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© 2002 American Society for Clinical Oncology Dose-Dense Anthracycline-Based Chemotherapy for Node-Positive Breast CancerByFrom the Division of Medical Oncology, University of Washington, and Fred Hutchinson Cancer Research, Seattle, WA. Address reprint requests to Georgiana Ellis, MD, Division of Medical Oncology, Seattle Cancer Care Alliance, 825 Eastlake Ave E, G3-200, Seattle, WA 98109-1023; email: gellis{at}u.washington.edu
PURPOSE: Theoretical considerations and clinical experience suggest that dose-dense chemotherapy may be superior to other approaches using the same drugs. We studied a dose-dense combination of doxorubicin and cyclophosphamide, with or without fluorouracil, as adjuvant therapy. PATIENTS AND METHODS: Patients with resected breast cancer were treated if they were node-positive and estrogen receptor–negative, positive for overexpression of Her-2-neu, or had four or more involved nodes. Doxorubicin was given weekly to a total dose of 480 mg/m2. Cyclophosphamide 60 mg/m2 was given daily by mouth during the period of doxorubicin treatment. The first 30 patients received fluorouracil at 300 mg/m2/wk intravenously concurrently with doxorubicin administration. In the last 22, it was omitted because of symptomatic hand-foot syndrome in the majority of patients. Filgrastim (granulocyte colony-stimulating factor [G-CSF]) was administered during chemotherapy every day except the day of intravenous administration and continued until 1 week after the completion of the chemotherapy. RESULTS: Between October 20, 1992, and June 10, 1997, we enrolled 52 patients. The mean delivered dose-intensity for doxorubicin was 18.6 mg/m2/wk. Hospitalization was required in 6% of patients for reversible febrile neutropenia. There were no acute treatment-related deaths, but one patient subsequently died of acute leukemia with a characteristic translocation for anthracycline-related exposure. At 5 years, the event-free survival was 86% for all patients (95% confidence interval, 75% to 95%). CONCLUSION: Continuous dose-dense chemotherapy with G-CSF support produced encouraging results, which seem to be superior to those expected with "standard" doxorubicin and cyclophosphamide chemotherapy. It deserves a test in the form of a randomized trial where this approach to anthracycline-based treatment is compared with intermittent administration.
THREE CONCEPTS related to dose have been postulated in the chemotherapy of breast cancer.1 The first is that of dose response. This implies the importance of achieving a high-peak drug concentration with the intent of overcoming resistance and is usually relevant to treatment regimens given in a pulsed fashion over a short period of time, requiring substantial inpatient supportive care and often the infusion of bone marrow-derived stem cells. The second concept relates to dose-intensity, commonly expressed as milligrams per square meter per week.2 This concept is generally applicable in the context of outpatient therapy and implies repeated administration over time but without reference to frequency. Dose density implies a strategy of multifractionated dosing at intervals that are closer together than those customarily used.3 It has been applied in regimens where growth factor support was used to permit dosing at 2- rather than 3-week intervals.4,5 However, in these programs, the concept of sequential, single-agent therapy was applied as well, making the contribution of dose density per se difficult to interpret. We have attempted to apply the principle of near maximal frequency of drug administration (weekly and daily) to delivery of a multidrug regimen given simultaneously, rather than sequentially. This possesses the advantage of providing tumor cell exposure to agents with multiple mechanisms of action and potential non–cross-resistance, which may result in incremental cell kill as opposed to sequential single-agent exposure. Assuming the administration of a threshold dose, dose density should result in prolonged tumor exposure times to drugs at potentially therapeutic concentrations. In addition, the multifractionated approach permits real-time monitoring to make dose adjustments and preclude more severe toxicity. In studies of weekly chemotherapy given with concurrent granulocyte colony-stimulating factor (G-CSF) support, our group has demonstrated the feasibility and safety of such an approach, making it possible to combine the principles of dose-intensity and dose density in the management of patients with advanced, anthracycline-pretreated disease.6-8 Furthermore, Ellis et al9 demonstrated the feasibility, safety, and efficacy of combining weekly doxorubicin, daily oral cyclophosphamide, and concurrent G-CSF in a Southwest Oncology Group trial of patients with locally advanced breast cancer. We describe here the results of the application of this basic program to patients with node-positive resected disease.
