Timely CIN Clinical Management
Dr. Lyman: My own practice has historically been primarily breast cancer. Although I have, over the years, focused on other cancer types, lung cancer, leukemias and so forth. But my more recent experience, and certainly with the current regimens, has been around breast cancer. Of course, most patients with breast cancer do not present with metastatic disease. They come in with the hope of a curative treatment, which is a combined modality treatment. Either surgery followed by adjuvant chemotherapy, and often radiation therapy if they have had a breast sparing surgery, a lumpectomy. In more and more we’re doing what we call neoadjuvant chemotherapy in these patients. That is treating them with the chemotherapy to reduce the size of the tumor. That will make, often, surgery more amenable or a lesser procedure.
At the same time maintain the opportunity for cure. But clearly, the combination of chemotherapy, surgery, and then sometimes radiation therapy is the hallmark of breast cancer therapy. To achieve optimal results there, the goal again is to eradicate as much of the tumor—as much as possible with perhaps the anticipation if there are any cells remaining after all this aggressive treatment, the host—the patient’s immune system may kick in and eradicate the remaining tumor cells. But again, these patients are at increased risk of neutropenia, severe neutropenia in some cases, and infection, either febrile neutropenia or pneumonia or some type of serious infection. Again, in the COVID-19 era, we’ve of course adjusted our approach to patients. We generally and historically, and there are clinical guidelines from the American Society of Clinical Oncology, the National Comprehensive Cancer Network, the European Society of Medical Oncology, historically, over the last couple of decades have recommended in patients receiving chemotherapy at quite a high risk of febrile neutropenia, usually defined around 20% or greater, those patients should routinely receive growth factor prophylaxis to reduce the risk of febrile neutropenia.
Again, if that risk if less than 10%, probably don’t need such aggressive supportive care, because there are side effects, of course, from any agent, including supportive care agents. Between 10 and 20% risk of febrile neutropenia, it was left pretty much to the clinician’s judgement of what that individual patient’s risk was based on, again, their organ function, their age, a whole variety of factors that may add to the risk of the chemotherapy itself. But as COVID-19 has come on, of course we’ve had a number of challenges. One is running the risk, and unfortunately, this is resurging as we speak across the country, running the risk of overwhelming the healthcare system, which is already challenged just taking care of the COVID-19 patients that come in.
So the issues that have come up are, you know, do you delay chemotherapy in a newly diagnosed patient? Do you somehow alter their treatment, modify their treatment, and so forth? While some of that was done early on, more and more institutions are trying to still deliver the potentially curative chemotherapy on schedule despite the pandemic and the risk. Now that risk, of course, is a two-way sword. It’s a risk to the patient to come in and might be exposed to COVID-19, which on top of this is a serious life-threatening infection, particularly in immunosuppressed patients like cancer patients. But it also exposed healthcare staff, nurses, doctors, and so forth, if the patient has contracted the virus. So the idea of reducing the exposure of the patient and the staff by preventing complications, such as neutropenia, has become even more pressing and urgent.
So in the summer, early summer actually, the various guideline groups began to modify their guideline recommendations to cope with this serious COVID pandemic. We published an interim NCCN growth factor guidelines or supportive care guidelines for patients receiving cancer chemotherapy saying, no longer is this intermediate risk group where the febrile neutropenia risk might be at the discretion of the clinician is a judgement call, we recommended that those patients be routinely prophylax. So we extended it or broadened the indication for aggressive supportive care in these patients.
Again, with a dual intent. One is to reduce the risk as far as possible in these patients of getting a bacterial infection or another infection on top, potentially, of COVID-19, but also reducing their exposure to the healthcare system and their need to come in and be treated for—receive their supportive care treatment in the hospital. So more and more of these patients are being treated in the ambulatory setting. Of course we’re using telemedicine a lot to reduce those exposures. But the main thrust of the guideline modifications are broadening and doing everything we can, even more than we have traditionally done, to reduce the risk of febrile neutropenia.
Now we’ve been studying the COVID-19 pandemic in the cancer population now since March through the CCC19 consortium and now have over 5,000 patients with cancer and confirmed COVID-19 in that consortium. We have reported that originally in The Lancet. – – published the early results in the fits 1,000 cancer patients with COVID-19 and then subsequently at the American Society of Cancer Research—American Society of Cancer Research, most recently the European Society of Medical Oncology, updating as the numbers increased, we were able to look in more detail. One of the risk factors for mortality in these patients with cancer, going through chemotherapy, and at risk for both neutropenic complications and also COVID-19. What we’ve seen, although the data continues to be evolved, is that low blood counts in general are a risk factor for early mortality in the COVID positive cancer patient being treated. This includes not only low neutrophils, which increase the risk by about 60% for mortality, but also low lymphocyte counts, lymphocytes that fight viral infections more aggressively.
