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Importance of TLS Prevention Measures

Insights From: Michael R. Bishop, MD, University of Chicago; Anthony R. Mato, MD, MSCE, Memorial Sloan Kettering Cancer Center
Published: Friday, May 08, 2020



Transcript:

Michael R. Bishop, MD: Preventive measures are so important in TLS [tumor lysis syndrome] because you really don’t want TLS to evolve. It’s a very preventable entity. It is just as important to recognize, so once you get it to tumor lysis syndrome, it becomes more difficult to reverse that process because the damage is already done. The key is just like in almost anything—if you could prevent it, then you’re not going to have clinical manifestations. The most important portion is the recognition of patients at risk for tumor lysis so that you can begin preventive measures with them.

We generally think about the patients who are at risk for tumor lysis syndrome as having malignancies that are very responsive to chemotherapy or having a high proliferative rate, meaning that the turnover rate among the cells is very high. Generally, a high proliferation rate correlates with their sensitivity to chemotherapy. Again, that’s not necessarily the case, because there are certain therapies for which we will have a very high response rate. But the tumor may not have a high proliferative rate.

Other patients who are at risk have large, bulky disease because of the larger amount of tumor. When it starts to lyse it will have a greater amount of content and then overwhelm the body. There are patients who present clinically who have pre-existing conditions that make them more vulnerable, particularly patients who have pre-existing renal disease, therefore their clearance is going to be less.

There are also patients with preexisting cardiac abnormalities, including arrhythmias, that are going to be more susceptible to the potential complications of tumor lysis syndrome. The other patients are to be identified when they present already with electrolyte abnormalities, which may occur as a result of their disease. They may present septic, and therefore they’re not perfusing their organs well and have low blood pressure. There are patients who are dehydrated, and the perfusion of the kidneys makes them more susceptible to the potential complications of tumor lysis syndrome.

There are preventive strategies, and it’s multifaceted. The keys are identifications of the patient at risk, which we talked about previously. Hydration becomes a key element, and you’re not only hydrating the patient, but you also have to make sure the patient is producing urine. If you keep giving tons and tons of fluid and the patient is not producing any urine, you’re defeating the purpose.
             
Sometimes, as part of that hydration process, you need to include diuretics. If the patient is urinating well on their own, that’s fine. But if you see that they are not, you need to perhaps help them through the administration of furosemide. If you also say that there is low urine output, you need to be thinking about this potential obstruction. That obstruction could be anatomical.
             
Maybe they have a large tumor mass in their abdomen and therefore they might need to be stented. Or there’s already the formation of the uric acid crystals that we had talked about previously or another form of crystals that can occur in the process the tumor lysis. The next portion is that you need to give agents that lower uric acid levels. If a patient already has high uric acid levels, you’re going to be thinking about using a uric oxidase or such a drug as rasburicase to try to get those uric acid levels low or lowered.
             
If a patient comes in with relatively normal uric acid levels, you could think about the use of allopurinol. This is because allopurinol prevents the conversion of xanthine into uric acid, so it’s a preventive measure in that regard. Coming back finally is the monitoring for this. There are multiple things that need to be monitored, particularly all the electrolytes—potassium, sodium. Included in this are calcium and uric acid.
             
Another laboratory value that’s extremely important is LDH [lactate dehydrogenase], because LDH serves as a surrogate marker for that proliferation rate that you can observe with cancer cells, particularly hematologic malignancies. You will see a surge in the LDH during that process of tumor lysis. You can monitor if you think your treatment is being successful by seeing a subsequent decline in the LDH.

Anthony R. Mato, MD, MSCE: Regarding the preventive measures for TLS, the major strategy here is to prevent even laboratory TLS from occurring. Laboratory TLS is our numerical problem—elevated potassium, elevated phosphate, and a decrease in calcium, for example. They stay laboratory as long as they don’t lead to a clinical consequence. The clinical consequences of the ones I already mentioned are kidney dysfunction, renal failure, cardiac arrhythmia, and neurological consequences.
             
The strategies to prevent laboratory TLS from happening in the first place are the combination of frequent monitoring of labs, electrical monitoring of the heart, aggressive intravenous [IV] or oral fluid intake, and uric acid–lowering agents. All those things are given prior to a TLS event occurs to try to ensure that those don’t occur in the first place. If the event does occur—for example, an elevated potassium level—we can increase fluids. We can increase monitoring. We can give drugs like sodium polystyrene, which can help lower the potassium level. There are measures aimed at prevention and measures aimed at treatment. If a uric acid is elevated while getting fluids and allopurinol, for example, one might give a drug light recombinant urate oxidase to lower their uric acid acutely so that doesn’t further lead to damage of the kidney.

