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The development of bleomycin-associated pulmonary fibrosis with permanent restrictive disease is dose dependent, usually occurring at doses greater than 200 U/m² to 400 U/m², higher than those used in pediatric malignancies.[181,182,183] One study evaluated lung function in 20 pediatric Hodgkin lymphoma patients treated with MOPP (mechlorethamine [HN 2], vincristine [Oncovin], prednisone, and procarbazine)/ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) and 15 Gy to 25 Gy mantle radiation and found 55% to have abnormal diffusing capacity.[184] Another study evaluated serial pulmonary function in children treated with COP (cyclophosphamide, vincristine, and prednisone)/ABVD and mantle radiation therapy and found 65% to 73% to have only mildly decreased or normal diffusing capacity.[185] One other study reviewed pulmonary toxicity in survivors of childhood ALL, Hodgkin lymphoma, and non-Hodgkin lymphoma (NHL) and found some abnormalities as measured by pulmonary function testing.[186,187] Clinical symptoms were uncommon and generally did not correlate with pulmonary function test results in these studies.

Patients who are treated with HSCT are at increased risk of pulmonary toxicity, related to pre-existing pulmonary dysfunction (e.g., asthma, pretransplant therapy), the preparative regimen that may include cyclophosphamide, busulfan, carmustine, TBI, and the presence of GVHD.[188,189,190,191,192,193,194] Although most survivors of transplant are not clinically compromised, restrictive lung disease may occur. Obstructive disease is less common, as is late onset pulmonary syndrome, which includes the spectrum of restrictive and obstructive disease. Bronchiolitis obliterans with or without organizing pneumonia, diffuse alveolar damage, and interstitial pneumonia may occur as a component of this syndrome, generally between 6 and 12 months posttransplant. Cough, dyspnea, or wheezing may occur with either normal chest x-ray or diffuse/patchy infiltrates; however, most patients are symptom free.[192,193]

The true prevalence or incidence of pulmonary dysfunction in childhood cancer survivors is not clear. For children treated with HSCT, there is significant clinical disease. No large cohort studies have been performed with clinical evaluations coupled with functional and quality-of-life assessments. An analysis of self-reported pulmonary complications of 12,390 survivors of common childhood malignancies has been reported by the CCSS. This cohort includes children treated with both conventional and myeloablative therapies. Compared with siblings, survivors had an increased relative risk (RR) of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen therapy, abnormal chest wall, exercise-induced shortness of breath and bronchitis, with RRs ranging from 1.2 to 13.0 (highest for lung fibrosis and lowest for bronchitis). The 25-year cumulative incidence of lung fibrosis was 5% for those who received chest radiation therapy and less than 1% for those who received pulmonary toxic chemotherapy. For more subjective complaints, the 25-year cumulative incidences were higher, as follows: chronic cough, 15% for combined chest radiation therapy and pulmonary toxic chemotherapy, 12% chest radiation therapy alone, 6% pulmonary toxic chemotherapy alone; exercise-induced shortness of breath, 20% chest radiation therapy and pulmonary toxic chemotherapy, 15% chest radiation therapy alone, 6% pulmonary toxic chemotherapy alone. Treatment-related risk factors included chest radiation for lung fibrosis, supplemental oxygen therapy, recurrent pneumonia, exercise-induced shortness of breath, and chronic cough. Cyclophosphamide increased risk for exercise-induced shortness of breath, supplemental oxygen therapy, chronic cough, bronchitis, and recurrent pneumonia. Bleomycin increased risk for supplemental oxygen therapy, bronchitis, and chronic cough. Busulfan increased risk of chronic cough and pleurisy. Doxorubicin was associated with an increased risk of emphysema, supplemental oxygen therapy, chronic cough, and shortness of breath. Nitrosoureas were associated with an increased risk of supplemental oxygen therapy. Three survivors had undergone a lung transplant, and another three survivors developed adenocarcinoma of the lung as a second malignancy. Risk continues to increase with time since diagnosis.[195] With changes in the doses of radiation therapy employed since the late 1980s, the incidence of these abnormalities is likely to decrease.