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Published on 9 June 2010

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Management of myelosuppression in cancer patients

teaser

Lynne Eldridge
MD
University of Minnesota
Minneapolis
The New York Times
About.com
New York USA

New generation chemotherapy agents have the potential to cause problems with the production of blood cells we are not yet aware of so, pharmacists will play a critical role in patient care as he/she monitors and balances these issues

Myelosuppression, a reduction in blood cells produced by the bone marrow, is common in cancer patients and can have a tremendous physical, emotional and financial impact. Symptoms of fatigue, the development of infections and bleeding can seriously affect quality of life. Dose reductions and treatment delays may affect treatment response and long-term survival, and healthcare costs related to complications of myelosuppression place a significant burden on society.

Myelosuppression most commonly occurs as a side-effect of cancer treatments such as chemotherapy, but can be related to other conditions associated with cancer as well. Several pharmaceutical agents are now available to assist in the management of myelosuppression, and more are being evaluated in clinical trials that have the potential to reduce the risk of cancer treatments. That said, an awareness of the symptoms of anaemia, neutropenia and thrombocytopenia, potential complications related to these diagnoses, and conservative management modalities should remain at the forefront in our clinical repertoire.

Management of anaemia

Anaemia is defined as a deficiency in the number of red blood cells or haemoglobin circulating in the body, resulting in a diminished ability of the blood to carry oxygen to the tissues. A diagnosis of anaemia is made when the haemoglobin falls below 13.5g/dl in men, and 12g/dl for women. Anaemia can further be classified as:

  • Mild-a haemoglobin of 10-11g/dl.
  • Moderate- a haemoglobin of 8-10g/dl.
  • Severe- haemoglobin less than 8g/dl.

During cancer treatment, anaemia may occur for several reasons including:

  • The cytotoxic effect of chemotherapy on the bone marrow.
  • Bleeding following surgery for cancer.
  • Renal insufficiency.
  • The cancer itself (anaemia of chronic disease).
  • Nutritional deficiencies related to the metabolic effects of cancer, as well as side-effects from chemotherapy such as mouth sores, nausea and taste changes.

Symptoms of anaemia are usually noted when the haemoglobin level falls below 11g/dl and may include:

  • Fatigue (one of the most annoying symptoms of cancer).
  • Shortness of breath.
  • Tachycardia.
  • Pale skin.
  • Lightheadedness and dizziness.
  • Chest pain.

In patients with underlying cardiac disease, anaemia can be very serious as it adds to an already compromised perfusion state. Anaemia is also considered a poor prognostic factor in cancer survival.

Management of anaemia may be broken down into conservative management, replacement via transfusion, iron supplementation and the use of pharmaceuticals to stimulate formation of new red blood cells.

Conservative management
Educating patients about their condition can go a long way in managing mild anaemia. This may include a discussion about coping with fatigue, and advice on living with anaemia, such as standing up slowly to prevent falls. Adequate sleep and drinking plenty of fluids can be helpful, whereas beverages containing caffeine and alcohol can exacerbate symptoms.

Transfusions
The most rapid method to improve anaemia, especially anaemia that is severe, is with transfusions of packed red blood cells. Side-effects may include fever and chills and transfusion of blood products carries the risk of a transfusion reaction or transmission of infectious diseases.

Iron supplementation
Both oral and IV iron supplementation may be considered to improve anaemia. Because iron supplementation functions at the level of formation of blood cells, it may take several weeks to restore a normal haemoglobin level after therapy. Oral supplements are best taken with an empty stomach, yet some people are unable to tolerate this due to abdominal discomfort. Milk and antacids can interfere with absorption as well. If oral supplementation is not tolerated, IV injections of iron may be used. Common side-effects include a metallic taste, flushing, myalgias and arthralgias, and the potential for allergic reactions.

Recombinant human erythropoietin erythopoiesis-stimulating agents (ESAs)
Erythropoietin is a hormone produced by the kidneys to stimulate formation of red blood cells. Recombinant human erythropoietin agents that are currently available include:

  • Epoetin alpha, EPO (Epogen, Procrit).
  • Darbepoetin alfa (Aranesp).

