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Abstract

Modern cancer treatment has substantially increased the survival and curability of patients with various malignancies. Therefore, favorable prognosis mandates for the evaluation of long-term complications of treatment. Since the late 1970s, adjuvant combination chemotherapy for operable breast cancer has come into widespread use. Several recent studies have estimated the risk of acute myeloid leukemia associated with these regimens. The purpose of this analysis is to discuss the risk of leukemia after early breast cancer therapy, the types of leukemia, and the relationship between the risk of leukemia and treatment with different cytotoxic agents (alkylating agents, antimetabolities, topoisomerase II inhibitors, dose-dense therapy, high-dose therapy and growth factor use) and radiotherapy.

Keywords

alkylating agents busulphan chlorambucil CMF-based adjuvant CT cyclophosphamide dose-dense therapy high-dose therapy lomustine myelodysplasia refractory anemia with excessive blasts secondary myelodysplasia therapy-related AML topoisomerase II inhibitors

Secondary acute leukemia, mostly myeloid (AML) or myelodysplasia (MDS), is a well-known long-term complication in patients who have received chemotherapy and/or radiation therapy for a previous malignancy [1 –7]. While acute toxicities of anticancer therapy are well documented and the mortality due to treatment is rather low, clinical interest is focusing on long-term effects such as the development of secondary leukemia, which is rather poorly documented.

Secondary AML is defined either as the disease arising after exposure to cytotoxic agents (i.e., drugs, radiation or chemicals) or as a subsequent event issuing from another hematologic disorder, usually MDS. Thus the term secondary AML fundamentally encompasses post-myelodysplastic AML and therapy-related AML (t-AML). Secondary leukemias following MDS account for 60–70% of all secondary leukemia cases [8 –11]. The myelodysplastic syndromes can arise de novo or be related to exposure to ionizing radiation or myelotoxic drugs [12,13]. The incidence of de novo MDS is approximately three new cases per 100,000 people per year, although some authors have reported a higher incidence [12]. Therapy-related MDS (t-MDS) in the MD Anderson hospital series, USA, before 1991 represented 27% of all MDS [13], and were probably more common than overt t-AML, considering that macro-cytosis and cytopenias, the hallmarks of MDS, can easily be overlooked in patients with a previous cancer diagnosis. Cytogenetic abnormalities are qualitatively similar in both de novo and t-MDS, but they are more frequently observed in t-MDS. A greater percentage of patients with t-MDS present a high value (associated with a poor prognosis) in the International Prognostic Scoring System (IPSS), which uses information about blood counts, cytogenetics, and percent marrow blasts to distinguish four prognostic groups: low, intermediate (INT)-1, INT-2, and high, with very different survival expectations, and more than 50% of t-MDS will evolve into AML [13,14]. Therapy-related AMLs constitute approximately 5 to 10% of all diagnosed AML cases [15,16]; it has been frequently described to occur after treatment for Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, multiple myeloma, myeloproliferative diseases, breast cancer, ovarian cancer, and testicular cancer. The risk of developing a t-AML varies depending on the underlying previous malignancy and previous therapies.

Risk of leukemia after treatment of a first malignancy

The risk of developing a second malignancy has been estimated to range from 8 to 12% at 20 years after the diagnosis and treatment of a first cancer [17,18]. Therefore, a second malignant neoplasm is more frequent than expected from general population rates, particularly after a first cancer in childhood. A secondary leukemia following chemo-radiotherapy for a primary neoplasm is most probably related to these treatments but may also reflect an increased susceptibility to cancer [18,19]. Epidemiologic studies reported increased risks of leukemia after treatment with chemotherapeutic agents, including alkylating substances (busulphan, chlorambucil, lomustine, cyclophosphamide or melphalan) or topoisomerase II inhibitors (epipodophyllotoxins or anthracyclines), and after radiation therapy [5,15,20,21].

Treatment-related leukemia types

Regardless of the primary cancer, therapy-induced leukemias exhibit certain characteristics that differentiate them from spontaneously occurring leukemias. Two types of secondary leukemia are distiguishable, the first form following therapy with alkylating agents and the second developing after treatment with topoisomerase II inhibitors [22].

The first type, following therapy with alkylating agents, occurs after an average interval of 5–7 years, is often preceded by a preleukemic period of MDS and is frequently described as M1 and M2 according to the French–American–British (FAB) classification. Clonal chromosome aberrations are frequently observed, including monosomy or deletions on chromosomes 5 and/or 7 in 60 and 90% of the cases; the most common cytogenetic findings are losses of chromosomes 5 or 7 and deletions at 7q36. Other complex aberrations involve chromosomes 3, 12, 17 and 21 [23].

The second type of therapy-related leukemia is induced by topoisomerase II targeted drugs such as etoposide, anthracyclines or anthracenediones. This type of AML occurs after a median period of 2 years and is not preceded by a myelodysplastic syndrome. According to the FAB classification, M4 or M5 are observed more frequently and cytogenetic analysis shows a higher frequency of rearrangements of chromosome band 11q23, t(8;21), t(15;17), inv(16) or t(8;16) than in de novo AML cases [5 –7,20,25 –29].

Refractory anemia with excessive blasts (RAEB) and refractory anemia with excessive blasts in transformation (RAEB-t) have been found to be the most common types of chemotherapy-induced MDS forms [16,24]. Exposure to ionizing radiation has previously been associated with genomic insult and an increased risk of AML/MDS [45]. The role of radiation therapy in the development of secondary leukemia in breast cancer will also be discussed.

