Immunothérapie et radiothérapie

Radiotherapy, primarily known for its cytotoxic effect on the tumor cells, via the induction of DNA damages, has the ability to induce a systemic antitumoral response. By an immunologic cell death, tumor cells exposed to radiation release a large amount of neoantigenes and pro-inflammatory mediators, acting as an in situ vaccine, resulting in an tumor regression within the primary irradiated site, but also in the distant “out of field” secondary tumors. However, this phenomenon is extremly rare with radiotherapy alone, suggesting that the radiation-induced antitumor immunity is not sufficient for overcoming the tumor's and its microenvironnement immunosuppressing effect. Over the last years, many scientific data and preclinical studies have demonstrated that the combination of local irradiation with immune therapy has a synergistic action in inducing an antitumoral immunity, thus enhancing an abscopal effect. In this article, we summarize the main mechanisms cancer harnesses to evade the control of the immune system and how ionising radiations can induce an antitumor immunity. A focus reports then on recent preclinical and clinical research built on this background of combined radiation and immune therapy, which bear the great potential to further improve anticancer therapies.     

L’imagerie en radiothérapie

The goal of radiation therapy is to deliver a high-dose of radiation to the tumour or target region to improve local control of disease and a low-dose to normal soft tissues to limit side effects. Conformal radiation therapy, intensity modulated radiotherapy (IMRT), brachytherapy and stereotactic radiosurgery have been developed to achieve the desired dose distribution. They require precise imaging of internal anatomy so that it is well adapted to the tumour and organs at risk. Indeed, morphological imaging such as computed tomography is already recommended for radiotherapy planning. But radiation oncologists are also considering other imaging modalities for treatment planning and imaging tools capable of controlling patient motion during treatment. The aim of this article is to present and illustrate the place of imaging during treatment planning and delivery via techniques such as: 4D computed tomography, morphological and functional MRI, positron emission tomography, and imaging devices mounted on accelerators.     

Oxygénothérapie hyperbare et radiothérapie : entre mythe et réalité

Worldwide, more than a million people receive each year a curative radiotherapy. While local control and overall survival are steadily increasing, 5 to 15% of patients still develop above grade 2 late toxicities. Late toxicities treatments are complex. Hyperbaric oxygenation was shown to induce revascularization and healing of injured tissues, but indications are still debated. Through a literature review, we summarized the hyperbaric oxygenation indications in radiation-induced late toxicities. We also studied the knowledge and practice of French local radiation therapists. It seems that hyperbaric oxygen therapy can be a conservative treatment of haemorrhagic cystitis and radiation-induced pain, in case of drug therapies failure. Often associated with a significant morbidity and mortality, surgery could be avoided. The risk of complications in case of tooth extraction in irradiated tissues is also reduced. However, the role of hyperbaric oxygenation for mandibular osteoradionecrosis, radiation-induced proctitis, enteritis, lymphoedema, brachial plexopathy, skin and neurological sequelae seems more questionable since studies results are conflicting. Future outcomes of phase III studies are expected to clarify the role of hyperbaric oxygenation in the management of radio-induced toxicities, including for head and necks complications.     

Inhibiteurs de PARP et radiothérapie

PARP inhibition is a promising therapeutic approach for solid cancers that present defects in DNA double-strand break repair. It could also serve as a clinically meaningful aid to radiotherapy. This article presents an overview of mechanistic, pre-clinical and clinical data that substantiate this hypothesis but also could help determine its potential pitfalls.     

Érythropoïétine et radiothérapie

Erythropoietin (EPO) is a glycoprotein hormone. This hormone is a growth factor for red blood cells precursors in the bone marrow. The decrease of oxygen partial pressure, a reduced number of erythrocytes caused by bleeding or excessive destruction, or increased tissues oxygen requirements lead to increased secretion of EPO. Its action takes place on bone marrow erythroblastic cells through specific receptors. EPO stimulates the proliferation of red cell precursors stem cells in the bone marrow, thus increasing their production in one to two weeks. The effectiveness of EPO at increasing haemoglobin and improving patients’ quality of life has been demonstrated by several studies. However, its use in radiotherapy remains controversial. While tumour hypoxia caused by anaemia is a factor of radio resistance and thus a source of local failure, tumour expression of EPO receptors presents a significant risk for tumour progression and neo-angiogenesis, which would be increased during the administration of EPO. The purpose of this article is to answer the question: is there a place for EPO in combination with radiotherapy in the management of cancer?     

Associations d’hormonothérapie et de radiothérapie pour le cancer de prostate

Combination of radiotherapy and androgen deprivation is now considered as the standard of care for patients with a localized prostate cancer but poor prognosis factors. Two groups of randomized trials have led to this recommendation: some have compared radiotherapy alone versus hormonal treatment and radiotherapy: these trials demonstrated, now with a long follow-up, an improvement in 10-year survival for the combined treatment. Three recent trials compared androgen deprivation alone or combined with radiotherapy; a benefit in survival was also demonstrated in favour of the combination. Some questions remained concerning the optimal duration of hormonal treatment, in view of its potential side effects. Patients in the intermediate prognostic groups could receive a short-term androgen deprivation, but those with a high Gleason score must be treated with a long-term hormonal treatment. Modalities of radiotherapy, regarding volumes and dose must also be précised in the next years.     

