In 2005, while taking a winter vacation in Florida with her fiancé, Bonnie Barklow noticed a lump in her left breast. Upon her return home in March, the lump was biopsied, and she was diagnosed with localized breast cancer. The tumor was treated with Taxol, a chemotherapy drug. The tumor went into remission, and Barklow continued to take her yearly winter trips to Florida.
This past January, during one such trip, Barklow was treated for what she thought was pneumonia. Her breathing difficulties turned out to be due to breast cancer recurrence, which this time had metastasized to her chest cavity. "You'd think I had something against Florida!" she jokes.
These days Barklow travels from her home in Baileyville, Ill., to Madison for weekly cancer treatments. Her oncologist, Tom McFarland of UW Health, has her on a therapy regime that includes Taxotere (similar to Taxol), as well as a relatively new drug called Avastin.
Avastin was approved this February for the treatment of metastatic breast cancer, in conjunction with other drugs. Barklow believes it's making a difference.
"I tell you, when I'm on the Avastin, I have extra energy," she says from a hospital recliner, while an infusion pack drips drugs into the port embedded in her chest. "I have to tell myself to sit down and take a break."
Her fiancé, John Slechta, who alternately keeps a watchful eye on the chemo infusion packs, the nurse and the stock fluctuations on his laptop, nods in agreement.
Dr. McFarland, who spoke about Barklow's case with her permission, is confident she'll be a responder. She's not had any fluid drained from her chest cavity since her treatments began in March. A CT scan in April showed the continued presence of cancer cells in the left side of her chest cavity, while the right side remained free of cancer cells.
Avastin is part of a newer and more expensive generation of cancer medications called biologics, or targeted therapies. Unlike chemotherapy, which attacks cancer in a scorched-earth fashion, targeted therapies hone in on a specific aspect of the cancer disease process, and interrupts it in any number of ways.
But Avastin's exciting potential comes with a high sticker price. For an average-size person, a regimen that includes Avastin and chemotherapy can cost $11,000 a month just for the Avastin. That compares to about $300 a month for paclitaxel (the generic form of Taxol) and about $1,500 for Taxotere.
Barklow's insurance statements put the charge for the combination regimen at more than $12,000 per month.
The cost might be easier to justify if there were not also concerns about Avastin's long-term effectiveness. A clinical trial involving 700 women found that Avastin extended a tumor's time to progression by about six months for half the patients who received it as part of a combined regimen.
But in most cases the tumor will eventually progress. That is partly why an advisory panel, on a 5-4 vote, recommended against approval. But the Food and Drug Administration decided against this advice.
Such decisions add a big question mark to the already challenging question of how best to manage health care costs. How much money is too much when trying to save someone's life, especially if the benefits are not so clear? It's not an easy question to answer.
Fine line
Created after years of research by the drug company Genentech, Avastin is designed to interrupt a tumor cell's ability to create new blood vessels, a necessary delivery system for food and oxygen to the growing tumor. It was initially approved for treatment of metastatic colon cancer in 2004, and two years later for non-squamous lung cancer. Recently, doctors treating Sen. Edward Kennedy's brain tumor were contemplating adding Avastin to his post-surgical regimen.
What makes Avastin interesting is its vast array of potential new uses, and the costs that come with them. Indeed, Avastin's widest use is not even cancer-related: It is being used off-label to treat age-related macular degeneration, a major cause of blindness in old age. (A drug's use is considered off-label when it is prescribed for a treatment other than what is approved by the FDA. This is not illegal, but patients often pay for such use out-of-pocket, as insurance companies will only pay for FDA-approved uses.)
A closer look at the FDA approval process reveals the fine line interested parties must walk in either advocating for, or arguing against, a given drug.
Julie Gralow, a medical oncologist at the Fred Hutchison Cancer Research Center in Seattle, Wash., had patients enrolled in the Avastin clinical trial for breast cancer, and observed the deliberations during the FDA advisory committee approval process. She was not a member of the advisory board.
"It was good that the drug was approved without survival benefit demonstrated," says Gralow. "How much is an extra six months of no progression worth? To the patient, it's unlimited."
For cancer patients, says Gralow, "Every time disease appears in another site, there is the emotional component of having to plan the next therapy. It's a letdown to hear that a tumor has grown. You have to shift gears."
That said, Gralow cautions, "We can't keep affording all these exciting new biologics for everyone. We should mandate up front that studies find ways to figure out the percentage of people who can really benefit so that the drug is specific to the population."
