Second Malignancies Following Adjuvant Chemotherapy

Abstract & Commentary

Synopsis: HEC, as delivered in this trial, cannot be recommended in clinical practice because of the lack of superiority over classic CMF and because of the increased risk of AML observed in this arm. Prolongation of conventional anthracycline-based treatment beyond the current standard of 4-6 cycles is not recommended in clinical practice.

Source: Bernard-Marty C, et al. Ann Oncol. 2003;14(5):693-698.

The benefits related to the administration of adjuvant chemotherapy in breast cancer are well established. Significant reductions in the risk of relapse and death are observed in both node-positive and node-negative patients. However, long-term survivors appear to be at increased risk for developing treatment-related complications. This issue could raise doubts about the risk/benefit ratio in patients with very favorable prognosis, in whom the absolute survival gain from chemotherapy may be < 5%. The increased risk of leukemia in patients with early breast cancer treated with alkylating agents, particularly melphalan, is well documented.1 More recently, topoisomerase-II inhibitors, including anthracyclines and anthracenediones, have also been associated with the occurrence of acute myelogenic leukemia and myelodysplastic syndrome.2-4 A prospective multicenter phase III trial was conducted comparing 2 epirubicin-cyclophosphamide regimens with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).5 As part of the analysis of the study, the incidence of secondary malignancy was evaluated.

The long-term toxicity of treatment of cancer patients with a good tumor-related prognosis is extremely important. Chronic morbidity and increased mortality from treatment can negate the benefit of the treatment. This has been exemplified in the analysis of outcomes with Hodgkin’s disease.6 There have also been a number of trials that show patients being treated in the adjuvant setting for breast cancer have an increased risk of leukemia and possibly solid tumors. The current Belgian trial consisted of 770 patients younger than age 70 with histologically confirmed, node-positive breast cancer were considered eligible for the study. After primary surgery, patients were randomized to: 1) CMF using oral cyclophosphamide 100 mg/m2 orally days 1-14; and i.v. methotrexate and 5-fluorouracil i.v. days 1 and 8, cycles every 28 days for 6 cycles; 2) EC (epirubicin 60 mg/m2 i.v. day 1 and cyclophosphamide 500 mg/m2 i.v. day 1, cycles every 21 days); or 3) HEC (epirubicin 100 mg/m2 i.v. day 1 and cyclophosphamide 830 mg/m2 i.v. day 1, cycles every 21 days). Both anthracycline-based regimens were administered for 8 cycles. At a median follow-up of 73 months, the following 8-year actuarial rates of second solid primaries were observed: CMF 5.5% (95% confidence interval [CI], 1.5-9.5%), EC 4.1% (95% CI, 0.1-8.1%), and HEC 7.2% (95% CI, 3.2-11.2%) (P = .79 by log rank test). Three secondary acute myeloid leukemias (AML) were reported, all in the HEC arm (incidence = 1.2%, 95% CI, 0.0-2.5%), which by a 3-arm comparison allows us to conclude that HEC is statistically different (borderline significance) from CMF and EC (P = .05). The first AML case was an M5 AML, according to the French-American-British (FAB) classification, and occurred 21 months after randomization. Cytogenetic analysis showed a 11q23 translocation. The second case was an M6 AML showing multiple chromosomal abnormalities, diagnosed 57 months after randomization. The third case was an M5 AML with a translocation t(9;11), which occurred 32 months after randomization. There was no statistical difference in the development of solid tumors between the 3 arms.

Comment by Stuart M. Lichtman, MD, FACP

It is widely recognized that there are 2 different syndromes of chemotherapy-induced acute nonlymphocytic leukemia. The first is related to the use of alkylating agents and involves a first stage of myelodysplasia, with a maximal incidence between 5 and 10 years of follow-up. Its morphology is usually of the M1 or M2 type, with frequent deletion of chromosomes 5 and 7. 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.

This paper suggests 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).7

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. 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.8,9

The long-term toxicity of cancer treatment is of critical concern, particularly in patients with a good prognosis. This paper demonstrates the potential leukemogenic effect of anthracyclines that seems to be dose-related. It emphasizes that prospective randomized trials are necessary to demonstrate the efficacy of regimens and their potential toxicity that can mitigate the benefit of the therapeutic regimen.

Dr. Lichtman, Associate Professor of Medicine, NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY.


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8. Arriagada R, et al. Ann Oncol. 2002;13(9):1378-1386.

9. Arriagada R, Gutierrez J. Ann Oncol. 2003;14(5): 663-665.