Treatment of Metastatic Colorectal Cancer

Janine M. Daviesa and Richard M. Goldbergb

The treatment of metastatic colorectal cancer (mCRC) has become increasingly complex and
nuanced as treatments have evolved over the last decade. During that time, treatment has evolved
from single agent 5-fluorouracil (5FU) chemotherapy to combination chemotherapy, and more
recently to the inclusion of monoclonal antibodies. As such, mCRC is evolving into a chronic
disease in which the median overall survival (mOS) is in excess of 2 years and the 5-year survival
is 10%. This review highlights the chemotherapy advances in the treatment of mCRC and focuses
on the antibody therapies that have provided incremental improvements in survival. Additionally,
we will discuss the management of resectable and unresectable liver metastases, and directed liver
therapies.
The treatment of metastatic colorectal cancer (mCRC) has become increasingly complex and
nuanced as treatments have evolved over the last decade. During that time, treatment has evolved
from single agent 5-fluorouracil (5FU) to combination chemotherapy and more recently the
inclusion of monoclonal antibodies. As such, mCRC is evolving into a chronic disease in which the
median overall survival (mOS) is in excess of 2 years and the 5-year survival is 10%. This review
highlights the chemotherapy advances in the treatment of mCRC and focuses on the antibody
therapies that have provided incremental improvements in survival. Additionally, we will discuss
the management of resectable and unresectable liver metastases and directed liver therapies.
Semin Oncol 38:552-560 © 2011 Elsevier Inc. All rights reserved.

TRADITIONAL CHEMOTHERAPY ences in toxicity depending on the regimen.2– 4 How-

ever, a meta-analysis found that response rates (RRs)

W ith current 5-year survival of 10% for pa-

tients with metastatic colorectal cancer
(mCRC),1 it is hard to believe that less than
15 years ago, single-agent 5-fluorouracil (5FU), an intra-
venous fluoropyrimidine, with leucovorin (LV) was the
only treatment that demonstrated benefit for the treat-
ment of mCRC since the 1950s. While variations in the
administration of 5FU were examined, there were no
major differences in survival outcomes with bolus com-
pared with infusional regimens, yet there were differ-
aDrug Development/GI Oncology, Division of Hematology and Oncol-
ogy, University of North Carolina at Chapel Hill, Chapel Hill, NC.
bDivision of Hematology and Oncology, University of North Carolina at
Chapel Hill, Chapel Hill, NC.
Financial Disclosures: R.M.G. is a consultant/advisory to and has re-
search funding from Sanofi-Aventis, Bristol Meyers Squibb, and
Amgen.
Supported in part by Alberta Heritage Foundation for Medical Research
Clinical Fellowship and Canadian Association of Medical Oncology
Fellowship (J.M.D.).
Address correspondence to Richard M. Goldberg, MD, Division of
Hematology and Oncology, University of North Carolina at Chapel
Hill, 170 Manning Dr, CB #7305, Chapel Hill, NC 27599. E-mail:
Goldberg@med.unc.edu.
0270-9295/ - see front matter
© 2011 Elsevier Inc. All rights reserved.
doi:10.1053/j.seminoncol.2011.05.009
and progression-free survival (PFS) were improved in
those treated with bimonthly bolus and continuous-
infusion 5FU/LV (modified LV5FU2) compared with
the monthly bolus 5FU/LV (Mayo) regimen.4 While
there was more hand-foot syndrome with infusion, the
bolus 5FU regimen was associated with increased mu-
cositis and grade 3/4 toxicity, including neutropenia.4
The relative contribution of LV has only been shown in
one meta-analysis to provide a small survival benefit,
from 10.5 to 11.7 months.5 However, with preclinical
evidence suggesting increased inhibition of DNA syn-
thesis resulting in enhanced anti-tumor effects, it
continues to be used. In the intervening period,
capecitabine, an oral fluoropyrimidine, has demon-
strated at least equivalence with 5FU/LV in the met-
astatic setting.6,7 As may be expected from the ad-
ministration schedule (twice daily for 2 weeks, every
3 weeks), its side effect profile mimics that of infu-
sional 5FU.
