Conquering Chemotherapy-How advances in the management of neutropenia have led to advances in curative therapy.

By Maria G. Essig, MS, ELS

If you were to ask the average person—even the most health conscious of your friends—what their neutrophil count is, chances are you would get a blank stare. But as a cancer patient receiving chemotherapy treatment, you might be all too aware of not only what neutrophils are, but what your count is and what that means in relation to your treatment.  This is because you probably know that neutrophils are the body’s first line of defense against infection.  And cancer patients receiving chemotherapy must have adequate numbers of these cells in order to safely receive chemotherapy and keep their treatment on track.

Each day, the bone marrow of a healthy adult produces 60 billion (60,000,000,000,000!) neutrophils, a type of white blood cell that attacks bacteria and fungi entering the body. The neutrophils are produced in the bone marrow and released regularly into circulation. Together with red blood cells and platelets, these three basic blood cell types comprise your blood supply. Neutrophils live only a short time?within six to eight hours they either surround and destroy infectious bacteria and are eliminated from the body or are broken down naturally.

The rapid production of neutrophils is normally advantageous, but for patients receiving chemotherapy, the normal production process is thrown off course. This is because chemotherapy destroys rapidly dividing cells, a characteristic of cancer cells and blood producing bone marrow cells. As the number of neutrophils decreases, the risk of serious infection increases.  When the loss of neutrophils is significant, the result is neutropenia.

Fortunately, chemotherapy-induced neutropenia can be prevented in most patients with the use of Neulasta® (pegfilgrastim) or Neupogen® (filgrastim)—blood cell growth factors that increase white blood cell production. Blood cell growth factors are naturally occurring substances called cytokines that regulate certain critical functions in the body. They are responsible for stimulating cells in the bone marrow to produce more white blood cells.

Diagnosing Neutropenia

A blood count is a measurement of the number of blood cells an individual has in circulation, based on laboratory evaluation of a blood sample. You should have billions of these blood cells circulating throughout your body. However, certain circumstances may cause you to have fewer cells than is considered normal, a condition called “low blood counts.” The laboratory test that is conducted to measure the number of blood cells is called a “complete blood count,” or CBC, and is typically performed immediately before and 7-10 days after each chemotherapy treatment.

Doctors diagnose neutropenia by evaluating the CBC and determining the absolute neutrophil count (ANC). The ANC reflects the number of immature and mature neutrophils. The average number of neutrophils in a liter (just over one quart) of blood is close to 4 billion, although people of African descent generally have lower levels. Most doctors define mild neutropenia as neutrophil levels from 1000 to 1500 neutrophils per milliliter (one-thousandth of a liter; also called a cubic centimeter) of blood. Moderate neutropenia is generally defined as 500 to 1000 neutrophils per milliliter. Severe neutropenia exists when neutrophil levels drop below 500 cells per milliliter.

Dangers of Neutropenia

Patients receiving chemotherapy who develop neutropenia are affected in several ways.  First, neutropenia increases a patient’s risk of fever and infection. The loss of front-line protection opens the body to infection by the numerous bacteria living on the skin or in the gastrointestinal tract. However, because the body’s immune system has been compromised and cannot launch a full-scale attack, frequently the first and only symptom of an infection is a fever. Neutropenia that results in a fever is called febrile neutropenia, and it must be treated immediately to prevent the infection from spreading throughout the bloodstream–a serious condition known as septicemia, which can lead to organ failure.

In addition to the direct dangers posed by neutropenia, the condition can also prompt doctors to alter a patient’s chemotherapy treatment.   When the absolute neutrophil count drops below 1000 doctors may elect to reduce the dose of chemotherapy or delay its administration in order to avoid worsening the neutropenia. This need to alter the chemotherapy treatment can compromise the success of the treatment in patients who don’t receive their chemotherapy according to the planned dose at the appropriate time.  Research results released in 1995 revealed that breast cancer patients who receive at least 85 percent of scheduled chemotherapy treatments experience a higher survival rate than those who miss more treatment sessions. Similarly, people with non-Hodgkin’s lymphoma who undergo at least 75 percent of planned treatments face increased survival odds.   In short, when neutropenia necessitates a reduction in the planned dose and schedule of chemotherapy treatment, the chance for the best outcome from treatment is reduced. 

Dose Dense Therapy

Not only can reducing the dose of chemotherapy prevent cancer patients from having the best chance of survival, but increasing the dose and frequency of chemotherapy administration appears to increase survival in some patients.  Chemotherapy regimens have historically been administered every three weeks. More frequent administration was precluded by the frequent development of neutropenia and its accompanying complications.  However, recent therapeutic advances in the treatment of neutropenia have resulted in the emergence of dose-dense chemotherapy as a more viable treatment option.

