Colorectal cancer market | Nature Reviews Drug Discovery

You have full access to this article via your institution. Download PDF Colorectal cancer (CRC) is a significant challenge to the healthcare system as one of the leading forms of cancer in

the United States, affecting an estimated 147,500 people a year and causing an estimated 57,000 deaths (Fig. 1). The estimated annual cost of treating CRC in the United States, according to

the US Center for Disease Control and Prevention, is around US $6.5 billion including lost productivity and direct medical costs. OLDIES BUT GOODIES Since the 1950s, the mainstay of

first-line CRC chemotherapy has been 5-fluorouracil (5-FU) used either alone or, more often, in combination with leucovorin (LV, folonic acid), which improves the potency of 5-FU. Despite

there being essentially only one therapy, a variety of regimens were developed that varied their dose, the manner in which they were administered (single bolus or infusion over many hours),

the frequency of dosing (daily or weekly) and the duration of treatment (weeks or months). It was not until a French study by de Gramont _et al_. that a difference was shown between

administering 5-FU as an infusion versus as an initial bolus (that is, 400 mg per m2)1. Results from this front-line study showed that the former led to statistically significant improvement

in overall survival by approximately 1.2 months (that is, to 14.3 months versus 13.1 months). In 1995, irinotecan (Camptosar; Pfizer) was approved in Europe (France) and Japan, and later in

the United States (1996), for the treatment of patients with relapsed/refractory metastatic CRC. Shortly after its approval, it was realized that irinotecan used in conjunction with 5-FU/LV

significantly improved overall survival versus the traditional bolus-administered 5-FU/LV regimen (14.6 months versus 12.6 months)2. The new combination, called the Saltz regimen, rapidly

became the standard of care and in 2000 was approved for use in front-line patients in the United States. Around the same time as the European approval of irinotecan, oxaliplatin (Eloxatin;

Sanofi-Synthelabo) was also approved for use as first- and second-line therapy in CRC patients. It was not until 2004 that the FDA finally approved oxaliplatin for front-line use in

combination with 5-FU/LV, as a regimen called FOLFOX. The slower approval in the United States was primarily the result of differences between US and EU regulators over the use of

appropriate clinical endpoints (specifically overall survival and disease-free survival). Comparative front-line studies of FOLFOX4 and the Saltz regimen have shown that the former

significantly improves overall survival rates (19.5 months versus 14.8 months)3. As such, US oncologists are now increasingly using the FOLFOX regimen as the standard of care in front-line

CRC patients. THE ICING ON THE CAKE Modern chemotherapy regimens are likely to remain the backbone of existing front-line treatment regimens, in particular the use of 5-FU/LV. However, with

the advent of new targeted agents, the ability to extend overall survival is increasing. In February 2004, bevacizumab (Avastin; Genentech/Roche) was approved in the United States as a

first-line treatment in combination with 5-FU/LV-containing regimens. As an anti-vascular endothelial growth factor antibody, the drug has a very different mechanism of action to other

cancer therapies. In pivotal trials, bevacizumab in combination with the Saltz regimen was significantly more effective at increasing overall survival rates than Saltz alone (20.3 versus

15.6 months)4. Interestingly, on approval, the FDA gave bevacizumab a broad label, allowing it to be used in combination with the Saltz regimen and with FOLFOX despite the lack of late-stage

data to support the latter combination. Results from a second-line bevacizumab-plus-FOLFOX study are not expected until 2005, and trials in the first-line are not expected until 2007. STEEP

PRICE TAG The nature of healthcare funding in the United States is changing with the introduction of the new Medicare Bill signed in December 2003. Cancer has received particular attention,

not only because of the high unmet clinical need, but also because of the rising cost of treatments. This is particularly true for CRC, for which newly developed drugs are being used as

additive therapies to existing chemotherapy regimens, rather than replacing them as occurs in many other disease areas. Treatment patterns have evolved from the use of less expensive,

generic combinations (5-FU/LV) to those that include irinotecan or oxaliplatin, and now drugs such as bevacizumab. On approval, the average wholesale price of bevacizumab was set at US

$2,200 per 400 mg vial or roughly US $44,000 per patient over ten months of treatment. This is on top of an estimated US $42,000 for patients receiving the Saltz regimen or US $19,000 for

patients receiving FOLFOX. Although further targeted therapies might not be added to the cocktail, the current steep jump in treatment costs is likely to raise a few eyebrows among would-be

payers, especially given that FOLFOX4 is nearly as effective at improving overall survival rates as bevacizumab plus Saltz, and at a fraction of the cost. FUTURE PERSPECTIVES Recently, a

number of targeted biological agents have entered the market (bevacizumab and cetuximab (Erbitux; ImClone)), and others are predicted to follow soon (for example, panitumumab (ABX-EGF;

Amgen/ Abgenix)). We believe that several factors still need to play out with respect to US healthcare reimbursement policies, including possible off-label use restrictions and clinical

trial results with new combinations, before it will be possible to estimate the true impact of biologics on the future cost of CRC treatment. MARKET INDICATORS Older generation drugs, such

as 5-FU (plus LV) remain the mainstay of modern chemotherapy strategies (Table 1). However, CRC treatment continues to rapidly evolve as new chemotherapy combinations are investigated and

novel products are introduced (Table 2). Despite this, new chemotherapies such as irinotecan and oxaliplatin used in combination with 5-FU/LV have significantly extended overall patient

survival. In 2004, CRC treatment took another step forward with the introduction of targeted agents (Fig. 2). At a time when healthcare costs are spiralling upwards in the United States, the

addition of these agents to existing CRC regimens has significantly increased treatment costs. The problem for payers is balancing the increased costs with the additional benefit to

patients. REFERENCES * de Gramont, A. et al. Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus

continuous infusion for advanced colorectal cancer: A French intergroup study. _J. Clin. Oncol_ 15, 808–815 (1997). Article  CAS  Google Scholar  * Saltz, L. B. et al. Irinotecan Study

Group: irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. _N. Engl. J. Med._ 343, 905–914 (2000). Article  CAS  Google Scholar  * Goldberg, R. M. A randomized

controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. _J. Clin. Oncol._ 22, 23–30

(2004). Article  CAS  Google Scholar  * Hurwitz, H. 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). Abstract 3646 ASCO

2003 Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * biotech analysts at Schwab SoundView Capital Markets, 265 Franklin Street, Boston, 02110, Massachusetts, USA Richard E.

T. Smith, Ronald C. Renaud & Eric Hoffman Authors * Richard E. T. Smith View author publications You can also search for this author inPubMed Google Scholar * Ronald C. Renaud View

author publications You can also search for this author inPubMed Google Scholar * Eric Hoffman View author publications You can also search for this author inPubMed Google Scholar

CORRESPONDING AUTHOR Correspondence to Richard E. T. Smith. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Smith, R., Renaud, R. & Hoffman, E.

Colorectal cancer market. _Nat Rev Drug Discov_ 3, 471–472 (2004). https://doi.org/10.1038/nrd1419 Download citation * Issue Date: 01 June 2004 * DOI: https://doi.org/10.1038/nrd1419 SHARE

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