Originally published as JCO Early Release 10.1200/JCO.2006.08.9383 on April 2 2007

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Intensive Dose-Dense Compared With High-Dose Adjuvant Chemotherapy for High-Risk Operable Breast Cancer: Southwest Oncology Group/Intergroup Study 9623

Halle C.F. Moore, Stephanie J. Green, Julie R. Gralow, Scott I. Bearman, Danika Lew, William E. Barlow, Clifford Hudis, Antonio C. Wolff, James N. Ingle, Helen K. Chew, Anthony D. Elias, Robert B. Livingston, Silvana Martino

From the Cleveland Clinic Foundation, Cleveland, OH; Southwest Oncology Group Statistical Center; Puget Sound Oncology Consortium, Seattle, WA; University of Colorado Health Sciences Center, Denver, CO; Memorial Sloan-Kettering Cancer Center, New York, NY; Sidney Kimmel Comprehensive Cancer at Johns Hopkins, Baltimore, MD; Mayo Clinic, Rochester, MN; University of California-Davis, Sacramento; and The Angeles Clinic and Research Institute, Santa Monica, CA

Address reprint requests to Southwest Oncology Group (S9623) Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217

	ABSTRACT

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Purpose: Southwest Oncology Group (SWOG)/Intergroup study 9623 was undertaken to compare treatment with an anthracycline-based adjuvant chemotherapy regimen followed by high-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell support (AHPCS) with a modern dose-dense dose-escalated (nonstandard) regimen including both an anthracycline and a taxane.

Patients and Methods: Participants in this phase III randomized study had operable breast cancer involving four or more axillary lymph nodes and had completed mastectomy or breast-conserving surgery. Patients were randomly assigned to receive four cycles of doxorubicin and cyclophosphamide followed by HDC with AHPCS or to receive sequential dose-dense and dose-escalated chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide. The primary end point of this study was disease-free survival (DFS).

Results: Among 536 eligible patients, there was no significant difference between the two arms for DFS or overall survival (OS). Estimated five-year DFS was 80% (95% CI, 76% to 85%) for dose-dense therapy and 75% (95% CI, 69% to 80%) for transplantation. Estimated 5-year OS was 88% (95% CI, 84% to 92%) for dose-dense therapy and 84% (95% CI, 79% to 88%) for transplantation.

Conclusion: There is no evidence that transplantation was superior to dose-dense dose-escalated therapy. Transplantation was associated with an increase in toxicity and a possibly inferior outcome, although the hazard ratios were not significantly different from 1.

	INTRODUCTION

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Prospects for long-term survival following surgical treatment of localized breast cancer have significantly improved with widespread use of adjuvant systemic chemotherapy. In the worldwide overview, combination chemotherapy was associated with an approximate 23% reduction in the risk of breast cancer recurrence with the greatest absolute benefit in younger women with lymph node–positive disease.¹ Modern regimens including both an anthracycline and a taxane have further improved on these results.^2-4 Despite these advances, breast cancer remains the most common cause of death for women with lymph node–positive disease, indicating a need for more effective therapies.

Because of evidence of a dose-response effect of many chemotherapy drugs used to treat breast cancer, and because of its potentially curative role in hematologic malignancies, high-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell transplantation (AHPCT) has been widely investigated for the treatment of breast cancer. By the mid-1990s, breast cancer had become the most common indication in North America for AHPCT.⁵ This was true despite the lack of convincing evidence that this approach benefited patients. Although several randomized studies suggested a reduction in recurrence risk among subsets of breast cancer patients,^6-10 there has been no convincing evidence of a survival benefit to HDC. Intriguing suggestions of benefit in subgroups of breast cancer patients and the prospect of reducing transplantation-related mortality with improved supportive care have kept interest in HDC with AHPCT for breast cancer alive.

