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Anthracyclines, Mitoxantrone, Radiotherapy, and Granulocyte Colony-Stimulating Factor: Risk Factors for Leukemia and Myelodysplastic Syndrome After Breast Cancer
Abstract
To determine the risk factors for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer.
We conducted a case-control study among women treated for breast cancer between 1985 and 2001 in French general hospitals, cancer centers, or clinics. We included 182 AML and MDS patients and 534 matched controls. Breast cancer characteristics, type of treatment, and family history of cancer were compared in both groups.
The risk of AML/MDS was increased after topoisomerase-II inhibitor–based chemotherapy (P < 10−16) and was higher for mitoxantrone-based chemotherapy than for anthracycline-based chemotherapy (relative risk [RR] = 15.6; 95% CI, 7.1 to 34.2; and RR = 2.7; 95% CI, 1.7 to 4.5, respectively). After adjustment for other treatment components, the risk of AML/MDS in patients who received radiotherapy was multiplied by 3.9 (95% CI, 1.4 to 10.8) but was not increased by alkylating agents. Patients receiving granulocyte colony-stimulating factor (G-CSF) support had an increased risk of AML/MDS (RR = 6.3; 95% CI, 1.9 to 21), even when controlling for chemotherapy doses. Similar results were obtained when AML and MDS were considered separately.
This large case-control study demonstrates that the risk of AML/MDS is much higher with mitoxantrone-based chemotherapy than with anthracyclines-based chemotherapy in a population of women recently treated for breast cancer. The risk of AML/MDS associated with mitoxantrone must be kept in mind when using this drug to treat diseases other than breast cancer (eg, prostate cancer or multiple sclerosis). In addition, our study suggests the need to monitor the long-term effects of G-CSF therapy.
Breast cancer is the most common tumor in women; the worldwide number of new patients reached 1,050,000 in 2000.1 The use of adjuvant chemotherapy to treat breast cancer has been extended over the past years from node-positive women to lower risk patients.2,3 Anthracycline-containing chemotherapy has been demonstrated4 to be more efficacious than alkylating-based chemotherapy and is currently the gold standard. Mitoxantrone, a topoisomerase-II inhibitor with a similar mechanism of action to that of anthracyclines but with fewer adverse effects such as hair loss, demonstrated its efficacy in metastatic breast cancer and was used for awhile in Europe during the 1990s to treat localized breast cancer.
Several studies have recently suggested that anthracyclines and mitoxantrone increase the risk of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in women treated for breast cancer.5-12 We evaluated this risk in a large multicenter case-control study of women treated for breast cancer between 1985 and 2001, taking into account other risk factors.
Patients who developed AML or MDS after a breast cancer were studied. A questionnaire was sent in June 2001 to all oncologists and hematologists working in France to identify patients, and new patients were registered prospectively until August 2002. To avoid overselection of patients treated with mitoxantrone, we selected patients who were either identified by a hematologist (therefore independent of breast cancer treatment) or reported by a cancer center with a computerized patient registry. Clinicopathologic data, including bone marrow aspiration and biopsy reports, were reviewed by one of the authors (P.F.) to confirm eligibility for the study and to classify the disease according to French-American-British criteria. A total of 182 eligible patients were included in the present analysis (138 with AML and 44 with MDS). Among the 138 patients with cytogenetic and/or molecular biology evaluation, 109 had cytogenetic or molecular abnormalities, which are listed in Table 1. For simplicity, all of these patients are hereinafter referred to as leukemia patients.
For each patient with AML/MDS, three control patients were to be randomly selected, matching for age at breast cancer, date of breast cancer diagnosis, follow-up period, and, when possible, hospital. More than 95% of the controls were selected from computerized hospital registries.
Assuming that 30% of the women treated for breast cancer received mitoxantrone or anthracyclines in France at that time, 200 leukemia patients matched with 600 control patients were necessary to have a 95% chance of detecting a risk increased by a factor of 2, using a two-sided test and a type I error of 1%.13 The analysis was based on 182 AML/MDS patients compared with 534 matched controls.
For each patient, trained research assistants collected demographic data, family history of cancer, and clinical data, including information on all events and treatments during the matched time period, using standardized forms. Data sources included medical records, medical prescriptions, medical correspondence, pharmacy delivery lists, daily nursing records, and, for radiotherapy, treatment sheets and control and simulation x-ray films.
The cumulative chemotherapy dose was computed for each cytotoxic drug. Within a pharmacologic group, the dose of each drug was converted into the dose of a reference drug, as described elsewhere.14 For alkylating agents, we also combined exposures by summing milligrams per meter squared or, alternatively, millimoles per meter squared, which is a usual practice. For the total dose of anthracyclines, we considered both the cumulative dose of each agent separately and the overall cumulative dose of anthracyclines expressed as a doxorubicin-equivalent dose; doxorubicin 50 mg/m2 was considered equivalent to epirubicin 75 mg/m2 or pirarubicin 50 mg/m2. We also considered the timing of administration of anthracyclines and mitoxantrone (1 injection every 21 days v fractionated schedules: either days 1 and 8 every 21 days or 2 to 3 consecutive days every 21 days).
The mean radiation dose received by the active bone marrow was computed with estimated doses received by 128 skeletal points weighted and summed according to methods described elsewhere.15 This estimation was available for 59 leukemia patients and 145 matched controls who had received radiotherapy.
Conditional logistic regression was used to estimate the relative risk (RR) of AML/MDS associated with specific therapies by comparing the exposure history of each patient with AML/MDS with that of the individually matched controls. Nested models were compared using likelihood ratio tests. Two-sided P values and 95% CIs were computed. For each studied factor, the RR of AML/MDS was estimated in univariate and multivariate analyses controlling for other risk factors. To correct for multiple testing, we considered as significant in the final models two-sided P < .01.
To study the relationship between the dose of chemotherapy or radiotherapy and the risk of AML/MDS, we divided patients into subgroups according to dose distribution and calculated the RR in each subgroup compared with patients who had not been exposed to the treatment under study.
To study the risks of leukemia associated with the adjuvant treatment of breast cancer, the RRs were secondarily estimated after excluding patients with metastatic disease at diagnosis and also after excluding patients with recurrence or secondary tumor. The robustness of the final model was studied considering separately the 138 AML patients matched with their 403 controls and the 44 MDS patients matched with their 131 controls.
The median age at diagnosis of breast cancer was 52.2 years (range, 27 to 86 years) both for leukemia patients and for controls. Among leukemia patients, 146 (80%) developed AML/MDS while in first complete remission of a nonmetastatic breast cancer. The median interval between the diagnosis of the first tumor and the onset of AML/MDS was 3.1 years (range, 0.5 to 15 years).
As detailed in Table 2, tumor size, node involvement, histologic grade, and secondary events were associated with an increased risk of AML/MDS in the univariate analysis. None of these factors remained significantly associated with an increased risk of AML/MDS after controlling for treatment.
A family history of cancer was not significantly more frequent in leukemia patients than in controls. In particular, we found no excess family history of breast/ovary cancer in first- or second-degree relatives among leukemia patients compared with controls (24.4% v 28.1%, respectively).
