colon CA Management Principle for PG, UG

colon CA Management Principle for PG, UG

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44. INITIAL THERAPY?

45. SECOND-LINE AND SUBSEQUENT THERAPY OPTIONS

Previous oxaliplatin-based therapy without
irinotecan

Previous irinotecan-based therapy without
‘oxaliplatin

Previous therapy with oxaliplatin and
irinotecan

Previous therapy without oxaliplatin or
irinotecan

not previously given)?

73. NCCN Categories of Evidence and Consensus

Category 2A Based upon | | evidence, there is uniform NCCN consensus (285% support of the Panel) that the
intervention is appropriate.

Category 3 d upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

NCCN Categories of Preferen

Other recommended Other is that m som

iterven or sig s affordable for simi

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NOA] Cancer
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This discussion corresponds to the NCCN
Guidelines for Colon Cancer. A section of this

discussion was updated on March 31, 2025. The
last full discussion update was January 17, 2025.

Management of Metastatic Di
Surgical Management of Color
Local Therapies for Metastaseg
Peritoneal Carcinomatosis.
Determining Resectabilty
Neoadjuvant Therapy and Cont

Perioperative Therapy for Re:

Systemic Ther

‘Workup and Management of S

Workup and Management of Mj
Endpoints for Advanced/CRC d
Post-Treatment Surveillance.

Survivorship.

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Disease... |
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Summar

75. National
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fme year, an estimated 53,010
Ir combined.! Despite these high
tal cancers per 100,000 people
2005 and, more recently, 38.7 in

g for decades
males) and is currently down by

E improvements in incidence of
je a result of cancer prevention

tment modalities.
1es in incidence among those,

% annually between 2011 and
Is vary by race and ethnicity with
Individuals and lowest in Asian

fue of inequity in mortality rates

Ins for these racial inequities
Ence, access to health care and
orbidities, and tumor

ong those <65 years, with a 1%
jears and 2% annual increase in

event (AE) profiles, which the aut
profiles,

This Di |
Oncology (NCCN Guidelines?) far
with the clinical presentation of th
gastroenterologist, and address
management, perioperative treat
recurrent and metastatic disease,
guidelines, clinicians should be al
guidelines adhere to the TNM (t
(see Table 1 in the algorithm).

The complete details of the Di

76. National
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plecting studies in humans
ed to the following article types
se Ill; Clinical Trial, Phase IV:

ed Controlled Trial: Meta-

tion Studies. The data from key

additional sources deemed as
by the Panel during the

J this version of the Discussion
h-level evidence is lacking are
el evidence and expert opinion.

‘CN Guidelines endeavor to use
Ling: anti-racist, anti-classist, anti-
lanti-weight-biased; and inclusiv
pd gender identities. NCCN
Inguage. instead focusing on

guage is both more accurate
dress the needs of individuals of
ties. NCCN Guidelines will

Risk Assessment
Approximately 20% of colon can
clustering, and first-degree relat
or invasive CRC are at increased]
to CRC includes well-defined inh
syndrome (also known as heredig
familial adenomatous polyposis (A
that all patients with colon cancer
and considered for risk assessm:
for Colorectal 1 ning,
trial (RCT) suggest that most indi
and with one first-degree relativ
years or two first-degree relative
safely be screened u

SRC is a heterogeneous di
reported a molecular classification
(microsatellite instability [MSI] Imı
unstable (see Lynch Syndrome al
strong immune activation; CM:

unstable, with marked WNT and
(Metabolic), epithelial, with evideı

77. National
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in an MMR gene through

fome, patients usually undergo
Ind performing an initial test on
two different initial tests can be
y individuals who might have
al (IHC) analysis for MMR protein

cause of mutation; of 2) analysis
Ency (dMMR).and is detected as.

J elements in tumor tissue caused
hits? Testing the BRAF gene for
at MLH1 expression is absent in
tation indicates that MLH1

matic methylation of the promoter
rmline mutation.22.Testing.for
p used to determine this.

jer comprehensive cancer centers
sting on all newly diagnosed
Irdiess of family history to

netic testing for Lynch
If this approach; referred to as
irmed for CRC, and this approach

approach

The NCCN Colon/Rectal Cancer

Immunotherapy for (MMRIMS
Disease in the First-Line and No)
infrastructure needs to be in placı
case. A more detailed discussion |

The Role of Vitamin D in CRC
Prospective studies have sugge:
contribute to CRC inciden:
decrease CRC risk.

shown that lo

patients with CRC.*!

five studies totaling

78. National
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Éd significantly based on the
ating that only individuals with

patients with CRC. Several studies
ot improve survival) In
lind, phase Il SUNSHINE trial
fie (PFS) for patients with
| o standard treatment plus high
led to those randomized to
Ih D supplementation (13.0 vs
Ioniticant (HR, 0.64; 95% Cl, 0-
ificant difference between high?
tation for overall response rate
tute of Medicine (now known as
Juded that data supporting a role
Ine health, and not in cancer and
e lack of level 1 evidence, the
lutine screening for vitamin D
Din patients with CRC

‘consumption, and healthy diet) h

63 (95% Cl, 0.54-0.74) compat
fewer of the factors.” Other larg}
adherence to healthy lifestyle fac

me data sugg:

development of CRC.

analysis of 15 cohort studies (>9
only found an association betwe
consumption of nonfermented mi

including the consumption of fish
of aspirin or nonsteroidal anti-nfi
decrease the risk for CRC, °° al
association is limited and variable|
Task Force (USPSTF) guidance À
aspirin for CRC prevention, the]

insufficient evidence that aspirin |

In addition, some data suggest th]

79. National
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ease risk, at least in women. '
suggest that 1 year of low-dose
ith previously resected colorectal
plinood of subsequent adenomas
Its with CRC and diabetes appear
out diabetes, ''2.'!® patients with
seem to have a Survival benefit
The data regarding the

NM system. The TNM categories
rectal and colon cancer; these
ing system.

lanual, T1 tumors involve the
ph the submucosa into the

| through the muscularis propria

[face of the visceral peritoneum:
herent to other organs or

Éncer staging is Very important in.
shown that patients with T4,NO.

Nib (2=3 positive lymph nodes):
more positive nodes). In addition

mesentery, or non-peritonealize

regional nodal metastasis (ie, sate
as Nic. Within each T-stage, sun
(NO, N1a, Nb, N2a, and N2b)

Metastatic disease is classified ag
to only one site/solid organ (inclu

tumor regional drainage area) are|
multiple distant sites or solid orga
carcinomatosis. The 8' edition of

includes the M1c category for pe}
blood-borne metastasis to viscer

metastases havea shorter PFS dl
involvement.

Pathology
CRCs y

pathologic examination of the surg
should be included tn the report
following: grade of the cancer: de
adjacent structures (T); number

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[eumterential resection margin
sue closest to the deepest
ırgically by blunt or sharp

fend it corresponds to any aspect
losal layer of mesothelial cells.” It
leur to remove the viscus. The

Institute a surgical margin. The

[colonic segments with non-
Ion that are completely

hsverse colon, the mesenteric.

ial margin.” On pathologic

je demarcation between the.

with lymph node harvest are i
instance, the extent and quality of
on the node harvest.'** The numi
from a surgical specimen also var
tumor grade or site.

lymph nodes in patients who have
are easier to find, and that such fi
Another possibilty is that the und
yield and prognosis in parallel. Fa

increased lymph node retrieval. 4

Regardless of the mechanism for
recommends examination of 212
supported by CAP" and the 8%
Manual,” which also specify path
Notably, emerging evidence suggl
provide an adequate assessment]
colon cancer, itis recommended

81. National
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mre Luis
that the lymph node ratio does
ffects of both the number of
lymph nodes examined. 152

¡ode evaluation for colon cancer
1g more accurate staging of nodal
tastatic disease in the sentinel

| the sentinel node for
[hematoxyin and eosin (H&E)

ls and the identification of

lave been reported. 152158

sing regional lymph nodes for
56153152 The 8 edition of the
dusters of 10 to-20 tumor cells
Im in diameter, but <2 mm in
mictometastases have been
he study of 312 consecutive
itive cytokeratin staining was
Relapse occurred in 14% of
p 4.7% of those with negative
013). A 2012 systematic review.
lusion, finding decreased

deposits are thought to arise froı
‘occasionally, PNI:155.5

in the pathology report, because
with reductions in DFS and OS.
one study showed that patients w
had a 91.5% 5-year survival rate
rate for patients with pNO tumors
< 0001)

Perineural Invasion

je shown that
significantly worse prognosis,
retrospective analysis of 269 con]
tumors resected at one institution
in patients with tumors without PN
nearby neural structures. 23 Multi
rectal cancer showed that patient
significantly worse 5-year DFS col
0008). 8 Similar result
disease.1?7 A meta-analysis that i
also found that PNI is asso:

82. National
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onference (|

In a selected hot spot measuring
three tiers: low (0-4 buds).
buds).

fade tumor budding in pT 1 CRC or
creased risk of lymph node
Hor assessing tumor budding were
ported tumor budding as an,
Il colon cancer. A retrospect

Ve study evaluated 174 stage Il
ing.'% This study also used the
to be independently associated
-tier tumor
br all patients. The difference was
ho received no adjuvant
DSS was 98% for low-tier tumor
08). A post-hoc analysis of the
ki that tumor budding is an

appendicitis. Management and tr

are dependent on classification, q
neoplasms. ® Appendiceal neopl
classified as neuroendocrine ne
goblet cell adenocarcinomas (GC,
mucinous), and signet ring cell
Mucinous neoplasms can be fur
appendiceal mucinous neoplasm:
mucinous neoplasms (HAMNS),
without signet ring cells. Both cold

and treated similariy. 195.197
epithelial and neuroendocrine el]
goblet cells. Neuroend:

cells (ECLs) and often produce st

Appendiceal Adenocarcinomas

Histopathologic features of LAMN
of low-grade mucinous epitheliun
propria, submucosa, muscularis pf
can also present with fibrosis of $
resembling diverticulum, and mut
outside of the appendix.”-1%% HAM

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mere uno
Por additional mutations in TP53,
heir more aggressive
ienocarcinomas resemble
pce of infiltrative invasion (instead
À the mucinous neoplasms)
er subclassified based on the
composed of :s50% signetring
ladenocarcinoma with signet ring
, then the tumor is

oe produce an

the intracellular mucin displaces

Bic ring-like appearance. Ithhas

of signet ring cells leads to a
corly differentiated)

Ing cells have a 5-year OS."

in this study: RAS-mutant/GNAS-
typically clinically indolent; GNAS}
chemotherapy resistance; and TA
highly eneuploid and aggressive.

regardless of histopathology. 1%

Goblet Cell and Neuroendocrine
Appendiceal goblet cell carcinom
14% to 19% of primary appendi
glandular epithelial cells and neur
are considered mixed adenoneu
display the IHC staining consister
behave more aggressively like ar
recommended to clinically treat
Appendic

neuroendocrine card
jejunumfileum, appendix, or cecu
bowel wall and can often product
tumors when found in the append

1
]
]
|
]
]
]
|
1
aggressively when found in the of

84. National
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e increased suspicion of an
150 years of age witha family
jolon cancer, and/or unexplained
treated nonoperatively (typically
is crucial to ensure that the

tion may suggest an appendiceal

Is challenging and symptoms may
ancers, or varying abdominal
dered at initial presentation
endoscopy, tumor biopsy and in
lough medical history and physical
a CT or MRI with an irregular or
eal carcinoma.2"° Non-specific
btorandial discomfort may also be
vement. Colonoscopy
jagnosed with mucinous

an increased risk of colonic

Workup-and Management of L
Adenocarcinoma

A screening colonoscopy i

AA to rule out synchronous large
abdomen, and p

tumor and any possibility of meta
tumors may be managed with app}
are obtained during resection anc
invasion. #5 T1 and T2 tumors wit
angiolymphatic invasion or positi
right hemicolectomy and removal]
resection and staging.'*

Extrapolating from CRC, patients
stage Il colonic-type AA should bl
chemotherapy. '®° A univariate and
patients diagnosed with stage Il 4
resection and adjuvant chemothe}
chemotherapy on-OS. Out of 61

administered in 9.4% (N = 48) of
individuals.?'4-For patients with sf

with adjuvant chemotherapy and 4

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picion of active disease (eg,
pite unremarkable imaging,

Appendiceal

oplasms causes varying risk of
Distant metastasis in colonic-

[din 23% to 37% of cases with the
the peritoneum, with metastasis

215 The pathologic M stage

ellular mucin only (Mia),

b), and non-intraperitoneal

beyond the peritoneum, then

Colon Cande

Lines for

¡on-mucinous) tend to
hrough various ways of
adenocarcinoma can arise from
lastic epithelial cells. This results
icin and tumor cells within the
bithelial cells adhering to the

growth.?'” High-grade mucinous q
synonymous with the previous cl
carcinomatosis (PMCA), presenti
cellularity, high mitotic ind
invasion of underlying organs. An}
of signet ring cells is denoted M
PMCA-S

Cytotoxic chemotherapy with effi
reasonable to use other targeted
BRAF mutation, or HER2 status,
recommendations within the N:

N R
epidermal growth factor receptor|
tumor is RAS/RAF wild-type. Are
Patients with AA was conducted t
adjuvant chemotherapy followed
patients with AA were enrolled in|
achieved a cytoreductive score o
received adjuvant chemotherapy.
compared to 2.88 years in those
chemotherapy (P= .02). This incl

86. National
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latic spread to the peritoneum,

E curative. S and HIPEC
ity, and itis imperative that a
Brform extensive preoperative
ation therapy. The intent of CRS
{fore the initiation of HIPEC.

