10/16/22, 8:16 AM Colon Cancer - StatPearls - NCBI Bookshelf

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Colon Cancer
Saran Lotfollahzadeh; Alejandro Recio-Boiles; Burt Cagir.

Author Information
Last Update: July 10, 2022.

Continuing Education Activity

Colorectal cancer (CRC) is the third most common diagnosis and second deadliest malignancy
for both sexes combined. The incidence of new cases and mortality has been steadily declining
for the past years, except for younger adults (younger than 50 years), possibly related to an
increase in cancer screening and better therapy modalities. This activity outlines the etiology,
epidemiology, clinical staging and stage-wise treatment of colon cancer.

Objectives:

Describe the pathophysiology of colon cancer.

Outline the clinical presentation of colon cancer.

Identify the favorable and unfavorable risk factors for upfront surgical resection, post-
surgical adjuvant therapy, and biomarker expression driven therapeutic decision-making.

Discuss the role of early involvement of an interprofessional team including clinicians,

nutritionists and dieticians, palliative service, social workers and case managers in helping
improve the quality of life for patients diagnosed with colon cancer.

Access free multiple choice questions on this topic.

Introduction
Colorectal cancer (CRC) is the third most common diagnosis and second deadliest malignancy
for both sexes combined. CRC has both strong environmental associations and genetic risk
factors. The incidence of new cases and mortality has been steadily declining for the past years,
except for younger adults (younger than 50 years), possibly related to an increase in cancer
screening and better therapy modalities. Approximately 5% of all CRC are attributed to two
inherited syndromes, Familial Adenomatous Polyposis, and Lynch syndrome. The change of the
normal colonic epithelium to a precancerous lesion and ultimately an invasive carcinoma
requires an accumulation of genetic mutations either somatic (acquired) and/or germline
(inherited) in an approximately 10 to 15-year period. [1][2][3]Chromosomal instability,
mismatch repair, and CpG hypermethylation are the major pathways to CRC. The most important
prognostic colon cancer indicator is the pathological stage at presentation. All new CRC cases
should be universally screen for DNA mismatch repair/microsatellite status, and RAS/BRAF
mutational testing when considering for prognostic and predictive of chemotherapy efficacy. In
almost all patients, a diagnostic or screening colonoscopy is required for tissue biopsy
pathological confirmation of colon carcinoma. Baseline computed tomography (CT) of the chest,
abdomen, and pelvis with contrast and carcinoembryonic antigen (CEA) are the preferred cost-
effective, colon-cancer staging studies done before surgical resection. Surgical resection is the
main treatment modality for localized early-stage colon cancer. Adjuvant therapy could augment
the chance of cure on high-risk patients with colon cancer. Oligo-metastatic, liver and lung, and
local-recurrence patients with colon cancer are potential curable candidates with multimodality
therapies. Palliative systemic therapy is reserved for non-surgical colon cancer candidates aiming
to improve quality of life and prolong life expectancy.[4][5][6]

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Etiology
Colon cancer (Cca) could present as sporadic (70%), familial clustering (20%) and inherited
syndromes (10%). Sporadic Cca average age diagnosis is older than 50 years and mostly linked
to environmental factors, different from a minority of patients with a true inherited pattern that
carries a higher risk at a younger age (younger than 50 years), and the remaining 20% are
familial clustering in the absence of identifiable inherited syndrome. The most common inherited
CRC syndromes are familial adenomatous polyposis (FAP) and Lynch syndrome (hereditary
non-polyposis colorectal cancer [HNPCC]). [7][8]Approximately 5% of all CRC cancers are
attributed to these two inherited syndromes, but as many as 10% to 15% of unselected CRC
patients will carry high-risk mutation not related to FAP or HNPCC.

Personal or family history of CRC, adenomatous polyps and polyps with villous or tubulovillous
dysplasia indicate a high risk for synchronous and metachronous CRC primary cancer up to 3%
to 5% at 5 years or even longer after resection requiring a closer screening interval. Inflammatory
bowel disease (IBD), mainly ulcerative colitis, has a well-known association with Cca, with an
estimated incidence 0.5% per year between 10 and 20 years after the time of IBD diagnosis and
1% per year after that reaching a 30% risk probability by the fourth decade of patients with
pancolitis. Crohn's disease may increase Cca risk, particularly if present in the ileocolic region.

Childhood cancer survivors who received abdominal radiation (greater than 30 Gy) are at risk of
CRC, and screening is recommended 10 years later or at age 35. Other illnesses that increase the
risk higher of CRC are diabetes mellitus/insulin resistance, uncontrolled acromegaly disease, and
long-term immunosuppressed renal transplant.

Epidemiologic study results indicate strong environmental and lifestyle associations for CRC.
Modest weak increased CRC risks are seen with obesity, red/processed meat, tobacco, alcohol,
androgen deprivation therapy, and cholecystectomy among others. On the other hand, large
population studies with variable strength evidence have found CRC protective factors such as
physical activity, diet (fruits and vegetables, fiber, resistant starch, fish), vitamin supplements
(folate, folic acid, pyridoxine B6, calcium, vitamin D, magnesium), garlic and coffee, and drugs
[aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), hormonal replacement therapy in
postmenopausal, statins, bisphosphonate and angiotensin inhibitors].

Interestingly, a randomized controlled clinical trial found that 600 mg of aspirin in Lynch
syndrome had a protective effect against colorectal adenomas and cancer with substantially
reduced cancer incidence after 55.7 months with an HR of 0.56 [95% confidence interval (CI);
0.32, 0.99; p = 0.05].

Epidemiology
CRC affects approximately 135,439 estimated new patients with a corresponding 95,520 (70%)
due to Cca in the United States every year. Among all cancers sites, it is the second leading cause
of death in the United States, with an estimated 50,260 deaths, when colon and rectum are
combined. The CRC incidence rate has been declining 3% per year since 2004 although
increasing by 2% per year among screened young adults (younger than 50 years). [9][10][11]The
prior reflects an uptake on screening patterns and removal of precancerous lesions. CRC
incidence varies worldwide with higher rates in developed countries than in unindustrialized
countries. Low socioeconomic status has an increased risk of CRC associated with poor risk
behavior and access to medical care. White American lifetime average incidence of CRC is 5%
but is higher in men (greater than 20%) than in woman and African Americans (greater than
25%) than non-Hispanic whites. Findings from epidemiologic studies indicate a gradual
anatomic distribution of Cca, shifting from the left-distal colon toward the right sided or
proximal end, once more related to more effective left-sided screening modalities. From 1975 to
2014, there has been a 51% decrease in the mortality of CRC in the United States, attributed to

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early detection and improvement of treatment modalities. National Cancer Institute estimates that
65% of all treated patients for Cca will be alive at the 5-year mark.

