PracticeUpdate: You were involved in an important, recently published trial that compared darbepoetin alfa to placebo among patients with advanced NSCLC receiving myelosuppressive chemotherapy. Have there been past studies of EPO agonists in this setting?
Dr. Henry: Those of us who've been around a while and have a history of using ESA as they came to be in the ‘80s, know this long history that was exciting, and then worrisome and disappointing, depending. What I mean to say is that when they were invented from cloning of darbepoetin alfa or epoetin alfa for various types of anemia, we were really excited because dialysis patients stopped having as many transfusions, if any. Then in the ‘90s, [in] chemotherapy patients for anemia it was working. As we got toward the end of the ‘90s, we were giving higher doses to try and make people the normal above 12, above 13, above 14, and we started to see a safety signal. This caused a stop on these kinds of studies, because what's going on? Why are patients not doing as well? Maybe the survival signal is worse in patients getting hard doses of ESA.
This caused an ODAC, an oncology drug advisory committee, FDA to be convened in 2007, where all this data was put forward. Aadly, at this meeting, it was concluded based on not really complete datasets, which evolved afterwards, that ESA: this is a black box warning. ESAs were shortening survival of cancer patients and made the tumor grow faster. Both dispelled; those conclusions we think are incorrect.
Based on two studies, one you just asked about, I was involved with a darbepoetin one. These are both FDA-mandated, taking metastatic non-small cell lung cancer patients who were anemic and randomizing them to placebo or darbepoetin alfa. The other mandated trial was in breast cancer metastatic, and this was epoetin alfa, either in chemo-induced anemia, metastatic breast, epoetin alfa, or placebo. These were large trials, both reporting out now and showed the same thing.
To stay with the one you asked me about, the non-small cell lung metastatic, the survivals were not shorter in those patients getting darbepoetin alfa, nor did tumors progress faster. Based on the evolving data up to that ODAC, and since, we thought that's what these two trials, they were double-blind, would conclude, and they did. I think in 2020, we could conclude that the ESAs are safe when used permanently.
In our country, 10 and less is the FDA rule. It's probably not necessary, but nevertheless, it's the FDA rule, under 10 to start and a hard stop when you get to 10. I think they're safe to use and do not make tumors progress faster, nor survival, shorter. There is one caveat. There is data to show that if you continue giving an ESA when it's not working, the hemoglobin is going down, transfusions start to be necessary. That's the patient where the ship is sinking, so to speak, and to continue the ESA may make it sink faster. I do bail out and recommend that others bail out giving an ESA: if it's not working, hemoglobin falling, transfusion required, 6 to 8 weeks of this, stop. You could then cause harm.
PracticeUpdate: Is there an algorithm that you could provide a user for how to treat chemotherapy-induced anemia among patients with advanced malignancies?
Dr. Henry: Yes, such an algorithm would rule out other causes. We have to put quickly on our hematology hat and check the retic count. It's under productive anemia. We have to be sure the iron is replete fetal folate. These are not often the case, but could be iron deficiency, especially needs to be ruled out. Is the creatinine okay? Is there renal insufficiency? Is it a sick bone marrow? Other causes. Once briefly other causes are ruled out by those analyses, then it's the chemotherapy. An ESA would be appropriate. Again, I recommend about 6 to 8 weeks of this using darbepoetin alfa or epoetin alfa. If no response or, in particular, declining hemoglobins and transfusion necessary, then stop.
If I could mention one more thing, I mentioned the patients need to be iron replete. Interestingly, when you give an ESA, makes sense, you're asking the bone marrow to make more blood and it might need more fuel. This was studied through the early 2000s and some 10, 12 studies all giving either an ESA alone or an ESA with intravenous iron and several of the different products, IV irons, all showed the same thing. Responses are better if you give ESA with intravenous iron, as opposed to just ESA alone. Good thing to remember.