Portal-hypertension features are associated with ascites occurrence and survival in patients with hepatocellular carcinoma treated by external radiotherapy.

BACKGROUND AND AIMS: We studied the impact of Portal hypertension (PHT) on ascites occurrence and on radiotherapy outcome in cirrhotic patients with hepatocellular carcinoma (HCC). METHOD: All cirrhotic patients that received radiotherapy for HCC between 2012 and 2022 were included. Portal hypertension-Score was built using univariate analysis with the presence of esophageal varices (EV), platelet count, history of acute variceal bleeding (AVB) and spleen size. Time-to-events data were estimated using Kaplan-Meier method with log-rank and Cox-models. RESULTS: 60 patients were included (female 27%, age 67 years-old, Child-Pugh A 82%, alcoholic/non-alcoholic steatohepatitis/hepatitis C virus 55/40/32%). 38% and 15% presented history of ascites and AVB respectively, 25% had large EV, 53.5% presented PHT score ≥ 5. 92% were BCLC-0/A, median tumor size was 30 mm. At 6 months, ascites incidence was 19% and precluded access to further HCC treatment for all patients with HCC recurrence. All PHT parameters included in the score and PHT score ≥ 5 (hazard ratio (HR) = 14.07, p = 0.01) were associated with ascites occurrence. Transplantation free survival and recurrence free survival at 1 year were 56% and 47% respectively. Albi grade 3 (HR = 3.01; p = 0.04) was independently associated with Transplantation free survival. CONCLUSION: Radiotherapy should be cautiously performed in patients with PHT score ≥ 5 because of ascites occurrence risk precluding access to further HCC treatments.

Long-Term Outcomes in Head and Neck Paragangliomas Managed with Intensity-Modulated Radiotherapy.

OBJECTIVES: Head & Neck Paragangliomas have been historically relying on surgery mostly, with worsened quality of life and major sequelae. Conventional external radiation therapy seems to offer an equivalent control rate with a low toxicity profile. The aim of this study was to assess the safety and efficiency of intensity-modulated radiation therapy in Head & Neck paragangliomas. METHODS: This is a retrospective monocentric study conducted in a referral center, including all patients treated with IMRT, whether as an exclusive or post-operative treatment for a tympanic and jugular, carotid, or vagal paraganglioma. Data collection was performed through the manuscript and computerized medical files, including consultation, operative, imaging, pathological analyses, delineation, and treatment planning reports. Success was defined as the complete or partial regression or stabilization without progression, or relapse in accordance with the RECIST criteria. Acute toxicities and long-term sequelae were assessed. RESULTS: Our cohort included 39 patients included between 2011 and 2021: 18 patients treated for a TJ PG (45.9%), 11 patients for a carotid PG (28.4%), and 9 for a vagal PG (23.1%). Twenty-nine patients had IMRT as an exclusive treatment (74.4%), whereas 10 patients had a post-operative complementary treatment (25.6%). Median follow-up in our cohort was 2318 days (average = 2200 days, 237-5690, sd = 1281.9). Among 39 patients, 37 were successfully controlled with IMRT (94.8%), and the toxicity profile was low without any major toxicity. CONCLUSION: IMRT seems an ideal treatment, whether exclusive or post-operative for Head & Neck paragangliomas. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:607-614, 2023.

Phase 1 Study of the Combination of Escalated Total Marrow Irradiation Using Helical Tomotherapy and Fixed High-Dose Melphalan (140 mg/m²) Followed by Autologous Stem Cell Transplantation at First Relapse in Multiple Myeloma.

PURPOSE: A second intensification is an option at first relapse in multiple myeloma (MM) after more than 36 months of initial remission. Many conditioning regimens have been tested, with or without total body irradiation (TBI). Recently, it was found that TBI could be replaced by total marrow irradiation (TMI) using helical tomotherapy, with promising results. METHODS AND MATERIALS: This study was a prospective multicenter phase 1 trial that aimed to determine the maximum tolerated dose (MTD) of TMI administered in association with melphalan 140 mg/m², followed by autologous stem cell transplantation as consolidation at first relapse in MM. Four dose levels were explored: 8 Gy, 10 Gy, 12 Gy, and 14 Gy. The dose-limiting toxicity (DLT) was defined as grade 4 neutropenia >15 days, grade 4 thrombopenia >28 days, and all other grade 4 nonhematologic toxic effects except nausea, vomiting, alopecia, mucositis, and reaction to autologous stem cell infusion. RESULTS: Thirteen patients were included; only 1 DLT at the third escalated dose level (12 Gy) was observed, whereas 1 patient was treated at 14 Gy with no adverse events. The MTD was not reached. The rate of acute toxicity was low: 38% of grade 3-4 diarrhea, mucositis, or unexplained fever. Regarding the lungs, the mean dose administered was systematically less than 8 Gy. After a median follow-up of 55 months, 70% of participants were alive. Of these 13 patients, 38.5% were in very good partial response and 30.8% were in complete response. Three of them were progression-free. Six patients were long survivors, still alive after 55 months of follow-up. CONCLUSIONS: Total marrow irradiation provides good results with a good tolerance profile at first relapse in MM and makes it possible to increase the dose delivered to the planning target volume while sparing organs at risk. This technique could be discussed for all regimens before auto- or allo-stem cell rescue when TBI is required.

