Originally published as JCO Early Release 10.1200/JCO.2007.11.8851 on November 19 2007

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Randomized Trial of High-Dose Chemotherapy With Autologous Peripheral-Blood Stem-Cell Support Compared With Standard-Dose Chemotherapy in Women With Metastatic Breast Cancer: NCIC MA.16

Michael Crump, Stefan Gluck, Dongsheng Tu, Doug Stewart, Mark Levine, Peter Kirkbride, Janet Dancey, Susan O'Reilly, Tsiporah Shore, Stephen Couban, Caroline Girouard, Susan Marlin, Lois Shepherd, Kathleen I. Pritchard

From the National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada

Corresponding author: Michael Crump, MD, Princess Margaret Hospital, 610 University Ave, Rm 5-108, Toronto, Canada M5G 2M9; e-mail: michael.crump{at}uhn.on.ca

	ABSTRACT

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Purpose We conducted a multicenter, randomized trial to compare progression-free survival (PFS), overall survival (OS), and quality of life in women with metastatic breast cancer (MBC) receiving high-dose chemotherapy plus autologous stem-cell transplantation (ASCT; HDCT) compared with standard-dose therapy.

Patient and Methods Between April 1997 and December 2000, 386 women with MBC and no prior chemotherapy for metastatic disease were registered. After initial response to anthracycline- or taxane-based induction chemotherapy, 224 patients were randomly assigned: 112 to high-dose cyclophosphamide, mitoxantrone, and carboplatin chemotherapy and ASCT (HDCT), and 112 to standard therapy (ST). Median age was 47 years (range, 25 to 67 years). Thirty two percent of women randomly assigned had estrogen and progesterone receptor–negative breast cancer, 42% had visceral metastases, and 58% had bone metastases. Complete remission rates before random assignment were 11% for those receiving HDCT and 12% for those receiving ST.

Results After a median follow-up of 48 months, 79 deaths were observed in the HDCT arm and 77 deaths were observed in the ST arm; seven patients (6%) in the HDCT arm died as a result of toxicity. The median OS was 24 months for the HDCT arm (95% CI, 21 to 35 months) and 28 months for ST (95% CI, 22 to 33 months; hazard ratio [HR], 0.9; 95% CI, 0.6 to 1.2; P = .43). PFS was 11 months for HDCT and 9 months for ST (HR, 0.6 in favor of HDCT; 95% CI, 0.5 to 0.9; P = .006).

Conclusion HDCT did not improve OS in women with MBC when used as consolidation after response to induction chemotherapy.

	INTRODUCTION

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At least one third of women with operable breast cancer will eventually develop distant metastases despite adjuvant chemotherapy, hormone therapy, and radiation.¹ The median survival of women with metastatic breast cancer that is no longer hormonally responsive or is estrogen receptor (ER) negative is 18 to 24 months, and fewer than 5% live 5 years.² Throughout the 1990s, reports suggested that long-term disease-free survival could be achieved with high-dose chemotherapy using alkylating-agent combinations supported by autologous bone marrow or peripheral-blood stem-cell transplantation (ASCT).^3-6 By the mid-1990s, breast cancer had become the most common indication for ASCT in North America.⁷

Although 20% to 30% of women undergoing ASCT after response to standard-dose chemotherapy were reported to be alive and disease-free at 3 to 5 years, ASCT is associated with considerable toxicity, expense, and a treatment related-mortality up to 10%.^3-7 It has also been unclear to what extent patient selection accounted for the apparent improvement in survival suggested by uncontrolled trials.⁸ At the time this study was designed and initiated, only one small controlled trial had been reported, suggesting an improvement in overall survival (OS) after two courses of high-dose chemotherapy supported by ASCT (HDCT) compared with standard therapy (ST).⁹ Subsequently, those data were found to be falsified.¹⁰

This study was performed to determine if the addition of one course of high-dose chemotherapy and ASCT in women with metastatic breast cancer responding to optimal chemotherapy could improve OS compared with standard-dose chemotherapy, and to evaluate the impact of this treatment on quality of life (QOL).