Only with clinical trials of oxaliplatin and irinotecan
did we see more substantial gains in survival. Among
the first of these studies was a phase III study of infu-
sional 5FU with and without irinotecan.8 Overall sur-
vival (OS) improved from 14 to 17 months (P ⫽ .031)
and 1-year survival from 59% to 69% with the addition

552 Seminars in Oncology, Vol 38, No 4, August 2011, pp 552-560

Treatment of metastatic colorectal cancer
of irinotecan.8 Simultaneously, a comparison of weekly
bolus irinotecan and 5FU/LV (IFL regimen), daily bolus
5FU for 5 days each month (Mayo regimen), and single-
agent irinotecan was underway.9 Survival was signifi-
cantly better in the IFL group (14.8 months, P ⫽ .04)
than either the Mayo regimen or single agent irinotecan
(the latter 12.6 v 12.0 months, P ⫽ not significant
[NS]).9 Toxicities of irinotecan include diarrhea, vom-
iting, alopecia, neutropenia, and infection.8,9 Since
then, the BICC-C (Bolus, Infusional or Capecitabine
with Camptosar-Celecoxib) trial of infusional 5FU/LV
and irinotecan (FOLFIRI) has demonstrated superiority
over the IFL regimen for PFS (7.6 v 5.9 months, P ⫽
.004) but failed to do so for OS (23.1 v 17.6 months,
P ⫽ .09).10 Capecitabine and irinotecan (CapeIRI) was
fraught with toxicity and had similar OS and PFS results
as IFL, supporting the preference for FOLFIRI treat-
ment.10
On the heels of irinotecan came a treatment option
with oxaliplatin in combination with 5FU/LV (FOLFOX).
While survival was not improved for FOLFOX4 (the
number merely indicating modifications of the
FOLFOX regimen) compared with 5FU/LV (16.2 v 14.7
months, P ⫽ .12), PFS improved by nearly 3 months,
and the lack of difference was thought to be due, in
part, to crossover to salvage chemotherapy.11 Oxalipla-
tin-induced peripheral neuropathy and hypersensitivity
reactions differentiated this treatment from irinotecan.
Capecitabine also was combined with oxaliplatin in the
NO16966 trial, demonstrating noninferiority of CapeOx
compared with FOLFOX for both median OS (mOS) and
PFS.12
A head-to-head comparison of irinotecan- and oxalip-
latin-based regimens in the N9741 trial was the first to
demonstrate the superiority of FOLFOX over both the
IFL regimen (mOS 19.5 v 15.0 months, P ⫽ .0001) and
irinotecan/oxaliplatin combination (IROX, mOS 17.4
months, P ⫽ .04).13 While the use of second-line ther-
apies was different between the two arms, given the
commercial availability of irinotecan, only 60% of pa-
tients in the FOLFOX group received irinotecan,
whereas 24% of patients in the IFL group received
oxaliplatin, this survival difference was confirmed in a
subsequent comparison of FOLFOX versus reduced-
dose IFL, in which there were similar rates of second-
line therapy.14 With the inferiority of IFL compared
with FOLFIRI based on cross-study comparisons, a trial
comparing FOLFIRI with FOLFOX subsequently found
no significant differences in RR, time to progression
(TTP), or OS between the regimens.15 This helped
clarify that initial treatment with either regimen could
be based on individual patient factors and potential
toxicities rather than differences in efficacy.15 A later
study demonstrated that either FOLFOX or FOLFIRI
followed by the other combination at the time of pro-
gression did not impact PFS or OS.16
The use of second-line or salvage therapy was felt to
553
affect survival in the FOCUS (Fluorouracil, Oxaliplatin,
and CPT-11 [irinotecan] Use and Sequencing)17 and
CAIRO (CApecitabine, IRinotecan, Oxaliplatin)18 trials.
