Adjuvant or Salvage Radiation Therapy for Prostate Cancer after Prostatectomy: Current Status, Controversies and Perspectives.

Nearly one-third of the patients who undergo prostatectomy for prostate cancer have a biochemical recurrence (BCR) during follow-up. While several randomized trials have shown that adjuvant radiation therapy (aRT) improves biochemical control, this strategy has not been widely used because of the risk of toxicity and the fear of overtreating patients who would not have relapsed. In addition, the possibility of close PSA monitoring in the era of ultrasensitive assays enables to anticipate early salvage strategies (sRT). Three recent randomized trials and their meta-analysis have confirmed that aRT does not improve event-free survival compared to sRT, imposing the latter as the new standard of treatment. The addition of androgen deprivation therapy (ADT) to RT has been shown to improve biochemical control and metastasis-free survival, but the precise definition of to whom it should be proposed is still a matter of debate. The development of genomic tests or the use of artificial intelligence will allow more individualized treatment in the future. Therapeutic intensification with the combination of new-generation hormone therapy and RT is under study. Finally, the growing importance of metabolic imaging (PET/CT) due to its performance especially for low PSA levels will help in further personalizing management strategies.

Hypoxia Imaging and Adaptive Radiotherapy: A State-of-the-Art Approach in the Management of Glioma.

Severe hypoxia [oxygen partial pressure (pO2) below 5-10 mmHg] is more frequent in glioblastoma multiforme (GBM) compared to lower-grade gliomas. Seminal studies in the 1950s demonstrated that hypoxia was associated with increased resistance to low-linear energy transfer (LET) ionizing radiation. In experimental conditions, the total radiation dose has to be multiplied by a factor of 3 to achieve the same cell lethality in anoxic situations. The presence of hypoxia in human tumors is assumed to contribute to treatment failures after radiotherapy (RT) in cancer patients. Therefore, a logical way to overcome hypoxia-induced radioresistance would be to deliver substantially higher doses of RT in hypoxic volumes delineated on pre-treatment imaging as biological target volumes (BTVs). Such an approach faces various fundamental, technical, and clinical challenges. The present review addresses several technical points related to the delineation of hypoxic zones, which include: spatial accuracy, quantitative vs. relative threshold, variations of hypoxia levels during RT, and availability of hypoxia tracers. The feasibility of hypoxia imaging as an assessment tool for early tumor response to RT and for predicting long-term outcomes is discussed. Hypoxia imaging for RT dose painting is likewise examined. As for the radiation oncologist's point of view, hypoxia maps should be converted into dose-distribution objectives for RT planning. Taking into account the physics and the radiobiology of various irradiation beams, preliminary in silico studies are required to investigate the feasibility of dose escalation in terms of normal tissue tolerance before clinical trials are undertaken.

Does East meet West? Towards a unified vision of the management of Nasopharyngeal carcinoma.

Nasopharyngeal cancer (NPC) is notable for its wide geographic variation, with incidences as high as 30 in 100,000 in endemic regions but < 1 in 100,000 worldwide. This review aims to identify areas where there could be differences in prognosis, management or outcomes among countries with high or low incidence of NPC. The incidence has generally declined both in endemic and non-endemic regions throughout the years, which may be attributed to the decrease in exposure to risk factors such as early exposure to salted fish and smoking. Ethnicity has an impact both on incidence and prognosis, with Southeast Asians having the highest incidence but also better survival. Concurrent chemoradiotherapy, with or without adjuvant and/or induction chemotherapy, is the standard of care for locoregionally advanced disease, as reflected in clinical practice guidelines. Despite improvements in management, a proportion of patients relapse. Salvage treatment is associated with significant morbidity due to the critical location of the nasopharynx and the toxicities of initial therapy. Clinical expertise is paramount, but is easier to attain in endemic regions and high volume centers where enrollment of patients in clinical trials is more feasible. Collaboration between low and high incidence countries and between low and high volume facilities is key to improving NPC prognosis worldwide.

The complexity of tumor shape, spiculatedness, correlates with tumor radiomic shape features.

