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.

Overweight and Obesity Causes over 124,000 New Cancers a Year in Europe

According to estimates from a new modeling study, at least 124,000 new cancers in 2008 in Europe may have been caused by excess body weight. The proportion of cases of new cancers attributable to a body mass index of 25kg/m2 or more were highest among women and in central European countries such as the Czech Republic, Latvia, Slovenia and Bulgaria.

The lead author of a study called ‘Incident cancer burden attributable to excess body mass index in 30 European countries’, published in the International Journal of Cancer, Dr Andrew Renehan, told oncologists and other medical professionals gather together in Berlin, Germany during the combined 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology: “As more people stop smoking and fewer women take hormone replacement therapy, it is possible that obesity may become the biggest attributable cause of cancer in women within the next decade.”

Dr Renehan, who is a senior lecturer in cancer studies and surgery at the University of Manchester (UK), and his colleagues in the UK, The Netherlands and Switzerland, created a sophisticated model to estimate the proportion of cancers that could be attributed to excess body weight in 30 European countries. Using data from a number of sources including the World Health Organization and the International Agency for Research on Cancer, they estimated that in 2002 (the most recent year for which there are reliable statistics on cancer incidence in Europe) there had been over 70,000 new cases of cancer attributable to excess BMI out of a total of nearly 2.2 million new diagnoses across the 30 European countries.

The percentage of obesity-related cancers varied widely between countries, from 2.1% in women and 2.4% in men in Denmark, to 8.2% in women and 3.5% in men in the Czech Republic. In Germany it was 4.8% in women and 3.3% in men, and in the UK it was 4% in women and 3.4% in men.

Then, the researchers projected the figures forward to 2008, taking into account what was known about shifts in the distribution of BMI, the dramatic decline in women’s use of hormone replacement therapy (HRT) from 2002 onwards following research that showed it increased the risk of breast cancer, and the wider use of PSA screening for prostate cancer in men.

They found that the number of cancers that could be attributed to excess body weight increased to 124,050 in 2008. In men, 3.2% of new cancers could be attributed to being overweight or obese and in women it was 8.6%. The largest number of obesity-related new cancers was for endometrial cancer (33,421), post-menopausal breast cancer (27,770) and colorectal cancer (23,730). These three accounted for 65% of all cancers attributable to excess BMI.

“I must emphasize that we are trying not to be sensationalist about this,” said Dr Renehan. “These are very conservative estimates, and it’s quite likely that the numbers are, in fact, higher.”

The number of new cases of obesity-related esophageal cancer was particularly high in the UK relative to the rest of Europe. “This country accounts for 54% of new cases across all 30 countries,” said Dr Renehan. “This may be due to synergistic interactions between smoking, alcohol, excess body weight and acid reflux – and is currently an area where research is required.”

Until 2002 when HRT use dropped dramatically following the results of the Women’s Health Initiative Trial (USA) that showed an increased risk of breast cancer in women taking HRT, Dr Renehan said that HRT masked and diluted the effects of obesity on the incidence of breast cancer. “In women who used HRT it wasn’t clear what proportions of breast cancers were caused by HRT or by obesity. In women who don’t take HRT, the effect of obesity was much clearer. Now that far fewer women are using HRT, it is much easier to see the effect of obesity on the incidence of breast cancer, and also on endometrial cancer. Consequently, the proportions of these cancers attributable to obesity have increased.”

Dr Renehan said that although European countries were taking steps to tackle the obesity epidemic, this study underlined the urgency of the task and the scale of the problems caused by increasingly overweight populations.

“The overall size of the burden of increasing cancer incidence should inform health policy. For example, it is clear that, in both relative and absolute terms, obesity-related cancer is a greater problem for women than for men. At a country level, it is a greater problem for central European countries like the Czech Republic, whereas it is less of a problem in France and Denmark. Similarly, obesity-related esophageal cancer seems to be a substantial and unique problem in the UK.

“The study also identifies priorities for research into certain cancers, namely endometrial, breast and colorectal cancers. In the face of an unabating obesity epidemic, and apparent failure of public health policies to control weight gain, there is a need to look at alternative strategies, including pharmacological approaches.”

Dr Renehan’s own research is trying to relate these epidemiological findings back to the biological mechanisms that are at work. His research uses the observed interactions between excess BMI and cancer risk to guide questions in the laboratory.

For more information:

• ECCO15 – ESMO 34 Abstract no: 327, Oncopolicy session: Drug and lifestyle mediated prevention initiatives in Europe. Thursday 11.15-12.15 hrs CEST (Hall 3)

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.