The Unaffordably High Cost of Cancer Drugs

Tne problem of health care that has quietly arisen and not been publicly addressed is the multiplicity of costs associated with the use of new cancer drugs. These new drugs are being approved that add only a few months of life, are mostly marginally effective as add-ons to other drugs, cost many thousands of dollars, and produce a multitude of adverse effects which can lead to further hospitalizations, death, and/or more drug treatments. Few people are raising critical questions: What is the cost to the individual, both financially and in reduced quality of life? What is the cost to the health care system? And if there are limited health care dollars along with millions of citizens without health care, doesn’t this issue merit discussion?

We use as an example the treatment of metastatic colorectal cancer. The main drugs used for its treatment are the older drug fluorouracil, and the newer drugs irinotecan, oxaliplatin, cetuximab, and bevacizumab (see Table).

Fluorouracil (with leucovorin) has been the standard treatment since the early 1960s. Fluorouracil works by blocking the formation of some of the required building blocks of DNA and RNA, which are necessary for cell division and growth. Fluorouracil is toxic but does not stay in the body long so that if there are adverse effects, they are more easily dealt with (half of the fluorouracil is gone in about 15 minutes and most is gone after 1.5 hours).

In 1996, irinotecan (Camptosar) was approved. It binds to and blocks an enzyme that is needed for DNA synthesis, causing double-strand breaks in the DNA that mammalian cells cannot efficiently repair. Irinotecan is converted in the body into a form that is about 1000 times more potent as the parent drug. In contrast to fluorouracil, this drug stays in the body a relatively long time (half is gone in about a day so it takes about a week for all of it to disappear).

In 2002, oxaliplatin (Eloxatin) was approved. Eloxatin forms chemical links with DNA preventing it from replicating and forming RNA. The drug stays in the body a very long time; it takes about 2 weeks for half the drug to be removed from the body and about 2 months for all to disappear.

In 2004, cetuximab (Erbitux) was approved. It is a monoclonal antibody that binds to the epidermal growth factor receptor, a protein that is present in cell membranes. Erbitux prevents not only the epidermal growth factor from binding to cells but inhibits other growth factors as well. Cells stop growing and begin to die. The drug stays in the body a long time; it takes about 5 days for half the drug to be removed from the body and about 1 month for all to disappear.

Also in 2004, bevacizumab (Avastin) was approved. It is a monoclonal antibody that binds to the vascular endothelial growth factor and prevents it from binding with its receptors on endothelial cells (such as the cells lining blood vessels). Avastin causes the reduction in blood vessel growth in a mouse model. This drug stays in the body a very long time; it takes about 20 days for half the drug to be removed from the body and about 4 months for all to disappear making treatment of adverse events more difficult.

An article in the New England Journal of Medicine in 2004 compared the financial costs of 8 weeks of treatment for metastatic colorectal cancer. Monthly fluoruracil was compared with more recently approved drugs.

The two most expensive treatments employed cetuximab, yet the FDA-approved drug label for cetuximab states that, “Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Cetuximab”. In addition, although this drug supposedly works through blocking the epidermal growth factor receptor, the label states that there was no correlation of tumor response with either the number of receptors per cell or the percent of cells that had receptors.

And last but not least, adverse reactions increase when adding additional drugs. When cetuximab was added to irinotecan, there were increases (vs. cetuximab alone) in weakness and malaise (73 percent vs. 48 percent), abdominal pain (45 percent vs. 26 percent), diarrhea (72 percent vs. 25 percent), inflammation of the membranes of the mouth (26 percent vs. 10 percent), and decreases in white blood cells (that fight infection; 25 percent vs. <1 percent). An acneform rash of pustular-appearing lesions occurred in about 90 percent of all patients taking cetuximab, lesions that became infected in some cases.

In 2004, reviewers at the Food and Drug Administration concluded after an analysis of the drug company studies that there were no data that “demonstrate a clinical benefit, such as improvement in disease-related symptoms or survival” by adding oxaliplatin to FU/LV therapy.

Progress in most studies is determined by the change in tumor size as determined by radiographs using X-rays. This can be misleading since tumors are composed of a number of tissue types with the non-tumor types being more susceptible to treatment. When these other tumor types die, it may look like progress, but it leaves the original tumor to regrow.

Furthermore, drugs that target DNA are not magic bullets; they are not tumor-specific and many normal cells are targeted. Certain cells grow and reproduce all the time such as blood-forming cells in the bone marrow, germinal layers of the skin, and the epithelium of the gut. One reason for gastrointestinal problems is that the cells lining the gastrointestinal tract need to be frequently replaced. By preventing these cells from dividing, a variety of new problems emerge such as those seen with bevacizumab: gastrointestinal perforations and complications of wound healing.

The Cochrane Collaboration, an independent group of specialists who analyze the medical literature, concluded in 2005 that studies of anti-cancer drugs had not provided information about these drugs’ effects on quality of life. Since most clinical trials are done by drug companies that have a huge stake in getting drugs approved, this important aspect of treatment has often been left aside.

With drug sales for cancer treatments now the fastest growing drug sector and expected to double over the next five years, there is a clear need for discussion. When Avastin, for which there are no data that “demonstrate an improvement in disease-related symptoms or increased survival”, is talked about on financial pages as being “on track to become a blockbuster this year at its current rate of growth”, it is clear something is very wrong. In the end, several months are added to the end of life, but at what cost?