Pulmonary Complications of Anticancer Treatment

Pulmonary Complications of Anticancer Treatment

47 

Mitchell Machtay and Catalina V. Teba

S UMMARY

OF

K EY

P OI NT S

Radiation-Induced Lung Injury (Radiation Pneumonitis or Fibrosis)

• Risk factors include radiation dose and volume of lung irradiated, which may be expressed as mean lung dose or as the Vx, that is, the percentage of normal lung tissue irradiated to a dose above a certain threshold dose. • Older age, comorbidities (including chronic obstructive pulmonary disease), and low performance status are risk factors. • The location of the tumor is a risk factor; irradiation of lower lobe primary lung tumors may carry a higher risk than irradiation of other tumors, although this may reflect the higher lung volume irradiated with lower lobe tumors. • Biological factors can carry risk, including levels of circulating cytokines such as transforming growth factor–β and interleukin-6. • The predominant symptoms are dyspnea and hypoxia, especially upon exertion. • Fever (usually low grade if present at all), cough, pleuritic chest pain, and other pulmonary symptoms also frequently occur. • Diffusing capacity of the lung for carbon dioxide is the most sensitive pulmonary function. • Interstitial or ground-glass infiltrate usually corresponds to the irradiated volume. Consolidation, bronchiectasis, or pleural effusion may also be seen, particularly in later stages. • Findings at bronchoscopy are unremarkable. (Bronchial lavage may reveal lymphocytosis.)

• Pulmonary embolism, infection, and recurrent or progressive tumor must be ruled out. These conditions can coexist with and mimic radiation pneumonitis. • Response to corticosteroids is usually relatively rapid, at least for acute pneumonitis. • Prevention is far more important than treatment. Patients must be selected carefully for thoracic radiation, and irradiated volumes must be limited. • Corticosteroids are very useful in the management of acute and subacute pneumonitis, although they have no prophylactic or therapeutic value in the management of long-term radiation fibrosis. • A pulmonologist should be consulted for all grade 3 cases and most grade 2 cases. • Oxygen should be administered as indicated to prevent hypoxia. • Corticosteroids should be introduced at a relatively high dose (60 mg/day of prednisone), with slow tapering (over several weeks to months) for severe grade 2 or any grade 3 radiation pneumonitis. • If prolonged corticosteroid treatment is anticipated, prophylaxis against corticosteroid complications is needed, including gastrointestinal, infectious, and osteoporosis prophylaxis and dietary and pharmacologic management of hyperglycemia. • Antibiotics, bronchodilators, diuretics, and anticoagulation should be used as indicated for coexisting cardiopulmonary illnesses.

Drug-Induced Lung Injury

• Among the cytotoxic therapies, bleomycin, nitrosoureas, and

mitomycin or combinations of several potentially pneumotoxic agents that on their own may only have modest pneumotoxicity (e.g., gemcitabine and weekly docetaxel) are risk factors. • Bone marrow transplantation/ high-dose chemotherapy with or without total-body irradiation is a risk factor. • Immunotherapy may induce pulmonary toxicity, particularly combinations of multiple immunotherapeutic agents (e.g., an anti-PD1 agent plus an anti-CTLA4 agent). • Concurrent or recent thoracic radiation therapy is a risk factor. • Poor baseline pulmonary function is a risk factor. • Dyspnea and hypoxemia are predominant, but a wide range of possible symptoms exists. • Interstitial or ground-glass infiltrate usually is diffuse throughout both lungs and may be worse in the lower lobes. • Findings at bronchoscopy are unremarkable. (Bronchial lavage may reveal lymphocytosis.) • Pulmonary embolism, infection, and progressive tumor must be ruled out and may coexist with drug-induced lung injury. • Injury is usually, but not universally, responsive to corticosteroids; it is less likely to respond well to steroids than radiation pneumonitis but more likely to respond well than late radiation fibrosis. • When the diagnosis is suspected, the suspected causative agent should be discontinued. Continued

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716 Part II: Problems Common to Cancer and Therapy

• Consultation with a pulmonologist is necessary. • Oxygen should be administered as indicated to prevent hypoxia. (High fraction of inspired oxygen levels may be dangerous in bleomycin-related pneumonopathy.)

• High doses of corticosteroids (≥60 mg/day of prednisone) with slow taper may be needed for severe grade 2 or any grade 3 pneumonitis. • If prolonged corticosteroid treatment is anticipated, prophylaxis against corticosteroid complications entails gastrointestinal, infectious and

understanding of and intervention against the complex molecular processes that cause and maintain these pathologic states.

Although they are relatively uncommon, pulmonary disorders are among the most feared complications of anticancer therapy. Of course, systemic therapy and radiotherapy should only be performed when benefits of treatment outweigh the risks, and therapies should use an optimized minimum dose to achieve therapeutic goals. Many patients with cancer are elderly and have one or more underlying comorbidities; therefore a relatively minor insult to the lungs can result in respiratory failure and death. The two major categories of pulmonary complications are radiation pneumonopathy (RP), also known as radiation-induced lung toxicity (RILT) and drug-induced pneumonopathy. These conditions do not include other major categories of pulmonary disease in patients with cancer, such as pulmonary embolism and infection. Nor do they include anatomic complications of tumor and medical-surgical interventions, such as pulmonary hemorrhage and fistula. Radiation therapy or chemotherapy contributes to those multifactorial problems of the respiratory system, but these topics are covered elsewhere in this textbook. This chapter focuses on direct lung injury from radiation or systemic therapy. Radiation pneumonopathy and drug-induced pneumonopathy share several important features; most notably, they are usually processes of the interstitium of the lung and thus can cause marked impairment of gas exchange and dyspnea. Corticosteroids are the mainstay of management of both types of pneumonopathy but may provide only temporary relief and are associated with their own toxicities. Better techniques for avoiding treatment-related pneumonopathy—and better therapy for established pneumonopathy—will come only from improved

A

osteoporosis prophylaxis and dietary or pharmacologic management of hyperglycemia. • Antibiotics, bronchodilators, diuretics, and anticoagulation should be administered to manage coexisting cardiopulmonary illnesses.