Pathophysiology
The transformation of the normal colonic epithelium to a precancerous lesion (adenoma) and
ultimately to invasive carcinoma requires an accumulation of genetic mutations either somatic
(acquired) and/or germline (inherited). The theory of colonic carcinogenesis features a clonal
mutation evolution that gives a cell survival-immortality advantage and allows to develop more
mutations providing other cancer hallmarks as proliferation, invasion, metastasis, and others.[12]
[13] Clinical evidence has shown that CRCs frequently arise from adenomatous polyps that
typically acquire dysplastic changes in a 10 to 15-year period before developing invasive
carcinoma, and the early detection-removal of polyps will reduce the incidence of CRC. New
evidence has exposed that hamartomatous and serrated polyps could lead to CRC. There are
three major molecular pathways linked to CRC, chromosomal instability, mismatch repair, and
hypermethylation. The chromosomal instability pathway is a gain of mutations unbalancing
oncogene and tumor suppressors equilibrium as seen with mutations in the adenomatous
polyposis coli (APC), a hallmark of FAP. Cells with deficiency of DNA mismatch repair
(dMMR), commonly MLH1 or MSH2, accumulate errors within the genome that further will be
repeated causing high levels of microsatellite instability (MSI-H), a hallmark of Lynch
syndrome. CpG hypermethylation of DNA could activate or silence the expression of certain
genes, BRAF and MLH1 respectively. Sporadic oncogenes somatic mutations (RAS, SRC, MYC)
have been implicated in CRC, being RAS the most clinical relevance. RAS mutations variants
(HRAS, KRAS, NRAS) are found in 50% of CRC sporadic cases, currently being exploited on
CRC screening by stool-DNA testing, the absence of epidermal growth factor receptors (EGFR)
targeted therapy response and potential direct targeted agents. In the other hand, tumor
suppressors genes require bi-allelic loss (“two-hit model”) and are described in loss of APC 5q21
gene (80% sporadic), TP53 17p gene (50-70% sporadic), and DCC/SMAD2-4 18q gene (73%
sporadic). Specific MMR gene mutations could occur in hMSH2, hMLH1, hPMS1 and hPMS2,
hMSH6, and hMLH3; each one of them that interact with MLH1 and approximately found in
15% of all sporadic CRC causing a Lynch-like syndrome with MSI-H calling for universal
testing. MUTYH defects have a recessive inheritance pattern at a time requiring bi-allelic second
hit or in conjunction with APC gene mutation. Cyclooxygenase (COX-2) and peroxisome
proliferator–activating receptor (PPAR) genes have been implicated in CRC tumorigenesis
currently under investigation for chemo-protection.

Histopathology
The majority of all CRC are carcinomas, and more than 90% of those are adenocarcinomas and
others not frequently seen (adenosquamous, spindle, squamous and undifferentiated). CRC
adenocarcinoma can be further differentiated in cribriform comedo-type, medullary,
micropapillary, serrated, mucinous and signet-ring cell. Adenocarcinomas are categorized by the
percentage of gland formation into well (more than 95%), moderately (more than 50%) and
poorly (less than 49%) differentiated, but further divided in two-tier low-grade (well-
moderate)/high-grade (poor) with prognostic significance. Mucinous or signet ring cells
classification describe that more than half of the stain cells posses that particular characteristic.
Differential clinicopathological diagnosis is neuroendocrine, hamartomas, mesenchymal, and
lymphomas. Cytokeratin 20 (CK20) and caudal-type homeobox 2 (CDX2)
immunohistochemistry (IHC) can accurately identify CRC adenocarcinoma origin, except
medullary carcinoma with MSI-H expressing other markers such calretinin, CK7, SABT2, and
CDH17.

The tumor, node, metastasis (TNM) staging system of the American Joint Committee
on Cancer/Union for International Cancer Control (AJCC/UICC) 2017 is the preferred staging

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system for CRC. Worth noticing, peritoneal carcinomatosis (M1c) and nodal micrometastases
(cluster greater than 0.2 mm) are included as poor prognostic factors. Other prognostic indicators
that the classification continues to exclude are extramural deposits, lymphovascular invasion
(LVI), perineural invasion (PNI), poor histological grade, diagnostic serum CEA, MSI-H and
RAS/BRAF mutation status. The most important prognostic indicator is the pathological stage at
presentation supported by data from the SEER observed overall survival (OS) at 5-years rates for
colon in stage I includes 74%; stage IIA, 66%; stage IIB, 58%; stage IIC, 37%; stage IIIA, 73%;
stage IIIB, 46%; stage IIIC, 28%; and stage IV, 5%.

Complete surgical resection (R0) with all negative circumferential resection margins (CRM) is
an important goal to avoid local-distant recurrence (38% CRM+ versus 10% CRM-) and
furthermore increase survival. Lymph node involvement is the strongest outcome predictor and
the total number resected directly influence prognosis on Stage II (node-negative) and Stage III
(node-positive) disease. The current guideline recommends a minimum of 12 nodes surgical
resection. Lymph node ratio from the INT-0089 trial showed a 5-year overall survival (OS) of
80% with less than 0.05 LNR versus 50% more than 0.4 ratio. LVI, PNI, poor histological grade,
T4, bowel perforation and insufficient node sampling (<12) are consider a high-risk feature of
stage II Cca according to the American Society of Clinical Oncology (ASCO), National
Comprehensive Cancer Network (NCCN), and European Society for Medical Oncology
(ESMO), supporting the use of adjuvant chemotherapy.

The NCCN and the College of American Pathologists among other associations recommend
universal MMR/MSI status (15% to 20% sporadic CRC), BRAF p.V600 E (less than 10%
sporadic CRC) and RAS mutational (12% to 75% sporadic CRC) testing for prognostic and
predictive of chemotherapy efficacy. hMLH1 and hMSH2 IHC provides a high sensitive
(92.3%), and specific (100%) method, and positive (96.7%)/negative (100%) predictive value
method for screening for MMR/MSI status. MSI-H is synonymous with dMMR, and MSI-Stable
will refer to proficient MMR state. The prevalence of MSI-H in CRC is about 15% in stage II,
8% in stage III, and 4% to 5% in stage IV. BRAF gene mutation testing is indicated after a
negative MLH1 IHC indicating MLH1 gene down-regulation through somatic methylation.

Recently, six independent classification systems coalesced into four consensus molecular
subtypes (CMSs) with distinguishing features:

CMS1 (MSI- immune, 14%), hypermutated burden, dMMR, microsatellite unstable and
strong immune activation

CMS2 (canonical, 37%), high chromosomal instability, epithelial, marked WNT and MYC
signaling activation

CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation, KRAS mutation

CMS4 (mesenchymal, 23%), CpG hypermethylation, prominent transforming growth

factor-beta activation, stromal invasion and angiogenesis.

CMSs classification had a prognostic value, CMS1 good, CMS4 poor and CMS2/3 intermediate.

