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Metastatic Colorectal Cancer: Is There One Standard Approach?

Metastatic Colorectal Cancer: Is There One Standard Approach?

ABSTRACT: Despite enormous advances in the treatment of colorectal cancer, there is no single standard treatment approach for all patients. However, there are general principles of management that can be used to guide therapy. The clinician who fails to individualize therapy for colorectal cancer is likely not taking full advantage of all therapeutic options available. Reviewing key clinical evidence that can help inform decision-making, this article addresses important questions in colorectal cancer management, including: Should bevacizumab (Avastin) be a component of most patients' first-line treatment? Is there a role for continuing bevacizumab in subsequent regimens? Is there a role for cetuximab (Erbitux) in standard first-line chemotherapy? Are there practices in colorectal cancer that have become widely accepted without direct supportive data?

The past 10 years have seen enormous
changes in the options
available to patients with colorectal
cancer. In 1995, there was one
drug, fluorouracil (5-FU), approved
for the treatment of this disease. In
2005, there are six drugs on the market
for the management of colorectal
cancer, not including leucovorin,
which is a modifier of 5-FU but has
no intrinsic anticancer activity of its
own. Several other potentially useful
agents are in the late phases of clinical
development. With the availability
of so many options, the efficacy of our
treatment regimens has increased substantially.
So too, however, has the complexity
of the treatment decisions the
oncologist must wrestle with when
charting a course for his or her patient.

Is there a simple standard treatment
approach that can be adopted
for all patients with colorectal cancer?
No, not at this time. The progress
that has been made has not proceeded
in a neat, well-organized, linear fashion.
Many different approaches and
many different questions have been
explored in parallel, rather than in
series. Some of our more common
practices are based on solid comparative
data, while others are more appropriately
characterized as widely
accepted leaps of faith. However, there
are certain principles of management
that can be used to guide selections of
therapy. Rather than an exhaustive
review of all the data that support our
current practices, this manuscript will
instead address some of the more important
questions that confront us in
the area of colorectal cancer management,
and will review key clinical evidence
that can help inform our
decision-making.

When the evidence is strong, and
evidence to the contrary is little or
none, then clearly that evidence should
dictate our practices. However, there
are many circumstances in which the
evidence is equivocal, with an important
decision being either inadequately
addressed by available data, or there
being potentially conflicting data that
muddy the waters. In these cases, we
must critically consider which data
might reasonably be extrapolated from
to guide decision-making. With this
caveat in mind, I will explore the data
that address some of the more important
questions that arise in selecting
therapies for patients with metastatic
colorectal cancer, bearing in mind that
new data and options are arising frequently.
The answers and opinions offered
herein are based on available
information at the time of this writing.

BevacizumabFirst-Line Treatment
Should bevacizumab (Avastin) be
a component of most patients' firstline
treatment regimen? Yes. Rarely
in oncology have we had such compelling
and unopposed data as we do
on this topic. Bevacizumab is a humanized
monoclonal antibody that targets
a key substance known as
vascular endothelial growth factor
(VEGF).[1] How bevacizumab works
in metastatic colorectal cancer is the
subject of some debate. That it works
is a clearly established clinical fact.

It is clear that bevacizumab binds
to and thereby effectively neutralizes
circulating VEGF. This may have several
important effects that influence
tumor growth and survival. VEGF is
a centrally important component of
the proangiogenic pathway. As such,
new blood vessel formation necessary
to support tumor progression is
potentially inhibited by the decrease
or absence of circulating VEGF levels.
However, VEGF exerts other actions
that may be even more critical
to its therapeutic efficacy. Unlike mature,
long-established vasculature, the
newly formed blood vessels that support
a growing tumor have relatively
thin walls and are dependent on continued
growth factor (including
VEGF) for support and maintenance
of integrity. In the absence of sufficient
VEGF levels, these immature
vessels become fragile and leaky, and ultimately are degraded, leading to a
normalization of tumor vasculature.[2]

These changes would be anticipated
to deliver other, concurrently
administered, chemotherapy more effectively
to the tumor tissue. Additionally,
bevacizumab has been
demonstrated to lower intratumoral
interstitial pressure, further facilitating
transfer of other antineoplastic
agents from the bloodstream to the
tumor tissue.[3] To what degree each
of these mechanisms contributes to
the antitumor activity of bevacizumab
is a matter of conjecture at this time.

