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This chapter reviews and discusses approaches and strategies of personalized radiation therapy (PRT) for lung cancers at four different levels: (1) clinically established PRT based on a patient's histology, stage, tumor volume and tumor locations; (2) personalized adaptive radiation therapy (RT) based on image response during treatment; (3) PRT based on biomarkers; (4) personalized fractionation schedule. The current RT practice for lung cancer is partially individualized according to tumor histology, stage, size/location, and combination with use of systemic therapy. During-RT PET-CT image guided adaptive treatment is being tested in a multicenter trial. Treatment response detected by the during-RT images may also provide a strategy to further personalize the remaining treatment. Research on biomarker-guided PRT is ongoing. The biomarkers include genomics, proteomics, microRNA, cytokines, metabolomics from tumor and blood samples, and radiomics from PET, CT, SPECT images. Finally, RT fractionation schedule may also be personalized to each individual patient to maximize therapeutic gain. Future PRT should be based on comprehensive considerations of knowledge acquired from all these levels, as well as consideration of the societal value such as cost and effectiveness.
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Biomarcadores Tumorais/genética , Neoplasias Pulmonares/radioterapia , Medicina de Precisão/métodos , Compostos Radiofarmacêuticos/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/radioterapia , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos da radiação , Tomografia por Emissão de Pósitrons , Medicina de Precisão/instrumentação , Tolerância a Radiação/genética , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Carga Tumoral/efeitos da radiaçãoRESUMO
BACKGROUND: Lymphopenia is known for its significance on poor survivals in breast cancer patients. Considering full dosimetric data, this study aimed to develop and validate predictive models for lymphopenia after radiotherapy (RT) in breast cancer. MATERIAL AND METHODS: Patients with breast cancer treated with adjuvant RT were eligible in this multicenter study. The study endpoint was lympopenia, defined as the reduction in absolute lymphocytes and graded lymphopenia after RT. The dose-volume histogram (DVH) data of related critical structures and clinical factors were taken into account for the development of dense neural network (DNN) predictive models. The developed DNN models were validated using external patient cohorts. RESULTS: A total of 918 consecutive patients with invasive breast cancer enrolled. The training, testing, and external validating datasets consisted of 589, 203, and 126 patients, respectively. Treatment volumes at nearly all dose levels of the DVH were significant predictors for lymphopenia following RT, including volumes at very low-dose 1 Gy (V1) of organs at risk (OARs) including lung, heart and body, especially ipsilateral-lung V1. A final DNN model, combining full DVH dosimetric parameters of OARs and three key clinical factors, achieved a predictive accuracy of 75 % or higher. CONCLUSION: This study demonstrated and externally validated the significance of full dosimetric data, particularly the volume of low dose at as low as 1 Gy of critical structures on lymphopenia after radiation in patients with breast cancer. The significance of V1 deserves special attention, as modern VMAT RT technology often has a relatively high value of this parameter. Further study is warranted for RT plan optimization.
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Neoplasias da Mama , Aprendizado Profundo , Linfopenia , Dosagem Radioterapêutica , Humanos , Linfopenia/etiologia , Feminino , Neoplasias da Mama/radioterapia , Pessoa de Meia-Idade , Idoso , Órgãos em Risco/efeitos da radiação , Adulto , Radioterapia Adjuvante/efeitos adversos , Planejamento da Radioterapia Assistida por Computador/métodosRESUMO
Purpose: Radiation-induced lymphopenia is a well-recognized factor for tumor control and survival in patients with cancer. This study aimed to determine the role of radiation dose to the thymus and thoracic duct on radiation-induced lymphopenia. Methods and Materials: Patients with primary lung cancer treated with thoracic radiation therapy between May 2015 and February 2020 with whole blood count data were eligible. Clinical characteristics, including age, gender, histology, stage, chemotherapy regimen, radiation dosimetry, and absolute lymphocyte count (ALC) were collected. The thymus and thoracic duct were contoured by one investigator for consistency and checked by one senior physician. The primary endpoint was radiation-induced decrease in lymphocytes, defined as the difference in ALC (DALC) before and after radiation therapy. Results: The data of a total of 116 consecutive patients were retrospectively retrieved. Significant correlations were found between DALC and several clinical factors. These factors include stage, chemotherapy or concurrent chemoradiation, biologically effective dose (BED), mean lung dose, mean body dose, effective dose to immune cells (EDIC), mean thymus dose (MTD), and mean thoracic duct dose (MTDD) (all P < .05). Ridge regression showed that DALC = 0.0063 × BED + 0.0172 × EDIC + 0.0002 × MTD + 0.0147 × MTDD + 0.2510 (overall P = .00025 and F = 5.85). The combination model has the highest area under the curve of 0.77 (P < .001) when fitting the logistic regression model on DALC categorized as binary endpoint. The sensitivity and specificity of the combined model were 89% and 58%, respectively. Conclusions: This study demonstrated for the first time that radiation doses to the thymus and thoracic duct are strongly associated with radiation-induced lymphopenia patients with lung cancer. Further validation studies are needed to implement thymus and thoracic duct as organs at risk.
