The following is independent
commentary of the author, Betsy de Parry, who is a lymphoma survivor.
ECONOMIC INTERESTS THREATEN TO CRUSH PROVEN CANCER TREATMENT
By Betsy de Parry
January 5, 2007
In the fall of 1985, Sharon Apel, a young mother of three, was diagnosed with low-grade non-Hodgkin’s lymphoma, a cancer of the immune system which is the second fastest rising form of cancer and the fifth leading cause of cancer death. Sharon had the second most common form, called low-grade lymphoma, and she learned that chemotherapy would generally slow the disease, but invariably, the cancer always returned. Each subsequent relapse would require stronger, more toxic drugs, and the time between her treatments would decrease. According to her doctors, the disease would claim her life in five to ten years.
Over the next ten years, Sharon endured six different types of months-long chemotherapy regimens, and each remission period was shorter than the previous one, just as her doctors had predicted. Out of options by 1996, Sharon’s doctors recommended a clinical trial using a new technique to treat lymphoma. She traveled from her home in Kansas City to Stanford University in Palo Alto, California to receive it. Ten days later, she returned home and – with no further treatment – has been enjoying a full and healthy life ever since.
A miracle cure? Not quite yet, but a growing community of people like Sharon are living proof that the treatment, known as radioimmunotherapy, works – and works well for long periods of time for many patients with low-grade lymphoma. Yet this life-saving treatment may soon disappear from the market, a potential victim of profit taking precedence over people. And that could have implications for patients with many forms of cancer.
Radioimmunotherapy uses man-made antibodies to treat cancer. Antibodies recognize and seek foreign substances that invade the body and then mark the invaders for destruction by calling other components of the immune system into action. If only antibodies could be produced in the lab, scientists reasoned that they could use them to stimulate the human immune system to attack malignant cells.
In 1975, the first man-made antibodies, called monoclonal antibodies, were made in a lab in Cambridge, England. N Scientists soon began to produce different antibodies for different uses, but early trials fell short of expectations, and interest in the monoclonals dwindled to a few small biotech companies and academics.
One of those companies was Idec, now Biogen Idec, which, in collaboration with Genentech, made history in 1997 when the FDA approved the first monoclonal antibody for the treatment of cancer, specifically for low-grade lymphoma. The drug, known as Rituxan, identifies, then attaches to lymphoma cells. Ideally, this action triggers the body’s own immune system into attacking the diseased cells and causing them to self-destruct.
Several years earlier, in the late 1980’s, two University of Michigan scientists, Drs. Mark Kaminski and Richard Wahl, believed that monoclonal antibodies would be more successful if, instead of relying solely on the body’s own immune system, they could also carry radiation directly to the tumor cells. They began working with an antibody called B1, which recognizes and attaches to a specific protein, called CD20, which is located on the surface of B cells, from which virtually all lymphomas are derived. To that antibody, they attached minute quantities of a radioactive isotope known as I-131, which is a molecule that emits radiation. Effectively, this created a guided missile. The antibody seeks the target on the surface of cells, latches on, and calls the body’s own immune system into action. For an extra lethal effect, the I-131 emits a burst of radiation directly to the tumor. This dual-action drug became known as Bexxar.
In 1993 Idec began investigating its version of this treatment. To Rituxan, which was then still in the early stage of development, they added a different radioactive isotope called Yttrium-90. This combination became known as Zevalin.
Combining a monoclonal antibody with a radioactive isotope creates a radiolabeled antibody, and using radiolabeled antibodies for treatment is known as radioimmunotherapy, or RIT. Unlike chemotherapy, which requires months of treatment and often causes unpleasant, even life-threatening, side effects, RIT is given in two doses a week apart, and because it spares healthy cells, side effects are minimal. Better still for patients, years of clinical trials show that RIT produces better results than chemotherapy or Rituxan.
The FDA approved Zevalin and Bexxar for use in the treatment of low-grade lymphoma in 2002 and 2003 respectively. Years of impressive data seemed to guarantee that they would take a prominent place amidst the smorgasbord of treatment options.
They didn’t, as Ken’s Lacko’s experience clearly shows. Diagnosed in 2000, Ken, who lives in Arizona, has since undergone two chemotherapy regimens combined with Rituxan. When evidence of the disease recently began to re-appear, Ken started researching his options, learned about radioimmunotherapy and set out to find a doctor who would discuss it with him.
Instead, one doctor after another, four in all, recommended a bone marrow transplant, a risky procedure requiring months of recovery, something Ken did not want to do unless there was no other choice. RIT was too new, one doctor said. It would hurt his chances of future treatment if it didn’t work, said another. The third told him they didn’t use it at their clinic, without further explanation. The last simply never acknowledged the question. “I finally flew half way across the country to see Mark Kaminski,” said Ken, “who was the only doctor who would even discuss it with me, and after talking with him, that’s the next treatment I plan on doing. I’m enormously relieved.”
Ken’s story is not unique. The drugs have not been widely incorporated into treatment regimens. In fact, experts agree that in 2005 only approximately 5% of the lymphoma population eligible for Bexxar or Zevalin actually received it. They also agree that the percentage slipped to approximately 4% in 2006.