PULMONARY TOXICITY OF THORACIC RADIATION THERAPY Thoracic radiation is probably the most important cause of pulmonary toxicity in oncology. Lung toxicity from radiation is a clinically relevant issue for lymphoma, breast cancer, bone marrow transplantation (BMT), esophageal cancer, and lung cancer. Fig. 47.1 illustrates two different cases of radiation pneumonitis and their sequelae. The mechanisms behind RILT remain poorly understood despite decades of study. A detailed review of the histopathological and molecular events occurring in RP is beyond the scope of this chapter; several excellent reviews have been published.1,2 Irradiation damages endothelial cells, epithelial cells, and reticuloendothelial cells within the lung through several mechanisms, including apoptosis and induction of stress-response genes. It is now generally agreed that cytokines such as transforming growth factor–β (TGF-β) play a major role in promoting RP, including development of long-term fibrosis.3,4 It can be difficult histopathologically or molecularly to differentiate established radiation lung injury from other forms of end-stage lung disease, such as idiopathic pulmonary fibrosis, drug-induced injury, and even very advanced chronic obstructive pulmonary disease (COPD). Traditional clinical understanding of radiation induced lung injury recognizes two distinct syndromes: radiation pneumonitis (acute or subacute) and radiation fibrosis of the lung (late). Radiation

B

Figure 47.1  •  Case examples of radiation pneumonopathy. (A) This patient was treated with concurrent chemoradiotherapy (45 Gy) for limited stage

small cell lung cancer. About 2 months after treatment, she presented with cough and mild dyspnea on exertion (grade 2 by Common Terminology Criteria version 4 [CTCv4] criteria). Imaging showed infiltrates as shown; these corresponded quite precisely to the irradiated volume (inset). Of note, a positron emission tomography scan shows moderately increased fluorodeoxyglucose uptake. The patient’s symptoms responded dramatically to steroids. (B) This patient was treated with concurrent chemoradiotherapy (63 Gy) for stage III non–small cell lung cancer of the right upper lobe, hilum, and mediastinum. The tumor responded well, but about 6 months after treatment, progressive opacification of the right hemithorax was noted, along with pleural effusion. Symptoms, including dyspnea and cough, were grade 2 by CTCv4 criteria and improved with steroids but worsened when steroids were tapered. The decision was made to proceed with an exploratory thoracoscopy, both for diagnostic purposes (to rule out recurrent tumor) and therapeutic purposes (pleurodesis). Pathology showed no viable tumor, only intense inflammation and evolving fibrosis. Pleurodesis was successful. The patient continues monitoring and treatment with intermittent oxygen and steroids and antibiotics for acute exacerbations of symptoms.

Pulmonary Complications of Anticancer Treatment  •  CHAPTER 47 717

pneumonitis is characterized by intense interstitial inflammation and alveolar exudate. It develops over several weeks to months after irradiation and may resolve in 6 to 12 months, leaving behind a variable degree of pulmonary fibrosis. Radiation pulmonary fibrosis may, however, develop in the absence of clinically evident acute pneumonitis beginning several months after radiotherapy and progressing over years. Radiation pneumonitis usually responds well to corticosteroids; in contrast, corticosteroids do not influence the progression of radiation pulmonary fibrosis. In most cases, RP is confined to the regions of the lung within the radiation field or portal. This conventional wisdom has been challenged by several researchers who have found evidence of “out-of-field” radiation injury, which may be manifested in a syndrome similar to bronchiolitis obliterans with organizing pneumonia.5 Autoimmunity has been hypothesized as a mechanism of out-of-field radiation lung injury, with the possibility that localized lung damage triggers diffuse lymphocyte-mediated hypersensitivity against pulmonary self-antigens.6 Radiation lung injury may have any of a variety of clinical presentations, but the hallmark symptom is dyspnea out of proportion to other findings. This is associated with a decline in diffusing capacity of the lung for carbon monoxide (DLCO) pulmonary function test result. The most common imaging finding is an interstitial infiltrate corresponding to the radiation portals, but it is not unusual to find consolidation, nodularity, or even pleural effusions. The extent of radiographic findings does not necessarily correlate with the extent of symptoms or the patient’s clinical course. This makes the differential diagnosis among recurrent and possibly progressive cancer, infection, and radiation lung injury extremely difficult, particularly in patients with lung cancer.

Incidence of Radiation Lung Injury and Predictive Factors

Total lung volume (%)

Understanding the true incidence of RP is complicated by multiple factors, including ambiguities in defining and scoring this disease.7,8 Kocak and colleagues7 found that 28% of their suspected RP had confounding medical conditions that made the clinical diagnosis uncertain. Yirmibesoglu and colleagues8 concluded that 48% of RP cases were “hard to score” (versus “unambiguous”) because of confounding factors (e.g., tumor progression, acute exacerbation of COPD, and infection). Historically, RP was graded or scored on a scale developed by the Radiation Therapy Oncology Group (RTOG), dating back to the early 1970s.9 There are limitations to this system, including its arbitrary cutoff of 90 days between acute and late RP. The modern scale is

integrated with the general scoring system of toxicities and adverse events (common terminology criteria, i.e., CTC). The CTC system is now at version 4 (CTCv4), and its definitions and grading for select pulmonary events are shown in Table 47.1 (https://evs.nci.nih.gov/ ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf ). Separate scales are no longer used for early and late radiation therapyrelated events. Grade 3 pneumonitis is defined as “severe symptoms,” justifying the need for supplemental oxygen therapy; Grade 4 is life-threatening respiratory failure, and grade 5 is death. Grade 1 is “asymptomatic,” and grade 2 refers to symptomatic pneumonitis requiring intervention. The limitations of the system are that it is inherently subjective and based on physician assessment rather than a patient-reported-outcome. Nonetheless, the CTCv4 definitions provide a framework for reporting and analyzing this disease and its associated symptoms. The most important factor influencing development of clinically relevant radiation lung injury is the volume of lung irradiated; this issue is extensively discussed in the radiation oncology literature.10-14 The lung is considered a parallel-architecture organ, meaning that destruction of a small percentage of it should not cause overall organ dysfunction. This contrasts with organs such as the spinal cord, considered to be series architecture, in which destruction of one region leads to irreversible dysfunction downstream from the injury.15 The series-architectural model applies to some substructures within the lung, such as major bronchi or pulmonary vessels, in which the result of injury to a small volume can be catastrophic (e.g., fistula and massive hemorrhage). For a given patient treated with radiation, lung radiation dosimetry can be expressed as a dose-volume histogram (DVH) graph (see Fig. 47.2 for an example). The percentage of lung irradiated can be expressed as the “Vx,” where x is a certain dose in Gy. V20 indicates the percentage of a patient’s total lung volume irradiated to a dose of at least 20 Gy; V5 describes the percentage of lung irradiated to at least 5 Gy. Mean lung dose (MLD), expressed in Gy, can also be calculated. There are no threshold values for these parameters; the risk of RP rises significantly, sometimes steeply, as these values increase. The definitions of “acceptable” and “optimal” dose or volumes differ greatly based on the clinical scenario. An “acceptable” V5/V20/MLD and DVH for treating a bulky lung cancer may be “unacceptable” for treatment of early stage breast cancer. Of note, irradiation of the entire lung volume (bilateral lungs) is uncommon today, except as part of total-body irradiation for selected BMT conditioning regimens or as part of treatment of selected pediatric tumors.16 Whole ipsilateral lung irradiation is occasionally used as part of treatment for mesothelioma. As reviewed by Sampath and

100 90 80 70 60 50 40 30 20 10 0 0 3 6 9 13 16 19 22 25 28 32 35 38 41 44 47 50 54 57 60 63 66 69

Dose (Gy)

Figure 47.2  •  Graphic representation (yellow curve) of dose-volume histogram for total lung volume irradiated to a nominal dose of 63 Gy in a patient

with lung cancer. In this case, the V20 (the percentage of total lung volume receiving >20 Gy) is approximately 36%, which is considered a moderate-risk dose level for clinical radiation pneumonopathy.

718 Part II: Problems Common to Cancer and Therapy

Table 47.1  Common Terminology Criteria Version 4a Select Common Terminology Criteria for Adverse

Events Related to the Lung

Event

Grade 1b

Grade 2

Grade 3

Grade 4

Acute respiratory distress syndrome

N/A

N/A

Atelectasis

Asymptomatic clinical or diagnostic observations only; intervention not indicated

Life-threatening respiratory or hemodynamic compromise; intubation required Life-threatening respiratory or hemodynamic compromise; intubation or urgent intervention indicated

Carbon monoxide diffusion capacity (DLCO)

3–5 units below LLN; for follow-up, a decrease of 3–5 units (mL/min/mm Hg) below the baseline value

Symptomatic (e.g., dyspnea, cough), medical intervention indicated (e.g., chest physiotherapy, suctioning); bronchoscopic suctioning 6–8 units below LLN; for follow-up, an asymptomatic decrease of >5–8 units (mL/ min/mm Hg) below the baseline value

Present with radiologic findings; intubation not required Oxygen indicated; hospitalization or elective operative intervention indicated (e.g., stent, laser)

Cough

Mild symptoms; nonprescription intervention indicated Shortness of breath with moderate exertion

Dyspnea

FEV1 Hypoxia

99%–70% of predicted value N/A

Pleural effusion (nonmalignant)

Asymptomatic; clinical or diagnostic observations only; intervention not indicated

Pneumonitis or pulmonary infiltrates

Asymptomatic; clinical or diagnostic observations only; intervention not indicated

Pneumothorax

Asymptomatic; clinical or diagnostic observations only; intervention not indicated

Pulmonary fibrosis Mild hypoxemia; radiologic pulmonary fibrosis <25% of lung volume

N/A Asymptomatic decrease of >8 units drop; >5 units drop along with the presence of pulmonary symptoms (e.g., > grade 2 hypoxia or > grade 2 or higher dyspnea) N/A Moderate symptoms, medical Severe symptoms; limiting self-care ADLs intervention indicated; limiting instrumental ADLs Shortness of breath at rest; Life-threatening Shortness of breath with limiting self-care ADLs consequences; urgent minimal exertion; limiting intervention indicated instrumental ADLs 60%–69% of predicted value Decreased O2 saturation with exercise (e.g., <88% pulse oximetry); intermittent supplemental oxygen Symptomatic, intervention indicated (e.g., diuretics or limited therapeutic thoracentesis) Symptomatic; medical intervention indicated; limiting instrumental ADLs Symptomatic; intervention indicated (e.g., tube placement without sclerosis) or temporary chest tube Moderate hypoxemia; evidence of pulmonary hypertension; radiographic pulmonary fibrosis 25%–50%

≤49% of predicted value Life-threatening airway compromise; urgent intervention indicated (e.g., tracheotomy or intubation) Symptomatic with respiratory Life-threatening respiratory or hemodynamic compromise; distress and hypoxia; surgical intubation or urgent intervention including chest tube or pleurodesis indicated intervention indicated Life-threatening respiratory Severe symptoms; limiting compromise; urgent self-care ADLs; oxygen intervention indicated (e.g., indicated tracheotomy or intubation) Life-threatening Sclerosis or operation (or both) indicated; hospitalization consequences; urgent intervention indicated indicated 50%–59% of predicted value Decreased O2 saturation at rest (e.g., <88% pulse oximetry or PaO2 ≤55 mm Hg)

Severe hypoxemia; evidence of right-sided heart failure; radiographic pulmonary fibrosis >50%–75%

Life-threatening consequences (e.g., hemodynamic or pulmonary complications); intubation with ventilator support indicated; radiographic pulmonary fibrosis >75% with severe honeycombing

a This is an abbreviated or abridged version of the Common Terminology Criteria, Version 4; the complete version can be found at http://evs.nci.nih.gov/ftp1/CTCAE/About. html. b As with the older scoring systems, grade 5 (not shown) is death, and grade 0 is the absence of the particular toxicity. Note that for some adverse events, grades 1 to 2 (mild to moderate) might not be applicable (e.g., acute respiratory distress syndrome). Conversely, for some adverse events, grade 4 (life threatening) might not be applicable (e.g., cough). ADL, Activity of daily living; FEV1, forced expiratory volume in one second; LLN, lower limit of normal; N/A, not applicable; PaO2, partial arterial oxygen tension.

colleagues,17 the therapeutic index for whole- or bilateral-lung irradiation is extraordinarily narrow and highly dependent on total dose, fractionation, partial lung transmission shielding, and dose rate. A dose of 12-Gy total body irradiation has an approximately 11% rate of severe pneumonitis compared with approximately 2% when lung transmission shielding is used to reduce the lung dose to 6 Gy. At the other extreme, irradiation of small lung volumes, as with stereotactic body radiation therapy (SBRT, also known as radiosurgery)

for early-stage non–small cell lung cancer rarely results in high-grade RP despite its use in a compromised patient population.18,19 A recent randomized trial showed that SBRT had a lower rate of any-grade RP than conventional radiotherapy (19% versus 34%).20 Similarly, in tangential irradiation of the breast (after lumpectomy) or chest wall (after mastectomy), the risk of clinically significant RP is only about 1%, increasing to approximately 5% with the addition of irradiation of the regional (axillary or supraclavicular) nodes.21 An

Pulmonary Complications of Anticancer Treatment  •  CHAPTER 47 719

association between dose-volume irradiated and pneumonitis risk has also been shown in patients treated for esophageal carcinoma.22 Level I evidence of a strong relationship between RP and the volume irradiated comes from a randomized trial from China.23 The incidence of RP was significantly reduced from 29% to 17% with the use of “involvedfield” radiotherapy despite higher tumor radiotherapy doses in the involved field arm. Recent analyses suggest that in lung cancer treatment, radiation dose-volume exposure to the heart may be a contributing factor to RP.24,25 The recently completed randomized trial RTOG-0617 demonstrated unexpectedly worse survival with dose-escalated radiotherapy (74 Gy) versus more-standard 60 Gy dose, and heart–lung toxicity is hypothesized as a reason for this result.26 It has been suggested that intensity modulated radiation therapy (IMRT) reduces the risk of clinically significant RP, compared with older forms of radiotherapy.27 Although radiation dose-volume parameters are the major predictor of RP, the addition of systemic therapy must also be considered. In particular, concurrent gemcitabine with thoracic radiotherapy has a high rate of RP.28 Several other drugs, most notably the anthracyclines (e.g., doxorubicin), methotrexate, and bleomycin, should also be considered contraindicated during thoracic radiotherapy. Concurrent thoracic radiotherapy plus a taxane (paclitaxel or docetaxel) is commonly used and generally safe, although it has been suggested that the risk of RP might be slightly higher than with the cisplatin–etoposide combination.29 Fewer data exist regarding other systemic agents, including biological agents. Their use concurrently with thoracic radiotherapy should be viewed with caution. These agents are discussed briefly later in this chapter. Nontreatment factors that appear to be predictive of radiation lung injury have been extensively studied. A meta-analysis of 31 published studies showed that the most significant risk factors were older age, tumor volume location in the mid or lower lung, and presence of comorbidity.30 Interestingly, there was the suggestion of a “protective” effect of ongoing smoking. Cardiac comorbidity may be a risk factor for RP,31 in keeping with the suggestion that radiation dose to the heart may contribute to RP. Overall performance status has also been shown to correlate with development of clinical RP.32 Preexisting interstitial lung disease33 appears to predict for RP. There is recent interest in analyzing imaging, particularly FDG-PET (fluorodeoxyglucose–positron emission tomography) scans, for radiomic findings that may predict RP. There has been a suggestion that higher pretreatment standardized uptake value (SUV, a quantitative measure of the level of FDG) within “normal” lung parenchyma may predict for future RP.34,35 One small study suggested that an early FDG-PET scan in the first few weeks of radiotherapy might predict for RP based on elevation of SUV in lung tissue outside of the gross tumor.36 The risk of RILT may be higher in patients with certain genetic variations. Studies have explored ataxia-telangiectasia mutated (ATM) gene37 or TGFβ1 gene polymorphisms38,39 as they relate to radiation lung injury. Evaluation of these molecular metrics is not yet considered clinically standard.

Diagnosis and Management of Radiation Pneumonitis: Acute and Subacute With modern, three-dimensional conformal, multifield radiation therapy, SBRT, or IMRT, it is not possible to simply look for pathognomonic rectangular infiltrates on a chest radiograph to confirm RP. A patient who has undergone radiation treatment (particularly if a large volume of lung was irradiated to a dose >20 Gy) and has symptoms should undergo high-resolution computed tomography (CT) scanning. CT angiography may also be indicated to rule out a pulmonary embolism. Imaging will typically reveal an interstitial infiltrate, possibly ground-glass appearance, which can be very difficult to distinguish from an infection or recurrent or progressive tumor. Suspected moderate to severe RP should be evaluated by a pulmonologist for consideration of bronchoscopy to rule out infection, particularly if fever is present.40