Another approach to maximizing tumor-cell kill with adjuvant chemotherapy is to use optimal doses of active chemotherapy drugs administered sequentially with a shortened scheduling interval. This approach, called "dose-dense," increases dose intensity (drug delivery over time) by reducing the intertreatment interval for chemotherapy delivery. In a phase II study, adjuvant treatment with sequential dose-dense and dose-escalated paclitaxel, doxorubicin, and cyclophosphamide was associated with a promising 4-year disease-free survival (DFS) rate of 78% and an acceptable toxicity profile in women with high-risk node-positive breast cancer.¹¹

In 1996, Southwest Oncology Group (SWOG)/Intergroup study 9623 was initiated to determine whether near standard doses of adjuvant chemotherapy followed by HDC with AHPCT would be superior to an intensive dose-dense approach to adjuvant chemotherapy—a test of two experimental treatment arms. This study, led by the SWOG on behalf of the North American Breast Intergroup, is the first large randomized study comparing a more conventional anthracycline-based chemotherapy regimen followed by AHPCT to a modern dose-dense regimen including both an anthracycline and a taxane. Initial results have been reported in abstract form¹²; this article is the first complete reporting of the findings of this study.

	PATIENTS AND METHODS

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Patient Population
Patients were required to have histologically confirmed adenocarcinoma of the female breast with involvement of four or more axillary and/or intramammary lymph nodes. Initially, the study included patients with four to nine involved lymph nodes. In March 2000, following closure of competing trials, the study was amended to include patients with 10 or more involved lymph nodes. Patients with ipsilateral internal mammary or supraclavicular lymph node involvement and patients with T4 tumors were excluded. Enrolled patients had completed modified radical mastectomy or breast-conserving surgery with axillary dissection within 12 weeks of registration. A minimum of 10 axillary lymph nodes was sampled in all patients and surgical margins were negative. Patients underwent chest x-ray, bone scan, computed tomography scan of the chest, abdomen, and pelvis, as well as bilateral bone marrow aspirates and biopsies with no evidence of metastatic disease.

Adequate organ function and bone marrow reserve were required. Specifically, patients were to have AST and bilirubin 1.5x the institutional upper limit of normal; WBC count 3,000/µL; absolute neutrophil count 1,000/µL; platelets 100,000/µL; creatinine clearance 60 mL/min; forced vital capacity (FVC), forced expired volume in 1 second (FEV1), and diffusing capacity of the lung for carbon monoxide all 60% of predicted value; and a resting left ventricular ejection fraction 45% by multiple gated acquisition. Patients with significant cardiovascular disease, congestive heart failure, arrhythmias, or serious cardiac conduction abnormalities were excluded. Patients testing positive for HIV were excluded. Patients with a prior malignancy within 5 years other than synchronous breast cancers, in situ cancer of the breast or cervix, or adequately treated nonmelanoma skin cancer were excluded. Patients who had prior chemotherapy for any malignancy, prior radiotherapy to the breast, or prior hormonal therapy for breast cancer were excluded. All patients were informed of the investigational nature of this study and gave written informed consent in accordance with institution and federal guidelines.

Treatment
Patients were randomly assigned to arm 1 (sequential doxorubicin, paclitaxel, and cyclophosphamide [A-T-C]) or arm 2 (doxorubicin and cyclophosphamide followed by high-dose chemotherapy [AC-HD]) according to a dynamic allocations scheme, with study arms balanced with respect to the stratification factor.¹³ The stratification factor was type of primary therapy: mastectomy without radiotherapy, mastectomy with radiotherapy after chemotherapy, or breast-conserving therapy with radiotherapy after chemotherapy. Patients randomly assigned to arm 1 were to receive sequential dose-dense dose-escalated chemotherapy with filgrastim support. Patients randomly assigned to arm 2 were to receive four cycles of more conventional chemotherapy followed by high-dose chemotherapy with AHPCT. Treatment is listed in Table 1.

Arm 2 treatment consisted of four cycles of doxorubicin 80 mg/m² and cyclophosphamide 600 mg/m² (AC) in combination repeated every 3 weeks followed by HDC with AHPCT. Before HDC, patients underwent bone marrow harvest or collection of peripheral blood progenitor cells. HDC was administered within 2 weeks after stem cell collection and within 6 weeks after the final dose of induction chemotherapy. Adequate recovery of organ function was required, including a WBC 2,000/µL, ANC 1,000/µL, platelets 100,000/µL, and left ventricular ejection fraction 45%, before high-dose chemotherapy.

