June 2-6, 2006Atlanta, GeorgiaJohn Glaspy, MDThe content presented here was prepared by independent authors under the editorial supervision of OncoEd and is not endorsed or sanctioned by the 42nd Annual Meeting of the American Society of Clinical Oncology.
Several studies presented at the 2006 meeting of the American Society of Clinical Oncology (ASCO) could prove to have significant clinical impact in the area of supportive care. Of note were studies on the timing of therapy for myelosuppression, its role in clinical practice and in pediatric populations, complications associated with such therapy, and developments in treating anemia, particularly in patients with myelodysplastic syndromes.
Timing of Neulasta® (Pegfilgrastim) Therapy
Although the introduction of Neulasta has significantly improved our ability to support our patients during myelosuppressive chemotherapy with a minimum of inconvenience and interference with their daily activities, the current approach is to administer this single injection at least 24 hours after the completion of chemotherapy. This practice reflects both our concern that administration of Neulasta while chemotherapy is still acting on the marrow may increase myelosuppression and the demonstrated safety of administering this agent 24 hours after chemotherapy. However, this approach adds an additional office visit per chemotherapy cycle, and this visit often occurs on the day upon which the patient is experiencing the most acute effects of chemotherapy that make travel to the office a burden.
Several abstracts at ASCO 2006 reported work exploring this important issue. Vance and colleagues carried out a retrospective chart analysis of patients with early stage breast cancer receiving “dose dense,” (i.e. every two week) doxorubicin-containing chemotherapy. Sixty-four patients receiving a total of 211 doses of doxorubicin who had also received same day Neulasta therapy were identified. No severe neutropenia was observed and no cases of febrile neutropenia were recorded. Although this study does not provide data regarding the duration of neutropenia with same day, as opposed to next day, dosing of Neulasta, it does suggest that, if there is a difference, it is not great enough to abrogate the ability of Neulasta to reduce infection risk. Saven et al addressed the issue prospectively, in a randomized, double blind trial of same day vs. next day Neulasta in patients with lymphoma undergoing R-CHOP chemotherapy every 3 weeks, with duration of severe (grade 4) neutropenia as the endpoint. A total of 77 patients were enrolled. The mean duration of grade 4 neutropenia was 2.1 days in the same day group and 1.2 days in the next day group. The proportion of patients experiencing a duration of grade 4 neutropenia greater than 3 days during chemotherapy cycle 1 was similarly greater with same day dosing (36% vs. 15%). The observed incidence of febrile neutropenia and the administered chemotherapy dose intensity were the same in both groups. The authors recommend continuing next day administration as standard practice for patients receiving R-CHOP. However, a similar randomized, double blind trial was reported by Belani and colleagues (abstract # 7110) in 88 patients with lung cancer receiving the carboplatin/docetaxel chemotherapy couplet. Because the incidence of grade 4 neutropenia was very low, the mean duration was 0 days in both groups and obviously, no difference was observed. No febrile neutropenia was observed and there was no difference between groups in the proportion of patients receiving planned doses of chemotherapy.
Clearly, the issue of the efficacy of Neulasta administered on the same day as chemotherapy remains unsettled. This efficacy is likely to depend upon the chemotherapy regimen utilized, because: 1) there is variation in the clearance and duration of action of different chemotherapy drugs, 2) there is variation in the mechanisms of action and cell cycle dependence of chemotherapeutic agents and 3) chemotherapy regimens vary in terms of the severity of neutropenia induced and risk of febrile neutropenia conferred. The data available suggest that same day administration of Neulasta may be somewhat less effective than next day administration, but still has sufficient efficacy to satisfactorily reduce or even eliminate a moderate or low risk, while remaining inferior to next day dosing when the risk of severe, prolonged neutropenia is high. More regimen-specific data from studies with sufficient power to detect clinically relevant differences between the two schedules in the duration of severe neutropenia or the incidence of febrile neutropenia will be helpful in clarifying the issue and guiding clinical practice. The accumulating data do support a conclusion that same day administration is safe. Until more definitive data are available, next day administration of Neulasta should remain the default strategy for integrating this agent into chemotherapy, with same day administration remaining an option to be discussed when self administration is not feasible and a return to the clinic for next day injection would represent a significant hardship to the patient and the chemotherapy regimen being utilized is one for which there are data suggesting sufficient efficacy for same day dosing.