Pulse oximetry, even arterial blood gas testing, should be performed to assess the need for supplemental oxygen. Pulmonary function testing may be useful for assessing the severity of gas-exchange abnormalities, such as differentiating grade 2 versus grade 3 pneumonopathy among patients who are not hypoxemic at rest. The tests and procedures to be considered in the evaluation of patients with cancer who have suspected pneumonopathy are summarized in Table 47.2. This workup should be considered appropriate for either suspected radiation-related or chemotherapy-related pneumonopathy. If the clinical manifestations and test results are consistent with grade 2 or greater RP, administration of corticosteroids should be instituted in most cases. Controlled randomized trials of corticosteroids for RP have not been conducted with human subjects. However, the efficacy of corticosteroids has been well established in nonrandomized clinical studies41 and in preclinical models.42 No single “standard” dose schedule exists for steroid therapy for persons with RP; the exact schedule must be tailored to the individual patient. In general, for severe (grade 3) RP, prednisone, approximately 1 mg/kg/day, is indicated for 2 weeks. Most clinicians suggest starting with 60 mg/day of prednisone. After approximately 2 weeks, the dose should be tapered gently, by approximately 10 mg every 2 weeks. Brief hospitalization for intravenous administration of steroids may be indicated. Early onset of RP after the completion of radiotherapy may predict a more virulent course and therefore might require a more aggressive management approach.43 Moderate RP (grade 2) may be effectively managed with somewhat lower initial doses of steroids (e.g., 0.5–0.75 mg/kg/day of prednisone); however, the patient must be evaluated frequently to ascertain that his or her condition is not progressing to grade 3 or worse RP. It is not unusual for patients to have a symptomatic relapse in the setting of steroid taper.44 If relapse occurs, it is important to rule out concomitant infection. If the diagnosis of recurrent RP is confirmed, the steroid dose should be increased and titrated accordingly. With these guidelines, the typical patient with grade 3 or very intense grade 2 radiation lung injury may require steroids for up to 4 months. Some patients need steroids for considerably longer, although the benefit after 6 months is uncertain (when RP has generally resolved and becomes superseded by fibrosis). At the outset, the physician should explain to the patient the potential need and implications of longer term steroid use. A proton pump inhibitor or histamine2 blocker should be prescribed to counteract gastritis. Consideration should be given to evaluation for and medical prophylaxis against osteoporosis. Patients should be counseled about exercise (as tolerated by their pulmonary symptoms) and diet to minimize problems with steroidinduced hyperglycemia, muscle wasting, and other metabolic or systemic problems associated with steroids. Blood chemistry values, including fasting glucose, liver function tests, and albumin, should be checked periodically. If a diuretic is being used with steroids, it is important to check serum electrolyte levels frequently. Adrenal insufficiency should also be considered when steroids are tapered, and some patients may require long-term or even lifelong maintenance steroid replacement therapy. It is uncertain whether a low-dose “prophylactic” antibiotic should be prescribed. In any given patient with interstitial pneumonitis after thoracic radiotherapy, it can be very difficult to entirely rule out a concomitant infection, particularly if bronchoscopy or another invasive diagnostic procedure was not performed.40 In light of the profound lymphopenia that many patients have after chemoradiation therapy and steroid treatment, as with typical concurrent paclitaxel-radiation therapy regimens, it might be appropriate to prescribe an every-otherday dose of trimethoprim–sulfamethoxazole (Bactrim) when starting high-dose steroids for pneumocystis prophylaxis.45,46 If findings of a chest CT image suggest the presence of coexistent active infection, broader and more intense antibiotics are indicated. The patient should undergo bronchoscopy if no improvement occurs after several days of steroid and antibiotic therapy.

720 Part II: Problems Common to Cancer and Therapy

Table 47.2  Evaluation of Patients With Cancer Who Have Pulmonary Symptoms (Especially Dyspnea)

and Suspected Radiation or Chemotherapy Pneumonopathy

Studya

Rationale BASIC, MINIMAL WORKUP

CT of chest, preferably both with and without contrast

Assess extent, appearance, and location of infiltrates or effusions; correlate with radiation therapy or surgical data; rule out recurrent or progressive cancer and other causes of dyspnea Assess degree of hypoxia and possible need for supplemental oxygen Assess extent and type of pulmonary function (radiation or drug pneumonitis is a restrictive pattern, with DLCO often markedly abnormal compared with baseline levels) Rule out leukocytosis and leukopenia (possible signs of infection), anemia, and hepatic or renal insufficiency (all factors that can lead to pulmonary distress)

Pulse oximetry Pulmonary function testing (spirometry and DLCO) CBC and differential; chemistry panel

EXTENDED WORKUPb High-resolution pulmonary embolus protocol CT scan, V/Q scan, and/or pulmonary angiogram

Rule out pulmonary embolism

Electrocardiogram Blood test for B-type natriuretic peptide Arterial blood gas testing

Rule out cardiac ischemia and dysrhythmia Rule out CHF, which can occur concurrently with pneumonopathy More accurate measure of oxygenation than pulse oximetry; measurement of pH and CO2 levels Rule out sepsis and endocarditis Rule out infection (particularly if atypical infection is suspected) and assess for possible recurrent cancer Assessment of status of the cancer; possible role as adjuvant form of imaging the extent of lung injury Definitive diagnosis but high-risk procedure; avoid if diagnosis is highly likely and response to steroids is good

Blood cultures Bronchoscopy PET/CT scan Open lung biopsy (e.g., thoracoscopic biopsy)

a

Notice that chest radiograph is not a sufficiently sensitive or specific test to warrant inclusion in this table. An extended workup should be performed if the diagnosis is in question or if there is a possibility of coexisting cardiorespiratory problems. CBC, Complete blood cell count; CHF, congestive heart failure; CT, computed tomography; DLCO, diffusion capacity of the lung for carbon monoxide; PET, positron emission tomography; V/Q, ventilation/perfusion. b

The prognosis of grade 1 to 2 RP is relatively good with meticulous supportive care and the use of steroids as needed. Grade 3 RP, however, at least in patients with lung cancer, has a much worse prognosis.43 It is uncertain whether this worse prognosis is the direct result of RP or coexisting problems, including tumor recurrence and infection. Management of RP that is refractory to steroids or that occurs in a patient who has severe contraindications to steroids is uncertain. The literature includes case reports of the use of antirheumatic medications such as cyclosporine,47,48 but little scientific evidence supports their use. As described in the following sections, patients with RP should receive supportive care based on careful and frequent assessment of their symptoms and risk factors for further complications of their illness.

Management of Radiation Pulmonary Fibrosis: Chronic and Late Radiation pulmonary fibrosis, unlike acute RP, is not relieved with steroids. Some patients undergoing steroid therapy eventually start to experience worsening pulmonary function. This decline may be caused by pulmonary fibrosis but also may be caused at least in part by disorders such as infection, cardiac problems, and pulmonary embolism, and reevaluation is indicated. If it has been more than 6 months since the patient has undergone radiation therapy or chemotherapy, increasing the steroid dose is unlikely to yield benefit. Management of radiation pulmonary fibrosis is supportive. Emphasis is on administration of oxygen; bronchodilator therapy if needed; cardiopulmonary rehabilitation or exercise as tolerated;

avoidance of tobacco and other toxins; and management of comorbid conditions, including cardiac disease. Patients may benefit from a diuretic, particularly if right heart failure is occurring. Correction of anemia should be considered. The clinician should always be vigilant for acute secondary infection(s) requiring empiric antibiotics or, in some cases, bronchoscopy. Similarly, these patients have a risk of acute-on-chronic RP (i.e., radiation “recall” reactions), particularly if exposed to certain systemic drugs. The latter may benefit from steroids.

