Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section G – Complications of Therapy

Chapter 62 – Pulmonary Complications of Anticancer Treatment

Mitchell Machtay

SUMMARY OF KEY POINTS

Radiation Pneumonitis Risk Factors • Older age • Lower performance status • Lower baseline pulmonary function • Large radiation volume treated with more than a “threshold” dose (it is frequently debated what this threshold dose is; the range is from 5 to 20 Gy) • Cumulative radiation dose • Lower lobe primary tumor • Levels of cytokines such as TGF-β and interleukin-6 Diagnosis • The most predominant symptoms are dyspnea and hypoxia, especially on exertion. • Fever (usually low grade), cough, pleuritic chest pain, and other pulmonary symptoms are also common. • Diffusing capacity of the lung for carbon dioxide is the most sensitive value during pulmonary function testing. • Interstitial or ground-glass infiltrate usually, but not always, corresponds well to the irradiated volume. • Findings at bronchoscopy are relatively unremarkable (bronchial lavage may reveal lymphocytosis). • Pulmonary embolism, infection, and progressive tumor must be ruled out. These conditions can coexist with radiation pneumonitis. • Response to corticosteroids is usually rapid. Treatment • The best treatment is prevention. 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). • Consultation with a pulmonologist is necessary. • Oxygen is administered as indicated to prevent hypoxia. • High doses of corticosteroids (60 mg/day of prednisone) with slow tapering are needed for severe grade 2 or any grade 3 radiation pneumonitis. • If prolonged corticosteroid treatment is anticipated, prophylaxis against corticosteroid complications is needed. These measures include gastrointestinal prophylaxis, diet and pharmacologic management of hyperglycemia, infection prophylaxis, and osteoporosis prophylaxis. • Antibiotics, bronchodilators, diuretics, and anticoagulation are administered as indicated for coexisting cardiopulmonary illnesses. Drug-Induced Lung Injury Risk Factors • Usually, 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) • Bone marrow transplantation • Concurrent or recent thoracic radiation therapy • Lower baseline pulmonary function Diagnosis • Dyspnea and hypoxia 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 relatively 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) corticosteroid responsive; less likely to respond well to steroids than radiation pneumonitis but more likely to respond well than late radiation fibrosis. Treatment • When the diagnosis is suspected, the suspected causative agent should be discontinued. • Consultation with a pulmonologist is necessary. • Oxygen is administered as indicated to prevent hypoxia. (Note that high FiO2 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 prophylaxis, diet or pharmacologic management of hyperglycemia, infection prophylaxis, and osteoporosis prophylaxis. • Antibiotics, bronchodilators, diuretics, and anticoagulation are administered as indicated to manage coexisting cardiopulmonary illnesses.

INTRODUCTION

Although relatively uncommon, pulmonary disorders are among the most feared complications of anticancer therapy. Many cancer patients are elderly and/or suffering from one or more underlying comorbidities; therefore, a relatively minor challenge to the lungs can result in respiratory failure and death.

The two major categories of pulmonary complications are radiation pneumonopathy and drug-induced pneumonopathy. These conditions do not include other major categories of pulmonary disease in cancer patients, such as pulmonary embolism, infection (community-acquired, atypical, and aspiration pneumonia), and anatomic complications of tumor and/or medical-surgical interventions, such as pulmonary hemorrhage and fistula. Radiation therapy or chemotherapy can contribute to these multifactorial problems of the respiratory system.

Radiation pneumonopathy and drug-induced pneumonopathy share several important features, most notably that 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 at best may provide a only a temporary symptomatic improvement and at worst can cause life-threatening infections or other complications. Better techniques for avoiding treatment-related pneumonopathy—and better therapy for established pneumonopathy—will come only from improved understanding of and intervention against the complex molecular processes that cause and maintain these pathologic states.

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. Figure 62-1 illustrates a typical case of radiation pneumonitis and its sequelae.

Figure 62-1 Case example of radiation pneumonopathy. A, Diagnostic computed tomographic (CT) scan shows signs of advanced chronic obstructive pulmonary disease with bullous disease in an elderly man who had dyspnea and chest pain. Posteriorly located adenocarcinoma of the lung was found and clinically staged T3N0M0. B, Radiation simulation image. The patient underwent gross total surgical resection but was found to have positive tumor margins and received radical radiation therapy to the chest. C, CT scan. Approximately 6 weeks after radiation therapy, progressively severe dyspnea developed, culminating in profound dyspnea necessitating hospitalization. Grade 3 acute radiation pneumonitis in the right lung was found with left-sided pneumothorax. The patient was treated with steroids, antibiotics, and a Pleurx catheter. D, CT scan. Approximately 1 year later, the patient's condition was stable with no evidence of recurrent cancer. The patient had discontinued steroid therapy but needed intermittent oxygen therapy for radiation fibrosis of the right lung.

The mechanisms behind radiation-induced lung injury remain poorly understood despite decades of study. A detailed review of the histopathologic and molecular events occurring in radiation pneumonopathy is beyond the scope of this chapter; several excellent reviews have been published in the last decade. ^{[1] [2] [3]} Irradiation damages endothelial cells, epithelial cells (particularly surfactant-producing type II pneumocytes), 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 beta (TGF-β), play a major role in promoting radiation pneumonopathy, including development of long-term fibrosis. ^{[4] [5]} 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, or even very advanced chronic obstructive pulmonary disease. Traditional clinical understanding of radiation lung injury recognizes two distinct syndromes: radiation pneumonitis and radiation fibrosis of the lung. Radiation pneumonitis is characterized by intense interstitial inflammation and alveolar exudate. It develops over several weeks to months after irradiation and (if the host/patient survives) resolves within 6 to 12 months. Radiation pulmonary fibrosis, in contrast, generally does not begin until several months after radiation therapy but progresses relentlessly over years. Radiation pneumonitis usually responds well to corticosteroids; in fact, a dramatic response to steroids helps to distinguish this disorder from other diagnoses. In contrast, corticosteroids do not influence the progression of radiation pulmonary fibrosis.

