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OBJECTIVE Chordomas are rare bone neoplasms characterized by a high recurrence rate and no benefit from any approved medical treatment to date. However, the investigation of molecular alterations in chordomas could be essential to prognosticate, guide clinical decision-making, and identify theranostic biomarkers. The aim of this study was to provide a detailed genomic landscape of a homogeneous series of 64 chordoma samples, revealing driver events, theranostic markers, and outcome-related genomic features. METHODS The authors conducted whole-exome sequencing (WES), targeted next-generation sequencing, and RNA sequencing of 64 skull base and spinal chordoma samples collected between December 2006 and September 2020. Clinical, histological, and radiological data were retrospectively analyzed and correlated to genetic findings. RESULTS The authors identified homozygous deletions of CDKN2A/2B, PIK3CA mutations, and alterations affecting genes of SWI/SNF chromatin remodeling complexes (PBRM1 and ARID1A) as potential theranostic biomarkers. Using matched germline WES, they observed a higher frequency of a common genetic variant (rs2305089; p.(Gly177Asp)) in TBXT (97.8%, p < 0.001) compared to its distribution in the general population. PIK3CA mutation was identified as an independent biomarker of short progression-free survival (HR 10.68, p = 0.0008). Loss of CDKN2A/2B was more frequently observed in spinal tumors and recurrent tumors. CONCLUSIONS In the current study, the authors identified driver events such as PBRM1 and PIK3CA mutations, TBXT alterations, or homozygous deletions of CDKN2A/2B, which could, for some, be considered potential theranostic markers and could allow for identifying novel therapeutic approaches. With the aim of a future biomolecular prognostication classification, alterations affecting PIK3CA and CDKN2A/2B could be considered as poor prognostic biomarkers.

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.

OBJECTIVE Craniocervical junction (CCJ) chordomas are a neurosurgical challenge because of their deep localization, lateral extension, bone destruction, and tight relationship with the vertebral artery and lower cranial nerves. In this study, the authors present their surgical experience with the endoscope-assisted far-lateral transcondylar approach (EA-FLTA) for the treatment of CCJ chordomas, highlighting the advantages of this corridor and the integration of the endoscope to reach the anterior aspect and contralateral side of the CCJ and the possibility of performing occipitocervical fusion (OCF) during the same stage of surgery. METHODS Nine consecutive cases of CCJ chordomas treated with the EA-FLTA between 2013 and 2020 were retrospectively reviewed. Preoperative characteristics, surgical technique, postoperative results, and clinical outcome were analyzed. A cadaveric dissection was also performed to clarify the anatomical landmarks. RESULTS The male/female ratio was 1.25, and the median age was 36 years (range 14–53 years). In 6 patients (66.7%), the lesion showed a bilateral extension, and 7 patients (77.8%) had an intradural extension. The vertebral artery was encased in 5 patients. Gross-total resection was achieved in 5 patients (55.6%), near-total resection in 3 (33.3%), and subtotal resection 1 (11.1%). In 5 cases, the OCF was performed in the same stage after tumor removal. Neither approach-related complications nor complications related to tumor resection occurred. During follow-up (median 18 months, range 5–48 months), 1 patient, who had already undergone treatment and radiotherapy at another institution and had an aggressive tumor (Ki-67 index of 20%), showed tumor recurrence at 12 months. CONCLUSIONS The EA-FLTA provides a safe and effective corridor to resect extensive and complex CCJ chordomas, allowing the surgeon to reach the anterior, lateral, and posterior portions of the tumor, and to treat CCJ instability in a single stage.

Considering intracranial tumours, only few indications of protontherapy, such as chordoma, chondrosarcoma or uveal melanoma, are uniformly approved in the world. Other indications, excluding paediatric pathologies, are still debated. The aim of this article is to describe the rationale for the use of protonbeam irradiation for meningioma, pituitary adenoma, craniopharyngioma, paraganglioma, glioma, and schwannoma, and to inform the radiation oncologists if prospective studies or randomized studies are opened for inclusions. This article deals only with indications for adults.

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

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.

Radiation therapy (RT) is used for the treatment of sacral chordoma, in combination with surgery or alone for unresected tumours, to improve local control (LC) and potentially overall survival (OS). The purpose of the present study was to evaluate efficacy and toxicity of proton therapy (PT), and/or intensity modulated radiation therapy (IMRT), particularly Tomotherapy, for sacral chordoma treatment.After a median follow-up of 46 months (range, 0-125 months), eight local relapses were observed, and seven patients developed distant metastasis (particularly bone and lung). The 2- and 5- year local relapse rates were 11.4% CI (0.65-22.2%) and 29% (10.5-47.4%), respectively. Over the follow-up period, ten patients died (24.4%). The estimated 2- and 5-year OS rates were 91.4% CI (82.5-100%) and 74.5% (59.4-93.5%), respectively. Fibrosis,RT remains essential to improve local control in sacral chordoma. The combination of proton and photon seems to improve organ at risk sparing, resulting in a decreased rate of reported late toxicities.