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PURPOSE: To evaluate the feasibility of a synchronized moving grid (SMOG) system to remove scatter artifacts, improve the contrast-to-noise ratio (CNR), and reduce image lag artifacts in cone-beam CT (CBCT). METHODS: The SMOG system proposed here uses a rapidly oscillating, synchronized moving grid attached to the kV source. Multiple partial projections are taken at different grid positions to form a complete projection in each gantry position, before the gantry moves to the next position during a scan. The grid has a low transmission factor, and it is used for both scatter reduction and scatter measurement for postscan scatter correction. Experimental studies using a static grid and an enlarged CATphan phantom were performed to evaluate the potential CNR enhancement for different SMOG exposure numbers (1, 2, and 4). Simulation studies were performed to evaluate the image lag correction for different exposure numbers (2, 3, and 4) and grid interspace widths in SMOG using the data from an anthropomorphic pelvis phantom scan. Imaging dose of SMOG was also estimated by measuring the imaging dose in a CIRS CT dose phantom using a static grid. RESULTS: SMOG can enhance the CNR by 16% and 13% when increasing exposure number from 1 to 2 and from 2 to 4, respectively. This enhancement was more dramatic for larger phantoms and smaller initial exposure numbers. Simulation results indicated that SMOG could reduce the lag to less than 4.3% for 2-exposure mode and to less than 0.8% for 3-exposure mode when the grid interspace width was 1.4 cm. Increasing the number of exposures in SMOG dramatically reduced the residual lag in the image. Reducing the grid interspace width somewhat reduced the residual lag. Skin line artifacts were removed entirely in SMOG. Point dose measurement showed that imaging dose of SMOG at isocenter was similar as that of a conventional CBCT. CONCLUSIONS: Compared to our previously developed static-grid dual-rotation method, the proposed SMOG technique has the advantages of enhancing the CNR, correcting the image lag, and reducing the delivery time. Once implemented, SMOG has the potential to remove scatter and image lag artifacts, and significantly enhance CNR for CBCT using the same scanning time as conventional CBCT.
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Tomografia Computadorizada de Feixe Cônico/métodos , Algoritmos , Artefatos , Simulação por Computador , Desenho de Equipamento , Estudos de Viabilidade , Humanos , Processamento de Imagem Assistida por Computador/métodos , Modelos Estatísticos , Método de Monte Carlo , Oscilometria/métodos , Imagens de Fantasmas , Reprodutibilidade dos Testes , Espalhamento de Radiação , Pele/patologiaRESUMO
Current commercially available planning systems with Monte Carlo (MC)-based final dose calculation in IMRT planning employ pencil-beam (PB) algorithms in the optimization process. Consequently, dose coverage for SBRT lung plans can feature cold-spots at the interface between lung and tumor tissue. For lung wall (LW)-seated tumors, there can also be hot spots within nearby normal organs (example: ribs). This study evaluated two different practical approaches to limiting cold spots within the target and reducing high doses to surrounding normal organs in MC-based IMRT planning of LW-seated tumors. First, "iterative reoptimization", where the MC calculation (with PB-based optimization) is initially performed. The resultant cold spot is then contoured and used as a simultaneous boost volume. The MC-based dose is then recomputed. The second technique uses noncoplanar beam angles with limited path through lung tissue. Both techniques were evaluated against a conventional coplanar beam approach with a single MC calculation. In all techniques the prescription dose was normalized to cover 95% of the PTV. Fifteen SBRT lung cases with LW-seated tumors were planned. The results from iterative reoptimization showed that conformity index (CI) and/or PTV dose uniformity (UPTV) improved in 12/15 plans. Average improvement was 13%, and 24%, respectively. Nonimproved plans had PTVs near the skin, trachea, and/or very small lung involvement. The maximum dose to 1cc volume (D1cc) of surrounding OARs decreased in 14/15 plans (average 10%). Using noncoplanar beams showed an average improvement of 7% in 10/15 cases and 11% in 5/15 cases for CI and UPTV, respectively. The D1cc was reduced by an average of 6% in 10/15 cases to surrounding OARs. Choice of treatment planning technique did not statistically significantly change lung V5. The results showed that the proposed practical approaches enhance dose conformity in MC-based IMRT planning of lung tumors treated with SBRT, improving target dose coverage and potentially reducing toxicities to surrounding normal organs.
