Advanced Radiotherapy Techniques Research Articles

PSMA-PET/MRI-Based Focal Dose Escalation in Patients with Primary Prostate Cancer Treated with Stereotactic Body Radiation Therapy (HypoFocal-SBRT): Study Protocol of a Randomized, Multicentric Phase III Trial.

Simple SummaryProstate cancer (PCa) is the most diagnosed malignancy of men worldwide, and radiotherapy (RT) is a main treatment option for patients in all disease stages. Modern diagnostic imaging and RT techniques enable an effective and safe delivery of high RT doses and a reduction of treatment time. We present a study protocol of a phase III trial implementing most modern imaging techniques and RT approaches. We compare the standard RT treatment with an RT concept of reduced treatment time and focal dose escalation based on the patient’s individual tumor morphology. This HypoFocal-SBRT trial aims to individualize treatment of PCa patients.Technical advances in radiotherapy (RT) treatment planning and delivery have substantially changed RT concepts for primary prostate cancer (PCa) by (i) enabling a reduction of treatment time, and by (ii) enabling safe delivery of high RT doses. Several studies proposed a dose–response relationship for patients with primary PCa and especially in patients with high-risk features, as dose escalation leads to improved tumor control. In parallel to the improvements in RT techniques, diagnostic imaging techniques like multiparametric magnetic resonance imaging (mpMRI) and positron-emission tomography targeting prostate-specific-membrane antigen (PSMA-PET) evolved and enable an accurate depiction of the intraprostatic tumor mass for the first time. The HypoFocal-SBRT study combines ultra-hypofractionated RT/stereotactic body RT, with focal RT dose escalation on intraprostatic tumor sides by applying state of the art diagnostic imaging and most modern RT concepts. This novel strategy will be compared with moderate hypofractionated RT (MHRT), one option for the curative primary treatment of PCa, which has been proven by several prospective trials and is recommended and carried out worldwide. We suspect an increase in relapse-free survival (RFS), and we will assess quality of life in order to detect potential changes.

Identification of a Novel cGas/STING/Type I Interferon Specific Murine Cardiac Immune Landscape Following Radiation Therapy

<h3>Purpose/Objective(s)</h3> Cardiotoxicity from radiation treatment to the chest is a late toxicity that has been shown to increase with radiation dose. While clinical parameters and advances in radiation techniques have resulted in lower doses to the heart, the pathophysiologic mechanisms of radiation cardiotoxicity remains a debated topic. We have previously demonstrated that, in murine models, radiation activates a delayed, fibroblast-specific type I interferon response that is dependent on the cytosolic nucleic acid sensor, cGas and its downstream signaling protein STING. Indeed, STING knockout mice exhibit a survival advantage in comparison to wild type mice following a radiation challenge to the heart (20Gy x 1). In this study, we sought to evaluate the consequences of the type I interferon activation on cardiac tissue-specific white blood cell population and identify novel radiation-dependent changes of cardiac immune infiltrates. <h3>Materials/Methods</h3> All animal experiments were performed in accordance with IACUC guidelines. C57BL/6 wild type mice and C57BL/6 Tmem173^gt (catalytically inactive STING) were treated with either sham or 12 Gy single dose to the heart using opposing tangents. At 1 month, hearts were harvested and CD45+ positive cells were immunoprecipitated and sent for 3' single cell RNA (scRNA) sequencing using 10X genomics. ScRNA data was analyzed using Seurat 3.0 <h3>Results</h3> Our results show that radiation induces the upregulation of a subset of cardiac macrophages, interferon inducible cardiac (IFNIC) macrophages. This effect is that is abrogated in mice lacking a functional STING. Furthermore, we observed a general activation of innate immunity as evidenced by increases in the dendritic cell population as well as upregulation of non-classical class I MHC molecules in non-IFNIC macrophages. More surprisingly, we find that there is a marked increase in tissue specific B cell population following radiation, an effect that is completely abolished in mice lacking a functional STING. <h3>Conclusion</h3> We describe for the first time the immune landscape of heart tissue following radiation. We find a previously undescribed infiltration of IFNIC macrophages and a robust activation of an innate immunity. Furthermore, we find a strong effector humoral adaptive response, likely downstream. These findings open the possibility to further understand the role of immune infiltrates in mediation of normal tissue toxicity following radiation.

