NCI Managing Chemotherapy Side Effects / Nausea and Vomiting
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ASCO Nausea and Vomiting
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Types of medicine for nausea and vomiting
The medicines recommended for you depend on the type of treatment you are receiving and how likely it is to cause vomiting. The most common types of drugs used to manage nausea and prevent vomiting include:
NK1 receptor antagonist. Medicines in this group include:
Aprepitant (Emend)
Fosaprepitant (Emend injection)
Netupitant-palonosetron (Akynzeo)
Rolapitant (Varubi).
5-HT3 receptor antagonist. Medicines in this group include:
Granisetron (Kytril, Sancuso)
Ondansetron (Zofran)
Palonosetron (Aloxi)
Dolasetron (Anzemet)
Tropisetron (Navoban)
Ramosetron (Nasea)
Dopaminergic antagonist. Medicines in this group include:
Metoclopramide (Reglan)
Prochlorperazine (Compazine)
Dexamethasone (multiple brand names)
Olanzapine (Zyprexa)
NCI Managing Chemotherapy Side Effects / Diarrhea
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ASCO Diarrhea
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Medicines for diarrhea caused by chemotherapy: loperamide (Imodium) and diphenoxylate and atropine (Lomotil).
NCI Managing Chemotherapy Side Effects / Constipation
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ASCO Constipation
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Medicines for Constipation caused by chemotherapy: Ask your health care team about treatment, such as laxatives, an enema, or rectal suppository. Some of these may be harmful for some patients.
NCI Managing Chemotherapy Side Effects / Appetite Changes
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ASCO Appetite Loss
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Doctors may treat appetite loss and associated weight loss with certain medications, including:
Megestrol acetate (Megace) or medroxyprogesterone, which are forms of the progesterone hormone that can improve appetite and weight gain.
Steroid medications, which can increase appetite, improve a person's sense of well-being, and help with nausea, weakness, or pain.
Metoclopramide (Reglan), which helps move food out of the stomach and can prevent feeling full before eating enough food.
Dronabinol (Marinol), a cannabinoid made in the laboratory, which may stimulate appetite.
ASCO Taste Changes
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Medicines for Taste Changes caused by chemotherapy: Consider zinc sulfate supplements, which may improve taste for some people. However, talk with your doctor before taking any dietary supplements, especially during active treatment.
NCI Managing Chemotherapy Side Effects / Hair Loss (Alopecia)
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ASCO Hair Loss or Alopecia
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Managing Alopecia caused by chemotherapy:
Cold cap therapy. Wearing a cap or head covering with cold packs before, during, or after chemotherapy may help prevent hair loss from drugs given through a vein. The cold narrows the blood vessels in the skin on your head. This means that less of the drug could reach the hair follicles. The cold caps are generally available to rent online throughout your treatment. Talk with your health care team to find out if this approach may work for you.
Medications. A topical medication available over the counter, minoxidil, may be helpful to treat hair thinning from hormonal therapy or targeted therapy. It may also be useful for people whose hair did not fully grow back after chemotherapy, stem cell transplant, or radiation therapy. Sometimes, oral medications such as spironolactone (Aldactone) or finasteride (Propecia, Proscar) may also improve hair growth in these situations.
NCI Skin and Nail Changes
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ASCO Skin Conditions
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Managing Skin Conditions by chemotherapy:
Cold cap therapy. Wearing a cap or head covering with cold packs before, during, or after chemotherapy may help prevent hair loss from drugs given through a vein. The cold narrows the blood vessels in the skin on your head. This means that less of the drug could reach the hair follicles. The cold caps are generally available to rent online throughout your treatment. Talk with your health care team to find out if this approach may work for you.
Medicines for Skin Conditions caused by chemotherapy: A topical medication available over the counter, minoxidil, may be helpful to treat hair thinning from hormonal therapy or targeted therapy. It may also be useful for people whose hair did not fully grow back after chemotherapy, stem cell transplant, or radiation therapy. Sometimes, oral medications such as spironolactone (Aldactone) or finasteride (Propecia, Proscar) may also improve hair growth in these situations.
NCI Urinary and Bladder Problems
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NCI Managing Chemotherapy Side Effects / Urination Changes
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ASCO Urinary Incontinence
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Medicines for Urinary Incontinence caused by chemotherapy:
Medicines, such as oxybutynin (Ditropan, Ditropan XL) and tolterodine (Detrol, Detrol LA), or the antidepressants imipramine (Tofranil) and duloxetine (Cymbalta)
ASCO Osteoporosis
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Treating and managing bone loss
Treatment for bone loss often involves the use of bone-modifying drugs. These drugs slow the rate of bone thinning. They may also reduce new bone damage and promote healing. Patients who have bone pain from metastatic cancer also often receive these drugs. Bone-modifying drugs include:
Bisphosphonates, which block the cells that destroy bone, called osteoclasts
RANK ligand inhibitors, such as denosumab (Prolia, Xgeva)
Osteonecrosis of the jaw is a condition possibly linked with bone-modifying drugs. It is an uncommon but serious condition. The symptoms include pain, swelling, and infection of the jaw; loose teeth; and exposed bone.
Your doctor may recommend seeing a dentist before bone-strengthening treatment begins. But before having any dental procedures, tell your dentist you are receiving treatment with a bone-modifying drug.
Managing bone loss and its symptoms may also include:
Taking calcium and vitamin D supplements.The current recommendations are listed below. Before you take any vitamin or mineral supplement, talk with your doctor.
Vitamin D: 800 international units (IU) per day for women of all ages
Calcium supplements for women before menopause: 1,000 milligrams (mg) per day
Calcium supplements for women after menopause: 1,200 mg per day
Exercising. Weight-bearing physical activity such as walking, dancing, and stair climbing puts stress on your bones. This stress triggers the body to make cells that form bone. Regular weight-bearing exercise also builds strong muscles, which can help your balance. Your doctor can recommend an exercise plan based on your needs, physical abilities, and fitness level.
Maintaining a healthy weight. Eating a well-balanced diet is important to bone health. Being underweight can contribute to bone loss and fractures.
Preventing falls.