As detailed in Table 3, a larger proportion of patients with AML/MDS than controls were treated with chemotherapy, granulocyte colony-stimulating factor (G-CSF), radiotherapy, or hormonal treatment. High-dose chemotherapy followed by stem-cell transplantation was not a significant risk factor.
In the univariate analysis, the risk of AML/MDS was associated with each pharmacologic group considered separately (mitoxantrone, anthracyclines, epipodophyllotoxins, alkylating agents, antimetabolites, and spindle inhibitors). However, only topoisomerase-II inhibitors (mitoxantrone, anthracyclines, and epipodophyllotoxins) remained significantly associated with an increased risk of AML/MDS after controlling for the other types of drugs (Table 4).
Only seven leukemia patients (3.9%) and one control (0.2%) were treated with etoposide administered as second-line or later treatment after anthracycline-based chemotherapy. Only nine leukemia patients (5.0%) and six controls (0.9%) received both anthracyclines and mitoxantrone, and risks of AML/MDS were quite similar among patients who received mitoxantrone with and without anthracyclines compared with patients who received neither mitoxantrone nor anthracyclines (RR = 15.3; 95% CI, 6.92 to 33.9; and RR = 19.4; 95% CI, 4.88 to 77, respectively, when controlling for epipodophyllotoxin treatment). This is why we considered treatment with topoisomerase-II inhibitors in the following four mutually exclusive categories: patients who did not receive any of these drugs, patients who received only anthracyclines, patients who received mitoxantrone with or without anthracyclines but without epipodophyllotoxins, and patients who received epipodophyllotoxins. Taking the first group as the reference group, the risk was multiplied respectively by 3.42 (95% CI, 2.10 to 5.58), 15.4 (95% CI, 7.30 to 32.6), and 51.6 (95% CI, 5.94 to 451) in the other three groups (overall comparison test, P < 10−19). These results were stable when controlling for radiotherapy and treatment with G-CSF; in the multivariate analysis, the risk was multiplied respectively by 2.73 (95% CI, 1.65 to 4.54), 15.6 (95% CI, 7.10 to 34.2), and 38.5 (95% CI, 4.26 to 347; overall comparison test, P < 10−16). The risk associated with mitoxantrone was significantly higher than that associated with anthracyclines in both univariate and multivariate analyses.
Cumulative dose distribution of mitoxantrone and each anthracycline was similar between leukemia patients and controls (Table 4), and we observed no evidence of a dose-effect relationship between cumulative doses of these drugs and risk of AML/MDS both in the univariate analysis and in the multivariate analysis when controlling for radiotherapy and G-CSF.
The main anthracyclines used in this population were epirubicin (45 leukemia patients and 98 controls) and doxorubicin (31 leukemia patients and 52 controls). Studied as binary variables, the risk associated with epirubicin was similar to that associated with doxorubicin (RR = 1.86; 95% CI, 1.07 to 3.22; and RR = 2.72; 95% CI, 1.39 to 5.34, respectively, when controlling for mitoxantrone, epipodophyllotoxins, radiotherapy, and G-CSF). A study of the dose-effect relationship for each anthracycline separately showed that, in terms of RR of AML/MDS, 50 mg/m2 of doxorubicin and 100 mg/m2 of epirubicin were equivalent.
No difference in risk of AML/MDS was observed when comparing fractionated and standard schedules for anthracyclines or mitoxantrone (RR = 1.82; 95% CI, 0.54 to 6.15; P = .34).
When controlling for treatment with topoisomerase-II inhibitors and for other identified risk factors (radiotherapy and G-CSF), none of the other pharmacologic groups remained significant. In particular, treatment with alkylating agents did not increase the risk of AML/MDS when considered as a binary variable (RR = 1.15; 95% CI, 0.42 to 3.14; P = .78) or when studied as a dose-effect relationship (data not shown).
In the univariate analysis, the risk associated with radiotherapy increased with the extent of radiotherapy fields. Considering patients who were not irradiated as the reference group, the risk was multiplied by 2.39 (95% CI, 0.84 to 6.77) for patients who received only local breast radiotherapy, whereas it was multiplied by 5.17 (95% CI, 1.98 to 13.5) after regional radiotherapy (nodes ± breast) and by 8.21 (95% CI, 2.50 to 27) after radiotherapy to distant sites (radiotherapeutic ovarian ablation or irradiation of metastatic sites). In the univariate analysis, the risk increased with the mean radiation dose received by active bone marrow; in patients treated with radiotherapy, an increase of 1 Gy was associated with a risk ratio of 1.14 (95% CI, 1.04 to 1.25).
Controlling for treatment with topoisomerase-II inhibitors and G-CSF, radiotherapy remained a significant risk factor (RR = 3.89; 95% CI, 1.40 to 10.8) when considered as a binary variable, but no differences were observed according to the extent of radiotherapy fields (P = .91) or the mean radiation dose received by active bone marrow (P = .80). The risk associated with radiotherapy was significant even for local radiotherapy limited to the breast (RR = 3.56; 95% CI, 1.18 to 10.7).
Patients who received G-CSF had a significantly increased risk of AML/MDS, even when controlling for treatment with topoisomerase-II inhibitors and radiotherapy (RR = 6.26; 95% CI, 1.89 to 20.7). This result was stable after adjustment for mitoxantrone and anthracycline cumulative doses (RR = 4.16; 95% CI, 1.21 to 14.3; P = .02).
The reason for G-CSF treatment was not systematically recorded in medical files, so this factor could not be studied. Likewise, we could not explore the relationship between the risk of AML/MDS and the dose or duration of G-CSF treatment.
In the univariate analysis, women who received tamoxifen had a higher risk of AML/MDS than patients who did not. No relationship was observed between risk of AML/MDS and the daily dose or total duration of tamoxifen. When controlling for other risk factors (topoisomerase-II inhibitors, G-CSF, and radiotherapy), the risk was marginally increased with tamoxifen (RR = 1.65; 95% CI, 1.07 to 2.64; P = .022). This factor was not taken into account in the final explanatory model.
The following three factors attained significance in the multivariate analysis after consideration of all the treatments administered over the study period: treatment with topoisomerase-II inhibitors with a significantly higher risk with mitoxantrone than with anthracyclines, radiotherapy, and G-CSF (Table 5). Results were unchanged when focusing on adjuvant patients, after exclusion of patients with metastatic disease at diagnosis, and also after exclusion of patients with recurrence or secondary tumor. Results did not vary when risk factors for AML and MDS were considered separately (Fig 1).
This case-control study demonstrates, in a large French population, that treatment with topoisomerase-II inhibitors was a major risk factor for AML/MDS in women recently treated for breast cancer, with a higher risk with mitoxantrone than with anthracyclines. Our study also suggests that patients receiving G-CSF could have an increased risk of AML/MDS, even when controlling for chemotherapy doses. To our knowledge, this is one of the largest case-control studies evaluating the risk of AML/MDS after cancer treatment and the first to assess the risk related to mitoxantrone, anthracyclines, and G-CSF specifically.