From the start, several obstacles stood in the way of these drugs. One was that oncologists have no financial incentive to use them, the result of a program created in the late 1980’s by Medicare. That agency determines the amount physicians should be reimbursed based on the value of their services, and most private insurers base their reimbursements on Medicare’s fee schedule. The program was initially designed to reduce the cost of cancer care by moving treatments from hospitals to oncologists’ offices, but that move also allowed oncologists to profit from the drugs they administer in their offices, a fact which they are not required to disclose to patients.
Since Bexxar and Zevalin consist partly of a radioactive material, these drugs cannot be administered in oncologists’ offices. Instead, patients must be referred to nuclear medicine physicians or radiation oncologists for administration, and thus oncologists lose the income that is generated by drugs they can administer – namely, chemotherapy and Rituxan.
Lest oncologists come under fire for this practice, it must noted that they work within a system they did not create and that reimbursements for drugs also help to cover a host of services that are not billable, but patients should understand the financial implications of this system before deciding on a treatment plan.
Bexxar and Zevalin faced an even more formidable hurdle in the form of Rituxan. By the time Zevalin was approved in 2002, Rituxan had been on the market for five years and its sales that year soared to over a billion dollars - billion. Likewise, profits soared, and that created an internal conflict for Biogen Idec, which produced and marketed both Rituxan and Zevalin. How was the company going to convince doctors to use the new drug, for which they would not be paid, without jeopardizing Rituxan’s blockbuster success?
Despite the company’s own studies which showed that Zevalin produced nearly twice as many more complete responses than Rituxan, big business collided with great science when the company positioned Zevalin as a salvage therapy to be used only after Rituxan failed. That strategy deprived Bexxar, approved a year after Zevalin, of momentum before it ever got started in the marketplace, and both drugs fell victim to Rituxan’s financial success.
Unlike RIT, Rituxan was widely integrated into treatment options immediately upon approval. Although the drug has unquestionably helped to delay the progression of a disease that has been marked by multiple recurrences, it is also noteworthy that its application quickly expanded beyond FDA-approved use despite little data to support that practice when it started.
Rituxan was soon used as the initial treatment. It was combined with several types of chemotherapy. And more recently, oncologists began to use it as “maintenance therapy,” a strategy that requires patients to return to infusion centers for a few doses of the drug every few months for an indefinite period, usually two or more years, after chemotherapy treatments end. In theory, this approach would prevent the lymphoma from returning, and indeed, the FDA approved Rituxan for this use in September 2006. Yet neither a single clinical trial nor a published article has yet examined what options patients might have if they develop resistance to Rituxan when it is used long term.
And what of the psychological impact of remaining in treatment for two or more years after chemotherapy ends? After Ed Chacon-Lontin of Ann Arbor, Michigan, completed chemotherapy in March 2006, he wanted to understand all his options before signing on to maintenance therapy. He embarked on his own research and sought a second opinion from a physician at a university, where salaried oncologists do not benefit from the sale of drugs.
After careful consideration, Ed explains his decision against maintenance therapy: “The psychological impact of remaining in treatment for two more years, of going into the infusion treatment room with regularity, would make it hard for me to see myself as well. I wanted to focus on putting my life back together. Given the uncertainty of the benefit of maintenance vs. spending my precious energies living life outside the infusion center, it was a no-brainer.”
Studies of both Bexxar and Zevalin have clearly shown that both drugs produce longer remission periods than any other treatment that is currently available, especially when they are used earlier in treatment rather than after several types of chemotherapy and/or Rituxan have failed. Even more promising, one study, published in the New England Journal of Medicine in February 2005, showed that 59% of patients who received Bexxar as their first and only treatment – a treatment that took only one week - were disease-free after 5 years of follow up.
Teresa Singh of Ann Arbor, Michigan participated in that study. Diagnosed in July 1996, she took Bexxar two months later and remains cancer free to this day. . Says Teresa, “My sons were just 2 and 7 at the time I was diagnosed. They never had to watch me suffer through months of chemotherapy, and I got back to work 4 days after treatment.”
In September 2006, The Southwest Oncology Group, one of the largest clinical trials cooperative in the U.S., also reported promising results when Bexxar was combined with chemotherapy, although the total treatment time was approximately six months. Additionally, studies have shown that, if necessary, future treatments, including RIT, are available after taking either Bexxar or Zevalin.
While no treatment has yet proven to be perfect, the long and impressive data on RIT suggests that patients deserve to understand all their options before deciding on a course of therapy. How many would choose to stay in treatment for at least two and a half years with chemotherapy and Rituxan if they knew that a shorter and more effective therapy were available? That question was never put to patients. The two-and-a-half year option has quietly become the standard of care in the treatment of low-grade lymphoma.
It’s not surprising that Rituxan has become a cash cow. In 2005, its sales reached 1.8 billion dollars and were expected to top 2 billion in 2006 in the U.S. alone. On the other hand, Zevalin sales reached approximately 20 million dollars in 2005 and appeared to decline in 2006. Glaxo Smith Kline (GSK), which manufactures and markets Bexxar, won’t divulge the dollar amount of its sales, but experts generally agree that it has never reached the level of Zevalin’s since its approval.
