Radiotherapy in the management of synchronous metastatic lung cancer.

Metastatic lung cancer classically portends a poor prognosis. The management of metastatic lung cancer has dramatically changed with the emergence of immune checkpoint inhibitors, targeted therapy and due to a better understanding of the oligometastatic process. In metastatic lung cancers, radiation therapy which was only used with palliative intent for decades, represents today a promising way to treat primary and oligometastatic sites with a curative intent. Herein we present through a literature review the role of radiotherapy in the management of synchronous metastatic lung cancers.

Radiotherapy in the management of lung oligometastases.

In recent years, the development of both medical imaging and new systemic agents (targeted therapy and immunotherapy) have revolutionized the field of oncology, leading to a new entity: oligometastatic disease. Adding local treatment of oligometastases to systemic treatment could lead to prolonged survival with no significant impact on quality of life. Given the high prevalence of lung oligometastases and the new systemic agents coming with increased pulmonary toxicity, this article provides a comprehensive review of the current state-of-art for radiotherapy of lung oligometastases. After reviewing pretreatment workup, the authors define several radiotherapy regimen based on the localization and size of the oligometastases. A comment on the synergistic combination of medical treatment and radiotherapy is also made, projecting on future steps in this specific clinical setting.

Long duration of immunotherapy before radiosurgery might improve intracranial control of melanoma brain metastases.

PURPOSE: Despite significant advances that have been made in management of metastatic melanoma with immune checkpoint therapy, optimal timing of combination immune checkpoint therapy and stereotactic radiosurgery is unknown. We have reported toxicity and efficiency outcomes of patients treated with concurrent immune checkpoint therapy and stereotactic radiosurgery. PATIENTS AND METHODS: From January 2014 to December 2016, we analyzed 62 consecutive patients presenting 296 melanoma brain metastases, treated with gamma-knife and receiving concurrent immune checkpoint therapy with anti-CTLA4 or anti-PD1 within the 12 weeks of SRS procedure. Median follow-up time was 18 months (mo) (13-22). Minimal median dose delivered was 18 gray (Gy), with a median volume per lesion of 0.219 cm3. RESULTS: The 1-year control rate per irradiated lesion was 89% (CI 95%: 80.41-98.97). Twenty-seven patients (43.5%) developed distant brain metastases after a median time of 7.6 months (CI 95% 1.8-13.3) after gamma-knife. In multivariate analysis, positive predictive factors for intracranial tumor control were: delay since the initiation of immunotherapy exceeding 2 months before gamma-knife procedure (P=0.003) and use of anti-PD1 (P=0.006). Median overall survival (OS) was 14 months (CI 95%: 11-NR). Total irradiated tumor volume<2.1 cm3 was a positive predictive factor for overall survival (P=0.003). Ten patients (16.13%) had adverse events following irradiation, with four grade≥3. Predictive factors of all grade toxicity were: female gender (P=0.001) and previous treatment with MAPK (P=0.05). CONCLUSION: A long duration of immune checkpoint therapy before stereotactic radiosurgery might improve intracranial tumor control, but this relationship and its ideal timing need to be assessed in prospective trials.

[Efficacy and tolerance of salvage curative radiotherapy for patients with cervical relapse of differentiated thyroid carcinoma]. / Efficacité et tolérance de la radiothérapie externe pour les patients atteints d'une récidive d'un carcinome différencié de la thyroïde.

