J. Castelli

The synergistic effect of radiotherapy and immunotherapy: A promising but not simple partnership

Radiotherapy (RT) is one of the main components in the treatment of cancer. The better understanding of the immune mechanisms associated with tumor establishment and how RT affects inflammation and immunity has led to the development of novel treatment strategies. Several preclinical studies support the use of RT in combination with immunotherapy obtaining better local and systemic tumor control. Current ongoing studies will provide information about the optimal RT approach, but the development of reliable predictors of the response from the preclinical and the early phases of clinical studies is necessary to avoid discarding treatment strategies with significant clinical benefit. This review summarize the current concepts of the synergism between RT and immunotherapy, the molecular effects of RT in the tumor microenvironment, their impact on immune activation and its potential clinical applications in trials exploring this important therapeutic opportunity. Finally, the potential predictors of clinical response are discussed.

Revue généraleCancers de prostate : quelles techniques de radiothérapie pour quelles tumeurs ? Enjeux éthiques et méthodologiquesProstate cancer: What treatment techniques for which tumors? Ethical and methodological issues

The identification of the optimal radiation technique in prostate cancer is based on the results of dosimetric and clinical studies, although there are almost no randomized studies comparing different radiation techniques. The feasibility of the techniques depends also on the technical and human resources of the radiation department, on the cost of the treatment from the points of view of the society, the patient and the radiation oncologist, and finally on the choice of the patient. The slow evolution of prostate cancer leads to consider the biochemical failure as the main judgment criteria in the majority of the studies. A proper urinary radio-induced toxicity evaluation implies a long follow-up. Intensity-modulated radiotherapy (IMRT) combined with image-guided radiotherapy (IGRT) is recommended in case of high dose (≥76Gy) to the prostate, pelvic lymph nodes irradiation and hypofractionation schedules. For low-risk tumors, the aim of the treatment is to preserve quality of life, while limiting costs. Stereotactic body radiotherapy shows promising results, although the follow-up is still limited and phase III trials are ongoing. Focal radiation techniques are in the step of feasibility. For intermediate and high-risk tumors, the objective of the treatment is to increase the locoregional control, while limiting the toxicity. IMRT combined with IGRT leads to either a well-validated dose escalation strategy for intermediate risk tumors, or to a strategy of moderate hypofractionated schedules, which cannot be yet considered as a standard treatment. These combined radiation techniques allow finally large lymph node target volume irradiation and dose escalation potentially in the dominant intraprostatic lesion. The feasibility of simultaneous integrated boost approaches is demonstrated.

Nomogram to predict rectal toxicity following prostate cancer radiotherapy

Background To identify predictors of acute and late rectal toxicity following prostate cancer radiotherapy (RT), while integrating the potential impact of RT technique, dose escalation, and moderate hypofractionation, thus enabling us to generate a nomogram for individual prediction. Methods In total, 972 patients underwent RT for localized prostate cancer, to a total dose of 70 Gy or 80 Gy, using two different fractionations (2 Gy or 2.5 Gy/day), by means of several RT techniques (3D conformal RT [3DCRT], intensity-modulated RT [IMRT], or image-guided RT [IGRT]). Multivariate analyses were performed to identify predictors of acute and late rectal toxicity. A nomogram was generated based on the logistic regression model used to predict the 3-year rectal toxicity risk, with its accuracy assessed by dividing the cohort into training and validation subgroups. Results Mean follow-up for the entire cohort was 62 months, ranging from 6 to 235. The rate of acute Grade ≥2 rectal toxicity was 22.2%, decreasing when combining IMRT and IGRT, compared to 3DCRT (RR = 0.4, 95%CI: 0.3–0.6, p<0.01). The 5-year Grade ≥2 risks for rectal bleeding, urgency/tenesmus, diarrhea, and fecal incontinence were 9.9%, 4.5%, 2.8%, and 0.4%, respectively. The 3-year Grade ≥2 risk for overall rectal toxicity increased with total dose (p<0.01, RR = 1.1, 95%CI: 1.0–1.1) and dose per fraction (2Gy vs. 2.5Gy) (p = 0.03, RR = 3.3, 95%CI: 1.1–10.0), and decreased when combining IMRT and IGRT (RR = 0.50, 95% CI: 0.3–0.8, p<0.01). Based on these three parameters, a nomogram was generated. Conclusions Dose escalation and moderate hypofractionation increase late rectal toxicity. IMRT combined with IGRT markedly decreases acute and late rectal toxicity. Performing combined IMRT and IGRT can thus be envisaged for dose escalation and moderate hypofractionation. Our nomogram predicts the 3-year rectal toxicity risk by integrating total dose, fraction dose, and RT technique.

