Evaluation of reproducibility of tumor repositioning during multiple breathing cycles for liver stereotactic body radiotherapy treatment

AimTo evaluate the tumor repositioning during gated volumetric modulated arc therapy (VMAT) for liver stereotactic body radiotherapy(SBRT) treatment using implanted fiducial markers and intrafraction kilovoltage (kV) images acquired during dose delivery.Materials and methodsSince 2012, 47 liver cancer patients with implanted fiducial markers were treated using the gated VMAT technique with a Varian Truebeam STx linear accelerator. The fiducial markers were implanted inside or close to the tumor target before treatment simulation. They were defined at the maximum inhalation and exhalation phases on a 4-dimensionnal computed tomography (4DCT) acquisition. During the treatment, kV images were acquired just before the beam-on at each breathing cycle at maximum exhalation and inhalation phases to verify the fiducial markers positions. For the five first fractions of treatment in the first ten consecutive patients, a total of 2705 intrafraction kV images were retrospectively analyzed to assess the differences between expected and actual positions of the fiducial markers along the cranio-caudal (CC) direction during the exhalation phase.ResultsThe mean absolute intrafractional fiducial marker deviation along the CC direction was 1.0[[ce:hsp sp="0.25"/]]mm at the maximum exhalation phase. In 99%, 95% and 90% cases, the fiducial marker deviations were ≤4.5[[ce:hsp sp="0.25"/]]mm, 2.8[[ce:hsp sp="0.25"/]]mm and 2.2[[ce:hsp sp="0.25"/]]mm, respectively.ConclusionIntrafraction kV images allowed us to ensure the consistency of tumor repositioning during treatment. In 99% cases, the fiducial marker deviations were ≤4.5[[ce:hsp sp="0.25"/]]mm corresponding to our 5[[ce:hsp sp="0.25"/]]mm treatment margin. This margin seems to be well-adapted to the gated VMAT SBRT treatment in liver disease

Facteurs pronostiques des métastases cérébrales dans le cancer du sein

Objectifs: Déterminer les facteurs pronostiques cliniques et biologiques de survie globale (SG) des métastases cérébrales (MC) de cancers du sein, comparer les scores et classifications pronostiques existantes et étudier l'impact pronostique des traitements locaux et systémiques. Méthodes: Cette étude rétrospective bi-centrique a porté sur 250 patientes présentant des MC de cancer du sein avec statut HER2 et statut des récepteurs hormonaux (RH) connus. Résultats: La SG depuis le diagnostic de MC est de 8,9 mois. L'analyse comparative des scores pronostiques des MC montre une supériorité statistique du RPA (Recursive Partitioning Analysis). Parmi les sous-groupes biologiques de cancer du sein, les patientes HER2+ ont la meilleure SG (11,9 mois) devant les tumeurs RH+/HER2- (8,3 mois) et triple négative (RH-/HER2-) (5,9 mois) (p = 0,062). Le score RPA et le phénotype tumoral sont en analyse multiparamétrique des facteurs pronostiques de SG indépendants. Lorsque l'analyse inclut les traitements, les traitements locaux et la chimiothérapie ont également un impact pronostique. Dans la population HER2+, le traitement anti-HER2 après le diagnostic de MC est associé à une meilleure SG (15,2 contre 3,4 mois) (p < 0,001). L'intégration aux analyses de paramètres biologiques accorde une valeur pronostique au taux de LDH et à l'albuminémie. Conclusion: La survie des patientes atteintes de cancer du sein avec MC dépend du sous-type biologique tumoral et du score RP A. Une prise en charge multimodale associant traitements locaux et traitements systémiques (chimiothérapie et traitements ciblés anti-HER2 dans la population HER2+) améliore la survie de ces patientes.MONTPELLIER-BU Médecine UPM (341722108) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Comparative performances of prognostic indexes for breast cancer patients presenting with brain metastases

BACKGROUND: Several prognostic indexes (PI) have been developed in the brain metastases (BM) setting to help physicians tailor treatment options and stratify patients enrolled in clinical studies. The aim of our study was to compare the clinical relevance of the major PI for breast cancer BM. METHODS: Clinical and biological data of 250 breast cancer patients diagnosed with BM at two institutions between 1995 and 2010 were retrospectively reviewed. The prognostic value and accuracy of recursive partitioning analysis (RPA), graded prognostic assessment (GPA), basic score for BM (BS-BM), breast RPA, breast GPA, Le Scodan’s Score and a clinico-biological score developed in a phase I study (P1PS) were assessed using Cox regression models. PI comparison was performed using Harrell’s concordance index. RESULTS: After a median follow-up of 4.5 years, median overall survival (OS) from BM diagnosis was 8.9 months (CI 95%, 6.9–10.3 months). All PI were significantly associated with OS. Harrell’s concordance indexes C favored BS-BM and RPA. In multivariate analysis, the RPA, Le Scodan’s score and GPA were found to be the best independent predictors of OS. In multivariate analysis restricted to the 159 patients with known LDH and proteinemia, RPA 2 and 3, Le Scodan’s Score 3 and P1PS 2/3 were associated with worse survival. RPA was the most accurate score to identify patients with long (superior to 12 months) and short (inferior to 3 months) life expectancy. CONCLUSIONS: RPA seems to be the most useful score and performs better than new PI for breast cancer BM

