Chemotherapy-Induced Neutropenia and the AIM Higher Initiative

Chemotherapy-Induced Neutropenia and the AIM Higher Initiative

A Report from the 2005 Congress of the Oncology Nursing SocietyApril 28 May 1, 2005Orlando, FloridaJenny Maxon, RN, OncoEd Staff Writer

The role of the oncology nurse as the point of care between patients and physicians is gaining importance in the oncology setting, particularly in the realm of preventing or treating side effects of therapy. As healthcare providers are being placed under a greater patient-load burden, the efficiency with which side effects are handled is a crucial element to providing optimal healthcare. Many such side effects that once plagued oncology patients-forcing suboptimal delivery of therapy and drastically reducing quality of life-can now be prevented or managed with supportive care measures.

At the Oncology Nursing Societys 30th Annual Congress, held in Orlando, Fla., April 28 May 1, 2005, the Assessment-Information-Management (AIM) Higher initiative was presented as a tool for nurses to use in the clinical setting. The goal of the initiative is to implement risk assessment models, flow charts for early intervention and tracking of progress or patientreported side effects. The notion of a healthcare team, in which information for every patient is easily accessible for all levels of healthcare providers, as well as implementation of efficient, consistent and standardized information gathering and early intervention were topics of much discussion during the 2005 ONS meeting.

Through the gathering of results from peer-reviewed, published data, as well as documented trends of patients within each medical institution, the oncology nurse may present facts as well as solutions to physicians and other nurses with whom they work in order to proactively manage side effects. Whats more, encouraging patients to provide healthcare workers with feedback on their treatments and diseases is an important component in the prevention and early intervention of side effects.


The management of hematologic toxicities, such as neutropenia, is gaining more attention in the field of oncology as evidence indicates that a proactive, preventive approach or early aggressive intervention of toxicities may ultimately alter the delivery of care in the oncology patient. The active prevention of neutropenia is strongly associated with the successful delivery of optimal therapeutic doses of chemotherapy, as well as with the ability to administer dose-dense therapies when appropriate. Both result in better patient outcomes, improved quality of life, efficient time management for patients and caregivers, and a reduction in financial burden for both patients and the medical system.

Chemotherapy-induced neutropenia (CIN) remains one of the most common side effects caused by chemotherapy and can quickly develop into a life-threatening situation in patients undergoing treatment for cancer. It is associated with infection, hospitalization, intravenous antibiotics and antifungals, delay in chemotherapy cycles, reduction of chemotherapy doses, increased medical costs and a reduced quality of life. Fortunately, clinical management of CIN has progressed tremendously since the 1990s, prior to which the only option for managing CIN was the reduction or delay of chemotherapy doses.

Today, colony stimulating factors (CSFs) such as Neulasta® (pegfilgrastim) and Neupogen® (filgrastim) can prevent or drastically reduce the severity of CIN and allow physicians to administer optimal therapeutic doses of chemotherapy on time to patients who would otherwise be at a high risk of CIN. However, since not all patients are at risk for developing CIN, the delivery of CSFs to all cancer patients undergoing therapy would place an unreasonable financial burden on the medical system. Therefore, the current challenge in the prevention and reduction of CIN is to establish a standard for the selective use of CSFs in appropriate patients.

CIN Prophylaxis

It is imperative that healthcare providers are able to identify patients at risk for developing CIN prior to initiation of treatment, thereby allowing them to proactively deliver prophylaxis with CSFs. By applying risk assessment models and practice guidelines to identify patients at high-risk for CIN, it may be possible to achieve improved overall survival for patients suffering from cancer, as more patients will receive the optimal delivery of chemotherapy. Furthermore, the ever-growing addition of combination chemotherapy or dose-dense regimens that result in improved outcomes for patients with various types of cancer is being utilized in the clinical setting. With these newer treatment options comes an increased risk of CIN.

First-Cycle Growth Factor Use

The incidence of chemotherapy-induced neutropenic events is greatest during the first cycle of chemotherapy. Results from a prospective nationwide study including more than 4,000 patients indicated that neutropenic events occurred at a higher frequency in the first cycle of chemotherapy than during the three subsequent cycles combined.