Secondary leukemia & breast cancer

There has been significant improvement in survival and cure expectancy for patients with early breast cancer due to combined modality treatments involving surgery, adjuvant therapy (combination chemotherapy and hormonal manipulations) and radiation. The selection of the optimal form of combination therapy for breast cancer should take into account associated long-term risks, in particular the risk of secondary MDS and leukemia [30,31]. Specific risk factors for the development of a secondary leukemia after treatment for breast cancer are similar to those observed for other malignancies and include the combined use of chemotherapy and radiation therapy, the cumulative dose of specific agents, and the duration of therapy [30].

Alkylating agents (Table 1)

Table 1.

Cumulative risk of leukemia in breast cancer patients after conventional chemotherapy.

Group	Number of patients	Type of CT	Follow-up	Cumulative risk of MDS/AML	Patients with MDS/AML diagnosis (%)	Ref.
NSABP (seven trials)	5299	Melphalan-containing CT	10 years	1.68 ± 0.33%	0.60	[36]
ECOG (six trials)	2638	Cyclophosphamide-containing CT	10 years	0.2%	0.08	[32]
NCI Bethesda	13734	Different conventional regimens	10 years	0.7 ± 0.2%	0.17	[42]
Milan Cancer Center	2465	CMF	15 years	0.23 ± 0.15%	0.12	[43]
NSABP (six trials)	8563	AC Different dose-intensity of cyclophosphamide	5 years	1.01 ± 0.21%	0.50	[44]
MD Anderson	1474	Doxorubicin-containing CT	10 years	1.5%	0.94	[35]

AC: Adriamicin + cyclophosphamide; AML: Acute myeloid leukemia; CT: Chemotherapy; CMF: Cyclophosphamide, methotrexate + fluorouracil; ECOG: European Cooperative Oncology Group; MDS: Myelodysplasia; NCI: National Cancer Institute; NSABP: National Surgical Adjuvant Breast Project.

Fisher and colleagues examined the incidence of AML/MDS in a cohort of 8483 breast cancer patients participating in seven clinical trials conducted by the National Surgical Adjuvant Breast Project (NSABP) since 1971. Leukemia occurred in only 3 out of 2068 patients treated with surgery alone and the cumulative risk was 0.06% after 10 years in those free of metastases or second primary tumor. Five out of 646 women receiving postoperative regional radiation developed leukemia, with an overall risk of 1.39 at 10 years. A total of 27 cases of leukemia (0.5%) and 7 of myeloproliferative syndrome (0.1%) were recorded in 5299 patients who received melphalan-containing adjuvant regimens. The maximum cumulative risk of leukemia/MDS in chemotherapy recipients was 1.68 at 10-year follow-up. The risk of leukemia in patients free of metastases or a second primary tumor was 1.11 at 10 years, and when combined with myeloproliferative syndrome, 1.54; this risk magnitude is not significantly higher than that observed following radiation. No cases of leukemia were observed during the first 2 years after adjuvant chemotherapy or after the seventh year. These data, compared with the surveillance, epidemiology, and end results tumor registries (SEER) data, indicate a significantly increased relative risk of acute myelogenous leukemia following postoperative regional radiation and adjuvant chemotherapy [36].

Tallman and collegues reported data from 2638 patients aged 20–81 years (mean: 51 years) with primary operable breast cancer treated in six clinical trials investigating adjuvant therapies conducted by the European Cooperative Oncology Group (ECOG; E1180, E3181, E4181, E5177, E5181 and E6177) between 1978 and 1987 [32]. There were 19,200 person-years of follow-up and a mean follow-up duration of 7.3 years. Three patients developed a secondary MDS (with an 11q23 chromosomal abnormality) and no patients treated with standard-dose, cyclophosphamide-containing (100 mg/m²/day orally on days 1 to 14) adjuvant chemotherapy developed AML. One patient developed adult T-cell leukemia and although this disease is generally associated with human T-cell lymphotropic virus-1 infection, the presence of the 5q-chromosomal abnormality raises the question of the relationship to prior chemotherapy. The fact that only 4 out of 2638 patients (0.08%) developed a secondary hematologic disorder after adjuvant chemotherapy with standard doses of cyclophosphamide suggests that the risk with this treatment is small.

The absence of an increased risk of secondary AML in several published reports may be attributable to the relatively small populations studied [37 –41]. It is important to note that few patients in these reports received additional anthracyclines and no patient received hematopoietic growth factors.

Curtis and colleagues reported that among 13,734 women diagnosed with early breast cancer between 1973 and 1980 and included in the National Cancer Institute's SEER registration program, there was an overall excess AML risk of 11.5-fold [42]. The risk of AML associated with chemotherapy was 58 cases per 100,000 woman-years at risk and the probability of developing AML after 10 years was 0.7%. In addition, the risk of AML varied by the specific alkylating agent received. The highest risk was observed after melphalan exposure, a drug that is now rarely used in modern adjuvant programs. The excess of AML was most prominent for breast cancer patients treated during the early years of the adjuvant chemotherapy era. Patients treated from 1979 to 1982 remained at lower risk compared with patients treated from 1975 to 1978.

For both melphalan and cyclophosphamide, the risk of AML increases significantly with increasing cumulative drug doses. Cumulative cyclophosphamide doses below 20 g and of 20 g or more resulted in an approximately twofold and 5.7-fold increase in risk of secondary AML, respectively [30].