To be eligible for the study, patients had to have completely resected (pathologic margins negative), invasive breast cancer metastatic to axillary lymph nodes and fall in at least one of these categories: (1) positive for overexpression of Her-2-neu by immunohistochemistry; (2) hormone receptor–negative by immunohistochemistry; or (3) four or more axillary nodes positive. Liver function tests required a total bilirubin  2 mg/dL and transaminase levels two times the upper limit of normal, and serum creatinine had to be 1.5 mg/dL. All patients also underwent laboratory evaluation, which included a complete blood cell (CBC) and platelet count and evaluation of carcinoembryonic antigen and CA 27.29. A chest x-ray was performed in all patients, but other baseline imaging studies (eg, computed tomography, bone scans, and nuclear gated heart scans) were not required unless deemed to be clinically indicated. Patients with clinically apparent cardiac disease were excluded, as were those with a previous cancer diagnosis, a history of previous chemotherapy or radiation therapy, pregnancy, or evidence of active infection. Finally, all patients had to be able to give written informed consent and did so through a document approved by our human institutional review committee.
Treatment Plan A CBC with platelets and neutrophil determination was performed before each dose of planned weekly IV chemotherapy. Monthly blood chemistries were obtained to include standard liver function tests, lactate dehydrogenase, and creatinine. Nonhematologic toxicity was assessed and graded by the treating physician on a monthly basis.
Dose Modifications 5-FU. The guidelines were identical to those for doxorubicin. Cyclophosphamide. This drug was discontinued for 1 week for the same hematologic indications as for doxorubicin and resumed after recovery at a 25% dose reduction. Cyclophosphamide was omitted for mucositis severe enough to interfere with oral dosing. The drug was to be omitted for the development of hemorrhagic cystitis (no cases occurred). G-CSF. No dose adjustments were made unless the patient developed bone pain with an absolute neutrophil count more than 20,000/mL. In such cases, the dose was reduced by 25% to 50%.
Radiotherapy
Tamoxifen
Follow-Up Studies
Biostatistics Disease-free and overall survival. Actuarial estimates were made using the method of Kaplan and Meier starting from the date the patient was registered onto protocol. A recurrence at any site, including loco-regional, was counted as a recurrence.
Between October 20, 1992, and June 10, 1997, a total of 52 patients were entered onto the study. Their pretreatment characteristics are summarized in Table 1. All toxicity is reported according to the National Cancer Institute common toxicity criteria, version 2.
Hematologic Toxicity Hematologic toxicity is shown separately for the three-drug and two-drug combinations (Table 2). The dose of cyclophosphamide was the same in both, but the first included 5-FU and the second increased doxorubicin dose.
Combining the two regimens, grade 3 or 4 neutropenia was seen in 19 patients (36.5%), with three patients who required admission for febrile neutropenia (two on the three-drug and one on the two-drug regimen for chemotherapy). Anemia of grade 3 or 4 was seen in six patients, all on the three-drug regimen. Only one case of grade 3 and none of grade 4 thrombocytopenia occurred. One patient, a 28-year-old, developed acute myeloid leukemia at 10 months from the initiation of therapy. Cytogenetic studies revealed that this leukemia had the characteristic translocation (11q23) reported for anthracycline-related bone marrow disorders. The patient was placed on induction chemotherapy with cytarabine and daunorubicin, but failed to respond and died of intracerebral hemorrhage at 11 months on study. No other cases of leukemia or myelodysplasia were observed.
Nonhematologic Toxicity
Dose-Intensity Planned and delivered dose-intensities for each regimen are listed in Table 4. As expected, the delivered dose-intensity for doxorubicin was higher on the two-drug regimen (mean, 20.1 v 17.5 mg/m2/wk). The mean delivered dose-intensity was 88% of planned for FAC+G and 84% of planned for AC+G with respect to doxorubicin and identical for cyclophosphamide (81% of planned). On the 5-FU–containing regimen, mean delivered dose-intensity was 76% of planned for that agent.
