The role of radiation therapy for de novo metastatic bladder and renal cancers.

Metastatic bladder and renal cancers account respectively for 2.1% and 1.8% of cancer deaths worldwide. The advent of immune checkpoint inhibitors has revolutionized the management of metastatic disease, by demonstrating considerable improvements in overall survival. However, despite initial sensitivity to immune checkpoint inhibitors for most patients, both bladder and renal cancer are associated with short progression-free survival and overall survival, raising the need for further strategies to improve their efficacy. Combining systemic therapies with local approaches is a longstanding concept in urological oncology, in clinical settings including both oligometastatic and polymetastatic disease. Radiation therapy has been increasingly studied with either cytoreductive, consolidative, ablative or immune boosting purposes, but the long-term impact of this strategy remains unclear. This review intends to address the impact of radiation therapy with either curative or palliative intent, for synchronous de novo metastatic bladder and renal cancers.

Stereotactic body radiation therapy for bone oligometastases.

Stereotactic body radiation therapy is effective for the local management of oligometastases (at most five metastases) with a benefit in survival and local control. Most studies on the management of oligometastases focus on all oligometastatic sites in primary cancer and very few focus on a single oligometastatic site. In particular, there are few data on bone oligometastases, which represent one of the preferred sites for secondary cancer locations. This article focuses on the benefit of stereotactic radiotherapy for bone oligometastases of all cancers by histological types, and reviews the results of major studies in this field.

Indication and perspectives of radiation therapy in the setting of de-novo metastatic prostate cancer.

Prostate cancer is the most common cancer and the third leading cause of cancer mortality in men. Each year, approximately 10% of prostate cancers are diagnosed metastatic at initial presentation. The standard treatment option for de-novo metastatic prostate cancer is androgen deprivation therapy with novel hormonal agent or with chemotherapy. Recently, PEACE-1 trial highlighted the benefit of triplet therapy resulting in the combination of androgen deprivation therapy combined with docetaxel and abiraterone. Radiotherapy can be proposed in a curative intent or to treat local symptomatic disease. Nowadays, radiotherapy of the primary disease is only recommended for de novo low-burden/low-volume metastatic prostate cancer, as defined in the CHAARTED criteria. However, studies on stereotactic radiotherapy on oligometastases have shown that this therapeutic approach is feasible and well tolerated. Prospective research currently focuses on the benefit of intensification by combining treatment of the metastatic sites and the primary all together. The contribution of metabolic imaging to better define the target volumes and specify the oligometastatic character allows a better selection of patients. This article aims to define indications of radiotherapy and perspectives of this therapeutic option for de-novo metastatic prostate cancer.

Is oligometastatic disease an applicable and useful concept in haematologic malignancies? A narrative review of radiation therapy standards, modern techniques, and innovations.

PURPOSE: Haematologic malignancies are particular in that they can generally be cured, even when distant metastases are present at diagnosis, unlike solid malignancies. Systemic treatments, including chemotherapy, targeted therapies, and immunotherapy, are the standard of care with excellent results. The considerable progress made in the management of these diseases in the last 20years has redefined the role of radiation therapy as minor in many clinical situations. We propose a literature review of data, showing that radiation therapy still has a role in curative, salvage, and palliative therapy situations. MATERIAL AND METHODS: A document and literature search was carried out in the following databases: Medline and ClinicalTrial.gov, for the terms "radiotherapy", "haematologic malignancies", "Hodgkin lymphoma", "non-Hodgkin lymphoma", "CAR T cells", "multiple myeloma", "solitary plasmocytoma", "intensity-modulated radiotherapy", "extracranial stereotactic body radiation therapy" and "proton therapy references". RESULTS: Haemopathological malignancies include a wide range of diseases and radiation therapy indications have been assessed over the past 20years. Currently, radiation therapy is indicated for localized disease (solitary plasmocytoma), as an adjuvant (Hodgkin lymphoma), in palliative settings, or after systemic treatment in relapsed patients (chimeric antigen receptor [CAR] T-cells) with a low recurrence burden, which can therefore be considered "oligorecurrence". Radiation therapy, through total body irradiation, has important indications, thanks to its immunomodulatory and/or myeloablative effects. Moreover, recent technological developments have made possible significant improvement in safety, contributing to radiation therapy being positioned in the treatment strategy of several indications. CONCLUSIONS: Given the effectiveness of systemic treatments in hematologic malignancies, the oligometastasis stage is of little importance. A curative intent after local radiation therapy, even advanced stage, is possible, both with residual disease for advanced Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, or solitary plasmocytoma, and even without evidence of disease after chemotherapy for Hodgkin or non-Hodgkin lymphoma. The role of new treatments, such as CAR T cells, allows us to consider radiation therapy after systemic treatment of relapsed diseases with low volume recurrence, which can be considered oligorecurrence.

