Early Radiation Pneumonitis Research Articles

Timing of Radiation Pneumonitis in Patients with Stage 3 Non-Small-Cell Lung Cancer Receiving Consolidation Durvalumab after Chemoradiation

Purpose. Consolidation with durvalumab is standard of care in the management of unresectable stage 3 non-small-cell lung cancer (NSCLC) postchemoradiation, and pneumonitis is an independent potential treatment complication of both treatment strategies. This study seeks to determine the timing of radiation pneumonitis (RP) by receipt of durvalumab. In addition, we reviewed the preventative strategies guided by pathophysiology of pneumonitis. Methods. We identified patients with unresectable Stage 3 NSCLC who developed grade ≥2 RP after chemoradiotherapy. Time-to-RP was defined from date of completion of radiotherapy to date of radiological diagnosis of RP and accompanying clinical symptoms. Early RP was defined as RP within 2 months of completion of radiotherapy. Differences in time-to-RP by receipt of durvalumab were evaluated using Wilcoxon rank-sum test. Differences in those who had early vs late RP by receipt of durvalumab was evaluated using Fisher’s exact test. Logistic regression was used to evaluate patient and treatment factors associated with early RP. Results. Of the 144 patients with Stage 3 NSCLC who had definitive chemoradiotherapy, 31 (22%) developed grade ≥2 RP and were included in the study. There was one patient with grade 5 RP. The median age of the cohort was 67 years (range 41–87). The mean lung dose, V5Gy, and V20Gy were 15.8Gy (SD = 1.56), 60.14% (SD 2.73), and 29.96% (SD 1.82), respectively. Twelve (39%) patients received durvalumab. The median time-to-RP was 3.4 months (range: 1.7–7.2) and 2.3 months (range: 0.6–9.6) in patients who had durvalumab and no durvalumab, respectively (P=0.01). 83% (10/12) of patients who had durvalumab and 58% (11/19) of patients who did not have durvalumab had late RP (P=0.14). No other patient and treatment factors were associated with early RP. Conclusion. Patients on durvalumab may have late-onset RP; therefore, further studies with larger cohort of patients and development of new predictive models that incorporate evolving management are needed should preventative strategies of RP be considered in routine clinical practice.

An 18F-FDG PET/CT and Mean Lung Dose Model to Predict Early Radiation Pneumonitis in Stage III Non-Small Cell Lung Cancer Patients Treated with Chemoradiation and Immunotherapy.

Radiation pneumonitis (RP) that develops early (i.e., within 3 mo) (RPEarly) after completion of concurrent chemoradiation (cCRT) leads to treatment discontinuation and poorer survival for patients with stage III non-small cell lung cancer. Since no RPEarly risk model exists, we explored whether published RP models and pretreatment 18F-FDG PET/CT-derived features predict RPEarly Methods: One hundred sixty patients with stage III non-small cell lung cancer treated with cCRT and consolidative immunotherapy were analyzed for RPEarly Three published RP models that included the mean lung dose (MLD) and patient characteristics were examined. Pretreatment 18F-FDG PET/CT normal-lung SUV featured included the following: 10th percentile of SUV (SUVP10), 90th percentile of SUV (SUVP90), SUVmax, SUVmean, minimum SUV, and SD. Associations between models/features and RPEarly were assessed using area under the receiver-operating characteristic curve (AUC), P values, and the Hosmer-Lemeshow test (pHL). The cohort was randomly split, with similar RPEarly rates, into a 70%/30% derivation/internal validation subset. Results: Twenty (13%) patients developed RPEarly Predictors for RPEarly were MLD alone (AUC, 0.72; P = 0.02; pHL, 0.87), SUVP10, SUVP90, and SUVmean (AUC, 0.70-0.74; P = 0.003-0.006; pHL, 0.67-0.70). The combined MLD and SUVP90 model generalized in the validation subset and was deemed the final RPEarly model (RPEarly risk = 1/[1+e(- x )]; x = -6.08 + [0.17 × MLD] + [1.63 × SUVP90]). The final model refitted in the 160 patients indicated improvement over the published MLD-alone model (AUC, 0.77 vs. 0.72; P = 0.0001 vs. 0.02; pHL, 0.65 vs. 0.87). Conclusion: Patients at risk for RPEarly can be detected with high certainty by combining the normal lung's MLD and pretreatment 18F-FDG PET/CT SUVP90 This refined model can be used to identify patients at an elevated risk for premature immunotherapy discontinuation due to RPEarly and could allow for interventions to improve treatment outcomes.