Further Directions in Management and Trials There is no accepted pharmacotherapy for chronic RP or radiation fibrosis. There is retrospective evidence that radiation lung injury is reduced among patients taking an angiotensin-converting inhibitor,49-51 although this is controversial and not confirmed by any prospective data. Combinations of pentoxifylline with or without vitamin E have been reported to prevent and ameliorate radiation-induced fibrosis in preclinical models. A small randomized trial (47 patients) suggested that pentoxifylline–vitamin E, started with radiotherapy and continued for at least 3 months, was protective against all phases of radiation lung injury.52 As of the writing of this text, the small-molecule tyrosine kinase inhibitor (TKI) nintedanib, a drug the US Food and Drug Administration (FDA) approved for the treatment of idiopathic pulmonary fibrosis, is being tested prospectively against radiation lung injury. Increased understanding of the cytokine-based mechanisms of radiation lung injury may offer opportunities for intervention.53,54

Pulmonary Complications of Anticancer Treatment  •  CHAPTER 47 721

Because TGF-β is thought to be the dominant profibrotic cytokine and possible cause of radiation lung injury, anti–TGF-β agents are being studied. As of the writing of this text, one such agent, the antibody fresolimumab, is in a clinical trial among patients receiving lung SBRT. Currently, however, no molecularly targeted treatments for established radiation lung injury (RP or radiation pulmonary fibrosis) are clinically available. Steroids (for acute RP at least) remain the only known treatment.

PULMONARY TOXICITY OF SYSTEMIC ANTICANCER THERAPIES Many anticancer drugs can cause pulmonary toxicity, with the incidence ranging from less than 1% to more than 30%. The drugs that are most associated with pulmonary toxicity are the cytotoxic agents bleomycin, methotrexate, cytosine arabinoside, mitomycin, and the nitrosoureas (especially carmustine [BCNU]). Biologically targeted and immunotherapeutic agents also have risks of pneumonopathy, although arguably, the incidence and course are even more unpredictable than that for classic cytotoxic agents. Table 47.3 provides a broad categorization of anticancer therapies into high, moderate, and low risks of pneumotoxicity, although any individual patient may experience severe lung problems from any agent. Unlike thoracic radiation therapy, which usually affects only the portion of lung within the radiation field, systemic agents often cause diffuse pneumonitis or other changes. Although druginduced lung injury is relatively rare in comparison with RP, it can be intense and life threatening, particularly if not detected early. As with RP, corticosteroids are commonly used and may be effective, especially in early stages of injury. It is extremely important to rule out alternative and concurrent diagnoses (Table 47.4). Unlike radiation injury, drug-induced lung toxicity can occur at a time when it is possible to discontinue the offending agent. A review of some of the systemic agents associated with pulmonary toxicity follows.

Table 47.3  Anticancer Therapies Categorized by

Cytotoxic Chemotherapy Bleomycin is the chemotherapy drug most commonly associated with lung damage and is well known to concentrate within the lungs. There is an incidence of pneumonopathy, including both pneumonitis and chronic or permanent fibrosis, reported as high as 40%.55,56 The drug is used predominantly in the management of Hodgkin disease and germ cell tumors based on strong level I evidence of its value from high-quality randomized trials. These cancers occur mainly in younger patients with less underlying comorbidity than patients with lung cancer, and the drug is rarely used in other settings, specifically because of its potential for lung damage. There are many similarities between bleomycin lung injury and radiation lung injury, including both pneumonitic and fibrotic phases and the time delay (weeks to months) between treatment and the identification of toxicity. Bleomycin-induced lung infiltrates can be diffuse but may be limited to the basilar and subpleural areas of the lungs.55 As with radiation, dyspnea is the primary symptom of bleomycin lung toxicity, although other symptoms such as cough and fever often occur as well. DLCO is frequently abnormal and should be measured before starting bleomycin and periodically between cycles. There is controversy regarding what would represent a significant enough decline in DLCO to prompt discontinuation of the drug, with some investigators recommend using a 20% threshold cutoff. Regarding the maximal allowable cumulative dose of bleomycin, there is no absolute consensus, but some have suggested 400 units as the limit.56 It is important to note that occasionally, severe or even fatal pneumonopathy can occur with cumulative bleomycin doses less than 100 units. In addition to comorbidities of age and cumulative bleomycin dose, renal insufficiency is an important risk factor because bleomycin is renally excreted. This is of particular concern in patients who may be receiving nephrotoxic agents (e.g., cisplatin, which is commonly used with bleomycin in the treatment of germ cell tumors). Cigarette smoking and a history of thoracic radiotherapy are also risk factors. There is also an important association between bleomycin lung toxicity

Table 47.4  Pneumotoxicity Associated With Use of

Targeted Agents

Risk of Pneumotoxicity

Therapy

Examples

Highly pneumotoxic agents (risk of pulmonary SAE >5%)

Bleomycin, BCNU, mitomycin, interleukins, BMT (with or without TBI), large-volume thoracic radiation therapy (e.g., for stage III lung cancer), surgical resection for lung cancer Methotrexate, busulfan, melphalan, CCNU/ MeCCNU, cyclophosphamide, ifosfamide, fludarabine, gemcitabine, paclitaxel– docetaxel, most TKIs and mTor inhibitors, immune-checkpoint inhibitors, small-volume thoracic radiation therapy (e.g., breast cancer), non–lung cancer oncologic surgery 5-FU, capecitabine, cisplatin/carboplatin, doxorubicin, actinomycin-D, etoposide, topoisomerase inhibitors (topotecan, irinotecan), vinca alkaloids (vincristine, vinblastine, vinorelbine), temozolomide, tamoxifen, aromatase inhibitors for breast cancer, hormonal therapies for prostate cancer, steroids

Moderately pneumotoxic agents (risk of pulmonary SAE≈1%–5%)

Uncommon pneumotoxic agents (risk of pulmonary SAE <1% when given as a single agent)

BCNU, Carmustine; BMT, bone marrow transplantation; CCNU, lomustine; 5-FU, 5-fluorouracil; MeCCNU, semustine; mTor, mammalian target of rapamycin; SAE, serious adverse event; TBI, total body irradiation; TKI, tyrosine kinase inhibitor.