In most cases, radiation lung injury 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 (BOOP).^[6] In the most severe cases, diffuse acute respiratory distress syndrome can result from partial lung irradiation even with steroid treatment.^[7] 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.^[8]

Radiation lung injury may have any of a variety of clinical and radiographic presentations, but the hallmark symptom is generally dyspnea out of proportion to other findings. 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.^[9] This problem can make the differential diagnosis among recurrent/progressive cancer, infection, and radiation lung injury extremely difficult, particularly in patients with lung cancer. Positron emission tomography with fluorodeoxyglucose may be helpful for differentiating recurrence from radiation toxicity, although intense radiation pneumonitis and even actively developing fibrosis causes elevated fluorodeoxyglucose uptake.^[10]

Incidence of Radiation Lung Injury and Predictive Factors

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. ^{[11] [12] [13] [14] [15]} In radiation oncology, the lung is considered a parallel-architecture organ, meaning that destruction of very small portions of it should not cause overall organ dysfunction. In contrast, other organs, such as the spinal cord, are considered series-architecture organs, in which destruction of one region will lead to irreversible dysfunction downstream from that injury.^[16]

Irradiation of the entire lung volume (bilateral lungs) is uncommon today, except as part of total body irradiation for selected BMT conditioning regimens. As reviewed by Sampath and colleagues, the therapeutic index for whole-lung irradiation is extraordinarily narrow and highly dependent on total dose, fractionation, partial lung transmission shielding, and dose rate^[17]; a typical dose of 12 Gy total body irradiation has 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 rarely results in radiation pneumonitis. For example, in tangential irradiation of the breast (after lumpectomy) or chest wall (after mastectomy), the risk of clinically significant radiation pneumonitis is approximately 1%, increasing to approximately 5% with the addition of irradiation of the regional (axillary/supraclavicular) nodes. ^{[18] [19] [20]} Furthermore, radiation pneumonitis after small-volume thoracic radiation therapy such as this may be relatively mild and usually resolves completely.

Understanding the true incidence of radiation pneumonopathy is complicated by limitations of the historical and current standards for defining and grading this illness.^[19] The traditional scoring system developed by the Radiation Therapy Oncology Group (RTOG), which dates back to the early 1970s, is shown in Table 62-1 . ^{[20] [21]} This system is no longer endorsed by major academic centers or organizations because of its several limitations^[22]; however, understanding of this system is important because most modern publications rely on it. Among the limitations of the RTOG scoring system are that grade 1 radiation lung injury is almost certainly underreported and that the distinction between grade 2 and grade 3 toxicity is highly subjective. Furthermore, the RTOG has in the past arbitrarily divided toxicity scales into early versus late on the basis of a 90-day cutoff point from the start of radiation therapy; this is inappropriate for many types of complex radiation injuries such as pneumonopathy. The new Common Terminology Criteria (CTCv3) for adverse events has been adopted for current and future studies. ^{[23] [24]} The CTCv3.0 definitions and grading for selected pulmonary events are shown in Table 62-2 . There have been numerous changes to the scoring criteria in the pulmonology section, and separate scales are no longer used for early and late radiation therapy-related events.

Table 62-1 -- Traditional Scoring System for Radiation Lung Injury Based on the Radiation Therapy Oncology Group

Grade	(Acute) Radiation Pneumonopathy (Within 90 Days of Start of XRT)	(Late) Radiation Pneumonopathy (>90 Days After Start of XRT)
1	Mild, dry cough; dyspnea on significant exertion	Asymptomatic (e.g., slight radiographic findings only) or mild symptoms (e.g., dry cough).
2	Dyspnea on minimal exertion and/or persistent cough (requiring narcotics)	Moderate symptomatic fibrosis and/or pneumonitis (severe cough), fever, patchy radiographic appearances
3	Obvious severe radiation pneumonitis with dyspnea at rest and/or severe cough unresponsive to narcotics. Oxygen and/or steroids are indicated.	Severe symptomatic fibrosis/pneumonitis with dense radiographic changes
4	Life-threatening respiratory insufficiency requiring continuous oxygen/mechanical ventilation	Life-threatening respiratory insufficiency requiring continuous oxygen/mechanical ventilation
5	Death	Death

RTOG, 2000 #497;RTOG, 2000 #498.

Table 62-2 -- CTCv3.0 Selected Common Terminology Criteria for Adverse Events Related to the Lung

