| Japanese Journal of Clinical Oncology | Pages |
Editorial
How can we predict and prevent the occurrence of therapy-related Leukemias ?
Ryuzo Ueda, Second Department of Internal Medicine, Nagoya City University Medical School, Nagoya, Japan
Advances in the fields of chemotherapy and radiotherapy have improved the survival period of cancer patients over the last few decades. Unfortunately, an unpredicted disaster has also resulted from this medical progress, the `therapy-related leukemia (TRL)' which is increasingly a focus of attention for oncologists (1). It was initially described by hematologists, particularly among long-term survivors from Hodgkin's disease, whose treatment regimens included alkylating agents and combined-modality therapy using chemotherapy and radiotherapy. Based on accumulated experience, treatment regimens for Hodgkin's disease have been changed with the aim of providing long-term survival with no serious complications like TRL. However, a new variant type of TRL has been encountered since the 1970s when epipodophyllotoxins such as etoposide and teniposide found widespread application in combination chemotherapeutic regimens for various types of malignancies (2). Clearly the risk should have been borne in mind, because cytotoxic agents are intended to damage cellular DNA, RNA and the machinery essential for stable homeostasis of the cell. When the targeted alterations are unrepaired, they are lethal to cells. Occasionally, however, non-lethal damage in a single cell may involve critical genes for leukemogenesis, which leads to TRL after accumulation of further mutations. Cytogenetic analyses have revealed that chromosomal aberrations observed in TRL consist of two distinct types. One is the unbalanced aberration represented by -5/5q- and -7/7q- (3). It is closely associated with exposures to alkylating agents and/or ionizing radiations and is found in TRL, developing five to seven years after exposure. It is characterized by the presence of a period of therapy-related myelodysplastic syndrome (t-MDS) followed by transformation into refractory leukemias. The other is the balanced chromosomal aberration represented by chromosomal translocations, as are often found in de novo leukemias. The associated TRL usually develops a half year to five years after the exposure to topoisomerase II inhibitors such as epipodophyllotoxins and anthracyclins. Rearrangements often involve certain chromosomal loci such as 11q23 and 21q22, and recently, some of the target genes altered by these cytotoxic agents have been identified. MLL and AML1 genes mapped to 11q23 and 21q22 chromosomal loci represent such genes disrupted throughout interactions between topoisomerase II and its inhibitors (4). The MLL specific rearrangement leads to sudden onset TRL showing myelomonocytic features. In contrast, most important TRL-related genes, which are presumably located at chromosomes 5q31 and 7q22 and are responsible for the development of t-MDS, remain to be elucidated.
Clinically, high dose chemotherapy supported by either autologous or allogeneic stem cells is now applied for various types of cancers. This strategy is the best way to increase the relative dose intensity, although it has also alerted us to the high incidence of TRL development (5). According to previous reports regarding patients transplanted for lymphomas in the United States, the actual incidence of TRL increases by up to 4-18% in three to seven years after high dose chemotherapy (1). Also, additional effects of specific cytokines whichcan accelerate the TRL development must be taken into account. As the number of long-term survivors not only from hematologic malignancies but also from non-hematologic malignancies increases, oncologists have to face up to this problem. In fact, TRL developing in cases from non-hematologic malignancies constituted 56.8% of all these investigated in a large-scale Japanese study (Takeyama K and Ueda R, unpublished data). Therefore, we need to make treatment plans for cancer patients with long-term perspectives. Prospective clinical trials are desired to include informed consent with detailed explanation of the risk of TRL. Epidemiological analyses need to be conducted to identify the cytotoxic agents and their usage associated with frequent TRL development. In addition, basic research to identify TRL-associated genes and molecular mechanisms causing specific gene alterations is essential for a better understanding of TRL.
In this issue, Ando et al. report summarized data on thirteen TRL cases preceded by the use of cytotoxic agents for breast cancers (6). In spite of the retrospective nature of analysis, it is valuable in that the majority of the cases were demonstrated to have received chemotherapeutic regimens including prolonged administration of cyclophosphamide and high cumulative doses of anthracyclins. Although this chemotherapy in an adjuvant setting for preventing recurrence of disease is widely accepted, the authors warn us to reconsider the optimal regimens to lessen unfavorable late complications. They also describe a relatively favorable outcome for the TRL patients providing the combined regimens including cytarabine and idarubicin. Since the prognosis of the TRL is extremely poor, this is an important point.
Attempts to elucidate the background of hosts prone to developing TRL and safer regimens without any loss of benefit for cure must be carried out by prospective analyses in larger studies of all cancers together with efforts to identify molecular mechanisms leading to TRL.
References
This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: www-admin{at}oup.co.uk
Last modification: 22 Feb 1999
Copyright© 1999 Foundation for Promotion of Cancer Research
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||