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Sarcomas are rare tumours arising from mesenchymal tissue. A multimodal management in an expert centre combining surgery and radiotherapy is the current standard of care for localized soft-tissue sarcomas of the extremities, to enable limb-sparing strategies. The delivery of pre- radiotherapy or postoperative radiotherapy offers similar local control and survival rates but the toxicity profile is quite different: preoperative radiotherapy increases the risk of wound complications and postoperative radiotherapy affects long-term functional outcomes. While postoperative radiotherapy has long been the rule, especially in Europe, technical improvements with image-guided- and intensity-modulated radiotherapy associated with a better management of postoperative wounds has tended to change practices with more frequent preoperative radiotherapy. More recently the possibilities of a hypofractionated regimen or potentiation by nanoparticles to increase the therapeutic index plead in favour of a preoperative delivery of radiotherapy. The aim of this paper is to report pros and cons of pre- and post-operative radiotherapy for soft-tissue sarcomas.

International audience; Background and purpose: To assess the long-term outcomes of patients with squamous cell carcinoma of the anal canal (SCCAC) treated with Intensity-Modulated Radiation Therapy (IMRT).Material and methods: From 2007 to 2015, 193 patients were treated by IMRT for SCCAC. Radiotherapy delivered 45 Gy in 1.8 Gy daily-fractions to the primary tumor and elective nodal areas, immediately followed by a boost of 14.4-20 Gy to the primary tumor and involved nodes. Concurrent chemotherapy with 5-FU-mitomycin (MMC) or cisplatin was added for locally advanced tumors. Survivals were estimated by Kaplan-Meier method. Locoregional (LR) relapses were precisely assessed. Prognostic factors were evaluated by uni- and multivariate analyses. Late toxicity was scored according to the Common Toxicity Criteria for Adverse Events v4.0.Results: Median follow-up was 70 months (range, 1-131). Forty-nine men (25%) and 144 women (75%) were analyzed. Median age was 62 years. Tumor stages were I, II, III and IV in 7%, 24%, 63% and 6% of cases, respectively. Chemotherapy was delivered in 167 patients (87%), mainly MMC (80%). Five-year OS, DFS, CFS and LR control rates were 74%, 68%, 66% and 85%, respectively. Forty-one patients (21%) had a relapse: 22 were LR, mostly in-field (68%). Predictors for LR failure were exclusive radiotherapy, chemotherapy lacking MMC and treatment breaks >3 days. Overall late toxicity ≥grade 2 occurred in 43% of patients, with 24% grade 3 and one case of grade 4 (hematuria).Conclusion: CRT with IMRT assures excellent local control in locally advanced SCCAC with manageable long-term toxicity. Multicentric prospective trials are required to reinforce those results.

Introduction et but de l’etude Le traitement standard des recidives intraprostatiques isolees repose sur l’hormonotherapie. La prise en charge locale est discutee et souvent morbide. La reirradiation est une technique attrayante mais expose a un risque eleve de toxicite. La radiotherapie guidee par l’IRM permet d’obtenir des niveaux de doses eleves au niveau tumoral tout en diminuant les doses aux organes a risque. Le but de cette etude etait d’evaluer la toxicite aigue d’une reirradiation avec le systeme MRIdian® (ViewRay® Technologies, Inc.). Materiel et methodes Vingt patients pris en charge consecutivement a l’Institut du cancer de Montpellier (ICM) pour une recidive isolee intraprostatique prouvee d’un adenocarcinome de prostate entre le 21/10/2019 et le 13/03/2020 ont ete inclus. L’âge moyen des patients etait de 76 ans avec un indice de performance selon l’Organisation mondiale de la sante (OMS) de 0 ou 1. La concentration serique moyenne d’antigene specifique de la prostate avant la reirradiation etait de 6,45 μg/mL et l’International Prostate Symptom Score (IPSS) moyen de 8. L’intervalle moyen entre les deux irradiations etait de 9,9 ans. Quatre patients (soit 20 %) ont recu une hormonotherapie en concomitance. La radiotherapie etait adaptative pour sept patients (35 %). La dose prescrite etait de 30 Gy en cinq fractions pour 12 patients, 27,5 Gy en cinq fractions pour cinq patients, 30 Gy en six fractions pour deux patients et 38,7 Gy en neuf fractions pour un patient. Tous les patients ont ete revus en fin d’irradiation et 19 patients sur 20 a 6 semaines apres l’irradiation. Resultats et analyse statistique Les donnees de toxicite urinaire et rectale sont donnees dans le Tableau 1 . Seuls deux patients (10 %) ont vu une modification de l’IPSS entre le debut et la fin de l’irradiation avec un maximum de variation du score de 3 sur 35. Les profils de toxicite urinaire et digestive etaient semblables avant l’irradiation, en fin d’irradiation, et six semaines apres. Aucun patient n’a souffert de toxicite de grade superieur a 2. Pour tous les patients dont la concentration serique d’antigene specifique de la prostate a ete redosee six semaines apres la fin de l’irradiation (soit huit patients), une diminution a ete constatee avec une concentration moyenne avant l’irradiation de 5,95 μg/mL (extremes : 0,34–14,73 μg/mL) contre 3,63 (extremes : 0,08–13,09 μg/mL) a six semaines. Conclusion La reirradiation guidee par IRM des recidives intraprostatiques ne semble pas engendrer de toxicite aigue importante. Un recul plus important nous permettra d’evaluer la toxicite tardive et le benefice clinique.