NCI Sexual Health Issues in Men
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ASCO Hormone Deprivation Symptoms in Men
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Medicines for Osteoporosis in Men caused by chemotherapy: Men who have received androgen ablation therapy have a higher risk of osteoporosis. The following medical treatments help slow or stop bone loss especially in men. Your doctor may give these individually or in combination:
Alendronate (Binosto, Fosamax)
Pamidronate (Aredia) and zoledronic acid (Zometa)
Denosumab (Prolia, Xgeva)
Medicines for Hot flashes in Men caused by chemotherapy: Up to 75% of men receiving hormone treatments for prostate cancer have hot flashes. The following treatments may help reduce the number and severity of hot flashes in men:
Antidepressants, such as venlafaxine (Effexor) and sertraline (Zoloft)
Nonhormonal treatments, such as gabapentin (Gralise, Neurontin)
Progesterone, such as megestrol acetate (Ovaban, Pallace)
Exercise
Deep breathing and other relaxation techniques
A cooler room temperature
NCI Sexual Health Issues in Women
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ASCO Menopausal Symptoms in Women
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Ways to manage hot flashes
Hormone therapy is the most effective way to manage hot flashes for some women. However, women who are receiving hormonal or endocrine therapy for cancer may not be able to take hormone replacement therapy. For these women, other medicines such as paroxetine (multiple brand names), venlafaxine (Effexor), gabapentin (Neurontin), and clonidine (Catapres, Kapvay) can also help. However, talk with your doctor about these options. Ask about the risks and benefits.
Other options to help manage hot flashes include:
Exercise
Practice relaxation techniques, like deep breathing and other strategies to reduce stress
Keep room temperatures cool
Layer clothing to adjust during and after hot flashes
Some women may consider taking medicine or supplements.
Ways to manage or prevent osteoporosis:
Perform weight-bearing exercises, such as walking 20 to 30 minutes per day
Maintain a healthy body weight
Take vitamin D and calcium supplements. Ask about the recommended doses, based on your age.
In addition, your doctor may recommend a bone density test or medicine.
Ways to manage vaginal dryness
Use vaginal lubricants, estrogen creams, or an estrogen ring. Choose a product that works best for you and your partner. You may try a few before finding the right one.
Talk with your doctor before using an estrogen ring. It may not be the best choice. Particularly if you have estrogen receptor-positive breast cancer.
Hormone therapy
Menopausal hormone therapy (MHT) delivers estrogen and progesterone or progestin. Progestin is a form of progesterone made in a laboratory.
MHT may help relieve symptoms like hot flashes and osteoporosis. However, doctors don’t recommend the treatment for most women. Women receiving MHT may have increased risk of certain conditions.
For severe symptoms, doctors may recommend low doses of MHT for a short time. Meanwhile, women who have had a hysterectomy may receive estrogen-only MHT. A hysterectomy is the surgical removal of the uterus.
NCI Managing Chemotherapy Side Effects / Fatigue
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ASCO Fatigue
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Medicines for fatigue caused by chemotherapy: Some medications help people feel more alert and awake. Researchers are studying whether supplements, such as ginseng and vitamin D, may help.
NCI Sleep Problems (Insomnia) and Cancer Treatment
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ASCO Sleeping Problems: Insomnia
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Medicines for insomnia caused by chemotherapy: Medications may help relieve insomnia. However, you should only use these for a short time unless other treatments don’t work.
NCI Memory or Concentration Problems and Cancer Treatment
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NCI Managing Chemotherapy Side Effects / Memory Changes
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ASCO Attention, Thinking, or Memory Problems
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Medicines for cognitive problems caused by chemotherapy: Medications, including stimulants, cognition-enhancing drugs, and antidepressants
NCI Managing Chemotherapy Side Effects / Mouth and Throat Changes
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ASCO Mouth Sores or Mucositis
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Medicines for Mouth Sores or Mucositis caused by chemotherapy: Your doctor may recommend specific pain-relief strategies if you develop mouth sores. Options include the following:
A mouthwash solution that contains lidocaine, sometimes called magic mud, magic mouthwash, or triple mix
Over-the-counter drugs, such as acetaminophen (Tylenol). However, it is important to avoid taking aspirin during cancer treatment unless your doctor tells you otherwise.
Prescription pain medicine
ASCO Difficulty Chewing
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Medicines for Difficulty Chewing caused by chemotherapy: Your doctor may prescribe medicine if you have pain chewing. Some medicines reduce pain and inflammation. Others treat mouth or throat infections. Muscle relaxants treat jaw pain and stiffness.
ASCO Dental and Oral Health
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Medicines for Dental and Oral Health caused by chemotherapy: The specific treatment your doctor recommends will depend on your symptoms. There are several common treatments for dental and oral side effects:
Mouth rinses that contain salt and baking soda may help treat mouth sores. However, if you are taking high blood pressure medication, you may need to avoid mouth rinses with salt. There are also a variety of prescription rinses that may soothe sore spots.
Pain medications, including narcotics, may also be used to treat pain from mouth sores. Medications may be placed directly on the sores, taken by mouth, or given through an IV.
Antibiotics, antiviral drugs, and/or antifungal drugs are used to treat infections.
Drinking water and sugarless drinks may help manage dry mouth. Sucking on ice chips may also help. Avoid things that will dry out the mouth, such as soda, fruit juice, cigarettes, chewing tobacco, and alcohol.
Medications that produce saliva may help some people prevent or minimize dry mouth. Topical oral gels or other medications may help dry mouth caused by radiation therapy to the head and neck.
ASCO Dry Mouth or Xerostomia
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Medicines for Dry Mouth or Xerostomia caused by chemotherapy: Although dry mouth cannot be prevented, some treatments can help. These include:
Medicines that prevent or lessen the side effects of radiation treatment, such as amifostine (Ethyol).
Saliva substitutes and mouth rinses with hyetellose, hyprolose, or carmellose.
Medicines that stimulate the salivary glands, such as pilocarpine (Salagen) or cevimeline (Evoxac).
Other ways to stimulate the salivary glands, such as sucking on sugar-free candy or chewing sugarless gum.
Acupuncture, which some research suggests can help with dry mouth.