Vogel et al. also recently conducted a clinical trial to evaluate first cycle administration of Neulasta in women with breast cancer who were treated with single-agent Taxotere® (docetaxel).

[2]This phase III clinical trial included 928 patients who were randomly allocated to receive placebo or Neulasta on the day after chemotherapy. Both groups were well-balanced, with about 60% having metastatic disease in both arms and two-thirds having prior chemotherapy. The median age of patients was 52.

The incidence of grade 3 / 4 neutropenia was highest in the first cycle, approaching 80%, and remained in the 40-50% range for subsequent cycles. In cycles 2-4, there was a 6% febrile neutropenia rate in the placebo arm, compared to <1% in the Neulasta arm. Febrile neutropenia also occurred most commonly in cycle 1, where 11% of patients in the placebo arm experienced FN, compared to <1% in the Neulasta arm. Overall, the incidence of FN was 17% in the control group and 1% in the Neulasta group, which translates into a 94% reduction. Febrile neutropenia-related hospitalizations were reduced from 14% to 1% and IV anti-infective use was reduced from 10% to 2%, which represents 93% and 80% reduction, respectively.

These results indicate that the risk of developing neutropenic events, including febrile neutropenia, is highest during the first cycle of chemotherapy, underscoring the importance of prophylactic CSFs in first and subsequent cycles for high-risk patients.

Risk Assessment Models

Risk assessment models will ultimately guide healthcare providers in providing appropriate prophylaxis regimens for neutropenia.

According to the American Society of Clinical Oncology (ASCO), specific factors known to increase the risk of a patient developing CIN include the following:


  • Pre-existing neutropenia
  • History of febrile neutropenia
  • Open wounds
  • Active infection
  • Advanced age
  • Decreased immune function
  • Prior chemotherapy or radiation therapy
  • Co-morbid conditions
  • Specific chemotherapy agents associated with a high degree of myelosuppression

Specific patient populations at high risk for developing CIN include the following:

  • Early-stage breast cancer: patients receiving adjuvant chemotherapy with an absolute neutrophil count (ANC) < 500 in the first cycle (first-cycle ANC nadir risk model)

  • Non-Hodgkins lymphoma (NHL): patients receiving CHOP (cyclophosphamide, doxorubicin, Oncovin®, and prednisone) with a pre-treatment serum albumin < 3.5g/dL or tumor involvement of bone marrow, and patients with a lactate dehydrogenase levels >1x the normal level have a 72.2% risk of developing febrile neutropenia (FN) during the first cycle of chemotherapy. Patients with a low serum albumin alone or with a normal serum albumin and either elevated LDH or tumor involvement of bone marrow are at an intermediate risk of developing FN.

  • For patients over 70 receiving CHOP or other chemotherapy regimen of similar dose intensity, the NCCN Senior Adult Care Task Force and ASCO recommend routine prophylactic growth factor administration initiated in first cycle.


The 2005 National Comprehensive Cancer Network (NCCN) guidelines regarding myeloid growth factor support has recommended that patients with a 20% or greater risk of developing febrile neutropenia should receive GCSF prophylaxis on the first and subsequent cycles of chemotherapy (Table 1).


Early intervention for patients who develop CIN, but have no identifiable factors that lead to prophylaxis against CIN in the first treatment cycle is also important in reducing hospitalization or allowing for delivery of subsequent cycles with optimal dose intensity. For example, Rivera et al. conducted a study in which the first-cycle absolute neutrophil count (ANC) nadir assessment tool was utilized in patients receiving adjuvant therapy for breast cancer.

[8]Patients whose nadir falls below 500 ANC during the first cycle of treatment are considered to be at a high risk of developing CIN. According to the model, high-risk patients should receive prophylactic CSFs in all subsequent cycles of treatment and low-risk patients should receive CSFs if a neutropenic event occurs. In the Rivera study, breast cancer patients managed with the first-cycle ANC nadir risk model had a 2.7% rate of hospitalization due to febrile neutropenia (FN), compared to 7.1% of patients not managed with the risk model. Furthermore, only 4.7% of patients managed with the risk model did not receive at least 85% of planned doses on time, compared to 20% of patients not managed with the risk model.