Cases with higher PCI scores
k of benefit from CRS.2 The

cytoreduction is denoted with a
ction is denoted with a CO-2 or a
hed by the removal of all

Ineum or surrounding viscera. For
jor cannot be >2.5 mm in size.
lerapy is not effective against
ndiceal tumors and PMP, the
ltures also have an impact on the

extensiveretroperitone:

major resection); diffuse small b
and/or multiple sites of small bo\
candidate for surgery, treatment
guidelines, as found in the N

is best for patients when disease|

Clinical Presentation and
Disease

Workup and Management of tl
A malignant polyp is defined as ol
(pT1). Conversely, polyps classif
penetrated the submucosa and al
regional nodal metastasis." The
site during colonoscopy or within
appropriate. Testing for MMR/MS]
to help with diagnosis of Lynch
making.

Before making a decision about 4
resected adenomatous polyp or 4

87. National
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with pedunculated poly
cause of the high probability of a

b margins cannot be assessed; if
| thology, additional workup
fhemistry profile, carcinoembryonic
Emen/pevis CT, and consideration
Ketter assess for local staging and
fiagement of invasive
fetal on this workup). If

with en bloc removal of Iymph
scopic surgery is an option.”
malignant polyps include grade 3
Ive margin of resection. 77239
ps to the definition of what

A positive margin has been

1 to 2 mm of the transected
thin the diathermy of the

everal studies have shown that
feature associated with adverse

Patients Who present with invasive
require a complete staging worku
review, total colonoscopy, CBC, 4
baseline CT scans of the chest, q
MMR/MSI should be done at diag
syndrome and to inform treatmenf
intravenous (IV) and oral contrast]
inadequate or if CT with IV contraf
MRI with contrast plus a non-con

chest CT can identify lung metas
109% of patients with

patients found that resection of p

baseline for preoperative workup. |

without contrast and multiple slicii
cr]

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A meta-analysis found
urgery and for stenting followed
ported by the ESCO trial, an
itcomes between colonic stenting
gency surgery for malignant
alysis of comparative studies
Although 30-

Ed by colectomy.
e between the groups, the

permanent colostomy (OR [odds

enefit from neoadjuvant therapy
notherapy for MMR-proficient
ase, and either chemotherapy or
SI-H disease. If the cancer is
Hically inoperable, systemic

is recommended, possibly with

Preoperative therapy resulted in
postoperative therapy (P = .04), \
from the FOXTROT trial reported}
including 699 randomized to neo}
control group.25® The primary out
disease was 16.9% with heoadjuy
the control group, representing a
neoadjuvant chemotherapy. The
showed marked T and N downstd
Resection was more often histop
chemotherapy compared to conti

‘shown high rates of pathologicre:
in early-stage colon cancers prio
reported results from 115 enroll

colon cancer treated with ipilimun
population, 109 of 111 (98%; 954
pathologic disease response, inc|
and 68% pathologic complete reg

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| ‘oval of the regional lymph
jould be based on the tumor
Hel and arterial arcade containing
[such as those atthe origin of the
ph node), and suspicious Iymph
Lid also be biopsied or removed if
b be considered curative, and

an incomplete (R2) resection.

‘on the quality of colectomy.2%
outcomes of patients who had
(CME) to those who had a non-

| between the groups; however,
nulative death and di

| study found a possible OS
| lane Over surgery in the
bn of resection techniques by
[showed that CME with central
ntery and lymph node yields than
ferences in outcomes were not

Laparoscopic colectomy is an opt
cancer.210213 Ina small European
laparoscopic approach seemed tq
survival advantage, significant f
stays.2” More recently, a simil
patients with colon cancer randor
either a conventional open appro}
showed a nonsignificant absolute]
favoring open colectomy.?* Noni
could not be established becau
ofthe COLOR tria also showed sl
between open and laparoscopic s]
patients with CRC, no statistically
OS, DFS, and local recurrence w|
approaches.‘ Long-term follow
showed that the lack of difference
over a median of 62.9 months.

In another trial ( y
assigned to undergo either open |
curable colon cancer,

seen after a median of 7-year fol
and New Zealand also found no ¢

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proved, with reductions in the

lication rates after surgery.”

EnROL trial therefore compared
with an enhanced recovery

same in both arms, with the

y. which was significantly shorter
= 1033)

fo the laparoscopic approach
®” In general, the robotic
's and is more expensive but may

Adjuvant Chemotherapy for R

Choices for adjuvant therapy for
colon cancer depend.on the stag

+ Patients with stage | dised
disease do not require an

Patients with low-risk stag
observed without adjuvant
or 5-FU/LV. Based on res
possible long-term sequel
the Panel does not consid
oxaliplatin) to be an appro|
patients with stage Il dise

Patients with stage II dise:
for systemic recurrence.
features, including T4 tun
differentiated/undifferenti
PNI; tumor budding: bowel
perforation or close, inde!
inadequately sampled noc
considered for 6 months q

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platin therapy is believed to be

shown that patients with resected
py have a survival advantage over.
15317 For example, patients from
Ill or high-risk stage Il disease
lines for Colon Cancer had a
reatment did not adhere to these
lay of 852 patients with any stage
rial University Medical Center in
concordance with the
ines for Colon Cancer resulted in

Lac ENT) collaborative group

years), and that >
adjuvant therapies on OS. |
a new analysis by the ACCENT of
undergoing combination therapies
that 2- and 3-year DFS correlate:
stage Ill disease but not in those

Adjuvant Chemotherapy in Stage
The impact of adjuvant chemoth¢
cancer has been addressed in sel
studi " Results from a

studies showed that 5-year DFS i
did not receive adjuvant therapy w
it was 79.3% (95% Cl, 75.6-83.1
treated with adjuvant chemother:

with stage Ill-colon cancer, the 5:

92. National
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rapy for patients with stage 11
[Results from a post-hoc

tage II disease at a
| 0.62-1.14; P= 258). After
OS was observed in the stage Il
| 00: P= 98). In addition
characterized by at
1 perforation; bowel obstruction;
ion; <10 lymph nodes examined)
bd DFS compared with those
95% Cl, 0.50-1.02; P= .063)
the stage II population overall or
batures, Similar results were seen

n of oxaliplatin to adjuvant
cancer.227

ja from the community setting.
sis of outcomes of patients with

Results of another population-lev
published in 2016 suggest that th
with stage II colon cancer may bel

Decision-making regarding the u
stage II disease should incorpor
individualized for the patient, and]
specific characteristics of the di
related to the efficacy and possi
centering on patient choice."
clinical trial are options that shoul
risk stage Il colon cancer have a
benefit of adjuvant therapy is smi
features, on the other hand, tradit
to benefit from adjuvant chemothd
high-risk stage Il colon cancers
patients with disease with high-ri
while some patients

Furthermore, no data point to fea
adjuvant chemotherapy, and no d
of chemotherapy in patients with

Overall; the NCCN Panel support

93. National
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Network

to consider when deciding

In patients with stage Il disease.

of these genes (eg, methylation)

ld MSI (see Risk Assessment,
ified as either

cteristic are classified
Ined to have dMMR status are
E with MSI-H status,

ALH1, MSH2, MSH6, and/or

Is with Lynch syndrome, which is
pr cases.!%.192021 Somatic MMR,

lapproximately 19% of colorectal
somatic hypermethylation of the.
Jd with MLH7 gene inactivation, in

lat tumor specimens characterized
hisease than in stage Ill disease
* In another large study, the
s MSI-H was only 3,5% 3%

decreased benefit and possibly a

with a fluoropyrimidine alone in pi
retrospective study involving lon:

and Ill disease evaluated accordi
those characterized as MSI-L or

adjuvant therapy. Ho

did not show a statistically signifid
instead exhibiting a lower 5-year

surgery alone.**? Similarly, result
pooled data from adjuvant trials b
characterized as dMMR, adjuvant
detrimenta in patients with stage

disease.

Imcontrastto the findings of Sarg
stage Il CRC from the QUASAR
chemotherapy, showed that altho}
recurrence rate of dMMR tumors
did not predict benefitor detrimer
patients in the CALGB 9581 and
conclusion. MMR Status was pr
detrimental impact of adjuvant the}
regimen) in patients with stage II

94. National
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irculating Tumor DNA
|hopesor providingprognostic and
regarding adjuvant therapy in

[res the expression of seven
E genes as a prognostic classifier
recurrence.» Clinical validation
er from QUASAR*! and National
ect (NSABP) C-072 trials,
pnostic for recurrence, DFS, and
hre not predictive of benefit to
ate, and high recurrence risk
| 18%, and. 22%, respectively."
fence scores were related to
ging, MMR status, tumor grade,
[stage 11 and III disease. Similar

ee a
identify patients w

additional study Validated the rec
colon cancer treated with surgen)

ColoPrint quantifies the
of low versus high recurrence
IILCRC, the 5-year RFS rates wer

subset, patients ck
relapse (survival until first
22.4%and 9.9

nodes
for its ability to predict
cancer in a prospective trial (N

ColDx is a microarray-based mult
identify patients with stage II color

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lo system reported as percentiles
Hs in prespecified regions of the
the assay’s prognostic value in
el as its predictive value for
This study reported
the lowestrisk of
and 76.4% for
0.48; 95% Cl, 0.32-
0 correlated with prolonged time
fi). The benefit of adjuvant
la high Immunoscore for both
P011) tumors. The same was not
(P>\12)

INA) has also been studied as à
fe in stage I-III colon cancer. A
lents with stage I-III colon cancer
ld next-generation sequencing
nts with positive ctDNA assays
ce disease relapse than patients

(15% vs. 28%; RR, 1.82;,95% Cl
ctDNA-guided management grouf
management group (93.5%
results from the DYNAMIC study
OS data. Five-year RFS

Were 93.8% and 93.3% for ctDN,
respectively. "2

with stage ILIV resectable CRC.
months in this cohort, postsurgic
ted with

from adjuvant chemotherapy (H
support ctDNA as a prognostic my
assay and the value of quantificat
studies: Most importantly, the earl

96. National
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ve value in terms of the potential
Hrefore, the Panel believes that
Hs the use of multigene assays,
h estimate tisk of recurrence or
Released similar recommendations
| role in predicting chemotherapy

lencourages enrollment in clinical
jonal data on these assay

[with the age of the patient.»

acy of chemotherapy in older
lecause older patients are

klata speaking to these questions

vant therapy is beneficial in older.
3 patients from the linked SEER-
nefit for the use of 5-FU/LVin
(HR, 0.70; P< .001).%* Another
d with stage III colon
, including the SEER-

the NSABP C-07 trial showed th
gave no survival benefit in patien!
cancer (n= 396), with a trend tow
Cl, 0.86-1.62).° Similarly, in a si
patients aged 70 to 75 years vi]
benefit from the addition of
1.65),25

‘Another pooled analysis aimed t
derive a benefit with oxaliplatin-b}
treatment of high-risk stage I-III
included OS data from 1985 pati
based adjuvant chemotherapy re
patients <70 years, it did not yield]
Similar, results were seen for DF:

were improved with adjuvant CAF]
patients 270 years.

TOSCA trial (part of the IDEA col
multivariable analysis was correct

97. National
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instance, the ORs for 30-day

hrs compared to patients aged 60
1d 8.61 (95% Cl, 5.34-13.9),

f the other hand, had a

[-1.10). However, the absolute risk
br older patients (30-day mortality

| sed with age
i
|

JILV as adjuvant therapy seem to
However, the Panel cautions that
5-FUILV in patients 270 years

III colon cancer.

