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© 2003 American Society for Clinical Oncology Risk of Acute Leukemia Following Epirubicin-Based Adjuvant Chemotherapy: A Report From the National Cancer Institute of Canada Clinical Trials GroupFrom the National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada. Address reprint requests to Michael Crump, MD, Princess Margaret Hospital, 610 University Ave, Room 5-108, Toronto, Canada M5G 2M9; email: michael.crump{at}uhn.on.ca.
Purpose: Cyclophosphamide, epirubicin, and fluorouracil (CEF), compared with classical cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy. has lead to an improvement in relapse-free and overall survival in premenopausal women with node-positive breast cancer. We undertook this analysis to more accurately define the estimate of risk of secondary acute leukemia (sAL) following epirubicin-containing chemotherapy regimens. Patients and Methods: We assessed the conditional probability of sAL among 1,545 women who received adjuvant (n = 1,477) or neoadjuvant (n = 68) chemotherapy in four National Cancer Institute of Canada Clinical Trials Group trials from 1990 to 1999. The risks associated with epirubicin-containing regimens (CEF or epirubicin and cyclophosphamide [EC]) and other regimens (doxorubicin and cyclophosphamide [AC] or CMF) were determined. Results: A total of 10 cases of sAL were observed (eight acute myelogeneous leukemia, two acute lymphoblastic leukemia): seven among women treated with CEF, two who had received AC, and one following CMF. Using competing risk statistics, the conditional probability of sAL was 1.7% (95% confidence interval [CI], 0.5 to 3.6) among 539 women treated with CEF chemotherapy at a follow-up of 8 years, 0.4% (95% CI, 0% to 1.3%) among the 678 who received CMF, and 1.3% (95% CI, 0% to 4.7%) among the 231 treated with AC. The conditional probability of death from breast cancer at 8 years for the entire group of women treated with epirubicin-containing regimens in all four trials was approximately 34.9%. Conclusion: CEF chemotherapy for breast cancer carries a small increased risk of sAL compared with CMF. These estimates of acute leukemia risk are important in discussing treatment with women, especially patients with a lower risk of death from breast cancer, such as those with node-negative breast cancer.
ADJUVANT CHEMOTHERAPY (AC) decreases the risk of recurrence and death in women with lymph node-positive and node-negative primary breast cancer. The use of anthracycline-based chemotherapy in the adjuvant setting is associated with an improvement in disease-free and overall survival compared with nonanthracycline-containing regimens such as cyclophosphamide, methotrexate, and fluorouracil (CMF).1 Most trials that have demonstrated an improvement have substituted the anthracycline for methotrexate in CMF and maintained the same dose and schedule of cyclophosphamide and fluorouracil (FU).2 We have previously shown that cyclophosphamide, epirubicin, and fluorouracil (CEF; cyclophosphamide 75 mg/m2 orally days 1 to 14, epirubicin 60 mg/m2, and FU 500 mg/m2 intravenously [IV] on days 1 and 8) compared with classical CMF adjuvant chemotherapy (cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 60 mg/m2, and FU 600 mg/m2 IV on days 1 and 8) results in a 10% absolute improvement in relapse-free survival and a 7% absolute improvement in overall survival after 5 years in premenopausal women with axillary lymph node–positive primary breast cancer.3 Our study used slightly reduced doses of cyclophosphamide and FU in order to deliver a relatively high dose and dose-intensity of epirubicin. However, in that study, we observed five cases of acute leukemia among 351 eligible women treated with CEF. CEF is now widely accepted as the standard of care in Canada for women with lymph node–positive breast cancer, and it is also used for some patients with high-risk node-negative breast cancer. This regimen forms the control arm of the ongoing National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) adjuvant chemotherapy trial in node-positive and high-risk node-negative breast cancer. In light of this, and because the median follow-up of women at the time of analysis in our previous report was relatively short with respect to the potential development of secondary leukemia (59 months), we performed the present analysis to refine the estimate of this complication following epirubicin-based chemotherapy. We reviewed all women treated with chemotherapy on three adjuvant studies and one preoperative chemotherapy trial for locally advanced breast cancer, in order to evaluate a larger number of patients with longer follow-up.