Event	Grade 1	Grade 2	Grade 3	Grade 4
Acute respiratory distress syndrome	N/A	N/A	Present; intubation not required	Present; intubation required
Aspiration	Asymptomatic (“silent”)	Symptomatic (e.g., altered eating habits, coughing/choking episodes); medical intervention required	Clinical or radiographic signs of pneumonia; unable to aliment orally	Life-threatening aspiration pneumonia
Atelectesis	Asymptomatic	Symptomatic (e.g., dyspnea, cough), medical intervention indicated (e.g., bronchoscopy)	Severe; operative intervention (e.g., stent, laser) indicated	Life-threatening respiratory compromise
Carbon monoxide diffusion capacity (DLCO)	90% to 75% of predicted value	74% to 50% of predicted value	49 % to 25% of predicted value	<25% of predicted value.
Cough	Symptomatic, nonnarcotic medication used	Symptomatic, requires narcotics	Symptomatic and significantly interfering with sleep or activities of daily living	N/A
Dyspnea	Dyspnea on exertion but able to walk up one flight of stairs without stopping.	Dyspnea on exertion, unable to walk one flight of stairs or one city block without stopping	Dyspnea with activities of daily living	Severe dyspnea at rest; intubation/ventilator indicated
FEV1	90% to 75% of predicted value	74% to 50% of predicted value	49% to 25% of predicted value	<25% of predicted value
Fistula	Asymptomatic (imaging findings only)	Symptomatic; medical management	Symptomatic; invasive management indicated	Life-threatening consequences (e.g., requiring multiple thoracotomies)
Hypoxia	N/A	Decreased O2 saturation with exercise (<88% pulse oximetry)	Decreased O2 saturation at rest; continuous oxygen therapy indicated	Life-threatening; intubation/ventilator indicated
Pleural effusion (nonmalignant)	Asymptomatic	Symptomatic, requiring intervention such as diuretics or 1 to 2 therapeutic horacenteses	Symptomatic requiring supplemental oxygen, >2 thoracenteses and/or chronic indwelling catheter and/or pleurodesis	Life-threatening (e.g., causing hemodynamic instability and/or intubation/ventilator indicated)
Pneumonitis/pulmonary infiltrates	Asymptomatic (imaging finding)	Symptomatic but not interfering with activities of daily living	Symptomatic, interfering with activities of daily living; O2 indicated	Life-threatening; intubation/ventilator indicated
Pneumothorax	Asymptomatic (imaging finding)	Symptomatic, requiring intervention (e.g., hospitalization for observation or temporary chest tube)	Sclerosis and/or operative indication required	Life-threatening (e.g., causing hemodynamic instability and/or intubation/ventilator indicated)
Prolonged intubation (following elective surgery/intubation)	N/A	Extubated within 24 to 72 hours postoperatively	Extubated >72 hours	Tracheostomy indicated
Pulmonary fibrosis	Minimal imaging findings, estimated % of total lung volume that is fibrotic is estimated <25%	Estimated % of total lung volume that is fibrotic is 25% to 49%	Dense widespread infiltrates/consolidation with estimated % of total lung volume that is fibrotic 50% to 75%	Estimated % of total lung volume that is fibrotic is >75%; honeycombing

Note that this is an abbreviated/abridged version of the CTCv3; the complete version can be found at ctep.cancer.gov/forms/CTCAEv3.pdf. Note that 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., ARDS); conversely, for some adverse events, Grade 4 (life-threatening) might not be applicable (e.g., cough).

Despite limitations of the scoring systems for radiation lung injury, some clinical studies provide insight into the complex relations among volume of lung irradiated, regions of lung irradiated, radiation dose, and host factors. Table 62-3 summarizes the literature on this topic. Most clinical radiation oncology studies have focused on the concept of the dose-volume histogram (DVH), in which percentage of total lung irradiated is plotted against radiation dose. The concept of DVH and V20 is shown in Figure 62-2 . With modern radiation planning software integrating findings at computed tomography (CT), DVHs are easy to generate. However, there is no consensus on how to interpret these plots. Some researchers suggest that the most relevant information obtained from DVHs is the V20 (percentage of total lung volume irradiated to more than 20 Gy (conventionally fractionated radiation therapy); others recommend emphasizing V30 (percentage of total lung volume irradiated to >30 Gy), V13, V5, and so on. Other researchers recommend using mean lung dose or complex formulas based on multiple parameters of the DVH curve to predict radiation pneumonitis. Retrospective studies conducted with moderate to large samples of patients with analyzable DVHs and clinical courses consistently show that lung toxicity is associated with lung DVH characteristics that reflect large volumes of irradiated lung. However, studies have not clearly defined a safe lung DVH in therapy for lung cancer. It is clear that irradiation of a smaller lung volume results in less pneumonopathy; a randomized trial showed that the incidence of radiation pneumonitis was significantly reduced from 29% to 17% with the use of “involved-field” radiotherapy, despite the use of higher tumor radiotherapy doses in the involved field arm.^[25]

Table 62-3 -- Selected Clinical Studies of the Incidence and Severity of Radiation Pneumonopathy

Study	Patient Population	Rate of Grade 2 Pneumonopathy (%)	Rate of Grade 3+ Pneumonopathy (%)	Comments
LUNG CANCER STUDIES
Byhardt et al.[120]	388 patients treated with chemo-RT.	NS	17	2-dimensional, large-field XRT. Grade 3 RP 20% with concurrent chemo-RT versus 10% with sequential chemo-RT
Keller et al.[121]	488 patients with postoperative RT ± concurrent chemo	NS	3.5	Moderate (50 Gy) XRT dose; high performance status population.
Turrisi et al.[122]	417 patients (limited stage small cell cancer) with concurrent chemo-RT	12	5	No difference between once daily and twice a day XRT
Wang et al.[13]	223 patients treated with 3-D XRT + concurrent chemo	NS	32	Higher rate than other studies may reflect the use of actuarial statistics and CTCv3 definition
Hope et al.[123]	219 patients treated with high-dose 3-D XRT.	12	11	Strong association of RP with tumor location, lung DVH characteristics
STUDIES IN CANCERS OTHER THAN LUNG CANCER
Lind et al.[124] (breast cancer)	613 patients with breast cancer		NS	RP was significantly more common with regional nodal irradiation
Yu et al.[125] (breast cancer)	189 patients with breast cancer randomized between different chemo regimens prior to RT	5	<1	High rate (24% to 39%) of radiographic changes but low rate of clinical RP
Hughes-Davies et al.[126](Hodgkin's disease)	172 patients with bulky intrathoracic Hodgkin's disease	14	NS	1% fatal toxicity
Koh et al.[26] (Hodgkin's disease)	64 patients with Hodgkin's disease	3	<1	RP associated with larger lung volume irradiated
Cooper et al.[127](esophageal cancer)	117 patients with esophageal cancer treated with chemo-RT	NS	4
Ishikura et al.[128](esophageal cancer)	139 patients with esophageal cancer treated with chemo-RT	2	2	Radiation-induced cardiac complications and/or pleural effusions were more common than RP

Figure 62-2 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.

