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Originally published as JCO Early Release 10.1200/JCO.2007.14.3941 on March 3 2008 © 2008 American Society of Clinical Oncology. Randomized Phase II Adjuvant Trial of Dose-Dense Docetaxel Before or After Doxorubicin Plus Cyclophosphamide in Axillary Node-Positive Breast Cancer
From the Ohio State University Medical Center and Comprehensive Breast Health Services; Clinical Trials Office of the Comprehensive Cancer Center; Department of Psychiatry, The Ohio State University; Mid-Ohio Oncology/Hematology Inc, Columbus; Oncology Partners Network, Cincinnati, OH Corresponding author: Charles L. Shapiro, MD, Ohio State University, Arthur James Cancer Hospital & Research Institute, 320 W 10th St, Starling-Loving Hall, B421, Columbus, OH 43210; e-mail: charles.shapiro{at}osumc.edu
Purpose An anthracycline-based combination followed by, or combined with, a taxane is the sequence used in most adjuvant chemotherapy regimens. We hypothesized that administering the taxane before the anthracycline combination would be associated with fewer dose reductions and delays than the reverse sequence. To test this hypothesis, a randomized phase II multicenter adjuvant chemotherapy trial was performed. Patients and Methods Fifty-six patients with axillary node-positive, nonmetastatic breast cancer were randomly assigned either to group A (docetaxel [DOC] 75 mg/m2 intravenously [IV] every 14 days for four cycles followed by doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 [AC] IV every 14 days for four cycles); or to group B (AC followed by DOC) at the identical doses and schedule. Pegfilgrastim 6 mg subcutaneous injection was administered 1 day after the chemotherapy in all treatment cycles. The primary objective was to administer DOC without dose reductions or delays before or after AC and calculate the relative dose intensity (RDI) of DOC and AC. Results The majority of toxicities were grade 0 to 2 irrespective of sequence. The RDI for DOC was 0.96 and 0.82, respectively, in groups A (DOC followed by AC) and B (AC followed by DOC), with more frequent dose reductions occurring in group B (46% v 18%). The RDI for AC was 0.95 and 0.98 in groups A and B, respectively. Conclusion The administration of DOC before AC results in fewer DOC dose reductions and a higher RDI than the reverse sequence. Larger trials evaluating the sequence of DOC before anthracyclines are justified.
Anthracyclines and taxanes are mainstays in treating women with axillary node-positive breast cancer. Large adjuvant taxane trials were designed to test whether there was benefit to taxanes after, or combined with, anthracycline-containing regimens.1-4 Thus, the standard sequence of adjuvant anthracycline-based combinations followed by (or with) taxanes was based on several factors including the nonoverlapping toxicities of the drugs; the principles of clinical trial design where the results from prior trials inform the design of future trials,5 and historical precedent (ie, clinical trials that established the benefits of anthracyclines before the taxanes). There are relatively few phase II trials evaluating the sequence of taxanes followed by anthracyclines, and virtually all of them are in the metastatic or neoadjuvant treatment setting.6-13 These relatively small trials show that administering the taxane first is feasible and without apparent diminution of antitumor activity or a higher incidence of expected toxicities relative to historical controls. The recognition that adjuvant taxanes add benefit to anthracyclines led to trials evaluating the optimal schedule. Based on mathematical modeling of tumor growth,14,15 shortening the interval between treatment cycles from every 3 weeks to 2 weeks, or using a dose-dense schedule, improved the outcome for patients with breast cancer with axillary node-positive disease.16,17 Dose-dense doxorubicin and cyclophosphamide (AC) followed paclitaxel is now one of the treatment options for node-positive women as defined by the National Comprehensive Cancer Network.18 We hypothesized that dose-dense docetaxel (DOC) followed by AC would result fewer dose reductions and maintain a higher relative dose intensity (RDI) than the reverse sequence. To test this hypothesis, a randomized phase II trial was designed with the primary objective of administering DOC without dose reductions or delays before or after AC and calculating the RDI. The standard dose of DOC was 100 mg/m2 intravenously (IV) every 3 weeks. The DOC dose was reduced to 75 mg/m2 IV every 2 weeks because of the relatively high incidence of severe mucosal and skin toxicity with 100 mg/m2 with growth factor support every 2 weeks.19-23
Patients with the following characteristics were eligible: histologically confirmed axillary node-positive breast cancer; age  18 years; ECOG performance status of 0 to 1; prior lumpectomy or mastectomy; no evidence of metastatic disease; and normal end-organ and bone marrow function as defined by leukocytes 3,000/µL; absolute neutrophil count of 1,500/µL; platelets 100,000/µL; hemoglobin 8.0 g/dL; total bilirubin, AST, ALT, and alkaline phosphatase  the upper limit of institutional normal (ULN); and creatinine ULN. If the creatinine was greater than the ULN, the creatinine clearance had to be greater than 60 mL/min. Eligible patients had normal cardiac function as defined by a left ventricular ejection fraction (LVEF) 50% by echocardiogram or radionuclide ventriculography (multiple gated acquisition scan) and an ECG without evidence of uncontrolled arrhythmias. Women whose tumors were Her-2/neu overexpressing (either 3+ by immunohistochemistry or fluorescence in situ hybridization positive) were eligible if they chose not to participate in the ongoing adjuvant trastuzumab trials or were ineligible for those trials.
