Seminar

Colorectal cancer
Cathy Eng, Takayuki Yoshino, Erika Ruíz-García, Nermeen Mostafa, Christopher G Cann, Brittany O’Brian, Amala Benny, Rodrigo O Perez,
Chiara Cremolini

Lancet 2024; 404: 294–310 Despite decreased incidence rates in average-age onset patients in high-income economies, colorectal cancer is the
Published Online third most diagnosed cancer in the world, with increasing rates in emerging economies. Furthermore, early onset
June 20, 2024 colorectal cancer (age ≤50 years) is of increasing concern globally. Over the past decade, research advances have
https://doi.org/10.1016/
increased biological knowledge, treatment options, and overall survival rates. The increase in life expectancy is
S0140-6736(24)00360-X
attributed to an increase in effective systemic therapy, improved treatment selection, and expanded locoregional
Division of Hematology and
Oncology, Vanderbilt
surgical options. Ongoing develop­ments are focused on the role of sphincter preservation, precision oncology for
University Medical Center, molecular alterations, use of circulating tumour DNA, analysis of the gut microbiome, as well as the role of
Vanderbilt-Ingram Cancer locoregional strategies for colorectal cancer liver metastases. This overview is to provide a general multidisciplinary
Center, Nashville, TN, USA
perspective of clinical advances in colorectal cancer.
(Prof C Eng MD, B O’Brian BS,
A Benny BS); Department of
Gastroenterology and Introduction Germany, Brazil, the UK, Italy, and France.3 The incidence
Gastrointestinal Oncology, Recent developments in colorectal cancer research have rate in men is 44% greater than in women, with the
Cancer Center Hospital East,
sub­­stantially improved biological knowledge, treatment highest incidence rates being in Europe (eastern Europe
Kashiwa, Japan
(T Yoshino MD PhD); options, and overall survival (OS). Colorectal cancer was 20·2 per 100 000 men), Australia, and New Zealand,
Department of the third most diagnosed cancer worldwide in 2020, with followed by eastern Asia. In contrast, the incidence rates
Gastrointestinal Tumors and 2 million new cases.1 The estimated median age of onset in Africa and south Asia are less than ten per 100 000 men,
Translational Medicine
is 67 years, yet approximately 10% of patients are younger with the lowest male mortality being in southern Asia
Laboratory, Instituto
Nacional de Cancerologia, than 50 years. It is our intent to provide a global multi­ (3·9 per 100 000 men).1
Mexico City, Mexico disci­plinary perspective about developments in colorectal
(Prof E R-García MD MCs); cancer. Early-onset colorectal cancer (EOCRC)
Clinical Oncology, Ain Shams
Early-onset colorectal cancer (EOCRC) refers to adults
University, Cairo, Egypt
(N Mostafa MD); Department Incidence younger than 50 years. Globally, the annual percent
of Hematology/Oncology, Fox Studies in high-income countries have shown decreasing change for EOCRC increased by 7·9% (20–29 years),
Chase Cancer Center, incidence of colorectal cancer in older adults. However, 4·9% (30–39 years), and 1·6% (40–49 years) during
Philadelphia, PA, USA
(C G Cann MD); Hospital
increasing incidence is detected in emerging economies, 2004 to 2016.4 Pivotal analysis of the USA Surveillance,
Alemão Oswaldo Cruz, as well as in young adults (age <50 years) worldwide. Epidemiology, and End Results database (1975–2010)
São Paulo, Brazil In 2018, the International Agency for Research on Cancer estimates an increase of 90% and 124·2% for colon and
(R O Perez MD PhD); reported the highest incidence rates of colon cancer was rectal cancers, respectively, for the cohort aged 20–30 years
Department of Translational
Research and New
found in Europe, North America, Australia, New Zealand, by the year 2030.4 Overall, the concerning rise in EOCRC
Technologies in Medicine and and eastern Asia, with similar distribution for rectal has been validated in several subsequent studies
Surgery, University of Pisa, cancer.2 According to the International Agency for worldwide.5,6 We recommend that all patients with
Pisa, Italy Research on Cancer, by 2040, 3·2 million new cases will EOCRC be offered fertility counselling before initiating
(Prof C Cremolini MD PhD)
result in 1·6 million deaths (an increase of 63% and 73·4%, any type of therapy.7 Sperm, oocyte, and embryo
Correspondence to:
Prof Cathy Eng, Division of
respectively, relative to 2020). Over 80% of the cases are preservation remain commonly accepted standards, but
Hematology and Oncology, predicted to occur in high or very high Human Develop­ other approaches to fertility preservation should be
Vanderbilt University Medical ment Index (HDI) countries.1 discussed with a dedicated specialist.
Center, Vanderbilt-Ingram
Cancer Center, Nashville,
TN 37232, USA
Geographical distribution Metabolic syndrome
[email protected] In 2020, the USA and China reported the highest Metabolic syndrome includes hyperglycaemia,
incidence rates, followed by Japan, Russia, India, dyslipidaemia, abdominal obesity, and hypertension.
Epidemiological studies have investigated the association
between metabolic syndrome and colorectal cancer risk
Search strategy and selection criteria and mortality, with inconsistent results. A meta-analysis
We searched literature using PubMed and https://www.nccn.org determined that metabolic syndrome is associated with
from Jan 1, 1976 to Dec 31, 2022. Additional records were a 25% increase in incidence for both sexes and
identified through review of the reference sections of included 15% increase in cancer mortality in males.8 A nested
studies and reviewed in full text if they met title and abstract case-control study found that metabolic syndrome was
review criteria. Our search terms consisted of “colon cancer”, associated with EOCRC (odds ratio 1·25, 95% CI
“treatment”, “incidence”, “ctDNA”, “metastatic colorectal cancer”, 1·09–1·43); the presence of one, two, or three or more
“molecular subtypes”, “screening”, “colorectal cancer”, “early- metabolic conditions was associated with
onset colorectal cancer”, “young onset”, and “rectal cancer’’. 9%, 12%, and 31% higher risk of development,
respectively (ptrend<0·001).9,10

294 www.thelancet.com Vol 404 July 20, 2024

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Test preference Screen age Recommendations Note

US Preventive Services Task Force No preference ≥45 years, unless clinically Tiered approach with colonoscopy or FIT NA
and American Cancer Society indicated testing
Canadian Task Force on Preventive gFOBT, FIT, or a flexible 50–74 years, unless at high Either gFOBT or FIT every 2 years or a Does not recommend a colonoscopy
Health Care sigmoidoscopy risk for colorectal cancer flexible sigmoidoscopy every 10 years
EU gFOBT, FIT, or colonoscopy 50–74 years Most prefer FIT or FOBT as primary Some variation between countries on screening
screening every 1–2 years but some ages (eg, Sweden at 60–69 years vs France at
countries use a colonoscopy as a primary 55–74 years)
screening tool every 5–10 years
Asia Pacific Colorectal Cancer FIT or colonoscopy 50–75 years for average risk FIT every 2 years or a colonoscopy every NA
Working Group 10 years; recommends screening in
regions with high incidence (>30 cases
per 100 000 people)
Malaysia iFOBT 50–75 years For average risk population iFOBT is NA
preferred; for moderate-risk or high-risk
patients a colonoscopy is recommended
Middle East and North Africa None established None established None established Differences in culture and economic status among
Middle East and North African countries might be
responsible for absence of standard screening; the
United Arab Emirates is developing a cancer control
plan in line with WHO and EMRO framework;
Algeria testing iFOBT screenings for average risk
patients between 50 years and 74 years
Sub-Saharan Africa None established <50 years for high-risk None established New strategies using MAAA; use complete blood
patients count and demographic data to identify patients at
high risk of colorectal cancer; availability of
endoscopic services and cost affect other screening
methods
The National Bowel Cancer FIT 50–74 years Government provides biennial FIT NA
Screening Program, Australia screenings
Mexico None established None established None established No national standard currently but Mexico’s
National Institute of Cancer is one of many
institutions conducting campaigns and research
in the region to create standardised screening
using FIT in patients ≥50 years
Colombia FIT or colonoscopy ≥50 years Biennial screening with FIT or screening NA
every 10 years with colonoscopy
National Cancer Institute of FIT 50–75 years FIT then colonoscopy NA
Argentina
Chile iFOBT or colonoscopy 50–75 years iFOBT every 2 years or colonoscopy every International collaboration efforts, since 2012,
10 years between Chile and Japan have developed these
guidelines as well as increased colonoscopy training
EMRO=Eastern Mediterranean Regional Office. FIT=faecal immunochemical test. FORT=faecal occult blood test. gFOBT=guaiac faecal occult blood test (chemical used for detection). iFOBT=immunological faecal
occult blood test (antibodies used for detection). MAAA=multianalyte assays with algorithmic analysis. NA=not applicable.

