Expert Interview
Colorectal Cancer -- Moving Biologics Into the Adjuvant Setting: An
Expert Interview With Dr. John Marshall
Posted 10/25/2006


Editor's Note:

The biologic targeted agents bevacizumab and cetuximab are both
approved for the treatment of metastatic colorectal cancer (CRC). In
February 2004, bevacizumab, a monoclonal antibody directed against
vascular endothelial growth factor, became the first targeted
antiangiogenic agent to receive US Food and Drug Administration
approval for the treatment of cancer. The indication for bevacizumab
has recently been expanded from refractory disease to include first-
line treatment of metastatic colorectal cancer. Cetuximab, a
monoclonal antibody directed against the epidermal growth factor
receptor (EGFR), is also approved for the treatment of patients with
metastatic CRC who have progressed on irinotecan or for those unable
to tolerate treatment with irinotecan. Several clinical trials are
now underway to evaluate these agents in the adjuvant setting. Emma
Hitt, PhD, recently spoke with John Marshall, MD, Director of
Developmental Therapeutics and Gastrointestinal Oncology, at the
Lombardi Comprehensive Cancer Center at Georgetown University, in
Washington, DC, on behalf of Medscape to discuss the current status
of clinical trials evaluating biologics for the adjuvant treatment of
colorectal cancer. Dr. Marshall described some of the practical
implications and remaining unanswered questions regarding the use of
these agents in early stage disease.

Medscape: What is the rationale for using bevacizumab and other
biologics as part of adjuvant treatment for CRC?

Dr. Marshall: The current standard of care for the treatment of
patients with stage III CRC is 12 cycles of FOLFOX [5-fluorouracil (5-
FU), leucovorin, and oxaliplatin] chemotherapy for 6 months. Whether
or not to use that same chemotherapy to treat patients with stage II
disease is controversial, but many believe that these patients should
receive the same duration of FOLFOX chemotherapy.

We know that in the metastatic setting, the antiangiogenic agent
bevacizumab and the EGFR inhibitor cetuximab have significantly
improved outcomes. So the next question we need to ask is whether
these biologic agents, when added to FOLFOX in patients with stage II
or III disease, will further increase progression-free and overall
survival in the adjuvant setting.

You could imagine that an antiangiogenic agent such as bevacizumab
would be effective in the adjuvant setting. If microscopic metastatic
disease were present, bevacizumab could perhaps delay the onset of
disease progression and prevent development of angiogenesis,
necessary for tumor growth.

Medscape: One of the major trials evaluating bevacizumab in the
adjuvant setting is the National Surgical Adjuvant Breast and Bowel
Project (NSABP) C-08 trial[1] --what is the rationale for that trial
and its current status?

The NSABP C-08 trial randomized patients with stage II or III disease
to receive mFOLFOX-6 for 12 cycles with or without bevacizumab.
Patients assigned to bevacizumab plus chemotherapy also received an
additional 6 months of bevacizumab alone. The premise for treating
patients with an additional 6 months of bevacizumab is that this
might further improve the progression-free survival. However, the
addition of 6 months of single-agent bevacizumab is pretty
controversial. At least in the metastatic setting, there are no data
to suggest that single-agent bevacizumab will have activity, so what
additional benefit it might provide when given alone for a further 6
months is unclear. In addition, the drug is not without side effects
(eg, bowel perforation, stroke, heart attack, and bleeding). Although
rare, these risks have to be weighed against the benefits.

Nonetheless, the NSABP C-08 trial is a very important study, the
results of which could immediately change the standard of care. The
trial has already completed accrual, and we will have results from
the trial in about 2 to 3 years.

Medscape: Can you describe the AVANT trial,[2] which is also
evaluating adjuvant bevacizumab?

Dr. Marshall: The AVANT trial, also conducted in patients with stage
II or III colorectal cancer, started out as a 3-arm clinical trial
and has a very similar design to that of the NSABP C-08 trial.
Patients received FOLFOX-4 chemotherapy alone, FOLFOX-4 plus
bevacizumab, or XELOX (capecitabine/oxaliplatin) plus bevacizumab.
This clinical trial was stopped at one point because of a higher rate
of sudden death due to cardiovascular events in the
capecitabine/oxaliplatin plus bevacizumab arm. Although the trial has
since been reopened, the accrual to that study has been actually
quite slow due to those concerns. I believe this trial will
eventually complete its accrual, but results will probably take
longer than for the NSABP C-08 trial.

