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Resume Le cancer de prostate est considere comme une tumeur « hormonodependante ». L’inhibition de l’action pro-tumorale de la testosterone a rapidement trouve sa place dans la prise en charge des cancers de prostate metastatiques, puis s’est imposee aussi dans les cancers localises. Pour tirer profit de l’action locale de la radiotherapie et de l’action systemique de l’hormonotherapie, de nombreuses etudes ont montre un benefice clinique majeur, demontrant meme une action synergique a l’association des deux traitements. La radiotherapie associee a de l’hormonotherapie par analogues de la LH-RH represente a present un traitement de reference dans les cancers de prostate localises de risque intermediaire et de haut risque, en tirant profit de l’action directe de l’hormonotherapie contre les cellules tumorales, mais egalement de son action radiosensibilisante. Cet article fait le point sur les benefices cliniques de l’association radiohormonale et les mecanismes de cette action synergique, et developpe les perspectives que vont offrir prochainement les nouvelles molecules d’hormonotherapie.

Metastatic recurrence in an atypical site, such as the perineum, can occur after prostatectomy, cryotherapy, or brachytherapy, but is uncommon. To our knowledge, this is only the third case of perineal recurrence of prostatic cancer along a low dose rate brachytherapy needle track. A 64-year-old man was referred to an urologist with an increased PSA of 6.9 ng/mL in December 2008. There were no urinary symptoms. Prostatic biopsies revealed a Gleason 6 adenocarcinoma (3 + 3), and he was treated with low dose rate brachytherapy in May 2009. Sixty-seven seeds of iodine 125 were loaded under ultrasound control, and the PSA subsequently fell to a nadir of 1.19 ng/mL in November 2015. Eight years (May 2017) after the initial treatment, the PSA rose to 5.2 ng/mL. Pelvic MRI and choline PET revealed a nodule in the region of the left internal obturator muscle. Nodule biopsies confirmed prostatic origin. This perineal recurrence is thus most likely related to seeding of tumour cells along the track of a brachytherapy needle. To our knowledge, this is only the fourth case of perineal recurrence of prostatic cancer along a low-dose rate brachytherapy needle track. Perineal recurrence of prostatic cancer along a LDR brachytherapy needle track can occur. Improved imaging techniques may help to identify this type of recurrence earlier and optimise treatment.

Summary Background Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. Methods We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18–75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0–1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1–14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov ( NCT01804790 ) and is now complete. Findings Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4–61·6), 3-year disease-free survival rates were 76% (95% CI 69–81) in the neoadjuvant chemotherapy group and 69% (62–74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49–0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3–4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3–4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3–4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one ( Interpretation Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. Funding Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

Oligometastatic prostate cancer (PCa) is an intense area of research thanks to the development of novel PET tracers such as 18F-choline or 68Ga-PSMA. Several retrospective studies in patients with hormone-sensitive oligorecurrent PCa (usually up to 5 metastases with a controlled primary tumor) showed PSA response and a low toxicity profile of metastasis-directed therapies (MDT) such as Stereotactic Body Radiation Therapy (SBRT) or salvage lymph node dissection. More recently, randomized phase 2 studies showed that SBRT can delay the introduction of androgen deprivation, decrease biochemical relapses and increase overall survival. Regarding oligoprogressive metastatic castration-resistant PCa, limited data is however available. Based on these studies the European Association of Urology and the American Society of Radiotherapy EAU now recommend using MDT instead of observation. Several studies are undergoing in France and worldwide in order to confirm the exact role of MDT.

Purpose The ongoing phase 2/3 PRODIGE 26/CONCORDE trial compares chemoradiation therapy with and without dose escalation in patients with locally advanced or unresectable esophageal cancer. The results of a benchmark case procedure are reported here to evaluate the protocol compliance of participating centers as part of quality assurance for radiation therapy. Methods and Materials Volume delineation, target coverage, and dose constraints to the organs at risk (OARs) were assessed on treatment plans of a common benchmark case performed by each participating center. The centers were classified in 3 categories: per protocol, minor acceptable deviation (MiD), or major unacceptable deviation (MaD). A plan was rejected if ≥4 MiDs or 1 MaD were found. Results Thirty-5 centers submitted 43 plans. Among them, 14 (32.6%) were per protocol, 19 (44.2%) presented at least 1 MiD, 2 (4.6%) presented at least 1 MaD, and 8 (18.6%) presented both MiD and MaD. Overall, 11 (25.6%) plans were rejected. Only 1 plan was rejected because gross tumor volume was not correctly delineated. The OAR delineation was respected in all cases. Dose constraints to the OARs were respected in the majority of cases except for the heart, where one-third of the plans presented a deviation. As for the target volume, 3 plans (5.8%) had a major underdosage and 1 plan (1.9%) had a major overdosage. Overall, 58% of all treatments were planned with intensity modulated radiation therapy, whereas 42% were planned with 3-dimensional chemoradiation therapy. Significantly more plans in the intensity modulated radiation therapy group were accepted compared with the 3-dimensional chemoradiation therapy group (P = .03). Conclusion The high frequency of protocol deviations underlines the importance of a quality assurance program in clinical trials. Further work should assess the impact of quality assurance for radiation therapy on patient outcomes.