Table 1: Current international screening guidelines

Tobacco and alcohol use Screening

History of tobacco use is linearly associated with the Various screening methods are available; the most
incidence of colorectal cancer;11 however, the exact widely applied are the faecal immunochemical test and
mechanism is unknown. Besides DNA and colorectal colonoscopy.15–17 Multitarget faecal-DNA combines
mucosa damage by tobacco carcinogens, a recent study haemo­globin, DNA mutation analysis, and methylation.
showed that cigarette smoking could induce One example is Cologuard (Exact Science, USA), which
gut microbiota dysbiosis, promoting colorectal is available in the USA, Puerto Rico, and the UK.
tumourigenesis.12 Alcohol contributes to carcinogenesis Multitarget faecal-DNA has a higher single-application
by oxidative and non-oxidative metabolism, favouring sensitivity for advanced precancerous lesions.18 It is well
genetic abnormalities, epigenetic, cell signalling, documented that mortality from colorectal cancer is
and immune processes dysregulations.13 Alcohol reduced through screening and early detection, and
consumption is dose dependent and is linked to removal of preneo­ plastic lesions can reduce the
increased risk and mortality. People consuming at least incidence of cancer.19 Table 1 shows international
50 g/day of ethanol had a relative risk of 1·21 (95% CI screening guidelines. In 2004, the Asian Pacific Working
1·01–1·46).14 Group for Colorectal Cancer Screening was created, but

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disparities remain; low-income Asian economies often

osteosarcoma, and prostate

Brain, breast, kidney, lung,
do not have the resources needed to create a cancer

kidney, papillary thyroid,

registry.20 Collaborative efforts are underway with the
creation of the Asian National Cancer Centers Alliance,
with countries including China, India, Indonesia,
CHEK2 gene

1·4 in 100
Japan, South Korea, Mongolia, Singapore, Thailand, and
CHEK2

cancer
Viet Nam.
NA
NA
NA
NA
Hereditary syndromes
Autosomal recessive
MUYTH (MUY gene)

Breast, duodenal,
endometrial, and
stomach cancer
An essential discussion between health-care provider,
patient, and caregiver regarding family history should
>50 years
MUYTH

1 in 100

occur. A patient’s genetics might prove to be crucial

NA
NA

for their prognosis, treatment, and prevention of

leukaemia, and adrenocortical
malignancy in the patient and their relatives. Hereditary
Sarcomas (cancers of muscle,

breast cancer, brain tumours,

syndromes might result in a diagnosis of colorectal cancer

bone, or connective tissue),
p53 (17p13; 1q23) CHEK2

or other primary cancers (table 2). An example is Lynch

Li Fraumeni Syndrome

1 in 5000 to 1 in 20 000

Autosomal dominant

syndrome, which is attributed to a germline mutation of

the DNA mismatch repair genes. Immunohistochemical
identi­fication of a deficiency in a DNA mismatch repair
At any time

carcinoma
(22q12.1)

Variable
Variable

(dMMR) is shown through loss of expression of any of the

mismatch repair proteins MLH-1, MSH2, MSH6, and
PMS2. This loss indi­ cates microsatellite instability.
Breast cancer, colon cancer,

carcinoma, thyroid cancer,

Microsatellite instability status can be determined via PCR

and uterine leiomyomas
Cowden’s Syndrome

Autosomal dominant

or next-generation sequencing. It is recommended

melanoma, renal cell
Skin and mucous

germline testing be completed in all patients with EOCRC,

Hamartomas

dMMR, or a family history of colorectal cancer.21,22 An

1 in 200 000

membranes
20–30 years

exception is in the presence of loss of MLH-1 with a BRAFV600E

PTEN

(ie, Val600Glu) mutation, which is associated with MLH-1

hypermethylation and is attributed to sporadic colorectal
Biliary tree, desmoid tumours,

cancer.
medulloblastoma, pancreas,
hepatoblastoma (children),

papillary thyroid tumours,

small bowel, and stomach
Familial adenomatosis

Clinical presentation and diagnosis

Autosomal dominant

Although increases in colorectal cancer screening has

reduced overall incidence, many patients with EOCRC
>100 polyps
polyposis

1 in 8300
<35 years

present with advanced disease; low-income countries

cancer

without the necessary infrastructure have increased

APC

NA

mortality.23–25 Typical signs and symptoms include:

Autosomal dominant

haematochezia or melena, abdominal pain, otherwise

Cervical, gastric, and
pancreatic cancer

unexplained iron deficiency anaemia, or a change in

Peutz-Jegher’s

Hamartomas

bowel habits, or a combination thereof.26,27 Less common

19–65 years
<5000/year

presenting symptoms include abdominal distention,

STK-11

nausea, or vomiting, or a combination of these, which

NA

could indicate obstruction. Iron-deficiency anaemia from

small bowel, small intestine,

unrecognised blood loss is common in right-sided

stomach, and urinary tract
Mismatch repair proteins:

hepatobiliary, pancreatic,

(renal pelvis, ureter, and

colorectal cancers.28
Right side of the colon

Table 2: Hereditary colorectal cancer syndromes

Fewer than ten polyps
MLH-1, MSH2, MSH6,

Autosomal dominant

Brain, endometrial,

HNPCC=hereditary nonpolyposis colorectal cancer.

PMS2, and EPCAM

A colonoscopy is the most accurate diagnostic test to

Lynch (HNPCC)

localise and biopsy lesions, detect synchronous

40–60 years

neoplasms, and extract polyps. Synchronous colorectal

bladder)
1 in 279

cancers, defined as two or more distinct primary tumours

diagnosed within 6 months, separated by normal bowel
occurs in 3–5% of patients, raising the suspicion for
Lynch syndrome or MUTYH-associated polyposis
Associated cancers

