Annals of Oncology Advance Access originally published online on May 19, 2005
Annals of Oncology 2005 16(8):1343-1351; doi:10.1093/annonc/mdi251
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© 2005 European Society for Medical Oncology
Secondary leukemia after epirubicin-based adjuvant chemotherapy in operable breast cancer patients: 16 years experience of the French Adjuvant Study Group
1 Centre René Gauducheau, Nantes; 2 Institut Claudius Régaud, Toulouse; 3 Centre Eugène Marquis, Rennes; 4 Centre Oscar Lambret, Lille; 5 Centre Hospitalier Jules Courmont, Lyon; 6 Centre Georges-François Leclerc, Dijon; 7 Centre Antoine Lacassagne, Nice; 8 Centre Hospitalier André Boulloche, Montbéliard; 9 Clinique Saint-Vincent, Besançon; 10 Centre Hospitalier de Bretagne Sud, Lorient, France
* Correspondence to: Dr M. Campone, Département d'Oncologie Médicale, Centre René Gauducheau, Boulevard Jacques Monod, 44805 Nantes-St-Herblain Cedex, France. Tel: +33-2-40-67-99-77; Fax: +33-2-40-63-96-61; Email: m-campone{at}nantes.fnclcc.fr
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Abstract |
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Background: The purpose of this study was to evaluate incidence and risk factors of secondary leukemia after adjuvant epirubicin-based chemotherapy in breast cancer patients.
Patients and methods: Among eight French Adjuvant Study Group trials, 3653 patients were assessable: 2603 received epirubicin; 682 received hormonotherapy; and 368 had no systemic treatment. Chemotherapy was FEC regimen in 85% of cases (fluorouracil 500 mg/m2, epirubicin 50, 75 or 100 mg/m2, cyclophosphamide 500 mg/m2, three or six cycles). Epirubicin cumulative dose was <300 mg/m2 in 1045 patients; 300–600 mg/m2 in 1187; and 
600 mg/m2 in 286, followed by radiotherapy in 96% of cases. The median follow-up was 104 months.
Results: Eight cases of leukemia occurred in epirubicin-exposed patients and one in non-exposed patients. After 9 years, the risk of developing a leukemia was 0.34% (95% confidence interval 0.11–0.57) in epirubicin-exposed patients. In patients receiving chemotherapy, leukemia subtypes were: AML2 (two), AML3 (one), AML4 (three) and ALL (two). None of the classically recognized risk factors was significantly correlated with the occurrence of a leukemia.
Conclusion: Irrespective of the dose, the incidence of secondary leukemia after adjuvant epirubicin-based chemotherapy was low. After a long follow-up, the benefit/risk ratio for early breast cancer patients remained in favor of epirubicin-based adjuvant chemotherapy: eight cases (0.31%) occurred, and in some of them, treatment causality could be debatable.
Key words: adjuvant chemotherapy, breast cancer, epirubicin, secondary leukemia
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Introduction |
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Over the last decades, increasing evidence has been reported that cancer patients who have been successfully treated with DNA-targeted antiproliferative drugs may develop acute myeloid leukemia (AML), months to several years after completion of chemotherapy. These leukemias are generally referred as ‘secondary’ leukemia to highlight their temporal association with previous cytotoxic treatments. The increased rate of early tumor diagnosis and the efficacy of adjuvant chemotherapy has substantially increased the number of long-term survivors among cancer patients and allowed the detection of more long-term complications.
