Limited applicability and implementation of the international oncology treatments guidelines in low- and middle-income countries, an example from the Mediterranean area borders.

The quality of cancer care in the modern era is based on a precise diagnosis and personalized therapy according to patients and their disease based on validated guidelines with a high level of evidence. During cancer patients' management, the objective is first to make an accurate diagnosis and then offer the best treatment, validated beforehand in a multidisciplinary board meeting, with the best benefit/risk ratio. In the context of many low- and middle-income countries, the limited available means do not allow an adequate offer, resulting in non-optimal patients' care. In addition, in many low- and middle-income countries, priority can be given to other types of disease than cancer, which may considerably reduce allocation of specific resources to cancer care. Thus, the limited availability of systemic therapy, radiotherapy machines, brachytherapy and technological development may come up against another difficulty, that of geographical distribution of the means in the countries or a lack of expertise due to insufficient training programs. For all these reasons, the implementation of the guidelines established in Western countries could be impossible for many low- and middle-income countries which, moreover, have to face a completely different epidemiology of cancers compared to developed countries. In this work, we will discuss through a few examples of common cancers on both borders of the Mediterranean area, the applicability of the guidelines and the limits of their implementation for optimal cancer care.

Conformal radiotherapy in management of soft tissue sarcoma in adults.

We present the update of the recommendations of the French society of radiation oncology on soft tissue sarcomas. Currently, the initial management of sarcomas is very important as it may impact on patients' quality of life, especially in limb soft tissue sarcomas, and on overall survival in trunk sarcomas. Radiotherapy has to be discussed within a multidisciplinary board meeting with results of biopsy, eventually reexamined by a dedicated sarcoma pathologist. The role of radiotherapy varies according to localization of soft tissue sarcoma. It is part of the standard treatment in grade 2 and 3 sarcomas of the extremities and superficial trunk>5cm. In case of R1 or R2 resection, reexcision should be discussed. In such cases, it may be delivered preoperatively (50Gy/25 fractions of 2Gy) or postoperatively. In retroperitoneal sarcomas, preoperative conformal radiotherapy with or without modulated intensity cannot be proposed systematically in daily practice. Concomitant chemoradiotherapy cannot be considered a standard treatment. Intensity-modulated radiotherapy has become widely available. Other soft tissue sarcoma sites such as trunk, head and neck and gynaecological soft tissue sarcomas will be addressed, as well as other techniques that may be used such as brachytherapy and proton therapy.

Radiotherapy for nasopharyngeal cancer.

Nasopharyngeal cancers are a rarity in France. Radiotherapy is the cornerstone of treatment, frequently combined with chemotherapy. The technical modality of radiotherapy is complex in this disease, which is located in the vicinity of numerous organs at risk. In this article, we will present the updated guidelines of the French society for radiation oncology (Société française de radiothérapie oncologique, SFRO) on the indications, and technical details of radiotherapy in nasopharyngeal cancers.

Radiotherapy for oral cavity cancers.

Intensity modulated radiation therapy and brachytherapy are standard techniques of irradiation for the treatment of oral cavity cancers. These techniques are detailed in terms of indication, planning, delineation and selection of the volumes of interest, dosimetry and patients positioning control. This is an update of the guidelines of the French Society of Radiotherapy Correspondence.

Automation in radiotherapy treatment planning: Examples of use in clinical practice and future trends for a complete automated workflow.

Modern radiotherapy treatment planning is a complex and time-consuming process that requires the skills of experienced users to obtain quality plans. Since the early 2000s, the automation of this planning process has become an important research topic in radiotherapy. Today, the first commercial automated treatment planning solutions are available and implemented in a growing number of clinical radiotherapy departments. It should be noted that these various commercial solutions are based on very different methods, implying a daily practice that varies from one center to another. It is likely that this change in planning practices is still in its infancy. Indeed, the rise of artificial intelligence methods, based in particular on deep learning, has recently revived research interest in this subject. The numerous articles currently being published announce a lasting and profound transformation of radiotherapy planning practices in the years to come. From this perspective, an evolution of initial training for clinical teams and the drafting of new quality assurance recommendations is desirable.

Time of PTV is ending, robust optimization comes next.

