Pulmonary Medicine

Radiation-Induced Lung Injury

What every physician needs to know:

Radiation-induced lung injury, including radiation pneumonitis (ICD-9 508.0) and radiation fibrosis (ICD-9 508.1), is common among patients who have received radiation therapy, and it is the most common treatment-limiting toxicity among patients who receive thoracic radiation. The clinical presentation is typically cough, low-grade fever, with or without dyspnea, and radiographic changes that demonstrate a pattern of pneumonitis with ground glass opacities. It typically presents one to six months after therapy, while radiation-associated fibrosis tends to present six to twenty-four months following radiation therapy.

Classification:

Radiation-induced lung injury can be separated into early and late effects of radiation.

Early radiation effects manifest as radiation pneumonitis. Radiographic findings of lung injury are more much common than clinical symptoms of radiation-induced lung injury. Early lung injury tends to occur one to three months following radiation treatment, but it can present as late as six months after radiation exposure. The severity of lung injury varies widely among patients, ranging from asymptomatic to severe respiratory failure and death.

Late radiation-induced lung injury typically presents as pulmonary fibrosis. These findings are generally visible radiographically by six months, and almost all patients who develop radiation-induced pulmonary fibrosis show evidence by twenty-four months following radiation exposure. Although individuals with pneumonitis are more likely to develop radiation associated fibrosis, not all patients who develop fibrosis have a history of radiation pneumonitis.

Cryptogenic organizing pneumonia (COP) can also be seen following radiation therapy. Although COP has traditionally been included with the early manifestations of radiation lung injury, it can present later and last longer than traditional radiation pneumonitis, although its symptoms are similar. COP is also more commonly seen outside of the radiation field than is traditional radiation pneumonitis, often in the contralateral lung, and is more common among patients who have received radiation for breast cancer.

A rarer form of radiation-induced lung injury, referred to as radiation recall, can be seen in patients who receive chemotherapy after undergoing previous thoracic radiation, often years prior to the development of pneumonitis. The clinical and radiographic pattern mimics acute radiation pneumonitis and occurs in the prior radiation treatment field, despite the lack of recent radiation exposure.

Severity:

The clinical pattern of acute radiation pneumonitis can vary widely among patients. While the majority of patients are asymptomatic, some individuals have a rapidly progressive and potentially fatal course. In general, the earlier the onset of symptoms and the greater the reported severity, the more likely the patient is to suffer from a severe course of radiation pneumonitis.

In research studies, the severity of radiation pneumonitis is graded based on the clinical presentation. The grading system that is most commonly used is the Radiation Therapy Oncology Group system:

Grade 1: Mild symptoms of dry cough on exertion

Grade 2: Persistent cough requiring narcotic anti-tussive agents and/or dyspnea with minimal exertion, but not at rest

Grade 3: Severe cough that is nonresponsive to narcotic agents, and/or dyspnea at rest or radiographic evidence of acute pneumonitis

Grade 4: Severe respiratory insufficiency that requires continuous oxygen or assisted ventilation

Grade 5: Death

Are you sure your patient has radiation-induced lung injury? What should you expect to find?

Symptoms of radiation pneumonitis are non-specific and include cough, low-grade fever, and shortness of breath. These symptoms typically develop between four and twelve weeks following radiation treatment. On physical examination, the patient may have normal lung sounds, but patients occasionally have rales or a slight rub.

Radiation-induced lung injury almost always occurs inside the radiation ports. Direct radiation injury will be limited to areas that have received radiation, although patients can develop a hypersensitivity-type reaction to the radiation and can develop inflammation in the contralateral lung. With development of new radiation therapies (such as intensity-modulated radiation therapy), patients can develop areas of inflammation in the periphery around the lesion, while sparing the area immediately around the radiated target.

Unlike infectious pneumonias, radiation fibrosis often crosses anatomic boundaries; classically, the areas of fibrosis have a "straight line" of demarcation from the surrounding normal lung tissues (Figure 1) ( Figure 2).

Figure 1.

CT scan showing acute radiation pneumonitis following radiation therapy for non-small cell lung cancer.

Figure 2.

Chest readiograph demonstrating a straight-line radiographic pattern in the left upper lobe in a patient who underwent radiation therapy for non-small cell lung cancer.

Beware: there are other diseases that can mimic radiation-induced lung injury:

Although radiation pneumonitis is common among patients who have been treated with thoracic radiation, other conditions should be excluded, such as infection, recurrent cancer (especially lymphangitic spread of carcinoma), drug-induced pneumonitis, pulmonary hemorrhage, and cardiogenic pulmonary edema.

Individuals with infection tend to have symptoms consistent with infection, including cough, shortness of breath, and fever.