A Novel FDG PET and Mean Lung Dose Model to Identify Stage III NSCLC Patients at High Risk of Developing Early Radiation Pneumonitis

Early radiation pneumonitis (RPEarly) is a primary reason for the premature discontinuation of durvalumab consolidation and can lead to poor survival in patients with stage III non-small cell lung cancer (NSCLC). Currently, there are no RP risk models specifically tested for RPEarly. Here, we tested the applicability of published RP models for predicting RPEarly and explored the value of integrating pretreatment FDG-PET parameters. The cohort consisted of all 178 LA-NSCLC patients treated with concurrent chemoradiation (cCRT) and durvalumab between May 2017 and December 2021. RPEarly was defined as RP occurring within three months of cCRT completion; late RP (RPLate) was defined as any later occurring RP. The three published RP models analyzed included: 1) Mean lung dose (MLD), 2) MLD, age, pulmonary comorbidity, smoking status, and tumor location, and 3) MLD, age and pulmonary comorbidity. In addition, pretreatment FDG PET-CT scans were used to calculate SUV parameters from auto-segmented normal lung contours: 10th- and 90th percentile (SUVP10, SUVP90), maximum, mean (SUVmean), minimum, and standard deviation. The RP models were fit to RPEarly, RPLate, and RPEarly+Late in the 178 patients. To assess the association between FDG PET parameters and RP unbiasedly, the cohort was then randomly split, but enforcing similar RP rates, into a two-thirds derivation and a one-third validation subset. Model performance was assessed by AUC, p-values and the Hosmer-Lemeshow test (pHL; ideally ∼0.50). The rates of RPEarly, RPLate, and RPEarly+Late were 12%, 11%, and 23%, respectively (corresponding to 21, 20, and 41 events). Only the MLD model significantly predicted RPEarly (AUC = 0.70; p = 0.04; pHL = 0.84); none of the three models predicted RPLate or RPEarly+Late. Among the FDG PET parameters, SUVP10, SUVP90 and SUVmean predicted RPEarly with similar performance (AUC = 0.69-0.73; p = 0.005-0.01; pHL = 0.68-0.72), and, therefore, bivariate models were built between MLD and each of SUVP10, SUVP90 and SUVmean. Only the MLD + SUVP90 model generalized in the validation subset (AUC = 0.63; p = 0.03; pHL = 0.89) and was thus deemed the final model for RPEarly. A final re-fitting of all model coefficients to the whole cohort indicated improvement over using the published MLD alone model (AUC = 0.75 vs. 0.70; p-value = 0.0006 vs. 0.04; pHL = 0.67 vs. 0.84). Risk of RPEarly is thus estimated as: RPEarly = 1/(1 = e-x); x = -5.79 + (1.57*MLD) + (0.14* SUVP90). Patients at risk for RPEarly can be accurately identified prior to treatment by combining a re-fitted version of the published Mean Lung Dose model and pre-treatment FDG PET SUVP90 of the normal lung. This refined model can be used to identify patients with an exacerbated risk for premature durvalumab discontinuation due to RPEarly and could allow for interventions and/or the generation of "RPEarly sparing" treatment plans to improve overall treatment outcomes.

Polydatin alleviated radiation-induced lung injury through activation of Sirt3 and inhibition of epithelial-mesenchymal transition.

Radiation‐induced lung injury (RILI) is one of the most common and fatal complications of thoracic radiotherapy. It is characterized with two main features including early radiation pneumonitis and fibrosis in later phase. This study was to investigate the potential radioprotective effects of polydatin (PD), which was shown to exert anti‐inflammation and anti‐oxidative capacities in other diseases. In this study, we demonstrated that PD‐mitigated acute inflammation and late fibrosis caused by irradiation. PD treatment inhibited TGF‐β1‐Smad3 signalling pathway and epithelial–mesenchymal transition. Moreover, radiation‐induced imbalance of Th1/Th2 was also alleviated by PD treatment. Besides its free radical scavenging capacity, PD induced a huge increase of Sirt3 in culture cells and lung tissues. The level of Nrf2 and PGC1α in lung tissues was also elevated. In conclusion, our data showed that PD attenuated radiation‐induced lung injury through inhibiting epithelial–mesenchymal transition and increased the expression of Sirt3, suggesting PD as a novel potential radioprotector for RILI.