Evaluation of reproducibility of tumor repositioning during multiple breathing cycles for liver stereotactic body radiotherapy treatment

International audienceAIM:To evaluate the tumor repositioning during gated volumetric modulated arc therapy (VMAT) for liver stereotactic body radiotherapy(SBRT) treatment using implanted fiducial markers and intrafraction kilovoltage (kV) images acquired during dose delivery.MATERIALS AND METHODS:Since 2012, 47 liver cancer patients with implanted fiducial markers were treated using the gated VMAT technique with a Varian Truebeam STx linear accelerator. The fiducial markers were implanted inside or close to the tumor target before treatment simulation. They were defined at the maximum inhalation and exhalation phases on a 4-dimensionnal computed tomography (4DCT) acquisition. During the treatment, kV images were acquired just before the beam-on at each breathing cycle at maximum exhalation and inhalation phases to verify the fiducial markers positions. For the five first fractions of treatment in the first ten consecutive patients, a total of 2705 intrafraction kV images were retrospectively analyzed to assess the differences between expected and actual positions of the fiducial markers along the cranio-caudal (CC) direction during the exhalation phase.RESULTS:The mean absolute intrafractional fiducial marker deviation along the CC direction was 1.0 mm at the maximum exhalation phase. In 99%, 95% and 90% cases, the fiducial marker deviations were ≤4.5 mm, 2.8 mm and 2.2 mm, respectively.CONCLUSION:Intrafraction kV images allowed us to ensure the consistency of tumor repositioning during treatment. In 99% cases, the fiducial marker deviations were ≤4.5 mm corresponding to our 5 mm treatment margin. This margin seems to be well-adapted to the gated VMAT SBRT treatment in liver disease

Serum NSE, MMP-9 and HER2 extracellular domain are associated with brain metastases in metastatic breast cancer patients: predictive biomarkers for brain metastases?

International audienceBreast cancer (BC) is the second most common cause of brain metastases (BM). Predictive factors for BM have been widely studied in metastatic BC; however, there is no known serum tumor marker to accurately predict BM. Elevated serum S100ß protein and neuron-specific enolase (NSE) could reflect the brain damages induced by BM. Matrix metalloproteinase 9 (MMP-9) is involved in tumor invasion and metastatic dissemination, including BM. Also, HER2-amplified BC were shown to have a particular tropism for central nervous system (CNS). This study evaluated the correlation of these biomarkers with the presence of BM in metastatic BC patients. In this case-control study, 88 consecutive metastatic BC patients with BM (BM group) treated in our institution (2008-2015) were retrospectively selected, based on the availability of frozen serum samples for tumor marker determination. Patients were matched by age, tumor biology and number of previous metastatic chemotherapy lines to 162 metastatic BC patients without CNS involvement (control group). Serum NSE, MMP-9 and HER2 extracellular domain (ECD) levels were significantly higher in the BM group (p = 0.0051, p = 0.0062 and p = 0.0057, respectively). In multivariate analysis, serum HER2 and MMP-9 levels accurately discriminated patients with BM: odds ratios 4.4 (p < 0.001; 95%CI: 1.9-9.6) for HER2 ECD and 3.5 (p = 0.005; 95%CI: 1.5-8.4) for MMP-9. In multivariate analysis, HER2 ECD and NSE serum levels were independent prognostic factors in patients with BM. Serum HER2 ECD and MMP-9 appear to be associated with BM in metastatic BC patients. Their predictive value for BM still needs to be evaluated in further prospective studies

