Is single fraction the future of stereotactic body radiation therapy (SBRT)? A critical appraisal of the current literature.

Stereotactic Body Radiation Therapy (SBRT) is a standard of care for many localizations but the question of the optimal fractionation remains a matter of concern. If single fraction sessions are routinely used for intracranial targets, their utilization for mobile extracranial lesions is a source of debate and apprehension. Single session treatments improve patient comfort, provide a medico-economic benefit, and have proven useful in the context of the SARS-CoV 2 pandemic. However, both technical and radiobiological uncertainties remain. Experience from intracranial radiosurgery has shown that the size of the target, its proximity to organs at risk, tumor histology, and the volume of normal tissue irradiated are all determining factors in the choice of fractionation. The literature on the use of single fraction for extracranial sites is still scarce. Only primary and secondary pulmonary tumors have been evaluated in prospective randomized trials, allowing the integration of these fractionation schemes in daily practice, for highly selected cases and in trained teams. The level of evidence for the other organs is mainly based on dose escalation or retrospective trials and calls for caution, with further studies being needed before routine use in clinical practice.

[Extreme hypofractionation: New indications for breast cancer radiotherapy]. / Hypofractionnement extrême en pratique : les nouvelles indications dans les cancers du sein.

Due to the continuously increasing number of newly diagnosed breast cancer and limited health resources hypofractionated radiotherapy is a major topic. Recent results from randomized clinical trials assessing extreme hypofractionated radiotherapy for whole or partial breast radiotherapy are practice changing. Here we report toxicity and oncological outcomes from major recent trials of extreme hypofractionated breast irradiation and present an ongoing prospective implementation program. For whole breast irradiation, with a 10 years follow up, the UK-FAST trial demonstrated no significant difference in toxicity between a once weekly 5 fractions (5,7Gy/fr) regimen and a conventional 50Gy/25fr regimen. With a 5 years follow up, the FAST-Forward trial showed non inferiority on local control for a 5 fractions over 1 week (5,2Gy/fr) regimen versus standard 40Gy/15fr over 3 weeks with safe toxicity profile. For accelerated partial breast irradiation, in low-risk breast cancers patients, several phase III randomized trials confirmed that extreme hypofractionation is a valid option. With our "One Week Breast Radiotherapy" program, we propose the implementation of a one-week full workflow preparing and delivering 5 fractions over 1 week (26Gy) in selected patients with prospective follow-up. Several extreme hypofractionated breast radiotherapy regimens are validated and can be routinely discussed with patients in a share decision-making process following patient selection criteria and dosimetric constraints.

Efficacy of salvage stereotactic radiotherapy (SRT) for locally recurrent brain metastases after initial SRT and characteristics of target population.

OBJECTIVES: Due to a steadily growing use of stereotactic radiotherapy (SRT) for treatment of brain metastases (BMs), the in-field failure after an initial stereotaxy is an increasingly frequent problem. Repeat stereotactic radiotherapy (re-SRT) shows encouraging results in terms of local control. However, the evidence on prognostic factors limiting the overall survival (OS) of re-treated patients is scarce. Here, we sought to analyze the patients' and treatment characteristics influencing the survival outcomes after re-SRT. METHODS: Data of all patients with local failure of initial SRT treated from 2012 to 2019 were retrospectively reviewed and cases treated with salvage SRT were analyzed. We analyzed the impact of patients' and treatment characteristics on overall survival after re-SRT by Kaplan-Meier method and Cox regression models. Local and distant brain control, cause of death, and radionecrosis rate were also assessed. RESULTS: Forty-seven patients with 55 BMs treated with re-SRT were evaluated. Median OS after re-SRT was 9.2 months and the overall local control was 83.6%. Nine BMs (16.4%) presented local relapse (LR), 12 (21.8%) radionecrosis, while 21 patients (44.7%) developed new BMs. Only absence of extracranial metastases at BMs diagnosis (HR 0.42, CI 95%; 0.18-0.97), extracranial disease progression (HR 2.39, CI 95%; 1.06-5.38) and distant brain failure (HR 3.94, CI 95%; 1.68-9.24) after re-SRT were significantly associated with patients' survival. Extracranial progression following re-SRT was an independent prognosticator of worse OS. CONCLUSION: Re-SRT after LR presented excellent local control with acceptable RN rate and improved patients' survival, limited mainly by extracranial and distant brain progression.

