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In unresectable stage III non-small cell lung cancer (NSCLC), the standard of care for most fit patients is concurrent chemotherapy with normofractionated radiotherapy (NFRT), followed by durvalumab consolidation. Nevertheless, almost half of patients will present locoregional or metastatic intrathoracic relapse. Improving locoregional control thus remains an important objective. For this purpose, stereotactic body radiotherapy (SBRT) may be a relevant treatment modality. We performed a systematic review of the literature that evaluate the efficacy and safety of SBRT in this situation, either instead of or in addition to NFRT. Among 1788 unique reports, 18 met the inclusion criteria. They included 447 patients and were mainly prospective (n = 10, including 5 phase 2 trials). In none, maintenance durvalumab was administered. Most reported SBRT boost after NFRT (n = 8), or definitive tumor and nodal SBRT (n = 7). Median OS varied from 10 to 52 months, due to the heterogeneity of the included populations and according to treatment regimen. The rate of severe side effects was low, with

Definitive external beam radiotherapy (EBRT) is an unusual treatment of unresectable soft-tissue sarcomas (STS). Recent technical innovations and physical advantages of particle therapies may improve results of this therapeutic option. The role of this review was to report the clinical results of photon- and particle-based EBRT in unresectable STS.We performed a systematic review of the literature on Pubmed database to identify studies investigating the efficacy and safety of EBRT. The primary endpoint was local control (LC) and secondary endpoints were progression-free survival (PFS), overall survival (OS) and adverse events in a subset of patients with gross disease STS.We identified 29 studies involving 1409 patients (pts) evaluating photon (Definitive EBRT with dose 64-66 Gy seems to be a safe and efficient treatment for unresectable STS. Future clinical trials should assess the potential of biomarkers of response, thus identifying patients that could benefit from local treatment.

IntroductionThe objective of this study was to evaluate the efficacy and safety of adjuvant radiotherapy (aRT) in patients with soft-tissue sarcoma (STS) re-excised after unplanned tumor resection (UPR).Materials and MethodsFrom 2000 to 2015, we retrospectively evaluated patients with STS of limb or trunk who underwent post-UPR re-excision in our expert center and received or not aRT.ResultsMedian follow-up was 121 months (IQR 94-165). Among the 145 patients, 37 were not treated with aRT (no-RT) and 108 received aRT with a median radiation dose of 50 Gy (IQR 50-60). At 10 years, patients in the aRT and no-RT groups showed a cumulative incidence of local failure (10y-LF) of 14.7% and 37.7%, and a local recurrence-free survival (10y-LRFS) of 61.3% and 45.8%, respectively. Multivariate analysis identified aRT and age ≥70 years as independent predictors of both LF and LRFS, while grade 3 and deep-seated tumor were independent predictors of LRFS. In overall population, 10-year distant metastasis-free survival (10y-DMFS) and overall survival (10y-OS) were 63.7% and 69.4%. In multivariate analyses, age ≥70 years, grade 3, and deep-seated lesion were associated with shorter DMFS and OS. Acute severe adverse events were not significantly increased in aRT group (14.8% vs. 18.1%, P = .85) but dramatically increased if radiation dose exceeded 50 Gy (risk ratio 2.96 compared to ≤50 Gy, P = .04).ConclusionIn STS patients re-excised after UPR, 50 Gy aRT was safe and associated with reduced LF and longer LRFS. It seems to be beneficial even in absence of residual disease or in absence of initial adverse prognostic factors.

The use of definitive radiotherapy (dRT) in unresectable soft-tissue sarcomas (STS) is still controversial and recent data are scarce. We report clinical results of this therapeutic option. We retrospectively included STS patients treated between 2009 and 2020, with dRT for unresectable or with a measurable residual disease after R2 surgery. Response rate, local failure (LF), progression-free survival (PFS) and overall survival (OS) were evaluated. 116 patients with localized/locally advanced STS were treated from 2009 to 2020, with a median age of 71 years (range 18-92). Most tumors were deep-seated (96.6%), grade 2-3 (85.1%), located in the trunk or extremities (74.2%). Helical tomotherapy, volumetric modulated arc therapy, or stereotactic radiotherapy was performed in 39.7%, 19% and 8.6% of patients, respectively. The median equivalent dose in 2 Gy fractions (EQD2) was 60 Gy (IQR 52-65). At first follow-up, 66 (58.9%) and 25 (22%) patients had stable disease and partial response. After a median follow-up of 54.8 months (IQR 40.3-95.4), 3-year LF, PFS and OS were 43.2%, 16.6% and 34%, respectively. Median OS was 21.4 months (95%CI 14-26). The multivariate analysis identified grade 3 and AJCC T3-T4 stage to be associated with both shorter PFS and OS (all p

