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Hematopoietic Management in Oncology Practice

Hematopoietic Management in Oncology Practice

This timely and elegant article by Glaspy reviews current data supporting the clinical role of hematopoietic growth factors. As the author thoroughly discusses, the introduction of myeloid and erythroid regulatory proteins more than a decade ago has had a dramatic impact on the care of patients with a variety of cancers and hematologic disorders, as well as other diseases. A large body of research allows us to draw some important conclusions about the rational and appropriate use of these agents. However, as stated in this article, a number of important questions remain. A variety of preclinical and clinical findings demonstrate that granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) and granuloctye-macrophage colonystimulating factor (GM-CSF, sargramostim [Leukine]) are not identical, nor do they have equivalent biologic activity. Numerous randomized trials have demonstrated that in patients receiving myelosuppressive chemotherapy, prophylactic use of G-CSF reduces both the degree and duration of neutropenia. Several issues, however, need to be addressed further to allow us to best treat patients, particularly in the context of cost-effective use of medications and health-care resources. Dose and Schedule
As Glaspy notes, while a doseresponse relationship exists between G-CSF and neutrophil production, the optimal dose and schedule of G-CSF has not been fully explored. Several randomized trials have investigated a dose range of G-CSF, with no significant overall benefit demonstrated thus far for higher-dose therapy. However, it is reasonable to hypothesize that higher- dose therapy may be beneficial in selected populations. For example, it is possible that, in patients who develop febrile neutropenia de- spite receiving conventional doses of G-CSF, higher-dose therapy may be of benefit. Similarly, limited data have suggested that, in certain settings, lower- dose therapy may be as effective as the current clinically accepted dose. Further exploration of these questions could have a significant clinical impact and allow us to utilize expensive resources more efficiently. However, as Glaspy notes, it is important to emphasize that the dose and schedule of G-CSF should not be arbitrarily altered from that which has been proven effective, until such changes are supported by appropriate data and studies. Febrile Neutropenia
One clinically important issue reviewed in this article is the treatment of febrile neutropenia. Specifically, this refers to patients who have not received prophylactic G-CSF and develop febrile neutropenia secondary to myelosuppressive chemotherapy. Management of these patients remains controversial. However, several randomized clinical trials have now addressed this question. Interestingly, a consistent finding has been that therapy with G-CSF leads to a statistically significant decrease in the duration of grade 4 neutropenia that is of a clinically meaningful magnitude. Probably what has primarily hindered clinical acceptance of these data, however, is the lack thus far of a proven benefit in quality of life, cost-effectiveness, or survival. As to lack of a proven survival benefit, likely this is due to the fact that the mortality rate associated with febrile neutropenia in patients with solid tumors is low, many of these individual trials were relatively small in size, and therefore they are not adequately powered to detect a mortality difference. Indeed, a recent meta-analysis by Clark et al suggests that infectionrelated mortality may be improved in certain high-risk patients with febrile neutropenia who receive treatment with G-CSF.[1] In addition, this metaanalysis confirms a shorter time to adequate neutrophil recovery with the use of G-CSF in this setting (previously demonstrated in several individual trials) and a shorter length of hospitalization.[1] Although it is clearly important to demonstrate this conclusively with appropriately designed studies, one can readily hypothesize that the use of G-CSF in this setting may both improve quality of life and reduce overall health-care costs, if costs of hospitalization, antibiotics, and so forth are adequately captured. As noted in this review, some of these questions have perhaps become less critical with the availability of a pegylated formulation of G-CSF (Neulasta). This recently approved compound has an increased pharmacologic half-life compared to the parent moiety, and the data have demonstrated that this new formulation is at least equivalent therapeutically to conventional G-CSF, with no greater toxicity. However, several of the points noted above in regard to G-CSF are equally applicable to pegylated G-CSF. Although a reasonable dose is known, is this the optimal dose for all patients? In patients who develop febrile neutropenia despite prophylactic use of pegylated G-CSF, would a higher dose be of benefit? Would an altered dosing interval be effective in this setting? Are there specific low- or moderate-risk patient populations in whom lower-dose therapy might be equally effective? Concurrent Use of G-CSF and Chemotherapy