Continuous improvements have been made in the way to prescribe, record and report dose distributions since the therapeutic use of ionizing radiations. The international commission for radiation units and measurement (ICRU) has provided a common language for physicians and physicists to plan and evaluate their treatments. The PTV concept has been used for more than two decades but is becoming obsolete as the CTV-to-PTV margin creates a static dose cloud that does not properly recapitulate all planning vs. delivery uncertainties. The robust optimization concept has recently emerged to overcome the limitations of the PTV concept. This concept is integrated in the inverse planning process and minimizes deviations to planned dose distribution through integration of uncertainties in the planning objectives. It appears critical to account for the uncertainties that are specific to protons and should be accounted for to better exploit the clinical potential of proton therapy. It may also improve treatment quality particularly in hypofractionated photon plans of mobile tumors and more widely to photon radiotherapy. However, in contrast to the PTV concept, a posteriori evaluation of plan quality, called robust evaluation, using error-based scenarios is still warranted. Robust optimization metrics are warranted. These metrics are necessary to compare PTV-based photon and robustly optimized proton plans in general and in model-based NTCP approaches. Assessment of computational demand and approximations of robust optimization algorithms along with metrics to evaluate plan quality are needed but a step further to better prescribe radiotherapy may has been achieved.

Do all the linear accelerators comply with the ICRU 91's constraints for stereotactic body radiation therapy treatments?

Recent technological developments in linear accelerators (linacs) and their imaging systems have made it possible to routinely perform stereotactic radiotherapy (SRT) treatments. To ensure the security and quality of the treatments, national and international recommendations have been written. This review focuses on the recommendations of the report 91 of the International Commission on Radiation Units (ICRU) on stereotactic treatments with small photon beams and proposes to answer the question of the eligibility of the commercially available accelerators for the treatment of extra-cranial SRT (SBRT). The ICRU 91 report outlines important features needed to respect the constraints, which are high intensity photon beam, integrated image-guidance, high mechanical accuracy of the linac, multileaf collimator with reduced leaf width, bundled motion management and bundled 6 Dimensional "robotic" couch tabletop. Most of the contemporary linacs meet these recommendations, in particular, stereotactic dedicated linacs, or modern gantry-based linacs equipped with 3 dimensional cone-beam CT imaging and 2D-stereoscopic planar imaging. Commercially available ring-based linacs have some limitations: they offer only coplanar treatments, and couch movements are limited to translations and, some have limited imaging equipment and no ability to manage intrafraction motion. However, for performing SBRT, non-coplanar irradiations are not mandatory, contrarily to intracranial stereotactic irradiations. Furthermore, patients' rotations can be corrected, thanks to real-time adaptive radiotherapy available on MRI-linacs. Finally, significant improvements are expected in the short term to compensate the weaknesses of the current devices.

Volumetric and dosimetric comparison of two delineation guidelines for the radiation treatment of laryngeal squamous cell carcinoma.

PURPOSE: Three methods have been recently proposed for the delineation of the primary tumor clinical target volume (CTV-P) in Head and Neck Cancers: the anatomic method popularized in the French literature by Lapeyre et al. the geometric methods proposed by the DAHANCA group, and more recently the international guidelines promoted by Grégoire et al. integrating the latter two. The aim of this study was to perform a volumetric and dosimetric comparison of the French and the International consensus methods in laryngeal SCC. PATIENTS AND METHODS: Two radiation oncologists independently delineated the high dose and low dose primary tumor CTV in four patients with T2 or T3 N0-M0 laryngeal SCC following either the so-called French guidelines or the International guidelines. For the 4 cases, the GTV was delineated by a single radiation oncologist. Nodal CTVs were delineated by one radiation oncologist for the 4 cases using International guidelines. Dose optimization was then performed with VMAT (MONACO version 5.11) using 6 MeV photons. Differences in target volumes and dose distributions in OARs and PTVs were then evaluated with various metrics such as the DICE Similarity Coefficient and the homogeneity index. RESULTS: Major differences were observed in the CTV delineation between the 2 delineation methods for the low dose volumes and to a lower extend for the high dose volumes. These differences translated into variations in dose distribution favoring the International guidelines for decreasing dose to various OARs. Such differences toned down when dose distribution on the primary tumors PTVs and nodal PTVs were combined. CONCLUSION: This study demonstrated large differences in CTV delineation between the 2 delineation guidelines. Such differences translated into differences in dose distribution.