Radiomics extracts high-throughput quantitative data from medical images to contribute to precision medicine. Radiomic shape features have been shown to correlate with patient outcomes. However, how radiomic shape features vary in function of tumor complexity and tumor volume, as well as with method used for meshing and voxel resampling, remains unknown. The aims of this study are to create tumor models with varying degrees of complexity, or spiculatedness, and evaluate their relationship with quantitatively extracted shape features. Twenty-eight tumor models were mathematically created using spherical harmonics with the spiculatedness degree d being increased by increments of 3 (d = 11 to d = 92). Models were 3D printed with identical bases of 5 cm, imaged with a CT scanner with two different slice thicknesses, and semi-automatically delineated. Resampling of the resulting masks on a 1 × 1 × 1 mm3 grid was performed, and the voxel size of each model was then calculated to eliminate volume differences. Four MATLAB-based algorithms (isosurface (M1), isosurface filter (M2), isosurface remeshing (M3), and boundary (M4)) were used to extract nine 3D features (Volume, Surface area, Surface-to-volume, Compactness1, Compactness2, Compactness3, Spherical Disproportion, Sphericity and Fractional Concavity). To quantify the impact of 3D printing, acquisition, segmentation and meshing, features were computed directly from the stereolithography (STL) file format that was used for 3D printing, and compared to those computed. Changes in feature values between 0.6 and 2 mm slice acquisitions were also compared. Spearman's rank-order correlation coefficients were computed to determine the relationship of each shape feature with spiculatedness for each of the four meshing algorithms. Percent changes were calculated between shape features extracted from the original and resampled contoured images to evaluate the influence of spatial resampling. Finally, the percent change in shape features when the volume was changed from 25% to 150% of their original volume was quantified for three distinct tumor models and compared to the percent change observed when modifying the spiculatedness of the model from d = 11 to d = 92. Values extracted using isosurface remeshing method are the closest to the STL reference ones, with mean differences less than 10.8% (Compactness2) for all features. Seven of the eight features had strong significant correlations with tumor model complexity irrespective of the meshing algorithm (r > 0.98, p < 10-4), with fractional concavity having the lowest correlation coefficient (r = 0.83, p < 10-4, M2). Comparisons of features extracted from the 0.6 and 2 mm slice thicknesses showed that mean differences were from 2.1% (Compactness3) to 12.7% (Compactness2) for the isosurface remeshing method. Resampling on a 1 × 1 × 1 mm3 grid resulted in between 1.3% (Compactness3) to 9.5% (Fractional Concavity) mean changes in feature values. Compactness2, Compactness3, Spherical Disproportion, Sphericity and Fractional Concavity were the features least affected by volume changes. Compactness1 had a 90.4% change with volume, which was greater than the change between the least and most spiculated models. This is the first methodological study that directly demonstrates the relationship of tumor spiculatedness with radiomic shape features, that also produced 3D tumor models, which may serve as reference phantoms for future radiomic studies. Surface Area, Surface-to-volume, and Spherical Disproportion had direct relationships with spiculatedness while the three formulas for Compactness, Sphericity and Fractional Concavity had inverse relationships. The features Compactness2, Compactness3, Spherical Disproportion, and Sphericity should be prioritized as these have minimal variations with volume changes, slice thickness and resampling.

A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study.