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Neoplasias Pulmonares/cirurgia , Radiocirurgia , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Algoritmos , Tomografia Computadorizada Quadridimensional , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Método de Monte Carlo , Movimento , Imagens de Fantasmas , Doses de Radiação , Dosagem RadioterapêuticaRESUMO
The purpose of this study was to perform comprehensive measurements and testing of a Novalis Tx linear accelerator, and to develop technical guidelines for com-missioning from the time of acceptance testing to the first clinical treatment. The Novalis Tx (NTX) linear accelerator is equipped with, among other features, a high-definition MLC (HD120 MLC) with 2.5 mm central leaves, a 6D robotic couch, an optical guidance positioning system, as well as X-ray-based image guidance tools to provide high accuracy radiation delivery for stereotactic radiosurgery and stereotactic body radiation therapy procedures. We have performed extensive tests for each of the components, and analyzed the clinical data collected in our clinic. We present technical guidelines in this report focusing on methods for: (1) efficient and accurate beam data collection for commissioning treatment planning systems, including small field output measurements conducted using a wide range of detectors; (2) commissioning tests for the HD120 MLC; (3) data collection for the baseline characteristics of the on-board imager (OBI) and ExacTrac X-ray (ETX) image guidance systems in conjunction with the 6D robotic couch; and (4) end-to-end testing of the entire clinical process. Established from our clinical experience thus far, recommendations are provided for accurate and efficient use of the OBI and ETX localization systems for intra- and extracranial treatment sites. Four results are presented. (1) Basic beam data measurements: Our measurements confirmed the necessity of using small detectors for small fields. Total scatter factors varied significantly (30% to approximately 62%) for small field measurements among detectors. Unshielded stereotactic field diode (SFD) overestimated dose by ~ 2% for large field sizes. Ion chambers with active diameters of 6 mm suffered from significant volume averaging. The sharpest profile penumbra was observed for the SFD because of its small active diameter (0.6 mm). (2) MLC commissioning: Winston Lutz test, light/radiation field congruence, and Picket Fence tests were performed and were within criteria established by the relevant task group reports. The measured mean MLC transmission and dynamic leaf gap of 6 MV SRS beam were 1.17% and 0.36 mm, respectively. (3) Baseline characteristics of OBI and ETX: The isocenter localization errors in the left/right, posterior/anterior, and superior/inferior directions were, respectively, -0.2 ± 0.2 mm, -0.8 ± 0.2 mm, and -0.8 ± 0.4 mm for ETX, and 0.5 ± 0.7 mm, 0.6 ± 0.5 mm, and 0.0 ± 0.5 mm for OBI cone-beam computed tomography. The registration angular discrepancy was 0.1 ± 0.2°, and the maximum robotic couch error was 0.2°. (4) End-to-end tests: The measured isocenter dose differences from the planned values were 0.8% and 0.4%, measured respectively by an ion chamber and film. The gamma pass rate, measured by EBT2 film, was 95% (3% DD and 1 mm DTA). Through a systematic series of quantitative commissioning experiments and end-to-end tests and our initial clinical experience, described in this report, we demonstrate that the NTX is a robust system, with the image guidance and MLC requirements to treat a wide variety of sites - in particular for highly accurate delivery of SRS and SBRT-based treatments.
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Aceleradores de Partículas/normas , Radiocirurgia/instrumentação , Planejamento da Radioterapia Assistida por Computador/métodos , Desenho de Equipamento , Imagens de Fantasmas , Dosagem RadioterapêuticaRESUMO
Radiotherapy (RT) is one of the important modalities for cancer treatments. Mounting evidence suggests that the host immune system is involved in the tumor cell killing during RT, and future RT technology development should aim to minimize radiation dose to the immune system while maintaining a sufficient dose to the tumor. A brief history of RT technology development is first summarized. Three RT technologies, namely FLASH RT, proton therapy, and spatially fractionated RT (SFRT), are singled out for the era of immunotherapy. Besides the technical aspects, the mechanism of FLASH effect is discussed, which is likely the combined results of the recombination effect, oxygen depletion effect and immune sparing effect. The proton therapy should have the advantage of causing much less immune damage in comparison to X-ray based RT due to the Bragg peak. However, the relative biological effectiveness (RBE) uncertainty and range uncertainty may hinder the translation of this advantage into clinical benefit. Research approaches to overcome these two technical hurdles are discussed. Various SFRT approaches and their application are reviewed. These approaches are categorized as single-field 1D/2D SFRT, multi-field 3D SFRT and quasi-3D SFRT techniques. A 3D SFRT approach, which is achieved by placing the Bragg peak of a proton 2D SFRT field in discrete depths, may have special potential because all 3 technologies (FLASH RT, proton therapy and SFRT) may be used in this approach.
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Radiation-induced lymphopenia is known for its survival significance in patients with breast cancer treated with radiation therapy. This study aimed to evaluate the impact of radiotherapy on lymphocytes by applying machine learning strategies. We used Extreme Gradient Boosting (XGboost) to predict the event of lymphopenia (grade≥1) and conduced an independent validation. Then, we induced feature attribution analysis (Shapley additive explanation, SHAP) in explaining the XGboost models to explore the directional contribution of each feature to lymphopenia. Finally, we implemented the proof-of-concept clinical validation. The results showed that the XGboost models had rigorous generalization performances (accuracies 0.764 and ROC-AUC 0.841, respectively) in the independent cohort. The baseline lymphocyte counts are the most protective feature (SHAP = 5.226, direction of SHAP = -0.964). Baseline platelets and monocytes also played important protective roles. The usage of taxane only chemotherapy was less risk on lymphopenia than the combination of anthracycline and taxane. By the contribution analysis of dose, we identified that firstly lymphocytes were sensitive to a radiation dose less than 4Gy; secondly the irradiation volume was more important in promoting lymphopenia than the irradiation dose; thirdly the irradiation dose promoted the event of lymphopenia when the irradiation volume was fixed. Overall, our findings paved the way to clarifying the radiation dose volume effect. To avoid radiation-induced lymphopenia, irradiation volume should be kept to a minimum during the planning process, as long as the target coverage is not compromised.
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Neoplasias da Mama , Leucopenia , Linfopenia , Lesões por Radiação , Neoplasias da Mama/radioterapia , Feminino , Humanos , Leucopenia/etiologia , Linfopenia/etiologia , Aprendizado de Máquina , TaxoidesRESUMO
Background: Lymphopenia is a known significant factor for treatment outcome in cancer patients, with underlying risk factor poorly understood in breast cancer. We hypothesize that the effective dose to the circulating immune cells (EDIC) which was related with lymphopenia in lung cancer will also have significant effect for radiation induced lymphopenia (RIL) in patients with breast cancer. Material and Methods: Patients treated with adjuvant radiotherapy (RT) and with complete blood tests within one week from RT end/start (post/preRT) were eligible in this study. Radiation dosimetric factors were collected retrospectively, and EDIC for each patient was calculated based on the doses to lung, heart and total body according to the model description, as previously reported. RIL was defined by the CTCAE5.0 based on postRT peripheral lymphocyte count (PLC). Linear regression was first used to test the correlation between EDIC with post/preRT PLC ratio and postRT PLC, using all these as continuous variables. Normal tissue complication probability (NTCP) was used to develop models that predict the CTCAE graded RIL from EDIC. Results: A total of 735 patients were eligible. The mean post/preRT PLC ratio was 0.66 (95% CI: 0.64-0.68) and mean EDIC of breast cancer was 1.70Gy (95% CI: 1.64-1.75). Both post/preRT PLC ratio and postRT PLC were significantly correlated with EDIC (P<0.001), with R2 of 0.246. For patients with normal preRT PLC, the post/preRT PLC ratio was better associated with EDIC, and postRT PLC was expressed as PLC preRT × (0.89 - 0.16 × EDIC). For patients with preRT lymphopenia, postRT PLC was better associated with EDIC and it was 1.1 - 0.17 × EDIC. Using binned EDIC as the dose variable, the bootstrap validated NTCPs fit the data nicely with R2 of 0.93, 0.96, and 0.94 for grade-1, grade-2, and grade-3 RIL, respectively. The corresponding EDIC to induce 50% of grade-1, grade-2 and grade-3 RIL was 1.2, 2.1 and 3.7 Gy, respectively. Conclusion: EDIC is a significant factor for RIL in patients with breast cancer, and may be used to compute the risk of lymphopenia in each individual patient with the use of the conventional NTCP modeling. External validation is needed before the EDIC can be used to guide RT plan.
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PURPOSE: Radiation-induced damage, such as inflammation and fibrosis, can compromise ventilation capability of local functional units (alveoli) of the lung. Ventilation function as measured with ventilation images, however, is often complicated by the underlying mechanical variations. The purpose of this study is to present a 4DCT-based method to measure the regional ventilation capability, namely, regional compliance, for the evaluation of radiation-induced lung damage. METHODS: Six 4DCT images were investigated in this study: One previously used in the generation of a POPI model and the other five acquired at Henry Ford Health System. A tetrahedral geometrical model was created and scaled to encompass each of the 4DCT image domains. Image registrations were performed on each of the 4DCT images using a multiresolution Demons algorithm. The images at the end of exhalation were selected as a reference. Images at other exhalation phases were registered to the reference phase. For the POPI-modeled patient, each of these registration instances was validated using 40 landmarks. The displacement vector fields (DVFs) were used first to calculate the volumetric variation of each tetrahedron, which represents the change in the air volume. The calculated results were interpolated to generate 3D ventilation images. With the computed DVF, a finite element method (FEM) framework was developed to compute the stress images of the lung tissue. The regional compliance was then defined as the ratio of the ventilation and stress values and was calculated for each phase. Based on iterative FEM simulations, the potential range of the mechanical parameters for the lung was determined by comparing the model-computed average stress to the clinical reference value of airway pressure. The effect of the parameter variations on the computed stress distributions was estimated using Pearson correlation coefficients. RESULTS: For the POPI-modeled patient, five exhalation phases from the start to the end of exhalation were denoted by P(i), i = 1, ..., 5, respectively. The average lung volume variation relative to the reference phase (P5) was reduced from 18% at P1 to 4.8% at P4. The average stress at phase P(i) was 1.42, 1.34, 0.74, and 0.28 kPa, and the average regional compliance was 0.19, 0.20, 0.20, and 0.24 for i = 1, ..., 4, respectively. For the other five patients, their average R(v) value at the end-inhalation phase was 21.1%, 19.6%, 22.4%, 22.5%, and 18.8%, respectively, and the regional compliance averaged over all six patients is 0.2. For elasticity parameters chosen from the potential parameter range, the resultant stress distributions were found to be similar to each other with Pearson correlation coefficients greater than 0.81. CONCLUSIONS: A 4DCT-based mechanical model has been developed to calculate the ventilation and stress images of the lung. The resultant regional compliance represents the lung's elasticity property and is potentially useful in correlating regions of lung damage with radiation dose following a course of radiation therapy.
