ESMO @ ECC 2013: Younger Age in Patients with Metastatic Colorectal Cancer Associates with Poorer Outcome

An analysis from the ARCAD clinical trials programme.

New data from an analysis of data in the large ARCAD databank identify patients with metastatic colorectal cancer (mCRC) under the age of 40 years as a high-risk population for treatment failure and poorer overall- and progression-free survival. The findings were presented 29 September, 2013 during the Gastrointestinal Malignancies/Colorectal Cancer II Proffered Papers Session (Abstract E17-1484) at the 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress. The European Cancer Congresses are organised in joint partnership with ESSO, EACR, EONS and SIOPE as a forum for the latest in oncology research and to offer multidisciplinary and multi-professional educational opportunities in oncology. The 2013 Congress convened in Amsterdam, The Netherlands from 27 September until 1 October.

ESMO Comments bubble

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. Dr 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 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.
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.

Erika Martinelli*

*Erika Martinelli, ESMO spokesperson who was not involved in the study commented.

The risk change as a continuous function of age

Dr. Christopher Lieu of the Division of Medical Oncology, University of Colorado, Aurora, USA and colleagues conducted this analysis which aimed to assess whether age may be prognostic for overall survival (OS) and progression-free survival (PFS) in patients with mCRC. Previous investigations have made direct comparisons between patients who were categorized into groups of less than 40 years versus aged 40 and more years, thus giving broad pooled risk. This analysis determined whether and how risk changes as a continuous function of age to better clarify the age-response.

Colorectal cancer is mainly a disease affecting the older population;the median age at diagnosis is 69 years. Just 4.6% of the total incidence of CRC represents patients younger than 50 years of age but this incidence is on the rise; despite a trend towards decreased overall incidence in the western population, largely due to screening, overall incidence rates of CRC per 100,000 young adults (ages 20-49 years) increased 1.5% per year in men and 1.6% per year in women from 1992 to 2005.

Younger patients present more commonly with advanced stage III or IV disease. Screening is currently recommended for persons aged 50 and older. Hereditary factors account for just 5-7% of young-onset CRC cases, making screening the only way to detect CRC in young adults.

Poor performance status significantly associates with decreased survival in patients younger than 40 years

This analysis used the French ARCAD Foundation (Aide et Recherche en Cancerologie Digestive) CRC database which includes data from 20,326 patients who participated in 23 frontline phase III clinical trials, including trials with biologic agents. The endpoints of these trials were OS and PFS and primary covariates included age, sex, and performance status (PS). Cox proportional hazards models stratified by treatment arm within a study were used to model primary age effects, as well as interactions with and/or adjustments for sex and PS. Patients without events by 1 year were right-censored. Non-linearity of age on the log relative hazard of PFS and OS was modeled using restricted cubic splines.

The OS and PFS results were available for 19,900 patients; of these, 695 (3%) patients were younger than 40 years. Age was found to be significantly  prognostic for both OS (p < 0.0001) and PFS (p < 0.0001) with U-shaped risk for each endpoint; i.e., the highest risk of OS and PFS was evident in the youngest and oldest patients, while 57 to 61-year olds demonstrated the lowest risk of OS and PFS, respectively.

Patients with CRC in the youngest cohort experienced 30% increased risk of death and 28% increased risk of progression or death during the follow-up period. Patients with CRC in the oldest cohort who experienced a 72% increased risk of death and 19% increased risk of progression or death in the follow-up period.

Poor PS significantly associated with decreased survival in younger but not older patients (interaction p = 0.0001). Sex was statistically but not clinically significant as an adjustment variable in these models.

The authors found that, although the assessment of performance status may be subject to bias, poor performance status significantly associated with decreased survival in patients younger than 40 years. Young age associated with poorer OS and PFS in treated patients with mCRC and further studies identifying the biological differences between the disease experienced by older and younger patients are warranted.

The study authors disclosed no conflict of interest.