History and Physical

Most all CRC will present by diagnostic colonoscopy for suspicious signs and symptoms (80%),
asymptomatic, routine screening (11%), or incidental finding at an acute abdomen emergent
admission (7%). Patients diagnosed with routine cancer screening are frequently earlier stage
compared to advanced disease of incidental surgical findings. Diagnostic colonoscopy’s triggers
are blood per rectum (37%), abdominal pain (34%) and anemia (23%). Most common indications
of emergency surgery are an obstruction (57%), peritonitis (25%) and perforation (18%). Tumor
location on clinical presentation can be separated on left-sided with more changes in bowel
habits and hematochezia, and right-sided with obscured anemia impacting on late stage at
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diagnosis. Late presentation with metastatic disease at diagnosis will depend on the symptoms at
the organ-affected by the route of spread; to the liver via the portal system, to lungs via the
inferior vena cava, to supraclavicular adenopathy via lymphatic or to neighbor structures by
contiguous invasion. The provider should perform a thorough physical examination for signs of
ascites, hepatomegaly, and lymphadenopathy. A comprehensive family history is of great
relevance to identify familial clusters and inherent patterns that would alter surveillance and
therapy on the high-risk patient.

Evaluation
Initial evaluation may involve barium enema or CT colonography, but ultimately a colonoscopy
is required for tissue biopsy.[14][15][16] Colonoscopy sensitivity is about 94.7% (95% CI 90%
to 97%) and may miss from 2% to 6% of cases, mostly right-sided, pending on preparation
quality and hands experience. Flexible sigmoidoscopy is no replacement for a complete
diagnostic colonoscopy, still is a screening modality that reduces CRC mortality. The Federal
Drug Administration (FDA) has approved PILLCAM 2 for those non-obstructed patients with
incomplete colonoscopy, and not for routine screening. CRC screening modalities and
recommendations for average or high-risk patients are discussed in a different StatPearls chapter.
Routine laboratory workup with complete blood count, iron studies, basic metabolic panel, liver
function test and coagulation tests are not diagnostic but often useful. CEA greater than 5 ng/mL
has a poor prognostic value when present, but lacks diagnostic sensitivity 46% (95% CI 0.45 to
0.47) and has limited specificity 89% (95% CI 0.88 to 0.92). Pre-operative CEA is indicated on
all newly diagnosed Cca, normalization after surgical resection is expected and serial assays to
be monitored on follow up visits.

Baseline CT of the chest, abdomen, and pelvis with IV and oral contrast is the preferred cost-
effective staging imaging study before Cca surgical resection. CT abdomen and pelvis provides a
moderate strength initial assessment of accurately staging T (50%) and N (73%) but rather
provide immediate higher sensitivity for distant metastasis (87%). CT chest remains
controversial, as 9% will show indeterminate lesions, of that 11% represented metastatic lesions.
MRI and CT triple phase imaging have improved the detection of liver metastasis. Positron
emission tomography (PET) is not routinely indicated on the preoperative staging of Cca. Biopsy
of the suspicious metastatic site should be performed to confirm the diagnosis.

Treatment / Management
Surgical resection is the main treatment modality for localized non-metastatic stage Cca at any
age with acceptable performance status and optimized comorbidities. Endoscopic resection (ER)
is reserved for selected favorable-risk and early-stage colon carcinomas found in a polyp (cT0-1).
Neoadjuvant therapy is not standard of care for Cca and reserved for advanced disease surgical
conversion intend. Adjuvant therapy is recommended for all Cca stage III (node-positive) and
individualized by stage II with high-risk features. Surgery in conjunction with peri-chemotherapy
may provide a curative option on oligo-metastatic lung and liver disease. [17][18][6]Palliative
systemic chemotherapy is offered to non-surgical candidates with unresectable locally advanced
disease or high metastatic burden to improved quality of life and prolongs life expectancy.
Individualized local-recurrent disease patients may achieve cure with further multimodality
therapy. Rectal cancer treatment modalities are discussed in a different StatPearls chapter.

Endoscopic Resection

Local excisions by endoscopy should achieve complete tumor resection and adjacent tissue in
one block. ER is reserved for patients agreeable to a close, aggressive surveillance afterward, a
surgical resection for high-risk disease and/or non-surgical candidates. ER procedures are to be
an offer by an experienced physician at the center of excellence. Invasion of muscularis propia
(T2), poor histological grade, LVI, PNI, at the stalk or flat/depressed sessile polyp are considered

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ER, Cca, high-risk features and further need surgical resection. Cca polyp techniques include
endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) with high
success rate 90.3% (95% CI 88.2% to 92.5%) and a low recurrence 13.8% (95% CI 12.9% to
14.7%), being an invasive cancer in 0.3% (95% CI 0.1% to 0.4%) on favorable risk patients.
Major complications are perforation and bleeding with 6.5% and 1.5% respectively and
extremely low-mortality 0.8% (95% CI 0.01% to 0.15%). Regardless of the procedure, all lesions
should be tattooed to allow site identification on further required steps.

Surgical Resection

The main goal for invasive Cca is the complete resection of the tumor and potential
lymphovascular spread by a goal of a minimal negative proximal and distal margin of 5 cm for
colon cancer, and minimal proximal margin of 5 cm and distal of 2 cm for rectal carcinoma.
Circumferential/radial margin should be greater than 1 mm. The essentials of oncologic resection
involve central vascular ligation of the feeding main artery and complete mesocolic resection of
the involved colonic section. Oncologic resection requires removal of 12 or more lymph nodes.
The initial step for colectomy is accessing the retroperitoneum and elevating the mesentery of the
colon contained within the fascia of Toltd. In laparoscopic procedures, this dissection is started
medial to lateral fashion, but in open procedures, this dissection is done lateral to medial way. A
secondary aim is the restoration of the bowel continuity, either by one-stage primary anastomosis
or two-stage approach with temporary diversion. Conventional open colectomy or laparoscopic
colectomy is the preferred surgical modality. High-volume, experienced surgeons should perform
the laparoscopic approach. Experience with robotic surgery is under further investigation.
Potential palliative surgical procedures for unresectable Cca tumors include resection with
primary anastomosis, diverting colostomy, and internal bypass procedures.

Tumors of the appendix, cecum, ascending colon, and hepatic flexure requires right colectomy
with ligation of the right colic artery at its origin. The right branch of the middle colic artery and
ileocolic artery are also ligated. This procedure is completed with ill -mid-transverse colon
anastomosis. Transverse colon cancers require extended right colectomy due to the ease of the
procedure when compared to extended left colectomy. Extended right colectomy also involves
the ligation of the middle colic artery at its origin in addition to steps involving right colectomy.
This procedure is completed with ileac-descending colon anastomosis.

Patients with a distal transverse colon, splenic flexure, and descending colon cancers require left
colectomy. This procedure involves the ligation of the inferior mesenteric artery at its origin, as
well as ligation of the inferior mesenteric vein at the inferior border of the pancreas. The left
branch of the middle colic artery is also ligated. This procedure if completed with transverse
colon sigmoid or rectal anastomosis. Patients with sigmoid colon cancers undergo extended left
colectomy with colorectal anastomosis.

Patients with synchronous colon cancers (two or more foci) involving the intra-abdominal colon,
with distal malignant distal colonic obstruction, with Lynch (HNPCC), and with attenuated FAP
should undergo total abdominal colectomy; including cecum, ascending, transverse, descending
and sigmoid colons. Therefore this procedure involves ligation of ileocolic, right and middle
colic, and inferior mesenteric arteries. This procedure is completed with ileorectal anastomosis.