Factors that suggest recurrent neoplasm rather than radiation pneumonitis include symptom onset more than our months after treatment, known metastatic disease, steady progression of symptoms, radiographic changes outside of the radiation field, anemia, hemoptysis, and known prior documentation of tumor growth.

Cardiogenic pulmonary edema is more common among individuals with known underlying cardiac disease and those who have been exposed to chemotherapeutic agents like Adriamycin that are known to be associated with cardiomyopathies.

How and/or why did the patient develop radiation-induced lung injury?

Pulmonary radiation injury manifests in approximately 8 percent of patients who receive thoracic radiation. However, reports of the incidence of symptomatic radiation pneumonitis range from 1-34 percent of patients who receive thoracic radiation for malignancy. Similarly, approximately 43 percent of patients who are exposed to thoracic radiation therapy have radiographic evidence of radiation pneumonitis, although estimates range widely from 13-100 per cent.

Although predictive models have been designed to help determine which patients are at highest risk for developing radiation lung injury, these models have not been good at identifying which patients have lung injury.

Radiation-induced lung injury is due to direct--and potentially indirect--damage of lung tissue. Radiation treatment generates reactive oxygen and nitrogen species that produce oxidative injury to cellular structures and result in cellular death. Type I pneumocytes, the primary lung cells, are injured by radiation. Type II pneumocytes, which are less common than Type I pneumocytes and can de-differentiate into Type I pneumocytes, are stimulated by radiation exposure and exhibit hyperplasia and growth following such exposure.

The hyperplasia is associated with secretion of growth factors, as well as repair mechanisms to remove the surrounding dead cells. This process is initially associated with increased cytokine secretion, increased secretion of surfactant, lymphocyte migration into the damaged and surrounding tissue, tissue repair, and ultimately fibroplast proliferation and scarring.

The initial injury is thought to be due to the initial cell death with subsequent disease and pneumonitis because of damage to the alveolar/capillary membrane and subsequent interstitial and alveolar edema. The fibrotic injury is due to remodeling of the initially damaged lung tissue.

Which individuals are at greatest risk of developing radiation-induced lung injury?

The risk of developing radiation-induced lung injury was thought to be related primarily to the total dose of radiation delivered. Radiation pneumonitis rarely presents among patients treated with a dose of less than 20 Gy, while it almost always presents among patients who are treated with doses at 40 Gy or greater.

However, more recent studies suggest that the volume of the lung that receives more than 20 Gy (V20) and the total volume of lung spared from radiation exposure are better predictors of which patients will develop radiation-induced lung injury. In addition, patients who are treated with chemotherapy--especially those treated with actinomycin D, adriamycin, bleomycin, and busulfan--are at greater risk of injury, as these agents are known to potentiate the effects of radiation on the lungs. Older patients are at increased risk of radiation injury, as are patients whose neoplasms are located primarily in the lower lobes.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Laboratory tests are not typically helpful in establishing a diagnosis of radiation-induced lung injury. However, markers of infection (CBC, procalcitonin) can be helpful in identifying alternative diagnoses, such as infection. For patients with diffuse ground glass opacities following radiation therapy, bronchoscopy with bronchoalveolar lavage (BAL) can be useful in evaluating infection. Among patients for whom there is concern about possible lymphangitic spread of carcinoma, transbronchial biopsy can be helpful.

Levels of TGF-ß have been associated with an increased risk of developing radiation-induced lung injury, although results are conflicting and future studies are necessary to clarify its role in diagnosing radiation pneumonitis. Similarly, changes in plasma levels of interleukin 1, 6,8, and 10 have been associated with an increased risk of developing radiation pneumonitis, although this work is still preliminary and still needs to be replicated in a larger trial. Laboratory evaluation of these levels are seldom available in a timely manner.

What imaging studies will be helpful in making or excluding the diagnosis of radiation-induced lung injury?

Radiation pneumonitis is best visualized with computed tomography (CT) scan, although in severe cases radiographic evidence presents on standard chest radiographs (Figure 3). Frequently, radiographic evidence presents before or even in the absence of symptoms of lung injury.

Figure 3.

CT scan demonstrating straight-line pattern in a lesion in the left upper lobe in a patient following radiation therapy for non-small cell lung cancer.

The early radiographic pattern of injury is ground glass opacity on CT scan, typically within the radiation ports (Figure 4). However, with the introduction of newer radiation therapy techniques, including IMRT, an area of "skip" around the primary lesion can be seen, along with an area of clearing around the primary lesion and then areas of ground glass and consolidation occurring centimeters away from the primary lesion.

Figure 4.

Right upper lobe radiation fibrosis.