Introduction et but de l’etude Chez les patients atteints de cancer du rectum localement evolue pris en charge par chimioradiotherapie neoadjuvante, la chirurgie pourrait etre omise chez ceux presentant une reponse pathologique complete sans compromettre la survie sans progression et globale. Notre objectif etait de developper un modele radiomique base sur l’imagerie par resonance magnetique (IRM) et la tomodensitometrie avec contraste pour predire la reponse pathologique complete a la chimioradiotherapie neoadjuvante dans les cas de cancer du rectum. Materiel et methodes Tous les patients pris en charge pour un cancer du rectum localement evolue par une chimioradiotherapie neoadjuvante puis une chirurgie dans deux centres de l’Ouest de la France (Institut de cancerologie Bretagne Occidentale et Institut de cancerologie de l’Ouest) ont ete consideres. Les IRM pelviennes avant la chimioradiotherapie neoadjuvante et les scanographies avec injection de produit de contraste etaient obligatoires pour l’inclusion. La tumeur a ete segmentee manuellement sur les sequences axiales ponderees en T2 et en diffusion et sur la scanographie avec injection de produit de contraste. Quatre-vingt-huit parametres radiomiques ont ete extraits de chaque sequence a l’aide du logiciel interne Miras©, avec un total de 822 caracteristiques par patient. La cohorte globale a ete divisee au hasard en deux cohortes independantes (apprentissage : 70 % et test : 30 %). Une selection stricte des caracteristiques basee sur le coefficient de correlation de Spearman et l’aire sous la courbe (AUC) a ete developpee. Trois modeles de prediction de la reponse pathologique complete (clinique ou radiomique ou combine des deux) ont ete developpes sur la cohorte d’entrainement uniquement avec une approche de foret aleatoire et une validation interne Boostrap avec n = 1000 replications. Chaque modele a ensuite ete evalue sur l’ensemble de test, sur la base de l’AUC et du C-statistique calcule. Enfin, une harmonisation a posteriori, utilisant l’approche ComBat a ete appliquee pour tenir compte de l’heterogeneite des modalites d’imagerie. Resultats et analyse statistique Sur les 124 patients inclus, 14 avaient une reponse pathologique complete (11,3 %). Sur la cohorte d’apprentissage, le modele clinique base sur deux parametres (stade T initial et degre de differenciation) a obtenu une AUC de 0,67 et un C-statistique de 0,65. Le modele radiomique base sur un parametre (entropie de l’histogramme derive de la sequence T2) a obtenu une AUC de 1 et un C-statistique de 1. Le modele combine etait strictement identique au modele radiomique et avait donc les memes performances. Sur la cohorte de test, les modeles ont donne un C-statistique de 0,70, 0,73 et 0,73 pour les modeles clinique, radiomique et combine, respectivement. Enfin, apres harmonisation, le modele radiomique a obtenu un C-statistique de 0,77 sur la cohorte de test, tandis que le modele combine a donne un C-statistique de 0,75. Conclusion Le modele radiomique base sur les sequences d’IRM pretherapeutiques ponderees en T2 pourrait aider a predire la reponse pathologique complete apres la chimioradiotherapie neoadjuvante des cancers du rectum localement evolues.

Let (M_n)_n be a discrete martingale in L^p for p in ]1, 2] or p = 3. In this note, we give upper bounds on the superquantiles of M_n and the quantiles and superquantiles of M *_n = max(M 0 , M 1 ,. .. , M n).; Soit (M_n)_n une martingale discrète dans L^p pour p dans ]1,2] ou p=3. Dans cette note nous donnons des majorations des superquantiles de M_net des quantiles et superquantiles de M*_n = max (M_0,M_1, ... , M_n).

Background: Stereotactic body radiotherapy (SBRT) is a recognized treatment for colorectal cancer (CRC) metastases. We postulated that local responses could be improved by SBRT with a concomitant radiosensitizing agent (irinotecan). Methods: RADIOSTEREO-CAMPTO was a prospective multi-center phase 2 trial investigating SBRT (40&ndash, 48 Gy in 4 fractions) for liver and/or lung inoperable CRC oligometastases (&le, 3), combined with two weekly intravenous infusions of 40 mg/m2 Irinotecan. Primary outcome was the objective local response rate as per RECIST. Secondary outcomes were early and late toxicities, EORTC QLQ-C30 quality of life, local control and overall survival. Results: Forty-four patients with 51 lesions (liver = 39, lungs = 12) were included. Median age was 69 years (46&ndash, 84), 37 patients (84%) had received at least two prior chemotherapy treatments. Median follow-up was 48.9 months. One patient with two lung lesions was lost during follow-up. Assuming maximum bias hypothesis, the objective local response rate in ITT was 86.3% (44/51&mdash, 95% CI: [76.8&ndash, 95.7]) or 82.4% (42/51&mdash, 95% CI: [71.9&ndash, 92.8]). The observed local response rate was 85.7% (42/49&mdash, 95% CI: [75.9&ndash, 95.5]). The 1 and 2-year local (distant) progression-free survivals were 84.2% (38.4%) and 67.4% (21.3%), respectively. The 1 and 2-year overall survivals were 97.5% and 75.5%. There were no severe acute or late reactions. The EORTC questionnaire scores did not significantly worsen during or after treatment. Conclusions: SBRT with irinotecan was well tolerated with promising results despite heavily pretreated patients.