We did not attempt to identify all AML/MDS patients diagnosed in France among breast cancer survivors, and there is no national cancer registry. However, the procedure of selection of patients and controls, using electronic hospital files, allows us to ensure that leukemia patients and controls came from the same source population and minimizes the risk of overselection of leukemia patients receiving mitoxantrone. By going back systematically to each treatment center, we obtained a precise description of all treatment received by patients both as first-line treatment and subsequent treatment.
The first studies reporting leukemia after mitoxantrone-based chemotherapy did not specifically attribute the leukemogenic risk to this drug.16,17 The leukemogenic risk of mitoxantrone in patients treated for breast cancer was first suggested a few years later.18,19 In 2000, five studies reported on the leukemogenic risk of mitoxantrone in women treated for breast cancer. Four of these studies included less than 13 leukemia patients,7,8,10,11 and the fifth study described 121 patients with leukemia that occurred after breast cancer without controls.9 Seventy one of our 182 patients have previously been included in one of these studies. The actuarial risk of secondary AML/MDS was estimated at 0.7% at 3 years by Linassier et al,10 at 0.94% at 4 years by Kroger et al,20 at 1.1% at 5 years and 1.6% at 10 years by Saso et al,11 and at 2.2% at 4 years by Chaplain et al.8 Our study confirms the higher leukemogenic risk associated with mitoxantrone than with anthracyclines suggested by Chaplain et al8 and supports the decision taken in France in 2001 to withdraw mitoxantrone as adjuvant treatment in breast cancer.
In contrast to the results of Chaplain et al,8 we found no cumulative dose-effect relationship with mitoxantrone, which can be explained by the limited variation in the cumulative dose of mitoxantrone in our study population (71% of the controls received between 54 and 75 mg/m2 of mitoxantrone). Matching on hospital may also have led to overmatching on treatment doses.
The association between anthracyclines and AML/MDS that we observed is of major importance because anthracycline-based chemotherapy is currently the gold standard for breast cancer treatment. This result confirms the finding of our recent pediatric case-control study.14 Only a few case-control studies have previously evaluated this factor, and they failed to reach any clear conclusions.21-23 The occurrence of AML/MDS after exposure to anthracyclines has been widely described, especially in breast cancer randomized trials or registries6,12,24-26; anthracycline-based chemotherapy was found to be more leukemogenic than the cyclophosphamide, methotrexate, and fluorouracil regimen,24 although the risk of leukemia was generally considered to be relatively low. Our finding of a similar risk for epirubicin and doxorubicin is important when discussing which anthracycline to choose for adjuvant chemotherapy for breast cancer. In contrast to the study by Praga et al,5 no cumulative dose-effect relationship was observed, probably because of the limited variation in the cumulative dose of anthracyclines in our population.
Epipodophyllotoxins are very rarely administered for breast carcinoma. Their well-established leukemogenic effect was also demonstrated in our study, but this was based on very few patients.
We found no excess risk associated with alkylating agents in the multivariate analysis, even when considering MDS alone, despite the recognized leukemogenicity of these drugs. This can be explained by the close association between exposure to alkylating agents and to anthracyclines/anthracenedione in our population (only 14 of 344 patients who received alkylating agents did not receive anthracyclines or mitoxantrone) and the current choice and mode of administration of alkylating agents (cyclophosphamide, which is much less leukemogenic than melphalan,27 is now the standard alkylating agent in adjuvant treatment of breast cancer and is usually administered in sequential courses with a relatively low cumulative dose; median total dose of 3 g/m2). Studies of patients treated with cyclophosphamide-based chemotherapy (such as the cyclophosphamide, methotrexate, and fluorouracil regimen) did not show an increased risk of leukemia,6,28,29 except in one recent study with more than 20 years of follow-up.30
We found a positive association between radiotherapy and the risk of AML/MDS, whereas the leukemogenic risk of radiotherapy remains controversial. As in the National Surgical Adjuvant Breast and Bowel Project,12 we observed an increased risk even when radiotherapy was confined to the breast and the chest wall. In contrast to the study by Curtis et al,27 the leukemogenic effect in our study did not increase with the mean radiation dose received by the active bone marrow.
We found an increased risk of AML/MDS associated with G-CSF use in the multivariate analysis, even when controlling for chemotherapy doses. Two recent studies have reported similar findings.12,31 These results should be interpreted with caution. In the National Surgical Adjuvant Breast and Bowel Project trials,12 the increased leukemia risk could be partly related to high alkylator dose. In our study, G-CSF was mostly administered because of poor hematologic tolerance to chemotherapy, which could reflect drug accumulation as a result of an unusual metabolism or bone marrow sensitivity of the patient. Additional studies are required, and careful monitoring of long-term effects of G-CSF is needed.
The leukemogenic risk of tamoxifen we observed must also be considered with caution; the P value was not significant (P = .022) given the 1% limit chosen to control for multiple testing. No leukemogenic effect of tamoxifen has been reported to date in the literature12,32,33 except in one case report,34 and a link between hormonal therapy and AML/MDS would be hard to reconcile given our understanding of leukemia biology.
Surprisingly, when considered separately, MDS had the same risk factors as AML, mainly topoisomerase-II inhibitors. MDS has previously been shown to be mostly associated with treatment with alkylating agents.35,36 Therefore, the distinction between MDS with chromosome 5 and 7 abnormalities after alkylating agent administration and AML with a balanced chromosomal translocation linked to topoisomerase-II inhibitors37 may be oversimplified with regard to current cytotoxic treatments.
In conclusion, we showed for the first time that, in breast cancer patients, the leukemogenic potential of mitoxantrone is important and higher than that of anthracyclines. The risk of AML/MDS associated with mitoxantrone must be kept in mind when using this drug to treat other diseases than breast cancer (eg, prostate cancer or multiple sclerosis). In addition, our study suggests the need to monitor the long-term effects of G-CSF therapy, which may be more frequently used as a result of the increasing prevalence of intensive treatment regimens.
The authors indicated no potential conflicts of interest.
