Risk Of Radiation-induced Pneumonitis Research Articles

CBCT-guided adaptive radiotherapy using self-supervised sequential domain adaptation with uncertainty estimation.

Adaptive radiotherapy (ART) is an advanced technology in modern cancer treatment that incorporates progressive changes in patient anatomy into active plan/dose adaption during the fractionated treatment. However, the clinical application relies on the accurate segmentation of cancer tumors on low-quality on-board images, which has posed challenges for both manual delineation and deep learning-based models. In this paper, we propose a novel sequence transduction deep neural network with an attention mechanism to learn the shrinkage of the cancer tumor based on patients' weekly cone-beam computed tomography (CBCT). We design a self-supervised domain adaption (SDA) method to learn and adapt the rich textural and spatial features from pre-treatment high-quality computed tomography (CT) to CBCT modality in order to address the poor image quality and lack of labels. We also provide uncertainty estimation for sequential segmentation, which aids not only in the risk management of treatment planning but also in the calibration and reliability of the model. Our experimental results based on a clinical non-small cell lung cancer (NSCLC) dataset with sixteen patients and ninety-six longitudinal CBCTs show that our model correctly learns weekly deformation of the tumor over time with an average dice score of 0.92 on the immediate next step, and is able to predict multiple steps (up to 5 weeks) for future patient treatments with an average dice score reduction of 0.05. By incorporating the tumor shrinkage predictions into a weekly re-planning strategy, our proposed method demonstrates a significant decrease in the risk of radiation-induced pneumonitis up to 35% while maintaining the high tumor control probability.

Abstract P3-19-28: The impact of PM2.5 on the radiation-induced pneumonitis in patients with breast cancer

Abstract Purpose: Exposure to particulate matter (PM) air pollution has been associated with adverse effect on respiratory disease, but no study has investigated its impact on radiation-induced pneumonitis (RIP) in patients with breast cancer who received adjuvant radiation therapy (RT). Materials and Methods: We conducted a retrospective review of 2,762 breast cancer patients who received postoperative RT between 2017 and 2020 in a single institution. Particulate matter data including PM2.5 and PM10 were retrieved from the open dataset in the ‘Gyeonggi Data Dream’. We used the average, median and maximum values of the PM2.5 and PM10 measured during daytime when a patient visited to the hospital for RT. We excluded the patients when missing PM data exceeded 50% of the total treatment period (N=26). Finally, altogether 2,736 patients were analyzed. Results: Overall incidence rate of RIP was 1.74%. There were no significant differences in average value of PM2.5 and number of RT fractions between RIP (+) and RIP (-) groups, but marginal differences were found in RT techniques (3-dimentional conformal RT vs. intensity modulated RT, P=0.053) and proportion of PM2.5 value ≥ 35 (μg/m3) (P=0.053) between the two groups. After adjusting for age, RT technique, regional irradiation, fractionation and boost, the average value of PM2.5 was significantly associated with a higher risk of RIP (Odds ratio [OR] 1.05, 95% confidential incidence [CI] 1.00-1.10, P=0.047) when patients received ≥ 20 fractions of RT. Especially, PM2.5 ≥ 35 (μg/m3) showed significant higher risk of RIP (OR 4.32, 95% CI 1.34-13.87, P=0.014) in patients with ≥ 20 fractions of RT after adjustment of aforementioned covariates. Other PM data (median, maximum value of PM2.5 and all PM10 values) were not related to the RIP regardless of the number of RT fractions. Conclusion: This is the first study to reveal the association between PM2.5 and RIP in breast cancer patients who received 20 fractions or more of postoperative RT. Citation Format: Dong-Yun Kim, In Ah Kim, Bum-Sup Jang. The impact of PM2.5 on the radiation-induced pneumonitis in patients with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-28.