Radiation fibrosis, which can often be seen on chest radiograph, tends to present as a focal, non-anatomic, fibrotic pattern that is often associated with a straight line (Figure 1). The fibrosis almost universally appears in the areas exposed to radiation. Radiation fibrosis is characterized by consolidation, traction bronchiectasis, and volume loss (Figure 5).

Figure 5.

Acute pneumonitis of the left lower lobe in a patient whose biopsy showed cryptogenic organizing pneumonia following radiation for breast cancer.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of radiation-induced lung injury?

Pulmonary function tests are not diagnostic of radiation lung injury. However, the general pattern that develops following radiation injury, in both the early and late stage, tends to be a restrictive pattern with a symmetric reduction in both the FVC and FEV1, along with a decline in the TLC, RV, and DLCO. The decline in DLCO is the most frequently reported change in pulmonary function testing after radiation treatment, but it is a non-specific finding that can be seen in other forms of lung injury.

What diagnostic procedures will be helpful in making or excluding the diagnosis of radiation-induced lung injury?

Bronchoscopy with bronchoalveolar lavage (BAL) is frequently used in the diagnosis of radiation-induced lung injury. BAL cell count typically demonstrates increased lymphocyte count, with the majority of CD4+ lymphocytes in a pattern consistent with a hypersensitivity pattern. This pattern can also been seen in the non-irradiated lung. BAL can also be used to help exclude underlying infection, while the addition of trans-bronchial biopsy can be helpful in excluding progressive malignancy as a cause of the patient's symptoms.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of radiation-induced lung injury?

Lung biopsy is rarely needed to establish a diagnosis of radiation pneumonitis or fibrosis. However, in early radiation pneumonitis, if lung biopsy is performed, one would expect to see evidence of acute inflammation with interstitial inflammation and neutrophils with evidence of organizing pneumonia seen slightly later in the acute phase. Once fibrosis has developed, the pathologic pattern is one of interstitial thickening and fibroblastic proliferation that is typical of pulmonary fibrosis patterns.

Genetic studies suggest that a genetic component of the variance in radiation pneumonitis and fibrosis expression among patients is likely. However, these studies are still early, they have not been replicated, and the clinical utility of such gene analysis has not been demonstrated.

If you decide the patient has radiation-induced lung injury, how should the patient be managed?

Although there is limited data on the appropriate management of patients with radiation pneumonitis, treatment is reserved for patients with symptoms of acute radiation pneumonitis (typically Grade 2 and above). The most commonly used treatment is prednisone at a dose of 60-100 mg daily for two weeks, followed by a gradual taper over six to twelve weeks.

Antibiotics are not helpful unless there is documented infection. However, for patients with refractory pneumonitis who require doses of prednisone greater than 20 mg daily for several months, a consideration of prophylactic trimethoprim-sulfamethoxazole is appropriate to prevent development of Pneumocystis jiroveci pneumonia.

Anticoagulants have also not been shown to be beneficial.

Successful use of azathioprine and cyclosprine has been described but only in isolated case reports among individuals intolerant of prednisone. The routine use of these medications is not supported by current guidelines, although they could be considered for patients who have refractory pneumonitis or who cannot tolerate prednisone.

Unfortunately, no therapy has yet been shown to be beneficial in the treatment of radiation fibrosis. Previous studies have examined vitamin E and pentoxyfilline and have found little or no evidence of benefit. However, ongoing clinical trials of novel anti-fibrotic agents for idiopathic pulmonary fibrosis may yet show a benefit for patients with radiation-induced pulmonary fibrosis.

What is the prognosis for patients managed in the recommended ways?

Approximately 80 percent of patients who develop radiation pneumonitis respond to steroids, and the response is often dramatic. Complete resolution is frequently seen within a week of the initiation of treatment, with radiographic resolution within two weeks. However, in individuals with severe disease and those with long-standing symptoms, the pneumonitis can be refractory to even high doses of steroids.

Some patients develop recurrent disease when steroids are withdrawn. Typically, these patients respond to a longer steroid taper over four to six months.

Patients with COP are more likely to have a relapse of their disease following cessation of prednisone therapy, especially if a shorter taper is used initially.

What other considerations exist for patients with radiation-induced lung injury?

Because of the common nature of radiation-induced lung injury, more attention has been directed toward preventing the injury.

The most frequently used approach is modulating the dose of radiation in those patients at highest risk of developing radiation pneumonitis. However, decreasing the dose, although doing so is associated with decreased risk of lung injury, is also associated with decreased control of the primary malignancy. Given that several authors have designed scoring systems that help to predict which patients are most likely to develop lung injury, the dose can be adjusted or alternative techniques can be used to minimize the effective dose to the surrounding tissue. However, these scoring systems have been limited in their applicability and by the need for validation in other patient populations.

