Birgitta Versluijs

30 Pulmonary complications of chemotherapy Busulphan has long been recognized as a potentially pulmotoxic cytostatic drug. 6,11,17,26,27 Busulphan is almost exclusively applied within the preparative regimen for either au- tologous or allogeneic HCT and is usually combined with other chemotherapy agents, most frequently cyclophosphamide, melfalan or fludarabine. This makes it difficult to assess the relative contribution of busulphan to pulmonary late effects after HCT. Also, in the allogeneic transplant setting immune-mediated lung disease (Idiopathic Pneu- monia Syndrome, Bronchiolitis Obliterans Syndrome) may contribute to pulmonary in- jury. Busulphan can cause both acute lung problems, i.e. interstitial pneumonia, and late pulmonary function abnormalities. 6,11,17,26 It has been suggested that after busulphan obstructive lung involvement may be more common, 27 but in the allogeneic transplant setting immune-mediated lung disease may confound the busulphan effect. Late pul- monary damage may develop insidiously and symptoms include non-productive cough, dyspnoea, or fever. 6,11,28 It is unclear whether the risk of lung damage is dose dependent, although pulmonary toxicity has mostly been described after high cumulative transplan- tation doses. 11,18,22 Cyclophosphamide is one of the most widely used cytotoxic drugs in the treatment of paediatric malignancy and is frequently used in the preparative regimen for HCT as well. Cyclophosphamide is associated with early-onset interstitial pneumonia and late-onset more insidious disease that may progress to pulmonary fibrosis. 6,18,29,30 Pulmonary toxi- city of cyclophosphamide has almost exclusively been described in the setting of HCT conditioning, when other pulmotoxic therapy is also being used and immune mediated lung injury may play a role. This hampers the assessment of the pulmonary toxicity and late effects of cyclophosphamide by itself. Few cases have been described of pulmonary toxicity in patients who were not exposed to other pulmonary toxic modalities, such as radiotherapy. 29,30 In a study by Mulder et al. 7 in long-term childhood cancer survivors, high dose cyclophosphamide was not a significant risk factor for PFT abnormalities. There was no apparent relationship with dose or duration of cyclophosphamide use. 11,28 Although nitrosureas have been shown to be toxic to pulmonary tissue and are conside- red an indication for long-term PFT screening in childhood cancer survivors, only limi- ted data is available to support this notion. Of the nitrosurea derivatives, BCNU (carm- ustine) is applied in high dose preparative regimens for autologous HCT such as in the treatment of lymphoma. CCNU (lomustine) is used in the treatment of malignant brain tumours in children. BCNU has been found to cause pulmonary toxicity in a dose dependent way in 20-30% of the treated patients. 11 Pulmonary toxicity of CCNU has only been described in isolated case reports. 18,22,31 Early-onset toxicity of BCNU can present as interstitial pneumonia and fibrosis, but pulmonary fibrosis can also present as a late-onset complication. 31,32 Higher cumulative dose and younger age have been described as risk factors for pulmonary toxi- 2