PURPOSE: Radiation therapy is often the last resource treatment for cervical relapse in iodine refractory differentiated thyroid cancer. We present locoregional control data in patients with cervical relapse treated with curative intent radiation therapy with or without concomitant carboplatin. MATERIAL AND METHODS: This monocentric retrospective study gathered data on patients with differentiated thyroid carcinoma - vesicular or papillary - in relapse after thyroidectomy who received a curative intent cervical radiation therapy. Locoregional progression free survival (LRPFS), progression free survival (PFS), overall survival (OS) were gathered as well as acute and chronic adverse events assessed with the CTCAE v4. RESULTS: Thirty-nine patients were consecutively included between 2005 and 2019. The median follow-up was 36.6months. Fifteen patients (38%) had a locoregional relapse, locoregional control at 2years was 66.7%. The median LRPFS was 48months [32.9-not reached] and the median overall survival 49months [38.8-not reached]. In multivariate analysis, initial incomplete resection was associated with poorer OS (HR: 24.39 [3.57-166.78], P=0.00113) and LRPFS (HR: 33.91 [4.46-257.61], P=0.00066), extra nodal spread was associated with poorer LRPFS (HR: 13.45 [1.81-99,76], P=0.011). ECOG performance status was associated with OS (HR: 5.11 [1.57-16.66], P=0.00688). Carboplatin association with radiation therapy was not associated with improved survivals (OS: P=0.34, LRPFS: P=0.84). The rate of acute grade 3 toxicities was 14%. CONCLUSION: Salvage cervical radiation therapy was associated with a locoregional control of 66.7% at 2years with a reasonable toxicity rate. Carboplatin association with radiation therapy did not improve locoregional control nor overall survival in comparison with radiotherapy alone.

Histosurgical mapping of endoscopic endonasal surgery of sinonasal tumours to improve radiotherapy guidance.

PURPOSE: Endoscopic endonasal surgery (EES) is becoming a standard for most malignant sinonasal tumours. Margin analysis after piecemeal resection is complex and optimally relies on accurate histosurgical mapping. Postoperative radiotherapy may be adapted based on margin assessment mapping to reduce the dose to some sinonasal subvolumes. We assessed the use of histosurgical mapping by radiation oncologists (RO). MATERIAL AND METHODS: A French practice survey was performed across 29 ENT expert RO (2 did not answer) regarding integration of information on EES, as well as quality of operative and pathology reportsto refine radiotherapy planning after EES. This was assessed through an electronic questionnaire. RESULTS: EES was ubiquitously performed in France. Operative and pathology reports yielded accurate description of EES samples according to 66.7% of interviewed RO. Accuracy of margin assessment was however insufficient according to more than 40.0% of RO. Additional margins/biopsies of the operative bed were available in 55.2% (16/29) of the centres. In the absence of additional margins, quality of resection after EES was considered as microscopically incomplete in 48.3% or dubious in 48.3% of RO. As performed, histosurgical mapping allowed radiotherapy dose and volumes adaptation according to 26.3% of RO only. CONCLUSIONS: Standardized histosurgical mapping with margin and additional margin analysis could be more systematic. Advantages of accurate EES reporting could be dose painting radiotherapy to further decrease morbidity in sinonasal tumours.

Brachytherapy boost (BT-boost) or stereotactic body radiation therapy boost (SBRT-boost) for high-risk prostate cancer (HR-PCa).

Systematic review for the treatment of high-risk prostate cancer (HR-PCa, D'Amico classification risk system) with external body radiation therapy (EBRT)+brachytherapy-boost (BT-boost) or with EBRT+stereotactic body RT-boost (SBRT-boost). In March 2020, 391 English citations on PubMed matched with search terms "high risk prostate cancer boost". Respectively 9 and 48 prospective and retrospective studies were on BT-boost and 7 retrospective studies were on SBRT-boost. Two SBRT-boost trials were prospective. Only one study (ASCENDE-RT) directly compared the gold standard treatment [dose-escalation (DE)-EBRT+androgen deprivation treatment (ADT)] versus EBRT+ADT+BT-boost. Biochemical control rates at 9 years were 83% in the experimental arm versus 63% in the standard arm. Cumulative incidence of late grade 3 urinary toxicity in the experimental arm and in the standard arm was respectively 18% and 5%. Two recent studies with HR-PCa (National Cancer Database) demonstrated better overall survival with BT-boost (low dose rate LDR or high dose rate HDR) compared with DE-EBRT. These recent findings demonstrate the superiority of EBRT+BT-boost+ADT versus DE-EBRT+ADT for HR-PCa. It seems that EBRT+BT-boost+ADT could now be considered as a gold standard treatment for HR-PCa. HDR or LDR are options. SBRT-boost represents an attractive alternative, but the absence of randomised trials does not allow us to conclude for HR-PCa. Prospective randomised international phase III trials or meta-analyses could improve the level of evidence of SBRT-boost for HR-PCa.

