What is Nitrosoureas Toxicity?

Nitrosoureas are powerful chemotherapy drugs that can cause cells to die by damaging their DNA. Doctors use them to treat various types of cancer including types of brain cancer (malignant glioblastomas), Hodgkin’s and non-Hodgkin lymphomas, and tumors in the pancreatic islet cells. Carmustine, lomustine, and fotemustine are three commonly used types of nitrosoureas.

Nitrosoureas work as anti-cancer and cell-damaging agents by chemically modifying various compounds in the cells, affecting cells in various stages of their life cycle. Lomustine is unique because it can easily pass into the brain and is often used for a recurrent form of brain cancer called glioblastoma multiforme. In some European countries, doctors use fotemustine instead of lomustine. Carmustine, the first nitrosourea developed for public use, is not commonly used today due to its toxicity, the need for intravenous administration, and limited availability.

Doctors sometimes use nitrosoureas with other chemotherapy drugs or by themselves. For instance, they can be used in combination with drugs like procarbazine, lomustine, and vincristine to treat a type of brain cancer called oligodendroglioma. One nitrosourea called streptozocin has been found effective against pancreatic islet cell tumors.

Nitrosoureas, however, can have severe side effects. These can include damage to the white matter of the brain, lung problems, kidney damage, liver damage, nerve damage, bone marrow suppression, a higher risk of secondary leukemias, and numerous other side effects such as nausea, vomiting, mouth inflammation, hair loss, anemia, loss of appetite, and pain or swelling at the injection site. Because of these severe side effects, doctors choose nitrosoureas mostly for cases where tumors have come back or are not responding to other treatments. Finally, these drugs are mainly eliminated from the body through the kidneys.

What Causes Nitrosoureas Toxicity?

The Nitrosoureas are a group of chemotherapy drugs which contain a nitroso group and urea molecule. These drugs are often used to treat severe brain tumors (known as high-grade gliomas), recurring glioblastoma multiforme (a very aggressive type of brain cancer), lung cancers, and tumors in the pancreas. Additionally, they play a significant role in the BEAM treatment plan, which is commonly used for a type of transplant using your own stem cells (called autologous hematopoietic stem cell transplantation) for lymphoma, which is a type of cancer that starts in the cells that are part of the body’s immune system.

However, Nitrosoureas are usually not a first choice of treatment due to their serious side effects that can worsen with increased dosage.

Risk Factors and Frequency for Nitrosoureas Toxicity

According to the World Health Organization’s classification for brain tumors, high-grade gliomas are marked as grade III and IV. These make up about 80% of all malignant brain tumors and are the most common type of primary brain cancer. Unfortunately, these cancers have a bad prognosis, meaning the outcome is poor, with most patients living less than 2 years following diagnosis. The majority of these high-grade gliomas are a type known as glioblastomas, which make up 49.1% of these cases, and sadly only about 6.8% of patients with glioblastomas survive up to 5 years.

Signs and Symptoms of Nitrosoureas Toxicity

People with a history of aggressive brain tumors, such as high-grade malignant gliomas and glioblastoma multiforme, or other types of cancer that spreads (metastatic cancers) who are treated with a certain type of chemotherapy called nitrosoureas are at high risk of nitrosourea toxicity. It’s important to be aware of this if a family member is receiving treatment with nitrosoureas, as accidental or intentional ingestion could lead to drug toxicity.

In the short term, patients might experience symptoms like feeling sick, vomiting, and diarrhea. Over the long term, they might complain about being short of breath, having a dry cough, and retaining fluid.

When examined, patients with nitrosourea toxicity may show certain signs. They might have a rash composed of small red spots (petechial rash), fever, yellowing of the white part of the eyes (scleral icterus), and bleeding gums. This is usually due to a decrease in the production of blood cells (myelosuppression). On examining the chest, doctors might hear crackling sounds (fine crackles), find quickened breathing (tachypnea), and a dry cough. Patients may also have a hardened stomach (guarding), yellow skin (jaundice), tender abdomen, and abdominal pain.

