Originally published as JCO Early Release 10.1200/JCO.2009.23.0508 on August 3 2009

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High Rate of Febrile Neutropenia in Patients With Operable Breast Cancer Receiving Docetaxel and Cyclophosphamide

Pharmacy Department, Carlo Fidani Peel Regional Cancer Centre, Credit Valley Hospital, Mississauga, Ontario, Canada

Robert Myers, Brian Higgins, Jeff Myers, Sudha Rajagopal

Medical Oncology Department, Carlo Fidani Peel Regional Cancer Centre, Credit Valley Hospital, Mississauga, Ontario, Canada

To the Editor:

The study by Jones et al¹ compared adjuvant treatment with docetaxel and cyclophosphamide (TC) to doxorubicin and cyclophosphamide for patients with early-stage breast cancer. After 5 years, the study found a 6% absolute advantage in disease-free survival with the TC regimen. At San Antonio Breast Cancer Symposium 2007, an update was presented after a median 7 years of follow-up that demonstrated a survival benefit as well. Based on such results, adjuvant treatment of intermediate-risk breast cancer using TC has been adopted at the Carlo Fidani Peel Regional Cancer Centre (Mississauga, Ontario, Canada). The Jones et al study, however, noted a trend toward more febrile neutropenia (FN; 5% v 2.5%, P = .07) in the TC group. We would like to submit our experience in which a substantially higher incidence of FN occurred in patients who were treated with TC. As a result, we now institute granulocyte colony-stimulating growth factor (G-CSF) primary prophylaxis in all of our patients when possible. If G-CSF prophylaxis is not feasible, the dose of docetaxel is reduced. To date, there has not been any further febrile neutropenic events in our patients receiving TC. This letter encourages other centers to consider our experience in light of guidelines to initiate prophylaxis with growth factors when the risk of FN is high.²

The Carlo Fidani Peel Regional Cancer Centre conducted an assessment of the first 12 patients treated with the TC regimen, without growth factor prophylaxis, between January and July 2008, and noted a 50% incidence (6 of 12 patients) of FN. This rate of FN differed noticeably from the 5% incidence in the Jones et al study. Similar to the Jones et al study, our 12 patients had a mean age of 55 years, were surgically cured and eligible for adjuvant chemotherapy, with 1 or fewer positive nodes. At baseline, all patients had normal lab values and no active infection. Aside from one patient who received radiation in 1997, there was no previous chemotherapy or radiation therapy. The average dose of docetaxel and cyclophosphamide infused over the first cycle were 73 mg/m² and 590 mg/m², respectively. Having comparable patient characteristics, an explanation for the different FN rates observed could be the use of antibiotic prophylaxis in the Jones et al study. It is of interest to note that, in the original 2006 publication, the authors stated that no prophylactic growth factors were used and the use of prophylactic antibiotics was at the discretion of the treating physician, while in the 2009 article it states that prophylactic quinolones were recommended but not required.³ Based on the statement published in 2006, patients in our center did not receive prophylactic antibiotics before starting TC.

With our higher than expected rate of FN, a few options warrant consideration in order to treat patients safely with the TC regimen. They include prophylactic antibiotics, prophylactic G-CSF, and/or first-line chemotherapy dose reduction. The use of prophylactic antibiotics remains controversial due to concerns of antimicrobial resistance and lack of mortality benefit.^4–7 In regard to the use of prophylactic G-CSF, current guidelines recommend its use when the chemotherapy is associated with a high risk of FN. For example, the National Comprehensive Cancer Network (NCCN) myeloid growth factors guideline recommends prophylaxis when the clinical risk of FN exceeds 20%.² Our recent experience would therefore support first-line G-CSF use for primary prophylaxis in patients receiving TC. Lastly, one may consider decreasing the dose of TC in patients who are unable to receive G-CSF. Data from Japan suggest that a lowered TC dose may be effective with no FN reported.⁸

While there may be a clear benefit of using adjuvant TC chemotherapy over AC chemotherapy for disease-free and overall survival in operable breast cancer, our experience exemplifies the need for additional data to quantify the incidence and degree of FN in this patient population. Since this is a small sample, we cannot exclude the remote possibility that such a high FN rate may be due to chance. Nevertheless, the discrepancy in how the usage of prophylactic antibiotics were described between the 2006 and the 2009 publication and the lack of information as to the actual number of patients given prophylactic antibiotics on the study is a cautionary tale for the adoption of new treatment strategies into the community setting without all the data presented. Future studies should take into account whether prophylactic antibiotics and/or prophylactic G-CSF have decreased the rates of FN in their study results. Meanwhile, until more information about the adverse effects of the TC regimen becomes available, one should monitor the rates of FN at one's own institution and select a prophylaxis option that can decrease this occurrence.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Jones SE, Holmes FA, O'Shaughnessy J, et al: Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research Trial 9735. J Clin Oncol 27:1177–1183, 2009.[Abstract/Free Full Text]

2. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: myeloid growth factors, 2008 update. http://www.nccn.org/professionals/physician_gls/PDF/myeloid_growth.pdf.

3. Jones SE, Savin MA, Holmes FA, et al: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 24:5381–5387, 2006.[Abstract/Free Full Text]

4. Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Inf Dis 34:730–751, 2002.[CrossRef][Medline]

5. Timmer-Bone JN, Tjan-Heijnen VC: Febrile neutropenia: Highlighting the role of prophylactic antibiotics and granulocyte colony-stimulating factor during standard dose chemotherapy in solid tumors. Anti-Cancer Drugs 17:881–889, 2006.[CrossRef][Medline]

6. Gafter-Gvili A, Fraser A, Paul M, et al: Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev 4:CD004386; 2006.

7. Pascoe J, Cullen M: The prevention of febrile neutropenia. Curr Opin Oncol 18:325–329, 2006.[Medline]

8. Tashiro H, Sagawa T, Okada K, et al: The safety of docetaxel with cyclophosphamide (TC) therapy as adjuvant chemotherapy for Japanese women with operable breast cancer [in Japanese]. Gan To Kagku Ryoho 34:393–396, 2007.

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Soong, D. Articles by Rajagopal, S. PubMed PubMed Citation Articles by Soong, D. Articles by Rajagopal, S. Social Bookmarking                            What's this?