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Expert Perspectives

Identifying CIN Unmet Need
Video Transcript:

Dr. Lyman: So we generally define neutropenia based on the neutrophil count, which is a percentage of the total white blood count. So it can either be measured directly by laboratory assessment, or by knowing the percentage of the white count that consists of neutrophils, you can calculate that neutrophil level. When that neutrophil level falls below 1,500 or so, we consider that neutropenia. Until it gets down to about 1,000, we call it mild neutropenia. Down to 500 becomes moderate neutropenia. Below that it becomes severe neutropenia. That’s where a patient who has fever and severe neutropenia, and even in some patients even in the moderate neutropenia range, it they’re frail or have other risk factors, one might treat them or manage them like a patient with febrile neutropenia.

In certain cancers, and this is largely the hematologic malignancies, but occasionally in solid tumors, you have the neutrophil count becomes profoundly suppressed in the less than 100 range. There we know, every day the patients in that range, they have a serious, probably anywhere between 25 and 50% chance of infection. If they get an infection with counts that low, they have very little ability to fight off the infection and the fatality rate is high. So the basic dilemma for the oncologists and hematologists with a new patient is, you figure out, as I mentioned a minute ago, that there’s data on the chemotherapy that you’re planning to use based on clinical trials. You kind of know what proportion of patients developed severe neutropenia or febrile neutropenia.

Then you try to extrapolate to what this individual patient’s risk might be. If you wait until that patient becomes neutropenic, that—after you give chemotherapy, then it’s kind of too late to prevent neutropenia. Prevention means intervening before something occurs. In this case, when you see a patient, usually the blood counts are in the normal range when you start, but you’re anticipating, you’re predicting what the risk is for that patient over the next few days or week, 10 days that their neutrophils will fall below critical levels and they’ll develop a serious infection. So what we have done is we’ve developed risk models, risk assessment tools. My own group has published risk models that have—based on large population studies. These have been validated in other patient populations. We know a number of the risk factors that put a patient starting chemotherapy at significant increased risk of febrile neutropenia.

Older age is probably a factor, but in fact, what we have found is, if you adjust for all the comorbidities that older patients experience and are likely to have, then age is probably not a major factor. It’s the comorbidities, it’s the organ function, it’s the correlates to age that put the patient at greatest risk. Patients who have poor creatinine function, poor kidney function with an elevated creatinine or low glomerular filtration rate, they’re at increased risk. Patients who are—who’s liver is compromised and they can’t metabolize the drug, so they stay in the circulation longer time, put the patient at increased risk. Then patients with certain types of cancers are at greater risk. These largely correspond to the cancers that we treat most aggressively. Things like lymphoma, leukemia, small-cell lung cancer, so forth. But any cancer, of course, can be a—can represent a vulnerable population if you treat them with aggressive chemotherapy.

Then finally, an important risk factor we sometimes don’t focus on is the dose intensity that’s being given. We know what the patients received in the clinical trials, the randomized trials that led to drug approval. These are often selected patients with very few comorbidities, younger patients, patients who don’t have a lot of these other risk factors. So most of them probably received the full dose of chemotherapy on schedule, the schedule usually being every two, three, rarely every four weeks, of treatment with a time window in between to allow the recovery of the normal blood cells before the next chemotherapy’s delivered. However, in the real world, and our models are based on real world populations throughout the United States, we know that often patients that come in for cancer treatment aren’t these pristine low-risk patients, but they are patients with other comorbid conditions.

Again, they tend to be more elderly, they tend to be patients with other medical conditions that may put them at risk for febrile neutropenia, as well. So one has to look at the impact of the dose intensity. If you give the full dose, that’s the best chance of beating the cancer. At the same time, it’s the greatest risk of patients developing febrile neutropenia. We know in practice, often that dose intensity gets reduced because of these other risk factors. But that does mean down the road, in the future, their cancer is more likely to come back. So it’s a trade-off between preventing complications up front by lowering the chemotherapy or supporting them aggressively through their chemotherapy, keeping their blood counts as good as possible and going ahead with full dose or as close to full dose as you think they can tolerate.

Those patients will have a better chance at long-term survival. So all that assessment is done right up front. Then as the patient comes in for their subsequent cycles of chemotherapy, of course, you look at how they’ve done in between, since the earlier treatments. You may or may not have interim blood counts and see how low their blood has gone. We used to do that routinely. But in practice these days, often patients are reluctant and the physicians are reluctant to make the patient come in or get blood counts in between their treatments. But you at least want to look at where their blood counts are the day they come in for their next treatment.