Medscape: Are there any other late-phase trials of bevacizumab for
the adjuvant treatment of CRC?

Dr. Marshall: A randomized phase 3 trial[3] is also underway to study
combination chemotherapy with or without bevacizumab in patients who
have had surgery for stage II or III rectal cancer. In addition, a
phase 2 clinical trial, Eastern Cooperative Oncology Group (ECOG)
5202,[4] is identifying high-risk patients based on their genetic
profiles. This study is evaluating the feasibility of genetic
profiling using 2 genes: the DCC gene, also known as 18q loss of
heterozygosity, as well as the microsatellite instability (MSI) gene.

About 75% to 80% of patients with stage II disease will, in fact, be
cured by surgery, so if we treat, for example, 100 patients, we are
overtreating about 75 of those patients. Therefore, the goal of this
study is to determine whether we can identify the 25 or so patients
who may be at high risk and treat only those patients with
chemotherapy. Patients who are thought to be at low risk based on
their genetic profiles are not given chemotherapy and are simply
observed, whereas patients who have a high-risk genetic profile are
given FOLFOX-4 for 6 months or FOLFOX-4 for 6 months plus bevacizumab
for 12 months -- similar to the protocol used in the NSABP C-08
trial. This trial has only accrued a couple of hundred patients, but
it is a very selective study.

Medscape: Is bevacizumab often used off label in the adjuvant
setting, and what is your opinion about that?

Dr. Marshall: While I am fully supportive of the adjuvant clinical
trials with bevacizumab, and, frankly, I am hoping the results will
be positive, we have to remember that using bevacizumab off label in
the adjuvant setting is risky until adequate data are available. For
example, we were sure that irinotecan was going to work in the
adjuvant setting, but what we actually found was a significantly
increased toxicity rate in patients with early stage disease.

Bevacizumab has rare but significant acute toxicities associated with
its use. So, to risk using bevacizumab in the adjuvant setting for
the patient who will likely be cured with surgery is not appropriate
outside of the clinical trial. We know that there is a lot of usage
of bevacizumab outside of clinical trials, but it is going to take a
while to determine whether this drug actually is effective in the
adjuvant setting. I have not used adjuvant bevacizumab off label in
my practice.

Medscape: What about trials that are evaluating cetuximab and
panitumumab in the adjuvant setting?

Dr. Marshall: Basically, the rationale for using EGFR inhibitors in
the adjuvant setting would be similar to that for using bevacizumab.
These drugs have demonstrated a benefit in the metastatic and/or
refractory setting, and they are both working their way to earlier
front-line metastatic disease. Trials with the EGFR monoclonal
antibody cetuximab are underway in the adjuvant setting.

An Intergroup study (NCCTG-N0147; ECOG-N0147)[5] is currently
accruing patients and will evaluate 3 different combination
chemotherapy regimens with or without cetuximab for 6 months. Now
that the NSABP C-08 trial is closed, this trial should accrue very
rapidly. Another trial led by European researchers, called the PETACC-
8 study, will also include patients with fully resected stage III
colorectal cancer and will evaluate FOLFOX-4 with or without
cetuximab.[6]

One problem with cetuximab, though, is that it is often associated
with rash, which, in the adjuvant setting, may be particularly
difficult for patients to tolerate. So we are going to have to wait
to see what benefit may be observed with cetuximab in adjuvant
clinical trials, and how it may be balanced against the side effects.

Another monoclonal antibody directed against EGFR, panitumumab,
currently is not undergoing testing in the adjuvant setting, but
studies are being planned.

Medscape: Do you think there will be a role for single-agent use of
EGFR blockade in the adjuvant setting?

Dr. Marshall: EGFR blockade has shown single-agent activity.[7] The
proportion of responses is low, but some patients will respond to the
treatment. However, none of the studies so far is evaluating EGFR
blockade by itself -- as maintenance therapy, if you will -- in the
stage II or stage III setting. Currently, these agents are all being
evaluated with chemotherapy.

