With 2021 estimating 149,500 new cases and 52,980 deaths in the United States, colorectal
cancer (CRC) continues to be the third leading cause of cancer and the second leading
cause of cancer death for both genders (1). CRC traditionally is a malignancy seen
in older age [median age of diagnosis =66 years old] (2). However, the past decade
shows a shift toward a younger population as the median age in the early 2000s was
72 years old. Although most patients will be older age, the previous decades show
a decline in CRC (~30%) in the traditional population (≥65 years old) while incidence
rates have risen in those <50 years old. Surveillance and epidemiology reports show
a clear rise and continued expected rise in early-onset adult CRC (EOCRC), defined
as those patients diagnosed at 18–49 years old (3,4). Bailey et al. evaluated CRC
incidences during 1975–2010 which revealed a rise in estimated new CRC cases in patients
<50 years old (3). The authors reported that by 2030, it is estimated the incidence
rates for colon and rectal cancer are expected to increase by 90% and 124.2%, respectively
for patients 20–34 years old; and 27.7% and 46%, respectively for patients 35–49 years
old. Siegel et al. examined incidence patterns from 1974–2013 and concluded that individuals
born circa 1990 compared to those born circa 1950 have double the risk of colon cancer
and quadruple the risk of rectal cancer (4). Siegel et al. recently showed that since
1994, both genders have seen incidence rates increase >50% (5). Continued exploration
of birth cohort patterns can help continue to shed light on etiology and provide hypotheses
regarding occurrence.
Unlike many cancers of the gastrointestinal tract, CRC can be a preventable malignancy
and has robust screening guidelines and modalities in the United States for those
of older age (6–8). However, adherence to screening guidelines by the public continues
to limit success of these strategies. Given the recent incidence increases in EOCRC,
The American Cancer Society in 2018 lowered the traditional starting age of screening
for average risk patients [those without familial risk, family history, and certain
chronic illness such as inflammatory bowel disease (IBD)] from 50 to 45 years old
(6). Other national guidelines have recently followed suit in lowering the starting
age to 45 years old (7,8) which now mitigates provider hesitancy in ordering screening
for this age group due to reimbursement concerns. Time to adapt to these new guidelines
will be needed to determine an impact and if clinicians and the public will be adherent
in obtaining screening. Nationwide adoption of these new recommended guidelines would
hope to impact the percentage of patients in this age group that present with advanced
disease. Those 45–49 years of age represent 44% of the EOCRC population (9); therefore,
adapting to these new recommendations ideally would help to prevent or diagnose in
early stage in many EOCRC patients.
CRC is well known to derive from non-cancerous polyps formed 5–10 years prior to CRC
adenocarcinoma is formed (10). Therefore, a significant impact in prevention maybe
made with the reduction of 5 years in initiating screening as the development of these
pre-cancerous polyps have started to form well before age 45. Unfortunately, those
<45 years of age must rely on monitoring of symptoms in order to prevent or diagnosis
this malignancy at an early time point. At least patients may have more clear symptoms
in this population (rectal bleeding; changes in bowel habits) as EOCRC patients tend
to be diagnosed with left-sided tumors (44% rectal primary and 25% distal CRC) (9)
which tend to have less vague symptoms than those with right-sided tumors (fatigue;
abdominal pain; weight loss). The American Gastroenterological Association supports
endoscopy for any symptomatic patients; therefore, primary care physicians should
consider a low threshold for workup for rectal bleeding in those <45 years old (11).
Given that screening guidelines have only recently changed and lack traditional screening
methods in those <45 years of age, EOCRC is often diagnosed in advanced disease (~70%
of cases will have stage III or IV disease) (12,13). The advanced diagnosis is in
part likely related to being diagnosed long after symptoms have occurred. The CRC
Alliance reported survey results (n=1,195) of young adult living patients or survivors.
The results revealed relevant findings and concerns, most notably that 63% of responders
indicated waiting 3–12 months before visiting their doctor with 41% waiting at least
six months after they initial had experienced symptoms. Reasons for this lag time
could be related to lack of knowledge of worrisome symptoms, denial of symptoms, embarrassment,
lack of healthcare access, family and work obligations, and poor family/social support.