ASCO Difficulty Swallowing or Dysphagia
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Managing pain swallowing: Your doctor may prescribe medication if you have pain swallowing. Painful swallowing is called odynophagia. Some medications reduce inflammation and pain. Other medicines treat mouth or throat infections. Some pain medicines come as mouth rinses used before eating.
ASCO Weight Loss
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Medicines for Weight Loss caused by chemotherapy: Sometimes, doctors recommend specific medications to address weight loss. Options include:
Megestrol acetate (Megace). This is a progesterone hormone. It can improve appetite, weight gain, and sense of well-being.
Steroid medications. These can increase appetite and improve sense of well-being. They also help with nausea, weakness, or pain. Doctors often recommend steroids for short-term use. Long-term use of steroids may cause serious side effects.
Metoclopramide (Reglan) can prevent feeling full before eating enough food.
Pancreatic enzyme (lipase) replacement helps the body absorb fat.
Dronabinol (Marinol), a cannabinoid made in the laboratory, may stimulate appetite.
Other medications are being studied to help people with cancer improve their appetite and gain weight.
ASCO Weight Gain
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Managing fluid retention-related weight gain: Ask a doctor about prescribing a diuretic.
Lower the amount of salt in your diet.
NCI Managing Chemotherapy Side Effects / Swelling (Fluid retention)
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ASCO Fluid Retention or Edema
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Medicines for Fluid Retention or Edema caused by chemotherapy: Ask your doctor about prescription diuretics, which help get rid of extra fluid from the body by increasing urination.
Reduce the amount of salt in your diet.
NCI Nerve Problems (Peripheral Neuropathy)
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NCI Managing Chemotherapy Side Effects / Nerve Changes
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ASCO Peripheral Neuropathy
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Medicines for Neuropathy caused by chemotherapy:
Although medication cannot cure neuropathy, it may relieve the pain. However, it doesn’t relieve numbness.
For neuropathy pain, doctors commonly prescribe anticonvulsants and antidepressants. For neuropathy related to chemotherapy, ASCO recommends the antidepressant duloxetine (Cymbalta).
Prescription nonsteroidal anti-inflammatory drugs or analgesics are options for severe pain. Analgesics are very strong painkillers. Topical treatments may also help control pain. These include lidocaine patches and creams. Topical 1% menthol also seems helpful, based on early studies.
Additionally, your health care team may recommend over-the-counter medications for mild pain.
ASCO Nervous System Side Effects
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Managing nervous system side effects
Nervous system side effects can make it difficult for people to complete their usual daily activities. Some symptoms caused by cancer treatment will go away after treatment ends, but some may be ongoing. Although nerve damage and nervous system side effects may not be preventable, most are manageable if found early.
Early treatment can also prevent the symptoms from worsening. It is important to tell your doctor immediately if you have any of the symptoms listed above. Once diagnosed, management of nervous system side effects depends on the type of problem and the cause.
The following list provides several ways to manage nervous system problems. Talk with your health care team about which options are recommended for you.
Medicines. Some nervous system symptoms can be managed or treatment with medicines. These include:
Medicines for nausea and vertigo, such as meclizine (Antivert), prochlorperazine (Compazine), scopolamine patch (Transderm-Scop)
Antibiotics to treat infections
Corticosteroids to reduce inflammation and swelling
Antidepressants, such as drugs called selective serotonin or norepinephrine reuptake inhibitors (SSRIs or SNRIs) or amitriptyline (multiple brand names) or nortriptyline (Aventyl, Pamelor)
Medications to treat peripheral neuropathy
Pain management. You may have a variety of options to manage pain from nerve damage:
Pain medicines, including opioids
Nerve blocks and transcutaneous electric nerve stimulation (TENS), which provide pain relief
NCI Lymphedema
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ASCO Lymphedema
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Medicines for Lymphedema:
Your doctor may prescribe antibiotics to treat infections or drugs to relieve pain when necessary.
ASCO Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia)
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Treating hand-foot syndrome
When taking medications known to cause hand-foot syndrome, topical anti-inflammatory medications may help. These include corticosteroid creams such as clobetasol (multiple brand names) or halobetasol (Ultravate). In addition, your doctor may lower your chemotherapy dose or change your chemotherapy schedule. Your doctor may need to temporarily stop your chemotherapy until the symptoms of hand-foot syndrome improve.
The following options can be used to treat hand-foot syndrome:
Topical pain relievers, such as lidocaine (Lidothesin, Lidoderm, Xylocaine, Xylocitin). These are used as a cream or a patch over painful areas in the palms and soles.
Topical moisturizing exfoliant creams are available, either over the counter or through your doctor. Those containing urea, salicylic acid, or ammonium lactate are most useful.
Pain relievers, such as ibuprofen (multiple brand names), naproxen (multiple brand names), and celecoxib (Celebrex).
Ice packs under the hands and feet while chemotherapy is being given to prevent hand-foot syndrome from paclitaxel, docetaxel, or doxorubicin.
Nonhormonal medications
• Blood pressure–lowering medication. Prescription medications such as clonidine (0.05 mg twice daily or 0.1 mg patch once weekly) modify how blood vessels respond to the body’s instruction to release heat quickly.
• Antidepressants. The selective serotonin reuptake inhibitors (SSRIs) Brisdelle (paroxetine; 7.5 mg/d), fluoxetine (20 mg/d), or venlafaxine (37.5-75 mg/d) are options.
• Antiseizure drugs. Gabapentin (300 mg, 3 times daily) is another nonhormonal option for treating hot flashes.
• Laboratory hallmarks of TLS:
High potassium,
High uric acid,
High phosphorous,
Low calcium
• Symptoms of TLS:
Nausea and vomiting, shortness of breath, irregular heartbeat, clouding of urine, lethargy, and/or joint discomfort.
• TLS features:
Consider TLS prophylaxis for patients with the following risk factors:
◊Histologies of Burkitt lymphoma and lymphoblastic lymphoma; occasionally DLBCL,
◊Spontaneous TLS,
◊Elevated WBC
◊Bone marrow involvement
◊Pre-existing elevated uric acid,
◊Ineffectiveness/intolerance of allopurinol,
◊Renal disease or renal involvement by tumor.