Immunotherapy occupies a growing place in urologic oncology, mainly for kidney and bladder cancers. On the basis of encouraging preclinical work, the combination of immunotherapy with radiotherapy aims to increase the tumor response, including in metastatic tumors, which raises many hopes, which this article reviews., L’immunothérapie occupe une place grandissante en cancérologie urologique, principalement pour les cancers du rein et de la vessie. Sur la base de travaux précliniques encourageants, la combinaison de l’immunothérapie avec la radiothérapie ambitionne de majorer la réponse tumorale, y compris des tumeurs métastatiques ce qui suscite de nombreux espoirs dont cet article fait le bilan.

BackgroundIn unresectable metastatic rectal cancers, the surgery of the primitive tumor remains highly debated. Chemoradiotherapy (CRT) of the primitive could allow sufficient local control in order to avoid major and sometimes mutilating surgery. Dose escalation during CRT could increase this local control. The aim of this study was to evaluate the feasibility and tolerance of a CRT with radiation dose escalation delivered in intensity modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB), in metastatic low and middle rectal cancers.MethodsThis multicenter phase I study included six patients treated for unresectable synchronous metastatic low and middle rectal adenocarcinoma in two dose levels. Radiotherapy was delivered using IMRT with SIB. The dose escalation was 52.5 Gy (level 1) and 56.25 Gy (level 2) in the primary tumor, in 25 fractions of 2.1 Gy and 2.25 Gy, respectively. High-risk clinical target volume (CTV) and low-risk CTV received respectively 50 Gy and 45 Gy in 25 fractions in the two levels. Concomitant chemotherapy was oral capecitabine and CRT was performed after four cycles of mFOLOX6 chemotherapy. The dose-limiting toxicity (DLT) was defined by a toxicity requiring the interruption of radiotherapy for more than five consecutive fractions.ResultsAll six patients received the full course of treatment at scheduled doses. No patients had acute toxicity requiring interruption of radiotherapy therefore no DLT has been reported. No patients had acute toxicity ≥ 3. Concerning late toxicity, three patients experienced grade 3. After CRT, four patients had a partial response and one patient had a complete clinical response. Two patients were considered in local progression at 9.4 months and 20.4 months of inclusion.ConclusionsDose escalation at 56.25 Gy in the tumor lesion was possible with good acute tolerance. It needs to be evaluated in a larger study. It could allow sufficient local control in order to avoid mutilating surgery in these metastatic patients.Trial registrationNCT03634202. Registered 16 August 2018 – retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT03634202

Oligometastatic prostate cancer (PCa) is an intense area of research thanks to the development of novel PET tracers such as

International audience; Prostate cancer (PCa) pelvic radiotherapy fields are defined by guidelines that do not consider individual variations in lymphatic drainage. We examined the feasibility of personalized sentinel lymph node (SLN)-based pelvic irradiation in PCa. Among a SLN study of 202 patients, we retrospectively selected 57 patients with a high risk of lymph node involvement. Each single SLN clinical target volume (CTV) was individually segmented and pelvic CTVs were contoured according to Radiation Therapy Oncology Group (RTOG) guidelines. We simulated a radiotherapy plan delivering 46 Gy and calculated the dose received by each SLN. Among a total of 332 abdominal SLNs, 305 pelvic SLNs (beyond the aortic bifurcation) were contoured (mean 5.4/patient). Based on standard guidelines, CTV missed 67 SLNs (22%), mostly at the common iliac level (40 SLNs). The mean distance between iliac vessels and the SLN was 11mm, and despite a 15mm margin around the iliac vessels, 9% of SLNs were not encompassed by the CTV. Moreover, 42 SLNs (63%) did not receive 95% of the prescribed dose. Despite a consensus on contouring guidelines, a significant proportion of SLNs were not included in the pelvic CTV and did not receive the prescribed dose. A tailored approach based on individual SLN detection would avoid underdosing pelvic lymph nodes that potentially contain tumor cells.

Objective: Our objective was to develop a radiomics model based on magnetic resonance imaging (MRI) and contrast-enhanced computed tomography (CE-CT) to predict pathological complete response (pCR) to neoadjuvant treatment in locally advanced rectal cancer (LARC). Material: All patients treated for a LARC with neoadjuvant CRT and subsequent surgery in two separate institutions between 2012 and 2019 were considered. Both pre-CRT pelvic MRI and CE-CT were mandatory for inclusion. The tumor was manually segmented on the T2-weighted and diffusion axial MRI sequences and on CE-CT. In total, 88 radiomic parameters were extracted from each sequence using the Miras© software, with a total of 822 features by patient. The cohort was split into training (Institution 1) and testing (Institution 2) sets. The ComBat and Synthetic Minority Over-sampling Technique (SMOTE) approaches were used to account for inter-institution heterogeneity and imbalanced data, respectively. We selected the most predictive characteristics using Spearman’s rank correlation and the Area Under the ROC Curve (AUC). Five pCR prediction models (clinical, radiomics before and after ComBat, and combined before and after ComBat) were then developed on the training set with a neural network approach and a bootstrap internal validation (n = 1000 replications). A cut-off maximizing the model’s performance was defined on the training set. Each model was then evaluated on the testing set using sensitivity, specificity, balanced accuracy (Bacc) with the predefined cut-off. Results: Out of the 124 included patients, 14 had pCR (11.3%). After ComBat harmonization, the radiomic and the combined models obtained a Bacc of 68.2% and 85.5%, respectively, while the clinical model and the pre-ComBat combined achieved respective Baccs of 60.0% and 75.5%. Conclusions: After correction of inter-site variability and imbalanced data, addition of radiomic features enhances the prediction of pCR after neoadjuvant CRT in LARC.

