Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients

C. Bernard-Marty1, M. Mano1, M. Paesmans1, C. Accettura1, R. Munoz-Bermeo1, T. Richard1, K. Kleiber1, F. Cardoso1, J. P. Lobelle2, D. Larsimont1, M. J. Piccart1 and A. Di Leo1,+

1 Jules Bordet Institute, Brussels; 2 Pharmacia, Diegem, Belgium

Received 8 July 2002; revised 25 November 2002; accepted 19 December 2002


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Alkylating agents and topoisomerase-II inhibitors have been associated with the occurrence of secondary leukemias and myelodysplastic syndromes in breast cancer patients treated with adjuvant chemotherapy. Conversely, data on the occurrence of second solid malignancies in this setting are scarce.

Patients and methods:

This study retrospectively evaluates the occurrence of second hematological and solid malignancies in the context of a prospective multicenter phase III trial comparing epirubicin–cyclophosphamide at intermediate doses (EC), or at full doses (HEC), with classical cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in 777 patients with early breast cancer.

Results:

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% to 9.5%], EC 4.1% (95% CI 0.1% to 8.1%), and HEC 7.2% (95% CI 3.2% to 11.2%) (P = 0.79 by log rank test). Three secondary acute myeloid leukemias (AML) were reported, all in the HEC arm (incidence = 1.2%, 95% CI 0.0% to 2.5%), which by a three arm comparison allows us to conclude that HEC is statistically different (borderline significance) from CMF and EC (P = 0.05).

Conclusions:

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 four to six cycles is not recommended in clinical practice.

Key words: anthracyclines, breast cancer, second tumors


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The benefits related to the administration of adjuvant chemotherapy in breast cancer (BC) are well established. Significant reductions in the risk of relapse and death are observed in both node-positive and node-negative patients [1]. However, long-term survivors appear to be at increased risk for developing long-term 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% [1].

The increased risk of leukemia in patients with early breast cancer (EBC) treated with alkylating agents, particularly melphalan, is well documented [2]. More recently, topoisomerase-II inhibitors, including anthracyclines (daunorubicin, doxorubicin and epirubicin) and anthracenediones (mitoxantrone) [3, 4], have also been associated with the occurrence of acute myelogenic leukemia (AML) and myelodysplastic syndrome (MDS) [57]. Nevertheless, few individual trials have specifically investigated the long-term occurrence of second hematological and solid malignancies. A prospective multicenter phase III trial was conducted in Belgium from June 1988 through December 1996 to compare a full-dose epirubicin–cyclophosphamide regimen (HEC) with classical cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and with a moderate-dose epirubicin–cyclophosphamide regimen (EC) [8]. In this article we report in detail the incidence and nature of second malignancies observed during a median follow-up of 6 years.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients <70 years of age with histologically confirmed, node-positive BC were considered eligible for the study. Surgery consisted of modified radical mastectomy (MRM) or lumpectomy, plus axillary dissection. After informed consent, patients were randomized into one of the three study arms: (i) CMF as reported by Bonadonna et al. [9] [cyclophosphamide 100 mg/m2 orally days 1–14; methotrexate 40 mg/m2 intravenously (i.v.) days 1 and 8; and 5-fluorouracil 600 mg/m2 i.v. days 1 and 8, cycles every 28 days] for six cycles; (ii) EC (epirubicin 60 mg/m2 i.v. day 1 and cyclophosphamide 500 mg/m2 i.v. day 1, cycles every 21 days); or (iii) 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 eight cycles. Treatment duration was the same in the three study arms. The relative dose intensity (RDI) for each study drug was calculated based on the actually delivered dose/expected dose ratio in the planned time. The RDI for each study regimen was calculated as an arithmetic mean between the RDI of the two or three drugs belonging to the study regimen [8].