In the past, the FDA has used overall survival as the criterion for approving a new drug as first-line treatment. In the case of Avastin, it went against this historical approach.
Joanne Mortimer, a medical oncologist at the City of Hope Comprehensive Cancer Center in Duarte, Calif., was a member of the FDA advisory committee. Ultimately, she cast her vote in favor of approval for Avastin.
"I voted to approve it not because Avastin is this great drug, but because as first-line treatment, although it didn't show an overall survival advantage, it did show improvements in tumor shrinkage and doubled the time the disease was kept under control. The FDA has approved other drugs like Ixempra," she says, which is approved for second- and third-line treatment that "only showed a small improvement in progression-free survival."
Overall survival, then, seems to be a tricky benchmark to adhere to.
"Should overall survival be the guiding principle?" asks Timothy Hobday, a medical oncologist at the Mayo Clinic in Minnesota. "It depends on what day you ask me. There shouldn't be an absolute rule. Ideally, I'd like to see overall survival, but there are many examples of oncology drugs that were approved second- and third-line without a survival benefit."
Hobday's academic focus is on both breast and colorectal cancer. He has used Avastin for years and is more comfortable with it as a cancer drug than some breast cancer doctors might be. Regarding cost and survival, he points to the example of Tarceva, which was granted FDA approval in 2005 as first-line treatment in combination with Gemzar for inoperable pancreatic cancer. It showed a median overall survival benefit of almost 13 days compared with Gemzar alone, and cost thousands of dollars per month.
"Is that a more solid patient benefit than Avastin, which doubles time to progression, and doubles the time the patient feels good?" asks Hobday. As a practical matter, he notes that "Most patients don't bankrupt themselves for this drug, but some do." Having more and better information may help such patients make better decisions about what is worth paying for.
The true costs of care
It's not news that the costs of medical care are spiraling upward yearly, across almost all categories.
For example, patients unresponsive to standard AIDS drugs have as a last resort a novel and expensive drug called Fuzeon, which must be combined with a protease inhibitor. The yearly cost for the two drugs combined is over $36,000.
Cancer therapies can be even more expensive. Anna Barker, deputy director of the National Cancer Institute (NCI), has estimated that Americans will this year spend $219 billion just treating cancer.
For James Stewart, a medical oncologist formerly with UW Health, cancer has a "favored-nation status in the medical community" due to the dreaded nature of the disease. "Any cancer drug that shows even minor improvements becomes the new standard, regardless of cost." He is convinced this has not only driven up the cost of treating cancer, but contributed significantly to the rising cost of medical care in general.
Lee Vermeulen, director of the Center for Drug Policy, based at the UW Hospital and Clinics, says his experience leading pharmacy and therapeutics committees bears this out: "We regularly bring anti-hypertensive and other kinds of medications before the committee, and they are more likely to say no to putting these new drugs on formulary. For cancer, they rarely turn down a regimen."
Stewart and Vermeulen believe there needs to be a national discussion about the cost of health care treatment options. They say doctors are often conflicted or willingly ignorant about the true costs of care. All they know is that they are faced with a suffering patient who just wants to feel better.
But that approach may not be sustainable.
"If anything pushes policy in the U.S. to a place where we have a different way of funding health care," says Vermeulen, "it will be cancer care, because of the money we're spending and the return, or lack thereof, that we're getting for that investment."
Vermeulen is not surprised that the question "What's the charge?" cannot easily be answered by either physicians or patients. This charge, he says, includes the wholesale cost plus administration, stock, inventory and other costs. And in the end, most patients are shielded from these costs by their insurance plans.
Claudine Isaacs, director of the Clinical Breast Cancer Program at Georgetown University, agrees that most clinical researchers don't give much thought to costs. "It's not that our heads are buried in the sand," she says. "We're just not trained to think that way. If a patient is sitting in front of me, I think about them first."
McFarland is more blunt: "I don't make treatment decisions based on cost. I base my decisions on what I think is best for the patient."
Paying the price
Avastin is administered intravenously, so the cost is weight-based. That means it varies from patient to patient. Bonnie Barklow, in her early 60s, is petite and thin. Still, keeping her supplied with Avastin, in combination with other drugs and treatments, tops $150,000 a year.
Shannon Brownlee, a senior fellow at the New America Foundation and author of the book Overtreated, mentions the maxim among health care economists: "Anything below $100,000 per year of life saved is worth spending. It's toy money." But Barklow's regimen has tipped her past that point. The question "Is it worth it?" is suddenly a very uncomfortable one.
