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.

The Experience and Impact of Teenage Cancer Diagnosis Reveals Major Struggle

New research provides unique insight into what it is like for teenagers and young people to go through the process of obtaining a cancer diagnosis, revealing stories of prolonged suffering, acute distress and intense frustration for some over their symptoms not being taken seriously.

The study, presented by British researchers 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, is the first to have asked young people with cancer about their experiences from the time of first symptoms to diagnosis and provides lessons for catching the disease earlier and improving the care and experience of patients in this age group, about whom little is known.

Cancer is rare in teenagers and young people, with those aged between 15 and 24 years accounting for less than two percent of all cancer cases worldwide. But the rates are twice as high as they are in children and the disease is the most frequent cause of death in this age group after accidents. The long-term outcome for some tumor types is thought to be relatively poor compared with that for children and adults and delay in diagnosis is thought to be one of the key factors in this. The problem of diagnostic delay is widely acknowledged but is perhaps the least understood aspect of the young person’s cancer journey.

“While being diagnosed with a potentially life-threatening disease is a distressing experience for any patient, a cancer diagnosis, and the process leading up to it, can have a particularly poignant impact on teenagers because that stage of development already presents significant challenges in developing independence, identity and in coping with the world. Research in this area has been limited and better understanding of the complexities of their experience in the pre-diagnostic period is crucial if we are to provide the most comprehensive and sensitive care and improve their outcomes,” said one of the study’s researchers, Ms Susie Pearce, a health service researcher for young people with cancer at University College Hospital in London.

The researchers conducted narrative interviews with 24 young people aged between 16 and 24, two to four months after they had been diagnosed with solid tumors in one of four major centers in England. The medical notes of each participant were also analyzed in the study.

While the individual experiences varied in terms of how their symptoms evolved and were responded to, several common themes emerged. Key findings included a pattern of young voices not being heard, delays in diagnosis and a misconception among young people and society as a whole that young people don’t get cancer.

“While symptoms in some young people were promptly recognized by GPs and referred to specialists quickly, other patients recounted tales of protracted periods of suffering, with rationalization of their own symptoms or numerous disappointing visits to doctors and hospitals before the cancer was diagnosed,” said Pearce, adding that the time period between first symptoms and diagnosis ranged from eight weeks to 11 years.

Examples of symptoms being missed by general practitioners or accident and emergency doctors included being told it is normal to be tired, that symptoms are due to menstrual problems, fluid on the knee, irritable bowel syndrome, excess weight or lack of exercise.

“One consistent thread through these stories is young people’s perception that they were not being listened to and that cancer was being ruled out on age alone,” explained Pearce. “For instance, one eventually thought she was going mad after three months of headaches and 12 visits to the GP and A&E. Finally, after breaking down at the GP’s surgery, she was referred to the specialist and was later diagnosed with neuroblastoma. It seemed that extreme levels of worry and distress had to be reached before the right course of action was taken.”

In another case, a 22-year-old young woman who was diagnosed with colon cancer that had spread to the liver recounted a frustrating battle to be taken seriously after nine or ten years of suspicious symptoms such as food aversion, abdominal pain, frequent diarrhea and rectal bleeding from the age of 14 and two separate diagnoses of familial adenomatous polyposis, or FAP, a hereditary syndrome that carries a very high risk of colon cancer.

“Basically because I grew up with the symptoms no-one went ding din ding… red light warning, we need to do something about this,” she told the researchers. “I said ‘look, this is ridiculous. I am passing blood a lot, diarrhoea, tummy ache. I want to get it sorted because it’s ruining, not ruining but it’s taking over my life’ …They look at you and they say you are too young for this. If you are old, they will do something about it.”

Pearce noted: “She felt quite strongly that if she had been 40 or 50 her symptoms would have been picked up on at a very early stage and she would have been fine, but lots of cues were missed because nobody was thinking that she could have colon cancer.” Sadly, after her participation in the study, this young woman died.

In another example, a 23-year-old young woman who was diagnosed with ovarian cancer 10 months after her first symptoms said: “I wish they had just listened to me in the beginning. I’d like them more aware so you can’t just be shoved away out the door. It’s your life … it’s your whole world they are talking about and they are not taking it seriously.”

The researchers found that the reaction of others, particularly parents, was important in determining how long the patients were willing to put up with symptoms and how assertive they were at pushing for an answer to their concerns.

“There seemed to be a trigger point at which further help was sought. That threshold came when normal physical, social and emotional functioning became impossible and the symptoms could no longer be dismissed as normal,” Ms Pearce said. “Prompting, confirmation and support from others was crucial in the acknowledgment of threat and seriousness of the need for action.”

The sense of relief once they had arrived in specialist care was striking. They felt they were in safe hands, with experts whom they now had confidence in, the study found. However, some said their struggle to get to that point prompted them to lose trust in their GP or the hospital Accident & Emergency system and that they would be reluctant to seek the help of those professionals again.