The first reported chemo-induced leukemias were described after treatment of Hodgkin's disease [1
, 2]. They were associated with the use of alkylating agents, often combined with radiotherapy. These leukemias often present with a preleukemic phase (myelodysplastic syndrome, MDS), show specific unbalanced chromosomal aberrations (generally loss of genetic material in the q arm of chromosomes 5 and 7), seem to be cumulative-dose-related and typically arise after a latency period of more than 4 years [3]. At the end of the 1980s, a second class of secondary leukemia was described, associated with drugs interacting with the nuclear enzyme topoisomerase II (anthracyclines, anthracenediones, epipodophyllotoxins), which is involved in breakage and rejoining of DNA double strand. These leukemias are less frequently preceded by a preleukemic phase, often show specific balanced chromosomal aberrations (generally translocations 11q23 and 21q22), are not certainly dose-dependent and may arise after a shorter latency period, typically 1–3 years [3]. As regards the French–American–British (FAB) classification, secondary AML arising in patients treated with alkylating agents are generally, but not exclusively, of the M1–M2 subtypes, whereas secondary AML arising in patients treated with topoisomerase II inhibitors are generally of the M4–M5 subtypes [3].
The estimated risk of developing secondary leukemia after topoisomerase II inhibitors treatment varies widely between studies. These discrepancies have been attributed to different cumulative drug doses, different schedules and co-administration of other anti-neoplastic agents. Recently, the National Surgical Adjuvant Breast and Bowel Project (NSABP) reported AML and MDS observed across six trials using four cycles of AC (doxorubicin, cyclophosphamide) regimens at standard versus intensified dose of cyclophosphamide: the 5-year incidence of AML/MDS was sharply elevated in the more intense regimens [4]. An initial report of a Danish group found five cases of AML among 203 advanced breast cancer patients who received epirubicin combined with cyclophosphamide or cisplatin, or after exposure to other alkylating agents [5]. Afterwards, the risk related to epirubicin was questioned [6, 7]. Finally, the use of high-dose epirubicin regimens (>100 mg/m2) could increase this risk [8, 9]. Overall, in the high-dose regimens, with doxorubicin or epirubicin, confounding factors such as the use of granulocyte colony-stimulating factor (G-CSF) must be take into consideration [4, 9].
In order to clarify the risk to develop a secondary leukemia after epirubicin-based adjuvant chemotherapy for breast cancer, when used at classical doses, without G-CSF, the French Adjuvant Study Group (FASG) collected all cases occurring in the eight adjuvant trials conducted between 1986 and 2001, among 3653 assessable patients.
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Patients and methods |
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Study population
Between 1986 and 2001, 3653 women with operable breast cancer and follow-up, recruited from 32 institutions in France, were randomized in eight adjuvant trials (Table 1). The women had all undergone modified radical mastectomy or lumpectomy plus axillary dissection. The main eligibility criteria were World Health Organization (WHO) performance status
2, normal hematological (granulocyte count 2000/mm3, platelet count 100 000/mm3), hepatic (bilirubin 35 µmol/l) and renal (serum creatinine level 130 µmol/l) functions, and no cardiac dysfunction (baseline left ventricular ejection fraction 50%). Patients were excluded from the study if they had evidence of metastases, a documented history of cardiac disease or previous cancer (except treated basal cell and squamous cell carcinoma of the skin or cancer of the uterine cervix), a serious underlying medical illness or psychiatric disorder, inflammatory or locally advanced breast cancer before surgery, previous radiation therapy, or hormonotherapy or chemotherapy for breast cancer, or if start of treatment exceeded 42 days from initial surgery for breast cancer. Potentially eligible patients also underwent bone scan, chest radiograph, abdominal ultrasound or computed tomography scan, and contralateral mammography. Written informed consent was obtained from each patient in a standard procedure at each participating institution according to the French loi Huriet.
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Treatment regimens
Patients had received either epirubicin-based chemotherapy combined or not with tamoxifen, hormonotherapy alone, or no systemic treatment (Table 1). The allocated treatment was started within 42 days after initial surgery. Tamoxifen was given at the dose of 30 mg/day for 3 years, and started at the first chemotherapy cycle if both treatments were combined.