(table 2).29–32 For complete staging, patients should

Presentation

undergo chest, abdomen, and pelvic CT before surgical

Mutation

Incidence

Anatomy

resection or initiation of treatment.33

Genetic
Age

Serum markers are associated with colorectal cancer;

however, diagnostic ability to detect primary colorectal

296 www.thelancet.com Vol 404 July 20, 2024

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cancer is low.34,35 A meta-analysis concluded that the stage II disease, but when substratified by high-risk
pooled sensitivity of carcinoembryonic antigen was features for recurrence, the investigators noted an
only 46% (95% CI 0·45–0·47).36 False elevation in improvement in 3-year DFS of 82·1% versus 74·9%
carcinoembryonic antigen could be attributed to any (HR 0·74, 95% CI 0·52–1·06).47 To date, consideration of
inflammatory state (gastritis, peptic ulcer, or adjuvant chemotherapy in patients with stage II disease
diverticulitis), endocrinological disorders, and tobacco remains a matter of discussion with the patient.43
exposure.37,38 The dose-limiting toxicity for oxaliplatin is cumulative
peripheral neuropathy, which might be irreversible and
Pathogenesis commonly occurs at 4 months.48,49 Exploratory studies have
Prognostic classification beyond standard histology has been unsuccessful in reducing peripheral neuropathy;50–52
been characterised by the creation of consensus hence, consideration of reducing the duration of adjuvant
molecular subtypes (CMSs). This international effort of chemotherapy from 6 months to 3 months was pursued.48
transcriptome-wide analysis of primary tumours Although therapeutic options for adjuvant therapy
assessed the microenvironment, metabolic signatures, remain unchanged, the duration of treatment has been
genomic, epigenomic, molecular aberrations, and other refined. The International Duration Evaluation of
carcinogenesis pathways resulting in four molecular Adjuvant Therapy (IDEA) was a pooled international
subtypes: CMS1, CMS2, CMS3, and CMS4 (figure 1). collaboration (CALGB/SWOG 80702, IDEA France, SCOT,
Previously published data suggested CMSs might be ACHIEVE, TOSCA, and HORG) to determine whether
prognostic for OS in metastatic colorectal cancer 3 months of oxaliplatin-based adjuvant therapy was non-
tumours.39–41 Initially it was suggested that CMS1 inferior to 6 months in stage III colon cancer for the
(microsatellite instability-immune) had the worst primary prespecified endpoint of 3-year DFS with a
prognosis; however, these data were published before the secondary endpoint of OS.53 The upper limit of the
approval for immune checkpoint inhibitors for dMMR or two-sided 95% CI for non-inferiority 3-year DFS was 1·12;
microsatellite instability-high (MSI-H) tumours. the non-inferiority upper limit for OS was HR 1·11; non-
An immune-based assay to assess the tumour inferiority was declared if the one-sided false discovery
microenvironment and immunoscore quantifies CD3 and rate adjusted (FDRadj) p value was less than 0·025. The
CD8-positive T cells at the tumour centre and margin.42
The greater the immunoscore, the lower the risk of
recurrence. To date, the use of CMSs and immunoscore
une
have not been widely adopted in the clinical setting. imm
ability
Pathogenic risk factors for recurrence or distant metastatic ins
t
disease following surgical resection for locally advanced ite
tell Immune infiltration
sa
colon and rectal cancer include T4 tumours, N2 disease, and activation
o
icr

CM
Microsatellite
:m

suboptimal lymph node dissection (<12 lymph nodes),

S2
instability high
S1

: ca
perineural or lymphovascular invasion, presence of
CM

CIMP-positive

no
Hypermethylation

nic
tumour deposits or poorly differentiated histology or SCNA-low
al
WNT and MYC activation
signet ring tumours, or a combination thereof.43,44 BRAF and TGFBR2
Microsatellite stability
mutations
CIN-high
Early stage colon cancer CIMP-negative
e
CMS mixed typ

SCNA-high
Approximately 37% of patients present with stage I–II Major–minor pairing show 14%
37%
APC and TP53 mutations
intermediate states of the Superior survival after relapse
disease (T1-4N0M0) and 36% of patients present with respective molecular features 13%
stage III disease (T1-4N1-2M0) as defined by the American of the pure CMS types

Joint Committee on Cancer; there is an expected 5-year 13%

23%
OS of 70% for patients with stage II disease and 45–65%
for patients with stage III disease.45,46 The pivotal phase 3 Metabolic deregulation
Mixed microsatellite status
MOSAIC trial evaluated 6 months of adjuvant CIN-intermediate
chemotherapy in patients with stage II and III colon CIMP-low Stromal infiltration, TGF-β activation,
SCNA-intermediate EMT activation, angiogenesis
cancer. The trial established a 3-year disease-free survival KRAS and APC Microsatellite stability
(DFS) benefit with oxaliplatin-based chemotherapy versus mutations CIN-high
CM

CIMP-negative
S3

5-fluorouracil–leucovorin in patients with stage III

:m

SCNA-high
ab
et

oli Worse relapse-free survival and

disease (72·2% vs 65·3%, respectively; hazard ratio c worse overall survival
[HR] 0·76, 95% CI 0·62–0·92), culminating in US Food
and Drug Administration (FDA) approval.47 In contrast, hym
al
the role of adjuvant chemotherapy in all patients with esenc
CMS4: m
stage II disease has remained controversial due to the
lack of validated data. The MOSAIC investigators did not Figure 1: CMS of colorectal cancer
find adjuvant chemotherapy beneficial in all patients with CIMP=CpG island methylator phenotype. CMS=consensus molecular subtypes. CIN=chromosomal instability.

www.thelancet.com Vol 404 July 20, 2024 297

298
Phase N Recruiting Eligibility criteria Chemotherapy and radiation therapy regimen Primary Secondary endpoints
endpoints
Approaches to organ preservation
NCT02008656 (OPRA) 2 358 No Stage II (T3–4, N0) or stage III (any T or ≥N) Induction neoadjuvant chemotherapy group 3-year DFS 76% for LRFS 94% for groups 1 and 2 (not
(group 1): chemotherapy before chemoradiation, groups 1 and 2 significant; p=0·78); DMFS 84%
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eight cycles of FOLFOX or five cycles of capecitabine (not significant; (group 1) and 82% (group 2), p=0·67;
and oxaliplatin (CAPEOX) over ~15–16 weeks; after p=0·98) 3-year TME-free survival 41% (group 1)
2–4 weeks if stable or response then follow with and 53% (group 2), p=0·01; sphincter
chemoradiation with 5-FU or capecitabine; preservation overall 60% (group 2) and
consolidation neoadjuvant chemotherapy group 47% (group 1), p=0·02
(group 2): 6 weeks of chemoradiation therapy with
either 5-FU or capecitabine; after 2–4 weeks if stable
or response then follow with eight cycles of FOLFOX
or six cycles of CAPEOX
NCT02505750 (OPERA) 3 141 No cT2–cT3b, cN0, or cN1 <8 mm All patients first received neoadjuvant 3-year organ OS pending
adenocarcinoma of the low to mid rectum; chemoradiotherapy with EBRT 45 Gy in 25 fractions preservation
tumour <5 cm in diameter for 5 weeks with concurrent capecitabine group A 59%
NCT 02514278 3 Pending No cT2–3, N0–N1, M0 adenocarcinoma of the Group 1: neoadjuvant FOLFIRINOX for four cycles 1 year organ Rate of cCR, rate of radiological
(GRECCAR12) middle and lower rectum (<10 cm from (oxaliplatin intravenously, irinotecan intravenously, preservation; response, rate of pCR, rate of R0
anal verge); primary tumour <4 cm folinic acid intravenously, and 5-FU intravenously) results pending* resection, 3-year LRRR, 3-year OS,
followed by long-course chemoradiotherapy with 3-year DFS; results pending*
50 Gy in 25 fractions over 5 weeks, with capecitabine
daily; group 2: long-course chemoradiotherapy with
50 Gy in 25 fractions over 5 weeks, with capecitabine
daily; 8–-10 weeks post therapy, those who were
considered to have good response (residual tumour
≤2 cm per pelvic MRI) underwent local excision; poor
responders (residual tumour >2 cm) underwent TME
with adjuvant capecitabine
NCT04095299 (WW3) 3 Pending Yes cT1–3, M0 adenocarcinoma of the rectum, Group A: long-course chemoradiotherapy with 2-year rectal Rate of cCR at 4 months, RFS, OS, CFS;
≤4·5 cm, with lowest tumour edge located 50·4 Gy given over 28 fractions, with concomitant preservation; results pending*
at or below the peritoneal reflection capecitabine twice per day; group B 62 Gy to the results pending*
clinical tumour volume and 50·4 Gy to the elective
volume, given over 28 fractions with concomitant
capecitabine twice per day
NCT05646511 3 608 Yes T3–4 or ≥N Group A: five fractions of 5 Gy then 12 weeks CAPOX 3-year rectal cCR pending, clinical response
(ENSEMBLE) then evaluate for NOM; group B: five fractions of 5 Gy preservation pending, NOM pending, LRR pending,
then 12 weeks CAPOXIRI then evaluate for NOM OS pending, DMFS pending,
TME-free survival pending, TME-free
DFS pending
NCT04246684 (ACO/ 3 702 Yes Must meet one of the following: any cT3 (if Group A (control): five fractions of 5 Gy followed by Organ DFS, rate of cCR after TNT, rate of
ARO/AIO-18.1) the distal extent of the tumour is <6 cm nine cycles of consolidation chemotherapy of preservation; immediate TME after TNT, cumulative
from the anocutaneous line) or cT3c or d in mFOLFOX6 (or six cycles of CapeOx) followed by defined as survival incidence of locoregional regrowth
the middle third of the rectum (≥6–12 cm) re-staging at week 22–24; groupB (experimental): with sphincter after cCR, short and long-term toxicity,
with MRI evidence of extramural tumour fluoropyrimidin or oxaliplatin-based intact, no major OS, and QoL
spread into the mesorectal fat of more than chemoradiotherapy (1·8–45 Gy to the primary surgery, no stoma
5 mm (>cT3b) or cT3 with clear ≥cN based tumour and pelvic lymph nodes; followed by
on strict MRI criteria or cT4 tumours or any sequential boost of 9 Gy to the gross tumour volume)
middle or low third of rectum with clear followed by consolidation chemotherapy with six
MRI criteria for ≥N cycles of mFOLFOX6 (or four cycles of CAPOX)
followed by re-staging at week 22–24; in both
groups, for patients achieving a cCR, a watch and wait
option with close follow-up is scheduled; in case of
non-complete response, immediate TME surgery is
performed
(Table 3 continues on next page)