A retrospective analysis of the use of all three agents
(fluoropyrimidine, oxaliplatin, and irinotecan) con-
cluded that initial combination chemotherapy and use
of all three drugs during the disease course predicted
better outcomes than the use of fewer than three
drugs.19,20
The OPTIMOX2 study examined treatment breaks
after initial multi-agent treatment versus lower-intensity
treatment.21 Patients randomized to “maintenance
treatment,” consisting of mFOLFOX7 (six cycles) fol-
lowed by 5FU/LV until progression, at which time
therapy was re-escalated to mFOLFOX 7, had signifi-
cant improvements in PFS and duration of disease con-
trol. However, there was no statistically significant sur-
vival benefit in comparison to those in which 5FU/LV
was replaced by a complete break from chemotherapy
(mOS 23.8 v 19.5 months, P ⫽ .42) and 2-year OS was
50% and 39%, respectively.21 This suggested that a
chemotherapy-free interval may be appropriate for cer-
tain as yet undefined patients but that patients cannot
be identified prior to determination of their response.
The Medical Research Council COIN study also ad-
dressed the question of intermittent chemotherapy in
the first-line setting. Patients were randomized to con-
tinuous chemotherapy with fluoropyrimidine/oxalipla-
tin versus 12 weeks of the same therapy followed by a
break, with reinstitution of the same treatment at the
time of progression.22 This trial demonstrated that us-
ing chemotherapy-free intervals in this manner was not
inferior to continuous treatment, and in fact patients
generally reported better toxicity profiles and quality of
life.22
Refinements in the delivery of chemotherapy based
on performance status (PS) and older age have been
evaluated. Survival was significantly worse among pa-
tients with Eastern Cooperative Group (ECOG) PS 2
compared with PS 0 or 1 (mOS 8.5 v 17.3 months,
P ⬍.0001), but patients with PS 2 in fact derive similar
relative benefits from FOLFOX or FOLFIRI chemother-
apy than those with a better PS.23 Similarly, a pooled
analysis evaluated the safety and efficacy of FOLFOX4
among patients less than 70 years of age compared
with those 70 years and over.24 Generally, toxicities
were not greater among the older group, except for
neutropenia, thrombocytopenia, and fatigue, nor was
there a difference in survival.24 These studies support
clinical practice to treat those with a borderline PS and
older adults, although patients older than 80 years are
often not well represented in clinical trials.
TARGETED AGENTS
The promise of targeted agents, drugs that may in-
hibit one or more specific intracellular pathway(s) re-
554
sulting in arrested cell processes and cell death, is that
altered molecular pathways that promote cancerous
processes in a specific tumor can be overcome by such
agents. In mCRC, bevacizumab, cetuximab, and pani-
tumumab are newly established agents in the treatment
paradigm.
Bevacizumab
The antiangiogenic agent bevacizumab is a human-
ized vascular endothelial growth factor (VEGF) anti-
body that binds the VEGF ligand.25 Hopes were high for
this agent when, in the first clinical trial of IFL chemo-
therapy with and without bevacizumab, survival im-
proved from 15.6 to 20.3 months (P ⫽ .001).26 A
subsequent study (BICC-C), which initially compared
FOLFIRI with bolus 5FU/LV and irinotecan (mIFL), was
subsequently amended to include bevacizumab in both
arms, randomizing 117 patients.10 While the RR and
PFS were not significantly different, survival was better
among those that received FOLFIRI and bevacizumab
(28.0 v 19.2 months, P ⫽ .037).10,27 However, in the
highly anticipated XELOX-1 trial (Xeloda and oxalipla-
tin) with patients randomized to XELOX or FOLFOX4
and later amended to a second randomization to bev-
acizumab or placebo, there was only a small improve-
ment in PFS and no significant improvement in OS or
RR.28 In combination with 5FU/LV, a meta-analysis
demonstrated that median OS improved from 14.6 to
17.9 months with the addition of bevacizumab,29 dem-
onstrating a role for this agent in patients for whom
oxaliplatin or irinotecan therapy is not suitable. Side
effects of bevacizumab differ from other traditional
chemotherapies.10,26 –28 Close attention to and treat-
ment of these side effects, combined with a low thresh-
old to investigate based on a clinical suspicion of a
complication, may help to minimize their potential
impact.
