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Symptom Management and Supportive Care |
aSection of Hematology/Oncology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA; bCenter for Oncology Research and Treatment, PA, Dallas, Texas, USA; cUnion State Bank Cancer Center, Nyack Hospital, Nyack, New York, USA; dSt. Louis Cancer & Breast Institute, St. Louis, Missouri, USA; eAlvin & Lois Lapidus Cancer Institute, Baltimore, Maryland, USA; fAmgen Inc., Thousand Oaks, California, USA
Key Words. Pegfilgrastim • Chemotherapy • Febrile neutropenia • Cancer • Community medicine • Medical oncology
Correspondence: Howard Ozer, M.D., Ph.D., Section of Hematology-Oncology, University of Oklahoma Health Science Center, PO Box 26901, Williams Pavilion, Room WP2080, Oklahoma City, Oklahoma 73190, USA. Telephone: 405-271-4022; Fax: 405-271-3020; e-mail: howard-ozer{at}ouhsc.edu
Received October 12, 2006; accepted for publication February 3, 2007.
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Learning Objectives
Top
Learning Objectives
Abstract
Introduction
Patients and Methods
Results
Discussion
Disclosure of Potential...
Acknowledgments
References
Additional Reading
After completing this course, the reader will be able to:
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ABSTRACT |
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TopLearning ObjectivesAbstractIntroductionPatients and MethodsResultsDiscussionDisclosure of Potential...AcknowledgmentsReferencesAdditional Reading |
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18 years old with cancers other than leukemia or myelodysplastic syndrome, including those with major comorbidities, were eligible. Pegfilgrastim (6 mg) was to be administered 
24 hours after chemotherapy in all cycles (minimum, four cycles). A total of 2,112 patients was included in the analyses. The most common tumor types were breast cancer (46%), non-Hodgkin's lymphoma (15%), and non-small cell lung cancer (13%). Chemotherapies administered most often were a platinum plus a taxane (18%), and anthracycline plus an alkylating agent (18%), and a taxane plus an anthracycline plus an alkylating agent (16%). The percentage of patients with neutropenia-related hospitalization was 2.9% in cycle 1 and 5.6% across all cycles. Chemotherapy dose reductions and delays were attributed to neutropenia in 1.8% and 0.9% of patients, respectively, in cycle 2 and 2.9% and 2.1% of patients, respectively, across all cycles. Febrile neutropenia (absolute neutrophil count <1.0 x 109/l with temperature 38.2°C) occurred in 3.6% of patients in cycle 1 and in 6.3% of patients across all cycles. The most frequently reported serious adverse events were febrile neutropenia (3.4%), neutropenia (2.6%), and dehydration (2.6%). Bone pain (0.1%) was the only related serious adverse event reported in more than one patient. Data from this community-based study suggest that patients undergoing chemotherapy benefit from pegfilgrastim support beginning in the first cycle of chemotherapy. Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION |
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For many patients diagnosed with cancer, systemic chemotherapy is an effective means of treating the malignancy. Although individual chemotherapeutic agents vary in their myelosuppressive potential, combination regimens frequently are associated with a higher incidence of severe neutropenia compared with single-agent therapy, especially when given with curative intent [2–8]. The occurrence of severe or febrile neutropenia may be a life-threatening event, often requiring hospitalization and treatment with i.v. antibiotics. Following recovery, the chemotherapy dose may be reduced or delayed in subsequent cycles in an attempt to prevent recurrence of the neutropenia. These reductions in dose intensity may ultimately impact clinical outcomes.
Considerable data exist to support survival benefits when chemotherapy is administered at planned doses and according to schedule. Several studies have suggested that dose reductions of 20% or 30% have been associated with lower complete response rates and shortened survival among patients with lymphoma [9–11]. In patients with breast cancer, results from 30 years of follow-up data demonstrated improved relapse-free survival and overall survival benefit for patients receiving at least 85% of the planned chemotherapy dose, compared with patients given lower doses [12].