Each transplantation center exclusively used either the STAMP I or STAMP V HDC regimen. STAMP I consisted of cyclophosphamide 1.85 g/m²/d and cisplatin 55 mg/m²/d, each for 3 days (days –6, –5, and –4), followed by carmustine 600 mg/m² (BCNU; day –3). STAMP V consisted of cyclophosphamide 1.5 g/m²/d, carboplatin 200 mg/m²/d, and thiotepa 125 mg/m²/d for 4 days (days –7 through –4). Autologous hematopoietic progenitor cells were reinfused starting on day 0. A minimum of 6 x 10⁸/kg apheresed mononuclear cells or 2.0 x 10⁶/kg apheresed CD34+ cells were infused.

Patients on arm 2 received IV hydration during HDC to produce a diuresis of at least 250 mL/h. Bladder irrigation and/or continuous infusion Mesna was recommended to prevent hemorrhagic cystitis. Decisions regarding antibiotics, hyperalimentation, and transfusion of blood products were based on individual institutional guidelines.

For patients on both arms, tamoxifen 20 mg daily was initiated 4 weeks after the final chemotherapy cycle and was continued for 5 years in women who were postmenopausal or who were premenopausal with ER-positive and/or PR-positive tumors. Radiation of the ipsilateral remaining breast and supraclavicular lymph nodes was administered in women who underwent breast-conserving surgery. Radiation to the chest wall and supraclavicular lymph nodes was administered following modified radical mastectomy at the discretion of the treating physician. Locoregional irradiation started approximately 4 to 6 weeks after completion of all chemotherapy.

End Points and Definitions
The primary end point of the study was disease-free survival (DFS). DFS was defined as the time from registration to first documentation of relapse or death due to any cause. Relapse was considered to be the appearance of any new lesions during or after protocol treatment; whenever possible, relapse was to be documented histologically. Secondary end points included overall survival (OS) and toxicity analysis. OS was time from the date of registration to the date of death due to any cause.

For the purposes of this study, N2 disease describes ipsilateral axillary metastases fixed to one another or to other structures. Postmenopausal was defined as prior bilateral oophorectomy or more than 12 months since the last menstrual period without a prior hysterectomy. Premenopausal was defined as less than 6 months since the last menstrual period, no prior bilateral oophorectomy, and no administration of estrogen replacement. Patients not falling into one of these categories were classified as "other" menopausal status.

Statistical Analysis
The planned sample size was 1,000 patients. Approximately 350 events were required for a one-sided .025-level test to have 90% power to detect whether arm 2 (transplantation arm) would lead to a 45% improvement in DFS when compared with arm 1 (dose-dense therapy arm). Two interim analyses were planned after approximately one third and two thirds of the expected number of events had occurred. If either interim analysis showed the test of the hazard ratio (HR) in the predicted direction had a P value less than .005, then consideration would be given to stopping the trial. The final one-sided analysis was to be performed at the .02 level. In contrast, if the HR was inconsistent with 1.45 (at the .005 level) at the interim analysis, the trial might also be stopped due to lack of efficacy. After study closure, interim analysis times were respecified to be after one-third and two-thirds of the revised anticipated number of events, based on the smaller sample size and longer follow-up schedule. The trial met reporting criteria at the time of the second analysis. We now report the results with additional follow-up, using conventional two-sided 95% confidence interval for descriptive purposes. Kaplan-Meier plots, stratified log-rank tests, and Cox models were used to analyze DFS and OS.

	RESULTS

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Patient Characteristics
Enrollment began in July 1996 and was stopped in February 2001 due to slower than anticipated accrual after the release of data from transplantation trials in breast cancer showing no significant benefit from this approach. Five hundred thirty-six eligible patients were included in the survival analysis. Characteristics of the 271 patients on arm 1 and the 265 patients on arm 2 are listed in Table 2. Patients in arm 1 and arm 2 were well matched for age, hormone receptor status, menopausal status, N2 disease, T3 disease, and type of local therapy; although the transplantation arm of the study had noticeably more patients younger than 40 years with hormone receptor–positive tumors. Among patients randomly assigned to receive HDC with AHPCT, 14% were at transplantation centers using the STAMP I regimen whereas 86% were at centers using the STAMP V regimen.