10 studies involving >
adjuvant therapy after
pwed that each 4-week del
in OS, indicating that adjuvant
as the patientis medically able.
imilar analyses. In addition, a
stage Il or Ill colon cancer from
a delay of >6 weeks between

prolonged postoperative admissi
trial of the ECOG-ACRIN

Leucovorin Shortage

‘A shortage of LV has existed in
available to guide management ul
proposed strategies are empiric.
Options to help alleviate the prob]
is the use of levoleuc

200 mg/m? of levoleu

LV. Use of levoleucovorin should

Another option

all doses in all patients, because
likely to be as efficacious as high
QUASAR study found that 175
survival and 3-year recurrence ra
bolus 5-FU as adjuvant therapy to
Another study showed no differel

98. National
Comprehensive
Cancer
Network

|

|

| ‚as performed with
trol arm for allrecent and current
studies for CRC, and the Panel
d FOLFOX regimen for adjuvant

|< study have been reported with
* For patients with stage Il

UILV arm and 66.4% in the

icantly increased compared with
Lo: HR, 0.80; P=.016).
heral sensory neuropathy was

only 0.2% for patients r

database of adjuvant colon can
in patients with stage III dise:

Adjuvant Capecitabine and CAPI
Single-agent oral capecitabine
III colon cancer was shown to be
(Mayo Clinic regimen) with respe:
(0.87 (95% Cl, 0.75-1.00; P< .00 À
in the X-ACT trial. Final results)
reported? After a median follow
DFS and OS were maintained in 4

Capecitabine was also assessed

cancer in combination with ox

showed animproved 3.

(66.5% vs. 70.9%) 2"

years was improved in the CAPE
% VS. 67%; HR, 0.83; 95% CI

mpared CAPEOX to mFO

high-risk stage II colon cancer.°*

3-year DFS and 3-year OS. In ad

patient data from four RCTs re

capecitabine or 5-FU/LV improve]

99. National
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Cancer
Network

urotoxicity rates
(3% vs. 16% for FOLFOX:
de 2 neurotoxicity rates (14%
0001). Grade 2 and
with the shorter duration of
for CAPEOX).

not meet the prespecified cutoff
In. despite the small absolute
¡s. 75.5% for 6 months; HR, 1.07;

ithin certain subgroups,

CAPEOX (HR, 0.85; 95% Cl

not be proven for, months
195% Cl, 0.96-1.26). In the:high-
was inferior

b Cl, 1.07-1.35), whereas

3- to 6-month comparison with

E reported after an overall median

he final analysis, 5-year OS was

significant difference in 5
(HR, 1.02; 80% Cl, 0,88-1.17).°
IDEA Collaboration reported simil
For the TOSCA trial, 5-year RFS

months of CAPEOX, while the dif
3 and 6 months of FOLFOX (8.54
FOLFOX).*% The OS analysis of

reported an HR of 1.09 for OS in}
0.93-1.26,, P for superiority = 284
Group (HORG)-IDEA trial, 3-year 1
79.3% for 6 months of FOLFOX (
for 3 months versus 83.8% for 6

0.59-1.67).9%

ACHIEVE was another phase III
regarding duration of adjuvant
with stage Il colon cancer.295 T

100. National
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Cancer
Network

tients with high-risk stage I! colon
¡e 3-year DFS rate with CAPEOX
1% in the 6-month arm, with a

P< 0001) and lower rate of

rial°®® have reported similar
adjuvant therapy in patients:

[Ox or 3 to 6 months of FOLFOX
adjuvant therapy options for

ker. Three to 6 months of

ed as preferred adjuvant therapy

| colon cancer. Six months of
itabine are included as other
risk stage III colon cancer. For

ment are 6 months of

months of CAPEOX. Observation
gh-risk stage ll disease, In this
is preferred over the others.

IFLregimenin stage IIAII colon e
-FUILVirinotecan) has not been |
adjuvant setting:10203 Thus, data
containing regimens in the treat

In the NSABP C-08 trial comparit
months of mFOLFOX6 with beval
bevacizumab alone in patients wit
statistically significant benefitin 34
bevacizumab (HR, 0. 95% Cl,
Were seen after amedian follow-ij
IILAVANT trial evaluating bev cial
protocol also did not show a beng
adjuvant treatment of stage II or I
toward a detrimental effect to the
Furthermore, results of the open:
trial showed that bevacizumab had
setting when added to capecitabil
role in the adjuvant treatment of

The NCCTG Intergroup phase III

cetuximab to FOLFOX in the adjuf
In patients with wild-type or muta

101. National
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Cancer
Network

[gnificant trend towards improv
dmab to FOLFOX.*"! Therefore

7) compared the efficacy of FLOX
Hs with stage Il or Ill colon cancer.
ates of 4- and 7-year DFS, 29412
S or colon-cancer-specific
Were compared. Furthermore,
nificantly shorter in the group
00-1.43; P= .0497).% Grade
Were higher with FLOX than with
arisons were made, the incidence
siderably higher with FLOXthan
pde 3/4 diarrhea were 10.8% and
infusiona 5-FU/LV in the
of patients were reported to have
jal when receiving FLOX and
JOX is no longer recommended as

Intensity-modulated RT (IMRT),
treafment planning to focus radial
decrease toxicity to normal tissue,
called stereotactic ablative radiott
clinical situations, such as reirradl
recurrent disease or anatomical
delivery of recommended target
normal issue dose-volume consti

Management of Metastatic
Approximately 50% to 60% of pa
colorectal metastases
unresectable metastatic liver dis
frequently develops metachronou
with the liver being the mo:

102. National
Comprehensive
Cancer
Network

of patients who die of CRC have
tic liver disease being the cause
| autopsy reports of patients who
fs the only site of metastatic
al studies have
etastatic liver
Bertain ciinicopathologic factors,
Pisstases. the presence of more
terval of <12 months, have been
Énts with CRC
an be used for detection and
pening tool in distinct patient
lose who cannot safely receive
have indeterminate liver lesion
UCAS) have a high sensitivity for
of their high spacial resolution
{ation and not in the interstitial
-life (about 5 minutes), contrast
done repeatedly; if a patient has
ld be alengthy test. In addition
plogy or personnelwith the
nalyze the results. At this time

undergone resection of liver met
reported a median 5-year surviv
analyses and meta-analyses havı
metastases have a 5-year OS rat
+40 Therefore, decisions relating td
and subsequent selection for mel
junctures in the management of
(discussed further in Determining

Colorectal metastatic disease som
treatment recommendations disc
disease also apply to the treatmel
metastases." #24: A series of 2
pulmonary metasta

of 78%." Combined pulmonary
metastatic disease have been per
44% and an analysis of patients
by subsequent pulmonary resectl

Evidence supporting resection of
mCRC is limited. In a retrospecti
concurrent complete resection of

103. National
Comprehensive
Cancer
Network

the presence of extrahepatic
ndently associated with a poor
tive analysis Of 43 patients who

t disease, 5-year OS and PFS
respectively. A meta-analysis
with longer
rrences were solitary, smaller, or
lc disease derived more benefit
fensus is that re-resection of liver
carefully selected

tumor and resectable
with a staged or simultaneous
mendations for Resectable
For patients presenting with
rimary that is not acutely

imary is rarely indicated, and
naneuver (discussed further in

achieved.

long as all Visible disease is treat
resection is supported by recent d
(>93%) when thermal ablation wit
zone and margins can be achieve}
time.470 With this approach ablatio
small tumors that can be treated

declared over time. Most cases al
patients who develop multifocal p
spared the more morbid resectio

recurrence is seen, resection

resected or ablated,
Many patients, however, are not

that cannotbe ablated with clear

select patients with tiv.

cannot be resected of ablated, off
options may be offered 472475

104. National
Comprehensive
Cancer
Network

low. The exact role and timing-of
Ihe treatment of colorectal

plantablé pump during surgical

quent infusion of chemotherapy
he hepatic artery (ie, HAIC) is an
dy of patients who had

Hion of floxuridine with

FFU with or without LV was shown
otherapy regimen alone with
disease.*22:0! The study was not

phd (not significant) was seen
group receiving HAIC at later

f study included a phase Il
Lidy that randomized patients who
four colorectal

t (ITT) analysis.
ld a higher median 5-year hepatic

compared with systemic chemoth]
survival benefit of HAIC:42 R
HAIC may be usefulin the conver
aresectable status:#

Some of the uncertainties regard!
chemotherapy are

on the Use of HAIC include the p
requirement of'specific technical
should be considered selectively
experience in both the surgical a
procedure.

Arterially Directed Embolic Thera}

Transhepatic Arterial Chemoem|
TACE involves hepatic artery cat
chemotherapy followed by arteria
accepted variation for the treatm:
eluting bead TACE (DEB-TACE)

agent (DEBIRI). A randomized
months; P= 031) of DEBIRI wh
2013 meta-analysis identified five

105. National
Comprehensive
Cancer
Network

[dy demonstrated DEBIRI to be
technical success rate leading its
ubsequent-ine indications alone,
rated safety and efficacy of
viously mentioned trials, with an
Hing of patients who were able to

hi of 44 patients showed that
therapy can lengthen time to
[more following progression on
The effect on the primary
more pronounced (2.1 vs. 5.6
| tastases with yttrium-90 glass

j
center, phase II study resulted in

with colorectal primaries who
In the refractory setting, a CEA
lt the time of primary resection

ss Additional risk factors include
isease as well.as albumin and
the presence of extrahepatic

icrospheres. Several large case

Results from the phase III randon
resin microspheres with FOLF(
bevacizumab) were reported.5
of yttrium-90 radioembolization
colorectal liver metastases. Althot
ith PFS in the FOLFOX + bevac
monthsin the FOLFOX/yttrium-9q
43), a prolonged liver PFS was di
months for the FOLFOX/yttrium-
chemotherapy only arm; HR, 0.6

The FOXFIRE and FOXFIRE Gio}
manner as the SIRFLOX trial with}
allow assessment of oncologic ou
from 1103 patients in these three
as in the SIRFLOX trial with prold
treated by radioembolization but
as the finding of a median OS
chemotherapy compared to chem
atients with right-sided primary o]
008) Based on these data, fy
the role of radioembolization at el

106. National

Comprehensive
TANT Cancer

Network

microsphere transarterial
[patients with an overall response

L of 2100 Gy predicted a

1 months for those patients with

Impared to metastases with
absorbed dose of > 139 Gy
p with the greatest accuracy. The
63 Gy. While a dose-toxicity

nt was generally well-tolerated
tween dose and response in
hioembolization further

Jelivered dose and oncologic

metastatic. disease. However, pat
can also be considered for tumor]
that may not be optimal for resec
disease that can be ablated with
of the “test of time." Ablatve te
(RFA),4° 5"! microwave ablation (
coagulation (irreversible electrop
‘on theuse of RFA as a reasonaby
candidates and for recurrent dise
metastases that can be treated wi
data describe outcomes of MWA|
because of the ability of MWA to
particular, those related to the he
completely ablate tumors when Id

A prospective cohort study inves

potentially resectable CRC liver n

(SMWA) as opposed to hepatic re [Three-year OS rates were|
78% for SMWA versus 76% for resection (P= .861). Estimated 5-year os}
rates were 56% and 58%, respectively. Overall and major complication:
were lower after SMWA (P< .01), although hepatic retreatments werel
more frequent (percentage increase 78%, P < .01). This supports the use|
of ablation in selected patients with small resectable CRC liver]
Imetastases.

[COLLISION is a randomized phase Il trial comparing thermal ablation to}
Iresection of CRC liver metastases. According to an abstract presentation]
lof data from the COLLISON trial, thermal ablation

107. National

Comprehensive
TANT Cancer

Network

Inoninferior to liver resection in terms of local and distant PI
[OS.51* Thermal ablation showed lower rates of AEs, lower procedure.

related mortality, and a shorter median length of hospitalization. Based on]
[these results

tients to receive systemic
it bevacizúmab) or systemic
® No difference in OS was
years in the RFA group (27.6%
| P= .025). A’subsequent analysis
fe Population in this phase 11 ROT
jmbined modality arm (HR, 0.58;
and 8-year OS of 56.9%,
tality arm compared to-55.2%,
alone arm.455 This study
for patients receiving RFA in
jose treated by chemotherapy
FFA and MWA to systemic
fy in the treatment of CRC liver
rapy alone is no longer justified
© Furthermore, it

that the significance of margin cr
mutant metastases." Recent
have also indicated the superior
in improving local tumor control
liver metastases. The ongoing A
international multicenter single-
which mandates intraprocedural
reablation when margins are <5
control rates to over 90%

Regarding pulmonary ablation, a
French cancer centers that enrol
lung metastases (the majority cold
with RFA and 136 patients (24%)
years 1 through 4 were 40.2%,
Five-year OS after RFA in CRC pl
67.5% depending on risk factors.
the latest years with a report indi
tumors ablated with margins ol
within this database study was 1
pneumothoraces requiring proto

A multicenter, prospective phase|

108. National
Comprehensive
Cancer
Network

tudy aimed to evaluate the

br local tumor control in patients
years of follow-up. The cohort
ing tumors, each with a diameter
tumor control, both per tumor
luded cancer-specific survival,

at 3 and.5 years
3.3% and 75.0% per patient,
and 55.3% at 5 years, and OS
ars, Patient quality-of-life scores

discontinuation of chemotherapy
ry disease. "98. The median

hi between ablation and resuming
erapy)was 12.2 months. Patients

ja longer median chemotherapy-
(20.9 vs. 9:2 months).