Conception and design: Marie-Cécile Le Deley, Bruno Cutuli, Suzette Delaloge, Florent de Vathaire, Pierre Fenaux, Catherine Hill
Provision of study materials or patients: Bruno Cutuli, Suzette Delaloge, Claude Linassier, Pierre Fenaux
Collection and assembly of data: Marie-Cécile Le Deley, Stéphanie Clisant, Akthar Shamsaldin
Data analysis and interpretation: Marie-Cécile Le Deley, Florence Suzan, Bruno Cutuli, Suzette Delaloge, Claude Linassier, Pierre Fenaux, Catherine Hill
Manuscript writing: Marie-Cécile Le Deley, Florence Suzan, Pierre Fenaux, Catherine Hill
Final approval of manuscript: Marie-Cécile Le Deley, Florence Suzan, Bruno Cutuli, Suzette Delaloge, Akthar Shamsaldin, Claude Linassier, Stéphanie Clisant, Florent de Vathaire, Pierre Fenaux, Catherine Hill
We are indebted to all the doctors in the treating centers who identified cases, helped us to select controls or to collect data: Mme F. Accard, Nantes; Dr T. Altwegg, Dijon; Dr R. Angonin, Besançon; Dr C. Apfeldorfer, Orleans; Dr P. Arveux, Dijon; Dr I. Aubert, Toulon; Dr Azagury, Meulan; Dr F. Bachelot, Saint-Germain-en-Laye; Dr F. Bachelot, La-Garenne-Colombes; Mrs M. Ballot, Rouen; Dr JC. Balzon, Saintes; Dr N. Barbet, Macon; Dr C. Barin, Tours; Mr Barrelier, Nice; Pr J. Bassoulet, Saint-Grégoire; Dr C. Bayle, Villejuif; Dr JF. Berdah, Hyères; Dr J. Berlie, Saint-Germain-en-Laye; Dr J. Bertrand, Château-Renault; Dr C. Besson, Paris; Dr P. Biron, Lyon; Pr Blanc, Marseille; Dr B. Blaska-Jaulerry, Lagny-sur-Marne; Dr F. Bons-Rosset, Nîmes; Pr D. Bordessoule, Limoges; Dr A. Botton, Pontoise; Dr F. Boulbair, Belfort; Dr A. Bourguignat, Saint-Cloud; Dr J. Boyer, Le Mans; Dr J. Brandone, Marseille; Pr Breau, Bobigny; Dr N. Breteau, Orléans; Dr P. Brice, Paris; Pr P. Bryon, Lyon; Dr G. Buchonnet, Rouen; Dr J. Buffet-Miny, Besançon; Dr J. Buisine, Vandoeuvre-les-Nancy; Dr D. Caillot, Dijon; Dr L. Campion, Saint-Herblain; Dr E. Canat, Lyon; Dr J. Carenco, Saint-Michel; Dr E. Cart, Besançon; Pr J. Cassuto, Nice; Dr S. Chaib-Rassou, Troyes; Dr M. Chaury-Gourin, Limoges; Dr N. Cheron, Briis-sous-Forges; Mr Chevalier, Amboise; Dr P. Clavere, Limoges; Mrs C. Clément, Bourg-en-Bresse; Dr F. Collenot, Blois; Dr Collet, Le Mans; Dr Courdi, Nice; Dr C. Crosnier, Agen; Mrs N. Dastugue, Toulouse; Dr Daurelles, Martigues; Dr A. De la Rochefordière, Paris; Dr B. De Lafontan, Toulouse; Pr de Martinville, Lille; Dr Defrance, Lille; Dr S. Delanian, Paris; Dr Delmas, Villejuif; Dr T. Delozier, Caen; Dr A. Delpon, Le Mans; Dr R. Delva, Angers; Dr E. Desandes, Vandoeuvre-les-Nancy; Dr Devidas, Corbeil-Essonnes; Dr Dine, Troyes; Dr P. Dube, Amiens; Pr P. Duroux, Neuilly-sur-Seine; Dr G. Estrade, Saint-Michel; Mrs Evenou, Saint-Herblain; Dr D. Eychenne, Troyes; Dr M. Fabbro, Montpellier; Dr A. Falkenrodt, Strasbourg; Dr P. Faure, Nevers; Dr C. Félix-Faure, Avignon; Dr L. Fenoll, Saint-Doulchard; Dr Frobert, Bourg-en-Bresse; Mrs L. Gandon, Lyon; Dr F. Garcia, La Rochelle; Dr J. Gardais, Angers; Mrs T. Gargi, Lyon; Mrs C. Gauthier, Pontoise; Pr Gérard, Nice; Dr J. Goasguen, Rennes; Dr F. Gomez, Lyon; Dr L. Gonzague-Casabianca, Marseille; Dr Y. Goubely, Avignon; Mrs M. Grandjean, Dijon; Dr M. Grégoire, Vandoeuvre-les-Nancy; Dr O. Guerin, Angers; Dr P. Gueudet, Perpignan; Mrs Guitard, Bourg-en-Bresse; Dr M. Henry-Amar, Caen; Dr J. Hernandez, Saint-Martin-les-Boulogne; Pr P. Herve, Besancon; Dr F. Honhadel, Béthune; Pr D. Houzé de l'Aulnoit, Lomme; Dr Jacob, Tours; Dr M. Janvier, Saint-Cloud; Dr B. Joubert, Cherbourg; Dr N. Jouet-Rouverand, Lille; Dr G. Jung, Strasbourg; Dr P. Kerbrat, Rennes; Dr Y. Kerneis, Pontoise; Dr Kravanja, Strasbourg; Dr T. Kreitmann, Cannes-La-Bocca; Dr D. Langlois, La Rochelle; Dr H. Lauche, Montpellier; Dr J. Laurent, Rennes; Mrs M. Le Gall-Godard, Rennes; Dr A. Le Mevel-Le Pourhiet, Saint-Herblain; Pr P. Le Prise, Rennes; Dr E. Le Prise-Fleury, Rennes; Dr B. Le Vu, Paris; Mrs L. Leclerc, Paris; Pr Lederlin, Vandoeuvre-les-Nancy; Mr E. Legouffe, Montpellier; Dr L. Legros, Nice; Dr R. Leloup, Orléans; Dr M. Lepienne, Niort; Dr T. Leroy-Brasme, Tourcoing; Dr A. Lesoin, Lille; Pr M. Lessard, Strasbourg; Mrs R. Livet, Le Mans; Dr A. Loeb, Rouen; Dr A. Lortholary, Nantes; Dr E. Luporsi, Vandoeuvre-Les-Nancy; Pr Machover, Villejuif; Dr G. Magnin, Martigues; Dr F. Mahon, Pessac; Dr D. Maron, Avranches; Dr I. Marquis, Nancy; Dr A. Marre, Rodez; Dr M. Marrel, Narbonne; Dr H. Mathieu-Daude, Montpellier; Pr J. Mention, Amiens; Dr J. Micléa, Paris; Dr L. Miglianico, Saint-Grégoire; Dr P. Mital, Arras; Pr M. Monconduit, Rouen; Dr B. Mongodin, Montélimar; Dr P. Mornet, Saint-Germain-en-Laye; Dr P. Moskovtchenko, Colmar; Dr F. Mugneret, Dijon; Dr M. Nezri, Martigues; Dr H. Nguyen, Caen; Dr Paoli, Marseille; Dr P. Pardieu, Melun; Dr C. Pautas, Creteil; Dr B. Pellae-Cosset, Compiègne; Dr A. Petit, Tours; Dr B. Picon, Compiègne; Dr Piel-Desruisseaux, Lisieux; Dr J. Pietra, Toulon; Dr Y. Plumelle, Fort-de-France; Dr L. Prié, Saintes; Pr J. Pris, Toulouse; Dr C. Prot-Piganiol, Ris-Orangis; Dr P. Quetin, Strasbourg; Dr Raffoux, Paris; Dr A. Ramaioli, Nice; Mrs P. Ravart, Saint-Herblain; Dr D. Reynaud, Montpellier; Dr H. Rhliouch, Arras; Dr F. Riitano, Marseille; Dr P. Rodon, Blois; Dr S. Rohart-De Cordoue, Lille; Dr D. Sainty, Marseille; Dr A. Salemkour, Chartres; Dr P. Salze, Colmar; Dr Sauvage, Toulouse; Dr D. Serin, Avignon; Dr I. Sillet-Bach, Brive-la-Gaillarde; Dr Smadja, Paris; Dr C. Sohn, Toulon; Dr P. Solal-Celigny, Le-Mans; Dr C. Soussain, Meaux; Dr A. Stoppa, Marseille; Dr Surowka, Besançon; Dr Tadrist, Aix-en-Provence; Dr S. Théobald, Strasbourg; Pr A. Thyss, Nice; Dr C. Toulouse, Bordeaux; Pr X. Troussard, Caen; Dr Van Praagh, Clermont-Ferrand; Dr A. Vanoli, Saint-Rémy; Dr A. Vekhoff, Paris; Dr B. Vie, Caen; Dr J. Viguier, Paris; Dr L. Vila, Lyon; Dr J. Vilcoq, Brie-Comte-Robert.