“The stories related here are, sadly, far from unique. Doctors should be making urgent referrals when children or young people come to see them several times with the same problem and persistent parental anxiety should be sufficient reason for referral,” Pearce said, adding that the study recommends research into interventions such as education in schools and universities and better education of health professionals, including school nurses, university health centers and general practitioners so that classic signs are investigated properly and promptly.

The 23-year-old ovarian cancer patient’s advice to young people was: “Listen to your intuition and be strong. If you think something is wrong just keep pushing.”

The study was funded by CLIC Sargent, the UK-based children and young people’s cancer charity.

For more information:

• Abstract no: 4170. Experiences of Care proffered papers session, Tuesday 09.00 hrs CEST (Hall 10)

Also read these PubMed abstracts:

• Gurney JG, Krull KR, Kadan-Lottick N, Nicholson HS, Nathan PC, Zebrack B, Tersak JM, Ness KK. Social outcomes in the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2009 May 10;27(14):2390-5. Epub 2009 Feb 17. Review.
• Zeltzer LK, Recklitis C, Buchbinder D, Zebrack B, et al. Psychological status in childhood cancer survivors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2009 May 10;27(14):2396-404. Epub 2009 Mar 2
• Stein KD, Syrjala KL, Andrykowski MA. Physical and psychological long-term and late effects of cancer. Cancer. 2008 Jun 1;112(11 Suppl):2577-92. Review.
• Zeltzer LK, Lu Q, Leisenring W, Tsao JC, et al. Psychosocial outcomes and health-related quality of life in adult childhood cancer survivors: a report from the childhood cancer survivor study. Cancer Epidemiol Biomarkers Prev. 2008 Feb;17(2):435-46
• Zebrack BJ, Zevon MA, Turk N, Nagarajan R, et al, Psychological distress in long-term survivors of solid tumors diagnosed in childhood: a report from the childhood cancer survivor study. Pediatr Blood Cancer. 2007 Jul;49(1):47-51
• Turner J, Clavarino A, Yates P, Hargraves M, Connors V, Hausmann S. Development of a resource for parents with advanced cancer: what do parents want?
  Palliat Support Care. 2007 Jun;5(2):135-45.
• Van Dijk J, Imhof SM, Moll AC, Ringens PJ, Cohen-Kettenis PT, Rijmen F, Huisman J. Quality of life of adult retinoblastoma survivors in the Netherlands.
  Health Qual Life Outcomes. 2007 Jun 4;5:30.
• Abrams AN, Hazen EP, Penson RT. Psychosocial issues in adolescents with cancer.
  Cancer Treat Rev. 2007 Nov;33(7):622-30. Epub 2007 Apr 16. Review.
• Upton P, Eiser C. School experiences after treatment for a brain tumour.
  Child Care Health Dev. 2006 Jan;32(1):9-17.
• Stam H, Grootenhuis MA, Brons PP, Caron HN, Last BF. Health-related quality of life in children and emotional reactions of parents following completion of cancer treatment.
  Pediatr Blood Cancer. 2006 Sep;47(3):312-9.

Everolimus (Afinitor®) Licensed in UK for Advanced Kidney Cancer Patients After Failure of First Line Vascular Targeted Therapy

Everolimus (Afinitor®, Novartis AG, Basel, Switzerland) has recently been licensed in the United Kingdom for the treatment of advanced kidney cancer after failure of treatments which prevent the growth of the tumor’s blood vessels, which is essential for the cancer to survive. The European Commission (EC) approved everolimus for this use on 3rd August 2009 for patients with advanced kidney cancer whose disease progressed on or after treatment with VEGF-targeted therapy.

Everolimus belongs to a class of drugs called kinase inhibitors, which interfere with cell communication, preventing tumor growth. The drug is intended for those patients with advanced renal cell cancer who have already tried another kinase inhibitor, sunitinib (Sutent, Pfizer Inc., New York, USA) or sorafenib (Nexavar, Bayer HealthCare AG, Leverkusen, Germany).

Mechanism of Action
While sunitinib and sorafenib are multiple kinase inhibitors (acting on a number of cellular targets), everolimus works by blocking a specific protein known as the mammalian target of rapamycin or mTOR, a protein that acts as a central regulator of tumor cell division, blood vessel growth and cell metabolism.

A clinical trial studying the safety and effectiveness of everolimus was discontinued after an interim analysis showed that, in patients receiving the drug, the growth or spread of the tumor was delayed when compared to patients who did not receive the drug. In addition, disease progression was delayed approximately five months in half of the patients who received everolimus. In contrast, disease progression was delayed two months in patients who did not receive the drug.