• Treatment of TLS:
TLS is best managed if anticipated and treatment is started prior to chemotherapy.
Centerpiece of treatment includes:
◊Vigorous hydration
◊Management of hyperuricemia
◊Frequent monitoring of electrolytes and aggressive correction (essential)
First-line and at retreatment for hyperuricemia
◊Allopurinol or febuxostat if intolerant to allopurinol beginning 2–3 days prior to chemotherapy and continued for 10–14 days
or
Rasburicase (doses of 3 to 6 mg are usually effective. One dose of rasburicase is frequently adequate. Re-dosing should be individualized) is indicated for patients with any of the following risk factors:
- Urgent need to initiate therapy in a high-bulk patient
- Situations where adequate hydration may be difficult or impossible
- Acute renal failure
(Note: There are data to support that fixed-dose rasburicase is very effective in adult patients.
One dose of rasburicase is frequently adequate.)
If TLS is untreated, its progression may cause acute kidney failure, cardiac arrhythmias, seizures, loss of muscle control, and death.
Department of Clinical Haematology, Oxford University Hospitals (Mar 6, 2016)
British Committee for Standards in Haematology (15 April 2015)
HIGH RISK
• Aggressive lymphoma/leukemia (defined by REAL)
DLBCL,
Anaplastic large cell lymphoma,
Peripheral T-cell lymphomas,
Burkitt lymphoma,
Lymphoblastic lymphoma,
CLL
• AML
• Elevated plasma uric acid levels (>7.5 mg/dL) at baseline
• High-grade MDS with >10% bone marrow blast involvement
• CML in blast crisis
INTERMEDIATE (POTENTIAL) RISK
• Aggressive lymphoma/leukemia, not limited to the REAL definition, with LDH ≥2x the upper limit of normal
• Any stage III to IV lymphoma or leukemia
• Stage I or II disease with bulky lymph node/tumor (>5 cm) involvement
Tumor lysis syndrome refers to the constellation of metabolic disturbances that occurs when large numbers of neoplastic cells are killed rapidly, leading to the release of intracellular ions and metabolic byproducts into the systemic circulation. Clinically, the syndrome is characterized by rapid development of hyperuricemia,hyperkalemia, hyperphosphatemia, hypocalcemia, and acute kidney injury.
Tumor lysis syndrome arises most commonly after the start of initial chemotherapeutic treatment, but spontaneous cases have increasingly been documented in patients with high-grade hematologic malignancies.
Although tumor lysis syndrome has been reported with virtually every type of tumor, it is typically associated with bulky, rapidly proliferating, treatment-responsive tumors —typically, acute leukemias and high-grade non-Hodgkin lymphomas such as Burkitt lymphoma. The syndrome has also been reported with other hematologic malignancies and with solid tumors such as hepatoblastoma and stage IV neuroblastoma.
Because tumor lysis syndrome is potentially lethal, the main principles of management are identification of high-risk patients with initiation of preventive therapy and early recognition of metabolic and renal complications and the prompt administration of supportive care, including hemodialysis.
Blood Chemistry
High-risk patients should have laboratory monitoring (BUN, creatinine, phosphate, uric acid, and calcium levels) prior to therapy and for 48-72 hours after treatment induction. Follow measurements at least three times per day, or more often if evidence of tumor lysis syndrome develops. Lactate dehydrogenase should be checked at least on diagnosis and prior to treatment, as elevated values can reflect the potential for progressing to tumor lysis syndrome with the initiation of chemotherapy.
Most patients with tumor lysis syndrome have laboratory derangements in lactate dehydrogenase, potassium, phosphate, calcium, and uric acid, as well as abnormal renal functions, occurring 1-3 days after chemotherapy initiation. Hyperkalemia is often the first life-threatening abnormality.
Urine pH and output
If hyperuricemia develops, urine alkalinization prevents renal precipitation of uric acid but may increase the risk for nephrocalcinosis. If alkaline diuresis is employed, regular determinations of urine pH should guide the extent of therapy.
Because increased urine flow rates help to inhibit crystal deposition in renal tubules, close monitoring of urine output is necessary to assess adequacy of hydration. Monitoring urine output for signs of oliguric renal failure is also necessary
Cardiac monitoring
Frequent cardiac assessment (electrocardiography [ECG] or continuous cardiac monitoring) is necessary to monitor electrocardiographic changes, which may herald a lethal arrhythmia caused by potassium and calcium disturbances.
Histologic findings
Pathologic studies demonstrate deposits of uric acid within the distal renal tubule lumina, which cause intrarenal hydronephrosis. Uric acid crystals can also be seen within tubular epithelial cells and the medullary microcirculation. Uric acid precipitates may also occur in the renal pelvis and ureters, leading to hydronephrosis and acute renal failure from extrarenal sources.
The National Comprehensive Cancer Network advises that tumor lysis syndrome is best managed if it is anticipated and treatment is started before initiation of chemotherapy. Treatment centers on the following :
• Rigorous hydration
• Management of hyperuricemia
• Frequent monitoring of electrolytes and aggressive correction of abnormalities
The NCCN recommends allopurinol for first-line treatment and retreatment for hyperuricemia. Allopurinol is begun 2–3 days prior to chemotherapy and continued for 10–14 days
Alternatively, the NCCN recommends rasburicase when allopurinol is ineffective, and for patients with any of the following risk factors:
Presence of any high-risk feature
Urgent need to initiate therapy in a patient with high-bulk disease
Situations where adequate hydration may be difficult or impossible
Acute kidney injury
High-risk features for tumor lysis syndrome include the following :
Hematologic malignancies strongly associated with tumor lysis syndrome (eg, Burkitt lymphoma, lymphoblastic lymphoma, occasional cases of diffuse large B-cell lymphoma, chronic lymphocytic leukemia)
Spontaneous tumor lysis syndrome
Elevated white blood cell count
Bone marrow involvement
Pre-existing hyperuricemia
Renal disease or renal involvement by tumor
The NCCN notes that a single dose of 3–6 mg of rasburicase is frequently adequate. Redosing should be individualized.
