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Increased Risk of Acute Leukemia After Adjuvant Chemotherapy for Breast Cancer: A Population-Based Study

From the Registre des Cancers Gynécologiques de Côte d’Or, Faculté de Médecine; Centre d’Epidémiologie de Population de l’Université de Bourgogne, Faculté de Médecine; Centre Régional de Pharmacovigilance, Centre Hospitalier et Universitaire; and Registre des Hémopathies Malignes de Côte d’Or, Faculté de Médecine, Dijon, France.

Address reprint requests to Claire Bonithon-Kopp, MD, PhD, Centre d’Epidémiologie de Population de l’Université de Bourgogne, Faculté de Médecine, 7 bd Jeanne d’Arc, 21,033 Dijon Cedex, France; email bonithon{at}u-bourgogne.fr

	ABSTRACT

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PURPOSE: To quantify the risk of acute leukemia after adjuvant therapy, especially chemotherapy with topoisomerase II inhibitors.

PATIENTS AND METHODS: We performed a population-based study in a cohort of 3,093 women younger than 85 years who resided in the French administrative area of the Côte d’Or, who were given a first diagnosis of primary breast cancer between 1982 and 1996, and who received a curative treatment. Information about therapy and follow-up events was obtained from records of cancer registries that covered this area.

RESULTS: Until December 1998, 10 cases of acute leukemia, including nonlymphoid acute leukemia and refractory anemia with excess of blasts, occurred in patients before any local or distant recurrence. All cases developed in the first 4 years of follow-up. Compared with the general female population, the incidence rate of leukemia was significantly increased in women who received radiotherapy and chemotherapy (standardized incidence ratio, 28.5; P < .0001). A dose-dependent increase in the risk of leukemia was observed in women treated with mitoxantrone. Cox regression analysis showed that the risk of leukemia was significantly lower in patients treated with anthracyclines than in those treated with mitoxantrone at cumulative doses 13 mg/m².

CONCLUSION: The combination of adjuvant radiotherapy and chemotherapy with mitoxantrone induces a high risk of acute leukemia in patients with breast cancer. A leukemogenic effect of chemotherapy with anthracyclines cannot be ruled out with certainty. However, there are some suggestions that these topoisomerase II inhibitors might be less leukemogenic than mitoxantrone and could be preferred in an adjuvant setting.

	INTRODUCTION

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IN FRANCE, AS IN many Western countries, breast cancer is the most common cancer in women and its incidence has markedly increased in the last few decades.¹ Adjuvant polychemotherapy has been shown to be effective in reducing cancer recurrence and death for a wide range of women with early breast cancer.² However, improvement in long-term survival also increases the risk of long-term complications, which raises the problem of the benefit-risk ratio, especially in women whose breast cancer has a good prognosis. Leukemia is a major complication of cancer therapy that has been closely related to chemotherapy with some alkylating agents, such as melphalan,³ or with topoisomerase II inhibitors, such as epipodophyllotoxins.⁴ Several reports on patients with breast cancer also suggested that other topoisomerase II inhibitors, including anthracyclines^5,6 and mitoxantrone,⁷ might be potentially leukemogenic, without any firm conclusion being drawn. The purpose of this population-based cohort study was to quantify the risk of nonlymphoid acute leukemia (NLAL) and refractory anemia with excess of blasts (RAEB-t) after adjuvant chemotherapy among women with breast cancer in the French administrative area of the Côte d’Or.

	PATIENTS AND METHODS

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Study Population
The study population was composed of women who were first diagnosed with primary breast cancer between January 1, 1982, and December 31, 1996. They were identified from the population-based Registry of Gynecologic Cancers (administrative area of the Côte d’Or, France). Women included in the study cohort met the following eligibility criteria: at the time of diagnosis, they resided in the administrative area covered by the registry, they had received a curative surgical treatment, and they were younger than 85 years. Thus, among 3,540 women with a first diagnosis of breast cancer, 195 with detectable metastases at the time of diagnosis were excluded, together with 119 for whom surgical treatment was unknown and 133 who were older than 85 years, which led to a study cohort of 3,093 women.

Ascertainment of Cases of NLAL and RAEB-t
Information about the occurrence of NLAL and RAEB-t (which are referred to as leukemia, for the sake of simplicity) between January 1, 1982, and December 31, 1998, was obtained from several sources. First, the Registry of Hematological Malignancies (administrative area of the Côte d’Or, France) systematically records the personal history of severe diseases such as breast cancer. Second, the Registry of Gynecologic Cancers periodically updates follow-up data of patients with breast cancer. Twelve cases were identified by cross-referencing files from both registries. Furthermore, the Department of Oncohematology of the University Hospital is the only department authorized to treat acute hematologic malignancies in the administrative area of the Côte d’Or and in the bordering areas. A systematic review of oncohematologic medical records and myelograms of all women treated for NLAL and RAEB-t during the study period confirmed that no cases were missed by the registries.