Comparison of risk and predictors for early radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with radiotherapy with or without surgery

ObjectivesTo investigate risk and predictors for radiation pneumonitis (RP) and tolerance of lung to radiation in patients treated with thoracic radiotherapy (RT) with or without surgery. Methods and materialsA total of 433 consecutive patients with locally advanced non-small cell lung cancer were followed after three-dimensional conformal radiotherapy. Among them 284 received RT without surgical intervention and 149 received postoperative radiotherapy (PORT). RP was graded according to Common Terminology Criteria for Adverse Events version 4.0. ResultsThe rate of grade ≥2 and grade ≥3 RP was 50 and 16% in the PORT group compared with 38 and 9% in the non-surgical group (p<0.05 for each comparison). The lung volume was significantly smaller in PORT group than in no-surgical group (3181±915cm3 vs. 4010±1120cm3, p<0.05). Age, chemotherapy, mean lung dose (MLD) and planning target volume (PTV) were predictors of RP for both non-surgical group and PORT group. Mean heart dose (MHD) predicted RP in PORT group only (OR=1.28, p=0.003). Among patients who developed RP, V20, MLD, and MHD were significantly lower in PORT group than in no-surgical group (p<0.05 for each comparison). ConclusionsExcept MHD predicting RP in PORT group only, most of predictors for RP were consistent in patients treated with RT with or without surgery. Patients receiving PORT had a higher risk of RP than patients receiving RT without surgery did, possibly due to decreased lung volume and lower tolerance of lung to chemoradiotherapy.

Can Abnormalities on High-Resolution CT Predict Early Radiation Pneumonitis After Thoracic Radiation Therapy

Can Abnormalities on High-Resolution CT Predict Early Radiation Pneumonitis After Thoracic Radiation Therapy

Risk factors of radiation pneumonitis in lung cancer

7573 Background: The clinical syndrome of radiation pneumonitis develops in 5–15% of patients receiving thoracic radiotherapy for lung cancer. In this study, we evaluated and identified the clinical characteristics, clinical courses of patients who developed radiation pneumonitis compared with patients who did not develop radiation pneumonitis. Methods: One hundred and five lung cancer patients who underwent thoracic radiotherapy between January 2001 and January 2006 were evaluated and clinical characteristics were reviewed retrospectively. Results: The median age of total patients was 60.9 years old and 86 cases (81.9%) of non-small cell lung cancer and 19 cases (18.1%) of small cell lung cancer patients were enrolled. Forty-one cases(39.0%) developed radiation pneumonitis. Among these patients, 23 cases (56.1%) of early radiation pneumonitis, 15 (36.7%) of intermediate and 3 (7.2%) of late were classified by development time. By severity, 10 cases (24.4%) of Grade 1, 23 (56.1%) of Grade 2, 7 (17.1%) of Grade 3 and 1 of Grade 4 radiation pneumonitis were observed. 21cases (51.2%) of patients who developed radiation pneumonitis were treated with corticosteroid for mean duration of 9.8 weeks. Non-smoking history (p=0.046), concomitant other lung disease (p=0.021), and NTCP (Normal Tissue Complication Probability)≥30% (p=0.012) significantly increased risk of radiation pneumonitis development in multivariate analysis. Development of radiation pneumonitis did not affect survival (p=0.456). Conclusions: Radiation pneumonitis was developed in 39% of patients who had received thoracic radiation due to primary lung cancer and 56.1% cases of these radiation pneumonitis patients developed within 2 months. In this study, non-smoking history, concomitant other lung disease and NTCP≥30% were identified as risk factors of radiation pneumonitis, thus, more attention will be needed to these patients group. No significant financial relationships to disclose.