Calculating the individualized fraction regime in stereotactic body radiotherapy for non-small cell lung cancer based on uncomplicated tumor control probability function

BackgroundTo calculate the individualized fraction regime (IFR) in stereotactic body radiotherapy (SBRT) for non-small cell lung cancer (NSCLC) patients using the uncomplicated tumor control probability (UTCP, P+) function.MethodsThirty-three patients with peripheral lung cancer or lung metastases who had undergone SBRT were analyzed. Treatment planning was performed using the dose regime of 48 Gy in 4 fractions. Dose volume histogram (DVH) data for the gross tumor volume (GTV), lung, chest wall (CW) and rib were exported and the dose bin was multiplied by a certain percentage of the dose in that bin which ranged from 1 to 200% in steps of 1%. For each dose fraction, P+ values were calculated by considering the tumor control probability (TCP), radiation-induced pneumonitis (RIP), chest wall pain (CWP) and radiation-induced rib fracture (RIRF). UTCP values as a function of physical dose were plotted and the maximum P+ values corresponded to the optimal therapeutic gain. The IFR in 3 fractions was also calculated with the same method by converting the dose using the linear quadratic (LQ) model.ResultsThirty-three patients attained an IFR using the introduced methods. All the patients achieved a TCP value higher than 92.0%. The IFR ranged from 3 × 10.8 Gy to 3 × 12.5 Gy for 3 fraction regimes and from 4 × 9.2 Gy to 4 × 10.7 Gy for 4 fraction regimes. Four patients with typical tumor characteristics demonstrated that the IFR was patient-specific and could maximize the therapeutic gain. Patients with a large tumor had a lower TCP and UTCP and a smaller fractional dose than patients with a small tumor. Patients with a tumor adjacent to the organ at risk (OAR) or at a high risk of RIP had a lower UTCP and a smaller fractional dose compared with patients with a tumor located distant from the OAR.ConclusionsThe proposed method is capable of predicting the IFR for NSCLC patients undergoing SBRT. Further validation in clinical samples is required.

Propensity-score-matched evaluation of the incidence of radiation pneumonitis and secondary cancer risk for breast cancer patients treated with IMRT/VMAT

Propensity score matching evaluates the treatment incidence of radiation-induced pneumonitis (RP) and secondary cancer risk (SCR) after intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) for breast cancer patients. Of 32 patients treated with IMRT and 58 who received VMAT were propensity matched in a 1:1 ratio. RP and SCR were evaluated as the endpoints of acute and chronic toxicity, respectively. Self-fitted normal tissue complication probability (NTCP) parameter values were used to analyze the risk of RP. SCRs were evaluated using the preferred Schneider’s parameterization risk models. The dosimetric parameter of the ipsilateral lung volume receiving 40 Gy (IV40) was selected as the dominant risk factor for the RP NTCP model. The results showed that the risks of RP and NTCP, as well as that of SCR of the ipsilateral lung, were slightly lower than the values in patients treated with VMAT versus IMRT (p ≤ 0.01). However, the organ equivalent dose and excess absolute risk values in the contralateral lung and breast were slightly higher with VMAT than with IMRT (p ≤ 0.05). When compared to IMRT, VMAT is a rational radiotherapy option for breast cancer patients, based on its reduced potential for inducing secondary malignancies and RP complications.

A polymorphism in the DNA repair domain of APEX1 is associated with the radiation-induced pneumonitis risk among lung cancer patients after radiotherapy.