Phase I Dose Escalation Clinical Trial of Stereotactic Body Radiation Therapy (SBRT) for Limited Locoregional Recurrences of Ovarian Cancer

Radiation therapy is infrequently used in the treatment of advanced ovarian cancer due to the propensity for peritoneal spread and the dose limitations of large field techniques. However, for patients with limited sites of recurrence, advanced radiation techniques such as Stereotactic Body Radiation Therapy (SBRT) may offer an effective treatment option. There are many clinical trials supporting the safety and efficacy of SBRT for lung and liver tumors, but the role for abdominopelvic targets adjacent to gastrointestinal mucosa remains largely investigational, especially in this often heavily pretreated patient population.A single institution Phase I dose escalation study was conducted to determine the maximum tolerated dose (MTD) of SBRT for patients with limited (≤ 3 sites) abdominopelvic recurrences of ovarian cancer. We utilized a 3+3 design with 3 dose levels: 8 Gy x 3 fractions (DL1), 9 Gy x 3 fractions (DL2), and 10 Gy x 3 fractions (DL3). Dose limiting toxicity (DLT) was defined as treatment-related grade 3 or higher adverse events and the DLT monitoring period was 12 weeks after completion of SBRT prior to escalating to the next dose level. Secondary endpoints included toxicity, one-year local control (LC), progression-free survival (PFS), overall survival (OS), and quality of life (QOL) utilizing the EORTC QLQ-C30 assessment tool. Patients underwent tumor perfusion imaging as an exploratory endpoint. The median of each perfusion metric in the gross tumor volume (GTV) was computed at baseline, immediately following fraction one, and six weeks after completion of SBRT, and compared with a paired t-test.Sixteen patients were enrolled; 9 in the initial dose escalation and 7 in an expansion cohort. The initial dose escalation cohort has completed 12-month follow-up. Patients were enrolled according to the 3+3 design, with a safety break between levels, and the dose was safely escalated to DL3 with no DLT. There were no serious adverse events or any Grade 2 or higher SBRT-related toxicities, including bowel complications or bowel surgery. One-year LC, PFS, and OS were 92%, 44%, and 100%, respectively. The majority of patients received SBRT on study in lieu of systemic therapy (67%), and one-half of these patients remained off systemic therapy at one-year follow-up. At one year after completion of SBRT, global health status/QOL patient reported outcomes were maintained from baseline values. In perfusion imaging, we observed increases in GTV median permeability (P < 0.01) and blood flow (P = 0.03) after delivery of the first fraction of SBRT, and decreases in blood volume (P = 0.01) six weeks after treatment.This Phase I clinical trial offers preliminary evidence that SBRT can be delivered safely and can be effective in controlling limited locoregional recurrences of ovarian cancer, while maintaining quality of life. SBRT offers another potential tool in the armamentarium of treatments for gynecologic cancers with limited site recurrences.

Are Advanced Radiation Techniques Safe to Use in Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC)? Analysis Based on Pathologic Regression and Local Recurrence

