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Japanese Journal of Clinical Oncology Pages 28-32

Therapy-related Leukemia and Myelodysplastic Syndrome in Breast Cancer Patients Treated with Cyclophosphamide or Anthracyclines
Introduction
Patients and Methods
Results
   Patients and Primary Treatment
   Characteristics of TRL and t-MDS
   Clinical Course of TRL/t-MDS
Discussion
Acknowledgments
References
Therapy-related Leukemia and Myelodysplastic Syndrome in Breast Cancer Patients Treated with Cyclophosphamide or Anthracyclines

Therapy-related Leukemia and Myelodysplastic Syndrome in Breast Cancer Patients Treated with Cyclophosphamide or Anthracyclines

Masashi Ando, Masaru Narabayashi, Toru Watanabe, Yoshikazu Kamiya, Kazuto Togitani, Ryuji Tanosaki, Takeaki Takenaka, Kensei Tobinai and Isamu Adachi

Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

Background: Accumulation of data regarding therapy-related leukemia (TRL) or myelodysplastic syndrome (t-MDS) is critical for assessing the risk of developing such diseases and for subsequent decision-making processes for better treatment.
Methods: We evaluated the clinical characteristics of patients with TRL/t-MDS diagnosed at the National Cancer Center Hospital between January 1989 and September 1997. This report is concerned with those patients who initially had been treated with chemotherapeutic agents for breast cancer.
Results: Thirteen patients (median age, 55 years) developed TRL (n = 4) or t-MDS (n = 9). The median interval between the development of TRL/t-MDS and initial treatment was 94 months (range 23-190 months). For the primary therapy, all patients had received intense and prolonged treatment with cyclophosphamide (CPA) and/or anthracyclines including doxorubicin (DOX), with a median cumulative dose of 55 g/body (range 16.4-288.5 g) for CPA and 480 mg/m2 (range 395-625.5 mg/m2) for DOX. Seven patients were subsequently treated by chemotherapy and one received an allogeneic bone marrow transplantation.
Conclusions: Clinicians must remain alert to the risks associated with unproven medical practices which include long-term administration of alkylating agents. Selected patients with TRL/t-MDS may respond to intense salvage combination chemotherapy.

Key words:breast cancer - therapy-related leukemia - myelodysplastic syndrome - cyclophosphamide

Introduction

Therapy-related leukemia (TRL) and myelodysplastic syndrome (t-MDS) have been well recognized as unfavorable consequences of prior anti-cancer treatment (1-5), which most commonly occur following administration of alkylating agents such as cyclophosphamide (CPA) (1-3,5-7). They are characterized by a clinical preleukemic phase (MDS) which occurs 2-10 years following treatment and cytogenetic abnormalities involving chromosome 5 and/or 7 are frequently observed (6,7). Recently, the development of TRLs following chemotherapy which includes topoisomerase II inhibitors [doxorubicin (DOX), mitoxantrone (MIT) or 4-epidoxorubicin (Epi)] has been reported (8-11). This has been characterized as the acute onset of abnormalities in myelomonocytic or monocytic lineages, a lack of a preleukemic phase and the presence of balanced translocations at chromosome bands 11q23 or 21q22. TRLs induced by topoisomerase II inhibitors generally occur earlier than those induced by alkylating agents. Although the risks and mode of development of TRL/t-MDS may depend on the type, intensity and duration of the therapy, most of reports addressing this issue in patients with breast cancer have focused on the effect of short-term therapies applied in an adjuvant setting (12-17).

With the relative lack of information regarding the risk of developing TRL/t-MDS following prolonged administration of anticancer drugs, in this retrospective survey we evaluated our single-institute experience of the clinical characteristics of TRL/t-MDS that had developed in patients treated for primary breast cancer.

Patients and Methods

We reviewed the medical records of patients treated at the National Cancer Center Hospital of Japan (NCCH) who were diagnosed as having TRL or t-MDS between January 1989 and September 1997. Of 26 patients identified (TRL, n = 13; t-MDS, n = 13), this study only concerns 13 patients who had a prior history of breast cancer. The remainder of the patients had the uterus (n = 3), head and neck (n = 2), Hodgkin's disease (n = 2), non-Hodgkin's lymphoma (n = 1), rectum (n = 1), esophagus (n = 1), skin (n = 1), testis (n = 1) and ovary (n = 1) as a primary tumor. All these patients had received chemotherapy and/or radiotherapy for primary tumor. Since there were many patients with different backgrounds and medical situations at our institution, reliable mother-cohort-based analysis was difficult.