Association with alkylating agents & antimetabolites

Valagussa and collegues observed three cases of AML among 2241 patients treated with cyclophosphamide, methotrexate and 5-fluorouracil (CMF)-based adjuvant chemotherapy and followed for a median duration of 12 years [43]. The 15-year cumulative risk of AML was 0.23%, which corresponded to a nonsignificant 2.3-fold risk increase compared with the general population expectation. This risk translated into an estimated excess number of nine AML cases for 10,000 patients followed for 10 years, with the cumulative dose of cyclophosphamide in the Milan protocols ranging between 9.6 and 34 g (mean: 15.5 g). It is noteworthy that 39% of women treated with CMF-based chemotherapy in these series also received doxorubicin. Although one case of MDS was observed among the 882 women given both CMF and doxorubicin, there was no clear evidence for a synergistic effect of cyclophosphamide and doxorubicin on leukemia risk.

Association with alkylating agents & anti-topoisomerase II inhibitors

A recent prospective study of the ECOG on a large cohort of patients with early breast cancer demonstrated that the use of a standard dose of cyclophosphamide (100 mg/m²/day orally on days 1 to 14) did not increase the risk of secondary AML [32], while the association of alkylating agents and topoisomerase II inhibitors in advanced breast cancer has been reported to induce secondary leukemia at a higher frequency, with a cumulative risk at 3 years of 25 ± 10% [33]. In the adjuvant setting this combination (fluorouracil–doxorubicin–cyclophosphamide) has been reported to increase the risk by approximately twofold in comparison to the general population [35].

Six completed NSABP Phase III clinical studies have investigated adriamycin, ciclophosphamide (AC) regimens in operable breast cancer patients (protocols: B-15, B-16, B-18, B-22, B-23 and B-25). A crossprotocol analysis presented the incidence of AML/MDS from 8563 patients (representing 61,810 patient-years of follow-up) [44]. The chemotherapy regimens were defined according to their cyclophosphamide intensity, cumulative cyclophosphamide dose, and the presence or absence of growth factor support. A total of 43 patients (0.50%) developed AML/MDS. The incidence of AML/MDS associated with standard AC therapy was 0.32 cases per 1000 patient-years. The incidence of AML/MDS was significantly higher in the more intense regimens: in patients receiving two or four cycles of cyclophosphamide at 2400 mg/m² per cycle with granulocyte colony-stimulating factor (G-CSF) support, the incidence rate was 1.75 cases per 1000 patient-years, corresponding to a relative risk (RR) of 6.16 (p < 0.0001). The corresponding cumulative incidence of AML/MDS at 5 years was 1.01% (95% confidence interval [CI] 0.63–1.62%) for patients receiving the more intense regimens, compared with 0.21% (95% CI 0.11–0.41%) for patients treated with standard AC doses [45,46].

Topoisomerase II inhibitors (Table 2)

Table 2.

Risk of leukemia after regimens containing topoisomerase II inhibitors.

Group	Number of patients	Type of chemotherapy	Follow-up	Patients with MDS/AML diagnosis (%)	Ref.
CCTG	351	FEC	5 years	1.1	[48]
NSABP B-22	2305	AC Standard/intensive regimens (and/or increased C-dose)	5 years	0.26	[49]
NSABP B-25	2548	AC Standard/intensive regimens (and/or increased C-dose)	4 years	0.63	[34]
Righshospitalet	74	Epidoxorubicin + cisplatin	1.5 years	4 (3 patients)	[29]
Chaplain	449	Mitoxantrone-containing regimens	4 years	1.55 (7 patients)	[47]
Royal Marsden	1774	Mitoxantrone-containing regimens	5 years	0.5 (9 patients)	[52]

AC: Adriamicin + cyclophosphamide; AML: Acute myeloid leukemia; C: Cyclophosphamide; E: Epirubicin: F: Fluorouracil; MDS: Myelodysplasia; NSABP: National Surgical Adjuvant Breast Project.

Recently, several reports have shown an increased incidence of secondary MDS/AML of up to 8% after adjuvant chemotherapy containing the anthracenedione derivate mitoxantrone [32,52,65,66]. Saso and collegues [52] identified patients in the Royal Marsden Hospital database with breast carcinoma treated with mitoxantrone-based regimens (mitoxantrone, mitomycin, methotrexate from 1984 to 1992, 1282 patients; mitoxantrone and methotrexate from 1992 onwards due to the appearance of hemolytic-uremic syndrome with the use of mitomycin, 492 patients) in the adjuvant and neoadjuvant setting [53]. Patients also received local radiotherapy to the chest wall, and tamoxifen 20 mg daily. The median follow-up was 5 years. Five patients developed AML and four developed MDS, at a median age of 60 years, after treatment with mitoxantrone-based chemotherapy, giving an incidence of 15 per 100,000 years follow-up. The relative risk of developing MDS/AML was 10.1-times greater than in an age- and sex-matched normal population (95% CI 3.5–16.7). For MDS alone the risk was 8.6-times greater, and for leukemia alone it was 14.1-times greater than in the general population. Women with AML/MDS had received the following total drug doses: mitoxantrone 80 mg (range: 60–162 mg), methotrexate 310 mg (range: 265–400 mg), and in six cases mitomycin 45 mg (range: 39–51 mg).