We obtained long-term follow-up of women participating in four NCIC-CTG studies involving adjuvant chemotherapy for this analysis. Study MA.5 was a randomized trial in premenopausal, node-positive women with resected breast cancer comparing six cycles of CEF to six cycles of CMF.3 Study MA.11 enrolled premenopausal women with operable breast cancer (T1–3A, N0–2) on a dose escalation trial of cyclophosphamide 700 mg, 900 mg, or 1,100 mg/m2; epirubicin 70 mg/m2; and FU 500 mg/m2; all given IV every 2 weeks, supported by granulocyte colony-stimulating factor (G-CSF; filgrastim) for 12 cycles.4 Study MA.12 included premenopausal women with axillary node–positive or high-risk node-negative breast cancer treated with CEF, CMF, or AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2, every 3 weeks for four cycles), who were then randomly assigned to 20 mg of tamoxifen or placebo daily for 5 years. Study MA.10 was an intergroup trial in women of any age with T3N2 or N3, or T4NX or inflammatory breast cancer, randomly assigned to receive preoperative chemotherapy with either CEF for six cycles or epirubicin 60 mg/m2 plus cyclophosphamide 830 mg/m2 IV every 14 days supported by G-CSF for 12 doses.5 Only patients enrolled in Canada were included in this analysis. The total planned epirubicin dose in studies MA.5, MA.10, and MA.12 was 720 mg/m2 and 840 mg/m2 in study MA.11. Local radiation to the breast was given to all patients treated with lumpectomy and breast-conserving surgery in the MA.5 and MA.12 trials, but locoregional (nodal) radiation was not permitted. In study MA.11, regional nodal radiation was left to the discretion of the treating physician. Patients in study MA.10 received locoregional radiation treatment following preoperative chemotherapy, either preceding or after surgery, according to the stated practice of each participating center. All patients were followed up at 6-month intervals after the completion of therapy, and all events (breast cancer relapse, development of secondary myelodysplasia or acute leukemia, or death from any cause) were reported to the NCIC-CTG central office and entered into a central database. Reporting of second malignancies is a standard requirement on NCIC-CTG adjuvant breast cancer trials.6 For the purposes of this analysis, this database was updated to May 30, 2002. Young women with operable breast cancer who have received adjuvant chemotherapy, especially those who are premenopausal at diagnosis, face two competing risks during follow-up: recurrence and death from breast cancer, and development of leukemia secondary to treatment, which may also result in death. We used the competing risk method of Pepe and Mori7 to estimate the conditional probability of death from breast cancer and the conditional probability of developing acute leukemia or myelodysplasia. We calculated conditional probability rather than marginal probability because the risk of death from breast cancer is substantially higher than the risk of developing secondary leukemia over the period of follow-up of most reported adjuvant therapy trials. The conditional probability of developing acute leukemia or myelodysplasia at time t is defined as the probability of a patient developing secondary acute leukemia at time t, conditional on this patient not having died from any other cause by that time. Its estimate can be interpreted as the proportion of patients who have developed secondary leukemia at time t, among those who have survived to time t. The 95% confidence intervals (CIs) associated with the conditional probability estimates are also calculated based on the formula in the same paper. A test described by Pepe8 based on the cumulative weighted differences of conditional probability estimates was used to compare the conditional probabilities of acute leukemia between the patients treated by CEF and CMF in the MA.5 trial. All calculations and graph plots were performed using S-plus software (Statistical Sciences, Seattle, WA).
