John A. Glaspy, MD, MPH

Our paper, “Darbepoetin Alfa Administered Every 2 Weeks Alleviates Anemia in Cancer Patients Receiving Chemotherapy,” at the time of its publication almost a decade ago, was impactful and frequently cited.

Anemia is a frequent but insidious complication of cancer and its cytotoxic chemotherapy, contributing to debilitating fatigue, lethargy, cardiovascular problems, shortness of breath, and reduced cognitive function in individuals who often already have significant morbidity and diminished quality of life (QOL) as a consequence of their malignancy.

As the major regulator of erythropoiesis in man, erythropoietin inhibitsthe programmed cell death of committed erythroid precursors.In cancer patients, a relative erythropoietin deficiency is coupled witha decreased responsiveness to the substance mediated by the effects ofinflammatory cytokines on the marrow and on ferrrokinetics, leadingto a high incidence of anemia. Two recombinant human erythropoietin(rhEPO) preparations-epoetin alfa (Epogen, Procrit) and epoetinbeta (Marogen)-as well as a modified erythropoietic compound(darbepoetin alfa [Aranesp]) are in clinical use. Part 2 of this two-partseries on hematopoietic agents reviews the use of these erythropoieticfactors and their effect on the anemia that develops in cancer patients.Thrombopoietic factors and progenitor cell-mobilizing factors are alsobriefly addressed.

Hematopoietic growth factors have transformed the practice of oncology.The two major factors in clinical use are recombinant human(rh) granulocyte colony-stimulating factor (G-CSF, filgrastim[Neupogen]) and granulocyte-macrophage colony-stimulating factor(GM-CSF, sargramostim [Leukine]). These factors differ significantly intheir role in hematopoiesis and the regulation of mature effector cell function.G-CSF regulates both basal and neutrophil production and increasedproduction and release of neutrophils from the marrow in response toinfection. GM-CSF mediates its effects on the neutrophil lineage throughits effects on phagocytic accessory cells and its synergy with G-CSF, but itdoes not appear to have a role in basal hematopoiesis. Part 1 of this twopartseries focuses on the use of the myeloid growth factors rhG-CSF andrhGM-CSF to shorten the duration of chemotherapy-induced neutropeniaand thus prevent infection in cancer patients. In randomized trials,rhG-CSF has consistently decreased the duration of neutropenia duringall cycles of chemotherapy and reduced the risk of infection by 50% ormore. Trials of rhGM-CSF have not reported consistent results.

The objectives of this study were to assess the safety and efficacy of darbepoetin alfa (Aranesp) administered every 2 weeks in anemic patients with solid tumors receiving chemotherapy. This was an open-label, randomized,

Since our first "Quality of Life in Current Oncology Practice and Research" symposium was held at St. Mary Medical Center in Long Beach, California in February 1989, and published in ONCOLOGY in May 1990, there has been a marked increase in the use of quality of life measures to determine the outcomes of interventions in clinical oncology. Measuring the effects of anemia treatment with quality of life tools is a fine example of the importance of these tools to gauge the impact and clinical significance of interventions. It is, therefore, both timely and relevant that we dedicate our fifth symposium to the management of anemia in patients with cancer.

Barriers to use of erythropoietic therapy in cancer patients include nonresponse in a sizable proportion, resultant lowering of cost-effectiveness, and inconvenience. Darbepoetin alfa represents the outcome of efforts to develop agents with improved erythropoietic potency.

One of the most fundamental challenges to multicellular life is the delivery of sufficient oxygen and metabolic substrate to all cells and the rapid elimination of acid formed during cellular respiration. Thus it is logical to wonder whether anemia, by compromising these pathways, might contribute to the progression of cancer.

Given the clinical utility of myeloid growth factors and erythropoietin (Epogen, Procrit) in the management of many cancer patients, it is understandable that the cloning and introduction into clinical trials of thrombopoietin was greeted with great expectations for the future utilization of this molecule in oncology. Drs. Prow and Vadhan-Raj have written a well-referenced review that summarizes the preclinical biology of thrombopoietin and the evidence that it is the physiologic regulator of thrombopoiesis in animals and humans. The authors also synopsize some of the data from early clinical trials. My own interpretation of the clinical data obtained to date with both the full-length clone (recombinant human thrombopoietin [rhTPO]) and the pegylated, truncated molecule (pegylated recombinant human megakaryocyte growth and development factor [PEG-rHuMGDF]) differs somewhat from both our initial expectations and the perspective provided by the authors.

The myeloid growth factors G-CSF and GM-CSF have had an impact on the supportive care of cancer patients as well as on the strategies utilized in chemotherapy dose intensification. Therapy with these factors has not been