Chaplain and colleagues observed a cohort of 3093 women younger than 85 years at the time of breast cancer diagnosis and treated with curative surgery, radiotherapy (56.9%) and/or adjuvant chemotherapy with mitoxantrone or anthracyclines (31% radiotherapy and chemotherapy) [47]. A total of 12 women developed either nonlymphoid acute leukemia or RAEB-t. The risk of leukemia in women who received radiotherapy without chemotherapy was similar to that of the general population. In contrast, in women who received a combination of radiotherapy and chemotherapy, the risk of leukemia was 28-fold compared with that of women in the general population. This increased risk was observed in the first 4 years after 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. Moreover, the risk of leukemia was significantly increased in patients younger than 45 years and 45–64 years treated with regimens that contained mitoxantrone, whereas it was not significantly increased in women older than 65 years. The risk of leukemia was found to progressively increase with increasing cumulative doses of mitoxantrone and was especially high at cumulative doses of 13 mg/m² per cycle or more (4-years cumulative risk: 3.54%) and 56 mg/m² or more (3.89%), whereas for cumulative doses of less than 12 mg/m² (patients treated with a single perioperative cycle), the risk was 0.63%.

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 reported an increased risk of leukemia with these combinations used at standard dose.

In Levine's study, after 5 years of follow-up, four cases of AML had occurred in 351 patients treated with fluorouracil, epidoxorubicin and cyclophosphamide (FEC; 1.1%) [48]. A 10-year follow-up review reported the experience of the MD Anderson Cancer Center in 1474 Stage II and III breast cancer patients treated between 1974 and 1989 in four adjuvant and two neoadjuvant chemotherapy trials with fluorouracil, doxorubicin and cyclophosphamide (FAC) with or without additional drugs. In 1107 patients, FAC chemotherapy was given postoperatively; 367 patients received preoperative, as well as postoperative, chemotherapy. A total of 810 patients had surgery followed by radiotherapy and chemotherapy; 664 patients had surgery and chemotherapy alone. A total of 14 cases of leukemia were observed. Of these, 12 patients had received radiotherapy and chemotherapy, and 2 had received chemotherapy alone. Six of the reported patients with leukemia were treated with a cumulative cyclophosphamide dose of greater than 6 g/m². Five of these patients had received both radiotherapy and chemotherapy. The median latency period in the 14 patients was 66 months (range: 22–113). Six out of ten patients with adequate cytogenetic analyses had abnormalities that involved chromosomes 5 and/or 7. The 10-year estimated leukemia rate was 1.5% (95% CI 0.7–2.9%) for all patients treated, 2.5% (95% CI 1.0–5.1%) for the radiotherapy-plus-chemotherapy group, and 0.5% (95% CI 0.1–2.4%) for the chemotherapy-only group; this difference was statistically significant (p = 0.01). The 10-year estimated leukemia risk for cyclophosphamide at the higher dose (>6 g/m²) was 2% compared with 1.3% for the lower-dose group, a difference that was, however, not statistically significant (p = 0.53) [35].

The NSABP B-22 and B-25 studies investigating anthracyclines and cyclophosphamide showed a high rate of secondary leukemias correlating with the cumulative dose of cyclophosphamide (cumulative dose range: 2400 to 4800 mg/m²), with 6 cases (0.26%) in 2305 patients at 5 years and 16 cases (0.63%) in 2548 patients at 4 years, respectively [34,49].

Two additional 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 alone [35,50]. In both studies, the risk at 10 years, in the former group, was estimated to be approximately 2.5 to 2.7%.

Therapy-induced leukemia has also been associated with epidoxorubicin and cyclophosphamide [51]. Pedersen-Bjergaard and colleagues observed three cases of AML among 74 patients with advanced breast cancer who were treated with a combination of 4-epidoxorubicin and cisplatin and followed for an average period of 17 months [29]. The cumulative risk of AML was 16% at 33 months, which corresponded to an over 600-fold increased risk compared with the incidence of leukemia in the general population. No leukemias developed among 203 patients treated with epidoxorubicin alone and followed for an average of only 13 months; however, this was too short a period to draw any conclusions.

Anthracycline-based adjuvant regimens have been shown to yield results at least as good as those seen with CMF and in some trials they have shown superior outcomes. However, the risk of secondary AML with doxorubicin-containing regimens has been calculated to be 1.5% (0.7–2.9%) at 10 years [35] and the risk was significantly higher after chemo-radiotherapy than after chemotherapy alone (10-year actuarial risk: 2.5 vs 0.5%; p = 0.01).

Dose-dense therapy (Table 3)

Table 3.

Risk of leukemia in patients with early breast cancer after dose-dense therapy.

Group	Number of patients	Chemotherapy	Median follow-up	Number of MDS/AML diagnoses	Patients with MDS/AML diagnosis (%)	Ref.
GONO-MIG 1	1214	FEC14 × 6 vs FEC21 × 6	6.7 years	0	0	[57]
Henderson	3121	§AC × 4 →T × 4 (or none)	3 years	6 AML; 2 MDS; 1 ALL 4 AML; 4 MDS	0.17	[59]
Intergroup Trial C9741	2005	A (3 weeks) × 4 →T (3 weeks) × 4 →C (3 weeks) × 4 A (2 weeks) × 4 →T (2 weeks) × 4 →C (2 weeks) × 4 AC (3 weeks) × 4 →T (3 weeks) × 4 AC (2 weeks) × 4 →T (2 weeks) × 4	3 years	11 AML/MDS	0.18	[60]
IBCSG 15	344	HD-EC × 3 EC/AC × 4 →CMF × 3	5.8 years	1 case (local recurrence with concurrent AML)	–	[PERS. DATA]

A: Adriamycin; ALL: Acute lymphoid leukemia; AML: Acute myeloid leukemia; C: Cyclophosphamide; E: Epirubicin; F: Fluorouracil; M: Methotrexate; MDS: Myelodysplasia; T: Paclitaxel.