Radiotherapy (RT), delivered after completion of chemotherapy, was mandatory after lumpectomy but optional after MRM, according to local policies. Two tangential 60cobalt photon fields were used for the chest wall or the breast, for a total ICRU (International Commission on Radiation Units and Measurements) dose of 50 Gy. The supraclavicular and internal mammary nodes were treated with a mixed beam (1/3 photons and 2/3 electrons) for a total ICRU dose of 50 Gy. All fields were treated 5 days per week, 2 Gy per fraction, during 5 weeks with a 60cobalt. In cases of breast-conserving surgery, a 10 Gy electron boost was delivered to the tumor bed [8].

Postmenopausal patients with positive or unknown estrogen (ER) and/or progesterone receptors (PgR) received tamoxifen 40 mg daily for 5 years, starting after the last cycle of chemotherapy [8].

The follow-up included a detailed medical history and physical examination every 3 months until the end of the second year and every 6 months thereafter, until the fifth year. The workup was performed after the end of chemotherapy and once a year thereafter, and included a routine hemato-chemistry survey, bone scan, chest X-ray, liver ultrasound and mammography. After the fifth year, only yearly mammography and physical examinations continued to be performed [8].

Pathology reports from all the second malignancies were centrally reviewed by a medical oncologist (C. B.-M.). Queries were addressed to investigators as needed. In some cases, in which the pathology report was considered unclear or insufficient, a senior pathologist (D. L.) reviewed the corresponding tumor slides. All malignant tumors other than BC, in situ cervical carcinoma or basal cell carcinoma of the skin, diagnosed after randomization were considered as second primaries. Second BCs were evaluated separately, based on the following procedure: (i) contra-lateral BCs were systematically compared with the original BC to allow differential diagnosis between second primaries and BC relapse; (ii) all cases of ipsi-lateral breast tumors were considered as disease recurrences.

Duration of follow-up was calculated for all patients; follow-up duration for deceased patients was taken to be the date of the last database update (April 2000). For patients who were still alive, the follow-up duration was complete and defined as the time elapsed between randomization and last contact. Actuarial rates of second solid malignancies in each treatment arm were estimated by the Kaplan–Meier method and compared using the log rank test (censoring all events other than second solid malignancies). Confidence intervals (CIs) at 95% were calculated using an asymptotic normal distribution. For AML, only crude incidence was reported (only three cases were documented, all in the same study arm).


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient population
The study was conducted from June 1988 to December 1996. Seven hundred and seventy-seven patients were eligible: 255 patients in the CMF arm, 267 patients in the EC arm and 255 patients in the HEC arm. The median follow-up for each arm was 75 (range 5–139), 71 (range 7–132) and 75 (range 4–139) months, respectively. Treatment groups were similar in terms of baseline characteristics, such as age, number of positive axillary nodes, pathological tumor size, tumor grade and type of surgery (mastectomy or breast-saving surgery). Similarly, 58%, 52% and 54% of patients were considered as ER/PgR positive (>10 fmol/mg) in the CMF, EC and HEC arms, respectively, and ER/PgR was unknown in 16%, 17% and 17%, respectively. Of interest, the three study arms were also well balanced with regard to menopausal status, with 44%, 42% and 41% of postmenopausal patients in the CMF, EC and HEC arms, respectively [8].

Treatment
Median RDIs were as follows: 0.89 (range 0.03–1.13), 0.95 (range 0.25–1.42) and 0.90 (range 0.12–1.10) for the CMF, EC and HEC arms, respectively. Median number of administered cycles were as follows: six (range 1–6), eight (range 1–8) and eight (range 1–8) in the CMF, EC and HEC arms, respectively. Seventy-nine per cent of the 255 patients treated with HEC received postoperative RT and 38% received tamoxifen for a median treatment duration of 42 months. In the EC group, 84% of 267 patients received postoperative RT and 40% received tamoxifen for a median treatment duration of 36 months. Seventy-nine per cent of the 255 patients treated with CMF received postoperative RT and 43% received tamoxifen for a median treatment duration of 37 months.

Second primaries
Forty-eight cases of second primaries were reported by participating investigators. After central review, 36 were confirmed as second primaries. Twelve cases were excluded: five ipsilateral BCs, four metastatic BCs, one basal cell skin carcinoma, one endometrial hyperplasia and one in situ cervical carcinoma. Table 1 shows all the reported cases of second malignancies.