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 Phase N Recruiting Eligibility criteria Chemotherapy and radiation therapy regimen Primary Secondary endpoints
endpoints
(Continued from previous page)
NCT05610163 (JANUS) 2 312 Yes ≤12 cm from the anal verge: T4 N0 or any T, Group 1: long-course chemoradiation therapy then cCR rates DFS, organ preservation time, time to
≥N, or T3 N0 requiring abdominal perineal either FOLFOX regimen (consisting of leucovorin distant metastasis, OS, incidence of
resection or coloanal anastomosis intravenously, fluorouracil intravenously, and adverse events
oxaliplatin intravenously) or CapeOx (consisting of
capecitabine orally, and oxaliplatin intravenously);
patients undergo CT scan, MRI, biospecimen
collection and sigmoidoscopy throughout the trial
and a biopsy during screening; group 2: long-course

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chemoradiation therapy then FOLFIRINOX regimen
(consisting of leucovorin intravenously, fluorouracil
intravenously, irinotecan intravenously, and
oxaliplatin intravenously); patients undergo CT scan,
MRI, biospecimen collection, and sigmoidoscopy
throughout the trial and a biopsy during screening
Neoadjuvant approaches to rectal cancer
NCT01804790 (PROIDGE/ 3 461 No Stages cT3 with risk of local recurrence or Group A (control) chemoradiotherapy 5 weeks 3-year DFS 76% 3-year OS 91% (group B) and 88%
Néofirinox) cT4, M0 and for which a multidisciplinary (50 Gy, 2 Gy/session; 25 fractions) + capecitabine (group B) and 69% (group A), p=0·0773;
meeting recommend preoperative (800 mg/m² twice per day for 5 days in 7 days, (group A), p=0·034 3-year metastasis-free survival 79%
chemoradiotherapy excluding weekends), then 6–8 weeks after (group B) and 72% (group A), p=0·17;
chemoradiation, surgery with TME, followed by local regional recurrence rate 4%
adjuvant chemotherapy for 6 months, either (group B) and 6% (group A); 3-year
mFolfox6* or capecitabine; group B (experimental): cancer-specific survival rates: 92%
neoadjuvant mFolfirinox* for six cycles; followed by (group B) and 89% (group A)
5 weeks of chemoradiotherapy 50 Gy + capecitabine
(800 mg/m² twice per day for 5 days in 7 days);
surgery with TME 6–8 weeks after chemoradiation
followed by 3 months of adjuvant chemotherapy
(either mFolfox6 or capecitabine)
NCT01558921 (RAPIDO) III 920 No Locally advanced tumour fulfilling at least Group A (control): standard long course 3-year disease- OS group A (88·8%) and group B
one of the following criteria on pelvic MRI chemoradiotherapy; arm B (experimental): short related treatment (89·1%), p=0·59;
indicating high risk of failing locally or course five fractions of 5 Gy radiation scheme; failure: group A 3-year locoregional failure group A
systemically: T4a, cT4b, or N2; positive followed by 6 cycles of combination chemotherapy (30·4%) and (6 %) and group B (8·3%), p=0·12;
MRF; or enlarged lateral nodes (>1 cm) CAPOX (or FOLFOX4) and surgery group B (23·7%), toxicity of grade 3 or worse occurred in
p=0·019 48% (group B) and 25% (group A)
during preoperative treatment; 35% of
all participants had toxicity in
postoperative chemotherapy
NCT02533271 (STELLAR) 3 599 Yes cT3–4 or regional LN, or both positivity Group 1: short-course radiation (5 Gy in five fractions 3-year DFS: 64·5% 3-year OS 86·5% (group 1) and 75·1%
without distant metastasis; primary over 1 week) followed by CapeOX for four cycles (group 1) and (group 2), p=0·033; 3-year DMFS
tumour located in the distal or middle third starting 7–14 days post radiation; TME was performed 62·3% (group 2), 77·1% (group 1) and 75·3% (group 2)
of the rectum 6–8 weeks after preoperative treatment, followed by p<0·002 for non-
two cycles of CapeOX; group 2: chemotherapy and inferiority
radiation therapy with 50 Gy in 25 fractions over
5 weeks, with concurrent capecitabine; TME was
performed 6–8 weeks after preoperative treatment,
followed by six cycles of CapeOx
NCT04928807 (UNION) 3 230 Yes T3–4 or ≥N Group A: five fractions of 5 Gy followed by pCR 39·8% vs 3-year EFS pending,
camrelizumab and CAPOX twice (preoperatively), 15·3%, p<0·001 OS pending, R0 resection rate pending,
TME, followed by six cycles of adjuvant camrelizumab 3-year DFS pending
and CAPOX; group B: long-course concurrent
chemoradiotherapy, followed by CAPOX for two
cycles (preoperatively) followed by TME and then
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CAPOX for six cycles

(Table 3 continues on next page)

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primary endpoint of DFS (HR 1·07, 95% CI 1·00–1·15) for

5-FU=5-fluorouracil. cCR=clinical complete response. CFS=cancer-free survival. CR=complete response. DFS=disease-free survival. DMFS=distant metastasis-free survival. EBRT=external beam radiation therapy. EFS=event-free survival. LN=lymph node.