// Stephane Supiot 1 , Loic Campion 1 , Pascal Pommier 2 , Melanie Dore 1 , Clement Palpacuer 1 , Severine Racadot 2 , Emmanuel Rio 1 , Gerard A. Milano 3 , Celine Mahier - Ait Oukhatar 4 and Christian Carrie 2 1 Departments of Radiation Oncology and Biostatistics, Institut de Cancerologie de l'Ouest, Nantes, France 2 Department of Radiation Oncology, Centre Leon Berard, Lyon, France 3 Laboratoire d’Oncopharmacologie, Centre Antoine-Lacassagne, Nice, France 4 Groupe des Essais Precoces, Unicancer, Paris, France Correspondence to: Stephane Supiot, email: Stephane.supiot@ico.unicancer.fr Keywords: abiraterone; prostate cancer; prostate bed radiotherapy; salvage radiotherapy; rising PSA Received: March 24, 2018 Accepted: April 04, 2018 Published: April 24, 2018 ABSTRACT Background: To establish the maximum tolerated dose of abiraterone acetate plus prednisone (AA) combined with salvage radiotherapy (SRT) and goserelin in a phase 1 study in men with rising PSA following radical prostatectomy. Methods: AA was given during one month before SRT at 1000 mg PO once daily, then 750 mg (Dose Level 1, DL1) or 1000 mg (DL2) during 5 months combined with 6-months goserelin by injection on the first day of irradiation (scheme NEO) or one month before starting SRT (scheme CONCO). Results: In scheme NEO at DL1, 2/9 patients did not achieve castration levels of testosterone. 4/9 patients (44%) presented with grade 3 liver enzyme elevation. In scheme CONCO testosterone dropped to undetectable levels. At DL1, 6 patients were recruited, with no dose limiting toxicities. At DL2, 2/3 patients presented with grade 3 liver enzyme elevation occurring during SRT. Conclusions: When AA was administered without goserilin, only 78% achieved castration levels. AA combined with SRT and goserilin did not increase pelvic toxicity, but lead to an unsuspected high frequency of grade 3 liver toxicity. The phase II recommended dose of AA combined to goserelin and SRT is 750 mg.

Purpose/Objective(s) Increasing dose of chemoradiotherapy in locally advanced esophageal cancer unsuitable for surgery has been a matter of debate in the last 2 decades. Advances in tumor staging and radiation targeting with modern imaging and IMRT should allow further testing exclusive radiation dose escalation in esophageal cancer. Materials/Methods We performed a multicenter, randomized, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 28 centers in France between 07/06/2011 and 11/10/2019. Eligible participants had confirmed stage I-III biopsy proven esophageal carcinoma, ECOG 0-2 and sufficient caloric intake. Patients were randomly assigned (1:1) to receive 50Gy in 25 fractions over 5 weeks (standard arm) or 66Gy in 33 fractions over 6.5 weeks (experimental arm). Elective nodal irradiation (40Gy) was delivered in both groups. Concomitant chemotherapy was FOLFOX-4 for 3 courses followed by 3 adjuvant courses. Random allocation to treatment groups was done by a central computerized randomization procedure by minimization, stratified by center, histology, weight loss, and technique of radiotherapy. The primary endpoint was 2-year locoregional progression-free survival (LRPFS). Results 109 participants were randomly allocated to the 50Gy arm and 108 to the 66Gy group (intention-to-treat population). 177 men (81.6%) and 40 women (18.4%) were included with a mean age of 62.6 years (± 7.8). 191 patients (88.4%) had squamous cell cancer and 25 (11.6%) has adenocarcinoma. Most of the patients had stage III tumors (74% vs 26% for stage I-II). IMRT was delivered in 169 patients (80.1%) and 3D conformal in 42 patients (19.9%). 59 patients (54.1%) have died in the 50Gy group and 65 patients (60.2%) in the 66Gy group with a median follow up 35.3 months (range: 2.0-65.7) and 35.5 months (range: 1.3-60.7), respectively. Median overall survival was 25.2 months (95% CI 17.8-NR) in the 50Gy group and 23.5 months (14.5-32.2) in the 66Gy group (HR 1.14, 95% CI 0.82-1.59; P = 0.44). Median LRPFS was 16.2 months (95% CI 10.9-26.0) in the 50Gy group and 18.4 months (12.2-25.7) in the 66Gy group (HR 1.03, 95% CI 0.75-1.40; P = 0.88). The 2-year LRPFS rates were 42.7% (95% CI 33.2%-51.8%) and 43.8% (95% CI 34.1%-54.1%). No significant differences were recorded in the rates of late adverse events between the treatment groups (P = 0.14). The rates of grade 3/4 toxicities in the 50Gy group were 29.5%/0% and 24.0%/5.3% in the 66Gy group. 5 toxic deaths (4.6%) occurred in the 50Gy group and 7 (6.7%) in the 66Gy group. One and 2 toxic deaths out of the 5 in the 50Gy were related to radiotherapy or chemotherapy, respectively. Two and 3 out of the 7 toxic deaths in the 66Gy were related to radiotherapy or chemotherapy, respectively. Conclusion Dose escalated chemoradiotherapy delivering 66Gy is not more toxic than 50Gy but did not improve locoregional progression-free survival. Chemoradiotherapy delivering 50Gy should be definitely admitted as a standard dose.