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Tomografia Computadorizada Quadridimensional/métodos , Lesões por Radiação/diagnóstico por imagem , Lesões por Radiação/fisiopatologia , Elasticidade/efeitos da radiação , Humanos , Complacência Pulmonar/efeitos da radiação , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/fisiopatologia , Ventilação Pulmonar/efeitos da radiação , Estresse Fisiológico/efeitos da radiaçãoRESUMO
PURPOSE: Tumor control probability (TCP) models have been proposed to evaluate and guide treatment planning. However, they are usually based on the dose volume histograms (DVHs) of the planning target volume (PTV) and may not properly reflect the substantial variation in tumor burden from the gross tumor volume (GTV) to the microscopic extension (ME) and to the margin of PTV. In this study, the authors propose a TCP model that can account for the effects of setup uncertainties and tumor cell density decay in the ME region. METHODS: The proposed TCP model is based on the total surviving clonogenic tumor cells (CTCs) after irradiation of a known dose distribution to a region with a CTC distribution. The CTC density was considered to be homogeneous within the GTV, while decreasing exponentially in the ME region. The effect of random setup uncertainty was modeled by convolving the dose distribution with a Gaussian probability density function, represented by a standard deviation, sigma. The effect of systematic setup uncertainty was modeled by summing each calculated TCP for all potential offsets in a Gaussian probability, represented by sigma. The model was then applied to simplified cases to demonstrate the concept. TCP dose responses were calculated for various GTV volumes, DVH shapes, CTC density decay coefficients, probabilities of lymph node metastasis, and random and systematic errors. The slopes of the dose falloff to cover the CTC density decay in the ME region and the margins to compensate setup errors were also analyzed in generalized cases. RESULTS: The sigmoid TCP dose response curve shifted to the right substantially for a larger GTV, while modestly for cold spots in DVH. A dose distribution with a uniform dose within the GTV, and a linear dose falloff in the ME region, tended to cause a minimal TCP deterioration if a proper dose falloff slope was used. When the dose falloff slope was less steep than a critical slope represented by kT, the D50, which is the prescription dose at TCP=50%, and gamma50, which is the TCP slope at TCP=50%, varied little with different dose falloff slopes. However, both D50 and gamma50 deteriorated fast when the slopes were steeper than kT. The random setup error tended to shift the TCP curve to the right, while the systematic error tended to compress the curve downward. For combined random and systematic errors, we demonstrated that based on the model, a margin of mean square root of (0.75 sigma)2 + (1.15 sigma)2 added to the GTV was found to cause a TCP change corresponding to 2% drop at TCP=90%, or 0.5 Gy shift in D50. CONCLUSIONS: This study conceptually demonstrated that a TCP model incorporating the effects of tumor cell density variation and setup uncertainty may be used to guide radiation treatment planning.
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Modelos Biológicos , Neoplasias/patologia , Neoplasias/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Incerteza , Contagem de Células , Sobrevivência Celular/efeitos da radiação , Metástase Linfática , Dosagem RadioterapêuticaRESUMO
BACKGROUND: Effective dose to immune cell (EDIC), an estimated radiation dose to the circulating lymphocytes, is of significance for overall survival (OS) in non-small cell lung cancer. This study aimed to validate the EDIC's OS effect on limited-stage small cell lung cancer (LS-SCLC). METHOD AND MATERIALS: This study included LS-SCLC patients received definitive chemo-radiation in one single center from 2012 to 2017. All patients had multiple complete-blood-count tests including lymphocyte count at pre-, during- and end- radiotherapy. EDIC, computed according to doses of the lung, heart, and the total body, was assessed for its correlation with lymphocyte nadir, OS and progression free survival (PFS). RESULTS: Of 503 eligible patients, the mean EDIC was 7.34 Gy. The mean lymphocyte nadir was 0.48 × 109 cells/L, significantly lower than 1.65 × 109 cells/L at pre-radiotherapy (p < 0.001). EDIC was significantly correlated with lymphocyte nadir under both univariate (p < 0.001) and multivariable linear regression (p < 0.001). Multivariable analysis showed EDIC (HR = 0.1072, p = 0.005) and lymphocyte nadir (HR = 0.345, p = 0.003) were both significant for OS. EDIC was also significant for PFS (HR = 1.046, p = 0.026). The C-indexes of OS prediction were 0.593, 0.617, 0.676, and 0.684, for lymphocyte nadir alone, EDIC alone, combined lymphocyte nadir model, and combined EDIC model, respectively. CONCLUSIONS: This study demonstrated that EDIC is an independent predictor for lymphocyte nadir, PFS and OS. EDIC may serve as a predictor for lymphocyte nadir and a surrogate marker for OS in LS-SCLC. More attention should be paid to EDIC to decease the lymphocyte toxicity and improve survival.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Contagem de Linfócitos , Linfócitos , Carcinoma de Pequenas Células do Pulmão/terapiaRESUMO
The aim of this work is to study the dosimetric effect from generated synthetic computed tomography (sCT) from magnetic resonance (MR) images using a deep learning algorithm for Gamma Knife (GK) stereotactic radiosurgery (SRS). The Monte Carlo (MC) method is used for dose calculations. Thirty patients were retrospectively selected with our institution IRB's approval. All patients were treated with GK SRS based on T1-weighted MR images and also underwent conventional external beam treatment with a CT scan. Image datasets were preprocessed with registration and were normalized to obtain similar intensity for the pairs of MR and CT images. A deep convolutional neural network arranged in an encoder-decoder fashion was used to learn the direct mapping from MR to the corresponding CT. A number of metrics including the voxel-wise mean error (ME) and mean absolute error (MAE) were used for evaluating the difference between generated sCT and the true CT. To study the dosimetric accuracy, MC simulations were performed based on the true CT and sCT using the same treatment parameters. The method produced an MAE of 86.6 ± 34.1 Hundsfield units (HU) and a mean squared error (MSE) of 160.9 ± 32.8. The mean Dice similarity coefficient was 0.82 ± 0.05 for HU > 200. The difference for dose-volume parameter D95 between the ground true dose and the dose calculated with sCT was 1.1% if a synthetic CT-to-density table was used, and 4.9% compared with the calculations based on the water-brain phantom.