A total of 1,545 women who were entered onto the four chemotherapy trials form the basis of this analysis. The number of patients treated with each regimen, median follow-up, and accrual periods are presented in Table 1  . The follow-up of patients treated with each chemotherapy regimen varies, from a median of 4.9 years for patients receiving AC (in the MA.12 trial) to a median of 9 years for patients receiving CEF. The patient and tumor characteristics of the women receiving adjuvant chemotherapy are presented in Table 2. The median age of all patients is 45 years, with a range from 23 to 79 years. From Table 2, it can be seen that the baseline characteristics vary for patients treated with the different chemotherapy regimens, which reflects the differences in eligibility criteria between the studies. Approximately two thirds of all patients had hormonally responsive (estrogen receptor- or progesterone receptor-positive) tumors. One half to two-thirds of women in each trial received radiation to the breast or regional nodes and chest wall following the completion of chemotherapy (though complete information on radiation dose and fields is not available for some of the women on study MA.12 who were registered but not randomly assigned to tamoxifen or placebo).
Ten women who participated in these four trials developed secondary acute leukemia (Table 3 ). There were seven cases of acute leukemia, five acute myeloid leukemia (AML) cases, and two acute lymphoblastic leukemia (ALL) cases among the 539 women receiving CEF, with two women with AML among 231 women receiving AC chemotherapy, and one case of AML among 678 women receiving CMF. None of the 97 patients who received dose-intensive epirubicin plus cyclophosphamide supported by G-CSF have developed secondary leukemia. Central pathologic review of the diagnosis of leukemia was not required, but all reports were reviewed by an experienced hematopathologist (L.S.). All patients completed the full number of cycles of chemotherapy required in the protocol and received greater than 85% of the prescribed dose of cyclophosphamide. The median interval from completion of chemotherapy to diagnosis of acute leukemia was 18 months (range, 14 to 79 months), and nine of the 10 patients were diagnosed within 30 months. Of the eight women with AML, the subtype was French-American-British (FAB) M4 or M5 (myelomonocytic or monocytic) in five patients, promyelocytic (M3) in one patient, and unspecified in two. Bone marrow cytogenetic analysis was performed in seven patients: it was normal in two, bore a translocation involving chromosome 11q23 in three, and the t(15;17) translocation typical of acute promyelocytic leukemia was present in one. Studies to detect rearrangement of the mixed lineage leukemia (MLL) gene at 11q239 were not performed. One woman developed AML 79 months after completing CMF chemotherapy; bone marrow karyotype was typical of secondary leukemia observed after alkylating agent exposure, with a complex karyotype including 5q- and trisomy 8.
Six of the eight women diagnosed with secondary AML died either while pancytopenic following induction chemotherapy, or shortly thereafter from refractory leukemia. Two patients are alive and in remission following chemotherapy treatment (one ALL and one AML-M3), and two are alive following bone marrow transplantation (one unspecified AML, and one pre-B ALL with a t[9;11] translocation).
The cumulative risk of developing acute leukemia following epirubicin-containing regimens (CEF or epirubicin and cyclophosphamide [EC]) among 636 patients across the four trials is 1.7% at 8 years (95% CI, 0% to 3.5%), which is similar to the risk seen in the original cohort of 356 patients treated by CEF on the MA.5 trial with longer follow-up (2.1%; 95% CI, 0% to 4.6%). There is a trend that the risk of secondary AML in the 716 women enrolled on the MA.5 trial is higher for those treated with CEF compared with that for women who received CMF (0.5%; 95% CI, 0% to 1.7%; P = .059, Pepe’s cumulative weighted difference test; Fig 1
Eight hundred two of 1,451 patients in this cohort (55.3%) received adjuvant radiation, and seven have developed sAL. Three women of 649 who did not receive radiation have developed sAL. At 8 years, the probability of secondary leukemia following radiation is 1.3% (95% CI, 0% to 1.9%), compared with 0.80% (95% CI, 0 to 2.7%) among women who did not receive adjuvant radiation (Fig 3 ).
