Journal of Cancer Therapy, 2010, 1, 195-196
doi:10.4236/jct.2010.14030 Published Online December 2010 (
Copyright © 2010 SciRes. JCT
Diminishing Returns in the Treatment of
Metastatic Colorectal Cancer: Are Patients
Reaching a Survival Plateau
Riccardo Lencioni 1, James Chen 2
1 Department of Hepatology and Liver Transplantation, Pisa University Hospital and School of Medicine, Pisa, Italy; 2 Light Sciences
Oncology, Inc., Bellevue, Washington, USA.
Received October 11th, 2010; revised October 23rd, 2010; accepted October 27th, 2010.
Despite the evolution o f treatment for metastatic colorectal cancer (MCRC) over the past decade, improvements in sur-
vival endpoints have appeared to reach a plateau. The addition of expensive targeted biologic agents to the therapeutic
armamentarium against MCRC have not drastically increased survival, particularly in the realm of second and third
line patients, as tumor resistan ce remains an issu e. Original app roaches to treatin g MCRC are needed in order to raise
the apparent surviva l ceiling in these patients.
Keywords: Colorectal Cancer, Chemotherapy, Molecular Targeted Agents
Metastatic colorectal cancer (MCRC) is a deadly solid
tumor, and its incidence is still increasing in parts of the
world, notably Asia [1]. In the United States there are
approximately 150,000 new cases diagnosed per year [2].
Worldwide, approximately 1.2 million cases occur each
year [3].
Drug therapy for MCRC has undergone an evolution
over the past decade—from 5-fluorouracil (5-FU)-based
therapy, to combination and sequential th erapies that also
incorporate the chemotherapeutics irinotecan and ox-
aliplatin, to the recent addition of targeted agents. Cur-
rently, patients with a good performance status typically
begin on oxaliplatin plus 5-FU/leucovorin (FOLFOX) or
irinotecan plus 5-FU/leucovorin (FOLFIRI), with bevaci-
zumab added to either regimen. Median survival time
under the best circumstances is about 20 months, pro-
vided the patient can tolerate exposure to multiple lines
of chemotherapy [3]. Efforts to improve overall survival
have resulted in the development of a number of targeted
agents used at various stages of therapy, including
bevacizumab, cetuximab, and panitumumab. Bevacizu-
mab, approved by the FDA in combination with iri-
notecan, fluorouracil, and leucovorin, primarily targets
the vascular endothelial growth factor (VEGF) pathway,
while cetuximab and panitumumab target the epidermal
growth factor (EGF) pathway [4,5]. Despite the addition
of new targeted agents to the chemotherapy backbone,
the 5-year survival of patients with metastatic disease is
only 8% [6].
What has targeted therapy added in terms of MCRC
survival? Bevacizumab has been investigated in the
first-line setting in randomized trials. In a large dou-
ble-blinded first-line study, patients received XELOX or
FOLFOX4, then either bevacizumab or placebo. The re-
sponse rate and median overall survival time were not
significantly different between the two groups [3].
Bevacizumab has not been tested in a randomized con-
trolled first-line setting with FOLFIRI, and pooled stud-
ies involving bevacizumab have not conclusively demon-
strated that its addition to standard front-line regimens
increases survival beyond what is curren tly achiev ed with
FOLFOX or FOLFIRI alone [2,7,8]. Pooled analysis of
the impact of adding bevacizumab to chemotherapy in a
recent Cochrane review revealed a median survival of
20.5 months, which approximates survival achieved with
usage of the three chemotherapeutic agents alone [9,10].
Cetuximab has been demonstrated to increase median
overall survival by 1.5 months in the third-line setting,
but no difference has been noted in the second- or
first-line setting [2,3]. Panitumumab has received the
most recent United States approval for MCRC after fail-
ure of first- and second-line therapy. In the pivotal trial,
Diminishing Returns in the Treatment of Metastatic Colorectal Cancer: Are Patients Reaching a Survival Plateau
Copyright © 2010 SciRes. JCT
no difference in overall survival was noted when com-
pared to best supportive care alone [3].
Solid trial data and subs equent clinical experience sup-
port the use of the three main cytotoxic agents—irinotecan,
oxaliplatin and the fluoropyrimidines—which by all ac-
counts have increased survival in a meaningful manner [2,
3]. Studies involving cytostatic targeted agents have, on
the other hand, demonstrated marginal incremental bene-
fit, with significant added cost and emergence of new
classes of side effects [2].
