Microsoft word - febrile neutropenia with tc.docx

Neutropenic Fever with Taxotere and Cytoxan Febrile Neutropenia with Docetaxel / Cyclophosphamide (TC) as Adjuvant Therapy in Breast Cancer
The NCCN guidelines version 2.2011 lists TC as one of the five preferred category 1 recommendations inthe adjuvant treatment of early stage breast cancer. Because of this and the available data, TC is acommonly utilized regimen in such settings. Docetaxel and Cyclophosphamide are general yadministered every 21 days for a total of four cycles at doses of 75mg/m2 and 600mg/m2 respectively inthe TC regimen. The most recent NCCN guidelines on the use of myeloid growth factors (version1.2011) do not list TC as either high or intermediate risk for development of febrile neutropenia. Despitethis, Oncology Analytics has observed frequent usage and requests by oncologists for the use ofpegfilgrastim or filgrastim as primary prophylaxis with this regimen. In view of this, Oncology Analyticsundertook a literature review to identify the approximate risk of neutropenic fever with TC.
The pivotal phase 3 trial which investigated TC in the adjuvant breast cancer setting was the USOncology-9735, which now has been published twice (Jones SE. 2006; Jones SA.2009). The trialrandomized more than 1000 patients to either AC or TC, and 506 patients were evaluated for safety onthe TC arm. No prophylactic white blood cel growth factors were administered in the study. Evaluationshowed a 51% incidence of Grade 4 neutropenia (ANC < 500/µL), and 10% incidence of Grade 3neutropenia (ANC 500-< 1000/µL). Despite a very significant high rate of Grade 3 / 4 neutropenia, theevent of neutropenic fever occurred in only 25 patients (5%) out of 506 (Jones SE. 2006). At the time ofre-publication of the trial in 2009, the data was analyzed by an age cut-off of 65 years. Among thosewho were less than 65 years of age (n = 428), the rate of Grade 3 / 4 neutropenia and febrileneutropenia were 60% and 4% respectively. Patients who were deemed to be elderly with age ≥ 65 (n = 78), the incidence of Grade 3 / 4 neutropenia and febrile neutropenia were 52% and 8% respectively(Jones SAE. 2009). Clearly, age influenced the incidence of febrile neutropenia in the study, though theincreased incidence in this pivotal US Oncology study stil remained within the cut-off (10%) whereincidence is deemed to be low risk.
In response to the relatively lower risk of febrile neutropenia in a large number (> 500) of patientsreceiving TC in the pivotal Jones study, Soong et al from Canada responded with a letter, whichmentioned their observation of 50% (6 out of 12 patients) developing febrile neutropenia in the absenceof primary prophylaxis (Soong D. 2009).
Many retrospective or observational studies have since also commented on febrile neutropenia risk withTC. An observational study in a group of 39 patients treated with TC in the adjuvant setting reported a Copyright 2011 Oncology Analytics Inc.
Neutropenic Fever with Taxotere and Cytoxan 33% incidence of febrile neutropenia. (Vandenberg T. 2010). Another retrospective analysis showed arisk of febrile neutropenia of 25% (Chan A. 2009) In a Japanese experience, in which four cycles of TC were administered to 53 breast cancer patients, theGrade 4 neutropenia was 71.7%, Grade 3 neutropenia was 25% and the febrile neutropenia rate was28% (Takabatake D. 2009) Another retrospective study from Hongkong showed the risk of Grade 3 / 4 neutropenia and febrileneutropenia of 95% and 21% respectively (Tsz-Kok Y. 2009).
A recent report from a community practice in Australia in 74 patients showed that adjuvant TC resultedin an overal incidence of neutropenic fever of 21.6% (Kotasek D. 2011) The largest experience with TC is from the pivotal US oncology trial (n > 500), and this showed low risk offebrile neutropenia in both patients below and above 65 years of age. However, none of the othergroups in their retrospective analyses came close to the rates shown by the Jones trial. The otherpublications are limited by their much lesser sample size and retrospective nature. Despite theselimitations, it is the opinion of the Oncology Analytics that the col ective experience of so many differentgroups should not be simply ignored even though these observations are not coming from prospectiveor randomized trials. Coupled with this is the high rate of Grade 3 / 4 neutropenia seen in the Jones trial.
Clearly TC is a myelosuppressive regimen, though it is not clear why this high rate of Grade 3 / 4neutropenia did not translate into the clinical events of febrile neutropenia in the Jones trial.
In view of al the above, it is the opinion of Oncology Analytics that TC should be treated as having anintermediate risk for neutropenic fever, despite the fact that the NCCN guidelines do not include TC inthe list of intermediate risk regimens. Accordingly, if the patient has any additional clinical risk factor forneutropenic fever, such as age > 65 years, primary prophylaxis with white blood cel growth factors isconsidered appropriate.
1. NCCN Guidelines version 2.2011; Invasive breast cancer. BINV-K Page 1 of 52. NCCN Guidelines version 1.2011; Myeloid Growth Factors. MGF-A Page 1 and 2 of 5 Copyright 2011 Oncology Analytics Inc.
Neutropenic Fever with Taxotere and Cytoxan 3. Jones SE et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol.
2006;24(34):5381-7 4. Jones SE et al. Docetaxel With Cyclophosphamide Is Associated With an Overal Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Fol ow-Up of US Oncology ResearchTrial 9735. J clin Oncol. 2009;27(8):1177-83 5. Vandenberg T et al. Febrile neutropenia rates with adjuvant docetaxel and Cyclophosphamide chemotherapy in early breast cancer: discrepancy between published reports and community practice—a retrospective analysis. Current Oncology 2010;17(2):2-3 6. Soong D et al. High Rate of Febrile Neutropenia in Patients With Operable Breast Cancer Receiving Docetaxel and Cyclophosphamide. J Clin Oncol. 2009;27(26):e101-102 7. Chan A et al. Impact of colony stimulating factors to reduce febrile neutropenic events in breast cancer patients receiving Docetaxel plus cyclophosphamide chemotherapy. Supportive Care 8. Takabatake D et al. Feasibility Study of Docetaxel with Cyclophosphamide as Adjuvant Chemotherapy for Japanese Breast Cancer Patients. Jpn J Clin Oncol. 2009;39(8):478-483 9. Tsz-Kok Y et al. Toxicity of docetaxel plus cyclophosphamide as adjuvant therapy for breast cancer in Chinese patients – the Hong Kong experience. Asia-Pacific Journal of Clinical oncology 10. Kotasek D et al. Febrile neutropenia rates during docetaxel and cyclophosphamide (TC) adjuvant therapy in early breast cancer (EBC). Proc ASCO 2011; Abstract 1101 Copyright 2011 Oncology Analytics Inc.

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