Régis Ferrand

Radiotherapeutic factors in the management of cervical-basal chordomas and chondrosarcomas.

OBJECTIVE:To define prognostic factors for local control and survival in 90 consecutive patients treated by fractionated photon and proton radiation for chordoma or chondrosarcoma of the cranial base and upper cervical spine. METHODS:Between December 1995 and December 2000, 90 patients (median age, 51.3 yr; range, 10–85 yr; male/female ratio, 3:2) were treated by a combination of high-energy photons and protons. Sixty-four patients had a chordoma, and 26 had a chondrosarcoma. The proton component was delivered by the 201-MeV proton beam of the Centre de Protonthérapie d’Orsay. The median total dose delivered to the gross tumor volume (GTV) was 67 cobalt Gray equivalents (range, 22–70 cobalt Gray equivalents). RESULTS:With a median follow-up of 34 months (range, 3–74 mo), treatment of 25 tumors failed locally. The 3-year local control rates were 69.2% (±6.0%) and 91.6% (±8.4%) for chordomas and chondrosarcomas, respectively. According to multivariate analysis, a small tumor volume excluded from the 95% isodose line (P = 0.032; relative risk [RR], 0.098; 95% confidence interval [CI], 0.01–0.81) and a controlled tumor (P = 0.049; RR, 0.19; 95% CI, 0.04–0.99) were independent favorable prognostic factors for overall survival. On multivariate analysis, a high minimum dose (P = 0.02; RR, 2.8; 95% CI, 1.2–6.6), a high tumor control probability (P = 0.02; RR, 3.8; 95% CI, 1.2–12.5), a high dose delivered to 95% of the GTV (P = 0.03; RR, 3.4; 95% CI, 1.15–10.2), a high GTV encompassed by the 90% isodose line (P = 0.01; RR, 3.29; 95% CI, 1.29–8.44), and a small GTV excluded from the 90% isodose line (P = 0.036; RR, 0.4; 95% CI, 0.1–0.9) were independent favorable prognostic factors for local control. CONCLUSION:In chordomas and chondrosarcomas of the cranial base and cervical spine treated by surgical resection and then by high-dose photon and proton irradiation, local control is mainly dependent on the quality of radiation, especially dose uniformity within the GTV. Special attention must be paid to minimize underdosed areas because of the close proximity of critical structures and to redefine and possibly escalate dose constraints to tumor targets in future studies in view of the low toxicity observed to date.

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

PURPOSE To 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. PATIENTS AND METHODS Thirty 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. RESULTS With 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). CONCLUSIONS High-dose combined fractionated photon-proton therapy is well tolerated in children and allows excellent local control with minimal long-term toxicity.

Experimental determination and verification of the parameters used in a proton pencil beam algorithm

We present an experimental procedure for the determination and the verification under practical conditions of physical and computational parameters used in our proton pencil beam algorithm. The calculation of the dose delivered by a single pencil beam relies on a measured spread-out Bragg peak, and the description of its radial spread at depth features simple specific parameters accounting individually for the influence of the beam line as a whole, the beam energy modulation, the compensator, and the patient medium. For determining the experimental values of the physical parameters related to proton scattering, we utilized a simple relation between Gaussian radial spreads and the width of lateral penumbras. The contribution from the beam line has been extracted from lateral penumbra measurements in air: a linear variation with the distance collimator-point has been observed. Analytically predicted radial spreads within the patient were in good agreement with experimental values in water under various reference conditions. Results indicated no significant influence of the beam energy modulation. Using measurements in presence of Plexiglas slabs, a simple assumption on the effective source of scattering due to the compensator has been stated, leading to accurate radial spread calculations. Dose measurements in presence of complexly shaped compensators have been used to assess the performances of the algorithm supplied with the adequate physical parameters. One of these compensators has also been used, together with a reference configuration, for investigating a set of computational parameters decreasing the calculation time while maintaining a high level of accuracy. Faster dose computations have been performed for algorithm evaluation in the presence of geometrical and patient compensators, and have shown good agreement with the measured dose distributions.

Monte Carlo modelling of the treatment line of the Proton Therapy Center in Orsay

This paper presents the main results of a Monte Carlo simulation describing the Orsay Proton Therapy Center (CPO) beam line. The project aimed to obtain a prediction of the dose distribution in a water phantom within 2% accuracy in the dose value and a 2 mm of range. The simulation tool used was MCNPX, version 2.5.0, and included all the elements of the CPO beam line. A new algorithm of multiple Coulomb scattering has been incorporated in MCNPX, resulting in a better prediction of the spatial dose distribution and absolute values of the deposited energy. The simulations of 3D dose profiles in water show a very good agreement with measured data to within 2%. We first performed a comparative analysis of the dosimetry in heterogeneous phantoms between the pencil beam algorithm and MCNPX. The simulations give a better agreement with experimental data compared to the pencil beam approach. In a second phase, we simulated the patient-dependent fields along with the spatial dose distributions in a water phantom. The simulated response of a Pixel chamber located 2 m upstream of the water phantom revealed a good agreement with the measured data to within 1%. The results presented herein support the applicability of Monte Carlo models for absolute dosimetry and for design purposes regarding existing and new beam lines at CPO. This work completes a series of publications reporting the progress in the development of a Monte Carlo simulation tool for the CPO beam line dedicated for the treatment of head and neck tumours.