Arguably, a survival ceiling is being reached for most
patients with MCRC. Ongoing investigations of the cy-
tostatic drugs erlotinib, gefitinib, sun itinib, vatalanib, and
other antiangiogenesis inhibitors are unlikely to provide
further major survival improvements in patients with
advanced CRC. Further, the PACCE and CAIRO2 trials,
which combined VEGF and EGFR inhibitors with che-
motherapy, demonstrated worse outcomes for the com-
binations of VEGF with EGFR inhibitors [6]. Current
approaches in development are encumbered by intrinsic
or acquired tumor resistance coincident with dose-limit-
ing toxicity and high cost, preventing truly meaningful
improvements in longevity and affordability, with fewer
drug-related side effects. New, very original approaches
to MCRC beyond targeted therapy deserve increased at-
tention and development efforts.
2. Acknowledgements
The authors take full responsibility for the scope, direc-
tion and content of the manuscript. They would like to
thank Research Analysis Library for the assistance in the
literature review and in the preparation of the draft man-
uscript. Editorial assistance was supported by Light Sci-
ence Oncology, Inc.
[1] J. J. Sung, J. Y. Lau, G. P. Young, Y. Sano, H. M. Chiu, J.
S. Byeon, K. G. Yeoh, K. L. Goh, J. Sollano, R. Rer-
knimitr, T. Matsuda, K. C. Wu, S. Ng, S. Y. Leung, G.
Makharia, V. H. Chong, K. Y. Ho, D. Brooks, D. A. Lie-
berman and F. K. Chan, “Asia Pacific Consensus Rec-
ommendations for Colorectal Cancer Screening,” Gut,
Vol. 57, No. 8, 2008, pp. 1166-1176.
[2] S. K. Maithel and M. I. D'Angelica, “An Update on Ran-
domized Clinical Trials in Advanced and Metastatic Co-
lorectal Carcinoma,” Surgical Oncology Clinics of North
America, Vol. 19, No. 1, 2010, pp. 163-181.
[3] C. H. Kohne and H. J. Lenz, “Chemotherapy with Tar-
geted Agents for the Treatment of Metastatic Colorectal
Cancer,” Oncologist, Vol. 14, No. 5, 2009, pp. 478-488.
[4] M. H. Cohen, J. Gootenberg, P. Keegan and R. Pazdur,
“FDA Drug Approval Summary: Bevacizumab Plus
FOLFOX4 as Second-line Treatment of Colorectal Can-
cer,” Oncologist, Vol. 12, No. 3, 2007, pp. 356-361.
[5] H. Hurwitz, L. Fehrenbacher, W. Novotny, T. Cartwright,
J. Hainsworth, W. Heim, J. Berlin, A. Baron, S. Griffing,
E. Holmgren, N. Ferrara, G. Fyfe, B. Rogers, R. Ross and
F. Kabbinavar, “Bevacizumab Plus Irinotecan,
Fluorouracil, and Leucovorin for Metastatic Colorectal
Cancer,” New England Journal of Medicine, Vol. 350, No.
23, 2004, pp. 2335-2342.
[6] P. Comella, R. Casaretti, A. Avallone and L. Franco,
“Optimizing the Management of Metastatic Colorectal
Cancer,” Critical Reviews in Oncology/Hematology, Vol.
75, No. 1, 2010, pp. 15-26.
[7] F. Montagnani, C. Migali and G. Fiorentini, “Progres-
sion-free Survival in Bevacizumab-based First-line Treat-
ment for Patients with Metastatic Colorectal Cancer: Is It
a Really Good End Point?” Journal of Clinical Oncology,
Vol. 27, No. 28, 2009, pp. e132-133.
[8] S. Welch, K. Spithoff, R. B. Rumble and J. Maroun,
“Bevacizumab Combined with Chemotherapy for Patients
with Advanced Colorectal Cancer: A Systematic Re-
view,” Annual Oncology, Vol. 21, No. 6, 2010, pp.
[9] J. Capdevila, F. J. Ramos, T. Macarulla, E. Elez and J.
Tabernero, “The Role of Salvage Treatment in Advanced
Colorectal Cancer,” Critical Reviews in Oncol-
ogy/Hematology, Vol. 71, No. 1, 2009, pp. 53-61.
[10] A. D. Wagner, D. Arnold, A. A. Grothey, J. Haerting and
S. Unverzagt, “Anti-angiogenic Therapies for Metastatic
Colorectal Cancer”. Cochrane Database of Systematic
Reviews, No. 3, 2009, pp. CD005392.