For the primary study end point of DFS, there were 58 events on arm 1 and 70 events on arm 2. There was no significant difference between the two arms (Fig 1). The HR from the Cox model analysis adjusted for factors associated with DFS (menopausal status, N2 disease, T3 disease, and the stratification factor, ie, type of local therapy) was 0.8 (95% CI, 0.59 to 1.19; P = .32) for DFS. There were 36 and 46 deaths on arms 1 and 2, respectively, with no significant difference in overall survival between the two treatment groups (Fig 2). The adjusted HR was 0.81 (95% CI, 0.52 to 1.25; P = .34) for OS. Adjustment for number of nodes and tumor stage had little effect on the treatment HR for both DFS and OS.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Disease-free survival by treatment group. Two-sided stratified log-rank P = .35.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival by treatment group. Two-sided stratified log-rank P = .40.

Toxicity
Toxicity was greater in arm 2 (Table 3). Fifty-nine percent of patients in arm 1 experienced grade 4 hematologic toxicity, consisting primarily of leukopenia, neutropenia, and anemia. In arm 2, 62% of patients experienced grade 4 hematologic adverse events during the induction treatment and 92% of patients experienced grade 4 hematologic toxicity during transplantation. Hematologic toxicity in arm 2 consisted primarily of leukopenia, neutropenia, and thrombocytopenia.

Five instances of myelodysplastic syndrome with or without acute leukemia were reported; two in the intensive dose-dense arm (arm 1) and three in the transplantation arm (arm 2). One additional instance of acute promyelocytic leukemia and a case of myelofibrosis were reported in arm 1.

	DISCUSSION

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The results reported here demonstrate that adjuvant chemotherapy with AC followed by HDC with AHPCT is associated with greater upfront toxicity with no suggestion of improvement in recurrence risk or survival when compared with a modern taxane-containing dose-dense regimen. There was a suggestion of inferiority for transplantation, but the differences were not significantly different. The lack of survival advantage to high-dose chemotherapy with AHPCT is consistent with previous randomized studies of high-dose chemotherapy for early-stage breast cancer.^5-10,14-16 Unlike some previously reported studies,^6-9 these results do not suggest a trend toward a reduction in recurrence risk in the transplantation arm, even in younger patients.

Several prior studies demonstrated improvement in or a trend toward improvement in EFS with the addition of HDC with AHPCS to standard anthracycline-based adjuvant chemotherapy in breast cancer patients with extensive lymph node involvement,^6-8 or in subsets such as younger patients⁹ or those with Her2/neu–negative tumors.¹⁷ In general, these studies used nontaxane, conventionally scheduled, anthracycline-containing control arms. Our study does not rule out the possibility that high-dose chemotherapy with AHPCT adds to the efficacy of four cycles of AC. In fact, the 5-year disease-free survival of 75% in arm 2 is superior to what would be anticipated in this high-risk group of node-positive breast cancer patients treated with standard AC chemotherapy. For example, women with any degree of axillary lymph node involvement (including 47% with fewer than four involved lymph nodes) randomly assigned to AC chemotherapy on CALGB trial 9344 experienced a 5-year DFS of 65%.² Cross-trial comparisons, however, are notoriously unreliable and the more rigid patient eligibility criteria and referral bias associated with a transplantation trial could explain much or all of this difference.¹⁸ Nevertheless, what is clear from the current report is that any additional reduction in recurrence achieved with the high-dose approach is no better than what can be achieved by adding a taxane and by optimizing drug dosing and scheduling.

It is worth noting that the current study tested two nonstandard arms, a sequential dose-dense/dose-escalated regimen in arm 1 versus AC with a higher cumulative doxorubicin dose followed by HDC with AHPCT. Given the results of trials showing a lack of improved outcome when dose-escalating cyclophosphamide or doxorubicin beyond current standard dosing,^2,19,20 it is unlikely that the results achieved with arm 1 would be significantly different to those that might be achieved with more conventional chemotherapy dosing as was used in CALGB 9741,²¹ although less toxicity was observed in the dose-dense arm of that study using conventional doses of doxorubicin and cyclophosphamide. The authors, therefore, do not recommend using the dose-escalated dose-dense regimen used in this trial for routine clinical practice.

