[Inflammatory and immune biomarkers of radiation response]. / Biomarqueurs inflammatoires et immunologiques de réponse à la radiothérapie.

In radiotherapy, the treatment is adapted to each individual to protect healthy tissues but delivers most of time a standard dose according to the tumor histology and site. The only biomarkers studied to individualize the treatment are the HPV status with radiation dose de-escalation strategies, and tumor hypoxia with dose escalation to hypoxic subvolumes using FMISO- or FAZA-PET imaging. In the last decades, evidence has grown about the contribution of the immune system to radiation tumor response. Many preclinical studies have identified some of the mechanisms involved. In this context, we have realised a systematic review to highlight potential inflammatory and immune biomarkers of radiotherapy response. Some are inside the tumor microenvironment, as lymphocyte infiltration or PD-L1 expression, others are circulating biomarkers, including different types of hematological cells, cytokines and chemokines.

[Cancer, radiotherapy and immune system]. / Cancer, radiothérapie et système immunitaire.

Novel paradigms emerge in oncology today. Systemic treatments are more effective and diversified along with an increased life expectancy in oligometastatic patients. Stereotactic radiotherapy using hypofractionation opens new perspectives for local tumour control. The area of radiobiology has expanded with integration of tumour microenvironment in which radiation-induced inflammation mediators and immune system play a major role. Immunity checkpoints inhibitors experience a major development. This rapidly evolving field seems involved in the abscopal effects, especially when radiation is combined with checkpoints inhibitors, as demonstrated in numerous preclinical studies and several clinical trials. Paradoxically, irradiation also produces immunosuppressive effects. This manuscript aims to report the dual effects of ionizing radiation on the immune system and reviews some results of the combination of radiation and immunity chekpoints inhibitors and also research perspectives.

[Intraprostatic fiducials in stereotactic radiotherapy for prostate cancer]. / Fiduciels intraprostatiques dans le cadre de la radiothérapie stéréotaxique du cancer de la prostate.

PURPOSE: Image-guided radiotherapy for prostate cancer is widely used in radiotherapy departments. Intraprostatic gold fiducial markers are used to visualize prostate position and motion before and during treatment. The aim of this report is to describe our experience of implanting intraprostatic fiducial markers under local anesthesia before hypofractionated stereotactic radiotherapy for prostate cancer and to assess its tolerance and reproducibility. PATIENTS AND METHODS: Over a 6 and a half year period, 226 patients with prostate cancer received a stereotactic radiotherapy using the CyberKnife® system (Accuray) in our institution. Eighteen patients were treated for recurrence after prostatectomy; these patients were excluded from the study. Among the 208 remaining patients, 94 patients (45.2%) received stereotactic radiotherapy as a boost after external beam radiotherapy (three fractions of 6Gy); 36 patients (17.3%) were had a re-irradiation (six fractions of 6Gy) and 78 patients (37.5%) had a exclusive stereotactic radiotherapy (68 patients received five fractions of 7.25Gy and 11 patients five fractions of 6.25Gy). Four markers were implanted in all patients using transrectal ultrasound; the procedure was performed under local anesthesia, using transperineal access. The four fiducial markers were implanted in two strands with two fiducial each one, 1cm apart. In order to follow the recommendations of the image-guided radiotherapy system, the two strands of the two markers were located on the same plane in the middle of the prostate, at least 2cm apart from the midline. After insertion, correct positioning of fiducials markers was verified by X-ray. Dosimetry scanning was performed after the implantation procedure; prostate position tracking was possible before and during treatment through the kilovoltage incorporated system of the robotic accelerator. Clinical data, X-ray verification and dosimetry scanner have been retrospectively reviewed for all patients. RESULTS: The tolerance to procedure was excellent; only four patients (1.8%) described pain related to implant. No urinary side effects were reported. Median time from fiducial implantation to dosimetry scanner was 16 days (4-113 days). Four fiducials were found within the prostate at dosimetry scanner in 181 patients and three in 27 remaining patients. All intraprostatic fiducials were used to track the prostate gland before and during treatment. CONCLUSIONS: Intraprostatic fiducial markers implantation is a safe and reproducible procedure that allows us to have reliable prostate information before and during stereotactic radiotherapy.

[Not Available].