[Preoperative versus postoperative radiotherapy in soft tissue sarcomas: State of the art and perspectives]. / Radiothérapie préopératoire versus postopératoire dans les sarcomes des tissus mous : état des lieux et perspectives.

Radiation therapy is a standard treatment for limbs soft tissue sarcomas. Preoperative versus postoperative radiotherapy has been a controversial topic for years. With preoperative irradiation, the treatment volume is more limited, the delivered dose possibly lower and the tumor volume easier to delimit. Only one randomized trial compared these two irradiation sequences. The results in terms of local control and survival were equivalent but the risk of acute postoperative complications was higher if irradiation was administered before surgery. However, in the latest update of this trial, patients who received adjuvant irradiation exhibited more severe late toxicity than those treated preoperatively. In addition, with modern irradiation techniques such as conformal with image-guided intensity modulated radiotherapy and flap coverage techniques, the incidence of complications after preoperative irradiation were lower than historically published rates. Locally advanced proximal sarcomas and the failure of other neoadjuvant treatments are nowadays classical indications for preoperative irradiation. As with other neoadjuvant treatments, induction radiotherapy must be personalized according to the histological subtype, the tumor site and the benefit/risk ratio, which is best appreciated by a multidisciplinary surgical and oncological team in a specialized center in the management of soft-tissue sarcomas.

Pulse-dose-rate interstitial brachytherapy in anal squamous cell carcinoma: clinical outcomes and patients' health quality perception.

PURPOSE: To examine clinical outcomes and quality of life of patients with anal squamous cell carcinoma treated with interstitial pulsed-dose-rate brachytherapy (PDR-BT) with a boost to residual tumor after external radiotherapy. MATERIAL AND METHODS: Medical records of patients receiving a brachytherapy boost after radiotherapy for anal squamous cell carcinoma in our Institute between 2008 and 2019 were retrospectively reviewed. After receiving pelvic irradiation ± concurrent chemotherapy, patients received PDR-BT boost to residual tumor, in order to deliver a minimal total dose of 60 Gy. Patients' outcomes were analyzed, with primary focus on local control, sphincter preservation, morbidity, and quality of life. RESULTS: A total of 42 patients were identified, included 24, 13, and 5 patients with I, II, and III tumor stages, respectively. Median brachytherapy (BT) dose was 20 Gy (range, 10-30 Gy). Median dose per pulse was 42 cGy (range, 37.5-50 cGy). With median follow-up of 60.4 months (range, 5.4-127.4 months), estimated local control and colostomy-free survival rates at 5 years were both 88.7% (95% CI: 67.4-96.4%). The largest axis of residual lesion after external beam radiation therapy (EBRT) and poor tumor shrinkage were associated with more frequent relapses (p = 0.02 and p = 0.007, respectively). Out of 40 patients with more than 6 months follow-up, only one experienced severe delayed toxicity (fecal incontinence). Health quality perception was very good or good in 20 of 22 (91%) patients, according to their replies of quality-of-life surveys. A total dose ≥ 63 Gy was associated with higher number of anorectal grade 1+ toxicities (n = 1.5 vs. n = 0.61, p = 0.02). CONCLUSIONS: In this cohort of 42 patients with mainly I and II tumor stages, PDR-BT boost allowed for local control in 88.7% of patients, with only one grade 3 anorectal toxicity.

Prospective evaluation of intensity-modulated radiotherapy toxicity in extremity soft tissue sarcomas patients: A role for irradiated healthy soft tissue volume?