So we also see in actually high neutrophil counts, probably indicating an infection has already occurred, pose a risk to the patient. Then many of the risk factors we’ve talked about before, such as increased creatinine, meaning poor kidney function, and so forth. The one challenge here in the COVID-19 era with the conventional myeloid growth factors, GCSF and so forth, is that there are studies that have shown that they may increase the levels of cytokines in the body. It’s part of the response to a hematopoietic growth factor treatment. In some patients with COVID-19 who are getting sicker and sicker and end up with acute respiratory distress syndrome, we know those patients also have increased cytokine levels. In fact, in the extreme version, we’ve defined that as the cytokine release syndrome.
So while we have not—we do not have really detailed study of the interaction of GCSF and growth factors with patients with acute respiratory distress syndrome, the guidelines have added the warning that if your patient is deteriorating, developing acute respiratory distress syndrome, you may well want to avoid GCSF and the hematopoietic growth factors because the unknown is whether they would worsen the cytokine release syndrome and increase the chance of COVID related mortality. So again, we’re learning as we go with this. It’s being rapidly evaluated as the data comes in. But one thing we have learned is how to better manage patients, both with cancer and even those without cancer, who develop COVID-19. How better to get them through the complications, particular if they’re hospitalized, ended up in the intensive care unit on a ventilator. High-dose corticosteroids have shown to help some in that setting. Other agents are a little more controversial. We soon will have vaccines, hopefully, that will improve this situation. But for the time being, we’re left trying to support these patients in the most rational and safe fashion we can. So it does require, literally, daily if not hourly supervision, evaluation of these patients to know the best next steps to taking care of them.
Early in the pandemic, of course, we were kind of flying by the seat of our pants. Often the question, again, came up, should we hold treatment. We thought initially, well, this might last a month or two, a few weeks delay in treatment might be the better part of valor rather than expose the patient to a serious complication on top of the COVID-19. But as time has gone by, and of course now we’re probably going to be into 2021 before we have really a good COVID preventative strategy, so in the meantime, as I had mentioned earlier, we’ve learned how to manage many of the patients. There’s still a very high mortality rate with certain populations getting COVID-19. So it’s nothing to be taken lightly.
We need to be all doing whatever we can to prevent it, particularly in the cancer patient. But in the oncology and hematology space, most have come to the resignation or recognition that we need to move on. These patients need treatment. Their treatment cannot be delayed further. Or if we’ve invoked modifications, again, oral treatments instead of intravenous or parenteral treatments, we need to make sure that whatever treatments these patients are getting, particularly in the curative setting, are still giving them the best chance of curability, best chance or eradicating the tumor. We no longer have the false luxury of delaying things thinking that it won’t matter anymore. It clearly does matter when your treatments are delayed by many weeks or certainly months. So again, we are proceeding, but then using as optimal support of care as possible as we move forward with that. So I would say that the types of treatments being given today are not that much different, in most cases, than what we have used and have been proven effective and potentially curative in the past. The use of oral treatments, you know, have found a role in management of some cancers. It’s somewhat of a false narrative to think that they don’t have their own side effects, including myelosuppression. In fact, I find some patients don’t tolerate the oral treatments as well as they do the intravenous treatments. Of course, you have to depend on compliance and adherence to those. They have other side effects.
So I think the bottom line is, we’ve pretty much come to realization we need to proceed with conventional chemotherapy, again, in the curative setting as we have done in the past. Just be more aggressive with our supportive care to protect the patient as much as possible. Then where possible, telemedicine, so the patient doesn’t have to make trips in just to have a quick examination or a blood count done. That can be done in other settings. The idea, again, is to reduce as much exposure to the healthcare system as possible. But at the same time, making sure we’re not missing anything, educating patients that, again, fever during their course of chemotherapy could be a sign of a serious problem. Of course, there’s always COVID, but the more common cause of fever in a patient going through cancer treatment will be neutropenia and bacterial infection. So these patients do need to be monitored, whether it’s remotely or in person and we’ll get through it. But it certainly has posed challenges for all of us, including some of my colleagues getting COVID-19 and having some significant complications from that. So we’re all trying to get through this, but in the meantime, patients need to be treated optimally, both in terms of their cancer treatment but their supportive care, as well.
So the risk of neutropenia complications and febrile neutropenia in patients receiving conventional chemotherapy usually, again, every two, three weeks, sometimes four weeks, is generally, again, within four or five days, sometimes a little bit longer. The neutrophil count goes down significantly. It reaches a low point between the seven and ten, sometimes a little bit earlier than that, and then gradually recovers.