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Table 1. Documented second malignancies
 
Hematological second primaries
Six cases of secondary hematological malignancies were reported, all occurring in anthracycline-treated patients (Table 1).

One patient aged 51 developed a non-Hodgkin’s lymphoma (diffuse histiocytic), stage IIIB, 73 months after allocation to the HEC arm. She had received total cumulative doses of 12 000 mg and 1440 mg for cyclophosphamide and epirubicin, respectively. No RT or tamoxifen had been administered.

A second patient aged 55 years developed a chronic lymphocytic leukemia (CLL) (type B, stage A) 41 months after allocation to the HEC arm. Cumulative doses of cyclophosphamide and epirubicin were 13 280 mg and 1600 mg, respectively. Tamoxifen had been given for 5 years. No RT had been delivered.

The third case was a CLL (type B) diagnosed in a 57-year-old patient, 141 months after allocation to the EC arm. Cumulative doses of cyclophosphamide and epirubicin were 6600 mg and 792 mg, respectively. She had received tamoxifen for 5 years. No RT had been administered.

Most importantly, three cases of AML were reported and are summarized in Table 2. All of them occurred in the HEC arm. The first case was an M5 AML, according to the French–American–British (FAB) classification [10], and occurred 21 months after randomization. Cytogenetic analysis showed a 11q23 translocation. The second case was an M6 AML showing multiple chromosomic 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. All the cases of AML were fatal. The increased crude incidence of AML in the HEC arm had borderline statistical significance (1.18%; 95% CI 0% to 2.5%) when compared with the two other arms (P = 0.05) in a three arm overall comparison.


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Table 2. Characteristics of patients developing acute myeloid leukemia
 
Second solid primaries
Thirty cases of second solid primaries were documented (Table 1). Contra-lateral BC was reported in 16 patients. Four cases of gynecological malignancies were reported: one squamous carcinoma of the uterine cervix, one endometrial cancer and the two epithelial ovarian cancers. Other primaries were less frequently reported: three thyroid medullary carcinomas, two bronchogenic carcinomas, two colorectal carcinomas, two melanomas and one glioblastoma. Eleven of these cases occurred in the CMF arm (seven contra-lateral BCs, two colon carcinomas, one melanoma and one thyroid cancer), eight in the EC arm (four contra-lateral BCs, one endometrial cancer, one melanoma, one thyroid carcinoma and one non-small-cell lung cancer) and 11 in the HEC arm (five contra-lateral BCs, one cervical cancer, two ovarian cancers, one non-small-cell lung cancer, one thyroid cancer and one glioblastoma). Both cases of lung cancer occurred in patients with a history of smoking.

Actuarial rates of second solid malignancies at 5 years were as follows: CMF arm, 3.0% (95% CI 1.0% to 5.0%); HEC arm, 3.0% (95% CI 1.0% to 5.0%); and EC, 1.8% (95% CI 0% to 3.8%). At 8 years, the figures were, respectively, 5.5% (95% CI 1.5% to 9.5%), 7.2% (95% CI 3.2% to 11.2%) and 4.1% (95% CI 0.1% to 8.1%). No difference was detectable between the three study arms (log rank test, P = 0.79).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This retrospective study investigates the occurrence of second cancers in a population of node-positive BC patients entered in a phase III randomized trial comparing two different doses of an anthracycline-based regimen (HEC or EC) with CMF [8]. At 73 months of follow-up, a statistically significant increase in the crude incidence rate of AML was seen in patients allocated to the HEC arm (i.e. no cases of AML among the 255 and 267 patients receiving CMF or EC, respectively; three cases of AML among 255 patients treated with HEC, crude rate 1.18%, 95% CI 0% to 2.5%, P = 0.05 for an overall three arm comparison).

Our results are very similar to those already reported by Levine et al. [11]. In the Canadian study, four cases of AML were reported among 351 patients treated with an epirubicin-based regimen (crude rate 1.13%), while no cases were documented among the 359 patients receiving CMF. However, it is important to point out that, different from the Belgian trial, an advantage in terms of disease-free survival and overall survival in favor of the anthracycline-based arm was observed in the Canadian trial.