Data Collection From the Registry of Gynecologic Cancers
Information about demographic characteristics, date of breast cancer diagnosis, lymph node involvement and metastases at the time of diagnosis, date of eventual distant or local recurrence, and treatment was obtained from registry records. The only information systematically recorded was regarding the primary treatment of breast cancer. This information concerned the type of surgery (mammectomy or tumorectomy), the use of radiotherapy or hormonal therapy, which was mainly tamoxifen (yes or no), and the type of chemotherapy. At the time of registration, treatment data were extracted from hospital records by trained physicians and were periodically updated. No details about doses and fields of irradiation or about doses of chemotherapy were routinely recorded. With respect to chemotherapy, our interest was focused on protocols that contained either mitoxantrone or anthracyclines, because these agents are frequently used in the Côte d’Or area. For the purpose of the study, all hospital records of women who received mitoxantrone were secondarily reviewed to obtain information on cumulative doses of mitoxantrone. This information was available for 448 of 449 women. Cumulative doses ranged from 10 mg/m² to 106 mg/m², and the median was 48 mg/m². Because of the trimodal distribution of cumulative doses of mitoxantrone, patients were divided into three categories: cumulative dose 12 mg/m², between 13 and 55 mg/m², and 56 mg/m². The first category was mainly composed of women who received a single dose of mitoxantrone in a perioperative protocol (179 of 185 patients). All other women received mitoxantrone in postoperative protocols in combination with other cytostatic drugs, generally fluorouracil and cyclophosphamide. In some cases, these postoperative protocols have been associated with a perioperative protocol. Among women who did not receive mitoxantrone, the most common types of chemotherapy were regimens that included anthracyclines such as doxorubicin or epidoxorubicin. Various chemotherapeutic agents were used in combination with anthracyclines, but the most common regimens associated cyclophosphamide and fluorouracil. Other chemotherapeutic regimens that contained neither mitoxantrone nor anthracyclines were pooled into a single category. Among them, the most common regimen was the combination of cyclophosphamide, methotrexate, and fluorouracil (CMF regimens).

Period at Risk and Statistical Analysis
Information about vital status and follow-up events was periodically updated at the Registry of Gynecologic Cancers. The period at risk started on the date of diagnosis of breast cancer and ended on the date of diagnosis of local or distant recurrence, diagnosis of second breast cancer, or diagnosis of leukemia or death, whichever occurred first. When none of these events occurred, the follow-up period ended on the last known follow-up, on the 85th birthday, or on December 31, 1998, whichever occurred first. No data on medical treatment of recurrence were available in the Registry because of the usual multiplicity of chemotherapeutic agents used in such circumstances, which explains why data were censored at the date of recurrence.

The number of person-years was calculated by 5-year age groups. The age-standardized incidence ratio was used to compare the rates of leukemia in the cohort with those of the general population in the Côte d’Or area. There were marginal variations in the incidence rates of acute leukemia in the general population between the period from 1982 to 1989 and the period from 1990 to 1996. The number of expected cases was obtained by multiplying the number of person-years in each 5-year age group by the specific incidence rates for age, sex, and calendar period (1982 to 1989 or 1990 to 1997) of the population of the Côte d’Or. Estimates of 95% confidence intervals (CIs) and the significance tests were calculated with the assumption that the number of observed cases followed a Poisson distribution.

A within-cohort analysis was performed with the Cox regression model to estimate the relative risk associated with adjuvant chemotherapy and the 95% CIs. The main objective was to compare the risk of leukemia in women who received mitoxantrone with that observed in women who received anthracyclines or in women who received neither mitoxantrone nor anthracyclines. Thus, the mitoxantrone group was considered as the reference group. Potential confounding factors included in the model were the age at diagnosis of breast cancer ( 44 years, 45 to 64 years, or > 64 years), lymph node involvement (none, one or two nodes, or three nodes), period of diagnosis (1982 to 1989 or 1990 to 1996), and hormonal therapy. The Kaplan-Meier method was used to estimate the cumulative risk of leukemia at 4 years.