PURPOSE OF THE STUDY: To evaluate the efficacy of fractionated stereotactic reirradiation with CyberKnife (CK) performed in 6 patients with high grade gliomas treated in Luxembourg with local recurrence (LR). PATIENTS AND METHODS: Between 04.2014 and 06.2016, 6 patients with multiform grade IV gliomas LR were reirradiated with CK (protocol CNER re-RT CFB 1), as reirradiation. The mean time between primary radiotherapy and local recurrence (LR) is 14.1 months [4 - 38]. CK is performed with a dose of 36 Gy in 6 fractions (5 cases) and 30 Gy in 3 fractions (1 case) Results : LR after CK (progression free survival) is 3.4 months [2 - 7] (5 cases assessment). Mean survival after CK is 12 months [3 - 22] (3 cases assessment). Mean survival after initial diagnosis is 37 months [17 - 58] (3 cases assessment). No toxicity is noticed (4 cases assessment). Time to first progression after primary treatment is a strong predictor for survival. Fractionated stereotactic reirradiation with CK is well tolerated and effective (survival) in patients with LR high grade gliomas. In accordance with these results, the CFB Conseil Scientifique recommends a new paradigm for MRI follow-up high grade gliomas. After first line treatment, an MRI has to be performed every 3 months, to identify LR earlier, and to offer the patients a way of salvage with CK option, in order to increase his chances of better survival.

A new laparoscopic method of bowel radio-protection before pelvic chemoradiation of locally advanced cervix cancers.

BACKGROUND: Chemoradiation therapy (CRT) has become the mainstay of locally advanced cervical carcinomas (LACC). However, the price to pay is a significant rate of both early and late colo-rectal toxicities, which may impact on survivors' quality of life. To reduce the incidence of such complications, we suggest a simple technique of pelvic radioprotection. MATERIALS AND METHODS: An omental flap is created which is placed to fill the Douglas pouch to both increase the space between rectum and uterine cervix and prevent small bowel to fall in and to be exposed to radiation. In addition, a long sigmoid loop is retracted and fixed in the left paracolic gutter to prevent its irradiation as well. RESULTS: From May 2011 to May 2012, 51 successive LACC patients were offered this procedure in addition of a laparoscopic staging. All but 2 with too small an omentum benefitted from omentoplasty, while sigmoidopexy was performed in all but one patient with a long and free sigmoid loop. No immediate adverse effect was observed. The volume of retro-uterine omental flap averaged 7.17 ± 3.79 cm(3). Sequential measurements of the utero-rectal space throughout CRT duration showed a real and durable increase in the distance between these organs, resulting in a drop in the dose of irradiation to recto-sigmoid. With 10 ± 4.5-month median follow-up, we did not observe any rectal or small bowel early or late adverse effects of CRT. CONCLUSIONS: Although this series is preliminary, this simple procedure, feasible by laparoscopy (or laparotomy), seems effective to prevent recto-sigmoid as well as small bowel from radio-induced complications due to pelvic CRT.

[Permanent iodine-125 implants brachytherapy: results after 10 years of experience in Liège University Hospital]. / La curiethérapie prostatique par implants permanents d'iode 125: résultats après 10 ans d'expérience au CHU de Liège.

Permanent implant iodine-125 brachytherapy is an attractive treatment option for men with localized prostate cancer and is an alternative approach to radical prostatectomy. Overall survival and biochemical relapse free survival are similar with both treatments but the toxicity is different. More potency preservation, less incontinence and one day hospitalisation are attractive for the patient with brachytherapy. On the other side, pre-existing obstructive or irritative urinary symptoms at baseline have to guide the patient to a surgical approach. A patient has to be able to select one of these two therapeutic opportunities through a complete transparent information. In this paper, we related our permanent implant iodine-125 brachytherapy experience. Overall survival, biochemical relapse free survival and registred toxicity are similar to those published in the literature.

[Laparoscopic radical hysterectomy after initial brachytherapy for stage IB1 cervical cancer: feasibility and results]. / Colpohystérectomie élargie par laparoscopie après curiethérapie préopératoire pour cancer du col utérin (stade 1B1) : faisabilité et résultats.

