Therapy-related malignancies: a review.

Abstract

Although many cytostatic drugs have been shown to be both mutagenic and carcinogenic in experimental systems, only the alkylating agents have been demonstrated with certainty to induce malignancy in man. Thus, therapy with almost all alkylating agents in clinical use today results in a highly increased risk of acute nonlymphocytic leukaemia (ANLL). Other types of leukaemia are not observed in excess following cancer chemotherapy, and only one type of solid tumour has been convincingly related to treatment with cytostatic drugs: carcinoma of the urinary bladder following cyclophosphamide and the now abandoned alkylating agent chlornaphazine.Low dose total‐body irradiation, as in the atomic bomb explosions of World War II, is known to induce ANLL, acute lymphoblastic leukaemia and chronic myelogenous leukaemia, as well as various solid tumours and multiple myeloma in man. High voltage radiotherapy, by comparison, has been found to be followed by a moderately increased risk of ANLL in only a few studies. This phenomenon has been related to cell kill rather than to malignant transformation of haematopoietic stem cells within the fields of irradiation. A moderately increased risk of various solid tumours and of non‐Hodgkin's lymphomas has been observed with a long follow up, particularly in series of patients treated for Hodgkin's disease. This excess possibly represents both radiotherapy‐induced solid tumours and a general predisposition to development of solid tumours and non‐Hodgkin's lymphomas as part of the natural history of the primary malignancy.The risk of therapy‐related acute nonlymphocytic leukaemia (t‐ANLL) is dose‐dependent and possibly directly proportional to the total cumulative dose af alkylating agents. It increases with patient age, like the risk of de‐novo ANLL, and it levels out 7–8 years after cessation of therapy with alkylating agents. Most cases of t‐ANLL present in a preleukaemic phase with refractory cytopenia. Already at this early stage the characteristic chromosome abnormalities can be observed in the bone marrow, most often loss of the whole, or parts of the long arms, of chromosomes no 5 and/or no 7. The cytogenet‐ic abnormalities are of diagnostic, prognostic and perhaps also of pathogenetic significance for t‐ANLL.