Expanding the ApplicationDecember 8-11, 2004San Antonio, TXLee Schwartzberg, MD, FACP
A significant benefit from dose-dense chemotherapy in the adjuvant treatment of breast cancer (demonstrated in Intergroup Trial 9741) caused a paradiagm shift in the treatment approach to this disease.
By shortening the interval between treatments without increasing the dose itself, this chemotherapy schedule delivered a 26% improvement in disease free survival and a 31% improvement in overall survival for lymph node-positive patients. In order to achieve dose density, patients were scheduled to receive G-CSF with Neupogen® (filgrastim) on days 3-10 of every 14-day cycle. Interestingly, patients receiving dose-dense therapy with Neupogen® actually had less febrile neutropenia and significantly less grade 4 neutropenia compared to those receiving standard three-week regimens. However, more red blood cell transfusions were necessary in the dose-dense groups. This hematologic toxicity, as well as the inconvenience of daily G-CSF for multiple weeks, makes the delivery of dose-dense chemotherapy somewhat more complex than a standard three-week treatment. Strategies to reduce hematologic toxicity and streamline care are of great interest.
At the 27th Annual San Antonio Breast Cancer Symposium in December 2004, Burstein, et al presented a prospective clinical trial using long-acting growth factors in support of dose-dense chemotherapy.
Using identical chemotherapy to that used in C9741 (dose-dense doxorubicin and cyclophosphamide (AC) followed by dose-dense paclitaxel every two weeks), these investigators substituted Neulasta® (pegfilgrastim) 6 mg SQ on the day after chemotherapy, once per cycle instead of daily Neupogen®. The primary endpoint of the study was the rate of febrile neutropenia. Overall, only two cases (1.5%) of febrile neutropenia occurred, both occurred during AC and resolved without sequelae. The mean neutrophil count on the first day of each cycle rose during treatment and was highest during paclitaxel therapy. Towards the end of the study, a cohort of patients was added without steroid premedication after the first cycle of paclitaxel. This group had a lower peak of neutrophils on the day of each treatment, averaging around 10,000/µl, as compared to 12-15,000/µl in the group receiving steroid premedication. Treatment delays for neutropenia were rare and only a few patients had treatment delays for infection.
Additionally, Aranesp® (darbopoetin alfa) 200 mcg SQ every 2 weeks was initiated as soon as patients developed anemia with a hemoglobin <12 gm/dl. An algorithm was followed for dose escalations and dose reductions of Aranesp®. Aranesp® use was high, with 92% of patients requiring therapy (i.e. developing a hemoglobin <12 gm/dl; mild anemia). About half of the patients were on Aranesp® at any given time. No patient in this trial required red blood cell transfusions. The authors concluded that the long-acting growth factors Neulasta® and Aranesp® provided effective support for this dose-dense regimen in early stage breast cancer, with minimal hematologic toxicity, and that both agents were safe to give in this setting.
Schwartzberg, et al presented a retrospective analysis of 73 patients treated with dose-dense AC and a taxane with Neulasta® support in a community-based large cancer clinic.
Use of an erythropoetic agent was at the discretion of the treating physician. The incidence of febrile neutropenia was 1.3%. Grade 4 neutropenia occurred in 11%. An overshoot of the ANC count was again seen more commonly on day 1 of the taxane cycles (mean ANC 9738/µl vs. 7265/µl for AC cycles), but there were no clinical sequelae. Dose delays for neutropenia occurred in three patients and five patients had dose delays for non-neutropenic infections. Similar to results of Burstein’s trial, 96% of patients developed some degree of anemia. Two-thirds were placed on an erythropoietic agent with an average of 7.5 weeks on this therapy. Because the threshold to initiate an erythropoetic agent was not specified, in this trial the mean nadir hemoglobin level was lower, with a drop from a mean starting hemoglobin of 13.1 gm/dl to a nadir of 10.2 gm/dl.
Response to erythropoetic therapy was good, with an average rise in hemoglobin at the end of chemotherapy to 11.7 gm/dl. Thirty-nine patients received Aranesp® every two weeks and nine patients received Procrit® (epoetin alfa) weekly. Two patients (3%) required PRBC transfusions. The authors concluded Neulasta® was effective at maintaining dose-dense therapy, with dose delays for complications of neutropenia rare. Anemia developed early during dose-dense chemotherapy and may become more severe in the absence of a pre-specified approach to intervene early.