After progression on first line 5FU/irinotecan, a
three-arm study (ECOG 3200) comparing FOLFOX4,
FOLFOX4/bevacizumab, and single-agent bevacizumab
was undertaken.30 The single-agent bevacizumab arm
was discontinued due to inadequate efficacy. FOLFOX/
bevacizumab demonstrated a median OS of 12.9
months compared with 10.8 months with FOLFOX (1
year OS 56 v 43%, hazard ratio [HR] 0.75, P ⫽ .0011)
with improvements in RR and PFS.30
A meta-analysis to evaluate the impact of bevaci-
zumab in combination with chemotherapy in mCRC,
concluded that its use was associated with decreased
mortality (HR 0.79, P ⫽ .0005), improved PFS (HR
0.63, P ⫽ .0004), and RR (1.5, P ⫽ .02).31 This provides
more convincing evidence of benefit in light of some of
the negative studies. Overall, bevacizumab has been
adopted in both first- and second-line mCRC treatment
settings. Likely, bevacizumab has contributed to the
small but incremental improvements in the survival of
J.M. Davies and R.M. Goldberg
patients with mCRC, but identification of a predictive
marker or subset of patients that derive benefit from
the therapy has been fraught with disappointment.
The optimal duration of chemotherapy with tar-
geted agents has been extensively debated given the
mechanism of action, toxicities, inconvenience, and
costs of these agents. It has been hypothesized that the
maximal benefit of bevacizumab may be with continu-
ation until or beyond disease progression. In the Span-
ish Cooperative Group MACRO trial, first-line CapeOx/
bevacizumab for six cycles followed by maintenance
bevacizumab until progression was compared with on-
going CapeOx/bevacizumab until progression.32 While
survival was not different (23.4 v 21.7 months, P ⫽ NS)
nor was PFS, it turns out that both groups received a
similar number of cycles of therapy and therefore did
not really compare this component of therapy.32 Likely
maintenance bevacizumab is non-inferior to continu-
ous CapeOx/bevacizumab, but further evaluations are
ongoing (DREAM, CAIRO-3, and AIO-ML21768 studies)
before we can comfortably endorse bevacizumab main-
tenance. Some suggestion has been made of continua-
tion of bevacizumab beyond the first disease progres-
sion based on an analysis of registry data,33 but this
requires validation in a clinical trial. Another phase III
study is assessing continued bevacizumab with second-
line chemotherapy after progression with first-line
chemotherapy/bevacizumab. To date, safety data have
been favorable.34
Cetuximab
Cetuximab is a chimeric IgG1 epidermal growth
factor receptor (EGFR) monoclonal antibody that binds
the extracellular domain of EGFR, preventing ligand
binding and its downstream effects. Cetuximab also
may participate in antibody-dependent cell-mediated
cytotoxicity.35,36 In contrast to bevacizumab, which
lacks a known predictive marker of efficacy, cetuximab
provides benefit to a specific subgroup of patients. The
unmutated KRAS gene (wild-type [WT]) is such a
marker. Patients harboring a RAS gene mutation (MT),
accounting for up to 40% of patients with mCRC, do
not derive benefit from treatment with this antibody to
EGFR.37,38
Initial phase II studies of cetuximab looked at both
its single-agent activity and its activity with irinotecan
in refractory tumors, based on the preclinical activity of
cetuximab inducing tumor responses in irinotecan-re-
fractory xenografts when re-exposed to irinotecan. As a
single agent in irinotecan-refractory, EGFR-positive (by
immunohistochemistry) mCRC disease, 45% had a par-
tial response (PR) or stable disease (SD) lasting at least
12 weeks with a median TTP of 1.4 months.39 Among
the responders, the median duration of response was
4.2 months.39 With the cetuximab/irinotecan combina-
tion in irinotecan-refractory tumors, a RR of 23% was
Treatment of metastatic colorectal cancer
demonstrated.40 Concurrently, a randomized trial of
cetuximab with or without irinotecan was conducted
in EGFR-expressing, irinotecan-refractory mCRC.41 The
overall RR was 11% as a single agent and 23% in com-
bination (P ⫽ .007), with disease control rates (sum of
patients that responded and those with SD) of 32% and
56%, respectively (P ⬍.001). TTP was significantly im-
proved but mOS was not statistically significant, al-
though the study was not powered to detect such a
difference.41 Later, retrospective data suggested that
tumors that did not overexpress EGFR could respond
to cetuximab, which fit with the lack of relationship
between intensity of EGFR expression and clinical ac-
tivity.42 All of these studies were based on unselected
patient groups, prior to our understanding of the role
of KRAS mutational status.
