Respiratory Disorders in Cancer Survivors

Chapter 95


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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)


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.


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


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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


Diffuse alveolar hemorrhage


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


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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


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.


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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). 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.



Part VII Bibliography


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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