Fig 1. Stability of treatment effects according to the type of hemopathy. Adjusted relative risks and 95% CIs were estimated in a model including mitoxantrone, anthracyclines, granulocyte colony-stimulating factor (G-CSF), and radiotherapy as binary variables. AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.
|
| Cytogenetic or Molecular Assessment | No. of Patients | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AML | MDS† (n = 44) | Total Patients (n = 182) | |||||||||||||
| M1 (n = 16) | M2 (n = 27) | M3 (n = 27) | M4 (n = 21) | M5 (n = 22) | Other* (n = 25) | ||||||||||
| At least one abnormality‡ | 10 | 25 | 23 | 15 | 13 | 8 | 15 | 109 | |||||||
| Chromosome 5 abnormality | 1 | 6 | 0 | 1 | 1 | 1 | 11 | 21 | |||||||
| Chromosome 7 abnormality | 3 | 6 | 2 | 2 | 2 | 3 | 8 | 26 | |||||||
| Rearrangement involving 11q23§ | 5 | 7 | 0 | 3 | 8 | 1 | 2 | 26 | |||||||
| Rearrangement involving 21q22‖ | 0 | 10 | 1 | 0 | 0 | 1 | 2 | 12 | |||||||
| Translocation t(15;17)(q22;q21) | 0 | 0 | 23 | 0 | 0 | 0 | 0 | 23 | |||||||
| Inv(16)(p13;q22) | 0 | 0 | 0 | 8 | 1 | 0 | 0 | 9 | |||||||
| Translocation t(9;22)(q34;q11) | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 3 | |||||||
| Other | 2 | 10 | 5 | 6 | 5 | 1 | 5 | 34 | |||||||
| No abnormality | 3 | 1 | 2 | 4 | 3 | 6 | 10 | 29 | |||||||
| Not explored | 3 | 1 | 2 | 2 | 6 | 11 | 19 | 44 | |||||||
Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.
*AML-M0 (n = 6), AML-M6 (n = 4), AML-M7 (n = 1), biphenotypic acute leukemia (n = 3), and AML unclassified (n = 11).
†Refractory anemia (n = 7), refractory anemia with ring sideroblasts (n = 1), refractory anemia with excess of blasts (n = 19), refractory anemia with excess of blasts in transformation (n = 6), chronic myelomonocytic leukemia (n = 4), and unclassified MDS (n = 7).
‡Among the 109 patients with cytogenetic or molecular abnormalities, 51 had multiple abnormalities. The most frequent association was the combination of chromosome 5 and 7 abnormalities (n = 13).
§Rearrangement involving 11q23 was t(9;11)(p21;q23) in 14 patients and t(11;19)(q23;p13) in six patients.
‖Rearrangement involving 21q22 was t(8;21)(q22;q22) in 10 patients and t(3;21) in three patients.
|
| Characteristic | Patients With Leukemia (n = 182) | Matched Controls* (n = 534) | Univariate Analysis | Multivariate Analysis† | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | RR | 95% CI | P | RR | 95% CI | P | |||||||
| Tumor size | < .0003 | .74 | ||||||||||||||
| T0 + T1 | 69 | 38.1 | 288 | 54.0 | 1‡ | 1‡ | ||||||||||
| T2 | 82 | 45.3 | 192 | 36.0 | 1.86 | 1.27 to 2.73 | 1.11 | 0.72 to 1.71 | ||||||||
| T3 + T4 | 30 | 16.6 | 53 | 9.9 | 2.58 | 1.49 to 4.46 | 0.88 | 0.44 to 1.74 | ||||||||
| Nodal involvement | < .0001 | .64 | ||||||||||||||
| N0 | 107 | 59.4 | 403 | 76.0 | 1‡ | 1‡ | ||||||||||
| N1a | 43 | 23.9 | 84 | 15.8 | 2.03 | 1.29 to 3.17 | 1.28 | 0.77 to 2.13 | ||||||||
| N1b + N2 + N3 | 30 | 16.7 | 43 | 8.1 | 3.01 | 1.72 to 5.28 | 1.13 | 0.58 to 2.21 | ||||||||
| Metastastic disease at diagnosis | .68 | |||||||||||||||
| No | 178 | 97.8 | 525 | 98.3 | 1‡ | |||||||||||
| Yes | 4 | 2.2 | 9 | 1.7 | 1.29 | 0.40 to 4.20 | ||||||||||
| Histologic type | .02§ | .40§ | ||||||||||||||
| Invasive ductal | 147 | 81.7 | 404 | 76.4 | 1‡ | 1‡ | ||||||||||
| Infiltrating lobular | 19 | 10.6 | 52 | 9.8 | 1.00 | 0.57 to 1.78 | 0.94 | 0.48 to 1.81 | ||||||||
| Ductal in situ | 4 | 2.2 | 44 | 8.3 | 0.25 | 0.09 to 0.71 | 0.46 | 0.14 to 1.47 | ||||||||
| Other | 10 | 5.6 | 29 | 5.5 | 0.93 | 0.44 to 1.97 | 1.43 | 0.61 to 3.31 | ||||||||
| Histologic grade according to SBR system | .34 | |||||||||||||||
| SBR I | 35 | 23.0 | 115 | 26.9 | 1‡ | |||||||||||
| SBR II | 72 | 47.4 | 217 | 50.8 | 1.05 | 0.64 to 1.72 | ||||||||||
| SBR III | 45 | 29.6 | 95 | 22.3 | 1.43 | 0.83 to 2.45 | ||||||||||
| Estrogen receptor | .09 | .60 | ||||||||||||||
| Negative | 52 | 33.1 | 109 | 26.0 | 1‡ | 1‡ | ||||||||||
| Positive | 105 | 66.9 | 310 | 74.0 | 0.70 | 0.46 to 1.06 | 1.14 | 0.70 to 1.85 | ||||||||
| Recurrence or secondary solid tumor | .04 | .99 | ||||||||||||||
| No | 150 | 82.4 | 472 | 88.4 | 1‡ | 1‡ | ||||||||||
| Yes‖ | 32 | 17.6 | 62 | 11.6 | 1.66 | 1.03 to 2.68 | 0.99 | 0.56 to 1.77 | ||||||||
| Family history of cancer in first- or second-degree relative | .38 | |||||||||||||||
| No | 74 | 50.0 | 242 | 55.6 | 1‡ | |||||||||||
| Yes | 74 | 50.0 | 193 | 44.4 | 1.20 | 0.80 to 1.78 | ||||||||||
NOTE. Percentages may not add up to 100 because of rounding.