	RESULTS

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Descriptive Characteristics of the Study Cohort
During the period from 1982 to 1996, 3,093 women younger than 85 years who resided in the administrative area of the Côte d’Or received curative surgery for breast cancer. Their characteristics according to the type of treatment are described in Table 1. Among them, 2,768 women (89.5%) received adjuvant treatment with radiotherapy and/or chemotherapy. The most common type of adjuvant treatment was either radiotherapy alone (56.9%) or in combination with chemotherapy (31.0%). Compared with women who received surgical treatment alone or in association with radiotherapy, women who received chemotherapy were younger and were more likely to have had a diagnosis of breast cancer during the period from 1990 to 1996, to have presented an involvement of three or more lymph nodes, and to have received hormonal therapy. The chemotherapeutic approach showed large variations between the periods from 1982 to 1989 and from 1990 to 1996. Among women who received adjuvant chemotherapy, the proportion of those treated with mitoxantrone increased from 8.0% to 66.2% (P < 10^-4), whereas the proportion of those treated with anthracyclines decreased from 42.0% to 30.5% (P < 10^-4).

Because status of treatment for breast cancer recurrence was not known for the entire cohort, these two cases were not taken into account in the analysis and women with breast cancer recurrence contributed to person-years only for the period before the recurrence. The risk of leukemia in the entire cohort was significantly higher than that expected on the basis of rates in the general population (person-years, 16,249; age-standardized incidence ratio, 7.4; 95% CI, 3.5 to 13.5; P < .0001). Two cases of acute leukemia occurred in the period from 1982 to 1989, and eight cases during the period from 1990 to 1996. Thus, the standardized incidence ratios were slightly higher in the latter period (person-years, 11,984; age-standardized incidence ratio, 8.7; 95% CI, 3.7 to 17.1; P < .0001) than in the former (person-years, 4,265; age-standardized incidence ratio, 5.8; 95% CI, 0.7 to 21.0; P < .09). As indicated in Table 2, no cases of leukemia were observed in women who did not receive any adjuvant radiotherapy. The risk of leukemia in women who received radiotherapy without chemotherapy was similar to that of the general population. On the other hand, in women who received a combination of radiotherapy and chemotherapy, the risk of leukemia was multiplied by 28 compared with that of women in the general population. This increased risk was observed in the first 4 years after the date of diagnosis of breast cancer, with a cumulative rate at 4 years of 0.14% in patients who received radiotherapy without chemotherapy and of 1.12% in those who received a combination of radiotherapy and chemotherapy.

Risk of Leukemia in Within-Cohort Analysis
The adjusted relative risks of leukemia associated with the various types of chemotherapy are listed in Table 4. Compared with women who received another type of chemotherapy, women who received mitoxantrone were more likely to have been diagnosed with breast cancer after 1990, to have been free of any node involvement at diagnosis, and to have used hormonal therapy. Thus, adjustment was made for age, node involvement, period of diagnosis, and use of hormonal therapy. In this within-cohort analysis, women who received mitoxantrone at cumulative doses 13 mg/m² were considered as the reference group. Compared with the reference group, the risk of leukemia was approximately divided by 10 in patients who received anthracyclines (P = .04) and by 40 in the pooled group of women who did not receive any chemotherapy or who received chemotherapy that contained neither mitoxantrone nor anthracyclines (P < .001). On the other hand, the risk of leukemia was divided by five in patients who received low cumulative doses of mitoxantrone, but this decrease in risk was not significant. The exclusion of women treated with chemotherapy that contained neither mitoxantrone nor anthracyclines only marginally affected these results: compared with the group of patients with moderate and high cumulative doses of mitoxantrone, relative risks of leukemia were 0.22 (95% CI, 0.02 to 2.30; P = .21) for the group of patients with low cumulative doses of mitoxantrone, 0.093 (95% CI, 0.01 to 0.88; P = .038) for the anthracycline group, and 0.030 (95% CI, 0.003 to 0.230; P < .001) for the group without chemotherapy.

	DISCUSSION

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This study provides some evidence that the increase in leukemia risk was mainly a result of the use of mitoxantrone. It is of interest to note that all women treated with mitoxantrone had received it at relatively low cumulative doses that were compatible with usually recommended doses (12 to 14 mg/m² per cycle). The dose-dependent effect of mitoxantrone strongly suggests a causal relationship. However, a significant excess risk was only observed in women who received mitoxantrone in postoperative protocols and in combination with other cytostatic drugs. Thus, we cannot firmly exclude the possibility that the period of administration and/or the synergistic effects of other drugs are responsible, at least partly, for increasing risk in women who received moderate or high cumulative doses of mitoxantrone. On the other hand, we failed to find any significant excess in leukemia risk, compared with the general population, among patients treated with anthracyclines (doxorubicin or epidoxorubicin) or with regimens that contained neither mitoxantrone nor anthracyclines.