Medscape: What are some of the remaining unanswered questions about
the use of biologics in earlier-stage disease?

Dr. Marshall: One of the unanswered questions is how long to
administer adjuvant therapy. Currently we use 6 months of treatment,
but it would be useful to determine whether 4 months of therapy would
be equally effective. We have not asked that question on a large
scale in CRC. One small British study,[8] for example, found that 3
months of 5-FU was just as effective as 6 months of therapy, and we
have never really followed up on this issue. From a cost and side-
effect perspective, if 3 months of chemotherapy were as good as 6
months, this would obviously benefit patients and payers alike. So
this is a question that we ultimately need to ask with biologics in
the adjuvant setting as well.

We also need to establish how to individualize treatment. The E5202
study[4] is asking this question in high-risk patients with stage II
disease, but many patients are still being overtreated -- even those
with stage III disease. Therefore, as new technology becomes
available, it will be important to use arrays and genetic profiling
to determine who should receive chemotherapy and who should not.

Thus, establishing duration of therapy and identifying patients who
will benefit the most, I think, are the 2 biggest questions we are
trying to answer when considering using these agents in the adjuvant
setting.

References
Fluorouracil, Leucovorin, and Oxaliplatin With or Without Bevacizumab
in Treating Patients Who Have Undergone Surgery for Stage II or Stage
III Colon Cancer. Available at:
http://www.clinicaltrials.gov/ct/show/NCT00096278?order=1. Accessed
October 18, 2006.
Combination Chemotherapy With or Without Bevacizumab in Treating
Patients Who Have Undergone Surgery for Stage II or Stage III Colon
Cancer. Available at:
http://www.clinicaltrials.gov/ct/gui/show/NCT00112918. Accessed
October 18, 2006.
Combination Chemotherapy With or Without Bevacizumab in Treating
Patients Who Have Had Surgery for Stage II or Stage III Rectal
Cancer. Available at:
http://www.clinicaltrials.gov/ct/show/NCT00303628. Accessed October
18, 2006.
Oxaliplatin, Leucovorin, and Fluorouracil With or Without Bevacizumab
in Treating Patients Who Have Undergone Surgery for Stage II Colon
Cancer. Available at:
http://www.clinicaltrials.gov/ct/gui/show/NCT00217737. Accessed
October 18, 2006.
Comparison of Combination Chemotherapy Regimens With or Without
Cetuximab in Treating Patients Who Have Undergone Surgery for Stage
III Colon. Available at:
http://clinicaltrials.gov/ct/show/NCT00079274. Accessed October 18,
2006.
Combination Chemotherapy With or Without Cetuximab in Treating
Patients With Stage III Colon Cancer That Was Completely Removed by
Surgery. Available at:
http://www.clinicaltrials.gov/ct/show/NCT00265811. Accessed October
18, 2006.
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and
cetuximab plus irinotecan in irinotecan-refractory metastatic
colorectal cancer. N Engl J Med. 2004;351:337-345. Abstract
Chau I, Norman AR, Cunningham D, et al. A randomised comparison
between 6 months of bolus fluorouracil/leucovorin and 12 weeks of
protracted venous infusion fluorouracil as adjuvant treatment in
colorectal cancer. Ann Oncol. 2005;16:549-557. Abstract


Related Links
Resource Centers
Colorectal Cancer


Biologic Therapies in Cancer


Funding Information

Supported by an independent educational grant from Genentech




Interviewee affiliation: John Marshall, MD, Associate Professor of
Medicine; Chief, Hematology and Oncology, Georgetown University,
Washington, DC


Disclosure: Emma Hitt, PhD, has disclosed no relevant financial
relationships.

Disclosure: John Marshall, MD, has disclosed that he has received
grants for educational activities from, served as an advisor or
consultant to, and served on the speaker's bureaus of Roche, Sanofi,
Bristol-Myers Squibb, Genentech, and Pfizer.


Medscape Hematology-Oncology. 2006;9(2) ©2006 Medscape