Original paperCyberKnife® M6™: Peripheral dose evaluation for brain treatments

PURPOSE This study evaluates the peripheral dose (PD) delivered to healthy tissues for brain stereotactic radiotherapy treatments (SRT) performed with a CyberKnife M6™ Robotic Radiosurgery System and proposes a model to estimate PD before treatment. METHOD PD was measured with thermoluminescent dosimeters. Measurements were performed to evaluate the influence of distance, collimator type (fixed or Iris™) and aperture size on PD for typical brain treatment plans simulated on an anthropomorphic phantom. A model to estimate PD was defined by fitting functions to these measurements. In vivo measurements were subsequently performed on 30 patients and compared to the model-predicted PD. RESULTS PD (in cGy) was about 0.06% of MU at 15cm for a 20mm fixed collimator and 0.04% of MU for the same aperture with Iris™ collimator. In vivo measurements showed an average thyroid dose of 55mGy (σ=18.8mGy). Computed dose for thyroid, breast, umbilicus and gonads showed on average a relative difference of 3.4% with the in vivo dose (σ=12.4%). CONCLUSION PD at the thyroid with Iris™ was about a third lower than with a fixed collimator in case of brain SRT. Despite uncertainties (use of anthropomorphic PD to estimate patient specific PD, surface PD to estimate OAR PD) the model allows PD to be estimated without in vivo measurements. This method could be used to optimise PD with different planning strategies.

Contraintes de doses aux organes à risque en radiothérapie conformationnelle et stéréotaxique : intestin grêle et duodénum

Radiotherapy of abdominopelvic primary or secondary lesions in conformational or stereotactic techniques is in full development. The small bowel is highly sensitive to irradiation and is the main organ at risk limiting prescription doses. This literature review aims to define the dose constraints to the small bowel and the duodenum in conformational and stereotactic body radiotherapy. The small bowel including the duodenum, jejunum and ileum is delineated on the simulation scanner. The radio-induced intestinal toxicities are acute related to the cellular depopulation of the intestinal mucosa, and late of more complex pathophysiology associating depletion in stem cells, microangiopathy, chronic inflammation and fibrosis. The main predictive factor of intestinal toxicity is the dose-volume ratio. In conformational radiotherapy, the dose constraints to the duodenum are: V25Gy<45% and V35Gy<20%. The jejunum and ileum dose constraints are for delineation by intestinal loop or peritoneal cavity respectively: V15Gy<275mL or V15Gy<830mL and V45Gy<150mL. In stereotactic body radiotherapy, small bowel dose constraints depend on fractionation and are defined on a small volume and on a maximum dose at one point. Intestinal toxicity is also dependent on factors intrinsic to the patient and radiosensitizers such as targeted therapies or chemotherapies. With the development of new techniques allowing dose escalation on the tumour and the development of inverse planning, the definition of dose constraints to the small bowel is essential for current practice.

( 18 F)-FDG PET/CT parameters to predict survival and recurrence in patients with locally advanced cervical cancer treated with chemoradiotherapy