A major limitation of our study lies in the small number of cases of leukemia that developed during the study period, which resulted in a low statistical power and some imprecision in risk estimates. Although the 95% CI of the standardized incidence ratio was large in women who received mitoxantrone at cumulative doses 13 mg/m² (standardized incidence ratio, 116.1; 95% CI, 42.6 to 253.1), its lower limit was compatible with a substantial increase in the leukemia risk. In some treatment subgroups, we found relatively high values of standardized incidence ratios that did not reach statistical significance. Clearly, the lack of significance should not be interpreted as evidence of the safety of these treatments, especially of chemotherapy that included anthracyclines.

In recent years, several studies have reported leukemia cases in patients with breast cancer treated with mitoxantrone,^7-12 but to our knowledge, only one of them attempted to quantify the risk of leukemia.⁷ This study was performed in a small cohort of 196 women with breast cancer treated with an adjuvant combination of cyclophosphamide, mitoxantrone, and fluorouracil and followed up during an average of 4.8 years. The authors reported a standardized incidence ratio of 38, a value consistent with our estimate. In another study, a small group of 71 patients with advanced breast cancer were treated with combination chemotherapy that included prednimustine, methotrexate, mitoxantrone, fluorouracil, and tamoxifen.¹³ The high risk of leukemia, as reflected by a standardized incidence ratio of 339, was ascribed to prednimustine, an alkylating agent, although a synergistic effect of mitoxantrone could not be ruled out.

In the present study, mitoxantrone that was used at cumulative doses 13 mg/m² was nearly always used in association with cyclophosphamide and fluorouracil. Until recently, alkylating agents such as melphalan have been the only cytostatic drugs used in the treatment of breast cancer that have been firmly established as highly leukemogenic.^3,14,15 In a case-control study performed in a cohort of 82,700 women with invasive breast cancer between 1973 and 1985, the risk of leukemia was 31 times greater among patients treated with melphalan than in those who did not receive alkylating agents. Cyclophosphamide was much less leukemogenic and induced only a moderate three-fold increase in the risk, which was influenced by the cumulative dose of the alkylating agent. In the present study, cyclophosphamide was used in nearly all chemotherapeutic protocols so that no specific risk estimates could be calculated. No leukemia occurred in women treated with regimens that contained no mitoxantrone or anthracyclines (mainly, CMF regimens). Similarly, previous studies carried out among patients with early breast cancer did not suggest any increased risk of leukemia after CMF adjuvant chemotherapy compared with that of the general population.^16,17 Thus, there is no clear evidence that cyclophosphamide at doses currently used in adjuvant treatment of breast cancer may induce an increased risk of leukemia when it is associated with methotrexate and fluorouracil. On the other hand, we cannot exclude the responsibility of this alkylating agent in combination with topoisomerase II inhibitors such as mitoxantrone or anthracyclines.

Anthracyclines, especially doxorubicin and, more recently, epidoxorubicin, have been widely used in the adjuvant treatment of breast cancer in association with cyclophosphamide. Relatively few studies are supportive of an increased risk of leukemia with this combination.^6,18,19 Two studies have suggested that the 10-year risk of developing leukemia was significantly higher among patients who received radiotherapy plus doxorubicin-containing chemotherapy than in those with chemotherapy only.^18,19 In both studies, the 10-year risk in the former group was estimated to be approximately 2.5% to 2.7%. Therapy-induced leukemia has also been associated with high-dose epidoxorubicin and cyclophosphamide⁶ and with epidoxorubicin alone or in combination with cisplatin.⁵ In the present study, we did not differentiate patients who received doxorubicin regimens from those who received epidoxorubicin regimens. Furthermore, only one woman among those who underwent anthracycline-containing chemotherapy developed leukemia during the study period, and thus, our estimate of a 4-year cumulative risk of 0.41% should be taken with caution. Although the risk of leukemia was not significantly different from that of the general population, the high value of the standardized incidence ratio (11.4) and its large CI (95% CI, 0.3 to 63.7) do not allow a slight leukemogenic effect of the association of radiotherapy plus anthracycline-containing chemotherapy to be excluded.