To examine the association of tag single nucleotide polymorphisms (tagSNPs) (rs1130409, rs1760944, rs2307486 and rs3136817) in APEX1 with the risk of severe radiation-induced pneumonitis (RP) after radiotherapy among Han Chinese patients with lung cancer. A total of 168 patients with lung cancer who were receiving radiotherapy were prospectively recruited. RP was evaluated according to the Radiation Therapy Oncology Group. A case-control study was performed. The case group included patients with RP grade of ≥3, while the control group comprised patients with RP grades <3. Four tagSNPs of APEX1 were genotyped in 126 patients with complete follow-up by multi-SNaPshot® (Genesky Biotechnologies Inc., Shanghai, China) genotyping assays. RESULTS were assessed by a logistic regression model for RP risk and Mantal-Cox log-rank test for the cumulative RP probability by the genotypes. rs1130409 was associated with severe RP. GT genotype of rs1130409 was significantly higher in patients with RP than in those of the control group [68.8% vs 41.8%; p = 0.025; resulting odds ratio (OR), 5.98]. Patients with lung cancer bearing the G allele had a 5.83-fold higher risk of RP than those with the wild TT genotype [OR = 5.83; 95% confidence interval (CI), 1.27-26.90; p = 0.024], and this was further confirmed by the binary regression adjusted by some confounding factors, including Karnofsky performance scale, concurrent chemotherapy-radiotherapy and lung volume receiving >30 Gy (OR = 6.96; 95% CI, 1.36-35.77; p = 0.02). rs1130409 was also associated with the time to occurrence of severe RP (p = 0.04). Three-dimensional model APEX1 protein showed that rs1130409 is located in the random coil structure corresponding to the DNA repair function region. rs1130409 of APEX1 can be a predictor of RP grades ≥3 among patients with lung cancer.

ATM Polymorphisms Predict Severe Radiation Pneumonitis in Patients With Non-Small Cell Lung Cancer Treated With Definitive Radiation Therapy

The ataxia telangiectasia mutated (ATM) gene mediates detection and repair of DNA damage. We investigated associations between ATM polymorphisms and severe radiation-induced pneumonitis (RP). We genotyped 3 potentially functional single nucleotide polymorphisms (SNPs) of ATM (rs1801516 [D1853N/5557G>A], rs189037 [-111G>A] and rs228590) in 362 patients with non-small cell lung cancer (NSCLC), who received definitive (chemo)radiation therapy. The cumulative severe RP probabilities by genotypes were evaluated using the Kaplan-Meier analysis. The associations between severe RP risk and genotypes were assessed by both logistic regression analysis and Cox proportional hazard model with time to event considered. Of 362 patients (72.4% of non-Hispanic whites), 56 (15.5%) experienced grade ≥3 RP. Patients carrying ATM rs189037 AG/GG or rs228590 TT/CT genotypes or rs189037G/rs228590T/rs1801516G (G-T-G) haplotype had a lower risk of severe RP (rs189037: GG/AG vs AA, adjusted hazard ratio [HR] = 0.49, 95% confidence interval [CI], 0.29-0.83, P=.009; rs228590: TT/CT vs CC, HR=0.57, 95% CI, 0.33-0.97, P=.036; haplotype: G-T-G vs A-C-G, HR=0.52, 95% CI, 0.35-0.79, P=.002). Such positive findings remained in non-Hispanic whites. ATM polymorphisms may serve as biomarkers for susceptibility to severe RP in non-Hispanic whites. Large prospective studies are required to confirm our findings.

Does VMAT for treatment of NSCLC patients increase the risk of pneumonitis compared to IMRT ? – A planning study

Background. Volumetric modulated arc therapy (VMAT) for treatment of non-small cell lung cancer (NSCLC) patients potentially changes the risk of radiation-induced pneumonitis (RP) compared to intensity modulated radiation therapy (IMRT) if the dose to the healthy lung is changed significantly. In this study, clinical IMRT plans were used as starting point for VMAT optimization and differences in risk estimates of RP between the two plan types were evaluated. Material and methods. Fifteen NSCLC patients prescribed 66 Gy in 2 Gy fractions were planned with IMRT and subsequently with single arc VMAT. Dose metrics were evaluated for target and lung together with population averaged dose volume histograms. The risk of RP was calculated using normal tissue complication probability (NTCP) models. Finally, applicability of the plans was tested through delivery on an Elekta accelerator. Results. When changing from IMRT to VMAT only modest differences were observed in the dose to the lung and target volume. On average, fractions of lung irradiated to doses between 18 Gy and 48 Gy were statistically significant reduced using VMAT compared to IMRT. For the fraction of lung receiving more than 20 Gy the reduction was 1.2% percentage points: (range –0.6 –2.6%). The evaluated toxicity were smaller with VMAT compared to IMRT, however only modest differences were observed in the NTCP values. The plans were delivered without any problems. The average beam on time with VMAT was 83 s. This was a reduction of 141 s (ranging from 37 s to 216 s) compared to IMRT. Conclusions. Using IMRT as reference for the VMAT optimization it was possible to implement VMAT in the clinic with no increase in estimated risk of RP. Thus, toxicity is not expected to be a hindrance to using VMAT and will profit from the shorter delivery time with VMAT compared to IMRT.

