J.-L. Habrand

Combined Proton and Photon Conformal Radiotherapy for Intracranial Atypical and Malignant Meningioma

PURPOSEnTo evaluate retrospectively the efficacy of conformal fractionated radiotherapy combining proton and photon beams after primary surgery for treatment of atypical and malignant meningiomas.nnnPATIENTS AND METHODSnBetween September 1999 and October 2006, 24 patients (12 male, 12 female) with histopathologically proven meningioma (atypical 19, malignant 5) received postoperative combined radiotherapy with a 201-MeV proton beam at the Centre Protontherapie dOrsay and a high-energy photon beam. Six patients underwent gross total resection and 18 a subtotal resection. Median gross tumor volume and clinical target volume were 44.7 cm(3) and 153.3 cm(3), respectively. Mean total irradiation dose was 65.01 CGE (cobalt gray equivalent), with a mean proton total dose of 34.05 CGE and a mean photon total dose 30.96 CGE.nnnRESULTSnThe median (range) follow-up interval was 32.2 (1-72) months. The overall mean local relapse-free interval was 27.2 (10-50) months, 28.3 (10-50) months for atypical meningioma and 23 (13-33) months for malignant meningioma. Ten tumors recurred locally. One-, 2-, 3-, 4-, 5-, and 8- year local control rates for the entire group of patients were 82.9% +/- 7.8%, 82.9% +/- 7.8%, 61.3% +/- 11%, 61.3% +/- 11%, 46.7% +/- 12.3%, and 46.7% +/- 12.3%, respectively. One-, 2-, 3-, 4-, 5-, and 8- year overall survival rates were 100%, 95.5% +/- 4.4%, 80.4% +/- 8.8%, 65.3% +/- 10.6%, 53.2% +/- 11.6%, and 42.6% +/- 13%, respectively. Survival was significantly associated with total dose. There was no acute morbidity of radiotherapy. One patient developed radiation necrosis 16 months after treatment.nnnCONCLUSIONSnPostoperative combination of conformal radiotherapy with protons and photons for atypical and malignant meningiomas is a well-tolerated treatment producing long-term tumor stabilization.

Proton Therapy in Pediatric Skull Base and Cervical Canal Low-Grade Bone Malignancies

PURPOSEnTo evaluate outcomes and tolerance of high-dose photon and proton therapy in the management of skull base and cervical canal primary bony malignancies in children.nnnPATIENTS AND METHODSnThirty children were treated postoperatively with high-dose photon-proton (29 patients) or protons-only (1 patient) radiotherapy. Twenty-six patients had chordomas (CH), 3 had low-grade chondrosarcomas (CS), and 1 had an aggressive chondroma (AC). The mean age was 12.8 years. At the time of radiation, all but 1 patient had a gross residue. The anatomic sites affected were skull base (n = 16), cervical canal (n = 1), or both (n = 13). Mean total dose was 68.4 cobalt Gray equivalents, conventionally fractionated.nnnRESULTSnWith a mean follow-up of 26.5 months, 5 of 30 children failed locally: 5 of 5 lesions were CH, 5 of 5 patients had experienced pain at presentation (p = 0.03), and 4 of 5 had cervical extension (p = 0.07). The 5-year overall survival/progression-free survival rates for CS and CH were 100%/100% and 81%/77%, respectively. Side effects were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Acute toxicity ranged between 0 and 2. Late toxicity of radiotherapy was severe in 1 patient (Grade 3 auditory) and minor or mild in the rest of the population (7 patients with Grade 2 pituitary dysfunction).nnnCONCLUSIONSnHigh-dose combined fractionated photon-proton therapy is well tolerated in children and allows excellent local control with minimal long-term toxicity.

Résultats préliminaires de la protonthérapie du mélanome de la choroïde au centre de protonthérapie d'Orsay (CPO): Les 464 premiers cas

Resume But de letude Analyse retrospective des resultats preliminaires du traitement par protons du melanome de la choroide au centre de protontherapie dOrsay. 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 Lanalyse 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. Lanalyse multifactorielle a montre une correlation significative entre le resultat visuel et le volume tumoral initial, la presence initiale dun 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.

Positron Emission Tomography/Computed Tomography Imaging of Residual Skull Base Chordoma Before Radiotherapy Using Fluoromisonidazole and Fluorodeoxyglucose: Potential Consequences for Dose Painting

PURPOSEnTo 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.nnnPATIENTS AND METHODSnSeven 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.nnnRESULTSnOf 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).nnnCONCLUSIONnFMISO 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.