Serious side-effects of ESAs include high blood pressure and deep vein thrombosis. Some recent studies also suggest that they may increase cancer growth and lower overall survival.[1]

For this reason, ESMO has published recommendations on when these agents should be considered. They are not recommended unless a patient is being treated with chemotherapy and should be used with caution if chemotherapy has the potential of being curative. ESAs may be considered for individuals undergoing palliative chemotherapy with a haemoglobin of less than 10 (with a goal of increasing haemoglobin to less than 12), or with a haemoglobin of 10 to 12 accompanied by symptoms (off-label use).[2] An improvement in haemoglobin following treatment is usually noted after two weeks.

Management of neutropaenia
Neutropenia is defined as a decrease in the number of neutrophils circulating in the blood. Neutrophils are the form of white blood cells instrumental in eliminating pathogenic bacteria and fungi from the body. A normal white blood cell count (WBC) is in the range of 4,000 to 10,000 WBCs/mm[3]. A normal absolute neutrophil count (ANC) is in the range of 2,000 to 6,000 neutrophils/mm[3]. Neutropenia can be classified as:

  • Mild- ANC of 1000 to 1500 -associated with minimal risk of infection.
  • Moderate-ANC of 500-1000 -associated with a moderate risk of infection.
  • Severe-ANC less than 500-associated with a high risk of contracting an infection.

Neutropenia occurs in roughly half of cancer patients, most commonly as a side effect of the cytotoxic effect of chemotherapy on the bone marrow. Other causes may include radiation therapy, sequestration of neutrophils in the spleen with hypersplenism, infiltration of the bone marrow (in haematologic malignancies), nutritional deficiencies (such as B12 and folic acid) and several viral and bacterial infections which may be present in the patient with cancer.

There are no symptoms of neutropenia per se. Symptoms to watch for include those related to subsequent infections that develop, and may include:

  •    Fever.
  •    Chills.
  •    Haematuria or pain with urination (UTI).
  •    Back pain (kidney infection).
  •    Cough or shortness of breath (pneumonia).
  •    Redness, swelling or discharge around an incision, IV    site or chemotherapy port.

Management of neutropenia
The main goals in managing neutropenia, are to prevent infection, close monitoring to allow for early detection of infections and aggressive management of infections when they occur. Neutrophil counts are usually lowest- reach their nadir- approximately 7 to 14 days following chemotherapy.

Conservative management
Primary prevention of infections in the neutropenic patient is of outmost importance. In no other area of oncology practice is the cliche “an ounce of prevention is worth a pound of cure” more applicable. Education of the cancer patient should include:

  • Careful hand washing (despite being fairly obvious, studies suggest a large percentage of patients do not understand the importance).
  • Avoiding large crowds.
  • Minimising contact with individuals known to have an infection.
  • Avoiding contact with people who have recently been vaccinated with live viruses.
  • Making food choices to minimise risk, such as avoiding raw eggs and undercooked meat, fish, or seafood.
  • Practicing good skin hygiene and minimising the risk of bacterial entry by using an electric razor, not trimming cuticles and with women, using sanitary napkins rather than tampons.

Medical management
Antibiotics
Antibiotics may be used prophylactically, or therapeutically after an infection occurs. With severe neutropenia, hospitalisation with broad spectrum antibiotics is often recommended when an infection occurs.

White blood cell growth factors (haematopoietic colony stimulating actors)
Growth factors may be used to stimulate formation of neutrophils in the bone marrow. When they are prescribed, they are usually given as an injection 24 hours following a round of chemotherapy and in that setting, may reduce the chance that a patient will be hospitalised for febrile neutropenia. Febrile neutropenia is defined as an axillary temperature of greater than 38.5 C that is present for more than one hour, along with an ANC of less than 500.

