Radiation-induced lung injury: current evidence

Radiation induces a loss of the alveolar barrier function by destroying epithelial and endothelial cells. The inflammatory response induces a cycle of increased inflammation, vascular permeability, and cytokine release within days or weeks [32, 48]. Macrophage accumulation and activation contribute to the development of hypoxia, stimulating the production of reactive oxygen species and reactive nitrogen species (ROS/RNS) and proinflammatory, profibrogenic and proangiogenic cytokines that perpetuate a non-healing tissue response that leads to chronic radiation injury [49]. The changes induced by radiation can be divided into five phases according to exposure time (see Fig. 1).

Radiation recall pneumonitis (RRP) is an acute inflammatory response in a previously irradiated lung after the administration of systemic antineoplastic agents [55]. It often begins after exposure to the triggering agent but may occur at any time during treatment. The time elapsed from treatment onset to the presence of RRP ranges from hours to years, and the severity does not correlate with the interval of time between radiotherapy and antineoplastic treatment [56]. Taxanes and anthracyclines are the most common drugs related to RRP. Like nivolumab or durvalumab, immune-checkpoint inhibitors have reported higher incidences of severe pneumonitis in the irradiated lungs of previously treated NSCLC patients [34, 57]. Chemotherapy agents may be more likely than immunotherapy to be related to RRP; thus, the rate and severity of this phenomenon will change as the use of immunotherapy and targeted therapies become the preferable upfront treatment in the majority of clinical scenarios.

Clinical diagnosis often complicated due to the presence of non-specific symptoms that may be related to either pre-existing pathologies or malignant diseases. Thoracic radiation produces acute and late clinical manifestations after lung injury. RILI can divide into an acute phase (< 6 months), also called RP, and a chronic phase (> 6 months) known as RF [58‐60]. Some authors refer to the acute phase as the development of pneumonitis that lasts from 4 to 12 weeks after radiation [61]. In acute lung injury, patients may experience an exacerbation of previous respiratory symptoms or new clinical manifestations, such as dyspnea and coughing, which occur in 20–40% of cases [62]. Severe signs and symptoms are less frequent but involve hypoxemia and respiratory failure. Conversely, the chronic phase manifests itself as progressive respiratory insufficiency or progressed severity of previous symptoms, particularly dyspnea. Non-specific signs and symptoms include tachypnea, cyanosis, crackles or pleural rub under thorax examination, chest pain, malaise, and occasionally, fever. Moreover, less frequent RP clinical features may include hemoptysis, airway obstruction, pulmonary vascular damage, bronchitis, respiratory infections, pleural effusion, and pneumothorax. The physical examination finding may include pleural friction rub, moist rales, and signs of consolidation.

There are different grading systems defined pneumonitis severity, regarding clinical, radiological changes, and type of treatment or medical support required. The most commonly used are the Radiation Therapy Oncology Group (RTOG) [63], the Common Terminology Criteria for Adverse Events v. 5.0 (CTCAE v 5.0) [64], and the Southwest Oncology Group Criteria (SWOG) [65]. RP events scored by the RTOG and CTCAE v 5.0 standards classify symptoms and image findings into five grades, while the SWOG score focuses on treatment requirements (see Table 1).

There is a broad spectrum of imaging findings after radiation injury that can mimic other etiologies. The extension of RP damage varies according to the radiological image observed. It can display from scarce patchy lesions within the irradiated field with fading of the pulmonary vasculature to very extensive lesions with well-defined areas of consolidation. A chest X-ray is the first tool used in approaches to RP. Radiographic lung damage sees in lung volumes irradiated at doses under 20 Gy. Newer techniques like VMAT or IMRT have the potential to deliver lower doses of radiation distributed in lung volumes. V5, V10, and V15 dose constraints are correlated with RP, however, V5 has linked with symptomatic RP [66]. VMAT and IMRT should be employed as the prefer radiation techniques in addition to strict dosimetric constraints. CT-scan is more sensitive than chest radiography for detecting subtle lung injury following radiation treatment. Different CT findings have described in RP: diffuse ground-glass opacity, modified conventional, mass-like consolidation with volume loss and traction bronchiectasis, and scar-like [48, 67, 68].

Conventional RF generally involves the entirety of irradiated lung tissue. Acute image findings are usually confined to the radiation field and appear as ground-glass opacities that may progress to the organizing or consolidation phases [61, 68]. Also, it can be present as ipsilateral pleural effusion and atelectasis. Lung opacities may gradually resolve over six months without radiological sequelae or with minimal damage [51]. Late radiological findings result from unresolved acute RP. They include diminished volume, linear scarring, consolidation, and traction bronchiectasis.