Tolérance à l'irradiation des tissus sains: moelle épinière

Radiation myelopathy is one of the most dreadful complications of radiation therapy. Despite multiple animal experiments and human autopsic series, its pathogenesis remains largely unknown. In most instances, the classical aspect of myelomalacy combines glial and vascular injuries in various sequences. Recent studies point out the role of oligodendrocytes and their precusors, as well as of intercellular mediators (cytokines and stress molecules). The clinical presentation comprises a spectrum of non specific neurological symptoms whose evolution is sometimes regressive but more commonly progressive and life-threatening. Usually, it occurs following a latent period of six months to two years after irradiation of the cervical, thoracic or upper lumbar spine to a dose in excess of 50 Gy, conventionally fractionated. Nonetheless, these typical features can be altered by extrinsic factors, such as hypofractionation/acceleration of the dose, multiple surgical procedures, chemotherapy especially megatherapy, or neurotoxic drugs. Conversely, hyperfractionated regimens that take into account protracted half-time repair of sublethal damages to the CNS, as well as sophisticated estimates of the dose to the cord and QA programs during the treatment course minimize such risks.

La protonthérapie : bases, indications et nouvelles technologies

With over 70,000 patients treated worldwide, protontherapy has an evolution on their clinical applications and technological developments. The ballistic advantage of the Bragg peak gives the possibility of getting a high conformation of the dose distribution to the target volume. Protontherapy has accumulated a considerable experience in the management of selected rare malignancies such as uveal melanomas and base of the skull chordomas and chondrosarcomas. The growing interest for exploring new and more common conditions, such as prostate, lung, liver, ENT, breast carcinomas, as well as the implementation of large pediatric programs advocated by many experts has been challenged up to now by the limited access to operational proton facilities, and by the relatively slow pace of technical developments in terms of ion production, beam shaping and modelling, on-line verification etc. One challenge today is to deliver dynamic techniques with intensity modulation in clinical facilities as a standard treatment. We concentrate in this paper on the evolution of clinical indications as well as the potentialities of new technological concepts on ion production, such as dielectric walls and laser-plasma interactions. While these concepts could sooner or later translate into prototypes of highly compact equipments that would make easier the implantation of cost-effective hospital-based facilities, the feasibility of their clinical use must still be proved.

Évolution des indications cliniques en hadronthérapie 2008–2012

Hadrontherapy, a type of radiation therapy dealing with heavy charged particles, has become for the past decade one of the most sophisticated and attractive approach in the management of cancer. This is related with major technological innovations that have made available, at a relatively cheap cost, compact proton accelerators equipped with rotational gantries. The implementation of pencil beam scanning should also make treatment planning and delivery much easier and faster than conventional approaches. Until now, approximately 100,000 patients have been treated with protons worldwide. Due to more complex technological and biological challenges, light ion therapy - mainly carbon ions - has developed at a lower pace, except in Japan where most of the 15,000 treated patients have been enrolled. Current indications for protons include firstly, locally aggressive tumours non or incompletely resected, that are located close to critical normal structures: ocular melanomas, skull base and spinal canal low grade sarcomas, selected ENT carcinomas (like adenoid cystic); secondly, improvement of tolerance to radiations: delayed, mainly in paediatric malignancies, due to the exquisite sensitivity of organs under development (including to carcinogenesis); immediate, on bone marrow, mucosae… mainly in concomitant radiation-chemotherapy interactions (tested in esophagus, and lung). Most promising indications for carbon ions include inoperable highly radioresistant primaries, such as mucosal melanomas, high grade bone and soft part sarcomas, and pancreatic carcinomas. Altered fractionations are also of interests that could translate in clinical and economical benefits. Controversies have risen whether more common indications, like prostate, should also be explored.

Chordoma in children: Case-report and review of literature

We report an exceptional case of a very late local failure in a 9-year-old boy presenting with a chordoma of the cranio-cervical junction. The child was initially treated with a combination of surgical resection followed by high dose photon-proton radiation therapy. This aggressive therapy allowed a 9-year remission with minimal side-effects. Unfortunately, he subsequently presented with a local failure managed with a second full-dose course of protons. The child died one year later from local bleeding of unclear etiology.

Reprint of “Chordoma in children: Case-report and review of literature” ☆

We report an exceptional case of a very late local failure in a 9-year-old boy presenting with a chordoma of the cranio-cervical junction. The child was initially treated with a combination of surgical resection followed by high dose photon-proton radiation therapy. This aggressive therapy allowed a 9-year remission with minimal side-effects. Unfortunately, he subsequently presented with a local failure managed with a second full-dose course of protons. The child died one year later from local bleeding of unclear etiology.

Investigation of ectopic recurrent skull base and cervical chordomas: The Institut Curie's proton therapy center experience

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).