Different doses of adriamycin (60, 75, 90 mg/m²).

Dose-dense regimens have been used in an attempt to increase cell kill in the adjuvant setting in patients at high-risk of relapse. Chemotherapy regimens include several drugs, most of them with a potential leukemogenic effect. Between 1992 and 1997, 1214 patients with early breast cancer were randomly assigned to receive six courses of FEC either every 3 or 2 weeks with the support of growth factors in the more intense regimen. At a median follow-up period of 6.7 years, no cases of acute leukemia were reported [57].

A multicenter study conducted by the EORTC comparing the efficacy of a standard anthracycline-based regimen (cyclophosphamide: 75 mg/m² orally days 1 to 14; epirubicin: 60 mg/m² days 1 and 8; and fluorouracil: 500 mg/m² days 1 and 8; six cycles every 28 days) with a dose-intensified anthracycline regimen (epirubicin: 120 mg/m² day 1; cyclophosphamide: 830 mg/m² day 1; and G-CSF; six cycles every 14 days) in the primary treatment of locally advanced breast cancer enrolled 448 patients and the median follow-up was 5.5 years. Again, no cases of secondary MDS or AML were reported [58].

Henderson and colleagues conducted a study investigating three different doses of doxorubicin (60, 75 or 90 mg/m²) for four cycles with or without the addition of four cycles of paclitaxel [59]. Between May 1994 and April 1999, 3121 patients were randomized, the median time of follow-up of the last report was 69 months and three-quarters of the patients were observed for at least 5 years. There were no significant differences in the incidences of leukemias and MDS in any of the study arms. In the AC-only arms, six cases of AML, two cases of MDS, and one case of acute lymphoid leukemia were observed. In patients treated with additional paclitaxel, four cases of AML, four cases of MDS, and no cases of acute lymphoid leukemia were reported. Growth factors (G-CSF) were given routinely to patients receiving doxorubicin at a dose of 90 mg/m² (1057 patients in total), but only after an episode of febrile neutropenia for the others.

Between 1997 and 1999, 2005 patients were enrolled in the Integroup Trial C9741 examining in a 2 × 2 factorial design dose density (2 vs. 3 weeks) and treatment sequence (concurrent vs. sequential) of doxorubicin, paclitaxel and cyclophosphamide, with filgrastim. The median age of the patients was 50 years and the median follow-up period was 3 years. A total of 58 patients developed second primaries, including 11 cases of AML or MDS diagnosed from 10 to 42 months after study entry. The 3-year incidence of AML or MDS was 0.18% [60]. This is similar to the previously discussed study (cumulative risk: 0.17%) for a similar patient population with the same median follow-up period of 3 years [59].

High-dose chemotherapy

Limited data have been published studying the risk of secondary leukemia in breast cancer patients who have received high-dose chemotherapy (HDCT) followed by bone marrow or autologous stem-cell reinfusion [61,62]. A total of 494 patients with node-positive breast cancer received HDCT followed by autologous stem-cell transplantation as adjuvant therapy between November 1989 and December 1997 in 55 European centers and were reported to the European Bone Marrow Transplant registry [63]. The median age of the patients at the time of stem-cell transplantation was 45 years (range: 22–62 years). Stem-cell source was bone marrow in 55 patients and peripheral blood stem cells in 309 patients. After a median follow-up period of 48 months (range: 1–108 months), 1 out of 364 patients developed secondary leukemia (AML) 18 months after the application of three cycles of epirubicin and cyclophosphamide with a cumulative dose of 960 mg epirubicin and 19 g cyclophosphamide. The type of AML was M4 (according to FAB-criteria) and the cytogenetic analysis showed a translocation t(9;11)(p22;q23).

Kröger evaluated the incidence of secondary MDS/AML in 305 breast cancer patients after mitoxantrone-based high-dose conditioning regimens [64]. After a median follow-up period of 57 months (range: 10–125), 3 out of 305 patients developed secondary leukemia; a cumulative incidence of secondary leukemia of 0.94%. All three patients developed AML without preceding MDS within 2 years after HDCT.

Bergh and colleagues randomized 525 women younger than 60 years of age with high-risk primary breast cancer to receive nine cycles of tailored FEC to hematologic equitoxicity with G-CSF support (n = 251), or three cycles of FEC at standard doses followed by HDCT with cyclophosphamide, thiotepa and carboplatin, and peripheral blood stem cell or bone marrow support (n = 274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. In the tailored FEC group there were six patients who developed AML and three MDS diagnoses [67].

Horthobagyi and colleagues conducted a prospective randomized trial to compare standard-dose chemotherapy with the same therapy followed by HDCT in patients at high risk of relapse. All 78 patients received eight cycles of FAC and patients were randomized to an additional two cycles of high-dose cyclophosphamide, etoposide and cisplatin with autologous hematopoietic stem cell support (39 patients) or no additional chemotherapy (39 patients). In the FAC/HDCT group, one patient developed AML [68].

