Anthracyclines: is more, better and/or more dangerous?

R. Arriagada and J. Gutiérrez

1Instituto de Radiomedicina, Santiago(IRAM), Américo Vespucio Norte 1314, Vitacura, Santiago; 2Hematology and Medical Oncology Department, Clínica Las Condes, Santiago, Chile *(E-mail: datacenter@gocchi.cl)

It may seem a strange principle to enunciate

as the very first requirement in a Hospital that

it should do the sick no harm.

Florence Nightingale, Notes on Hospitals, 1863.

Acute non-lymphocytic leukemia is a rare late-effect of the use of adjuvant cytotoxic drugs in breast cancer patients. However, its importance is related to the extremely poor short-term survival of this drug-induced hematologic disease.

It is widely recognized that there are two different syndromes of chemo-induced acute non-lymphocytic leukemia. The first is related to the use of alkylating agents, and involves a first stage of myelodysplasia [1], with a maximal incidence between 5 and 10 years of follow-up [2]. Its morphology is usually of the M1 or M2 type [1], with frequent deletion of chromosomes 5 and 7 [3]. The second syndrome is related to the use of topoisomerase II inhibitors, such as anthracyclines. Patients do not develop a previous period of myelodysplasia and the morphology includes a monocytic M4 or M5 component. The induction period is shorter, 2 or 3 years, and there are translocations in 11q23, 21q22 and 3q23 [4, 5].

Chemotherapy-induced leukemia was first recognized after long-term follow-up of patients treated for Hodgkin’s disease [6]. Anthracycline-based chemotherapy, such as doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD), is considered less leukemogenic than alkylating-based schedules such as mustine, vincristine, procarbazine and prednisone (MOPP) [7]. Among the alkylating agents used in the treatment of breast cancer patients, melphalan is considered the most leukemogenic drug, as shown in a NSABP randomized trial [8]. On the other hand, cyclophosphamide, at least at the doses used in the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) schedule, has not been shown to increase the acute leukemia risk compared with the general population. In a review of six ECOG protocols, including 2638 patients with a median follow-up of 7.3 years, the estimated incidence of myelodysplastic syndrome and acute leukemia was 26 per 100 000 person-years, similar to that estimated in the general population [9]. In a randomized trial conducted in Stockholm, including 1113 patients, which compared 12 cycles of adjuvant CMF with locoregional radiotherapy, no leukemia was reported with a median follow-up of 7.3 years [10]. In addition, a group from Milan reported a cumulative incidence of 0.23% at 15 years in a cohort of 2465 patients treated with CMF [11].

Leukemogenic risk is higher with the use of topoisomerase II inhibitors [12, 13]. It seems that a major risk exists with the use of mitoxantrone [14]. However, a higher risk is also related to the use of anthracyclines, such as doxorubicin and epidoxorubicin [8, 15, 16].

In this issue of Annals of Oncology, Bernard-Marty et al. [17] suggest that the effect of epidoxorubicin-based chemotherapy is dose- or cumulative dose-related. Their results are consistent with those published by the National Cancer Institute of Canada (NCI-C) [18]. The risk of acute myeloid leukemia was observed in these trials with an epidoxorubicin dose of 100 and 120 mg/m2 per cycle, and a cumulative dose of 800 and 720 mg/m2, respectively. In a Belgian trial, in patients treated with an epidoxorubicin dose of 60 mg/m2 per cycle and a cumulative dose of 480 mg/m2, no acute leukemia was reported. These results are consistent with a recently published French trial, conducted in 835 high-risk postmenopausal patients treated with adjuvant tamoxifen and randomized to FEC/FAC at an anthracycline dose of 50 mg/m2 per cycle and a cumulative dose of 300 mg/m2, in which no differences were found in the incidence of acute leukemia [19].

Other issues to be considered in the report of new primary malignancies are related to the duration of follow-up, the registration of adverse events and the methodology used in the calculation of event rates. Late complications of adjuvant treatments, generally ignored in early reports, need randomized trials with a long-term follow-up [20]. Similarly, the knowledge of new primary malignancies potentially related to the use of adjuvant treatments has been acquired through the long-term follow-up of large randomized trials, such as the appearance of endometrial adenocarcinoma whose risk is increased with the administration of tamoxifen, as initially reported by the Stockholm group [21] and later confirmed in other trials [22]. In acute non-lymphocytic leukemias, the induction period is shorter [5]. In the first report of a Belgian trial [23], three cases of acute myeloid leukemia have already been reported, with a median follow-up of 4.6 years, no other cases were found with an additional follow-up of 1.5 years. In a NCI-C trial [18], four cases of acute myeloid leukemia were observed with a median follow-up of 4.9 years. In the high epidoxorubicin dose group of a French adjuvant trial [24], only one case of such a leukemia type was observed with a median follow-up of 5.5 years. Updated results of these trials would be highly appealing.

In the past, several trials recorded only the first tumor event, and together with several patients lost to follow-up after the first or second date of analyses, under-reporting remains possible. More recently, interest in second and late events has increased and hence the necessity for long-term follow-up. Finally, the methodology for the determination of event rates is a matter of concern, as it has become clear that tumor or toxic events after initial treatment are not independent. In an extreme theoretical situation, in which patients who do not receive adjuvant treatment die of their initial disease and those benefiting from such treatment have a high probability of cure, only treated patients would be at risk of a late complication. The existence of such competition among different events is generally acknowledged [25] and different solutions have been proposed [10, 2628]. This issue is important in the determination of precise rates of relatively rare events, such as new primary malignancies. The usual methodology used to censor events after a first event is particularly ill-adapted for this determination. In the absence of a methodology that takes into account competing risks, it is preferable to consider first and subsequent events, i.e. total cumulative rates [29]. In the report by Bernard-Marty et al. [17], the authors considered crude incidence of acute myeloid leukemias, despite the censoring of all events other than second solid malignancies.

Bearing in mind the results reported in different series and the long-term hazards related to adjuvant treatments, it is highly relevant to consider the benefit–toxicity relationship of such treatments. Anthracycline-based regimens have shown overall to be more effective in terms of disease-free survival than CMF-like treatments [30]. However, it seems that the modality of CMF delivery is important to the size of treatment benefit [31]. Indeed, the reported Belgian trial [17, 23] did not show a significant difference between the benefit of a classic CMF regimen and a standard epidoxorubicin dose; only the high epidoxorubicin schedule was superior, as also shown in a similar French adjuvant trial [24]. However, the greater benefit of higher doses should be balanced with the higher risk of incidence of a lethal disease such as acute myeloid leukemia. This higher risk may only be justified in a high-risk metastatic population with non-endocrine responsive disease. Indeed, two large trials published recently have shown that anthracycline-based chemotherapy or classic CMF add only a very small benefit, if any, in patients with endocrine responsive disease [19, 32]. A better definition of endocrine responsive disease, not only based on a semiquantitative hormone receptor determination, would be of value in defining target populations. Also, newly developed biologic tools, such as genetic profile determination by micro-arrays [33], could, in future, be incorporated into randomized trials to define new and powerful predictive factors of treatment effects. We certainly need knowledge of such factors to indicate potentially dangerous therapies to those patients who would receive an undoubted treatment benefit.

R. Arriagada1* & J. Gutiérrez2

1Instituto de Radiomedicina, Américo Vespucio Norte 1314, Vitacura, Santiago; 2Hematology and Medical Oncology Department, Clínica Las Condes, Santiago, Chile (*E-mail: datacenter@gocchi.cl)

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