Meta-analysis of randomized clinical trials (including COLOR trial, CLASSIC trial, and COST
trial) indicates that laparoscopic-assisted colectomy surgery for Cca provides the same outcomes
for 5-year overall survival (OS) (69% versus 68%) and disease-free survival (DFS) (76% versus
75%) as open laparotomy. Reported conversion rates from laparoscopic to open remains at 20%
as described in the United States Intergroup Clinical Outcomes of Surgical Therapy (COST) trial.
Positive margins have been retrospectively found in 5.3% of Cca resection with a worse OS
(hazard ratio [HR] 3.39, 95% CI 2.41 to 4.77). Sentinel lymph node biopsy is not considered a
standard of care and consensus guidelines recommend 12 lymph nodes or more with improved 5-
year OS at 90% regardless open or laparoscopic approach. Locoregional recurrence can occur up
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to 12% of Cca resection and is classified into four categories: anastomotic; mesenteric/nodal;
retroperitoneal; and peritoneal. Poor prognostic factors include more than one site of recurrence
and involvement of the mesentery/nodal basin whereas the ability to obtain an R0 resection was
the strongest predictor of outcome, and these patients had a median survival of 66 months.[19]

Surgery alone can be curative for patients with stage I disease. For stage III disease (node-
positive), the 5-year survival rate is 20% to 50% with surgical resection alone thus adjuvant
therapy is recommended. For patients with stage II disease, the 5-year survival fluctuates
between 50% and 65%. Factors other than the stage adversely affect the outcome. These include
old age, male gender, performances status, pMMR/MSI-S status, LVI, PNI, pre-operative CEA
level greater than 5, poor histological grade, mucinous or signet ring features, the extent of local
invasion T4, bowel perforation/obstruction, and insufficient node sampling less than 12.
Mutations in KRAS and BRAF have not shown to be a negative prognostic impact in the adjuvant
setting. Adjuvant therapy for stage II with high-risk features should be individualized.[20][2][3]
[21][22]

Adjuvant Therapy

There is no role for adjuvant chemotherapy for patients with Cca stage I. Low-risk stage II Cca
patients can opt for surveillance without adjuvant therapy, individualized discussion with medical
oncology or enrolled in a clinical trial. Current ASCO, NCCN and ESMO guidelines strongly
recommend adjuvant therapy for selected stage II with high-risk/pMMR/MSI-S disease and all
stage III (node-positive). For adjuvant therapy Cca, 3-year DFS is an acceptable surrogate
marker for 5-year OS recognized by the FDA based on the results of the Adjuvant Colon Cancer
End Points study group (ACCENT trial). Guides advocate delivering adjuvant chemotherapy
within 6 to 8 weeks of surgical resection pending on patient health recovery. A meta-analysis
demonstrated that a 4-week beyond the time to adjuvant chemotherapy was associated with a
significant decrease in both overall survivals (HR, 1.14; 95% CI, 1.10-1.17) and disease-free
survival (HR, 1.14; 95% CI, 1.10-1.18). An oxaliplatin-based combination is preferred over
monotherapy either by FU/LV (MOSAIC trial, NSABP C-07 trial) or capecitabine (XELOXA
trial). The standard recommended length of adjuvant therapy is six months and a potentially non-
inferiority three months is under current investigation by the International Duration Evaluation of
Adjuvant Chemotherapy (IDEA) trial for low-risk patients or oxaliplatin dose-limiting
neurotoxicity. The recommendation is to use full weight-based chemotherapy dosing particularly
on those with the intention to cure.[23][24][25]

Adjuvant fluorouracil-based chemotherapy became a standard of care in stage III Cca in the early
1990s by the first randomized clinical trial, the National Surgical Adjuvant Breast and Bowel
Project (NSABP) C-01, to achieve a significant improvement in DFS and OS. Evidence from a
subsequent NSABP C-03 trial demonstrated that fluorouracil (5-FU) combined with leucovorin
(LV) provided a superior DFS and OS at three years with six months of adjuvant therapy over
NSABP C-01 lomustine, vincristine, and 5-FU. For more than a decade, 5-FU/LV remained the
standard in adjuvant therapy until oxaliplatin, irinotecan, and capecitabine (oral FU pro-drug)
based combinations were utilized for the treatment of advanced CRC.

Oxaliplatin was approved as part of adjuvant treatment for stage III Cca after the 2004 MOSAIC
trial. Investigators randomly assigned patients who had undergone curative colon resection for
stage II (40%) or III (60%) to receive FU/LV alone (LV 200 mg/m as a 2-hour infusion, followed
by bolus FU 400 mg/m, and then a 22-hour infusion of FU 600 mg/m, every 2 weeks) or with
oxaliplatin (FU/LV plus 85 mg/m day 1 every 14 days, a regimen termed FOLFOX4) for 6
months. Adding oxaliplatin (FOLFOX4) significantly improved 5-year DFS rates to 73.3%
versus 67.4% FU/LV group, [(HR)= 0.80; 95% CI, 0.68 to 0.93; P = .003] and 6-year OS rates
were 78.5% and 76.0% in the FOLFOX4 and FU/LV groups, respectively (HR = 0.84; 95% CI,
0.71 to 1.00; P = .046). Stratified, 6-year OS rates for patients with stage III disease were 72.9%
and 68.7%, respectively (HR = 0.80; 95% CI, 0.65 to 0.97; P = .023) but no significant

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difference in OS was seen in the stage II population. A 10-year OS long-term follow up results
corroborated before mentioned trend results. Neuropathy was seen 92% of FOLFOX4 patients,
being 13% severe grade and almost all reversible. The United States oncologists had made
further modifications to the regimen including FOLFOX6 (single day regimen) and FOLFOX7
(no FU bolus). In a retrospective review of unselected patients with stage II disease, the 5-year
DFS benefit for FOLFOX compared with FU/LV alone was no statistically significant (84%
versus 80%, HR for recurrence 0.84, p = 0.26), but it significantly exceeded 5% for patients
(82% versus 77%) on stage II tumors with high-risk clinical features (poor histological grade,
T4, perforation/obstruction, less than 10 lymph nodes sampling, PNI, and LVI).

In 2011, two other trials confirmed the value of oxaliplatin-based regimen as a component of
adjuvant chemotherapy for stages II and III colon cancer above FU/LV monotherapy. The
NSABP C-07 phase III clinical trial evaluated the impact on DFS of adding oxaliplatin to bolus
weekly FU combined with LV as surgical adjuvant therapy for stage II (29%) and III (71%) Cca
patients. After intent of curative resection, patients were randomly assigned to either FU (500
mg/m2 IV) bolus weekly for 6 weeks plus LV (500 mg/m2 IV) weekly for 6 weeks during each
8-week cycle for three cycles (FU/LV), or the same FU/LV regimen with oxaliplatin (85 mg/m2
IV) administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). In the
NSABP C-07 trial, the 8-year OS was similar between treatment groups (HR, 0.88; 95% CI, 0.75
to 1.02; .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; .002). The
effect of oxaliplatin on OS did not differ by stage of disease (II versus III = 0.38 for OS; 0.37 for
DFS) but did vary by age (less than 70 versus greater than 70 0.39) with a similar trend for DFS
(p = 0.073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80;
95% CI, 0.68 to 0.95; P = .013), but no positive effect was seen in older patients. FLOX regimen
was associated with higher hospitalization for diarrhea (5.5% versus 3%), and a total of 1.2% of
patients died of any cause within 60 days of receiving chemotherapy, with no significant
difference between regimens.

