Immunothérapie et radiothérapie dans la prise en charge du cancer du sein : rationnel et synthèse de la littérature sur les applications cliniques actuelles

The discovery of immunotherapy led to understand the major role of immune system during the tumor process. Conventional treatments, such as chemotherapy, are directly tumoricidal. New drugs are developed to target specifically the immune system to make it regain its ability to recognize and eliminate cancer cells. Radiotherapy is used for a long time for its local action, but its systemic role, based on its impact on immunity, is now better known. Breast cancer was wrongly considered poorly immunogenic and put aside the amazing progress in this new area of treatment. In this article, we would like to present the pre-clinical and clinical rationales to associate immunotherapy to radiotherapy in the management of breast cancer.     

Association de radiothérapie et d’hormonothérapie dans la prise en charge des cancers localisés de la prostate : où en est-on ?

Radiotherapy and androgen deprivation therapy play a major role in the management of prostate cancer. Indeed, radiotherapy and hormone therapy are combined in a neoadjuvant and concomitant setting for intermediate risk cancers but also in an adjuvant setting in high risk or locally advanced prostate cancer. The benefice of this association was suggested by preclinical studies and demonstrated later by several randomized trials. However, as these trials were conducted before the era of dose escalation the role of androgen deprivation therapy in this case is less clear. Moreover, as hormonal therapy can lead to a significant morbidity and a decrement in quality of life its indications must be carefully weighed especially in case of intermediate risk cancer witch represent a heterogeneous group with distinct prognostic subgroups.     

Marges en radiothérapie du cancer de la vessie

Radical cystectomy is the gold standard treatment of invasive bladder carcinoma, but conservative treatment is a serious option for selected patients. It comprises a transurethral resection, as complete as possible, before a radiation therapy of the whole bladder and pelvis, with a concomitant chemotherapy. Bladder wall movements during the treatment course lead to the use of wide margins to cover the clinical target volume. Planning target volume margins must be anisotropic to correspond to the mobility of each bladder zone: 10 mm in the inferior portion, 15 mm in lateral directions, and 20 to 25 mm in anterior and superior directions. The development of image-guided radiotherapy and adaptative radiotherapy should lead to a reduction of these margins. Besides, partial bladder radiotherapy is showing encouraging results, by reducing the clinical target volume in well-selected patients.     

Place de la radiothérapie dans la prise en charge des lymphomes malins non hodgkiniens

The purpose of this review was to summarize recent data about lastest retrospective and prospective studies dealing with radiotherapy of non-Hodgkin lymphoma, in order to precise the schedule and the role of this treatment. A systematic review was done by searching studies on the website http://www.pubmed.gov (Medline) using the following keywords: radiotherapy, radiation therapy, non-Hodgkin lymphoma. The management of non-Hodgkin lymphoma varies a lot according to the histological type and stage. The dose of radiotherapy has been studied in only one randomized trial, which concluded that there was no difference between the low dose and the high dose arms. Radiotherapy is a very good option in follicular, cutaneous, digestive or orbital non-Hodgkin lymphoma. A recent post hoc analysis of randomized trials on radiotherapy for high-grade non-Hodgkin lymphoma strongly suggested a benefit of additional radiotherapy after chemotherapy in some situations. Radiotherapy of low-grade non-Hodgkin lymphoma is a very good option, while its use on high-grade non-Hodgkin lymphoma is sometimes recommended but further randomized trials are ongoing to better understand its role.     

Personnalisation de la dose,du volume et du fractionnement de la radiothérapie du sein

Randomized trials demonstrated similar overall survival between mastectomy and breast-conservative surgery followed by adjuvant radiation therapy. Breast-conservative surgery, with adjuvant radiation therapy, with or without neoadjuvant systemic therapy has become the standard of care for women with early or locally advanced breast cancer. Nevertheless, certain cardiac, lung or cutaneous toxicities may alter the long-term body image and the quality of life of a limited number of patients who consider having had “overtreatment” or treatment outside the best knowledge of science. In case of low-risk breast cancer, several trials have evaluated the carcinologic outcome in absence of radiation therapy after breast-conservative surgery. Local recurrences increased in case of breast-conservative surgery alone but without impact on overall survival. Multiple debates have emerged in order to select the most appropriate evaluation criteria. Finally, a large consensus has considered that reducing local recurrences is important but with modern technologies and after identifying patients of individual radiosensitivity. Indeed, in case of a low absolute risk of local recurrence, radiation therapy techniques have been developed to allow a focal treatment especially for patients with high risk of developing late effects. This kind of compromise takes into account the reduction risk of local recurrences but also the probability of developing radiation-induced cutaneous sequelae. In the same way, for patients considered at high risk of recurrence, the huge volumes need specific techniques to better cover the targets while protecting the surrounding critic organs such as heart and lung. Intensity-modulated radiation therapy and the local high boost may help to decrease local recurrences of these more extended and aggressive diseases while considering the individual radiosensitivity that paves the way of long-term sequelae. In this article, we detail a personalized approach of breast radiation therapy considering the absolute risk of local recurrences and the probability of radiation-induced toxicity appearance.     