Locoregional radiotherapy was delivered within 6 weeks after initial surgery in the hormonotherapy and no systemic treatment groups. In the chemotherapy group, radiotherapy was delivered within 30 days after the third chemotherapy cycle in the FASG 01 and 02 trials, and within 30 days after the last chemotherapy cycle in the other trials. After mastectomy, radiation to the chest wall, supraclavicular area, internal mammary chain and, in case of pN1 tumor, axillary area was delivered, and consisted of 50 Gy in 25 fractions for each target. Patients who underwent lumpectomy received local radiation to the breast that consisted of 55 Gy in 27 fractions plus a complementary breast irradiation of 10–15 Gy, and local radiation to the supraclavicular area, internal mammary chain and axillary area (in case of pN1 tumor) consisting of 50 Gy in 25 fractions for each target.
For chemotherapy, preventive use of G-CSF and antibiotics were prohibited. An absolute granulocyte count <2000/mm3 or a platelet count <100 000/mm3 on day 21 led to a treatment interruption of at least 1 week. Treatment was stopped if hematological recovery took >3 weeks. The epirubicin dose was reduced by 50% if serum bilirubin levels were 35–50 µmol/l, and treatment was stopped if bilirubin levels exceeded 50 µmol/l. The tolerability of chemotherapy was evaluated before each cycle: an electrocardiogram and a complete blood count were performed on day 21, and non-hematological toxicity was evaluated during the period between each cycle, according to WHO criteria. Subjects underwent clinical and biochemical assessments every 6 months during the 5-year follow-up period, and yearly thereafter. A radiologic assessment was performed every year during the 5-year follow-up period, and every 2 years thereafter.
Data management and data analysis
Patients enrolled in the FASG trials were followed from the time of randomization until death. If a patient was lost to follow-up, a letter was sent to her general practitioner to obtain information. Patients presenting with abnormal blood count during the scheduled biochemical follow-up were referred to a hematologist, and data given by the hematology laboratory were reported in the case report form. Cases of secondary leukemia and MDS were reported by the investigators to Pfizer France, and then transmitted to Pfizer Oncology Pharmacovigilance, Milan. In the same time, each report was declared to the French Health Authorities.
We compared the occurrence of secondary leukemia between patients who received or not adjuvant epirubicin. The risk of developing a secondary leukemia was compared between the two groups using a log-rank analysis. We computed the per-year incidence according to the number of patients in each group who were at risk at each diagnosis time. The patients were considered at risk from the date of randomization until death or last follow-up.
We determined the role of different risk factors using a log-rank test. In patients who received chemotherapy, we compared the risk according to cumulative dose and dose-intensity of epirubicin and cyclophosphamide. In the whole population, we determined the risk according to age, menopausal status, radiotherapy and hormonotherapy.
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Results |
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Patient and treatment characteristics
Among patients randomized in the FASG trials, overall 3653 patients were assessable for follow-up: 2603 received epirubicin-based adjuvant chemotherapy and 1050 received either hormonotherapy alone (n=682) or no systemic treatment (n=368). The main patient and tumor characteristics were significantly different between the two groups. The prognostic features for eligibility criteria in the various protocols were different, and patients randomized in chemotherapy groups presented with worse prognostic factors (Table 2). The median follow-up was 8 years. The distribution of follow-up duration is described in Figure 1.
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Overall, 96% of patients received radiotherapy, with significantly more patients irradiated in the chemotherapy group (97% versus 93%; P <0.0001). In patients who received radiotherapy, there was no difference according to the administration of chemotherapy either for the irradiation of internal mammary chain (66% versus 68%) or for the mean doses delivered on this area (47 Gy). In the 2603 patients who received chemotherapy, regimens were FEC 50 in 59%, FEC 75 in 7%, FEC 100 in 19%, epirubicin–vinorelbine in 9%, and weekly single-agent epirubicin in 6%. The cumulative dose and dose-intensity of epirubicin and cyclophosphamide are described in Table 3. The distribution of epirubicin cumulative dose was <300 mg/m2 in 1045 patients; 300–600 mg/m2 in 1187;
600 mg/m2 in 286; and unknown in 85. The distribution of cyclophosphamide cumulative dose was <1500 mg/m2 in 149 patients; 1500–3000 mg/m2 in 907; 3000 in 1115; and unknown in 85. As regards hormonotherapy, 36% of patients who received chemotherapy were concurrently treated with tamoxifen.