Introduction et but de l’etude La reponse abscopale est un phenomene rare, communement defini par l’observation d’une reponse objective mais a distance du site tumoral irradie. Notre objectif etait d’examiner l’incidence de la reponse abscopale chez les patients atteints de melanome metastatique necessitant une radiotherapie palliative. Materiel et methodes Les dossiers des patients atteints de melanome metastatique pris en charge entre janvier 1998 et fevrier 2020 dans quatre centres de radiotherapie ont ete analyses. Les patients presentant une resistance primaire ou secondaire aux inhibiteurs de points de controle immunitaire ou sans traitement systemique, necessitant une radiotherapie palliative ont ete inclus. Les criteres d’exclusion etaient la radiotherapie cerebrale et les traitements anti-BRAF anterieurs ou concomitants. La reponse abscopale etait definie comme une reponse objective selon RECIST et/ou iRECIST pour au moins une metastase non irradiee a distance (≥ 1 cm) de la lesion irradiee. Le critere d’evaluation principal etait le taux de reponse abscopale. Les criteres secondaires etaient la duree de survie globale, de survie sans progression, le taux de controle local et la toxicite evaluee par les CTCAE v5. Resultats et analyse statistique Au cours de la periode consideree, 118 patients ont ete pris en charge pour un melanome metastatique necessitant une radiotherapie palliative extracrânienne. Quinze patients ont presente une reponse abscopale (soit 12,7 %). Les lesions irradiees etaient regressives ou stables chez 87,3 % des patients apres la radiotherapie. Avec un suivi median de 7,7 mois (intervalle : 0,2 a 242,2 mois), les durees medianes de survie sans progression et de survie globale apres la radiotherapie etaient respectivement de 3,6 mois (intervalle de confiance a 95 % [IC 95 %] : 2,7–4,4 mois) et de 8,5 mois (IC 95 % : 4,3–12,6 mois) et etaient significativement plus longues chez les patients ayant presente une reponse abscopale par rapport a ceux qui n’en avaient pas presente : 28 contre 6,6 mois (p Conclusion La reponse abscopale apres la radiotherapie d’un melanome metastatique est un phenomene peu courant mais semble influencer le pronostic. Elle pourrait etre favorisee par plusieurs irradiations concomitantes ou par une inflammation induite par une infection.

In this paper we give new deviation inequalities for martingales with increments bounded from above. Our results are based on an improvement of the results of Bennett (1968) for random variables bounded from above.

319 Background: NBTXR3, a first-in-class radioenhancer composed of functionalized hafnium oxide nanoparticles, is administered by one time intratumoral injection (ITI) and activated by radiotherapy (RT), such as stereotactic body RT (SBRT). NBTXR3 increases RT energy deposit inside tumor cells and subsequently increases tumor cell death compared to RT alone, while sparing healthy tissues. SBRT is well-tolerated in hepatocellular carcinoma (HCC) or liver metastases (mets) and a valuable alternative for patients not eligible for surgery or radiofrequency ablation. However, energy dose deposit to tumor cells is limited due to potential toxicity to surrounding healthy tissues. Patients with unresectable liver cancers including patients with liver or renal dysfunction might benefit from NBTXR3. A Phase 1 clinical trial was conducted to evaluate the safety and Recommended Phase 2 Dose (RP2D) of NBTXR3 activated by SBRT [NCT02721056] in these patients, here we report the results. Methods: A 3+3 dose escalation scheme tested 5 NBTXR3 levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 ITI was followed by SBRT (45 Gy / 3 fractions / 5-7 days or 50 Gy / 5 fractions / up to 15 days) in patients with HCC or liver mets. Primary endpoints included RP2D determination and early DLT incidence. Secondary endpoints include safety profile, liver disease scores evolution, and early efficacy by response rate (mRECIST for HCC/RECIST 1.1 for liver mets). Results: 23 patients were treated: 6 patients at 10% (2 SBRT doses tested due to organ constraints), 4 patients each at 15% and 22% (due to fiducial displacement and ITI shift), 3 patients at 33% and 6 patients at 42%. No early DLT was observed at any dose level. 1 SAE (grade 3 late onset bile duct stenosis) related to NBTXR3 and RT occurred at 22%. There were 11 AEs related to NBTXR3 and/or ITI, of which grade 3 AEs were: 2 abdominal pain (ITI related; 15%) and 1 late onset bile duct stenosis (22%), lesion close to the bile duct. No NBTXR3 or ITI related grade 4-5 AEs were observed. RT related AEs were as expected with SBRT. No clinically meaningful changes in Child-Pugh score or APRI were observed post-treatment. CT-scan showed NBTXR3 present within the tumor without leakage to surrounding healthy tissues. Best observed responses (MRI) in injected target lesions from HCC patients (n = 15) were 5 CRs (33.3%), 5 PRs(33.3%), 1 SD (6.7%), 2 NE (13.3%), 2 patients did not have post baseline MRI and for liver mets (n = 8) were 5 PRs (62.5%), 2 SD (25.0%) and 1 NE (12.5%). Conclusions: No early DLTs were observed and NBTXR3 demonstrated a good safety and tolerability profile. The RP2D was determined to be 42% of tumor volume. Initial efficacy is promising and highlights the potential for NBTXR3 to address an unmet medical need in patients with unresectable primary or metastatic liver cancers. Clinical trial information: NCT02721056.