	PATIENTS AND METHODS

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Eligibility
Women were eligible for registration if they had metastatic breast cancer or locoregional recurrence (chest wall or axillary lymph node) after mastectomy and had not previously received chemotherapy for metastases. Patients had to be 16 years of age, have an Eastern Cooperative Oncology Group performance status 0 to 2, and could not have experienced disease progression within 3 months of completing of adjuvant chemotherapy or have CNS metastases. Written informed consent was obtained before registration and again at the time of random assignment. The research ethics boards of all participating centers approved the study.

Baseline investigations including chest x-ray or computed tomography scan, bone scan (with plain x-rays of positive areas), and computed tomography scan of the liver were performed before chemotherapy initiation. Women with measurable lesions, with no evidence of disease (NED) after surgical resection of a solitary site of metastasis, and with only bone metastases or other nonmeasurable disease were eligible.

Induction Chemotherapy
All patients received four cycles of induction chemotherapy and were then assessed for response. The protocol recommended chemotherapy depending on prior treatment: fluorouracil 600 mg/m² and cyclophosphamide 600 mg/m², with either epirubicin 70 mg/m² or doxorubicin 60 mg/m² for those with no prior anthracycline; other regimens with equivalent anthracycline dose-intensity, or single-agent anthracyclines, were also permitted. Women with prior anthracycline exposure received paclitaxel 175 mg/m² or docetaxel 100 mg/m². Chemotherapy was administered every 3 weeks. Concurrent bisphosphonates for bone metastases were permitted. Filgrastim (granulocyte colony-stimulating factor [G-CSF]) was recommended if low treatment-day neutrophil counts or febrile neutropenia occurred.

Random Assignment
All patients underwent clinical and radiologic re-evaluation for response within 3 weeks after the fourth cycle of chemotherapy: complete response (CR) was defined as disappearance of all clinical and radiologic evidence of tumor (including nonmeasurable disease) and tumor-related symptoms; partial response (PR) was defined as 50% decrease in sum of measurable lesions, no new lesions, and improvement or stability of nonmeasurable disease; partial response, nonmeasurable disease (PRNM; including women with only nonmeasurable disease, such as disease confined to bone) was defined as stable or improved disease, no new lesions, and partial or complete resolution of symptoms; NED was defined as no evidence of new disease during induction. Patients with disease not satisfying these criteria were considered to have experienced progression and were taken off study.

Women with CR, PR, PRNM, or who remained NED after induction were stratified by four variables know to influence outcome¹¹: response (CR/NED v PR/PRNM), type of induction treatment (anthracycline-based v taxane-based treatment), hormone receptor status (estrogen receptor [ER] or progesterone receptor [PgR] positive, no prior tamoxifen v ER- and PgR-negative v progression after tamoxifen), and site of disease (visceral v nonvisceral), and were randomly assigned to one of two arms: HDCT or ST.

HDCT. Women in this arm received two additional cycles of induction treatment, followed by peripheral-blood stem-cell (PBSC) mobilization, usually with chemotherapy and G-CSF according to local institutional practice. Collection of a minimum of 2 x 10⁶ CD34-positive cells per kilogram and complete restaging before HDCT were required. Patients with disease progression were removed from study and given alternative therapy.

HDCT consisted of cyclophosphamide 1500 mg/m²/d, mitoxantrone 17.5 mg/m²/d, and carboplatin 450 mg/m²/d, each administered during 1 hour daily for 4 consecutive days,¹² and PBSCs infused 2 days later (day 0). G-CSF 5 µg/kg/d subcutaneoulsy was recommended starting day 5 to 7 until the absolute neutrophil count was more than 1.5 x 10⁹/L. Prophylactic antibiotics and blood product transfusion were provided according to local center policy.

ST. Women randomly assigned to ST received two additional cycles of induction therapy, and then continued treatment to a cumulative doxorubicin dose of 450 mg/m² or epirubicin 840 mg/m², or a total of eight cycles of single-agent taxane. Maintenance chemotherapy was permitted according to local practice.

Additional Therapy (both treatment arms)
All patients with ER- and/or PgR-positive disease not previously treated with tamoxifen were administered tamoxifen 20 mg/d orally after protocol therapy, until disease progression; aromatase inhibitors were administered if there had been prior tamoxifen use. Patients receiving ASCT with solitary bony or nodal metastases were required to receive involved-field radiation (usually 30 Gy in 10 fractions); radiation was allowed at physician discretion in the ST arm. Surgery to remove the breast primary in women presenting with metastatic breast cancer was permitted.

Response Assessment and Follow-Up
Overall response was assessed 6 weeks after ASCT and 13 to 15 weeks after day 1 of cycle 6 in the ST arm, by the same criteria as at random assignment. Patients with new lesions on bone scan but no symptoms of progression in bone or elsewhere, and with corresponding x-rays that were normal or showed sclerosis in the area(s) of increased uptake, were considered responders.¹³ Serum tumor markers were not used to assess response or as part of routine follow-up to detect disease progression.¹⁴ Routine radiologic follow-up was not required, but patients were assessed clinically every 3 months and investigated if progressive disease was suspected.

QOL Assessment
The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 questionnaire, the Functional Assessment of Cancer Treatment bone marrow transplant subscale (FACT-BMT), and a five-question trial-specific checklist were used, at baseline, on day 1 of cycles 5 and 6 of chemotherapy, at the time of neutrophil recovery, 4 to 6 weeks after ASCT in the HDCT arm and 13 to 15 weeks after day 1 of cycle 6 in the ST arm, then every 3 months until progression in both arms.

Statistical Methods
It was assumed that 2-year survival would be 30% in the ST arm and 48% after HDCT. To detect this 18% improvement (corresponding to a hazard ratio [HR] of 0.61) with 80% power and one-sided 5% level, 102 deaths were required among 192 patients accrued during 4 years. The original protocol had been amended to increase power, but after the first report of the North American Intergroup Trial, which showed no benefit from the addition of high-dose chemotherapy,¹⁵ accrual to the present trial declined dramatically and it was decided to return to the original sample size and close the study in December 2000. A planned analysis was performed in April 2001¹⁶ and updated in April 2004.

All patients randomly assigned were included in the analysis of efficacy end points. OS, the primary end point, was defined as time from random assignment to death as a result of any cause; progression-free survival (PFS), defined as time from random assignment to date of progressive disease or death without progression, was not a prespecified end point, but was analyzed according to a prespecified analysis plan. OS and PFS were described by Kaplan-Meier curves, and the stratified log-rank statistic¹⁷ was used to compare them between treatment arms. All eligible patients who received at least one cycle of postrandomization induction chemotherapy were included in the safety analysis based on treatments received. Fisher's exact test was used to compare response rates and incidence of adverse events between arms.

Responses to the EORTC Quality of Life Questionnaire C30 were scored based on the EORTC manual¹⁸ and responses to the first 12 questions in FACT-BMT module were condensed into one FACT-BMT subscale based on an algorithm reported by McQuellon.¹⁹ Differences from baseline were calculated at each assessment and compared between arms using Wilcoxon rank sum test. All P values are two sided.

	RESULTS

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Patient Characteristics
Between April 1997 and December 2000, 386 patients were registered (Fig 1). Two hundred twenty-four patients (58%) demonstrated adequate response to induction chemotherapy and consented to random assignment: 112 were assigned to HDCT and 112 were assigned to ST. One patient receiving ST was subsequently found ineligible (< PR to induction chemotherapy). Baseline characteristics of patients are listed in Table 1. Median age was 47 years (range, 25 to 67 years) and the majority had an excellent performance status. One third had hormone receptor–negative disease. The most common site of metastatic disease was bone, followed by regional lymph nodes, liver, breast, and lung. Approximately 25% presented with metastatic disease at diagnosis and had received no adjuvant therapy.

View larger version (33K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CONSORT diagram for National Cancer Institute of Canada Clinical Trials Group MA.16. PR, partial response; ASCT, autologous stem-cell transplantation.

Response
At the time of planned post-treatment reassessment, 10% of women in the HDCT arm and 13% in the ST arm had a CR. PRs were seen in 59% and 52%, respectively. Twenty-one percent in HDCT, compared to 1% in ST, were not assessable for final response because they never received ASCT (n = 21), died before response assessment (n = 4), or had progressive disease confirmed after having received ASCT (n = 1). The mean number of days from random assignment until final response assessment was 123 days (range, 68 to 259 days) for HDCT and 128 days (range, 91 to 198 days) for ST.

OS and PFS
After median follow-up of 48 months, 156 deaths were observed (79 in the HDCT arm and 77 in the ST arm). Median OS for patients receiving HDCT was 24 months (95% CI, 21 to 35), compared with 28 months (95% CI, 22 to 33) for ST (HR, 0.9; 95% CI, 0.6 to 1.2; P = .43; Fig 2). Three-year survival for HDCT was 37% (95% CI, 28% to 47%) and was 38% for ST (95% CI, 29% to 48%). There was no difference in OS between arms among those who had CR or NED after induction chemotherapy (median, not reached v 2.5 years; P = .33); for those without visceral disease (median, 2.9 v 2.5 years; P = .91); or by type of induction therapy (anthracycline: median, 3.0 v 2.5 years; P = .50; taxane: median, 1.4 v 1.5 years, P = .30). Although the primary analysis was according to intention to treat, there was no difference in OS when patients who were randomly assigned to HDCT but did not receive it were removed (median, 2.29 v 2.34 years; P = .41). Median PFS for HDCT was 11 months; 9 months for ST (HR, 0.8; 95% CI, 0.5 to 0.9; P = .006; Fig 3)

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival from random assignment according to treatment arm (P = .43, log-rank test).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Progression-free survival from random assignment according to treatment arm (P = .006, log-rank test).

Three women developed second malignancies: one patient had received HDCT (epithelial ovarian cancer) and two patients had received ST (renal cell carcinoma and second primary breast cancer). No secondary myelodysplasia or acute leukemia was seen.

QOL
At baseline, 94% of patients receiving HDCT and 99% of patients receiving ST finished the QOL assessments. Compliance rates (the number of QOL forms received divided by number still participating in the study) were 70% for those in the HDCT arm and 82% for those in the ST arm at final response assessment. At first follow-up, mean change scores showed significantly worse results in the HDCT arm for physical function (P < .0001), role function (P = .0007), social function (P < .0001), fatigue (P < .0001), dyspnea (P = .05), global QOL scale (P < .0001), and FACT-BMT subscale (P = .0008). At the 6- and 9-month follow-up, patients receiving HDCT reported worse dyspnea (P = .045), and bruising and bleeding (P = .01).

	DISCUSSION

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We report mature results of a large randomized trial comparing HDCT versus ST for women with chemotherapy-sensitive metastatic breast cancer. Cyclophosphamide, mitoxantrone, and carboplatin, supported by PBSC, after induction chemotherapy tailored to prior exposure to adjuvant chemotherapy, did not result in an increase in OS in metastatic breast cancer. Exclusion of patients assigned to HDCT who did not receive it did not alter this conclusion. We could not identify any subgroup that derived greater benefit with HDCT than with ST, such as those with CR or NED before transplantation, although the power of these comparisons was small. We did observe a statistically significant improvement in PFS. However, regularly scheduled radiologic reassessment of disease status was not required after chemotherapy completion; hence, assessment of PFS may be subject to observer bias.

Although our trial was relatively large, the number of deaths observed provides a power of only 93% to detect an HR of 0.61 (corresponding to 18% improvement in 2-year survival) at a one-sided level of .05. In contrast, retrospective comparison of patients treated with conventional-dose chemotherapy in a series of Cancer and Leukemia Group B trials, with those receiving ASCT reported to the North American Blood and Marrow Transplant registry,²⁰ included 1,079 women and had statistical power to detect a 20% improvement in 3-year survival. That analysis suggested survival improvement for ASCT. However, despite matching attempts, significant imbalances in prognostic factors persisted that may have influenced nonrandomized comparison. This result is contradicted by the recent Cochrane Collaboration meta-analysis of six cooperative group trials, which showed improvement in PFS but not OS.²¹ Large, prospective, randomized trials evaluating stem-cell transplantation are difficult to perform, and those currently available, including ours, have limited power to detect small but clinically important differences in survival.²²

Although the CR rate after HDCT reported here is somewhat lower than in other phase II or III trials, it is similar to that reported by Stadtmauer,²³ and reflects the patient populations treated, specifically, the large percentage of patients in our study with bone metastases in whom complete resolution of bone scan abnormalities is uncommon, and therefore the best achievable response is PR. Nonetheless, unlike trials reporting a higher CR rate after ASCT,²⁴ our study did show improvement in PFS.

Since the initial presentation of results of this study, a number of randomized trials of high-dose therapy versus standard-dose chemotherapy have been published, with some differences in trial design.^22,24-28 The results of our trial are consistent with those of the North American Intergroup, which added a single high-dose treatment supported by ASCT.²³ However, in addition, our study design incorporated chemotherapy using taxanes, required tamoxifen following chemotherapy in women with hormone-sensitive cancers, recommended aromatase inhibitors, permitted bisphosphonates for bone metastases, and used involved-field radiotherapy for limited bony or soft tissue/nodal disease.

The median survival of women in the HDCT arm of our study and that reported by Stadtmauer et al²³ are essentially the same (24 months). Approximately one third of patients in both studies are alive at 3 years. Treatment-related mortality from HDCT in our study was 6%, consistent with North American Blood and Marrow Transplant Registry data,⁷ and is not likely to explain the lack of improvement in OS observed. HDCT produced significantly more severe and fatal toxicity than ST and worse QOL during and immediately after treatment; these factors are important when considering the modest improvement in PFS in the HDCT arm.

Two recent reports from Duke University (Durham, NC) demonstrated improvements in PFS from the addition of high-dose therapy using cyclophosphamide, cisplatin, and carmustine in women with CR to induction chemotherapy²⁷ and with disease limited to bone.²⁸ However, these trials were designed to test the effect of early versus late high-dose therapy strategy, and thus were unlikely to show improvement in OS. In addition, the duration of chemotherapy treatment in the standard arms was limited to two to four cycles, and adjunctive treatments such as bisphosphonates, involved-field irradiation, and aromatase inhibitors were not used. Two trials from Germany, evaluating the addition of two cycles of high-dose therapy supported by PBSCs (tandem transplantation) compared with ST,²⁶ or single versus tandem transplantation,²⁴ showed no statistically significant improvement in PFS or OS. Only the trial recently published by Lotz et al²² demonstrated an improvement in OS after ASCT, but this trial randomly assigned only 61 patients and was closed prematurely because of slow accrual.

On the basis of our results, there is no role for HDCT requiring autologous HSCT in women with metastatic breast cancer outside of a well-designed, scientifically meritorious clinical trial. Recent randomized studies of new therapeutic agents have demonstrated significant improvements in OS in women with metastatic breast cancer,^29-33 and additional evaluation of ASCT will have to take place in the context of other emerging therapies. As illustrated by the example of high-dose therapy for metastatic breast cancer, as promising as early phase II results may be, randomized controlled trials must remain the standard by which to judge the value of the addition of new agents or strategies for the treatment of metastatic breast cancer.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

	AUTHOR CONTRIBUTIONS

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Conception and design: Michael Crump, Stefan Gluck, Dongsheng Tu, Mark Levine, Peter Kirkbride, Janet Dancey, Susan O'Reilly, Tsiporah Shore, Stephen Couban, Caroline Girouard, Susan Marlin, Lois Shepherd, Kathleen I. Pritchard

Administrative support: Susan Marlin, Lois E. Shepherd

Provision of study materials or patients: Doug Stewart, Mark Levine, Susan O'Reilly, Tsiporah Shore, Stephen Couban, Caroline Girouard, Kathleen I. Pritchard

Collection and assembly of data: Michael Crump, Stefan Gluck, Dongsheng Tu, Janet Dancey, Susan Marlin, Lois Shepherd

Data analysis and interpretation: Michael Crump, Stefan Gluck, Dongsheng Tu, Janet Dancey, Lois Shepherd, Kathleen I. Pritchard

Manuscript writing: Michael Crump, Stefan Gluck, Dongsheng Tu, Kathleen I. Pritchard

Final approval of manuscript: Michael Crump, Stefan Gluck, Dongsheng Tu, Doug Stewart, Mark Levine, Peter Kirkbride, Janet Dancey, Susan O'Reilly, Tsiporah Shore, Stephen Couban, Caroline Girouard, Susan Marlin, Lois Shepherd, Kathleen I. Pritchard

	NOTES

 
published online ahead of print at www.jco.org on November 19, 2007.

Michael Crump and Stefan Gluck contributed equally to the design and conduct of this trial and should both be considered first authors.

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

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Submitted March 25, 2007; accepted August 1, 2007.

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