The neurological examination might be difficult unless the doctor is familiar with a patient’s normal neurological status. This is because brain tumors, radiation therapy, or surgery to remove the tumor may cause neurological deficits. However, some signs like cranial nerve palsy (weakness of cranial nerves), physical weakness, and slower thinking might be detected.

Short term symptoms: nausea, vomiting, diarrhea
Long term symptoms: shortness of breath, dry cough, fluid retention
Physical signs: petechial rash, fever, scleral icterus, bleeding gums
Chest exam: diffuse fine crackles, tachypnea, dry cough
Abdominal exam: guarding, jaundice, abdominal tenderness, pain
Neurological exam: cranial nerve palsy, motor weakness, cognitive slowing

Testing for Nitrosoureas Toxicity

In order to check for delayed myelosuppression, a health condition where your body doesn’t make enough blood cells, doctors will usually order a complete blood count. This is a lab test that measures the different components of your blood. Additionally, a comprehensive metabolic panel may be performed. This test will help your doctor see if there is any irregularities in your body’s chemical balance, if your kidneys are functioning properly, or if there’s any damage to your liver.

The doctors may also take chest x-rays or CT scans. Chest x-rays can be used to reveal any unusual spots in the lungs, while a CT scan can provide more detailed images, potentially showing architectural distortions in the lung such as honeycombing, traction bronchiectasis, reticulation, and thickening of the walls between the lobes of the lung.

Physicians might also use a test measuring how well you absorb a gas called carbon monoxide, as changes in this function could be an early sign of lung damage. Pulmonary function tests are useful to determine the severity of any damage to lung tissue.

Hydroxyproline is a compound that can be used to measure the extent of scarring in the lungs (also known as pulmonary fibrosis). However, how useful this measurement is for patients with fibrosis caused by drugs known as nitrosoureas is not clear. In patients treated with a drug called Carmustine, doctors might look at how fast fatty acids are being made in certain lung cells. This can serve as a sign of possible lung damage caused by the medication.

Treatment Options for Nitrosoureas Toxicity

If someone experiences toxicity from nitrosourea, a type of cancer drug, they need to stop using it right away because there’s no specific cure or reversal for its damaging effects. These patients may need care and monitoring in a hospital, with treatments focused on addressing the particular toxic effects, especially on blood cells and kidneys.

One such effect is myelosuppression, which is a decrease in the production of blood cells causing low counts of platelets and red blood cells. These patients might be given a transfusion of platelets, cells that help with clotting, and red blood cells, which carry oxygen around the body. This helps to keep blood counts at safe levels until the body can make more blood cells itself, which might take a few weeks after finishing chemotherapy.

In cases where the hemoglobin is low, erythropoietic agents might be used. Hemoglobin is a protein in red blood cells that carries oxygen from the lungs to the rest of the body. Erythropoietic agents stimulate the bone marrow to produce more red blood cells and reduce the need for more transfusions. The US Food and Drug Administration recommends using these agents when hemoglobin levels fall below 10 g/dL and aiming for levels between 10 and 12 g/dL.

If the patient also has a depleted number of white blood cells, they run a high risk of getting infections. Prophylactic antibiotics, used to prevent infections before they start, might be administered. They should follow strict precautions to avoid getting infections, and the choice of antibiotic will depend on local factors such as common bacterial strains and patterns of antibiotic resistance.

Nitrosourea can damage the kidneys (nephrotoxicity), and people experiencing this need to be monitored closely and kept well-hydrated. They may need treatments to correct any related abnormalities in protein function or metabolism to protect the kidneys as much as possible.

Nitrosourea can also cause a disease called pulmonary fibrosis, which is when lung tissue becomes damaged and scarred, making it harder to breathe. Although corticosteroids have been used to treat and prevent nitrosourea-induced pulmonary fibrosis, the studies haven’t shown any benefit for people who use corticosteroids while undergoing nitrosourea therapy. It’s important to know that this lung damage might continue to worsen even after a patient stops nitrosourea treatment.