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Imageamento por Ressonância Magnética/métodos , Método de Monte Carlo , Neoplasias/cirurgia , Redes Neurais de Computação , Imagens de Fantasmas , Radiocirurgia/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Aprendizado Profundo , Humanos , Processamento de Imagem Assistida por Computador/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Órgãos em Risco/efeitos da radiação , Prognóstico , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/métodos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodosRESUMO
PURPOSE: Radiation therapy (RT)-induced lymphopenia (RIL) is linked with inferior survival in esophageal and pancreatic cancers. Previous work has demonstrated a correlation between spleen dose and RIL risk. The present study correlates spleen dose-volume parameters with fractional lymphocyte loss rate (FLL) and total percent change in absolute lymphocyte count (%ΔALC) and suggests spleen dose constraints to reduce RIL risk. METHODS AND MATERIALS: This registry-based study included 140 patients who underwent RT for pancreatic (n = 67), gastroesophageal (n = 61), or biliary tract (n = 12) adenocarcinoma. Patient-specific parameters of lymphocyte loss kinetics, including FLL and %ΔALC, were calculated based on serial ALCs obtained during RT. Spearman's rho was used to correlate spleen dose-volume parameters with %ΔALC, end-treatment ALC, and FLL. Multivariable logistic regression was used to identify predictors of ≥grade 3 and grade 4 RIL. RESULTS: Spleen dose-volume parameters, including mean spleen dose (MSD), all correlated with %ΔALC, end-treatment ALC, and FLL. Controlling for baseline ALC and planning target volume (PTV), an increase in any spleen dose-volume parameter increased the odds of developing ≥grade 3 lymphopenia. Each 1-Gy increase in MSD increased the odds of ≥grade 3 RIL by 18.6%, and each 100-cm3 increase in PTV increased the odds of ≥grade 3 lymphopenia by 20%. Patients with baseline ALC < 1500 cells/µL had a high risk of ≥grade 3 RIL regardless of MSD or PTV. FLL was an equally good predictor of ≥grade 3 lymphopenia as any spleen dose-volume parameter. CONCLUSIONS: In patients undergoing RT for upper abdominal malignancies, higher spleen dose is associated with higher per-fraction lymphocyte loss rates, higher total %ΔALC, and increased odds of severe lymphopenia. Spleen dose constraints should be individualized based on baseline ALC and PTV size to minimize RIL risk, although our findings require validation in larger, ideally prospective data sets.
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BACKGROUND: This study aimed to investigate radiation-induced lymphopenia and its potential risk factors in patients with breast cancer receiving adjuvant radiotherapy. METHODS: Breast cancer patients received adjuvant radiotherapy (RT) at our hospital with peripheral lymphocyte counts (PLC) at pre-and immediately after RT (post-RT) were eligible. The primary endpoints were any grade of lymphopenia post-RT and nadir-PLC/pre-PLC <0.8. Patient characteristics, tumor factors, and treatment factors were collected for risk assessment. Data are presented as mean and 95% confidence interval (CI) unless otherwise specified. Matched analysis was used to compare the statistical significance between different RT techniques. RESULTS: A total of 735 consecutive patients met the study criteria. The mean PLC was 1.58×109/L before and 0.99×109/L post-RT (P<0.001). At the end of RT, 60.5% of patients had lymphopenia. Univariate and multivariable logistic analyses showed that RT technique involving RapidArc, mean lung dose, and chemotherapy were significant risk factors (P<0.05) for lymphopenia. RT technique was the only significant risk factor (P<0.05) for nadir-PLC/pre-PLC <0.8. Patients treated with RapidArc had a significantly greater reduction of PLC along with greater V5 of the lungs, even after matching mean lung dose and radiated volume. CONCLUSIONS: Lymphopenia is common in patients with breast cancer after adjuvant RT. RT technique is the only significant factor for lymphopenia and nadir-PLC/pre-PLC <0.8, suggesting the significance of RT technique choice to minimize lymphopenia and improve treatment outcomes.
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BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) can be a potential fatal toxicity of stereotactic body radiation therapy (SBRT) for medically inoperable non-small cell lung cancer (NSCLC). This study aimed to examine the risk factors that predict RP and explore dosimetric tolerance for safe practice in a large institutional series of NSCLC patients. MATERIALS AND METHODS: Patients with early-stage and locally recurrent NSCLC who received lung SBRT between 2002 and 2015 formed the study population. The primary endpoint was grade 2 or above radiation pneumonitis (RP2). Lungs were re-contoured consistently by one radiation oncologist according to the RTOG atlas for organs at risk. Dosimetric factors were computed consistently with exclusion of gross tumor volume of either ipsilateral, contralateral, or total lungs. RESULTS: A total of 339 patients were eligible. With a median follow-up of 47 months, RP2 was recorded in 10% patients. History of respiratory comorbidity, previous thoracic radiation, right lung location, mean lung doses of total or ipsilateral lung, and total lung volume receiving 20 Gy were all significantly associated with the risk of RP2. The dosimetric parameters of contralateral lung, including mean dose and volume receiving more than 5, 10, and 20 Gy, were not significantly associated with RP2 (ps > 0.05). A model of combining significant clinical and dosimetric factors had a predictive accuracy AUC of 0.76. According to this model, RP2 can be limited to <10% should the patient have no previous lung radiation and the mean dose of total and ipsilateral lungs be kept less than 6 Gy and 20 Gy, respectively. CONCLUSION: Dosimetric factors of total or ipsilateral lung together with important clinical factors were significant risk factors for symptomatic radiation pneumonitis after SBRT. Constraining mean lung dose can limit clinically significant lung toxicity.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Pneumonite por Radiação , Radiocirurgia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Humanos , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia , Pneumonite por Radiação/epidemiologia , Pneumonite por Radiação/etiologia , Radiocirurgia/efeitos adversos , Fatores de RiscoRESUMO
Background: We hypothesized that the Effective radiation Dose to the Immune Cells (EDIC) in circulating blood is a significant factor for the treatment outcome in patients with locally advanced non-small-cell lung cancer (NSCLC). Methods: This is a secondary study of a phase III trial, NRG/RTOG 0617, in patients with stage III NSCLC treated with radiation-based treatment. The EDIC was computed as equivalent uniform dose to the entire blood based on radiation doses to all blood-containing organs, with consideration of blood flow and fractionation effect. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and local progression-free survival (LPFS). The EDIC-survival relationship was analyzed with consideration of clinical significant factors. Results: A total of 456 patients were eligible. The median EDIC values were 5.6 Gy (range, 2.1-12.2 Gy) and 6.3 Gy (2.1-11.6 Gy) for the low- and high-dose groups, respectively. The EDIC was significantly associated with OS (hazard ratio [HR] = 1.12, p = 0.005) and LPFS (HR = 1.09, p = 0.02) but PFS (HR = 1.05, p = 0.17) after adjustment for tumor dose, gross tumor volume and other factors. OS decreased with an increasing EDIC in a non-linear pattern: the two-year OS decreased first with a slope of 8%/Gy when the EDIC < 6 Gy, remained relatively unchanged when the EDIC was 6-8 Gy, and followed by a further reduction with a slope of 12%/Gy when the EDIC > 8 Gy. Conclusions: The EDIC is a significant independent risk factor for poor OS and LPFS in RTOG 0617 patients with stage III NSCLC, suggesting that radiation dose to circulating immune cells is critical for tumor control. Organ at risk for the immune system should be considered during RT plan.
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PURPOSE: The authors propose a combined scatter reduction and correction method to improve image quality in cone-beam computed tomography (CBCT). Although using a beam-block approach similar to previous techniques to measure the scatter, this method differs in that the authors utilize partially blocked projection data obtained during scatter measurement for CBCT image reconstruction. This study aims to evaluate the feasibility of the proposed approach. METHODS: A 1D grid, composed of lead septa, was placed between the radiation source and the imaging object for scatter measurement. Image data were collected from the grid interspace regions while the scatter distribution was measured in the blocked regions under the grid. Scatter correction was performed by subtracting the measured scatter from the imaging data. Image information in the penumbral regions of the grid was derived. Three imaging modes were developed to reconstruct full CBCT images from partial projection data. The single-rotation half-fan mode uses interpolation to fill the missing data. The dual-rotation half-fan mode uses two rotations, with the grid offset by half a grid cycle, to acquire two complementary sets of projections, which are then merged to form complete projections for reconstruction. The single-rotation full-fan mode was designed for imaging a small object or a region of interest. Full-fan projection images were acquired over a 360 degrees scan angle with the grid shifting a distance during the scan. An enlarged Catphan phantom was used to evaluate potential improvement in image quality with the proposed technique. An anthropomorphic pelvis phantom was used to validate the feasibility of reconstructing a complete set of CBCT images from the partially blocked projections using three imaging modes. Rigid-body image registration was performed between the CBCT images from the single-rotation half-fan mode and the simulation CT and the results were compared to that for the CBCT images from dual-rotation mode and conventional CBCT images. RESULTS: The proposed technique reduced the streak artifact index from 58% to 1% in comparison with the conventional CBCT. It also improved CT number linearity from 0.880 to 0.998 and the contrast-to-noise ratio (CNR) from 4.29 to 6.42. Complete sets of CBCT images with overall improved image quality were achieved for all three image modes. The longitudinal resolution was slightly compromised for the single-rotation half-fan mode. High resolution was retained for the dual-rotation half-fan and single-rotation full-fan modes in the longitudinal direction. The registration error for the CBCT images from the single-rotation half-fan mode was 0.8 +/- 0.3 mm in the longitudinal direction and negligible in the other directions. CONCLUSIONS: The proposed method provides combined scatter correction and direct scatter reduction. Scatter correction may eliminate scatter artifacts, while direct scatter reduction may improve the CNR to compensate the CNR degradation due to scatter correction. Complete sets of CBCT images are reconstructed in all three imaging modes. The single-rotation mode can be used for rigid-body patient alignment despite degradation in longitudinal resolution. The dual-rotation mode may be used to improve CBCT image quality for soft tissue delineation in adaptive radiation therapy.