[Stereotactic body radiation therapy for primary kidney cancer]. / Radiothérapie stéréotaxique des carcinomes rénaux primitifs.

The incidence of primary renal cancer is increasing, particularly in elderly patients who may have comorbidities and/or a surgical contraindications. Stereotactic body radiotherapy has primarily been evaluated retrospectively to date. The most commonly used dose schedules are 40Gy in five fractions, 42Gy in three fractions, and 26Gy in one fraction. The results in terms of local control and toxicity are very encouraging. The advantages of stereotactic body radiotherapy compared to thermal ablative treatments are its non-invasive nature, absence of general anesthesia, ability to treat larger lesions, and those close to the renal hilum. Prospective evaluations are still necessary.

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.

[Relationship between doses to anatomical structures and erectile dysfunction after radiotherapy for prostate cancer: A systematic review]. / Relations entre doses dans les structures anatomiques et dysfonction érectile après radiothérapie pour un cancer de la prostate : revue systématique de la littérature.

PURPOSE: During prostatic radiotherapy, damage to several anatomical structures could be the cause of erectile dysfunction: corpora cavernosa, internal pudendal arteries, penile bulb, and neurovascular bundles. Numerous studies have analysed the correlations between the dose received by these structures and erectile function. The objective of this article is to make a systematic review on current knowledge. MATERIALS AND METHODS: A systematic review was performed in the Medline database using the search engine PubMed. Keywords for the search included: erectile dysfunction, penile bulb, corpora cavernosa, cavernosum, neurovascular bundles, radiation therapy, cancer, prostate cancer. The selected articles must study a correlation between erectile dysfunction and the dose received by anatomical structures. A total of 152 articles were identified. Of these 152 articles, 45 fulfilled the defined selection criteria. RESULTS: For corpora cavernosa, seven studies were identified, only two studies demonstrated a significant correlation between the dose received by corpora cavernosa and the occurrence of erectile dysfunction. For penile bulb, only 15 of 23 studies showed a correlation. A mean dose on the penile bulb greater than 20Gy was found to be predictive of erectile dysfunction. None of the eight trials concerning neurovascular bundles succeeded to show a correlation between dose and erectile dysfunction. Only one study evaluated the relationship between the dose received by internal pudendal arteries and erectile dysfunction but was found to be negative. However, vessels-sparing studies showed good results on erectile function preservation without compromising the target volume. CONCLUSION: We currently have little data to show a correlation between erectile dysfunction and sexual structures. It would be necessary to have additional prospective studies evaluating the impact of an optimization on these sexual structures on erectile dysfunction.

Insights on the carbon footprint of radiotherapy in France.