Fanconi anemia is a rare genetic disorder characterized by congenital malformations, progressive bone marrow failure and increased incidence of acute myeloid leukemia and squamous cell carcinomas. Treatment of these malignancies is challenging because the defective DNA repair characteristic of the disorder amplifies the toxicity of chemotherapy and radiation. We report the case of a 25-year-old woman with Fanconi anemia who presented with an extensive perineal recurrence of a small squamous cell carcinoma of the vagina, who was treated with neoadjuvant radiotherapy. This caused grade III radiodermatitis and grade II anemia, recovery from which delayed pelvic exenteration for two months. Despite this radical surgical intervention, the patient relapsed and died six months post-operatively. This case illustrates the challenge of planning treatment for locally advanced carcinomas associated with Fanconi anemia, in which the prospect of local control must be tempered by the apprehension of toxicity.

There are very few data on the expansion from the clinical target volume (CTV) to the planning target volume (PTV) in the anal cancer treatment. This article aims to collect the different elements needed for the construction of a PTV from scientific data based on a literature analysis. We reviewed the articles published in the medical literature from the last 20years. They concerned setup errors and internal organ mobility of the different volumes of patients treated by conformational radiotherapy and intensity-modulated radiotherapy (anal canal, meso-rectum, common, intern and extern, inguinal and pre-sacral lymph nodes). CTV to PTV margins admitted in the guidelines and atlas of consensus groups (SFRO, RTOG, AGITG) are from 0.7 to 1cm in all directions, based on expert's opinions but not on scientific data. There are no specific studies on the canal anal mobility. Most of the data are from other pelvis cancers (gynecologic, rectum and prostate). Setup errors can be reduced by daily imaging. Patient repositioning and immobilization modalities are mostly local habits rather than scientific consensus. A three-dimensional 1cm margin is generally admitted. Margins reduction must be careful and has to be assessed.

Recent technological developments led to develop the concept of focused liver radiation therapy. We must distinguish primary and secondary tumors as the indications are restricted and must be discussed as an alternative to surgical or medical treatments. For hepatocellular carcinoma 5 to 10cm (or more), a conformational radiation with or without intensity modulation is performed. Stereotactic body radiotherapy (SBRT) is being evaluated and is increasingly proposed as an alternative to radiofrequency ablative treatment for primary or secondary tumors (typically less than 5cm). Tumor (and liver) movements induced by respiratory motions must be taken into account. Strict dosimetric criteria must be met with particular attention to the dose-volume histograms to liver and the hollow organs, including cases of SBRT.

Resume Objectif Evaluer la valeur pronostique de differents facteurs pretherapeutiques definis avec la tomographie par emission de positons au ( 18 F)-fluorodesoxyglucose (TEP-FDG) pour le cancer de l’œsophage localise. Patients et methodes Nous avons realise une etude retrospective monocentrique a partir des dossiers de 83 patients atteints de cancers de l’œsophage traites a visee curative. La chimioradiotherapie a ete soit exclusive, soit suivie de chirurgie. Les criteres constitutifs, carcinologiques et derives de la TEP-FDG ( maximum standardized uptake value [SUV max ], volume tumoral metabolique de la lesion primitive [ metabolically active tumour volume ] defini soit avec le logiciel « fuzzy locally adaptive bayesian » [MATV FLAB ], soit avec un seuillage [MATV seuil ], et le total lesion glycolysis [TLG FLAB et TLG seuil ]) ont ete correles avec la survie. Resultats La duree mediane de suivi etait de 21,8 mois (0,16–104). La duree mediane de survie etait de 22 mois (intervalle de confiance a 95 % [IC95 %] : 15,2–28,9). Il y a eu 67 deces, 49 lies au cancer et 18 a une autre cause. Aucun des facteurs testes n’avait un impact significatif sur la survie globale. Pour la survie specifique, en analyse unifactorielle, le MATV FLAB ( p = 0,025), le TLG FLAB ( p = 0,04) et le TLG seuil ( p = 0,04) avaient un impact significatif. En analyse multifactorielle, seul le MATV FLAB avait un impact significatif ( p = 0,049) : MATV FLAB inferieur a 18 cm 3 : 31,2 mois (IC95 % : 21,7–non atteint) et MATV FLAB superieur a 18 cm 3 : 20 mois (IC95 % : 11,1–228,9). Conclusion Sur la TEP-FDG initiale, le volume metabolique defini avec l’algorithme de segmentation automatique FLAB etait un facteur pronostique interessant qui merite d’etre evalue sur une cohorte plus importante de patients.