The standard treatment for extremity soft tissue sarcomas is based on the association of surgery and radiotherapy. This strategy allows local control improvement with the risk of increased toxicity. There is therefore a growing interest to identify those patients who will benefit from radiotherapy and those who will have the same local control with surgery alone. Furthermore, the development of toxicity has been correlated with the extension of the irradiated volume and the volume receiving high doses. Technological development as intensity modulated radiotherapy and image-guided radiotherapy allows limited irradiated volume improving the protection of the organs at risk leading to clinical benefit improvement. Moreover, efforts are being done to improve local control for the patients at high risk of local relapse. In this paper, we discuss all these mentioned aspects.

Purpose The aim of this study was to evaluate the impact of the time interval (TI) between surgery and adjuvant radiotherapy (RT) in soft tissue sarcoma (STS). Methods and materials Data from 1131 patients treated between 1990 and 2014 were retrospectively reviewed. Inclusion criteria were: limb or superficial trunk wall STS (R0 or R1 resection) and adjuvant RT. The impact of TI on 10-year local relapse-free survival (LRFS) and 10-year overall survival (OS) was analyzed using a Log-rank test and then Cox Model. Results The median TI was 82days (range, 18–346). With a median follow-up of 235months (range, 2–296months), the 10-year LRFS was 57.5% (±2%) and the 10-year OS was 64.2% (±2%). With a TI of 19–39days, 40–79days, 80–119days, and ⩾120days, 10-year LRFSs were 65.3%, 55.5%, 56.9% and 61.2% ( p =0.465), and 10-year OSs were 72.8%, 60.7%, 66.4% and 62.1% ( p =0.347), respectively. After adjustment for the factors significantly ( p ⩽0.05) associated with LRFS and OS, TI did not alter LRFS ( p =0.182) either OS ( p =0.335). Conclusions In this retrospective STS database study, the TI between surgery and start of adjuvant RT did not seem to affect outcomes.

Soft tissue sarcomas are rare tumours. Conservative surgery followed by postoperative radiation therapy represents the gold standard in the majority of cases. Postoperative radiotherapy improves local control without affecting survival. Besides the quality of surgical excision, which remains the major prognostic factor, the importance of the irradiation volume and particularly margins used in external beam radiotherapy were also found to influence local control of the disease. In this study, we propose to conduct a literature review on the present state of our knowledge on this subject in the form of an articulated controversy: in favour or opposed to large margins in external radiotherapy.

e14609 Background: Radiotherapy (RT) can prime an anti-tumor immune response. Unfortunately, this response rarely generates total tumor destruction and abscopal effect. When activated by RT, intratumorally (IT) administered hafnium oxide nanoparticles (NBTXR3) locally increase radiation dose deposit and tumor cell death compared to RT alone. We hypothesized that NBTXR3 + RT could enhance the anti-tumor immune response, both in mice and humans. Methods: Murine CT26 cells were injected in both flanks of immunocompetent mice. When tumor volume reached 50-120mm3, NBTXR3 (or vehicle) was injected IT in right flank tumors only, then irradiated (3x4Gy). Mice were sacrificed when tumors reached 800mm3. Alternatively, tumors were collected 3 days after last RT fraction and immune cell infiltrates analyzed by immunohistochemistry (IHC). Patients (pts) with locally advanced Soft Tissue Sarcoma (STS) (NCT02379845) received NBTXR3 + RT or RT alone. Pre- and post-treatment (biopsy and resection, respectively) tumor tissues from pts were analyzed by IHC and Digital Pathology for immune biomarkers ( > 16 pts per arm). Results: In mice, IHC analyses showed an increase of CD8+ T cells infiltrates in both flanks of mice treated with NBTXR3+RT, while this was not observed in animals treated with RT alone. Furthermore, ICH analysis of post- vs pre-treatment samples from STS pts showed a marked increase of CD8+ and PD1 biomarkers for pts treated with NBTXR3 + RT, while no differences were seen for pts treated with RT alone. Conclusions: NBTXR3 + RT markedly changes the tumor immune profile in a similar manner in mice and pts with STS. We hypothesize that this adaptive immune response could help convert a local tumor microenvironment to a “hot” phenotype and thus improve the efficacy of immune checkpoint inhibitors. These results led us to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative RT (SABR) in combination with anti-PD-1 antibody in pts with locoregionally recurrent or metastatic (to lung or liver) Head and Neck squamous cell carcinoma HNSCC, as well as in metastatic non-small cell lung cancer (NSCLC) and liver metastasis patients [NCT03589339].

Background Motion management is a major challenge in abdominal SBRT. We present our study of SBRT for liver tumors using intrafraction motion review (IMR) allowing simultaneous KV information and MV delivery to synchronize the beam during gated RapidArc treatment. Materials and methods Between May 2012 and March 2015, 41 patients were treated by liver SBRT using gated RapidArc technique in a Varian Novalis Truebeam STx linear accelerator. PTV was created by expanding 5 mm from the ITV. Dose prescription ranged from 40 to 50 Gy in 5–10 fractions. The prescribed dose and fractionation were chosen depending on hepatic function and dosimetric results. Thirty-four patients with a minimal follow-up of six months were analyzed for local control and toxicity. Accuracy for tumor repositioning was evaluated for the first ten patients. Results With a median follow-up of 13 months, the treatment was well tolerated and no patient presented RILD, perforation or gastrointestinal bleeding. Acute toxicity was found in 3 patients with G1 abdominal pain, 2 with G1 nausea, 10 with G1 asthenia and 1 with G2 asthenia. 6 patients presented asymptomatic transitory perturbation of liver enzymes. In-field local control was 90.3% with 7 complete responses, 14 partial responses and 7 stabilisations. 3 patients evolved “in field”. 12 patients had an intrahepatic progression “out of field”. Mean intrafraction deviation of fiducials in the craneo-caudal direction was 0.91 mm (0–6 mm). Conclusion The clinical tolerance and oncological outcomes were favorable when using image-guided liver SBRT with real-time adaptive tumor gating.

Radiation therapy is now widely accepted as an efficacious treatment of localized prostate cancer. Recent advances, namely with the development of conformal radiotherapy, allowed to increase the total dose in the target volumes with greater local control. A forward step achieved with intensity modulated radiotherapy (IMRT) in terms of therapeutic ratio between target volumes and critical organs. IMRT offers an inverse planning dosimetry and a modulation of the fields during irradiation. This article presents recent technical and clinical advances in IMRT focused on prostate cancer.

Combined radiation and hormone therapies have become common clinical practice in recent years for locally-advanced prostate cancers. The use of such concomitant therapy in the treatment of breast disease has been infrequently reported in the literature, but seems justified given the common hormonal dependence of breast cancer and the potential synergistic effect of these two treatment modalities. As adjuvant therapy, two strategies are used in daily clinical practice: upfront aromatase inhibitors or sequentially after a variable delay of tamoxifen. These molecules may, thus, interact with radiotherapy. Retrospectives studies recently published did not show any differences in terms of locoregional recurrences between concurrent or sequential radiohormonotherapy. Lung and skin fibroses due to concurrent treatment are still under debate. Nevertheless, late side effects appeared to be increased by such a treatment, particularly in hypersensitive patients identified at risk by the lymphocyte predictive test. Concurrent radiohormonotherapy should, thus, be delivered cautiously at least for these patients. This article details the potent advantages and risks of concurrent use of adjuvant hormonotherapy and radiotherapy in localized breast cancers.