The XELOXA trial, a multicenter, randomized trial compared capecitabine plus oxaliplatin
(XELOX) with bolus FU/LV as adjuvant therapy for patients with stage III Cca. Patients were
randomly assigned to XELOX (O: 130 mg/m(2) on day 1 plus X: 1000 mg/m(2) twice daily on
days 1 to 14 every 3 weeks for 24 weeks) or the standard bolus FU/LV adjuvant regimen.
XELOX improved DFS and OS compared with bolus FU/LV in patients with resected stage III
Cca after a median follow-up of almost 7 years (DFS 63% versus 56%, HR, 0.80; 95% CI; 0.69;
0.93; p = 0.0045 and OS 73% versus 67%, HR, 0.83; 95% CI, 0.70 to 0.99; P = .04). XELOX
was associated with more neurotoxicity, hand-foot syndrome, and thrombocytopenia. Patients on
capecitabine are recommended not to take proton pump inhibitor due to poor absorption of
higher gastric pH. Another trial established that six months of oral capecitabine monotherapy is a
safe and equally effective alternative to conventional FU/LV for stage III colon cancer.

There is a role for adjuvant chemotherapy for selected patients with stage II high-risk disease.
The largest study of Stage II Cca, the UK QUick And Simple And Reliable (QUASAR) trial
randomly assigned non-stratified patients (e.g., high-risk and low-risk) to have FU/LV with or
without levamisole (later removed) as adjuvant chemotherapy following surgical resection. The
relative risk (RR) of death from any cause with chemotherapy versus observation alone was 0.82
(95% CI 0.70 to 0.95; p=0.008) and for recurrence RR 0.78 (0.67-0.91; p=0.001) after ten years
follow-up. Although the absolute improvement in survival with FU/LV was 3.6%, the quality of
the trial has been question due to a poor median of 6 lymph node dissection (greater than 60%
with less than 12 lymph nodes), a group of patients received radiation therapy (14%) or portal
infusion chemotherapy (6%), which does not meet current standards. The ACCENT retrospective
analysis has demonstrated a trend toward an improved of 10-year DFS and OS for stage II with
chemotherapy compared to observation regardless of the risk feature with high-risk disease (51%
versus 35%). The identification of high-risk prognostic factors might help distinguish patients at
higher risk of relapse which will more likely benefit from adjuvant therapy. Datasets confirmed

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that patients with stage II Cca without high-risk features and MSI-H/dMMR have an excellent
prognosis and do not need to be treated with adjuvant chemotherapy, but remains uncertain for
those with high-risk disease.

Irinotecan-based regimens are effective in palliative therapy for advanced CRC, but for unknown
reasons, none of the three major phase III trials (CALGB89803, PETACC-3, ACCORD) using
combination regimens of irinotecan plus FU/LV has demonstrated to be significantly superior in
3-year DFS when compared with FU/LV alone. The role of novel targeted agents, bevacizumab
(antibody against VEGF) and cetuximab (antibody against EGFR), have been investigated in the
adjuvant setting in large phase III trials. Three major trials have failed to demonstrate any benefit
of adjuvant bevacizumab with FOLFOX (NSABP C-08), XELOX (AVANT) or Capecitabine
(QUASAR2). Cetuximab was also tested as a component of adjuvant therapy in stage III Cca
added to FOLFOX backbone, unfortunately, failed to improve outcome even on preselected
KRAS wild-type tumor, and was detrimental to KRAS-mutated patients. Cetuximab lack of
efficacy was later confirmed in the PETACC-8 trial on patients with RAS and BRAF wild-type
stage III Cca.

Based on prior clinical trial results, the standard adjuvant chemotherapy for stage III Cca is an
oxaliplatin-containing regimen (FOLFOX, XELOX, FLOX) administered for six months.
Capecitabine or FU/LV monotherapy should be reserved for patients who are not considered
optimal candidates for oxaliplatin (e.g., pre-existing neuropathy). Stage III Cca patient with MSI-
high/deficient-MMR tumors are intrinsically resistant to adjuvant FU monotherapy, requiring the
addition of oxaliplatin to overcome the resistance and impact outcomes. Patients with Stage II
Cca and any high-risk combination should discuss risk and benefit of adjuvant therapy.
Retrospective analysis from trials did not document a significant improvement with the addition
of oxaliplatin to 5-FU/LV for patients over age 70, and only younger patients had a statistically
significant benefit regarding DFS, OS, and time to tumor recurrence. At this point in time,
irinotecan-based and targeted therapies have no indication in the adjuvant therapy of Cca outside
of investigational trials. There is no conclusive evidence to recommend standard RT alone or
combined CRT in the adjuvant setting. There are two web-based validated tools to calculate the
relative risk of disease recurrence and mortality based on clinicopathological features and
potential adjuvant benefit (an ACCENT by the Mayo Clinic and Adjuvant! Online).
Furthermore, gene profiling by Oncotype DX Colon, ColDX or ColoPrint are currently available
in clinical practice to assist in risk assessment but has no valid predictive value t, thus not
recommended by clinical practice guidelines.

Neoadjuvant Therapy

The role of pre-operative chemotherapy for patients with Cca is currently on a phase III
FOxTROT trial (NCT00647530) after promising results of their pilot study. The Foxtrot
collaborative group randomized locally advanced resectable (T3 greater than 5 mm invasion
beyond muscularis propia and T4) candidates to 3 preoperative cycles of FOLFOX (O; 85
mg/m(2), LV; 175 mg, FU; 400 mg/m(2) bolus, then 2400 mg/m(2) by 46 hour infusion), surgery
and nine additional cycles or surgery and 12 adjuvant cycles. Findings favored neo-adjuvant
therapy with a tumor regression (31% versus 2%), node-positive (1% versus 20%) and negative
margins (4% versus 20%) resulting in a significant downstaging (p=0.04).

Systemic Therapy

More than half of all CRC patients will develop metastasis and the majority to the liver (80% to
90%). The prognosis for advanced non-resectable and metastatic CRC patients with best
supportive care is poor by a mOS 5 to 6 months, except for a subset of patients with oligo-
metastatic hepatic or pulmonary patient that are potentially curable with peri-operative
chemotherapy. The goals of systemic therapy for advanced non-resectable and metastatic CRC of
therapy are palliation of symptoms, improvement of the quality of life and prolong survival.
Systemic therapy for cancers of the colon and rectum are addressed jointly by clinical research
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and practice. In the 1990s, FU/LV monotherapy was the standard first-line therapy with an
approximately mOS 12 months. It was until the early 2000s that the addition of oxaliplatin and
irinotecan to the backbone of FU/LV resulted in an improvement of mOS to nearly 24 months.
The introduction of biologic agents monoclonal antibodies (MAbs) targeting vascular endothelial
growth factors (VGFRs) and epidermal growth factors receptor (EGFR) further enhanced the
efficacy of systemic medical therapy with mOS reaching 36 months and when exposed to
multiple lines of therapy an impressive 20% 5-year OS even at a metastatic stage.