Electrophysiology-based stratification of pancreatic tumorigenicity by label-free single-cell impedance cytometry.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer lacking specific biomarkers that can be correlated to disease onset, promotion and progression. To assess whether tumor cell electrophysiology may serve as a marker for PDAC tumorigenicity, we use multi-frequency impedance cytometry at high throughput (∼350 cells/s) to measure the electrical phenotype of single PDAC tumor cells from xenografts, which are derived from primary pancreatic tumors versus those from liver metastases of different patients. A novel phase contrast metric based on variations in the high and low frequency impedance phase responses that is related to electrophysiology of the cell interior is found to be systematically altered as a function of tumorigenicity. PDAC cells of higher tumorigenicity exhibited lowered interior conductivity and enhanced permittivity, which is validated by the dielectrophoresis on the respective cell types. Using genetic analysis, we suggest the role of dysregulated Na+ transport and removal of Ca2+ ions from the cytoplasm on key oncogenic KRAS-driven processes that may be responsible for lowering of the interior cell conductivity. We envision that impedance cytometry can serve as a tool to quantify phenotypic heterogeneity for rapidly stratifying tumorigenicity. It can also aid in protocols for dielectrophoretic isolation of cells with a particular phenotype for prognostic studies on patient survival and to tailor therapy selection to specific patients.

Diagnostic performance of imaging techniques for detecting of local recurrence after prostate brachytherapy.

PURPOSE: The purpose of this study was to evaluate MRI and fluorocholine PET/CT diagnostic performances for the detection of local recurrence following prostate brachytherapy for localised prostate cancer. MATERIAL AND METHODS: In this single-centre study, we retrospectively reviewed data from 21 patients treated by brachytherapy for localised prostate cancer and diagnosed with biochemical recurrence according to Phoenix Criteria, who underwent MRI and fluorocholine PET/CT. We included patients with local relapse suspicion according to imaging exams, with biopsy for the final assessment of local recurrence. Patient analysis data were supplemented by segment analysis using an 8-segment model. RESULTS: The fluorocholine PET/CT was positive for 81% and negative for 19% of patients. The sensitivity and specificity were 92% and 33% with diagnosis accuracy of 67%. The MRI was positive for 57% and negative for 43% of patients. The sensitivity and specificity were 67% and 56% with diagnosis accuracy of 62%. There was no statistically significant difference between fluorocholine PET/CT and MRI accuracy (P=0.63). On a segment-based analysis, the sensitivity and specificity were 44% and 82% for fluorocholine PET/CT with diagnosis accuracy of 78%. For MRI, specificity was 91% diagnosis accuracy was 82%. CONCLUSION: Both MRI and fluorocholine PET/CT permit to highlight local recurrence sites after prostate brachytherapy. Confirmation biopsies are, however, necessary since this accuracy is insufficient.

[From bunker construction to patient treatment: quality controls applied to modern radiotherapy techniques]. / De la construction du bunker à la prise en charge du patient : contrôles qualité des techniques modernes de radiothérapie.

Installation and use of a new radiotherapy device require an adequate quality and safety policy. The process leading to the commissioning of an accelerator following the construction of a bunker includes, among other tasks, the installation of the accelerator, the verification of compliance with the specifications, the signature of the acceptance specification as well as the process of characterization and modeling of the accelerator before its clinical use. The emergence of modern radiotherapy techniques, such as intensity modulated conformational radiotherapy and stereotactic radiotherapy, has resulted in more complex quality controls. The purpose of this article is to explain the different stages of the implementation of innovative radiotherapy techniques and to specify their features.

[Quality and safety policy implementation for a new radiotherapy device]. / Mise en place d'une politique de qualité et de sécurité lors de l'installation d'un nouvel équipement dans un service de radiothérapie.

