Colorectal cancer (CRC) constitutes approximately 3% of all newly diagnosed cancers
in India. The incidence of CRC is increasing in our country as opposed to the global
trend of decreasing rates.[1]
[2]
Approximately a quarter to a third of these are identified in people in the prime
of their most productive age (<40 years, also called young onset CRC [YO-CRC]) and
at an advanced stage (III or IV).[3]
[4]
The global standardized incidence of YO-CRC increased from 3.05/100,000 population
in 1990 to 3.85/100,000 population by 2019. The increase was higher in countries that
had a higher socioeconomic level of living. There was especially a significance increase
in the incidence of YO-CRC in Vietnam, Caribbean, and Saudia Arabia.[5]
The U.S. SEER database showed that between 2010 and 2015 YO-CRC accounted for 5,350
patients. This group had a higher incidence of mucinous/signet ring histology and
was predominantly composed of non-Caucasian individuals. About a quarter of them (28.6%)
were right-sided tumors.[6]
[7]
[8]
It is projected that by 2030 CRC will be the leading cause of death in the United
States for people in the age group of 20 to 49 years.[9]
In India, their percentage remains unchanged from 2014 to 2021.[4] YO-CRC is characterized by being predominantly left sided (rectal) and with a signet
ring histology.
YO-CRC has a greater percentage of high-risk features, a higher chance of recurrence,
and a higher cancer-specific mortality.[10] Why this happens in the younger CRC patients is still to be understood.
A 10-year study included 4,758 consecutive patients, with 771 (16%) patients below
the age of 50 years. Male YO-CRC patients had higher rectal cancer, were poorly differentiated,
and were diagnosed at an advanced stage. Among female YO-CRC patients, left-sided
tumors were more prevalent. Both relapse-free survival (RFS) and overall survival
(OS) were worse in the YO-CRC group.[11]
In a 1-year Chinese study involving 991 YO-CRC patients and 3,581 older patients,
the patients in the former group were found to be more educated, more aware, and willing
for gene testing. They also had more extensive metastatic disease at presentation.[12]
Integrated multi-omics (combined datasets from genomics, epigenomics, proteomics,
transcriptomics, and metabolomics) is likely to help unravel various complex biological
mechanisms responsible for driving aggressiveness in YO-CRC.[13]
About 5% of all CRCs develop in the background of well-defined inherited syndromes.
Another 30% show increased familial risk, probably also related to inheritance.[14] Common syndromes leading to higher risk include Lynch's syndrome (also known as
hereditary nonpolyposis colorectal cancer [HNPCC]) and familial adenomatous polyposis
(FAP). There is some evidence that pathogenic germline variants are seen in approximately
20% of cases with YO-CRC.[15]
[16] The Ohio (N = 450) and Michigan (N = 403) studies showed germline mutations associated with Lynch's syndrome (8.4 and
13.9%, respectively), FAP (1.1 and 2.5%, respectively), and MUTYH-associated polyposis
(MAP; 0.9 and 0.5% respectively).
A study conducted between 2014 and 2021 included 100 YO-CRC cases. Only 31% underwent
genetic testing, especially among those who were to receive chemotherapy or those
with family history of cancer. Among them, the rate of pathologic germline genetic
variants was higher as compared with the older CRC patients.[17]
Several genetic and clinical differences as compared with LO-CRC have been documented.
YO-CRC presents at a more advanced stage and progresses more rapidly, suggesting that
a young tissue environment is often more promotional.[18]
A prospective study performed molecular profiling of patients with CRC. They divided
the patients into pediatric CRC (N = 8), YO-CRC (teenagers and young adults; N = 30), and late onset CRC (LO-CRC; N = 56). They found that pediatric patients showed mutations of RNF43 and amplification
of CDK6. The molecular alterations in RAS, VEGF, mTOR, and AMPK pathways were found
in the nonpediatric group and did not differ between YO-CRC and LO-CRC. They proposed
that the pediatric CRC group has the potential to benefit from PI3K AKT and CDK6 inhibitors.[19]
Environmental risk factors and lifestyle choices considered important are obesity,
type 2 diabetes mellitus (DM), decreased physical activity, and high intake of junk
food.
Between 1998 and 2018, a total of 1,087 YO-CRC and 2,554 older-onset CRC patients
were studied. YO-CRC patients had lower intake of vegetables and higher consumption
of processed meat and spicy food.[20]
Increase incidence of YO-CRC is following the global increasing trend of type 2 DM
(which increased from 30 million cases in 1964 to 171 million cases by 2004). In fact,
a Swedish study quantifies that those younger than 50 years and diagnosed with type
2 DM have a 3.5-fold higher risk of YO-CRC.[21]
Change in colonic microbiota has also been linked with use of antibiotics. In the
Nurses' Health Study (16,642 individuals who underwent screening colonoscopy after
the age of 60 years and had extensive medical records going back decades),[22] 1,195 had colonic adenomas (considered premalignant lesions). Exposure to antibiotics
at least 10 years earlier was significantly associated with the presence of this premalignant
lesion, with a strong dose–response correlation. The six-study meta-analysis supports
this association, it being stronger for colon (as compared with rectal) cancer and
use of penicillin or cephalosporin.[23]
[24]
[25]
[26]
Fusobacterium nucleatum, Bacteroides fragilis, and Escherichia coli are the most common gut bacteria that are related to LO-CRC,[27] and below we discuss their involvement in YO-CRC.[28]
In a study, 170 samples from 66 YO-CRC and 104 LO-CRC patients were compared with
those from 49 non-CRC controls. YO-CRC patients showed more disruption involving the
citrate cycle and arginine biosynthesis pathways.[29]
An interesting microbiome study looked at samples from 276 patients with CRC. This
included 136 samples from YO-CRC patients and 140 from LO-CRC patients. The bioinformatic
analysis included the use of PhyloSeq, MicrobiomeSeq, MetagenomeSeq, and NetComi.