The pathological diagnosis of primary breast cancer was made with surgically resected specimens. The diagnosis of TRL or t-MDS was based on morphological and standard cytochemical examinations of the bone marrow aspirates and classified according to the French-American-British (FAB) classifications (18,19). G-banded chromosomal analysis of bone marrow aspirates was performed in selected patients. The cumulative doses of anthracycline derivatives which were administered in selected patients for primary and/or recurrent tumors were adjusted to the equivalent DOX dose as follows: DOX doses = 1/2 × Epi dose and 5 × MIT dose.

Results

Patients and Primary Treatment

There were 13 patients who had a prior history of chemotherapy-treated breast cancer and subsequently developed TRL or t-MDS, all whom had received a mastectomy between July 1981 and June 1992. Eleven patients received the mastectomy at NCCH and two at other hospitals. The estimated number of patients with node-positive breast cancer treated with mastectomy and chemotherapy in adjuvant settings at the NCCH in the same period was known to be 1012. The median age of the 13 patients at the primary operation was 50 years (range 34-59 years). An interval history of plural cancer, which developed between the occurrence of breast cancer and TRL/t-MDS, was noted in two patients; one had gastric cancer which developed 6 years after the primary treatment and the other had sarcoma of the uterus 12 years later. These two patients underwent surgical resection of the tumor with no additional chemotherapy.

Table 1. Characteristics of primary treatment for breast cancer
Case No. Age (years)a History of breast cancer recurrence Primary chemotherapeutic agentsb Radiotherapy (total dose:Gy) Cyclophosphamide Doxorubicin
For Adjuvant For Recurrent Disease Duration (month) Cumulative dose (g/body) Duration (months) Cumulative dosec (mg/m2)
For Adjuvant For Recurrent Disease
1 59 No CPA, TAM None Para sternum and neck (50) 94 - 135 - -
2 39 Yes CPA, MTX, 5-FU, VCR CPA, TAM Chest wall for recurrence (61.6) 52 24 288.5 - -
3d 52 Yes CPA, MTX, 5-FU CPA, MMC, TAM Chest wall for recurrence (48) 12 35 57.1 - -
4 52 Yes UFT, TAM, MPA CPA, MTX, 5-FU, Epi, MIT, MMC Spine, chest wall for recurrence (67) - 25 55 7 395
5 50 Yes CPA, 5-FU, Epi, MPA, TAM Epi, CPA, TEPAe, VLB, MMC None 14 4 16.4 18 525
6 46 Yes CPA, TAM CPA, MTX, DOX, 5-FU, MIT, MMC, TAM, MPA None 12 36 48.3 12 625.5
7d 39 Yes None CPA, 5-FU, TAM None - 66 187.6 - -
8 37 Yes TAM CPA, TAM, MPA Para sternum and neck (50) - 65 113 - -
9 34 No CPA None None 6 - 18 - -
10 56 Yes CPA CPA, DOX, TAM None 21 26 67.2 13 480
11 53 Yes UFT CPA, DOX Para sternum and neck (60) - 12 16.8 12 480
12 45 Yes None CPA, MTX, 5-FU, DOX, Paclitaxel Spine for recurrence (30) - 24 46.2 16 436
13 34 Yes None UFT, CPA, MTX, DOX, MIT, 5-FU, TAM Chest wall for recurrence (50) - 24 33.6 23 880
CPA, cyclophosphamide; DOX, doxorubicin; Epi, 4-epidoxorubicin; 5-FU, 5-fluorouracil; MMC, mitomycin C; MIT, mitoxantrone; MPA, medroxyprogesterone acetate; MTX, methotrexate; TAM, tamoxifen; TEPA, thio-TEPA; UFT,tegafur uracil; VCR, vincristine; VLB, vinblastine.
aAge at operation.
bIncluding endocrine therapy.
cAnthracyclines converted into DOX as follows (mg/m2): epirubicin/2; mitoxantrone ×5.
dComplicating plural malignancies (solid tumor).
ePatient received high-dose chemotherapy supported with autologous bone marrow transplantation for recurrence.

