J. Leseur

Radiothérapie conformationnelle par modulation d’intensité des tumeurs pédiatriques

Approximately 40-50% of children with cancer will be irradiated during their treatment. Intensity-modulated radiotherapy (IMRT) by linear accelerator or helical tomotherapy improves dose distribution in target volumes and normal tissue sparing. This technology could be particularly useful for pediatric patients to achieve an optimal dose distribution in complex volumes close to critical structures. The use of IMRT can increase the volume of tissue receiving low-dose radiation, and consequently carcinogenicity in childhood population with a good overall survival and long period of life expectancy. This review will present the current and potential IMRT indications for cancers in childhood, and discuss the benefits and problems of this technology aiming to define recommendations in the use of IMRT and specific doses constraints in pediatry.

Long-term side effects of radiotherapy for pediatric localized neuroblastoma

Introduction: Neuroblastoma (NB) is the most frequent indication for extracranial pediatric radiotherapy. As long-term survival of high-risk localized NB has greatly improved, we reviewed treatment-related late toxicities in pediatric patients who received postoperative radiotherapy (RT) for localized NB within two French prospective clinical trials: NB90 and NB94. Patients and methods: From 1990–2000, 610 children were enrolled. Among these, 35 were treated with induction chemotherapy, surgery, and RT. The recommended RT dose was 24 Gy at ≤ 2 years, 34 Gy at > 2 years, ± a 5 Gy boost in both age groups. Results: The 22 patients still alive after 5 years were analyzed. The median follow-up time was 14 years (range 5–21 years). Late effects after therapy occurred in 73 % of patients (16/22), within the RT field for 50 % (11/22). The most frequent in-field effects were musculoskeletal abnormalities (n = 7) that occurred only with doses > 31 Gy/1.5 Gy fraction (p = 0.037). Other effects were endocrine in 3 patients and second malignancies in 2 patients. Four patients presented with multiple in-field late effects only with doses > 31 Gy. Conclusion: After a median follow-up of 14 years, late effects with multimodality treatment were frequent. The most frequent effects were musculoskeletal abnormalities and the threshold for their occurrence was 31 Gy.

Long-term side effects of radiotherapy for pediatric localized neuroblastoma : results from clinical trials NB90 and NB94.

Introduction: Neuroblastoma (NB) is the most frequent indication for extracranial pediatric radiotherapy. As long-term survival of high-risk localized NB has greatly improved, we reviewed treatment-related late toxicities in pediatric patients who received postoperative radiotherapy (RT) for localized NB within two French prospective clinical trials: NB90 and NB94. Patients and methods: From 1990–2000, 610 children were enrolled. Among these, 35 were treated with induction chemotherapy, surgery, and RT. The recommended RT dose was 24 Gy at ≤ 2 years, 34 Gy at > 2 years, ± a 5 Gy boost in both age groups. Results: The 22 patients still alive after 5 years were analyzed. The median follow-up time was 14 years (range 5–21 years). Late effects after therapy occurred in 73 % of patients (16/22), within the RT field for 50 % (11/22). The most frequent in-field effects were musculoskeletal abnormalities (n = 7) that occurred only with doses > 31 Gy/1.5 Gy fraction (p = 0.037). Other effects were endocrine in 3 patients and second malignancies in 2 patients. Four patients presented with multiple in-field late effects only with doses > 31 Gy. Conclusion: After a median follow-up of 14 years, late effects with multimodality treatment were frequent. The most frequent effects were musculoskeletal abnormalities and the threshold for their occurrence was 31 Gy.

Tomographie par émission de positons au (18F)-fluorodésoxyglucose dans les cancers du col utérin : évaluation ganglionnaire et valeur pronostique/prédictive des données de la tumeur primitive

