- Email: [email protected]
Comparing Clinical Characteristics and Outcomes of Young-onset and Late-onset Colorectal Cancer: An International Collaborative Study
Accepted Manuscript Comparing Clinical Characteristics and Outcomes of Young Onset to Late Onset Colorectal Cancer, An International Collaborative Study Young Soo Rho, M.D, Marine Gilabert, M.D, Ph.D, Karol Polom, M.D, Ph.D, Archil Aladashvili, M.D, Ph.D, Katerina Kopeckova, M.D, Vera Megdanova, M.D, Niamh Coleman, MBBCH MRCP, Megan Greally, MBBCH MRCP, Daniele Marrelli, M.D, Franco Roviello, M.D, Ph.D, Ray McDermott, MB BCh BAO, PhD, MBA, Veneta Petrova, M.D, Zhasmina Mihaylova, M.D, Ph.D, Zbynek Bortlicek, Jana Prausova, M.D, Ph.D, Gerald Batist, M.D, Laurent Azoulay, Ph.D, Petr Kavan, M.D, Ph.D PII:
S1533-0028(17)30125-1
DOI:
10.1016/j.clcc.2017.03.008
Reference:
CLCC 365
To appear in:
Clinical Colorectal Cancer
Received Date: 31 July 2016 Revised Date:
26 January 2017
Accepted Date: 9 March 2017
Please cite this article as: Rho YS, Gilabert M, Polom K, Aladashvili A, Kopeckova K, Megdanova V, Coleman N, Greally M, Marrelli D, Roviello F, McDermott R, Petrova V, Mihaylova Z, Bortlicek Z, Prausova J, Batist G, Azoulay L, Kavan P, Comparing Clinical Characteristics and Outcomes of Young Onset to Late Onset Colorectal Cancer, An International Collaborative Study, Clinical Colorectal Cancer (2017), doi: 10.1016/j.clcc.2017.03.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Comparing Clinical Characteristics and Outcomes of Young Onset to Late Onset Colorectal Cancer, An International Collaborative Study
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Young Soo Rho M.D1, Marine Gilabert M.D, Ph.D2, Karol Polom M.D, Ph.D3, Archil
Aladashvili M.D, Ph.D4, Katerina Kopeckova M.D5, Vera Megdanova M.D7, Niamh Coleman MBBCH MRCP8, Megan Greally MBBCH MRCP8, Daniele Marrelli M.D3, Franco Roviello
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M.D, Ph.D3, Ray McDermott MB BCh BAO, PhD, MBA7, Veneta Petrova M.D7, Zhasmina Mihaylova M.D, Ph.D7, Zbynek Bortlicek6, Jana Prausova M.D, Ph.D5, Gerald Batist M.D1,9,
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Laurent Azoulay Ph.D1,9,10, Petr Kavan M.D, Ph.D1,9
McGill University Faculty of Medicine, Gerald Bronfman Department of Oncology, Montréal,
Canada
Paoli-Calmettes Institute, Department of Medical Oncology, Marseille, France
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University of Siena, General and Oncological Surgery Department, Siena, Italy
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National Cancer Center, GI Cancer Research Unit and Oncology Surgery, Tbilisi, Georgia
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2nd Faculty of Medicine-Charles University Prague and Motol University Hospital, Department
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of Oncology, Prague, Czech Republic Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno
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Military Medical Academy, Department of Medical Oncology, Sofia, Bulgaria
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St Vincent's University Hospital, Medical Oncology, Dublin, Ireland
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Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital – McGill University,
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Montreal, Canada
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Department of Epidemiology, Biostatistics, and Occupational Health, McGill University,
Montreal, Canada. Running Title: Young vs Late Onset Colorectal Cancer
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Funding Source: no specific funding
Correspondence:
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Petr Kavan, M.D, Ph.D
Montreal, Quebec, H3T1E2 Room E-715 Phone: 514-340-8222 ext 5525 Fax: 514-340-7575
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E-mail: [email protected]
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3755, Cote-Ste-Catherine
Conflict of Interest: no conflict of interest from all authors
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MicroAbstract
Colorectal cancer in young patients is often diagnosed late, when it is advanced stages. These
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patients have more resistant and aggressive disease, despite similar clinical treatment patterns when compared to those with late onset disease.
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Abstract Background: Compared with the general population, the incidence of young onset (YO) colorectal cancer (CRC) is increasing. However, a significant knowledge gap exists in the
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clinical characteristics, treatment patterns, and outcomes for these patients.
Methods: Six international tertiary cancer centers conducted a retrospective study. Young onset (YO) patients, 18–44 years old, and late onset (LO) patients, >44 years old, who were diagnosed
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with histologically proven colorectal adenocarcinoma from June 2003 to June 2014 were
enrolled. Patients were randomly chosen from each center’s database, and patient demographics
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and treatment information were collected. Data were then centralized and the final analysis was performed at a single institution. Cox proportional hazards models were used to estimate crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) progression-free survival (PFS) and mortality, and YO was compared with LO. Site-specific HRs were pooled using a
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random-effects meta-analysis.
Results: Overall, 498 patients including 224 YO (male, 129; mean age, 37±5.5 years) and 274 LO (male, 167; mean age, 64.8±9.5 years) were included. At the time of diagnosis, 137 (61.2%)
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YO and 122 (44.5%) LO patients had metastatic disease. For both cohorts, the three most common presenting symptoms were pain, hematochezia, and weight loss. Surgery was
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performed in 141 (63.0%) YO and 219 (79.9%) LO patients. Longitudinal noncurative treatment patterns were similar, but more biological therapy was used for these YO patients. Pooled PFS analysis in first-line noncurative treatment favored LO (HR, 1.96; 95% CI: 1.04–3.68). Mortality analysis showed no significant differences between groups (for YO: HR, 1.53; 95% CI: 0.91– 2.58). Conclusions: Despite similar treatment patterns and survival outcomes, YO disease may be
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clinically more aggressive.
Key Words: young onset colorectal cancer, adolescent and young adults, treatment pattern, real
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world, metastatic colorectal cancer
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Introduction Colorectal cancer (CRC) is the third most common type of cancer in the world, with an estimated 1.36 million patients being diagnosed in 2012. Its incidence varies significantly across
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geographical regions, but 14 of the 20 countries with the highest CRC rates are located in Europe and Canada1. However, a steady decrease in the incidence of CRC has been observed in the United States2. A recent, large-scale analysis of the Surveillance, Epidemiology, and End Results
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(SEER) project from 1975 and 2010 showed an overall decrease in the incidence rate of 0.92%. However, the same study demonstrated that individuals younger than 50 years have an increased
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rate of CRC3. This was echoed in research based on the California Cancer Registry, which further demonstrated that individuals with CRC in the young onset (YO) group are being diagnosed more frequently and they present with a more advanced stage of cancer4. CRC is generally thought to be a disease of the elderly, with almost all cases occurring in patients over
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55 years of age5. However, a non-negligible one in 10 cases occurs in patients under the age of 50 years6; at the current rate, this number is expected to double by 20303. This finding causes great concern, because it suggests a reduced ability to cure the disease and poorer survival
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outcomes.
In the past decade, multiple population-based studies have demonstrated a slow increase
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in the incidence of CRC in the YO population3, 7, 8. Although few additional studies have been conducted, CRCs in YO patients have been shown to be unique in terms of etiology9 and biology10. However, a significant knowledge gap exists in understanding the implications of these differences in a real-world setting; with modern advances in CRC treatment, the YO patient population’s clinical outcomes requires exploration. Therefore, a multi-institutional, multinational retrospective review was conducted to assess treatment patterns and outcomes of
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YO patients with CRC and to compare the results with those of their late-onset (LO) patient
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counterparts.
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Materials and Methods Patient Population Six international tertiary cancer centers were involved in the study, as follows: Jewish
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General Hospital, McGill University, Canada (CA); Siena University, Italy (IT); Second Faculty of Medicine, Charles University Prague and Motol University Hospital, Czech Republic (CZ); National Cancer Center, Georgia (GE); St Vincent’s University Hospital, Ireland (IE); and
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Military Medical Academy, Bulgaria (BG). YO patients aged 18–44 years and LO patients over 44 years of age who had been diagnosed with pathological-proven adenocarcinoma of the colon
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or rectum from June 2003–June 2014 were included.
There is currently no single consensus on what constitutes a YO CRC patient. Generally, previous studies have considered YO patients to be those of pre-screening age, with an upper limit of 39–49 years. Therefore, an age of 44 years was chosen as the median age, and this age is
national standard11.
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Study Variables
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before the recommended screening age of 50 years. The upper age limit is recognized as YO by a
Using a standardized template designed and provided by CA, all institutions collected
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available information by reviewing the available physical charts and electronic health records at their respective institutions, using a random selection of patients. The following information was collected when available: patient demographics, presenting symptoms, personal history of cancer (including familial adenomatous polyposis (FAP) and Lynch syndrome), family history of cancer, TNM staging information following the seventh edition of the American Joint Committee on Cancer, surgical treatment, noncurative (NC; metastatic) chemotherapy and biological
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treatment (up to two different lines as previously defined12), progression date after each therapy, and survival information.
