This year at the 28th annual congress of the Oncology Nursing Society, several aspects of chemotherapy induced neutropenia (CIN) were addressed. Much emphasis was placed on prevention and early intervention of neutropenia with assessment of patient risk factors and of a proactive approach utilizing growth factors. The impact of neutropenia on quality of life, financial burdens of neutropenia on the medical system and the integration of the long-acting growth factor Neulasta™ (pegfilgrastim) were topics discussed at the meeting.

Neutropenia

Neutropenia is the primary dose-limiting toxicity of myelosuppressive therapy. Neutropenia may lead to life-threatening infections and result in hospitalization, intravenous antibiotics or intravenous antifungals resulting in increased medical costs, a decreased quality of life and dose delays or reductions which may ultimately affect survival.

Preventing CIN through risk assessments and models

Neutropenia risk models in different cancers involving specific treatment regimens and particular patient characteristics are being developed so a proactive approach to the management of CIN may be adopted allowing for the safe delivery of optimal chemotherapy. Prophylaxis against neutropenia in all patients would not be feasible in terms of resource utilization, as this practice would place a significant financial burden on the medical system due to the use of colony stimulating factors (CSFs) in patients who might not develope neutropenia. Therefore, risk models may to determine prophylaxis in appropriate patient populations. ¹

Known risk factors for developing CIN : ²

• Prior febrile neutropenia
• Elderly
• Comorbid conditions
• Prior chemotherapy or radiation
• Decreased immune function
• Open wounds
• Active infection
• Certain chemotherapy agents with a high degree of myelosuppression being utilized in treatment regimen
• Preexisting neutropenia

• 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) ³
  
• Non-hodgkin’s lymphoma (NHL): patients receiving CHOP (cyclophosphamide, doxorubicin, Oncovin, and prednisone) with a pre-treatment serum albumin < 3.5gldL 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. ⁴ 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.
  
• Patients over 70 years 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 ⁵

Patients with these characteristics are considered high-risk for the development of CIN and prophylactic measures are clinically appropriate. For example, the first-cycle ANC nadir risk model designates a breast cancer patient to be at high risk for developing CIN if the ANC falls below 500 during the initial cycle of adjuvant treatment and at low risk if ANC levels remain at 500 or higher during the initial cycle. 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 study by Rivera et al., breast cancer patients managed with the first-cycle ANC nadir risk model had a 2.7% rate of hospitalization due to 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. ⁶

In another clinical study evaluating the use of the first-cycle ANC nadir risk model in early stage breast cancer, researchers from the Oncology Clinic and the Rocky Mountain Cancer Center in Colorado compared high-risk patients who received a prophylactic CSF in all cycles following the initial cycle, with low-risk patients who received a CSF only if they developed FN or CIN-related dose reductions. The patients in this study were also compared to a historical control group treated with similar chemotherapy regimens. The delivery of 85% of the planned dose on time (PDOT) has demonstrated optimal outcomes in early-stage breast cancer and the researchers in this study used this as a measurement of effectiveness. ⁷ 

In this study, 95% of the high-risk and low-risk patients received at least 85% of PDOT. Only 78.7% of patients in the historical group received at least 85% PDOT. Hospitalization and FN were higher in the high-risk patients compared to the low-risk patients; however, overall hospitalization and FN were significantly lower in the study group, compared to the historical group. Results from this trial present more evidence supporting the use of prophylactic CSFs in high-risk patients according to the first-cycle ANC nadir risk model. Utilizing models such as this, healthcare providers can proactively evaluate risk factors to determine which patients should receive a prophylactic CSF in order to receive optimal treatment. ⁷

CIN in Dose-Dense Regimens

The importance of proactively managing CIN has recently become even more relevant due to research that suggests dose-dense (shortened time between cycles) regimens significantly improve survival in some cancers. Dose-dense regimens typically cannot be administered without the support of CSFs.

Pfreundschuh, et al. conducted a clinical trial comparing dose-dense regimens to standard-dose regimens of CHOP and CHOEP (CHOP plus etoposide) in patients over 60 years of age with non-Hodgkin's lymphoma. The dose-dense regimens were supported with Neupogen® (filgrastim). The time to treatment failure and overall survival were both significantly improved in patients treated with dose-dense regimens, compared to patients treated with standard doses. The results from this trial indicate that elderly patients can tolerate dose-dense therapy when CSFs are routinely used and achieve the same survival benefit as their younger counterparts. ⁸

The latest published study by Citron, et al. (CALGB 9741) reported a 31% proportional reduction in mortality with dose-dense regimens compared with conventional doses in adjuvant therapy for breast cancer. Doxorubicin, paclitaxel and cyclophosphamide were either administered in combination or sequentially in conventional-dose regimens without CSFs unless neutropenia developed or dose-dense regimens supported with CSFs and were directly compared. At a median follow-up of 3 years, there was less grade 4 neutropenia in the dose-dense arms, compared to the conventional dose arms and no patient died of CIN complications. Disease-free survival was 82% in dose-dense arms, compared to 75% in conventional-dose arms. ⁹

These trials underscore the importance of prophylactic growth factors in allowing for more intense dosing which results in improved survival, even in elderly patients. Future clinical trials may evaluate dose-dense regimens in a variety of cancers, potentially impacting survival for a significant portion of patients.

