Dosimetric Risk Factors for Acute Radiation Pneumonitis in Patients With Prior Receipt of Immune Checkpoint Inhibitors

PurposeDosimetric parameters (e.g., mean lung dose (MLD), V20, and V5) can predict radiation pneumonitis (RP). Constraints thereof were formulated before the era of combined immune checkpoint inhibitors (ICIs) and radiotherapy, which could amplify the RP risk. Dosimetric predictors of acute RP (aRP) in the context of ICIs are urgently needed because no data exist thus far.Methods and MaterialsAll included patients underwent thoracic intensity-modulated radiotherapy, previously received ICIs, and followed-up at least once. Logistic regression models examined predictors of aRP (including a priori evaluation of MLD, V20, and V5), and their discriminative capacity was assessed by receiver operating characteristic analysis.ResultsMedian follow-up of the 40 patients was 5.3 months. Cancers were lung (80%) or esophageal (20%). ICIs were PD-1 (85%) or PD-L1 (15%) inhibitors (median 4 cycles). Patients underwent definitive (n=19), consolidative (n=14), or palliative (n=7) radiotherapy; the median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR, 51.8-64 Gy). Grades 1-5 aRP occurred in 25%, 17.5%, 15%, 2.5%, and 5%, respectively. The only variables associated with any-grade aRP were V20 (p=0.014) and MLD (p=0.026), and only V20 with grade ≥2 aRP (p=0.035). Neither the number of prior ICI cycles nor the delivery of concurrent systemic therapy significantly associated with aRP risk. Graphs were constructed showing the incrementally increasing risk of aRP based on V20 and MLD (continuous variables).ConclusionsThis is the first study illustrating that V20 and MLD may impact aRP in the setting of prior ICIs. However, these data should not be extrapolated to patients without pre-radiotherapy receipt of prior ICIs, or to evaluate the risk of chronic pulmonary effects. If these results are validated by larger studies with more homogeneous populations, the commonly accepted V20/MLD dose constraints could require revision if utilized in the setting of ICIs.

Potential Morbidity Reduction for Lung Stereotactic Body Radiation Therapy Using Respiratory Gating

We investigated the potential of respiratory gating to mitigate the motion-caused misdosage in lung stereotactic body radiotherapy (SBRT). For fourteen patients with lung tumors, we investigated treatment plans for a gating window (GW) including three breathing phases around the maximum exhalation phase, GW40-60. For a subset of six patients, we also assessed a preceding three-phase GW20-40 and six-phase GW20-70. We analyzed the target volume, lung, esophagus, and heart doses. Using normal tissue complication probability (NTCP) models, we estimated radiation pneumonitis and esophagitis risks . Compared to plans without gating, GW40-60 significantly reduced doses to organs at risk without impairing the tumor doses. On average, the mean lung dose decreased by 0.6 Gy (p < 0.001), treated lung V20Gy by 2.4% (p = 0.003), esophageal dose to 5cc by 2.0 Gy (p = 0.003), and maximum heart dose by 3.2 Gy (p = 0.009). The model-estimated mean risks of 11% for pneumonitis and 12% for esophagitis without gating decreased upon GW40-60 to 7% and 9%, respectively. For the highest-risk patient, gating reduced the pneumonitis risk from 43% to 32%. Gating is most beneficial for patients with high-toxicity risks. Pre-treatment toxicity risk assessment may help optimize patient selection for gating, as well as GW selection for individual patients.

Preliminary Study on the Effect of 4DCT-Ventilation-Weighted Dose on the Radiation Induced Pneumonia Probability (RIPP)