[Impact of dynamic IMRT and tomotherapy in pelvic cancers: a prospective dosimetric study with 51 patients]. / Apport de la RCMI rotationnelle et de la tomothérapie hélicoïdale dans les cancers pelviens : étude dosimétrique prospective sur 51 patients.

PURPOSE: To compare the dosimetric results of different techniques of dynamic intensity modulated radiation therapy (IMRT) in patients treated for a pelvic cancer with nodal irradiation. PATIENTS AND METHODS: Data of 51 patients included prospectively in the Artpelvis study were analyzed. Thirty-six patients were treated for a high-risk prostate cancer (13 with helical tomotherapy, and 23 with Rapid'Arc(®)) and 15 patients were treated for a localized anal cancer (nine with helical tomotherapy and six with Rapid'Arc(®)). Plan quality was assessed according to several different dosimetric indexes of coverage of planning target volume and sparing of organs at risk. RESULTS: Although some dosimetric differences were statistically significant, helical tomotherapy and Rapid'Arc provided very similar and highly conformal plans. Regarding organs at risk, Rapid'Arc(®) provided better pelvic bone sparing with a lower non-tumoral integral dose. CONCLUSION: In pelvis cancer with nodal irradiation, Rapid'Arc and helical tomotherapy provided very similar plans. The clinical evaluation of Artpelvis study will verify this equivalence hypothesis.

[Localized Ewing sarcoma of the spine: a preliminary dose-escalation study comparing innovative radiation techniques in a single patient]. / Sarcomes d'Ewing localisés du rachis chez l'enfant : étude préliminaire d'escalade de dose comparant les techniques innovantes.

PURPOSE: Although radiosensitive, spinal locations of Ewing's sarcomas are challenging for the radiation oncologist due to poor radiation tolerance of the spinal cord. However, some favorable anatomical compartments - that may represent more than 20% - were associated with a better outcome and could benefit from a radiation dose escalation using the most recent radiation therapy techniques. MATERIALS AND METHODS: We performed a dose escalation study on one patient, declined in two scenarios: (1) a tumour located within a single vertebral body and (2) a locally advanced disease involving the vertebral foramen and paraspinal soft tissues. Five dose-levels are proposed: 44.8Gy, 54.4Gy, 59.2Gy, 65.6Gy and 70.4Gy (1.6Gy per session, 8Gy per week). The 3D-conformational technique is compared with static intensity modulated radiation therapy (IMRT), helical tomotherapy, volumetric modulated arc therapy (VMAT), stereotactic body robotic radiation therapy (SBRT) and protontherapy (passive scattering). Two constraints had to be respected in order to skip to the next level: the planned target volume (PTV) coverage must exceed 95% and the D(2%) on the spinal cord shall not exceed a given constraint set at 50Gy in case 1 and 44Gy in case 2 due to initial neurological sufferance. RESULTS: Only protontherapy, SBRT, helical tomotherapy and VMAT appear able to reach the last dose level while respecting the constraints in case 1. On the other hand, only helical tomotherapy seems capable of reaching 59.2Gy on the PTV in case 2. CONCLUSION: With the most recent radiation therapy techniques, it becomes possible to deliver up to 70.4Gy in a favorable compartment in this sham patient. Unfavorable compartments can receive up to 59.2Gy. Definitive radiation therapy may be an interesting local treatment option to be validated in an early phase trial.

[Nasopharyngeal cancer]. / Cancers du cavum de l'adulte.

The main objective of this work was to propose recommendations concerning the delineation of the target volume of the nasopharyngeal cancers, the planification of the treatment, and describe the expected results about the efficacity and the toxicities. Theses recommendations are based upon anatomy, natural history of theses tumors, and upon published experiences from different teams working with IMRT.

Heavy element enhanced synchrotron stereotactic radiotherapy as a promising brain tumour treatment.

