Combination of Abiraterone Acetate, Prostate Bed Radiotherapy, and Luteinizing Hormone-releasing Hormone Agonists in Biochemically Relapsing Patients After Prostatectomy (CARLHA): A Phase 2 Clinical Trial.

BACKGROUND: The relevance of next-generation hormone therapies and circulating tumor cells (CTCs) are not elucidated in biochemical recurrence after prostatectomy. OBJECTIVE: To evaluate the combination of abiraterone acetate plus prednisone (AAP), prostate bed radiotherapy (PBRT), and goserelin in biochemically relapsing men after prostatectomy, and to investigate the utility of CTCs. DESIGN, SETTING, AND PARTICIPANTS: In this single-arm multicenter phase 2 trial, 46 biochemically relapsing men were enrolled between December 2012 and January 2019. The median follow-up was 47 mo. INTERVENTION: All patients received AAP 1000 mg daily (but 750 mg during PBRT), salvage PBRT, and goserelin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 3-yr biochemical recurrence-free survival (bRFS) when prostate-specific antigen (PSA) levels were ≥0.2 ng/ml. The secondary outcomes included alternative bRFS (alt-bRFS) when PSA levels were ≥0.5 ng/ml and safety assessment. CTC count was assessed. RESULTS AND LIMITATIONS: The 3-yr bRFS and alt-bRFS were 81.5% (95% confidence interval or CI [66.4-90.3%]) and 95.6% (95% CI [83.5-98.9%]), respectively. The most common acute radiotherapy-related adverse effect (AE; all grades was pollakiuria (41.3%). The most common late AE (all grades) was urinary incontinence (15.2%). Grade 3-4 acute or late radiotherapy-related AEs were scarce. Most frequent AEs nonrelated to radiotherapy were hot flashes (76%), hypertension (63%), and hepatic cytolysis (50%, of which 20% were of grades 3-4). Of the patients, 11% had a CTC count of ≥5, which was correlated with poorer bRFS (p = 0.042) and alt-bRFS (p = 0.008). The association between CTC count and higher rates of relapse was independent of the baseline PSA level and PSA doubling time (p = 0.42 and p = 0.09, respectively). This study was nonrandomized with a limited number of patients, and few clinical events were reported. CONCLUSIONS: Adding AAP to salvage radiation therapy and goserelin resulted in high bRFS and alt-bRFS. AEs remained manageable, although a close liver surveillance is advised. CTC count appears as a promising biomarker for prognosis and predicting response to treatment. PATIENT SUMMARY: Our study was a phase 2 clinical trial that exhibited the efficacy and tolerance of a novel androgen-receptor targeting agent (abiraterone acetate plus prednisone) in patients with prostate cancer who experienced rising prostate-specific antigen after radical prostatectomy, in combination with prostate bed radiotherapy. The results also indicated the feasibility and potential value of circulating tumor cell detection, which constitutes a possible advance in managing prostate cancers.

Gynecological carcinosarcomas: Overview and future perspectives.

Gynecologic carcinosarcoma (CS) are rare and aggressive tumors composed of high-grade carcinoma and sarcoma. Carcinosarcoma account for less than 5% of uterine and ovarian carcinoma and patients have poor outcome with a 5-year overall survival of less than 30%. In early-stage setting, the treatment mainstay is surgery and adjuvant chemoradiotherapy or adjuvant chemotherapy in uterine (UCS) and ovarian CS (OCS), respectively. In metastatic or advanced stage disease, chemotherapy is the rule with a lower response rate and poorer prognosis compared to other high-grade carcinomas. Although very few treatment options are available, CS are often excluded from the clinical trials precluding therapeutic improvement. However, recent molecular advances are paving the way for new therapeutic strategies. In the current proposal, we extensively review the uterine and ovarian carcinosarcomas including epidemiology, pathology, genomic landscape, as well as current therapies and future perspectives.

Recommandations pour la pratique clinique Nice/Saint-Paul-de-Vence 2022­2023 : prise en charge du cancer de l'endomètre localisé.