One flaw with the use of DVH analysis to predict radiation pneumonopathy is that the DVH is based solely on anatomic data, with no consideration of lung physiology or the patient's underlying health. In a DVH, every cubic centimeter of lung tissue is considered to have the same physiologic utility to the patient. This might be accurate for relatively young and healthy individuals such as Hodgkin's disease patients, who have a modest risk of radiation pneumonopathy,^[26] but is almost certainly wrong for elderly smokers with cancer of the lung or esophagus. Among lung cancer patients, a higher risk of radiation pneumonopathy is seen for lower-lobe cancer treatment. ^{[15] [27]} Nuclear medicine scans such as lung ventilation/perfusion scans may therefore be a useful adjunct to radiation planning.^[28]Although radiation dose-volume parameters are the major predictor of radiation pneumonopathy, other factors are important. Some of these are treatment-related factors, including daily radiation fraction size^[29] and the use of concurrent chemotherapy. The issue of chemotherapy has been particularly controversial and difficult to study. It appears that neoadjuvant chemotherapy before radiotherapy does not greatly affect the risk of radiation pneumonopathy. However, concurrent chemoradiotherapy probably increases the risk significantly; the maximum tolerated dose of localized radiotherapy with concurrent chemotherapy for non-small-cell lung cancer is generally considered to be 74 Gy.^[30] Higher doses are achievable with radiotherapy alone. ^{[14] [31]} A combination of concurrent radiotherapy and gemcitabine appears to have a particularly high rate of radiation pneumonopathy, and extreme caution is advised for this combination.^[32] Several other drugs, most notably the anthracyclines (e.g., doxorubicin), methotrexate, and bleomycin, should be considered contraindicated during thoracic radiotherapy. Concurrent thoracic radiotherapy plus a taxane (paclitaxel or docetaxel) is a commonly used and generally safe combination, although it has been suggested that the risk of radiation pneumonopathy might be slightly higher than expected from historical series based on older chemo-RT regimens, particularly with weekly taxane schedules. ^{[33] [34]} It may be especially prudent to use three-dimensional radiotherapy techniques and to carefully analyze lung DVH parameters in patients who are receiving a concurrent taxane.

Nontreatment factors that appear to be predictive of radiation lung injury have been studied. Not surprisingly, pretreatment performance status has been shown to correlate with development of clinical radiation pneumonopathy.^[35] Underlying pretreatment pulmonary function is probably an important factor as well,^[36] although study results have been inconsistent. ^{[37] [38]} This might be because in many cases, poor pretreatment pulmonary function is due to effects of the cancer itself, in which case an effective treatment (such as radiotherapy) may substantially improve rather than harm pulmonary function.

Diagnosis and Management of (Acute and Subacute) Radiation Pneumonitis

With modern, conformal, multifield radiation therapy, it is no longer possible to simply look for pathognomonic rectangular infiltrates on a chest radiograph. A patient who has recently undergone radiation treatment and has dyspnea or other pulmonary symptoms of greater than grade 1 intensity should undergo CT scanning, in some cases with high-resolution CT imaging. CT angiography may also be indicated to rule out pulmonary embolism. Imaging will typically reveal an interstitial infiltrate and/or ground-glass appearance, which can be very difficult to distinguish from an infection. Suspected moderate to severe radiation pneumonopathy should be evaluated by a pulmonologist for consideration of bronchoscopy to rule out infection, particularly if fever is present.^[39]

Pulse oximetry or arterial blood gas testing should be performed to assess the need for supplemental oxygen. Pulmonary function testing, especially the diffusion capacity of the lung for carbon monoxide (DLCO) test, is useful as part of the diagnostic workup, in particular to assess the severity of gas-exchange dysfunction. Spirometric parameters of pulmonary function are frequently reversible after radiation pneumonopathy, while DLCO abnormalities are less likely to improve.^[40] The tests and procedures to be considered in evaluation of cancer patients with suspected pneumonopathy are summarized in Table 62-4 . This workup should be considered appropriate for either suspected radiation-related or chemotherapy-related pneumonopathy.

Table 62-4 -- Evaluation of the Cancer Patient with Pulmonary Symptoms (Especially Dyspnea) and Suspected Radiation or Chemotherapy Pneumonopathy

Study	Rationale
Basic, minimal workup
CT of chest, preferably both with and without contrast	Assess extent/appearance/location of infiltrates/effusions; correlate with radiation therapy and/or surgical data. Rule out recurrent/progressive cancer and/or other etiologies for dyspnea.
Pulse oximetry	Assess degree of hypoxia and possible need for supplemental oxygen.
Pulmonary function testing (spirometry and DLCO)	Assess extent and type of pulmonary function (radiation/drug pneumonitis is a restrictive pattern, with DLCO often markedly abnormal compared with baseline levels).
CBC/diff; chemistry panel	Rule out leukocytosis and/or leucopenia (possible signs of infection), anemia, hepatic and/or renal insufficiency (all factors that can lead to pulmonary distress).
Extended workup (if diagnosis is in question and/or if there is possibility of coexisting cardiorespiratory problems)
High-resolution pulmonary-embolus protocol CT scan, V/Q scan and/or pulmonary angiogram	Rule out pulmonary embolism.
Electrocardiogram	Rule out cardiac ischemia and/or dysrhythmia.
Blood test for B-type natriuretic peptide (BNP)	Rule out CHF.
Arterial blood gas testing	More accurate measure of oxygenation than pulse oximetry; measurement of pH and CO2 levels.
Blood cultures	Rule out sepsis and/or endocarditis.
Bronchoscopy	Rule out infection (particularly if atypical infection is suspected) and assess for possible recurrent cancer.
PET/CT scan	Assessment of status of the cancer; possible role as adjuvant form of imaging the extent of lung injury.
Open lung biopsy (e.g., thoracoscopic biopsy)	Definitive diagnosis but high-risk procedure. Avoid if diagnosis is highly likely and response to steroids is good.

Notice that chest x-ray is not a sufficiently sensitive or specific test to warrant inclusion in this table.