Table 2. Patient characteristics with TRL and t-MDS and clinical course
Case No. Age (years)a Latent period (months)b Duration (months)c Type of disease (FAB classification) Chromosomal analysis Mitoses abnormal/normal Therapy for TRL/t-MDS Survival time at TRL/t-MDS (months) Outcome
1 65 94 94 MDS (RAEB)
->AML (M2)		 -   None 2 Sepsis
2 52 150 76 MDS (RAEB in T) 45, XX, -7 17/3 None 11 Bleeding
3 60 94 47 MDS (RA)
->AML (M0)		 -   BHAC/MIT/VP-16 3 Bleeding
4 60 92 53 AML (M0) -   None 1 Lymphangitisd
5 54 23 39 MDS (RA) 46, XX   None 5 Sepsis
6 60 170 45 AML (M5b) 46, XX add(12) (11q) 18/2 IDR/Ara-C 12 Hepatic failured
7 50 72 66 MDS
(RA->RAEB in T)		 45, XX, -7 20/0 IDR/Ara-C 12+ Alivee
8 47 119 67 MDS (RAEB in T) 45, X, -X, t(7;11) (q22;q23) 1/19 IDR/Ara-C 15+ Alivef
9 49 178 6 AML (M2) 46, XX, der(13;14) (q10;q10) 20/0 IDR/Ara-C 15+ Alivee
10 74 170 47 MDS (RAEB in T) 44, XX, -5, -7, der(21)t(2;21) (q13;q21) 12/8 IDR/Ara-C 7 Pneumonia
11 55 28 26 AML (M4) 46, XX   None 0.5 Bleeding
12 53 163 26 MDS (RAEB in T) 46, XX   IDR/Ara-C 5+ Alivee
13 50 190 43 MDS (RAEB in T) 46, XX   Allogeneic BMT 4 Pneumonia
AML, acute myeloblastic leukemia; MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB, RA with excessive blasts; RAEB in T, RAEB in transformation; Ara-C, cytosine arabinoside; BHAC, behenoyl Ara-C; BMT, bone marrow transplantation; CR, complete remission; IDR, idarubicin; MIT, mitoxantrone; VP-16, etoposide.
aAge at diagnosis of TRL or t-MDS.
bDuration between initiation of chemotherapy or radiotherapy for breast cancer and development of leukemia.
cDuration of chemotherapy for breast cancer.
dDeath due to breast cancer.
eAlive with progression of breast cancer and leukemia.
fAlive with progression of breast cancer and remission of leukemia.

All patients had received various combinations of therapies incorporating chemotherapy, endocrine therapy and radiotherapy for adjuvant and/or recurrent breast cancer as summarized in Table 1. Radiotherapy was administered to eight patients and endocrine therapy was used in 12 patients. For chemotherapy, CPA and DOX were the primary drugs for selection with a sporadic additional use of fluoropyrimidines. Case 5 received high-dose chemotherapy including CPA and thiotepa supported with autologous bone marrow transplantation for recurrent disease. This patient received granulocyte colony-stimulating factor (G-CSF) for high-dose chemotherapy. After primary treatment, three patients had no evidence of active cancer on diagnosis of TRL or t-MDS (cases 1, 9 and 13).

Characteristics of TRL and t-MDS

The characteristics of patients with TRL and t-MDS are summarized in Table 2. Five patients presented with pancytopenia in a routine follow-up examination and an unscheduled evaluation was made in three patients who complained of fatigability. TRL and t-MDS were diagnosed 23-190 months (median 94 months) after the initiation of chemotherapy or radiotherapy for breast cancer. Nine patients presented with MDS; of whom two developed subsequent transformation to acute myeloblastic leukemia (AML), 2 and 4 months later, respectively. Four patients presented with AML and three of them had been treated with anthracycline-containing chemotherapies for breast cancer. The initial diagnosis of case 7 was refractory anemia (RA), which subsequently converted to RA with excess blasts in transformation (RAEB in T) after 23 months. Six of the 10 patients who underwent cytochromosomal analysis showed a variety of cytogenetic abnormalities. The involvement of chromosomes 5 and/or 7 was observed in three patients. Case 8 had abnormality of chromosome 11q23, but she had not been exposed to anthracycline or epipodophyllotoxins.

Notably, in this series all patients received oral CPA for a median of 47 months (range 6-94 months), with a median cumulative dose of 55 g/body (range 16.4-288.5 g). In seven patients, oral CPA was administered in adjuvant settings for 6-94 months (median 14 months). The median cumulative dose of anthracycline derivatives administered in seven patients was 480 mg/m2 (range 395-880 mg/m2), when adjusted to the equivalent DOX dose. The median duration of anthracycline treatment was 13 months (range 7-18 months).

Clinical Course of TRL/t-MDS

Induction chemotherapy for TRL and t-MDS (RAEB in T) could not be administered owing to the patient's refusal (n = 2) and poor organ function or progressive breast cancer (n = 2). These patients shortly died of sepsis (n = 3) or tumor progression (n = 1). Seven patients were treated with multi-drug combination chemotherapy and case 13 received allogeneic bone marrow transplantation (BMT) from an HLA-matched related donor as shown in Table 2. She died of pneumonia 40 days after confirmed engraftment.

Two of the seven patients who were treated with a combination chemotherapy died of complications or metastatic breast cancer, respectively. Three of the six patients who were treated with combination of idarubicin (IDR) and cytosine arabinoside (Ara-C) achieved complete remission. Two subsequently recurred 3 and 4 months later, respectively. Currently, four patients are surviving 5-15 months after the development of TRL/t-MDS on a therapeutic regimen including IDR and Ara-C.