The International Breast Cancer Study Group (IBCSG) conducted a randomized trial of high-dose epirubicin and cyclophosphamide (EC; epirubicin: 200 mg/m², cyclophosphamide 4 g/m² as four divided doses) for three cycles supported by peripheral blood progenitor cells versus standard EC/AC × 4 followed by classic CMF × 3 as adjuvant treatment for high-risk breast cancer patients (age ≤65 years). From 1995 to 2000, 344 women were included. The median follow-up was of 5.8 years. Only one case of AML was diagnosed in a patient with concurrent diagnosis of local recurrence [PERSONAL DATA, JULY 1998].

Growth factors & secondary leukemia

There has been speculation that growth factors may be leukemogenic and that the increased risk of AML/MDS associated with aggressive chemotherapy may result from growth factor use [69]. The National Cancer Institute (NCI) alerted clinicians to the possibility that patients, entered on a NCI-sponsored cooperative group trial of doxorubicin and cyclophosphamide adjuvant therapy for breast cancer, could have been at high risk of developing secondary AML. Secondary AML following standard doses of doxorubicin and cyclophosphamide is uncommon, the high risk in this trial could has been resulted from its higher-than-standard doses of chemotherapy. However, the characteristics of these AMLs were of the ones following treatment with topoisomerase II-active agents, especially etoposide. This type of secondary AML is rare after treatment with either cyclophosphamide or doxorubicin at any dose. The NCI analysis raises the possibility that another component of the trial, hematopoietic growth factors to decrease the toxicities related to myelosuppression, could play an important role in the development of secondary AML. Growth factors not only stimulate hematopoietic progenitor proliferation and differentiation, they also regulate hematopoietic cell survival by interfering with apoptosis (programmed cell death). Inhibition of apoptosis by a variety of genetic factors is an important mechanism of oncogenesis, and appears to be the initiating event in some malignancies. Growth factor-mediated suppression of the apoptotic death of hematopoietic progenitors damaged by chemotherapy may contribute to the leukemic transformation [69].

In NSABP B-22 and B-25 studies, the effect of mandated G-CSF could be tested, but the number of events is too small (ten in total). Some indirect evidence correlating the use of G-CSF to subsequent presentation of AML/MDS can, however, be obtained from protocol B-25, where the use of growth factor was mandated and daily doses of G-CSF were recorded. There was considerable variation in total G-CSF doses across patients, resulting from differences in the number of days required to achieve granulocyte counts in excess of 10,000/μl and also from dose increases dictated by the protocol after incidents of febrile neutropenia or severe infection. A total of 18 of the 22 patients in B-25 study with a diagnosis of AML/MDS received G-CSF doses in excess of the median dose administered to all B-25 patients (242 μg/kg). Controlling for treatment arm, patient age, and operation, the estimated risk of AML/MDS for patients receiving more than the median dose of G-CSF was 3.58 (95% CI 1.18–10.90; p = 0.02). The use of G-CSF was undoubtedly correlated with other factors that could not be adequately accounted for, including treatment with ciprofloxacin or other antibiotics, the use of which was not documented in the research data. It is also possible that patients achieving an unusually high plasma level of doxorubicin and/or cyclophosphamide are at higher risk for AML/MDS and are simultaneously at higher risk for febrile neutropenia and severe infection. In this case, an association would be supposed between use of G-CSF and subsequent AML/MDS that may have no causal basis [44].

Radiotherapy

The increase in the leukemia rates seen in the survivors of Nagasaki/Hiroshima was first noted a few years after their radiation exposure and the maximal increase was noted from 7 to 12 years after the radiation exposure. By 30 years after the exposure, the leukemia rates returned to normal. In contrast to the experience with leukemias, an increased incidence of solid tumors was not noted until 15 years after the exposure but the increased incidence of solid tumors has persisted until the present time [70].

Smith and colleagues investigated the effect of low volume breast irradiation on the incidence of AML/MDS in patients receiving AC chemotherapy. AML/MDS occurred at more than twice the rate than in patients who underwent no radiotherapy (RR: 2.38; p = 0.006) [44]. Fisher and colleagues reported an increased risk of AML in patients receiving regional radiotherapy in early NSABP trials using both melphalan-based chemotherapy and no systemic treatment [36].

In a case-control study of a cohort of 82,700 women with breast cancer diagnosed between 1973 and 1985, Curtis and colleagues collected detailed information about therapy for 90 patients with leukemia and 264 matched controls [30]. The dose of radiation to the active marrow was estimated from individual radiotherapy records (mean dose: 7.5 Gy). The risk of AML was significantly increased in women after regional radiotherapy alone (RR: 2.4) and in women who received combined radiation plus anticancer drugs (RR: 17.4). The dose-dependent risk was observed after radiotherapy and treatment with melphalan and cyclophosphamide. Melphalan was ten-times more leukemogenic than cyclophosphamide (RR: 31.4 vs 3.1). There was little increase in the risk associatied with total cyclophosphamide doses of less than 20 mg.

In an analysis of the SEER registry, Anderson and Bryant (unpublished work) similarly report an increased risk of secondary AML owing to radiotherapy in operable breast cancer. In addition, Diamandidou and colleagues evaluated the incidence of treatment-related leukemias in breast cancer patients treated in four adjuvant and two neoadjuvant chemotherapy trials with or without radiotherapy, at the MD Anderson Cancer Center [35]. Treatment for these patients consisted of alkylating agents and/or topoisomerase II inhibitors (fluorouracil, doxorubicin and cyclophosphamide with or without other drugs). The 10-year estimated leukemia rate was 1.5% for all patients treated, 2.5% for the radiotherapy plus chemotherapy group, and 0.5% for the chemotherapy only group; this difference was statistically significant (p = 0.01).