Predictive factors for radiation-induced pulmonary toxicity after three-dimensional conformal chemoradiation in locally advanced non-small-cell lung cancer

Radiation pneumonitis (RP) is a restricting complication of non-small-cell lung cancer irradiation. Three-dimensional conformal radiotherapy (3D-CRT) represents an advance because exposure of normal tissues is minimised. This study tries to identify prognostic factors associated with severe RP. Eighty patients with stage IIIA (20%) and IIIB (80%) NSCLC treated with cisplatin- based induction chemotherapy followed by concurrent chemotherapy and hyperfractionated 3D-CRT (median dose: 72.4 Gy, range: 54.1-85.9) were retrospectively evaluated. Acute and late RP were scored using RTOG glossary. Potential predictive factors evaluated included clinical, therapeutic and dosimetric factors. The lungs were defined as a whole organ. Univariate and multivariate analyses were performed. Early and late RP grade>or=3 were observed in two patients (2%) and 10 patients (12%), respectively. Five patients (6%) died of pulmonary toxicity, 3 of whom had pre-existing chronic obstructive pulmonary disease (COPD). Median time to occurrence of late RP was 4.5 months (range: 3-8). Multivariate analysis showed that COPD (OR=10.1, p=0.01) and NTCPkwa>30% (OR=10.5, p=0.007) were independently associated with late grade>or=3 RP. Incidence of RP>or=3 grade for patients with COPD and/or NTCPkwa>30% was 25% vs. 4% for patients without COPD and NTCPkwa<30% (p=0.01). Risk of severe RP was higher for patients with COPD and/or NTCPkwa>30% (OR=7.3; CI 95%=1.4-37.3, p=0.016). COPD and NTCP are predictive of severe RP. Careful medical evaluation and meticulous treatment planning are of paramount importance to decrease the incidence of severe RP.

Antibody to avb6 Integrin Prevents Radiation-Induced Lung Fibrosis

Purpose/Objective: The development of pulmonary fibrosis limits the dose of therapeutic lung radiation. The pleiotrophic cytokine TGFb is thought to be central to this process and to other fibrotic diseases. The integrin avb6 activates TGFb from its latent form, and plays an important role in localizing TGFb effects; it is dramatically upregulated on lung epithelial cells before fibrosis develops after injury. Furthermore, knockout mice that lack avb6 are protected from lung fibrosis after radiation exposure, as well as from other fibrotic stimuli such as bleomycin. This makes inhibition of the avb6 integrin a possible therapeutic target and, to that end, a monoclonal antibody has been developed. Blockade at another level in this pathway by soluble TGFb receptor, which inhibits all TGFb activity, prevents early radiation pneumonitis and bleomycin-induced fibrosis. We compared the effects of anti-avb6 mAb and soluble TGFb receptor on the late pulmonary fibrotic response after thoracic radiation in a mouse model. Materials/Methods: We injected 149 C57BL/6 mice with various doses of anti-avb6 antibodies (0.3 mg/kg, 1 mg/kg and 10mg/kg), soluble TGFb receptor (5 mg/kg), or appropriate controls (PBS and IgG), starting 15 weeks after 14Gy thoracic radiation. Mice were monitored daily and sacrificed if in respiratory distress or moribund. We assessed fibrosis in mice sacrificed at 26 weeks by calculating the percent fibrosis area of paraffin-embedded, formalin-fixed tissue sections that were stained with Masson trichrome. Expression of avb6 was assessed by immunohistochemistry. Results: We found that the antibody caused a dose-dependent attenuation of fibrosis. Soluble TGFb receptor also inhibited fibrosis, but did not block the upregulation of avb6. Kaplan-Meier analysis showed no survival benefit as a result of avb6 blockade; in fact, there was a trend to excess mortality in the high-dose group (p=0.08). Conclusions: The prevention of pulmonary fibrosis by the late administration of either soluble TGFb receptor or antibody to avb6 clearly demonstrate that radiation-induced pulmonary fibrosis is a TGFb-dependent process. Although TGFb upregulates the avb6 integrin in vitro, we did not observe that blockade of TGFb activity altered avb6 expression in vivo. The 1 mg/kg dose of anti-avb6 but not the 0.3 mg/kg dose blocked fibrosis. However the trend to higher mortality with treatment with the higher dose antibody (10 mg/kg), if confirmed in further experiments, may indicate that partial rather than high-level inhibition of avb6-mediated TGFb activation may yield optimal results. These results support further investigation into blockade of avb6 as a therapeutic modality.