Agent

Pneumotoxicity

Gefitinib, erlotinib Imatinib, dasatinib

Acute interstitial lung disease Pneumonitis, pleural effusions, pulmonary hypertension Acute interstitial pneumonitis Pneumonitis, radiation recall pneumonitis Pulmonary embolus, pulmonary hemorrhage Bronchospasm, bronchiolitis, pulmonary fibrosis Pulmonary interstitial fibrosis, infusionrelated bronchospasm, interstitial pneumonitis Dyspnea, hypoxia, pulmonary hemorrhage (after solid organ transplant) Pneumonitis Interstitial pneumonitis

Crizotinib Sorafenib, sunitinib Bevacizumab Cetuximab, panitumumab Rituximab, ofatumumab Alemtuzumab Ipilimumab Everolimus, temsirolimus Thalidomide/ lenalidomide Bortezomib

Pulmonary embolism, pneumonitis, organizing pneumonia, eosinophilic pneumonia Bronchiolitis obliterans organizing pneumonia

722 Part II: Problems Common to Cancer and Therapy

and exposure to high oxygen concentrations, particularly as part of an operative procedure(s). Patients and their surgeons and anesthesiologists must be informed of the need to limit the fraction of inspired oxygen (FiO2) during any procedure to the lowest level necessary. Extreme caution is advised when supplemental oxygen is being electively prescribed for patients treated with bleomycin, especially those who are currently undergoing or recently finished bleomycin (within less than 12 months) or have documented bleomycin pneumonopathy.57 Bleomycin pneumonitis is rarely fatal; one study estimated a lethality risk of about 3%, with a suggestion that older age was associated with a higher risk for death.58 Most patients achieve complete or nearcomplete recovery.58-62 Corticosteroids may have some benefit,56,59,63 although the data are not as clear as for radiation pneumonitis. Some cases of steroid-responsive bleomycin pneumonitis or fibrosis may represent early hypersensitivity, bronchiolitis obliterans with organizing pneumonia–like events. After bleomycin chemotherapy, survivors may have significant declines in pulmonary function for approximately 6 months, but by 2 years after chemotherapy, few have significant respiratory dysfunction. Although bleomycin is considered the most pneumotoxic cytotoxic chemotherapy agent, many chemotherapeutic, across many classes, are associated with lung injury. Typically, these cause interstitial pneumonitis similar to bleomycin-induced toxicity. Among the antimetabolites, methotrexate is the drug most closely associated with pneumonopathy. Gemcitabine, a more commonly used drug today, is rarely associated with pneumonitis as a single agent, but it can potentiate drug-induced pneumonopathy when combined with pneumotoxic agents such as bleomycin or thoracic radiotherapy. The combination of gemcitabine plus a taxane appears to have increased lung toxicity risk compared with either agent alone. Alkylating agents (e.g., cyclophosphamide) can also be associated with pneumonopathy, particularly when given at high doses for bone marrow or stem cell transplant procedures. It is difficult to isolate the effect of these agents in the transplant setting because these patients sustain numerous other potential insults to the lungs. The subclass of alkylators most associated with lung toxicity are the nitrosoureas (e.g., BCNU), with which pulmonary toxicity is considered potentially dose limiting, and concerns about it have limited the use of this entire class of agents. The typical pattern of lung injury is progressive pulmonary fibrosis, dependent on age and cumulative dose. This does not appear to be a steroid-responsive condition. In other chemotherapeutic classes, mitomycin is known for its potential lung toxicity, with a variety of presentations that may include pleural effusions. Mitomycin-induced lung toxicity is difficult to predict and not clearly dose related, estimated to occur in about 5% of patients, although one study tested patients with serial DLCOs and found that 28% of patients had significant (>20%) decreases in DLCO. Mitomycin-induced pulmonary toxicity is thought to generally be steroid responsive. Anthracycline drugs (e.g., doxorubicin) are well known for their cardiac risk but less associated with direct lung injury. However, the combination with anthracyclines with concurrent thoracic radiotherapy can cause considerable pneumonitis. For example, a randomized trial of concurrent versus sequential chemoradiotherapy, including doxorubicin, for small cell lung cancer was stopped early because of a large number of fatal pneumonopathy events.64 The taxanes similarly have relatively low risk of direct lung injury, although docetaxel may have a slightly higher risk than paclitaxel, and weekly schedules may be more pneumotoxic than every-3-week schedules65; as noted earlier in the radiation section, concurrent taxane–radiotherapy regimens may have a somewhat higher risk of pneumonitis than cisplatin–radiotherapy.

Biologically Targeted Agents Increasingly, cytotoxic therapies such as chemotherapy and radiotherapy are being replaced or supplemented by agents that target cancer cells