Angiogenesis and tumor microenvironment: bevacizumab in the breast cancer model

International audienceSolid tumors require blood vessels for growth, and many new cancer therapies are directed against the tumor vasculature. Antiangiogenic therapies should destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. According to Jain et al., an alternative hypothesis could be that certain antiangiogenic agents can also transiently "normalize" the abnormal structure and function of tumor vasculature to make it more efficient for oxygen and drug delivery. With emphasize on the research works of Jain et al., the aim of this review is to describe the impact of antivascular endothelial growth factor (VEGF) therapy on "pseudo-normalization" of tumor vasculature and tumor microenvironment, its role in early and metastatic breast cancer, and the clinical evidence supporting this original concept. The phase III clinical trials showed that extended tumors, metastatic or locally advanced, are likely to benefit from bevacizumab therapy in combination with chemotherapy, assuming that a high level of tumor neoangiogenesis as in triple-negative tumors is the best target. In adjuvant setting, the lower level of tumor vasculature could mask a potential benefit of anti-VEGF therapy. All these findings highlight the need to identify biomarkers to help in the selection of patients most likely to respond to anti-VEGF therapy, to better understand the mechanism of angiogenesis and of resistance to anti-VEGF therapy according to molecular subtypes

External validation of Modified Breast Graded Prognostic Assessment for breast cancer patients with brain metastases: A multicentric European experience

BACKGROUND: Several prognostic scores have been developed to estimate survival of breast cancer (BC) patients with brain metastases (BM). Modified Breast Graded Prognostic Assessment (GPA), based on a single-institution cohort of 1552 patients, has been proposed as refinement of Breast-GPA. In addition to age, tumour subtype and KPS, Modified Breast-GPA comprises number of BM. This study was designed to validate Modified Breast-GPA. PATIENTS AND METHODS: Clinical data of 668 BC patients diagnosed with BM at four institutions between 1996 and 2016 were reviewed. Patients were classified by Breast-GPA and Modified Breast-GPA. Overall survival (OS) was calculated from time of BM diagnosis to death or last follow-up. Cox proportional models were used to calculate hazard-ratios and their 95% CI. The performances of Breast-GPA and Modified Breast-GPA were compared using Harrell's concordance index. RESULTS: Median age at BM diagnosis was 56 years (range 24-85). At last follow-up, 632 patients (94.6%) had died. Median OS was 8.1 months (95% CI 6.9-9.4). The number of BM (1-3 vs. >3) was significantly associated with OS in univariate analysis (p 3 BM was identified as a negative prognostic factor in multivariate analysis. Both Breast-GPA and Modified Breast-GPA accurately predicted OS (p < 0.001 for both scores). Performance of Modified Breast-GPA was better: concordance indices were 0.6390 (95% CI, 0.6381 to 0.6399) and 0.6647 (95% CI, 0.6639 to 0.6655) for Breast-GPA and Modified Breast-GPA, respectively (p < 0.001). CONCLUSIONS: This work provides the first external independent validation of Modified Breast-GPA and confirms its better performance as compared to Breast-GPA

Hormone receptors status: a strong determinant of the kinetics of brain metastases occurrence compared with HER2 status in breast cancer

Breast cancer (BC) metastatic behavior varies according to the hormone receptors (HR) and HER2 statuses. Indeed, patients with triple-negative (TN) and HER2+ tumors are at higher risk of brain metastases (BM). The objective of this multinational cohort was to evaluate BM kinetics depending on the BC subtype. We retrospectively analyzed a series of BC patients with BM diagnosed in four European institutions (1996-2016). The delay between BC and BM diagnoses (BM-free survival) according to tumor biology was estimated with the Kaplan-Meier method. A multivariate analysis was performed using the Cox proportional hazards regression model. 649 women were included: 32.0% HER2-/HR+, 24.8% TN, 22.2% HER2+/HR- and 21.0% HER2+/HR+ tumors. Median age at BM diagnosis was 56 (25-85). In univariate analysis, BM-free survival differed depending on tumor biology: HER2-/HR+ 5.3 years (95% CI 4.6-5.9), HER2+/HR+ 4.4 years (95% CI 3.4-5.2), HER2+/HR- 2.6 years (95% CI 2.2-3.1) and TN 2.2 years (95% CI 1.9-2.7) (p\u2009<\u20090.001). It was significantly different between HR+ and HR- tumors (5.0 vs. 2.5 years, p\u2009<\u20090.001), and between HER2+ and HER2- tumors (3.2 vs. 3.8 years, p\u2009=\u20090.039). In multivariate analysis, estrogen-receptors (ER) and progesterone-receptors (PR) negativity, but not HER2 status, were independently associated with BM-free survival (hazard ratio\u2009=\u20091.36 for ER, p\u2009=\u20090.013, 1.31 for PR, p\u2009=\u20090.021, and 1.01 for HER2+ vs. HER2- tumors, p\u2009=\u20090.880). HR- and HER2+ tumors are overrepresented in BC patients with BM, supporting a higher risk of BM in these biological subtypes. HR status, but not HER2 status, impacts the kinetics of BM occurrence