  • Key Clinical Trial-The pivotal
    trial that demonstrated the utility of
    bevacizumab in colorectal cancer was
    reported by Hurwitz et al.[4] In a
    randomized, double-blind, placebocontrolled
    trial of approximately
    800 patients, half received the thenstandard
    IFL (irinotecan [Camptosar],
    5-FU by weekly bolus, and leucovorin)[
    5] plus a placebo, and half received
    the same chemotherapy plus
    bevacizumab at a dose of 5 mg/kg
    every other week.

    The major efficacy parameters are
    shown in Table 1. Patients who received
    bevacizumab had a median
    survival that was almost 5 months
    longer than those who did not. Other
    supportive end points such as progression-
    free survival were increased
    as well. The subjective toxicity-that
    which the patient was overtly aware
    of-was essentially nil, such that a
    placebo control was realistically possible.
    That is not to say that side effects were not encountered: There was
    roughly a 10% increased risk of serious
    hypertension (which responded to
    oral medication), a 1.5% risk of gastrointestinal
    perforation, and a 2.5%
    increased risk of arterial thrombotic
    events. Clearly, these represent major
    and potentially lethal complications.

    But are these side effects reason
    enough to eschew routine use of frontline
    bevacizumab? No, in my opinion.
    Taken as a whole, side effects
    notwithstanding, patients who received
    bevacizumab responded better
    and lived longer than those who did
    not. In discussion of these risks with
    patients, I have likened the decision to
    add bevacizumab to their chemotherapy
    to the decision to use a seat belt.
    While there is a possibility that in an
    accident the seat belt might actually
    cause an injury, it is far more likely to
    prevent one. Likewise, bevacizumab
    may cause a complication, but it is more
    likely to benefit the patient. Older patients
    and patients with a history of
    significant cardiovascular or cerebrovascular
    disease appear to be at
    increased risk for arterial thrombotic
    complications from bevacizumab, and
    these factors should be considered
    when individualizing therapy.

  • ECOG 3200-Other data have
    corroborated the efficacy of bevacizumab
    in metastatic colorectal cancer.
    The Eastern Cooperative
    Oncology Group (ECOG) 3200 study,
    recently reported in abstract form, randomized
    829 bevacizumab-naive patients
    who had failed previous
    chemotherapy with both 5-FU and
    irinotecan (together or individually) to
    receive either bevacizumab, FOLFOX
    (biweekly infusional 5-FU, leucovorin,
    and oxaliplatin [Eloxatin]), or
    bevacizumab plus FOLFOX. The
    bevacizumab-alone arm was closed
    early due to concerns of inferior efficacy.
    The final data for this arm have
    not yet been reported at the time of
    this writing. The overall survival
    benefit for the bevacizumab-plus-
    FOLFOX arm over FOLFOX alone
    was 12.5 vs 10.7 months (P < .002).[6]

    Of note, the incidence of grade 3
    neurotoxicity was increased in the
    bevacizumab/FOLFOX group compared
    to those receiving FOLFOX alone (14.9% vs 8.4%). While this
    may be simply a result of the greater
    time on therapy leading to increasing
    oxaliplatin exposure, the possibility
    of bevacizumab facilitating platinum
    entry into neurons and so exacerbating
    oxaliplatin neurotoxicity cannot
    be excluded at this time. It will be
    instructive, when data are available,
    to see if the neuropathy incidence over
    time is similar between the two arms,
    or if the neurotoxicity appears earlier
    in the bevacizumab-containing arm.

  • Other Trials-Three other studies
    thus far have provided supportive
    evidence of the efficacy of bevacizumab
    in colorectal cancer. A trial
    reported by Kabbinavar et al demonstrated
    improved response rates and
    progression-free survivals for bevacizumab
    in conjunction with 5-FU/leucovorin,
    as did a smaller randomized
    phase II trial.[7,8] Neither of these
    trials was designed or powered to detect
    a survival benefit. More recently,
    the preliminary results of a small randomized
    phase II trial adding bevacizumab
    to cetuximab (Erbitux) and to
    cetuximab plus irinotecan in bevacizumab-
    naive patients suggested a
    strong improvement in response rate
    and time to tumor progression as compared
    to historical controls.[9]

    In short, all of the data suggest that
    adding bevacizumab to active chemotherapy
    in bevacizumab-naive patients
    improves antitumor activity.
    Why then, are some oncologists
    choosing to routinely not use bevacizumab
    in the management of their
    patients? I do not know. One argument
    that has been offered is that the
    survival time on the IFL/bevacizumab
    trial (20.5 mo) did not differ substantially
    from the survival time in the
    FOLFOX arm of the recent intergroup
    N9741 trial.[10] This is a specious
    argument. First, it is a cross-study
    comparison of two trials conducted
    with different investigators and different
    patient populations, making the
    comparison inappropriate and invalid.
    Second, even if one wishes to explore
    the comparison, there is a marked imbalance
    in availability of second-line
    treatment that would negate the validity
    of the survival comparison, even
    if such a comparison were statistically valid. All of the patients who received
    FOLFOX in the N9741 intergroup
    trial had access to second-line
    irinotecan. Most of the patients who
    received IFL/bevacizumab in the Hurwitz
    trial did not have access to second-
    line oxaliplatin, since the drug had
    not received commercial approval in
    the United States at the time. Furthermore,
    of the limited number of patients
    who received oxaliplatin as second-line
    therapy in the Hurwitz trial, we do not
    have data as to what percentage received
    FOLFOX vs oxaliplatin alone.
    Oxaliplatin alone is now known to be
    substantially inferior to FOLFOX in
    second-line therapy,[11] although this
    was not known when the Hurwitz study
    was conducted.

Subsequent Regimens
Is there a role for continuing bevacizumab
in subsequent regimens after
progressing through a first-line bevacizumab-
containing regimen? I don't
think so. It should be emphasized that
there are essentially no data at this
time that specifically address this
question. However, there are no data
whatsoever that support the practice
of continuing bevacizumab with subsequent
regimens. In general, we require
evidence that an intervention is
useful before we adopt it as a standard
practice. Until and unless we
have evidence to support continuation
of bevacizumab in serial regimens,
I would consider such use
inappropriate.

Some clinicians have mistakenly
interpreted the recently presented
ECOG 3200 study as support for
continuation of bevacizumab in second-
line treatment. This study, as discussed
above,[6] shows a modest but
statistically significant survival advantage
in patients who, after failing
irinotecan and 5-FU, received FOLFOX
plus bevacizumab vs FOLFOX alone.
However, all of the patients who entered
this trial were bevacizumabnaive
when they started second-line
therapy. These data therefore say
nothing about the usefulness of second-
line bevacizumab in patients who
have already received the drug in firstline
therapy.

Since we have virtually no data on
the mechanisms of bevacizumab resistance,
we can hardly invoke a mechanistic
rationale for continuation. We
know that bevacizumab carries with
it a risk of serious and even potentially
fatal toxicities in the form of gastrointestinal
perforation, heart attacks,
and strokes. So I believe we must
guard against being seduced by the
very mild subjective toxicities of bevacizumab;
just because the drug does
not make patients feel unwell does
not mean there is not a potentially
serious downside to its continuation.
It should be recalled that the once
rhetorical question of "what harm
could it do?" was used as a justification
by some for routinely adding high
doses of cyclooxygenase (COX)-2
inhibitors to chemotherapy regimens
in the absence of clinical data to support
this practice.