The most frequent adverse reactions in the trial (occurring in at least 20 percent of patients) included inflammation in the mouth, loss of strength, diarrhea, poor appetite, fluid buildup in the extremities, shortness of breath, coughing, nausea, vomiting, rash, and fever. Laboratory tests of blood samples determined that at least half of all patients experienced anemia, low white blood counts, high cholesterol and high triglycerides and high blood sugar.

Patients with advanced renal cell cancer have limited options once tumors progress after first line standard therapy. Now, phase III trials show that everolimus more than doubles the median time without tumor growth and reduces the risk of disease worsening or death by 67% compared with placebo.

Prior to this date, there were no licensed treatment options in the United Kingdom for advanced renal cell carcinoma patients whose cancer progressed while on or after treatment with these targeted therapies.

Incidence
Advanced renal cell carcinoma, the most common type of kidney cancer, accounts for approximately 2% of all new cancers. In the UK, the incidence of kidney cancer is increasing, due in part to obesity and smoking.

Renal cell cancer originates in the lining of the small tubules in the kidney that filter waste products from the blood. The cancer is resistant to such standard treatments as radiation therapy and chemotherapy, and the initial treatment for most patients is surgical removal of the kidney. If the cancer is confined to the kidney, the five-year survival rate is 60 to 70 percent. However, if left untreated, the tumor can spread to neighboring lymph nodes and eventually to other organs, considerably reducing the survival rate.

"I am delighted that there is now a proven treatment option available to people living with advanced kidney cancer in the UK, who have progressed after treatment with a targeted therapy. The availability of Afinitor is an important step in ensuring this population of poor prognosis patients have the potential to control their disease even further," said Tim Eisen, Professor of Medical Oncology at the University of Cambridge.

Expert consensus opinion, recently published in a review article in the British Journal of Hospital Medicine, has been updated to recommend everolimus as a Second-Line Therapy treatment option for advanced kidney cancer therapy after progression on targeted therapies.

Data that led to the European approval show that everolimus, when compared with placebo, more than doubled the median time without tumor growth or death in patients with advanced kidney cancer whose disease progressed following prior vascular targeted therapy (4.9 vs. 1.9 months). The data showed the reduction of the risk of disease progression or death by 67% based on the primary endpoint of progression-free survival (PFS) (hazard ratio=0.33 with 95% confidence interval 0.25 to 0.43; P<0.001.>

Every year there are 7,000 newly diagnosed cases of kidney cancer which also causes around 3,700 deaths a year," said Pat Hanlon, Kidney Cancer UK. "While many of these cancer patients will be diagnosed early and undergo surgery to cure them, 40% of patients will be diagnosed in the advanced stages when prognosis is extremely poor and the cancer is notoriously difficult to treat."

James Whale, Founder of The James Whale Fund for Kidney Cancer, adds: "We at the Fund are pleased everolimus has been granted a license in the UK as, given the poor prognosis of kidney cancer, it is critical for people living with the disease to have access to life-extending treatments. This has been proven to provide benefit to kidney cancer patients, enabling them to spend precious time with family and friends."

The U.S. Food and Drug Administration (FDA) approved everolimus oral tablets for the treatment of patients with advanced kidney cancer whose disease has progressed after treatment with other cancer therapies in March 2009. Following the approval in the US National Comprehensive Cancer Network (NCCN) updated the NCCN Clinical Practice Guidelines in Oncology™ for Kidney Cancer to reflect th eFDA approval of everolimus.

For more information:

• Afinitor® website (for non-US healthcare professionals)
• Afinitor® website (for US healthcare professionals)
• EPARs for Authorised Medicinal Products for Human Use
• Escudier, B et al. 72O - Phase III Randomised Trial of Everolimus (RAD001) vs Placebo in Metastatic Renal Cell Carcinoma. Presented at the European Society for Medical Oncology (ESMO) 33rd Congress, Stockholm, Sweden on 16 September 2008
• Escudier B, Kataja V; ESMO Guidelines Working Group. Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009 May;20 Suppl 4:81-2.
• Motzer RJ, Escudier B, Oudard S, Hutson TE, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22.
• Nathan P, Wagstaff J, Porfiri E, Powles T, Eisen T. UK Guidelines for the Systemic Treatment of Renal Cell Carcinoma. Br J Hosp Med (Lond). 2009 May;70(5):284-6. Review.
• Eisen T, Oudard S, Szczylik C, Gravis G, et al; TARGET Study Group. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst. 2008 Oct 15;100(20):1454-63. Epub 2008 Oct 7.
• McLaughlin JK, Lipworth L, Tarone RE. Epidemiologic aspects of renal cell carcinoma.
  Semin Oncol. 2006 Oct;33(5):527-33. Review.
• Motzer RJ, Agarwal N, Beard C, Bolger GB, et al. NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw. 2009 Jun;7(6):618-30.
• Highlights of the NCCN 13th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care™, published as a supplement to The Oncology Report: The mTOR pathway as a new target.