PURPOSE In cervix carcinoma: (a) to evaluate the ability of ((18)F)-fluorodeoxyglucose (FDG) positron emission tomography (PET) in the lymph node detection; (b) to investigate the prognostic and predictive value of the primary cervical PET parameters. PATIENTS AND METHODS Ninety patients treated for cervix carcinoma and evaluated initially by MRI and FGD PET were included. The performances of FDG-PET for lymph node detection (relatively to the lymph node dissection) have been described (sensitivity, specificity, positive predictive value and negative predictive value). PET tumour parameters analyzed were: maximum standard uptake value (SUVmax), the volume and the maximum diameter. The prognostic and predictive values of these parameters were investigated. The tumour response was evaluated on surgical specimens. RESULTS PET detected the cervical tumour with a sensitivity of 97% (mean values: SUVmax=15.8, volume=27 mm(3), maximum diameter=47). For the detection of the lymph nodes, the values of sensibility, specificity, positive predictive value and negative predictive value were: 86, 56, 69 and 78% in the pelvic, and 90, 67, 50 and 95% for the para-aortic area, respectively. The SUVmax was correlated with histologic response (P=0.04). The frequency of partial histological response was significantly higher for tumour SUVmax>10.9 (P=0.017). The maximum PET diameter and pathologic response had an impact on disease-free survival and overall survival in multivariate analysis (P<0.05). CONCLUSION PET has high sensitivity in detecting pelvic and para-aortic lymph nodes. Some primary cervical tumour PET parameters are useful as prognostic and predictive factors.

Techniques récentes en radiothérapie externe pédiatrique

Despite the risk of long-term side effects, external radiation therapy remains a cornerstone of the treatment for many cancers in childhood, in particular for brain tumours and head and neck cancers. Conformal radiation has been the standard of care since several decades. However, new techniques, including stereotactic radiation, intensity-modulated radiation therapy, or protontherapy have proven many advantages in adults, and are more and more discussed in pediatric management due to a favourable cost/benefit rate in some situations. The aim of this article is to point out the potential indications as well as the limits of these new techniques in childhood.

Detection of bladder metabolic artifacts in 18F-FDG PET imaging

Positron emission tomography using (18)F-fluorodeoxyglucose ((18)F-FDG-PET) is a widely used imaging modality in oncology. It enables significant functional information to be included in analyses of anatomical data provided by other image modalities. Although PET offers high sensitivity in detecting suspected malignant metabolism, (18)F-FDG uptake is not tumor-specific and can also be fixed in surrounding healthy tissue, which may consequently be mistaken as cancerous. PET analyses may be particularly hampered in pelvic-located cancers by the bladder׳s physiological uptake potentially obliterating the tumor uptake. In this paper, we propose a novel method for detecting (18)F-FDG bladder artifacts based on a multi-feature double-step classification approach. Using two manually defined seeds (tumor and bladder), the method consists of a semi-automated double-step clustering strategy that simultaneously takes into consideration standard uptake values (SUV) on PET, Hounsfield values on computed tomography (CT), and the distance to the seeds. This method was performed on 52 PET/CT images from patients treated for locally advanced cervical cancer. Manual delineations of the bladder on CT images were used in order to evaluate bladder uptake detection capability. Tumor preservation was evaluated using a manual segmentation of the tumor, with a threshold of 42% of the maximal uptake within the tumor. Robustness was assessed by randomly selecting different initial seeds. The classification averages were 0.94±0.09 for sensitivity, 0.98±0.01 specificity, and 0.98±0.01 accuracy. These results suggest that this method is able to detect most (18)F-FDG bladder metabolism artifacts while preserving tumor uptake, and could thus be used as a pre-processing step for further non-parasitized PET analyses.

Random forests to predict tumor recurrence following cervical cancer therapy using pre- and per-treatment 18 F-FDG PET parameters

The ability to predict tumor recurrence after chemoradiotherapy of locally advanced cervical cancer is a crucial clinical issue to intensify the treatment of the most high-risk patients. The objective of this study was to investigate tumor metabolism characteristics extracted from pre- and per-treatment 18F-FDG PET images to predict 3-year overall recurrence (OR). A total of 53 locally advanced cervical cancer patients underwent pre- and per-treatment 18F-FDG PET (respectively PET1 and PET2). Tumor metabolism was characterized through several delineations using different thresholds, based on a percentage of the maximum uptake, and applied by region-growing. The SUV distribution in PET1 and PET2 within each segmented region was characterized through 7 intensity and histogram-based parameters, 9 shape descriptors and 16 textural features for a total of 1026 parameters. Predictive capability of the extracted parameters was assessed using the area under the receiver operating curve (AUC) associated to univariate logistic regression models and random forest (RF) classifier. In univariate analyses, 36 parameters were highly significant predictors of 3-year OR (p<;0.01), AUC ranging from 0.72 to 0.83. With RF, the Out-of-Bag (OOB) error rate using the totality of the extracted parameters was 26.42% (AUC=0.72). By recursively eliminating the less important variables, OOB error rate of the RF classifier using the nine most important parameters was 13.21% (AUC=0.90). Results suggest that both pre- and per-treatment 18F-FDG PET exams provide meaningful information to predict the tumor recurrence. RF classifier is able to handle a very large number of extracted features and allows the combination of the most prognostic parameters to improve the prediction.