CIN Adversely Affects Quality of Life

Little attention has been placed on the impact that CIN has on the quality of life of cancer patients. Researchers from Memphis recently conducted patient interviews to evaluate what aspects of quality of life are impacted by CIN. The 34 patients in this study were undergoing the first cycle of a 21-28 day regimen of myelosuppressive chemotherapy and were interviewed when ANC levels indicated grade IV neutropenia. The most common complaint was fatigue, described in terms of weakness, tiredness and exhaustion. Disruptions in daily routines and social isolation resulting from the management of infection and illness were also common. Psychological effects included sadness and anxiety due to cancer and its treatment, and reduced feelings of self worth as normal roles were unable to be fulfilled. These results suggest that CIN may impact a patient’s quality of life more than previously thought, further necessitating a need for prevention or early intervention of CIN. ¹⁰

As quality of life concerns due to CIN are capturing more attention, the development of tools to help understand and quantify these concerns will aid healthcare workers in the management of CIN. A new informational tool, referred to as the FACT-N (Functional Assessment of Cancer Therapy - Neutropenia), is likely to be incorporated into future clinical trials to evaluate the effects of CIN on the quality of life of cancer patients. It is the first neutropenia-specific quality of life tool that can be given to patients and will help to provide understanding and clinical direction for healthcare providers. ¹¹

Financial Burden of CIN

Besides impacting patient outcome and quality of life, CIN also places a considerable financial burden on the medical system. Researchers from the West Clinic in Memphis Tennessee have addressed the issue of economic impact by developing a model that evaluates several aspects of the management and care necessary for a patient with CIN. Within the community oncology clinics, many variables attribute to the financial stress of patients with CIN which are often overlooked. These variables which may seem trivial in scope can result in significant resource utilization over time.

The model developed includes the following items: "patient medical encounters (chemotherapy administration, nadir check, G-CSF treatment, etc.); practice medical events (phlebotomy, nurse triage, billing, etc.); medical tasks (specific, discrete behaviors of medical staff that constitute medical events such as patient teaching, hanging an IV antibiotic, marking the fee ticket, etc); and practice costs defined by dollar figures corresponding to the time expended by paid employees including physicians, nurses, technicians, and all supporting staff in performing medical tasks." The model is being used to assess the financial burdens associated with managing patients with CIN in community oncology settings. ¹²

Involving the Patient

It is necessary for patients to play a role in the early detection of CIN in order to prevent FN and the development of life-threatening infections. A patient’s role, however, is largely dependent upon the information they receive from oncology nurses or physicians. Consistent, standardized patient education may enable nurses to provide better care. Researchers from the Waukesha Memorial Hospital in Wisconsin issued a survey to 79 oncology patients to assess patient knowledge and understanding of CIN and to help guide the development of teaching strategies. Results from the survey indicated that the majority of patients had a thermometer, yet nearly one-third of patients did not know when to take their temperature. Sixty percent of patients did not know when to contact their physician or oncology nurse and 50% of patients did not know how to contact their physician after clinic hours. Approximately one-third of patients did not know the signs and symptoms of infection and 41% could not describe self-care measures.

These alarming results indicate the need for education for all patients being treated with chemotherapy and in particular those at high-risk for CIN. These researchers suggest implementing educational programs to all patients receiving chemotherapy. Education programs should include providing a thermometer, information and review on how and when to take temperatures, making refrigerator magnets with after-hours phone numbers and utilizing a tool for self-care following chemotherapy. Additional education may be necessary for patients at high-risk for CIN, including those with leukemia, lymphoma, sarcoma, undergoing stem cell transplantation, and a history of prior FN. These high-risk patients may benefit from additional information regarding when and why to be concerned about CIN, the length of risk, ways to reduce their risk, and what to do if signs and symptoms or fever or infection develop. The researchers have planned full implementation and follow-up assessment of this teaching tool in their institution to ensure patients are educated and to enhance a patient’s role in the prevention and early intervention of CIN. ¹³

Oncology centers may wish to adopt a standardized teaching tool to raise awareness of their role in the prevention or early intervention of CIN. To further address the issue of standardized teaching to patients about neutropenia, members of the Oncology Nursing Society (ONS) have formed an ONS Neutropenia Special Interest Group which began in 2000. This group is compiling data regarding neutropenia to develop standard guidelines to facilitate consistent teaching by oncology nurses to their patients. The intent of this group is to ultimately “establish a set of national evidence-based neutropenic precaution guidelines and patient/caregiver teaching strategies”. Members of the special interest group hope to soon gather data for all phases of the development of the guidelines and initiate implementation. ¹⁴

Elderly and Neutropenia

The majority of patients with non-Hodgkin's 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. Although elderly patients with NHL can achieve the same benefits with treatment as younger patients, some elderly patients are not offered the same treatment.