The question of performing placebo-
controlled trials to address the issue
of continuation of bevacizumab
has been raised. An argument made
against this design is that the long
half-life of bevacizumab would confound
such trials, as residual drug in
the placebo arm would influence the
outcome. I do not believe, however,
that this would pose a major impediment
to addressing the issue. The
question at hand is, does the patient
benefit from the modest but real risk
and the considerable expense of continuing
bevacizumab administration?
If a trial shows convincing evidence
of a benefit for continuing bevacizumab,
then let's do it. If a trial shows
no benefit, then whether it is a negative
trial because second-line repeat
exposure to bevacizumab was inactive
or because there was a carryover
effect from first-line bevacizumab is
an interesting but moot point; it would
still be a negative trial indicating that
continued administration of bevacizumab
is not beneficial.

To the argument that trastuzumab
(Herceptin) treatment is often continued
in multiple lines of therapy in
HER2-positive breast cancer, it is appropriate
to point out that (1) this is a different disease, (2) this is a different
drug working on a different target by
a different mechanism, and (3) there
is a remarkable paucity of data supporting
the practice of continued use
of trastuzumab in serial regimens in
breast cancer.

CetuximabFirst-Line Treatment
Is there a role for cetuximab in
standard first-line chemotherapy? Perhaps
there will be, but as of now, no.
Cetuximab is a monoclonal antibody
that binds to the epidermal growth
factor receptor (EGFR) and blocks
ligand from binding to the receptor,
thereby blocking receptor activation.[
12] Cetuximab has been convincingly
and consistently shown to have
activity as a single agent in irinotecanrefractory
colorectal cancer[13-15] and
to have a higher response rate and
longer time to tumor progression
when given concurrently with a continuation
of irinotecan after irinotecan
failure.[14,16]

It is only in the irinotecan-refractory
setting that definitive data for
cetuximab are available. We have no
randomized data to support the addition
of cetuximab to first-line therapy
of colorectal cancer. In the refractory
setting, when there are no available
active agents, activity in a nonrandomized
phase II trial is meaningful.
In the front-line setting, when given
in conjunction with active chemotherapy
regimens, there is little that can be
determined other than the feasibility
(or lack thereof) of the combination. A
promising degree of activity in a small
phase II trial does not establish that a
combination is appropriate for routine
use, nor does a less than outstanding
response rate in a small phase II trial
mean that a combination is without substantial
merit. In the front-line setting,
only a randomized trial can establish
the relative safety and efficacy of the
new combination.

Several small phase II pilot trials
have explored the feasibility of combining
cetuximab with front-line
regimens,[17-19] and the recent intriguing
activity of cetuximab combined
with bevacizumab in the salvage
setting suggests that this double antibody
combination in conjunction with
front-line therapy should be investigated
as well.[9] The preliminary data
for cetuximab-based front-line combinations
show encouraging response
rates, especially with oxaliplatinbased
combinations. These small
phase II trials in well selected patients
are not, however, a reason to
adopt front-line cetuximab as part of
routine practice. Rather, these studies
support the conduct of randomized
studies of these regimens to
critically evaluate the appropriateness
of incorporation of cetuximab
into first-line regimens. Until the results
of these studies are known, the
benefits and risks of cetuximab in
front-line therapy are unknown, both
in terms of relative safety and efficacy,
and routine use of these combinations
in front-line care cannot be
recommended.

Immunohistochemical Testing
Is immunohistochemical (IHC)
testing of EGFR necessary or appropriate
for the use of cetuximab? No.
From a medical and scientific perspective,
it is neither reasonable nor
appropriate. The currently available
tests for "determining" the EGFR status
of a tumor have no clinical usefulness
whatsoever.

There is absolutely no prospective
clinical evidence that supports the use
of these tests in this setting. In the
original report on cetuximab plus
irinotecan,[16] the response rates for
1+, 2+, and 3+ positive patients, as
determined by an independent response
assessment committee, were
virtually identical. The same was
found to be true in a larger confirmatory
trial.[14] In all of these studies,
patients felt to be "negative" for the
EGFR were excluded from treatment.

