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
•Many patients remain asymptomatic for years.
•Incidence measures vary; the prevalence of RDCS may be as high as 30%.
•Possible causes of RDCS include
•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)
•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)
•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.
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
▪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
—Chronic nonproductive cough
—Progressive exercise intolerance
▪Pleuritic chest pain
▪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
▪Rapid onset of dyspnea
▪Recent weight gain
▪Sudden onset of progressive dyspnea
▪Obstructive defect at spirometry
•Features that may be present with all causes
—Supplemental oxygen requirement
Cancer survivors may be affected by respiratory problems common among the general pediatric population.
•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
▪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
▪Increased numbers of fibroblasts
▪Type II cell hyperplasia
—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
•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.
•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
Resources for Families
•Childhood Cancer Survivor Study: An Overview (National Cancer Institute). www.cancer.gov/types/childhood-cancers/ccss
•Late Effects of Treatment for Children’s Cancer (CureSearch). curesearch.org/Late-Effects-of-Treatment-for-Childhood-Cancer
•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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CHAPTER 89: RESPIRATORY DISORDERS ASSOCIATED WITH COLLAGEN VASCULAR DISEASE
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CHAPTER 90: VASCULITIS-RELATED RESPIRATORY DISORDERS
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CHAPTER 91: GRANULOMATOUS RESPIRATORY DISORDERS
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CHAPTER 93: RESPIRATORY DISORDERS ASSOCIATED WITH CEREBRAL PALSY AND NEURODEGENERATIVE DISEASES
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CHAPTER 94: RESPIRATORY DISORDERS ASSOCIATED WITH NEUROMUSCULAR DISEASE
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CHAPTER 95: RESPIRATORY DISORDERS IN CANCER SURVIVORS
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