Thermal-ablation of vertebral metastases prevents adverse events in patients with differentiated thyroid carcinoma.

PURPOSE: To evaluate a strategy that used thermal-ablation of vertebral metastases (VM) to prevent vertebral related events (VRE) in patients with differentiated thyroid cancer (DTC). METHODS: This single center study retrospectively reviewed records and post-operative imaging of all DTC patients treated with thermal-ablation for asymptomatic VMs. Rate of local tumor control at first post-operative imaging, 12 and 24 months after thermal-ablation and rate of VREs at 12 and 24 months among the treated VMs were reported. New VMs that occurred during the follow-up and were not considered for additional thermal-ablation were moniroted and VREs were reported. RESULTS: Thermal-ablation was used to achieve local control of 41 VMs in 28 patients. Median post-treatment follow-up was 22 months [range: 12-80] and the mean delay for first post-operative imaging was 2 months [range: 0.6-7.5]. Local control at first post-operative imaging, 12 and 24 months was achieved in 87.8%, 82.9% and 75.6%, respectively. Among the treated VMs the rates of VRE was 7.3% at 2 years, significantly lower if local control was achieved at first post-operative imaging than if it was not (0% vs 30%, p = 0.011, OR = 0.184 [95%CI = 0.094-0.360]). After thermal-ablation procedures, 19 news VMs occurred in 11 patients (39.2%) with a median interval of 8 months [range 1-26] and remained untreated. Among these untreated VMs, the rate of VREs at 2 years was significantly higher compared to the treated VMs: (36.8% vs. 7.3%, p = 0.008, OR = 0.135, [95%CI = 0.030-0.607]). CONCLUSION: local tumor control of VMs using thermal-ablation decreases the risk of VREs in DTC patients.

Reirradiation with concurrent bevacizumab for recurrent high-grade gliomas in adult patients.

PURPOSE: To analyse feasibility, prognostic factors and patterns of recurrence after concurrent reirradiation and bevacizumab for recurrent high-grade gliomas. PATIENTS AND METHODS: Between 2009 and 2015, 35 patients (median 57-year-old; 21 men, 14 women) with WHO grade III (n=11) or grade IV (n=24) gliomas were included in this retrospective and consecutive single-centre study. All patients received bevacizumab (median number of treatments: 12) concomitant with reirradiation (median dose: 45Gy, median number of fractions: 18) for recurrence with median 22 months (range: 5.6-123.7 months) from first irradiation (median dose: 60Gy). RESULTS: The median follow-up was 9.2 months from reirradiation. The median overall survival from reirradiation was 10.5 months (95% confidence interval [95% CI]: 4.9-16.1) and the progression-free survival from reirradiation was 6.7 months (95% CI: 2.9-10.5). The median overall survival from initial diagnosis was 44.6 months (95% CI: 32-57.1). No grade 3 toxicity or above was reported. Prognostic factors significantly correlated with better overall survival in univariate analysis were: age at least 55 (P=0.024), initial surgery (P=0.003), and 2Gy equivalent dose (EQD2) at least 50Gy at reirradiation (P=0.046). Twenty-two patients bevacizumab-naïve at time of reirradiation had a significantly increased overall survival from reirradiation compared to patients treated with reirradiation after bevacizumab failure (17.7 vs. 5.4 months, P<0.001) as well as overall survival from initial diagnosis (58.9 vs. 33.5 months, P=0.006). This outcome was similar in patients with initial glioblastomas (P=0.018) or anaplastic gliomas (P=0.021). There was no correlation between overall survival and gross tumour volume or planning target volume, frontal localization, or number of salvage therapies before reirradiation (P>0.05). CONCLUSIONS: Concomitant reirradiation with bevacizumab in high-grade recurrent gliomas shows encouraging results in terms of survival and toxicities. Our data suggest that reirradiation should be favoured at initiation of bevacizumab, with EQD2 at least 50Gy.

[Repair and time-dose factor: The example of spinal cord irradiation]. / Réparation et facteur temps : l'exemple de l'irradiation médullaire.

The question whether a reirradiation is possible, with either curative of palliative intent, is a frequent issue and a true therapeutic challenge, in particular for a critical organ sensitive to cumulative dose, such as the spinal cord. Preclinical experimental data, based on debatable models that are hardly transferable to patients, suggest that there is a possibility of reirradiation, beyond the classical threshold for dose constraints, taking into account the "time-dose factor". Although the underlying biological mechanisms are however uncertain, scarce clinical data seem to confirm that the tolerance of spinal cord to reirradiation does exist, provided that a particular attention to total dose is given. In the context where modern stereotactic irradiation facilities expand therapeutic perspectives, we review the literature on possibilities of reirradiation, through the example of spinal cord reirradiation.