Purpose: The purpose of the present study was to evaluate the feasibility of using 4-dimensional computed tomography (4DCT)-ventilation-weighted dose analysis to predict radiation-induced pneumonia probability (RIPP). Methods and Materials: The study population for this retrospective analysis included 16 patients with stage III lung cancer. Each patient’s 4DCT images, including end-inhale and end-exhale sequences, were used for the deformable image registration, and the Hounsfield units (HU) density-change was used to calculate the ventilation. A previously established equation was used to convert the original dose (OD) D 0, i in the lungs in the original plan (OP) to the weighted-dose (WD) D w, i in the weighted plan (WP). The patients were divided into 2 groups, one with radiation-induced pneumonia (RIP), and one without. The Spearman correlation analysis was used to analyze the correlation of RIP with ΔV20 (ΔV x = V w, x in the WP – V 0, x in the OP), ΔMLD (ΔMLD = mean lung dose (MLD) in the WP – MLD in the OP), and ΔV5. Results: The results showed that 5 of the 16 patients were suffering from acute RIP, 4 of which had higher ΔV20 and ΔMLD values than the rest of the patients. The results of the Spearman correlation analysis for those 4 patients were as follows: RIP vs. ΔV20, r = 0.5123; RIP vs. ΔMLD, r = 0.5119; RIP vs. ΔV5, r = 0.1904. Conclusions: The 4DCT-ventilation-based weighted-dose analysis showed some correlation between RIPP and both ΔV20 and ΔMLD, when comparing the weighted-dose and the conventional dose-volume histogram (DVH) analyses.

The Risk Factors for Radiation Pneumonitis After Single-Fraction Carbon-Ion Radiotherapy for Lung Cancer or Metastasis

There are no studies on the risk factors of radiation pneumonitis (RP) after carbon-ion radiotherapy at a dose of 50 Gy (relative biological effectiveness (RBE)) in a single fraction. The objective of this study was to identify factors associated with RP after radiotherapy, including dose–volume parameters. Ninety-eight patients without a history of thoracic radiotherapy who underwent treatment for solitary lung tumors between July 2013 and April 2016 were retrospectively analyzed. Treatment was planned using Xio-N. The median follow-up duration was 53 months, and the median clinical target volume was 32.3 mL. Three patients developed grade 2 RP, and one patient developed grade 3 interstitial pneumonitis. None of the patients developed grade 4 or 5 RP. The dose-volume parameters of the normal lung irradiated at least with 5–30 Gy (RBE), and the mean lung dose was significantly lower in patients with grade 0–1 RP than in those with grade 2–3 RP. Pretreatment with higher SP-D and interstitial pneumonitis were significant factors for the occurrence of symptomatic RP. The present study showed a certain standard for single-fraction carbon-ion radiotherapy that does not increase the risk of RP; however, further validation studies are needed.

Risk factors for radiation pneumonitis in lung cancer patients with subclinical interstitial lung disease after thoracic radiation therapy

Background Previous studies have found that patients with subclinical interstitial lung disease (ILD) are highly susceptible to developing radiation pneumonitis (RP) after thoracic radiation therapy. In the present study we aimed to evaluate the incidence of and risk factors for RP after thoracic intensity-modulated radiation therapy in lung cancer patients with subclinical ILD. Methods We retrospectively analyzed data from lung cancer patients with subclinical ILD who were treated with thoracic intensity-modulated radiation therapy with a prescribed dose of ≥ 50 Gy in our institution between January 2016 and December 2017. Results Eighty-seven consecutive lung cancer patients with subclinical ILD were selected for the study. The median follow-up period was 14.0 months. The cumulative incidence of grades ≥ 2 and ≥ 3 RP at one year was 51.0% and 20.9%, respectively. In the multivariate analysis, a mean lung dose ≥ 12 Gy was a significant risk factor for grade ≥ 2 RP (p = 0.049). Chemotherapy with gemcitabine in the past, V5 ≥ 50%, and subclinical ILD involving ≥ 25% of the lung volume were significantly associated with grade ≥ 3 RP (p = 0.046, p = 0.040, and p = 0.024, respectively). Conclusion Mean lung dose is a significant risk factor for grade ≥ 2 RP. Lung cancer patients who have received chemotherapy with gemcitabine in the past, V5 ≥ 50%, and those with subclinical ILD involving ≥ 25% of lung volume have an increased risk of grade ≥ 3 RP in lung cancer patients with subclinical ILD.