British guidelines include the following recommendations for prevention of tumor lysis syndrome :
Patients due to receive chemotherapy for any hematological malignancy should be assessed for risk of tumor lysis syndrome
Low-risk patients can be managed with careful monitoring of fluid status and laboratory results, with a low threshold for recourse to intravenous fluids and consideration of allopurinol therapy
Intermediate-risk patients should be offered up to 7 days of allopurinol prophylaxis, along with increased hydration once cancer treatment is initiated, or until risk of tumor lysis syndrome has resolved
High-risk patients should be offered prophylaxis with rasburicase, along with increased hydration
In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, do not use rasburicase; treat such patients with fluids and allopurinol and monitor them carefully
Urinary alkalinization is not recommended for tumor lysis syndrome prophylaxis
Guideline recommendations on the use of rasburicase for prevention are listed below :
Most high-risk adults can be treated with a single fixed dose of 3 mg rasburicase, but this must be followed by careful monitoring of clinical and biochemical parameters, with repeat dosing if required
Most high-risk children can be treated with a single dose of 0.2 mg/kg rasburicase, followed by close laboratory and clinical monitoring; use of a fixed dose of 3 mg seems reasonable, but cannot be firmly recommended on the basis of current evidence
The addition of allopurinol is unnecessary and has the potential to reduce the effectiveness of rasburicase
Urate assays taken while patients are receiving rasburicase must be sent to the laboratory on ice, to prevent falsely low assay results
Diet
Patients who are not restricted to a nothing-by-mouth diet could theoretically benefit from restriction of intake of foods that contain high levels of potassium, phosphorus, or uric acid.
Surveillance
Patients at high risk and those with evidence of tumor lysis syndrome should have the following levels monitored at least three times daily:
Blood urea nitrogen (BUN),
Creatinine,
Uric acid,
Potassium,
Calcium,
Phosphate,
Lactate dehydrogenase (LDH)
Monitoring should continue for the first 48-72 hours after chemotherapy initiation. Some patients may need to be placed on dialysis prior to the initiation of therapy.
Hydration
Volume depletion is a major risk factor for tumor lysis syndrome and must be corrected vigorously. Aggressive IV hydration not only helps to correct electrolyte disturbances by diluting extracellular fluid, it also increases intravascular volume. Increased volume enhances renal blood flow, glomerular filtration rate, and urine volume to decrease the concentration of solutes in the distal nephron and medullary microcirculation.
Ideally, IV hydration in high-risk patients should begin 24-48 hours prior to initiation of cancer therapy and continue for 48-72 hours after completion of chemotherapy.
Continuous infusion rates as high as 4-5 L daily (or 3 L/m2 daily), yielding urine volumes of at least 3 L daily, should be given unless the patient's cardiovascular status indicates impending volume overload.
Diuresis
The use of furosemide or mannitol for osmotic diuresis has not proven to be beneficial as front-line therapy. In fact, these modalities may contribute to uric acid or calcium phosphate precipitation in renal tubules in a volume-contracted patient.
Diuretics should be reserved for well-hydrated patients with insufficient diuresis, and furosemide alone should be considered for the normovolemic patient with hyperkalemia or for the patient with evidence of fluid overload.
Urinary alkalinization
The use of isotonic sodium bicarbonate solutions intravenously to promote alkaline diuresis has the potential benefit of solubilizing, and thus minimizing, intratubular precipitation of uric acid. The goal is to increase urinary pH to 7.0 to maximize uric acid solubility in renal tubules and vessels.
Drawbacks to systemic alkaline therapy include magnification of clinical hypocalcemia by shifting ionized calcium to its nonionized form. An increased likelihood of calcium phosphate precipitation in renal tubules is an additional drawback. For these reasons, routine urine alkalinization is controversial, and if it is employed, it must include close monitoring of urinary pH, serum bicarbonate, and uric acid levels to guide therapy and avoid overzealous alkalinization. Consider withdrawing sodium bicarbonate from IV fluid solutions once serum bicarbonate levels reach 30 mEq/L, urinary pH exceeds 7.5, or serum uric acid levels have normalized.
If urinary alkalinization is not achieved with exogenous bicarbonate solutions despite increasing serum bicarbonate levels, IV acetazolamide at doses of 250-500 mg daily (5 mg/kg daily) may be added to decrease proximal tubule bicarbonate reabsorption, thereby increasing urinary pH.
Treatment of Hyperkalemia
Aggressively treat and monitor hyperkalemia. Immediately restrict dietary potassium and remove potassium from IV fluids. Acute treatment modalities include IV infusion of glucose plus insulin to promote redistribution of potassium from the extracellular to the intracellular space, and IV calcium gluconate as cardioprotection for potassium levels greater than 6.5 mmol/L or for patients with electrocardiographic alterations.
IV hydration with alkaline fluid can also increase intracellular uptake of potassium. Potassium-wasting diuretics may be employed with caution since these may worsen renal precipitation in the volume-contracted patient. Long-term therapy, such as oral potassium-exchange resins, should be given immediately because of the transient effectiveness of acute treatment modalities. If these measures fail to control serum potassium, dialysis should be initiated promptly.
Treatment of Hyperphosphatemia and Hypocalcemia
Hyperphosphatemia is managed with oral phosphate binders and the same solution of glucose plus insulin used for the control of hyperkalemia. Hyperphosphatemia may lead to hypocalcemia, which usually resolves as phosphate levels are corrected.
In some cases, depressed serum 1,25-dihydroxycholecalciferol levels contribute to hypocalcemia, and administration of calcitriol may correct calcium levels. Such therapy, however, should not be undertaken until serum phosphate levels have normalized to avoid metastatic calcium phosphate calcifications. As a rule, do not correct hypocalcemia unless evidence of neuromuscular irritability exists, as indicated by a positive Chvostek or Trousseau sign.
Dialysis
If the previously described therapies for the complications of tumor lysis syndrome fail, consider early initiation of dialysis. Dialysis prevents irreversible renal failure and other life-threatening complications. Indications for dialysis include persistent hyperkalemia or hyperphosphatemia despite treatment, volume overload, uremia, symptomatic hypocalcemia, and hyperuricemia.