VMAT, deep inspiratory breath hold (DIBH) and adaptive replanning (ART), are increasingly used for LA-NSCLC to improve conformality and reduce treatment toxicity. Yet, impact of these advanced techniques on pathologic response (PR) and local recurrence (LR) is lacking. We evaluated VMAT, DIBH and ART compared to 3D-conformal radiation therapy (3DCRT) and free breathing (FB), hypothesizing that PR and LR would be unaffected.Retrospective analysis of PR and LR in patients with LA-NSCLC treated in a single academic center between 2012-2021 with platinum based chemoradiation (CRT) followed by completion resection. Radiation techniques assessed: VMAT, DIBH and ART (due to tumor shrinkage during treatment).gender, smoking, stage, GTV, tumor histology, tumor location, dose (Gy), chemotherapy, and time interval between CRT and surgery.PR and LR. PR was converted to a binary variable: Major pathologic regression (MPR) (complete response or ≤10% residual tumor cells) vs. residual tumor (> 10% residual tumor cells). Pathological assessment was blinded to radiation technique. LR was determined by CT or PET-CT. Statistical analysis was by logistic regression.Characteristics of patients (n = 106) with LA-NSCLC were: median age: 63 (range 43-79), males: 73/106 (69%), mean radiation dose: 60.7 Gy (SD 4.6 Gy), median GTV: 115cc (range 19-448), and median time interval (CRT-surgery): 65d (range 28-424d). Radiation techniques were: 3DCRT-FB (n = 51, 48 %), VMAT-FB (n = 40, 38%), VMAT-DIBH (n = 15, 14%), and ART (n = 24, 22.6%). Overall MPR was 73/106 (68.9%). MPR was not significant for VMAT (40/55, 73%) vs. 3DCRT (33/51, 64.7%) (OR 0.7, NS) or DIBH (11/15, 73%) vs. FB (62/91, 68%) (OR-1.1, NS). MPR was significant for ART (20/24, 83%) vs. no-ART (53/82, 64.6%) (OR 3.2, P = 0.037), never smokers (6/18, 33%) vs. smokers (65/86, 75%) (OR-0.49, P = 0.007), GTV > 115cc (45/55, 81%) vs. GTV ≤115 cc (28/51, 55%) (OR-0.27, P = 0.007), and time interval between CRT and surgery > 66 d (44/53, 83%) vs. time interval ≤ 65 d (29/53, 55%) (OR-0.2, P = 0.002). The following variables did not corelate with MPR: age, gender, histology, stage, lower lobe location, chemotherapy type and dose > 60 Gy. LR occurred in 17/106 patients. LR trended lower with: ART (1/24, 4%) vs. no ART (16/81, 20%) (HR 1.25 P = 0.7), DIBH (1/15, 6.7%) vs. FB (16/90, 17.8%) (HR-0.86, P = 0.7), and VMAT (6/54, 11%) vs. 3D CRT (11/51, 21%) (HR 0.7, P = 0.6).Pathologic and radiographic comparisons show use of VMAT, DIBH and ART in LA-NSCLC did not adversely influence pathologic regression or LR. Use of ART was associated with increased MPR and reduced LR. GTV, smoking status and time interval between CRT and surgery were associated with MPR. Further investigation of these variables is planned.

Advanced radiotherapy technique in hepatocellular carcinoma with portal vein thrombosis: Feasibility and clinical outcomes.

In Thailand, individuals with hepatocellular carcinoma (HCC) who develop portal vein tumor thrombosis (PVTT) have a restricted treatment option because to the extent of the disease, poor underlying liver function, and non-coverage of immuno/targeted therapy. Radiotherapy (RT) plays an increasingly important function in these patients. To investigate the feasibility, efficacy, and adverse event rates, we performed a retrospective analysis of patients with HCC with PVTT who underwent 3-dimensional conformal radiation (3DCRT), intensity-modulated radiation (IMRT), volumetric-modulated radiotherapy (VMAT), and stereotactic body radiotherapy (SBRT) in a single-institution. To examine clinical results in terms of overall survival (OS), local control (LC), response of primary tumor and PVTT, hepatic and gastrointestinal adverse reaction, and prognosis variables for OS and LC. Between July 2007 and August 2019, non-metastatic HCC with PVTT patients treated with RT were retrospectively reviewed and evaluated. The analysis included data from 160 patients. The mean age of the patients was 60.8 years ((95% CI 58.2-62.0). The median diameter of the tumor was 7.7 cm (range: 1-24.5). 85 (54.5%) individuals had PVTT in the main or first branch. At 1.8-10 Gy per fraction, the mean biologically effective dose (BED) as α/β ratio of 10 was 49.6 (95% CI 46.7-52.5) Gy10. The median survival time was 8.3 (95% CI 6.1-10.3) months. Survival rates at one and two years were 39.6% and 17.1%, respectively. Estimated incidence of local failure using competing risk analysis were 24% and 60% at 1 and 2 years, respectively. The overall response rate was 74%, with an 18.5 percent complete response rate. In multivariate analysis, tumor size, overall response, and radiation dose were all significant prognostic variables for OS. Hepatic unfavorable events of grade 3 and 4 were for 14.1% of the total. There was no occurrences of grade 3-4 gastrointestinal toxicity, either acute or late. Additionally, there were no treatment-related mortality. Advanced RT is regarded as a safe and effective therapeutic option for HCC with PVTT. Overall survival was clearly related to tumor size, radiation dose, and tumor/PVTT response. Individuals with BED 56 Gy10 had significantly better overall survival than patients with BED 56 Gy10. A prospective randomized trial is required to validate these outcomes in order to corroborate these findings.