Taken together, these studies demonstrate dose-dense AC followed by taxane therapy every two weeks can be successfully supported with long-acting growth factors. The advantage to the patient is a marked reduction in trips to the clinic to receive injections. Additionally, early intervention with erythropoetic therapy presumably reduces the risk of transfusions and maintains hemoglobin levels in the near normal range. This strategy leads to improved quality of life and decreased incidence of fatigue. These supportive care interventions may therefore improve the tolerability and safety of a highly effective and broadly adopted adjuvant treatment program.
Neulasta® given once per cycle has previously been demonstrated to be at least effective as daily Neupogen® in breast cancer patients receiving doxorubicin and Taxotere® together, a regimen associated with approximately 40% risk of febrile neutropenia in the absence of growth factors. However, the need for prophylactic growth factor support has not been documented in situations where the risk of febrile neutropenia is somewhat lower.
Vogel, et al presented findings from a phase 3 clinical trial in breast cancer patients receiving single agent Taxotere® randomized to receive placebo or Neulasta® on the day after chemotherapy.
The regimen was chosen on the expectation that approximately 20% of patients would experience febrile neutropenia without prevention and the study was powered to detect at least a 40% reduction in the incidence of febrile neutropenia. Patients were scheduled to receive four cycles of Taxotere®, have ECOG PS of 0-2, and have normal hematologic values. Both groups were well-balanced, with about 60% having metastatic disease in both arms and two-thirds having prior chemotherapy. The median age was 52.
The results were striking: a 17% incidence of febrile neutropenia was seen in the placebo group vs. 1% in the Neulasta® group (p<0.0001, odds ratio 15.2), representing a 94% reduction in the incidence of this complication of chemotherapy. For secondary endpoints, febrile neutropenia-related hospitalizations were reduced from 14% to 1% (p<0.001, odds ratio 11.99) by Neulasta® and IV anti-infective use was reduced from 10% to 2% (p<0.0001, odds ratio 7.47).
The authors analyzed the risk of febrile neutropenia by cycle. Febrile neutropenia occurred most commonly in cycle 1, where 11% of patients in the placebo arm experienced febrile neutropenia, compared to <1% in the Neulasta® arm. Even in cycles 2-4, there was a 6% febrile neutropenia rate in the placebo arm, compared to <1% in the Neulasta® arm. 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.
Neulasta® was safe, with slightly more bone and musculoskeletal pain observed compared to placebo. Interestingly, the serious adverse event rate was cut in half for Neulasta®, from 24% to 2%, and the fatal adverse events were 3% in the placebo arm vs. 1% in the Neulasta® arm.
The authors concluded that Neulasta® is extremely effective when used with first and subsequent cycles of moderate myelosuppressive chemotherapy having an expected febrile neutropenia rate of 15-20% in the absence of growth factor use. Since the majority of febrile neutropenia occurs in the first cycle therapy, it is important to consider Neulasta® as primary prevention in order to provide maximal protection to appropriate patients receiving this intensity of chemotherapy.
Citron ML, Berry DA, Cirrincione 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. J Clin Oncol. 2003 Apr 15; 21(8): 1431-9.
Burstein HJ, Parker LM, Doherty J, et al. Use of the long-acting hematopoietic growth factors pegfilgrastim and darbepoetin alfa in support of dose-dense adjuvant chemotherapy. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 1055.
Schwartzberg L, Tauer K, Fortner B, et al. Dose dense chemotherapy (DDC) supported by pegfilgrastim (PEG) and an erythropoietic agent (EA) in operable breast cancer. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 6035.
Vogel C, Rader M, Tyulandin S, et al. Pegfilgrastim nearly abrogates occurrence of neutropenic events early in the course of chemotherapy: results of a phase 3, randomized, double-blind, placebo-controlled study of patients with breast cancer receiving docetaxel. Special Issue: 27th Annual San Antonio Breast Cancer Symposium. 2004; 88:S1. Abstract 5044.