BACKGROUND: The aim of this study was to examine the feasibility and to report the results of laparoscopic radical hysterectomy (LRH) after initial uterovaginal brachytherapy (BT) for stage IB1 cervical cancer. PATIENTS AND METHODS: We retrospectively reviewed in two Comprehensive Cancer Centers patients who had undergone initial BT followed 6 to 8 weeks later by LRH and lymph node dissection. RESULTS: Between 2003 and 2010, 162 patients had undergone LRH. The procedure was feasible using this approach in 160 (98.8%) cases (2 conversions to laparotomy). Eight peroperative complications had occurred. Nineteen patients had nodal involvement. Peri- or postoperative ureteral morbidity had occurred in 10 (6%) patients. Twenty-four (15%) patients had experienced postoperative dysuria. Histologically, only 9 patients had residual cervical disease>5 mm and only 1 patient had parametrial lymphovascular space involvement (associated with nodal spread). No patient had vaginal disease or involved surgical margins. After a median follow-up of 39 months (range, 3-118), 9 patients had relapsed. Five-year overall survival was 95% (88.2%-97.9%). CONCLUSIONS: Radical hysterectomy using a laparoscopic approach is feasible and reproducible after initial BT for stage IB1 cervical cancer and is associated with excellent survival. Morbidity is very close to that reported in patients treated using upfront surgery. In this large series, the morbidity associated with parametrial dissection and the fact that parametrial spread was observed in only 0.6% of the patients suggest that a simple extrafascial hysterectomy is perhaps sufficient in this context.

[Image-guided adaptive brachytherapy in the treatment of patients with cervix cancer]. / Curiethérapie intégrant l'imagerie dans la prise en charge des patientes atteintes d'un cancer du col utérin.

Deep modifications have occurred these last years in the brachytherapy use in patients with cervix cancer. Imaging allowed a more precise definition of the volumes of interest linked to the tumour and its extension as well as a better visualization of organs at risk. Recommendations on delineation modalities were published in 2005, leading to definition homogeneity, even if large variations are still observed among centres, in terms of techniques and doses. These new definitions also served as basis for new applicators development, allowing a combination of interstitial and endocavitary techniques. Results from centres using image-guided brachytherapy (MRI in particular) evidenced local control improvement, without increase in complications. Retrospective and prospective studies are currently under evaluation. These studies will likely be able to determine dose required to sterilize tumours, as a function of stage and size, as well as dose limits for organs at risk.

[High dose rate prostate brachytherapy]. / Curiethérapie prostatique de haut débit de dose.

This article aims at presenting the interest of high dose rate brachytherapy in the radiation treatment of prostatic adenocarcinoma. We will discuss successively the biological and dosimetric specificity of brachytherapy for this particular cancer. Afterwards, we will review the main phase II and III studies, the therapeutic indications in the daily practice from the evidence based medicine as well as the techniques of external beam radiation therapy for the same indications. Finally, the principal avenues of development will be discussed.

[Permanent implant prostate cancer brachytherapy: 2013 state-of-the art]. / Curiethérapie du cancer prostatique par implants permanents : le point en 2013.

With an experience of more than 25 years for the pioneers (and more than 14 years in France), permanent implant brachytherapy using iodine 125 seeds (essentially) is now recognized as a valuable alternative therapy for localized low-risk prostate cancer patients. The possible extension of the indications of exclusive brachytherapy towards selected patients in the intermediate-risk group has now been confirmed by several studies. Moreover, for the other patients in the intermediate-risk group and for the patients in the high-risk group, brachytherapy, as an addition to external radiotherapy, could represent one of the best ways to escalate the dose. Different permanent implant brachytherapy techniques have been proposed; preplanning or real-time procedure, loose or stranded seeds (or both), manual or automatic injection of the seeds. The main point here is the ability to perfectly master the procedure and to comply with the dosimetric constraints, which have been recently redefined by the international societies, such as the GEC-ESTRO group. Mid- and long-term results, which are now available in the literature, indicate relapse-free survival rates of about 90% at 5-10 years, the best results being obtained with satisfactory dosimetric data. Comparative data have shown that the incontinence and impotence rates after brachytherapy seemed to be significantly inferior to what is currently observed after surgery. However, a risk of about 3 to 5% of urinary retention is usually reported after brachytherapy, as well as an irritative urinary syndrome, which may significantly alter the quality of life of the patients, and last several months. In spite of those drawbacks, with excellent long-term results, low rates of incontinence and impotence, and emerging new indications (focal brachytherapy, salvage brachytherapy after localized failure of an external irradiation), permanent implant prostate brachytherapy can be expected to be proposed to an increasing number of patients in the next future.

[Is adaptive intensity-modulated radiotherapy for uterine cervix carcinoma necessary?]. / La radiothérapie (conformationnelle avec modulation d'intensité) adaptative est-elle nécessaire pour les carcinomes du col utérin ?

PURPOSE: To observe on ten patients, the changes of different pelvic structures during a Stade IB2-IIB cervix cancer tomotherapy course delivering 60Gy over 5.5 weeks and evaluate the rationale of adaptive treatments. MATERIALS AND METHODS: Each of the six weekly mega voltage CT-scan (MVCT) exams performed the same day of the week were analyzed. The centro-pelvic CTV volume was contoured as well as the organs at risk (OAR). The dose delivered was recalculated while those to 2%, 50% and 98% of the centro-pelvic CTV as well as to 2 cm(3), 10 cm(3) and 50 cm(3) of the OAR were analyzed. RESULTS: The mean decrease in volume of the centro-pelvic CTV was 13% and non-significant (P>0.2). However four tumors decreased from 21% to 42%. This decrease was centripetal. Likewise, the fraction doses to 2%, 50% and 98% were respectively 2.14±0.08Gy, 2.02±0.14 Gy, 1.8±0.34Gy at week 1 and 2.13±0.1 Gy, 2.06±0.12Gy, 1.88±0.24Gy at week 6 (P>0.2). The doses delivered to 2 cm(3), 10 cm(3) and 50 cm(3) of the different OAR did not change at a significant level (P>0.05) too, except the dose to 50 cm(3) of non-sigmoid bowel moving from 1.69±0.16Gy at week 1 to 1.78±0.14Gy at week 6 (P=0.05). CONCLUSION: As a whole, adaptive therapy does not seem mandatory in this population of stages IB2-IIB cancers. A complementary study on more advanced stages is however necessary.

Results and special considerations when treating elderly patients with CyberKnife®: a review of 345 cases.

The relatively recent introduction of CyberKnife® in the field of radiotherapy has prompted the question of accessibility and usefulness of this technique for seniors. From June 2007 to June 2009, we treated 345 patients of all ages with CyberKnife as part of a single-center study. Median age was 61 years (range, 8-86 years). Ninety-eight patients were over 70 and 17 were older than 80. The treatment could not be completed with 2% (2/98) patients over 70 vs. 3.6% (9/247) among the younger (ns). Physiologic or psychologic problems in maintaining position for a long time were not more frequent among those over 70. The same was true with those over 80. Patients over 70 years old are able to tolerate CyberKnife treatment as efficiently as their younger counterparts. Elderly patients should not be restricted from access to CyberKnife radiosurgery with curative intent.

[Functional MR Imaging: new tool to predict outcome for cervical carcinoma of uterus treated by concomitant radiochemotherapy?]. / IRM fonctionnelle: nouvel outil pour prédire la réponse des cancers du col utérin à la chimioradiothérapie concomitante?

The treatment of advanced cervix is concomitant radiochemotherapy. Local prognosis and global survival depend on tumoral volume, locoregional extension and radio sensitivity of the lesion. This one is function of tumoral hypoxia, tumoral interstitial pressure and existence of an anaemia. DCE-MRI allows to quantify pilot vascular parameters of the first two factors. Combined analysis: tumoral volume, anaemia and vascular parameters before and in the course of treatment allows a strong correlation with the risk of local recurrence and global survival.

[Partial breast irradiation: the role of brachytherapy. A new treatment option for early breast cancer]. / L'irradiation partielle du sein et le rôle de la curiethérapie: une nouvelle approche thérapeutique pour les carcinomes mammaires de bon pronostic.

Early breast cancer can be treated by conservative surgery followed by partial breast irradiation. This recent treatment replaces classical external beam whole breast radiotherapy. Several techniques are available but most experience does exist with interstitial catheter based brachytherapy. This well tolerated treatment shortens the treatment time and offers a good local control and cosmetic outcome, comparable to the best classical treatments, as confirmed by the first published results. These good results can only be obtained by rigorous patient selection and very precise 3D imaging and source implantation techniques.

[How I treat...fibroproliferative scars]. / Comment je traite...les cicatrices fibroprolifératives.

Following a skin injury like burn, surgery or a trauma, fibroproliferatives scars are responsible of cosmetic, psychologic and symptomatic disorders. Keloids are benign and occur secondary to an imbalance between the synthesis of extracellular matrix and its degradation. There is a lot of therapeutic modalities available. Despite this, recurrence and sometimes increasing lesions are the major complications. Surgery with adjuvant therapy like steroids injections, radiotherapy, silicone materials seems today the best therapeutic choice. A best physiopatholgy's comprehension is at the base of new treatments, but their efficacity still need to be demonstrate in larger studies.

[Prostate brachytherapy: current states and future prospects]. / La curiethérapie prostatique: réalités et perspectives.