FLASH radiotherapy: Considerations for multibeam and hypofractionation dose delivery

Current interest in ultra-high-dose-rate radiation therapy (FLASH) has arisen from the observed protection of various normal tissues exposed to high single doses in preclinical studies [1]. In this context ‘ultra-high-dose-rate’ is considered to be ≥40 Gy/s (c.f. a conventional (CONV) dose-rate ≥ 0.01 Gy/s) [2,3] (Fig. 1). While existing preclinical and clinical application of FLASH has used only a single beam, some proponents of FLASH have suggested the use of multiple beams to achieve the same conformal dose distributions obtainable using advanced radiotherapy techniques such as scanned beam proton therapy with conventional radiation dose-rates [4].

Dose calculation accuracy for photon small fields in treatment planning systems with comparison by Monte Carlo simulations

Abstract Purpose: Advanced radiation therapy techniques use small fields in treatment planning and delivery. Small fields have the advantage of more accurate dose delivery, but with the cost of some complications in dosimetry. Different dose calculation algorithms imported in various treatment planning systems (TPSs) which each of them has different accuracy. Monte Carlo (MC) simulation has been reported as one of the accurate methods for calculating dose distribution in radiation therapy. The aim of this study was the evaluation of TPS dose calculation algorithms in small fields against 2 MC codes. Methods: A linac head was simulated in 2 MC codes, MCNPX, and GATE. Then three small fields (0.5×0.5, 1×1 and 1.5×1.5 cm2) were simulated with 2 MC codes, and also these fields were planned with different dose calculation algorithms in Isogray and Monaco TPS. PDDs and lateral dose profiles were extracted and compared between MC simulations and dose calculation algorithms. Results: For 0.5×0.5 cm2 field mean differences in PDDs with MCNPX were 2.28, 4.6, 5.3, and 7.4% and with GATE were -0.29, 2.3, 3 and 5% for CCC, superposition, FFT and Clarkson algorithms respectively. For 1×1 cm2 field mean differences in PDDs with MCNPX were 1.58, 0.6, 1.1 and 1.4% and with GATE were 0.77, 0.1, 0.6 and 0.9% for CCC, superposition, FFT and Clarkson algorithms respectively. For 1.5×1.5 cm2 field mean differences in PDDs with MCNPX were 0.82, 0.4, 0.6 and -0.4% and with GATE were 2.38, 2.5, 2.7 and 1.7% for CCC, superposition, FFT and Clarkson algorithms respectively. Conclusions: Different dose calculation algorithms were evaluated and compared with MC simulation in small fields. Mean differences with MC simulation decreased with the increase of field sizes for all algorithms.

928TiP Induction versus adjuvant gemcitabine/cisplatin in locally advanced non-metastatic nasopharyngeal carcinoma: A randomised phase III trial

The standard of care for locally advanced nasopharyngeal carcinoma is radical chemoradiation (CRT). Recent advances in radiation techniques and supportive measures resulted in improvement of locoregional control and quality of life. However distant failure is still the main challenging reason of poor survival Addition of systemic therapy to concurrent CRT is widely used and accepted as an option to reduce these failures, however selection of chemotherapy regimen and timing in relation to CRT is controversial.

Radiation Induces Valvular Interstitial Cell Calcific Response in an in vitro Model of Calcific Aortic Valve Disease

Background: Mediastinal ionizing radiotherapy is associated with an increased risk of valvular disease, which demonstrates pathological hallmarks similar to calcific aortic valve disease (CAVD). Despite advances in radiotherapy techniques, the prevalence of comorbidities such as radiation-associated valvular disease is still increasing due to improved survival of patients receiving radiotherapy. However, the mechanisms of radiation-associated valvular disease are largely unknown. CAVD is considered to be an actively regulated disease process, mainly controlled by valvular interstitial cells (VICs). We hypothesize that radiation exposure catalyzes the calcific response of VICs and, therefore, contributes to the development of radiation-associated valvular disease.Methods and Results: To delineate the relationship between radiation and VIC behavior (morphology, calcification, and matrix turnover), two different in vitro models were established: (1) VICs were cultured two-dimensional (2D) on coverslips in control medium (CM) or osteogenic medium (OM) and irradiated with 0, 2, 4, 8, or 16 Gray (Gy); and (2) three-dimensional (3D) hydrogel system was designed, loaded with VICs and exposed to 0, 4, or 16 Gy of radiation. In both models, a dose-dependent decrease in cell viability and proliferation was observed in CM and OM. Radiation exposure caused myofibroblast-like morphological changes and differentiation of VICs, as characterized by decreased αSMA expression. Calcification, as defined by increased alkaline phosphatase activity, was mostly present in the 2D irradiated VICs exposed to 4 Gy, while after exposure to higher doses VICs acquired a unique giant fibroblast-like cell morphology. Finally, matrix turnover was significantly affected by radiation exposure in the 3D irradiated VICs, as shown by decreased collagen staining and increased MMP-2 and MMP-9 activity.Conclusions: The presented work demonstrates that radiation exposure enhances the calcific response in VICs, a hallmark of CAVD. In addition, high radiation exposure induces differentiation of VICs into a terminally differentiated giant-cell fibroblast. Further studies are essential to elucidate the underlying mechanisms of these radiation-induced valvular changes.