Discussion

This study has an obvious limitation in that the population studied has a heterogeneous background and lacks appropriate comparable cohorts of patients who were treated in currently designed protocol studies at the NCCH. With these limitations, the exact estimation of the frequency of secondary malignancy in our patient population is difficult. Nevertheless, the available data are still informative for consideration of therapy-related malignancies.

The leukemogenic potential of alkylating agents appears to be dose and intensity dependent (7,14,17,20). Curtis et al. (14) reported that the risk of TRL/t-MDS among breast cancer patients treated with a cumulative CPA dose >20 g/body was 5.7-fold compared with those without alkylating agents. They also showed that the relative risk of TRL and t-MDS in patients who received CPA for <12 months was 1.2, whereas it was 7.1 in those who received CPA for a longer duration (>18 months). In another study, those who received a cumulative CPA dose of >10 g/body had a slightly higher risk of TRL (2.0; 95% CI 0.5-5.0) compared with those who had less (1.3; 95% CI 0.4-3.0) (17). In our study, 10 of the 13 patients received CPA for more than 24 months and the cumulative dose exceeded 20 g/body.

In our series, seven patients received additional anthracyclines. An increased incidence of TRL has also been reported following chemotherapy with topoisomerase II inhibitors, mainly anthracyclines (3,8-10,16,17). Additionally, patients with breast cancer treated by chemotherapy in combination with radiotherapy were associated with a higher risk of TRL (12,14,17,21). Diamandidou et al. (17) reported that the risk of TRL in breast cancer patients treated with chemotherapy alone was 0.5, compared with 2.5 when radiotherapy was further added. On the other hand, the incidence of TRL/t-MDS after an autologous stem cell transplant procedure has been ill-defined. We observed that one patient treated with high-dose chemotherapy including CPA with stem cell support developed MDS. Also in our study, only one patient received G-CSF. The effect of the use of cytokines such as G-CSF on the incidence of TRL/t-MDS following chemotherapy is unknown. The impact of these therapeutic factors on the development of TRL/t-MDS needs to be clarified in future studies.

Cytogenetic abnormalities involving chromosomes 5 and/or 7, which has been the hallmark of TRL and t-MDS occurring after extensive therapy with alkylating agents, were observed in three of the 10 patients in our series. Interestingly, four of the 10 patients showed normal chromosomal analysis despite extensive exposure to leukemogenic agents. In previous studies, normal karyotype has been reported in 13 of 91 (22) and in three of 63 patients (6). The value of our methods used for the detection of chromosomal abnormalities in these patients needs to be clarified in a prospective study.

Adjuvant chemotherapy for breast cancer is a well established treatment modality. It has been reported that the benefits of short-term adjuvant chemotherapy exceed the risk of TRL/t-MDS (15-17). However, in this study we have demonstrated that the possible marginal benefits of prolonged use of alkylating agent-containing regimens in delaying cancer recurrence, if any, are negated by the presence of an unacceptably high incidence of second malignancies.

The prognosis of TRL/t-MDS is generally believed to be poor, with a poor response to chemotherapy, which causes further exaggerated complications by recurrence of basic disorders in elderly patient populations (7,22,23). Although the number of patients reviewed in this study was very small and with a very short follow-up, four of the six patients who were treated with the combination of IDR and Ara-C are currently surviving.

In conclusion, we have reported on 13 patients who developed TRL/t-MDS after primary treatment for breast cancer, in which CPA and/or anthracycline drugs were intensely used for a long period. This mode of unproven medical practice should be seriously re-evaluated with regard to the obviously existing disadvantages of second malignancies. Our present analysis suggests a possibility that selected patients with TRL/t-MDS may respond to intense salvage combination chemotherapy. To address this, a clinical study conducted by the Japan Adult Leukemia Study Group is in progress.

Acknowledgmentgs

We thank Dr Yoichi Takaue for useful comments on the manuscript and Drs Akio Kohno, Chihiro Konda, Kunihiko Takeyama, Takeshi Kitahara, Takuya Fukushima, Toshiya Yokozawa and Masanori Shimoyama for their diagnosis and treatment of TRL and t-MDS.

References

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Received August 17, 1998; accepted October 12, 1998
For reprints and all correspondence: Masaru Narabayashi, Department of Medical Oncology, National Cancer Center Hospital, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: mnarabay{at}gan2.ncc.go.jp
Abbreviations: TRL, therapy-related leukemia; t-MDS, therapy-related myelodysplastic syndrome; CPA, cyclophosphamide; DOX, doxorubicin; MIT, mitoxantrone; Epi, 4-epidoxorubicin; AML, acute myeloblastic leukemia; RA, refractory anemia; RAEB in T; RA with excess blasts in transformation; BMT, bone marrow transplantation; IDR, idarubicin; Ara-C, cytosine arabinoside

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