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.

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.

Sarcomas are a common type of tumor within the pediatric population. The utilization of proton therapy as a primary attribute the ability to spare adjacent healthy tissue, therefore, proton therapy has become a preferential indication in pediatrics compared to other photon irradiation modalities. Proton therapy is also a proven and historically validated irradiation technique in the treatment of chondrosarcomas and chordomas of the skull base and spine. Additionally, proton therapy can potentially limit irradiated healthy tissue volumes in adults and limit the risk of acute and late toxicities. The evaluation of the effectiveness of proton therapy in sarcomas is underway in many clinical situations in prospective trials, some of which are randomized.

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.

A patient enrolled in a clinical trial (NCT02802969) with suspicion of chordoma underwent an [F]FAZA PET/CT, a radiolabeled nitroimidazole analog of hypoxia PET imaging. The patient's images showed a different tumor profile compared to those observed in other hypoxic or nonhypoxic chordoma patients. The motivation for using [F]FAZA pharmacokinetic imaging was to compare this profile with histologically confirmed cases of chordoma. Through visual imaging and quantification of blood and tumor time-activity curves, we excluded the hypothesis that it was a chordoma, diagnosing a paraganglioma.

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.

Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS).From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE]; range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively.With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS.Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended.

Background and purpose Skull-base chondrosarcoma (ChSa) is a rare bone tumor and the outcome of patients with this malignancy has been documented only in a limited number of series with a restricted number of patients. Objective This study was conducted to assess the outcome and prognostic factors of a large cohort of ChSa patients treated with radiotherapy in two proton therapy centers. Materials and methods From 1996 to 2015, 251 (male, 43.4%) patients (mean age, 42.0 ± 16.2 years) were treated with protons with (n = 135; 53.8%) or without photons (n = 116; 46.2%). Median delivered dose was 70.2 GyRBE. Failure-free survival (FFS), overall survival (OS) and CTCAE grade ≥3 toxicity free survival (TFS) were calculated using the Kaplan–Meier method. Results After a median follow-up of 88.0 months for surviving patients, local and distant failures were observed in 12 (4.8%) and 4 (1.6%) patients, respectively. Late failures >6 years were observed in 4 (33.3%) patients. The estimated 7-year FFS was 93.1%. Twenty-five (10%) patients died. The estimated 7-year OS was 93.6%. Tumor volume (p = 0.006) and optic pathway compression (p = 0.027) were significantly associated with the risk of treatment failure on univariate analysis. Treatment failure was significantly associated with a higher risk of death (hazard ratio = 126). The estimated 7-year TFS was 84.2%. Conclusions The outcome of skull-base ChSa patients treated with high-dose protons with or without photons is excellent, particularly for patients with small tumors with no optic pathway compression. Treatment failure was however associated with a significantly increased risk of death.

Sarcomas are a common type of tumor within the pediatric population. The utilization of proton therapy as a primary attribute the ability to spare adjacent healthy tissue, therefore, proton therapy has become a preferential indication in pediatrics compared to other photon irradiation modalities. Proton therapy is also a proven and historically validated irradiation technique in the treatment of chondrosarcomas and chordomas of the skull base and spine. Additionally, proton therapy can potentially limit irradiated healthy tissue volumes in adults and limit the risk of acute and late toxicities. The evaluation of the effectiveness of proton therapy in sarcomas is underway in many clinical situations in prospective trials, some of which are randomized.

Background Cervical and skull base chordomas may relapse locally, marginally, or in ectopic sites (ie, surgical pathway, lymph nodes, prevertebral space, subdural space, or distant organs). Methods Among 371 patients treated between 1995 and 2010, we matched the initial dosimetry with the 3D imaging of recurrence and selected the patients with isolated ectopic recurrence. Results During our follow-up, we identified 13 patients who developed ectopic relapses (n = 18) in the form of lung metastasis (n = 2), axial dissemination (n = 6), nodal recurrence (n = 2), subcutaneous metastasis (n = 3), and/or seeding along the surgical pathway (n = 5). Despite treatment of these 13 patients with radiation, surgical interventions, and/or chemotherapy, we could only salvage 5 patients with recurrence in surgical pathway, whereas the remaining 8 patients succumbed to a poor prognosis. Conclusion Our study emphasizes an urgent need for prediction and early diagnosis of ectopic relapses in patients with cervical and skull base chordoma to improve accuracy of their aggressive treatments. © 2015 Wiley Periodicals, Inc. Head Neck, 2015

In this chapter we present: I. The physical bases of proton therapy, going from microscopic concepts to macroscopic features II. The technology and the logistics, which evolve to more and more compact and cheaper facilities with the capability to perform adaptive radiation therapy III. The most usual clinical indications, moving toward (nearly) all indications of radiation therapy IV. Some research orientations, rediscovering physics, and radiation biology V. Basic elements to conceive and build a clinical center VI. Conclusions: The need to learn from others and also to innovate