TNT=total neoadjuvant therapy. *mFolfirinox=oxaliplatin (85 mg/m² in 2 h at day 1), irinotecan (180 mg/m² in 90 min at D1), folinic acid (400 mg/m² simultaneously in 2 h at day 1). During the irinotecan infusion add 5-FU continuous infusion for 48
OS: arm A (89·5%) vs group B (90·2%),
Path CR: arm A (24%) vs arm B (22%);
the full analysis was not met. Non-inferiority for 3 months

LRFS=local recurrence-free survival. LRRR=locoregional recurrence rate. NOM=non-operative management. OS=overall survival. pCR=pathologicAL complete response. QoL=quality of life. RFS=relapse-free survival. TME=tumour microenvironment.
of capecitabine–oxaliplatin (CAPOX; HR 0·95, 0·85–1·06)
was met but not for FOLFOX (HR 1·16, 1·06–1·26). In an

HR 1·04 (95% CI 0·74–1·44)

exploratory analysis when tumours were stratified as low
Secondary endpoints

risk (T1-3N1M0) versus high risk (T4 or N2, or both),

3 months was non-inferior to 6 months for the low-risk
tumours, with a 3-year DFS of 83·1% and 83·3%,
respectively (HR 1·01, 0·90–1·12). For high-risk tumours,
the 3-year DFS rate for 6 months of therapy was superior
(95% CI 0·74–1·14) regardless of treatment (64·4% vs 62·7%, respectively;
Pelvic R0 resection
rate: arm A (99%)

(78·6%), HR 0·92
(80·8%) vs arm B

HR 1·12, 1·03–1·23). A reduction in treatment-related

vs arm B (97%);

toxicities of grade 2 or more was noted for 3 months

DFS: arm A
endpoints

(16·6% with FOLFOX and 14·2% with CAPOX) versus

Primary

6 months (47·7% with FOLFOX and 44·9% with CAPOX)

of adjuvant therapy.
then FOLFOX for six cycles postoperatively; if R1, then
then the patient will proceed directly to surgery; if R0,
therapy; if the tumour has decreased in size by ≥ 20%,

After a median follow-up of 72·3 months, the

the patient proceeds to adjuvant chemoXRT; arm B:
standard chemoradiotherapy followed by TME and
Group A: FOLFOX chemotherapy for six cycles then

tumour; if the tumour has not decreased by ≥20%,

MRI scan or endorectal ultrasound to examine the

the patient will have chemotherapy and radiation

Chemotherapy and radiation therapy regimen

secondary endpoint of OS for non-inferiority was not

met (5-year OS was 82·4% [95% CI 81·4–83·3] vs 82·8%
[81·8–83·8] for 3 months and 6 months, respectively;
HR 1·02 [0·95–1·11]; non-inferiority FDRadj p=0·058),
adjuvant FOLFOX for eight cycles

with an absolute difference in OS of only 0·4%.54 For

patients treated with CAPOX, 5-year OS was 82·1%
(95% CI 80·5–83·6) versus 81·2% (95% CI 79·2–82·9;
HR 0·96, 95% CI 0·85–1·08) for 3 months and
6 months, respectively; non-inferiority FDRadj p=0·033),
with an absolute difference in OS of 0·9%. However, in
patients treated with FOLFOX, 5-year OS was 82·6%
(95% CI 81·3–83·8) versus 83·8% (82·6–85·0; HR 1·07,
0·97–1·18; non-inferiority FDRadj p=0·34), with an
absolute difference in OS of −1·6%. Based on these
findings, 3 months of CAPOX is reasonable. However, if
Stage II or III T2 N1, T3 N0, or T3 N1

FOLFOX is the preferred regimen, a 6 month duration

is recommended. When making these decisions, the
patients’ existing comorbidities must also be considered.
Despite not meeting the primary endpoint for full
Recruiting Eligibility criteria

analysis, providers in the USA have widely adopted the

3 months of CAPOX regimen.55
A novel approach is the consideration of neoadjuvant
chemotherapy before colon resection.56 The phase 3
FOxTROT trial randomly assigned patients with T3-4,
N0-2, M0 colon cancer to 6 weeks of modified FOLFOX
h (1200 mg/m² at day 1 and day 2), every 14 days for four cycles.

preoperatively plus adjuvant chemotherapy versus

No

Table 3: Rectal total neoadjuvant chemotherapy trials

adjuvant chemotherapy alone (2:1).57 The objective was to

determine a 25% proportional reduction in 2-year
recurrence with neoadjuvant chemotherapy with
1194

80% power at p less than 0·05. The investigators noted an

N

improvement of reduced residual disease or recurrence

Phase

within 2 years of 16·9% (neoadjuvant chemotherapy)

(Continued from previous page)

NCT01515787 (PROSPECT) 3

versus 21·5% (adjuvant chemotherapy; HR 0·72, 95% CI

0·54–0·98; p=0·037), corresponding to a 28% lower
Omission of radiation

recurrence rate with neoadjuvant chemotherapy. In

contrast, the phase 3 OPTICAL trial provided 3 months of
neoadjuvant oxaliplatin chemotherapy versus standard
adjuvant chemotherapy and noted no statistical difference
in 3-year DFS.58 At this time neoadjuvant systemic therapy
is exploratory.

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Early stage rectal cancer Early stage (T1–2, N0) rectal cancers are a distinct
Management of non-metastatic rectal cancer has become entity, where TME alone could result in excellent
increasingly complex over the last decade. Because rectal outcomes. However, there is now an interest in total
cancers are below the peritoneal reflection, dedicated pelvic neoadjuvant therapy and sphincter preservation with or
MRI is crucial to delineate the tumour, mesorectal fascia, without local excision, with additional studies in develop­
and the circumferential resection margin.59,60 Surgical ment.74,78–80 In contrast, the phase 3 PROSPECT trial
approach to total mesorectal excision (TME) has been (NCT01515787) determined non-inferiority of DFS for
explored extensively. Laparoscopic surgery has been found the omission of radiation therapy when patients have
to be equivocal to open surgery for locoregional recurrence, had adequate tumour response (defined as >20%
DFS, and OS.61,62 The use of robotic surgery when compared clinically) following 3 months of neoadjuvant oxaliplatin-
with open laparotomy does not significantly reduce the risk based chemotherapy in mid to high lying tumours.81
of conversion to open laparotomy. Lastly, exploration of the use of immune checkpoint
Historically, neoadjuvant chemoradiation therapy has inhibition in dMMR or MSI-H rectal cancer (<5%) has
been a standard of care, but can cause chronic bowel and been pursued. Promising early single-institution
bladder toxicity, as well as sexual dysfunction. Therefore, data suggest 6 months of single-agent PD1 blockade
selection of treatment strategies is influenced by (NCT05723562) in dMMR or MSI-H tumours might
oncological and functional outcomes, location of the result in high clinical complete response with sphincter
tumour, sphincter preservation, and the possibility of preservation and is being validated in a multicentre
deferring surgery. Following standardised imple­ phase 2 trial (NCT05723562).82 EA2201 (NCT04751370) is
mentation of TME, the risk of locoregional recurrence is an ongoing multicentre phase 2 trial exploring the
less of a concern with negative margins (R0).63,64 Thus, role of combination immunotherapy (nivolumab plus
patients with a threatened circumferential resection ipilumumab).
margin on preoperative MRI are optimal candidates for
neoadjuvant chemoradiation treatment.65 Historically, Metastatic colorectal cancer
adjuvant chemotherapy is offered following TME but General principles
with modest compliance rates.66 Thus, new strategies The life expectancy of patients with metastatic colorectal
incorporating neoadjuvant systemic chemotherapy to cancer (mCRC) has increased in the last decade, with a
increase compliance, reduce toxicity, and improve distant median OS of 32–40 months, attributable to effective
metastases-free survival are being explored.67–69 Such systemic therapy, treatment selection, locoregional
modifications include induction chemoradiation therapy treatment options, and novel approaches due to clinical
(before chemotherapy) or consolidative chemotherapy trial developments.83–86 For patients with surgically
(following chemoradiation), before consideration of unresectable mCRC, the expected 5-year OS is 15·6%.46
TME.70 Collectively named total neoadjuvant therapy, this The increased adoption of parenchyma-sparing liver
is an accepted new standard of care. Multiple studies surgery enables repeated surgical intervention.87 With
using short-course or long-course radiation have shown optimal integration of systemic and locoregional
the benefits of local disease control, including complete approaches, cure is feasible in a small percentage of
resolution of the primary tumour (complete pathological patients with mCRC.88 The expected 5-year OS for a
response), with sphincter preservation and possibly patient with resected liver metastases is 35–65%.89,90
deferring TME (table 3).33,71,72 Local ablative techniques (eg, thermal ablation or
Additional risk factors include extramural venous stereo­tactic body radiotherapy) can also be considered
invasion, tumour deposits, extensive nodal metastases and could contribute to DFS and potentially OS.91–94
(cN2), and advanced T stage (T3 or T4). Although there There­fore, multi­disciplinary management is imperative
might be subtle differences in the various approaches or to in­dividua­ lise therapeutic strategies for optimal
the sequence of therapy (table 3), one notable difference outcomes, with repeat diagnostic imaging at 2-month
is that induction chemoradiation therapy (before chemo­ and 3-month intervals to determine degree of
therapy) might achieve sphincter preservation for clinical response.90
or near complete response but must be followed using a For initially unresectable metastases, resection of the
stringent programme of clinical, endoscopic, and primary tumour has not been proven to improve the
radiological surveillance.73–77 In the USA, JANUS is a 5-year OS in an asymptomatic patient.95–97 In the phase 3
phase 2/3 randomised trial investigating the role of dose SYNCHRONOUS trial, patients were randomly
intensification with an investigational group of fluoro­ assigned to systemic chemotherapy or surgical
pyrimidine plus oxaliplatin plus irinotecan (FOLFOXIRI). resection of the primary tumour. No improvement in
An ongoing German phase 3 trial (NCT04246684) is OS (18·6 months vs 16·7 months; not siginificant)
exploring the role of organ preservation as a primary following surgical resection of the primary tumour was
endpoint when providing induction short-course versus achieved and this is not recommended unless clinically
long-course radiation followed by consolidative indicated;95 24·1% of patients randomly assigned to the
chemotherapy. surgical group never received systemic chemotherapy.