through mechanisms independent from direct DNA damage. These drugs may take the form of small-molecule inhibitors of intracytoplasmic or intranuclear biologic molecules, or they may be antibodies against receptors on tumor cells or vascular cells in or around the tumor. Although some of these agents have been used for several decades, they are still quite new compared with conventional chemotherapy or radiotherapy, and thus full toxicity profiles, including lung toxicity risks, are not fully understood. Tyrosine kinase inhibitors against the intracytoplasmic portion of the epidermal growth factor receptor (EGFR), including gefitinib and erlotinib, are among the best studied targeted therapies. Because they are primarily used against lung cancer, there has been substantial interest in studying the effects of these orally administered drugs on the lungs. These anti-EGFR agents are associated with an uncommon but sometimes very severe syndrome of interstitial pneumonitis, with an estimated risk of fatal pneumonitis of approximately 0.6%,66 perhaps higher in the Asian population. It appears that antibodies against the EGFR receptor (e.g., cetuximab) have a lower risk of pneumonopathy than these anti-EGFR TKIs. As of the writing of this chapter, there are now more than 15 FDA-approved TKIs for a variety of cancers. Some are relatively highly specific for a single target (e.g., the BRAF inhibitors vemurafenib and dabrafenib), and others target multiple kinases, including some within tumor cells and some within tumor-associated vascular cells (e.g., sunitinib). A review of each specific agent and its risk of lung toxicity is beyond the scope of this chapter. However, any of the TKIs can cause lung toxicity with a pattern similar to that seen with the antiEGFR agents described earlier, with interstitial lung infiltrates, ground-glass appearance, and dyspnea as the predominant symptom.67 The TKI dasatinib, an inhibitor of BCR-ABL and SRC kinase, has been associated with sterile, exudative pleural effusions in up to 35% of patients, and it can also directly cause pulmonary hypertension. One of the most recently developed TKIs, idelalisib, which directly targets PI3K and is approved for selected recurrent B-cell hematologic malignancies, has been associated with a relatively high rate of pneumotoxicity. This is particularly evident (≤18%) when the drug is combined with additional agents.68 Among the monoclonal antibodies, agents such as rituximab and ofatumumab (anti-CD20 antibodies used in B-cell malignancies) are commonly associated with immediate infusion reactions that may include dramatic respiratory symptoms (e.g., bronchospasm). Acute or subacute pneumonitis and other signs of direct pulmonary injury are less common but have been reported. Vascular-targeted antibodies (e.g., bevacizumab, directed against vascular endothelial growth factor) are associated with a risk of pulmonary hemorrhage, which may be caused by bronchovascular fistula adjacent to gross tumor. Thalidomide and lenalidomide, complex antiangiogenic and immunomodulatory agents, are associated with venous thromboembolic disease and pulmonary emboli; direct lung injury is not especially common with these agents. Drugs that affect the mammalian target of rapamycin (mTOR) may be associated with pneumonitis as a class effect. The etiology is unclear. Clinicopathologic patterns include interstitial pneumonitis with or without fibrosis, bronchiolitis obliterans organizing pneumonia, or alveolar hemorrhage.69 Immune-mediated mechanisms of pneumonitis are supported by lung biopsies, bronchoalveolar lavage findings, and the observed clinical response to corticosteroids. In clinical studies with these agents, including temsirolimus or everolimus, some pneumonitis cases have been severe and occasionally fatal. Radiographic findings consistent with drug-induced pneumonitis were detected in 36% of patients receiving temsirolimus for advanced neuroendocrine tumors and endometrial carcinoma.70 Only half of the patients with radiographic changes had clinical symptoms of pneumonitis, and drug treatment was continued in some cases without worsening of the pneumonitis.70 In a placebo-controlled randomized trial of everolimus for advanced renal cell carcinoma, clinical pneumonitis was suspected in 37 (13.5%) of the 274 patients who received this drug.69

Pulmonary Complications of Anticancer Treatment  •  CHAPTER 47 723

In general, when a diagnosis of biologic-drug-induced pneumopathy is made, after critically considering other diagnoses in a patient presenting with dyspnea, the drug should be permanently discontinued. Steroids should be instituted, and most cases of biologic drug–induced pneumonitis are steroid responsive. The decision on when to challenge with a different agent in a similar class of drugs is highly individualized, and there is little high-level evidence guidance thus far from the literature.

Immunotherapy-Related Pulmonary Toxicity Immunomodulatory anticancer agents are among the oldest classes of biological therapies. Historically, the only immunotherapeutics used were interleukins and interferons; these are uncommonly used today because of their toxicity profile. Pneumonopathy associated with interleukins or interferons occasionally occurs,71 as does a syndrome of noncardiogenic pulmonary edema. In the past several years, there has been intense interest in, and multiple indications for, monoclonal antibody therapies against immune-checkpoint proteins on T lymphocytes or antigen-presenting cells. Most notably, these include antibodies such as ipilimumab against the CTLA-4 receptor on cytotoxic T-cells or against the PD-1 receptor on T cells (or its ligand the PD-L1 receptor, found on tumor cells or antigen-presenting cells). These antibodies are associated with a risk of noninfectious (presumably autoimmune) pneumonitis, among many other toxicities, including dermatologic, gastrointestinal, neurologic, endocrinologic, and so on. As with other drug-induced pneumonitis syndromes, this presents with interstitial, often ground-glass–appearing, infiltrates and can progress to causing severe dyspnea. Data regarding the absolute risk of pneumonitis with these agents are still evolving.72-74 To summarize, the risk of clinically significant pneumonitis appears to be between 1% and 4% with a single agent and about 6% with combination immunotherapy (e.g., nivolumab plus ipilimumab). There is the suggestion that higher doses of ipilimumab may be more likely to promote pneumonitis. The time range for immune-checkpoint inhibitor pneumonitis is highly variable, with reports ranging from as early as 1 week after starting the agent to 1 year or longer after being on the agent. The management of immunotherapy-induced pneumonitis is arguably more complicated than management of pneumonitis induced by radiation or other drugs because the primary treatment (corticosteroids) would be expected to negate the anticancer benefit of the offending drug. As shown in Table 47.5, it is generally agreed that patients who have grade 3 or greater immunotherapy-induced pneumonitis should permanently discontinue the drug and be treated with high-dose steroids, similarly to that described for small-molecule drugs. However,

Table 47.5  Suggested Management Guidelines for

Immune-Checkpoint Inhibitor–Related Pneumonitis

Grade of Pneumonitis

Treatment

Grade 1

•

Grade 2

• • • • •

Grade 3 or 4

• • • • •

Continue therapy with close monitoring including frequent chest imaging. Stop the agent and administer corticosteroids. Consider pulmonology consultation and possible bronchoscopy. Provide frequent chest imaging and clinical examinations. Upon improvement to grade 1 or less, taper steroids and consider rechallenge with the agent based upon risk-to-benefit assessment. Permanent discontinuation of the agent if a second episode of grade 2 pneumonitis occurs. Permanent discontinuation of the agent. High-dose corticosteroids. Pulmonary consultation and possible bronchoscopy. Upon improvement to grade 1 or less, taper steroids but do not rechallenge with the agent. For steroid-refractory cases, consider infliximab.

the management of grade 1 to 2 immunotherapy-induced pneumonitis is more uncertain. It may involve only a temporary discontinuation of the drug, resuming the therapy with a dose reduction after (or even during the taper of ) a course of steroids. Clearly, a patient who has developed even low-grade pneumonitis from an immunotherapeutic should be rechallenged only with extreme caution and attention to the potential risk of relapse into high-grade pneumonitis. These risks must be carefully balanced against the expected benefits of the therapy, which in the case of immunotherapy, may at times be dramatic.

ACKNOWLEDGMENT We thank Ms. Denise Moore for her assistance in preparation of this chapter. The complete reference list is available online at ExpertConsult.com.

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Pulmonary Complications of Anticancer Treatment  •  CHAPTER 47 724.e1 724.e1

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