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Statistical Analysis
All information was collected and centralized to CA, where descriptive and statistical analysis was performed. Cox proportional hazards models were used to estimate crude and
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adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of progression-free survival 1 (PFS 1; time from first-line treatment to progression or death) and PFS 2 (time from second-line
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treatment to progression or death), and YO with LO patients were compared. The models were adjusted for sex, primary tumor location, metastasis at diagnosis, T (T of TNM), and year of diagnosis. DerSimonian and Laird random-effects models were used with inverse variance
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weighting to pool site-specific estimates13.
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Results Patient Demographics Overall, 498 patients were enrolled including 224 YO (male, 129; mean age, 37±5.5
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years; range, 24–44 years) and 274 LO patients (male, 167; mean age, 64.8±9.5 years; range, 45– 95 years). At time of diagnosis, 137 (61.2%) YO and 122 (44.5%) LO patients had been
diagnosed with metastatic disease. In the YO cohort, the closest familial cancer history was
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reported to be first-degree family in 55 (24.6%) patients and second-degree family in 14 (6.3%) patients. In the LO cohort, 37 (13.5%) patients had a first-degree history of cancer and 8 (2.9%)
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patients had a second-degree family history. A history of familial syndrome hereditary nonpolyposis colorectal cancer (HNPCC) and FAP were see in 8 (3.6%) and 17 (7.6%) YO patients and 5 (1.8%) and 14 (5.1%) LO patients, respectively. For both YO and LO patients, the three most common presenting symptoms were pain, hematochezia, and weight loss in 126
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(56.3%), 100 (44.6%), and 79 (35.3%) YO patients and 141 (51.5%), 116 (42.3%), and 93 (33.9%) LO patients, respectively (Table 1).
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Cancer Profile
The primary location of the cancer in YO was the colon in 103 (46.0%) patients and the
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rectosigmoid in 19 (8.5%) patients; of these 52 (42.6%) patients had left-sided disease, 43 (35.2%) patients had right-sided disease, and in 27 (22.1%) patients, it was unknown. YO rectal cancer was seen in 102 (45.5%) patients. In the LO patients, 157 (57.3%) and 28 (10.2%) had colon and rectosigmoid cancer respectively, with 99 (53.5%) patients having left-sided disease, 77 (41.6%) patients having right-sided disease, and in 9 (4.9%), it was unknown. LO rectal cancer was seen in 86 (31.1%) patients. Although KRAS oncogene molecular testing was
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unknown/not tested in most of the YO and LO populations, of those tested, wild-type (WT) tumors were present more frequently for both the YO (54 [23.9%]) and LO (95 [34.7%]) patients (Table 2). Of the tested tumors, 24 (10.6%) of YO and 54 (19.7%) of LO patients had the KRAS
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mutation. BRAF testing was not performed at all centers and, therefore, this data was not collected.
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Treatment Patterns
Surgery was performed in 141 (63.0%) YO and 219 (79.9%) LO patients. Longitudinal
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treatment patterns of chemotherapy and biological treatment information in the first- and secondline metastatic (NC) setting were available for CA, CZ, IE, and BG (YO n=132, LO n=117). For first-line NC treatment, most YO and LO patients received oxaliplatin-based chemotherapy; specifically, the two most commonly used regimens were CAPOX and FOLFOX. CAPOX was
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used in 24 (18.2%) YO and 24 (20.5%) LO patients, whereas FOLFOX was used in 55 (41.7%) YO and 34 (29.1%) LO patients. Bevacizumab was the most frequently used biological treatment in both cohorts, with 65 (49.2%) and 48 (36.4%) patients receiving it in the YO and LO groups,
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respectively. For second-line treatment, irinotecan-based chemotherapy was most frequently used in both YO and LO. FOLFIRI was administered for 25 (18.9%) YO and 21 (17.9%) LO
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patients. Irinotecan monotherapy was more frequently used compared with the first-line, with 10 (7.6%) YO and 8 (6.8%) LO patients receiving it. Although bevacizumab was used most frequently as a biological treatment in both cohorts, there was more heterogeneity in the secondline biological treatment in YO, where 11 (8.3%) patients received cetuximab and 6 (4.5%) patients received panitumumab. In both lines, a FOLFIRINOX regimen was never used in LO
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but it was used in YO for first-line therapy in 3 (2.3%) patients and second-line therapy in 2 (1.5%) patients (Table 3).
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Survival
PFS data were available for CA, CZ, IE, and BG. Individual analysis of all centers
showed a trend towards shorter PFS 1 in YO, with a statistically significant HR of 14.75 (95%
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CI: 1.36–160.12) in the IE cohort. Overall analysis of PFS 1 demonstrated an HR of 1.96 (95% CI: 1.04–3.68; Table 4, Figure 1). PFS 2 showed more heterogeneous results, with an overall HR
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of 1.26 (95% CI: 0.74–2.16; Table 5, Figure 2). Analysis of overall mortality was performed for all sites. Country-specific analysis of HRs showed no statistical difference between the YO and LO groups except at the CZ site, with an HR of 4.71 (95% CI: 1.56–14.20; Table 6) favoring YO. In a pooled analysis, YO did not demonstrate an increased mortality risk when compared to
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the LO group, with an HR of 1.53 (95% CI: 0.91–2.58; Table 7, Figure 3).
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Discussion YO, the ‘Lost Tribe’ YO represents the group of adolescents and young adult patients who form a distinct
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patient population within oncology. They are unique in terms of types of cancer, biology, and the extraordinary psychosocial challenges intrinsic to this juncture in life, which renders their
management complex. However, they are also known to be the “lost tribe” because they are in
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between pediatric and older adult groups. They are often underrepresented in clinical trials14, and the understanding of their disease and needs remains unresolved. To date, cancer in the YO
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group is the leading cause of disease-related death15.
Patient Characteristics, Risk Factors, and Presenting Symptoms
The two cohorts exhibited a nearly two-fold difference in mean age at diagnosis.
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However, both groups showed male predominance. According to a previous study, a family history of CRC can raise the risk of CRC when diagnosed before 45 years of age (odds ratio [OR] 5.3; 95% CI: 2.3–12.0). The same research showed that there was a 30% increased risk of
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CRC in patients with a family history of cancer (excluding intestinal cancer). One of the most comprehensive literature analyses performed to date on YO (<40 years old) patients with CRC
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was conducted by O’Connell and colleagues9. This review also showed a 22.7% family history of cancer on average (range, 3.2–61%). In our YO patients, a similar result was seen, where 32.7% had a family history of cancer (all forms of cancer) and 24.6% had a cancer history involving a first-degree relative. LO patients had lower overall and first-degree relative histories of cancer; however, this result must be interpreted with caution because a significant proportion of the data (31.8%) was unknown or not reported, and there was possibility of a recall bias. Well-
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known familial syndromes associated with CRC in YO populations include HNPCC (also known as Lynch syndrome) and FAP. Both are inherited in an autosomal-dominant fashion. HNPCC causes different germline mutations in 1 of 4 mismatch repair genes, and depending on the
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mutation type, age-dependent risk factors for developing CRC vary16. The reported rates of CRC in YO patients with HNPCC range from 5–10%17-19. For patients with FAP, virtually all develop CRC before the age of 50 years if left untreated. The overall rate of identifiable hereditary cancer
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syndrome has been reported to be as high as 35% in patients less than 35 years old, but this was based on a single institutional study from a tertiary cancer center and it likely overestimates the
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true rate. In our cohort, which was multi-institutional but included tertiary cancer centers, total familial syndrome was seen in 11.2% of YO and 6.9% of LO patients. However, HNPCC was only found in 3.6% of all patients. Although most of the YO population had undergone testing for familial syndrome, as is often done in clinical practice, 30.3% of LO cases were either
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unknown or not reported. The three most common presenting symptoms were pain, hematochezia, and weight loss. These symptoms were similarly found to be most frequent in previous studies9. It would be clinically pertinent to keep CRC in mind as a differential diagnosis
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for the YO group when these symptoms are present.
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CRC Characteristics
YO patients presented much more frequently with rectosigmoid and rectal cancer than
their LO counterparts, as in previously reports9, 20. For colon cancer, left-sided disease was more common for both the YO and LO groups. Many more YO patients presented with metastatic disease at the time of diagnosis than did LO patients. Molecular testing in metastatic CRC has now become the standard of care in North America and in most of Europe. In our study, 34.5%
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of YO and 54.4% of LO patients had KRAS mutation testing (Table 2). However, this does not show the true rate of clinical molecular testing, because our study included patients from 2003 and KRAS was not introduced until 200923. Significant variations also exist between countries
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and institutions for the frequency and methods of analysis (e.g. KRAS exon 2 vs. 2, 3, 4).