¡combination with resection)
Itastatic disease that is entirely
margins. Use of surgery,

tumor debulking vs. 27.5 months|
95% CI, 0:70-1.10; P= .2:

Liver or Lung-Directed External À
EBRT to metastatic sites can be ¢|
patient has a limited number of
other select locations; orif the pat
clinical trial. It should be delivere:
‘should not be Used in place of su
include three-dimensional confor
IMRT. which uses computer-assi
radiation to the tumor site and pol
tissue 118.5258

While. CRC has been shown to b
histology,° multiple studies hi
with minimal toxicity using SBRT
lung®®°5s5 metastases. In addition]
treat multiple metastatic le
randomized phase Il trial with mul
number of CRC origin, an
demonstrated an improvement in
standard-of-care treatment.’ An]

109. National
Comprehensive
Cancer
Network

C have peritoneal
loneum as the only site-of

pstases generally have a shorter

5 The goal of
metastases is palliative, rather
ystemic therapy (see Systemic
ease) with palliative surgery or,
nding obstruction, 5% If an RO

ion of isolated
experienced centers. The Panel
Jon or rectal stents
el perforation.°2559

ic Intraperitoneal Chemotherapy
have addressed the

without
RCT of this approach, Verwaal et
dard therapy (5-FU/LV with or
ve CRS and HIPEC with

given to 33 of 47 patients. OS
ld 22.3 months in the HIPEC arm.

point is that the trial included pati
appendiceal origin, a group that I
CRSHIPEC approach. 555857751
reported median OS times of 30 a
carcinomatosis of colorectal origi
treated with HIPEC or with CRS 4
chemotherapy.“ The median O:
from mucinous appendiceal carci
of publication. Aretrospective inte
15-year survival rates of 63% and |
from mucinous appendiceal carci
HIPEC was not shown to be assq
study, whereas completeness of
PMP, optimal treatment is stil un

More recently, the randomized, pf
reported results from 265 patient
carcinomatosis who received star

chemotherapy before and/or after
treatment plus HIPEC with oxalip!
study reported no significant diff
months ih the HIPEC arm versus!
While the morbidity rates did not c

110. National
Comprehensive
Cancer
Network

approach have not been Well

[gested that the hyperthermia
Results of retrospective

not affect outcomes from the
trial compared systemic 5-
I 5-FU without heat 5%: Although
accrual, analysis suggested that
p been superior to the systemic
38%; P = 04) for patients with

ality are associated with this
RCTs and 12 other studies
% to 44% and mortality rates
recurrences after the procedure.
[are reportedly decreasing with
5% mortality rates at centers of
roach have not been definitively

Versial

| use of perioperative system
[tonel metastases. An

proportions of patients on the st
CRSHIPEC (89% vs. 86%) and 1
versus 33% between the perioper
respectively. Grade 23 systemi
35% of patients and ORRS M
(major pathologic response) follo

The Panel currently believes that
chemotherapy can be considere
patients with limited peritoneal mi
achieved. However, the significa
HIPEC, as well as the conflicting
approach very controversial.

Determining Resectability
The consensus of the Panel is thy
resectable mORC should undergf
multidisciplinary team, including a
experiences hope áugeon in d
assess resectability status. The A
for resection of metastatic diseas: À
resection of all evident disease v

111. National
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Cancer
Network

ctability of patients
lof Synchronous Metastatic

In to Resectability

hetastatic colorectal disease have

fe with liver-limited unresectable
critical structures, cannot be

hed, preoperative systemic

H in highly selected cases in an

les and convert them to a

jth large numbers of metastatic
achieve an RO'resection simply

by. as the probability of complete

stemic therapy alone is low.

feng unresectable dis:

i

4

E highly selected cases, how
ant response to conversion
table to resectable disease

complications following hepatectd

after the patients disease b
addressing various conversion th}

metastases were treated with FO!
tumor reduction and 17 patients (
toundergo resection after amedia
In another study, 1104 patients w
metastases were treated with che}
the majority of cases, and 138 p
responders" underwent secondal
rate for these 138 patient
retrospective analysis of 795 pre!
enrolled in the Intergroup N9741
mostly oxalipla

112. National
Comprehensive
Cancer
Network

bas higher in the group receiving
OS of 23.4 versus 16.7 months

je disease as an

egimens. See the following
nent approaches.

ith initially unresectable
rgical re-evaluation be planned 2

al re-evaluation every 2 months
iated with chemotherapy include
usoidal dilatation, steatosis, or
lopment of hepatotoxicity, itis
performed as soon as possible

while receiving abev:

group receiving chemotherapy al
3.49 ly: P 8

bevacizumab or chemotherapy al

the incidence of wound healing cf

was low (1.3% vs. .0:5%;

quality-of-life scores
bevacizumab than in those recei\
liver metastases, but no conclusi
endpoint of DES!

The role of bevacizumab in the pl
disease is feltto be potentially cor
in tumor size, has also been stud
bevacizumab modestly improves
regimens."°'5 Thus, when an in

use of bevacizumab with oxalipla
resectability setting are mixed. Or

113. National
Comprehensive
Cancer
Network

bevacizumab with
le.

iplatin-

and TRIBE2 studies compared
lo chemotherapy doublets
Ib for oligometastatic mCRC.*!? In
bm these studies, the benefits of
to the doublet were retained in
pstatic disease, with interaction P
and ORR outcome measures.
Jude that FOLFOXIRI provides a
when used as upfront treatment
ts, such as resection. The
jo compared FOLFOXIRI to
With bevacizumab for patients
hors in one of its cohorts.*!9 This
F LFOXIRI in combination with
Jd with the doublets (10.6 months

Int FOLFOXIRI plus bevacizumab
nab reported a higher RO

More recent favorable results of
FOLFIRI, FOLFOX, or FOLFOXI
inhibitors for the purpose of con
resectable disease have been rep
Il trial, patients were randomized

FOLFOXG or FOLFIRI."2? Retros|
treatment arms combined resecte

‘chemotherapy in patients with wil
addition of cetuximab (P < .0001

the median OS of the entire cohdl
months), with no difference betw

chemotherapy (mFOLFOX6 or FA
alone in patients with unresectabl
primary endpoint was the rate of

evaluation by a multidi

patients in the cetuximab arm an

arm were determined to be eligib|
resection rates were 25.7% in th

arm (P< .01). In addition, surget

compared to unresected participa
patients receiving cetuximab (46.

cetuximab arm and 36.0 vs. 19.6

114. National
Comprehensive
Cancer
Network

h-resectable mCRC.225.0F the

fvertible metastases, 75% were
FOLFOXIRI + panitumumab

bne. ORR was also improved in
LI alone while PFS was similar

pwed a trend in favor of the

dy compared mFOLFOXIRI plus
imumab as initial therapy for 43:

IF wild-type mCRO:2162 This trial
erapy regimen did not provide

5%), early
47%), RO
PFS (12,7 vs, 12.3 months)
panitumumab and mFOLFOX
jing these data, the NCCN Panel
FOLFIRINOX with cetuximab or

While there-are no clinical trial dal
studies have reported notable res

or MORO. >! The Panel not
monitor for signs of progression
previously resectable tumor to bq
concem for any regimen being u
resectable mCRC setting, the ris
compared to traditional chemoth

Perioperative Therapy for Res
Disease

Perioperative administration of cl
patients undergoing liver or lung
with the goal of increasing the lik
will be eradicated. A meta-anal

115. National
Comprehensive
Cancer
Network

land safetyftoxicity issues

in the guidelines. Biologi
fretastatic setting, with the

tn unresectable disease that may
leckpoint inhibitor immunotherapy
tion-positive dise:

Nuating use of perioperative

after surgery) for patients with

solute improvements in 3-year

25) for all eligible patients and all
hen chemotherapy in

‘only arm and 59% of the
thermore, a multi-institutional
ly and efficacy of preoperativ

liver metastases demonstrated
OS and PFSrates were

ENTES AVEO
The Panel thus recommends agal
perioperative treatment for resec
The Panel also notes that cetuxi
with caution in patients with unres]
converted to a resectable status.

The optimal sequencing of syster
unclear, Patients with resectable
followed by postoperative adjuval
perioperative (neoadjuvant plus pl
Used.

Potential advantages of preoperal
micrometastatic disease, determi
(which canbe prognostic and hel

avoidance of local therapy for thd
progression. Potential disadvant

opportunity" forresection becausd
or achievement of a complete re:
identify areas for resection.

with CRC receiving preoperative
still present in most of the origin

were examined pathologically de:

116. National

Comprehensive
TANT Cancer

Network

lin-based chemotherapeutic
5322 Toreducethe development

H is usually limited to 2 to 3

y monitored by a multidisciplinary

q
| agents. The choice of therapy is
[erapy, the type and timing of prior
por, and the differing toxicity

h the specific regimens listed in
P lines of therapy, itis important to
psenta continuum of care and that
Dr than discrete.” For example, if
frita treatment regimen butis
ing neurotoxicity, continuation of
would still be considered initial

apy include: 1) preplanned
je exhibiting a tumor response or
ogressive: and 2) plans for

‘Sequencing and Timing of Thera
Few studies have addressed the
metastatic disease. Prior to the u
randomized patients to different s
suggest that there is litle differen
therapy is given in first line or if |
followed by more intensive comb|

Results from arandomized study
FOLFOX regimens as initial therq
sequential therapy with the altern|
showed neither sequence to be si
or median OS." A combined anal
trials in advanced CRC provided

increase in median survival and ad
(ie, 5-FU/LV, oxaliplatin, irinoteca
care.*** Furthermore, OS was not]
which these drugs were receive

A study of 6286 patients from nit
risks associated with intensive fir
treatment showed similar therape}
Performance status of 2 or 1 or

117. National

Comprehensive
TANT Cancer

Network

lusing a fluoropyrimidine with bevacizumab followed by the addition of]
loxaliplatin at first progression.*** Sequential treatment showed superiority
in terms of time to failure of strategy (15.2 vs. 7.8 months; P< .001);|
however, median OS was similar between the sequential and combination
1.28; P= .61) and

farm (51.7% vs. 33.1%;

regimen to be preferable over
isease. The Panel also does not
used as part of initial therapy (ie,
none). See First-Line Systemic

data supporting bevacizumab
rt of the initial therapy regimen,

temic therapy

Most studies that have reported
Le, detailing institutional

or targeted therapies
ded that a retreatment approach
toxicity data. However, these
Herentiate between patients who
compared to other reasons,
domized phase II FIRE-4 trial
ing first-line treatment efficacy of

progression on that regimen is nd
Maintenance Therapy

Interest in the use of a maintenar
treatment of unresectable mCR(
involves intensive firstdine therap
progression in patients whose di
treatment.

The CAIROS study was an open.
assessing maintenance therapy

until second progression (PFS2),
the primary endpoint of PFS2 wa]
arm (8.5 vs. 11.7 months; HR, Of
54% of patients overall receiving q
Quality of life was not affected by}
patients in the maintenance group
the maintenance period. Anon-sig
seen in the maintenance arm (18
95% Cl; 0.68-1.01; P= .06). An

118. National
Comprehensive
Cancer
Network

EOXIbevacizumab to no

therapy with

vacizumab alone,®®" The planned
pry therapy after first progression
[or strategy: defined as time from
ath, and initiation of treatment

7.6) for the no

1-8.5) for the

Jd 6.1 months (95% Cl, 5.3-7.4)
jared with
[mab alone was noninferior,
erapy was not. However, only
led the re-induction therapy, thus
[was one of the secondary
Ifference was seen between the

trial that investigated the effect of
no treatment during

duction chemotherapy with 12
ledian tumor control duration was
pnd 8.9 months and OS was 21.7

0.96), and no difference in OS w:
0.83; 95% Cl, 0.63-1.1; P= 2).
holidays versus bevacizumab mal
demonstrated.

progression on bevaci
bevacizumab or bevacizumab plu
advantage in PFS (5.4 vs. 4.9 mo}

06) and. OS (24.9 vs. 2

type tumors 1 A meta-analysis i
Patients) and concluded that main
bevacizumab/erlotinib si
manageable toxicity.””