Dose dense chemotherapy refers to chemotherapy treatment that is administered as frequently as possible with the goal of delivering the greatest amount of chemotherapy over the shortest period of time, thereby delivering the maximum amount of chemotherapy drug to the cancer. Dose-dense treatment is given every two weeks rather than at the conventional three-week interval.

Researchers have reported that patients with early stage breast cancer who are treated with dose-dense chemotherapy live longer without cancer recurrence than patients treated with conventional chemotherapy.  Doctors designed a clinical study to determine whether dose dense chemotherapy could improve outcomes in women with breast cancer.  Women were treated with standard chemotherapy drugs administered either every three weeks (conventional treatment), or every two weeks (dose-dense).  Because of the risk of neutropenia, all patients treated with the dose dense therapy were also treated with Neupogen®, a white blood cell growth factor that increases production of neutrophils. Four years after completing treatment, 82 percent of patients treated with dose-dense therapy survived without cancer recurrence, compared to only 75 percent of those treated with the conventional three week chemotherapy regimen.

Although the use of dose dense chemotherapy is increasing rapidly, less than 50 percent of women with early stage breast cancer are currently treated in this manner, despite the evidence that a dose dense regimen reduces the risk of cancer recurrence and improves survival.  Market research conducted in March 2005 with 200 medical oncologists found that only 47 percent of early stage breast cancer patients with node positive disease, and less than five percent of patients with node negative cancer, were treated with dose dense chemotherapy. 

Dangers posed by neutropenia are also greater for elderly adults, malnourished individuals and patients undergoing multiple therapies (such as chemotherapy combined with steroids). The risks increase with each cycle of chemotherapy. Thus, neutropenia occurring in an early round of therapy is likely to return in subsequent cycles. And this complication cannot be taken lightly. One out of five cancer patients who develop febrile neutropenia experience consequences, such as infections that require intravenous antibiotic delivery in the hospital. Depending on the type of cancer, the mortality rate resulting from neutropenia in cancer patients ranges from 4 to 30 percent.

Prevention and Treatment of Neutropenia

When it comes to neutropenia, an ounce of prevention is worth a pound of cure. A major goal of cancer therapy is to maintain a healthy level of neutrophils in order to prevent neutropenia and the threat of infection, which, in turn, will allow the delivery of chemotherapy to fight the cancer at the full dose according to the treatment plan.  The blood cell growth factors Neulasta® (pegfilgrastim) or Neupogen® (filgrastim) can be administered to stimulate the bone marrow to increase neutrophil production.

Both Neupogen® and Neulasta® are blood cell growth factors approved by the Food and Drug Administration for the prevention of chemotherapy-induced neutropenia . Neupogen® has been studied extensively and used for the treatment of chemotherapy-induced neutropenia since 1991. Neulasta® which requires less frequent administration than Neupogen®   was approved by the FDA in 2002. Neulasta® helps the bone marrow create more neutrophils, which are crucial to the body’s ability to fight infection. With acceptable neutrophil counts, patients are also more likely to stay on their chemotherapy schedule as originally planned.

Multiple clinical trials have shown that Neulasta® and Neupogen® reduce the severity and duration of neutropenia associated with many kinds of chemotherapy regimens. By reducing the duration and severity of neutropenia, Neupogen® has been shown to decrease a patient’s risk of fever and admission to the hospital for treatment of neutropenic fever. The drawback of Neupogen®, however, is that it must be administered daily. In an effort to address the daily dose requirements of Neupogen®, researchers developed Neulasta®. Neulasta® may be administered as a single dose for each chemotherapy cycle. In two clinical trials, a single dose of Neulasta® has been proven to be as effective as an average of 11 daily injections of Neupogen® for the management of neutropenia.[1] [2] The most common side effect you may experience with Neulasta® is aching in the bones and muscles. If this happens, it can usually be relieved with a non-aspirin pain reliever, such as acetaminophen. It is also possible to have an allergic reaction to Neulasta®.

Use of Neupogen® and Neulasta® has also been shown to increase the likelihood that patients will receive their chemotherapy according to the treatment plan. Neulasta® is generally well tolerated, with minimal side effects. Approximately one of four patients treated will experience some mild aching or discomfort in their bones. Symptoms persist only while being used and can typically be treated with non-narcotic analgesic medicines.  Given the option, most patients would prefer to take steps to help protect themselves against infection caused by neutropenia, rather than deal with the problems cause by an infection after it develops. However, on average, fewer than 10% of patients receive protection from infection at the beginning of their chemotherapy.[3] Yet up to half of patients receiving chemotherapy develop dangerously low white blood cell counts, potentially placing them at risk of life-threatening infections.[4]  

Most Recent Clinical Trial Results

The American Society of Clinical Oncology (ASCO) recommends the use of colony-stimulating factors to prevent neutropenia for therapies carrying a high risk of neutropenia. However, Charles L. Vogel, MD FACP, a breast medical oncologist and medical director of the Cancer Research Network, in Plantation, Florida, believes that these drugs could benefit many other patients who did not qualify under the ASCO guidelines.

