Severe Early-Onset Toxicities From 5-FU or Capecitabine
Insights From: Samuel J. Klempner, MD, The Angeles Clinic and Research Institute; Cedar Sinai Medical Center; Alice Beers, RN, BSN, OCN, MedStar Health System
Alice Beers, RN, BSN, OCN: There certainly can be some risk factors that we would see in patients for grade 3/4 toxicities, but not what you would think. You certainly could have a patient who has some renal dysfunction. They may develop more toxicities when they’re given capecitabine. That’s why we need to evaluate those patients ahead of treatment to see what their organ function is. But I think the thing that’s really frightening about some of the toxicities that we’re seeing—early-onset toxicities with these drugs, as well as what we see in an overdose case—is that you’re not really guaranteed what’s going to happen with that patient. So, a patient who you could think will have no trouble at all can become very, very ill very, very quickly. For a patient where you say, “Oh, you’re going to be completely fine; these are really well-tolerated drugs,” and they end up in the hospital unable to eat and drink because they’ve got severe mucositis, those are situations where I think we as providers have to realize that this is not a benign set of drugs that no one’s going to have a reaction to. This is something that does happen to people, and we have to really stop, listen, evaluate, and treat people with antidotes when it’s appropriate.
A trigger for urgent intervention for a patient who’s receiving 5-FU or capecitabine—whether it’s in a situation where they have had an overdose, where it’s a situation where they’ve had an early-onset toxicity—is having a low threshold for treatment. We don’t want to have a patient wait. We don’t want to take a “wait and see” approach, because you certainly could be missing the opportunity. In terms of being able to administer an antidote such as Vistogard, you have a window of opportunity. The drug needs to be given within 96 hours of when the patient has completed their treatment, when you’ve identified their overdose, or when you’ve discontinued their treatment because of toxicity. There is efficacy that will drop off dramatically if you’re missing that window, and it’s also a matter of now waiting to see whether or not the patient has some sort of metabolic issue. We have in the past said, “Oh, we’re going to wait and get DPD testing.” Well, the problem with DPD testing is that it misses a very significant number of people who actually have some sort of metabolic processing issue. We can send testing out, and you don’t know—are you going to miss your 96-hour window because you’re waiting on the testing, and then you’ve missed your opportunity to treat the patient? There is a large number of people who are not going to have a result that shows up, as they’re DPD deficient, and yet you are seeing every single sign and symptom that they’ve got severe side effects, severe toxicity.
Samuel J. Klempner, MD: The recognition of serious or life-threatening toxicities from 5-FU or capecitabine can be broken down into the common toxicities, but more severe and often earlier onset. So, for example, starting from the top down, stomatitis or mucositis is not uncommon. But within grading criteria, grade 3/4 is someone who has involvement of the majority of the mucosal surfaces of the mouth, people who have pain and difficulty swallowing, people who have oral bleeding from significant mucosal involvement. That is refractory to standard supportive measurements like oral rinses and oral antifungal agents.
These are all consistent with significantly above or outside of the normal toxicities that would be expected. The same level of mucositis can actually be extended through the whole GI tract from mouth to anus. And so, patients who present with refractory diarrhea—more than 5 to 8 bowel movements per day that are watery and often associated with some bleeding—patients who are unable to maintain adequate hydration by mouth and require intravenous hydration or hospital admission, those are early or severe warning signs.
Early cytopenias are relatively uncommon with capecitabine. The rates of the neutropenia and febrile neutropenia are relatively low. So, patients who are on capecitabine develop an early drop in their blood counts—so, like a white blood cell count going from 4 to 0.1 in a matter of a short period of time. And that patient developing fever would be considered severe and potentially life-threatening. Similarly, with intravenous 5-FU, patients who discontinue the drug after their infusion completes and call 2 days later with fever and easy bruising, bleeding, or mucosal irritation, that would be a severe warning sign. The refractory nausea/vomiting is another GI toxicity that can be considered severe or life-threatening.
When we think about refractory nausea or vomiting, grade 3/4 events, these are people who are unable to take in any food, people who require IV antiemetics; they’re not responsive to oral antinausea drugs. They require intravenous nutritional support or fluid. And then probably the most concerning are the neurotoxicities and the cardiac toxicities. Neurotoxicity is not an expected side effect from either capecitabine or infusional 5-FU. So, if a patient or family member reports confusion, altered thinking, or neurologic deficits and seizures, any of those events would be considered severe and warrant immediate intervention.
Similarly, cardiac toxicity is not an expected event. Although it’s well described, it’s not an expected event from normal dosing of 5-FU or capecitabine. So, people who present with cardiac-sounding chest pains or central chest pain radiating into the left arm, people who present with symptomatic palpitations and are diagnosed with arrhythmia on electric cardiogram, those are all things that are not expected and warrant immediate intervention.
Alice Beers, RN, BSN, OCN: In terms of more severe toxicities, grade 3/4, I can talk with you about a case we had several months ago. It was really before we had awareness of the need to administer an antidote such as Vistogard. A patient came in, got a treatment. The family called in the following day. The daughter reported that her mother was confused, brought her into the emergency room, and the patient was indeed confused. She also had cardiac toxicity, so when she had a cardiac evaluation done, she had dropped her ejection fraction 25%. That is certainly not something that we would normally expect to see with 5-FU, but it’s an established toxicity. The patient also had renal failure. Whether that was as a result of her 5-FU or from her oxaliplatin or a combination of both, it was there. The patient ended up being admitted to the hospital. She developed some cytopenias and had to be transfused. So, we had a patient who started treatment 1 day and came into the emergency room the following day, within an extremely short period of time. Again, not a situation of overdose. This was early-onset toxicity. She had cardiac toxicity, had neurotoxicity, and ended up with renal dysfunction.
