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Background Craniopharyngioma (CP) in adults is a rare benign tumor associated with many morbidities, with limited contemporary studies to define treatment, and follow-up guidelines. Methods A single-center retrospective study was conducted on patients aged ≥ 18 years from 2006–2018 with CP and who were treated with proton therapy (PT). Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS), local recurrence-free survival (LRFS), and toxicity were characterized using Kaplan–Meier and Cox regression analyses. Results Ninety-one patients met the criteria, with a median age of 37 years (range 18–82 years). PT was conducted after tumor resection in 88 patients (97%), in 64 patients (70.3%) as an adjuvant strategy and in 27 (29.7%) after recurrent disease. Three patients received exclusive PT. A median MRI follow-up of 39 months revealed 35.2% complete response, 49.5% partial response, and 9.9% stable disease. Five patients developed local recurrence (LR). The pattern of failure study showed that these five LR were within the GTV volume. The 5-year LRFS was 92.0% [CI 95% 84.90–99.60]. All the patients were alive at the end of the follow-up. Patients requiring treatment adaptation during PT tend to have a higher risk of LR (P = .084). Endocrinopathy was the most frequent grade ≥ 2 late toxicity. Among patients who were symptom-free before the start of treatment, none developed hearing toxicity but four (9.8%) developed visual disorders and 10 (11.3%) symptomatic memory impairment. Patients with large tumors had a higher risk of developing symptomatic memory impairment (P = .029). Conclusion Adults with CP treated with PT have favorable survival outcomes, with acceptable late toxicity. Prospective quality-of-life and neurocognitive studies are needed to define late adverse effects better.

OBJECTIVE Chordomas represent one of the most challenging subsets of skull base and craniovertebral junction (CVJ) tumors to treat. Despite extensive resection followed by proton-beam radiation therapy, the recurrence rate remains high, highlighting the importance of developing efficient treatment strategies. In this study, the authors present their experience in treating clival and CVJ chordomas over a 29-year period. METHODS The authors conducted a retrospective study of clival and CVJ chordomas that were surgically treated at their institution from 1991 to 2020. This study focuses on three aspects of the management of these tumors: the factors influencing the extent of resection (EOR), the predictors of survival, and the outcomes of the endoscopic endonasal approaches (EEAs) compared with open approaches (OAs). RESULTS A total of 265 surgical procedures were performed in 210 patients, including 123 OAs (46.4%) and 142 EEAs (53.6%). Tumors that had an intradural extension (p = 0.03), brainstem contact (p = 0.005), cavernous sinus extension (p = 0.004), major artery encasement (p = 0.01), petrous apex extension (p = 0.003), or high volume (p = 0.0003) were significantly associated with a lower EOR. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 52.1% and 75.1%, respectively. Gross-total resection and Ki-67 labeling index < 6% were considered to be independent prognostic factors of longer PFS (p = 0.0005 and p = 0.003, respectively) and OS (p = 0.02 and p = 0.03, respectively). Postoperative radiation therapy correlated independently with a longer PFS (p = 0.006). Previous surgical treatment was associated with a lower EOR (p = 0.01) and a higher rate of CSF leakage after EEAs (p = 0.02) but did not have significantly lower PFS and OS compared with primary surgery. Previously radiation therapy correlated with a worse outcome, with lower PFS and OS (p = 0.001 and p = 0.007, respectively). EEAs were more frequently used in patients with upper and middle clival tumors (p = 0.002 and p < 0.0001, respectively), had a better rate of EOR (p = 0.003), and had a lower risk of de novo neurological deficit (p < 0.0001) compared with OAs. The overall rate of postoperative CSF leakage after EEAs was 14.8%. CONCLUSIONS This large study showed that gross-total resection should be attempted in a multidisciplinary skull base center before providing radiation therapy. EEAs should be considered as the gold-standard approach for upper/middle clival lesions based on the satisfactory surgical outcome, but OAs remain important tools for large complex chordomas.