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Description, incidence rate and risk factors of secondary leukemia
Among the 2603 patients who received adjuvant epirubicin-based chemotherapy, eight cases (0.31%) of secondary leukemia occurred without any cases of MDS (Table 4). One case of secondary leukemia occurred in a patient who received tamoxifen alone as adjuvant therapy, then received for relapse a first-line chemotherapy with epirubicin (cumulative dose 300 mg/m2), and a second line with mitoxantrone (cumulative dose 108 mg/m2). Secondary leukemias were classified morphologically according to the FAB criteria, with the following subtypes: AML2 in two patients, AML3 in one patient, AML4 in three patients who received adjuvant chemotherapy and in one patient who received chemotherapy only for metastatic disease, and ALL in two patients (Table 4). All these patients had received radiotherapy. The causality of adjuvant chemotherapy was probable in four cases (cases 1, 4, 5 and 6): the AML2 occurred 49 months after three cycles of FEC 75, and the three AML4 occurring 8, 58 and 81 months after adjuvant chemotherapy. The causality of epirubicin is more debatable for the AML2, which was diagnosed >10 years after three cycles of FEC 50 (case 2), for the AML3 (case 3) and for both cases of ALL (cases 7 and 8). The AML4 diagnosed in a patient who had previously relapsed was probably related to mitoxantrone (18 months after initiation of mitoxantrone). As regards the onset period, two cases occurred shortly after chemotherapy initiation (cases 3 and 5), and the main peak was during the fifth year following treatment.
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Before relapse, secondary leukemia occurred only in patients who received adjuvant chemotherapy. The 9-year cumulative risk was 0.34% [95% confidence interval (CI) 0.11% to 0.57%] (Table 5). In patients who received adjuvant chemotherapy, there was no statistical difference according to the epirubicin cumulative dose or dose intensity (Table 5). The analysis of the other risk factors such as cyclophosphamide cumulative dose or dose intensity, hormonotherapy, internal mammary chain irradiation, age, or menopausal status did not demonstrate a significant role in the occurrence of secondary leukemia (Table 5).
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Discussion |
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We evaluated the incidence of treatment-related leukemia in 3653 patients who received epirubicin-based adjuvant chemotherapy in the eight trials conducted by the FASG from 1986 to 2001. Among the 2603 patients who received epirubicin, we reported eight cases of secondary leukemia (0.31%) with a 9-year cumulative incidence of 0.34%. One patient presented with an AML4 after receiving adjuvant tamoxifen then chemotherapy with epirubicin then mitoxantrone for relapse. None of the recognized risk factors was correlated with the occurrence of secondary leukemia. This lack of correlation could be due to the low number of cases. Topoisomerase II inhibitor-induced secondary leukemia often present with clinical, morphological and cytogenetic characteristics: no pre-leukemic phase, AML4 or AML5 according to FAB classification, and specific chromosomal aberrations involving the MLL gene localized on chromosome 11, band q23 [10
]. This aberration is considered as the main indicator of topoisomerase II inhibitor-induced secondary leukemia. With anthracyclines, other common aberrations were observed such as t(8;21), t(3;21), inv(16), and t(8;16) [10]. In the FASG patients, two cases had chromosome aberrations consistent with anthracycline-based chemotherapy (cases 4 and 5).