A model for the lateral penumbra in water of a 200‐MeV proton beam devoted to clinical applications

An experimental approach for modeling the lateral penumbra of a proton beam has been investigated. Measurements were made with a silicon diode in a water tank. Several geometrical configurations (phantom position, collimator-to-surface distance, collimator diameter, bolus thickness, air gap, etc.) and beam characteristics (range, modulation, etc.) have been studied. The results show that the lateral penumbra is almost independent of the beam modulation and the diameter of the collimator. The use of scaled variables for depth and penumbra allows us to represent the increase in penumbra with depth for any configuration with a second order polynomial function, provided that the penumbra at the entrance of the medium and at the depth of the range are known.

Intraocular inflammation after proton beam irradiation for uveal melanoma

AIM To describe the inflammatory reaction that can occur following proton beam irradiation of uveal melanomas based on a large series of patients and to try to determine the risk factors for this reaction. METHODS Data from a cohort of patients with uveal melanoma treated by proton beam irradiation between 1991 and 1994 were analysed. The presence of inflammation was recorded and evaluated. Kaplan-Meier estimates and statistical analysis of general and tumour related risk factors were performed. RESULTS 28% of patients treated during this period presented with ocular inflammation (median follow up 62 months). Risks factors were essentially tumour related and were correlated with larger lesions (height > 5 mm, diameter > 12 mm, volume > 0.4 cm3). Multivariate analysis identified initial tumour height and irradiation of a large volume of the eye as the two most important risk factors. Ocular inflammation usually consisted of mild anterior uveitis, resolving rapidly after topical steroids and cycloplegics. The incidence of inflammation after proton beam irradiation of melanomas seems higher than previously reported and is related to larger lesions. Evidence of inflammation associated with uveal melanoma has been described and seems to be associated with tumour necrosis (spontaneous or after irradiation). The appearance of transient inflammation during the follow up of these patients may be related to the release of inflammatory cytokines during tumour necrosis. CONCLUSION Inflammation following proton beam irradiation is not unusual. It is correlated with larger initial tumours and may be related to tumour necrosis.

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

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.

Calibration of CT Hounsfield units for proton therapy treatment planning: use of kilovoltage and megavoltage images and comparison of parameterized methods

Proton beam range is of major concern, in particular, when images used for dose computations are artifacted (for example in patients with surgically treated bone tumors). We investigated several conditions and methods for determination of computed tomography Hounsfield unit (CT-HU) calibration curves, using two different conversion schemes. A stoichiometric methodology was used on either kilovoltage (kV) or megavoltage (MV) CT images and the accuracy of the calibration methods was evaluated. We then studied the effects of metal artifacts on proton dose distributions using metallic implants in rigid phantom mimicking clinical conditions. MV-CT images were used to evaluate relative proton stopping power in certain high density implants, and a methodology is proposed for accurate delineation and dose calculation, using a combined set of kV- and MV-CT images. Our results show good agreement between measurements and dose calculations or relative proton stopping power determination (<5%). The results also show that range uncertainty increases when only kV-CT images are used or when no correction is made on artifacted images. However, differences between treatment plans calculated on corrected kV-CT data and MV-CT data remained insignificant in the investigated patient case, even with streak artifacts and volume effects that reduce the accuracy of manual corrections.

Le traitement par neutrons : hadronthérapie partie II : bases physiques et expérience clinique

Neutrons have radiobiological characteristics, which differ from those of conventional radiotherapy beams (photons) and which offer a theoretical advantage over photons to fight radioresistance by the differential relative biological effect of them between normal and tumour tissues. Neutron therapy beneficed of great interest between 1975 and 1985. Many of phase III trials were conducted and indications have been definitively deducted of them. After briefly describing the properties of neutron beams, this review discusses the indication of neutron therapy on the basis of the clinical results. Salivary, prostate tumours and sarcomas are the main indications of neutron therapy. In concern to the prostate cancers, other alternative treatments reduce the neutron therapy field. For sarcomas, the lack of randomised trials limits the impact of the interest of neutrons. For other tumours, the ratio benefice/risk of neutron therapy is inferior to these obtained with photons and they could not be considered like classical indications.

Proton beam therapy (PT) in the management of CNS tumors in childhood.

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 persistant 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 radiaton-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.