Modern radiotherapy techniques (intensity-modulated radiotherapy, volumetric-modulated arctherapy, image-guided radiotherapy) or stereotactic radiotherapy are in expansion in most French cancer centres. The arrival of such techniques requires updates of existing equipment or implementation of new radiotherapy devices with adapted options. With the arrival of these new devices, there is a need to develop a quality and safety policy. This is necessary to ease the process from the setup to the first treated patient. The quality and safety policy is maintained to ensure the quality assurance of the radiotherapy equipment. We conducted a review of the literature on the quality and safety policy in the French legal framework that can be proposed when implementing a new radiotherapy device.

[Chemoradiation for oesophageal cancer: A critical review of the literature]. / Chimioradiothérapie des cancers de l'œsophage : revue critique de la littérature.

Locally advanced oesophageal cancer treatment requires a multidisciplinary approach with the combination of chemotherapy and radiotherapy for preoperative and definitive strategy. Preoperative chemoradiation improves the locoregional control and overall survival after surgery for locally advanced oesophageal cancer. Definitive chemoradiation can also be proposed for non-resectable tumours or medically inoperable patients. Besides, definitive chemoradiation is considered as an alternative option to surgery for locally advanced squamous cell carcinomas. Chemotherapy regimen associated to radiotherapy consists of a combination of platinum derived drugs (cisplatinum or oxaliplatin) and 5-fluorouracil or a weekly scheme combination of carboplatin and paclitaxel according to CROSS protocol in a neoadjuvant strategy. Radiation doses vary from 41.4Gy to 45Gy for a preoperative strategy or 50 to 50.4Gy for a definitive treatment. The high risk of lymphatic spread due to anatomical features could justify the use of an elective nodal irradiation when the estimated risk of microscopic involvement is higher than 15% to 20%. An appropriate delineation of the gross tumour volume requires an exhaustive and up-to-date evaluation of the disease. Intensity-modulated radiation therapy represents a promising approach to spare organs-at-risk. This critical review of the literature underlines the roles of radiotherapy for locally advanced oesophageal cancers and describes doses, volumes of treatment, technical aspects and dose constraints to organs-at-risk.

[Advances in the management of cervical lymphadenopathies of unknown primary with intensity modulated radiotherapy: Doses and target volumes]. / Évolutions dans la prise en charge des métastases ganglionnaires cervicales sans cancer primitif retrouvé : doses et volumes cibles de la radiothérapie avec modulation d'intensité.

The definition of nodal and/or mucosal target volumes for radiation therapy for lymphadenopathies of unknown primary is controversial. Target volumes may include all nodal areas bilaterraly and be pan-mucosal or unilateral, selective, including the sole oropharyngeal mucosa. This review presents current recommendations in light of changes in the TNM classification, Human papillomavirus status and therapeutic advances. We conducted a systematic review of the literature with the following keywords: lymphadenopathy; head and neck; unknown primary and radiation therapy. There are no direct comparative studies between unilateral or bilateral nodal irradiation or pan-mucosal and selective mucosal irradiation. Contralateral lymph node failure rates range from 0 to 6% after unilateral nodal irradiation and 0 and 31% after bilateral irradiation. Occurrence of a mucosal primary varies between 0 and 19.2%. Initial clinical presentation and Human papillomavirus status are critical to define mucosal target volumes. Intensity-modulated radiotherapy is recommended (rather than three-dimensional irradiation) to avoid toxicities. Systemic treatments have similar indications as for identified primary head and neck cancers. Failures do not appear superior in case of unilateral nodal irradiation but comparative studies are warranted due to major biases hampering direct comparisons. Human papillomavirus status should be incorporated into the therapeutic strategy and practice-changing TNM staging changes will need to be evaluated.

[Hippocampus, brainstem and brain dose-volume constraints for fractionated 3-D radiotherapy and for stereotactic radiation therapy: Limits and perspectives]. / Contraintes de dose en radiothérapie conformationnelle fractionnée et en radiothérapie stéréotaxique dans les hippocampes, le tronc cérébral et l'encéphale : limites et perspectives.