The first reported chemo-induced leukemias were described after treatment with melphalan. Curtis et al. [11] identified risk factors of secondary leukemia occurrence after breast cancer adjuvant treatment. This case–control study, in a cohort of 82 700 women given a diagnosis of breast cancer from 1973 to 1985, reported 84 secondary leukemias and six MDS; the main risk factors were radiotherapy, chemotherapy with alkylating agents, and chemotherapy–radiotherapy combination. Melphalan was 10 times more leukemogenic than cyclophosphamide (relative risk 31.4 versus 3.1). According to this analysis, Curtis et al. [11] estimated that low risks (two-fold increases) were associated with adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate, fluorouracil) in current use, and 6 months of CMF therapy would result in an additional five cases of leukemia per 10 000 patients within 10 years of breast cancer diagnosis. However, acute leukemia is rare in patients treated with CMF. Valagussa et al. [12] reported a 0.23% cumulative rate of acute leukemia over 15 years in 2465 patients who received CMF. According to the NSABP [4] and M. D. Anderson [13] results, the increase in cyclophosphamide cumulative dose clearly increases the risk of secondary leukemia. AC regimens employing intensified doses of cyclophosphamide requiring G-CSF support were characterized by increased rates of subsequent AML/MDS (Table 6). In the NSABP review [4], there were 43 cases among 8563 analyzed patients, with 20 AML and 23 MDS. Whereas the relationship between secondary leukemia and cyclophosphamide dose seems to be established, it remains unclear for anthracyclines.
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With doxorubicin, Bonadonna et al. [14
] reported one case of MDS, after 10 years, in 405 patients treated with sequential or alternating doxorubicin and CMF regimens. The NSABP [4], M. D. Anderson [13] and Eastern Cooperative Oncology Group [15] results confirmed these data. Similarly, there was no case of secondary AML in the OncoFrance trial [16] after 16 years of follow-up among patients treated with the AVCF regimen as adjuvant therapy. A study conducted by the Southwest Oncology Group [17] reported two cases of AML in the FAC-M treatment arm: one AML4 and one AML5, which occurred 11 and 22 months after chemotherapy, respectively. However, the analysis conducted by the NSABP showed a standardized incidence rate of 7 (95% CI 3.5–12.5) for standard AC regimens [4], which was higher from those observed with CMF (1.5- to 2-fold increase risk). We can infer from these data that leukemia risk associated with cyclophosphamide regimens including an anthracyclines is higher than for the standard CMF regimen.
As for doxorubicin, the results reported with epirubicin did not demonstrate clearly an increase in the incidence of secondary leukemia. In metastatic setting, Pedersen-Bjergaard et al. [5] reported five cases of AML in 203 patients treated with epirubicin; two cases had previously received either melphalan–CCNU combination or a cyclophosphamide cumulative dose >6 g/m2. The other patients had received cisplatin, fluorouracil or cyclophosphamide, but not epirubicin single-agent. The authors concluded that cisplatin could potentialize the leukemogenic effect of epirubicin. Afterwards, this hypothesis was not confirmed by a study conducted by Riggi et al. [6]: among 1563 patients treated with an epirubicin–cisplatin combination, three cases of AML occurred with an incidence of 0.2%, which was similar to that observed by Bonadonna et al. [14] with CMF.
In the adjuvant setting, several studies have reported the incidence rate of secondary leukemia after epirubicin-based adjuvant chemotherapy (Table 6). As the role of doxorubicin cumulative dose has not been studied, the use of high-dose (>600 mg/m2) epirubicin regimens could increase this risk [8, 9, 18]. In the three studies using epirubicin cumulative dose >600 mg/m2, the incidence of AML/MDS varied from 1.2% to 3.6%, but these epirubicin high-dose regimens were combined with a cyclophosphamide dose >6 g/m2, and in two of these trials prophylactic G-CSF was used (Table 6). In the Canadian trial [8], there were four cases of AML (M4 and M5), among which one 11q23 translocation was reported, and one case of ALL. In the Danish trial [9], the cyclophosphamide cumulative exceeded 10 g/m2: this is the only trial using epirubicin in adjuvant setting where MDS occurred. In the EORTC trial [18], the FAB subtypes were AML5 in two cases (21 and 32 months), and AML6 in one (57 months). In one case of AML5, an anthracycline-related chromosomal aberration involving the MLL gene was found. In the ICCG trial [19], there were no confounding factors, as it used epirubicin single-agent with a cumulative dose of 600 mg/m2, without G-CSF support. In this trial, there were two cases of AML4 among 303 patients (0.66%) occurring at 18 and 50 months. In the FASG trials, the dose of cyclophosphamide was fixed at 500 mg/m2 per cycle, there was no preventive use of G-CSF and epirubicin cumulative dose did not exceed 600 mg/m2. In these conditions, the incidence rate of AML remained low (0.23%).