BACKGROUND Currently, different postoperative predictors of chordoma recurrence have been identified. Tumor growth rate (TGR) is an image-based calculation that provides quantitative information of tumor's volume changing over time and has been shown to predict progression-free survival (PFS) in other tumor types. OBJECTIVE To explore the usefulness of TGR as a new preoperative radiological marker for chordoma recurrence. METHODS A retrospective single-institution study was carried out including patients reflecting these criteria: confirmed diagnosis of chordoma on pathological analysis, no history of previous radiation, and at least 2 preoperative thin-slice magnetic resonance images available to measure TGR. TGR was calculated for all patients, showing the percentage change in tumor size over 1 mo. RESULTS A total of 32 patients were retained for analysis. Patients with a TGR ≥ 10.12%/m had a statistically significantly lower mean PFS (P

Background: Palbociclib, a small-molecule inhibitor of cyclin-dependent kinases (CDK4 and CDK6), combined with letrozole increases progression-free survival among patients with previously untreated ER-positive, HER2 negative advanced breast cancer. However, the data on the safety of the concomitant association between Palbociclib and radiation therapy are scarce. The purpose of our study was to retrospectively evaluate the tolerance of the first patients treated with this concomitant combination at Institut Curie. Materials and methods: Between April 2017 and July 2019, 27 women with ER-positive, HER2 negative metastatic breast cancer received locoregional and/or symptomatic irradiation at a metastatic site concomitantly with Palbociclib at a daily dose of 125 mg, from d1 to d21 every 28 days. Palbociclib was always associated with an endocrine treatment: Letrozole (17 patients /27, with or without an LHRH analogue) or Fulvestrant (10 patients /27). Median age at the time of diagnosis of metastases was 60 years (range, 35-85 years). Thirty-two sites were irradiated: 9 patients received post-operative locoregional radiation therapy, including the chest wall or breast and lymph node areas, and 23 sites of metastases were irradiated: 15 at the spine (3 cervical, 6 thoracic, 4 lumbar, 2 sacral), 2 pelvic lesions, 4 peripheral skeletal lesions, 1 brain lesion and 1 choroidal lesion (two patients received locoregional treatment and irradiation in one metastatic site and two patients were treated in two different metastatic sites). The dose prescribed for locoregional mammary radiotherapy was 50 Gy in 25 fractions and varied for the treatment of metastatic sites: 20 Gy in 5 fractions (n=14), 30 Gy in 10 fractions (n=7) and 8 Gy in 1 fraction (n=1). The brain metastasis was stereotactically treated (1 fraction of 18 Gy). The primary endpoint was toxicity scored according to the common terminology criteria for NCI adverse events, version v4.0. Results: Median follow-up was 22 months (range, 4 to 54). Mean number of days of Palbociclib during radiation therapy was 8.7 days (range, 1 to 23 days). Most common acute toxicities were radiodermatitis (12/27, including 1 grade 3, 2 grade 2 and 9 grade 1) and neutropenia (13/27, including 1 grade 4, 7 grade 3, 5 grade 2). Palbociclib had to be stopped during the radiation therapy of three patients (3/27): one patient treated locoregionally (bilateral breast and lymph nodes irradiation) developed a grade 3 radiodermatitis and febrile neutropenia, another treated locoregionally developed grade 2 dysphagia (loss of 4 kg in 1 month) and one patient treated for sacral metastases (20 Gy in 4 fractions) developed grade 3 proctitis. Of the 19/27 patients with a follow-up of more than 6 months none developed late toxicities. Conclusion: Concomitant administration of Palbociclib with radiation therapy was reasonably well tolerated in our series of 27 patients. Caution should be exercised when a large volume is irradiated, and when the dose per fraction is high. It remains unsure whether the interruption-causing side effects of Palbociclib was based on synergistic toxicity with radiation therapy. We suggest that our findings are to be confirmed in prospective registration studies collecting larger number of patients. Citation Format: Arnaud Beddok, Alexandre Arsene-Henry, Baptiste Porte, Kim Cao, Louis Bazire, Nathaniel Scher, Alain Labib, Ilan Darmon, Joëlle Otz, Mathieu Minsat, Hamid Mammar, François Clément Bidar, Alain Fourquet, Paul Cottu, Phlip Poortmans, Youlia Kirova. A retrospective study of 27 patients with ER-positive, HER2 negative metastatic breast cancer treated with concomitant palbociclib and radiation therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-05.

Chordomas are rare neoplasms characterized by a high recurrence rate and a poor long-term prognosis. Considering their chemo-/radio-resistance, alternative treatment strategies are strongly required, but their development is limited by the paucity of relevant preclinical models. Mutations affecting genes of the SWI/SNF complexes are frequently found in chordomas, suggesting a potential therapeutic effect of epigenetic regulators in this pathology. Twelve PDX models were established and characterized on histological and biomolecular features. Patients whose tumors were able to grow into mice had a statistically significant lower progression-free survival than those whose tumors did not grow after in vivo transplantation (p = 0.007). All PDXs maintained the same histopathological features as patients’ tumors. Homozygous deletions of CDKN2A/2B (58.3%) and PBRM1 (25%) variants were the most common genomic alterations found. In the tazemetostat treated PDX model harboring a PBRM1 variant, an overall survival of 100% was observed. Our panel of chordoma PDXs represents a useful preclinical tool for both pharmacologic and biological assessments. The first demonstration of a high antitumor activity of tazemetostat in a PDX model harboring a PBRM1 variant supports further evaluation for EZH2-inhibitors in this subgroup of chordomas.

