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Expert Interview
Targeted Therapies for Colorectal Cancer: An Expert Interview With
Richard M. Goldberg, MD


Medscape Hematology-Oncology 7(1), 2004. © 2004 Medscape

Posted 06/28/2004

Trial results first presented at the 2003 American Society of
Clinical Oncology (ASCO) demonstrated an important role for targeted
therapies in the management of colorectal cancer (CRC).[1,2] The
addition of the angiogenesis inhibitor bevacizumab to irinotecan, 5-
fluorouracil (5-FU), and leucovorin (IFL) in patients with metastatic
CRC conferred a significant improvement in both progression-free and
overall survival,[1] whereas the addition of the epidermal growth
factor receptor (EGFR) inhibitor cetuximab to irinotecan conferred a
significant improvement in time to progression.[2] In an interview
with Shira Berman of Medscape Hematology-Oncology, Richard M.
Goldberg, MD, Professor of Medicine and Division Chief of Hematology-
Oncology at the University of North Carolina School of Medicine in
Chapel Hill, discussed the role that targeted therapies are likely to
play in the management of CRC in the years to come.

Medscape: By way of background, why is there a need for targeted
therapies in CRC?

Dr. Goldberg: In truth, we could ask the question of why targeted
therapies are needed in any cancer. Chemotherapy doesn't cure cancer
in most cases, so the targeted therapies provide another outlet for
trying to interrupt the neoplastic process. Two kinds of approaches
have been taken so far in CRC. The first approach targets the blood
vessels needed to feed the tumor with drugs, such as the vascular
endothelial growth factor (VEGF) inhibitor bevacizumab. The second
approach targets cell-surface molecules, such as EGFR, which are
inhibited by drugs, such as cetuximab and panitumumab (ABX-EGF), on
which we saw some promising data at this year's meeting.[3] These
agents are being used as another way to disrupt neoplastic cell
proliferation.

Medscape: At last year's ASCO, we saw good results with both
bevacizumab and cetuximab in this setting. What role do you see these
agents playing in the management of CRC?

Dr. Goldberg: Bevacizumab has taken the field by storm, and is now a
common component of first-line therapy. We're awaiting studies in the
second-line setting and studies are about to begin in the adjuvant
setting. It's clear that bevacizumab is an active compound. And now
that we know that, we have to refine the circumstances under which
should be best used. There are a number of questions that still
remain. For example, is the survival benefit specific to its use with
IFL or is generally active in other chemotherapy regimens? In Dr.
Hurwitz's trial,[1] the small number of patients randomized to 5-FU
and leucovorin plus bevacizumab showed some improvement before the
treatment arm was discontinued, suggesting that the benefits are not
specific to IFL but that the agent is generally synergistic with
chemotherapy. And, obviously, we're eager to find out if it's active
with oxaliplatin-based regimens in addition to 5-FU-based and
irinotecan/5-FU-based regimens.

The same issues apply with cetuximab -- it is currently indicated for
use with or without irinotecan in patients who are refractory to
irinotecan. It will be interesting to see how it works in first-line
therapy, how it can be used in the adjuvant setting, and how it will
work in combination with oxaliplatin-based regimens.

Trying to understand the universal applicability of both of these
agents is a crucial bit of research that still needs to be done.

Medscape: Did you see any data presented at this year's ASCO that
look promising?

Dr. Goldberg: There were some data on the use of cetuximab with
FOLFOX and FOLFIRI that looked promising;[4] it was also interesting
to see a very high response rate for the EGFR inhibitor gefitinib in
combination with chemotherapy for CRC.[5]

It's clear that these agents are active and that they will play more
and more of a role over time in the management of colorectal cancer.
But the challenge still remains to determine the best way to
integrate them into the current therapeutic strategies.


References
Hurwitz H, Fehrenbacher L, Cartwright T, et al. Bevacizumab (a
monoclonal antibody to vascular endothelial growth factor) prolongs
survival in first-line colorectal cancer (CRC): results of a phase
III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-
fluorouracil, leucovorin) as first-line therapy in subjects with
metastatic CRC. Proc Am Soc Clin Oncol. 2003;22. Abstract 3646.
Cunningham D, Humblet Y, Seina S, et al. Cetuximab (C225) alone or in
combination with irinotecan (CPT-11) in patients with epidermal
growth factor receptor (EGFR)-positive, irinotecan-refractory
metastatic colorectal cancer (MCRC). Proc Am Soc Clin Oncol.
2003;22:252. Abstract 1012.
Hecht JR, Patnaik A, Malik I, et al. ABX-EGF monotherapy in patients
(pts) with metastatic colorectal cancer (mCRC): an updated analysis.
Proc Am Soc Clin Oncol. 2004;23:248. Abstract 3511.
Tabernero JM, Van Cutsem E, Sastre J, et al. An international phase
II study of cetuximab in combination with oxaliplatin/5-fluorouracil
(5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of
patients with metastatic colorectal cancer (CRC) expressing Epidermal
Growth Factor Receptor (EGFR). Preliminary results. Proc Am Soc Clin
Oncol. 2004;23:248. Abstract 3512.
Fisher GA, Kuo T, Cho CD, et al. A phase II study of gefitinib in
combination with FOLFOX-4 (IFOX) in patients with metastatic
colorectal cancer. Proc Am Soc Clin Oncol. 2004;23:249. Abstract 3514.



Disclosure: Shira Berman has no significant financial interests or
relationships to disclose.

Disclosure: Richard M. Goldberg, MD, has disclosed that he has
received grant support for clinical research from Genentech, Pfizer,
and Sanofi-Synthelabo.