ch.B., assistant clinical professor of radiology at the University of California San Francisco.

CT colonography, an imaging study performed to detect pre-cancerous polyps in the large intestine, begins with an abdominal CT scan, which creates cross-sectional images of all structures in the abdomen including the spine. Computer software then arranges the CT images to create an interior or "fly-through" view of the colon.

Using the same CT images, another software application can create three-dimensional images of the spine, allowing bone mineral density to be measured. Low bone mineral density is usually associated with osteoporosis, a disease in which bones become fragile and more likely to break.
In the study conducted at the San Francisco Veterans Administration Hospital, the researchers evaluated the results of 35 patients who underwent CT colonography and bone mineral density testing with dual-energy x-ray absorptiometry (DEXA), a standard bone density screening tool. Patients included 30 males and five females ranging in age from 54 to 79.

The results of the study showed excellent agreement between the DEXA bone mineral density scores and the data generated through the CT colonography study.

"The bone density measurements obtained from CT colonography were comparable to the DEXA results," Dr. Aslam said. "Both tests identified osteoporotic bones."

Most physicians recommend that adults undergo CT colonography or conventional colonoscopy every seven to 10 years beginning at age 50.

"CT colonography isn’t a replacement for DEXA testing, but it could be a way to screen more people for osteoporosis," Dr. Aslam said. "When an individual undergoes CT colonography, we can also obtain a bone density measurement with no additional radiation and at minimal cost."

According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, 10 million Americans over age 50 have osteoporosis. Approximately 34 million Americans are at risk due to low bone mass. Detecting osteoporosis early provides for early intervention and treatment.

Virtual colonoscopy at a Glance

• CT colonography may be used to screen for both colorectal cancer and osteoporosis.
• Bone mineral density measurements obtained with CT colonography were in agreement with dual-energy x-ray absorptiometry (DEXA) scores.
• Approximately 10 million Americans have osteoporosis, and 34 million are at risk for the disease..

Click here for the abstract (Assessment of Bone Mineral Density on CT Colonography)