Our results, as well as the Canadian data, seem to differ substantially from those of other trials comparing either non-anthracycline-based regimens with anthracyclines, or two different dose intensities of the same anthracycline-based regimen [1221] (Table 3).


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Table 3. Incidence of AML in adjuvant trials evaluating an anthracycline-based regimen
 
These differences in the incidence of AML could be explained by the fact that, as is shown in Table 3, the planned cumulative dose of anthracyclines was the highest in the Belgian and in the Canadian trials (epirubicin 100 mg/m2 on day 1 every 3 weeks for eight cycles and 60 mg/m2 on days 1 and 8 every 4 weeks for six cycles, respectively) [8, 11]. Most trials listed in Table 3 report much lower cumulative doses of epirubicin (below 500 mg/m2, and in two of them 540 [20] and 600 mg/m2 [13], respectively).

Recently, the results of a phase III adjuvant trial have been reported [21]. In this trial, doxorubicin and cyclophosphamide, administered either sequentially or in combination, have been compared in more than 3000 EBC patients. Interestingly, cumulative doses of both drugs, as well as treatment duration, were the same in the two study arms. At a median follow-up of 5 years, an increased risk of MDS and secondary leukemias was reported in patients receiving the sequential and more dose-intensive treatment. This study suggests that even when the impact of cumulative doses on the risk of second tumors is eliminated, a correlation seems to exist between the increase in doxorubicin and cyclophosphamide dose intensity and the risk of second tumors.

Of note, in the Belgian and in the Canadian trials, RT was administered to a significant proportion of patients (79% in the Belgian study, 48% in the Canadian study), and full-dose cyclophosphamide (i.e. 830 mg/m2 day 1 every 3 weeks for eight cycles in the Belgian trial, and 75 mg/m2 days 1–14 every 4 weeks for six cycles in the Canadian trial) was given in combination with epirubicin, although the different routes of administration (oral versus i.v.) may complicate the comparison of cyclophosphamide dose intensity between these two trials [8, 11]. Interestingly, data on more than 8000 patients, recently presented by the National Surgical Adjuvant Breast and Bowel Project, suggests that intensified doses of cyclophosphamide and in-breast RT might be correlated with increased risk of secondary AML and MDS [22]. Thus, factors other than cumulative doses and dose intensity may also play a role.

With regard to the occurrence of second solid malignancies, our data do not suggest a correlation with the administration of full doses of epirubicin. Nevertheless, it is important to point out that the relatively low incidence of secondary solid tumors, their heterogeneity and also the increased risk of second tumors in the population of EBC patients, are all potential caveats that should be taken into account when interpreting these data. In this specific context, the results of the Cancer and Leukaemia Group B trial, in which more than 3000 patients have been randomly treated with three different doses of doxorubicin (60 versus 75 versus 90 mg/m2 every 3 weeks for four cycles), might shed some light [23].

Of note, only three patients developed hematological malignancies other than AML. Nevertheless, we point out that contrary to AMLs, the association between second CLLs or lymphomas and administration of chemotherapy has never been clearly demonstrated.

In summary, the results of this study do not support the use of the HEC regimen, as administered in this trial, because of the lack of superiority over classic CMF [8], and because of the increased risk of AML observed during the follow-up period. The AML rate appears to be similar to that reported in the Canadian trial, and could at least in part be explained by the higher cumulative doses of epirubicin given in these trials. Evidence suggests that cumulative doses of anthracyclines may increase the risk of secondary AMLs. Accordingly, prolongation of anthracycline-based treatment beyond the standard four to six cycles cannot be recommended outside the context of well designed clinical trials.


    Footnotes
 
+ Correspondence to: Dr A. Di Leo, Department of Chemotherapy, Jules Bordet Institute, 125 Boulevard de Waterloo, 1000 Brussels, Belgium. Tel: +32-2-541-31-80-81; Fax: +32-2-541-30-90; E-mail: angelo.dileo{at}bordet.be Back


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 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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