During the period those neutrophils are in the severe range, less than 500, and of course, the lower they go, the more severe and the higher risk those patients are for infection. Every day a patient is in that range, they are at risk for sepsis, for infection, for what we call febrile neutropenia or organ infections like pneumonia. So that’s a period of considerable risk. The purpose of conventional supportive care here has been to shrink that period of vulnerability. Instead of a period of five to seven days when the blood counts are quite profoundly low, to reduce that to zero ideally, but then perhaps to a couple of days so that the cumulative risk of these serious complications becomes less and adaptive depression in the neutrophils is less and ideally is kept below—kept above that 500 threshold.
So we’re very focused on that. I think most of us have looked at the literature and realized that the course of neutrophils following chemotherapy have generally been fairly carefully characterized in the randomized trials that led to FDA approval, in demonstration of efficacy and safety. But at the same time, in the real world population of patients with the other risk factors that we’ve talked about, renal dysfunction, liver dysfunction, and age and other comorbidities, those risks go up proportionately with these other risk factors. So with the hematopoietic growth factors, we certainly try to lessen the severity of depression, lessen the nadir, and shorten the period that the below the levels that put them at exceedingly high risk. During that time period, they need to be, again, education here is a big factor.
Patients have to be educated about how developing a fever, they need to monitor their temperature, they need to report any elevation in the temperature, certainly over 101 degrees Fahrenheit. I think even over 100, it’s probably worth a call to let your provider—let your oncologist know that you have that so they’re aware of it and can make any recommendation. But if the temperature does go up and certainly stays up for more than an hour, that’s a medical emergency in a patient who’s been receiving chemotherapy. They need to have their blood counts assessed and, again, if it’s in that critical range, less than 500, and there’s a clear fever, a documented fever, that’s febrile neutropenia.
That needs to be treated as a medical emergency with empiric broad spectrum antibiotics. We try to manage some of the low-risk patients with no other problems in the outpatient setting, but most of these patients still need to be hospitalized. In the era of COVID-19 it becomes increasingly challenging to find hospital beds, but they do need to be treated aggressively with empiric broad spectrum antibiotics.
It’s important for all of us to remember, and this goes back 20, 30 years with my own research, that the cycle of greatest risk for neutropenic complications and febrile neutropenia is that first cycle. This confuses some people because they—the patient hasn’t had chemotherapy yet, at least most of the time with the new patient. So why should that be the period of greatest risk? Well, the reason is because if a patient develops a problem in cycle 1, you usually just don’t let it go. You do something. Now if you haven’t already prophylaxed the patient with supportive care, with hematopoietic growth factor or some of the newer therapies, then you’re going to bring those in the second cycle and subsequent cycles. Again, if your patient’s not being treated for cure, you might modify the dose or delay the treatment some with the idea that you want to maintain the patient’s quality of life as high as possible. But in the curative setting, that’s—the goal, again, is curing the cancer.
So again, it’s nothing magical about cycle 1, other than the fact that that’s when—that’s the black box. You don’t know what that individual patient’s risk is. You can run the models that we’ve developed, they’re pretty good, but they’re not perfect. So patients may get into trouble that you didn’t anticipate would, and so you didn’t give any prophylactic supportive care. Or despite GCSF, for instance, we know some patients get severe febrile neutropenia anyway. That risk is lower, at least 50%, but it’s not zero.
So patients may develop these complications. That fist cycle is one that kind of really is the greatest concern. It also sets the tone for the subsequent cycles. If you end up needing a compromise to chemotherapy in cycle 1, many of my colleagues say, well, I’ll just—I’ll do that and if they do fine then I’ll go back up to full dose. But they never do because you don’t—when the patient has done okay in the first cycle, you don’t necessarily want to change anything that you’ve done during that cycle. So by the end of the treatment course, several cycles, when you add it all up, you’ve actually made serious reductions in their chemotherapy dose intensity and probably reduced their risk of—avoiding recurrence of the cancer months or years later.
So again, that cycle 1 is so critical. Despite the fact that I’ve done research on hematopoietic growth factors and GCSF, again, for decades, for many years, and continue to do so, as I said, it’s not perfect. We always need to be looking for better, more effective and safe ways of preventing these serious complications. As I mentioned earlier, cytotoxic myelosuppressive chemotherapy is going to be with us for the foreseeable future, despite the new therapies coming along, which are often added onto or given subsequent to myelosuppressive therapy.
So neutropenia will continue to be a major problem and barrier for patients to getting through full and effective doses of chemotherapy.
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