Respiratory Disorders in Cancer Survivors
Matthew Schefft, DO, MSHA, FAAP, and H. Joel Schmidt, MD, FAAP, FCCP
Introduction/Etiology/Epidemiology
•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
—Neuroblastoma
—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
—Infections
—Drug-induced origins
—Radiation therapy
—Surgery
—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.
Pathophysiology
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)
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.
•Mechanisms
—Cytotoxicity
—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)
—Acute
▪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.
—Chronic
▪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
•Infectious
—Acute onset
—Fever
—Productive cough
—Hypoxia
•Drug induced
—Chronic nonproductive cough
—Progressive exercise intolerance
•Radiation induced
—Pneumonitis—early
▪Insidious onset
▪Low-grade fever
▪Pleuritic chest pain
▪Pleural rub
▪Overlying skin erythema
—Fibrosis
▪Develops over 6–24 months
▪Can be associated with pulmonary hypertension if severe
▪Generally confined to the target area
▪Stable by 18–24 months
•HSCT
—Pulmonary edema
▪Rapid onset of dyspnea
▪Recent weight gain
▪Bibasilar crackles
▪Hypoxemia
▪Sudden onset of progressive dyspnea
▪Fever
▪Hypoxemia
▪Nonproductive cough
—Bronchiolitis obliterans
▪Gradual-onset dyspnea
▪Wheezing
▪Obstructive defect at spirometry
•Features that may be present with all causes
—Malaise
—Dyspnea
—Tachypnea
—Cough
—Supplemental oxygen requirement
—Recurrent pneumonia
Differential Diagnosis
Cancer survivors may be affected by respiratory problems common among the general pediatric population.
•Allergies (asthma)
•Infection
•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)
—Atelectasis
—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
•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
Management
•Withdraw the offending agent if symptoms are acute.
•As-yet unproven efforts to cease inflammatory progression have included
—Systemic corticosteroids
—Inhaled steroids
—Etanercept
—Azithromycin
—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.
•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). 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
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.
CHAPTER 86: PULMONARY COMPLICATIONS OF IMMUNE DEFICIENCIES
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CHAPTER 87: RESPIRATORY DISORDERS ASSOCIATED WITH SICKLE CELL DISEASE
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CHAPTER 88: RESPIRATORY CONSIDERATIONS IN CHILDREN WITH CONGENITAL HEART DISEASE
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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 92: RESPIRATORY DISORDERS ASSOCIATED WITH GASTROINTESTINAL AND HEPATIC DISEASE
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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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