Elderly and CIN

The majority of patients with non-Hodgkins lymphoma (NHL) are 55 years or older, and, as the population ages, treatment of elderly patients will become more common. Elderly patients provide a unique set of challenges for healthcare providers, which include a reduced tolerance to chemotherapy and a greater susceptibility to the development of CIN as their stem cell reserves tend to be lower than those of their younger counterparts.

Clinical trials have demonstrated that the prophylactic use of CSFs initiated during the first cycle of chemotherapy allows elderly patients to safely tolerate full dose intensity. As mentioned previously, ASCO and the NCCN Senior Adult Care Task Force guidelines call for prophylactic CSFs initiated during the first cycle of dose-intense regimens for patients over 70.

In a study by Gomez, et al., it was demonstrated that most treatment-related deaths in the elderly occur during the first cycle of CHOP chemotherapy, with 83% of events caused by infection.

[9]According to these results, prophylaxis for CIN at initiation of chemotherapy may allow patients to tolerate optimal chemotherapy doses, which may ultimately result in improved survival in the patients over the age of 70 receiving CHOP regimens or other regimens that cause similar myelosuppression. Clinical studies are ongoing to specifically evaluate the incidence of neutropenia in the elderly population and to use this information to develop customized risk assessment models.

Timing of CSF Use

Treatment with CSFs should be implemented according to a risk assessment model, or if a patient has already developed severe CIN as defined by an ANC < 500 or a low, persistent ANC that results in treatment delays or dose reductions.

[10]Patients who already have full-blown CIN can begin CSF treatment immediately, while patients who are considered high-risk should be given CSFs 24 to 48 hours after the completion of chemotherapy through the time of expected nadir for that chemotherapy regimen and on all subsequent cycles. The time to initiate treatment with CSFs is not at the time of nadir, as this leaves patients exposed to FN and infection. CSF use 24 to 48 hours following chemotherapy begins the maturation process of neutrophils so that acceptable levels of mature neutrophils are already in circulation at the time of expected nadir.

Neulasta is a long-acting version of Neupogen and requires only one fixed-dose 6 mg injection per chemotherapy cycle, compared to weight-based, daily doses of Neupogen in the management of CIN. Neulasta is self-regulating in that its structural modifications minimize renal excretion, which forces the drug back into circulation until cleared by neutrophils. Results from clinical studies have recently indicated that Neulasta is not only more convenient, but just as effective or possibly superior to Neupogen at preventing or reducing the severity of neutropenia.




It is extremely important to consider the convenience and ease of one-time dosing with Neulasta, as the time of both the patient and the healthcare provider spent in dealing with CIN plays a part in overwhelming time demands on oncology staff and detracts from quality of life for patients. The results of a recent study evaluating patient time and CIN indicated that the average time for a laboratory visit was over 2 hours, an average visit for oral antibiotics was nearly 2.5 hours, an average visit for intravenous antibiotics was over 3 hours, a visit to manage neutropenia was approximately 2 hours, and neutropenia-related hospitalization was 6.34 days.

[14]Often, patients have to disrupt their day, as well as a caretakers day, for transportation, a waiting period prior to their appointment, and a waiting period following their appointment for management of CIN. Neulasta given just once per chemotherapy cycle may circumvent a large portion of these inconveniences.

In summary, prevention of CIN with CSFs in high-risk patients has long-reaching consequences, including a reduced financial and time management burden on the medical system and oncology staff, a reduction in the risk of severe infection, hospitalization and even death caused by CIN, and an increased rate of adherence to prescribed dose on time aministration of chemotherapy regimens as patients are able to better tolerate increased cumulative doses of therapy. Furthermore, prophylactic, preventive CSF use can allow patients to maintain a more normal life with reduced time commitments to clinical visits, reduced caretaker commitments, and finally, an improvement in quality of life as infection rates are reduced.

Risk-assessment models utilized prior to initiation of therapy, as well as increased communication between patients and healthcare providers, will be key in providing optimal management of CIN through prophylactic CSF use, with the ultimate hope that CIN will become a rare side effect experienced by cancer patients undergoing therapy.