Abbreviations: RR, relative risk; MD, missing data; SBR, Scarff-Bloom-Richardson.
*The analysis was based on 182 leukemia patients compared with 534 matched controls; one leukemia patient had four controls (extra control selected because eligibility of one control was initially doubtful), 168 leukemia patients had three controls, and 13 leukemia patients had two controls (third control not found). The control women were matched for age at breast cancer, date of diagnosis, hospital, and follow-up period. The follow-up period for each control had to be at least as long as the study period of the matched patient, defined as the interval between diagnosis of the breast cancer and leukemia onset. Matching criteria were not strictly met for 45 controls (8%); the difference in age was greater than 24 months (maximum, 61 months) for 23 controls, the difference in the date of diagnosis was greater than 24 months (maximum, 43 months) for seven controls, and 17 controls were not selected in the same hospital as their matched patients.
†Adjusted RR and P values were estimated, for each factor separately, controlling for exposure to topoisomerase-II inhibitors, radiotherapy, and granulocyte colony-stimulating factor.
‡Reference category.
§When considering ductal in situ compared with all other histologic types (invasive ductal, infiltrating lobular, and other), P = .002 in univariate analysis, and P = .14 in multivariate analysis.
‖Secondary events included contralateral breast cancer (eight leukemia patients and 11 controls), local relapse (five leukemia patients and 26 controls), nodal relapse (two leukemia patients and four controls), secondary metastasis (16 leukemia patients and 17 controls), and other secondary solid tumors (six leukemia patients and 11 controls). Secondary solid tumors were endometrial carcinoma (two leukemia patients and two controls), non-Hodgkin's lymphoma (two leukemia patients), colon cancer (one leukemia patient and three controls), and other cancers (one leukemia patient and six controls). All the salvage treatments administered for secondary events are taken into account in the analysis; secondary solid tumors were treated with chemotherapy alone in one leukemia patient and one control, radiotherapy alone in one leukemia patient and three controls, chemotherapy plus radiotherapy in one leukemia patient and no controls, and no chemotherapy and no radiotherapy in three leukemia patients and seven controls.
|
| Characteristic | Patients With Leukemia (n = 182) | Matched Controls* (n = 534) | Univariate Analysis | Multivariate Analysis† | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | RR | 95% CI | P | RR | 95% CI | P | |||||||
| Chemotherapy | < 10−14 | < 10−9 | ||||||||||||||
| No | 49 | 26.9 | 305 | 57.1 | 1‡ | 1‡ | ||||||||||
| Yes | 133 | 73.1 | 229 | 42.9 | 4.81 | 3.09 to 7.48 | 3.83 | 2.42 to 6.06 | ||||||||
| Radiotherapy§ | .0002 | .009 | ||||||||||||||
| No | 6 | 3.3 | 60 | 11.2 | 1‡ | 1‡ | ||||||||||
| Yes | 176 | 96.7 | 474 | 88.8 | 4.71 | 1.80 to 12.3 | 3.22 | 1.20 to 8.67 | ||||||||
| Hormonal treatment | .0002 | .03 | ||||||||||||||
| No | 73 | 40.1 | 292 | 54.7 | 1‡ | 1‡ | ||||||||||
| Yes | 109 | 59.9 | 242 | 45.3 | 2.07 | 1.40 to 3.05 | 1.58 | 1.04 to 2.39 | ||||||||
| G-CSF | < 10−5 | .003 | ||||||||||||||
| No | 166 | 91.2 | 527 | 98.7 | 1‡ | 1‡ | ||||||||||
| Yes | 16‖ | 8.8 | 7 | 1.3 | 8.56 | 3.11 to 23.5 | 4.53 | 1.54 to 13.4 | ||||||||
| High-dose chemotherapy plus stem-cell transplantation | .12 | .89 | ||||||||||||||
| No | 179 | 98.3 | 532 | 99.6 | 1‡ | 1‡ | ||||||||||
| Yes | 3 | 1.7 | 2 | 0.4 | 4.16 | 0.69 to 25.0 | 1.15 | 0.14 to 9.39 | ||||||||
Abbreviation: RR, relative risk; G-CSF, granulocyte colony-stimulating factor; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome.
*The control women were matched for age at breast cancer, date of diagnosis, hospital, and follow-up period (see Table 2).
†Adjusted RR and P values were estimated by multivariate analysis in a model including the five factors of the table.
‡Reference category.
§Information on radiotherapy fields was available for all patients; 35 leukemia patients and 170 controls received only local radiotherapy to the breast, 144 leukemia patients and 339 controls received regional radiotherapy (nodes ± breast), and 16 leukemia patients and 22 controls were irradiated on distant sites (radiotherapeutic ovarian ablation or irradiation of metastatic sites). The mean radiation dose received by the active bone marrow was estimated for 59 leukemia patients and 145 matched controls who had received radiotherapy; the median dose was 5.3 Gy in leukemia patients (quartile 1 to quartile 3, 3.3 to 8.2 Gy; range, 0.25 to 22 Gy) and 4.2 Gy in controls (quartile 1 to quartile 3, 2.1 to 6.7 Gy; range, 0.28 to 18.8 Gy).
‖Leukemias occurring after concomitant use of G-CSF were AML M0 (n = 1), M1 (n = 2), M2 (n = 2), M4 (n = 2), M5 (n = 3), and M6 (n = 1); refractory anemia (n = 1); refractory anemia with excess of blasts (n = 1); and unclassified MDS (n = 3). The median interval between the diagnosis of the first tumor and the onset of AML/MDS was 2.7 years (range, 1.1 to 12.5 years). The 13 patients with WBC counts available at the time of diagnosis of breast cancer had normal WBC counts at that point. Information on WBCs after the end of treatment was available for 10 patients; four patients had a normal WBC count, and six had leukopenia.