We see a range of toxicities with capecitabine and 5-FU, both early-onset and as a result of overdose. I think if you think about the common side effects of 5-FU and capecitabine, one of the things we always talk to people about is diarrhea, and certainly nausea and vomiting could be experienced, although not as common. So, if you have a patient who is calling the office and saying, “I’m having so much diarrhea that I can’t control my bowels; I’m not really able to eat and drink because I’m having severe nausea,” then we would say, “Hey, why don’t you come in; we’ll see how you’re doing.” We will draw some lab work on them, and they could have some abnormalities because they’ve become dehydrated.
But then your index of suspicion stops because their blood counts started to drop. And, although people can certainly have cytopenias as a result of any chemotherapy, we certainly don’t see them to a very significant extent in many patients who are getting capecitabine or 5-fluorouracil, and we certainly don’t expect to see them within a couple of days of when people have either completed or had therapy interrupted. So, that raises your index of suspicion that this is a patient who clearly could be experiencing early-onset toxicity. They could end up being admitted to the hospital because their blood counts have dropped such that they’re going to end up being septic, requiring transfusion support, requiring antibiotics, but, hopefully, not requiring admission to the ICU.
Samuel J. Klempner, MD: The cardiac toxicities of 5-FU and oral 5-FU are uncommon and sometimes not immediately recognized by physicians, and this is really because of the rarity. So, it’s not something that the average oncologist is going to see maybe more than once or twice during their career. And this really comes back to education of all of the office staff, as well as some of the patient educational materials that are given for patients being prescribed 5-FU. Like many clinical practices, we have informational sheets about 5-FU and capecitabine when patients are given these drugs. And on those sheets, cardiac toxicity is a listed potential complication. And so, certainly physicians, as well as patients, need to refresh themselves about these things periodically.
Reading the information that you’re giving the patient helps remind clinicians and office staff across the board that cardiac toxicity is a well-described chemotherapy-associated event, particularly with 5-FU and somewhat less so with oral 5-FU or capecitabine. But it can still go underrecognized by clinicians, and so any cardiac-sounding symptom—whether it’s chest pain, shortness of breath, or palpitations—needs to be worked up, and clinicians need to think about whether or not this may be attributable to the chemotherapy agent that they’re prescribing. And certainly, office staff, nursing, and pharmacy represent another level of checks and balances to remind us that this may be a chemotherapy-related side effect.
Alice Beers, RN, BSN, OCN: I think the physician’s and nurse’s ability to connect cardiac toxicity to the use of capecitabine and 5-FU is an area where we still need a lot of education and eye opening, if you will. I’ve worked in oncology for a very long time. I’ve worked as an infusion nurse. Over the course of my practice, I have seen the occasion where you give someone some 5-FU and all of a sudden, they’re experiencing chest pain. And everybody panics; you obviously treat the patient appropriately. You’re not just going to pass it off. You get out the resources and you say, “Oh yes, there’s an incidence of coronary artery spasm. We think that’s what that is.” We tell the patient and family, “You’ll be fine. We’re going to get you checked out, but this is something that happens very rarely.” There’s a larger spectrum of things that happen. Patients can have a myocardial infarction. They can have a decrease in their ventricular ejection fraction. They can have arrhythmias. There are, unfortunately, cases of cardiac arrest and death. And so, we don’t see these commonly.
I think it is something that people have to realize is a possible side effect, and we just can’t say, “Oh, there’s such a low incidence of that, I’m not really going to worry about it or keep it in my thinking.” These things do happen. We had a patient who ended up in the hospital a day after she had started a 5-FU infusion—an otherwise healthy woman—and her ejection fraction was evaluated and found to be 25%. She ended up recovering, and she was able to move on with her life, was not able to continue with treatment. But it was a very serious side effect and took a couple of months before her heart returned to normal function.
In terms of central nervous system toxicities with capecitabine and 5-FU, I think the thing that, really, people have to be aware of is that people should not be at the point where they are so fatigued that they can’t get out of bed. They should not be at the point where they’re having confusion. We shouldn’t be getting a phone call from a family member that Mom or Dad is having confusion, and they’re very worried about them. I think it’s also a matter of patient education. Some people read the bottles of the anti-nausea medicine that they’re given to take home and the label may say, “May cause drowsiness.” We have to educate people that a neurotoxicity is not that you’re a little bit sleepy and you may take a nap because you’ve taken an anti-nausea pill, but it is someone who is difficult to wake up—people who say, “Hey, I went to bed at 4 o’clock yesterday afternoon because I wasn’t feeling well, and at 10 o’clock the following morning, I could barely wake myself up.” Those are really serious concerns for neurotoxicity.
We commonly see skin toxicities with both 5-FU and capecitabine. I think one of the things that we differentiate, certainly in patients with capecitabine, is the degree of hand-foot syndrome. We tell patients that they may have some redness, some cracking, and some drying of the skin on the hands and the feet. Those will certainly progress the longer patients have been on therapy. But we worry about the patient with early skin toxicity. So, if a patient calls you and says, “I’m not really sure what’s going on, but I have a red rash—my skin looks like I’m sunburnt all over all,” those are things that are not normal in patients who are, especially, starting out with these treatments. And that would be an index of suspicion that they’re starting to experience a dermal toxicity. For patients who are not metabolizing these drugs or have had an overdose, they can rapidly progress from a situation where they’ve got a little bit of a red rash to a very quick scenario where they’re experiencing significant cracking, peeling, and sloughing of their skin and may require hospitalization—because skin is your defense against infection, and their skin is starting to break down. You’ve got to bring them in and hospitalize them to protect them from serious side effects.