However, in the tested patients, the KRAS mutation rate fell within the expected range24. A recent molecular subtype analysis in CRC patients showed that the “type 5” group (MSI-high,
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BRAF- & KRAS-mutation negative, non-CpG island methylator phenotype) was present in
significant portion of young patients aged <40 and 40–49 years (10% and 20%, respectively).
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This may have particular implications for the rapidly emerging field of immune-based therapies25. Further studies have shown that other molecular biomarkers may be specifically useful for YO, including PRL, RBM3, Wrap53, p53, and DNA status26, and their clinical utility should be explored. Additionally, microsatellite instability status for this study was not
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assessed. However, this analysis may be important for future studies because it is seen up to 15– 20% of cases and it is associated with patient prognosis related to their response to therapy27.
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Treatment and Survival
Treatment details for YO CRC patients have not been well characterized. In this real-life
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study, we observed that more surgery occurred in LO patients. However, this is likely a reflection of the cohort, because more YO patients had metastatic disease. Although our data could not be used to examine the longitudinal approach to surgical treatment, a recent study by Abdelsattar et al. showed that in cases of CRC with distant metastasis, YO patients were more likely to receive surgical therapy for their primary tumors28. Moreover, as reported by Hu et al., age less than 50 years was associated with primary tumor resection. However, they also found
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that more primary tumor resection does not necessarily confer improved survival29. NC chemotherapy treatment rates were similar in both groups, although it should be noted that FOLFIRINOX was only used in YO patients. In both cohorts, there was heterogeneity in first-
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and second-line NC chemotherapy (Table 3). This likely represents a combination of factors including evaluation of treatment regimens over the course of the study period, institutional and national differences, and individualized therapeutic choice that is often decided with the patients
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themselves. Biological treatment was used more often in the YO group. This practice likely reflects YO patients’ general ability to tolerate (or perhaps greater perceived tolerability) more
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treatment. Kneuertz et al. observed similar patterns of YO patients receiving more treatment in all stages, with minimal gain in survival compared with their LO counterparts. In this research, the effect, efficacy, and survival associated with these therapies were examined in a NC setting, which for this disease, represents all but surgical treatment of metastatic disease. PFS in the first-
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line treatment of metastatic disease was longer for LO; one explanation for this difference is that it illustrates the aggressive nature of cancer in YO. Although individual site-specific analysis showed a trend in general PFS that favored LO, in each institutional analysis, IE was the sole
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statistically significantly center favoring LO. IE’s patient characteristics did not significantly differ in this study, and the group’s sample size was small. However, in-depth information was
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acquired, allowing for multiple adjustments in the analysis. This is a novel observation that was not found in the retrospective analysis performed by Vatandoust et al.30, and we believe that it merits further exploration. Overall survival for YO patients compared to LO counterparts has been the subject of debate by many researchers. Studies have supported both worse survival31-33 and better survival34-38 for YO patients. This variability was well represented in our study. Only one institution, CZ, showed that YO patients had a better survival rate. Although the reason for
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this has yet to be clarified, one noteworthy point is the LO group’s small sample size. While the overall analysis showed that neither group had a better outcome, and the generally heterogeneity of the patients, treatments, and institutions makes any other conclusion risky, and the few
Future Directions in Understanding YO patients with CRC
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cancers in the younger group.
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exceptions we found do not adequately answer the question of biological differences in these
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Our study raised multiple important issues. First, a consensus still needs to be established concerning the definition of what truly constitutes a YO patient with CRC. Thus far, most studies have considered those below the screening to be YO, but the lower cut-off age has been challenged39. This definition maybe a crucial step to unify and better understand CRC in young adults. Second, more molecular-based studies must become routine to characterize YO patients
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with CRC. Although our study, with its limited KRAS data, has shown similar rates of oncogene mutation, other routinely used biomarkers such as BRAF/NRAS and MSI should be tested, and novel biomarkers should be sought. There are major implications to these molecular profiles,
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including targeted chemicals and immune-based treatments40. Finally, as we have demonstrated,
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there is heterogeneity in terms of practice patterns across countries. These differences and variabilities should be further explored to optimize patient treatment and care.
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Clinical Practice Points •
Compared to the general population, the incidence of young onset (YO) colorectal cancer (CRC) is increasing. Previous studies have found that this population’s CRC is unique in
•
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etiology and biology when compared to late onset (LO) disease.
Our real-life multi-institutional, multinational study showed that both cohorts have the same three most common presenting symptoms: pain, hematochezia, and weight loss. Longitudinal noncurative treatment patterns for both YO and LO were similar, but more biological therapy was used for YO.
Pooled PFS analysis in first-line noncurative treatment favored LO, possibly suggesting
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more aggressive or less responsive disease in YO patients.
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Mortality analysis showed no significant differences between the two groups.
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Eur J Cancer. 2010;46: 2788-2798.
28. Abdelsattar ZM, Wong SL, Regenbogen SE, Jomaa DM, Hardiman KM, Hendren S. Colorectal cancer outcomes and treatment patterns in patients too young for average-risk screening. Cancer. 2016;122: 929-934. 29. Hu CY, Bailey CE, You YN, et al. Time trend analysis of primary tumor resection for stage IV colorectal cancer: less surgery, improved survival. JAMA Surg. 2015;150: 245-251.
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30. Vatandoust S, Price TJ, Ullah S, et al. Metastatic Colorectal Cancer in Young Adults: A Study From the South Australian Population-Based Registry. Clin Colorectal Cancer. 2016;15: 32-36.
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31. Taylor MC, Pounder D, Ali-Ridha NH, Bodurtha A, MacMullin EC. Prognostic factors in colorectal carcinoma of young adults. Can J Surg. 1988;31: 150-153.
32. Marble K, Banerjee S, Greenwald L. Colorectal carcinoma in young patients. J Surg Oncol.
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1992;51: 179-182.
33. Cusack JC, Giacco GG, Cleary K, et al. Survival factors in 186 patients younger than 40
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years old with colorectal adenocarcinoma. J Am Coll Surg. 1996;183: 105-112. 34. Adloff M, Arnaud JP, Schloegel M, Thibaud D, Bergamaschi R. Colorectal cancer in patients under 40 years of age. Dis Colon Rectum. 1986;29: 322-325.
35. Beckman EN, Gathright JB, Ray JE. A potentially brighter prognosis for colon carcinoma in
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the third and fourth decades. Cancer. 1984;54: 1478-1481.
36. Heys SD, Sherif A, Bagley JS, Brittenden J, Smart C, Eremin O. Prognostic factors and survival of patients aged less than 45 years with colorectal cancer. Br J Surg. 1994;81: 685-688.
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37. Lee PY, Fletcher WS, Sullivan ES, Vetto JT. Colorectal cancer in young patients: characteristics and outcome. Am Surg. 1994;60: 607-612.
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38. Forbes SS, Sutradhar R, Paszat LF, Rabeneck L, Urbach DR, Baxter NN. Long-term survival in young adults with colorectal cancer: a population-based study. Dis Colon Rectum. 2010;53: 973-978.
39. Mork ME, You YN, Ying J, et al. High Prevalence of Hereditary Cancer Syndromes in Adolescents and Young Adults With Colorectal Cancer. J Clin Oncol. 2015;33: 3544-3549.
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40. Friedrich T, Leong S, Lieu CH. Beyond RAS and BRAF: a target rich disease that is ripe for
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picking. J Gastrointest Oncol. 2016;7: 705-712.
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Table 1. Characteristics of YO versus LO patients with colorectal cancer Characteristic YO LO Total 224 274 Country Bulgaria 22 (9.8) 22 (8.0) Canada 40 (17.9) 46 (16.8) Czech 44 (19.6) 20 (7.3) Georgia 78 (34.8) 76 (27.7) Ireland 26 (11.6) 29 (10.6) Italy 14 (6.3) 81 (29.6) Age at diagnosis, years (mean, SD) 37.0 (5.5) 64.8 (9.5) Males, n (%) 129 (57.6) 167 (60.9) Symptom at presentation* Pain 126 (56.3) 141 (51.5) Hematochezia 100 (44.6) 116 (42.3) Weight loss 79 (35.3) 93 (33.9) Closest cancer family history In first-degree relative 55 (24.6) 37 (13.5) 14 (6.3) 8 (2.9) In first-degree relative Unknown degree 6 (2.7) 8 (2.9) 149 (66.5) 134 (48.9) None Unknown/Not reported 0 (0.0) 87 (31.8) Familial syndrome 8 (3.6) 5 (1.8) HNPCC 17 (7.6) 14 (5.1) FAP 199 (88.8) 172 (62.8) None Unknown/Not reported 16 (7.1) 83 (30.3) *Not mutually exclusive
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Abbreviations: YO: young onset; LO: late onset; SD: standard deviation; HNPCC: hereditary nonpolyposis colorectal cancer; FAP: familial adenomatous polyposis
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YO 224 103 (46.0) 102 (45.5) 19 (8.5) 0 (0.0) 122
Left Right Unknown KRAS Wild-type Mutation UKN/not tested Metastasis at diagnosis Yes No Unknown T (T of TNM) T1 T2 T3 T4 TX N (N of TNM) 0 1 2 NX
52 (42.6) 43 (35.2) 27 (22.1)
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Rectosigmoid Unknown Colon
LO 274 157 (57.3) 86 (31.3)
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Table 2. Cancer Profile Characteristic Total Colon Rectal
28 (10.2) 3 (1.1) 185
99 (53.5) 77 (41.6) 9 (4.9)
54 (24.1) 24 (10.7) 146 (65.2)
95 (34.7) 54 (19.7) 125 (45.6)
137 (61.2) 78 (34.8) 9 (4.0)
122 (44.5) 123 (44.9) 29 (10.6)
12 (5.4) 25 (11.2) 83 (37.1) 56 (25.0) 48 (21.1)
1 (0.4) 39 (14.2) 149 (54.4) 60 (21.9) 25 (9.1)
58 (25.9) 59 (26.3) 49 (21.9) 58 (25.9)
86 (31.4) 95 (34.7) 59 (21.5) 34 (12.5)
Abbreviations: YO: young onset; LO: late onset; NC: noncurative; UKN: unknown
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Table 3. Treatment Characteristics
141 (63.0) 76 (33.9) 7 (3.1)
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24 (18.2) 55 (41.7) 1 (0.8) 8 (6.1) 3 (2.3) 5 (3.8) 0 (0.0) 1 (0.8) 0 (0) 2 (1.5) 1 (0.8)
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Characteristic Surgery Yes No Unknown First-line NC Chemotherapy* CAPOX FOLFOX CAPIRI FOLFIRI FOLFIRINOX FLOX IROX 5FU-Irinotecan Capecitabine 5FU-Leucovorin Irinotecan None Unknown Trial Second-line NC Chemotherapy* CAPOX FOLFOX CAPIRI FOLFIRI FOLFIRINOX FLOX IROX 5FU-Irinotecan Capecitabine 5FU-Leucovorin Irinotecan None Unknown Trial First-line NC Biological* Bevacizumab Cetuximab Panitumumab Regorafenib
219 (79.9) 51 (18.6) 4 (1.5) 24 (20.5) 34 (29.1) 2 (1.7) 11 (9.4) 0 (0.0) 1 (0.9) 2 (1.7) 0 (0.0) 4 (3.4) 1 (0.9) 1 (0.9)
27 (20.5) 5 (3.8) 0 (0)
37 (31.6) 0 (0.0) 0 (0.0)
3 (2.3) 4 (3.0) 4 (3.0) 25 (18.9) 2 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.8) 1 (0.8) 10 (7.6) 76 (57.6) 3 (2.3) 2 (1.5)
2 (1.7) 8 (6.8) 8 (6.8) 21 (17.9) 0 (0.0) 0 (0.0) 1 (0.9) 2 (1.7) 1 (0.9) 0 (0.0) 8 (6.8) 61 (52.1) 0 (0.0) 5 (4.3)
65 (49.2) 7 (5.3) 3 (2.3) 0 (0.0)
48 (36.4) 5 (3.8) 1 (0.8) 0 (0.0)
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3 (2.3) 60 (45.5) 0 (0.0) 5 (3.8) 17 (12.9) 4 (3.0) 3 (2.3) 0 (0.0) 88 (66.7) 0 (0.0)
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Aflibercept 0 (0.0) None 51 (38.6) Unknown 6 (4.5) Second-line NC Biological* Aflibercept 1 (0.8) Bevacizumab 17 (12.9) 11 (8.3) Cetuximab Panitumumab 6 (4.5) Regorafenib 1 (0.8) 94 (71.2) None 2 (1.5) Unknown *Data collected and reported for CA, CZ, IE, BG only; YO n=132, LO n=117
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Abbreviations: YO: young onset; LO: late onset; NC: noncurative; CAPOX: Capecitabine + Oxaliplatin; FOLFOX: LV5FU2 (48h) + Oxaliplatin; CAPIRI: Capecitabine + Irinotecan; FOLFIRI: LV5FU2 + Irinotecan; FOLFIRINOX: LV5FU2 + Irinotecan+ Oxaliplatin; FLOX: LV5FU2 (bolus) + Oxaliplatine; IROX: Irinotecan + Oxaliplatin
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Table 4. Hazard ratios for the association between age group and disease progression for first-line chemotherapy among patients with colorectal cancer Number of patients
Events
Personyears
Incidence ratea (95% CI)
Bulgaria LO YO
19 15
15 12
19 9
79.3 (44.4-130.8) 130.4 (67.4-227.9)
Canada LO YO
30 30
20 24
39 29
Czech Republic LO YO
12 40
9 30
13 38
Ireland LO YO
8 8
7 7
Adjusted HR (95% CI)b
1.00 (Reference) 2.20 (0.95-5.08)
1.00 (Reference) 2.30 (0.94-5.61)
50.8 (31.0-78.4) 83.2 (53.3-123.8)
1.00 (Reference) 1.52 (0.84-2.76)
1.00 (Reference) 1.18 (0.62-2.25)
70.3 (32.2-133.5) 78.7 (53.1-112.3)
1.00 (Reference) 1.29 (0.61-2.74)
1.00 (Reference) 2.12 (0.85-5.30)
119.1 (47.9-245.4) 318.4 (128.0-656.0)
1.00 (Reference) 7.80 (1.52-39.94)
1.00 (Reference) 14.75 (1.36-160.12)
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Crude HR (95% CI)
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Age group
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Abbreviations: YO: young onset; LO: late onset; HR: hazard ratio; CI: confidence interval a Per 100 person-years. b adjusted for sex and year of diagnosis. Bulgaria additionally adjusted for N of TNM; Czech Republic additionally adjusted for N of TNM and metastasis at diagnosis; Ireland additionally adjusted for metastasis at diagnosis.
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Table 5. Hazard ratios for the association between age group and disease progression of second-line chemotherapy among patients with colorectal cancer Events
Personyears
Incidence ratea (95% CI)
Crude HR (95% CI)
Adjusted HR (95% CI)b
Bulgaria LO YO
15 12
11 11
8 7
159.4 (796-285.2) 143.6 (71.7-257.0)
1.00 (Reference) 0.80 (0.33-1.97)
1.00 (Reference) 0.95 (0.37-2.48)
Canada LO YO
28 12
17 12
34 11
50.4 (29.4-80.7) 107.5 (55.5-187.7)
1.00 (Reference) 2.10 (0.98-4.52)
1.00 (Reference) 1.89 (0.84-4.28)
Czech Republic LO YO
7 26
6 19
5 14
129.8 (47.6-282.6) 136.9 (82.4-213.8)
1.00 (Reference) 1.13 (0.45-2.85)
1.00 (Reference) 1.13 (0.41-3.11)
Ireland LO YO
6 4
5 3
1.00 (Reference) 0.72 (0.17-3.11)
1.00 (Reference) 0.09 (0.00-4.30)
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Number of patients
Age group
2 1
241.2 (78.3-563.0) 201.1 (41.5-587.6)
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Abbreviations: YO: young onset; LO: late onset; HR: hazard ratio; CI: confidence interval a Per 100 person-years b adjusted for sex and year of diagnosis. Bulgaria additionally adjusted for N of TNM; Czech Republic additionally adjusted for N of TNM and metastasis at diagnosis; Ireland additionally adjusted for metastasis at diagnosis.