Synchrotron stereotactic radiotherapy (SSR) is a treatment that involves selective accumulation of high-Z elements in tumours followed by stereotactic irradiation, in CT mode, with monochromatic X-rays from a synchrotron source, tuned at an optimal energy. The irradiation geometry, characteristic X-rays, photoelectrons, and Auger electrons generated on high-Z atoms by kilovoltage X-rays produce a localized dose enhancement. Two complimentary SSR approaches have been successfully developed in the past 5 years in our team, and may be promising in high-grade glioma management: iodine-enhanced SSR, with an iodinated contrast agent; and Pt-enhanced SSR; a concomitant radio-chemotherapy treatment with locoregional injection of platinated chemotherapy drugs. The results for iodine-enhanced SSR using contrast agents are presented in this paper. IUdR-enhanced SSR was also tested in this study. Up to 15 Gy, intracarotid infusion of iodine significantly improved the rats' survival compared to irradiation alone. SSR provides the most protracted survivals of F98 glioma-bearing rats. The technique is currently transferred to clinical trials. Iodine-enhanced SSR will be implemented first, because of its simplicity; and pave the way for Pt-enhanced SSR, the most efficient technique, but still needing to be improved in terms of intrinsic toxicity.

[The stereotactic body radiation therapy: initiation and clinical program]. / Principe et mise en oeuvre de la radiothérapie en conditions stéréotaxiques extracrânienne.

We fully describe an innovative radiotherapy technique called Stereotactic Body Radiation Therapy (SBRT), and explain how this technique is commonly used for clinical purpose at the anticancer center Léon-Bérard (Lyon, France). In this technique, a non-invasive stereotactic body frame is used to locate the tumor site with a great precision. This frame is combined with a system, which enables to track the respiratory motions (Active Breathing Control (ABC) or diaphragmatic compression (DC)) in order to reduce the treatment margins for organ motion due to breathing. Thus, the volume of normal tissues that will be irradiated is considerably reduced. The dosimetry is realized with 3 CT exams performed in treatment conditions. The 3D patient "repositioning" is done with a volume CT acquisition (kV) combined with orthogonal images (kV and MV). The SBRT requires a system to limit the organ motions. Although the ABC seems to be more fastidious for patient, it would enable to use smaller margins than with DC technique. Nevertheless, the ABC is not compatible with volume CT acquisitions, which considerably improve the patient repositioning. In conclusion, the quality of repositioning and the high level of conformation enable to deliver high equivalent doses (>100 Gy) in hypofractionated mode, without increasing the treatment toxicity. The SBRT employs the last technologic innovations in radiotherapy and is therefore considered as a new efficient tool for solid tumors treatment.

Lack of cell death enhancement after irradiation with monochromatic synchrotron X rays at the K-shell edge of platinum incorporated in living SQ20B human cells as cis-diamminedichloroplatinum (II).

In this paper we describe the results of experiments using synchrotron radiation to trigger the Auger effect in living human cancer cells treated with a widely used chemotherapy drug: cis-diamminedichloroplatinum (II) (cisplatin). The experiments were carried out at the ID17 beamline of the European Synchrotron Radiation Facility, which produces a high-fluence monochromatic beam that is adjustable from 20 to 80 keV. Cisplatin was chosen as the carrier of platinum atoms in the cells because of its alkylating-like activity and the irradiation was done with monochromatic beams above and below the platinum K-shell edge (78.39 keV). Cell survival curves were comparable with those obtained for the same cells under conventional irradiation conditions. At a low dose of cisplatin (0.1 microM, 48 h), no difference was seen in survival when the cells were irradiated above and below the K-shell edge of platinum. Higher cisplatin concentrations were investigated to enhance the cellular platinum content. The results with 1 microM cisplatin for 12 h showed no difference when the cells were irradiated with beams above or below the platinum K-shell edge with the exception of the higher cell death resulting from drug toxicity. The intracellular content of platinum was significant, as measured macroscopically by inductively coupled plasma mass spectrometry. Its subcellular localization and particularly its presence in the cell nucleus were verified by microscopic synchrotron X-ray fluorescence. This was the first known attempt at K-shell edge photon activation of stable platinum in living cells with a platinum complex used for chemotherapy. Its evident toxicity in these cells leads us to put forth the hypothesis that cisplatin toxicity can mask the enhancement of cell death induced by the irradiation above the K-shell edge. However, K-shell edge photon activation of stable elements provides a powerful technique for the understanding of the biological effects of Auger processes. Further avenues of development are discussed.