Respiratory Disorders in Cancer Survivors

Chapter 95


Respiratory Disorders in Cancer Survivors

Matthew Schefft, DO, MSHA, FAAP, and H. Joel Schmidt, MD, FAAP, FCCP


With longer survival after pediatric cancer comes a greater likelihood of long-term complications, some of which may be respiratory in nature.

The most common cancers associated with respiratory disease in cancer survivors (RDCS) are

Any condition that requires bone marrow transplantation

Acute myeloid leukemia

Astrocytoma and other brain tumors


Hodgkin disease

Many patients remain asymptomatic for years.

Incidence measures vary; the prevalence of RDCS may be as high as 30%.

Possible causes of RDCS include


Drug-induced origins

Radiation therapy


Metastatic disease

Idiopathic causes

Identifying the specific cause of RDCS is complicated.

Multiple drugs and possible drug-drug interactions can make identifying the exact cause of toxicity difficult.

Multiple drugs, radiation therapy, surgery, metastatic disease, and infection can all be involved.


Infectious Causes of RDCS

Susceptibility to infections due to chemotherapy-related immunosuppression contributes to RDCS through sequelae such as fibrosis and airway remodeling.

Notable organisms include

Pneumocystis jirovecii (formerly Pneumocystis carinii)

Fungal (Aspergillus, Mucor, Fusarium, and Candida species)

Viral (adenovirus, especially in patients with stem cell transplants, respiratory syncytial virus, and cytomegalovirus)

Drug-Induced RDCS

May be dose related or dose independent (Table 95-1).

Bleomycin toxicity is dose related: Pulmonary function impairment can occur at any dose but is more likely at higher doses.

Methotrexate toxicity is thought to be dose independent: The likelihood of pulmonary function impairment does not vary according to the dose administered.

Mechanisms of chemotherapeutic agent–induced toxicity include

Reactive oxygen metabolites

Interference with collagen metabolism (dose independent)

Radiation-Induced RDCS

Dose dependent (Table 95-1)

The incidence of RDCS increases with higher radiation doses.

The effects of the cumulative dose include

Increased risk when the total dose is >15 Gy

Universal changes noted when the total dose is >40 Gy

Effects of the daily dose: For a given cumulative dose, RDCS is more likely to occur when the dose is administered over fewer fractions.

Coadministration of chemotherapeutic agents increases the risk of RDCS.

Coadministration of oxygen increases the risk of RDCS.

Patient susceptibility is variable.

Host factors, such as innate inflammatory response to treatment, affect the natural course of RDCS.



Cytokine-induced fibrosis

Hematopoietic Stem Cell Transplantation

A unique subset of patients with pulmonary complications

Hematopoietic stem cell transplantation (HSCT) is usually performed after failed courses of chemotherapy and radiation therapy.

Pulmonary complications are the most common cause of morbidity and mortality after HSCT.

Types of injury (Figure 95-1)


Pulmonary edema: 2–3 weeks after transplantation

Diffuse alveolar hemorrhage: 1–6 weeks after transplantation




Gemcitabine Figure 95-1. Timeline of pulmonary toxicity after cancer treatment.


Bronchiolitis obliterans (also known as constrictive bronchiolitis and obliterative bronchiolitis and sometimes bronchiolitis obliterans syndrome if there is no biopsy confirmation) is a severe expression of graft versus host disease occurring months after transplantation.

Pulmonary fibrosis occurring months to years after transplantation

Clinical Features


Acute onset


Productive cough


Drug induced

Chronic nonproductive cough

Progressive exercise intolerance

Radiation induced


Insidious onset

Low-grade fever

Pleuritic chest pain

Pleural rub

Overlying skin erythema


Develops over 6–24 months

Can be associated with pulmonary hypertension if severe

Generally confined to the target area

Stable by 18–24 months


Pulmonary edema

Rapid onset of dyspnea

Recent weight gain

Bibasilar crackles


Diffuse alveolar hemorrhage

Sudden onset of progressive dyspnea



Nonproductive cough

Bronchiolitis obliterans

Gradual-onset dyspnea


Obstructive defect at spirometry

Features that may be present with all causes





Supplemental oxygen requirement

Recurrent pneumonia

Differential Diagnosis

Cancer survivors may be affected by respiratory problems common among the general pediatric population.