Purpose To detect the presence of hypoxic tissue, which is known to increase the radioresistant phenotype, by its uptake of fluoromisonidazole (18F) (FMISO) using hybrid positron emission tomography/computed tomography (PET/CT) imaging, and to compare it with the glucose-avid tumor tissue imaged with fluorodeoxyglucose (18F) (FDG), in residual postsurgical skull base chordoma scheduled for radiotherapy. Patients and Methods Seven patients with incompletely resected skull base chordomas were planned for high-dose radiotherapy (dose ≥70 Gy). All 7 patients underwent FDG and FMISO PET/CT. Images were analyzed qualitatively by visual examination and semiquantitatively by computing the ratio of the maximal standardized uptake value (SUVmax) of the tumor and cerebellum (T/C R), with delineation of lesions on conventional imaging. Results Of the eight lesion sites imaged with FDG PET/CT, only one was visible, whereas seven of nine lesions were visible on FMISO PET/CT. The median SUVmax in the tumor area was 2.8 g/mL (minimum 2.1; maximum 3.5) for FDG and 0.83 g/mL (minimum 0.3; maximum 1.2) for FMISO. The T/C R values ranged between 0.30 and 0.63 for FDG (median, 0.41) and between 0.75 and 2.20 for FMISO (median,1.59). FMISO T/C R >1 in six lesions suggested the presence of hypoxic tissue. There was no correlation between FMISO and FDG uptake in individual chordomas ( r = 0.18, p = 0.7). Conclusion FMISO PET/CT enables imaging of the hypoxic component in residual chordomas. In the future, it could help to better define boosted volumes for irradiation and to overcome the radioresistance of these lesions. No relationship was founded between hypoxia and glucose metabolism in these tumors after initial surgery.

Resume Nous presentons les resultats de deux etudes retrospectives, l’une concernant les reirradiations des tumeurs rachidiennes et la seconde, celles des tumeurs pulmonaires. Il s’agit dans le premier cas de tumeurs malignes primitives ou secondaires localisees dans ou au contact des corps vertebraux et du cordon medullaire ayant deja ete irradiees a pleine dose. Dans le cas des tumeurs pulmonaires, il s’agit de reirradiation d’une tumeur primitive ou secondaire apres une radiotherapie exclusive ou associee a une chimiotherapie. Aucune toxicite precoce de grade 3 ou 4 n’a ete retrouvee. Les resultats preliminaires sont encourageants. L’utilisation du CyberKnife ® represente une avancee therapeutique majeure dans la prise en charge des lesions rachidiennes et pulmonaires irradiees. La possibilite d’epargner au mieux les organes a risques et d’augmenter la dose dans le volume cible tumoral en sont les principaux avantages.

Purpose To present the results of uveal melanomas treated at Nice Teaching Hospital. Methods and Materials This retrospective study included 886 consecutive patients referred to our clinic for the treatment of uveal melanomas by proton beam radiotherapy from June 1991 to December 2007. Survival rates were determined by using Kaplan-Meier estimates, and prognostic factors were evaluated using the log-rank test or Cox model. Results The number (percent total) of subjects staged according to the TNM classification system (6th edition) of malignant tumors included 39 stage T1 (4.4%), 420 stage T2 (47.40%), 409 stage T3 (46.16%), and 18 stage T4 (2.03%) patients. The median follow-up was 63.7 months. The Kaplan-Meier overall survival rate at 5 years according to the sixth edition TNM classification was 92% for T1, 89% for T2, 67% for T3, and 62% for T4; and at 10 years, 86% for T1, 78% for T2, 43% for T3, and 41% for T4. Five factors were found to be associated with an increased death rate: advanced age, tumor thickness, largest tumor basal diameter, tumor volume, and tumor volume-to-eyeball volume ratio. The metastasis-free survival rates were 88.3 % at 5 years and 76.4 % at 10 years. The local control rates were 93.9% at 5 years and 92.1% at 10 years. The ocular conservation rates were 91.1% at 5 years and 87.3% at 10 years. Conclusions We report the results of a large series of patients treated for uveal melanomas with a very long follow-up. Despite the large tumor volume treated, our results were similar to previously published findings relating to proton beam therapy.