TGF-β1 Gene Polymorphisms are not Associated with Risk of Radiation-induced Pneumonitis in Chinese

TGF-β1 Gene Polymorphisms are not Associated with Risk of Radiation-induced Pneumonitis in Chinese

Association of P53 and ATM Polymorphisms With Risk of Radiation-Induced Pneumonitis in Lung Cancer Patients Treated With Radiotherapy

Radiation-induced pneumonitis (RP) is the most common dose-limiting complication in lung cancer patients treated with radiotherapy. Accumulating evidence indicates that P53 and the ataxia telangiectasia-mutated protein (ATM)-dependent signaling response cascade play a crucial role in radiation-induced diseases. Consistent with this, our previous study showed that a functional genetic ATM polymorphism was associated with increased RP risk. To evaluate the role of genetic P53 polymorphism in RP, we analyzed the P53 Arg72Pro polymorphism in a cohort including 253 lung cancer patients receiving thoracic irradiation. We found that the P53 72Arg/Arg genotype was associated with increased RP risk compared with the 72Pro/Pro genotype. Furthermore, the P53 Arg72Pro and ATM -111G>A polymorphisms display an additive combination effect in intensifying the risk of developing RP. The cross-validation test showed that 63.2% of RP cases can be identified by P53 and ATM genotypes. These results indicate that genetic polymorphisms in the ATM-P53 pathway influence susceptibility to RP and genotyping P53 and ATM polymorphisms might help to identify patients susceptible to developing RP when receiving radiotherapy.

ATM Polymorphisms Are Associated With Risk of Radiation-Induced Pneumonitis

Since the ataxia telangiectasia mutated (ATM) protein plays crucial roles in repair of double-stranded DNA breaks, control of cell cycle checkpoints, and radiosensitivity, we hypothesized that variations in this gene might be associated with radiation-induced pneumonitis (RP). A total of 253 lung cancer patients receiving thoracic irradiation between 2004 and 2006 were included in this study. Common Terminology Criteria for Adverse Events version 3.0 was used to grade RP. Five haplotype-tagging single nucleotide polymorphisms (SNPs) in the ATM gene were genotyped using DNA from blood lymphocytes. Hazard ratios (HRs) and 95% confidence intervals (CIs) of RP for genotypes were computed by the Cox model, adjusted for clinical factors. The function of the ATM SNP associated with RP was examined by biochemical assays. During the median 22-month follow-up, 44 (17.4%) patients developed grade > or = 2 RP. In multivariate Cox regression models adjusted for other clinical predictors, we found two ATM variants were independently associated with increased RP risk. They were an 111G > A) polymorphism (HR, 2.49; 95% CI, 1.07-5.80) and an ATM 126713G > A polymorphism (HR, 2.47; 95% CI, 1.16-5.28). Furthermore, genotype-dependent differences in ATM expression were demonstrated both in cell lines (p < 0.001) and in individual lung tissue samples (p = 0.003), which supported the results of the association study. Genetic polymorphisms of ATM are significantly associated with RP risk. These variants might exert their effect through regulation of ATM expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy.