Geometrical and dosimetrical uncertainties in hypofractionated radiotherapy of the lung: A review

The application of high precision hypofractionated regimes (a.k.a. stereotactic body radiotherapy (SBRT)) to the treatment of lung cancer is a ‘success story’ of radiotherapy. From the technical perspective, lung SBRT is a challenging technique as all aspects of the treatment workflow, from imaging to dose calculation to treatment delivery, should be carefully handled in order to ensure consistency between planned and delivered dose.In this review such technical aspects are presented and discussed, looking at what has been developed over the years.The use of imaging techniques such as slow-CT, breath-hold CT, four-dimensional CT and mid-ventilation is reviewed, presenting the main characteristics of each approach but not necessarily to single out ‘the best’ solution.Concerning dose calculation, a number of studies clearly separate dose algorithms that should be considered inadequate for lung SBRT (e.g. simple pencil beam algorithms) from approaches such as convolution algorithms, Monte Carlo, and solution of the transport equation, that are much better at handling the combination of small fields and heterogenenous geometries that make dose calculation not trivial.Patient positioning and management of intrafraction motion have been two areas of significant developments, to the point where it is difficult to identify which solution represents the best compromise between technical complexity and clinical effectiveness. The review analyses several of these methods, outlining the residual uncertainties associated with each of them.Last but not least, two subjects are discussed, adaptive therapy and particle therapy, that may represent in the near future additional tools for the technical improvement of lung SBRT.     

IGRT and motion management during lung SBRT delivery

Patient motion can cause misalignment of the tumour and toxicities to the healthy lung tissue during lung stereotactic body radiation therapy (SBRT). Any deviations from the reference setup can miss the target and have acute toxic effects on the patient with consequences onto its quality of life and survival outcomes. Correction for motion, either immediately prior to treatment or intra-treatment, can be realized with image-guided radiation therapy (IGRT) and motion management devices. The use of these techniques has demonstrated the feasibility of integrating complex technology with clinical linear accelerator to provide a higher standard of care for the patients and increase their quality of life.     

Clinical verification of treatment planning dose calculation in lung SBRT with GATE Monte Carlo simulation code

PurposeThis study aims to use GATE/Geant4 simulation code to evaluate the performance of dose calculations with Anisotropic Analytical Algorithm (AAA) in the context of lung SBRT for complex treatments considering images of patients.MethodsFour cases of non-small cell lung cancer treated with SBRT were selected for this study. Irradiation plans were created with AAA and recalculated end to end using Monte Carlo (MC) method maintaining field configurations identical to the original plans. Each treatment plan was evaluated in terms of PTV and organs at risk (OARs) using dose-volume histograms (DVH). Dosimetric parameters obtained from DVHs were used to compare AAA and MC.ResultsThe comparison between the AAA and MC DVH using gamma analysis with the passing criteria of 3%/3% showed an average passing rate of more than 90% for the PTV structure and 97% for the OARs. Tightening the criteria to 2%/2% showed a reduction in the average passing rate of the PTV to 86%. The agreement between the AAA and MC dose calculations for PTV dosimetric parameters (V₁₀₀; V₉₀; Homogeneity index; maximum, minimum and mean dose; CI_Paddick and D_2cm) was within 18.4%. For OARs, the biggest differences were observed in the spinal cord and the great vessels.ConclusionsIn general, we did not find significant differences between AAA and MC. The results indicate that AAA could be used in complex SBRT cases that involve a larger number of small treatment fields in the presence of tissue heterogeneities.     

Estimation of delivered dose to lung tumours considering setup uncertainties and breathing motion in a cohort of patients treated with stereotactic body radiation therapy

IntroductionDose-response relationships for local control of lung tumours treated with stereotactic body radiotherapy (SBRT) have proved ambiguous, however, these have been based on the prescribed or planned dose. Delivered dose to the target may be a better predictor for local control. In this study, the probability of the delivered minimum dose to the clinical target volume (CTV) in relation to the prescribed dose was estimated for a cohort of patients, considering geometrical uncertainties.Materials and methodsDelivered doses were retrospectively simulated for 50 patients treated with SBRT for lung tumours, comparing two image-guidance techniques: pre-treatment verification computed tomography (IG1) and online cone-beam computed tomography (IG2). The prescribed dose was typically to the 67% isodose line of the treatment plan. Simulations used in-house software that shifted the static planned dose according to a breathing motion and sampled setup/matching errors. Each treatment was repeatedly simulated, generating a multiplicity of dose-volume histograms (DVH). From these, tumour-specific and population-averaged statistics were derived.ResultsFor IG1, the probability that the minimum CTV dose (D_98%) exceeded 100% of the prescribed dose was 90%. With IG2, this probability increased to 99%.ConclusionsDoses below the prescribed dose were delivered to a considerably larger part of the population prior to the introduction of online soft-tissue image-guidance. However, there is no clear evidence that this impacts local control, when compared to previous published data.     