PD-0356: 18F-FDG PET parameters during radio-chemotherapy to predict tumor recurrence in cervical cancer

These prospective study included 53 patients treated for locally advanced cervical cancer by external beam radiation therapy with concurrent chemotherapy, followed by brachytherapy and + surgery. All patients were evaluated by FDG PET/CT before treatment (PET1) and at 40 Gy (PET2). PET-parameters analysed were: maximum standardized uptake value (SUVmax1, SUVmax2), metabolic tumour volume (MTV1, MTV2), and total lesion glycolysis (TLG1, TLG2). MTV1 and MTV2 were automatically segmented (region-growing) using different thresholds (between 30% and 80% of SUVmax). The recurrence were defined based on clinical examination, MRI and PET imaging. Median follow-up was 30 months [range: 8-60]. A total of 13 patients developed disease recurrence and 7 died of disease. The predictive capabilities of the PET parameters to predict overall recurrence were tested using Cox proportional hazards regression models (p values calculated). Comparisons among different models were done by calculating the Harrel’s C-index (c).

Treatment plan library based on population shape analysis for cervical adaptive radiotherapy.

External radiotherapy is extensively used to treat cervix carcinoma. It is based on the acquisition of a planning CT scan on which the treatment is optimized before being delivered over 25 fractions. However, large pertreatment anatomical variations, hamper the dose delivery accuracy, with a risk of tumor under-dose and healthy organs over-dose resulting to recurrence and toxicity. We propose to generate a patient-specific treatment library based on a population analysis. First, the cervix meshes of the population were registered towards a template anatomy using a deformable mesh registration (DMR). The DMR follows an iterative point matching approach based on the local shape context (histogram of cylindrical neighbor coordinates and normalized geodesic distance to the cervix base), a topology constraint filter, a thin-plate-spline interpolation and a Gaussian regularization. Second, a standard principal component analysis (PCA) model was generated to estimate the dominant deformation modes of the population. Posterior PCA was computed to generate different potential anatomies of the target. For a new patient, her cervix was registered towards the template and her pre-treatment library was modeled. This method was applied on the data of 19 patients (282 images), using a leave-one-patient-out. The DMR was evaluated using point-to-point distance (mean: 1.3 mm), Hausdorff distance (5.7 mm), dice coeffi- cient (0.96) and mean triangle area difference (0.49 mm2 ). The performances of two modeled libraries (2 and 6 modeled anatomies) were compared to a classic pre-treatment library based on 3 planning CTs, showing better results according to both target and healthy organs coverage.

Pediatric Localized Intracranial Ependymomas: A Multicenter Analysis of the Société Française de lutte contre les Cancers de l'Enfant (SFCE) from 2000 to 2013

PURPOSE The objective of this study was to analyze survival and prognostic factors for children, adolescents, and young adults treated with postoperative radiation therapy (RT) for intracranial ependymoma. METHODS AND MATERIALS Between 2000 and 2013, 202 patients aged ≤25 years were treated in the 13 main French pediatric RT reference centers. Their medical records were reviewed for information, treatments received, and survival rates. All children had received postoperative RT- conformal, intensity modulated, or proton beam. In 2009, the prescribed standard dose in France rose from 54 Gy to 59.4 Gy. RESULTS Median follow-up was 53.8 months (95% confidence interval [CI] 47-63.5). Median age at RT was 5 years (range 1-22), and 32% of the children treated were aged <3 years. Regarding treatment, 85.6% of patients underwent gross total resection, 62% of patients received conformal RT (vs 29% for intensity modulated RT and 8% for proton beam RT), 62.4% of patients received a dose >54 Gy, and 71% received chemotherapy. Of the 84 relapses, 75% were local. The cumulative incidence of local relapse was 24.4% (95% CI 18.2-31.2) at 3 years and 31.3% (95% CI 24-38.9) at 5 years. The 5-year disease-free survival (DFS) and overall survival rates were 50.4% (95% CI 42.2-58) and 71.4% (95% CI 63.1-78.2). Tumor grade was the only prognostic factor for local relapse and DFS. Tumor grade, age, and extent of resection were independent prognostic factors for overall survival. CONCLUSIONS We confirmed several clinical and tumoral prognostic factors in a large French multicenter study. DFS for intracranial ependymoma remains low, and new biological and imaging markers are needed to distinguish among different subtypes, adapt treatments, and improve survival.