Logothérapie,groupe de paroles et analyse existentielle en cours de radiothérapie : expérience pilote d’un centre parisien de radiothérapie

Objective

A pilot study has been carried out to assess the benefit of a pilot support group based on existential analysis and logotherapy (therapy centred on the sense of existentialism), alongside the medical treatment of breast cancer.

Materials and Methods

A group of women under the care of the Hartmann Oncology Institute in the final phase of treatment for breast cancer were selected to take part in the support group during this very specific transition period between being ill and resuming a “normal” life.

Results

Between December 2015 and June 2016, eight women participated in the support group. Results taken from an assessment session and a satisfaction survey completed by all participants demonstrate the importance of talking, the relationships created session after session within the group and the support provided by the synergy between the group and its leaders in order to assert a new lifestyle dynamic — a noodynamic according to the terminology of Viktor Frankl (1905–1997), the psychiatrist who created logotherapy — and to give a new purpose to their life.

Conclusions

The results from the support groups on the quality of life of patients treated for breast cancer are encouraging, and establishing these groups alongside logotherapy would be advantageous for a larger number of patients.

     

Innovations et recherche en radiothérapie en France

Significant advances in radiation therapy have recently been observed. Important technological advances allow for greater precision in defining target volumes and organs at risk, which will certainly impact the risk/benefit ratio for cancer care, particularly in the new setting of therapeutic associations using new drugs. Despite the major role of radiation therapy in the multidisciplinary management of several cancers, pharmaceutical industry support for radiation therapy trials that do not involve drugs remains nil. Thus, grant applications for radiotherapy studies are mainly oriented towards institutional clinical research. At the same time, research in radiation therapy has changed considerably. In France, since the beginning of the year 2000, the Cancer Institute (INCa) has considered radiation oncology modernisation as one of the health priorities. In their programs, substantial grants have been allocated to the evaluation of innovative techniques, including financial issues and their potential generalisation throughout the country. Funding for clinical research programs has also been allocated to significant projects that will impact future clinical practice. In this article, we aim to describe the various plans for restructuring radiation therapy in France, and make an inventory of the innovative projects in clinical and technology research that involve public and private institutions.     

Fatigue et radiothérapie Revue de la littérature

Fatigue is a common complaint for the cancer patient during and after radiotherapy, according to the published studies. Fatigue is a subjective symptom mostly underestimated by oncologists and other care givers. Etiology is complex, poorly understood in spite of obvious causes like insomnia, nausea, pain, depression, psychological distress, anemia, hypothyroidism, menopause disturbances, treatment adverse effects. Fatigue presents multifactorial and multidimensional aspects. To evaluate it, many tools can be used as single-item, unidimensional and multidimensional instruments. Practically, the open discussion with the patient throughout radiotherapy is essential to define it. Taking charge fatigue requires its acknowledgement by radiotherapist, treatment of associated symptoms with a multidisciplinary approach.     

Contraintes de dose en radiothérapie conformationnelle fractionnée et en radiothérapie stéréotaxique dans les hippocampes,le tronc cérébral et l’encéphale : limites et perspectives

Cerebral radiation-induced toxicities after radiotherapy (RT) of brain tumors are frequent. The protection of organs at risk (OAR) is crucial, especially for brain tumors, to preserve cognition in cancer survivors. Dose constraints of cerebral OAR used in conventional RT, radiosurgery (SRS) and stereotactic radiotherapy (SRT) are debated. In fact, they are based on historical cohorts or calculated with old mathematical models. Values of α/β ratio of cerebral OAR are also controversial leading to misestimate the equivalent dose in 2 Gy fractions or the biological equivalent dose, especially during hypofractionated RT. Although recent progresses in medical imaging, the diagnosis of radionecrosis remains difficult. In this article, we propose a large review of dose constraints used for three major cerebral OAR: the brain stem, the hippocampus and the brain.     

Les carcinomes du nasopharynx Les modalités de la radiothérapie et les associations de la radiothérapie et de la chimiothérapie: état actuel et perspectives

Nasopharyngeal carcinoma (NPC) is a highly radiosensitive and chemosensitive. In the patient with locally advanced Humours, the results of conventional radiotherapy are unsatisfactory with significant rates of both local recurrences and distant metastases. The aim of this review is to report the innovative strategies for treatment of the nasopharyngeal carcinoma. Altered fractionation techniques can improve local control. The impact of the innovative techniques, including conformai radiation, stereotactic radiation and IMRT, on survival, must be evaluated in randomised trials. The encouraging early results obtained with concurrent (more than sequential) chemotherapy and radiotherapy must be confirmed in prospective randomized trial in endemic areas.     

