Combination Methotrexate Chemotherapy for GTT Increases the Incidence of Second Tumors


Although Rustin and colleagues found no increase in second tumor incidence in a previous analysis of women treated with chemotherapy for gestational trophoblastic tumors (GTT), a further analysis of risk of second tumors was performed in the 1377 women treated in their unit until 1990 because of more patient-years at risk. Health questionnaires were returned by 93.3% of patients living in the United Kingdom who successfully completed chemotherapy. Incidence density analysis was performed based on 15,279 person-years of observation available. Standard incidence ratio (SIR) was used to estimate the relative risk (RR) of second tumors associated with the treatment. To calculate the expected number, the actual incidence rates observed by the Thames Cancer Registry during the same calendar period of observation were used. The investigators found an overall 50% excess of risk (RR = 1.5; 95% confidence interval [CI], 1.1-2.1; P < 0.011). There were 37 second tumors, when 24.5 were expected. For specific tumors, the risk was significantly increased for myeloid leukemia (RR = 16.6), colon cancer (RR = 4.6), and breast cancer when the survival exceeded 25 years (RR = 5.8). The risk was not significantly increased among the 554 women receiving single-agent therapy (RR = 1.3). Leukemias only developed in patients receiving etoposide plus other cytotoxic drugs. The authors conclude that there is a slight increased risk of second tumors after sequential or combination chemotherapy for GTT. This increase has become apparent since the introduction of etoposide and longer follow-up. (Rustin GJS, et al. J Clin Oncol 1996;14:2769-2773.)


This is the first publication to report an increased risk of second tumors in women treated for GTT. In retrospect, the reason that the authors' initial study found no increased risk and this study did is quite simple: there have been an additional 12 years of follow-up since that initial study, with an increase of patient-years at risk from 3522 in the initial study to 15,279 in the current study. There has always been a concern about second malignancies in patients who receive chemotherapy. Consistent with the findings of other studies, the leukemias generally appear within the first five years after treatment, and the solid tumors appear later. There are, of course, other examples of an increased risk of second malignancies in patients treated with chemotherapy for gynecological cancers. In the 1970s, we began to appreciate that women with ovarian cancer who were treated with prolonged alkylating agents, such as melphalan or cyclophosphamide, were at increased risk for developing acute myeloid leukemias. The degree of increased risk was directly related to the duration of exposure to the alkylating agent and to the total cumulative dose. Furthermore, melphalan was found to be more leukemogenic than cyclophosphamide. Within the past few years, we have learned that patients with testicular cancer and other cancers who receive etoposide are at increased risk of developing acute monomyelocytic leukemias. This type of leukemia differs from the classical alkylating agent-related leukemia in that it has a short latency period, appears to have a reasonable rate of cure, and has a specific genetic defect unlike that of the latter. Of course, the results of this study will require confirmation from other large series. In the meantime, young women with GTT for whom etoposide may be indicated should be apprised of the possible association. The increased risk of solid tumors is also quite interesting, particularly the risk of secondary breast cancers more than 25 years after exposure.