V. Calugaru

Radiobiological Characterization of Two Therapeutic Proton Beams With Different Initial Energy Spectra Used at the Institut Curie Proton Therapy Center in Orsay

PURPOSE Treatment planning in proton therapy uses a generic value for the relative biological efficiency (RBE) of 1.1 throughout the spread-out Bragg peak (SOBP) generated. In this article, we report on the variation of the RBE with depth in the SOBP of the 76- and 201-MeV proton beams used for treatment at the Institut Curie Proton Therapy Center in Orsay. METHODS AND MATERIALS The RBE (relative to (137)Cs γ-rays) of the two modulated proton beams at three positions in the SOBP was determined in two human tumor cells using as endpoints clonogenic cell survival and the incidence of DNA double-strand breaks (DSBs) as measured by pulse-field gel electrophoresis without and with enzymatic treatment to reveal clustered lesions. RESULTS The RBE for induced cell killing by the 76-MeV beam increased with depth in the SOBP. However for the 201-MeV protons, it was close to that for (137)Cs γ-rays and did not vary significantly. The incidence of DSBs and clustered lesions was higher for protons than for (137)Cs γ-rays, but did not depend on the proton energy or the position in the SOBP. CONCLUSIONS Until now, little attention has been paid to the variation of RBE with depth in the SOBP as a function of the nominal energy of the primary proton beam and the molecular nature of the DNA damage. The RBE increase in the 76-MeV SOBP implies that the tumor tissues at the distal end receives a higher biologically equivalent dose than at the proximal end, despite a homogeneous physical dose. This is not the case for the 201-MeV energy beam. The precise determination of the effects of incident beam energy, modulation, and depth in tissues on the linear energy transfer-RBE relationship is essential for treatment planning.

Chondromyxoid fibroma of the skull base: Differential diagnosis and radiotherapy. Two case reports and a review of the literature

Chondromyxoid fibromas are uncommon tumours mostly arising in long bones of young males. Involvement of the skull base is extremely rare. We describe two new cases of base of the skull chondromyxoid fibromas. The tumours were incompletely excised and irradiated with protons because of the high risk of complications of another surgical procedure. The rationale for proton therapy was based on the intimate relations between the tumour and the organs at risk. Skull base chondromyxoid fibroma is a very rare, slowly growing benign tumour that can cause severe disabilities due to tumour compression of critical structures. Only surgical resection has been shown to be relatively effective. We report two cases of incompletely excised lesions treated by postoperative high-dose radiation including proton therapy with no active disease and complication. Our review of the literature allows us to conclude that histological diagnosis of lesions in this site is a trap for pathologists and that radiotherapy is not contraindicated.

Chondrosarcomas of the base of the skull in Ollier's disease or Maffucci's syndrome Three Case Reports and Review of the Literature

Olliers disease is a rare disease characterized by constitutional bone dysplasia with multiple enchondromas. The combination of haemangioma and chondromatoses is known as Maffuccis syndrome. Malignant degeneration of bone dysplasia into chondrosarcoma is a well-known complication, but a lesion of the base of the skull is exceptional. It is a slowly growing low-grade malignant tumour. Three new cases of chondrosarcoma of the base of the skull occurring in one patient with Marfuccis syndrome and two patients with Olliers disease are reported and these cases are discussed in the light of the literature. A multidisciplinary approach, comprising surgery and radiotherapy, achieved good results.

Efficacy and Safety of Adjuvant Proton Therapy Combined With Surgery for Chondrosarcoma of the Skull Base: A Retrospective, Population-Based Study

PURPOSE 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). METHODS AND MATERIALS 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. RESULTS 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, age <40 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. CONCLUSIONS 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.

Role of chemotherapy and molecularly targeted agents in the treatment of adenoid cystic carcinoma of the lacrimal gland

Adenoid cystic carcinoma (ACC) is the most common malignant epithelial cancer of the lacrimal gland. Despite a slow rate of growth, ACCs are ultimately associated with poor clinical outcome. Given the rarity of this disease, most recommendations regarding therapy are guided by expert opinion and retrospective data rather than level 1 evidence. Surgery and postoperative radiation therapy are commonly used as initial local treatment. In patients at high risk of recurrence, concomitant platinum-based chemotherapy may be added to postoperative radiotherapy in an attempt to enhance radio-sensitivity. While encouraging responses have been reported with intra-arterial neoadjuvant chemotherapy, this strategy is associated with substantial toxicity and should be considered investigational. For patients with metastatic disease not amenable to surgery or radiotherapy, chemotherapy may have a role based on its modest efficacy in non-lacrimal ACC. Similarly, molecular targeted agents may have a role, although the agents tested to date in non-lacrimal ACC have been disappointing. A better understanding of the biology of ACC will be crucial to the future success of developing targeted agents for this disease.