Objective To investigate on the feasibility and safety of a new approach which consists of delaying instrumentation after destabilizing craniovertebral junction (CVJ) chordoma surgery, allowing proton beam radiotherapy to be performed in a metal-free tumoral cavity. Design This is a retrospective series of a prospectively maintained database. Participants Five consecutive patients operated on for a CVJ chordomas for which instrumentation after tumor resection was deferred to after radiotherapy treatment. Main Outcome Measures The main outcome consisted of measurements of the following parameters: C0–C2 angle, atlanto-dens interval (ADI), condylar gap, and the position of the dens relative to McGregor's line and coronal inclination, performed at 3 different times for all patients: before tumor surgery (baseline), before instrumentation surgery, and after instrumentation surgery. Results For all patients, CVJ parameters deteriorated during the delay period, but stayed within normal limits for most. Because of radiological instability, one patient necessitated instrumentation before receiving radiotherapy. All parameters except condylar gap were partially corrected after instrumentation. No new neurological symptom or evolving neck pain occurred during the delay period. Conclusion Delayed instrumentation of CVJ chordomas can be a safe alternative that might lead to improved subsequent radiotherapeutical treatment. Patient's selection and close clinical and radiological follow-up are mandatory for the success of this approach.

Background: Chordomas are considered as rare bone neoplasms characterized by a high level of recurrence and a poor long-term prognosis. Considering their chemo-radio-resistance, alternative treatment strategies are therefore strongly requested, but their development is limited by the paucity of relevant preclinical models. Mutations affecting genes of the SWI/SNF complex including PBMR1 are frequently found in chordomas, suggesting a potential therapeutic effect of epigenetic regulators in this indication. Methods: Thirty-eight chordoma specimens derived from primary patients’ tumors were grafted into nude mice. Relationship between grafted tumors and clinical, biological and therapeutic features of corresponding patients were investigated. We subjected the established PDX models to histopathological and genetic examination; finally, a therapeutic program focused on the EZH2-inhibition was performed in one PDX model. Results: Twelve PDX models were established and characterized on histological and biomolecular features. Patients whose tumors were able to grow into mice had a statistically significant lower progression-free survival than those whose tumors did not grow after in vivo transplantation (p=0.007). All PDXs maintained the same histopathological features as patients’ tumors. Homozygous deletions of CDKN2A/2B (58.3%) and PBRM1 (25%) variants were the most common genomic alterations found. In the tazemetostat treated PDX model harboring a PBRM1 variant, an overall survival of 100% was observed. Conclusion: Our panel of chordoma PDXs represents a useful preclinical tool for both pharmacologic and biological assessments. The first demonstration of a high antitumor activity of tazemetostat in a PDX model harboring a PBRM1variant supports further evaluation of EZH2-inhibitors in this subgroup of chordomas. Citation Format: Thibault Passeri, Ahmed Dahmani, Julien Masliah-Planchon, Adnan Naguez, Marine Michou, Rania El-Botty, Sophie Vacher, Rachida Bouarich, André Nicolas, Marc Polivka, Coralie Franck, Anne Schnitzler, Fariba Némati, Sergio Roman-Roman, Franck Bourdeaut, Homa Adle-Biassette, Hamid Mammar, Sébastien Froelich, Ivan Bièche, Didier Decaudin. Dramatic in vivo efficacy of the EZH2-inhibitor tazemetostat in PBRM1-mutated human chordoma xenograft [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB567.