Another phase Ill trial investigate
maintenance phase; after initial tr
PFS, the primary endpoint, was 6
maintenance group and 3.4 montf

119. National
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Cancer
Network

ed decision-making with patients,
jative.

highly similar to and has no

xisting biologic therapy. Several

market, including biosimilars to,

Ihe NCCN Guidelines for Colon
ICCN Panel has agreed that
approved biosimilar may be

stuzumeb wherever these,

ICCN Guidelines for Colon

ent of advanced CRC or mCRC
NCCN Panel has expanded its
sting, Currently, determination of
BRAF mutations, as well as HER2
lot previously done), are

esting may be carried out for

ith NGS being preferred.

lg able to pick up rare and

type mORC who received EGFR
received combination cytotoxic cl
received the targeted therapy

mutations (46%) than those who

KRAS and NRAS Mutations

The MAPK pathway of RASIRAF

mutationsin components of this p
negative predictive markers, ess
therapies. A sizable body of litera
mutation in exons 2, 3, or 4 of ei

essentially nsensive to cetuxim
Panel therefore strongly recomin
tumor (either primary tumor or mq
Patients with known KRAS- or NR
with either cetuximab or panitumuf
other anticancer agents, because}
and the exposure totoxicty and e
to this is when cetuximab or pani

sotorasib or adagrasib for tumor}

Systemic Therapy Options for KA

120. National
Comprehensive
Cancer
Network

IV (21.8%), and G13D(18:8%),5
17% of KRAS-mutated mCRC
prognostic value of KRAS
plients with KRAS exon 2-mutant
tients with tumors without such
outcomes with

Ih tumors with Wild-type
3 or 4 or in NRAS exons 2, 3,
's with tumors without
in exons 3 and 4 of
lof NRAS. A predefined
in PRIME revealed that PFS (HR,
DS (HR, 1.21; 95%C1,11:01=1.45:
tumors with any KRAS or NRAS.
Is FOLFOX compared to tho:
results show that panitumumab
NRAS-mutant tumors and may
patients.

cussed in Cetuximab or

[Line Therapy, bel

positive disease in combination w

A retrospective studyby De Rood
13 mutations (G13D) in. KRAS md
response. Another retrospective s

panitumumab.

assessed the benefit of cetuxim:
refractory mCRC whose tumors
primary endpointof 4-month prod]
no responses were seen. Prelimil
CREAM trial also did not see ab
Patients with KRAS G13D-mutan y
were reported after treatment wit
irinotecan-refractory population.
the same conclusion: that tumors
likely to respond to EGFR inhibite
mutations.

The recommendation for RAS tes]
apreference regarding regimen
this early establishment of RAS sf

121. National
Comprehensive
Cancer
Network

\$ genotyping can be performed
ay tumor or a metastasis: Fresh
hr the purpose of RAS genotyping
lr the primary tumor or a

characterized by a
701 BRAF mutations are,

prs that do not have RAS

[product of the non-mutated BRAF

Jd KRAS protein in the EGER

hauct is believed to be

ly bypassing inhibition of EGFR

[ve subset analyses of patients
fig suggest that although a BRAF
s regardless of treatment, patients

In subsequent lines of therapy, r
mutated BRAF is a marker of resi
first-line setting of metastatic dis:
primary tumor samples from pat
disease show

response rate to cetuximab (
type BRAF (124/326, 38.09
multicenter randomized controles
conclusion, with a suggestion of
panitumumab to irinotecan in the
of patients with BRAF-mutant tu

A meta-analysis published in 201
phase Il trial that compared cet
therapy or best supportive care i
colorectal tumors with BRAF muta
settings).”'* The addition of an EG
0.88; 95% Cl, 0.67-1.14; P= .33)
63), or ORR (RR, 1,31; 95% Cl,
control arms. Similarly. another m
found that cetuximab and panitut
95% Cl

BRAF-mutant tumors.719

122. National
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Cancer
Network

patients with stage II and II!
trial showed that the BRAF
with MSI-Lor MSS tumors (HR,
‘over, an updated analysis of the
metastatic colorectal tumors
prognosis than those with the
tation status predicted: OS.in the
-0.73; P =.001).72
mors in the COIN trial was 8.8
Mutations and wild-type KRAS
nths and 20.1 months,
analysis of the NO147 and:C-08
Jgnificantly associated with wor
Je 111 colon cancer, with astronger
the distal colon. Results from a
885
y accompany specific high-risk
ticular, an association was

1 a obi
the Non-First-Line Setting, below
genotyping of tumor tissue (eithe
diagnosis of stage IV disea
H/dMMR and BRAF-V600E, first
would generally be preferred and
in a later line of therapy,

HER2 Amplification/Overexpress|
HER? is a member of the same fi

RAS/BRAF-wild type tumors (rep
molecular diagnostic methods ha
„92 and HER2-targeted therg
‘subsequent therapy options in pq
ression (see Systemic TI
Disease, below).7997% Based on
Cancer recommend testing for H|
mCRC. More information on HER
the Principles of Pathologic and
algorithm,

123. National
Comprehensive
Cancer
Network

ical trials and was 6.5% in the
[sionals Follow-up Study.2#079778
ations, which Gan encode mutant
ped and targeted by the immune
Ends 1 and 2 (PD-L1 and PD-L2)
response by binding to the
receptor on T-effector cells: This
pn unchecked immune response.
I evade the immune system.” it
[tumors may be sensitive to PD-1
f vas confirmed in clinical trials,
fons for checkpoint inhibitors for
inhibitor Immunotherapy for
Positive Diseasein the First-Line
s, below), The NCCN Guidelines
AMR or MSI testing for all patients
ancer. In addition to its role as a

proofreading functions that corre}
replication. Pathologic variants wi
proteins resultsin loss of the prod
acquisition of downstream mutatich
POLE or POLD? are found in pol
polyposis (PPAP), which predisp. 1
carcinomas. Management recom

the NCCN Guidelines

G Ei

‘occur in approximately 2% to 8%

somatic POLD1 pathologic varian!

Similar to dMMR/MSI-H, CRC wi
a more favorable prognosis for std
response; although this associatig
disease. Since POLE/POLD! A
hypermutated phenotype in CRC. |
that pMMR CRC with POLE/POL|
from checkpoint inhibitor therapy]
patients with POLE mutation-posi
identified POLE mutations, 15.09
and 69.1% were of unknown sig

124. National
Comprehensive

[cOn] Cancer
Network

laimed to characterize the molecular

ALK, ROS1, and NTRK rearranged mC

timated that
gene fusions. "7% A study of
jad NTRK fusions, found that
lat were wild-type for KRAS.
ity of the CRCs harboring NTRK
Filarly, in a smaller study that
nd clinical landscape of
76.9% of NTRK rearranged
hibitors are treatment options for
'usion-positive (see Systemic
ive Disease in the Non-First-Line

ceptor-tyrosine kinase that plays

2), in those with right-sided t
those with unresected primary tul

samples compared to RET-negat
RET gene fusion-positive sample:
highly
for patients with mCRC that is RE]
for RET Gene Fusion-Positive Di
below)

Tumor Mutational Burden

Tumor mutational burden (TMB)
coding mutations within a given eq
be quantified using NGS techniq
Potential biomarker for response
has been FDA-approved for pati
TMB-high (TMB-H) solid tumors
treatment and have no satisfactor
is defined in the label as=10 mu
test. This approval was based on|
study that enrolled patient 4
TMB-H tumors who were treated y

125. National

126. National

127. National
Comprehensive

128. National
Comprehensive
Cancer
Network

ional 5-FU regimens seem to be
ny bolus regimen of 5-FU is
ther irinotecan or oxaliplatin

nds using the IFL regimen

ped mortality and decreased

LC trial9147% and inferior to
[point in the therapy continuum. 5-
latin should be administered via
becitabine can be used with

y results for the use of
first-line treatment of mCRC.

rhea, and dehydration.®" In this
| The EORTC study 40015 also
Is discontinued after enrollment of

IR! in combination with

differing toxicity profiles reported
in both arms. Finally, a randomiz
study group compared CAPEOX
DapelRI regimen plus bevacizum
similar toxicities.”®2 Because of th
DapelR! combination, which may
European descent, the Panel dog
CapelRI/Bev for the first-ine tred

Dther drug combinations that hav
tfialsfor the treatment of advancı
cetuximab plus brivanib, erlotinib
FOLFOX/CAPEOX, and atezoliz
regimens are not recommended

Results from two randomized pha|
therapy with more than one biolo,
‘outcomes and can causé increast
addition of panitumumab to a regi
based chemotherapy plus bevaci
shorter PFS and higher tox

gene groups." Simi

addition of cetuximab to a regime}

129. National
Comprehensive
Cancer
Network

ith an increased incidence of
Its of the OPTIMOX1 study
g oxaliplatin-free intervals
id not affect OS in patients
disease 5 Other trials
latment breaks, with or without
‘city can be minimized with
He-analysis of RCTs also
jystemic therapy does not
treatment. ® Therefore, the
Lie/timing of the administration of
iscontinuation of oxaliplatin from
y considered after 3 months of
rotoxicity, with other drugs in the
ths or until time of tumor
Ltoxicity on oxaliplatin should not

OS for patients receiving the OP!

undergoing-an early, pre-planned
IS, 23.8 vs. 19:5 months; P

disease control, which was the pı

statistical significance at 13.1 mon

therapy and

046), 08

The CONcePT trial also tested ar
patients with advanced CRC and
sensory neuropathy (P= .037) où
of oxaliplatin breaks also improv

= 0026) and time to tumor progré

Early data suggested that calcium
oxaliplatin-related neurotoxicity.
double-blind NO8CB study, whict

cancer receiving adjuvant FOLF
placebo, found that calcium/magi |
sensory neurotoxicity,’ The Par
calcium/magnesium infusions for

CAPEOX for First-Line Therapy

130. National
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Cancer
Network

ntinuation of
buld be strongly considered after
proach®®%), or sooner for
rugs in the regimen maintained
logy Group Trial showed that this
ive in first-line therapy with
‘ed FOCUSA:N trial compared
ive monitoring in patients with
While there was no significant
b(15.2 monthsin the capecitabine
bring arm [adjusted HR:0.93; P
ecitabine arm (3.88 months
pnitoring arm [adjusted HR, 0.40;

xaliplatin should not receive
inless they experience near-total
pl recommends against the use of
xaliplatin-related neurotoxicity.*"

apecitabine use, the Panel noted
may accumulate
quire dose modification: 2) the

hand-foot skin reactions were asi
41.0 months; P=.001; HR, 0.

