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Late Effects of Treatment for Childhood Cancer (PDQ®)

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Late Effects of the Respiratory System

Specific chemotherapeutic agents, thoracic irradiation, pulmonary/chest wall surgery, and hematopoietic stem cell transplantation (HSCT) can compromise respiratory function in long-term survivors of childhood cancer. The effects of early lung injury from cancer treatment may be exacerbated by the decline in lung function associated with normal aging, other comorbid chronic health conditions, or smoking. The quality of current evidence regarding this outcome is limited by retrospective data collection, small sample size, cohort selection and participation bias, description of outcomes following antiquated treatment approaches, and variability in time since treatment and method of ascertainment.

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.

Results from selected cohort studies featuring long-term pulmonary function outcomes include the following:

  • An analysis of self-reported pulmonary complications of 12,390 survivors of common childhood malignancies has been reported by the Childhood Cancer Survivor Study.[1] 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.
  • The incidence of self-reported pulmonary dysfunction among a subset of adults in the cohort treated for central nervous system (CNS) malignancies with craniospinal radiation (per 1,000 person-years) was 9.1 (95% CI, 7.8–10.6) for emphysema/obliterative bronchiolitis and more than 3.0 for asthma, chronic cough, and need for extra oxygen. High rates of late onset pulmonary dysfunction occurring more than 5 years after diagnosis were also observed.[2]
  • Dutch investigators reported outcomes of 193 childhood cancer survivors evaluated by pulmonary function testing at a median follow-up of 18 years after diagnosis. Pulmonary function impairment (CTCAE grade 2 or higher) was identified in 85 patients (44.0%) and included obstructive deficits (2.1%), restrictive deficits (17.6%), and decreased carbon monoxide diffusion capacity (39.9%). Multivariate logistic regression models showed that, compared with bleomycin treatment only, treatment with radiation therapy, radiation therapy combined with bleomycin, and radiation therapy combined with surgery were associated with the highest risk of pulmonary function impairment.[3]

Respiratory complications following radiation therapy

Radiation exposing the lung parenchyma can result in pulmonary dysfunction related to reduced lung volume, impaired dynamic compliance, and deformity of both the lung and chest wall. The potential for chronic pulmonary sequelae is related to the radiation dose administered, the volume of lung irradiated, and the fractional radiation therapy doses.[4] Combined-modality therapy including radiation and pulmonary toxic chemotherapy or thoracic/chest wall surgery increases the risk of pulmonary function impairment.[3]

Chronic pulmonary complications reported after treatment for pediatric malignancies include restrictive or obstructive chronic pulmonary disease, pulmonary fibrosis, and spontaneous pneumothorax.[5] These sequelae are uncommon after contemporary therapy, which most often results in subclinical injury that is detected only by imaging or formal pulmonary function testing.

Pulmonary outcomes reported from selected cohort studies treated with thoracic radiation therapy include the following:

  • 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.[6] 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.[7,8]
  • For survivors of pediatric Hodgkin lymphoma, the prevalence of pulmonary symptoms using contemporary involved-field techniques is reported to be low. However, they still exhibit substantial subclinical dysfunction.[9]
  • 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.[7,8]
  • 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.[7,8,10]

Respiratory complications following chemotherapy

Chemotherapy agents with potential pulmonary toxic effects 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. Combined-modality therapy including pulmonary toxic chemotherapy and thoracic radiation or thoracic/chest wall surgery increases the risk of pulmonary function impairment.[3] Outcomes observed among cohorts treated with pulmonary toxic chemotherapy include the following:

  • 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.[10-12]
  • More current pediatric regimens for Hodgkin lymphoma using radiation therapy and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) have shown a significant incidence of asymptomatic pulmonary dysfunction after treatment, which appears to improve with time.[13-15] However, grades 3 and 4 pulmonary toxicity has been reported in 9% of children receiving 12 cycles of ABVD followed by 21 Gy of radiation.[12]
  • ABVD-related pulmonary toxic effects 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.[16]

Respiratory complications associated with HSCT

Patients undergoing HSCT are at increased risk of pulmonary toxic effects related to the following:[17-19]

  • Preexisting pulmonary dysfunction (e.g., asthma, pretransplant therapy).
  • Conditioning regimens, including cyclophosphamide, busulfan, or carmustine.
  • Total-body irradiation.
  • GVHD.

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.[20,21] 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.[18,22,23]

Other factors associated with respiratory late effects

Additional factors contributing to chronic pulmonary toxic effects include superimposed infection, underlying pneumonopathy (e.g., asthma), respiratory toxic effects, 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,[24] but the long-term effect of lung surgery for children with cancer is not well defined.

Pulmonary complications may also be exacerbated by smoking cigarettes or other substances. While smoking rates in survivors of childhood cancer tend to be lower than the general population, it is still important to prevent initiation of smoking and promote cessation in this distinct population.[25]

Pulmonary function evaluations of 433 adult childhood cancer survivors treated with pulmonary toxic modalities demonstrated significantly higher risk for pulmonary dysfunction among smokers compared to nonsmokers. Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) median values among current and former smokers were lower than those who had never smoked. Median FEV1/FVC values were lower among those who smoked less than 6 pack-years and those who smoked 6 pack-years or more compared with those who had never smoked suggesting that survivors who are former or current have an increased risk for future obstructive and restrictive lung disease.[26]

Table 14. Respiratory Late Effects
Predisposing TherapyRespiratory EffectsHealth 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.[27]

References

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  • Updated: December 12, 2014