AIM: To prospectively assess toxicities of curative-intent intensity-modulated conformal radiotherapy (IMRT) in patients with extremity soft tissue sarcomas (ESTS). METHODS: Data from 59 consecutive patients with ESTS between 2014 and 2019 were both retrospectively and prospectively analysed. Toxicity data were collected both by confidential mailed survey (39% completed) and medical charts, and graded according to CTCAE v5.0. Normal tissues dosimetric data (healthy soft tissue segment, joint and bone) were included. The healthy soft tissue segment was created by adding 5 cm on either side of the PTV on CT axial slices, the PTV and bone (and articulation if present) were then removed from the generated volume. RESULTS: IMRT was delivered post-operatively for nearly half of patients (n = 24, 41%), preoperatively for 18 (31%) and exclusively for 17 (28%; salvage: 13% or immediately inoperable: 15%). The median total dose delivered to the planned target volume (PTV) was 50.4 Gy (36-68 Gy) and 13 patients (22%) received a boost. With a median follow-up of 27 months (6-94 months), a total of 87 late effects were identified in 44/59 (75%) patients: 89% G1-2, and 11% G3-4. The main G1-2 toxicities were: functional limitation (36%), oedema (29%), gait disorders (20%), neurological disorders (20%) and chronic pain (32%). G3-4 toxicities were pain (n = 2), arterial stricture (n = 1) and a chronic wound requiring skin graft (n = 2). No bone fracture was observed. Quality of life was rated as good or very good in 70% patients who completed the survey. Larger (>3500 cm3) healthy soft tissue segment volume was associated with decreased late toxicities (p = 0.02). No other predictive factor of toxicity was identified. The 2-year rates of local control, overall survival and recurrence-free survival were 90%, 90% and 64%, respectively. CONCLUSION: Healthy soft tissue segment volume influenced toxicity. Long-term prospective monitoring in a homogeneous population remains critical to assess the impact of IMRT induced chronic toxicity in ESTS patients. This should ideally lead to a validated normal tissue dose constraint (e.g.: healthy soft tissue segment volume > 3500 cm3) to recommend for practitioners to help reduce the late toxicity risk.

Hypnosedation for endocavitary uterovaginal applications: A pilot study.

PURPOSE: Implantations for uterovaginal brachytherapy are usually performed under general or spinal anesthesia, which are not without risk. As it is a rather short procedure and since postoperative pain is minimal, hypnosedation was proposed to selected patients requiring endocavitary applications as part of their routine treatment. METHODS AND MATERIALS: Consecutive patients requiring intracavitary uterovaginal brachytherapy from January to October 2019 were included if they accepted the procedure. A premedication was systematically administered. Hypnosedation was based on an Ericksonian technique. The procedure was immediately interrupted if the patient requested it, in cases of extreme anxiety or pain. Procedure was in that case rescheduled with a "classical" anesthesia technique. RESULTS: A total of 20 patients were included. Four patients had to be converted toward a general anesthesia: one because of a fibroma on the probe's way and three young patients with a very anteverted/retroverted uterus that was painful at every mobilization. Mean and maximum pain scores during implant were 2.9/10 and 5.1/10, respectively. The most painful maneuver was cervical dilation for 45% of the patients, followed by mold insertion in 40% of cases. About 85% of the patients declared that hypnosis helped them relax; 90% of the patients would recommend the technique. No procedure-related complication occurred. CONCLUSION: With a 70% success rate (correct implant with mean pain and anxiety scores < 5), one can conclude that uterovaginal brachytherapy implantation under hypnosedation is feasible and received a high satisfaction rate from the patients. This technique may reduce overall treatment time in a context of difficult access to the OR and to anesthesiologists, while reducing anesthetic drugs resort and postoperative nausea.

Polymerase proofreading domain mutations: New opportunities for immunotherapy in hypermutated colorectal cancer beyond MMR deficiency.

Immune checkpoint inhibition is a new therapeutic strategy that has shown promising efficacy in many cancer types. Significant activity associated with mismatch repair (MMR) deficiency has been observed in hypermutated, microsatellite unstable (MSI) metastatic colorectal cancer (CRC). Beyond deficient-MMR tumors, somatic or germline DNA polymerase D1 (POLD1) or DNA polymerase E (POLE) alterations cause a hypermutated phenotype in CRC. This recently identified and rare subgroup of proficient-MMR tumors may also benefit from immunotherapy. In this review, we provide a comprehensive overview of recent data on CRC tumors harboring POLD1 or POLE mutations, with a focus on their molecular, histological, and clinical features. We also examine the evidence supporting the development of immune checkpoint inhibitors in this specific subgroup of CRC patients.