The inclusion of the anthracyclines doxorubicin and epirubicin in the adjuvant therapy of breast cancer has lead to an improvement in freedom from breast cancer recurrence and overall survival.1 Epirubicin has been shown to be less toxic and as effective as doxorubicin in the treatment of advanced breast cancer.10 We have reported that compared with the CMF regimen, at 5 years CEF resulted in an improvement in relapse-free survival from 53% to 63%, and an improvement in overall survival from 70% to 77% in premenopausal women with node-positive breast cancer.3 Five cases of secondary leukemia were observed among the women receiving CEF in that study, compared with only one patient treated with CMF. It is reassuring to note that we have not observed any additional cases of leukemia among women enrolled in that trial, with a median follow-up that now extends to 9 years. In the current analysis, which includes more than 1,500 women receiving adjuvant or neoadjuvant chemotherapy, the cumulative risk of sAL is 2.0% at 8 years among women treated with CEF chemotherapy. This is similar to the 10-year risk of 1.5% following FAC chemotherapy reported by Diamandidou et al11 using the Kaplan-Meier method, which does not take into account the competing risk of death from breast cancer. Importantly, in the group of women followed up on in our study who received CEF or EC, the competing risk of death from breast cancer at 8 years is approximately 34.9% (95% CI, 29.2% to 40.7%), which much outweighs the risk of sAL. The follow-up of the women in our study treated with AC is shorter than for CEF, and is shorter than that reported by Smith et al12 for standard-dose AC. This could serve to underestimate the sAL risk in the AC cohort in our analysis and longer follow-up of this group would be required. Secondary AML has been associated with the use of alkylating agents, topoisomerase II inhibitors, and radiation for the treatment of a number of cancers.13 Women with breast cancer treated with melphalan-containing adjuvant chemotherapy are at considerable risk of secondary AML,14 but the risk associated with CMF reported by the Eastern Cooperative Oncology Group15 and that from the Milan Cancer Institute16 was not much higher than in the general population. In the recent overview analysis of adjuvant chemotherapy in operable breast cancer, there was no significant increase in deaths attributed to other cancers in women receiving polychemotherapy.1 Other reports, however, including a population-based study from France, have shown that the inclusion of mitoxantrone, an anthracenedione which inhibits topoisomerase II as part of adjuvant therapy, increases the risk of secondary leukemia in a dose-dependent fashion.17,18 The cases of secondary myeloid and lymphoid leukemia that we have observed are consistent with a causal role for the anthracycline component of the CEF regimen. Leukemia arose after a short latent period (less than 24 months from completion of chemotherapy in seven of nine patients), the morphologic subtype was predominantly myelomonocytic or monocytic (FAB M4 or M5), and most patients in whom bone marrow karyotyping was performed had a balanced chromosome translocation involving band 11q23. Chromosomal breakpoints at 11q23, the locus for the MLL gene, are significantly more common in patients treated with topoisomerase II inhibitors, although these drugs are also frequently combined with alkylating agents and radiation.19 In reports of secondary leukemia following adjuvant chemotherapy containing mitoxantrone, balanced chromosomal translocations were the most common cytogenetic abnormalities seen, and the course of AML was typical of that caused by topoisomerase II inhibitors.17,18 The relative importance of the total dose of epirubicin received by our patients, the schedule of administration and the concomitant administration of oral cyclophosphamide (versus intravenous) is difficult to determine. A recent study from the French Adjuvant Study Group reported only two cases of acute leukemia out of 565 patients receiving FU, epirubicin, and cyclophosphamide (FEC; all given intravenously) chemotherapy, a regimen in which all drugs are given intravenous every 21 days, at a median follow-up of 5.5 years.20 In another study, three cases of AML were reported among 255 women receiving intensified EC chemotherapy, while none of the women treated with standard-dose EC or with CMF developed AML after 4 years of follow-up.21 On the other hand, Bergh et al22 reported a rate of secondary myelodysplasia and acute leukemia following the use of "tailored" FEC chemotherapy—in which all drugs are given intravenously, with doses