Background Radiotherapy for retroperitoneal sarcomas remains controversial and a technical challenge considering the threshold of contiguous critical organs tolerance. We performed consecutive RapidArc dosimetric plans in preoperative or postoperative setting. Methods A dosimetric study was carried out from six preoperative (group A) and four postoperative (group B) CT-scans, performed in 7 patients. Prescribed dose was 45 and 50 Gy for groups A and B, respectively. The planning target volume (PTV) was defined as the clinical target volume (CTV) plus 5 mm. The CTV encompassed the gross tumor volume (GTV) plus 10 mm or the tumoral bed. The dosimetric plans were optimized on a RapidArc Eclipse console using the progressive resolution algorithm, PRO version 8.8. Normalization method allowed the coverage of 99% of the PTV by 95% of the dose. Results Mean PTV were 2318.5 ± 2223.9 cc [range 348-6198 cc] and 698.3 ± 216.6 cc [range 463 -933 cc] for groups A and B, respectively. Plans were optimized for single arcs in group B and for single or two arcs in group A. The contralateral kidney volume receiving 5 Gy (V5Gy) was 21.5 ± 23.3% [range 0-55%] and 3.1 ± 2.6% [range 0-7.3%] for groups A and B, respectively. The mean dose received by 1% of the kidney (D1%) was 5.6 ± 2.4 Gy [range 3.6 -7.6 Gy] for group A and 5.4 ± 0.7 Gy [range 4.3-6 Gy] for group B. The volume of small bowel excluding the PTV (small bowel-PTV) that received 40 Gy and 30 Gy (V40Gy and V30Gy) in group A were 7.5 ± 4.4% [range 5.4-14.1%] and 18.5 ± 7.1% [range 10-30.4%], respectively. In group B, small bowel-PTV V40Gy and V30Gy were 4.7 ± 3.3% [range 3.3-8%] and 21.6 ± 7.5% [range 9.4-30%] respectively. In a second step, we treated two patients in the postoperative group. Treatment time delivery with one arc was 74 seconds. No severe acute toxicity was observed. Conclusion RapidArc technology for retroperitoneal sarcomas showed acceptable dosimetric results in preoperative or postoperative clinical situation. From the first treated patients, acute tolerability was good to excellent.

Purpose In this paper, we used the Intrafration Motion Review technique (IMR, Varian medical system), which allows simultaneous kV/MV utilization to analyse the liver motion during gated RapidArc stereotactic treatment. Materials and methods Eight liver cancer patients with implanted fiducial markers were treated using the gated RapidArc technique with a Varian Novalis Truebeam linear accelerator. Four 4D computed tomography (CT) scans were acquired using Real time Position Management (RPM) system to study the reproducibility of liver motion. The cine 4D CT images were separated into 10 phases CT series based on respiratory motion information. A Maximum Intensity Projection (MIP) and an Average Intensity Projection (Ave-IP) CT series were generated. The Internal Target Volume (ITV) was outlined in the MIP CT series. The Planning Target Volume (PTV) was created by adding a 5 mm margin from the ITV. The fiducials were marked in the exhalation and/or in the inhalation phase making possible the intrafraction verification. The treatment planning is realized in the Ave-IP CT series. The patient's alignment is set based on markers using daily cone beam CT (CBCT). During the treatment, kV images were acquired at each exhalation or inhalation phase when the respiratory signal cross the upper and lower gating threshold defined during the respiratory learning process. The positions of the fiducials markers were compared with their expected positions. Results The average (±SD) conformity index CIPTV = (VPTV95% (cc)/ VPTV (cc)) * (VPTV95% (cc)/ Viso95% (cc)) was 0.93 ± 0.02 and homogeneity index HIPTV = (D2% - D98%)/Dmedian was 0.09 ± 0.02. The average MU/Gy was 147 ± 25. The room occupation's time was 53, 30, 20, 24, 24 min respectively for the five first fractions. The average kV images acquired per fraction were 35 with a maximum of 74 images and a minimum of 12 images. The average gating errors of the fiducials in the Superior–Inferior (SI) direction during the intrafraction was 0,91 mm with a maximum of 6 mm. Conclusion For tumor motion, monitoring intra-fraction by IMR ensures with certainty the PTV irradiation estimates with a systematic checking of the position of the target volume (fiducials) when this one come inside the region of treatment.