Hemodialysis is preferred over peritoneal dialysis because of better phosphate and uric acid clearance rates. Continuous hemofiltration also has been used and is effective in correcting electrolyte abnormalities and fluid overload.
Because hyperkalemia can recur after dialysis is initiated and because of the high phosphate burden in some patients with tumor lysis syndrome, electrolyte levels must be monitored frequently and dialysis repeated as needed.
Allopurinol
Allopurinol is a xanthine oxidase inhibitor; it is administered to reduce the conversion of nucleic acid byproducts to uric acid in order to prevent urate nephropathy and subsequent oliguric renal failure. It is usually given orally at 600 mg daily for prophylaxis and 600-900 mg daily (up to a maximum of 500 mg/m2 daily) for treatment of tumor lysis syndrome. Patients unable to take oral medications can be given IV allopurinol.
Adverse effects include mild-to-severe rash, xanthine stone-induced urolithiasis, acute interstitial nephritis, pneumopathy, fever, and eosinophilia.
Moreover, the inhibition of uric acid synthesis promotes an increase of xanthine in plasma and the renal system; although reported to be rare, xanthine has the capacity to precipitate in the renal tubules.
Dose reduction is necessary in renal insufficiency or if the medication is given concomitantly with mercaptopurine, 6-thioguanine, or azathioprine (since allopurinol interferes with the metabolism of these agents).
Febuxostat
Febuxostat (Uloric) is a novel xanthine oxidase inhibitor that does not appear to have the hypersensitivity profile of allopurinol. In addition, this agent does not require dosing modification for renal impairment. Initial studies suggested that febuxostat is effective and safe for preventing tumor lysis syndrome.
The Febuxostat for Tumor Lysis Syndrome Prevention in Hematologic Malignancies (FLORENCE) trial found that febuxostat provided better control of serum uric acid compared with allopurinol, with comparable renal function preservation and safety profile. In FLORENCE, 346 patients with hematologic malignancies at intermediate to high risk for tumor lysis syndrome were randomized to receive 120 mg of febuxostat or 200-600 mg of allopurinol daily, starting 2 days before induction chemotherapy, for 7-9 days. Mean area under curve for serum uric acid was was 514.0 ± 225.71 mg h/dL for febuxostat versus 708.0 ± 234.42 mg h/dL for allopurinol (P< 0.0001).
In a Japanese phase III trial comparing febuxostat with allopurinol for prevention of thyperuricemia in 100 patients with malignant tumors receiving chemotherapy, febuxostat was no-inferior to allopurinol. No differences in safety outcomes with the either medication was noted.
Febuxostat is much more expensive than allopurinol. However, in patients with renal impairment or hypersensitivity to allopurinol, febuxostat may be a reasonable choice for prophylaxis of tumor lysis syndrome, pending the publication of further clinical trial results.
Rasburicase
Rasburicase (recombinant urate oxidase) can be used when uric acid levels cannot be lowered sufficiently by standard approaches. Rasburicase is useful in cases of hyperuricemia and has been shown to be safe and effective in both pediatric and adult patients. It also has a more rapid onset of action than allopurinol.
Humans do not express urate oxidase, which catalyses the conversion of poorly soluble uric acid to soluble allantoin. By converting uric acid to water-soluble metabolites, urate oxidase effectively decreases plasma and urinary uric acid levels.
Unlike allopurinol, uricase does not increase excretion of xanthine and other purine metabolites; therefore, it does not increase tubule crystallization of these compounds.
Rasburicase is administered by intramuscular injection or IV infusion at dosages ranging from 50-100 U/kg daily. It is contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency and pregnancy.
In G6PD deficiency, excess hydrogen peroxide accumulates as rasburicase breaks down uric acid and accelerates catabolism of its precursors xanthine and hypoxanthine; this accumulation places patients at risk for hemolytic anemia and methemoglobinemias. Some authorities recommend screening for G6PD deficiency prior to administration of the drug.
In addition, because humans do not express urate oxidase, rasburicase can potentially elicit an immune response.
Rasburicase is approved by the US Food and Drug Administration (FDA) for the initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and hyperuricemia. Rasburicase is indicated only for a single course of treatment. A study by Nauffal in 92 adult patients wtih tumor lysis syndrome found that uric acid levels normalized in 95% of patients after a single 6-mg dose of rasburicase.
Uricosuric Recombinant Enzyme
Recombinant form of urate oxidase that catalyzes the breakdown of uric acid to allantoin
Used in the initial treatment of hyperuricemia in patients with leukemia, lymphoma, or solid tumors who are receiving anticancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid
Hemolysis and methemoglobinemia have been reported; do not administer rasburicase in patients with glucose-6 phosphate dehydrogenase (G6PD) deficiency
WARNING: HYPERSENSITIVITY REACTIONS, HEMOLYSIS, METHEMOGLOBINEMIA, AND INTERFERENCE WITH URIC ACID MEASUREMENTS
Hypersensitivity Reactions: ELITEK can cause serious and fatal hypersensitivity reactions including anaphylaxis. Immediately and permanently discontinue ELITEK in patients who experience a serious hypersensitivity reaction.
Hemolysis: Do not administer ELITEK to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Immediately and permanently discontinue ELITEK in patients developing hemolysis. Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting ELITEK.
Methemoglobinemia: ELITEK can result in methemoglobinemia in some patients. Immediately and permanently discontinue ELITEK in patients developing methemoglobinemia.
Interference with Uric Acid Measurements: ELITEK enzymatically degrades uric acid in blood samples left at room temperature. Collect blood samples in pre-chilled tubes containing heparin and immediately immerse and maintain sample in an ice water bath. Assay plasma samples within 4 hours of collection.
SUPPLIED: Elitek Intravenous Inj Pwd F/Sol: 1.5mg, 7.5mg
For the prevention and treatment of hyperuricemia in patients with leukemia, lymphoma, or solid tumors who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.
NOTE: The FDA has designated rasburicase as an orphan drug for the treatment of malignancy-associated or chemotherapy-induced hyperuricemia.
Weight-based dosing for the initial management of plasma uric acid levels.
Intravenous dosage
0.2 mg/kg IV over 30 minutes once daily for up to 5 days.