If the clinical manifestations and test results are consistent with grade 2 or greater radiation pneumonitis, administration of corticosteroids should be instituted in most cases. Controlled randomized trials of corticosteroids for radiation pneumonitis have not been conducted with human subjects. However, the efficacy of corticosteroids has been well established in nonrandomized clinical studies^[41] and in preclinical models.^[42] There is no single “standard” dose schedule for steroid therapy for radiation pneumonopathy; the exact schedule must be tailored to the individual patient. In general, for severe (grade 3) radiation pneumonitis, prednisone approximately 1 mg/kg/day is indicated for 2 weeks. Brief hospitalization for intravenous administration of steroids may be indicated. Early onset of radiation pneumonitis following the completion of radiotherapy may predict a more virulent course and therefore might require a more aggressive management approach.^[7] Moderate radiation pneumonitis (grade 2) may be effectively managed with somewhat lower initial doses of steroids (e.g., 0.5 to 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 radiation pneumonitis. After several weeks, the dose should be tapered gently, by approximately 10 mg every 2 weeks. It is not unusual for patients to have a symptomatic relapse in the setting of steroid taper.^[43] If relapse occurs, it is important to rule out concomitant infection. If the diagnosis of recurrent radiation pneumonitis is confirmed, the steroid dose should be increased and titrated accordingly.

With these guidelines, the typical patient with grade 3 or intense grade 2 radiation lung injury will take steroids for approximately 2 to 4 months. Some patients need steroids for considerably longer, although the benefit after 6 months is dubious (when radiation pneumonitis has generally resolved and might be 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 steroid-induced hyperglycemia and muscle wasting. 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.

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 other invasive diagnostic procedure was not done.^[39] In light of the profound lymphopenia that most patients have after chemoradiation therapy and steroid treatment (as with typical concurrent paclitaxel-radiation therapy regimens), it might be appropriate to prescribe an every-other-day dose of trimethoprim-sulfamethoxazole (Bactrim) when starting high-dose steroids. ^{[44] [45]} If findings at chest CT suggest the presence of coexistent active infection, broader and more intense antibiotics are indicated. The patient should undergo bronchoscopy if there is no improvement after several days of steroid and antibiotic therapy.

The prognosis of grade 1 to 2 radiation pneumonitis is relatively good with meticulous supportive care and the use of steroids as needed. Grade 3 radiation pneumonitis, however, at least in lung cancer patients, has a much worse prognosis. ^{[7] [13]} It is uncertain whether this is the direct result of radiation pneumonitis or coexisting problems, including tumor recurrence and infection.

It is uncertain how to manage radiation pneumonopathy that is refractory to steroids and/or in the patient who has severe contraindications to steroids. There have been case reports of the use of antirheumatic medications such as cyclosporin, ^{[46] [47]} but there is little scientific evidence to support their use.

As described in the following sections, patients with radiation pneumonitis should receive supportive care based on careful and frequent assessment of their symptoms and risk factors for further complications of their illness.

Management of (Chronic and Late) Radiation Pulmonary Fibrosis

Although radiation pneumonitis usually is relieved with steroids, radiation pulmonary fibrosis is not. Some patients undergoing steroid therapy for radiation pneumonitis 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 and/or chemotherapy, increasing the steroid dose is unlikely to yield benefit.

Management of radiation pulmonary fibrosis is supportive. Emphasis is on administration of oxygen, management of acute infection, bronchodilator therapy if needed, gentle diuresis if needed, and maximization of the other components of tissue oxygen delivery (e.g., cardiac and blood pressure medications and correction of anemia). Acute episodes of radiation pneumonitis may still occur, particularly if the patient receives a “radiation recall” type of drug; therefore, steroids might be needed periodically. It is unknown whether pulmonary rehabilitation programs involving exercise and weight maintenance are helpful for radiation pulmonary fibrosis. Patients who are disabled or immobilized owing to their pulmonary insufficiency might benefit from DVT prophylaxis. Tobacco should be strictly avoided.

Trials of Prevention or Management of Radiation Pulmonary Fibrosis

As is shown in Table 62-5 , results of studies have suggested that prophylactic administration of amifostine during thoracic radiation therapy ameliorates radiation pneumonopathy. ^{[48] [49]} However, these data are based on preclinical data supporting the role of amifostine as a protective agent against radiation pulmonary fibrosis. However, at this time, the routine use of amifostine is not standard, since the “positive” studies were relatively small, while a larger confirmatory study was disappointing.^[50] In addition, amifostine is logistically and financially difficult to deliver and is associated with its own toxicities (nausea, fatigue, skin rash). Its effectiveness is likely highly correlated with dose and schedule, and amifostine has no known role or rationale as a treatment once radiation has been completed.

Table 62-5 -- Randomized Trials of the Effect of Amifostine on Radiation Pneumonopathy after Radiation Therapy (± Chemotherapy) for Lung Cancer

Study	Patients/Characteristics	Amifostine Dose	Grade 2+ RP Without Amifostine (%)	Grade 2+ RP with Amifostine (%)
Antonadou et al.[129]	97 patients with Stage III NSCLC treated to 55 to 60 Gy without chemo	340 mg/m2/day	43	9 (P = 0.001)
Antonadou et al.[130]	73 patients with stage III NSCLC treated to 55 to 60 Gy + chemo	300 mg/m2/day	56	19 (P = 0.002)
Komaki et al.[131]	53 patients with Stage III NSCLC treated to 69.6 Gy + chemo	500 mg twice per week	16[*]	0[*] (Grade 3) (P = 0.02)
Movsas et al.[50]	205 patients with Stage III NSCLC treated to 69.6 Gy + chemo	500 mg four times per week	27	27

NSCLC, non-small cell lung carcinoma; RP, radiation pneumonopathy.

*	Grade 3 RP.

