Fatal Radiation Pneumonitis: Literature Review and Case Series

Patient A

A 74-year-old white man received a diagnosis of stage IIIB (T4N2M0) squamous cell carcinoma of the lung. The large primary tumor was located in the right lower lobe with right hilar and lower paratracheal lymph node involvement. Medical history included chronic obstructive pulmonary disease, hypertension, coronary artery disease, hyperlipidemia, and hemochromatosis. He had an 80 pack-year smoking history, having quit 12 years before his lung cancer diagnosis. Pulmonary function tests revealed a forced expiratory volume in 1 second (FEV₁) of 70% predicted and a diffusion capacity for carbon monoxide (DLCO) of 41% predicted. Karnofsky index (KI) was 80%. Treatment consisted of concurrent carboplatin plus paclitaxel chemotherapy and volumetric modulated arc therapy (VMAT) delivering 60 Gy in 30 fractions with daily cone beam computed tomography (CBCT) for image guidance. The internal gross tumor volume (iGTV) measured 1161 mL, the clinical target volume (CTV) 1468 mL, and the planning target volume (PTV) 2014 mL. The total lung volume CTV was 3731 mL. The dose-volume histogram (DVH) of his lungs (lungs-CTV) showed a volume receiving 5 Gy or higher (V_5Gy) of 88% (contralateral lung V_5Gy 89%), V_10Gy of 70%, and V_20Gy of 29%. Mean lung-CTV dose (MLD) was 18.6 Gy. Mean heart dose (MHD) was 22 Gy and heart V_60Gy was 2%. Treatment was tolerated well without any ≥G2 toxicities.

On a routine follow-up visit 12 days after end of treatment (EOT), the patient reported cramping in the chest, shortness of breath, fatigue, and some dysphagia. At that time, symptoms were treated symptomatically. Twenty-six days after EOT, the patient presented for a follow-up appointment having symptoms of pleuritic chest pain, shortness of breath, orthopnea, and nonproductive cough; no fevers were reported, and SpO2 was 95%. Computed tomography chest imaging was only remarkable for a possible new metastatic focus in the right upper lobe. After a brief admission he was discharged on a prednisone taper for presumed radiation pneumonitis and pain medication with symptomatic improvement. Three weeks later, while still on steroids, he was readmitted with chest pain and acute hypoxic respiratory failure with SpO2 of 88% requiring treatment with a bilevel positive air pressure machine. His computed tomography imaging at readmission showed diffuse interval ground glass opacity changes and septal thickening, with some bilateral apical sparing and peripheral left lung sparing (Fig. 1). He was started on high-dose methylprednisolone and empirical antibiotics for a differential diagnosis inclusive of organizing pneumonia, opportunistic infection, and radiation pneumonitis. The infectious workup was mostly inconclusive and nonspecific, with the patient remaining afebrile during his hospitalization while having a mild neutrophil-predominant leukocytosis (13.6 on arrival) attributed to steroid therapy. He had negative blood cultures, a negative nasopharyngeal direct respiratory panel, and a negative Legionella urine antigen test. Fungitell was elevated, but Platelia testing was negative for invasive aspergillosis, and his induced sputum culture only showed mixed respiratory flora. Vancomycin was suspended after his negative cultures and he was started on a course of Bactrim to cover for possible Pneumocystis jiroveci pneumonia in addition to completing 7 days of Zosyn. Owing to worsening respiratory failure, the patient was treated in the intensive care unit (ICU). Unfortunately, he failed to improve and died on the thirteenth day of his readmission, 2 months after the end of radiation treatment.

Patient B

A 72-year-old black woman was diagnosed with stage IIIA (T2N2M0) squamous cell carcinoma of the left lower lobe (LLL) with questionable involvement of a right hilar lymph node. Past medical history included diabetes mellitus type 2, hypertension, hyperlipidemia, osteoarthritis, obesity, and a cerebral meningioma that was resected 5 years earlier. She had a 30 pack-year smoking history and quit 9 years before her cancer diagnosis. Her KI was 80%, and pulmonary function tests showed a FEV₁ of 130% predicted with DLCO of 68% predicted. Owing to presumed contralateral hilar involvement, the patient initially received weekly carboplatin and paclitaxel that was stopped prematurely after 3 cycles owing to severe peripheral neuropathy. Six months after chemotherapy she received a diagnosis of tumor progression in the LLL. She then underwent VMAT (60 Gy in 30 fractions, no concurrent systemic therapy) with daily CBCT for image guidance, which was tolerated well with only mild dysphagia. The volumes for iGTV, CTV, PTV, and lung-CTV were 85 mL, 191 mL, 363 mL, and 2741 mL, respectively. The lung DVH (lungs-CTV) showed a V_5Gy of 92% (CL V_5Gy 92%), V_10Gy of 81%, and V_20Gy of 32%. MLD was 20 Gy. MHD was 29.8 Gy and heart V_60Gy 3%.