150 Background: Everolimus is able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving everolimus together with hormonotherapy and radiation therapy may kill more tumor cells. Methods: We conducted a phase I trial to evaluate the impact of everolimus (RAD001), an mTOR inhibitor, in patients treated concurrently with radiotherapy (RT) and ablative androgen treatment in high-risk locally advanced prostate cancer. Inclusion criteria were high-risk locally advanced non metastatic prostate cancer defined as clinical stage ≥ T3 or Gleason score ≥ 8 or PSA ≥ 20. The week before the beginning of RT, RAD001 was administered at different dose levels, twice daily, until the last day of irradiation. A nonsteroid antiandrogen was also given for 1 month at the beginning of RT. Prostate and seminal vesicle were irradiated up to 74Gy in 37 fractions of 2Gy with concomitant long-term LHRH analogue. The starting dose of RAD001 was 5mg/d with subsequent dose levels of 7.5 and 10 mg/d. The primary endpoint was the determination of the maximum tolerated dose (MTD). Dose escalation was implemented according to the continual reassessment method (CRM). Results: Fifteen patients were enrolled and 14 were assessable for toxicity and response. Significant toxicities were demonstrated at the 7.5 and 10 mg/d dose levels. Dose-limiting toxicity (DLT) occurred in two patients at dose level 7.5 mg/d and characterized by a grade 3 diarrhea and a grade 3 hydronephrosis due to dehydration and kidney lithiasis. DLT also occurred in two patients at dose level 10 mg/d (grade 3 diarrhea and grade 3 laryngopharyngeal infection). The MTD was reached at 7.5 mg/day (dose-level II). The recommended dose of RAD001 was 5 mg/d. After a median follow-up of 22 months, 12 patients are alive, 1 is dead (not related to cancer) and 2 patients had relapsed. Conclusions: Concomitant hormone-radiotherapy and everolimus is well-tolerated with mucositis, hypercholesterolemia, and urinary disorders. The recommended phase-II trial dose of everolimus in this combined setting is 5 mg/day. Clinical trial information: NCT00943956.

Background:The impact of postmastectomy radiotherapy (PMRT) on survival has been controversial for decade in intermediate-risk patients.We present here our monocentric long-term carcinologic and quality of life results in the subset of patients classified at intermediate risk and treated with PMRT.Material and Methods: From 1990 to 2000, 1622 patients received adjuvant radiotherapy after mastectomy. Among them, 421 were defined at intermediate risk of local recurrence i.e. (i) one to 3 positive nodes (ii) negative node but younger than 35 years old and/or pT3-T4 and/or grade 3 and/or invasive multifocality and/or lymphovascular invasion. PMRT consisted in a 50 Gy-electron therapy to the chest wall with node irradiation if indicated. Adjuvant chemotherapy and/or hormonotherapy were administered according to our local guideline. Patients were visited every 6 months for at least 10 years. Quality of life questionnaires (EORTC QLQC30/BR23) were filled in at the last medical visit.Results: Median age was 57 years (range, 27-80). One-hundred thirty five patients (32%) and 286 (68%) were premenopausal and menopausal, respectively. Seventy-five percent of the patients presented a ductal invasive carcinoma and 55% one to three positive axillary nodes. The median number of nodes was 13 (range, 3-27). 77% of the patients presented an axillary dissection with more than 10 nodes. 32% of the nodes were associated with capsular effraction. In the node negative subgroups, grade 3, lymphovascular invasion, multifocality, pT3-4, and age < 35 were found in 57%, 19%, 33%, and 4%, respectively. Extensive DCIS was found in 227 patients (54%). Hormonal receptors (ER and/or PR) were positive in 321 patients (76%) and therefore treated with postoperative tamoxifen for 5 years. Adjuvant chemotherapy was delivered in 126 patients and mainly included anthracyclin. HER2 status was not available at that time in our center. Chest wall RT was delivered in all patients to a median total dose of 50 Gy (range, 43-62). Sus-clavicular and internal mammary chain were irradiated in 294 and 346 patients, respectively. With a 10-y median follow-up, 12 (2.8%) and 74 (17.6%) patients presented locoregional and metastatic recurrences, respectively. Locoregional-free survival (LRFS) was 98.3% and 97.1% at 5 and 10 years, respectively. None of the 12 patients presented metastasis before local recurrence. Multifactorial analysis showed a significant impact of LRFS on metastatic-free survival (p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4112.