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Colorectal Cancer
Therapeutic Armamentarium in Metastatic Colorectal Cancer
Teresa Macarulla,
1
Ben Markman
2
and Josep Tabernero
3
1. Physician; 2. Fellow; 3. Head Gastrointestinal Tumours and Phase 1 Unit,
Medical Oncology Department, Vall d´Hebron University Hospital, Barcelona
Abstract
Colorectal cancer is one of the most frequently diagnosed malignancies in both men and women and, despite recent advances, the
prognosis in the metastatic setting remains poor. In the last decade the introduction of new chemotherapeutic agents has improved the
median overall survival of these patients. The demonstration that deregulation and/or activation of selected kinase proteins are common
phenomena in patients with colon cancer has prompted the development of new biologic therapies targeting such proteins. Further,
inhibition of the angiogenesis process can result in efficacy advantage. To date, three targeted therapies have been approved for the
treatment of patients with metastatic colorectal cancer: bevacizumab, cetuximab and panitumumab. New treatments directed against
other molecular targets are being developed in order to improve these results.
Keywords
Colon cancer, chemotherapy, bevacizumab, cetuximab, panitumumab, targeted therapies
Disclosure: Teresa Macarulla and Ben Markman have no conflicts of interest to declare. Josep Tabernero has participated in the advisory boards of Amgen, Imclone, Merck,
MSD, Onyx, Pfizer, Pharmamar, Roche and sanofi-aventis, has been involved in symposia sponsored by Amgen, Bayer, Merck, MSD, Pfizer, Roche and sanofi-aventis and has
provided expert testimony at the European Medicines Agency (EMEA) sponsored by Amgen.
Received: 7 July 2009 Accepted: 3 August 2009
Correspondence: Josep Tabernero, Medical Oncology Department, Vall d’Hebron University Hospital, P Vall d’Hebron, 119–129, 08035 Barcelona, Spain.
E:
jtabernero@vhio.net
Colorectal cancer (CRC) remains one of the most common tumour study, conducted by Douillard et al. (with an infusional 5FU/LV
types and a leading cause of cancer death worldwide. The American regimen),
5
confirmed this data. The results of these two prospective
Cancer Society (ACS) estimates that 148,610 people were diagnosed phase III randomised, controlled, multicentre, multinational clinical
with, and 55,170 people died of, CRC last year in the US.
1
Despite trials in patients with previously untreated mCRC served as the basis
these statistics, mortality from CRC has decreased over the past for US and European approval of irinotecan/5FU/LV for this
30 years, possibly because of better treatment modalities. Until a indication. At the same time, de Gramont et al.
3
published the results
few years ago, treatment options for CRC patients were limited to of a phase III trial which concluded that the combination of infusional
5-fluorouracil (5FU). However, the introduction of two new cytotoxic FU/LV and oxaliplatin (FOLFOX) prolonged progression-free survival
drugs, irinotecan and oxaliplatin, has resulted in significant progress (PFS) (median 9 months versus 6.2 months; p=0.0003) with
in the treatment of metastatic CRC (mCRC).
2,3
Recently, three novel acceptable tolerability. However, this combination failed to
targeted agents have been approved for the treatment of mCRC: demonstrate a statistically significant increase in OS (median 16.2
bevacizumab, cetuximab and panitumumab. As a consequence, the months versus 14.7 months; p=0.12). For this reason the FOLFOX
armamentarium of treatment options for patients with CRC is rapidly regimen was only approved in Europe as first-line treatment in
expanding. In spite of these advances, the prognosis for patients mCRC. With the results of the Goldberg trial in 2004,
6
oxaliplatin was
with mCRC remains poor, with a five-year survival rate less than 5%. approved in the US for the treatment of mCRC. In this study, 795
Therefore, new strategies are needed to improve this prognosis. In patients with mCRC were randomised to receive IFL, FOLFOX or
this article we review the therapeutic options in mCRC. irinotecan and oxaliplatin (IROX). The results of the FOLFOX group
were significantly superior to the IFL and IROX groups. At that time,
The Chemotherapy Era two 5FU-based infusional regimens with oxaliplatin (FOLFOX) or
Until a few years ago, 5FU and 5FU in combination with leucovorin irinotecan (FOLFIRI) became the most popular schedules used
(LV) were the treatment options for patients with CRC. Some clinical worldwide for the treatment of patients with mCRC.
trials evaluated different schedules and doses of these two drugs,
infusional schedules of 5FU and combinations with LV being the most The Gruppo Oncologico del Nord-Ovest (GONO) Italian group
attractive regimens. Nevertheless, the median overall survival (mOS) published the results of a very provocative trial evaluating a new
remained around 12 months.
4
Saltz et al.
2
demonstrated in a phase III chemotherapy combination.
7
In this phase III trial, 244 patients were
trial with 628 patients that the addition of irinotecan to bolus 5FU/LV randomised to receive FOLFIRI or the combination of oxaliplatin,
(IFL) increased the mOS from 12.6 to 14.8 months (p=0.04). Another infusional 5FU/LV and irinotecan (FOLFOXIRI). The response rate (RR)
64 © TOUCH BRIEFINGS 2009
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