Can bleomycin toxicity in the treatment of testis cancer be batch related?
Authors: A.J. Birtle, R.A. Huddart, A.H. Horwich, D.P. Dearnaley, Z. Alexander
Journal: Annals of Oncology (2005)

Bleomycin is an antibiotic complex derived from Streptomyces verticullis culture and excreted by the kidneys. Bleomycin toxicity, predominately skin and pulmonary, has been described since the drug's introduction into testicular cancer management in the 1960s [1.Umezawa H. Maeda K. Takeuchi T. et al.New antibiotics, bleomycin A and B.J Antibiot (Tokyo). 1966; 19: 200-209PubMed Google Scholar]. Previous data from the Royal Marsden have described a 6.8% rate of pulmonary toxicity in an 835-patient series, with increased risk occurring in patients >40 years old, those with impaired glomerular filtration rate (GFR) (<80 ml/min) or with stage IV disease, or if a cumulative dose >300 000 IU was given [2.O'Sullivan J.M. Huddart R.A. Norman A.R. et al.Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours.Ann Oncol. 2003; 14: 91-96Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar]. No relation to bleomycin batch has been described previously. At the end of 2003/early 2004, we encountered a number of patients with bleomycin toxicity and decided to investigate whether there was an identifiable cause. We identified 19 patients treated at least in part from the same bleomycin batch (435000 Kyowa). Cumulative bleomycin dose, schedule, prognostic group and bleomycin risk factors were reviewed. Five out of 19 patients (26%) developed grade ≥3 skin or lung toxicity at total doses of 90 000–300 000 IU, requiring cessation of drug ± corticosteroids. Pulmonary toxicity was observed in three out of 19 (15.8%), a much higher rate than that seen in our previous series [2.O'Sullivan J.M. Huddart R.A. Norman A.R. et al.Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours.Ann Oncol. 2003; 14: 91-96Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar]. When stratified for stage, GFR, age, prognostic group and chemotherapy schedule, no apparent causal relationship was seen in the patients with toxicity (Table 1). This association may be due to chance, but given that the only common factor among the group was of the shared bleomycin batch, we are suspicious that this was the causal element.Table 1Characteristics of patients treated using same bleomycin batch (n = 19)Patients with toxicity (n = 5)Patients without toxicity (n = 14)Prognostic group Good39 Intermediate11 Poor14 Pretreatment EDTA, ml [mean (range)]127 (79–143)126 (76–164)Regime 3-day BEP39 5-day BEP11 CBOP-BEP13Gemcitabine/carboplatin/ bleomycin01Total bleomycin dose, IU [median (range)]180 000 (90 000–300 000)270 000 (150 000–360 000)Amount of bleomycin from same batch, % [median (range)]100 (all patients)67 (10–100)BEP, bleomycin, etoposide and cisplatin; CBOP, carboplatin, bleomycin, vincristine, and cisplatin. Open table in a new tab BEP, bleomycin, etoposide and cisplatin; CBOP, carboplatin, bleomycin, vincristine, and cisplatin. Batch-related bleomycin toxicity has not to our knowledge been described previously, and we would be interested in hearing the experiences of other physicians using bleomycin doses from this batch. We would encourage establishing a central pharmacy database to enable reporting of all bleomycin toxicity so that batch details may be recorded and patients receiving the drug from a highlighted batch may be identified.