The French healthcare system is responsible for 8% of the national footprint. Achieving a net zero emissions scenario will require a 4-5 fold decrease of carbon emissions in the coming years. The carbon footprint of radiation therapy has not been specifically studied to date. In this review we summarize the content of the carbon footprint dedicated session at the annual meeting of the French society of radiation oncology (SFRO). We discuss the French healthcare system carbon footprint and its major drivers and our work on the estimation of the carbon footprint of external beam radiation therapy in the French setting. We developed a dedicated methodology to estimate the carbon footprint related to radiation therapies, and describe the main drivers of emissions based on a single centre as an example, namely patient's rides, accelerators acquisition and maintenance and data storage. Based on the carbon footprint calculated in our centres, we propose mitigation strategies and an estimation of their respective potential. Our results may be extrapolated to other occidental settings by adapting emission factors (kilograms of carbon per item or euro) to other national settings. External beam radiation therapy has a major carbon footprint that may be mitigated in many ways that may impact how radiation therapy treatments are delivered, as well as the national organization of the radiotherapy sector. This needs to be taken into account when thinking about the future of radiotherapy.

[The morbidity and mortality review meetings in radiotherapy departments: Procedure, implementation and prospects of the "Proust" French national project]. / Revue de morbidité et mortalité en radiothérapie : procédure, implémentation et perspectives du projet national français « Proust ¼.

Radiation-induced acute and late toxicity depends on several parameters. The type, severity and duration of morbidity are mainly related to irradiated volume, total dose and its fractionation and the intrinsic radiosensitivity of the patients. The follow-up of these toxicities is essential. However, unlike many specialties, morbidity and mortality reviews procedures are not developed as part of quality governance programs in radiation therapy departments for the monitoring of toxicity which sometimes hinder the patients' quality of life. One French survey published within the framework of the project entitled Prospective Registration of Morbidity and Mortality, Individual Radiosensitivity and Radiation Technique (Proust), conclude that there was a lack of knowledge of morbidity and mortality reviews and considerable confusion between these reviews and other quality processes without perspective for the local morbidity and mortality reviews development in a large number of the participated centers. In this article, we will discuss the procedure of the "ideal morbidity and mortality reviews" and its implementation through a monocentric experience started in 2015. Thus, the Proust project is a unique opportunity to implement and standardize a national morbidity and mortality reviews implementation in radiation therapy departments by involving the French regions.

[Understanding/acceptance of radiotherapy: An ethical dilemma resolved by an ethics of care]. / Compréhension/acceptation de la radiothérapie : un dilemme éthique résolu par une éthique de la considération et de la sollicitude.

PURPOSE: Ethical questions are poorly investigated specifically in radiation oncology. The objective of the study was to identify and understand the main ethical issue in radiation oncology. MATERIALS AND METHODS: A quantitative analysis was based on the answers to a questionnaire of 200 professionals from 22 radiation oncology departments. The questionnaire mainly aimed to characterize the main ethical issue. A monocentric qualitative analysis was based on semi-structured interviews focused on the main identified ethical issue, carried out with eight technologists, and 20 patients undergoing radiotherapy. RESULTS: The main ethical issue was the understanding and/or acceptance of the treatment by the patients (71 %), which frequently arises (more than once a month) (52 %), and corresponds to an ethical tension between the principles of respect for autonomy and beneficence (the good as viewed by the patient) as defined by Beauchamp and Childress. The technologists, wish the patient to be fully involved in his treatment, with the even possibility of refusing it. However, excluding paternalism and autonomic relentlessness, the technologists have the feeling of acting for the good of the patients by treating them with radiation, even if the patients are not always aware of it, because they are within a situation of vulnerability. If the hierarchy of principles is a compromise alternative, this problem is finally well resolved by the effective implementation of an ethic of consideration and solicitude, restoring the patient capabilities, i.e. the maximum development of his potentialities in his situation of vulnerability. Beyond the legal dimension, patient information is crucial and must consider the specific temporality of the patient. CONCLUSION: The main ethical issue in radiation oncology is the understanding and/or acceptance of the treatment involving the development of an ethic of consideration and solicitude.

Could conventionally fractionated radiation therapy coupled with stereotactic body radiation therapy improve local control in bone oligometastases?