Disease-Free Survival and Overall Survival With a median follow-up of 65 months, the 5-year actuarial disease-free survival was 85% for the two regimens combined (Fig 1). No difference was apparent between FAC+G and AC+G (widely overlapping confidence intervals [CIs]). The 95% CIs on our observed result at 5 years are 75% to 94%. Overall survival is projected as 86% at 5 years for the regimens combined (Fig 2). We compared disease-free and overall survival by hormone receptor status (positive v negative) and by Her-2-neu status (positive v negative). In neither case was a statistically significant difference observed. There have been a total of eight relapses (four on FAC+G and four on AC+G) occurring at 6 to 61 months on the study (median, 10 months). The sites involved were locoregional in five patients (four at the primary site and one in axillary nodes), supraclavicular lymph nodes and bone in one patient, liver, lung, and bone in one patient, and liver only in one patient. There were no sites of initial relapse in the CNS.
We report here the outcome of two regimens using a very dose-dense and moderately dose-intense approach. To our knowledge, doxorubicin on a weekly basis combined with continuous oral cyclophosphamide has only been previously reported by our group. Another unique aspect of this approach is the use of growth factor support on a concurrent basis with adjuvant chemotherapy. If one assumes that a delivered doxorubicin dose-intensity of 15 mg/m2/wk is at a threshold for optimal outcome, it seems that the growth factor support is needed; in our previous experience with a continuous FAC regimen that had identical planned dose-intensities to those described here, only 19% of patients received a mean doxorubicin dose-intensity of more than 15 mg/m2/wk (G.K. Ellis, unpublished data), whereas 90% of patients receiving the identical regimen, except for the use of G-CSF, were able to achieve this level of doxorubicin dose-intensity. The use of concurrent G-CSF support raises concerns about the possibility of enhanced leukemogenesis. Indeed, our only treatment-related death in this experience was from acute leukemia, with its onset at 5 months from completion of treatment, and the characteristic 11q23 translocation seen with anthracycline-related myelodysplasia and acute leukemia.10 However, we have now treated a total of 185 patients with these regimens in the adjuvant or neoadjuvant setting, of whom 132 were not included in this report because they were node-negative, locally advanced at presentation, or went on to receive high-dose consolidation or other systemic chemotherapy; so far, our single patient is the only case observed. It therefore seems likely that the true incidence of acute leukemia related to this approach is in the same range of approximately 1% reported by others for anthracycline-based adjuvant therapy.11,12 Further support for this contention is lent by the evidence that G-CSF does not act primarily at the level of the bone marrow stem cell,13 by the observation that its use in the treatment of acute leukemia is not deleterious,14 and by its reported efficacy in the treatment of aplastic anemia.15 The acute hematologic toxicity of this regimen was quite acceptable. Five patients had grade 4 neutropenia (10%), and three required hospitalization for neutropenic fever (four if the patient admitted with presumed Pneumocystis pneumonia and lymphopenia is included). This may be contrasted to the need for hospital admission in 69% of the patients reported by Hudis et al5 with a sequential dose-dense approach that used these two drugs as consecutive single agents given at much higher individual doses. In that study, the planned dose-intensity for doxorubicin was much higher for the period of drug administration (45 mg/m2/wk over 6 weeks). However, if one calculates dose-intensity planned for doxorubicin over the entire period of administered chemotherapy as described by Hryniuk el al,16 it would be 15 mg/m2 for the study of Hudis et al,5 which is lower than our planned intensities of 20 and 24 mg/m2/wk in the current study. Furthermore, the total planned dose of doxorubicin in both of our regimens was 480 mg/m2, given over 20 to 24 weeks, whereas in the study of Hudis et al5 it was 270 mg/m2. The incidence of grade 3 nonhematologic toxicities in our experience was 10 (19%) of 52 patients, including the case hospitalized for Pneumocystis infection. This is similar to the 24% reported by Hudis et al5. Our observed disease-free survival of 85% at 5 years (95% CI, 75% to 94%) may be contrasted to that observed in two large, randomized trials in which doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2, given every 3 weeks, was the control arm (Table 5). 