Younger patients with metastasized colorectal cancer represent a high-risk group that is less likely to respond to anti-cancer treatments. According to new research presented at the 2013 European Cancer Congress (ECC2013), being held in Amsterdam, The Netherlands, from September 27 until October 1, 2013, their disease is more likely to progress and they are at greater risk of death than other age groups. [1]

An analysis of 20,034 patients in 24 phase III clinical trials for colorectal cancer, of which 695 patients (3%) were younger than 40 years of age, showed that the youngest and oldest patients had the highest risk of their disease progressing and of dying, compared to middle-aged patients.[2] When compared to 57-year-olds, the youngest patients had a 30% increased risk of dying from the disease, and, when compared to 61-year-olds, they had a 28% increased risk of their disease progressing and metastasizing during the first year of follow-up after randomization and the start of treatment. The oldest patients had a 72% increased risk of death and a 19% increased risk of their disease metastasising compared to the 57 and 61-year-olds during the follow-up period.

Increased risk
Christopher Lieu, MD, an assistant professor at the University of Colorado’s School of Medicine Division of Medical Oncology in Denver, Colorado (USA), explained: ?Although colorectal cancer occurs in only 4.6% of patients who are younger than 50 years of age, the incidence of the disease has been increasing at a rate of 1.5% per year from 1992 to 2005 in this age group. The most dramatic increases have been observed in the 20-29 year-old group, where there has been an annual 5.2% increase in cases in men and a 5.6% increase in women, and in the 30-39 year-old group, where there has been an annual 3% increase in men and a 2% increase in women.”[2]

Changing risk
?The reasons why the incidence is increasing in younger patients remain unknown, although genetic predisposition, environmental factors, fewer early cancer detections in this population, or a combination of these factors are thought to play a role. We carried out this study to see whether age was associated with time until cancer progresses or the patient dies. We also wanted to get a better picture of the age-response relationship and identify how risk changes as people age, rather than simply comparing one group (patients younger than 40 years of age) with another group (patients older than 40 years of age).?

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This study, performed on a large case series of patients, reinforces the concept that younger people diagnosed with colorectal cancer have a high risk of disease progression and death.

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Altered cut-off approach
Previous studies in this field have split the population into two mutually exclusive groups, establishing rigid limits between patients younger and older than 40 or 50 years of age. The new research, however, did not use this cut-off approach and it includes data spanning all ages. ?The reason why we did this is because we believe that a 49-year-old patient with colorectal cancer may be different than a 20-year-old. By including them in the same group of people younger than 50 years old we might be mistakenly considering them to be the same,? Lieu explained.

Lieu and his colleagues analysed information from a database of clinical trials in advanced colorectal cancer supported by the French Aide et Recherche en Canc?rologie DigestiveFoundation (ARCAD; 151 Rue du Faubourg Saint Antoine
75011 Paris, France), which includes the 20,034 patients from 24 phase III clinical trials who were on their first treatment for the disease, plus additional patient data from other trials in which patients might be on second or third lines of different treatments, having not responded to their initial therapy.

Out of these patients, 20,011 were evaluable for analysis of survival time and time until the disease progressed. ?Analysis of this incredibly large population of patients has allowed us to answer meaningful questions, such as the outcomes of young versus older patients. Our results show that young age is associated with worse overall survival and progression-free survival. Young patients with metastatic colorectal cancer represent a group who are at high risk for treatment failure,? Lieu noted.

Ongoing research needed
Despite the comprehensive nature of the study, more research will be required to identify why colorectal cancer in younger people appears to be more aggressive. ?Further studies identifying biological differences are warranted,? Lieu said. He and his group are currently collaborating along these lines with a research group at the University of Texas MD Anderson Cancer Center (Texas, USA).

?While colorectal cancer overwhelmingly occurs in older people, we must not forget that people younger than 50 can develop it too. The study by Lieu and his colleagues is important as it shows that these younger patients may have a worse prognosis if their disease has metastasised. Doctors and patients need to be aware of this so that they are alert to the early symptoms of colorectal cancer, and treatment can be given before the disease has started to spread,? noted current ECCO President, Professor Cornelis van de Velde, MD, PH.D.

Worldwide collaboration
Commenting on the study results, Professor Erika Martinelli, Assistant Professor in Medical Oncology at Seconda Universit? Studi di Napoli Policlinico Federico II, Naples, Italy, and a board member of ESMO, the European Society for Medical Oncology, said: ?Considerable controversy exists concerning the outcome of younger patients with colorectal cancer and it is a critical topic because the incidence of this cancer is increasing in the younger population. Lieu and his colleagues have contributed important scientific evidence from a worldwide collaboration of clinicians and scientists specialising in gastrointestinal cancer, and they have confirmed that patients younger than 40 years of age have a worse prognosis. These patients have poor overall survival and progression-free survival, and this was not influenced by sex or performance status.”

?The conclusions are intriguing because the study has been performed on a large case series of patients (the ARCAD database is one of the largest in gastrointestinal oncology), reinforcing the concept that younger people diagnosed with colorectal cancer survive less well, in spite of being in better overall condition and with fewer other medical problems,” Martinelli further noted. ?This evaluation of the prognostic significance of age needs further analysis aimed at identifying any biological characteristics or markers that make the cancer disease of young people more aggressive and less responsive to drugs,? he concluded.

For more information:
[1] Abstract no: 2158: The impact of young age on survival in patients with metastatic colorectal cancer: analysis from the ARCAD Clinical Trials Program. What: Gastrointestinal malignancies ? colorectal cancer II proffered papers session. When 09.00 a.m. CEST, Sunday 29 September 2013. Location: RAI Auditorium.
[2] Siegel RL, Jemal A, Ward EM Increase in incidence of colorectal cancer among young men and women in the United States. Cancer Epidemiol Biomarkers Prev. 2009 Jun;18(6):1695-8. doi: 10.
1158/1055-9965.EPI-09-0186. [Article][PubMed]

Educational Book
The Educational Book from ECC 2013 is published as a supplement to the European Journal of Cancer. [Download]

Note: All figures correspond to patients? outcome within one year of initiating first-line ? the initial ? treatment in phase III clinical trials. These trials are designed to assess the effectiveness of medical treatments and their value in clinical practice.

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