This past September, Biogen Idec quietly decided to put Zevalin on the chopping block, stating that “The Zevalin divestment will permit Biogen Idec to focus additional resources and activities on accelerating oncology products with higher short term potential.” Potential for whom? Stockholders? Patients? Doctors?
So far, no buyer has been announced, and the company discontinued promoting and marketing the drug on December 31. It has stated that Zevalin will continue to be available while it is for sale, but no one has said for how long. With an expensive manufacturing plant designed specifically for Zevalin production, the question must be asked how long a publicly held company can justify holding on to valuable real estate that is not returning its investment.
GSK was the only hope for the future of radioimmunotherapy, but this past December 19, the company announced a partnership with Danish-based Genmab to co-develop and commercialize Genmab’s monoclonal antibody which is in late stage development for low-grade lymphoma. Genmab has the option to co-promote its antibody with GSK, and if that happens, Bexxar will face the same internal corporate conflict that forced Biogen Idec to abandon Zevalin.
Rituxan, as well as the five other FDA-approved monoclonal antibodies, have been enormous financial successes for their manufacturers. In fact, they have been so successful (financially) that in the U.S. alone, there are currently 160 different monoclonal antibodies for use in various types of cancer in clinical trials or awaiting FDA approval.
Conversely, interest in developing radiolabeled antibodies appears to be waning. Bexxar and Zevalin, the only two FDA-approved radioimmunotherapy drugs, did not blaze a successful commercial trail for others to follow, and if these two drugs, giant leaps in the treatment of lymphoma, can’t make it commercially, research for RIT in the treatment for all kinds of cancer is in danger.
Peter Patterson, Vice President of Pharmaceutical Markets at MDS Nordion, the Canadian-based company which manufactures Yttrium-90, I-131 and most of the other radioactive materials used for medical purposes, remarks that scientists studying radioimmunotherapy for potential use in various types of cancer have already been hearing from pharmaceutical companies, “Hey, guys, it’s a neat idea, but we haven’t seen a success story.” Until they do, it is unlikely that companies will take the risk to commercialize future radioimmunotherapy drugs. And for cancer patients, that will delay or even halt promising new treatments.
It is ironic that RIT is threatened just as some medical experts are beginning to whisper the very word that lymphoma patients have longed to hear: cure. Dr. Lee Nadler, who in 1979 discovered the B1 antibody which became the foundation of Bexxar and who is now senior vice president of Experimental Medicine at the Dana-Farber Cancer Institute, says, “I wholeheartedly believe that either Zevalin or Bexxar, if appropriately integrated into our best present regimens, would improve the overall survival of patients and even increase the number of cures.”
For that very reason, Ken and Ed are worried about the fate of the drugs. Though optimistic, Ed is also realistic that future treatment may be necessary, and if it is, he says, “I would hope to have as many options as possible available, including radioimmunotherapy. I would hate to see option doors close due to lack of profits.” Adds Ken, “I’m counting on Bexxar being there when I need it. The thought that it wouldn’t be scares the hell out of me.”
After such a faltering start, can radioimmunotherapy survive? The solution to its salvation is complex, and it will require a diligent and united effort by all who stand to benefit: drug companies, oncologists and patients.
Within the fiercely competitive world of business, drug companies must strike that delicate balance between satisfying stockholders who demand returns on their investments and patients who deserve promising and proven therapies. Specifically, GSK must take great care to prevent its upcoming monoclonal antibody from laying Bexxar to waste.
Medicare and insurers should provide incentives for the referring oncologist to collaborate with the administering physician. Such incentives would give Bexxar and Zevalin a fair chance to compete against drugs that oncologists can administer in their offices.
But it is patients themselves who may hold the quickest solution. If they initiate dialogue about RIT with their oncologists, then oncologists, with their patients’ best interest at heart, may be more willing to incorporate it in the treatment strategy, and that could drive sales to a level that would convince drug manufacturers to safeguard these life-saving drugs.
The war on cancer will never be won if drugs like Bexxar and Zevalin are allowed to fade into medical history. Untold millions of dollars spent to develop them will have been wasted. And patients will have lost a valuable treatment option. The obstacles they face must be overcome. Patients like Ed and Ken are counting on it.
One final note: RIT has been maligned as too expensive for a single treatment. I’ve seen spreadsheets used by reimbursement specialists comparing various treatments and none of them takes into account the cost of chemo-related side effects (which of course vary from patient to patient) or the time lost from work or the emotional burden of undergoing months of treatment. My actual expenses for the twelve months in 2002 were:
$ 36,929.50 for RIT, including the drugs, all the necessary tests, doctors visits, scans, etc.
$162,409.72 for everything else – chemo, hospitalizations, side effects, etc., etc., etc.*
No wonder insurance premiums are out of sight!
*I couldn’t get RIT any earlier because it was under FDA review at the time I needed treatment.
I started on CVP (after two treatments, it was suspended because it didn’t work), then went to R-CHOP (it, too, failed after 5 treatments)
