Letter to the Editor

Figure 1 Trends of the mean nadir levels of white blood cells and platelet counts each year following MMC treatment. A significant decrease of the mean nadir levels of white blood cell counts is seen in 1997–1998 and in platelets counts in 1995–1998 compared to those of 1990–1991, respectively (*: P < 0.01, **: P < 0.0001). Grade III/IV bone marrow toxicity was seen in 6% (8/135) of patients during the course of 1990–1996, whereas it was seen in 35% (15/43) during 1997–1998 (P < 0.0001). Patients who had previously been administered anti-cancer drugs and who had had diseases that might affect bone marrow function are excluded from the data Sir MMC, a product of Streptomyces caespitosus , is known to be one of the most active agents for various neoplasms and has widely used throughout the world for over 40 years (Wakaki e 1958; Hortobagyi, 1985). Recently, however, we have notice unexpected increase in MMC’s toxicity. Although the reasons this are under investigation, we feel it necessary to draw matter to the attention of clinicians who prescribe the drug. From 1990 to 1996, we performed a prospective random clinical trial comparing the effects of CMF versus MMC pl CMF (MCMF) in the treatment of node-positive, premenopau breast cancer patients (age ≤ 50) in an adjuvant setting afte obtained informed consent. In the MCMF group, the dose time schedule of MMC was 14 mg/m 2 on day 1 immediately afte surgery, and 8 mg/m 2 on day 2, and 6 cycles of CM chemotherapy were started after recovery from the toxicity MMC, usually after one month. Total enrolled number of patie was 283. The main toxic effect of MMC monotherapy was b marrow suppression, but patients were well tolerated during course of the trial. After a median follow-up of 5.7 years, a sta tically significant advantage of MMC plus CMF over CMF alo in relapse-free survival was observed ( P = 0.0058), but not in overall survival (the 36th ASCO #364). After the end of the tr we adopted a MCMF regimen as a standard therapy for patie the same condition in view of the favorable results obtain However, this time we noticed a gradual, and unexpected significant increase of MMC related bone marrow toxicity fro about 1995 or 1996 (Figure 1). As the change in toxicity was unequivocal, we tried to clarify causes. In a survey of possible dependent factors, no app differences were revealed regarding the distribution of patient disease stage, actually administered dose, or time schedu administration between patients who participated in the trial recent non-trial patients, or between patients who developed g III/IV toxicity and those who did not. Following this, another tw possible causes were explored. First, we tested the consisten the quality of MMC itself against various lots of products phys ally and chemically using spectrography (HPLC), chroma graphy, net weight deviation, and bioassay of MMC’s po against bacteria, but we found no differences. The comp (Kyowa Hakko Kogyo Co) carried out an in vivo animal toxic test using BALB/C mice, but the results showed no difference the bone marrow toxicity between product lots produced in 1