In addition to patient lag time to seek medical help, most patients reported being
misdiagnosed given low index of physician suspension in this age group. Most common
patients’ symptoms were wrongfully attributed to hemorrhoids or IBD. Sixty-seven percent
reported seeing at least two physicians before they were diagnosed (some seeing up
to four physicians). Data indicate a total average time to diagnosis in these patients
as ~7–10 months’ time (217–271 days) from symptom onset to medical contact. Compared
to those with average onset, Scott et al. reported a median time of rectal cancer
symptom onset to diagnosis of 217 days in those <50 years old compared to 29.5 days
in those >50 years old (14). Therefore, education is a clear first step to alert the
public and front-line primary care community of the changing incidence of this malignancy,
the new screening guidelines supported by USPSTF, a lower threshold for initiating
workup of GI symptoms, and removing barriers to obtaining a clear and early diagnosis.
The etiology for EOCRC is likely multifactorial and many hypotheses have been proposed.
Most cases (70–80%) occur sporadically and are not related to a familial risk (15).
Therefore, other outlooks of why these patients are developing this malignancy are
needed. Globally, EOCRC rise is unique in high income areas such as the United States,
Australia, Canada, Germany, and the United Kingdom (16). Traditional risk factors
include obesity, lack of physical activity, non-Mediterranean Western diet, and diet
high in red and processed meats and low in fiber (17). Some of these traditional factors
are likely contributing to the EOCRC rise as the rise in obesity seen in the United
State is clear. The National Center for Health Statistics for adults ≥20 years old
show >80% are overweight, obese, or severely obese. From 1999–2000 through 2017–2018,
the US obesity rate increased from 30.5% to 42.4% and severely obese cases increased
from 4.7% to 9.2% (18). Additionally, human environmental external (antibiotics) and
internal exposures (gut microbiota) affecting the microbiome are under investigation
(19). Life exposures to certain elements (Westernized diets, poor diet, red/processed
meats, obesity, stress, antibiotics, synthetic dyes, monosodium glutamate, titanium
dioxide, high-fructose corn syrup, smoking, alcohol, unhealthy cooking practices)
could be contributing to EOCRC as well as the impact of early life exposures are being
evaluated (mode of nutritional provision in infancy, mode of birth delivery, early
age antibiotic use, maternal stress/nutrition/infection) for cause (17).
Current guidelines do not distinguish CRC treatment based on age (20). In 2014, Lieu
et al. reported on outcomes based on certain factors (performance status, age, and
metastatic site) in Aide et Recherche en Cancérologie Digestive (ARCAD) database (n=20,023;
24 first-line trials) demonstrated early-age onset mCRC was a poor prognostic factor
in treatment naïve patients (21). The authors reported that compared to middle age
patients, younger patients had an increased risk of death (19%) and progression (22%)
with first-line treatment. You et al. reported on characteristics between EOCRC to
late-onset CRC using the National Cancer Database (22). In this analysis, EOCRC patients
had more advanced stage disease at diagnosis and more frequently exhibited poor clinicopathological
features like mucinous or signet ring histology and more poorly differentiated tumors.
Additionally, Jácome et al. showed a greater negative impact of certain biomarkers
for EOCRC in patients with CRC liver metastectomy (23) Analyses such as these and
the fact that traditional standard of care therapy was studied in an older population,
practitioners often took the approach of providing more aggressive treatment strategies
(front-line triplet chemotherapy; more metastatic surgical approaches; overtreatment
via adjuvant therapy). Kneuertz et al. conducted a nationwide study of US hospitals
accredited by the American College of Surgeons Commission on Cancer to compare EOCRC
(age 18–49) and later-onset (age 65–75) who underwent surgical resection and adjuvant
therapy. The authors found that younger patients were more likely to receive systemic
chemotherapy at all stages compared to later onset CRC patients with even 6% of stage
I patients receiving adjuvant chemotherapy which is not standard of care for stage
I. They concluded that young adults received significantly more adjuvant therapy with
only minimal gain compared to older patients (24). Unfortunately, these more intensive
treatment strategies have not led to clear benefits.
With whole genome sequencing, classifying malignancies molecularly has gained traction
with the hope to provide more insight into personalized medicine approaches. CRC has
been classified into consensus molecular subtypes (CMS) molecularly into four types
(CMS1) microsatellite-instability (MSI) immune characterized by hypermutated, MSI-high,
diffuse immune infiltrate, BRAF mutated, CpG island methylator phenotype positive
(CIMP), and somatic copy number alterations (SCNA)-low (CMS2) canonical characterized
by MSI-stable, chromosomal instability, CIMP negative, SCNA-high, WNT and MYC activation
(CMS3) metabolic characterized by MSI-stable, CIMP-positive, SCNA-intermediate, mutations
in KRAS, PIK3CA, PTEN, APC (CMS4) mesenchymal characterized by MSI-stable, CIMP-negative,
SCNA-high, TGF-beta activation, stromal infiltration, angiogenesis (25). All with
distinctions of incidence, molecular characteristics, and survival. A study performed
at our center by Willauer et al. attempted to differentiate clinical and molecular
features of EOCRC (26). The results showed that early-onset patients were more likely
to have synchronous metastatic disease, MSI disease, distal colon or rectal tumors,
and less likely to have BRAF V600 mutations compared to patients aged ≥50. Patients
<40 were predominantly CMS1 or CMS2 while CMS3 and CMS4 were uncommon in their evaluation.