In some cases, pleural thickening and mediastinum traction may be observed [48]. In advanced stages, shrinkage of the pulmonary parenchyma and areas of fibrosis along the path of the radiation beam may be visible. RF and loss of lung volume may continue to evolve for as long as 24 months, resulting in architectural distortion [53] (see Fig. 2). Kouloulias et al. proposed a CT grading scale to categorize lung damage's extension and characteristics in 5 scores, but further studies are required to validate its use [50].

Reduced baseline mechanical function measured by spirometry, plethysmography, and gas exchange abnormalities on the diffusion lung capacity of carbon monoxide test (DLCO) has elucidated as predictive factors for RP [16, 54]. The lung is not a uniform organ, and patients with lung cancer experience distinct changes in response to RT in different functional regions [37]. After RT, a mild decrease in the forced expiratory volume in 1 s (FEV₁) may indicate minor development of bronchial obstruction due to tissue swelling. Declines in forced vital capacity (FVC) and total lung capacity (TLC) indicate a degree of lung stiffening since both are indicators of lung compliance. As larger volumes are irradiated, a more significant decrease in lung compliance seems to appear, affecting FVC, TLC, and, subsequently, FEV₁. A reduction of DLCO after RT refers to an interstitial lung tissue damage that compromises the gas transfer through the alveolocapillary membrane. The six-minute walking test (6-MWT) is a useful predictor tool for RP in patients undergoing thoracic irradiation for lung carcinoma. A 6-MWT/FVC ratio below 4 ft/l predicts chronic RP [69]. A prospective study in NSCLC patients evaluating lung function with a broad range of lung function tests showed that a reduction in baseline FEV₁ (p = 0.02) and DLCO (p = 0.02), together with an increase in the fractional exhaled nitric oxide (FeNO) test (p = 0.04), correlate with the development of RP [70]. Likewise, a reduction in lung function observed before symptoms appear in patients with radiation-induced lung injury. Pulmonary function tests have proven to be useful tools for the early detection of lung tissue changes secondary to radiation [71, 72].

Diagnoses of RP require clinical correlation and exclusion of the most common pathologies that mimic lung toxicity, mainly disease progression and infection. It is essential to differentiate these conditions to provide adequate treatment and proper management. RP is a diagnosis established by clinical suspicion or radiological findings; in selected cases, a lung biopsy helped to rule out confounders.

The mainstay of treatment in acute pneumonitis consists of administering a systemic corticosteroid cycle at high doses for symptomatic patients or those with sub-acute onset, grade ≥ 2; however, few controlled studies have evaluated the efficacy of RP treatment in humans. Oral prednisone generally prescribed at 1–2 mg/kg/day before tapering down over 3–12 weeks, depending on institutional recommendations, is an option [73]. For grades 3–4, intravenous corticosteroids equivalent to methylprednisolone at 2–4 mg/kg/day tapered over six weeks is recommended. Glucocorticoids reduce inflammation and inhibit TNF-induced nitric oxide-mediated endothelial cell and lymphocyte toxicity. Prophylaxis for Pneumocystis Jirovecci recommended for patients with risk factors and those taking high dose corticosteroids (see Fig. 3) [74, 75]. The use of inhaled corticosteroids ensures that the highest dose is deposited in the airway, thus decreasing side effects. Although there is no fixed treatment dosage, inhaled steroids have shown efficacy as a treatment option for RP grade 2 [76]. However, few studies have assessed the efficacy of inhaled steroids in cancer patients. It is well-known that patients with chronic disease (radiation fibrosis) are unlikely to benefit from glucocorticoid therapy [60].

Several strategies have tested prophylactically or in the early stages of RP to avoid fibrosis development; however, despite positive results, none of the following are standard of care in the current clinical practice. Pentoxifylline has immunomodulatory and anti-inflammatory properties mediated by the suppression of TNF-α and IL-1, which may play a role in treating of RF. The effects of pentoxifylline at a dose of 400 mg, taken orally three times a day for eight weeks, have proven to improve clinical signs, symptoms, and a reduction in lung fibrosis [77]. It significantly reduces the presence of fibrosis with alpha tocopherol (vitamin E) for six months [78‐80].

Amifostine is a radioprotector agent that functions via free radical scavenging. In animal models, it diminishes the concentration of TGF-β1 [81]. Two meta-analyses evaluated and verified the benefit of amifostine at reducing the risk of RP vs. placebo/non-treatment, without affecting tumor response [82, 83].

Angiotensin-converting enzyme inhibitors (ACE-inhibitors) exhibit significant antifibrotic activity against collagen accumulation in the lungs; however, its effectiveness has proved in retrospective trials [84, 85]. Since excess collagen synthesis is a crucial histopathologic feature of RF, other drugs, such as colchicine, penicillamine, statins, and interferon-gamma, may also have the potential to modify the progression of fibrosis.

Recently, nintedanib has emerged as a promising form of treatment and prophylaxis for RF (NTC 02452463, NTC02496585), since it showed benefits reducing the annual FVC decline in patients with idiopathic pulmonary fibrosis that shares similar pathophysiology [86].