Current availability of nine different antineoplastic classes and more than a dozen drug options
fluoropyrimidines (FU), capecitabine (CAP), S-1, tegafur plus uracil (UFT), irinotecan,
oxaliplatin, anti-EGFRs (cetuximab, panitumumab), anti-VEGFRs (bevacizumab, ramucirumab),
recombinant fusion protein (aflibercept), tyrosine kinase inhibitors (regorafenib), antimetabolites
(TAS-102), immunotherapy (nivolumab, pembrolizumab) for mCRC has resulted in an
abundance of therapeutic possibilities with different combinations and sequences not yet
established. The most appropriate treatment regimen is conceivably the one that generates the
highest overall response rate (ORR), greatest impact to metastases for surgical conversion and/or
ultimately offers the longest PFS and OS, balanced with a favorable toxicity profile. Predictive
biomarker (RAS/BRAF type and MMR/MSI status), primary location (tumor and metastasis),
patient (performance status and comorbidities) and therapy goals (palliate or conversion) can
help guide treatment decisions for specific patient subpopulations.

For otherwise healthy candidates, the standard first-line treatment approach is to start with a
FOLFOX, CAPOX or FOLFIRI regimen plus anti-EGFR (cetuximab or panitumumab) when the
tumor is RAS/BRAF wild-type and left-sided or anti-VGFR (bevacizumab) when the tumor is
RAS/BRAF mutated or right-sided. At progression of disease or unacceptable toxicity switch to
the opposite second-line regimen with either continuation of prior anti-VGFR or new biological
agent regardless of the tumor location. ASCO, ESMO, and NCCN recommend comprehensive
testing of KRAS, NRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), 4 (codons 117 and
146) and BRAF V600E for anti-EGFR candidates based the results of the Panitumumab
Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to
Determine Efficacy (PRIME) trial and other major meta-analyses. Biological agents additions to
chemotherapy backbone have significantly improved ORR, DFS, and OS in the first and second-
line setting. Cetuximab and panitumumab have comparable efficacy in first, second line addition
and even single agent salvage therapy, but may share cross-resistance limiting use after
progression of anti-EGFRs. Bevacizumab can be continued beyond progression of first-line to
second-line therapy (e.g., RAS/BRAF-mutated) but not in conjunction with the new anti-EGFRs
candidate (e.g., RAS/BRAF wild-type and left sided). For patients who progressed anti-VEGF
bevacizumab may consider aflibercept or ramucirumab addition to backbone chemotherapy
regimen.

Sequential single agents remains a valid option for mCRC patients compared to combination
treatments demonstrated in the United Kingdom Medical Research Council's FOCUS
(Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing) and the Dutch Colorectal Group
CAIRO (capecitabine, irinotecan, oxaliplatin) trials, although biological agents were not used on
both trials, and most of all patients did not receive all three drugs. Multiple phase III trials have
confirmed similar ORR, PFS, and OS between FOLFOX and FOLFIRI regimens, even with
added anti-VEGFs or anti-EGFRs. In clinical practice, the choice between FOLFOX and
FOLFIRI is based on treatment toxicity profile. CAPOX combination is a statistically non-
inferior substitute to FOLFOX regimen in PFS and OS with tolerable toxicity profile; conversely,
XELIRI had shown higher intolerable rates of gastrointestinal toxicities. Maintenance therapy
with low dose capecitabine-bevacizumab after the first-line FOLFOX-bevacizumab good
response is an accepted treatment option based on CAIRO3 trial results. Complete
discontinuation of chemotherapy may be detrimental and remains controversial, but intermittent
therapy has not resulted in significant reduced OS but the rather better quality of life.

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FOLFOXIRI with or without bevacizumab is reserved for conversion approach in potential

resectable liver/lung metastasis on selected excellent performance status patients. Patients not fit
for triple or doublet therapies, consensus-based guidelines recommend FU/LV IV or capecitabine
PO monotherapy. For patients after FOLFOX, CAPOX, FOLFIRI, anti-VEGFs and anti-EGFRs
agent progression that remains eligible for further chemotherapy may consider regorafenib or
TAS-102 salvage therapy, or alternative, immunotherapy is approved for MSI-H/dMMR tumors.
Novel targeted agents may be available through clinical trials at different lines of therapies
failure.

Recommended treatment monitoring consists of close observation of signs/symptoms of adverse

reaction (before each treatment cycle and as needed), frequent checking on blood work
parameters (before each treatment cycle and as indicated), CEA levels serial assays (every 1 to 3
months) and radiographic evaluation by Response Evaluation Criteria In Solid Tumors (RECIST)
(every 2 to 3 months) by a multidisciplinary team. Patients should frequently be screen for
somatic symptoms and psychosocial distress.

Selected Landmark Clinical Trials

Cytotoxic Chemotherapy

Fluorouracil-Leucovorin (FU/LV): An updated-meta analysis compared to FU-alone resulted in

higher ORR (21% versus 11%) and 1-year OS (47% versus 37%) favoring FU/LV. The two most
commonly used regimens in the United States include the Mayo regimen (bolus FU: 425 mg/m2
and LV: 20 mg/m2 on days 1 to 5 every 4 to 5 weeks) and the Roswell Park regimen (Bolus FU:
500 mg/m2 and LV: 500 mg/m2 administered weekly for 6 out of 8 weeks). Further improved by
the de Gramont regimen (LV: 200 mg/m2 as a 2-hour infusion followed by bolus FU: 400 mg/m2
and 22-hour infusion FU: 600 mg/m2 for 2 consecutive days every 2 weeks) with significantly
better ORR (33% vs 14%), PFS (7 versus 5 months) and OS (15.5 versus 14.2 months) with
significantly less grade 3/4 toxicities (23.9% vs 11.1%) compared to the Mayo regimen.

Capecitabine (CAP): A phase III clinical trial by Hoff PM et al. prospectively randomly assigned
patients to oral CAP (1250 mg/m2 twice daily for 14 days every 21 days) or FU/LV (the Mayo
regimen) resulting in non-inferior ORR (24.8% versus 15.5%), time to progression (TTP 4.3
versus 4.7 months) and mOS (12.5 versus 13.3 months), respectively. Common side effects of
CAP included diarrhea (overlapping toxicities with irinotecan), hyperbilirubinemia and hand-
foot syndrome. CAP has never been directly compared with infusional FU/LV (de Gramont
regimen), CAPOX versus infusional FOLFOX has shown to be of similar efficacy in the
treatment of advanced CRC, as shown by the phase TREE-1 trial and AIO trial. In the United
States clinical practice, dose-reducing CAP by about 20% (1000 mg/m2) alone or in combination
regimens does not appear to decrease the treatment efficacy, but it greatly improves the side
effect profile of the treatment. Other alternative oral fluoropyrimidines not approved in the
United States include S1-derived three different agents tegafur-uracil, gimeracil and oteracil, and
raltitrexed.