In a clinical trial, the first rasburicase dose was given 4 to 24 hours prior to the first cycle of chemotherapy and IV hydration (4 to 5 liters per day) was begun 24 to 48 hours before the initiation of chemotherapy.
The primary endpoint of uric acid response rate (defined as the percentage of patients achieving or maintaining plasma uric acid concentration of 7.5 mg/dL during days 3 to 7) was significantly higher with single-agent rasburicase compared with single-agent allopurinol (87% vs. 66%; p = 0.001) in adult patients with active leukemia or lymphoma at high risk for hyperuricemia and tumor lysis syndrome (TLS) following anti-cancer therapy in a multicenter, randomized (1:1:1), 3-arm, parallel-group, phase III trial (n = 275).
Sequential therapy with rasburicase and allopurinol did not significantly improve the response rate compared with single-agent allopurinol (78% vs. 66%; p = 0.06). All treatment failures (11%) occurred in the single-agent allopurinol arm. Single-agent rasburicase resulted in significantly fewer laboratory assessed TLS cases (defined as changes in 2 or more laboratory values indicating TLS within 7 days of cytotoxic chemotherapy) compared with single-agent allopurinol (21% vs. 41%; p < 0.05). The median time to plasma uric acid control (from baseline) was 4 hours, 4 hours, and 27 hours in the single-agent rasburicase, sequential treatment, and single-agent allopurinol arms, respectively. Treatment consisted of rasburicase 0.2 mg/kg IV once daily for 5 days (n = 92); rasburicase 0.2 mg/kg IV once daily on days 1, 2, and 3 and allopurinol 300 mg PO once daily on days 3, 4, and 5 (n = 92); and allopurinol 300 mg PO once daily for 5 days (n = 91). Patients with relapsed or refractory leukemia or lymphoma, a history of asthma or severe or life-threatening atopic allergy, and glucose-6-phosphate dehydrogenase (G6PD) deficiency were excluded from this trial.
(Note: There are data to support that fixed-dose rasburicase is very effective in adult patients.
One dose of rasburicase is frequently adequate.)
Fixed-dose therapy†.
Intravenous dosage
3 mg and 6 mg (range, 1.5 to 7.5 mg) IV were the most frequently evaluated fixed doses of rasburicase in retrospective studies; most patients required only 1 fixed dose to achieve normalized uric acid levels. A single, 7.5-mg fixed dose of rasburicase was evaluated in a small, prospective, case-controlled study. Most patients in this study received additional supportive care measures to prevent tumor lysis syndrome such as allopurinol and/or alkalinization.
SUPPLIED
Allopurinol/Allopurinol Sodium/Aloprim Intravenous Inj Pwd F/Sol: 500mg
Allopurinol/Zyloprim Oral Tab: 100mg, 300mg
For the prevention of acute hyperuricemia during chemotherapy or radiation treatment of leukemia, lymphoma, or solid tumors that may cause tumor lysis syndrome.
NOTE: The correct dose and frequency of dosage for maintaining the serum uric acid concentration within the normal range are best determined by using the serum uric acid concentration as an index. Allopurinol is not recommended for the treatment of asymptomatic hyperuricemia. Discontinue allopurinol when the potential for overproduction of uric acid is no longer present.
Intravenous dosage
NOTE: Allopurinol sodium for injection is only indicated for patients who cannot tolerate oral therapy.
200—400 mg/m2/day IV as a single dose or in equally divided infusions at 6-, 8-, or 12-hour intervals. Start treatment 24—48 hours prior to the start of chemotherapy, when possible. Doses > 600 mg/day IV do not seem to be more effective than lower doses.
Oral dosage
600—800 mg PO per day in 2—3 divided doses for 2—3 days along with a high fluid intake.
Renal Impairment
NOTE: The correct dose and frequency of dosage for maintaining the serum uric acid concentration within the normal range are best determined by using the serum uric acid level as an index. Allopurinol is not recommended for the treatment of asymptomatic hyperuricemia. Serious toxicity may occur, especially in patients with impaired renal function (see Adverse Events).
CrCl 121-140 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 400 mg/day PO or IV has also been suggested.
CrCl 101-120 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 350 mg/day PO or IV has also been suggested.
CrCl 81-100 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 300 mg/day PO or IV has also been suggested.
CrCl 61-80 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 250 mg/day PO or IV has also been suggested.
CrCl 41-60 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 200 mg/day PO or IV has also been suggested.
CrCl 21-40 ml/min: No specific dosage adjustments are recommended by the manufacturer ; 150 mg/day PO or IV has also been suggested.
CrCl 10—20 ml/min: According to the manufacturer, 200 mg/day PO or IV; 100 mg/day PO or IV has also been suggested.
CrCl 3—9 ml/min: According to the manufacturer, 100 mg/day PO or IV; 100 mg PO or IV every other day has also been suggested.
CrCl < 3 ml/min: According to the manufacturer, 100 mg PO or IV q24 hours or longer; 100 mg PO or IV every third day has also been suggested.
BOXED WARNING
Cardiac disease, mortality, myocardial infarction, stroke
Use with caution in patients with a history of stroke or myocardial infarction, preexisting cardiac disease, or other cardiac risk factors. Limit the use of febuxostat to patients who are not treated effectively or experience severe adverse effects from allopurinol. A large safety clinical trial showed an increased risk of cardiovascular death and all-cause mortality with febuxostat use vs. allopurinol. Instruct patients to recognize the signs and symptoms of myocardial infarction and stroke, and to seek medical help immediately if they experience such symptoms. During a postmarketing safety study that compared patients treated with febuxostat or allopurinol (n = 6,190), febuxostat use was associated with an increased risk of cardiovascular death (15 deaths per 1,000 patients vs. 11 deaths per 1,000 patients treated for 1 year; hazard ratio 1.34 [95% CI 1.03 to 1.73]) and all-cause mortality (26 deaths per 1,000 patients vs. 22 deaths per 1,000 patients treated for 1 year; hazard ratio 1.22 [95% CI 1.01 to 1.47]) versus allopurinol. All-cause mortality was primarily driven by cardiovascular events. The primary endpoint was a composite of major adverse cardiovascular events (MACE): cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina with urgent revascularization. Febuxostat was not significantly different from allopurinol in outcomes related to the composite primary endpoint (hazard ratio 1.03 [95% CI 0.89 to 1.21]); it was when each outcome was analyzed separately that significant differences were noted.