Taxane and anthracyline-containing chemotherapy regimens have now become standard in the treatment of moderate to high-risk early breast cancer. Studies comparing weekly or every-2-week administration of paclitaxel-containing chemotherapy to standard every-3-week administration have highlighted the importance of chemotherapy scheduling for some drugs.^21,22 A number of preclinical studies suggest that continuous dosing of chemotherapy with a very short interdose interval, so called "metronomic" scheduling, may enhance the antiangiogenic effects of chemotherapy.^23-25 A phase II study of metronomic scheduling of doxorubicin and cyclophosphamide with or without fluorouracil in high-risk node-positive breast cancer demonstrated an excellent 5-year EFS of 86%.²⁶ The question of optimal chemotherapy scheduling in the treatment of early-stage breast cancer is addressed in Intergroup study SWOG 0221, in which metronomic scheduling of doxorubicin and cyclophosphamide chemotherapy and weekly scheduling of paclitaxel chemotherapy is compared with every-2-week scheduling of these drugs in a two-by-two factorial design.

Dose-dense sequential administration of dose-escalated doxorubicin, paclitaxel, and cyclophophamide was associated with less toxicity and with efficacy that is at least equivalent to near-standard doses of doxorubicin and cyclophosphamide chemotherapy followed by HDC with AHPCT. In the adjuvant treatment of breast cancer, the era of dose escalation to the limits of tolerability seems to be over. Continued improvement in breast cancer survival will more likely be achieved with the inclusion of more effective chemotherapy agents and targeted therapies with appropriate use of predictive markers, as well as through optimizing drug scheduling.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: N/A Leadership: N/A Consultant: Clifford Hudis, Amgen, Sanofi-Aventis; James N. Ingle, Novartis, AstraZeneca Stock: N/A Honoraria: Halle C.F. Moore, Abraxis, Genentech; Julie R. Gralow, Roche, Novartis, Genentech; Clifford Hudis, Amgen, Bristol-Myers Squibb Research Funds: Julie R. Gralow, Roche, Novartis, Lilly, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Aventis Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Stephanie J. Green, Scott I. Bearman, Clifford Hudis, James N. Ingle, Anthony D. Elias, Robert B. Livingston, Silvana Martino

Administrative support: Robert B. Livingston, Silvana Martino

Provision of study materials or patients: Julie R. Gralow, Scott I. Bearman, Clifford Hudis, Antonio C. Wolff, James N. Ingle, Helen K. Chew, Anthony D. Elias

Collection and assembly of data: Julie R. Gralow, Scott I. Bearman, James N. Ingle

Data analysis and interpretation: Halle C.F. Moore, Stephanie J. Green, Julie R. Gralow, Scott I. Bearman, Danika Lew, William E. Barlow, Clifford Hudis, Antonio C. Wolff, Helen K. Chew, Anthony D. Elias, Silvana Martino

Manuscript writing: Halle C.F. Moore, William E. Barlow, Clifford Hudis, Antonio C. Wolff, Anthony D. Elias

Final approval of manuscript: Halle C.F. Moore, Julie R. Gralow, Scott I. Bearman, William E. Barlow, Clifford Hudis, Antonio C. Wolff, James N. Ingle, Helen K. Chew, Anthony D. Elias, Robert B. Livingston, Silvana Martino

	NOTES

 
published online ahead of print at www.jco.org on April 2, 2007.

Supported in part by the following PHS Cooperative Agreement grants from the National Cancer Institute, Department of Health and Human Services: Grants No. CA38926, CA32102, CA46441, CA42777, CA45377, CA68183, CA76429, CA63844, CA22433, CA04919, CA35281, CA46368, CA58658, CA46113, CA76447, CA46282, CA13612, CA35090, CA35262, CA12644, CA20319, CA45450, CA76448, CA58416, CA58686, CA45560, CA58415, CA37981, CA35192, CA58861, CA45807, CA27057, CA35996, CA14028, CA35176, CA76462, CA04920, CA77651, CA16116, CA21115, and CA25224.

Presented in abstract format at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005 (abstr 572). This article is an update and the first complete reporting of SWOG/Intergroup study 9623.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
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Submitted August 28, 2006; accepted November 20, 2006.

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