Today, the majority of patients with cancer receive treatment in community oncology practices [13]. Whereas oncology patients previously underwent therapy at specialized academic centers, now an estimated 80% are treated in the community setting [14]. Community practices are equipped with on-site laboratory services, procedure capabilities, and infusion centers staffed by qualified oncology nurses and pharmacists to adequately care for patients with cancer [14].
The incidence of neutropenia-related complications and how they subsequently affect the delivery of chemotherapy to patients receiving treatment in community practices is largely unknown. Likewise, the impact of first- and subsequent-cycle growth factor use in the community setting has not been studied extensively. Therefore, we conducted this large, prospective study (the First Cycle Intervention Results in Successful Treatment [FIRST] study) to assess neutropenia and its complications in patients with a broad range of tumor types receiving myelotoxic chemotherapy with pegfilgrastim support in all cycles in the community practice setting. We also compared the incidence of first-cycle febrile neutropenia in our study with data reflecting current community practice to evaluate the impact of pegfilgrastim use in cycle 1, when most neutropenic events occur. Results from interim analyses have been reported previously [15], and we now report the final data.
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PATIENTS AND METHODS |
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The study was conducted primarily at community-based oncology practices in the U.S. The appropriate institutional review boards (IRBs) reviewed and approved the protocol and informed consent forms. Per protocol, all patients were to sign an IRB-approved informed consent before any study-specific procedures, including chemotherapy initiation, were performed.
Treatments and Observations
Included patients were to receive a minimum of four cycles of a myelosuppressive chemotherapeutic regimen chosen by the investigator. Cycle lengths of 14, 21, and 28 days were allowed. Pegfilgrastim (6 mg) was to be administered approximately 24 hours after completion of chemotherapy in each cycle. For 14-day regimens, chemotherapy administration was required on day 1, followed by pegfilgrastim on day 2, thus prohibiting enrollment of patients receiving the 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or folinic acid, fluorouracil, and irinotecan (FOLFIRI) regimens. A CBC, including differential, was performed before administration of chemotherapy in each cycle and at the anticipated absolute neutrophil count (ANC) nadir in cycles 1 and 2. For most 21- and 28-day cycles, the nadir was anticipated between day 7 and 14; for 21- and 28-day cycles with chemotherapy given on days 1 and 8, the nadir was expected between days 10 and 15. For 14-day cycles, the nadir was anticipated on day 1 of the subsequent cycle.
Study Objectives, Hypothesis, and Endpoints
The primary objective of the study was to evaluate neutropenic hospitalizations and chemotherapy dose delays or reductions resulting from myelosuppression in cancer patients receiving pegfilgrastim with every cycle of chemotherapy. Secondary objectives included assessment of grade 3 and 4 neutropenia, febrile neutropenia, and i.v. antibiotic use. Additionally, the protocol specified that the study endpoints would be compared with an external dataset (such as the Awareness of Neutropenia in Chemotherapy Registry data) to assess the effect of pegfilgrastim use beginning in cycle 1 compared with current community practice [16]. The hypothesis for the study was that cancer patients with a wide array of tumor types treated with a variety of myelosuppressive therapies and pegfilgrastim in all chemotherapy cycles would have few neutropenic hospitalizations and would experience minimal alterations in chemotherapy dose and schedule. The primary study endpoints were the incidence of neutropenic hospitalization and chemotherapy dose delays or reductions resulting from myelosuppression. Secondary endpoints included the incidence of neutropenia, febrile neutropenia, and i.v. antibiotic use. Serious adverse events were tabulated; no other adverse event data were collected in this study.
Statistical Methods
The expected sample size for this open-label, noncomparative study was approximately 2,500 patients and the criteria were based on data reported by Lyman et al. [17]. The overall rate of neutropenic hospitalization was anticipated to be 2%–10%, and the overall rates of dose reduction and delay were expected to be 15%–30%. To ensure adequate numbers of patients with the less commonly occurring tumor types, the more common tumor types were expected to accrue large numbers of patients because our study sequentially enrolled patients with minimal selection and disruption to community oncology practices. All patients who provided informed consent before study-specific invasive procedures were performed and received at least one dose of pegfilgrastim were included in the analyses. Data were collected and analyzed for a maximum of eight cycles of chemotherapy. Statistics were descriptive, with 95% confidence intervals generated for point estimates when appropriate, and no adjustment for multiplicity was made. Efficacy data are presented for all patients and for the three most common tumor types (breast cancer, non-Hodgkin's lymphoma [NHL], and non-small cell lung cancer [NSCLC]), which included approximately 75% of all patients. Neutropenia was graded as follows: grade 4, ANC <0.5 x 109/l; grade 3–4, ANC <1.0 x 109/l. Fever was defined as temperature 38.2°C, and investigators determined whether the criteria were met. Both investigator-reported and calculated chemotherapy dose reductions (10% reduction from cycle 1 dose) and delays (7 days) are presented. Calculation of average relative dose intensity (ARDI) for patients who received common standard chemotherapy regimens for breast cancer or NHL was performed as an exploratory analysis; all other analyses were prespecified. Hospitalizations, febrile neutropenia, grade 3 and 4 neutropenia, physician-reported dose delay and reduction, and serious adverse events were summarized in two planned interim analyses [18, 19].
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RESULTS |
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Patient demographics and baseline characteristics are presented in Table 1. The mean age was 59 years, and 36% of patients were 65 years old. Most patients were female and had good performance status scores. About one half of the patients had late-stage disease, and approximately one fourth had a major comorbidity. The most common tumor types were breast cancer, NHL, and NSCLC. Compared with other tumor types, patients with breast cancer were younger and had earlier stage disease and a better performance status score. Previous cancer treatments were most common among patients with ovarian and lung cancers, and comorbidity was most common among patients with lung cancer.
Planned chemotherapeutic agents are presented in Table 2. Overall, anthracyclines, taxanes, alkylating agents, and platinum agents were the most frequently planned agents. The mean (standard deviation [SD]) number of chemotherapy cycles planned per patient was 5.5 (1.5), and the mean (SD) number of cycles started per patient was 4.6 (2.0). Most regimens were administered every 21 days (68%), and most patients were given a combination regimen consisting of either two (51%) or three (35%) chemotherapeutic agents (Fig. 1). The most commonly used combinations were the following: a platinum plus a taxane (18%), an anthracycline plus an alkylating agent (18%), and a taxane plus an anthracycline plus an alkylating agent (16%). Of 1,726 patients receiving a day-1-only chemotherapy regimen and pegfilgrastim in cycle 1, 1,659 (96%) received pegfilgrastim on cycle day 2.
Febrile Neutropenia and Neutropenia
The incidence of febrile neutropenia and neutropenia in cycle 1 and across all cycles is presented in Table 3. Overall rates of febrile neutropenia were low, with 3.2%–3.6% of patients (depending on the definition used) having events in cycle 1 and 5.6%–6.3% having events across all cycles. Grade 4 neutropenia was reported for 15.1% of patients in cycle 1 and 21.8% of patients across all cycles. Rates of febrile neutropenia, grade 3–4 neutropenia, and grade 4 neutropenia were highest in patients with NHL, compared with patients with breast cancer or NSCLC.
Neutropenia-Related Hospitalization
Hospitalizations related to neutropenia or febrile neutropenia (as reported by the investigators) are shown in Figure 2. Overall, few patients required hospitalization for neutropenia or febrile neutropenia in either cycle 1 or across all cycles. By tumor type, neutropenia- and febrile neutropenia-related hospitalization occurred most often in patients with NHL and infrequently in patients with breast cancer or NSCLC.
Chemotherapy Dose Reduction and Delay
Reductions in chemotherapy dose for any reason were reported in 7.3% of patients in cycle 2 and 16.8% of patients across all cycles (Fig. 2). Neutropenia was reported as causing a dose reduction in only 1.8% of patients in cycle 2 and 2.9% of patients across all cycles. Some of the more common reasons for dose reduction included adverse events other than neutropenia (2.3% and 6.9% in cycles 2 and across cycles, respectively) and investigator decision (2.0% and 5.6% in cycles 2 and across cycles, respectively). When compared with chemotherapy doses administered in cycle 1, a 10% reduction in dose was observed in 7.0% of patients in cycle 2 and 16.1% of patients across all cycles. Among the three most common tumor types, overall dose reductions occurred most often in patients with NHL.
Treatment delays for any reason were reported for 7.5% of patients in cycle 2 and 20.1% of patients across cycles. The most common reasons for delays in chemotherapy administration were adverse events other than neutropenia (2.3% and 7.1% in cycle 2 and across all cycles, respectively) and other reasons (2.0% and 6.0%, in cycle 2 and across cycles, respectively). Dose delays were attributed to neutropenia in 0.9% of patients in cycle 2 and 2.1% of patients across all cycles (Fig. 2). Among the three most common tumor types, reported delays in chemotherapy resulting from neutropenia were highest for patients with NHL. Chemotherapy delays of 7 days were observed for 4.6% of patients in cycle 2 and 17.2% of patients across all cycles.
Delivered ARDI was calculated for common standard chemotherapy regimens administered to patients with either breast cancer or NHL. Slightly over half of the patients with breast cancer received one of four regimens containing doxorubicin and cyclophosphamide (AC) (AC every 21 days, AC every 14 days, sequential AC and paclitaxel, or docetaxel plus AC). For patients with NHL, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP with rituximab (R-CHOP) were given most often. The mean ARDI for patients with breast cancer receiving one of the four standard regimens was in the range of 87%–94% (Table 4). For patients with NHL receiving CHOP or R-CHOP, the mean ARDI was 77%.
Antibiotic Use
i.v. antibiotics were administered for any reason (including prophylaxis) to 6.0% of patients in cycle 1 and 12.1% of patients across all cycles. Administration of i.v. antibiotics because of febrile neutropenia occurred in 1.8% of patients in cycle 1 and 3.6% of patients across all cycles. Administration of i.v. antibiotics because of neutropenia occurred in 3.0% of patients in cycle 1 and 5.7% of patients across all cycles. In cycle 1, 8.6% of NHL patients, 2.1% of breast cancer patients, and 1.5% of NSCLC patients received i.v. antibiotics in response to a neutropenic event. Across all cycles, 14.8% of NHL patients, 4.5% of breast cancer patients, and 3.4% of NSCLC patients received i.v. antibiotics in response to neutropenia.
Oral antibiotics were administered for any reason to 14.9% of patients in cycle 1 and 33.0% of patients across all cycles. In response to a neutropenic event, oral antibiotics were administered to 6.5% of patients in cycle 1 and 12.0% of patients across all cycles.
Serious Adverse Events
Serious adverse events were reported in 21.7% of patients and were reported more often in patients with NHL (31.3%) and NSCLC (28.7%) than in patients with breast cancer (12.9%). Among all patients, the most frequently reported serious adverse events were febrile neutropenia (3.4%), neutropenia (2.6%), dehydration (2.6%), and nausea (2.4%). Less than 1% (0.5%) of patients had serious adverse events that were considered by the investigator to have been related to study drug. Bone pain (0.1%) was the only related serious adverse event that was reported in more than a single patient. Seventy-one patients (3.4%) died during the study. Fifteen patient deaths (0.7%) were attributed to infections, including two (0.1%) for septic shock (one neutropenia associated).
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DISCUSSION |
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TopLearning ObjectivesAbstractIntroductionPatients and MethodsResultsDiscussionDisclosure of Potential...AcknowledgmentsReferencesAdditional Reading |
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Our study was designed to evaluate pegfilgrastim use in the community oncology practice setting. Over 300 centers in the U.S. participated in the study, most of which were community-based. To emulate a patient population representative of that treated by community oncologists, our inclusion criteria were less restrictive than most clinical trials and permitted entry of patients with nearly any type of cancer, major comorbidities such as diabetes or cardiovascular disease, and poor performance status. Except for excluding the FOLFOX and FOLFIRI regimens, investigators were free to choose the dose and type of chemotherapy administered to each patient.
The majority of neutropenia occurs early in the course of chemotherapy. In patients receiving CHOP chemotherapy for NHL, over 50% of first occurrences of febrile neutropenia occurred in cycle 1, and 74% occurred within cycles 1 and 2 [20]. Data from a nationwide, prospective registry study of over 2,000 patients with a variety of tumor types also suggest that the initial episode of a neutropenic event is most likely to occur during the first cycle of chemotherapy, regardless of tumor type [16, 21]. Patients in the registry study may or may not have received growth factors in cycle 1, according to the site's standard practice, and the rate of first-cycle febrile neutropenia (fever or infection and ANC <1.0 x 109/l) was 8%. In contrast, pegfilgrastim was administered to all patients in our study (the FIRST study) beginning in cycle 1, and the corresponding rate of febrile neutropenia (temperature 38.2°C and ANC <1.0 x 109/l) was 3.6% (Fig. 3). Compared with results from the registry study, our study data suggest that patients receiving chemotherapy in community practices benefit from pegfilgrastim support in cycle 1. Our community-based study data also compare well with first-cycle febrile neutropenia rates achieved in a randomized, placebo-controlled clinical trial evaluating pegfilgrastim support for moderately myelosuppressive chemotherapy, further supporting pegfilgrastim use beginning in cycle 1 (Fig. 3) [22]. It is interesting to note that most cases of febrile neutropenia occurred with an ANC <0.5 x 109/l rather than <1.0 x 109/l.
Recent reports indicate that reductions in dose intensity are common among patients undergoing chemotherapy in clinical practices. In a nationwide survey of community oncology practices, over half of the patients received <85% relative dose intensity adjusted to the reference dose intensity of AC [17]. A similar analysis of records from over 4,500 patients with NHL found substantial reductions in chemotherapy dose intensity in half of the patients [23]. Other retrospective analyses have also concluded that a sizeable proportion of patients undergoing treatment in a variety of practice settings receive less than optimal chemotherapy [24, 25]. Reductions in dose intensity can occur from the outset, when physicians decide that patients cannot tolerate full doses for reasons such as age or comorbidity, or they can occur in response to side effects resulting from the chemotherapy administration itself. Although dose reductions, whether planned or reactive, may increase the patient's ability to tolerate treatment, they may ultimately reduce the survival benefit associated with the cancer therapy. In our study, pegfilgrastim was administered beginning in cycle 1 and the majority of patients did not have a dose reduction or treatment delay. Further, in a subset of patients receiving standard chemotherapy regimens, the ARDI was approximately 90% for patients with breast cancer and about 80% for patients with NHL.
Our study was limited by the biases inherent in an open-label, noncomparative study design. In the absence of a control arm, we compared our data with historical data from the registry study with good results. However the assumption of comparable study populations needs to be confirmed, and subsequent adjustments for differences in patient characteristics, chemotherapy regimens, and growth factor use need to be made to attribute this benefit to pegfilgrastim. Although the patients in our study were typical of those routinely seen by oncology practices, we did not include a representative number of patients with colorectal cancer because of the exclusion of the newer FOLFOX and FOLFIRI regimens. In addition, the adverse event profile of pegfilgrastim could not be assessed because of the open-label design of the study and the collection of only serious adverse event data.
Data from our community-based study suggest that patients undergoing chemotherapy benefit from pegfilgrastim use beginning in the first cycle of chemotherapy. Neutropenic events occurred infrequently, and chemotherapy doses were maintained in this population of "real world" patients. These data support the use of pegfilgrastim as an adjunct to chemotherapy administration in community practice.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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ACKNOWLEDGMENTS |
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This study was sponsored by Amgen Inc., Thousand Oaks, CA. Two authors (B.D. and L.D.) are employees and stockholders of Amgen Inc. Four additional authors (H.O., B.M., M.R., and S.N.) have declared a financial interest in Amgen Inc.
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REFERENCES |
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TopLearning ObjectivesAbstractIntroductionPatients and MethodsResultsDiscussionDisclosure of Potential...AcknowledgmentsReferencesAdditional Reading |
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ADDITIONAL READING |
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This article has been cited by other articles:
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  T. J. Smith and J. L. Khatcheressian Re: Neutropenic events in community practices reduced by first and subsequent cycle pegfilgrastim use. Oncologist, December 1, 2007; 12(12): 1464 - 1464. [Full Text] [PDF]
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