TLS is an acute event. Generally, when it occurs, it’s happening on the scale of minutes to hours to days, usually in patients who are in academic, community, or inpatient settings. The goal of minimizing the risk is to manage them no matter where they are. If they’re home, they should drink more fluids immediately and come in for additional lab tests.
             
If they are in the clinical setting, they should be given IV fluids. They should be given measures to lower the particular electrolyte abnormalities and potentially be admitted. If it’s a life-threatening event—such as someone who’s comatose, intubated, has a life-threatening arrhythmia, or requires dialysis—they may not be as easily handled in a community setting and may need to be transferred.
             
But it’s not the type of event that, when it occurs, you have time to pick which hospital you want to be cared at. The best way to manage the event is to manage them immediately where they are and then think about the level of acuity that’s needed to address the event fully.

Usually TLS occurs in a small percentage of patients. It can occur on a scale of minutes to hours to days. Chemotherapy is not going to occur 3 weeks from now. It will occur today or tomorrow. But most of the time, it’s minutes to hours from the time of exposure.

When you’re thinking about the complications of TLS, 1 of the issues may be renal dysfunction. The standard of care for managing renal dysfunction is to increase renal perfusion largely by oral or intravenous fluids. There are certain circumstances where the kidneys can’t be managed by these conservative measures—either they have volume issues, the kidneys need to be unloaded in the setting of progression of renal failure, or electrolytes are difficult to manage with standard interventions.

Thinking about IV fluids, there are certain ones that are very standard, like normal saline and others that probably should not be used. Lactated Ringer’s, for example, is an alkalinized fluid that contains calcium and potassium. It may increase the risk of calcium phosphate deposition in the kidney. In addition, we’re trying to keep potassium lower, so it makes no sense to infuse potassium simultaneously.
             
Some people have used sodium bicarbonate added to…increase the solubility of uric acid. I would argue against that as not being the standard of care, because while it might slightly increase the uric acid solubility, it’s not enough to be clinically significant. That change in pH will decrease the solubility of calcium phosphate and lead to crystallization in the kidneys, which may defeat the purpose and actually make the renal function worse.
             
It’s very important when you’re taking care of these patients, particularly if they’re residents who are managing the patients who may not be familiar with prophylaxis or treatment to watch very closely what fluids are being used for patients.

Transcript Edited for Clarity
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Transcript:

Michael R. Bishop, MD: Preventive measures are so important in TLS [tumor lysis syndrome] because you really don’t want TLS to evolve. It’s a very preventable entity. It is just as important to recognize, so once you get it to tumor lysis syndrome, it becomes more difficult to reverse that process because the damage is already done. The key is just like in almost anything—if you could prevent it, then you’re not going to have clinical manifestations. The most important portion is the recognition of patients at risk for tumor lysis so that you can begin preventive measures with them.

We generally think about the patients who are at risk for tumor lysis syndrome as having malignancies that are very responsive to chemotherapy or having a high proliferative rate, meaning that the turnover rate among the cells is very high. Generally, a high proliferation rate correlates with their sensitivity to chemotherapy. Again, that’s not necessarily the case, because there are certain therapies for which we will have a very high response rate. But the tumor may not have a high proliferative rate.

Other patients who are at risk have large, bulky disease because of the larger amount of tumor. When it starts to lyse it will have a greater amount of content and then overwhelm the body. There are patients who present clinically who have pre-existing conditions that make them more vulnerable, particularly patients who have pre-existing renal disease, therefore their clearance is going to be less.

There are also patients with preexisting cardiac abnormalities, including arrhythmias, that are going to be more susceptible to the potential complications of tumor lysis syndrome. The other patients are to be identified when they present already with electrolyte abnormalities, which may occur as a result of their disease. They may present septic, and therefore they’re not perfusing their organs well and have low blood pressure. There are patients who are dehydrated, and the perfusion of the kidneys makes them more susceptible to the potential complications of tumor lysis syndrome.

There are preventive strategies, and it’s multifaceted. The keys are identifications of the patient at risk, which we talked about previously. Hydration becomes a key element, and you’re not only hydrating the patient, but you also have to make sure the patient is producing urine. If you keep giving tons and tons of fluid and the patient is not producing any urine, you’re defeating the purpose.
             
Sometimes, as part of that hydration process, you need to include diuretics. If the patient is urinating well on their own, that’s fine. But if you see that they are not, you need to perhaps help them through the administration of furosemide. If you also say that there is low urine output, you need to be thinking about this potential obstruction. That obstruction could be anatomical.
             