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5-fluorouracil–leucovorin or
All others
capecitabine plus bevacizumab

No
5-fluorouracil–leucovorin or
capecitabine plus bevacizumab
Left sided and RAS or
dMMR or MSI-H Immunotherapy BRAF wild type
5-fluorouracil–leucovorin or
No
capecitabine plus anti-EGFR
pMMR or Appropriate
microsatellite candidate for
stable combination Doublet plus anti-EGFR*
chemotherapy?
RAS or BRAF wild type
Resectable
Doublet or FOLFOXIRI‡ plus
metastases
bevacizumab*†

Doublet plus bevacizumab or

Standard RAS mutation
Surgical resection With or without Yes FOLFOXIRI‡ plus bevacizumab
treatment with or without adjuvant
locoregional chemotherapy Doublet plus bevacizumab or
treatment BRAF mutation
FOLFOXIRI‡ plus bevacizumab
Yes

Perioperative Surgical resection Perioperative

chemotherapy with or without chemotherapy
Alternative locoregional
treatment treatment

Figure 2: Multidisciplinary tumour board encourages therapeutic algorithm for first-line treatment in mCRC
Blue box indicates the starting point for treatment. Lavender boxes indicate molecular alteration. Green boxes indicate treatment options. A clinical trial should
always be considered if available. EGFR=epidermal growth factor receptor. dMMR=deficient mismatch repair. mCRC=metastatic colorectal cancer.
MSI-H=microsatellite instability high. pMMR=proficient mismatch repair. *Mainly if left-sided tumours. †Mainly if right-sided tumours. ‡Only if younger than
75 years (age 71–75 years with Eastern Cooperative Oncology Group performance status 0).

First-line therapy for metastatic colorectal cancer Medicines Agency approval as monotherapy or in
Determining the first-line systemic therapy used in combination for patients intolerant of 5-fluoropyrimidine.103
initially unresectable mCRC is based on molecular and RAS mutations are well established predictors of
clinical drivers commonly determined by next generation resistance to anti-epidermal growth factor receptor (EGFR)
sequencing. Approximately 5% of all patients have dMMR agents (cetuximab and panitumumab) providing minimal
or MSI-H tumours and can achieve a clinically relevant benefit in BRAFV600E mutated tumours.104–106 In addition,
benefit from the use of immune check­ HER2 (also known as ERBB2)-amplified tumours are also
point inhibitors.98 The randomised KEYNOTE-177 trial resistant to anti-EGFR therapy.107 Right-sided pMMR or
established the anti-PD-1, pembrolizumab as a new microsatellite-stable colon tumours have a reduced OS as
standard of care versus standard chemotherapy in well as intrinsic resistance to anti-EGFR agents even if
treatment-naive patients.99 Additional promising data RAS and BRAF are wild-type.108 The phase 3 PARADIGM
were noted for the combination of the anti-CTLA4, study prospectively showed prolonged OS in combination
ipilimumab, and the anti-PD-1, nivolumab, in the single with FOLFOX–panitumumab versus FOLFOX–beva­
arm phase 2 Checkmate-142 study.100 The magnitude of cizumab alone in left-sided RAS wild-type mCRC and is a
the benefit with the addition of an anti-CTLA4 remains preferred regimen.86.109
under investigation.101 In patients fit for intensified chemotherapy, FOLFOXIRI
In unresectable proficient mismatch repair (pMMR) or with bevacizumab provides substantial benefit over
microsatellite-stable mCRC, morbidity, molecular muta­ doublets or bevacizumab in terms of OS, progression-free
tion status, and primary tumour location are major drivers survival (PFS), overall response rate, and resection rate.110
for treatment choice (figure 2). Comorbidity, age, and However, the TRIPLETE study showed no benefit from a
Eastern Cooperative Oncology Group performance status modified schedule of FOLFOXIRI plus panitumumab
influence the intensity of the chemotherapy backbone, versus FOLFOX–panitumumab in an RAS and BRAF
ranging from monotherapy with fluoro­pyrimidines to the wild-type primarily left-sided treatment-naive cohort.111
addition of oxaliplatin-based (FOLFOX or CAPOX) or For patients with surgically unresectable pMMR or
irinotecan-based (FOLFIRI) doublets versus the triple microsatellite-stable tumours, first-line combinations are
combination of 5-fluoruracil, oxaliplatin and irinotecan generally administered for up to 4–6 months, followed by
(FOLFOXIRI).102,103 S1 (tegafur/gimeracil–oteracil) is an maintenance chemotherapy with a fluoropyrimidine and
oral fluoropyrimidine used in Asia yet received European the same targeted agent until disease progression or

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intolerance to provide a continuum of care to improve

A
OS.102 Although age is not an absolute contraindication to Matched treatment ESCAT OncoKb level
score126–128
any treatment, a complete geriatric assessment is recom­
mended to assess treatment tolerance and compliance in RAS mutation ·· ·· ··
KRAS Gly12Cys mutation Adagrasib or sotorasib with or ·· 3A
all patients.112 without cetuximab
BRAF V600E
(ie, Val600Glu) mutation Encorafenib plus cetuximab I-A 1
Peritoneal disease dMMR or microsatellite instability high Pembrolizumab or dostarlimab
(dMMR)
I-A 1