Patients were excluded for the following: pre-existing
The treatment schema is illustrated in Figure 2. Patients in group A received DOC 75 mg/m2 IV every 14 days over 1 hour for a total of four cycles followed by doxorubicin 60 mg/m2 IV push over 2 to 5 minutes and cyclophosphamide 600 mg/m2 IV (AC) over 30 to 60 minutes; group B was the reverse sequence with the identical doses and schedule. Patients received 8 mg of oral dexamethasone 12 hours before, immediately before, and 12 hours after DOC. In each cycle, all patients received 6 mg pegfilgrastim subcutaneously the day after each chemotherapy treatment. Epoetin alpha or darbopoetin was used at the discretion of the treating physician.
Assessment of LVEF was performed within 4 weeks of starting chemotherapy, after four treatment cycles, and with 4 weeks of completing eight treatment cycles. CBCs were obtained before each scheduled treatment cycle.
Dose Reductions and Delays
Statistical Methods A 1:1 fixed-block randomization with a block size of 9 was used. After eligibility was confirmed at the coordinating center (the Ohio State University Medical Center and Comprehensive Breast Health Services, Columbus, OH), randomization occurred and the group assignment was then sent to the outside institution. The only stratification factor was ECOG performance status of 0 or 1. The treatment groups were designed as parallel phase II trials,24 without inferential statistical comparisons planned or performed in recognition of the possible false positive results in randomized phase II trials.25 The RDI per patient was calculated by the dividing the total cumulative drug doses the patient actually received per time (in mg/m2/wk) by the protocol-intended cumulative doses per time (in mg/m2/wk). The mean RDI was then calculated for each treatment group.
Fifty-six patients were enrolled between October 2004 and June 2006 (Table 1). The median age was 51 years (range, 33 to 75 years); all patients had an ECOG performance status of 0; 45% were premenopausal; 66% were hormone receptor positive; 73% were stage II, and the median number of positive axillary lymph nodes was 2 (range, 1 to 35). One patient (4%) in group A was HER-2/neu 3+ and chose not participate in an ongoing randomized adjuvant trastuzumab trial during the enrollment period.
Toxicity The majority of hematologic toxicities in both treatment groups were limited to grades 1 and 2 (Table 2). One patient (4%) had grade 4 febrile neutropenia in group A, and one patient (4%) had grade 4 thrombocytopenia in group B. In each treatment group, one patient (4%) required a transfusion of packed RBCs. Grade 4 nonhematologic toxicities were observed in two patients (7%; Table 3). One patient (4%) in group A had abdominal pain and one patient (4%) in group B had non-neutropenic infection with pneumonia and sepsis. No patients developed symptomatic congestive heart failure, myocardial infarction, or serious arrthymia. The median LVEF at baseline and after four and eight cycles was 61%, 58%, and 63% in group A, and 60%, 62%, and 60% in group B, respectively.
Grade 3 or higher toxicities that resulted in DOC dose reductions, delays, or both are described in Table 4. The primary difference was the greater frequency of total DOC dose reductions in group B (18% v 46% for groups A and B, respectively). Four patients (7%) were removed from study for toxicity or voluntary withdrawal. After four cycles of DOC, one patient (4%) in group A developed a prolonged duration of thrombocytopenia, and in group B, after four cycles of AC, one patient (4%) developed non-neutropenic pneumonia and sepsis requiring hospitalization and prolonged course IV antibiotics. Two patients (7%) in group B voluntary withdrew their consent after two and four cycles of AC, respectively. Although neither of these patients met protocol-specified criteria for removal from study, treatment-related toxicity was primarily responsible.