The patient presented approximately 2 months from the end of radiation treatment with diabetic ketoacidosis, seizure, and weakness. She was admitted for 8 days and was ultimately discharged to a skilled nursing facility on 3 L/min supplemental oxygen. Chest x-ray at 2 months posttreatment did not show significant changes except for tumor regression. She completed 7 days of antibiotics but was readmitted 4 days after hospital discharge with worsening hypoxia with SpO2 in the 60s, cough, and fever of 38.4°C. The patient was admitted to the ICU, and a new painful bone metastasis in the hip was diagnosed. Chest x-ray at admission showed worsening airspace disease. A chest CT 3 days later, or 2 months and 10 days from EOT, showed signs of new airspace disease with wide spread groundglass and reticular opacities with nodularity in the upper lobes and the LLL (Fig. 1). She was placed on intravenous methylprednisolone, bronchodilators (ipratropium and albuterol), and restarted broad-spectrum antibiotics, having a working diagnosis of acute on chronic hypoxic respiratory failure due to radiation pneumonitis and pneumonia. She had a negative direct respiratory pathogen panel, a negative Legionella urine antigen test, and negative blood cultures. She improved while completing a week of Vancomycin and Zosyn and was transferred out of the ICU, but decompensated shortly thereafter. Antibiotics were restarted with a new chest x-ray showing interval changes again concerning for a new or worsening pneumonia, but she remained afebrile and repeat blood cultures were negative. A new chest CT 1 week later revealed worsening ground glass and consolidative opacities in addition to her shrunken lung mass. The patient failed to significantly improve during hospitalization and died 1 month after readmission, or 15 weeks from EOT.

Patient C

A 52-year-old African woman received a diagnosis stage IV (T4N2M1) adenocarcinoma of the LLL with involvement of the pleura, pericardium, mediastinal, and subcarinal lymph nodes, and presumed small pulmonary metastases. She had no history of tobacco use and no significant past medical history with a KI of 100%. Tumor pathology was negative for epithelial growth factor receptor and anaplastic lymphoma kinase with 70% programmed death-ligand 1 positivity. She underwent initial immunotherapy with pembrolizumab for 4 cycles but had disease progression. She was subsequently switched to carboplatin and paclitaxel for 4 cycles and received maintenance pemetrexed. She then developed a lytic lesion in the T12 vertebra and underwent SBRT. Two months later, owing to primary tumor progression without evidence of progressive disease elsewhere and the patient's desire for aggressive treatment, IMRT (60 Gy in 30 fractions, no concurrent systemic therapy) to the LLL primary lesion and involved lymph nodes was performed using 6 fields with daily CBCT for image guidance. The volumes of iGTV, CTV, PTV, and lungs-CTV were 108 mL, 190 mL, 391 mL, and 2642 mL, respectively. Lung DVH (lungs-CTV) showed a V_5Gy of 90% (CL V_5Gy 88%), V_10Gy of 67%, and V_20Gy of 34%. MLD was 17.8 Gy. MHD was 18.8 Gy and heart V_60Gy was 5%.