To our knowledge, no previous studies attempted to compare the risk of secondary leukemia in women treated with anthracyclines with that in those treated with mitoxantrone. Despite its limited statistical power, our study suggests that, in association with radiotherapy, mitoxantrone used at cumulative doses 13 mg/m² might have a significantly higher leukemogenic potential than anthracyclines. Although mitoxantrone has been proven to be effective in metastatic breast cancer, in some European countries it is frequently used in adjuvant settings in place of anthracyclines because it induces less cardiotoxicity and fewer acute side effects, such as alopecia.^20,21 Thus, in women with early breast cancer and potential long survival, short-term beneficial effects of mitoxantrone should be weighed against possible long-term life-threatening side effects. With a 4-year cumulative risk of leukemia of 3.9% at high cumulative doses, the benefit-risk ratio of mitoxantrone-containing adjuvant chemotherapy seems largely questionable.

In conclusion, the combination of adjuvant radiotherapy and postoperative chemotherapy with mitoxantrone induces a high risk of leukemia in patients with breast cancer. Although the leukemogenic potential of anthracyclines needs to be more thoroughly assessed in larger studies, our results suggest that it might be lower than that of mitoxantrone. In the present state of knowledge, anthracyclines known to have the lowest cardiotoxicity could be preferred to mitoxantrone in the adjuvant setting. The risk of mitoxantrone-induced leukemia after adjuvant treatment for other solid malignancies remains to be assessed.

	ACKNOWLEDGMENTS

 
Supported by grants from the Agence Française de Sécurité Sanitaire des Produits de Santé and by grant no. 4AE202 from the Caisse Nationale de l’Assurance Maladie des Travailleurs Salaries–Institut National de la Sante et de la Recherche Medicale, Paris, France.

	REFERENCES

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5. Pedersen-Bjergaard J, Sigsgaard TC, Nielsen D, et al: Acute monocytic or myelomonocytic leukemia with balanced chromosome translocations to band 11q23 after therapy with 4-epi-doxorubicin and cisplatin or cyclophosphamide for breast cancer. J Clin Oncol 10:1444-1451, 1992[Abstract/Free Full Text]

6. Shepherd L, Ottaway J, Myles J, et al: Therapy-related leukemia associated with high-dose 4-epi-doxorubicin and cyclophosphamide used as adjuvant chemotherapy for breast cancer. J Clin Oncol 12:2514-2515, 1994[Free Full Text]

7. Kumpulainen EJ, Hirvikovski PP, Pukkala E, et al: Cancer risk after adjuvant chemo- or chemohormonal therapy of breast cancer. Anticancer Drugs 9:131-134, 1998[Medline]

8. Detourmignies L, Castaigne S, Stoppa AM, et al: Therapy-related acute promyelocytic leukemia: A report of 16 cases. J Clin Oncol 10:1430-1435, 1992[Abstract/Free Full Text]

9. 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 7:745-746, 1996[Abstract/Free Full Text]

10. Mellilo LMA, Sajeva MER, Musto P, et al: Acute myeloid leukemia following 3M (mitoxantrone, mitomycin, methotrexate) chemotherapy for advanced breast cancer. Leukemia 11:2211-2212, 1997 (letter)[Medline]

11. Mitchell PLR, Treleaven J, Swansbury GJ, et al: Secondary acute myeloid leukemia (AML) and myelodysplasia (MDS) following mitoxantrone given as adjuvant therapy for breast cancer. Proc Am Soc Clin Oncol 15:127a, 1996 (abstr 173)

12. Philpott NJ, Bevan DH, Gordon-Smith EC: Secondary leukaemia after MMM combined modality therapy for breast carcinoma. Lancet 341:1289-1290, 1993 (letter)

13. Anderson M, Philip P, Pedersen-Bjergaard J: High risk of therapy-related leukemia and preleukemia after therapy with prednimustine, methotrexate, 5-fluorouracil, mitoxantrone, and tamoxifen for advanced breast cancer. Cancer 65:2460-2464, 1990[Medline]

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[Abstract/Free Full Text]

15. Haas JF, Kittelmann B, Mehnert WH, et al: Risk of leukemia in ovarian tumour and breast cancer patients following treatment by cyclophosphamide. Br J Cancer 55:213-218, 1987[Medline]

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[Abstract/Free Full Text]

17. 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[Abstract/Free Full Text]

18. Buzdar R, Iwaniec J, Kau S, et al: Secondary leukemia following adjuvant doxorubicin-containing chemotherapy for stage II or III breast cancer. Proc Am Soc Clin Oncol 10:59a, 1991 (abstr 112)

19. 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[Abstract/Free Full Text]

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Submitted October 12, 1999; accepted April 10, 2000.

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