PURPOSE: To describe clinical outcomes of stereotactic body radiation therapy (SBRT) applied alone or as a boost after a conventionally fractionated radiation therapy (CFRT) for the treatment of bone oligometastases. MATERIAL AND METHODS: This retrospective cohort study included patients treated with SBRT from January 2007 to December 2015 in the Institut de cancérologie de Lorraine in France. The inclusion criteria involved adults treated with SBRT for one to three bone metastases from a histological proven solid tumor and a primary tumor treated, an Eastern Cooperative Oncology Group (ECOG) score inferior or equal to 2. Local control (LC), overall survival (OS), progression free survival (PFS), bone progression incidence (BPI), skeletal related events free survival (SRE-FS), toxicity and pain response were evaluated. RESULTS: Forty-six patients and 52 bone metastases were treated. Twenty-three metastases (44.2%) received SBRT alone mainly for non-spine metastases and 29 (55.8%) a combination of CFRT and SBRT mainly for spine metastases. The median follow-up time was 22months (range: 4-89months). Five local failures (9.6%) were observed and the cumulative incidences of local recurrence at 1 and 2years respectively were 4.4% and 8% with a median time of local recurrence of 17months (range: 4-36months). The one- and two-years OS were 90.8% and 87.4%. Visceral metastasis (HR: 3.40, 95% confidence interval [1.10-10.50]) and a time from primary diagnosis (TPD)>30months (HR: 0.22 [0.06-0.82]) were independent prognostic factors of OS. The 1 and 2years PFS were 66.8% and 30.9% with a median PFS time of 18months [13-24]. The one- and two-years BPI were 27.7% and 55.3%. In multivariate analysis, unfavorable histology was associated with worse BPI (HR: 3.19 [1.32-7.76]). The SRE-FS was 93.3% and 78.5% % at 1 and 2years. The overall response rate for pain was 75% in the evaluable patients (9/12). No grade≥3 toxicity nor especially no radiation induced myelopathy (RIM), two patients developed asymptomatic vertebral compression fractures. CONCLUSION: The sole use of SBRT or its association with CFRT is an efficient and well-tolerated treatment that allows high LC for bone oligometastases.

[Characteristics of radiotherapy for adolescents and young adults]. / Caractéristiques de la radiothérapie chez les adolescents et les jeunes adultes.

Radiotherapy for adolescents and young adults is complex in several aspects. The population is very heterogeneous and has characteristics derived from both paediatric and adult populations both in terms of pathology (anatomical pathology, response to treatment) and the patient's physical, biological and psychological characteristics. This article reviews the characteristics to be taken into account in adolescent and young adult patients radiotherapy and more particularly in some of the most common diseases.

Recommendations for stereotactic body radiation therapy for spine and non-spine bone metastases. A GETUG (French society of urological radiation oncolgists) consensus using a national two-round modified Delphi survey.

Background and purpose: The relevance of metastasis-directed stereotactic body radiation therapy (SBRT) remains to be demonstrated through phase III trials. Multiple SBRT procedures have been published potentially resulting in a disparity of practices. Therefore, the french society of urological radiation oncolgists (GETUG) recognized the need for joint expert consensus guidelines for metastasis-directed SBRT in order to standardize practice in trials carried out by the group. Materials and methods: After a comprehensive literature review, 97 recommendation statements were created regarding planning and delivery of spine bone (SBM) and non-spine bone metastases (NSBM) SBRT. These statements were then submitted to a national online two-round modified Delphi survey among main GETUG investigators. Consensus was achieved if a statement received ≥ 75 % agreements, a trend to consensus being defined as 65-74 % agreements. Any statement without consensus at round one was re-submitted in round two. Results: Twenty-one out of 29 (72.4%) surveyed experts responded to both rounds. Seventy-five statements achieved consensus at round one leaving 22 statements needing a revote of which 16 achieved consensus and 5 a trend to consensus. The final rate of consensus was 91/97 (93.8%). Statements with no consensus concerned patient selection (3/19), dose and fractionation (1/11), prescription and dose objectives (1/9) and organs at risk delineation (1/15). The voting resulted in the writing of step-by-step consensus guidelines. Conclusion: Consensus guidelines for SBM and NSBM SBRT were agreed upon using a validated modified Delphi approach. These guidelines will be used as per-protocole recommendations in ongoing and further GETUG clinical trials.