adjusted to produce a predefined neutrophil and platelet nadir—of 4.5% at 3 years, or 11 cases per 1,000 patient years. Although adjuvant chemotherapy using intensified epirubicin-based chemotherapy has been shown to be superior to CMF, taken together, these regimens seem to carry a small increased risk of acute leukemia. Which of these regimens is superior in terms of reducing the risk of death from breast cancer or safer from the point of view of secondary leukemia, is unknown and requires further research. The excess cases of secondary AML reported by the National Adjuvant Breast and Bowel Project (NSABP) had karyotypes compatible with the high-doses of alkylating agents used in the trials B22 and B25,23,24 though abnormalities of chromosome 11q23 were also reported.12 The relative risk of secondary AML following intensified AC with cyclophosphamide given at a dose of 2,400 mg/m2 compared with standard dose AC was 6.81 (for those receiving two cycles) and 5.46 (for women receiving four cycles).12 The cumulative incidence of secondary AML for all women treated with four doses of standard AC was 0.21% at 5 years compared with 1.01% for the intensified regimens. Although this seems to be a lower incidence than with CEF, to be able to state this with confidence would require a direct comparison of the two regimens. In our own analysis, there was no apparent difference in the conditional probability of leukemia between those treated with epirubicin (1.7%) and those who received AC (1.3%), though the number of patients treated is much smaller than that reported by Smith et al.12 In this analysis, we observed an approximately 1.6-fold increase in risk of secondary leukemia among women who received postoperative radiation compared with those who did not. A dose-dependent increase in risk of leukemia following radiation for breast cancer was described by Curtis et al,25 who reported a relative risk of secondary leukemia of 2.4 after radiation alone, which increased to 17.4 following radiation and alkylating agent chemotherapy. The NSABP recently reported an increased relative risk of secondary AML of 2.37 among women who received breast radiation following lumpectomy (P = .008) after treatment with adjuvant AC chemotherapy.12 These results suggest that the risk of sAL is increased following adjuvant radiation, regardless of the type of systemic chemotherapy used. Concern has been raised that the use of myeloid growth factors to support intensified adjuvant chemotherapy may contribute to the risk of secondary leukemia.19 Only a minority of the patients enrolled on the studies in this report received G-CSF, and none developed sAL. Smith et al12 observed that the risk of sAL in patients participating in NSABP study B25 who received greater than the median total dose of G-CSF was 3.58, relative to those who received less than the median dose. However, this was not a randomized comparison, and a third of the patients had experienced disease recurrence before developing MDS or AML. The association of sAL with G-CSF use may not be causal, but could reflect underlying pharmacokinetic variation, for which a greater degree of myelosuppression and need for more intensive growth factor support may be a marker. Recent investigations have demonstrated that polymorphisms in genes encoding enzymes important in the metabolism of alkylating agents26 and topoisomerase II inhibitors27 may predispose to the development of sAL after chemotherapy. The contribution of myeloid growth factors to risk of sAL following chemotherapy requires further study, but their use as secondary prophylaxis or to support more intensive regimens that have been shown to reduce recurrence risk28 remains appropriate. In conclusion, we have shown that in a larger number of women with lymph node-positive or high-risk node-negative breast cancer, and 5 to 8 years median follow-up, the incidence of secondary acute leukemia after adjuvant CEF chemotherapy is of a similar magnitude to that in our previous report, and, importantly, may not be different from currently used regimens such as AC, or AC followed by paclitaxel.29 These estimates are relevant to discussions of adjuvant systemic treatment with patients, in order to appropriately balance the long-term risk of leukemia with the long-term risk of death from breast cancer. They will also be important in evaluating future trials testing the addition of new agents to epirubicin-containing regimens in the adjuvant therapy setting.
We thank Dr Ian Tannock for his helpful comments on an earlier version of the manuscript, and Tony Panzarella and Andrew Day for their assistance with the statistical programming.
1. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930–942, 1998[CrossRef][Medline]
2. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer. J Clin Oncol 19:3817–3827, 2001 3. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared to cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16:2651–2658, 1998[Abstract] 4. Findlay B, Tonkin K, Crump M, et al: A dose escalation trial of adjuvant CEF chemotherapy with G-CSF for premenopausal women with node-positive breast cancer. Proc Am Soc Clin Oncol 15:99, 1996
5. Therasse P, Mauriac L, Welnicka-Jaskiewicz M, et al: Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: An EORTC-NCIC-SAKK multicenter study. J Clin Oncol 21:843–850, 2003
6. Smith MA, Rubinstein L, Cazenave L, et al: Report of the Cancer Therapy Evaluation Program monitoring plan for secondary acute myeloid leukemia following treatment with epipodophyllotoxins. J Natl Cancer Inst 85:554–558, 1993 7. Pepe MS, Mori M: Kaplan-Meier, marginal or conditional probability curves in summarizing competing risks failure time data? Stat Med 12:737–751, 1993[Medline] 8. Pepe MS: Inference for events with dependent risks in multiple endpoint studies. J Am Stat Assoc 86:770–778, 1991[CrossRef] 9. Andersen MK, Christiansen DH, Jensen BA, et al: Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: Report on two new cases and review of the literature since 1992. Br J Haematol 114:539–543, 2001[CrossRef][Medline] 10. French Epirubicin Study Group: A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol 6:679–688, 1988[Abstract]
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. Smith RE, Bryant J, DeCillis A, et al: Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol 21:1195–1204, 2003
13. Pedersen-Bjergaard J, Rowley JD: The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation. Blood 83:2780–2786, 1994
14. 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
15. Tallman MS, Gray R, Bennett JM, et al: Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: The Eastern Cooperative Oncology Group experience. J Clin Oncol 13:1557–1563, 1995
16. Valagussa P, Moliterni A, Terenziani M, et al: Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer. Ann Oncol 5:803–808, 1994
17. Chaplain G, Milan C, Sgro C, et al: Increased risk of acute leukemia after adjuvant chemotherapy for breast cancer: A population-based study. J Clin Oncol 18:2836–2842, 2000
18. Linassier C, Barin C, Calais G, et al: Early secondary acute myelogenous leukemia in breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and radiation therapy. Ann Oncol 11:1289–1294, 2000 19. Secker-Walker LM, Moorman AV, Bain BJ, et al: Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities: EU Concerted Action 11q23 Workshop. Leukemia 12:840–844, 1998[CrossRef][Medline]
20. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 19:602–611, 2001
21. Piccart MJ, Di Leo A, Beauduin M, et al: Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 19:3103–3110, 2001 22. Bergh J, Wiklund T, Erikstein B, et al: Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: A randomised trial. Scandinavian Breast Group 9401 study. Lancet 356:1384–1391, 2000[CrossRef][Medline]
23. Fisher B, Anderson S, Wickerham 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
24. 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 25. Curtis RE, Boice JD, Jr., Stovall M, et al: Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med 326:1745–1751, 1992[Abstract]
26. Felix CA, Walker AH, Lange BJ, et al: Association of CYP3A4 genotype with treatment-related leukemia. Proc Natl Acad Sci USA 95:13176–13181, 1998
27. Allan JM, Wild CP, Rollinson S, et al: Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. Proc Natl Acad Sci U S A 98:11592–11597, 2001
28. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of intergroup trial c9741/cancer and leukemia group B trial 9741. J Clin Oncol 21:1431–1439, 2003 29. Mamounas EP: Evaluating the use of paclitaxel following doxorubicin/cyclophosphamide in patients with breast cancer and positive axillary nodes. Adjuvant Therapy for Breast Cancer: NIH Consensus Development Conference, Bethesda, MD, National Institutes of Health, Nov 1–3, 2000, 2002 Submitted August 21, 2002; accepted May 30, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