Evolving Practice Pattern of Palliative Radiation Therapy for Bone Metastases from Lung Cancer in Australia

AimsRadiation therapy is an effective treatment for bone metastases. Single-fraction conformal radiation therapy (SF-CRT) is equally effective as multifraction radiation therapy for the management of uncomplicated bone metastases. There has been a rapid development of advanced radiation therapy techniques (ART) in radiation oncology. We evaluated the changing pattern of SF-CRT and ART use for the management of bone metastases in lung cancer. Materials and methodsThis was a state-wide population-based cohort of lung cancer patients from Victoria, Australia, who received radiation therapy for bone metastases between 2012 and 2017. The primary outcomes were proportion of radiation therapy courses using: SF-CRT and ART. We identified a subcohort in which radiation therapy was delivered at the end of life (EOL), i.e. within 30 days of death. The Cochran–Armitage test for trend was used to evaluate the change in pattern of SF-CRT and ART use over time. Multivariable analyses were used to identify factors associated with the primary outcomes. ResultsOf the 4335 courses of radiation therapy for bone metastases in lung cancer, 20% were SF-CRT – increasing from 19% in 2012 to 26% in 2017 (P-trend = 0.004). In multivariate analyses, treatment to the rib, shoulder, hip or extremities, and treatment in public institutions were independently associated with SF-CRT use, but the effect of year of radiation therapy was no longer significant. Five per cent of radiation therapy was delivered using ART, increasing markedly from 2016 onwards (P-trend < 0.001). In multivariate analyses, treatment in private institutions and more recent years of treatment were independently associated with the use of ART. There were 587 courses of radiation therapy delivered at the EOL, with SF-CRT more commonly used closer to death – 53%, 29% and 25% of radiation therapy within 7 days, 8–14 days and 15–30 days of death, respectively. ConclusionSF-CRT continued to be underutilised for bone metastases in lung cancer in Australia, including at the EOL. We observed an increase in ART use for bone metastases from 2016, which occurred contemporaneously with changes in government funding.

Advanced Radiotherapy Techniques for Mediastinal Lymphomas: Results from an Italian Survey

Background: Multiple methods have been implemented to limit the impact of radiotherapy on patients affected by mediastinal lymphoma, including breathing control techniques, image-guided radiotherapy (IGRT) and intensity-modulated radiotherapy (IMRT), although the actual diffusion of such techniques is unclear. No surveys have been published to date evaluating the techniques adopted at different centers. Methods: A survey with a dedicated questionnaire was submitted to 195 Italian radiotherapy centers, assessing items regarding the characteristics of the center and clinical practice in the treatment of mediastinal lymphomas. Results: A total of 43 centers (22%) responded, the majority of which were university hospitals (37.2%) or cancer care centers (27.9%). In 95.4% of the centers, IMRT was used in the clinical practice, and the most frequently employed techniques were VMAT (48.8% of centers) and non-rotational IMRT (31.7%). Comparison of multiple plans was performed by 66.7% of the responding centers. Dose constraints for organs at risk were consistently prescribed. IGRT techniques were adopted by 93% of the centers, while breathing control or gating techniques were routinely used by only 25.6% of the centers. A necessity to standardize OAR constraints and define guidelines was perceived by almost all participants. Conclusions: Modern radiotherapy techniques are widely used in the Italian centers, although with heterogeneous characteristics.

Neurocognitive Outcomes in Pediatric Patients Following Brain Irradiation.