BACKGROUND: Because responses of patients with cancer to immunotherapy can vary in success, innovative predictors of response to treatment are urgently needed to improve treatment outcomes. We aimed to develop and independently validate a radiomics-based biomarker of tumour-infiltrating CD8 cells in patients included in phase 1 trials of anti-programmed cell death protein (PD)-1 or anti-programmed cell death ligand 1 (PD-L1) monotherapy. We also aimed to evaluate the association between the biomarker, and tumour immune phenotype and clinical outcomes of these patients. METHODS: In this retrospective multicohort study, we used four independent cohorts of patients with advanced solid tumours to develop and validate a radiomic signature predictive of immunotherapy response by combining contrast-enhanced CT images and RNA-seq genomic data from tumour biopsies to assess CD8 cell tumour infiltration. To develop the radiomic signature of CD8 cells, we used the CT images and RNA sequencing data of 135 patients with advanced solid malignant tumours who had been enrolled into the MOSCATO trial between May 1, 2012, and March 31, 2016, in France (training set). The genomic data, which are based on the CD8B gene, were used to estimate the abundance of CD8 cells in the samples and data were then aligned with the images to generate the radiomic signatures. The concordance of the radiomic signature (primary endpoint) was validated in a Cancer Genome Atlas [TGCA] database dataset including 119 patients who had available baseline preoperative imaging data and corresponding transcriptomic data on June 30, 2017. From 84 input variables used for the machine-learning method (78 radiomic features, five location variables, and one technical variable), a radiomics-based predictor of the CD8 cell expression signature was built by use of machine learning (elastic-net regularised regression method). Two other independent cohorts of patients with advanced solid tumours were used to evaluate this predictor. The immune phenotype internal cohort (n=100), were randomly selected from the Gustave Roussy Cancer Campus database of patient medical records based on previously described, extreme tumour-immune phenotypes: immune-inflamed (with dense CD8 cell infiltration) or immune-desert (with low CD8 cell infiltration), irrespective of treatment delivered; these data were used to analyse the correlation of the immune phenotype with this biomarker. Finally, the immunotherapy-treated dataset (n=137) of patients recruited from Dec 1, 2011, to Jan 31, 2014, at the Gustave Roussy Cancer Campus, who had been treated with anti-PD-1 and anti-PD-L1 monotherapy in phase 1 trials, was used to assess the predictive value of this biomarker in terms of clinical outcome. FINDINGS: We developed a radiomic signature for CD8 cells that included eight variables, which was validated with the gene expression signature of CD8 cells in the TCGA dataset (area under the curve [AUC]=0·67; 95% CI 0·57-0·77; p=0·0019). In the cohort with assumed immune phenotypes, the signature was also able to discriminate inflamed tumours from immune-desert tumours (0·76; 0·66-0·86; p<0·0001). In patients treated with anti-PD-1 and PD-L1, a high baseline radiomic score (relative to the median) was associated with a higher proportion of patients who achieved an objective response at 3 months (vs those with progressive disease or stable disease; p=0·049) and a higher proportion of patients who had an objective response (vs those with progressive disease or stable disease; p=0·025) or stable disease (vs those with progressive disease; p=0·013) at 6 months. A high baseline radiomic score was also associated with improved overall survival in univariate (median overall survival 24·3 months in the high radiomic score group, 95% CI 18·63-42·1; vs 11·5 months in the low radiomic score group, 7·98-15·6; hazard ratio 0·58, 95% CI 0·39-0·87; p=0·0081) and multivariate analyses (0·52, 0·35-0·79; p=0·0022). INTERPRETATION: The radiomic signature of CD8 cells was validated in three independent cohorts. This imaging predictor provided a promising way to predict the immune phenotype of tumours and to infer clinical outcomes for patients with cancer who had been treated with anti-PD-1 and PD-L1. Our imaging biomarker could be useful in estimating CD8 cell count and predicting clinical outcomes of patients treated with immunotherapy, when validated by further prospective randomised trials. FUNDING: Fondation pour la Recherche Médicale, and SIRIC-SOCRATE 2.0, French Society of Radiation Oncology.

Locally advanced cervical cancer with bladder invasion: clinical outcomes and predictive factors for vesicovaginal fistulae.

OBJECTIVE: We report outcomes of cervical cancer patients with bladder invasion (CCBI) at diagnosis, with focus on the incidence and predictive factors of vesicovaginal fistula (VVF). RESULTS: Seventy-one patients were identified. Twenty-one (30%) had para-aortic nodal involvement. Eight had VVF at diagnosis. With a mean follow-up time of 34.2 months (range: 1.9 months-14.8 years), among 63 patients without VVF at diagnosis, 15 (24%) developed VVF. A VVF occurred in 19% of patients without local relapses (9/48) and 40% of patients with local relapse (6/15). Two-year overall survival (OS), disease-free survival (DFS) and local control rates were 56.4% (95% CI: 44.1-67.9%), 39.1% (95% CI: 28.1-51.4%) and 63.8% (95% CI: 50.4-75.4%), respectively. Para-aortic nodes were associated with poorer OS (adjusted HR = 3.78, P-value = 0.001). In multivariate analysis, anterior tumor necrosis on baseline MRI was associated with VVF formation (63% vs 0% at 1 year, adjusted-HR = 34.13, 95% CI: 4.07-286, P-value = 0.001), as well as the height of the bladder wall involvement of >26 mm (adjusted-HR = 5.08, 95% CI: 1.38-18.64, P-value = 0.014). CONCLUSIONS: A curative intent strategy including brachytherapy is feasible in patients with CCBI, with VVF occurrence in 24% of the patients. MRI patterns help predicting VVF occurrence. METHODS: Patients with locally advanced CCBI treated with (chemo)radiation ± brachytherapy in our institute from 1989 to 2015 were analyzed. Reviews of baseline magnetic resonance imaging (MRI) scans were carried out blind to clinical data, retrieving potential parameters correlated to VVF formation (including necrosis and tumor volume).