Conclusions

The occurrence of two different malignancies in one and the same individual may have several origins. It may represent chance occurrence, may be linked to common carcinogenic risk factors, may result from host susceptibility factors or may be associated with the treatment for the primary tumor. Secondary leukemia is quite rare in patients treated for a prior cancer, but the risk for developing a leukemia appears increased compared with the general population. It is important to note the heterogeneity of available data in terms of comparison with different populations, making the assessment of the risk particularly difficult.

The majority of patients who developed secondary leukemia following chemotherapy for their primary tumor had been treated with alkylating agents and radiation therapy. Further investigation of the influence of the administration schedule, the extent of the possible interaction between radiotherapy and chemotherapy and the modifying effect of host factors on the risk of treatment-related AML is needed. In patients with early breast cancer treated with adjuvant therapy modalities including cytotoxics and radiation therapy, the risk of developing a secondary MDS/AML needs further attention, in particular with the use of combination modalities including cytotoxic therapies with leukemogenic effect (alkylating agents and anthracyclines) and radiation therapy, which appear to have additive leukemogenic effect. Risk is low with combination chemotherapies of the CMF type, but are higher with the combination of cyclophosphamide and anthracyclines. No specific information on the risk for treatment-related leukemia after standard dose of anthracyclines is available. The overall risk correlates with the cumulative dose of cyclophosphamide and is further increased after combination with radiotherapy; the additional use of growth factors needed for the prevention of neutropenia in regimens with higher-dose cytotoxics may further increase the risk of secondary MDS/AML. Exact documentation of the type of secondary leukemia, the therapy administered (including the application schedule and doses), as well as long-term follow-up are necessary in order to answer the numerous remaining questions.

International cooperation is required to obtain the patient numbers needed to perform statistically relevant subgroup analyses in order to detect specific risk constellations and the accumulation of rare secondary cancers.

Future perspective

A long and careful follow-up is needed in patients treated for early breast cancer in order to assess long-term risks, including secondary leukemia, after adjuvant treatment with cytotoxics and/or radiation therapy. This is even more medically and humanly important if we consider that an increasing number of patients will remain disease-free for many years after treatment.

Executive summary

Epidemiology

Treatment-related acute myeloid leukemia (AML) and myelodysplasia (MDS) are long-term complications in patients who received chemotherapy and/or radiation therapy for a neoplastic disease.

Secondary leukemias following MDS account for 60–70% of all secondary leukemia cases.

Secondary AML constitutes approximately 5–10% of all AML cases.

The risk of developing a treatment-related AML varies depending on the underlying previous malignancy and the previous therapies.

Epidemiologic studies report increased risks of leukemia after treatment with chemotherapy with alkylating agents and topoisomerase II inhibitors.

Pathology & genetic assessment

Two types of chemotherapy-induced leukemia are clearly distinguishable, the first type after therapy with alkylating agents (with an interval of 5–7 years since the end of treatment) and the second after therapy with topoisomerase II inhibitors (with time interval of 2 years). According to the French-American-British classification, the first type is more commonly M1 and M2 and the second type M4 and M5. The alkylating-agent-related secondary MDS or secondary AML present chromosome aberrations as monosomy or deletions on chromosomes 5 and/or 7 in 60–90% of cases, losses of chromosomes 5 or 7 and deletions at 7q36. The therapy-related leukemias induced by topoisomerase II inhibitors present rearrangements of chromosome band 11q23, t (8;21), t(17;17), inv(1 6) or t(8;16).

Secondary leukemia risk in breast cancer

Specific risk factors for secondary leukemias related to the treatment of breast cancer are similar to the therapy-related leukemias observed after other first malignancies (combination of chemotherapy and radiotherapy, cumulative dose of the cytotoxic agents, duration of therapy).

Risk of leukemia after alkylating agents

Since 1971 the incidence of AML/MDS has been examined in a cohort of 8483 breast cancer patients in seven National Surgical Adjuvant Breast Project (NSABP) trials. 5299 patients received melphalan-containing regimens. The cumulative risk of leukemia in this group of patients was 1.68 at 10-years of follow-up.

Tallman and colleagues collected data on 2638 breast cancer patients treated in six clinical trials conducted by the European Cooperative Oncology Group (ECOG). The cumulative risk to develop a MDS/AML in 10 years of follow-up was 0.2%.

Curtis and colleagues analyzed 13,734 women treated for early breast cancer, and the risk of developing AML after 10-years was 0.7%.

For both melphalan and cyclophosphamide, the risk of AML increases significantly with increasing cumulative drug doses. Cumulative cyclophosphamide doses below 20 g, and 20 g or more resulted in an approximately two- and 5.7-fold increase in risk of secondary AML, respectively.

Six completed NSABP Phase III clinical studies have investigated adriamycin, ciclophosphamide (AC) regimens in operable breast cancer patients and a second analysis of these protocols presented the incidence of AML/MDS depending on the drug dosage in the combination. The AML/MDS risk was elevated in the more intense regimens compared with standard dose AC. The corresponding cumulative incidence of AML/MDS at 5 years was 1.01% for patients receiving the more intense regimens compared with 0.21% for patients treated with standard AC.