Other nonspecific antioxidants have been studied as means of decreasing radiation fibrosis, although they are not necessarily specific for the lung. ^{[51] [52] [53]} Gene therapy to deliver antioxidants to the lung is under study. Researchers from the University of Pittsburgh have developed a system in which the gene for the potent antioxidant enzyme manganese superoxide dismutase can be transfected into a plasmid and administered by inhalation.^[52] This approach, still highly experimental, might offer a treatment without the systemic effects that amifostine and steroids induce.

The use of angiotensin-converting enzyme inhibitors, particularly captopril, has shown promise in preclinical rodent studies.^[57] The mechanism of efficacy is unclear and might be related to the beneficial vasodilatory effects of these drugs on small blood vessels or might be due to antioxidant activity. One ongoing RTOG trial is testing the potential efficacy of captopril versus usual supportive care for lung cancer patients who are receiving radiation therapy and are thought to be at significant risk of radiation pneumonopathy. Increased understanding of the cytokine-based mechanisms of radiation lung injury may offer opportunities for intervention. ^{[53] [54]} Because TGF-β is thought to be the dominant profibrotic cytokine and perhaps even a cause of radiation pneumonitis, attempts are underway to develop molecules with anti-TGF-β activity. As one example, keratinocyte growth factor, which is FDA-approved for amelioration of bone marrow transplant-associated mucositis, is under study in preclinical models of radiation fibrosis.^[55]

Other Forms of Radiation-Induced Lung Injury

There is increasing recognition that high-dose radiation can contribute to other serious problems within the lung. One of the most feared complications is bronchopleural fistula, a postoperative complication that is significantly increased by the use of preoperative radiation therapy or chemoradiotherapy and is very difficult to manage. ^{[56] [57]} Patients who receive neoadjuvant chemoradiation for stage III lung cancer should be considered for additional bronchial stump reinforcement (e.g., intercostal muscle flap) at the time of surgery in an effort to minimize this risk.

Endobronchial brachytherapy for palliation of obstructive endobronchial malignant tumors is associated with an approximately 10% risk of severe pulmonary complications, including massive hemoptysis and bronchial stenosis.^[58] It often is difficult to differentiate the contribution of irradiation to these serious events from the contribution of the tumor itself. It should be noted that with the recent significant increase in external beam radiotherapy doses, similar complications are occasionally seen without brachytherapy as well.^[59] It is likely that radiotherapy dose per fraction and the use of concurrent chemotherapy increase the risk of these understudied types of complications. As is shown in the case example in Figure 62-1 , radiation lung injury can be associated with pneumothorax, perhaps as a result of radiation fibrosis causing increased traction on the lung as well as direct radiation injury to the pleura.^[60]

PULMONARY TOXICITY OF SYSTEMIC ANTICANCER THERAPIES

Many chemotherapy drugs can cause pulmonary toxicity, the incidence ranging from less than 1% to more than 30%. The drugs that are most associated with pulmonary toxicity are bleomycin, methotrexate, cytosine arabinoside, mitomycin, and the nitrosoureas (especially carmustine [BCNU]). Table 62-6 is 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.

Table 62-6 -- Anticancer Therapies Categorized by Risk of Pneumotoxicity

Highly pneumotoxic agents (risk of pulmonary SAE probably >5%)	Bleomycin; BCNU; mitomycin; interleukins. Bone marrow transplantation (with or without TBI).
	Large-volume thoracic radiation therapy (e.g., T4N3 lung cancer). Surgical resection for lung cancer.
Moderately pneumotoxic agents (risk of pulmonary SAE probably 1% to 5%)	Methotrexate; busulfan; melphalan; CCNU/MeCCNU; cyclophospamide; ifosfamide; fludarabine; gemcitabine; paclitaxel/docetaxel. Small-volume thoracic radiation therapy (e.g., breast cancer). Non-lung cancer oncologic surgery.
Uncommonly pneumotoxic agents (risk of pulmonary SAE probably <1%)	5-FU; capecitabine; cisplatin/carboplatin; doxorubicin; actinomycin-D; etoposide; topotecan/irinotecan; vincristine/vinblastine; vinorelbine; temozolomide; tamoxifen; aromatase inhibitors for breast cancer. Hormonal therapies for prostate cancer; steroids.
Pneumotoxicity risks present but of uncertain frequency	Anti-EGFR agents (e.g., ZD-1839); monoclonal
	Antibodies (e.g., anti-VEGF MoAb_; imatinib (Gleevac).

BCNU, carmustine; CCNU, lomustine; EGFR, epidermal growth factor receptor; 5-FU, 5-fluorouracil; MeCCNU, semustine; MoAb, monoclonal antibody; SAE, serious adverse event; TBI, total body irradiation; VEGF, vascular endothelial growth factor.

Unlike thoracic radiation therapy, which usually affects only the portion of lung within the radiation field, systemic agents often cause diffuse pneumonopathy. Although it is relatively rare in comparison with radiation pneumonopathy, chemotherapy-induced lung injury can be extremely intense and can even have a higher fatality rate than radiation pneumonitis. As with radiation pneumonitis, corticosteroids are commonly used and may be effective, particularly in early stages of injury. It is particularly important to rule out alternative and concurrent diagnoses (see Table 62-4 ). Unlike radiation injury, drug-induced lung toxicity can occur in a time frame during which it is possible to discontinue the offending agent. A review of some of the systemic agents associated with pulmonary toxicity follows.