Clinical trials have demonstrated that the prophylactic use of CSFs initiated during the first cycle of chemotherapy allow elderly patients to safely tolerate full PDOT, providing optimal therapeutic benefit. 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 years of age. Future direction utilizing risk assessment models and prophylactic CSFs may allow a significant portion of elderly patients with NHL to be treated with the same regimens and dose intensity as younger patients, providing a potential for significant improvements in outcome. ¹⁵

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 the cause of 83% of events being infection. Prophylaxis for CIN at initiation of chemotherapy allows the delivery of optimal chemotherapy doses resulting in improved survival in the patients over the age of 70 receiving CHOP regimens or other dose intense regimens. Further clinical studies are ongoing to specifically evaluate the elderly population in regards to neutropenia and develop customized risk assessment models. ¹⁶

Neulasta™ (pegfilgrastim)

Both healthcare providers and patients are encouraged by results from recent clinical trials indicating that dose-dense regimens may lead to significantly improved survival in breast cancer and NHL, compared to standard dosing schedules. With dose-dense regimens, CSFs used before the first cycle and all subsequent cycles enhance support of neutrophil levels throughout treatment, allowing delivery of optimal therapeutic doses and ultimately impacting survival. Newer CSFs such as Neulasta™ (pegfilgrastim) that require one dose for each course of chemotherapy and are as effective as daily dosing regimens with Neupogen® (filgrastim) will allow for easier and more convenient prophylaxis of CIN.

Neulasta™, a pegylated, long-acting form of Neupogen® is given only once per chemotherapy cycle at a fixed dose. Less frequent dosing results in fewer injections and fewer office visits for patients. This also allows caregivers to spend less time scheduling appointments, giving patient care to treat CIN, and provides more time to attend to other patients and work-related activities.

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 been published indicating that Neulasta™ is not only more convenient, but just as effective or possibly superior to Neupogen® at preventing or reducing the severity of neutropenia. ¹

Researchers from U.S. Oncology retrospectively analyzed data collected from two clinical trials utilizing the chemotherapy combination of Taxotere® and doxorubicin with CSF support with Neupogen® or Neulasta™ in the treatment of patients with breast cancer. Without CSF support, 40% of patients typically develop FN with this chemotherapy combination. FN occurred in 10% and 18% of younger patients who received Neulasta™ and Neupogen®, respectively, and 15% and 22% of elderly patients who received Neulasta™ and Neupogen®, respectively. Hospitalizations and intravenous anti-infective use were both significantly lower in the group of patients who received Neulasta™ in all age groups, compared to those who received Neupogen®. Neulasta™ was well tolerated in all age groups. ¹⁷

In the treatment of aggressive and intermediate NHL, CHOP-R (CHOP plus Rituxan®) is the therapeutic regimen of choice. With data indicating superiority of dose-dense regimens in some cancers including dose-dense CHOP (14-day versus 21-day regimen), researchers from the Mid-Ohio Oncology/Hematology in Ohio evaluated the use of Neulasta™ in support of dose-dense CHOP-R. Eligibility included previously untreated intermediate or aggressive NHL or relapsed low-grade NHL. Rituxan® was given on day 1, CHOP on day 3 and Neulasta™ on day 4. Approximately 90% of treatment doses were given on time with no dose reductions and approximately 26% of patients developed FN. These results further support the effectiveness of Neulasta™ in dose-dense chemotherapy regimens. ¹⁸

Conclusion

The prevention and management of CIN is an important component in the treatment of a cancer patient. Since CIN can be a dose-limiting toxicity and dose-dense therapies are emerging as superior to conventional therapies, early assessment and prevention of CIN is increasingly important to ensure optimal patient outcomes. Recent research also suggests decreased QOL in patients with CIN, adding another important dimension to be considered. With new agents such as Neulasta™ requiring only one dose per chemotherapy cycle, healthcare providers can more efficiently provide optimal chemotherapy treatment with minimal disruptions to patients and their caregivers.

References:

1) Proceedings from the 2003 annual congress of the Oncology Nursing Society. Are oncology nurses the strongest link? Effective management of chemotherapy-associated neuropathy, anemia, and neutropenia. Symposium May 1, 2003. Presenter: Kristen Fessele.

2) American Society of Clinical Oncology Guidelines. 2000:3563.

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