Stereotactic radiotherapy for early lung cancer: Evidence-based approach and future directions

AimTo review key studies evaluating stereotactic radiotherapy in the setting of early-stage non-small cell lung cancer (NSCLC) for inoperable or high-risk patients, and discuss areas of ongoing research and clinical trials.BackgroundThe use of stereotactic radiotherapy for the treatment of early stage non-small cell lung cancer (NSCLC) has increased rapidly over the past decade. Numerous studies have reported outcomes for patients treated with SBRT who are unfit for surgical resection, or at high risk of surgical complications.Materials and methodsA narrative review.ResultsThe preponderance of evidence suggests that SBRT is associated with excellent local control (∼90% at 3 years) and a favorable toxicity profile. In patients with higher operative risks, such as the elderly and patients with severe COPD, SBRT may provide a less-toxic treatment than surgery with similar oncologic outcomes. Ongoing studies are evaluating the use of SBRT for locally advanced or oligometastatic NSCLC.ConclusionsA large body of evidence now exists to support the use of SBRT for early-stage NSCLC. Decisions regarding the optimal choice of treatment should be individualized, and made in the context of a multidisciplinary team.     

Predictive value of vascular calcification identified in 4D planning CT of lung cancer patients treated with stereotactic body radiation therapy

PurposeThe aim was to identify vascular calcification in 4DCT scan of lung cancer patients and establish the association between overall survival (OS) and vascular calcification, as surrogate for vascular health.MethodsVascular calcification within the thoracic cavity were segmented in 334 lung cancer patients treated with stereotactic body radiation therapy (SBRT). This has been done automatically on 4D planning CT and average reconstruction scans. Correlation between cardiac comorbidity and calcification volumes was evaluated for patients with recorded Adult Co-Morbidity Evaluation (n = 303). Associations between the identified calcifications and OS were further investigated.ResultsThe volume of calcification from the average scan was significantly lower than from each phase (p < 0.001). The highest level of correlations between cardiac comorbidity and volume of the calcifications were found for one phase representing inhale and two phases representing exhale with the least motion blurring due to respiration (p < 0.005). The volume of the calcifications was subsequently averaged over these three phases. The average of calcification volumes over the three phases (denoted by inhale-exhale) showed the highest likelihood in univariate analysis and was chosen as vascular calcification measure. Cox-model suggested that tumor volume (Hazard Ratio [HR] = 1.46, p < 0.01) and inhale-exhale volume (HR = 1.05, p < 0.05) are independent factors predicting OS after adjusting for age, sex, and performance status.ConclusionIt was feasible to use. It 4DCT scan for identifying thoracic calcifications in lung cancer patients treated with SBRT. Calcification volumes from inhale-exhale phases had the highest correlation with overall cardiac comorbidity and the average of the calcification volume obtained from these phases was an independent predictive factor for OS.     

On the use of AAA and AcurosXB algorithms for three different stereotactic ablative body radiotherapy (SABR) techniques: Volumetric modulated arc therapy (VMAT), intensity modulated radiation therapy (IMRT) and 3D conformal radiotherapy (3D-CRT)

AimThe purpose of this study was to investigate the dosimetric characteristics of three stereotactic ablative body radiotherapy (SABR) techniques using the anisotropic analytical algorithm (AAA) and Acuros XB algorithm. The SABR techniques include coplanar volumetric modulated arc therapy (C-VMAT), non-coplanar intensity modulated radiation therapy (NC-IMRT) and non-coplanar three-dimensional conformal radiotherapy (NC-3D CRT).BackgroundSABR is a special type of radiotherapy where a high dose of radiation is delivered over a short time. The treatment outcome and accuracy of the dose delivered to cancer patients highly depend on the dose calculation algorithm and treatment technique.Materials and methodsTwelve lung cancer patients underwent 4D CT scanning, and three different treatment plans were generated: C-VMAT, NC-IMRT, NC-3D CRT. Dose calculation was performed using the AAA and Acuros XB algorithm. The dosimetric indices, such as conformity index (CI), homogeneity index, dose fall-off index, doses received by organs at risk and planning target volume, were used to compare the plans. The accuracy of AAA and Acuros XB (AXB) algorithms for the lung was validated against measured dose on a CIRS thorax phantom.ResultsThe CIs for C-VMAT, NC-IMRT and NC-3D CRT were 1.21, 1.28 and 1.38 for the AAA, respectively, and 1.17, 1.26 and 1.36 for the Acuros XB algorithm, respectively. The overall dose computed by AcurosXB algorithm was close to the measured dose when compared to the AAA algorithm. The overall dose computed by the AcurosXB algorithm was close to the measured dose when compared to the AAA algorithm.ConclusionThis study showed that the treatment planning results obtained using the Acuros XB algorithm was better than those using the AAA algorithm in SABR lung radiotherapy.     

Comparison of radiomic features in diagnostic CT images with and without contrast enhancement in the delayed phase for NSCLC patients

PurposeTo compare radiomic features extracted from diagnostic computed tomography (CT) images with and without contrast enhancement in delayed phase for non-small cell lung cancer (NSCLC) patients.MethodsDiagnostic CT images from 269 tumors [non-contrast CT, 188 (dataset NE); contrast-enhanced CT, 81 (dataset CE)] were enrolled in this study. Eighteen first-order and seventy-five texture features were extracted by setting five bin width levels for CT values. Reproducible features were selected by the intraclass correlation coefficient (ICC). Radiomic features were compared between datasets NE and CE. Subgroup analyses were performed based on the CT acquisition period, exposure value, and patient characteristics.ResultsEighty features were considered reproducible (0.5 ≤ ICC). Twelve of the sixteen first-order features, independent of the bin width levels, were statistically different between datasets NE and CE (p < 0.05), and the p-values of two first-order features depending on the bin width levels were reduced with narrower bin widths. Sixteen out of sixty-two features showed a significant difference, regardless of the bin width (p < 0.05). There were significant differences between datasets NE and CE with older age, lighter body weight, better performance status, being a smoker, larger gross tumor volume, and tumor location at central region.ConclusionsContrast enhancement in the delayed phase of CT images for NSCLC patients affected some of the radiomic features and the variability of radiomic features due to contrast uptake may depend largely on the patient characteristics.     

Local control of 1–5 fraction radiotherapy regimens for spinal metastases: an analysis of the impacts of biologically effective dose and primary histology

BackgroundThis analysis evaluates the impacts of biologically effective dose (BED) and histology on local control (LC) of spinal metastases treated with highly conformal radiotherapy to moderately-escalated doses.Materials and methodsPatients were treated at two institutions from 2010–2020. Treatments with less than 5 Gy per fraction or 8 Gy in 1 fraction were excluded. The dataset was divided into three RPA classes predictive of survival (1). The primary endpoint was LC.Results223 patients with 248 treatments met inclusion criteria. Patients had a median Karnofsky Performance Status (KPS ) of 80, and common histologies included breast (29.4%), non-small cell lung cancer (15.7%), and prostate (13.3%). A median 24 Gy was delivered in 3 fractions (BED: 38.4 Gy) to a median planning target volume (PTV) of 37.3 cc. 2-year LC was 75.7%, and 2-year OS was 42.1%. Increased BED was predictive of improved LC for primary prostate cancer (HR = 0.85, 95% CI: 0.74–0.99). Patients with favorable survival (RPA class 1) had improved LC with BED ≥ 40 Gy (p = 0.05), unlike the intermediate and poor survival groups. No grade 3–5 toxicities were reported.ConclusionsModerately-escalated treatments were efficacious and well-tolerated. BED ≥ 40 Gy may improve LC, particularly for prostate cancer and patients with favorable survival.     

The effect of rectal gas on dose distribution during prostate cancer treatment using full arc and partial arc Volumetric Modulated Arc Therapy (VMAT) treatment plans

Background/AimIn this study, we investigated the effect of rectal gas on the dose distribution of prostate cancer using a volumetric modulated arc therapy (VMAT) treatment planning.Materials and MethodsThe first is the original structure set, clinical target volume (CTV), the rectum, and the bladder used clinically. The second is a structure set (simulated gas structure set) in which the overlapping part of the rectum and PTV is overwritten with Hounsfield Unit −950 as gas. Full arc and limited gantry rotation angle with VMAT were the two arcs. The VMAT of the full arc was 181°–179° in the clockwise (CW) direction and 179°–181° in the counterclockwise (CCW) direction. Three partial arcs with a limited gantry rotation angle were created: 200°–160 °CW and 160°–200 °CCW; 220°–140 °CW and 140°–220 °CCW; and finally, 240°–120 °CW and 120°–240 °CCW. The evaluation items were dose difference, distance to agreement, and gamma analysis.ResultIn the CTV, the full arc was the treatment planning technique with the least effect of rectal gas. In the rectum, when the gantry rotation angle range was short, the pass rate tended to reduce for all evaluation indices. The bladder showed no characteristic change between the treatment planning techniques in any of the evaluation indices.ConclusionsThe VMAT treatment planning with the least effect on dose distribution caused by rectal gas was shown to be a full arc.     

DNA adducts in relation to lung tumour outcome are not markers of susceptibility following a single dose treatment of SWR, BALB/c and C57BL/6J mice with N-nitrosodiethylamine

The formation of DNA adducts by the covalent binding of genotoxic chemicals to DNA represents a valuable marker for assessing exposure to carcinogens but as yet the role of DNA adducts as a biomarker of carcinogenic susceptibility still needs to be clearly ascertained. To address this question an animal study was instigated using mice (SWR (high), BALB/c (intermediate) and C57BL/6J (low)) varying in their susceptibility to lung carcinogenesis. Groups of animals from each strain were dosed with a single intraperitoneal injection of saline or N -nitrosodiethylamine (NDEA) at 15 or 90 mg kg^-1 body weight. Lung and liver tissues were removed at different time points following dosing. Further groups of mice dosed with the same regime had urine samples collected 24 h post dosing and were then left up to 18 months to allow for the development of tumours. Immunoslot-blot analysis was used for the determination of N-7 ethylguanine (N-7EtG) and O⁶ ethylguanine (O⁶EtG) adduct levels in the DNA from the tissues and gas chromatography-mass spectrometry (GC-MS) was used to determine N-3 ethyladenine (N-3EtA) adduct levels in the urine samples. Levels of alkyltransferase (ATase) were also determined in the tissues. The results showed that the DNA adduct levels and persistence were similar across the three strains of mice following dosing with 15 and 90 mg kg^-1 NDEA. High levels of adducts were observed in the urine of the BALB/c strain, implying an increased metabolic or repair capacity in this strain. However there were no differences in the levels of ATase in the lung and liver of the three strains of mice following dosing with 15 mg kg^-1 NDEA. The incidence of tumours in C57BL/6J mice was lower compared with the other two strains and showed a dose dependent increase. The results from this study show that the differences in susceptibility to lung carcinogenesis between the three strains of mice do not appear to be linked to the formation of the two adducts detected. These results imply that dosing with NDEA resulted in toxicity which may have led to cell death and induction of tumours by compensatory cell proliferation. Although these results do not allow decisive conclusions to be drawn concerning the relationship between total levels of DNA adducts and differences in carcinogenic susceptibility for the three strains of mice it is clear that the increased presence of a DNA adduct in the target tissue increases the likelihood of tumour development.     

3D image-based dosimetry for Yttrium-90 radioembolization of hepatocellular carcinoma: Impact of imaging method on absorbed dose estimates

BackgroundTo improve therapy outcome of Yttrium-90 selective internal radiation therapy (⁹⁰Y SIRT), patient-specific post-therapeutic dosimetry is required. For this purpose, various dosimetric approaches based on different available imaging data have been reported. The aim of this work was to compare post-therapeutic 3D absorbed dose images using Technetium-99m (^99mTc) MAA SPECT/CT, Yttrium-90 (⁹⁰Y) bremsstrahlung (BRS) SPECT/CT, and ⁹⁰Y PET/CT.MethodsTen SIRTs of nine patients with unresectable hepatocellular carcinoma (HCC) were investigated. The ^99mTc SPECT/CT data, obtained from ^99mTc-MAA-based treatment simulation prior to ⁹⁰Y SIRT, were scaled with the administered ⁹⁰Y therapy activity. 3D absorbed dose images were generated by dose kernel convolution with scaled ^99mTc/⁹⁰Y SPECT/CT, ⁹⁰Y BRS SPECT/CT, and ⁹⁰Y PET/CT data of each patient. Absorbed dose estimates in tumor and healthy liver tissue obtained using the two SPECT/CT methods were compared against ⁹⁰Y PET/CT.ResultsThe percentage deviation of tumor absorbed dose estimates from ⁹⁰Y PET/CT values was on average −2 ± 18% for scaled ^99mTc/⁹⁰Y SPECT/CT, whereas estimates from ⁹⁰Y BRS SPECT/CT differed on average by −50 ± 13%. For healthy liver absorbed dose estimates, all three imaging methods revealed comparable values.ConclusionThe quantification capabilities of the imaging data influence ⁹⁰Y SIRT tumor dosimetry, while healthy liver absorbed dose values were comparable for all investigated imaging data. When no ⁹⁰Y PET/CT image data are available, the proposed scaled ^99mTc/⁹⁰Y SPECT/CT dosimetry method was found to be more appropriate for HCC tumor dosimetry than ⁹⁰Y BRS SPECT/CT based dosimetry.