Use of gEUD for predicting ear and pituitary gland damage following proton and photon radiation therapy

OBJECTIVE To determine the relationship between the dose to the inner ear or pituitary gland and radiation-induced late effects of skull base radiation therapy. METHODS 140 patients treated between 2000 and 2008 were considered for this study. Hearing loss and endocrine dysfunction were retrospectively reviewed on pre- and post-radiation therapy audiometry or endocrine assessments. Two normal tissue complication probability (NTCP) models were considered (Lyman-Kutcher-Burman and log-logistic) whose parameters were fitted to patient data using receiver operating characteristics and maximum likelihood analysis. The method provided an estimation of the parameters of a generalized equivalent uniform dose (gEUD)-based NTCP after conversion of dose-volume histograms to equivalent doses. RESULTS All 140 patients had a minimum follow up of 26 months. 26% and 44% of patients experienced mild hearing loss and endocrine dysfunction, respectively. The fitted values for TD50 and γ50 ranged from 53.6 to 60.7 Gy and from 1.9 to 2.9 for the inner ear and were equal to 60.6 Gy and 4.9 for the pituitary gland, respectively. All models were ranked equal according to Akaikes information criterion. CONCLUSION Mean dose and gEUD may be used as predictive factors for late ear and pituitary gland late complications after skull base proton and photon radiation therapy. ADVANCES IN KNOWLEDGE In this study, we have reported mean dose effects and dose-response relationship of small organs at risk (partial volumes of the inner ear and pituitary gland), which could be useful to define optimal dose constraints resulting in an improved therapeutic ratio.

Nanoparticules et radiothérapie

BACKGROUND Nanoparticles have emerged in oncology as new therapeutic agents of distinct biochemical and physical properties, and pharmacokinetics. Current rationale and clinical applications in combination with radiation therapy were analyzed. MATERIAL AND METHODS A review of the literature was conducted on nanoparticles as radiosensitizers, with a focus on metallic nanoparticles and radiosensitization mechanisms. RESULTS Nanoparticles are mainly used as vectors for drugs or to potentiate dose deposit selectively in irradiated tissues. Preclinical data suggest a predominating effect in the kilovoltage range through a photoelectric effect and a potential in the megavoltage range under a combination of physical and biochemical (diameter, concentration, site of infusion etc) conditions. Several clinical trials are ongoing with metallic/crystalline nanoparticles. CONCLUSION Nanoparticles have shown a potential for better therapeutic index with radiation therapy, which is being increasingly investigated clinically.

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.

Clinical complementarities between proton and carbon therapies.

Protons are characterised by low LET, but compared with photons and electrons have an improved physical depth dose distribution. Some indications for protons, i.e., ocular melanoma, chordoma and chondrosarcoma of the base of skull or cervical spine, are now accepted by the radiation oncology community as the treatment of choice. Others are still under evaluation, e.g. meningioma, locally advanced nasopharynx tumours, paediatric tumours. Neutrons have the biological advantage of a high LET, but their distribution of dose is in most cases suboptimal. Despite this, there are radiobiological arguments leading to expect that neutrons might be of some benefit in patients with tumours that are resistant to photons, slowly growing or containing a high proportion of hypoxic cells. There is some clinical evidence or rationale for a potential high LET advantage for locally extensive (I think that the current (jargon) word is extended in English..) salivary gland tumours, locally extensive(extended) prostate carcinoma, slowly growing inoperable soft tissue sarcoma, adenocarcinoma, adenoid cystic carcinoma of the paranasal sinuses, melanoma and rectal carcinoma. Light ions combine the high LET advantage of neutrons and the improved physical depth dose distribution of protons. The opportunity offered by an optimised distribution of dose should open a new era for high-LET particles, especially in deeply situated x-ray resistant tumours, where the use of neutron beams was restricted by the low quality of their depth-dose profiles. Preliminary results are encouraging.

SynthèseNanoparticules et radiothérapieNanoparticles and radiation therapy

BACKGROUND Nanoparticles have emerged in oncology as new therapeutic agents of distinct biochemical and physical properties, and pharmacokinetics. Current rationale and clinical applications in combination with radiation therapy were analyzed. MATERIAL AND METHODS A review of the literature was conducted on nanoparticles as radiosensitizers, with a focus on metallic nanoparticles and radiosensitization mechanisms. RESULTS Nanoparticles are mainly used as vectors for drugs or to potentiate dose deposit selectively in irradiated tissues. Preclinical data suggest a predominating effect in the kilovoltage range through a photoelectric effect and a potential in the megavoltage range under a combination of physical and biochemical (diameter, concentration, site of infusion etc) conditions. Several clinical trials are ongoing with metallic/crystalline nanoparticles. CONCLUSION Nanoparticles have shown a potential for better therapeutic index with radiation therapy, which is being increasingly investigated clinically.