Irinotecan (IRI): In a landmark phase II clinical trial, patients with FU-refractory mCRC were
randomly assigned either single-agent IRI (300 mg/m2 every 3 weeks) or BSC, showed a
significant 1-year OS (36% versus 14%) with improved quality of life (performance status,
weight loss, and pain-free), respectively. Following this, three key trials were conducted to test
the role of IRI versus FU/LV in the front-line setting. A three-arm trial compared three treatment
regimens: the Roswell Park regimen, IRI plus FU/LV weekly bolus regimen (IFL or Saltz
regimen); and IRI alone.

The results of the trial significantly favored IFL with an ORR (39% versus 21%) and mOS (14.8
versus 12.6 months). In Europe, three pivotal phase III trials compared the FU/LV regimens to
FOLFIRI regimens (the Douillard regimen-IRI: 180 mg/m2 on day 1, FU: 400 mg/m2 bolus
followed by 600 mg/m2 over 22 hours, both on days 1 and 2, and LV: 200 mg/m2 on days 1 and

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2). The Douillard FOLFIRI regimen trial demonstrated a significant ORR (49% versus 31%),
TTP (6.7 versus 4.4 months) and extended mOS (17.4 versus 14.1 months). Higher side effects
of irinotecan-group were diarrhea, myelosuppression, and alopecia. Of note, IRI combinations
require an adequate biliary function for its active glucuronide metabolite, SN-38, be excreted.
Approximately 10% of United States patients are homozygous for the UGT1A1*28 allele
polymorphism increasing SN-38 bioavailability and therefore recommended starting with a
lower dose of irinotecan.

Oxaliplatin (OXA): OXA has very limited activity in CRC as a single agent thus not
recommended unless synergist with fluoropyrimidines. In phase III trial, FU/LV (de Gramont
regimen) was compared with or without OXA (OXA: 85 mg/m2 on day 1 over 2 hours
FOLFOX4 regimen) as first-line therapy for patients with mCRC. FOLFOX4 regimen had
significantly higher ORR (51% versus 22%), PFS (9 versus 6 months) but comparable mOS
(16.2 versus 14.7 months) with more grade 3/4 neutropenia, diarrhea, and neurotoxicity. Because
no overall survival benefit was achieved in these first-line trials, the FDA did not approve OXA
for CRC until years later for second-line therapy that showed prolonged PFS and increased ORR
compared with FU/LV for patients who experienced disease progression while receiving first-line
IRI-regimens. The most important side effect and dose-limiting toxicity of OXA is neurotoxicity.
It may present as an acute and reversible, cold-triggered sensory neuropathy, or a chronic dose-
limiting cumulative sensory neurotoxicity.

Irinotecan versus Oxaliplatin-based regimens: After encouraging results of previous trials

conducted in the United States and Europe using OXA and IRI, the North Central Cancer
Treatment Group (NCCTG)/Intergroup trial N9741 performed a pivotal and practice-changing
trial comparing FOLFOX4, the standard combination IFL and new IROX combination
(OXA:85 mg/m plus IRI 200 mg/m, both on day 1 every 3 weeks). The N9741 results
demonstrated the superiority of FOLFOX compared with IFL and IROX as first-line therapy for
mCRC with ORR (45% versus 31% versus 36%), PFS (8.7 versus 6.9 versus 6.7 months) and
mOS (19.5 versus 15 versus 17.3 months), respectively. The toxicity profile likewise favored
FOLFOX, except for neurotoxicity. FOLFOX emerged as new standard first-line therapy with
rapid and widespread adaptation in the United States.

VEGF Inhibitors

Bevacizumab (BEV): In randomized placebo-controlled phase III trial, IFL plus BEV (5 mg/kg
every 2 weeks) was assessed in first-line therapy for mCRC. For the first time, the addition of an
anti-VEGF inhibitor was validated as an efficacious antineoplastic treatment by significantly
improving ORR (45% versus 35%), PFS (10.6 versus 6.2 months), and mOS (20.3 versus 15.6
months). This trial was the first phase III validation of an antiangiogenic agent as an effective
treatment option in human malignancy. Subsequently, FOLFOX-BEV also showed to improve
mOS in first-line (TREE-2 trial 23.7 versus 18.2 months) and second-line (ECOG 3200 trial
12.9 versus 10.8 months) settings. The AVEX phase III trial selected patients age 70 or older,
who were not deemed to be candidates for OXA or IRI-based chemotherapy first-line regimens,
to receive CAP regimen alone or with BEV (7.5 mg/kg intravenously on day 1 given every 3
weeks). The study showed a significantly longer mPFS (9.1 versus 5.1 months) and a remarkable
improvement in mOS (20.7 versus 16.8 months) for CAP-BEV than with CAP alone,
respectively. Prolonged VEGF inhibition with BEV beyond the first-line progression was
evaluated by the European TML (ML18147) phase III trial, which randomly assigned to
progression within three months to either continue second-line with or without BEV. The mOS,
primary endpoint of the study, favored BEV-chemotherapy based continuation 11.2 months
versus 9.8 months chemotherapy alone. This effect was confirmed in PFS (5.7 versus 4.1
months) but not in ORR (4% versus 5%). The toxicity profile observed with BEV consists of
hypertension, bleeding, gastrointestinal perforations, impaired wound healing and arterial-venous
thrombotic events.

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Aflibercept (AFL): AFL was evaluated in the second-line setting among patients who had all
progressed OXA-based with or without BEV first-line chemotherapy by the placebo-controlled
phase III VELOUR trial. Patients randomly selected to receive FOLFIRI with AFL (4 mg/kg IV
every 2 weeks) had a significant improvement in ORR (19.8% versus 11.1%), PFS
(6.9 versus 4.7 months and mOS (13.5 versus 12.1 months).

The aflibercept arm toxicity profile had an intensified rate of grade 3/4 diarrhea, mucositis,
neutropenia, infection, and fatigue plus hypertension, proteinuria, hemorrhage, and arterial-
venous thromboembolic events, usually seen in FOLFIRI-BEV second-line.

Ramucirumab (RAM): In a double-blind placebo-controlled phase III RAISE trial, the addition
FOLFIRI-RAM (8mg/IV every two weeks) as second-line therapy for patients progressing with a
FOLFOX-BEV improved PFS (5.7 versus 4.5 months) and mOS (13.3 versus 11.7 months).
Grade 3/4 neutropenia, hypertension, diarrhea and fatigue was worse on the combination arm.