The Oligopelvis 2 studies is based on the assumption that salvage pelvic radiotherapy may prolong the interval between the first and the second intermittent hormone therapy sequence in pelvic lymph node oligometastatic prostate cancer. This phase 3 study will compare intermittent hormone therapy (standard arm) alone or combined with salvage pelvic radiotherapy (experimental arm).

International audience; Due to the heterogeneity of tumour mass segmentation methods and lack of consensus, our study evaluated the prognostic value of pretherapeutic positron emission tomography with fluorodeoxyglucose (FDG-PET) metabolic parameters using different segmentation methods in patients with localized anal squamous cell carcinoma (SCC). Eighty-one patients with FDG-PET before radiochemotherapy were retrospectively analyzed. Semiquantitative data were measured with three fixed thresholds (35%, 41% and 50% of Maximum Standardized Uptake Value (SUVmax)) and four segmentation methods based on iterative approaches (Black, Adaptive, Nestle and Fitting). Metabolic volumes of primary anal tumour (P-MTV) and total tumour load (T-MTV: P-MTV+ lymph node MTV) were calculated. The primary endpoint was event-free survival (EFS). Seven multivariate models were created to compare FDG-PET tumour volumes prognostic impact. For all segmentation thresholds, PET metabolic volume parameters were independent prognostic factor and T-MTV variable was consistently better associated with EFS than P-MTV. Patient's sex was an independent variable and significantly correlated with EFS. With fixed threshold segmentation methods, 35% of SUVmax threshold seemed better correlated with EFS and the best cutoff for discrimination between a low and high risk of event occurrence was 40 cm 3. Determination of T-MTV by FDG-PET using fixed threshold segmentation is useful for predicting EFS for primary anal SCC. If these data are confirmed in larger studies, FDG-PET could contribute to individualized patient therapies.

537 Background: Treatment of unresectable liver cancer or liver metastases (mets) by stereotactic body radiotherapy is well tolerated but limited by the need to preserve liver function. Increasing energy deposition in the tumor while at the same time maintaining the dose in healthy tissue remains a major challenge in radiation oncology that could be achieved by NBTXR3 (hafnium oxide nanoparticles) when activated by radiotherapy (RT). NBTXR3 augments energy dose deposit within tumor cells, increasing tumor cell death compared to RT alone, while sparing healthy tissues. Patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets) may benefit from the mode of action of NBTXR3. A phase I/II clinical trial has been conducted to evaluate NBTXR3 activated by SBRT in these pts [NCT02721056]. Methods: The Phase I used a 3+3 dose escalation scheme with 5 NBTXR3 dose levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 was administered by intratumoral injection (ITI) followed by SBRT (45 Gy / 3 fractions / 5 to 7 days or 50 Gy / 5 fractions / 15 days). Primary endpoints were identification of the recommended Phase II Dose and early DLTs. Secondary endpoints included safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and early efficacy by response rate (mRECIST/RECIST 1.1). Results: The dose escalation levels of 10, 15, 22 and 33% are completed (n = 17): 6 pts at 10% (2 SBRT doses tested due to organ constraints), 4 pts each at 15% and 22% (due to fiducial displacement and ITI shift) and 3 pts at 33%. No early DLT was observed and only one SAE (bile duct stenosis) related to NBTXR3 and RT occurred. CPS and APRI did not show clinically meaningful changes post-treatment and CT-scan showed no leakage of NBTXR3 into surrounding tissues. Best response for HCC (n = 8) were 5CR, 3PR and for mets (n = 6) the results were: 3 PR, 3SD. Conclusions: ITI of NBTXR3 is feasible, demonstrated a very good safety and tolerability profile up to the 33% dose level. Recruitment needs to be finalized at the 42% dose level. Based on early efficacy results NBTXR3 has the potential to address an unmet medical need in pts with unresectable primary or metastatic liver cancer. Clinical trial information: NCT02721056.

BACKGROUND AND PURPOSE Intensity-modulated radiation therapy (IMRT) is currently indicated to treat anal squamous cell carcinoma (ASCC). Conformal dose delivery and steep dose gradients may cause marginal misses. We analyzed patterns of locoregional recurrences (LRR) and delineation quality to determine IMRT-specific predictive factors. MATERIAL AND METHODS Lymph node area delineation was classified as "compliant" or "non-compliant" according to experts' workgroup recommendations. The recurrence volume (Vrecur) was delineated on initial planning-CT by recurrence imaging registration. The Vrecur was determined to be "in-field" (IF), "marginal" (ML), or "out-of-field" (OF) in regard to the 95% isodose coverage. RESULTS Out of 165 patients, 30 had LRR. Among the 27 local recurrences (LR), 20 (74%) were IF, 4 (15%) ML, and 2 (7%) OF. Fourteen patients had regional recurrence (RR), amounted to 33 separate recurrence sites (RS). RS were mostly localized in inguinal (n = 12;36,4%), external iliac (n = 7;21.1%), presacral (n = 4;12.1%) and common iliac (n = 3;9.1%) nodes. Eighteen (54.5%) RS were IF, 6 (18.2%) ML, and 9 (27.3%) OF. Performance status ≥2 (p = 0.007) and active smoking (p = 0.025) were predictors of LR. Immunodepression (p = 0.012), external iliac involvement (p