[A randomized controlled trial of metastases-directed treatment in patients with metastatic prostate cancer using stereotactic body irradiation: A GETUG-AFU trial]. / Rôle de la radiothérapie ablative des métastases chez les patients atteints de cancer de la prostate oligométastatique hormonosensible : un essai du Groupe d'étude des tumeurs urogénitales et de l'Association française d'urologie.

The goal of treatment of metastatic prostate cancer remains palliation. The oligometastatic state could be the right time to intensify therapy by introducing metastases directed treatments. The aim of this trial was to evaluate the benefit of radiotherapy to all macroscopic metastatic sites and to the primary disease in patients with hormone sensitive oligometastatic prostate cancer.

[Spinal stereotactic body radiotherapy: French assessment in 2016]. / État des lieux de la radiothérapie en conditions stéréotaxiques vertébrale en France en 2016.

PURPOSE: Stereotactic body radiotherapy to vertebral column remains uncommon practice and only relevant in selected group of patients. The main objective of the study was to describe the current state of medical practices of stereotactic body radiotherapy to vertebral column in France in 2016 and to assess the diversity of practices to identify areas for improvement and establish a common database set for this technique. MATERIALS AND METHODS: A questionnaire was written with contribution of a medical physicist, a radiation oncologist, an information technologist and a radiotherapy resident. The questionnaire was distributed online to a radiation oncologists and a medical physicists partner of selected French radiotherapy specialized centres that provide stereotactic body radiotherapy to vertebral metastasis from April to June 2016. The questionnaire surveyed the following topics: patients' selection, simulation, targeted volume and organs at risk delineation, prescription, dosimetric implementation and image guidance. RESULTS: A total of 31 centres were surveyed. Seventy eight per cent of centres (n=21) completed the questionnaire. The "ideal" patient for spine stereotactic radiotherapy according to these institutions has a good performance status, a long life expectancy, controlled primary tumour with oligometastatic spread. The most prescribed protocol was 30Gy in three fractions. For clinical target volume delineation, about two thirds of centres used the International Spine Radiosurgery Consortium (ISRC) recommendations (Noël G et al.,2006). CONCLUSION: This study identified some consistency of practices in some aspects despite the lack of consensus guidelines. Nevertheless, further studies are needed to establish consensus of planning and treatment.

[Prophylactic axillary radiotherapy for breast cancer]. / Radiothérapie axillaire prophylactique des cancers du sein.

Adjuvant radiotherapy, after breast conserving surgery or mastectomy for breast cancer, improves overall survival while decreasing the risk of recurrence. However, prophylactic postoperative radiotherapy of locoregional lymph nodes for breast cancer, particularly of the axillary region, is still controversial since the benefits and the risks due to axillary irradiation have not been well defined. To begin with, when performing conformal radiotherapy, volume definition is crucial for the analysis of the risk-benefit balance of any radiation treatment. Definition and contouring of the axillary lymph node region is discussed in this work, as per the recommendations of the European Society for Radiotherapy and Oncology (ESTRO). Axillary recurrences are rare, and the recent trend leads toward less aggressive surgery with regard to the axilla. In this literature review we present the data that lead us to avoid adjuvant axillary radiotherapy in pN0, pN0i+ and pN1mi patients even without axillary clearance and to perform it in some other situations. Finally, we propose an update about the potential toxicity of adjuvant axillary irradiation, which is essential for therapeutic decision-making based on current evidence, and to guide us in the evolution of our techniques and indications of axillary radiotherapy.

Paranasal sinus cancer.

Paranasal sinus cancers are rare, aggressive tumours that are usually diagnosed at an advanced stage. They differ from other upper aerodigestive tract tumours in terms of risk factors (wood dust exposure) and premalignant lesions (inverted papillomas). The diagnosis should be suspected in the presence of unilateral and continuous nasal sinus symptoms or bone lysis or a heterogeneous opacity on imaging. The definitive positive diagnosis is based on histological examination. Staging must comprise face, brain, neck and chest CT as well as face and brain MRI. Tumours are stage T3-T4 in two-thirds of cases and are associated with cervical lymph node involvement in 10% of squamous cell carcinomas and 4% of adenocarcinomas. These tumours must be managed in reference centres experienced in all of the various treatment modalities. Treatment decisions must be based on a multidisciplinary approach comprising local, regional and national REFCOR expertise (French rare head and neck cancer network). Optimal treatment is surgical resection with clear margins associated with adjuvant intensity-modulated radiotherapy (IMRT). Although it has been improved over recent decades, the prognosis remains poor with local recurrences occurring in 38% of cases and a five-year overall survival of about 63%.