AIM Higher Initiative

As the prevention or reduction of neutropenia and/or anemia has become a reality for oncology patients, the creation of a system to provide this care to all high-risk patients with efficiency must be implemented, as the majority of healthcare institutions treating oncology patients do not yet have these systems effectively in place. Oncology nurses are in an optimal position to deliver symptom prevention or intervention within the healthcare system, as they spend extended amounts of time with patients, provide interface between patients and physicians, and are knowledgeable of symptom management. However, organizational challenges exist which create hurdles to the implementation of an effective system within the realm of supportive care. However, through planning and gathering of evidenced-based data, the ultimate goal of a proactive approach in the prevention of side effects may be obtained and routinely utilized within each oncology practice.

The AIM Higher initiative is a program for oncology nurses to strategically implement an efficient tool in the institution in which they work for the prevention and early intervention of side effects. It was designed to improve assessment, information provision, and management of five key chemotherapy-related symptoms: anemia, neutropenia, nausea/vomiting, diarrhea/constipation, and depression/anxiety. Prompting of the AIM Higher initiative was the realization that lack of uniformity exists within healthcare facilities with regard to patient assessment, patient teaching and symptom management.

[15]A recent study including 15 community oncology centers that evaluated assessment, information provision and symptom management indicated the following:


  • Lack of standardized risk assessments and symptoms
  • Inconsistent or no standardized process for ongoing assessment of symptoms
  • Insufficient severity assessment of symptoms
  • Inadequate documentation of assessment

Information Provision

  • Inadequate communication processes among the oncology team
  • Lack of established process for pre-chemotherapy teaching for new patients
  • Inconsistent teaching processes for existing patients
  • Inadequate processes for providing consistent, standardized materials (materials unavailable, multiple suppliers of materials)
  • Little or no documentation of patients teaching and level of understanding


  • Few guidelines exist for symptom management
  • Inconsistent use of existing guidelines (lack of integration into clinical care, lack of unity among oncology team)
  • Lack of documentation (lack of patient progress along pathway, lack of easy to follow plan of care)
  • Non-existent or sporadic referral systems for patient issues

With the lack of standardized and easy to use guidelines, prevention or early intervention of side effects is difficult to attain within an oncology practice. The AIM Higher initiative was designed to provide a systematic approach to assessment, information provision and symptom management of the patient that can be used by oncology nurses and physicians.

The initiative has three main steps:

Practice Analysis

  • Establishes baseline
  • Informs practice teams
  • Generates motivation

Quality Improvement Plan

  • Establishes key goals and objectives
  • Defines and prioritizes action items
  • Fosters understanding and collaboration


  • Strategic start date and milestones
  • Gradual phase in of action items
  • Begins constant improvement process

The implementation of change within the workplace begins with evidence-based data. Collection of evidence from peer-reviewed data, as well as trends from within the healthcare facility in which the oncology nurse works should be presented in a scheduled meeting to a physician(s) and other nurses. Both the identified problem and solution should be well documented. In addition to evidence-based data, a definitive plan for change involving all aspects of the healthcare team must be created. Within the AIM Higher initiative, key components to bringing about change include the following:

  • Champion model nurse, physician, practice administrator who will act as lead role in the process
  • Resources training, networking, SOS e-Tablet Patients Information System
  • Program evaluation IRB-approved protocol detailing procedures for analysis and implementation of Assessment, Information, and Management processes

The patient also plays an integral role in the AIM Higher initiative. E-Tablets, or computer-type questionnaires, are completed by the patient prior to each visit. In addition to answering specific questions, patients are also able to voice concerns or questions of their own on the e-Tablet. E-Tablets allow nurses and physicians to assess areas of concern of each patient prior to the actual visit, so that time with healthcare providers may be focused. In addition, patients are prompted to assess their own situation with detailed questions. E-Tablets maximize the opportunity during medical visits to touch base on all realms of supportive care, and minimize the potential that patients or physicians will forget or leave out any important information. Through trends established with answers gathered from e-Tablet questionnaires, identification of side effects may be caught and treated early, and patients at high risk of developing a side effect may be identified and undergo appropriate prophylaxis.