RDI The overall mean RDI for DOC was 0.96 in group A and 0.81 in group B. The RDI for AC was 0.95 and 0.98, respectively (Table 4). Figure 3 describes the mean RDI per cycle. The lowered DOC RDI for group B was based on the more frequent dose reductions and missing treatment cycles.
Neither treatment sequence was effective according the protocol-specified definition described in statistical section (23 or more patients completed DOC within 10 weeks without dose reductions or delays). Nonetheless, these results suggest that dose-dense DOC followed by AC is preferred because it has fewer dose reductions and a higher RDI than the reverse sequence. These findings are consistent with the other recent randomized phase II trial with similar patients that received either DOC (100 mg/m2 every 2 weeks for four cycles) followed by epirubicin and cyclophosphamide (EC; 75 mg/m2 and 500 mg/m2, respectively, for four cycles) or the reverse sequence with pegfilgrastin.20 The RDI for DOC were nearly identical to the current trial (Table 3) with 0.96 and 0.81 for DOC followed by EC and EC followed by DOC, respectively, and more than 0.95 for EC, irrespective of sequence. A similarly designed randomized phase II trial in metastatic breast cancer patients without prior chemotherapy for metastasis was performed by the North Central Cancer Treatment Group.7 Patients received either DOC (100 mg/m2 every 3 weeks for three cycles) followed by AC (60 and 600 mg/m2 every 3 weeks for three cycles) or the reverse sequence. Although the trial was stopped early for failure to meet the protocol-specified response rates,24 it is instructive to review the RDI for the 34 patients who were enrolled. Similar to the results in the current trial, the RDI of DOC was higher when it was administered before AC (0.85 v 0.42) whereas the RDI of AC was similar irrespective of sequence. In contrast, the results in another randomized phase II trial showed the RDI of DOC was similar whether it was administered before or after fluorouracil, epirubicin, and cyclophosphamide.8 The RDI was higher (0.97 v 0.89) and the pathologic complete response rate was nearly two-fold improved (17% v 9%) and when weekly DOC was followed by dose-dense doxorubicin as opposed to the reverse sequence in a randomized neoadjuvant phase II trial.26 Other phase II trials in the metastatic or neoadjuvant setting suggest that DOC followed by anthracyclines is devoid of severe and unexpected toxicities and the antitumor efficacy is within the range of the trials in which anthracycline-containing regimens were administered first followed by DOC.6,9-13 A limitation in all of these phase II trials, including our own, is the small samples with resultant wide confidence intervals surrounding estimates of toxicities, RDI, and antitumor efficacy. An adequately powered randomized phase III trial is required before definitive conclusions are reached regarding the toxicities, RDI, and antitumor efficacy of DOC before or after anthracyclines. Nonetheless, there is ample rationale for testing the sequencing of these drugs in a phase III trial. Is dose-dose DOC feasible to give to patients? DOC at 100 mg/m2 IV every 3 weeks after AC was recently evaluated in large adjuvant trial with a 5% incidence of grade 3 or higher mucositis and a 16% incidence of febrile neutropenia without growth factor.27 The incidence of grade 3 or higher mucosal and palmar-plantar erythroydsyesthesia (hand-foot syndrome) with DOC 100 mg/m2 IV every 2 weeks with growth factor support ranges between 20% to 40%.19-23 This degree of toxicity was felt to be unacceptable, hence the dose was reduced to 75 mg/m2. At this dose, DOC was well tolerated with only a 4% to 7% incidence of grade 3 and a 4% incidence of grade 4 nonhematologic toxicities when DOC was administered before AC (Table 4). We also measured quality of life using the M.D. Anderson Symptom Inventory,28 and the Functional Assessment of Therapy-Breast (FACT-B; version 4),29 before, during, and after treatment in a small subset of 20 randomly assigned patients (38%; data not shown). These instruments were added after the trial was opened for accrual in order to evaluate whether it was feasible for patients to complete these questionnaires during therapy. All 20 patients completed the instruments at the three time points. The ratings were similar in both treatment sequences, but this should be interpreted with caution because of the small sample size and the fact that this was neither a primary or secondary objective of the trial. Is there an underlying biologic rationale that would support treatment with taxanes first? In preclinical experiments, the sequence of administration of anthracyclines and taxanes may affect the relative cross-resistance to these drugs. Isogenic MCF-7 breast cancer cells made resistant to either doxorubicin or paclitaxel were tested for patterns of cross-resistance to