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The Price Tag on Progress — Chemotherapy for Colorectal Cancer
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     From the 1960s until the mid-1990s, fluorouracil was the primary chemotherapeutic agent available for the treatment of colorectal cancer. During the past decade, the Food and Drug Administration (FDA) has approved five new drugs for metastatic colorectal cancer. Irinotecan (approved in 1996) and oxaliplatin (2002) are cytotoxic agents that interfere with DNA replication, and capecitabine (1998) is an oral formulation of fluorouracil. This spring, the monoclonal antibodies bevacizumab and cetuximab, targeting vascular endothelial growth factor and epithelial growth factor receptor, respectively, were approved by the FDA for use in conjunction with cytotoxic regimens.

    Better systemic therapy has considerably improved prognosis. Without chemotherapy, the median duration of survival among patients with metastatic colorectal cancer was eight months. With fluorouracil, it increased to 12 months. After 2002, the availability of three cytotoxic agents (fluorouracil, irinotecan, and oxaliplatin) further extended the median survival to 21 months. Although clinical-trial data are not yet mature, bevacizumab and cetuximab are likely to prolong median survival beyond 21 months. But despite the panoply of options, treatment remains palliative, and there is not yet evidence that the new therapies increase cure rates.

    In the wake of the optimism generated by recent trial results, patients experience sticker shock when they encounter the prices of chemotherapy drugs. Physicians find themselves in the undesirable position of having to help patients make decisions about whether the potential clinical benefits warrant the financial strain that even the copayments for these medications may create. Consider the drug costs for a patient with colorectal cancer who is 170 cm tall, weighs 70 kg, and receives chemotherapy for eight weeks — the duration typically required to determine response. The Mayo Clinic regimen (fluorouracil and leucovorin) costs $63. The FOLFOX regimen (fluorouracil, leucovorin, and oxaliplatin) costs $11,889, and FOLFOX combined with bevacizumab costs $21,033 (see Table). The near-doubling of the median survival achieved over the past decade has been accompanied by a staggering 340-fold increase in drug costs — just for the initial eight weeks of treatment.

    Table. Estimated Drug Costs for Eight Weeks of Treatment for Metastatic Colorectal Cancer.

    The combination of irinotecan and cetuximab for second- and third-line treatment of metastatic colorectal cancer, as described by Cunningham et al. in this issue of the Journal (pages 337–345), increases the median survival by 1.7 months. In the United States, the regimen costs approximately $30,790 for an eight-week course. Assuming that an average patient continues to receive treatment until the median time to progression, 8 months of front-line therapy followed by 4.1 months of irinotecan–cetuximab therapy would cost $161,000. In 2004, 32,000 people in the United States will receive a diagnosis of stage IV colorectal cancer, and recurrent metastatic disease will develop in an additional 24,000. The drug costs for an eight-week course of initial treatment for these 56,000 patients will be approximately $666 million — or $1.2 billion with the addition of monoclonal-antibody therapy. Unfortunately, such costly treatment will not provide a cure; one can only speculate about the relative effect of directing these resources toward screening and prevention. These cost estimates are exclusively for drugs; they do not include the costs of preparation, administration and supervision, or supportive medications. They presume that every single milligram of drug is effectively utilized. Yet cetuximab, for example, is manufactured only in a 100-mg vial, and because the medication cannot be stored for long periods, leftovers go to waste, particularly in small practice environments.

    How should we determine whether these interventions are worth their immense cost? As individual physicians, our primary responsibility is to serve as advocates for our patients, and we neither want nor are equipped to address difficult questions of social policy. Cost-effectiveness analyses conducted from the societal perspective estimate the incremental costs per additional year of survival and place new interventions in that context. But they have not been routinely performed alongside clinical trials of cancer therapies, and ultimately, they cannot answer the underlying moral and policy questions raised by expensive treatments such as cetuximab and bevacizumab. The Centers for Medicare and Medicaid Services (CMS) has made decisions about coverage on the basis of the "reasonable and necessary" clause in the original statute that established Medicare in 1965. There has been no political will to deny coverage for effective interventions on the basis of cost. The public has engaged very little in the deliberations used to reach influential decisions about Medicare coverage.

    The Medicare Modernization Act, passed by Congress at the end of 2003, mandates changes in the way oncologists are reimbursed for delivering chemotherapy. But this recent focus deflects attention from the more important underlying issue, which is that drug prices are astronomical. Why? Although the CMS is by far the largest health care purchaser in the United States, it is prohibited by Congress from negotiating with the pharmaceutical industry over prices. This legislation, together with the strong patent-protection system and prohibitions on the importation of drugs from other countries, secures high prices and high profits for pharmaceutical manufacturers. Reexamining these restrictions and encouraging the pharmaceutical industry to reassess its prices would be a valuable place to start.

    At this pace, escalating drug costs will pose an insurmountable obstacle for the realization of advances in biomedical research. The system for financing drug development, pricing drugs, and setting reimbursement policies must be restructured. The pharmaceutical industry maintains that high drug prices are necessary to support the research initiatives that keep new products in the pipeline. It points to the vast sums often spent on the development of drugs that go nowhere. Economic analyses of the costs of drug development are lacking, but it is clear that costs are borne by both the public and the private sectors. Early scientific work that led to the discovery of bevacizumab and cetuximab was financed with federal dollars. The pharmaceutical industry translated these fundamental insights into the development of commercial products. The rising stock prices of the publicly traded companies that manufacture these drugs reveal that, development costs notwithstanding, the risk-adjusted return on pharmaceutical products is very high indeed. The drug costs that support these stock prices threaten to overwhelm our ability to pay for health care. Both the public sector and the pharmaceutical industry must therefore develop a better process for pricing.

    As the largest funding source for biomedical research and the largest health care payer, the federal government will need to assume a leadership role in such deliberations. We Americans will need to confront questions that we have long been able to avoid. Just how much are we as a society willing to spend on the treatment of advanced cancer? What standards should we apply in determining the medical necessity of a particular intervention? To what extent are we willing to permit a patient's ability to pay to dictate the treatment that is used? The failure to tackle these issues may one day threaten the integrity of the Medicare system. More immediately, it will exacerbate economic disparities in cancer care, which are already an enormous problem.

    As physicians, we will find that discussions about financing cancer treatment will intrude on our examination rooms more frequently. The high costs of new drugs such as bevacizumab and cetuximab mean that non-Medicare health plans are likely to deny coverage or, alternatively, to raise premiums. For some patients who lack or have been denied coverage, drug costs will be insurmountable; others will obtain loans and remortgage their homes to finance their treatment. Even for privileged, middle-class patients who have insurance coverage, copayments will cause economic hardship. Modest gains in survival will be offset by anxiety about financing treatment.

    As a society, we are reluctant to systematically deny access to expensive treatments that extend life by only a few weeks, but the morality of refusing to make deliberated choices is itself questionable.

    Source Information

    From the Memorial Sloan-Kettering Cancer Center, New York.

    Related Letters:

    Cetuximab in Colon Cancer

    Holmer A. F., Martin M. J., Costa A. F., Sander G. B., Picon P. D., Schrag D., Chau I., Cunningham D.(Deborah Schrag, M.D., M.P)