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Table 6. Hazard ratios for the association between age group and overall mortality among patients with colorectal cancer (Institution Analysis) Personyears
Incidence rate a (95% CI)
Crude HR (95% CI)
Adjusted HR (95% CI) b
22 22
6 8
50 44
12.0 (4.4-26.1) 18.2 (7.8-35.8)
1.00 (Reference) 1.19 (0.41-3.49)
1.00 (Reference) 1.23 (0.37-4.06)
46 40
10 12
140 108
7.1 (3.4-13.1) 11.1 (5.7-19.4)
1.00 (Reference) 1.82 (0.77-4.30)
1.00 (Reference) 2.02 (0.83-4.91)
20 44
6 30
46 113
13.0 (4.8-28.4) 26.5 (17.9-37.9)
1.00 (Reference) 2.18 (0.90-5.31)
1.00 (Reference) 4.71 (1.56-14.20)
76 78
18 26
124 104
14.5 (8.6-22.9) 25.0 (16.3-36.6)
1.00 (Reference) 1.68 (0.92-3.08)
1.00 (Reference) 1.47 (0.80-2.71)
29 26
7 6
49 47
14.3 (5.7-29.4) 12.8 (4.7-27.8)
1.00 (Reference) 0.73 (0.24-2.28)
1.00 (Reference) 0.37 (0.07-1.91)
388 61
10.1 (7.1-13.7) 6.6 (1.8-16.8)
1.00 (Reference) 0.63 (0.23-1.77)
1.00 (Reference) 0.99 (0.33 -3.03)
81 14
39 4
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Events
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Bulgaria LO YO Canada LO YO Czech Republic LO YO Georgia LO YO Ireland LO YO Italy LO YO
Number of patients
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Age group
Abbreviations: YO: young onset; LO: late onset; HR: hazard ratio; CI: confidence interval a Per 100 person-years b adjusted for sex, year of diagnosis, and surgery. Bulgaria additionally adjusted for N of TNM; Czech Republic and Georgia additionally adjusted for N of TNM and metastasis at diagnosis; Ireland and Italy additionally adjusted for metastasis at diagnosis
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Table 7. Hazard ratios for the association between age group and overall mortality among patients with colorectal cancer (Pooled Analysis) Events
Personyears
Incidence rate a (95% CI)
274 224
86 86
795 478
10.8 (8.7-13.4) 18.0 (14.4-22.2)
Adjusted HR (95% CI) b
1.00 (Reference) 1.40 (0.97-2.02)
1.00 (Reference) 1.53 (0.91-2.58)
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37.1%
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Abbreviations: YO: young onset; LO: late onset; HR: hazard ratio; CI: confidence interval a Per 100 person-years b Meta-analysis results
Crude HR (95% CI) b
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LO YO
Number of patients
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Figure 1. Forest plot demonstrating HR at all sites, and comparing PFS 1 of YO to LO.
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Figure 2. Forest plot demonstrating HR at all sites, and comparing PFS 2 of YO to LO.
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Figure 3. Forest plot demonstrating HR at all sites, and comparing mortality of YO to LO.
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S1533-0028(17)30125-1
DOI:
10.1016/j.clcc.2017.03.008
Reference:
CLCC 365
To appear in:
Clinical Colorectal Cancer
Received Date: 31 July 2016 Revised Date:
26 January 2017
Accepted Date: 9 March 2017
Please cite this article as: Rho YS, Gilabert M, Polom K, Aladashvili A, Kopeckova K, Megdanova V, Coleman N, Greally M, Marrelli D, Roviello F, McDermott R, Petrova V, Mihaylova Z, Bortlicek Z, Prausova J, Batist G, Azoulay L, Kavan P, Comparing Clinical Characteristics and Outcomes of Young Onset to Late Onset Colorectal Cancer, An International Collaborative Study, Clinical Colorectal Cancer (2017), doi: 10.1016/j.clcc.2017.03.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Comparing Clinical Characteristics and Outcomes of Young Onset to Late Onset Colorectal Cancer, An International Collaborative Study
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Young Soo Rho M.D1, Marine Gilabert M.D, Ph.D2, Karol Polom M.D, Ph.D3, Archil
Aladashvili M.D, Ph.D4, Katerina Kopeckova M.D5, Vera Megdanova M.D7, Niamh Coleman MBBCH MRCP8, Megan Greally MBBCH MRCP8, Daniele Marrelli M.D3, Franco Roviello
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M.D, Ph.D3, Ray McDermott MB BCh BAO, PhD, MBA7, Veneta Petrova M.D7, Zhasmina Mihaylova M.D, Ph.D7, Zbynek Bortlicek6, Jana Prausova M.D, Ph.D5, Gerald Batist M.D1,9,
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Laurent Azoulay Ph.D1,9,10, Petr Kavan M.D, Ph.D1,9
McGill University Faculty of Medicine, Gerald Bronfman Department of Oncology, Montréal,
Canada
Paoli-Calmettes Institute, Department of Medical Oncology, Marseille, France
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University of Siena, General and Oncological Surgery Department, Siena, Italy
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National Cancer Center, GI Cancer Research Unit and Oncology Surgery, Tbilisi, Georgia
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2nd Faculty of Medicine-Charles University Prague and Motol University Hospital, Department
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of Oncology, Prague, Czech Republic Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno
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Military Medical Academy, Department of Medical Oncology, Sofia, Bulgaria
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St Vincent's University Hospital, Medical Oncology, Dublin, Ireland
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Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital – McGill University,
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Montreal, Canada
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10
Department of Epidemiology, Biostatistics, and Occupational Health, McGill University,
Montreal, Canada. Running Title: Young vs Late Onset Colorectal Cancer
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Funding Source: no specific funding
Correspondence:
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Petr Kavan, M.D, Ph.D
Montreal, Quebec, H3T1E2 Room E-715 Phone: 514-340-8222 ext 5525 Fax: 514-340-7575
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E-mail: [email protected]
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3755, Cote-Ste-Catherine
Conflict of Interest: no conflict of interest from all authors
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MicroAbstract
Colorectal cancer in young patients is often diagnosed late, when it is advanced stages. These
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patients have more resistant and aggressive disease, despite similar clinical treatment patterns when compared to those with late onset disease.
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Abstract Background: Compared with the general population, the incidence of young onset (YO) colorectal cancer (CRC) is increasing. However, a significant knowledge gap exists in the
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clinical characteristics, treatment patterns, and outcomes for these patients.
Methods: Six international tertiary cancer centers conducted a retrospective study. Young onset (YO) patients, 18–44 years old, and late onset (LO) patients, >44 years old, who were diagnosed
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with histologically proven colorectal adenocarcinoma from June 2003 to June 2014 were
enrolled. Patients were randomly chosen from each center’s database, and patient demographics
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and treatment information were collected. Data were then centralized and the final analysis was performed at a single institution. Cox proportional hazards models were used to estimate crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) progression-free survival (PFS) and mortality, and YO was compared with LO. Site-specific HRs were pooled using a
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random-effects meta-analysis.
Results: Overall, 498 patients including 224 YO (male, 129; mean age, 37±5.5 years) and 274 LO (male, 167; mean age, 64.8±9.5 years) were included. At the time of diagnosis, 137 (61.2%)
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YO and 122 (44.5%) LO patients had metastatic disease. For both cohorts, the three most common presenting symptoms were pain, hematochezia, and weight loss. Surgery was
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performed in 141 (63.0%) YO and 219 (79.9%) LO patients. Longitudinal noncurative treatment patterns were similar, but more biological therapy was used for these YO patients. Pooled PFS analysis in first-line noncurative treatment favored LO (HR, 1.96; 95% CI: 1.04–3.68). Mortality analysis showed no significant differences between groups (for YO: HR, 1.53; 95% CI: 0.91– 2.58). Conclusions: Despite similar treatment patterns and survival outcomes, YO disease may be
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clinically more aggressive.
Key Words: young onset colorectal cancer, adolescent and young adults, treatment pattern, real
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world, metastatic colorectal cancer
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Introduction Colorectal cancer (CRC) is the third most common type of cancer in the world, with an estimated 1.36 million patients being diagnosed in 2012. Its incidence varies significantly across
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geographical regions, but 14 of the 20 countries with the highest CRC rates are located in Europe and Canada1. However, a steady decrease in the incidence of CRC has been observed in the United States2. A recent, large-scale analysis of the Surveillance, Epidemiology, and End Results
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(SEER) project from 1975 and 2010 showed an overall decrease in the incidence rate of 0.92%. However, the same study demonstrated that individuals younger than 50 years have an increased
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rate of CRC3. This was echoed in research based on the California Cancer Registry, which further demonstrated that individuals with CRC in the young onset (YO) group are being diagnosed more frequently and they present with a more advanced stage of cancer4. CRC is generally thought to be a disease of the elderly, with almost all cases occurring in patients over
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55 years of age5. However, a non-negligible one in 10 cases occurs in patients under the age of 50 years6; at the current rate, this number is expected to double by 20303. This finding causes great concern, because it suggests a reduced ability to cure the disease and poorer survival
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outcomes.
In the past decade, multiple population-based studies have demonstrated a slow increase
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in the incidence of CRC in the YO population3, 7, 8. Although few additional studies have been conducted, CRCs in YO patients have been shown to be unique in terms of etiology9 and biology10. However, a significant knowledge gap exists in understanding the implications of these differences in a real-world setting; with modern advances in CRC treatment, the YO patient population’s clinical outcomes requires exploration. Therefore, a multi-institutional, multinational retrospective review was conducted to assess treatment patterns and outcomes of
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YO patients with CRC and to compare the results with those of their late-onset (LO) patient
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counterparts.
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Materials and Methods Patient Population Six international tertiary cancer centers were involved in the study, as follows: Jewish
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General Hospital, McGill University, Canada (CA); Siena University, Italy (IT); Second Faculty of Medicine, Charles University Prague and Motol University Hospital, Czech Republic (CZ); National Cancer Center, Georgia (GE); St Vincent’s University Hospital, Ireland (IE); and
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Military Medical Academy, Bulgaria (BG). YO patients aged 18–44 years and LO patients over 44 years of age who had been diagnosed with pathological-proven adenocarcinoma of the colon
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or rectum from June 2003–June 2014 were included.