The statistical approaches in these trials are different and this makes it difficult to compare the different reports: for example, the reports by Tallman [32]; Curtis [42]; Valagussa [43]; and NSABP studies [44] compare the incidence of secondary leukemia for breast cancer patients to the incidence in women with tumors, whereas the reports of the ECOG [35]; Saso [52]; and Chaplain [47] compare with the general population. However, it remains firm that alkylating agents, in particular at cumulative dosages of more than 20 g, are leukemogenic in patients with breast cancer.

Secondary leukemia & topoisomerase II inhibitors

A significantly increased risk of leukemia has been observed in patients treated with regimens containing mitoxantrone. In a population-based study a cohort of 3093 women younger than 85 years at diagnosis was treated with adjuvant therapies including radiotherapy and/or chemotherapy. In women who received a combination of radiotherapy and chemotherapy, the risk of leukemia was 28-fold that of women in the general population. Moreover, the risk of leukemia was significantly increased, in particular in patients treated with mitoxantrone-containing regimens, and the risk of leukemia was found to increase with cumulative doses of mitoxantrone. The excess of risk was high when mitoxantrone was administered at cumulative doses of 13 mg/m² per cycle or more.

Anthracyclines, especially doxorubicin and epidoxorubicin, have been used in the adjuvant therapy of breast cancer in association with cyclophosphamide. Few studies are supportive of an increased risk of leukemia with this combination at standard doses. In Levine's study, after 5 years of follow-up, four cases of AML occurred in 351 patients treated with fluorouracil, epidoxorubicin and cyclophosphamide (FEC).

The risk of secondary AML with doxorubicin-containing regimens has been reported by Diamandidou and colleagues to be 1.5% at 10-years and the risk was significantly higher after chemo-radiotherapy than after chemotherapy alone.

Dose-dense therapy

In a randomized study conducted between 1992 and 1997, patients with early breast cancer received six cycles of FEC21 or six cycles of FEC14, and at a median follow-up of 6.7 years no cases of acute leukemia were reported. In a trial conducted by Venturini and colleagues, women with early breast cancer were treated with increasing doses of doxorubicin with or without the addition of paclitaxel to a standard adjuvant chemotherapy. There were no significant differences in the incidence of leukemia and myelodysplasia in any of the study arms.

The Intergroup Trial C9741 reported the results of dose-density and treatment-sequence regimens with doxorubicin, cyclophosphamide and paclitaxel. The 3-year incidence of AML or MDS was 0.18% and is similar to the incidence reported by Henderson and colleagues (cumulative risk: 0.17%) for a similar patient group at the same median follow-up period of 3 years.

High-dose chemotherapy

Limited data have been published on the risk of secondary leukemia in breast cancer patients treated with high-dose chemotherapy (HDCT) followed by autologous stem-cell transplantation.

In a European analysis of 494 patients with node-positive breast cancer that had received HDCT followed by autologous stem-cell transplantation, after a median follow-up of 48 months, only 1 out of 364 patients developed secondary leukemia.

Another study evaluated the incidence of secondary MDS/AML in 305 patients treated with mitoxantrone-based high-dose regimens. After a median follow-up of 57 months, 3 out of 305 patients developed secondary leukemia.

Horthobagyi conducted a prospective randomized trial to compare standard-dose chemotherapy (fluorouracil, doxorubicin and cyclophosphamide [FAC]) with the same therapy followed by HDCT. In the FAC/HDCT group, one patient developed AML.

Leukemia & granulocyte colony-stimulating factor

There have been speculations that growth factors may be leukemogenic and that the increased risk of AML/MDS associated with aggressive chemotherapy may result from growth factor use. In two NSABP studies the effect of granulocyte colony-stimulating factor (G-CSF) was tested.

A long-rank analysis was conducted in the NSABP B-25 trial to determine whether the total G-CSF dose given during adjuvant therapy was correlated with the incidence of AML/MDS for AC regimen. A total of 18 of the 22 patients in B-25 study that had a diagnosis of AML/MDS had received G-CSF doses in excess of the median dose administered to all patients.

Leukemia & radiotherapy

Exposure to radiation has been associated with genomic insult and increased risk of AML/MDS. In a case-control study of 82,700 patients with breast cancer, Curtis and colleagues collected data from nine patients who developed leukemia. They had received a radiation dose to active marrow estimated at 7.5 Gy. The risk of AML was significantly increased in women after application of regional radiotherapy alone (relative risk: 2.4) and in women who received radiation plus anticancer drugs (RR: 17.4).

Future perspective

The risk of developing secondary leukemia must be regarded as a possible long-term complication of modern cancer therapy. Although leukemia occurs in few patients with early breast cancer, significantly elevated risks have been linked to treatments with regional radiation and alkylating agents. Anthracyclines that are frequently used in the adjuvant setting do not themselves seem to increase the risk of leukemia when used at standard doses. The use of growth factors such as G-CSF will need further attention, in particular in combination with alkylating agents and radiation therapy. It is important to organize international cooperation in order to standardize assessment of risk estimates and to perform statistically robust analyses for the detection of leukemia risks in specific subpopulations.

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Leukemia Risk after Adjuvant Treatment of Early Breast Cancer

Abstract

Keywords

Risk of leukemia after treatment of a first malignancy

Treatment-related leukemia types

Secondary leukemia & breast cancer

Alkylating agents (Table 1)

Association with alkylating agents & antimetabolites

Association with alkylating agents & anti-topoisomerase II inhibitors

Topoisomerase II inhibitors (Table 2)

Dose-dense therapy (Table 3)

High-dose chemotherapy

Growth factors & secondary leukemia

Radiotherapy

Conclusions

Future perspective

References