Baseline lymphopenia should not be used as exclusion criteria in early clinical trials investigating immune checkpoint blockers (PD-1/PD-L1 inhibitors).

INTRODUCTION: A number of phase I immunotherapy trials for cancer patients incorporate the absolute lymphocyte count (ALC) as an inclusion criteria. This study aims to assess whether ALC is associated with a lack of response to anti-PD-1/PD-L1 in early clinical trials. METHODS: All consecutive patients treated with anti-PD-1/PD-L1 monotherapy in phase I trials in our institution between December 2011 and January 2014 were reviewed. Baseline ALC, neutrophil-to-lymphocyte ratio (NLR), Royal-Marsden Hospital (RMH) prognostic score, objective response rate (ORR) and disease control rate (DCR = SD + PR + CR, stable disease (SD), partial response (PR), complete response (CR)) defined by Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 were retrieved. RESULTS: Out of a total of 167 patients, 48 (28.7%) and 8 patients (4.8%) had baseline ALCs of <1 G/l and <0.5 G/l, respectively. The RECIST change (%) was not correlated with ALC (G/l) (Spearman's rho = -0.06, P = 0.43). We did not observe any difference in terms of ORR (8.3% versus 15.1%, P = 0.32) or of DCR (58.3% versus 61.3%, P = 0.73) between patients with ALC <1 G/l versus >1 G/l. When using 0.5 G/l as ALC threshold, we did not find any difference either in ORR or in DCR. In a multivariate Cox regression analysis, baseline ALC was not associated with overall survival, whereas the RMH and the number of previous lines of treatment remained independent prognostic factors. CONCLUSIONS: Baseline ALC was not associated with response to anti-PD-1/PD-L1 in cancer patients enrolled in phase I trials. Patients should not be excluded from early phase clinical trials testing immune checkpoints blockers because of ALC.

Vaginal dose assessment in image-guided brachytherapy for cervical cancer: Can we really rely on dose-point evaluation?

PURPOSE: Although dose-volume parameters in image-guided brachytherapy have become a standard, the use of posterior-inferior border of the pubic symphysis (PIBS) points has been recently proposed in the reporting of vaginal doses. The aim was to evaluate their pertinence. METHODS AND MATERIALS: Nineteen patients who received image-guided brachytherapy after concurrent radiochemotherapy were included. Per treatment, CT scans were performed at Days 2 and 3, with reporting of the initial dwell positions and times. Doses delivered to the PIBS points were evaluated on each plan, considering that they were representative of one-third of the treatment. The movements of the applicator according to the PIBS point were analysed. RESULTS: Mean prescribed doses at PIBS -2, PIBS, PIBS +2 were, respectively, 2.23 ± 1.4, 6.39 ± 6.6, and 31.85 ± 36.06 Gy. Significant differences were observed between the 5 patients with vaginal involvement and the remaining 14 at the level of PIBS +2 and PIBS: +47.60 Gy and +7.46 Gy, respectively (p = 0.023 and 0.03). The variations between delivered and prescribed doses at PIBS points were not significant. However, at International commission on radiation units and measurements rectovaginal point, the delivered dose was decreased by 1.43 ± 2.49 Gy from the planned dose (p = 0.019). The delivered doses at the four points were strongly correlated with the prescribed doses with R(2) ranging from 0.93 to 0.95. The movements of the applicator in regard of the PIBS point assessed with the Digital Imaging and Communications in Medicine coordinates were insignificant. CONCLUSION: The doses evaluated at PIBS points are not impacted by intrafractional movements. PIBS and PIBS +2 dose points allow distinguishing the plans of patients with vaginal infiltration. Further studies are needed to correlate these parameters with vaginal morbidity.