Place de la radiothérapie stéréotaxique extracrânienne dans la prise en charge des patients atteints de cancer

Extracranial stereotactic radiotherapy has developed considerably in recent years and is now an important part of the therapeutic alternatives to be offered to patients with cancer. It offers opportunities that have progressively led physicians to reconsider the therapeutic strategy, for example in the case of local recurrence in irradiated territory or oligometastatic disease. The literature on the subject is rich but, yet, there is no real consensus on therapeutic indications. This is largely due to the lack of prospective, randomized studies that have evaluated this technique with sufficient recoil. We propose a review of the literature on the technical aspects and indications of extracranial stereotactic radiotherapy.     

Bénéfices de la radiothérapie avec asservissement respiratoire dans le traitement du cancer du sein

PurposeThe purpose of this study was to compare free-breathing radiotherapy, end-expiration gating and end-inspiration gating for left breast cancer, with respect to the target volume coverage and dose to organs at risk.Patients and methodsSixteen patients underwent 3D and 4D simulation CT. For each patient, five dosimetric plans were compared: free breathing, end-inspiration gating, end-expiration gating, and two optimised plans with a 3 mm reduction of the posterior field edge to create optimised end-inspiration and end-expiration plans. Dose–volume parameters, including planning target volume coverage and dose to lung, heart and left anterior descending coronary artery were analysed.ResultsPlanning target volume coverage was adequate and similar in the five dosimetric plans (P = 0.49). Significant advantage was found for end-inspiration gating in sparing the ipsilateral lung, heart and left anterior descending coronary artery compared to free-breathing 3D radiotherapy. Optimised end-inspiration was even more favourable than end-inspiration gating (P < 0.05), with less dose delivered to the ipsilateral lung, heart and left anterior descending coronary artery. When compared to end-expiration gating, end-inspiration gating dosimetric outcomes were similar regarding lung and left anterior descending coronary artery doses, but the heart dose was inferior on the end-inspiration gating compared to end-expiration gating.ConclusionBreathing-adapted radiation therapy allowed for dose reduction to organs at risk (left lung, heart and left anterior descending coronary artery), while keeping the same planning target volume coverage. Therefore it can be considered as an interesting option for left breast cancer radiation treatment.     

Cancers du col utérin : nouveautés dans la prise en charge en oncologie radiothérapie

During the recent past years, the therapeutic management of locally advanced cervical cancer patients has consistently improved, with the integration of image guided brachytherapy and dose escalation strategies leading to an improvement of local control rates. In parallel, the evolution of external beam radiotherapy techniques and the better control of organs at risk doses in brachytherapy have contributed to decrease the probability of severe normal tissue complication. In case of advanced disease, patients prognosis remains however marked by a high risk of distant failure, and this finding has encouraged the assessment of various research pathways in order to better predict and/or prevent tumor relapse. Major studies are being conducted or have been published, and the place of chemoradiation and brachytherapy has been confirmed as first intent treatment in case of locally advanced disease. Numerous prospective or retrospective data, few of which are reviewed there, have been integrated as part of a strategy aimed at being more and more personalized. Next steps of therapeutic optimization will include the assessment of multiparameters radiological tools, but will also rely on a better understanding of radiobiological pathways involved in local or systemic response to irradiation, and the most promising of those is probably the anti-tumor immune response.     

Place de la radiothérapie stéréotaxique dans la prise en charge des tumeurs hépatiques

Stereotactic radiotherapy is a high-precision technique based on the administration of high doses to a limited target volume. This treatment constitutes a therapeutic progress in the management of many tumours, especially hepatic ones. If surgery remains the standard local therapy, stereotactic radiotherapy is first dedicated to inoperable patients or unresectable tumours. Patients with moderately altered general status, preserved liver function and tumour lesions limited in number as in size are eligible to this technique. Results in terms of local control are satisfying, regarding primary tumours (notably hepatocellular carcinomas) as metastases stemming from various origins. If treatment protocols and follow-up modalities are not standardized to this day, iconographic acquisition using four-dimensional computed tomography, target volumes delineation based on morphological and/or metabolic data, and image-guided radiotherapy contribute to an oncologic efficacy and an improved sparing of the functional liver. The purpose of this literature review is to report the results of the main works having assessed stereotactic radiotherapy in the management of primary and secondary liver tumours. Technical particularities of this radiation modality will also be described.     