The harmful effects of nitrosourea, a type of chemotherapy drug, can be mistaken for several other health issues. Here are the different categories of conditions that may be mistaken for nitrosourea toxicity:

Pulmonary, or lung-related causes, such as various types of lung disease including pulmonary fibrosis, sarcoidosis, or pneumonia.
Rheumatological, or joint and connective tissue-related issues, such as dermatomyositis, polymyositis, mixed connective tissue disease, pneumoconiosis, systemic lupus erythematosus, rheumatoid arthritis, and scleroderma.
Hepatological, or liver-related problems, such as infectious hepatitis, chemical hepatitis, cirrhosis, and tumor metastasis.
Hematological, or blood-related conditions, resulting from effects of myelosuppression such as malignancy-associated myelofibrosis, autoimmune disorders, aplastic anemia, and anemia of chronic disease.
Nephrological, or kidney-related causes, such as prerenal azotemia, acute tubular necrosis, and other causes of acute kidney injury.
Neurological, or nerve-related causes, such as intoxication, tumor recurrence, and delirium.

What to expect with Nitrosoureas Toxicity

Patients who are undergoing therapy with a type of drug called ‘nitrosoureas’ often already have a serious health outlook before treatment begins. For example, high-grade gliomas, a kind of aggressive brain tumor, have an average survival rate of less than 2 years. To put this into perspective, the average survival rate of patients with specific types of brain tumors, like ‘glioblastoma multiforme’ and ‘anaplastic astrocytoma’, is around 14.1 months.

Despite these intense situations, nitrosoureas have shown positive results in treating high-grade gliomas. For example, patients treated with a nitrosourea drug called CCNU had an increased survival period of 5.3 months on average, and those treated with ACNU experienced a survival gain of 8.9 months.

However, not all side effects are positive. In some cases, patients developed a lung condition known as ‘pulmonary fibrosis’ due to a different nitrosourea drug called BCNU – resulting in a 30% to 40% mortality rate. People already suffering from lung diseases or with a history of smoking are particularly at risk for developing this condition after nitrosourea therapy.

Possible Complications When Diagnosed with Nitrosoureas Toxicity

Possible health problems from nitrosourea toxicity can include permanent bone marrow damage and scarring, irreversible lung scarring and reduced lung function, kidney failure, types of blood cancer, and heart failure.

Signs of liver damage usually disappear within a few weeks, but liver tests can still show signs of liver cell death for several months. People who receive doses over 1400 mg/m2 are at a much higher risk of lung scarring. According to the 2022 FDA guidelines, lung damage could show up years after treatment and could even be fatal, especially if the treatment was administered in childhood.

Important Health Risks:

Permanent bone marrow damage and scarring
Irreversible lung scarring and reduced lung function
Kidney failure
Blood cancers
Heart failure
Signs of liver damage that could last several months
Risks of lung damage for high-dose recipients
Possible fatal lung damage years after treatment

Preventing Nitrosoureas Toxicity

Patients who are on nitrosourea chemotherapy need to be aware of the signs and symptoms of nitrosourea toxicity. Nitrosourea toxicity refers to harmful effects that can happen if too much of this chemotherapy drug is taken. If these symptoms become severe, it’s best to go to the emergency room immediately. Additionally, nitrosourea drugs should be stored in a secure place where children cannot accidentally get to them and possibly ingest them.

Frequently asked questions

The toxicity of Nitrosoureas is due to their severe side effects, which can include damage to the white matter of the brain, lung problems, kidney damage, liver damage, nerve damage, bone marrow suppression, a higher risk of secondary leukemias, and numerous other side effects such as nausea, vomiting, mouth inflammation, hair loss, anemia, loss of appetite, and pain or swelling at the injection site.

Nitrosoureas toxicity is common due to their serious side effects that can worsen with increased dosage.