One month after lung IMRT the patient was found to have a single brain metastasis in her right temporal lobe for which she had a craniotomy and mass resection followed by WBRT to 30 Gy. She was then started on Taxotere chemotherapy. Nine weeks later, or 14 weeks after her lung IMRT, she was admitted with dry cough, pain in the lower chest, shortness of breath with SpO2 of 96%, tachycardia, and hypotension. She was neutropenic and developed fevers of 38.6°C. She also was found to have a pulmonary embolism associated with right lower extremity deep vein thrombosis and was started on anticoagulation, with antibiotics for suspected pneumonia. During her admission, her respiratory status worsened and she was transferred to the ICU. CT chest imaging showed diffuse ground glass opacities in the LLL and lingual and small bilateral pleural effusions. She was started on methylprednisolone for suspected RP and subsequently improved. A chest CT obtained 5 days after starting steroid treatment showed significant reduction of ground glass changes consistent with her clinical improvement. After briefly being discharged, she returned to the hospital 2 days later with increased difficulty breathing, cough, and a low fever. She had a chest tube placed for an enlarged left-sided pleural effusion and started broad-spectrum antibiotics. In addition to her effusions, imaging showed basilar consolidative airspace disease on the right and diffusely scattered ground glass opacities, as well as progression of pulmonary metastases. The patient failed to respond to intensive care treatment and ultimately died 5 months from the end of her lung radiation therapy. The ultimate cause of death in this patient was not identified with certainty. Although other conditions, such as status post pembrolizumab application, pneumonia, pleural effusion, disease progression, and pulmonary embolism, might have also played a role, RP was thought to be the likely major cause of the patient's symptoms.

Clinical symptoms, time to onset, and duration

Clinical symptoms of RP have not been described systematically in great detail. The predominant symptom at the time of clinical manifestation of RP is dyspnea with nonproductive cough. Fever has been reported to occur in about 30% of patients at the time of initial diagnosis of G5 RP.37, 39 Sekine et al³⁹ reported on the clinical symptoms of pneumonitis in 385 lung cancer patients treated to 50 to 70 Gy. Patients with fatal pneumonitis (3.6%) showed higher rates of dyspnea and fever initially and during the clinical course of pneumonitis compared with patients with lower grade pneumonitis. Although there might be an initial response to steroid treatment, patients with G5 RP often do not respond to steroids at all or fail to have further therapeutic response at the time of symptom recurrence.34, 38 All of our patients developed dyspnea and 2 of them also had localized chest pain, perhaps related to pleuritic involvement at the time of onset of RP symptoms. Patient C had low-grade fevers and neutropenia; no evidence of infection was found. The actual cause of the fever remained unclear.

RP typically results in initial clinical symptoms after a latency period of 6 weeks to 6 months after the end of radiation therapy. Several authors reported early clinical manifestation of RP for patients with high-grade pneumonitis12, 32, 40 and patients with higher radiation dose to the lung.³³ Literature review indicates that particularly patients with G5 RP treated for locally advanced disease experienced pneumonitis symptoms earlier than patients with lower grade pneumonitis.13, 18, 34 In some reports, patients started to develop RP symptoms during radiation therapy¹⁸ or within the first month after treatment.14, 35 Sekine et al³⁹ reported that radiographic signs of RP appeared at a significantly shorter median interval after radiation therapy of only 2.4 weeks in patients with G5 RP compared with 9.9 weeks in patients not requiring steroids. Khalil et al¹³ who reported a 9% rate of G5 RP found a shorter time to onset of RP symptoms in G5 patients (1.4-2.5 months) compared with other ≥G3 RP (within first 6 months) after the start of radiation therapy. These authors also reported a significantly shorter survival for G5 RP patients compared with patients with G2 and G3 RP (median 3.3 months vs 16.3 months). After tomotherapy with or without chemotherapy, Song et al¹⁴ reported G5 RP in 4 of 37 patients (11%). Time to G5 RP was 11 days (range 0-24) from end of therapy compared with 32 days (range 0-215) for patients with lower grade RP. Lee et al¹⁸ reported G5 RP in 5 of 60 patients. Patients developed symptoms during treatment and up to 6 weeks post RT, and all died between 1 and 3 months. Zhuang et al³⁵ reported on 3 of 24 patients treated with IMRT and erlotinib developing G5 RP during and up to 3 weeks after RT. Patients died one to 6 weeks after the onset of symptoms. Early symptom onset was also observed in our patients where the first signs of RP were seen between 1 and 3 months, and survival post radiation therapy was 2 to 5 months.

The time course of G5 RP in SBRT seems to be more delayed, with onset reported after a median of 75 days (range, 14-204 days) from the start of radiation therapy and a median survival of 53 days (4-802) in a large series of 1789 patients with 1% G5 RP.²⁴ Tekatli et al²² reported G5 RP in 6 of 63 patients treated with SBRT for >5 cm tumors. Patients survived 4.8 to 42.8 months from treatment start.