Radiothérapie et thérapie ciblée pour la prise en charge du cancer du sein : mise au point

The purpose of this study was to review the current knowledge regarding combinations of the most commonly used targeted therapies or those under development for the management of breast cancer with radiation therapy. Several studies have shown that the combination of radiation therapy and tamoxifen increased the risk of radiation-induced lung toxicity; therefore, the two modalities are generally not given concurrently. The combination of HER2 inhibitors (trastuzumab, pertuzumab) and radiation therapy appeared to be safe. However, trastuzumab emtansine (T-DM1) should not be given concomitantly with brain radiation therapy because this combination may increase the risk of brain radionecrosis. The combination of radiation therapy with other new targeted therapies such as new selective estrogen receptor modulators (SERDs), lapatinib, cell cycle inhibitors, immune checkpoint inhibitors, or molecules acting on DNA damage repair seems feasible but has been mainly evaluated on retrospective or prospective studies with small numbers of patients. Moreover, there is a great heterogeneity between these studies regarding the dose and fractionation used in radiotherapy, the dosage of systemic treatments and the sequence of treatments used. Therefore, the combination of these new molecules with radiotherapy should be proposed sparingly, under close monitoring, pending the ongoing prospective studies cited in this review.     

Quelle place pour la radiothérapie dans la prise en charge des cancers du pancréas localisés ?

At diagnosis, about 15% of patients with pancreatic cancer present with a resectable tumour, 50% have a metastatic tumour, and 25% a locally advanced tumor (non-metastatic but unresectable due to vascular invasion) or borderline resectable. Despite the technical progress made in the field of radiation therapy and the improvement of the efficacy of chemotherapy, the prognosis of these patients remains very poor. Recently, the role of radiation therapy in the management of pancreatic cancer has been much debated. This review aims to evaluate the role of radiation therapy for these patients.     

Immunothérapie et cancer du sein

Immunotherapy development is increasing in several types of tumor, including breast cancer. A large number of studies have focused on the evaluation of tumor-infiltrating lymphocytes, or TILS, as a prognostic and predictive factor, and it seems that a breast cancer sub-type with high rates of TILS has a better prognosis. It can be assumed that these tumors would be good candidates for immunotherapy. Concerning immune checkpoint inhibitors, preliminary results from anti-PD1 administration for breast cancer are less impressive than in other types of cancer, but there are signs of activity in a small proportion of patients who may benefit from treatment over an extended period. At the same time, vaccines targeting various tumor antigens (HER2, Tn, etc.) were developed, and have shown ability to induce an anti-tumor immune response. The future is therefore to a combination of these vaccines with immunotherapy. Nevertheless, the presence of a biomarker to predict response is lacking and we need to identify which patients would benefit from these new and expansive therapies.     

Innovations thérapeutiques en radiothérapie du cancer de la prostate localisé

Intensity-modulated radiation therapy, image-guided radiation therapy with fiducial markers and prostate brachytherapy allow the delivery of dose escalation for localized prostate cancer with very low rates of long-term toxicity and sequelae. Nowadays, modern radiotherapy techniques make it possible to shorten treatment time with hypofractionation, to better protect surrounding healthy tissues and to escalate the dose even further. Advances in radiotherapy are closely linked to advances in magnetic resonance imaging (MRI) and/or PET imaging. Functional imaging makes it possible to deliver personalised pelvic nodal radiotherapy, targeting the nodal areas at higher risk of microscopic involvement. In patients with an index lesion at baseline or at failure, MR-based focal therapy or focal dose escalation with brachytherapy or stereotactic body radiation therapy is also currently investigated. MR-based adaptive radiotherapy, which makes it possible to track prostate shifts during radiation delivery, is another step forward in the integration of MR imaging in radiation delivery.     

Facteurs de risque d’asthénie en cours de la radiothérapie des cancers du sein et de la prostate

PurposePatients frequently report asthenia during radiation. The present study aimed at identifying the correlation between numerous clinical and tumoral factors and asthenia in breast and prostate cancer patients treated by curative radiotherapy.Materials and methodsA retrospective study was conducted at the Lucien Neuwirth Cancer Institute (France). All breast and prostate cancer patients undergoing curative radiotherapy during 2015 were screened (n = 806). Patient's self-evaluation of asthenia and radiotherapy tolerance was assessed through verbal analogic scale (0/10 to 10/10). Data about toxicities, travel distance and travel time, tumor's characteristics, radiotherapy treatment planning, previous cancer therapies, were collected from medical records.Results500 patients were included (350 in the breast cancer group and 150 in the prostate cancer group). In all, 86% of patients in the breast cancer group reported asthenia, with a 5/10 median score. In all, 54% of patients in the prostate cancer group reported asthenia, with a 2/10 median score. Univariate analysis showed correlation between asthenia and radiotherapy tolerance as well as tumor staging, in the prostate cancer group. No other correlation was evidenced.ConclusionRadiotherapy-related fatigue is a common side effect. This study showed that most of the factors related to patients or disease that are commonly used to explain fatigue during curative treatments, seem finally to be not correlated with asthenia.     

Place de la radiochirurgie et de la radiothérapie stéréotaxique hypofractionnée dans la prise en charge des métastases cérébrales

Brain metastases management is still controversial even though many trials are trying to define the respective roles of neurosurgery, whole-brain radiotherapy, single-dose stereotactic radiotherapy and fractionated stereotactic radiotherapy. In this article, we review data from trials that examine the role of radiosurgery and fractionated stereotactic radiotherapy in the management of brain metastases.