17,18 In these National Surgical Adjuvant Breast and Bowel Project (NSABP) studies, the disease-free survival for the control arm was 62% and 65%, respectively, at 5 years. When we examined the mix of known prognostic factors for our study and the NSABP trials, the differing results do not seem to be explained by the proportion of patients with relatively low, intermediate, or high nodal burden. Similarly, the proportion entered with estrogen receptor–positive disease is identical. In our trial, 42% of patients entered had Her-2-neu overexpression (an enriched fraction related to our eligibility criteria for protocol entry). Although this proportion is not given for the NSABP trial, it is likely to be much lower (15% to 20% is the range generally reported in unselected series).19,20
Recently, a phase III randomized trial was reported that compared a dose-dense approach with weekly paclitaxel to standard dosing every 3 weeks.21 This study, reported by Green et al21 at the M.D. Anderson Cancer Center, Houston, TX, was carried out as a comparison of neoadjuvant treatment programs in resectable breast cancer. The pathologic complete remission rate was 31% for weekly and 14% for every 3-week drug administration in an analysis of the first 125 patients entered. Ellis et al9 for the Southwest Oncology Group recently reported on the use of the AC+G regimen (identical to that reported here except for a treatment duration of 16 rather than 20 weeks) in patients with locally advanced and inflammatory breast cancer who were not thought to be operative candidates. AC+G in that trial was given as neoadjuvant therapy, and the primary end point was the assessment of pathologic response at the primary site. In that study, 26% of patients entered had a pathologic complete response compared with an incidence of 9% to 13% reported in the literature for this patient population in studies from the M.D. Anderson group.22,23 The toxicity profile in the neoadjuvant trial was essentially identical to that reported here. The Southwest Oncology Group has now embarked on a prospective, randomized trial of continuous AC+G versus the standard regimen of AC at 60 and 600 mg/m2 every 3 weeks, given for an equivalent period of time as neoadjuvant therapy for locally advanced and inflammatory patients. We believe that the results reported here justify a randomized trial as well in the setting of resected, node-positive disease. Whether such a comparison should involve concurrent administration of a fluorinated pyrimidine (as in FAC+G) versus a similar three-drug regimen given intermittently cannot be addressed by our results. It is certainly possible that FAC+G might prove superior in a randomized comparison to AC+G. However, the hand-foot syndrome encountered would be problematic for some patients (though not medically threatening). Our view is that the role of a fluorinated pyrimidine is best assessed in a design that permits its administration in sequence. Such a design has now been adopted for a new United States Intergroup trial in patients with estrogen receptor/progesterone receptor–negative, node-positive, or high-risk node-negative cancers (G.T. Budd for the Southwest Oncology Group, principal investigator). It will involve initial comparison of AC+G as described here versus the NSABP standard of AC given every 3 weeks, with the duration of each regimen to be 18 weeks (six cycles of AC). There will then be a second randomization to the combination of docetaxel and capecitabine (an orally available fluorinated pyrimidine) versus docetaxel alone, given every 3 weeks for four cycles. Eligibility criteria for this study are presently limited to hormone receptor–negative disease because to date, that is the group that seems to benefit from the addition of a taxane sequentially.
Supported in part by a grant from Amgen Pharmaceuticals, Thousand Oaks, CA.
