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Late Effects of Treatment for Childhood Cancer (PDQ®)

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Late Effects of the Respiratory System

Acute and chronic pulmonary complications reported after treatment for pediatric malignancies include radiation pneumonitis, pulmonary fibrosis, and spontaneous pneumothorax. These sequelae are uncommon after contemporary therapy and most often result in subclinical injury that is detected only by imaging or formal pulmonary function testing. Chemotherapy agents with potential pulmonary toxicity commonly used in the treatment of pediatric malignancies include bleomycin, busulfan, and the nitrosoureas (carmustine and lomustine). These agents induce lung damage on their own or potentiate the damaging effects of radiation to the lung. Thus, the potential for acute or chronic pulmonary sequelae must be considered in the context of the specific chemotherapeutic agents and the radiation dose administered, the volume of lung irradiated, and the fractional radiation therapy doses.[1]

Acute pneumonitis manifested by fever, congestion, cough, and dyspnea can follow radiation therapy alone at doses greater than 40 Gy to focal lung volumes, or after lower doses when combined with dactinomycin or anthracyclines. Fatal pneumonitis is possible after radiation therapy alone at doses to the whole lung greater than 20 Gy, but is possible after lower doses when combined with chemotherapy. Infection, graft-versus-host disease (GVHD) in the setting of bone marrow transplant, and pre-existing pulmonary compromise (e.g., asthma) all may influence this risk. Changes in lung function have been reported in children treated with whole-lung radiation therapy for metastatic Wilms tumor. A dose of 12 Gy to 14 Gy reduced total lung capacity and vital capacity to about 70% of predicted values, and even lower if the patient had undergone thoracotomy. In a study of 48 survivors of pediatric malignant solid tumors with a median follow-up of 9.7 years after median whole-lung irradiation doses of 12 Gy (range, 10.5–18 Gy), only nine patients (18.8%) reported respiratory symptoms. However, abnormalities in forced vital capacity, forced expiratory volume in 1 second, total lung capacity, and diffusion capacity were common (58%–73%). Focal boost irradiation was also significantly associated with additional abnormalities.[2] Reducing the size of the daily radiation fractions (e.g., from 1.8 Gy per day to 1.5 Gy per day) decreases this risk.[3,4] Administration of bleomycin alone can produce pulmonary toxicity and, when combined with radiation therapy, can heighten radiation reactions. Chemotherapeutic agents such as doxorubicin, dactinomycin, and busulfan are radiomimetic agents and can reactivate latent radiation damage.[3-5]

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 treatment protocols for pediatric malignancies.[5-7] More current pediatric regimens for Hodgkin lymphoma using radiation therapy and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) have shown a significant incidence of asymptomatic pulmonary dysfunction after treatment, which appears to improve with time.[8-10] However, grade 3 and 4 pulmonary toxicity has been reported in 9% of children receiving 12 cycles of ABVD followed by 21 Gy of radiation.[7] In addition, ABVD-related pulmonary toxicity may result from fibrosis induced by bleomycin or “radiation recall” pneumonitis related to administration of doxorubicin. Pulmonary veno-occlusive disease has been observed rarely and has been attributed to bleomycin chemotherapy.[11]

Patients undergoing hematopoietic stem cell transplant (HSCT) are at increased risk of pulmonary toxicity, related to (1) preexisting pulmonary dysfunction (e.g., asthma, pretransplant therapy); (2) the preparative regimen that may include cyclophosphamide, busulfan, and carmustine; (3) total-body irradiation; and (4) the presence of GVHD.[12-17] Although most survivors of transplant are not clinically compromised, restrictive lung disease may occur and has been reported to increase in prevalence with increasing time from HSCT, based on limited data from longitudinally followed cohorts.[18,19] 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.[14,20-22]

Additional factors contributing to chronic pulmonary toxicity include superimposed infection, underlying pneumonopathy (e.g., asthma), cigarette use, respiratory toxicity, chronic GVHD, and the effects of chronic pulmonary involvement by tumor or reaction to tumor. Lung lobectomy during childhood appears to have no significant impact on long-term pulmonary function,[23] but the long-term effect of lung surgery for children with cancer is not well defined.

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 Childhood Cancer Survivor Study.[24] 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. With changes in the doses of radiation therapy employed since the late 1980s, the incidence of these abnormalities is likely to decrease.

Table 14. Pulmonary Late Effects
Predisposing Therapy Pulmonary Effects Health Screening/Interventions 
DLCO = diffusing capacity of the lung for carbon monoxide; GVHD = graft-versus-host disease.
Busulfan; carmustine (BCNU)/lomustine (CCNU); bleomycin; radiation impacting lungs; surgery impacting pulmonary function (lobectomy, metastasectomy, wedge resection)Subclinical pulmonary dysfunction; interstitial pneumonitis; pulmonary fibrosis; restrictive lung disease; obstructive lung diseaseHistory: cough, shortness of breath, dyspnea on exertion, wheezing
Pulmonary exam
Pulmonary function tests (including DLCO and spirometry)
Chest x-ray
Counsel regarding tobacco avoidance/smoking cessation
In patients with abnormal pulmonary function tests and/or chest x-ray, consider repeat evaluation before general anesthesia
Pulmonary consultation for patients with symptomatic pulmonary dysfunction
Influenza and pneumococcal vaccinations
Hematopoietic cell transplantation with any history of chronic GVHDPulmonary toxicity (bronchiolitis obliterans, chronic bronchitis, bronchiectasis)History: cough, shortness of breath, dyspnea on exertion, wheezing
Pulmonary exam
Pulmonary function tests (including DLCO and spirometry)
Chest x-ray
Counsel regarding tobacco avoidance/smoking cessation
In patients with abnormal pulmonary function tests and/or chest x-ray, consider repeat evaluation before general anesthesia
Pulmonary consultation for patients with symptomatic pulmonary dysfunction
Influenza and pneumococcal vaccinations

Refer to the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers for respiratory late effects information including risk factors, evaluation, and health counseling.

References
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