Development of peritoneal metastases might occur in up dMMR or microsatellite instability high Nivolumab plus ipilimumab I-A 1
to 17% of colorectal cancers with isolated peritoneal BRAF non-V600E
mutation BRAF blockade (eg, PLX8394) ·· 4
MET amplification or fusion MET blockade IIIA* 4†
disease in up to 2% of patients.113 These tumours HER2 or ERBB2 amplification HER2 blockade‡ II-B 2
commonly have multiple poor prognostic features: right- NTRK gene fusion Entrectinib I-C 1
NTRK gene fusion Larotrectinib I-C 1
sided colonic origin; BRAFV600E mutation tumour type; ATM mutation Olaparib IIIA ··
and poorly differentiated histology with mucinous or PIK3CA mutation Alpelisib IIIA 4
signet ring features.114 Additional challenges exist due to POLE mutation Anti-PD1 or anti-PD-L1 IIIA ··
RET or ALK fusions Selpercatinib§ IIIA 1
the reduced sensitivity of diagnostic imaging in assessing RET or ALK fusions ALK blockade¶ IIIA ··
the degree of tumour burden.115 A meta-analysis of No genomic alterations ·· ·· ··
14 randomised phase 3 trials noted that patients with B
isolated and non-isolated peritoneal disease fared worse KRAS Gly12Cys mutation
for OS than patients with non-peritoneal metastases.116 RAS mutation
BRAFV600E mutation
Three recent phase 3 trials evaluated the role of dMMR or microsatellite instability high
cytoreductive surgery and hyperthermic intraperitoneal BRAFnon-V600E mutation
chemotherapy (HIPEC): PRODIGE-7 was specifically in MET amplification or fusion
HER2 or ERBB2 amplification
mCRC with peritoneal disease and COLOPEC and NTRK gene fusion
PROPHYLOCHIP-PRODIGE-15 were conducted in high- ATM mutation
PIK3CA mutation
risk recurrent patients.117–119 PRODIGE-7 suggested there POLE mutation
might be a potential role for cytoreductive surgery but no RET or ALK fusions
No genomic alterations
role for HIPEC in patients with stage IV disease.
Unfortunately, COLOPEC and PROPHYLOCHIP did not
show any benefit for HIPEC in patients with high-risk
stage III disease. Current treatment recommendations
are systemic chemotherapy with shared decision making
involving multidisciplinary management and the
consideration of cytoreductive surgery in select cases; the
role of HIPEC remains investigational.102,113,120
Figure 3: Clinical actionability (A) and distribution (B) of genomic alterations in mCRC
Progression or intolerance after first-line therapy Boxes represent prevalence in 100 patients. For example, RAS mutation makes up approximately 43% of
mutations, of which 4% are KRAS Gly12Cys mutation. dMMR=deficient mismatch repair. ESCAT=ESMO Scale of
Following first-line chemotherapy, if there is evidence of Clinical Actionability for molecular Targets. *Savolitinib for MET amplification. †Crizotinib for MET fusions.
progression or intolerance of therapy, normal laboratory ‡Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, trastuzumab–deruxtecan, or trastuzumab plus
values, and adequate Eastern Cooperative Oncology Group tucatinib. §Selpercatinib for RET fusions. ¶ALK inhibitors for ALK fusions.
performance status, consideration of second-line therapy is
initiated. Commonly, the alternate regimen is then provided on local regulatory approvals (figure 3).126–128 For NTRK
(oxaliplatin-based therapy will transition to irinotecan-based rearranged tumours (<0·5%), larotrectinib and
therapy and vice versa). The choice of the treatment is entrectinib received agnostic approval both in Europe,
mainly driven by the patients’ comorbidities, previous Japan, and the USA.129,130 Patients with BRAFV600E mutated
treatment outcome and tolerance, and RAS mutational tumours (<10%) are recommended to receive the
status. As a general principle, switching to the alternate BRAFV600E inhibitor encorafenib with cetuximab after
doublet chemo­therapy is common, but the reintroduction receiving at least one line of therapy, showing improved
of the same chemotherapy backbone is reasonable if there OS over conventional treatment.131 Several phase 2 trials
is previous prolonged PFS or chemotherapy-free interval.121 have investigated anti-HER2 strategies (trastuzumab plus
Continuation of anti-vascular growth factor agents lapatinib, pertuzumab, or tucatinib, trastuzumab–
(bevacizumab, aflibercept, and ramucirumab) is associated deruxtecan) in previously treated mCRC HER2-positive
with improved OS,122–124 whereas the continuation of anti- (3–5%) tumours.132–134 The MOUNTAINEER trial evaluated
EGFR agents did not improve OS.125 the combination of tucatinib and trastuzumab in
HER2-positive refractory mCRC with a response rate of
Advanced lines of treatment: precision oncology 38·1% (95% CI 27·7–49·3), progression-free survival of
mCRC is now fragmented in several molecular entities 8·2 months, and overall surival of 24·1 months.134 The
with potentially actionable targeted options varying based benefit of therapy was in the HER2 equivocal

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immunohistochemical or fluorescence in situ recommended at 1 year, then every 3–5 years after surgery.
hybridisation or HER2-positive immunohistochemical Chest-abdominal and pelvic CT scans is recommended
tumour types. Tucatinib is the first FDA-approved drug every 6–12 months for 5 years. Monitoring with PET-CT is
anti-HER2 regimen in refractory mCRC. The not recommended.33,148 For patients with stage IV disease
MOUNTAINEER-3 trial (NCT05253651) is an ongoing who have undergone metastatic resection, close
frontline trial of FOLFOX with or without tucatinib plus surveillance is recommended with sequential diagnostic
trastuzumab. The KRAS Gly12Cys mutation is rare (5%) imaging due to the high risk of recurrence.
with promising data when combined with anti-EGFR
therapy.135 Codebreak 300 (NCT05198934) randomly Outstanding research questions
assigned mCRC patients to two different doses of Role for circulating tumour DNA
sotorasib plus panitumumab or the treating physician’s The value of diagnostic circulating tumour DNA (ctDNA)
choice of trifluridine–tipiracil or regorafenib.136 The analysis remains uncertain. Technologies such as plasma-
investigators fulfilled their primary endpoint of PFS of based assays of ctDNA are being developed with the goal of
5·6 months (960 mg; 95% CI 4·2–6·3) and 3·9 months detecting multiple types of cancers. However, these tests
(240 mg; 3·7–5·8) versus the control group of 2·2 months. are pending validation and are not currently recommended
The phase 3 trial KRYSTAL-10 (NCT04793958) is ongoing, for cancer screening.150 The potential role of ctDNA for
which is evaluating the combination of the KRAS minimal residual disease was originally noted following
Gly12Cys inhibitor, MRTX849, and cetuximab with co- surgical resection in patients with stage II colon cancer and
primary endpoints of OS and PFS. correlated with minimal residual disease and likelihood of
For chemorefractory patients not bearing any targetable recurrent disease.151 The Australian phase 3 DYNAMIC trial
molecular alteration, trifluridine–tipiracil, fruquintinib, indicated that a postoperative ctDNA-guided approach to
and regorafenib have been shown to improve OS.137–144 In stage II colon cancer reduced the use of adjuvant
combination, trifluridine–tipiracil and bevacizumab has chemotherapy without compromising recurrence-free
been determined to be superior for OS versus trifluridine– survival.152 Ongoing prospective phase 3 clinical trials are
tipiracil alone, resulting in its new FDA and European underway internationally, including CIRCULATE-US
Medicines Agency indication.140 The highly selective oral (NCT05174169), CIRCULATE-Japan (consisting of three
VEGFR-1, VEGFR-2, and VEGFR-3 inhibitor, fruquintinib, clinical trails: GALAXY, ALTER, and VEGA), and
showed OS benefit over placebo in two phase 3 randomised DYNAMIC III (ACTRN12617001566325). These trials aim
trials (FRESCO and FRESCO2).143,144 FRESCO2 fulfilled the to clarify clinical outcomes by reducing or intensifying
primary endpoint of OS independent of previous exposure therapy on the basis of minimal residual disease.153,154
to regorafenib or trifluridine–tipiracil, or both (HR 0·662, To monitor the emergence of acquired mutations,
95% CI 0·549–0·800), as well as the secondary endpoint of randomised interventional studies are required to assess
PFS (HR 0·321, 95% CI 0·267–0·386).144 Fruquintinib whether dynamic changes in treatment based on ctDNA
subsequently received FDA approval. Pembrolizumab is assessment can improve outcomes to a change in the
agnostically approved in the USA and Japan for patients subsequent therapy or the intensification of therapy.155
with tumours, with tumour mutational burden of more
than ten mutations per DNA megabase, although the Screening asymptomatic populations
benefit is limited in microsatellite-stable and tumour Studies show high specificity and encouraging sensitivity
mutational burden-high mCRC.145 findings with error-corrected sequencing, which might be
combined with protein biomarkers, genome-wide
Surveillance fragmen­ ta­tion patterns, and methylation-based ctDNA
Patients with localised colorectal cancer, following assays.156–159 Large studies are ongoing, with results
curative surgery and adjuvant chemotherapy, are under pending.
close surveillance for 5 years since it is expected that
30–50% of patients will relapse, most occurring within Other points of discussion
this timeframe.146 It should be noted surveillance EGFR rechallenge
guidelines might vary by medical society, region, or Rechallenging with anti-EGFR monoclonal antibodies
country. Below is a general overview of the National has shown promising initial outcomes in patients with
Comprehensive Cancer Network, the European Society wild-type RAS in small non-randomised studies.160–162
for Medical Oncology, and pan-Asian guidelines with However, secondary resistant genomic alterations such
some slight variability.147–149 as EGFR extracellular domain, BRAF gene, and
For patients with stage I disease, a colonoscopy is amplification of ERBB2, RAS, or MET are also
recommended at years 1, 3, and 5 after surgery. For associated with efficacy outcomes; therefore, refinement
patients with stage II or III disease, clinical assessment of eligible patients who are more likely to benefit from
and review of blood carcinoembryonic antigen levels are EGFR rechallenge using multiple genotypes is
recommended at baseline and every 3–6 months for required.163,164 Further investigation is warranted to
2–3 years, then biannually until 5 years. Colonoscopy is determine the optimal timing of molecular testing by