[Image-guided and adaptive radiotherapy]. / Radiothérapie guidée par l'image et adaptative.

Image-guided radiotherapy (IGRT) aims to take into account anatomical variations occurring during irradiation by visualization of anatomical structures. It may consist of a rigid registration of the tumour by moving the patient, in case of prostatic irradiation for example. IGRT associated with intensity-modulated radiotherapy (IMRT) is strongly recommended when high-dose is delivered in the prostate, where it seems to reduce rectal and bladder toxicity. In case of significant anatomical deformations, as in head and neck tumours (tumour shrinking and decrease in volume of the salivary glands), replanning appears to be necessary, corresponding to the adaptive radiotherapy. This should ideally be "monitored" and possibly triggered based on a calculation of cumulative dose, session after session, compared to the initial planning dose, corresponding to the concept of dose-guided adaptive radiotherapy. The creation of "planning libraries" based on predictable organ positions (as in cervical cancer) is another way of adaptive radiotherapy. All of these strategies still appear very complex and expensive and therefore require stringent validation before being routinely applied.

[From image-guided radiotherapy to dose-guided radiotherapy]. / De la radiothérapie guidée par l'image à la radiothérapie guidée par la dose.

PURPOSE: In case of tumour displacement, image-guided radiotherapy (IGRT) based on the use of cone beam CT (tomographie conique) allows replacing the tumour under the accelerator by rigid registration. Anatomical deformations require however replanning, involving an estimation of the cumulative dose, session after session. This is the objective of this study. PATIENTS AND METHODS: Two examples of arc-intensity modulated radiotherapy are presented: a case of prostate cancer (total dose=80 Gy) with tomographie conique (daily prostate registration) and one head and neck cancer (70 Gy). For the head and neck cancer, the patient had a weekly scanner allowing a dose distribution calculation. The cumulative dose was calculated per voxel on the planning CT after deformation of the dose distribution (with trilinear interpolation) following the transformation given by a non-rigid registration step (Demons registration method) from: either the tomographie conique (prostate), or the weekly CT. The cumulative dose was eventually compared with the planned dose. RESULTS: In cases of prostate irradiation, the "cumulative" dose corresponded to the planned dose to the prostate. At the last week of irradiation, it was above the planned dose for the rectum and bladder. The volume of rectal wall receiving more than 50 Gy (V50) was 20% at the planning and 26% at the end of treatment, increasing the risk of rectal toxicity (NTCP) of 14%. For the bladder wall, V50 were 73% and 82%, respectively. In head and neck, the "cumulative" dose to the parotid exceeded the planned dose (mean dose increasing from 46 Gy to 54 Gy) from the 5th week of irradiation on, suggesting the need for replanning within the first 5 weeks of radiotherapy. CONCLUSION: The deformable registration estimates the cumulative dose delivered in the different anatomical structures. Validation on digital and physical phantoms is however required before clinical evaluation.

[Cone beam CT based image guided radiotherapy: implementation and clinical use]. / Radiothérapie guidée par la tomographie conique (cone beam computed tomography): mise en oeuvre et applications cliniques.

The kV cone beam CT (CBCT) consists of an X-ray tube and a flat panel detector placed perpendicularly to the treatment beam, allowing the acquisition of hundreds of projections in one rotation of the gantry about the patient. Available in all new linear accelerators, the CBCT provides volumetric imaging in treatment position proving the realization of image- and dose-guided radiotherapy (IGRT and DGRT). The clinical indications correspond to mobile tumours irradiating with high precision required techniques, such as stereotactic, hypofractionated or high dose radiotherapy. The clinical experience is still very limited and concerns mainly prostate, head and neck and lung tumours. The registration and treatment protocols are briefly described. Quality control and training are major issues. CBCT based IGRT is a new technique which needs to be optimized. However, it should provide significant clinical benefit in combination with intensity modulated radiotherapy and new imaging modalities for target delineation.