Very young patients (<30) were less likely to have mutations in APC and more likely
to have signet ring histology. EOCRC also appeared to affect a greater number of Hispanic
patients <40. Only a very small number of early-onset patients with metastatic disease
(28/634 or 4%) had a recognized hereditary syndrome or IBD in the MDACC molecular
cohort. Cercek et al. conducted a review at Memorial Sloan Kettering Cancer Center.
Clinical, histopathologic, and genomic characteristics were compared between EOCRC
[two groups: (I) 35 years old; (II) 36–49 years old] and average-onset CRC (≥50 years
old) (27). The authors excluded those with hereditary syndromes and IBD from all but
the germline analysis. EOCRC had more left-sided tumors, rectal bleeding, and abdominal
pain as presenting characteristics. When evaluating the MSS group, no differences
were seen histopathologically. Treatment response and survival were similar amongst
age cohorts in those with MSS advanced CRC. Jin et al. reported in a similar fashion
on clinical and molecular characteristics on early-onset stage III colon cancer patients
(28). Patients were pulled for review from the Adjuvant Colon Cancer Endpoint database.
Sex, race, performance status, risk group, tumor sidedness, and T stage were similar
to those ≥50 years old. EOCRC patients were more frequently MSI/deficient mismatch
repair and less likely to have BRAFV600E. The authors concluded that tumor biology
was a more important prognostic factor than age of onset. More analysis on those with
sporadic microsatellite stable (MSS) EOCRC patients is needed to determine if molecular
differences between EOCRC vs. late-onset CRC tumors exist. Continued efforts are needed
to identify personalized therapeutic approaches in these patients.
EOCRC patients not only have to process the life altering news of a cancer diagnosis,
treatment, and stage but they also need to overcome a variety of unique challenges
faced in this age group. Providers must be aware of these challenges including issues
with body image, sexual dysfunction, fertility preservation, financial barriers, lack
of insurance, treatment adherence, educational/work pursuits, psychological/social
support, anxiety, depression, child-rearing while undergoing therapy, and in some
cases palliative and end-of-life care (29). For example, CRC treatment can cause deleterious
effects to both men and women reproductive potential (30). Abdominal and/or pelvic
radiation can damage the ovaries and testes which is unavoidable with rectal cancers
with current treatment schema in early-stage disease. Chemotherapy can lead to premature
ovarian failure and high infertility risk. Holowatyj et al. recently reported on the
unmet needs specifically in CRC and proposed path forward regarding prioritizing sexual
health (30). Additionally, there is a rise in CRC diagnosed during pregnancy in EOCRC
due to the rise in EOCRC and current trends in delayed childbearing as we have reported
the challenges present in these cases through our center’s experience (31).
Given these unique challenges, we recommend a multidisciplinary care model for EOCRC
patient management involving many key disciplines and are in the process of activating
such a dedicated center at our institution. Discipline and rationale outlined in Table
1. Mendelsohn et al. reported on their 2-year experience at Memorial Sloan Kettering
Cancer Center of a dedicated program for young onset CRC (32). The goals of the program
were to provide coordinated and systematic clinical care to comprehensively address
the unique needs of these patients and to establish a research infrastructure to study
the etiology. The authors identified some important points of this population that
virtual setting interaction would be more well received than phone calls and extensive
counseling. They found that nutrition, sexual health, and psychology/psychiatry referrals
were found to be most useful. Timing of these services were identified as a challenge.
In summary, EOCRC is a unique patient population and unfortunately represents commonplace
in oncology clinics worldwide. Providers must be aware of the unique challenges that
young patients with cancer are burdened with. We believe vital steps for transformative
management of these patients is to initiate a culture of dedicated centers that target
these specific needs along with continued research pathways to investigate etiology,
molecular and clinical distinctions, translational science, and trust such efforts
represent the best path forward for designing novel clinical trials dedicated to EOCRC.