Imaging findings

Typical radiographic changes after radiation therapy display diffuse or patchy ground glass opacities or consolidation. Although radiographic changes of pneumonitis are often confined to the treatment fields, cases of G5 RP after tomotherapy, IMRT, SBRT, and 3-dimensional conformal radiation therapy (3DCRT) typically display more diffuse interstitial and infiltrative changes that cover large areas of both lungs.7, 9, 14, 31, 41 Patients with lung changes extending beyond the radiation fields seem to have a worse prognosis. Wang et al³⁴ reported on 31 patients with ≥G3 RP. Thirteen patients developed out-of-field pneumonitis, had a latent period of 53 ± 26 days and died after median 33 days without response to steroids, except for transient improvement in 2 patients. Comparably, 18 patients developed in-field pneumonitis, exhibiting a latent period of 70 ± 32 days with median survival of 160 days. Similar to the associated clinical symptoms, radiographic changes associated with RP appear sooner in patients with G5 RP than in lower grade pneumonitis. Sekine et al³⁹ reported a median duration from the end of radiation therapy to the onset of radiographic change of 9.9 weeks (–2.9 to 45.1) for patients who did not need steroids, compared with 6.7 weeks (0-24.5) for patients with higher grade pneumonitis, and 2.4 weeks (0.4-10.1) for G5 RP. In this report, 79% of patients with G5 RP developed the first radiographic changes before 6 weeks and none after 12 weeks compared with 27% and 35% in patients not requiring steroids and 41% and 14% in patients requiring steroids, but without fatal outcome. Typically in G5 RP, once initial radiographic signs become manifest, radiographic changes quickly spread to involve large areas of the lung. Three out of 5 patients with G5 RP reported by Lee et al¹⁸ developed focal consolidation in the radiation fields during treatment or within 1 month after EOT that progressed to involve the whole lung; the other 2 patients presented with bilateral lung infiltration 4 to 6 weeks after RT with rapid progression. The extent of radiographic changes in our described patients is shown in Figure 1. Symptoms preceded radiographic changes by days and weeks; only when symptoms became severe did airspace disease become visible on imaging. As demonstrated in Figure 1, in 2 of our patients the low dose lung volumes were found to overlap with the observed extent of the lung changes. With ongoing consolidation resulting in lung deformation in patient C, no clear overlap pattern between dose and lung changes could be identified.

Radiation dose factors and treatment technique

Radiation dose to the lung has frequently been investigated as a predictor of RP. Mean lung dose, relative percentages of the whole lung volume receiving defined doses, particularly V_20Gy, and normal tissue complication probability values have classically been associated with the RP risk.³ They have been used in routine clinical treatment, ongoing clinical trial protocols, and treatment guidelines. The identified threshold doses depend on a large variety of factors such as the use of heterogeneity correction, the method used to calculate lung volumes, for example, whole lung minus GTV, CTV or PTV, and whether chemotherapy is delivered together with radiation therapy among others.³ In a metaanalysis by Palma et al,¹ including 836 patients treated with 3DCRT or IMRT, G5 RP was observed in 16 cases (1.9%). V_20Gy was associated with an increased risk of G5 RP (odds ratio 1.09 for every 1% increase). In addition, ≥2 Gy dose per fraction was also identified with a higher G5RP risk. The risk for G5 RP was 7% for a fraction size >2 Gy versus 1.5% for ≤2 Gy. Graham et al²⁷ reported G5 RP in 4 of 99 patients after 3DCRT, with all 4 patients having a V_20Gy ≥35%. Similarly, Tsujino et al,³³ who reported 2 cases of G5 RP after 3DCRT found that the patients with G5 RP had a mean V_20Gy of 34.5% ± 3.5%. In the report by Lee et al,¹⁸ patients with G5 RP did not have higher lung doses than patients with lower grade RP; however, doses were rather high overall with MLD between 15.2 Gy and 26.7 Gy, V_20Gy of 29.5% to 57.7%, and V_30Gy of 24.8% to 42.6%.