Hepatic disease
Use febuxostat with caution in patients with severe hepatic disease (Child-Pugh Class C) and in patients with elevated transaminase concentrations. Fatal and non-fatal hepatic failure as well as increases in transaminase concentrations above the upper limit of normal (ULN), specifically AST and ALT, have been observed. No relationship between the incidence of transaminase elevations and febuxostat dose was identified. Obtain liver function tests (ALT, AST, alkaline phosphatase, and total bilirubin) prior to febuxostat initiation. After the initiation of febuxostat therapy, liver-function testing is recommended at 2 months, 4 months, and periodically thereafter. Liver function should be assessed immediately in patients with symptoms suggestive of liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. If abnormal liver function is detected (ALT more than 3 times the ULN), interrupt febuxostat therapy to determine probable cause; do not restart febuxostat in these patients without an alternative explanation for abnormal liver function. Patients with ALT more than 3 times the ULN and bilirubin more than 2 times the ULN with no alternative explanations may experience severe drug-induced liver injury and should not be restarted on febuxostat. Febuxostat may be restarted with caution in patients with lower elevations of ALT or bilirubin with alternative probable cause.
Renal impairment
Use febuxostat with caution in patients with severe renal impairment (CrCl less than 30 mL/minute); dose adjustments are required. In a study of febuxostat in patients with varying degrees of renal function, the renal elimination of febuxostat and metabolites was inversely related to the degree of renal impairment. Further, a statistically significant linear relationship was identified between measured creatinine clearance and febuxostat AUC (unbound), and between measured creatinine clearance and febuxostat half-life. Plasma uric acid concentrations decreased and adverse events occurred at similar rates regardless of renal impairment. Febuxostat has not been studied in patients receiving dialysis.
Hepatitis B virus (HBV):
• Hepatitis B surface antigen (HBsAg) and Hepatitis B core antibody (HBcAb) testing for all patients receiving anti-CD20 antibody therapy
Quantitative hepatitis B viral load by PCR and surface antibody only if one of the screening tests is positive
• Note: Patients receiving IV immunoglobulin (IVIG) may be HBcAb-positive as a consequence of IVIG therapy.
• Prophylactic antiviral therapy with entecavir is recommended for any patient who is HBsAg-positive and receiving anti-lymphoma therapy. If there is active disease (PCR+), it is considered treatment/ management and not prophylactic therapy. In cases of HBcAb positivity, prophylactic antiviral therapy is preferred; however, if there is a concurrent high-level hepatitis B surface antibody, these patients may be monitored with serial hepatitis B viral load.
Entecavir is preferred based on Huang YH, et al. J Clin Oncol 2013;31:2765-2772; Huang H et al. JAMA 2014;312:2521-2530.
Avoid lamivudine due to risks of resistance development.
Other antivirals including adefovir, telbivudine, and tenofovir are proven active treatments and are acceptable alternatives.
Monitor hepatitis B viral load with PCR monthly through treatment and every 3 months thereafter.
◊If viral load is consistently undetectable, treatment is considered prophylactic.
◊If viral load fails to drop or previously undetectable PCR becomes positive, consult hepatologist and discontinue anti-CD20 antibody therapy.
Maintain prophylaxis up to 12 mo after oncologic treatment ends
◊Consult with hepatologist for duration of therapy in patient with active HBV.
Hepatitis C virus (HCV):
• New evidence from large epidemiology studies, molecular biology research, and clinical observation supports an association of HCV and B-cell NHL. Recently approved direct-acting antiviral agents (DAA) for chronic carriers of HCV with genotype 1 demonstrated a high rate of sustained viral responses.
Low-grade B-cell NHL◊According to the American Association for the Study of Liver Diseases, combined therapy with DAA should be considered in asymptomatic patients with HCV genotype 1 since this therapy can result in regression of lymphoma.
Aggressive B-cell NHL◊Patients should be initially treated with chemoimmunotherapy regimens according to NCCN Guidelines for NHL.◊Liver functional tests and serum HCV RNA levels should be closely monitored during and after chemoimmunotherapy for development of hepatotoxicity. ◊Antiviral therapy should be considered in patients in complete remission after completion of lymphoma therapy.
Progressive multifocal leukoencephalopathy (PML):
• Caused by the JC virus and is usually fatal.
Diagnosis made by PCR of CSF and in some cases brain biopsy.
• No known effective treatment.
• Clinical indications may include changes in behavior such as confusion, dizziness or loss of balance, difficulty talking or walking, and vision problems.
• Rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis can occur. Expert consultation with dermatology is recommended.
• Re-challenge with the same monoclonal antibody is not recommended in patients experiencing rare complications to chosen anti-CD20 monoclonal antibody (rituximab, obinutuzumab, or ofatumumab). An alternative anti-CD20 monoclonal antibody (obinutuzumab or ofatumumab) could be used for patients with intolerance to rituximab, regardless of histology. It is unclear that the use of alternative anti-CD20 monoclonal antibody poses the same risk of recurrence.
Rituximab Rapid Infusion
• If no infusion reactions were experienced with prior cycle of rituximab, a rapid infusion over 90 minutes can be used.
Rituximab-Related Neutropenia
• Usually delayed in onset weeks to months after last exposure
• Occurs in up to 10% of patients
• Can be severe, but usually not presenting with infections
• Can be initially observed for spontaneous recovery, but if prolonged a short course of G-CSF is indicated
• IVIG has been anecdotally successful in patients refractory to G-CSF
Renal Dysfunction Associated with Methotrexate
• Consider use of glucarpidase if significant renal dysfunction and methotrexate levels are >10 microM beyond 42 to 48 hours. Leucovorin remains a component in the treatment of methotrexate toxicity and should be continued for at least 2 days following glucarpidase administration. However, be aware that leucovorin is a substrate for glucarpidase, and therefore should not be administered within two hours prior to or following glucarpidase.
Immunizations
• See NCCN Guidelines for Survivorship - General Principles of Immunizations.