taxanes and anthracyclines, respectively.30 MCF-7 cells resistant to doxorubicin were 4,700- and 14,600-fold resistant to paclitaxel and DOC, respectively, and had higher mRNA and protein expression of P-glycoprotein and breast cancer resistance protein. In contrast, MCF-7 resistant to paclitaxel had only four-fold cross-resistance to doxorubicin with lower expression of these proteins. Whether there are differential antitumor benefits depending on the sequence of administration of anthracyclines or taxanes is testable in the clinic. However, relatively few trials have addressed this question.31,32 The largest trial to directly test the sequence hypothesis was Intergroup trial E1193.32 More than 450 patients with untreated metastatic breast cancer were randomly assigned to receive either paclitaxel or doxorubicin, and at the time of disease progression there was a protocol-specified cross-over to the other drug. There were no statistically significant differences in response rates, time to treatment failure, or overall survival between paclitaxel followed doxorubicin or the reverse sequence. Thus, clinically meaningful differential patterns of cross-resistance in patients are not dependent on the sequence of anthracyclines and paclitaxel in patients with metastatic breast cancer. Whether this is true for all taxanes or in the adjuvant setting is unknown. Preliminary studies suggest that it may be possible to predict response, or resistance, to neoadjuvant DOC and anthracyclines using gene-expression profiling.33-39 In addition, the molecular subtypes of breast cancer have differential responses to neoadjuvant chemotherapy,40,41 and these gene expression profiles may change after exposure chemotherapy.35,42,43 Finally, pharmacogenomics of DOC may affect toxicities and antitumor efficacy.44,45 These factors represent end points that are feasible to include in a randomized trial designed to test the sequence hypothesis in a neoadjuvant setting. DOC administered prior anthracycline-containing regimens may have advantages over the reverse sequence when reduced toxicity and maintaining the highest RDI are considerations. National Surgical Adjuvant Breast and Bowel Project trial B-40 is an ongoing randomized neoadjuvant trial in which DOC alone, or in combination with capecitabine or gemcitabine, is followed by AC with or without bevacizumab.46 This trial and others support the sequencing of DOC followed by AC in National Surgical Adjuvant Breast and Bowel Project B-40. It is our opinion that a formal phase III neoadjuvant trial testing the sequence of DOC and anthracycline-containing regimens is justified and to our knowledge has not been performed.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Charles L. Shapiro, Sanofi-Aventis Expert Testimony: None Other Remuneration:
Conception and design: Donn Young, Charles L. Shapiro Administrative support: Susan Ottman Provision of study materials or patients: Ewa Mrozek, Kari Kendra, Mark Knapp, Tarel Patel, Mark E. Thompson, James F. Maher, Timothy D. Moore, Charles L. Shapiro Collection and assembly of data: Shannon Puhalla, Susan Ottman, Nancy J. Merriman, Charles L. Shapiro Data analysis and interpretation: Shannon Puhalla, Donn Young, Anne McVey, Charles L. Shapiro Manuscript writing: Shannon Puhalla, Charles L. Shapiro Final approval of manuscript: Shannon Puhalla, Ewa Mrozek, Donn Young, Susan Ottman, Anne McVey, Kari Kendra, Nancy J. Merriman, Mark Knapp, Tarel Patel, Mark E. Thompson, James F. Maher, Timothy D. Moore, Charles L. Shapiro
published online ahead of print at www.jco.org on March 3, 2008. Supported by a research grant from Sanofi-Aventis. Data management support by BridgeSite Clinical Research, Columbus, OH. Charles L. Shapiro was the recipient of an unrestricted educational grant from Sanofi-Aventis to support a breast cancer fellowship. Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 14-17, 2006. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Chang JC, Wooten EC, Tsimelzon A, et al: Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. J Clin Oncol 23:1169-1177, 2005 44. Bosch TM, Huitema ADR, Doodeman VD, et al: Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res 12:5786-5793, 2006 45. Lewis LD, Miller AA, Rosner GL, et al: A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and Caucasian cancer patients: CALGB 9871. Clin Cancer Res 13:3302-3311, 2007 46. National Surgical Adjuvant Breast and Bowel Project: Nearly 50 years of clinical trial history. www.nsabp.pitt.edu Submitted September 10, 2007; accepted December 10, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .10, and β = .10. If seven of nine patients completed DOC in 10 weeks without dose reductions or delays, then an additional 19 patients were treated. Of the 28 patients per group, if 23 or more completed the DOC within 10 weeks without dose reductions or delays then the sequence was effective. 