Cerebral radiation-induced toxicities after radiotherapy (RT) of brain tumors are frequent. The protection of organs at risk (OAR) is crucial, especially for brain tumors, to preserve cognition in cancer survivors. Dose constraints of cerebral OAR used in conventional RT, radiosurgery (SRS) and stereotactic radiotherapy (SRT) are debated. In fact, they are based on historical cohorts or calculated with old mathematical models. Values of α/ß ratio of cerebral OAR are also controversial leading to misestimate the equivalent dose in 2Gy fractions or the biological equivalent dose, especially during hypofractionated RT. Although recent progresses in medical imaging, the diagnosis of radionecrosis remains difficult. In this article, we propose a large review of dose constraints used for three major cerebral OAR: the brain stem, the hippocampus and the brain.

[Lung dose constraints for normo-fractionated radiotherapy and for stereotactic body radiation therapy]. / Doses aux organes à risque en radiothérapie conformationnelle et en radiothérapie stéréotaxique : les poumons.

Radiation-induced lung disease (RILD) is common after radiation therapy and represents cornerstone toxicities after treatment of thoracic malignancies. From a review of literature, the objective of this article was to summarize clinical and non-clinical parameters associated with the risk of RILD in the settings of normo-fractionated radiotherapy and stereotactic body radiation therapy (SBRT). For the treatment of lung cancers with a normo-fractionated treatment, the mean lung dose (MLD) should be below 15-20Gy. For a thoracic SBRT, V20Gy<10% and MLD<6Gy are recommended. One should pay attention to central tumors and respect specific dose constraints to the bronchial tree. The recent technological improvements may represent an encouraging way to decrease lung toxicities. Finally, our team developed a calculator in order to predict the risk of radiation pneumonitis.

Applicability of a high-throughput shotgun plasma protein screening approach in understanding maternal biological pathways relevant to infant birth weight outcome.

There are reports linking maternal nutritional status, smoking and environmental chemical exposures to adverse pregnancy outcomes. However, biological bases for association between some of these factors and birth outcomes are yet to be established. The objective of this preliminary work is to test the capability of a new high-throughput shotgun plasma proteomic screening in identifying maternal changes relevant to pregnancy outcome. A subset of third trimester plasma samples (N=12) associated with normal and low-birth weight infants were fractionated, tryptic-digested and analyzed for global proteomic changes using a MALDI-TOF-TOF-MS methodology. Mass spectral data were mined for candidate biomarkers using bioinformatic and statistical tools. Maternal plasma profiles of cytokines (e.g. IL8, TNF-α), chemokines (e.g. MCP-1) and cardiovascular endpoints (e.g. ET-1, MMP-9) were analyzed by a targeted approach using multiplex protein array and HPLC-Fluorescence methods. Target and global plasma proteomic markers were used to identify protein interaction networks and maternal biological pathways relevant to low infant birth weight. Our results exhibited the potential to discriminate specific maternal physiologies relevant to risk of adverse birth outcomes. This proteomic approach can be valuable in understanding the impacts of maternal factors such as environmental contaminant exposures and nutrition on birth outcomes in future work. BIOLOGICAL SIGNIFICANCE: We demonstrate here the fitness of mass spectrometry-based shot-gun proteomics for surveillance of biological changes in mothers, and for adverse pathway analysis in combination with target biomarker information. This approach has potential for enabling early detection of mothers at risk for low infant birth weight and preterm birth, and thus early intervention for mitigation and prevention of adverse pregnancy outcomes. This article is part of a Special Issue entitled: Can Proteomics Fill the Gap Between Genomics and Phenotypes?

An efficient sample preparation method for high-throughput analysis of 15(S)-8-iso-PGF2α in plasma and urine by enzyme immunoassay.