Background and Purpose: Limb sparing surgery and radiotherapy is the main treatment of patients harboring soft tissue sarcoma of the extremity. There is limited data regarding the prognostic impact of histologic response after pre-operative radiotherapy. Patients and Methods: Between 2010 and 2018, 123 patients were treated with a pre-operative radiotherapy for soft tissue sarcoma at Leon Berard Centre (Lyon, France) and were retrospectively reviewed. All patients received a dose of 50 Gy in 25 fractions. The histologic response has been analysed by considering the following factors: necrosis ? 90%, percentage of viable tumor cells ? 10% and fibrosis ? 10%. Overall survival (OS), local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS) and event-free survival (EFS) were evaluated. Results: Median follow up was 33.2 months (range 2.3-128.1 months). Local recurrence occurred in 9 patients (7.5%) and 40 patients (33%) presented a distant recurrence. The 2 and 5-year OS was 84% and 63%. Histologic response factors (necrosis ? 90%, viable tumor cells ? 10% and fibrosis ? 10%) were not predictive in DRFS and EFS. In multivariate analysis, grade was the only significant prognostic factor for EFS P=0.0087. Among the 14 patients with ? 10% viable cells after irradiation 13 presented a metastatic evolution within 6 months. Conclusion: This study showed that current histological response evaluation based on necrosis, fibrosis and viable cells could not predict clinical outcomes after radiotherapy for extremity soft tissue sarcoma. A significant proportion of patients with a good response after pre-operative radiotherapy present a metastatic recurrence.

Background Evaluation of response to neoadjuvant radiotherapy (NART) does not consider soft tissue sarcoma (STS) heterogeneity. We aimed to investigate radiological and pathological response of 4 major histotypes. Methods Extremity or trunk STS patients who received 50 Gy NART between 2009 and 2020 were retrospectively included. Relative variation in tumor size (RVTS) and pathological response were reported in the overall population and in undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), myxoid liposarcoma (MLS) and synovial sarcoma (SS) patients to identify response modalities of each histotype. Results Among the 121 included patients, 49, 19, 13 and 11 presented UPS, MFS, MLS and SS. Median RVTS were 0% (IQR -18-+18), +8% (IQR 0-+24), −12% (IQR -20–3) and −11% (IQR -15–9), respectively (p = 0.001). Median viable cells were 10%, 60%, 20% and 70% (p = 0.007). In overall population, pathological complete response and median necrosis were 27.7% and 10% without significant correlation to histotype (p = 0.18 and 0.06). Nineteen (38.8%) UPS specimens presented cysts that were emptied during the sampling process and distorted the microscopic response evaluation. Infiltrative growth pattern was observed in 28% and 38.9% UPS and MFS patients. Five (38.5%) MLS presented mature adipocytes without proven prognostic value. Cysts were observed in 36% of SS specimens. In the absence of initial tumor limits, the great viable cellularity of SS may be overestimated by their nodular aspect. Conclusion After NART, we highlighted disparate response of UPS, frequent progression of MFS, and confirmed MLS and SS radiosensitivity. Response must be interpreted with caution and consider the histotype-specific patterns.

Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with either proton or photon irradiation. NMRI mice bearing MIA PaCa-2 xenografts were treated with olaparib and/or gemcitabine and irradiated with 10 Gy photon or proton. First, a significant growth inhibition was obtained after 10 Gy proton irradiation compared to 10 Gy photon irradiation (p = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine (p = 0.05), olaparib (p = 0.034) or proton therapy (p &lt, 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy (p = 0.024). Simultaneously, whole RNA sequencing profiling showed differentially expressed genes implicated in categories such as DNA repair, type I interferon signaling and cell cycle. Moreover, a large amount of lncRNA was dysregulated after proton therapy, gemcitabine and olaparib. This is the first study showing that addition of olaparib to gemcitabine-based chemoradiotherapy improved significantly local control in vivo, especially after proton therapy. RNA sequencing profiling analysis presented dynamic alteration of transcriptome after chemoradiation and identified a classifier of gemcitabine response.