In the first study to demonstrate both a survival
benefit and preservation of quality of life (QOL), treat-
ment-refractory mCRC patients with EGFR-expressing
tumors were randomized to cetuximab and best sup-
portive care (BSC) or BSC alone in the National Cancer
Institute of Canada (NCIC) CO17 trial.43 Median sur-
vival increased from 4.6 months with BSC alone to 6.1
months with cetuximab and BSC (P ⫽ .005) with 1 year
OS of 16% and 21%, respectively. This trial also sug-
gested that the severity of rash correlated with OS.
Cetuximab also was associated with better QOL than
BSC alone in the context of less deterioration of phys-
ical function and global health status.43 It is important
to note that this survival benefit was prior to knowl-
edge of KRAS status as a predictor of response.
The Medical Research Council COIN trial, described
earlier in the context of assessment of the role of
breaks in chemotherapy, also evaluated first-line con-
tinuous fluoropyrimidine/oxaliplatin with or without
cetuximab.44 Interestingly, this trial contradicts other
studies as there was neither an OS nor PFS benefit for
KRAS WT patients treated with cetuximab.44 This is
quite puzzling but suggests there are biologic factors
that have yet to be elucidated.
Once the role of KRAS was understood, two clinical
trials (Oxaliplatin and Cetuximab in First-Line Treat-
ment of Metastatic Colorectal Cancer [OPUS] and Ce-
tuximab Combined with Irinotecan in First-Line Ther-
apy for Metastatic Colorectal Cancer [CRYSTAL])
retrospectively demonstrated the benefits of cetuximab
in the front-line setting among patients with KRAS WT
tumors. In the OPUS study, patients with KRAS MT
gene status had a detrimental effect of therapy when
treated with cetuximab/FOLFOX compared to those
who received FOLFOX alone (PFS 5.5 v 8.6 months,
P ⫽ .0192).38 Those with KRAS WT tumors had better
PFS (7.7 v 7.2 months, P ⫽ .016).38 The CRYSTAL study
combined FOLFIRI with cetuximab and also retrospec-
tively evaluated treatment effects based on KRAS mu-
tational status.37 Among patients with KRAS WT tu-
mors, PFS improved from 8.7 months to 9.9 months
555
with cetuximab, whereas no difference was noted for
KRAS MT gene tumors.37 Updated combined analyses
of the CRYSTAL and OPUS studies confirmed that pa-
tients with KRAS WT tumors treated with cetuximab
had a better survival than those without (23.5 v 19.5
months, P ⫽ .0062) and improved PFS.45
Following analysis of the CRYSTAL and OPUS trials
by KRAS mutational status, questions have come up as
to the role of the downstream kinase BRAF, its prog-
nostic role, and its predictive role with regards to
cetuximab. KRAS and BRAF mutations are mutually
exclusive.46,47 BRAF mutations have been found in up
to 10% of tumors.46,48,49 The COIN trial demonstrated
clear prognostic effects by mutation status; KRAS WT
and “all” WT tumors (for KRAS, BRAF, and NRAS)
demonstrating better outcomes, whereas there was
worse prognosis for KRAS, “any” mutation (KRAS,
BRAF, or NRAS), and particularly for BRAF mutations.44
While BRAF MT was initially thought to predict worse
response (RR and PFS) to EGFR inhibitors, these studies
lacked control groups treated with chemotherapy
alone,46,48,49 and a subsequent pooled analysis of data
from both studies suggested that BRAF mutational sta-
tus, while prognostic, does not in fact predict response
to cetuximab. mOS for KRAS WT/BRAF WT tumors
was 24.8 months with cetuximab (v 21.1 months with
chemotherapy alone, P ⫽ .041). KRAS WT/BRAF MT
tumors, while exhibiting dramatically worse outcomes
overall, trended to improved OS, from 9.9 months
without cetuximab to 14.1 months with the agent (P ⫽
.079), PFS and RR.45 Of note, there were only 70 pa-
tients with KRAS WT/BRAF MT tumors. This contrasts
to the retrospective data that suggested a lack of ben-
efit for patients treated with cetuximab who had BRAF
MT tumors.46 Thus BRAF mutation may be a prognostic
marker but does not predict benefit from cetuximab.