While planning practice changes such as implementation of risk-assessment models, utilization of e-Tablets and proactive prophylaxis against side effects, oncology nurses must keep in mind that other staff members, clinical management or physicians may present barriers to the change. Issues such as staffing, reimbursement, financial feasibility (cost vs. benefit) and patient satisfaction must be addressed in the planning period, with a demonstration that the change makes sense from a business standpoint in addition to improving patient outcomes. Finally, once the practice change has been accepted and implemented within the healthcare facility, evaluation of the new system should occur through either formal or informal studies.


The oncology nurse is in a unique position to bring about change within the workplace, particularly in the management of side effects caused by treatment for cancer. With the highly effective growth factors Neulasta and Aranesp providing prophylaxis and intervention in chemotherapy-induced neutropenia or anemia, an efficient and proactive approach to preventing these side effects can be implemented in every medical clinic that treats oncology patients. Through the prevention of chemotherapy-induced neutropenia or anemia, optimal doses of therapy may be delivered, patient hospitalization and medical costs may be reduced, and quality of life of patients may be improved. The utilization of the AIM Higher initiative may provide a tool for change in the implementation of nurse-oriented prevention or management of side effects, or may provide a sample from which to initiate change.


[1]Crawford J, Wolff DA, Culakova E, et al. First cycle risk of severe and febrile neutropenia in cancer patients receiving systemic chemotherapy: results from a prospective nationwide study. Program and Abstracts of the 46th Annual Meeting of the American Society of Hematology. San Diego, Calif. 2004; Abstract #2210.

[2]Vogel CL, Wojtukiewicz MZ, Carroll RR, 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. Journal of Clinical Oncology. 2005;23:1178-1184.

[3]American Society of Clinical Oncology Guidelines. 2000:3563.

[4]Silber J, Fridman M, DiPaola R, et al. First-cycle blood counts and subsequent neutropenia, dose reduction, or delay in early-stage breast cancer therapy. Journal of Clinical Oncology. 1998;16:2392-2400.

[5]Intragumtornchai T, Sutheesophon J, Sutcharitchan P, Swasdikul D. A predictive and febrile neutropenia after the first course of CHOP chemotherapy in patients with aggressive non-Hodgkins lymphoma. Leukemia and Lymphoma. 2000;37:351-360.

[6]Balducci L, Yates J. General guidelines for the management of older patients with cancer. Oncology. 2000;14:221-227.

[7]National Comprehensive Cancer Network. Oncology Practice Guidelines: Myeloid Growth Factors. Available at: Accessed July 2005


[8]Rivera E, Erder M, Fridman M, et al. Delivering full planned dose on time (PDOT) chemotherapy (CT) while lowering the incidence of febrile neutropenia (FN) hospitalizations; initial results from a prospective study (N=528) providing filgrastim support to high risk breast cancer patients (BCP). Breast Cancer Research and Treatment. 2001;69:209.< /SPAN>

[9]Gomez H, Hidalgo M, Casanova Z, et al. Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkins lymphoma: results of a multivariate analysis. Journal of Clinical Oncology. 1998;16:2065-2069.

[10]Kristin Fessele. Oncology nursing practice: advancing the role in managing hematologic toxicities. Proceedings of the 29th Annual Congress of the Oncology Nursing Society. Anaheim, Calif. 2004.

[11]Bedell C. Pegfilgrastim was observed to be as safe and effective as filgrastim in elderly patients with breast cancer. Proceedings of the 2003 Annual Congress of the Oncology Nursing Society. Abstract #102.

[12]Green M, Koelbl H, Baselga J. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Annals of Oncology. 2003:14:29-35.

[13]Bosi A, Szer J, Kassis J, et al. A multicentre, double-blind, randomized, phase 2 trial comparing pegfilgrastim with filgrastim as an adjunct to chemotherapy for acute myeloid leukemia (AML). Proceedings from the 46th Annual Meeting of the American Society of Hematology (ASH). December 2004. Abstract # 866.

[14]Tauer K. Advances in supportive care management: new models and data that impact a multidisciplinary approach. Proceedings from the 29th Annual Congress of the Oncology Nursing Society. Anaheim, Calif. 2004.

[15]Kelley Moore. AIM Higher: a landmark initiative to assessment, information, and management of patient symptoms. Proceedings of the 30th Annual Congress of the Oncology Nursing Society. Orlando, Fla. 2005. Presented Sunday, May 1, 2005.