Resume Objectif de l’etude La radiotherapie par CyberKnife® est devenue un traitement cle dans la prise en charge multidisciplinaire des metastases, des tumeurs malignes primitives ou benignes localisees dans ou au contact des corps vertebraux et du cordon medullaire. Les objectifs sont pour les tumeurs spinales d’ameliorer la reponse clinique et le controle tumoral, y compris dans des cas de reirradiation. Patients et methodes Nous presentons les resultats obtenus chez les premiers patients traites par CyberKnife® entre le 1er decembre 2006 et le 31 decembre 2007 pour des tumeurs spinales ou paraspinales. Nos objectifs primaires etaient d’evaluer la faisabilite et la tolerance d’une irradiation stereotaxique utilisant le CyberKnife®. Nos objectifs secondaires etaient les taux de controle local precoces, de survie sans progression locale et de survie globale. L’evaluation a eu lieu tout les trois mois par un examen clinique et par une imagerie. Elle s’est faite selon les criteres RECIST. Resultats De decembre 2006 a decembre 2007, 16 patients ont ete traites avec le CyberKnife®. Treize patients avaient ete pretraites, dont trois irradies dans la moelle a des doses considerees comme maximales. Trois patients n’avaient jamais ete traites. L’âge median le jour du traitement etait de 58,6 ans (36–74). Les symptomes les plus frequents etaient la douleur (n = 8) et un deficit moteur (n = 4). La dose mediane delivree etait de 30 Gy (16–50). Le nombre de fractions median etait de trois (1–5). Des reactions aigues ont ete observees chez trois patients, mais aucun n’a ete atteint de myelite aigue. Le taux de survie globale a 18 mois etait 72 % et la duree moyenne de survie de 18,2 mois [intervalle de confiance a 95 % (IC 95 %) : 15,4–20,9]. Le taux de survie sans progression locale a 18 mois etait de 58 % et la duree moyenne de survie de 16,9 mois (IC 95 % : 13,6–20,2). Conclusion L’utilisation du CyberKnife® represente une avancee therapeutique majeure dans la prise en charge des tumeurs paramedullaires. La possibilite d’epargner au mieux le cordon medullaire et d’augmenter la dose dans le volume cible tumoral en sont les principaux avantages.

Image-guided frameless fractionated stereotactic radiotherapy can be performed with millimetric accuracy using the CyberKnife (Accuray Inc. Sunnyvale, USA) equipped with an integrated tracking system for intra- and extracranial lesions. Highly conformal hypofractionated irradiation has been used to treat lesions with curative or palliative intent. It is advantageous for radioresistant tumors, re-irradiating lesions, boosting small volumes and treating tumors that move with respiration. It also limits travel costs and improves the quality of life. Over 60,000 patients have been treated worldwide using CyberKnife including 600 patients in the three French cancer centres of Nice, Nancy and Lille. These expert Cyberknife centres follow quality assurance programs and work together with the "Haute Autorite de sante" and the French National Cancer Institute (INCa) to promote clinical developments. The CyberKnife has been used to treat intracranial lesions including (but not limited to) meningiomas, acoustic schwannomas, brain oligometastases, as well as skull base tumors like chordomas, or para- or intraspinal tumors, and extracranial tumors such as lung cancers. Currently, extracranial stereotactic radiotherapy is particularly attractive for tumors moving with respiration and is being evaluated in liver, prostate and re-irradiation including head and neck tumors.

Resume Objectif de l’etude Decrire les modalites therapeutiques pour les cancers localises de la prostate traites par irradiation conformationnelle de 76 Gy avec ou sans hormonotherapie. Evaluer les resultats preliminaires en termes de survie, de controle biochimique et de toxicite. Patients et methode Entre janvier 1998 et juin 2001, 321 patients atteints d’un cancer localise de la prostate ont ete irradies a l’institut Curie. Pour cette etude, les tumeurs ont ete stratifiees selon les trois groupes pronostiques du Memorial Sloan-Kettering Cancer Center (1998) : favorable (23 %), intermediaire (36,5 %), defavorable (40,5 %). Une privation androgenique, principalement neoadjuvante, inferieure ou egale a un an a ete prescrite a 93,8 % des patients (72,6 % inferieure ou egale a six mois). Les doses d’irradiation prescrites dans les volumes cibles previsionnels etaient les suivantes : prostate : 76 Gy ; vesicules seminales : 56 a 76 Gy ; ganglions pelviens : 44 Gy pour 16,8 % des patients. Resultats La probabilite de survie actuarielle globale a cinq ans etait de 94 % (intervalle de confiance a 95 % : 90–97 %). La duree mediane du suivi post-therapeutique etait de 36 mois (neuf a 66 mois). Les probabilites de survie actuarielle sans echec biochimique a 48 mois etaient statistiquement differentes entre les trois groupes pronostiques, que ce soit selon la definition de l’echec biologique proposee par le consensus de l’American Society for Therapeutic Radiology and Oncology (ASTRO) de 1997 ou celle du Fox Chase Cancer Center (FCCC) de 2000, respectivement 87 et 94 %, 78 et 84 %, 54 et 58 % dans les groupes favorable, intermediaire et defavorable (p Conclusions Ces resultats sont comparables a ceux des series publiees precedemment pour un suivi equivalent. L’impact de l’escalade de dose associee a une courte privation androgenique sur le controle local, la survie et les complications necessitent un suivi de longue duree et une analyse approfondie.