[Clinical research in radiation oncology: how to move from the laboratory to the patient?] / Recherche clinique en oncologie radiothérapie : comment passer du laboratoire au patient ?

Translational research in radiation oncology is undergoing intense development. An increasingly rapid transfer is taking place from the laboratory to the patients, both in the selection of patients who can benefit from radiotherapy and in the development of innovative irradiation strategies or the development of combinations with drugs. Accelerating the passage of discoveries from the laboratory to the clinic represents the ideal of any translational research program but requires taking into account the multiple obstacles that can slow this progress. The ambition of the RadioTransNet network, a project to structure preclinical research in radiation oncology in France, is precisely to promote scientific and clinical interactions at the interface of radiotherapy and radiobiology, in its preclinical positioning, in order to identify priorities for strategic research dedicated to innovation in radiotherapy. The multidisciplinary radiotherapy teams with experts in biology, medicine, medical physics, mathematics and engineering sciences are able to meet these new challenges which will allow these advances to be made available to patients as quickly as possible.

DNA repair inhibitors and radiotherapy.

Radiotherapy (RT) is one of the main cancer treatments and grows in importance due to improved techniques. DNA damage caused by ionizing radiation creates DNA strand breaks that trigger an intervention of DNA repair pathways involving numerous proteins and enzymes. In recent years, we have identified DNA repair inhibitors as targets for inhibiting cellular repair systems and thus causing cell death. Combining RT with these DNA repair inhibitors appears to be a new approach for cancer treatment, but safety and real efficiency of this combination in practice is unclear. Numerous trials are underway in various diseases and initial results are promising overall, yet remain controversial.

Cost-effectiveness of hypofractionated versus conventional radiotherapy in patients with intermediate-risk prostate cancer: An ancillary study of the PROstate fractionated irradiation trial - PROFIT.

PURPOSE: To evaluate the cost-effectiveness of moderate Hypofractionated Radiotherapy (H-RT) compared to Conventional Radiotherapy (C-RT) for intermediate-risk prostate caner (PCa). METHODS: A prospective randomized clinical trial including 222 patients from six French cancer centers was conducted as an ancillary study of the international PROstate Fractionated Irradiation Trial (PROFIT). We carried-out a cost-effectiveness analysis (CEA) from the payer's perspective, with a time horizon of 48 months. Patients assigned to the H-RT arm received 6000 cGy in 20 fractions over 4 weeks, or 7800 cGy in 39 fractions over 7 to 8 weeks in the C-RT arm. Patients completed quality of life (QoL) questionnaire: Expanded Prostate Cancer Index Composite (EPIC) at baseline, 24 and 48 months, which were mapped to obtain a EuroQol five-dimensional questionnaire (EQ-5D) equivalent to generate Quality Adjusted Life Years (QALY). We assessed differences in QALYs and costs between the two arms with Generalized Linear Models (GLMs). Costs, estimated in euro (€) 2020, were combined with QALYs to estimate the Incremental Cost-effectiveness ratio (ICER) with non-parametric bootstrap. RESULTS: Total costs per patien were lower in the H-RT arm compared to the C-RT arm €3,062 (95 % CI: 2,368 to 3,754) versus €4,285 (95 % CI: 3,355 to 5,215), (p < 0.05). QALY were marginally higher in the H-RT arm, however this difference was not significant: 0.044 (95 % CI: - 0.016 to 0.099). CONCLUSIONS: Treating localized prostate cancer with moderate H-RT could reduce national health insurance spending. Adopting such a treatment with an updated reimbursement tariff would result in improving resource allocation in RT management.