Background Current research that combines radiation with targeted therapy may dramatically improve prognosis of pancreatic ductal adenocarcinoma (PDAC). We investigated preclinical outcomes of DNA repair inhibitor targeted therapy associated with radiotherapy. Methods We searched Pubmed database to identify publications assessing DNA damage targeted therapies in preclinical models of PDACin vitro and in vivo. Standard enhancement ratio, median survival and growth delay were extracted. Results We identified fourteen publications using DNA repair targeted therapies in preclinical models of PDAC. Ten publications comprising twenty-eight experiments evaluated radiosensitization with different DNA repair inhibitors in vitro and displayed cell killing by a factor of 1.35 ± 0.047. Moreover, 86 % (24/28) of in vitro experiments showed radiosensitization with DNA damage response inhibitor. However, only 60 % (9/15) of the in vivo experiments presented radiosensitization effects. Conclusion DNA repair targeted therapies use promising radiosensitizers for PDAC and could successfully be translated into clinical trials.

Retroperitoneal sarcomas (RPSs) are rare diseases, and the 5-year overall survival rate remains low. Management of RPSs is challenging, and the quality of treatment strategy is a crucial prognostic factor. Treatment decisions and the treatment department to which the patients is referred must be centralized. Overall survival rate is positively correlated with the number of patients treated in the centers. En bloc surgery is the standard of care for effective treatment and potential for cure, whereas perioperative chemotherapy or radiotherapy has not yet been validated. Pre- or postoperative radiotherapy was considered controversial, but the STRASS trial publication illustrated that preoperative radiation could be useful in some conditions. Retroperitoneal liposarcoma might become a future target of prospective trials. Furthermore, some retrospective studies have shown that preoperative radiotherapy increases the rate of R0-R1 resections. This article reviews the role of external beam radiotherapy in the management of RPS and highlights the optimal volumes, doses, and radiotherapy techniques for the treatment of RPS. As accurately predicting prognosis in patients with RPS is challenging, we also emphasize the utility of nomograms in the field of radiotherapy. However, these nomograms do not include radiotherapy as a predictive factor. Although some authors could conclude that use of radiotherapy should be avoided based on the results of the STRASS trial, some data argue that radiotherapy still has utility in select cases.

BACKGROUND Brain metastasis (BM) are frequently surrounded by brain edema with a variable extension. This pathological increase in the water mass from the interstitial or intracellular space is the source of neurological symptoms but some studies also showed a prognosis impact of this edema. Nevertheless, the current edema evaluation methods are poorly reproducible and were not extensively evaluated. From a series of patients with brain metastasis, we analyzed factors influencing perilesional edema extension in function of three edema descriptors which were qualitatively evaluated: the absolute cumulative intracranial edema volume (CIEV, in mL), the edema on tumor volume ratio (ER), and the Edema Theoretical Thickness (ETT, in mm), new factor designed to be more independent from geometrical considerations. MATERIAL AND METHODS Clinical, biological and imaging factors were retrospectively recorded from patients referred for upfront stereotactic radiotherapy of one to three BMs. CIEV, ER and ETT were calculated for each patient. Non-colinear factors were selected using the Farrar-Glauber test. Impact of these factors on edema was tested with an univariate then a multivariate linear regression for each edema descriptor. Each resulting regression model was qualitatively evaluated using the F-test, R square value and residuals calculation. RESULTS Between January 2012 to December 2017, 182 patients were included. Upon 20 potentially prognostic factors recorded, 10 were kept, including clinical, biological and imaging factors. In the multivariate analysis, the CIEV was influenced by the cumulative intracranial tumor volume (CITV) (coefficient of 1.95, p CONCLUSION Being significantly influenced by the cumulative brain tumor volume and the extracerebral disease control, the ETT might be a factor to include in future BM works because its strong relationships with confounding factors and its ability to provide robust intra and inter subjects comparisons.