Cervical and skull base chordomas may relapse locally, marginally, or in ectopic sites (ie, surgical pathway, lymph nodes, prevertebral space, subdural space, or distant organs).Among 371 patients treated between 1995 and 2010, we matched the initial dosimetry with the 3D imaging of recurrence and selected the patients with isolated ectopic recurrence.During our follow-up, we identified 13 patients who developed ectopic relapses (n = 18) in the form of lung metastasis (n = 2), axial dissemination (n = 6), nodal recurrence (n = 2), subcutaneous metastasis (n = 3), and/or seeding along the surgical pathway (n = 5). Despite treatment of these 13 patients with radiation, surgical interventions, and/or chemotherapy, we could only salvage 5 patients with recurrence in surgical pathway, whereas the remaining 8 patients succumbed to a poor prognosis.Our study emphasizes an urgent need for prediction and early diagnosis of ectopic relapses in patients with cervical and skull base chordoma to improve accuracy of their aggressive treatments. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1238-E1246, 2016.

This study reports the results of proton beam radiotherapy based on a retrospective series of patients treated for uveal melanoma at the Orsay Center.Between September 1991 and September 2001, 1,406 patients with uveal melanoma were treated by proton beam radiotherapy. A total dose of 60 cobalt Gray equivalent (CGE) was delivered in 4 fractions on 4 days. Survival rates were determined using Kaplan-Meier estimates. Prognostic factors were determined by multivariate analysis using the Cox model.The median follow-up was 73 months (range, 24-142 months). The 5-year overall survival and metastasis-free survival rates were 79% and 80.6%, respectively. The 5-year local control rate was 96%. The 5-year enucleation for complications rate was 7.7%. Independent prognostic factors for overall survival were age (p0.0001), gender (p0.0003), tumor site (p0.0001), tumor thickness (p = 0.02), tumor diameter (p0.0001), and retinal area receiving at least 30 CGE (p = 0.003). Independent prognostic factors for metastasis-free survival were age (p = 0.0042), retinal detachment (p = 0.01), tumor site (p0.0001), tumor volume (p0.0001), local recurrence (p0.0001), and retinal area receiving at least 30 CGE (p = 0.002). Independent prognostic factors for local control were tumor diameter (p = 0.003) and macular area receiving at least 30 CGE (p = 0.01). Independent prognostic factors for enucleation for complications were tumor thickness (p0.0001) and lens volume receiving at least 30 CGE (p = 0.0002).This retrospective study confirms that proton beam radiotherapy ensures an excellent local control rate. Further clinical studies are required to decrease the incidence of postirradiation ocular complications.

Resume Objectif. – Definir les facteurs pronostiques du controle local et de la survie globale chez 100 patients consecutifs atteints d'un chordome de la base du crâne ou du rachis cervical haut, traites par une irradiation fractionnee associant des faisceaux de protons et de photons precedee ou non d'une chirurgie d'exerese. Patients et methodes. – Entre decembre 1993 et aout 2002, 100 patients (âge median : 53 ans [8–85], sex-ratio M/F : 3/2) ont ete traites par une association de photons de haute energie et de protons. La protontherapie etait realisee au centre de protontherapie d'Orsay (CPO) par un faisceau d'energie 201 MeV. La dose totale mediane delivree dans le volume tumoral etait de 67 GyECo, (60–71). L'irradiation a ete precedee d'une chirurgie d'exerese consideree comme complete dans 16 cas, incomplete dans 75 cas et d'une biopsie dans neuf cas. Resultats. – Avec une duree de surveillance mediane de 31 mois [0–87], 25 tumeurs ont evolue localement. Les taux de controle local a deux et quatre ans etaient respectivement de 86,3 % (± 3,9 %) et de 53,8 % (± 7,5 %). Apres analyse multifactorielle, deux facteurs independants reduisaient le taux de controle local : moins de 95 % du volume tumoral total inclus dans l'isodose 95 % ( p = 0,048 ; RR : 3,4 IC95 % [1,01–11,8]) et une dose minimale dans le volume tumoral inferieure a 56 GyECo ( p = 0,042 ; RR : 2,3 IC95 % [1,03–5,2]). Dix patients etaient decedes. Les taux de survie globale a deux et cinq ans etaient respectivement de 94,3 % (± 2,5 %) et de 80,5 % (± 7,2 %). Apres analyse multifactorielle, le controle de la tumeur ( p = 0,005 ; RR : 21 IC95 % [2,2–200]) etait le seul facteur pronostique independant de la survie globale. Conclusion. – Pour les chordomes de la base du crâne et du rachis cervical haut traites par une chirurgie et une irradiation associant photons et protons, l'homogeneite de la dose dans le volume tumoral, est un facteur majeur du controle local. Une attention particuliere doit etre portee pour reduire les zones « sous-dosees » proches des organes critiques. Dans cet objectif, la reduction du volume tumoral cible par exerese chirurgicale reste primordiale. De plus, etant donne la bonne tolerance des organes critiques, une augmentation de dose pourrait etre envisagee pour faciliter une distribution de dose homogene dans le volume cible tumoral.