Experience with dose escalation using CHARTWEL (continuous hyperfractionated accelerated radiotherapy weekend less) in non-small-cell lung cancer

Results from the multicentre randomized trial of CHART (continuous, hyperfractionated, accelerated radiotherapy) in non-small-cell lung cancer (NSCLC) showed a significant increase in survival (P=0.004) compared with conventional radiotherapy and a therapeutic benefit relative to late radiation-induced morbidity. However, 60% of patients died because of failure to control locoregional disease. These findings have stimulated interest in assessing the feasibility of dose escalation using a modified CHART schedule. Acute and late morbidity with a CHARTWEL (CHART WeekEnd Less) schedule of 54 Gy in 16 days was compared with that observed with 60 Gy in 18 days in patients with locally advanced NSCLC. The incidence and severity of dysphagia and of analgesia were scored using a semiquantitative clinical scale. Late radiation-induced morbidity, namely pulmonary, spinal cord and oesophageal strictures, were monitored using clinical and/or radiological criteria. Acute dysphagia and the analgesia required to control the symptoms were more severe and lasted longer in patients treated with CHARTWEL 60 Gy (P< or = 0.02). However, at 12 weeks, oesophagitis was similar to that seen with 54 Gy and did not lead to consequential damage. Early radiation pneumonitis was not increased but, after 6 months, there was a higher incidence of mild pulmonary toxicity compared with CHARTWEL 54 Gy. No cases of radiation myelitis, oesophageal strictures or of grade 2 or 3 lung morbidity have been encountered. CHARTWEL 60 Gy resulted in an enhancement of oesophagitis and grade 1 lung toxicity compared with CHARTWEL 54 Gy. These were of no clinical significance, but may be important if CHARTWEL is used with concomitant chemotherapy. These results provide a basis for further dose escalation or the introduction of concurrent chemotherapy.

Repair in the mouse lung during low dose-rate irradiation

The thorax of CBA mice was exposed to 60Co gamma-rays at dose rates ranging from 100 to 2 cGy/min. Iso-effect doses (ED50) were calculated for early and late lung damage from dose-response curves for breathing rate and lethality. A continuous increase in tolerance for early radiation pneumonitis was seen as the dose rate was reduced, reaching a dose recovery factor (DRF) of 2.6 at 2 cGy/min. There was significantly less dose sparing with 2 cGy/min for the rise in breathing rate during expression of late damage (DRF = 2.1). The lower DRF compared well with that obtained from late measurements of pleural fluid levels. Comparison with fractionation experiments indicated incomplete repair at 2 cGy/min with further dose recovery expected at even lower dose rates or at doses per fraction below 200 cGy. Since the dose-rate dependence of damage to haemopoietic tissue is less marked, this study predicts an advantage of employing low dose-rate total-body irradiation (TBI) in the treatment of bone-marrow transplant patients. A further gain in the therapeutic index may be expected using a hyperfractionated regime with small doses per fraction.

Oxygen-dependent protection of radiation lung damage in mice by WR 2721.

The modification of early and late radiation damage to the mouse lung by oxygen and WR 2721 has been studied by measurement of breathing rate, lethality, pleural fluid and hydroxyproline content. Protection by hypoxia and sensitization by hyperoxia of early radiation pneumonitis were demonstrated. There was a tendency for the protective effect of WR 2721 to decrease as the breathed oxygen concentration was raised above normal levels. WR 2721 protection of the late damage was higher (PF = 1.6-1.65) than was seen for early pneumonitis (PF = 1.3-1.35) when either breathing rate or lethality were used. Protection factors (PF) gained from measurements of pleural fluid at a year after treatment were similar to those for other endpoints of late damage (PF = 1.7). In contrast, the measurement of fibrosis through determination of lung hydroxyproline at 1 year gave a somewhat lower protection factor for WR 2721. In the same experiments the degree of epilation on the dorsal thorax was scored at 6 weeks. One hundred per cent oxygen gave enhancement (dose enhancement factor (DEF) = 1.2), 9 per cent oxygen reduced damage (DEF less than 0.7) and WR 2721 gave PF values in excess of 1.4 at all oxygen concentrations used. This showed that the radiation response of hair follicles was more sensitive to WR 2721 or to changes of oxygen than the lung. The results presented indicate a competitive interaction between WR 2721 and oxygen for the same injury site causing a shift in the oxygen K curve to higher oxygen concentrations. The validity of applying functional or survival measurements to assess the extent of pulmonary fibrosis is discussed.

Early Radiation Pneumonitis: A Physiological and Anatomical Study

Early Radiation Pneumonitis: A Physiological and Anatomical Study