When the use of prophylactic granulocyte-colony stimulating factor (G-CSF) to reduce febrile neutropenia (FN) was decreased in patients receiving chemotherapy for breast cancer, it led to a more than 5-fold increase in FN episodes and an early end to the clinical trial.
The study involving 167 patients was published in the December 1 issue of the Journal of Clinical Oncology.
In this prospective open-label phase 3 trial, the researchers, led by Maureen J. Aarts, MD, from Maastricht University Medical Center in the Netherlands, compared 2 treatment regimens in patients with early-stage breast cancer. All patients had a risk for FN of at least 20%.
One group of patients was randomly assigned to the G-CSF pegfilgrastim during all 6 cycles of chemotherapy, which is the standard of care. The other group was randomly assigned pegfilgrastim in only the first 1 or 2 cycles of chemotherapy.
The idea of limiting the use of G-CSF came from the observation that the highest incidence of FN is seen in the first 2 cycles of chemotherapy. The researchers posited that the abbreviated approach would be considered equivalent to the standard of care if there was an increase of no more than a 7.5% in cases of FN.
The benchmark was quickly surpassed, and an independent data monitoring committee advised that the trial be halted. At that point, 30 of 83 patients (36%) in the abbreviated group had experienced an episode of FN, whereas 8 of the 84 patients (10%) in the standard group had.
The unadjusted odds ratio (OR) for FN in the abbreviated group compared with the standard group was 5.4 (95% confidence interval [CI], 2.3 - 2.6). After adjustment for patient-specific risk factors, the adjusted OR was 5.8 (95% CI, 2.5 - 13.8). The unadjusted hazard ratio (HR) for the time to first FN event was 4.1 (95% CI, 1.9 - 9.0), and the adjusted HR was 4.2 (95% CI, 1.9 - 9.1).
The occurrence of grade 3 or 4 neutropenia was far higher in the abbreviated group than in the standard group (51% vs 6%).
"This study demonstrated that primary pegfilgrastim prophylaxis cannot be limited to the first 2 chemotherapy cycles because of an unacceptable high FN rate," Dr. Aarts and colleagues write. "In fact, this rate is as high as that reported in previous studies of TAC [docetaxel, doxorubicin, and cyclophosphamide] chemotherapy without primary G-CSF prophylaxis."
"On the basis of our results, we can only recommend continued use. Whether administration should continue past the third cycle was not tested, and hence, our recommendation cannot speculate on that. Therefore, we recommend primary G-CSF prophylaxis throughout all chemotherapy cycles in patients at risk for FN," they conclude.
Concerns About Cost of G-CSF Therapy
The cost of the G-CSF treatment, coupled with its increasing use with anthracycline and taxane therapy, is driving a discussion of the economics of its use.
In 2012, the American Society of Clinical Oncologists (ASCO) noted that there was "clear overuse" of CSF therapy, and highlighted this as 1 of 5 cancer practices that must stop. ASCO urged oncologists to reduce use of this prophylactic measure, particularly in patients who are not at the recommended risk level for FN. However, in their study, Dr. Aarts and colleagues followed ASCO guidelines, using G-CSF only in patients with a risk for FN above 20%.
Most of the therapy was adjuvant (87% in the standard group and 82% in the abbreviated group), and more than 90% of the patients in the trial were treated with a TAC regimen every 3 weeks (96% in the standard group and 93% in the abbreviated group).
This heavy use of TAC means these findings have little bearing for many oncologists in the United States, said Daniel Hayes, MD, Clinical director of the breast oncology program and Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Comprehensive Cancer Center in Ann Arbor.
"While this study basically says what I thought — that using a growth factor every 3 weeks decreases FN, for me it's a moot point. In my practice, and in many practices I'm aware of, most of us use doxorubicin and cyclophosphamide every two weeks, so most of us use a growth factor anyway. Most of us give pegfilgrastim every 2 weeks with doxorubicin and cyclophosphamide so we can get our patients through therapy sooner."
In an accompanying study, Dr. Aarts's research team evaluated the cost effectiveness of pegfilgrastim prophylaxis for FN. They conclude that skipping G-CSF after the first 2 chemo cycles saved an average of €3491 per patient. They estimate that nationwide, this would translate into a saving of €14.3 million each year.
However, this resulted in an unexpected and substantial increase in FN incidence. The researchers calculate that the incremental cost-effectiveness ratio for preventing an FN episode by giving G-CSF with every chemotherapy cycle, compared with only for the first 2 cycles, worked out to €13,112 per patient.
"When one is willing to pay at least €13,122 per patient with FN episodes prevented, 6 cycles of G-CSF prophylaxis is considered a cost-effective strategy," they conclude.
The authors of both studies and Dr. Hayes have disclosed no relevant financial relationships.
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