Simple SummarySince inception, radiation therapy in pediatric brain tumor patients has been associated with neurocognitive decline and persistent impairment. Recently published studies suggest improved cognitive outcomes with advanced radiation techniques due to increased conformality. Our study compares different treatment modalities through longitudinal assessment of seven neurocognitive domains as well as examining the overall effect on scholastic performance in long-term follow-up more than four years after treatment. Comprehensive data were available due to interdisciplinary cooperation of pediatric neuro-oncologists, radiation oncologists, neurosurgeons, and clinical psychologists. To our knowledge, only a few such detailed testing results have been published, allowing a more granular examination of neurocognitive outcomes rather than basic IQ testing. Our study was able to show no differences in performance after adding modern conformal proton or photon radiation therapy to surgery compared to surgery alone. We could rule out radiation therapy as severe confounding factor in neurocognitive decline after brain tumor treatment in our study.Advanced radiation techniques can reduce the severity of neurocognitive sequelae in young brain tumor patients. In the present analysis, we sought to compare neurocognitive outcomes after proton irradiation with patients who underwent photon radiotherapy (RT) and surgery. Neurocognitive outcomes were evaluated in 103 pediatric brain tumor patients (proton RT n = 26, photon RT n = 30, surgery n = 47) before and after treatment. Comparison of neurocognitive outcomes following different treatment modalities were analyzed over four years after treatment completion. Longitudinal analyses included 42 months of follow-up after proton RT and 55 months after photon RT and surgery. Neurocognitive assessment included standardized tests examining seven domains. A comparison of neurocognitive outcomes after RT (proton and photon with >90% additional surgery) and surgery showed no significant differences in any neurocognitive domain. Neurocognitive functioning tests after proton RT failed to identify alterations compared to baseline testing. Long-term follow up over four years after photon RT showed a decrease in non-verbal intelligence (−9.6%; p = 0.01) and visuospatial construction (−14.9%; p = 0.02). After surgery, there was a decline in non-verbal intelligence (−10.7%; p = 0.01) and processing speed (14.9%; p = 0.002). Differences in neurocognitive outcomes between RT and surgical cohorts in direct intermodal comparison at long-term follow-up were not identified in our study, suggesting that modern radiation therapy does not affect cognition as much as in the past. There were no alterations in long-term neurocognitive abilities after proton RT, whereas decline of processing speed, non-verbal intelligence, and visuospatial abilities were observed after both photon RT and surgery. Domains dependent on intact white matter structures appear particularly vulnerable to brain tumor treatment irrespective of treatment approach.

Diallyl Disulfide Attenuates Ionizing Radiation-Induced Migration and Invasion by Suppressing Nrf2 Signaling in Non-small-Cell Lung Cancer.

Non–small-cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths. Radiotherapy remains the primary treatment method for NSCLC. Despite great advances in radiotherapy techniques and modalities, recurrence and resistance still limit therapeutic success, even low-dose ionizing radiation (IR) can induce the migration and invasion. Diallyl disulfide (DADS), a bioactive component extracted from garlic, exhibits a wide spectrum of biological activities including antitumor effects. However, the effect of DADS on IR-induced migration and invasion remains unclear. The present study reported that IR significantly promoted the migration and invasion of A549 cells. Pretreatment with 40 μM DADS enhanced the radiosensitivity of A549 cells and attenuated IR-induced migration and invasion. In addition, 40 μM DADS inhibited migration-related protein matrix metalloproteinase-2 and 9 (MMP-2/9) expression and suppressed IR-aggravated EMT by the upregulation of the epithelial marker, E-cadherin, and downregulation of the mesenchymal marker, N-cadherin, in A549 cells. Furthermore, DADS was found to inhibit the activation of Nrf2 signaling. Based on our previous results that knockdown of Nrf2 by siRNA suppressed IR-induced migration and invasion in A549 cells, we speculated that DADS attenuated IR-induced migration and invasion by suppressing the activation of Nrf2 signaling in A549 cells.

Developments in radiation techniques for thoracic malignancies.

Radiation therapy is a cornerstone of modern lung cancer treatment alongside surgery, chemotherapy, immunotherapy and targeted therapies. Advances in radiotherapy techniques have enhanced the accuracy of radiation delivery, which has contributed to the evolution of radiation therapy into a guideline-recommended treatment in both early-stage and locally advanced nonsmall cell lung cancer. Furthermore, although radiotherapy has long been used for palliation of disease in advanced lung cancer, it is increasingly having a role as a locally ablative treatment in patients with oligometastatic disease.This review provides an overview of recent developments in radiation techniques, particularly for non-radiation oncologists who are involved in the care of lung cancer patients. Technical advances are discussed, and findings of recent clinical trials are highlighted, all of which have led to a changing perception of the role of radiation therapy in multidisciplinary care.