1. Livingston RB: Dose intensity and high dose therapy. Cancer 74: 1177-1183, 1994 (suppl 3)[CrossRef][Medline]
2. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4: 1162-1170, 1986 3. Norton L: Adjuvant breast cancer therapy: Current status and future strategies-growth kinetic and the improved drug therapy of breast cancer. Semin Oncol 26: 1-4, 1999 (suppl 3)[Medline]
4. Hudis C, Fornier M, Riccio L, et al: 5-Year results of dose-intensive sequential adjuvant chemotherapy for women with high-risk node-positive breast cancer: A phase II study. J Clin Oncol 17: 1118-1126, 1999
5. Hudis C, Seidman A, Baselga J, et al: Sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide for resectable high-risk breast cancer: Feasibility and efficacy. J Clin Oncol 17: 93-100, 1999 6. Livingston RB, Ellis GK, Gralow JR, et al: Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 15: 1395-1400, 1997[Abstract]
7. Ellis GK, Gralow JR, Irving Pierce H, et al: Infusional paclitaxel and weekly vinorelbine chemotherapy with concurrent filgrastim for metastatic breast cancer: High complete response rate in a phase I-II study of doxorubicin-treated patients. J Clin Oncol 17: 1407-1412, 1999 8. Gralow JR, Ellis GK, Williams MA, et al: Docetaxel + vinorelbine with concurrent G-SCF support: Phase II study in stage IV breast cancer. Proc Am Soc Clin Oncol 19: 106a, 2000 (abstr 410) 9. Ellis GK, Green SJ, Livingston RB, et al: Neoadjuvant doxorubicin, cyclophosphamide and G-CSF (AC+G) for locally advanced breast cancer (LABC), a southwest oncology group phase II study. Proc Am Soc Clin Oncol 19: 85a, 2000 (abstr 326)
10. Rowley JD, Reshmi S, Sobulo O, et al: All patients with the t(11: 16)(q23;p13.3) that involves MLL and CBP have treatment related hematologic disorders. Blood 90: 535-541, 1997
11. Diamandidou E, Buzdar AU, Smith TL, et al: Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 14: 2722-2730, 1996
12. Fisher B, Rockette H, Fisher ER, et al: Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: The NSABP experience. J Clin Oncol 3: 1640-1658, 1985 13. Martinez C, Urbano-Ispizua A, Rozman M, et al: Effects of short-term administration of G-CSF (filgrastim) on bone marrow progenitor cells: Analysis of serial marrow samples from normal donors. Bone Marrow Transplant 23: 15-19, 1999[CrossRef][Medline]
14. Heil G, Hoelzer D, Sanz MA, et al: A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia: The International Acute Myeloid Leukemia Study Group. Blood 90: 4710-4718, 1997 15. Sonoda Y, Ohno Y, Fujii H, et al: Multilineage response in aplastic anemia patients following long term administration of filgrastim (recombinant human granulocyte colony stimulating factor). Stem Cells 11: 543-554, 1993[Medline] 16. Hryniuk W, Bush H: The importance of dose-intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2: 1162-1170, 1986
17. Fisher B, Anderson S, Wicherham DL, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15: 1858-1869, 1997
18. Fisher B, Anderson S, DeCillis A, et al: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17: 3374-3388, 1999
19. Allred DC, Clark GM, Tandon AK, et al: HER-2/neu in node-negative breast cancer: Prognostic significance of overexpression influenced by the presence on in situ carcinoma. J Clin Oncol 10: 599-605, 1992
20. Pauletti G, Dandekar S, Rong H, et al: Assessment of methods for tissue-based detection of the HER-2/neu alteration in human breast cancer: A direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol 18: 3651-3664, 2000 21. Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel (P) followed by FAC in the neo-adjuvant setting provides improved pathologic complete remission (PCR) rates compared to standard paclitaxel followed by FAC therapy-preliminary results of an ongoing prospective randomized trial. Proc Am Soc Clin Oncol 20: 33a, 2001 (abstr 129) 22. Hortobagyi GN, Ames FC, Buzdar AU, et al: Management of stage III primary breast cancer with primary chemotherapy, surgery, and radiation therapy. Cancer 62: 2507-2516, 1988[CrossRef][Medline] 23. Kuerer HM, Newman LA, Buzdar AU, et al: Pathologic tumor response in the breast following neoadjuvant chemotherapy predicts axillary lymph node status. Cancer J Sci Am 4: 230-236, 1998[Medline] Submitted December 21, 2002; accepted May 22, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1,500/mm3, but the dose was reduced by 25%. If grade 3 or higher mucositis developed, the drug was omitted for at least 1 week or to clearance of the mucositis. 