Anti-EGFR Monoclonal Antibodies

Cetuximab (CET): CET monotherapy (400 mg/m2 followed by a weekly infusion of 250 mg/m2)
for patients who had experienced disease progression on prior FU, OXA and IRI-based therapy
had an improved ORR (40% vs. 11%) and mOS (6.1 versus 4.6 months) compared to BSC. The
EPIC and BOND trials proved PFS and ORR superiority of IRI-CET over IRI-alone on patients
with prior IRI failure, without significantly improving survival. A large multicenter randomized
phase III CRYSTAL trial, FOLFIRI with or without cetuximab in treatment naïve CRC patients,
confirmed that selected KRAS wild-type patients have a significantly higher ORR, PFS, and
mOS (23.5 versus 20 months). The benefit of FOLFOX-CET remains uncertain with three trials
(OPUS, CALBG 80203, CALBG 80405) showing modest significant ORR and PFS
improvements but no mOS benefit, and three other trials (MRC COIN, NORDIC VII, New
EPOC) with no resulted benefit. CET arm had higher-grade diarrhea, magnesium-wasting
syndrome, infusion reaction and ocular-skin toxicity, last correlated to response rate.

Panitumumab (PAN): Single-agent PAN (6 mg/kg every 2 weeks) was compared to BSC in a
large international phase III trial in chemotherapy-refractory mCRC patients. PAN had an ORR
(37% similar to CET) and modest prolonged mPFS (8 versus 7.3 weeks), but mOS was not
increased likely because crossed over from BSC to the PAN arm. The ASPECCT phase III trial
compared head-to-head PAN versus CET monotherapies on chemotherapy-refractory patients
and showed non-inferior mOS (10 months) with similar expected toxicity profile. FOLFOX4-
PAN benefit in first-line setting was seen in phase III PRIME trial with mPFS improvement (9.6
versus 8 months) and trend for mOS (23.0 versus 19.7 months) not significant at 55 weeks
follows up.

VEGF Inhibitors Versus Anti-EGFR Monoclonal Antibodies

The FIRE-3 trial recruited treatment naïve mCRC KRAS exon2 wild-type patients and randomly
assigned to receive FOLFIRI_CET or FOLFIRI-BEV. The primary endpoint of the trial,
objective response rate analyzed by intention-to-treat analysis, was not reached (CET 62% versus
BEV 58%, p = 0.18). Although no difference in PFS was noted (CET 10 versus BEV 10.3
months), the mOS was significantly longer in the FOLFIRI-CET arm (CET 28.7 versus BEV
25.0 months; HR, 0.77; p = 0.017). An updated analysis, which accounted for additional
mutations in KRAS exon 3 and 4, as well as NRAS mutations exon 2 and 3, demonstrated a
longer mOS survival of 33.1 months for FOLFIRI-CET. In contrast, the U.S. Intergroup study,
CALGB/South-west Oncology Group (SWOG) 80405 trial that compared FOLFOX or FOLFIRI
(dealer’s choice) with CET compared with BEV as first-line therapy had no difference in mOS
(30 versus 29.9 months, respectively), not even whit expanded RAS-mutated analysis. The
preliminary retrospective analysis suggests that patients treated with CET for KRAS wild-type
left-sided tumors mOS are significantly higher than right-sided counterpart by 33.3 versus 19.4
months, respectively. Combination therapy with VEGF inhibitors and anti-EGFRs monoclonal

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antibody have failed even detrimental in multiple trials (BOND-2, PACCE, CAIRO-2), thus not
recommended.

Salvage Therapy for Refractory Disease

Regorafenib (REG): REG (160mg PO daily for three weeks of 4 weeks cycle) efficacy was
investigated in a placebo-controlled, multicenter international, randomized, phase III CORRECT
trial after progression of multiple therapies. REG compared with placebo had ORR (41% versus
15%), PFS (1.9 versus 1.7 months) and modest mOS benefit (6.4 versus 5.0 months) but
significant (p = 0.0052). The observed toxicity profile with regorafenib was hand-foot skin
reaction, fatigue, hypertension, diarrhea, and rash, with a 1.6% fatal hepatic failure. The
CONCUR trial later confirmed REG benefit.

Trifluridine-tipiracil (TAS-102): the international, double-blind, placebo-controlled randomized-

controlled, phase III RECOURSE study of patients with refractory showed that TAS-102
(35 mg/m2 orally twice daily on days 1 through 5 and 8 to 12 of each 28-day cycle) improved
ORR (44% versus 16%), DFS and mOS (7.1 versus 5.3 months); The most adverse event was
neutropenia (38%), febrile neutropenia (4%) and one treatment-related death.

Immune Checkpoint Inhibitors

Pembrolizumab (PEM): In a phase II study, PEM (10 mg/kg every 14 days) was given to 11
heavily pretreated patients with dMMR mCRC with a remarkable ORR of 71% and PFS rate of
67%. An expanded cohort of 54 patients, PEM showed OOR of 50% and an 89% disease control
rate with the durable response for more than a year, not seen in pMMR CRC.

Nivolumab (NIV): In CheckMate-142, NIV (3mg/kg every 2 weeks) was given to 74 dMMR
CRC patients resulted in 31% objective response, 69% disease control, and median duration
response not reached at 12 months.

Differential Diagnosis

Arteriovenous Malformation (AVM)

Carcinoid tumors

Crohn’s disease

Gastrointestinal lymphoma

Ischemic bowel

Ileus

Small intestine carcinomas

Small intestine diverticulosis

Ulcerative colitis

Enhancing Healthcare Team Outcomes

an interprofessional team including physician/nursing staff, nutritionist/dietitian, palliative
service, social worker and case manager should be invited to participate and contribute in all new
CRC diagnosis, treatment, and survivorship patient care. Screening for colorectal cancer is
essential to identify premalignant lesions which have been shown to reduce the mortality of this
disease but currently is underutilized.

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Extended third-generation, blood-relative, family history pedigree from CRC patients can
identify those at risk of an unrecognized hereditary syndrome and further offer early and
aggressive screening on survivor’s own risk and family members.

For all CRC patients during and after completion of treatment, a discussion on lifestyle changes,
including to follow a healthy diet, obtain and maintain ideal body weight, establish an active
exercise routine, minimize alcohol consumption and quitting smoking, should be encouraged.
[26][27]

CRC patients should be regularly screened for early identification of symptoms of psychosocial
stress and offer early preventive interventions that would improve the quality of life and reduce
suffering.

Review Questions

Access free multiple choice questions on this topic.

Comment on this article.

Figure

Adenocarcinoma. Central comedonecrosis: necrotic debris

inside the neoplastic gland. Contributed by Fabiola Farci, MD

Figure

Colorectal cancer (CRC). In this image the neoplastic glands

infiltrate the pericolic adipose tissue; this finding classifies as
colorectal adenocarcinoma TNM stage pT3 (pathological
staging). Contributed by Fabiola Farci, MD

Figure

Colorectal cancer (CRC). Lymphatic space invasion by

neoplastic cells. This is considered a negative prognostic
factor, regardless of tumor grade or stage. Contributed by
Fabiola Farci, MD

Figure

Liver metastasis. A neoplastic nodule circumscribed by

fibrous and inflammatory tissue, composed by glandular
structures. This is an example of metastatic colorectal cancer
(CRC), adenocarcinoma; this finding classifies as
adenocarcinoma TNM stage pM1. (more...)

Figure

Colorectal cancer (CRC). In this image the neoplastic glands

infiltrate the peritoneal mesothelium; this finding classifies as
adenocarcinoma TNM stage pT4. Contributed by Fabiola
Farci, MD

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