Although several methods have been reported on the analysis of the oxidative stress marker 15(S)-8-iso-prostaglandin-F2alpha (8-iso-PGF2α) in biological fluids, they either involve extensive sample preparation and costly technology or require high sample volume. This study presents a sample preparation method that utilizes low sample volume for 8-iso-PGF2α analysis in plasma and urine by an enzyme immunoassay (EIA). In brief, 8-iso-PGF2α in deproteinized plasma or native urine sample is complexed with an antibody and then captured by molecular weight cut-off filtration. This method was compared with two other sample preparation methods that are typically used in the analysis of 8-iso-PGF2α by EIA: Cayman's affinity column purification method and solid-phase extraction on C-18. The immunoaffinity purification method described here was superior to the other two sample preparation methods and yielded recovery values of 99.8 and 54.1% for 8-iso-PGF2α in plasma and urine, respectively. Analytical precision (relative standard deviation) was ±5% for plasma and ±15% for urine. The analysis of healthy human plasma and urine resulted in basal 8-iso-PGF2α levels of 31.8 ± 5.5 pg/mL and 2.9 ± 2.0 ng/mg creatinine, respectively. The robustness and analytical performance of this method makes it a promising tool for high-throughput screening of biological samples for 8-iso-PGF2α.

90-day repeated inhalation exposure of surfactant Protein-C/tumor necrosis factor-alpha, (SP-C/TNF-alpha) transgenic mice to air pollutants.

Tumor necrosis factor (TNF)-alpha, a cytokine present in inflammed lungs, is known to mediate some of the adverse effects of ozone and inhaled particles. The authors evaluated transgenic mice with constitutive pulmonary expression of TNF-alpha under transcriptional regulation of the surfactant protein-C promoter as an animal model of biological susceptibility to air pollutants. To simulate a repeated, episodic exposure to air pollutants, wild-type and TNF mice inhaled air or a mixture of ozone (0.4 ppm) and urban particles (EHC-93, 4.8 mg/m3) for 4 h, once per week, for 12 consecutive weeks and were sacrificed 20 h after last exposure. TNF mice exhibited chronic lung inflammation with septal thickening, alveolar enlargement, and elevated protein and cellularity in bronchoalveolar lavage fluid (genotype main effect, p < .001). Repeated exposure to pollutants did not result in measurable inflammatory changes in wild-type mice and did not exacerbate the inflammation in TNF mice. The pollutants decreased recovery of alveolar macrophages in tavage fluid of both wild-type and TNF mice (exposure main effect, p < .001). Exacerbation of the rate of protein nitration reactions specifically in the lungs of TNF mice was revealed by the high ratio of 3-nitrotyrosine to L-DOPA after exposure to the air pollutants (Genotype x Exposure factor interaction, p = .014). Serum creatine kinase-MM isoform increased in TNF mice exposed to pollutants (Genotype X Exposure factor interaction, p = .043). The marked pollutant-related nitration in the lungs of the TNF mice reveals basic differences in free radical generation and scavenging in the inflamed lungs in response to pollutants. Furthermore, elevation of circulating creatine kinase-MM isoform specifically in TNF mice exposed to pollutants suggests systemic adverse impacts from lung inflammatory mediators, possibly on muscles and the cardiovascular system.

MultiDimensional Voice Program analysis in children with vocal cord nodules.

Computer-assisted voice analysis has recently been introduced as a noninvasive approach to the management of paediatric dysphonia. The aim of this study was to determine which parameters of voice analysis distinguish vocal cord nodules from normal patterns. Following diagnosis by flexible nasolaryngoscopy, 12 male children with vocal cord nodules, aged 7 to 12, underwent voice analysis by MultiDimensional Voice Program (MDVP; Kay Elemetrics, Lincoln Park, NJ, USA). These subjects were divided into two age groups (7-9 years, n = 5; 10-12 years, n = 7) and compared to age-matched controls. Results suggest that across all age groups, subjects with vocal cord nodules had statistically significant (p < .01) elevations in absolute jitter, jitter percent, relative average perturbation, pitch period perturbation quotient, smoothed amplitude perturbation quotient, and fundamental frequency variation. Further studies are required to assess the role of MDVP in the diagnosis of other voice pathologies and the monitoring of voice therapy.