The addition of bevacizumab is a
therapy 2520 With resp
bevac

analysis of >2000 patients suppot
combinations.°°

FOLFIRI for First-Line Therapy
Evidence for the comparable effi
from a crossover study in which
FOLFIRIasinitial therapy and wer
disease progression.'%? Similar re
obtained when these regimer
support for this conclusion has cq
comparing the efficacy and toxicit
previously untreated patients with|
in response rate, PFS times, and|

A randomized phase III stud

131. National
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Cancer
Network

y certain genetic polymorphisms
ith accumulation of unconjugated

q of the Crigler-Najar and Gilbert
¡sed with caution and at a

UGT1A1 genotype." The
every 3 weeks was 850 mg, 700
“4/1728, and *28/°28 genotypes,

the UGT1A1"28 allele, which is
Bion and, hence, reduced levels of
f added to the label for irinotecan
[f the drug should be used in
T1A1"28. A practical approach
ith respect to patients receiving

CUNT PUS Bev y
bevacizumab with regard to PFS.
bevacizumab to FOLFIRI is recon
alternatively, cetuximab or panitu
characterized by wild-type RAS/
regimen.*e6.107.637638

Infusional 5-FU/LV and Capecita
For patients with impaired tolerar
guidelines recommend infusional
bevacizumab as an option.’
Withino improvement in fu
therapy should receive best supn
improvementin functional status
specified for initial therapy for ad
associated with capecitabine use |
In a pooled analysis of results fro
patients with a potentially curativa
randomly assigned to either postd
FU/LV or observation alone after
months in the chemotherapy arm
surgery alone (HR, 1.32; 95% Cl,
difference in OS.**:

132. National
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Cancer
Network

In investigated in two randomized
[NO group, statistically significant
fis; HR, 0.63: P = 0006) and

70; P = 032) were observed in

| citterence was seen between
han OS was 19.5 and 21.5 months
ely; P= 337). Both studies

[OLFOXIRI arm (eg, significant

p rate of toxic death were reported
the GONO trialwith amedian.

|

ja,°% diarrhea, alopecia, and

|

he The improvements in. PFS

Ing bevacizumab to FOLFIRINOX:
table metastatic disease. Results
ial showed that

ficreased PFS (12.1 vs. 9.7

i
Ri/bevacizumab in patients

Hs who received prior adjuvant

À
À
[
Min in the adjuvant regimen).

bevacizumab followed by FOLFIR
679 patients with unresectable, pl
primary endpoint of median PFS |
compared to 16.4 months for thel]
0.63-0.88; P

the FOLFOXIRI group compared

Results from the randomized phq

FOLFOXIRIbevacizumab arm (
the primary endpoint of overall (
95% CI, -11

A pooled analysis of TRIBE and
individual patient data from CHAR
TRIBE2" reached similar conclu}
analyses concluded that first-line}
bevacizumab yields signifi

133. National
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Cancer
Network

hours)
Bon to have greater toxicity
fin? over 46 hours) is a starting
Lis in the United States
| antibody that blocks the activity.
ft role in tumor angiogenesis,
fed biosimilars may be substituted
fs recommended within thes
ore information): Pooled results
have shown that the addition of
ved OSin patients with
+ receiving these regimens
d analysis of the results of these
lumab to 5-FU/LV was associated
[6 months for regimens consisting
ithout bevacizumab (P = 008)
ing bevacizumab plus IFL

not reach statistical significance (
077).*'® Researchers hav
study comparisons of NO

between trials, although th

occurred after the responses wal
analyses evaluating the benefit of
Br CAPEOX inticated that bevac

134. National
Comprehensive
Cancer
Network

ef for the use of bevacizumab
eta-analysis of six randomized

y of bevacizumab in
fpevacizumab gave a PFS (HR,

1d OS (HR, 0.84; 95% Cl, 0.77—
jr, subgroup analyses showed that

ith stage IV CRC diagnosed
).357 The survival

st-line chemotherapy appears to

e addition of bevacizumab to
r incidence of treatment-related
E 95% Cl, 1,021.73; P:
lenia (12.2%), and GI perforation

therapy in patients with CRC.
surgery, such as peritoneal stripy
perforation. A small cohort of pat
an unacceptably high rate of GI p
bevacizumab.

may be a risk factor for Gl perfora
primary. tumor does not seem to i
FDA approved a safety label wari
sometimes fatal and usually se:
perforation; or fistula formation al

Use of bevacizumab may interfer}
retrospective evaluation of data f
patients undergoing chemothera;
therapy for mCRC indicated that
‘complications was increased for
surgical procedure while receivin|
compared with the group rect
major surgery (13%,
chemotherapy plı

administered after surgery, with 4
bevacizumab administration of at

135. National
Comprehensive
Cancer
Network

es of the drug’?") between the last
rgery. Additionally, re-initiation of
6 to 8 weeks postoperatively.

tion of anti-VEGF therapy might
ice, more aggressive tumors on
Étrospective meta-analysis of five
I trials including 4205 patients
lor pancreatic cancer found no
vith discontinuation

Its are supported by results from
ial included patients with stage I!
recurrence, mortality, (or mortality
een patients receiving

rol arm. These results suggest
ith bevacizumab us:

ne Therapy in KRAS/NRAS Wild-

onal antibodies directed against
Ing pathways. Panitumumab is a

MCRC29! Patients w
not be treated with either cetuxing
combination with other anticancerf
chance of benefit and the expost
justified (see Biomarkers for Sys
Mutations, above for more inforn
below.

Administration of either cetuxim:
with severe infusion reactions, inf
patients, respectively.”° Bas |
administration of panitumumab sch
experiencing severe infusion reach
side effect of both of these agen]
infusion reactions. The incidence]
cetuximab and panitumumab see!
presence and severity of skin re

drugs have been shown to predid
survival, 563 66 685.688 An NCCN tas

dermatologic and other toxicities

Cetuximab and panitumumab ha

venous thromboembolic and othd

136. National
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Cancer
Network

EGER inhibitors in mCRC.
ith mCRC treated with cetuximab,
first-line or subsequent lines of
lyzed based on sidedness of the
En in the patients with right-sided
e rate of 41% in those with left-
PFS was 2/3 and 6.6 months in
Imors, respectively (HR, 3.9)

/e value of primary tumor
forsisin the first-line treatment of

ed primary tumors (cecum to
with bevacizumab than if treated
% C1.0.93-1.99, P= 10).
left-sided primary tumors (splenic
led with cetuximab than if treated
l50-0.99; P= .04).°°' Os was
jzumab in the left-sided primary
ed in the right-sided primary
tive analyses of other

his finding.

‘or panitumumab in the first-line tr
also suggests that sidednessis pr
in subsequent lines of therapy,

definitive studies. Until such data}
RAS/BRAF wild-type tumors can
cetuximab in subsequent\ines of]

Cetuximab with FOLFIRI: Use of
disease was investigated in the
randomly assigned to receive FO}
Retrospective analyses of the sul
tumor status showed a statistical
with the addition of cetuximab in
0.68; 95% CI, 0.50-0.94; P=.02)
PFS for patien

was confirmed in a publication of}
data.” This study included a retr
exon 2 wild-type population and f
cetuximab (23.5 vs, 20.0 months}
cetuximab did not affect the quai
trial. As has been seen with ot
DRYSTAL trial were re-analyzed

137. National
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Cancer
Network

led ORR (61% vs. 37%; OR, 2.54;
disease progression (7.7 vs. 7.2
95% Cl, 0.36-0.91; P= .016)

setof patients with KRAS exon 2
nificant

rting the statistically
ized by KRAS

months in both groups; P-

kimab to FOLFOX or CAPEOX as

ly advanced CRC or mCRC and
alyses of the COIN trial

nefitto the addition of cetu

this result, reporting benefits in Ff

(20.7 vs. 17.8 months; P = .02), 4

with first-line cetuximab plus FO!
tients

Panitumumab with FOLFOX: Pa

FOLFOX6%8827 or FOLFIRI“* has
treatment of patients with mCRC. |
randomized PRIME trial comparin
FOLFOXalonein patients with KI
showed a statistically significant i
0.58-0.90; P= .004) and OS (HRI
the addition of panitumumab.°°° TH
and panitumumab remains an opt
advanced or metastatic disease. |
had a detrimental impact on PFS

mutated KRAS/NRAS in the PRIN

NRAS Mutations within Biomarka]

138. National
Comprehensive
Cancer
Network

878) or deepness

diarrhea occurred in
¡anitumumab versus 23% of
mumab group

faring CAPEOX/cetuximab versus
fended RAS/BRAF/PIK3CA wild-
ss no significant difference in

Ituximab versus,

66.7%, respectively (P= .298)

ICI, 74.2%-94.4%) for the

h (95% Cl, 73.9%-96.9%) for the
se data, the Panélinow

br panitumumab in-addition to

b for initial therapy for advanced

lumab in First-Line Therapy: The
E-3 trial from the German AIO

| plus cetuximab to-FOLFIRI plus
lwild-type, metastatic disease.

population of 31 months with cet
bevacizumab, along with improve
the per-protocol population with q
the groups and the advantage for|
left-sided primary tumors.

The phase Ill PARAL
bevacizumab

M trial. ev

panitumumab showed a signi

of the first-lineregimen compared
the left-sided tumor population (
the full analysis set(36.2vs. 31.3|
between the treatment groups, RI
with panitumumab. The Panel no
separate until well after the medi
panitumumab may be related to w|
therapy rather than the choice of

Results of the phase II! CALGB/H
FOLFOX/FOLFIRI with cetuximalf
this study, patients with wild-type]

139. National
Comprehensive

[cOn] Cancer
Network

y ep ae
1, 0.44-0.96; P=.03). A trend. vith 60% of patie|
28.9 months; HR, 0.63; 95% Cl, crossing over to pembrolizumab

IF the PEAK trial confirmed that course of the study.
PFS compared to
vild-type RAS tumors (12.8 vs, A follow-up health-related quality-
96; P= .029).""° Although these Part of KEYNOTE-177 revealed d
are hindered By the small sample » ‚Quality of life with pembrolizumab versus chemotherapy based on]
European Organisation for Research and Treatment of Cancer Quality of
Life Questionnaires (P = .0002).*

mab may be more cost-effective
for mCRC,% although more Likewise, the phase Il Che 1
in combination with ipilimumab fof
mCr In the first-line cohort, |
ition of cetuximab, panitumumab, 53% 82%) and DCR 84% (95% q
valent choices inthe firstiine,=» up of 29months: Thirteen percer
response and the median duratior]
]

Peas: a or POLE/POLD1 treatment-related AEs and AEs led

Y 2022 abstract reported 5-year fol
by investigator assessment incre:
progressive disease rate of 16%.
51% and 72%, respectively. Addi

(including nivolumab alone or in

E YNOTE:177 study evaluated the

140. National
Comprehensive
Cancer
Network

Ion of nivolumab plus ipilimumab.
IS compared to. chemotherapy,

progression ordeath (HR, 0.21
pafety signals were observed, and

(23%
E irmunotherapy combination end
not yet been presented.

itors are generally well tolerated,
je-mediated—occur inas many as
¡common immune-mediated side
tract, lungs, and endocrine
approximately 3% to 7% of

is one of the most serious side

fends pembrolizumab
fin combination with ipiimumab,
Is with MSI-H/dMMR mCRC.
is recommended. The
mab is category 2B when
to concerns about potential

Second-Line or Subsequent Syst

The recommended therapy optior
have received prior therapy are d

and are outlined in the guidelines;
after first progression has been sh
to best supportive care °° orinfug
etal,* median PFS was 4,2 mon!
5 FU( 030), whereas Cunnin|

year of 36.2% in the group recel
supportive care group (P= .0001

that there wasno OS benefit to FA]
alone.“ Furthermore, no signifid
the Intergroup N9841 trial when Y
monotherapy after first progress)

A meta-analysis of randomized tr
agent after first-line treatment im
toxicity.# Another meta-analysis|
continuing an anti-angiogenic agi
angiogenic agent in first-line. D}
are discussed below.

Cetuximab and Panitumumab in

141. National
Comprehensive
Cancer
Network

bf response to EGER inhibitors in
waits more definitive studies to
lable, all patients with

sidered for panitumumab or

y if neither was previously gi

b and Primary Tumor Sidedness,

ie agent in the setting of mCRC
aliplatin/irinotecan-based

trial # In a retrospective analysis

nown KRAS exon 2 tumor status,

Supportive care was shown to be

Jild-type tumors." PFS was 12.3

panitumumab arm. Response

0% in the wild-type and mutant

se Ill trial compared single-agent

tients with wild-type KRAS

aiplatin- and irinotecan-based

lof OS was improved with

0.73; 95% Cl, 0.57=0.93; P

panitumumeb in combination w
second-line therapyhas an acceı
multicenter PICCOLO trial; which
irinotecan/panitumumab, did not
in patients with wild-type KRAS/

Cetuximab has been studied bot
combination with irinotecan™® in y
progression on initial therapy not!
for metastatic disease. Results of |
irinotecan with or without cetuxin
showed significant improvement i
irinotecan and cetuximab compar
KRAS status was not determ ned
the cetuximab-containing arm (ef
imbalances) ** In a re-analysis off
months; HR, 0.57; 95% Cl, 0.46-
5.0%; OR, 8.1: 4.04-1
cetuximab plus irinotecan compas

142. National
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Cancer
Network

umab and 10.0 months (95% CI
h Cl, 0.84-1.11). The incidence of
je final analysis of ASPECCT

imab (HR, 0.98; 95% Cl, 0.82-

lose disease progressed on first
OLFIRI plus
ab.’ No difference was seen in

Cl, 0.6:
these treatment effects y

Similar results were reported froi
randomized BEBYP trial, in which

bevacizumab plus a different che
on bevacizumab was 6.8 months
arm (HR, 0.70; 95% Cl, 0.52-0.9
was also seen in the bevacizumal

04): The EAGLE trial randomized
following oxaliplatin-based thera

therapy with FOLFIRI plus either
difference was seen in PFS or tim
indicating that 5 mg/kg of bevaciz]
line treatment of mCRC.