“Even a 20 percent rate of neutropenia results in hospitalization in a large percentage of [cancer] patients?that’s still too high,” says Dr. Vogel. So he assembled a team of researchers from the United States, Poland, Russia and Mexico to conduct a phase III clinical trial involving 928 women with breast cancer being treated with Taxotere® (docetaxel). The treatment regimen carried only a 20 percent risk of neutropenia.

Researchers randomly assigned the women to receive either Neulasta® or a placebo on day two of the 21-day Taxotere® chemotherapy cycle. If a patient experienced a fever above 100.7°F, they received Neulasta® in each subsequent cycle of chemotherapy. The results were conclusive. Febrile neutropenia occurred in 1 percent of Neulasta® patients compared to 17 percent of patients receiving placebo. Fourteen percent of patients on placebo required hospitalization for neutropenia-related complications compared to 1 percent of patients receiving Neulasta®. Plus, placebo patients were five times more likely to require IV antibiotics for infection control than were patients receiving Neulasta® (10 percent versus 2 percent, respectively).

“It is a very important observation that Neulasta® can almost totally eliminate one of the most feared complications that we have [resulting from chemotherapy],” comments Dr. Vogel. “Febrile neutropenia can lead to death. Being able to reduce the rate of febrile neutropenia can reduce the risk of toxic death, and it will certainly reduce the number of hospitalizations.”

Dr. Vogel hopes these clinical trial results will persuade members of the American Society of Clinical Oncology to lower the guideline threshold for use of colony-stimulating factors in chemotherapy patients. “Too many people get hospitalized for febrile neutropenia,” Dr. Vogel emphasizes. “We now have a tool to use that can prevent that.”

The major side effect of the colony-stimulating factors is bone pain caused by pressure exerted by the growing neutrophils inside the bone marrow. For most patients bothered by this side effect, ibuprofen or acetaminophen usually takes care of the pain. For patients whose pain is not controlled by these pain relievers, narcotic drugs are available.

Conclusion

  • The development of drug therapies directed at preventing neutropenia—and thereby allowing patients to proceed with their prescribed chemotherapy—has allowed physicians to develop treatment regimens, like dose dense therapy, that actually increase a patients’ chances for a positive outcome.

Patient Actions to Prevent Infection

Most patients would prefer to prevent infection, rather than having to deal with its results. Your first line of defense should always be prevention. In addition to Neulasta®, other ways to avoid infection include these simple but effective steps:

Always wash your hands with soap and plenty of water. Many infections are transmitted through hands and things that you touch, such as doorknobs. Washing your hands thoroughly is the most important thing you can do to prevent infection.

Avoid people with colds or the flu.

Avoid large crowds, to reduce the likelihood of coming into contact with sick people.

Bathe daily and carefully dry your skin.

Take steps to prevent cuts or scrapes, as these provide entry points for infection:

Use an electric razor instead of a blade to avoid cuts.

Use caution with sharp objects.

Wear gloves when appropriate.

If you have a cut or scrape, keep it covered with a clean bandage until it heals.

Prevent cracks in your skin by using lotion.

Cook your food thoroughly to kill any potential microorganisms that may be on raw food.

References

Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvent cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up, N Engl J Med. 1995;332:901-906

Kwak, LW, Halpern J, Olshen RA, Horning SJ. Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: Results of a tree-structured survival analysis. J Clin Oncol. 1990;8:963-977

Citron ML, Berry DA, Cirrincione C, Hudis C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of intergroup trial C9741/Cancer and Leukemia Group B trial 9741. Journal of Clinical Oncology 2003;21:1431-9.

Shin DD, Godwin JE. Neutropenia [eMedicine Clinical Medicine Knowledge Base Web site]. February 7, 2002. Available at http://www.emedicine.com/med/topic1640.htm. Accessed April 20, 2005

Shin DD, Godwin JE. Neutropenia [eMedicine Clinical Medicine Knowledge Base Web site]. February 7, 2002. Available at http://www.emedicine.com/med/topic1640.htm. Accessed April 20, 2005

American Society of Clinical Oncology. Recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol. 1994;12:2471-2508

Vogel CL, Wojtukiewicz MZ, Carroll RR, Tjulandin SA, Barajas—Figueroa LJ, Wiens BL et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005; 23:1178-1184

Vogel CL, Wojtukiewicz MZ, Carroll RR, Tjulandin SA, Barajas—Figueroa LJ, Wiens BL et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: A multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol. 2005; 23:1178-1184

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