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Journal of Clinical Oncology, Vol 25, No 6 (February 20), 2007: pp. 656-661 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.0847 Sequenced Compared With Simultaneous Anthracycline and Cyclophosphamide in High-Risk Stage I and II Breast Cancer: Final Analysis From INT-0137 (S9313)
From the Puget Sound Oncology Consortium; Southwest Oncology Group Statistical Center, Seattle, WA; University of California School of Medicine, Los Angeles, CA; Baylor College of Medicine, Houston, TX; Indiana University Medical Center, Indianapolis, IN; Dana-Farber Cancer Institute, Boston, MA; Mayo Clinic, Rochester, MN; University of Arkansas for Medical Science, Little Rock, AR; and the Angeles Clinic and Research Institute, Santa Monica, CA Address reprint requests to Southwest Oncology Group (SWOG-9313) Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: pubs{at}swog.org
PURPOSE: We conducted a phase III randomized study of two adjuvant treatment schedules of doxorubicin (A) and cyclophosphamide (C) in early-stage breast cancer to determine if administration of sequential single agents (A  C) results in superior disease-free survival (DFS) and overall survival (OS) versus the same total dose given in combination (AC).
PATIENTS AND METHODS: High-risk node-negative or low-risk node-positive breast cancer patients received AC given: (arm I) concurrently (AC) doxorubicin 54 mg/m2 and cyclophosphamide 1.2 g/m2 intravenously (IV) every 3 weeks for six cycles; or (arm II) in sequence (A
RESULTS: Between 1994 and 1997, 3,176 patients were randomly assigned. Arms were well balanced; 48% of eligible patients were node-negative and 48% were estrogen receptor–positive. No significant differences in OS or DFS were observed; 5-year estimates of OS (95% CI) were 88% (87% to 90%) on AC and 89% (87% to 91%) on A CONCLUSION: The overall result does not support superiority of dose-intense sequenced single agents. The greater toxicity of higher doses of single agents does not support their sequential use.
Dose-intensity, duration, density, and sequencing of adjuvant anthracycline-based chemotherapy regimens in breast cancer have been examined in numerous clinical trials. While cumulative results of such trials have shown improved outcomes, the optimal doxorubicin plus cyclophosphamide (AC) program remains to be determined. Increased dose-intensity of cyclophosphamide, methotrexate, and fluorouracil (CMF) -type regimens appears to improve outcomes, as reported in a retrospective analysis.1 Dose-intensity of the anthracycline (in AC) must be maintained above a moderate threshold, but efforts to further increase the dose-intensity of the anthracycline have resulted in mixed conclusions and excessive toxicity.2-4 Cancer and Leukemia Group B (CALGB) 8541 demonstrated that a minimum moderate dose-intensity (15 mg/m2/wk rather than 7.5 mg/m2/wk) of doxorubicin is critical for efficacy.5-7 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-22 and B-25 showed that increasing the dose of cyclophosphamide results in increased leukemogenicity without an improved breast cancer outcome.8,9 Improved dose-intensity is an appealing strategy to allow increased exposure to pharmacologically significant levels of the therapeutic agent. Dose-intensity is defined by the amount of treatment delivered per unit of time, wherein 60 mg/m2 of doxorubicin given at 3-week intervals results in a dose-intensity of 20 mg/m2/wk. The optimal dose of doxorubicin appears to be 20 to 24 mg/m2/wk, based on studies with doxorubicin4 (or epirubicin)6,7 given every 3 weeks with cyclophosphamide.
Sequencing chemotherapy regimens has received relatively little scrutiny. The European Institute of Oncology (Milan, Italy) showed that alternating therapies, rather than sequencing (CMF and AC) reduces efficacy10; however, the two study arms were not well-balanced. Norton et al11 proposed an optimal strategy based on mathematical modeling in which single agents are given sequentially at high dose-intensity.11,12 The Memorial Sloan-Kettering Cancer Center (New York, NY) has used a sequential doxorubicin followed by cyclophosphamide (A The present study design isolated the treatment schedule. Questions of sequence and intensity were distinguished, maintaining total dose and duration constant. Patients in both arms received identical total doses of both chemotherapeutic agents followed by tamoxifen (if hormone receptor–positive or postmenopausal). Earlier preliminary analysis reported in abstract form found no significant differences between the treatment arms.15 Herein, we present the final analysis of INT-0137.