[Quantification of the volumetric benefit of image-guided radiotherapy (IGRT) in prostate cancer: margins and presence probability map]. / Bénéfice volumétrique de la radiothérapie guidée par l'image dans les cancers prostatiques : marges et cartographies de probabilité de présence.

PURPOSE: To quantify the prostate and seminal vesicles (SV) anatomic variations in order to choose appropriate margins including intrapelvic anatomic variations. To quantify volumetric benefit of image-guided radiotherapy (IGRT). PATIENTS AND METHODS: Twenty patients, receiving a total dose of 70 Gy in the prostate, had a planning CT scan and eight weekly CT scans during treatment. Prostate and SV were manually contoured. Each weekly CT scan was registered to the planning CT scan according to three modalities: radiopaque skin marks, pelvis bone or prostate. For each patient, prostate and SV displacements were quantified. 3D maps of prostate and SV presence probability were established. Volumes including minimal presence probabilities were compared between the three modalities of registration. RESULTS: For the prostate intrapelvic displacements, systematic and random variations and maximal displacements for the entire population were: 5mm, 2.7 mm and 16.5mm in anteroposterior axis; 2.7 mm, 2.4mm and 11.4mm in superoinferior axis and 0.5mm, 0.8mm and 3.3mm laterally. Margins according to van Herk recipe (to cover the prostate for 90% of the patients with the 95% isodose) were: 8mm, 8.3mm and 1.9 mm, respectively. The 100% prostate presence probability volumes correspond to 37%, 50% and 61% according to the registration modality. For the SV, these volumes correspond to 8%, 14% and 18% of the SV volume. CONCLUSIONS: Without IGRT, 5mm prostate posterior margins are insufficient and should be at least 8mm, to account for intrapelvic anatomic variations. Prostate registration almost doubles the 100% presence probability volume compared to skin registration. Deformation of SV will require either to increase dramatically margins (simple) or new planning (not realistic).

[Image-guided radiotherapy: rational, modalities and results]. / Radiothérapie guidée par l'image : pourquoi, comment et résultats.

The objective of Image-Guided Radiotherapy (IGRT) is to take in account the inter- or/and intrafraction anatomic variations (organ motion and deformations) in order to improve treatment accuracy. The IGRT should therefore translate in a clinical benefit the recent advances in both tumor definition thanks to functional imaging, and dose distribution thanks to intensity modulated radiotherapy. The IGRT enables direct or indirect tumor visualization during radiation delivery. If the tumor position does not correspond with the theoretical location of target derived from planning system, the table is moved. In case of important uncertainties related to target deformation, a new planning can be discussed. IGRT is realized by different types of devices which can vary in principle and as well as in their implementation: from LINAC-integrated-kV (or MV)-Cone Beam CTs to helicoidal tomotherapy, Cyberknife and Novalis low-energy stereoscopic imaging system. These techniques led to a more rational choice of Planning Target Volume. Being recently introduced in practice, the clinical results of this technique are still limited. Nevertheless, until so far, IGRT has showed promising results with reports of minimal acute toxicity. This review describes IGRT for various tumor localizations. The dose delivered by on board imaging should be taken in account. A strong quality control is required for safety and proper prospective evaluation of the clinical benefit of IGRT.

[Paget disease, complicated by Ki-1 lymphoma with G-CSF growth factor secretion]. / Maladie de Paget compliquée d'un lymphome Ki-1 avec sécrétion de facteur de croissance G-CSF.

Development of lysis within an area of pagetic bone suggests a sarcoma. We report the case of a 61-year-old woman who had increasingly severe pain in her right hip and a decline in general health. The roentgenogram of the pelvis showed previously known pagetic lesions of the right half of the pelvis and osteolysis of the roof of the acetabulum. Additional imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) disclosed a pelvic tumor extending on either side of the right ilium. The peripheral white blood cell count was markedly elevated (93,000/mm3) as a result of inappropriate secretion of granulocyte-colony-stimulating factor. The tumor was an anaplastic large cell lymphoma of T-cell origin with CD30 positivity, i.e., a Ki-1 lymphoma. Most CD30-positive lymphomas are high-grade tumors. There has been only one previous report of Ki-1 lymphoma with production of granulocyte-colony-stimulating factor and hyperleukocytosis. It has been suggested that cytokines may influence tumor growth. Unusual features in our case include development of the Ki-1 lymphoma in an area of pagetic bone and presence of a leukemic syndrome due to increased production of a growth factor.