A long-standing theoretical concern in hematopoiesis has been the issue of concurrent use of G-CSF and chemotherapy, which might cause myeloid progenitor cells to be more sensitive to cytotoxic agents as G-CSF induces these cells to enter the proliferative phase of the cell cycle. Thus, concurrent use of G-CSF and chemotherapy might be associated with increased severity of neutropenia. Some limited older clinical data have suggested this possibility. Interestingly, however, at least one recent clinical trial that addressed this issue did not demonstrate an adverse effect for concurrent administration of G-CSF, compared to conventionally dosed G-CSF administered 24 hours after the completion of chemotherapy. This was noted in breast cancer patients who were receiving high-dose vinorelbine.[2] Additionally, recent preclinical data suggest that G-CSF can be safely and effectively administered concurrently with at least several commonly used cytotoxic agents. This question has assumed greater importance over the last couple of years with the more frequent use of weekly and other novel schedules of cytotoxic agents. In light of the availability of pegylated G-CSF, the question of concurrent use of growth factor assumes even greater importance, because if proven effective, it would allow a single subcutaneous injection to be administered immediately after chemotherapy. The inconvenience of having to wait 24 hours after chemotherapy before administering growth factor therapy would be eliminated. Dr. Skip Burris and I are currently testing this concept in a randomized clinical trial evaluating same day vs conventionally dosed pegylated G-CSF therapy in breast cancer patients receiving the TAC regimen (docetaxel [Taxotere], doxorubicin [Adriamycin], cyclophosphamide [Cytoxan, Neosar]). This issue has become particularly timely in the adjuvant therapy of nodepositive breast cancer. Cancer and Leukemia Group B 9741 has recently demonstrated a significantly superior efficacy of a dose-dense every-2-week schedule of doxorubicin, cyclophosphamide, and paclitaxel compared to a conventionally dosed every-3-week schedule in women with node-positive breast cancer.[3] This dose-dense regimen was given with conventional prophylactic G-CSF to all patients. The safety and efficacy of pegylated G-CSF combined with such dosedense therapies will also need to be evaluated, given its prolonged clearance and the possibility of a negative impact of concurrent cytotoxics and myeloid growth factors. Anemia in Cancer Patients
Glaspy nicely reviews some important historical points that put in perspective the current data (and current practices) with regard to the treatment of anemia in cancer patients. Probably to a greater extent than for myeloid growth factors, the optimal dose and schedule of recombinant human erythropoietin (rhEPO, Epogen, Procrit) and darbepoetin alfa (Aranesp) remain to be defined. The author nicely summarizes the critical clinical literature that defines our current management of anemia. It is important to note that recent literature has clearly demonstrated a significant relationship between hemoglobin level and quality of life. Evolving data have shown that what had once generally been considered modest decreases in hemoglobin levels are clearly associated with substantial symptoms that have a negative impact on patients. A thought-provoking point made in this article concerns the evolving data supporting the concept that the patients who may benefit most from the treatment of anemia-ie, those with hemoglobin levels of 11 to 12 g/dL- are the ones who have historically been least likely to receive therapy. Indeed, this article nicely puts into perspective many of the historical issues and background concepts that have led to our current approach to treating anemia in cancer patients. Current data supporting the dose and schedule of both rhEPO and darbepoetin alfa are well summarized. The author thoroughly reviews pilot data suggesting that alternative doses and schedules of darbepoetin alfa may ultimately be more effective and lead to a more rapid rise in hemoglobin levels. The current widely accepted dosing schedule of darbepoetin alfa (ie, every-2-week therapy) is reviewed, and it is briefly noted that pilot data suggest that darbepoetin alfa might be effective when administered on an every-3-week schedule. In fact, a recently published study has demonstrated that the every-3-week schedule of darbepoetin alfa is clearly effective, and further provides reasonable insights into the appropriate dose on this schedule.[4] Recent data have demonstrated that effective treatment of anemia in cancer patients is associated with significant improvements in fatigue and other parameters of quality of life. Glaspy notes several interesting points that distinguish the therapy of anemia in renal patients from that in hematology and oncology patients. Importantly, he explains that the toxicities of red blood cell growth factors are significantly less severe in patients who do not have end-stage renal disease, and that, in fact, we should be exploring approaches that might lead to more rapid relief of anemia-related symptoms in our patients. Conclusions
Finally, this paper nicely reviews the current "hot issues" in the treatment of anemia, particularly as they relate to cancer patients. In addition to further study exploring the dose and schedule of erythropoietin and darbepoetin alfa, Glaspy points out that critically undefined relationships of iron metabolism, and potentially iron therapy, require further research. Provocative recent findings suggest a possible relationship between anemia and overall survival in a variety of different cancers. Whether these findings merely demonstrate an association, and not a causal relationship, remains to be conclusively proven. Perhaps anemia is a surrogate marker of patients who have poorer survival for unrelated reasons. Alternatively, anemia could be causally related to these outcomes, perhaps due to the impact of effectiveness of therapies, or perhaps due to other as yet not fully characterized physiologic relationships. Perhaps therapy of anemia may ultimately lead to better outcomes and cure in patients with a variety of cancer types.

Disclosures

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.

References

1. Clark OA, Lyman G, Castro AA, et al: Colony stimulating factors for chemotherapy induced febrile neutropenia. Cochrane Database Syst Rev 3:1-30, 2003.
2. Livingston RB, Ellis GK, Gralow JR, et al: Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 15:1395-1400, 1997.
3. 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 (erratum appears in J Clin Oncol 21:2226, 2003). J Clin Oncol 2:1431-1439, 2003.
4. Kotasek D, Steger G, Faught W, et al: Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind, placebo-controlled, randomised study. Eur J Cancer 39:2026-2034, 2003.
 
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