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ctDNA assays in this patient population. Several studies surgery alone.186 The investigators reported improved
are ongoing.165,166 DFS, but no statistical benefit in OS.187 Similarly,
JCOG0603 was a randomised phase 2/3 trial that allowed
Microbiome unlimited hepatic metastases and noted improved DFS
Abundant evidence links the gut microbiome to colorectal with adjuvant mFOLFOX6 following hepatic resection
cancer development.167 Gut microbes interact with the versus hepatic resection alone, but no difference in OS.188
host immune system and influence anti-tumour immune Therefore, the role of neoadjuvant and adjuvant
responses. Patients with colorectal cancer have reduced chemotherapy following liver resection remains a matter
bacterial diversity compared with healthy individuals, of discussion between the provider and patient.
and studies indicate that Firmicutes, Bacteroidetes, Resurgence for the role of hepatic arterial infusion for
enterotoxigenic Bacteroides fragilis, and the oral anaerobe colorectal cancer liver metastases has been generated.
Fusobacterium nucleatum are enriched in colorectal Earlier data were criticised for largely being retrospective.
cancer.168,169 However, there is no clear understanding The role of hepatic arterial infusion is currently being
regarding the function of each bacterial strain, its investigated in newly diagnosed patients (PUMP;
mechanism of action in anti-tumour immunity, and the EA2222; NCT05863195). ERASur is a phase 3 trial
therapeutic effect on cancer treatment. Encouraging data evaluating the role of systemic chemotherapy with and
have been reported on the role of faecal microbiome without stereotactic radiation therapy, ablation, and
transplant (FMT) in patients with melanoma for surgery for the primary endpoint of OS rate
overcoming drug resistance.170 However, a broader role (NCT05673148). Similarly, a concept of neoadjuvant
for FMT is unknown. FMT is being explored in patients systemic therapy followed by repeat local liver directed
with MSI-H or dMMR mCRC initially resistant to anti- therapy is being investigated for OS versus upfront liver
PD-1 therapy (NCT04729322). directed therapy (Collision Relapse; NCT05861505).
Liver transplantation is an aggressive treatment for
EOCRC patients with colorectal cancer with liver metastases. Three
Although it is presumed patients with EOCRC are decades ago, the European Liver Transplant Registry
more likely to have a hereditary syndrome, the majority reported a summary that showed 1-year and 5-year OS
of EOCRC are sporadic with no obvious cause. rates of 62% and 18%, respectively. Systemic therapy for
Approximately 30% are related to family history but the mCRC was not adequately effective during this period,
exact cause of EOCRC is unknown.171–175 Earlier analyses making liver transplantation unfeasible. Over the past
show EOCRC is characterised by different clinico­ two decades, the efficacy of systemic therapy for mCRC
pathological features compared with average-onset CRC, has substantially improved, and the outcomes of liver
but others note no difference in molecular alterations;176–178 transplantation for colorectal cancer with liver metastases
microbiome work is ongoing.179 The prognosis of EOCRC have also increased. The NORDIC group conducted a
is controversial; some studies suggest favourable OS, single-arm prospective clinical trial with revised selection
whereas others suggest reduced OS.180 criteria. They reported that the 2-year DFS was 44% in the
SECA II study.189,190 These results indicate that liver
Artificial intelligence transplantation could have a promising role, although
There is burgeoning interest in the use of artificial additional validation is warranted. Several randomised
intelligence (AI) and its effect on cancer care. trials (NCT01479608, NCT0259734, and NCT03494946) are
Computational data integration and synthesis might ongoing. These trials are trying to determine whether
predict the response to systemic therapy and patient there is any benefit to having liver transplantation for OS.
prognosis.181,182 AI might also be used at the molecular Large-scale prospective randomised controlled trials with
level, for example in genomics, proteomics, meta­ long-term follow-up is necessary to elucidate the
bolomics, and transcriptomics. AI is currently being used effectiveness of such an approach for OS.
for colorectal cancer screening and to improve detection
of adenomas.183 Caution is still warranted since data Conclusion
consistency and interpretation continues to be refined.184 Colorectal cancer remains a common malignancy globally.
There are approximately 50 FDA-approved AI-associated Prevention through screening techniques is crucial to
or AI-associable equipped medical devices for clinical reducing its incidence, especially in developing countries,
oncology.185 where the highest incidence rates are expected to occur.
Colorectal cancer screening techniques are further
Controversies and uncertainties: addressing liver complicated by a lack of uniform international guidelines.
metastasis Colorectal cancer screening reduces associated morbidity
EORTC 40983 was a phase 3 randomised trial in and would decrease mortality if a sufficient fraction of
resectable colorectal liver metastases designed to individuals were screened appropriately. Of the growing
evaluate the role of perioperative FOLFOX4 for six cycles concern is the unknown cause of EOCRC due to the rising
before surgery followed by adjuvant therapy versus incidence in young patients.

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The field of colorectal cancer is evolving, and not just in 14 Cai S, Li Y, Ding Y, Chen K, Jin M. Alcohol drinking and the risk of
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