Chemoradiotherapy by intensity-modulated radiation therapy with simultaneous integrated boost in locally advanced or oligometastatic non-small-cell lung cancer—a two center experience

Purpose Integrating moderate hypofractionation to the macroscopic tumor with elective nodal irradiation while sparing the organs at risk (OAR) in chemoradiotherapy of locally advanced non-small-cell lung cancer. Methods From 2010–2018, treatment, patient and tumor characteristics of 138 patients from two radiation therapy centers were assessed. Chemoradiotherapy by intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) to the primary tumor and macroscopic lymph node metastases was used. Results A total of 124 (90%) patients received concurrent chemotherapy. 106 (76%) patients had UICC (Union for International Cancer Control) stage ≥IIIB and 21 (15%) patients had an oligometastatic disease (UICC stage IV). Median SIB and elective total dose was 61.6 and 50.4 Gy in 28 fractions, respectively. Furthermore, 64 patients (46%) had an additional sequential boost to the primary tumor after the SIB-IMRT main series: median 6.6 Gy in median 3 fractions. The median cumulative mean lung dose was 15.6 Gy (range 6.2–29.5 Gy). Median follow-up and radiological follow-up for all patients was 18.0 months (range 0.6–86.9) and 16.0 months (range 0.2–86.9), respectively. Actuarial local control rates at 1, 2 and 3 years were 80.4, 68.4 and 57.8%. Median overall survival and progression-free survival was 30.0 months (95% confidence interval [CI] 23.5–36.4) and 12.1 months (95% CI 8.2–16.0), respectively. Treatment-related toxicity was moderate. Radiation-induced pneumonitis grade 2 and grade 3 occurred in 13 (9.8%) and 3 (2.3%) patients. Conclusions Chemoradiotherapy using SIB-IMRT showed promising local tumor control rates and acceptable toxicity in patients with locally advanced and in part oligometastatic lung cancer. The SIB concept, resulting in a relatively low mean lung dose, was associated with low numbers of clinically relevant pneumonitis. The overall survival appears promising in the presence of a majority of patients with UICC stage ≥IIIB disease.

Volume-based algorithm of lung dose optimization in novel dynamic arc radiotherapy for esophageal cancer

This study aims to develop a volume-based algorithm (VBA) that can rapidly optimize rotating gantry arc angles and predict the lung V5 preceding the treatment planning. This phantom study was performed in the dynamic arc therapy planning systems for an esophageal cancer model. The angle of rotation of the gantry around the isocenter as defined as arc angle (θA), ranging from 360° to 80° with an interval of 20°, resulting in 15 different θA of treatment plans. The corresponding predicted lung V5 was calculated by the VBA, the mean lung dose, lung V5, lung V20, mean heart dose, heart V30, the spinal cord maximum dose and conformity index were assessed from dose–volume histogram in the treatment plan. Correlations between the predicted lung V5 and the dosimetric indices were evaluated using Pearson’s correlation coefficient. The results showed that the predicted lung V5 and the lung V5 in the treatment plan were positively correlated (r = 0.996, p < 0.001). As the θA decreased, lung V5, lung V20, and the mean lung dose decreased while the mean heart dose, V30 and the spinal cord maximum dose increased. The V20 and the mean lung dose also showed high correlations with the predicted lung V5 (r = 0.974, 0.999, p < 0.001). This study successfully developed an efficient VBA to rapidly calculate the θA to predict the lung V5 and reduce the lung dose, with potentials to improve the current clinical practice of dynamic arc radiotherapy.

Cone-Beam-CT Guided Adaptive Radiotherapy for Locally Advanced Non-small Cell Lung Cancer Enables Quality Assurance and Superior Sparing of Healthy Lung