The continuation of bevacizumab}
was also studied in a community
analysis of 573 patients from the
medical record system.” Bevaci
associated with a longer OS (HR.
post-progression OS (HR, 0.74

143. National
Comprehensive
Cancer
Network

s that the
progressed ona

hen an angiogenic agent is used
flibercept and

ing bevacizumab with second-line
regimen that did not contain,

(data to support adding

sion on that same regimen. The

Hy in patients who experienced.
Inon-bevacizumab=containing
cizumab to second-line FOLFOX

001 1).**8 Use of single-agent
se it was shown to have inferior
e or FOLFOX plus bevacizumab

FOLFIRIZIv-aflibercept

95% Cl, 0:71-0:94; P=.0l

the VELOUR trial found that mec]
the placebo arm was 12:6 month
months (95% Cl, 9.8-13.8

and 13.9 months (95% Cl,

13.5) in patients with no prior be

it the placebo group.%* The mos
were asthenia/fatigue, infections]
thromboembolic events.

tivity of FOLFIRI plus zi
progressed on FOLFIRI plus bev
suggest activity of single-agent zi
ziv-aflibercept to FOLFIRI in first
phase II AFFIRM study had no bel
Panel added ziv-aflibercept as a
‚combination with FOLFIRI or iring

144. National
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Cancer
Network

[he primary endpoint of OS in the
pnd 11.7 months in the

ctively, for an HR of 0.84 (9%
hproved with the addition of

hths for the two arms (HR, 0.79;
loup analysis of the RAISE trial
Ind safety among patient

mor status, time to progression

he RAISE trial were 11.5% inthe
bo arm. The most common grade
tension, diarrhea, and fatigue. In
trials showed that ramucirumab
boembolic events, venous
Éding, or high-grade GI bleeding
esults suggest that ramucirumab
pents in that it does not increase

fal, the Panel added ramucirumab
ith FOLFIRI or

Positive Disease in the Non-Firs
A combination of the BRAF inhibi
binimetinib, with cetuximab has bl
phase II! BEACON trial for metas}
CRC.57087' The safety lead-in of
efficacy results with an ORR of 4]
29 patients included in the effi
patients in the safety lead-in, the
fatigue (13%), anemia (10%), incl
increased aspartate transaminası
infections (10%).57

Sübsequentiy, the randomized pd
similarly encouraging results, inci
portion of the study, 665 patients
triplet combination, an encorafen§
regimen of cetuximab plus either
BEACON reported a median OS 4
months for the control, doublet, à
confirmed ORRs were 1.8%, 19.
orhigher AE rates were highest}

]

binimetinib did not improve OS 0)
assessments

145. National
Comprehensive
Cancer
Network

[

Hed by the Panel as options for

uzumab in
y tucatinib. These regimens (with
[propriate for patients with
ERC when intensive therapy is not
{that FDA-approved biosimilars.
fever the therapy isrecommended
above, for more information). The

ination regimen of the HER2
as studied in a subsé

tudy #75 This sub: 7
plified’ mCRC who were treated
trastuzumab. ORR

lapatinib. ORR

seven partial respor

percent of patients treated with tr
‘AEs, including fatigue (four patiel
increased bilirubin (one patient).

Trastuzumäb Plus Tucatinib: A cı
inhibitors trastuzumab and tucati
1 MOUNTAINEER trial. This tr
chemotherapy-refractory, HER:
all/patients on this study were tre
while later, patient:

(cohort B). Of the 84 patients wh
and B, the confirmed ORR was 3
patients having a complete respoı
the most common AE was diarrhe
received the combination had tuc
injury. colitis, and fatigue)

146. National
Comprehensive
Cancer
Network

pponses were reported in cohorts
A had received prior anti-HER2
8%. The most common grade 23
Jd neutrophil count (22%) and
:STINY-CRCO1, no respon
A. confirmed ORR was 45.3%, all
ledian duration of responseof 7,0
Ind 15.5 months, respectively. Of
Lents on this trial developed
lated to T-DXA, including three

ither 5.4 or 6.4 mg/kg T-DXA, An
ting an ORR of 37.8% for the 5.4
-DXd showed antitumor activity
in those who were previously
ing that this agent may be

12C Mutation-Positive Disease in

sotorasib monotherapy. It include]
harboring the KRAS G12C mutatig
CRC, 7.1% had a confirmed resp
prespecified subset analysis of th
investigated sotorasib monothera
KRAS G12C mutation.** OR was}
atients. Grade 23 treatment
treated with sotorasib monotheral
looked at various doublets includ

investigated the combination of sd

dose expansion cohort reported
16.6%-46.5%).%5 Median PFS a
respectively. Grade

Who received th

KRYSTAL-1 is a phase 1/2 clinica
of adagrasib, alone or in combine
patients with advanced solid tumo}
publication of this Study reported}
mutated mCRC treated with adagí
combination with cetuximab (
response was reported in 19% ol

147. National
Comprehensive
Cancer
Network

fecian follow-up of 11:9 months,
End median duration of response
jonths and median OS was 15.9

dMMR/MSI-H or POLE/POLD1
irst-Line Setting

MMRIMSI- OLD?

la checkpoint inhibitor as fi

een received and the patient is a
ira different therapy was used in
immunotherapy is also,

setting

nodlonal antibody that binds to,
leraction with PD-L1 and PD-L2
id response. 55 A phase II study
in 11: patients with dMMR CRC
patients with dMMR non-
progressive metastatic
ns had progressed through two
lendpoints were the immune-

one previous line of therapy.

into two cohorts based on wheth
including fluoropyrimidine, oxalip
lines of therapy (cohort B). O
with the median duration of respt
publication. Median PFS was 2.3]
and B, respectively. Median OSy
not been reached for cohort B. T
occurred in/16% of patients in co}
pancreatitis, fatigue, increased al
lipase being most common.

Nivolumab is another humanized
Was studied with or without pilin
11, multi-cohort, CheckMate-142 tr}
74 patients with dMMR CRC wha
these patients was 31.1%

having diseas: control for atleast]
had not yetbeen reached at the ti
50% and 73%, respectively, at 1

148. National
Comprehensive
Cancer
Network

lepth analysis of the safety profile
ckMate-142 trial reported that
being of special clinical interest
enal, and skin events) tended to
fusing evidence-based treatment
year long-term data from this
73). PFS and OS at 4

ntibody, dostarlimab-gxly, has
I adult patients with dMMR

have progressed on or following
alternative treatment Options.

inhibitor immunotherapy is also rd
POLE/POLD1 mutations.

‘Systemic Therapy Options for N'
the Non-First-Line Setting

Studies have estimated that abou
fusions. #7 Three targeted thel
repotrectinib have been FDA-app}
Metastatic, unresectable solid tun
no satisfactory alternative treatm

the primary tumor. The Panel rec

be appropriate for most patients
CRC

Larotrectinib: A pooled anal
adults, a phase I/II involving child!
involving adolescents and adults;
larotrectinib in 55 patients with N]
including four patients with colon
ORR was 75% (95% Cl, 61-85) b
67-90) by investigator assessmer

149. National
Comprehensive
Cancer
Network

, 2.8-36.5). Responses were
Its to be censored: Of the &
a partial response and 50% had

jee global phase I/II studies
TRK.2) tested the efficacy and
ith advanced or metastatic NTRK'

jr the whole population, ORR was

|
I
[
[Mas 11 months (95% CI, 8.0-

Cl, 14.9-NE) by independent

E 10 months (95% Cl, 7.1-NE). Of
recorded as having a
Ns. 60%) was observed among
tasis, indicating that entrectinib
was found to be well-tolerated as
|: or2 and managed with dos
iscontinue therapy due to

1 trial tested repotrectinib in two
n-positive advanced solid tumors,
rt, who received repotrectinib as

Selpercatinib for RET. Gene Fusi
Line Setting

In the ongoing phase 1/2 LIBRE
the highly selective RET kinase in|
in a diverse group of patients wit
including 10 patients with colon cf
received a median of 2 prior lines
received 3 or more prior lines of
evaluable patients, the ORR for t
was 43.9% (95% CI, 28.5-60.3)
(95% Cl, 2.5-55.6). There were
neither patient had colon cancer.
13.2 months (95% Cl, 7.4-26.2)
18 months (95% Cl, 10.7-NE), an}
months (95% Cl, 9.2-NE). For th}
duration of response was 9.4 mo]
‘common grade 3 or higher treatr
and transaminitis. The most com
drug-induced livery injury, fatigue|
permanently discontinue selpercä

150. National
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Cancer
Network

nts whose disease progressed on:
with placebo or regorafenib. "

[6.4 months forregoraferib vs. 50
D.64-0.94: P= .005). PFS was
ys. 4:7 months; HR, 0.49:

CONCUR trial was performed in
and Vietnam, '°°' Patients

| to receive regorafenib or plac
imens. After amedian follow-up of
was met in the 204 randomized:
rm vs. 6.3 months in the placebo
001)

sin the regorafenib arm of the
ction (17%), fatigue (10%),
fash/desquamation (6%). 12°
0.3% of 1100 patients treated
Ineta-analysis of four studies that
ferib for CRC, Gl'stromal tumor
ellular carcinoma, the overall
Ind-foot skin reactions was 60.5%

world clinical practice. 1005 The safl
all of these trials were consistent

The randomized, phase Il ReDO:
alternative dose schedule to redu
1100 Of the 116 evaluabl

the most common AES were also

compared to the standard dosing

agreed that a dos lation str
approach for regorafenib dosing,

also supported alterna

and safe in patients with previous

Regorafenib has only shown acti
progressed on all standard ther
regorafenib as an additional line
refractory to chemotherapy. It c
tipiracil or fruquintinib; no data in

Trifuridine-Tipiracil (TAS-102)

Trifluridine-tipiracil is an oral com}

151. National
Comprehensive
Cancer
Network

3 y y os
15% Cl, 0.58-0.81; P< 001). 1010
dary endpointof PFS (1-7 vs. 2.0
< 001). The most common AES
OURSE were neutropenia
jutropenia (4%); one drug-related
eillance study did not reveal any
f the RECOURSE
regardless of age, geographical

1d bevacizumab has also been

legimenwas initially studied in the
[subsequentrandomized phase I
h and without bevacizumab. 15
trials, the phase ll SUNLIGHT,
e-tipiracil plus bevacizumab to
ith previously treated mCRC. 1%!
lusty received a fluoropyrimidine,
ived an anti: VEGF antibody, and
se had received an anti-EGFR
bevacizumab combination

I
[
[
B 8 vs. 7.5 months; HR, 0.61; 95%

alone or regorafenib "8

Based on these data, the Panel al
bevacizumab, as a treatment optig
progressed through standard thet
preferred over trifluridine-tipir

regorafenib or fruquintinib; no daf
therapies, although real-world dal

adherence to trifluridine-tpiracil à

similar OS benefit from trifluriding

as the 656 patients who did not (

The combination of trifluridine-ti
studied inthe first-line setting in
and the phase II TASCO1 study. À
trifluridine-tipiracil plus bevacizu
patients who w

similar OS and PFS results betwd
concerns about the hematologic
tipiracil compared to cap
recommend trfluridine-tipiracil, w
therapy for mCRC.

152. National
Comprehensive
Cancer
Network

Median PFS was also longer with
6; P < .001). FRESCO:

i 97% of patients
ly and nearly half had progressed
fib. Patients received fruquintinib
1.8 months on placebo) and just
cities. Median OS was 7.4
B months with placebo (HR, 0:66:
B AEs occurred in 63% of patients
50% who received placebo. The
tinib were hypertension (14%)
(6%). Based on these data, the
Is a treatment option for mCRC
lable regimens. It can-be given

lorafenib; no data inform the best
q

disease (see Biomarkers for Sys!
tumor is known to have a RAS or
indicated, as amplification is very
be used to detect these biomark:
detecting other rare and actionab
fusions).

The Panel strongly discourages
staging, baseline imaging, or rou
recommends consideration of a pl
selected cases if prior anatomi
potentially surgically curable M1
scan is to evaluate for unrecogni
preclude the possibility of surgical
of patients with resectable metact |
PETICT inthe workup of potential
impact of PET/CT on survival, sul
of patients after PET/CT. For
2.7% of patients because additior

153. National
Comprehensive
Cancer
Network

jon after surgery or infection. 1027
ed as part of the preoperative
gically resectable M1 liver

last may be of use when the PET
respect to the extent of disease

cludes patients with metastatic
for whom a surgical cure may

jsease will preclude the possibility
tabilty for the most part refers to
ause of involvement of critical
fPgression is accomplished with
Iy and Conversion to Resectabilty

pf the multidisciplinary treatment
font evaluation by a surg
lary or lung metastases.