Brownlee thinks it needn't be. She contends that patients simply need better decision-making tools to guide them through treatment decisions, and those tools need to include frank discussions about cost. She points to the Foundation for Informed Medical Decision-Making as a good place to start.
Decision-making tools, which can range from questionnaires to videos that walk patients through discussions with their doctors, are not designed to drive patients to a heartless decision like, "too expensive, guess it's time to call it quits." They are designed to factor in patient values and priorities, with cost being one important factor.
"Patients should really understand what the tradeoffs are, and cost should be one of those tradeoffs," says Brownlee. "For example, patients on Medicare have a 20% co-pay. Even if they are covered for an infused drug, they are responsible for 20% of the cost." If Barklow was on Medicare, she'd be responsible for about $30,000 out-of-pocket, unless she has supplemental insurance.
There are ways to lower drug costs, like determining the shortest duration of treatment that will effectively treat an illness. For example, Herceptin, also a Genentech drug, is approved to treat a certain kind of breast cancer for a period of one year. Would six months or three months be just as effective?
"Genentech," says Gralow, "is not motivated to support a new study looking at a shorter treatment time because its FDA-approved indication is for one year." But France is nonetheless conducting such a study, comparing the efficacy of Herceptin in breast cancer patients for six months versus one year.
Another strategy is determining the lowest effective dose. Hobday notes the difference in the Avastin dosage for two of its uses: "In colorectal cancer, the standard dose is 5 mg/kg every two weeks. In breast cancer, the standard dose is 10 mg/kg every two weeks. You've doubled the cost." He mentions a lung-cancer trial in which patients received either 7.5 or 15 mg/kg of Avastin every three weeks. "The take-home message was that it was not clear that more was better."
For its part, Genentech runs the Avastin Patient Assistance Program, which according to the company's website "seeks to limit the overall expense of Avastin in FDA-approved indications," regardless of insurance status.
Barklow is currently covered by Blue Cross/Blue Shield, a premium insurance plan. So far, to her knowledge, Blue Cross has not put her drug regimen on Tier 4 status, a recent move by private insurers to charge patients a quarter to a third of the cost for certain drugs, including cancer drugs.
However, Barlow noticed recently that Blue Cross/Blue Shield is starting to question the cost of the Avastin and has not yet negotiated a price with UW Health for payment. The price for the Taxotere has been settled on.
"All I know is, I'm responsible for $1,600 a year out-of-pocket." she says. "After that, I shouldn't have to worry about this. You better believe I'm keeping a close watch on this now."
Barklow admits she did not have significant conversations with McFarland regarding the cost of her therapy in the beginning, nor did she use a decision-making tool to decide if the cost was worth it. Like many patients faced with a life-threatening illness, her attitude is: "I've got cancer, give me everything in your arsenal to take care of it."
A repeat CT scan in July showed that the cancer cells on the left side of her chest had gone into "pockets," meaning they weren't floating about as freely as they had been previously. The presence of a tiny amount of fluid on the right side presented a "sliver" of concern, but McFarland says this is not an indication that her disease is progressing. He recommended two extra cycles of the regimen, and then a reassessment. Barklow agreed.
McFarland offers an upbeat assessment of Barklow's progress: "What tells me she is having a clinical response is that she hasn't had to have fluid drained from her chest cavity since she began treatment. Although there are still cells that are causing problems, her disease is considered stable. It hasn't progressed."
Yet unclear is whether Barklow will remain stable past that initial six-month period and enjoy a one-year window of progression-free disease.
Now nearly at the end of her six-month treatment plan, she remains in good spirits, despite increased pain in her fingernails and toes compared to her last bout with chemotherapy, and some heartburn after her infusions.
"I can't say I've had too many problems with it," she says. "The mind rules a lot of it. You just can't sit around and let aches and pains bother you. I've been on this for so long I think I just got used to it." After a beat, she adds, "But I won't miss it when I'm done with it."
Online decision-making tools
Foundation for Informed Medical Decision Making
http://www.informedmedicaldecisions.org
Dartmouth-Hitchcock Comprehensive Breast Program
http://www.dhmc.org/webpage.cfm?site_id=2&org_id=65&gsec_id=0&sec_id=0&item_id=1376
Ottawa Health Research Institute
A one-page guide that can be used for any decision:
http://decisionaid.ohri.ca/docs/das/OPDG.pdf
A two-page guide for people making health or social decisions:
http://decisionaid.ohri.ca/docs/das/OPDG_2pg.pdf
An A-Z inventory of decision aids: http://decisionaid.ohri.ca/AZinvent.php