The paper presents the characteristics, the place and the limits of brachytherapy in prostate radiotherapy. While sparing the rectal wall, erectile function as well as urinary continence, I(125) and Pd(103) permanent implants represent interesting approaches for good prognosis tumours in comparison to surgery or conformal external beam radiotherapy with similar cure rates. Overcoming easily the problems of organ motion and patient positioning while allowing doses per fraction as high as 10 Gy, brachytherapy is an excellent boosting method in the treatment of intermediate or unfavourable prognosis tumours of which alpha/beta is 1,5 Gy. Encouraging biological control rates of 80-90% have been published in phase II trials. Compared to external beam radiotherapy, the heterogeneity of irradiation inside the clinical target volume should increase the probability of cure as for a specific dose, a significant part will be overdosed. So far, 120-130% of the prescribed doses are delivered to the peripheral zone at the origin of 70% of tumours. On the opposite, this heterogeneity is inducing an overdosage of the urethral bed at the price of higher toxicity levels in situations of previous obstructive syndrome and urethral stenosis. A better integration of the therapeutic modalities available, brachytherapy included, should increase our curative possibilities in the radiation treatment of prostatic cancer.

PSA kinetics after external beam radiotherapy alone or combined with an iridium brachytherapy boost to deliver 85 grays to prostatic adenocarcinoma.

PURPOSE: Increasing the dose to prostatic adenocarcinoma in conformal external beam therapy (EBT) has resulted in increased levels of PSA normalization and increased percentage of biochemical disease-free survival rates. However technical problems due to prostate motion inside the pelvis or patients' set-up make difficult the realization of the EBT boost fields above 72 Gy. Brachytherapy which overcomes these problems was investigated to deliver the boost dose to achieve 85 Gy. PSA nadir which has been identified as the strongest independent predictor of any failure in many studies has been used as the end point for early evaluation of this work. PATIENTS AND METHODS: In a retrospective way we report on 163 patients' PSA kinetics after EBT alone to 68 Gy or EBT first and a brachytherapy boost up to 75 or 85 Gy. RESULTS: At 12 months follow-up, PSA nadirs percentage < or = 0.5 or < or = 1 ng/ml increased from 7.5 and 20.7% after 68 Gy EBT to 49.8 and 71.2% after a brachytherapy boost to deliver 85 Gy (p < 0.0001). In the Cox PH model analysis, the total dose remained the most important factor for predicting PSA normalization. CONCLUSIONS: These results are in accordance with the most recent results published after conformal EBT at the same 80 Gy level of dose. If confirmed on a higher number of patients they could place brachytherapy among the most accurate methods of boosting in the radiation treatment of prostatic carcinoma.

Feasibility study combining low dose rate (192)Ir brachytherapy and external beam radiotherapy aiming at delivering 80-85 Gy to prostatic adenocarcinoma.

BACKGROUND: Increasing the radiation dose to prostatic adenocarcinoma has provided higher local control rates. A total of 80 Gy seem necessary to achieve this goal but patient set-up and prostate motion remain difficult problems to solve in conformal radiotherapy. Brachytherapy which overcomes these points could be an alternative way to external beam boost fields. We wanted to transpose the irradiation models largely used in cervix cancer treatment combining external beam radiotherapy and low dose rate brachytherapy. MATERIALS AND METHODS: In 71 patients with 19.5 and 13 ng/ml mean and median PSA levels, respectively, a dose escalation from 74 to 85 Gy was performed in four groups. RESULTS: Shifting from intraoperative placement of sources vectors (Group I) to positioning under ultrasound controls (groups II-IV), improving the implantation shape and optimizing radiation delivery to urethral bed have reduced the total dose to rectal wall under 65 Gy and to urethra under 100 Gy. Rectal/prostate dose ratio was lowered from 0.7 (Groups I-II) to 0.58 (Groups III-IV) while avoiding problems resulting from pelvic bone arch interference, prostate volume or seminal vesicles location. The mean and median follow-up periods are 28 and 18 months. In Groups III and IV 85% of patients without hormonotherapy treated with 80-85 Gy normalized PSA under 1 ng/ml within 6 months. No severe late effect has been noted for patients implanted under echographic control. CONCLUSIONS: The method described allows to deliver 85 Gy. Longer follow-up is however needed but the levels of dose delivered are not expected to induce prohibitive side effects.

Modern brachytherapy: current state and future prospects.

This article reviews the current trends and future developments in brachytherapy. Established techniques including interstitial and high-dose rate brachytherapy are discussed with particular reference to lung, oesophageal, cervical and endometrial cancer. Intra-operative high-dose rate brachytherapy and other new techniques are also mentioned.