Dose–Volume Predictors for Patient-reported Late Diarrhoea, Faecal Incontinence and Urgency after Pelvic Radiotherapy

AimsPelvic radiotherapy adds significantly to the curative treatment of many pelvic malignancies. However, this cure comes at a cost for many patients, where late bowel toxicities, such as faecal incontinence, urgency and diarrhoea, adversely affect quality of life. Despite the implementation of advanced radiotherapy techniques in many centres, there are deficiencies in our knowledge of how to make best use of these techniques to minimise these late toxicities, with dose–volume constraints specifically for late effects needing definition. The aims of this study were to establish dose–volume predictors for patient-reported late bowel toxicities and derive constraints for clinical use to reduce the risk of these toxicities. Materials and methodsAll radiotherapy patients treated in our institution between 2012 and 2014 for gynaecological and urological cancers (bladder, prostate where pelvic nodes are treated) were identified. Patients were sent patient-reported toxicity questionnaires at 12 and 24 months after treatment. Planning computed tomography scans were retrospectively contoured with different definitions of bowel as organs at risk (OARs). Dose–volume data for each OAR were collected and predictors of these toxicities found using multivariate analysis. For those dose–volume predictors found to be significant on multivariate analysis, statistically significant and clinically relevant dose–volume constraints were derived. Furthermore, data collected were used to validate constraints from published studies. ResultsFaecal urgency, incontinence and diarrhoea rates were found in 52, 23.5 and 18.7% of the 203 patients included at 12 months following radiotherapy. Dose–volume parameters for sigmoid colon and large bowel were significant for these toxicities, and constraints for these OARs were derived, which are promising. A previously published constraint for bowel loops was validated with our data. ConclusionsThe sigmoid colon and large bowel are important OARs for the development of faecal urgency, incontinence and diarrhoea. Promising constraints for these OARs were derived, which require further validation before prospective clinical use.

Selection of Mediastinal Lymphoma Patients for Proton Therapy Within the Proton Collaborative Group Registry: Concordance With the ILROG Guidelines.

As patients with mediastinal lymphoma are typically young with curable disease, advanced radiation techniques such as proton therapy are often considered to minimize subacute and late toxicity. However, it is unclear which mediastinal lymphoma patients are treated with proton therapy. Within a prospective, multi-institutional proton registry, we characterized mediastinal lymphoma patients treated with proton therapy and assessed concordance with consensus recommendations published in 2018 by the International Lymphoma Radiation Oncology Group (ILROG). Eligible patients included those with lymphoma of the mediastinum treated exclusively with proton therapy for whom digital imaging and communications in medicine (DICOM) treatment data were available for review. Given the challenge with reliably visualizing the left mainstem coronary artery, the inferior-most aspect of the left pulmonary artery (PA) was used as a surrogate. Extent of disease was characterized as upper mediastinum (above level of left PA), middle mediastinum (below left PA but at or above level of T8), or low mediastinum (below T8). Between November 2012 and April 2019, 56 patients were treated and met inclusion criteria. Patients treated with proton therapy were young (median, 24 y; range: 12 to 88), with over half being female (55%). Patients were most commonly treated at initial diagnosis (86%) and had Hodgkin lymphoma (79%). Most patients (96%) had mediastinal disease that extended down to the level of the heart: 48% had middle and 48% had low mediastinal involvement. Nearly all patients (96%) met the ILROG consensus recommendations: 95% had lower mediastinal disease, 46% were young females, and 9% were heavily pretreated. Heart (mean) and lung dose (mean, V5, V20) were significantly associated with lowest extent of mediastinal disease. Mediastinal lymphoma patients treated with proton therapy are typically young with lower mediastinal involvement. Within a prospective, multi-institutional proton registry, nearly all treated patients fit the ILROG consensus recommendations regarding which mediastinal lymphoma patients may most benefit from proton therapy.

The Importance of Tumor Stem Cells in Glioblastoma Resistance to Therapy.