Background The purpose of the study was to evaluate clinical results and complications of a combination of proton and photon irradiation administered to 17 children with selected central nervous system (CNS) tumors. Procedure Between July 1994 and September 2000, 17 children, aged from 5 to 17 years (median: 12 years) with intracranial benign (6 cases) or malignant (11 cases) tumors, were treated with photons (median dose: 40 Gy; 24–54) and protons (median dose: 20 CGE; 9–31) at the Centre de Protontherapie d'Orsay (CPO). Results Mean follow-up was 27 months (3–81). Two patients recurred locally (one marginal and one in situ). Fifteen patients are alive and doing well. Overall, 12, 24, and 36-month local control rate was 92 ± 8% and, 12, 24, and 36-month overall survival rates were 93 ± 6%, 83 ± 11%, and 83 ± 11%, respectively. Clinical initial symptoms remained stable or subsided in all patients. Early toxicities were in the expected range. Conclusions With a mean 27 months follow-up, protontherapy was well tolerated for doses upto 69 CGE and with an excellent local control rate. Med Pediatr Oncol 2003;40:309–315. © 2003 Wiley-Liss, Inc.

To evaluate the efficacy and the tolerance of an escalated dose of external conformal fractionated radiation therapy combining photons and protons in the treatment of intracranial meningiomas. Patients and Methods: Between December 1995 and December 1999, 17 patients received a treatment by 201-MeV proton beam at the Centre de Protontherapy d'Orsay (CPO) for a meningioma. Five patients presented a histologically atypical or malignant meningioma, twelve patients a benign one that was recurrent or rapidly progressive. In two cases radiotherapy was administered in the initial course of the disease and in 15 cases at the time of relapse. A highly conformal approach was used combining high-energy photons and protons for approximately 2/3 and 1/3 of the total dose. The median total dose delivered within gross tumor volume was 61 Cobalt Gray Equivalent CGE (25–69). Results: Median follow-up was 37 months (17–60). The 4-year local control and overall survival rates were 87.5 ± 12% and 88.9 ± 11%, respectively. One patient failed locally within the clinical tumor volume. One patient died of intercurrent disease. A complete or partial clinical improvement was seen in most of patients. Radiologically, there were eleven stable diseases and five partial responses. In 12/15 recurrent cases, the free interval after radiotherapy is longer than that achieved by the initial surgery. This radiotherapy was well tolerated. Conclusions: In both benign and more aggressive meningiomas, the combination of conformal photons and protons with a dose escalated by 10–15% offers clinical improvements in most patients as well as radiological long-term stabilization.

To report the clinical features and outcomes of iris melanomas treated by proton beam therapy. A retrospective study was conducted at the Croix-Rousse University Hospital of Lyon, Department of Ophthalmology, in 36 patients treated by proton beam therapy for presumed (n = 29) and confirmed (n = 7) iris melanomas between July 1997 and October 2010. Ciliary body melanomas with iris involvement were excluded. The patients’ mean age was 54.4 years (range, 22–82 years). The average tumor diameter was 3.8 mm (range, 2.5–8.0). The iridocorneal angle was invaded by the tumor in 47 % of cases (n = 17), the ciliary body in 17 % of cases (n = 6), and the sclera in 3 % (n = 1). Raised intraocular pressure was present before treatment in 11.1 % of cases (n = 4). Tumor biopsy was performed in 19 % of cases (n = 7). Four patients had undergone an initial incomplete surgical excision of tumor before radiotherapy. Surgical preparation of the eye with tantalum ring positioning had been performed in all cases 3–4 weeks before irradiation. The prescribed dose was 60 Cobalt Gray Equivalent (CGE) of proton beam radiotherapy delivered in four fractions on four consecutive days. The median follow-up was 50 months (mean 60.5, range 15–136). One patient (2.7 %) was lost to follow-up. None of the patients showed tumor progression, local recurrence, or metastasis. None of the patients required secondary enucleation. Cataract was developed in 62 % of patients, glaucoma in two cases (6 %) after irradiation, and hyphema with the aggravation of pre-existing glaucoma in one patient. No patients developed neovascular glaucoma. Proton beam therapy appears to be the treatment of choice for the conservative treatment of iris melanomas with excellent tumor control and an acceptable rate of complications. Longer follow-up studies on a larger series is necessary to consolidate these results.

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.

Prospective analysis of local tumor control, survival, and treatment complications in 44 consecutive patients treated with fractionated photon and proton radiation for a chordoma or chondrosarcoma of the skull base.Between December 1995 and December 1998, 45 patients with a median age of 55 years (14-85) were treated using a 201-MeV proton beam at the Centre de Protonthérapie d'Orsay, 34 for a chordoma and 11 for a chondrosarcoma. Irradiation combined high-energy photons and protons. Photons represented two-thirds of the total dose and protons one-third. The median total dose delivered within the gross tumor volume was 67 cobalt Gray equivalent (CGE) (range: 60-70).With a mean follow-up of 30.5 months (range: 2-56), the 3-year local control rates for chordomas and chondrosarcomas were 83.1% and 90%, respectively, and 3-year overall survival rates were 91% and 90%, respectively. Eight patients (18%) failed locally (7 within the clinical tumor volume and 1 unknown). Four patients died of tumor and 2 others of intercurrent disease. In univariate analysis, young age at time of radiotherapy influenced local control positively (p0.03), but not in multivariate analysis. Only 2 patients presented Grade 3 or 4 complications.In skull-base chordomas and chondrosarcomas, the combination of photons with a proton boost of one-third the total dose offers an excellent chance of cure at the price of an acceptable toxicity. These results should be confirmed with a longer follow-up.

