Late Effects of Treatment for Childhood Cancer (PDQ®) 10/11 –Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version - National Cancer Institute

Late Effects of Treatment for Childhood Cancer (PDQ®)–Health Professional Version

Late Effects of the Respiratory System

In This Section

• Respiratory complications after radiation therapy
• Respiratory complications after chemotherapy
• Respiratory complications associated with HSCT
• Other factors associated with respiratory late effects

Respiratory function may be compromised in long-term survivors of childhood cancer who were treated with the following therapies:

• Specific chemotherapeutic agents.
• Thoracic radiation therapy.
• Pulmonary/chest wall surgery.
• Hematopoietic stem cell transplantation (HSCT).

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. No large cohort studies have been performed that include clinical evaluations coupled with functional and quality-of-life assessments.

The true prevalence or incidence of pulmonary dysfunction in childhood cancer survivors is not clear. For children treated with HSCT, significant clinical disease has been observed.

Evidence (selected cohort studies describing long-term pulmonary function outcomes):

1. The incidence of self-reported pulmonary dysfunction among adults treated for central nervous system malignancies with craniospinal irradiation (per 1,000 person-years) was 9.1 (95% confidence interval, 7.8–10.6) for emphysema/obliterative bronchiolitis and more than 3.0 for asthma, chronic cough, and the need for extra oxygen. High rates of late onset pulmonary dysfunction occurring more than 5 years after diagnosis were also observed.[1]
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.[2]
   • Pulmonary function impairment (Common Terminology Criteria for Adverse Events 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 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 when compared with bleomycin treatment only.
3. In a longitudinal study evaluating the magnitude and trajectory of pulmonary dysfunction among 121 childhood cancer survivors (median time from diagnosis to last evaluation, 17.1 years) treated with potentially pulmonary-toxic therapy (e.g., bleomycin, busulfan, pulmonary radiation therapy), survivors were significantly more likely to have restrictive and diffusion defects than were healthy controls.[3]
   • Age younger than 16 years at diagnosis and exposure to more than 20 Gy of chest radiation were associated with increased odds of restrictive defects, whereas female sex and chest radiation dose were associated with diffusion abnormalities.
   • Decline in pulmonary function over time was largely related to changes in diffusion capacity. The odds of decline in diffusion function over time showed a fourfold increase among females and 24-fold increase among survivors treated with more than 20 Gy of chest radiation. Compared with survivors with normal diffusion, those with diffusion defects were significantly more likely to be symptomatic and have poorer health-related quality-of-life scores, with decreases in the domains of physical functioning, role limitation as a result of physical health, and low energy/increased fatigue.
4. Childhood Cancer Survivor Study investigators compared self-reported pulmonary outcomes and their impact on daily activities among 5-year cancer survivors (median, 25 years from diagnosis) and a sibling cohort.[4]
   • Survivors were more likely to report chronic cough, the need for oxygen, lung fibrosis, and recurrent pneumonia than were siblings despite lower rates of smoking.
   • By age 45 years, the cumulative incidence of any pulmonary condition was 29.6% for survivors. Survivors with chronic pulmonary conditions (e.g., chronic cough) were more likely to report activity limitations than were those without these conditions.
   • Pulmonary complications contributed to an almost sixfold excess risk of death among survivors and demonstrated significant associations with exposure to platinum and lung radiation.

Respiratory complications after radiation therapy

Radiation therapy that exposes 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.[5] Combined-modality therapy including radiation therapy and pulmonary toxic chemotherapy or thoracic/chest wall surgery increases the risk of pulmonary function impairment.[2,6]

Chronic pulmonary complications reported after treatment for pediatric malignancies include restrictive or obstructive chronic pulmonary disease, pulmonary fibrosis, and spontaneous pneumothorax.[7] 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.

Evidence (selected cohort studies describing pulmonary outcomes):

1. A study of 48 survivors of pediatric malignant solid tumors followed for a median of 9.7 years after median whole-lung radiation doses of 12 Gy (range, 10.5–18 Gy) reported the following:[8]
   • Only nine patients (18.8%) reported respiratory symptoms. However, abnormalities in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), total lung capacity, and diffusion capacity were common (58%–73%).
   • Focal-boost radiation therapy was significantly associated with additional abnormalities.
   • 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.[9,10]
2. For survivors of pediatric Hodgkin lymphoma, the prevalence of pulmonary symptoms using contemporary involved-field techniques is reported to be low. However, many exhibit substantial subclinical dysfunction.[11]
3. Changes in lung function have been reported in children treated with whole-lung radiation therapy for metastatic Wilms tumor.[9,10]
   • 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.
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 underlying radiation damage.[9,10,12]

Respiratory complications after 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 therapy or thoracic/chest wall surgery increases the risk of pulmonary function impairment.[2]

Evidence (outcomes among cohorts treated with pulmonary toxic chemotherapy):

1. 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.[12-14]
2. 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.[15-17] However, grades 3 and 4 pulmonary toxicity was reported in 9% of children receiving 12 cycles of ABVD followed by 21 Gy of extended-field radiation.[14]
3. ABVD-related pulmonary toxic effects may result from fibrosis induced by bleomycin or radiation recall pneumonitis related to administration of doxorubicin.
4. Pulmonary veno-occlusive disease has been observed rarely and has been attributed to bleomycin chemotherapy.[18]

Respiratory complications associated with HSCT

Patients undergoing HSCT are at increased risk of pulmonary toxic effects related to the following:[19-21]

• Preexisting pulmonary dysfunction (e.g., asthma, pretransplant therapy).
• Conditioning regimens, including cyclophosphamide, busulfan, or carmustine.
• Total-body irradiation.
• Graft-versus-host disease (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.[22,23] 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.[20,24,25]

Other factors associated with respiratory late effects

Additional factors contributing to chronic pulmonary toxic effects include superimposed infection, underlying pneumonopathy (e.g., asthma), chest wall abnormalities, respiratory toxic effects, chronic GVHD, and the effects of chronic pulmonary involvement by tumor or reaction to tumor.[6] Lung lobectomy during childhood appears to have no significant impact on long-term pulmonary function,[26] 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.[27]

Evidence (pulmonary dysfunction in former or current smokers):

1. Pulmonary function evaluations of 433 adult childhood cancer survivors treated with pulmonary toxic modalities demonstrated significantly higher risk of pulmonary dysfunction in smokers than in nonsmokers.[28]
   • FEV1/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 smokers have an increased risk of future obstructive and restrictive lung disease.

Table 16 summarizes respiratory late effects and the related health screenings.

Table 16. Respiratory Late Effectsa

Predisposing Therapy	Respiratory Effects	Health Screening/Interventions
DLCO = diffusing capacity of the lung for carbon monoxide; GVHD = graft-versus-host disease.
aAdapted from the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult CancersExit Disclaimer.
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 disease	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
Hematopoietic cell transplantation with any history of chronic GVHD	Pulmonary 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 CancersExit Disclaimer for respiratory late effects information including risk factors, evaluation, and health counseling.[29]

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