Does the concurrent use of anthracycline and granulocyte colony-stimulating factor influence the risk of secondary leukaemia in breast cancer women?

Topoisomerase II inhibitors and alkylating agents induce secondary acute leukaemia (sAL) differently. The risk of this complication peaks 5–10 years after the start of chemotherapy in patients receiving alkylating agents. These patients frequently present with myelodysplasia (MDS), which may then progress to overt acute myeloid leukaemia (AML). Unlike the sAL associated with alkylating agents, that induced by anthracylines is monocytic, involves a specific cytogenetic abnormality (11q23) and develops within a few years (generally 2–3 years) after treatment, without prior MDS in some cases [1Go].

Although granulocyte colony-stimulating factor (G-CSF) induced the growth of primary acute myeloid leukaemic blasts in vitro in about 50% of cases, it was not leukaemogenic and even had an antileukaemic effect in some preclinical models [2Go]. In early breast cancer, Crump et al. [3Go] found no cases of sAL among patients given epirubicin-based adjuvant chemotherapy plus G-CSF, and Citron et al. [4Go] reported no correlation between the use of G-CSF and the incidence of sAL among 2005 patients randomized to standard or dose-dense chemotherapy. Conversely, in the cross-protocol analysis on six complete NSABP trials with different regimens of anthracycline and cyclophosphamide, Smith et al. found a positive association between the use and the dose of G-CSF and the risk of sAL in patients receiving standard anthracycline and dose-intensified cyclophosphamide [5Go]; the estimated risk of AML/MDS was 3.58 for patients given more than the median dose of G-CSF (242 µg/kg).

A total of 497 evaluable stage I–II breast cancer patients were randomly assigned to receive epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 i.v. (hEC) on day 1 every 21 days for four cycles with or without lonidamine and with or without prophylactic G-CSF according to a factorial 2 x 2 design [6Go]. Among these patients we encountered, at median follow-up of 55 months, a 58-year-old woman who developed AML (monocytic, M5) 19 months after completion of chemotherapy. She had received filgrastim (480 µg/day s.c) every other day on days 8, 10, 12 and 14 of each hEC course and chest-wall irradiation (50 Gy plus a boost of 10 Gy) after completion of chemotherapy. She died 10 days after diagnosis of sAL. Although the cumulative epirubicin dose (480 mg/m2) was less than that reported by Crump et al. [3Go], we found no other cases of sAL among the 243 evaluable patients in our series receiving hEC without G-CSF. Thus the crude incidence of sAL after adjuvant hEC with G-CSF support was 0.41%.

The case presented here and the recent update on the incidence of sAL after adjuvant chemotherapy for early breast cancer deserve some consideration. Several studies have demonstrated the possibility of achieving a modest to moderate increase in dose intensity using growth factors as an adjunct to higher-dose or dose-dense chemotherapy regimens, which were able to improve the clinical outcome. However, since the dose intensity of anticancer therapy has increased in parallel with the introduction of G-CSF in current clinical practice, distinguishing the contribution of intensified therapy versus G-CSF is often difficult. Above all, the leukaemogenic hazards of cancer treatment should always be weighed against its therapeutic benefits. Considering the recent development of indications even for subgroups of patients at moderate risk of relapse, it is crucial to balance the absolute survival benefit against the risk of severe complications caused by chemotherapy itself, particularly secondary acute leukaemia. In conclusion, this single case cannot prove the role of G-CSF in the development of sAL, but does point out the importance of being prudent when prescribing high-dose chemotherapy with growth factor support.

S. Di Cosimo*, G. Ferretti, P. Papaldo, P. Carlini, A. Fabi, E. M. Ruggeri, A. Alimonti, C. Nardoni and F. Cognetti

Division of Medical Oncology A, Regina Elena Cancer Institute, Rome, Italy

(*Email: sdicosimo{at}hotmail.com)

References

1. Shapiro CL, Rech A. Side effects of adjuvant treatment of breast cancer. N Engl J Med 2001; 344: 1997–2008.[Free Full Text]

2. Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. N Engl J Med 1992; 327: 99–106.[ISI][Medline]

3. 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 2003; 21: 3066–3071.[Abstract/Free Full Text]

4. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21: 1431–1439.[Abstract/Free Full Text]

5. Smith RE, Bryant J, DeCillis A, Anderson S. National Surgical Adjuvant Breast and Bowel Project Experience. 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 2003; 21: 1195–1204.[Abstract/Free Full Text]

6. Papaldo P, Lopez M, Cortesi E et al. The addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high dose epirubicin and cyclophosphamide. J Clin Oncol 2003; 21: 3462–3468.[Abstract/Free Full Text]





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