Ironous Liver or Lung Metastases
Inchronous liver metastases,

may be recommended for pMMR
HIPOLE/POLD1 disease where d
not given neoadjuvantly, although]
this setting remains controversial
patients with liver-oniy CRC met
hepatectomy followed by 12,cou
year DFS was significantly longer
tohepatectomy alone (49.8% vs.
= ,006). However, the 5-year OS
compared to hepatectomy with ad]

If a patient with resectable liver of
surgery, the Panel recommends

chemotherapy for 2 to 3 months
[preferred], FOLFIRI [category 21
followed by synchronous or stage}
then adjuvant chemotherapy; or

(see neoadjuvant options above)|
disease, then adjuvant chemothe|
available, as well as their own ins]

154. National
Comprehensive
Cancer
Network

-positive disease, any of the

Pcommended for metastat
setting. Overall; combined
uld notexceed 6 months.

PLD? mutation-positive
jease should preferentially receive
fir first-line option as long as the
and no prior immunotherapy has
reevaluated every 2 to 3 months
rapy: resection, with or without
temic therapy based on disease

disease that is deemed to be
It Therapy and Conversion to
regimens with high response

í
[
biens should be reevaluated for

therapy regimens for advanced al

Disease). Patients with disease t
receive systemic therapy for adv
treatment selection bas
recommended. Debulking surger
recommended.

Results from one study suggest
and PFS from resection of th
colorectal metastases. !°° Other $
analyses also have shown a poteı
the SEER database and the Nati
survival benefit of primary tumor

On the other hand, a different an}

155. National
Comprehensive
Cancer
Network

se who were randomized to

Imore, the prospective, multicenter
tients with an asymptomatic
ltastatic disease who received

Iced an acceptable level of

je primary tumor. 2 The median
ic improvement in the primary is

Bion are uncommon in this
In of systemic chemotherapy. In
resection of the primary does not
love OS. #? Another systematic
studies that compared open to

fs setting. °° The laparoscopic
hospital stays (P < .001), fewer
Jd lower estimated blood loss (P <

igh the possible
in the setting of

Recommendations for Synchrond
For patients with peritoneal met
cause imminent obstruction, pall
resection, diverting colostomy, a
tenting, followed by systemic the}

The primary treatment of patient
chemotherapy. As mentioned ab
Hyperthermic Intraperitoneal Chel
that the treatment of disseminate!
and/or intraperitoneal chemother
centers for selected patients with}
RO resection can be achieved. H4
mortality associated with HIPEC,
efficacy, make this approac

Workup and Management of
On documentation of metachron:
e with dedicated contrast-
the disease extent using PETICTI
cases if a surgical cure of M1 dis]
juncture to promptly characterize|
identify possible sites of extrahey

156. National
Comprehensive
Cancer
Network

IV disease is diagnosed; a tumor
for KRAS/NRAS and BRAF

ell as MSI/MMR testing if not
define whether targeted therapies
bptions (see Biomarkers for

of the multidisciplinary treatment
ation by a surgeon
The
Ic disease is distinguished from
o including an evaluation of the
of the patient and through the

rding to whether they
y or immunotherapy. For patients
Hatic disease, treatment i

ofregimens based on
SI-H or

ic disease, neoadjuvant

or is an option, if no previous

of biologic agents in these setting
based therapy was previously adı

]
Patients determined to have a
imaging scan (including those cof
receive an systemic therapı

or immunotherapy history (see S4 4
Therapy, above). In the case of I
without systemic 5-FU/LV (categq
experience in the surgical and md
procedure. Patients receiving pal
monitored with CT or MRI scans

Endpoints for Advanced C|
In the past few years, there has 4

are most appropriate for clinical t
is an outcome that is rarely mea:

is inconsistent at best, especialy

administered:!0%-1070 In 2011, The

157. National
Comprehensive
Cancer
Network

e endpoint, time to tumor growth,
0721073 Further evaluation of these
ted

it chemotherapy, if administered,
ith CRC is performed to evaluate
hiscover a recurrence that is

[ty new metachronous neoplasms
fa from 20,898 patients enrolled in
pwed that 80% of recurrences

| resection of the primary tumor,
currences occurred in the first 5

1

|

1

|

| of patients with stage II and/or

$pectively in several older

J ses of RCTS designed to

fs of surveilance: "intensive
suggested to be of benefit to

|Furthermore, a population-based

CT combination arm (2.3% in the|
CEA group; 8% inthe CT group
In this study, no mortality benefit
both was observed compared wit
vs. 15.9%; difference, 2.3%; 95%
concluded that any strategy of si
survival advantage over a sympto|
COLOFOL trial of 2509 patients \
testing with C

a high-frequency sun

and 36 months post
differencein 5-year overall mortal
two screening approaches.

The CEAwatch trial compared ust
every 2 months, with imaging per
twice, in 3223 patients at 11 hosp
Netherlands.1"%* The intensive C4
detection of more recutrences ané
curative intent than usual follow-u|
disease was shorter. Another ran

158. National
Comprehensive
Cancer
Network

[tine more intensive surveillance
year OS, but did result in more
pion cancer. Surgical treatment of
patients receiving minimal
patients receiving lower intensity
eiving no CEA but higher intensity
feximum surveillance group with

P abstract that reported final RFS
Bly a me

lan follow-up of 7.8 years,
of patients (89.5% metastatic
Five-year RES rates were 73.2%
jut CT (P = .052) while they were
screening, respectively. The
but not CEA screening,
alive-intent surgical treatment of
vith CT Surveillance.

on of optimal strategies for
ative CRC Surgery, and the
nsensus. The Panel

ater INTESS VEO at
grade dysplasia) is found. In this
1 year

The following Panel recommend
pertain to patients with stage 11/11
treatment (ie, no known residual
examination should be given evel

patients with stage III disease and
clinician determines that the pated
curative surgery. 17.0% Colonos
year after resection (or at 3-6 md
preoperatively because of an ob
typically recommended at 3 y |
unless follow-up colonoscopy indi
polyp >1 am, or high-grade dysplq
berepeated in 1 year. More fn
in patients who present with colon}
abdominal, and pelvic CT scan a)
(category 2B for more frequently}
disnts io id

159. National
Comprehensive
Cancer
Network

ing second cancers,

0% Furthermore, Use of
has not been shown to improve
Jcurrence of the original CRC.
leatment surveillancı
patients with Lynch

the presence of potentially
the lung and liv

committee has endorsed th:
pnd Secondary Prevention
bncer from Cancer Care Ontario
slightly from the surveillance
lines for Colon Cancer. While
chest CT annually for 3 years in

N Panel recommends semi-
gory 28 for more frequent than
‘commendation on the fact that

219 The American

showed that 27% of patients with|
intent resection and that 25% of t
the initial population) were free o]

Panel recommendations for surv

with no evidence of disease (neq
1
1
|
]

undergo contrast-enhanced CT y
every 3 to 6 months in the first 2
28 for frequency <6 months)

stage disease. Again, use of PE

recommended: An analysis of pat

liver metastases found that the fr

correlate with time to

Those scanned once per year

for those scanned 3 to 4 times pq
ss may be sufficient in this pc

160. National
Comprehensive
Cancer
Network

hith most being single high

fot 5to 15 ng/mL."! In this study,
re, and all results >35 ng/mL

[systematic review and meta-
ificity of CEA at a cutoff of 10
3-79) and 97% (95% Cl, 90-99),
bst-resection, aCEA cutoff of 10

jquality CT scansis vanishingly.
jaysis found 11 studies (510

T in this setting. "% The pooled
the detection of tumor recurrence
D 2% (95% Cl, 66.4-85

88 patients treated for CRC
Huivocal conventional imaging
PETICT had a sensitivity of 88%
In of recurrences."

care to the primary care physiciar
primary care provider should hav
with roles communicated to the p
overall summary of treatments rel
treatments, and systemic therapi
resolution of acute toxicities, long}
late sequelae of treatment shoul
health behavior recommendation:

Disease preventive measures, su
detection through periodic screer]
breast, cervical, or prostate canc
monitoring are recommended (sel
Additional health monitoring shou
Gare of a primary care physician.
therapeutic relationship with april
lifetime. 108

Other recommendations include
cancer or the treatment of colon
incontinence (eg, patients with st
common to CRC survivors includ
neuropathy, fatigue, insomnia, cd

161. National
Comprehensive
Cancer
Network

topics with potential relevance to
pression, and Distress; Cognitive
junction: Healthy Lifestyles; and

Joyment, insurance, and disability

haracteristics, such as smoking
Hveging in regular exercise, and
Jated with improved outcomes
a cancer
|
|
i

atients with stage III colon cancer

hemotherapy trial, DFS we

kercise in which the patients

Mity in the CALGB/SWOG 80702

In addition, astudy of a large

Ih 111 CRC showed an association
CRO specific:

RUN N
Similar results were seen in othel
prospective studies. 2:12 Dietar
also found to have positive effect
RC survivors in a randomized si

A retrospective study of patients
in NSABP'trials from 1989to 199.
kg/m? had an increased risk of di
from the ACCENT database also
prognostic impact on outcomes i
Undergoing adjuvant therapy. |"
Prevention Study-II Nutrition Coh
mCRC found that pre-diagnosis
associated with higher all-cause 4
analysis of prospective cohort st
Was associated with increased CA
Dther analyses confirm the incre
patients with obesity. %!128:1141

In contrast, pooled data from fir
database indicate that a low BMI

of progression and death in the rf
may not be. "2 In addition, result

162. National
Comprehensive
Cancer
Network

Ined grains and concentrated

} with an improved outcome in
[There is also Some evidence that
land calcium may be associated
[stage 1 11,or Ill CRC." Analysis
er dietary glycemic load was also
Lrrence and mortality in patients
is of the data from CALGB 89803

h stage II!
id processed meats and mortality
her supported by data from the
ort, in which survivors with

dysfunction:1!5°

Secondary Chemoprevention ff
Limited data suggest a link betw
statin use and increased survival
four studies found that post-diagn}
95% CI, 0.68-0.85; P< .001) and
Cl,'0.60-0.81; P<.001).1

‘Abundant data show that low-do:
CRC decreases the risk of recur
population-based, observational,
patients with CRC in Norway foui
associated with improved CRC-
0:92) and:OS (HR, 0.95; 95% Cl
that tumor mutationsin PIKSCA
although the data are some

have also been suggested,""

RCTs showed that while non-as;
recurrence, low-dose aspirin was
risk-to-benefit profile. 11%

Based on these data, the Panel bj

163. National
Comprehensive
Cancer
Network

ISI and MMR status at diagnosis
considerably at all stages of
results.

resectable colon cancer is an en
lectomy. Adequate pathologic
s is important with a goal of
jemotherapy is recommended for
an option for. some patients with
fregimensfor adjuvant therapy, as
rapy, depends on the pathologic
ce. Patients with resectable T4b
be treated with neoadjuvant

er or lung should be considered
tes for surgery and if all original
on (RO) and/or ablation. Six

y should be administered to
pus resectable metastatic disease.
ould likely convert a patient from
tate (ie, conversion therapy), this

rather than discrete. Principles to
pre-planned strategies for alterin|
presence and absence of disea:
adjusting therapy for patients wh
to fluoropyrimidine-, oxaliplatin.
chemotherapy regimens, immund
are becoming an increasingly im
landscape. Combination of a biol
Panitumumab) with some of the
depending on available data. Sys|
Progressive disease depend on
status of the tumor.

164. National
Comprehensive

NCCN Cancer
Network

fends in colorectal cancer
[stage in the United Stat
573-580. Available at

et al. Colorectal cancer stati
54. Available at:

basing disparities in the age-
1cers in the United States, 1

The Growing Challenge of.
Incology (Williston Park)

Association of Age With
| Survival in Patients With
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j.nim.nihg

cancer as a risk factor for benign]
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requires reliable data on
Med Genet 2004:41:801

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http: alm.nih.g

14. Quintero E, Carrillo M, Leoz

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bittp:/Awwiv;nebi-him.nih. gov/pubr

15. Hampel H, Frankel WL, Marti
Lynch syndrome among patients
2008:26:5783-5788. Available at |
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Lynch HT, de la Chapelle A.
Med 2003:348:919-932. Available
nttp:/Avww-ricbi_nim nih, gov/pubr

165. National
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NCCN Cancer
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t al. Incidence of hereditary
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28. Ladabaum U, Wang G; Terdi
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NCCN Cancer
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NCCN Cancer
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