International audience; Background: Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality. Furthermore the replication-dependent activity of PARP inhibitor helps to maintain the differential effect between tumoral and healthy tissues. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, also participate to their radio-sensitization effect. Materials and Methods: Here, after highlighting mechanisms of PARP inhibitors radiosensitization we methodically searched PubMed, Google Scholar, Cochrane Databases and meeting proceedings for human pre-clinical and clinical studies that evaluated PARP inhibitor radiosensitizing effect. Enhancement ratio, when available, was systematically reported. Results: Sixty four studies finally met our selection criteria and were included in the analysis. Only three pre-clinical studies didn't find any radiosensitizing effect. Median enhancement ratio vary from 1,3 for prostate tumors to 1,5 for lung cancers. Nine phase I or II trials assessed safety data. Conclusion: PARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.

Hematologic malignancies may require, at one point during their treatment, allogeneic bone marrow transplantation. Total body irradiation combined with chemotherapy or radiomimetic used in allogeneic bone marrow transplantation is known to be very toxic. Total body irradiation (TBI) induces immunosuppression to prevent the rejection of donor marrow. TBI is also used to eradicate malignant cells and is in sanctuary organs that are not reached by chemotherapy drugs. TBI has evolved since its introduction in the late fifties, but acute and late toxicities remain. Helical tomotherapy, which is widely used for some solid tumors, is a path for the improvement of outcomes and toxicities in TBI because of its sparing capacities. In this article, we first review the practical aspects of TBI with patient positioning, radiobiological considerations and total dose and fractionation prescriptions. Second, we review the use of intensity modulated radiation therapy in bone marrow transplantation with a focus on helical tomotherapy TBI, helical tomotherapy total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) and their dosimetric and clinical outcomes. Finally, we review the perspective of dose escalation and the extension to older patients and patients with comorbidity who do not benefit from a standard bone marrow transplantation conditioning regimen.

Background: Surgery for anal canal cancer (ACC) and anal margin cancer (AMC) is the only curative option after failure of chemoradiotherapy (CRT). This study aimed to determine the efficacy of surgery for ACC or AMC after failed CRT. Methods: This was a single-centre, retrospective study of 161 patients initially treated with CRT. We compared the survival rates of patients successfully treated by CRT with those of patients whose CRT failed (both surgically salvaged and treated palliatively). Results: Thirty-one patients underwent surgery with curative intent, 20 received palliative treatment after failure of CRT, and 110 had effective CRT. The 5-year overall survival (OS) rate was significantly higher among patients with successful CRT than among patients who underwent surgery with curative intent (86 vs. 66%, p < 0.001). On the other hand, the 5-year OS of patients treated with curative surgery was significantly better than that of patients who underwent palliative treatment (66 vs. 13.5%, p < 0.001). The postoperative morbidity and mortality rates were 32 and 3%, respectively. Considering patients with failed CRT, curative surgery was the only factor prognostic of favourable OS in the multivariate analysis. Conclusion: Curative surgery after failure of CRT for ACC or AMC remains an effective treatment to improve survival in two-thirds of cases, resulting in high but manageable morbidity.

TomoDirect (TD) can only operate in free-breathing. The purpose of this study is to compare TD with breath-hold 3D conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) techniques for left breast treatments, and to determine if the lack of respiratory gating is a handicap for cardiac sparing.15 patients treated for left breast had two computed tomography simulation, in free breathing (FB) and in deep-inspiration breath-hold (DIBH). Four treatments were planned: TD-FB, 3DCRT-FB, 3DCRT-DIBH and IMRT-DIBH. Dose to PTV, heart, lungs, right breast and patient were compared.A slightly lower cardiac mean dose is found for 3DCRT-DIBH than for TD-FB group (1.99Gy Vs 2.89Gy, p=0.0462), while no statistical difference is found for heart V20. TD-FB plans show the best PTV dose homogeneity (0.053, p0.001) and the lowest left lung mean dose (5.16Gy, p0.001). No major differences are found for the other organs.TomoDirect and breath-hold 3DCRT are complementary techniques for left breast treatments: for a minority of patients, respiratory gating is mandatory to lower cardiac dose; for the remaining majority of patients, TomoDirect achieves better PTV homogeneity and reduced left lung dose, with cardiac dose equivalent to 3DCRT-DIBH.