Resume Objectif de l'etude D'octobre 1993 a juillet 1998, 48 patients adultes dont les dossiers etaient evaluables et qui etaient atteints d'une tumeur intracrânienne agressive, ont fait l'objet d'une etude de phase I–II de toxicite et d'efficacite d'une irradiation a dose escaladee de 10 a 15 % par une combinaison de photons (deux tiers de la dose) et de protons (un tiers de la dose). Patients et methodes Etaient exclus les gliomes de grade I et IV. Ces patients ont egalement beneficie d'une dosimetrie tridimensionnelle basee sur des images tomodensitometriques et par resonance magnetique de haute definition, d'un reperage stereotaxique par microbilles intracrâniennes et d'une contention rigoureuse par masque en plastique thermoforme. La dose moyenne delivree etait selon le type histologique de 63 Gy et 67 Gy (doses corrigees pour une efficacite biologique relative moyenne des protons estimee a 1,1) et ont generalement ete delivrees a raison de cinq seances de 1,8 Gy par semaine. Resultats Avec une duree de surveillance mediane de 18 mois (extremes: 4–58), le taux de controle local de ces tumeurs extracerebrales (chordomes, chondrosarcomes, meningiomes agressifs) etait de 33 sur 34 (97 %); pour les tumeurs parenchymateuses, il n'etait que de six sur 14 (43 %). Seuls deux des 48 patients (5 %) ont souffert d'une complication radique cliniquement severe (lobe temporal et chiasma). Conclusion Dans notre experience, l'irradiation de haute dose des tumeurs du systeme nerveux central s'avere peu toxique si elle est realisee avec un fractionnement classique et selon une approche stereotaxique; elle est egalement tres efficace dans certaines tumeurs des enveloppes et de la base du crâne.

At the Centre de Protontherapie d'Orsay, nine children with intra-cranial malignancies were treated between July 1994 and January 1998. Immediate and late tolerances were excellent in all cases (follow-up 2 to 50 months). Two patients recurred locally (marginal failures), seven are alive and doing well. At Loma Linda, 28 children were treated between 1991 and 1994, 16 for a benign tumor of the brain and twelve for a malignant one. With a follow-up of seven to 49 months, three patients died (grade 2 to 4 gliomas), one is living with a persistent disease. Four children had treatment-related toxicity (one cataract, two hormonal failures and two seizures). The other children are doing well. At MGH Boston, 18 children with skull base-cervical spine chordomas have been reported. At five years, actuarial survival and disease-free survival have been 68 and 63%, respectively. Children with cervical sites had a worse prognosis (p = 0.008). Four children had radiation-related morbidity: two pituitary failures, one temporal lobe necrosis, one temporal muscle fibrosis. In this experience, such rare tumors seemed to behave in children like in adults.

Stereotactic radiotherapy delivered in a high-dose single fraction is an effective technique to obliterate intracranial arteriovenous malformations (AVM). To attempt to analyze the relationships between dose, volume, and obliteration rates, we studied a group of patients treated using single-isocenter treatment plans.From May 1986 to December 1989, 100 consecutive patients with angiographically proven AVM had stereotactic radiotherapy delivered as a high-dose single fraction using a single-isocenter technique. Distribution according to Spetzler-Martin grade was as follows: 79 grade 1-3, three grade 4, 0 grade 5, and 18 grade 6. The target volume was spheroid in 74 cases, ellipsoid in 11, and large and irregular in 15. The targeted volume of the nidus was estimated using two-dimensional stereotactic angiographic data and, calculated as an ovoid-shaped lesion, was 1900 +/- 230 mm3 (median 968 mm3; range 62-11, 250 mm3). The mean minimum target dose (Dmin) was 19 +/- 0.6 Gy (median 20 Gy; range: 3-31.5). The mean volume within the isodose which corresponded to the minimum target dose was 2500 +/- 300 mm3 (median 1200 mm3; range 75-14 900 mm3). The mean maximum dose (Dmax) was 34.5 +/- 0.5 Gy (median 35 Gy; range 15-45). The mean angiographic follow-up was 42 +/- 2.3 months (median 37.5; range 7-117).The absolute obliteration rate was 51%. The 5-year actuarial obliteration rate was 62.5 +/- 7%. After univariate analysis, AVM obliteration was influenced by previous surgery (p = 0.0007), Dmin by steps of 5 Gy (p = 0.005), targeted volume of the nidus (or = 968 mm3 vs.968 mm3; p = 0.015), and grade according to Spetzler-Martin (grade 1-3 vs. grade 4-6; p = 0.011). After multivariate analysis, the independent factors influencing AVM obliteration were the Dmin [relative risk (RR) 1.9; 95% confidence interval (CI) 1.4-2.5; p0.0001] and grade distribution according to Spetzler-Martin (RR 1.4; 95% CI 1.1-1.7; p = 0.010). Delayed complications were observed in eight patients. The 5-year actuarial rate of delayed complications was 7.4%.After stereotactic radiotherapy delivered in a single high dose using a single-isocenter technique, the success rate for complete obliteration is independently correlated to Dmin but does not seem to be influenced by Dmax and the targeted volume of the nidus.