The YO-CRC group had higher left-sided, rectal, and stage IV cancers. They also had
higher microbial α diversity and were enriched for Akkermansia and Bacteroides species. Interestingly patients expressing Akkermansia had smaller tumor sizer and better OS, whereas those expressing Fusobacterium correlated with bigger tumor size and shorter OS.[30]
Another study found no difference in the gut microbiome spectrum between the two groups.[31]
The impact of treatment is more profound among the YO-CRC patients. Surgery-related
factors include permanent bowel dysfunction, low anterior resection syndrome, sphincter
loss, and permanent ostomy.[32] In addition, they can develop urinary dysfunction, perianal/peristomal disorders,
stricture formation, and sexual dysfunction. They, in turn, lead to problems related
to diet, clothing, professional work, travel, sports, and other social activities.
No wonder YO-CRC patients face anxiety, body image issues, and embarrassment about
bowel movements—existing for up to 10 years after diagnosis.[33]
[34] Challenges with financial toxicity and oncofertility cannot be overemphasized. YO-CRC
patients face more out-of-pocket expenses and medical debt for prolonged periods.[35] It often leads to skipping medication or meals, compromising treatment outcomes.
Young patients are frequently underinsured and may suffer significant disruptions
to professional and financial growth. A survey included patients between 2019 and
2021 was conducted among patients diagnosed earlier with CRC. As compared with age-matched
controls, YO-CRC patients had a higher composite financial toxicity score (higher
for females, food insecurity, delays in essential medical care, greater need for mental
health counseling, out-of-pocket cost of filling prescriptions).[36]
In view of the central and state government schemes in India, management of cancer
patients is largely supported by public funding. It is therefore interesting to look
at direct medical spending as a method of evaluating cost to the government health
department. A study from Canada compared this between 1,058 YO-CRC patients and 12,619
LO-CRC patients. Their findings are shown in [Table 1]. Interestingly the YO-CRC group's total cancer-related cost was higher by 39% (C$144,702
vs. C$104,368), mainly due to the more aggressive use of targeted therapy, chemotherapy,
and radiation therapy—factors that have not improved the OS.[37]
Table 1
Direct medical spending (by government) for CRC patients (Canadian data; in Canadian
dollars; 1 Canadian dollar = 61 INR)[37]
|
Parameter
|
YO-CRC
|
LO-CRC
|
|
1
|
Before diagnosis of cancer (1 year)
|
6,711
|
8,056
|
|
2
|
Cancer related
|
|
A
|
Initial (diagnosis + treatment)
|
50,216
|
37,842
|
|
B
|
Continuing after completion of cancer treatment
|
8,361
|
5,014
|
|
C
|
End of life cancer related
|
86,125
|
61,512
|
|
D
|
Total CRC related
|
1,44,702
|
1,04,368
|
|
3
|
Non-cancer-related end of life
|
77,273
|
23,316
|
The psychosocial impact of financial toxicity, in turn, affects quality of life.[34] Options for sperm, embryo, and/or oocyte preservation need to be discussed.[38] So also the likelihood of successful fertility preservation and pregnancy outcome.[39]
In conclusion, the management of YO-CRC needs special attention. A multidisciplinary
proactive approach to anticipate and address the entire spectrum of needs will go
a long way in providing optimal outcome in this group.
International guidelines clearly specify that management of CRC should not differ
between YO-CRC and older CRC patients. A retrospective, population-based, cohort study
included 32,363 patients with CRC diagnosed from 2010 to 2021. This group comprised
130 YO-CRC patients and 668 LO-CRC patients. The YO-CRC patients were more likely
to be offered adjuvant chemotherapy (even in stage II; p = < 0.001) or multi-agent therapy (stages II and III; p = < 0.01) without any associated increase in survival.[40] Unfortunately, this trend of using more aggressive treatment in YO-CRC persists,
without any evidence of a survival benefit.
The application of artificial intelligence and deep learning algorithms can accelerate
the process, perhaps even identify novel markers to guide personalized management
of CRC.[41]
Having said that, we have access to a simple fecal immunohistochemical screening test
that has been demonstrated to be sensitive (97%) and specific (99.8% negative predictive
value).[42] Also, there are data to indicate the screening benefit of using next-generation
multitarget stool DNA test.[43] Is it time for mass screening in India, at least in the high-risk population?