Maybe they have a large tumor mass in their abdomen and therefore they might need to be stented. Or there’s already the formation of the uric acid crystals that we had talked about previously or another form of crystals that can occur in the process the tumor lysis. The next portion is that you need to give agents that lower uric acid levels. If a patient already has high uric acid levels, you’re going to be thinking about using a uric oxidase or such a drug as rasburicase to try to get those uric acid levels low or lowered.
             
If a patient comes in with relatively normal uric acid levels, you could think about the use of allopurinol. This is because allopurinol prevents the conversion of xanthine into uric acid, so it’s a preventive measure in that regard. Coming back finally is the monitoring for this. There are multiple things that need to be monitored, particularly all the electrolytes—potassium, sodium. Included in this are calcium and uric acid.
             
Another laboratory value that’s extremely important is LDH [lactate dehydrogenase], because LDH serves as a surrogate marker for that proliferation rate that you can observe with cancer cells, particularly hematologic malignancies. You will see a surge in the LDH during that process of tumor lysis. You can monitor if you think your treatment is being successful by seeing a subsequent decline in the LDH.

Anthony R. Mato, MD, MSCE: Regarding the preventive measures for TLS, the major strategy here is to prevent even laboratory TLS from occurring. Laboratory TLS is our numerical problem—elevated potassium, elevated phosphate, and a decrease in calcium, for example. They stay laboratory as long as they don’t lead to a clinical consequence. The clinical consequences of the ones I already mentioned are kidney dysfunction, renal failure, cardiac arrhythmia, and neurological consequences.
             
The strategies to prevent laboratory TLS from happening in the first place are the combination of frequent monitoring of labs, electrical monitoring of the heart, aggressive intravenous [IV] or oral fluid intake, and uric acid–lowering agents. All those things are given prior to a TLS event occurs to try to ensure that those don’t occur in the first place. If the event does occur—for example, an elevated potassium level—we can increase fluids. We can increase monitoring. We can give drugs like sodium polystyrene, which can help lower the potassium level. There are measures aimed at prevention and measures aimed at treatment. If a uric acid is elevated while getting fluids and allopurinol, for example, one might give a drug light recombinant urate oxidase to lower their uric acid acutely so that doesn’t further lead to damage of the kidney.

TLS is an acute event. Generally, when it occurs, it’s happening on the scale of minutes to hours to days, usually in patients who are in academic, community, or inpatient settings. The goal of minimizing the risk is to manage them no matter where they are. If they’re home, they should drink more fluids immediately and come in for additional lab tests.
             
If they are in the clinical setting, they should be given IV fluids. They should be given measures to lower the particular electrolyte abnormalities and potentially be admitted. If it’s a life-threatening event—such as someone who’s comatose, intubated, has a life-threatening arrhythmia, or requires dialysis—they may not be as easily handled in a community setting and may need to be transferred.
             
But it’s not the type of event that, when it occurs, you have time to pick which hospital you want to be cared at. The best way to manage the event is to manage them immediately where they are and then think about the level of acuity that’s needed to address the event fully.

Usually TLS occurs in a small percentage of patients. It can occur on a scale of minutes to hours to days. Chemotherapy is not going to occur 3 weeks from now. It will occur today or tomorrow. But most of the time, it’s minutes to hours from the time of exposure.

When you’re thinking about the complications of TLS, 1 of the issues may be renal dysfunction. The standard of care for managing renal dysfunction is to increase renal perfusion largely by oral or intravenous fluids. There are certain circumstances where the kidneys can’t be managed by these conservative measures—either they have volume issues, the kidneys need to be unloaded in the setting of progression of renal failure, or electrolytes are difficult to manage with standard interventions.

Thinking about IV fluids, there are certain ones that are very standard, like normal saline and others that probably should not be used. Lactated Ringer’s, for example, is an alkalinized fluid that contains calcium and potassium. It may increase the risk of calcium phosphate deposition in the kidney. In addition, we’re trying to keep potassium lower, so it makes no sense to infuse potassium simultaneously.
             
Some people have used sodium bicarbonate added to…increase the solubility of uric acid. I would argue against that as not being the standard of care, because while it might slightly increase the uric acid solubility, it’s not enough to be clinically significant. That change in pH will decrease the solubility of calcium phosphate and lead to crystallization in the kidneys, which may defeat the purpose and actually make the renal function worse.
             
It’s very important when you’re taking care of these patients, particularly if they’re residents who are managing the patients who may not be familiar with prophylaxis or treatment to watch very closely what fluids are being used for patients.

Transcript Edited for Clarity
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