A second-line study was conducted to evaluate iri-
notecan with or without cetuximab following failure of
fluoropyrimidine/oxaliplatin combination.50 Based on
the initial planned analysis of all patients, there was
an improvement in PFS but no difference in OS.50
When subsequently analyzed by KRAS status for pre-
sentation to the US Food and Drug Administration’s
Oncology Drugs Advisory Committee, there was an
improvement in PFS and RR for those with KRAS WT
tumors treated with cetuximab, but only 23% of pa-
tients were KRAS-evaluable.51
The side effects of cetuximab include acneiform
rash, paronychial cracking, and less commonly allergic
or anaphylactic infusion reactions and hypomag-
nesemia.39,41,43,50 In combination with irinotecan, there
is an increase in grade 3/4 diarrhea.41,50 With regard to
infusion reactions, it is important to note that there are
geographic variations with reactions being more pre-
dominant in parts of the southeastern United States and
specifically among those with a history of atopy.52 Fur-
ther investigation determined that IgE antibodies to
556
galactose-␣-1,3-galactose, which is present on the ce-
tuximab molecule, are present prior to cetuximab ex-
posure, hypothesized to be from natural exposure, and
may explain risk of anaphylactic reaction with the
initial infusion.53
At this time, while FOLFOX and FOLFIRI are inter-
changeable frontline combinations, it is not clear there is
a preferable antibody to use up front. A phase III clinical
trial is in progress (Cancer and Leukemia Group B
[CALGB]/Southwest Oncology Group [SWOG] 80405) to
determine if chemotherapy (FOLFOX or FOLFIRI) with
randomization to either bevacizumab or cetuximab is
superior in the initial management and will also evaluate
downstaging effects resulting in resectable disease.
Panitumumab
Another EGFR inhibitor, panitumumab, has demon-
strated efficacy as a single agent in refractory mCRC.54,55
While the results were not striking given that median
PFS improved from 7.3 weeks with BSC to 8 weeks
with panitumumab and mOS was not significantly dif-
ferent,55 there was significant crossover as most pa-
tients from the BSC arm received panitumumab
through an extension study.54 At that time the impact
of KRAS status on response was not yet known. How-
ever, the initial study demonstrated that patients with
increased severity of skin toxicity (grade 2– 4) from
panitumumab had better PFS and favored better OS
than those with grade 1 skin toxicity.55 Additionally, in
contrast to cetuximab, there was only one infusion
reaction (grade 2) and no antibodies to panitumumab
were detected.55 These findings were corroborated in
the extension study.54 In a reanalysis based on KRAS
status, there was a clear benefit in PFS among those
with KRAS WT tumors (median PFS 7.3 v 12.3 weeks,
P ⬍.0001) but no difference for patients with KRAS MT
tumors.56
In the first-line setting, the PRIME study (Panitu-
mumab Randomized Trial in Combination with Chemo-
therapy for Metastatic Colorectal Cancer to Determine
Efficacy) combined FOLFOX4 with or without panitu-
mumab.57 Given the emergence of KRAS data, it was
amended to prospectively assess the efficacy of these
regimens by KRAS status. Among those with KRAS WT
tumors, PFS increased from 8.0 to 9.6 months with
panitumumab (P ⫽ .02). OS favored treatment with
panitumumab (19.7 v 23.9 months, P ⫽ .07). Patients
with KRAS MT tumors had worse PFS with the sug-
gestion of worse OS.57
FOLFIRI with or without panitumumab has been
evaluated in the second-line setting.58 Prospective anal-
ysis by KRAS status demonstrated an improvement in
PFS (5.9 v 3.9 months, P ⫽ .004) and an improvement