[Intermediate-risk prostate cancer treated with exclusive external irradiation: Focus on anatomical sites of recurrence in two French trials]. / Cancer de la prostate de risque intermédiaire traité par irradiation externe exclusive : focus sur les sites anatomiques de récidive dans deux essais français.

PURPOSE: Retrospective description of anatomical sites of relapse based on (18F)-choline PET-CT, (68Ga)-prostatic specific-membrane antigen PET-CT, bone scan, and prostate magnetic resonance imaging (MRI) data. MATERIALS AND METHODS: From two French prospective cohorts, patients treated with exclusive radiotherapy for an intermediate-risk cancer were identified during their follow-ups. They were included if they presented a rising of the prostate-specific antigen (PSA) associated with the realization of an imaging showing the sites of recurrences. RESULTS: Two hundred and sixty-three patients were included. After a median follow-up of 76 months (interquartile range [IQR] 67-95), 65 patients had biochemical recurrence and positive imaging. The median nadir PSA was 0.6ng/mL and the median PSA at recurrence was 3.4ng/mL. A single lesion was found in 48% of cases, 2 to 4 lesions in 43% of cases and more than 4 lesions in 9% of cases. The sites of relapse identified were prostate (37/65), prostate only (19/65), seminal vesicles (9/65) Pelvic nodes (35/65), extrapelvic nodes (15/65) and bone (13/65). CONCLUSIONS: The majority of relapses presented as a single lesion localized in the pelvis.

[Endocrine side effects of radiation therapy: Diagnosis, prevention, and treatment]. / Effets secondaires endocriniens de la radiothérapie : diagnostic, prévention et traitements.

Endocrine complications after radiotherapy are usually delayed and require prolonged follow-up by the radiation oncologist. Endocrine glands are dispersed throughout the body and can be included in the radiation field of several tumors. As the symptomatology can sometimes be insidious and non-specific, their screening is based on a directed clinical examination but also on systematic hormonal assays. The thyroid gland is particularly radiosensitive, and hypothyroidism is generally observed for doses of more than 30Gy. After cervical irradiation, it is recommended to perform a TSH assay every 6 to 12months. The risk of secondary thyroid cancer only concerns children and exists even at low doses, systematic screening is required. The risk of pituitary insufficiency is dose-dependent, with different sensitivity for each axis. In children, the main concern is the early detection of somatotropic insufficiency in order to prevent the risk of short stature. Reproductive function can be impaired after receiving 4-6Gy requiring fertility preservation. Endocrine side effects can be treated to improve quality of life; therefore, we propose several approaches to be followed in order to promote screening and treatment.

Radiotherapy of bone metastases.

We present the update of the recommendations of the French society of oncological radiotherapy on bone metastases. This is a common treatment in the management of patients with cancer. It is a relatively simple treatment with proven efficacy in reducing pain or managing spinal cord compression. More complex treatments by stereotaxis can be proposed for oligometastatic patients or in case of reirradiation. In this context, increased vigilance should be given to the risks to the spinal cord.

External radiotherapy for prostatic cancers.

We present the update of the recommendations of the French society of oncological radiotherapy on external radiotherapy of prostate cancer. External radiotherapy is intended for all localized prostate cancers, and more recently for oligometastatic prostate cancers. The irradiation techniques are detailed. Intensity-modulated radiotherapy combined with prostate image-guided radiotherapy is the recommended technique. A total dose of 74 to 80Gy is recommended in case of standard fractionation (2Gy per fraction). Moderate hypofractionation (total dose of 60Gy at a rate of 3Gy per fraction over 4 weeks) in the prostate has become a standard of therapy. Simultaneous integrated boost techniques can be used to treat lymph node areas. Extreme hypofractionation (35 to 40Gy in five fractions) using stereotactic body radiotherapy can be considered a therapeutic option to treat exclusively the prostate. The postoperative irradiation technique, indicated mainly in case of biological recurrence and lymph node involvement, is detailed.