Recommendations for clinical practice, Nice/Saint-Paul-de-Vence 2022-2023: Management of localized endometrial cancer Endometrial cancer is the most frequent gynecological cancers in industrialized countries and its incidence increases. The newmolecularclassification allows determination of the risk of recurrence and helps orienting therapeutic management. Surgery remains the cornerstone of treatment. Minimally invasive approach must be preferred for stages I and II. Surgery includes hysterectomy with bilateral adnexectomy, sentinel lymph node biopsy even in high risk diseases and omentectomy for non-endometrioid tumors (except in case of clear cells tumors). Fertility preservation can be proposed in low grade, stage I tumors without myometrial involvement. In stage III/IV disease, lymph node debulking without totallymphadenectomy is indicated. In case of peritoneal carcinomatosis, first-line cytoreductive surgery is recommended if complete resection can be achieved. Adjuvant therapy is not recommended in low risk tumors. In intermediate risk tumors, curietherapy is indicated. In tumors with high-intermediate risk, curietherapy and external radiotherapy are indicated according to prognostic factors (stage II, lymphovascular invasion); adjuvant chemotherapy can be considered on a case-by-case basis. In high risk tumors, chemotherapy and external radiotherapy are recommended using a concomitant or sequential approach.

Evaluation of different algorithms for automatic segmentation of head-and-neck lymph nodes on CT images.

PURPOSE: To investigate the performance of 4 atlas-based (multi-ABAS) and 2 deep learning (DL) solutions for head-and-neck (HN) elective nodes (CTVn) automatic segmentation (AS) on CT images. MATERIAL AND METHODS: Bilateral CTVn levels of 69 HN cancer patients were delineated on contrast-enhanced planning CT. Ten and 49 patients were used for atlas library and for training a mono-centric DL model, respectively. The remaining 20 patients were used for testing. Additionally, three commercial multi-ABAS methods and one commercial multi-centric DL solution were investigated. Quantitative evaluation was assessed using volumetric Dice Similarity Coefficient (DSC) and 95-percentile Hausdorff distance (HD95%). Blind evaluation was performed for 3 solutions by 4 physicians. One recorded the time needed for manual corrections. A dosimetric study was finally conducted using automated planning. RESULTS: Overall DL solutions had better DSC and HD95% results than multi-ABAS methods. No statistically significant difference was found between the 2 DL solutions. However, the contours provided by multi-centric DL solution were preferred by all physicians and were also faster to correct (1.1 min vs 4.17 min, on average). Manual corrections for multi-ABAS contours took on average 6.52 min Overall, decreased contour accuracy was observed from CTVn2 to CTVn3 and to CTVn4. Using the AS contours in treatment planning resulted in underdosage of the elective target volume. CONCLUSION: Among all methods, the multi-centric DL method showed the highest delineation accuracy and was better rated by experts. Manual corrections remain necessary to avoid elective target underdosage. Finally, AS contours help reducing the workload of manual delineation task.

[Treatments for rare ovarian tumors: What's new?] / Avancées thérapeutiques dans la prise en charge des tumeurs rares malignes ovariennes.

Even if each rare ovarian tumor (ROT) has a low incidence, the sum of all these entities represents almost the half of all ovarian neoplasms. Thus, development of dedicated clinical trial emerged as a prerequisite to improve their managements. Owing to the spreading of dedicated institutional networks and (supra)national collaborations, the number of clinical trials has increased the past few years, with different types of trials; while some focused on specific molecular features, others assessed innovative molecules. Furthermore, relevant randomized clinical trials were designed as a mean to position new treatment options. Currently, innovative molecular-driven trials, based on master protocol trials are emerging and may shed light towards the improvement of personalized medicine regarding ROT.

Practical and technical key challenges in head and neck adaptive radiotherapy: The GORTEC point of view.

Anatomical variations occur during head and neck (H&N) radiotherapy (RT) treatment. These variations may result in underdosage to the target volume or overdosage to the organ at risk. Replanning during the treatment course can be triggered to overcome this issue. Due to technological, methodological and clinical evolutions, tools for adaptive RT (ART) are becoming increasingly sophisticated. The aim of this paper is to give an overview of the key steps of an H&N ART workflow and tools from the point of view of a group of French-speaking medical physicists and physicians (from GORTEC). Focuses are made on image registration, segmentation, estimation of the delivered dose of the day, workflow and quality assurance for an implementation of H&N offline and online ART. Practical recommendations are given to assist physicians and medical physicists in a clinical workflow.

Combined intra-cavitary and interstitial image-guided adaptative brachytherapy for cervical stump carcinomas: technical and clinical results of six patients.

Purpose: According to European guidelines for cervix cancers, the management of cervical stump cancers should follow recommendations for patients without previous sub-total hysterectomy, but may require adaptation of radiotherapy modalities, especially brachytherapy (BT). However, data with modern BT technics are very scarce. Material and methods: From May 2013 to March 2020, 6 patients (age range, 71-88 years) with cervical stump squamous cell carcinoma (previously treated by sub-total hysterectomy) have been treated with external beam radiotherapy (intensity-modulated radiation therapy - IMRT, 45 Gy in 25 fractions, 5 patients, or 50.4 Gy in 28 fractions, 1 patient), with concomitant chemotherapy in 2 patients, followed by image-guided adaptive brachytherapy with pulsed-dose-rate in 5 patients or high-dose-rate in 1 patient. We used Utrecht BT applicator (Elekta®), with the implant of interstitial needles within the parametrium (unilaterally in 3 and bilaterally in 3 patients), and/or within the residual cervix (3 patients). Dosimetry was based on GEC-ESTRO recommendations. Results: The median high-risk (HR) and intermediate-risk (IR) clinical target volumes (CTV) were 14.5 cc (range, 12-35 cc) and 40 cc (range, 31-62 cc), respectively. The median dose (D90) delivered to HR and IR CTVs were 81.2 (range, 78.2-89.8) and 68.95 (range, 64.3-72.3) Gy EQD2, respectively. With a 26.5 months median follow-up (range, 10-92 months), we did not observe any local or distant recurrence. No grade 2 or more acute or late toxicities were reported. Conclusions: Cervix brachytherapy with Utrecht applicator using interstitial needle is safe and effective in cervical stump cancer patients.

Eligibility criteria according to EAU/ESTRO/SIOG guidelines for exclusive iodine-125 brachytherapy for intermediate-risk prostate adenocarcinoma patients: impact on relapse-free survival.

PURPOSE: Iodine-125 (125I) brachytherapy (BT) alone for intermediate-risk (IR) prostate adenocarcinoma (PCA) is controversial. The purpose of the study was to investigate potential predictive factors in selected IR-PCA patients treated with BT. MATERIAL AND METHODS: Among 547 patients treated with 125I BT between 2003 and 2013, 149 IR-PCA cases were selected according to NCCN classification after an additional exclusion of patients with prostate specific antigen (PSA) > 15 ng/ml and ISUP group 3. A relapse was defined as a biochemical failure, using ASTRO Phoenix definition, or a relapse identified on imaging. Survival curves were estimated with Kaplan-Meier method. Potential prognostic variables including EAU/ESTRO/SIOG guidelines eligibility criteria were analyzed using univariate and Cox's proportional hazards regression analysis. RESULTS: Of the 149 IR patients, 112 were classified as favorable, with 69 cases eligible to BT according to EAU/ESTRO/SIOG guidelines, and 37 patients were identified as unfavorable as per NCCN. Androgen deprivation therapy (ADT) was applied in 6 patients only. Percentage of positive biopsy cores were ≤ 33% and ≥ 50% for 119 and 11 patients, respectively. With a median follow-up of 8.5 years, 30 patients experienced a relapse. 10-year overall survival, progression-free survival (PFS), and relapse-free survival (RFS) were 84% (95% CI: 75-90%), 66% (95% CI: 56-75%), and 77% (95% CI: 67-84%), respectively. Failure to meet EAU/ESTRO/SIOG criteria was significantly associated with a lower RFS (p = 0.0267, HR = 2.37 [95% CI: 1.10-5.08%]). CONCLUSIONS: Brachytherapy is an effective treatment for selected IR-PCA cases. Patients who were not eligible according to EAU/ESTRO/SIOG guidelines demonstrated a lower RFS.

Salvage brachytherapy with or without external beam radiotherapy for oral or oropharyngeal squamous cell carcinomas in previously irradiated areas: carcinologic and toxicity outcomes of 25 patients.

PURPOSE: The aim of this study was to assess outcomes of salvage brachytherapy for oral and oropharyngeal squamous cell carcinoma in previously irradiated areas. MATERIAL AND METHODS: This was a retrospective study with 25 patients, treated between 1997 and 2016 for primary (21 cases) or recurrent (4 cases) oral or oropharyngeal squamous cell carcinomas in previously irradiated areas. Fifteen patients were treated with salvage brachytherapy (BT) alone, while 10 patients additionally received external beam radiotherapy (EBRT). Median BT dose was 45 Gy (range, 15-64 Gy), and a median total cumulative dose was 57 Gy (range, 40-70 Gy). Patient age, tumor stage, radiotherapy dose, and time between first treatment and recurrence were analyzed as prognostic factors. RESULTS: Median overall survival (OS) was 16 months. Patients with less advanced (T1) tumors survived significantly longer (27 vs. 14.5 months, p = 0.046). Five patients experienced a local recurrence, and only one of them was treated with a total dose greater than 60 Gy. In multivariate analysis, patients with T1 lesions had a significant higher OS rate compared to patients with larger lesions (HR = 6.25, 95% CI: 1.18-33.1%, p = 0.031). Patients who received more than 60 Gy had a non-significant, 80% increased OS than those treated with a lower dose (p = 0.072). There was four grade 3 acute toxicities, and no grade 3 or more late toxicities. CONCLUSIONS: Multimodal treatment, including salvage BT, may offer a curative option for selected patients with an acceptable risk of severe toxicity for the treatment of primary or recurrent tumors in previously irradiated areas.

Evaluation of fully automated a priori MCO treatment planning in VMAT for head-and-neck cancer.

PURPOSE: Automated planning techniques aim to reduce manual planning time and inter-operator variability without compromising the plan quality which is particularly challenging for head-and-neck (HN) cancer radiotherapy. The objective of this study was to evaluate the performance of an a priori-multicriteria plan optimization algorithm on a cohort of HN patients. METHODS: A total of 14 nasopharyngeal carcinoma (upper-HN) and 14 "middle-lower indications" (lower-HN) previously treated in our institution were enrolled in this study. Automatically generated plans (autoVMAT) were compared to manual VMAT or Helical Tomotherapy planning (manVMAT-HT) by assessing differences in dose delivered to targets and organs at risk (OARs), calculating plan quality indexes (PQIs) and performing blinded comparisons by clinicians. Quality control of the plans and measurements of the delivery times were also performed. RESULTS: For the 14 lower-HN patients, with equivalent planning target volume (PTV) dosimetric criteria and dose homogeneity, significant decrease in the mean doses to the oral cavity, esophagus, trachea and larynx were observed for autoVMAT compared to manVMAT-HT. Regarding the 14 upper-HN cases, the PTV coverage was generally significantly superior for autoVMAT which was also confirmed with higher calculated PQIs on PTVs for 13 out of 14 patients, whereas PQIs calculated on OARs were generally equivalent. Number of MUs and total delivery time were significantly higher for autoVMAT compared to manVMAT. All plans were considered clinically acceptable by clinicians. CONCLUSIONS: Overall superiority of autoVMAT compared to manVMAT-HT plans was demonstrated for HN cancer. The obtained plans were operator-independent and required no post-optimization or manual intervention.

Virtual reality distraction during uterovaginal brachytherapy applicators' removal: A pilot comparative study.

PURPOSE: To assess the relevance of virtual reality distraction (VR) during uterovaginal brachytherapy applicators' removal, as an alternative to nitrous oxide (N2O) conscious sedation, to decrease anxiety and pain perception. METHODS AND MATERIALS: We prospectively evaluated 35 patients treated with cervical brachytherapy for locally or locally advanced cervical cancer. Brachytherapy applicators were removed in the patient's room at the end of the treatment. Patients were assigned to N2O conscious sedation (reference group) or VR (experimental group). Anxiety and pain were evaluated with the STAI-E score and with Visual Analogical Scales (VAS). RESULTS: Fourteen patients were treated with VR and 21 with N2O. STAI-E baselines scores were 35 in the VR group and 38 in the reference group and declined to 30 and 28, respectively after procedure. The mean VAS-anxiety was 2.9 before and 2.7 at the peak in the VR group versus 4.1 and 1.6, respectively in the reference group. The mean VAS-pain was 1.0 before, 3.1 at the peak and 0.4 after the procedure in the experimental group, versus 1.8, 2.0, and 0.6 respectively in the N2O group. Four patients in the VR group experienced mild nausea/vomiting or dizziness during the procedure. The preparation duration was higher in the VR group, with a similar duration for the removal itself. CONCLUSIONS: Replacing a medical gas by a virtual reality device was feasible and led to acceptable levels of pain and anxiety. Prospective randomized trials are needed to confirm efficacy and to determine which patients could benefit the most from this approach.