|
| Pharmacologic Group | Patients With Leukemia (n = 182) | Matched Controls (n = 534) | Univariate Analysis | Multivariate Analysis* | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | RR | 95% CI | P | RR | 95% CI | P | |||||||
| Mitoxantrone† | < 10−13 | < 10−15 | ||||||||||||||
| No | 123 | 67.6 | 468 | 87.6 | 1‡ | 1‡ | ||||||||||
| Yes | 59 | 32.4 | 66 | 12.4 | 9.78 | 4.88 to 19.6 | 12.8 | 6.13 to 26.6 | ||||||||
| Anthracyclines§ | < 10−4 | < 10−6 | ||||||||||||||
| No | 101 | 55.5 | 379 | 71.0 | 1‡ | 1‡ | ||||||||||
| Yes | 81 | 44.5 | 155 | 29.0 | 2.32 | 1.55 to 3.47 | 3.11 | 1.96 to 4.96 | ||||||||
| Epipodophyllotoxins‖ | .0002 | .009 | ||||||||||||||
| No | 175 | 96.1 | 533 | 99.8 | 1‡ | 1‡ | ||||||||||
| Yes | 7 | 3.9 | 1 | 0.2 | 20.1 | 2.47 to 164 | 9.84 | 1.18 to 82.1 | ||||||||
| Alkylating agents¶ | < 10−12 | .34 | ||||||||||||||
| No | 55 | 30.2 | 317 | 59.4 | 1‡ | 1‡ | ||||||||||
| Yes | 127 | 69.8 | 217 | 40.6 | 4.30 | 2.82 to 6.55 | 1.51 | 0.65 to 3.50 | ||||||||
| Antimetabolites | < 10−9 | .89 | ||||||||||||||
| No | 64 | 35.2 | 325 | 60.9 | 1‡ | 1‡ | ||||||||||
| Yes | 118 | 64.8 | 209 | 39.1 | 3.33 | 2.26 to 4.92 | 1.05 | 0.52 to 2.13 | ||||||||
| Spindle inhibitors** | < 10−5 | .35 | ||||||||||||||
| No | 142 | 78.0 | 485 | 90.8 | 1‡ | 1‡ | ||||||||||
| Yes | 40 | 22.0 | 49 | 9.2 | 3.09 | 1.87 to 5.09 | 1.33 | 0.74 to 2.39 | ||||||||
Abbreviations: RR, relative risk; Q, quartile.
*The model included mitoxantrone, anthracyclines, and epipodophyllotoxins. RR and P values were estimated by multivariate analysis adjusted for these three variables, with each other factor being added separately.
†The median cumulative dose of mitoxantrone was 69 mg/m2 (Q1 to Q3, 52 to 73 mg/m2; range, 9 to 99 mg/m2) in patients and 68 mg/m2 (Q1 to Q3, 48 to 72 mg/m2; range, 8 to 106 mg/m2) in controls.
‡Reference category.
§The anthracyclines used were doxorubicin in 31 leukemia patients (median dose, 262 mg/m2; Q1 to Q3, 149 to 314 mg/m2; range, 46 to 450 mg/m2) and 52 controls (median dose, 233 mg/m2; Q1 to Q3, 146 to 279 mg/m2; range, 29 to 404 mg/m2), epirubicin in 45 leukemia patients (median dose, 309 mg/m2; Q1 to Q3, 275 to 450 mg/m2; range, 139 to 793 mg/m2) and 98 controls (median dose, 319 mg/m2; Q1 to Q3, 293 to 429 mg/m2; range, 49 to 779 mg/m2), and pirarubicin in six leukemia patients and six controls.
‖The only epipodophyllotoxin used was etoposide.
¶The alkylating agents used were cyclophosphamide in 124 leukemia patients (median dose, 2,991 mg/m2; Q1 to Q3, 2,652 to 4,903 mg/m2; range, 561 to 11,233 mg/m2) and 211 controls (median dose, 2,982 mg/m2; Q1 to Q3, 2,455 to 3,616 mg/m2; range, 561 to 17,187 mg/m2), mitomycin in 11 leukemia patients and eight controls, thiotepa in six leukemia patients and five controls, ifosfamide in two leukemia patients and no controls, melphalan in one leukemia patient and two controls, dacarbazine in one leukemia patient and no controls, and lomustine in no leukemia patients and one control.
**The spindle inhibitors used were vincristine in 18 leukemia patients and 23 controls, vindesine in 13 leukemia patients and 16 controls, vinorelbine in 12 leukemia patients and 12 controls, vinblastine in no leukemia patients and one control, docetaxel in five leukemia patients and four controls, and paclitaxel in three leukemia patients and four controls.
|
| Risk Factor | No. | All Patients (N = 182 patients/534 controls) | After Exclusion of Patients With Metastatic Disease at Diagnosis (n = 178 patients/525 controls) | After Exclusion of Patients With Metastatic Disease at Diagnosis and/or Recurrence or Secondary Solid Tumor (n = 146 patients/464 controls) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| RR | 95% CI | P | RR | 95% CI | P | RR | 95% CI | P | ||||||||
| Topoisomerase-II inhibitors | < 10−16 | < 10−16 | < 10−11 | |||||||||||||
| None | 51/318 | 1* | 1* | 1* | ||||||||||||
| Anthracyclines only | 67/149 | 2.73 | 1.65 to 4.54 | 2.61 | 1.57 to 4.33 | 2.84 | 1.61 to 5.03 | |||||||||
| Mitoxantrone | 57/66 | 15.6 | 7.10 to 34.2 | 17.45† | 7.91 to 38.5 | 16.35† | 6.42 to 41.6 | |||||||||
| Epipodophyllotoxins† ± anthracyclines | 7/1 | 38.5 | 4.26 to 347 | |||||||||||||
| Radiotherapy | .003 | .002 | .02 | |||||||||||||
| No | 6/60 | 1* | 1* | 1* | ||||||||||||
| Yes | 176/474 | 3.89 | 1.40 to 10.8 | 4.54 | 1.48 to 13.9 | 3.51 | 1.11 to 11.1 | |||||||||
| G-CSF | .0009 | .001 | .001 | |||||||||||||
| No | 166/527 | 1* | 1* | 1* | ||||||||||||
| Yes | 16/7 | 6.26 | 1.89 to 20.7 | 6.28 | 1.84 to 21.5 | 8.88 | 2.00 to 39.4 | |||||||||
Abbreviations: RR, relative risk; G-CSF, granulocyte colony-stimulating factor.
*Reference category.
†We pooled patients who received epipodophyllotoxins with patients who received mitoxantrone because of the small number of patients who received epipodophyllotoxins in adjuvant treatment.
published online ahead of print at www.jco.org on December 11, 2006.
