Two articles published this afternoon in the Lancet and the Canadian Medical Association Journal once again remind us that just because something looks good in cancer treatment doesn’t mean it is good, and may actually cause harm.
You may remember the controversy that surfaced a couple of years ago about medications called ESAs which were (and continue to be) used to boost the red blood cell counts of patients with cancer.
What did today’s studies report that has me so concerned? Basically that there was no situation—whether or not patients were on active chemotherapy or whether they were simply being treated for anemia associated with their cancer—where these drugs did not increase the risk of death.
As the story unfolded at the time, it appeared that these medicines not only improved anemia in cancer patients, but also increased the risk of death. There was a considerable outcry, guidelines from respected medical organizations were quickly changed, Medicare put definitive treatment guidelines in place, and the Food and Drug Administration eventually changed their guidance on how the drugs could be used.
Now, two years later, we have these new reports that take the story one chapter further, and may be the end of these drugs in routine practice, barring special circumstances.
The Lancet study was particularly well done. Internationally recognized experts in study design and analysis identified a number of research trials where these drugs were administered to increase red blood cell counts. The trials included those performed by the companies that manufactured the drugs, as well as others run by investigators not affiliated with the drug companies. Basically, these trials compared patients who were treated with the ESAs to patients who did not receive the drugs but were given blood transfusions when needed.
After identifying the studies, the researchers went back and were able to obtain the actual patient records for almost 14,000 patients. They looked at the risk of death while the patients were being actively treated and at their overall survival.
Bottom line, the patients who were under active treatment with ESAs had a 17% greater chance of death if they received the ESAs compared to the patient who received blood transfusions. Overall survival for all patients was significantly decreased as well. It didn’t make much of a difference, according to the authors, whether or not the patients were on active treatment for their cancer, although the increased rate of death was a bit less if a patient was receiving chemotherapy as opposed to other treatments for their cancer such as radiation therapy.
There was a greater increase in deaths for patients who started with more severe anemia. There was a lower rate of deaths in patients who had prior thromboembolic events, such as deep vein thrombophlebitis or pulmonary embolism. The reason for this was unclear, and it is possible that those patients were on blood thinners that may have prevented new blood clots from forming.
The authors concluded:
“The findings of this individual patient data meta-analysis show that erythropoiesis-stimulating agents increase mortality in all patients with cancer, and a similar increase might exist in patients on chemotherapy. Most randomised trials and previous meta-analyses have shown that erythropoiesis-stimulating agents increase haemoglobin concentrations, reduce the need for transfusions, and reduce fatigue. In clinical practice, the increased risks of death and thromboembolic events should be balanced against the benefits of treatment with erythropoiesis-stimulating agents, taking into account each patient’s clinical circumstances and preferences.”
The Canadian study took a more traditional approach to this question, through carefully studying and combining the published information from several research papers that met pre-determined requirements.
These investigators essentially came to the same conclusions: use of ESAs decreased survival, in large part because of an increased incidence of what we call “thrombotic events,” namely deaths related to blood clots traveling in the body, usually into the lung (pulmonary embolism).
However, this study pointed out that ESAs did decrease the need for blood transfusions and did increase the quality of life for patients who received them.
Their conclusion was essentially the same as the investigators in the Lancet paper:
“Use of erythropoiesis-stimulating agents in patients with cancer-related anemia improved disease-specific measures of quality of life and decreased the use of blood transfusions. However, use of the agents led to an increased risk of all-cause mortality and serious adverse events. We found no evidence that the risks or benefits of treatment differed among patients who did or did not meet recently revised criteria for the use of these agents in patients with cancer. Our findings suggest that existing practice guidelines should be revised to recommend against the routine use of erythropoiesis-stimulating agents as an alternative to blood transfusion in patients with anemia related to cancer.”
So what are we to conclude from all of this discussion?
First and foremost, these studies basically sound a warning that the use of these medicines in any patient with cancer—whether or not they are on active treatment—should be preceded by a detailed discussion of the benefits and the risks, understanding that the risk of death from the treatment is not some abstract theory.
If you decide to use ESAs, you will be balancing the risk of an “adverse event” against the possibility that it may in fact improve your quality of life. That improvement comes at a cost: possibly shortening your life.
It is clearly no fun to have to get a blood transfusion. But it is less fun to have an embolism and all of the associated consequences, which include the possible loss of a life.
There is also a larger story here, and that is the question of how we got here in the first place.
These medicines have been around a long time. They were one of the first “biologic therapies” that entered active clinical practice back in the late 1980’s and early 1990’s. They came on the scene when we were very concerned about the safety of the blood supply. At the time, they were hailed as a scientific miracle.
Their use grew and grew and grew. More and more patients received them, including for off-label indications without evidence to support some of that use. Doctors were willing to give them, and some doctors pushed the envelope aiming for higher and higher red blood counts because they said that patients felt better. The costs of these drugs to various reimbursement programs such as Medicare went up and up and up.
All this while some doctors were encouraged to use these medicines through incentive programs that included rebates, which in one well documented situation amounted to millions of dollars.
And then, clues started to appear that maybe these drugs weren’t as safe as everyone thought they were.
This is the type of experience that should give all of us pause. We should know as much as possible about the drugs we use to treat patients, including cancer patients where we are willing to accept more risks than in otherwise healthy patients, given the serious nature of the disease.
We can’t always get to “truth” on these issues, but we need to do a better job of asking the right questions at the right time. Who knows how many people have had their lives shortened because we failed to ask those questions? Who knows how much harm has been caused?
We should take the lessons of ESAs, embody those lessons, and try to move closer to the truth of what we do, understanding both the benefits and the harms of the treatments we offer.
Just because someone has cancer, and may be near the end of their days, doesn’t mean that we should ignore the evidence and not help people make informed decisions at what is arguably the most difficult time of their lives.