If it’s low, if it’s still low or hasn’t returned to normal, then there may have to be some dose adjustment or if you had not given them optimal supportive care like a bone marrow stimulant, then you certainly would want to add it on at that point. We call that secondary prophylaxis, whereas giving the growth factors or the bone marrow stimulant right from the very beginning is primary prophylaxis. But again, the idea is to give it before the patient becomes neutropenic. Although usually it’s given, at least conventional growth factors are given a day, two or three days after chemotherapy. You don’t want to give them the same day as chemotherapy if you can avoid it. But before they become neutropenic, as I said earlier, once the neutropenia has developed, the studies done a number of years ago show that you’ve kind of lost the opportunity to prevent these complications.

When you start patient on chemotherapy, usually their blood counts are normal and their neutrophils are normal because they haven’t been exposed to the chemotherapy yet. Yet you know, based on the patient’s condition, the treatment you’re planning to give, the studies that have been done on that treatment, and again, a whole host of these risk factors that patients often have, you try to anticipate. It’s not a perfect science, by any means. Again, we have risk models and you can plug in values to those and come up with a guesstimate of what that patient’s risk is. So it is anticipating something that hasn’t happened yet, if you want to try to prevent it. Because as I mentioned, once it occurs, once the patient is severely neutropenic, even without fever, the opportunity to reduce the risk is lost.

Now what some oncologists and hematologists do, they’ll give prophylactic antibiotics, usually oral antibiotics, trying to reduce the risk of infection knowing the patient may be going through a period of neutropenia in between their treatments. The nadir, the low point of the neutrophils, is usually somewhere between five and ten days. The average is probably six, seven days depending on the chemotherapy. Then it begins to recover. With, again, aggressive supportive care, you can speed up that recovery. But for a period of time, the patient will probably have low blood counts.

The problem with the prophylactic antibiotics is, while they may reduce the risk of infection some, there are two major issues. One is, they don’t affect the blood marrow. So a patient is still going to be neutropenic for a period of time. So the risk, to some extent, will still be there. The bigger concern, and this has been promoted by the Infectious Disease Society of America, is evidence that routine use of prophylactic antibiotics in cancer clinics, in hospitals, leads to an increased rate of antimicrobial resistance, resistance to common antibiotics. Because the bacteria that survive and live in those clinical environments develop a resistance.

So then if a patient comes in and gets infected with one of those resistant bacteria, the antibiotics, even aggressive antibiotics may not work. So we don’t recommend routinely giving prophylactic antibiotics. Perhaps except in some of the hematologic malignancies where the profound neutropenia occurs and the risk is so high. Rather, we recommend if you think the patient’s at serious rick of febrile neutropenia and it’s complications, use some type of prophylaxis that stimulated the bone marrow and brings the neutrophils up more rapidly and reduces that risk.

So the risk of febrile neutropenia in patients, again, is correlated with the dose intensity. The amount of chemotherapy drug per unit time that’s delivered. So again, we generally use fairly standard regimens where the does is prescribed for a given cancer, a different—as specific stage of cancer. In the early stage setting, of course, it’s important to—if the treatment intent is curative as opposed to the more advanced metastatic setting where it may be more—considered more palliative, that is you’re not necessarily and probably don’t have a realistic opportunity for curing the patient, but you’d like to control the disease as long as possible without making them seriously ill and spending many of their days in the hospital.

So the intent of treatment is very important and guides how aggressively you maintain the dose intensity of the chemotherapy. In the early stage setting where this might be in adjuvant patient receiving chemotherapy or neo-adjuvant where it’s given—the chemotherapy is given before surgery, generally when the treatment intent is curative, you want to give as full a dose of chemotherapy on schedule as possible. To do that often requires and is enabled by aggressive supportive care to stimulate recovery of the bone marrow.

In the advanced disease setting, where again, it’s more about quality of life than overall longevity, you can still use supportive care, but your goals here are somewhat different. Again, the main thing is quality of life. If maintaining that patient on full dose chemotherapy means lowering their quality of life because of complications or multiple visits to the doctor, reducing the dose of the chemotherapy or delaying the treatment can also be a reasonable strategy. So again, very important right up front, you kind of discuss with the patients and agree what are the goals of treatment here. That should be a shared decision making with the patient and the family.

They should understand, there’s always trade-offs, there’s always risks versus benefits, but you want to make sure you’re striving to achieve the goals that you’ve all agreed upon. Again, for early stage patients, that’s usually, number one goal is to cure the cancer, or at least give them the best chance of that. That means maintaining the dose intensity as high as possible, as full as possible, usually with aggressive supportive care.

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