PurposeTo evaluate the potential of cone-beam-CT (CB-CT) guided adaptive radiotherapy (ART) for locally advanced non-small cell lung cancer (NSCLC) for sparing of surrounding organs-at-risk (OAR).Materials and MethodsIn 10 patients with locally advanced NSCLC, daily CB-CT imaging was acquired during radio- (n = 4) or radiochemotherapy (n = 6) for simulation of ART. Patients were treated with conventionally fractionated intensity-modulated radiotherapy (IMRT) with total doses of 60–66 Gy (pPlan) (311 fraction CB-CTs). OAR were segmented on every daily CB-CT and the tumor volumes were modified weekly depending on tumor changes. Doses actually delivered were recalculated on daily images (dPlan), and voxel-wise dose accumulation was performed using a deformable registration algorithm. For simulation of ART, treatment plans were adapted using the new contours and re-optimized weekly (aPlan).ResultsCB-CT showed continuous tumor regression of 1.1 ± 0.4% per day, leading to a residual gross tumor volume (GTV) of 65.3 ± 13.4% after 6 weeks of radiotherapy (p = 0.005). Corresponding PTVs decreased to 83.7 ± 7.8% (p = 0.005). In the actually delivered plans (dPlan), both conformity (p = 0.005) and homogeneity (p = 0.059) indices were impaired compared to the initial plans (pPlan). This resulted in higher actual lung doses than planned: V20Gy was 34.6 ± 6.8% instead of 32.8 ± 4.9% (p = 0.066), mean lung dose was 19.0 ± 3.1 Gy instead of 17.9 ± 2.5 Gy (p = 0.013). The generalized equivalent uniform dose (gEUD) of the lung was 18.9 ± 3.1 Gy instead of 17.8 ± 2.5 Gy (p = 0.013), leading to an increased lung normal tissue complication probability (NTCP) of 15.2 ± 13.9% instead of 9.6 ± 7.3% (p = 0.017). Weekly plan adaptation enabled decreased lung V20Gy of 31.6 ± 6.2% (−3.0%, p = 0.007), decreased mean lung dose of 17.7 ± 2.9 Gy (−1.3 Gy, p = 0.005), and decreased lung gEUD of 17.6 ± 2.9 Gy (−1.3 Gy, p = 0.005). Thus, resulting lung NTCP was reduced to 10.0 ± 9.5% (−5.2%, p = 0.005). Target volume coverage represented by conformity and homogeneity indices could be improved by weekly plan adaptation (CI: p = 0.007, HI: p = 0.114) and reached levels of the initial plan (CI: p = 0.721, HI: p = 0.333).ConclusionIGRT with CB-CT detects continuous GTV and PTV changes. CB-CT-guided ART for locally advanced NSCLC is feasible and enables superior sparing of healthy lung at high levels of plan conformity.

A Novel Nomogram Containing Acute Radiation Esophagitis Predicting Radiation Pneumonitis in Thoracic Cancer Receiving Radiotherapy

BackgroundRadiation-induced pneumonitis (RP) is a non-negligible and sometimes life-threatening complication in patients with thoracic radiation. We initially aimed to ascertain the predict value of acute radiation-induced esophagitis (SARE, grade≥2) to symptomatic RP (SRP, grade≥2) among thoracic cancer patients receiving radiotherapy. Based on that, we also established a novel nomogram model to provide individualized risk assessment for SRP.MethodsPatients with thoracic cancer who were treated with thoracic radiation from Jan 2018 to Jan 2019 in Shandong Cancer Hospital and Institute were enrolled prospectively. All patients were followed up during and after radiotherapy (RT) to observe the appearance of esophagitis and pneumonitis. Variables were analyzed by univariate and multivariate analysis using the logistic regression model, and a nomogram model was established to predict SRP by "R" version 3.6.0.ResultsA total of 123 patients were enrolled (64 esophageal cancer, 57 lung cancer and 2 mediastinal cancer) in this study prospectively. RP grades of 0, 1, 2, 3, 4 and 5 occurred in 29, 57, 31, 0, 3 and 3 patients, respectively. SRP appeared in 37 patients (30.1%). In univariate analysis, SARE was shown to be a significant predictive factor for SRP (P < 0.001), with the sensitivity 91.9% and the negative predictive value 93.5%. The incidence of SRP in different grades of ARE were as follows: Grade 0-1: 6.5%; Grade 2: 36.9%; Grade 3: 80.0%; Grade 4: 100%. Besides that, the dosimetric factors considering total lung mean dose, total lung V5, V20, ipsilateral lung mean dose, ipsilateral lung V5, and mean esophagus dose were correlated with SRP (all P < 0.005) by univariate analysis. The incidence of SRP was significantly higher in patients whose symptoms of RP appeared early. SARE (HR 34.408, P = 0.001), mean esophagus dose and ipsilateral mean lung dose were still significant in multivariate analysis, and they were included to build a predictive nomogram model for SRP.ConclusionsSARE was an easy index that can reflect patients’ radiosensitivity visually, which could be an applicable predictor for SRP in patients receiving thoracic radiation. And the nomogram could assist in accurate prediction to SRP in clinic.