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Tomografia Computadorizada de Feixe Cônico/métodos , Processamento de Imagem Assistida por Computador/métodos , Algoritmos , Artefatos , Humanos , Aceleradores de Partículas , Imagens de Fantasmas , Radiometria/métodos , Dosagem Radioterapêutica , Reprodutibilidade dos Testes , Espalhamento de RadiaçãoRESUMO
Radiation-induced lymphopenia (RIL) is associated with worse survival in patients with solid tumors, as well as lower response rates to checkpoint inhibitors. While single-fraction total-body irradiation is known to result in exponential decreases in the absolute lymphocyte count (ALC), the kinetics of lymphocyte loss after focal fractionated exposures have not previously been characterized. In the current study, lymphocyte loss kinetics was analyzed among patients undergoing focal fractionated radiotherapy for clinical indications. This registry-based study included 419 patients who received either total-body irradiation (TBI; n = 30), stereotactic body radiation therapy (SBRT; n = 73) or conventionally fractionated chemoradiation therapy (CFRT; n = 316). For each patient, serial ALCs were plotted against radiotherapy fraction number. The initial three weeks of treatment for CFRT patients and the entirety of treatment for SBRT and TBI patients were fit to exponential decay in the form ALC(x) = ae-bx, where ALC(x) is the ALC after x fractions. From those fits, fractional lymphocyte loss (FLL) was calculated as FLL = (1 - e-b) * 100, and multivariable regression was performed to identify significant correlates of FLL. Median linearized R2 when fitting the initial fractions was 0.98, 0.93 and 0.97 for patients receiving TBI, SBRT and CFRT, respectively. In CFRT patients, apparent ALC loss rate slowed after week 3. Fitting ALC loss over the entire CFRT course therefore required the addition of a constant term, "c". For TBI and SBRT patients, treatment ended during the pure exponential decay phase. Initial FLL varied significantly with treatment technique. Mean FLL was 35.5%, 24.3% and 10.77% for patients receiving TBI, SBRT and CFRT, respectively (P < 0.001). Significant correlates of FLL varied by site and included field size, dose per fraction, mean spleen dose, chemotherapy backbone and age. Finally, total percentage ALC loss during radiotherapy was highly correlated with FLL (P < 0.001). Lymphocyte depletion kinetics during the initial phase of fractionated radiotherapy are characterized by pure exponential decay. Initial FLL is strongly correlated with radiotherapy planning parameters and total percentage ALC loss. The two groups with the highest FLL received no concurrent chemotherapy, suggesting that ALC loss can be a consequence of radiotherapy alone. This work may assist in selecting patients for adaptive radiotherapy approaches to mitigate RIL risk.
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Quimiorradioterapia/efeitos adversos , Linfócitos/citologia , Linfócitos/efeitos da radiação , Radiocirurgia/efeitos adversos , Adulto , Idoso , Contagem de Células , Fracionamento da Dose de Radiação , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
INTRODUCTION: Associations between radiation-induced lymphopenia (RIL) and survival have been extensively reported. However, the immune system is not considered as an organ-at-risk (OAR) in radiotherapy. This study aimed to develop the framework of an immune OAR model that may be utilized to predict and minimize RIL. METHODS: A dynamic model was first developed for lymphocyte trafficking among 5 compartments of the immune system. Radiation dose to the circulating lymphocytes in each compartment was calculated based on the doses to fixed structures of each immune compartment and blood flow patterns. A RIL model was developed based on lymphocyte dynamics, lymphocyte radiosensitivity and reproductivity, and the dose to the lymphocytes. The model was tested in 51 patients by fitting it to weekly-measured absolute lymphocyte counts (ALC) for each patient, considering lymphocyte radiosensitivity and reproductivity as patient-dependent fitting parameters. RESULTS: The fitting was almost perfect for 20 patients, with sum of square of errors (SSE) between measured and predicted ALCs < 0.5. It was acceptable for another 27 patients, with SSE = 0.5~4.0. Only 4 patients had SSE > 4.0. The fitting also provided a method of in vivo estimation of radiosensitivity (α) for each patient. The median α was 0.40 Gy-1 for the 51 patients, consistent with in vitro measured data of 0.41 Gy-1 in the literature. CONCLUSION: We have presented a framework of developing an immune OAR model that has the potential to predict and minimize RIL in radiotherapy.