Patients This intergroup trial was coordinated by the Southwest Oncology Group (S9313), with participation from the Eastern Cooperative Group, North Central Cancer Treatment Group (NCCTG 93-30-51), and CALGB 9394. It was open for accrual from April 1994 to May 1997 to patients with early-stage high-risk breast cancer. Patients were eligible if tumors were estrogen receptor (ER) –negative and progesterone receptor (PR) –negative and > 1 cm, > 2 cm regardless of hormone receptor status, or node-positive, with 1 to 3 positive axillary nodes, stage I or II by the most recent American Joint Committee on Cancer guidelines.16 Patients with ductal carcinoma in situ, lobular carcinoma in situ in addition to invasive disease (including TxN1a), metaplastic carcinoma, and bilateral synchronous tumors were eligible. Recurrent, locally advanced disease, pure tubular, papillary, mucinous, sarcoma, lymphoma, apocrine, adenocystic, or squamous cell breast cancers were excluded. Primary surgical treatment was required, mastectomy or breast-sparing procedure, and axillary dissection, with a minimum of six nodes removed and examined. The extent of further staging studies was left to the discretion of the treating physician. However, a minimum of a chest x-ray, contralateral mammogram, and no clear gross and microscopically positive surgical margins was required. Normal baseline cardiac ejection function, hematological function, and hepatic and renal functions were also required. Patients were informed of the experimental nature of the study and were provided written informed consent in accordance with institutional and federal guidelines.
Treatment
The sequential dosing schedule of the experimental arm was intended to be similar to concurrent phase II studies at the Memorial Sloan-Kettering Cancer Center using doxorubicin at 75 mg in a q3 week schedule in sequence with cyclophosphamide at 3 g/m2 every 2 weeks supported by G-CSF.13 Reduction of cyclophosphamide and institution of G-CSF and prophylactic antibiotics was based on safety concerns. Doses of the regimens were designed such that all patients received the same total dose of each drug (324 mg/m2 doxorubicin, 7.2 g/m2 of cyclophosphamide) and were treated during an 18-week period. However, in the experimental sequential arm, the dose-intensity of both drugs was increased (27 v 18 mg/m2/wk of doxorubicin and 1,200 v 400 mg/m2/wk of cyclophosphamide) and calculated for the period of intended delivery of each drug. SWOG toxicity criteria were employed.17 Complete blood cell counts were obtained before each treatment. If absolute neutrophil count was less than 1,500 per microliter, chemotherapy was withheld until neutrophil count recovery, but no dose reductions were allowed. If treatment delay was greater than 2 weeks, the patient was removed from protocol treatment. Dose was not adjusted for anemia, nor for transfusion. For grade 4 thrombocytopenia (platelets < 25,000 per microliter), the chemotherapy dose was reduced by 25%. The doxorubicin dose was reduced for grade 2 toxicity (transaminases 2.6-5) and held for grade 3 (transaminases > 5 x institutional upper limit of normal [IULN] t. bilirubin 1.5-3 x IULN). Patients were removed from the protocol for grade 4 (transaminases > 20 x IULN or t. bilirubin > 3 x IULN) or persistent grade 3 hepatotoxicity. The doxorubicin dose was reduced for mucositis, and both doxorubicin and cyclophosphamide were reduced for grade 4 nausea and vomiting. External beam radiation therapy was deferred until after chemotherapy, but it must have been planned before trial entry for patients treated with less than a mastectomy. Premenopausal women with hormone receptor–positive tumors, and all postmenopausal women, were treated daily with tamoxifen 20 mg orally for 5 years after chemotherapy.
Design It was hypothesized that sequential therapy should be superior to combined. The sample size of 1,500 patients per arm was chosen such that one-sided .05 level log-rank test of the equality of disease-free survival (DFS) distributions would have power .9 to detect a hazard ratio (HR) of 1.3 in favor of sequential treatment. Levels for two interim tests were specified to be .005, with the final analysis to be done at the .045 level.18 In addition, a tissue sample block (when available) from patients enrolled onto INT-0137 was collected for future biologic correlative studies.
Statistical Methods
For time-to-event data, the Kaplan-Meier method19 was used for estimating distributions. The log-rank test20 was used for testing DFS and overall survival (OS) differences between arms. Cox models21 were used for assessing association of patient characteristics with survival and DFS, for testing treatment-patient characteristic interactions, and for estimating HRs.
All reported P values are two sided. One-sided values also are given for the primary comparison (AC DFS v A After treatment, patients were followed for 5 years at 6-month intervals and then annually to monitor for relapse, long-term cardiac effects, recurrence or second primary, tamoxifen compliance, death, and cause of death.
Between April 1994 and May 1997, 3,176 women enrolled onto a study. Criteria for early stopping and reporting were not met at either interim analysis, so accrual and follow-up were completed as planned. The median follow-up for patients still alive at time of analysis is 7.2 years.
Sixty-two patients (2%) were ineligible: 14 had insufficient baseline documentation of eligibility, 14 lacked documented high-risk disease, eight had positive margins, nine had more than three lymph nodes involved, six did not have invasive adenocarcinoma, three had inadequate left ventricular ejection fraction, and eight were ineligible for miscellaneous reasons. There are 1,590 eligible patients on the AC arm and 1,524 on A Patient characteristics, summarized in Table 1, show well-balanced arms for age, menopausal status, race, ethnicity, type of surgery, number of positive nodes, receptor status, and tumor size. Overall, 52% of the patients on study had one to three positive nodes, 48% were ER-positive, and the majority had T2 primary tumors (only 7% had tumor size > 5 cm).
Eighty-eight percent of patients on the AC arm completed chemotherapy compared with 84% on the A C arm. Two thirds of the patients went off treatment early because of toxicity or adverse effects.
DFS
OS OS is shown in Figure 2B. The sequential arm also is not superior with respect to survival (two-sided, log-rank P = .25). The 5-year estimate for AC is 88% (95% CI, 87% to 90%) versus 89% (87% to 91%) for A C. Factors associated with survival were the same factors as for DFS, with the addition of menopausal status. After adjustment for these, the estimated AC/A C HR is 1.11, with 95% CI from 0.93 to 1.32.
Subset Analysis
Progressive Disease Outcomes
Toxicity Only a subset of toxicities was recorded: grade 4 to 5 hematologic and grade 3 to 5 nonhematologic toxicities. Two treatment-related deaths occurred, both on the A C arm, one due to Aspergillus and one due to pulmonary embolism. More patients on the AC arm had grade 4 hematologic toxicities than on AC (P < .0001), shown in Table 3. However, grade 4 nonhematologic toxicities occurred with equal and modest (8%) frequency (P = .99), as presented in Table 4. Grade 3 toxicities were manageable, observed as maximum degree in 9% (AC) and 8% (AC). Cardiac, diarrhea, dyspnea, fever without infection, infection, malaise/fatigue/lethargy, pharynx/esophagitis, phlebitis/thrombosis/embolism, and stomatitis were significantly worse in the sequential arm, while vomiting was significantly worse in the combined AC arm. Nausea, reported in 13% of AC-treated patients and 11% of A C, was not significantly different between arms. Grade 3 or 4 congestive heart failure was seen in 0.4% and 1.1% of patients treated with AC and AC, respectively.
Second Primaries Sixty-three nonbreast second primaries have been reported on the AC arm, including six each with lung, colon, and endometrial cancer; five with squamous cell and eight with basal cell cancer; four with ovarian; three each with cervical, melanoma, and thyroid; nine with acute myeloid leukemia (AML); and four with myelodysplastic syndrome (MDS). Sixty six have been reported on A C, including 10 with lung cancer; nine with basal cell; six each with ovarian and colon; five with squamous cell cancer; four with endometrial; three each with pancreas, melanoma, and sarcoma; 11 with AML; and four with MDS. Twenty-eight patients (0.9%) overall developed AML/MDS at a rate of 0.138 per 100 person-years of follow-up. No difference in the rates of AML/MDS were seen between the two arms (P = .69).
Delivered Dose-Intensity
Long-term follow-up of INT-0137 demonstrates the outcomes in both arms, which compare favorably with contemporaneous NSABP studies using concurrent doxorubicin and cyclophosphamide.8,9 We administered a dose-intense program of AC and modified the sequence (but neither total dose nor duration) of treatment in the experimental arm to sequence the two drugs as single agents and to increase the dose intensity and density. We found no significant difference between the protocol-specified outcomes in the two well-balanced arms with relatively younger women with high-risk early-stage breast cancer.
In the trial reported herein, the dose-intensity in the experimental A
Final analysis of INT-0137 demonstrates safety and feasibility of the administration of a dose-intense sequential A
The authors indicated no potential conflicts of interest.
Conception and design: Hannah M. Linden, Charles M. Haskell, Stephanie J. Green, C. Kent Osborne, George W. Sledge Jr, Silvana Martino Administrative support: Charles M. Haskell, C. Kent Osborne, Silvana Martino Provision of study materials or patients: Charles M. Haskell, Charles L. Shapiro, James N. Ingle, Laura F. Hutchins Collection and assembly of data: Charles M. Haskell Data analysis and interpretation: Hannah M. Linden, Charles M. Haskell, Stephanie J. Green, George W. Sledge Jr, James N. Ingle, Danika Lew, Robert B. Livingston Manuscript writing: Hannah M. Linden, Charles M. Haskell, C. Kent Osborne, George W. Sledge Jr, James N. Ingle, Robert B. Livingston Final approval of manuscript: Hannah M. Linden, Charles M. Haskell, Charles L. Shapiro, James N. Ingle, Robert B. Livingston, Silvana Martino Other: Silvana Martino [SWOG Breast Cancer Committee Chair]
Supported in part by the US Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: Grants No. CA38926, CA32102, CA49883, CA21115, CA25224, CA31946, CA32291, CA37981, CA35431, CA45377, CA58416, CA22433, CA58686, CA46113, CA04919, CA46441, CA58861, CA46282, CA35261, CA27057, CA76132, CA35192, CA76447, CA76462, CA45450, CA76429, CA63845, CA12644, CA20319, CA63844, CA45560, CA58415, CA14028, CA58658, CA42777, CA35119, CA35090, CA35117, CA13612, CA16385, CA67575, CA68183, CA46368, CA04920, CA74647, and CA52654. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 tests for contingency tables were used for testing differences in toxicities.