More recently, with the increasing use of tomotherapy, IMRT, and VMAT, treatments resulting in larger low-dose lung volumes, lung V_5Gy and V_10Gy, and low dose contralateral lung volumes have been identified as factors contributing to the RP risk.7, 13, 14 For tomotherapy some authors recommend to specifically include low V_5Gy and V_{10 Gy} limits for the total and contralateral lung. For example, Song et al¹⁴ using tomotherapy recommended a contralateral lung V_5Gy < 60% in addition to conventional dose parameters. In their report, a contralateral lung V_5Gy > 80% was associated with a 20-fold increase of treatment-related death. One of the most remarkable reports by Khalil et al¹³ showed an increase of G5 RP after the introduction of IMRT and a reduction of the G5 RP risk when using a low dose constraint, V_5Gy ≤ 60%. Two of our patients received VMAT and one received fixed-field IMRT, resulting in large V_5Gy volumes of the total and contralateral lung while meeting conventional dose thresholds. In our patients, no V_5Gy constraints were used for plan optimization.

For SBRT, several authors reported an increased high-grade pneumonitis risk with higher lung dose, whereas others did not find a lung dose-RP correlation. Higher V_5Gy, V_10Gy, V_20Gy, and MLD have been associated with high-grade pneumonitis risk after SBRT by several authors.2, 7, 15, 16, 23, 29 Using VMAT, Hof et al³⁶ identified total lung V_5Gy, contralateral lung V_5Gy, and contralateral MLD as factors associated with high-grade RP in ≥5 cm tumors. Onishi et al²⁰ reported that G5 RP was significantly higher for V_20Gy ≥ 10%.

In addition to treatment technique, dose distributions are affected by tumor size and field length. It is not surprising that larger tumors and tumors in the lower lobes that often include mediastinal lymph nodes have been associated with a higher RP risk.1, 2, 31, 32 With long superior-inferior volumes, large parts of the lungs are traversed by the radiation beams. Total lung volumes, lung volumes spared from radiation or PTV or lung volume ratios might therefore play a role for predicting RP risk. Lung-CTV volumes are typically used to create mean lung dose and relative V_xGy volumes. Absolute lung or lung-CTV volumes are not commonly used to assess the risk for pulmonary toxicity. Lung-CTV volumes and PTV or lung volume ratios were reported in RTOG 0617.⁴² When comparing our data with RTOG 0617 data, our patients had on average lower lung-CTV volumes potentially indicating a higher RP risk. However, in RTOG 0617 IMRT patients had less pneumonitis than 3DCRT patients despite statistically larger PTV volumes, lower lung-CTV volumes, and larger PTV or lung volume ratios. The importance of lung-CTV volumes is therefore not clear and needs to be investigated further. Radiation therapy for locally advanced tumors in the lower lobes can also result in a higher heart dose, which was found to be associated with G5 RP,¹³ whereas tumor location does not appear to affect heart dose for SBRT treatments of early stage disease.⁴³

With the increasing use of image guidance, imaging dose needs to be considered as well. All of our patients underwent daily CBCT imaging. Assuming a daily CBCT imaging dose of 3 cGy, an additional dose of about 1 Gy to a large lung volume needs to be added to the dose delivered through the therapy beams. This equates to about 20% of the 5 Gy dose volume that has been found to be relevant for RP in several studies. For assessment of the correct dose-RP relationship, verification imaging doses should therefore be considered.

Interstitial lung disease

Interstitial lung disease (ILD), also called interstitial pneumonia, interstitial pneumonitis, or usual interstitial pneumonia, has been identified by several recent reports as a significant risk factor for high-grade and G5 RP after SBRT.15, 16, 19, 20, 22, 23, 36, 37, 44 G5 RP was reported in 7% to 21% of patients with ILD.16, 19, 20 Yoshitake et al²³ found a 17% incidence of G5 RP in patients with ILD compared with 0% in patients without ILD. In a recent review by Chen et al,¹⁷ the increased risk for toxicity in patients with ILD was confirmed and dose recommendations were given to avoid mortality in this population. The authors suggested the constraints of V_20Gy ≤6.5% and MLD ≤4.5 Gy. ILD was also identified as a significant risk factor for G5 RP in several studies reporting outcomes after conventionally fractionated radiation therapy.7, 8, 18, 41 None of our patients showed pretreatment ILD.