Supported by the Institut Gustave-Roussy, the Fondation de France (Comité Leucémies), the Association pour la Recherche sur le Cancer, and Wyeth Laboratory, France.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
We thank all the women who agreed to participate; Lorna Saint-Ange for editing; Guillemette Antoni, Yassine Benmebarek, Dominique Godfrin, Marie-Gabrielle Dondon, and Muriel Wartelle for data collection and data management; and all the physicians at treating centers who helped us (Appendix, online only).
| 1. | Parkin DM, Bray F, Ferlay J, et al: Estimating the world cancer burden: Globocan 2000. Int J Cancer 94::153,2001-156, Crossref, Medline, Google Scholar |
| 2. | Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Natl Cancer Inst 90::1601,1998-1608, Crossref, Medline, Google Scholar |
| 3. | Zujewski J, Liu ET: The 1998 St. Gallen's Consensus Conference: An assessment. J Natl Cancer Inst 90::1587,1998-1589, Crossref, Medline, Google Scholar |
| 4. | Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352::930,1998-942, Crossref, Medline, Google Scholar |
| 5. | Praga C, Bergh J, Bliss J, et al: Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: Correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23::4179,2005-4191, Link, Google Scholar |
| 6. | Bernard-Marty C, Mano M, Paesmans M, et al: Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients. Ann Oncol 14::693,2003-698, Crossref, Medline, Google Scholar |
| 7. | Carli PM, Sgro C, Parchin-Geneste N, et al: Increase therapy-related leukemia secondary to breast cancer. Leukemia 14::1014,2000-1017, Crossref, Medline, Google Scholar |
| 8. | 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::2836,2000-2842, Link, Google Scholar |
| 9. | Cutuli B, Janvier M, de la Rochefordiere A, et al: Leukemia and pre-leukemic conditions occurring after treatment of breast cancer. Presse Med 29::135,2000-138, Medline, Google Scholar |
| 10. | 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::1289,2000-1294, Crossref, Medline, Google Scholar |
| 11. | Saso R, Kulkarni S, Mitchell P, et al: Secondary myelodysplastic syndrome/acute myeloid leukaemia following mitoxantrone-based therapy for breast carcinoma. Br J Cancer 83::91,2000-94, Crossref, Medline, Google Scholar |
| 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::1195,2003-1204, Link, Google Scholar |
| 13. | Breslow NE, Day NE: Statistical methods in cancer research. Volume I: The analysis of case-control studies. IARC Sci Publ 32::5,1980-338, Medline, Google Scholar |
| 14. | Le Deley MC, Leblanc T, Shamsaldin A, et al: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: A case-control study by the Societe Francaise d'Oncologie Pediatrique. J Clin Oncol 21::1074,2003-1081, Link, Google Scholar |
| 15. | Christy M: Mathematical phantoms representing children of various ages for use in estimates of internal dose. Washington, DC, US Nuclear Regulatory Commission, ORNL Report NUREG/CRE, 1159, 1980 Google Scholar |
| 16. | Andersson M, Storm HH, Mouridsen HT: Carcinogenic effects of adjuvant tamoxifen treatment and radiotherapy for early breast cancer. Acta Oncol 31::259,1992-263, Crossref, Medline, Google Scholar |
| 17. | Philpott NJ, Bevan DH, Gordon-Smith EC: Secondary leukaemia after MMM combined modality therapy for breast carcinoma. Lancet 341::1289,1993, Google Scholar |
| 18. | Cremin P, Flattery M, McCann SR, et al: Myelodysplasia and acute myeloid leukaemia following adjuvant chemotherapy for breast cancer using mitoxantrone and methotrexate with or without mitomycin. Ann Oncol 7::745,1996-746, Crossref, Medline, Google Scholar |
| 19. | Melillo LM, Sajeva MR, Musto P, et al: Acute myeloid leukemia following 3M (mitoxantrone, mitomycin and methotrexate) chemotherapy for advanced breast cancer. Leukemia 11::2211,1997-2213, Crossref, Medline, Google Scholar |
| 20. | Kroger N, Damon L, Zander AR, et al: Secondary acute leukemia following mitoxantrone-based high-dose chemotherapy for primary breast cancer patients. Bone Marrow Transplant 32::1153,2003-1157, Crossref, Medline, Google Scholar |
| 21. | Arkad'eva MA, Zaridze DG: The risk of the occurrence of acute nonlymphoblastic leukemia in patients with malignant neoplasms undergoing radio- and chemotherapy. Vopr Onkol 37::1086,1991-1090, Medline, Google Scholar |
| 22. | Boivin JF, Hutchison GB, Zauber AG, et al: Incidence of second cancers in patients treated for Hodgkin's disease. J Natl Cancer Inst 87::732,1995-741, Crossref, Medline, Google Scholar |
| 23. | Tucker MA, Meadows AT, Boice JD, et al: Leukemia after therapy with alkylating agents for childhood cancer. J Natl Cancer Inst 78::459,1987-464, Crossref, Medline, Google Scholar |
| 24. | Crump M, Tu D, Shepherd L, et al: Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: A report from the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21::3066,2003-3071, Link, Google Scholar |
| 25. | Fumoleau P, Kerbrat P, Romestaing P, et al: Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol 21::298,2003-305, Link, Google Scholar |
| 26. | Fumoleau P, Roche H, Kerbrat P, et al: Long-term benefit/risk ratio of epirubicin-based adjuvant chemotherapy in operable breast cancer patients: 7-year analysis in 3577 pts of French Adjuvant Study Group (FASG) trials. Proc Am Soc Clin Oncol 23::23,2003, (abstr 91) Google Scholar |
| 27. | 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::1745,1992-1751, Crossref, Medline, Google Scholar |
| 28. | 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::1557,1995-1563, Link, Google Scholar |
| 29. | Valagussa P, Moliterni A, Terenziani M, et al: Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer. Ann Oncol 5::803,1994-808, Crossref, Medline, Google Scholar |
| 30. | Weiss RB, Woolf SH, Demakos E, et al: Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate, and fluorouracil-based adjuvant chemotherapy: A study by the Cancer and Leukemia Group B. J Clin Oncol 21::1825,2003-1835, Link, Google Scholar |
| 31. | Relling MV, Boyett JM, Blanco JG, et al: Granulocyte colony-stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment. Blood 101::3862,2003-3867, Crossref, Medline, Google Scholar |
| 32. | Andersson M, Storm HH, Mouridsen HT: Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer. J Natl Cancer Inst 83::1013,1991-1017, Crossref, Medline, Google Scholar |
| 33. | Haas JF, Kittelmann B, Mehnert WH, et al: Risk of leukaemia in ovarian tumour and breast cancer patients following treatment by cyclophosphamide. Br J Cancer 55::213,1987-218, Crossref, Medline, Google Scholar |
| 34. | Yalcin S, Gullu I, Demiroglu H, et al: Acute leukaemia during tamoxifen therapy. Med Oncol 14::61,1997-62, Crossref, Medline, Google Scholar |
| 35. | Pedersen-Bjergaard J, Larsen SO: Incidence of acute nonlymphocytic leukemia, preleukemia, and acute myeloproliferative syndrome up to 10 years after treatment of Hodgkin's disease. N Engl J Med 307::965,1982-971, Crossref, Medline, Google Scholar |
| 36. | Rowley JD, Golomb HM, Vardiman JW: Nonrandom chromosome abnormalities in acute leukemia and dysmyelopoietic syndromes in patients with previously treated malignant disease. Blood 58::759,1981-767, Crossref, Medline, Google Scholar |
| 37. | Pedersen-Bjergaard J, Christiansen DH, Andersen MK, et al: Causality of myelodysplasia and acute myeloid leukemia and their genetic abnormalities. Leukemia 16::2177,2002-2184, Crossref, Medline, Google Scholar |
