The 2006 San Antonio Breast Cancer Symposium brought together over 8,000 people from all corners of the globe for the unifying purpose of sharing the current state-of-the-art on all aspects of breast cancer.  As usual, this years symposium devoted time to significant advances in the entire spectrum of the disease including prevention, screening, prognostic factors, adjuvant chemotherapy, hormonal therapy and treatment of metastatic disease. This report discusses developments in supportive care for the treatment of breast.

Anemia and Fatigue

Maintaining quality of life while dealing with chemotherapeutic side effects or the complications of the disease itself is a major focus of breast cancer care. A great deal of work has firmly established the linkage between anemia and fatigue in cancer patients. The use of erythropoietic stimulating proteins to treat anemia, reduce fatigue and improve overall sense of well-being for chemotherapy-induced anemia (CIA) is well established and potentially important in women with breast cancer who have up to a two-thirds chance of becoming anemic.[1]

Refinements in the Treatment of CIA

Several papers at the symposium addressed refinements to the treatment of chemotherapy-induced anemia. Aapro et al. presented a trial of patients with MBC scheduled to receive anthracyclines and/or taxane-based therapies with a hemoglobin <12.9 gm/dl at screening to be randomized to epoetin beta 30,000 U SQ weekly or a placebo control for 24 weeks.[2] Mean hemoglobin levels increased from 11.7 to 13.3 gm/dl in the epoetin beta arm compared to no change in the control arm. After 18 months of follow up, 27% of patients were alive in both groups. No difference in PFS (p=0.448) or OS (p=0.522) were detected, but epoetin beta significantly reduced the risk for transfusion (HR=0.59, p=0.0097).  Thirteen percent of patients had a venous thromboembolic event compared to 6% in the control arm, but only 3% (8 pts) in the control arm had serious events compared to 4% (10 pts) in the epoetin beta group.

Early Intervention in CIA

Another study conducted a randomized comparison with early intervention with Aranesp® (darbepoetin alfa) 200 mcg every 2 weeks when the hemoglobin declined to < 11.5 gm/dl compared to waiting until the hemoglobin was < 10 gm/dl in patients receiving dose dense Adriamycin and cyclophosphamide followed by Taxol® (paclitaxel) .[3] The incidence of developing grade 2 anemia was significantly lower (p=0.043) in the early intervention arm, and the time maintained in the intended target hemoglobin rate of 11-13 gm/dl during dose dense chemotherapy was significantly longer for patients with early intervention with Aranesp.  The clinical benefit established by these and other studies of early intervention with erythropoetic stimulating proteins is clear but comes at a cost to both the patient and society.  Thus, it was reassuring to see a study evaluating cost effectiveness of the early intervention approach.[4] Early intervention reduced transfusion requirements, and, importantly, reduced drug utilization by demonstrating that the average dose of epoetin alfa in the early intervention patients was less than patients who initiated at more anemic levels. Further analyses of these types will help firmly establish the cost effectiveness benefit of treatment of chemotherapy-induced anemia.

Myelosuppression

The most common dose limiting toxicity for chemotherapy is myelosuppression. At the same time, there is abundant evidence from both retrospective and prospective studies that maintaining full doses of chemotherapy on schedule in the adjuvant treatment of breast cancer provides the best results. Despite the ability to abrogate myelosuppression in high risk regimens and patients by appropriate prophylactic use of growth factors, many clinicians choose instead to lower doses.

Dose Intensity and Hematological Toxicity

A registry study of 117 U.S. community oncology practices evaluated dose intensity and hematologic toxicity in older individuals receiving systemic chemotherapy.[5] About 3/4 of patients over 65 years of age and 85% of patients less than 65 had stage I-III disease. The average relative dose intensity (RDI) delivered was higher in younger patients compared to patients >65 years of age (p<0.01). Significantly fewer older patients received prophylactic colony stimulating factors over 4 cycles of therapy (18.7%), while 27.3 % of younger patients received such support (p<0.01). In contrast, there was no significant difference in erythropoietin usage by age.

In older patients, anthracycline containing regimens were more likely to cause febrile neutropenia or severe neutropenia (p<0.01), thrombocytopenia (p<0.01), or anemia (p<0.01). Prophylactic use of CSF was documented in 15% of patients. Of concern is the fact that 43% of older patients had a planned RDI > 85% by their physicians, but in fact only 15.9% received this degree of dose intensity. These results suggest there is substantial room for improvement in delivering dose by more appropriate use of growth factor.

Prophylactic Growth Factor Use

Defining exactly who the patients are most likely to benefit from prophylactic growth factor use in the adjuvant setting was the focus of several reports at this year’s meeting. Lyman, et.al presented a prospective validation study of their risk model predicting neutropenic complications in early stage breast cancer patients receiving adjuvant chemotherapy.[6] Factors associated with 1st cycle severe or febrile neutropenia were derived from a data set of patients in a registry trial and included the number of myelosuppressive agents, chemotherapy regimen, planned RDI > 85%, use of certain concomitant medications, hyperglycemia and elevated creatinine. A validation data set was able to separate patients into a bimodal distribution for high risk of 1st cycle neutropenic events of 53% vs. 5% in low risk patients. By using this risk model judiciously, clinicians could potentially improve patient care by applying prophylactic growth factor usage in a more targeted fashion, reducing unnecessary dose reduction while making this supportive therapy more cost effective.

The U.S. Oncology group took another approach to this issue by reviewing the number of neutropenic events that occurred in two of their trials both utilizing standard every three week Adriamycin at 60 mg/m2 and cyclophosphamide 600 mg/m2 without prophylactic growth factors.[7] The incidence of febrile neutropenia in cycle 1 was 3.4% and rose to 6% if both cycle 1 and 2 were considered. This level is well below the 10-20% risk, at which point NCCN guidelines indicate growth factors should be considered prophylactically. It would be interesting to apply a risk model to patients from this study to ascertain if the model accurately predicted the group with events.

Dose Dense Setting

Finally, in dose dense chemotherapy, growth factor usage is considered mandatory to allow shorter cycle times of chemotherapy. A group from Memorial Sloan-Kettering Cancer Center presented a pilot study of growth factor omission during the Taxol portion of dose dense chemotherapy.[8] Unfortunately, 40% of patients were unable to receive all four doses of Taxol on time without utilization of Neulasta® (pegfilgrastim) and the need was not predictable by prior WBC or ANC. This group plans further studies to refine growth factor use in this setting.

Conclusion

In sum, there is growing evidence that patients can be selected for need for growth factor usage prior to initiating adjuvant chemotherapy for breast cancer, allowing for more patients to receive the full schedule of planned dose on time and yielding the best long term results in this curative setting.

References

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[1] Ludwig H, Van Belle S, Barrett-Lee P, et al.  The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. European Journal of Cancer 2004;40(15):2293-2306.