in RRs (35 v 10%, P ⬍.001) but no significant difference
in OS. No difference was noted in PFS nor OS in
patients with KRAS mutations. Evaluation of “patient-
J.M. Davies and R.M. Goldberg
reported outcomes,” based on self-report of QOL using
a visual analog scale, demonstrated both clinically and
statistically significant improvements in QOL among
KRAS WT patients treated with panitumumab but not
among KRAS MT patients; another evaluation method
that included specific components of health-related
QOL did not demonstrate any difference.58
Side effects of panitumumab differ somewhat from
those of cetuximab. While the skin toxicity, diarrhea,
and hypomagnesemia persist, an additional toxicity is
stomatitis/oral mucositis.57,58 Notably, there are very
few infusion reactions associated with this treat-
ment.57,58 As with cetuximab, there are data to suggest
that patients with KRAS WT tumors with worse skin
toxicity have better outcomes.56 In order to manage the
skin toxicity, an interesting randomized phase II study
used open label panitumumab with or without a pre-
emptive skin treatment regimen.59 This demonstrated
that the risk of grade 2 or higher skin toxicities could
be halved with such a protocol, yet did not negatively
impact efficacy. Pre-emptive treatments included skin
moisturizer application daily, sunscreen prior to out-
door activity, topical steroid applied daily, and doxycy-
cline 100 mg daily.59
Several questions emerge from these studies. First,
the results of the COIN study are in contrast to multiple
other studies and it is not clear what factors underlie
this difference. Second, the relative merits of one EGFR
antibody over another is not clear. However, panitu-
mumab is an alternative treatment option for patients
in order to avoid hypersensitivity to cetuximab. Third,
the relative benefits based on the underlying chemo-
therapy regimen is not known. At this time, there are
no studies that have compared anti-VEGF to anti-EGFR
therapy. However, we anticipate more clarity from the
CALGB 80405 phase III randomized clinical trial, com-
paring chemotherapy (FOLFOX or FOLFIRI) with ei-
ther bevacizumab or cetuximab.
Dual Inhibition
Despite the advances with VEGF and EGFR inhibi-
tors in addition to chemotherapy, double antibody in-
hibition has not proven to be successful. In fact, two
studies demonstrated worse toxicity and efficacy, the
Panitumumab Advanced Colorectal Cancer Evaluation
(PACCE) study combining bevacizumab and panitu-
mumab,60 and the CAIRO2 study combining bevaci-
zumab and cetuximab,61 halting enrollment to the dual
antibody arms of other ongoing studies.
Perifosine
The newest agent with potential activity is perifos-
ine, an oral alkylphospholipid that inhibits multiple
intracellular signal transduction pathways, including
AKT and nuclear factor-␬ B (NF-␬B), and activates an
apoptotic pathway via JNK.62 A randomized phase II
Treatment of metastatic colorectal cancer
clinical trial evaluated perifosine in a placebo-con-
trolled trial with capecitabine in second- or third-line
treatment of mCRC. Median OS was significantly better
in all patients (17.7 v 10.9 months, P ⫽ .0161), and
among those that were 5FU refractory (15.1 v 6.6
months, P ⫽ .0112), as were PFS and RR. Grade 1/2
toxicities were higher in the perifosine-treated pa-
tients, including diarrhea, fatigue, nausea, and mucosi-
tis, as well as grade 3/4 hand-foot syndrome and ane-
mia.62 These findings are very encouraging, yet require
a more definitive study. A phase III trial, Xeloda and
Perifosine Evaluation in Colorectal cancer Treatment
(X-PECT), is now in progress.