Influence of postoperative radiotherapy target volumes in unilateral head and neck carcinoma of unknown primary: A multicentric study using propensity score.

OBJECTIVE: To compare the impact of two radiation modalities on loco-regional control, survival and tumour emergence, after node dissection for an unilateral head and neck carcinoma of unknown primary (HNCUP). MATERIALS AND METHODS: This is a multicentric retrospective study of 138 patients with unilateral HNCUP treated between 2002 and 2017. The absence of primary tumour was assessed by a systematic panendoscopy and positron emission tomography. Neck dissection was initially performed for all patients. Radiation Therapy was delivered on ipsilateral lymph node areas in 62 cases (44%: UL-RT group) and on bilateral lymph node areas and the entire pharyngeal mucosa in 77 cases (56%: COMP-RT group). Impact of radiation modalities on locoregional control and overall survival was assessed using propensity score matching method in order to balance baseline characteristics between the two groups. RESULTS: The population included 80.4% men, 80.4% smokers, 32.6% P16 positive tumours and 71.0% extracapsular extension. After a median follow-up of 5 years, the locoregional control rate was 80.3% in the UL-RT group and 75.3% in the COMP-RT group (p = 0.688). The corresponding rate of contralateral lymph node recurrence was 0% versus 2.6% (p = 0.503) and the rate of tumour emergence was 11.5% versus 9.1% (p = 0.778). No significant difference was observed between the UL-RT and the COMP-RT groups for overall survival (p = 0.9516), specific survival (p = 0.4837) or tumour emergence (p = 0.9034). CONCLUSION: UL-RT seems to provide similar outcomes as COMP-RT in unilateral HNCUP post-operative management.

Salvage low-dose-rate brachytherapy for local recurrences after prostatectomy and adjuvant or salvage external beam irradiation: Feasibility study on five patients and literature review.

PURPOSE: To assess the feasibility and tumor outcome of re-irradiation with low-dose-rate brachytherapy for macroscopic local recurrences after radical prostatectomy (RP) followed by adjuvant or salvage external beam radiation therapy (EBRT). METHODS AND MATERIALS: Between 2011 and 2018, five men with histologically proven local failure within the prostate (4) or seminal vesicle bed (1) after RP and adjuvant or salvage EBRT (median dose: 67.5 Gy) underwent a salvage brachytherapy (S-BT). The median delay after EBRT was 86 months (range 75-234). Two patients were castration-resistant at the time of S-BT. The gross tumor volume was defined on a multiparametric MRI and transrectal US imaging. Echo-guided transperineal implants of Iodine-125 seeds were optimized with a per-operative dosimetry and delivered with the seed-selectron. RESULTS: A high conformity was achieved with a high dose to the CTV (D95% > 145 Gy in all but one) and very low dose to the rectum, urethra, and bladder. With a median followup of 21 months, all but one patient experienced nodes and/or bone metastases. Local control was achieved in 3/4 of evaluable patients (local failure distant to the treated volume in one). To date, no Grade 2 or more late toxicities were observed. CONCLUSION: For selected patients, focal local recurrence brachytherapy after PR and EBRT appears technically feasible and safe, but the efficacy remains uncertain as the majority of patients quickly relapsed at other sites. Large prospective studies are still required to better select patients who will benefit from this strategy.

Intensity-modulated radiation therapy of anal squamous cell carcinoma: Relationship between delineation quality and regional recurrence.

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 < 0.001), and non-compliant delineation for ≥10 areas (p = 0.005) were predictors of RR. CONCLUSIONS: New predictive factors for recurrences of ASSC treated with IMRT have been found, suggesting that the delineation accuracy is essential for regional control.