The year 1991 was truly a water shed year in medical oncology, as three events resulted in a paradigm shift in the tolerability, safety, and symptom management of chemotherapy delivery. The first two events moved chemotherapy administration from a user-unfriendly hospital inpatient environment to what evolved into a highly efficient, sophisticated, outpatient system led by private practitioners of medical oncology. Ondansetron (Zofran), the first of the 5HT3-receptor antagonists, provided reliable prophylaxis of immediate chemotherapy-induced nausea and vomiting in highly emetogenic regimens.[ 1] Recombinant human granulocyte colony-stimulating factor (rhG-CSF, filgrastim [Neupogen]), if dosed appropriately, significantly reduced the duration of severe neutropenia through its role as the primary regulator of increased production and release of granulocytes from the bone marrow. The third event, the initial publication of a trial conducted by Abels et al, which evaluated recombinant human erythropoietin (rhEPO, epoetin alfa [Epogen, Procrit]) in the treatment of anemia associated with cancer, led to regulatory approval of this agent for chemotherapy-induced anemia only 14 years after the initial isolation of erythropoietin, 6 years after successful cloning of the gene, and 2 years after rhEPO received approval for treatment of anemia in the renal dialysis setting. Although ondansetron and rhG-CSF were quickly adopted into clinical practice, the use of rhEPO would remain limited until much later in the decade, due to its inconvenient schedule and a lack of appreciation of its benefit. New Mindset
These three events set the tone for the decade as the oncologist's mindset changed from the "no pain, no gain" of the 1980s to an appropriate weighing of treatment benefit/toxicity ratios. Chemotherapy that was clearly palliative began to be given in least-toxic regimens, as the use of sequential single agents and weekly regimens gained acceptance. Pain management turned from ablative neurosurgical procedures to new vehicles-both mechanical devices and drug formulations- for the delivery of pain medication. Surgical morbidity was decreased by procedures such as sentinel node biopsy, which would eliminate the need for roughly threequarters of the axillary node dissections performed in breast cancer patients, reducing the incidence of lymphedema and neurasthesia, with similar results in melanoma. Quality of life became accepted as a meaningful end point, not just in trials of supportive care, but also in trials of cytotoxic and biologic agents. Conformal radiotherapy limited organ toxicity, and now intensity-modulated radiotherapy promises to be even more effective by not only limiting toxicity but also allowing escalation of dose to the tumor. In this issue of ONCOLOGY, Dr. John Glaspy reviews the development, application, and future prospects of recombinant DNA-derived bone marrow growth factors. This is another of this author's insightful and thoughtprovoking articles on a subject he has championed since the early 1990s. In his usual style, Dr. Glaspy asks hard questions such as: Why do we find ourselves in the situation of using less than optimal doses of these agents due to cost limitations, and why are nephrologists more uniform and more successful in treating anemia than hematologists? Tremendous advances in the tolerability, safety, and efficacy of cancer treatment have resulted from recombinant DNA-derived bone marrow growth factors. Dose-dense chemotherapy is not feasible without myeloid growth factors. Pegylated rhG-CSF (pegfilgrastim [Neulasta]) has greatly improved the convenience and feasibility of administration, making it available to more patients with its singledose- per-cycle pharmacokinetics. Inadequate Practice Policies
Despite this progress, there remains inadequate use of rhG-CSF or pegylated rhG-CSF in regimens associated with a high risk of neutropenia. In practice, we unfortunately continue to find ourselves debating whether the risk of neutropenia needs to be 40%, as in prior American Society of Clinical Oncology guidelines, or the costeffective threshold of 20% when indirect costs are included in the analysis. We frequently find third-party payors and, even worse, some physicians continuing to require documented prior neutropenia before instituting therapy with myeloid growth factors. This occurs despite the highest risk of febrile neutropenia occurring in the first cycle of a chemotherapy regimen and, despite antibiotic therapy and other supportive care, carrying up to a 7% risk of death. rhEPO and darbepoetin alfa (Aranesp) have received regulatory approval only for the treatment of chemotherapy-induced anemia, not for chronic anemia of cancer. Three decades ago, Berlin stated that he had not seen, and did not expect to see, any remarkable new data on anemia of cancer. That changed dramatically with the isolation of erythropoietin and the eventual cloning of its gene. Almost a decade ago, Jerry Spivak, who has been a thought leader in this area for 2 decades, noted that erythropoietin was the first hematopoietic growth factor to be discovered and entered into clinical trials, extolling physicians to use it appropriately in the anemia of cancer and other anemias of chronic disease. He cautioned, at a time when this technology was just promising to unveil its potential benefit, that "a recombinant growth factor would be a terrible thing to waste." Through site-directed mutagenesis, we now have darbepoetin alfa with its longer half-life allowing less frequent dosing. However, millions of patients with other forms of anemia of chronic disease, as well as the patients previously mentioned with chronic anemia of cancer-all sharing a common etiology of relatively reduced erythropoietin production and reduced bone marrow responsiveness to this growth factor-remain basically untreated with recombinant growth factor. The other anemias of chronic disease, moreover, are untested in clinical trials 14 years after epoetin alfa's introduction into clinical use. These patients have a wide variety of diseases ranging from congestive heart failure to inflammatory bowel disease, as well as rheumatoid and other inflammatory arthritis conditions. They also include elderly individuals who are recovering from prior trauma, surgery, and medical complications and remain hospitalized in acute and chronic hospital facilities because they are unable to perform rehabilitative therapy, often simply due to anemia-related fatigue. Much has been accomplished in this field, but there is still much to be done. I salute Dr. Glaspy for championing these issues for more than a decade and congratulate him on his orderly, comprehensive, and thoughtprovoking article in this issue.
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. De Mulder PH, Seynaeve C, Vermorken JB, et al: Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind, crossover study. Ann Intern Med 113:834-840, 1990.
2. Lieschke GJ, Burgess AW: Granulocyte colony-stimulating factor and granulocytemacrophage colony-stimulating factor (1). N Engl J Med 327:28-35, 1992.
3. Abels RI, Larholt KM, Krantz KD, et al: Recombinant human erythropoietin (r-HuEPO) for the treatment of anemia in cancer, in Murphy MJ (ed): Blood Cell Growth Factors: Their Present and Future Use in Hematology and Oncology, p 122. Proceedings of the Beijing Symposium. Dayton, Ohio, Alpha Med, 1991.
4. Berlin NI: Anemia of cancer. Ann NY Acad Sci 230:209, 1974.
5. Spivak JL: Recombinant human erythropoietin and the anemia of cancer. Blood 84:997- 1004, 1994.