There was no direct comparison of leukemogenic risk between doxorubicin and epirubicin. Recently, the NCIC [20] assessed the conditional probability of secondary leukemia among 1545 women who received adjuvant or neo-adjuvant chemotherapy in four trials. Patients had received EC/CEF with epirubicin cumulative dose of 720–840 mg/m2, AC with doxorubicin cumulative dose of 240 mg/m2, or CMF. At 8 years, the conditional probability of secondary leukemia was 1.7% with EC/CEF regimens, 1.3% with AC regimen and 0.4% with CMF. Although the number of patients treated with AC chemotherapy is small, the cumulative incidence following AC seems similar to that after epirubicin-containing regimens, but anthracycline-based chemotherapy involves a small increased risk of secondary leukemia compared with CMF.
Finally, the relationship between ALL and topoisomerase II inhibitors has not been clarified. Several trials have described the occurrence of ALL, but often these cases were not included as directly chemo-induced secondary leukemia. Andersen et al. [21] reviewed the literature since 1992. They identified 23 cases of ALL with balanced translocations with 11q23; all these patients had previously received at least one topoisomerase II inhibitor. For the authors, these results indicate that patients with ALL and balanced translocations to chromosome band 11q23 following chemotherapy with topoisomerase II inhibitors should be included with cases of MDS or AML in calculations of the risk of leukemia. In the FASG patients, we have reported two cases of ALL: cytogenetics was unknown in one, and a translocation (9;22) was diagnosed in the other. In spite of a lack of specific topoisomerase II inhibitor aberrations, we have included these two ALL in our calculations.
Anthracycline-based adjuvant chemotherapy has significantly improved breast cancer outcome. The long-term toxicity, such as secondary leukemia or cardiotoxicity, must not outweigh this benefit. Alkylating agents, combined with radiotherapy or other cytotoxic drugs, increase the risk of developing secondary AML/MDS. When used at conventional doses, like classical CMF, this risk did not differ from the overall population [12]. Thereafter, the use of anthracyclines involved an additional risk of AML that was different from that with alkylating agents. Among the 2603 patients who received epirubicin at conventional doses in the FASG trials, we did not find a higher risk than with CMF, or the overall population. On the other hand, this risk does not seem to differ between doxorubicin and epirubicin. When epirubicin was used at higher doses, the incidence rate of secondary AML could be higher, but confounding factors must be taken into account and results must be interpreted cautiously.
In the future, combination with taxanes, sequential treatments, treatment duration >18 weeks and extensive use of hematopoietic growth factors must be carefully monitored in order to avoid an increase risk of secondary AML. To date, the use of taxanes does not appear to increase this risk. With paclitaxel used sequentially with AC either every 21 days or in dose-dense regimens, the incidence rate was 0.51% at 5 years and 0.55% at 3 years [22, 23]. As regards docetaxel used concurrently with AC, the 5-year incidence was 0.27% [24]. In all these new combinations, the follow-up must be longer to clearly establish their safety in terms of secondary leukemia.
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Acknowledgements |
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We are indebted to Dr Elisabeth Luporsi (Centre Alexis Vautrin, Nancy, France) for her statistical contribution. Isabelle Chapelle-Marcillac provided editorial assistance in the preparation of the manuscript. This work was supported by grants from Pfizer, France.
Received for publication October 22, 2004. Revision received March 18, 2005. Accepted for publication March 29, 2005.
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