There is currently no single consensus on what constitutes a YO CRC patient. Generally, previous studies have considered YO patients to be those of pre-screening age, with an upper limit of 39–49 years. Therefore, an age of 44 years was chosen as the median age, and this age is
national standard11.
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Study Variables
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before the recommended screening age of 50 years. The upper age limit is recognized as YO by a
Using a standardized template designed and provided by CA, all institutions collected
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available information by reviewing the available physical charts and electronic health records at their respective institutions, using a random selection of patients. The following information was collected when available: patient demographics, presenting symptoms, personal history of cancer (including familial adenomatous polyposis (FAP) and Lynch syndrome), family history of cancer, TNM staging information following the seventh edition of the American Joint Committee on Cancer, surgical treatment, noncurative (NC; metastatic) chemotherapy and biological
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treatment (up to two different lines as previously defined12), progression date after each therapy, and survival information.
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Statistical Analysis
All information was collected and centralized to CA, where descriptive and statistical analysis was performed. Cox proportional hazards models were used to estimate crude and
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adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of progression-free survival 1 (PFS 1; time from first-line treatment to progression or death) and PFS 2 (time from second-line
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treatment to progression or death), and YO with LO patients were compared. The models were adjusted for sex, primary tumor location, metastasis at diagnosis, T (T of TNM), and year of diagnosis. DerSimonian and Laird random-effects models were used with inverse variance
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weighting to pool site-specific estimates13.
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Results Patient Demographics Overall, 498 patients were enrolled including 224 YO (male, 129; mean age, 37±5.5
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years; range, 24–44 years) and 274 LO patients (male, 167; mean age, 64.8±9.5 years; range, 45– 95 years). At time of diagnosis, 137 (61.2%) YO and 122 (44.5%) LO patients had been
diagnosed with metastatic disease. In the YO cohort, the closest familial cancer history was
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reported to be first-degree family in 55 (24.6%) patients and second-degree family in 14 (6.3%) patients. In the LO cohort, 37 (13.5%) patients had a first-degree history of cancer and 8 (2.9%)
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patients had a second-degree family history. A history of familial syndrome hereditary nonpolyposis colorectal cancer (HNPCC) and FAP were see in 8 (3.6%) and 17 (7.6%) YO patients and 5 (1.8%) and 14 (5.1%) LO patients, respectively. For both YO and LO patients, the three most common presenting symptoms were pain, hematochezia, and weight loss in 126
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(56.3%), 100 (44.6%), and 79 (35.3%) YO patients and 141 (51.5%), 116 (42.3%), and 93 (33.9%) LO patients, respectively (Table 1).
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Cancer Profile
The primary location of the cancer in YO was the colon in 103 (46.0%) patients and the
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rectosigmoid in 19 (8.5%) patients; of these 52 (42.6%) patients had left-sided disease, 43 (35.2%) patients had right-sided disease, and in 27 (22.1%) patients, it was unknown. YO rectal cancer was seen in 102 (45.5%) patients. In the LO patients, 157 (57.3%) and 28 (10.2%) had colon and rectosigmoid cancer respectively, with 99 (53.5%) patients having left-sided disease, 77 (41.6%) patients having right-sided disease, and in 9 (4.9%), it was unknown. LO rectal cancer was seen in 86 (31.1%) patients. Although KRAS oncogene molecular testing was
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unknown/not tested in most of the YO and LO populations, of those tested, wild-type (WT) tumors were present more frequently for both the YO (54 [23.9%]) and LO (95 [34.7%]) patients (Table 2). Of the tested tumors, 24 (10.6%) of YO and 54 (19.7%) of LO patients had the KRAS
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mutation. BRAF testing was not performed at all centers and, therefore, this data was not collected.
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Treatment Patterns
Surgery was performed in 141 (63.0%) YO and 219 (79.9%) LO patients. Longitudinal
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treatment patterns of chemotherapy and biological treatment information in the first- and secondline metastatic (NC) setting were available for CA, CZ, IE, and BG (YO n=132, LO n=117). For first-line NC treatment, most YO and LO patients received oxaliplatin-based chemotherapy; specifically, the two most commonly used regimens were CAPOX and FOLFOX. CAPOX was
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used in 24 (18.2%) YO and 24 (20.5%) LO patients, whereas FOLFOX was used in 55 (41.7%) YO and 34 (29.1%) LO patients. Bevacizumab was the most frequently used biological treatment in both cohorts, with 65 (49.2%) and 48 (36.4%) patients receiving it in the YO and LO groups,
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respectively. For second-line treatment, irinotecan-based chemotherapy was most frequently used in both YO and LO. FOLFIRI was administered for 25 (18.9%) YO and 21 (17.9%) LO
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patients. Irinotecan monotherapy was more frequently used compared with the first-line, with 10 (7.6%) YO and 8 (6.8%) LO patients receiving it. Although bevacizumab was used most frequently as a biological treatment in both cohorts, there was more heterogeneity in the secondline biological treatment in YO, where 11 (8.3%) patients received cetuximab and 6 (4.5%) patients received panitumumab. In both lines, a FOLFIRINOX regimen was never used in LO
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but it was used in YO for first-line therapy in 3 (2.3%) patients and second-line therapy in 2 (1.5%) patients (Table 3).
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Survival
PFS data were available for CA, CZ, IE, and BG. Individual analysis of all centers
showed a trend towards shorter PFS 1 in YO, with a statistically significant HR of 14.75 (95%
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CI: 1.36–160.12) in the IE cohort. Overall analysis of PFS 1 demonstrated an HR of 1.96 (95% CI: 1.04–3.68; Table 4, Figure 1). PFS 2 showed more heterogeneous results, with an overall HR
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of 1.26 (95% CI: 0.74–2.16; Table 5, Figure 2). Analysis of overall mortality was performed for all sites. Country-specific analysis of HRs showed no statistical difference between the YO and LO groups except at the CZ site, with an HR of 4.71 (95% CI: 1.56–14.20; Table 6) favoring YO. In a pooled analysis, YO did not demonstrate an increased mortality risk when compared to
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the LO group, with an HR of 1.53 (95% CI: 0.91–2.58; Table 7, Figure 3).
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Discussion YO, the ‘Lost Tribe’ YO represents the group of adolescents and young adult patients who form a distinct
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patient population within oncology. They are unique in terms of types of cancer, biology, and the extraordinary psychosocial challenges intrinsic to this juncture in life, which renders their
management complex. However, they are also known to be the “lost tribe” because they are in
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between pediatric and older adult groups. They are often underrepresented in clinical trials14, and the understanding of their disease and needs remains unresolved. To date, cancer in the YO
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group is the leading cause of disease-related death15.
Patient Characteristics, Risk Factors, and Presenting Symptoms
The two cohorts exhibited a nearly two-fold difference in mean age at diagnosis.
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However, both groups showed male predominance. According to a previous study, a family history of CRC can raise the risk of CRC when diagnosed before 45 years of age (odds ratio [OR] 5.3; 95% CI: 2.3–12.0). The same research showed that there was a 30% increased risk of
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CRC in patients with a family history of cancer (excluding intestinal cancer). One of the most comprehensive literature analyses performed to date on YO (<40 years old) patients with CRC
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was conducted by O’Connell and colleagues9. This review also showed a 22.7% family history of cancer on average (range, 3.2–61%). In our YO patients, a similar result was seen, where 32.7% had a family history of cancer (all forms of cancer) and 24.6% had a cancer history involving a first-degree relative. LO patients had lower overall and first-degree relative histories of cancer; however, this result must be interpreted with caution because a significant proportion of the data (31.8%) was unknown or not reported, and there was possibility of a recall bias. Well-
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known familial syndromes associated with CRC in YO populations include HNPCC (also known as Lynch syndrome) and FAP. Both are inherited in an autosomal-dominant fashion. HNPCC causes different germline mutations in 1 of 4 mismatch repair genes, and depending on the
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mutation type, age-dependent risk factors for developing CRC vary16. The reported rates of CRC in YO patients with HNPCC range from 5–10%17-19. For patients with FAP, virtually all develop CRC before the age of 50 years if left untreated. The overall rate of identifiable hereditary cancer
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syndrome has been reported to be as high as 35% in patients less than 35 years old, but this was based on a single institutional study from a tertiary cancer center and it likely overestimates the
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true rate. In our cohort, which was multi-institutional but included tertiary cancer centers, total familial syndrome was seen in 11.2% of YO and 6.9% of LO patients. However, HNPCC was only found in 3.6% of all patients. Although most of the YO population had undergone testing for familial syndrome, as is often done in clinical practice, 30.3% of LO cases were either
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unknown or not reported. The three most common presenting symptoms were pain, hematochezia, and weight loss. These symptoms were similarly found to be most frequent in previous studies9. It would be clinically pertinent to keep CRC in mind as a differential diagnosis
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for the YO group when these symptoms are present.