Alternatively, medications have been tried in an attempt to prevent the development of lung injury. Although prednisone has been used as a treatment for pneumonitis, several studies have shown that pre-treatment does not prevent the development of pneumonitis. Pneumonitis can also develop when the prophylactic steroids are withdrawn.

Captopril has been shown to be effective in prevention of lung injury in an animal model of radiation pneumonitis. However, in a subsequent retrospective study, captopril was not shown to be effective in preventing lung injury in humans.

Amifostine, a prodrug designed to scavenge oxygen-free radicals, was shown in one study to decrease the risk of radiation-induced pneumonitis and esophagitis. In the study of 146 patients with localized lung cancer, pneumonitis was seen in 9 percent of the patients treated with amifostine compared with 43 percent of the patients treated with placebo. However, this study has not been replicated, and current guidelines do not suggest the routine use of this medication.

What’s the evidence?

Carver, JR, Shapiro, CL, Ng, A, Jacobs, L, Schwartz, C, Virgo, KS. "American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects.". J Clin Oncol. vol. 25. 2007. pp. 3991-4008.

(Expert panel review of the literature surrounding radiation-induced pulmonary fibrosis and recommendations for treatment.)

Choi, YW, Munden, RF, Erasmus, JJ, Park, KJ, Chung, WK, Jeong, SC, Park, CK. "Effects of radiation therapy on the lung: radiologic appearance and differential diagnosis". Radiographics. vol. 24. 2004. pp. 985-998.

(A pictorial review of the radiographic findings of radiation-induced pneumonitis and fibrosis.)

Graves, PR, Siddiqui, F, Anscher, MS, Movsas, B. "Radiation pulmonary toxicity: from mechanisms to management". Semin Radiat Oncol. vol. 20. 2010. pp. 201-207.

(A comprehensive review of the proposed mechanisms of radiation induced lung injury as well as the treatment to date.)

Grills, IS, Yan, D, Martinez, AA, Vicini, FA, Wong, JW, Kestin, LL. "Potential for reduced toxicity and dose escalation in the treatment of inoperable non-small cell lung cancer: a comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation". Int J Rad Onc Bio Phys. vol. 57. 2003. pp. 875-890.

(A highly detailed analysis of the physics of newer modes of radiation therapy and their potential to cause radiation lung injury. the study uses prospective planning sequences among eighteen patients with non-small cell lung cancer.)

Hartsell, WF, Scott, CB, Dundas, GS, Mohuddin, M, Meredith, RF, Rubin, P, Weigensberg, IJ. "Can serum markers be used to predict acute and late toxicity in patients with lung cancer? analysis of RTOG 91-03". Am J Clin Oncol. vol. 30. 2007. pp. 368-376.

(A prospective study of the risks of radiation pneumonitis based on circulating cytokine levels, including TNF-α, Il-1 and IL-6. The study finds that high levels of IL-6 are associated with an increased risk of developing pneumonitis.)

Jenkins, P, Watts, J. "An improved model for predicting radiation pneumonitis incorporating clinical and dosimetric variables". Int J Rad Onc Bio Phys. vol. 80. 2011. pp. 1023-1029.

(Retrospective study using multivariate analysis of clinical, dosimetric ,and physiological parameters to identify a predictive assessment tool called the Transfer Factor Spared for patients at risk of radiation pneumonitis. The developed model had an area under the receiver operator characteristic curve of 0.778. This paper suggests that models can be helpful in predicting which patients are at risk for radiation pneumonitis and should be considered for a reduction in dose.)

Martin, C, Romero, S, Sanchez-Paya, J, Massuti, B, Arriero, JM, Hernandez, L. "Bilateral lymphocytic alveolitis: a common reaction after unilateral thoracic radiation". Eur Resp J. vol. 13. 1999. pp. 727-732.

(A case control series of twenty-six patients with breast cancer who received unilateral thoracic radiation compared with twenty-one healthy controls. All patients underwent bronchoscopy. Patients who had received radiation were more likely to have lymphocytic alveolitis, and cellular levels were higher among patients with symptomatic pneumonitis. Findings were also seen in the non-irradiated lung field, suggesting a hypersensitivity type of reaction.)

Park, HJ, Kim, KJ, Park, SH, Kay, CS, Oh, JS. "Early CT findings of tomotherapy-induced radiation pneumonitis after treatment of lung malignancy.". AJR. vol. 193. 2009. pp. W209-W213.

(Retrospective review of the radiographic changes among patients who underwent tomotherapy for a lung malignancy and a description of the changes in the radiographic patterns of lung injury.)
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