Allergies (asthma)


Autoimmune issues

Secondary cancer

Diagnostic Considerations

Chest radiographs may demonstrate

Diffuse alveolar or interstitial involvement (drug induced, edema, or posthemorrhagic) (Figure 95-2)

Focal involvement (targeted radiation)


Normal findings (common with early bronchiolitis obliterans)

Lung computed tomographic (CT) images may demonstrate

Early evidence of parenchymal disease

Findings in bronchiolitis obliterans

Decreased lung attenuation, mostly in the lower lobes (the most common CT finding in bronchiolitis obliterans)

Segmental or subsegmental bronchial dilation

Decreased peripheral vascularity

Centrilobular nodules

Nonhomogeneous air trapping on exhalation images

Pulmonary function testing (PFT) may include

Spirometry results that show obstructive disease

Lung volume testing results that show restrictive disease

Diminished diffusion capacity

Exercise-induced hypoxia and intolerance


Figure 95-2. Acute bleomycin toxicity in a 14-year-old girl with persistent cough who had undergone treatment for Hodgkin lymphoma. A. Frontal chest radiograph demonstrates diffuse, ill-defined parenchymal markings. B. Follow-up radiograph obtained 2 years later shows resolution of toxic changes.

Lung biopsy findings may include

Drug-induced disease

Increased numbers of fibroblasts

Type II cell hyperplasia

Interstitial thickening

Blood in >30% of alveolar surfaces in diffuse alveolar hemorrhage

Fibrosis, found in radiation-induced injury

Inflammatory-cell small-airway infiltrate, typically sparing the interstitium, found in bronchiolitis obliterans


Withdraw the offending agent if symptoms are acute.

As-yet unproven efforts to cease inflammatory progression have included

Systemic corticosteroids

Inhaled steroids



Fluticasone-azithromycin-montelukast combination

Supportive care

Expected Outcomes/Prognosis

Most cancer survivors will not experience pulmonary toxicity.

Many survivors with pulmonary manifestations have subclinical disease that does not limit daily activity.

The most common chronic manifestations include chronic cough, lung fibrosis, recurrent pneumonia, and oxygen requirement (Figure 95-3).

Cumulative incidence of pulmonary mortality is 1.2% at 35 years after cancer diagnosis.


Figure 95-3. Incidence of pulmonary complications over time for pediatric cancer survivors, including A. any pulmonary condition, B. asthma, C. chronic cough, D. emphysema, E. need for extra oxygen, F. lung fibrosis, and G. recurrent pneumonia. From Dietz AC, Chen Y, Yasui Y, et al. Risk and impact of pulmonary complications in survivors of childhood cancer: a report from the childhood cancer survivor study. Cancer. 2016;122(23):3687–3696. Copyright 2016 American Cancer Society.

When to Refer

Early referral to a pulmonologist is indicated if a childhood cancer survivor has any of the symptoms consistent with toxicity. It is important to ensure accurate diagnosis, treatment of reversible causes, and potential abatement of progression.

Monitoring and Prevention

Routine PFT

Preoperative evaluation

Resources for Families

Childhood Cancer Survivor Study: An Overview (National Cancer Institute).

Late Effects of Treatment for Children’s Cancer (CureSearch).

Clinical Pearls

RDCS is a common complication of childhood cancer treatment.

The cumulative incidence of RDCS increases over time.

RDCS can result from infection, chemotherapy, radiation therapy, or consequences of the cancer itself.

Symptoms of RDCS are often slow and insidious in onset.

Early referral to a pulmonologist is recommended at the earliest signs that are concerning for RDCS.

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Aug 22, 2019 | Posted by in PEDIATRICS | Comments Off on Respiratory Disorders in Cancer Survivors

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