Aim: The purpose of this study was to investigate prospectively the predictive value of positron emission tomography with proton magnetic resonance spectroscopic imaging (MRSI) and 18F-fluorodeoxyglucose (FDG-PET) performed the 1st month after surgery and before radio- chemotherapy in 43 patients with glioblastoma (GBM). Patients and methods: Metabolite concentrations were quantified using LCModel. Overall survival (OS) and progression free survival (PFS) were calculated including all 43 patients using Kaplan-Meier curves, and the Cox proportional hazard model was used to calculate the predictor of survival. Results: At the end of the follow-up period, all patients died within a period of 1–70.2 months. In 32 patients (74.4%), increased FDG-uptake was seen around the resection cavity and abnormal metabolic profiles on MRSI, indicative of residual disease, were present in all patients. There was no significant difference between the median OS in patients with hypometabolic FDG lesions compared to patients with hypermetabolic FDG lesions. On univariate analysis, normalized choline-containing compounds/creatine (nCho/Cr) and normalized lactate/creatine (nLac/Cr) were significantly predictive of OS and nLac/Cr and normalized N-Acetylaspartylglutamate and NAcetylaspartate/ creatine (NAA/Cr) were significantly predictive of PFS. Conclusions: nCho/Cr and nLac/Cr ratio after surgery and before radio-chemotherapy were independent metabolic predictive factors of OS times in newly diagnosed patients with GBM.

Meningiomas represent the most common tumours of the central nervous system in adults. Risk factors include ionizing radiation, female hormones exposure, head trauma, cell phone use, breast cancer and family history of meningioma. Despite complete surgical resection, natural history of meningiomas often includes local recurrence but very few metastatic meningiomas have been reported. Here, we report the case of a metastatic meningioma. A 43-year-old woman was firstly treated for a symptomatic parietal meningioma WHO grade II by surgical resection followed by an irradiation of the surgical bed. After surgical resection and irradiation, the patient recovered incompletely. Two months after the end of the radiation treatment, the patient presented at the emergency unit for sciatic pain revealing bone metastases that has been histologically confirmed. Moreover, imaging led to the diagnosis of liver and lungs metastasis. Despite lack of guidelines for metastatic meningioma, few treatments have been used and published for recurrent and multiple meningioma management. In case studies, some partial responses have been seen with mifepristone and improved progression-free survival rates have been obtained with hydroxyurea and sunitinib. Metastasis in meningioma is very uncommon and no specific management has been described. Hydroxyurea, sunitinib and mifepristone could be options if no clinical trial data is available.

Objectif La radiotherapie stereotaxique hypofractionnee est une option therapeutique reconnue dans le traitement de la maladie oligometastatique. Nous avons evalue l’efficacite et la tolerance d’une irradiation stereotaxique de metastases ganglionnaires dans une population de patients oligometastatiques, selon deux schemas therapeutiques. Patients et methodes Entre novembre 2010 et septembre 2013, vingt patients oligometastatiques atteints de trente adenopathies (cervicales, thoraciques, abdominales et pelviennes) non operables ont recu une radiotherapie stereotaxique hypofractionnee. L’âge median etait de 60 ans (43–86 ans). La dose de prescription dans le volume cible previsionnel (PTV) etait de 33 Gy (huit lesions) ou 23,1 Gy (22 lesions) en trois fractions a l’isocentre avec une isodose d’enveloppe respectivement de 70 % et 90 %. La mediane des volumes des volumes cibles previsionnels etait de 15,9 cm3 [2–157 cm3]. Le suivi median etait de 16 mois. La reevaluation a ete faite par tomographie par emission de positons (TEP)-scanographie au fluorodesoxyglucose (TEP-FDG) chez 17 patients. Resultats Quinze patients n’etaient atteints que d’une metastase ganglionnaire unique captant le (18F)-FDG avant le traitement. Apres radiotherapie stereotaxique, les taux de controle local a 6 et 12 mois etaient respectivement de 90 % (intervalle de confiance a 95 % : 80,9–99,8 %) et 73 % (56–90 %). La duree mediane de survie sans progression etait de 20 mois. Un volume cible previsionnel de plus de 35 cm3 etait un facteur de pronostic defavorable de controle local (p = 0,038) et de survie sans progression (p = 0,025). En ce qui concerne les deux schemas therapeutiques, il n’y avait pas de difference significative en termes de controle local et de survie sans progression. Deux cas de toxicite de grade 2 digestive ont ete observes. Conclusions Cette etude montre que la radiotherapie stereotaxique hypofractionnee peut etre consideree pour des metastases ganglionnaires comme efficace et bien toleree. Dans la limite d’un suivi median limite, ces resultats sont concordants avec les donnees de la litterature. Cependant, une etude prospective de validation est necessaire.