INITIALLY RESECTABLE LIVER METASTASES
With a solitary liver metastasis or a small burden of
metastatic disease, it may be possible for patients to
undergo surgical resection, which has been reported in
up to 25% of selected patient cohorts.63 While there has
not been a randomized study to evaluate whether che-
motherapy or surgery or both is the best management
of initially resectable liver metastases, multiple surgical
series suggest that metastectomy provides improved
survival in comparison to control groups.64
The only randomized data evaluating the role of
perioperative chemotherapy in the context of resect-
able liver metastases is the EORTC’s (EPOC) trial that
demonstrated that perioperative FOLFOX chemother-
apy was superior to surgery alone (PFS HR 0.76, P ⫽
.023).65 However, in the analysis based on the primary
endpoint, in which patients who were unresectable at
the time of surgery were censored, there was only a
trend to improved PFS (median PFS 18.7 v 11.7
months, P ⫽ .058).65 Optimal timing of chemotherapy
with regards to surgical intervention requires further
elucidation, but this provides support for the use of
perioperative chemotherapy in this setting. Now, the
role of antibody therapy will be evaluated including the
phase II Biologics, Oxaliplatin and Surgery (BOS) study
of the EORTC.
INITIALLY UNRESECTABLE LIVER METASTASES
Initially unresectable metastases represent a more
common scenario for oncologists and published series
have reported that 10% to 40% of selected patients
become resectable with chemotherapy with or without
antibody treatments.66,67 Five-year survival rates of 37%
following this so-called “conversion therapy” and sub-
sequent hepatectomy have been reported depending
on surgical techniques and patient selection.68 Unfor-
tunately, up to 80% of these patients will eventually
recur despite partial hepatectomy.69
In large, randomized controlled trials of first line
therapies for mCRC, RRs of 30% to 55% have been
seen with oxaliplatin-11,13,15,16,28,70 and irinotecan-
557
based8,9,13,15,16,26 regimens. Metastectomy rates are usu-
ally less than 10% in studies in which rates were re-
ported9,13,15,16,28,70 but up to 31% with oxaliplatin.16,70
With the use of biologic therapies, response rates have
been even better, ranging from 34% to 68% with either
bevacizumab26,28,29,71 or cetuximab,72–74 with curative-
intent resections in up to 23% of patients.73 One retro-
spective study reported that of those that became re-
sectable, 25% did so following second- or third-line
therapy,75 challenging our conventional thinking that
responses following the failure of first-line therapy are
less clinically significant. Impressively, 10-year OS for
downstaged patients that underwent partial hepatec-
tomy was 30%, a rate not yet demonstrated for any
other treatment.75 Given that radiologic complete re-
sponse is not a proxy for pathologic complete re-
sponse,76 it seems logical that surgical resection could
improve survival. Clearly strides are being made in
converting initially unresectable to resectable metasta-
ses. Safety profiles of the drugs, particularly liver failure
and operative outcomes, need to continue to be mon-
itored as we are more aggressive in treating such pa-
tients.
DIRECTED THERAPIES
Given that liver metastases generally are life-limiting
in mCRC, liver-directed therapies have been evaluated.
Radiofrequency ablation (RFA) for unresectable liver
metastases with chemotherapy was compared with
standard chemotherapy alone in a randomized phase II
trial.77 All patients would undergo resection as appro-
priate. This study suffered from low accrual and was
stopped early. There was no survival benefit from RFA
treatment, although PFS improved (17 v 10 months,
P ⫽ .025).
CONCLUSIONS
In less than two decades, the treatment landscape
for mCRC has broadened dramatically with the use and
combination of traditional chemotherapies and bio-
logic agents. Despite the improvements in mCRC care,
it is certainly disheartening that our treatments eventu-
ally almost always fail our patients. Ongoing refinements
to the use of these agents and the development of newer
agents can only improve the care that oncologists offer.
Newer treatments are likely to focus on subsets of pa-
tients with appropriate predictive markers.
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