PURPOSE To identify predictive (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-based parameters for locoregional control, disease-free survival and overall survival, by testing different thresholds of metabolic tumor volume and total lesion glycolysis in patients with locally-advanced cervical cancer. PATIENTS AND METHODS Thirty-seven patients treated with standard chemoirradiation underwent a pretreatment (18F)-FDG-PET/CT. Using different thresholds of maximum standardized uptake value, the following PET parameters were computed: maximum standardized uptake value, mean standardized uptake value, metabolic tumor volume and total lesion glycolysis for primary tumor and lymph nodes and a new parameter combining the metabolic tumor volume and the distance between lymph nodes and the primary tumor, namely metabolic node distance. Correlation between PET and clinical parameters with clinical outcome (overall survival, disease-free survival, and locoregional control) was assessed using univariate and multivariate analyses (Cox model). RESULTS In univariate analyses, PET/CT parameters associated with overall survival and disease-free survival were: metabolic tumor volume and total lesion glycolysis of the primary tumor, total lesion glycolysis of lymph nodes and metabolic node distance. The most predictive threshold segmentation for metabolic tumor volume and total lesion glycolysis was 48% of maximum standardized uptake value for the primary tumor and 30% for the lymph nodes. In multivariate Cox analysis, the total lesion glycolysis of primary tumor 48% and metabolic node distance were the two independent risk factors for overall survival (P<0.01), disease-free survival (P<0.01) and locoregional control (P=0.046). CONCLUSION Total lesion glycolysis of primary tumor and distance between the invaded positive lymph node and the primary tumor seem to have the highest predictive value when compared to classical clinical prognostic parameters and may be useful to identify high risk groups at time of diagnosis and to tailor the therapeutic approach in locally-advanced cervical cancer.

Doses dans les organes à risque en radiothérapie conformationnelle et en radiothérapie en conditions stéréotaxiques : la vessie

Bladder dose constraints in case of conformational radiotherapy/intensity-modulated radiotherapy and stereotactic radiotherapy are reported from the literature, in particular from the French radiotherapy society RECORAD recommendations, according to the treated pelvic tumor sites. The dose-volume effect on urinary toxicity is not clearly demonstrated, making difficult to establish absolute dose constraints for the bladder. In case of high-dose prostate cancer radiotherapy, the bladder dose constraints are: V60Gy<50% and maximum dose<80Gy for standard fractionation and V60Gy<5%, V48Gy<25% and V41Gy<50% for moderate hypofractionation (20 fractions of 3Gy). In case of prostate stereotactic radiotherapy (five fractions of 7.25Gy), the most frequent dose constraints in the literature are V37Gy<10cm3 and V18Gy<40%. In case of conformational radiotherapy of cervix cancer, postoperative endometrium, anal canal and rectum, the recommendations are V40Gy<40% and D2% lower than the prescribed dose.

EP-1642: Comparison between a conventional IMRT planning method and a new automated planning method.

Purpose or Objective: The inverse planning for IMRT is variable due to a high number of parameters to be defined by the operator. So the quality of treatment plan depends on the level of operator expertise. The aim of this study was to evaluate the automatic “AutoPlanning” planning tool implemented in Pinnacle v9.10 TPS (Philips) for IMRT Step&Shoot (S&S) and VMAT techniques for three localisations: prostate, pelvis and head and neck (H&N) with integrated boost technique with three dose level.

EP-1797: Pelvic lymph node PTV margins in prostate IMRT

Material and Methods: The planning CT scans (CT0) and 7 per-treatment weekly CT scans of 20 patients having received IMRT for prostate cancer were used. The main pelvic vessels were manually delineated: common iliac (CI), external iliac (EI) and internal iliac (II) of both sides. The central lines of the vessels were first defined thanks to a 3D workstation (EndoSize®, Therenva) dedicated to the preoperative sizing before endovascular interventions. A pelvic bone registration was then performed. For a given vascular segment, the distance between its central line CL0 from CT0 and its central line CLi from the weekly CTs were calculated.The central line CL0 of each vascular segment was sampled every mm. The distance corresponded to the mean value of the distances between corresponding points of the two central lines (CL0 and CLi). The correspondance was established by considering the cross-section plane othogonal to CL0 at a given point and its intersection with CLi. For each patient, the mean and the standard deviation (SD) of the measurements of the 7 fractions were determined. The systematic error (∑) of the whole population was calculated as the SD of the mean values. The random error (σ) of the whole population was calculated as the root mean square of the standard deviation values. The margins were calculated both with M. Van Herk formula (IJROBP 2000) and by geometrically computing margins covering 99% of the vessels displacements.