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CRC Characteristics
YO patients presented much more frequently with rectosigmoid and rectal cancer than
their LO counterparts, as in previously reports9, 20. For colon cancer, left-sided disease was more common for both the YO and LO groups. Many more YO patients presented with metastatic disease at the time of diagnosis than did LO patients. Molecular testing in metastatic CRC has now become the standard of care in North America and in most of Europe. In our study, 34.5%
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of YO and 54.4% of LO patients had KRAS mutation testing (Table 2). However, this does not show the true rate of clinical molecular testing, because our study included patients from 2003 and KRAS was not introduced until 200923. Significant variations also exist between countries
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and institutions for the frequency and methods of analysis (e.g. KRAS exon 2 vs. 2, 3, 4).
However, in the tested patients, the KRAS mutation rate fell within the expected range24. A recent molecular subtype analysis in CRC patients showed that the “type 5” group (MSI-high,
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BRAF- & KRAS-mutation negative, non-CpG island methylator phenotype) was present in
significant portion of young patients aged <40 and 40–49 years (10% and 20%, respectively).
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This may have particular implications for the rapidly emerging field of immune-based therapies25. Further studies have shown that other molecular biomarkers may be specifically useful for YO, including PRL, RBM3, Wrap53, p53, and DNA status26, and their clinical utility should be explored. Additionally, microsatellite instability status for this study was not
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assessed. However, this analysis may be important for future studies because it is seen up to 15– 20% of cases and it is associated with patient prognosis related to their response to therapy27.
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Treatment and Survival
Treatment details for YO CRC patients have not been well characterized. In this real-life
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study, we observed that more surgery occurred in LO patients. However, this is likely a reflection of the cohort, because more YO patients had metastatic disease. Although our data could not be used to examine the longitudinal approach to surgical treatment, a recent study by Abdelsattar et al. showed that in cases of CRC with distant metastasis, YO patients were more likely to receive surgical therapy for their primary tumors28. Moreover, as reported by Hu et al., age less than 50 years was associated with primary tumor resection. However, they also found
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that more primary tumor resection does not necessarily confer improved survival29. NC chemotherapy treatment rates were similar in both groups, although it should be noted that FOLFIRINOX was only used in YO patients. In both cohorts, there was heterogeneity in first-
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and second-line NC chemotherapy (Table 3). This likely represents a combination of factors including evaluation of treatment regimens over the course of the study period, institutional and national differences, and individualized therapeutic choice that is often decided with the patients
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themselves. Biological treatment was used more often in the YO group. This practice likely reflects YO patients’ general ability to tolerate (or perhaps greater perceived tolerability) more
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treatment. Kneuertz et al. observed similar patterns of YO patients receiving more treatment in all stages, with minimal gain in survival compared with their LO counterparts. In this research, the effect, efficacy, and survival associated with these therapies were examined in a NC setting, which for this disease, represents all but surgical treatment of metastatic disease. PFS in the first-
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line treatment of metastatic disease was longer for LO; one explanation for this difference is that it illustrates the aggressive nature of cancer in YO. Although individual site-specific analysis showed a trend in general PFS that favored LO, in each institutional analysis, IE was the sole
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statistically significantly center favoring LO. IE’s patient characteristics did not significantly differ in this study, and the group’s sample size was small. However, in-depth information was
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acquired, allowing for multiple adjustments in the analysis. This is a novel observation that was not found in the retrospective analysis performed by Vatandoust et al.30, and we believe that it merits further exploration. Overall survival for YO patients compared to LO counterparts has been the subject of debate by many researchers. Studies have supported both worse survival31-33 and better survival34-38 for YO patients. This variability was well represented in our study. Only one institution, CZ, showed that YO patients had a better survival rate. Although the reason for
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this has yet to be clarified, one noteworthy point is the LO group’s small sample size. While the overall analysis showed that neither group had a better outcome, and the generally heterogeneity of the patients, treatments, and institutions makes any other conclusion risky, and the few
Future Directions in Understanding YO patients with CRC
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cancers in the younger group.
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exceptions we found do not adequately answer the question of biological differences in these
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Our study raised multiple important issues. First, a consensus still needs to be established concerning the definition of what truly constitutes a YO patient with CRC. Thus far, most studies have considered those below the screening to be YO, but the lower cut-off age has been challenged39. This definition maybe a crucial step to unify and better understand CRC in young adults. Second, more molecular-based studies must become routine to characterize YO patients
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with CRC. Although our study, with its limited KRAS data, has shown similar rates of oncogene mutation, other routinely used biomarkers such as BRAF/NRAS and MSI should be tested, and novel biomarkers should be sought. There are major implications to these molecular profiles,
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including targeted chemicals and immune-based treatments40. Finally, as we have demonstrated,
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there is heterogeneity in terms of practice patterns across countries. These differences and variabilities should be further explored to optimize patient treatment and care.
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Clinical Practice Points •
Compared to the general population, the incidence of young onset (YO) colorectal cancer (CRC) is increasing. Previous studies have found that this population’s CRC is unique in
•
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etiology and biology when compared to late onset (LO) disease.
Our real-life multi-institutional, multinational study showed that both cohorts have the same three most common presenting symptoms: pain, hematochezia, and weight loss. Longitudinal noncurative treatment patterns for both YO and LO were similar, but more biological therapy was used for YO.
Pooled PFS analysis in first-line noncurative treatment favored LO, possibly suggesting
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•
more aggressive or less responsive disease in YO patients.
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Mortality analysis showed no significant differences between the two groups.
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•
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40. Friedrich T, Leong S, Lieu CH. Beyond RAS and BRAF: a target rich disease that is ripe for