Glioblastoma (GBM) is known to be the most common and lethal primary malignant brain tumor. Therapies against this neoplasia have a high percentage of failure, associated with the survival of self-renewing glioblastoma stem cells (GSCs), which repopulate treated tumors. In addition, despite new radical surgery protocols and the introduction of new anticancer drugs, protocols for treatment, and technical advances in radiotherapy, no significant improvement in the survival rate for GBMs has been realized. Thus, novel antitarget therapies could be used in conjunction with standard radiochemotherapy approaches. Targeted therapy, indeed, may address specific targets that play an essential role in the proliferation, survival, and invasiveness of GBM cells, including numerous molecules involved in signal transduction pathways. Significant cellular heterogeneity and the hierarchy with GSCs showing a therapy-resistant phenotype could explain tumor recurrence and local invasiveness and, therefore, may be a target for new therapies. Therefore, the forced differentiation of GSCs may be a promising new approach in GBM treatment. This article provides an updated review of the current standard and experimental therapies for GBM, as well as an overview of the molecular characteristics of GSCs, the mechanisms that activate resistance to current treatments, and a new antitumor strategy for treating GSCs for use as therapy.

Effectiveness of Image-Guided Radiotherapy in Adjuvant Radiotherapy on Survival for Localized Breast Cancer: A Population-Based Analysis.

PurposeImage-guided radiotherapy (IGRT) is an advanced radiotherapy technique to improve the radiotherapy delivery. We aimed to compare the overall survival (OS) for localized breast cancer (LBC) patient treated with adjuvant conventional fractionated radiotherapy (CFRT) using IGRT vs those without IGRT via a population-based analysis.Patients and MethodsEligible LBC patients diagnosed between 2011 and 2013 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders between groups. The hazard ratio (HR) of death and other outcomes were compared between IGRT and non-IGRT. We also evaluated OS in various supplementary analyses.ResultsOur primary analysis included 6490 patients in whom covariates were well balanced after PS weighing. The HR for death when IGRT was compared with non-IGRT was 1.02 (95% confidence interval 0.80–1.31, P = 0.86). There were also no significant differences in the supplementary analyses.ConclusionWe found that OS of LBC patients treated with adjuvant CFRT was not statistically different between those treated with IGRT versus without IGRT. This was the first study in this regard to our knowledge but randomized controlled trials were needed to confirm our finding.

The Landmark Series: Locally Advanced Pancreatic Cancer and Ablative Therapy Options.

Locally advanced pancreatic cancer (LAPC) is a challenging disease to treat. There is consensus that systemic chemotherapy should be the first line of therapy for most patients. However, there is no consensus on how to manage those patients who do not have sufficient response to become candidates for resection but also do not have distant progression after weeks or months of systemic therapy. Radiation therapy is the most commonly used and best-studied local ablative therapy. One recent randomized controlled trial (LAP-07) failed to demonstrate an overall survival benefit for conventional chemoradiation therapy after induction chemotherapy versus chemotherapy alone. This study had several limitations, and ongoing studies are re-evaluating the role of chemoradiation after more effective chemotherapy regimens as well as more advanced radiation techniques. In parallel, there has been increasing interest in other thermal and non-thermal methods of ablation. In particular, irreversible electroporation has gained traction for treatment of LAPC, with at least one ongoing randomized controlled trial designed to address its role compared with systemic chemotherapy alone. Multiple preclinical and clinical studies are investigating combinations of local ablation and immunotherapy with the goal of generating immune responses that will meaningfully improve outcomes.

Oligometastatic non-small-cell lung cancer. Current management

In the past decade, major developments have improved the survival of patients with oligometastatic non-small cell lung cancer (NSCLC). About 20% - 50% of patients with NSCLC present with oligometastases at diagnosis. For this group of patients, it seems that an increase in survival would justify aggressive local therapies. The development of minimally invasive surgery and advanced radiotherapy techniques like stereotactic body radiation therapy (SBRT) makes local control possible for selected patients with metastatic NSCLC. The advantage of SBRT over surgery is that it is a non-invasive technique, with minimum side effects, and is more suitable for fragile and elderly patients, non-candidates for surgery, or patients who refuse surgery. The purpose of this review is to summarize the latest scientific evidence on the management of oligometastatic NSCLC, focusing on the role of radiotherapy. The initial treatment recommended for patients with oligometastatic NSCLC is systemic therapy. Patients should be considered for radical treatment to both the primary tumor and oligometastases. Aggressive local therapy comprises surgery and/or definitive radiotherapy such as SRS or SBRT, and may be preceded or followed by systemic treatment. Recent clinical evidence from Phase II trials reports benefits in terms of PFS in patients with good performance status and long disease-free periods, with good response to systemic therapy, especially in EGFR wild-type tumors. Phase I and II trials have shown that radiotherapy combined with immunotherapy can improve tumor response rate and possibly overall survival. The recommendation is also to include OM patients in ongoing clinical trials.