Better Understanding the Role of Neulasta in Oncology Practice
Neulasta is a relatively new agent for the treatment of chemotherapy-induced neutropenia and several interesting abstracts at ASCO 2006 reported additional information with respect to clinical issues with the use of this agent. One important consideration for any new agent with demonstrated safety and efficacy in well controlled clinical trials is the results observed when it enters clinical oncology practice. Ozer and colleagues reported the final results of a large observational study of Neulasta use during chemotherapy in 2,112 patients in 319 community practices. The Neulasta was given 24 hours after chemotherapy and was initiated during cycle 1. The incidence of febrile neutropenia was low during the first cycle (1.7%) and over all treated cycles (3.5%). These compare favorably to rates observed in the Neulasta arms of carefully controlled randomized trials, supporting a conclusion that Neulasta is effective in routine oncology practice.
Neulasta Versus Neupogen in the Pediatric Population
Another frequent question regarding new agents is safety and efficacy in the pediatric population, a clinical setting where the daily injection of Neupogen® (filgrastim), while effective, is particularly problematic in terms of patient tolerance. Fox et al reported the results of a randomized trial (N=34) of Neupogen (5 mcg/kg/d) vs. Neulasta (100 mcg/kg) in children with sarcoma receiving intensive chemotherapy.Neulasta was associated with higher G-CSF blood levels and with a shorter duration of severe neutropenia than Neupogen, supporting a conclusion that Neulasta is effective and can be integrated into pediatric protocols previously utilizing Neupogen to support chemotherapy. The safety profiles were similar for the two agents. This trend suggesting, if anything, superior efficacy in of Neulasta compared to Neupogen has been a consistent observation in randomized trials comparing the two agents in adults and is both unexplained and intriguing.
Complications of Myeloid Growth Factor Therapy
Two issues that potentially complicate Neulasta and Neupogen therapy during chemotherapy were the subject of abstracts at ASCO 2006. Bone pain is a well documented complication of myeloid growth factor therapy. During the early development of Neulasta, there was a concern that, due to its much longer half life, therapy with this agent would be associated with an increased incidence of bone pain compared to Neupogen. In randomized trials comparing Neupogen with Neulasta bone pain has not been more common or severe with Neulasta, an observation that has been attributed to the “self-regulation” of G-CSF levels conferred by the clearance of Neulasta by neutrophils and their precursors. The incidence of bone pain has not been specifically addressed in the community setting, however.
Kirshner and colleagues studied the incidence of bone pain in an observational trial in cancer chemotherapy patients (most frequently patients with breast cancer receiving dose dense adjuvant therapy) treated with Neulasta in one large community practice. Pain was self reported on a ten point scale; pain scores of 6 or greater were grouped together; the authors noted that pain in these patients tended to also be more diffuse and of longer duration. This level of pain was observed in 18 (24%) of cases, and was not relieved by over the counter analgesics in 12% of patients. Interestingly, the pain observed in this trial was during the first two to three days following Neulasta therapy; prior studies of myeloid growth factor bone pain have suggested that pain of this etiology peaks during the later part of the chemotherapy cycle, when the marrow is recovering following a nadir. No formal quality of life studies were carried out, and no “control” data, measuring bone pain patterns in patients receiving Neupogen or chemotherapy without myeloid growth factor, were presented. These limitations aside, this study is of interest and generates a hypothesis (i.e. that bone pain associated with Neulasta therapy is more common in practice than has been reported in large, well controlled clinical trials and tends to occur very early in the chemotherapy cycle) that is worth testing.
Suara et al reported the results of a retrospective chart review of patients with breast cancer receiving adjuvant chemotherapy (dose dense in the Neulasta and Neupogen groups and every three weeks in the no growth factor control group). Their hypothesis was that, because neutrophils can express MUC-1, Neulasta therapy might be associated with an elevation of serum CA 15-3 levels that could be misinterpreted as progression of disease. The sample size was quite small (Neulasta N=29, Neupogen N=10, control N=37) and the consistent frequency and timing of CA15-3 monitoring in the three groups was not reported. The authors did report more CA15-3 increases in the Neulasta group; this was not significantly different from the number of elevations in the Neupogen group, but was greater than observed in the control group. This is an interesting observation, and, until more definitive data are available, clinicians should be aware that Neulasta and Neupogen therapy may complicate interpretation of CA15-3 levels. This issue would be more interesting if it were shown to occur in the setting of metastatic breast cancer, where monitoring of CA15-3 is more useful and correct interpretation of levels of greater clinical importance.