Purpose Limited pelvic nodal relapse of prostatic cancer is a paramount challenge for locoregional salvage treatments. Salvage whole pelvis radiation therapy as considered in the BLINDED trial is an attractive option, but there are concerns about its toxicity. This article describes early toxicity with the technique. Methods and Materials BLINDED was a prospective multicenter phase 2 trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron emission tomography–positive pelvic lymph nodes, combined with 6-month androgen blockade. The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathologic pelvic lymph nodes. Early toxicity was defined as toxicity until 1 year after radiation therapy. Patients quality of life was assessed using the European Organisation for Research and Treatment of Cancer questionnaires (QLQ-C30 and QLQ-PR25). Results Seventy-four patients were recruited in 15 French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included 67 patients. Half had received prior prostatic irradiation. Median age was 67.7 ± 6.5 years. Grade 2 acute urinary toxicity was observed in 9 of 67 patients (13.4%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Three patients (4.4%) had grade 3 urinary toxicity. Grade 2 acute digestive toxicity was observed in 10 of 67 patients (14.9%), and grade 2 1-year toxicity occurred in 4 of 67 patients (6%). Patients with prior prostate bed irradiation did not exhibit increased urinary or digestive toxicity. The European Organisation for Research and Treatment of Cancer questionnaire scores at 1 year did not worsen significantly. Conclusions The acute and 1-year toxicity of the BLINDED protocol was satisfactory, even in patients with a history of prostatic irradiation.

In this note we give upper bounds on the quantiles of the one-sided maximum of a nonnegative submartingale in the class $L\log L$ or the maximum of a submartingale in $L^p$. Our upper bounds involve the entropy in the case of nonnegative martingales in the class $L\log L$ and the $L^p$-norm in the case of submartingales in $L^p$. Starting from our results on entropy, we also improve the so-called bounded differences inequality. All the results are based on optimal bounds for the conditional value at risk of real-valued random variables.

Introduction et but de l’etude Pour les cancers du rectum metastatiques non resecables, une chimioradiotherapie de la tumeur primitive avec escalade de dose pourrait permettre un taux de controle local suffisant afin d’eviter une chirurgie lourde et parfois mutilante. L’objectif de cette etude etait d’evaluer la faisabilite et la tolerance d’une escalade de dose d’irradiation au cours de la chimioradiotherapie du cancer primitif chez les patients atteints de cancer du rectum metastatique non resecable. Materiel et methodes Cette etude de phase I multicentrique a inclus six patients atteints d’un adenocarcinome du bas et du moyen rectum metastatique synchrone non resecable traite par irradiation avec deux paliers de dose. L’irradiation etait delivree en radiotherapie conformationnelle avec modulation d’intensite, avec boost integre simultane. L’escalade de dose consistait a delivrer respectivement 52,5 Gy (palier 1) et 56,25 Gy (palier 2) dans la tumeur primitive, en 25 fractions de 2,1 Gy et 2,25 Gy. Les volumes cible anatomocliniques a haut risque et a bas risque recevaient respectivement 50 Gy et 45 Gy en 25 fractions dans les deux paliers. La chimioradiotherapie, a base de capecitabine, etait realisee apres quatre cycles de chimiotherapie par l’association de 5-fluoro-uracile, d’acide folinique et d’oxaliplatine (protocole mFolox6). La toxicite limitant la dose etait definie par une toxicite necessitant l’arret de la radiotherapie plus de cinq seances consecutives. Resultats et analyse statistique Les six patients ont recu l’ensemble du traitement aux doses planifiees. Aucun patient n’a souffert de toxicite necessitant l’arret de la radiotherapie ou de toxicite aigue de grade 3 ou plus. Aucune toxicite limitant la dose n’a donc ete rapportee. Une toxicite tardive de grade 3 est survenue chez trois patients. Apres la chimioradiotherapie, quatre patients etaient en situation de reponse partielle et un de reponse clinique complete. Conclusion L’escalade de dose a 56,25 Gy dans la lesion tumorale a ete possible avec une bonne tolerance aigue. Elle necessite d’etre evaluee dans une etude a plus grand effectif. Elle pourrait permettre un taux de controle local suffisant dans l’objectif d’eviter une chirurgie mutilante chez ces patients atteints de cancer metastatique.

Node-positive prostate cancer patients represent a small proportion of all prostate cancers for whom limited prospective information is available. Most retrospective or cohort data strongly suggest however that radiotherapy combined with androgen-depriving therapies is the preferable treatment in this setting. Only randomized clinical trials would be able to better define both radiotherapy (dose? volume? fractionation?) and androgen-depriving therapies (duration? role of novel androgen-depriving therapy?) modalities.

In this paper we give efficient constants in the Fuk-Nagaev inequalities. Next we derive new upper bounds on the weak norms of martingales from our Fuk-Nagaev type inequality.

In this chapter, we are interested in extensions of the classical maximal inequalities of Kolmogorov and Doob to weakly dependent sequences. Here we adapt previously known tools to the context of weakly dependent sequences. In Sect. 3.2, we give a maximal inequality for second-order moments of the maximum of partial sums.