Only two reports thus far have specifically
explored the use of cetuximab-
based therapy in EGFR-negative
patients. Lenz et al reported a small
series of nine EGFR-negative patients
who were treated with single-agent
cetuximab; two patients responded.[
15] Independent radiology review
of the nine patients confirmed one
partial response and classified four
patients as having achieved stable disease.
(Recall that up to a 49% regression
is classified as stable disease from
a regulatory perspective.)

A somewhat larger set of patients
was recently reported by Chung et
al,[20] who reviewed the experience
with cetuximab at Memorial Sloan-
Kettering Cancer Center for patients
who initiated treatment with cetuximab
during the first 3 months of its
commercial availability. The computerized
pharmacy records were used to
eliminate recall bias in identifying all
patients who received this drug.
Records were then reviewed to identify
patients who were negative for
EGFR by IHC staining. Of 16 EGFRnegative
patients, 14 had received
cetuximab plus irinotecan and 2 had
received single-agent irinotecan alone.
(As would be expected, both patients
who received cetuximab alone had
indications of significant comorbidities
and poor performance status, and
one received only two doses of cetuximab.)
A review of scans by a reference
radiologist first confirmed that
all 16 patients had demonstrated tumor
growth on a prior irinotecanbased
regimen. Further review then
identified four confirmed partial responses
to cetuximab-based therapy,
all of which were durable at a 6-week
(or later) follow-up scan. All four responders,
as well as two additional
minor responders, had received cetuximab
plus irinotecan.

Clearly, the idea that patients who
lack IHC expression of EGFR are incapable
of responding to cetuximab
is overtly false (Table 2). This does
not mean that EGFR is not the target
for cetuximab. Rather, it means that the
currently available IHC techniques are
seriously flawed and are essentially useless
from a clinical perspective. In truth,
since it has been demonstrated that IHC
expression of EGFR can vary over storage
time and be influenced by the type
of fixative used,[21] as well as vary
from primary to metastasis, it is not
reasonable to believe that these stains
will be sufficiently sensitive and specific
to allow for definitive selection
or exclusion of patients.

The implications of these findings
are clear: Currently available IHC
stains for EGFR have failed to show
any predictive value in terms of the
efficacy of cetuximab-based therapy;
thus, no clinical decision should be
made on the basis of these stains, and
they should not be performed in routine
practice. No patient who is felt to
be otherwise appropriate for cetuximab-
based therapy should be excluded
from such therapy solely on the
basis of a negative EGFR IHC stain.
Similarly, a high degree of EGFR expression
is meaningless in terms of
predicting for cetuximab activity, in
colorectal cancer or otherwise, and
this should not be used as justification
for use of the drug.

Leaps of Faith

Are there practices in colorectal
cancer that have become widely accepted
without direct supportive data?
Yes. We have, as a community, been
willing to make certain leaps of faith.

FOLFOX Variations
One of the most interesting of these
leaps is the move from FOLFOX4,
which is the US Food and Drug Administration
(FDA)-approved schedule,
to modified FOLFOX6, which is
currently being investigated in the
National Cancer Institute (NCI)-supported
intergroup studies and is in
widespread use in clinical practice.
FOLFOX4 includes 85 mg/m2 of oxaliplatin,
with leucovorin and bolus
5-FU being given for 2 consecutive
days. In FOLFOX6, the oxaliplatin
dose was raised to 100 mg/m2, and
the leucovorin dose was doubled on
day 1 and omitted on day 2. The bolus
5-FU was given on day 1 only, and the
infusional 5-FU dose was doubled from
600 mg/m2/d to 1,200 mg/m2/d. In
modified FOLFOX6, the dose of oxaliplatin
was dropped to the 85 mg/m2
dose of FOLFOX4.

No head-to-head comparisons of
any of these regimens have or will be
done. That modified FOLFOX6 has
become a de facto standard regimen
at our institution and in the gastrointestinal
intergroup studies is, in my opinion,
quite reasonable, but it is not
based directly on data.

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