Bleomycin

Bleomycin is the chemotherapy drug most commonly associated with lung damage. The reported incidence ranges from 3% to 40%. ^{[61] [62]} This drug is used predominantly in the management of Hodgkin's disease and germ cell tumors, cancers that occur mainly in younger patients with less underlying pulmonary comorbidity than lung cancer patients. There are a number of similarities between bleomycin pneumonopathy and radiation pneumonopathy, including two patterns of disease (pneumonitis and fibrosis). As with radiation, the clinical manifestations of bleomycin lung toxicity usually occur weeks to months after the initiation of treatment. The infiltrates can be diffuse or limited to basilar and subpleural aspects of the lungs.^[63] A nodular pattern occasionally occurs, mimicking cancer progression. Imaging other than CT scanning is investigational, although there are reports of abnormal fluorodeoxyglucose-PET scan results in bleomycin pneumonopathy.^[64]

As in radiation pneumonopathy, dyspnea is the primary symptom of bleomycin lung toxicity, although, as is the case with radiotherapy, other symptoms such as cough and fever often occur as well. Pulmonary function testing shows a restrictive pattern; DLCO is frequently abnormal. DLCO should be measured before bleomycin is started and periodically between cycles. A significant decrease in DLCO should prompt consideration of discontinuation of this drug. Although there is no consensus on what represents a “significant decrease” in DLCO, some investigators have conservatively used a criterion of a 20% decrease to warrant discontinuation of bleomycin.^[65]

There appears to be an association between cumulative bleomycin dose and risk of pneumonopathy. Again, there is no consensus regarding the absolute maximum cumulative bleomycin dose for an individual patient; values of 300 to 400 mg maximum have been suggested. ^{[61] [66]} (A typical cumulative dose of bleomycin from six cycles of ABVD (Hodgkin's disease) is approximately 120 mg/m².) Again, however, it must be stressed that occasionally life-threatening or even fatal pneumonopathy can occur with cumulative bleomycin doses less than 100 mg. Another important predictive factor (in addition to age and dose) for bleomycin pneumonopathy appears to be renal insufficiency, ^{[61] [66]} which is particularly concerning in patients who are receiving nephrotoxic agents such as cisplatin. Other possible risk factors may include concomitant use of a colony-stimulating factor,^[67] combined treatment with radiotherapy, and concomitant delivery with gemcitabine. ^{[69] [70]} Exposure to high oxygen concentrations, as part of operative anesthesia, has been associated with potentiation of bleomycin pneumonopathy, particularly in animal models,^[71] and in some cases led to acute respiratory distress syndrome. ^{[72] [73]} Extreme caution is advised when supplemental oxygen is being electively prescribed for bleomycin-treated patients, especially those who are currently undergoing or recently finished bleomycin (less than 12 months) and/or have documented bleomycin pneumonopathy.^[74]

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.^[75] Most patients achieve complete or near-complete recovery. ^{[75] [76] [77] [78] [79]} Corticosteroids may have some benefit, ^{[61] [76] [80]} although the data are not as clear as those for radiation pneumonitis. Some cases of steroid-responsive bleomycin pneumonitis/fibrosis may represent early hypersensitivity, BOOP-like events. After bleomycin chemotherapy, cancer survivors may have significant declines in pulmonary function for approximately 6 months, but by 2 years after chemotherapy, few have significant respiratory dysfunction.

Antimetabolites

Methotrexate, which is commonly used in therapy for rheumatoid arthritis as well as for cancer, is the antimetabolite drug that is most commonly linked to pulmonary injury. It can cause interstitial pneumonitis similar to that caused by bleomycin and other drugs. ^{[81] [82] [83] [84]} Steroid therapy may be indicated for severe cases.

Gemcitabine has become one of the most commonly used chemotherapy drugs for solid tumors, including lung cancer. When gemcitabine is used as a single agent in previously untreated cancer patients, the risk of significant pulmonary toxicity is small, although it is associated with an occasional severe respiratory insufficiency that may be related to capillary leak syndrome.^[85] However, increasing data suggest that combinations of gemcitabine with other agents may severely potentiate those agents’ pneumonopathy (see discussion in previous sections regarding thoracic radiotherapy and bleomycin), in particular, the combination of gemcitabine with taxanes. ^{[86] [87]} Steroid therapy can be a useful adjunct to supportive treatment.^[77] Gemcitabine may also be associated with radiation recall pneumonitis, even a year or more after thoracic radiation therapy. Gemcitabine radiation recall reaction appears to be more likely to affect parenchymal organs such as the lung than the more common dermatologic radiation recall reactions associated with other chemotherapeutic agents.^[78]

Fludarabine is now commonly used to manage hematologic malignant disease, including chronic lymphocytic leukemia, and, like other antimetabolite drugs, is relatively well tolerated. In approximately 8% of cases, fludarabine causes pulmonary toxicity characterized by fever and interstitial pneumonitis. ^{[79] [88]} Although this syndrome is probably steroid responsive, it is critical to rule out opportunistic infection given the patient population usually treated with this drug.

Alkylators and Nitrosoureas

Alkylators and nitrosoureas are frequent components of conditioning regimens for BMT, a procedure that is associated with a high rate of pulmonary toxicity. It is difficult to isolate the effect of these drugs in this setting, in which many other insults to the lung often occur, but it is likely that they contribute, particularly at BMT dose intensity. ^{[85] [86]} Results suggest that pulmonary toxicity from BMT with whole-body irradiation-containing regimens is similar to that from regimens without whole-body irradiation. ^{[89] [90]} This underscores the relationship between high-dose alkylator therapy and pneumonopathy.

In the non-BMT setting, classic alkylators, such as cyclophosphamide, ifosfamide, and melphalan, have occasionally been associated with interstitial pneumonitis and acute or subacute dyspnea that may be steroid responsive. ^{[91] [92]} However, these drugs have caused long-term pulmonary fibrosis, even several decades after treatment.^[91]

For nitrosoureas such as BCNU, pulmonary injury is considered a dose-limiting toxicity and has been well studied.^[93] The predominant problem with these agents is pulmonary fibrosis, which appears to be chronic and dependent on dose and patient age. ^{[94] [95] [96]} In one study, BCNU pulmonary fibrosis in patients treated for glioma was rare at cumulative doses less than 960 mg/m².^[96] The association between other nitrosoureas and pulmonary toxicity is not commonly reported but does occasionally occur. ^{[97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109]} The pulmonary fibrosis that is caused by nitrosoureas does not appear to be steroid responsive. The unpredictable and untreatable nature of nitrosourea-induced pneumonopathy has recently limited the use of these drugs in several settings.^[98]

Anthracyclines and Other Antitumor Agents

Essentially every cytotoxic chemotherapy has been associated with pulmonary toxicity. Case reports and/or literature reviews can be identified even for drugs that are rarely associated with pneumonopathy, such as vinorelbine,^[99] paclitaxel,^[100] and oxaliplatin.^[101] Response to steroids has been variable. Several other agents, however, deserve special mention.