Purpose : We present a comparative planning of different approaches for external radiotherapy in age-related maculopathies. Materials and methods : Calculated dose distributions and dose–volume histograms for (a) bilateral irradiation with 6 MV photons, (b) a single lateral-oblique beam using either photons, electrons or protons and (c) an anterior circular proton beam. Results : For lateral photon or electron beams the dose to the lens is usually lower than 10% of the dose to the macula. The entrance doses for bilateral photon beams are about 50% which increase up to 100% at the orbital bone. About 5 mm of optic nerves are irradiated at the maximal dose while the optic chiasma is spared. A single photon beam gives 50% of the dose to the fellow eye. The electron beam spares the fellow eye but gives a rather inhomogeneous dose to the target volume. For a lateral proton beam, 4 mm of optic nerve receives 90% of the dose, the skin dose is at least 70% of the dose to the macula and the lens and the fellow eye are spared. An anterior proton beam gives 90% of the dose to 1 mm of optic nerve and the 50% isodose approaches the periphery of the lens. Conclusion : Doses to the critical structures can be dramatically diminished for all the techniques by reducing the beam size, but only if very precise set-up techniques are used. Proton beams are an attractive solution, but the impact of such a choice on the use of proton facilities and on the national health system should be carefully evaluated, as well as the risk of radio-induced secondary neoplasias.

Resume But de l'etude Analyse retrospective des resultats preliminaires du traitement par protons du melanome de la choroide au centre de protontherapie d'Orsay. Patients et methodes Entre septembre 1991 et septembre 1995, 612 patients atteints de melanome malin de la choroide ont ete traites par protons a Orsay. Les elements du bilan initial des 464 premiers patients ont ete analyses, ainsi que les resultats de 305 patients a 1 an de suivi, de 1 69 patients a 2 ans de suivi et de 59 patients a trois ans de suivi. Resultats L'analyse unifactorielle a montre que le taux actuariel de recidive locale est de 5 %, le taux de survie a 3 ans de 88 % et le taux brut de metastases de 5 %. Cette analyse a aussi montre que le volume tumoral initial est le facteur qui a le plus influence le resultat visuel et le risque de metastase. L'analyse multifactorielle a montre une correlation significative entre le resultat visuel et le volume tumoral initial, la presence initiale d'un decollement de la retine et la dose totale delivree au nerf optique et a la macula. Conclusion La protontherapie du melanome de la choroide permet, dans la plupart des cas, une conservation oculaire sans modification de la survie. Le resultat visuel depend avant tout du siege et du volume de la tumeur.

Purpose To compare treatment planning between combined photon–proton planning (CP) and proton planning (PP) for skull base tumors, so as to assess the potential limitations of CP for these tumors. Methods and Materials Plans for 10 patients were computed for both CP and PP. Prescribed dose was 67 cobalt Gray equivalent (CGE) for PP; 45 Gy (photons) and 22 CGE (protons) for CP. Dose–volume histograms (DVHs) were calculated for gross target volume (GTV), clinical target volume (CTV), normal tissues (NT), and organs at risk (OARs) for each plan. Results were analyzed using DVH parameters, inhomogeneity coefficient (IC), and conformity index (CI). Results Mean doses delivered to the GTVs and CTVs with CP (65.0 and 61.7 CGE) and PP (65.3 and 62.2 Gy CGE) were not significantly different ( p > 0.1 and p = 0.72). However, the dose inhomogeneity was drastically increased with CP, with a mean significant incremental IC value of 10.5% and CP of 6.8%, for both the GTV ( p = 0.01) and CTV ( p = 0.04), respectively. The CI 80% values for the GTV and CTV were significantly higher with PP compared with CP. Compared with CP, the use of protons only led to a significant reduction of NT and OAR irradiation, in the intermediate-to-low dose (≤80% isodose line) range. Conclusions These results suggest that the use of CP results in levels of target dose conformation similar to those with PP. Use of PP significantly reduced the tumor dose inhomogeneity and the delivered intermediate-to-low dose to NT and OARs, leading us to conclude that this treatment is mainly appropriate for tumors in children.