Purpose/Objective(s) Proton therapy (PT) is being increasingly used for craniopharyngioma. Most series focus on pediatric population. Real therapeutic gain of PT in adults has yet to be demonstrated. We evaluated the outcomes of all adult craniopharyngioma patients treated at our institution using PT to report outcomes for disease control, tumor response and treatment-related toxicity. Materials/Methods We reviewed medical records from 93 histological proven adult craniopharyngioma patients treated with PT at our institution from December 2006 to November 2018. Endpoints were overall survival, disease control and toxicity. The median age at PT was 36.5 years (18-82). Ninety patients were treated after at least one tumor resection prior PT (20 patients as adjuvant treatment after incomplete surgery, 70 for recurrent disease) and 3 as exclusive PT. Patients received double-scattered conformal proton therapy to a mean dose of 54 GyRBE in 1.8 GyRBE/fraction (range 52.2–54 GyRBE). Toxicity was collected according CTCAE v5. Results With median clinical and radiographic follow-up of 37 and 31 months, respectively, the 3-year local control and overall survival rates were 100% and 93.5%, respectively. At last follow up, 16 patients remained in complete remission, 47 in partial remission, 24 with stable disease and 6 patients had a local relapse. Six patients required treatment replanning due to tumor changes during radiotherapy. There were two acute grade 3 toxicity events (one visual field decline and one headache). Two late grade 2 side-effects occurred (one visual field decline and one visual acuity deterioration) and one grade 3 neurocognitive dysfunction following radiotherapy. One patient with pre-existing visual field declines experienced grade 4 visual loss five months after PT and after receiving bevacizumab. Conclusion Fractionated PT appears as an effective and safe treatment for adult craniopharyngioma compared to IMRT and 3DRT. Although the integral dose in normal tissues decreases drastically, the benefit of PT remains uncertain in adult patients. Prospective quality-of-life and neurocognitive studies are needed to better define late toxicity. Only prospective trials in adult population should define the role of RT in terms of techniques, prescribed doses, fractionation and sparing of organs at risk. Author Disclosure N. Scher: None. G. Bentahila: None. A. Beddok: None. C. Alapetite: None. S. Helfre: None. S. Bolle: None. H. Mammar: None. R. Dendale: None. V. Calugaru: None. L. Feuvret: None.

Resume Objectif de l’etude L’objectif de cette etude etait d’evaluer l’efficacite et la tolerance d’un complement de dose de protons pour les patients atteints d’un cancer du nasopharynx localement evolue. Patients et methodes De novembre 1999 a septembre 2016, 17 patients atteints d’un cancer du nasopharynx de stade III–IVa ont ete pris en charge au centre de protontherapie d’Orsay de l’institut Curie. Les aires ganglionnaires cervicales bilaterales ont ete traitees par des photons a la dose de 40–54 Gy. La tumeur et ses extensions microscopiques ont recu une dose complementaire de protons pour atteindre la dose de 70–78 Gy. Tous les patients ont recu une chimiotherapie concomitante. Le controle local, la survie sans recidive et la survie globale ont ete determines, ainsi que la toxicite aigue et tardive. Resultats Les caracteristiques des patients etaient : un âge median de 49 ans, le sexe masculin pour 71 % des cas, 88 % des cancers etaient de stade IVa avec une majorite T4N0M0 (82 %). La mediane de suivi etait de 99 mois. Les probabilites de controle local et de survie globale actuarielle ont ete respectivement 94 % et 88 % a 2 ans, 86 % et 74 % a 5 ans, 86 % et 66 % a 10 ans. La toxicite tardive de grade ≥ 3 a ete la perte auditive (23,5 %) et une osteo-radio-necrose de l’os sphenoide (5,9 %). Conclusion Le complement de dose de protons semble donc une bonne alternative pour le traitement des cancers du nasopharynx localement evolues, en particulier pour ceux de stade T4N0M0.

Small choroidal melanomas have a better prognosis than large tumours. However, these small tumours can spread, often late in their course. The aim of the study was to analyse survival and tumour characteristics of six cases of late metastatic diseases after conservative treatment.A retrospective study was conducted at the Croix-Rousse University Hospital of Lyon among 523 patients treated between 1991 and 2010 by proton beam therapy (508) or brachytherapy with 106 (Ru/Rh) (15) for uveal melanomas. We have selected patients with small choroidal melanoma (thickness≤3 mm and diameter≤9 mm) (59 patients), who have developed hepatic metastases (six of 59).At the time of diagnosis, median age was 57 years (range, 37-82 years). The mean tumour thickness was 2.9 mm (range 2.5-3 mm), and the mean diameter was 7 mm (5-8 mm). Orange pigment was observed in four cases, subretinal fluid was observed in two cases, and one tumour touched the optic disc. Five patients had proton beam therapy. One patient had beta brachytherapy (106 Ru/106 Rh). Average follow-up was 8.3 years (range 4.2-11.8 years). None of the six patients developed local tumour recurrence. The mean survival time after diagnosis of melanoma was 9.8 years (range, 4.9-14.6 years). The average time from treatment of primary tumour to detection of liver metastasis was 7 years (range 3.9-12 years). The mean survival time from the diagnosis of metastasis was 35.2 months (range 9-101 months). Small melanoma-related death was 0% at 3 years, 1.7% at 5 years, 5.1% at 10 years and 10.2% at 15 years in our series.Despite a small tumoral size and an early and effective local treatment, six of 59 small choroidal melanomas have developed metastasis after local treatment. Small tumours represent a significant risk of metastasis.