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Table 1. Characteristics of YO versus LO patients with colorectal cancer Characteristic YO LO Total 224 274 Country Bulgaria 22 (9.8) 22 (8.0) Canada 40 (17.9) 46 (16.8) Czech 44 (19.6) 20 (7.3) Georgia 78 (34.8) 76 (27.7) Ireland 26 (11.6) 29 (10.6) Italy 14 (6.3) 81 (29.6) Age at diagnosis, years (mean, SD) 37.0 (5.5) 64.8 (9.5) Males, n (%) 129 (57.6) 167 (60.9) Symptom at presentation* Pain 126 (56.3) 141 (51.5) Hematochezia 100 (44.6) 116 (42.3) Weight loss 79 (35.3) 93 (33.9) Closest cancer family history In first-degree relative 55 (24.6) 37 (13.5) 14 (6.3) 8 (2.9) In first-degree relative Unknown degree 6 (2.7) 8 (2.9) 149 (66.5) 134 (48.9) None Unknown/Not reported 0 (0.0) 87 (31.8) Familial syndrome 8 (3.6) 5 (1.8) HNPCC 17 (7.6) 14 (5.1) FAP 199 (88.8) 172 (62.8) None Unknown/Not reported 16 (7.1) 83 (30.3) *Not mutually exclusive
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Abbreviations: YO: young onset; LO: late onset; SD: standard deviation; HNPCC: hereditary nonpolyposis colorectal cancer; FAP: familial adenomatous polyposis
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YO 224 103 (46.0) 102 (45.5) 19 (8.5) 0 (0.0) 122
Left Right Unknown KRAS Wild-type Mutation UKN/not tested Metastasis at diagnosis Yes No Unknown T (T of TNM) T1 T2 T3 T4 TX N (N of TNM) 0 1 2 NX
52 (42.6) 43 (35.2) 27 (22.1)
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Rectosigmoid Unknown Colon
LO 274 157 (57.3) 86 (31.3)
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Table 2. Cancer Profile Characteristic Total Colon Rectal
28 (10.2) 3 (1.1) 185
99 (53.5) 77 (41.6) 9 (4.9)
54 (24.1) 24 (10.7) 146 (65.2)
95 (34.7) 54 (19.7) 125 (45.6)
137 (61.2) 78 (34.8) 9 (4.0)
122 (44.5) 123 (44.9) 29 (10.6)
12 (5.4) 25 (11.2) 83 (37.1) 56 (25.0) 48 (21.1)
1 (0.4) 39 (14.2) 149 (54.4) 60 (21.9) 25 (9.1)
58 (25.9) 59 (26.3) 49 (21.9) 58 (25.9)
86 (31.4) 95 (34.7) 59 (21.5) 34 (12.5)
Abbreviations: YO: young onset; LO: late onset; NC: noncurative; UKN: unknown
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Table 3. Treatment Characteristics
141 (63.0) 76 (33.9) 7 (3.1)
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24 (18.2) 55 (41.7) 1 (0.8) 8 (6.1) 3 (2.3) 5 (3.8) 0 (0.0) 1 (0.8) 0 (0) 2 (1.5) 1 (0.8)
LO
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YO
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Characteristic Surgery Yes No Unknown First-line NC Chemotherapy* CAPOX FOLFOX CAPIRI FOLFIRI FOLFIRINOX FLOX IROX 5FU-Irinotecan Capecitabine 5FU-Leucovorin Irinotecan None Unknown Trial Second-line NC Chemotherapy* CAPOX FOLFOX CAPIRI FOLFIRI FOLFIRINOX FLOX IROX 5FU-Irinotecan Capecitabine 5FU-Leucovorin Irinotecan None Unknown Trial First-line NC Biological* Bevacizumab Cetuximab Panitumumab Regorafenib
219 (79.9) 51 (18.6) 4 (1.5) 24 (20.5) 34 (29.1) 2 (1.7) 11 (9.4) 0 (0.0) 1 (0.9) 2 (1.7) 0 (0.0) 4 (3.4) 1 (0.9) 1 (0.9)
27 (20.5) 5 (3.8) 0 (0)
37 (31.6) 0 (0.0) 0 (0.0)
3 (2.3) 4 (3.0) 4 (3.0) 25 (18.9) 2 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.8) 1 (0.8) 10 (7.6) 76 (57.6) 3 (2.3) 2 (1.5)
2 (1.7) 8 (6.8) 8 (6.8) 21 (17.9) 0 (0.0) 0 (0.0) 1 (0.9) 2 (1.7) 1 (0.9) 0 (0.0) 8 (6.8) 61 (52.1) 0 (0.0) 5 (4.3)
65 (49.2) 7 (5.3) 3 (2.3) 0 (0.0)
48 (36.4) 5 (3.8) 1 (0.8) 0 (0.0)
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3 (2.3) 60 (45.5) 0 (0.0) 5 (3.8) 17 (12.9) 4 (3.0) 3 (2.3) 0 (0.0) 88 (66.7) 0 (0.0)
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Aflibercept 0 (0.0) None 51 (38.6) Unknown 6 (4.5) Second-line NC Biological* Aflibercept 1 (0.8) Bevacizumab 17 (12.9) 11 (8.3) Cetuximab Panitumumab 6 (4.5) Regorafenib 1 (0.8) 94 (71.2) None 2 (1.5) Unknown *Data collected and reported for CA, CZ, IE, BG only; YO n=132, LO n=117
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Abbreviations: YO: young onset; LO: late onset; NC: noncurative; CAPOX: Capecitabine + Oxaliplatin; FOLFOX: LV5FU2 (48h) + Oxaliplatin; CAPIRI: Capecitabine + Irinotecan; FOLFIRI: LV5FU2 + Irinotecan; FOLFIRINOX: LV5FU2 + Irinotecan+ Oxaliplatin; FLOX: LV5FU2 (bolus) + Oxaliplatine; IROX: Irinotecan + Oxaliplatin
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Table 4. Hazard ratios for the association between age group and disease progression for first-line chemotherapy among patients with colorectal cancer Number of patients
Events
Personyears
Incidence ratea (95% CI)
Bulgaria LO YO
19 15
15 12
19 9
79.3 (44.4-130.8) 130.4 (67.4-227.9)
Canada LO YO
30 30
20 24
39 29
Czech Republic LO YO
12 40
9 30
13 38
Ireland LO YO
8 8
7 7
Adjusted HR (95% CI)b
1.00 (Reference) 2.20 (0.95-5.08)
1.00 (Reference) 2.30 (0.94-5.61)
50.8 (31.0-78.4) 83.2 (53.3-123.8)
1.00 (Reference) 1.52 (0.84-2.76)
1.00 (Reference) 1.18 (0.62-2.25)
70.3 (32.2-133.5) 78.7 (53.1-112.3)
1.00 (Reference) 1.29 (0.61-2.74)
1.00 (Reference) 2.12 (0.85-5.30)
119.1 (47.9-245.4) 318.4 (128.0-656.0)
1.00 (Reference) 7.80 (1.52-39.94)
1.00 (Reference) 14.75 (1.36-160.12)
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Crude HR (95% CI)
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Abbreviations: YO: young onset; LO: late onset; HR: hazard ratio; CI: confidence interval a Per 100 person-years. b adjusted for sex and year of diagnosis. Bulgaria additionally adjusted for N of TNM; Czech Republic additionally adjusted for N of TNM and metastasis at diagnosis; Ireland additionally adjusted for metastasis at diagnosis.
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Table 5. Hazard ratios for the association between age group and disease progression of second-line chemotherapy among patients with colorectal cancer Events
Personyears
Incidence ratea (95% CI)
Crude HR (95% CI)
Adjusted HR (95% CI)b
Bulgaria LO YO
15 12
11 11
8 7
159.4 (796-285.2) 143.6 (71.7-257.0)
1.00 (Reference) 0.80 (0.33-1.97)
1.00 (Reference) 0.95 (0.37-2.48)
Canada LO YO
28 12
17 12
34 11
50.4 (29.4-80.7) 107.5 (55.5-187.7)
1.00 (Reference) 2.10 (0.98-4.52)
1.00 (Reference) 1.89 (0.84-4.28)
Czech Republic LO YO
7 26
6 19
5 14
129.8 (47.6-282.6) 136.9 (82.4-213.8)
1.00 (Reference) 1.13 (0.45-2.85)
1.00 (Reference) 1.13 (0.41-3.11)
Ireland LO YO
6 4
5 3
1.00 (Reference) 0.72 (0.17-3.11)
1.00 (Reference) 0.09 (0.00-4.30)
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Number of patients
Age group
2 1
241.2 (78.3-563.0) 201.1 (41.5-587.6)
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Abbreviations: YO: young onset; LO: late onset; HR: hazard ratio; CI: confidence interval a Per 100 person-years b adjusted for sex and year of diagnosis. Bulgaria additionally adjusted for N of TNM; Czech Republic additionally adjusted for N of TNM and metastasis at diagnosis; Ireland additionally adjusted for metastasis at diagnosis.
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Table 6. Hazard ratios for the association between age group and overall mortality among patients with colorectal cancer (Institution Analysis) Personyears
Incidence rate a (95% CI)
Crude HR (95% CI)
Adjusted HR (95% CI) b
22 22
6 8
50 44
12.0 (4.4-26.1) 18.2 (7.8-35.8)
1.00 (Reference) 1.19 (0.41-3.49)
1.00 (Reference) 1.23 (0.37-4.06)
46 40
10 12
140 108
7.1 (3.4-13.1) 11.1 (5.7-19.4)
1.00 (Reference) 1.82 (0.77-4.30)
1.00 (Reference) 2.02 (0.83-4.91)
20 44
6 30
46 113
13.0 (4.8-28.4) 26.5 (17.9-37.9)
1.00 (Reference) 2.18 (0.90-5.31)
1.00 (Reference) 4.71 (1.56-14.20)
76 78
18 26
124 104
14.5 (8.6-22.9) 25.0 (16.3-36.6)
1.00 (Reference) 1.68 (0.92-3.08)
1.00 (Reference) 1.47 (0.80-2.71)
29 26
7 6
49 47
14.3 (5.7-29.4) 12.8 (4.7-27.8)
1.00 (Reference) 0.73 (0.24-2.28)
1.00 (Reference) 0.37 (0.07-1.91)
388 61
10.1 (7.1-13.7) 6.6 (1.8-16.8)
1.00 (Reference) 0.63 (0.23-1.77)
1.00 (Reference) 0.99 (0.33 -3.03)
81 14
39 4
TE D
M AN U
SC
RI PT
Events
EP
Bulgaria LO YO Canada LO YO Czech Republic LO YO Georgia LO YO Ireland LO YO Italy LO YO
Number of patients
AC C
Age group
Abbreviations: YO: young onset; LO: late onset; HR: hazard ratio; CI: confidence interval a Per 100 person-years b adjusted for sex, year of diagnosis, and surgery. Bulgaria additionally adjusted for N of TNM; Czech Republic and Georgia additionally adjusted for N of TNM and metastasis at diagnosis; Ireland and Italy additionally adjusted for metastasis at diagnosis
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Table 7. Hazard ratios for the association between age group and overall mortality among patients with colorectal cancer (Pooled Analysis) Events
Personyears
Incidence rate a (95% CI)
274 224
86 86
795 478
10.8 (8.7-13.4) 18.0 (14.4-22.2)
Adjusted HR (95% CI) b
1.00 (Reference) 1.40 (0.97-2.02)
1.00 (Reference) 1.53 (0.91-2.58)
I²
37.1%
AC C
EP
TE D
M AN U
Abbreviations: YO: young onset; LO: late onset; HR: hazard ratio; CI: confidence interval a Per 100 person-years b Meta-analysis results
Crude HR (95% CI) b
RI PT
LO YO
Number of patients
SC
Age group
30
SC
RI PT
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EP
TE D
M AN U
Figure 1. Forest plot demonstrating HR at all sites, and comparing PFS 1 of YO to LO.
AC C
Figure 2. Forest plot demonstrating HR at all sites, and comparing PFS 2 of YO to LO.
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SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
Figure 3. Forest plot demonstrating HR at all sites, and comparing mortality of YO to LO.
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