Advances in the Management of Anemia in Oncology Practice
Although the erythropoiesis stimulating proteins (ESPs) recombinant erythropoietin and darbepoetin have become very important in the management of chemotherapy-induced anemia (CIA), reducing transfusion risk and fatigue levels, their uniform and universal integration into routine oncology practice has been limited primarily by the resistance of CIA to ESP therapy. This has resulted in relatively high dose requirements-compared, for example to dialysis patients-and, even at high doses, a significant proportions of patients remaining unresponsive, fatigued and at risk for red cell transfusion. The net effect is that the cost effectiveness of ESPs in the management of CIA does not compare favorably to settings in which their value in anemia management is unquestioned. It has long been known that even normal subjects, when treated with ESPs, can evidence iron-restricted erythropoiesis, presumably due to rate limiting mobilization from storage iron, and may respond better to treatment with the addition of iron supplementation, particularly when administered parenterally. The recent discovery and characterization of the polypeptide hepcidin, the production of which by the liver is increased in inflammatory states including cancer and which has the effect of decreasing iron absorption from the gastrointestinal tract and inhibiting the mobilization of storage iron, has provided a framework for understanding the potential for parenteral iron to overcome the resistance to ESPs observed in patients with chronic illnesses such as cancer. In one randomized trial that has already been published, patients with CIA receiving epoetin alfa who received parenteral iron had an erythropoietic response that was significantly better than patients receiving epoetin alfa alone or with oral iron. This trial, while interesting, has been awaiting confirmation in subsequent trials.
Vandebroek and colleagues presented an interim analysis of a very important trial. Patients with CIA were randomized (N=198) to receive Aranesp® (darbepoetin alfa), 500 mcg every three weeks, with or without parenteral iron, 200 mg every three weeks. For patients randomized to parenteral iron, a higher hemoglobin response rate was observed. More importantly, a lower risk of transfusion and a greater improvement in fatigue scores were observed in the parenteral iron group. These clinical outcomes have not been reported in previous CIA iron studies. If the interim data are indicative of the final conclusions of this study when complete, analyzed and published, this study will be an important one in guiding the way for improved erythropoietic management in oncology.
Aranesp in the Management of Anemia in Myelodysplasia
One of the most vexing problems in hematology practice has been the management of anemia in the setting of the myelodysplastic syndromes. These patients often become transfusion dependent and sometimes transfusion refractory and suffer the fatigue and functional impairments of chronic anemia. Therapy with ESPs has resulted in some improvement in a minority of patients, usually utilizing doses even higher than those employed in the treatment of CIA. Paquette and colleagues reported a planned interim analysis of a large (N=209 enrolled, 129 reported here with 28 weeks of follow up) trial of Aranesp, 500 mcg every three weeks for anemic patients with low or intermediate risk (IPSS definition) myelodysplasia. The observed major response rate has been 54% in ESA-naïve patients and 27% in patients previously treated with ESPs. These data are encouraging both because of the excellent response rates observed and the relatively low (by MDS standards) doses of Aranesp employed. An exploratory analysis of these data reported by Gabrilove suggested that baseline endogenous erythropoietin level and FAB subtype may help to predict response to this drug in this setting.
 Vance KT, Carpenter J. Same day administration of pegfilgrastim with dose dense doxorubicin in early breast cancer patients. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 671.
 Saven A, Schwartzberg L, Kaywin P, et al. Randomized, double-blind, phase 2 study evaluating same-day vs. next-day administration of pegfilgrastim with R-CHOP in non-Hodgkin’s lymphoma patients. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 7570.
 Belani C, Ramalingam S, Al-Janadi A, et al. A randomized double-blind phase II study to evaluate same-day vs. next day administration of pegfilgrastim with carboplatin and docetaxel in patients with NSCLC. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 7110.
 Ozer H, Mirtsching M, Rader M, et al. Final results of a large, community-based, prospective study evaluating the impact of first and subsequent cycle pegfilgrastim on neutropenic events in patients receiving myelosuppressive chemotherapy. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 8569.
 Fox E, Jayaprakash N, Widemann BC, et al. Randomized trial and pharmacokinetic study of pegfilgrastim vs. filgrastim in children and young adults with newly diagnosed sarcoma treated with dose intensive chemotherapy. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 9020.
 Kirshner JJ. Pegfilgrastim (N) induced bone pain (NIBP): Incidence, risk factors and management in a community practice. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 8598.
 Saura C, Vilar E, Cortes J, et al. Pegfilgrastim induces elevation of serum CA 15-3 in breast carcinoma patients after receiving dose-dense adjuvant chemotherapy. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 8595.
 Vandebroek A, Gaede B, Altintas S, et al. A randomized open-label study of darbepoetin alfa administered every 3 weeks with or without parenteral iron in anemic subjects with nonmyeloid malignancies receiving chemotherapy. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 8612.
 Paquette R, Gabrilove J, Lyons R, et al. Darbepoetin alfa for treating anemia in low-risk myelodysplastic syndrome patients: Interim results after 27/28 weeks. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 6564.
 Gabrilove J, Paquette R, Lyons R, et al. Darbepoetin alfa for treating anemia in patients with low-risk myelodysplastic syndromes: Exploratory analysis of baseline predictors of response. Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Georgia. 2006. Abstract # 6579.