Signs and symptoms of Nitrosoureas Toxicity include: - Short term symptoms: nausea, vomiting, diarrhea - Long term symptoms: shortness of breath, dry cough, fluid retention - Physical signs: petechial rash, fever, scleral icterus, bleeding gums - Chest exam: diffuse fine crackles, tachypnea, dry cough - Abdominal exam: guarding, jaundice, abdominal tenderness, pain - Neurological exam: cranial nerve palsy, motor weakness, cognitive slowing

People with a history of aggressive brain tumors, such as high-grade malignant gliomas and glioblastoma multiforme, or other types of cancer that spreads (metastatic cancers) who are treated with a certain type of chemotherapy called nitrosoureas are at high risk of nitrosourea toxicity. Accidental or intentional ingestion of nitrosoureas can also lead to drug toxicity.

The doctor needs to rule out the following conditions when diagnosing Nitrosoureas Toxicity: - Pulmonary diseases including pulmonary fibrosis, sarcoidosis, or pneumonia. - Rheumatological issues such as dermatomyositis, polymyositis, mixed connective tissue disease, pneumoconiosis, systemic lupus erythematosus, rheumatoid arthritis, and scleroderma. - Hepatological problems like infectious hepatitis, chemical hepatitis, cirrhosis, and tumor metastasis. - Hematological conditions resulting from myelosuppression such as malignancy-associated myelofibrosis, autoimmune disorders, aplastic anemia, and anemia of chronic disease. - Nephrological causes such as prerenal azotemia, acute tubular necrosis, and other causes of acute kidney injury. - Neurological causes like intoxication, tumor recurrence, and delirium.

The types of tests needed for Nitrosoureas Toxicity include: - Complete blood count (CBC) to measure the different components of blood and check for myelosuppression. - Comprehensive metabolic panel to assess chemical balance, kidney function, and liver damage. - Chest x-rays or CT scans to detect lung abnormalities such as spots, architectural distortions, and thickening of lung walls. - Pulmonary function tests to determine the severity of lung tissue damage. - Measurement of carbon monoxide absorption to assess lung function. - Hydroxyproline measurement to evaluate the extent of scarring in the lungs. - Assessment of fatty acid production in lung cells to detect lung damage caused by Carmustine. - Monitoring of blood cell counts and kidney function. - Transfusion of platelets and red blood cells to maintain safe blood counts. - Use of erythropoietic agents to stimulate red blood cell production. - Prophylactic antibiotics to prevent infections. - Close monitoring and hydration to protect against nephrotoxicity. - Corticosteroids may not be beneficial for nitrosourea-induced pulmonary fibrosis.

The toxicity from Nitrosourea is treated by stopping the use of the drug immediately. There is no specific cure or reversal for the damaging effects of Nitrosourea. Patients may require care and monitoring in a hospital, with treatments focused on addressing the specific toxic effects, particularly on blood cells and kidneys. This may involve transfusions of platelets and red blood cells to maintain safe blood counts, the use of erythropoietic agents to stimulate the production of red blood cells, prophylactic antibiotics to prevent infections, and close monitoring and hydration to protect the kidneys. However, there is no known effective treatment for Nitrosourea-induced pulmonary fibrosis.

The side effects when treating Nitrosoureas Toxicity include: - Myelosuppression, which leads to low counts of platelets and red blood cells - Possible need for transfusion of platelets and red blood cells to maintain safe blood counts - Use of erythropoietic agents to stimulate the production of red blood cells - Increased risk of infections due to depleted white blood cells, requiring prophylactic antibiotics - Kidney damage (nephrotoxicity), requiring close monitoring and hydration - Potential development of pulmonary fibrosis, causing lung damage and scarring - Limited effectiveness of corticosteroids in treating nitrosourea-induced pulmonary fibrosis - Possible long-term health risks, including permanent bone marrow damage, irreversible lung scarring and reduced lung function, kidney failure, blood cancers, and heart failure - Signs of liver damage that may persist for several months - Higher risk of lung scarring for recipients of high doses, especially in childhood - Potential for fatal lung damage years after treatment.

Oncologist.