The antibiotic chemotherapy drug mitomycin is well known as a potentially pneumotoxic agent that can cause noncardiogenic pulmonary edema, pneumonitis, and pleural effusion. Toxicity is difficult to predict and not clearly dose related ^{[102] [103] [104] [105] [106] [107] [108] [109] [110] [111]} but is estimated to occur in 5% of patients or more.^[103] In a prospective study of patients treated with mitomycin, 28% of patients tested had significant (>20%) declines in DLCO, and 5% had grade 3+ lung toxicity. ^{[103] [104] [105] [106] [107] [108] [109] [110] [111] [112]} Mitomycin-induced pulmonary toxicity appears to be steroid responsive.^[104]

Anthracyclines are vital drugs for the treatment of breast cancer among other malignancies; while they are associated with significant cardiac risk (which can mimic pulmonary toxicity), they rarely independently cause pneumonopathy. However, the combination of anthracyclines such as doxorubicin with thoracic radiotherapy can be highly toxic. For example, a randomized trial of concurrent versus sequential chemoradiotherapy (including doxorubicin) for small cell lung carcinoma was closed early because six fatal cases of pneumonopathy developed among 82 patients who were treated concurrently.^[105] There may be a risk of radiation recall-like reactions in patients receiving doxorubicin after high-dose thoracic radiation therapy, at least in the vulnerable lung cancer population.^[106]

Like the anthracyclines, the taxanes (paclitaxel and docetaxel) are widely used solid tumor antineoplastics. Docetaxel seems to be more associated with pneumonopathy than does paclitaxel. The risk of pneumonitis appears to be schedule-related, with a significantly higher risk with the use of weekly (versus every 3 weeks) docetaxel.^[107] This contrasts with the nonpulmonary toxicities of this drug, which appear to be lessened with the weekly schedule.^[107] Docetaxel has also been associated with enhancement of radiation pneumonopathy in lung cancer patients.^[108] The combination of paclitaxel plus radiotherapy following anthracycline-based chemotherapy might not be feasible in breast cancer patients owing to pulmonary toxicity^[109] despite the relatively modest amounts of lung in the irradiated field. As was noted previously, the combination of taxanes with gemcitabine appears to result in a significant risk of pneumonopathy^[78] and should be used with extreme caution in patients with underlying lung disease.

Biologic Agents

Increasingly, cytotoxic therapies such as chemotherapy and/or radiotherapy are being replaced or supplemented by “biologic” agents that kill or inhibit cancer cells through highly specific pathways independent of direct DNA damage. Many of these drugs are still very new, and their toxicity profiles are still being generated. Therefore, data regarding pulmonary toxicity of these agents are incomplete.

Immunomodulatory anticancer agents are one of the oldest classes of biologic therapies. Pneumonopathy associated with interleukins or interferons occasionally occurs,^[110] as well as a syndrome of noncardiogenic pulmonary edema, which differs from typical drug-induced interstitial pneumonitis.^[111] Noncardiogenic pulmonary edema is generally reversible with steroids and supportive care and rarely progresses to fibrosis.

Several randomized trials suggested that the addition of interferon to conventional lung cancer therapy increased the risk of pneumonopathy. ^{[112] [113]}

Targeted therapies against signal transduction pathways have become a heralded advance in several hematologic and solid tumor types. Most of these drugs have not been studied extensively enough to fully characterize their pulmonary risks. Two agents that have been well studied are the oral tyrosine kinase inhibitors (against the intracellular portion of the epidermal growth factor receptor) gefitinib and erlotinib ( Fig. 62-3 ). These agents are associated with an uncommon but sometimes very severe syndrome of interstitial pneumonitis. This pneumonitis appears to be more common in the Japanese population, with a reported incidence of about 3%.^[114] In a placebo-controlled trial of patients with advanced lung cancer, erlotinib was not associated with an increased risk of serious pulmonary adverse events.^[115]

Figure 62-3 Case example of drug-induced interstitial pneumonitis that was presumed to be related to erlotinib. This patient previously underwent chemotherapy and right pneumonectomy but developed recurrent disease. Erlotinib was started, but the patient developed progressive dyspnea 1 month later. CT scan revealed interstitial pneumonitis of the (remaining) left lung. Erlotinib was discontinued, and steroids were started, but the patient soon thereafter died of progressive cancer.

The risk of pneumonopathy from targeted therapies does not appear to be limited to the lung cancer population. Imatinib, used for several types of hematologic malignancies and gastrointestinal stromal tumors, has been associated with interstitial pneumonitis as well.^[116] The anti-CD20 antibody Rituximab has been rarely implicated in pneumonopathy.^[117]

At this time, there are no specific contraindications to the use of signal transduction inhibitory agents based on pulmonary risk; however, current protocols call for the drugs to be discontinued if thoracic imaging reveals evidence of interstitial pneumonitis.

A final category of potentially pneumotoxic drug agents are the antiangiogenic compounds. These are relatively rarely associated with typical drug-induced pneumonitis.^[118] However, the prototype antibody against VEGF, bevacizumab, has been associated with life-threatening pulmonary hemorrhage. This seems to be more associated with centrally located squamous cell lung carcinomas and might be related to rapid tumor response resulting in bronchovascular fistula. Further studies and means of predicting who is at risk for this devastating complication and how to avoid it are necessary in order to advance the use of this class of agents.^[119]

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