Because these agents are quite costly in addition to carrying potential side-effects, The European Society for Medical Oncology (ESMO) has devised clinical recommendations on when they should be used. According to ESMO, prophylactic use should be limited to patients in whom the risk of febrile neutropenia is greater than 20%, special circumstances are present, or if a chemotherapy dose reduction or delay would be detrimental to outcome. Special circumstances
they cite include a diagnosis of HIV, or when chemotherapy is given as a potentially curative therapy (rather than palliative). For treatment, the use of these agents should be considered in settings of increased morbidity and mortality, such as sepsis, prolonged neutropenia and tissue infections.[3]

White blood cell stimulating agents currently available include:

  • Filgrastim (Neupogen) – granulocyte stimulating factor.
  • Pegfilgrastim (Neulasta) – PEGylated granulocyte colony-stimulating factor.
  • Sargramostim (Leukine, Prokine) – granulocyte macrophage colony-stimulating factor.

Side-effects most commonly experienced by patients treated with white blood cell growth factors include bone pain, fever, malaise and the burden of multiple injections.

Management of thrombocytopenia
Thrombocytopenia is defined as a decreased level of platelets circulating in the blood. A normal platelet count is the range of 150,000 to 400,000 platelets/mm[3]. Thrombocytopaenia is diagnosed when the platelet level falls below 150,000/mm[3], although significant bleeding does not usually occur unless the level is below 20,000/mm[3]. Degrees of thrombocytopenia as classified by the US National Cancer Institute are:

  • Grade 1 – platelet count greater than 75,000.
  • Grade 2 – 50,000-75,000.
  • Grade 3 – 10,000-50,000.
  • Grade 4 – less than 10,000.

Thrombocytopenia may occur as a side-effect of chemotherapy, due to bleeding, or occur due to coexisting conditions that can result in thrombocytopenia. The incidence of thrombocytopenia during cancer treatment is expected to increase, as new chemotherapy agents are introduced which have a propensity to cause thrombocytopenia. An example of these is the newer tyrosine kinase inhibitors.

Symptoms of thrombocytopenia may include:

  • Easy bruising.
  • Petechiae.
  • Bleeding.
  • Heavy menstrual periods.
  • Nosebleeds.
  • Arthralgias and myalgias.
  • Headaches.

Management of thrombocytopenia
Conservative Management
Management of thrombocytopenia begins with educating patients about how to lower their risk of bleeding. Patients should be instructed to avoid activities that may predispose them to injury, such as contact sports. The use of gentle toothbrushes, electric razors and careful attention to bowel care to prevent constipation are helpful. It is also wise to discuss other medications that can increase the risk of bleeding such as aspirin, NSAIDS and herbal supplements that have been associated with an increased risk of bleeding.

Medical management
Platelet transfusions
Platelet transfusions may be used prophylactically for thrombocytopenia following chemotherapy, or therapeutically, if bleeding complications occur. The most common side-effect is a fever. As with red blood cell transfusions, platelet transfusions carry the rare risk of transfusion reactions or transmission of infectious diseases.

Thrombopoietic Agents
Oprelevkin (interleukin-11, Neumega), is currently approved for the prevention of chemotherapy-induced thrombocytopenia. Though oprelevkin has a narrow therapeutic index, the most common side-effect of this medication is fluid retention.  Several other platelet stimulating agents are being evaluated in clinical trials, with few side-effects other than a mild headache.[3]

Peripheral Blood Stem Cells
Some cancer centres have begun to combine stem cells obtained from peripheral blood with oprelevkin or other platelet stimulating agents, to assess their effectiveness when used along with high-dose intensive chemotherapy.

The future of myelosuppression management
Just as new agents are being developed to manage cancer-related myelosuppression, new generation chemotherapy agents have the potential to cause problems with the production of blood cells we are not yet aware of. The pharmacist of today will play a critical role in patient care as he/she monitors and balances these issues.

References
1. Scrijvers, D, F Roila. Annals of Oncology 2009;20(Suppl 4):iv159-iv161.
2. Bohlius J, et al. Cochrane Database of Systematic Reviews (Online). 2009;3:CD007303.
3. Crawford J, et al. Annals of Oncology 2009;20(Suppl 4):iv162-iv165.
4. Vadhan-Raj S. Seminars in Hematology 2009;46(1 Suppl 2):S26-32.



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