Innovations en radiothérapie

Radiotherapy is a major treatment for cancer curability. During recent years, radiotherapy has gained in precision and reproducibility using major technological advances. Three-dimensional conformal radiotherapy has been implemented into routine practice with the delineation of tumor volumes and organs at risk and the use of dosimetry (integrating dose constraints and dose-volume histograms). Intensity-modulated radiation therapy (IMRT) can ??sculpt?? the dose around treatment volumes to spare normal tissues more efficiently. Image-guided radiation therapy is now widely used to control the position of the target during a treatment course. Dynamic arctherapy is a way to optimize IMRT using arctherapy, an old concept that makes IMRT delivery quicker and accessible for a larger patient load. Concepts in radiotherapy are strong and will be deployed on all radiotherapy units. Radiation oncology is probably only at its dawn. These innovations open a promising future for improvements in the cure of cancer.     

Biopsie liquide : cellules tumorales circulantes et radiothérapie

Circulating tumor cells (CTCs) are released actively from the primary tumor and/or metastatic sites and can be used for a real-time liquid biopsy of the cancer. Technological progress has allowed the detection and characterization of these rare cells to obtain molecular and phenotypic information complementary of standard biopsies; their clinical relevance is well established. Radiotherapy improves the loco-regional control of the tumor; however, its effect on the prognostic value of CTCs associated with the risk of systemic dissemination of cancer is open to question and discussed in this review.     

Radiochirurgie et radiothérapie stéréotaxique des schwannomes vestibulaires

Purpose of the studyIn order to investigate the role of radiosurgery and stereotactic radiotherapy in the management of vestibular schwannomas, we have reviewed our own prospective cohort and the main series of the modern literature.Patients and methodsBetween July 14th 1992 and June 1st 2011, 2991 vestibular schwannomas were operated on the Stereotactic and Functional Neurosurgery Department of Timone University Hospital. All the patients have been evaluated prospectively, with a follow up longer than 3 years for 2336 patients, excluding patients suffering from type 2 neurofibromatosis (148 patients). In 7% of the patients, the vestibular schwannoma had previously been resected. According to Koos classification, in 17.6% of the patients, vestibular schwannomas were stage I, 51.8% stage II, 27% stage III and 3.6% stage IV. The mean tumour volume was 2.63 cm³. According to Garner Robertson classification, the hearing was still functional at the time of radiosurgery in 46% and subnormal in 20.9% of the patients.ResultsLong term tumour control was achieved in 97.5% of the patients. A transient facial palsy was observed in 0.5% of the cases. The rate of trigeminal injury was 0.5%. Useful hearing was preserved at 3 years in 78%. This rate reached 95% in patients with no past history of sudden hearing loss. Other predictors of functional hearing preservation are the young age, the small size of the lesion and a dose to the modiulus of the cochlea lower than 4 Gy. We observed no radio-induced tumour. Only large, Koos IV vestibular schwannomas are contraindicated for upfront radiosurgery. In these patients, we propose a combined approach with a deliberately partial microsurgical removal, followed by a radiosurgery of the residue.ConclusionThis cohort is unique by the size of the population and the length of the follow up and results demonstrate the efficacy of radiosurgery and its safety, especially its high rate of hearing preservation.     

Stratégies d’immunothérapie dans les cancers colorectaux

Recent studies have underlined the close link between immune response and prognosis of patients with colorectal cancer (CRC). Immune response understanding combined with biotechnology progress of the last years has allowed development of immunotherapy strategies in CRC. Immunotherapy strategies are divided in “active” or “passive” strategies (patients immune system stimulation or not) and considering the activation of antigen specific immune response or not. These immunotherapy strategies are well tolerated and induced cellular and humoral response correlated with clinical response. Many monoclonal antibodies targeting signalisation pathways or angiogenic growth factors have demonstrated their efficacy in CRC. Multiple vaccine strategies, using different tumour associated antigens, have demonstrated a biological efficacy but with poor clinical results. Results are more promising in adjuvant setting but need to be confirmed by randomized trials. Adoptive immunotherapy with transfer of tumour associated antigen specific T cell is probably the most promising strategy. Actually, except monoclonal antibodies, immunotherapy is not used in clinical practice in CRC due to the lack of results and absence of standardisation.     

Doses aux organes à risque en radiothérapie conformationnelle et en radiothérapie stéréotaxique : les poumons

Radiation-induced lung disease (RILD) is common after radiation therapy and represents cornerstone toxicities after treatment of thoracic malignancies. From a review of literature, the objective of this article was to summarize clinical and non-clinical parameters associated with the risk of RILD in the settings of normo-fractionated radiotherapy and stereotactic body radiation therapy (SBRT). For the treatment of lung cancers with a normo-fractionated treatment, the mean lung dose (MLD) should be below 15–20 Gy. For a thoracic SBRT, V20 Gy < 10% and MLD < 6 Gy are recommended. One should pay attention to central tumors and respect specific dose constraints to the bronchial tree. The recent technological improvements may represent an encouraging way to decrease lung toxicities. Finally, our team developed a calculator in order to predict the risk of radiation pneumonitis.